AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Yellow fever was first recognized in an outbreak occurring in the New World in 1648. It is a member of the flavivirus family (group B arbovirus). The Flavivirus genus is composed of more than 68 arthropod transmitted viruses, of which 30 are known to cause human disease. Other flaviviral infections include dengue, Japanese encephalitis, and tick-borne encephalitis. It is important to consider this group of viruses in the clinical differential of CNS infection, hemorrhagic fever, and acute febrile illnesses with arthropathy.

It is surmised that the yellow fever virus most likely was introduced by slave-trading vessels from West Africa infested with Aedes aegypti (mosquito), with similar outbreaks occurring in port cities in the New World and in Europe. Sanitation measures, such as piped water, greatly diminished the transmission of the disease. The viral cause of yellow fever was not discovered until after 1928, which led to Theiler's discovery of the attenuated 17D vaccine strain in the 1930s that earned him a Nobel Prize.

Despite the effectiveness of this vaccine, outbreaks continue to recur periodically because of the fragmentary vaccine implementation in many areas.

Pathophysiology

The pathophysiology of yellow fever infection was largely inferred from vaccine studies in rhesus monkeys using the attenuated 17D vaccine. After inoculation in rhesus monkeys, the virus replicated initially in local lymph nodes, followed by blood-borne spread and subsequent replication mostly occurring in regional lymph tissue, spleen, and bone marrow followed by the liver, lung, and adrenal glands.

The liver and kidneys demonstrate the greatest degree of pathologic changes. Hemorrhage and erosion of the gastric mucosa lead to hematemesis popularly known as "black vomit." Hepatocellular damage is characterized by lobular necrosis with the subsequent formation of Councilman bodies. Albuminuria and renal insufficiency evolve secondary to the prerenal component of yellow fever, ultimately leading to acute tubular necrosis with advanced disease. Fatty infiltration of the myocardium, including the conduction system, can lead to myocarditis and arrhythmias.

CNS findings can be attributed to cerebral edema and hemorrhages compounded on metabolic disturbances. The bleeding diathesis of this disease can be attributed to reduced hepatic synthesis of clotting factors, thrombocytopenia, and platelet dysfunction. The terminal event of shock can be attributed to a combination of direct parenchymal damage and a systemic inflammatory response.

Frequency

United States

The last epidemic of yellow fever in North America occurred in New Orleans in 1905 during which more than 3000 cases were met with 452 deaths. Because Aedes aegypti (see Physical) now has reinfested the southeastern United States, autochthonous transmission in the United States is possible.

International

Yellow fever transmission predominately occurs in areas of sub-Saharan Africa and South America 15° north and 10° south of the equator. It has never been documented in Asia. Yellow fever epidemics were dominant in Africa from 1986-1991, with close to 20,000 cases and 6000 deaths. This is considered to be grossly underestimated because of underreporting. These epidemics commonly include 30-1000 cases and have fatality ratios of 20-50%. In areas of West Africa, 200,000 endemic cases may occur annually. In South America, an annual mean of 100 cases has been reported for the last 25 years. These cases predominate from January to March among males aged 15- 45 years who work outdoors in agriculture and forestry. The last outbreak in the western hemisphere occurred in 1954 in Trinidad. Yellow fever's range continues to expand, now including areas in which it previously was believed to be eradicated (eg, eastern and southern African countries).

In South America, sporadic infections occur almost exclusively in forestry and agricultural workers from exposure in or near the forests. In Africa, the virus is transmitted in 3 geographic regions: West and Central Africa savanna zones during the rainy season, urban locations and villages in Africa, and, to a lesser extent, the jungle regions.

Mortality/Morbidity

Yellow fever ranges in severity from a self-limited infection to hemorrhagic fever that carries a 50% mortality rate. Fatality rates are higher in the young. Early appearance of jaundice (day 3) indicates a poor prognosis. Transaminase elevations reflect the degree of hepatic injury and are prognostic. Individuals who survive the toxic phase may experience renal failure. Convalescence with symptoms of weakness and fatigue may last up to 3 months.

