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Latest thinking on glandular fever

Despite its usually self-limiting nature, glandular fever can

have severe consequences ­

Dr Benny Cherian explains

Glandular fever, 'the kissing disease', although usually self-limiting, can occasionally have fatal consequences. Officially known as infectious mononucleosis (IM), it is a clinical entity described as fever, lymphadenopathy and prostration in previously healthy young adults. Epstein-Barr virus (EBV) accounts for 80-90 per cent of cases. Fever, pharyngitis and lymphadenopathy represent the classic clinical triad of IM.

Prodromal symptoms include malaise, anorexia, fatigue, headache and fever, all of which persist through the acute phase of the illness. Symptoms of IM usually peak seven days after their onset and dissipate over the next one to three weeks. Splenic enlargement can occur in 50-60 per cent of cases and usually resolves by the fourth week of illness.

Less common clinical features of IM include upper airway compromise, abdominal pain, rash, hepatomegaly and jaundice2. Rash occurs in about 5 per cent of patients. A pruritic maculopapular rash develops in 90 to 100 per cent of patients with IM who receive ampicillin, usually seven to 10 days after administration of the first dose2. The frequency of jaundice varies with age.

Primary EBV infection is usually asymptomatic in children but 30-50 per cent of adults acquiring a primary infection will have IM. The chance of acute EBV infection developing into IM appears to increase with age. It is estimated to occur in less than 10 per cent of children but in 20 per cent to 70 per cent of adolescents and young adults1.

Laboratory tests

Leucocytosis is commonly present with an increase in peripheral mononuclear cells.

The atypical lymphocytes in the IM are atypical T cells reactive to the EBV infected B cells. There can be polyclonal B cell activation and resultant production of polyclonal antibodies. This can in turn give rise to positive tests for heterophile antibodies, rheumatoid factor, cold agglutinins and so on.

Mild thrombocytopenia is found in 50 per cent and mild haemolytic anaemia in up to 3 per cent of cases. Mild transaminase elevations occur1. Up to 16 per cent of patients may have abnormalities on urinalysis, including proteinuria, pyuria and microscopic haematuria.

Most useful for IM is the serologic test for heterophile antibodies. These IgM antibodies bind to red blood cells from non-human species. The commonly used Monospot test can be positive in up to 90 per cent of cases. Heterophile antibodies usually appear within a week after IM begins and are generally shortlived. They peak during weeks two to five but can persist at low levels for up to a year.

One study3 found fewer than half of children aged under four to have detectable heterophile antibodies at any time. Tests for viral capsid antigen (VCA) IgM can be useful in heterophile antibody negative cases. VCA IgM becomes rapidly positive within one to two weeks of infection and can remain positive up to six months3. It is advisable to do VCA IgM in children with IM under the age of 144. The presence of VCA IgM usually indicates acute EBV infection. Tests like VCA IgG and EBV nuclear antigen IgG can be useful but are available in fewer centres.

False-positive heterophile tests, though rare, can occur in patients with lymphoma, hepatitis and autoimmune diseases.

Differential diagnoses of IM should include group A ?-haemolytic streptococcal pharyngitis and viral upper respiratory tract infections, which can mimic IM.

Other infectious agents besides EBV and even neoplasms can cause IM-like syndrome1. Atypical lymphocytosis can be seen with cytomegalovirus, acute HIV, toxoplasmosis, rubella, roseola and hepatitis A infections.

Only 3-10 per cent of people over the age of 40 are susceptible to EBV. The presenting symptoms and signs are often different from those in younger patients. Fever is present in more than 90 per cent of patients but pharyngitis and lymphadenopathy are seen in under half. Jaundice occurs in more than 20 per cent.

Older patients with IM often undergo evaluation for hepatobiliary disease, neoplasms, collagen vascular diseases or bacterial infections.

The diagnosis of IM should be considered in patients with an unexplained fever for over a week or cholestatic jaundice without a defined cause and initial lymphoma and lymphocytic leukaemia.

Serological tests will not ascertain infectiousness but show whether the patient was infected and how recently (see above).

Managing uncomplicated IM

In the vast majority of patients, IM is self-limited. Most symptoms resolve spontaneously within three weeks without specific treatment. The treatment of uncomplicated IM is supportive.

 · NSAIDs for pain and fever (avoid aspirin).

 · Bedrest during the febrile phase.

 · Avoid vigorous activity for three to four weeks to allow splenomegaly to resolve and avoid the risk of splenic rupture.

