Clinical Topic A-Z Clinical Speciality

Glandular fever

Glandular fever
D007244Infectious Mononucleosis
Ear, nose and throatInfections and infestations
2010-02-22Last revised in February 2010

Glandular fever - Summary

Glandular fever is an infectious disease caused by the Epstein–Barr virus (EBV) which is a member of the human herpes virus (HPV) family.

The incubation period of glandular fever is thought to be about 33–49 days.

Glandular fever is not particularly infectious and is spread through contact with saliva, usually from asymptomatic carriers.

In most people, the disease is self-limiting and lasts 2–3 weeks. However, as with all HPV infections, the virus remains in the body for life.

Complications are rare and include upper airways obstruction, fatigue lasting longer than 6 months, mood disorders, splenic rupture, and haematological complications.

In immunosuppressed people, EBV infection may result in malignant disease, such as Hodgkin's lymphoma and nasopharyngeal carcinoma.

Suspect glandular fever if there is profound fatigue plus fever, lymphadenopathy, and sore throat; or a sore throat that fails to improve, or becomes worse, after several days.

In people older than 40 years of age, glandular fever is rare and may present atypically. In children, EBV infection is usually asymptomatic.

Tests which help to confirm the diagnosis of glandular fever include:

In healthy adults and children older than 12 years of age — a full blood count with differential white cell count and a Monospot test (heterophile antibodies) in the second week of the illness.

In children younger than 12 years of age and in people who are immunocompromised at any age — blood tests for EBV serology after the person has been ill for at least 7 days.

Liver function tests usually show an elevation in aspartate aminotransferase and alanine aminotransferase to a level two to three times the upper limit of normal.

The differential diagnosis of glandular fever includes:

Other causes of sore throat, especially streptococcal sore throat.

Other causes of lymphadenopathy, e.g. leukaemia and lymphoma.

Other viral infections that may present with a glandular-fever like illness with an atypical lymphocytosis, e.g. rubella, acute toxoplasmosis, and mumps.

To manage glandular fever:

Paracetamol or ibuprofen help to relieve pain and fever.

Reassurance that symptoms usually last for 2–3 weeks and tiredness is common should be given. Exclusion from work or school is not necessary.

The person should be encouraged to do as much as they are able to do. However, they should avoid contact or collision sports or heavy lifting for the first month of the illness (to prevent splenic rupture).

Advice on limiting the spread of the disease should be given (e.g. avoid kissing and sharing eating utensils).

The person should be advised to seek urgent medical advice if they develop unusual symptoms such as stridor or respiratory difficulty.

Amoxicillin or ampicillin, corticosteroids (unless severe complications are present), or acyclovir (there is no clinical benefit on the symptoms of acute glandular fever) are not recommended.

Immediate admission to hospital is necessary for anyone with upper airways obstruction, dehydration or reluctance to take any fluids, or suspected splenic rupture.

Urgent specialist advice should be sought if it is suspected that potentially serious complications have developed.

Have I got the right topic?

1months3060monthsBoth

This CKS topic covers the diagnosis and management of glandular fever (infectious mononucleosis) in primary care.

There are separate CKS topics on Sore throat - acute and Tiredness/fatigue in adults.

The target audience for this CKS topic is healthcare professionals working within the NHS in the UK, and providing first contact or primary health care.

How up-to-date is this topic?

How up-to-date is this topic?

Changes

Last revised in February 2010

February 2013 — minor update. The 2013 QIPP options for local implementation have been added to this topic [NICE, 2013].

October 2012 — minor update. The 2012 QIPP options for local implementation have been added to this topic [NPC, 2012].

July 2011 — minor update. More exact paracetamol dosing for children has been introduced by the Medicines and Healthcare products Regulatory Agency [MHRA, 2011]. Prescriptions have been updated to reflect the revised dosing. Issued in July 2011.

May 2011 — minor update. The 2010/2011 QIPP options for local implementation have been added to this topic [NPC, 2011]. Issued in June 2011.

October 2009 to February 2010 — this is a new CKS topic. The evidence-base has been reviewed in detail, and recommendations are clearly justified and transparently linked to the supporting evidence.

Update

New evidence

Evidence-based guidelines

No new evidence-based guidelines since 1 August 2009.

HTAs (Health Technology Assessments)

No new HTAs since 1 August 2009.

Economic appraisals

No new economic appraisals relevant to England since 1 August 2009.

Systematic reviews and meta-analyses

No new systematic review or meta-analysis since 1 August 2009.

Primary evidence

No new randomized controlled trials published in the major journals since 1 August 2009.

New policies

No new national policies or guidelines since 1 August 2009.

New safety alerts

No new safety alerts since 1 August 2009.

Changes in product availability

No changes in product availability since 1 August 2009.

Goals and outcome measures

Goals

To make an accurate diagnosis

To provide appropriate advice

QIPP — Options for local implementation

QIPP — Options for local implementation

Non-steroidal anti-inflammatory drugs (NSAIDs)

Review the appropriateness of NSAID prescribing widely and on a routine basis, especially in people who are at higher risk of both gastrointestinal (GI) and cardiovascular (CV) morbidity and mortality (e.g. older patients).

If initiating an NSAID is obligatory, use ibuprofen (1200 mg per day or less) or naproxen (1000 mg per day or less).

Review patients currently prescribed NSAIDs. If continued use is necessary, consider changing to ibuprofen (1200 mg per day or less) or naproxen (1000 mg per day or less).

Review and, where appropriate, revise prescribing of etoricoxib to ensure it is in line with MHRA advice and the NICE clinical guideline on osteoarthritis [CSM, 2005; NICE, 2008].

Co-prescribe a proton pump inhibitor (PPI) with NSAIDs for people with osteoarthritis, rheumatoid arthritis, or low back pain (for people over 45 years) in accordance with NICE guidance [NICE, 2008; NICE, 2009a; NICE, 2009b].

Take account of drug interactions when co-prescribing NSAIDs with other medicines (see Summaries of Product Characteristics). For example, co-prescribing NSAIDs with ACE inhibitors or angiotensin receptor blockers (ARBs) may pose particular risks to renal function; this combination should be especially carefully considered and regularly monitored if continued.

