Yellow fever – 7 Interesting Facts

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Synopsis

Key Points

  1. Yellow fever is caused by a flavivirus endemic to parts of Africa and South America; transmitted by the bite of an infected mosquito (Aedes or Haemagogus species)
  2. Most infected persons are asymptomatic or have mild flulike symptoms, and the disease resolves without complication
  3. About 15% to 25% of patients experience a triphasic illness in which mild manifestations are followed by a brief period of improvement, succeeded by onset of severe illness characterized by jaundice, bleeding diathesis, and multiorgan failure 1
  4. Diagnosis is suggested by patient symptoms, residence location or recent travel history, vaccination history, clinical presentation, hematologic indicators of coagulopathy, and abnormal liver function test results
  5. Treatment is supportive. Mild disease is treated with acetaminophen or similar nonaspirin therapy for pain and fever. Severe disease requires critical care measures including adequate hydration, blood pressure support, and efforts to reverse coagulopathy and prevent stress-induced gastritis
  6. In cases with phase 3 (toxic phase) disease, case fatality is 20% to 50%, leading to an estimated overall mortality of about 5% 2
  7. Mainstay of prevention is vaccination of those who live in or travel to areas where transmission occurs; mosquito control and avoidance of mosquito bites through the use of screens, bed nets, protective clothing, and repellents are also important

Pitfalls

  • Yellow fever vaccine is a live (attenuated) virus vaccine. Though effective, it is contraindicated in immunocompromised persons, and has (rarely) been associated with severe viscerotropic disease mimicking wild-type infection, primarily in those older than 60 years

Terminology

Clinical Clarification

  • Yellow fever is infection due to yellow fever virus, a flavivirus endemic to parts of Africa and South America; transmitted by the bite of an infected mosquito
  • While some patients are asymptomatic or have mild illness, infection may result in severe febrile illness with jaundice
  • In severe cases (about one-quarter of infections), disease progression occurs as a triphasic illness in which mild manifestations are followed by a brief period of improvement, then by onset of severe illness characterized by jaundice, bleeding diathesis, and multiorgan failure 1

Classification

  • Clinical infection is classified into 3 phases, although only a minority of patients with yellow fever experience the third phase
    • Phase 1 (infection) 1
      • After 3- to 6-day incubation period, abrupt onset of fever and nonspecific symptoms occur (eg, headache, malaise, myalgias, nausea, lightheadedness)
      • This phase can last up to 3 days, during which time viremia occurs
    • Phase 2 (remission) 1
      • Characterized by symptom improvement and resolution of viremia; marks beginning of recovery in most patients
      • In those who progress to more severe disease, this period of transient improvement may last a few hours or up to 2 days
    • Phase 3 (toxic phase) 3
      • Occurs in 15% to 25% of infections. Mortality rate is high (20%-50%); death typically occurs within 7 to 10 days 1 3
      • Marked by return of fever associated with abdominal pain, vomiting, jaundice, hemorrhagic manifestations, renal failure, and coma
      • Antibodies specific to virus become detectable during this phase

Diagnosis

Clinical Presentation

  • From Jentes ES et al: The revised global yellow fever risk map and recommendations for vaccination, 2010: consensus of the Informal WHO Working Group on Geographic Risk for Yellow Fever. Lancet Infect Dis. 11(8):622-32, 2011, Figure 3.Areas with risk of yellow fever virus transmission in South America, 2010.
  • From Jentes ES et al: The revised global yellow fever risk map and recommendations for vaccination, 2010: consensus of the Informal WHO Working Group on Geographic Risk for Yellow Fever. Lancet Infect Dis. 11(8):622-32, 2011, Figure 4.Areas with risk of yellow fever virus transmission in Africa, 2010. São Tomé and Príncipe was classified as low potential for exposure.
  • From Lupi O et al: Hemorrhagic fever and arboviruses. In: Tyring SK et al, eds: Tropical Dermatology. 2nd ed. Elsevier; 2017:127-50, Figure 12.18.Jaundice due to yellow fever.

