Applied Evidence

An extensive and expensive evaluation for irritable bowel syndrome (IBS) can be avoided if your patient is aged <50 years and is not experiencing alarm symptoms (hematochezia, 10 lbs weight loss, fever, anemia, nocturnal or severe diarrhea), has not recently taken antibiotics, and has no family history of colon cancer. An algorithm ( Figure ) indicates when work-up is needed and what it should entail.

Newer medications that act on 5HT receptors have proven effective in improving quality of life (global symptom reduction). Evidence supports the use of several traditional medications to reduce individual symptoms of IBS, but not for global symptom reduction.

FIGURE
Evaluating possible irritable bowel syndrome

Who gets irritable bowel syndrome?

Ten percent to 15% of the North American population has IBS, and twice as many women as men have it.¹ Symptoms usually begin before the age of 35 years, and many patients can trace their symptoms back to childhood.² Onset in the elderly is rare.³ The disorder is responsible for approximately 50% of referrals to gastroenterologists.⁴

The company IBS keeps

Comorbid psychiatric illness is common with IBS, but few patients seek psychiatric care.⁵ Depression, anxiety, and somatoform disorders are seen in 94% of patients with IBS. IBS is common in patients with chronic fatigue syndrome (51%), fibromyalgia (49%), temporomandibular joint syndrome (64%), and chronic pelvic pain (50%).⁶ IBS often follows stressful life events,^5,7,8 such as a death in the family or divorce. It tends to be chronic, intermittent, and relapsing.³

The symptoms of IBS can overlap with those of other illnesses, including thyroid dysfunction (diarrhea or constipation), functional dyspepsia (abdominal pain), Crohn’s disease or ulcerative colitis (diarrhea, abdominal pain), celiac sprue (diarrhea), polyps and cancers (constipation or abdominal pain), and infectious diarrhea.

Elusive physiologic mechanism

Several physiologic mechanisms have been proposed for IBS symptoms: altered gut reactivity in response to luminal stimuli, hypersensitive gut with enhanced pain response, and altered brain-gut biochemical axis.⁹ Though the symptoms of irritable bowel syndrome appear to have a physiologic basis, there are no structural or biochemical markers for the disease.

Use symptom-based criteria for diagnosis

Consider a diagnosis of IBS when a patient complains of abdominal discomfort and altered bowel habits. In the absence of a structural or biochemical marker, IBS must be diagnosed according to symptom-based criteria–such as Manning, Rome I, or Rome II–which have been developed for research and epidemiologic purposes. Though their clinical utility remains unproven, these criteria (delineated in Table 1 ) are the crux of clinical diagnosis for IBS.^4,10-14 Subtypes of IBS have been described (diarrheapredominant IBS or constipation-predominant IBS), but they are not diagnostically useful, since the treatment goal is improved quality of life.

TABLE 1
Symptom-based criteria for irritable bowel syndrome

Dubious value of diagnostic tests

The literature regarding the value of diagnostic testing for IBS is controversial. Symptom-based criteria have varied in many studies, as have the criteria used to enroll patients and the measured outcomes of treatment (reduction in abdominal pain, in diarrhea, or in constipation, or improvement in quality of life). Because of these discrepancies, it is difficult to apply the literature clinically. Of the 6 landmark studies that considered the value of diagnostic testing for IBS patients,^15-20 only 2 compared IBS patients with groups of healthy controls.^17,19

Test results yield little. Most research in this area has compared the prevalence of specific illnesses in the general population with the yield of positive test results for these illnesses among persons meeting the symptom-based diagnostic criteria for IBS.

Two studies^15,16 determined the incidence of abnormal test results in patients who met the Manning or Rome I criteria for IBS. In these studies, most diagnostic tests yielded positive results in 2% (range, 0%-8.2%) of patients or less, except for thyroid and lactose intolerance testing. That is equivalent to the incidence in the general population. The prevalence of thyroid disorders and lactose malabsorption was higher in IBS patients (6% and 22%-26%, respectively), but prevalence in the general population is similarly higher (5%-9% and 25%). Based on these results, testing for thyroid disease or lactose malabsorption is indicated only for patients exhibiting symptoms of these disorders (fatigue/weight change or diarrhea related to diertary intake of dairy products, respectively).

An exception. Some clinicians propose that diagnostic testing for patients with IBS symptoms should be driven by the pretest probability of organic disease (prevalence) compared with the general population. Cash²¹ found the pretest probability of inflammatory bowel disease, colorectal cancer, and infectious diarrhea is less than 1% among IBS patients without alarm symptoms ( Table 2 ). He demonstrated that patients with IBS had a 5% pretest probability of celiac sprue compared with healthy patients (<1% prevalence). Therefore, testing for celiac sprue (eg, complete blood count, antiendomysial antibody, and antigliadin antibody) may be considered for patients with diarrhea.^6,21,22 Sigmoidoscopy,^15,17 rectal biopsy,¹⁷ and abdominal ultrasound¹⁸ have low positive yield in patients meeting the diagnostic criteria for IBS.

TABLE 2
Probability of organic disease in irritable bowel syndrome patients

How to proceed

Those under 50 years of age who have no alarm symptoms can forgo further testing. Testing for celiac sprue and lactose malabsorption might be considered for patients with diarrhea that improves or worsens with change in diet (strength of recommendation [SOR]: C).

Threshold for treatment

Treatment for IBS is indicated when both patient and physician believe global symptoms (abdominal discomfort, bloating, altered bowel habits) have diminished the quality of life (SOR: C). The goal of treatment is to alleviate all IBS symptoms (SOR: C). Treating altered bowel habits (constipation, diarrhea, and fecal urgency) without addressing other IBS symptoms (eg, abdominal pain) is inferior treatment.^23,24

Treatment options for IBS

Treatments for IBS include medications, behavior therapy, and complimentary and alternative therapies. Medications traditionally prescribed include bulking agents, anticholinergics/antispasmodics, antidiarrheals, and antidepressants. A 5HT₃ receptor antagonist and a 5HT₄ receptor partial agonist are now available. Table 3 summarizes the traditional treatments in terms of efficacy, strength of recommendations, and outcomes measured. Alternative and complimentary therapies appear in Table 4 .

As Brandt²⁴ has noted, the evidence for treatment effectiveness is difficult to review and summarize, because the quality of studies has been poor. Most studies did not use healthy control groups, and the numbers of participants were small. Many studies did not use blinded placebo groups. Outcomes measured varied among the studies, with most of them measuring reductions of individual bowel symptoms (eg, diarrhea or constipation). Quality-of-life tools were used in other studies to measure reduction in global IBS symptoms (eg, IBS Quality of Life ²⁵ ). Because of these discrepancies, there is no sound evidence for traditional therapies.

TABLE 3
Treatments for irritable bowel syndrome

TABLE 4
Complementary and alternative treatments for irritable bowel syndrome

Medications

Strength of recommendation: A. The recently approved 5HT₄ receptor agonist tegaserod (Zelnorm) is more effective than placebo at relieving global symptoms in women with constipation (number needed to treat [NNT]=3.9-17).^26-30 Diarrhea can be a serious side effect.

The 5HT₃ receptor antagonist alosetron (Lotronex) is more effective than placebo at relieving global IBS symptoms in women with diarrhea (NNT=2.5-8.3).^31-35 Severe constipation can be an adverse effect. The prescribing of alosetron is currently restricted to physicians who participate in the manufacturer’s risk management program.

In addition to these serotoninergic agents, others in this class are being developed and undergoing clinical trials. The knowledge being gained about 5HT receptors may revolutionize the care of patients with IBS.

Strength of recommendation: B. Tricyclic antidepressants are no more effective than placebo at relieving global IBS symptoms, but they do decrease abdominal pain (NNT=3.2-5).^36-39

Loperamide is no more effective than placebo at relieving IBS global symptoms, but it may be used to treat diarrhea (NNT=2.3-5).^31,40-42

Bulking agents (such as calcium polycarbophil or psyllium) are no more effective than placebo at relieving IBS global symptoms, but they may decrease constipation (NNT=2.2-8.6).^31,36,43-47

Peppermint oil may be helpful for abdominal pain, but global symptom reduction has not been demonstrated.^31,48-49 Only a few studies have looked at the use of antispasmodic agents for IBS. They are of poor quality and used small numbers with no placebo controls.^23,31,36,43

Strength of recommendation: C. There are limited studies evaluating the selective serotonin reuptake inhibitors (SSRIs) fluoxetine and paroxetine. Paroxetine was shown in 1 study to improve quality of life.⁵⁰ Fluoxetine reduced abdominal pain, but did not improve quality of life.⁵¹

Behavioral and complementary/alternative therapies

Relaxation therapy, hypnotherapy, and cognitive therapy are effective at relieving individual IBS symptoms, but have not been shown to reduce global IBS symptoms (SOR: B).^52-57 Other alternative therapies (eg, guar gum⁴⁴ [SOR: B], ginger⁴⁸ [SOR: B], and pancreatic enzymes⁴⁸ [SOR: C]) have been studied, but high-quality studies considering global improvement have not been published.

Promote self-awareness

Quality-of-life assessment should be done routinely in the care of IBS patients. Provide support, empathy, and basic behavior modification tools. Educate patients and their families on the theoretical biochemical basis of this illness, and help them connect symptoms with stressors, to facilitate lifestyle modification.

Correspondence
Keith B. Holten, MD, Clinton Memorial Hospital/University of Cincinnati Family Practice Residency, 825 W. Locust St., Wilmington, OH, 45177. E-mail: [email protected].

An extensive and expensive evaluation for irritable bowel syndrome (IBS) can be avoided if your patient is aged <50 years and is not experiencing alarm symptoms (hematochezia, 10 lbs weight loss, fever, anemia, nocturnal or severe diarrhea), has not recently taken antibiotics, and has no family history of colon cancer. An algorithm ( Figure ) indicates when work-up is needed and what it should entail.

Newer medications that act on 5HT receptors have proven effective in improving quality of life (global symptom reduction). Evidence supports the use of several traditional medications to reduce individual symptoms of IBS, but not for global symptom reduction.

FIGURE
Evaluating possible irritable bowel syndrome

Who gets irritable bowel syndrome?

Ten percent to 15% of the North American population has IBS, and twice as many women as men have it.¹ Symptoms usually begin before the age of 35 years, and many patients can trace their symptoms back to childhood.² Onset in the elderly is rare.³ The disorder is responsible for approximately 50% of referrals to gastroenterologists.⁴

The company IBS keeps

Comorbid psychiatric illness is common with IBS, but few patients seek psychiatric care.⁵ Depression, anxiety, and somatoform disorders are seen in 94% of patients with IBS. IBS is common in patients with chronic fatigue syndrome (51%), fibromyalgia (49%), temporomandibular joint syndrome (64%), and chronic pelvic pain (50%).⁶ IBS often follows stressful life events,^5,7,8 such as a death in the family or divorce. It tends to be chronic, intermittent, and relapsing.³

The symptoms of IBS can overlap with those of other illnesses, including thyroid dysfunction (diarrhea or constipation), functional dyspepsia (abdominal pain), Crohn’s disease or ulcerative colitis (diarrhea, abdominal pain), celiac sprue (diarrhea), polyps and cancers (constipation or abdominal pain), and infectious diarrhea.

Elusive physiologic mechanism

Several physiologic mechanisms have been proposed for IBS symptoms: altered gut reactivity in response to luminal stimuli, hypersensitive gut with enhanced pain response, and altered brain-gut biochemical axis.⁹ Though the symptoms of irritable bowel syndrome appear to have a physiologic basis, there are no structural or biochemical markers for the disease.

Use symptom-based criteria for diagnosis

Consider a diagnosis of IBS when a patient complains of abdominal discomfort and altered bowel habits. In the absence of a structural or biochemical marker, IBS must be diagnosed according to symptom-based criteria–such as Manning, Rome I, or Rome II–which have been developed for research and epidemiologic purposes. Though their clinical utility remains unproven, these criteria (delineated in Table 1 ) are the crux of clinical diagnosis for IBS.^4,10-14 Subtypes of IBS have been described (diarrheapredominant IBS or constipation-predominant IBS), but they are not diagnostically useful, since the treatment goal is improved quality of life.

TABLE 1
Symptom-based criteria for irritable bowel syndrome

Dubious value of diagnostic tests

The literature regarding the value of diagnostic testing for IBS is controversial. Symptom-based criteria have varied in many studies, as have the criteria used to enroll patients and the measured outcomes of treatment (reduction in abdominal pain, in diarrhea, or in constipation, or improvement in quality of life). Because of these discrepancies, it is difficult to apply the literature clinically. Of the 6 landmark studies that considered the value of diagnostic testing for IBS patients,^15-20 only 2 compared IBS patients with groups of healthy controls.^17,19

Test results yield little. Most research in this area has compared the prevalence of specific illnesses in the general population with the yield of positive test results for these illnesses among persons meeting the symptom-based diagnostic criteria for IBS.

Two studies^15,16 determined the incidence of abnormal test results in patients who met the Manning or Rome I criteria for IBS. In these studies, most diagnostic tests yielded positive results in 2% (range, 0%-8.2%) of patients or less, except for thyroid and lactose intolerance testing. That is equivalent to the incidence in the general population. The prevalence of thyroid disorders and lactose malabsorption was higher in IBS patients (6% and 22%-26%, respectively), but prevalence in the general population is similarly higher (5%-9% and 25%). Based on these results, testing for thyroid disease or lactose malabsorption is indicated only for patients exhibiting symptoms of these disorders (fatigue/weight change or diarrhea related to diertary intake of dairy products, respectively).

An exception. Some clinicians propose that diagnostic testing for patients with IBS symptoms should be driven by the pretest probability of organic disease (prevalence) compared with the general population. Cash²¹ found the pretest probability of inflammatory bowel disease, colorectal cancer, and infectious diarrhea is less than 1% among IBS patients without alarm symptoms ( Table 2 ). He demonstrated that patients with IBS had a 5% pretest probability of celiac sprue compared with healthy patients (<1% prevalence). Therefore, testing for celiac sprue (eg, complete blood count, antiendomysial antibody, and antigliadin antibody) may be considered for patients with diarrhea.^6,21,22 Sigmoidoscopy,^15,17 rectal biopsy,¹⁷ and abdominal ultrasound¹⁸ have low positive yield in patients meeting the diagnostic criteria for IBS.

TABLE 2
Probability of organic disease in irritable bowel syndrome patients

How to proceed

Those under 50 years of age who have no alarm symptoms can forgo further testing. Testing for celiac sprue and lactose malabsorption might be considered for patients with diarrhea that improves or worsens with change in diet (strength of recommendation [SOR]: C).

Threshold for treatment

Treatment for IBS is indicated when both patient and physician believe global symptoms (abdominal discomfort, bloating, altered bowel habits) have diminished the quality of life (SOR: C). The goal of treatment is to alleviate all IBS symptoms (SOR: C). Treating altered bowel habits (constipation, diarrhea, and fecal urgency) without addressing other IBS symptoms (eg, abdominal pain) is inferior treatment.^23,24

Treatment options for IBS

Treatments for IBS include medications, behavior therapy, and complimentary and alternative therapies. Medications traditionally prescribed include bulking agents, anticholinergics/antispasmodics, antidiarrheals, and antidepressants. A 5HT₃ receptor antagonist and a 5HT₄ receptor partial agonist are now available. Table 3 summarizes the traditional treatments in terms of efficacy, strength of recommendations, and outcomes measured. Alternative and complimentary therapies appear in Table 4 .

As Brandt²⁴ has noted, the evidence for treatment effectiveness is difficult to review and summarize, because the quality of studies has been poor. Most studies did not use healthy control groups, and the numbers of participants were small. Many studies did not use blinded placebo groups. Outcomes measured varied among the studies, with most of them measuring reductions of individual bowel symptoms (eg, diarrhea or constipation). Quality-of-life tools were used in other studies to measure reduction in global IBS symptoms (eg, IBS Quality of Life ²⁵ ). Because of these discrepancies, there is no sound evidence for traditional therapies.

TABLE 3
Treatments for irritable bowel syndrome

TABLE 4
Complementary and alternative treatments for irritable bowel syndrome

Medications

Strength of recommendation: A. The recently approved 5HT₄ receptor agonist tegaserod (Zelnorm) is more effective than placebo at relieving global symptoms in women with constipation (number needed to treat [NNT]=3.9-17).^26-30 Diarrhea can be a serious side effect.

The 5HT₃ receptor antagonist alosetron (Lotronex) is more effective than placebo at relieving global IBS symptoms in women with diarrhea (NNT=2.5-8.3).^31-35 Severe constipation can be an adverse effect. The prescribing of alosetron is currently restricted to physicians who participate in the manufacturer’s risk management program.

In addition to these serotoninergic agents, others in this class are being developed and undergoing clinical trials. The knowledge being gained about 5HT receptors may revolutionize the care of patients with IBS.