[NICE, 2013]

Background information

Definition

What is it?

Glandular fever (also known as infectious mononucleosis) is an infectious, usually self-limiting, disease caused by the Epstein–Barr virus (EBV) which is a member of the human herpes virus family [Johannsen and Kaye, 2009].

The incubation period of glandular fever is thought to be about 33–49 days [Richardson et al, 2001]. However, this is speculative and has not been confirmed [Johannsen and Kaye, 2009].

Glandular fever is not particularly infectious and is spread through contact with saliva, such as through kissing or sharing food and drinks, usually from asymptomatic carriers [Charles, 2003; CDC, 2006]. Small children may be infected by chewing toys that have been contaminated with the virus [HPA, 2009].

Natural history

What is the natural history of glandular fever?

In most people, the disease is self-limiting and lasts 2–3 weeks [Johannsen and Kaye, 2009]:

The sore throat is usually severe for 3–5 days and then resolves over the next 7–10 days.

The fever usually lasts for 10–14 days but is usually low grade for the last 5–7 days.

Acute fatigue is common and lasts for a few weeks [White et al, 1998].

Some people (9–22%) have persistent fatigue that lasts several months [White et al, 1998]. Most people with persistent fatigue recover within 2 years.

As with all human herpes virus infections, Epstein-Barr virus (EBV) infection leads to a lifelong latent carrier state (the virus remains in the body for life).

Periodic reactivation results in the intermittent asymptomatic shedding of EBV particles into the saliva throughout the lifetime of carriers [CDC, 2006].

In immunosuppressed people, infection with Epstein–Barr virus may result in malignant disease, such as lymphoproliferative disease, primary central nervous system lymphoma, Hodgkin's lymphoma, and nasopharyngeal carcinoma [Johannsen and Kaye, 2009].

Prevalence

How common is it?

CKS found no recent data on the incidence and prevalence of glandular fever in the UK.

A GP with a list size of 2,500 patients may expect to see four people with glandular fever per year [Fry, 1980].

Looking at the prevalence of the antibody to the Epstein–Barr virus:

A survey found that about 50% of people in the UK in 1969 had acquired the antibody by 4 years of age and 90% by 40 years of age [Pereira et al, 1969].

A cross-sectional study found that 75% (1496/2006) of students registered at Edinburgh University during 1999–2000 were seropositive [Higgins et al, 2007].

A prospective cohort study of 241 students who were seronegative found that 46% (110) became seropositive whilst at university [Crawford et al, 2006].

Data collected 40 years ago in the US found that [Henke et al, 1973]:

The peak age for symptomatic primary infection was 17–19 years, with 9–11 cases per thousand men per year, and 6–7 cases per thousand women per year.

In people younger than 10 years of age, the incidence of diagnosed primary infection is less that one case per thousand people per year. However, primary infection is usually not diagnosed in people in this age group, as it is often asymptomatic.

In people older than 35 years of age, the incidence of glandular fever-type illness is very low: one case per 50,000 men and one case per 20,000 women per year.

Complications

What are the complications?

Complications are rare and include:

Upper airways obstruction

Due to gross enlargement of the tonsils [Charles, 2003].

Peritonsillar abscess (rare) [Monem et al, 1999].

Fatigue lasting longer than 6 months — may develop in a minority of people.

A prospective study of 301 adolescents with glandular fever found that 13% met the criteria for chronic fatigue syndrome at 6 months and 4% met the criteria at 2 years [Katz et al, 2009].

Mood disorders

A prospective cohort study found that [White et al, 1998]:

A major depressive disorder (measured using the Hospital Anxiety and Depression scale [HADS]) occurred in 28% (30/108) of people with glandular fever due to the Epstein–Barr virus (EBV) at the onset of the illness compared with 11% (6/54) of people with an upper respiratory tract infection and 14% (12/83) people with non Epstein–Barr glandular fever, but the median length of the depression was only 3 weeks in all three groups and usually resolved without treatment.

Generalized anxiety occurred at the onset of the infection in 6% of people with glandular fever due to either EBV, an upper respiratory tract infection, or non-Epstein–Barr glandular fever. This fell to 4% of people in each of the three groups by 6 months.

The authors concluded that infection with EBV is probably not a cause of any prolonged psychiatric disorder.

Splenic rupture — is unusual (0.1–0.2% of people with glandular fever) and usually occurs in the second or third week of the illness [Aldrete, 1992; Foreman and Mackler, 2005].

About half of splenic ruptures are spontaneous, and half follow trauma (which may be mild) [Johannsen and Kaye, 2009].

Haematological complications [Johannsen and Kaye, 2009] include:

Autoimmune haemolytic anaemia occurs in 0.5–3% of people. The haemolysis becomes clinically apparent in the second or third week of the illness and resolves over 1–2 months.

Mild thrombocytopenia is common. Severe thrombocytopenia (platelet counts of less than 1000 cells/mm3) is rare but has been associated with death due to intracerebral bleeding.

Mild neutropenia is common and self limiting. Rarely, a severe neutropenia may cause death from neutropenic sepsis or pneumonia. This is unlikely to happen with a neutrophil count above 1 x 109 cells/L. Young children are more likely to develop neutropenia than older people.

Neurological complications occur in less than 1% of people and most people (85%) make a full recovery. Neurological complications are the most frequent cause of death in glandular fever, and include [Johannsen and Kaye, 2009]:

Encephalitis.

Aseptic meningitis.

Bell's palsy.

Transverse myelitis.

Guillain–Barré syndrome.

Optic neuritis, retrobulbar neuritis, mononeuritis multiplex, and cranial nerve palsies.

Brachial plexus neuropathy.

Hemiplegia.

Cardiac complications — these include [Ebell, 2004; Johannsen and Kaye, 2009]:

Pericarditis and myocarditis.

Cardiac conduction anomalies.

Renal complications — acute interstitial nephritis and very rarely acute renal failure [Ebell, 2004; Johannsen and Kaye, 2009].

