Applied Evidence

Antinuclear antibodies (ANA) are a spectrum of auto­antibodies that react with various nuclear and cytoplasmic components of normal human cells. Their detection is important in the diagnosis of some connective tissue diseases (CTD)—eg, systemic lupus erythematosus (SLE), Sjögren’s syndrome (SS), scleroderma, polymyositis, or mixed connective tissue disease (MCTD). Unfortunately, ANA tests are often used indiscriminately in daily clinical practice.¹

When is ANA testing warranted?

Indiscriminate use of ANA testing can yield positive results that falsely point to CTD in a high proportion of patients and thereby lead to further inappropriate testing and errant management decisions.When clinical probability of connective tissue diseases is low, the presence of ANA in the serum can indicate chronic infection, neoplasm, or advancing age. To wit: The presence of ANA in the serum can be associated with any number of factors, such as genetic predisposition (eg, through histocompatibility locus DR3), environmental agents (viruses, drugs), chronic infections, neoplasms, and advancing age.¹ Therefore, the test should not be ordered in a patient with low pre-test probability of CTD. Moreover, higher titers of ANA are more clinically significant than lower titers. In one multicenter study, 31.7% of healthy individuals were ANA-positive at a serum dilution of 1:40, but only 5% were ANA-positive at a dilution of 1:160.²

What is the clinical significance of different immunofluorescent patterns?

Immunofluorescent ANA testing not only determines if such antibodies are present in a patient’s serum but also reveals informative antibody patterns. Five distinct patterns of fluorescence are possible and can help differentiate between various CTDs (TABLE³):
1. Homogenous, in which the entire nucleus fluoresces, is seen in SLE and discoid lupus erythematosus (DLE).
2. Rim, in which the nuclear perimeter fluoresces, is seen most often in CREST (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome and SLE.
3. Speckled, in which the nucleus fluoresces in a speckled pattern, can be seen in a variety of CTDs, including Sjögren’s syndrome, MCTD, SLE, and scleroderma.
4. Nucleolar, in which the nucleolus fluoresces, is associated with scleroderma.
5. Cytoplasmic, in which fluorescence occurs outside the nucleus, typically occurs with poly/dermatomyositis, primary biliary cirrhosis, or autoimmune hepatitis.

What is the next step if ANA is positive?

A positive ANA result warrants additional studies to identify specific autoantibodies suggested by the fluorescence pattern and by a patient’s signs and symptoms.

Following up diagnostic clues

Think systemic lupus erythematosus when a patient has a photosensitive butterfly rash, arthralgia, pleuritic chest pain, fever, or urine sediment consistent with nephritis. Most systemic autoimmune diseases have a highly characteristic profile of autoantibodies to cellular antigens. A patient’s clinical features and ANA fluorescence pattern should direct additional testing.

Photosensitive butterfly rash, arthralgias/arthritis, pleuritic chest pain, fever of unknown cause, and urine sediment consistent with nephritis point to a diagnosis of SLE. Order an assay for anti-double-stranded DNA (dsDNA) antibodies, which, if present, confirm the diagnosis.⁴ Also order an assay for anti-Sm antibodies, which are highly specific for SLE but found only in 30% to 40% of SLE patients.⁴

Raynaud’s phenomenon, skin hardening or thickening, stiffness and tightening of the skin on the fingers, hands and forearms, tight and mask-like skin on the face, dry cough, shortness of breath, and difficulty in swallowing are features of scleroderma. If you suspect this disorder, order an assay for anti-Scl-70 anti­bodies. These antibodies are highly specific for scleroderma, but sensitivity of the assay is only 15% to 20%.⁵

Calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia indicate CREST syndrome. Anti-centromere antibodies are highly specific for CREST syndrome; sensitivity on assay is 50% to 90%.⁶

MCTD combines features of rheumatoid arthritis, SLE, myositis, and scleroderma. Order an assay of anti-RNP (ribonucleoprotein) antibodies. Although anti-RNP antibodies are also found in 25% to 30% of patients with SLE, they typically appear in the company of anti-Sm antibodies.⁷ Isolated high titers of anti-RNP antibodies point to MCTD, and sensitivity on assay is 100%.⁸ Their absence on testing, therefore, excludes the diagnosis of MCTD.

RNP, anti-Ro/SS-A, La/SS-B, and Sm are also referred to as extractable nuclear antigens (ENA). Assays of antibodies to ENA and anti-dsDNA are warranted only if the ANA assay result is positive. It is rare to have a positive anti-ENA antibody test (with the exception of antibodies to cytoplasmic antigens) in the absence of a positive ANA test.⁹

Dry eyes, dry mouth, joint pain and swelling, and swelling of parotid glands point to Sjögren’s syndrome. Anti-Ro/SS-A and La/SS-B antibodies are associated with Sjögren’s syndrome, but are also found in seronegative SLE.¹⁰ Therefore, if patients with features suggestive of SLE have a negative result on a dsDNA antibody assay, test for anti-Ro/SS-A and La/SS-B antibodies.

Muscle weakness and soreness, purplish discoloration of the upper eyelids, and purplish-red discoloration of the knuckles suggest dermatomyositis. Muscle biopsy and electromyography will clinch the diagnosis. Also test for anti–Jo-1 antibodies, which are associated with pulmonary involvement in polymyositis.¹¹

ANA’s continuing role—prognosis and disease activity

Besides confirming a diagnosis of CTD in patients with suggestive clinical features, ANA testing serves 2 additional purposes: to help determine a patient’s prognosis and to monitor CTD activity. Consider the following:

• Patients with Sjögren’s syndrome who test positive for anti-Ro/SS-A antibodies have aggressive, extra-glandular disease that can cause vasculitis, purpura, lymphadenopathy, leukopenia, and thrombocytopenia.¹²
• The presence of anti-Ro/SS-A in the circulation of pregnant women with SLE confers a higher risk of neonatal lupus erythematosus and of congenital heart block in their newborns.¹³
• Severe interstitial lung disease is frequently found in scleroderma patients who test positive for anti-Scl-70.¹⁴ Antibodies to aminoacyl-tRNA synthetases—including anti–Jo-1, as mentioned earlier—are associated with pulmonary involvement in polymyositis patients.¹¹
• A positive ANA test result in Raynaud’s phenomenon increases the likelihood that the patient will develop a systemic rheumatic disease; a negative result reduces this likelihood.¹⁵
• While the ANA test is not useful for diagnosing juvenile chronic arthritis (JCA), it is useful to test for ANA in patients with known JCA. A positive test result should prompt screening for uveitis.¹⁶
• An ANA test is not necessary for diagnosing antiphospholipid antibody syndrome (APS). However, the presence of ANA in a patient with APS increases the likelihood that APS is secondary to SLE.¹⁷

Monitoring disease activity

Documenting titers of anti-dsDNA antibodies may help in monitoring the disease activity of SLE in some patients. However, changes in titers of anti-dsDNA should be interpreted in the clinical context of the SLE Disease Activity Index.¹⁸

CORRESPONDENCE
Habib U. Rehman, MB, Department of Medicine, Regina Qu’Appelle Health Region, Regina General Hospital, 1440–14th Avenue, Regina, SK, S4P 0W5, Canada; habib31@sasktel.net

Antinuclear antibodies (ANA) are a spectrum of auto­antibodies that react with various nuclear and cytoplasmic components of normal human cells. Their detection is important in the diagnosis of some connective tissue diseases (CTD)—eg, systemic lupus erythematosus (SLE), Sjögren’s syndrome (SS), scleroderma, polymyositis, or mixed connective tissue disease (MCTD). Unfortunately, ANA tests are often used indiscriminately in daily clinical practice.¹

When is ANA testing warranted?

Indiscriminate use of ANA testing can yield positive results that falsely point to CTD in a high proportion of patients and thereby lead to further inappropriate testing and errant management decisions.When clinical probability of connective tissue diseases is low, the presence of ANA in the serum can indicate chronic infection, neoplasm, or advancing age. To wit: The presence of ANA in the serum can be associated with any number of factors, such as genetic predisposition (eg, through histocompatibility locus DR3), environmental agents (viruses, drugs), chronic infections, neoplasms, and advancing age.¹ Therefore, the test should not be ordered in a patient with low pre-test probability of CTD. Moreover, higher titers of ANA are more clinically significant than lower titers. In one multicenter study, 31.7% of healthy individuals were ANA-positive at a serum dilution of 1:40, but only 5% were ANA-positive at a dilution of 1:160.²

What is the clinical significance of different immunofluorescent patterns?

Immunofluorescent ANA testing not only determines if such antibodies are present in a patient’s serum but also reveals informative antibody patterns. Five distinct patterns of fluorescence are possible and can help differentiate between various CTDs (TABLE³):
1. Homogenous, in which the entire nucleus fluoresces, is seen in SLE and discoid lupus erythematosus (DLE).
2. Rim, in which the nuclear perimeter fluoresces, is seen most often in CREST (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome and SLE.
3. Speckled, in which the nucleus fluoresces in a speckled pattern, can be seen in a variety of CTDs, including Sjögren’s syndrome, MCTD, SLE, and scleroderma.
4. Nucleolar, in which the nucleolus fluoresces, is associated with scleroderma.
5. Cytoplasmic, in which fluorescence occurs outside the nucleus, typically occurs with poly/dermatomyositis, primary biliary cirrhosis, or autoimmune hepatitis.

What is the next step if ANA is positive?

A positive ANA result warrants additional studies to identify specific autoantibodies suggested by the fluorescence pattern and by a patient’s signs and symptoms.

Following up diagnostic clues

Think systemic lupus erythematosus when a patient has a photosensitive butterfly rash, arthralgia, pleuritic chest pain, fever, or urine sediment consistent with nephritis. Most systemic autoimmune diseases have a highly characteristic profile of autoantibodies to cellular antigens. A patient’s clinical features and ANA fluorescence pattern should direct additional testing.

Photosensitive butterfly rash, arthralgias/arthritis, pleuritic chest pain, fever of unknown cause, and urine sediment consistent with nephritis point to a diagnosis of SLE. Order an assay for anti-double-stranded DNA (dsDNA) antibodies, which, if present, confirm the diagnosis.⁴ Also order an assay for anti-Sm antibodies, which are highly specific for SLE but found only in 30% to 40% of SLE patients.⁴

Raynaud’s phenomenon, skin hardening or thickening, stiffness and tightening of the skin on the fingers, hands and forearms, tight and mask-like skin on the face, dry cough, shortness of breath, and difficulty in swallowing are features of scleroderma. If you suspect this disorder, order an assay for anti-Scl-70 anti­bodies. These antibodies are highly specific for scleroderma, but sensitivity of the assay is only 15% to 20%.⁵

Calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia indicate CREST syndrome. Anti-centromere antibodies are highly specific for CREST syndrome; sensitivity on assay is 50% to 90%.⁶

MCTD combines features of rheumatoid arthritis, SLE, myositis, and scleroderma. Order an assay of anti-RNP (ribonucleoprotein) antibodies. Although anti-RNP antibodies are also found in 25% to 30% of patients with SLE, they typically appear in the company of anti-Sm antibodies.⁷ Isolated high titers of anti-RNP antibodies point to MCTD, and sensitivity on assay is 100%.⁸ Their absence on testing, therefore, excludes the diagnosis of MCTD.

RNP, anti-Ro/SS-A, La/SS-B, and Sm are also referred to as extractable nuclear antigens (ENA). Assays of antibodies to ENA and anti-dsDNA are warranted only if the ANA assay result is positive. It is rare to have a positive anti-ENA antibody test (with the exception of antibodies to cytoplasmic antigens) in the absence of a positive ANA test.⁹

Dry eyes, dry mouth, joint pain and swelling, and swelling of parotid glands point to Sjögren’s syndrome. Anti-Ro/SS-A and La/SS-B antibodies are associated with Sjögren’s syndrome, but are also found in seronegative SLE.¹⁰ Therefore, if patients with features suggestive of SLE have a negative result on a dsDNA antibody assay, test for anti-Ro/SS-A and La/SS-B antibodies.

Muscle weakness and soreness, purplish discoloration of the upper eyelids, and purplish-red discoloration of the knuckles suggest dermatomyositis. Muscle biopsy and electromyography will clinch the diagnosis. Also test for anti–Jo-1 antibodies, which are associated with pulmonary involvement in polymyositis.¹¹

ANA’s continuing role—prognosis and disease activity

Besides confirming a diagnosis of CTD in patients with suggestive clinical features, ANA testing serves 2 additional purposes: to help determine a patient’s prognosis and to monitor CTD activity. Consider the following:

• Patients with Sjögren’s syndrome who test positive for anti-Ro/SS-A antibodies have aggressive, extra-glandular disease that can cause vasculitis, purpura, lymphadenopathy, leukopenia, and thrombocytopenia.¹²
• The presence of anti-Ro/SS-A in the circulation of pregnant women with SLE confers a higher risk of neonatal lupus erythematosus and of congenital heart block in their newborns.¹³
• Severe interstitial lung disease is frequently found in scleroderma patients who test positive for anti-Scl-70.¹⁴ Antibodies to aminoacyl-tRNA synthetases—including anti–Jo-1, as mentioned earlier—are associated with pulmonary involvement in polymyositis patients.¹¹
• A positive ANA test result in Raynaud’s phenomenon increases the likelihood that the patient will develop a systemic rheumatic disease; a negative result reduces this likelihood.¹⁵
• While the ANA test is not useful for diagnosing juvenile chronic arthritis (JCA), it is useful to test for ANA in patients with known JCA. A positive test result should prompt screening for uveitis.¹⁶
• An ANA test is not necessary for diagnosing antiphospholipid antibody syndrome (APS). However, the presence of ANA in a patient with APS increases the likelihood that APS is secondary to SLE.¹⁷

Monitoring disease activity

Documenting titers of anti-dsDNA antibodies may help in monitoring the disease activity of SLE in some patients. However, changes in titers of anti-dsDNA should be interpreted in the clinical context of the SLE Disease Activity Index.¹⁸

CORRESPONDENCE
Habib U. Rehman, MB, Department of Medicine, Regina Qu’Appelle Health Region, Regina General Hospital, 1440–14th Avenue, Regina, SK, S4P 0W5, Canada; habib31@sasktel.net

Antinuclear antibodies (ANA) are a spectrum of auto­antibodies that react with various nuclear and cytoplasmic components of normal human cells. Their detection is important in the diagnosis of some connective tissue diseases (CTD)—eg, systemic lupus erythematosus (SLE), Sjögren’s syndrome (SS), scleroderma, polymyositis, or mixed connective tissue disease (MCTD). Unfortunately, ANA tests are often used indiscriminately in daily clinical practice.¹

When is ANA testing warranted?

Indiscriminate use of ANA testing can yield positive results that falsely point to CTD in a high proportion of patients and thereby lead to further inappropriate testing and errant management decisions.When clinical probability of connective tissue diseases is low, the presence of ANA in the serum can indicate chronic infection, neoplasm, or advancing age. To wit: The presence of ANA in the serum can be associated with any number of factors, such as genetic predisposition (eg, through histocompatibility locus DR3), environmental agents (viruses, drugs), chronic infections, neoplasms, and advancing age.¹ Therefore, the test should not be ordered in a patient with low pre-test probability of CTD. Moreover, higher titers of ANA are more clinically significant than lower titers. In one multicenter study, 31.7% of healthy individuals were ANA-positive at a serum dilution of 1:40, but only 5% were ANA-positive at a dilution of 1:160.²

What is the clinical significance of different immunofluorescent patterns?

Immunofluorescent ANA testing not only determines if such antibodies are present in a patient’s serum but also reveals informative antibody patterns. Five distinct patterns of fluorescence are possible and can help differentiate between various CTDs (TABLE³):
1. Homogenous, in which the entire nucleus fluoresces, is seen in SLE and discoid lupus erythematosus (DLE).
2. Rim, in which the nuclear perimeter fluoresces, is seen most often in CREST (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome and SLE.
3. Speckled, in which the nucleus fluoresces in a speckled pattern, can be seen in a variety of CTDs, including Sjögren’s syndrome, MCTD, SLE, and scleroderma.
4. Nucleolar, in which the nucleolus fluoresces, is associated with scleroderma.
5. Cytoplasmic, in which fluorescence occurs outside the nucleus, typically occurs with poly/dermatomyositis, primary biliary cirrhosis, or autoimmune hepatitis.

What is the next step if ANA is positive?

A positive ANA result warrants additional studies to identify specific autoantibodies suggested by the fluorescence pattern and by a patient’s signs and symptoms.

Following up diagnostic clues

Think systemic lupus erythematosus when a patient has a photosensitive butterfly rash, arthralgia, pleuritic chest pain, fever, or urine sediment consistent with nephritis. Most systemic autoimmune diseases have a highly characteristic profile of autoantibodies to cellular antigens. A patient’s clinical features and ANA fluorescence pattern should direct additional testing.

Photosensitive butterfly rash, arthralgias/arthritis, pleuritic chest pain, fever of unknown cause, and urine sediment consistent with nephritis point to a diagnosis of SLE. Order an assay for anti-double-stranded DNA (dsDNA) antibodies, which, if present, confirm the diagnosis.⁴ Also order an assay for anti-Sm antibodies, which are highly specific for SLE but found only in 30% to 40% of SLE patients.⁴

Raynaud’s phenomenon, skin hardening or thickening, stiffness and tightening of the skin on the fingers, hands and forearms, tight and mask-like skin on the face, dry cough, shortness of breath, and difficulty in swallowing are features of scleroderma. If you suspect this disorder, order an assay for anti-Scl-70 anti­bodies. These antibodies are highly specific for scleroderma, but sensitivity of the assay is only 15% to 20%.⁵

Calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia indicate CREST syndrome. Anti-centromere antibodies are highly specific for CREST syndrome; sensitivity on assay is 50% to 90%.⁶

MCTD combines features of rheumatoid arthritis, SLE, myositis, and scleroderma. Order an assay of anti-RNP (ribonucleoprotein) antibodies. Although anti-RNP antibodies are also found in 25% to 30% of patients with SLE, they typically appear in the company of anti-Sm antibodies.⁷ Isolated high titers of anti-RNP antibodies point to MCTD, and sensitivity on assay is 100%.⁸ Their absence on testing, therefore, excludes the diagnosis of MCTD.

RNP, anti-Ro/SS-A, La/SS-B, and Sm are also referred to as extractable nuclear antigens (ENA). Assays of antibodies to ENA and anti-dsDNA are warranted only if the ANA assay result is positive. It is rare to have a positive anti-ENA antibody test (with the exception of antibodies to cytoplasmic antigens) in the absence of a positive ANA test.⁹

Dry eyes, dry mouth, joint pain and swelling, and swelling of parotid glands point to Sjögren’s syndrome. Anti-Ro/SS-A and La/SS-B antibodies are associated with Sjögren’s syndrome, but are also found in seronegative SLE.¹⁰ Therefore, if patients with features suggestive of SLE have a negative result on a dsDNA antibody assay, test for anti-Ro/SS-A and La/SS-B antibodies.

Muscle weakness and soreness, purplish discoloration of the upper eyelids, and purplish-red discoloration of the knuckles suggest dermatomyositis. Muscle biopsy and electromyography will clinch the diagnosis. Also test for anti–Jo-1 antibodies, which are associated with pulmonary involvement in polymyositis.¹¹

ANA’s continuing role—prognosis and disease activity

Besides confirming a diagnosis of CTD in patients with suggestive clinical features, ANA testing serves 2 additional purposes: to help determine a patient’s prognosis and to monitor CTD activity. Consider the following:

• Patients with Sjögren’s syndrome who test positive for anti-Ro/SS-A antibodies have aggressive, extra-glandular disease that can cause vasculitis, purpura, lymphadenopathy, leukopenia, and thrombocytopenia.¹²
• The presence of anti-Ro/SS-A in the circulation of pregnant women with SLE confers a higher risk of neonatal lupus erythematosus and of congenital heart block in their newborns.¹³
• Severe interstitial lung disease is frequently found in scleroderma patients who test positive for anti-Scl-70.¹⁴ Antibodies to aminoacyl-tRNA synthetases—including anti–Jo-1, as mentioned earlier—are associated with pulmonary involvement in polymyositis patients.¹¹
• A positive ANA test result in Raynaud’s phenomenon increases the likelihood that the patient will develop a systemic rheumatic disease; a negative result reduces this likelihood.¹⁵
• While the ANA test is not useful for diagnosing juvenile chronic arthritis (JCA), it is useful to test for ANA in patients with known JCA. A positive test result should prompt screening for uveitis.¹⁶
• An ANA test is not necessary for diagnosing antiphospholipid antibody syndrome (APS). However, the presence of ANA in a patient with APS increases the likelihood that APS is secondary to SLE.¹⁷

Monitoring disease activity

Documenting titers of anti-dsDNA antibodies may help in monitoring the disease activity of SLE in some patients. However, changes in titers of anti-dsDNA should be interpreted in the clinical context of the SLE Disease Activity Index.¹⁸

CORRESPONDENCE
Habib U. Rehman, MB, Department of Medicine, Regina Qu’Appelle Health Region, Regina General Hospital, 1440–14th Avenue, Regina, SK, S4P 0W5, Canada; habib31@sasktel.net

CASE › Jane T, age 42, comes to see you because of right knee pain that she’s had for about 6 months. She denies any trauma. Ms. T describes the pain as vague and poorly localized, but worse with activity. She says she started a walking/running program 9 months ago, when she was told she was overweight (body mass index, 29). She has lost 10 pounds since then, Ms. T says, and hopes to lose more by continuing to exercise. upon further review, you find that Ms. T has had increasing pain while ascending and descending stairs and that the pain is also exacerbated when she stands after prolonged sitting.

If Ms. T were your patient, what would you include in a physical examination and how would you diagnose and treat her?

Knee pain is a common presentation in primary care. While traumatic knee pain is frequently addressed in the medical literature, little has been written about chronic nontraumatic nonarthritic knee pain like that of Ms. T. Thus, while physical exam tests often lead to the correct diagnosis for traumatic knee pain, there is limited information on the use of such tests to determine the etiology of chronic knee pain.

This review was developed to fill that gap. In the pages that follow, we provide general guidance on the diagnosis and treatment of chronic nontraumatic knee pain. The conditions are presented anatomically—anterior, lateral, medial, or posterior—with common etiologies, history and physical exam findings, and diagnosis and treatment options for each (TABLE).^1-31

Anterior knee pain

Patellofemoral pain syndrome

Patellofemoral pain syndrome is the most common cause of anterior knee pain. Taping or bracing—along with physical therapy—may help reduce the pain.
Patellofemoral pain syndrome (PFPS), the most common cause of anterior knee pain, is a complex entity with an etiology that has not been well described.² The quadriceps tendon, medial and lateral retinacula, iliotibial band (ITB), vastus medialis and lateralis, and the insertion of the patellar tendon on the anterior tibial tubercle all play a role in proper tracking of the patellofemoral joint; an imbalance in any of these forces leads to abnormal patellar tracking over the femoral condyles, and pain ensues. PFPS can also be secondary to joint overload, in which excessive physical activity (eg, running, lunges, or squats) overloads the patellofemoral joint and causes pain.

Risk factors for PFPS include strength imbalances in the quadriceps, hamstring, and hip muscle groups, and increased training, such as running longer distances.^4,32 A recent review showed no relationship between an increased quadriceps (Q)-angle and PFPS, so that is no longer considered a major risk factor.⁵

Diagnosis. PFPS is a diagnosis of exclusion, and is primarily based on history and physical exam. Anterior knee pain that is exacerbated when seated for long periods of time (the “theater sign”) or by descending stairs is a classic indication of PFPS.¹ Patients may complain of knee stiffness or “giving out” secondary to sharp knee pain and a sensation of popping or crepitus in the joint. Swelling is not a common finding.²

A recent meta-analysis revealed limited evidence for the use of any specific physical exam tests to diagnose PFPS. But pain during squatting and pain with a patellar tilt test were most consistent with a diagnosis of PFPS. (The patellar tilt test involves lifting the lateral edge of the patella superiorly while the patient lies supine with knee extended; pain with <20° of lift suggests a tight lateral retinaculum). Conversely, the absence of pain during squatting or the absence of lateral retinacular pain helps rule it out.² A physical exam of the cruciate and collateral ligaments should be performed in a patient with a history of instability. Radiography is not needed for a diagnosis, but may be considered if examination reveals an effusion, the patient is age 50 years or older, or no improvement occurs after 8 to 12 weeks of treatment.³³

Treatment. The most effective and strongly supported treatment for PFPS is a 6-week physiotherapy program focusing on strengthening the quadriceps and hip muscles and stretching the quadriceps, ITB, hamstrings, and hip flexors.^4,5 There is limited information about the use of nonsteroidal anti-inflammatory drugs (NSAIDs), but they can be considered for short-term management.²

Patellar taping and bracing have shown some promise as adjunct therapies for PFPS, although the data for both are non-conclusive. There is a paucity of prospective randomized trials of patellar bracing and a 2012 Cochrane review found limited evidence of its efficacy.³⁴ But a 2014 meta-analysis revealed moderate evidence in support of patellar taping early on to help decrease pain,⁶ and a recent review suggests that it can be helpful in both the short and long term.⁷

Taping or bracing may be useful when combined with a tailored physical therapy program. Evidence for treatments such as biofeedback, chiropractic manipulation, and orthotics is limited, and they should be used only as adjunctive therapy.⁴

CASE › When you examine Ms. T, you find no swelling of the affected knee. You perform the tilt test, which elicits pain. Squatting causes some pain, as well. You diagnose PFPS and provide a referral for 6 weeks of physiotherapy.

Patellar subluxation or chronic dislocation

Patellofemoral instability (PFI) occurs when the patella disengages completely from the trochlear groove.¹¹ PFI’s etiology also relates to the complexity of the patellofemoral joint. Here, too, stability of the joint is achieved with a combination of soft tissue and bony restraints. At full extension and early flexion of the knee, however, the mechanisms of stability are limited, resulting in increased instability. Other associated factors include Q-angle, lateral pull from a tight ITB, and opposing forces from the vastus lateralis and vastus medialis obliquus (VMO).^8-10

Risk factors for PFI. The most common predisposing factors for PFI are trochlear dysplasia, patella alta, and lateralization of the tibial tuberosity or patella.^10,11 Older patients (mostly women) have an increased risk for patellofemoral instability. Older patients, predominately women, have an increased risk for PFI.⁹ Patients usually have a history of patellar subluxation or dislocation in their youth, with approximately 17% of those who had a first dislocation experiencing a recurrence.⁹ A family history of PFI is common, as well.¹⁰

Diagnosis. Patients with PFI often present with nonspecific anterior knee pain secondary to recurrent dislocation.¹³ Notable physical exam findings are:

• a positive J sign (noted if the patella suddenly shifts medially during early knee flexion or laterally during full extension)
• decreased quadriceps (specifically VMO) and hamstring strength and flexibility
• patellar hypermobility, which should be no more than a quarter to a half of the patellar diameter bilaterally
• pain during a patellar tilt test

• a positive patellar apprehension test.¹⁰ (With the patient lying with the knee flexed to 20°, place thumbs on the medial patella and push laterally; the patient will straighten leg with pain or “apprehension” prior to patellar dislocation.)

Plain radiography should be ordered in all cases to assess for osseous trauma/ deformity and to help guide surgical consideration. Magnetic resonance imaging (MRI) can provide additional information when significant soft tissue damage is suspected or the patient does not improve with conservative therapy.^8,11

Treatment. A recent Cochrane review showed that conservative treatment (VMO strengthening, bracing, and proprioceptive therapy) prevented future dislocations more effectively than surgical intervention.¹¹ However, surgery is indicated when obvious predisposing anatomic conditions (osteochondral fracture, intra-articular deformity, or a major tear of a medial soft tissue stabilizer) are clearly shown on imaging.^8,11

Patellar tendinopathy (jumper’s knee)

Patellar tendinopathy, an overuse injury often called “jumper’s knee” because it is associated with high-intensity jumping sports like volleyball and basketball, is an insertional tendinopathy with pain most commonly at the proximal patellar tendon.¹⁰ The pathology of the injury is poorly understood, but is believed to be the result of an impaired healing response to microtears.^12,14

Diagnosis. Patients with patellar tendinopathy typically present with anterior suprapatellar pain aggravated by activity. Classically, the pain can occur in any of 4 phases:¹² 1. pain isolated after activity; 2. pain that occurs during activity but does not impede activity; 3. pain that occurs both during and after the activity and interferes with competition
; 4. a complete tendon disruption. 

