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Yellow Fever Workup

  • Author: Mary T Busowski, MD; Chief Editor: Mark R Wallace, MD, FACP, FIDSA  more...
 
Updated: Jun 26, 2015
 

Approach Considerations

Laboratory abnormalities during the initial viremic phase of yellow fever include leukopenia, often present at the onset of illness, and elevation of direct bilirubin and hepatic transaminases on days 2-3 of the illness.[3, 17] Transaminase levels increase relative to the degree of hepatic injury.

In the toxic phase, end-organ dysfunction is reflected by laboratory values, as follows:

  • Prothrombin time, activated partial thromboplastin time, international rationalized ratio (INR), and clotting times are invariably prolonged
  • Diminished levels of factor VIII, fibrinogen, and platelets, along with the presence of fibrin split products, indicate presence of DIC
  • Albuminuria usually is noted via urinalysis studies; proportional rises in blood urea nitrogen (BUN) and creatinine will be present in serum

Complete blood count

Findings in a complete blood count (CBC) for patients with yellow fever include the following:

  • Leukopenia with relative neutropenia
  • Thrombocytopenia as part of a consumptive coagulopathy
  • Initial hemoconcentration, increased hemoglobin and hematocrit levels
  • Subsequent hemorrhage and hemodilution resulting in decreasing complete blood cell counts

Coagulation studies

Coagulation studies reveal the following in patients with yellow fever:

  • Reduced fibrinogen and clotting factors II, V, VII, VIII, IX, and X and the presence of fibrin split products indicate disseminated intravascular coagulation
  • Decreased synthesis of clotting factors may result in an elevated prothrombin time
  • Prolonged clotting times may be found

Chemistries

Chemistry studies in patients with yellow fever show the following:

Urinalysis

Urinalysis in patients with yellow fever reveals the following:

  • Elevated urinary protein levels
  • Elevated urobilinogen levels

Imaging studies

Chest radiography is used to evaluate the extent of pulmonary edema, to reveal secondary bacterial pulmonary infections, and to aid in ventilator management if intubation is required.

When mental status changes occur late in the illness, a brain computed tomography (CT) scan is helpful in determining whether intracranial hemorrhage is the cause.

ECG and cardiac monitoring

Electrocardiography (ECG) may identify prolongation of PR and QT intervals.[1] Arrhythmias are commonly due to myocarditis. Cardiac involvement by yellow fever is evidenced by ST-T wave abnormalities.

Electrolyte abnormalities, hypoxia, and hypoperfusion states also are common causes of arrhythmias in patients who are severely ill.

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Specific Tests for Yellow Fever Virus

Rapid detection methods

Rapid detection methods include the following:

  • Detection of yellow fever antigen using monoclonal enzyme immunoassay in serum specimens
  • Detection of viral genome sequences in tissue or in blood or other body fluid using polymerase chain reaction (PCR) assay

Serologic testing methods

Serologic tests, such as enzyme-linked immunosorbent assay (ELISA), aid in making an exact diagnosis. Confirmation is difficult because of cross-reactivity with other viruses, particularly in Africa, where multiple flaviviruses exist. Ruling out other flaviviruses is often aided by a detailed travel history.[3]

Immunoglobulin M (IgM) antibody-capture enzyme-linked immunosorbent assay (MAC-ELISA) is used to detect the specific IgM for yellow fever; a single positive serum titer is diagnostic. This assay is 95% sensitive when serum specimens are collected 7-10 days after the onset of illness.

A confirmed case of yellow fever infection is defined as a clinically compatible case and 4-fold rise in antibody titer in a patient who has no history of a recent yellow fever vaccination and cross-reactivity to other flaviviruses has been excluded. During the acute phase of the illness, 3-10 days from onset of symptoms, a positive IgM ELISA provides a probable diagnosis.A rise in yellow fever–specific antibody titer in paired acute and convalescent samples confirms a laboratory diagnosis.

Immunohistochemical staining of tissues

Immunohistochemical staining of tissues (liver, heart, or kidneys) for the yellow fever antigen can also provide a definitive diagnosis.[3] One should not attempt a liver biopsy during infection because of the risk of complications from hemorrhage.

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Liver Function Tests

Transaminitis precedes the appearance of jaundice, and the degree of liver dysfunction in the acute phase may be predictive of the clinical course.

Liver function tests also reveal the following:

  • Serum AST levels - Exceed ALT levels
  • Direct bilirubin levels - Elevated
  • Hypoalbuminemia - Albuminuria, decreased synthesis, and extravasation of albumin through damaged capillary endothelium
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Histologic Findings

In the acute phase of yellow fever, gross examination of liver biopsy reveals a mottled yellow (boxwood) color and friable texture. With the availability of serology to provide diagnosis, a liver biopsy is likely not necessary to provide diagnostic confirmation of infection, and the risks versus benefits of a liver biopsy need to be carefully considered. During acute illness, a liver biopsy should be avoided.

Histopathologic changes consistent with yellow fever include midzonal necrosis with sparing of cells around the central vein and portal tracts, steatosis, and Councilman bodies. Councilman bodies are acidophilic inclusion bodies resulting from apoptotic death of hepatocytes; they are characteristic of viral hemorrhagic fevers and other acute viral hepatitis. Late in the illness, biopsy may reveal only severe, nonspecific necrotic changes.