Hepatic failure is rare. However, liver function tests are abnormal in about 90% of people with glandular fever. The increase in hepatic enzymes peaks in the second week of the illness and then declines over the next 3–4 weeks [Johannsen and Kaye, 2009].

In people with HIV, EBV infection has also been associated with [Cohen, 2000]:

Oral hairy leukoplakia.

Diffuse interstitial pneumonitis.

Non-Hodgkin's lymphoma including central nervous system lymphomas.

People who are immunosuppressed after transplantation may developed a post-transplantation lymphoproliferative disease [Johannsen and Kaye, 2009].

Very rarely, glandular fever develops into a life-threatening progressive illness [Cohen, 2000]:

Chronic active EBV infection is rare and can start as a typical glandular fever infection that progresses to a severe illness [Okano et al, 1991; Cohen, 2000]. It is associated with extremely high virus-specific antibody titres [Cohen, 2000]. The prognosis is poor with most people dying of progressive pancytopenia, hypogammaglobulinemia, or nasal lymphoma [Johannsen and Kaye, 2009].

X-linked lymphoproliferative syndrome (Duncan's syndrome) [Cohen, 2000; Thomas, 2009] is a sex-linked disease of male children who cannot control infection with the EBV. Most develop severe or fatal illness. Acquired hypogammaglobulinemia or malignant lymphomas may develop. The treatment is bone marrow transplantation and without treatment 70% of children die by 10 years of age.

Haemophagocytic lymphohistiocytosis may occur as a result of chronic active EBV infection or X-linked lymphoproliferative syndrome, or it may develop as a separate clinical entity. It usually affects children younger than 3 years of age, who develop high fever, pancytopenia, liver dysfunction, and coagulopathy. The prognosis without treatment is poor, but the survival rate is up to 75% with treatment [Johannsen and Kaye, 2009].

Diagnosis

Diagnosis of glandular fever

When to suspect glandular fever

When should I suspect glandular fever?

Suspect glandular fever if there is profound fatigue plus all three of:

Fever (present in 90% of people).

Lymphadenopathy (present in up to 100% of people). Posterior cervical lymphadenopathy is the most common. There may also be anterior cervical, submandibular, suboccipital, postauricular, epitrochlear, axillary, and inguinal lymphadenopathy. Nodes are mildly tender and mobile.

Sore throat (present in up to 90% of people). This is usually the most severe that the person has ever had. There may be:

Tonsillar enlargement (present in up to 91%). The tonsils may meet in the middle.

Pharyngeal redness with exudate (present in up to 33%).

Adenoidal enlargement which may cause obstruction to the nasopharynx.

Palatal petechiae (present in up to 60%). The petechiae are 1–2 mm in diameter and occur in crops lasting 3–4 days.

Also suspect glandular fever in a person with a sore throat that fails to improve, or becomes worse, after several days.

Glandular fever is difficult to distinguish from other causes of sore throat (especially streptococcal sore throat).

Other clinical features that may support a diagnosis include:

Prodromal symptoms (usually a history that lasts for several days), such as general malaise, myalgia, chills, sweats, fever, anorexia, feelings of abdominal fullness, and retro-orbital headache.

Splenomegaly (present in 50%). The spleen reaches maximum size at the beginning of the second week of illness and regresses over 7–10 days.

Periorbital oedema (present in up to 33%).

Hepatomegaly (10–15%), although more often there is mild tenderness in the right hypochondrium.

A rash (present in 5%) that may be macular, petechial, like scarlet fever, urticarial, or erythema multiforme-like.

Jaundice (present in 5%).

A maculopapular rash after being treated with amoxicillin.

In people older than 40 years of age, glandular fever is rare and may present atypically.

Without sore throat and lymphadenopathy in more than 50% of people.

With unexplained fever of more than 2 weeks' duration (fever is present in over 90% of older adults with glandular fever).

With jaundice (about 20% of older adults with glandular fever are jaundiced).

In a child, infection with the Epstein–Barr virus is usually asymptomatic.

Basis for recommendation

Basis for recommendation

Clinical features

Clinical features of glandular fever are based on expert opinion in textbooks [Isaacs and Jones, 2003; Johannsen and Kaye, 2009].

Presentation in adults older than 40 years of age

The clinical features of glandular fever in adults older than 40 years of age are based on expert opinion in narrative reviews [Axelrod and Finestone, 1990; Auwaerter, 1999; Godshall and Kirchner, 2000] and a textbook [Johannsen and Kaye, 2009].

Investigations

What investigations should I do?

To confirm a diagnosis of glandular fever:

In children older than 12 years of age and in immunocompetent adults, arrange a full blood count with differential white cell count and a Monospot test (heterophile antibodies) in the second week of the illness.

Glandular fever is likely if the full blood count has more than 20% atypical lymphocytes, or more than 10% atypical lymphocytes and the lymphocyte count is more than 50% of the total white cell count. For other causes of atypical lymphocytosis, see Differential diagnosis. Some laboratories use the term 'reactive' instead of 'atypical'.

If the Monospot test is negative and it is clinically indicated, repeat 7 days later, or

If a rapid diagnosis is needed (for example if a urgent return to sports is desired), send blood for Epstein–Barr viral serology.

If two Monospot tests are negative, test for cytomegalovirus and toxoplasmosis only if the person is immunocompromised or pregnant. Test for HIV in at-risk people (after appropriate counselling).

In children younger than 12 years of age and in people who are immunocompromised at any age, arrange blood tests for Epstein–Barr viral serology after the person has been ill for at least 7 days.

Taking a throat swab routinely is not recommended.

Consider checking liver function tests.

Usually aspartate aminotransferase, and alanine aminotransferase are elevated to a level two to three times the upper limit of normal. Consider alternative possible diagnoses if they are 10 times the upper limit of normal.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion in textbooks [Pagana and Pagana, 2002; Johannsen and Kaye, 2009], a narrative review [Ebell, 2004], and a best practice in primary care pathology review [Smellie et al, 2007].

