Brett H. Foreman, MD

Evidence summary

The annual incidence of infectious mononucleosis is somewhere between 345 and 671 cases per 100,000 in the US; it is highest in the adolescent age group.¹ Splenic rupture is the leading cause of death in infectious mononucleosis, occurring in 0.1% to 0.2% of all cases.^{1- 4} Based on this figure, approximately 100 cases of rupture may occur yearly in the US, only a few of which are reported.

A retrospective analysis of 8116 patients with infectious mononucleosis at the Mayo Clinic estimated the risk of spontaneous splenic rupture to be 0.1% of cases, correlating with rates found in other studies. The study’s criteria for definite spontaneous rupture are: no recent trauma; recent symptoms; hematologic, serologic, and histologic (splenic) evidence of infectious mononucleosis. Five patients with rupture (average age, 22) were identified; 3 were male. Splenectomy was performed for all patients. Follow-up over 33-years found all patients healthy with minimal subsequent illness.³

A review of 55 cases found almost all splenic ruptures occurred between the fourth and twenty-first days of illness, and that all affected spleens were enlarged, although only half were palpable on exam. Ninety percent of the ruptures occurred in males, and more than half were nontraumatic. There was no correlation between severity of illness and susceptibility to splenic rupture. No specifics were given on duration of illness or how splenomegaly was diagnosed.⁴

The best technique for identifying splenic enlargement and determining risk of rupture is unclear. In a case-control study, 29 patients were admitted to an ear, nose, and throat department with infectious mononucleosis and were evaluated serially for splenic and hepatic enlargement by ultrasound. Diagnosis was based on clinical picture, a positive heterophile test, and other blood tests. Four patients were included despite negative serology due to compelling clinical presentations and symptoms. Serial ultrasound imaging showed that all had enlarged spleens (mean enlargement 50%–60%); 50% had hepatic enlargement (5%–20% enlargement). The patients were compared with a control group of 8 patients admitted with peritonsillar abscess, as verified by tonsillectomy. No controls had hepatic or splenic enlargement. Physical examinations detected splenomegaly in only 17% of the study patients. The exams were conducted by house staff without blinding, randomization, or tests of reproducibility. Ultrasound scanning was completed on days 1, 3, 5, 10, 20, 90, and 120. The spleen was significantly larger in the infectious mononucleosis group than in the control group for the first 30 days, and no difference in size was found over the subsequent 3 months. No correlation existed between laboratory values and enlargement of the spleen or liver.⁵

No quality studies evaluate the risks of physical activity in infectious mononucleosis. Case reports of rupture have found comparable rates between traumatic and nontraumatic causes. In addition, no clinical trials evaluate imaging in decisions regarding return to activity and its effect on splenic rupture. Ultrasound is often used in the athletic setting for these decisions but no evidence supports its use as routine practice. The routine use of ultrasound for this purpose would cost more than $1 million to prevent 1 traumatic rupture.⁶

Recommendations from others

Clinical Sports Medicine recommends athletes refrain from sporting activities until all acute symptoms resolve and contact sports avoided while the spleen is enlarged. No recommendation is given on determining spleen size.⁷

Team Physician Handbook recommends athletes do no cardiovascular work, lifting, strength training, or contact sports for 2 weeks because of the risk of splenic rupture. Activity is then gradually increased as the athlete improves. Athletes are to avoid contact or weight-lifting for 4 weeks unless they feel well and ultrasound reveals a normal-sized spleen.⁸

Sports Medicine Secrets advises ultrasound or CT of the spleen to be obtained if there is any suspicion of splenomegaly or if return to play before 4 weeks is contemplated. Light athletic activity may be resumed approximately 3 weeks after symptom onset if the spleen is not tender or enlarged on examination, the patient is afebrile, liver enzymes are normal, and all other complications are resolved. Contact sports may be resumed 4 weeks after symptom onset if there is no documentation of splenomegaly, the athlete feels ready, and all other complications have resolved.⁹

Evidence summary

The annual incidence of infectious mononucleosis is somewhere between 345 and 671 cases per 100,000 in the US; it is highest in the adolescent age group.¹ Splenic rupture is the leading cause of death in infectious mononucleosis, occurring in 0.1% to 0.2% of all cases.^{1- 4} Based on this figure, approximately 100 cases of rupture may occur yearly in the US, only a few of which are reported.

