Although the exact cause of knee OA is unclear, its incidence increases with age and it is particularly prevalent among women and those who are obese and have occupations requiring heavy lifting and frequent kneeling or squatting.^3-6 Lifelong sport-specific activity^7,8 and joint injury⁹ also seem to increase the risk for knee OA. Knee malalignment also may predispose people to knee OA,¹⁰ and the presence of early degenerative changes predicts progression of the disease.¹¹ The disability and pain associated with knee OA correlate with a loss of quadriceps femoris muscle strength and limited joint range of motion.^12-14

Medications and surgery carry substantial risks. Pharmacologic interventions for knee OA include nonsteroidal anti-inflammatory drugs, acetaminophen, and cyclooxygenase-2-selective inhibitors.^15-17 While each of these drugs reduces pain and improves function, potential side effects include gastrointestinal, cardiovascular, renal, and hepatic complications.^16,18-21

Effective surgical options—most appropriate for advanced OA—include high-tibial osteotomy and total knee arthroplasty (TKA). There is good evidence that arthroscopic surgery is not an effective intervention for knee OA, yielding results for pain and function equivalent to those seen with knee capsule injections of saline, tidal irrigation, and placebo surgery.^22-25 TKA reduces pain, improves function, and decreases arthritis-related costs in older individuals with advanced knee OA.^26,27 However, this procedure is not without risk.²⁸ Total knee replacement in patients younger than 55 years is associated with increased mortality.²⁹ Reported adverse outcomes of TKA include death, deep vein thrombosis, pulmonary embolus, deep wound infections,^30,31 arterial lacerations, amputations,³² postoperative ileus,³³ fractures, joint stiffness, and ligamentous instability.³⁴ Viscosupplementation reduces pain and improves function, most evident at 5 to 13 weeks posttreatment, with few reported serious complications and moderate rates of local complications.³⁵

Physical therapy is beneficial for mild to moderate OA and confers very low risk. Both physical therapy and exercise programs for OA have demonstrated benefit in a variety of settings.^36-42 As shown in 2 independently conducted randomized controlled trials (RCTs) (one placebo controlled and one with an alternate treatment comparison), manual physical therapy applied during a small number of clinical sessions and supplemented by home exercise yields large reductions in pain and stiffness and improvements in functional ability persisting to 1 year as measured on the WOMAC Osteoarthritis Index,^1,2 a validated self-report outcome instrument for OA of the hip and knee.⁴³ In these studies, 60% of subjects receiving manual physical therapy and exercise achieved more than 50% improvement in WOMAC scores (pain, stiffness, and function) postintervention. Additionally, 83% achieved more than the minimal clinically important difference (MCID) of 12% improvement.^1,2 Physical therapy and exercise combined also decreased the need for TKA and long-term medication use.^1,2

For an intervention that benefits most patients, there is clearly an interest in determining predictors of treatment failure⁴⁴ to expedite referral for alternative care. When the time or resources required to attend physical therapy appointments would create financial or personal hardships, more appropriate interventions may be home-based physical therapy exercise programs or medications and injections. Equally important, patients for whom knee OA rehabilitation is predicted to fail can be reprioritized for physical therapy aimed at coexisting conditions or injuries such as a functionally limiting impingement syndrome of the shoulder or chronic degenerative back or hip conditions.

Methods

Using a retrospective combined-cohort study design, we reviewed baseline patient examinations from 2 RCTs^1,2 to identify variables that indicate which individuals with knee OA are unlikely to benefit from manual physical therapy and exercise, and to thereby develop a preliminary CPR. We extracted data from the research folders of all study participants. The institutional review board of Brooke Army Medical Center determined that the study was exempt from review. From April to December 2008, we prepared an extensive database of examination findings and performed analyses to determine the variables that predict likely treatment nonsuccess with manual physical therapy and exercise. Improvement of <12% in the total WOMAC score after 4 weeks of treatment defined nonsuccess.⁴⁵

Data sets from the previously published trials contained 22 variables measured at baseline that were potential predictors of nonsuccess. We combined these variables with an additional 145 variables manually retrieved from standardized examination forms used for each subject, for a total of 167 potential predictors. We combined only data from treatment groups receiving manual therapy and exercise.

We limited the extent of some examination procedures in the earlier studies, due to the high level of symptoms experienced by some subjects at rest and during the initial examination. For example, if there was severe pain with active knee flexion, we did not perform passive manual overpressure to flexion; nor did we record a finding. Thus, the total number of data points for each subject varied somewhat.

Data analysis

We compared success and nonsuccess groups with 2-tailed unpaired t-tests for continuous variables, and chi-square tests for categorical variables. We additionally performed logistic regression analysis on potential predictors that yielded P values <.10, using a forward conditional stepwise procedure with probability levels set to .05 for entry and .10 for removal from the model. Predictors retained by the final logistic regression model comprised the CPR.

We coded each patient in the data set as positive or negative for each predictor in the CPR. To determine a cut score, we dichotomized the single retained continuous predictor variable using receiver-operator characteristic (ROC) curve analysis and the Youden index.⁴⁶ For each CPR level (ie, increasing number of predictors positive), we constructed a 2 × 2 contingency table with numbers of patients with true-positive test results, false-positive test results, true-negative test results, and false-negative test results. We characterized prognostic performance of the CPR by calculating sensitivity, specificity, and positive likelihood ratios for each level of positive predictors. To determine overall prognostic accuracy, we added true positives and true negatives and divided by the total number of patients in the cross tabulation.

For each CPR level, we derived posttest probabilities of nonsuccess from generalized pretest probability (incidence of treatment nonsuccess in the sample) and the positive likelihood ratios.⁴⁷ Finally, to determine how consistently the CPR performed with subjects in the original studies,^1,2 we generated separate cross-tabulations and prognostic accuracy statistics from each RCT.

Results

Baseline patient attributes are summarized in TABLE 1. Of the 101 subjects in the combined data set, 17 (16.8%) met the definition of nonsuccess. Among 47 continuous-scale variables available, 11 predictors significantly discriminated between those in the treatment success and nonsuccess groups. Among 120 categorical-scale variables, 15 predictors significantly discriminated between groups. We identified 6 potential predictors for entry into the final logistic regression analysis: height, assistive device type, prone knee bend degrees, baseline WOMAC visual analog scale (VAS) for difficulty descending stairs, anterior cruciate ligament (ACL) laxity, and pain with passive patellofemoral glide.

TABLE 1
Baseline descriptive summaries of patients (n=101)

The final regression model retained 3 predictors comprising the CPR: height, ACL laxity, and pain with passive patellofemoral glides. We dichotomized height with a cut point of 1.71 m (5’7”), which corresponded with a deflection point at the upper left extent of the ROC curve (area under the curve=0.72; 95% CI, 0.57-0.87; P=.001). We thus deemed a patient 1.71 m or taller as positive for nonsuccess. We considered a patient with laxity of the ACL as positive for nonsuccess if a test result on the Lachman test (or the anterior drawer test) was positive (any grade other than 0). We regarded passive patellofemoral glide as positive for nonsuccess if a patient reported pain with any direction of passive gliding motion imposed by the therapist. The final regression model was a good fit to the data: Hosmer & Lemeshow test χ² = 2.90 (P=.940); Nagelkerke R²=0.680.

TABLE 2 presents prognostic accuracy profiles for each predictor in the CPR; TABLE 3 summarizes the accuracy for each level of the multivariate CPR. Values in TABLE 3 reflect complete sets of data for the 3 predictors found for 50 patients. Of those 50 patients, 6 (12%) were in the nonsuccess group.

TABLE 2
Prognostic accuracy statistics for individual predictors

With any 2 of the 3 tests positive, the CPR yielded a sensitivity of 83% (95% CI, 44%-97%), specificity of 98% (95% CI, 88%-100%), and positive likelihood ratio of 36.7 (95% CI, 5.1-263.0). Only 2 patients out of 50 were misclassified (one false positive and one false negative) at this level of the CPR, yielding an overall prognostic accuracy of 96% (95% CI, 87%-99%). Application of the positive likelihood ratio for a patient with any 2 positive tests yielded a posttest probability of 88% for nonsuccess with this treatment.

TABLE 3
Prognostic accuracy statistics for 3-level clinical prediction rule

In the sensitivity analysis, the CPR performed similarly well for patients in each of the 2 original studies when applied separately to the groups of patients. Among the 30 patients from the first trial² who had data for all 3 predictors in the CPR, only one was misclassified (a false positive), yielding a prognostic accuracy of 97% (95% CI, 83%-99%). Among the 20 patients from the second trial¹ who had data for all 3 predictors, only one was misclassified (a false negative), yielding a prognostic accuracy of 95% (95% CI, 76%-99%).

DISCUSSION

Family physicians and physical therapists should be able to discuss with confidence how any given patient with knee OA will likely respond to treatment options. Our study is a preliminary step toward defining the population of patients with knee OA who are unlikely to benefit from manual physical therapy and exercise. We found such patients to be those with height >1.71 m, ACL laxity, and pain with passive glides of the patellofemoral joint.

A limitation of our study is the retrospective nature of gathering data. However, retrospective CPR derivation studies have made valuable contributions to many areas of medical practice.^48-53 Additionally, if there had been uniformly available data across all patients, there may have been other, perhaps more powerful, predictors for treatment nonsuccess.

Applying the clinical prediction rule in practice

Actual cases of knee osteoarthritis (OA) evaluated by one of the authors (GD)

A 48-year-old female elementary teacher was referred for physical therapy due to right knee pain and a diagnosis of OA that was limiting her ability to climb stairs and squat to work with children in the classroom. Her goals were to be able to perform these physical activities with less pain and to reduce her anti-inflammatory medications. However, she also worried about taking time away from her job to attend physical therapy appointments. She was 1.63 m (5’4”) tall and had a body mass index of 27.5 kg/m². Her knee was stable to ligamentous testing, with mild limitation and pain with active and passive movement of both the tibiofemoral and the patellofemoral joints. She had weakness of the quadriceps and hip abductors, and moderate tightness of the calf muscles in both lower extremities.

Given the presence of only a single predictor for nonsuccess (pain with passive movement of her patella), the likelihood that this patient would not respond to manual physical therapy and exercise was just 27%, according to the clinical prediction rule. The impairments to movement, strength, and flexibility found during the physical examination typically can be successfully addressed with manual physical therapy. Additionally, one of the patient’s goals was to reduce her medication use—a reported outcome of the clinical trials used for deriving the rule.^1,2 This patient was a good candidate for the intervention, with an acceptably small chance of not achieving a clinically meaningful benefit.

A 50-year-old male soldier 1.95 m (6’5”) tall was referred for physical therapy to ameliorate chronic pain due to tricompartmental knee OA. He exhibited anterior ligamentous laxity and felt severe pain with manually performed passive patellar glides (FIGURES 1 AND 2). He also had a rotator cuff tear and a mild traumatic brain injury from a roadside bomb blast. With 3/3 predictors for failure, the likelihood of reducing this patient’s knee symptoms with manual therapy and exercise was just 20%. The physical therapist and referring physician jointly decided to focus a small number of physical therapy visits on the patient’s shoulder, while giving rehabilitation priority to ongoing cognitive therapy appointments.

FIGURE 1
Lachman test

With the patient’s knee flexed at 30°, draw the proximal tibia anteriorly to observe movement of the tibia relative to the femur and thereby gauge anterior cruciate ligament integrity. Laxity is suggested by increased movement relative to the opposite knee.

FIGURE 2
Passive patellofemoral glide

With the patient’s knee slightly flexed, apply light pressure to the medial border of the patella, moving it laterally and taking care not to compress the patella. Repeat the procedure superiorly, inferiorly, and medially. A positive test is pain experienced with any of the glides.

Patient height >1.71 m is the least intuitive of the predictors for nonsuccess, but that underscores the value of data-driven prediction rules. Variables regarded as unimportant in a typical clinical assessment may show clinical usefulness if validated in independent studies. It may be that in taller patients with knee OA, biomechanical forces are such that a positive response to conservative therapy is less likely—particularly in the presence of ligamentous laxity or patellofemoral dysfunction.

For most patients with knee OA, the combined intervention of manual physical therapy and exercise is clinically beneficial, relatively inexpensive, and has no known adverse effects.⁵⁴ However, unique circumstances may increase the importance of determining the likelihood that a patient will benefit. A validated CPR will facilitate timely decisions for those relatively few patients requiring alternative interventions. Although the rule is preliminary and needs to be validated, these results provide current best evidence to define patients with knee OA who are unlikely to respond to manual physical therapy and exercise.

Although the exact cause of knee OA is unclear, its incidence increases with age and it is particularly prevalent among women and those who are obese and have occupations requiring heavy lifting and frequent kneeling or squatting.^3-6 Lifelong sport-specific activity^7,8 and joint injury⁹ also seem to increase the risk for knee OA. Knee malalignment also may predispose people to knee OA,¹⁰ and the presence of early degenerative changes predicts progression of the disease.¹¹ The disability and pain associated with knee OA correlate with a loss of quadriceps femoris muscle strength and limited joint range of motion.^12-14

Medications and surgery carry substantial risks. Pharmacologic interventions for knee OA include nonsteroidal anti-inflammatory drugs, acetaminophen, and cyclooxygenase-2-selective inhibitors.^15-17 While each of these drugs reduces pain and improves function, potential side effects include gastrointestinal, cardiovascular, renal, and hepatic complications.^16,18-21

Effective surgical options—most appropriate for advanced OA—include high-tibial osteotomy and total knee arthroplasty (TKA). There is good evidence that arthroscopic surgery is not an effective intervention for knee OA, yielding results for pain and function equivalent to those seen with knee capsule injections of saline, tidal irrigation, and placebo surgery.^22-25 TKA reduces pain, improves function, and decreases arthritis-related costs in older individuals with advanced knee OA.^26,27 However, this procedure is not without risk.²⁸ Total knee replacement in patients younger than 55 years is associated with increased mortality.²⁹ Reported adverse outcomes of TKA include death, deep vein thrombosis, pulmonary embolus, deep wound infections,^30,31 arterial lacerations, amputations,³² postoperative ileus,³³ fractures, joint stiffness, and ligamentous instability.³⁴ Viscosupplementation reduces pain and improves function, most evident at 5 to 13 weeks posttreatment, with few reported serious complications and moderate rates of local complications.³⁵

Physical therapy is beneficial for mild to moderate OA and confers very low risk. Both physical therapy and exercise programs for OA have demonstrated benefit in a variety of settings.^36-42 As shown in 2 independently conducted randomized controlled trials (RCTs) (one placebo controlled and one with an alternate treatment comparison), manual physical therapy applied during a small number of clinical sessions and supplemented by home exercise yields large reductions in pain and stiffness and improvements in functional ability persisting to 1 year as measured on the WOMAC Osteoarthritis Index,^1,2 a validated self-report outcome instrument for OA of the hip and knee.⁴³ In these studies, 60% of subjects receiving manual physical therapy and exercise achieved more than 50% improvement in WOMAC scores (pain, stiffness, and function) postintervention. Additionally, 83% achieved more than the minimal clinically important difference (MCID) of 12% improvement.^1,2 Physical therapy and exercise combined also decreased the need for TKA and long-term medication use.^1,2

For an intervention that benefits most patients, there is clearly an interest in determining predictors of treatment failure⁴⁴ to expedite referral for alternative care. When the time or resources required to attend physical therapy appointments would create financial or personal hardships, more appropriate interventions may be home-based physical therapy exercise programs or medications and injections. Equally important, patients for whom knee OA rehabilitation is predicted to fail can be reprioritized for physical therapy aimed at coexisting conditions or injuries such as a functionally limiting impingement syndrome of the shoulder or chronic degenerative back or hip conditions.

