INTRODUCTION
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.
METHODS
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.
;)
TABLE 1: Clinical Manifestations of IM, Based in Part on
Ref. 10Common 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
TABLE 2: Laboratory Evidence of IM
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).
TABLE 3: Sensitivity and Specificity of Clinical Determinations of Splenomegaly
TABLE 4: Methods of Estimating Splenic Dimensions
TABLE 5-a: Estimates of the Normal Dimensions of the Spleen
TABLE 5-b: Estimates of the Normal Dimensions of the Spleen
TABLE 6: Influence of Body Build Upon Splenic Dimensions
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
Methodology
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
Splenomegaly
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).
TABLE 7: Differential Diagnosis of Splenic Enlargement Based in Part on
Ref. 145Peaking 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
TABLE 8: Published Information on Relationship Between IM and CFS
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.
CONCLUSIONS
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.
REFERENCES
1. Auwaerter PG. Infectious mononucleosis: return to play. Clin Sports Med. 2004;23:485–497.
2. Brodsky AL, Heath CW. Infectious mononucleosis; epidemioloic patterns at United States colleges and universities. Am J Epidemiol. 1972;96:87–93.
3. Chang RS, Char DF, Jones JH, et al Incidence of infectious mononucleosis at the Universities of California and Hawaii. J Infect Dis. 1979;140:479–486.
4. Pottgiesser T, Wolfarth B, Schumacher YO, et al Epstein-Barr virus serostatus: no difference despite aberrant patterns in athletes and control group. Med Sci Sports Exerc. 2006;38:1782–1791.
5. Macsween KF, Higgins CD, McAulay KA, et al Infectious mononucleosis in University students in the United Kingdom: evaluation of the clinical features and consequences of the disease. Clin Infect Dis. 2010;50:699–706.
6. Rutkow IM. Rupture of the spleen in infectious mononucleosis; A critical review. Arch Surg. 1970;113:718–720.
7. Rawsthorne GB, Cole TP, Kyle J. Spontaneous rupture of the spleen in infectious mononucleosis. Br J Surg. 1970;57:396–398.
8. Shephard RJ. Responses of the human spleen to exercise. J Sports Sci. 2016;34:929–936.
9. Hoagland RJ. Infectious mononucleosis. Prim Care. 1975;2:295–307.
10. Kinderknecht JJ. Infectious mononucleosis and the spleen. Curr Sports Med Rep. 2002;1:116–120.
11. Lambore S, McSherry J, Kraus AS. Acute and chronic symptoms of mononucleosis. J Fam Pract. 1991;33:33–37.
12. Maki DG, Reich RM. Infectious mononucleosis in the athlete. Diagnosis, complications, and management. Am J Sports Med. 1982;10:62–73.
13. Ebell MH. Epstein-Barr virus infectious mononucleosis. Am Fam Phys. 2004;70:1279–1287.
14. Bell AT, Fortune B. What test is the best for diagnosing infectious mononucleosis? J Fam Pract. 2006;55:799–802.
15. Linderholm M, Boman J, Juto P, et al Comparative evaluation of nine kits for rapid diagnosis of infectious mononucleosis and Epstein-Barr virus specific serology. J Clin Microbiol. 1994;32:259–261.
16. Putukian M, O'Connor FG, Stricker P, et al Mononucleosis and athletic participation: an evcidence-based subject review. Clin J Sports Med. 2008;18:309–315.
17. Robertson P, Beynon S, Whybin R, et al Measurement of EBV-IgG AntiVCA avidity aids the early and reliable diagnosis of primary EBV infection. J Med Virol. 2003;70:617–623.
18. Vetter V, Kreutzer L, Bauer G. Differentiation of primary from secondary anti-EBNA-1-negative cases by determination of avidity of VCA-IgG. Clin Diagn Virol. 1994;2:29–39.
