Onchocerciasis - An Overview - Amrita Institute of Medical Sciences ...

Amrita Journal of MedicineVol. 8, No: 2July - Dec 2012. Page 1 - 44REview ARTICLEOnchocerciasis - An OverviewB. RanganathanAbstractOnchocerciasis, a helminth infection shows a disproportionately large prevalence in low-income, West and Central African nations whereit is one of the chief causes of avoidable blindness. The loss of productivity due to young, able-bodied people leaving their fertile farmlandfor the fear of contracting the disease leads to famine and poverty which, in turn, impede access to eye care and other medical servicesin these regions of the world. An attempt is made through this article to facilitate better understanding of the disease and its treatment aswell as to give an overview of some of the steps taken in controlling this endemic condition.Key words: Onchocerciasis, helminths, nodules, ivermectin, doxycyclineINTRODUCTIONA Neglected Tropical Disease(NTD) caused by the parasite Onchocercavolvulus; onchocerciasistrails only trachoma as an infectiouscause of blindness worldwide. Thecausative filarial roundworm is almostexclusively a parasite of manand is transmitted through infectedblackflies belonging to the genusSimulium. Onchocerciasis is alsocalled “river blindness” because theinsect vector that transmits the infectionthrives in fertile riverside areasthat most often remain uninhabitedfor the fear of infection, which, ifcontracted, can potentially lead toblindness.(generally more than three months)to blackflies. According to estimatesof the expert committee of the WorldHealth Organization (WHO), 37 millionpeople are infected and another100-120 million reside in areas thatput them at risk of infection. Furtherputting things into perspective, about800,000 people have visual impairmentand 270,000 people are blind 1 .BiologyThe life cycle of the causal nematodeis illustrated in Figure 1. Someinteresting aspects of the life cycleinclude the adult worms residing inthe subcutaneous nodules for upto15 years, the female worms beinglarger than their male counterpartsand capable of producing microfilariaefor approximately 9 years, theunsheathed circulating microfilariaehaving a life span of 2 years subsequentto which they develop intofirst-stage (L1) and finally into thethird-stage infective larvae (L3) overa period of about 2 weeks inside thebody of the blackfly which ingestFigure 1: Onchocerca volvulus life cycle (Adapted from http://www.dpd.cdc.gov/dpdx)Epidemiology & Risk FactorsAs a public health problem, onchocerciasisis locally transmitted inthirty countries of Africa (where about99% of the infected people live),thirteen foci located in six countriesin the Americas (Brazil, Colombia,Ecuador, Guatemala, Mexico andVenezuela) and in Yemen in theMiddle East 1 . As the disease, unlikemalaria, requires repeated bites ofinfected blackflies, the risk of infectionis negligible in casual travelersto these places but is significantlyenhanced in missionaries, PeaceCorps and other long-term volunteerssusceptible to sustained exposureDept. of Pharmaceutical Chemistry, AIMS, Kochi.5

