may edition file


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editor’s note

editor’s note

Dear Doctor,

May 2019 / Vol. 6 / Issue 1

Founder AUGUST & 2018 Editor / Vol: 5 / Issue: 4

CH Unnikrishnan

Executive Editor

S Harachand

Science Editor

Dr Rajanikant Vangala

Consulting Editors

Dr Founder Shivanee & Editor Shah

Jeetha CH Unnikrishnan D’Silva






Copy S Harachand Editor

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Science Editor


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Photo Copy Editor Editor

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Advisory Dr Sumit Ghoshal Board






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Phone: Dr Sekar +91 Seshagiri 9821435120

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© 2018 NextGen Science Media Pvt. Ltd, RNI Number KERENG/2012/44529

This time, let me also invite your attention to a deserving cause in the context

of a recently held conference of Undiagnosed Diseases Network International

in Delhi. Dear Doctor The conference re-emphasised the need for more collaborative

efforts from the clinical as well as the scientific community to investigate

the We cause know of rare you are diseases. busy. There It is always has been reassuring an increased that the interest trust and among faith the of

clinician hundreds community, of patients mainly your some healing research touch enthusiastic keeps you geneticists busy in this since noble most

of these profession. conditions In the are hectic linked practice, to some it’s or quite other natural genetic that disorders, you might collecting miss

valuable out on data some from of the real-world latest developments experience as well in emerging as dedicated medicine. researches. In this era

But, of millions innovation, of patients medical suffering science from is getting such diseases redefined are almost still left by untreated the day. Old

as technologies research hasn’t are yet being culminated replaced in to by development the new in the of blink effective of an treatment eye. Robots

for and many artificial disorders intelligence or they are are not taking really over accessible a good to part a large of the section procedures, of the

patient while population. genomics and This molecular should change. science unveil the mysteries of life further.

Today’s We are need fortunate is for to the have young such and breakthroughs enthusiastic clinicians as they help from specialists across the like




rise above


the expectations

where the disease

of today’s



is huge,


to dedicate a

fraction of their time to observe the patients who come with rare symptoms,

and try to analyse the cause and take it forward with communities like UDNI.

Similarly, it is also a time when India is witnessing revolutionary growth in

Perhaps, you yourself can help provide a solution. As Dr I C Verma, the father

healthcare industry, especially in the private sector, wherein an increasing

of Indian medical genetics, advises in this edition’s Holy Grail, this is the age

number of doctors are taking up multiple roles of clinician, researcher and

of genomic medicine and do spend some time to learn this technology and

entrepreneur. This requires expansion of your focus to a wider canvas. In

try to interpret your findings in its light.

this context, it becomes important how a busy professional like you can

In many ways, this is applicable to even the age-old and established


keep pace

as well,








the cover story

in a








well-recognised medical condition. The story extensively talks about the

changing At Future concepts Medicine, of asthma which is since conceived recent studies and crafted observed by a that team there of senior is

no journalists, one universal scientists definition and for doctors, this disease. our aim The is heterogeneity to help you do of just asthma that. We

prompts are equipped us to look to at bring it more you as the an latest umbrella from term. the science of care from across

In the Straight world Talk, in an Dr interesting Vijay Chandru, convenient founder of Strand way, supplemented Life Sciences, by calls the for best a

renewed of views effort and to analyses from India’s the actual masters disease in each burden field. as We the present country you hasn’t this

understood specialised its knowledge actual patient vehicle population, that plugs not only you into under the rare emerging diseases world but of

also care widely seamlessly. prevalent Come, cancer-like let’s join afflictions. hands in this information journey.

Happy CH Unnikrishnan


C H Unnikrishnan futuremedicineindia FutureMedIndia



Vol 6 Issue 1

May 2019

₹ 250.00



MAY 2019



















06 Letters

08 News updates

30 Pulmonology

32 Drug approvals

52 Research snippets

56 Hospital news

62 Devices&gadgets

72 Guidelines

90 Events

96 Calendar

98 Holy grail



Muralidharan Nair


Dr Rajani Kanth Vangala


Dr Arun Bhatt





Doctors are the most

vulnerable when it comes

to workplace violence









Vijay Chandru











Several promising therapy

regimens are underway to

deal with the hereditary

haemolytic disease





It’s important that

we recognize that

asthma treatment

is not “one size

fits all”,

Andy Nish MD

Fellow of American

Academy of Allergy,

Asthma &

Immunology, USA









The emergence of biologics as

RISEN an add-on therapy AGAIN?

has opened

up an exciting front in the new


era of








curable disease suffers a

backlash as cases shoot up in

several regions


letters to the editor








Better medium for

getting updates

₹ 250.00

VOL 5 | ISSUE 12


APRIL 2019








Hello sir,

I found this magazine from

our medical college library

3 months ago. As a medical

student I am interested

in knowing new updates

in medical field and this

magazine really helps to fulfill

it. Special thanks to the editor

for the same. Is there any

special subscription offer for

medical students?


Medical Student


Rich in content

Dear editor,

I have gone through the cover

story regarding the topic

Malaria published in April 19

issue. It was very informative

story and it covered all latest

updates of the topic. Honestly

great work by the editorial


Dr. Vineeth


To be noticed more


The article “Starting to forget”

based on Alzheimer’s in

February issue was really an

important topic and it is to be

delivered to all doctors as well

as public. Lot of people in our

society are suffering from this

disease and not recognizing

by their beloved people since

they are considering it as

geriatric problem.

Dr. Jacob Mathews


Hats off

Dear sir,

Great work by team Future

Medicine. I just completed

my reading at a stretch while

traveling from Mumbai to

Pune. The articles were fresh,

catching and interesting. This is

the a magazine we are looking

for and hats off guys for the


Dr. Hafiz Hamza


Guidance from medical



I have been a subscriber of

Future Medicine for the last 4

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news updates

J&J donates

10,000 more doses

of bedaquiline

to India

Johnson & Johnson (J&J)

will be providing an

additional 10,000 courses of

bedaquiline free of charge

to Indian patients through

US Agency for International

Development (USAID), for

a total of 20,000 donated


Earlier, 10, 000 courses

of the drug to treat multidrug

resistant TB have been

supplied through Janssen

Pharmaceutical Companies,

J&J in 2016 as part of a

global donation programme,

operated in partnership with

USAID under conditional

access programme (CAP).

“Ensuring access to

bedaquiline in India is a top

priority for J&J, given the

country’s high burden of

MDR-TB,” said Paul Stoffels,

vice chair of the Executive

Committee and chief scientific

officer, Johnson & Johnson, in

a statement.

Following this, India

will be able to procure

bedaquiline via the Stop TB

Partnership’s Global Drug

Facility at J&J’s special-effort

price of $400, announced in

July 2018. This price enables

More drug combos

under scanner

India may ban more fixed dose

combinations (FDCs), currently available

in the market, which are suspected to be


The Drugs Technical Advisory Board

(DTAB), which advises the drug regulator on

safety issues of pharmaceutical products,

has constituted a sub-committee to

examine some 150-odd FDCs, reports said.

The government slapped a ban on 344

FDCs in 2016 following a report submitted

by a panel led by Kokate, vice-chancellor of

KLE University in Karnataka.

Deliberating on a petition filed by drug

companies challenging the government’s

ban, the Supreme Court referred the matter

to DTAB for a fresh review in December

2017. The SC asked the board to check

whether these drugs should continue to be


As per order, an expert panel under

the chairmanship of Dr Kshirsagar

reviewed the safety and efficacy of these

drugs and recommended to continue the

ban as the FDCs in question had no

rational basis.

the company to support

manufacturing, distribution

and surveillance programmes

to safeguard the antibiotic’s

effectiveness, he added.

There are an estimated

135,000 new cases of drugresistant

TB in India every

year, and currently less

than 30% of these patients

are diagnosed and put on

an appropriate treatment


The government of India

has set the ambitious goal

of ending TB by 2025, five

years ahead of the global

Sustainable Development Goal

(SDG) target of 2030.

India to regulate

OPS as drugs

India will regulate organ

preservative solutions (OPS)

as drugs, according to a new

official notification.

The government has

included Organ Preservative

Solutions (OPS) to the list of

notified medical devices placing

it under the purview of Section

3 (b) (iv) of the Drugs and

Cosmetics (D&C) Act 1940 with

immediate effect.

Section 3(b) of the Drugs

and Cosmetics (D&C) Act 1940

talks about “drugs” as inclusive

of such devices intended for

internal or external use in the

diagnosis, treatment, mitigation

or prevention of disease or

disorder in human beings or


8 / FUTURE MEDICINE / May 2019

According to a Gazette

notification, issued to this

effect, the government

specified OPS intended for

external or internal use in

human beings as drugs. OPS is

a crucial medical device that is

used to supply oxygen and vital

nutrients to harvested organs,

thereby increasing their life and

maintaining their vitality.

Drug regulator

slaps safety

alerts on


Drugs Standard Control

Organisation (CDSCO)

has ordered drug companies

manufacturing certain

commonly used antibiotics to

carry safety warning on the

labels of these medicines.

The drug regulator wanted

to ensure that this information

is made available to the

general public.

The decision comes

after the National Coordination

Centre of

the Pharmacovigilance

Programme of India

(PvPI) sounded caution on

commonly used antibiotics

including cefotaxime, ofloxacin

and cefixime.

PvPI reported the risk of

developing Stevens-Johnson

Syndrome and toxic epidermal

necrolysis among people


using the antibiotic ofloxacin.

Injectable cefotaxime has

been implicated for causing


The PvPI recommended

that CDSCO take necessary

steps to incorporate the

adverse drug reactions in

the prescribing leaflet of

these drugs marketed in the

country, reports said.

The subject expert

committee under the

Drug Controller General

India (DCGI) examined

PvPI’s suggestions and

recommended to incorporate

safety cautions in its packages

of all such antibiotics.


qualification for

super specialty

courses revised

The Medical Council

of India has revised

the feeder qualifications

of six super specialty

courses. Feeder

qualification for 2 DM

(Doctor of Medicine) and

4 MCh courses (Master of

Chirurgie) has been revised

through an amendment

to the older regulations

Postgraduate Medical

Education Regulations, 2000

and are effective from April 1,


The council has removed

many other redundant

qualifications which act as

prior requirements to various

DM and MCh courses through

a gazette notification.

Following the amendment,

candidates with MD in

General Medicine or Radiation

Oncology can now pursue

DM (Medical Oncology). The

prior requirements were MD

(Medicine), MS (Radiotherapy),

MD (Paediatrics). For DM

(Interventional Radiology),

earlier the feeder qualification

was stated as MD (Radiology)

and now the name has

been changed to MD


Similarly, the candidate

qualified with MS (General

Foetus over 20 weeks can be aborted to

save a life: Bombay HC

Aregistered clinician

can perform medical

termination of pregnancy

(MTP) on a foetus that has

crossed the legal abortion

limit of 20 weeks without

the court’s permission if it is

deemed necessary to save

the life of the woman, the

Bombay high court said in a

recent ruling.

The permission for MTP,

however, still has to be

sought when a pregnancy

has exceeded 20 weeks

and the woman “fears its

continuation would involve

grave injury to her physical or

mental health or where there

is a substantial risk that if

the child were born, it would

suffer from such physical or

mental abnormalities as to be

seriously handicapped”.

In such cases, the

pregnant woman will have

to seek permission from the

high court and unless such

permission is granted, no

registered medical practitioner

can terminate such pregnancy,

the HC ruled.

The court directed the

state government to establish

medical boards in every

district to examine pregnant

women and to furnish reports

in cases where women

have approached courts for

permission after 20 weeks

of gestation, within three

months, reports said.

May 2019 / FUTURE MEDICINE / 9

Surgery) can now go for MCh

Surgical Oncology. Earlier

the prior requirements were

MS (Surgery), MS (ENT), MS

(Orthopaedics), MD (Obst.

& Gyn). Surgeons with MS

(General Surgery) can apply

for MCh (Head & Neck

Surgery). Earlier they were

MS (ENT) or MS (General

Surgery) or MCh (Plastic &

Reconstructive Surgery) or

MCh (Surgical Oncology) or

MCh (Neuro Surgery).

Generic eribulin

launched in India

Ageneric version of the anticancer

drug eribulin, which

is currently marketed under

the brand name Halaven by

Eisai Pharmaceuticals, is now

available in India.

The generic eribulin will be

40% cheaper than Halavan,

said Emcure Pharmaceuticals,

which launched the cancer


Eribulin, originally isolated

halichondrin B from the

natural Japanese marine

sponge Halichondria okadai,

was approved by the US FDA

on November 15, 2010 for the

treatment of metastatic breast


Considered less toxic,

eribulin is currently used as

second-line treatment for

relapsing triple-negative breast

cancer. Triple-negative breast

cancer is tough to treat as the

patients with this sub-type

are tested negative for all

the three receptor proteins —

oestrogen, progesterone as

well as HER2.

Eisai won the second

approval from the US FDA for

eribulin in January 2016 or the

treatment of liposarcoma in

patients who had undergone



Presently, eribulin is being

investigated for use in various

cancers such as non-small cell

lung cancer, prostate cancer

and sarcoma.

Measles cases

shoot up

globally: WHO

Reported cases of measles

rose by 300 per cent

Stop Thal to prevent thalassemia

Kanakia Health Care,

Mumbai, has created a

program called STOP THAL

under the guidance of Dr

Swati Kanakia, a paediatric

haemato-oncologist with

a PhD in Thalassemia from

Mumbai University. STOP

THAL, Screening

for Thalassemia and Opting

for PREVENTION, is aimed

at preventing thalassemia

major cases in an effort

to reduce the disease

burden. Dr Kanakia firmly

believes that the only way

to reduce thalassemia

major cases is by


However, how does

one suspect thalassemia?

The “Magic Mantra” for

considering thalassemia

minor is low or normal

hemoglobin, high RBC

count, microcytosis and

a normal RDW. This is

followed up by hemoglobin

electrophoresis, which

detects only beta

thalassemia. If there is

a strong suspicion of

thalassemia despite a

normal Hb electrophoresis,

mutations for the alpha

thalassemia gene may be

carried out to clinch the


Each and every doctor

can play a pivotal role by

considering thalassemia

on a regular CBC report

done for any reason.

Dr Kanakia hopes that

STOP THAL will prove

to be useful in reducing

thalassemia major cases.

The program, available at


com/stopthal/, helps one

to estimate the chances

of having a completely

normal, thalassemia minor,

or thalassemia major child.

It will be an important

asset to increase awareness

amongst thalassemia

patients, and doctors may

use it as an aid for patient


in the first three months

of 2019 compared to the

same period in 2018, shows

preliminary global data by


This follows consecutive

increases over the past two


Measles, a highly

contagious airborne viral

infection, can be entirely

prevented through a twodose

vaccine. But vaccination

rates have been slipping in

recent months.

Global coverage with

the first dose of measles

vaccine has stalled at 85

percent for several years.

This is still short of the 95

percent needed to prevent

outbreaks, and leaves

many people in many

communities at risk. Second

dose coverage, while

increasing, stands at 67


“While this data is

provisional and not yet

complete, it indicates a

clear trend. Many countries

are in the midst of sizeable

measles outbreaks, with

all regions of the world

experiencing sustained rises

in cases,” WHO said in a


Current outbreaks

include the Democratic

Republic of the Congo,

Ethiopia, Georgia, Kazakhstan,

Kyrgyzstan, Madagascar,

Myanmar, Philippines,

Sudan, Thailand and Ukraine,

causing many deaths –

mostly among young


Over recent months,

spikes in case numbers

have also occurred in

countries with high overall

vaccination coverage,

including the United States

of America as well as Israel,

Thailand, and Tunisia. The

agency noted that only

about one in 10 actual

measles cases are reported,

meaning the early

trends for 2019 likely

underestimate the severity

of the outbreaks.

10 May 2019

Transvaginal mesh banned in US

amid safety concerns

The US Food and Drug

Administration ordered the

manufacturers of all remaining

surgical mesh products

indicated for the transvaginal

repair of pelvic organ prolapse

(POP) to stop selling and

distributing their products

immediately. The order is the

latest in a series of escalating

safety actions related to

protecting the health of the

thousands of women each

year who undergo surgery

transvaginally to repair POP.

The FDA has determined

that the manufacturers, Boston

Scientific and Coloplast, have

not demonstrated a reasonable

assurance of safety and

effectiveness for these devices,

which is the premarket review

standard that now applies

to them since the agency

reclassified them in class III

(high risk) in 2016.

As part of the 2016

reclassification, manufacturers

were required to submit and

obtain approval of

premarket approval (PMA)

applications, the agency’s

most stringent device review

pathway, in order to continue

marketing their devices in the


“In order for these mesh

devices to stay on the market,

we determined that we

needed evidence that they

worked better than surgery

without the use of mesh to

repair POP. That evidence was

lacking in these premarket

applications, and we couldn’t

assure women that these

devices were safe and effective

long term,” said Jeffrey Shuren,

MD, director of the FDA’s Center

for Devices and Radiological


In 2002, the first mesh

device for transvaginal repair

of POP was cleared for use

as a class II moderate-risk

device. About 1 in 8 women

has surgery to repair POP over

her lifetime, and a subset of

these surgeries are completed

transvaginally with the use of

surgical mesh.

Two manufacturers

have been marketing three

surgical mesh products for

transvaginal repair of POP. In

reviewing the PMAs submitted

by the two manufacturers,

the agency determined they

failed to provide an adequate

assessment of the long-term

safety of these devices and

failed to demonstrate an

acceptable long-term benefit

of these devices compared

to transvaginal surgical tissue

repair without the use of mesh,

the agency said in a press


InARI signs MoU with NTTE Med

University on translational research

The present translational

research in India will

not be able to achieve its

objectives unless important

changes in education

and training modules

are addressed. The T1

(bench to bedside) and T2

(bedside to bench) phases

of translational research

are complementary and

need important resources

— mostly financial — that

require quality collaborations

between clinical and

molecular scientists. It is

important to note that in

India, a lot of emphasis was

given to develop physicianscientists

(T2) and despite

all the euphoria, innovations

in the biomedical field have

been negligible. The T1 cycle

that exploits the expertise of

research scientists outside

medical institutes like

universities and academic

institutions has not been well

integrated. It is extremely

important to link molecular

networks with clinical

observations to complete

the T1-T2 cycle. Especially

in a country as big as ours

with our low investment in

research, more emphasis

must be given to biomedical

related problems where the

scientific community works

in tandem with clinicians. In

this direction, the Institute

for Applied Research and

Innovation (InARI) and NITTE

Medical University have

joined hands by signing

an MoU to create training,

education and research

programmes suitable for

Indian healthcare needs.

InARI focuses on applied

research with direct benefits

to the society and healthcare

is its top priority. By signing

this MoU with NITTE Medical

University, a premier medical

institute, a new chapter

has begun in translational

research for India

Prof Dr Satheesh Kumar Bhandary (Vice Chancellor of NITTE Medical

University), Dr Rajani Kanth Vangala (Founder and Managing Trustee

of InARI), Dr Poornima V (co-founder and trustee – InARI), Dr Suchetha

Kumari (Head of Research, NITTE Medical University)

May 2019 / FUTURE MEDICINE / 11




Several promising therapy regimens are underway to deal with the

hereditary haemolytic disease


Thalassemia comes from two Greek

words “Thalassa” and “emia”

meaning “sea” and “blood”. This

naming has a unique meaning as the

disease affects the hemoglobin and

was described almost 90 years ago

by Cooley and Lee. Two gene clusters

controlling haemoglobin synthesis are

located on chromosome 16 (α-like

globins) and chromosome 11 (β-like

globins) in such a manner that they

are differentially expressed at different

stages of development like embryonic,

foetal and adult. This is seen in

β-globin gene cluster where, ε-gene is

only expressed in early embryos and

two γ-genes, which are expressed

during gestation, are found in foetal

haemoglobin (Hb F, α2γ2). The δ-gene

used in diagnosing thalassemias is a

component of Hb A2 (α2δ2), whereas

α and β-globins combine to form

major haemoglobin component Hb

A (α2β2) carried by adult red blood

cells. The heritable mutations in α and

β gene clusters in thalassemias results

in defective haemoglobin which binds

to less oxygen and also reduces the

transport of oxygen.

There are three types of

β-thalassemia, based on the β-globin

chain imbalance and severity of

anaemia; namely minor, intermedia and

major. Several mutations have been

identified and were classified into silent

— which have no effect, mild — leading

to a reduction in β-globin production

levels, and severe — causing a complete

absence of the β-globin gene product.

The minor trait or carrier patients have

heterozygous inheritance of mutations

and are often clinically asymptomatic.

Patients with the major trait have severe

anaemia from infancy and become

life-long dependents on transfusion.

However, β –thalassemia intermedia has

variable anaemia of mild to moderate

requiring variable transfusions.

β-thalassemia major and intermedia







can be due to several homozygous or

compound heterozygous inheritances

of mutations in β-globin gene. Different

modifications like the extent of

α-globin to β-globin chain imbalance,

ineffective erythropoiesis and the

severity of anaemia cause β-thalessemia

intermedia, rather than β-thalessemia

major in most patients. Most frequent

are mutations in the β-globin

gene, second are co-inheritance of

α-thalassemia, higher levels of γ-chains

of globin and sustained production of

foetal haemoglobin after infancy. The

last factor — hereditary persistence of

foetal haemoglobin — can be due to

several rare mutations like deletions of

upstream promoter or regulatory region

but the presence of an intact gene,

and the complete deletion of δ-globin

and β-globin genes. These patients

have one intact γ-globin gene which

is called δβ-thalassemia. Some of the

other complications, such as dominant

inclusion body β-thalassemia, have a

triplicated or quadruplicated α-genotype

along with β-heterozygosity or E/

β-thalassemia where β-thalassemia is

co-inherited with a structural variant of

hemoglobin E.

Clinical categories

The classification of α-thalassemia

is dependent on how both the α-globin

genes are deleted or reduced in activity

due to mutations. The first group of

α+-thalassemias are of several types,

but are dominated by –α3.7 and –α4.2

that correspond to the lengths of

deletion in the α-globin gene. The other

α+-thalassemias have several point

mutations, the most common being

chain-termination mutant haemoglobin

Constant Spring called αCSα. The second

group α0-thalassemias are due to

deletion of both the α-globin genes (-/-

), which might occur in heterozygous

condition with α+-thalassemias (-α/- or

αCSα/-). The ATR-16 syndrome, which

involves α-globin gene on chromosome

16, was shown to be associated

with mental retardation, also called

α-thalassemia x-linked intellectual

disability (ATRX).

The clinical categorization of

thalassemias is being simplified based

on clinical-management criteria. As

transfusion remains the major form of

12 / FUTURE MEDICINE / May 2019

therapy, the patients are divided into

transfusion-dependent thalassemia

(TDT) and non-transfusion-dependent

thalassemia (NTDT). The NTDT may

still need a transfusion but not at the

same rate as TDT, primarily for the

prevention or management of certain

diseases. Patients with β-thalassemia

intermedia, haemoglobin H and

moderate forms of haemoglobin E/βthalassemia

usually constitute NTDT. The

TDT patients have β-thalassemia major

and severe forms of haemoglobin E/βthalassemia.

Suppressing the abnormal

erythropoiesis by transfusion can control

downstream pathological mechanisms

in thalassemia. Some of the long-term

follow-up studies which evaluated birth

cohorts of patients with β-thalassemia

major found that transfusion along

with iron-chelation improves survival.

Transfusion therapy, however, does

have the risk of secondary-iron overload

as the human body does not have a

means to excrete iron. Patients receiving

2-4 units of blood per month will have

5,000-10,000 mg of iron per year. This

leads to more iron than the capacity

of transferrin, thus causing hepatic

and extrahepatic tissue damage. The

extra non transferrin-bound iron also

can transport into cardiomyocytes,

hepatocytes, pancreatic β cells and

anterior pituitary cells, generating

reactive-oxygen species damaging

subcellular organelles.

Controlling iron overload

The iron overload warrants prompt

diagnosis in NTDT as it can cause

substantial morbidity and mortality and

in patients with TDT, excess iron can

be seen as early as 2-6 years of age.

Cardiomyopathy has been observed

as a leading cause of mortality in

TDT patients, whereas osteoporosis,

thrombosis, pulmonary hypertension,

silent strokes, hypogonadism,

hypothyroidism and renal diseases

are strongly associated with NTDT

iron overload. Of the several methods,

serum ferritin assessment is commonly

used to indicate the need for initiation

of iron-chelation therapy, for example

in TD. Maintaining concentrations

lower than 1000µg/L of ferritin leads

to better-sustained therapy. Serum

ferritin concentrations above 2500

µg/L are strongly associated with an

increased risk of cardiac and other

diseases. Superconducting Quantum

Interference Device (SQUID) is one of

the important technologies to assess

liver iron concentration, but is not widely

used. Magnetic Resonance Imaging

(MRI) has become the best alternative

for non-invasive liver iron concentration

evaluation. There are three iron chelators

currently available for iron overload

namely deferoxamine, deferasirox and


Traditionally, splenectomy is

performed as an alternative or as

an adjunct to transfusion therapy.

However, it has become obsolete in

patients with TDT due to potential

infections, but is used in NTDT. In

patients with β-thalessemia intermedia,

there is an increased risk of long-term

thrombosis along with end-organ

damage as the spleen also acts as

a reservoir of toxic iron. Presently,

splenectomy is recommended only

for patients who are unable to receive

transfusion and iron-chelating therapy

and also have clinical symptoms of

splenomegaly or hypersplenism.

One of the best cures available for

thalassemia with more than 80%

disease-free survival is the replacement

of mutant haematopoietic cells with

haematopoietic stem cells when

matched sibling donors are available.

Further improvements in the graftversus-host

disease and inducing

graft tolerance have resulted in more

unrelated donors with overall survival of

65%. These improvements are showing

that more novel therapies are in good

progress and might result in better

treatment regimes for thalassemia.

The author is medical scientist and former

director of SGRF, Bangalore

May 2019 / FUTURE MEDICINE / 13


the catalyst

Bridging the trust deficit

Time for private players to think in tandem with

policy directions


The private sector healthcare delivery

in India has been the bedrock of

healthcare capability and capacity,

particularly in the area of high-end

secondary, tertiary and quaternary care.

Multi-specialty, corporate hospital chains

have been the flag bearers of capacity and

capability growth in high-end care over the

last decade or more, but they are currently

struggling with the changing dynamics of

healthcare business, which is rendering

traditional business models suboptimal.

While private sector promoters and investors

see the changing dynamics characterised

by increasing focus on affordability as an

overbearing development, in my view, this

was imminent, if not long overdue. The

reason why this was possibly missed by the

leaders and managers could be traced to the

key tenets of their belief system. In essence, I

have observed three, distinct tenets:

Relative affordability compared to

international prices: This has been an

overwhelming influence in the minds of

leaders of the private healthcare industry

in India and has been a real deterrent in

facilitating the requisite focus on affordable

care in India. I could never understand the

rationale behind this belief, as it has very

little practical relevance for the consumer or

payor for whom the affordability is defined

by the size of their own pocket not by what

would have been the relative burden in a

hypothetical situation of being in a foreign

land. This has singularly contributed in

catalysing a self-righteous attitude among

healthcare managers and leaders, which

manifested in the use of price increases

as the key tool for realising commercial

objectives, instead of focusing on efficiency

and the evolution of an operating

model that responds effectively to the

consumer context.

