Dengue and Other Hemorrhagic Viral Infections

Siripen Kalayanarooj

Rakesh Lodha

KEY POINTS

Dengue Hemorrhagic Fever and Dengue Shock Syndrome

Dengue infection is now endemic in more than 100 countries. It is caused by dengue virus (four serotypes) that belongs to Flaviviridae family.

The clinical manifestations of dengue virus infection vary from asymptomatic to severe, life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) that require intensive care.

DHF and DSS are characterized by profound capillary leak and thrombocytopenia.

Suggested pathogenic mechanisms include increased replication of a serotype of dengue virus enhanced by the presence of nonneutralizing antibodies, complement activation, and increased cytokine levels.

Laboratory findings include hemoconcentration and thrombocytopenia.

The diagnosis is confirmed by viral culture (initial 5 days of illness), detection of NS1 antigen or demonstration of specific IgM antibodies (after first 5 days of illness).

Supportive care and proper fluid therapy are the cornerstones of management. Fluid therapy is guided by clinical response and monitoring of hematocrit.

No specific antiviral drugs for dengue infection are available.

Early detection and proper fluid therapy can reduce case fatality rates in DHF/DSS to <1%.

Viral Hemorrhagic Fevers

VHF, caused by various viruses belonging to the Flaviviridae family (Kyasanur forest disease, Omsk, dengue, and yellow fever viruses), the Bunyaviridae family (Congo, Hantaan, and Rift Valley fever viruses), the Arenaviridae family (Junin, Machupo, Guanarito, and Lassa viruses), and the Filoviridae family (Ebola and Marburg viruses) are characterized by hemorrhagic manifestations.

Ebola, Marburg, Lassa, and Crimean-Congo hemorrhagic fever viruses can spread from person to person.

The clinical manifestations of these syndromes are quite similar. The severity in variable and the case fatality rates may be up to 90%. The diagnosis can be confirmed by viral isolation or serologic tests.

The principle involved in management of all of these diseases, especially hemorrhagic fever with renal syndrome (HFRS), is the reversal of dehydration, hemoconcentration, renal failure, and protein, electrolyte, or blood losses.

IV ribavirin may be effective in reducing mortality in Lassa fever and HFRS.

DENGUE INFECTIONS

Background

Dengue viral infections can present with a wide spectrum of clinical illnesses from the common dengue fever (DF) to the more severe presentations of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) (1). Increasing reports of unusual presentations of dengue have caused the World Health Organization (WHO) Southeast Asian Region Office (SEARO) to add a classification of expanded dengue syndrome (EDS) (or unusual manifestation of dengue, UD), which includes severe CNS, liver, myocardial, or abdominal dysfunction (2). More than half of the EDS or UD cases are due to prolonged shock and delay in diagnosis of DSS, the remaining cases are due to dengue infections in hosts with comorbidities or co-infections. Although uncommon, there are reports of dengue with neurological involvement (3,4,5,6,7) and one report of confirmed dengue viral encephalitis from Brazil (8).

Epidemiology

Dengue infections were reported more than 370 years ago in tropical, subtropical, and temperate areas. Early reports (1953-1979) of DHF as a distinct entity originated from Southeast Asia and Western Pacific Regions and the majority of cases were children below 15 years of age. Since the 1980s, the incidence of dengue has increased dramatically and become a major world health problem. Both adults and children, male and female are susceptible hosts to dengue infections. The WHO and the Pediatric Dengue Vaccine Initiative (PDVI) have estimated that about 2.5-3.6 billion people (approximately half of the world population in tropical and subtropical countries) are at risk of dengue infection. An estimated 50-400 million dengue infections with 100 million symptomatic cases occur worldwide every year (2,9). About 500,000 DHF patients require hospitalization and approximately 12,500 of those die each year (case fatality rate [CFR] of 2.5%) (2). In 1993, the 46th World Health Assembly
adopted a resolution on dengue prevention and control, which urged that strengthening national and local programs for the prevention and control of dengue be among the foremost health priorities of countries where the disease is endemic. Currently more than 130 countries from Asia, Australia, Central and South Americas, Eastern Mediterranean, and Africa have reported dengue infections. Without early diagnosis and proper management, the CFR may be as high as 10%-30%. With WHO SEARO (1,2) guidelines for dengue management and modern intensive supportive therapy, such rates can be reduced to less than 1%. The dengue CFR in Southeast Asia (Bangladesh, Bhutan, India, Indonesia, Maldives, Myanmar, Nepal, Sri Lanka, Thailand, and Timor Leste) was reported as 0.79% (ranged from 0% to 2.2%) in 2009 (2).