Methods

Using a retrospective combined-cohort study design, we reviewed baseline patient examinations from 2 RCTs^1,2 to identify variables that indicate which individuals with knee OA are unlikely to benefit from manual physical therapy and exercise, and to thereby develop a preliminary CPR. We extracted data from the research folders of all study participants. The institutional review board of Brooke Army Medical Center determined that the study was exempt from review. From April to December 2008, we prepared an extensive database of examination findings and performed analyses to determine the variables that predict likely treatment nonsuccess with manual physical therapy and exercise. Improvement of <12% in the total WOMAC score after 4 weeks of treatment defined nonsuccess.⁴⁵

Data sets from the previously published trials contained 22 variables measured at baseline that were potential predictors of nonsuccess. We combined these variables with an additional 145 variables manually retrieved from standardized examination forms used for each subject, for a total of 167 potential predictors. We combined only data from treatment groups receiving manual therapy and exercise.

We limited the extent of some examination procedures in the earlier studies, due to the high level of symptoms experienced by some subjects at rest and during the initial examination. For example, if there was severe pain with active knee flexion, we did not perform passive manual overpressure to flexion; nor did we record a finding. Thus, the total number of data points for each subject varied somewhat.

Data analysis

We compared success and nonsuccess groups with 2-tailed unpaired t-tests for continuous variables, and chi-square tests for categorical variables. We additionally performed logistic regression analysis on potential predictors that yielded P values <.10, using a forward conditional stepwise procedure with probability levels set to .05 for entry and .10 for removal from the model. Predictors retained by the final logistic regression model comprised the CPR.

We coded each patient in the data set as positive or negative for each predictor in the CPR. To determine a cut score, we dichotomized the single retained continuous predictor variable using receiver-operator characteristic (ROC) curve analysis and the Youden index.⁴⁶ For each CPR level (ie, increasing number of predictors positive), we constructed a 2 × 2 contingency table with numbers of patients with true-positive test results, false-positive test results, true-negative test results, and false-negative test results. We characterized prognostic performance of the CPR by calculating sensitivity, specificity, and positive likelihood ratios for each level of positive predictors. To determine overall prognostic accuracy, we added true positives and true negatives and divided by the total number of patients in the cross tabulation.

For each CPR level, we derived posttest probabilities of nonsuccess from generalized pretest probability (incidence of treatment nonsuccess in the sample) and the positive likelihood ratios.⁴⁷ Finally, to determine how consistently the CPR performed with subjects in the original studies,^1,2 we generated separate cross-tabulations and prognostic accuracy statistics from each RCT.

Results

Baseline patient attributes are summarized in TABLE 1. Of the 101 subjects in the combined data set, 17 (16.8%) met the definition of nonsuccess. Among 47 continuous-scale variables available, 11 predictors significantly discriminated between those in the treatment success and nonsuccess groups. Among 120 categorical-scale variables, 15 predictors significantly discriminated between groups. We identified 6 potential predictors for entry into the final logistic regression analysis: height, assistive device type, prone knee bend degrees, baseline WOMAC visual analog scale (VAS) for difficulty descending stairs, anterior cruciate ligament (ACL) laxity, and pain with passive patellofemoral glide.

TABLE 1
Baseline descriptive summaries of patients (n=101)

The final regression model retained 3 predictors comprising the CPR: height, ACL laxity, and pain with passive patellofemoral glides. We dichotomized height with a cut point of 1.71 m (5’7”), which corresponded with a deflection point at the upper left extent of the ROC curve (area under the curve=0.72; 95% CI, 0.57-0.87; P=.001). We thus deemed a patient 1.71 m or taller as positive for nonsuccess. We considered a patient with laxity of the ACL as positive for nonsuccess if a test result on the Lachman test (or the anterior drawer test) was positive (any grade other than 0). We regarded passive patellofemoral glide as positive for nonsuccess if a patient reported pain with any direction of passive gliding motion imposed by the therapist. The final regression model was a good fit to the data: Hosmer & Lemeshow test χ² = 2.90 (P=.940); Nagelkerke R²=0.680.

TABLE 2 presents prognostic accuracy profiles for each predictor in the CPR; TABLE 3 summarizes the accuracy for each level of the multivariate CPR. Values in TABLE 3 reflect complete sets of data for the 3 predictors found for 50 patients. Of those 50 patients, 6 (12%) were in the nonsuccess group.

TABLE 2
Prognostic accuracy statistics for individual predictors

With any 2 of the 3 tests positive, the CPR yielded a sensitivity of 83% (95% CI, 44%-97%), specificity of 98% (95% CI, 88%-100%), and positive likelihood ratio of 36.7 (95% CI, 5.1-263.0). Only 2 patients out of 50 were misclassified (one false positive and one false negative) at this level of the CPR, yielding an overall prognostic accuracy of 96% (95% CI, 87%-99%). Application of the positive likelihood ratio for a patient with any 2 positive tests yielded a posttest probability of 88% for nonsuccess with this treatment.

TABLE 3
Prognostic accuracy statistics for 3-level clinical prediction rule

In the sensitivity analysis, the CPR performed similarly well for patients in each of the 2 original studies when applied separately to the groups of patients. Among the 30 patients from the first trial² who had data for all 3 predictors in the CPR, only one was misclassified (a false positive), yielding a prognostic accuracy of 97% (95% CI, 83%-99%). Among the 20 patients from the second trial¹ who had data for all 3 predictors, only one was misclassified (a false negative), yielding a prognostic accuracy of 95% (95% CI, 76%-99%).

DISCUSSION

Family physicians and physical therapists should be able to discuss with confidence how any given patient with knee OA will likely respond to treatment options. Our study is a preliminary step toward defining the population of patients with knee OA who are unlikely to benefit from manual physical therapy and exercise. We found such patients to be those with height >1.71 m, ACL laxity, and pain with passive glides of the patellofemoral joint.

A limitation of our study is the retrospective nature of gathering data. However, retrospective CPR derivation studies have made valuable contributions to many areas of medical practice.^48-53 Additionally, if there had been uniformly available data across all patients, there may have been other, perhaps more powerful, predictors for treatment nonsuccess.

Applying the clinical prediction rule in practice

Actual cases of knee osteoarthritis (OA) evaluated by one of the authors (GD)

A 48-year-old female elementary teacher was referred for physical therapy due to right knee pain and a diagnosis of OA that was limiting her ability to climb stairs and squat to work with children in the classroom. Her goals were to be able to perform these physical activities with less pain and to reduce her anti-inflammatory medications. However, she also worried about taking time away from her job to attend physical therapy appointments. She was 1.63 m (5’4”) tall and had a body mass index of 27.5 kg/m². Her knee was stable to ligamentous testing, with mild limitation and pain with active and passive movement of both the tibiofemoral and the patellofemoral joints. She had weakness of the quadriceps and hip abductors, and moderate tightness of the calf muscles in both lower extremities.

Given the presence of only a single predictor for nonsuccess (pain with passive movement of her patella), the likelihood that this patient would not respond to manual physical therapy and exercise was just 27%, according to the clinical prediction rule. The impairments to movement, strength, and flexibility found during the physical examination typically can be successfully addressed with manual physical therapy. Additionally, one of the patient’s goals was to reduce her medication use—a reported outcome of the clinical trials used for deriving the rule.^1,2 This patient was a good candidate for the intervention, with an acceptably small chance of not achieving a clinically meaningful benefit.

A 50-year-old male soldier 1.95 m (6’5”) tall was referred for physical therapy to ameliorate chronic pain due to tricompartmental knee OA. He exhibited anterior ligamentous laxity and felt severe pain with manually performed passive patellar glides (FIGURES 1 AND 2). He also had a rotator cuff tear and a mild traumatic brain injury from a roadside bomb blast. With 3/3 predictors for failure, the likelihood of reducing this patient’s knee symptoms with manual therapy and exercise was just 20%. The physical therapist and referring physician jointly decided to focus a small number of physical therapy visits on the patient’s shoulder, while giving rehabilitation priority to ongoing cognitive therapy appointments.

FIGURE 1
Lachman test

With the patient’s knee flexed at 30°, draw the proximal tibia anteriorly to observe movement of the tibia relative to the femur and thereby gauge anterior cruciate ligament integrity. Laxity is suggested by increased movement relative to the opposite knee.

FIGURE 2
Passive patellofemoral glide

With the patient’s knee slightly flexed, apply light pressure to the medial border of the patella, moving it laterally and taking care not to compress the patella. Repeat the procedure superiorly, inferiorly, and medially. A positive test is pain experienced with any of the glides.

Patient height >1.71 m is the least intuitive of the predictors for nonsuccess, but that underscores the value of data-driven prediction rules. Variables regarded as unimportant in a typical clinical assessment may show clinical usefulness if validated in independent studies. It may be that in taller patients with knee OA, biomechanical forces are such that a positive response to conservative therapy is less likely—particularly in the presence of ligamentous laxity or patellofemoral dysfunction.

For most patients with knee OA, the combined intervention of manual physical therapy and exercise is clinically beneficial, relatively inexpensive, and has no known adverse effects.⁵⁴ However, unique circumstances may increase the importance of determining the likelihood that a patient will benefit. A validated CPR will facilitate timely decisions for those relatively few patients requiring alternative interventions. Although the rule is preliminary and needs to be validated, these results provide current best evidence to define patients with knee OA who are unlikely to respond to manual physical therapy and exercise.

Although the exact cause of knee OA is unclear, its incidence increases with age and it is particularly prevalent among women and those who are obese and have occupations requiring heavy lifting and frequent kneeling or squatting.^3-6 Lifelong sport-specific activity^7,8 and joint injury⁹ also seem to increase the risk for knee OA. Knee malalignment also may predispose people to knee OA,¹⁰ and the presence of early degenerative changes predicts progression of the disease.¹¹ The disability and pain associated with knee OA correlate with a loss of quadriceps femoris muscle strength and limited joint range of motion.^12-14

Medications and surgery carry substantial risks. Pharmacologic interventions for knee OA include nonsteroidal anti-inflammatory drugs, acetaminophen, and cyclooxygenase-2-selective inhibitors.^15-17 While each of these drugs reduces pain and improves function, potential side effects include gastrointestinal, cardiovascular, renal, and hepatic complications.^16,18-21

Effective surgical options—most appropriate for advanced OA—include high-tibial osteotomy and total knee arthroplasty (TKA). There is good evidence that arthroscopic surgery is not an effective intervention for knee OA, yielding results for pain and function equivalent to those seen with knee capsule injections of saline, tidal irrigation, and placebo surgery.^22-25 TKA reduces pain, improves function, and decreases arthritis-related costs in older individuals with advanced knee OA.^26,27 However, this procedure is not without risk.²⁸ Total knee replacement in patients younger than 55 years is associated with increased mortality.²⁹ Reported adverse outcomes of TKA include death, deep vein thrombosis, pulmonary embolus, deep wound infections,^30,31 arterial lacerations, amputations,³² postoperative ileus,³³ fractures, joint stiffness, and ligamentous instability.³⁴ Viscosupplementation reduces pain and improves function, most evident at 5 to 13 weeks posttreatment, with few reported serious complications and moderate rates of local complications.³⁵

Physical therapy is beneficial for mild to moderate OA and confers very low risk. Both physical therapy and exercise programs for OA have demonstrated benefit in a variety of settings.^36-42 As shown in 2 independently conducted randomized controlled trials (RCTs) (one placebo controlled and one with an alternate treatment comparison), manual physical therapy applied during a small number of clinical sessions and supplemented by home exercise yields large reductions in pain and stiffness and improvements in functional ability persisting to 1 year as measured on the WOMAC Osteoarthritis Index,^1,2 a validated self-report outcome instrument for OA of the hip and knee.⁴³ In these studies, 60% of subjects receiving manual physical therapy and exercise achieved more than 50% improvement in WOMAC scores (pain, stiffness, and function) postintervention. Additionally, 83% achieved more than the minimal clinically important difference (MCID) of 12% improvement.^1,2 Physical therapy and exercise combined also decreased the need for TKA and long-term medication use.^1,2

For an intervention that benefits most patients, there is clearly an interest in determining predictors of treatment failure⁴⁴ to expedite referral for alternative care. When the time or resources required to attend physical therapy appointments would create financial or personal hardships, more appropriate interventions may be home-based physical therapy exercise programs or medications and injections. Equally important, patients for whom knee OA rehabilitation is predicted to fail can be reprioritized for physical therapy aimed at coexisting conditions or injuries such as a functionally limiting impingement syndrome of the shoulder or chronic degenerative back or hip conditions.

Methods

Using a retrospective combined-cohort study design, we reviewed baseline patient examinations from 2 RCTs^1,2 to identify variables that indicate which individuals with knee OA are unlikely to benefit from manual physical therapy and exercise, and to thereby develop a preliminary CPR. We extracted data from the research folders of all study participants. The institutional review board of Brooke Army Medical Center determined that the study was exempt from review. From April to December 2008, we prepared an extensive database of examination findings and performed analyses to determine the variables that predict likely treatment nonsuccess with manual physical therapy and exercise. Improvement of <12% in the total WOMAC score after 4 weeks of treatment defined nonsuccess.⁴⁵

Data sets from the previously published trials contained 22 variables measured at baseline that were potential predictors of nonsuccess. We combined these variables with an additional 145 variables manually retrieved from standardized examination forms used for each subject, for a total of 167 potential predictors. We combined only data from treatment groups receiving manual therapy and exercise.

We limited the extent of some examination procedures in the earlier studies, due to the high level of symptoms experienced by some subjects at rest and during the initial examination. For example, if there was severe pain with active knee flexion, we did not perform passive manual overpressure to flexion; nor did we record a finding. Thus, the total number of data points for each subject varied somewhat.

Data analysis

We compared success and nonsuccess groups with 2-tailed unpaired t-tests for continuous variables, and chi-square tests for categorical variables. We additionally performed logistic regression analysis on potential predictors that yielded P values <.10, using a forward conditional stepwise procedure with probability levels set to .05 for entry and .10 for removal from the model. Predictors retained by the final logistic regression model comprised the CPR.

