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  More than 20 RNA viruses within four families (Flaviviridae, Arenaviridae, Filoviridae, and Bunyaviridae) cause viral hemorrhagic fevers (VHFs).

  
  
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  The prevalent VHFs are dengue HF, yellow fever (YF), Lassa fever (LF), Rift Valley fever (RVF), and hemorrhagic fever with renal syndrome (HFRS).

  
  
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  Emerging VHFs include Chapare, Lujo, Alkhurma, severe fever with thrombocytopenia syndrome (SFTS), and novel hantaviruses.

  
  
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  Hantaviruses cause HFRS in the Old World and hantavirus cardiopulmonary syndrome (HCPS) in the New World. HCPS manifests as low-pressure pulmonary edema, pleural effusions, and cardiogenic shock, but not VHF.

  
  
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  Mosquitoes are the vector of dengue, YF, and RVF.

  
  
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  Ticks are the vector of Crimean-Congo HF (CCHF), Omsk HF (OHF), Kyasanur forest disease (KFD), Alkhurma HF, and SFTS.

  
  
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  Arenaviruses and hantaviruses are rodent-borne zoonoses.

  
  
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  Exposure to domestic animals is a major mode of infection in RVF and CCHF.

  
  
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  RVF causes simultaneous epizootics in animals and large epidemics in humans.

  
  
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  Dengue and Seoul hantavirus are urban infections. YF is endemic in jungles and African savannas, but also causes urban epidemics. The other VHFs are rural infections because of the distribution of ticks and rodent or bat reservoirs.

  
  
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  Nosocomial infections are a feature of CCHF, filoviruses, arenaviruses, Andes hantavirus, and SFTS bunyavirus. This risk is high when standard precautions for blood-borne pathogens are not followed. Attempting viral isolation requires high biosafety level precautions (BSL 3 or 4 for most VHF pathogens).

  
  
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  The incubation period usually is shorter than 2 weeks, but longer with hantaviruses. The onset of illness usually is sudden, but insidious with arenaviruses.

  
  
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  Clues to dengue fever are urban acquisition, break-bone fever, rash, hemoconcentration, and thrombocytopenia. Danger signs for dengue HF include abdominal pain, persistent vomiting, effusions, mucosal bleed, lethargy, restlessness, liver enlargement, hemoconcentration, and severe thrombocytopenia.

  
  
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  YF vaccine–associated viscerotropic disease (YEL-AVD) is encountered only rarely in recipients who are older or have abnormal thymus function.

  
  
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  Clues to LF are insidious onset, sore throat, chest pain, cervicofacial edema, high maternal mortality and fetal loss during pregnancy, and irreversible deafness.

  
  
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  Clues to filovirus (Marburg and Ebola) infections are a rash around the fifth day, severe bleeding, jaundice, person-to-person transmission in community outbreaks and nosocomial settings, and a very high mortality rate.

  
  
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  A delayed-onset rash is characteristic of dengue, filoviruses, and LF.

  
  
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  Jaundice and liver failure are typical of YF, CCHF, RVF, and filovirus HF.

  
  
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  Bleeding is often severe with CCHF, filoviruses, South American VHFs, and Hantaan virus–associated HFRS, but only rarely so in dengue and LF.

  
  
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  Neurological complications are seen in South American HF, KFD, Alkhurma HF, and a small minority of RVF virus infection.

  
  
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  Acute kidney injury is typical in HFRS and YF, and also seen in HCPS.

  
  
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  Ribavirin is proven effective in Lassa fever and HFRS, and may be effective in South American HF and CCHF.

Viral hemorrhagic fever (VHF) starts with a nonspecific febrile prodrome associated with protean manifestations, followed by widespread endovascular insult, viral immunosuppression, multiorgan damage, hemorrhagic complications, and shock. The mortality rate depends on the pathogen, the inoculum size, and host factors.

