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Home , Cervical lymphadenopathy, Infectious mononucleosis, Toxoplasmosis

EDUCATION CLINICAL REVIEW

Infectious mononucleosis • Link to this article online for CPD/CME credits Paul Lennon,1 Michael Crotty,2 John E Fenton1

1 Department of Otolaryngology, is commonly seen in both the SOURCES AND SELECTION CRITERIA Head and Neck Surgery, University community and the hospital setting. Patients usually pre- Hospital Limerick, Dooradoyle, We performed an electronic search through Medline, Limerick, Ireland, and Graduate sent with a and often presume that an anti- Scopus, Google Scholar, the Cochrane Database of Entry Medical School, University of biotic is required. It is therefore important to dispel the Systematic Reviews, and the Cochrane central register Limerick, Ireland many myths relating to the condition with appropriate 2 of controlled trials using the search terms “infectious General Practice, Synergy Medical patient education. Knowledge of the clinical course of the mononucleosis”, “glandular ”, “Epstein-Barr ”, Clinic, Sherwood Park, Edmonton, Alberta, Canada disease, as well as potential complications, is paramount. “”, and “”. The search was limited Correspondence to: P Lennon In an information age, difficult questions may arise for a to articles in English. We excluded studies carried out [email protected] general practitioner, emergency doctor, or trainee in ear, primarily on children. Priority was given to data from Cite this as: BMJ 2015;350:h1825 nose, and throat medicine. The aim of this review is to meta-analyses, reviews, and randomised controlled trials. doi: 10.1136/bmj.h1825 assist those who encounter infectious mononucleosis in Research on infectious mononucleosis was also given priority over articles exclusively relating to Epstein-Barr the adolescent and adult population. virus. We also examined guidelines produced by the US Center for Disease Control and Prevention and the UK What is infectious mononucleosis and what causes it? National Institute for Health and Care Excellence, as well It would be most accurate to consider infectious mono- as clinical trials registries of the , United nucleosis as a non-genetic syndrome, defined by the Kingdom, and European Union.w1-w3 classic triad of fever, , and cervical lymphad- enopathy, where is also present. For many doctors the terms Epstein-Barr virus and infectious mon- These low titres of infectious virus account for the low onucleosis are synonymous. Epstein-Barr virus causes to moderate contagiousness of the disease and the thebmj.com approximately 90% of the cases of infectious mononu- apparent requirement of intimate contact for disease Previous articles in this w12 cleosis, with the remainder due largely to cytomegalo- . During an active the viral load series virus, human herpesvirus 6, , HIV, and may be increased, and therefore some precautions about ЖЖRelapse in multiple adenovirus.1 w4 The World Health Organization’s ICD-10 contact should be mentioned (cough etiquette, hand sclerosis (international classification of diseases, 10th revision) hygiene, kissing, sharing or utensils); however, (BMJ 2015;350:h1765) has four subheadings for infectious mononucleosis (or as most of the population is positive for Epstein-Barr ЖЖThe management of B27 in the manual.w5) To confuse things further the mul- virus, special precautions against transmission are not acute testicular pain in tiple synonyms for infectious mononucleosis (glandular necessary in most cases.w13 Childhood infection, which children and adolescents fever, monocytic angina, Pfeiffer’s disease, Filatov’s is usually subclinical, is associated with poor hygiene (BMJ 2015;350:h1563) disease, Drusenfieber, and even the kissing disease) are and over-crowding. In lower socioeconomic groups ЖЖManagement of severe still included in ICD-9, which will be in use in the United most of the population will have acquired immunity w6 3 acute dental States until 1 October 2015. by . After an of four to w14 (BMJ 2015;350:h1300) The Epstein-Barr virus is a ubiquitous herpesvirus, seven weeks, Epstein-Barr virus infection of adoles- ЖЖSudden cardiac death with more than 90% of the world’s population infected cents or adults results in infectious mononucleosis in up by adulthood.w7 The virus is one of our most effective to 70% of cases.4 Most symptoms tend to resolve in two in athletes w8 (BMJ 2015;350:h1218) parasites and remains as a lifelong, latent infection, by to four weeks, although approximately 20% of patients integrating itself into the life cycle of healthy B lympho- continue to mention a sore throat at one month.w15 Reac- ЖЖTemporomandibular cytes.2 w9 There is persistent low grade replication and the tivation of Epstein-Barr virus may occur in immunocom- disorders w17 virus is shed intermittently into pharyngeal secretions, promised patients and, rarely, in immunocompetent (BMJ 2015;350:h1154) particularly saliva, through which it is transmitted.w10 w11 patients, which may lead to Epstein-Barr virus associated