History

  • History of residence in or recent travel to sub-Saharan Africa or South America is essential information
  • In symptomatic patients, onset of illness is 3 to 6 days after inoculation by an infected mosquito 4
  • Phase 1 is characterized by a sudden onset of nonspecific flulike symptoms
    • Chills
    • Headache, may be severe
    • Myalgias, especially in lower back
    • Nausea and vomiting
    • Weakness and exhaustion
  • Phase 2 is characterized by resolution of symptoms or minimal symptoms
  • Phase 3 is characterized by reappearance of phase 1 symptoms with increased severity; may be accompanied by new symptoms
    • Abdominal pain is common
    • Hemorrhagic symptoms may develop (eg, epistaxis, gingival bleeding, hematemesis, melena, hematuria, uterine bleeding)
    • Urine output may be reduced or absent secondary to renal failure and/or dehydration

Physical examination

  • Phase 1
    • Patients appear generally ill, even toxic
    • Temperature may reach 41 °C 2 or higher; paradoxical bradycardia may be observed (Faget sign)
    • Conjunctival injection and facial flushing may be seen, but physical findings are otherwise unremarkable
  • Phase 3
    • Patients appear profoundly ill; may be confused, delirious, somnolent, or unresponsive
    • Fever recurs; progressive multiorgan failure may be associated with onset of shock and declining blood pressure
    • Icteric sclerae and jaundiced skin are typical
    • Spontaneous bleeding may be present from mucosal surfaces (eg, nose, mouth, rectum, vagina)
    • Epigastric tenderness may be elicited; liver is generally not enlarged 5

Causes and Risk Factors

Causes

  • Flavivirus infection transmitted by the bite of an infected mosquito (Aedes or Haemagogus species)

Risk factors and/or associations

Age
  • Infants and elderly adults are at higher risk for severe disease and mortality 1
Other risk factors/associations
  • Endemic to portions of sub-Saharan Africa and tropical South America
    • CDC publishes maps showing regional areas in which yellow fever occurs 6
    • Highest prevalence is in Africa; up to 90% of all cases occur in Africa 1
  • Rural versus peridomestic or urban settings
    • In South America, mosquito vectors are largely present in jungle habitats of affected areas; most cases occur among young men who work in the forestry or lumbering industries, or in clearing land for agricultural use 7
    • In endemic areas in Africa, transmission is more indiscriminate, as mosquito vectors live in closer contact to human habitation, breeding in water containers; young children without preexisting immunity are at highest risk 8
  • Seasonal variation
    • Transmission is related to the rainy season in some geographical regions, particularly areas where mosquito vector is largely present in jungle habitats
      • In areas of East Africa 9 and South America 4 with yellow fever, prevalence peaks during rainy seasons
      • In affected parts of West Africa, 4 prevalence peaks shortly after rainy season
    • Seasonal variation is less marked in regions where transmission commonly occurs in closer proximity to human settlement (urban or peridomestic) 9
  • Travel
    • Estimated risk for the unimmunized traveler to acquire disease is much higher in endemic areas of West Africa than in endemic areas of South America (50 in 100,000 travelers in West Africa versus 5 in 100,000 travelers in South America during a 2-week stay) 4

Diagnostic Procedures

Primary diagnostic tools

  • Diagnosis is suggested by patient symptoms, residence location or recent travel history, vaccination history, and hematologic and biochemical abnormalities
  • Confirm diagnosis with laboratory tests 2 10
    • Molecular diagnostics 11
      • Yellow fever virus RNA may be detected in blood or urine early in infection (within first 10 days); however, viral RNA is often undetectable by the time the disease is clinically suspected
    • Serology 10
      • Assay for virus-specific antibodies (IgM or IgG) is usually the initial test; several testing methods exist but may not be widely available, even in areas where yellow fever occurs
      • Standard laboratory procedure dictates that positive results are confirmed with plaque reduction neutralizing test, owing to risk of false-positive results
    • Local availability of testing platforms is limited; specimens may be sent to the CDC Arbovirus Diagnostic Laboratory for testing. A combined approach using several methodologies is often taken, and diagnosis may not be confirmed except retrospectively 12
  • Yellow fever is a nationally notifiable disease in the United States 13
  • Nonspecific tests done in the evaluation and management of a severe febrile illness with jaundice and abnormal bleeding may include CBC, coagulation studies, and liver and renal function tests 8