VHF viruses belong to four families of enveloped, single-stranded RNA viruses: Flaviviridae, Arenaviridae, Filoviridae, and Bunyaviridae (Table 80-1). They infect humans through exposure to animals (zoonosis), or through the bite of an arthropod vector. Person-to-person transmission occurs with some viruses both in community and in health care settings. The geographic distribution of VHFs is limited by the distribution of the arthropod vector or the natural reservoir.^1,2

VHFs are identified in North America, mostly in travelers. Dengue fever (DF) is often diagnosed in travelers, but severe DF is not common.^3-7 Yellow fever (YF) is occasionally reported in travelers even though most of those at risk of exposure are immunized.^8,9 Lassa fever (LF) and filovirus HF have been reported in travelers.^10-15 Such travel-associated infections may increase in the future due to increased high-risk “adventure” travel to remote areas of the world where VHF viruses are prevalent.

Acquisition of VHF in the United States occurs. Dengue is present on US territory.^16,17 Significant rates of Seoul hantavirus infection are reported in rats trapped in US cities and at-risk human populations have evidence of prior infection.^18-20 Lab accidents and person-to-person transmission of VHF viruses have occurred in Western countries.^21,22 Rift Valley fever could be introduced into Europe or the United States.²³ Bioterrorism is a significant threat with VHF pathogens listed on the group A bioterrorism agent list.²⁴ The manifestations of VHFs depend on the specific pathogens, but with significant overlap (Table 80-2). Physicians should consider the diagnosis of VHF in the appropriate setting and recognize the severity of illness, the need to implement specific measures to prevent spread, and the potential benefits of ribavirin.

FLAVIVIRIDAE

VHF-causing Flaviviridae include dengue and YF, which are highly prevalent over wide geographic areas, and three geographically restricted infections: Omsk hemorrhagic fever, Kyasanur forest disease, and Alkhurma HF.

Dengue Fever and Dengue Hemorrhagic Fever

The Pathogen and the Life Cycle Dengue virus (DENV) is an enveloped positive-strand RNA flavivirus. Its genome encodes three structural proteins and seven nonstructural proteins.²⁵ There are four serotypes (DENV-1, DENV-2, DENV-3, and DENV-4) and multiple genotypes.

DF is an urban disease. DENV is transmitted from person to person through the bite of Aedes mosquitoes. Aedes aegypti, the most important vector of DF, is broadly distributed in the tropical and subtropical regions of the world and is well adapted to survival within and around urban homes where its larvae infest water-filled artificial containers.²⁶ The tiger mosquito (Aedes albopictus) was introduced into the United States with recycled tires in the 1980s and has spread to at least 30 states.²⁶ DF outbreaks have been seen in Hawaii, Texas, and the Florida Keys.^16,17,27

A primitive sylvatic transmission cycle of DENV involves canopy-dwelling mosquitoes and primates of Asia and Africa.²⁶ DENV can be transmitted through transfusion.²⁸ Infection of pregnant women near term may result in fetal and neonatal illness.²⁹

Pathogenesis Infection by one serotype (primary dengue infection) causes homotypic long-term immunity with development of neutralizing antibodies, but only transiently protective cross-immunity to the three other serotypes.³⁰ Over time, falling cross-reactive antibodies are unable to prevent infection by heterotypic serotypes. When subsequent heterotypic infection occurs (secondary dengue infection), there is a greater risk of severe illness. Secondary dengue infection is associated with antibody-dependent enhancement (ADE): The binding of nonneutralizing heterotypic antibody to DENV creates virus-antibody complexes that activate the complement and bind to Fc-receptor-bearing monocytes and macrophages, resulting in increased phagocytosis and intracellular replication with prolonged viremia. Antibodies to dengue structural precursor-membrane protein (prM) are highly cross-reactive and might be involved in ADE.^30,31 Dengue is more severe in children between 4 and 12 months old who are born to seropositive mothers: Maternal antibody that crosses the placenta is initially protective but at low levels may later result in ADE.³⁰ Dengue HF (DHF) outbreaks are frequently recognized in hyperendemic dengue regions where multiple serotypes cocirculate.

