American Medical Society of Sports Medicine Position Statement: Mononucleosis and Athletic Participation

Abstract

Infectious mononucleosis (IM) is a common illness in children and young adults caused primarily by the Epstein–Barr Virus (EBV). Transmission occurs primarily through sharing oral secretions, thus IM is known as the “kissing disease.” Common clinical manifestations include fever, pharyngitis, posterior cervical lymphadenopathy, and splenomegaly. Atypical lymphocytosis and transaminase elevations are common, and the diagnosis of IM is confirmed with laboratory findings of a positive heterophile antibody (“Monospot”), polymerase chain reaction, or antibodies specific to EBV. Individuals with acute IM may be quite symptomatic and not feel well enough to participate in sports. Splenic enlargement is common, with rupture a relatively rare occurrence, typically occurring within a month of symptom onset, but this risk complicates sports participation, and is often the reason for restricting activity. The management of IM is primarily supportive, with no role for antivirals or corticosteroids. The variability of clinical presentation and the risk of splenic rupture in patients with IM present clinicians with challenging return to play/return to sport (RTS) decisions. This position statement updates the Evidence-Based Subject Review on Mononucleosis by the American Medical Society for Sports Medicine published in 2008 and reviews the epidemiology, clinical manifestations, laboratory assessment, and management including RTS for the athlete with IM. This statement also addresses complications, imaging, special considerations, diversity and equity considerations, and areas for future clinical research. Understanding the evidence regarding IM and sport is essential when communicating with athletes and their families and incorporating shared decision-making in the RTS decision.

INTRODUCTION

Infectious mononucleosis (IM) is a common illness encountered frequently by a wide variety of healthcare providers who treat athletes. The epidemiology, clinical presentation, laboratory, and imaging considerations are well understood and have not changed significantly, whereas the challenges of incorporating a shared decision-making (SDM) model^1–5 in the return to play (RTP)/return to sport (RTS) decision represent a relatively new consideration for the sports medicine physician. Return to play is the process of returning an athlete to participate in his/her/their sport.⁵ RTS is applicable to all sports and athletes.^5,6 For the purposes of this statement, we will use RTS to include both. The RTS decision includes factors such as the age of the athlete, severity of illness, sport of choice, timing within the season, and the athlete's psychological readiness. Given the risks for splenic rupture, avoiding high-intensity exercise for a minimum of 2 weeks and not allowing return to contact/collision sports for at least 3 to 4 weeks have been the recommendation.^4,5,7–11

The American Medical Society for Sports Medicine (www.AMSSM.org) published a statement, “Mononucleosis and athletic participation: an evidence-based subject review” previously,¹⁰ and given the advancements in the science regarding imaging, splenic rupture, and SDM in sports medicine, it was felt that an update and formal Position Statement was needed. The AMSSM is a multidisciplinary organization of sports medicine physicians dedicated to education, research, advocacy, and the care of athletes of all ages, abilities, and backgrounds. Most AMSSM members are primary care physicians with fellowship training and added qualification in sports medicine who then combine their practice of sports medicine with their primary specialty. American Medical Society for Sports Medicine includes members who specialize solely in nonsurgical sports medicine and serve as team physicians at the youth level, MLB, MLS, NBA, NCAA, NFL, NHL, NWSL, WNBA, and with Olympic and Paralympic teams. By nature of their training and experience, sports medicine physicians are ideally suited to provide comprehensive medical care for athletes, sports teams, or active individuals who are simply looking to maintain a healthy lifestyle.

This updated statement on IM in the athlete underscores the importance of recognizing and diagnosing IM, being mindful of variabilities of this illness among populations worldwide, including addressing diversity, equity, and inclusion considerations, and management, complications, and RTS considerations in athletes. Sports medicine physicians should understand the role of SDM by providing evidence-based guidance to other healthcare providers, athletes, and the athletes' support network (eg, parents, coaches, administrators). Table 1 presents the summary of evidence-based key points to be addressed in this statement. Future research should address issues related to health inequities, advancements in evaluation/treatment that result in positive patient-oriented outcomes, the correlation of changes in relative spleen size to the risk for splenic rupture, and the possibility for earlier RTS assuming the athlete is feeling well clinically.