Full blood count with differential white cell count

Lymphocytosis is classical and peaks during the second or third week of the illness. This is often referred to as 'mononuclear lymphocytosis', although lymphocytes by definition are mononuclear. Lymphocytes and monocytes form 60–70% of the total white cell count, which usually varies between 12,000 and 18,000 cells/mm3 but may be as high as 50,000 cells/mm3. The classic finding is atypical lymphocytes which usually form about 30% of the total lymphocyte count (range few to 90%). These atypical lymphocytes are found in other illnesses as well as glandular fever.

Monospot test (heterophile antibodies)

Heterophile antibodies (detected by the Monospot test) are present in approximately 90% of people older than 12 years of age who have glandular fever [Johannsen and Kaye, 2009]. Heterophile antibody titres decrease rapidly after the fourth week of the illness [CDC, 2006].

Blood should be taken in the second or third week of the illness, because false-negative results are common if taken earlier. False-negative rates may be 25% in week 1 of infection, falling to approximately 5% in week 3 [Ebell, 2004; Smellie et al, 2007]. Repeat testing is recommended in suspected cases if an initial test is negative [Smellie et al, 2007]. Heterophile antibody titres decrease rapidly after the fourth week of the illness [CDC, 2006].

False-negative rates are also reported to be higher in children younger than 12 years of age, in whom specific antibody testing is recommended, and in immunocompromised people in whom immunological testing is considered potentially unreliable [Ebell, 2004; Smellie et al, 2007].

Most older adults will be positive for heterophile antibodies 2–5 weeks after the onset of glandular fever symptoms [Godshall and Kirchner, 2000].

As cytomegalovirus and toxoplasmosis are usually self-limiting infections, expert opinion in a clinical pathology review is that only people who are immunocompromised or pregnant should be tested after two negative heterophile antibody tests. HIV testing may be necessary in at-risk people, as HIV infection may present as a glandular fever-like illness [Smellie et al, 2007].

False-positive results are rare and have been reported in people with hepatitis, lymphoma, and HIV [Johannsen and Kaye, 2009].

Epstein–Barr viral serology

Epstein–Barr virus-specific antibodies to Epstein–Barr viral capsid antigen are rarely needed but may be useful in people who are heterophile negative, in children younger than 12 years of age, and in immunocompromised people [Smellie et al, 2007]. The antibodies to the viral capsid antigen are either IgM or IgG. They both appear after 7 days of illness; IgG antibodies persist for life, whereas IgM antibodies disappear after 3 months [Pagana and Pagana, 2002].

Recommendation not to take a throat swab routinely

Throat swabs cannot differentiate between infection and carriage, they have poor sensitivity, results take up to 48 hours to be reported, and the analysis is relatively expensive [Little and Williamson, 1996; MeReC, 1999; SIGN, 1999]. The results of throat swabs vary according to technique, culture site, and culture conditions [Cooper et al, 2001].

Group-A beta-haemolytic streptococcus can be isolated from up to 30% of people presenting with sore throat [Bisno, 2005]. However, figures for asymptomatic carriage range from 6–40% [Little and Williamson, 1996]. Carriers have low infectivity and are not at risk of developing complications.

Liver function tests

Expert opinion is that liver function tests may provide additional support to the diagnosis of infectious mononucleosis by showing a hepatitic picture. If liver changes occur they usually develop early in the illness [Smellie, Personal Communication, 2010].

Differential diagnosis

What else might it be?

The differential diagnosis of glandular fever includes:

Other causes of sore throat, especially streptococcal sore throat (see the CKS topic on Sore throat - acute). In streptococcal sore throat:

Lymphadenopathy is usually anterior cervical and submandibular (posterior cervical lymphadenopathy is most common in glandular fever).

There is no splenomegaly or hepatomegaly in adults but an enlarged spleen has been described in children.

Fatigue is less prominent.

It is possible for glandular fever and streptococcal sore throat to co-exist.

Other causes of lymphadenopathy, for example:

Painful lymphadenopathy: local infection or inflammation.

Painless progressive enlargement of a lymph node.

Lymphoma.

Metastatic solid tumour.

Leukaemia. Lymphadenopathy is a rare presenting feature of leukaemia. If leukaemia is suspected, check a full blood count with a differential white cell count immediately.

Other viral infections that may present with a glandular-fever like illness with an atypical lymphocytosis:

Cytomegalovirus primary infection — may present with splenomegaly, hepatomegaly, and a negative heterophile antibody test. Sore throat and lymphadenopathy are rare.

Acute toxoplasmosis. Lymphocytosis is mild, but there may be hepatomegaly, splenomegaly, and a false-positive heterophile antibody test.

Viral hepatitis — may cause malaise, fever, lymphadenopathy, and atypical lymphocytosis. Usually the lymphocytes are less than 10% of the number of leukocytes and the hepatocellular enzyme levels are markedly elevated.

Primary HIV-1 infection — may present with pharyngitis, fever and lymphadenopathy, skin lesions, rash, diarrhoea, weight loss, nausea, and vomiting.

Rubella — may rarely present with a fever, lymphadenopathy, and atypical lymphocytosis.

Human herpes virus-6 primary infection (roseola) — most infections are mild with a modest number of atypical lymphocytes.

Mumps.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion in a textbook [Litman and Baum, 2006; Straus, 2006; Johannsen and Kaye, 2009] and a narrative review [Ebell, 2004].

Streptococcal sore throat may mimic glandular fever

In streptococcal sore throat, the lymphadenopathy is usually anterior cervical and submandibular and there is no splenomegaly [Johannsen and Kaye, 2009] although splenomegaly has occasionally been described in children [Higgins, 1992]. Fatigue is less prominent [Ebell, 2004].

Co-existence of glandular fever and streptococcal infection

A retrospective study investigated the occurrence of glandular fever in 222 children diagnosed with group-A beta-haemolytic streptococcal infection [Rush and Simon, 2003].

Three groups were evaluated:

Those with glandular fever alone (176 children).

Those diagnosed with a group-A beta-haemolytic streptococcal pharyngitis who did not improve and were subsequently diagnosed as having glandular fever (41 children).

Those initially diagnosed with glandular fever and who within 2 weeks were also diagnosed with pharyngitis due to group-A beta-haemolytic streptococcal infection (5 children).