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Contributor Information and Disclosures
Author

Mary T Busowski, MD Chief, Division of Infectious Diseases, Orlando VA Medical Center; Infectious Disease Faculty Practice/Internal Medicine Faculty Practice, Orlando Health; Assistant Professor of Medicine, Florida State University College of Medicine; Assistant Professor of Medicine, University of Central Florida College of Medicine

Mary T Busowski, MD is a member of the following medical societies: American Academy of Hospice and Palliative Medicine, American College of Physicians, American Medical Association, Florida Medical Association, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Coauthor(s)

Mark R Wallace, MD, FACP, FIDSA Clinical Professor of Medicine, Florida State University College of Medicine; Clinical Professor of Medicine, University of Central Florida College of Medicine

Mark R Wallace, MD, FACP, FIDSA is a member of the following medical societies: American College of Physicians, American Medical Association, American Society for Microbiology, Infectious Diseases Society of America, International AIDS Society, Florida Infectious Diseases Society

Disclosure: Nothing to disclose.

Janelle L Robertson, MD Staff Physician, Department of Infectious Diseases, Wilford Hall Medical Center

Janelle L Robertson, MD is a member of the following medical societies: American College of Physicians

Disclosure: Nothing to disclose.

Chief Editor

Mark R Wallace, MD, FACP, FIDSA Clinical Professor of Medicine, Florida State University College of Medicine; Clinical Professor of Medicine, University of Central Florida College of Medicine

Mark R Wallace, MD, FACP, FIDSA is a member of the following medical societies: American College of Physicians, American Medical Association, American Society for Microbiology, Infectious Diseases Society of America, International AIDS Society, Florida Infectious Diseases Society

Disclosure: Nothing to disclose.

Acknowledgements

Joseph U Becker, MD Fellow, Global Health and International Emergency Medicine, Stanford University School of Medicine

Joseph U Becker, MD is a member of the following medical societies: American College of Emergency Physicians, Emergency Medicine Residents Association, Phi Beta Kappa, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Richard B Brown, MD, FACP Chief, Division of Infectious Diseases, Baystate Medical Center; Professor, Department of Internal Medicine, Tufts University School of Medicine

Richard B Brown, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Chest Physicians, American College of Physicians, American Medical Association, American Society for Microbiology, Infectious Diseases Society of America, and Massachusetts Medical Society

Disclosure: Nothing to disclose.

Dan Danzl, MD Chair, Professor, Department of Emergency Medicine, University of Louisville Hospital

Dan Danzl, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, Kentucky Medical Association, Society for Academic Emergency Medicine, and Wilderness Medical Society

Disclosure: Nothing to disclose.

Aleksandr Gleyzer, MD, FAAEM Assistant Professor, Department of Emergency Medicine, State University of New York Downstate Medical Center; Attending Physician, Department of Emergency Medicine, Kings County Medical Center and Brooklyn Veterans Affairs Medical Center

Aleksandr Gleyzer, MD, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine and International Society of Travel Medicine

Disclosure: Nothing to disclose.

Thomas E Herchline, MD Professor of Medicine, Wright State University, Boonshoft School of Medicine; Medical Director, Public Health, Dayton and Montgomery County, Ohio

Thomas E Herchline, MD is a member of the following medical societies: Alpha Omega Alpha, Infectious Diseases Society of America, and Infectious Diseases Society of Ohio

Disclosure: Nothing to disclose.

Emily Nichols, MD Clinical Assistant Instructor, State University of New York Downstate Medical Center, Kings County Hospital Center

Emily Nichols, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, Emergency Medicine Residents Association, and National Medical Association

Disclosure: Nothing to disclose.

Mark L Plaster, MD, JD Executive Editor, Emergency Physicians Monthly

Mark L Plaster, MD, JD is a member of the following medical societies: American Academy of Emergency Medicine and American College of Emergency Physicians

Disclosure: M L Plaster Publishing Co LLC Ownership interest Management position

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Mark R Wallace, MD, FACP, FIDSA Clinical Professor of Medicine, Florida State University College of Medicine; Head of Infectious Disease Fellowship Program, Orlando Regional Medical Center

Mark R Wallace, MD, FACP, FIDSA is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Tropical Medicine and Hygiene, and Infectious Diseases Society of America

Disclosure: Nothing to disclose.

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Yellow fever virus. Image courtesy of the Centers for Disease Control and Prevention.
This female Aedes aegypti mosquito is shown after landing on a human host. The A aegypti mosquito is a known transmitter of dengue fever and yellow fever. A aegypti is sometimes referred to as the yellow fever mosquito. The viruses are transferred to the host when he or she has been bitten by a female mosquito. Image courtesy of the CDC/World Health Organization (WHO).
Global distribution of yellow fever. Image courtesy of the Centers for Disease Control and Prevention.
Transmission cycles of yellow fever in Africa and South America. Adapted from Annu Rev Entomol. 2007. 52:209-29.
 
 
 
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