TABLE 1. - Summary of Key Points

1.	Clinical manifestations of IM can be nonspecific. Physical examination techniques have poor sensitivity and specificity in identifying relative splenic enlargement. Inter-rater reliability for physical examination is also poor. Laboratory confirmation of IM is useful. SOR A
2.	Supportive care is the treatment for uncomplicated IM in athletes. The role of other treatments, including antivirals and oral corticosteroids in reducing time until RTS remains unclear. Corticosteroids are indicated when IM is complicated by impending airway obstruction, hemolytic anemia, severe thrombocytopenia, or myocarditis. SOR B
3.	Imaging of the spleen is not necessary in the routine management of the athlete with IM unless splenic injury and/or rupture is suspected. Most if not all athletes have at least some degree of splenic enlargement early in their illness and there are no data that correlate spleen size to splenic rupture. SOR B
4.	The use of measuring splenic size at a single time point has not been demonstrated because of the wide variability of normal values and lack of a clear association between splenic size and associated complications. SOR B
5.	If imaging is obtained to evaluate for splenic injury or rupture, CT is recommended given the additional detail provided. If imaging is indicated for determining spleen size and/or early RTS, serial US imaging can be considered. SOR B
6.	It is reasonable to engage in a trial of supervised, nonimpact, low-intensity activity 2 wk from the onset of symptoms for those athletes who are afebrile, have an adequate energy level, and have an improving clinical examination. Conversely, delaying RTS should be considered in the presence of ongoing clinical signs/symptoms, lack of athlete readiness, and/or IM-associated complications. Treatment must therefore be individualized. SOR C
7.	It is unclear what role exercise has on the natural history of IM disease. It appears that premature (earlier than 2 to 3 wk from symptom onset) return to activities requiring heavy exertion may prolong the duration of symptoms, most notably fatigue, and may be associated with overtraining and/or a decrease in performance. There are some data, however, to suggest that early return to low-level exercise is beneficial. Given these uncertainties, a shared decision-making (SDM) model for return-to-sport decisions is recommended. SOR C
8.	The time for safe return to contact play is unclear, although given the risk for splenic rupture, a time frame of at least 3 to 4 wk from onset of symptoms is recommended. SDM should be used for individualized RTS decisions. In situations where an athlete with acute IM is considering an early return to activity (before 3 to 4 wk from symptom onset for contact sport) serial ultrasound imaging could be considered to confirm that the spleen size is decreasing or stable in size. SOR C

IM, infectious mononucleosis; RTS, return to play; SDM, shared decision-making; CT, computed tomography; SOR, Strength of Recommendation.¹²

METHODOLOGY

Writing Team Selection Process

The Publications Committee of AMSSM contacted the lead author (MP) of the original Evidence-Based Subject Review on Mononucleosis and the Athlete¹⁰ with the request to chair and update the 2008 Position paper to a Society Position Stand; a co-author on the 2008 paper (CAM) was chosen as co-chair. A call for nominations that included the AMSSM membership at large, the AMSSM Diversity Special Interest Group and the AMSSM Women in Leadership Group was performed, and the Chair and Co-chair selected the writing group that included one or more representatives from each group, an outside consultant who provided expertise in imaging, and the services of an outside librarian. The lead author created a Project Plan that included the proposed outline and writing group which was approved by the AMSSM Board of Directors. One of the selected writing group members decided to withdraw from participating based on time commitments. All final authors have disclosed financial and other relevant conflicts of interest, if any, related to the research and written presentation of their work.

Writing Group Processes

Once approved, the writing group met and reviewed the outline, created teams to address each component of the outline, and discussed the search process. The keywords used for the Position Statement included the following: IM, Epstein–Barr virus (EBV), cytomegalovirus, mono-like illness, spleen rupture, sport, RTP, hepatosplenomegaly, splenomegaly, fatigue, Hoagland, Burkitt lymphoma, posterior lymphadenopathy, Monospot, spleen ultrasound and imaging, and chronic fatigue.

Each team provided the librarian with keywords and any references to known articles on their subject. A faculty librarian from the Health Sciences Library and Informatics Center at the University of New Mexico conducted the searches summarized in the Supplemental Digital Content 1 (see Table, https://links.lww.com/JSM/A378). These searches had to be sensitive enough to find relevant references without overwhelming team members with many false negative results. The librarian primarily used Medical Subject Headings (MeSH) terms supplemented with keywords when no MeSH equivalent existed or when a keyword or text word would focus the search more efficiently. The searches (see Table, Supplemental Digital Content 1, https://links.lww.com/JSM/A378) did not use the degrees of sensitivity often found in systematic or in scoping reviews. The librarian provided the maximum amount of transparency with this text and the searches summarized in the Supplemental Digital Content 1 (see Table, https://links.lww.com/JSM/A378) allow another researcher to replicate the librarian's results from May 2021.

The authors chose to use the Strength of Recommendations Taxonomy (SORT) Grading system in developing our recommendations (Table 2).¹² This was used in the previous document and felt to be most useful for the sports medicine provider in understanding the literature and the potential biases related.

TABLE 2. - Strength of Recommendation Definitions¹²

Strength of Recommendation	Definition
A	Consistent, good-quality patient-oriented evidence*
B	Inconsistent or limited-quality patient-oriented evidence*
C	Consensus, disease-oriented evidence,† usual practice, expert opinion, or case series for studies of diagnosis, treatment, prevention, or screening

^*Patient-oriented evidence measures outcomes that matter to patients: morbidity, mortality, symptom improvement, cost reduction, quality of life.