Diagnosis of group-A beta-haemolytic streptococcal infection was confirmed by a rapid streptococcal agglutination test and glandular fever was confirmed by the measurement of antibody to the Epstein–Barr virus antigens.

Numbers were small but did suggest that co-existence of glandular fever and streptococcal infection does occur.

Management

Management

Scenario: Management : covers the management of acute glandular fever, and advice about the management of persistent fatigue.

Scenario: Management

Scenario: Management of glandular fever

1months3060monthsBoth

Treatment and advice

How do I treat and advise a person with glandular fever?

Advise paracetamol or ibuprofen to relieve pain and fever.

Explain the expected course of the illness and reassure the person that symptoms usually last for 2–3 weeks. Tiredness is common.

Advise the person:

That exclusion from work or school is not necessary.

To return to normal activities as soon as possible. If they are tired, they should tailor their activities to what they can manage comfortably. Bed rest is not a requirement.

To limit spread of the disease, they should avoid kissing and sharing eating utensils, and thoroughly clean all articles that may have been contaminated by saliva.

To avoid contact or collision sports, or heavy lifting for the first month of the illness (the spleen is enlarged in most people with glandular fever and may rupture).

Advise the person to seek urgent medical advice if they:

Develop stridor or respiratory difficulty.

Cannot swallow adequate fluids.

Become systemically very unwell.

Develop abdominal pain (the pain of splenic rupture may start abruptly or gradually, and is usually in the left hypochondrium).

Do not prescribe:

Amoxicillin or ampicillin, as this will cause a rash in most people with glandular fever.

Corticosteroids, unless severe complications are present.

Aciclovir, as this has no clinical benefit on the symptoms of acute glandular fever.

Basis for recommendation

Basis for recommendation

Analgesics

Oral analgesics are recommended for the symptomatic relief of sore throat [MeReC, 1999; SIGN, 1999; RCPCH, 2000; MeReC, 2006]. A systematic review found oral analgesics (paracetamol, nonsteroidal anti-inflammatory drugs, aspirin) to be helpful in relieving symptoms of sore throat [Thomas et al, 2000]. See the Supporting evidence section on Systemic analgesics in the CKS topic on Sore throat - acute. Evidence indicates that, for short-term use (7 days), paracetamol and ibuprofen are equally well tolerated, and both are better tolerated than aspirin. See the Supporting evidence section on Safety of short term ibuprofen in the CKS topic on Sore throat - acute.

Local analgesics are licensed for the symptomatic relief of sore throat. However, the evidence for flurbiprofen lozenges and benzydamine gargle is poor, and they are not recommended. See the Supporting evidence sections on Flurbiprofen lozenges and Benzydamine in the CKS topic on Sore throat - acute.

Advice on the expected course of the illness

These recommendations are based on information in a textbook [Johannsen and Kaye, 2009]. There is evidence from a prospective cohort study that illness beliefs may predict chronic fatigue. It is therefore important to reassure the person that the illness is usually self limiting. There is evidence from two prospective cohort studies and a retrospective cohort study that people with glandular fever are more likely to have acute fatigue than people who have had an ordinary upper respiratory tract infection.

Advice on level of activity

Limited evidence from a small randomized trial indicates that a brief intervention encouraging graded physical activity may help to prevent the development of chronic fatigue. The authors of this trial have concluded that definitive randomized controlled trials are needed to determine whether a brief intervention carried out when glandular fever is diagnosed may help to prevent the development of chronic fatigue. The results also indirectly suggest that general advice to rest may be unhelpful. [Candy et al, 2004]. Until the results of this further research are available, it seems sensible to encourage a return to normal activity as soon as possible.

Not recommending bed rest

Traditionally, people with glandular fever have been advised to rest. Limited evidence from a small randomized controlled trial indicates that most people with acute glandular fever are told to rest by their GP despite limited evidence from a systematic review that the level of activity during the acute stage of the illness and also during recovery may be a risk factor for prolonged illness.

A prospective study done more than 40 years ago is still quoted. In this study, 83 students with glandular fever admitted to hospital were quasi-randomized to either unrestricted activity or strict bed rest [Dalrymple, 1964]. A further 48 students were not ill enough to be hospitalized and were ambulatory and attended outpatients. The study found that:

Only 10% of the students experienced fatigue lasting longer than 6 weeks.

Strict bed rest did not shorten the duration of symptoms and may have prolonged fatigue and debility.

There were potential biases in the trial design, but the results lend no support to advocating bed rest.

Advice regarding transmission

The advice that exclusion from work or school is not necessary is based on advice from the Health Protection Agency [HPA North West, 2007].

Advice regarding when to resume sporting activities/heavy lifting

These recommendations are based on advice in a textbook [Johannsen and Kaye, 2009] and narrative reviews [Ebell, 2004; Putukian et al, 2008].

The incidence of splenic rupture is highest in the second and third week of the illness [Putukian et al, 2008; Johannsen and Kaye, 2009] although rupture has occurred up to 7 weeks after the onset of the illness [Putukian et al, 2008].

There is no specific guidance on when it is safe to resume sporting activities without risk of splenic rupture. A time of 4 weeks seems prudent and is recommended by experts in narrative reviews [Burroughs, 2000; Ebell, 2004]. Athletes should be informed that the risk of splenic rupture is never zero [Putukian et al, 2008].

Advice regarding seeking advice if symptoms suggest airways obstruction or if there is difficulty swallowing

This recommendation is based on expert opinion in a guideline from the Scottish Intercollegiate Guidelines Network [SIGN, 1999].

Advice regarding seeking medical advice regarding the development of abdominal pain

Abdominal pain is unusual in glandular fever, and splenic rupture should be suspected if abdominal pain occurs [Johannsen and Kaye, 2009]. Abdominal pain often extends to the left supraclavicular region. The diagnosis is supported by findings of splenomegaly, tender spleen, and peritoneal irritation [Aldrete, 1992].

Advice not to prescribe amoxicillin or ampicillin

Prescribing amoxicillin or ampicillin will produce a generalized, itchy maculopapular rash in over 90% of people with glandular fever [Johannsen and Kaye, 2009].