Inordinate focus on experience: The quest

to offer a differentiated experience from

public healthcare facility is understandable,

but in the course of time, this has stretched

beyond a limit, which has not only resulted

in higher capital and operations cost, but

has given a perception of insensitivity to the

large masses of population who were neither

used to that kind of experience nor were

seeking it, but had little or no option but to

avail them in the absence of affordable and

credible alternatives. In some ways, what is

perhaps a welcome offering for a minuscule

percentage of the population with the means

is being perceived as vulgar compulsion by

the masses. Barring some extreme exceptions,

most of the time, the experience factors do

not contribute as significantly to the overall

cost of delivery when compared to the

perception it creates of expenditure that the

poor consumer perceives as an avoidable


Making healthcare affordable is

government’s responsibility, not ours:

This tenet has a rational basis, without doubt,

and it is also true that the government has

failed miserably to offer a credible alternative

through public health delivery systems or

to facilitate a robust ecosystem for health

education to ensure adequate supply of

clinical talent, particularly at the specialist

level. This has significantly contributed to

the excessive use of private care as well as

the high cost of private care. But the irony is

that the private sector was happy until the

government started taking responsibility for

affordable care and is now unhappy when

it is pursuing the same with great intensity.

That’s where the private sector erred, in

assuming that government ownership of

14 / FUTURE MEDICINE / May 2019

affordable healthcare will come on its terms,

with the government playing the role of

the payor, and will help them expand their

market without changing their character. In

reality, government ownership will expand

the market significantly, but can find its

sustainability only by changing the economics

significantly to match its fiscal capacity, given

the large percentage of needy population

(approximately 70 percent).

In conclusion, it is a fact that the vision of

corporate healthcare chains (and even many

of the trust hospitals whose commercial

agenda seem no weaker than those of

“for profit” healthcare enterprises) for their

enterprise was not really in tandem with

the needs of the vast majority of India’s

population, even though they have played

a stellar role in providing quality healthcare

to multitudes of needy customers both rich

and poor. However, it is equally true that

government policies should target

the good of the greatest population







and hence it is imperative that private

healthcare providers must not waste time

in defending status quo, but put in all their

managerial, financial and entrepreneurial

might to redefine their vision for the future in

a way that is in harmony with the needs of

the larger chunks of the population as well

as the policy direction. This will, in fact, go

a long way in bridging the significant trust

deficit that exists between private players

and policymakers, leading to better mutual

empathy, and consequently, more effective

policies, principles and practices for the

benefit of all.

The author has long-standing association with

EY India but the views are strictly personal.

May 2019 / FUTURE MEDICINE / 15

cover story


16 / FUTURE MEDICINE / May 2019




The emergence of biologics as an

add-on therapy has opened up an

exciting front in the new era of

severe asthma treatment


Asthma is a heterogeneous disease, characterised by

inflammation of the air passages of the lungs.

World over, an estimated 235 million people suffer

from asthma, a chronic condition characterised by symptoms

such as difficulty in breathing, tightness in the chest and


Caused by a combination of complex environmental

and genetic interactions, the underlying mechanisms of this

airway disorder is yet to be fully figured out.

Since there is no known cure for the disease, symptoms

are controlled through therapeutic interventions.

Corticosteroids, mostly in the inhaled form, is the centerpiece

of the current treatment to check the inflammatory process.

Inhaled bronchodilators and/or leukotriene pathway inhibiting

agents are also added if symptoms remain uncontrolled.

The drug regimen, comprising inhaled corticosteroids

(ICS) and long-acting beta agonists (LABA), has been used

to manage asthma symptoms successfully in most of the


However, 10%–20% of patients do not achieve control

with the current gold standard of care. This population of

May 2019 / FUTURE MEDICINE / 17


Rapidly-expanding suite

of biologics to reduce

asthma exacerbations

Monoclonal antibodies

(mAbs) are antibodies

produced artificially through

genetic engineering and

related techniques.

mAbs target various

proteins that influence cell

activity, such as receptors or

other proteins present on

the surface of normal and

cancer cells. These biologic

therapeutics are currently

used extensively

to treat cancer,



inflammatory conditions etc.

Several mAbs have been developed

to target asthma phenotypes.


Omalizumab is directed against

immunoglobulin E (IgE). It binds

circulating IgE, causing decreased IgE

levels, inhibition of IgE binding with its

receptors, and downregulation of IgE

receptors on mast cells, basophils and

dendritic cells. This results in decreased

release of inflammatory mediators

related to the allergic response.

Omalizumab is the only biologic

therapy approved for paediatric use in

children 6 years and older.

A recent Cochrane review of

omalizumab use in adults and children

with asthma found that omalizumab use

compared with placebo reduced asthma


In the adolescent/adult studies, high

levels of type 2 inflammatory markers

such as fractional exhaled nitric

oxide (FeNO) levels, eosinophilia,

periostin levels, and IgE

levels23 have predicted

severe refractory asthmatics is at increased risk of morbidity

and mortality, and make up the majority of the economic

costs of asthma, studies indicate.

Also, the long-term use of some asthma treatments,

especially oral steroids, come with noticeable risks.

Phenotypic pathways

Search for newer, safer and better treatments for severe

asthma has opened the door to exploring and identifying

different types of this disease.

Over the last decade, specific phenotypes and

endotypes of asthma have been evaluated, leading to more

personalised, targeted approaches to fit patient-specific

disease, abandoning the one-size-fits-all treatments.

A better understanding of the role of the inflammatory

modulators involved in asthma paved the way for the

development of therapies using biologics as a treatment


Today, biologic therapies, which are made from

living organisms using recombinant DNA technology, are

increasingly being considered in patients with severe asthma.

People with a severe form of the disease constantly struggle

with persistent symptoms. This makes it tough for them to

maintain a good quality of life.

Traditionally, asthma is classified based on severity.

Experts today hold that asthma is no longer single disease.

Rather, it is increasingly recognised as an umbrella term — just

like cancer or arthritis — for various phenotypes. Finding ways

to identify subgroups that respond well to different types of

treatments is a current, critical goal of asthma research.

18 / FUTURE MEDICINE / May 2019

improved response to omalizumab.

A 2003 analysis of pooled clinical

trial data reported a malignancy risk of

0.5% in omalizumab-treated patients.


Currently in development, ligelizumab

is a humanized anti-IgE monoclonal

antibody that binds circulating IgE. In

a phase 1 study, ligelizumab has been

shown to be more potent at suppressing

free IgE and IgE bound to mast cells and

basophils than omalizumab.

In a phase 2 double-blind parallelgroup

trial in 37 adults with mild allergic

asthma, ligelizumab elicited a 3-fold

greater provocative concentration of

allergen, causing a 15% decrease in

FEV1 compared with omalizumab and

16-fold greater than placebo at 12

weeks. Ligelizumab was administered

subcutaneously every 2 weeks. So far,

no studies have been done in children

or adolescents, and there is no data on

phenotypic response.


Mepolizumab targets IL5, a cytokine

that promotes both the activation

and longevity of eosinophils. The

Mepolizumab as Adjunctive Therapy in

Patients with Severe Asthma (MENSA)

study randomised 576 adolescents and

adults with severe eosinophilic asthma

found that asthma exacerbations

requiring oral corticosteroids (OCS) were

reduced 47% and 53% with IV and SC

mepolizumab compared with placebo,

respectively. Asthma exacerbations

requiring an ED visit were reduced 32%

and 61% with intravenous (IV) and

subcutaneous (SC) mepolizumab.

The 3 randomized controlled trials

included only patients with eosinophilic

asthma on the basis that an antibody

that reduces eosinophil levels would be

most effective in eosinophilic asthma.

Mepolizumab has been shown to

decrease eosinophil counts in both

serum and sputum.

There are no studies on children

above 12 years old, as of now, although

many studies included adolescents.

Mepolizumab is approved by USFDA

as add-on maintenance therapy in

patients who are 12 years and older

with eosinophilic asthma.


Two randomised, double-blind, placebocontrolled

trials (RDBPCT) have been

conducted on reslizumab in adolescents

and adults with eosinophilic asthma.

A phase 3 trial of 374 adolescents

and adults aged 12–75 years with

inadequately controlled eosinophilic

asthma. This study noted improved

asthma control compared with placebo.

However, the quality of life measure

trended to improve in the 0.3mg/

kg dose of reslizumab but was only

significant for the higher dose.

Two duplicate RDBPCTs (phase

3) in adolescents and adults with

uncontrolled eosinophilic asthma with

serum eosinophils =400 cells/µL on

medium-to-high dose ICS therapy

noted a significant reduction in asthma

exacerbation frequency as well as

improvements in time to exacerbation,

asthma control, and quality of life

As with mepolizumab, the presence

of eosinophilia as a biomarker for

reslizumab efficacy was demonstrated

in an RDBPCT of reslizumab in adult

asthmatics, which demonstrated no

clinically significant effect on either lung

function or symptom control in patients

unselected for baseline eosinophil levels.

Reslizumab has been shown to

decrease blood eosinophil counts,

but studies are not available to show

differentiation between responders and

One of these phenotypic pathways is thought to be type 2

pathway — T helper 2 (Th2). About half of the individuals with

severe asthma exhibit the type 2 phenotype, with increase in

Th2 cells. There is an increase in the number of CD4+ T cells,

predominantly TH2 cells, in the airways of asthmatic patients,

whereas in normal airways, TH1 cells predominate. TH2 cells

have a central role in asthmatic inflammation. Also called the

“atopic” pathway, it refers to a hypersensitive reaction to an

allergen. Patients with typ2 phenotype release cytokines such

as interleukin [IL]-4, IL-5, IL-13, which drive immunoglobulin E

(IgE) production.

Targeting the cause

The majority of asthma patients are also allergic. IgE, the

antibody intimately involved in allergic responses, is the target

of omalizumab, the first approved monoclonal antibody

treatment for asthma.

“Since omalizumab was first introduced to the United

States market in 2003, it, and other more recent biologics

for asthma, have made a tremendous difference in the lives

of many asthmatics. Their impact can be likened to the

introduction of the combination of inhaled steroids and longacting

beta agonists in the 1990s, which allowed a number

of asthmatics to attain greater control of their asthma and a

number of severe asthmatics to get off of systemic steroids,”

says Dr Andy Nish, MD Fellow of American Academy of

Allergy, Asthma & Immunology (FAAAAI), USA.

The asthma biologic drug research pipeline today contains

12% monoclonal and 17% non-monoclonal antibodies.

Some groups of white blood cells, such as eosinophils,

May 2019 / FUTURE MEDICINE / 19


nonresponders in the magnitude of

reduction in blood eosinophils.

Reslizumab is USFDA approved for

add-on therapy in adults aged 18 and

older with eosinophilic asthma.


An RDBPCT of 369 adults with severe

asthma requiring oral steroid therapy

use noted that benralizumab use of 30

mg SC either every 4 weeks or every

8 weeks reduced median final oral

glucocorticoid dose from baseline by

75%, compared with a 25% reduction

in the placebo group. Benralizumab

use reduced the annual exacerbation

rate by 55% versus placebo when

administered every 4 weeks and by 70%

when administered every 8 weeks. No

significant effect on forced respiratory

volume 1 (FEV1) was noted.

Increased blood eosinophil levels

of more than 300 cells/µL have

been identified in some studies as a

biomarker of benralizumab efficacy.

However, a pooled analysis of SIROCCO

and CALIMA study data supported the

use of benralizumab in patients with

blood eosinophil counts =150 cells/

µL73 and a newly released subsequent

pooled analyses extended the efficacy

irrespective of eosinophil count,

although noting that the higher the

eosinophil count the greater the benefit.

Benralizumab is FDA approved

for patients with severe asthma aged

12 years and above, who have an

eosinophilic phenotype.


Dupilumab is a human monoclonal

antibody to the alpha subunit of the IL4

receptor, thereby blocking the activity of

IL4 and IL13. Dupilumab is the only drug

approved for self-administration.

The IL4 cytokine is an essential

cytokine to T helper 2 (Th2) cell

polarization, whereas the IL13 cytokine

is associated with periostin production

in the bronchial epithelial cells,

ultimately resulting in smooth muscle

contraction, mucous production, airway

remodeling and hyper-responsiveness.

IL13 also works with IL4 to result in IgE


An RDBPCT of dupilumab use in

104 adults aged between 18 and 65

years with moderate-to-severe

asthma and high blood or sputum

eosinophil counts above 300 cells/

µL and 3% respectively on mediumto-high

dose ICS plus LABAs resulted

in an 87% reduction in asthma

exacerbations and increased time to

asthma exacerbation despite stopping

LABA and ICS therapy while on

dupilumab compared with placebo.

There was noted improvement in

FEV1 as early as the second week

of treatment, which was maintained

for the 12 weeks of the study. An

RDBPCT of dupilumab using 300mg

SC every 2 weeks for 24 weeks in 210

adults with OCS-dependent asthma

noted a 59% decrease in severe

exacerbations in the dupilumab group

despite a -70.1% reduction in OCS.

An RDBPCT of 1902 adolescents

and adults with uncontrolled asthma

noted that dupilumab reduced severe

exacerbations by 47.7% compared

with placebo while increasing FEV1.

Dupilumab has been shown to

reduce FeNO levels and other levels

of Th2 inflammation including TARC,

eotaxin-3, and IgE.

Dupilumab has been approved by

US FDA for adolescents and adults aged

12 years and older with moderate-to-

are found to be critically involved in the inflammatory process

in the airways that results in the loss of lung function in

asthma. Several products have been developed to inhibit

the production, the function, and the survival of eosinophils.

These antibodies seem to work particularly well in individuals

with high eosinophil counts prior to treatment and who

have not responded to current treatment with inhaled

corticosteroids. Collectively, these products are well tolerated

and are effective in reducing eosinophil numbers and

preventing asthma exacerbations.

Multiple antibodies seek to tackle cytokines, which are

key in fuelling allergic-type responses and inflammation. But

the therapeutic agents that single out individual cytokines

for targeting proved to be largely ineffective due to the

overlapping effects of cellular signalling proteins. However,

antibodies blocking the effect of more than one cytokine have

shown promise.

Mepolizumab, reslizumab, and benralizumab are targeted

towards IL5, a cytokine that promotes both the activation and

longevity of eosinophils. Dupilumab is an anti-IL4 cytokine

antibody which is essential for Th2 cell polarization. Whereas,

biologic tralokinumab, that targets IL13 cytokine, is currently

under phase 2 development. IL13 is associated with periostin

production in the bronchial epithelial cells, ultimately resulting

in smooth muscle contraction, mucous production, airway

remodelling and hyper-responsiveness.

Today, clinicians have more than 10 years of clinical

experience with IgE targeting omalizumab and extensive trial

data with anti-eosinophil antibody mepolizumab. Unlike for

most drugs, outcomes in clinics with omalizumab have often

20 / FUTURE MEDICINE / May 2019

severe asthma as add-on maintenance



Lebrikizumab is a humanized

monoclonal antibody against IL13. IL13

also works with IL4 to result in IgE

production. The IL4 receptor (alpha

subunit) is critical for both IL4 and IL13

signal transduction.

A phase 2 RDBPCT of lebrikizumab

using 250 mg dosage strength SC once

a month in 219 adults with asthma

uncontrolled on medium-to-high

dose ICS therapy noted a significant

improvement in FEV1 after 12 weeks of

lebrikizumab (5.5% points higher than

placebo) although no significant change

was noted in several other secondary

efficacy outcomes including asthma


Another phase 2 RDBPCT of 212

adults aged 18–65 years not receiving

ICS therapy noted no significant

improvement in FEV1 with multiple

different doses of lebrikizumab

compared with placebo even with

stratification based on periostin levels,

although there was a reduced risk of

treatment failure in all lebrikizumab dose


Periostin levels have emerged from

the mentioned studies as a biomarker

strongly correlated with lebrikizumab

efficacy. Lebrikizumab has been

associated with a decrease in FeNO,

with greater reductions in FeNO in the

high periostin groups.

There are a small number of studies

thus far that are limited to the adult



Tralokinumab targets IL13. A phase

2 RDBPCT of multiple doses of

tralokinumab in 194 adults aged 18–65

years with moderate-to-severe asthma

noted no significant improvement in

control with tralokinumab although

there was a significant decrease in betaagonist


A phase 2 RDBPCT of tralokinumab

in 452 adults with severe uncontrolled

asthma noted that tralokinumab use of

300 mg SC every 2 or 4 weeks did not

result in significant percentage change

in annual asthma exacerbation rates.

Prebronchodilator FEV1 was significantly

increased in the tralokinumab every 2

weeks group compared with placebo

but not in the tralokinumab every

4 weeks group. Subgroup analysis

identified adults with a high baseline

serum dipeptidyl peptidase-4, or high

serum periostin levels had improved

FEV1, asthma control and exacerbation



Tezepelumab is a human anti-TSLP

monoclonal immunoglobulin that

prevents binding of TSLP with its

receptor, preventing TSLP-initiated

inflammatory responses through the

activation of dendritic cells and mast

cells. There has only been one proofof-concept

RDBPCT of tezepelumab

in 31 adults with allergic asthma that

noted attenuation of both the early and

late asthmatic responses, with a 45.9%

smaller decrease in FEV1 during the

late phase response after 12 weeks of


A phase 2 RDBPCT of tezepelumab

in adults with uncontrolled asthma

despite medium-to-high ICS and

LABA therapy noted significant

reductions in exacerbation rates with

tezepelumab, independent of baseline

serum eosinophil levels, as well as an

improvement in FEV1. No studies have

been done in the paediatric population,

the biomarker profile of those most likely

to respond remains unknown.

Many small molecule drugs are also

showing great promise.

been better than those seen in clinical

trials. It is considered a surprising feature of

omalizumab in clinical practice.

Rising incidence; dearth of biomarkers

Estimates show that the incidence of

asthma may have increased as much as

12% over the past decade. Several theories

postulate as to why the incidence of asthma

is on the rise.

First, asthma is more recognized and

coded as such, as opposed to in the past,

when it may have been diagnosed using

terms such as bronchitis, explains Dr Nish.

According to him, allergic diseases, in







general, have been increasing; not only

asthma, but also allergic rhinitis, food

allergy and atopic dermatitis. “One theory

is called the hygiene hypothesis, that

our lymphocytes no longer have to fight

infection as much as in the past, so they are

becoming more Th2 cells and producing

allergic disease,” he remarks.

Air pollution has been linked to

increased incidence of asthma in children,

as has exposure to cigarette smoke,

particularly if the mother smokes while

pregnant. In addition, if a child’s diet is

leading to obesity, it can be associated with

an increased risk of asthma. Caesarean

May 2019 / FUTURE MEDICINE / 21

irths change gut flora and increase the risk of asthma too.

So, the rise in asthma is likely multifactorial.

Even though biologic therapies allow the selection of

patients suitable for intervention with antibody infusions,

defining a set of predictive and monitoring biomarkers

to assess the likelihood of a patient who will respond to

a biologic continues to be a challenge. It is also difficult

to determine whether there is a favourable response to

continuing the biologic. Biomarkers, which will provide a

profile of those patients most likely to respond favourably and

also to discontinue medication if there is a low likelihood of a

response, are yet to be a reality. It took several years to define

the subgroup of patients with severe asthma who respond to

anti-IL-5 treatment.

The concept of subtypes of asthma is new and clinically

still evolving. Much has been made of endotypes, with many

different pathways described as potentially contributing to

the asthma phenotype. There has been much debate about

type 2 (IgE and eosinophilia driven by IL-4, IL-5 and IL-13) and

non-type 2 asthma. The RASP-UK study, adjusting therapy

according to type 2 biomarkers, exhaled nitric oxide, blood

eosinophils and serum periostin (an IL-13 induced epithelial

“We recognize

that asthma

treatment is not

‘one size fits all’”

Andy Nish, MD is Fellow of American

Academy of Allergy, Asthma &

Immunology (FAAAAI) and the President

of Northeast Georgia Physicians Group

(NGPG) — Allergy and Asthma, GA. Dr Nish

talks about the impact of biologics therapy

in asthma, as well as the other advances

in better defining and managing the

chronic airway inflammatory disease. Edited


Nearly half a dozen biologics are now

approved to treat asthma. And many more

are under development. Can biologics

eventually replace the current line of

steroid-centred management of the

symptoms and offer a lasting solution, if

not a permanent cure, for the disease?

Biologics have made a tremendous

difference in the lives of many asthmatics.

However, it is unlikely that the biologics

will be able to completely replace current

asthma therapies. For one, the biologics

target a specific pathway which provides a

narrower therapeutic efficacy than current

standard therapies. And asthmatics in the

intermittent, mild persistent and moderate

persistent categories can typically be

controlled with currently available therapies

with a very acceptable risk to benefit

ratio. In addition, the current costs of

manufacturing the biologics make them

cost-prohibitive to be used broadly.

Unfortunately, the currently available

biologics have not been shown to have

disease-modifying properties for asthma.

Studies have shown that asthma returns

to its previous state of inflammation and

pathology over time once the biologics are


So, it’s unlikely that biologics, as we

currently know them, can function as

22 / FUTURE MEDICINE / May 2019

monotherapy for asthma or produce a

cure, but then twenty years ago who

could have known of the advances we

have available today.

Apart from monoclonals, what are

the other approaches using biologics,

currently being explored to address


Despite the advances and benefits

of currently available biologics, which

are genetically engineered proteins,

continued improvement is welcomed

and there are definitely holes in our

treatment choices. For the Th17 (non

T2) type asthmatic, there are currently

no highly effective biologics. Whereas

currently 98% of all asthma treatment

is small particle, the research pipeline

contains 12% monoclonal and 17%

non-monoclonal antibodies.

The incidence of asthma is on

the rise the world over despite

wider availability of effective and

comparatively less costly medicines

to control the attacks. Why?

It is estimated that asthma may

have increased as much as 12% over

the past decade. There are a number

of theories as to why the incidence

of asthma is on the rise. In reality, it is

probable that a number of these are


First, it is suggested that asthma is

more recognized and coded as such.

Allergic disease, in general, has

been increasing, not only asthma

but also allergic rhinitis, food allergy,

and atopic dermatitis. One theory is

called the hygiene hypothesis, that our

lymphocytes no longer have to fight

infection as much as in the past, so

they are becoming more Th2 cells and

producing allergic disease.

Air pollution has been linked to

increased incidence of asthma in

children, as has exposure to cigarette

smoke, particularly if the mother

smokes while pregnant. In addition, if

a child’s diet is leading to obesity and

overweight, it can be associated with

an increased risk of asthma. Birth by

It’s unlikely that biologics,

as we currently know

them, can function as

monotherapy for asthma or

produce a cure.

Andy Nish MD

Fellow of American Academy of

Allergy, Asthma & Immunology, USA

c-section changes the gut flora and

increases the risk of asthma also.

So, the rise in asthma is likely

multifactorial, but the good news is

that we do have more and better

asthma medicines to use over time.

Some of the experts in the field

argue that the term “asthma”

needs to be redefined, giving more

emphasis on the heterogeneity of

the disease. What is your comment?

I definitely agree with this concept.

As we have learned particularly

in recent years, there is so much

heterogeneity in the pathology of

asthma and the inflammation thereof

and response to treatment.

The more medicines that have been

developed, the more we learn about

which patients do or don’t respond to

particular of those medicines, and

then research helps to delineate why

that is.

Some patients are primarily T2

driven and some primarily Th17 driven.

Some are primarily eosinophil driven

and some primarily neutrophils. Some

asthmatics respond dramatically to very

small doses of inhaled corticosteroids

and some respond minimally to

very high doses of inhaled or even

systemic steroids. It’s important that we

recognize that asthma treatment is not

“one size fits all”.

Are corticosteroids being

overprescribed for managing


If the question is in regard to

inhaled steroids, I would suggest

that the answer is no. It may even be

that inhaled steroids are not being

prescribed often enough, partly

because of steroid phobia, particularly

on the part of parents. Other studies

have suggested that asthma is

underdiagnosed in general and the

severity is underappreciated.

It is recommended by experts

that the drug of choice for the firstline

treatment of mild, moderate

and severe persistent asthma is

inhaled steroids, of course with other

medicines as needed as severity


We have good evidence from

longitudinal studies that, if inhaled

steroids affect children’s final adult

height, it is a minimal effect and that

other potential side effects, in general,

present a favourable risk to benefit

ratio. It is worth pointing out that

inhaled steroids are in microgram

doses and systemic steroids, if needed

for an asthma flare, are in milligram

doses, or 1000 times stronger.

It is important to note that

objective measures, such as

pulmonary function tests, should be

used to make sure that treatment is

effective, and at the lowest possible

dose for the fewest side effects.

May 2019 / FUTURE MEDICINE / 23

protein), should help define which patients have controlled

type 2 disease, and which have a non-type 2 mechanism

driving their symptoms.

The outlook for severe non-allergic asthma, however, is

less rosy at present. This is because a lot of efforts have been

devoted to finding effective drugs for severe allergic asthma,

but severe non-allergic asthma has not been the focus of

as much research. This is an area where more research is

urgently needed, believes leading organisations like Asthma


But many researchers are still uncertain about the

existence of non-type 2 asthma in the severe asthma


“For the Th17 (non T2) type asthmatic, there are currently

no highly effective biologics,” points out Dr Nish.

Clinical trials should inform on the role of biomarkers

in determining treatment response. Benefits of anti-

IL-5 approaches with mepolizumab, reslizumab and

benralizumab, and dupilumab (anti-IL4/IL-13) have been

documented by large clinical trials. Phase III studies of

lebrikizumab (anti-IL-13) did not show significant clinical

benefit compared to placebo. The lebrikizumab phase 3

studies did not enrich for exacerbations.

Efficacy in children — Expanding evidence

Asthma in childhood is quite different from asthma in

adulthood. Phenotypically, paediatric asthma is more

commonly allergic in nature. Likewise, the prevalence of

asthma is higher in male children, whereas adult females

have more severe and persistent disease. Hence, results

from adult studies may not be extrapolated to the paediatric

population. Evidence is expanding for biologic therapies

such as omalizumab in children, despite the fact that

evidence is limited for most of these drugs in the case of

adult-onset asthma.

Omalizumab is now approved up to 6 years of age in

some countries. This makes it the first choice for children

with severe asthma if the serum IgE is within limits.

Mepolizumab and benralizumab, the anti-IL5 therapies, are

available for use in some countries for adolescents of 12

years of age. The treatment is likely to reduce exacerbations

in cases where the blood eosinophil count is more than 300

cells/µL and perhaps 150 cells/µL. Dupilimab, which has

been found not having significant adverse effects in adult

studies, is being considered for home administration.

Adjunctives for uncontrolled asthma

Omalizumab and anti-IL5 medications are currently

included for use in patients with severe asthma, including

children and adolescents, by several international asthma

guidelines. The National Heart, Lung and Blood Institute’s

Expert Panel 3 (NHLBI EPR3) guideline recommends the

use of omalizumab as adjunctive therapy in patients above

12 years who have atopic, severe and persistent asthma
















Binds circulating

IgE—↓IgE levels,

downregulation of IgE

receptors on mast cells,

basophils, and dendritic


Binds circulating

IgE—↓IgE levels,

downregulation of IgE

receptors on mast cells,

basophils, dendritic cells.

