The Journal of Family Practice

EVIDENCE SUMMARY

A systematic review and meta-analysis of 15 RCTs with a total enrollment of 5540 assessed the efficacy of opioids in adults with chronic low back pain of at least 12 weeks’ duration.¹ Five low-quality studies (1378 patients) that compared tramadol with placebo found tramadol to be moderately superior to placebo for relieving pain (standard mean difference [SMD]= -0.55; 95% confidence interval [CI], -0.66 to -0.44) but only modestly better for improving function (SMD= −0.18; 95% CI, -0.29 to -0.07).

Six trials with 1887 patients compared strong opioids (morphine, hydromorphone, oxycodone, oxymorphone, and tapentadol) with placebo. The opioids were better than placebo for improving pain (SMD= -0.43; 95% CI, -0.52 to -0.33) and function (SMD= -0.26; 95% CI, -0.37 to -0.15). The general interpretation of SMD effect size is 0.2=small, 0.5=medium, 0.8=large. In this case, larger negative numbers correlate with greater improvement.

How opioids stack up against NSAIDs

Two separate double-blind, double-dummy studies randomized adults with low back pain of at least 12 weeks’ duration to receive celecoxib 200 mg twice daily (404 and 398 patients, respectively) or tramadol 50 mg 4 times daily (392 and 404 patients, respectively) for 6 weeks.² The primary outcome measure was at least a 30% improvement in pain using a 0 (no pain) to 10 (worst possible pain) scale. In both studies, more patients taking celecoxib had positive responses than patients taking tramadol (63% vs 50%, P<.001, and 64% vs 55%, P<.008, respectively).

A small RCT (36 patients who had suffered low back pain for more than 6 months) randomized patients to one of 3 treatment groups for 16 weeks: oxycodone as much as 20 mg/d (13 patients); naproxen as much as 1 g/d (12 patients); or oxycodone and sustained-release morphine (titrated up to 200 mg morphine equivalent/d (11 patients).³ After 16 weeks, patients receiving oxycodone or naproxen were treated with oxycodone and sustained-release morphine for another 16 weeks, as were patients already receiving this therapy. Pain was assessed on a 0 (none) to 100 (worst possible pain) scale.

Both opioid groups had significantly less pain on average (59.8 for oxycodone, 54.9 for titrated morphine) than the naproxen group (65.5; F=16.07; P<.001) but no significant difference in activity level. However, an independent analysis of the naproxen group and titrated morphine group found no significant difference in either pain relief (SMD= -0.58; 95% CI, -1.42 to 0.26) or disability (SMD= -0.06; 95% CI, -0.88 to 0.76) between the 2 groups.⁴

How does long-term opioid use affect pain and function?

Two prospective cohort studies have evaluated long-term opioid use. The first (715 patients) used a Roland-Morris Disability Questionnaire (RMDQ) to assess disability at 6 months in patients taking opioids compared with patients not taking opioids.⁵ Patients using opioids showed an increase in RMDQ score of 1.18 units (95% CI, 0.17-2.19) on a 0 to 24 scale, with 24 representing greatest disability.

Short-term treatment with opioids provides modest relief of chronic low back pain, but only minimal improvement in function compared with placebo.

The second study evaluated pain and function in 1843 adults with acute back injuries taking opioids for a year.⁶ Pain, rated on a 0 to 10 scale, decreased from 7.7 at baseline to 6.8 at one year (no P value). At the end of the first quarter, the RMDQ score decreased from 18.8 at baseline (the end of the first quarter) to 17.5 at one year (no P value). Clinically meaningful improvement in pain and function (30% or more) occurred in 26% (95% CI, 18%-36%) and 16% (95% CI, 10%-25%) of patients, respectively.