Strength of recommendation: B. Tricyclic antidepressants are no more effective than placebo at relieving global IBS symptoms, but they do decrease abdominal pain (NNT=3.2-5).^36-39

Loperamide is no more effective than placebo at relieving IBS global symptoms, but it may be used to treat diarrhea (NNT=2.3-5).^31,40-42

Bulking agents (such as calcium polycarbophil or psyllium) are no more effective than placebo at relieving IBS global symptoms, but they may decrease constipation (NNT=2.2-8.6).^31,36,43-47

Peppermint oil may be helpful for abdominal pain, but global symptom reduction has not been demonstrated.^31,48-49 Only a few studies have looked at the use of antispasmodic agents for IBS. They are of poor quality and used small numbers with no placebo controls.^23,31,36,43

Strength of recommendation: C. There are limited studies evaluating the selective serotonin reuptake inhibitors (SSRIs) fluoxetine and paroxetine. Paroxetine was shown in 1 study to improve quality of life.⁵⁰ Fluoxetine reduced abdominal pain, but did not improve quality of life.⁵¹

Behavioral and complementary/alternative therapies

Relaxation therapy, hypnotherapy, and cognitive therapy are effective at relieving individual IBS symptoms, but have not been shown to reduce global IBS symptoms (SOR: B).^52-57 Other alternative therapies (eg, guar gum⁴⁴ [SOR: B], ginger⁴⁸ [SOR: B], and pancreatic enzymes⁴⁸ [SOR: C]) have been studied, but high-quality studies considering global improvement have not been published.

Promote self-awareness

Quality-of-life assessment should be done routinely in the care of IBS patients. Provide support, empathy, and basic behavior modification tools. Educate patients and their families on the theoretical biochemical basis of this illness, and help them connect symptoms with stressors, to facilitate lifestyle modification.

Correspondence
Keith B. Holten, MD, Clinton Memorial Hospital/University of Cincinnati Family Practice Residency, 825 W. Locust St., Wilmington, OH, 45177. E-mail: [email protected].

An extensive and expensive evaluation for irritable bowel syndrome (IBS) can be avoided if your patient is aged <50 years and is not experiencing alarm symptoms (hematochezia, 10 lbs weight loss, fever, anemia, nocturnal or severe diarrhea), has not recently taken antibiotics, and has no family history of colon cancer. An algorithm ( Figure ) indicates when work-up is needed and what it should entail.

Newer medications that act on 5HT receptors have proven effective in improving quality of life (global symptom reduction). Evidence supports the use of several traditional medications to reduce individual symptoms of IBS, but not for global symptom reduction.

FIGURE
Evaluating possible irritable bowel syndrome

Who gets irritable bowel syndrome?

Ten percent to 15% of the North American population has IBS, and twice as many women as men have it.¹ Symptoms usually begin before the age of 35 years, and many patients can trace their symptoms back to childhood.² Onset in the elderly is rare.³ The disorder is responsible for approximately 50% of referrals to gastroenterologists.⁴

The company IBS keeps

Comorbid psychiatric illness is common with IBS, but few patients seek psychiatric care.⁵ Depression, anxiety, and somatoform disorders are seen in 94% of patients with IBS. IBS is common in patients with chronic fatigue syndrome (51%), fibromyalgia (49%), temporomandibular joint syndrome (64%), and chronic pelvic pain (50%).⁶ IBS often follows stressful life events,^5,7,8 such as a death in the family or divorce. It tends to be chronic, intermittent, and relapsing.³

The symptoms of IBS can overlap with those of other illnesses, including thyroid dysfunction (diarrhea or constipation), functional dyspepsia (abdominal pain), Crohn’s disease or ulcerative colitis (diarrhea, abdominal pain), celiac sprue (diarrhea), polyps and cancers (constipation or abdominal pain), and infectious diarrhea.

Elusive physiologic mechanism

Several physiologic mechanisms have been proposed for IBS symptoms: altered gut reactivity in response to luminal stimuli, hypersensitive gut with enhanced pain response, and altered brain-gut biochemical axis.⁹ Though the symptoms of irritable bowel syndrome appear to have a physiologic basis, there are no structural or biochemical markers for the disease.

Use symptom-based criteria for diagnosis

Consider a diagnosis of IBS when a patient complains of abdominal discomfort and altered bowel habits. In the absence of a structural or biochemical marker, IBS must be diagnosed according to symptom-based criteria–such as Manning, Rome I, or Rome II–which have been developed for research and epidemiologic purposes. Though their clinical utility remains unproven, these criteria (delineated in Table 1 ) are the crux of clinical diagnosis for IBS.^4,10-14 Subtypes of IBS have been described (diarrheapredominant IBS or constipation-predominant IBS), but they are not diagnostically useful, since the treatment goal is improved quality of life.

TABLE 1
Symptom-based criteria for irritable bowel syndrome

Dubious value of diagnostic tests

The literature regarding the value of diagnostic testing for IBS is controversial. Symptom-based criteria have varied in many studies, as have the criteria used to enroll patients and the measured outcomes of treatment (reduction in abdominal pain, in diarrhea, or in constipation, or improvement in quality of life). Because of these discrepancies, it is difficult to apply the literature clinically. Of the 6 landmark studies that considered the value of diagnostic testing for IBS patients,^15-20 only 2 compared IBS patients with groups of healthy controls.^17,19

Test results yield little. Most research in this area has compared the prevalence of specific illnesses in the general population with the yield of positive test results for these illnesses among persons meeting the symptom-based diagnostic criteria for IBS.

Two studies^15,16 determined the incidence of abnormal test results in patients who met the Manning or Rome I criteria for IBS. In these studies, most diagnostic tests yielded positive results in 2% (range, 0%-8.2%) of patients or less, except for thyroid and lactose intolerance testing. That is equivalent to the incidence in the general population. The prevalence of thyroid disorders and lactose malabsorption was higher in IBS patients (6% and 22%-26%, respectively), but prevalence in the general population is similarly higher (5%-9% and 25%). Based on these results, testing for thyroid disease or lactose malabsorption is indicated only for patients exhibiting symptoms of these disorders (fatigue/weight change or diarrhea related to diertary intake of dairy products, respectively).

An exception. Some clinicians propose that diagnostic testing for patients with IBS symptoms should be driven by the pretest probability of organic disease (prevalence) compared with the general population. Cash²¹ found the pretest probability of inflammatory bowel disease, colorectal cancer, and infectious diarrhea is less than 1% among IBS patients without alarm symptoms ( Table 2 ). He demonstrated that patients with IBS had a 5% pretest probability of celiac sprue compared with healthy patients (<1% prevalence). Therefore, testing for celiac sprue (eg, complete blood count, antiendomysial antibody, and antigliadin antibody) may be considered for patients with diarrhea.^6,21,22 Sigmoidoscopy,^15,17 rectal biopsy,¹⁷ and abdominal ultrasound¹⁸ have low positive yield in patients meeting the diagnostic criteria for IBS.

TABLE 2
Probability of organic disease in irritable bowel syndrome patients

How to proceed

Those under 50 years of age who have no alarm symptoms can forgo further testing. Testing for celiac sprue and lactose malabsorption might be considered for patients with diarrhea that improves or worsens with change in diet (strength of recommendation [SOR]: C).

Threshold for treatment

Treatment for IBS is indicated when both patient and physician believe global symptoms (abdominal discomfort, bloating, altered bowel habits) have diminished the quality of life (SOR: C). The goal of treatment is to alleviate all IBS symptoms (SOR: C). Treating altered bowel habits (constipation, diarrhea, and fecal urgency) without addressing other IBS symptoms (eg, abdominal pain) is inferior treatment.^23,24

Treatment options for IBS

Treatments for IBS include medications, behavior therapy, and complimentary and alternative therapies. Medications traditionally prescribed include bulking agents, anticholinergics/antispasmodics, antidiarrheals, and antidepressants. A 5HT₃ receptor antagonist and a 5HT₄ receptor partial agonist are now available. Table 3 summarizes the traditional treatments in terms of efficacy, strength of recommendations, and outcomes measured. Alternative and complimentary therapies appear in Table 4 .

As Brandt²⁴ has noted, the evidence for treatment effectiveness is difficult to review and summarize, because the quality of studies has been poor. Most studies did not use healthy control groups, and the numbers of participants were small. Many studies did not use blinded placebo groups. Outcomes measured varied among the studies, with most of them measuring reductions of individual bowel symptoms (eg, diarrhea or constipation). Quality-of-life tools were used in other studies to measure reduction in global IBS symptoms (eg, IBS Quality of Life ²⁵ ). Because of these discrepancies, there is no sound evidence for traditional therapies.

TABLE 3
Treatments for irritable bowel syndrome

TABLE 4
Complementary and alternative treatments for irritable bowel syndrome

Medications

Strength of recommendation: A. The recently approved 5HT₄ receptor agonist tegaserod (Zelnorm) is more effective than placebo at relieving global symptoms in women with constipation (number needed to treat [NNT]=3.9-17).^26-30 Diarrhea can be a serious side effect.

The 5HT₃ receptor antagonist alosetron (Lotronex) is more effective than placebo at relieving global IBS symptoms in women with diarrhea (NNT=2.5-8.3).^31-35 Severe constipation can be an adverse effect. The prescribing of alosetron is currently restricted to physicians who participate in the manufacturer’s risk management program.

In addition to these serotoninergic agents, others in this class are being developed and undergoing clinical trials. The knowledge being gained about 5HT receptors may revolutionize the care of patients with IBS.

Strength of recommendation: B. Tricyclic antidepressants are no more effective than placebo at relieving global IBS symptoms, but they do decrease abdominal pain (NNT=3.2-5).^36-39

Loperamide is no more effective than placebo at relieving IBS global symptoms, but it may be used to treat diarrhea (NNT=2.3-5).^31,40-42

Bulking agents (such as calcium polycarbophil or psyllium) are no more effective than placebo at relieving IBS global symptoms, but they may decrease constipation (NNT=2.2-8.6).^31,36,43-47

Peppermint oil may be helpful for abdominal pain, but global symptom reduction has not been demonstrated.^31,48-49 Only a few studies have looked at the use of antispasmodic agents for IBS. They are of poor quality and used small numbers with no placebo controls.^23,31,36,43

Strength of recommendation: C. There are limited studies evaluating the selective serotonin reuptake inhibitors (SSRIs) fluoxetine and paroxetine. Paroxetine was shown in 1 study to improve quality of life.⁵⁰ Fluoxetine reduced abdominal pain, but did not improve quality of life.⁵¹

Behavioral and complementary/alternative therapies

Relaxation therapy, hypnotherapy, and cognitive therapy are effective at relieving individual IBS symptoms, but have not been shown to reduce global IBS symptoms (SOR: B).^52-57 Other alternative therapies (eg, guar gum⁴⁴ [SOR: B], ginger⁴⁸ [SOR: B], and pancreatic enzymes⁴⁸ [SOR: C]) have been studied, but high-quality studies considering global improvement have not been published.

Promote self-awareness

Quality-of-life assessment should be done routinely in the care of IBS patients. Provide support, empathy, and basic behavior modification tools. Educate patients and their families on the theoretical biochemical basis of this illness, and help them connect symptoms with stressors, to facilitate lifestyle modification.

Correspondence
Keith B. Holten, MD, Clinton Memorial Hospital/University of Cincinnati Family Practice Residency, 825 W. Locust St., Wilmington, OH, 45177. E-mail: [email protected].

Though findings on history and physical examination are sometimes sufficient to make a diagnosis of tinea infection, a potassium hydroxide (KOH) study usually is required for confirmation. Even the KOH study can be misleading, however, if a patient recently self-administered a topical antifungal agent. This article describes the varying appearance of tinea infections according to their anatomic location, and outlines a careful work-up.

Highly effective and affordable over-the-counter medications have proliferated, and short-course therapy is available. Based on systematic reviews of randomized, controlled studies, it is possible to recommend specific first-line therapies for tinea infections.

Manifestations of tinea infection

Clinical manifestations of tinea vary with anatomic location, duration of infection, and pathogen. In general, zoophilic dermatophytes evoke a more vigorous host response than the anthropophilic species.⁵ Shared features of many dermatophyte infections include erythema, scaling, pruritus, ring formation, and central clearing of lesions. Table 1 reviews published data on the diagnostic value of selected clinical signs in suspected tinea infection.⁶

TABLE 1
Diagnostic value of selected signs and symptoms in tinea infection

Tinea pedis

Tinea of the foot may manifest as interdigital, plantar, or acute vesicular disease. Toe webs and soles of the feet are the sites most commonly affected. Tinea pedis occurs most commonly in postpubertal adolescents and adults, but may be seen in children.⁷

With interdigital infection, toe webs may become scaly, pruritic, and fissured. Interaction of bacteria and infecting dermatophytes may lead to a white, soggy maceration.⁸ Extension from the web space to the dorsal or plantar surface commonly occurs.

In chronic plantar or moccasin-type tinea pedis, the entire surface of the sole may be covered with fine, white scale and may assume a hyperkeratotic appearance. Chronic web infection may lead to acute inflammation characterized by vesicles, pustules, and bullae over the sole or the dorsum of the foot.⁵

Differential diagnosis. The differential diagnosis includes dry skin, pitted keratolysis, erythrasma, and contact dermatitis. Some conditions may appear very similar to tinea pedis, increasing the importance of KOH prep and fungal culture.

Tinea pedis may be distinguished from erythrasma by lack of bright coral appearance when examined with a Wood’s lamp. Tinea pedis infections also lack the well-demarcated erosions, or pits, of pitted keratolysis. Evidence of concurrent onychomycosis should increase the suspicion that tinea pedis is the correct diagnosis.

Tinea manuum

Tinea of the hand is usually analogous to moccasin-type tinea pedis. The palm appears hyperkeratotic and has very fine white scale that emphasizes the normal lines of the hand. Tinea of the dorsal surface of the hand usually occurs in the classic ringworm pattern. Tinea manuum is often seen in association with tinea pedis and onychomycosis. Many clinicians are familiar with the “one hand, two feet” syndrome, in which the palmar surfaces of both feet and one hand are infected (Figure 1).⁹ Onychomycosis often occurs in association with this presentation of tinea.

Differential diagnosis. The pattern of tinea manuum may be confused with those of eczema, contact dermatitis, palmar psoriasis, or even normal, rough hands. Unilateral involvement, presence of fingernail onychomycosis, lack of history indicating irritant or allergen exposure, and absence of psoriatic nail changes should increase the suspicion of palmar tinea manuum.

FIGURE 1
Tinea pedis

Tinea cruris

Tinea of the groin is most common in adult males and is promoted by a warm, moist environment. Tinea cruris begins in the crural fold and spreads onto the thigh. The interior portion of the lesion is usually erythematous or slightly brown in light-skinned individuals. The leading edge often advances in a sharply demarcated semicircle with a raised, slightly scaling border. The lesion is most often bilateral, sparing the skin of the scrotum. Pruritus is common and increases as sweat macerates the irritated skin.

Differential diagnosis. Candidiasis, intertrigo, and erythrasma can cause similar lesions. It is helpful to recall that candidiasis may involve the scrotum and penis while tinea cruris does so rarely. An additional helpful feature is the characteristic bright coral appearance of erythrasma when examined with a Wood’s lamp, absent in cases of tinea cruris.

Tinea corporis and tinea faciale

Tinea infections of the face and body begin as flat, scaly, and often pruritic macules that subsequently develop a raised border and begin to spread radially. As the ring expands, the central portion of the lesion often clears. This pattern leads to the formation of irregular circles that gives tinea corporis its common name, ringworm (Figure 2).

Tinea faciale is less common, but generally has a similar appearance with central clearing of lesions. Tinea faciale may not always exhibit the sharply demarcated border of tinea corporis.

Differential diagnosis. Eczema, impetigo, early pityriasis rosea, and localized psoriasis can mimic tinea corporis. History of exposure to persons or animals (typically house pets) with known ringworm should increase suspicion of tinea corporis. Current or past evidence of psoriasis or eczema should broaden the differential to include atypical presentations of these diseases.

FIGURE 2
Tinea corporis

Diagnosing tinea: history and exam not enough

In some cases, findings on history and physical evaluation are so characteristic of tinea that they alone may allow the clinician to make a firm diagnosis. However, studies have shown that relying upon history and physical examination may result in a many missed diagnoses.⁶ Accordingly, consider tinea in all instances of papulosquamous skin disease and follow up appropriately. Figure 3 presents a simple algorithm for diagnosis and treatment of suspected tinea infection.

FIGURE 3
Evaluating possible tinea infection of the skin

Koh preparation

An important adjunct in diagnosing tinea is the office-based KOH wet mount preparation ( Figure 4 ), permitting direct visualization of fungal hyphae in keratinized material of the stratum corneum. Detailed protocols for preparation and interpretation of the KOH slide for diagnosis of dermatophytosis are well described in many other sources.¹⁰

FIGURE 4
KOH preparation

Performing the test

The slide is prepared by combining skin scrapings from the leading edge of a lesion with a small amount of 20% potassium hydroxide. A cover slip is applied and the slide is gently heated prior to microscopy examination under high power. Table 2 summarizes the utility of clinical diagnosis and KOH preparation in diagnosis of tinea infection. History and physical examination should be combined with KOH preparation when making the diagnosis of epidermal dermatophyte infection (strength of recommendation [SOR]=B).⁶ (For an explanation of evidence ratings, see page 865.)

