32-04: Viral Hemorrhagic Fevers

General Considerations

Genus Ebolavirus is a single-stranded RNA virus in the Filoviridae family. Four different species of Ebolavirus have been identified to cause human disease. Fruit bats are possible reservoir for Ebolavirus. Zoonotic transmission to humans occurs via contact with the reservoir or an infected primate. Ebolavirus can continue to be transmitted among humans who have direct contact with infected body fluids. To acquire EVD, the virus must enter the body via mucous membranes, nonintact skin, sexual intercourse, breastfeeding, or needlesticks. Traditional burial practices in Africa (which entail considerable contact with the corpse) and unprotected direct care of persons with EVD are associated with highest transmission risk. Ebolavirus has been detected in semen up to 9 months after recovery from infection.

EVD has a 2–21-day incubation period. Prior to manifestation of symptoms, Ebolavirus is not transmissible. Even at symptom onset, the risk of transmission is low but increases over time.

The first Ebola outbreak occurred in 1976 as a simultaneous epidemic in the Democratic Republic of Congo and South Sudan. Subsequent outbreaks were confined to the Democratic Republic of Congo, Uganda, and Sudan until March 2014 when the first Ebola case in West Africa was identified in Guinea. Zaire ebolavirus was the associated species. This Ebola outbreak grew to be larger than all prior Ebola outbreaks combined. The number of EVD cases spread rapidly; there were at least 10 affected countries, especially Guinea, Liberia, and Sierra Leone. Many cases and deaths in these countries occurred among healthcare workers. In the United States, 11 persons were treated for Ebola. Most were healthcare workers who were evacuated to the United States and 4 patients were diagnosed in the United States. In total, 35 outbreaks of Ebola have occurred in Africa since 1976.

Sierra Leone contained its last EVD outbreak as of March 2016. Guinea was declared free of EVD transmission in June 2016. Liberia declared the end of its last outbreak in June 2016. The WHO reports that the West African Ebola outbreak was associated with 28,616 cases and 11,310 deaths during the approximately 2-year interval of the outbreak between March 2014 and March 2016.

Two outbreaks were reported in May and August of 2018, both in the Democratic Republic of Congo (where outbreaks also were reported in 2014 and 2017), and while the isolates from the two outbreaks were both the same species, complete genetic homogeneity between the isolates was not present. As of March 9, 2020, 3444 cases (3310 confirmed and 134 probable) and 2264 deaths were reported from 29 health zones in the Democratic Republic of Congo, including 171 cases among healthcare workers.

Clinical Findings

A. Symptoms and Signs

At symptom onset, early-stage EVD most typically presents as a nonspecific febrile illness. Along with fever, patients tend to experience headache, weakness, dizziness, malaise, fatigue, myalgia, and arthralgia. After 3–5 days, patients with later stage EVD may develop abdominal pain, severe nausea, vomiting, and diarrhea accompanying the febrile illness. This stage of the illness may continue for a week during which time neurologic symptoms gain prominence. Encephalitis is commonly observed and manifested as confusion, slowed cognition, agitation, and occasional seizures. Hypovolemic shock develops in most patients, but hemorrhagic manifestations (gastrointestinal bleeding, diffuse mucosal bleeding, conjunctival bleeding) develop in only 1–5% of patients. Respiratory symptoms are not typical for EVD, although interstitial pneumonia and respiratory failure are reported.

B. Laboratory Findings

During the first few days of symptoms, diagnosis may be made via several modalities, including antigen-capture ELISA, IgM ELISA, RT-PCR, or virus isolation. Blood samples obtained within the first 3 days of illness and tested by RT-PCR should be repeated if results are negative and clinical symptoms and signs persist. RNA levels peak a median of 7 days after illness onset. Later in the disease course or after recovery, IgM and IgG serologic tests may be sent. After about 10 days, IgM antibodies begin to develop, and, after approximately 2 weeks, an IgG antibody response develops. Postmortem diagnosis may be made by using immunohistochemistry, RT-PCR, or virus isolation.

Given that filoviruses infect dendritic cells and then hepatocytes and renal cortical cells, laboratory findings typically include a low platelet count (and a thrombotic thrombocytopenic purpura syndrome has been postulated with the probable cause multifactorial), leukopenia, and transaminitis (aspartate aminotransferase [AST] greater than alanine aminotransferase [ALT]). As nonspecific symptoms progress to a severe systemic inflammatory response, coagulopathy with evidence of platelet dysfunction and disseminated intravascular coagulopathy (DIC) often develops. Whether DIC is a common cause of bleeding has not yet been firmly established because clinical measurements of fibrinogen, prothrombin time, fibrin split products, and platelets are not routinely taken in the communities where most outbreaks have occurred. Additional observed laboratory abnormalities include hypoalbuminemia, electrolytes imbalance, and increased serum creatinine level. Elevated blood urea nitrogen, AST, and creatinine upon presentation are associated with higher mortality.

Differential Diagnosis

The differential diagnosis varies with the stage of illness. Early-stage EVD is commonly mistaken for malaria, typhoid, and other viral illnesses. As gastrointestinal symptoms develop, health providers should also consider viral hepatitis, toxins, leptospirosis, and rickettsial diseases. In later stage EVD, bacterial, viral, and parasitic illnesses, including cholera and, in children, rotavirus infection can present with severe gastroenteritis and shock. Encephalitis must be differentiated from the confusion associated with uremia. Hemorrhagic manifestations raise suspicion for EVD but could be due to leukemia, thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome, or disseminated intravascular coagulation. Travel and contact history are crucial when considering the differential diagnosis in areas where Ebola is not endemic.