We coded each patient in the data set as positive or negative for each predictor in the CPR. To determine a cut score, we dichotomized the single retained continuous predictor variable using receiver-operator characteristic (ROC) curve analysis and the Youden index.⁴⁶ For each CPR level (ie, increasing number of predictors positive), we constructed a 2 × 2 contingency table with numbers of patients with true-positive test results, false-positive test results, true-negative test results, and false-negative test results. We characterized prognostic performance of the CPR by calculating sensitivity, specificity, and positive likelihood ratios for each level of positive predictors. To determine overall prognostic accuracy, we added true positives and true negatives and divided by the total number of patients in the cross tabulation.

For each CPR level, we derived posttest probabilities of nonsuccess from generalized pretest probability (incidence of treatment nonsuccess in the sample) and the positive likelihood ratios.⁴⁷ Finally, to determine how consistently the CPR performed with subjects in the original studies,^1,2 we generated separate cross-tabulations and prognostic accuracy statistics from each RCT.

Results

Baseline patient attributes are summarized in TABLE 1. Of the 101 subjects in the combined data set, 17 (16.8%) met the definition of nonsuccess. Among 47 continuous-scale variables available, 11 predictors significantly discriminated between those in the treatment success and nonsuccess groups. Among 120 categorical-scale variables, 15 predictors significantly discriminated between groups. We identified 6 potential predictors for entry into the final logistic regression analysis: height, assistive device type, prone knee bend degrees, baseline WOMAC visual analog scale (VAS) for difficulty descending stairs, anterior cruciate ligament (ACL) laxity, and pain with passive patellofemoral glide.

TABLE 1
Baseline descriptive summaries of patients (n=101)

The final regression model retained 3 predictors comprising the CPR: height, ACL laxity, and pain with passive patellofemoral glides. We dichotomized height with a cut point of 1.71 m (5’7”), which corresponded with a deflection point at the upper left extent of the ROC curve (area under the curve=0.72; 95% CI, 0.57-0.87; P=.001). We thus deemed a patient 1.71 m or taller as positive for nonsuccess. We considered a patient with laxity of the ACL as positive for nonsuccess if a test result on the Lachman test (or the anterior drawer test) was positive (any grade other than 0). We regarded passive patellofemoral glide as positive for nonsuccess if a patient reported pain with any direction of passive gliding motion imposed by the therapist. The final regression model was a good fit to the data: Hosmer & Lemeshow test χ² = 2.90 (P=.940); Nagelkerke R²=0.680.

TABLE 2 presents prognostic accuracy profiles for each predictor in the CPR; TABLE 3 summarizes the accuracy for each level of the multivariate CPR. Values in TABLE 3 reflect complete sets of data for the 3 predictors found for 50 patients. Of those 50 patients, 6 (12%) were in the nonsuccess group.

TABLE 2
Prognostic accuracy statistics for individual predictors

With any 2 of the 3 tests positive, the CPR yielded a sensitivity of 83% (95% CI, 44%-97%), specificity of 98% (95% CI, 88%-100%), and positive likelihood ratio of 36.7 (95% CI, 5.1-263.0). Only 2 patients out of 50 were misclassified (one false positive and one false negative) at this level of the CPR, yielding an overall prognostic accuracy of 96% (95% CI, 87%-99%). Application of the positive likelihood ratio for a patient with any 2 positive tests yielded a posttest probability of 88% for nonsuccess with this treatment.

TABLE 3
Prognostic accuracy statistics for 3-level clinical prediction rule

In the sensitivity analysis, the CPR performed similarly well for patients in each of the 2 original studies when applied separately to the groups of patients. Among the 30 patients from the first trial² who had data for all 3 predictors in the CPR, only one was misclassified (a false positive), yielding a prognostic accuracy of 97% (95% CI, 83%-99%). Among the 20 patients from the second trial¹ who had data for all 3 predictors, only one was misclassified (a false negative), yielding a prognostic accuracy of 95% (95% CI, 76%-99%).

DISCUSSION

Family physicians and physical therapists should be able to discuss with confidence how any given patient with knee OA will likely respond to treatment options. Our study is a preliminary step toward defining the population of patients with knee OA who are unlikely to benefit from manual physical therapy and exercise. We found such patients to be those with height >1.71 m, ACL laxity, and pain with passive glides of the patellofemoral joint.

A limitation of our study is the retrospective nature of gathering data. However, retrospective CPR derivation studies have made valuable contributions to many areas of medical practice.^48-53 Additionally, if there had been uniformly available data across all patients, there may have been other, perhaps more powerful, predictors for treatment nonsuccess.

Applying the clinical prediction rule in practice

Actual cases of knee osteoarthritis (OA) evaluated by one of the authors (GD)

A 48-year-old female elementary teacher was referred for physical therapy due to right knee pain and a diagnosis of OA that was limiting her ability to climb stairs and squat to work with children in the classroom. Her goals were to be able to perform these physical activities with less pain and to reduce her anti-inflammatory medications. However, she also worried about taking time away from her job to attend physical therapy appointments. She was 1.63 m (5’4”) tall and had a body mass index of 27.5 kg/m². Her knee was stable to ligamentous testing, with mild limitation and pain with active and passive movement of both the tibiofemoral and the patellofemoral joints. She had weakness of the quadriceps and hip abductors, and moderate tightness of the calf muscles in both lower extremities.

Given the presence of only a single predictor for nonsuccess (pain with passive movement of her patella), the likelihood that this patient would not respond to manual physical therapy and exercise was just 27%, according to the clinical prediction rule. The impairments to movement, strength, and flexibility found during the physical examination typically can be successfully addressed with manual physical therapy. Additionally, one of the patient’s goals was to reduce her medication use—a reported outcome of the clinical trials used for deriving the rule.^1,2 This patient was a good candidate for the intervention, with an acceptably small chance of not achieving a clinically meaningful benefit.

A 50-year-old male soldier 1.95 m (6’5”) tall was referred for physical therapy to ameliorate chronic pain due to tricompartmental knee OA. He exhibited anterior ligamentous laxity and felt severe pain with manually performed passive patellar glides (FIGURES 1 AND 2). He also had a rotator cuff tear and a mild traumatic brain injury from a roadside bomb blast. With 3/3 predictors for failure, the likelihood of reducing this patient’s knee symptoms with manual therapy and exercise was just 20%. The physical therapist and referring physician jointly decided to focus a small number of physical therapy visits on the patient’s shoulder, while giving rehabilitation priority to ongoing cognitive therapy appointments.

FIGURE 1
Lachman test

With the patient’s knee flexed at 30°, draw the proximal tibia anteriorly to observe movement of the tibia relative to the femur and thereby gauge anterior cruciate ligament integrity. Laxity is suggested by increased movement relative to the opposite knee.

FIGURE 2
Passive patellofemoral glide

With the patient’s knee slightly flexed, apply light pressure to the medial border of the patella, moving it laterally and taking care not to compress the patella. Repeat the procedure superiorly, inferiorly, and medially. A positive test is pain experienced with any of the glides.

Patient height >1.71 m is the least intuitive of the predictors for nonsuccess, but that underscores the value of data-driven prediction rules. Variables regarded as unimportant in a typical clinical assessment may show clinical usefulness if validated in independent studies. It may be that in taller patients with knee OA, biomechanical forces are such that a positive response to conservative therapy is less likely—particularly in the presence of ligamentous laxity or patellofemoral dysfunction.

For most patients with knee OA, the combined intervention of manual physical therapy and exercise is clinically beneficial, relatively inexpensive, and has no known adverse effects.⁵⁴ However, unique circumstances may increase the importance of determining the likelihood that a patient will benefit. A validated CPR will facilitate timely decisions for those relatively few patients requiring alternative interventions. Although the rule is preliminary and needs to be validated, these results provide current best evidence to define patients with knee OA who are unlikely to respond to manual physical therapy and exercise.

Evidence summary

AAAs occur in 5% to 10% of men and 0.5% to 1.5% of women between 65 and 79 years of age.^1,2 Risk factors include age, smoking, male sex, and family history.² AAAs are 3 to 5 times more likely in patients with a smoking history.² Approximately 9000 deaths annually are linked to AAAs in the United States, mostly in men older than 65 years.² Mortality after rupture approaches 80% for patients who reach a hospital and 50% for patients who undergo emergent surgery.²

Screening reduces AAA deaths in men, but not all-cause mortality

A Cochrane review assessing the use of ultrasound to screen for AAA analyzed 4 population-based RCTs involving 127,891 men and 9342 women.¹ Participants in each trial were randomly assigned to screening with ultrasound or no intervention.

The reviewers reported that screening significantly reduced mortality from AAA in men 65 to 79 years of age (odds ratio [OR]=0.60; 95% confidence interval [CI], 0.47-0.78). They found no support for decreased mortality in women (OR=1.99; 95% CI, 0.36-10.88).

The study also found no significant reduction in all-cause mortality 3 to 5 years after screening in men 65 to 79 years of age (OR=0.95; 95% CI, 0.85-1.07) or women (OR=1.06; 95% CI, 0.93-1.21), probably because of the low overall incidence of AAA.¹ For men 65 to 79 years of age, the NNS is 769 over 3 years to prevent one death.¹

Limitations of the study include disproportionate male representation because only 1 of the 4 trials in the Cochrane review enrolled women. Moreover, the analysis didn’t include smoking, although smoking increases the risk of AAA 3- to 5-fold. The NNS may be significantly different for smokers than nonsmokers.^1,2

Recommendations

The US Preventive Services Task Force (USPSTF) recommends a one-time ultrasound screening for AAA in men between 65 and 74 years of age who have ever smoked.² The USPSTF advises against routine screening in women and concludes that insufficient evidence exists to advocate for or against routine screening in men 65 to 74 years who have never smoked.²

The Canadian Society for Vascular Surgery recommends a population-based screening program for men 65 to 75 years of age who are candidates for surgery and are willing to participate.³

Acknowledgements

The opinions and assertions contained herein are the private views of the authors and not to be construed as official nor as reflecting the views of the United States Air Force Medical Service or the US Air Force at large.

Evidence summary

AAAs occur in 5% to 10% of men and 0.5% to 1.5% of women between 65 and 79 years of age.^1,2 Risk factors include age, smoking, male sex, and family history.² AAAs are 3 to 5 times more likely in patients with a smoking history.² Approximately 9000 deaths annually are linked to AAAs in the United States, mostly in men older than 65 years.² Mortality after rupture approaches 80% for patients who reach a hospital and 50% for patients who undergo emergent surgery.²

Screening reduces AAA deaths in men, but not all-cause mortality

A Cochrane review assessing the use of ultrasound to screen for AAA analyzed 4 population-based RCTs involving 127,891 men and 9342 women.¹ Participants in each trial were randomly assigned to screening with ultrasound or no intervention.

The reviewers reported that screening significantly reduced mortality from AAA in men 65 to 79 years of age (odds ratio [OR]=0.60; 95% confidence interval [CI], 0.47-0.78). They found no support for decreased mortality in women (OR=1.99; 95% CI, 0.36-10.88).

The study also found no significant reduction in all-cause mortality 3 to 5 years after screening in men 65 to 79 years of age (OR=0.95; 95% CI, 0.85-1.07) or women (OR=1.06; 95% CI, 0.93-1.21), probably because of the low overall incidence of AAA.¹ For men 65 to 79 years of age, the NNS is 769 over 3 years to prevent one death.¹

Limitations of the study include disproportionate male representation because only 1 of the 4 trials in the Cochrane review enrolled women. Moreover, the analysis didn’t include smoking, although smoking increases the risk of AAA 3- to 5-fold. The NNS may be significantly different for smokers than nonsmokers.^1,2

Recommendations

The US Preventive Services Task Force (USPSTF) recommends a one-time ultrasound screening for AAA in men between 65 and 74 years of age who have ever smoked.² The USPSTF advises against routine screening in women and concludes that insufficient evidence exists to advocate for or against routine screening in men 65 to 74 years who have never smoked.²

The Canadian Society for Vascular Surgery recommends a population-based screening program for men 65 to 75 years of age who are candidates for surgery and are willing to participate.³

Acknowledgements

The opinions and assertions contained herein are the private views of the authors and not to be construed as official nor as reflecting the views of the United States Air Force Medical Service or the US Air Force at large.

Evidence summary

AAAs occur in 5% to 10% of men and 0.5% to 1.5% of women between 65 and 79 years of age.^1,2 Risk factors include age, smoking, male sex, and family history.² AAAs are 3 to 5 times more likely in patients with a smoking history.² Approximately 9000 deaths annually are linked to AAAs in the United States, mostly in men older than 65 years.² Mortality after rupture approaches 80% for patients who reach a hospital and 50% for patients who undergo emergent surgery.²

Screening reduces AAA deaths in men, but not all-cause mortality

A Cochrane review assessing the use of ultrasound to screen for AAA analyzed 4 population-based RCTs involving 127,891 men and 9342 women.¹ Participants in each trial were randomly assigned to screening with ultrasound or no intervention.

The reviewers reported that screening significantly reduced mortality from AAA in men 65 to 79 years of age (odds ratio [OR]=0.60; 95% confidence interval [CI], 0.47-0.78). They found no support for decreased mortality in women (OR=1.99; 95% CI, 0.36-10.88).

The study also found no significant reduction in all-cause mortality 3 to 5 years after screening in men 65 to 79 years of age (OR=0.95; 95% CI, 0.85-1.07) or women (OR=1.06; 95% CI, 0.93-1.21), probably because of the low overall incidence of AAA.¹ For men 65 to 79 years of age, the NNS is 769 over 3 years to prevent one death.¹

Limitations of the study include disproportionate male representation because only 1 of the 4 trials in the Cochrane review enrolled women. Moreover, the analysis didn’t include smoking, although smoking increases the risk of AAA 3- to 5-fold. The NNS may be significantly different for smokers than nonsmokers.^1,2

Recommendations

The US Preventive Services Task Force (USPSTF) recommends a one-time ultrasound screening for AAA in men between 65 and 74 years of age who have ever smoked.² The USPSTF advises against routine screening in women and concludes that insufficient evidence exists to advocate for or against routine screening in men 65 to 74 years who have never smoked.²

The Canadian Society for Vascular Surgery recommends a population-based screening program for men 65 to 75 years of age who are candidates for surgery and are willing to participate.³

Acknowledgements

The opinions and assertions contained herein are the private views of the authors and not to be construed as official nor as reflecting the views of the United States Air Force Medical Service or the US Air Force at large.

At its October 2011 meeting, the Advisory Committee on Immunization Practices (ACIP) recommended to the CDC that quadrivalent human papilloma virus vaccine (HPV4, Gardasil) be routinely given to all males ages 11 to 21 and to men ages 22 to 26 who have sex with men or who are HIV positive, if they have not been previously vaccinated. This replaces a 2009 recommendation that stated HPV4 vaccine could be used in males to prevent genital warts, but stopped short of advocating routine use for all males.¹

There were 3 reasons the previous recommendation did not include HPV4 for routine vaccination of males:

1. The vaccine had been shown to be effective only for prevention of genital warts.
2. The cost effectiveness of the vaccine for use in boys was poor and, in modeling, it yielded less benefit as more females were vaccinated.
3. It was thought that a more effective approach to preventing HPV disease would be to emphasize high rates of vaccination of females.