TABLE 2
Diagnostic value of clinical diagnosis and KOH prep in tinea infection

Caveats

Though a rapid and inexpensive test, the KOH preparation has limitations. Some physicians have little experience interpreting KOH preparations, thus reducing the value of the test. Some patients with clinically significant tinea infections may be using over-the-counter topical antifungal medications, thus reducing the likelihood that fungal hyphae will be visualized at the office visit.

In cases where clinical suspicion of tinea infection is high, and the result of a KOH prep is negative, tissue should be submitted for fungal culture. Fungal culture is not typically available in the primary care office setting and usually requires submission of the sample to a reference or hospital laboratory.

Dermatophyte test medium

Dermatophyte test medium may be prepared and used in the office. It is mixed with a phenol indicator that turns red on exposure to alkaline metabolites of fungal growth. This medium is sensitive and usually exhibits color change within one week.¹¹ Most primary care offices do not use dermatophyte test medium, however, because of its short shelf life and because the Clinical Laboratory Improvement Amendments classification requires that this test be performed by qualified laboratory personnel.

Treatment: topical and oral agents

Treatment of tinea infections may rely on antifungal medications singly or in combination. Antifungal agents are classified by their chemical structure—imidazoles, allylamines, benzylamines, and others—and act by different mechanisms to limit the availability of ergosterol, an essential component for normal function of fungal cell membranes.

Most tinea infections may be treated with topical agents alone. Oral therapy is required most often for:

• hyperkeratotic areas as on the palms or soles
• widespread or extensive infection
• immunocompromised patients
• persons intolerant of topical therapy
• failure of topical therapy
• chronic infection

Efforts to educate patients in proper hygiene and infection control may help. Specifically, remind patients that risk of tinea cruris and tinea pedis may be reduced if they wear nonocclusive footwear, use only clean and dry socks and undergarments, wear shower shoes, and apply absorbent powders. Eradication of fungal nail infections may help in controlling tinea pedis and tinea manuum. Caution in making contact with animals or people that have known tinea infections may reduce the incidence of tinea corporis.

Topical therapy

Topical antifungal agents are widely available in both prescription and over-the-counter forms. Preference of a specific agent may be difficult due to the limited number of head-to-head comparisons among these drugs. When recommending or prescribing an agent, consider efficacy, dosing regimen, cost, formulation, and availability. The most important topical antifungal agents are divided into 2 major classes—imidazoles and allylamines—although other agents are also used. Table 3 provides information on commonly used topical antifungal agents.

Imidazoles. Imidazoles are widely available as over-the-counter and prescription forms. Topical members of this class are clotrimazole, miconazole, econazole, ketoconazole, oxiconazole, and sulconazole. Miconazole and clotrimazole are available without a prescription. As a class, imidazoles are primarily fungistatic and are generally well-tolerated.¹² Meta-analysis has failed to reveal significant differences in efficacy among members of this class.¹³ Imidazoles are efficacious with a pooled relative risk of failure to cure of 0.38 at 6 weeks after the initiation of therapy for tinea pedis (level of evidence [LOE]=1a).¹³

Current guidelines recommend twice-daily application for clotrimazole, miconazole, and econazole; ketoconazole, oxiconazole, and sulconazole may be applied once daily.¹⁴ When using imidazoles, usually prescribe a 2-week course for tinea cruris or tinea corporis, and a 4-week course for tinea pedis.¹⁵ In cases of inflammatory dermatophytosis, a combination agent containing clotrimazole and the corticosteroid betamethasone dipropionate may be used for a short initial period (LOE=4).¹⁶ Many experts recommend that combination steroid agents be used with caution, for no more than a few days, and with a plan for short-term follow-up.

Allylamines. A second, newer group of antifungal agents are the allylamines. Topical allylamines, including terbinafine and naftifine, are generally considered fungicidal. Terbinafine has recently been made available over-the-counter as 1% cream and 1% solution, while naftifine remains a prescription medication. Both agents are efficacious, with cure rates for dermatomycosis greater than 75%.^17,18 Naftifine and terbinafine have exhibited long periods of activity in the skin and are therefore administered only once a day.¹⁹ Additionally, terbinafine has been shown effective in treating superficial mycoses in much shorter courses than typically required for imidazoles.²⁰

In a systematic review of available randomized controlled trials, allylamines were found to be more efficacious than imidazoles in treating tinea pedis (LOE=1a).¹³ Terbinafine has also been compared with imidazoles for treatment of tinea cruris and tinea corporis and found to be significantly more effective (LOE=1b).²¹

Previous pharmacoeconomic analyses of imidazole versus allylamine topical therapy for dermatophyte infection have presented conflicting conclusions, with some reporting that the greater cost of allylamine agents outweighs their slightly greater efficacy,²² while others concluded that the more efficacious medication initially is more cost effective.²³ In the United States, terbinafine was approved for over-the-counter sale in 1999. Since then, the cost of terbinafine to consumers has declined significantly, to the point where it is now comparable to over-the-counter imidazoles (see Table 3 ). Allylamines have demonstrated some degree of intrinsic anti-inflammatory activity.²⁴

Butenafine. Butenafine is a topical benzylamine antifungal structurally related to the allylamines. Butenafine is fungicidal and has efficacy similar to the allylamines. In a 1-week trial of therapy for tinea pedis with twice-daily butenafine, mycological cure rates in excess of 75% were observed (LOE=1b).²⁵ In a trial of short-term therapy of tinea corporis, butenafine applied once-daily for 14 days led to high cure rates, symptom improvement, and increasing effectiveness 4 weeks after therapy was concluded (LOE=1b).²⁶ In treatment of tinea cruris, butenafine was highly effective in achieving mycologic cure after 2 weeks of once-daily treatment (LOE=1b).²⁷

Few trials directly compare butenafine and other topical agents, but in stand-alone or placebo-controlled trials, butenafine has demonstrated efficacy similar to the allylamines terbinafine and naftifine. Butenafine was approved for over-the-counter sale in the United States in 2000.

Ciclopirox. Ciclopirox is a substituted pyridone unrelated to the imidazole or allylamine agents. In double-blind, placebo-controlled trials, ciclopirox demonstrated significant efficacy in treating dermatophyte infections (LOE=1b).²⁸ In head-to-head trials with the imidazole agent clotrimazole, ciclopirox demonstrated equivalent or slightly greater efficacy (LOE=1b).^29,30

Ciclopirox applied twice daily is usually effective within 4 weeks of treatment. Ciclopirox is available only by prescription in the United States and is more expensive than most other topical antifungal agents. Ciclopirox has demonstrated intrinsic antiinflammatory activity equivalent to the allylamines (LOE=1b).³¹ Due to the availability of agents with comparable or superior efficacy at much lower costs, ciclopirox should not be considered a first- or second-line agent in treating epidermal tinea infections.

Tolnaftate. Tolnaftate is an over-the-counter antifungal agent that has been available in the US since 1965. Tolnaftate is inexpensive and has often been used in powder formulation as prophylaxis against tinea, especially tinea pedis.

In systematic reviews of available placebo-controlled trials, 1% tolnaftate was shown to be less effective against tinea pedis than the azoles and allylamines, with a number needed to treat of 3.6 for tinea pedis (LOE=1a).¹³ A comparative study has shown tolnaftate to be inferior to clotrimazole in the treatment of tinea pedis.³² With its demonstrated inferiority to the azoles and allylamines, tolnaftate should not be considered a first- or second-line treatment for tinea infections.

TABLE 3
Topical antifungal medications

Oral antifungal agents

Oral antifungal agents are used for dermatophyte infections that are widespread, chronic, or markedly inflammatory, or that affect hyperkeratotic areas as in palmar or plantar tinea. They are also use for those with immuno-suppression,¹⁶ and for those in whom treatment with topical drugs has been unsatisfactory. Agents include griseofulvin, the azoles (ketoconazole, itraconazole, and fluconazole), and the allylamine terbinafine. Table 4 summarizes pertinent comparative data regarding these agents.

Griseofulvin. Griseofulvin is the oldest of the systemic antifungal agents used for tinea infections, available for more than 40 years. Griseofulvin acts on susceptible fungal cells by inhibiting microtubule function. Griseofulvin is taken by adults once daily at 500 mg, for 4 to 6 weeks, and has demonstrated efficacy in the treatment of tinea infections.³³

In a systematic review of comparative trials, oral griseofulvin was found to be significantly inferior to oral terbinafine in the treatment of tinea pedis (LOE=1a).³³ Likewise, terbinafine was found to be superior to griseofulvin in the treatment of tinea corporis and tinea cruris (LOE=1b).³⁴ In comparisons with ketoconazole, griseofulvin was equivalent in the treatment of dermatophytosis (LOE=2a).³⁵

Griseofulvin has also been compared with itraconazole in various treatment schedules for tinea corporis, tinea cruris, tinea pedis, and tinea manus; it was found to be inferior in all treatment durations to a maximum of 3 months (LOE=1b).³⁶ In head-to-head comparisons between griseofulvin and fluconazole in the treatment of tinea corporis and tinea cruris, outcomes were not statistically significantly different, although a trend toward better clinical cures in the fluconazole arm was identified (LOE=1b).³⁷

Azoles. Studies have made limited comparisons among the azoles (ketoconazole, itraconazole, and fluconazole) in the treatment of dermatophytosis. Small comparisons with limited power between itraconazole and fluconazole³⁸ and between ketoconazole and fluconazole³⁹ have demonstrated similar cure rates of about 90% for all 3 agents (LOE=1b). In a placebo-controlled comparison for treatment of tinea cruris and tinea corporis, 100 mg/d of itraconazole for 14 days was highly curative (LOE=1b).⁴⁰ In placebo-controlled trials of the treatment of tinea pedis, itraconazole was found to provide statistically significant cure rates in as little as 1 week (LOE=1b).⁴¹

Systematic review of trials between itraconazole (100 mg/d for 4 weeks) and terbinafine (250 mg/d for 2 weeks) for tinea pedis showed a non-statistically significant trend toward higher cure rate in those treated with terbinafine (LOE=1a).³³

There are limited placebo-controlled trials evaluating fluconazole in the treatment of superficial fungal infections of the skin. In an open, noncomparative trial employing once-weekly dosing of fluconazole 150 mg for 1 to 4 weeks for tinea corporis and tinea cruris, clinical cure rate was 92% with long-term clinical cure rate of 88% (LOE=2b).⁴² Another study randomized 240 adults with skin dermatophytosis or cutaneous candidiasis to either flucona-zole 150 mg/wk or fluconazole 50 mg/d for a maximum of 4 weeks (non-tinea pedis) to 6 weeks (tinea pedis) with positive clinical response of greater than 90% in both arms of treatment (LOE=2b).⁴³ Fluconazole has not been evaluated in direct comparison with terbinafine in the treatment of dermatophytic skin infections. Comparisons between azoles and griseofulvin have been discussed above.

Terbinafine. Oral terbinafine is effective in the treatment of skin dermatophytes. In a double-blind, placebo-controlled study of terbinafine 125 mg taken twice daily for 6 weeks, 65% of patients had mycologic cure at 2 weeks post-treatment (LOE=1b).⁴⁴ In an open, noncon-trolled study of terbinafine 125 mg daily for one week, 100% mycologic cure was achieved in the treatment of tinea corporis and tinea cruris (LOE=2b).⁴⁵

As noted above, terbinafine has shown efficacy superior to griseofulvin and itraconazole. No well-designed, comparative study was identified that showed any oral antifungal agent to be superior to terbinafine in the treatment of dermatophytic skin infections.

TABLE 4
Oral antifungal medications in the treatment of dermatomycosis

Summary of treatment recommendations

Based upon review of the available literature, it is recommended that clinicians consider the affordable and highly effective topical agents terbinafine and butenafine as first-line therapy for patients with uncomplicated epidermal tinea infections. While also highly effective, naftifine should be considered a second-line treatment due to its prescription-only availability and increased cost. The topical azoles clotrimazole and miconazole are marginally less effective than the allylamines, but are widely available and inexpensive. The prescription drug ciclopirox is slightly superior to the azoles, but its expense and availability make it a less desirable choice for most patients. Tolnaftate is cheap and widely available, but its relative inferiority to other topical agents limits its use in treatment of tinea infections. Tolnaftate may have some utility as a prophylactic against epidermal tinea infections in susceptible individuals.⁴⁶

For patients with complicated epidermal tinea infections as described above, or for those with confirmed infection and treatment failure using topical agents, oral antifungal medications should be used. Terbinafine and itraconazole are both highly effective and safe in treating tinea infections. Despite their relatively high cost, either of these agents may be considered first-line therapies. Fluconazole has been evaluated in limited trials, but data at this time are insufficient to recommend that it be considered a first-line agent in treatment of epidermal tinea infection.

Griseofulvin may be considered a second-line agent as it has been shown to be clearly less efficacious than either terbinafine or itraconazole. Oral ketoconazole has a limited role in the treatment of tinea infections. It has demonstrated efficacy equivalent to or slightly superior to griseofulvin, but its association with potentially severe liver injury makes it a very problematic choice.

Adverse reactions

As with any systemic medication, adverse effects may occur with oral antifungal agents. Oral antifungal agents are generally considered safe in the treatment of skin dermatophytoses. In systemic review of trials of oral antifungal agents in the treatment of tinea pedis, the most commonly identified adverse events were gastrointestinal complaints such as diarrhea or nausea, headaches, and skin complaints.³³

Of particular note, ketoconazole has been repeatedly related to potentially serious hepatotoxicity, especially when used in longer duration of treatment.⁴⁷ One large cohort study found the incident rate of acute liver injury to be 134.1 per 100,000 person-months among ketoconazole users, compared with 10.4 and 2.5 for itraconazole and terbinafine, respectively.⁴⁸ Accordingly, baseline and monthly laboratory studies are advised when using ketoconazole.⁴⁹

Serious complications associated with the use of topical antifungal agents are rare. As with any topical medication, local irritation and dermatitis may occur.

Correspondence
Brian Thomas, MD, NOLF-IB, Bldg 184, Box 357140, San Diego, Ca 92135. E-mail: [email protected].

Though findings on history and physical examination are sometimes sufficient to make a diagnosis of tinea infection, a potassium hydroxide (KOH) study usually is required for confirmation. Even the KOH study can be misleading, however, if a patient recently self-administered a topical antifungal agent. This article describes the varying appearance of tinea infections according to their anatomic location, and outlines a careful work-up.

Highly effective and affordable over-the-counter medications have proliferated, and short-course therapy is available. Based on systematic reviews of randomized, controlled studies, it is possible to recommend specific first-line therapies for tinea infections.

Manifestations of tinea infection

Clinical manifestations of tinea vary with anatomic location, duration of infection, and pathogen. In general, zoophilic dermatophytes evoke a more vigorous host response than the anthropophilic species.⁵ Shared features of many dermatophyte infections include erythema, scaling, pruritus, ring formation, and central clearing of lesions. Table 1 reviews published data on the diagnostic value of selected clinical signs in suspected tinea infection.⁶

TABLE 1
Diagnostic value of selected signs and symptoms in tinea infection

Tinea pedis

Tinea of the foot may manifest as interdigital, plantar, or acute vesicular disease. Toe webs and soles of the feet are the sites most commonly affected. Tinea pedis occurs most commonly in postpubertal adolescents and adults, but may be seen in children.⁷

With interdigital infection, toe webs may become scaly, pruritic, and fissured. Interaction of bacteria and infecting dermatophytes may lead to a white, soggy maceration.⁸ Extension from the web space to the dorsal or plantar surface commonly occurs.

In chronic plantar or moccasin-type tinea pedis, the entire surface of the sole may be covered with fine, white scale and may assume a hyperkeratotic appearance. Chronic web infection may lead to acute inflammation characterized by vesicles, pustules, and bullae over the sole or the dorsum of the foot.⁵

Differential diagnosis. The differential diagnosis includes dry skin, pitted keratolysis, erythrasma, and contact dermatitis. Some conditions may appear very similar to tinea pedis, increasing the importance of KOH prep and fungal culture.

Tinea pedis may be distinguished from erythrasma by lack of bright coral appearance when examined with a Wood’s lamp. Tinea pedis infections also lack the well-demarcated erosions, or pits, of pitted keratolysis. Evidence of concurrent onychomycosis should increase the suspicion that tinea pedis is the correct diagnosis.

Tinea manuum

Tinea of the hand is usually analogous to moccasin-type tinea pedis. The palm appears hyperkeratotic and has very fine white scale that emphasizes the normal lines of the hand. Tinea of the dorsal surface of the hand usually occurs in the classic ringworm pattern. Tinea manuum is often seen in association with tinea pedis and onychomycosis. Many clinicians are familiar with the “one hand, two feet” syndrome, in which the palmar surfaces of both feet and one hand are infected (Figure 1).⁹ Onychomycosis often occurs in association with this presentation of tinea.

