Role of the endothelium in viral hemorrhagic fevers - Benh Vien ...

Role of the endothelium in viral hemorrhagic fevers
Clarence J. Peters, MD; Sherif R. Zaki, MD, PhD
Objective: To describe endothelial participation in the pathogenesis
of viral hemorrhagic fevers and certain other acute infectious
diseases.
Data Extraction and Synthesis: Survey of published literature
on viral hemorrhagic fevers interpreted in light of observations in
patients and research on those diseases.
Conclusions: Endothelial involvement is an extremely important
factor in the clinical syndrome termed viral hemorrhagic
fever. Endothelial dysfunction is important in the genesis
of bleeding, which is not universal and is commonly seen
only in the presence of thrombocytopenia or severe platelet
dysfunction. The pathogenesis of endothelial dysfunction varies
in the different diseases. In some situations, direct endothelial
infection is important in increased vascular permeability,
changes in the procoagulant vs. anticoagulant balance, or
cytokine production. In all the viral hemorrhagic fevers studied
to date, cytokine induction is an important factor and also acts
on the endothelium. Poor myocardial contractility is a very
important issue in viral hemorrhagic fever and is not caused by
direct viral infection of the heart; it is increasingly being
recognized that these patients present with low cardiac output
and high peripheral resistance and that they respond poorly to
fluid infusion. The clinical findings in viral hemorrhagic fever
differ from those in the sepsis syndrome and should be studied
and interpreted separately; this approach will sharpen therapeutic
approaches and could shed light on the problems of
sepsis in general. (Crit Care Med 2002; 30[Suppl.]:S268–S273)
KEY WORDS: cytokines; disseminated intravascular coagulation;
endothelium; sepsis; viral hemorrhagic fever
Viral hemorrhagic fever (VHF)
is a syndrome just as is pneumonia.
There are common
features among the viruses
and the pathogenesis of the different infections.
However, there are also very significant
differences. One of the major
questions that remains unanswered in
VHF research is how the rather different
viral genomes activate distinctive and
also common pathways of disease.
VHFs share a considerable number of
clinical findings. Acute infection begins
with fever, myalgia, and malaise and
progresses to prostration. This phase typically
lasts for 3–4 days, during which
time vascular manifestations begin to
emerge, such as vascular dysregulation,
increased vascular permeability, and
small-vessel damage. Infection of the vascular
endothelium may be common to all
From the John Sealy Distinguished University Chair
in Tropical and Emerging Virology, University of Texas
Medical Branch, Galveston, TX (CJP), and the Infectious
Disease Pathology Activity National Center for
Infectious Disease, Atlanta, GA (SRZ).
Presented, in part, at the Margaux Conference on
Critical Illness, Sedona, AZ, November 14–18, 2001.
Address requests for reprints to: Clarence J. Peters,
MD, University of Texas Medical Branch, 3.146
Keiller Building, 301 University Boulevard, Galveston,
TX 77555-0609. E-mail: cjpeters@utmb.edu
Copyright © 2002 by Lippincott Williams & Wilkins
VHFs. Hemorrhage is usually seen in the
disease states in which thrombocytopenia
is present or platelet function is severely
depressed. The bleeding is always diffuse
and reflects diffuse capillary damage;
however, the volume of hemorrhage is
usually not the major factor in the demise
of the patient.
The degree and pattern of multiple
organ compromise vary with the disease.
Physical signs usually point to involvement
of the vascular system (1). Conjunctival
injection—a frequent observation
in patients with VHF—has been
noted since the earliest days of yellow
fever, when it was illustrated in the 1821
epidemic on the southern coast of Spain
(2). This indicator of diffuse vascular involvement
often progressed to diffuse
mucosal hemorrhage—the final throes of
this disease—in these patients. The same
findings are evident in contemporary patients
with hemorrhagic fever with renal
syndrome (Hantaan virus) or Bolivian
hemorrhagic fever (HF; Machupo virus)
(Fig. 1).
Hemorrhages are generally mucosal
and petechial. Increased vascular permeability
is also common and may be evidenced
clinically as periorbital edema and
hemoconcentration. Usually, the hemoconcentration
is modest, but in hantavirus pulmonary
syndrome (HPS) and HF with renal
syndrome, the hematocrit values may exceed
60% to 65%.
HF VIRUSES
The causative viruses belong to four
families (Table 1). Members of each family
share many common features in their
pathogenesis, although there are significant
differences between families and, at
times, between genera within families
(3).
HF viruses are all small RNA viruses.
