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Objectives: Infectious mononucleosis (IM) is a clinical syndrome that is characterised by lymphadenopathy, fever and sore throat. Although generally not considered a serious illness, IM can lead to significant loss of time from school or work due to profound fatigue, or the development of chronic illness. This study aimed to derive and externally validate clinical prediction rules (CPRs) for IM caused by Epstein-Barr virus (EBV)., Design: Prospective cohort study., Setting and Participants: 328 participants were recruited prospectively for the derivation cohort, from seven university-affiliated student health centres in Ireland. Participants were young adults (17-39 years old, mean age 20.6 years) with sore throat and one other additional symptom suggestive of IM. The validation cohort was a retrospective cohort of 1498 participants from a student health centre at the University of Georgia, USA., Main Outcome Measures: Regression analyses were used to develop four CPR models, internally validated in the derivation cohort. External validation was carried out in the geographically separate validation cohort., Results: In the derivation cohort, there were 328 participants, of whom 42 (12.8%) had a positive EBV serology test result. Of 1498 participants in the validation cohort, 243 (16.2%) had positive heterophile antibody tests for IM. Four alternative CPR models were developed and compared. There was moderate discrimination and good calibration for all models. The sparsest CPR included presence of enlarged/tender posterior cervical lymph nodes and presence of exudate on the pharynx. This model had moderate discrimination (area under the receiver operating characteristic curve (AUC): 0.70; 95% CI: 0.62-0.79) and good calibration. On external validation, this model demonstrated reasonable discrimination (AUC: 0.69; 95% CI: 0.67-0.72) and good calibration., Conclusions: The alternative CPRs proposed can provide quantitative probability estimates of IM. Used in conjunction with serological testing for atypical lymphocytosis and immunoglobulin testing for viral capsid antigen, CPRs can enhance diagnostic decision-making for IM in community settings., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Infectious mononucleosis (IM) is a clinical syndrome, usually caused by the Epstein Barr virus (EPV), characterised by lymphadenopathy, fever and sore throat. Most cases of symptomatic IM occur in older teenagers or young adults. Usually IM is a benign self-limiting illness and requires only symptomatic treatment. However, occasionally the disease course can be complicated or prolonged and lead to decreased productivity in terms of school or work. Antiviral medications have been used to treat IM, but the use of antivirals for IM is controversial. They may be effective by preventing viral replication which helps to keep the virus inactive. However, there are no guidelines for antivirals in IM., Objectives: To assess the effects of antiviral therapy for infectious mononucleosis (IM)., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 3, March 2016), which contains the Cochrane Acute Respiratory Infections (ARI) Group's Specialised Register, MEDLINE (1946 to 15 April 2016), Embase (1974 to 15 April 2016), CINAHL (1981 to 15 April 2016), LILACS (1982 to 15 April 2016) and Web of Science (1955 to 15 April 2016). We searched the World Health Organization (WHO) International Clinical Trials Registry Platform and ClinicalTrials.gov for completed and ongoing trials., Selection Criteria: We included randomised controlled trials (RCTs) comparing antivirals versus placebo or no treatment in IM. We included trials of immunocompetent participants of any age or sex with clinical and laboratory-confirmed diagnosis of IM, who had symptoms for up to 14 days. Our primary outcomes were time to clinical recovery and adverse events and side effects of medication. Secondary outcomes included duration of abnormal clinical examination, complications, viral shedding, health-related quality of life, days missing from school or work and economic outcomes., Data Collection and Analysis: Two review authors independently assessed studies for inclusion, assessed the included studies' risk of bias and extracted data using a customised data extraction sheet. We used the GRADE criteria to rate the quality of the evidence. We pooled heterogeneous data where possible, and presented the results narratively where we could not statistically combine data., Main Results: We included seven RCTs with a total of 333 participants in our review. Three trials studied hospitalised patients, two trials were conducted in an outpatient setting, while the trial setting was unclear in two studies. Participants' ages ranged from two years to young adults. The type of antiviral, administration route, and treatment duration varied between the trials. The antivirals in the included studies were acyclovir, valomaciclovir and valacyclovir. Follow-up varied from 20 days to six months. The diagnosis of IM was based on clinical symptoms and laboratory parameters.The risk of bias for all included studies was either unclear or high risk of bias. The quality of evidence was graded as very low for all outcomes and so the results should be interpreted with caution. There were statistically significant improvements in the treatment group for two of the 12 outcomes. These improvements may be of limited clinical significance.There was a mean reduction in 'time to clinical recovery as assessed by physician' of five days in the treatment group but with wide confidence intervals (CIs) (95% CI -8.04 to -1.08; two studies, 87 participants). Prospective studies indicate that clinical signs and symptoms may take one month or more to resolve and that fatigue may be persistent in approximately 10% of patients at six-month follow-up, so this may not be a clinically meaningful result.Trial results for the outcome 'adverse events and side effects of medication' were reported narratively in only five studies. In some reports authors were unsure whether an adverse event was related to medication or complication of disease. These results could not be pooled due to the potential for double counting results but overall, the majority of trials reporting this outcome did not find any significant difference between treatment and control groups.There was a mean reduction in 'duration of lymphadenopathy' of nine days (95% CI -11.75 to -6.14, two studies, 61 participants) in favour of the treatment group.In terms of viral shedding, the overall effect from six studies was that viral shedding was suppressed while on antiviral treatment, but this effect was not sustained when treatment stopped.For all other outcomes there was no statistically significant difference between antiviral treatment and control groups., Authors' Conclusions: The effectiveness of antiviral agents (acyclovir, valomaciclovir and valacyclovir) in acute IM is uncertain. The quality of the evidence is very low. The majority of included studies were at unclear or high risk of bias and so questions remain about the effectiveness of this intervention. Although two of the 12 outcomes have results that favour treatment over control, the quality of the evidence of these results is very low and may not be clinically meaningful. Alongside the lack of evidence of effectiveness, decision makers need to consider the potential adverse events and possible associated costs, and antiviral resistance. Further research in this area is warranted.