Differential diagnosis. The pattern of tinea manuum may be confused with those of eczema, contact dermatitis, palmar psoriasis, or even normal, rough hands. Unilateral involvement, presence of fingernail onychomycosis, lack of history indicating irritant or allergen exposure, and absence of psoriatic nail changes should increase the suspicion of palmar tinea manuum.

FIGURE 1
Tinea pedis

Tinea cruris

Tinea of the groin is most common in adult males and is promoted by a warm, moist environment. Tinea cruris begins in the crural fold and spreads onto the thigh. The interior portion of the lesion is usually erythematous or slightly brown in light-skinned individuals. The leading edge often advances in a sharply demarcated semicircle with a raised, slightly scaling border. The lesion is most often bilateral, sparing the skin of the scrotum. Pruritus is common and increases as sweat macerates the irritated skin.

Differential diagnosis. Candidiasis, intertrigo, and erythrasma can cause similar lesions. It is helpful to recall that candidiasis may involve the scrotum and penis while tinea cruris does so rarely. An additional helpful feature is the characteristic bright coral appearance of erythrasma when examined with a Wood’s lamp, absent in cases of tinea cruris.

Tinea corporis and tinea faciale

Tinea infections of the face and body begin as flat, scaly, and often pruritic macules that subsequently develop a raised border and begin to spread radially. As the ring expands, the central portion of the lesion often clears. This pattern leads to the formation of irregular circles that gives tinea corporis its common name, ringworm (Figure 2).

Tinea faciale is less common, but generally has a similar appearance with central clearing of lesions. Tinea faciale may not always exhibit the sharply demarcated border of tinea corporis.

Differential diagnosis. Eczema, impetigo, early pityriasis rosea, and localized psoriasis can mimic tinea corporis. History of exposure to persons or animals (typically house pets) with known ringworm should increase suspicion of tinea corporis. Current or past evidence of psoriasis or eczema should broaden the differential to include atypical presentations of these diseases.

FIGURE 2
Tinea corporis

Diagnosing tinea: history and exam not enough

In some cases, findings on history and physical evaluation are so characteristic of tinea that they alone may allow the clinician to make a firm diagnosis. However, studies have shown that relying upon history and physical examination may result in a many missed diagnoses.⁶ Accordingly, consider tinea in all instances of papulosquamous skin disease and follow up appropriately. Figure 3 presents a simple algorithm for diagnosis and treatment of suspected tinea infection.

FIGURE 3
Evaluating possible tinea infection of the skin

Koh preparation

An important adjunct in diagnosing tinea is the office-based KOH wet mount preparation ( Figure 4 ), permitting direct visualization of fungal hyphae in keratinized material of the stratum corneum. Detailed protocols for preparation and interpretation of the KOH slide for diagnosis of dermatophytosis are well described in many other sources.¹⁰

FIGURE 4
KOH preparation

Performing the test

The slide is prepared by combining skin scrapings from the leading edge of a lesion with a small amount of 20% potassium hydroxide. A cover slip is applied and the slide is gently heated prior to microscopy examination under high power. Table 2 summarizes the utility of clinical diagnosis and KOH preparation in diagnosis of tinea infection. History and physical examination should be combined with KOH preparation when making the diagnosis of epidermal dermatophyte infection (strength of recommendation [SOR]=B).⁶ (For an explanation of evidence ratings, see page 865.)

TABLE 2
Diagnostic value of clinical diagnosis and KOH prep in tinea infection

Caveats

Though a rapid and inexpensive test, the KOH preparation has limitations. Some physicians have little experience interpreting KOH preparations, thus reducing the value of the test. Some patients with clinically significant tinea infections may be using over-the-counter topical antifungal medications, thus reducing the likelihood that fungal hyphae will be visualized at the office visit.

In cases where clinical suspicion of tinea infection is high, and the result of a KOH prep is negative, tissue should be submitted for fungal culture. Fungal culture is not typically available in the primary care office setting and usually requires submission of the sample to a reference or hospital laboratory.

Dermatophyte test medium

Dermatophyte test medium may be prepared and used in the office. It is mixed with a phenol indicator that turns red on exposure to alkaline metabolites of fungal growth. This medium is sensitive and usually exhibits color change within one week.¹¹ Most primary care offices do not use dermatophyte test medium, however, because of its short shelf life and because the Clinical Laboratory Improvement Amendments classification requires that this test be performed by qualified laboratory personnel.

Treatment: topical and oral agents

Treatment of tinea infections may rely on antifungal medications singly or in combination. Antifungal agents are classified by their chemical structure—imidazoles, allylamines, benzylamines, and others—and act by different mechanisms to limit the availability of ergosterol, an essential component for normal function of fungal cell membranes.

Most tinea infections may be treated with topical agents alone. Oral therapy is required most often for:

• hyperkeratotic areas as on the palms or soles
• widespread or extensive infection
• immunocompromised patients
• persons intolerant of topical therapy
• failure of topical therapy
• chronic infection

Efforts to educate patients in proper hygiene and infection control may help. Specifically, remind patients that risk of tinea cruris and tinea pedis may be reduced if they wear nonocclusive footwear, use only clean and dry socks and undergarments, wear shower shoes, and apply absorbent powders. Eradication of fungal nail infections may help in controlling tinea pedis and tinea manuum. Caution in making contact with animals or people that have known tinea infections may reduce the incidence of tinea corporis.

Topical therapy

Topical antifungal agents are widely available in both prescription and over-the-counter forms. Preference of a specific agent may be difficult due to the limited number of head-to-head comparisons among these drugs. When recommending or prescribing an agent, consider efficacy, dosing regimen, cost, formulation, and availability. The most important topical antifungal agents are divided into 2 major classes—imidazoles and allylamines—although other agents are also used. Table 3 provides information on commonly used topical antifungal agents.

Imidazoles. Imidazoles are widely available as over-the-counter and prescription forms. Topical members of this class are clotrimazole, miconazole, econazole, ketoconazole, oxiconazole, and sulconazole. Miconazole and clotrimazole are available without a prescription. As a class, imidazoles are primarily fungistatic and are generally well-tolerated.¹² Meta-analysis has failed to reveal significant differences in efficacy among members of this class.¹³ Imidazoles are efficacious with a pooled relative risk of failure to cure of 0.38 at 6 weeks after the initiation of therapy for tinea pedis (level of evidence [LOE]=1a).¹³

Current guidelines recommend twice-daily application for clotrimazole, miconazole, and econazole; ketoconazole, oxiconazole, and sulconazole may be applied once daily.¹⁴ When using imidazoles, usually prescribe a 2-week course for tinea cruris or tinea corporis, and a 4-week course for tinea pedis.¹⁵ In cases of inflammatory dermatophytosis, a combination agent containing clotrimazole and the corticosteroid betamethasone dipropionate may be used for a short initial period (LOE=4).¹⁶ Many experts recommend that combination steroid agents be used with caution, for no more than a few days, and with a plan for short-term follow-up.

Allylamines. A second, newer group of antifungal agents are the allylamines. Topical allylamines, including terbinafine and naftifine, are generally considered fungicidal. Terbinafine has recently been made available over-the-counter as 1% cream and 1% solution, while naftifine remains a prescription medication. Both agents are efficacious, with cure rates for dermatomycosis greater than 75%.^17,18 Naftifine and terbinafine have exhibited long periods of activity in the skin and are therefore administered only once a day.¹⁹ Additionally, terbinafine has been shown effective in treating superficial mycoses in much shorter courses than typically required for imidazoles.²⁰

In a systematic review of available randomized controlled trials, allylamines were found to be more efficacious than imidazoles in treating tinea pedis (LOE=1a).¹³ Terbinafine has also been compared with imidazoles for treatment of tinea cruris and tinea corporis and found to be significantly more effective (LOE=1b).²¹

Previous pharmacoeconomic analyses of imidazole versus allylamine topical therapy for dermatophyte infection have presented conflicting conclusions, with some reporting that the greater cost of allylamine agents outweighs their slightly greater efficacy,²² while others concluded that the more efficacious medication initially is more cost effective.²³ In the United States, terbinafine was approved for over-the-counter sale in 1999. Since then, the cost of terbinafine to consumers has declined significantly, to the point where it is now comparable to over-the-counter imidazoles (see Table 3 ). Allylamines have demonstrated some degree of intrinsic anti-inflammatory activity.²⁴

Butenafine. Butenafine is a topical benzylamine antifungal structurally related to the allylamines. Butenafine is fungicidal and has efficacy similar to the allylamines. In a 1-week trial of therapy for tinea pedis with twice-daily butenafine, mycological cure rates in excess of 75% were observed (LOE=1b).²⁵ In a trial of short-term therapy of tinea corporis, butenafine applied once-daily for 14 days led to high cure rates, symptom improvement, and increasing effectiveness 4 weeks after therapy was concluded (LOE=1b).²⁶ In treatment of tinea cruris, butenafine was highly effective in achieving mycologic cure after 2 weeks of once-daily treatment (LOE=1b).²⁷

Few trials directly compare butenafine and other topical agents, but in stand-alone or placebo-controlled trials, butenafine has demonstrated efficacy similar to the allylamines terbinafine and naftifine. Butenafine was approved for over-the-counter sale in the United States in 2000.

Ciclopirox. Ciclopirox is a substituted pyridone unrelated to the imidazole or allylamine agents. In double-blind, placebo-controlled trials, ciclopirox demonstrated significant efficacy in treating dermatophyte infections (LOE=1b).²⁸ In head-to-head trials with the imidazole agent clotrimazole, ciclopirox demonstrated equivalent or slightly greater efficacy (LOE=1b).^29,30

Ciclopirox applied twice daily is usually effective within 4 weeks of treatment. Ciclopirox is available only by prescription in the United States and is more expensive than most other topical antifungal agents. Ciclopirox has demonstrated intrinsic antiinflammatory activity equivalent to the allylamines (LOE=1b).³¹ Due to the availability of agents with comparable or superior efficacy at much lower costs, ciclopirox should not be considered a first- or second-line agent in treating epidermal tinea infections.

Tolnaftate. Tolnaftate is an over-the-counter antifungal agent that has been available in the US since 1965. Tolnaftate is inexpensive and has often been used in powder formulation as prophylaxis against tinea, especially tinea pedis.

In systematic reviews of available placebo-controlled trials, 1% tolnaftate was shown to be less effective against tinea pedis than the azoles and allylamines, with a number needed to treat of 3.6 for tinea pedis (LOE=1a).¹³ A comparative study has shown tolnaftate to be inferior to clotrimazole in the treatment of tinea pedis.³² With its demonstrated inferiority to the azoles and allylamines, tolnaftate should not be considered a first- or second-line treatment for tinea infections.

TABLE 3
Topical antifungal medications

Oral antifungal agents

Oral antifungal agents are used for dermatophyte infections that are widespread, chronic, or markedly inflammatory, or that affect hyperkeratotic areas as in palmar or plantar tinea. They are also use for those with immuno-suppression,¹⁶ and for those in whom treatment with topical drugs has been unsatisfactory. Agents include griseofulvin, the azoles (ketoconazole, itraconazole, and fluconazole), and the allylamine terbinafine. Table 4 summarizes pertinent comparative data regarding these agents.

Griseofulvin. Griseofulvin is the oldest of the systemic antifungal agents used for tinea infections, available for more than 40 years. Griseofulvin acts on susceptible fungal cells by inhibiting microtubule function. Griseofulvin is taken by adults once daily at 500 mg, for 4 to 6 weeks, and has demonstrated efficacy in the treatment of tinea infections.³³

In a systematic review of comparative trials, oral griseofulvin was found to be significantly inferior to oral terbinafine in the treatment of tinea pedis (LOE=1a).³³ Likewise, terbinafine was found to be superior to griseofulvin in the treatment of tinea corporis and tinea cruris (LOE=1b).³⁴ In comparisons with ketoconazole, griseofulvin was equivalent in the treatment of dermatophytosis (LOE=2a).³⁵

Griseofulvin has also been compared with itraconazole in various treatment schedules for tinea corporis, tinea cruris, tinea pedis, and tinea manus; it was found to be inferior in all treatment durations to a maximum of 3 months (LOE=1b).³⁶ In head-to-head comparisons between griseofulvin and fluconazole in the treatment of tinea corporis and tinea cruris, outcomes were not statistically significantly different, although a trend toward better clinical cures in the fluconazole arm was identified (LOE=1b).³⁷

Azoles. Studies have made limited comparisons among the azoles (ketoconazole, itraconazole, and fluconazole) in the treatment of dermatophytosis. Small comparisons with limited power between itraconazole and fluconazole³⁸ and between ketoconazole and fluconazole³⁹ have demonstrated similar cure rates of about 90% for all 3 agents (LOE=1b). In a placebo-controlled comparison for treatment of tinea cruris and tinea corporis, 100 mg/d of itraconazole for 14 days was highly curative (LOE=1b).⁴⁰ In placebo-controlled trials of the treatment of tinea pedis, itraconazole was found to provide statistically significant cure rates in as little as 1 week (LOE=1b).⁴¹

Systematic review of trials between itraconazole (100 mg/d for 4 weeks) and terbinafine (250 mg/d for 2 weeks) for tinea pedis showed a non-statistically significant trend toward higher cure rate in those treated with terbinafine (LOE=1a).³³

There are limited placebo-controlled trials evaluating fluconazole in the treatment of superficial fungal infections of the skin. In an open, noncomparative trial employing once-weekly dosing of fluconazole 150 mg for 1 to 4 weeks for tinea corporis and tinea cruris, clinical cure rate was 92% with long-term clinical cure rate of 88% (LOE=2b).⁴² Another study randomized 240 adults with skin dermatophytosis or cutaneous candidiasis to either flucona-zole 150 mg/wk or fluconazole 50 mg/d for a maximum of 4 weeks (non-tinea pedis) to 6 weeks (tinea pedis) with positive clinical response of greater than 90% in both arms of treatment (LOE=2b).⁴³ Fluconazole has not been evaluated in direct comparison with terbinafine in the treatment of dermatophytic skin infections. Comparisons between azoles and griseofulvin have been discussed above.

Terbinafine. Oral terbinafine is effective in the treatment of skin dermatophytes. In a double-blind, placebo-controlled study of terbinafine 125 mg taken twice daily for 6 weeks, 65% of patients had mycologic cure at 2 weeks post-treatment (LOE=1b).⁴⁴ In an open, noncon-trolled study of terbinafine 125 mg daily for one week, 100% mycologic cure was achieved in the treatment of tinea corporis and tinea cruris (LOE=2b).⁴⁵

As noted above, terbinafine has shown efficacy superior to griseofulvin and itraconazole. No well-designed, comparative study was identified that showed any oral antifungal agent to be superior to terbinafine in the treatment of dermatophytic skin infections.

TABLE 4
Oral antifungal medications in the treatment of dermatomycosis

Summary of treatment recommendations

Based upon review of the available literature, it is recommended that clinicians consider the affordable and highly effective topical agents terbinafine and butenafine as first-line therapy for patients with uncomplicated epidermal tinea infections. While also highly effective, naftifine should be considered a second-line treatment due to its prescription-only availability and increased cost. The topical azoles clotrimazole and miconazole are marginally less effective than the allylamines, but are widely available and inexpensive. The prescription drug ciclopirox is slightly superior to the azoles, but its expense and availability make it a less desirable choice for most patients. Tolnaftate is cheap and widely available, but its relative inferiority to other topical agents limits its use in treatment of tinea infections. Tolnaftate may have some utility as a prophylactic against epidermal tinea infections in susceptible individuals.⁴⁶

For patients with complicated epidermal tinea infections as described above, or for those with confirmed infection and treatment failure using topical agents, oral antifungal medications should be used. Terbinafine and itraconazole are both highly effective and safe in treating tinea infections. Despite their relatively high cost, either of these agents may be considered first-line therapies. Fluconazole has been evaluated in limited trials, but data at this time are insufficient to recommend that it be considered a first-line agent in treatment of epidermal tinea infection.

Griseofulvin may be considered a second-line agent as it has been shown to be clearly less efficacious than either terbinafine or itraconazole. Oral ketoconazole has a limited role in the treatment of tinea infections. It has demonstrated efficacy equivalent to or slightly superior to griseofulvin, but its association with potentially severe liver injury makes it a very problematic choice.

Adverse reactions

As with any systemic medication, adverse effects may occur with oral antifungal agents. Oral antifungal agents are generally considered safe in the treatment of skin dermatophytoses. In systemic review of trials of oral antifungal agents in the treatment of tinea pedis, the most commonly identified adverse events were gastrointestinal complaints such as diarrhea or nausea, headaches, and skin complaints.³³

Of particular note, ketoconazole has been repeatedly related to potentially serious hepatotoxicity, especially when used in longer duration of treatment.⁴⁷ One large cohort study found the incident rate of acute liver injury to be 134.1 per 100,000 person-months among ketoconazole users, compared with 10.4 and 2.5 for itraconazole and terbinafine, respectively.⁴⁸ Accordingly, baseline and monthly laboratory studies are advised when using ketoconazole.⁴⁹

Serious complications associated with the use of topical antifungal agents are rare. As with any topical medication, local irritation and dermatitis may occur.

Correspondence
Brian Thomas, MD, NOLF-IB, Bldg 184, Box 357140, San Diego, Ca 92135. E-mail: [email protected].