Laboratory

  • Yellow fever–specific IgM and IgG antibodies 14
    • Positive IgM antibody confirmed by plaque reduction neutralization establishes diagnosis of acute yellow fever
    • Alternatively, a 4-fold rise in yellow fever IgG antibody levels between acute and convalescent serum samples confirms diagnosis retrospectively
    • False-positive results may occur secondary to:
      • Cross-reactivity with other flaviviruses (eg, dengue, West Nile) 10
      • Long-lived IgM antibodies induced by vaccine in patients vaccinated in the previous 3 to 4 years 15
  • CBC and coagulation studies
    • May reveal leukopenia early in disease course; leukocytosis often follows 10
    • In patients who enter the toxic phase, thrombocytopenia develops; prothrombin time/INR and clotting times are prolonged; fibrinogen levels may be low and fibrin degradation products may be present 8 10
  • Liver function tests 8
    • Transaminase levels may be mildly elevated during early (phase 1) disease, but they rise sharply during toxic phase
    • AST level may exceed ALT level owing to spillage of RBC and myocardial enzymes along with hepatocellular injury
    • Hyperbilirubinemia may be marked
  • Renal function testing, electrolyte, and acid-base status 8
    • As the toxic period (phase 3) progresses, urine output may decrease, with concomitant increases in urine protein and serum creatinine levels
    • Multiorgan failure is accompanied by metabolic acidosis and variable electrolyte abnormalities

Differential Diagnosis

Most common

  • Coinfection has been reported; diagnosis of another disease or viral infection does not preclude yellow fever, and vice versa
  • Other viral hemorrhagic diseases (Related: ) Dengue virus infection
    • Includes dengue, Lassa fever, Rift Valley fever, Ebola disease, South American hemorrhagic fevers, and Crimean-Congo hemorrhagic fever (Related: Ebola virus disease)
    • Similar to yellow fever, some hemorrhagic diseases (dengue, Crimean-Congo hemorrhagic fever, Rift Valley fever) are caused by arboviruses (ie, transmitted by a tick or mosquito)
    • Like yellow fever, these viral diseases may present with significant fever and bleeding diatheses
    • Congo-Crimean hemorrhagic fever and Rift Valley fever may present with jaundice in addition to fever and hemorrhagic manifestations; both occur in areas of Africa in which yellow fever is endemic
    • Unlike yellow fever, jaundice is not a common feature in dengue, Lassa fever, Ebola disease, or South American hemorrhagic fevers
    • Diagnosis of these infections is usually made by serology or molecular testing
  • Viral hepatitis
    • Hepatic infection and inflammation due to a number of specific hepatotrophic viruses (A, B, C, D, E) as well as other viruses in which liver involvement may occur as 1 manifestation of a more broadly systemic disease (eg, cytomegalovirus, Epstein-Barr virus)
    • Like yellow fever, fever and jaundice are characteristic; transaminase elevations may range from moderate to very high
    • Unlike yellow fever, hemorrhagic manifestations are uncommon in acute infection except in cases of fulminant hepatitis B or E
    • Definitive differentiation is based on serologic or molecular diagnosis
  • Malaria
    • Protozoal infection transmitted by mosquitoes in areas of Africa and South America where yellow fever is endemic
    • Characterized by fever, chills, sweats, headache, nausea, vomiting, body aches, and general malaise
    • Jaundice is less common but occurs in severe cases; hemorrhagic manifestations are uncommon
    • Differentiated and diagnosed by blood films that demonstrate malaria parasite on microscopic examination and antigen-based malaria rapid diagnostic tests
  • Leptospirosis
    • Bacterial infection transmitted by exposure to infected body fluids (typically animals)
    • Like yellow fever, clinical course may evolve in phases interrupted by an afebrile, minimally symptomatic period of improvement
    • Characterized by high fever, headache, chills, muscle aches, vomiting, jaundice, abdominal pain, diarrhea, oliguria, petechiae, and ecchymoses
    • Unlike yellow fever, eye pain, conjunctival injection, cough, pulmonary findings, and hepatosplenomegaly are often prominent in severe cases
    • Laboratory confirmation of acute disease is problematic; presence of specific IgM antibody is helpful when demonstrable

Treatment

Goals

  • No effective antiviral treatment has been identified
  • Management focuses on alleviation of symptoms and standard critical care support for severely ill patients

Disposition

Admission criteria

Admit patients who need aggressive supportive care (eg, parenteral hydration, hemodynamic support, bleeding control)

Criteria for ICU admission
  • Admit to ICU in cases of shock, hemorrhage, or encephalopathy