Examination should include an assessment of the patellar tendon for localized thickening, nodularity, crepitus, and focal suprapatellar tenderness. The muscle-tendon function should be evaluated by assessing knee mobility and strength of the quads via straight leg raise, decline squat, or single leg squats.¹² The Victorian Institute of Sport Assessment (VISA) questionnaire can be used to quantify the symptoms and to help track the patient’s progress throughout therapy.³¹ There are no proven special tests or radiologic studies to aid in the diagnosis of patellar tendinopathy,¹⁴ but magnetic resonance imaging (MRI) can be used for further evaluation when findings are equivocal.³⁵

Treatment. A wide range of options, from eccentric training—eg, 3 sets of 15 repetitions performed twice a day for 12 weeks—and physical therapy to platelet-rich plasma (PRP) injections, sclerosing injections, and surgery, are available for the treatment of patellar tendinopathy.^13-15 While no specific data have proven the superiority of any one therapy, expert consensus recommends eccentric exercise as initial therapy, performed for 12 weeks.^14,15

Three weeks of platelet-rich plasma injections helped 75% of patients with patellar tendinopathy return to their pre-symptom activity level within 90 days. It’s also interesting to note that a recently published study showed that 3 weekly PRP injections helped 75% of patients—all of whom failed to respond to 4 months of eccentric therapy—return to their pre-symptom activity level within 90 days.¹⁶ Corticosteroid injections should not be used to treat patellar tendinopathy due to the risk of tendon rupture.¹⁵ Orthopedic referral for surgical intervention should be considered for patients who fail to respond after 3 to 6 months of conservative therapy.¹⁴

Lateral knee pain

Iliotibial band tendinopathy


Iliotibial band syndrome (ITBS) is a common source of lateral knee pain, particularly in runners, cyclists, and endurance athletes.^17-19,36,37 The exact pathophysiology behind this diagnosis is debatable, but the most accepted etiology is inflammation generated from micro trauma to the soft tissues with inadequate healing time, resulting in persistent inflammation. ITBS is often associated with excessive overall running mileage, a sudden increase in mileage, or an abrupt change in training.^18,37

Patients with ITBS often complain of persistent nontraumatic knee pain that worsens with repetitive knee flexion. Diagnosis. Patients often complain of persistent nontraumatic lateral knee pain that worsens with repetitive knee flexion (eg, running or cycling).^17-19,37 A physical exam will often reveal pain over the lateral femoral condyle and a positive Noble’s test (FIGURE 1). A positive Ober’s test (FIGURE 2) is suggestive of ITBS, as well. The sensitivity and specificity of these tests are not well established, but in patients performing repetitive knee flexion activities with subjective lateral knee pain, pain over the lateral femoral condyle and a positive Ober’s and/or Noble’s test suggest an ITBS diagnosis.¹⁸ Imaging is not indicated initially, but MRI should be used in refractory cases to rule out other etiologies.^17,19

Treatment. First-line therapy for ITBS is conservative,^17-19,36,37 often involving a combination of techniques such as refraining from the activity that triggers the pain, NSAIDs, activity modification to reduce the strain over the ITB, myofascial release via foam rollers, and physical therapy focused on stretching the iliotibial band, tensor fasciae latae, and gluteus medius while strengthening the gluteus medius and core muscles.¹⁷ No single program has been shown to be better than another.

Corticosteroid injections are second-line therapy and have been shown to improve pain compared with placebo up to 2 weeks post injection.^17,19 When symptoms persist for more than 6 months despite conservative treatment, surgical intervention may be indicated.^18,19 Patients who experience temporary pain relief with corticosteroid injections often respond best to surgery.³⁶

Medial knee pain

Medial plica syndrome

Because of its anatomic location, the medial plica—which can be palpated in up to 84% of the population²⁰—is susceptible to impingement by the medial femoral condyle or the patellofemoral joint. Trauma with repetitive knee movement leads to inflammation and thickening of the plica, resulting in medial plica syndrome.^20,38 Initial inflammation may be triggered by blunt trauma, a sudden increase in activity, or transient synovitis.²²

Diagnosis. Medial plica syndrome is a challenging diagnosis. Patients generally have nonspecific complaints of aching medial knee pain, locking, and catching similar to complaints of a medial meniscal injury.²⁰

A mediopatellar plica test was more accurate than an MRI in diagnosing medial plica syndrome, according to a recent systematic review. Evaluation should include the mediopatellar plica test, which is performed with the patient lying supine with the knee fully extended. Pressure is placed over the inferomedial patellofemoral joint, creating an impingement of the medial plica between the finger and the medial femoral condyle. Elimination or marked diminishing of pain with knee flexion to 90° is considered a positive test.²¹

A recent systematic review found this test to be more diagnostically accurate than an MRI (sensitivity of the test is 90% and specificity is 89%, vs 77% and 58%, respectively, for MRI) for detection of medial plica syndrome. Ultrasound is almost as accurate, with a sensitivity of 90% and specificity of 83%.³⁹

Treatment of medial plica syndrome centers on physiotherapy and quadriceps strengthening,²⁰ augmented with NSAIDs. Intra-articular corticosteroid injections are considered second-line treatment.^20,22 An orthopedics referral is indicated to consider arthroscopic plica removal for refractory cases.^20,22

Pes anserine bursitis

The anserine bursal complex, located approximately 5 cm distal to the medial joint line, is formed by the combined insertion of the sartorius, gracilis, and semitendinosus tendons,³⁹ but the exact mechanism of pain is not well understood. Whether the pathophysiology is from an insertional tendonitis or overt bursitis is unknown, and no studies have focused on prevalence or risk factors. What is known is that overweight individuals and women with a wide pelvis seem to have a greater predilection and those with pes planus, diabetes, or knee osteoarthritis are at increased risk.²³

Diagnosis. Medial knee pain reproduced on palpation of the anatomical site of insertion of the pes anserine tendon complex supports a diagnosis of pes anserine bursitis, with or without edema. Radiologic studies are not needed, but may be helpful if significant bony pathology is suspected. Ultrasound, computed tomography (CT), and MRI are not recommended.²³

Treatment. Resting the affected knee, cryotherapy, NSAIDs, and using a pillow at night to relieve direct bursal pressure are recommended.³³ Weight loss in obese patients, treatment of pes planus, and control of diabetes may be helpful, as well. Although the literature is limited and dated, corticosteroid injection has been found to reduce the pain and may be considered as second-line treatment.^24-26

Posterior knee pain

Popliteal (Baker’s) cyst

The popliteal fossa contains 6 of the numerous bursa of the knee; the bursa beneath the medial head of the gastrocnemius muscle and the semimembranosus tendon is most commonly involved in the formation of a popliteal cyst.⁴⁰ It is postulated that increased intra-articular pressure forces fluid into the bursa, leading to expansion and pain. This can be idiopathic or secondary to internal derangement or trauma to the knee.⁴¹ Older age, a remote history of knee trauma, or a coexisting joint disease such as osteoarthritis, meniscal pathology, or rheumatoid arthritis are significant risk factors for the development of popliteal cysts.²⁷

Diagnosis. Most popliteal cysts are asymptomatic in adults and discovered incidentally after routine imaging to evaluate other knee pathology. However, symptomatic popliteal cysts present as a palpable mass in the popliteal fossa, resulting in pain and limited range of motion.

During the physical exam with the patient lying supine, a medial popliteal mass that is most prominent with the knee fully extended is common. A positive Foucher’s sign (the painful mass is palpated posteriorly in the popliteal fossa with the knee fully extended; pain is relieved and/or the mass reduced in size with knee flexion to 45°) suggests a diagnosis of popliteal cyst.^27,28

Radiologic studies are generally not needed to diagnose a popliteal cyst. However, if diagnostic uncertainty remains after the history and physical exam, plain knee radiographs and ultrasound should be obtained. This combination provides complementary information and helps rule out a fracture, arthritis, and thrombosis as the cause of the pain.²⁷ MRI is helpful if the diagnosis is still in doubt and for patients suspected of having significant internal derangement leading to cyst formation. Arthrography or CT is generally not needed.^27,41

Treatment. As popliteal cysts are often associated with other knee pathology, management of the underlying condition often leads to cyst regression. Keeping the knee in flexion can decrease the available space and assist in pain control in the acute phase.²⁷ Cold packs and NSAIDs can also be used initially. Cyst aspiration and intra-articular steroid injection have been shown to be effective for cysts that do not respond to this conservative approach.²⁷ However, addressing and managing the underlying knee pathology (eg, osteoarthritis, meniscal pathology, or rheumatoid arthritis) will prevent popliteal cysts from recurring.

When the problem is painful knee effusion

A prompt orthopedic referral is essential when you suspect an infectious joint. Nontraumatic knee effusion can be the primary source of knee pain or the result of underlying pathology. We mention it here because clinical suspicion is paramount in diagnosing a septic joint, a serious cause of painful knee effusion that warrants prompt treatment.

As in other causes of knee pain, a detailed history of the character of the pain is essential. Septic arthritis and crystalline disease (gout, pseudogout) should be suspected in patients without a history of trauma who cannot bear weight. Systemic complaints point to an infection and, with the exception of a possible low-grade fever, are not typically seen in crystalline disease. Notable findings include an erythematous, hot, swollen knee and pain with both active and passive movement.

Plain radiographs of the knee should be ordered to rule out significant trauma or arthritis as the etiology. It is important to perform joint aspiration with synovial fluid analysis. Fluid analysis should include a white blood cell (WBC) count with differential, Gram stain and cultures, and polarized light microscopy (not readily available in an outpatient setting).²⁹

Synovial fluid analysis characteristics suggestive of a septic joint include turbid quality, WBC >50,000 per mm³, an elevated protein content, and a low glucose concentration.³⁰ Gram stain and culture will help identify the infectious agent. Orthopedic referral should not be delayed in patients with a suspected infectious joint. Corticosteroids should not be injected during aspiration if infection is being ruled out.

CASE › When Ms. T returns for a follow-up visit 8 weeks later, she states that the knee pain has resolved and that she has returned to running. She has lost an additional 8 pounds and continues to diet. And, at the advice of her physical therapist, she is continuing her physiotherapy regimen at home to prevent a recurrence of PFPS.

CORRESPONDENCE
Carlton J. Covey, MD, FAAFP, Nellis Family Medicine Residency Program, 4700 Las Vegas Boulevard North, Nellis Air Force Base, NV 89191; carlton.covey@us.af.mil

CASE › Jane T, age 42, comes to see you because of right knee pain that she’s had for about 6 months. She denies any trauma. Ms. T describes the pain as vague and poorly localized, but worse with activity. She says she started a walking/running program 9 months ago, when she was told she was overweight (body mass index, 29). She has lost 10 pounds since then, Ms. T says, and hopes to lose more by continuing to exercise. upon further review, you find that Ms. T has had increasing pain while ascending and descending stairs and that the pain is also exacerbated when she stands after prolonged sitting.

If Ms. T were your patient, what would you include in a physical examination and how would you diagnose and treat her?

Knee pain is a common presentation in primary care. While traumatic knee pain is frequently addressed in the medical literature, little has been written about chronic nontraumatic nonarthritic knee pain like that of Ms. T. Thus, while physical exam tests often lead to the correct diagnosis for traumatic knee pain, there is limited information on the use of such tests to determine the etiology of chronic knee pain.

This review was developed to fill that gap. In the pages that follow, we provide general guidance on the diagnosis and treatment of chronic nontraumatic knee pain. The conditions are presented anatomically—anterior, lateral, medial, or posterior—with common etiologies, history and physical exam findings, and diagnosis and treatment options for each (TABLE).^1-31

Anterior knee pain

Patellofemoral pain syndrome

Patellofemoral pain syndrome is the most common cause of anterior knee pain. Taping or bracing—along with physical therapy—may help reduce the pain.
Patellofemoral pain syndrome (PFPS), the most common cause of anterior knee pain, is a complex entity with an etiology that has not been well described.² The quadriceps tendon, medial and lateral retinacula, iliotibial band (ITB), vastus medialis and lateralis, and the insertion of the patellar tendon on the anterior tibial tubercle all play a role in proper tracking of the patellofemoral joint; an imbalance in any of these forces leads to abnormal patellar tracking over the femoral condyles, and pain ensues. PFPS can also be secondary to joint overload, in which excessive physical activity (eg, running, lunges, or squats) overloads the patellofemoral joint and causes pain.

Risk factors for PFPS include strength imbalances in the quadriceps, hamstring, and hip muscle groups, and increased training, such as running longer distances.^4,32 A recent review showed no relationship between an increased quadriceps (Q)-angle and PFPS, so that is no longer considered a major risk factor.⁵

Diagnosis. PFPS is a diagnosis of exclusion, and is primarily based on history and physical exam. Anterior knee pain that is exacerbated when seated for long periods of time (the “theater sign”) or by descending stairs is a classic indication of PFPS.¹ Patients may complain of knee stiffness or “giving out” secondary to sharp knee pain and a sensation of popping or crepitus in the joint. Swelling is not a common finding.²

A recent meta-analysis revealed limited evidence for the use of any specific physical exam tests to diagnose PFPS. But pain during squatting and pain with a patellar tilt test were most consistent with a diagnosis of PFPS. (The patellar tilt test involves lifting the lateral edge of the patella superiorly while the patient lies supine with knee extended; pain with <20° of lift suggests a tight lateral retinaculum). Conversely, the absence of pain during squatting or the absence of lateral retinacular pain helps rule it out.² A physical exam of the cruciate and collateral ligaments should be performed in a patient with a history of instability. Radiography is not needed for a diagnosis, but may be considered if examination reveals an effusion, the patient is age 50 years or older, or no improvement occurs after 8 to 12 weeks of treatment.³³

Treatment. The most effective and strongly supported treatment for PFPS is a 6-week physiotherapy program focusing on strengthening the quadriceps and hip muscles and stretching the quadriceps, ITB, hamstrings, and hip flexors.^4,5 There is limited information about the use of nonsteroidal anti-inflammatory drugs (NSAIDs), but they can be considered for short-term management.²

Patellar taping and bracing have shown some promise as adjunct therapies for PFPS, although the data for both are non-conclusive. There is a paucity of prospective randomized trials of patellar bracing and a 2012 Cochrane review found limited evidence of its efficacy.³⁴ But a 2014 meta-analysis revealed moderate evidence in support of patellar taping early on to help decrease pain,⁶ and a recent review suggests that it can be helpful in both the short and long term.⁷

Taping or bracing may be useful when combined with a tailored physical therapy program. Evidence for treatments such as biofeedback, chiropractic manipulation, and orthotics is limited, and they should be used only as adjunctive therapy.⁴

CASE › When you examine Ms. T, you find no swelling of the affected knee. You perform the tilt test, which elicits pain. Squatting causes some pain, as well. You diagnose PFPS and provide a referral for 6 weeks of physiotherapy.

Patellar subluxation or chronic dislocation

Patellofemoral instability (PFI) occurs when the patella disengages completely from the trochlear groove.¹¹ PFI’s etiology also relates to the complexity of the patellofemoral joint. Here, too, stability of the joint is achieved with a combination of soft tissue and bony restraints. At full extension and early flexion of the knee, however, the mechanisms of stability are limited, resulting in increased instability. Other associated factors include Q-angle, lateral pull from a tight ITB, and opposing forces from the vastus lateralis and vastus medialis obliquus (VMO).^8-10

Risk factors for PFI. The most common predisposing factors for PFI are trochlear dysplasia, patella alta, and lateralization of the tibial tuberosity or patella.^10,11 Older patients (mostly women) have an increased risk for patellofemoral instability. Older patients, predominately women, have an increased risk for PFI.⁹ Patients usually have a history of patellar subluxation or dislocation in their youth, with approximately 17% of those who had a first dislocation experiencing a recurrence.⁹ A family history of PFI is common, as well.¹⁰

Diagnosis. Patients with PFI often present with nonspecific anterior knee pain secondary to recurrent dislocation.¹³ Notable physical exam findings are:

• a positive J sign (noted if the patella suddenly shifts medially during early knee flexion or laterally during full extension)
• decreased quadriceps (specifically VMO) and hamstring strength and flexibility
• patellar hypermobility, which should be no more than a quarter to a half of the patellar diameter bilaterally
• pain during a patellar tilt test

• a positive patellar apprehension test.¹⁰ (With the patient lying with the knee flexed to 20°, place thumbs on the medial patella and push laterally; the patient will straighten leg with pain or “apprehension” prior to patellar dislocation.)

Plain radiography should be ordered in all cases to assess for osseous trauma/ deformity and to help guide surgical consideration. Magnetic resonance imaging (MRI) can provide additional information when significant soft tissue damage is suspected or the patient does not improve with conservative therapy.^8,11

Treatment. A recent Cochrane review showed that conservative treatment (VMO strengthening, bracing, and proprioceptive therapy) prevented future dislocations more effectively than surgical intervention.¹¹ However, surgery is indicated when obvious predisposing anatomic conditions (osteochondral fracture, intra-articular deformity, or a major tear of a medial soft tissue stabilizer) are clearly shown on imaging.^8,11

Patellar tendinopathy (jumper’s knee)

Patellar tendinopathy, an overuse injury often called “jumper’s knee” because it is associated with high-intensity jumping sports like volleyball and basketball, is an insertional tendinopathy with pain most commonly at the proximal patellar tendon.¹⁰ The pathology of the injury is poorly understood, but is believed to be the result of an impaired healing response to microtears.^12,14

Diagnosis. Patients with patellar tendinopathy typically present with anterior suprapatellar pain aggravated by activity. Classically, the pain can occur in any of 4 phases:¹² 1. pain isolated after activity; 2. pain that occurs during activity but does not impede activity; 3. pain that occurs both during and after the activity and interferes with competition
; 4. a complete tendon disruption. 

Examination should include an assessment of the patellar tendon for localized thickening, nodularity, crepitus, and focal suprapatellar tenderness. The muscle-tendon function should be evaluated by assessing knee mobility and strength of the quads via straight leg raise, decline squat, or single leg squats.¹² The Victorian Institute of Sport Assessment (VISA) questionnaire can be used to quantify the symptoms and to help track the patient’s progress throughout therapy.³¹ There are no proven special tests or radiologic studies to aid in the diagnosis of patellar tendinopathy,¹⁴ but magnetic resonance imaging (MRI) can be used for further evaluation when findings are equivocal.³⁵

Treatment. A wide range of options, from eccentric training—eg, 3 sets of 15 repetitions performed twice a day for 12 weeks—and physical therapy to platelet-rich plasma (PRP) injections, sclerosing injections, and surgery, are available for the treatment of patellar tendinopathy.^13-15 While no specific data have proven the superiority of any one therapy, expert consensus recommends eccentric exercise as initial therapy, performed for 12 weeks.^14,15

Three weeks of platelet-rich plasma injections helped 75% of patients with patellar tendinopathy return to their pre-symptom activity level within 90 days. It’s also interesting to note that a recently published study showed that 3 weekly PRP injections helped 75% of patients—all of whom failed to respond to 4 months of eccentric therapy—return to their pre-symptom activity level within 90 days.¹⁶ Corticosteroid injections should not be used to treat patellar tendinopathy due to the risk of tendon rupture.¹⁵ Orthopedic referral for surgical intervention should be considered for patients who fail to respond after 3 to 6 months of conservative therapy.¹⁴

Lateral knee pain

Iliotibial band tendinopathy


Iliotibial band syndrome (ITBS) is a common source of lateral knee pain, particularly in runners, cyclists, and endurance athletes.^17-19,36,37 The exact pathophysiology behind this diagnosis is debatable, but the most accepted etiology is inflammation generated from micro trauma to the soft tissues with inadequate healing time, resulting in persistent inflammation. ITBS is often associated with excessive overall running mileage, a sudden increase in mileage, or an abrupt change in training.^18,37

Patients with ITBS often complain of persistent nontraumatic knee pain that worsens with repetitive knee flexion. Diagnosis. Patients often complain of persistent nontraumatic lateral knee pain that worsens with repetitive knee flexion (eg, running or cycling).^17-19,37 A physical exam will often reveal pain over the lateral femoral condyle and a positive Noble’s test (FIGURE 1). A positive Ober’s test (FIGURE 2) is suggestive of ITBS, as well. The sensitivity and specificity of these tests are not well established, but in patients performing repetitive knee flexion activities with subjective lateral knee pain, pain over the lateral femoral condyle and a positive Ober’s and/or Noble’s test suggest an ITBS diagnosis.¹⁸ Imaging is not indicated initially, but MRI should be used in refractory cases to rule out other etiologies.^17,19

Treatment. First-line therapy for ITBS is conservative,^17-19,36,37 often involving a combination of techniques such as refraining from the activity that triggers the pain, NSAIDs, activity modification to reduce the strain over the ITB, myofascial release via foam rollers, and physical therapy focused on stretching the iliotibial band, tensor fasciae latae, and gluteus medius while strengthening the gluteus medius and core muscles.¹⁷ No single program has been shown to be better than another.

Corticosteroid injections are second-line therapy and have been shown to improve pain compared with placebo up to 2 weeks post injection.^17,19 When symptoms persist for more than 6 months despite conservative treatment, surgical intervention may be indicated.^18,19 Patients who experience temporary pain relief with corticosteroid injections often respond best to surgery.³⁶

Medial knee pain

Medial plica syndrome

Because of its anatomic location, the medial plica—which can be palpated in up to 84% of the population²⁰—is susceptible to impingement by the medial femoral condyle or the patellofemoral joint. Trauma with repetitive knee movement leads to inflammation and thickening of the plica, resulting in medial plica syndrome.^20,38 Initial inflammation may be triggered by blunt trauma, a sudden increase in activity, or transient synovitis.²²

Diagnosis. Medial plica syndrome is a challenging diagnosis. Patients generally have nonspecific complaints of aching medial knee pain, locking, and catching similar to complaints of a medial meniscal injury.²⁰

A mediopatellar plica test was more accurate than an MRI in diagnosing medial plica syndrome, according to a recent systematic review. Evaluation should include the mediopatellar plica test, which is performed with the patient lying supine with the knee fully extended. Pressure is placed over the inferomedial patellofemoral joint, creating an impingement of the medial plica between the finger and the medial femoral condyle. Elimination or marked diminishing of pain with knee flexion to 90° is considered a positive test.²¹

A recent systematic review found this test to be more diagnostically accurate than an MRI (sensitivity of the test is 90% and specificity is 89%, vs 77% and 58%, respectively, for MRI) for detection of medial plica syndrome. Ultrasound is almost as accurate, with a sensitivity of 90% and specificity of 83%.³⁹

Treatment of medial plica syndrome centers on physiotherapy and quadriceps strengthening,²⁰ augmented with NSAIDs. Intra-articular corticosteroid injections are considered second-line treatment.^20,22 An orthopedics referral is indicated to consider arthroscopic plica removal for refractory cases.^20,22

Pes anserine bursitis

The anserine bursal complex, located approximately 5 cm distal to the medial joint line, is formed by the combined insertion of the sartorius, gracilis, and semitendinosus tendons,³⁹ but the exact mechanism of pain is not well understood. Whether the pathophysiology is from an insertional tendonitis or overt bursitis is unknown, and no studies have focused on prevalence or risk factors. What is known is that overweight individuals and women with a wide pelvis seem to have a greater predilection and those with pes planus, diabetes, or knee osteoarthritis are at increased risk.²³

Diagnosis. Medial knee pain reproduced on palpation of the anatomical site of insertion of the pes anserine tendon complex supports a diagnosis of pes anserine bursitis, with or without edema. Radiologic studies are not needed, but may be helpful if significant bony pathology is suspected. Ultrasound, computed tomography (CT), and MRI are not recommended.²³

Treatment. Resting the affected knee, cryotherapy, NSAIDs, and using a pillow at night to relieve direct bursal pressure are recommended.³³ Weight loss in obese patients, treatment of pes planus, and control of diabetes may be helpful, as well. Although the literature is limited and dated, corticosteroid injection has been found to reduce the pain and may be considered as second-line treatment.^24-26

Posterior knee pain

Popliteal (Baker’s) cyst

The popliteal fossa contains 6 of the numerous bursa of the knee; the bursa beneath the medial head of the gastrocnemius muscle and the semimembranosus tendon is most commonly involved in the formation of a popliteal cyst.⁴⁰ It is postulated that increased intra-articular pressure forces fluid into the bursa, leading to expansion and pain. This can be idiopathic or secondary to internal derangement or trauma to the knee.⁴¹ Older age, a remote history of knee trauma, or a coexisting joint disease such as osteoarthritis, meniscal pathology, or rheumatoid arthritis are significant risk factors for the development of popliteal cysts.²⁷

Diagnosis. Most popliteal cysts are asymptomatic in adults and discovered incidentally after routine imaging to evaluate other knee pathology. However, symptomatic popliteal cysts present as a palpable mass in the popliteal fossa, resulting in pain and limited range of motion.

During the physical exam with the patient lying supine, a medial popliteal mass that is most prominent with the knee fully extended is common. A positive Foucher’s sign (the painful mass is palpated posteriorly in the popliteal fossa with the knee fully extended; pain is relieved and/or the mass reduced in size with knee flexion to 45°) suggests a diagnosis of popliteal cyst.^27,28

Radiologic studies are generally not needed to diagnose a popliteal cyst. However, if diagnostic uncertainty remains after the history and physical exam, plain knee radiographs and ultrasound should be obtained. This combination provides complementary information and helps rule out a fracture, arthritis, and thrombosis as the cause of the pain.²⁷ MRI is helpful if the diagnosis is still in doubt and for patients suspected of having significant internal derangement leading to cyst formation. Arthrography or CT is generally not needed.^27,41

Treatment. As popliteal cysts are often associated with other knee pathology, management of the underlying condition often leads to cyst regression. Keeping the knee in flexion can decrease the available space and assist in pain control in the acute phase.²⁷ Cold packs and NSAIDs can also be used initially. Cyst aspiration and intra-articular steroid injection have been shown to be effective for cysts that do not respond to this conservative approach.²⁷ However, addressing and managing the underlying knee pathology (eg, osteoarthritis, meniscal pathology, or rheumatoid arthritis) will prevent popliteal cysts from recurring.

When the problem is painful knee effusion

A prompt orthopedic referral is essential when you suspect an infectious joint. Nontraumatic knee effusion can be the primary source of knee pain or the result of underlying pathology. We mention it here because clinical suspicion is paramount in diagnosing a septic joint, a serious cause of painful knee effusion that warrants prompt treatment.

As in other causes of knee pain, a detailed history of the character of the pain is essential. Septic arthritis and crystalline disease (gout, pseudogout) should be suspected in patients without a history of trauma who cannot bear weight. Systemic complaints point to an infection and, with the exception of a possible low-grade fever, are not typically seen in crystalline disease. Notable findings include an erythematous, hot, swollen knee and pain with both active and passive movement.

Plain radiographs of the knee should be ordered to rule out significant trauma or arthritis as the etiology. It is important to perform joint aspiration with synovial fluid analysis. Fluid analysis should include a white blood cell (WBC) count with differential, Gram stain and cultures, and polarized light microscopy (not readily available in an outpatient setting).²⁹

Synovial fluid analysis characteristics suggestive of a septic joint include turbid quality, WBC >50,000 per mm³, an elevated protein content, and a low glucose concentration.³⁰ Gram stain and culture will help identify the infectious agent. Orthopedic referral should not be delayed in patients with a suspected infectious joint. Corticosteroids should not be injected during aspiration if infection is being ruled out.

CASE › When Ms. T returns for a follow-up visit 8 weeks later, she states that the knee pain has resolved and that she has returned to running. She has lost an additional 8 pounds and continues to diet. And, at the advice of her physical therapist, she is continuing her physiotherapy regimen at home to prevent a recurrence of PFPS.

CORRESPONDENCE
Carlton J. Covey, MD, FAAFP, Nellis Family Medicine Residency Program, 4700 Las Vegas Boulevard North, Nellis Air Force Base, NV 89191; carlton.covey@us.af.mil

CASE › Jane T, age 42, comes to see you because of right knee pain that she’s had for about 6 months. She denies any trauma. Ms. T describes the pain as vague and poorly localized, but worse with activity. She says she started a walking/running program 9 months ago, when she was told she was overweight (body mass index, 29). She has lost 10 pounds since then, Ms. T says, and hopes to lose more by continuing to exercise. upon further review, you find that Ms. T has had increasing pain while ascending and descending stairs and that the pain is also exacerbated when she stands after prolonged sitting.

If Ms. T were your patient, what would you include in a physical examination and how would you diagnose and treat her?

Knee pain is a common presentation in primary care. While traumatic knee pain is frequently addressed in the medical literature, little has been written about chronic nontraumatic nonarthritic knee pain like that of Ms. T. Thus, while physical exam tests often lead to the correct diagnosis for traumatic knee pain, there is limited information on the use of such tests to determine the etiology of chronic knee pain.

This review was developed to fill that gap. In the pages that follow, we provide general guidance on the diagnosis and treatment of chronic nontraumatic knee pain. The conditions are presented anatomically—anterior, lateral, medial, or posterior—with common etiologies, history and physical exam findings, and diagnosis and treatment options for each (TABLE).^1-31

Anterior knee pain

Patellofemoral pain syndrome

Patellofemoral pain syndrome is the most common cause of anterior knee pain. Taping or bracing—along with physical therapy—may help reduce the pain.
Patellofemoral pain syndrome (PFPS), the most common cause of anterior knee pain, is a complex entity with an etiology that has not been well described.² The quadriceps tendon, medial and lateral retinacula, iliotibial band (ITB), vastus medialis and lateralis, and the insertion of the patellar tendon on the anterior tibial tubercle all play a role in proper tracking of the patellofemoral joint; an imbalance in any of these forces leads to abnormal patellar tracking over the femoral condyles, and pain ensues. PFPS can also be secondary to joint overload, in which excessive physical activity (eg, running, lunges, or squats) overloads the patellofemoral joint and causes pain.

Risk factors for PFPS include strength imbalances in the quadriceps, hamstring, and hip muscle groups, and increased training, such as running longer distances.^4,32 A recent review showed no relationship between an increased quadriceps (Q)-angle and PFPS, so that is no longer considered a major risk factor.⁵

Diagnosis. PFPS is a diagnosis of exclusion, and is primarily based on history and physical exam. Anterior knee pain that is exacerbated when seated for long periods of time (the “theater sign”) or by descending stairs is a classic indication of PFPS.¹ Patients may complain of knee stiffness or “giving out” secondary to sharp knee pain and a sensation of popping or crepitus in the joint. Swelling is not a common finding.²

A recent meta-analysis revealed limited evidence for the use of any specific physical exam tests to diagnose PFPS. But pain during squatting and pain with a patellar tilt test were most consistent with a diagnosis of PFPS. (The patellar tilt test involves lifting the lateral edge of the patella superiorly while the patient lies supine with knee extended; pain with <20° of lift suggests a tight lateral retinaculum). Conversely, the absence of pain during squatting or the absence of lateral retinacular pain helps rule it out.² A physical exam of the cruciate and collateral ligaments should be performed in a patient with a history of instability. Radiography is not needed for a diagnosis, but may be considered if examination reveals an effusion, the patient is age 50 years or older, or no improvement occurs after 8 to 12 weeks of treatment.³³

Treatment. The most effective and strongly supported treatment for PFPS is a 6-week physiotherapy program focusing on strengthening the quadriceps and hip muscles and stretching the quadriceps, ITB, hamstrings, and hip flexors.^4,5 There is limited information about the use of nonsteroidal anti-inflammatory drugs (NSAIDs), but they can be considered for short-term management.²

Patellar taping and bracing have shown some promise as adjunct therapies for PFPS, although the data for both are non-conclusive. There is a paucity of prospective randomized trials of patellar bracing and a 2012 Cochrane review found limited evidence of its efficacy.³⁴ But a 2014 meta-analysis revealed moderate evidence in support of patellar taping early on to help decrease pain,⁶ and a recent review suggests that it can be helpful in both the short and long term.⁷

Taping or bracing may be useful when combined with a tailored physical therapy program. Evidence for treatments such as biofeedback, chiropractic manipulation, and orthotics is limited, and they should be used only as adjunctive therapy.⁴

CASE › When you examine Ms. T, you find no swelling of the affected knee. You perform the tilt test, which elicits pain. Squatting causes some pain, as well. You diagnose PFPS and provide a referral for 6 weeks of physiotherapy.