19. Broderick G, Katz BZ, Fletcher MA, et al Cytokine expression profiles of immune imbalance in postmononucleosis chronic fatigue. J Transl Med. 2012;10:191.
20. Rea TD, Russo JE, Kafon W, et al Prospective study of the natural history of infectious mononucleosis caused by Epstein-Barr virus. J Am Board Fam Pract. 2001;14:234–242.
21. Barkun A, Camus M, Meagher T, et al Splenic enlargement and Traube's space: how useful is percussion? Am J Med Sci. 1989;87:562–566.
22. Barkun AN, Camus M, Green L, et al The bedside assessment of splenic enlargement. Am J Med. 1991;91:512–518.
23. Grover SA, Barkun AN, Sackett DL. The rational clinical examination. Does this patient have
splenomegaly? JAMA. 1993;270:2218–2221.
24. Tamayo SG, Rickman LS, Mathews WC, et al Examiner dependence on physical diagnostic tests for the detection of
splenomegaly: a prospective study with multiple observers. J Gen Int Med. 1993;8:69–75.
25. Farley DR, Zietlow SP, Bannon MP, et al Spontaneous rupture of the spleen due to infectious mononucleosis. Mayo Clin Proc. 1992;67:846–853.
26. De Odorico I, Spaulding KA, Pretorius DH, et al Normal splenic volumes estimated using three-dimensional ultrasonography. J Ultrasound Med. 1999;18:231–236.
27. Henderson JM, Heymsfield SB, Horowitz J, et al Measurement of liver and spleen volume by computed tomography. Assessment of reproducibility and changes found following a selective distal splenorenal shunt. Radiology. 1981;141:525–527.
28. Prassopoulos P, Cavouras D. CT assessment of Normal splenic size in children. Acta Radiol. 1994;35:152–154.
29. Strauss LG, Clorius JH, Frank T, et al Single photon emission computerized tomography (SPECT) for estimates of liver and spleen volume. J Nucl Med. 1984;25:81–85.
30. Yetter EM, Acosta KB, Olson MC, et al Estimating splenic volume: sonographic measurements correlated with helical CT determination. Am J Radiol. 2003;181:1615–1620.
31. Silverman S, DeNardo GL, Siegel E. Determination of spleen size by scintigraphy. Cancer Biother Radiopharm. 1999;14:407–411.
32. Markisz JA, Treves ST, Davis RT. Normal hepatic and splenic size in children: scintigraphic determination. Pediatr Radiol. 1987;17:273–276.
33. Zhang B, Lewis SM. Use of radionuclide scanning to estimatesize of spleen in vivo. J Clin Pathol. 1987;40:508–511.
34. Blendis LM, Williams R, Kreel L. Radiological determination of spleen size. Gut. 1969;10:433–435.
35. Sprogøe-Jakobsen S, Sprogøe-Jakobsen U. The weight of the Normal spleen. Forensic Sci Int. 1997;88:215–223.
36. Allsop P, Peters AM, Arnot RN, et al Intrasplenic blood cell kinetics in man before and after brief maximal exercise. Clin Sci (Lond). 1992;93:47–54.
37. Laub M, Hvid-Jacobsen K, Hovind P, et al Spleen emptying and venous hematocrit in humans during exercise. J Appl Physiol. 1993;74:1024–1026.
38. Wolski LA. The Impact of Splenic Release of Red Cells on Hematocrit Changes During Exercise [PhD, Dissertation]. Vancouver, BC: School of Human Kinetics, University of British Columbia; 1998.
39. Pietri H, Boscaini M. Determination of a splenic volumetric Index by ultrasonic scanning. J Ultrasound Med. 1984;3:19–23.
40. Rodrigues AJ, Rodrigues CJ, Germano MA, et al Sonographic estimate of normal spleen volume. Clin Anat. 1995;8:252–255.