Though findings on history and physical examination are sometimes sufficient to make a diagnosis of tinea infection, a potassium hydroxide (KOH) study usually is required for confirmation. Even the KOH study can be misleading, however, if a patient recently self-administered a topical antifungal agent. This article describes the varying appearance of tinea infections according to their anatomic location, and outlines a careful work-up.

Highly effective and affordable over-the-counter medications have proliferated, and short-course therapy is available. Based on systematic reviews of randomized, controlled studies, it is possible to recommend specific first-line therapies for tinea infections.

Manifestations of tinea infection

Clinical manifestations of tinea vary with anatomic location, duration of infection, and pathogen. In general, zoophilic dermatophytes evoke a more vigorous host response than the anthropophilic species.⁵ Shared features of many dermatophyte infections include erythema, scaling, pruritus, ring formation, and central clearing of lesions. Table 1 reviews published data on the diagnostic value of selected clinical signs in suspected tinea infection.⁶

TABLE 1
Diagnostic value of selected signs and symptoms in tinea infection

Tinea pedis

Tinea of the foot may manifest as interdigital, plantar, or acute vesicular disease. Toe webs and soles of the feet are the sites most commonly affected. Tinea pedis occurs most commonly in postpubertal adolescents and adults, but may be seen in children.⁷

With interdigital infection, toe webs may become scaly, pruritic, and fissured. Interaction of bacteria and infecting dermatophytes may lead to a white, soggy maceration.⁸ Extension from the web space to the dorsal or plantar surface commonly occurs.

In chronic plantar or moccasin-type tinea pedis, the entire surface of the sole may be covered with fine, white scale and may assume a hyperkeratotic appearance. Chronic web infection may lead to acute inflammation characterized by vesicles, pustules, and bullae over the sole or the dorsum of the foot.⁵

Differential diagnosis. The differential diagnosis includes dry skin, pitted keratolysis, erythrasma, and contact dermatitis. Some conditions may appear very similar to tinea pedis, increasing the importance of KOH prep and fungal culture.

Tinea pedis may be distinguished from erythrasma by lack of bright coral appearance when examined with a Wood’s lamp. Tinea pedis infections also lack the well-demarcated erosions, or pits, of pitted keratolysis. Evidence of concurrent onychomycosis should increase the suspicion that tinea pedis is the correct diagnosis.

Tinea manuum

Tinea of the hand is usually analogous to moccasin-type tinea pedis. The palm appears hyperkeratotic and has very fine white scale that emphasizes the normal lines of the hand. Tinea of the dorsal surface of the hand usually occurs in the classic ringworm pattern. Tinea manuum is often seen in association with tinea pedis and onychomycosis. Many clinicians are familiar with the “one hand, two feet” syndrome, in which the palmar surfaces of both feet and one hand are infected (Figure 1).⁹ Onychomycosis often occurs in association with this presentation of tinea.

Differential diagnosis. The pattern of tinea manuum may be confused with those of eczema, contact dermatitis, palmar psoriasis, or even normal, rough hands. Unilateral involvement, presence of fingernail onychomycosis, lack of history indicating irritant or allergen exposure, and absence of psoriatic nail changes should increase the suspicion of palmar tinea manuum.

FIGURE 1
Tinea pedis

Tinea cruris

Tinea of the groin is most common in adult males and is promoted by a warm, moist environment. Tinea cruris begins in the crural fold and spreads onto the thigh. The interior portion of the lesion is usually erythematous or slightly brown in light-skinned individuals. The leading edge often advances in a sharply demarcated semicircle with a raised, slightly scaling border. The lesion is most often bilateral, sparing the skin of the scrotum. Pruritus is common and increases as sweat macerates the irritated skin.

Differential diagnosis. Candidiasis, intertrigo, and erythrasma can cause similar lesions. It is helpful to recall that candidiasis may involve the scrotum and penis while tinea cruris does so rarely. An additional helpful feature is the characteristic bright coral appearance of erythrasma when examined with a Wood’s lamp, absent in cases of tinea cruris.

Tinea corporis and tinea faciale

Tinea infections of the face and body begin as flat, scaly, and often pruritic macules that subsequently develop a raised border and begin to spread radially. As the ring expands, the central portion of the lesion often clears. This pattern leads to the formation of irregular circles that gives tinea corporis its common name, ringworm (Figure 2).

Tinea faciale is less common, but generally has a similar appearance with central clearing of lesions. Tinea faciale may not always exhibit the sharply demarcated border of tinea corporis.

Differential diagnosis. Eczema, impetigo, early pityriasis rosea, and localized psoriasis can mimic tinea corporis. History of exposure to persons or animals (typically house pets) with known ringworm should increase suspicion of tinea corporis. Current or past evidence of psoriasis or eczema should broaden the differential to include atypical presentations of these diseases.

FIGURE 2
Tinea corporis

Diagnosing tinea: history and exam not enough

In some cases, findings on history and physical evaluation are so characteristic of tinea that they alone may allow the clinician to make a firm diagnosis. However, studies have shown that relying upon history and physical examination may result in a many missed diagnoses.⁶ Accordingly, consider tinea in all instances of papulosquamous skin disease and follow up appropriately. Figure 3 presents a simple algorithm for diagnosis and treatment of suspected tinea infection.

FIGURE 3
Evaluating possible tinea infection of the skin

Koh preparation

An important adjunct in diagnosing tinea is the office-based KOH wet mount preparation ( Figure 4 ), permitting direct visualization of fungal hyphae in keratinized material of the stratum corneum. Detailed protocols for preparation and interpretation of the KOH slide for diagnosis of dermatophytosis are well described in many other sources.¹⁰

FIGURE 4
KOH preparation

Performing the test

The slide is prepared by combining skin scrapings from the leading edge of a lesion with a small amount of 20% potassium hydroxide. A cover slip is applied and the slide is gently heated prior to microscopy examination under high power. Table 2 summarizes the utility of clinical diagnosis and KOH preparation in diagnosis of tinea infection. History and physical examination should be combined with KOH preparation when making the diagnosis of epidermal dermatophyte infection (strength of recommendation [SOR]=B).⁶ (For an explanation of evidence ratings, see page 865.)

TABLE 2
Diagnostic value of clinical diagnosis and KOH prep in tinea infection

Caveats

Though a rapid and inexpensive test, the KOH preparation has limitations. Some physicians have little experience interpreting KOH preparations, thus reducing the value of the test. Some patients with clinically significant tinea infections may be using over-the-counter topical antifungal medications, thus reducing the likelihood that fungal hyphae will be visualized at the office visit.

In cases where clinical suspicion of tinea infection is high, and the result of a KOH prep is negative, tissue should be submitted for fungal culture. Fungal culture is not typically available in the primary care office setting and usually requires submission of the sample to a reference or hospital laboratory.

Dermatophyte test medium

Dermatophyte test medium may be prepared and used in the office. It is mixed with a phenol indicator that turns red on exposure to alkaline metabolites of fungal growth. This medium is sensitive and usually exhibits color change within one week.¹¹ Most primary care offices do not use dermatophyte test medium, however, because of its short shelf life and because the Clinical Laboratory Improvement Amendments classification requires that this test be performed by qualified laboratory personnel.

Treatment: topical and oral agents

Treatment of tinea infections may rely on antifungal medications singly or in combination. Antifungal agents are classified by their chemical structure—imidazoles, allylamines, benzylamines, and others—and act by different mechanisms to limit the availability of ergosterol, an essential component for normal function of fungal cell membranes.

Most tinea infections may be treated with topical agents alone. Oral therapy is required most often for:

• hyperkeratotic areas as on the palms or soles
• widespread or extensive infection
• immunocompromised patients
• persons intolerant of topical therapy
• failure of topical therapy
• chronic infection

Efforts to educate patients in proper hygiene and infection control may help. Specifically, remind patients that risk of tinea cruris and tinea pedis may be reduced if they wear nonocclusive footwear, use only clean and dry socks and undergarments, wear shower shoes, and apply absorbent powders. Eradication of fungal nail infections may help in controlling tinea pedis and tinea manuum. Caution in making contact with animals or people that have known tinea infections may reduce the incidence of tinea corporis.

Topical therapy

Topical antifungal agents are widely available in both prescription and over-the-counter forms. Preference of a specific agent may be difficult due to the limited number of head-to-head comparisons among these drugs. When recommending or prescribing an agent, consider efficacy, dosing regimen, cost, formulation, and availability. The most important topical antifungal agents are divided into 2 major classes—imidazoles and allylamines—although other agents are also used. Table 3 provides information on commonly used topical antifungal agents.

Imidazoles. Imidazoles are widely available as over-the-counter and prescription forms. Topical members of this class are clotrimazole, miconazole, econazole, ketoconazole, oxiconazole, and sulconazole. Miconazole and clotrimazole are available without a prescription. As a class, imidazoles are primarily fungistatic and are generally well-tolerated.¹² Meta-analysis has failed to reveal significant differences in efficacy among members of this class.¹³ Imidazoles are efficacious with a pooled relative risk of failure to cure of 0.38 at 6 weeks after the initiation of therapy for tinea pedis (level of evidence [LOE]=1a).¹³

Current guidelines recommend twice-daily application for clotrimazole, miconazole, and econazole; ketoconazole, oxiconazole, and sulconazole may be applied once daily.¹⁴ When using imidazoles, usually prescribe a 2-week course for tinea cruris or tinea corporis, and a 4-week course for tinea pedis.¹⁵ In cases of inflammatory dermatophytosis, a combination agent containing clotrimazole and the corticosteroid betamethasone dipropionate may be used for a short initial period (LOE=4).¹⁶ Many experts recommend that combination steroid agents be used with caution, for no more than a few days, and with a plan for short-term follow-up.

Allylamines. A second, newer group of antifungal agents are the allylamines. Topical allylamines, including terbinafine and naftifine, are generally considered fungicidal. Terbinafine has recently been made available over-the-counter as 1% cream and 1% solution, while naftifine remains a prescription medication. Both agents are efficacious, with cure rates for dermatomycosis greater than 75%.^17,18 Naftifine and terbinafine have exhibited long periods of activity in the skin and are therefore administered only once a day.¹⁹ Additionally, terbinafine has been shown effective in treating superficial mycoses in much shorter courses than typically required for imidazoles.²⁰

In a systematic review of available randomized controlled trials, allylamines were found to be more efficacious than imidazoles in treating tinea pedis (LOE=1a).¹³ Terbinafine has also been compared with imidazoles for treatment of tinea cruris and tinea corporis and found to be significantly more effective (LOE=1b).²¹

Previous pharmacoeconomic analyses of imidazole versus allylamine topical therapy for dermatophyte infection have presented conflicting conclusions, with some reporting that the greater cost of allylamine agents outweighs their slightly greater efficacy,²² while others concluded that the more efficacious medication initially is more cost effective.²³ In the United States, terbinafine was approved for over-the-counter sale in 1999. Since then, the cost of terbinafine to consumers has declined significantly, to the point where it is now comparable to over-the-counter imidazoles (see Table 3 ). Allylamines have demonstrated some degree of intrinsic anti-inflammatory activity.²⁴

Butenafine. Butenafine is a topical benzylamine antifungal structurally related to the allylamines. Butenafine is fungicidal and has efficacy similar to the allylamines. In a 1-week trial of therapy for tinea pedis with twice-daily butenafine, mycological cure rates in excess of 75% were observed (LOE=1b).²⁵ In a trial of short-term therapy of tinea corporis, butenafine applied once-daily for 14 days led to high cure rates, symptom improvement, and increasing effectiveness 4 weeks after therapy was concluded (LOE=1b).²⁶ In treatment of tinea cruris, butenafine was highly effective in achieving mycologic cure after 2 weeks of once-daily treatment (LOE=1b).²⁷

Few trials directly compare butenafine and other topical agents, but in stand-alone or placebo-controlled trials, butenafine has demonstrated efficacy similar to the allylamines terbinafine and naftifine. Butenafine was approved for over-the-counter sale in the United States in 2000.

Ciclopirox. Ciclopirox is a substituted pyridone unrelated to the imidazole or allylamine agents. In double-blind, placebo-controlled trials, ciclopirox demonstrated significant efficacy in treating dermatophyte infections (LOE=1b).²⁸ In head-to-head trials with the imidazole agent clotrimazole, ciclopirox demonstrated equivalent or slightly greater efficacy (LOE=1b).^29,30

Ciclopirox applied twice daily is usually effective within 4 weeks of treatment. Ciclopirox is available only by prescription in the United States and is more expensive than most other topical antifungal agents. Ciclopirox has demonstrated intrinsic antiinflammatory activity equivalent to the allylamines (LOE=1b).³¹ Due to the availability of agents with comparable or superior efficacy at much lower costs, ciclopirox should not be considered a first- or second-line agent in treating epidermal tinea infections.

Tolnaftate. Tolnaftate is an over-the-counter antifungal agent that has been available in the US since 1965. Tolnaftate is inexpensive and has often been used in powder formulation as prophylaxis against tinea, especially tinea pedis.

In systematic reviews of available placebo-controlled trials, 1% tolnaftate was shown to be less effective against tinea pedis than the azoles and allylamines, with a number needed to treat of 3.6 for tinea pedis (LOE=1a).¹³ A comparative study has shown tolnaftate to be inferior to clotrimazole in the treatment of tinea pedis.³² With its demonstrated inferiority to the azoles and allylamines, tolnaftate should not be considered a first- or second-line treatment for tinea infections.

TABLE 3
Topical antifungal medications

Oral antifungal agents

Oral antifungal agents are used for dermatophyte infections that are widespread, chronic, or markedly inflammatory, or that affect hyperkeratotic areas as in palmar or plantar tinea. They are also use for those with immuno-suppression,¹⁶ and for those in whom treatment with topical drugs has been unsatisfactory. Agents include griseofulvin, the azoles (ketoconazole, itraconazole, and fluconazole), and the allylamine terbinafine. Table 4 summarizes pertinent comparative data regarding these agents.

Griseofulvin. Griseofulvin is the oldest of the systemic antifungal agents used for tinea infections, available for more than 40 years. Griseofulvin acts on susceptible fungal cells by inhibiting microtubule function. Griseofulvin is taken by adults once daily at 500 mg, for 4 to 6 weeks, and has demonstrated efficacy in the treatment of tinea infections.³³

In a systematic review of comparative trials, oral griseofulvin was found to be significantly inferior to oral terbinafine in the treatment of tinea pedis (LOE=1a).³³ Likewise, terbinafine was found to be superior to griseofulvin in the treatment of tinea corporis and tinea cruris (LOE=1b).³⁴ In comparisons with ketoconazole, griseofulvin was equivalent in the treatment of dermatophytosis (LOE=2a).³⁵

Griseofulvin has also been compared with itraconazole in various treatment schedules for tinea corporis, tinea cruris, tinea pedis, and tinea manus; it was found to be inferior in all treatment durations to a maximum of 3 months (LOE=1b).³⁶ In head-to-head comparisons between griseofulvin and fluconazole in the treatment of tinea corporis and tinea cruris, outcomes were not statistically significantly different, although a trend toward better clinical cures in the fluconazole arm was identified (LOE=1b).³⁷

Azoles. Studies have made limited comparisons among the azoles (ketoconazole, itraconazole, and fluconazole) in the treatment of dermatophytosis. Small comparisons with limited power between itraconazole and fluconazole³⁸ and between ketoconazole and fluconazole³⁹ have demonstrated similar cure rates of about 90% for all 3 agents (LOE=1b). In a placebo-controlled comparison for treatment of tinea cruris and tinea corporis, 100 mg/d of itraconazole for 14 days was highly curative (LOE=1b).⁴⁰ In placebo-controlled trials of the treatment of tinea pedis, itraconazole was found to provide statistically significant cure rates in as little as 1 week (LOE=1b).⁴¹

Systematic review of trials between itraconazole (100 mg/d for 4 weeks) and terbinafine (250 mg/d for 2 weeks) for tinea pedis showed a non-statistically significant trend toward higher cure rate in those treated with terbinafine (LOE=1a).³³

There are limited placebo-controlled trials evaluating fluconazole in the treatment of superficial fungal infections of the skin. In an open, noncomparative trial employing once-weekly dosing of fluconazole 150 mg for 1 to 4 weeks for tinea corporis and tinea cruris, clinical cure rate was 92% with long-term clinical cure rate of 88% (LOE=2b).⁴² Another study randomized 240 adults with skin dermatophytosis or cutaneous candidiasis to either flucona-zole 150 mg/wk or fluconazole 50 mg/d for a maximum of 4 weeks (non-tinea pedis) to 6 weeks (tinea pedis) with positive clinical response of greater than 90% in both arms of treatment (LOE=2b).⁴³ Fluconazole has not been evaluated in direct comparison with terbinafine in the treatment of dermatophytic skin infections. Comparisons between azoles and griseofulvin have been discussed above.