Sex

Jungle yellow fever is most common among healthy young males as a result of occupational risk.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

To arrive at a diagnosis, consider the patient's clinical features and their places and dates of travel, including the epidemiologic history of the places visited, immunizations, and activities.

• An incubation period of 3-6 days indicates that travelers may be viremic before demonstrating symptoms.
• Clinical symptoms manifest in 1 in 20 partially immune patients and 1 in 5 immunologically naïve patients.
• Initial symptoms, listed below, correspond to the viremic phase (period of infection) and are followed by a transient (up to 24 h) remission.
• • Fever and chills
  • Severe headache
  • Back pain
  • Myalgia
  • Nausea
  • Prostration
• The toxic phase (ie, period of intoxication) of yellow fever develops as the fever returns.
• • Clinical symptoms include high fever, headache, lumbosacral back pain, nausea, vomiting, abdominal pain, and somnolence.
  • Hepatic-induced coagulopathy produces hemorrhagic manifestations, including the characteristic black vomit (hematemesis), epistaxis, gum bleeding, and petechial and purpuric hemorrhages.
  • Systemic manifestations include deepening jaundice and albuminuria.
• In the late stages of disease hypotension, shock, metabolic acidosis, acute tubular necrosis, myocardial dysfunction, and arrhythmia dominate the picture.
• Confusion, seizure, and coma distinguish the late CNS manifestations of the disease. Death usually follows within 7-10 days of onset.
• Secondary bacterial infections are frequent complications in patients who survive the critical period of illness.

Physical

• Altered mental status
• Fever
• Relative bradycardia (Faget sign)
• Conjunctival injection
• Other physical findings such as jaundice occur as disease progresses

Causes

• Two types of yellow fever exist, the jungle type and the urban type.
• • In jungle yellow fever, Haemagogus mosquitoes in South America and Aedes africanus in Africa acquire the disease from monkeys, which serve as hosts for the virus.
    • Mosquitoes then bite and infect humans, usually young men engaged in forestry or agricultural activities.
    • This results in sporadic outbreaks in South America and Africa.
  • In urban yellow fever, humans serve as viremic hosts and the disease is spread between humans by the domestic mosquito vector, A aegypti.
    • Because of widespread control of this vector in the 1930s, urban yellow fever has become uncommon.
    • However, these mosquitoes recently reinvaded South America; thus, the potential for transmission exists.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Crimean-Congo hemorrhagic fever
Rift valley fever
Typhoid fever
Typhus

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• A complete blood count (CBC) often indicates leukopenia and thrombocytopenia.
• LFTs may indicate elevated direct bilirubin and hepatic transaminases.
• Prothrombin time, activated partial thromboplastin time, international rationalized ratio (INR), and clotting times are prolonged invariably.
• Diminished levels of factor VIII, fibrinogen, and platelets, along with the presence of fibrin split products, indicate presence of disseminated intravascular coagulation (DIC).
• Albuminuria usually is noted with proportional rises in BUN.

Other Tests

• Make a specific diagnosis using serologic tests such as enzyme-linked immunosorbent assay (ELISA).
• • Laboratory diagnosis of yellow fever in travelers depends principally on serological testing of serum immunoglobulins. Immunoglobulin M (IgM) testing by ELISA is the preferred method of testing. This assay is 95% sensitive when serum specimens are collected 7-10 days after the onset of illness.
  • Paired acute and convalescent sera indicate the diagnosis.
  • Polymerase chain reaction can be used to identify viral ribonucleic acid (RNA) during acute infection, but clinical experience is limited.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Prehospital Care

Patients with hemodynamic instability should undergo prehospital fluid resuscitation. Adherence to universal precautions is mandatory to prevent transmission to health care workers.

Emergency Department Care

Treatment principally is symptomatic and preventative.