Binds IL5, which recruits

eosinophils from the

bone marrow and

promotes activation and

longevity of eosinophils

Binds IL5, which recruits

eosinophils from the

bone marrow and

promotes activation and

longevity of eosinophils

Binds IL5 receptor,

preventing binding of


Blocks activity of IL4

and IL13

Binds IL13, thereby

blocking its activity

Binds IL13, thereby

blocking its activity

Prevents binding of

TSLP with its receptor,

preventing TSLPinitiated


response through

activation of dendritic

cells and mast cells

Antagonist to CRTh2,

which is a PGD2

receptor that mediates

inflammatory effects

through production of

mast cells and other

allergic cells



SC every 2–4

weeks based on

body weight and

serum IgE level

SC every 2 weeks

SC every 4 weeks

IV every 4 weeks

SC every 4 or 8


SC every 2 week

SC every 4 weeks

SC every 2–4


IV every 2–4 weeks

Orally once a day

inadequately controlled with high-dose ICS and LABA


The Global Initiative for Asthma (GINA) 2017 update

recommends phenotype-guided add-on treatment with

omalizumab in patients above 6 years with severe allergic

asthma with elevated IgE, and mepolizumab or reslizumab

in patients above 12 years with eosinophilic asthma as step

24 / FUTURE MEDICINE / May 2019




Researchers at the MRC-Asthma UK

Centre in Allergic Mechanisms of

Asthma and Cardiff University found

that people with asthma have more of a

special type of calcium receptor in their

lungs than people without asthma.

Called calcium-sensing receptors or

CaSR, they sit on the surface of a cell,

respond to chemicals in the environment

such as pollutants or allergens that trigger


The scientists later found that a class

of drugs called calcilytics can inhibit


‘Calcilytic’ drugs can reverse or abolish

twitchiness of the airways which are

responsible for the symptoms of asthma,

say researchers.

Existing drugs, such as preventer

inhalers, address this problem only

indirectly, by reducing the inflammation

of the airways which is thought to be one

of the triggers for this twitchiness, while

reliever inhalers make the muscle cells

relax, temporarily alleviating the blockage.

By using calcilytic drugs, the cause of

the twitchiness can be directly targeted,

instead of working on the reaction,

regardless of what has caused it. It can

thus treat all asthma.

The challenge now is to develop a

form of these drugs which can be inhaled

safely to the airways and then explore

their effects in people with asthma.

The next logical step will be clinical

trials to see if the drugs work.

4 (medium dose ICS +LABA) therapy.

The Canadian Thoracic Society (CTS) recommends

omalizumab in patients above 6 years with severe asthma

that is inadequately controlled on high dose ICS and at least

1 other controller, sensitization to more than 1 perennial

aeroallergen, and serum IgE levels between 30 and 1,300

IU/mL (6–11 years) or 30–700 IU/mL in patients above 12

May 2019 / FUTURE MEDICINE / 25

years. The CTS also recommends anti-IL5 therapies in adults

with severe eosinophilic corticosteroid-dependent asthma

in an attempt to decrease or withdraw oral corticosteroids


Benefits ‘at best Incremental’

Omalizumab, mepolizumab, reslizumab, benralizumab,

and dupilumab are currently the five US FDA-approved

monoclonal antibodies that affect the pathways involved

in either allergic or type 2 inflammatory phenotypes of

asthma. Presently, there are no head to head randomized

or observational trials to study the comparative clinical

effectiveness of these mAbs. Estimates from Cochrane

meta-analyses showed that all five drugs reduced the

annual exacerbation rate by about 50% with overlapping

confidence intervals. The average improvement for four of

the drugs, compared with a placebo, is modest and none

of them reach the minimally important difference, although

all were statistically significant. Dupilumab had the largest

reduction in exacerbations and benralizumab the smallest,

according to a meta-analysis by the Institute for Clinical

and Economic Review (ICER), an independent nonprofit

research organisation. The risk for serious

adverse events was low for all five drugs. The only

consistent and common adverse event was

injection-site reactions. The dosing schedule

varies between the drugs. Dupilumab is

given every two weeks, omalizumab is given

every two to four weeks, mepolizumab and

reslizumab are given every four weeks, and after the first

three doses, benralizumab is given every eight weeks.

Notably, none of the drugs prevented most

exacerbations requiring systemic corticosteroids or improved

average daily quality of life to a degree considered clinically

significant. Thus, the overall health benefit for all five drugs

is at best incremental, notes ICER report.

“Unfortunately, the currently available biologics have

not been shown to have disease-modifying properties for

asthma,” comments Dr Nish, who is also the President of

Northeast Georgia Physicians Group (NGPG) — Allergy and

Asthma, GA. Studies have shown that asthma returns to

its previous state of inflammation and pathology over time

once the biologics are stopped, he adds.

The long-term safety and effectiveness of these

drugs, however, is yet to be established particularly in

older patients. For omalizumab and mepolizumab, longterm

extension trials and real-world experience provide

supportive but uncontrolled evidence. Response to therapy

is yet to be well-defined to help guide patients and

clinicians in deciding when to stop one therapy and consider

switching to another.

At what cost?

Biologics comes with high treatment costs. Analysis indicate

that biologic agents provide gains in quality-adjusted

survival over the standard of care alone. Exacerbation

reductions and chronic oral steroid reductions are

potentially the most influential benefit associated with

biologic therapy.

A survey by the Asthma and Allergy Foundation of

America involving 805 Americans living with asthma,

including 185 with severe, uncontrolled asthma, found that

an average of 82% chose effectiveness as a key criterion

while an average of 52% cited cost as a key criterion for

selecting a therapy.

Patients report that their asthma prevents them from

living the life that they want to live, besides impacting their

loved ones. They also fear the side effects of corticosteroids

and want to minimize the use of both systemic and inhaled

corticosteroids as much as possible.

26 / FUTURE MEDICINE / May 2019

Looking for loci

Asthma is a multifactorial

disease with a complex genetic

inheritance. Collective evidence

suggests that genetic factors account

for approximately 60–80% of its

susceptibility. More than a hundred

genetic variations positioned

throughout the genome have been

implicated in asthma susceptibility.

However, studies could replicate only

a subset of these genes. Besides, the

exact mechanism of the interaction of

these genotypes with the environment

is not clearly understood.

The incidence of asthma, which

is the highest in childhood, tends to

show a bias towards boys. While boys

are at a higher risk of asthma in early

childhood, girls are more frequently

affected after puberty. Hypersensitivity

to aeroallergens is the key feature

of childhood-onset asthma. Atopic

dermatitis and hay fever are closely

associated with asthma, constituting

what is known as the atopic triad.

Genetic factors determining the

age of onset of asthma has been

traced to diverse chromosomal loci.

Two regions — 5q13 and 1p31 — with a

suggestive linkage to time of onset of

asthma, have been specifically identified

in French families. Also, a region on

7q was found linked to asthma in the

same population, but with different

risks. The -28G allele of the RANTES

promoter region at chromosome 17q

increased the risk of late-onset asthma

in Japanese individuals

A genome-wide association (GWA)

study revealed that the 17q12-21 region









is predominantly a locus of childhoodonset

asthma. Despite these findings,

it is not clear whether sex differences

in asthma risk at different ages can be

explained by genetic factors.

Molecular genetic studies suggest

an association of a variant on

chromosome 5, situated within the

TSLP gene, among patients with severe

asthma. Similarly, polymorphisms within

the beta2-adrenergic receptor gene,

the IL-4 gene and the TGF-ß1 and CD14

genes have been shown to play a role

in asthma severity.

Positional cloning identified five

asthma genes or gene complexes,

including ADAM33, PHF11, DPP10, GRPA

and SPlNK5. Though the functions of

these genes are largely obscure, the

expression of DPP10, GRPA and SPlNK5

in terminally differentiating epithelium

suggests that they respond to the

external environment.

Many of the genes identified by

candidate gene studies, including lL13

that modifies mucous production, FccRl-

/J which modifies an allergic trigger

on mast cells, and microbial pattern

recognition receptors of the innate

immune system, may also exert their

effects within the cells that make up the


There is also evidence of genetic

heterogeneity within the clinical

expression of asthma. In spite of the

high heritability of asthma susceptibility,

genetic factors account for only around

35% of the variation in the age at onset

and for around 25% of the variation

in the overall symptomatic severity of

the disease and for even less of the

variation in the severity of individual

asthma symptoms such as wheezing,

shortness of breath, chest tightness and

cough, according to studies.

Given the high cost of these therapies, GINA

recommends the use of biologics in patients whose

asthma is refractory or relatively refractory to

conventional inhaled therapies.

Biologics are also indicated for eosinophilic

asthma. Eosinophils are part of the immune

response to parasitic infections. It is unknown if the

therapies that decrease eosinophil counts will affect

patients’ ability to fight such infections. Current

guidelines recommend that physicians treat patients for

existing parasitic infections prior to initiating anti IL-5


Researchers call for designing a large, pragmatic trial

comparing all available drugs in order to clarify whether

or not there are clinically important differences between

the drugs.

May 2019 / FUTURE MEDICINE / 27


Asthma is increasing in many parts of the world,

notably in developing nations.



people suffer from asthma. It is

estimated that asthma has increased as

much as 12% over the past decade


people die of asthma every year




deaths occur in

low and




28 / FUTURE MEDICINE / May 2019









Americans use more inhalers

than any other population




Asia Pacific


of population

suffer from



of Indian

population are






Middle East & Africa


Asthma is a well-recognized medical condition.

However, there is not one universal, agreed-upon

definition for the disease

The Global Initiative for Asthma (GINA)

defines the condition as “a chronic

inflammatory disorder of the airways in

which many cells and cellular elements

play a role. The chronic inflammation

is associated with airway hyperresponsiveness

that leads to recurrent

episodes of wheezing, breathlessness,

chest tightness and coughing, particularly

at night or in the early morning. These

episodes are usually associated with

widespread but variable airflow obstruction

within the lung that is often reversible

either spontaneously or with treatment”.

Concepts of asthma have changed

substantially over the past 50 years.

GINA now explicitly emphasises the

heterogeneity of asthma and uses the

term asthma as an umbrella term like

anaemia, arthritis and breast cancer.

Unlike with anaemia, arthritis or cancer,

evidence about underlying mechanisms of

asthma is incompletely understood.

Years ago, when we had fewer

medicines with which to treat asthma,

and a much more basic concept of the

disease as primarily bronchoconstriction,

it was easier to think of it as one

disease, says Dr Andy Nish, MD, Fellow of

American Academy of Allergy, Asthma &

Immunology (FAAAAI), USA.

“Now, it’s probably much more

appropriate to think of it as a syndrome

whose patients have in common

reversible airflow disease, bronchial

hyperresponsiveness, airway inflammation

and typically symptoms of wheezing,

coughing, shortness of breath and chest

tightness brought on by some common

factors such as viruses, weather changes,

exercise, smoke,etc, “ he adds.

Many studies exploring the

inflammatory pathways are restricted to

patients with severe asthma.

For the diagnosis and management

of asthma, clinicians rely on evidencebased

recommendations, including those

developed as formal clinical practice

guidelines. Different bodies make different

recommendations from the same

evidence, as is the case with the UK in

asthma guidelines published by the British

Thoracic Society/Scottish Intercollegiate

Guideline Network (BTS/SIGN) and the

National Institute for Health and Care

Excellence (NICE).

Therefore, it is essential to have

national or regional guidelines in order to

provide locally-specific recommendations.

Spirometry and breathomics

Presently, there is no precise test for

asthma diagnosis. Diagnosis is typically

based on the pattern of symptoms

and the response to therapy over time.

Clinicians suspect asthma if there is a

history of recurrent wheezing, coughing

or difficulty in breathing, and these

symptoms occur or worsen due to

exercise, viral infections, allergens or air

pollution. Spirometry is then used to

confirm the diagnosis.

Spirometry is the single best test

for asthma. If the FEV1 measured by

this technique improves more than

12% and increases by at least 200

milliliters following the administration of

a bronchodilator such as salbutamol, it is

supportive of the diagnosis. It, however,

may be normal in those with a history of

mild asthma.

COPD overlap

Asthma is a chronic obstructive condition.

But it is not considered as a part of

chronic obstructive pulmonary disease

(COPD). One of the most characteristic

features of efficacy studies in asthma and

COPD is their restriction to “pure” asthma

and “pure” COPD, point out asthma


COPD refers specifically to

combinations of disease that are

irreversible, such as bronchiectasis, chronic

bronchitis and emphysema. Unlike these

diseases, the airway obstruction in asthma

is usually reversible; however, if left

untreated, the chronic inflammation from

asthma can lead the lungs to become

irreversibly obstructed due to airway

remodelling. Unlike emphysema, asthma

affects the bronchi, not the alveoli.

May 2019 / FUTURE MEDICINE / 29





A novel modality, BT aims to prevent the structural changes in

airway smooth muscle


Asthma is a complex inflammatory

disorder of the airways

characterized by airway hyperresponsiveness

(AHR) and variable

airflow obstruction. Although advances

in clinical and basic research over

the past few decades have led to the

development of effective treatments

and dissemination of detailed disease

management guidelines, difficult-totreat

asthma continues to affect 5-10%

of adults with this disorder.

Bronchial thermoplasty (BT) is

a modality for treating asthma and

is thought to prevent the chronic

structural changes that occur in airway

smooth muscle (ASM) in individuals

with asthma. BT targets ASM via the

delivery of a controlled specific amount

of radiofrequency (RF) energy (RF

ablation [RFA]) to the airway wall

through a dedicated catheter.

It is an innovative treatment

whose clinical efficacy and safety are

beginning to be better understood.

Since this is a device-based therapy,

the overall evaluation of risk-benefit

is unlike that of pharmaceutical

products; safety aspects, regulatory

requirements, study design and effect

30 / FUTURE MEDICINE / May 2019

size assessment may be unfamiliar.

The mechanisms of action and optimal

patient selection need to be addressed

in further rigorous clinical and scientific



Candidates for bronchial thermoplasty

include adults with severe persistent

asthma who require regular

maintenance medications of inhaled

corticosteroids (>1000 µg/day of

beclomethasone or the equivalent) and

a long-acting beta agonist (≥100 µg/

day of salmeterol or the equivalent).

These patients would have received

add-on therapies such as leukotriene

modifiers, omalizumab, or oral

corticosteroids (≤10 mg/day).

These patients should be on stable

maintenance asthma medications

according to accepted guidelines,

should have a pre-bronchodilator

forced expiratory volume in 1 second

(FEV1) of 60% or more of predicted,

and should have a stable asthma

status (FEV1 within 10% of the best

value, no current respiratory tract

infection, and no severe asthma

exacerbation within the preceding 4


Patients are usually selected

on the basis of the AIR 2 trial. The

patient should be stable in terms

of asthma status, defined as a post

bronchodilator FEV1 within 15% of

baseline values with no respiratory

tract infection or asthma exacerbations

within the preceding 14 days.


Contraindications for BT include the


• Presence of an implantable

electronic device

• Known hypersensitivity to drugs

used during bronchoscopy

• Severe comorbid conditions that

would increase the risk of adverse


Patients are not considered

candidates for BT if they had three or

more hospitalisations for asthma, three

or lower respiratory tract infections and

four or more oral corticosteroids used

for asthma in the previous year.

Although the benefits of BT may

be large, the potential harm may be

large as well, and the long-term side

effects are unknown. Studies are still

needed to assess exacerbation rates

and long-term effects on lung function.

It remains to be determined which

phenotypes will respond best to BT,

what the effects may be on obstructed

patients with an FEV1 higher than

60%, and what the applicability of the

procedure may be in patients receiving

systemic steroid therapy

Procedure considerations

BT is performed via fibreoptic

bronchoscopy in three separate

procedures, separated by

approximately 3 weeks, as






demonstrated by previous studies.]

Dividing the treatments into three

bronchoscopy sessions minimizes

the risk of inducing an asthma

exacerbation or diffuse airway oedema.

It also avoids excessive procedural

length. BT takes longer (30-60

minutes) than a standard fiber-optic

bronchoscopy (5-20 minutes) does,

and the longer duration implies the

use of larger doses of medication for


All accessible airways are treated,

with the exception of the right middle

lobe, because of the theoretical

concern about the risk of inducing

right-middle-lobe syndrome.]

Oxygen delivery should be started

via a nasal or oral cannula during

the procedure, with appropriate

monitoring of vital signs. Heart rate,

pulse oximetry, and noninvasive blood

pressure should be continuously



Patients may experience respiratoryrelated

adverse events such as cough,

wheezing, and chest tightness during

the treatment period. Most of these

symptoms occur within 1 day of the

procedure and resolve in an average of

7 days with standard therapy.

It is unclear why an intervention

aiming at a reduction of smoothmuscle

mass would not affect

FEV1. Given that the number of

exacerbations is reduced with no

change in FEV1, it may be that altered

response to the inflammatory triggers

plays a role in addition to the reduction

in smooth-muscle mass.


Recurrent lung atelectasis secondary

to fibrin plugs has been reported

as an early complication of BT.

In the susceptible patient, high

thermal stimulation may lead to

an inflammatory reaction with

microvascular alteration, induced

either by heat or by the release of

inflammatory mediators. Lung abscess

has also been described as a direct

complication; thus, collecting and

publishing safety data continue to

be important. A prospective cohort

study performed as part of the

TASMA trial reported a high incidence

of acute radiologic abnormalities

after BT. Postprocedural CT of

the chest identified four different

radiologic patterns: (1) peribronchial

consolidations with surrounding

ground-glass opacities (94%), (2)

atelectasis (38%), (3) partial bronchial

occlusions (63%), and (4) bronchial

dilatations (19%). These complications

resolved without clinical impact in

virtually all cases.

The author is Head, Department of

Respiratory Medicine, Medical Trust

Hospitals, Cochin

May 2019 / FUTURE MEDICINE / 31

drug approvals


capsule for

weight loss

Plenity manufactured by the

Gelesis has been granted

approval by USFDA as an aid

in weight management in

adults with a body mass index

(BMI) of 25–40 kg/m2, when

used in conjunction with diet

and exercise.

It is an oral, non-systemic,

superabsorbent hydrogel

capsule which when taken

together with diet and

exercises aids in weight

loss by inducing satiety and

reducing hunger.

The drug can be

administered in the form

of capsules that could be

taken with water before

dinner and lunch. It is made

of two naturally derived

compounds called cellulose

and citric acid which are cross

linked together in a manner

that they create a threedimensional


The hydrogel-based

capsule release thousands

of non-aggregating gel-like

particles that rapidly

absorbs water in the stomach.

These small gellike particles

have an elasticity of plantbased

foods but they do

not have any caloric value.

These gel particles increase

the elasticity of the contents

stored in the stomach and

intestine giving out a feeling

of fullness that aids in weight


The clinical studies

of Plenity have shown

positive effects on weight




designation to


Genfit announced that its

lead product candidate

elafibranor was granted

Breakthrough Therapy

Designation by the US FDA

for the treatment of primary

biliary cholangitis (PBC)

in adults with inadequate

response to ursodeoxycholic

acid (UDCA).

Elafibranor is a first-inclass

double peroxisome

proliferator-activated receptor

alpha and delta (PPAR alpha/

delta) agonist which has

produced positive results

in a phase 2 clinical trial

evaluating its safety and

efficacy in adults with PBC

and inadequate response to


Elafibranor is also

currently evaluated in a phase

3 clinical trial in non-alcoholic

steatohepatitis (NASH).

Genfit presented detailed

results from its positive phase

2 clinical trial evaluating

elafibranor in PBC during

the European Association for

Hormone therapy

for menopausal


The US FDA has approved

first of its kind capsule

Bijuva which contains

progesterone and

estradiol, announced


It is the first bioidentical

hormone therapy

combination that has been

approved by the FDA.

The approval is based

on the Bijuva clinical

development programme

that included the pivotal

phase III Replenish Trial.

This trial evaluated the

safety and efficacy of

Bijuva in generally healthy,

postmenopausal women

with a uterus for the

the Study of the Liver (EASL)

annual International Liver

Congress (ILC).

In a 12-week doubleblind

randomized placebocontrolled

phase 2 trial of

non-cirrhotic patients with

PBC and with inadequate

response to UDCA, elafibranor

showed a significant decrease

of alkaline phosphatase (ALP)

levels, resulting in significant

treatment of moderate to

severe hot flashes.

The co-primary efficacy

endpoints in the Replenish

Trial were the change from

baseline in the number

and severity of hot flashes

at weeks 4 and 12 as

compared to placebo.

Bijuva demonstrated

a statistically significant

reduction from baseline

in both the frequency and

severity of hot flashes

compared to placebo while

reducing the risks to the

endometrium. The results

of the trial were published

in the journal Obstetrics &


treatment effects versus

placebo on the primary



stem cell

therapy for



he US FDA has granted

Fast Track Designation for

CTX001 for the treatment of

transfusion-dependent beta

thalassemia (TDT).

CTX001 is an

investigational, autologous,

gene-edited haematopoietic

stem cell therapy for patients

suffering from severe


32 / FUTURE MEDICINE / May 2019

form of haemoglobin.

The elevation of HbF by

CTX001 has the potential

to alleviate transfusion

requirements for TDT patients

and painful and debilitating

sickle crises for SCD patients.

Speedy approval

for erdafitinib

to treat bladder


had previously not responded

to anti-PD-L1/PD-1 therapy.

Erdafitinib is the first

approved drug in a class

known as FGFR inhibitors

that targets growth factor

receptors involved in cell

growth and division.

In February 2019, CRISPR

Therapeutics and Vertex

announced that the first

patient had been treated with

CTX001 in a phase 1/2 clinical

study of patients with TDT,

marking the first companysponsored

use of a CRISPR/

Cas9 therapy in a clinical trial.

The Phase 1/2 open-label

trial is designed to assess

the safety and efficacy of

a single dose of CTX001 in

patients ages 18 to 35 with

TDT, non-beta zero/beta zero

subtypes. The companies are

also evaluating CTX001 for the

treatment of sickle cell disease

(SCD) and received Fast Track

Designation for CTX001 from

the FDA in January 2019 for


In CTX001 therapy, a

patient’s haematopoietic

stem cells are engineered

to produce high levels of

foetal haemoglobin (HbF)

in red blood cells. HbF is a

form of the oxygen-carrying

haemoglobin that is naturally

present at birth and is

then replaced by the adult

Erdafitinib (Balversa) has

been granted accelerated

approval by US FDA to treat

adult patients with locally

advanced or metastatic

bladder cancer that has a

type of susceptible genetic

alteration known as FGFR3 or


Patients should be

selected for therapy with

erdafitinib using an FDAapproved


diagnostic device.

The efficacy of erdafitinib

was studied in a clinical trial

that included 87 patients with

locally advanced or metastatic

bladder cancer, with FGFR3

or FGFR2 genetic alterations,

that had progressed following

treatment with chemotherapy.

The overall response rate

in these patients was 32.2%,

with 2.3% having a complete

response and almost 30%

having a partial response.

The response lasted for an

average of approximately fiveand-a-half


Responses to erdafitinib

were seen in patients who

Sakigake desig

for valemetostat

in Japan


aiichi Sankyo announced

that valemetostat, an

investigational and potential

first-in-class EZH1/2 dual

inhibitor, has received

Sakigake Designation for the

treatment of adult patients

with relapsed/refractory

peripheral T-cell lymphoma

(PTCL) by the Japan Ministry

of Health, Labour and Welfare


Valemetostat targets

epigenetic regulation by

inhibiting both the EZH1

(enhancer of zeste homolog

1) and EZH2 enzymes that act

through histone methylation

to regulate gene expression.

Reactivation of the silenced

genes results in decreased

proliferation of EZH2-

expressing cancer cells.

Preclinical research has

shown that valemetostat

suppressed trimethylation of

H3K27 in cells more strongly

than EZH2 selective inhibitors.

Valemetostat also displayed

antitumour activity in various

haematological malignancies

in preclinical models.

Sakigake Designation

was granted based on the

May 2019 / FUTURE MEDICINE / 33

Olaparib to treat advanced

breast cancer in EU

The European Commission has

approved olaparib (Lynparza) as

monotherapy for the treatment of adult

patients with germline

BRCA1/2-mutations (gBRCAm), and

who have human epidermal growth

factor receptor 2 (HER2)-negative

locally-advanced or metastatic breast


Patients receiving the therapy

should have previously been treated

with an anthracycline and a taxane in

the (neo)adjuvant or metastatic setting

unless they were unsuitable for these

treatments. Patients with hormone

receptor (HR)-positive breast cancer

should also have progressed on or

after prior endocrine therapy or be

considered unsuitable for endocrine


The approval was based on data

from the randomised, open-label, phase

III OlympiAD trial which tested olaparib

vs. physician’s choice of chemotherapy

(capecitabine, eribulin, or vinorelbine).

In the trial, olaparib provided patients

with a statistically-significant median

progression-free survival improvement

of 2.8 months.

This is the third indication for

olaparib in the EU, said AstraZeneca

and MSD.

preliminary results of an

ongoing phase 1 study

assessing the safety and

efficacy of valemetostat in

patients with non-Hodgkin

lymphomas (NHL) including

PTCLs, which were presented

at the 2017 annual meeting

of the American Society of

Hematology (ASH).

The Sakigake Designation

System promotes R&D in

Japan, driving early practical

application for innovative

pharmaceutical products,

medical devices, and

regenerative medicines.


+ lamivudine

combo for HIV1

The US FDA approved

dolutegravir and

lamivudine (Dovato) as a

complete regimen for the

treatment of HIV-1 infection

in adults with no antiretroviral

treatment history.

This is the first FDAapproved

two-drug, fixed-

dose, complete regimen for

HIV-infected adults who

have never received

treatment for HIV, ViiV

Healthcare said.

The efficacy and safety

of Dovato, one tablet taken

daily, were demonstrated in

two identical, randomized,

double-blind, controlled

clinical trials in 1,433 HIVinfected

adults with no prior

antiretroviral treatment


The trials showed that

a drug regimen containing

dolutegravir and lamivudine

had a similar effect of

reducing the amount of

HIV in the blood compared

to another drug regimen,

which included dolutegravir,

emtricitabine, and tenofovir.

Fast track for

oral tebipenem

to treat UTI

The US FDA has granted

Fast Track designation to

SPR994, an oral carbapenem

for complicated UTI and

acute pyelonephritis.

SPR994 is tebipenem

pivoxil hydrobromide —

an oral formulation of

tebipenem, an antibiotic in

the carbapenem class.

The preclinical models of

SPR994 have already shown

its efficacy against gram

negative bacteria including

E. coli, producing extendedspectrum


(ESBLs) and ESBLs producing

Klebsiella pneumoniae,

similar to IV ertapenem.

The drug has been

already given Qualified

Infectious Disease Product

(QIDP) designation.

Completion of phase

1, double-blind, placebocontrolled,

ascending dose,

a multi-cohort study has

enabled dose selection for

the company’s upcoming

phase 3 trial, ADAPT-PO.

This will be a randomized,

double-blind, double-dummy,

multicentre, prospective

study designed to assess

the efficacy, safety, and

pharmacokinetics of

tebipenem vs intravenous (IV)

ertapenem in patients with

complicated UTI or AP.