A retrospective analysis of 8116 patients with infectious mononucleosis at the Mayo Clinic estimated the risk of spontaneous splenic rupture to be 0.1% of cases, correlating with rates found in other studies. The study’s criteria for definite spontaneous rupture are: no recent trauma; recent symptoms; hematologic, serologic, and histologic (splenic) evidence of infectious mononucleosis. Five patients with rupture (average age, 22) were identified; 3 were male. Splenectomy was performed for all patients. Follow-up over 33-years found all patients healthy with minimal subsequent illness.³

A review of 55 cases found almost all splenic ruptures occurred between the fourth and twenty-first days of illness, and that all affected spleens were enlarged, although only half were palpable on exam. Ninety percent of the ruptures occurred in males, and more than half were nontraumatic. There was no correlation between severity of illness and susceptibility to splenic rupture. No specifics were given on duration of illness or how splenomegaly was diagnosed.⁴

The best technique for identifying splenic enlargement and determining risk of rupture is unclear. In a case-control study, 29 patients were admitted to an ear, nose, and throat department with infectious mononucleosis and were evaluated serially for splenic and hepatic enlargement by ultrasound. Diagnosis was based on clinical picture, a positive heterophile test, and other blood tests. Four patients were included despite negative serology due to compelling clinical presentations and symptoms. Serial ultrasound imaging showed that all had enlarged spleens (mean enlargement 50%–60%); 50% had hepatic enlargement (5%–20% enlargement). The patients were compared with a control group of 8 patients admitted with peritonsillar abscess, as verified by tonsillectomy. No controls had hepatic or splenic enlargement. Physical examinations detected splenomegaly in only 17% of the study patients. The exams were conducted by house staff without blinding, randomization, or tests of reproducibility. Ultrasound scanning was completed on days 1, 3, 5, 10, 20, 90, and 120. The spleen was significantly larger in the infectious mononucleosis group than in the control group for the first 30 days, and no difference in size was found over the subsequent 3 months. No correlation existed between laboratory values and enlargement of the spleen or liver.⁵

No quality studies evaluate the risks of physical activity in infectious mononucleosis. Case reports of rupture have found comparable rates between traumatic and nontraumatic causes. In addition, no clinical trials evaluate imaging in decisions regarding return to activity and its effect on splenic rupture. Ultrasound is often used in the athletic setting for these decisions but no evidence supports its use as routine practice. The routine use of ultrasound for this purpose would cost more than $1 million to prevent 1 traumatic rupture.⁶

Recommendations from others

Clinical Sports Medicine recommends athletes refrain from sporting activities until all acute symptoms resolve and contact sports avoided while the spleen is enlarged. No recommendation is given on determining spleen size.⁷

Team Physician Handbook recommends athletes do no cardiovascular work, lifting, strength training, or contact sports for 2 weeks because of the risk of splenic rupture. Activity is then gradually increased as the athlete improves. Athletes are to avoid contact or weight-lifting for 4 weeks unless they feel well and ultrasound reveals a normal-sized spleen.⁸

Sports Medicine Secrets advises ultrasound or CT of the spleen to be obtained if there is any suspicion of splenomegaly or if return to play before 4 weeks is contemplated. Light athletic activity may be resumed approximately 3 weeks after symptom onset if the spleen is not tender or enlarged on examination, the patient is afebrile, liver enzymes are normal, and all other complications are resolved. Contact sports may be resumed 4 weeks after symptom onset if there is no documentation of splenomegaly, the athlete feels ready, and all other complications have resolved.⁹

Evidence summary

The annual incidence of infectious mononucleosis is somewhere between 345 and 671 cases per 100,000 in the US; it is highest in the adolescent age group.¹ Splenic rupture is the leading cause of death in infectious mononucleosis, occurring in 0.1% to 0.2% of all cases.^{1- 4} Based on this figure, approximately 100 cases of rupture may occur yearly in the US, only a few of which are reported.