41. Ishibashi H, Higuchi N, Shimamura R, et al Sonographic assessment of spleen size. J Clin Ultrasound. 1991;19:21–25.
42. Downey MT. Estimation of splenic weight from ultrasonographic measurements. Can Assoc Radiol J. 1992;43:273–277.
43. Larson SM, Tuell SH, Moores KD, et al Dimensions of the normal adult spleen and prediction of spleen weight. J Nucl Med. 1971;12:123–126.
44. Prassopoulos P, Daskalogiannaki M, Raissaki M, et al Determination of normal splenic volume on computed tomography in relation to age, gender and body habitus. Eur Radiol. 1997;7:246–248.
45. Samuels LD. Estimation of spleen size from posterior spleen scans. J Can Assoc Radiol. 1969;20:192–198.
46. Spencer RP. Relationship of surface area on roentgenograms and radioisotopic scans to organ volumes. J Nucl Med. 1967;8:785–791.
47. Ayers AB. The spleen. In: Grainger RG, Allison DJ, eds. Diagnostic Radiology: An Anglo-American Textbook of Imaging. Edinburgh, Scotland: Churchill Livingstone; 1992:2403.
48. Meire H, Farrant P. The liver. In: Baxter GM, Allan PLP, Morley P, eds. Clinical Diagnostic Ultrasound. Oxford, United Kingdom: Blackwell Science; 1999:379–380.
49. Fried AM. Retroperitoneum, pancreas, spleen, and lymph nodes. In: McGahan JP, Goldberg BB, eds. Diagnostic Ultrasound: A Logical Approach. Philadelphia, PA: Lippincott-Raven; 1998:777.
50. Rosenberg HK, Markowitz RI, Kolberg H, et al Normal splenic size in infants and children: sonographic measurements. Am J Radiol. 1991;157:119–121.
51. Boyd E. Normal variability in weight of the adult human liver and spleen. Arch Pathol. 1933;16:350–372.
52. Myers J, Segal RJ. Weight of the spleen. I. Range of Normal in a non-hospital population. Arch Pathol. 1974;98:33–35.
53. Spielmann AL, DeLong DM, Kliwer MA. Sonographic evaluation of spleen size in tall, healthy athletes. Am J Radiol. 2004;184:45–49.
54. Niederau C, Sonnenberg A, Muller J, et al Sonographic measurements of the normal liver, spleen, pancreas, and portal vein. Radiology. 1983;149:537–540.
55. Dommerby H, Stangerup SE, Stangerup M, et al Hepatosplenomegaly in infectious mononucleosis, assessed by ultrasound scanning. J Laryngol Otol. 1986;100:573–579.
56. Hosey RG, Mattacola CG, Kriss V, et al Ultrasound assessment of spleen size in collegiate athletes. Br J Sports Med. 2006;40:251–254.
57. Hosey RG, Kriss V, Uhl TL, et al Ultrasonographic evaluation of splenic enlargement in athletes with acute infectious mononucleosis. Br J Sports Med. 2008;42:974–977.
58. Daneshbod K, Liao KT. Hyaline degeneration of splenic follicular arteries in infectious mononucleosis: histochemical and electron microscope studies. Am J Clin Pathol. 1973;59:473–479.
59. Brolinson PG, McGinley S. Autoimmune hepatitis and
splenomegaly: commentary. Clin J Sports Med. 2008;18:96.
60. Waninger KN, Harcke HT. Determination of safe return to play for athletes recovering from infectious mononucleosis. A review of the literature. Clin J Sports Med. 2005;15:410–416.
61. Johnson MA, Cooperberg PL, Boisvert J, et al Spontaneous
splenic rupture in infectious mononucleosis: sonographic diagnosis and follow-up. AJR Am J Roentgenol. 1981;136:111–114.
62. McLean ER, Diehl W, Edoga JK, et al Failure of conservative management of
splenic rupture in a patient with mononucleosis. J Pediatr Surg. 1987;22:1034–1035.
63. Asgari MM, Begos DG. Spontaneous
splenic rupture in infectious mononucleosis: a review. Yale J Biol Med. 1997;70:175–182.