Advice not to prescribe corticosteroids

Corticosteroids have been prescribed for glandular fever since the 1950s for their anti-inflammatory effect. They are still widely used in the US, where a retrospective cohort study found that 45% of 206 people with glandular fever had been prescribed them [Thompson et al, 2005].

There is concern that the immunosuppressive effects of corticosteroids may predispose the person to infection (such as peritonsillar abscess) or even contribute to subsequent development of Epstein–Barr virus-related cancer.

A Cochrane systematic review concluded evidence was insufficient to recommend corticosteroid treatment for symptom control in glandular fever, as there was no clear evidence for its effectiveness.

Expert opinion in a narrative review is that corticosteroid use should be reserved for severe complications, such as upper airways obstruction, acute haemolytic anaemia, active cardiac involvement, or neurological disease [Cohen, 2000].

Advice not to prescribe aciclovir

Good evidence from a meta-analysis indicates that treatment with aciclovir offers no clinical benefit [Torre and Tambini, 1999].

Referral

When should I refer a person with glandular fever?

Admit immediately anyone with:

Upper airways obstruction.

Dehydration or reluctance to take any fluids.

Suspected splenic rupture.

Seek urgent specialist advice if you suspect that potentially serious complications have developed.

If the person has HIV/AIDS, seek their permission to inform the relevant HIV or genito-urinary medicine clinic so that they can be monitored.

For information about when to refer someone with persistent fatigue after glandular fever, see the section on Referral in the CKS topic on Tiredness/fatigue in adults.

Basis for recommendation

Basis for recommendation

These recommendations are based on widely held expert opinion [SIGN, 1999; Johannsen and Kaye, 2009].

People with HIV/AIDS

A monospot test may be unreliable and falsely positive, so blood should be sent for Epstein–Barr serology. See Investigations.

Monitoring is important, as HIV/AIDS is a risk factor for complications.

Fatigue related to glandular fever

How should I manage fatigue related to glandular fever?

Explain that:

Fatigue is more common with glandular fever than with other viral upper respiratory tract infections. In most people, this resolves within 4 weeks.

A few people experience tiredness for 6 months or longer after the initial infection, and even then this usually resolves by 2 years.

Encourage the person to do as much as they are able to do.

For management of people with persistent fatigue, see the section on Treatment in the CKS topic on Tiredness/fatigue in adults.

Basis for recommendation

Basis for recommendation

Acute fatigue is common after glandular fever

Evidence from a two prospective cohort studies and a retrospective cohort study indicates that people with glandular fever are more likely to have acute fatigue than people who have had an ordinary upper respiratory tract infection. The fatigue is also more likely to last for longer.

Development of fatigue lasting longer than 6 months

Good evidence from cohort studies indicates that a few people with glandular fever will have persistent fatigue lasting several months. Most people will have recovered 2 years after the illness.

Encourage the person to do as much as they are able

CKS found no trials that have studied the effect of activity and inactivity on recovery in people with persistent fatigue after glandular fever. This recommendation is therefore based on expert opinion. There is limited evidence from a systematic review that reduced physical activity during the acute stage of the illness and also during recovery may be a risk factor for a prolonged illness. Evidence from a prospective cohort study indicates that illness beliefs may predict chronic fatigue [Candy et al, 2002].

Evidence

Evidence

Supporting evidence

Evidence

CKS found no studies on the diagnosis of glandular fever, and therefore recommendations about diagnosis (including investigations) are based on expert opinion found in text books and narrative reviews.

CKS has reviewed the evidence on treatments for glandular fever (corticosteroids and antivirals) and the evidence on fatigue (acute and persistent) associated with glandular fever.

Corticosteroids

Evidence on the use of corticosteroids

Evidence is insufficient to recommend the use of corticosteroids for symptom control in glandular fever.

A Cochrane systematic review [Candy and Hotopf, 2006] examined the evidence on efficacy and safety of corticosteroids for symptom control in glandular fever.

Method

Seven randomized controlled trials met the inclusion criteria. Four studies (191 participants) compared a corticosteroid with placebo. Three trials (175 participants) compared a corticosteroid given with another drug (aciclovir, valaciclovir, or aspirin) with placebo.

Studies were small and likely to be underpowered.

It was not possible to combine the results of the studies as the studies used different corticosteroid preparations and dosages, different diagnostic definitions of glandular fever, and the participants were of different ages.

Results

Sore throat: in the short term (12 hours), corticosteroids were significantly more effective than placebo at relieving sore throat (two studies). This benefit was not maintained in the medium-term (60–72 hours). Additionally, corticosteroids were no more effective at relieving sore throat in the long-term (1–4 weeks).

Fatigue: corticosteroids in combination with valaciclovir were found to be more effective than placebo in the medium term (20 days) at resolving or improving fatigue (one underpowered study). Corticosteroids alone were not found to be more effective than placebo at resolving or improving tiredness (two studies).

Harms

Severe adverse effects that may have been related to the corticosteroid treatment were reported by three participants.

Conclusion

The authors concluded that evidence was insufficient to recommend corticosteroid treatment for symptom control in glandular fever, as there was no clear evidence for their effectiveness.

Aciclovir

Evidence on the use of aciclovir

Good evidence from a meta-analysis indicates that aciclovir does not have a significant clinical effect on the symptoms of acute glandular fever.

A meta-analysis of five randomized controlled trials that included 339 people with mild, moderate, and severe glandular fever studied the clinical effectiveness of aciclovir [Torre and Tambini, 1999].

There was no statistically significant symptomatic benefit from the use of aciclovir.

Although aciclovir reduced viral shedding, this was not evident 3 weeks after use.

The authors concluded that clinical data did not support the use of this drug.

Fatigue

Evidence on fatigue

Acute fatigue

Evidence on acute fatigue associated with glandular fever

Evidence from two prospective cohort studies and a retrospective cohort study indicates that people with glandular fever are more likely to have acute fatigue than people who have had an ordinary upper respiratory tract infection (URTI). The fatigue is also more likely to last for longer.