However the pathogenesis of severe dengue also involves cross-reactive activated memory T lymphocytes, proinflammatory cytokines (IFN-γ, TNF-α, and IL-10) that mediate increased endothelial permeability and the interval between dengue primary and secondary infections. A number of host factors (young age, female sex, non-African ancestry, and specific HLA alleles) predict severe dengue.^30,31 Viral factors are relevant: The serotypes DENV-2 and DENV-3 are most often found in severe dengue. Virulent DENV genotypes cause epidemics of DHF and severe primary dengue.³²

Epidemiology DF is a global public health problem. After WWII, the incidence of DF greatly increased in Asia where rapid urbanization and poorly maintained cities led to enormous A aegypti proliferation.³³ The first DHF outbreak was recognized in the Philippines in the 1950s.³³ Dengue was uncommon in the Americas from 1947 to 1980 due to a successful vector elimination program.³⁴ Because of rapid urbanization, the vector reinfested Latin America. From 1981, dengue epidemics were recognized in Latin America and the Caribbean islands. More recently, the incidence of DF has increased in Eastern and Western Africa. Dengue is endemic in more than 100 countries of Asia, Africa, and Latin America with annually a modeled 50 to 100 million infections, 500,000 DHF cases, and more than 20,000 deaths.³⁵ DF is common in travelers to Latin America, the Caribbean, and South Central or Southeast Asia.^5,7

The Clinical Spectrum DENV causes asymptomatic infections, mild fever, DF, DHF, and dengue shock syndrome (DSS). The incubation period is on average 4 to 7 days (range 3-14 days).

In DF (classic dengue) there is sudden onset of fever associated with headache, retroorbital pain, low back pain, body aches (break-bone fever), anorexia, vomiting, sore throat, and generalized skin flushing or mottling. The fever is high (102°F-105°F) for 2 to 7 days, may drop for 12 to 24 hours then recurs (saddleback fever). A relative bradycardia is noted. The conjunctivae are injected, extraoccular movements are painful, the pharynx is erythematous, and lymphadenopathy is present. A maculopapular rash appears on illness day 2 to 6. Sometimes it is a generalized erythema with islands of normal skin (“a sea of red with islands of white”). Children with dengue tend to appear quiet and uncomfortable. At the end of the febrile phase, hemorrhagic manifestations may appear, usually limited to petechiae or mild epistaxis. Laboratory tests show leukopenia, neutropenia, thrombocytopenia, and elevated transaminases. Usually the thrombocytopenia worsens, the hematocrit rises, and lymphocytosis appears, but DF is self-limiting.

In DHF, after a typical prodrome, as the fever resolves, signs of circulatory failure and/or hemorrhagic manifestations appear.^26,30-34 Danger signs include intense and continuous abdominal pain, persistent vomiting, clinical fluid accumulation, mucosal bleed, lethargy, restlessness, liver enlargement >2 cm, and the combination of hemoconcentration and rapidly worsening thrombocytopenia.^36,37 In severe dengue, an acute increase in vascular permeability leads to plasma leakage (hemoconcentration), clinical effusions (pleural, pericardial, and peritoneal effusions; hydrops of the gallbladder), and hypotension. Hemorrhagic complications are usually mild (petechiae) but may be more severe (purpura, large ecchymoses, bleeding at sites of venipuncture, and gastrointestinal bleed). Shock (DSS) is due to intravascular hypovolemia from plasma leakage rather than from bleeding. In epidemics associated with virulent DENV serotypes, there are many severe primary dengue cases with hepatomegaly, high transaminases, and liver failure.^26,32 The liver pathology shows midzonal necrosis and Councilman bodies like in YF.²⁶ Myocarditis and neurologic presentations are rare manifestations of severe dengue.³⁸

The World Health Organization (WHO) published two clinical classifications to categorize severity of dengue. A first classification defined DF, DHF, and DSS.^33,39 A recent classification defines dengue without danger signs, dengue with danger signs, and severe dengue⁴⁰ (Table 80-3).