THE BOTTOM LINE • Infectious mononucleosis is a clinical diagnosis, caused by Epstein-Barr virus in 90% of cases, although in some patients (, high risk HIV population) further investigations are warranted • Treatment should be supportive, with steroids given only in cases of airway compromise • Treatment with antiviral agents has yet to be shown to be of benefit • Patients wanting to return to contact sports before one month should undergo abdominal ultrasonography to rule out

• Splenic rupture should be considered with any in infectious BERNARD/CNRI/SPL J PR mononucleosis Infectious mononucleosis characterised by enlarged atypical the bmj | 25 April 2015 29 EDUCATION CLINICAL REVIEW

Diagnostic tests for infectious mononucleosis tious mononucleosis and at least a 50% lymphocytosis (10% atypical), the diagnosis should be confirmed by the Sensitivity Specificity 6 Tests (%) (%) Comment heterophile (monospot) test. Using a lower rate w24 w25 Infectious mononucleosis of lymphocytosis has been shown to give a greater 8 w26 w27 Full count: rate of false negative results (table). The heterophile L/WCC >50%+10% atypical lymphocytesw75 61 95 An increase in count tends test may also be falsely negative in up to 25% of adults in 1 6 L/WCC >35% 84 72 to lead to a greater specificity but poorer the first week of symptoms. It is not always necessary sensitivity8 definitively to diagnose a for infectious mononucleo- Monospot 71-98 91-99 Results vary between different available commercial kitsw76 sis, but specific antibody tests are available. Patients are Antibody to VCA or EBNA 97 94 May have replaced monospot as standard considered to have a primary Epstein-Barr virus infection investigation in some countries if they are positive for antiviral capsid IgM but do Bacterial not have to Epstein-Barr virus nuclear antigen, Antistreptolysin O titre Peak value 3-6 weeks after infection, and which would suggest past infection. Levels of antiviral cap- thus not of value in acute setting sid antigen IgG will also increase in the acute phase and w77 Throat swab 78 99 Delay of 2-3 days for result persist for the rest of the patient’s life, whereas the anti­ w78 Rapid streptococcal antigen test 84 94 Increased cost viral capsid antigen IgM will disappear after 4-6 weeks. The L/WCC=lymphocyte to white cell count ratio; VCA=antiviral capsid antigen; EBNA=Epstein-Barr virus nuclear antigen. p­resence of antiviral capsid antigen IgG and Epstein-Barr virus nuclear antigen suggest past infection.9 A recent review l­ymphoproliferative conditions. These conditions are a found that real time polymerase chain reaction and meas- heterogeneous group of diseases that often need to be urement of Epstein-Barr virus viral load provide useful tools treated with .w18 Diagnoses depend on the for the early diagnosis of infectious mononucleosis in cases specific disease but are often associated with an increased with inconclusive serological results.10 In a small number of viral load.w19 Chronic active Epstein-Barr virus infection cases, where the patient is either pregnant or in a high risk is a rare condition that is typified by severe, chronic, or group for HIV infection (injecting drug user or men who have recurrent infectious mononucleosis-like symptoms after sex with men), further testing for , HIV, and a well documented primary infection with Epstein-Barr other possible causes for infectious mononucleosis should virus in a previously healthy person.5 Chronic active be undertaken.w28 w29 Figure 1 presents an algorithm for Epstein-Barr virus infection is occasionally associated diagnosing­ infectious mononucleosis.w30 with the development of .w20 How is it treated? How is it diagnosed? Infectious mononucleosis is a viral illness in most cases, Infectious mononucleosis may account for as little as 1% and as such it can be treated with rest, hydration, analge- of patients who present with a sore throat to their doctor.w21 sia, and antipyretics. Inadvertent treatment with Non-specific prodromal symptoms of fever, chills, and results in a fine macular in 90% of patients.w8 This may