Chapter 28: Baffling viral and protozoal infections

Almost any infection, especially if subacute or insidious in its onset, can be baffling and can belong to the ‘fever of undetermined origin’ group of infections. Syphilis and tuberculosis were the great mimics of the past. Now malaria and Epstein–Barr mononucleosis (EBM) can be regarded as important mimics. EBM (Epstein–Barr mononucleosis, infectious mononucleosis, glandular fever) can be a perennial baffler and can be confused with HIV infection in its primary clinical phase. Any of the febrile diseases can be confusing before declaring themselves with classic symptoms such as the jaundice of hepatitis or the rash of dengue fever, or before serological tests become positive.

Viral and protozoal infections that can present as masquerades include:

• HIV infection (especially primary)

• EBV

• TORCH organisms: toxoplasmosis, rubella, CMV, HSV

• hepatitis A, B, C, D, E

• mosquito-borne infections: malaria, dengue fever, yellow fever/other haemorrhagic fevers, Japanese encephalitis, Ross River fever, West Nile fever

The TORCH organisms (TORCH being an acronym for toxoplasmosis, rubella, CMV and herpes) are well known for their adverse intra-uterine effects on the fetus. Three are viral (toxoplasmosis is a protozoan) and the first three of these fetal pathogens are acquired by passage across the placenta. Most of these organisms are noted for being opportunistic infections in immunocompromised patients, especially in later stage HIV infection.

The mosquito-borne infections causing encephalitis and haemorrhagic fevers are mainly viral, apart from the protozoan causing malaria, and are of particular significance in travellers returning from endemic areas (refer to CHAPTER 15).

The major protozoal diseases of humans are:

• blood: malaria, trypanosomiasis

• GIT: giardiasis, amoebiasis, cryptosporidium

• tissues: toxoplasmosis, leishmaniasis, babesiosis

Most of the world’s serious protozoal infections—malaria, African trypanosomiasis, leishmaniasis, amoebiasis—occur in tropical areas and are listed and explained in CHAPTER 15.

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.

Screening tests are:

• FBE, especially WCC

• EBV-specific antibodies

• serological test for CMV (specific antibodies)

• serological test for toxoplasmosis (specific antibodies—acute and convalescent)

• HIV antibody test (ELISA)

• NAAT (PCR) testing

Epstein–Barr mononucleosis

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).

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

Clinical features

The typical clinical features are presented in TABLE 28.2 and FIGURE 28.2.

The rash

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).

The complications of EBM are presented in TABLE 28.3 and the differential diagnoses in TABLE 28.4.

Diagnosis

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:

• hepatitis

• Hodgkin lymphoma

• acute leukaemia

Prognosis

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.

Treatment

• 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)

Post-EBM malaise

Some young adults remain debilitated and depressed for some months. Lassitude and malaise may extend up to a year or so.

Cytomegalovirus infection

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

Clinical features

Three important clinical manifestations are described.

1. Perinatal disease

   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).

2. 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.

3. 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.

Treatment

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

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

1. asymptomatic lymphadenopathy (the commonest)

2. lymphadenopathy with a febrile illness, similar to EBM

3. acute primary infection: a febrile illness similar to acute leukaemia or EBM; a rash, myocarditis, pneumonitis, chorioretinitis and hepatosplenomegaly can occur

4. neurological abnormalities—includes headache and neck stiffness, sore throat and myalgia

5. 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

Diagnosis is by serological tests (to show a four-fold rise in antibodies), which are sensitive and reliable.

Treatment

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.

Life-threatening viral respiratory infections include the virulent influenza viruses such as avian (bird) influenza and swine influenza and severe acute respiratory distress syndrome (SARS). These conditions are presented in CHAPTER 49.

Mosquito-borne infections have devastating consequences in tropical regions (see CHAPTER 15), while others cause less morbidity and include Ross River fever.

Epidemic polyarthritis of Ross River virus (RRV), which is an alpha virus, occurs in all states of Australia. It is most prevalent in mosquito-prone areas (especially during the summer) and in tropical and temperate coastal regions and inland riverine areas.⁷ Subclinical infection is common with variable clinical manifestations.