Virus

DF, DHF, DSS, and EDS are caused by infection with any of the four dengue virus (DENV) serotypes, DENV-1, DENV-2, DENV-3, or DENV-4. These four dengue viruses are small (50 nm), single-stranded RNA viruses, belonging to the genus Flavivirus and family Flaviviridae based on antigenic and biologic characteristics. A fifth serotype, the first in 50 years, has been recently reported (10). The Dengue virion consists of a nucleocapsid with cubic symmetry enclosed in a lipoprotein envelope. The dengue virus genome codes for three structural proteins (capsid protein [C], membrane-associated protein [M], and envelope protein [E]) and seven nonstructural proteins (NS1, NS2a, NS2b, NS3, NS4a, NS4b, NS5). NS1 (45 kDa) is of diagnostic and pathological importance. Infection with any one serotype confers lifelong immunity to that serotype and temporary cross-protection (months) to secondary infection with one of the other serotypes. All four dengue viruses have been associated with epidemics of DF with a varying degree of severity (with or without DHF) (2). Infection with DENV-2 is more likely to cause shock than other serotypes, whereas DENV-3 is associated with more liver involvement (11,12,13).

Transmission

Aedes aegypti and Aedes albopictus mosquitoes are the two most important vectors of dengue viruses for human transmission. Dengue virus can also be transmitted through blood transfusion and by vertical transmission. The transmission of dengue depends on biotic (virus and host) and abiotic factors (temperature, humidity, and rainfall). The extrinsic incubation period in mosquito is 8-12 days before the mosquito can transmit the viruses and thereafter, remains infected for the rest of its life (4-6 weeks). The typical incubation period after a mosquito bite to a human (intrinsic incubation period) is 4-6 days (range 3-14 days) (2). Knowledge of the incubation period allows the physician to rule out dengue when symptoms arise in a traveler >14 days after return from an endemic area.

PATHOGENESIS AND PATHOPHYSIOLOGY

Dengue viruses are inoculated by an Aedes mosquito bite and then spread to regional lymph nodes and reticulo-endothelial organs, where they multiply and ultimately enter the blood stream. The association between the occurrences of DHF/DSS with secondary infections implicates immuno-pathogenesis. Both innate immunity (NK cells and complement system) and adaptive immunity (humoral and cell-mediated immunity) play role in this pathogenesis of DHF/DSS (14,15). Enhancement of immune activation during secondary dengue infection

leads to an exaggerated cytokine response resulting in increased vascular permeability (16). The leakage in DHF/DSS is unique because of selective leakage of plasma in the pleural and peritoneal spaces and because of the short duration of leakage, 24-48 hours. The potential for a rapid recovery and the absence of vascular inflammation indicate functional changes in vascular integrity rather than structural damage of the endothelium (2,17,18,19).

The dendritic cells (DCs) are antigen-presenting cells of the immune system and reside in tissues that are in contact with the external environment (skin, nose, stomach, intestine, and lungs). The DCs in the tissues internalize the virus, where it resides in cystic vacuoles, vesicles, and endoplasmic reticulum.

After the phagocytosis and antigen processing, the DCs release a number of cytokines, including tumor necrosis factor (TNF)-α and interferon (IFN)-α, which lead to activation of other virus-infected and virus-uninfected DCs in a paracrine manner. IFN-γ is an important second signal for secretion of bioactive IL-12 from DCs in addition to its effect on the expression of molecules that are involved in stimulating an antigen-specific T-cell response. During a secondary dengue infection, memory T cells produce early IFN-γ and CD40L in the DC microenvironment, leading to greater DC activation, T-cell stimulation, and cytokine release (especially IL-12). The viremia may be cleared, but the cascade of events initiated by the early, poorly controlled type 1 cytokine response (a strong cellular immune response—usually involving IL-2, IFN-γ, IL-12, and TNF-β) contributes to the pathogenesis of DHF/DSS. Increased levels of TNF-α, soluble TNF-α receptor, and IFN-γ levels are present in patients with DHF/DSS as compared with those with DF (14,15,16).