Patellar subluxation or chronic dislocation

Patellofemoral instability (PFI) occurs when the patella disengages completely from the trochlear groove.¹¹ PFI’s etiology also relates to the complexity of the patellofemoral joint. Here, too, stability of the joint is achieved with a combination of soft tissue and bony restraints. At full extension and early flexion of the knee, however, the mechanisms of stability are limited, resulting in increased instability. Other associated factors include Q-angle, lateral pull from a tight ITB, and opposing forces from the vastus lateralis and vastus medialis obliquus (VMO).^8-10

Risk factors for PFI. The most common predisposing factors for PFI are trochlear dysplasia, patella alta, and lateralization of the tibial tuberosity or patella.^10,11 Older patients (mostly women) have an increased risk for patellofemoral instability. Older patients, predominately women, have an increased risk for PFI.⁹ Patients usually have a history of patellar subluxation or dislocation in their youth, with approximately 17% of those who had a first dislocation experiencing a recurrence.⁹ A family history of PFI is common, as well.¹⁰

Diagnosis. Patients with PFI often present with nonspecific anterior knee pain secondary to recurrent dislocation.¹³ Notable physical exam findings are:

• a positive J sign (noted if the patella suddenly shifts medially during early knee flexion or laterally during full extension)
• decreased quadriceps (specifically VMO) and hamstring strength and flexibility
• patellar hypermobility, which should be no more than a quarter to a half of the patellar diameter bilaterally
• pain during a patellar tilt test

• a positive patellar apprehension test.¹⁰ (With the patient lying with the knee flexed to 20°, place thumbs on the medial patella and push laterally; the patient will straighten leg with pain or “apprehension” prior to patellar dislocation.)

Plain radiography should be ordered in all cases to assess for osseous trauma/ deformity and to help guide surgical consideration. Magnetic resonance imaging (MRI) can provide additional information when significant soft tissue damage is suspected or the patient does not improve with conservative therapy.^8,11

Treatment. A recent Cochrane review showed that conservative treatment (VMO strengthening, bracing, and proprioceptive therapy) prevented future dislocations more effectively than surgical intervention.¹¹ However, surgery is indicated when obvious predisposing anatomic conditions (osteochondral fracture, intra-articular deformity, or a major tear of a medial soft tissue stabilizer) are clearly shown on imaging.^8,11

Patellar tendinopathy (jumper’s knee)

Patellar tendinopathy, an overuse injury often called “jumper’s knee” because it is associated with high-intensity jumping sports like volleyball and basketball, is an insertional tendinopathy with pain most commonly at the proximal patellar tendon.¹⁰ The pathology of the injury is poorly understood, but is believed to be the result of an impaired healing response to microtears.^12,14

Diagnosis. Patients with patellar tendinopathy typically present with anterior suprapatellar pain aggravated by activity. Classically, the pain can occur in any of 4 phases:¹² 1. pain isolated after activity; 2. pain that occurs during activity but does not impede activity; 3. pain that occurs both during and after the activity and interferes with competition
; 4. a complete tendon disruption. 

Examination should include an assessment of the patellar tendon for localized thickening, nodularity, crepitus, and focal suprapatellar tenderness. The muscle-tendon function should be evaluated by assessing knee mobility and strength of the quads via straight leg raise, decline squat, or single leg squats.¹² The Victorian Institute of Sport Assessment (VISA) questionnaire can be used to quantify the symptoms and to help track the patient’s progress throughout therapy.³¹ There are no proven special tests or radiologic studies to aid in the diagnosis of patellar tendinopathy,¹⁴ but magnetic resonance imaging (MRI) can be used for further evaluation when findings are equivocal.³⁵

Treatment. A wide range of options, from eccentric training—eg, 3 sets of 15 repetitions performed twice a day for 12 weeks—and physical therapy to platelet-rich plasma (PRP) injections, sclerosing injections, and surgery, are available for the treatment of patellar tendinopathy.^13-15 While no specific data have proven the superiority of any one therapy, expert consensus recommends eccentric exercise as initial therapy, performed for 12 weeks.^14,15

Three weeks of platelet-rich plasma injections helped 75% of patients with patellar tendinopathy return to their pre-symptom activity level within 90 days. It’s also interesting to note that a recently published study showed that 3 weekly PRP injections helped 75% of patients—all of whom failed to respond to 4 months of eccentric therapy—return to their pre-symptom activity level within 90 days.¹⁶ Corticosteroid injections should not be used to treat patellar tendinopathy due to the risk of tendon rupture.¹⁵ Orthopedic referral for surgical intervention should be considered for patients who fail to respond after 3 to 6 months of conservative therapy.¹⁴

Lateral knee pain

Iliotibial band tendinopathy


Iliotibial band syndrome (ITBS) is a common source of lateral knee pain, particularly in runners, cyclists, and endurance athletes.^17-19,36,37 The exact pathophysiology behind this diagnosis is debatable, but the most accepted etiology is inflammation generated from micro trauma to the soft tissues with inadequate healing time, resulting in persistent inflammation. ITBS is often associated with excessive overall running mileage, a sudden increase in mileage, or an abrupt change in training.^18,37

Patients with ITBS often complain of persistent nontraumatic knee pain that worsens with repetitive knee flexion. Diagnosis. Patients often complain of persistent nontraumatic lateral knee pain that worsens with repetitive knee flexion (eg, running or cycling).^17-19,37 A physical exam will often reveal pain over the lateral femoral condyle and a positive Noble’s test (FIGURE 1). A positive Ober’s test (FIGURE 2) is suggestive of ITBS, as well. The sensitivity and specificity of these tests are not well established, but in patients performing repetitive knee flexion activities with subjective lateral knee pain, pain over the lateral femoral condyle and a positive Ober’s and/or Noble’s test suggest an ITBS diagnosis.¹⁸ Imaging is not indicated initially, but MRI should be used in refractory cases to rule out other etiologies.^17,19

Treatment. First-line therapy for ITBS is conservative,^17-19,36,37 often involving a combination of techniques such as refraining from the activity that triggers the pain, NSAIDs, activity modification to reduce the strain over the ITB, myofascial release via foam rollers, and physical therapy focused on stretching the iliotibial band, tensor fasciae latae, and gluteus medius while strengthening the gluteus medius and core muscles.¹⁷ No single program has been shown to be better than another.

Corticosteroid injections are second-line therapy and have been shown to improve pain compared with placebo up to 2 weeks post injection.^17,19 When symptoms persist for more than 6 months despite conservative treatment, surgical intervention may be indicated.^18,19 Patients who experience temporary pain relief with corticosteroid injections often respond best to surgery.³⁶

Medial knee pain

Medial plica syndrome

Because of its anatomic location, the medial plica—which can be palpated in up to 84% of the population²⁰—is susceptible to impingement by the medial femoral condyle or the patellofemoral joint. Trauma with repetitive knee movement leads to inflammation and thickening of the plica, resulting in medial plica syndrome.^20,38 Initial inflammation may be triggered by blunt trauma, a sudden increase in activity, or transient synovitis.²²

Diagnosis. Medial plica syndrome is a challenging diagnosis. Patients generally have nonspecific complaints of aching medial knee pain, locking, and catching similar to complaints of a medial meniscal injury.²⁰

A mediopatellar plica test was more accurate than an MRI in diagnosing medial plica syndrome, according to a recent systematic review. Evaluation should include the mediopatellar plica test, which is performed with the patient lying supine with the knee fully extended. Pressure is placed over the inferomedial patellofemoral joint, creating an impingement of the medial plica between the finger and the medial femoral condyle. Elimination or marked diminishing of pain with knee flexion to 90° is considered a positive test.²¹

A recent systematic review found this test to be more diagnostically accurate than an MRI (sensitivity of the test is 90% and specificity is 89%, vs 77% and 58%, respectively, for MRI) for detection of medial plica syndrome. Ultrasound is almost as accurate, with a sensitivity of 90% and specificity of 83%.³⁹

Treatment of medial plica syndrome centers on physiotherapy and quadriceps strengthening,²⁰ augmented with NSAIDs. Intra-articular corticosteroid injections are considered second-line treatment.^20,22 An orthopedics referral is indicated to consider arthroscopic plica removal for refractory cases.^20,22

Pes anserine bursitis

The anserine bursal complex, located approximately 5 cm distal to the medial joint line, is formed by the combined insertion of the sartorius, gracilis, and semitendinosus tendons,³⁹ but the exact mechanism of pain is not well understood. Whether the pathophysiology is from an insertional tendonitis or overt bursitis is unknown, and no studies have focused on prevalence or risk factors. What is known is that overweight individuals and women with a wide pelvis seem to have a greater predilection and those with pes planus, diabetes, or knee osteoarthritis are at increased risk.²³

Diagnosis. Medial knee pain reproduced on palpation of the anatomical site of insertion of the pes anserine tendon complex supports a diagnosis of pes anserine bursitis, with or without edema. Radiologic studies are not needed, but may be helpful if significant bony pathology is suspected. Ultrasound, computed tomography (CT), and MRI are not recommended.²³

Treatment. Resting the affected knee, cryotherapy, NSAIDs, and using a pillow at night to relieve direct bursal pressure are recommended.³³ Weight loss in obese patients, treatment of pes planus, and control of diabetes may be helpful, as well. Although the literature is limited and dated, corticosteroid injection has been found to reduce the pain and may be considered as second-line treatment.^24-26

Posterior knee pain

Popliteal (Baker’s) cyst

The popliteal fossa contains 6 of the numerous bursa of the knee; the bursa beneath the medial head of the gastrocnemius muscle and the semimembranosus tendon is most commonly involved in the formation of a popliteal cyst.⁴⁰ It is postulated that increased intra-articular pressure forces fluid into the bursa, leading to expansion and pain. This can be idiopathic or secondary to internal derangement or trauma to the knee.⁴¹ Older age, a remote history of knee trauma, or a coexisting joint disease such as osteoarthritis, meniscal pathology, or rheumatoid arthritis are significant risk factors for the development of popliteal cysts.²⁷

Diagnosis. Most popliteal cysts are asymptomatic in adults and discovered incidentally after routine imaging to evaluate other knee pathology. However, symptomatic popliteal cysts present as a palpable mass in the popliteal fossa, resulting in pain and limited range of motion.

During the physical exam with the patient lying supine, a medial popliteal mass that is most prominent with the knee fully extended is common. A positive Foucher’s sign (the painful mass is palpated posteriorly in the popliteal fossa with the knee fully extended; pain is relieved and/or the mass reduced in size with knee flexion to 45°) suggests a diagnosis of popliteal cyst.^27,28

Radiologic studies are generally not needed to diagnose a popliteal cyst. However, if diagnostic uncertainty remains after the history and physical exam, plain knee radiographs and ultrasound should be obtained. This combination provides complementary information and helps rule out a fracture, arthritis, and thrombosis as the cause of the pain.²⁷ MRI is helpful if the diagnosis is still in doubt and for patients suspected of having significant internal derangement leading to cyst formation. Arthrography or CT is generally not needed.^27,41

Treatment. As popliteal cysts are often associated with other knee pathology, management of the underlying condition often leads to cyst regression. Keeping the knee in flexion can decrease the available space and assist in pain control in the acute phase.²⁷ Cold packs and NSAIDs can also be used initially. Cyst aspiration and intra-articular steroid injection have been shown to be effective for cysts that do not respond to this conservative approach.²⁷ However, addressing and managing the underlying knee pathology (eg, osteoarthritis, meniscal pathology, or rheumatoid arthritis) will prevent popliteal cysts from recurring.

When the problem is painful knee effusion

A prompt orthopedic referral is essential when you suspect an infectious joint. Nontraumatic knee effusion can be the primary source of knee pain or the result of underlying pathology. We mention it here because clinical suspicion is paramount in diagnosing a septic joint, a serious cause of painful knee effusion that warrants prompt treatment.

As in other causes of knee pain, a detailed history of the character of the pain is essential. Septic arthritis and crystalline disease (gout, pseudogout) should be suspected in patients without a history of trauma who cannot bear weight. Systemic complaints point to an infection and, with the exception of a possible low-grade fever, are not typically seen in crystalline disease. Notable findings include an erythematous, hot, swollen knee and pain with both active and passive movement.

Plain radiographs of the knee should be ordered to rule out significant trauma or arthritis as the etiology. It is important to perform joint aspiration with synovial fluid analysis. Fluid analysis should include a white blood cell (WBC) count with differential, Gram stain and cultures, and polarized light microscopy (not readily available in an outpatient setting).²⁹

Synovial fluid analysis characteristics suggestive of a septic joint include turbid quality, WBC >50,000 per mm³, an elevated protein content, and a low glucose concentration.³⁰ Gram stain and culture will help identify the infectious agent. Orthopedic referral should not be delayed in patients with a suspected infectious joint. Corticosteroids should not be injected during aspiration if infection is being ruled out.

CASE › When Ms. T returns for a follow-up visit 8 weeks later, she states that the knee pain has resolved and that she has returned to running. She has lost an additional 8 pounds and continues to diet. And, at the advice of her physical therapist, she is continuing her physiotherapy regimen at home to prevent a recurrence of PFPS.

CORRESPONDENCE
Carlton J. Covey, MD, FAAFP, Nellis Family Medicine Residency Program, 4700 Las Vegas Boulevard North, Nellis Air Force Base, NV 89191; carlton.covey@us.af.mil

When a public health intervention succeeds and achieves long-term suppression of the target problem, an unfortunate irony is that, with time, the intervention can seem less vital. So it is with vaccines. Many patients and physicians today have never experienced the infectious diseases that once caused millions of deaths and much disability each year, and they therefore do not appreciate the impact these diseases had when they were prevalent.

It is estimated that just 9 of the routinely recommended vaccines prevent 42,000 deaths and 20 million cases of disease in every birth cohort.¹ With many of these diseases thus held at bay, attention shifted instead to the supposed risks of vaccines. Many people mistakenly believe a vaccine’s potential for harm is more likely than the chance of acquiring the disease it prevents, and they therefore refuse vaccines for themselves and their children, with little chance in the short term of suffering an adverse outcome for their decision.

In this review—which can inform primary care physicians’ discussions with vaccine-hesitant patients—we first highlight 2 preventable diseases, measles and Haemophilus influenzae type b (Hib) infection. Recent residency graduates may never see these diseases thanks to sustained vaccination programs. However, the risk of acquiring these infections has not disappeared entirely. After considering these examples, we examine the totality of the morbidity and mortality prevented by vaccination and describe the safety of current vaccines and the systems in place to assure their continued safety.

Measles: No longer endemic to the United States, but still a risk from importation


In the pre-vaccine era, measles (rubeola) infected more than 500,000 Americans annually and killed roughly 500.² This highly communicable systemic acute viral infection was once considered universal in childhood. After vaccine licensure in 1963, widespread immunization reduced the incidence by more than 98%, and by 2000 it had eliminated endemic measles from the United States. However, the disease has now reappeared—largely due to international travel and neglect in becoming vaccinated. As of October 31, 2014, the United States had 20 outbreaks and 603 cases of measles reported in 2014—a dramatic increase over recent years.³

Clinical appearance. Acute measles infection is characterized by high fever, cough, coryza, conjunctivitis, and rash. Koplik spots are a 24^- to 72-hour pathognomonic exanthem of blue-white spots 1 to 3 mm in diameter on an erythematous base along the buccal mucosa. The resolving exanthem coincides with the eruption of a blanching, maculopapular exanthem originating at the hairline, progressing down the trunk and out to the limbs (sparing the palms and soles), coalescing, and then fading with a fine desquamation in the same order of appearance over 7 days. Additional associated symptoms include anorexia, diarrhea, and generalized lymphadenopathy.^2,4

Complications are common with measles. Acute measles infection is rarely fatal. However, serious complications occur in nearly one-third of reported cases.² During the 1989-1991 measles resurgence in the United States, more than 100 deaths occurred among the 55,000 cases reported.^5-7 In early 2011, the United States saw the highest reported number of measles cases since 1996 due to importation. Of the 118 reported cases, 105 (89%) occurred in unvaccinated people, 47 (40%) required hospitalization, and 9 individuals developed pneumonia.⁸

While acute measles is rarely fatal, serious complications occur in nearly one-third of cases. Complications of measles infection are shown in TABLE 1.^2,4 Pneumonia (viral or superimposed bacterial) accounts for 60% of measles-related deaths.² Neurologic complications, while less frequent, can be severe.

Acute encephalitis occurs in 1 in 1000 to 2000 cases and presents within a week following the exanthem with fever, headache, vomiting, meningismus, change in mental status, convulsions, and coma.² Encephalitis has a fatality rate of 15%, leaving another 25% with residual neurologic damage.² Subacute sclerosing panencephalitis (SSPE) occurs in 5 to 10 cases per million (in the United States), on average 7 years after the initial measles infection.^9,10 After an insidious onset, behavior and intellect deteriorate, followed by ataxia, myoclonic seizures, and ultimately death. In the United States, the number of reported cases of SSPE has declined with the reduction in measles cases. However, in countries with less robust measles immunization eradication programs, the risk of developing SSPE remains.^9,10

Hib: Contained but not eradicated

Hib was once the leading cause of meningitis and a major cause of other invasive bacterial diseases, but it has been greatly controlled since the advent of routine Hib vaccination in 1990.¹¹ Hib is an encapsulated, gram-negative coccobacillus. There are 6 major capsular serotypes of Haemophilus influenzae, but serotype b was linked to major invasive disease in humans 95% of the time.¹² The spectrum of diseases caused by Hib is seen in TABLE 2.^13-15 Hib is transmitted by respiratory droplets from noninfected as well as infected carriers. Asymptomatic nasal carriage in the pre-vaccine era varied from 0.5% to 5%.¹²

Hib is primarily a disease of young children, with almost all cases occurring in children younger than 5 years of age (66% in those younger than 18 months). Other risk factors for invasive disease are those that increase the spread of respiratory droplets: crowding, lower socioeconomic status, day care attendance, large household size, and school-aged siblings. American Indian and Alaskan Native populations remain at higher risk due to incomplete vaccination rates and the sociodemographic risk factors noted above. Breastfeeding is protective.¹²

Three percent to 6% of cases of invasive Hib disease are fatal; another 20% can have long-term sequelae such as hearing loss. In the early 1990s, the peak incidence of Hib disease reached 41 cases per 100,000 population.¹² The reduction in incidence of Hib disease brought about by universal vaccination has been attributed to individual immunity, decreased asymptomatic nasal carriage, and herd immunity.¹²

Despite this progress, Hib continues to evade eradication. In Minnesota in 2008, 5 children, ages 5 months to 3 years, contracted invasive Hib disease (3 with meningitis, 1 with pneumonia, 1 with epiglottitis).¹⁶ Of the 5, only one was up to date with Hib vaccination; the others had not received vaccine because of shortages or parent refusal. These children were unrelated and had not been in contact with each other.

In a daycare outbreak in the United Kingdom, 2 cases of Hib disease (meningitis and septic arthritis) were identified in fully immunized children younger than 18 months, presumably due to a lack of complete vaccine efficacy.¹⁷ A study of nasal carriage (performed just prior to rifampin prophylaxis) among other attendees and caregivers revealed 3 asymptomatic carriers.¹⁷ Although Hib is largely well-contained in developed countries due to vaccination policies, the burden of disease in developing countries is estimated to be approximately 8.1 million serious illnesses with 371,000 deaths annually.¹³

The totality of morbidity and mortality prevented by vaccines

It is estimated that using just 9 routinely recommended vaccines prevents 
42,000 deaths and 20 million cases of disease in every birth cohort. Measles and Hib are 2 examples of vaccine-preventable diseases and the reduction in morbidity and mortality achievable with vaccines. TABLE 3¹⁸ summarizes the number of pre-vaccine era cases for selected diseases. Routine vaccination against 7 common childhood diseases not only prevents many thousands of deaths, as mentioned earlier,¹ but it saves $13.5 billion in direct costs in each birth cohort and saves society $68.8 billion in costs that include disability and lost productivity of both patients and caregivers.¹

Put simply, every dollar spent on the vaccination program saves $10 in direct and indirect costs to society.¹ Sustaining these successes and averting the resurgence of contained diseases requires a commitment to high immunization rates without delays and lapses—an effort made more challenging in light of misinformation about vaccine safety and resultant parental vaccine hesitancy.

Vaccine safety is ensured
 by rigorous systems


Despite an impressive record of safety, vaccines still cause anxiety among patients and parents in family practices. A recent survey identified concerns of long-term complications, autism, and thimerosal effects to be foremost on the minds of parents, whereas short-term effects were of much less concern.¹⁹ Causation of autism related to vaccines has been dismissed; the initial linkages have been shown to be fraudulent.²⁰ With the exception of some influenza vaccine preparations, thimerosal is no longer present in routinely administered children’s vaccines and has been shown not to be associated with autism.^21,22 To address parents’ and patients’ concerns about vaccine safety, and especially those surrounding short- and long-term complications, physicians should have a general understanding of the pre- and post-licensure mechanisms in the United States.

Pre-licensure safety is under the purview of vaccine manufacturers and the Center for Biologics Evaluation and Research at the US Food and Drug Administration (http://www.fda.gov/biologicsbloodvaccines/vaccines/default.htm). For licensure, manufacturers must provide clinical data to demonstrate sufficient safety and efficacy. Accordingly, pre-licensure assessments are conducted in a “closed system” under a research protocol. The vaccine recipients are volitional research subjects selected according to inclusion and exclusion criteria. They are also compensated. However, sample sizes are rarely large enough to exclude rare serious adverse events.

Once licensure has been granted, the focus of safety then shifts to the “open system” of usual clinical practice. Vaccine recipients are unselected members of the general population and may have underlying medical conditions, and sometimes—such as with school entry mandates—are less volitional. In this sphere, the responsible parties for safety include the government, manufacturers, and health care systems.

Three ongoing systems function to assure vaccine safety: the Vaccine Adverse Event Reporting System (VAERS), the Vaccine Safety Datalink (VSD), and the Clinical Immunization Safety Assessment (CISA) Network.^23,24

VAERS serves as an early warning system for coincidental safety signals and can generate hypotheses for further investigation.^24,25 It is characterized by high sensitivity but low specificity as it relies on voluntary reporting from health care personnel, parents, and others. This system was instrumental in identifying the initial cases of intussusception attributable to the rotavirus vaccine, RotaShield.²⁶

The VSD is a network of 10 large, geographically diverse and linked health maintenance organizations that cover about 3% of the US population. Within this “real time” network, vaccination (exposure) can be compared with outpatient, emergency department, hospital, and laboratory data (health outcomes), while accounting for demographic variables (confounders).^27,28 VSD studies linked the measles, mumps, rubella, and varicella vaccine to febrile seizures²⁹ and showed no relationship between cumulative vaccine antigen exposure and autism.³⁰

The CISA was established in 2001 to investigate the pathophysiologic mechanisms and biologic risks of adverse effects following immunization and to provide evidence-based vaccine safety assessments.

Based on all available evidence, routinely recommended vaccines have attained a very high level of safety. As with other preventive services, immunizations are generally provided to healthy individuals to maintain good health; thus, a low tolerance for significant adverse events exists. Well over 100 million doses of vaccines are given each year, yet the VAERS receives, on average, only 28,000 adverse event reports per year.

These reports comprise mild, moderate, and severe reactions to vaccines, but also adverse events that may not be related in any way other than chronologically to the vaccine’s administration. Despite this relatively low number of real safety concerns, it is still more likely that patients will know someone who has had a vaccine-related adverse event than someone who has had some of the diseases the vaccines prevent.³¹

Final thoughts

Current anti-vaccine sentiments appear to arise from varying perspectives.To appreciate the benefit 
of vaccine acceptance,
 we need only look to Europe, where high levels of vaccine refusal has led to a resurgence of vaccine-preventable diseases such as measles. Some are held by parents of children who have allegedly suffered a severe vaccine related adverse event; others by those opposed to government-mandated school immunization requirements; and some from those who have a dislike of vaccine manufacturers. These sentiments persist in part because of a low level of vaccine preventable diseases: When such illnesses are no longer deemed a threat, those who have concerns about vaccine safety, no matter how invalid, believe their concerns should trump all other considerations.

To appreciate the true benefit of vaccine acceptance, we need only look to Europe, where the anti-vaccine movement has led to high levels of vaccine refusal and a resurgence of vaccine-preventable diseases, such as measles, with their associated morbidity and mortality.³² In advocating for continued acceptance and widespread use of vaccines, family physicians can convey to patients and parents the magnitude of associated health benefits while confidently attesting to the effectiveness and safety of vaccines.

CORRESPONDENCE
John Epling, MD, MSEd, Department of Family Medicine, SUNY Upstate Medical University, 475 Irving Ave, Suite 200, Syracuse, NY 13210; eplingj@upstate.edu

When a public health intervention succeeds and achieves long-term suppression of the target problem, an unfortunate irony is that, with time, the intervention can seem less vital. So it is with vaccines. Many patients and physicians today have never experienced the infectious diseases that once caused millions of deaths and much disability each year, and they therefore do not appreciate the impact these diseases had when they were prevalent.

It is estimated that just 9 of the routinely recommended vaccines prevent 42,000 deaths and 20 million cases of disease in every birth cohort.¹ With many of these diseases thus held at bay, attention shifted instead to the supposed risks of vaccines. Many people mistakenly believe a vaccine’s potential for harm is more likely than the chance of acquiring the disease it prevents, and they therefore refuse vaccines for themselves and their children, with little chance in the short term of suffering an adverse outcome for their decision.

In this review—which can inform primary care physicians’ discussions with vaccine-hesitant patients—we first highlight 2 preventable diseases, measles and Haemophilus influenzae type b (Hib) infection. Recent residency graduates may never see these diseases thanks to sustained vaccination programs. However, the risk of acquiring these infections has not disappeared entirely. After considering these examples, we examine the totality of the morbidity and mortality prevented by vaccination and describe the safety of current vaccines and the systems in place to assure their continued safety.

Measles: No longer endemic to the United States, but still a risk from importation


In the pre-vaccine era, measles (rubeola) infected more than 500,000 Americans annually and killed roughly 500.² This highly communicable systemic acute viral infection was once considered universal in childhood. After vaccine licensure in 1963, widespread immunization reduced the incidence by more than 98%, and by 2000 it had eliminated endemic measles from the United States. However, the disease has now reappeared—largely due to international travel and neglect in becoming vaccinated. As of October 31, 2014, the United States had 20 outbreaks and 603 cases of measles reported in 2014—a dramatic increase over recent years.³

Clinical appearance. Acute measles infection is characterized by high fever, cough, coryza, conjunctivitis, and rash. Koplik spots are a 24^- to 72-hour pathognomonic exanthem of blue-white spots 1 to 3 mm in diameter on an erythematous base along the buccal mucosa. The resolving exanthem coincides with the eruption of a blanching, maculopapular exanthem originating at the hairline, progressing down the trunk and out to the limbs (sparing the palms and soles), coalescing, and then fading with a fine desquamation in the same order of appearance over 7 days. Additional associated symptoms include anorexia, diarrhea, and generalized lymphadenopathy.^2,4

Complications are common with measles. Acute measles infection is rarely fatal. However, serious complications occur in nearly one-third of reported cases.² During the 1989-1991 measles resurgence in the United States, more than 100 deaths occurred among the 55,000 cases reported.^5-7 In early 2011, the United States saw the highest reported number of measles cases since 1996 due to importation. Of the 118 reported cases, 105 (89%) occurred in unvaccinated people, 47 (40%) required hospitalization, and 9 individuals developed pneumonia.⁸

While acute measles is rarely fatal, serious complications occur in nearly one-third of cases. Complications of measles infection are shown in TABLE 1.^2,4 Pneumonia (viral or superimposed bacterial) accounts for 60% of measles-related deaths.² Neurologic complications, while less frequent, can be severe.