A prospective cohort study included 108 people with confirmed (101) or probable (7) Epstein–Barr infection, 83 people with non-Epstein–Barr glandular fever, and 54 people with an ordinary URTI who were followed up at 1-month, 2-month, and 6-month intervals [White et al, 1998].

To meet the criteria for acute fatigue syndrome, the participants had to meet all of the following four criteria:

Physical fatigue for at least 2 weeks.

Two or more of the following symptoms: sleeping more than usual, poor concentration, retardation, irritability, or anhedonia.

Significant incapacity on the Schedule for Affective Disorders and Schizophrenia (SADS) global incapacity assessment scale.

No current or previous psychiatric disorder (except phobias).

An acute fatigue syndrome occurred in 47% of people with glandular fever at the beginning of the illness compared with 20% of people with an ordinary URTI (relative risk 2.3, 95% CI 1.3 to 4.1) and lasted a median of 8 weeks, compared with 3 weeks in people with an ordinary URTI.

A prospective study of the natural history of glandular fever caused by the Epstein–Barr virus included 150 people with acute glandular fever and followed them up 1, 2, and 6 months after the onset of the illness. Most of the people included in this study were white, single, and students with an average age of 21.3 years [Rea et al, 2001]:

At 1 month, most symptoms and signs had resolved and laboratory tests had returned to normal. Fatigue was still present in 28% of people.

At 2 months, there was little further change in fatigue or other residual symptoms.

Fatigue and sleeping too much gradually improved over the next few months.

A retrospective cohort study included 134 students with glandular fever and 105 students with a URTI and found that [Lambore et al, 1991]:

During the acute phase, fatigue was more common in the students with glandular fever than in the students with an upper respiratory tract infection (p < 0.0001).

The median duration of symptoms was 3–4 weeks in the glandular fever group and 1–2 weeks in the students who had a URTI (p = 0.001).

Persistent fatigue

Evidence on persistent fatigue after glandular fever

Good evidence from cohort studies indicates that a few people with glandular fever will have persistent fatigue lasting several months. Most people will have recovered 2 years after the illness.

A systematic review explored the longitudinal course of the illness at 6 months or beyond after the onset of glandular fever [Candy et al, 2002]. The prevalence of prolonged illness lasting for more than 2 months varied from 1.5–56.0%. The following studies were included:

A prospective cohort study of 150 people with glandular fever found that 12% had failed to recover by 6 months and still had fatigue, pharyngitis, and cervical lymphadenopathy [Buchwald et al, 2000].

A prospective study of the natural history of glandular fever caused by the Epstein–Barr virus included 150 people with acute glandular fever who were followed up 1, 2, and 6 months after the onset of the illness. Most of the people included in this study were white, single, and students with an average age of 21.3 years [Rea et al, 2001]. At 6 months symptoms of glandular fever were reported in less than 10% of people. It was not known whether this was due to the residual symptoms of glandular fever persisting or whether this reflected the underlying frequency of these symptoms in the population.

A prospective cohort study of 108 people with confirmed (101) or probable (7) Epstein–Barr infection, 83 people with non-Epstein–Barr glandular fever, and 54 people with an ordinary upper respiratory tract infection (URTI) were followed up 1 month, 2 months, and 6 months after the onset of the illness [White et al, 1998]. At 6 months of follow up, the only symptoms that were significantly more common in the group of people who had had glandular fever were:

Physical fatigue (40% of people who had had Epstein–Barr virus infection, 29% of people who had had non-Epstein–Barr infection, and 8% of people who had had a URTI [Chi-squared 10.6, degrees of freedom (DF) 2, p = 0.005]).

Sleeping too much (22% of people who had had Epstein–Barr virus infection, 14% of people who had had non-Epstein–Barr infection, and 2% of people who had had a URTI [Chi-squared 9.85, DF 2, p = 0.007]).

The prevalence of chronic fatigue syndrome varied from 9–22%, depending on the definition used, compared with 0–6% after a URTI.

A prospective cohort study that listed common symptoms for the fatigue syndrome that followed glandular fever: physical and mental fatigue, sleeping too much, poor concentration, retardation, anhedonia, irritability, social withdrawal, emotional lability, transient swelling of the lymph glands when tired, and transient sore throat when tired [White et al, 1995].

Two retrospective studies were also reviewed:

One included 134 students with glandular fever and 105 students with an upper respiratory tract infection and found that 6% of the students who had had glandular fever had symptoms that persisted for over 1 year [Lambore et al, 1991].

A small retrospective study of 25 white students with glandular fever found that 16% still had symptoms at 48 weeks [Thompson et al, 1969].

A retrospective review of 337 student health records found that 1.5% of students with glandular fever had fatigue 2 months after the onset [Chang and Bittner, 1991].

A prospective cohort study screened 301 adolescents who had had glandular fever for non-recovery [Katz et al, 2009]:

At 6 months follow up, seventy had not recovered and of these 53 people were clinically evaluated. Of those who were clinically evaluated, 39 (13% of the original sample) met the criteria for chronic fatigue syndrome at 6 months.

At 12 months follow up, 36 of the 39 people diagnosed as having chronic fatigue syndrome at the 6 month evaluation were evaluated and 22 (7% of the original sample) met the criteria for chronic fatigue syndrome.

At 24 months follow up, 19 of the 22 people diagnosed as having chronic fatigue syndrome at the 12 month evaluation were evaluated and 13 (4% of the original sample) met the criteria for chronic fatigue syndrome.

This was 20 times higher that the prevalence of chronic fatigue syndrome in the general adolescent population (0.2%), suggesting that glandular fever may be a risk factor for the development of chronic fatigue syndrome.

Predictors of poor outcome

Evidence on predictors of poor outcome

There is limited evidence from a systematic review that the person's level of activity during the acute stage of the illness and also during recovery may be a risk factor for a prolonged illness. Evidence from a prospective cohort study indicates that illness beliefs may predict chronic fatigue.

A systematic review looked at possible predictive factors for prolonged illness in people with glandular fever [Candy et al, 2002].

The review included 10 studies: six prospective cohort studies, two retrospective cohort studies, one retrospective review, and one quasi-randomized RCT.

