Differentials
Malaria infection
SIGNS / SYMPTOMS
Anaemia, jaundice, and persistent chills and fever are more common with malaria.
Residence in/travel from malaria-endemic region.
Inadequate or absent malaria chemoprophylaxis.
INVESTIGATIONS
Giemsa-stained thick and thin blood smears: positive for Plasmodium species.
Rapid malaria antigen test: positive for Plasmodium species.
Dengue fever
SIGNS / SYMPTOMS
Biphasic fever and biphasic rash (transient generalised macular rash followed by a second morbilliform, maculopapular rash).
Bone pain.
INVESTIGATIONS
Detection of virus in serum, immunoglobulins (IgM and IgG), or both by enzyme-linked immunosorbent assay (ELISA) antibody capture, monoclonal antibody, or haemagglutination.
FBC: thrombocytopaenia; decreased total WBC count and neutrophils; changing neutrophil-to-lymphocyte ratio; and elevated haematocrit may develop rapidly, particularly before the critical phase of infection.
Chikungunya virus
SIGNS / SYMPTOMS
Polyarthralgia is common during the acute phase.
Carpal tunnel syndrome may also develop, but is less common than polyarthralgia.
Absence of bleeding tendency and circulatory failure.
INVESTIGATIONS
Enzyme-linked immunosorbent assay (ELISA)/indirect fluorescent antibody (IFA): positive for chikungunya antibodies.
Reverse transcription-polymerase chain reaction: positive for chikungunya viral RNA.
Zika virus
SIGNS / SYMPTOMS
Zika is now found in the Americas and overlaps geographically with VEEV distribution.
Symptoms (fever, headache, myalgias) are similar, but Zika disease tends to be milder.
Rash and conjunctivitis are more common with Zika.
INVESTIGATIONS
The diagnosis is confirmed by reverse transcription-polymerase chain reaction. Serology tests are available, but they strongly cross-react with other flaviviruses, such as dengue and West Nile virus.
Yellow fever
SIGNS / SYMPTOMS
Patients with yellow fever usually have a more toxic appearance and evidence of hepatitis. The liver may be tender and enlarged on examination.
Elevated aminotransferases are more prominent.
Deterioration can occur with renal and liver failure and with haemorrhagic manifestations.
INVESTIGATIONS
The diagnosis is confirmed via detection of IgM by enzyme-linked immunosorbent assay (ELISA), molecular diagnosis, or direct virus isolation.
Mayaro virus infection
SIGNS / SYMPTOMS
In Mayaro virus infection, similar to chikungunya, arthralgias and arthritis are prominent features.
Does not cause encephalitis, but systemic symptoms may be similar.
INVESTIGATIONS
The diagnosis, similar to other arboviruses, can be made via serology, reverse transcription-polymerase chain reaction, or direct virus isolation.
Haemorrhagic fevers
SIGNS / SYMPTOMS
Encompasses diseases caused by viruses from four distinct families: arenavirus, bunyavirus, filovirus (including Ebola), and flavivirus.
Initially, there may be no differentiating signs or symptoms; however, progression to severe disease with bleeding from skin and mucosae, together with the relatively narrow geographic location of infection, helps in the differential diagnosis. Of note, severe haemorrhage does occur occasionally in VEEV disease.
INVESTIGATIONS
Diagnosis is based on antibody detection or molecular diagnosis.
Direct isolation is recommended in biosafety level 4 laboratories.
West Nile virus infection
SIGNS / SYMPTOMS
No differentiating signs or symptoms.
West Nile virus neuroinvasive disease is rarely seen in children, unlike VEEV infection.
INVESTIGATIONS
One of the following: 4-fold increase in the antivirus antibody titre between acute and convalescent serum; isolation of virus from tissue, blood, or cerebrospinal fluid (CSF); detectable IgM antibody to virus in single serum or CSF sample.
Typhoid fever
SIGNS / SYMPTOMS
Pulse-temperature dissociation may occur in typhoid fever. The rash is macular and has a preference for the abdominal area.
Hepatosplenomegaly, gastrointestinal bleeding, abnormal mental status, and frank sepsis may occur after the third week of infection.
INVESTIGATIONS
Diagnosis is confirmed by isolation of Salmonella enterica in blood, urine, stool, or bone marrow cultures.
Serological antibody titres measured during acute and convalescent periods may also be used for diagnosis.
Leptospirosis
SIGNS / SYMPTOMS
Neurological involvement is less common with leptospirosis.
With severe infection, jaundice, renal failure, and bleeding can occur.
There is usually a history of exposure to contaminated water or soil, or contact with infected animals or their excrement.
INVESTIGATIONS
Diagnosis depends on detection of antibodies, real-time polymerase chain reaction, or, less commonly, cultures of blood or urine.
Serology (microscopic agglutination test): positive for leptospirosis.
Measles
SIGNS / SYMPTOMS
The exanthema starts in the face and extends centrifugally, then it darkens in three to four days and desquamates after a week or so.
Koplick's spots in the buccal mucosa are pathognomonic of measles.