Acute encephalitis occurs in 1 in 1000 to 2000 cases and presents within a week following the exanthem with fever, headache, vomiting, meningismus, change in mental status, convulsions, and coma.² Encephalitis has a fatality rate of 15%, leaving another 25% with residual neurologic damage.² Subacute sclerosing panencephalitis (SSPE) occurs in 5 to 10 cases per million (in the United States), on average 7 years after the initial measles infection.^9,10 After an insidious onset, behavior and intellect deteriorate, followed by ataxia, myoclonic seizures, and ultimately death. In the United States, the number of reported cases of SSPE has declined with the reduction in measles cases. However, in countries with less robust measles immunization eradication programs, the risk of developing SSPE remains.^9,10

Hib: Contained but not eradicated

Hib was once the leading cause of meningitis and a major cause of other invasive bacterial diseases, but it has been greatly controlled since the advent of routine Hib vaccination in 1990.¹¹ Hib is an encapsulated, gram-negative coccobacillus. There are 6 major capsular serotypes of Haemophilus influenzae, but serotype b was linked to major invasive disease in humans 95% of the time.¹² The spectrum of diseases caused by Hib is seen in TABLE 2.^13-15 Hib is transmitted by respiratory droplets from noninfected as well as infected carriers. Asymptomatic nasal carriage in the pre-vaccine era varied from 0.5% to 5%.¹²

Hib is primarily a disease of young children, with almost all cases occurring in children younger than 5 years of age (66% in those younger than 18 months). Other risk factors for invasive disease are those that increase the spread of respiratory droplets: crowding, lower socioeconomic status, day care attendance, large household size, and school-aged siblings. American Indian and Alaskan Native populations remain at higher risk due to incomplete vaccination rates and the sociodemographic risk factors noted above. Breastfeeding is protective.¹²

Three percent to 6% of cases of invasive Hib disease are fatal; another 20% can have long-term sequelae such as hearing loss. In the early 1990s, the peak incidence of Hib disease reached 41 cases per 100,000 population.¹² The reduction in incidence of Hib disease brought about by universal vaccination has been attributed to individual immunity, decreased asymptomatic nasal carriage, and herd immunity.¹²

Despite this progress, Hib continues to evade eradication. In Minnesota in 2008, 5 children, ages 5 months to 3 years, contracted invasive Hib disease (3 with meningitis, 1 with pneumonia, 1 with epiglottitis).¹⁶ Of the 5, only one was up to date with Hib vaccination; the others had not received vaccine because of shortages or parent refusal. These children were unrelated and had not been in contact with each other.

In a daycare outbreak in the United Kingdom, 2 cases of Hib disease (meningitis and septic arthritis) were identified in fully immunized children younger than 18 months, presumably due to a lack of complete vaccine efficacy.¹⁷ A study of nasal carriage (performed just prior to rifampin prophylaxis) among other attendees and caregivers revealed 3 asymptomatic carriers.¹⁷ Although Hib is largely well-contained in developed countries due to vaccination policies, the burden of disease in developing countries is estimated to be approximately 8.1 million serious illnesses with 371,000 deaths annually.¹³

The totality of morbidity and mortality prevented by vaccines

It is estimated that using just 9 routinely recommended vaccines prevents 
42,000 deaths and 20 million cases of disease in every birth cohort. Measles and Hib are 2 examples of vaccine-preventable diseases and the reduction in morbidity and mortality achievable with vaccines. TABLE 3¹⁸ summarizes the number of pre-vaccine era cases for selected diseases. Routine vaccination against 7 common childhood diseases not only prevents many thousands of deaths, as mentioned earlier,¹ but it saves $13.5 billion in direct costs in each birth cohort and saves society $68.8 billion in costs that include disability and lost productivity of both patients and caregivers.¹

Put simply, every dollar spent on the vaccination program saves $10 in direct and indirect costs to society.¹ Sustaining these successes and averting the resurgence of contained diseases requires a commitment to high immunization rates without delays and lapses—an effort made more challenging in light of misinformation about vaccine safety and resultant parental vaccine hesitancy.

Vaccine safety is ensured
 by rigorous systems


Despite an impressive record of safety, vaccines still cause anxiety among patients and parents in family practices. A recent survey identified concerns of long-term complications, autism, and thimerosal effects to be foremost on the minds of parents, whereas short-term effects were of much less concern.¹⁹ Causation of autism related to vaccines has been dismissed; the initial linkages have been shown to be fraudulent.²⁰ With the exception of some influenza vaccine preparations, thimerosal is no longer present in routinely administered children’s vaccines and has been shown not to be associated with autism.^21,22 To address parents’ and patients’ concerns about vaccine safety, and especially those surrounding short- and long-term complications, physicians should have a general understanding of the pre- and post-licensure mechanisms in the United States.

Pre-licensure safety is under the purview of vaccine manufacturers and the Center for Biologics Evaluation and Research at the US Food and Drug Administration (http://www.fda.gov/biologicsbloodvaccines/vaccines/default.htm). For licensure, manufacturers must provide clinical data to demonstrate sufficient safety and efficacy. Accordingly, pre-licensure assessments are conducted in a “closed system” under a research protocol. The vaccine recipients are volitional research subjects selected according to inclusion and exclusion criteria. They are also compensated. However, sample sizes are rarely large enough to exclude rare serious adverse events.

Once licensure has been granted, the focus of safety then shifts to the “open system” of usual clinical practice. Vaccine recipients are unselected members of the general population and may have underlying medical conditions, and sometimes—such as with school entry mandates—are less volitional. In this sphere, the responsible parties for safety include the government, manufacturers, and health care systems.

Three ongoing systems function to assure vaccine safety: the Vaccine Adverse Event Reporting System (VAERS), the Vaccine Safety Datalink (VSD), and the Clinical Immunization Safety Assessment (CISA) Network.^23,24

VAERS serves as an early warning system for coincidental safety signals and can generate hypotheses for further investigation.^24,25 It is characterized by high sensitivity but low specificity as it relies on voluntary reporting from health care personnel, parents, and others. This system was instrumental in identifying the initial cases of intussusception attributable to the rotavirus vaccine, RotaShield.²⁶

The VSD is a network of 10 large, geographically diverse and linked health maintenance organizations that cover about 3% of the US population. Within this “real time” network, vaccination (exposure) can be compared with outpatient, emergency department, hospital, and laboratory data (health outcomes), while accounting for demographic variables (confounders).^27,28 VSD studies linked the measles, mumps, rubella, and varicella vaccine to febrile seizures²⁹ and showed no relationship between cumulative vaccine antigen exposure and autism.³⁰

The CISA was established in 2001 to investigate the pathophysiologic mechanisms and biologic risks of adverse effects following immunization and to provide evidence-based vaccine safety assessments.

Based on all available evidence, routinely recommended vaccines have attained a very high level of safety. As with other preventive services, immunizations are generally provided to healthy individuals to maintain good health; thus, a low tolerance for significant adverse events exists. Well over 100 million doses of vaccines are given each year, yet the VAERS receives, on average, only 28,000 adverse event reports per year.

These reports comprise mild, moderate, and severe reactions to vaccines, but also adverse events that may not be related in any way other than chronologically to the vaccine’s administration. Despite this relatively low number of real safety concerns, it is still more likely that patients will know someone who has had a vaccine-related adverse event than someone who has had some of the diseases the vaccines prevent.³¹

Final thoughts

Current anti-vaccine sentiments appear to arise from varying perspectives.To appreciate the benefit 
of vaccine acceptance,
 we need only look to Europe, where high levels of vaccine refusal has led to a resurgence of vaccine-preventable diseases such as measles. Some are held by parents of children who have allegedly suffered a severe vaccine related adverse event; others by those opposed to government-mandated school immunization requirements; and some from those who have a dislike of vaccine manufacturers. These sentiments persist in part because of a low level of vaccine preventable diseases: When such illnesses are no longer deemed a threat, those who have concerns about vaccine safety, no matter how invalid, believe their concerns should trump all other considerations.

To appreciate the true benefit of vaccine acceptance, we need only look to Europe, where the anti-vaccine movement has led to high levels of vaccine refusal and a resurgence of vaccine-preventable diseases, such as measles, with their associated morbidity and mortality.³² In advocating for continued acceptance and widespread use of vaccines, family physicians can convey to patients and parents the magnitude of associated health benefits while confidently attesting to the effectiveness and safety of vaccines.

CORRESPONDENCE
John Epling, MD, MSEd, Department of Family Medicine, SUNY Upstate Medical University, 475 Irving Ave, Suite 200, Syracuse, NY 13210; eplingj@upstate.edu

When a public health intervention succeeds and achieves long-term suppression of the target problem, an unfortunate irony is that, with time, the intervention can seem less vital. So it is with vaccines. Many patients and physicians today have never experienced the infectious diseases that once caused millions of deaths and much disability each year, and they therefore do not appreciate the impact these diseases had when they were prevalent.

It is estimated that just 9 of the routinely recommended vaccines prevent 42,000 deaths and 20 million cases of disease in every birth cohort.¹ With many of these diseases thus held at bay, attention shifted instead to the supposed risks of vaccines. Many people mistakenly believe a vaccine’s potential for harm is more likely than the chance of acquiring the disease it prevents, and they therefore refuse vaccines for themselves and their children, with little chance in the short term of suffering an adverse outcome for their decision.

In this review—which can inform primary care physicians’ discussions with vaccine-hesitant patients—we first highlight 2 preventable diseases, measles and Haemophilus influenzae type b (Hib) infection. Recent residency graduates may never see these diseases thanks to sustained vaccination programs. However, the risk of acquiring these infections has not disappeared entirely. After considering these examples, we examine the totality of the morbidity and mortality prevented by vaccination and describe the safety of current vaccines and the systems in place to assure their continued safety.

Measles: No longer endemic to the United States, but still a risk from importation


In the pre-vaccine era, measles (rubeola) infected more than 500,000 Americans annually and killed roughly 500.² This highly communicable systemic acute viral infection was once considered universal in childhood. After vaccine licensure in 1963, widespread immunization reduced the incidence by more than 98%, and by 2000 it had eliminated endemic measles from the United States. However, the disease has now reappeared—largely due to international travel and neglect in becoming vaccinated. As of October 31, 2014, the United States had 20 outbreaks and 603 cases of measles reported in 2014—a dramatic increase over recent years.³

Clinical appearance. Acute measles infection is characterized by high fever, cough, coryza, conjunctivitis, and rash. Koplik spots are a 24^- to 72-hour pathognomonic exanthem of blue-white spots 1 to 3 mm in diameter on an erythematous base along the buccal mucosa. The resolving exanthem coincides with the eruption of a blanching, maculopapular exanthem originating at the hairline, progressing down the trunk and out to the limbs (sparing the palms and soles), coalescing, and then fading with a fine desquamation in the same order of appearance over 7 days. Additional associated symptoms include anorexia, diarrhea, and generalized lymphadenopathy.^2,4

Complications are common with measles. Acute measles infection is rarely fatal. However, serious complications occur in nearly one-third of reported cases.² During the 1989-1991 measles resurgence in the United States, more than 100 deaths occurred among the 55,000 cases reported.^5-7 In early 2011, the United States saw the highest reported number of measles cases since 1996 due to importation. Of the 118 reported cases, 105 (89%) occurred in unvaccinated people, 47 (40%) required hospitalization, and 9 individuals developed pneumonia.⁸

While acute measles is rarely fatal, serious complications occur in nearly one-third of cases. Complications of measles infection are shown in TABLE 1.^2,4 Pneumonia (viral or superimposed bacterial) accounts for 60% of measles-related deaths.² Neurologic complications, while less frequent, can be severe.

Acute encephalitis occurs in 1 in 1000 to 2000 cases and presents within a week following the exanthem with fever, headache, vomiting, meningismus, change in mental status, convulsions, and coma.² Encephalitis has a fatality rate of 15%, leaving another 25% with residual neurologic damage.² Subacute sclerosing panencephalitis (SSPE) occurs in 5 to 10 cases per million (in the United States), on average 7 years after the initial measles infection.^9,10 After an insidious onset, behavior and intellect deteriorate, followed by ataxia, myoclonic seizures, and ultimately death. In the United States, the number of reported cases of SSPE has declined with the reduction in measles cases. However, in countries with less robust measles immunization eradication programs, the risk of developing SSPE remains.^9,10

Hib: Contained but not eradicated

Hib was once the leading cause of meningitis and a major cause of other invasive bacterial diseases, but it has been greatly controlled since the advent of routine Hib vaccination in 1990.¹¹ Hib is an encapsulated, gram-negative coccobacillus. There are 6 major capsular serotypes of Haemophilus influenzae, but serotype b was linked to major invasive disease in humans 95% of the time.¹² The spectrum of diseases caused by Hib is seen in TABLE 2.^13-15 Hib is transmitted by respiratory droplets from noninfected as well as infected carriers. Asymptomatic nasal carriage in the pre-vaccine era varied from 0.5% to 5%.¹²

Hib is primarily a disease of young children, with almost all cases occurring in children younger than 5 years of age (66% in those younger than 18 months). Other risk factors for invasive disease are those that increase the spread of respiratory droplets: crowding, lower socioeconomic status, day care attendance, large household size, and school-aged siblings. American Indian and Alaskan Native populations remain at higher risk due to incomplete vaccination rates and the sociodemographic risk factors noted above. Breastfeeding is protective.¹²

Three percent to 6% of cases of invasive Hib disease are fatal; another 20% can have long-term sequelae such as hearing loss. In the early 1990s, the peak incidence of Hib disease reached 41 cases per 100,000 population.¹² The reduction in incidence of Hib disease brought about by universal vaccination has been attributed to individual immunity, decreased asymptomatic nasal carriage, and herd immunity.¹²

Despite this progress, Hib continues to evade eradication. In Minnesota in 2008, 5 children, ages 5 months to 3 years, contracted invasive Hib disease (3 with meningitis, 1 with pneumonia, 1 with epiglottitis).¹⁶ Of the 5, only one was up to date with Hib vaccination; the others had not received vaccine because of shortages or parent refusal. These children were unrelated and had not been in contact with each other.

In a daycare outbreak in the United Kingdom, 2 cases of Hib disease (meningitis and septic arthritis) were identified in fully immunized children younger than 18 months, presumably due to a lack of complete vaccine efficacy.¹⁷ A study of nasal carriage (performed just prior to rifampin prophylaxis) among other attendees and caregivers revealed 3 asymptomatic carriers.¹⁷ Although Hib is largely well-contained in developed countries due to vaccination policies, the burden of disease in developing countries is estimated to be approximately 8.1 million serious illnesses with 371,000 deaths annually.¹³

The totality of morbidity and mortality prevented by vaccines

It is estimated that using just 9 routinely recommended vaccines prevents 
42,000 deaths and 20 million cases of disease in every birth cohort. Measles and Hib are 2 examples of vaccine-preventable diseases and the reduction in morbidity and mortality achievable with vaccines. TABLE 3¹⁸ summarizes the number of pre-vaccine era cases for selected diseases. Routine vaccination against 7 common childhood diseases not only prevents many thousands of deaths, as mentioned earlier,¹ but it saves $13.5 billion in direct costs in each birth cohort and saves society $68.8 billion in costs that include disability and lost productivity of both patients and caregivers.¹

Put simply, every dollar spent on the vaccination program saves $10 in direct and indirect costs to society.¹ Sustaining these successes and averting the resurgence of contained diseases requires a commitment to high immunization rates without delays and lapses—an effort made more challenging in light of misinformation about vaccine safety and resultant parental vaccine hesitancy.

Vaccine safety is ensured
 by rigorous systems


Despite an impressive record of safety, vaccines still cause anxiety among patients and parents in family practices. A recent survey identified concerns of long-term complications, autism, and thimerosal effects to be foremost on the minds of parents, whereas short-term effects were of much less concern.¹⁹ Causation of autism related to vaccines has been dismissed; the initial linkages have been shown to be fraudulent.²⁰ With the exception of some influenza vaccine preparations, thimerosal is no longer present in routinely administered children’s vaccines and has been shown not to be associated with autism.^21,22 To address parents’ and patients’ concerns about vaccine safety, and especially those surrounding short- and long-term complications, physicians should have a general understanding of the pre- and post-licensure mechanisms in the United States.

Pre-licensure safety is under the purview of vaccine manufacturers and the Center for Biologics Evaluation and Research at the US Food and Drug Administration (http://www.fda.gov/biologicsbloodvaccines/vaccines/default.htm). For licensure, manufacturers must provide clinical data to demonstrate sufficient safety and efficacy. Accordingly, pre-licensure assessments are conducted in a “closed system” under a research protocol. The vaccine recipients are volitional research subjects selected according to inclusion and exclusion criteria. They are also compensated. However, sample sizes are rarely large enough to exclude rare serious adverse events.

Once licensure has been granted, the focus of safety then shifts to the “open system” of usual clinical practice. Vaccine recipients are unselected members of the general population and may have underlying medical conditions, and sometimes—such as with school entry mandates—are less volitional. In this sphere, the responsible parties for safety include the government, manufacturers, and health care systems.

Three ongoing systems function to assure vaccine safety: the Vaccine Adverse Event Reporting System (VAERS), the Vaccine Safety Datalink (VSD), and the Clinical Immunization Safety Assessment (CISA) Network.^23,24

VAERS serves as an early warning system for coincidental safety signals and can generate hypotheses for further investigation.^24,25 It is characterized by high sensitivity but low specificity as it relies on voluntary reporting from health care personnel, parents, and others. This system was instrumental in identifying the initial cases of intussusception attributable to the rotavirus vaccine, RotaShield.²⁶

The VSD is a network of 10 large, geographically diverse and linked health maintenance organizations that cover about 3% of the US population. Within this “real time” network, vaccination (exposure) can be compared with outpatient, emergency department, hospital, and laboratory data (health outcomes), while accounting for demographic variables (confounders).^27,28 VSD studies linked the measles, mumps, rubella, and varicella vaccine to febrile seizures²⁹ and showed no relationship between cumulative vaccine antigen exposure and autism.³⁰

The CISA was established in 2001 to investigate the pathophysiologic mechanisms and biologic risks of adverse effects following immunization and to provide evidence-based vaccine safety assessments.

Based on all available evidence, routinely recommended vaccines have attained a very high level of safety. As with other preventive services, immunizations are generally provided to healthy individuals to maintain good health; thus, a low tolerance for significant adverse events exists. Well over 100 million doses of vaccines are given each year, yet the VAERS receives, on average, only 28,000 adverse event reports per year.

These reports comprise mild, moderate, and severe reactions to vaccines, but also adverse events that may not be related in any way other than chronologically to the vaccine’s administration. Despite this relatively low number of real safety concerns, it is still more likely that patients will know someone who has had a vaccine-related adverse event than someone who has had some of the diseases the vaccines prevent.³¹

Final thoughts

Current anti-vaccine sentiments appear to arise from varying perspectives.To appreciate the benefit 
of vaccine acceptance,
 we need only look to Europe, where high levels of vaccine refusal has led to a resurgence of vaccine-preventable diseases such as measles. Some are held by parents of children who have allegedly suffered a severe vaccine related adverse event; others by those opposed to government-mandated school immunization requirements; and some from those who have a dislike of vaccine manufacturers. These sentiments persist in part because of a low level of vaccine preventable diseases: When such illnesses are no longer deemed a threat, those who have concerns about vaccine safety, no matter how invalid, believe their concerns should trump all other considerations.

To appreciate the true benefit of vaccine acceptance, we need only look to Europe, where the anti-vaccine movement has led to high levels of vaccine refusal and a resurgence of vaccine-preventable diseases, such as measles, with their associated morbidity and mortality.³² In advocating for continued acceptance and widespread use of vaccines, family physicians can convey to patients and parents the magnitude of associated health benefits while confidently attesting to the effectiveness and safety of vaccines.

CORRESPONDENCE
John Epling, MD, MSEd, Department of Family Medicine, SUNY Upstate Medical University, 475 Irving Ave, Suite 200, Syracuse, NY 13210; eplingj@upstate.edu

From the 1960s to the ’90s, the prevalence of gout more than doubled among US residents.¹ In the years since,^1-5 gout has become increasingly prevalent worldwide. The key causes—an aging population, poor diet, widespread use of diuretics to treat cardiovascular disease, and comorbidities that promote hyperuricemia—have made the presentation of gout more complex and harder to manage, as well.^4-6

In fact, gout is frequently poorly managed. Initiation and maintenance of urate-lowering therapy (ULT)—as well as monitoring of serum urate—is not done often enough, and there is significant variation in medications used to treat gout. As a result, recommended serum urate targets commonly remain unattained.^7-9

We can do better. Enhanced understanding of risk factors for gout, augmented by recent research and the approval of 2 new pharmacologic agents (febuxostat in 2009¹⁰ and pegloticase in 2010¹¹), led to the American College of Rheumatology (ACR)’s first edition of gout guidelines, published in 2012.^12,13 The key components of gout management—patient education, lifestyle modifications, and pharmacologic therapy—are detailed in the text and tables that follow.

Understanding gout

Gout is actually a heterogeneous spectrum of diseases. It is characterized by an elevated serum urate concentration, with recurrent attacks of acute arthritis associated with monosodium urate crystals in synovial fluid leukocytes, but may also include tophi— typically painless nodular deposits of monosodium urate crystals in tissues in and around the joints—interstitial renal disease, and uric acid nephrolithiasis.¹⁴ Symptoms occur when the excess uric acid, the result of inefficient excretion rather than overproduction,^2,12,14,15 is deposited in restricted joint spaces.

Who’s at risk?

Risk factors include numerous cardiovascular and metabolic conditions, such as increased adiposity, hypertension, dyslipidemia, heart failure, insulin resistance, hyperglycemia, and renal disease.^3,6,12 Older age, genetics, poor diet, alcohol consumption, and medications associated with hyperuricemia, such as loop and thiazide diuretics and low-dose acetylsalicylic acid, are risk factors, as well.

Defined as a serum urate level ≥6.8 mg/dL—the point at which urate becomes insoluble in extracellular fluids^12,16,17—hyperuricemia is the most important modifiable risk factor for the development of gout. It can precipitate painful episodic attacks and complications such as chronic arthritis, urolithiasis, and tophi.¹²

What you’ll see

Patients often present with acute onset of pain and inflammation of a single joint, usually the first metatarsophalangeal. Other joints and soft tissues that may be involved to a lesser extent include (in order of frequency) the insteps, ankles, heels, knees, fingers, and elbows.¹⁴ Polyarticular attacks are an atypical manifestation and are sometimes confused with rheumatoid arthritis or osteoarthritis, particularly in the elderly.

Asymptomatic hyperuricemia alone does not establish a diagnosis of gout and there is no evidence to support urate-lowering therapy for isolated hyperuricemia. Clinical evaluation should include a history of symptom severity, disease burden, and comorbidities, and a thorough physical examination focused on findings such as tophi and acute and chronic synovitis.¹² Imaging studies are not recommended for the evaluation of gout because therapy is guided by symptoms.¹⁴

Asymptomatic hyperuricemia alone does not establish a diagnosis of gout, and there is no evidence to support ULT for isolated hyperuricemia. However, advice regarding lifestyle modifications and treatment of associated comorbidities may be warranted for such patients.¹⁸

How best to manage gout

Optimal gout management encompasses nonpharmacologic therapy, symptom management of acute attacks, and combination anti-inflammatory and ULT prophylaxis for patients with chronic gout.^12,13 It is important to work with patients to track and document both the number and the severity of acute attacks occurring over a 12-month period so that those who qualify for ULT can begin it without delay.¹² It is important to discuss treatment objectives and management of comorbidities, as well.

Review the medications the patient is taking, and consider eliminating prescription drugs associated with hyperuricemia if the risks outweigh the benefits.^19-21 In many cases, however, lifestyle modification—ie, eating a heart-healthy diet, exercising regularly, and losing weight—may do more to prevent gout attacks and manage complications than stopping medications that provide cardioprotection.⁶ The ACR divides food and beverages into 3 simple categories—avoid, limit, or encourage (TABLE 1.)¹²

Responding to an acute attack

Whenever possible, initiate pharmacologic therapy within 24 hours of symptom onset, because this has been associated with decreased pain and shorter duration of an acute attack.^8,13 The choice of drug should be guided by the severity of the attack, as determined by both a pain score on a visual analog scale (VAS) and the number of affected joints; patient preference, prior response, and associated comorbidities are also important considerations (TABLE 2^8,13,14). When medications are prescribed for acute attacks or chronic gout, a discussion of adverse effects, drug interactions, contraindications, cost, and the importance of adherence is needed, as well.

For mild to moderate pain (≤6 out of 10 on a VAS) involving a few small joints or one or 2 large joints, monotherapy with a nonsteroidal anti-inflammatory drug (NSAID), a corticosteroid, or colchicine is recommended. For severe pain (>6 out of 10) and/or polyarticular involvement (≥4 joints in more than one region of the body), combination therapy is recommended (eg, colchicine and either an NSAID or a corticosteroid).¹³ Prednisone, methylprednisolone, and adrenocorticotropic hormone are options for patients who are NPO. Acute gout therapy should be continued until the attack resolves, which can range from 5 to 14 days.¹³

Colchicine considerations. The dose of colchicine recommended by the ACR for an acute gout attack (1.2 mg loading dose, followed by 0.6 mg one hour later, then followed after 12 hours, as needed, by up to 0.6 mg once or twice a day) is substantially lower than the dosing schedule used historically (1.0 mg loading dose, followed by 0.5 mg every 2-3 hours). Higher doses have not proven to be more effective, however, and typically led to gastrointestinal toxicity, causing patients to stop taking the drug before acute symptoms resolved.^8,13,22

Keep in mind, too, that colchicine therapy should not be initiated more than 36 hours after symptom onset, as therapy is less effective beyond this time frame.^8,13 In addition, concurrent use with P-glycoprotein and CYP3A4 inhibitors—eg, clarithromycin and erythromycin and some antifungals, antiretrovirals, calcium-channel blockers, immunosuppressants, and statins—may increase the risk of colchicine toxicity and should be avoided.

Treating chronic gout

Management of recurrent or progressive gout is aimed at reducing and maintaining serum urate levels <6.0 mg/dL, using ULT (TABLE 3^12,23-25) combined with anti-inflammatory prophylaxis to reduce the frequency of gout flares and the size and number of tophi.^12,23 Patients who meet one or more of the following criteria qualify for ULT:

• the presence of tophi

• ≥2 acute attacks per year
• chronic kidney disease (CKD) stages 2 through 5

• a history of urolithiasis.¹²

Both ULT and anti-inflammatory therapy should be started after an acute gout attack resolves, but patients already on prophylactic therapy should continue the regimen both during and after acute attacks to avoid more frequent exacerbations.^9,12 If gout symptoms persist despite a serum urate level of <6.0 mg/dL, increase the dose of ULT to achieve a target of <5 mg/dL to reduce the frequency of flares and the size and number of tophi.^12,26

Allopurinol, a xanthine oxidase inhibitor, is typically used as first-line ULT due to efficacy and low cost.¹³ Febuxostat, also a xanthine oxidase inhibitor, is an additional first-line option, although the US Food and Drug Administration issued a warning based on postmarketing reports of hepatic failure.²⁵ In the case of a xanthine oxidase allergy or intolerance, probenecid may be used as an alternative first-line therapy. First-line agents for anti-inflammatory prophylaxis include low-dose colchicine (0.6 mg once or twice daily) and low-dose NSAIDs. Oral corticosteroids (<10 mg/d) are considered second-line therapy.¹³

Allopurinol hypersensitivity. Although allopurinol is generally well tolerated, about 2% of patients develop a mild rash and up to 5% of patients stop taking it because of an adverse effect.²⁵ More importantly, allopurinol hypersensitivity syndrome (AHS) is rare but potentially fatal; in the United States, it is estimated that one in every 1000 patients treated with allopurinol will develop AHS.^12,27

Allopurinol hypersensitivity syndrome is rare, but potentially fatal. AHS is characterized by a rash (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis), eosinophilia, leukocytosis, fever, hepatitis, and renal failure.^12,25 There is no cure; the mainstay of treatment is early diagnosis, withdrawal of allopurinol, and supportive care.²⁵ Because of the high mortality rate (20%-25%),^12,27 genetic screening for allele HLA-B*5801 prior to starting allopurinol therapy is recommended for patients in high-risk groups: Koreans with CKD (stage 3 or worse) and all Han Chinese and Thai patients, regardless of kidney function.¹² Alternative therapies should be used for patients who test positive for the allele.

Duration of therapy

Pharmacologic treatment of an acute gout attack should continue until the attack resolves, which can range from 5 to 14 days. The duration of treatment for chronic gout is far longer.

Anti-inflammatory prophylaxis should continue for whichever is greater: 3 months after the target serum urate level is achieved for patients with no evidence of tophi; or 6 months after the target serum urate level is achieved and previously detected tophi have resolved.¹³

ULT should continue indefinitely,¹² with monitoring of serum urate levels every 2 to 5 weeks until the target is achieved and every 6 months thereafter.

Not responding to therapy? Consider nonadherence, refractory gout

Studies have found that less than half of patients started on urate-lowering therapy take their medication as prescribed for the entire first year of therapy. If a patient is not responding as expected, consider whether he or she is taking the medication as prescribed. Gout therapy has one of the lowest adherence rates of any chronic disorder.^7,8,12,28-30 Studies have found that less than half of patients started on ULT take their medication as prescribed for the entire first year of therapy.^9,28

To promote adherence, schedule more frequent follow-up appointments after initiating urate-lowering therapy. Evidence suggests that nonadherence is especially likely among younger and healthier individuals, possibly because they have little experience managing chronic conditions or needing ongoing care.^28-30 Such patients may also be unsure of when and how to take their medication. To promote adherence, physicians should schedule more frequent follow-up appointments after initiating ULT to assess management of the disease and stress the importance of following the medication regimen as prescribed.^9,28

Not all patients who don’t respond to ULT are nonadherent, of course. Some have refractory gout. If uric acid levels do not reach the goal of <6 mg/dL (or <5 mg/dL) at the maximum dose of a first-line xanthine oxidase inhibitor, add a uricosuric agent such as probenecid, fenofibrate, or losartan.¹²

Pegloticase, a pegylated recombinant form of urate oxidase enzyme that converts uric acid to allantoin³¹ (a water-soluble metabolite of uric acid), is a possible therapeutic option for patients who do not achieve adequate serum urate levels and continue to have symptoms of gout.¹² Candidates for pegloticase therapy, which is administered intravenously, include adult patients with gout refractory to conventional ULT or excessive uric acid accumulation due to chemotherapy and those with contraindications to conventional ULT.