^†Disease-oriented evidence measures intermediate, physiologic, or surrogate endpoints that may or may not reflect improvements in patient outcomes (ie blood pressure, blood chemistry, physiologic function and pathologic findings).

DIVERSITY, EQUITY, AND INCLUSIVITY STATEMENT

In general, there is a paucity of literature addressing IM and the athlete related to health disparities, especially those related to diversity, equity, and inclusion. In the review of the literature that we performed, certain health disparities were apparent and related to socioeconomic status (SES), ethnicity, and country of origin as discussed in the epidemiology section. Furthermore, in the imaging section, the “normative values” for spleen size are largely based on Caucasian individuals, and a difference in spleen size reported in certain racial categories was observed in one study. Race is a social construct that is used to group people based on physical characteristics, behavioral patterns, and geographic location. Racial categories are broad, poorly defined, vary by country, and change over time. People who are assigned to the same racial category do not necessarily share the same genetic ancestry; therefore, there are no underlying genetic or biological factors that unite people within the same racial category. Using race as a biological marker for disease states or as a variable in medical diagnosis and treatment, the true health status of a patient may not be accurately assessed, which can lead to racial health disparities. Additional research is needed to explore possible health disparities related to diversity, equity, and inclusion in the clinical care of athletes with IM.

EPIDEMIOLOGY

The only source of EBV infection are humans, with¹³ transmission occurring primarily through oral secretions, explaining why it has been described as “the kissing disease.”^14,15 EBV transmission can also occur with sharing cups or food or other close contact with oral secretions such as sneezing. Spread via fomites has not been well-described. Given the long incubation period of EBV (30-50 days), it can be challenging to determine the source of infection.^13,15,16 In a study of children <16 years old with a clinical diagnosis of IM, 85.4% were because of EBV and 14.6% were because of cytomegalovirus (CMV).¹⁷ The clinical presentation of CMV-IM is very similar to EBV-IM.^17,18

Annually, the rate of symptomatic IM in young adults between 15 and 19 years old is estimated to be between 200 and 800 cases per 100,000.¹⁹ It is estimated that 30% to 50% of freshmen entering college remain susceptible to developing symptomatic IM, with an annual incidence of 1% to 5%.²⁰ In a recent epidemiologic study of EBV seropositivity in the United Kingdom, with a large sample size of 2325 participants, 96.4% of women and 95.5% of men by age 20 to 25 years were seropositive for EBV.²¹ These data are consistent with several older studies of worldwide seropositivity rates. It is well documented that EBV seropositivity increases with age and this study found that each year increase in age corresponded to a 12% increase in the rate of seropositivity.²¹

It is not uncommon for EBV to go unrecognized in youth, given that symptoms are generally less severe than in older adults.¹³ Most children have predominantly respiratory symptoms with EBV infection and are labeled as a cold without specific testing for EBV.²² Adolescents, however, typically have more severe symptoms.¹⁶ Further variability exists according to worldwide differences between developed and less developed countries. In more developed regions, EBV most commonly occurs in patients between 5 years old and 25 years old.^19,23

There is no evidence to suggest that IM is more or less prevalent in the student-athlete population than among non–student-athletes. Infectious mononucleosis is, however, more prevalent in groups of people who live together, such as college students living in dorms or active military personnel,²⁰ and is the most common cause of lost time for new Army recruits.²⁴ Data from the United Kingdom demonstrate a higher incidence of EBV infection in 3-year-old children living in cities when compared with those in rural environments.²⁵ In this prospective study, they also found that lower SES and overcrowding in the house also increased the odds of having been infected.²⁵

A systematic review of 77 articles from 32 countries looked at predictors of EBV serostatus to help better define goals for vaccine development.²⁶ Factors such as age, sex, living environment, SES, ethnicity, and country of origin were examined to determine whether there was a difference in seropositivity. Studies that were focused on groups of people under 25 years old demonstrated increased seropositivity with age. There was no consistent difference in male versus female seropositivity. In this systematic review, crowded living environments did not demonstrate a difference in seropositivity, except for those exposed to second-hand smoke.²⁵ Those from lower SES had higher rates of seropositivity at a younger age, but more research needs to be conducted in this area. It is challenging to determine whether the change is because of a lower SES or other confounding variables also observed in this population such as the multiple biologic factors this population also is faced with including chronic stress, increased proinflammatory immune factors, lower overall immunity, and possibly shorter telomere length.²⁶ These biologic factors will make the patient more susceptible to infection.

EVIDENCE-BASED ISSUES

1. Clinical manifestations of IM can be nonspecific. Physical examination techniques have poor sensitivity and specificity in identifying relative splenic enlargement. Inter-rater reliability for physical examination is also poor. Laboratory confirmation of IM is useful.

