Four infections—EBV, primary HIV, CMV and toxoplasmosis—produce almost identical clinical presentations and tend to be diagnosed as glandular fever or pseudoglandular fever. It is important for the first contact practitioner to consider all four possibilities, especially keeping in mind the possibility of HIV infection.
A worthwhile approach is to make a provisional diagnosis based on the clinical variations as presented in TABLE 28.1.
Table 28.1Clinical features differentiating HIV, EBV, CMV and toxoplasmosis infections (all can present with a similar illness) |Favorite Table|Download (.pdf) Table 28.1 Clinical features differentiating HIV, EBV, CMV and toxoplasmosis infections (all can present with a similar illness)
|Feature ||EBV infection ||HIV infection ||CMV infection ||Toxoplasmosis |
|Onset ||Insidious ||Acute ||Insidious ||Insidious or acute |
|Fever || |
|A feature ||Quotidian (afternoon spikes) ||Low grade |
|Fatigue/malaise ||Common ||Common, severe ||Common ||Common |
|Tonsillar hypertrophy ||Common ||Mild enlargement ||Uncommon ||Uncommon |
|Exudative pharyngitis ||Common ||Rare ||Rare ||Occurs |
|Mucocutaneous ulcers ||Rare ||Common ||Unknown ||Unknown |
|Skin rash ||About 5% ||Common ||About 5% ||About 10% |
|Jaundice ||About 8% ||Rare ||Uncommon ||Uncommon |
|Diarrhoea ||Unknown ||Occurs ||Unknown ||Unknown |
|Cervical lymphadenopathy ||Common ||Common ||Uncommon ||Common (a feature) |
|Hepatomegaly ||About 8% ||Rare ||Common ||Occasional |
|Splenomegaly ||About 50% ||Rare ||About 50% ||Up to 30% |
|Atypical lymphocytes ||In 80–90% ||In <50% ||Common ||Uncommon |
FBE, especially WCC
serological test for CMV (specific antibodies)
serological test for toxoplasmosis (specific antibodies—acute and convalescent)
HIV antibody test (ELISA)
NAAT (PCR) testing
EBM is a febrile illness caused by the human herpes virus 4 (Epstein–Barr) virus, one of the eight known herpes viruses. It can mimic diseases such as HIV primary infection, streptococcal tonsillitis, viral hepatitis and acute lymphatic leukaemia. There are three forms: the febrile, the anginose (with sore throat, see FIG. 28.1) and the glandular (with lymphadenopathy).
Tonsillitis of Epstein–Barr mononucleosis. This is often confused with bacterial tonsillitis.
It may occur at any age but usually between 10 and 35 years; it is commonest in the 15–25 years age group. In most young children primary EBV infection is asymptomatic.
Occurrence and transmission
EBM has an annual incidence of 4–5 new cases in a population of 2500.1 It usually affects people in their late teenage years or early 20s. It is endemic in most countries, affecting over 95% of the adult population worldwide. Subclinical infection is common in young children. The incubation period is at least 1 month but data are insufficient to define it accurately.
EBV is excreted in oropharyngeal secretions during the illness and for some months (sometimes years) after the clinical infection. EBM has a low infectivity and isolation is not necessary. It is apparently transmitted only by close contact, such as kissing and sharing drinking vessels.
Progress of the primary infection is checked partly by specific antibodies (which might prevent cellto- cell spread of the virus) and partly by a cellular immune response, involving cytotoxic T-cells, which eliminates the infected cells. This response accounts for the clinical picture. The virus is never eliminated from the body. The nature of EBV is not yet fully understood.
Second attacks and fatalities do occur and there is a possible association between EBM and lymphoma.3
The typical clinical features are presented in TABLE 28.2 and FIGURE 28.2.
Table 28.2Clinical features of EBM1,2,4 |Favorite Table|Download (.pdf) Table 28.2 Clinical features of EBM1,2,4
|Slow onset malaise 1–6 weeks |
|Headaches, anorexia |
|Blocked nose—mouth breathing |
|Nasal quality to voice |
|Sore throat (85%) |
|Anorexia, nausea ± vomiting |
|Rash—primary 5% |
|Clinical findings |
|Exudative pharyngitis (84%) |
|Petechiae of palate (not pathognomonic) (11%) |
|Lymphadenopathy, especially posterior cervical |
|Splenomegaly (50%) |
|Jaundice ± hepatomegaly (5–10%) |
|Clinical or biochemical evidence of hepatitis |
Clinical features of Epstein–Barr mononucleosis
DxT sore throat + fever + lymphadenopathy ➜ EBM
The rash of EBM is almost always related to antibiotics given for tonsillitis. The primary rash, most often non-specific, pinkish and maculopapular (similar to that of rubella), occurs in about 5% of cases only.
The secondary rash is most often precipitated by one of the penicillins, especially ampicillin or amoxycillin. About 90–100% of patients prescribed ampicillin or amoxycillin will be affected; up to 50% of those given penicillin will develop the rash. It can be extensive and sometimes has a purplish tinge (see FIG. 28.3).
Typical purplish maculopapular rash of EBM precipitated by ampicillin prescribed for the acute tonsillitis of EBM
The complications of EBM are presented in TABLE 28.3 and the differential diagnoses in TABLE 28.4.