• Closely monitor patients for hypovolemia, oliguria, hypoxia, acidosis, and electrolyte imbalance. Hypotension and hypoxia may aggravate hepatic and renal injury.
• Intravascular volume may decrease secondary to sequestration in the extravascular space or to fluid loss through insensible losses, vomiting, and capillary leak.
• If oxygenation and hydration do not improve hemodynamic parameters, or if myocardial dysfunction is present, monitor pulmonary artery pressures.
• When facilities for flotation-tip (eg, Swan-Ganz) catheters are not available, monitor central venous pressure, peripheral blood pressure, and regional blood flow (eg, capillary refill, urinary output).
• Use of cooling blankets and tepid sponging can reduce fever and, thus, oxygen consumption.
• Hypothermia frequently occurs late in the disease course and is corrected with gradual rewarming.
• Nasogastric suction is essential to prevent gastric distention and aspiration of gastric contents. H2-receptor antagonists and sucralfate also may be valuable in preventing gastric bleeding.
• Consider parenteral alimentation. Hypoglycemia can be prevented by infusion of 10-20% glucose solution.
• Replacement of red blood cells, clotting components, and other volume expanders are used to treat hemorrhage and shock.
• Renal failure may necessitate dialysis. Consider dopamine for patients not responding to hydration, but dobutamine may offer the advantage of its positive chronotropic effect. Avoid drugs that are dependent on hepatic metabolism while medication doses should be adjusted for reduced renal function.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

No specific antiviral therapy is available for yellow fever. Specific chemotherapies under investigation include interferon and ribavirin. When interferon is administered to monkeys within 8 hours of infection, mortality is reduced; however, interferon is ineffective when given at 24 hours. Using interferon in combination with other immune-enhancing drugs is continuing to be researched. Ribavirin, although effective in vitro, has not been shown to be effective in vivo because of an inability to achieve sufficient concentrations in the blood. A drug-screening program at the US Army Medical Research Institute of Infectious Diseases has identified some agents effective against yellow fever in vitro.

Adjunctive measures include nonhepatotoxic antipyretics to reduce fever and pain and an H2-receptor antagonist to prevent gastric bleeding. Use of heparin for documented cases of DIC is controversial. Avoid drugs that act centrally, including phenothiazines, barbiturates, and benzodiazepines because they may precipitate or aggravate encephalopathy. Avoid drugs dependent on hepatic metabolism, and, in cases of reduced renal function, medications should be renally dosed.

Drug Category: Antiviral vaccines

Prevention is the best defense against yellow fever. Persons who plan to travel to yellow-fever endemic areas should be vaccinated. Onset of immunity may start in 7-10 days following vaccination. The World Health Organization (WHO) requires revaccination every 10 years to maintain travelers' vaccination certificates. In the United States, Vaccination certificates are valid for 10 years beginning 10 days after initial vaccination or revaccination.

Between 1996 and 2001, out of 300 million worldwide yellow fever vaccine recipients, 7 patients have been documented as developing severe illness potentially related to yellow fever vaccination. This association is under further investigation by the Food and Drug Administration (FDA) and Centers for Disease Control and Prevention (CDC). Healthcare providers are encouraged to report cases of febrile illness potentially caused by yellow fever vaccination to the CDC/FDA Vaccine Adverse Events Reporting System.

Drug Category: Histamine H2 antagonists

Useful as an adjunctive therapy to prevent gastric bleeding. H2-receptor antagonists are highly selective, do not affect the H1 receptors, and are not anticholinergic agents. These are potent inhibitors of all phases of gastric acid secretion. They inhibit secretions caused by histamine, muscarinic agonists, and gastrin.

Drug Name	Nizatidine (Axid)
Description	Competitively inhibits histamine at the H2 receptor of gastric parietal cells, resulting in reduced gastric acid secretion, gastric volume, and reduced hydrogen concentrations.
Adult Dose	300 mg PO hs or 150 mg bid
Pediatric Dose	<6 months: Not established 6-10 mg/kg PO qd (for 6 months-12 years, divide dose bid) >12 years: Administer as in adults
Contraindications	Documented hypersensitivity; impaired renal function
Interactions	May reduce efficacy of cefpodoxime, delavirdine, digestive enzymes, iron salts, and ketoconazole
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	If changes in renal function occur during therapy, adjust dose or discontinue treatment; Serious reactions include thrombocytopenia, leukopenia, pancytopenia, and cholestatic jaundice

