Estimates of the prevalence of infectious mononucleosis (IM) show substantial variation, depending on the thoroughness of population testing and the diagnostic criteria that are applied. The annual infection rate for 253 000 US university entrants, based upon a typical clinical picture, atypical lymphocytes, and a positive heterophile antibody test,1–3 was estimated to be as high as 1% to 3%. However, reports of a greater prevalence in athletes than in sedentary subjects were not confirmed in comparisons of serological status between 202 advanced endurance athletes and 200 controls.4
The clinical manifestations of IM can seriously compromise both athletic performance and academic study for several weeks.5 Physical activity is normally restricted during the acute phase of the disease because of fears of splenic rupture and a possible progression to chronic fatigue syndrome (CFS).6,7
The present review seeks an evidence for appropriate management of the active individual with IM. It considers issues of diagnosis, examines methods of determining splenomegaly and other measures of disease status, explores the potential relationship of the disease to CFS, and makes a critical assessment of the risks of exercise at various points in the disease process.
The database of Ovid/MEDLINE was searched without restriction from January 1996 to June 2015. The terms “exercise”(43 688 hits), “exercise therapy” (22 666 hits), “sports” (94 292 hits), “athletes” (4298 hits), “physical activity/motor activity” (173 449 hits), and “phyical fitness” (14 310 hits) were combined, using the “OR” function, to yield 235 801 unique citations. Infectious mononucleosis (1297 hits), splenomegaly (2946 hits), and splenic injury/rupture (1726 hits) were similarly combined using the “OR” function to identify 5824 unique citations. A combination of the 2 searches using the “AND” function yielded 65 abstracts for detailed consideration. The normal physiology of exercise and the spleen has recently been reviewed.8 Articles relating to exercise and normal functioning of the spleen were thus excluded, along with articles discussing direct splenic trauma. Because of wide interspecies differences in splenic function,8 animal research was also set aside. This preliminary triage left 34 articles relevant to the present analysis. The material fell into several broad categories: the nature of IM and its potential progression to the CFS (10 articles), reports of spontaneous splenic rupture in patients with IM (9 articles), methods of determining splenic size (4 articles), and recommendations for management of the infected athlete (11 articles). The articles thus identified were greatly supplemented by a perusal of “similar articles” in the MEDLINE and PubMed databases, pertinent items in journal reference lists, and a search of the author's personal files. Where possible, the quality of individual reports was examined in terms of sample size, experimental design, and criteria for the diagnosis of IM.
RESULTS AND DISCUSSION
Issues in the Diagnosis of Infectious Mononucleosis
A long incubation period (30-50 days) blurs the detection of disease onset and hampers a clear description of disease course. Acute clinical manifestations such as a painful posterior cervical adenopathy, malaise and fatigue, fever, sweating, a sore throat, pharyngitis, and anorexia9–11 are relatively consistent (Table 1) but unfortunately are nonspecific indicators of infection.
Common laboratory evidence of IM (Table 2) includes a lymphocytosis, with >10% atypical lymphocytes and a positive heterophile IgM antibody test.12–14 These basic laboratory measures can be supplemented by a search for Epstein–Barr nuclear antigen and IgG and IgM viral capsid antigens (VCA)14–16; although several times more expensive than the basic tests, the latter group of indicators are more sensitive, particularly in the early phases of infection. False-positive results may still arise from past infections, a problem that can be addressed by determining the avidity of VCA IgG, or making an immunoassay with a late marker antigen.4,17,18 Other less reliable laboratory evidence of infection includes abnormal liver function tests, particularly circulating alkaline phosphatase concentrations,12 and increased concentrations of circulating proinflammatory cytokines.19
In the first few weeks of disease, the spleen is enlarged,20 but this is not a good diagnostic marker. Clinical attempts to detect splenomegaly are highly fallible (Table 3), and even in the laboratory, differences of methodology (Table 4) and the spread of normal values are such (Table 5) that serial measurements are needed to avoid missing pathological enlargement of what was initially a small spleen. Moreover, differential diagnosis must consider a multiplicity of other causes of splenic enlargement (Table 6).