Pegloticase is associated with anaphylactic and infusion reactions, requires extensive monitoring, and costs thousands of dollars per month, however. Thus, it is important to carefully evaluate the extent of disease burden (ie, gout symptoms and effect on quality of life) and determine whether the patient has taken ULT and uricosuric drugs as prescribed before considering this option. Pegloticase requires the same anti-inflammatory prophylaxis as other forms of ULT, but there is no consensus on the duration of use.¹²

CORRESPONDENCE
Tatum Mead, PharmD, University of Missouri-Kansas City School of Pharmacy, Health Sciences Building, Room 2243, 2464 Charlotte Street, Kansas City, MO 64108-2792; meadt@umkc.edu

From the 1960s to the ’90s, the prevalence of gout more than doubled among US residents.¹ In the years since,^1-5 gout has become increasingly prevalent worldwide. The key causes—an aging population, poor diet, widespread use of diuretics to treat cardiovascular disease, and comorbidities that promote hyperuricemia—have made the presentation of gout more complex and harder to manage, as well.^4-6

In fact, gout is frequently poorly managed. Initiation and maintenance of urate-lowering therapy (ULT)—as well as monitoring of serum urate—is not done often enough, and there is significant variation in medications used to treat gout. As a result, recommended serum urate targets commonly remain unattained.^7-9

We can do better. Enhanced understanding of risk factors for gout, augmented by recent research and the approval of 2 new pharmacologic agents (febuxostat in 2009¹⁰ and pegloticase in 2010¹¹), led to the American College of Rheumatology (ACR)’s first edition of gout guidelines, published in 2012.^12,13 The key components of gout management—patient education, lifestyle modifications, and pharmacologic therapy—are detailed in the text and tables that follow.

Understanding gout

Gout is actually a heterogeneous spectrum of diseases. It is characterized by an elevated serum urate concentration, with recurrent attacks of acute arthritis associated with monosodium urate crystals in synovial fluid leukocytes, but may also include tophi— typically painless nodular deposits of monosodium urate crystals in tissues in and around the joints—interstitial renal disease, and uric acid nephrolithiasis.¹⁴ Symptoms occur when the excess uric acid, the result of inefficient excretion rather than overproduction,^2,12,14,15 is deposited in restricted joint spaces.

Who’s at risk?

Risk factors include numerous cardiovascular and metabolic conditions, such as increased adiposity, hypertension, dyslipidemia, heart failure, insulin resistance, hyperglycemia, and renal disease.^3,6,12 Older age, genetics, poor diet, alcohol consumption, and medications associated with hyperuricemia, such as loop and thiazide diuretics and low-dose acetylsalicylic acid, are risk factors, as well.

Defined as a serum urate level ≥6.8 mg/dL—the point at which urate becomes insoluble in extracellular fluids^12,16,17—hyperuricemia is the most important modifiable risk factor for the development of gout. It can precipitate painful episodic attacks and complications such as chronic arthritis, urolithiasis, and tophi.¹²

What you’ll see

Patients often present with acute onset of pain and inflammation of a single joint, usually the first metatarsophalangeal. Other joints and soft tissues that may be involved to a lesser extent include (in order of frequency) the insteps, ankles, heels, knees, fingers, and elbows.¹⁴ Polyarticular attacks are an atypical manifestation and are sometimes confused with rheumatoid arthritis or osteoarthritis, particularly in the elderly.

Asymptomatic hyperuricemia alone does not establish a diagnosis of gout and there is no evidence to support urate-lowering therapy for isolated hyperuricemia. Clinical evaluation should include a history of symptom severity, disease burden, and comorbidities, and a thorough physical examination focused on findings such as tophi and acute and chronic synovitis.¹² Imaging studies are not recommended for the evaluation of gout because therapy is guided by symptoms.¹⁴

Asymptomatic hyperuricemia alone does not establish a diagnosis of gout, and there is no evidence to support ULT for isolated hyperuricemia. However, advice regarding lifestyle modifications and treatment of associated comorbidities may be warranted for such patients.¹⁸

How best to manage gout

Optimal gout management encompasses nonpharmacologic therapy, symptom management of acute attacks, and combination anti-inflammatory and ULT prophylaxis for patients with chronic gout.^12,13 It is important to work with patients to track and document both the number and the severity of acute attacks occurring over a 12-month period so that those who qualify for ULT can begin it without delay.¹² It is important to discuss treatment objectives and management of comorbidities, as well.

Review the medications the patient is taking, and consider eliminating prescription drugs associated with hyperuricemia if the risks outweigh the benefits.^19-21 In many cases, however, lifestyle modification—ie, eating a heart-healthy diet, exercising regularly, and losing weight—may do more to prevent gout attacks and manage complications than stopping medications that provide cardioprotection.⁶ The ACR divides food and beverages into 3 simple categories—avoid, limit, or encourage (TABLE 1.)¹²

Responding to an acute attack

Whenever possible, initiate pharmacologic therapy within 24 hours of symptom onset, because this has been associated with decreased pain and shorter duration of an acute attack.^8,13 The choice of drug should be guided by the severity of the attack, as determined by both a pain score on a visual analog scale (VAS) and the number of affected joints; patient preference, prior response, and associated comorbidities are also important considerations (TABLE 2^8,13,14). When medications are prescribed for acute attacks or chronic gout, a discussion of adverse effects, drug interactions, contraindications, cost, and the importance of adherence is needed, as well.

For mild to moderate pain (≤6 out of 10 on a VAS) involving a few small joints or one or 2 large joints, monotherapy with a nonsteroidal anti-inflammatory drug (NSAID), a corticosteroid, or colchicine is recommended. For severe pain (>6 out of 10) and/or polyarticular involvement (≥4 joints in more than one region of the body), combination therapy is recommended (eg, colchicine and either an NSAID or a corticosteroid).¹³ Prednisone, methylprednisolone, and adrenocorticotropic hormone are options for patients who are NPO. Acute gout therapy should be continued until the attack resolves, which can range from 5 to 14 days.¹³

Colchicine considerations. The dose of colchicine recommended by the ACR for an acute gout attack (1.2 mg loading dose, followed by 0.6 mg one hour later, then followed after 12 hours, as needed, by up to 0.6 mg once or twice a day) is substantially lower than the dosing schedule used historically (1.0 mg loading dose, followed by 0.5 mg every 2-3 hours). Higher doses have not proven to be more effective, however, and typically led to gastrointestinal toxicity, causing patients to stop taking the drug before acute symptoms resolved.^8,13,22

Keep in mind, too, that colchicine therapy should not be initiated more than 36 hours after symptom onset, as therapy is less effective beyond this time frame.^8,13 In addition, concurrent use with P-glycoprotein and CYP3A4 inhibitors—eg, clarithromycin and erythromycin and some antifungals, antiretrovirals, calcium-channel blockers, immunosuppressants, and statins—may increase the risk of colchicine toxicity and should be avoided.

Treating chronic gout

Management of recurrent or progressive gout is aimed at reducing and maintaining serum urate levels <6.0 mg/dL, using ULT (TABLE 3^12,23-25) combined with anti-inflammatory prophylaxis to reduce the frequency of gout flares and the size and number of tophi.^12,23 Patients who meet one or more of the following criteria qualify for ULT:

• the presence of tophi

• ≥2 acute attacks per year
• chronic kidney disease (CKD) stages 2 through 5

• a history of urolithiasis.¹²

Both ULT and anti-inflammatory therapy should be started after an acute gout attack resolves, but patients already on prophylactic therapy should continue the regimen both during and after acute attacks to avoid more frequent exacerbations.^9,12 If gout symptoms persist despite a serum urate level of <6.0 mg/dL, increase the dose of ULT to achieve a target of <5 mg/dL to reduce the frequency of flares and the size and number of tophi.^12,26

Allopurinol, a xanthine oxidase inhibitor, is typically used as first-line ULT due to efficacy and low cost.¹³ Febuxostat, also a xanthine oxidase inhibitor, is an additional first-line option, although the US Food and Drug Administration issued a warning based on postmarketing reports of hepatic failure.²⁵ In the case of a xanthine oxidase allergy or intolerance, probenecid may be used as an alternative first-line therapy. First-line agents for anti-inflammatory prophylaxis include low-dose colchicine (0.6 mg once or twice daily) and low-dose NSAIDs. Oral corticosteroids (<10 mg/d) are considered second-line therapy.¹³

Allopurinol hypersensitivity. Although allopurinol is generally well tolerated, about 2% of patients develop a mild rash and up to 5% of patients stop taking it because of an adverse effect.²⁵ More importantly, allopurinol hypersensitivity syndrome (AHS) is rare but potentially fatal; in the United States, it is estimated that one in every 1000 patients treated with allopurinol will develop AHS.^12,27

Allopurinol hypersensitivity syndrome is rare, but potentially fatal. AHS is characterized by a rash (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis), eosinophilia, leukocytosis, fever, hepatitis, and renal failure.^12,25 There is no cure; the mainstay of treatment is early diagnosis, withdrawal of allopurinol, and supportive care.²⁵ Because of the high mortality rate (20%-25%),^12,27 genetic screening for allele HLA-B*5801 prior to starting allopurinol therapy is recommended for patients in high-risk groups: Koreans with CKD (stage 3 or worse) and all Han Chinese and Thai patients, regardless of kidney function.¹² Alternative therapies should be used for patients who test positive for the allele.

Duration of therapy

Pharmacologic treatment of an acute gout attack should continue until the attack resolves, which can range from 5 to 14 days. The duration of treatment for chronic gout is far longer.

Anti-inflammatory prophylaxis should continue for whichever is greater: 3 months after the target serum urate level is achieved for patients with no evidence of tophi; or 6 months after the target serum urate level is achieved and previously detected tophi have resolved.¹³

ULT should continue indefinitely,¹² with monitoring of serum urate levels every 2 to 5 weeks until the target is achieved and every 6 months thereafter.

Not responding to therapy? Consider nonadherence, refractory gout

Studies have found that less than half of patients started on urate-lowering therapy take their medication as prescribed for the entire first year of therapy. If a patient is not responding as expected, consider whether he or she is taking the medication as prescribed. Gout therapy has one of the lowest adherence rates of any chronic disorder.^7,8,12,28-30 Studies have found that less than half of patients started on ULT take their medication as prescribed for the entire first year of therapy.^9,28

To promote adherence, schedule more frequent follow-up appointments after initiating urate-lowering therapy. Evidence suggests that nonadherence is especially likely among younger and healthier individuals, possibly because they have little experience managing chronic conditions or needing ongoing care.^28-30 Such patients may also be unsure of when and how to take their medication. To promote adherence, physicians should schedule more frequent follow-up appointments after initiating ULT to assess management of the disease and stress the importance of following the medication regimen as prescribed.^9,28

Not all patients who don’t respond to ULT are nonadherent, of course. Some have refractory gout. If uric acid levels do not reach the goal of <6 mg/dL (or <5 mg/dL) at the maximum dose of a first-line xanthine oxidase inhibitor, add a uricosuric agent such as probenecid, fenofibrate, or losartan.¹²

Pegloticase, a pegylated recombinant form of urate oxidase enzyme that converts uric acid to allantoin³¹ (a water-soluble metabolite of uric acid), is a possible therapeutic option for patients who do not achieve adequate serum urate levels and continue to have symptoms of gout.¹² Candidates for pegloticase therapy, which is administered intravenously, include adult patients with gout refractory to conventional ULT or excessive uric acid accumulation due to chemotherapy and those with contraindications to conventional ULT.

Pegloticase is associated with anaphylactic and infusion reactions, requires extensive monitoring, and costs thousands of dollars per month, however. Thus, it is important to carefully evaluate the extent of disease burden (ie, gout symptoms and effect on quality of life) and determine whether the patient has taken ULT and uricosuric drugs as prescribed before considering this option. Pegloticase requires the same anti-inflammatory prophylaxis as other forms of ULT, but there is no consensus on the duration of use.¹²

CORRESPONDENCE
Tatum Mead, PharmD, University of Missouri-Kansas City School of Pharmacy, Health Sciences Building, Room 2243, 2464 Charlotte Street, Kansas City, MO 64108-2792; meadt@umkc.edu

From the 1960s to the ’90s, the prevalence of gout more than doubled among US residents.¹ In the years since,^1-5 gout has become increasingly prevalent worldwide. The key causes—an aging population, poor diet, widespread use of diuretics to treat cardiovascular disease, and comorbidities that promote hyperuricemia—have made the presentation of gout more complex and harder to manage, as well.^4-6

In fact, gout is frequently poorly managed. Initiation and maintenance of urate-lowering therapy (ULT)—as well as monitoring of serum urate—is not done often enough, and there is significant variation in medications used to treat gout. As a result, recommended serum urate targets commonly remain unattained.^7-9

We can do better. Enhanced understanding of risk factors for gout, augmented by recent research and the approval of 2 new pharmacologic agents (febuxostat in 2009¹⁰ and pegloticase in 2010¹¹), led to the American College of Rheumatology (ACR)’s first edition of gout guidelines, published in 2012.^12,13 The key components of gout management—patient education, lifestyle modifications, and pharmacologic therapy—are detailed in the text and tables that follow.

Understanding gout

Gout is actually a heterogeneous spectrum of diseases. It is characterized by an elevated serum urate concentration, with recurrent attacks of acute arthritis associated with monosodium urate crystals in synovial fluid leukocytes, but may also include tophi— typically painless nodular deposits of monosodium urate crystals in tissues in and around the joints—interstitial renal disease, and uric acid nephrolithiasis.¹⁴ Symptoms occur when the excess uric acid, the result of inefficient excretion rather than overproduction,^2,12,14,15 is deposited in restricted joint spaces.

Who’s at risk?

Risk factors include numerous cardiovascular and metabolic conditions, such as increased adiposity, hypertension, dyslipidemia, heart failure, insulin resistance, hyperglycemia, and renal disease.^3,6,12 Older age, genetics, poor diet, alcohol consumption, and medications associated with hyperuricemia, such as loop and thiazide diuretics and low-dose acetylsalicylic acid, are risk factors, as well.

Defined as a serum urate level ≥6.8 mg/dL—the point at which urate becomes insoluble in extracellular fluids^12,16,17—hyperuricemia is the most important modifiable risk factor for the development of gout. It can precipitate painful episodic attacks and complications such as chronic arthritis, urolithiasis, and tophi.¹²

What you’ll see

Patients often present with acute onset of pain and inflammation of a single joint, usually the first metatarsophalangeal. Other joints and soft tissues that may be involved to a lesser extent include (in order of frequency) the insteps, ankles, heels, knees, fingers, and elbows.¹⁴ Polyarticular attacks are an atypical manifestation and are sometimes confused with rheumatoid arthritis or osteoarthritis, particularly in the elderly.

Asymptomatic hyperuricemia alone does not establish a diagnosis of gout and there is no evidence to support urate-lowering therapy for isolated hyperuricemia. Clinical evaluation should include a history of symptom severity, disease burden, and comorbidities, and a thorough physical examination focused on findings such as tophi and acute and chronic synovitis.¹² Imaging studies are not recommended for the evaluation of gout because therapy is guided by symptoms.¹⁴

Asymptomatic hyperuricemia alone does not establish a diagnosis of gout, and there is no evidence to support ULT for isolated hyperuricemia. However, advice regarding lifestyle modifications and treatment of associated comorbidities may be warranted for such patients.¹⁸

How best to manage gout

Optimal gout management encompasses nonpharmacologic therapy, symptom management of acute attacks, and combination anti-inflammatory and ULT prophylaxis for patients with chronic gout.^12,13 It is important to work with patients to track and document both the number and the severity of acute attacks occurring over a 12-month period so that those who qualify for ULT can begin it without delay.¹² It is important to discuss treatment objectives and management of comorbidities, as well.

Review the medications the patient is taking, and consider eliminating prescription drugs associated with hyperuricemia if the risks outweigh the benefits.^19-21 In many cases, however, lifestyle modification—ie, eating a heart-healthy diet, exercising regularly, and losing weight—may do more to prevent gout attacks and manage complications than stopping medications that provide cardioprotection.⁶ The ACR divides food and beverages into 3 simple categories—avoid, limit, or encourage (TABLE 1.)¹²

Responding to an acute attack

Whenever possible, initiate pharmacologic therapy within 24 hours of symptom onset, because this has been associated with decreased pain and shorter duration of an acute attack.^8,13 The choice of drug should be guided by the severity of the attack, as determined by both a pain score on a visual analog scale (VAS) and the number of affected joints; patient preference, prior response, and associated comorbidities are also important considerations (TABLE 2^8,13,14). When medications are prescribed for acute attacks or chronic gout, a discussion of adverse effects, drug interactions, contraindications, cost, and the importance of adherence is needed, as well.

For mild to moderate pain (≤6 out of 10 on a VAS) involving a few small joints or one or 2 large joints, monotherapy with a nonsteroidal anti-inflammatory drug (NSAID), a corticosteroid, or colchicine is recommended. For severe pain (>6 out of 10) and/or polyarticular involvement (≥4 joints in more than one region of the body), combination therapy is recommended (eg, colchicine and either an NSAID or a corticosteroid).¹³ Prednisone, methylprednisolone, and adrenocorticotropic hormone are options for patients who are NPO. Acute gout therapy should be continued until the attack resolves, which can range from 5 to 14 days.¹³

Colchicine considerations. The dose of colchicine recommended by the ACR for an acute gout attack (1.2 mg loading dose, followed by 0.6 mg one hour later, then followed after 12 hours, as needed, by up to 0.6 mg once or twice a day) is substantially lower than the dosing schedule used historically (1.0 mg loading dose, followed by 0.5 mg every 2-3 hours). Higher doses have not proven to be more effective, however, and typically led to gastrointestinal toxicity, causing patients to stop taking the drug before acute symptoms resolved.^8,13,22

Keep in mind, too, that colchicine therapy should not be initiated more than 36 hours after symptom onset, as therapy is less effective beyond this time frame.^8,13 In addition, concurrent use with P-glycoprotein and CYP3A4 inhibitors—eg, clarithromycin and erythromycin and some antifungals, antiretrovirals, calcium-channel blockers, immunosuppressants, and statins—may increase the risk of colchicine toxicity and should be avoided.

Treating chronic gout

Management of recurrent or progressive gout is aimed at reducing and maintaining serum urate levels <6.0 mg/dL, using ULT (TABLE 3^12,23-25) combined with anti-inflammatory prophylaxis to reduce the frequency of gout flares and the size and number of tophi.^12,23 Patients who meet one or more of the following criteria qualify for ULT:

• the presence of tophi

• ≥2 acute attacks per year
• chronic kidney disease (CKD) stages 2 through 5

• a history of urolithiasis.¹²

Both ULT and anti-inflammatory therapy should be started after an acute gout attack resolves, but patients already on prophylactic therapy should continue the regimen both during and after acute attacks to avoid more frequent exacerbations.^9,12 If gout symptoms persist despite a serum urate level of <6.0 mg/dL, increase the dose of ULT to achieve a target of <5 mg/dL to reduce the frequency of flares and the size and number of tophi.^12,26

Allopurinol, a xanthine oxidase inhibitor, is typically used as first-line ULT due to efficacy and low cost.¹³ Febuxostat, also a xanthine oxidase inhibitor, is an additional first-line option, although the US Food and Drug Administration issued a warning based on postmarketing reports of hepatic failure.²⁵ In the case of a xanthine oxidase allergy or intolerance, probenecid may be used as an alternative first-line therapy. First-line agents for anti-inflammatory prophylaxis include low-dose colchicine (0.6 mg once or twice daily) and low-dose NSAIDs. Oral corticosteroids (<10 mg/d) are considered second-line therapy.¹³

Allopurinol hypersensitivity. Although allopurinol is generally well tolerated, about 2% of patients develop a mild rash and up to 5% of patients stop taking it because of an adverse effect.²⁵ More importantly, allopurinol hypersensitivity syndrome (AHS) is rare but potentially fatal; in the United States, it is estimated that one in every 1000 patients treated with allopurinol will develop AHS.^12,27

Allopurinol hypersensitivity syndrome is rare, but potentially fatal. AHS is characterized by a rash (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis), eosinophilia, leukocytosis, fever, hepatitis, and renal failure.^12,25 There is no cure; the mainstay of treatment is early diagnosis, withdrawal of allopurinol, and supportive care.²⁵ Because of the high mortality rate (20%-25%),^12,27 genetic screening for allele HLA-B*5801 prior to starting allopurinol therapy is recommended for patients in high-risk groups: Koreans with CKD (stage 3 or worse) and all Han Chinese and Thai patients, regardless of kidney function.¹² Alternative therapies should be used for patients who test positive for the allele.

Duration of therapy

Pharmacologic treatment of an acute gout attack should continue until the attack resolves, which can range from 5 to 14 days. The duration of treatment for chronic gout is far longer.

Anti-inflammatory prophylaxis should continue for whichever is greater: 3 months after the target serum urate level is achieved for patients with no evidence of tophi; or 6 months after the target serum urate level is achieved and previously detected tophi have resolved.¹³

ULT should continue indefinitely,¹² with monitoring of serum urate levels every 2 to 5 weeks until the target is achieved and every 6 months thereafter.

Not responding to therapy? Consider nonadherence, refractory gout

Studies have found that less than half of patients started on urate-lowering therapy take their medication as prescribed for the entire first year of therapy. If a patient is not responding as expected, consider whether he or she is taking the medication as prescribed. Gout therapy has one of the lowest adherence rates of any chronic disorder.^7,8,12,28-30 Studies have found that less than half of patients started on ULT take their medication as prescribed for the entire first year of therapy.^9,28

To promote adherence, schedule more frequent follow-up appointments after initiating urate-lowering therapy. Evidence suggests that nonadherence is especially likely among younger and healthier individuals, possibly because they have little experience managing chronic conditions or needing ongoing care.^28-30 Such patients may also be unsure of when and how to take their medication. To promote adherence, physicians should schedule more frequent follow-up appointments after initiating ULT to assess management of the disease and stress the importance of following the medication regimen as prescribed.^9,28

Not all patients who don’t respond to ULT are nonadherent, of course. Some have refractory gout. If uric acid levels do not reach the goal of <6 mg/dL (or <5 mg/dL) at the maximum dose of a first-line xanthine oxidase inhibitor, add a uricosuric agent such as probenecid, fenofibrate, or losartan.¹²

Pegloticase, a pegylated recombinant form of urate oxidase enzyme that converts uric acid to allantoin³¹ (a water-soluble metabolite of uric acid), is a possible therapeutic option for patients who do not achieve adequate serum urate levels and continue to have symptoms of gout.¹² Candidates for pegloticase therapy, which is administered intravenously, include adult patients with gout refractory to conventional ULT or excessive uric acid accumulation due to chemotherapy and those with contraindications to conventional ULT.

Pegloticase is associated with anaphylactic and infusion reactions, requires extensive monitoring, and costs thousands of dollars per month, however. Thus, it is important to carefully evaluate the extent of disease burden (ie, gout symptoms and effect on quality of life) and determine whether the patient has taken ULT and uricosuric drugs as prescribed before considering this option. Pegloticase requires the same anti-inflammatory prophylaxis as other forms of ULT, but there is no consensus on the duration of use.¹²

CORRESPONDENCE
Tatum Mead, PharmD, University of Missouri-Kansas City School of Pharmacy, Health Sciences Building, Room 2243, 2464 Charlotte Street, Kansas City, MO 64108-2792; meadt@umkc.edu

CASE › Bob A, age 48, comes to his family physician (FP) to ask for authorization for extended medical leave from his job as an electrician. He frequently misses days at work and complains of stress on the job, saying his coworkers look down on him and make cruel jokes at his expense. He reports having chronic interpersonal conflicts and no significant relationships with family members or friends. Mr. A refuses a referral to a psychiatrist because he fears he will be “locked up and forced to take medications.”

If Mr. A were your patient, how would you proceed?

Personality disorders (PDs) are patterns of inflexible and maladaptive personality traits and behaviors that cause subjective distress and significant social or occupational impairment.¹ An individual with a PD tends to have a limited repertoire of responses to the rough-and-tumble of life, with coping mechanisms that often perpetuate difficulty and distress. Examples include distrust and suspiciousness of others’ motives (paranoid PD); disregard and violation of the rights of others (antisocial PD); instability in interpersonal relationships, self-image, and affect (borderline PD); and social inhibition, feelings of inadequacy, and hypersensitivity to negative evaluation (avoidant PD).¹

FPs may view patients with PDs as “difficult patients” because of their frequent crises and the interpersonal problems they bring into the physician-patient relationship.^2,3 Help, of course, can come in the way of a referral to a psychotherapist who specializes in treating PDs. But you can also make use of some evidence-based psychotherapy techniques to improve your patients’ lives and the quality of the physician-patient relationship. This article focuses on identifying and managing PDs in family practice, using practical strategies drawn from empirically supported therapies.

PDs are more common 
than you might suspect


Personality disorders are associated with a greater incidence of serious medical illness and reduced social functioning. The overall prevalence of PD in the community ranges from 4.4% to 14.8%, with no consistent pattern of sex differences.⁴ Between 31.4% and 45.5% of psychiatric outpatients and up to 24% of primary care patients likely meet criteria for at least one PD.^5-7 PDs impede recovery from other mental disorders,⁸ increase the risk for suicide,⁹ and are associated with substance abuse, impulsivity, and violence.^10,11 Personality pathology also is associated with greater incidence of serious medical illness^12,13 and reduced social functioning.¹⁴ Not surprisingly, patients with PDs frequently use medical and social services.¹⁵

PDs tend to be underdiagnosed, perhaps partly because of concern about stigmatization, but also due to difficulties in identifying and classifying these disorders. Published in 2013, the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) originally was to include a major revision of PDs—reflecting concern about the limitations of PD categories—but ultimately the existing categories were retained (TABLE 1).¹ There is considerable overlap among PD categories; many patients meet the criteria for more than one PD, but it is unlikely that they actually suffer from several distinct PDs. Other patients—perhaps even the majority—are best diagnosed with “unspecified personality disorder” because they do not neatly fit into one of these categories.

Suspect your patient has a PD? Evaluate these 2 areas


Identifying patients who have PDs in primary care is useful for 2 reasons: to explore the option of specialty treatment for patients who may be amenable to it, and to improve management of the patient’s complaints in the primary care setting, including a smoother doctor-patient interaction. In either case, determining the specific DSM-5 diagnosis is less important than recognizing core personality impairment: an ingrained disturbance in one’s perceptions of self and others. This can be done by paying attention to how the patient adapts to life’s challenges and if he or she has problematic interpersonal tendencies, including difficulties in the doctor-patient relationship.

Unfortunately, assessing and diagnosing PDs in the primary care setting can be challenging. Limited time doesn’t allow for extensive, personality-focused interviews. Self-report screening tools are limited, because patients may underreport key interpersonal problems such as lack of empathy. Furthermore, very few patients seek help from their FP in addressing personality dysfunction; PDs typically are identified while investigating other complaints.

The most reliable and useful areas to evaluate in a patient you suspect may have a PD are identity (one’s sense of who one is and can be) and interpersonal relationships, including the capacity for empathy and intimacy.^16,17 These should be considered longitudinally and in the context of the individual’s stage of development. For example, identity is generally less stable among adolescents compared to middle-aged adults.

A cohesive sense of identity allows one to embrace life’s tasks and challenges, to develop and strive toward personal goals, and to handle setbacks and disappointments. A person with a stable identity may develop a depressive reaction to difficult life circumstances, but with some assistance can generally bounce back and re-engage in his or her personal goals. By contrast, an individual with an unstable sense of self may feel chronically insecure and empty, with limited capacity to constructively deal with life’s ups and downs. Patients with borderline PD, for example, try to manage a fragmented identity by frantically clinging to others, while narcissistic patients tend to suppress a fragile sense of self by putting forth an arrogant and entitled attitude.

Determining the specific diagnosis of a patient you suspect has a personality disorder is less important than recognizing core personality impairment. How does the patient interact with others? As is the case with identity, an individual’s capacity for interpersonal functioning is developed early in life, through interactions with primary caregivers. Mental maps of who we are and what we can expect from others are formed and reinforced in attachment relationships, such as those with our parents; traumatic attachments, including abuse or neglect by a caregiver or loved one, are strongly associated with PD.^18,19 The resulting belief structures guide subsequent interpersonal functioning, and become interactively reinforced. For example, a person whose internal map of relationships includes others abandoning him might behave in a clingy manner, which may ultimately induce others to reject him, thus creating a self-fulfilling prophecy.

Distorted interpersonal expectations can impair a person’s capacity for sustained intimate connections (a troubled relationship history is characteristic of PDs) and limit empathic functioning.²⁰ Other people’s actions may be interpreted according to the patient’s belief structures rather than with an open mind about the other person’s experience.

Focus on the physician-patient relationship


The interpersonal dysfunction of patients with PDs will often surface in the physician-patient relationship, serving as a clue to broader interpersonal dysfunction. An FP’s relatively innocuous oversight, for example, might be taken as proof of suspected incompetence in the eyes of a patient with paranoid or narcissistic tendencies. Or a patient with a recurrent complaint who repeatedly rejects the physician’s interventions probably oscillates between seeking and rejecting nurturance in other relationships, as well. A patient who tends to make sarcastic remarks regarding the doctor’s earnest efforts likely holds negative views of others and sabotages potentially positive interactions.

So what strategies are best for managing these types of scenarios?

Bringing up a potential diagnosis of PD may be a delicate matter for the FP; patients might experience this as a jarring diagnosis in the absence of a thorough psychiatric evaluation. If the FP decides to explore whether the patient is open to discussing the relationship between moods, behaviors, and personality features, he or she can begin this conversation by noting that, as with physical health, we all have our vulnerabilities, and that these vulnerabilities may be strengthened through specialist consultation and support. In this way, the patient can view a referral as an opportunity to explore herself with professional support. If a psychiatrist or psychotherapist colleague does become involved, it is important to clarify the roles of treatment providers and to communicate with one another, should difficulties arise.