Corticosteroids are generally given to patients with impending airway obstruction, profound thrombocytopenia or haemolytic anaemia.

Aciclovir does not seem to affect either the severity or duration of IM but it does reduce shedding of the virus5. It appears to have little role in the management of IM.

Complications of IM include upper airway obstruction, splenic rupture, fatigue and other relatively rare manifestations. Upper airway obstruction and splenic rupture can be life-threatening complications.

Splenic rupture is estimated to occur in 0.1 to 0.2 per cent of cases. This invariably occurs in the presence of splenomegaly, which is found in half of IM cases. Warning signs like abdominal pain, rare in IM, should be sought and the patient referred urgently.

The risk of splenic rupture is higher in those returning to contact sports. Patients may present with left or right hypochondrial pain and about half will also have pain referred to the left shoulder (Kehr's sign). Tachycardia and hypotension may also be present.

Neurological complications develop in

1 to 2 per cent of patients. Cranial nerve palsies, Guillain-Barre syndrome, encephalitis and peripheral neuropathies can occur.

Death has resulted from myocarditis or cardiac conduction abnormalities associated with IM. Keratitis, uveitis, retinopathy, choroiditis, periorbital cellulitis, haemolytic uremic syndrome, rhabdomyolysis-associated renal failure, nephrotic syndrome, fulminant hepatic failure, fibrosing alveolitis, aplastic anaemia, immune complex disease and acute monarthritis have been reported in the setting of acute IM.

Termination is not indicated for IM in pregnancy due to the rarity of harmful effect on the baby and no confirmed link.

IM in the immunosuppressed can result in atypical presentations, graft rejection or failure in post-transplant patients and lymphoproliferative disorders. X-linked lymphoproliferative disorder is a genetic disorder due to defective lymphocyte signalling pathway and patients can die of fulminant EBV infection or those who survive develop hypogammaglobulinaemia and lymphomas in later life.

EBV infection and glandular fever have been linked with chronic fatigue syndrome. There is little evidence to support this belief.

EBV is not as infectious as many other infectious diseases. People are unlikely to catch it by being in the same room.

Restricting intimate contact during acute mononucleosis can reduce the transmission of EBV but will hamper contact with seropositive persons.

Transmission of EBV during asymptomatic viral shedding can occur long after the acute illness.

Avoiding intimate contact is reasonable in the few instances when the complications of infection could be devastating.

Test for cure or infectiousness is not a practical option for the reason that prolonged viral shedding from the nasopharynx can occur in the asymptomatic phase and convalescence.

Epstein-Barr virus

Epstein-Barr virus is a DNA virus belonging to the herpes virus family. EBV infection is ubiquitous in nature and distributed worldwide. In the developing countries almost all the infections occur in early childhood. Infection in the developed world occurs in adolescence in 15-20 per cent of cases, of which 50 per cent of infections can be symptomatic.

The incidence of IM is 30 times higher in white people than in black people in the US1. There is no difference in prevalence between men and women. Transmission is mainly via oral secretions and it was called a 'kissing disease'. The virus can only be transmitted by intimate contact.

The virus can remain in the respiratory secretions of asymptomatic and recovering patients. Nobody in the UK is currently culturing respiratory secretions as the process is cumbersome and of limited value.

Key points

 · The vast majority of cases are self-limiting and resolve within three weeks

 · Epstein-Barr virus accounts for most, but not all cases of infectious mononucleosis

 · Counsel active patients about the risk of splenic injury

 · The most useful test to diagnose IM is the serological test for heterophile antibodies

References

1 Schooley RT. Epstein-Barr virus (infectious mononucleosis).

In: Mandell GL et al. Eds. Mandell, Douglas and Bennett's principles and practice of infectious diseases. 4th edition. New York: Churchill Livingstone, 1995:1364-77

2 Auwaerter PG. Infectious mononucleosis in middle age.

JAMA 1999;281:454-9

3 Sumaya CV, Ench Y. Epstein-Barr virus infectious mononucleosis in children: part II. Heterophile antibody and viral-specific responses. Pediatrics 1985;75:1011-19

4 Crawford DH. Epstein-Barr Virus. In: Zuckerman AJ et al. Eds. Principles and Practice of Clinical Virology. 3rd edition.

John Wiley & Sons, England, 1995:109-34

5 Andersson J, Ernberg I. Management of Epstein-Barr virus infections. Am J Med. 1988;85:107-15

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