They are characterized by marked aerosol
infectivity, although the reasons for this
are unclear. The aerosol stability and infectiousness
of these viruses do not make
them highly transmissible among humans,
presumably because virus-containing
aerosols are not usually generated by
patients; however, preparation of biological
weapons with these agents is a reality
(4).
All of these viruses cause disease during
the period of viremia; that is, they are
“typhoidal” in nature (The virus circulates
for a long period of time, and the
viremia corresponds to the period of
acute illness; when the viremia clears, the
patient recovers.). The exceptions to this
are the hantavirus diseases, which are
immunopathologic. Although the disease
syndrome, VHF, is common to each of
these viruses, the pathogenesis of each
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esponse. Most of these diseases are worst
while the virus is actively replicating in the
organs and released to circulate in the
blood. Only in the hantavirus diseases and
in dengue HF does the classic, virusspecific
immune response seem to play a
role in causing the clinical manifestations,
and in those diseases, immunopathology is
an important part of the disease process.
In the case of dengue virus, in the overwhelming
majority of cases, HF follows sequential
infections with different serotypes;
it is not included in Table 1 because it is not
one of the primary VHFs. There is now
considerable information that suggests that
immune enhancement and immunopathology
are the major factors in the genesis
of this syndrome, which is primarily a vascular
permeability disease.
ARENAVIRUSES
Figure 1. Top, patient with hemorrhagic fever with renal syndrome showing subconjunctival hemorrhage
of the bulbar conjunctivae and vascular congestion of the palpebral conjunctivae. Bottom,
patient with Bolivian hemorrhagic fever, a South American arenavirus hemorrhagic fever, with diffuse
mucosal bleeding. Reproduced with permission from Peters et al (1).
Table 1. Viral hemorrhagic fevers
Arenaviridae Lassa fever and South American
HF (Argentine, Bolivian, etc.)
Bunyaviridae
Phlebovirus Rift Valley fever
Nairovirus Crimean Congo HF
Hantavirus HF with renal syndrome and
Hantavirus pulmonary
syndrome
Filovirus Marburg HF and Ebola HF
Flavivirus Yellow fever, KFD, and Omsk
HF
HF, hemorrhagic fever; KFD, Kyasanur Forest
disease.
differs, and the ways in which the viruses
interact with cells are similarly different
(Tables 2 and 3).
PATHOGENESIS OF HF
Some of these viruses cause almost no
cytopathic effects, whereas others are
highly destructive to the cells they infect.
Pro-inflammatory cytokine induction (particularly
tumor necrosis factor [TNF]-), in
cases in which it has been measured, is a
general finding. Disseminated intravascular
coagulation (DIC) occurs in some but
Crit Care Med 2002 Vol. 30, No. 5 (Suppl.)
Table 2. Similarities among hemorrhagic fever
viruses
Similarities
Vascular syndrome
Dysregulation
Increased permeability
Diffuse damage
Small RNA viruses, 1–2 10 6 d
Lipid envelope
Aerosol infectivity
Persist in nature independently of humans
Table 3. Differences among hemorrhagic fever
viruses
Differences
Replication strategy
Virion structure and morphogenesis
Cytopathic effects in mammalian cells
Sensitivity to antiviral effects of interferon
Pathogenesis of infection
Human immune response
Survival strategy in nature
not in others. Involvement of the liver also
varies. HF is a single syndrome but not a
stereotypical disease (3, 5).
One of the important pathogenetic differences
involves the role of the immune
The arenaviruses, which cause Lassa
fever in Africa and Argentine and Bolivian
HF in South America, are particularly
interesting; furthermore, arenavirus infections
occur reasonably frequently in
predictable sites, providing a pool of patients
for study. Throat swabs from patients
demonstrate a small amount of virus,
but titers are low and inconstant.
Person-to-person transmission is not
very high, except possibly through sexual
intercourse in convalescence, but patients
develop effusions quite regularly.
High-titered virus is present in the
Lassa fever effusion. Arenavirus infection
of the mesothelial cells on the surface of
the organs bathed in the effusion suggests
a direct effect of the infection on the
exudation of fluid (5). Figure 2 shows the
pleural surface of a patient with Lassa
fever. The mesothelium is very intensely
stained for viral antigen. Arenaviruses
also infect the capillary endothelium of
many organs in the body.