Complications

Hypovolemic shock and multiorgan failure are the most common complications of EVD. Hemorrhage can occur in late stages. Rhabdomyolysis is reported frequently and may explain many of the associated laboratory abnormalities. Coinfections with malaria or bacteria (or both) are important considerations and can occur before presentation and during treatment of EVD. The virus is known to persist in immunologically privileged sites, such as the CNS, eye, and testes; however, viral relapse is uncommon. Post-EVD musculoskeletal pain, headache, auditory symptoms including hearing loss, and ocular symptoms (uveitis being the most common ocular finding) may develop. EVD survivors exhibit high rates of neuropsychological long-term sequelae including depression, anxiety, and posttraumatic stress disorder.

Treatment

Treatment is supportive. Several studies have shown that intravenous fluids can reduce the mortality rates to less than 50%. Despite the wide availability of oral rehydration salts, mortality approximates 70% in endemic areas. In these studies, the amount of intravenous fluid replacement was relatively less than what would be used in countries with developed health systems. Among patients treated in the United States or Europe, almost all received intravenous fluids, electrolyte supplementation, and empiric antibiotic therapy. Invasive or noninvasive mechanical ventilation and continuous renal replacement therapy are necessary in many cases. This increased level of care likely contributed to the decreased mortality (19%) among these patients. The use of individual air-conditioned biosecure cubicles is preferred to the burdensome protective equipment used during the 2014 West African outbreaks and allows for more time spent with patients.

There are no approved medications for the treatment of EVD. Administration of convalescent plasma does not result in improved survival. Several drugs have advanced to clinical trials; however, some trials were terminated due to low enrollment or lack of efficacy. Monoclonal antibodies that have been tested include mAb114 (a monoclonal antibody isolated from a survivor of the 1995 outbreak in the Democratic Republic of the Congo), ZMapp (a cocktail of three chimeric monoclonal antibodies against Z ebolavirus), and REGN-EB3 (another cocktail of three monoclonal antibodies against Z ebolavirus). ZMapp showed some therapeutic benefit, but many of these patients received multiple agents and were not part of randomized controlled trials. The PREVAIL II study evaluated ZMapp for treatment of EVD and found it to be safe and well tolerated but failed to establish efficacy due to low enrollment numbers. REGN-EB3 is given as a single dose, does not require freezing, and shows efficacy in nonhuman primates, including reduction in mortality. Starting in November 2018, the Pamoja Tulinde Maisha (PALM) trial enrolled 681 Congolese patients to receive one of four investigational drugs: mAb114, ZMapp, REGN-EB3, or remdesivir (GS-5734; a novel nucleotide analog prodrug). In August 2019, the study’s independent data and safety monitoring board recommended stopping the trial early because preliminary results from 499 patients suggested that those taking REGN-EB3 or mAb114 had a greater chance of survival than patients who received the other two drugs (mortality with mAb-114 or REGN-EB3 was 6–11% compared to 24–33% mortality for those who received ZMapp or remdesivir).

In the 2018 outbreak in the Democratic Republic of the Congo, the two antivirals used were remdesivir and the RNA-dependent RNA polymerase inhibitor favipiravir. Mathematical models show a high likelihood of efficacy for both agents against EVD if given within 3–4 days of infection, and the efficacy of remdesivir is theoretically 100% while that of favipiravir is 60%. Remdesivir has been administered under compassionate use to two Ebola patients, both of whom survived and is currently in phase 2 clinical development for the treatment of EVD and long-term clearance of Ebola virus in male survivors with virus persistence in semen (NCT02818582). Although both agents were effective in nonhuman primates and one study in man found favipiravir to be effective in patients with low to moderate viremia, a more recent trial of favipiravir in 99 participants found no difference in mortality for persons with low or high viral loads compared to historical controls.

Aside from supportive treatment and experimental therapeutics, patients typically receive empiric antimalarial agents in endemic areas and broad-spectrum antibiotics. GS-5734 is an experimental medication that showed therapeutic efficacy in a non-human primate model of Ebola virus infection. It has been administered under compassionate use to two Ebola patients, both of whom survived, and is currently in phase 2 clinical development for the treatment of EVD and long-term clearance of Ebola virus in male survivors with virus persistence in semen (NCT02818582).

Prognosis

Children under 5 years of age and adults older than 40 have a high risk of death from EVD. Pregnancy is a risk factor for severe illness and death. In the 2014–2016 outbreak, the average maternal mortality was 86%. Immunosuppressed patients had shorter incubation time, rapid progression of disease, and poor outcomes. A higher baseline viral load was a strong predictor of mortality. In general, poor overall medical care confers a poor prognosis. Among survivors, protective antibodies persist for at least 10 years.

Prevention

Risk reduction should focus on preventing wildlife to human transmission and reducing human to human transmission by surveillance, early detection and isolation of cases, contact tracing, containment measures (disinfection, hygiene, and sanitation), strict droplet and contact precautions in health care setting, and reduction of sexual transmission in Ebola survivors. The WHO recommends that men avoid sexual activity or use barrier protection during intercourse for 12 months from onset of symptoms or until their semen tests negative twice for Ebola virus.