The mechanism of antibody-dependent enhancement has been proposed (16,20). It has been observed that sequential infection with any two of the four serotypes of dengue virus results in DHF/DSS in an endemic area. Serotype cross-reactive antibodies generated from previous primary infection with a particular dengue viral serotype are not highly specific for the other serotypes involved in secondary infections. These crossreactive antibodies bind to the virions but are unable to neutralize them. There is an enhanced uptake of antibody-coated virions, which results in greater antigen presentation by the infected dendritic cells to the T cells and more rapid activation and proliferation of memory T cells. The cytokines produced by the activated T cells have an important role in the pathogenesis of the DHF/DSS (14,15).

Cytokines are implicated in the pathogenesis of vascular compromise and hemorrhage in dengue virus infection. Dengue viral infection causes the release of both inflammatory and inhibitory cytokines, and the net outcome will depend on the balance of cytokine actions. The levels of T-cell activation markers (soluble IL-2 receptor, soluble CD4 and CD8, IL-2, IFN-γ), monokines (TNFα, IFN-β), and granulocyte-macrophage colony-stimulating factor (GM-CSF) are increased with even higher levels present in patients who develop DHF/DSS. Elevated IL-6 levels are associated with a higher incidence of both shock and ascites. Similarly, high levels of IL-8 can be recovered from serum and pleural fluid of patients with DSS (16).

Complement activation mediated by nonstructural viral protein NS1 leads to local and systemic generation of anaphylatoxins and terminal complement complex (SC5b-9), which may contribute to the pathogenesis of the vascular leakage that occurs in patients with DHF/DSS (16).

Endothelial cells also undergo apoptosis, which causes disruption of the endothelial cell barrier and the syndrome of generalized vascular leakage. The mast cells may play a role in the initiation of chemokine-dependent host responses to
dengue virus infection. Assessment of microvascular leakage using strain-gauge plethysmography in children with DHF and DSS found that, although the coefficient of microvascular permeability (Kf) was higher in children with either DHF or DSS as opposed to that in healthy controls, no significant difference existed between the two groups (DHF, DSS), suggesting a similar pathogenic mechanism (21).

Dengue viral infection is commonly associated with thrombocytopenia; one postulated mechanism is molecular mimicry. Antibodies against dengue virus proteins, especially NS1, cross-react with platelet surface proteins and cause thrombocytopenia. These antibodies cause both platelet lysis via complement activation and the inhibition of adenosine diphosphate-induced platelet aggregation. Like the markers of inflammation, the titers of these immunoglobulin M (IgM) antibodies are increased in patients with DHF/DSS compared with DF (15). Dengue virus infection can also activate blood clotting and fibrinolytic pathways. Mild disseminated intravascular coagulation (DIC) (22), liver injury, and thrombocytopenia together contribute to hemorrhagic tendency.

Central nervous system (CNS) involvement also has been identified (3,4,6,7,23) and has been attributed to direct neurotropic effect of dengue virus (8).

The degree of viral load correlates with severity of DHF/DSS (24,25).

The risk factors for DHF/DSS are (16,19):

Virus strain—DENV-2 > DENV-3, DENV-4 > DENV-1
Preexisting antidengue antibody
Age of host—younger children are at increased risk
Secondary infection
Genetic predisposition (26,27)
Hyperendemicity—two or more virus serotypes circulating simultaneously at high level.