Diagnosis In primary dengue infection, IgM then IgG antibodies appear at the end of the febrile phase and the titers rise slowly. In secondary dengue infection, IgG antibodies appear early in the acute phase and the titers rise rapidly. IgM are positive in 80% by day 5 of illness. Various techniques to detect dengue antibodies are commercially available: Capture ELISA is highly sensitive and specific. Dengue IgM is not serotype specific and may cross-react with other flaviviruses.^25,41 Detection of NS1 antigen by ELISA confirms the diagnosis early in the acute phase with a good sensitivity (82%) before IgM appears.^25,41 PCR and viral isolation are only useful in epidemiological research.

Management of Severe Dengue Patients with DF should not receive aspirin or ibuprofen but should be kept well hydrated. Patients with danger signs may deteriorate rapidly. Patients with severe dengue are admitted to the ICU to help manage fluid balance. Intravenous isotonic crystalloid fluids (0.9% normal saline or lactated Ringer solution) are helpful to reverse hemoconcentration but excessive infusion may result in pulmonary edema. To manage refractory shock, colloidal solutions (plasma or dextran) and vasopressors have been tried. WHO guidelines for the management of severe dengue in small hospitals emphasize fluid management based on hemoconcentration and body weight.⁴²

Dengue only requires BSL-2 precautions, and there is no person-to-person transmission.

Yellow Fever

The Pathogen and the Life Cycle Yellow fever virus (YFV) is a flavivirus transmitted from person to person through the bite of female Aedes aegypti and other mosquitoes. The genome encodes three structural proteins and seven nonstructural proteins.^43,44 There is only one serotype, but there are at least seven genotypes.⁴⁴ YF is present in tropical and subtropical regions of Africa and America. YF was endemic in North America and Europe but has been eradicated. YF has never been endemic in Asia, but the vector is present.

Pathogenesis The pathogenesis of YF has been studied in macaques. After inoculation by an infected mosquito, YFV replicates locally in dendritic cells and draining lymph nodes. Viremia seeds lymphoid tissues and the liver. YFV infects first the Kupffer cells then the hepatocytes, resulting in steatosis and virus-induced apoptosis with formation of Councilman bodies (apoptotic hepatocytes).⁴⁵

Epidemiology YF originated in Africa and was introduced to America with the slave trade. It was a major scourge in the 18th and 19th centuries in Africa and America, but vector control and the development of an effective vaccine have decreased the prevalence.

There are three transmission cycles: The jungle and the urban cycles are present in both America and Africa, but the intermediate cycle is only present in the African savannas. The jungle cycle is maintained in the forest canopy between monkeys and mosquitoes. Human infection occurs occasionally. In the savanna, treehole-breeding Aedes mosquitoes transmit YFV from monkeys to people and from person to person. The urban cycle is due to A aegypti transmission of YFV from person to person with large epidemics.⁴³ There are an estimated 200,000 clinical cases annually, 90% in Africa, with 30,000 deaths.^8,46

Three million persons from nonendemic countries travel to endemic areas. During epidemics, the risk of infection of unvaccinated travelers may be as high as 1 in 267.⁴⁶ In countries with high rates of immunization, outbreaks are rare; however, the risk of jungle YF is unaffected (zoonotic transmission). At-risk travelers without contraindications should be immunized and provided with an international certificate of vaccination.⁴³ CDC publishes YF distribution maps and lists country-specific immunization requirements in the “yellow book.”^47,48

The Clinical Spectrum YFV infection may lead to asymptomatic infection, nonspecific fever, or a severe HF. Case fatality of clinical cases is 20% to 50%.