The classic triad of fever, pharyngitis, and lymphadenopathy was described by Hoagland in 1975.²⁶ It is common to have a prodrome of malaise and headache and fever (rarely >40°C or >104°F) that can last up to 3 weeks. Exudative pharyngitis and tonsillar enlargement are typical and, in rare cases, can lead to airway compromise.¹³ Occasionally, patients can present with periorbital edema. Rare manifestations include jaundice, central nervous system complications, and myocarditis. A systematic review conducted by Ebell et al concluded that although typical symptoms (eg, sore throat, fever, fatigue, adenopathy) in isolation or combination should prompt consideration of IM, their diagnostic value was limited.²³ In this systematic review, if a patient did not have sore throat (sensitivity 0.81; Likelihood Ratio range 0.51-0.62) or a headache (sensitivity, 0.66; LR range 0.63-0.73), the likelihood of IM was reduced.²³

History alone can raise concern for IM. Emphasis is often placed on the presence of specific clinical findings for diagnostic purposes, yet it is recommended the healthcare provider maintain a level of suspicion with how the individual presents as a whole. A 2021 systematic review and meta-analysis by Cai et al²⁸ concluded that the presence of various signs and symptoms in the diagnosis of IM lack sensitivity. However, splenomegaly, palatial petechiae, posterior cervical lymphadenopathy, and axillary or inguinal lymphadenopathy significantly increased the likelihood of IM. Cai et al²⁸ did caution that the lymphadenopathy data were extrapolated from a single study. Furthermore, it was noted that hematologic findings are diagnostically more accurate than clinical presentations; thus, serologic testing is indicated to confirm clinical suspicion of IM.

Lymphadenopathy

Posterior cervical chain lymph node (LN) involvement is characteristic of IM, although it can also occur in conjunction with the more typical anterior chain LN involvement observed in bacterial tonsillitis/pharyngitis.²⁹ Involvement of the LN in axillary and inguinal regions is common and can further distinguish it from other etiologies.^23,28 Nodes are often moderately tender and typically large, peaking in early illness, and subsiding over months.³⁰

Oropharyngeal Findings

Tonsillitis is common and a number of etiologies should be considered including Group A Beta-hemolytic streptococcus (co-existent in up to 30% of cases), Neisseria gonococcus, and other viruses such as adenovirus, HIV, and acute herpes simplex virus. In IM, exudative pharyngitis is observed in more than 50% of patients in addition to marked tonsillar hyperplasia and edema. The exudate, often white, gray–green, or with necrotic features, can be impressive, and is often treated unnecessarily with antibiotics in the absence of confirmed bacterial infection. Palatal petechiae is noted in IM, but is nonspecific, because it is also observed in Group A Streptococcus infections.^12,13,19

Skin Findings

A fine maculopapular, urticarial, purpuric, or petechial rash is frequently present. A more intense and pruritic maculopapular or morbilliform rash may occur 2 to 10 days after initiation of an antibiotic for a concurrent bacterial infection. This rash has been mostly reported after the use of penicillin class drugs, but has also been described with tetracyclines, cephalosporins, and macrolides.^31–33

Abdominal Findings

In most patients with IM, relative splenomegaly occurs, with concurrent hepatomegaly in a small percentage of these. The presence of abdominal pain or left shoulder pain (Kehr sign) should raise concern for a splenic injury.³⁴ The reliability of physical examination in detecting splenomegaly has demonstrated wide variability.³¹ An early study evaluated the clinical utility of physical examination and found that if palpation and percussion tests were positive, the sensitivity was 46%, although the specificity was 97%.³⁵ The ability to teach clinical techniques to examine the spleen has not been assessed, and the reliability in patients with well-developed abdominal musculature or who have a large body size is inconsistent. In addition, there have been case reports of splenic rupture occurring during abdominal examinations because of deep palpation,^36,37 further complicating this assessment. Despite these limitations, a gentle and careful abdominal examination remain a component of the clinical assessment.

Laboratory Assessment

Hoagland criteria state that to confirm the diagnosis of IM, there must be at least 50% lymphocytes with at least 10% atypical lymphocytes on a peripheral blood smear occurring in the presence of the IM “triad” (fever, pharyngitis and adenopathy), with serologic testing indicated to confirm the diagnosis of IM.^11,27 A positive heterophile test, elevated liver transaminases, and the presence of EBV viral capsid antigen (VCA) IgM antibodies support the diagnosis of IM. In patients over 16 years old, the heterophile antibody latex agglutination test has a sensitivity of 87% (range 79-95) and a specificity of 91% (range 82-99).¹¹ False-positive tests can occur in those with a history of previous IM infection, lymphoma, hepatitis, or autoimmune disease.³⁸ False-negative rates can occur during the first week of illness, decrease with time from symptom onset, and are higher in younger children. A lymphocyte count of <4000 mm³ has a 99% negative predictive value for IM.^28,29 Only about 50% of patients with IM symptoms and a positive heterophile antibody test meet all of Hoagland criteria.¹¹

Hepatic transaminase levels are commonly elevated in IM and may aid in the diagnosis. One recent study of 199 collegiate athletes undergoing mono testing showed elevated transaminase levels in 100% of the patients with Monospot and antibody-confirmed acute IM, whereas only 3% of the cohort without acute IM had this lab abnormality.³⁹ However, the importance of these transient elevations and any potential correlation to splenomegaly remains unclear and are not typically used to make RTP decisions.