Pneumonia is a frequent complication.
INVESTIGATIONS
Diagnosis is made by detection of IgM antibodies, polymerase chain reaction, or viral culture.
Rubella
SIGNS / SYMPTOMS
Prominent lymphadenopathy affecting posterior cervical, posterior auricular, and suboccipital lymph nodes is common.
Enanthema on the soft palate (Forchheimer spots) can occur.
Orchitis can be a complication.
INVESTIGATIONS
Diagnosis is made by antibody detection or rarely via viral culture.
Rocky Mountain spotted fever
SIGNS / SYMPTOMS
The rash tends to evolve into a purpuric appearance. It classically affects palms and soles.
Common complications include: encephalitis, adult respiratory distress syndrome, cardiac arrhythmias, coagulopathy, gastrointestinal bleeding, and skin necrosis.
Rocky Mountain spotted fever is also endemic in parts of Central and South America.
INVESTIGATIONS
The diagnosis is made by detection of antibodies, direct immunofluorescence, or immunoperoxidase staining in skin biopsies. Polymerase chain reaction can be used, but sensitivity is low early in the course of the disease.
Epstein-Barr (EBV) infection
SIGNS / SYMPTOMS
Encephalitis is very rare.
Maculopapular and pruritic rash may follow administration of ampicillin or amoxicillin.
Complications such as airway obstruction from massive adenopathy and spleen rupture may occur.
Course tends to be more prolonged for EBV (weeks) compared with VEEV (days).
INVESTIGATIONS
Diagnosis is made by detection of heterophile antibodies or EBV-specific antibodies and by DNA detection.
Acute retroviral syndrome following HIV infection
SIGNS / SYMPTOMS
A history of recent sexual contact is usually obtained.
During the acute retroviral syndrome, pharyngitis can be prominent.
Rash may affect the palms and soles.
INVESTIGATIONS
The best diagnostic method for acute retroviral syndrome is quantitative plasma HIV RNA level (viral load) by reverse transcription-polymerase chain reaction and antigen/antibody immunoassay.
St. Louis encephalitis infection
SIGNS / SYMPTOMS
No differentiating signs or symptoms, but symptoms are generally milder.
St. Louis encephalitis virus occurs throughout the Americas.
Elderly people are at highest risk of neuroinvasive disease.
INVESTIGATIONS
One of the following: 4-fold increase in the antivirus antibody titre between acute and convalescent serum; isolation of virus from tissue, blood, or cerebrospinal fluid (CSF); detectable IgM antibody to virus in single serum or CSF sample.
Herpes simplex virus (HSV) encephalitis
SIGNS / SYMPTOMS
An oral or genital ulcer may be present, or the patient may have a recent history of such an ulcer.
While fever and headache are common, myalgias, arthralgias and vomiting are less common.
INVESTIGATIONS
HSV polymerase chain reaction of cerebrospinal fluid is diagnostic.
MRI often reveals hyperintensity of the temporal lobes on T2-weighted images.
Eastern equine encephalitis virus (EEEV) infection
SIGNS / SYMPTOMS
No differentiating signs or symptoms, although neurological sequelae may be more severe.
North American EEEV infections occur mainly in North America and the Caribbean.
INVESTIGATIONS
Enzyme-linked immunosorbent assay (ELISA) with plaque reduction neutralisation test: positive for EEEV antibodies (IgG or IgM).
Western equine encephalitis virus (WEEV) infection
SIGNS / SYMPTOMS
No differentiating signs or symptoms.
WEEV infections occur mainly on the west coast of the US.
INVESTIGATIONS
One of the following: 4-fold increase in the antivirus antibody titre between acute and convalescent serum; isolation of virus from tissue, blood, or cerebrospinal fluid (CSF); detectable IgM antibody to virus in single serum or CSF sample.
South American haemorrhagic fever
SIGNS / SYMPTOMS
Signs and symptoms on presentation may be similar to VEEV infection.
Progression to severe disease with bleeding from mucosae, together with the relatively narrow geographical location of infection, helps in the differential diagnosis.
INVESTIGATIONS
Diagnosis is based on reverse transcription-polymerase chain reaction (RT-PCR), or enzyme-linked immunosorbent assay (ELISA) if RT-PCR is unavailable.
Diagnostic testing requires a biosafety level 4 laboratory.
Tuberculous meningitis
SIGNS / SYMPTOMS
No differentiating signs or symptoms.
Birth in tuberculosis-prevalent countries.
INVESTIGATIONS
Detection of acid-fast bacilli in cerebrospinal fluid using polymerase chain reaction.
CT/MRI: can show cerebral tuberculomas or basilar arachnoiditis.[37]
Bacterial meningitis
SIGNS / SYMPTOMS
May be no differentiating signs or symptoms, however a non-blanching petechial or purpuric rash can be present with bacterial meningitis.
Viral meningitis
SIGNS / SYMPTOMS
A non-blanching petechial or purpuric rash is typical of viral meningitis.
INVESTIGATIONS
cerebrospinal fluid: polymerase chain reaction positive for specific viruses.
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