Amrita Journal of Medicinethe microfilariae during a bloodmeal from an infectedindividual.Clinical ManifestationsIt is the larvae (microfilariae) that cause most of theonchocerciasis symptoms in affected individuals. Sincethe larvae can migrate through the human body withoutprovoking an immune response, some onchocercainfectedpeople maybe without symptoms. Those withsymptoms will be characterized by one or more of thefollowing: typically itchy skin rashes, nodules underthe skin that provide a secure microenvironment forthe worms (skin manifestations) and vision changes(eye manifestations). A rather uncommon symptom isthe non-painful swelling of lymph glands.The intense and relentless itching, a subcutaneousinflammatory response to the dying microfilariae, resultsin dermatitis and the skin becoming swollen andchronically thickened, a condition called “lizard skin”.Additionally, the loss of elastic tissue in the skin givesit a “cigarette-paper” appearance. Over time, the skinmay take up an appearance commonly referred to as“leopard skin” wherein it loses some of its pigments, andon dark skin the features resemble the skin of a leopard 2 .Some microfilariae migrate to the eye - where they canbe found in all the internal tissues, except the lens - anddie there causing severe inflammation, bleeding andscarring. This initially results in reversible lesions mainlyon the cornea that progresses to permanent clouding ofthe cornea without proper treatment, ultimately resultingin blindness 3 . There can also be an inflammatoryevent in the optic nerve, primarily impairing peripheralvision, which, in turn progresses to full-blown blindness,if left untreated.DiagnosisThe most definitive diagnosis procedure involves theexamination for microfilariae in skin snip biopsies 4 . Typicallysix 1-2 mg shavings of the skin from different partsof the body are incubated in physiological saline solutionfor 24 hours upon which larvae promptly emergefrom the skin and can be microscopically visualized.Although this is a highly specific procedure and is consideredthe gold standard for diagnosing the infection,it lacks adequate sensitivity in low-intensity infections.In such cases, a polymerase chain reaction (PCR) of theskin snip can increase the sensitivity. However, thistechnology has yet to be commercialized.In patients with nodules in the skin, performing nodulectomyallows for identification of the microfilariae inthe tissue 4 . For epidemiological surveys, a non-invasiveprocedure - palpation for nodules - is employed. As acautionary note, this diagnostic aid must be judged agedependently:the proportion of palpable nodules is verylow in children, increases to about 30% in 10-year oldsand plateaus at about 40% in aged people 5 .In the optic manifestations of the infection, a slit-lampexamination of the anterior part of the eye can helpvisualize the larvae or the lesions they have caused 4 . Afew highly sensitive antibody tests have been developedfor diagnosing filarial infections in general. These testspromptly detect exposure of an individual to filaria butthey suffer from two main drawbacks viz. their lack ofspecificity in pinpointing the type of filarial infectionand their inability in determining past versus currentinfections 6 . More recently, several onchocerca-specificserological tests have been developed such as the OV-16antigen antibody test and the OV luciferase immunoprecipitationsystem (LIPS). However, these assays arecurrently only available in the research setting, are noteconomically viable in the mass-scale scenario requiredto address such infections and more importantly, are notyet approved as diagnostic tools.TREATMENTIt is desirable to initiate treatment for people whoare definitively diagnosed with onchocerciasis beforeit proceeds to cause debilitating and disfiguring skindisease, long-term pruritis and blindness. Before embarkingon therapy, however, it is common practiceto confirm co-infection with Loa loa, another filarialparasite endemic to the same regions as O. volvulus,as this helminth can be responsible for the severe sideeffects to the medications used to treat onchocerciasis.Standard TherapyWith the introduction of the broad-spectrumantiparasitic agent ivermectin by Merck in the mid-1980s, traditional anthelmintic drugs like suramin(characterized by multiple systemic toxicities) anddiethylcarbamazine (DEC which apparently acceleratesonchocercal blindness) have gradually run out of favourin treating o. volvulus infection. Apart from being thefirst safe and effective treatment for onchocerciasis,under the brand name Mectizan®, ivermectin is extensivelyused in veterinary practice in the United States(Stromectol®), Europe (Ivomec®) and in many othercountries for the control of endo- and ectoparasites indomestic animals 7 .Ivermectin: ChemistryCommercial ivermectin, the drug of choice foronchocerciasis, is a 4:1 mixture of semisynthetic hydrogenatedavermectins B1a and B1b which are membersof a family of structurally complex antibiotics producedby fermentation of a strain of Streptomyces avermitilis.The structure (Figure 2), established by a combination6

Amrita Journal of MedicineOnchocerciasis - An Overviewof spectroscopic and x-ray crystallographic techniques,comprises a pentacyclic 16-membered macrocycle asthe aglycone linked to a disaccharide made of twooleandrose sugar residues 8 . The two components of themixture differ only by one carbon atom with B1a beinga higher homologue of B1b.Figure 2: Structure of ivermectinMode of ActionIvermectin destroys the larvae (microfilariae) that areresponsible for the skin as well as the eye manifestationsof the infection. Although it does not kill the adult worms(macrofilariae), it does sterilize the females and preventsthe release of microfilariae from the adult females residinginside the human host. Pharmacologically, the drugbinds and activates glutamate-gated chloride channels(GluCls) - invertebrate-specific members of the ligandgatedion channel (LGIC) family - inducing a tonicparalysis of the nematode musculature. Stimulation ofthe release of the inhibitory neurotransmitter gammaaminobutyricacid (GABA) in the nervous system of theworm is also attributed as another molecular mode ofaction 9 .PharmacokineticsIvermectin is usually administered orally as tabletswherein it exhibits good absorption 10 . Injections arealso available although the mass-scale administrationbefitting an endemic infection precludes the parenteralroute as a viable option. It is unable to cross themammalian blood-brain barrier (BBB) due to P-glycoprotein-mediatedefflux 11 . It is metabolized by hepaticCYP450, primarily by CYP3A4 isoform, into at least tenhydroxylated and demethylated products 10 .Side Effects & ContraindicationsTreatment with ivermectin in humans has no majorside effects; the itching becomes more pronouncedwith therapy because of the death of the microfilariaebut this is not accompanied by worsening of the eyesymptoms. As alluded to earlier, people co-infectedwith loaiasis exhibit encephalitic reaction to ivermectintreatment which can be fatal. The drug is contraindicatedin children under five, or those who weigh less than15 kg. Clinical evidence of ivermectin therapy inpregnant women suggests that the risk of blindnessoutweighs the risk of ivermectin exposure after the firsttrimester with no detectable evidence of congenital abnormalitiesin children of ivermectin-treated mothers 12 .Evolving TherapyUse and safety of doxycycline - a well-establishedsemisynthetic member of the tetracycline group of antibiotics,introduced in the late-1960s by Pfizer - has beenreported in field trials 13 conducted in the mid-2000s forcontaining onchocerciasis. It destroys the endosymbioticricketssia-like Wolbachia bacteria crucial for theembryogenesis of o. volvulus that are resident in thereproductive tracts of the filarial nematodes 14 , therebymaking the worms sterile and consequently reducing thetransmission of the infection. A six-week oral regimen ofdoxycycline sterilizes 80-90% of the females 20 monthsafter treatment and almost completely eliminates therelease of microfilariae 15 .Since doxycycline does not kill the microfilariae,treatment with ivermectin should be given several daysprior to doxycycline therapy in order to provide symptomrelief to the patient 16 . Sufficient clinical data is notyet available to objectively comment on the safety ofsimultaneous treatment of onchocerciasis with these twoagents. As the mild side effects of ivermectin therapy areattributed to the increased death of the microfilariae anddoxycycline does not lead to the death of the larvae,the side effect profile of doxycycline parallels its profilewhen used conventionally as an antibacterial. Accordingto available data 17 , doxycycline administration inonchocerciasis patients co-infected with Loa loa is consideredsafe when the counts of the latter microfilariaein such individuals is less than 8000/ml. Doxyxcyclineis contraindicated in children under nine years of age,in pregnant and lactating women 18 .7