The new recommendation takes into account recent evidence demonstrating that the vaccine prevents anal intraepithelial neoplasia (AIN) in males, in addition to genital warts. Moreover, vaccination rates in females remain low, which makes vaccinating males more cost effective and additionally protective for females.

Female vaccination rates lower than expected

Despite its effectiveness and safety record, HPV vaccination has had a slow rate of acceptance among females ages 13 to 17 years. Coverage for this group documented in the last national vaccine survey was 48.7% for one dose and 32% for the recommended 3 doses.²

The vaccine is effective in preventing cervical intraepithelial neoplasia (TABLE 1),³ condyloma, and vaginal intraepithelial neoplasia in women ~15 to 26 years of age. Large studies of vaccine safety have documented no serious adverse reactions, other than syncope, which could occur as frequently as 17.9/10,000 females and 12.5/10,000 males.⁴ Another study that involved post-licensure safety data from >600,000 HPV4 doses found no increased risk for a variety of outcomes, including Guillain-Barré syndrome, stroke, venous thromboembolism, appendicitis, seizures, syncope, allergic reactions, and anaphylaxis.^5,6

TABLE 1
HPV vaccine efficacy against HPV type-related CIN2+ in females ages ~15 to 26 years³

HPV-associated disease in males

HPV causes anal, penile, and oropharyngeal cancers in males, with about 7500 cancers occurring each year in the United States.³ In addition, about 1% of sexually active males in America have genital warts at any one time.⁷ HPV types 6 and 11 cause about 90% of cases.¹

The HPV4 vaccine—when all 3 doses are given—is 89.3% effective in preventing genital warts related to HPV types 6 and 11. Even a single dose is 68.1% effective (95% CI, 48.8–80.7).¹ New evidence shows that HPV4 prevents AIN, which can lead to anal cancer.⁸ Effectiveness in preventing AIN 2/3 is 74.9% (95% CI, 8.8–95.4) in those completing 3 doses before onset of infection with one of the HPV types contained in vaccine. Notably, these results were obtained in a subgroup analysis of men who have sex with men. And although the reduction in AIN is expected to lower the incidence of anal cancer, ongoing studies require time to confirm this. If such a reduction is confirmed (and vaccination is started at age 12 in the general male population), the number-needed-to-vaccinate to prevent one case of genital warts would be 18, and to prevent one case of anal cancer, 1581.⁶

No studies have evaluated efficacy of HPV4 in preventing penile or oropharyngeal cancers.

Men who have sex with men at high risk
Men who have sex with men have higher rates of AIN, anal cancers, and genital warts than the general male population.³ Those who are additionally HIV positive have higher rates of genital warts, which are also more difficult to treat.³ AIN is also more common in HIV-infected males.³ The HPV4 vaccine is immunogenic in those who are HIV infected, although the resulting antibody titers are lower than in other populations.

A look at the 2 HPV vaccines
Two HPV vaccines are available (TABLE 2).³ HPV4 vaccine protects against HPV 6, 11, 16, and 18. Bivalent (HPV2, Cervarix) vaccine contains antigens from HPV 16 and 18. Both vaccines are approved for use in females for the prevention of cervical cancer; HPV4 is preferred if protection against genital warts is also desired. Only HPV4 has been licensed for use in males.

TABLE 2
A look at the human papillomavirus vaccines³

HPV vaccine is effective, but costly

A major consideration with HPV vaccines is their cost. With 3 doses required and each dose costing about $130,⁹ cost effectiveness is poor when preventing uncommon diseases such as cervical and anal cancer, and a relatively benign disease such as genital warts. Male vaccination at age 12 years, when added to a female vaccination program, costs about $20,000 to $40,000 per quality-adjusted life year (QALY) if all potential HPV morbidity is included, not just that which has been proven to be prevented by the vaccine (assuming oral and penile cancer will also be prevented). Counting only HPV disease demonstrated to be prevented by the vaccine, the result is $75,000 to $250,000+ per QALY.⁶ Vaccinating males older than 21 years results in a cost per QALY 2 to 4 times that of vaccinating males younger than 18 years.¹⁰

A final decision. After considering these factors, ACIP approved a set of recommendations at its October 2011 meeting that will become official once they are published in the Morbidity and Mortality Weekly Report. (See “ACIP recommendations for HPV vaccine use in males”.)

At its October 2011 meeting, the Advisory Committee on Immunization Practices (ACIP) recommended to the CDC that quadrivalent human papilloma virus vaccine (HPV4, Gardasil) be routinely given to all males ages 11 to 21 and to men ages 22 to 26 who have sex with men or who are HIV positive, if they have not been previously vaccinated. This replaces a 2009 recommendation that stated HPV4 vaccine could be used in males to prevent genital warts, but stopped short of advocating routine use for all males.¹

There were 3 reasons the previous recommendation did not include HPV4 for routine vaccination of males:

1. The vaccine had been shown to be effective only for prevention of genital warts.
2. The cost effectiveness of the vaccine for use in boys was poor and, in modeling, it yielded less benefit as more females were vaccinated.
3. It was thought that a more effective approach to preventing HPV disease would be to emphasize high rates of vaccination of females.

The new recommendation takes into account recent evidence demonstrating that the vaccine prevents anal intraepithelial neoplasia (AIN) in males, in addition to genital warts. Moreover, vaccination rates in females remain low, which makes vaccinating males more cost effective and additionally protective for females.

Female vaccination rates lower than expected

Despite its effectiveness and safety record, HPV vaccination has had a slow rate of acceptance among females ages 13 to 17 years. Coverage for this group documented in the last national vaccine survey was 48.7% for one dose and 32% for the recommended 3 doses.²

The vaccine is effective in preventing cervical intraepithelial neoplasia (TABLE 1),³ condyloma, and vaginal intraepithelial neoplasia in women ~15 to 26 years of age. Large studies of vaccine safety have documented no serious adverse reactions, other than syncope, which could occur as frequently as 17.9/10,000 females and 12.5/10,000 males.⁴ Another study that involved post-licensure safety data from >600,000 HPV4 doses found no increased risk for a variety of outcomes, including Guillain-Barré syndrome, stroke, venous thromboembolism, appendicitis, seizures, syncope, allergic reactions, and anaphylaxis.^5,6

TABLE 1
HPV vaccine efficacy against HPV type-related CIN2+ in females ages ~15 to 26 years³

HPV-associated disease in males

HPV causes anal, penile, and oropharyngeal cancers in males, with about 7500 cancers occurring each year in the United States.³ In addition, about 1% of sexually active males in America have genital warts at any one time.⁷ HPV types 6 and 11 cause about 90% of cases.¹

The HPV4 vaccine—when all 3 doses are given—is 89.3% effective in preventing genital warts related to HPV types 6 and 11. Even a single dose is 68.1% effective (95% CI, 48.8–80.7).¹ New evidence shows that HPV4 prevents AIN, which can lead to anal cancer.⁸ Effectiveness in preventing AIN 2/3 is 74.9% (95% CI, 8.8–95.4) in those completing 3 doses before onset of infection with one of the HPV types contained in vaccine. Notably, these results were obtained in a subgroup analysis of men who have sex with men. And although the reduction in AIN is expected to lower the incidence of anal cancer, ongoing studies require time to confirm this. If such a reduction is confirmed (and vaccination is started at age 12 in the general male population), the number-needed-to-vaccinate to prevent one case of genital warts would be 18, and to prevent one case of anal cancer, 1581.⁶

No studies have evaluated efficacy of HPV4 in preventing penile or oropharyngeal cancers.

Men who have sex with men at high risk
Men who have sex with men have higher rates of AIN, anal cancers, and genital warts than the general male population.³ Those who are additionally HIV positive have higher rates of genital warts, which are also more difficult to treat.³ AIN is also more common in HIV-infected males.³ The HPV4 vaccine is immunogenic in those who are HIV infected, although the resulting antibody titers are lower than in other populations.

A look at the 2 HPV vaccines
Two HPV vaccines are available (TABLE 2).³ HPV4 vaccine protects against HPV 6, 11, 16, and 18. Bivalent (HPV2, Cervarix) vaccine contains antigens from HPV 16 and 18. Both vaccines are approved for use in females for the prevention of cervical cancer; HPV4 is preferred if protection against genital warts is also desired. Only HPV4 has been licensed for use in males.

TABLE 2
A look at the human papillomavirus vaccines³

HPV vaccine is effective, but costly

A major consideration with HPV vaccines is their cost. With 3 doses required and each dose costing about $130,⁹ cost effectiveness is poor when preventing uncommon diseases such as cervical and anal cancer, and a relatively benign disease such as genital warts. Male vaccination at age 12 years, when added to a female vaccination program, costs about $20,000 to $40,000 per quality-adjusted life year (QALY) if all potential HPV morbidity is included, not just that which has been proven to be prevented by the vaccine (assuming oral and penile cancer will also be prevented). Counting only HPV disease demonstrated to be prevented by the vaccine, the result is $75,000 to $250,000+ per QALY.⁶ Vaccinating males older than 21 years results in a cost per QALY 2 to 4 times that of vaccinating males younger than 18 years.¹⁰

A final decision. After considering these factors, ACIP approved a set of recommendations at its October 2011 meeting that will become official once they are published in the Morbidity and Mortality Weekly Report. (See “ACIP recommendations for HPV vaccine use in males”.)

At its October 2011 meeting, the Advisory Committee on Immunization Practices (ACIP) recommended to the CDC that quadrivalent human papilloma virus vaccine (HPV4, Gardasil) be routinely given to all males ages 11 to 21 and to men ages 22 to 26 who have sex with men or who are HIV positive, if they have not been previously vaccinated. This replaces a 2009 recommendation that stated HPV4 vaccine could be used in males to prevent genital warts, but stopped short of advocating routine use for all males.¹

There were 3 reasons the previous recommendation did not include HPV4 for routine vaccination of males:

1. The vaccine had been shown to be effective only for prevention of genital warts.
2. The cost effectiveness of the vaccine for use in boys was poor and, in modeling, it yielded less benefit as more females were vaccinated.
3. It was thought that a more effective approach to preventing HPV disease would be to emphasize high rates of vaccination of females.

The new recommendation takes into account recent evidence demonstrating that the vaccine prevents anal intraepithelial neoplasia (AIN) in males, in addition to genital warts. Moreover, vaccination rates in females remain low, which makes vaccinating males more cost effective and additionally protective for females.

Female vaccination rates lower than expected

Despite its effectiveness and safety record, HPV vaccination has had a slow rate of acceptance among females ages 13 to 17 years. Coverage for this group documented in the last national vaccine survey was 48.7% for one dose and 32% for the recommended 3 doses.²

The vaccine is effective in preventing cervical intraepithelial neoplasia (TABLE 1),³ condyloma, and vaginal intraepithelial neoplasia in women ~15 to 26 years of age. Large studies of vaccine safety have documented no serious adverse reactions, other than syncope, which could occur as frequently as 17.9/10,000 females and 12.5/10,000 males.⁴ Another study that involved post-licensure safety data from >600,000 HPV4 doses found no increased risk for a variety of outcomes, including Guillain-Barré syndrome, stroke, venous thromboembolism, appendicitis, seizures, syncope, allergic reactions, and anaphylaxis.^5,6

TABLE 1
HPV vaccine efficacy against HPV type-related CIN2+ in females ages ~15 to 26 years³

HPV-associated disease in males

HPV causes anal, penile, and oropharyngeal cancers in males, with about 7500 cancers occurring each year in the United States.³ In addition, about 1% of sexually active males in America have genital warts at any one time.⁷ HPV types 6 and 11 cause about 90% of cases.¹

The HPV4 vaccine—when all 3 doses are given—is 89.3% effective in preventing genital warts related to HPV types 6 and 11. Even a single dose is 68.1% effective (95% CI, 48.8–80.7).¹ New evidence shows that HPV4 prevents AIN, which can lead to anal cancer.⁸ Effectiveness in preventing AIN 2/3 is 74.9% (95% CI, 8.8–95.4) in those completing 3 doses before onset of infection with one of the HPV types contained in vaccine. Notably, these results were obtained in a subgroup analysis of men who have sex with men. And although the reduction in AIN is expected to lower the incidence of anal cancer, ongoing studies require time to confirm this. If such a reduction is confirmed (and vaccination is started at age 12 in the general male population), the number-needed-to-vaccinate to prevent one case of genital warts would be 18, and to prevent one case of anal cancer, 1581.⁶

No studies have evaluated efficacy of HPV4 in preventing penile or oropharyngeal cancers.

Men who have sex with men at high risk
Men who have sex with men have higher rates of AIN, anal cancers, and genital warts than the general male population.³ Those who are additionally HIV positive have higher rates of genital warts, which are also more difficult to treat.³ AIN is also more common in HIV-infected males.³ The HPV4 vaccine is immunogenic in those who are HIV infected, although the resulting antibody titers are lower than in other populations.

A look at the 2 HPV vaccines
Two HPV vaccines are available (TABLE 2).³ HPV4 vaccine protects against HPV 6, 11, 16, and 18. Bivalent (HPV2, Cervarix) vaccine contains antigens from HPV 16 and 18. Both vaccines are approved for use in females for the prevention of cervical cancer; HPV4 is preferred if protection against genital warts is also desired. Only HPV4 has been licensed for use in males.

TABLE 2
A look at the human papillomavirus vaccines³

HPV vaccine is effective, but costly

A major consideration with HPV vaccines is their cost. With 3 doses required and each dose costing about $130,⁹ cost effectiveness is poor when preventing uncommon diseases such as cervical and anal cancer, and a relatively benign disease such as genital warts. Male vaccination at age 12 years, when added to a female vaccination program, costs about $20,000 to $40,000 per quality-adjusted life year (QALY) if all potential HPV morbidity is included, not just that which has been proven to be prevented by the vaccine (assuming oral and penile cancer will also be prevented). Counting only HPV disease demonstrated to be prevented by the vaccine, the result is $75,000 to $250,000+ per QALY.⁶ Vaccinating males older than 21 years results in a cost per QALY 2 to 4 times that of vaccinating males younger than 18 years.¹⁰

A final decision. After considering these factors, ACIP approved a set of recommendations at its October 2011 meeting that will become official once they are published in the Morbidity and Mortality Weekly Report. (See “ACIP recommendations for HPV vaccine use in males”.)

CASE As part of a routine physical examination, urinalysis reveals that a patient new to your practice is excreting an excessive level of protein. The patient is physically fit and shared during the history taking that he is an avid runner. The physical examination and other laboratory values were unremarkable. How concerned should you be about the finding of proteinuria?

Exercise-induced proteinuria is generally benign and a function of the intensity—rather than the duration—of exercise.¹ It occurs most often among athletes participating in such sports as running, swimming, rowing, football, or boxing.² It’s also transient—lasting 24 to 48 hours.¹ Recognizing exercise-induced proteinuria is fairly straightforward—once you know what to look for.

But first, a word about the processes at work.

Diverse processes that work alone—or together

The normal range of protein excretion in healthy individuals is 150 to 200 mg of protein per day, of which albumin constitutes 10 to 20 mg.³ Individuals with proteinuria persistently higher than this level need further evaluation.