The arenaviruses are not highly cytopathic,
and thus, it is not clear what
mechanism is involved in the alteration
of vascular endothelial function or how
much of the functional change is caused
by direct infection and how much is from
the cytokine activation that is evident in
the arenaviral HF. Pro-inflammatory cytokines
are elevated, and in Argentine
HF, there is a correlation between mortality
and the levels of TNF- and interferon
(IFN) (6–8). Arenavirus infection
has also been shown to cause a loss of
cellular function—such as growth hormone
secretion in the murine pituitary
or neurohumoral transmitter secretion
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The clinical findings
in viral hemorrhagic
fever differ
from those in the sepsis syndrome
and should be studied
and interpreted separately;
this approach will sharpen
therapeutic approaches and
could shed light on the problems
of sepsis in general.
Figure 2. Pleural surface of patient with Lassa fever.
in cultured neurotransmitter cells—
without any detectable sign of cellular
damage or interruption of the basic life
functions of the cell (9). Hence, these
viruses may exert reasonably selective
and specific actions on function without
any overt signs of cellular damage.
The role of soluble mediators in VHF
was first investigated in guinea pigs infected
with Pichinde virus (10). (Pichinde
virus is an arenavirus that does not cause
disease in humans and thus provides a
useful model for the laboratory study of
arenavirus HF.) The lesions visible on
detailed histopathologic study were not
sufficient to suggest the cause of death,
and the marked extension of infection
beyond any zone of morphologic damage
suggested that disease is associated with
an alteration of function rather than
overt cytopathology—and direct viral interference
with endothelial cell function
is a possibility (9). A role for soluble mediators
presumed to be involved in the
pathogenesis of septic or late hemorrhagic
shock has also been considered,
and several have been found to be markedly
altered in Pichinde virus infections,
including leukotrienes (11), plateletactivating
factor (12), and endorphins
(13). TNF- is also activated in the
Pichinde-infected guinea pig (14). Supportive
evidence for the role of soluble
factors comes from the observations that
cardiovascular depression is an important
component of the disease in the absence
of direct cardiac infection virus (15).
Intensive studies of coagulation have
failed to identify major isolated defects in
coagulation pathways, fibrinolysis, or the
presence of DIC to explain bleeding in
arenavirus disease (16). In any case,
bleeding is marked in the South American
diseases, presumably related to vascular
damage and the associated severe
thrombocytopenia. Bleeding occurs less
frequently in Lassa fever, but when it
does, it is in a setting of mild thrombocytopenia
but marked loss of platelet
function measured in vitro (17, 18).
RIFT VALLEY FEVER
Rift Valley fever is perhaps unique in
having a highly variable clinical presentation
that includes VHF, encephalitis,
and retinal disease (19). Development of
Rift Valley fever is often associated with
marked hepatitis. The pathogenesis in
humans is not known, but extensive studies
in monkeys have shown that an important
determinant is late secretion of
IFN- (20). If IFN- is detectable within
6–12 hrs of infection, the course will be
mild. Later onset of the IFN response is
associated with more severe disease, DIC,
microangiopathic hemolytic anemia, and
intravascular deposition of fibrin thrombi
(21). The virus itself causes rapid cell
death in all mammalian cells tested, including
human endothelial cell cultures
(19). It seems likely that the delay in
IFN- response is sufficient to allow
more extensive infection of vascular endothelium
and that direct viral damage
destroys the antithrombotic lining of capillaries,
including the glomeruli.
CRIMEAN CONGO HF
Crimean Congo HF virus causes a severe
HF but is not highly cytopathic. The
mechanism for hemorrhage is not
known, but there is clinical evidence of
DIC (22). Of all the VHFs, this infection is
associated with the most florid hemorrhage
and also seems to be associated
with the highest frequency of large ecchymoses.
More detailed clotting and cytokine
studies would be of considerable
interest. Immunohistochemical and in
situ hybridization studies have primarily
focused on liver tissues and have shown
involvement of hepatocytes and endothelial
cells (23). The other tissues studied
showed a few endothelial cells and occasional
mononuclear phagocytes to be
positive. There is modest cellular necrosis
generally associated with the presence
of antigen in hepatocytes. As with all the
nonhantavirus diseases discussed here,
there is marked clinical improvement at
the onset of the immune response and
disappearance of viremia.
HANTAVIRUSES
Hantaviruses from American rodents
cause HPS, which is associated with a
marked and abrupt increase in pulmonary
capillary permeability (24). HPS is
confined to the Americas. Unlike most
VHFs, the disease process in HPS is
mainly confined to the thoracic cavity.