Amrita Journal of MedicineTable 1: Treatment regimens for Onchocerca volvulus infectionsDrug Adult Dose Pediatric DoseIvermectinDoxycycline150 μg/kg PO in one dose every 6months for 15 years200 mg PO daily for 6 weeks150 μg/kg PO in one dose every 6months for 15 years200 mg PO daily for 6 weeksThe typical dosage and duration of treatment usingthese agents is summarized in Table 1. It is importantto note that doxycycline is not standard therapy and itsapplication depends upon the opinion of the doctorin prescribing it as a treatment option. If the patientis unable to tolerate 200 mg of oral doxycycline dailythat is required to kill adult worms, 100 mg PO daily issufficient to sterilize female nematodes.PREVENTION & CONTROLThere are no vaccines or medications to preventgetting infected with o. volvulus. Personal protectionmeasures against insect bites are the only preventionefforts one can take to avoid the infection. These includewearing full-sleeve shirts and long pants duringthe day when blackflies bite, applying a spray or lotionof 30-50% of N,N-Diethyl-meta-toluamide (DEET) onexposed skin and wearing permethrin-treated clothing.Large-scale onchocerciasis control measures havebeen initiated and successfully operating for morethan three decades. Beginning in 1974, onchocerciasiscontrol program (OCP) for effective vector controlwas implemented in West Africa. With the availabilityof the inexpensive ivermectin (Mectizan®), MectizanDonation Program (MDP) was established in 1987to oversee Merck’s donation of the drug for effectivecontrol of onchocerciasis to needy communities worldwide.The enormous success of this program resultedin a partnership of GlaxoSmithKline with Merck whichsubsequently included elimination of lymphatic filariasiswithin the mandate of the MDP and began donatingalbendazole along with ivermectin. In 1992, a Non-Governmental Development Organization (NGDO)Coordination Group for onchocerciasis control wasformed under the supervision of WHO to promoteworldwide interest in and garner support for the use ofivermectin in endemic countries to eliminate this publichealth menace.Under the aegis of WHO, African Program for OnchocerciasisControl (APOC) was set up in 1995 witha goal of eliminating onchocerciasis as a disease ofpublic health importance in Africa. Community-DirectedTreatment with Ivermectin (CDTI) involving active communityparticipation is at the core of APOC’s strategywith over one million Community Directed Distributors(CDDs) delivering over half a billion treatments in morethan 146,000 African communities since the inceptionof the program. This strategy has been so popular andeffective that it is now being extended to include deliveryof other health interventions.The Carter Centre, a NGDO, has since 1996, assistednational Ministries of Health in eleven African andSouth/Central American countries by imparting healtheducation and distributing ivermectin. The centre is alsothe sponsoring agency for the Onchocerciasis EliminationProgram of the Americas (OEPA), a partnershipprogram including the governments of the six endemiccountries, Pan American Health Organization (PAHO), aprivate sector (Merck & Co. Inc.), a specialized researchinstitution (Centres for Disease Control and Prevention,CDC) and another NGDO, Lions Club InternationalFoundation. With the continued thrust under the OEPAumbrella 19 , the blindness attributable to the infection hasbeen eliminated from Colombia (2007), Ecuador (2009),followed by Mexico and Guatemala (2011); and theprogram efforts remain focused in Brazil and Venezuela.CONCLUSIONSOnchocerciasis was included on the priority diseaselist of VISION 2020, a global initiative for theelimination of avoidable blindness - a joint program ofWHO and the International Agency for the Preventionof Blindness (IAPB) with an international membershipof NGDOs, professional associations, eye care institutionsand corporations. With the clearly demonstrablesuccess of burgeoning partnerships, it seems likely thatonchocerciasis shall be eliminated in most, if not in allthe endemic communities in the world 20 and the goalof removing this condition from the priority disease listof VISION 2020 seems increasingly within reach.REFERENCES1. Report of a WHO Expert Committee on onchocerciasiscontrol. WHO Technical Report Series 1995;852.2. Murdoch ME, Asuzu MC, Hagan M, et al. Onchocerciasis:the clinical and epidemiological burden of skin disease inAfrica. Ann Trop Med Parasitol 2002;96:283-96.8

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