Diverse processes leading to proteinuria—working alone or concomitantly—occur at the level of the nephron.³

Glomerular proteinuria results from increased filtration of macromolecules such as albumin across the glomerular capillary barrier. This type of proteinuria can occur with different glomerulopathies, upright posture, or exercise.⁴

Researchers have not identified the mechanisms leading to postexercise proteinuria, but there are several theories. (For more on this, see “Why does exercise increase protein excretion?”.)

Tubular proteinuria is due to a deranged tubular apparatus with an intact glomerulus. This results in the escape of β2-microglobulin and immunoglobulin light chains from proximal tubular reabsorption. It is often missed on dipstick testing, which detects only albumin. This type of proteinuria is usually seen in tubulointerstitial diseases or in patients with idiopathic nephrotic syndrome.⁵

Overflow proteinuria occurs when small molecular light chains escape the glomerular filtration barrier and overwhelm the tubular reabsorptive capacity. This type of proteinuria can be seen in multiple myeloma, and is detectable by protein-to-creatinine ratio or urine protein electrophoresis.

The surest means of detecting proteinuria
Albumin excretion >300 mg/d is called macroalbuminuria, overt proteinuria, or dipstick-positive proteinuria. Albumin persistently excreted in the urine between 30 and 300 mg/d is referred to as microalbuminuria.

Because microalbuminuria is not detectable by a standard urine dipstick test, some providers routinely screen for protein with the microalbumin-to-creatinine ratio. A first-voided morning urine specimen is recommended, but random urine samples are an acceptable alternative.⁶ The microalbumin-to-creatinine ratio is recommended as a screen for early diabetic nephropathy and other kidney diseases. And a positive test result may also suggest increased risk of cardiovascular disease.⁶ Microalbuminuria is defined as persistent albumin excretion between 30 and 300 mg/d.⁷

When exercise is a factor, here’s what to look for

As noted earlier, exercise-induced proteinuria is a function of the intensity of the exercise. Moderate and strenuous (vigorous) exercise are the 2 types of exercise that come into play when discussing proteinuria. Differentiating them is not precise, but is often defined by maximal oxygen consumption (vigorous=60% of VO₂max; moderate <60% VO₂max); metabolic equivalents (vigorous=6 METS; moderate <6 METS); walking/running speeds (various); and heart rate reserve (vigorous=60% HRR; moderate <60% HRR).⁸

Moderate exercise produces glomerular proteinuria, with an increase in macromolecular (albumin) filtration across the glomerular barrier. Strenuous exercise increases glomerular filtration of low-molecular-weight proteins (β2-microglobulin), which overwhelm the reabsorbing capacity of the tubular apparatus, causing temporary dysfunction and tubular proteinuria.⁹ Thus, the pathophysiology is mixed, with a major contribution from glomerular proteinuria.¹⁰

Strenuous exercise can cause protein excretion to exceed 1.5 mg/min.¹¹ However, it seldom rises beyond 1 to 2 g/d,⁴ and this increase usually reverts to normal physiologic levels within 24 to 48 hours after exercise.¹²

Exercise-induced proteinuria is biphasic.¹³ Increased protein excretion occurs 30 minutes after exercise and is related to changes in intraglomerular hemodynamics and the resulting saturation of the renal tubules. Around 24 hours after exercise, oxidative stress on the glomeruli causes another slight elevation in albumin excretion without changes in β2-microglobulin, thereby indicating glomerular proteinuria exclusively.

Even the pros aren’t exempt. Exercise-induced proteinuria does not decrease with regular physical training. This was demonstrated in a study of 10 well-trained professional cyclists for whom strenuous exercise increased overnight protein excretion of both tubular and glomerular origin despite ongoing regular physical training.¹⁴

Creatine supplements do not increase proteinuria. A study of creatine supplementation in animal models noted no changes in 24-hour proteinuria or albumin excretion in both normal and two-thirds-nephrectomized animals.¹⁵ Another study compared creatine use with nonuse in athletes who had been training regularly and strenuously (12- 18 h/wk) for 5 to 10 years. They were evaluated for 10 months to 5 years. The groups exhibited equivalent urine excretion rates for albumin and creatinine, with no deleterious effect on kidney function.¹⁶

What happens when chronic disease is factored into the exercise equation?
Patients with a 2- to 20-year history of insulin-dependent diabetes without chronic kidney disease (CKD) who exhibited normal albumin excretion at baseline were more likely to develop proteinuria after exercise than healthy controls.^17,18 The postulated cause was undetected glomerular changes due to diabetes. An exercise-provocation test may one day be useful in predicting future development of nephropathy, but further studies are needed.^19-21

Exercise increases proteinuria immediately in individuals with metabolic disorders like obesity, through a mechanism different from diabetes mellitus. Proteinuria in the obese population is thought to be glomerular in origin, as opposed to both tubular and glomerular proteinuria in diabetic nephropathy.^22,23

In CKD, low-intensity exercise long term does not promote proteinuria or lead to rapid progression of CKD. In one study, obese patients (body mass index >30 kg/m²) with diabetes and CKD stage II to IV who exercised 3 times weekly (aerobic training for 6 weeks, followed by 18 weeks of supervised home exercise) increased their stamina and exhibited slight, statistically insignificant decreases in resting systolic blood pressure and 24-hour proteinuria.²⁴ A 12-week low-intensity aquatic exercise program for 26 patients with mild to moderate CKD decreased blood pressure and proteinuria and slightly improved glomerular filtration rate (GFR).²⁵ These results for proteinuria and GFR were shown previously in rats with subtotal nephrectomy.²⁶

Elevated urinary albumin excretion with exercise is significantly higher in patients with acromegaly when compared with normal healthy subjects. The underlying pathology is thought to occur at the glomerular filtration barrier with intact tubular function. Somatostatin analog treatment for acromegaly leads to reductions in postexercise albuminuria.^27,28

How to manage suspected exercise-induced proteinuria

When interpreting the meaning of proteinuria detected on routine urinalysis, keep in mind the temporal relevance between exercise and urine collection. If urine is found to have been collected within 24 hours of intense exercise, repeat testing in the absence of prior exercise on at least one other occasion to differentiate between transient and persistent proteinuria. In confirming transient proteinuria after exercise, reassure the patient that it is a benign condition. This holds true as well for routine microalbumin-to-creatinine urine testing in patients with diabetes who exercise. If the result of a repeat test is high, turn your attention to another possible cause of proteinuria, such as diabetic nephropathy.

Screening for proteinuria during sports preparticipation examinations is not recommended because the diagnostic utility is low.²⁹ Researchers performed urine dipstick testing for protein, blood, and glucose in preparticipation assessments of 701 students.²⁹ They detected proteinuria in 40 students and glucosuria in one. Follow-up testing with first-voided morning urine specimens and glucose tolerance testing was normal in all students.

CORRESPONDENCE Fahad Saeed, MD, 313 Brook Hollow, Hanover, NH 03755; fahadsaeed20@gmail.com

CASE As part of a routine physical examination, urinalysis reveals that a patient new to your practice is excreting an excessive level of protein. The patient is physically fit and shared during the history taking that he is an avid runner. The physical examination and other laboratory values were unremarkable. How concerned should you be about the finding of proteinuria?

Exercise-induced proteinuria is generally benign and a function of the intensity—rather than the duration—of exercise.¹ It occurs most often among athletes participating in such sports as running, swimming, rowing, football, or boxing.² It’s also transient—lasting 24 to 48 hours.¹ Recognizing exercise-induced proteinuria is fairly straightforward—once you know what to look for.

But first, a word about the processes at work.

Diverse processes that work alone—or together

The normal range of protein excretion in healthy individuals is 150 to 200 mg of protein per day, of which albumin constitutes 10 to 20 mg.³ Individuals with proteinuria persistently higher than this level need further evaluation.

Diverse processes leading to proteinuria—working alone or concomitantly—occur at the level of the nephron.³

Glomerular proteinuria results from increased filtration of macromolecules such as albumin across the glomerular capillary barrier. This type of proteinuria can occur with different glomerulopathies, upright posture, or exercise.⁴

Researchers have not identified the mechanisms leading to postexercise proteinuria, but there are several theories. (For more on this, see “Why does exercise increase protein excretion?”.)

Tubular proteinuria is due to a deranged tubular apparatus with an intact glomerulus. This results in the escape of β2-microglobulin and immunoglobulin light chains from proximal tubular reabsorption. It is often missed on dipstick testing, which detects only albumin. This type of proteinuria is usually seen in tubulointerstitial diseases or in patients with idiopathic nephrotic syndrome.⁵

Overflow proteinuria occurs when small molecular light chains escape the glomerular filtration barrier and overwhelm the tubular reabsorptive capacity. This type of proteinuria can be seen in multiple myeloma, and is detectable by protein-to-creatinine ratio or urine protein electrophoresis.

The surest means of detecting proteinuria
Albumin excretion >300 mg/d is called macroalbuminuria, overt proteinuria, or dipstick-positive proteinuria. Albumin persistently excreted in the urine between 30 and 300 mg/d is referred to as microalbuminuria.

Because microalbuminuria is not detectable by a standard urine dipstick test, some providers routinely screen for protein with the microalbumin-to-creatinine ratio. A first-voided morning urine specimen is recommended, but random urine samples are an acceptable alternative.⁶ The microalbumin-to-creatinine ratio is recommended as a screen for early diabetic nephropathy and other kidney diseases. And a positive test result may also suggest increased risk of cardiovascular disease.⁶ Microalbuminuria is defined as persistent albumin excretion between 30 and 300 mg/d.⁷

When exercise is a factor, here’s what to look for

As noted earlier, exercise-induced proteinuria is a function of the intensity of the exercise. Moderate and strenuous (vigorous) exercise are the 2 types of exercise that come into play when discussing proteinuria. Differentiating them is not precise, but is often defined by maximal oxygen consumption (vigorous=60% of VO₂max; moderate <60% VO₂max); metabolic equivalents (vigorous=6 METS; moderate <6 METS); walking/running speeds (various); and heart rate reserve (vigorous=60% HRR; moderate <60% HRR).⁸

Moderate exercise produces glomerular proteinuria, with an increase in macromolecular (albumin) filtration across the glomerular barrier. Strenuous exercise increases glomerular filtration of low-molecular-weight proteins (β2-microglobulin), which overwhelm the reabsorbing capacity of the tubular apparatus, causing temporary dysfunction and tubular proteinuria.⁹ Thus, the pathophysiology is mixed, with a major contribution from glomerular proteinuria.¹⁰

Strenuous exercise can cause protein excretion to exceed 1.5 mg/min.¹¹ However, it seldom rises beyond 1 to 2 g/d,⁴ and this increase usually reverts to normal physiologic levels within 24 to 48 hours after exercise.¹²

Exercise-induced proteinuria is biphasic.¹³ Increased protein excretion occurs 30 minutes after exercise and is related to changes in intraglomerular hemodynamics and the resulting saturation of the renal tubules. Around 24 hours after exercise, oxidative stress on the glomeruli causes another slight elevation in albumin excretion without changes in β2-microglobulin, thereby indicating glomerular proteinuria exclusively.

Even the pros aren’t exempt. Exercise-induced proteinuria does not decrease with regular physical training. This was demonstrated in a study of 10 well-trained professional cyclists for whom strenuous exercise increased overnight protein excretion of both tubular and glomerular origin despite ongoing regular physical training.¹⁴

Creatine supplements do not increase proteinuria. A study of creatine supplementation in animal models noted no changes in 24-hour proteinuria or albumin excretion in both normal and two-thirds-nephrectomized animals.¹⁵ Another study compared creatine use with nonuse in athletes who had been training regularly and strenuously (12- 18 h/wk) for 5 to 10 years. They were evaluated for 10 months to 5 years. The groups exhibited equivalent urine excretion rates for albumin and creatinine, with no deleterious effect on kidney function.¹⁶

What happens when chronic disease is factored into the exercise equation?
Patients with a 2- to 20-year history of insulin-dependent diabetes without chronic kidney disease (CKD) who exhibited normal albumin excretion at baseline were more likely to develop proteinuria after exercise than healthy controls.^17,18 The postulated cause was undetected glomerular changes due to diabetes. An exercise-provocation test may one day be useful in predicting future development of nephropathy, but further studies are needed.^19-21

Exercise increases proteinuria immediately in individuals with metabolic disorders like obesity, through a mechanism different from diabetes mellitus. Proteinuria in the obese population is thought to be glomerular in origin, as opposed to both tubular and glomerular proteinuria in diabetic nephropathy.^22,23

In CKD, low-intensity exercise long term does not promote proteinuria or lead to rapid progression of CKD. In one study, obese patients (body mass index >30 kg/m²) with diabetes and CKD stage II to IV who exercised 3 times weekly (aerobic training for 6 weeks, followed by 18 weeks of supervised home exercise) increased their stamina and exhibited slight, statistically insignificant decreases in resting systolic blood pressure and 24-hour proteinuria.²⁴ A 12-week low-intensity aquatic exercise program for 26 patients with mild to moderate CKD decreased blood pressure and proteinuria and slightly improved glomerular filtration rate (GFR).²⁵ These results for proteinuria and GFR were shown previously in rats with subtotal nephrectomy.²⁶

Elevated urinary albumin excretion with exercise is significantly higher in patients with acromegaly when compared with normal healthy subjects. The underlying pathology is thought to occur at the glomerular filtration barrier with intact tubular function. Somatostatin analog treatment for acromegaly leads to reductions in postexercise albuminuria.^27,28

How to manage suspected exercise-induced proteinuria

When interpreting the meaning of proteinuria detected on routine urinalysis, keep in mind the temporal relevance between exercise and urine collection. If urine is found to have been collected within 24 hours of intense exercise, repeat testing in the absence of prior exercise on at least one other occasion to differentiate between transient and persistent proteinuria. In confirming transient proteinuria after exercise, reassure the patient that it is a benign condition. This holds true as well for routine microalbumin-to-creatinine urine testing in patients with diabetes who exercise. If the result of a repeat test is high, turn your attention to another possible cause of proteinuria, such as diabetic nephropathy.

Screening for proteinuria during sports preparticipation examinations is not recommended because the diagnostic utility is low.²⁹ Researchers performed urine dipstick testing for protein, blood, and glucose in preparticipation assessments of 701 students.²⁹ They detected proteinuria in 40 students and glucosuria in one. Follow-up testing with first-voided morning urine specimens and glucose tolerance testing was normal in all students.

CORRESPONDENCE Fahad Saeed, MD, 313 Brook Hollow, Hanover, NH 03755; fahadsaeed20@gmail.com

CASE As part of a routine physical examination, urinalysis reveals that a patient new to your practice is excreting an excessive level of protein. The patient is physically fit and shared during the history taking that he is an avid runner. The physical examination and other laboratory values were unremarkable. How concerned should you be about the finding of proteinuria?