Dacomitinib to

treat patients

with NSCLC

in EU

Pfizer Inc. announced that

the EC has approved

34 / FUTURE MEDICINE / May 2019

under the Priority Review



to treat


Amgen and UCB

announced that the

US FDA has approved


(Evenity) for the treatment

of osteoporosis in

postmenopausal women at

high risk for fracture.


has a dual effect that both

increases bone formation and

to a lesser extent reduces

bone resorption. A full course

of the therapy is 12 monthly


The FDA based its

approval of romosozumabaqqg

on the results of two

phase 3 studies. In the

placebo-controlled FRAME

study, treatment with

dacomitinib (Vizimpro), a

tyrosine kinase inhibitor

(TKI), as monotherapy for

the first-line treatment

of adult patients with

locally advanced or

metastatic non-small cell

lung cancer (NSCLC) with

epidermal growth factor

receptor (EGFR)-activating


The EC approval of

dacomitinib was supported

by data from ARCHER 1050,

a randomized, multicentre,

multinational, open-label,

phase 3 study conducted in

patients with unresectable,

metastatic or recurrent

NSCLC, harbouring EGFR

exon 19 deletion or exon 21

L858R substitution


Dacomitinib is also

approved in the US for the

first-line treatment of patients

with metastatic NSCLC with

EGFR exon 19 deletion or

exon 21 L858R substitution

mutations as detected

by an FDA-approved test.

Additionally, it is approved

in Japan for EGFR gene

mutation-positive, inoperable

or recurrent NSCLC, and

in Canada for the first-line

treatment of adult patients

with unresectable locally

advanced or metastatic

NSCLC with confirmed

EGFR exon 19 deletion or

exon 21 L858R substitution

mutations. The applications

in the US and Japan were

reviewed and approved

Cladribine as oral treatment for

multiple sclerosis

Cladribine (Mavenclad) has been granted approval

to treat relapsing forms of multiple sclerosis (MS) in

adults by the USFDA.

Cladribine is not recommended for MS patients

with clinically isolated syndrome. Because of its safety

profile, the use of the drug is generally recommended

for patients who have had an inadequate response to, or

are unable to tolerate, an alternate drug indicated for the

treatment of MS.

The efficacy of cladribine was shown in a clinical

trial in 1,326 patients with relapsing forms of MS who

had at least one relapse in the previous 12 months. The

drug significantly decreased the number of relapses

experienced by these patients compared to placebo.

Cladribine also reduced the progression of disability

compared to placebo.


resulted in a significant

reduction of new vertebral

fracture at 12 months

compared to placebo.

This significant reduction

in fracture risk persisted

through the second year in

women who received the

drug during the first year and

transitioned to denosumab

compared to those who

transitioned from placebo to


In addition,


significantly increased bone

mineral density at the

lumbar spine, total hip and

femoral neck compared

to placebo at 12 months.

Following the transition

from romosozumab-aqqg

to denosumab at month 12,

BMD continued to increase

through month 24.

In the active-controlled

ARCH study, treatment

with romosozumab-aqqg

for 12 months followed by

12 months of alendronate

significantly reduced the

incidence of new vertebral

fracture at 24 months.

May 2019 / FUTURE MEDICINE / 35

straight talk





VIJAY CHANDRU, Co-Founder and

Director, Strand Life Sciences, and INAE

Distinguished Technologist at Indian

Institute of Science, is an academic

turned entrepreneur. He got his PhD

in mathematics of decision sciences at

MIT in 1982. He taught and conducted

research in computational mathematics of

optimization, geometry, logic and biology

at Purdue University (1982-1993) and

the Indian Institute of Science (1992-

2005). The vision that drove him to

entrepreneurship was to create successful,

world-class, technology innovation

companies out of India. In 1998, he joined

hands with kindred spirits to create the

Simputer (a handheld computer). He also

co-founded PicoPeta Simputers, which

commercialized the Simputer to create

the Amida Simputer. Strand Life Sciences

started out as an exciting life science

informatics company based in Bangalore,

India. Strand, which has captured around

30% of the global market for analytics

software in research biology for the

various “omics” - genomics, proteomics,

metabolomics, etc., is a global, personalized

medicine company that uses clinical

genomics for oncology and inherited

disorders. He also helped create non-profit

agencies that work for neglected disease

communities. In an exclusive interview

with Editor CH UNNIKRISHNAN, Chandru,

who is pursuing the vision of affordable

precision medicine, says that India needs

to do a lot more to have clarity on its

actual disease burden, especially rare and

undiagnosed diseases. Edited excerpts:

India is one of the large geographies where the burden

of rare and undiagnosed diseases, mainly linked to genetic

disorders, is high with a prevalence of around 70 million.

But the country still doesn’t have accurate data or a

registry to formulate appropriate policies or a budget to

take care of the patients. Why?

We still don’t have a clear understanding of the actual

disease burden in the country, especially in case of the rare

and undiagnosed diseases linked to genetic causes. I think

the challenge here is that there has been no systematic

surveying. As per information from government agencies,

at least all the diseases that have been given the disability

status will show up in census data by the 2020-21 survey,

which will start giving us some clue. With this, at least major

disabilities like hemophilia, thalassemia, sickle cell anaemia,

muscular dystrophy, multiple sclerosis and perhaps a few

more will be captured and those numbers will be known

with better accuracy. Secondly, there is also a hope that

because there are a lot of patient communities, awareness

activities, camps, etc. happening now, that will help slowly

build the data, as these platforms will be able to provide

useful information and numbers.

ICMR has announced that it will build a registry of

rare diseases in India. We will have to wait and see how

successful that effort will be. Though the apex medical

research body was claimingly successful in building India’s

cancer registry, the numbers still do not seem very

accurate. While the cancer registry shows about 1.3 million

new cases per year, there seems to be something wrong

with this number. For instance, China, which has almost the

same level of disease burden as India, had recently declared

its data of new cancer patients as 4.1 million per year. So,

apparently, the data claimed by the Indian

registry has probably underestimated the prevalence.

ICMR is using some kind of sampling technique and then

extrapolating it. But for some reason, this number seems

conservative, I feel.

On rare diseases, it’s true that some pharma companies

36 / FUTURE MEDICINE / May 2019

Vijay Chandru


have somewhat better-estimated data since

they have information that is collected

from doctors or directly from the market.

But when you ask these companies

about lysosomal storage disorders, they

estimate it as a few hundreds. Similarly,

many haematologists estimate thalassemia

cases at 1 to 1.5 lakh patients. So, where is

this number of 70 million patients of rare

diseases that are projected at every forum

coming from, I often wonder. China has

published that their population with rare

diseases as 20 million. I agree that India

has more consanguineous marriage within

the same community, among other factors,

that cause genetic disorders. But still, such

a huge difference! So, we don’t know what

the numbers are. But I feel there is plenty

Where is this

number of

70 million

patients of rare

diseases that

are projected

at every forum

coming from, I

often wonder.

of work to be done to have a clarity on the

actual disease burden. These numbers are

important to formulate our priorities,

where funds should be given and what

sort of facilities have to be created, among


There are government bodies like IGIB

and ICMR, private companies and charity

organisations working to address patient

needs. At what stage are these works at

present, any idea?

As far as rare diseases are concerned,

some areas have seen better progress.

For example, patient tracking and

diagnosis in haematological disorders are

comparatively better organised and there

is a lot of work currently going on. While

May 2019 / FUTURE MEDICINE / 37

that the allocation of the budget is not possible unless the

government knows the burden.

But I think it is just a matter of time; It will happen and

the good thing is that the country is looking at healthcare

much more seriously now and it is also an era when medical

records are largely being digitized. Even for rare diseases,

the country is looking much more carefully at the data and

digital records from various sources.

What about the therapy side?

The therapy side is always a challenge. There are many

therapies that are used for the maintenance of patients.

Those therapies, I think, patient communities and hospitals

are tracking and providing. But even then, we don’t have

a comprehensive list of medicines. Rather, none has put

together a good collection of information about medicines

that the patients would need for rare diseases. By this,

what I am referring to is the kind of a comprehensive

list that India prepared on essential medicines, that the

country’s physicians would require along with all other

related information about availability, pricing of generics and

patented products and so on, when the country was about

to sign the Dunkel Draft. Such a list needs to be prepared

for rare diseases as well, detailing the use, cost, availability

and accessibility. Such an effort will help in ensuring the

availability and accessibility of treatment for Indian patients

in case of rare diseases. Otherwise, a large section of the

population will still be left untreated as most of the targeted

treatments currently available in the market is beyond the

reach of the mass.

activities for muscular disorders is slowly

picking up, other segments like primary

immuno-deficiency and others are still

poorly covered and there is very little

help for patients at present. Overall, I think

we have a fundamental issue of really

starting to think about evidence-based

planning for the care of rare diseases,

moving away from the eminence-based


I remember, the health Secretary of

Karnataka once asked us (the industry),

while the state was proposing a draft on its

health policy, if we can provide data about

the actual burden and he made it a point

The genetic study of the Indian population, which is

essential to address rare diseases, is still minuscule. What

needs to be done to expand it?

There are some broad-based genetic studies that are

being planned as part of projects like Genome India and so

on. But there are also more focused cohort studies such as

the neurological disorder study that is done by NIMHANS

etc., going on in parallel. So, it has slowly started to build up,

but the volume of work is yet to pick up. However, the good

thing is that the country has the capacity now.

Large sequencers have been set up at least in five to six

locations in the country. So, the ability to run the sequences

to do the bioinformatics has been built and we are in a

position to do it. But if you ask me if we have done it, I would

say it is not very visible. Though a few companies, including

Strand Life Sciences and MedGenome, have probably

generated a fair amount of data, I don’t think academic

groups have done as much. However, since capacities have

been built, they seem to be getting adequately funded

shortly. Going forward, we will see better, and more data

being generated as things are moving in the right direction.

Rare diseases are definitely on the agenda and it is time to

think positive.

38 / FUTURE MEDICINE / May 2019


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case reports


A unique case where the least invasive option of minimally invasive

cardiac surgery is employed

Mrs Malliga, a 63-year old lady from Ambattur in

Chennai, had been suffering from chest pain for the

past six months. As her condition worsened and

the chest pains increased, she was brought to

Apollo Hospital Chennai, where she consulted with Dr.

Mohammed M Yusuf, a cardiothoracic surgeon specializing

in Minimally Invasive Cardiac Surgery and Dr Damodharan,

Senior Consultant Cardiologist. Mrs Malliga complained of

chest pain on minimal exertion. Her case history

showed that she was diabetic and had slightly higher

cholesterol levels than normal, two high-risk factors for

heart disease.

An angiography revealed blocks in three major arteries

that supply blood to the heart. Typically in such cases, an

open-heart bypass surgery or stents would be indicated.

Keeping the history of diabetes and cholesterol in mind, an

open-heart bypass surgery was deemed the best treatment

option. This procedure involves using a healthy blood vessel

from another part of the body to allow blood to bypass the

block in the vessel. For blocks in the left anterior descending

artery, a healthy artery from the chest wall itself is preferred.

However, for other less important arteries, surgeons may use

veins from the leg as well.

“A bypass surgery is more effective for blocks in the

major arteries, compared with stents. The majority of stents

are beneficial for up to 5-10 years, after which blocks may

reappear”, says Dr Yusuf. While the treatment outcome is

excellent and mortality rates are extremely low in bypass

surgeries, the procedure involves making a 6-8 inch long

incision in the chest and cutting through the breastbone to

access the heart, resulting in a considerably long recovery

period that can last up to 4 months.

Recent advances in open-heart surgery techniques

include minimally invasive approaches that require smaller

incisions and offer faster recovery periods. Instead of the

large 6-8 inch incision for the conventional bypass surgery, a

smaller cut in the chest is sufficient for a minimally invasive

procedure. This reduces morbidity and brings the recovery

time to 2 weeks. Dr Yusuf and his medical team have been

performing minimally invasive bypass surgeries for over a

year with excellent results.

More recently, robotic assistance to perform the

procedure has gained interest. Dr Yusuf and his team opted

to conduct this minimally invasive operation using robotic

assistance rather than the conventional

approach. Two of the three major blood

vessels of the patient were severely blocked

and required bypass surgery. The blocks

in other vessels could be treated with

angiography stent insertion. Dr Yusuf’s

team, therefore, decided on a 2-step

approach. Under the guidance of Dr Frank

Vanpraet, Director of Robotic and Minimally

Invasive Cardiac Surgery, OLV Hospital, Aalst,

Belgium, Dr Yusuf performed the minimally

invasive coronary artery bypass grafting

surgery using robotic assistance. In the







second step, two days after the first

surgery, Dr Damodharan performed

angiography and drug-eluting stent insertion

for the remaining blocks in Mrs Malliga’s

coronary arteries. This was done with the

assistance of a specialized intravascular


Robot-assisted minimally invasive

coronary artery bypass grafting has several

advantages, as it is the least invasive

option among minimally invasive cardiac

surgeries. This technique lowers the risk

of complications such as stroke, excessive

blood loss, and infection. Patients also

have reduced pain, smaller scars and

faster recovery periods and it is ideal

for multivessel blocks. “Even though it is

more expensive than conventional bypass

40 / FUTURE MEDICINE / May 2019

surgeries, it should be recommended for young patients

who would like to get back to work immediately and in

high-risk patients with other comorbidities”, says Dr Yusuf.

With our lifestyle changes, more and more young people

are suffering from heart conditions and such quick recovery

treatment approaches are likely to be more economical in

the long run.

Robotic Minimally Invasive Hybrid Revascularization is

already being performed in countries such as Japan, United

Kingdom and the United States. However, this was the first

instance of the minimally invasive approach with robotic

assistance in India.

The multiple step approach used for

Mrs Malliga showed excellent results as

she was discharged in 48 hours after the

procedure and has since returned to full

normal activity. She will, of course, be

regularly followed up to ensure that no new

complications arise.


May 2019 / FUTURE MEDICINE / 41

case reports


Extracorporeal membrane oxygenation must be initiated for ARDS

as soon as standard therapy starts failing

Nagesh, a middle-class executive

at a local shopping mall in Bengaluru, was


suffering from fever and severe shortness of

breath and was admitted to St. John’s Hospital,

Bengaluru. His clinical history indicated no comorbidities or

other illnesses; however, he had recently travelled to

another city.

As his condition was worsening, he was diagnosed with

severe community-acquired pneumonia and admitted to

the intensive care unit where he was started on anti-flu

medicines and placed on a mechanical

ventilator to help with breathing. However,

his oxygen parameters did not improve

even after artificial ventilation in the prone

position after sixteen hours. Doctors at

St. John’s recommended extracorporeal

membrane oxygenation (ECMO) support as

a last, life-saving resort. ECMO is a medical

device used to supply oxygen to circulating

blood through an oxygenator in an effort

42 / FUTURE MEDICINE / May 2019

to bypass the requirement of an injured or non-functional


Unfortunately, most hospitals do not have ECMO facilities

in India and St John’s hospital is no exception. The medical

team at St. John’s therefore reached out to Narayana Health

City, Bengaluru, for assistance. Ideally, Nagesh would be

transferred to Narayana Health City before ECMO treatment.

However, his condition was critical, and he was not able to

be transported. In a life-saving move, the 12-member ECMO

team led by Dr Harish M M, consultant and in-charge of the

multi-disciplinary intensive care unit, Narayana Health City,

came to St John’s with a portable ECMO unit, initiated venovenous

ECMO at St John’s, and then transferred Nagesh to

Narayana Health City while on ECMO support.

At Narayana Health City, Nagesh underwent a repeat

X-ray, while his previous treatment regime of Tamiflu and

antibiotics was continued along with the ECMO. Because of

his deteriorating condition in terms of clinical presentation

with bilateral infiltration and a low response to ventilation

support, he was considered to be a case of severe acute

respiratory distress syndrome (ARDS). A tracheal aspirate

was used for molecular testing using polymerase chain

reaction to identify the causative agent for the respiratory

illness. Molecular testing has the benefit of being rapid as

well as having high sensitivity, and within 24 hours, he was

confirmed with H1N1 infection.

ARDS is a severe form of lung injury and is defined based

on the development of acute dyspnea and hypoxemia within

7 days after the insult, along with radiographic changes

showing bilateral infiltrates. ARDS can be classified as mild

to severe, depending on the ratio of the partial pressure of

oxygen in the patient’s arterial blood (PaO2) to the fraction

of oxygen in the inspired air (FiO2). If this is ratio is less than

100, the patient is classified as suffering from severe ARDS.

Nagesh’s PaO2/FiO2 ratio was less than 100, classifying him

as having severe ARDS.

While there is no specific therapy for ARDS, treatment

should depend on the underlying condition, along with

appropriate supportive care and artificial ventilation. Nagesh

was continued on Tamiflu and ECMO and a broad-spectrum

antibiotic to prevent bacterial infections during ventilation


The decision to remove ECMO support is dependent on

the oxygen levels as well as the general condition of the

patient. Absence of high-grade fever and infections, normal

electrolytes, a normal heart rate and brain function are

all factors indicating whether the patient can be weaned

of the ECMO support. Though blood culture is a definitive

indicator of infection, its yield is very poor especially when

patients are already on antibiotics. Other indirect indicators

of infection, including WBC count, body temperature,

and infiltration in the lungs are monitored daily, whereas

biomarkers like procalcitonin, C reactive protein etc.

are monitored every 2-4 days. Once these biochemical

parameters return to normal, the patient

can be weaned off ECMO. Even after

discharge, sequelae of ARDS, such as

weight loss, fatigue, functional compromised

life, myopathy etc. can often linger for


Nagesh had to be supported on ECMO

for 12 days before his PaO2/FiO2 ratio

started to stabilise and his lung function

returned to normal. After discharge, he was

continued on multivitamins, and followed

up after 1 week. Luckily, he did not have to

witness prolonged effects of ARDS and he

returned to normalcy at the 1-week follow


According to Dr Harish, ECMO comes

with a high cost, running into a few lakhs.

However, the most important criteria for






starting ECMO therapy is that the pathology

should be reversible. It is not recommended

for severe stroke or advanced cancer

patients with ARDS, who may already be

bedridden. Side effects of ECMO include

bleeding, air embolism, low platelet counts

(platelets may be destroyed in the external

tubes), and hemolysis. Platelet or blood

transfusions may often be required to

address platelet/blood loss.

Despite the costs and side effects,

ECMO must be initiated early once standard

therapy (including prone ventilation) for

ARDS fails, as ARDS will not respond to

ECMO once the lung moves to a fibrotic

phase. While few hospitals have ECMO

facilities, Dr Harish advocates that patients

should be referred to a suitable health care

centre as early as possible and definitely

no later than 2 sessions of ineffective

ventilation in prone position.


May 2019 / FUTURE MEDICINE / 43

case reports





Should an ECG rule out a heart attack, consider performing an echo

to check for aortic dissection

Satish (name changed) suddenly

started having chest pains and was rushed to a


local hospital in Pallakad, Kerala. As an ex-army

man, he had never experienced such pain and his family

assumed he was having a heart attack. However, all initial

tests that were run were negative and an echo cardiography

was performed. The echo showed an aortic dissection and

Satish was transferred to Amrita Hospital, Kochi, which has a

dedicated Centre for Aortic Diseases and Marfan Syndrome.

Here he was immediately rushed to the operation theatre

without further ado by the medical team led by Dr Praveen

Varma, Head of Cardiovascular and Thoracic Surgery.

An aortic dissection is a tear in the inner lining of

the aorta, just above the aortic valve, and results due to

increased stress within the walls of the aorta. Type A aortic

dissection such as this one is a life-threatening medical

emergency requiring immediate surgery, without which

mortality can be almost 100%. Once the aorta dilates from

the normal range of 2.5-3 cm to 4.5-5 cm, it is likely to

dissect. Right before the team started operating on Satish,

his aortic wall ruptured outside However, the procedure was

already underway, and the medical team remained unfazed

as they proceeded with the aortic root

replacement surgery, which is a complex

surgery often taking 8-10 hours.

This procedure involves multiple steps.

The first step involves a surgical technique

called total circulatory arrest in which the

body is cooled to less than 18°C before

cutting off blood circulation to the whole

body. The cool temperatures allow the brain

to survive the circulatory arrest, however,

brain activity must be closely monitored

to ensure that the cool temperatures keep

the brain quiescent throughout the surgery.

This is critical while performing delicate

procedures on large blood vessels such as in

this case. The patient is typically connected

to a cardiopulmonary bypass, an external

heart-lung machine, which drains the blood

out of the body and cools it to less than 18

°C. Brain activity is monitored by monitoring

blood flow to the brain by Near Infrared

Spectroscopy. Once the brain function has

44 / FUTURE MEDICINE / May 2019

stopped, the actual aortic root replacement surgery can

commence. This was done following the Bentall procedure,

in which the aortic valve, the aortic root and the ascending

aorta are replaced with a composite graft, and the coronary

arteries are then re-implanted into the new graft. Once the

replacement surgery is completed, the blood is warmed

again, and the patient is then returned to normal blood flow

and brain activity.

Satish’s surgery went well, and he was kept in the ICU

for 2 days and discharged 8 days post-surgery. Now he is

on strong anti-hypertensive drugs, which will be his lifelong

companions. He is also given a blood thinner to ensure the

proper functioning of the new artificial mechanical valve.

While aortic dissection and rupture are relatively

uncommon, major risk factors are uncontrolled high blood

pressure, atherosclerosis, cocaine abuse, bicuspid aortic

valve, or genetic diseases such as Turner’s syndrome or

Marfan syndrome. Patients with Turner’s syndrome have

a missing or structurally altered X-chromosome resulting

in many abnormalities including aortic valve defects.

Marfan syndrome is caused due to an autosomal dominant

mutation in the FBN1 gene which encodes a protein called

fibrillin 1. This protein is an extracellular matrix glycoprotein

that provides structural support to connective tissue

throughout the body. Patients with Marfan syndrome have

typical visual clinical features of elongated limbs, fingers

and toes, and scoliosis. Marfan syndrome may also affect

other organs including eyes, bones, lungs, and heart. Marfan

syndrome patients are at a high risk of aortic dilation, aortic

aneurysm and mitral valve prolapse, and aortic dissection

which may well be the most serious of all

the complications associated with Marfan


In 2016, a special Centre for Aortic

Diseases and Marfan Syndrome was

started at Amrita Hospital, Kochi. This

is the only such center in India that is

dedicated to patients with Marfan syndrome

and other aortic diseases. It comprises

of a multidisciplinary team including

cardiologists, surgeons, ophthalmologists,

geneticists, obstetricians as well as

radiologists. These doctors together offer

comprehensive care including genetic

counselling and associated medical support

as required. The cardiovascular surgeons

are skilled to deal with the most serious

complications like aortic ruptures. Today










over 50 patients are registered with this

clinic and undergo regular screenings every

6 months. In case clinical observations

indicate that the aorta is dilating, elective

aortic root replacement may also be offered.

According to Dr Varma, even though

aortic diseases and acute aortic syndromes

are more catastrophic and complicated,

they are not given much importance in India

and are often overlooked and misdiagnosed

as heart attacks. Should an ECG rule out a

heart attack, consider performing an echo

to check for aortic dissection. Patients with

aortic dissection should immediately be

transferred to the nearest hospital with

surgical expertise.


May 2019 / FUTURE MEDICINE / 45

case reports


Alpha thalassemia is under-reported in India because of the need for genetic

testing to confirm the blood disorder

Two-and-a-half-year-old Pratik (name changed), a

normal, seemingly healthy child, was visiting his

paediatrician for a regular check-up. The paediatrician

thought that Pratik was pale looking and requested a

complete blood count investigation to be done. The results

indicated low haemoglobin levels, high RBC counts, and

high red cell distribution width. In addition, cells were small,

indicative of microcytic hypochromic anaemia. Pratik was

therefore suspected to have iron deficiency anaemia and

serum iron studies were done. These also showed evidence of

iron deficiency and Pratik was started on iron supplements. At

the one month follow up, his repeat complete blood counts

showed improved haemoglobin levels. However, the RBC

count was still high and the microcytosis was severe. He was

referred to Dr Swati Kanakia, Paediatric Hemato-Oncologist,

Lilavati Hospital and Research Center, Mumbai. Based on

complete blood count results, Dr Kanakia suspected Pratik

may have thalassemia minor.

Thalassemia is a genetic disorder in which

the body produces low levels of functional

haemoglobin. Haemoglobin is made up of

alpha and beta chains. Depending on which

protein levels are affected, a patient can have

either alpha thalassemia or beta thalassemia.






Based on the severity of clinical features,

alpha thalassemia can be classified as a silent

carrier, thalassemia trait, haemoglobin H

disease, or hydrops fetalis. Beta thalassemia

can be classified as thalassemia minor,

thalassemia intermediate or thalassemia

major. Alpha thalassemia is caused due to

mutations in the HBA1 or HBA2 gene on


16, while beta thalassemia is caused due

to mutations in the HBB gene on

chromosome 11.

46 / FUTURE MEDICINE / May 2019

Haemoglobin electrophoresis is a low cost, easily available

test which takes only 24 hours and can rapidly confirm the

diagnosis of beta thalassemia. It is therefore typically done

first. However, alpha thalassemia cannot be detected by this

method and requires genetic testing. Results on Pratik’s blood

sample ruled out beta thalassemia. However, because of the

persistent high RBC count and severe microcytosis, Dr Kanakia

suggested genetic testing to look for mutations in the alpha

haemoglobin chain. Genetic test results revealed a mutation

in the HBA1 gene, confirming that Pratik was a silent carrier

for alpha thalassemia. Similar genetic tests done on Pratik’s

mother showed that she was also a silent carrier. However, her

complete blood count results were absolutely normal, and she

showed no signs of haemoglobin deficiency

or microcytic anaemia. The reason for Pratik’s

iron deficiency turned out to be because of

his diet as he was predominantly on milk. Had

the doctors not pursued the reason for his

microcytic anaemia, Pratik and his mother’s

alpha thalassemia silent carrier status might

have gone undetected.

With genetic testing conveniently

available, screening for thalassemia should be

considered in patients who seem to have iron

deficiency anaemia with microcytic anaemia

and high RBC counts. Correct diagnosis can

prevent incorrect supplementation with

iron and avoid excessive investigation in an

attempt to treat ‘suspected’ refractory iron

deficiency. Further, patients like Pratik, who

are silent carriers, can be counselled so as to

prevent thalassemia cases later.

In India, beta thalassemia is much more

prevalent than alpha thalassemia and is a

major public health concern. Because of the

need for genetic testing to confirm alpha

thalassemia, it is likely that alpha thalassemia

is under-reported as well. “The main goal is to

prevent the birth of children with thalassemia

major”, says Dr Kanakia. If Pratik’s father was

also a carrier for alpha thalassemia, Pratik’s

siblings could have a much more severe

version of thalassemia that may require

regular blood transfusions and even bone

marrow transplantation. Treatment can be

very expensive and heavily dependent on

the availability of suitable donors for bone

marrow transplantation. It is therefore

important to screen for carriers of alpha and

beta thalassemia. This will help in identifying

future pregnancies that need to undergo

prenatal testing to rule out severe forms of


In an effort to aid patient education and

prevent thalassemia major cases, Dr Kanakia

and Kanakia Health Care have created a

programme called Stop Thal, Screening for

Thalassemia and Opting for Prevention. The

programme helps one estimate the chances

of having a completely normal, thalassemia

minor, or thalassemia major child and would

increase awareness amongst thalassemia

patients and prove to be useful in reducing

thalassemia major incidents.