64. Sakulsky SB, Wallace RB, Silverstein MN, et al Ruptured spleen in infectious mononucleosis. Arch Surg. 1967;94:349–352.
65. King RB. Spontaneous rupture of the spleen in infectious mononucleosis. N Engl J Med. 1941;224:1056–1060.
66. Khoo SG, Ullah I, Manning KP, et al Spontaneous
splenic rupture in infectious mononucleosis. Ear Nose Throat J. 2007;86:300–301.
67. Rotolo JE. Spontaneous
splenic rupture in infectious mononucleosis. Am J Emerg Med. 1987;5:383–385.
68. Safran D, Bloom GP. Spontaneous
splenic rupture following infectious mononucleosis. Am Surg. 1990;56:601–605.
69. Alberty R. Surgical implications of infectious mononucleosis. Am J Surg. 1981;141:559–561.
70. Bell JS, Mason JM. Sudden death due to spomntaneous rupture of the spleen from infectious mononucleosis. J Forensic Sci. 1980;25:20–24.
71. Papadakis M. Infectious mononucleosis. West J Med. 1982;137:141–144.
72. Ali J. Spontaneous rupture of the spleen in patients with infectious mononucleosis. Can J Surg. 1993;36:49–52.
73. Jones TJ, Pugsley WG, Grace RH. Fatal spontaneous rupture of the spleen in asymptomatic infectious mononucleosis. J R Coll Surg Edinb. 1985;30:398.
74. Schumacher MJ. Serum immunoglobulin and transferrin levels after childhood splenectomy. Arch Dis Child. 1970;45:114–117.
75. DiCataldo A, Puleo S, Li Destri G, et al Splenic trauma and overwhelming postsplenectomy infection. Br J Surg. 1987;74:343–345.
76. Eln SH, Shandling B, Simpson JS, et al Nonoperative management of traumatic spleen in children: how and why. J Pediatr Surg. 1978;13:117–119.
77. Fleming WR. Spontaneous
splenic rupture in infectious mononucleosis. Aust NZ J Surg. 1991;61:389–390.
78. Stockinger ZT. Infectious mononucleosis presenting as spontaneous
splenic rupture without other symptoms. Mil Med. 2003;168:722–724.
79. Guth AA, Pachter HL, Jacobowietz GR. Rupture of the pathologic spleen: is there a role for nonoperative therapy? J Trauma. 1996;41:214–218.
80. Schuler JG, Filtzer H. Spontaneous
splenic rupture. The role of nonoperative management. Arch Surg. 1995;130:662–665.
81. Toorenvliet BR, Kortekaas RT, Niggebrigge AH. Conservatieve behandeling van een spontane miltruptuur bij een patiënt met de ziekte van Pfeiffer. Conservative treatment of a spontaneous
splenic rupture in a patient with infectious mononucleosis [in Dutch]. Ned Tijdschr Geneeskd. 2002;146:1696–1698.
82. Longo WE, Baker CC, McMillen MA, et al Nonoperative management of adult Blunt splenic trauma: criteria for successful outcome. Ann Surg. 1989;210:626–629.
83. Oski FA. Management of a football player with mononucleosis. Pediatr Infect Dis J. 1994;13:938–939.
84. MacDonald KL, Osterholm MT, LeDell KH, et al A case-control study to assess possible triggers and cofactors in
chronic fatigue syndrome. Am J Med. 1996;100:548–554.
85. Moss-Morris R, Spence MJ, Hou R. The pathway from glandular fever to
chronic fatigue syndrome: can the cognitive behavioural model provide the map? Psychol Med. 2011;41:1099–1107.
86. Fukuda K, Strauss SE, Hickle I, et al The
Chronic Fatigue Syndrome: a comprehensive approach to its definition and study. Ann Intern Med. 1994;121:953–959.