There are two Ebola vaccines being used in the ongoing epidemic in the Democratic Republic of the Congo. The recombinant vesicular stomatitis virus (rVSV)-based vaccine expressing Z ebolavirus (ZEBOV) glycoprotein is found to be highly effective in disease prevention after 10 days from receiving the vaccine. Side effects, such fever, myalgia, chills, fatigue, headaches, and oligoarthritis, developed in most of the persons who received the vaccine. rVSV-ZEBOV (marketed as Ervebo) showed promising results in phase III clinical trials (most study participants had persistent antibody levels at 1 year; NCT02503202). In addition, it was tested in a clinical trial conducted in Guinea during the 2014–16 Ebola outbreak in West Africa and was found to offer a high level of protection against Ebola (100% efficacy). rVSV-ZEBOV is the only Ebola vaccine candidate that has so far been able to demonstrate clinical effectiveness. It is being used in the ongoing outbreak in the Democratic Republic of the Congo (where more than 250,000 persons have been vaccinated as of November 11, 2019 including pregnant women and young children) and was approved by the European Medicines Agency (EMA) on November 11, 2019 and by the US FDA on December 19, 2019. The adenovirus/vaccinia virus vector vaccine is also deployed in the current outbreak in the Democratic Republic of the Congo; EMA approval for this vaccine is pending. The adenovirus/vaccinia virus vector vaccine is actually a two-dose series of two different vaccines, Ad26.ZEBOV (replication-incompetent recombinant adenovirus 26 expressing the ZEBOV [Mayinga strain] glycoprotein) and MVA-BN-Filo (a nonreplicating modified vaccinia Ankara-Bavarian Nordic virus vector expressing the glycoproteins of Zaire and Sudan ebolaviruses, Marburg virus, and the nucleoprotein of Tai Forest virus), given about 6 weeks apart (NCT03140774). This vaccine is being tested in a clinical trial in the Democratic Republic of the Congo at a dose that has shown 100% protective efficacy in nonhuman primate studies and that is well tolerated and immunogenic in extensive phase I–II trials. Nevertheless, concerns remain about public acceptance of an investigational two-dose vaccine when an approved one-dose vaccine (rVSV-ZEBOV) is already available.

There are 11 other Ebola vaccines in various stages of clinical testing, including a recombinant Ebola virus glycoprotein nanoparticle formulated with a saponin-based Matrix-M adjuvant.

Risk stratification may be useful in deciding when and to whom to administer antiviral postexposure prophylaxis. A high-risk exposure is defined as penetrating sharps injury from used device or through contaminated gloves or clothing, direct contact with an infected patient (alive or deceased) or their bodily fluids with broken skin or mucous membranes such as eyes, nose, or mouth. The ZEBOV vaccine was used in the setting of postexposure prophylaxis among healthcare workers and found to be effective, but the evidence is limited to case series. The vaccine-mediated immunity requires an average of 10 days to develop and might not be fast enough in certain cases to prevent infection.

Current studies focus on isolation of cross-reactive monoclonal antibodies across Ebola virus species. The use of different preparations of combination monoclonal antibodies (ZMapp and MIL-77E) as postexposure prophylaxis during the West African outbreak failed to show statistical significance, and the conclusion was that the benefit was modest, at best. Newer forms of monoclonal antibodies include virus-like particles (VLP), mucin-deleted glycoproteins, and bispecific binding proteins (which bind Ebola proteins as well as those of related viruses such as the Sudan virus). The use of antiviral agents in postexposure prophylaxis is another alternative that, to date, also shows no clear survival benefit. The agent brincidofovir, for example, was not studied further because of inadequate sample size in Liberia.

When to Admit

Persons living in or returning from a country with high rates of Ebola transmission should be monitored for 21 days and admitted to a health care facility when symptoms meeting the WHO case definition of a suspected EVD case develop, in accordance with the screening protocol designated by the respective country’s governmental health decision-making body.

This diverse group of illnesses results from infection with one of several single-stranded RNA viruses (members of the families Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae). Flaviviruses, such as the pathogens causing dengue and yellow fever, and Filoviridae, causing EVD, are discussed in separate sections.

Lassa fever is a rodent-associated disease caused by an Old-World arenavirus. Rodents shed the virus in urine and droppings and transmit the virus to humans either by direct contact with these materials, ingestion, or inhalation of aerosolized particles. Lassa fever is mostly endemic in West Africa, where 500,000 cases and 10,000 deaths are seen annually. Case fatality rates in hospitalized patients in West Africa are up to 50%. Other arenaviruses include the Junin virus (cause of Argentinian hemorrhagic fever) and the Lujo virus. Lujo virus was first described in 2008 in Zambia where it caused a small cluster of nosocomial infections.

The bunyavirus hemorrhagic fevers include hantaviruses (discussed separately), Crimean Congo hemorrhagic fever (CCHF), Rift Valley fever, and several newly emerging viruses such as the one that causes severe fever with thrombocytopenia syndrome (SFTS).

CCHF is a disease transmitted from ticks and livestock. Human-to-human transmission can occur in the community or hospital setting by contact with infected body secretions. The geographic distribution is widespread with cases reported from Africa, Asia, the Middle East, and Eastern Europe, with increased incidence recently in the East Mediterranean region. Butchers and slaughterhouse workers in southeastern Iran are at high risk for infection with the CCHF pathogen. Turkey reported the largest outbreak yet in 2002, with nearly 10,000 recorded cases.

Rift Valley fever is transmitted from livestock animals, infected mosquitoes, and flies. To date, there is no human-to-human transmission. Risk factors for acquiring Rift Valley fever include working with abortive animal tissue; slaughtering, skinning, or sheltering animals; and drinking unpasteurized milk. Rift Valley fever causes outbreaks in Africa, Madagascar, and the Arabian Peninsula.