Terbinafine. Oral terbinafine is effective in the treatment of skin dermatophytes. In a double-blind, placebo-controlled study of terbinafine 125 mg taken twice daily for 6 weeks, 65% of patients had mycologic cure at 2 weeks post-treatment (LOE=1b).⁴⁴ In an open, noncon-trolled study of terbinafine 125 mg daily for one week, 100% mycologic cure was achieved in the treatment of tinea corporis and tinea cruris (LOE=2b).⁴⁵

As noted above, terbinafine has shown efficacy superior to griseofulvin and itraconazole. No well-designed, comparative study was identified that showed any oral antifungal agent to be superior to terbinafine in the treatment of dermatophytic skin infections.

TABLE 4
Oral antifungal medications in the treatment of dermatomycosis

Summary of treatment recommendations

Based upon review of the available literature, it is recommended that clinicians consider the affordable and highly effective topical agents terbinafine and butenafine as first-line therapy for patients with uncomplicated epidermal tinea infections. While also highly effective, naftifine should be considered a second-line treatment due to its prescription-only availability and increased cost. The topical azoles clotrimazole and miconazole are marginally less effective than the allylamines, but are widely available and inexpensive. The prescription drug ciclopirox is slightly superior to the azoles, but its expense and availability make it a less desirable choice for most patients. Tolnaftate is cheap and widely available, but its relative inferiority to other topical agents limits its use in treatment of tinea infections. Tolnaftate may have some utility as a prophylactic against epidermal tinea infections in susceptible individuals.⁴⁶

For patients with complicated epidermal tinea infections as described above, or for those with confirmed infection and treatment failure using topical agents, oral antifungal medications should be used. Terbinafine and itraconazole are both highly effective and safe in treating tinea infections. Despite their relatively high cost, either of these agents may be considered first-line therapies. Fluconazole has been evaluated in limited trials, but data at this time are insufficient to recommend that it be considered a first-line agent in treatment of epidermal tinea infection.

Griseofulvin may be considered a second-line agent as it has been shown to be clearly less efficacious than either terbinafine or itraconazole. Oral ketoconazole has a limited role in the treatment of tinea infections. It has demonstrated efficacy equivalent to or slightly superior to griseofulvin, but its association with potentially severe liver injury makes it a very problematic choice.

Adverse reactions

As with any systemic medication, adverse effects may occur with oral antifungal agents. Oral antifungal agents are generally considered safe in the treatment of skin dermatophytoses. In systemic review of trials of oral antifungal agents in the treatment of tinea pedis, the most commonly identified adverse events were gastrointestinal complaints such as diarrhea or nausea, headaches, and skin complaints.³³

Of particular note, ketoconazole has been repeatedly related to potentially serious hepatotoxicity, especially when used in longer duration of treatment.⁴⁷ One large cohort study found the incident rate of acute liver injury to be 134.1 per 100,000 person-months among ketoconazole users, compared with 10.4 and 2.5 for itraconazole and terbinafine, respectively.⁴⁸ Accordingly, baseline and monthly laboratory studies are advised when using ketoconazole.⁴⁹

Serious complications associated with the use of topical antifungal agents are rare. As with any topical medication, local irritation and dermatitis may occur.

Correspondence
Brian Thomas, MD, NOLF-IB, Bldg 184, Box 357140, San Diego, Ca 92135. E-mail: [email protected].

In which direction, and how aggressively, should the investigation proceed when common and obvious causes of venous thromboembolism—recent surgery, trauma, immobilization, or malignancy—are absent from a patient’s history?

Two causes of hypercoagulability warrant consideration: occult malignancy and coagulation disorders resulting in thrombophilia. This review provides guidance on diagnostic testing and extent of the work-up, summarized in an algorithm (Figure).

FIGURE
Evaluating idiopathic venous thromboembolism

Malignancy and Venous Thromboembolism

Armand Trousseau first described the association between VTE and cancer nearly 150 years ago.⁵ For patients with known malignancy, a search for other possible causes of thrombosis is seldom needed (strength of recommendation [SOR]=B).

However, for individuals with idiopathic DVT or pulmonary embolism (PE), the clinician’s dilemma is in deciding how aggressively to look for occult malignancy. In a prospective study of 738 patients with objectively verified symptomatic deep vein thrombosis (DVT), cancer was the most common underlying cause and emerged as a major predictor of recurrent thrombotic events.⁶ Unfortunately, no laboratory test predicts occult cancer among patients with VTE.⁷

Risk of malignancy in per spective

Evidence of malignancy is usually discovered when taking a patient’s history and conducting a physical examination. Searching beyond the history and physical exam is seldom revealing.

In 1992, Prandoni and colleagues⁸ published a report of a study of 262 patients with symptomatic DVT, 250 of whom were followed for 2 years. One hundred seven patients had recognized nonmalignant risk factors for DVT and were not evaluated for cancer. Of the 155 patients with idiopathic venous thrombosis, 5 (3.3%) were discovered to have occult carcinoma. Malignancy was suggested in 4 of the 5 by history or physical examination.

In a similar study, Hettiarachchi et al⁹ evaluated 400 patients with confirmed DVT and found 70 (18%) had a diagnosis of cancer at the time of presentation. Of the remaining 326 patients (4 were lost to follow-up), 189 had recognized risk factors for DVT, 3 (1.6%) of whom were also found to have cancer; and 137 patients had unexplained DVT, 10 of whom (7.3%) were found to have occult carcinoma. As in the Prandoni study, most of the patients subsequently discovered to have cancer (10 of 13, 77%) had suggestive clinical findings in the history or physical examination.⁹

Venous thromboembolism and specific types of cancer

Two large, retrospective epidemiologic studies reviewed cases of thousands of patients in the Danish and Swedish National Patient Registries.^10,11 Investigators for these studies found an approximately 30% increase in the diagnosis of cancer among patients with VTE compared with the general population. Because of their large size, both of these studies were able to demonstrate a significant association between thrombosis and pancreatic, liver, and ovarian cancers.

For liver and pancreatic cancers, consensus opinion suggests that early diagnosis does not change prognosis. Similarly, although some experts recommend ultrasound and Ca-125 testing to investigate possible ovarian cancer, no data support use of these tests in ovarian cancer screening.¹²

An evaluation of the Danish National Registry data has suggested that cancer diagnosed at the time of, or within a year of, the diagnosis of VTE is usually advanced and is associated with a poor prognosis.¹³ Indeed, the authors of the Danish study concluded that for patients with VTE, “[our] pragmatic recommendation [is] to use only simple methods of screening and to look for cancer in patients with signs and symptoms of cancer.”¹³

Recommended work-up

We conclude the literature^8-13 does not support an aggressive search for hidden cancer in a patient with idiopathic VTE (SOR=B). Routine evaluation should include a careful history and physical examination. Because of their low cost, reliability, and ready availability, studies such as a complete blood count, basic chemistry panel, liver function tests, and urinalysis may be considered (SOR=B ). Examples of findings during the initial history, physical exam, and laboratory studies that should prompt further evaluation include anorexia, weight loss, cough, abdominal bloating, unexplained anemia, hyponatremia, hematuria, and abnormal liver enzymes.

Unnecessary studies. Some authorities recommend a chest radiograph in the routine evaluation for occult malignancy,⁹ but its clinical utility for patients without pulmonary symptoms has not been clearly demonstrated. Because of their expense and low test yield, we do not advocate the use of more elaborate screens for occult malignancy, such as computerized tomography, magnetic resonance imaging, or serologic tumor markers.

Caveat. In the past, nearly all patients with pulmonary embolism or DVT were hospitalized to receive treatment with continuous intravenous heparin. Presumably these patients routinely received a careful history evaluation, physical examination, and standard blood work.

With increased use of low-molecular-weight heparins (given subcutaneously once or twice daily), many individuals with VTE are candidates for treatment partially or totally on an outpatient basis.^14,15 Be sure that individuals receiving outpatient treatment for idiopathic VTE receive the same attention and routine work-up as hospitalized patients.

Coagulation disorders and Venous Thromboembolism

With advances in laboratory testing, more than half of idiopathic VTE cases can be attributed to a specific coagulation disorder. Data show that in a randomly selected group of patients with newly discovered DVT, 24% to 37% have an inherited predisposition to thrombosis.^16-19

Deficiencies in protein C, protein S, and antithrombin were the first causes of inherited thrombophilia to be identified;^20-22 however, these deficiencies are not particularly common. The most common causes of thrombophilic coagulation disorders are activated protein C resistance, the prothrombin gene G20210A mutation, and hyperhomocysteinemia.

When to look for prothrombotic defects

If, after ruling out occult malignancy, the cause of VTE remains uncertain, be judicious in deciding whether to run more tests for prothrombotic defects. We advocate pursuing further testing for patients likely to have an underlying hypercoagulable disorder, and for whom the identification of such a disorder would have management implications.

A decision to pursue testing with other patients should be made on a case-by-case basis. The yield in testing is low for many prothrombotic disorders, some tests are affected adversely by anticoagulation therapy, and the influence of a positive test result on patient management decisions remains unclear in many cases. Finally, serologic evaluation for thrombophilia would be costly if conducted for all patients with VTE, and the potential clinical benefit would be small.

Although large epidemiologic studies are lacking to help identify patients at increased risk of a hypercoagulable disorder, patients with clinically significant inherited thrombophilia tend to have VTE at a young age.^23-25

In addition, advanced age alone is often regarded as an identifiable risk factor for DVT. A recent retrospective study demonstrated the risk for DVT rose rapidly during the 6th through 8th decades of life.²⁶

We generally recommend testing for hypercoagulable disorders upon discovering one of the following findings:

• The first thrombotic event occurs when the patient is younger than 50 years
• A family history of VTE exists
• Episodes of unexplained VTE recur (SOR=C).

Activated protein C resistance (Factor V Leiden mutation)

Prevalence. Approximately 90% of cases of activated protein C resistance are due to a substitution of glutamine for arginine at position 506 on the factor V gene, the so-called Leiden mutation.²⁷

Factor V Leiden mutation varies greatly by race. In North America, this mutation is found in the heterozygous form in approximately 5% of Caucasians, 2% of Hispanics, 1% of African Americans, and less than 0.5% of Asians.²⁸ Persons heterozygous for factor V Leiden have approximately a 7-fold increase in the relative risk;²⁹ persons homozygous for the mutation have approximately an 80-fold increase in the relative risk.³⁰

Detection. Activated protein C resistance is typically assessed by mixing patient plasma with factor V-deficient plasma. This clotting assay is not affected by oral anticoagulation medication but is affected by heparin. A positive test result for activated protein C resistance typically warrants a polymerase chain reaction assay to distinguish the factor V Leiden mutation from other causes of activated protein C resistance.

Testing considerations. Although factor V Leiden mutation is the cause of activated protein C resistance in most cases, we recommend that activated protein C resistance testing be done first, as it is a less expensive and more widely available test than the DNA-based factor V Leiden mutation test. However, if a patient is taking heparin at the time of evaluation for thrombophilia, it may be necessary to defer activated protein C resistance testing or proceed directly to factor V Leiden DNA-based testing.

Prothrombin gene G2 0210A mutation

Prevalence. Like the factor V Leiden mutation, the prothrombin gene G20210A mutation is more common among Caucasians than among those of African or Asian descent.³¹ Prothrombin mutation is estimated to cause a 2.5-fold relative risk of first DVT.³²

Testing considerations. If cost or availability of the polymerase chain reaction assay are issues, a reasonable course of action would be to reserve the assay for patients with factor V Leiden mutation. Data suggest that patients with both factor V and prothrombin gene G20210A mutations are at significantly higher risk for recurrent VTE; consider prolonged anticoagulation.³³

Hyperhomocysteinemia

Evidence accumulating over the past decade has shown an increased risk of VTE with elevated homocysteine levels. A case-control study by den Heijer et al³⁴ in 1996 demonstrated a relative risk for first thrombosis of 2.5 in those with a homocysteine level above the 95th percentile of the control group’s levels (which in that study corresponded to a homocysteine level of 18.5 micromoles per liter or above). This predisposition to thrombosis has also been demonstrated in subsequent meta-analyses.^35,36

When homocysteine levels are elevated in the presence of factor V Leiden or the prothrombin gene G20210A mutation, risk of thrombosis appears to increase beyond that associated with any one defect alone, perhaps as high as 50-fold risk.^37-39

Management Implications of Test Results

If testing for activated protein C resistance is possible and the result is positive, confirmatory testing for factor V Leiden is indicated. If the patient is homozygous for factor V Leiden (rare), or is heterozygous for factor V Leiden and has the prothrombin gene G20210A defect, consider a prolonged course of anticoagulation, perhaps even for the rest of the patient’s life.

We base these suggestions on the high rate of VTE detected among individuals who are homozygous for factor V Leiden³⁰ and on a recent study that showed the relative risk of recurrent thrombosis to be 2.6 for those with factor V Leiden and prothrombin gene G20210A mutations, versus for those heterozygous for factor V Leiden alone.³³ This recent study also showed that the relative risk of recurrent thrombosis was not increased in those heterozygous for the Factor V Leiden mutation alone compared to those without this mutation.³³

If either the factor V Leiden or the prothrombin gene G20210A mutation is present, consider prolonging the planned course of anticoagulation (although the data to support this decision are less compelling). Data are limited and conflicting regarding the appropriate length and intensity of anticoagulation therapy for patients with inherited prothrombotic defects.^33,40-42 When prolonging anticoagulation for these patients, try to balance the risk of a recurrent thrombotic event with the risk of a bleeding complication from chronic anticoagulation.

Prolonged anticoagulation may also be indicated if the homocysteine level is elevated and either the factor V Leiden or the prothrombin gene G20210A mutation is present. In addition, therapy with folate, pyridoxine, and vitamin B12 should be initiated in cases of elevated homocyteine levels. We recommend the use of these vitamins based on a meta-analysis which demonstrated that folate supplementation at a dose of 0.5 mg to 5 mg/day lowered homocysteine levels by approximately 25% and vitamin B12 supplementation at a dose of 0.5 mg/day led to a further reduction of approximately 7%. In this same meta-analysis, pyridoxine at a mean dose of 16.5 mg daily did not demonstrate further lowering of the homocysteine level; however, as it is safe, inexpensive and well-tolerated, we still recommend its use.⁴³

Finally, while less common than the hypercoagulable states discussed above, the antiphospholipid antibody syndrome should be targeted as part of first-tier testing because of its clear impact on management. If the antiphospholipid antibody testing (such as the lupus anticoagulant or anticardiolipin antibody) results are positive, lifelong anticoagulation⁴⁴ and perhaps a higher target international normalized ratio are considerations.

Second-tier testing: Pursuing less common defects

If the preceding evaluation is unrevealing for a patient with high-risk characteristics, consider pursuing “second-tier” testing. Such testing may include functional and immunologic assays for protein C, protein S, and anti-thrombin III deficiencies, all of which are heterozygous abnormalities caused by multiple mutations and, thus, not detectable with genetic assays.

Patients will likely be taking anticoagulation medication when these tests are administered; thus, test results must be interpreted with caution. Testing for these deficiencies is most reliable if conducted at least 2 weeks after anticoagulation has been discontinued. Again, the incidence of protein C, protein S, and antithrombin III deficiencies is low, and the yield of testing therefore is also likely to be low.

We would not recommend discontinuing anticoagulation to conduct testing for these uncommon defects once it has been initiated following an acute thrombotic event. Rather, testing should be pursued once the planned course of anticoagulation with warfarin has been completed (for example, 6 to 9 months).

Other inherited thrombophilic disorders include heparin cofactor II deficiency, plasminogen deficiency, dysfibrinogenemia, factor XII deficiency, and increased factor VIII coagulant activity. These disorders are rare and their clinical importance remains unclear. Testing for these disorders, if desired, is best conducted in consultation with a hematologist or coagulation specialist.

Corresponding author
Charles F.S. Locke, MD, Johns Hopkins Community Physicians, 2360 W. Joppa Rd., Baltimore, MD 21093. E-mail: [email protected].

In which direction, and how aggressively, should the investigation proceed when common and obvious causes of venous thromboembolism—recent surgery, trauma, immobilization, or malignancy—are absent from a patient’s history?

Two causes of hypercoagulability warrant consideration: occult malignancy and coagulation disorders resulting in thrombophilia. This review provides guidance on diagnostic testing and extent of the work-up, summarized in an algorithm (Figure).

FIGURE
Evaluating idiopathic venous thromboembolism

Malignancy and Venous Thromboembolism

Armand Trousseau first described the association between VTE and cancer nearly 150 years ago.⁵ For patients with known malignancy, a search for other possible causes of thrombosis is seldom needed (strength of recommendation [SOR]=B).

However, for individuals with idiopathic DVT or pulmonary embolism (PE), the clinician’s dilemma is in deciding how aggressively to look for occult malignancy. In a prospective study of 738 patients with objectively verified symptomatic deep vein thrombosis (DVT), cancer was the most common underlying cause and emerged as a major predictor of recurrent thrombotic events.⁶ Unfortunately, no laboratory test predicts occult cancer among patients with VTE.⁷

Risk of malignancy in per spective

Evidence of malignancy is usually discovered when taking a patient’s history and conducting a physical examination. Searching beyond the history and physical exam is seldom revealing.