A retrospective analysis of 8116 patients with infectious mononucleosis at the Mayo Clinic estimated the risk of spontaneous splenic rupture to be 0.1% of cases, correlating with rates found in other studies. The study’s criteria for definite spontaneous rupture are: no recent trauma; recent symptoms; hematologic, serologic, and histologic (splenic) evidence of infectious mononucleosis. Five patients with rupture (average age, 22) were identified; 3 were male. Splenectomy was performed for all patients. Follow-up over 33-years found all patients healthy with minimal subsequent illness.³

A review of 55 cases found almost all splenic ruptures occurred between the fourth and twenty-first days of illness, and that all affected spleens were enlarged, although only half were palpable on exam. Ninety percent of the ruptures occurred in males, and more than half were nontraumatic. There was no correlation between severity of illness and susceptibility to splenic rupture. No specifics were given on duration of illness or how splenomegaly was diagnosed.⁴

The best technique for identifying splenic enlargement and determining risk of rupture is unclear. In a case-control study, 29 patients were admitted to an ear, nose, and throat department with infectious mononucleosis and were evaluated serially for splenic and hepatic enlargement by ultrasound. Diagnosis was based on clinical picture, a positive heterophile test, and other blood tests. Four patients were included despite negative serology due to compelling clinical presentations and symptoms. Serial ultrasound imaging showed that all had enlarged spleens (mean enlargement 50%–60%); 50% had hepatic enlargement (5%–20% enlargement). The patients were compared with a control group of 8 patients admitted with peritonsillar abscess, as verified by tonsillectomy. No controls had hepatic or splenic enlargement. Physical examinations detected splenomegaly in only 17% of the study patients. The exams were conducted by house staff without blinding, randomization, or tests of reproducibility. Ultrasound scanning was completed on days 1, 3, 5, 10, 20, 90, and 120. The spleen was significantly larger in the infectious mononucleosis group than in the control group for the first 30 days, and no difference in size was found over the subsequent 3 months. No correlation existed between laboratory values and enlargement of the spleen or liver.⁵

No quality studies evaluate the risks of physical activity in infectious mononucleosis. Case reports of rupture have found comparable rates between traumatic and nontraumatic causes. In addition, no clinical trials evaluate imaging in decisions regarding return to activity and its effect on splenic rupture. Ultrasound is often used in the athletic setting for these decisions but no evidence supports its use as routine practice. The routine use of ultrasound for this purpose would cost more than $1 million to prevent 1 traumatic rupture.⁶

Recommendations from others

Clinical Sports Medicine recommends athletes refrain from sporting activities until all acute symptoms resolve and contact sports avoided while the spleen is enlarged. No recommendation is given on determining spleen size.⁷

Team Physician Handbook recommends athletes do no cardiovascular work, lifting, strength training, or contact sports for 2 weeks because of the risk of splenic rupture. Activity is then gradually increased as the athlete improves. Athletes are to avoid contact or weight-lifting for 4 weeks unless they feel well and ultrasound reveals a normal-sized spleen.⁸

Sports Medicine Secrets advises ultrasound or CT of the spleen to be obtained if there is any suspicion of splenomegaly or if return to play before 4 weeks is contemplated. Light athletic activity may be resumed approximately 3 weeks after symptom onset if the spleen is not tender or enlarged on examination, the patient is afebrile, liver enzymes are normal, and all other complications are resolved. Contact sports may be resumed 4 weeks after symptom onset if there is no documentation of splenomegaly, the athlete feels ready, and all other complications have resolved.⁹

Evidence summary

The RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan) study¹ —a multicenter, randomized, double-blind, placebo-controlled trial—followed 1513 patients with type 2 diabetes and nephropathy over a mean of 3.4 years. Patients were randomized to receive losartan (Cozaar) or placebo, both taken in addition to conventional anti-hypertensive therapy (but not including renin-angiotensin-aldosterone system antagonist medications). The primary outcome was a composite of a doubling of serum creatinine, end-stage renal disease, or death. The number needed to treat (NNT) for the composite outcome was 34. The NNT for a doubling of the serum creatinine was 25, and for end-stage renal disease was 17.