Three to six days after infection through a mosquito bite, the “period of infection” starts with a sudden onset of fever and systemic symptoms (headache, low back pain, and myalgia). Relative bradycardia and injection of the conjunctivae, face, and tip of the tongue are characteristic. Labs show leukopenia, neutropenia, and elevated transaminases. After 3 to 6 days, the fever resolves and viremia is cleared (period of remission). In 75% to 85% of cases, the illness resolves (abortive YF). In 15% to 25% of cases, a 3- to 8-day long period of intoxication manifests as a severe VHF with fever, jaundice, vomiting, epigastric pain, renal failure, prostration, and hemorrhagic complications. The liver is tender. Hemorrhagic manifestations are severe: petechiae, ecchymoses, bleeding from puncture sites, epistaxis, gum bleeding, metrorrhagia, melena, and coffee ground emesis (black vomit). Laboratory abnormalities include neutrophilic leukocytosis, elevated transaminases, hyperbilirubinemia, proteinuria, elevated creatinine, thrombocytopenia, and coagulopathy. Patients with hepatorenal syndrome have a high mortality. Refractory shock, encephalopathy, metabolic acidosis, hypoglycemia, and hypothermia predict a poor outcome. Convalescence results in resolution of liver and kidney abnormalities.⁴³

Diagnosis Confirming the diagnosis of YF relies on serology using IgM-capture ELISA, MIA (microsphere-based immunoassay), and IgG ELISA.⁴⁷

Management of Yellow Fever There is no specific therapy and management is supportive.^43,49

17D Yellow Fever Vaccine Since 1937, at least 500 million doses of the live, attenuated 17D YF vaccine have been administered. Protective immunity develops in >95% of recipients and lasts for at least 30 years, but the WHO recommends a booster every 10 years. Vaccination of travelers prevents both infection and spread of YF by viremic travelers.⁴⁶

The vaccine is very safe overall.⁵⁰ Anaphylaxis is reported in 0.8 per 100,000 doses, often with a history of allergy to eggs or gelatin. YF vaccine–associated neurologic disease (YEL-AND) rarely complicates primary YF immunization as manifested by viral encephalitis, acute disseminated encephalomyelitis (ADEM), and Guillain-Barré syndrome (GBS). YF vaccine is contraindicated in infants younger than 9 months old due to a higher risk of YEL-AND. The risk of YEL-AND is 0.4 to 0.8 cases per 100,000 doses overall, but higher above age 65.^46,51,52

YF vaccine–associated viscerotropic disease (YEL-AVD) has been recognized in primary vaccines since 1998.^53-55 Two to five days after immunization, there is sudden onset of fever, headache, and myalgia, with progression to a severe multisystemic illness (hypotension, thrombocytopenia, renal failure, abnormal liver function, respiratory failure, pulmonary infiltrates, pleural effusion, myocarditis, and encephalitis) with a 60% mortality rate. Vaccine virus is readily isolated. The risk of YEL-AVD is only 0.3 to 0.5 per 100,000 doses overall, but increases with age over 60 and prior thymus disorder.^56-59

Infection Control and Prevention of Nosocomial Transmission YF requires BSL-3. Strict precautions for VHFs are required until YF is confirmed.

Omsk Hemorrhagic Fever: Omsk hemorrhagic fever (OHF) was recognized in 1941 in western Siberia in persons exposed to muskrats or their skins. The virus (OHFV) was isolated in 1947. The natural cycle involves the meadow tick Dermacentor reticulatus and small animals. Muskrats introduced from Canada to western Siberia in the thirties are highly susceptible and shed OHFV for weeks, which amplified the natural cycle. After a short incubation (3-7 days), patients develop sudden onset of a high fever with headache, myalgias, conjunctival injection, and flushing of the face and neck. Bleeding from mucosal surfaces is typical, and severe cases may be complicated by gastrointestinal bleeding and hemoptysis. Some patients have a rash. Most improve within 1 to 2 weeks but about a third develop a second fever with recurrence of the initial symptoms, bleeding, meningoencephalitis, renal involvement, or pneumonia. The mortality rate is 1% to 2%.