be seen in infectious mononucleosis. These should be distinguished from an urticarial rash seen in an symptoms may also be present in cases of viral pharyngitis, allergic reaction. Studies have shown that symptoms expe- commonly caused by rhinovirus, adenovirus, and coronavi- rienced by patients are more severe for infectious mononu- rus. Whereas these generally give rise to symptoms cleosis than for bacterial tonsillitis.w16 Antiviral treatment of a ,w21 clinically infectious mononucleosis with aciclovir has been shown significantly to decrease should be suspected in anyone who presents with fever, the rate of oropharyngeal Epstein-Barr virus shedding.w31 pharyngitis, and cervical (the classic Some early trials found a significant positive overall effect triad).w22 Lymphadenopathy may be prominent in both the in cases of infectious mononucleosis treated with aciclo- anterior and the posterior triangles of the neck, which dis- virw32 and that it was useful in severe cases, with airway tinguishes infectious mononucleosis from bacterial - compromise. However, a meta-analysis of five studies litis (where the lymphadenopathy is usually limited to the found no evidence to support its use in the acute setting: an upper anterior cervical chain). These signs were found in improvement in oropharyngeal symptoms was observed in 98% of patients with a diagnosis of infectious mononucleo- 25 out of 59 (42.4%) patients treated with aciclovir and in sis.6 Other common physical signs include palatal petechiae 18 out of 57 (31.6%) control patients (odd ratio 1.6, 95% (25-50%), splenomegaly (8%),w15 (7%), confidence interval 0.7 to 3.6; P=0.23).11 Other antiviral and (6-8%),w23 with a transitory derangement of treatments such as and ganciclovirw33 have Lymphadenopathy function tests (in particular increased aspartate ami- shown some promise in the treatment of severe infectious may be prominent notransferase and alanine aminotransferase levels, return- mononucleosis and its complications and immunocompro- in both the anterior ing to normal after 20 days) seen in 80-90% of patients.7 mised people. Two trials are in progress,w2 but at present w34 and the posterior Anecdotally, a “whitewash”’ on the may also the routine use of both drugs is not advocated. Anaero- triangles of the help to distinguish infectious mononucleosis from the more bic antibacterial agents such as have been neck, which speckled exudate of bacterial tonsillitis and the suggested to hasten recovery in infectious mononucleosis of a viral pharyngitis that is void of exudate. In the primary by suppression of the oral anaerobic flora that contribute distinguishes care setting a clinical diagnosis alone may be sufficient to to the inflammatory process.w35 This finding was borne out infectious allow adequate management of a patient. However, should in some clinical studies,w36-w41 with a recent randomised mononucleosis from a definitive diagnosis be sought, the Hoagland criteria state controlled trial showing the beneficial effects of metroni- bacterial tonsillitis that in patients presenting with clinically suspected infec- dazole in severe infectious mononucleosis by shortening

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The incidence of splenic rupture is Triad of fever, pharyngitis, and lymphadenopathy less than 1% Full blood count and heterophile antibody High risk patients Mild symptoms test sent, single blood sample taken

Heterophile positive Heterophile negative HIV test Pregnant

Diagnosis of infectious Lymphocytosis > × /L Lymphocytosis < × /L Cytomegalovirus mononucleosis and/or atypical lymphocytes and no atypical lymphocytes Toxoplasmosis HIV

Epstein-Barr virus Epstein-Barr virus serology not Antiviral capsid antigen IgM and Epstein-Barr virus nuclear antigen warranted, consider other diagnoses

IgM positive IgM negative If clinically indicated Diagnosis of heterophile Cytomegalovirus negative Epstein-Barr virus HIV infectious mononucleosis Human herpesvirus

Positive Negative

Other possible diagnoses Toxoplasmosis Viral Adenovirus pharyngitis Acute leukaemia Lymphoma