Exercise-induced proteinuria is generally benign and a function of the intensity—rather than the duration—of exercise.¹ It occurs most often among athletes participating in such sports as running, swimming, rowing, football, or boxing.² It’s also transient—lasting 24 to 48 hours.¹ Recognizing exercise-induced proteinuria is fairly straightforward—once you know what to look for.

But first, a word about the processes at work.

Diverse processes that work alone—or together

The normal range of protein excretion in healthy individuals is 150 to 200 mg of protein per day, of which albumin constitutes 10 to 20 mg.³ Individuals with proteinuria persistently higher than this level need further evaluation.

Diverse processes leading to proteinuria—working alone or concomitantly—occur at the level of the nephron.³

Glomerular proteinuria results from increased filtration of macromolecules such as albumin across the glomerular capillary barrier. This type of proteinuria can occur with different glomerulopathies, upright posture, or exercise.⁴

Researchers have not identified the mechanisms leading to postexercise proteinuria, but there are several theories. (For more on this, see “Why does exercise increase protein excretion?”.)

Tubular proteinuria is due to a deranged tubular apparatus with an intact glomerulus. This results in the escape of β2-microglobulin and immunoglobulin light chains from proximal tubular reabsorption. It is often missed on dipstick testing, which detects only albumin. This type of proteinuria is usually seen in tubulointerstitial diseases or in patients with idiopathic nephrotic syndrome.⁵

Overflow proteinuria occurs when small molecular light chains escape the glomerular filtration barrier and overwhelm the tubular reabsorptive capacity. This type of proteinuria can be seen in multiple myeloma, and is detectable by protein-to-creatinine ratio or urine protein electrophoresis.

The surest means of detecting proteinuria
Albumin excretion >300 mg/d is called macroalbuminuria, overt proteinuria, or dipstick-positive proteinuria. Albumin persistently excreted in the urine between 30 and 300 mg/d is referred to as microalbuminuria.

Because microalbuminuria is not detectable by a standard urine dipstick test, some providers routinely screen for protein with the microalbumin-to-creatinine ratio. A first-voided morning urine specimen is recommended, but random urine samples are an acceptable alternative.⁶ The microalbumin-to-creatinine ratio is recommended as a screen for early diabetic nephropathy and other kidney diseases. And a positive test result may also suggest increased risk of cardiovascular disease.⁶ Microalbuminuria is defined as persistent albumin excretion between 30 and 300 mg/d.⁷

When exercise is a factor, here’s what to look for

As noted earlier, exercise-induced proteinuria is a function of the intensity of the exercise. Moderate and strenuous (vigorous) exercise are the 2 types of exercise that come into play when discussing proteinuria. Differentiating them is not precise, but is often defined by maximal oxygen consumption (vigorous=60% of VO₂max; moderate <60% VO₂max); metabolic equivalents (vigorous=6 METS; moderate <6 METS); walking/running speeds (various); and heart rate reserve (vigorous=60% HRR; moderate <60% HRR).⁸

Moderate exercise produces glomerular proteinuria, with an increase in macromolecular (albumin) filtration across the glomerular barrier. Strenuous exercise increases glomerular filtration of low-molecular-weight proteins (β2-microglobulin), which overwhelm the reabsorbing capacity of the tubular apparatus, causing temporary dysfunction and tubular proteinuria.⁹ Thus, the pathophysiology is mixed, with a major contribution from glomerular proteinuria.¹⁰

Strenuous exercise can cause protein excretion to exceed 1.5 mg/min.¹¹ However, it seldom rises beyond 1 to 2 g/d,⁴ and this increase usually reverts to normal physiologic levels within 24 to 48 hours after exercise.¹²

Exercise-induced proteinuria is biphasic.¹³ Increased protein excretion occurs 30 minutes after exercise and is related to changes in intraglomerular hemodynamics and the resulting saturation of the renal tubules. Around 24 hours after exercise, oxidative stress on the glomeruli causes another slight elevation in albumin excretion without changes in β2-microglobulin, thereby indicating glomerular proteinuria exclusively.

Even the pros aren’t exempt. Exercise-induced proteinuria does not decrease with regular physical training. This was demonstrated in a study of 10 well-trained professional cyclists for whom strenuous exercise increased overnight protein excretion of both tubular and glomerular origin despite ongoing regular physical training.¹⁴

Creatine supplements do not increase proteinuria. A study of creatine supplementation in animal models noted no changes in 24-hour proteinuria or albumin excretion in both normal and two-thirds-nephrectomized animals.¹⁵ Another study compared creatine use with nonuse in athletes who had been training regularly and strenuously (12- 18 h/wk) for 5 to 10 years. They were evaluated for 10 months to 5 years. The groups exhibited equivalent urine excretion rates for albumin and creatinine, with no deleterious effect on kidney function.¹⁶

What happens when chronic disease is factored into the exercise equation?
Patients with a 2- to 20-year history of insulin-dependent diabetes without chronic kidney disease (CKD) who exhibited normal albumin excretion at baseline were more likely to develop proteinuria after exercise than healthy controls.^17,18 The postulated cause was undetected glomerular changes due to diabetes. An exercise-provocation test may one day be useful in predicting future development of nephropathy, but further studies are needed.^19-21

Exercise increases proteinuria immediately in individuals with metabolic disorders like obesity, through a mechanism different from diabetes mellitus. Proteinuria in the obese population is thought to be glomerular in origin, as opposed to both tubular and glomerular proteinuria in diabetic nephropathy.^22,23

In CKD, low-intensity exercise long term does not promote proteinuria or lead to rapid progression of CKD. In one study, obese patients (body mass index >30 kg/m²) with diabetes and CKD stage II to IV who exercised 3 times weekly (aerobic training for 6 weeks, followed by 18 weeks of supervised home exercise) increased their stamina and exhibited slight, statistically insignificant decreases in resting systolic blood pressure and 24-hour proteinuria.²⁴ A 12-week low-intensity aquatic exercise program for 26 patients with mild to moderate CKD decreased blood pressure and proteinuria and slightly improved glomerular filtration rate (GFR).²⁵ These results for proteinuria and GFR were shown previously in rats with subtotal nephrectomy.²⁶

Elevated urinary albumin excretion with exercise is significantly higher in patients with acromegaly when compared with normal healthy subjects. The underlying pathology is thought to occur at the glomerular filtration barrier with intact tubular function. Somatostatin analog treatment for acromegaly leads to reductions in postexercise albuminuria.^27,28

How to manage suspected exercise-induced proteinuria

When interpreting the meaning of proteinuria detected on routine urinalysis, keep in mind the temporal relevance between exercise and urine collection. If urine is found to have been collected within 24 hours of intense exercise, repeat testing in the absence of prior exercise on at least one other occasion to differentiate between transient and persistent proteinuria. In confirming transient proteinuria after exercise, reassure the patient that it is a benign condition. This holds true as well for routine microalbumin-to-creatinine urine testing in patients with diabetes who exercise. If the result of a repeat test is high, turn your attention to another possible cause of proteinuria, such as diabetic nephropathy.

Screening for proteinuria during sports preparticipation examinations is not recommended because the diagnostic utility is low.²⁹ Researchers performed urine dipstick testing for protein, blood, and glucose in preparticipation assessments of 701 students.²⁹ They detected proteinuria in 40 students and glucosuria in one. Follow-up testing with first-voided morning urine specimens and glucose tolerance testing was normal in all students.

CORRESPONDENCE Fahad Saeed, MD, 313 Brook Hollow, Hanover, NH 03755; fahadsaeed20@gmail.com

Shoulder pain is a common reason for visits to primary care physicians, who are most likely to diagnose it as rotator cuff tendinitis^1,2—often erroneously. The complexity of the joint and the overlapping pathologies that may present as shoulder pain highlight the need to take a closer look when dealing with this diagnostic challenge.

Often, a targeted medical history—including the mechanism of injury and pain-provoking and pain-relieving factors—and a problem-based physical examination (incorporating many of the maneuvers highlighted in the text and tables that follow) will lead to an accurate diagnosis without the need for imaging studies. We recommend that imaging be reserved for patients who don’t respond to conventional treatments, cases in which the diagnosis is in doubt, and instances in which surgical intervention is being considered.

The 3 cases* that follow, and the take-away message incorporated in each, will give you an opportunity to test—and to hone—your shoulder pain diagnostic skill.

CASE 1 The history: Jesse, a 17-year-old student who’s active in football and track, came in during track season complaining of severe left shoulder pain. He denied any traumatic event or previous injury to the shoulder, but reported that any motion involving the shoulder caused pain. It hurt at night, the patient said, when he lay on his left side.

The physical: No muscle atrophy, redness, or swelling was evident, nor was there any indication of asymmetry or ecchymosis in the affected area. Jesse’s neck range of motion was normal; he had a very hard time with any active motion of the shoulder, however, because of the pain.

Evaluation of scapular motion demonstrated scapular dyskinesis^3,4 without winging. Passive motion of the glenohumeral joint was much better than active motion. Strength testing appeared to be grossly intact but was limited by the pain. Shoulder impingement testing was positive. Sensation and deep tendon reflexes were intact.

Patients' names have been changed to protect their privacy

What’s the diagnosis?

Subacromial bursitis, suggested by the patient’s pain and altered scapular motion, was our working diagnosis, and we administered a subacromial injection of corticosteroid with lidocaine, for diagnostic as well as therapeutic purposes. Reexamination after the injection revealed immediate partial improvement in resting pain, range of motion, and strength. We referred Jesse to physical therapy with a focus on scapular stabilization and rotator cuff strength.

Three months later, Jesse returned to our office, complaining of weakness in his left shoulder. The pain had subsided a week after his first appointment, so he’d never gone to physical therapy. The weakness, which he had first noticed about 2 months after starting a lifting program in preparation for football season, was limited to resistance exercises, especially overhead shoulder presses and bench press. There were no other changes in his history, and he reported no reinjuries.

Physical examination revealed atrophy of the supraspinatus and infraspinatus muscles (FIGURE 1) and external rotation and shoulder abduction (in the scapular plane) resistance tests revealed weakness of these muscles. There was no scapular winging. The cervical spine exam was normal, and neurovascular status was intact in both upper extremities.

FIGURE 1
Severe shoulder pain, followed by weakness

New evidence points to nerve injury. Based on Jesse’s current history and physical, nerve injury was our new working diagnosis. (We considered the possibility of a rotator cuff tear, but this was not corroborated by the history.)

We ordered an electromyogram/nerve conduction velocity study to localize the lesion. The test revealed a brachial plexitis/neuritis (also known as Parsonage-Turner syndrome or brachial amyotrophy). The etiology of most atraumatic brachial plexopathies is unknown, and most are thought to be viral or autoimmune in nature.^5,6

A classic case of Parsonage-Turner syndrome. The typical presentation of Parsonage-Turner syndrome (like Jesse’s) is one of acute, intense shoulder pain for no known reason. After 1 to 3 weeks, the pain resolves and the patient is left with weakness, usually of the supraspinatus and infraspinatus muscles. The weakness typically resolves with time, but full resolution may take 6 to 9 months.^5,6 (In Jesse’s case, it took about 6 months.)

The take-away message: Look beyond the shoulder
As this case illustrates, not all shoulder pain originates in the shoulder. When evaluating shoulder pain, it is essential to consider other causes. The differential diagnosis for shoulder pain includes cervical spine disorders, cholecystitis (right shoulder), diaphragmatic irritation (eg, in the case of splenic rupture, usually involving the left shoulder), cardiac disease, and thoracic outlet syndrome.⁷

Evaluation of the cervical spine should be part of a complete shoulder examination. It is vital to follow a systematic approach that carefully assesses the cervical region for the possibility of nerve root impingement and radicular dysfunction masquerading as a primary shoulder disorder. (TABLE 1^8,9 details pain and sensory distribution patterns, reflex involvement, and potential motor impairments associated with various spinal nerve root levels.)

TABLE 1
Assessing the cervical spine

Practitioners should develop their own approach to “clearing the neck.” A logical order is to note posture of the head/neck/shoulders, observe active motion, perform palpation and provocative tests, and then assess neurologic function with sensation/reflex/strength testing. Provocative tests that can help to identify cervical involvement relating to shoulder pain include Spurling’s maneuver, axial compression test, abduction relief sign, and Lhermitte’s sign.^10,11

CASE 2 The history: Mark, a 17-year-old, right-handed volleyball player, presented with right shoulder pain, which he felt whenever he spiked or served the ball. The pain started last season, Mark said, diminished during the months when he wasn’t playing, then got progressively worse as his activity level increased. The pain was in the posterior aspect of the shoulder.

The physical: Physical examination revealed a well-developed, but thin (6’4”, 170 pounds) young man who was not in distress. The general examination was benign, and a joint-specific exam showed no asymmetry or atrophy on inspection and no tenderness to palpation over the posterior and anterior soft tissues of the right shoulder. Rotator cuff testing yielded intact strength for all 4 muscles, but external rotation and supraspinatus testing elicited pain. The crank test, drawer sign, load and shift test, relocation test, and sulcus sign, detailed in TABLE 2,^12-14 were all positive for shoulder instability; the Clunk and O’Brien tests were negative, and the contralateral shoulder exam was within normal limits. General joint laxity was observed, with the ability to oppose the thumb to the volar forearm and hyperextension noted in both elbows and knees. There were no outward signs of connective tissue disease.

Because of the chronicity of Mark’s pain and the progressive nature of his symptoms, we ordered radiographs, including anterior-posterior, lateral axillary, and scapular Y views. These films showed a nearly skeletally mature male without bony abnormalities; the humeral head was well located in the glenoid.

TABLE 2
Testing for shoulder instability^12-14

What’s the diagnosis?

Multidirectional instability with recurrent subluxations and probable acute rotator cuff tendinitis was our provisional diagnosis. Treatment focused on physical therapy, with a concentration on scapular stabilization and rotator cuff strengthening.

Shoulder instability is relatively common and represents a spectrum of disorders ranging from dislocation to subluxation to simple laxity.^12,13 A complete loss of humeral articulation within the glenoid fossa is evidence of dislocation, whereas subluxation includes approximation of the humeral head to the limits of the glenoid rim. Dislocation typically results from trauma, whereas subluxation can be the result of microtrauma and repetitive overuse injury. Anterior instability is the most common type and is reported in as many as 95% of all dislocations.¹³

The take-away message: Rule out instability
The shoulder is one of the most complex joints in the body. The rotator cuff structures, the glenoid labrum, and the collective capsular ligaments provide structural stability to the glenohumeral joint.^12,13 The shoulder is vulnerable to instability because the shallow glenoid fossa offers little bony support for the humeral head. Thus, instability should always be included in an assessment of shoulder pain.

Key factors to consider in identifying shoulder instability include the location of the pain, the direction of traumatic force applied, the presence of a known complete dislocation vs apprehension with specific movement, the position of the arm in which pain is elicited, a previous occurrence of instability (subluxation or dislocation), and the presence of tingling or numbness.^12-14 The maneuvers detailed in TABLE 2^12-14 can help identify instability, as they did in this case. Patients with hypermobility are at increased risk for shoulder instability, so a targeted exam and patient history aimed at identifying signs and symptoms of hypermobility is needed, as well.