The 2-year IRMA (Irbesartan Microalbuminuria) study,² a multicenter, randomized, double-blind, placebo-controlled trial, randomized 590 patients with type 2 diabetes, hypertension, and persistent microalbuminuria to receive 150 or 300 mg of irbesartan (Avapro) or placebo. Additional antihypertensive agents were allowed in each arm with the exception of ACE inhibitors, ARBs, and dihydropyridine calcium-channel blockers. The primary outcome was the development of overt nephropathy defined by a urinary albumin excretion rate >200 μg/min that is at least 30% higher than the baseline rate. This trial showed that irbesartan delayed progression to nephropathy independent of its effect on blood pressure compared with conventional therapy (NNT=16 at the 150-mg dose and NNT=11 at the 300-mg dose).

A third double-blind, placebo-controlled trial—IDNT (Irbesartan Diabetic Nephropathy Trial³ —randomized 1715 patients to irbesartan, amlodipine (Norvasc), or placebo for a median follow-up of 2.6 years. Each group could also use other conventional antihypertensive therapy (but again excluding ACE inhibitors, ARBs, and calcium-channel blockers). Irbesartan reduced progression of nephropathy (defined by doubling of the serum creatinine) and the onset of end-stage renal disease more effectively than amlodipine (NNT=12) or placebo (NNT=16). Irbesartan did not decrease cardiovascular mortality, nonfatal myocardial infarction, heart failure resulting in hospitalization, neurologic deficit caused by a cerebrovascular event, or above-ankle lower-limb amputation.

The mortality benefit with ARBs has not been as consistent as that shown with ACE inhibitors. Both classes of drugs conferred reduced mortality as seen with ramipril in the HOPE (Heart Outcomes Prevention Evaluation) trial⁴ and losartan in the LIFE (Losartan Intervention For Life) trial.⁵ However, a survival benefit was not seen with irbesartan in the RENAAL and IDNT trials.

Recommendation from others

The American Diabetes Association recommends both ACE inhibitors and ARBs for the treatment of early nephropathy in hypertension to delay the progression of microalbuminuria to macroalbuminuria and overt nephropathy.⁶

Evidence summary

The RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan) study¹ —a multicenter, randomized, double-blind, placebo-controlled trial—followed 1513 patients with type 2 diabetes and nephropathy over a mean of 3.4 years. Patients were randomized to receive losartan (Cozaar) or placebo, both taken in addition to conventional anti-hypertensive therapy (but not including renin-angiotensin-aldosterone system antagonist medications). The primary outcome was a composite of a doubling of serum creatinine, end-stage renal disease, or death. The number needed to treat (NNT) for the composite outcome was 34. The NNT for a doubling of the serum creatinine was 25, and for end-stage renal disease was 17.

The 2-year IRMA (Irbesartan Microalbuminuria) study,² a multicenter, randomized, double-blind, placebo-controlled trial, randomized 590 patients with type 2 diabetes, hypertension, and persistent microalbuminuria to receive 150 or 300 mg of irbesartan (Avapro) or placebo. Additional antihypertensive agents were allowed in each arm with the exception of ACE inhibitors, ARBs, and dihydropyridine calcium-channel blockers. The primary outcome was the development of overt nephropathy defined by a urinary albumin excretion rate >200 μg/min that is at least 30% higher than the baseline rate. This trial showed that irbesartan delayed progression to nephropathy independent of its effect on blood pressure compared with conventional therapy (NNT=16 at the 150-mg dose and NNT=11 at the 300-mg dose).