The review investigated clinical features, psychological factors, demographic factors (age and sex), and functional status (such as physical fitness, period of absence from work or school).

One of the included studies was a prospective cohort study of 108 people with confirmed (101) or probable (7) Epstein–Barr infection, 83 people with non-Epstein–Barr glandular fever, and 54 people with an ordinary upper respiratory tract infection that concluded that lower physical fitness was a predictor for persistent fatigue. A previous history of psychiatric illness was also predictive of a chronic fatigue syndrome at 6 months of follow up [White et al, 2001].

One of the included studies was a prospective cohort study that found that a higher temperature during the illness, older age, and impaired physical functioning were linked to failure to recover at 2 months, and that female sex, greater family support, and a greater number of life events before the onset of the glandular fever illness were associated with failure to recover at 6 months [Buchwald et al, 2000].

The authors concluded that the level of activity during the acute stage of the illness, and also during recovery, may be risk factors for prolonged illness.

A prospective cohort study explored the immunological, endocrine, behavioural, and cognitive responses to acute glandular fever in a primary care setting in order to find out which risk factors predicted a chronic course [Candy et al, 2003]. Seventy-one people agreed to participate, and 69% were followed up at 3 months, 87% at 6 months, and 70% at 1 year.

Predictors for fatigue at 3-month follow up were severity of the initial illness, belief that it would take over a month to recover or would have serious consequences (illness perceptions), and increased immune activation (measured by CD4 and CD8 counts).

Predictors of fatigue at 6-month follow up were illness perceptions.

Predictors of fatigue at 12-month follow up were being female and older age.

This study was a pilot and is small with a poor response to follow up at 3 months and 12 months. It was also part of a randomized controlled trial and the interventions in the trial may have affected illness perception in particular. The results should therefore be interpreted with caution. However, in support of the result, the authors comment that illness perception has predicted poorer health outcomes for other conditions, such as type 2 diabetes and myocardial infarction.

Advice for people with acute glandular fever

Evidence on current advice given by GPs to people with acute glandular fever

There is limited evidence from a small randomized controlled trial that most people with acute glandular fever are told to rest by their GP despite evidence that rest may be unhelpful.

A randomized controlled trial investigated the advice given by their GP recalled by people with glandular fever [Candy et al, 2005].

Seventy-one people agreed to participate and were asked the question 'When glandular fever was diagnosed, what advice were you given?'. The advice that they recalled included the following:

General advice to rest: 50 (70%).

Take time off work or school: 12 (17%).

Avoid vigorous activities/sport: 5 (7%).

The authors expressed concern that this advice may have been given in a general way without also giving advice to resume normal activities as soon as possible. There is evidence that inactivity during convalescence may delay recovery. Advising rest might encourage people to expect a long convalescence and delayed recovery.

Brief interventions to prevent chronic fatigue

Evidence on a brief intervention to prevent the development of chronic fatigue

There is limited evidence from a small randomized controlled trial (RCT) that a brief intervention encouraging graded physical activity may help to prevent the development of chronic fatigue.

There is evidence that reduced levels of fitness and expectations of a long convalescence are risk factors for the development of fatigue after glandular fever. The authors of an RCT therefore piloted a psycho-educational intervention aimed at improving recovery from glandular fever. Sixty-nine participants were randomized to receive either a fact sheet about glandular fever with no advice on rehabilitation; or an individual treatment session aiming to restore physical function, two follow-up telephone calls, and an information booklet specifically designed for the project [Candy et al, 2004]. The study found that:

There was no difference between the groups at 3 months and no significant difference at 12 months.

There were fewer people with fatigue in the intervention group at 6 months compared with the control group (odds ratio 0.31, 95% CI 0.09 to 0.91).

This study is small and needs to be repeated as a larger RCT. It also indirectly suggests that general advice to rest may be unhelpful.

Search strategy

Scope of search

A literature search was conducted for guidelines and systematic reviews on primary care management of glandular fever.

Search dates

Dates not restricted – August 2009

Key search terms

Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline.

infectious mononucleosis/, infectious mononucleosis.tw, glandular fever.tw.

Table 1 . Key to search terms.
Search commands Explanation
/ indicates a MeSh subject heading with all subheadings selected
.tw indicates a search for a term in the title or abstract
exp indicates that the MeSH subject heading was exploded to include the narrower, more specific terms beneath it in the MeSH tree
$ indicates that the search term was truncated (e.g. wart$ searches for wart and warts)
Sources of guidelines

National Institute for Health and Care Excellence (NICE)

Scottish Intercollegiate Guidelines Network (SIGN)

National Guidelines Clearinghouse

New Zealand Guidelines Group

British Columbia Medical Association

Canadian Medical Association

Institute for Clinical Systems Improvement

Guidelines International Network

National Library of Guidelines

National Health and Medical Research Council (Australia)

Alberta Medical Association

University of Michigan Medical School

Michigan Quality Improvement Consortium

Royal College of Nursing

Singapore Ministry of Health

Health Protection Agency

National Resource for Infection Control

CREST

World Health Organization

NHS Scotland National Patient Pathways

Agency for Healthcare Research and Quality

TRIP database

Patient UK Guideline links

UK Ambulance Service Clinical Practice Guidelines

RefHELP NHS Lothian Referral Guidelines

Medline (with guideline filter)

Sources of systematic reviews and meta-analyses

The Cochrane Library :

Systematic reviews

Protocols

Database of Abstracts of Reviews of Effects

Medline (with systematic review filter)

EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

NIHR Health Technology Assessment programme

The Cochrane Library :

NHS Economic Evaluations

Health Technology Assessments

Canadian Agency for Drugs and Technologies in Health

International Network of Agencies for Health Technology Assessment

Sources of randomized controlled trials

The Cochrane Library :

Central Register of Controlled Trials

Medline (with randomized controlled trial filter)

EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

Bandolier

Drug & Therapeutics Bulletin

MeReC

NPCi

BMJ Clinical Evidence

DynaMed

TRIP database

Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

Department of Health

Health Management Information Consortium (HMIC)

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