Clinical Determinations of Splenomegaly
Clinical assessments of splenomegaly are relatively ineffective (Table 3). The reported sensitivity and specificity of clinical examination varies widely from one observer to another (interobserver agreement for percussion, κ = 0.19-0.4121 and for palpation, κ = 0.56-0.7022), depending on whether the study is routine or experimental,23 on the method of palpation or percussion that is used, on the obesity of the individual, and on the proportion of enlarged spleens in the patient sample. Tamayo et al24 compared 3 techniques of palpation (bimanual, ballottement, and from above) and 3 techniques of percussion (Nixon, Castell, and Barkun methods). The figures cited (Table 3) are for the most effective of each of these approaches (ballottement and Castell percussion). A further important objection to attempts at clinical estimates of splenomegaly is the risk that over-vigorous palpation can cause the rupture of an infected spleen.25
Laboratory Determinations of Splenic Size
Splenic dimensions are commonly determined by 2D or 3D ultrasonography26; this avoids unnecessary exposure to irradiation when monitoring repeatedly for changes in spleen size. Other laboratory approaches include computed tomography (CT),27–30 scintigraphy using 99Technetium sulfur colloid31,32 or 113Indium-labeled granulocytes or platelets,33 and simple radiography.34 Measurements of splenic volume have also been made at autopsy.35
The average values reported for healthy adults depend substantially on the choice of methodology. De Odorico et al26 compared the results for 2D and 3D ultrasonography. They concluded that the 3D method was the more reliable of the 2 options, and gave systematically lower estimates, but that the need for multiple determinations made 2D data more practical in normal clinical practice. Radionuclide data generally indicate larger volumes than ultrasonography, and in some instances, the scintigraphic findings have been compromised by a failure to exclude emissions from adjacent organs such as the kidneys and lungs. Perhaps because of post-mortem changes in the shape of the spleen, autopsy values have tended to be smaller than the data obtained by ultrasonography. It is thus inappropriate to make comparisons of absolute dimensions across methodologies.
Determinations of Splenic Dimensions
Because of problems in determining the absolute volume of what is an irregularly shaped organ, some authors have simply reported percentage changes in their initial estimate of splenic volume (Table 4).36–38 Others have gauged splenomegaly in terms of length rather than volume or have calculated an arbitrary volumetric “index.”39–41 A wide range of formulae have been proposed to estimate splenic volumes.30,31,33,42–46 Many of these formulae show a close correlation with the weights of resected spleens and can be used to judge changes in the size of an individual's spleen, but it is difficult to compare absolute values between authors.
Normal Dimensions of the Healthy Spleen
Various texts have suggested that at ultrasonography, the normal length of the adult spleen is in the range 12 to 14 cm,47–49 although such estimates have often been based upon small and rather heterogeneous samples. Experimental values are summarized in Table 5.
Rosenberg et al50 proposed age-related upper limits of length increasing from 7 cm at 12 months to 12 cm in girls and 13 cm in boys aged >15 years. Using 3D ultrasonography, De Odorico et al26 estimated that the normal adult spleen had a length of 8.9 cm, a height of 8.6 cm, and a thickness of 4.0 cm, with an estimated ellipsoid volume of 164 mL; these data were said to agree with subsequent measurements on 3 cadavers to within 2%. Zhang and Lewis33 used a radionuclide technique; they not only set an upper limiting volume of 256 mL but also claimed that their estimates differed by only 0.2 ± 6.7% from post-mortem measurements. Other autopsy data defined 2.5% to 97.5% confidence limits of 61–364 mL for a sample of 1266 men and 63 to 310 mL for a sample of 316 women. Such ranges imply an SD of approximately ±68 mL about respective mean values of 213 and 187 mL for men and women.51 The axial CT data of Henderson et al27 imply a similar SD of ±76 mL, but the post-mortem data of Myers and Segal52 show a smaller SD, approximating ±38 mL.
Influence of Body Build
The extent of splenomegaly must often be assessed in children, adolescents and athletes with unusual body builds. In children, splenic dimensions show moderately strong relationships to standing height, body mass, and age, commonly with correlation coefficients of 0.7 to 0.8 (Table 6).
Some observers have reported the modest effects of height in adults, particularly in tall athletes such as basketball players,35,53 but this seems only to be true if the sample includes extreme body types. Others have found correlation coefficients between body size and splenic dimensions were too weak (r < 0.03) to warrant any adjustments of norms.44,54
Relationship to Disease Status
Challenges to the use of laboratory determinations of splenic size as a component in the diagnosis of IM include not only interindividual variation but also methodology-related differences in absolute values, and the wide variety of formulae that have been used to calculate the volume of a complex-shaped organ from its linear dimensions.
Some authors have claimed that in IM, the difference from normal data is large enough to allow a confident diagnosis of splenic enlargement. Thus, Dommerby et al55 claimed that at ultrasonography, all infected individuals showed a splenic enlargement of at least 25%, and 3 days after the first symptoms, spleen lengths and widths were on average 50% to 60% greater than that of in a control group with other throat infections; splenic dimensions progressively returned to normal over 4 weeks, as the IM abated. In contrast, Hosey et al56 found that in 7% of healthy university athletes, the sonographic length and breadth of the spleen were such that these individuals would have been classed as having splenomegaly. Although there was an average 33.6% increase in size of the spleen with infection,57 this was no more than the commonly reported SD of normal values (above). Moreover, the many other possible causes of splenomegaly must be considered in reaching a diagnosis (Table 7).