Recommendations for specialist referral

  • Consult infectious disease specialist for aid in diagnosis and communication with public health officials
  • Consult critical care specialist for management of severe metabolic derangements and hemodynamic instability

Treatment Options

Acetaminophen is recommended for fever control and analgesia 16

  • Avoid aspirin and NSAIDs owing to increased risk of bleeding

Administer oral or IV hydration as needed, and administer pressor support (eg, dopamine) 8 if adequate hydration does not maintain blood pressure 16

Use H₂ blockers or sucralfate to reduce risk of gastrointestinal bleeding 17

Transfuse blood and/or fresh frozen plasma and administer vitamin K as needed for uncontrolled bleeding 17

Address electrolyte and other metabolic disturbances in standard fashion 8

Maintain nutrition; avoid hypoglycemia 8

Drug therapy

  • Antiulcer agents
    • For stress gastritis prophylaxis or active treatment of stress ulceration in critically ill patients
      • Famotidine
        • Famotidine Solution for injection; Infants, Children, and Adolescents: 1 to 2 mg/kg/day IV divided every 8 to 12 hours.
        • Famotidine Solution for injection; Adults: 20 mg IV every 12 hours.
      • Cimetidine
        • Cimetidine Hydrochloride Oral solution; Adults: 300 mg PO or via NG tube 4 times daily. 18
      • Sucralfate
        • Sucralfate Oral tablet; Adults: Doses of 4, 6, or 9 g/day in divided doses have been used.
  • Vitamin K
    • Vitamin K (Phytonadione) Solution for injection; Infants, Children, and Adolescents: 5 to 10 mg IM/subcutaneously, repeated as necessary.
    • Vitamin K (Phytonadione) Solution for injection; Adults: 2 to 25 mg IM/subcutaneously, repeated as needed.
  • Dopamine
    • Dopamine Hydrochloride Solution for injection; Infants, Children, and Adolescents: 1 to 5 mcg/kg/minute continuous IV infusion; titrate in increments of 2.5 to 5 mcg/kg/minute to attain hemodynamic goals. Usual dosage range: 2 to 20 mcg/kg/minute.
    • Dopamine Hydrochloride Solution for injection; Adults: 2 to 5 mcg/kg/minute continuous IV infusion; titrate in 5 to 10 mcg/kg/minute increments to attain hemodynamic goals. Usual dosage range: 2 to 20 mcg/kg/minute. Max: 50 mcg/kg/minute.

Nondrug and supportive care

  • Hydration
    • Medecins sans Frontieres clinical guideline recommends a solution of oral rehydration salts or parenteral Ringer lactate 16

Complications and Prognosis

Complications

  • Renal failure may persist and require dialysis
  • Hemorrhage may occur and may be difficult to control, especially if gastrointestinal, genitourinary, or pulmonary in origin
  • Secondary bacterial sepsis is common and must be treated with appropriate antibiotics

Prognosis

  • In clinically evident cases (ie, with phase 3 [toxic phase] disease), case fatality rate is 20% to 50%, leading to an estimated overall mortality of about 5% 2
  • Those that survive toxic phase of disease may require prolonged convalescence; jaundice and transaminase elevations may persist for weeks, but chronic liver disease does not occur 4
  • Rarely, death may occur during convalescence, possibly due to cardiac complications (eg, myocarditis, arrhythmia) 4