Evidence supports 
2 forms of psychotherapy


Treatment for PDs has seen considerable growth over the past decade, largely due to research on therapies that target the troubling self-injurious and suicidal features of borderline PD. Considerable evidence shows that specialized psychotherapy can significantly reduce suffering and improve functioning among these patients. The 2 major evidence-based treatments for patients with borderline PD are dialectical behavior therapy (DBT) and psychodynamic therapy.

DBT is an intensive cognitive-behavioral approach that teaches patients how to regulate their emotions and develop an accepting, mindful attitude toward their mental experience.²¹ Several randomized controlled trials (RCTs) have demonstrated the effectiveness of DBT in reducing hospitalizations and self-injurious and suicidal behavior in patients with borderline PD.²²

Psychodynamic therapy, which focuses on helping patients discover how unconscious conflicts influence their present moods and behaviors, has also been validated by multiple RCTs for patients with borderline PD.^23-25 Like DBT, empirically supported psychodynamic therapy tends to be structured, long-term (>12 months), and often intensively delivered in multiple sessions per week. However, a recent study found that a less-intensive, general psychodynamic therapy, along with occasional medication management, was equivalent to intensive DBT.²⁶

Although the research has focused primarily on borderline PD, these approaches can be applied to other PDs. These therapies focus on understanding one’s emotional and behavioral patterns, developing a healthy self-concept, and improving interpersonal relationships—areas that are relevant treatment targets across all PD types.

Indeed, studies of day treatment programs that explicitly welcome patients with a range of PD types have had promising findings.²⁷ Day treatment involves an intensive array of therapies, mostly in a group format; patients work together to support and embolden one another to make positive changes. Unfortunately, FPs may be challenged to find appropriate services for patients who are amenable to psychotherapy; public mental health resources tend to lag far behind best practices in the case of PD.

Medication might improve symptoms, not personality deficits

Judicious, circumscribed use of medications to target specific symptoms may be helpful for some patients with personality disorders. Most research on pharmacotherapy for PDs has focused on borderline PD; findings have been mixed and fairly limited.²⁸ Medication cannot address underlying identity and relational deficits, and will not result in remission of PD. Nonetheless, judicious, circumscribed use of medications to target specific symptoms may be helpful for some patients. Selective serotonin reuptake inhibitors can reduce anger and impulsive aggression in patients with borderline PD.^28,29

Atypical antipsychotics may help reduce impulsive aggression or transient psychotic symptoms.^28-30 For example, olanzapine and aripiprazole can reduce anxiety, anger/aggression, paranoia, and interpersonal sensitivity in borderline PD.^31,32 Mood stabilizers such as valproate, lamotrigine, and topiramate may also help some borderline patients, although they do so by reducing impulsivity and aggression rather than improving core unstable identity and affect.^28,29

Carefully obtained informed consent is necessary because of the danger of adverse effects with many of these medications; for example, antipsychotics have been associated with metabolic syndrome and weight gain that can threaten a patient’s already fragile self-image.³³ Polypharmacy is also a potential problem: Well-intentioned physicians may be prompted to offer multiple medications in response to patients’ unremitting complaints of distress, when a psychotherapeutic approach may need to be the primary treatment. The bottom line is that medications do not resolve personality dysfunction, and are best used symptomatically as adjuncts to psychotherapy.^28,30

Steps you can take 
during the office visit


Although it is not feasible for most FPs to provide comprehensive treatment for PD, key elements from specialized therapies can be integrated into your management of these patients. Steps you can take include using validation, promoting mentalization, and managing countertransference.

Validation, which is a component of DBT, is providing the expressed acknowledgement that the patient is entitled to her feelings.A supportive acknowledgement from you
 may counter
 a patient’s expectation
 of being invalidated,
 and over time, reduce the patient’s defensive 
rigidity. This is not the same as agreeing with a position the patient has taken on an issue, but rather conveying the sense that one sees how the patient might feel the way she does. A study of women with borderline PD and substance abuse found a validation intervention by itself was significantly helpful.³⁴ Validation can contribute to a “corrective emotional experience.” For instance, your supportive acknowledgement of a patient with a history of abuse or neglect may counter the patient’s expectation of being invalidated, and over time this can reduce the patient’s defensive rigidity.

Mentalization. Psychodynamic treatment involves a similar tack; clinicians empathize with the patient’s emotional state while also demonstrating a degree of separateness from the emotion.^23-25 This promotes mentalization in the patient—the ability to contemplate one’s own and others’ subjective mental states.¹⁸ Mentalization is often impaired in PD patients, who presume to “know” what others are thinking. A patient, for instance, “just knows” that her friend secretly hates her, based on a vaguely worded text message.

Point out that while your patient is entitled to feel what he’s feeling, it may not be in his best interest
 to act on those feelings without considering the consequences. You can help patients with mentalization by taking an inquisitive “not knowing” stance and by emphasizing a collaborative and reflective approach toward a given problem—to examine the issue together, from all sides. You can point out that while a patient is entitled to feel whatever he is feeling, it may not be in his best interest to act on the feelings without adequately considering the potential consequences of the action. This helps the patient to distinguish thoughts, feelings, and impulses from behavior. It also teaches the value of anticipatory thinking, impulse control, and affect regulation.

Countertransference. Managing your emotional reactions to a patient with PD is a well-documented challenge.³⁵ Your feelings about the patient, known as countertransference, can range from considerable concern and sympathy to severe frustration, bewilderment, and frank hostility. A common reaction is the sense that one must “do something” to respond to the patient’s emotional distress or interpersonal pressure. This may trigger an impulse to give advice or offer tests or medications despite knowing that these are unlikely to be helpful. A more useful response may be to tolerate such feelings and listen empathically to the patient’s frustration. Recognizing subtle countertransference can guard against extreme reactions and maintain an appropriate clinical focus. Discussion with a trusted colleague can be helpful.

Recognizing countertransference can guard against extreme reactions and maintain an appropriate clinical focus. Psychodynamic approaches consider managing countertransference to be a therapeutic intervention, even when psychotherapy is not explicitly being carried out. Strong emotional responses may reflect something that the patient needs the physician to experience, as the patient cannot bear to experience it himself. The patient needs to see—and learn from—the physician’s handling of unbearable (for the patient) feelings. This occurs at a level of unconscious communication and may be repeated over time. Although not discussed with the patient, a physician’s capacity for self-containment and provision of undisrupted, good medical care is in itself a psychotherapeutic accomplishment.

CASE › Based on Mr. A’s history of interpersonal conflicts and perceived persecution by coworkers, the FP consults with a psychotherapist colleague, who says Mr. A’s chronic mistrust and social isolation suggest he may have a severe identity disturbance and unspecified PD with paranoid and schizoid features. Because Mr. A refuses to see a therapist, his FP decides to focus on promoting small improvements in Mr. A’s interpersonal interactions and reducing absenteeism at work.

The FP validates Mr. A’s feelings (“it can be very stressful to constantly feel like others are at odds with you”) and tries to promote mentalizing (“I want to understand more about what you think regarding your work situation and your coworkers. Let’s try to look at this from all perspectives—maybe we can come up with some new ideas.”)

Despite wanting to help his patient, the FP feels uneasy and reluctant to engage with Mr. A, who likely evokes such feelings to keep others at a distance. The FP tactfully seeks to remain Mr. A’s ally without endorsing his distorted interpretation of events. Given Mr. A’s paranoid rejection of therapy, the FP refrains from making further such recommendations. The FP’s interventions, however, may help Mr. A warm to the idea of further help over time, and the FP’s supportive stance will help to ameliorate the patient’s distress. (For 2 additional examples of how FPs can use the strategies described in this article to help patients with PDs, see TABLE 2.)

CORRESPONDENCE
David Kealy, MSW, Psychotherapy Program, Department
of Psychiatry, University of British Columbia, #420-5950 University Boulevard, Vancouver, BC Canada V6T 1Z3; david.kealy@ubc.ca

CASE › Bob A, age 48, comes to his family physician (FP) to ask for authorization for extended medical leave from his job as an electrician. He frequently misses days at work and complains of stress on the job, saying his coworkers look down on him and make cruel jokes at his expense. He reports having chronic interpersonal conflicts and no significant relationships with family members or friends. Mr. A refuses a referral to a psychiatrist because he fears he will be “locked up and forced to take medications.”

If Mr. A were your patient, how would you proceed?

Personality disorders (PDs) are patterns of inflexible and maladaptive personality traits and behaviors that cause subjective distress and significant social or occupational impairment.¹ An individual with a PD tends to have a limited repertoire of responses to the rough-and-tumble of life, with coping mechanisms that often perpetuate difficulty and distress. Examples include distrust and suspiciousness of others’ motives (paranoid PD); disregard and violation of the rights of others (antisocial PD); instability in interpersonal relationships, self-image, and affect (borderline PD); and social inhibition, feelings of inadequacy, and hypersensitivity to negative evaluation (avoidant PD).¹

FPs may view patients with PDs as “difficult patients” because of their frequent crises and the interpersonal problems they bring into the physician-patient relationship.^2,3 Help, of course, can come in the way of a referral to a psychotherapist who specializes in treating PDs. But you can also make use of some evidence-based psychotherapy techniques to improve your patients’ lives and the quality of the physician-patient relationship. This article focuses on identifying and managing PDs in family practice, using practical strategies drawn from empirically supported therapies.

PDs are more common 
than you might suspect


Personality disorders are associated with a greater incidence of serious medical illness and reduced social functioning. The overall prevalence of PD in the community ranges from 4.4% to 14.8%, with no consistent pattern of sex differences.⁴ Between 31.4% and 45.5% of psychiatric outpatients and up to 24% of primary care patients likely meet criteria for at least one PD.^5-7 PDs impede recovery from other mental disorders,⁸ increase the risk for suicide,⁹ and are associated with substance abuse, impulsivity, and violence.^10,11 Personality pathology also is associated with greater incidence of serious medical illness^12,13 and reduced social functioning.¹⁴ Not surprisingly, patients with PDs frequently use medical and social services.¹⁵

PDs tend to be underdiagnosed, perhaps partly because of concern about stigmatization, but also due to difficulties in identifying and classifying these disorders. Published in 2013, the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) originally was to include a major revision of PDs—reflecting concern about the limitations of PD categories—but ultimately the existing categories were retained (TABLE 1).¹ There is considerable overlap among PD categories; many patients meet the criteria for more than one PD, but it is unlikely that they actually suffer from several distinct PDs. Other patients—perhaps even the majority—are best diagnosed with “unspecified personality disorder” because they do not neatly fit into one of these categories.

Suspect your patient has a PD? Evaluate these 2 areas


Identifying patients who have PDs in primary care is useful for 2 reasons: to explore the option of specialty treatment for patients who may be amenable to it, and to improve management of the patient’s complaints in the primary care setting, including a smoother doctor-patient interaction. In either case, determining the specific DSM-5 diagnosis is less important than recognizing core personality impairment: an ingrained disturbance in one’s perceptions of self and others. This can be done by paying attention to how the patient adapts to life’s challenges and if he or she has problematic interpersonal tendencies, including difficulties in the doctor-patient relationship.

Unfortunately, assessing and diagnosing PDs in the primary care setting can be challenging. Limited time doesn’t allow for extensive, personality-focused interviews. Self-report screening tools are limited, because patients may underreport key interpersonal problems such as lack of empathy. Furthermore, very few patients seek help from their FP in addressing personality dysfunction; PDs typically are identified while investigating other complaints.

The most reliable and useful areas to evaluate in a patient you suspect may have a PD are identity (one’s sense of who one is and can be) and interpersonal relationships, including the capacity for empathy and intimacy.^16,17 These should be considered longitudinally and in the context of the individual’s stage of development. For example, identity is generally less stable among adolescents compared to middle-aged adults.

A cohesive sense of identity allows one to embrace life’s tasks and challenges, to develop and strive toward personal goals, and to handle setbacks and disappointments. A person with a stable identity may develop a depressive reaction to difficult life circumstances, but with some assistance can generally bounce back and re-engage in his or her personal goals. By contrast, an individual with an unstable sense of self may feel chronically insecure and empty, with limited capacity to constructively deal with life’s ups and downs. Patients with borderline PD, for example, try to manage a fragmented identity by frantically clinging to others, while narcissistic patients tend to suppress a fragile sense of self by putting forth an arrogant and entitled attitude.

Determining the specific diagnosis of a patient you suspect has a personality disorder is less important than recognizing core personality impairment. How does the patient interact with others? As is the case with identity, an individual’s capacity for interpersonal functioning is developed early in life, through interactions with primary caregivers. Mental maps of who we are and what we can expect from others are formed and reinforced in attachment relationships, such as those with our parents; traumatic attachments, including abuse or neglect by a caregiver or loved one, are strongly associated with PD.^18,19 The resulting belief structures guide subsequent interpersonal functioning, and become interactively reinforced. For example, a person whose internal map of relationships includes others abandoning him might behave in a clingy manner, which may ultimately induce others to reject him, thus creating a self-fulfilling prophecy.

Distorted interpersonal expectations can impair a person’s capacity for sustained intimate connections (a troubled relationship history is characteristic of PDs) and limit empathic functioning.²⁰ Other people’s actions may be interpreted according to the patient’s belief structures rather than with an open mind about the other person’s experience.

Focus on the physician-patient relationship


The interpersonal dysfunction of patients with PDs will often surface in the physician-patient relationship, serving as a clue to broader interpersonal dysfunction. An FP’s relatively innocuous oversight, for example, might be taken as proof of suspected incompetence in the eyes of a patient with paranoid or narcissistic tendencies. Or a patient with a recurrent complaint who repeatedly rejects the physician’s interventions probably oscillates between seeking and rejecting nurturance in other relationships, as well. A patient who tends to make sarcastic remarks regarding the doctor’s earnest efforts likely holds negative views of others and sabotages potentially positive interactions.

So what strategies are best for managing these types of scenarios?

Bringing up a potential diagnosis of PD may be a delicate matter for the FP; patients might experience this as a jarring diagnosis in the absence of a thorough psychiatric evaluation. If the FP decides to explore whether the patient is open to discussing the relationship between moods, behaviors, and personality features, he or she can begin this conversation by noting that, as with physical health, we all have our vulnerabilities, and that these vulnerabilities may be strengthened through specialist consultation and support. In this way, the patient can view a referral as an opportunity to explore herself with professional support. If a psychiatrist or psychotherapist colleague does become involved, it is important to clarify the roles of treatment providers and to communicate with one another, should difficulties arise.

Evidence supports 
2 forms of psychotherapy


Treatment for PDs has seen considerable growth over the past decade, largely due to research on therapies that target the troubling self-injurious and suicidal features of borderline PD. Considerable evidence shows that specialized psychotherapy can significantly reduce suffering and improve functioning among these patients. The 2 major evidence-based treatments for patients with borderline PD are dialectical behavior therapy (DBT) and psychodynamic therapy.

DBT is an intensive cognitive-behavioral approach that teaches patients how to regulate their emotions and develop an accepting, mindful attitude toward their mental experience.²¹ Several randomized controlled trials (RCTs) have demonstrated the effectiveness of DBT in reducing hospitalizations and self-injurious and suicidal behavior in patients with borderline PD.²²

Psychodynamic therapy, which focuses on helping patients discover how unconscious conflicts influence their present moods and behaviors, has also been validated by multiple RCTs for patients with borderline PD.^23-25 Like DBT, empirically supported psychodynamic therapy tends to be structured, long-term (>12 months), and often intensively delivered in multiple sessions per week. However, a recent study found that a less-intensive, general psychodynamic therapy, along with occasional medication management, was equivalent to intensive DBT.²⁶

Although the research has focused primarily on borderline PD, these approaches can be applied to other PDs. These therapies focus on understanding one’s emotional and behavioral patterns, developing a healthy self-concept, and improving interpersonal relationships—areas that are relevant treatment targets across all PD types.

Indeed, studies of day treatment programs that explicitly welcome patients with a range of PD types have had promising findings.²⁷ Day treatment involves an intensive array of therapies, mostly in a group format; patients work together to support and embolden one another to make positive changes. Unfortunately, FPs may be challenged to find appropriate services for patients who are amenable to psychotherapy; public mental health resources tend to lag far behind best practices in the case of PD.

Medication might improve symptoms, not personality deficits

Judicious, circumscribed use of medications to target specific symptoms may be helpful for some patients with personality disorders. Most research on pharmacotherapy for PDs has focused on borderline PD; findings have been mixed and fairly limited.²⁸ Medication cannot address underlying identity and relational deficits, and will not result in remission of PD. Nonetheless, judicious, circumscribed use of medications to target specific symptoms may be helpful for some patients. Selective serotonin reuptake inhibitors can reduce anger and impulsive aggression in patients with borderline PD.^28,29

Atypical antipsychotics may help reduce impulsive aggression or transient psychotic symptoms.^28-30 For example, olanzapine and aripiprazole can reduce anxiety, anger/aggression, paranoia, and interpersonal sensitivity in borderline PD.^31,32 Mood stabilizers such as valproate, lamotrigine, and topiramate may also help some borderline patients, although they do so by reducing impulsivity and aggression rather than improving core unstable identity and affect.^28,29

Carefully obtained informed consent is necessary because of the danger of adverse effects with many of these medications; for example, antipsychotics have been associated with metabolic syndrome and weight gain that can threaten a patient’s already fragile self-image.³³ Polypharmacy is also a potential problem: Well-intentioned physicians may be prompted to offer multiple medications in response to patients’ unremitting complaints of distress, when a psychotherapeutic approach may need to be the primary treatment. The bottom line is that medications do not resolve personality dysfunction, and are best used symptomatically as adjuncts to psychotherapy.^28,30

Steps you can take 
during the office visit


Although it is not feasible for most FPs to provide comprehensive treatment for PD, key elements from specialized therapies can be integrated into your management of these patients. Steps you can take include using validation, promoting mentalization, and managing countertransference.

Validation, which is a component of DBT, is providing the expressed acknowledgement that the patient is entitled to her feelings.A supportive acknowledgement from you
 may counter
 a patient’s expectation
 of being invalidated,
 and over time, reduce the patient’s defensive 
rigidity. This is not the same as agreeing with a position the patient has taken on an issue, but rather conveying the sense that one sees how the patient might feel the way she does. A study of women with borderline PD and substance abuse found a validation intervention by itself was significantly helpful.³⁴ Validation can contribute to a “corrective emotional experience.” For instance, your supportive acknowledgement of a patient with a history of abuse or neglect may counter the patient’s expectation of being invalidated, and over time this can reduce the patient’s defensive rigidity.

Mentalization. Psychodynamic treatment involves a similar tack; clinicians empathize with the patient’s emotional state while also demonstrating a degree of separateness from the emotion.^23-25 This promotes mentalization in the patient—the ability to contemplate one’s own and others’ subjective mental states.¹⁸ Mentalization is often impaired in PD patients, who presume to “know” what others are thinking. A patient, for instance, “just knows” that her friend secretly hates her, based on a vaguely worded text message.

Point out that while your patient is entitled to feel what he’s feeling, it may not be in his best interest
 to act on those feelings without considering the consequences. You can help patients with mentalization by taking an inquisitive “not knowing” stance and by emphasizing a collaborative and reflective approach toward a given problem—to examine the issue together, from all sides. You can point out that while a patient is entitled to feel whatever he is feeling, it may not be in his best interest to act on the feelings without adequately considering the potential consequences of the action. This helps the patient to distinguish thoughts, feelings, and impulses from behavior. It also teaches the value of anticipatory thinking, impulse control, and affect regulation.

Countertransference. Managing your emotional reactions to a patient with PD is a well-documented challenge.³⁵ Your feelings about the patient, known as countertransference, can range from considerable concern and sympathy to severe frustration, bewilderment, and frank hostility. A common reaction is the sense that one must “do something” to respond to the patient’s emotional distress or interpersonal pressure. This may trigger an impulse to give advice or offer tests or medications despite knowing that these are unlikely to be helpful. A more useful response may be to tolerate such feelings and listen empathically to the patient’s frustration. Recognizing subtle countertransference can guard against extreme reactions and maintain an appropriate clinical focus. Discussion with a trusted colleague can be helpful.

Recognizing countertransference can guard against extreme reactions and maintain an appropriate clinical focus. Psychodynamic approaches consider managing countertransference to be a therapeutic intervention, even when psychotherapy is not explicitly being carried out. Strong emotional responses may reflect something that the patient needs the physician to experience, as the patient cannot bear to experience it himself. The patient needs to see—and learn from—the physician’s handling of unbearable (for the patient) feelings. This occurs at a level of unconscious communication and may be repeated over time. Although not discussed with the patient, a physician’s capacity for self-containment and provision of undisrupted, good medical care is in itself a psychotherapeutic accomplishment.

CASE › Based on Mr. A’s history of interpersonal conflicts and perceived persecution by coworkers, the FP consults with a psychotherapist colleague, who says Mr. A’s chronic mistrust and social isolation suggest he may have a severe identity disturbance and unspecified PD with paranoid and schizoid features. Because Mr. A refuses to see a therapist, his FP decides to focus on promoting small improvements in Mr. A’s interpersonal interactions and reducing absenteeism at work.

The FP validates Mr. A’s feelings (“it can be very stressful to constantly feel like others are at odds with you”) and tries to promote mentalizing (“I want to understand more about what you think regarding your work situation and your coworkers. Let’s try to look at this from all perspectives—maybe we can come up with some new ideas.”)

Despite wanting to help his patient, the FP feels uneasy and reluctant to engage with Mr. A, who likely evokes such feelings to keep others at a distance. The FP tactfully seeks to remain Mr. A’s ally without endorsing his distorted interpretation of events. Given Mr. A’s paranoid rejection of therapy, the FP refrains from making further such recommendations. The FP’s interventions, however, may help Mr. A warm to the idea of further help over time, and the FP’s supportive stance will help to ameliorate the patient’s distress. (For 2 additional examples of how FPs can use the strategies described in this article to help patients with PDs, see TABLE 2.)

CORRESPONDENCE
David Kealy, MSW, Psychotherapy Program, Department
of Psychiatry, University of British Columbia, #420-5950 University Boulevard, Vancouver, BC Canada V6T 1Z3; david.kealy@ubc.ca

CASE › Bob A, age 48, comes to his family physician (FP) to ask for authorization for extended medical leave from his job as an electrician. He frequently misses days at work and complains of stress on the job, saying his coworkers look down on him and make cruel jokes at his expense. He reports having chronic interpersonal conflicts and no significant relationships with family members or friends. Mr. A refuses a referral to a psychiatrist because he fears he will be “locked up and forced to take medications.”

If Mr. A were your patient, how would you proceed?

Personality disorders (PDs) are patterns of inflexible and maladaptive personality traits and behaviors that cause subjective distress and significant social or occupational impairment.¹ An individual with a PD tends to have a limited repertoire of responses to the rough-and-tumble of life, with coping mechanisms that often perpetuate difficulty and distress. Examples include distrust and suspiciousness of others’ motives (paranoid PD); disregard and violation of the rights of others (antisocial PD); instability in interpersonal relationships, self-image, and affect (borderline PD); and social inhibition, feelings of inadequacy, and hypersensitivity to negative evaluation (avoidant PD).¹

FPs may view patients with PDs as “difficult patients” because of their frequent crises and the interpersonal problems they bring into the physician-patient relationship.^2,3 Help, of course, can come in the way of a referral to a psychotherapist who specializes in treating PDs. But you can also make use of some evidence-based psychotherapy techniques to improve your patients’ lives and the quality of the physician-patient relationship. This article focuses on identifying and managing PDs in family practice, using practical strategies drawn from empirically supported therapies.

PDs are more common 
than you might suspect


Personality disorders are associated with a greater incidence of serious medical illness and reduced social functioning. The overall prevalence of PD in the community ranges from 4.4% to 14.8%, with no consistent pattern of sex differences.⁴ Between 31.4% and 45.5% of psychiatric outpatients and up to 24% of primary care patients likely meet criteria for at least one PD.^5-7 PDs impede recovery from other mental disorders,⁸ increase the risk for suicide,⁹ and are associated with substance abuse, impulsivity, and violence.^10,11 Personality pathology also is associated with greater incidence of serious medical illness^12,13 and reduced social functioning.¹⁴ Not surprisingly, patients with PDs frequently use medical and social services.¹⁵

PDs tend to be underdiagnosed, perhaps partly because of concern about stigmatization, but also due to difficulties in identifying and classifying these disorders. Published in 2013, the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) originally was to include a major revision of PDs—reflecting concern about the limitations of PD categories—but ultimately the existing categories were retained (TABLE 1).¹ There is considerable overlap among PD categories; many patients meet the criteria for more than one PD, but it is unlikely that they actually suffer from several distinct PDs. Other patients—perhaps even the majority—are best diagnosed with “unspecified personality disorder” because they do not neatly fit into one of these categories.

Suspect your patient has a PD? Evaluate these 2 areas


Identifying patients who have PDs in primary care is useful for 2 reasons: to explore the option of specialty treatment for patients who may be amenable to it, and to improve management of the patient’s complaints in the primary care setting, including a smoother doctor-patient interaction. In either case, determining the specific DSM-5 diagnosis is less important than recognizing core personality impairment: an ingrained disturbance in one’s perceptions of self and others. This can be done by paying attention to how the patient adapts to life’s challenges and if he or she has problematic interpersonal tendencies, including difficulties in the doctor-patient relationship.

Unfortunately, assessing and diagnosing PDs in the primary care setting can be challenging. Limited time doesn’t allow for extensive, personality-focused interviews. Self-report screening tools are limited, because patients may underreport key interpersonal problems such as lack of empathy. Furthermore, very few patients seek help from their FP in addressing personality dysfunction; PDs typically are identified while investigating other complaints.

The most reliable and useful areas to evaluate in a patient you suspect may have a PD are identity (one’s sense of who one is and can be) and interpersonal relationships, including the capacity for empathy and intimacy.^16,17 These should be considered longitudinally and in the context of the individual’s stage of development. For example, identity is generally less stable among adolescents compared to middle-aged adults.

A cohesive sense of identity allows one to embrace life’s tasks and challenges, to develop and strive toward personal goals, and to handle setbacks and disappointments. A person with a stable identity may develop a depressive reaction to difficult life circumstances, but with some assistance can generally bounce back and re-engage in his or her personal goals. By contrast, an individual with an unstable sense of self may feel chronically insecure and empty, with limited capacity to constructively deal with life’s ups and downs. Patients with borderline PD, for example, try to manage a fragmented identity by frantically clinging to others, while narcissistic patients tend to suppress a fragile sense of self by putting forth an arrogant and entitled attitude.

Determining the specific diagnosis of a patient you suspect has a personality disorder is less important than recognizing core personality impairment. How does the patient interact with others? As is the case with identity, an individual’s capacity for interpersonal functioning is developed early in life, through interactions with primary caregivers. Mental maps of who we are and what we can expect from others are formed and reinforced in attachment relationships, such as those with our parents; traumatic attachments, including abuse or neglect by a caregiver or loved one, are strongly associated with PD.^18,19 The resulting belief structures guide subsequent interpersonal functioning, and become interactively reinforced. For example, a person whose internal map of relationships includes others abandoning him might behave in a clingy manner, which may ultimately induce others to reject him, thus creating a self-fulfilling prophecy.

Distorted interpersonal expectations can impair a person’s capacity for sustained intimate connections (a troubled relationship history is characteristic of PDs) and limit empathic functioning.²⁰ Other people’s actions may be interpreted according to the patient’s belief structures rather than with an open mind about the other person’s experience.

Focus on the physician-patient relationship


The interpersonal dysfunction of patients with PDs will often surface in the physician-patient relationship, serving as a clue to broader interpersonal dysfunction. An FP’s relatively innocuous oversight, for example, might be taken as proof of suspected incompetence in the eyes of a patient with paranoid or narcissistic tendencies. Or a patient with a recurrent complaint who repeatedly rejects the physician’s interventions probably oscillates between seeking and rejecting nurturance in other relationships, as well. A patient who tends to make sarcastic remarks regarding the doctor’s earnest efforts likely holds negative views of others and sabotages potentially positive interactions.

So what strategies are best for managing these types of scenarios?

Bringing up a potential diagnosis of PD may be a delicate matter for the FP; patients might experience this as a jarring diagnosis in the absence of a thorough psychiatric evaluation. If the FP decides to explore whether the patient is open to discussing the relationship between moods, behaviors, and personality features, he or she can begin this conversation by noting that, as with physical health, we all have our vulnerabilities, and that these vulnerabilities may be strengthened through specialist consultation and support. In this way, the patient can view a referral as an opportunity to explore herself with professional support. If a psychiatrist or psychotherapist colleague does become involved, it is important to clarify the roles of treatment providers and to communicate with one another, should difficulties arise.

Evidence supports 
2 forms of psychotherapy


Treatment for PDs has seen considerable growth over the past decade, largely due to research on therapies that target the troubling self-injurious and suicidal features of borderline PD. Considerable evidence shows that specialized psychotherapy can significantly reduce suffering and improve functioning among these patients. The 2 major evidence-based treatments for patients with borderline PD are dialectical behavior therapy (DBT) and psychodynamic therapy.

DBT is an intensive cognitive-behavioral approach that teaches patients how to regulate their emotions and develop an accepting, mindful attitude toward their mental experience.²¹ Several randomized controlled trials (RCTs) have demonstrated the effectiveness of DBT in reducing hospitalizations and self-injurious and suicidal behavior in patients with borderline PD.²²

Psychodynamic therapy, which focuses on helping patients discover how unconscious conflicts influence their present moods and behaviors, has also been validated by multiple RCTs for patients with borderline PD.^23-25 Like DBT, empirically supported psychodynamic therapy tends to be structured, long-term (>12 months), and often intensively delivered in multiple sessions per week. However, a recent study found that a less-intensive, general psychodynamic therapy, along with occasional medication management, was equivalent to intensive DBT.²⁶

Although the research has focused primarily on borderline PD, these approaches can be applied to other PDs. These therapies focus on understanding one’s emotional and behavioral patterns, developing a healthy self-concept, and improving interpersonal relationships—areas that are relevant treatment targets across all PD types.