Pathology

Most fatalities in DHF/DSS occur within 24 hours after shock. The following are the autopsy finding from hundreds of DHF/DSS death in Thailand in the year 1960 (17). Gross findings reveal some degree of hemorrhage in the skin and subcutaneous tissue. Hemorrhage may appear as hemorrhagic rash, petechiae, or ecchymosis, especially around needle puncture marks. Frank hemorrhage may appear in patches in the subcutaneous tissue. The heart typically shows flameshaped subendocardial hemorrhage in the left ventricular septum and occasionally over the papillary muscles. Hemorrhage may be present in nasal mucosa, gums, gastrointestinal tract, and the liver (subcapsular). While hemorrhage may be striking, especially in cases with prolonged shock, the amount of hemorrhage is not excessive and frank bleeding in serous cavities is rare. Adrenal cortical tissue hemorrhage was found in only two cases. The meninges and brain show only petechial hemorrhage. Massive bleeding into the brain and spinal tissue have not been reported. Serous effusion with high protein content (> 1 g/dL) is common in the pleural, abdominal, and occasionally in the pericardial space. The amount of effusion results in a significant fluid loss in the 24-hour period before death. Analysis of the effusion shows a high protein content, mostly albumin and low-molecular-weight globulin, thus rendering it an exudate rather than a transudate, even though there is only small number of leukocytes in the fluid. Analysis of the plasma in the blood reveals corresponding low levels of protein, especially albumin. The most striking findings at autopsy are the negative findings—no gross pathologic damage to major organs in rapidly fatal DHF/DSS nor evidence of suprainfections (bacterial pneumonia, cystitis, or pyelonephritis).

The pathology of DHF/DSS in fatal cases generally reveals no gross or microscopic evidence of severe organ pathology to explain the cause of death. In cases with prolonged shock, consequences of shock on organs, intravascular clotting, and hemorrhage are seen. Despite some display of neurological symptoms (encephalopathy) there is no convincing evidence of encephalitis (neuronal damage due to dengue virus) but there has been one report of dengue encephalitis from Brazil (8). Dengue encephalitis/encephalopathy has been reported with serological or virological confirmation but no pathological confirmation.

Bone marrow biopsy reveals hypocellularity early (in the febrile phase) which may contribute to hemorrhage, while at the time of shock and in most fatal cases, the bone marrow appears normocellular or even hypercellular. Young megakaryocytes proliferate and enter the circulation in high numbers.

The kidneys show immune complex glomerulonephritis with deposition of immunoglobulin and complement on the glomerular capillaries.

Classification

Dengue classifications have been controversial. Figure 89.1 shows the 1997 WHO classification of dengue, which has been criticized because it does not include all dengue cases, especially those with severe or unusual manifestations (28,29,30,31,32). DHF can be subdivided into grades I-IV on the basis of severity. The WHO SEARO modified the 1997 WHO classification slightly to recognize the following dengue infection syndromes: viral-like illness, dengue fever (DF), dengue hemorrhagic fever (DHF), dengue shock syndrome (DSS), and expanded (atypical or unusual) dengue syndrome (EDS) (2). Figure 89.2 shows the 2009 WHO classification, which divides dengue into uncomplicated and severe cases. In practice, many clinicians in endemic areas prefer the WHO SEARO classification.

DHF (DHF grades I and II), DSS (DHF grades III and IV), and EDS are considered severe in the 2009 WHO classification because they may lead to complications and death without proper management. DHF grades I and II are non-shock cases: a grade of II requires that the patient has spontaneous bleeding while a grade of I requires only a positive tourniquet test (see below). DHF grades III and IV are shock cases; a grade of IV requires that the patients have prolonged and profound shock with no blood pressure or no palpable pulse. The majority of dengue presentations (up to 80%-90% of symptomatic cases) are DF, which is mostly a mild illness and rarely leads to death.

DHF and DSS patients differ from DF patients because of plasma leakage during the critical phase. Minor bleeding manifestations, petechiae, epistaxis, and gum bleeding are usually found in all dengue infected patients, but significant bleeding mostly occurs in DHF/DSS and EDS patients. EDS was not described in the first three decades of DHF outbreaks (between 1950s and 1980s). While EDS is still uncommon, there are now increasing reports of EDS especially in countries with new outbreaks and especially in adult patients. The majority of EDS cases are the result of prolonged shock with manifestations of multiple organs failure, comorbidities, and co-infections in dengue-infected hosts. EDS

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