Marburg hemorrhagic fever differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief:

Differentiating Marburg Hemorrhagic Fever from other Diseases

Marburg hemorrhagic fever must be differentiated from other diseases that may cause fever, abdominal pain, diarrhea, vomiting and bleeding such as:

• Ebola hemorrhagic fever
• Lassa hemorrhagic fever
• Crimean-Congo hemorrhagic fever
• Malaria
• Typhoid fever
• Shigellosis
• Cholera
• Leptospirosis
• Plague,
• Rickettsiosis
• Relapsing fever
• Meningitis
• Hepatitis
• Other viral hemorrhagic fevers

Virus	Disease	Incubation Period	Symptoms						Laboratory findings
			Prodromal phase					Illness phase
			Fever	Headache	Myalgia	Abdominal pain	Hemorrhage
Filoviruses	Marburg Hemorrhagic Fever	5-10	+	+	+	+	+	Clinically indistinguishable Maculopapular rash on the trunk (chest, back, stomach) Multiorgan failure
	Ebola	2-21	+	+	+	+	+
Bunyaviruses	Crimean-Congo hemorrhagic fever (CCHF)	13	+	+	+	+	+	Red eyes, a flushed face, a red throat, and petechiae (red spots) on the palate changes in mood and sensory perception.
	Hantavirus Infection	9 -33	+	+	+	-	+	Flushing of the face Injection of the conjunctiva Prostration
	Rift Valley fever	2-6	+	-	+	-	-	Most commonly mild disease with recovery in 2 weeks Encephalitis, or inflammation of the brain Hemorrhagic fever, which occurs in less than 1% of overall RVF
Arenaviruses	Lassa fever	7-21	+	+	+	-	-	Deafness Respiratory distress Repeated vomiting Facial swelling Pain in the chest, back, and abdomen, and shock.encephalitis Hemorrhage only 20% have severe disease
	Lujo hemorrhagic fever	7-13						Morbilliform rash of the face and trunk Face and neck swelling Pharyngitis Diarrhea
	Lymphocytic choriomeningitis (LCM)	8-13	+	+	+	-	-	Meningitis, encephalitis, meningoencephalitis Acute hydrocephalus Myocarditis
Flaviviruses	Alkhurma hemorrhagic fever (AFD)	2-4	+	-	+	-	-	Neurologic symptoms Hemorrhagic symptoms only in severe form. Multi-organ failure	Thrombocytopenia, Leukopenia Elevated liver enzymes
	Kyasanur Forest Disease (KFD)	3-8	+	+	+	+	+	Biphasic Complete recovery by 2 week Wave of symptoms in 3 rd week with tremors, and vision deficits.	Pancytopenia
	Omsk hemorrhagic fever	3-8	+	+	+	+	+	Biphasic Complete recovery by 2 week Wave of symptoms in 3 rd week with encephalitis	Pancytopenia

Treatment should be based on the most likely etiology of fever according to local epidemiology. If the fever continues after 3 days of recommended treatment, and if the patient has signs such as bleeding or shock, a viral hemorrhagic fever should be considered. It is important to review the patient’s history for any contact with someone who was ill with fever and bleeding or who died from an unexplained illness with fever and bleeding.

Shown below is a table summarizing the typical findings of the differential diagnoses of MHF.

Disease	Findings
Shigellosis & other bacterial enteric infections	Presents with diarrhea, possibly bloody, accompanied by fever, nausea, and sometimes toxemia, vomiting, cramps, and tenesmus. Stools contain blood and mucous in a typical case. A search for possible sites of bacterial infection, together with cultures and blood smears, should be made. Presence of leucocytosis distinguishes bacterial infections.
Typhoid fever	Presents with fever, headache, rash, gastrointestinal symptoms, with lymphadenopathy, relative bradycardia, cough and leucopenia and sometimes sore throat. Blood and stool culture can demonstrate causative bacteria.
Malaria	Presents with acute fever, headache and sometime diarrhea (children). Blood smears must be examined for malaria parasites. Presence of parasites does not exclude concurrent viral infection. Antimalarial must be prescribed in an attempt at therapy.
Lassa fever	Disease onset is usually gradual, with fever, sore throat, cough, pharyngitis, and facial edema in the later stages. Inflammation and exudation of the pharynx and conjunctiva are common.
Yellow fever and other Flaviviridae	Present with hemorrhagic complications. Epidemiological investigation may reveal a pattern of disease transmission by an insect vector. Virus isolation and serological investigation serves to distinguish these virus. Confirmed history of previous yellow fever vaccination will rule out yellow fever.
Others	Viral hepatitis, leptospirosis, rheumatic fever, typhus, and mononucleosis produce signs and symptoms that may be confused with Ebola in the early stages of infection.
Table adapted from WHO Guidelines For Epidemic Preparedness And Response: Ebola Haemorrhagic Fever