More specific antibody tests for EBV include VCA IgG, VCA-IgM, and Epstein–Barr nuclear antigen (EBNA) antibodies, although these tests may be more expensive and take longer to result than hepatic transaminase levels. Viral capsid antigen IgM appears early in infection and typically disappears at the 4- to 6-week mark. Viral capsid antigen IgG appears during acute infection, peaks 2 to 4 weeks after onset, then declines slightly and persists for life. Thus, these results must be taken in aggregate to determine whether a patient has acute IM. Epstein–Barr nuclear antigen antibodies generally appear 2 to 4 months after onset and also persist for life.⁴⁰

Immunoglobulin M and IgG antibodies to EBV VCA have a sensitivity of 97% and specificity of 94%¹¹ and are more useful than a positive heterophile test in confirming the diagnosis of IM (positive likelihood ratio of 16 vs 9.7-28) and superior to a heterophile test if negative in excluding EBV-IM (negative likelihood ratio of 0.03 vs 0.14-0.18 for heterophile Ab tests).^41,42 Because EBNA appears late in the course of IM with persistence for life, when detected early in the illness, one should consider another diagnosis. Quantitative PCR testing for the presence of EBV DNA can also be used to confirm the diagnosis.

Tests such as EBV DNA amplification in lymphocytes and the monitoring of viral load via PCR are not used routinely in clinical practice. Abnormalities in the complete blood count such as an absolute and relative lymphocytosis with greater than 10% atypical lymphocytes on a peripheral blood smear have been associated with acute IM, but are nonspecific and can be present in those with non-EBV illnesses. Cytomegalovirus is the causative agent in a minority of IM cases, and CMV antibody titers should be considered in patients with a history consistent with that of IM and negative EBV antibodies.^43,44

Overall, IM remains a clinical diagnosis suggested by history/physical examination that is then confirmed with selected laboratory testing. Although a positive Monospot (heterophile antibody) in the appropriate clinical setting is suggestive of acute IM, further laboratory testing such as liver transaminases and EBV or CMV antibody titers can be helpful in confirming the diagnosis.

SOR Recommendation grade: A

2. Supportive care is the treatment for uncomplicated IM in athletes. The role of other treatments, including antivirals and oral corticosteroids in reducing time until RTS remains unclear. Corticosteroids are indicated when IM is complicated by impending airway obstruction, hemolytic anemia, severe thrombocytopenia, or myocarditis.

Symptoms of IM usually resolve within 4 to 8 weeks, although a more protracted time course can occur in some individuals.^9,30,45 The management of IM is primarily supportive in nature, with no clear role for antivirals or corticosteroids. Important components of treatment include administering antipyretics and analgesics as necessary for fever, throat pain, and myalgias and providing adequate fluid and nutritional intake. In addition, education regarding transmission to others and avoiding significant exertion while symptomatic is important. If concomitant bacterial pharyngitis is present (eg, Streptococcus), antibiotics are indicated. In individuals with pharyngitis, airway compromise can occur and is an indication for the use of corticosteroids. Illness can also be especially severe in immunocompromised individuals.

SORT Recommendation grade: B

3. Imaging of the spleen is not necessary in the routine management of the athlete with IM unless splenic injury and/or rupture is suspected. Most if not all athletes have at least some degree of splenic enlargement early in their illness and there are no data that correlate spleen size to splenic rupture.

Assessment of Spleen Size

Unless the spleen is substantially enlarged, physical examination is insensitive in detecting splenomegaly.^15,46 Computed tomography (CT) imaging provides the most accurate assessment of splenic size.^47,48 Ultrasound imaging is also highly reliable for assessing spleen size and is often the preferred imaging modality because of its wide availability, low cost, and lack of ionizing radiation.^47,48 Ultrasound can also screen for potential complications of IM such as a splenic infarct, capsular hematoma, or frank splenic rupture.^47,48 If a splenic complication is detected or suspected, CT is typically performed to fully characterize the injury.^47,48