RECOMMENDATIONS

The 2007 clinical practice guideline on low back pain from The American College of Physicians and American Pain Society recommends opioids, including tramadol, for patients with severe back pain who don’t get adequate relief from acetaminophen or NSAIDs.⁷

The 2009 National Institute for Health and Care Excellence (NICE) guidelines for early management of persistent, nonspecific low back pain recommend considering strong opioids (buprenorphine, fentanyl, and oxycodone) for short-term use in severe pain and referral to a specialist for patients requiring prolonged use of strong opioids.⁸

The 2013 British Pain Society guidelines for low back and radicular pain recommend tight restrictions on the use of strong opioids. They also recommend giving the lowest possible dose of opioids for the shortest time possible.⁹

EVIDENCE SUMMARY

A systematic review and meta-analysis of 15 RCTs with a total enrollment of 5540 assessed the efficacy of opioids in adults with chronic low back pain of at least 12 weeks’ duration.¹ Five low-quality studies (1378 patients) that compared tramadol with placebo found tramadol to be moderately superior to placebo for relieving pain (standard mean difference [SMD]= -0.55; 95% confidence interval [CI], -0.66 to -0.44) but only modestly better for improving function (SMD= −0.18; 95% CI, -0.29 to -0.07).

Six trials with 1887 patients compared strong opioids (morphine, hydromorphone, oxycodone, oxymorphone, and tapentadol) with placebo. The opioids were better than placebo for improving pain (SMD= -0.43; 95% CI, -0.52 to -0.33) and function (SMD= -0.26; 95% CI, -0.37 to -0.15). The general interpretation of SMD effect size is 0.2=small, 0.5=medium, 0.8=large. In this case, larger negative numbers correlate with greater improvement.

How opioids stack up against NSAIDs

Two separate double-blind, double-dummy studies randomized adults with low back pain of at least 12 weeks’ duration to receive celecoxib 200 mg twice daily (404 and 398 patients, respectively) or tramadol 50 mg 4 times daily (392 and 404 patients, respectively) for 6 weeks.² The primary outcome measure was at least a 30% improvement in pain using a 0 (no pain) to 10 (worst possible pain) scale. In both studies, more patients taking celecoxib had positive responses than patients taking tramadol (63% vs 50%, P<.001, and 64% vs 55%, P<.008, respectively).

A small RCT (36 patients who had suffered low back pain for more than 6 months) randomized patients to one of 3 treatment groups for 16 weeks: oxycodone as much as 20 mg/d (13 patients); naproxen as much as 1 g/d (12 patients); or oxycodone and sustained-release morphine (titrated up to 200 mg morphine equivalent/d (11 patients).³ After 16 weeks, patients receiving oxycodone or naproxen were treated with oxycodone and sustained-release morphine for another 16 weeks, as were patients already receiving this therapy. Pain was assessed on a 0 (none) to 100 (worst possible pain) scale.

Both opioid groups had significantly less pain on average (59.8 for oxycodone, 54.9 for titrated morphine) than the naproxen group (65.5; F=16.07; P<.001) but no significant difference in activity level. However, an independent analysis of the naproxen group and titrated morphine group found no significant difference in either pain relief (SMD= -0.58; 95% CI, -1.42 to 0.26) or disability (SMD= -0.06; 95% CI, -0.88 to 0.76) between the 2 groups.⁴

How does long-term opioid use affect pain and function?

Two prospective cohort studies have evaluated long-term opioid use. The first (715 patients) used a Roland-Morris Disability Questionnaire (RMDQ) to assess disability at 6 months in patients taking opioids compared with patients not taking opioids.⁵ Patients using opioids showed an increase in RMDQ score of 1.18 units (95% CI, 0.17-2.19) on a 0 to 24 scale, with 24 representing greatest disability.

Short-term treatment with opioids provides modest relief of chronic low back pain, but only minimal improvement in function compared with placebo.

The second study evaluated pain and function in 1843 adults with acute back injuries taking opioids for a year.⁶ Pain, rated on a 0 to 10 scale, decreased from 7.7 at baseline to 6.8 at one year (no P value). At the end of the first quarter, the RMDQ score decreased from 18.8 at baseline (the end of the first quarter) to 17.5 at one year (no P value). Clinically meaningful improvement in pain and function (30% or more) occurred in 26% (95% CI, 18%-36%) and 16% (95% CI, 10%-25%) of patients, respectively.

