Approach
CCHF is a notifiable disease. Any suspected cases must be immediately reported to the local or state health department. Any clinical laboratory handling specimens should also be notified. The case definition for CCHF may differ from country to country depending on available diagnostic facilities and includes a long list of differential diagnoses.
Isolation and personal protective equipment (PPE)
Bunyaviruses are highly infectious and are transmitted human-to-human after direct contact with infected blood and body fluids. Therefore, it is recommended that when caring for any patient with suspected or documented CCHF virus infection, specific barrier precautions should be implemented immediately. A study following the CCHF epidemic in Turkey reported the lack of airborne transmission of CCHF to healthcare workers.[62] Standard precautions include hand hygiene and use of gloves, gowns, face shields, and masks. While these are normally sufficient to offer protection, if a procedure may generate an aerosol, healthcare workers should consider wearing an N95 or FFP2 respirator (European Norm [EN] 61010-1).[40][61]
To minimise risk of needlestick injuries, sharps containers should be available at all times, and the use of safety-engineered devices should also be considered.[40][61]
The World Health Organization (WHO) produces detailed guidance on PPE:
WHO: steps to put on personal protective equipment Opens in new window
WHO: steps to remove personal protective equipment Opens in new window
The WHO has also produced guidance on collecting and shipping samples from patients with suspected CCHF:
History
A detailed history helps to clarify the level of risk for CCHF, as well as assess the possibility of other causes of an acute febrile syndrome.
People living or working in endemic areas are at high risk of infection. However, recent travel to endemic regions is also an important risk factor. Tick-exposure history, and whether measures were taken to help prevent tick bites, can also help to assess the risk. Contacts of infected patients (including healthcare workers and household contacts) are at risk of infection, especially if they did not use appropriate protective equipment.
The incubation period for CCHF virus ranges from 1-9 days, but 30 days of incubation period was reported from Turkey.[39] Patients initially exhibit a non-specific prodrome, which typically lasts less than 1 week. Symptoms typically include high fever, headache, malaise, arthralgias, myalgias, nausea, abdominal pain, and rarely diarrhoea.[46] Death is typically preceded by haemorrhagic diathesis, shock, and multi-organ system failure 1-2 weeks following onset of symptoms. The disease has been reported to be milder among children.[40][63]
Physical examination
Early signs typically include fever, hypotension, conjunctivitis, and a skin rash (macular or petechial). Later, patients may develop signs of progressive haemorrhage including conjunctival haemorrhage, haematuria, haematemesis, and melaena. These patients may progress to disseminated intravascular coagulation (DIC) and circulatory shock.[40][63]
Case definition
While the case definition for CCHF may differ between locations, the following may be used as a general guide.[64]
Suspected case:
History:
Fever, myalgia, malaise, diarrhoea
Tick-exposure history or contact with a human or an animal with CCHF infection
Residency or travel to a CCHF-endemic region
Physical examination:
Macular or petechial rash or bleeding.
Probable case:
Suspected case findings, plus
Thrombocytopenia, leukopenia, elevated liver function tests (LFTs) and lactate dehydrogenase levels.
Confirmed case:
Elevation of CCHF IgM antibodies or positive polymerase chain reaction (PCR) on blood or body fluids of the patient.
The Centers for Disease Control and Prevention also produce a general case definition for viral haemorrhagic fevers.[65]
Initial investigations
Molecular testing:
Should be ordered in all patients with suspected CCHF infection while the patient is in isolation. Reverse transcriptase-polymerase chain reaction (RT-PCR) is a very sensitive rapid test, although careful attention must be paid to the potential for false-positive results. The development of one-step real-time RT-PCR assays has been hampered by the high diversity of genome sequence.[40][66][67][68][69]
Malaria investigations:
Indicated in malaria-endemic areas or when indicated from travel history. Giemsa-stained thick and thin blood smears and rapid diagnostic tests are the tests of choice for malaria screening.
Other investigations
Serology:
Seroconversion with detection of CCHF virus IgM antibodies or a ≥fourfold increase in antibody titre between two successive blood samples is evidence of a recent infection.[16][17][69] The serological diagnosis is valid several days after the onset of the disease; nevertheless, the antibody response is rarely observed in fatal cases.[70]
ELISA is commonly used and has a sensitivity greater than 90%. It has been reported to be more sensitive than immunofluorescence assay (IFA).[71] All native antigens have to be produced in a biosafety level (BSL)-4 laboratory and irradiated prior to use.
IgM and IgG antibodies are usually detected 4-5 days after the onset of symptoms. The maximum IgM titre is at 2-3 weeks after onset of the disease, and generally normalises within 4 months. IgG antibodies remain detectable for several years.[72]
Full blood count (FBC):
A decrease in platelet count and marked lymphopenia can be seen in the initial stages of infection; however, this is not diagnostic. This is often followed by neutrophil leukocytosis, along with normalisation of thrombocytopenia. Anaemia is not usually seen at the early phase of the disease, but may develop late in the disease course. Leukocytosis may persist and show immature forms. Patients with severe disease may show a progressive decline in platelet count as a manifestation of disseminated intravascular coagulation.
Coagulation studies:
Abnormalities may include prolonged bleeding time, prothrombin time, and activated partial thromboplastin time; elevated fibrin degradation products; and decreased fibrinogen.
LFTs:
Both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are usually elevated; however, most studies show that AST rises out of proportion to ALT, and this is suggestive of systemic tissue damage rather than hepatocellular injury.
Abnormal liver function may lead to a poor prognosis.[73]
Renal function:
May be elevated and may indicate acute kidney injury. Especially useful in patients with diarrhoea and vomiting. Urinalysis may show haematuria or proteinuria
Serum electrolytes:
May be abnormal and may indicate acute kidney injury. Especially useful in patients with diarrhoea and vomiting. Useful to guide correction of electrolytes and fluid replacement.
Lactate dehydrogenase:
A level >4 mmol/L (36 mg/dL) may indicate persistent hypo-perfusion and sepsis.[40]
Creatine phosphokinase:
Levels more than twice the upper limit of normal may indicate systematic muscular stress.
Viral isolation:
Viral culture is the definitive test; however, the 2-10 days required for the virus to grow means the test takes too long to be clinically useful.[72]
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