Indeed, studies of day treatment programs that explicitly welcome patients with a range of PD types have had promising findings.²⁷ Day treatment involves an intensive array of therapies, mostly in a group format; patients work together to support and embolden one another to make positive changes. Unfortunately, FPs may be challenged to find appropriate services for patients who are amenable to psychotherapy; public mental health resources tend to lag far behind best practices in the case of PD.

Medication might improve symptoms, not personality deficits

Judicious, circumscribed use of medications to target specific symptoms may be helpful for some patients with personality disorders. Most research on pharmacotherapy for PDs has focused on borderline PD; findings have been mixed and fairly limited.²⁸ Medication cannot address underlying identity and relational deficits, and will not result in remission of PD. Nonetheless, judicious, circumscribed use of medications to target specific symptoms may be helpful for some patients. Selective serotonin reuptake inhibitors can reduce anger and impulsive aggression in patients with borderline PD.^28,29

Atypical antipsychotics may help reduce impulsive aggression or transient psychotic symptoms.^28-30 For example, olanzapine and aripiprazole can reduce anxiety, anger/aggression, paranoia, and interpersonal sensitivity in borderline PD.^31,32 Mood stabilizers such as valproate, lamotrigine, and topiramate may also help some borderline patients, although they do so by reducing impulsivity and aggression rather than improving core unstable identity and affect.^28,29

Carefully obtained informed consent is necessary because of the danger of adverse effects with many of these medications; for example, antipsychotics have been associated with metabolic syndrome and weight gain that can threaten a patient’s already fragile self-image.³³ Polypharmacy is also a potential problem: Well-intentioned physicians may be prompted to offer multiple medications in response to patients’ unremitting complaints of distress, when a psychotherapeutic approach may need to be the primary treatment. The bottom line is that medications do not resolve personality dysfunction, and are best used symptomatically as adjuncts to psychotherapy.^28,30

Steps you can take 
during the office visit


Although it is not feasible for most FPs to provide comprehensive treatment for PD, key elements from specialized therapies can be integrated into your management of these patients. Steps you can take include using validation, promoting mentalization, and managing countertransference.

Validation, which is a component of DBT, is providing the expressed acknowledgement that the patient is entitled to her feelings.A supportive acknowledgement from you
 may counter
 a patient’s expectation
 of being invalidated,
 and over time, reduce the patient’s defensive 
rigidity. This is not the same as agreeing with a position the patient has taken on an issue, but rather conveying the sense that one sees how the patient might feel the way she does. A study of women with borderline PD and substance abuse found a validation intervention by itself was significantly helpful.³⁴ Validation can contribute to a “corrective emotional experience.” For instance, your supportive acknowledgement of a patient with a history of abuse or neglect may counter the patient’s expectation of being invalidated, and over time this can reduce the patient’s defensive rigidity.

Mentalization. Psychodynamic treatment involves a similar tack; clinicians empathize with the patient’s emotional state while also demonstrating a degree of separateness from the emotion.^23-25 This promotes mentalization in the patient—the ability to contemplate one’s own and others’ subjective mental states.¹⁸ Mentalization is often impaired in PD patients, who presume to “know” what others are thinking. A patient, for instance, “just knows” that her friend secretly hates her, based on a vaguely worded text message.

Point out that while your patient is entitled to feel what he’s feeling, it may not be in his best interest
 to act on those feelings without considering the consequences. You can help patients with mentalization by taking an inquisitive “not knowing” stance and by emphasizing a collaborative and reflective approach toward a given problem—to examine the issue together, from all sides. You can point out that while a patient is entitled to feel whatever he is feeling, it may not be in his best interest to act on the feelings without adequately considering the potential consequences of the action. This helps the patient to distinguish thoughts, feelings, and impulses from behavior. It also teaches the value of anticipatory thinking, impulse control, and affect regulation.

Countertransference. Managing your emotional reactions to a patient with PD is a well-documented challenge.³⁵ Your feelings about the patient, known as countertransference, can range from considerable concern and sympathy to severe frustration, bewilderment, and frank hostility. A common reaction is the sense that one must “do something” to respond to the patient’s emotional distress or interpersonal pressure. This may trigger an impulse to give advice or offer tests or medications despite knowing that these are unlikely to be helpful. A more useful response may be to tolerate such feelings and listen empathically to the patient’s frustration. Recognizing subtle countertransference can guard against extreme reactions and maintain an appropriate clinical focus. Discussion with a trusted colleague can be helpful.

Recognizing countertransference can guard against extreme reactions and maintain an appropriate clinical focus. Psychodynamic approaches consider managing countertransference to be a therapeutic intervention, even when psychotherapy is not explicitly being carried out. Strong emotional responses may reflect something that the patient needs the physician to experience, as the patient cannot bear to experience it himself. The patient needs to see—and learn from—the physician’s handling of unbearable (for the patient) feelings. This occurs at a level of unconscious communication and may be repeated over time. Although not discussed with the patient, a physician’s capacity for self-containment and provision of undisrupted, good medical care is in itself a psychotherapeutic accomplishment.

CASE › Based on Mr. A’s history of interpersonal conflicts and perceived persecution by coworkers, the FP consults with a psychotherapist colleague, who says Mr. A’s chronic mistrust and social isolation suggest he may have a severe identity disturbance and unspecified PD with paranoid and schizoid features. Because Mr. A refuses to see a therapist, his FP decides to focus on promoting small improvements in Mr. A’s interpersonal interactions and reducing absenteeism at work.

The FP validates Mr. A’s feelings (“it can be very stressful to constantly feel like others are at odds with you”) and tries to promote mentalizing (“I want to understand more about what you think regarding your work situation and your coworkers. Let’s try to look at this from all perspectives—maybe we can come up with some new ideas.”)

Despite wanting to help his patient, the FP feels uneasy and reluctant to engage with Mr. A, who likely evokes such feelings to keep others at a distance. The FP tactfully seeks to remain Mr. A’s ally without endorsing his distorted interpretation of events. Given Mr. A’s paranoid rejection of therapy, the FP refrains from making further such recommendations. The FP’s interventions, however, may help Mr. A warm to the idea of further help over time, and the FP’s supportive stance will help to ameliorate the patient’s distress. (For 2 additional examples of how FPs can use the strategies described in this article to help patients with PDs, see TABLE 2.)

CORRESPONDENCE
David Kealy, MSW, Psychotherapy Program, Department
of Psychiatry, University of British Columbia, #420-5950 University Boulevard, Vancouver, BC Canada V6T 1Z3; david.kealy@ubc.ca

Foot ulcers and other lower-limb complications secondary to diabetes are common, complex, costly, and associated with increased morbidity and mortality.^1-6 Unfortunately, patients often have difficulty recognizing the heightened risk status that accompanies the diagnosis of diabetes, particularly the substantial risk for lower limb complications.⁷ In addition, loss of protective sensation (LOPS) can render patients unable to recognize damage to their lower extremities, thus creating a cycle of tissue damage and other foot complications. Strong evidence suggests that consistent provision of foot-care services and preventive care can reduce amputations among patients with diabetes.^7-9 However, routine foot examination and rapid risk stratification is often difficult to incorporate into busy primary care settings. Data suggest that the diabetic foot is adequately evaluated only 12% to 20% of the time.¹⁰

In response to the need for more consistent foot exams, an American Diabetes Association (ADA) task force lead by 2 of the authors of this article (AB and DA) created the Comprehensive Foot Examination and Risk Assessment.⁵ This set the standard for the detailed investigation of lower limb pathology by a specialist, but was not well suited for other practice settings, including primary care. One reason is that it would be difficult to complete the comprehensive examination during a typical 15-minute primary care office visit. In addition, certain examination parameters require the use of neurologic and vascular assessment equipment and training not available in all health care settings.¹¹

This exam takes substantially less time to complete than
 a comprehensive exam and eliminates common barriers to frequent assessment. With these thoughts in mind, we set out to develop an exam that could be done by a wide range of health care providers—one that takes substantially less time to complete than a comprehensive exam and eliminates common barriers to frequent assessment. The exam, which we’ll describe here, consists of 3 components: taking a patient history, performing a physical exam, and providing patient education. And best of all, it should only take 3 minutes.

The patient history (1 minute)

Patients may present with concerns about their feet, but may not be able to differentiate between benign and threatening symptoms. A thorough medical history can identify factors that may increase patients’ risk of developing lower-limb complications. Reviewing the patient’s medical history also can help guide the physical exam.

Review the patient’s diabetic history, blood glucose control, and previous diabetic complications. Ask patients about their history of peripheral vascular disease, quality of peripheral protective sensation, and previous lower-limb interventions and operations (TABLE 1^5,12). Patients with diabetes and suboptimal glycemic control have an increased risk for LOPS, chronic and recalcitrant ulcers, and wound infections.² Additionally, patients with diabetes and a previous lower extremity amputation are at high risk for reulceration.^5,12 Lastly, nicotine use and smoking are common pathogenic risk factors that contribute to peripheral artery disease (PAD).¹³

Physical examination (1 minute)

Careful inspection of the feet should be performed at every visit for patients with confirmed or suspected diabetes. Because up to 50% of patients with significant sensory loss due to neuropathy may be completely asymptomatic,¹⁴ failing to search for early signs of infection (FIGURE 1), skin breakdown, ulcer formation (FIGURE 2), skin temperature changes, and inadequate vascular perfusion may allow complications to develop.⁵ TABLE 2^5,15,16 outlines the essential components—dermatologic, neurologic, musculoskeletal, and vascular—of a rapid lower limb physical exam.

The dermatologic exam. This serves as a barometer for early intervention, and often results in a limb-saving referral to a specialist. Carefully 
examine the areas 
between the 
toes, where
 deeper lesions
 may go
 unnoticed. It should begin with a global inspection for discolorations, calluses, wounds, fissures, macerations, nail dystrophy, or paronychia.⁵ Skin discoloration or loss of hair growth may be the first signs of vascular insufficiency, while calluses and hypertrophic skin often are precursors to ulcers.^5,17-19 Inspection of the toes should include a search for fungal, ingrown, or elongated nails. Carefully examine the areas between the toes, where deeper lesions may go unnoticed.⁵

The neurologic exam. Without protective sensation, patients with neuropathy are at a heightened risk of unrecognized injury and are unlikely to mention their deformities to medical staff.^20-23 Consequently, skin deterioration may unknowingly progress to ulceration that requires extensive medical intervention or amputation.

Neuropathic LOPS is easily detectable, yet it is linked to at least 75% of all nontraumatic diabetic amputations.^20-23 Adiminished vibratory perception threshold (VPT) is one of the earliest indicators of neuropathic LOPS and is the best predictor of long-term lower extremity complications.^1,24,25 However, VPT devices are expensive and time-consuming to operate, and they require training to ensure proper use. The Semmes-Weinstein monofilament is a well-documented alternative to VPT for predicting ulcer risk^26-28 and has long been advocated as an essential component of a thorough foot exam.⁵ The 128 Hz tuning fork is another regularly used alternative.⁵ However, physicians would need to purchase one of these devices and receive training on how to use it, and, in the case of the monofilament, to regularly stock replacements to maintain accurate results.¹⁶

No testing devices are needed to conduct the Ipswich Touch Test, and it is as sensitive and specific as the monofilament test. The Ipswich Touch Test (IpTT) is an alternative neurologic test that requires only the physician’s index finger. During the IpTT, the physician instructs the patient to close his or her eyes while the physician lightly rests his or her finger on each of the patient’s first, third, and fifth toes for 1 to 2 seconds (FIGURE 3). Patients are instructed to respond with a “yes” when they feel the physician’s touch. In a head-to-head trial, diagnostic results of the IpTT directly paralleled those of the monofilament in detecting LOPS; IpTT was also equally sensitive and specific (k=.88, indicating almost perfect agreement; P<.0001).²⁹ The IpTT’s use of only 6 palpation points, constant availability, and accuracy make it a first-line neurologic test for rapidly screening the feet of a patient with diabetes.

Neuromuscular/musculoskeletal exam. Neuromuscular disturbances, such as a reduction in the strength of dorsiflexion and plantar flexion, may indicate a complicated neurologic compromise.⁵ In addition to being aesthetically problematic, musculoskeletal deformities such as a hammer toe, claw toe (FIGURE 4), or bunion can cause significant pain and/or gait disturbance, and can increase patients’ risk for ulceration.³⁰ These deformities also may compromise patients’ general health and grossly escalate their risk of falls and resultant injuries.^5,31 Therefore, patients who present with previously unreported musculoskeletal deformities should be referred to a specialist.³¹

Charcot neuroarthropathy is
 a devastating complication that classically presents as a hot, red, swollen foot; the redness resolves upon elevation. Also screen patients for Charcot neuroarthropathy (FIGURE 5), a devastating complication that classically presents as a hot, red, swollen foot; the redness resolves upon elevation.³² Charcot neuroarthropathy is hypothesized to be a dysregulation of normal bone metabolism typically occurring secondary to diabetic neuropathy and repetitive minor trauma.^33,34 This dysregulation leads to joint instability and disorganization of normal midfoot bone architecture.^31,32 Charcot neuroarthropathy is an urgent pathology that requires management by a foot specialist.³⁵

Vascular exam. PAD is particularly common in patients with diabetes and contributes to the development of impaired healing in up to half of foot ulcers.^13,18,36-39 Bilateral femoral, popliteal, posterior tibial, or dorsalis pedis pulses should be assessed by palpation; a diminished or absent pulse is a key indicator of vascular compromise.^40,41 An integrated care approach between foot specialists and vascular surgeons results in optimal treatment.

Patient education (1 minute)

It is imperative to include patients in their treatment process to reduce the likelihood of complications and, ultimately, decrease the incidence of amputations.^12,42 Patient education improves patients’ self-reported home care behaviors, even at the most fundamental levels.^43,44 TABLE 3^5,15,45 lists topics to cover during patient education.

A lack of appropriate patient education regarding diabetes is a factor in >90% of recurrent ulcers.Patients’ lack of understanding about self-care for diabetes is a common barrier to prevention.²³ El-Nahas et al⁴⁶ found a lack of appropriate education regarding diabetes was a factor in more than 90% of recurrent ulcers, which emphasizes the need for repeated education for at-risk patients.^47,48 Involve all levels of medical staff in the effort to educate patients on the importance of foot screenings, both at home and in-office. Even with proper patient education, many patients may be in various stages of coping with this all-consuming yet frequently asymptomatic condition, which makes the need for repeated patient education even more critical.

Who to refer, and when

After completing the 3-minute foot exam, create a treatment and follow-up plan, focusing on the need for referral to a specialist. TABLE 4 outlines suggested indications, priorities, and timelines for referral based on ADA guidelines.⁵ It incorporates the ADA’s patient risk categories (very low, low, moderate, and high risk) and also provides a recommended frequency for patient follow-ups.

Care for patients with lower extremity complications of diabetes mellitus is time-consuming and expensive. The brief exam described here can help you to rapidly identify patients at risk for these complications and prompt you to provide timely referrals to appropriate specialists.

CORRESPONDENCE
David G. Armstrong, DPM, MD, PhD, Professor, Department of Surgery, Director, Southern Arizona Limb Salvage Alliance (SALSA), 1501 N. Campbell Avenue, Tucson, AZ 85724-5072; armstrong@usa.net

Foot ulcers and other lower-limb complications secondary to diabetes are common, complex, costly, and associated with increased morbidity and mortality.^1-6 Unfortunately, patients often have difficulty recognizing the heightened risk status that accompanies the diagnosis of diabetes, particularly the substantial risk for lower limb complications.⁷ In addition, loss of protective sensation (LOPS) can render patients unable to recognize damage to their lower extremities, thus creating a cycle of tissue damage and other foot complications. Strong evidence suggests that consistent provision of foot-care services and preventive care can reduce amputations among patients with diabetes.^7-9 However, routine foot examination and rapid risk stratification is often difficult to incorporate into busy primary care settings. Data suggest that the diabetic foot is adequately evaluated only 12% to 20% of the time.¹⁰

In response to the need for more consistent foot exams, an American Diabetes Association (ADA) task force lead by 2 of the authors of this article (AB and DA) created the Comprehensive Foot Examination and Risk Assessment.⁵ This set the standard for the detailed investigation of lower limb pathology by a specialist, but was not well suited for other practice settings, including primary care. One reason is that it would be difficult to complete the comprehensive examination during a typical 15-minute primary care office visit. In addition, certain examination parameters require the use of neurologic and vascular assessment equipment and training not available in all health care settings.¹¹

This exam takes substantially less time to complete than
 a comprehensive exam and eliminates common barriers to frequent assessment. With these thoughts in mind, we set out to develop an exam that could be done by a wide range of health care providers—one that takes substantially less time to complete than a comprehensive exam and eliminates common barriers to frequent assessment. The exam, which we’ll describe here, consists of 3 components: taking a patient history, performing a physical exam, and providing patient education. And best of all, it should only take 3 minutes.

The patient history (1 minute)

Patients may present with concerns about their feet, but may not be able to differentiate between benign and threatening symptoms. A thorough medical history can identify factors that may increase patients’ risk of developing lower-limb complications. Reviewing the patient’s medical history also can help guide the physical exam.

Review the patient’s diabetic history, blood glucose control, and previous diabetic complications. Ask patients about their history of peripheral vascular disease, quality of peripheral protective sensation, and previous lower-limb interventions and operations (TABLE 1^5,12). Patients with diabetes and suboptimal glycemic control have an increased risk for LOPS, chronic and recalcitrant ulcers, and wound infections.² Additionally, patients with diabetes and a previous lower extremity amputation are at high risk for reulceration.^5,12 Lastly, nicotine use and smoking are common pathogenic risk factors that contribute to peripheral artery disease (PAD).¹³

Physical examination (1 minute)

Careful inspection of the feet should be performed at every visit for patients with confirmed or suspected diabetes. Because up to 50% of patients with significant sensory loss due to neuropathy may be completely asymptomatic,¹⁴ failing to search for early signs of infection (FIGURE 1), skin breakdown, ulcer formation (FIGURE 2), skin temperature changes, and inadequate vascular perfusion may allow complications to develop.⁵ TABLE 2^5,15,16 outlines the essential components—dermatologic, neurologic, musculoskeletal, and vascular—of a rapid lower limb physical exam.

The dermatologic exam. This serves as a barometer for early intervention, and often results in a limb-saving referral to a specialist. Carefully 
examine the areas 
between the 
toes, where
 deeper lesions
 may go
 unnoticed. It should begin with a global inspection for discolorations, calluses, wounds, fissures, macerations, nail dystrophy, or paronychia.⁵ Skin discoloration or loss of hair growth may be the first signs of vascular insufficiency, while calluses and hypertrophic skin often are precursors to ulcers.^5,17-19 Inspection of the toes should include a search for fungal, ingrown, or elongated nails. Carefully examine the areas between the toes, where deeper lesions may go unnoticed.⁵

The neurologic exam. Without protective sensation, patients with neuropathy are at a heightened risk of unrecognized injury and are unlikely to mention their deformities to medical staff.^20-23 Consequently, skin deterioration may unknowingly progress to ulceration that requires extensive medical intervention or amputation.

Neuropathic LOPS is easily detectable, yet it is linked to at least 75% of all nontraumatic diabetic amputations.^20-23 Adiminished vibratory perception threshold (VPT) is one of the earliest indicators of neuropathic LOPS and is the best predictor of long-term lower extremity complications.^1,24,25 However, VPT devices are expensive and time-consuming to operate, and they require training to ensure proper use. The Semmes-Weinstein monofilament is a well-documented alternative to VPT for predicting ulcer risk^26-28 and has long been advocated as an essential component of a thorough foot exam.⁵ The 128 Hz tuning fork is another regularly used alternative.⁵ However, physicians would need to purchase one of these devices and receive training on how to use it, and, in the case of the monofilament, to regularly stock replacements to maintain accurate results.¹⁶

No testing devices are needed to conduct the Ipswich Touch Test, and it is as sensitive and specific as the monofilament test. The Ipswich Touch Test (IpTT) is an alternative neurologic test that requires only the physician’s index finger. During the IpTT, the physician instructs the patient to close his or her eyes while the physician lightly rests his or her finger on each of the patient’s first, third, and fifth toes for 1 to 2 seconds (FIGURE 3). Patients are instructed to respond with a “yes” when they feel the physician’s touch. In a head-to-head trial, diagnostic results of the IpTT directly paralleled those of the monofilament in detecting LOPS; IpTT was also equally sensitive and specific (k=.88, indicating almost perfect agreement; P<.0001).²⁹ The IpTT’s use of only 6 palpation points, constant availability, and accuracy make it a first-line neurologic test for rapidly screening the feet of a patient with diabetes.

Neuromuscular/musculoskeletal exam. Neuromuscular disturbances, such as a reduction in the strength of dorsiflexion and plantar flexion, may indicate a complicated neurologic compromise.⁵ In addition to being aesthetically problematic, musculoskeletal deformities such as a hammer toe, claw toe (FIGURE 4), or bunion can cause significant pain and/or gait disturbance, and can increase patients’ risk for ulceration.³⁰ These deformities also may compromise patients’ general health and grossly escalate their risk of falls and resultant injuries.^5,31 Therefore, patients who present with previously unreported musculoskeletal deformities should be referred to a specialist.³¹

Charcot neuroarthropathy is
 a devastating complication that classically presents as a hot, red, swollen foot; the redness resolves upon elevation. Also screen patients for Charcot neuroarthropathy (FIGURE 5), a devastating complication that classically presents as a hot, red, swollen foot; the redness resolves upon elevation.³² Charcot neuroarthropathy is hypothesized to be a dysregulation of normal bone metabolism typically occurring secondary to diabetic neuropathy and repetitive minor trauma.^33,34 This dysregulation leads to joint instability and disorganization of normal midfoot bone architecture.^31,32 Charcot neuroarthropathy is an urgent pathology that requires management by a foot specialist.³⁵

Vascular exam. PAD is particularly common in patients with diabetes and contributes to the development of impaired healing in up to half of foot ulcers.^13,18,36-39 Bilateral femoral, popliteal, posterior tibial, or dorsalis pedis pulses should be assessed by palpation; a diminished or absent pulse is a key indicator of vascular compromise.^40,41 An integrated care approach between foot specialists and vascular surgeons results in optimal treatment.

Patient education (1 minute)

It is imperative to include patients in their treatment process to reduce the likelihood of complications and, ultimately, decrease the incidence of amputations.^12,42 Patient education improves patients’ self-reported home care behaviors, even at the most fundamental levels.^43,44 TABLE 3^5,15,45 lists topics to cover during patient education.

A lack of appropriate patient education regarding diabetes is a factor in >90% of recurrent ulcers.Patients’ lack of understanding about self-care for diabetes is a common barrier to prevention.²³ El-Nahas et al⁴⁶ found a lack of appropriate education regarding diabetes was a factor in more than 90% of recurrent ulcers, which emphasizes the need for repeated education for at-risk patients.^47,48 Involve all levels of medical staff in the effort to educate patients on the importance of foot screenings, both at home and in-office. Even with proper patient education, many patients may be in various stages of coping with this all-consuming yet frequently asymptomatic condition, which makes the need for repeated patient education even more critical.

Who to refer, and when

After completing the 3-minute foot exam, create a treatment and follow-up plan, focusing on the need for referral to a specialist. TABLE 4 outlines suggested indications, priorities, and timelines for referral based on ADA guidelines.⁵ It incorporates the ADA’s patient risk categories (very low, low, moderate, and high risk) and also provides a recommended frequency for patient follow-ups.

Care for patients with lower extremity complications of diabetes mellitus is time-consuming and expensive. The brief exam described here can help you to rapidly identify patients at risk for these complications and prompt you to provide timely referrals to appropriate specialists.

CORRESPONDENCE
David G. Armstrong, DPM, MD, PhD, Professor, Department of Surgery, Director, Southern Arizona Limb Salvage Alliance (SALSA), 1501 N. Campbell Avenue, Tucson, AZ 85724-5072; armstrong@usa.net

Foot ulcers and other lower-limb complications secondary to diabetes are common, complex, costly, and associated with increased morbidity and mortality.^1-6 Unfortunately, patients often have difficulty recognizing the heightened risk status that accompanies the diagnosis of diabetes, particularly the substantial risk for lower limb complications.⁷ In addition, loss of protective sensation (LOPS) can render patients unable to recognize damage to their lower extremities, thus creating a cycle of tissue damage and other foot complications. Strong evidence suggests that consistent provision of foot-care services and preventive care can reduce amputations among patients with diabetes.^7-9 However, routine foot examination and rapid risk stratification is often difficult to incorporate into busy primary care settings. Data suggest that the diabetic foot is adequately evaluated only 12% to 20% of the time.¹⁰

In response to the need for more consistent foot exams, an American Diabetes Association (ADA) task force lead by 2 of the authors of this article (AB and DA) created the Comprehensive Foot Examination and Risk Assessment.⁵ This set the standard for the detailed investigation of lower limb pathology by a specialist, but was not well suited for other practice settings, including primary care. One reason is that it would be difficult to complete the comprehensive examination during a typical 15-minute primary care office visit. In addition, certain examination parameters require the use of neurologic and vascular assessment equipment and training not available in all health care settings.¹¹

This exam takes substantially less time to complete than
 a comprehensive exam and eliminates common barriers to frequent assessment. With these thoughts in mind, we set out to develop an exam that could be done by a wide range of health care providers—one that takes substantially less time to complete than a comprehensive exam and eliminates common barriers to frequent assessment. The exam, which we’ll describe here, consists of 3 components: taking a patient history, performing a physical exam, and providing patient education. And best of all, it should only take 3 minutes.

The patient history (1 minute)

Patients may present with concerns about their feet, but may not be able to differentiate between benign and threatening symptoms. A thorough medical history can identify factors that may increase patients’ risk of developing lower-limb complications. Reviewing the patient’s medical history also can help guide the physical exam.

Review the patient’s diabetic history, blood glucose control, and previous diabetic complications. Ask patients about their history of peripheral vascular disease, quality of peripheral protective sensation, and previous lower-limb interventions and operations (TABLE 1^5,12). Patients with diabetes and suboptimal glycemic control have an increased risk for LOPS, chronic and recalcitrant ulcers, and wound infections.² Additionally, patients with diabetes and a previous lower extremity amputation are at high risk for reulceration.^5,12 Lastly, nicotine use and smoking are common pathogenic risk factors that contribute to peripheral artery disease (PAD).¹³

Physical examination (1 minute)

Careful inspection of the feet should be performed at every visit for patients with confirmed or suspected diabetes. Because up to 50% of patients with significant sensory loss due to neuropathy may be completely asymptomatic,¹⁴ failing to search for early signs of infection (FIGURE 1), skin breakdown, ulcer formation (FIGURE 2), skin temperature changes, and inadequate vascular perfusion may allow complications to develop.⁵ TABLE 2^5,15,16 outlines the essential components—dermatologic, neurologic, musculoskeletal, and vascular—of a rapid lower limb physical exam.

The dermatologic exam. This serves as a barometer for early intervention, and often results in a limb-saving referral to a specialist. Carefully 
examine the areas 
between the 
toes, where
 deeper lesions
 may go
 unnoticed. It should begin with a global inspection for discolorations, calluses, wounds, fissures, macerations, nail dystrophy, or paronychia.⁵ Skin discoloration or loss of hair growth may be the first signs of vascular insufficiency, while calluses and hypertrophic skin often are precursors to ulcers.^5,17-19 Inspection of the toes should include a search for fungal, ingrown, or elongated nails. Carefully examine the areas between the toes, where deeper lesions may go unnoticed.⁵

The neurologic exam. Without protective sensation, patients with neuropathy are at a heightened risk of unrecognized injury and are unlikely to mention their deformities to medical staff.^20-23 Consequently, skin deterioration may unknowingly progress to ulceration that requires extensive medical intervention or amputation.

Neuropathic LOPS is easily detectable, yet it is linked to at least 75% of all nontraumatic diabetic amputations.^20-23 Adiminished vibratory perception threshold (VPT) is one of the earliest indicators of neuropathic LOPS and is the best predictor of long-term lower extremity complications.^1,24,25 However, VPT devices are expensive and time-consuming to operate, and they require training to ensure proper use. The Semmes-Weinstein monofilament is a well-documented alternative to VPT for predicting ulcer risk^26-28 and has long been advocated as an essential component of a thorough foot exam.⁵ The 128 Hz tuning fork is another regularly used alternative.⁵ However, physicians would need to purchase one of these devices and receive training on how to use it, and, in the case of the monofilament, to regularly stock replacements to maintain accurate results.¹⁶

No testing devices are needed to conduct the Ipswich Touch Test, and it is as sensitive and specific as the monofilament test. The Ipswich Touch Test (IpTT) is an alternative neurologic test that requires only the physician’s index finger. During the IpTT, the physician instructs the patient to close his or her eyes while the physician lightly rests his or her finger on each of the patient’s first, third, and fifth toes for 1 to 2 seconds (FIGURE 3). Patients are instructed to respond with a “yes” when they feel the physician’s touch. In a head-to-head trial, diagnostic results of the IpTT directly paralleled those of the monofilament in detecting LOPS; IpTT was also equally sensitive and specific (k=.88, indicating almost perfect agreement; P<.0001).²⁹ The IpTT’s use of only 6 palpation points, constant availability, and accuracy make it a first-line neurologic test for rapidly screening the feet of a patient with diabetes.