Table 28.3Complications of EBM1 |Favorite Table|Download (.pdf) Table 28.3 Complications of EBM1
|Antibiotic-induced skin rash |
|Prolonged debility |
|Respiratory tract: |
Table 28.4Differential diagnoses of EBM1 |Favorite Table|Download (.pdf) Table 28.4 Differential diagnoses of EBM1
|Other agents that cause typical EBM syndrome |
|Exudative tonsillitis resembling EBM |
|Hepatitis A, B, C, D, E |
|Lymphadenopathy, fever and splenomegaly |
|Complications of EBM without other manifestations |
The following laboratory tests confirm the diagnosis of EBM:
WCC shows absolute lymphocytosis.
Blood film shows atypical lymphocytes.
Paul–Bunnell or Monospot test for heterophil antibody is positive (although positivity can be delayed or absent in 10% of cases).
Diagnosis confirmed (if necessary) by EBV-specific antibodies, viral capsid antigen (VCA) antibodies—IgM, IgG and EB nuclear antigen (EBN-A).
Culture for EBV and tests for specific viral antibodies are not performed routinely.
False positives for the Paul–Bunnell test are:
EBM usually runs an uncomplicated course over 6–8 weeks. Major symptoms subside within 2–3 weeks. Patients should be advised to take about 4 weeks off work.
Supportive measures (no specific treatment)
Rest (the best treatment) during the acute stage, preferably at home and indoors
NSAIDs or paracetamol to relieve discomfort
Gargle soluble aspirin or 30% glucose to soothe the throat
Advise against alcohol, fatty foods, continued activity, especially contact sports (risk of splenic rupture)
Ensure adequate hydration
Corticosteroids reserved for: neurological involvement, thrombocytopenia, threatened airway obstruction (not recommended for uncomplicated cases)
Some young adults remain debilitated and depressed for some months. Lassitude and malaise may extend up to a year or so.
CMV has a worldwide distribution and causes infections that are generally asymptomatic. The virus (human herpes virus 5) may be cultured from various sites of healthy individuals. It has its most severe effects in the immunocompromised, especially those with AIDS, and also in recipients of solid organ transplants and bone marrow grafts; 90% of AIDS patients are infected with CMV and 95% have disseminated CMV at autopsy. CMV infection can be an important development following massive blood transfusion, including those given to infants or from organ transplantation. The incubation period of CMV ranges from 20 to 60 days and the illness generally lasts about 2 to 6 weeks.2
Three important clinical manifestations are described.
Intrauterine infection may cause serious abnormalities in the fetus, including CNS involvement (microcephaly, hearing defects, motor disturbances), jaundice, hepatosplenomegaly, haemolytic anaemia and thrombocytopenia. Up to 30% of CMV-affected infants have mental retardation3 (see CHAPTER 109).
Acquired CMV infection
In healthy adults, CMV produces an illness similar to EBM with fever, malaise, arthralgia and myalgia, generalised lymphadenopathy and hepatomegaly. However, cervical lymphadenopathy and exudative pharyngitis are rare.
The infection may be spread by blood transfusion, and CMV should be suspected on clinical grounds in a patient with a febrile illness resembling EBM following major surgery, such as open heart surgery or kidney transplantation, and where extensive transfusion has been necessary.
The fever often manifests as quotidian intermittent fever spiking to a maximum in the mid-afternoon and falling to normal each day (see FIG. 28.4). There is often a relative lymphocytosis with atypical lymphocytes but the heterophil antibody test is negative. Liver function tests are often abnormal.
Diagnosis: Specific diagnosis can be made by demonstrating rising antibody titres from acute and convalescent (2 weeks) sera. A four-fold increase indicates recent infection. PCR testing can be used. The virus can be isolated from the urine and blood.
CMV disease in the immunocompromised host
Disseminated CMV infection occurs in the immune-deficient person, notably HIV infection causing opportunistic severe pneumonia, retinitis (a feature of AIDS), encephalitis and diffuse involvement of the gastrointestinal tract.
Cytomegalovirus infection: typical quotidian intermittent fever pattern
In the patient with normal immunity no treatment apart from supportive measures is required, as the infection is usually self-limiting. In immunosuppressed patients various antiviral drugs, such as ganciclovir, foscarnet and fomivirsen (intraocular) have been used with some benefit.5
Toxoplasmosis, which is caused by Toxoplasma gondii, an obligate intracellular protozoan, is a worldwide, albeit rare, infection. The definitive host in its life cycle is the cat (or pig or sheep) and the human is an intermediate host. However, clinical toxoplasmosis is very uncommon. Infection in humans usually occurs through eating foodstuffs contaminated by infected cat faeces. Its main clinical importance is an opportunistic infection.
The five major clinical forms of toxoplasmosis are:5
asymptomatic lymphadenopathy (the commonest)
lymphadenopathy with a febrile illness, similar to EBM
acute primary infection: a febrile illness similar to acute leukaemia or EBM; a rash, myocarditis, pneumonitis, chorioretinitis and hepatosplenomegaly can occur
neurological abnormalities—includes headache and neck stiffness, sore throat and myalgia
congenital toxoplasmosis—this is a rare problem but if it occurs it typically causes CNS involvement and has a poor prognosis
In the immunocompromised, clinical forms 3 and 4 are typical features with meningoencephalitis being a serious development.
Diagnosis is by serological tests (to show a four-fold rise in antibodies), which are sensitive and reliable.
Patients with a mild illness or with asymptomatic infection require no treatment. Children under 5 years may be treated to avoid the possible occurrence of chorioretinitis. Symptomatic patients are treated with pyrimethamine plus sulphadiazine. Clindamycin is usually used in pregnant patients.