Differentials
Malaria infection
SIGNS / SYMPTOMS
Residence in/travel from malaria-endemic region.
Inadequate or absence of malaria chemoprophylaxis.
Difficult to distinguish from CCHF infection without diagnostic testing.
INVESTIGATIONS
Giemsa-stained blood film: positive for Plasmodium species.
Rapid diagnostic tests: positive for Plasmodium species.
Ebola virus infection
SIGNS / SYMPTOMS
There are no differentiating signs or symptoms.
Epidemiological features can help differentiate between the viral haemorrhagic fevers.
INVESTIGATIONS
Reverse transcription-polymerase chain reaction (RT-PCR): positive for Ebola virus.
It is recommended that appropriate confirmatory tests for Ebola virus infection are performed before, or in tandem with, differentiating tests if Ebola virus infection is suspected.
Lassa fever
SIGNS / SYMPTOMS
There are no differentiating signs or symptoms.
Epidemiological features can help differentiate between the viral haemorrhagic fevers.
Exposure to rats in endemic areas.
INVESTIGATIONS
RT-PCR: positive for Lassa virus.
Typhoid fever
SIGNS / SYMPTOMS
Exposure to contaminated water/food, direct faecal-oral contact, age <5 or >50 years, malnutrition, poor hygiene and cramped conditions, chronic illness, and travel to endemic areas.
INVESTIGATIONS
Blood or stool culture: positive for Salmonella enterica.
Leptospirosis
SIGNS / SYMPTOMS
There are no differentiating signs or symptoms; however, a history of exposure may be helpful.
Exposure to contaminated water or soil contaminated by infected rodents.[75]
More common in tropical climates.
INVESTIGATIONS
PCR: positive.
Serology: positive.
It is recommended that appropriate confirmatory tests for CCHF are performed before, or in tandem with, differentiating tests if CCHF is suspected.
Influenza infection
SIGNS / SYMPTOMS
Respiratory signs or symptoms (e.g., cough, nasal congestion) are more common.
INVESTIGATIONS
Viral culture or PCR: detection of seasonal influenza virus or viral RNA.
FBC: normal.
Sepsis
SIGNS / SYMPTOMS
Bacterial sepsis with an unclear origin is a common presentation in developing countries. Often turns out to be deep abdominal infection, upper urinary tract infection, endocarditis, or discitis.
Diarrhoea is often absent.
INVESTIGATIONS
Blood cultures: positive.
Rickettsial diseases
SIGNS / SYMPTOMS
Includes murine typhus, African tick-bite fever, and epidemic typhus.[76]
Eschar is typical.
Lymphadenopathy may be present.
Discrete rash.
INVESTIGATIONS
Serology: positive for Rickettsia species.
Eschar PCR: positive for Rickettsia species.
West Nile virus infection
SIGNS / SYMPTOMS
Residence in/travel from West Nile virus-endemic region.
Visual disturbances common.
Rarely causes neuroinvasive disease (e.g., encephalitis, meningitis, flaccid paralysis syndrome).
Difficult to distinguish from CCHF virus infection without diagnostic testing.
INVESTIGATIONS
West Nile virus-specific IgM in serum or CSF: positive.
Rift Valley fever
SIGNS / SYMPTOMS
Residence in/travel from Rift Valley fever virus-endemic region.
Contact with mosquitoes or infected animals.
INVESTIGATIONS
RT-PCR: positive for Rift Valley fever virus.
Marburg virus infection
SIGNS / SYMPTOMS
There are no differentiating signs or symptoms.
Epidemiological features can help differentiate between the viral haemorrhagic fevers.
Exposure to bats, caves, or mining.
INVESTIGATIONS
RT-PCR: positive for Marburg virus.
Omsk haemorrhagic fever/Kyasanur Forest disease
SIGNS / SYMPTOMS
There are no differentiating signs or symptoms in the initial phase.
CNS involvement may occur in the second phase.[77]
Epidemiological features can help differentiate between the viral haemorrhagic fevers.
INVESTIGATIONS
Serum or CSF serology: positive for relevant IgM/IgG antibodies.
Yellow fever
SIGNS / SYMPTOMS
Residence in/travel from yellow fever endemic region.
Contact with mosquitoes or infected monkeys.
Jaundice more common in early disease.
Relative bradycardia.
INVESTIGATIONS
Serology (IgM ELISA or haemagglutination inhibition): positive for yellow fever virus RNA, increasing IgG titres.
Hantavirus
SIGNS / SYMPTOMS
Residence in/travel from hantavirus-endemic regions.
Residence in/travel to densely forested areas with large rodent populations.
Exposure to rodent faeces, urine, or carcasses, or rodent bite.
Pulmonary or renal involvement.
INVESTIGATIONS
RT-PCR detection of hantavirus RNA.
Onset of severe pulmonary distress.