A third double-blind, placebo-controlled trial—IDNT (Irbesartan Diabetic Nephropathy Trial³ —randomized 1715 patients to irbesartan, amlodipine (Norvasc), or placebo for a median follow-up of 2.6 years. Each group could also use other conventional antihypertensive therapy (but again excluding ACE inhibitors, ARBs, and calcium-channel blockers). Irbesartan reduced progression of nephropathy (defined by doubling of the serum creatinine) and the onset of end-stage renal disease more effectively than amlodipine (NNT=12) or placebo (NNT=16). Irbesartan did not decrease cardiovascular mortality, nonfatal myocardial infarction, heart failure resulting in hospitalization, neurologic deficit caused by a cerebrovascular event, or above-ankle lower-limb amputation.

The mortality benefit with ARBs has not been as consistent as that shown with ACE inhibitors. Both classes of drugs conferred reduced mortality as seen with ramipril in the HOPE (Heart Outcomes Prevention Evaluation) trial⁴ and losartan in the LIFE (Losartan Intervention For Life) trial.⁵ However, a survival benefit was not seen with irbesartan in the RENAAL and IDNT trials.

Recommendation from others

The American Diabetes Association recommends both ACE inhibitors and ARBs for the treatment of early nephropathy in hypertension to delay the progression of microalbuminuria to macroalbuminuria and overt nephropathy.⁶

Evidence summary

The RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan) study¹ —a multicenter, randomized, double-blind, placebo-controlled trial—followed 1513 patients with type 2 diabetes and nephropathy over a mean of 3.4 years. Patients were randomized to receive losartan (Cozaar) or placebo, both taken in addition to conventional anti-hypertensive therapy (but not including renin-angiotensin-aldosterone system antagonist medications). The primary outcome was a composite of a doubling of serum creatinine, end-stage renal disease, or death. The number needed to treat (NNT) for the composite outcome was 34. The NNT for a doubling of the serum creatinine was 25, and for end-stage renal disease was 17.

The 2-year IRMA (Irbesartan Microalbuminuria) study,² a multicenter, randomized, double-blind, placebo-controlled trial, randomized 590 patients with type 2 diabetes, hypertension, and persistent microalbuminuria to receive 150 or 300 mg of irbesartan (Avapro) or placebo. Additional antihypertensive agents were allowed in each arm with the exception of ACE inhibitors, ARBs, and dihydropyridine calcium-channel blockers. The primary outcome was the development of overt nephropathy defined by a urinary albumin excretion rate >200 μg/min that is at least 30% higher than the baseline rate. This trial showed that irbesartan delayed progression to nephropathy independent of its effect on blood pressure compared with conventional therapy (NNT=16 at the 150-mg dose and NNT=11 at the 300-mg dose).

A third double-blind, placebo-controlled trial—IDNT (Irbesartan Diabetic Nephropathy Trial³ —randomized 1715 patients to irbesartan, amlodipine (Norvasc), or placebo for a median follow-up of 2.6 years. Each group could also use other conventional antihypertensive therapy (but again excluding ACE inhibitors, ARBs, and calcium-channel blockers). Irbesartan reduced progression of nephropathy (defined by doubling of the serum creatinine) and the onset of end-stage renal disease more effectively than amlodipine (NNT=12) or placebo (NNT=16). Irbesartan did not decrease cardiovascular mortality, nonfatal myocardial infarction, heart failure resulting in hospitalization, neurologic deficit caused by a cerebrovascular event, or above-ankle lower-limb amputation.

The mortality benefit with ARBs has not been as consistent as that shown with ACE inhibitors. Both classes of drugs conferred reduced mortality as seen with ramipril in the HOPE (Heart Outcomes Prevention Evaluation) trial⁴ and losartan in the LIFE (Losartan Intervention For Life) trial.⁵ However, a survival benefit was not seen with irbesartan in the RENAAL and IDNT trials.

Recommendation from others

The American Diabetes Association recommends both ACE inhibitors and ARBs for the treatment of early nephropathy in hypertension to delay the progression of microalbuminuria to macroalbuminuria and overt nephropathy.⁶