Ultrasonographic assessment of splenic size is measured with a single longitudinal diameter or by calculating a splenic volume. Fairly robust normative values for splenic length and volume have been established for adults stratified by height and sex based on a retrospective review of 1230 healthy Caucasian volunteers.⁴⁹ Similarly, normative values for splenic length and volume in Caucasian neonates and children have also been established, with one of the largest studies in the pediatric population.⁵⁰ However, these normative values as absolute thresholds in non-Caucasian populations should be used with caution because there is some heterogeneity in splenic size based on race, with African-American subjects generally having smaller spleens compared with Caucasian subjects, even when controlling for height and weight.⁵¹

Splenic Enlargement During Infectious Mononucleosis

Patients diagnosed with IM demonstrate some degree of splenic enlargement during their illness, beginning within a few days after symptom onset, with rapid early enlargement that peaks 1 to 3 weeks after the onset of symptoms.^9,52,53

O'Connor et al⁸ evaluated spleen size using ultrasound in 19 hospitalized patients diagnosed with IM and found that although most (16 of 19 subjects) of the spleens measured within the normal range (defined as measuring less than 12 cm in length, 7 cm wide and 4 cm deep) 4 weeks after diagnosis, 16% (3 of 19 subjects) did not. These 3 patients were re-imaged at 8 weeks and were subsequently in the normal range. The authors used serial ultrasound to confirm resolution of splenomegaly at 1 month after diagnosis and, in some cases, at 2 months after diagnosis before resuming athletic activities. Limitations in this study include the small sample size and that these were patients hospitalized with IM and thus may not be representative of the general population with IM. Moreover, baseline measurements were not obtained; therefore, it is unknown when or whether the spleens had truly returned to their pre-illness size. This study demonstrates the use of serial US assessments and the natural history of spleen size in IM infection.

In a study by Hosey et al,⁵³ baseline measurements of splenic size were assessed in 1822 NCAA Division 1 athletes. The 20 individual athletes who were subsequently diagnosed with IM underwent weekly splenic ultrasounds and physical examinations until splenic measurements returned to baseline, reached a plateau, or the patient was lost to follow-up. They found that all patients with IM had some degree of splenic enlargement, with the maximum splenic length increasing a mean of 33.6% from baseline values (range 3.9% to 95.8%). Peak splenic enlargement was reached at a mean of 12.3 days (range 6-23 days) after the onset of IM symptoms. A linear model demonstrated a fairly predictable decrease in spleen size of approximately 1% per day after reaching peak splenic enlargement. All but 1 had resolution of splenomegaly by 4 to 6 weeks.⁵³

SOR Recommendation grade: B

4. The use of measuring splenic size at a single time point has not been demonstrated because of the wide variability of normal values and lack of a clear association between splenic size and associated complications.

In the absence of baseline assessments, determining when an individual's spleen has returned to its normal size can be challenging. Despite the established normative values for splenic size,^49,50 there is a wide range of values that are considered within the normal range. In one study of 142 healthy adult volunteers, spleen volumes varied from 38.6 mL to 1448.1 mL⁴⁸ and spleen length varied from 6.4 to 14.5 cm.⁴⁹ Relying on measurements from a single time-point could, therefore, result in under-diagnosis and over-diagnosis of splenic enlargement. For example, a 178-cm woman with a splenic volume of 300 mL would technically be within the normal range; however, if this individual had a baseline splenic volume of 200 mL, then the initial value would indicate relative splenomegaly. Conversely, approximately 31.7% of tall male collegiate athletes and 12.8% of tall female collegiate athletes have a splenic length that is greater than 12 cm at baseline, which would be considered enlarged by some criteria.⁷ These patients may, therefore, never technically meet RTS criteria if the wide variability of normal spleen sizes is not recognized and there are no baseline measurements to assess for true IM-related splenic enlargement. This highlights the notion that a single assessment of splenic size in time is not as meaningful as serial sonographic measurements to document a decrease in size or stability over time.

SOR Recommendation grade: B

5. If imaging is obtained to evaluate for splenic injury or rupture, CT is recommended given the additional detail provided. If imaging is indicated for determining spleen size and/or early RTS, serial US imaging can be considered.

Imaging Recommendations

Computed tomography imaging is indicated when there is concern for splenic rupture or other splenic complication.^47,48 In the absence of a baseline spleen measurement, serial ultrasounds can demonstrate a decrease in and/or stabilization of splenic size.⁵³ The use of ultrasound can, however, raise healthcare costs¹¹ without evidence of improvement in patient-oriented outcomes, but can be of utility to the sports medicine clinician for the reasons presented in this Position Statement (eg, assessment of spleen size, when used in serial assessments, RTS decisions).

SOR Recommendation grade: B

6. It is reasonable to engage in a trial of supervised, nonimpact, low-intensity aerobic activities 2 weeks from the onset of symptoms for those athletes who are afebrile, have an adequate energy level, and have an improving clinical examination. Conversely, delaying RTS should be considered in the presence of ongoing clinical signs/symptoms, lack of athlete readiness, and/or IM-associated complications. Treatment must, therefore, be individualized.