Neuromuscular/musculoskeletal exam. Neuromuscular disturbances, such as a reduction in the strength of dorsiflexion and plantar flexion, may indicate a complicated neurologic compromise.⁵ In addition to being aesthetically problematic, musculoskeletal deformities such as a hammer toe, claw toe (FIGURE 4), or bunion can cause significant pain and/or gait disturbance, and can increase patients’ risk for ulceration.³⁰ These deformities also may compromise patients’ general health and grossly escalate their risk of falls and resultant injuries.^5,31 Therefore, patients who present with previously unreported musculoskeletal deformities should be referred to a specialist.³¹

Charcot neuroarthropathy is
 a devastating complication that classically presents as a hot, red, swollen foot; the redness resolves upon elevation. Also screen patients for Charcot neuroarthropathy (FIGURE 5), a devastating complication that classically presents as a hot, red, swollen foot; the redness resolves upon elevation.³² Charcot neuroarthropathy is hypothesized to be a dysregulation of normal bone metabolism typically occurring secondary to diabetic neuropathy and repetitive minor trauma.^33,34 This dysregulation leads to joint instability and disorganization of normal midfoot bone architecture.^31,32 Charcot neuroarthropathy is an urgent pathology that requires management by a foot specialist.³⁵

Vascular exam. PAD is particularly common in patients with diabetes and contributes to the development of impaired healing in up to half of foot ulcers.^13,18,36-39 Bilateral femoral, popliteal, posterior tibial, or dorsalis pedis pulses should be assessed by palpation; a diminished or absent pulse is a key indicator of vascular compromise.^40,41 An integrated care approach between foot specialists and vascular surgeons results in optimal treatment.

Patient education (1 minute)

It is imperative to include patients in their treatment process to reduce the likelihood of complications and, ultimately, decrease the incidence of amputations.^12,42 Patient education improves patients’ self-reported home care behaviors, even at the most fundamental levels.^43,44 TABLE 3^5,15,45 lists topics to cover during patient education.

A lack of appropriate patient education regarding diabetes is a factor in >90% of recurrent ulcers.Patients’ lack of understanding about self-care for diabetes is a common barrier to prevention.²³ El-Nahas et al⁴⁶ found a lack of appropriate education regarding diabetes was a factor in more than 90% of recurrent ulcers, which emphasizes the need for repeated education for at-risk patients.^47,48 Involve all levels of medical staff in the effort to educate patients on the importance of foot screenings, both at home and in-office. Even with proper patient education, many patients may be in various stages of coping with this all-consuming yet frequently asymptomatic condition, which makes the need for repeated patient education even more critical.

Who to refer, and when

After completing the 3-minute foot exam, create a treatment and follow-up plan, focusing on the need for referral to a specialist. TABLE 4 outlines suggested indications, priorities, and timelines for referral based on ADA guidelines.⁵ It incorporates the ADA’s patient risk categories (very low, low, moderate, and high risk) and also provides a recommended frequency for patient follow-ups.

Care for patients with lower extremity complications of diabetes mellitus is time-consuming and expensive. The brief exam described here can help you to rapidly identify patients at risk for these complications and prompt you to provide timely referrals to appropriate specialists.

CORRESPONDENCE
David G. Armstrong, DPM, MD, PhD, Professor, Department of Surgery, Director, Southern Arizona Limb Salvage Alliance (SALSA), 1501 N. Campbell Avenue, Tucson, AZ 85724-5072; armstrong@usa.net

Despite a high vaccination rate, pertussis is the only vaccine-preventable disease whose incidence is on the rise.^1-3 The Centers for Disease Control and Prevention (CDC) reported 48,277 laboratory-confirmed cases in 2012—the most since 1955—and 20 pertussis-related deaths.⁴ And while only 28,639 pertussis cases were reported in 2013, more than 17,000 cases had already been reported through August 15, 2014, suggesting that the incidence may again be on the rise this year.⁴

This uptick is likely due to a combination of factors, including a growing awareness of pertussis, and therefore a lower threshold for physicians to test for it. In addition, there’s some evidence that the immunity provided by the currently used pertussis vaccines may wane over time. Recently reported epidemics, including those in California this year and in 2010, as well as in Washington in 2011, have added to this concern.⁵ This article outlines what you can do to improve prevention, diagnosis, and treatment of pertussis.

A 3-stage course of disease

Bordetella pertussis is an aerobic, gram-negative bacterium that causes symptoms by producing multiple antigenic and biologically active components, including pertussis toxin, filamentous hemagglutinin, and agglutinogens. The bacteria adhere to the cilia in the respiratory tract and initiate an inflammatory cascade that paralyzes the cilia and inhibits the respiratory functions responsible for clearing secretions, largely through an immune-mediated response.

Pertussis has an incubation period of approximately 7 days, but this can last as long as 3 to 6 weeks. The 3 stages in the course of the disease are:⁶

• Catarrhal. This stage lasts 1 to 2 weeks and is characterized by coryza, sneezing, and a mild, occasional cough.
• Paroxysmal. This stage lasts 1 to 6 weeks, and is characterized by periods of severe coughing “fits” that include the inspiratory "whoop." These coughing episodes may occur more often at night and may worsen in intensity and frequency in the first 2 to 3 weeks and then gradually decrease. This stage also may include posttussive vomiting.
• Convalescent. During this stage, the cough begins to wane.

Vaccination: Don’t forget adults

The 2 vaccines used to prevent pertussis are DTaP (diphtheria-tetanus-acellular pertussis) and Tdap (tetanus-diphtheria-acellular pertussis). The difference between the 2 is that the Tdap vaccine contains a reduced dose of the diphtheria and acellular pertussis vaccines. DTaP is designed primarily for children younger than 7 years of age. Tdap is given to older children and adults. The CDC and Advisory Committee on Immunization Practices recommend that children receive 5 doses of DTaP, one dose at each of the following ages: 2, 4, 6, and 15 to 18 months and at 4 to 6 years.⁷ All adults 19 years of age and older who have not yet received a dose of Tdap should receive a single dose regardless of when they last received any immunization for tetanus or diphtheria.^7-10 A one-time Tdap booster should be given to all adults in place of a tetanus booster (TABLE 1).^7-10

What about pregnant women? Tdap should be administered to every pregnant woman between 27 to 36 weeks gestation regardless of Tdap history.^7,11 This strategy allows maternal antibodies to transfer to the infant, thus providing some protection to the newborn prior to pediatric vaccinations.

All adults ages ≥19 years who have not yet received a dose of Tdap should receive a single dose regardless of when they last received any immunization for tetanus or diphtheria. Is the vaccine becoming less effective? Since 1991, the number of cases of pertussis reported in previously vaccinated adolescents and adults has increased, which suggests waning immunity.^12,13 Another recent trial investigating the acellular pertussis vaccine found that immunity decreases dramatically 5 years after the fifth dose.¹⁴

Recommendations on who should receive pertussis vaccination have been expanded to include adolescents and adults, including pregnant women and those ages 65 and older in close contact with infants, and this should decrease the overall incidence of disease through decreased communicability.¹⁵ Current recommendations call for a single adult vaccination; however, ongoing studies are evaluating whether a booster later in life might be necessary.¹⁵

Diagnosis needs to be
 confirmed by lab testing


Any patient who reports having a persistent cough should be considered for pertussis testing and treatment, and any clinician who triages such patients should ask detailed questions about the characteristics and duration of the patient’s symptoms. Antibiotics do not appear 
to shorten the duration of pertussis symptoms unless given 
in the catarrhal phase. However, while a prolonged cough is the hallmark of pertussis, there are many other potential causes of this symptom. Therefore, diagnosis of pertussis requires a combination of clinical and laboratory testing, because clinical parameters alone are neither sensitive nor specific enough for pertussis infection.

TABLE 2¹⁶ outlines the clinical and laboratory diagnostic criteria for pertussis from the CDC and the World Health Organization. Suspect pertussis in a patient who’s had a cough for more than 14 days that includes an inspiratory “whoop.” In infants, pertussis should be suspected in those with symptoms that suggest cough and associated apnea.¹⁶ Order laboratory testing for any patients who have clinical signs or symptoms of pertussis.

Four methods of lab testing for pertussis infection are polymerase chain reaction (PCR), direct fluorescent antibody (DFA) testing, serologic testing, and culture (TABLE 3).^17-19 The sensitivity of these tests is as follows: PCR, 90% to 95%; DFA, 50% to 60%; serologic testing, 70% to 80%; and culture, 50% to 70%. The specificity is: PCR, 95% to 98%; DFA, 90% to 100%; serologic testing, 90% to 100%; and culture, 100%.

PCR is the preferred method because of its rapid turnaround and fairly high sensitivity. The reliability of PCR decreases, however, for a patient who’s had a cough for more than 2 weeks because the individual may have transitioned to the convalescent phase, when less bacterial DNA remain.

Results from DFA testing also are rapidly available, but the need for specialized equipment and a well-trained examiner of the specimen limits widespread use of this test. It also is not particularly sensitive for pertussis.

Serologic testing is less reliable in patients who have received an acellular pertussis vaccine and is not helpful in the first few weeks of infection.

The sensitivity of culture is best if the sample is collected appropriately (more on this in a bit) and within the first 2 weeks of symptoms (catarrhal stage). Culture is also very specific.

Given the strengths and weakness of the different tests, an acceptable method of laboratory confirmation is to obtain PCR and/or culture within the first 2 weeks of symptoms in all age groups.^17-20 Testing after 2 weeks should include a combination of PCR and serology.¹⁷ It is essential that the clinical specimen used for PCR or culture testing for pertussis is properly collected. (See “Collecting a swab for pertussis testing” below.²¹)

Collecting a swab for pertussis testing

The illustration below shows the correct swab and sampling method. Swab tips may be polyester (such as Dacron or rayon) or they may be nylon-flocked. Cotton-tipped or
calcium alginate swabs are not acceptable because the residue will inhibit DNA assays.²¹
The specimen must be obtained from the posterior nasopharynx and not the nares or oropharynx. The Centers for Disease Control and Prevention offers a video that demonstrates how to properly collect a specimen for testing at http://www.cdc.gov/pertussis/clinical/diagnostic-testing/specimen-collection.html.

Tx is effective when started early

Antibiotics are an effective treatment for pertussis, but they need to be started within the first few weeks of developing symptoms. Studies have not found evidence that antibiotics shorten the duration of pertussis symptoms unless they are given in the catarrhal phase.^22,23 It can be challenging to get treatment started during this window, however, because patients may put off seeking care for symptoms they perceive as only minor, such as a cough, until the disease progresses. In addition, physicians may not suspect pertussis in patients who present with a cough they have had for only a short time, and therefore may not test for it.

It may be necessary to rely on clinical suspicion when deciding whether to initiate treatment for pertussis before testing to confirm the diagnosis. For patients in whom clinical suspicion of pertussis is high and who may be in contact with high-risk individuals, it may be acceptable to begin treatment before receiving lab test results.^24,25 A recent Cochrane meta-analysis²⁶ recommended initiating treatment to render a patient who has pertussis “noninfectious” but without an expectation of diminishing symptoms.

Limited role for prophylaxis. There is little evidence that prophylactic treatment for pertussis can decrease the spread of the disease. Studies that investigated potential benefits of prophylactic treatment for pertussis have been inconclusive, except for individuals who are in close contact with an infant younger than 6 months of age who has not been fully immunized.^27,28

A macrolide antibiotic is generally used to treat pertussis (TABLE 4).^25-30 Consider starting treatment before lab results are
 in when clinicial suspicion is high and the patient may be in contact with high-risk individuals. Erythromycin had been the drug of choice, but recent studies have found similar efficacy for azithromycin and clarithromycin.²⁹ For infants younger than one month of age, azithromycin is preferred because in addition to being as effective as other macrolides, it has a better adverse effect profile.²⁹ For patients who are at least 2 months of age, trimethoprim-sulfamethoxazole is an acceptable alternative to a macrolide.

The CDC recommends that any adolescent or adult who has a cough and has had close contact with an individual with a laboratory-confirmed case of pertussis within the past 21 days should be treated.³⁰ Close contacts younger than 7 years of age who have not received the first 4 doses of the pertussis vaccine should be offered treatment.

CORRESPONDENCE
Gary Rivard, DO, Family Medicine Residency Program, Central Maine Medical Center, 76 High Street, Lewiston, ME 04282; rivardga@cmhc.org

Despite a high vaccination rate, pertussis is the only vaccine-preventable disease whose incidence is on the rise.^1-3 The Centers for Disease Control and Prevention (CDC) reported 48,277 laboratory-confirmed cases in 2012—the most since 1955—and 20 pertussis-related deaths.⁴ And while only 28,639 pertussis cases were reported in 2013, more than 17,000 cases had already been reported through August 15, 2014, suggesting that the incidence may again be on the rise this year.⁴

This uptick is likely due to a combination of factors, including a growing awareness of pertussis, and therefore a lower threshold for physicians to test for it. In addition, there’s some evidence that the immunity provided by the currently used pertussis vaccines may wane over time. Recently reported epidemics, including those in California this year and in 2010, as well as in Washington in 2011, have added to this concern.⁵ This article outlines what you can do to improve prevention, diagnosis, and treatment of pertussis.

A 3-stage course of disease

Bordetella pertussis is an aerobic, gram-negative bacterium that causes symptoms by producing multiple antigenic and biologically active components, including pertussis toxin, filamentous hemagglutinin, and agglutinogens. The bacteria adhere to the cilia in the respiratory tract and initiate an inflammatory cascade that paralyzes the cilia and inhibits the respiratory functions responsible for clearing secretions, largely through an immune-mediated response.

Pertussis has an incubation period of approximately 7 days, but this can last as long as 3 to 6 weeks. The 3 stages in the course of the disease are:⁶

• Catarrhal. This stage lasts 1 to 2 weeks and is characterized by coryza, sneezing, and a mild, occasional cough.
• Paroxysmal. This stage lasts 1 to 6 weeks, and is characterized by periods of severe coughing “fits” that include the inspiratory "whoop." These coughing episodes may occur more often at night and may worsen in intensity and frequency in the first 2 to 3 weeks and then gradually decrease. This stage also may include posttussive vomiting.
• Convalescent. During this stage, the cough begins to wane.

Vaccination: Don’t forget adults

The 2 vaccines used to prevent pertussis are DTaP (diphtheria-tetanus-acellular pertussis) and Tdap (tetanus-diphtheria-acellular pertussis). The difference between the 2 is that the Tdap vaccine contains a reduced dose of the diphtheria and acellular pertussis vaccines. DTaP is designed primarily for children younger than 7 years of age. Tdap is given to older children and adults. The CDC and Advisory Committee on Immunization Practices recommend that children receive 5 doses of DTaP, one dose at each of the following ages: 2, 4, 6, and 15 to 18 months and at 4 to 6 years.⁷ All adults 19 years of age and older who have not yet received a dose of Tdap should receive a single dose regardless of when they last received any immunization for tetanus or diphtheria.^7-10 A one-time Tdap booster should be given to all adults in place of a tetanus booster (TABLE 1).^7-10

What about pregnant women? Tdap should be administered to every pregnant woman between 27 to 36 weeks gestation regardless of Tdap history.^7,11 This strategy allows maternal antibodies to transfer to the infant, thus providing some protection to the newborn prior to pediatric vaccinations.

All adults ages ≥19 years who have not yet received a dose of Tdap should receive a single dose regardless of when they last received any immunization for tetanus or diphtheria. Is the vaccine becoming less effective? Since 1991, the number of cases of pertussis reported in previously vaccinated adolescents and adults has increased, which suggests waning immunity.^12,13 Another recent trial investigating the acellular pertussis vaccine found that immunity decreases dramatically 5 years after the fifth dose.¹⁴

Recommendations on who should receive pertussis vaccination have been expanded to include adolescents and adults, including pregnant women and those ages 65 and older in close contact with infants, and this should decrease the overall incidence of disease through decreased communicability.¹⁵ Current recommendations call for a single adult vaccination; however, ongoing studies are evaluating whether a booster later in life might be necessary.¹⁵

Diagnosis needs to be
 confirmed by lab testing


Any patient who reports having a persistent cough should be considered for pertussis testing and treatment, and any clinician who triages such patients should ask detailed questions about the characteristics and duration of the patient’s symptoms. Antibiotics do not appear 
to shorten the duration of pertussis symptoms unless given 
in the catarrhal phase. However, while a prolonged cough is the hallmark of pertussis, there are many other potential causes of this symptom. Therefore, diagnosis of pertussis requires a combination of clinical and laboratory testing, because clinical parameters alone are neither sensitive nor specific enough for pertussis infection.

TABLE 2¹⁶ outlines the clinical and laboratory diagnostic criteria for pertussis from the CDC and the World Health Organization. Suspect pertussis in a patient who’s had a cough for more than 14 days that includes an inspiratory “whoop.” In infants, pertussis should be suspected in those with symptoms that suggest cough and associated apnea.¹⁶ Order laboratory testing for any patients who have clinical signs or symptoms of pertussis.

Four methods of lab testing for pertussis infection are polymerase chain reaction (PCR), direct fluorescent antibody (DFA) testing, serologic testing, and culture (TABLE 3).^17-19 The sensitivity of these tests is as follows: PCR, 90% to 95%; DFA, 50% to 60%; serologic testing, 70% to 80%; and culture, 50% to 70%. The specificity is: PCR, 95% to 98%; DFA, 90% to 100%; serologic testing, 90% to 100%; and culture, 100%.

PCR is the preferred method because of its rapid turnaround and fairly high sensitivity. The reliability of PCR decreases, however, for a patient who’s had a cough for more than 2 weeks because the individual may have transitioned to the convalescent phase, when less bacterial DNA remain.

Results from DFA testing also are rapidly available, but the need for specialized equipment and a well-trained examiner of the specimen limits widespread use of this test. It also is not particularly sensitive for pertussis.

Serologic testing is less reliable in patients who have received an acellular pertussis vaccine and is not helpful in the first few weeks of infection.

The sensitivity of culture is best if the sample is collected appropriately (more on this in a bit) and within the first 2 weeks of symptoms (catarrhal stage). Culture is also very specific.

Given the strengths and weakness of the different tests, an acceptable method of laboratory confirmation is to obtain PCR and/or culture within the first 2 weeks of symptoms in all age groups.^17-20 Testing after 2 weeks should include a combination of PCR and serology.¹⁷ It is essential that the clinical specimen used for PCR or culture testing for pertussis is properly collected. (See “Collecting a swab for pertussis testing” below.²¹)

Collecting a swab for pertussis testing

The illustration below shows the correct swab and sampling method. Swab tips may be polyester (such as Dacron or rayon) or they may be nylon-flocked. Cotton-tipped or
calcium alginate swabs are not acceptable because the residue will inhibit DNA assays.²¹
The specimen must be obtained from the posterior nasopharynx and not the nares or oropharynx. The Centers for Disease Control and Prevention offers a video that demonstrates how to properly collect a specimen for testing at http://www.cdc.gov/pertussis/clinical/diagnostic-testing/specimen-collection.html.

Tx is effective when started early

Antibiotics are an effective treatment for pertussis, but they need to be started within the first few weeks of developing symptoms. Studies have not found evidence that antibiotics shorten the duration of pertussis symptoms unless they are given in the catarrhal phase.^22,23 It can be challenging to get treatment started during this window, however, because patients may put off seeking care for symptoms they perceive as only minor, such as a cough, until the disease progresses. In addition, physicians may not suspect pertussis in patients who present with a cough they have had for only a short time, and therefore may not test for it.

It may be necessary to rely on clinical suspicion when deciding whether to initiate treatment for pertussis before testing to confirm the diagnosis. For patients in whom clinical suspicion of pertussis is high and who may be in contact with high-risk individuals, it may be acceptable to begin treatment before receiving lab test results.^24,25 A recent Cochrane meta-analysis²⁶ recommended initiating treatment to render a patient who has pertussis “noninfectious” but without an expectation of diminishing symptoms.

Limited role for prophylaxis. There is little evidence that prophylactic treatment for pertussis can decrease the spread of the disease. Studies that investigated potential benefits of prophylactic treatment for pertussis have been inconclusive, except for individuals who are in close contact with an infant younger than 6 months of age who has not been fully immunized.^27,28

A macrolide antibiotic is generally used to treat pertussis (TABLE 4).^25-30 Consider starting treatment before lab results are
 in when clinicial suspicion is high and the patient may be in contact with high-risk individuals. Erythromycin had been the drug of choice, but recent studies have found similar efficacy for azithromycin and clarithromycin.²⁹ For infants younger than one month of age, azithromycin is preferred because in addition to being as effective as other macrolides, it has a better adverse effect profile.²⁹ For patients who are at least 2 months of age, trimethoprim-sulfamethoxazole is an acceptable alternative to a macrolide.

The CDC recommends that any adolescent or adult who has a cough and has had close contact with an individual with a laboratory-confirmed case of pertussis within the past 21 days should be treated.³⁰ Close contacts younger than 7 years of age who have not received the first 4 doses of the pertussis vaccine should be offered treatment.

CORRESPONDENCE
Gary Rivard, DO, Family Medicine Residency Program, Central Maine Medical Center, 76 High Street, Lewiston, ME 04282; rivardga@cmhc.org

Despite a high vaccination rate, pertussis is the only vaccine-preventable disease whose incidence is on the rise.^1-3 The Centers for Disease Control and Prevention (CDC) reported 48,277 laboratory-confirmed cases in 2012—the most since 1955—and 20 pertussis-related deaths.⁴ And while only 28,639 pertussis cases were reported in 2013, more than 17,000 cases had already been reported through August 15, 2014, suggesting that the incidence may again be on the rise this year.⁴

This uptick is likely due to a combination of factors, including a growing awareness of pertussis, and therefore a lower threshold for physicians to test for it. In addition, there’s some evidence that the immunity provided by the currently used pertussis vaccines may wane over time. Recently reported epidemics, including those in California this year and in 2010, as well as in Washington in 2011, have added to this concern.⁵ This article outlines what you can do to improve prevention, diagnosis, and treatment of pertussis.

A 3-stage course of disease

Bordetella pertussis is an aerobic, gram-negative bacterium that causes symptoms by producing multiple antigenic and biologically active components, including pertussis toxin, filamentous hemagglutinin, and agglutinogens. The bacteria adhere to the cilia in the respiratory tract and initiate an inflammatory cascade that paralyzes the cilia and inhibits the respiratory functions responsible for clearing secretions, largely through an immune-mediated response.

Pertussis has an incubation period of approximately 7 days, but this can last as long as 3 to 6 weeks. The 3 stages in the course of the disease are:⁶

• Catarrhal. This stage lasts 1 to 2 weeks and is characterized by coryza, sneezing, and a mild, occasional cough.
• Paroxysmal. This stage lasts 1 to 6 weeks, and is characterized by periods of severe coughing “fits” that include the inspiratory "whoop." These coughing episodes may occur more often at night and may worsen in intensity and frequency in the first 2 to 3 weeks and then gradually decrease. This stage also may include posttussive vomiting.
• Convalescent. During this stage, the cough begins to wane.

Vaccination: Don’t forget adults

The 2 vaccines used to prevent pertussis are DTaP (diphtheria-tetanus-acellular pertussis) and Tdap (tetanus-diphtheria-acellular pertussis). The difference between the 2 is that the Tdap vaccine contains a reduced dose of the diphtheria and acellular pertussis vaccines. DTaP is designed primarily for children younger than 7 years of age. Tdap is given to older children and adults. The CDC and Advisory Committee on Immunization Practices recommend that children receive 5 doses of DTaP, one dose at each of the following ages: 2, 4, 6, and 15 to 18 months and at 4 to 6 years.⁷ All adults 19 years of age and older who have not yet received a dose of Tdap should receive a single dose regardless of when they last received any immunization for tetanus or diphtheria.^7-10 A one-time Tdap booster should be given to all adults in place of a tetanus booster (TABLE 1).^7-10

What about pregnant women? Tdap should be administered to every pregnant woman between 27 to 36 weeks gestation regardless of Tdap history.^7,11 This strategy allows maternal antibodies to transfer to the infant, thus providing some protection to the newborn prior to pediatric vaccinations.

All adults ages ≥19 years who have not yet received a dose of Tdap should receive a single dose regardless of when they last received any immunization for tetanus or diphtheria. Is the vaccine becoming less effective? Since 1991, the number of cases of pertussis reported in previously vaccinated adolescents and adults has increased, which suggests waning immunity.^12,13 Another recent trial investigating the acellular pertussis vaccine found that immunity decreases dramatically 5 years after the fifth dose.¹⁴

Recommendations on who should receive pertussis vaccination have been expanded to include adolescents and adults, including pregnant women and those ages 65 and older in close contact with infants, and this should decrease the overall incidence of disease through decreased communicability.¹⁵ Current recommendations call for a single adult vaccination; however, ongoing studies are evaluating whether a booster later in life might be necessary.¹⁵

Diagnosis needs to be
 confirmed by lab testing


Any patient who reports having a persistent cough should be considered for pertussis testing and treatment, and any clinician who triages such patients should ask detailed questions about the characteristics and duration of the patient’s symptoms. Antibiotics do not appear 
to shorten the duration of pertussis symptoms unless given 
in the catarrhal phase. However, while a prolonged cough is the hallmark of pertussis, there are many other potential causes of this symptom. Therefore, diagnosis of pertussis requires a combination of clinical and laboratory testing, because clinical parameters alone are neither sensitive nor specific enough for pertussis infection.

TABLE 2¹⁶ outlines the clinical and laboratory diagnostic criteria for pertussis from the CDC and the World Health Organization. Suspect pertussis in a patient who’s had a cough for more than 14 days that includes an inspiratory “whoop.” In infants, pertussis should be suspected in those with symptoms that suggest cough and associated apnea.¹⁶ Order laboratory testing for any patients who have clinical signs or symptoms of pertussis.

Four methods of lab testing for pertussis infection are polymerase chain reaction (PCR), direct fluorescent antibody (DFA) testing, serologic testing, and culture (TABLE 3).^17-19 The sensitivity of these tests is as follows: PCR, 90% to 95%; DFA, 50% to 60%; serologic testing, 70% to 80%; and culture, 50% to 70%. The specificity is: PCR, 95% to 98%; DFA, 90% to 100%; serologic testing, 90% to 100%; and culture, 100%.

PCR is the preferred method because of its rapid turnaround and fairly high sensitivity. The reliability of PCR decreases, however, for a patient who’s had a cough for more than 2 weeks because the individual may have transitioned to the convalescent phase, when less bacterial DNA remain.

Results from DFA testing also are rapidly available, but the need for specialized equipment and a well-trained examiner of the specimen limits widespread use of this test. It also is not particularly sensitive for pertussis.

Serologic testing is less reliable in patients who have received an acellular pertussis vaccine and is not helpful in the first few weeks of infection.

The sensitivity of culture is best if the sample is collected appropriately (more on this in a bit) and within the first 2 weeks of symptoms (catarrhal stage). Culture is also very specific.

Given the strengths and weakness of the different tests, an acceptable method of laboratory confirmation is to obtain PCR and/or culture within the first 2 weeks of symptoms in all age groups.^17-20 Testing after 2 weeks should include a combination of PCR and serology.¹⁷ It is essential that the clinical specimen used for PCR or culture testing for pertussis is properly collected. (See “Collecting a swab for pertussis testing” below.²¹)

Collecting a swab for pertussis testing

The illustration below shows the correct swab and sampling method. Swab tips may be polyester (such as Dacron or rayon) or they may be nylon-flocked. Cotton-tipped or
calcium alginate swabs are not acceptable because the residue will inhibit DNA assays.²¹
The specimen must be obtained from the posterior nasopharynx and not the nares or oropharynx. The Centers for Disease Control and Prevention offers a video that demonstrates how to properly collect a specimen for testing at http://www.cdc.gov/pertussis/clinical/diagnostic-testing/specimen-collection.html.

Tx is effective when started early

Antibiotics are an effective treatment for pertussis, but they need to be started within the first few weeks of developing symptoms. Studies have not found evidence that antibiotics shorten the duration of pertussis symptoms unless they are given in the catarrhal phase.^22,23 It can be challenging to get treatment started during this window, however, because patients may put off seeking care for symptoms they perceive as only minor, such as a cough, until the disease progresses. In addition, physicians may not suspect pertussis in patients who present with a cough they have had for only a short time, and therefore may not test for it.

It may be necessary to rely on clinical suspicion when deciding whether to initiate treatment for pertussis before testing to confirm the diagnosis. For patients in whom clinical suspicion of pertussis is high and who may be in contact with high-risk individuals, it may be acceptable to begin treatment before receiving lab test results.^24,25 A recent Cochrane meta-analysis²⁶ recommended initiating treatment to render a patient who has pertussis “noninfectious” but without an expectation of diminishing symptoms.

Limited role for prophylaxis. There is little evidence that prophylactic treatment for pertussis can decrease the spread of the disease. Studies that investigated potential benefits of prophylactic treatment for pertussis have been inconclusive, except for individuals who are in close contact with an infant younger than 6 months of age who has not been fully immunized.^27,28

A macrolide antibiotic is generally used to treat pertussis (TABLE 4).^25-30 Consider starting treatment before lab results are
 in when clinicial suspicion is high and the patient may be in contact with high-risk individuals. Erythromycin had been the drug of choice, but recent studies have found similar efficacy for azithromycin and clarithromycin.²⁹ For infants younger than one month of age, azithromycin is preferred because in addition to being as effective as other macrolides, it has a better adverse effect profile.²⁹ For patients who are at least 2 months of age, trimethoprim-sulfamethoxazole is an acceptable alternative to a macrolide.

The CDC recommends that any adolescent or adult who has a cough and has had close contact with an individual with a laboratory-confirmed case of pertussis within the past 21 days should be treated.³⁰ Close contacts younger than 7 years of age who have not received the first 4 doses of the pertussis vaccine should be offered treatment.

CORRESPONDENCE
Gary Rivard, DO, Family Medicine Residency Program, Central Maine Medical Center, 76 High Street, Lewiston, ME 04282; rivardga@cmhc.org