A new bunyavirus was identified in 2010 in central and northeastern China and was named for its symptoms: severe fever with thrombocytopenia syndrome (SFTS) virus. SFTS is transmitted by tick bite (Ixodidae family, including the tick Haemaphysalis longicornis, which is found in Asia as well as among animals [rarely humans] in the eastern United States). It may also be transmitted between humans through direct contact with infected blood or secretions. Another virus (Heartland virus), identified in the United States, is similar to the SFTS virus. Transmission occurs via the Lone Star tick (Amblyomma americanum). The virus appears to be amplified in deer and raccoons. In the United States, most cases are reported from the Midwest and southern states.

Clinical Findings

A. Symptoms and Signs

The incubation period varies between species, ranging from 2 to 21 days. The clinical symptoms in the early phase of a viral hemorrhagic fever are indistinguishable from other viral illnesses. Due to lack of specific symptoms on presentation, viral hemorrhagic fevers are an important cause to consider in fever of unknown origin in children in endemic areas. The late phase is more specific and is characterized by organ failure, altered mental status, and hemorrhage. Exanthems and mucosal lesions can occur.

In advanced stages, significant edema, pleural effusion, and fewer hemorrhagic manifestations compared with EVD can develop in patients with Lassa fever and Lujo virus infection. Hearing loss in various degrees is the most common complication of Lassa fever infection. Mortality in pregnant patients during the third trimester and fetal mortality are very high.

CCHF has more prominent hemorrhagic manifestations. Patients have red eyes, flushed face, red throat, and petechiae that progress to severe uncontrollable bleeding. Severe headaches are common in CCHF and correlate with the severity of vascular damage, vasodilatation, and cytokine release.

Rift Valley fever disease can present with three distinct syndromes: (1) ocular disease; retinitis is the most common complication and permanent vision loss develops in 1–10% of patients; (2) meningoencephalitis occurs in less than 1% of cases; these patients have headache, coma, or seizures 1–4 weeks after initial symptoms and a low mortality but a high morbidity with neurologic deficits that can be severe; and (3) hemorrhagic fever; patients present 2–4 days after illness and show evidence of severe liver impairment and later hemorrhages; the hemorrhagic state occurs in less than 1% of patients, but the case-fatality ratio of such patients reaches about 50%.

B. Laboratory Findings

Laboratory features usually include thrombocytopenia, leukopenia (although with Lassa fever leukocytosis is noted), anemia, elevated liver biochemical tests, and abnormalities consistent with disseminated intravascular coagulation.

Special care should be taken for handling clinical specimens of suspected cases. Laboratory personnel should be warned about the diagnostic suspicion, and the CDC must be contacted for guidance. The diagnosis may be made by antigen detection (by ELISA), culture of the virus (the “gold standard” for Lassa virus diagnosis), PCR, or demonstration of a fourfold rise in antibody titer. CCHF is best diagnosed with an IgM serology, although IgG ELISA or immunofluorescence and quantitative RT-PCR are nearly as effective. Isolation of the viruses in culture requires a biosafety level 4 laboratory. Serologic assays are attendant with early false-negative and late false-positive assays. Newer technologies are emerging with increased sensitivities for detection of viruses causing viral hemorrhagic fever, such as the Luminex MagPix platform using microspheres.

Differential Diagnosis

The differential diagnosis for hemorrhagic fever includes meningococcemia or other septicemias, Rocky Mountain spotted fever, dengue, typhoid fever, and malaria. SFTS differential diagnosis includes anaplasmosis, hemorrhagic fever with renal syndrome, or leptospirosis. The likelihood of acquiring hemorrhagic fevers among travelers is low.

Treatment & Prevention

Patients should be placed in private rooms with standard contact and droplet precautions. Barrier precautions to prevent contamination of skin or mucous membranes should also be adopted by the caring personnel. Airborne precautions should be considered in patients with significant pulmonary involvement or undergoing procedures that stimulate cough.

Supportive care is the mainstay of therapy. There is no approved antiviral medication, but ribavirin is shown to be effective in vitro and in vivo against certain viruses (Lassa virus, CCHF, and Rift Valley fever pathogens). Early diagnosis and management can reduce mortality. Serum from convalescent Lassa fever patients was shown to be ineffective as a source of protective antibodies early studies, but currently monoclonal antibodies against Lassa virus glycoprotein are being evaluated as a treatment strategy. A cocktail of three human monoclonal antibodies (Arevirumab-3) rescued 100% of macaques at advanced stages of disease more than a week postinfection.

Postexposure prophylaxis with ribavirin in the management CCHF appears to be effective; however, little data exist to support its efficacy for Lassa fever and other arenaviruses. The antitrypanosomal agent suramin may be effective against the Rift Valley fever virus. Sorafenib, a tyrosine kinase inhibitor approved for treatment of renal cell and hepatocellular carcinoma, has antiviral activity against Rift Valley fever virus. A combination of monoclonal antibodies that cross-react with the glycoproteins of Lassa virus has been tested in macaques with promising results.

An inactivated vaccine is available for Rift Valley fever but is not licensed and is not commercially available. There are no vaccines approved for other viruses causing viral hemorrhagic fever. Several vaccines have been developed for Lassa virus but only one has entered clinical trials. A one-dose vaccine for Lassa virus that consists of a measles vector simultaneously expressing LASV glycoprotein and nucleoprotein was successfully tested in monkeys and is undergoing further clinical evaluation (NCT04055454). Two vaccines against CCHF, a DNA vaccine and an adenovirus-based vaccine expressing the nucleocapsid protein of CCHFV have been developed and tested in mouse models with demonstration of significant protection. A vaccine is also under development in Argentina for Argentinian hemorrhagic fever.