In 1992, Prandoni and colleagues⁸ published a report of a study of 262 patients with symptomatic DVT, 250 of whom were followed for 2 years. One hundred seven patients had recognized nonmalignant risk factors for DVT and were not evaluated for cancer. Of the 155 patients with idiopathic venous thrombosis, 5 (3.3%) were discovered to have occult carcinoma. Malignancy was suggested in 4 of the 5 by history or physical examination.

In a similar study, Hettiarachchi et al⁹ evaluated 400 patients with confirmed DVT and found 70 (18%) had a diagnosis of cancer at the time of presentation. Of the remaining 326 patients (4 were lost to follow-up), 189 had recognized risk factors for DVT, 3 (1.6%) of whom were also found to have cancer; and 137 patients had unexplained DVT, 10 of whom (7.3%) were found to have occult carcinoma. As in the Prandoni study, most of the patients subsequently discovered to have cancer (10 of 13, 77%) had suggestive clinical findings in the history or physical examination.⁹

Venous thromboembolism and specific types of cancer

Two large, retrospective epidemiologic studies reviewed cases of thousands of patients in the Danish and Swedish National Patient Registries.^10,11 Investigators for these studies found an approximately 30% increase in the diagnosis of cancer among patients with VTE compared with the general population. Because of their large size, both of these studies were able to demonstrate a significant association between thrombosis and pancreatic, liver, and ovarian cancers.

For liver and pancreatic cancers, consensus opinion suggests that early diagnosis does not change prognosis. Similarly, although some experts recommend ultrasound and Ca-125 testing to investigate possible ovarian cancer, no data support use of these tests in ovarian cancer screening.¹²

An evaluation of the Danish National Registry data has suggested that cancer diagnosed at the time of, or within a year of, the diagnosis of VTE is usually advanced and is associated with a poor prognosis.¹³ Indeed, the authors of the Danish study concluded that for patients with VTE, “[our] pragmatic recommendation [is] to use only simple methods of screening and to look for cancer in patients with signs and symptoms of cancer.”¹³

Recommended work-up

We conclude the literature^8-13 does not support an aggressive search for hidden cancer in a patient with idiopathic VTE (SOR=B). Routine evaluation should include a careful history and physical examination. Because of their low cost, reliability, and ready availability, studies such as a complete blood count, basic chemistry panel, liver function tests, and urinalysis may be considered (SOR=B ). Examples of findings during the initial history, physical exam, and laboratory studies that should prompt further evaluation include anorexia, weight loss, cough, abdominal bloating, unexplained anemia, hyponatremia, hematuria, and abnormal liver enzymes.

Unnecessary studies. Some authorities recommend a chest radiograph in the routine evaluation for occult malignancy,⁹ but its clinical utility for patients without pulmonary symptoms has not been clearly demonstrated. Because of their expense and low test yield, we do not advocate the use of more elaborate screens for occult malignancy, such as computerized tomography, magnetic resonance imaging, or serologic tumor markers.

Caveat. In the past, nearly all patients with pulmonary embolism or DVT were hospitalized to receive treatment with continuous intravenous heparin. Presumably these patients routinely received a careful history evaluation, physical examination, and standard blood work.

With increased use of low-molecular-weight heparins (given subcutaneously once or twice daily), many individuals with VTE are candidates for treatment partially or totally on an outpatient basis.^14,15 Be sure that individuals receiving outpatient treatment for idiopathic VTE receive the same attention and routine work-up as hospitalized patients.

Coagulation disorders and Venous Thromboembolism

With advances in laboratory testing, more than half of idiopathic VTE cases can be attributed to a specific coagulation disorder. Data show that in a randomly selected group of patients with newly discovered DVT, 24% to 37% have an inherited predisposition to thrombosis.^16-19

Deficiencies in protein C, protein S, and antithrombin were the first causes of inherited thrombophilia to be identified;^20-22 however, these deficiencies are not particularly common. The most common causes of thrombophilic coagulation disorders are activated protein C resistance, the prothrombin gene G20210A mutation, and hyperhomocysteinemia.

When to look for prothrombotic defects

If, after ruling out occult malignancy, the cause of VTE remains uncertain, be judicious in deciding whether to run more tests for prothrombotic defects. We advocate pursuing further testing for patients likely to have an underlying hypercoagulable disorder, and for whom the identification of such a disorder would have management implications.

A decision to pursue testing with other patients should be made on a case-by-case basis. The yield in testing is low for many prothrombotic disorders, some tests are affected adversely by anticoagulation therapy, and the influence of a positive test result on patient management decisions remains unclear in many cases. Finally, serologic evaluation for thrombophilia would be costly if conducted for all patients with VTE, and the potential clinical benefit would be small.

Although large epidemiologic studies are lacking to help identify patients at increased risk of a hypercoagulable disorder, patients with clinically significant inherited thrombophilia tend to have VTE at a young age.^23-25

In addition, advanced age alone is often regarded as an identifiable risk factor for DVT. A recent retrospective study demonstrated the risk for DVT rose rapidly during the 6th through 8th decades of life.²⁶

We generally recommend testing for hypercoagulable disorders upon discovering one of the following findings:

• The first thrombotic event occurs when the patient is younger than 50 years
• A family history of VTE exists
• Episodes of unexplained VTE recur (SOR=C).

Activated protein C resistance (Factor V Leiden mutation)

Prevalence. Approximately 90% of cases of activated protein C resistance are due to a substitution of glutamine for arginine at position 506 on the factor V gene, the so-called Leiden mutation.²⁷

Factor V Leiden mutation varies greatly by race. In North America, this mutation is found in the heterozygous form in approximately 5% of Caucasians, 2% of Hispanics, 1% of African Americans, and less than 0.5% of Asians.²⁸ Persons heterozygous for factor V Leiden have approximately a 7-fold increase in the relative risk;²⁹ persons homozygous for the mutation have approximately an 80-fold increase in the relative risk.³⁰

Detection. Activated protein C resistance is typically assessed by mixing patient plasma with factor V-deficient plasma. This clotting assay is not affected by oral anticoagulation medication but is affected by heparin. A positive test result for activated protein C resistance typically warrants a polymerase chain reaction assay to distinguish the factor V Leiden mutation from other causes of activated protein C resistance.

Testing considerations. Although factor V Leiden mutation is the cause of activated protein C resistance in most cases, we recommend that activated protein C resistance testing be done first, as it is a less expensive and more widely available test than the DNA-based factor V Leiden mutation test. However, if a patient is taking heparin at the time of evaluation for thrombophilia, it may be necessary to defer activated protein C resistance testing or proceed directly to factor V Leiden DNA-based testing.

Prothrombin gene G2 0210A mutation

Prevalence. Like the factor V Leiden mutation, the prothrombin gene G20210A mutation is more common among Caucasians than among those of African or Asian descent.³¹ Prothrombin mutation is estimated to cause a 2.5-fold relative risk of first DVT.³²

Testing considerations. If cost or availability of the polymerase chain reaction assay are issues, a reasonable course of action would be to reserve the assay for patients with factor V Leiden mutation. Data suggest that patients with both factor V and prothrombin gene G20210A mutations are at significantly higher risk for recurrent VTE; consider prolonged anticoagulation.³³

Hyperhomocysteinemia

Evidence accumulating over the past decade has shown an increased risk of VTE with elevated homocysteine levels. A case-control study by den Heijer et al³⁴ in 1996 demonstrated a relative risk for first thrombosis of 2.5 in those with a homocysteine level above the 95th percentile of the control group’s levels (which in that study corresponded to a homocysteine level of 18.5 micromoles per liter or above). This predisposition to thrombosis has also been demonstrated in subsequent meta-analyses.^35,36

When homocysteine levels are elevated in the presence of factor V Leiden or the prothrombin gene G20210A mutation, risk of thrombosis appears to increase beyond that associated with any one defect alone, perhaps as high as 50-fold risk.^37-39

Management Implications of Test Results

If testing for activated protein C resistance is possible and the result is positive, confirmatory testing for factor V Leiden is indicated. If the patient is homozygous for factor V Leiden (rare), or is heterozygous for factor V Leiden and has the prothrombin gene G20210A defect, consider a prolonged course of anticoagulation, perhaps even for the rest of the patient’s life.

We base these suggestions on the high rate of VTE detected among individuals who are homozygous for factor V Leiden³⁰ and on a recent study that showed the relative risk of recurrent thrombosis to be 2.6 for those with factor V Leiden and prothrombin gene G20210A mutations, versus for those heterozygous for factor V Leiden alone.³³ This recent study also showed that the relative risk of recurrent thrombosis was not increased in those heterozygous for the Factor V Leiden mutation alone compared to those without this mutation.³³

If either the factor V Leiden or the prothrombin gene G20210A mutation is present, consider prolonging the planned course of anticoagulation (although the data to support this decision are less compelling). Data are limited and conflicting regarding the appropriate length and intensity of anticoagulation therapy for patients with inherited prothrombotic defects.^33,40-42 When prolonging anticoagulation for these patients, try to balance the risk of a recurrent thrombotic event with the risk of a bleeding complication from chronic anticoagulation.

Prolonged anticoagulation may also be indicated if the homocysteine level is elevated and either the factor V Leiden or the prothrombin gene G20210A mutation is present. In addition, therapy with folate, pyridoxine, and vitamin B12 should be initiated in cases of elevated homocyteine levels. We recommend the use of these vitamins based on a meta-analysis which demonstrated that folate supplementation at a dose of 0.5 mg to 5 mg/day lowered homocysteine levels by approximately 25% and vitamin B12 supplementation at a dose of 0.5 mg/day led to a further reduction of approximately 7%. In this same meta-analysis, pyridoxine at a mean dose of 16.5 mg daily did not demonstrate further lowering of the homocysteine level; however, as it is safe, inexpensive and well-tolerated, we still recommend its use.⁴³

Finally, while less common than the hypercoagulable states discussed above, the antiphospholipid antibody syndrome should be targeted as part of first-tier testing because of its clear impact on management. If the antiphospholipid antibody testing (such as the lupus anticoagulant or anticardiolipin antibody) results are positive, lifelong anticoagulation⁴⁴ and perhaps a higher target international normalized ratio are considerations.

Second-tier testing: Pursuing less common defects

If the preceding evaluation is unrevealing for a patient with high-risk characteristics, consider pursuing “second-tier” testing. Such testing may include functional and immunologic assays for protein C, protein S, and anti-thrombin III deficiencies, all of which are heterozygous abnormalities caused by multiple mutations and, thus, not detectable with genetic assays.

Patients will likely be taking anticoagulation medication when these tests are administered; thus, test results must be interpreted with caution. Testing for these deficiencies is most reliable if conducted at least 2 weeks after anticoagulation has been discontinued. Again, the incidence of protein C, protein S, and antithrombin III deficiencies is low, and the yield of testing therefore is also likely to be low.

We would not recommend discontinuing anticoagulation to conduct testing for these uncommon defects once it has been initiated following an acute thrombotic event. Rather, testing should be pursued once the planned course of anticoagulation with warfarin has been completed (for example, 6 to 9 months).

Other inherited thrombophilic disorders include heparin cofactor II deficiency, plasminogen deficiency, dysfibrinogenemia, factor XII deficiency, and increased factor VIII coagulant activity. These disorders are rare and their clinical importance remains unclear. Testing for these disorders, if desired, is best conducted in consultation with a hematologist or coagulation specialist.

Corresponding author
Charles F.S. Locke, MD, Johns Hopkins Community Physicians, 2360 W. Joppa Rd., Baltimore, MD 21093. E-mail: [email protected].

In which direction, and how aggressively, should the investigation proceed when common and obvious causes of venous thromboembolism—recent surgery, trauma, immobilization, or malignancy—are absent from a patient’s history?

Two causes of hypercoagulability warrant consideration: occult malignancy and coagulation disorders resulting in thrombophilia. This review provides guidance on diagnostic testing and extent of the work-up, summarized in an algorithm (Figure).

FIGURE
Evaluating idiopathic venous thromboembolism

Malignancy and Venous Thromboembolism

Armand Trousseau first described the association between VTE and cancer nearly 150 years ago.⁵ For patients with known malignancy, a search for other possible causes of thrombosis is seldom needed (strength of recommendation [SOR]=B).

However, for individuals with idiopathic DVT or pulmonary embolism (PE), the clinician’s dilemma is in deciding how aggressively to look for occult malignancy. In a prospective study of 738 patients with objectively verified symptomatic deep vein thrombosis (DVT), cancer was the most common underlying cause and emerged as a major predictor of recurrent thrombotic events.⁶ Unfortunately, no laboratory test predicts occult cancer among patients with VTE.⁷

Risk of malignancy in per spective

Evidence of malignancy is usually discovered when taking a patient’s history and conducting a physical examination. Searching beyond the history and physical exam is seldom revealing.

In 1992, Prandoni and colleagues⁸ published a report of a study of 262 patients with symptomatic DVT, 250 of whom were followed for 2 years. One hundred seven patients had recognized nonmalignant risk factors for DVT and were not evaluated for cancer. Of the 155 patients with idiopathic venous thrombosis, 5 (3.3%) were discovered to have occult carcinoma. Malignancy was suggested in 4 of the 5 by history or physical examination.

In a similar study, Hettiarachchi et al⁹ evaluated 400 patients with confirmed DVT and found 70 (18%) had a diagnosis of cancer at the time of presentation. Of the remaining 326 patients (4 were lost to follow-up), 189 had recognized risk factors for DVT, 3 (1.6%) of whom were also found to have cancer; and 137 patients had unexplained DVT, 10 of whom (7.3%) were found to have occult carcinoma. As in the Prandoni study, most of the patients subsequently discovered to have cancer (10 of 13, 77%) had suggestive clinical findings in the history or physical examination.⁹

Venous thromboembolism and specific types of cancer

Two large, retrospective epidemiologic studies reviewed cases of thousands of patients in the Danish and Swedish National Patient Registries.^10,11 Investigators for these studies found an approximately 30% increase in the diagnosis of cancer among patients with VTE compared with the general population. Because of their large size, both of these studies were able to demonstrate a significant association between thrombosis and pancreatic, liver, and ovarian cancers.

For liver and pancreatic cancers, consensus opinion suggests that early diagnosis does not change prognosis. Similarly, although some experts recommend ultrasound and Ca-125 testing to investigate possible ovarian cancer, no data support use of these tests in ovarian cancer screening.¹²

An evaluation of the Danish National Registry data has suggested that cancer diagnosed at the time of, or within a year of, the diagnosis of VTE is usually advanced and is associated with a poor prognosis.¹³ Indeed, the authors of the Danish study concluded that for patients with VTE, “[our] pragmatic recommendation [is] to use only simple methods of screening and to look for cancer in patients with signs and symptoms of cancer.”¹³

Recommended work-up

We conclude the literature^8-13 does not support an aggressive search for hidden cancer in a patient with idiopathic VTE (SOR=B). Routine evaluation should include a careful history and physical examination. Because of their low cost, reliability, and ready availability, studies such as a complete blood count, basic chemistry panel, liver function tests, and urinalysis may be considered (SOR=B ). Examples of findings during the initial history, physical exam, and laboratory studies that should prompt further evaluation include anorexia, weight loss, cough, abdominal bloating, unexplained anemia, hyponatremia, hematuria, and abnormal liver enzymes.

Unnecessary studies. Some authorities recommend a chest radiograph in the routine evaluation for occult malignancy,⁹ but its clinical utility for patients without pulmonary symptoms has not been clearly demonstrated. Because of their expense and low test yield, we do not advocate the use of more elaborate screens for occult malignancy, such as computerized tomography, magnetic resonance imaging, or serologic tumor markers.

Caveat. In the past, nearly all patients with pulmonary embolism or DVT were hospitalized to receive treatment with continuous intravenous heparin. Presumably these patients routinely received a careful history evaluation, physical examination, and standard blood work.

With increased use of low-molecular-weight heparins (given subcutaneously once or twice daily), many individuals with VTE are candidates for treatment partially or totally on an outpatient basis.^14,15 Be sure that individuals receiving outpatient treatment for idiopathic VTE receive the same attention and routine work-up as hospitalized patients.

Coagulation disorders and Venous Thromboembolism

With advances in laboratory testing, more than half of idiopathic VTE cases can be attributed to a specific coagulation disorder. Data show that in a randomly selected group of patients with newly discovered DVT, 24% to 37% have an inherited predisposition to thrombosis.^16-19

Deficiencies in protein C, protein S, and antithrombin were the first causes of inherited thrombophilia to be identified;^20-22 however, these deficiencies are not particularly common. The most common causes of thrombophilic coagulation disorders are activated protein C resistance, the prothrombin gene G20210A mutation, and hyperhomocysteinemia.

When to look for prothrombotic defects

If, after ruling out occult malignancy, the cause of VTE remains uncertain, be judicious in deciding whether to run more tests for prothrombotic defects. We advocate pursuing further testing for patients likely to have an underlying hypercoagulable disorder, and for whom the identification of such a disorder would have management implications.