There is an initial febrile prodrome lasting
4–5 days. Patients subsequently develop
bilateral alveolar pulmonary
edema, which progresses rapidly. Patients
exhibit thrombocytopenia—and this is
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useful diagnostically—although hemorrhage
is not common. The development
of shock and severe arterial desaturation
ushers in the phase during which about
40% of patients will die. Five to 7 days
after the onset of shock and arterial desaturation,
patients who survive the initial
24–48 hrs will usually be extubated,
breathing well, and shortly thereafter,
able to leave the hospital. Clearly, this
syndrome cannot reflect endothelial cell
death, but rather functional changes in
permeability. This is reinforced by the in
vitro findings that the virus itself has no
effect on permeability of microvascular
pulmonary endothelial cells (25).
Patients present with antiviral antibody
and large numbers of circulating
activated CD8 lymphocytes, some of
which can be cloned and are virus specific;
when stimulated with viral antigen,
they produce interleukin-2 and IFN-. In
tissues from patients dying from HPS,
virtually all of the pulmonary endothelium
is infected with the virus. Many of
the lymphoid cells infiltrating the lung
parenchyma are CD8 T lymphocytes
(26), and many are producing interleukin-2,
TNF-, and IFN- (27). These lung
lymphocytes are responsible for inducing
a reversible increase in permeability, mediated
at least in part by TNF-. Table 4
shows the markedly elevated cytokine
measurements in patients in New Mexico
with HPS (28). Increases in TNF- have
also been observed, particularly in those
patients who die (FT Koster, unpublished
observations) (28).
Although there are clear parallels in
the inflammatory cytokine profile in sera
from patients with acute respiratory distress
syndrome and sepsis, patients who
die from HPS usually do not have overt
multiple organ failure. Indeed, one of the
interesting developments after the identification
of the hantaviral etiology of the
1993 epidemic was finding a clearly demarcated
syndrome within the acute respiratory
distress syndrome category.
This previously unrecognized syndrome,
HPS, differed from acute respiratory distress
syndrome in etiology, pathogenesis,
clinical findings, and pathology.
FILOVIRUSES
The filovirus family comprises Ebola
and Marburg viruses and exercises a considerable
grip on the public’s imagination.
New information has emerged on
the molecular pathogenesis of filovirus
infections (Fig. 3) (29). The Ebola Zaire
subtype is the most pathogenic of the
filoviruses, with a case fatality of around
90%. It is a very invasive, cytopathic virus
with a primary target of macrophages,
although it rapidly spreads to involve the
endothelium and parenchymal cells of
many organs (30); cytokines are also activated
(31).
Molecular studies of the pathogenesis
of the related Marburg filovirus have been
reported (29, 32, 33). During the early
stages of pathogenesis, Marburg virus–
infected macrophages release cytokines
that lead to endothelial cell disorganization
and increased permeability. TNF- is
clearly a major player in the increased
endothelial permeability as judged by the
ability of specific antibodies to block the
pathogenic effects of infected macrophage
supernatants. The permeability defects
are accompanied by disruption of
some of the molecules important for intercellular
adhesion, including catenins,
cadherins, and plakoglobin. Cytokine secretion
has also been implicated in the
severe apoptosis in lymphoid organs of
Ebola virus model systems and may play a
role in patients (30, 31, 34). However,
cytokine elaboration is but one of the
possible causes of death in fatal filovirus
infections. Macrophages certainly secrete
pro-inflammatory cytokines, but the virus
also directly infects endothelium
(with consequent virus-induced damage
and DIC), and there is, in addition, extensive
cytopathic involvement of the parenchymal
cells of multiple organs.
HF VIRUS SUMMARY
There are both common themes and
differences in the pathogenesis of VHF
(Table 5). Endothelial infection is common
and can be limited or widespread. In
Table 4. Immune markers in sera of patients with
hantavirus pulmonary syndrome a
Immune Marker Survive Fatal
Soluble CD4 NS 1
Soluble CD8 1 1
IL-2 NS NS
IFN- NS 1
IL-4 1 1
IL-6 NS 1
Soluble IL-2 receptor NS 1
NS, not significant; 1, markedly increased;
IFN-, interferon-; IL, interleukin; NS, not significantly
different from acute respiratory disease
syndrome or sepsis controls.
a Data reproduced with permission from
Simpson et al (28).
Figure 3. Pathogenesis of Marburg virus (MBGV) infection. BM, basement membrane; CAM, cell
adhesion molecule; E, erythrocyte; EC, endothelial cell; N, nucleus; V, vacuole; Vir, virus. Reproduced
with permission from Feldmann and Klenk (29).
Crit Care Med 2002 Vol. 30, No. 5 (Suppl.)