The main method of preventing Rift Valley fever is vaccination of susceptible livestock before outbreaks occur. Several vaccines have been developed for Rift Valley fever control in livestock, but only one, the Smithburn vaccine (a live attenuated virus), is produced commercially and used in East Africa. An inactivated vaccine has been developed for humans but is neither licensed nor commercially available.

When to Admit

• Persons with symptoms of any hemorrhagic fever and who have been in possible endemic area should be isolated for diagnosis and symptomatic treatment.

• Isolation is particularly important because diseases due to some of these agents, such as Lassa virus, are highly transmissible to health care workers.

General Considerations

Dengue virus belongs to the genus Flavivirus and has four distinct serotypes that can cause infection. Infection with one serotype does not confer immunity to the other serotypes. Dengue is transmitted primarily from human to human by the bite of the Aedes mosquito. Healthcare-associated transmission (needlestick or mucocutaneous exposure) and vertical transmission occur rarely. Transmission via bone marrow and solid organ transplant is also known to occur. WHO reports that dengue is currently endemic in 128 countries, mostly in tropical and subtropical regions with 3.9 billion persons at risk for infection. An estimated 390 million cases of dengue fever occur annually (with 96 million manifesting clinical disease including at least 500,000 with severe disease and up to 25,000 deaths). The surge of cases is associated with climatic factors, travel, and urbanization. Thus, along with malaria, dengue is one of the two most common vector-borne diseases of humans. Dengue is also the second overall cause of a febrile illness (after malaria and excluding common upper respiratory viral infections) in travelers returning from developing countries.

Most dengue cases occur in Asia (75% of cases) and Latin America. Bangladesh is currently experiencing a severe dengue outbreak. As of November 30, 2019, there have been 100,107 cases including 129 deaths, mostly due to serotype 3.

There are several factors that contribute to intermittent outbreaks in these regions, including the season of the year when rainfall is optimal for mosquito breeding, presence of a large population with no previous immunity to the specific serotype, and frequent contact between people and the vector.

In the United States, even though dengue is endemic in Northern Mexico and the Aedes mosquito is common in the southern states, outbreaks are uncommon. Most cases occur in travelers, immigrants, or inhabitants of US territories that are endemic to the dengue virus. Puerto Rico experiences periodic large outbreaks, as did Hawaii in 2015 and 2016. There were 264 locally acquired cases of dengue fever from Hawaii; 46 (17.4%) of the cases were among children; all cases were serotype 1.

The incubation period is usually 7–10 days. When the virus is introduced into susceptible populations, usually by viremic travelers from endemic countries, epidemic attack rates range from 50% to 70%.

Clinical Findings

A. Symptoms and Signs

A history of travel to a dengue-endemic area within 14 days of symptom onset is helpful in establishing a diagnosis. Most infected patients are asymptomatic. Only 20% develop symptoms ranging from mild disease (dengue fever) to severe hemorrhagic fever to fatal shock (dengue shock syndrome). In 1997 the WHO classified symptomatic dengue into dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. The 2009 WHO classification of dengue is the following: dengue without warning signs; dengue with warning signs; and severe dengue. This classification was criticized for lacking clarity and mixing distinct disease phenotypes within each category and was not adopted by all countries.

After the incubation period, the febrile phase begins abruptly with nonspecific symptoms, high fever, chills, facial flushing, malaise, retroorbital eye pain, generalized body pain, and arthralgia. Some patients might have maculopapular rash, sore throat, and conjunctival injection. Not all patients have all symptoms or fever. Mild hemorrhagic manifestations can be seen. Most of the patients will recover, and fever is usually cleared by day 8.

A subset of patients, especially those with suboptimally controlled type 2 diabetes, may progress to severe dengue, which is defined by the presence of plasma leakage, hemorrhage, or organ involvement. Hematocrit drop may be the earliest sign and an indicator of the severity of plasma leakage. Pleural effusion and ascites can develop and may be detected by lateral decubitus chest radiograph or ultrasound before clinical detection. Increasing liver size, persistent vomiting, and severe abdominal pain are indications of plasma leakage. Signs of hemorrhage such as ecchymoses, gastrointestinal bleeding, and epistaxis appear. Severe organ involvement may develop, such as hepatitis, encephalitis, and myocarditis.

Shock develops in patients when a critical volume of plasma is lost through leakage. Decrease in the level of consciousness, hypothermia, hypoperfusion resulting in metabolic acidosis, progressive organ impairment, and disseminated intravascular coagulation leading to severe hemorrhage should raise concern for shock. Acute kidney injury in dengue largely occurs with shock syndrome and shows a high mortality.

After the critical phase, the patient enters the recovery phase, where extravascular compartment fluid is reabsorbed and the bleeding stops. Vital signs and laboratory abnormalities normalize.

B. Laboratory Findings

Leukopenia is characteristic, and elevated transaminases are found frequently in dengue fever. Thrombocytopenia, fibrinolysis, and hemoconcentration occur more often in the hemorrhagic form of the disease. In other forms of disease, especially in children, anemia is more common. The erythrocyte sedimentation rate (ESR) is often normal in most cases.

The nonspecific nature of the illness mandates laboratory verification for diagnosis, usually with IgM and IgG ELISAs after the febrile phase. Virus is recovered from the blood by PCR or detection of the specific viral protein NS1 by ELISA during the first few days of infection. Immunohistochemistry for antigen detection in tissue samples and dried blood spots can also be used. Thrombocytopenia and blood vessel fragility in remote settings can be assessed with a tourniquet cuff test.