Peaking of splenomegaly occurs around the 12th day of infection, and a change in dimensions over serial measurements provides a clearer indication of infection. Serial measurements on healthy controls show intraindividual changes in spleen length of <10%.57
Rupture of the Enlarged Spleen
The effects of the disease process upon tissue structures make the enlarged spleen vulnerable to rupture,58 and the regression of splenomegaly is often used in guiding a return to normal athletic activity. Dommerby et al55 suggested that although the initial enlargements of the liver and spleen were unrelated to abnormal hepatic enzyme levels, regression of these 2 indicators occurred in parallel over the course of the following month, as the disease resolved. However, there remain uncertainties about the sensitivity of illness severity and splenic enlargement as measures of the risk of impending splenic rupture.12,59,60
Rupture usually occurs during the first 3 to 4 weeks of infection,12,61 although at least one case was reported 7 weeks after onset of the illness,61 and one recurrent rupture was seen 10 weeks after the first symptoms.62 Most incidents of splenic rupture are concentrated in sports where violent contacts and collisions are commonplace, but damage can also follow a Valsalva manoeuvre,63,64 and in some instances, the injury seems to be “spontaneous.”65 Analysis of a series of 8116 patients with IM documented 5 actual and 4 suspected cases of atraumatic splenic rupture.25 Given the vague nature of symptoms in some cases of IM, the risk of spontaneous rupture remains uncertain, but a prevalence of 0.1% to 0.5% has been suggested for infected athletes.63,66 Evidence of rupture should be sought if the patient begins to complain of acute abdominal pain.67 Free intraperitoneal blood may also irritate the diaphragm, with referral of pain to the shoulder or the scapula.61,68,69 After rupture, radiography, ultrasonography, and/or CT may reveal not only an enlarged spleen but also an accumulation of fluid in the peritoneum and a subcapsular hematoma.61,66
Management of Ruptured Spleen
Early splenectomy was once regarded as the safest option after splenic rupture, but this reflected an overestimation of the associated mortality.6 There are occasional fatalities after a “spontaneous” rupture,69–73 but such incidents are rare12 and do not warrant a hasty splenectomy. Removal of the spleen may compromise subsequent immune responses.74 Moreover, some reports have shown 1% of deaths from an overwhelming meningeal or pneumococcal septicemia at operation,61,75–77 although this risk can be attenuated by the preoperative administration of pneumococcal and other vaccines.78
Many authors now regard conservative treatment as a better option, provided that the condition of the patient is stable and blood transfusion can be limited to <4 units to minimize the risks of transmitting hepatitis and HIV infections.63,79–81 Arguments raised against conservative management include a slower return of the athlete to competition, the risks of repeated blood transfusion, and the danger that the enlarged spleen may still contain hematomas that will cause a second rupture.25,66,68,73,79,82,83
Infectious Mononucleosis and Chronic Fatigue Syndrome
There have been suggestions that vigorous physical activity is both a risk factor for CFS and prolongs its course.84 If IM is indeed related to CFS, this could be a further argument for restricting activity during and immediately after infection.
During the postacute phase of IM, there are often complaints of persistent fatigue, daytime sleepiness and depression,11 and sometimes the characteristics of fatigue match the American Psychological Association criteria for the diagnosis of CFS,108 although the relationships of IM to CFS are inconsistent (Table 8).85–88 One major problem is that CFS seems to be a heterogeneous group of conditions, rather than a single entity.89 Epstein–Barr virus (EBV) is not universally detected in patients with CFS, but type 1 EBV in particular is present in a subset of cases who have previously experienced IM.90,91 Moreover, retrospective studies provide evidence of a prior illness resembling IM in many patients with CFS,92–94 and a prospective study of adolescents with IM found that 6 months later, 13% developed CFS.95,96 It remains unclear whether late complaints of fatigue indicate a lingering infection, as suggested by a continued elevation of proinflammatory cytokines19 or whether the infection triggered what is essentially a psychological disorder.85,97,98
A retrospective comparison of 47 CFS cases with matched controls found a greater number of the patients reporting exercise >3 times per week before onset of the disease (67% vs 40%),84 but the significance of this apparent difference (P < 0.02) was weakened by multiple (18) post hoc intergroup comparisons. In a prospective case–control study of 301 adolescents with IM, pedometer studies have found that CFS is usually associated with reduced levels of physical activity,99–101 but an increase of activity was again associated with an immediate worsening of symptoms.102 However, Huang et al95 found no differences of habitual activity between those who developed late fatigue and those who did not.