RECOMMENDATIONS

The 2007 clinical practice guideline on low back pain from The American College of Physicians and American Pain Society recommends opioids, including tramadol, for patients with severe back pain who don’t get adequate relief from acetaminophen or NSAIDs.⁷

The 2009 National Institute for Health and Care Excellence (NICE) guidelines for early management of persistent, nonspecific low back pain recommend considering strong opioids (buprenorphine, fentanyl, and oxycodone) for short-term use in severe pain and referral to a specialist for patients requiring prolonged use of strong opioids.⁸

The 2013 British Pain Society guidelines for low back and radicular pain recommend tight restrictions on the use of strong opioids. They also recommend giving the lowest possible dose of opioids for the shortest time possible.⁹

EVIDENCE SUMMARY

A systematic review and meta-analysis of 15 RCTs with a total enrollment of 5540 assessed the efficacy of opioids in adults with chronic low back pain of at least 12 weeks’ duration.¹ Five low-quality studies (1378 patients) that compared tramadol with placebo found tramadol to be moderately superior to placebo for relieving pain (standard mean difference [SMD]= -0.55; 95% confidence interval [CI], -0.66 to -0.44) but only modestly better for improving function (SMD= −0.18; 95% CI, -0.29 to -0.07).

Six trials with 1887 patients compared strong opioids (morphine, hydromorphone, oxycodone, oxymorphone, and tapentadol) with placebo. The opioids were better than placebo for improving pain (SMD= -0.43; 95% CI, -0.52 to -0.33) and function (SMD= -0.26; 95% CI, -0.37 to -0.15). The general interpretation of SMD effect size is 0.2=small, 0.5=medium, 0.8=large. In this case, larger negative numbers correlate with greater improvement.

How opioids stack up against NSAIDs

Two separate double-blind, double-dummy studies randomized adults with low back pain of at least 12 weeks’ duration to receive celecoxib 200 mg twice daily (404 and 398 patients, respectively) or tramadol 50 mg 4 times daily (392 and 404 patients, respectively) for 6 weeks.² The primary outcome measure was at least a 30% improvement in pain using a 0 (no pain) to 10 (worst possible pain) scale. In both studies, more patients taking celecoxib had positive responses than patients taking tramadol (63% vs 50%, P<.001, and 64% vs 55%, P<.008, respectively).

A small RCT (36 patients who had suffered low back pain for more than 6 months) randomized patients to one of 3 treatment groups for 16 weeks: oxycodone as much as 20 mg/d (13 patients); naproxen as much as 1 g/d (12 patients); or oxycodone and sustained-release morphine (titrated up to 200 mg morphine equivalent/d (11 patients).³ After 16 weeks, patients receiving oxycodone or naproxen were treated with oxycodone and sustained-release morphine for another 16 weeks, as were patients already receiving this therapy. Pain was assessed on a 0 (none) to 100 (worst possible pain) scale.

Both opioid groups had significantly less pain on average (59.8 for oxycodone, 54.9 for titrated morphine) than the naproxen group (65.5; F=16.07; P<.001) but no significant difference in activity level. However, an independent analysis of the naproxen group and titrated morphine group found no significant difference in either pain relief (SMD= -0.58; 95% CI, -1.42 to 0.26) or disability (SMD= -0.06; 95% CI, -0.88 to 0.76) between the 2 groups.⁴

How does long-term opioid use affect pain and function?

Two prospective cohort studies have evaluated long-term opioid use. The first (715 patients) used a Roland-Morris Disability Questionnaire (RMDQ) to assess disability at 6 months in patients taking opioids compared with patients not taking opioids.⁵ Patients using opioids showed an increase in RMDQ score of 1.18 units (95% CI, 0.17-2.19) on a 0 to 24 scale, with 24 representing greatest disability.

Short-term treatment with opioids provides modest relief of chronic low back pain, but only minimal improvement in function compared with placebo.

The second study evaluated pain and function in 1843 adults with acute back injuries taking opioids for a year.⁶ Pain, rated on a 0 to 10 scale, decreased from 7.7 at baseline to 6.8 at one year (no P value). At the end of the first quarter, the RMDQ score decreased from 18.8 at baseline (the end of the first quarter) to 17.5 at one year (no P value). Clinically meaningful improvement in pain and function (30% or more) occurred in 26% (95% CI, 18%-36%) and 16% (95% CI, 10%-25%) of patients, respectively.