Screening and Prevention

Prevention

  • Vaccination is recommended for residents of endemic regions and for most travelers to areas of endemicity; additionally, some countries require immunization for entry, certified by an officially designated vaccine center 4
    • Current information on areas of transmission and vaccine requirements can be found in the CDC Yellow Book (Health Information for International Travel) 19
    • A list of designated vaccine centers in the United States can be obtained from state or local health authorities, or via CDC 20
      • Travelers to endemic areas should be aware that vaccine must be given 10 days in advance to generate protective immunity
    • 17D yellow fever vaccine is available worldwide in various formulations
      • Attenuated live-virus vaccine, 0.5 mL subcutaneously
      • Can be administered to patients without contraindications who are aged 9 months and older
      • WHO 21 and CDC 22 recommendations were recently revised, and they now state that 1 dose yields lifelong immunity in most people; as a result, the previous 10-year limitation on yellow fever certification for travel has been lifted. Exceptions include the following groups, who should receive boosters if risk of infection is ongoing:
        • Women who were pregnant when they were vaccinated
        • Those who have undergone hemopoietic stem cell transplant, and who had vaccine previously, should receive a booster dose when immunocompetent
        • Patients with HIV whose initial vaccine was given after acquiring HIV infection
          • A Cochrane review concluded that vaccine is less immunogenic in persons with HIV infection 23
        • People who travel under conditions of particularly high risk for acquiring infection (based on location and season)
        • Laboratory workers who handle yellow fever virus
      • Special populations
        • Contraindicated in the following:
          • Age younger than 6 months owing to risk of vaccine-associated encephalitis
          • Patients with AIDS, or HIV with CD4 cell count less than 200/mm (for children younger than 6 years, CD4 count less than 15% of lymphocyte total)
          • Patients with thymus disorders associated with immune system abnormalities
          • Patients with organ or stem cell transplants (in previous 2 years), primary immunodeficiencies, or malignancies
          • Patients undergoing radiation therapy or taking immunosuppressive medication (including those who received transplants more than 2 years prior and remain on immunosuppressants)
            • Includes corticosteroid regimens equivalent to prednisone at least 2 mg/kg or at least 20 mg/day for 2 weeks or more
          • Allergy to vaccine components
        • Cautious use in the following groups (ie, vaccinate only if yellow fever exposure is unavoidable and risk of acquiring disease is felt to exceed risk of adverse vaccine effects):
          • Age 60 years or older
          • Age 6 to 8 months
          • HIV infection with CD4 cell counts of 200 to 499/mm (for children younger than 6 years, 15%-24% of lymphocyte total)
          • Pregnant or breastfeeding women
        • Those for whom vaccine is contraindicated but who must travel to countries requiring certification of yellow fever vaccination may be given a written waiver to carry in place of the immunization document
      • Mild reactions (eg, low-grade fever, myalgias, swelling at site) occur in 11% to 33% of patients
      • Serious adverse events occur less frequently
        • Hypersensitivity reactions or anaphylaxis (eg, urticaria, rash, bronchospasm) occur in about 0.8 to 1.8 per 100,000 doses
        • Yellow fever vaccine–associated neurologic disease
          • Caused in some cases by direct invasion of central nervous system and, in others, by triggering an autoimmune response
          • Occurs as distinct syndromes, including Guillain-Barré syndrome, meningoencephalitis, acute disseminated encephalomyelitis, and bulbar palsies; most patients recover with appropriate care, but a few fatalities have been reported
          • In the United States, incidence is 0.4 to 0.8 per 100,000 doses; higher in those aged 60 years or older (1.6 per 100,000 doses in ages 60-69 years, 1.1-2.3 per 100,000 in ages 70 years and older)
        • Yellow fever vaccine–associated viscerotropic disease
          • Uncontrolled proliferation of vaccine virus strain, with multiorgan infection and failure mimicking wild-type disease
          • In the United States, incidence is 0.3 to 0.4 per 100,000 doses
          • Incidence is higher in older age groups (1.0 per 100,000 for ages 60-69 years, 2.3-3.2 per 100,000 in ages 70 years and older)
          • Mortality rates are high
          • Risk factors include older age and history of disease of the thymus or thymectomy
  • Avoid mosquito bites in areas of yellow fever transmission 19
    • Apply insect repellents containing DEET (diethyltoluamide), picaridin, oil of lemon eucalyptus, IR3535, or 2-undecanone
      • Higher concentrations of DEET give longer duration of protection
      • Oil of lemon eucalyptus should not be used for children younger than 3 years; most other repellents can be used for children older than 2 months. Mosquito netting can be draped over strollers or baby carriers
    • Wear protective clothing (eg, long sleeves and pants); permethrin treatment may add further protection
    • Use screens to exclude mosquitoes
    • Spatial repellents can be used to clear mosquitoes that remain inside after screens have been placed, and may provide some degree of temporary protection in the absence of screens
    • Use permethrin-treated bed nets if mosquitoes are not otherwise effectively excluded
  • Infection control
    • Avoid contributing to vector transmission by protecting patient from mosquitoes during first phase of infection (when viremia occurs) 7
    • Infected persons can transmit virus to mosquitoes and from infected mosquitoes to other susceptible humans

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