May 2019 / FUTURE MEDICINE / 47


the cellview

Future of thalassemia care:

An Indian perspective

Screening, along with proper genetic counseling, can help

eradicate the disease



The author is medical

scientist and former

director of SGRF,


In the past few decades, there have

been profound developments in the

management of thalassemia around

the world, as well as in India. Regular

transfusion and iron chelation have

drastically improved the quality of life for

patients and transformed thalassemia from

a fatal disease to a clinically manageable

one. Regular transfusions to maintain pretransfusion

haemoglobin levels to around

9-10g/dl has reduced complications such

as anaemia and compensatory bone

marrow expansion. Repetitive transfusions

lead to iron overload as each transfusion

has 200mg of iron, leading to significant

morbidity and mortality due to damage to

the heart, liver and other organs. Patients in

India develop iron overload complications

like hypogonadism, hypothyroidism,

hypoparathyroidism, diabetes mellitus and

cardiac disorders in the second decade of

life. Iron overload related hepatic diseases

like cirrhosis and fibrosis are very poorly

addressed in India. Some of the major

obstacles leading to high mortality are poor

availability of medical care, lack of safe

and adequate red blood cell transfusions

with high cost, and poor compliance with

chelation therapy. Splenectomy, which is

rare in western countries, is needed for

many patients in India due to insufficient

transfusions. Understanding these

requirements, the major diagnostic and

therapeutic approaches have changed.

Use of MRI scanning to assess iron

overload helps in understanding the

patient condition better to tailor treatments

with reduced co-morbidities. For cardiac

iron overload, non-invasive MRO based

relaxation parameters T2 and T2* are

used frequently. Low T2* indicates high

myocardial iron and is often associated

with poor ventricular function, arrhythmias

and a need for clinical intervention. With

respect to therapies, there are increased

instances of haematopoietic stem cell

transplantation (HSCT) since 1982, as this

gives a better chance of a cure. Even though

the majority of HSCT have been done from

HLA identical related donor, an unrelated

but properly selected match can give good

results too. Recently, more data is being

generated about using cord-blood-based

transplantation. In India, HSCT was not

considered as a life-saving procedure but an

elective option. However, with better quality

of molecular tissue tying, conditioning

regimens and support therapies, it is now

accepted as the better option. As patients

do not need life-long transfusions, it

becomes cost-effective and sustainable. It

is estimated that almost 12,000 children

are born with thalassemia to parents who

are asymptomatic carriers. The carrier

population in India, at about 3.3%, is

significant enough to give importance to

various aspects like prevention too. There

is a need to translate clinical and scientific

data to the population at large to bring

awareness, which in turn can enable

preventive screening. Screening results,

along with proper genetic counseling,

can help eradicate the disease. In small

countries like Cyprus, a near complete

elimination was possible due to mandatory

antenatal testing. We, in our country, have

to evolve with possible mechanisms to

enable people to overcome this disease.

48 / FUTURE MEDICINE / May 2019


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medical practice



Doctors are the most vulnerable

when it comes to workplace violence


research article

published in the

Indian Journal of

Psychiatry claims that

while violence against

doctors is prevalent world

over, Indian doctors face

more violence as compared to those

in western countries. Almost every day,

we hear of patients getting violent

against doctors for one reason or the


This has been attributed to various

factors like poor healthcare budget

allocation by the government, scarcity

of healthcare professionals and

even a lack of training on empathy

and communication in the medical


“It is the junior doctors that bear

the brunt of physical violence by

patients as per research,”

says Dr Jateen Ukrani,

consultant psychiatrist at PsyCare

Neuropsychiatry Centre, Delhi and

one of the authors of the research

paper: Violence against doctors: A viral


He adds that “in emergency rooms,

100% of doctors face some kind of

verbal violence”.

Often, government hospitals are

poorly equipped to deal with the

amount of patient load than what

they actually receive, which makes the

overall experience for the patient and

50 / FUTURE MEDICINE / May 2019

the doctors stressful. This becomes a

fertile soil for breeding violence.

Another factor that contributes

to this growing violence is the lack of

training on effective communication in

the medical curriculum. According to

Dr Indla Ramasubba Reddy, a senior

psychiatrist from VIMHANS Vijayawada,

“Communication and empathy are

not part of the medical curriculum.

These are important for being a good

medical professional. Psychiatrists can

help improve communication skills for

doctors and also help in identifying

early indicators of violence”.

Communication crucial

Experts also point out that with the

advancement of medical science, it has

become more investigation-oriented

which means there is less opportunity

to talk and interact with the patient.

Thus communication suffers, and

patients often don’t understand the

risks. This, combined with all other

factors, has led to a higher rate of

violence against doctors in India. This

leads to many doctors becoming

depressed or quitting the profession

prematurely or not taking risky cases.

“Women doctors are also not

spared from violence and are often

soft targets”, says Dr Varsha Ukrani,

senior psychiatrist from Pandit Madan

Mohan Malviya Hospital, Delhi. It is

pointed out that those working in Obs

& Gyn department are more prone to

violence than any other department.

Dr Vishal Indla, chief psychiatrist

at VIMHANS, Vijayawada says doctors

are the most vulnerable among

all professionals when it comes to

workplace violence due to various

factors ranging from poor budget

allocation for health and weak laws.

The study suggests that though





acts are in place in 19 states for

protecting doctors against violence,

these are not applied strictly,

and till date, no convictions have been

made. The government should work

on improving the infrastructure and

also on the proper implementation

of these acts, which will reduce the

burden of violence against doctors to

a great extent. Further, doctors are

advised to undergo workshops on the

enhancement of communication

skills and stress management to

deal with such situations. It is also

advised that institutions have a zero

tolerance policy towards violence

against their doctors, and that it

must be reported to the authorities

immediately. Such a thing is being

done abroad and needs to be

implemented in our country so that

healthcare delivery is done in a safe

and stress-free environment.

May 2019 / FUTURE MEDICINE / 51

esearch snippets

Removal of damaged mitochondria

may stop inflammatory diseases

Elsa Sanchez-Lopez et al have

discovered that eliminating damaged

mitochondria before they trigger

excessive inflammation may help

alleviate chronic inflammatory diseases.

NLRP3 inflammasome- a multiprotein

oligomer is responsible for the activation

of inflammatory responses in the body.

However, during mitochondrial damage

due to stress or bacterial toxins NLRP3

can remain ‘switched on’ leading to

excess inflammation. Researchers

have found that NLRP3 is deactivated

when damaged mitochondria are

eliminated during cellular cycling

called mitophagy. Scientists showed

that mitophagy can be induced by

inhibiting the uptake of the nutrient

choline by mitochondria. Choline is

taken up through specific transporters

and metabolized by enzyme choline

kinase (ChoK). Decreasing the uptake of

choline altered the mitochondrial lipid

profile, decreasing the ATP synthesis in

mitochondria. This activates the energy

sensor AMP-activated protein kinase

(AMPK) which stimulates mitophagy.

Choline uptake by cells was prevented

by inhibiting choline transporter CTL1 or

choline phosphorylation by using ChoK

inhibitors. This attenuated the NLRP3

inflammasome activation and IL-1β and

IL-18 cytokine production in stimulated

macrophages. Researchers also showed

that on treating a mouse model of

Muckle-Wells syndrome with ChoK

inhibitors reversed the inflammation.

The in vivo study

in mice showed that treatment with

ChoK inhibitors prevented acute

inflammation caused by uric acid

accumulation (seen in gout)

and a bacterial toxin. ChoK

inhibitor treatment also

reversed chronic


associated with a

genetic disease

called Muckle-

Well Syndrome

in mice which

is caused by

mutations in

NLRP3 genes.

Source: Cell Metabolism

April 11, 2019 DOI: https://doi.




Faecal microbiota transfer could

improve autism symptoms

Dae-Wook Kang et al have

demonstrated longterm

beneficial effects of

microbiota transfer therapy

(MTT) in children with autism

spectrum disorders (ASD). The

researchers had previously

conducted an open-label trial

of microbiota transfer

therapy in a cohort of

18 children in 2017.

The study involved 10

weeks of treatment,

including pre-treatment

with vancomycin, a

bowel cleanses, a

stomach acid suppressant, and fecal

microbiota transfer daily for seven to

eight weeks. Two years since the study,

a follow up conducted by researchers

revealed significant improvements in

gastrointestinal and autism-related

symptoms in accordance with an

increase in gut microbiota. Scientists

reported a 45% decrease in ASD

symptoms compared to baseline. At the

start of the study, 83% of participants

were rated to have severe autism. At the

end of the study, only 17% were severe,

39% were found to have moderate,

and 44% were below the cut-off for

moderate ASD. The findings showed

52 / FUTURE MEDICINE / May 2019

Oxytocin could help treat alcohol dependence

Brendan J. Tunstall et al demonstrated

that administration of neuropeptide

oxytocin may help normalize the alcohol

use disorder and thereby help reduce

alcohol addiction. The research was

performed using alcohol-dependent

rat models. The study demonstrated

that oxytocin administered systemically,

intranasally or into the brain blocked

excess drinking in alcohol-dependent

rats. Researchers found that the effect

was specific to enhanced alcohol

drinking problem in alcohol-dependent

models as the procedure did not affect

other normal behaviours or alcohol

drinking in the alcohol-independent

cohort. The researchers also found that

the oxytocin blocked neurotransmitter

gamma-aminobutyric acid (GABA)

signalling in the central nucleus of the

amygdala (CeA). CeA is a key brain

region in the network affected by

alcohol dependence. The study provides

evidence suggesting that oxytocin likely

blocks enhanced drinking by altering CeA

GABA transmission. The findings provide

evidence showing that aberrations in the

oxytocin signalling may underlie alcohol

use disorder which on targeting might

prove a promising therapy in people who

misuse alcohol.

Source: PLOS Biology April 16, 2019 https://doi.


persistence of change in gut microbiota

involving an increase in overall diversity

and abundance of beneficial microbes

including Bifidobacteria and Prevotella.

The results encourage intensive MTT

intervention as a promising therapy for

treating children with ASD who have GI

problems. The researchers recommend

in conducting future research involving

larger cohort trials.

Source: Scientific Reports April 9, 2019 volume 9,

Article number: 5821 (2019) https://www.nature.


Adiponectin plays key

in male bias of liver


Elisa Manieri et al discovered that a

decrease in a hormone secreted by

fat cells is responsible for an increased

risk of liver cancer in males. The

levels of hormone adiponectin

decrease in males during

puberty which make them

prone to a higher incidence

of hepatocellular carcinoma

(HCC) than women. HCC

risk is also higher among

obese individuals during

which the body secretes

low adiponectin levels.

Researchers found that

adiponectin protects against

liver cancer development

through the activation of AMPactivated

protein kinase (AMPK)

and p38α. The study showed that

testosterone in males activates JNK

protein (c-Jun N-terminal kinases) in

human and mice adipocytes. JNK protein

mediates inhibition of adiponectin

which results in their lower secretion.

The research also showed that genetic

deletion of JNK1 in mouse adipose

tissue resulted in higher adiponectin

levels and protection against HCC.

Quantification of circulating adiponectin

in mice models detected more than

twice the level in females than in males.

This correlated with the vigorous growth

of subcutaneously implanted mouse

HCC-derived tumour cells in males than

in females. Gender disparity in HCC was

confirmed by subcutaneously injecting

colon adenocarcinoma-derived tumour

cells or melanoma-derived tumour in

male and female mice models which

showed no difference in growth patterns.

The study unravels the relation between

sex hormones and adipocytes signalling

clarifying the disparity in liver cancer


Source: Journal of Experimental Medicine April

3, 2019 DOI: 10.1084/jem.20181288 http://


Alcohol-induced brain

damage continues

after cessation

Silvia De Santis et al show evidence

in the progression of damage within

the white matter of the brain during

the initial period of alcohol cessation.

The researchers used Diffusion

Tensor Imaging (DTI), a magnetic

resonance imaging-based

technique capable of detecting

the anisotropy of the brain’s

white matter tracts. The study

revealed that the damage

in the brain could continue

up to two to six weeks of

abstinence from alcohol. The

study involved 91 volunteers

of average 46 years of age

who had alcohol use disorder

(AUD) and were interned for

rehabilitation. A control group

involving 36 men without alcohol

problems with an average age

May 2019 / FUTURE MEDICINE / 53

of 41 years was also involved in the

study. The findings showed comparable

alterations in the white matter with

intense preferential involvement of

corpus callosum and fimbria which are

connected with memory and decision

making. The results were compared

in parallel with rat models showing

preference to alcohol consumption. 27

male rats showing AUD were compared

against 9 male control rats. The research

reveals that the damage progression

can still continue in the brain during

initial abstinence from severe alcohol


Source: JAMA Psychiatry April 3, 2019

doi:10.1001/jamapsychiatry.2019.0318 https://


can improve working

memory in elderly

Robert M. G. Reinhart et al

demonstrated that electrostimulation

can improve the working memory of

older adults by temporarily reversing

the age-related cognitive decline. The

study involved 42 people aged 20–29

years and 42 people aged 60–76 years

and was assessed in a working memory

task. The study showed that the core

feature of cognitive decline was caused

due to a disconnection between the two

brain networks of the frontotemporal

cortex. The researchers subjected the

older participants to 25 minutes of noninvasive

electrical stimulation across the

brain using electrodes with frequency

personalized to their individual brain

circuits. After the stimulation the cohort

showed a preferential increase in neural

synchronization patterns between the

frontotemporal regions of the brain. All

participants were subjected to test their

working memory. The results before

and after stimulation were compared

between the two cohorts. The findings

revealed that the older participants

showed a rapid improvement in working

memory that lasted for 50 minutes post

stimulation. The findings unveil a new

approach towards non-pharmacological

intervention in improving cognitive

decline by targeting aspects of agerelated

cognitive impairment.

Source: Nature Neuroscience April 8,2019 https://

—Compiled by Divya Choyikutty

Scientists `print’ 3D heart using patient’s own cells

Nadav Noor et al have successfully

printed the first 3D vascularised

engineered heart using a patient’s

own cells and biological materials.

The researchers utilized biopsy of

fatty tissue from the patient

for the study. The cells were

then reprogrammed to

become pluripotent stem

cells that differentiated

into cardiomyocytes and

endothelial cells. The

extracellular matrix (ECM)

which is a three-dimensional

network of extracellular

macromolecules such as collagen

and glycoproteins were processed into

personalized hydrogel that served as

the printing ink. The two cell types were

separately combined with the hydrogels

to form the bio ink for parenchymal

cardiac tissue and blood vessels. Blood

vessel architecture was developed by

mathematical modelling of oxygen

transfer. The researchers demonstrated

the ability to print functional, patient

specific, immune-compatible cardiac

patches with blood vessels forming the

entire heart. The study thus revealed

the first successful approach to 3D-print

personalized, thick, vascularised and

perfusable cardiac tissues which may

be developed for drug screening and

patient specific requirements in the


Source: Advanced Science 15 April 2019 https://

54 / FUTURE MEDICINE / May 2019


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hospital news

Everstone to buy controlling

stake in Sahyadri Hospitals

Everstone, an investment group, has

agreed to buy a 51% stake in Sahyadri

Hospitals Ltd (SHL).

Pune-based Sahyadri Hospitals is the

largest hospital chain in Maharashtra,

founded in 1994. Currently, it operates

five tertiary care and three secondary

care hospitals with 750 beds across

Pune, Nashik and Karad. Sahyadri has

more than 1,000 clinicians and 2,300

supporting staff, reports said.

The transaction is expected to

help Sahyadri further strengthen its

position as the leading healthcare

chain in Maharashtra and increase its

bed-count significantly in the next five


For Everstone, the deal will increase

its exposure to India’s healthcare sector

where it is already present in numerous

segments such as pharmaceuticals and


LVPEI completes

100 transplants

in rural India

V Prasad Eye Institute (LVPEI)

L performed its 100th corneal

transplant in a rural eye care centre at

Mudhole secondary eye centre.

Started in March 2016 with a

corneal transplant at the Institute’s

Dhulipalla secondary eye centre in

Guntur District, experts from LVPEI

have collectively performed a hundred

corneal transplants in a span of just

three years across the secondary

centre networks in Mudhole (Nirmal

District), Dhulipalla (Guntur District),

Venkatachalam (Nellore District) and

Paloncha (Bhadradri Kothagudem


“This achievement is an example

of a road never travelled,” stated Dr

Gullapalli N Rao, founder and chair, L V

Prasad Eye Institute in a statement.

India is home to half of the world’s

blind population. Out of the 15 million

blind people in the country, 6.8 million

are victims of corneal blindness. This

number is expected to rise to 10.6

million by 2020.

Healthcare sector outlook stable: ICRA

India’s healthcare sector outlook remains

stable despite regulatory headwinds, says

ICRA, an Indian credit rating agency.

The hospital sector’s performance has

been falling in the last two years due to

several regulatory restrictions, including

demonetisation, the cap on prices of

stents and knee implants by the National

Pharmaceutical Pricing Authority (NPPA),

stiff regulatory action by certain states

and the implementation of the Goods and

Services Tax (GST).

In the latest order, issued on March 8,

2019, the NPPA put a cap of 30 per cent

on the trade margin earned on 390 drugs

that are primarily used for treatment of

cancer. The price cap led to a reduction of

up to 87 per cent in the prices of the anticancer

drugs. The current order by NPPA

adds on to the list of products already

placed under price restrictions. Most of

the cancer-related drugs are high-value

medicines and are sold directly through

the hospital chains, oncology being one

of the highest-value-added specialty for

hospitals due to the increasing incidence

of cancer-related ailments. Nonetheless,

several oncology drugs are still out of the

purview of the price cap.

“The regulatory environment continues

to be the overarching challenge for the

hospital sector and the recent NPPA order

reinforces this view. The wide-ranging

regulatory restrictions from multiple

authorities have suppressed the margins

of the players,’’ said Shubham Jain, group

head and vice president – corporate sector

ratings, ICRA, in a statement.

However, hospitals’ decision on

repricing of service/product component of

packages and usage of different drugs is

expected to correct the lopsided pharma

component margins and partly negate

the impact of the current NPPA order, he


56 / FUTURE MEDICINE / May 2019

from the industry





With 15 million blinds, India is home for 50% of

the world’s total blind population, according to

a 2016 study by the World Health Organisation.

While the status hasn’t changed much in the last two years,

another most worrying fact is that the country is also one

of the geographies in the world where the number of

ophthalmologists in proportion to its total population is the

lowest. And thus, it wasn’t a surprise that why the country was

also infamous for the highest number of medical negligence

in the area of eye care until recently. While the cases of

negligence have significantly come down in the last few years,

the credit to a great extent should go to the technology players

who changed the scenario by bringing the much-needed

sophistication into this field of care. Sandeep Bothra, Country

Business Head- Surgical, Alcon Laboratories India, says that

most of the recent technologies, those were introduced in

the area of eye care in India, have visibly improved the way

the diagnosis and procedures are done in the eye care setups

and the emerging technologies will make the visualisation and

diagnosis more easier and accurate, in an interview with editor

CH Unnikrishnan. Edited excerpts:

Eye care scenario in India has been quite challenging

because of several factors including a shortage of

ophthalmologists, lack of better training and infrastructure

and accessibility issues with best technologies. Alcon has

been in India for some time now and could you tell us what

has been your experience so far and do you think the

market has improved in terms of quality of care?

Alcon as a global leader in eye care, we always try to

discover new ways to enhance sight and improve patient lives.

As we have been doing this successfully in this market through

innovative products, partnerships with eye care professionals

and programs that create greater access to quality eye care.

We identify and develop technologies that deliver better visual

outcomes and address unmet patient needs, continuously

improving the options that exist today. Since our research

team observes surgeries and visits clinics to gain real-world

insights, we also regularly meet with

eye care professionals to get their

feedback on our products and their

future needs. So, I can confidently say

that the technology and training have

significantly improved the situation in

the Indian eye care. Also, the customers,

as well as patients, have become quite

demanding as they are already aware

of the latest products and procedures.

It is also evident from the change that

the cases of medical negligence have

come down drastically in recent time.

And I am proud to say that our products

touch the lives of millions of people

each year living with conditions like

cataracts, glaucoma, retinal diseases,

and refractive errors. Since we are the

only company that offers the complete

line of ophthalmic surgical devices, as

well as a differentiated contact lens and

lens care portfolio, this also gives us a

premium and most trusted position in

the market.

Alcon, through its social

responsibility and advocacy efforts,

also help to create sustainable access

to eye care for patients around the

world, thereby reducing the incidence

of preventable blindness and visual

impairment. By investing in professional

education, the group help to advance

the eye care industry and ultimately

create better outcomes for patients and


How do you see the pricing scenario

here as the government is slowly

58 / FUTURE MEDICINE / May 2019

vast country with varied needs and priorities depending

on the profiles of different regions, optimising the

market opportunities will depend on the adaptability

of the players. Still, I feel the country offers ample

opportunities for both national and international


As you know, India is also a very competitive as

well as value conscious market with so many players,

including foreign and local brands in the ophthalmic

segment. So, what made you the largest and how do

you maintain the leadership?

The key factor that made us the market leader is

the unparalleled reach that we have in this market. We

are present in every corner of the market, spanning

from one end to the other in the length and breadth

of the country. In addition, we have the entire portfolio

of products catering to every disease and age groups.

The other important factor is the quality and innovation

that we maintain in every class of product knowing our

partners’ needs and helping them consistently with the

latest technologies, enhancing their choice of practice.

That’s why the surgeons love to work with us.

bringing cost regulation on most

medical devices, implants and

health equipment?

A couple of thoughts on this.

No doubt, the intention of the

government is noble as it wants to

expand the access of healthcare

to every stratum of society. But I

would say, the opportunity in India

for every segment is big enough

for everybody. In general, I think

the changes in market dynamics

will ultimately depend on how

these are rolled out and how agile

are the companies to adapt to the

changing requirements. India as a

The key factor

that made us the

market leader is

the unparalleled

reach that we have

in this market. We

are present in every

corner of the market,

spanning from one

end to the other in the

length and breadth of

the country.

What are the key challenges in this market?

In the current context, one of the challenges is how

do you ensure that our products and services are

available in the same quality across the country. For

example, if we want to sell or service our products in

Imphal or Mandya, Srinagar or Lakshadweep, I want

to ensure the same quality of service that I provide in

Mumbai or Delhi. But, managing the logistics of that is

a big challenge in such a vast country. Just to explain

the technical aspect of it, I would take the example

of a cataract surgery, where there are two important

equipment required—the main equipment and the

library of implants. In this case, we have to reach the

entire library even if the surgeon uses just one particular

implant, which is decided at the surgery table. So, we

need to make the stock available so that the doctor can

do the surgery without compromising the quality. And

this is about every geography and climatic conditions.

Similarly, the doctors, though fundamentally they are

the same everywhere, in India often need to balance

the quality of work as well as the value proposition

as the majority of the patients here still pay out of

pocket. While the lack of patient awareness is a

problem, the work pressure that is often faced by the

overstretched surgeons in this branch of medicine is

another big challenge. In India, there are only 12 to 13

ophthalmologists for a million patients, which is much

below the global average. So, we aim to overcome

these challenges, both at the patient side as well as the

clinical side using more innovative technologies.

May 2019 / FUTURE MEDICINE / 59



Speedy approval vs


Unless Indian regulators develop in-house expertise, the

fast-track approval for investigational drugs could put

clinical trial participants at high risk


Writer is a consultant

on clinical research &

development from


Recently released new Indian drug

rules have been hailed as allowing

fast and time-bound approval within

30 calendar days for clinical trials of “Indian

new drugs”. This step can improve “ease of

business”, support “Make in India”, and will

encourage innovation in drug discovery. But

this is a major shift from the uncertain and

long regulatory approval process of the last

few years. Hence, the concern is how Indian

health authorities (HA) plan to implement

this. Will the expedited approval be at the

cost of ensuring protection for Indian clinical

trial participants?

The rules define an “Indian new drug”

as 1) a drug discovered in India, or (2)

its research and development (R&D),

manufacture, and marketing are done

in India. Current Indian cost of R&D,

extrapolated from Dr Mashelkar

committee’s 1999 estimate of Rs 150 crores,

would be Rs 500 crores. In contrast, the

US R&D cost estimate of $ 2.6 billion (Tufts

Center 2016) or Rs 19,500 crores is 39

times higher! Considering the tremendous

cost advantage, quicker approval and

faster completion of clinical trials, western

companies would find it commercially

attractive to develop a new drug in India

in collaboration with an Indian partner.

Such collaborations will boost Indian drug

research capabilities.

New drug development begins with

phase I trials. In this first-in-human (FIH) trial,

serious adverse events (SAE) can jeopardize

the safety of clinical trial participants. In

2006, TGN1412 resulted in life-threatening

multiorgan failure in all 6 healthy volunteers

who received the first dose of the drug. In

2016, BIA 10-2474 caused the death of a

healthy volunteer and SAEs in 4 participants

who received the drug. Hence, thorough riskbenefit

assessment of an investigational new

drug (IND) is essential before approving FIH

clinical trial.

US Food and Drug Administration (FDA)

allows a pharma company to initiate

phase I trial 30-days after receiving IND

application. But FDA can place the trial

on-hold if it finds that human subjects

would be exposed to unreasonable and

significant risk. FDA has an in-house team

of pharmacologists, toxicologists and clinical

pharmacologists to review IND application.

Indian HA depends on IND committee for

review and approval of the phase I trial.

This committee, consisting of ICMR experts

and other consultants, meets at intervals

of 2-3 months to review pre-clinical data -

animal pharmacology, pharmacokinetic,

and toxicity - and decide whether the phase

I trial should be approved. The committee

may ask for additional pre-clinical data or

modifications in the clinical trial protocol.

For Indian R&D based pharma companies,

which have complained about long and

unpredictable IND review process, the new

30-day clinical trial approval is a dream

come true. However, unless Indian HA

develop in-house expertise or establish a

fast track IND committee process before the

30-day approval rule and have well-defined

post-approval oversight process and clinical

hold rules, Indian clinical trial participants

will be at high risk from investigational new


60 / FUTURE MEDICINE / May 2019


NextGen Molecular Medicine

NGM2 is a platform for clinical and molecular worlds to meet and

create better healthcare systems in India

A joint initiative of Institute for Applied Research

and Innovation and Future Medicine to

enable better clinical practices



• NextGen technologies

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NGM2 is a platform for clinical an


Breakthrough status to

preeclampsia device

Targeted Apheresis

Column for Preeclampsia

(TAC-PE) has been

granted a Breakthrough

Device Designation by the

USFDA, Advanced Prenatal

Therapeutics announced.

The device specifically

removes disease-causing

factors such as sFlt-1 from the

mother’s blood. It is intended

to treat preeclampsia, a

leading cause of prematurity

and maternal/foetal death,

and holds the potential to

substantially reduce

mortality, incidence or

severity of preterm birth, and

the use of neonatal intensive


The company is now

preparing for initial clinical

studies using the device.

The FDA grants

Breakthrough Device

Designation to devices

that provide more effective

treatment of life-threatening

or irreversibly debilitating

diseases. Devices must also

represent a breakthrough

technology, treat a disease

where no approved

alternatives exist, offer

significant advantages

over existing approved

alternatives, or otherwise

be in the best interest of


501k clearance for pain drug delivery device

Avanos Medical has

received US FDA 501(k)

clearance for its ON-Q with

bolus pump.

The new ON-Q with

bolus design incorporates

improvements that make it

simpler for providers and

patients to use while reducing

postoperative opioid use to

achieve pain management.

The new ON-Q bolus

provides customised control

for patients recovering

from post-surgical pain by

delivering continuous, nonopioid

medication to the

surgical site or peripheral

nerves for up to five days.

The bolus pump is

ergonomically designed to fit

comfortably in the patient’s

hand with an easy to remove

the priming tab and large

level indicator markings. The

device can also be used for

incisional applications.