Disease	Incubation period	Vector	Symptoms							Physical signs		Lab findings		Other findings	Treatment
			Fever	Cough	Rash	Joint pain	Myalgia	Diarrhea	Common hemorrhagic symptoms	Characterestic physical finding	Icterus	Plasma Creatine kinase	Confirmatory test
Leptospirosis	2 to 30 days	Rodents Domestic animals	Fever last for 4-7 days, remission for 1-2 days and then relapse	+	Present over legs Hemorrhagic rash	+	+ (Severe myalgia is characteristic of leptospirosis typically localized to the calf and lumbar areas)	+	Conjunctival hemorrhage, Hemoptysis	Conjunctival suffusion	+	Elevated	Microscopic agglutination test of urine	History of exposure to soil or water contaminated by infected rodents Recent history travel to tropical, sub tropical areas or humid areas	NSAIDs
Dengue	4 to 10 days	Aedes mosquito	Fever last for 1-2 days, remission for 1-2 days and then relapse for 1-2 days (Biphasic fever pattern)	-	Over legs and trunk pruritic rash May be hemorrhagic	+	+	-	Upper gastrointestinal bleeding	Painful lymphadenopathy	-	Normal	Serology showing positive IgM or IgG	Recent travel to South America, Africa, Southeast Asia	Supportive care Avoid aspirin and other NSAIDs
Malaria	Plasmodium falciparum: 9-14 days Plasmodium vivax: 12-18 days Plasmodium ovale: 18-40 days	Female Anopheles	Fever present daily or on alternate day or every 3 days depending on Plasmodium sps.	-	No rash	-	+	-	Bloody urine	Hepatosplenomegaly	+	Normal	Giemsa stained thick and thin blood smears	Recent travel to South America, Africa, Southeast Asia	Anti malarial regimen
Ebola	2 to 21 days.	No vector Human to human transmission Air born disease	+	+	Maculopapular non-pruritic rash with erythema Centripetal distribution	+	+	+ May be bloody in the early phase	Epistaxis Mucosal bleeding	Sudden onset of high fever with conjunctival injection and early gastrointestinal symptoms	-	Normal	RT-PCR	Recent visit to endemic area especially African countries	Isolation of the patient, supportive therapy
Influenza	1-4 days	No vector Air born disease	+	+	+/-	+	+	+	-	Fever and upper respiratory symptoms	-	Normal	Viral culture or PCR	Health care workers Patients with co-morbid conditions	Symptomatic treatment Oseltamivir or zanamivir
Yellow fever	3 to 6 days	Aedes or Haemagogus species mosquitoes	+	+	-	-	+	-	Conjunctival hemorrhage, Hemoptysis	Relative bradycardia (Faget's sign)	+	Normal	RT-PCR, Nucleic acid amplification test, Immuno-histochemical staining	Recent travel to  Africa, South and Central America, and the Caribbean. Tropical rain forests of south America	Symptomatic treatment, Anti-inflammatory drugs
Typhoid fever	6 to 30 days	No vector Air born disease	+	-	Blanching erythematous  maculopapularlesions on the lower chest and abdomen	+	+	+	Intestinal bleeding	Rose spots	-	Normal	Blood or stool culture showing salmonella typhi sps.	Residence in endemic area Recent travel to endemic area	Fluoroquinolones, Third generation cephalosporins, Azithromycin

References