Clinical features

• All age groups, especially 20–30 years

• Incubation period 3–21 days (usually 7–11)

Symptoms (major)

• Polyarthritis (75% of patients)—mainly fingers, wrists, feet, ankles and knees

• Maculopapular rash—widespread, often ‘subtle’, mainly trunk and limbs

• Myalgia

Other symptoms

• Pyrexia (mild)

• Headache

• Nausea

• Fatigue with excercise

Signs (which may be present) include joint swelling (mainly hands and feet), tenosynovitis around the wrists and ankles (poor prognostic sign), the rash and mild lymphadenopathy.

Outcome

In many patients the illness resolves within 2 to 6 weeks and most feel normal within 3 months, but some with a more severe arthritis can enter a chronic phase lasting 18 months or more. Depression is a common sequela.

Diagnosis

Diagnosis is by antibody testing of serum. The differential diagnosis includes other viral infections that cause arthritis, such as hepatitis B, rubella, Barmah Forest virus (a mosquito-borne virus) and dengue, and early rheumatiod arthritis and rheumatic fever.

Barmah Forest virus, which is common in Australia, has a similar clinical presentation but is less severe.⁸

Treatment

Treatment is symptomatic with bed rest and simple analgesics such as aspirin. NSAIDs are used for more severe cases. Oral corticosteroids are effective but should be avoided if possible. An inactivated RRV vaccine is being developed.⁹

The WHO, in its 1996 and 2011 reports,¹⁰ estimated that the leading cause of approximately 50 million deaths in the world was infectious diseases, which accounted for about one-third or 17 million deaths. Other figures included diseases of the circulatory system (15 million deaths, including ischaemic heart disease—7.7 million—and stroke—6.2 million) and cancer (6 million deaths, approximately 12%).

The reports indicated that nearly 50 000 people are dying every day from infectious diseases such as cholera, hepatitis B, malaria, tuberculosis and HIV (see TABLE 28.5). Tuberculosis tends to occur in people with HIV. At least 30 new infections have emerged in the past 20 years, and for many of them there is no treatment, cure or vaccine. These include some infections causing infant diarrhoea, Legionella pneumophila, Lyme borreliosis (Lyme disease), the Hantaan virus (which can cause a fatal haemorrhagic fever), HIV and hepatitis E and C.

The reports also said that until recently the struggle for control over infectious diseases had seemed almost over, with smallpox eradicated and six other diseases, including polio, leprosy and guinea-worm disease, singled out for eradication within a few years. A pleasing improvement occurred in measles and neonatal tetanus. However, half the world’s 6 billion people were at risk of many infectious diseases, since many that seemed under control such as tuberculosis and malaria were becoming more prevalent. Some, such as yellow fever and cholera, were striking in new regions. Other infections were resistant to drugs and virtually untreatable. The previously almost forgotten infections such as Yersinia (the plague) had re-emerged.

The deadly haemorrhagic fevers that have broken out in isolated epidemics include the zoonotic African diseases—Ebola haemorrhagic fever, Marburg haemorrhagic fever and Lassa fever. These are caused by filoviruses and for most no specific treatment is available.

Other deadly viruses include rabies (a rhabdo virus; see CHAPTER 15); the paramyxoviruses—Hanta (RNA) virus, which causes haemorrhagic and pulmonary complications; the henipavirus family, which are naturally harboured in fruit bats and include Hendra virus, Nipah virus and Cedar virus.

Another serious infection that emerged sporadically was the so-called ‘flesh eating’ Streptococcus A infection, which was a particularly virulent strain causing localised destruction of soft tissue.

West Nile encephalitis caused by a mosquito-transmitted virus and carried by birds has surfaced in the US and beyond, causing thousands of cases and hundreds of deaths.

The lessons to be learned include careful surveillance, attention to prevention, especially with effective immunisation programs, rational antibiotic prescribing and care with travelling to developing tropical countries.

Hand-out sheets from Murtagh’s Patient Education 7th edition:

• Glandular fever

• Hepatitis B

• Hepatitis C

• Influenza

• Malaria

• Pertussis