Ask the patient to attempt to:

• bend the thumb to the volar forearm
• place hands to the floor with hyperextended knees
• perform maximal hyperextension of the fifth metacarpophalangeal joint (>90° is a positive result).

Findings from the medical history that indicate a predisposition to instability include generalized joint laxity, Ehlers-Danlos syndrome, Marfan syndrome, osteogenesis imperfecta, hyperhomocysteinuria, hyperlysinemia, benign joint hypermobility syndrome, juvenile rheumatoid arthritis, and previous shoulder or patellar dislocations.

Imaging tips: Scapular Y and/or axillary lateral views should always be included when ordering imaging studies for suspected instability/dislocations, as 50% of posterior dislocations are missed on standard shoulder x-rays that do not include them.¹² In reviewing the x-rays, it is important to look for signs of a compression fracture of the posterior humeral head (known as a Hill-Sachs lesion) for anterior shoulder dislocations, and fractures to the anterior glenoid rim (known as a Bankart lesion).^12-14

CASE 3 The history: Robert, a right-handed, 50-year-old motorcycle instructor, came to our office because of chronic right shoulder pain. The pain, located over the anterior portion of the glenohumeral joint, developed insidiously about 3 or 4 years ago, the patient reported. He had finally decided to seek help because he’d recently experienced an acute exacerbation of pain brought on by shoveling snow, after which he also noticed associated weakness, a clicking/popping on active motion, and mild loss of motion.

The physical: Robert’s cervical spine exam was unremarkable. He demonstrated full active range of motion (ROM) without exacerbation of right shoulder symptoms, and special tests for disc pathology at the neck were negative. Active ROM testing of the right shoulder revealed full abduction, with only minimal pain; full flexion, with moderate pain noted initially at 49°; full extension, with a painful arc noted at 50°; and full horizontal adduction, with a painful arc noted at the halfway point. The testing also revealed that his right thumb was 3 inches lower than the left on reaching for the opposite scapula. At the superior aspect of the acromioclavicular (AC) joint, 2+ tenderness was noted; 3+ tenderness was noted at the greater tubercle of the humerus.

After inspecting the shoulder region for alterations in bony landmarks, muscle bulk, carrying position, and movement characteristics, palpation of the region was performed.

When assessing shoulder strength, there are a variety of tests for each functioning component of the rotator cuff structures (TABLE 3).^15-17 Manual muscle tests revealed: 4-/5 on external rotation (French horn test), 3+/5 on the lift-off test, and 5-/5 on all other tests for right shoulder function. Impingement testing was slightly positive, or pain producing, on Hawkins and Neer tests.^18,19 For the Hawkins test, the examiner flexes the arm to 90° of shoulder flexion with the elbow flexed at 90°, then internally rotates the shoulder. For the Neer test, the arm is fully elevated in the scapular plane and internally rotated by the examiner.

The subscapularis muscle, which functions primarily in internal rotation, is tested by the French horn and lift-off tests. The teres minor muscle, which performs external rotation, is tested by the French horn test of external rotation. And the supraspinatus muscle, which performs abduction and external rotation, is tested by the empty can (also known as the Jobe) and full can tests. Some researchers suggest that the empty can test is better for diagnosing impingement, based on evidence showing that the full can test is better at diagnosing supraspinatus tears because it causes less pain during testing.²⁰

TABLE 3
Suspect rotator cuff involvement?^7,15-17

What’s the diagnosis?

Rotator cuff tear was suspected because Robert had positive elements of the “rotator cuff triad”—supraspinatus weakness (as indicated by a positive empty can test), external rotation weakness (revealed by the French horn test), and a positive Hawkins impingement test. We ordered diagnostic studies, including plain radiographs, which revealed degenerative changes at the acromioclavicular joint, decreased acromiohumeral interval, and no significant changes at the glenohumeral joint (FIGURE 2), and magnetic resonance imaging (MRI) of the right shoulder. The MRI revealed a large, full-thickness rotator cuff tear of the supraspinatus tendon with retraction. A torn and retracted biceps tendon and AC joint osteoarthritis were also shown, likely causing a mass effect on the supraspinatus. The patient underwent surgery to repair the torn rotator cuff, with excellent results.

FIGURE 2
Chronic right shoulder pain

The take-away message: Keep the rotator-cuff triad in mind
Because none of the tests that comprise the triad is specific enough alone to diagnose a rotator cuff tear,^15,20,21 Murrell and Walton¹⁶ suggested that the 3 tests be considered together for diagnostic purposes. If all 3 are positive, there is a 98% chance of a rotator cuff tear; if 2 tests are positive and the patient is older than 60 years, the findings are suggestive of a tear; and if all 3 tests (plus the drop arm test) are negative, there is less than a 5% chance of a major rotator cuff tear.¹⁶

CORRESPONDENCE Nilesh Shah, MD, Summa Center for Sports Health, 20 Olive Street, Suite 201, Akron, OH 44310; ShahN@summahealth.org

Shoulder pain is a common reason for visits to primary care physicians, who are most likely to diagnose it as rotator cuff tendinitis^1,2—often erroneously. The complexity of the joint and the overlapping pathologies that may present as shoulder pain highlight the need to take a closer look when dealing with this diagnostic challenge.

Often, a targeted medical history—including the mechanism of injury and pain-provoking and pain-relieving factors—and a problem-based physical examination (incorporating many of the maneuvers highlighted in the text and tables that follow) will lead to an accurate diagnosis without the need for imaging studies. We recommend that imaging be reserved for patients who don’t respond to conventional treatments, cases in which the diagnosis is in doubt, and instances in which surgical intervention is being considered.

The 3 cases* that follow, and the take-away message incorporated in each, will give you an opportunity to test—and to hone—your shoulder pain diagnostic skill.

CASE 1 The history: Jesse, a 17-year-old student who’s active in football and track, came in during track season complaining of severe left shoulder pain. He denied any traumatic event or previous injury to the shoulder, but reported that any motion involving the shoulder caused pain. It hurt at night, the patient said, when he lay on his left side.

The physical: No muscle atrophy, redness, or swelling was evident, nor was there any indication of asymmetry or ecchymosis in the affected area. Jesse’s neck range of motion was normal; he had a very hard time with any active motion of the shoulder, however, because of the pain.

Evaluation of scapular motion demonstrated scapular dyskinesis^3,4 without winging. Passive motion of the glenohumeral joint was much better than active motion. Strength testing appeared to be grossly intact but was limited by the pain. Shoulder impingement testing was positive. Sensation and deep tendon reflexes were intact.

Patients' names have been changed to protect their privacy

What’s the diagnosis?

Subacromial bursitis, suggested by the patient’s pain and altered scapular motion, was our working diagnosis, and we administered a subacromial injection of corticosteroid with lidocaine, for diagnostic as well as therapeutic purposes. Reexamination after the injection revealed immediate partial improvement in resting pain, range of motion, and strength. We referred Jesse to physical therapy with a focus on scapular stabilization and rotator cuff strength.

Three months later, Jesse returned to our office, complaining of weakness in his left shoulder. The pain had subsided a week after his first appointment, so he’d never gone to physical therapy. The weakness, which he had first noticed about 2 months after starting a lifting program in preparation for football season, was limited to resistance exercises, especially overhead shoulder presses and bench press. There were no other changes in his history, and he reported no reinjuries.

Physical examination revealed atrophy of the supraspinatus and infraspinatus muscles (FIGURE 1) and external rotation and shoulder abduction (in the scapular plane) resistance tests revealed weakness of these muscles. There was no scapular winging. The cervical spine exam was normal, and neurovascular status was intact in both upper extremities.

FIGURE 1
Severe shoulder pain, followed by weakness

New evidence points to nerve injury. Based on Jesse’s current history and physical, nerve injury was our new working diagnosis. (We considered the possibility of a rotator cuff tear, but this was not corroborated by the history.)

We ordered an electromyogram/nerve conduction velocity study to localize the lesion. The test revealed a brachial plexitis/neuritis (also known as Parsonage-Turner syndrome or brachial amyotrophy). The etiology of most atraumatic brachial plexopathies is unknown, and most are thought to be viral or autoimmune in nature.^5,6

A classic case of Parsonage-Turner syndrome. The typical presentation of Parsonage-Turner syndrome (like Jesse’s) is one of acute, intense shoulder pain for no known reason. After 1 to 3 weeks, the pain resolves and the patient is left with weakness, usually of the supraspinatus and infraspinatus muscles. The weakness typically resolves with time, but full resolution may take 6 to 9 months.^5,6 (In Jesse’s case, it took about 6 months.)

The take-away message: Look beyond the shoulder
As this case illustrates, not all shoulder pain originates in the shoulder. When evaluating shoulder pain, it is essential to consider other causes. The differential diagnosis for shoulder pain includes cervical spine disorders, cholecystitis (right shoulder), diaphragmatic irritation (eg, in the case of splenic rupture, usually involving the left shoulder), cardiac disease, and thoracic outlet syndrome.⁷

Evaluation of the cervical spine should be part of a complete shoulder examination. It is vital to follow a systematic approach that carefully assesses the cervical region for the possibility of nerve root impingement and radicular dysfunction masquerading as a primary shoulder disorder. (TABLE 1^8,9 details pain and sensory distribution patterns, reflex involvement, and potential motor impairments associated with various spinal nerve root levels.)

TABLE 1
Assessing the cervical spine

Practitioners should develop their own approach to “clearing the neck.” A logical order is to note posture of the head/neck/shoulders, observe active motion, perform palpation and provocative tests, and then assess neurologic function with sensation/reflex/strength testing. Provocative tests that can help to identify cervical involvement relating to shoulder pain include Spurling’s maneuver, axial compression test, abduction relief sign, and Lhermitte’s sign.^10,11

CASE 2 The history: Mark, a 17-year-old, right-handed volleyball player, presented with right shoulder pain, which he felt whenever he spiked or served the ball. The pain started last season, Mark said, diminished during the months when he wasn’t playing, then got progressively worse as his activity level increased. The pain was in the posterior aspect of the shoulder.

The physical: Physical examination revealed a well-developed, but thin (6’4”, 170 pounds) young man who was not in distress. The general examination was benign, and a joint-specific exam showed no asymmetry or atrophy on inspection and no tenderness to palpation over the posterior and anterior soft tissues of the right shoulder. Rotator cuff testing yielded intact strength for all 4 muscles, but external rotation and supraspinatus testing elicited pain. The crank test, drawer sign, load and shift test, relocation test, and sulcus sign, detailed in TABLE 2,^12-14 were all positive for shoulder instability; the Clunk and O’Brien tests were negative, and the contralateral shoulder exam was within normal limits. General joint laxity was observed, with the ability to oppose the thumb to the volar forearm and hyperextension noted in both elbows and knees. There were no outward signs of connective tissue disease.

Because of the chronicity of Mark’s pain and the progressive nature of his symptoms, we ordered radiographs, including anterior-posterior, lateral axillary, and scapular Y views. These films showed a nearly skeletally mature male without bony abnormalities; the humeral head was well located in the glenoid.

TABLE 2
Testing for shoulder instability^12-14

What’s the diagnosis?

Multidirectional instability with recurrent subluxations and probable acute rotator cuff tendinitis was our provisional diagnosis. Treatment focused on physical therapy, with a concentration on scapular stabilization and rotator cuff strengthening.

Shoulder instability is relatively common and represents a spectrum of disorders ranging from dislocation to subluxation to simple laxity.^12,13 A complete loss of humeral articulation within the glenoid fossa is evidence of dislocation, whereas subluxation includes approximation of the humeral head to the limits of the glenoid rim. Dislocation typically results from trauma, whereas subluxation can be the result of microtrauma and repetitive overuse injury. Anterior instability is the most common type and is reported in as many as 95% of all dislocations.¹³

The take-away message: Rule out instability
The shoulder is one of the most complex joints in the body. The rotator cuff structures, the glenoid labrum, and the collective capsular ligaments provide structural stability to the glenohumeral joint.^12,13 The shoulder is vulnerable to instability because the shallow glenoid fossa offers little bony support for the humeral head. Thus, instability should always be included in an assessment of shoulder pain.

Key factors to consider in identifying shoulder instability include the location of the pain, the direction of traumatic force applied, the presence of a known complete dislocation vs apprehension with specific movement, the position of the arm in which pain is elicited, a previous occurrence of instability (subluxation or dislocation), and the presence of tingling or numbness.^12-14 The maneuvers detailed in TABLE 2^12-14 can help identify instability, as they did in this case. Patients with hypermobility are at increased risk for shoulder instability, so a targeted exam and patient history aimed at identifying signs and symptoms of hypermobility is needed, as well.

Ask the patient to attempt to:

• bend the thumb to the volar forearm
• place hands to the floor with hyperextended knees
• perform maximal hyperextension of the fifth metacarpophalangeal joint (>90° is a positive result).

Findings from the medical history that indicate a predisposition to instability include generalized joint laxity, Ehlers-Danlos syndrome, Marfan syndrome, osteogenesis imperfecta, hyperhomocysteinuria, hyperlysinemia, benign joint hypermobility syndrome, juvenile rheumatoid arthritis, and previous shoulder or patellar dislocations.

Imaging tips: Scapular Y and/or axillary lateral views should always be included when ordering imaging studies for suspected instability/dislocations, as 50% of posterior dislocations are missed on standard shoulder x-rays that do not include them.¹² In reviewing the x-rays, it is important to look for signs of a compression fracture of the posterior humeral head (known as a Hill-Sachs lesion) for anterior shoulder dislocations, and fractures to the anterior glenoid rim (known as a Bankart lesion).^12-14

CASE 3 The history: Robert, a right-handed, 50-year-old motorcycle instructor, came to our office because of chronic right shoulder pain. The pain, located over the anterior portion of the glenohumeral joint, developed insidiously about 3 or 4 years ago, the patient reported. He had finally decided to seek help because he’d recently experienced an acute exacerbation of pain brought on by shoveling snow, after which he also noticed associated weakness, a clicking/popping on active motion, and mild loss of motion.

The physical: Robert’s cervical spine exam was unremarkable. He demonstrated full active range of motion (ROM) without exacerbation of right shoulder symptoms, and special tests for disc pathology at the neck were negative. Active ROM testing of the right shoulder revealed full abduction, with only minimal pain; full flexion, with moderate pain noted initially at 49°; full extension, with a painful arc noted at 50°; and full horizontal adduction, with a painful arc noted at the halfway point. The testing also revealed that his right thumb was 3 inches lower than the left on reaching for the opposite scapula. At the superior aspect of the acromioclavicular (AC) joint, 2+ tenderness was noted; 3+ tenderness was noted at the greater tubercle of the humerus.

After inspecting the shoulder region for alterations in bony landmarks, muscle bulk, carrying position, and movement characteristics, palpation of the region was performed.