Differential Diagnosis

Distinguishing between dengue and other causes of febrile illness in endemic areas is difficult. Fevers due to dengue are more often associated with neutropenia and thrombocytopenia and with myalgias, arthralgias/arthritis, and lethargy among adults. Chikungunya is more apt to develop a chronic arthritis. The arboviral encephalitides require additional epidemiologic information and serologic data to make the diagnosis. Influenza and malaria are easily confused early in disease, although the rhinitis and malaise should help distinguish influenza, and the cyclicity of fevers and presence of splenomegaly should suggest malaria.

Complications

Usual complications include pneumonia, bone marrow failure, hepatitis, iritis, retinal hemorrhages and maculopathy, orchitis, and oophoritis. Neurologic complications (such as encephalitis, Guillain-Barré syndrome, phrenic neuropathy, subdural hematoma, cerebral vasculitis, and transverse myelitis) are less common. Acute disseminated encephalomyelitis has been linked with infection and the live dengue vaccine. Bacterial superinfection can occur. Oral complications include acute gingivitis, palatal bleeding, tongue plaques, xerostomia, and rarely osteonecrosis of the jaw.

Maternal infection poses a risk of hemorrhage in both the mother and the infant if infection occurs near term. Severe dengue is a risk factor for obstetric complications, cesarean delivery, fetal distress, and maternal morbidity.

Treatment

There are no specific therapeutic options for the clinical management of dengue besides supportive care. Treatment entails the appropriate use of volume replacement, blood products, and vasopressors. Acetaminophen is recommended for analgesic and antipyretic treatment. NSAID usage should be minimized and preferably avoided to decrease the risk of gastritis and bleeding, particularly in patients with a predilection for hemorrhage or when there are abnormalities in platelets, liver function, or clotting factors.

Platelet counts do not usefully predict clinically significant bleeding. Platelet transfusions may be considered for severe thrombocytopenia (less than 10,000/mcL) or when there is evidence of bleeding. However, benefit in the absence of bleeding may not be observed, and harm may be caused by delay in count recovery. Monitoring vital signs and blood volume may help in anticipating the complications of dengue hemorrhagic fever or shock syndrome.

Repurposed drugs, such as chloroquine, statins, and balapiravir, are being explored for the treatment of dengue, although none has shown clear therapeutic benefit. New research is focusing on monoclonal antibodies as a therapeutic option as well as drugs including peptide agents that target structural and nonstructural proteins of dengue virus essential to its replication.

Prognosis

Although fatalities occur with severe disease, the estimated mortality (2.5% of severe cases) appears to be diminishing, likely due to improved recognition of the disease and wider availability of supportive treatment. Causes of death include hemorrhagic fever (seen with recurrent disease) and occasionally fulminant hepatitis. Thrombocytopenia and acute hepatitis are predictors of severe dengue and higher mortality. Acute kidney injury in dengue shock syndrome portends poor prognosis. In general, the more severe forms of disease (hemorrhagic fever and shock) occur more often in Asia than in the Americas. Comorbidities of cardiovascular disease, diabetes, stroke, pulmonary disease, kidney disease, and older age are associated with more severe dengue.

Prevention

Preventive measures should be encouraged, such as control of mosquitoes by screening and insect repellents including long-lasting insecticides, particularly during early morning and late afternoon exposures. Screening blood transfusions for dengue is important, especially in endemic areas.

Dengvaxia (CYD-TDV), a recombinant, live, attenuated, tetravalent dengue vaccine, is FDA approved for children 9–16 years old with previous history of dengue infection and who live in endemic areas. It was first licensed in 2015 and now is approved in more than 20 countries. Trials evaluating the efficacy of this vaccine reported overall 56% efficacy; however, efficacy was lower in younger age groups, seronegative individuals at the time of vaccination, and those infected with dengue serotype 2. The vaccine is given as a 0-, 6-, and 12-month series. Serious side effects were no more common than in placebo recipients. Vaccination is indicated for those between ages 9 and 45 years. However, Dengvaxia carries an increased risk of severe dengue in those who experience their first natural dengue infection after vaccination (those who were seronegative at the time of vaccination). Thus, the WHO recommends limiting the vaccine to those who have had at least one dengue infection prior to vaccination and, for countries considering using Dengvaxia as part of their dengue control program, recommends pre-vaccination screening using dengue serology. Pregnant women and immunosuppressed persons should not be vaccinated. Another tetravalent dengue vaccine, a two-dose TAK-003, is currently in phase 3 clinical trials and has shown promising results (80.2% efficacy; NCT02747927).

Since 2011, researchers have been injecting a bacterium that blocks mosquitos’ ability to transmit viruses (such as dengue and Wolbachia pipientis) into the eggs of Aedes aegypti mosquitoes. In some study areas, as much as a 76% reduction in the rate of dengue has been observed.

General Considerations

Hantaviruses are enveloped RNA bunyaviruses naturally hosted in rodents, moles, and shrews. Hantavirus infection in humans can cause several disease syndromes. HFRS is primarily caused by Dobrava-Belgrade virus, Puumala virus, Seoul virus, and Hantaan virus in Asia and Europe. These viruses are called Old World hantaviruses. Nephropathia epidemica is a milder form of HFRS. Puumala virus is the most prevalent pathogen and is present throughout Europe. The HPS, also known as hantavirus cardiopulmonary syndrome, is caused mainly by Sin Nombre virus and Andes virus, the New World Hantaviruses in Americas (eFigure 32–3). While they share many clinical features, a specific strain is not associated with a specific syndrome and overlap is seen between the syndromes. The primary reservoirs include the field mouse for Hantaan virus HFRS, the bank vole for Puumula virus, and the deer mouse for SNV-HPS.