Return to Play/Sport Guidelines

The RTP or sport decision is an individualized one that includes an assessment of the patient's health status, evaluating the risk of participation (sport-specific issues) and other outside factors that modify the decision.^4–6 The assessment of health status includes medical factors such as age, personal medical history, symptoms and physical examination, lab tests, and psychological state. The sport modifiers include the type of sport (eg, collision, noncontact), position played, the level of competition, and the equipment used. Additional factors that modify the decision include the timing with respect to the season, the athlete's desire to participate, pressure from parents or coaches, financial conflicts of interest, and the fear of litigation.^4–6 Beyond what is observed in the physical examination and laboratory testing, it is imperative the healthcare provider consider additional social, emotional, and physical stressors incurred by this illness particularly when holding an athlete out from sport.³⁰

Previous guidelines, including the 2008 AMSSM review,¹⁰ focused on an RTS decision after clinical resolution of symptoms, refraining from high-intensity activity for the first 3 weeks of illness, and the absence of splenomegaly.^10,38,51,54 The RTS decision should be based on a patient-clinician collaboration care model¹ that supports physicians providing patients with the evidence and uncertainties regarding their medical illness and then making a shared decision regarding management.^2,3,6 In the athlete with IM, SDM requires that physicians and athletes collaborate to develop a plan based on the athlete's clinical presentation and evidence regarding risks and outcomes, while balancing this with the athlete's values and preferences.^2,36,55 In addition, the Team Physician must balance their primary role as the athlete's physician, with the role that they may have with the school or organization.⁵⁵ To date, however, there are no well-designed large clinical trials to assist sports medicine providers in these complex decisions.

SOR Recommendation grade: C

7. It is unclear what role exercise has on the natural history of IM. It appears that premature (earlier than 2 to 3 weeks from symptom onset) return to activities requiring heavy exertion may prolong the duration of symptoms, most notably fatigue, and may be associated with overtraining and/or a decrease in performance. There are some data, however, to suggest that early return to exercise is beneficial. Given these uncertainties, a shared decision-making model for RTP is recommended.

The Effect of Exercise on Infectious Mononucleosis

There is limited research regarding the effect of exercise on the natural history of IM disease. There is also a significant heterogeneity in the clinical manifestations that individuals experience, with some athletes feeling ill for only a few days versus others that are incapacitated with significant anorexia and fatigue. IM has been described as being associated with fatigue and overtraining,^23,27,28,38 yet there is no research regarding risk factors, including early return to exercise, for developing these complications. The risk of exercise early in viral illness, and in IM in particular, is limited. Research in military cadets (n = 16) with IM has demonstrated no significant difference in aerobic capacity and no detrimental effects in those allowed to participate in light exercise ad lib as soon as they become afebrile, compared with those restricted from activity for 2 weeks.⁵⁶ Although there has been concern that early exercise is harmful or increases the risk for complications (eg, myocarditis,⁵⁷ prolonged illness,⁵⁸ or splenic rupture^9,45), this assumption has been questioned.⁵⁸ A study of 18 to 29 year olds infected with rhinovirus, who subsequently participated in moderate exercise did not demonstrate worsening or prolongation of their symptoms when compared with those who did not exercise.⁵⁹ In addition, studies of winter sport athletes have confirmed that athletes will often participate with upper respiratory viral illness without any adverse effect.^60,61 This, along with anecdotal reports of athletes who continued to participate without significant complications (eg, because of a delayed IM diagnosis or serologic evidence for undiagnosed previous IM infection) provides support for considering low-level, supervised activity earlier than 3 weeks, underscoring the importance of an individualized management plan. The resumption of light activity assumes that the activity will avoid any chest or abdominal trauma, will not involve significant exertion or Valsalva activities, and that the athlete is asymptomatic. Progression of noncontact sport-specific activity should then be gradually increased as judged by the athlete's clinical progress.

SOR Recommendation grade: C

8. The time for safe return to contact play is unclear, although given the risk for splenic rupture, a time frame of at least 3 to 4 weeks from onset of symptoms is recommended. SDM should be used for individualized RTS decisions. In situations where an athlete with acute IM is considering an early return to activity (before 3 to 4 weeks from symptom onset for contact sport), serial ultrasound imaging could be considered to confirm that the spleen size is decreasing or stable in size.