When assessing shoulder strength, there are a variety of tests for each functioning component of the rotator cuff structures (TABLE 3).^15-17 Manual muscle tests revealed: 4-/5 on external rotation (French horn test), 3+/5 on the lift-off test, and 5-/5 on all other tests for right shoulder function. Impingement testing was slightly positive, or pain producing, on Hawkins and Neer tests.^18,19 For the Hawkins test, the examiner flexes the arm to 90° of shoulder flexion with the elbow flexed at 90°, then internally rotates the shoulder. For the Neer test, the arm is fully elevated in the scapular plane and internally rotated by the examiner.

The subscapularis muscle, which functions primarily in internal rotation, is tested by the French horn and lift-off tests. The teres minor muscle, which performs external rotation, is tested by the French horn test of external rotation. And the supraspinatus muscle, which performs abduction and external rotation, is tested by the empty can (also known as the Jobe) and full can tests. Some researchers suggest that the empty can test is better for diagnosing impingement, based on evidence showing that the full can test is better at diagnosing supraspinatus tears because it causes less pain during testing.²⁰

TABLE 3
Suspect rotator cuff involvement?^7,15-17

What’s the diagnosis?

Rotator cuff tear was suspected because Robert had positive elements of the “rotator cuff triad”—supraspinatus weakness (as indicated by a positive empty can test), external rotation weakness (revealed by the French horn test), and a positive Hawkins impingement test. We ordered diagnostic studies, including plain radiographs, which revealed degenerative changes at the acromioclavicular joint, decreased acromiohumeral interval, and no significant changes at the glenohumeral joint (FIGURE 2), and magnetic resonance imaging (MRI) of the right shoulder. The MRI revealed a large, full-thickness rotator cuff tear of the supraspinatus tendon with retraction. A torn and retracted biceps tendon and AC joint osteoarthritis were also shown, likely causing a mass effect on the supraspinatus. The patient underwent surgery to repair the torn rotator cuff, with excellent results.

FIGURE 2
Chronic right shoulder pain

The take-away message: Keep the rotator-cuff triad in mind
Because none of the tests that comprise the triad is specific enough alone to diagnose a rotator cuff tear,^15,20,21 Murrell and Walton¹⁶ suggested that the 3 tests be considered together for diagnostic purposes. If all 3 are positive, there is a 98% chance of a rotator cuff tear; if 2 tests are positive and the patient is older than 60 years, the findings are suggestive of a tear; and if all 3 tests (plus the drop arm test) are negative, there is less than a 5% chance of a major rotator cuff tear.¹⁶

CORRESPONDENCE Nilesh Shah, MD, Summa Center for Sports Health, 20 Olive Street, Suite 201, Akron, OH 44310; ShahN@summahealth.org

Shoulder pain is a common reason for visits to primary care physicians, who are most likely to diagnose it as rotator cuff tendinitis^1,2—often erroneously. The complexity of the joint and the overlapping pathologies that may present as shoulder pain highlight the need to take a closer look when dealing with this diagnostic challenge.

Often, a targeted medical history—including the mechanism of injury and pain-provoking and pain-relieving factors—and a problem-based physical examination (incorporating many of the maneuvers highlighted in the text and tables that follow) will lead to an accurate diagnosis without the need for imaging studies. We recommend that imaging be reserved for patients who don’t respond to conventional treatments, cases in which the diagnosis is in doubt, and instances in which surgical intervention is being considered.

The 3 cases* that follow, and the take-away message incorporated in each, will give you an opportunity to test—and to hone—your shoulder pain diagnostic skill.

CASE 1 The history: Jesse, a 17-year-old student who’s active in football and track, came in during track season complaining of severe left shoulder pain. He denied any traumatic event or previous injury to the shoulder, but reported that any motion involving the shoulder caused pain. It hurt at night, the patient said, when he lay on his left side.

The physical: No muscle atrophy, redness, or swelling was evident, nor was there any indication of asymmetry or ecchymosis in the affected area. Jesse’s neck range of motion was normal; he had a very hard time with any active motion of the shoulder, however, because of the pain.

Evaluation of scapular motion demonstrated scapular dyskinesis^3,4 without winging. Passive motion of the glenohumeral joint was much better than active motion. Strength testing appeared to be grossly intact but was limited by the pain. Shoulder impingement testing was positive. Sensation and deep tendon reflexes were intact.

Patients' names have been changed to protect their privacy

What’s the diagnosis?

Subacromial bursitis, suggested by the patient’s pain and altered scapular motion, was our working diagnosis, and we administered a subacromial injection of corticosteroid with lidocaine, for diagnostic as well as therapeutic purposes. Reexamination after the injection revealed immediate partial improvement in resting pain, range of motion, and strength. We referred Jesse to physical therapy with a focus on scapular stabilization and rotator cuff strength.

Three months later, Jesse returned to our office, complaining of weakness in his left shoulder. The pain had subsided a week after his first appointment, so he’d never gone to physical therapy. The weakness, which he had first noticed about 2 months after starting a lifting program in preparation for football season, was limited to resistance exercises, especially overhead shoulder presses and bench press. There were no other changes in his history, and he reported no reinjuries.

Physical examination revealed atrophy of the supraspinatus and infraspinatus muscles (FIGURE 1) and external rotation and shoulder abduction (in the scapular plane) resistance tests revealed weakness of these muscles. There was no scapular winging. The cervical spine exam was normal, and neurovascular status was intact in both upper extremities.

FIGURE 1
Severe shoulder pain, followed by weakness

New evidence points to nerve injury. Based on Jesse’s current history and physical, nerve injury was our new working diagnosis. (We considered the possibility of a rotator cuff tear, but this was not corroborated by the history.)

We ordered an electromyogram/nerve conduction velocity study to localize the lesion. The test revealed a brachial plexitis/neuritis (also known as Parsonage-Turner syndrome or brachial amyotrophy). The etiology of most atraumatic brachial plexopathies is unknown, and most are thought to be viral or autoimmune in nature.^5,6

A classic case of Parsonage-Turner syndrome. The typical presentation of Parsonage-Turner syndrome (like Jesse’s) is one of acute, intense shoulder pain for no known reason. After 1 to 3 weeks, the pain resolves and the patient is left with weakness, usually of the supraspinatus and infraspinatus muscles. The weakness typically resolves with time, but full resolution may take 6 to 9 months.^5,6 (In Jesse’s case, it took about 6 months.)

The take-away message: Look beyond the shoulder
As this case illustrates, not all shoulder pain originates in the shoulder. When evaluating shoulder pain, it is essential to consider other causes. The differential diagnosis for shoulder pain includes cervical spine disorders, cholecystitis (right shoulder), diaphragmatic irritation (eg, in the case of splenic rupture, usually involving the left shoulder), cardiac disease, and thoracic outlet syndrome.⁷

Evaluation of the cervical spine should be part of a complete shoulder examination. It is vital to follow a systematic approach that carefully assesses the cervical region for the possibility of nerve root impingement and radicular dysfunction masquerading as a primary shoulder disorder. (TABLE 1^8,9 details pain and sensory distribution patterns, reflex involvement, and potential motor impairments associated with various spinal nerve root levels.)

TABLE 1
Assessing the cervical spine

Practitioners should develop their own approach to “clearing the neck.” A logical order is to note posture of the head/neck/shoulders, observe active motion, perform palpation and provocative tests, and then assess neurologic function with sensation/reflex/strength testing. Provocative tests that can help to identify cervical involvement relating to shoulder pain include Spurling’s maneuver, axial compression test, abduction relief sign, and Lhermitte’s sign.^10,11

CASE 2 The history: Mark, a 17-year-old, right-handed volleyball player, presented with right shoulder pain, which he felt whenever he spiked or served the ball. The pain started last season, Mark said, diminished during the months when he wasn’t playing, then got progressively worse as his activity level increased. The pain was in the posterior aspect of the shoulder.

The physical: Physical examination revealed a well-developed, but thin (6’4”, 170 pounds) young man who was not in distress. The general examination was benign, and a joint-specific exam showed no asymmetry or atrophy on inspection and no tenderness to palpation over the posterior and anterior soft tissues of the right shoulder. Rotator cuff testing yielded intact strength for all 4 muscles, but external rotation and supraspinatus testing elicited pain. The crank test, drawer sign, load and shift test, relocation test, and sulcus sign, detailed in TABLE 2,^12-14 were all positive for shoulder instability; the Clunk and O’Brien tests were negative, and the contralateral shoulder exam was within normal limits. General joint laxity was observed, with the ability to oppose the thumb to the volar forearm and hyperextension noted in both elbows and knees. There were no outward signs of connective tissue disease.

Because of the chronicity of Mark’s pain and the progressive nature of his symptoms, we ordered radiographs, including anterior-posterior, lateral axillary, and scapular Y views. These films showed a nearly skeletally mature male without bony abnormalities; the humeral head was well located in the glenoid.

TABLE 2
Testing for shoulder instability^12-14

What’s the diagnosis?

Multidirectional instability with recurrent subluxations and probable acute rotator cuff tendinitis was our provisional diagnosis. Treatment focused on physical therapy, with a concentration on scapular stabilization and rotator cuff strengthening.

Shoulder instability is relatively common and represents a spectrum of disorders ranging from dislocation to subluxation to simple laxity.^12,13 A complete loss of humeral articulation within the glenoid fossa is evidence of dislocation, whereas subluxation includes approximation of the humeral head to the limits of the glenoid rim. Dislocation typically results from trauma, whereas subluxation can be the result of microtrauma and repetitive overuse injury. Anterior instability is the most common type and is reported in as many as 95% of all dislocations.¹³

The take-away message: Rule out instability
The shoulder is one of the most complex joints in the body. The rotator cuff structures, the glenoid labrum, and the collective capsular ligaments provide structural stability to the glenohumeral joint.^12,13 The shoulder is vulnerable to instability because the shallow glenoid fossa offers little bony support for the humeral head. Thus, instability should always be included in an assessment of shoulder pain.

Key factors to consider in identifying shoulder instability include the location of the pain, the direction of traumatic force applied, the presence of a known complete dislocation vs apprehension with specific movement, the position of the arm in which pain is elicited, a previous occurrence of instability (subluxation or dislocation), and the presence of tingling or numbness.^12-14 The maneuvers detailed in TABLE 2^12-14 can help identify instability, as they did in this case. Patients with hypermobility are at increased risk for shoulder instability, so a targeted exam and patient history aimed at identifying signs and symptoms of hypermobility is needed, as well.

Ask the patient to attempt to:

• bend the thumb to the volar forearm
• place hands to the floor with hyperextended knees
• perform maximal hyperextension of the fifth metacarpophalangeal joint (>90° is a positive result).

Findings from the medical history that indicate a predisposition to instability include generalized joint laxity, Ehlers-Danlos syndrome, Marfan syndrome, osteogenesis imperfecta, hyperhomocysteinuria, hyperlysinemia, benign joint hypermobility syndrome, juvenile rheumatoid arthritis, and previous shoulder or patellar dislocations.

Imaging tips: Scapular Y and/or axillary lateral views should always be included when ordering imaging studies for suspected instability/dislocations, as 50% of posterior dislocations are missed on standard shoulder x-rays that do not include them.¹² In reviewing the x-rays, it is important to look for signs of a compression fracture of the posterior humeral head (known as a Hill-Sachs lesion) for anterior shoulder dislocations, and fractures to the anterior glenoid rim (known as a Bankart lesion).^12-14

CASE 3 The history: Robert, a right-handed, 50-year-old motorcycle instructor, came to our office because of chronic right shoulder pain. The pain, located over the anterior portion of the glenohumeral joint, developed insidiously about 3 or 4 years ago, the patient reported. He had finally decided to seek help because he’d recently experienced an acute exacerbation of pain brought on by shoveling snow, after which he also noticed associated weakness, a clicking/popping on active motion, and mild loss of motion.

The physical: Robert’s cervical spine exam was unremarkable. He demonstrated full active range of motion (ROM) without exacerbation of right shoulder symptoms, and special tests for disc pathology at the neck were negative. Active ROM testing of the right shoulder revealed full abduction, with only minimal pain; full flexion, with moderate pain noted initially at 49°; full extension, with a painful arc noted at 50°; and full horizontal adduction, with a painful arc noted at the halfway point. The testing also revealed that his right thumb was 3 inches lower than the left on reaching for the opposite scapula. At the superior aspect of the acromioclavicular (AC) joint, 2+ tenderness was noted; 3+ tenderness was noted at the greater tubercle of the humerus.

After inspecting the shoulder region for alterations in bony landmarks, muscle bulk, carrying position, and movement characteristics, palpation of the region was performed.

When assessing shoulder strength, there are a variety of tests for each functioning component of the rotator cuff structures (TABLE 3).^15-17 Manual muscle tests revealed: 4-/5 on external rotation (French horn test), 3+/5 on the lift-off test, and 5-/5 on all other tests for right shoulder function. Impingement testing was slightly positive, or pain producing, on Hawkins and Neer tests.^18,19 For the Hawkins test, the examiner flexes the arm to 90° of shoulder flexion with the elbow flexed at 90°, then internally rotates the shoulder. For the Neer test, the arm is fully elevated in the scapular plane and internally rotated by the examiner.

The subscapularis muscle, which functions primarily in internal rotation, is tested by the French horn and lift-off tests. The teres minor muscle, which performs external rotation, is tested by the French horn test of external rotation. And the supraspinatus muscle, which performs abduction and external rotation, is tested by the empty can (also known as the Jobe) and full can tests. Some researchers suggest that the empty can test is better for diagnosing impingement, based on evidence showing that the full can test is better at diagnosing supraspinatus tears because it causes less pain during testing.²⁰

TABLE 3
Suspect rotator cuff involvement?^7,15-17

What’s the diagnosis?

Rotator cuff tear was suspected because Robert had positive elements of the “rotator cuff triad”—supraspinatus weakness (as indicated by a positive empty can test), external rotation weakness (revealed by the French horn test), and a positive Hawkins impingement test. We ordered diagnostic studies, including plain radiographs, which revealed degenerative changes at the acromioclavicular joint, decreased acromiohumeral interval, and no significant changes at the glenohumeral joint (FIGURE 2), and magnetic resonance imaging (MRI) of the right shoulder. The MRI revealed a large, full-thickness rotator cuff tear of the supraspinatus tendon with retraction. A torn and retracted biceps tendon and AC joint osteoarthritis were also shown, likely causing a mass effect on the supraspinatus. The patient underwent surgery to repair the torn rotator cuff, with excellent results.

FIGURE 2
Chronic right shoulder pain

The take-away message: Keep the rotator-cuff triad in mind
Because none of the tests that comprise the triad is specific enough alone to diagnose a rotator cuff tear,^15,20,21 Murrell and Walton¹⁶ suggested that the 3 tests be considered together for diagnostic purposes. If all 3 are positive, there is a 98% chance of a rotator cuff tear; if 2 tests are positive and the patient is older than 60 years, the findings are suggestive of a tear; and if all 3 tests (plus the drop arm test) are negative, there is less than a 5% chance of a major rotator cuff tear.¹⁶

CORRESPONDENCE Nilesh Shah, MD, Summa Center for Sports Health, 20 Olive Street, Suite 201, Akron, OH 44310; ShahN@summahealth.org