Drug Name	Ranitidine (Zantac)
Description	Competitively inhibits histamine at H2 receptor of gastric parietal cells, resulting in reduced gastric acid secretion, gastric volume, and reduced hydrogen concentrations.
Adult Dose	150 mg PO bid or 300 mg PO qhs; alternately, 50 mg/dose IV/IM q6-8h
Pediatric Dose	<2 weeks: 2 mg/kg PO divided bid ; alternately, 1.5 mg/kg IV initial, then 1.5 mg/kg IV divided bid Infusion: 0.04 mg/kg/h IV Children: 4-5 mg/kg PO IV/IM divided bid/tid; alternately, 2-4 mg/kg IV/IM divided tid/qid; infusion 0.1-0.125 mg/kg/h
Contraindications	Documented hypersensitivity; porphyria, impaired liver and renal function
Interactions	May decrease effects of ketoconazole, itraconazole, cefpodoxime, delavirdine, and digestive enzymes; may alter serum levels of ferrous sulfate, nondepolarizing muscle relaxants, diazepam, and oxaprozin
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in renal or liver impairment; if changes in renal function occur during therapy, consider adjusting dosage or discontinuing treatment; may cause thrombocytopenia and hepatotoxicity

Drug Category: Antipyretics

Treatment of yellow fever is symptomatic and supportive. Bed rest and mild analgesic-antipyretic therapy often help relieve associated lethargy, malaise, and fever.

Drug Name	Aspirin (Anacin, Bufferin, Ecotrin)
Description	Lowers elevated body temperature by vasodilating peripheral vessels, thereby enhancing dissipation of excess heat. Also acts on the heat-regulating center of hypothalamus to reduce fever.
Adult Dose	325-650 mg PO/PR q4h
Pediatric Dose	10-15 mg/kg PO/PR q4-6h; not to exceed 60-80 mg/kg/d
Contraindications	Documented hypersensitivity; liver damage, GERD, G-6-PD deficiency, hypoprothrombinemia, TTP, vitamin K deficiency, bleeding disorders, asthma; because of association of aspirin with Reye syndrome, do not use in children ( <16 y) with flu
Interactions	Effects may decrease with antacids and urinary alkalinizers; corticosteroids decrease salicylate serum levels; additive hypoprothrombinemic effects and increased bleeding time may occur with coadministration of anticoagulants, antiplatelets, COX-2 inhibitors, sulfinpyrazone, thrombolytics, and valproic acid derivatives; may antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid; doses > 2 g/d may potentiate glucose lowering effect of sulfonylurea drugs and insulin; mesalamine may increase ASA toxicity; combo therapy may increase methotrexate toxicity
Pregnancy	D - Unsafe in pregnancy
Precautions	May cause transient decrease in renal function and aggravate chronic kidney disease; avoid use in patients with severe anemia, with history of blood coagulation defects, or taking anticoagulants

Drug Name	Ibuprofen (Motrin, Advil, Nuprin)
Description	NSAID with analgesic and antipyretic activities. Although exact mode of action not known, appears to inhibit cyclooxygenase activity and prostaglandin synthesis. May inhibit lipoxygenase, leukotriene synthesis, lysosomal enzyme release, neutrophil aggregation, and various cell-membrane functions.
Adult Dose	200-400 mg PO q4-6h prn; not to exceed 3.2 g/d; take with food
Pediatric Dose	4-10 mg/kg PO q6-8h, not to exceed 50 mg/kg/d; take with food
Contraindications	Documented hypersensitivity; peptic ulcer disease, recent GI bleeding or perforation, renal insufficiency, high risk of bleeding, and CHF
Interactions	Coadministration with aspirin, probenecid, and leflunomide increases risk of inducing serious NSAID-related adverse effects; anticoagulants, antiplatelets, corticosteroids, COX-2 inhibitors, thrombolytics, valproic acid derivatives, and aspirins may increase risk of bleeding; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, ACE inhibitors, angiotensin II receptor blockers, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; monitor PT closely (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; may increase lithium toxicity, phenytoin levels may be increased when administered concurrently, acetaminophen, cyclosporin, may increase risk of nephrotoxicity, all quinolones may increase risk of CNS stimulation
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Category D in third trimester of pregnancy; caution in congestive heart failure, hypertension, and decreased renal and hepatic function; caution in anticoagulation abnormalities or during anticoagulant therapy