The diagnosis is confirmed by serology (OHFV IgG ELISA).⁶⁰

Kyasanur Forest Disease: Kyasanur forest disease (KFD) causes HF in Karnataka State in south India. People are infected through the bite of Haemaphysalis spinigera ticks, which feed on monkeys and other animals. After a short incubation, there is sudden onset of fever, along with headache, back pain, myalgia, vomiting, diarrhea, cough, and conjunctival injection, followed in some patients by hemorrhagic manifestations and neurological complications. Encephalitis may develop 1 to 2 weeks after apparent recovery. The case-fatality rate is 2% to 10%. A formol-inactivated vaccine is used in India, but its efficacy is limited.^61,62

Alkhurma Hemorrhagic Fever: Alkhurma hemorrhagic fever virus (ALKV) causes HF in Saudi Arabia and in travelers returning from Egypt. The natural cycle involves camels, sheep, and soft ticks (Ornithodoros savignyi). Humans get infected when butchering camels and sheep, drinking unpasteurized milk, or through tick bites. There is sudden onset of fever, headache, myalgia, arthralgia, vomiting, and in severe cases bleeding (epistaxis, ecchymoses, petechiae, hematemesis) or neurologic complications (encephalitis) with a high case-fatality rate.⁶³ KFDV and AHFV share >90% sequence homology, suggesting a common ancestral origin. Alkhurma virus might be a variant of KFD.⁶²

ARENAVIRIDAE

Arenaviridae are enveloped, negative-sense, single-stranded RNA viruses. Arenavirus refers to the granular appearance of virions: These grainy particles are ribosomes acquired from the host cell. The genome is divided in two segments.⁶⁴

The family Arenaviridae contains a single genus, Arenavirus, divided in two groups, the Tacaribe serocomplex (New World arenaviruses), which includes Junin, Machupo, Guanarito, and Sabiá viruses, and the Lassa-Lymphocytic choriomeningitis serocomplex (Old World arenaviruses), which includes two African VHF-causing arenaviruses: Lassa fever virus (LASV) in West Africa and Lujo virus, the cause of a small nosocomial outbreak in South Africa.⁶⁵ All are category A bioterrorism agents.

Each arenavirus causes chronic infection of a specific rodent reservoir and humans get infected when exposed to rodents or their excreta.

Lassa Fever

The Pathogen and the Life Cycle LASV chronically infects the multimammate rat (Mastomys natalensis), which lives in and around rural houses, food storage areas, and crop fields. The rodent excretes LASV in its urine, saliva, and respiratory secretions. Humans get infected when exposed to the rats or their aerosolized urine.

LASV was first identified in 1969, in a missionary nurse who had lived in Lassa, a Nigerian village.⁶⁶ There is a lot of genetic variation among the strains.⁶⁷

Pathogenesis LASV binds to the α-dystroglycan receptor on endothelial cells, resulting in a noncytolytic infection and production of high numbers of virions. In severe LF, there is high, sustained viremia because the host is unable to control viral replication, probably due to virus-induced immunosuppression. LASV impairs endothelial cell function: Increased microvascular permeability causes cervicofacial edema and pleural effusions, and endothelial dysregulation causes profound and refractory hypotension. In even severe LF, bleeding is limited to mucosal surfaces, there is no liver failure, thrombocytopenia is mild, and disseminated intravascular coagulation is uncommon.⁶⁸

Epidemiology LASV infects an estimated 300,000 to 500,000 and kills 5,000 to 10,000 people yearly in Western Africa.^67,69 The prevalence of LASV antibody ranges from 7% to 20% in endemic regions.⁶⁷ LF occurs in rural areas where Mastomys natalensis lives around homes. The rodent is present in most of sub-Saharan Africa, but the geographic distribution of LF is restricted to West Africa, from Senegal to Cameroon, with most outbreaks reported in Sierra Leone, Nigeria, Liberia, and Guinea. LASV transmission requires heavy precipitations: Modeling based on environmental factors predicts a risk map of LF that covers 80% of Sierra Leone and Liberia, 50% of Guinea, 40% of Nigeria, 30% of Côte d’Ivoire, Togo and Benin, and 10% of Ghana.⁷⁰ Higher risk of human infection is associated with substandard housing and rodent infestation.⁷¹

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