Aerosols of virus-contaminated rodent urine and feces are thought to be the main vehicle for transmission to humans. Person-to-person transmission is observed only with the Andes virus. Occupation is the main risk factor for transmission of all hantaviruses: animal trappers, forestry workers, laboratory personnel, farmers, and military personnel are at highest risk. Climate change appears to be impacting the incidence of hantavirus infection mainly through effects on reservoir ecology.

Clinical Findings

A. Symptoms and Signs

Vascular leakage is the hallmark of the disease for both syndromes, with kidneys being the main target with variants associated with HFRS and the lungs with variants associated with HPS.

1. HFRS

HFRS manifests as mild, moderate, or severe illness depending on the causative strain. A 2- to 3-week incubation period is followed by a protracted clinical course, typically consisting of five distinct phases: febrile period, hypotension, oliguria, diuresis, and convalescence phase. Various degrees of kidney involvement are usually seen. Puumala virus infection is often referred to as nephropathia epidemica. The kidney failure component appears to correlate with levels of the plasma adipokine resistin, which may by internalized or diffuse (as a capillary leak syndrome) and often confused with the complications of disseminated intravascular coagulation. Thromboembolic phenomena are also recognized complications. A secondary hemophagocytic lymphohistiocytosis can be seen with HFRS. Pulmonary edema is not typically seen but when present usually occurs in the final stages of disease (oliguric and diuretic phase). Encephalitis and pituitary involvement are rare findings with hantavirus infection, although a few cases are reported with Puumala virus infection. Patients may have persistent hematuria, proteinuria, or hypertension up to 35 months after infection. Smoking appears to exacerbate the viremia with the Puumala virus infection, and bradycardia can also be prominent.

2. HPS

The clinical course of HPS is divided into a febrile prodrome, a cardiopulmonary stage, oliguric and diuretic phase, followed by convalescence. A 14- to 17-day incubation period is followed by a prodromal phase, typically lasting 3–6 days, that is associated with myalgia; malaise; abdominal pain along with nausea, vomiting, and diarrhea; headache; chills; and fever of abrupt onset. An ensuing cardiopulmonary phase is characterized by the acute onset of pulmonary edema. In this stage, cough is generally present, abdominal pain and symptoms as above may dominate the clinical presentation, and in severe cases, significant myocardial depression occurs. Acute kidney injury and myositis may occur. Sequelae include neuropsychological impairments in some HPS survivors.

B. Laboratory Findings

Laboratory features include hemoconcentration and elevation in lactate dehydrogenase, serum lactate, and hepatocellular enzymes. Early thrombocytopenia and leukocytosis (as high as 90,000 cells/mcL in HPS) are seen in both HFRS and HPS. In HPS, immunoblasts (activated lymphocytes with plasmacytoid features) can be seen in blood, lungs, kidneys, bone marrow, liver, and spleen.

An indirect fluorescent assay and enzyme immunoassay are available for detection of specific IgM or low-avidity IgG virus-specific antibodies. A quantitative RT-PCR is available; however, the viremia of human hantavirus infections is short-term, and therefore, viral RNA cannot be readily detected in the blood or urine of patients unless for the more readily detected early viremia of the Andes variant.

A plaque reduction neutralization test remains a gold standard serologic assay and distinguishes between the different hantavirus species, although cross reaction between Old and New World viruses exist. This test needs to be performed in a laboratory with appropriate biosafety (level 3).

Differential Diagnosis

The differential diagnosis of the acute febrile syndrome seen with HFRS or early HPS includes scrub typhus, leptospirosis, and dengue. HPS requires differentiation from other respiratory infections caused by such pathogens as Legionella, Chlamydia, and Mycoplasma. Coxsackievirus infection should also be considered in the differential diagnosis.

Treatment

Treatment is mainly supportive. Cardiorespiratory support with vasopressors is frequently needed; extracorporeal membrane oxygenation may be required in severe cases of HPS. Intravenous ribavirin is used in HFRS (Hantaan virus) with some success in decreasing the severity of the kidney injury. Its effectiveness in HPS, however, is not established. The role of the entry receptor protocadherein-1 in HPS is a new avenue for investigation and control of disease.

Prevention

Because infection is thought to occur by inhalation of rodent waste, prevention is aimed at eradication of rodents in houses and avoidance of exposure to rodent excreta, including forest service facilities. Climatic changes often require particular attention to rodent populations in parks. Inactivated vaccines are used in several Asian countries where patients are at risk for HFRS.

Prognosis

The outcome is highly variable depending on severity of disease. HPS is a more severe disease than HFRS, with a mortality rate of about 40%. In Sin Nombre virus infections, the persistence of elevated IgG titers correlates with a favorable outcome.

General Considerations

Yellow fever is a zoonotic flavivirus infection transmitted by Aedes mosquitoes bite. There are three types of transmission cycles: sylvatic (or jungle; humans working or travelling in the forest are bitten by infected mosquitoes), intermediate (most common type of outbreak in Africa; mosquitoes infect both monkeys and people leading to outbreaks in separate villages), and urban (seen in large epidemics; infected mosquitoes transmit the virus from person to person). Elevated temperatures and increased rainfall are major determinants of transmission.

Yellow fever occurs in 47 endemic countries in Africa and in Central and South America. Around 90% of cases reported every year occur in sub-Saharan Africa. Adults and children are equally susceptible, though attack rates are highest among adult males because of their work habits. Modeling data from Africa in 2013 estimates the annual case load is 84,000 to 170,000 annual cases with 29,000 to 60,000 deaths. The number of susceptible vaccinees worldwide is estimated to be between 394 million and 473 million.