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the case of Rift Valley fever virus, the
virus has a highly destructive interaction
with any cell type infected, and although
there are no good human data, it seems
to destroy endothelium and lead to DIC
on a background of extensive liver damage.
The cytopathic and invasive nature
of filovirus infections contrasts sharply
with the findings from arenaviruses.
Ebola (Zaire subtype) is highly damaging
to the cells it infects, and this is important
in inducing vascular leakage, which
can be multiplied by DIC. Arenaviruses,
in contrast, infect the endothelium but
cause little direct cell damage; they may
induce cytokines or perturb endothelial
cell function, but this is in the absence of
obvious morphologic signs. Other viruses,
such as Hantaviruses, are virtually
noncytopathic, can infect cells in vitro
without inducing any permeability or
other major change, and depend on the
host immune response to induce changes
in vascular permeability. The flaviviruses,
such as yellow fever, are important
agents that require additional study
(Dengue HF differs from the rest of the
flaviviruses in having an immunopathologic
basis.).
High concentrations of pro-inflammatory
cytokines clearly play an important
role in the different HF infections, but
the mechanisms for cytokine induction
and their exact role are different and
poorly understood among the virus taxons.
The clotting defects are also quite
variable in both their obvious manifestations
and their pathogeneses.
VIRUSES AND BACTERIAL
SEPSIS
Table 5. Pathogenesis of viral hemorrhagic fevers (VHF)
VHF
Cytopathic
Effect
Critical care and pulmonary specialists
initially regard VHF as simply another
subset of the diseases that they deal
with daily. This is overly simplified and
overly reductionist. There are some striking
similarities, such as inflammatory cytokine
secretion and coagulation activation;
comparing and contrasting the
different conditions is likely to provide
important insights into both pathogenesis
and appropriate therapeutic intervention.
Often, no obviously lethal morphologic
lesions are present in VHF or in
sepsis, and patients with VHF (with the
exception of immunopathologic hantavirus
diseases and dengue HF) and sepsis
die with lymphoid depletion that is an
anatomic correlate of immunosuppression.
However, the hemodynamic patterns
that are classic in sepsis are not
typical of VHFs studied so far. The pathogenesis
of the low-output, high-resistance
state seen in patients with hantavirus
and dengue HF (35, 36), and in
arenavirus model infections (15), is unknown,
and additional studies in other
VHFs would be valuable (19). Multiple
organ dysfunction syndrome is not the
rule in the VHF, further indicating a patterning
in the different diseases. It seems
that the key similarity may be endothelial
involvement, either direct or through the
mediation of cytokines. The most important
questions that remain are how to
measure the dysfunction of the vascular
bed, why it occurs, and how it manifests
differentially in distinct organs.
OTHER INFECTIONS WITH
ENDOTHELIAL INVOLVEMENT
Endothelial
Infection
Cytokine
Activation DIC Liver
South American HF 2 4 No
Lassa 2 3 No 1–
2
Rift Valley fever 4 ? ? Yes 2–
3
Crimean Congo HF 1 1 ? Yes 2–
3
Hantavirus pulmonary syndrome 0 4 4 No
Filovirus HF 3 3 3 Yes 3
Yellow fever 2 ? ? No 4
DIC, disseminated intravascular coagulation; HF, hemorrhagic fever; ?, unknown; , variable, not
marked; 1, occurs regularly; 2, occurs regularly and is marked; 3, occurs regularly and is
moderately severe; 4, occurs regularly and is severe.
Other acute infectious diseases that
specifically involve the endothelium in
their pathogenesis include rickettsiae,
paramyxoviruses, and anthrax. Rickettsiae
are an important group of pathogenic
agents that specifically infect endothelium
and resemble VHF in their
clinical manifestations (37). The newly
discovered Nipah virus is a paramyxovirus
with epidemic potential in pigs and
that crosses species to kill humans. It
infects endothelium in the lung to cause
pulmonary disease and also gains entry to
the central nervous system by infecting
capillary endothelium with formation of
giant cells, resultant clotting, and microinfarcts,
followed by direct spread to
brain neurons (38).
Anthrax is of particular concern in today’s
climate of potential bioterrorism.
The typical patient with the inhalational
form of anthrax dies with massive endothelial
swelling, tissue edema, hemoconcentration,
and coagulation defects (39).
SUMMARY
The VHFs and several other infectious
diseases provide interesting models of the
participation of endothelium in disease
pathogenesis. Comparison to the sepsis
model can be enlightening to students of
both.
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