Studies have shown that

using bolus rates as low

as 3 ml in addition to the

basal rate can reduce the

total amount of anaesthetic

needed for pain relief. ON-Q

is indicated to significantly

reduce opioid use for surgical

patients and provide better

pain relief than opioids alone,

helping patients to get back

to normal faster after surgery.

62 / FUTURE MEDICINE / May 2019

located on the top face and

both sides of the monitor for

easy access and comfort.

Omron developed

Complete in partnership with

AliveCor, the market leader

in FDA-cleared personal EKG

technology. Complete uses

the advanced new algorithm

designed by AliveCor for

improved detection of the

possibility of Afib along with

trusted medical-grade blood

pressure measurement from


Complete is the recipient

of the iF Design Award 2019,

presented by iF International

Forum Design GmbH.

US FDA approves

novel portable

gas exchange



he US FDA has approved

the Gas Exchange Monitor,

a portable respiratory

monitoring device.

The device provides realtime,

clinically actionable

data measuring pulmonary

gas exchange in a wide



launches medical


Contec Americas Inc has

developed a new line

of medical-grade monitors

to meet the stringent

image quality and safety

requirements of clinical

applications. The initial release

of seven displays features

DICOM Part 14 image quality

and IEC 60601 compliance

with medical safety and

performance standards.

The monitors are designed

for original equipment

manufacturers (OEMs) looking

for versatile, long life solutions

suited for a wide variety

of hospital and laboratory


Contec’s new clinical

displays range in size from

15” to 27” and include 5-wire

resistive touch and projected

capacitive touch (PCAP)


The Legacy group features

a 4:3 aspect ratio.

Contec’s Modern

line boasts a sleek,


look, 16:9


aspect ratio, high

brightness up to 350

nits, wide viewing angles

up to 178 degrees and trueflat

front, IP65 rating for easy

cleaning and sanitation.

Contec’s new clinical

display line is part of a series

of new products which will be

introduced in 2019.


introduces home

BP monitor with

EKG capability

Omron Healthcare has

secured USFDA clearance

on its new Complete, the

first blood pressure monitor

with EKG capability in a single


Complete is an upper

arm blood pressure monitor

that allows users to

simultaneously monitor EKG

and blood pressure readings

at home. EKG readings can

be measured by touching

electrodes conveniently

Tack endovascular system for

PAD gets US FDA approval

Intact Vascular, Inc has received

the US FDA approval for the

Tack Endovascular System (6F), a

dissection repair device implanted

post-angioplasty in patients with

the peripheral arterial disease


The approval was based on

data from Intact Vascular’s Tack

Optimized Balloon Angioplasty

II (TOBA II) pivotal trial, which

demonstrated the safety and

effectiveness of the Tack implant

to resolve dissections following


The inflation of an angioplasty

balloon and resulting mechanical

stress inherently injures vessels

and creates dissections. If left

untreated, dissections can

compromise clinical outcomes,

resulting in acute thrombosis and

arterial occlusions, leading to lower

long-term patency rates and repeat


The TOBA II pivotal trial,

notably the first peripheral

vascular study to enroll

patients with 100%

dissected vessels, met all

primary endpoints with

92% of dissections completely

resolved following treatment, the

company reported.

May 2019 / FUTURE MEDICINE / 63

variety of respiratory disease,

manufactured and marketed

by MediPines.

The Novel physiologic

results on world elite

freedivers’ using the noninvasive

gas exchange

monitor were presented at

the Experimental Biology

2019 conference. The

new device makes it now

possible for a non-invasive

portable measurement that

can support evaluation and

trending of pulmonary gas

exchange status of a patient

in a point of care setting.

Freedivers place

themselves in extreme

conditions, which push the

outer limits of human lung

physiology and can lead

to a high oxygen deficit.

The device provided rapid

feedback to the research

team tasked with assessing

the freedivers’ gas exchange


Baxter launches



Floseal Hemostatic Matrix

has been granted approval

by the USFDA, Baxter

International announced.

Floseal has 20 per cent

fewer components and steps

to prepare, making it easier

and faster for operating room

(OR) nurses to get Floseal

in the hands of surgeons to

help stop bleeding during


The device has been

proven to perform quickly and

consistently across a range of

bleeds in surgical procedures.

A 13cm Malleable Applicator

is included with every kit that

allows surgeons to maneuver

the product into the proper


In this latest design, the

diluent ampoule has been

replaced by pre-filling the

existing mixing syringe so

that Floseal can be prepared

more quickly than the current


Both active and passive

adjunctive haemostatic

Cryotherapy device to treat

heavy menstrual bleeding

Cerene cryotherapy device

has been granted approval

by US FDA as a new approach

to treating heavy menstrual


The device uses cryotherapy

to freeze the endometrial

lining of the uterus to reduce

future menstrual bleeding in

premenopausal women who

are not planning to become


This procedure does not

require general anaesthesia. It

can, therefore, be performed

in the gynaecologist’s office

in contrast, heat-based

endometrial ablation devices

which are more often

performed with general

anaesthesia in hospitals.

CLARITY, the pivotal study

supporting the safety and

effectiveness of the Cerene

device and its FDA approval

included treatment of 242


At 12 months, the observed

reduction in menstrual bleeding

exceeded treatment goals.

64 / FUTURE MEDICINE / May 2019

agents are available to help

control bleeding in surgical

procedures when ligature or

conventional methods are

ineffective or impractical.

US FDA approves

Duaklir inhaler

for COPD

The US FDA has approved

Duaklir Pressair for the

maintenance treatment of

chronic obstructive pulmonary

disease (COPD).

Duaklir Pressair combines

aclidinium bromide, a longacting

muscarinic antagonist

(LAMA), and

formoterol fumarate, a

long-acting beta2 -adrenergic

agonist (LABA). It is intended

for twice-daily use with the

breath-actuated Pressair


The approval was

supported by data from the


and AMPLIFY studies which

included patients with

moderate to very severe


Results showed that

treatment with Duaklir

Pressair led to a statistically

significant increase in mean

change from baseline in

trough FEV1 and change from

baseline in 1-hour post-dose

FEV1 at week 24 relative to

formoterol fumarate 12mcg

and aclidinium 400mcg,


Circassia who is planning

to launch Duaklir in the US in

the second half of 2019 via its

dedicated COPD sales force.


launches spinal

device for pain


Medtronic has launched

Intellis platform for the

management of certain types

of chronic intractable pain.

EU nod for endoscopic ablation system

HeartLight X3 Endoscopic

Ablation System has

received European CE

Mark approval for ablation

treatment for atrial


HeartLight X3

Endoscopic Ablation System

is a third-generation

technology building upon

the advanced features of

the HeartLight Endoscopic

Ablation System, which

performs pulmonary vein

isolation (PVI) using laser

The platform was designed

to overcome limitations with

current spinal cord stimulation

(SCS) systems, such as battery

performance, and can power

the Evolve workflow, which

standardises guidance and

balances high-dose (HD)

and low-dose (LD) therapy


It can record and track

patient activity 24/7 and is

managed on the Samsung

Galaxy Tab S2 tablet interface,

enabling physicians to address

the subjective and personal

nature of chronic pain by

monitoring progress and

making modifications to better

suit their patients’ therapy


Intellis platform can help

optimize treatment and

improve patient-physician

energy to create lines

of scar tissue to block

the abnormal electrical

pathways that cause AFib.

Using direct tissue

visualization, titratable

laser energy, and compliant

balloon technology, the

HeartLight X3 System’s

unique RAPID mode

leverages a precise motor

control system that enables

uninterrupted, high-speed,

circumferential lesion

creation under the direct

communication by tracking

and sharing daily activities,

body positions and therapy

usage and by giving physicians

an objective look at mobility

and progress.

The device also addresses

a common patient complaint:

battery recharge issues.

control of the physician

resulting in consistently

reduced procedure times.

In the pivotal

confirmatory evaluation of

60 patients, the HeartLight

X3 System consistently

achieved very rapid PVI, in

as few as three minutes for

a single vein. The trial also

found that the System has

the potential to complete

all required ablations in less

than 20 minutes.

With Medtronic’s proprietary

Overdrive battery technology,

the Intellis battery can be fully

recharged from empty to full

in approximately one hour and

physicians can now estimate

recharge intervals based on

therapy settings.

Additional advances in

the device include secure

wireless Samsung Galaxy Tab

S2 programmers for physicians

that enable faster delivery

of evolving workflows and

software upgrades.

Medtronic neurostimulation

therapy for chronic intractable

pain uses a medical device

placed under a patient’s

skin to deliver mild electrical

impulses through a lead

implanted in the epidural

space to block pain signals

from going to the brain.

May 2019 / FUTURE MEDICINE / 65


EPIQ Elite ultrasound line

with vascular imaging

Royal Philips’ EPIQ Elite ultrasound

system offers a range of diagnostic

ultrasound solutions tailored to the needs

of specific medical specialties including

solution for vascular assessment and


In Obstetrics & Gynecology EPIQ Elite

delivers extraordinary image quality and

lifelike 3D scans to provide advanced fetal

assessment during all stages of pregnancy.

The Philips ultimate ultrasound solution

for vascular assessment provides superb

insight into the progression of vascular

disease. It brings 3D and 4D imaging to

vascular ultrasound for the first time that

effectively help analyze vascular disease

allowing clinicians to see into a vessel to

spot plaque and assess flow data over time.

The EPIQ Elite for obstetrics and

gynecology combines with innovative

transducers and software to offer an

integrated solution that enhances fetal

assessment and meets the specific needs

of obstetrics patients during the early

stages of pregnancy.


EPIQ Elite combines new display

technology, innovative transducers,

advanced software and enhanced

processing power.

xMATRIX transducer: Philips’ innovative

xMATRIX transducer can produce

extraordinary 3D vascular images, allowing

clinicians to easily see directly into a vessel

to evaluate plaque spatial location and

composition, as well as view 3D flow data

to quickly assess stenotic conditions.

‘xPlane’ imaging: proprietary to Philips

– allows clinicians to acquire two planes

simultaneously to improve accuracy of

data collection, and reduce exam time by


Icon-driven visual workflow : makes 3D

imaging easier, reducing the steps that the

clinician needs to take from 10 to one.

V9-2 transducer : The ergonomic,

lightweight V9-2 transducer is the first

high-frequency PureWave transducer

focused on getting fine detailed images as

early as possible to help clinicians easily

perform confident assessments of fetal


TrueVue : Paired with TrueVue, the

EPIQ Elite system allows clinicians to

manipulate a virtual light source around

the 3D images of the fetus, producing

images that are both incredibly lifelike and

that provide a high level of detail to enable

the identification of any abnormalities

early on in pregnancy.

aBiometry Assist : The Philips aBiometry

Assist application uses anatomical

intelligence to automate time spent

gathering measurements, reducing

examining time.

The combination of a new transducer

and advances in software makes the

assessment and diagnosis of vascular

conditions through easy to interpret

images. Ability to produce tailored

solution for obstetrics and gynecology

helps assess fetal health improving the

early detection of birth defects and

potential complications.

This is a sponsored article. FM editorial holds no responsibility for the information therein.

66 / FUTURE MEDICINE / May 2019





Started in 2016, the centre has trained

over 250 surgeons from all over India in

robotic assisted surgery


Technology in surgery has seen

several leaps of advances in

the past few decades;. from

conventional open surgeries to minimally

invasive procedures such as laparoscopic

techniques, video-assisted thoracoscopic

surgeries and more recently, robotic

assisted minimally invasive surgeries.

These innovations and technological

advances are primarily focused on

improving surgical procedures so that

the final outcome in terms of hospital

stay, procedural time, blood-loss, and

post-operative complications such as

infections and pain, are considerably


Robot-assisted minimally invasive

procedures are a fairly recent

development in the field of surgical

science. These types of procedures

mainly involve the use of computer

assistance for performing an array of

surgical manipulations through the

smallest of incisional openings. The

use of robotic assistance has several

known benefits, including improved

procedural dexterity, ergonomics,

safety and ease of surgery, all of which

translate to improved patient outcomes.

Some of the major surgical specialties

that have embraced robotic assisted

procedures include gynecology, urology,

gastroenterology, and thoracic surgery.

In terms of the actual procedure,

one of the primary advantages of using

robotic assistance is the magnification

of the surgical field that is available

to the surgeon. To put this in context,

surgical procedures performed under

conventional techniques do not allow

any magnification of the surgical site,

while moderate magnification (2.5 times)

is obtained in laparoscopic techniques.

However, robotic assisted methods allow

up to 10 times magnification, which

by far is a significant improvement

compared to its predecessors, and also

makes a huge difference in how the

68 / FUTURE MEDICINE / May 2019

I was trained at McGill

University, Montreal,

Canada, and now

it’s my turn to train


Dr Anupama R

Robotic Surgeon and

Professor in Gynecologic

Oncology, Amrita Institute

of Medical Sciences, Kochi

surgeon makes operative decisions

during the procedure. The second and

perhaps the most important advantage

that robotic assistance provides is the

way surgical instruments are negotiated

within the surgical site. In open

surgeries, the surgeon directly holds

the instruments, while in laparoscopic

techniques, the surgeon uses the

instruments by viewing them through a

screen that is connected to a peripheral

camera. However, in robotic assisted

procedures, the surgeon maneuvers the

instruments via a console. This consolebased

control of surgical instruments, in

addition to the enhanced magnification

of the surgical site, provides the surgeon

with an increased ability to be dexterous

and perform difficult surgical maneuvers

with ease.

Simple to learn

Considering the advantages offered

by the newer, minimally invasive

May 2019 / FUTURE MEDICINE / 69

techniques, it would appear that their

acceptance would be widespread.

However, adapting to viewing through

a camera in laparoscopic techniques

and maneuvering instruments through

an indirect console in robotic assisted

techniques is something that needs

skill-based adaptation for the surgeons.

Even leading surgeons may be unwilling

to perform procedures involving

newer techniques without training.

A well-known example is that of Dr.

Robert Cerfolio, previously at University

of Alabama and presently Chief of

Clinical Thoracic Surgery, NYU Langone

Center, New York, who is a leader in

the field of thoracic surgery and has

performed thousands of thoracic

surgical procedures. According to Dr

Balasubramoniam K. R., Cardiothoracic

Surgeon at Amrita Institute of Medical

Sciences, Kochi, “Even though Dr

Cerfolio had performed countless

open surgeries, he was initially

unable to adapt to the video-assisted

thoracoscopic surgeries. Nonetheless,

Dr. Cerfolio went on to do thousands

of robotic assisted surgeries and is

currently one of the leading surgeons

utilizing robotic assisted techniques

in his field.” Dr Balasubramoniam

underwent robotic surgery training

at the University of Alabama and has

since then performed over 150 robotic

assisted surgeries in the past few

years at Amrita Hospital. He recognizes

the true benefits of this technology

and highly recommends the need

for training and procuring the skills

required for performing robotic assisted


Such advances in technology

undoubtedly come with unique

challenges in terms of bringing

surgeons up to speed and can require

significant training to develop the

special skill sets required to use

the new technology. While all new

techniques require training, some

techniques are easier to master.

Robotic-assisted techniques are simple

to learn, and due to the significant

improvements and benefits of using

robotic assistance, surgeons worldwide

are embracing this technology.

However, formal training and

competency assessment are required.

Many of our renowned, experienced

Indian surgeons have had to go

abroad to complete training for robotic

assisted surgeries, spending money

and valuable time out of the country. A

training centre in India was a growing

need, and this was accomplished in


Dr A K K Unni, Professor and Head,

Central Animal Facility, Amrita Institute

of Medical Sciences, Kochi, explained to

me how it all came about over a cup

of tea and cookies. “Intuitive Surgical

Inc. reached out to our Medical Director

to set up a training center at Amrita

hospital. Why Amrita you may ask? One

of the major requirements of a training






centre is an animal facility where

training can be undertaken in large

animals. Amrita hospital already had

a large animal facility and was able to

provide the necessary support required.

Being a leading center for postgraduate

education and research, we also felt

that there was a dire necessity for

training potential surgeons in robotic

surgical techniques.’

The first and until very recently, the

only robotic surgery training center

in India, Amrita Centre for Robotic

Surgery Training and Animal Cath Lab

is a productive collaboration between

Intuitive Surgical Inc., and Amrita Institute

of Medical Sciences. This is a symbiotic

relationship where Intuitive Surgical Inc,

which is the only company that makes

the da Vinci system for robotic assisted

surgeries, provides trainers for the

robotic assistance equipment and Amrita

Hospital provides the infrastructure,

manpower, facilities and the animals

required for training.

Eligibility criteria

Dr Unni has laid out some basic

requirements for the training programme

to ensure that the programme is not

misused. He has put in place a minimum

academic qualification of MS or MCh for

a surgeon to be eligible for this training

programme. The surgeon’s affiliation

hospital must have their own robotic unit

or the surgeon should have prior robotic

surgery exposure. Further, the surgeon’s

institute must give an assurance that

the surgeon would be allowed to pursue

and utilize his training skills after the

training is completed. Once the surgeon

is found to be eligible to undergo the

training programme, he/she must first go

through an online course before visiting

Amrita for a 1-day training session. The

session starts with dry training on the

state of the art da Vinci surgical system

to familiarize the trainee with the system

and the instruments, followed by wet

70 / FUTURE MEDICINE / May 2019

training where surgeons get handson

training on anesthetized pigs. They

undergo training that covers a series of

exercises, including dissection, ligation of

vessels, suturing and energy applications.

At the end of the day, the trainees are

evaluated and then provided a certificate

for this basic training. So far, about 250

surgeons from all over India have been

trained and qualified from the Amrita

Center for Robotic Surgery Training.

The surgeons are also requested to

provide feedback on the training facility

and the programme, and the feedback

has been extremely positive so far.

The training does not end there. All

surgeons who undergo basic training are

recommended to observe real surgeries

before performing their first robotic

procedure on a patient. Then, to finally

complete the training, they are required

to perform 3-4 cases in the presence of

a proctor. There is however no sign off or

certificate provided at this stage.

Cadaver training

As of 2017, In addition to the basic

training in collaboration with Intuitive

Surgical, Amrita also offers an advanced

training programme for specialist

surgeons that involves training on

cadavers. Trained and experienced

robotic surgeons with expertise in

various specialties provide training

for this advanced programme. I was

fortunate to catch Dr Anupama R,

Robotic Surgeon and Professor in

Gynecologic Oncology at Amrita Institute

of Medical Sciences, Kochi, between

surgeries. She was instrumental in setting

up the Minimally Invasive and Robotic

Surgery Programme at Department of

Gynecologic Oncology in February 2015

and since then has performed over 500

robotic surgeries. She has also been

instrumental in the training programme

at Amrita and proctors for other trainees

across the country as well. When

asked how she manages training and

proctoring with her busy schedule, Dr

Anupama says, ‘‘I was trained at McGill

University, Montreal, Canada, and now it’s

my turn to train others.’’

While Amrita Centre for Robotic

Surgery Training remains the only animal

training facility in India, very recently, a

basic training center has been started in

Ramaiah Medical College, Bengaluru. This

new facility is currently equipped only

for training on cadaver models. Animal

training, however, will remain critical for

getting real, hands-on experience as a

first step towards patient surgeries.

Based on trainee conversions and

surgical outcomes in patients, Amrita

Centre for Robotic Surgery Training

has been ranked as the best training

center outside USA by Intuitive Surgicals,

which is a great achievement for all the

management and staff involved. Dr Unni

has set still higher goals and is in talks

with IRCAD, a renowned training center

in France, in an effort to make Amrita

Centre for Robotic Surgery Training one

of the best International training centers

in the world.

This is part of a series that features India’s

First & Most Unique institutions, facilities,

technologies, products etc in the medical and

healthcare space.

May 2019 / FUTURE MEDICINE / 71




72 / FUTURE MEDICINE / May 2019



Urinary incontinence can be a result of functional

abnormalities in the lower urinary tract or of illnesses.

Stress urinary incontinence is involuntary urine leakage

on effort, exertion, sneezing or coughing. Urgency urinary

incontinence is involuntary urine leakage accompanied or

immediately preceded by urgency (a sudden compelling

desire to urinate that is difficult to delay). Mixed urinary

incontinence is involuntary urine leakage associated with

both urgency and exertion, effort, sneezing or coughing.

Overactive bladder (OAB) is defined as urgency that occurs

with or without urgency urinary incontinence and usually with

frequency and nocturia.

Pelvic organ prolapse is defined as symptomatic descent

of 1 or more of the anterior vaginal wall, the posterior vaginal

wall, the cervix or uterus, or the apex of the vagina (vault

or cuff). Symptoms include a vaginal bulge or sensation

of something coming down, urinary, bowel and sexual

symptoms, and pelvic and back pain. These symptoms affect

women's quality of life.

The prevalence of pelvic organ prolapse is high; in primary

care in the UK, 8.4% of women reported vaginal bulge or

lump, and on examination, prolapse is present in up to 50%

of women. One in 10 women will need at least 1 surgical

procedure, and the rate of re‐operation is as high as 19%.

There is likely to be an increasing need for surgery for urinary

incontinence and pelvic organ prolapse because of the ageing

population, according to National Institute for Health and Care

Excellence (NICE),UK.

1.1 Organisation of specialist


Local multidisciplinary teams

1.1.1 Local multidisciplinary teams (MDTs)

for women with primary stress urinary

incontinence, overactive bladder or

primary prolapse should:

• review the proposed treatment for

all women offered invasive procedures

for primary stress urinary incontinence,

overactive bladder or primary prolapse

• review the proposed management

for women with primary stress urinary

incontinence, overactive bladder or

primary prolapse if input from a wider

range of healthcare professionals is


• work within an established clinical

network that has access to a regional


1.1.2 Local MDTs for women with primary

stress urinary incontinence, overactive

bladder or primary prolapse should


• 2 consultants with expertise in

managing urinary incontinence in

women and/or pelvic organ prolapse

• a urogynaecology, urology or

continence specialist nurse

• a pelvic floor specialist


• and may also include:

• a member of the care of the elderly


• an occupational therapist

• a colorectal surgeon.

1.1.3 Members of the local MDT (listed in

recommendation 1.1.2) should attend all

local MDT meetings.

Regional multidisciplinary teams

1.1.4 Regional MDTs that deal with

complex pelvic floor dysfunction and

mesh-related problems should review

the proposed treatment for women if:

• they are having repeat continence


• they are having repeat, same-site

prolapse surgery

• their preferred treatment option is

not available in the referring hospital

• they have coexisting bowel problems

that may need additional colorectal


• vaginal mesh for prolapse is a

treatment option for them

• they have mesh complications or

unexplained symptoms after mesh

surgery for urinary incontinence or


• they are considering surgery and

may wish to have children in the


1.1.5 Regional MDTs that deal with

complex pelvic floor dysfunction and

mesh-related problems should include:

• a subspecialist in urogynaecology

• a urologist with expertise in female


• a urogynaecology, urology or

continence specialist nurse

• a pelvic floor specialist


• a radiologist with expertise in pelvic

floor imaging

• a colorectal surgeon with expertise

in pelvic floor problems

• a pain specialist with expertise in

managing pelvic pain

• and may also include:

• a healthcare professional trained

May 2019 / FUTURE MEDICINE / 73

in bowel biofeedback and trans-anal


• a clinical psychologist

• a member of the care of the elderly


• an occupational therapist

• a surgeon skilled at operating in the

obturator region

• a plastic surgeon.

1.1.6 Regional MDTs that deal with

complex pelvic floor dysfunction and

mesh-related problems should have

ready access to the following services:

• psychology

• psychosexual counselling

• chronic pain management

• bowel symptom management

• neurology.

1.1.7 Members of the regional MDT (listed

in recommendation 1.1.5) should attend

regional MDT meetings when their

specific expertise is needed.

1.2 Collecting data on surgery and

surgical complications

1.2.1 Ask women having surgery

for stress urinary incontinence or

pelvic organ prolapse, or who have

experienced complications related

to these types of surgery, for their

consent to enter the data listed in

recommendation 1.2.2 in a national

registry. Give each woman a copy of her


1.2.2 Providers must ensure that

the following data are recorded in a

national registry of surgery for urinary

incontinence and pelvic organ prolapse

in women:

• the woman's NHS number

• hospital and consultant identifiers

• date and details of the procedure

• for procedures involving mesh, the

mesh material, manufacturer, product

unique identification code and type of

sutures used

• for procedures involving

colposuspension, the type of sutures


• for procedures involving bulking

agent, the bulking material,

manufacturer and product unique

identification code

• date and details of any investigation

for complications

• date and details of any surgical

or non-surgical intervention for


1.2.3 The national registry of surgery for

urinary incontinence and pelvic organ

prolapse in women must ensure that

follow‐up data are collected on key

short- and long-term (at least 5 years)

outcomes, including:

• validated relevant outcome


• adverse events including pain

• suspected and confirmed meshrelated


1.2.4 The national registry of surgery

for urinary incontinence and pelvic

organ prolapse in women should report

annually and be quality assured.

1.3 Assessing urinary incontinence

History taking and physical


1.3.1 At the initial clinical assessment,

categorise the woman's urinary

incontinence as stress urinary

incontinence, mixed urinary incontinence

or urgency urinary incontinence/

overactive bladder. Start initial

treatment on this basis. In mixed urinary

incontinence, direct treatment towards

the predominant symptom.

1.3.2 If stress incontinence is the

predominant symptom in mixed urinary

incontinence, discuss with the woman

the benefit of non-surgical management

and medicines for overactive bladder

before offering surgery.

1.3.3 During the clinical assessment seek

to identify relevant predisposing and

precipitating factors and other diagnoses

that may require referral for additional

investigation and treatment.

Assessing pelvic floor muscles

1.3.4 Undertake routine digital

assessment to confirm pelvic floor

muscle contraction before the use of

supervised pelvic floor muscle training

for the treatment of urinary incontinence.

Urine testing

1.3.5 Undertake a urine dipstick test

in all women presenting with urinary

incontinence to detect the presence of

blood, glucose, protein, leucocytes and

nitrites in the urine.

1.3.6 If women have symptoms of

urinary tract infection (UTI) and their

urine tests positive for both leucocytes

and nitrites, send a midstream urine

specimen for culture and analysis

of antibiotic sensitivities. Prescribe

an appropriate course of antibiotic

treatment pending culture results.

See the NICE guideline on urinary

tract infection (lower): antimicrobial

prescribing for more information.

1.3.7 If women have symptoms of UTI

and their urine tests negative for either

leucocytes or nitrites, send a midstream

urine specimen for culture and analysis

of antibiotic sensitivities. Consider the

prescription of antibiotics pending

culture results.

1.3.8 If women do not have symptoms

of UTI, but their urine tests positive for

both leucocytes and nitrites, do not

offer antibiotics without the results of

midstream urine culture.

1.3.9 If a woman does not have

symptoms of UTI and her urine tests

negative for either leucocytes or nitrites,

do not send a urine sample for culture

because she is unlikely to have UTI.

Assessing residual urine

1.3.10 Measure post-void residual volume

by bladder scan or catheterisation in

women with symptoms suggestive of

voiding dysfunction or recurrent UTI.

1.3.11 Use a bladder scan in preference

to catheterisation on the grounds of

acceptability and lower incidence of

adverse events.

Symptom scoring and quality-of-life


1.3.12 Use a validated urinary

incontinence-specific symptom and

quality-of-life questionnaire when

therapies are being evaluated.