Return to Contact Sport

Given the often mild, nonspecific nature of IM infections, the variability and challenges of determining the presence of splenomegaly, and the unpredictable risk of splenic rupture during athletics, it is essential that the sports medicine physician actively engage in SDM with the athlete to determine the time for clearance and RTS. Athletes with acute IM that continue to participate carry a small but unquantifiable risk of complications including splenic rupture and death.^9,45,62–64 The risk for splenic rupture has been estimated in an early IM review as 0.1% to 0.5%,⁶⁴ but the true incidence is likely lower given that IM is often subclinical or under-reported.^9,10,65,66 In a systematic review of case reports, 85 cases in 52 articles or abstracts of splenic ruptures associated with IM were reviewed, and they noted that the average time from the onset of symptoms to splenic rupture was 14 days, with a maximum time of 8 weeks.⁴⁵ The average age was 22 years old, 70% were men, and the splenic rupture was traumatic in only 14% of cases. Eighty eight percent of the splenic ruptures presented with abdominal pain, 32% of cases were treated nonoperatively, and the overall mortality was 9%.⁴⁵ In a retrospective review from the military by Sylvester et al,⁹ 42 cases of splenic rupture associated with confirmed IM diagnosis and known onset of symptoms were reported. The mean time from symptom onset to splenic rupture was 15.4 days, with an SD of 13.5 days, and a median of 11.5 days. 73.8% of splenic rupture occurred within 21 days (95% Confidence Interval [CI], 0.736 to 0.942) and 90.5% within 31 days (95% CI, 0.794-0.970). Similar to the other systematic review, most splenic rupture cases involved men (83.3%), below 25 years old (71.4%), and was atraumatic (80.5%). Interestingly, in 88.1% of their patients, the diagnosis of IM was made after their splenic rupture. They also had returned to pre-injury level of activity recorded for 35 patients and only 71.4% returned to full activity, with 45.7% returning within 90 days, and the other 25.7% returning within 180 days. Those (n = 10) who did not return to pre-injury levels of activity had persistent abdominal pain (n = 8), anxiety (n = 1) or unrelated concerns (n = 1). Unlike the other review, there were no fatalities reported.

The athlete (and their family, if indicated) should be educated about the probability and time frame for the occurrence of splenic ruptures in IM. Given the limitations and challenges of using physical examination or ultrasound to evaluate spleen size or splenomegaly, and in the setting of nearly universal splenic enlargement in acute IM cases, the ultimate decision for resuming physical activity and sports remains clinically based and individualized. In addition, there exist no guidelines specific to RTS in IM for athletes in whom a laboratory abnormality was detected during the initial assessment.^{35,38,65–67} Additional factors to consider in clearance decisions include the risk of contact and/or collision, the age of the athlete, timing within the athlete's season, and other athlete-specific factors (other medical conditions, psychological readiness to return). Given that the risk for splenic rupture peaks at 2 weeks after symptom onset, refraining from high exertional activities during that time and avoiding any contact activities for at least 3 weeks after symptom onset is recommended. If the athlete is clinically stable, and wants to return to participation in contact before the 3 to 4 week from symptom onset time-frame, serial US measurements to document that the spleen size is decreasing or stable in size, may provide further information for the physician and athlete in understanding the risks associated with RTS.

SOR Recommendation grade: C

Limitations and Future Areas For Clinical Research

Infectious mononucleosis is a common illness that affects predominantly young individuals and is associated with a wide range of clinical presentations. Invariably, symptomatic athletes are affected—even if for only a short period of time—with fever, pharyngitis, and lymphadenopathy being the predominant features. Since the initial AMSSM Statement on IM, very few studies^9,45 specific to IM have been performed, which is a limitation to our review. However, given the low risk of splenic rupture, the lack of evidence for an adverse effect of early exercise in other viral upper respiratory illness, and a reliance on SDM in making individualized RTS decisions, it was felt that an update was necessary. Additional research endeavors studying the role of oral steroids in the resolution of IM-associated symptoms and splenomegaly are needed. In addition, exploring other possible treatment options such as antiviral therapies or potential vaccines to decrease the length of clinical symptomatology or prevent disease are areas for future clinical research. Although IM and associated splenic enlargement are commonly encountered among athletic participants, splenic rupture is rare. As such, prospective clinical studies evaluating the risk of splenic rupture with varying degrees of splenomegaly and a variable timetable of return to activity are challenging. This practicality leaves clinicians without objective data on which to base RTS decisions. One potentially useful area of study would be to correlate patient symptoms, clinical examination, and laboratory findings with objective measurements of the spleen.

Another question that has not been addressed sufficiently is the role low-intensity exercise plays on the natural history of IM resolution.^56,68 Whether an athlete with IM who returns to athletic participation prematurely may subsequently have a prolonged course of recovery, prolonged fatigue, and/or a decrease in performance measures is an interesting question for future research.⁵⁸

Finally, there are many athletes who develop IM without seeking medical attention, and often participate in sports without any apparent complication or negative consequence. Why some athletes are less symptomatic than others remains unclear. Understanding the natural history of this sometimes-elusive disease will help determine whether athletes are kept out of activity unnecessarily.