A decision to pursue testing with other patients should be made on a case-by-case basis. The yield in testing is low for many prothrombotic disorders, some tests are affected adversely by anticoagulation therapy, and the influence of a positive test result on patient management decisions remains unclear in many cases. Finally, serologic evaluation for thrombophilia would be costly if conducted for all patients with VTE, and the potential clinical benefit would be small.

Although large epidemiologic studies are lacking to help identify patients at increased risk of a hypercoagulable disorder, patients with clinically significant inherited thrombophilia tend to have VTE at a young age.^23-25

In addition, advanced age alone is often regarded as an identifiable risk factor for DVT. A recent retrospective study demonstrated the risk for DVT rose rapidly during the 6th through 8th decades of life.²⁶

We generally recommend testing for hypercoagulable disorders upon discovering one of the following findings:

• The first thrombotic event occurs when the patient is younger than 50 years
• A family history of VTE exists
• Episodes of unexplained VTE recur (SOR=C).

Activated protein C resistance (Factor V Leiden mutation)

Prevalence. Approximately 90% of cases of activated protein C resistance are due to a substitution of glutamine for arginine at position 506 on the factor V gene, the so-called Leiden mutation.²⁷

Factor V Leiden mutation varies greatly by race. In North America, this mutation is found in the heterozygous form in approximately 5% of Caucasians, 2% of Hispanics, 1% of African Americans, and less than 0.5% of Asians.²⁸ Persons heterozygous for factor V Leiden have approximately a 7-fold increase in the relative risk;²⁹ persons homozygous for the mutation have approximately an 80-fold increase in the relative risk.³⁰

Detection. Activated protein C resistance is typically assessed by mixing patient plasma with factor V-deficient plasma. This clotting assay is not affected by oral anticoagulation medication but is affected by heparin. A positive test result for activated protein C resistance typically warrants a polymerase chain reaction assay to distinguish the factor V Leiden mutation from other causes of activated protein C resistance.

Testing considerations. Although factor V Leiden mutation is the cause of activated protein C resistance in most cases, we recommend that activated protein C resistance testing be done first, as it is a less expensive and more widely available test than the DNA-based factor V Leiden mutation test. However, if a patient is taking heparin at the time of evaluation for thrombophilia, it may be necessary to defer activated protein C resistance testing or proceed directly to factor V Leiden DNA-based testing.

Prothrombin gene G2 0210A mutation

Prevalence. Like the factor V Leiden mutation, the prothrombin gene G20210A mutation is more common among Caucasians than among those of African or Asian descent.³¹ Prothrombin mutation is estimated to cause a 2.5-fold relative risk of first DVT.³²

Testing considerations. If cost or availability of the polymerase chain reaction assay are issues, a reasonable course of action would be to reserve the assay for patients with factor V Leiden mutation. Data suggest that patients with both factor V and prothrombin gene G20210A mutations are at significantly higher risk for recurrent VTE; consider prolonged anticoagulation.³³

Hyperhomocysteinemia

Evidence accumulating over the past decade has shown an increased risk of VTE with elevated homocysteine levels. A case-control study by den Heijer et al³⁴ in 1996 demonstrated a relative risk for first thrombosis of 2.5 in those with a homocysteine level above the 95th percentile of the control group’s levels (which in that study corresponded to a homocysteine level of 18.5 micromoles per liter or above). This predisposition to thrombosis has also been demonstrated in subsequent meta-analyses.^35,36

When homocysteine levels are elevated in the presence of factor V Leiden or the prothrombin gene G20210A mutation, risk of thrombosis appears to increase beyond that associated with any one defect alone, perhaps as high as 50-fold risk.^37-39

Management Implications of Test Results

If testing for activated protein C resistance is possible and the result is positive, confirmatory testing for factor V Leiden is indicated. If the patient is homozygous for factor V Leiden (rare), or is heterozygous for factor V Leiden and has the prothrombin gene G20210A defect, consider a prolonged course of anticoagulation, perhaps even for the rest of the patient’s life.

We base these suggestions on the high rate of VTE detected among individuals who are homozygous for factor V Leiden³⁰ and on a recent study that showed the relative risk of recurrent thrombosis to be 2.6 for those with factor V Leiden and prothrombin gene G20210A mutations, versus for those heterozygous for factor V Leiden alone.³³ This recent study also showed that the relative risk of recurrent thrombosis was not increased in those heterozygous for the Factor V Leiden mutation alone compared to those without this mutation.³³

If either the factor V Leiden or the prothrombin gene G20210A mutation is present, consider prolonging the planned course of anticoagulation (although the data to support this decision are less compelling). Data are limited and conflicting regarding the appropriate length and intensity of anticoagulation therapy for patients with inherited prothrombotic defects.^33,40-42 When prolonging anticoagulation for these patients, try to balance the risk of a recurrent thrombotic event with the risk of a bleeding complication from chronic anticoagulation.

Prolonged anticoagulation may also be indicated if the homocysteine level is elevated and either the factor V Leiden or the prothrombin gene G20210A mutation is present. In addition, therapy with folate, pyridoxine, and vitamin B12 should be initiated in cases of elevated homocyteine levels. We recommend the use of these vitamins based on a meta-analysis which demonstrated that folate supplementation at a dose of 0.5 mg to 5 mg/day lowered homocysteine levels by approximately 25% and vitamin B12 supplementation at a dose of 0.5 mg/day led to a further reduction of approximately 7%. In this same meta-analysis, pyridoxine at a mean dose of 16.5 mg daily did not demonstrate further lowering of the homocysteine level; however, as it is safe, inexpensive and well-tolerated, we still recommend its use.⁴³

Finally, while less common than the hypercoagulable states discussed above, the antiphospholipid antibody syndrome should be targeted as part of first-tier testing because of its clear impact on management. If the antiphospholipid antibody testing (such as the lupus anticoagulant or anticardiolipin antibody) results are positive, lifelong anticoagulation⁴⁴ and perhaps a higher target international normalized ratio are considerations.

Second-tier testing: Pursuing less common defects

If the preceding evaluation is unrevealing for a patient with high-risk characteristics, consider pursuing “second-tier” testing. Such testing may include functional and immunologic assays for protein C, protein S, and anti-thrombin III deficiencies, all of which are heterozygous abnormalities caused by multiple mutations and, thus, not detectable with genetic assays.

Patients will likely be taking anticoagulation medication when these tests are administered; thus, test results must be interpreted with caution. Testing for these deficiencies is most reliable if conducted at least 2 weeks after anticoagulation has been discontinued. Again, the incidence of protein C, protein S, and antithrombin III deficiencies is low, and the yield of testing therefore is also likely to be low.

We would not recommend discontinuing anticoagulation to conduct testing for these uncommon defects once it has been initiated following an acute thrombotic event. Rather, testing should be pursued once the planned course of anticoagulation with warfarin has been completed (for example, 6 to 9 months).

Other inherited thrombophilic disorders include heparin cofactor II deficiency, plasminogen deficiency, dysfibrinogenemia, factor XII deficiency, and increased factor VIII coagulant activity. These disorders are rare and their clinical importance remains unclear. Testing for these disorders, if desired, is best conducted in consultation with a hematologist or coagulation specialist.

Corresponding author
Charles F.S. Locke, MD, Johns Hopkins Community Physicians, 2360 W. Joppa Rd., Baltimore, MD 21093. E-mail: [email protected].

To evaluate possible rupture of the anterior cruciate ligament (ACL), family physicians rely on the history and physical examination and primarily 3 diagnostic assessments: the anterior drawer test, the Lachman test, and the pivot shift test.^1-3 Preliminary findings from these tests, coupled with patient preference and physical demands, help select those who may need further work-up with arthroscopy or magnetic resonance imaging (MRI).⁴

We summarize the evidence for the diagnostic accuracy of physical diagnostic tests in assessing ACL ruptures of the knee.

If a patient’s physical demands are low, one might proceed with a trial of conservative therapy (especially when Lachman’s test is negative), which has shown to be favorable for selected patients.⁵ However, when a patient has high demands (as is the case with athletes), more advanced diagnostic tests (eg, MRI) seem to be indicated, irrespective of the findings of physical examination.

Methods

Selection of studies

A computerized literature search of MEDLINE (from 1966 to February 14, 2003) and EMBASE (1980 to February 14, 2003) was conducted to identify articles written in English, French, German, or Dutch. Key words were the medical subject headings “knee injuries,”knee joint,” and “knee,” and the text word “knee.” This set was combined with a set consisting of the main headings “joint instability” and “anterior cruciate ligament,” and the text words “laxity,” “instability,” “cruciate,” and “effusion.”

Finally, the results of these strategies were combined with a validated search strategy for the identification of diagnostic studies using the subject headings “sensitivity and specificity” (exploded), “physical examination” and “not (animal not [human and animal])” and the text words “sensitivit$,” “specificit$,” “false positive,” “false negative,” “accuracy,” and “screening,”⁶ supplemented with the text words “physical examination” and “clinical examination.” Also, the cited references of included publications were examined.

Studies were selected by 2 reviewers independently. Studies were eligible for inclusion if they addressed the accuracy of at least 1 physical diagnostic test for the assessment of ACL ruptures of the knee, and used arthrotomy, arthroscopy, or MRI as the gold standard.

Assessment of methodological quality and data abstraction

The methodological quality of the selected studies was assessed and data were abstracted by 2 reviewers independently. Quality assessment was accomplished with a checklist adapted from Irwig and colleagues⁷ and the Cochrane Methods Group on Systematic Review of Screening and Diagnostic Tests.⁸ (Table W1 and Table W1 cont.).

Statistical analysis

Statistical analysis was performed⁹ with a strategy adapted from Midgette and colleagues.¹⁰ The method consists of estimating a summary receiver operating characteristic (SROC) curve by metaregression, and exploring heterogeneity by adding study characteristics and study validity items to the regression model (a full description of this strategy is available online as Appendix A).^7-11

We performed an additional analysis according to a bivariate random effects model that accounts for heterogeneity of both sensitivity and specificity simultaneously, reflected in the width of the 95% confidence intervals.^12,13

The summary estimates of sensitivity and specificity were used to calculate the predictive value of a positive (PV+) and negative test result (PV–) for circumstances with varying prevalences of ACL ruptures. When summary estimates of both sensitivity and specificity could not be calculated, the summary estimate of sensitivity and the accompanying specificity, estimated from the SROC curve, were used to calculate predictive values.

Results

Selection of studies

The literature search revealed a total of 1090 potentially eligible studies, 17 of which were selected.^14-30 Two reports pertained to the same study,^15,16 and 1 additional study was found by reference tracking.² Thus, a total of 17 studies met the selection criteria.

Methodological quality and study characteristics

No study measured the index test (ie, the object of study) and reference standard independently (with blinding). Patients whose physical test results were abnormal were more likely to undergo the gold standard test—a factor that inflates sensitivity and decreases specificity. This verification bias was present in all but 2 studies.^15,27 No study was performed in a primary care setting.

A detailed description of the characteristics and methodological quality of the 17 included studies is available online (Appendix B, Table W2-1, Table W2-2, Table W2-3, and Table W3).

Accuracy of ACL tests

Details of the process of selecting studies for further meta-analysis are presented online (Appendix C).

Diagnostic accuracy of the ACL tests is shown in Table 1. Significant heterogeneity of sensitivity and specificity was seen with all ACL tests, and no significant subgroups were detected for any of the tests. The power of metaregression analysis, however, was low due to the small number of available studies (4 to 6) and because some characteristics exhibited no variation.

Anterior drawer test. Correlation of sensitivity and specificity for the anterior drawer test was positive (6 studies); thus, no SROC curve was estimated. Sensitivity of the anterior drawer test was 0.18–0.92, and specificity 0.78–0.98. According to the bivariate random effects model, the pooled sensitivity was 0.62 (95% confidence interval [CI], 0.42–0.78) and the pooled specificity was 0.88 (95% CI, 0.83–0.92) ( Figure 1A ).

TABLE 1
Diagnostic accuracy of the anterior drawer sign, Lachman test, and pivot shift test

FIGURE 1
Sensitivity vs 1–specificity of the 3 tests

Lachman test (Figure 2). The SROC curve of the Lachman test (6 studies) is shown in Figure 1B . Sensitivity ranged from 0.63 to 0.93, and specificity from 0.55 to 0.99. According to the bivariate random effects model the pooled sensitivity was 0.86 (95% CI, 0.76–0.92) and the pooled specificity was 0.91 (95% CI, 0.79–0.96).

Pivot shift test. The SROC curve of the pivot shift test (4 studies) is shown in Figure 1C . Sensitivity ranged from 0.18 to 0.48, and specificity from 0.97 to 0.99. Bivariate random effects pooling could not be performed; in this model 5 parameters must be estimated and only 4 studies were available.

Figure 3 shows the PV+ and PV– for all tests according to varying prevalences of ACL ruptures. The pivot shift test has the highest PV+ and the Lachman test the highest PV–. If the pivot shift test is positive, there is high probability of an ACL rupture, whereas a negative Lachman test rules out a rupture.

FIGURE 2
Lachman test

FIGURE 3
Predictive value vs prevalence of positive and negative test results

DISCUSSION

We reviewed 17 studies that examined the accuracy of physical diagnostic tests for assessing ACL ruptures of the knee. Of those tests, the pivot shift test seems to have favorable positive predictive value, and the Lachman test good negative predictive value. The anterior drawer test is of unproven diagnostic value in this setting. In view of the potential biases in the original studies, however, the accuracy of the various ACL tests might be overestimated and the poor quality of the studies impede sound conclusions about the usefulness of the tests for daily practice. In addition, no study has been performed in primary care.

Because test characteristics may be influenced substantially by referral filters leading to spectrum bias,³¹ and because primary care physicians will be less experienced in performing these tests, the tests will presumably be less accurate in a primary care setting. Furthermore, the pivot shift test is very difficult to perform, making it less attractive for the average primary care physician.

Future research

Useful answers would be derived from sound research on the diagnostic accuracy of the various tests (determined for each test separately and for all tests jointly) combined with patient characteristics (eg, age, physical fitness, and functional demands) and elements of the medical history (eg, type of trauma and nature of the complaints). The emergence of MRI will facilitate this research. Relevance to clinical practice would be enhanced by an assessment of the effect of a correct diagnosis on the functional outcome of patients.

Acknowledgments

The authors thank Afina Glas, MD, and Professor Koos Zwinderman, PhD, for their statistical advice. We are much obliged to 1 of the referees for his/her useful suggestions.

Corresponding author
Rob J.P.M. Scholten, MD, PhD, Dutch Cochrane Centre, Department of Clinical Epidemiology and Biostatistics, J2-273, Academic Medical Center, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands. E-mail: [email protected].

To evaluate possible rupture of the anterior cruciate ligament (ACL), family physicians rely on the history and physical examination and primarily 3 diagnostic assessments: the anterior drawer test, the Lachman test, and the pivot shift test.^1-3 Preliminary findings from these tests, coupled with patient preference and physical demands, help select those who may need further work-up with arthroscopy or magnetic resonance imaging (MRI).⁴

We summarize the evidence for the diagnostic accuracy of physical diagnostic tests in assessing ACL ruptures of the knee.

If a patient’s physical demands are low, one might proceed with a trial of conservative therapy (especially when Lachman’s test is negative), which has shown to be favorable for selected patients.⁵ However, when a patient has high demands (as is the case with athletes), more advanced diagnostic tests (eg, MRI) seem to be indicated, irrespective of the findings of physical examination.

Methods

Selection of studies

A computerized literature search of MEDLINE (from 1966 to February 14, 2003) and EMBASE (1980 to February 14, 2003) was conducted to identify articles written in English, French, German, or Dutch. Key words were the medical subject headings “knee injuries,”knee joint,” and “knee,” and the text word “knee.” This set was combined with a set consisting of the main headings “joint instability” and “anterior cruciate ligament,” and the text words “laxity,” “instability,” “cruciate,” and “effusion.”

Finally, the results of these strategies were combined with a validated search strategy for the identification of diagnostic studies using the subject headings “sensitivity and specificity” (exploded), “physical examination” and “not (animal not [human and animal])” and the text words “sensitivit$,” “specificit$,” “false positive,” “false negative,” “accuracy,” and “screening,”⁶ supplemented with the text words “physical examination” and “clinical examination.” Also, the cited references of included publications were examined.

Studies were selected by 2 reviewers independently. Studies were eligible for inclusion if they addressed the accuracy of at least 1 physical diagnostic test for the assessment of ACL ruptures of the knee, and used arthrotomy, arthroscopy, or MRI as the gold standard.

Assessment of methodological quality and data abstraction

The methodological quality of the selected studies was assessed and data were abstracted by 2 reviewers independently. Quality assessment was accomplished with a checklist adapted from Irwig and colleagues⁷ and the Cochrane Methods Group on Systematic Review of Screening and Diagnostic Tests.⁸ (Table W1 and Table W1 cont.).

Statistical analysis

Statistical analysis was performed⁹ with a strategy adapted from Midgette and colleagues.¹⁰ The method consists of estimating a summary receiver operating characteristic (SROC) curve by metaregression, and exploring heterogeneity by adding study characteristics and study validity items to the regression model (a full description of this strategy is available online as Appendix A).^7-11