Bladder diaries

1.3.13 Use bladder diaries in the initial

assessment of women with urinary

incontinence or overactive bladder.

Encourage women to complete a

74 / FUTURE MEDICINE / May 2019

minimum of 3 days of the diary covering

variations in their usual activities, such as

both working and leisure days.

Pad testing

1.3.14 Do not use pad tests in the routine

assessment of women with urinary


Urodynamic testing

1.3.15 Do not perform multichannel

filling and voiding cystometry before

primary surgery if stress urinary

incontinence or stress-predominant

mixed urinary incontinence is diagnosed

based on a detailed clinical history and

demonstrated stress urinary incontinence

at examination.

1.3.16 After undertaking a detailed

clinical history and examination,

perform multichannel filling and voiding

cystometry before surgery for stress

urinary incontinence in women who have

any of the following:

• urge-predominant mixed urinary

incontinence or urinary incontinence in

which the type is unclear

• symptoms suggestive of voiding


• anterior or apical prolapse

• a history of previous surgery for

stress urinary incontinence.

Other tests of urethral competence

1.3.17 Do not use the Q‐tip, Bonney,

Marshall and Fluid-Bridge tests in the

assessment of women with urinary



1.3.18 Do not use cystoscopy in the

initial assessment of women with urinary

incontinence alone.


1.3.19 Do not use imaging (MRI, CT,

X‐ray) for the routine assessment of

women with urinary incontinence. Do

not use ultrasound other than for the

assessment of residual urine volume.

Indications for referral to a specialist


1.3.20 In women with urinary

incontinence, indications for

consideration for referral to a specialist

service include:

• persisting bladder or urethral pain

• palpable bladder on bimanual or

abdominal examination after voiding

• clinically benign pelvic masses

• associated faecal incontinence

• suspected neurological disease

• symptoms of voiding difficulty

• suspected urogenital fistulae

• previous continence surgery

• previous pelvic cancer surgery

• previous pelvic radiation therapy.

1.3.21 Follow the recommendations on

referral for urinary tract cancer in the

NICE guideline on suspected cancer, for

women with haematuria or recurrent or

persistent unexplained UTI.

1.4 Non-surgical management of






urinary incontinence

Lifestyle interventions

1.4.1 Recommend a trial of caffeine

reduction to women with overactive


1.4.2 Consider advising women with

urinary incontinence or overactive

bladder and a high or low fluid intake to

modify their fluid intake.

1.4.3 Advise women with urinary

incontinence or overactive bladder who

have a BMI greater than 30 to lose


Physical therapies

Pelvic floor muscle training

1.4.4 Offer a trial of supervised pelvic

floor muscle training of at least 3

months' duration as first-line treatment

to women with stress or mixed urinary


1.4.5 Pelvic floor muscle training

programmes should comprise at least 8

contractions performed 3 times per day.

1.4.6 Do not use perineometry or pelvic

floor electromyography as biofeedback

as a routine part of pelvic floor muscle


1.4.7 Continue an exercise programme if

pelvic floor muscle training is beneficial.

Electrical stimulation

1.4.8 Do not routinely use electrical

stimulation in the treatment of women

with overactive bladder.

1.4.9 Do not routinely use electrical

stimulation in combination with pelvic

floor muscle training.

1.4.10 Electrical stimulation and/or

biofeedback should be considered for

women who cannot actively contract

pelvic floor muscles to aid motivation

and adherence to therapy.

Behavioural therapies

1.4.11 Offer bladder training lasting

for a minimum of 6 weeks as first-line

treatment to women with urgency or

mixed urinary incontinence.

1.4.12 If women do not achieve

satisfactory benefit from bladder

training programmes, the combination

of an overactive bladder medicine with

bladder training should be considered if

frequency is a troublesome symptom.


1.4.13 Do not offer transcutaneous sacral

nerve stimulation (surface electrodes

placed above the sacrum, often known

as transcutaneous electrical nerve

stimulation [TENS]) to treat overactive

bladder in women.

1.4.14 Do not offer transcutaneous

posterior tibial nerve stimulation for

overactive bladder.

1.4.15 Do not offer percutaneous

posterior tibial nerve stimulation (needles

inserted close to the posterior tibial

nerve) for overactive bladder unless:

• there has been a local MDT review


• non-surgical management including

overactive bladder medicine treatment

has not worked adequately and

May 2019 / FUTURE MEDICINE / 75


• the woman does not want

botulinum toxin type A or

percutaneous sacral nerve stimulation.

Absorbent containment products,

urinals and toileting aids

1.4.16 Do not offer absorbent

containment products, hand-held

urinals or toileting aids to treat urinary

incontinence. Offer them only:

• as a coping strategy pending

definitive treatment

• as an adjunct to ongoing therapy

• for long-term management of

urinary incontinence only after

treatment options have been explored.

1.4.17 Offer a review at least once a year

to women who are using absorbent

containment products for long-term

management of urinary incontinence.

The review should cover:

• routine assessment of continence

• assessment of skin integrity

• changes to symptoms, comorbidities,

lifestyle, mobility, medication, BMI, and

social and environmental factors

• the suitability of alternative

treatment options

• the efficacy of the absorbent

containment product the woman is

currently using and the quantities


1.4.18 Reviews for women who are

using absorbent containment products

for long-term management of urinary

incontinence should be carried out by


• a registered healthcare professional

who is trained in assessing continence

and making referrals to specialist

services or

• a non-registered healthcare worker,

under the supervision of a registered

healthcare professional who is trained

in assessing continence and making

referrals to specialist services.


1.4.19 Bladder catheterisation

(intermittent or indwelling urethral or

suprapubic) should be considered for

women in whom persistent urinary

retention is causing incontinence,

symptomatic infections or renal

dysfunction, and in whom this cannot

otherwise be corrected. Healthcare

professionals should be aware, and

explain to women, that the use

of indwelling catheters in urgency

urinary incontinence may not result in


1.4.20 Offer intermittent urethral

catheterisation to women with urinary

retention who can be taught to selfcatheterise

or who have a carer who can

perform the technique.

1.4.21 Give careful consideration to the

impact of long-term indwelling urethral

catheterisation. Discuss the practicalities,

benefits and risks with the woman or,

if appropriate, her carer. Indications for

the use of long-term indwelling urethral

catheters for women with urinary

incontinence include:

• chronic urinary retention in









women who are unable to manage

intermittent self-catheterisation

• skin wounds, pressure ulcers or

irritations that are being contaminated

by urine

• distress or disruption caused by bed

and clothing changes

• where a woman expresses

a preference for this form of


1.4.22 Indwelling suprapubic catheters

should be considered as an alternative

to long-term urethral catheters. Be

aware, and explain to women, that they

may be associated with lower rates

of symptomatic UTI, 'bypassing', and

urethral complications than indwelling

76 / FUTURE MEDICINE / May 2019

urethral catheters.

Products to prevent leakage

1.4.23 Do not use intravaginal and

intraurethral devices for the routine

management of urinary incontinence

in women. Do not advise women to

consider such devices other than for

occasional use when necessary to

prevent leakage, for example during

physical exercise.

Complementary therapies

1.4.24 Do not recommend

complementary therapies for the

treatment of urinary incontinence or

overactive bladder.

Medicines for overactive bladder

1.4.25 Before starting treatment with a

medicine for overactive bladder, explain

to the woman:

• the likelihood of the medicine being


• the common adverse effects

associated with the medicine

• that some adverse effects of

anticholinergic medicines, such as dry

mouth and constipation, may indicate

that the medicine is starting to have

an effect

• that she may not see substantial

benefits until she has been taking the

medicine for at least 4 weeks and

that her symptoms may continue to

improve over time

• that the long-term effects of

anticholinergic medicines for

overactive bladder on cognitive

function are uncertain.

1.4.26 When offering anticholinergic

medicines to treat overactive bladder,

take account of the woman's:

• coexisting conditions (such as

poor bladder emptying, cognitive

impairment or dementia)

• current use of other medicines that

affect total anticholinergic load

• risk of adverse effects, including

cognitive impairment.

1.4.27 For women who have a

diagnosis of dementia and for whom

anticholinergic medicines are an

option, follow the recommendations

May 2019 / FUTURE MEDICINE / 77

on medicines that may cause cognitive

impairment in the NICE guideline on


Choosing medicine

1.4.28 Do not offer women flavoxate,

propantheline or imipramine to treat

urinary incontinence or overactive


1.4.29 Do not offer oxybutynin

(immediate release) to older women

who may be at higher risk of a sudden

deterioration in their physical or mental


1.4.30 Offer the anticholinergic medicine

with the lowest acquisition cost to treat

overactive bladder or mixed urinary

incontinence in women.

1.4.31 If the first medicine for overactive

bladder or mixed urinary incontinence

is not effective or well-tolerated, offer

another medicine with a low acquisition


1.4.32 Offer a transdermal overactive

bladder treatment to women unable to

tolerate oral medicines.

1.4.33 For guidance on mirabegron, see

the NICE technology appraisal guidance

on mirabegron for treating symptoms of

overactive bladder.

1.4.34 The use of desmopressin may be

considered specifically to reduce nocturia

in women with urinary incontinence

or overactive bladder who find it a

troublesome symptom. Use particular

caution in women with cystic fibrosis

and avoid in those over 65 years with

cardiovascular disease or hypertension.

1.4.35 Do not use duloxetine as a

first-line treatment for women with

predominant stress urinary incontinence.

Do not routinely offer duloxetine as a

second-line treatment for women with

stress urinary incontinence, although it

may be offered as second-line therapy

if women prefer pharmacological to

surgical treatment or are not suitable

for surgical treatment. If duloxetine is

prescribed, counsel women about its

adverse effects.

1.4.36 Do not offer systemic hormone

replacement therapy to treat urinary


1.4.37 Offer intravaginal oestrogens to

treat overactive bladder symptoms in

postmenopausal women with vaginal


Reviewing medicine

1.4.38 Offer a face-to-face or telephone

review 4 weeks after starting a new

medicine for overactive bladder. Ask

the woman if she is satisfied with the

treatment and:

• if improvement is optimal, continue


• if there is no or suboptimal

improvement, or intolerable adverse

effects, change the dose or try an

alternative medicine for overactive








bladder (see recommendations 1.4.31

and 1.4.32), and review again 4 weeks


1.4.39 Offer a review before 4 weeks

if the adverse events of a medicine for

overactive bladder are intolerable.

1.4.40 Refer women who have tried

taking medicine for overactive bladder,

but for whom it has not been successful

or tolerated, to secondary care to

consider further treatment.

1.4.41 Offer a further face-to-face

or telephone review if a medicine

for overactive bladder or urinary

incontinence stops working after an

initial successful 4‐week review.

1.4.42 Offer a review in primary care

to women who remain on long-term

medicine for overactive bladder or

urinary incontinence every 12 months, or

every 6 months if they are aged over 75.

Invasive procedures for overactive


1.4.43 For women with overactive

bladder that has not responded to

non-surgical management or treatment

with medicine and who wish to discuss

further treatment options:

78 / FUTURE MEDICINE / May 2019

• offer urodynamic investigation

to determine whether detrusor

overactivity is causing her overactive

bladder symptoms and

• if detrusor overactivity is causing

her overactive bladder symptoms,

offer an invasive procedure in line with

recommendations 1.4.44 to 1.4.56 or

• if there is no detrusor overactivity,

seek advice on further management

from the local MDT in line with

recommendation 1.4.45.

Botulinum toxin type A injection

1.4.44 After a local MDT review, offer

bladder wall injection with botulinum

toxin type A to women with overactive

bladder caused by detrusor overactivity

that has not responded to non-surgical

management, including pharmacological


1.4.45 Consider treatment with

botulinum toxin type A after a local MDT

review for women with symptoms of

overactive bladder in whom urodynamic

investigation has not demonstrated

detrusor overactivity, if the symptoms

have not responded to non-surgical

management and the woman does not

wish to have other invasive treatments.

1.4.46 After a local MDT review, discuss

the benefits and risks of treatment with

botulinum toxin type A with the woman

and explain:

• the likelihood of complete or partial

symptom relief

• the process of clean intermittent

catheterisation, the risks, and how

long it might need to be continued

• the risk of adverse effects, including

an increased risk of urinary tract


• that there is not much evidence

about how long the injections work for,

how well they work in the long term

and their long-term risks.

1.4.47 Start treatment with botulinum

toxin type A only if the woman is willing,

in the event of developing significant

voiding dysfunction:

• to perform clean intermittent

catheterisation on a regular basis for

as long as needed or

• to accept a temporary indwelling

catheter if she is unable to perform

clean intermittent catheterisation.

1.4.48 Use 100 units as the initial dose

of botulinum toxin type A to treat







overactive bladder in women.

1.4.49 Offer a face-to-face or telephone

review within 12 weeks of the first

treatment with botulinum toxin type A

to assess the response to treatment and

adverse effects, and:

• if there is good symptom relief,

tell the woman how to self-refer for

prompt specialist review if symptoms

return, and offer repeat treatment as


• if there is inadequate symptom relief,

consider increasing subsequent doses

of botulinum toxin type A to 200 units

and review within 12 weeks

• if there was no effect, discuss with

the local MDT.

1.4.50 If symptom relief has been

adequate after injection of 100 units of

botulinum toxin type A but has lasted for

less than 6 months, consider increasing

subsequent doses of botulinum toxin

type A to 200 units and review within 12


1.4.51 Do not offer botulinum toxin type

B to women with overactive bladder.

Percutaneous sacral nerve stimulation

1.4.52 Offer percutaneous sacral

nerve stimulation to women after

local or regional MDT review if their

overactive bladder has not responded

to non-surgical management including

medicines and:

• their symptoms have not responded

to botulinum toxin type A or

• they are not prepared to accept

the risks of needing catheterisation

associated with botulinum toxin type


1.4.53 Discuss the long-term implications

of percutaneous sacral nerve stimulation

with women including:

• the need for test stimulation and

probability of the test's success

• the risk of failure

• the long-term commitment

• the need for surgical revision

• the adverse effects.

1.4.54 Tell women how to self-refer for

prompt specialist review if symptoms

return following a percutaneous sacral

nerve stimulation procedure.

Augmentation cystoplasty

1.4.55 Restrict augmentation cystoplasty

for the management of idiopathic

detrusor overactivity to women whose

condition has not responded to nonsurgical

management and who are

willing and able to self-catheterise.

Preoperative counselling for the

woman or her carer should include

common and serious complications:

bowel disturbance, metabolic acidosis,

May 2019 / FUTURE MEDICINE / 79

mucus production and/or retention in

the bladder, UTI and urinary retention.

Discuss the small risk of malignancy

occurring in the augmented bladder.

Provide life-long follow‐up.

Urinary diversion

1.4.56 Urinary diversion should be

considered for a woman with overactive

bladder only when non-surgical

management has failed, and if botulinum

toxin type A, percutaneous sacral

nerve stimulation and augmentation

cystoplasty are not appropriate or are

unacceptable to her. Provide life-long


1.5 Surgical management of stress

urinary incontinence

There is public concern about the use

of mesh procedures. For all of the

procedures recommended in this section,

including mesh procedures, there is

evidence of benefit but limited evidence

on the long-term adverse effects. In

particular, the true prevalence of longterm

complications is unknown.

1.5.1 If a woman is thinking about a

surgical procedure for stress urinary

incontinence, use the NICE patient

decision aid on surgery for stress urinary

incontinence to promote informed

preference and shared decision making.

Discussion with the woman should


• the benefits and risks of all surgical

treatment options for stress urinary

incontinence that NICE recommends,

whether or not they are available


• the uncertainties about the longterm

adverse effects for all procedures,

particularly those involving the

implantation of mesh materials

• differences between procedures

in the type of anaesthesia, expected

length of hospital stay, surgical

incisions and expected recovery period

• any social or psychological factors

that may affect the woman's decision.

1.5.2 If non-surgical management

for stress urinary incontinence has

failed, and the woman wishes to think

about a surgical procedure, offer

her the choice of:

• colposuspension (open or

laparoscopic) or

• an autologous rectus fascial sling.

Also include the option of a retropubic

mid-urethral mesh sling in this

choice but see recommendations

1.5.7 to 1.5.11 for additional guidance

on the use of mid-urethral mesh

sling procedures for stress urinary


1.5.3 Consider intramural bulking agents

to manage stress urinary incontinence if

alternative surgical procedures are not

suitable for or acceptable to the woman.

Explain to the woman that:

• these are permanent injectable


• repeat injections may be needed to

achieve effectiveness

• limited evidence suggests that they






are less effective than the surgical

procedures listed in recommendation

1.5.2 and the effects wear off over


• there is limited evidence on longterm

effectiveness and adverse events.

1.5.4 If an intramural bulking agent

is injected, give the woman written

information about the bulking agent,

including its name, manufacturer, date

of injection, and the injecting surgeon's

name and contact details.

1.5.5 If the woman's chosen procedure

for stress urinary incontinence is not

available from the consulting surgeon,

refer her to an alternative surgeon.

1.5.6 Providers must ensure that data

on surgical procedures for stress urinary

incontinence are recorded in a national

registry, as outlined in the section on

collecting data on surgery and surgical

complications in this guideline.

Mid-urethral mesh sling procedures

1.5.7 When offering a retropubic midurethral

mesh sling, advise the woman

that it is a permanent implant and

complete removal might not be possible.

1.5.8 If a retropubic mid-urethral mesh

sling is inserted, give the woman written

information about the implant, including

its name, manufacturer, date of insertion,

and the implanting surgeon's name and

contact details.

1.5.9 When planning a retropubic midurethral

mesh sling procedure, surgeons


• use a device manufactured from

type 1 macroporous polypropylene


• consider using a retropubic midurethral

mesh sling coloured for high

visibility, for ease of insertion and


1.5.10 Do not offer a transobturator

approach unless there are specific

clinical circumstances (for example,

previous pelvic procedures) in which the

retropubic approach should be avoided.

1.5.11 Do not use the 'top‐down'

retropubic mid-urethral mesh sling

approach or single-incision sub-urethral

short mesh sling insertion except as part

of a clinical trial.

Artificial urinary sphincters

1.5.12 Do not offer women an artificial

urinary sphincter to manage stress

urinary incontinence unless previous

surgery has failed.

1.5.13 For women who have had an

artificial urinary sphincter inserted:

• offer postoperative follow‐up and

• ensure access to review if needed.

Procedures that should not be offered

1.5.14 Do not offer women the following

procedures to treat stress urinary


• anterior colporrhaphy

• needle suspension

• paravaginal defect repair

• porcine dermis sling

80 / FUTURE MEDICINE / May 2019

• the Marshall–Marchetti–Krantz


Follow-up after surgery

1.5.15 Offer a follow‐up appointment

within 6 months to all women who have

had a surgical procedure to treat stress

urinary incontinence.

1.5.16 For women who have had

retropubic mid-urethral mesh sling

surgery, the follow‐up appointment

should include a vaginal examination to

check for exposure or extrusion of the

mesh sling.

1.5.17 Providers should ensure that

women who have had surgery for stress

urinary incontinence have access to

further referral if they have recurrent

symptoms or suspected complications.

See also assessing complications

associated with mesh surgery in this


1.5.18 For women whose primary surgical

procedure for stress urinary incontinence

has failed (including women whose

symptoms have returned):

• seek advice on assessment and

management from a regional MDT

that deals with complex pelvic floor

dysfunction or

• offer the woman advice about

managing urinary symptoms if she

does not wish to have another surgical

procedure, and explain that she can

ask for a referral if she changes her


1.6 Assessing pelvic organ prolapse

1.6.1 For women presenting in primary

care with symptoms or an incidental

finding of vaginal prolapse:

• take a history to include symptoms

of prolapse, urinary, bowel and sexual


• do an examination to rule out a

pelvic mass or other pathology and to

document the presence of prolapse

(see the sections on ovarian cancer

and bladder cancer in the NICE

guideline on suspected cancer)

• discuss the woman's treatment

preferences with her, and refer if


1.6.2 For women referred to secondary

care for an unrelated condition who have

incidental symptoms or an incidental

finding of vaginal prolapse, consider

referral to a clinician with expertise in


1.6.3 For women who are referred for

specialist evaluation of vaginal prolapse,

perform an examination to:

• assess and record the presence

and degree of prolapse of the

anterior, central and posterior vaginal

compartments of the pelvic floor, using

the POP‐Q (Pelvic Organ Prolapse

Quantification) system

• assess the activity of the pelvic floor


• assess for vaginal atrophy

• rule out a pelvic mass or other


1.6.4 For women with pelvic organ

prolapse, consider using a validated

pelvic floor symptom questionnaire to

aid assessment and decision making.

1.6.5 Do not routinely perform imaging

to document the presence of vaginal

prolapse if a prolapse is detected by

physical examination.

1.6.6 If the woman has symptoms of

prolapse that are not explained by

findings from a physical examination,

consider repeating the examination with

the woman standing or squatting, or at a

different time.

1.6.7 Consider investigating the following

symptoms in women with pelvic organ


• urinary symptoms that are

bothersome and for which surgical

intervention is an option

• symptoms of obstructed defaecation

or faecal incontinence (the NICE

guideline on faecal incontinence

in adults has recommendations

on baseline assessment of faecal


May 2019 / FUTURE MEDICINE / 81

• pain

• symptoms that are not explained by

examination findings.

1.7 Non-surgical management of

pelvic organ prolapse

1.7.1 Discuss management options with

women who have pelvic organ prolapse,

including no treatment, non-surgical

treatment and surgical options, taking

into account:

• the woman's preferences

• site of prolapse

• lifestyle factors

• comorbidities, including cognitive or

physical impairments

• age

• desire for childbearing

• previous abdominal or pelvic floor


• benefits and risks of individual


Lifestyle modification

1.7.2 Consider giving advice on lifestyle

to women with pelvic organ prolapse,

including information on:

• losing weight, if the woman has a

BMI greater than 30 kg/m2

• minimising heavy lifting

• preventing or treating constipation.

Topical oestrogen

1.7.3 Consider vaginal oestrogen for

women with pelvic organ prolapse

and signs of vaginal atrophy. For

recommendations on managing

urogenital atrophy, see managing shortterm

menopausal symptoms in the NICE

guideline on menopause.

1.7.4 Consider an oestrogen-releasing

ring for women with pelvic organ

prolapse and signs of vaginal atrophy

who have cognitive or physical

impairments that might make vaginal

oestrogen pessaries or creams difficult

to use.

Pelvic floor muscle training

1.7.5 Consider a programme of

supervised pelvic floor muscle training

for at least 16 weeks as a first option for

women with symptomatic POP‐Q (Pelvic

Organ Prolapse Quantification) stage 1

or stage 2 pelvic organ prolapse. If the

programme is beneficial, advise women

to continue pelvic floor muscle training



1.7.6 Consider a vaginal pessary for

women with symptomatic pelvic organ

prolapse, alone or in conjunction with

supervised pelvic floor muscle training.

1.7.7 Refer women who have chosen a

pessary to a urogynaecology service if

pessary care is not available locally.

1.7.8 Before starting pessary treatment:

• consider treating vaginal atrophy

with topical oestrogen

• explain that more than 1 pessary

fitting may be needed to find a

suitable pessary

• discuss the effect of different types

of pessary on sexual intercourse

• describe complications including

vaginal discharge, bleeding, difficulty

removing pessary and pessary


• explain that the pessary should

be removed at least once every 6

months to prevent serious pessary


1.7.9 Offer women using pessaries

an appointment in a pessary clinic

every 6 months if they are at risk of

complications, for example because

of a physical or cognitive impairment

that might make it difficult for them to

manage their ongoing pessary care.

1.8 Surgical management of pelvic

organ prolapse

There is public concern about the use

of mesh procedures. For all of the

procedures recommended in this section,

including mesh procedures, there is

some evidence of benefit, but limited

evidence on long-term effectiveness and

adverse effects. In particular, the true

prevalence of long-term complications is


1.8.1 Offer surgery for pelvic organ

prolapse to women whose symptoms

have not improved with or who have

declined non-surgical treatment.

1.8.2 If a woman is thinking about a

surgical procedure for pelvic organ

prolapse, use a decision aid (use the

NICE patient decision aids on surgery

for uterine prolapse and surgery for

vaginal vault prolapse where they apply)

to promote informed preference and

shared decision making. Discussion with

the woman should include:

• the different treatment options for

pelvic organ prolapse, including no

treatment or continued non-surgical


• the benefits and risks of each

surgical procedure, including changes

in urinary, bowel and sexual function

• the risk of recurrent prolapse

• the uncertainties about the longterm

adverse effects for all procedures,

particularly those involving the

implantation of mesh materials

• differences between procedures

in the type of anaesthesia, expected

length of hospital stay, surgical

incisions and expected recovery period

• the role of intraoperative prolapse

assessment in deciding the most

appropriate surgical procedure.

1.8.3 Do not offer surgery to prevent

incontinence in women having

surgery for prolapse who do not have


1.8.4 Explain to women considering

surgery for anterior or apical prolapse

who do not have incontinence that there

is a risk of developing postoperative

urinary incontinence and further

treatment may be needed.

1.8.5 If the woman's chosen procedure

for pelvic organ prolapse is not available

from the consulting surgeon, refer her to

an alternative surgeon.

1.8.6 If mesh is to be used in prolapse


• explain to the woman about the

type of mesh that will be used and

whether or not it is permanent

• ensure that details of the procedure

and its subsequent short- and longterm

outcomes are recorded in a

national registry (see collecting data

on surgery and surgical complications

in this guideline)

• give the woman written information

about the implant, including its name,

manufacturer, date of insertion, and

82 / FUTURE MEDICINE / May 2019

the implanting surgeon's name and

contact details.

1.8.7 Providers must ensure that data

on surgical procedures for pelvic organ

prolapse are recorded in a national

registry, as outlined in the section on

collecting data on surgery and surgical

complications in this guideline.

Surgery for uterine prolapse

1.8.8 Discuss the options for treatment

(see recommendation 1.8.2), including

non-surgical options, hysterectomy and

surgery that will preserve the uterus,

with women who have uterine prolapse.

1.8.9 For women considering surgery for

uterine prolapse:

• discuss the possible complications

and the lack of long-term evidence on

the effectiveness of the procedures

• use the NICE patient decision aid on

surgery for uterine prolapse to discuss

the benefits and risks of treatment,

including non-surgical options.

1.8.10 For women with uterine prolapse

who have no preference about

preserving their uterus, offer a choice of:

• vaginal hysterectomy, with or

without vaginal sacrospinous fixation

with sutures or

• vaginal sacrospinous hysteropexy

with sutures or

• Manchester repair.

Also include the option of sacrohysteropexy

with mesh (abdominal

or laparoscopic) in this choice but see

recommendation 1.8.6 for specific

guidance on the use of mesh in prolapse


1.8.11 For women with uterine prolapse

who wish to preserve their uterus, offer

a choice of:

• vaginal sacrospinous hysteropexy

with sutures or

• Manchester repair, unless the

woman may wish to have children in

the future.

Also include the option of sacrohysteropexy

with mesh (abdominal

or laparoscopic) in this choice but see

recommendation 1.8.6 for specific

guidance on the use of mesh in prolapse


1.8.12 If a synthetic polypropylene mesh

is inserted, the details of the procedure

and its subsequent short- and longterm

outcomes must be collected in a

national registry (see collecting data on

surgery and surgical complications in this


1.8.13 Ensure the proposed treatment

is reviewed by a regional MDT (see

recommendation 1.1.4) if the woman

wishes to have children in the future.