87. Shephard RJ.
Chronic fatigue syndrome: an up-date. Sports Med. 2001;31:167–194.
88. Sumaya CV. Serologic and virologic epidemiology of Epstein-Barr virus: relevance to chronic fatigue sydrome. Rev Infect Dis. 1991;13(suppl 1):S19–S25.
89. Vollmwer-Conna U.
Chronic fatigue syndrome in adolescence. Where to from here? Arch Pediatr Adolesc Med. 2010;164:880–881.
90. Crawford DH, Macsween KF, Higgins CD, et al A cohort study among University students: identification of risk factors for Epstein-Barr virus seroconversion and infectious mononucleosis. Clin Infect Dis. 2006;43:276–282.
91. Lerner AM, Begal SH, Deeter RG, et al IgM serum antibodies to Epstein-Barr virus are uniquely present in a subset of patients with the
chronic fatigue syndrome. In Vivo. 2004;18:101–106.
92. Feder HM, Dworkin PH, Orkin C. Outcome of 48 pediatric patients with chronic fatigue. A clinical experience. Arch Fam Med. 1994;3:1049–1055.
93. Krilov LR, Fisher M, Friedman SB, et al Course and outcome of chronic fatigue in children and adolescents. Pediatrics. 1998;102:360–366.
94. Smith MS, Mitchell J, Corey L, et al Chronic fatigue in adolescents. Pediatrics. 1991;88:195–202.
95. Huang Y, Katz BZ, Mears C, et al Post-infectious fatigue in adolescents: the role of physical activity. Arch Pediatr Adolesc Med. 2010;164:803–809.
96. Katz BZ, Shiraishi Y, Mears CJ, et al
Chronic fatigue syndrome after infectious mononucleosis in adolescents. Pediatrics. 2009;124:189–193.
97. Katz BZ, Jason LA.
Chronic fatigue syndrome following infections in adolescents. Curr Opin Pediatr. 2013;25:95–102.
98. Carter BD, Edwards JF, Kronenberger WG, et al Case control study of chronic fatigue in pediatric patients. Pediatrics. 1995;95:179–186.
99. Van der Werf SP, Prins JB, Vercoulen JH, et al Identifying physical activity patterns in
chronic fatigue syndrome using actigraphic assessment. J Psychosom Res. 2000;49:373–379.
100. Vercoulen JH, Bazelmans E, Swanink CM, et al Physical activity in
chronic fatigue syndrome: assessment and its role in fatigue. J Psychiatr Res. 1997;11:661–673.
101. Evering RMH, Tönis TM, Vollenbroek-Hutten MMR. Deviations in daily physical activity patterns in patients with the
chronic fatigue syndrome: a case control study. J Psychosom Res. 2011;71:129–135.
102. Meeus M, van Eupen I, van Baarle E, et al Symptom fluctuations and daily physical activity in patients with
chronic fatigue syndrome: a case-control study. Arch Phys Med Rehabil. 2011;52:1820–1826.
103. Becker JA, Smith JA. Return to play after infectious mononucleosis. Sports Health. 2014;6:232–238.
104. Candy B, Hotop M. Steroids for symptom control in infectious mononucleosis. Cochrane Database, Syst Rev. 2006;19:CD004402.
105. Tynell E, Aurelius E, Brandell A, et al Acyclovir and prednisolon treatment of acute infectious mononucleosis: a multicenter, double-blind, placebo-controlled study. J Infect Dis. 1996;174:324–331.
106. van der Horst C, Joncas J, Ahronheim G. Lack of effect of peroral acyclovir for the treatment of acute infectious mononucleosis. J Infect Dis. 1991;164:788–792.
107. Jenson HB. Virologic diagnosis, viral monitoring, and treatment of Epstein-Barr virus infectious mononucleosis. Curr Infect Dis Rep. 2004;6:200–207.
108. Lerner AM, Begal SH, Deeter RG, et al Valacyclovir treatment in Epstein-Barr virus subset
chronic fatigue syndrome: thirty-six months follow-up. In Vivo. 2007;21:707–714.