Meningococcal disease
SIGNS / SYMPTOMS
Rash characteristically petechial and begins earlier than in rickettsial infections, starting centrally and spreading peripherally.
Septic shock, DIC, and digital necrosis more likely.
INVESTIGATIONS
Blood cultures (and sometimes CSF cultures): positive for Neisseria meningitidis.
Lyme disease
SIGNS / SYMPTOMS
History of tick bite.
More chronic course and gradual onset.
Erythema chronicum migrans.
Lyme arthritis.
Chronic radicular paraesthesias.
INVESTIGATIONS
Positive serum antibody titre for Borrelia burgdorferi: total Lyme titre or positive IgG and IgM.
Western blot (IgM/IgG): to confirm positive titres.[78]
Brucellosis
SIGNS / SYMPTOMS
Exposure to unpasteurised milk products.
INVESTIGATIONS
Blood cultures: positive growth of Brucella species.
Serological tests (e.g., Wright agglutination or ELISA)
FBC: pancytopenia.
Q fever (Coxiella burnetii)
SIGNS / SYMPTOMS
Exposure to infected animals, occupational exposure, travel to or residence in endemic areas.
High fever (39°C to 40°C [102.2ºF to 104ºF]).
May have signs of atypical pneumonia.
INVESTIGATIONS
Immunofluorescence assay (IFA) of infected tissue: positive.
Staphylococcal or gram-negative sepsis
SIGNS / SYMPTOMS
Bacterial sepsis with an unclear origin is a common presentation in developing countries. Often turns out to be deep abdominal infection, upper urinary tract infection, endocarditis, or discitis.
Diarrhoea is often absent.
INVESTIGATIONS
Blood cultures: positive.
Toxic shock syndrome (TSS)
SIGNS / SYMPTOMS
An acute febrile illness that is associated with vomiting, diarrhoea, myalgia, strawberry tongue, and erythematous rash with subsequent desquamation.
Many develop acute respiratory distress, hypotension, and shock.
The disease is caused by staphylococcal or group A streptococcal infections.
INVESTIGATIONS
Isolation of staphylococcus or group A streptococcus serotypes that produce TSS-1 toxin.
Psittacosis
SIGNS / SYMPTOMS
Exposure to infected birds and mammals.
Upper and lower respiratory tract signs or symptoms more common.
INVESTIGATIONS
Microimmunofluorescence (MIF) antibody: paired sera positive for psittacosis antibodies.
Cultures of sputum, pleural fluid, conjunctival fluid, or clotted blood: positive for Chlamydia psittaci.
Septicaemic plague
SIGNS / SYMPTOMS
Exposure to fleas, residency in or travel to a plague-endemic area, and contact with infected animals.
INVESTIGATIONS
Positive culture for Yersinia pestis.
Rubella
SIGNS / SYMPTOMS
Typically a mild fever and generalised maculopapular rash improving in about 3 days. May also have non-tender lymphadenopathy of post-auricular, posterior cervical, and occipital lymph node groups; conjunctivitis; and arthralgias or arthritis.
INVESTIGATIONS
Rubella-specific IgM antibody or other specific test for rubella.
Measles infection
SIGNS / SYMPTOMS
Erythematous or brownish morbilliform rash spreading from the head and neck downwards and persisting for 3 to 7 days.
Coryza, cough, and conjunctivitis are usual.
A pathognomonic enanthem (Koplik's spots) occurs early in the disease.
INVESTIGATIONS
Positive serum measles anti-IgM antibody is the preferred test.
Significant rise in serum measles anti-IgG antibody in paired acute and convalescent specimens.
Isolation of measles virus from throat, nasopharynx, blood, or urine (usually processed by public health and reference laboratories only).
Thrombotic thrombocytopenic purpura
SIGNS / SYMPTOMS
Thrombocytopenia and a purpuric rash.
INVESTIGATIONS
Peripheral smears show schistocytes.
HELLP syndrome (pregnant women)
SIGNS / SYMPTOMS
May be mistaken for CCHF in a pregnant patient.
Brisk tendon reflexes are commonly found, as is RUQ abdominal tenderness.
Fever is not usual.
INVESTIGATIONS
Schistocytes, burr cells, and polychromasia on a peripheral blood smear are diagnostic.
Uric acid levels: typically elevated.
Haemolytic uraemic syndrome
SIGNS / SYMPTOMS
More commonly seen in children, especially those aged <5 years.
Patients demonstrate more bloody diarrhoea and renal failure.
Fever may be absent.
INVESTIGATIONS
Associated with Escherichia coli O157:H7 infection, which is detected in the stool.
Coronavirus disease 2019 (COVID-19)
SIGNS / SYMPTOMS
Residence in/travel to a country/area or territory with local transmission, or close contact with a confirmed or probable case of COVID-19, in the 14 days prior to symptom onset.
INVESTIGATIONS
Real-time reverse transcription polymerase chain reaction (RT-PCR): positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA.
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