Surgery for vault prolapse

1.8.14 Discuss the options for treatment

(see recommendation 1.8.2), including

non-surgical and surgical options, with

women who have vault prolapse.

1.8.15 For women considering surgery for

vault prolapse:

• discuss the possible complications








and the lack of long-term evidence on

the effectiveness of the procedures

• use the NICE patient decision aid

on surgery for vaginal vault prolapse

to discuss the benefits and risks of

treatment, including non-surgical


1.8.16 Offer women with vault prolapse a

choice of:

• vaginal sacrospinous fixation with

sutures or

• sacrocolpopexy (abdominal or

laparoscopic) with mesh.

See recommendation 1.8.6 for

specific guidance on the use of mesh in

prolapse surgery.

1.8.17 If a synthetic polypropylene mesh

is inserted, the details of the procedure

and its subsequent short- and longterm

outcomes must be collected in a

national registry (see collecting data on

surgery and surgical complications in this


Colpocleisis for vault or uterine


1.8.18 Consider colpocleisis for women

with vault or uterine prolapse who do

not intend to have penetrative vaginal

sex and who have a physical condition

that may put them at increased

risk of operative and postoperative


Surgery for anterior prolapse

1.8.19 Discuss the options for treatment

(see recommendation 1.8.2), including

non-surgical and surgical options, with

women who have anterior prolapse.

1.8.20 Offer anterior repair without mesh

to women with anterior vaginal wall


1.8.21 Consider synthetic polypropylene

or biological mesh insertion for women

with recurrent anterior vaginal wall

prolapse only after:

• regional MDT review and

• discussion with the woman about

the risks of mesh insertion (see

recommendation 1.8.2)

and if:

• apical support is adequate or

• an abdominal approach is


See recommendation 1.8.6 for

specific guidance on the use of mesh in

prolapse surgery.

1.8.22 If a synthetic polypropylene or

biological mesh is inserted, the details

of the procedure and its subsequent

short- and long-term outcomes must

be collected in a national registry (see

collecting data on surgery and surgical

complications in this guideline).

Surgery for posterior prolapse

1.8.23 Offer posterior vaginal repair

without mesh to women with a posterior

vaginal wall prolapse.

Follow-up after surgery

1.8.24 Offer women a review 6 months

after surgery for pelvic organ prolapse.

May 2019 / FUTURE MEDICINE / 83

Ensure that the review includes a vaginal

examination and, if mesh was used,

check for mesh exposure.

1.8.25 Providers should ensure that

women who have had surgery for pelvic

organ prolapse have access to further

referral if they have recurrent symptoms

or suspected complications. See also

assessing complications associated with

mesh surgery in this guideline.

1.9 Surgery for women with both

stress urinary incontinence and

pelvic organ prolapse

1.9.1 Consider concurrent surgery for

stress urinary incontinence and pelvic

organ prolapse in women with anterior

and/or apical prolapse and stress urinary


1.9.2 When considering concurrent

surgery for stress urinary incontinence

and pelvic organ prolapse, discuss

the options for treatment (see

recommendations 1.5.1 and 1.8.2) and

explain to the woman:

• that there is uncertainty about

whether the combined procedure is

effective for treating stress urinary

incontinence beyond 1 year, and that

stress urinary incontinence might

persist despite surgery

• the risk of complications related

to having surgery for stress urinary

incontinence at the same time as

prolapse surgery compared with the

risk of complications related to having

sequential surgery.

1.10 Assessing complications

associated with mesh surgery

1.10.1 For women who report newonset

symptoms after having mesh

surgery for urinary incontinence or pelvic

organ prolapse, evaluate whether the

symptoms might be caused by a meshrelated

complication. These symptoms

could include:

• pain or sensory change in the back,

abdomen, vagina, pelvis, leg, groin or

perineum that is:

• either unprovoked, or provoked

by movement or sexual activity and

• either generalised, or in the

distribution of a specific nerve, such as

the obturator nerve

• vaginal problems including

discharge, bleeding, painful sexual

intercourse, or penile trauma or pain in

sexual partners

• urinary problems including recurrent

infection, incontinence, retention, or

difficulty or pain during voiding

• bowel problems including difficulty

or pain on defaecation, faecal

incontinence, rectal bleeding or

passage of mucus

• symptoms of infection, either alone

or in combination with any of the

symptoms outlined above.

1.10.2 Refer women with a suspected

mesh-related complication to a






urogynaecologist, urologist or colorectal

surgeon for specialist assessment.

1.10.3 For women who are referred for

specialist evaluation of a suspected

mesh complication:

• take a history of all past surgical

procedures for prolapse or

incontinence using mesh, including the

dates, type of mesh and site of mesh

placement and the relationship of the

symptoms to the surgical procedure(s)

• consider using a validated pelvic

floor symptom questionnaire and a

pain questionnaire to aid assessment

and decision making

• perform a vaginal examination to:

• assess whether mesh is palpable,

exposed or extruded

• localise pain and its anatomical

relationship to mesh

• consider performing a rectal

examination, if indicated, to assess for

the presence of mesh perforation or


• consider performing a neurological

assessment to assess the distribution

of pain, if present, sensory alteration or

muscle weakness.

1.10.4 For women with a confirmed

mesh-related complication or

unexplained symptoms after a mesh


• refer to a consultant at a regional

centre specialising in the diagnosis

and management of mesh-related

complications or

• if the woman has a vaginal exposure

of mesh that is smaller than 1 cm 2

and no other symptoms, follow

recommendations 1.11.3 and 1.11.4 in

this guideline.

1.10.5 The responsible consultant should

develop an individualised investigation

plan for each woman with suspected or

confirmed mesh-related complications,

involving other members of the regional

MDT if needed, and use table 1 in this

guideline to inform decisions on possible


1.10.6 The responsible consultant must

ensure that details of any confirmed

mesh-related complications are:

• recorded in a national registry (see

the section on collecting data on

surgery and surgical complications in

this guideline) and

• reported to the Medicines and

Healthcare products Regulatory

Agency (MHRA).

1.11 Managing complications

associated with mesh surgery

General considerations before

removing mesh

1.11.1 If a woman who has had a mesh

procedure to treat urinary incontinence

or pelvic organ prolapse is thinking

about having the mesh removed, discuss

the decision with her and with a regional


1.11.2 When discussing surgery to

remove mesh, explain to the woman


• there is limited evidence on the

benefits of partial or complete removal

compared with no mesh removal

• surgery to remove mesh can have

significant complications including

organ injury, worsening pain, and

84 / FUTURE MEDICINE / May 2019


Investigation Type of mesh Indications Benefits and risks

Examination under


All types of mesh.

Pain or suspected:

• vaginal or rectal exposure or


• sinus tract, urinary or bowel fistula.

Cystourethroscopy All types of mesh. Suspected:

• urethral perforation

• bladder perforation

• fistula

• calculus on suture or mesh material.



MRI, protocolled and

reported by a clinician

with experience in

interpreting mesh


Ultrasound scan


transvaginal or

translabial, or 3D),

performed and

reported by a clinician

with experience in

interpreting mesh



Fluoroscopic studies

(cystography or contrast


Urinary flow studies

and post-void residual

volume assessment or



including nerve

conduction studies


laparoscopically or

vaginally placed

mesh for pelvic organ


Abdominally or

laparoscopically placed

mesh for pelvic organ


All types of mesh.

Vaginally placed mesh

to treat incontinence.

All types of mesh,

although CT is not

commonly used to

show implanted


Suspected bowel perforation by


• Pain.

• Suspected bowel entrapment

around mesh.

• Suspected adhesions secondary to

mesh placement.

Suspected mesh infection.

Anatomical mapping of suspected


Anatomical mapping and mesh

localisation to guide further surgery.

Back pain following abdominal mesh

placement with mesh attachment to

sacral promontory.

Identification of discitis or



Voiding dysfunction.

Suspected infection.

Suspected urethral mesh perforation.

Anatomical mapping to guide excision



urinary tract injury

bowel injury

bowel obstruction.


Allows diagnosis when not revealed by awake

examination or when an awake, examination

is not tolerated.


Anaesthetic risk.


• Allows diagnosis by direct visualisation.

• Aids management planning.


Anaesthetic risk and risk of urinary tract



• Allows diagnosis by direct visualisation.

• Aids management planning.


• Anaesthetic risk if carried out under


• Risk of bowel perforation.


• Allows diagnosis by direct visualisation.

• Aids management planning.


• Anaesthetic risk.

• Risks of laparoscopy, including bowel injury.


Shows implanted material and complications


Shows location of mesh in relation to the

vaginal wall and sacrum.


Generally regarded as safe, with a low risk of

short- and long-term harms. Risk of contrast

media injection.


Shows implanted material and local


Identifies mid-urethral slings.

Shows location of mesh in relation to the

vaginal wall and urethra.




May be useful in assessing for urinary fistulae

or bowel injury.


Potential radiation-related harms and risk of

contrast media injection.

All types of mesh. Suspected urinary or bowel fistula. Benefits

Aids management planning.


Potential radiation-related harms.

All types of mesh.

Voiding dysfunction.

Urinary incontinence.


Aids management planning.


Urinary tract infection and radiation risks if

fluoroscopy is used.

All types of mesh. Suspected nerve injury. Benefits

Allows diagnosis of impaired nerve function.


Nerve conduction studies are difficult to

perform and can induce more pain.

* Perform with water-soluble contrast media. Fluoroscopic studies and CT may be used according to local preference and expertise.

May 2019 / FUTURE MEDICINE / 85

urinary, bowel and sexual dysfunction

• it is not certain that removing the

mesh will relieve symptoms

• it might not be possible to remove

all of the mesh

• removing only part of the mesh

might be just as effective at improving

symptoms as removing all of it

• urinary incontinence or prolapse

can recur after the mesh has been


Managing vaginal complications

1.11.3 Discuss non-surgical treatment

with topical oestrogen cream with

women who have a single area of

vaginal mesh exposure that is smaller

than 1 cm 2 .

1.11.4 Offer a follow‐up appointment

within 3 months to women with vaginal

mesh exposure who choose treatment

with topical oestrogen cream.

1.11.5 Consider partial or complete

surgical removal of the vaginal portion of

mesh for women:

• who do not wish to have treatment

with topical oestrogen or

• if the area of vaginal mesh sling

exposure is 1 cm 2 or larger or

• if there is vaginal mesh extrusion or

• if there has been no response to

non-surgical treatment after a period

of 3 months.

1.11.6 Offer imaging and further

treatment to women who have signs

of infection in addition to vaginal mesh

exposure or extrusion.

1.11.7 Discuss with women who have

vaginal complications after mesh sling

surgery for stress urinary incontinence


• complete removal of the vaginal

portion of mesh sling is associated

with a greater risk of recurrence of

stress urinary incontinence than partial


• partial removal is associated with

a higher rate of further mesh sling


• complete removal might not be


1.11.8 Explain to women who have

vaginal complications after vaginally

placed mesh for pelvic organ

prolapse that:

• complete removal might not be


• complete removal has a higher risk

of urinary tract or bowel injury than

partial removal

• there may be a risk of recurrent


1.11.9 Explain to women who have

vaginal complications after abdominally

placed mesh for pelvic organ prolapse


• removal is associated with a risk of

urinary tract and bowel injury

• there is a risk of recurrent prolapse

• they might need abdominal surgery

to remove the mesh

• complete removal might not be


1.11.10 For women who have pain or

painful sexual intercourse suspected to

be related to previous mesh surgery:

• if specialist assessment indicates

a mesh-related complication, seek

advice from a regional MDT

• if assessment and investigation do

not show a mesh abnormality such

as vaginal extrusion or exposure, or

an infection, consider non-surgical

treatments such as pain management,

vaginal oestrogen, dilators, counselling

(including psychosexual counselling)

and physiotherapy

• if pain does not respond to initial

management, seek advice from a

regional MDT.

Managing urinary complications

1.11.11 Refer women who have mesh

perforating the lower urinary tract to a

centre for mesh complications for further

assessment or management. 1.11.12

For women with urinary symptoms

after mesh surgery for stress urinary

incontinence or pelvic organ prolapse

who are considering mesh removal

surgery, explain that:

• urinary symptoms might not improve

and new symptoms might occur after

complete or partial removal of the


• stress urinary incontinence might

recur after mesh removal, and the

risk of this happening is higher with

complete than with partial mesh


• complete removal of the mesh might

not be possible

• further treatment might be needed

for mesh complications, or recurrent or

persistent urinary symptoms

• there is a risk of adverse events such

as urinary tract fistula.

1.11.13 Discuss division of mesh sling with

women who have voiding difficulty after

mesh sling surgery.

1.11.14 Refer women considering excision

of mesh sling for persistent voiding

dysfunction to a centre specialising

in the diagnosis and management

of mesh-related complications for

assessment and management.

1.11.15 For women considering surgery

to alleviate voiding symptoms caused by

mesh surgery, explain that:

• the risk of recurrent stress urinary

incontinence is higher after mesh

excision than mesh division

• further surgery might be needed.

Managing bowel symptoms

1.11.16 For women who present with

functional bowel disorders after mesh

surgery for pelvic organ prolapse, follow

the recommendations in the NICE

guideline on faecal incontinence in adults

for women with faecal incontinence or

locally agreed protocols for women with

obstructed defecation.

1.11.17 For women with bowel

complications that are directly related

to mesh placement, such as erosion,

stricture or fistula, discuss treatment

with a regional MDT that has expertise

in complex pelvic floor dysfunction

and mesh-related problems. Use this

discussion to formulate an individualised

treatment plan with the woman.

1.11.18 Explain to women with bowel

complications directly related to mesh

placement that:

• complete removal might not be


• bowel symptoms might persist or

recur after mesh removal

• they might need a temporary or

permanent stoma after mesh


86 / FUTURE MEDICINE / May 2019

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7th Intl meet on rare diseases

puts India in focus

Experts highlight the importance of investigating the genetic disorders

which are largely left undiagnosed

India is home to an estimated

70 million people affected by

undiagnosed or rare diseases. Of

these, most are carriers of some

genetic disorder or the other. With

the advent of the latest sequencing,

newborn screening and other

technologies, a few genetic disorders

such as Down’s syndrome, beta

thalassemia and sickle cell anaemia

etc. are being well tracked and have

been found to be on the rise. Recent

estimates show that at least 21,400

children are born every year in India

with Down’s syndrome and another

9,000 to 10,000 children with

thalassemia. While these diseases

remain inadequately addressed as the

patients often do not recognize the

symptoms, the country’s problems







with rare and undiagnosed diseases

continue to be worrying as there aren’t

enough trained clinicians to detect

and diagnose them. So, it is anyone’s

guess as to how bad the scenario is

in a country of 1.2 billion population

with widely varied communities and

subgroups carrying different genetic

profiles and, potentially, an array of

known and unknown genetic mutations.

Not surprisingly, every year,

thousands of men, women and children

face uncertainty when healthcare

providers are unable to discover the

cause for their symptoms. In India, with

its low awareness of such diseases,

a large number of patients are left

with no treatment and succumb to

their condition. To make it worse, drug

researchers and the industry often

neglect such diseases even if they are

diagnosed, as the market size for such

rare disorders are either not estimated

or comparatively much smaller.

The message at the 7th International

Conference on ‘Rare and Undiagnosed

Diseases: Addressing Patient Needs

90 / FUTURE MEDICINE / May 2019

in India’ was loud and clear — to

make these relevant. The three-day

event organised in Delhi in April

by Undiagnosed Disease Network

International (UDNI), Institute of Medical

Genetics & Genomics at Sir Ganga

Ram Hospital, Wilhelm Foundation,

Organisation of Rare Diseases India

(ORDI) and Institute of Genomics

& Integrative Biology (IGIB) of CSIR

called for the best and most effective

collaborative efforts both nationally and

internationally to share such experiences

and find the way forward to solve and

help patients with such conditions.

“In India, the scenario is more

complex as the volume is enormous and

it has many communities and different

subgroups. Because we don’t have

the frequency of variance of each of

the subgroups, it becomes much more

difficult to diagnose new diseases,” said

William A Gahl from National Human

Genome Research Institute at the NIH,


Dr Gahl, who is also the Director at

NIH Undiagnosed Diseases Programme,

added that most of the rare and

undiagnosed diseases have got some

or other link with the genetic base. “We

have seen at the NIH itself about 1,200

to 1,250 patients and made some 320

diagnosis. We have discovered about 25

new diseases in the last ten years where

a gene is associated with a particular

phenotype of presentation.”

According to Dr I C Verma, advisor

and key member of the scientific

committee of the Conference, the

main message of the 7th International

Conference is that it is worth

investigating the cause of rare and

undiagnosed disorders, as this has

been made easier by the application

of massively parallel sequencing


“Knowing the diagnosis, one

proceeds to finding a treatment, which

is the main concern of the patient and

the family. Not knowing the diagnosis is

very frustrating,” quipped Dr Verma.

“Contrary to usual thinking, rare and

undiagnosed disorders affect a fairly

large number of people in India,” added

In India, the scenario is more

complex as the volume is

enormous and it has many

communities and different


Dr William A Gahl

Director, NIH Undiagnosed Diseases


Verma, Advisor & Senior Consultant and

Professor of Medical Genetics at Institute

of Medical Genetics and Genomics, Sir

Ganga Ram Hospital, while talking to

Future Medicine in a post-conference


Attended by some 370 registered

delegates, including practicing

clinicians, students and researchers,

the Conference was immensely rich in

content with about 60 speakers from

across the world sharing their case

studies, experiments, ideas and vision.

“One of the key objectives

ofconferring here was to communicate

to our Indian colleagues and medical

students about patients suffering from

undiagnosed diseases,” said Dr Ratna

Dua Puri, organizing chairperson of the

Conference, in an interview with Future


She added: “With a lot of the latest

May 2019 / FUTURE MEDICINE / 91

sequencing facilities now available

in the country and a fair number of

clinical geneticists able to do deep

phenotyping, we are able to help many

patients. But, despite all these, there

are still several cohorts with genetic

disorders left undiagnosed. So, it is

important to collaborate with colleagues

and link the work done here as well as

at other places and take the initiative

as a community. This was the other

main aim of this conference held in

partnership with Undiagnosed Disease

Network International.”

This kind of conferences are also

a wake-up call for countries like India,

where genetic and metabolic disorders

are usually diagnosed with poor


“On this front, the major challenges

in India at present include the small

number of trained clinicians specialising

in diagnosing and counselling genetic

disorders, the few state-funded

diagnostic and research laboratories, a

lack of funding for genetic diagnostic

tests and less accessibility for therapies

and other interventions,” said Dr

Meenakshi Bhat, Senior Consultant in

Clinical Genetics at Centre for Human

Genetics at Indira Gandhi Institute of

Child Health, Bangalore.

According to Dr Seema Kapoor,

in-charge of Genetics and Metabolism

Division of Maulana Azad Medical

College, New Delhi, though India has

achieved significant milestones towards

tracking genetic disorders through

It is worth investigating the

cause of rare and undiagnosed

disorders, as this has been

made easier by the application

of massively parallel sequencing


Dr I C Verma

Advisor and key member,

Scientific Committee

several government funded initiatives,

including newborn screening for many

congenital diseases since 2013, the

challenges that still invite discussion

are the feasibility of coverage in less

developed areas, hilly terrains and home


“Besides, the availability of good

counsellors and a well-integrated followup

system needs to be developed,” she


However, there is light at the end

of the tunnel. Among others, one of

the most recent collaborative research

programmes—The Genomics for

Understanding Rare Diseases: India

Alliance Network (GUaRDIAN) initiated

by the IGIB, has undertaken whole

exome and genome sequencing for

identification of variants and genes

implicated in rare genetic diseases.

“Using Mitochondrial rare genetic

disease examples, we will be able

to share our experiences from the

GUaRDIAN consortium where we

apply genome sequencing followed by

computational analysis and zebrafish

disease modelling to solve several

cases of undiagnosed diseases,” said Dr

Sridhar Sivasubbu, Principal Scientist at


No doubt, only collaborative models

will work in such a complex task of

diagnosing unknown diseases to find

treatments for them. Dr Gahl concludes

that since the first meeting of the UDNI

in Rome in 2014, there have been six

international meetings, culminating in

the 2019 conference in Delhi. In the

past five years, over a dozen countries

have established Undiagnosed Disease

Programmes and the Network has

created several common platforms to

share experiences, information and

views. The main focus of the Network

involves sharing of genotypic and

phenotypic data and best practices.

And this, amongst others, can

ultimately help advance the diagnosis

and care of rare and undiagnosed


92 / FUTURE MEDICINE / May 2019


Cahocon 2019 highlights need for

patient safety

5th edition of CAHO conference explores ways and means to minimize medical errors


The quality of service provided

by healthcare providers and

the related issue of patient

safety is a major concern of hospital

managements around the country.

Mistakes in the treatment and

healthcare services can not only affect

the well-being of individual patients

and their families but also create a trust

deficit between the healthcare provider

and the service consumers.

To discuss these questions and

to seek ways and means to minimize

errors at various levels, senior

management executives of leading

Indian hospitals got together in

Mumbai at the 5th national conference

of CAHO (Consortium of Accredited

Healthcare Organizations). These are

hospitals and healthcare organisations

that have obtained an accreditation

from the NABH (National Board of

Accreditation of Hospitals), a quasiofficial

certification body functioning

under the aegis of the Quality Council

of India (QCI).

The NABH, which was established

in 2005-06, offers accreditation at

two levels: An entry-level certificate

and full-accreditation. The entry level

certification was instituted along the

way when NABH leaders realised that

many hospitals were unable to meet

With accreditation, though it

has a cost attached to it, there

is an element of discipline

in the healthcare. This has

resulted in patient safety and

better treatment outcome


Dr Rajesndra Patankar

Chief Operating Officer

Nanavati Super Specialty Hospital

94 / FUTURE MEDICINE / May 2019

the criteria for full-accreditation at the


Discussing the healthcare scenario

before the accreditation system was

set up in India, Air Marshal (Dr) Pawan

Kapoor, vice chairman, RUS Education

and vice chancellor, Lincoln American

University stated that awareness of

quality issues in healthcare arose

when Consumer Protection Act 1986

was made applicable to doctors and

hospitals. Till then, mistakes and

mishaps involving clinicians were

carefully hidden with the express

purpose of protecting healthcare

practitioners from being blamed for

patient death or injury.

At present, about 600 large and

medium healthcare institutions, along

with about 218 small hospitals, have

been able to obtain the entry-level

certification from NABH, Air Marshal

Kapoor said. He also provided extensive

statistical data on improvements

recorded in accredited hospitals in

terms of fewer mistakes, better patient

outcomes and so on.

A highlight of the recent CAHO

conference was the launch of entry

level certification by the National

Accreditation Board for Laboratories

(NABL), which is a sister organization

of NABH. Currently, about 1,100

pathology labs have obtained the full

accreditation from NABL, which is

a really small number compared with

the total of about 50,000 to

80,000 laboratories present inall

over the country.

The NABL has not only launched

a number of schemes to enable small

laboratories to join the accreditation

system, but is also getting ready to

include the hundreds of radiology and

imaging laboratories under its ambit.

Dwelling on the impact of

The time has come to

have an accountability

on healthcare delivery

standards and accredit

healthcare organizations

based on the quality of

healthcare they provide to


Dr Aparna Jairam

Founder & Director

Asavalee Dr Aparna's Pathology

Laboratory and Co-organising

Secretary CAHOCon-2019

errors in patient care, Dr Krishnan

Sankaranayaranan, Patient Safety

Officer, with Tawam Hospital in

Abu Dhabi, pointed out that the

healthcare workers responsible for a

serious error wasare often impacted

almost as severely as the patient

concerned. In international literature,

this is being described as “becoming

the second victim”, the first victim

of the mistake being the affected


Dr Krishnan emphasized that the

second victim could suffer severe

depression and even denial of the

responsibility, and later self-doubt and

a loss of self-confidence. There have

been many instances where such a

healthcare professional might move

to a less stressful department in the

hospital, or in extreme cases move

away from the healthcare profession

completely, he said.

Dr Sanjay Oak, who has held a

number of top positions in public

health and education, including

that of vice chancellor of D Y Patil

University, Navi Mumbai, pointed out

that there were several gaps in the

way medical education was imparted

in most medical colleges. He said

there was an urgent need for modern

teaching methods, including simulation

modules, that could allow the students

to appreciate both the structure

and the functioning of the human

body without endangering an actual

human being.

May 2019 / FUTURE MEDICINE / 95


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2019 Nextgen genomics biology,

bioinformatics and technologies



The announced dates of the conferences may change

96 / FUTURE MEDICINE / May 2019





Advisor & Senior Consultant, Institute of Medical Genetics, Sir Ganga Ram Hospital, New Delhi

The age of genomic medicine is upon us and

we are rapidly moving into the era of precision

medicine. Young clinicians should spend time to

understand this technology and learn to interpret the


Catching this technology at an early age will also

help them significantly contribute to the society

by helping patients who suffer from rare and yet

undiagnosed diseases.

Addressing the medical needs of such patients is

one of the key responsibilities of the advanced medical

world of today. But, unfortunately, this hasn’t yet got

due attention from the young and emerging clinicians

here, unlike in the West.

In the western world, the need for addressing

rare and undiagnosed diseases, which are mostly

connected with genetic causes, has got serious

attention from the clinician community, especially the

young who are keen to devote time for research. This

is not only satisfying intellectually, but also translates

into financial gains if a new therapy is discovered.

Genetics and genomic studies have a lot more to

do in order to address rare and undiagnosed diseases.

But, sadly the current medical curriculum in India is

not geared to prepare students to understand or apply

genomics in healthcare.

In the UK, they are carrying out genomic studies

in 100,000 people at present, while in the US it

is an extensive study in about 1 million people,

to understand the interplay of genetics and the

environment to cause diseases.

Understanding this would lead to the development

of novel and precise preventive, therapeutic and

curative approaches. Moving a step ahead, the UK has

already announced that genomics will henceforth be a

part and parcel of national health services.

The younger generation in this profession, if

equipped with new and emerging technologies, can

contribute to the critical needs of patients who have

genetic as well as currently incurable diseases.

Precision medicine — the concept of tailoring the

medicine to the genetic as well as environmental

attributes of the patient —is the future. Be prepared

for it and apply it in your practice today.

— As told to CH Unnikrishnan

98 / FUTURE MEDICINE / May 2019

Sep 30 th - Oct 2 nd , 2019 - Mumbai, India


Early bird ends on

15 th June, 2019

Abstract submission

ends on 1 st July, 2019

NextGen Genomics, Biology, Bioinformatics and Technologies (NGBT) Conference is an international

meeting organized by SciGenom Research Foundation (SGRF), a not-for-profit organization working to

promote Science, Research and Education in India and rest of Asia.


• Learn about cutting edge developments in

genomics, biology, bioinformatics, drug

discovery, plant and animal sciences

• Network with scientists of global repute

• Meet national and international genomics,

biology and technology companies

• Interact with leaders from drug industry

• Explore collaboration opportunities

• Scholarship opportunities for students to support

their participation at the meeting


• Genomics technologies

• Population genomics

• Clinical/Medical genomics

• NIPT/Liquid biopsy

• Precision (personalized) medicine

• Cancer genomics


• Gene editing

• Signal transduction

• Cancer immunology

• Biomarkers

• Drug discovery

• Metagenomics

• Plant genomics/sciences

• Agriculture genomics/sciences

• Veterinary genomics/sciences

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+91- 8374 27 4074






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