109. Watt T, Oberfoell S, Balise R, et al Response to Valganciclovir in
chronic fatigue syndrome patients with human herpesvirus 6 and Epstein-Barr virus IgG antibody titers. J Med Virol. 2012;84:1967–1974.
110. Murray BJ. Medical complications of infectious mononucleosis. Am Fam Phys. 1984;30:195–199.
111. Penman HG. Fatal infectious mononucleosis a critical review. J Clin Pathol. 1970;23:765–771.
112. Dalrymple W. Infectious mononucleosis-2, relation of bedrest and activity to prognosis. Postgrad Med J. 1964;35:345–349.
113. Welch MJ, Wheeler L. Aerobic capacity after contracting infectious mononucleosis. J Orthop Sports Phys Ther. 1986;8:199–202.
114. Fraisse A, Paut O, Zandotti C, et al Le virus d'Epstein-Barr. Une cause inhabituelle de myocardite aiguë sévere chez l'enfant. Epstein-Barr virus. an unusual cause of severe acute viral myocarditis in children [in French]. Archiv Pédiatr. 2000;7:752–755.
115. Zabala Lopéz S, Vicario JM, Lerin FJ, et al Epstein-Barr myocarditis as the first symptom of infectious mononucleosis. Intern Med. 2010;49:569–571.
116. O'Connor TE, Skinner LJ, Kiely P, et al Return to contact sports following infectious mononucleosis: the role of serial ultrasonography. Ear Nose Throat J. 2011;90:E21–E24.
117. Bailey DM, Davies B, Budgett R, et al Recovery from infectious mononucleosis after altitude training in an elite middle distance runner. Br J Sports Med. 1997;31:153–154.
118. Berezin SW. Management of a football player with infectious mononucleosis. Pediat Infect Dis J. 1994;13:938–939.
119. Hosey RG, Rodenberg RE. Training room management of medical conditions: infectious diseases. Clin Sports Med. 2005;24:477–506.
120. Sevier TL. Infectious disease in athletes. Med Clin North Am. 1994;78:389–412.
121. Shah N, Richards D. Facilitating sport participation with a customized spleen guard: a case of a basketball player with
splenomegaly. Clin J Sports Med. 2008;18:92–95.
122. Jong MD, Bytomski J. Idiopathic
splenomegaly and return to play—men's soccer. Med Sci Sports Exerc. 2005;37(suppl):279–280.
123. Aronson MD, Komaroff AL, Pass TM, et al Heterophil antibody in adults with sore throat. Frequency and clinical presentation. Ann Intern Med. 1982;96:505–508.
124. Brigden ML, Au S, Thompson S, et al Infectious mononucleosis in an outpatient population: diagnostic utility of 2 automated hematology analyzers and the sensitivity and specificity of Hoagland's criteria in heterophile-positive patients. Arch Pathol Lab Med. 1999;123:875–881.
125. Bruu AL, Hjetland R, Holter E, et al Evaluation of 12 commercial tests for detection of Epstein-Barr virus-specific and heterophilic antibodies. Clin Diagn Lab Immunol. 2000;7:451–456.
126. Elgh F, Linderholm M. Evaluation of six commercially available kits using purified heterophile antigen for the rapid diagnosis of infectious mononucleosis compared with Epstein-Barr virus-specific serology. Clin Diagn Virol. 1996;7:17–21.
127. Pitetti R, Laus S, Wadowsky R. Clinical evaluation of a quantitative real time polymerase chain reaction assay for diagnosis of primary Epstein-Barr virus infection in children. Pediatr Infect Dis J. 2003;22:736–739.
128. Mason WR, Adams EK. Infectious mononucleosis: an analysis of 100 cases with particular attention to diagnosis, liver function tests and treatment of selected cases with prednisone. Am J Med Sci. 1958;236:447–459.