We may conclude that a small proportion of cases of IM do progress to CFS. More information is needed on the responses to exercise in such individuals, but as with other forms of CFS, it seems plausible that excessive physical activity may lead to worsening of condition.
Lessons for Overall Management
The general management of the patient with IM is largely symptomatic. There is no evidence of benefit from the routine administration of either corticosteroids103–105 or antiviral medications such as acyclovir.106,107 However, corticosteroids may be indicated if there is severe edematous airway obstruction,12 and antiviral medication may prove helpful in the late treatment of a specific subset of patients with long-term fatigue.108,109
Most patients make an uneventful recovery after a period of modified bed rest, although 5% of patients develop serious complications.110 Penman111 collected reports of some 100 episodes of IM with fatal outcomes, including deaths attributed to neurological complications, respiratory obstruction, myocarditis, and liver failure. For athletes, the most serious issues are usually pharyngitis, splenomegaly with the potential for splenic rupture,61 and a possible progression of continuing fatigue to one variant of CFS in the later phases of the disease. However, the factors triggering a progression to CFS and the nature of this relationship remain controversial.1,87,103
One controlled study of university students noted a slightly faster recovery with ad libitum physical activity,112 and another study involving army cadets found no complications from a return to light training as soon as the patients were afebrile.113 However, vigorous activity is unwise while the virus is active. In addition to issues of splenic rupture and progression to CFS, there is a slight risk of developing myocarditis, with chest pain, electrocardiogram abnormalities, and the release of cardiac troponin.114,115
Decisions on a return to light, noncontact activity and progressive reconditioning after IM are guided by (1) the regression of symptoms, (2) the normalization of splenic size as monitored by serial ultrasonography (although ultrasonography is not always practiced, and the interpretation of data can be difficult with extreme body types),116 and (3) epidemiologic data on the likelihood of splenic rupture at various times after onset of the illness. Rutkow6 somewhat arbitrarily recommended against athletic participation for as long as 6 months after infection. More recently, most authors have opted for only 3 to 4 weeks of rest if the athlete is asymptomatic and ultrasound demonstrates normal splenic dimensions.1,60,83,103,117–120 Nevertheless, there have been occasional episodes of splenic rupture as late as 7 weeks after the onset of infection. Thus, some authors still advise avoiding contact sports and activities demanding the Valsalva maneuver for at least 2 months, and highly trained athletes may take as long as 3 months to regain their previous level of performance.12
Shah and Richards121 suggested that athletes can be protected by a customized spleen guard immediately after infection, and others have advocated wearing a flak jacket,122 although there is as yet no good evidence of protection from such measures.
Infectious mononucleosis is sufficiently prevalent among adolescents and young adults that the condition must be suspected if an athlete presents with fever, swollen glands, a sore throat, and tiredness. Careful assessment is important, as symptoms are nonspecific, and a positive diagnosis of IM will require several months of absence from full competition. Physical examination must be reinforced by laboratory tests, including demonstration of a lymphocytosis with abnormal lymphocytes, a heterophile-positive slide test, and the appearance of specific EBV antigens. Palpation and percussion are ineffective methods of detecting associated splenomegaly. Even with of laboratory data, evaluation must take account of methodology, the formulae used in calculating dimensions, and the individual's body size. Sonographic data usually demonstrate an enlarged spleen during the first few weeks of infection, but dimensions may remain within what is a broad normal range. Splenic dimensions are more useful in following the course of the disease and in advising on the athlete's return to physical activity. The main risks to the athlete are splenic rupture and a progression to CFS. By 3 to 4 weeks after the onset of infection, the risks of injury from contact trauma, a Valsalva maneuver, or spontaneous rupture are sufficiently low to allow a graded return to physical activity. Sudden onset abdominal pain should nevertheless arouse suspicions of a ruptured spleen. Debate continues on the merits of surgical versus conservative treatment of such an incident. Surgical intervention may trigger a dangerous septicemia, and splenectomy is also associated with an ongoing compromise of immune function. These risks must be weighed carefully against the disadvantages of conservative treatment: a longer absence from competition, the need for substantial blood transfusions, and the possibility of a recurrent rupture of the spleen. Discussion continues on the frequency with which IM progresses to a form of CFS and on the possible factors that provoke prolonged fatigue. However, for most athletes, IM offers no more than the inconvenience of 4 weeks of restricted activity with little risk to long-term health.
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