Fig 1 | Algorithm for diagnosing infectious mononucleosis

hospital stays.12 Larger trials may be required before the results in severe impairment in daily functioning.w47 There use of metronidazole is routinely recommended. has been much debate about the cause of this disorder. Some authors suggest that it is precipitated by an acute infection, Are steroids of use in the treatment of infectious such as infectious mononucleosis, as many patients relate mononucleosis? the onset of their illness to an initial infection from which Several early reports supported the use of corticosteroids in they never recovered.w48 Prospective studies have reported the treatment of infectious mononucleosis.w42 Further trials an incidence of chronic syndrome of 7.3-12% in showed these effects to be short lived, with no significant adults six months after infectious mononucleosis.w49 w50 difference between the control and intervention arm.w43 However, the relation between A Cochrane review was therefore undertaken, which con- and infectious mononucleosis is still questionable. A study cluded that there was insufficient evidence and the trials of over 1300 patients diagnosed as having infectious mono- were too few, heterogeneous, and of poor quality to recom- nucleosis by serology, found that although 10% of patients mend steroid treatment for symptom control in glandular reported fatigue none fulfilled the criteria for chronic fatigue fever.13 Another more recent Cochrane review concluded syndrome.15 The cause of chronic fatigue syndrome is likely that corticosteroids increased the likelihood of both reso- to be multifactorial.­ lution and improvement of pain in participants with sore throat14; however, this review excluded publications on When is it safe to return to sports? patients with a diagnosis of infectious mononucleosis. Ster- Splenomegaly, evident on ultrasonography if not on oid treatment should be considered in cases of airway emer- palpation, occurs in almost all cases of infectious mono- gency, in an attempt to temporise or preclude the need for nucleosis, and the risk of splenic rupture has been well intubation or tracheotomy.w44 Despite these guidelines, the established.w54 A considerable number of 15-21 year use of corticosteroids remains w­idespread on a day to day olds will have infectious mononucleosis every year,w16 basis.w45 Several reports have mentioned the adverse effects and many of this population will be involved in con- of cortico­steroid use in infectious mononucleosis, including tact sports.w55 Strenuous or contact sports (for example, cases of peritonsillar cellulitis, acute onset diabetes mellitus, football, gymnastics, rugby, hockey, lacrosse, wrestling, and neurological sequelae.w46 diving, and basketball) or activities associated with increased intra-abdominal pressure, such as weightlift- Does infectious mononucleosis lead to chronic fatigue ing, may put athletes at most risk.w56Although recommen- syndrome? dations of when to return to sport range from three,w57 Chronic fatigue syndrome is defined as severe fatigue and four,w58 eight, and even up to 24 weeks,w59 no clinical disabling musculoskeletal and cognitive symptoms without guidelines are specific to infectious mononucleosis. The another explanation that lasts for at least six months and incidence of splenic rupture is less than 1%w15 and most the bmj | 25 April 2015 31 EDUCATION CLINICAL REVIEW