This decade has seen a resurgence of yellow fever, likely due to suboptimal vaccination coverage along with waning population-level immunity. Nigeria reported an outbreak of yellow fever in 2019; between August 29 and September 22, 231 suspected cases were reported, including 24 confirmed cases (of which there were 6 deaths). There has been an outbreak of yellow fever in Brazil since 2016. Between January 2016 and June 2018, 2153 cases were reported, including 744 deaths.

Clinical Findings

A. Symptoms and Signs

Most persons have no illness or only mild illness. The incubation period is 3–6 days in persons in whom symptoms develop.

1. Mild form

Symptoms are malaise, headache, fever, retroorbital pain, nausea, vomiting, and photophobia. Relative bradycardia (an increase in heart rate of fewer than 10 beats/min for a 1°C increase in temperature), conjunctival injection, and facial flushing may be present.

2. Severe form

Severe illness develops in about 15%. Initial symptoms are similar to the mild form, but brief fever remission lasting hours to a few days is followed by a “period of intoxication” manifested by fever and relative bradycardia (Faget sign), hypotension, jaundice, hemorrhage (gastrointestinal, nasal, oral), and delirium that may progress to coma.

B. Laboratory Findings

Leukopenia, elevated liver enzymes, and bilirubin can occur. Proteinuria is present and usually disappears completely with recovery. Bleeding dyscrasias with elevated prothrombin and partial thromboplastin times, decreased platelet count, and presence of fibrin-split products, can also occur.

In the early stages of the disease (up to 10 days), diagnosis is confirmed if yellow fever virus RNA is detected by RT-PCR in blood from a person with no history of recent yellow fever vaccination. PCR determinants can distinguish between wild type virus and vaccine-associated strains.

In later stages, serologic diagnosis can be made by using ELISA to measure IgM 3 days after the onset of symptoms; however, yellow fever vaccine and other flaviviruses, including dengue, West Nile, and Zika viruses, may give a false-positive ELISA test result. Thus, the presence of yellow fever virus–specific IgM antibody and negative ELISA panel for other relevant flaviviruses confirm the diagnosis. If ELISA is positive for other flaviviruses, the more specific plaque reduction neutralization assay should be done in reference laboratories, which measures the titer of the neutralizing antibodies in the serum toward the infecting virus.

Differential Diagnosis

It may be difficult to distinguish yellow fever from other viral hepatidites, malaria, leptospirosis, louse-borne relapsing fever, dengue, and other hemorrhagic fevers on clinical evidence alone. Albuminuria is a constant feature in yellow fever patients, and its presence helps differentiate yellow fever from other viral hepatitides. Serologic confirmation is often needed.

Treatment

No specific antiviral therapy is available. Treatment is directed toward symptomatic relief and management of complications. A clinical trial of sofosbuvir for treatment of yellow fever is underway in Brazil.

Prognosis

The mortality rate of the severe form is 20–50%, with death occurring most commonly between the sixth and the tenth days. Convalescence is prolonged, including 1–2 weeks of asthenia. Infection confers lifelong immunity to those who recover.

Prevention

The yellow fever vaccine, which is derived from the live attenuated 17D strain (with substrains 17D-204 and 17DD similar in efficacy and side effects) and currently given as a single dose for a lifetime, is the most effective way to prevent and control disease. A single dose of vaccine in the past was considered to provide lifelong immunity. While the 10-year booster dose is no longer recommended for most people, persistent seropositivity at 8 years post vaccination is only 85% (and below 60% in children vaccinated at 9–12 months of age). Thus, at-risk groups with waning immunity and high probability of exposure may consider receiving a second dose of vaccine after 10 years (these groups are listed at https://www.cdc.gov/yellowfever/healthcareproviders/vaccine-info.html).

Yellow fever vaccine is recommended for persons aged over 9 months who are traveling to or living in areas at risk for yellow fever virus transmission. This vaccine should never be given to children under 6 months old due to their higher risk of developing encephalitis related to the vaccine. WHO recommends that all endemic countries should include yellow fever vaccine in their national immunization programs. The egg-based method currently used to manufacture the vaccine prevents a fast increase in vaccine production, leading to occasional vaccine supply shortage. As a consequence of several large yellow fever outbreaks since 2016, a global shortage of the vaccine has occurred. One strategy that has been used to address this shortage is fractionating the available yellow fever vaccine doses. Vaccine manufacturers are working on new yellow fever vaccines based on cell culture and DNA technologies.

The vaccine is contraindicated in persons with severe egg allergies or who are severely immunocompromised, including patients with primary immunodeficiencies, HIV infection with CD4+ count below 200/mcL, thymus disorder with abnormal immune function, malignant neoplasms, transplantation, or immunosuppressive and immunomodulatory therapies. The vaccine should not be given to breastfeeding women or patients over 60 years of age because this age group is at higher risk for viscerotropic and neurologic disease. It should be administered at least 24 hours apart from the measles vaccine. Pregnant women should receive the vaccine only if they cannot defer travel to endemic areas (Chapter 30). Clinicians should be aware of rare but frequently fatal vaccine-induced reactions, including anaphylaxis, yellow fever vaccine–associated viscerotropic disease, and yellow fever vaccine–associated neurologic disease.

A 2017 initiative, the Eliminate Yellow Fever program, is composed of 50 organizations and is designed to increase surveillance and control in 40 countries of Africa and the Americas in an attempt to reach a billion at-risk individuals with seroprotection by 2026.

The best personal protective measures are to avoid mosquito bites. If not in an endemic area, the patient should be isolated from mosquitoes to prevent transmission, since blood in the acute phase is potentially infectious.