129. Halpern D, Copel M, Ashburn W, et al Correlation of liver and spleen size. Determinations by nuclear medicine studies and physical examination. Arch Int Med. 1974;134:123–124.
130. Ingeberg S, Støckel M, Sørensen PJ. Prediction of spleen size by routine radioisotope scintigraphy. Acta Haematol. 1983;69:243–248.
131. Riemenschneider PA, Whalen JP. The relative accuracy of estimation of enlargement of the liver and spleen by radiologic and clinical methods. Am J Roentgenol Rad Ther Nucl Med. 1965;94:462–468.
132. Sullivan S, Williams R. Reliability of clinical techniques for detecting splenic enlargement. Br Med J. 1976;2:1043–1044.
133. Westin J, Lanner SO, Larsson A, et al Spleen size in polycythemia: a clinical and scintigraphic study. Acta Med Scand. 1972;191:263–271.
134. Samuels LD, Stewart C. Estimation of spleen size in sickle cell anemia. J Nucl Med. 1970;11:12–14.
135. Leland FH. Normal spleen size. Radiology. 1970;97:589–592.
136. Frank K, Linhart P, Kortsik C, et al Sonographische Milzgrößenbestimmung: Normalmaße beim milzgesunden Erwachsenen [Sonographic determination of spleen size: normal dimensions in adults with a healthy spleen [in German]. Uktraschall Med. 1986;7:134–137.
137. Garby L, Lammert O, Kock KF, et al Weights of brain, heart, liver, kidneys and spleen in healthy and apparently healthy adult Danish subjects. Am J Hum Biol. 1993;5:291–296.
138. Hoefs JC, Wang FW, Lillen DL, et al A novel, simple method of functional spleen volume calculation by liver-spleen scan. J Nucl Med. 1999;40:1745–1755.
139. Krumbhaar EB, Lippencott SW. The postmortem weight of the “Normal” spleen at different ages. Am J Med Sci. 1939;197:344–358.
140. Loftus WK, Chow LTC, Metreweli C. Sonographic measurement of splenic length; correlation with measurement at autopsy. J Clin Ultrasound. 1999;27:71–74.
141. McCorkle R, Thomas B, Suffaletto H, et al Normative spleen size in tall healthy athletes: implications for safe return to contact sports after infectious mononucleosis. Clin J Sports Med. 2010;20:413–415.
142. Megremis SD, Vlachonikolos IG, Tsimigaki AM. Spleen length in childhood with US: normal values based on age, sex and somatometric parameters. Radiology. 2004;231:129–134.
143. Dittrich M, Milde S, Dinkel E, et al Sonographic biometry of liver and spleen size in childhood. Pediatr Radiol. 1983;13:206–211.
144. Konuṣ ÖL, Ozdemir A, Akkaya A, et al Normal liver, spleen, and kidney dimensions in neonates, infants and children: evaluation with sonography. Am J Radiol. 1998;171:1693–1698.
145. Turner J, Garg M.
Splenomegaly and sports. Curr Sports Med Rep. 2008;7:113–116.
146. Buchwald DS, Rea TD, Katon WJ, et al Acute infectious mononucleosis: characrteristics of patients who report failure to recover. Am J Med Sci. 2000;109:531–537.
147. Candy B, Chalder T, Cleare AJ, et al Predictors of fatigue following the onset of infectious mononucleosis. Psychol Med. 2003;33:847–855.
148. Hickie I, Davenport T, Wakefield D, et al Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ. 2006;333:575.
149. Marshall GS, Gesser RM, Yamanishi K, et al Chronic fatigue in children: clinical features, Epstein Barr virus and human herpesvirus 6 serology and long term follow-up. Pediatr Infect Dis J. 1991;10:287–290.
150. White PD, Thomas JM, Kangro HO, et al Predictions and associations of fatigue syndromes and mood disorders that occur after infectious mononucleosis. Lancet. 2001;358:1946–1954.