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• All cases of yellow fever identified in the United States warrant inpatient admission because of unfamiliarity with this disease.
• In settings outside urban areas, admission is predicated on the illness of the patient and the medical resources available.
• For patients with any evidence of end-organ injury (eg, jaundice, renal failure, bleeding) or hemodynamic instability, intensive care is optimal. However, this level of medical sophistication is not available in most areas where yellow fever is likely to be diagnosed.
• From a systems perspective, improving the local infrastructure is more practical than evacuation of patients.
• Suggested improvements include improved surveillance, early rapid diagnostic services, and specialized mobile teams to augment local clinical facilities.

Deterrence/Prevention

• Protect patients from mosquitoes with bed nets or screened rooms to avoid development of urban yellow fever.
• An excellent and widely available vaccine is available.
• • One 0.5 mL SC dose provides lifelong immunity in 95% of recipients.
  • Live attenuated vaccine is prepared in chick embryos; it is contraindicated in those with egg allergies, the individuals with immunosuppression, and during pregnancy.
  • For travel certification, revaccination is recommended every 10 years.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Special Concerns

• Current information is available from the CDC publication Health Information for International Travel. Information on vaccination requirements can be obtained online at Centers for Disease Control and Prevention, by fax at 404-332-4565, by phone at 404-332-4559, or by mail at Centers for Disease Control and Prevention, Atlanta, GA 30333.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Chan RC, Penney DJ, Little D, et al. Hepatitis and death following vaccination with 17D-204 yellow fever vaccine. Lancet. Jul 14 2001;358(9276):121-2. [Medline].
• Higgins JW, Jahrling P, Kende M, et al. Efficacy of ribavirin against virulent RNA virus infections. In: Clinical applications of ribavirin; Smith RA, Knight V, Smith JAD, eds. 1984;49-63.
• JAMA. China vs HIV. JAMA. Nov 13 1996;276(18):1461. [Medline].
• Martin M, Tsai TF, Cropp B, et al. Fever and multisystem organ failure associated with 17D-204 yellow fever vaccination: a report of four cases. Lancet. Jul 14 2001;358(9276):98-104. [Medline].
• Monath TP. Yellow fever: Victor, Victoria? Conqueror, conquest? Epidemics and research in the last forty years and prospects for the future. Am J Trop Med Hyg. Jul 1991;45(1):1-43. [Medline].
• Peters, C J. Infections caused by Arthropod and Rodent borne viruses. Principles of Internal Medicine. 2001;1:1152-1165.
• Robertson SE, Hull BP, Tomori O, et al. Yellow fever: A decade of reemergence. JAMA. 1996;276:1157-1162. [Medline].
• Sanders EJ, Tukei PM. Yellow fever: an emerging threat for Kenya and other east African countries. East Afr Med J. Jan 1996;73(1):10-2. [Medline].
• Shope R. Global climate change and infectious diseases. Environ Health Perspect. Dec 1991;96:171-4. [Medline].
• Stephen EL, Sammons ML, Pannier WL, et al. Effect of a nuclease-resistant derivative of polyriboinosinic- polyribocytidylic acid complex on yellow fever in rhesus monkeys (Macaca mulatta). J Infect Dis. Jul 1977;136(1):122-6. [Medline].
• Tsai, Theodore. Flaviviruses (Yellow Fever, Dengue, Dengue Hemorrhagic Fever, Japanese Encephalitis, St. Louis Encephalitis, Tick-Borne Encephalitis). Principles and Practice of Infectious Diseases. 2:1714-1733.
• Vasconcelos PF, Luna EJ, Galler R, et al. Serious adverse events associated with yellow fever 17DD vaccine in Brazil: a report of two cases. Lancet. Jul 14 2001;358(9276):91-7. [Medline].
• World Health Organization. Yellow fever in 1994 and 1995 [published erratum appears in Wkly Epidemiol Rec 1996 Nov 29;71(48):365]. Wkly Epidemiol Rec. Oct 18 1996;71(42):313-8. [Medline].

Article Last Updated: May 30, 2006