There is evidence Late Epstein-Barr virus infection with infectious v­accine against Epstein-Barr virus in theory could eradi- mononucleosis cate . In the only phase II trial of an that a history Early Epstein-Barr virus infection without infectious of infectious mononucleosis Epstein-Barr virus in humans, rates of infectious mononucleosis No Epstein-Barr virus infection mononucleosis were reduced in adults who were seronega- tive for Epstein-Barr virus, but the vaccine did not affect the significantly rate of Epstein-Barr virus infection.w65 The development increases the risk of of a vaccine is challenging for several reasons, not least multiple sclerosis the long period between primary infection with Epstein- Barr virus and the development of many Epstein-Barr virus related tumours or multiple sclerosis.20 To add further to the controversy it has been suggested that in lieu of a vac- cine, a smaller, but still substantial, number of cases of multiple sclerosis could be prevented by exposing children Multiple sclerosis incidence rate 19             to Epstein-Barr virus infection before adolescence. Age (years) Is there an increased risk of lymphoma or other Fig 2 | Incidence of multiple sclerosis by Epstein-Barr virus infection. Adapted from Thacker et al 200619 after infectious mononucleosis? The association of Epstein-Barr virus with malignancies occur in the initial three weeks of infectious mononucleo- such as Burkitt’s lymphomaw66 in children and nasopharyn- sis, although cases have been described much later.w60 geal carcinomaw67 is well established. This review, however, Cases of spontaneous splenic rupture have also been focuses on patients presenting with infectious mononucleo- described in the literature and doctors should have a high sis and it can be difficult to differentiate studies on Epstein- index of suspicion when abdominal pain is reported in Barr virus and infectious mononucleosis about the risk of the setting of infectious mononucleosis.w61 A recent study future malignancies. Two large Scandinavian cohort studies involved weekly ultrasound examinations until resolution found a 2.55 to 2.83 times increased risk of Hodgkin’s lym- of splenomegaly (fig 1). A mean increase in splenic length phoma in patients with a diagnosis of infectious mononu- of 33.6% was observed, with a peak in enlargement on aver- cleosis by heterophile antibody tests.21 w68 The results were age 12.3 days from the onset of clinical symptoms. Most similar in a recent British record linkage paper, which found cases of splenomegaly had resolved by 4-6 weeks and there a 3.44 risk ratio of Hodgkin’s lymphoma in the infectious was a predictable rate of splenic regression of approximately mononucleosis cohort.22 A review on Epstein-Barr virus 1% each day after reaching peak enlargement.17 Similar related malignancies from 2014 commented that Hodgkin’s results were reported in another paper, with nor- lymphoma is the only Epstein-Barr virus related malignancy, malising at one month in 84% of participants.w62 One study other than , for which there is a recommended that athletes wanting to return to contact body of evidence accumulated over time that establishes a sport at 3-4 weeks should have an ultrasound examination strong association.w69 For other malignancies, a large pro- to ensure that the had returned to normal size.w62 A spective study found no clear association between a history published in 2014 advocated individu- of clinical infectious mononucleosis and risk of invasive alised recommendations for athletes,18 and future work in breast ,w70 and one of the cohort studies found that this area may concentrate on splenic volume to allow a more lung cancer was significantly less likely in the cohort with accurate assessment of splenomegaly and risk. infectious mononucleosis.w71

Is multiple sclerosis caused by infectious mononucleosis? Can infectious mononucleosis cause any complications? There is evidence that a history of infectious mononucleosis Infectious mononucleosis in most cases resolves over a significantly increases the risk of multiple sclerosis19 and period of weeks, but may occasionally be exacerbated by that this association is far stronger than with other common a wide variety of complications. A list of complications can childhood infections or afflictions.w63 A meta-analysis con- be found at www.cdc.gov/epstein-barr/hcp.html. Neuro- cluded that the risk of multiple sclerosis seems to be great- logical disorders may occur in 1-5% of patients.w72 Theses est in those who were infected with Epstein-Barr virus at a include , meningoencephalitis, , optic later age (incidence begins to increase in adolescence, peaks neuritis, sudden sensorineural hearing loss, idiopathic around age 25 to 30 years, and declines to nearly zero by age facial palsy, and Guillain-Barré syndrome among others.w73 60) , with moderate risk for those infected with Epstein-Barr Haematological complications are more common, in par- virus in early childhood, and close to zero risk in those not ticular haemolytic anaemia (3%) and infected (fig 2).19 A more recent meta-analysis showed that (25-50%),w72 but also, rarely, aplastic anaemia, pancyto- Epstein-Barr virus is present in 100% of cases of multiple penia, and agranulocytosis. Other rare acute complica- sclerosis and therefore it has been suggested that the virus tions include , pericarditits,w74 , is not only a risk factor but also a prerequisite of multiple interstitial , rhabdomyolysis, and psychologi- sclerosis.w64 Whether the association between multiple scle- cal complications (“Alice in Wonderland” syndrome). The rosis and Epstein-Barr virus demonstrates a causal relation strength of association of infectious mononucleosis with is, however, strongly debated.w64 many of these complications is based on scattered case Although controversial, if proponents of the infectious reports, and the evidence of causation in many instances mononucleosis-multiple sclerosis theory are c­orrect, a is unconvincing.w72

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