RECOMMENDATIONS

The 2007 clinical practice guideline on low back pain from The American College of Physicians and American Pain Society recommends opioids, including tramadol, for patients with severe back pain who don’t get adequate relief from acetaminophen or NSAIDs.⁷

The 2009 National Institute for Health and Care Excellence (NICE) guidelines for early management of persistent, nonspecific low back pain recommend considering strong opioids (buprenorphine, fentanyl, and oxycodone) for short-term use in severe pain and referral to a specialist for patients requiring prolonged use of strong opioids.⁸

The 2013 British Pain Society guidelines for low back and radicular pain recommend tight restrictions on the use of strong opioids. They also recommend giving the lowest possible dose of opioids for the shortest time possible.⁹

EVIDENCE SUMMARY

Two RCTs that evaluated qHPV in young men for preventing outcomes associated with the 4 HPV subtypes in the vaccine (6, 11, 16, and 18) found that it reduced them by 50% to 66% using an intention-to-treat protocol (TABLE^1-4).

Vaccination reduces AIN and persistent infection in MSM

The first RCT evaluated a subset of 602 MSM from the second, larger RCT for preventing AIN and persistent HPV infection.¹ The intention-to-treat population included men with 5 or fewer lifetime sexual partners who had engaged in insertive or receptive anal intercourse or oral sex within the last year, were not necessarily HPV-negative at enrollment, and received at least one dose of vaccine (or placebo).

The vaccine reduced AIN associated with the 4 HPV types (6.3 vs 12.6 events per 100 person-years; relative risk reduction [RRR]=50.3%; 95% confidence interval [CI], 25.7-67.2; number needed to treat [NNT]=16 to prevent one AIN case per year) and with HPV of any type (13 vs 17.5 events per 100 person-years; RRR=25.7%; 95% CI, -1.1 to 45.6). It also reduced the rate of persistent HPV infection with the 4 HPV vaccine subtypes (8.8 vs 21.6 events per 100 person-years; RRR=59.4%; 95% CI, 43%-71%; NNT=8 to prevent one persistent HPV infection per year).

Investigators in the study also evaluated vaccine efficacy in a smaller subset (194 men) using per-protocol analysis and found higher prevention rates (78% for AIN due to HPV types 6, 11, 16, and 18). Investigators followed these subjects every 6 months for 36 months with polymerase chain reaction testing for HPV DNA, high-resolution anoscopy with anal cytology, and anal biopsy and histology if there were atypia.

The vaccine decreases persistent HPV infection and external genital lesions

The second RCT, including both MSM and heterosexual men, found that qHPV vaccine reduced rates of persistent HPV infection by 48%, and external genital lesions (condylomata or intraepithelial neoplasia involving the penis, perineum, or perianal area) by 66% associated with HPV types 6, 11, 16, and 18 using the intention-to-treat protocol.²

Investigators used the same protocols used in the first RCT, and the per-protocol population again had higher prevention rates (84% for any HPV type, 90% against the 4 vaccine types). The only adverse effect of the vaccine was injection site pain (57% vs 51% with placebo; P<.001).

The vaccine also helps older MSM

A nonconcurrent cohort study that evaluated qHPV vaccination among older MSM with previously treated high-grade AIN found a 50% decrease in recurrence rates in the 2 years after vaccination.³ Investigators recruited HIV-negative men, some of whom chose vaccination (not randomized), and followed them for 2 years. Study limitations included using medical records for data collection and the predominance of white, nonsmoking men with private insurance.

A post-hoc analysis of older men without previous anal condylomata (210 men) or with treated condylomata and no recurrence in the year before vaccination (103 men) found that qHPV vaccination was associated with 55% lower rates of anal condylomata.⁴

RECOMMENDATIONS

The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices recommends routine use of qHPV vaccine in males ages 11 through 21 years, and optional use in unvaccinated men as old as 26 years.⁵

EVIDENCE SUMMARY

Two RCTs that evaluated qHPV in young men for preventing outcomes associated with the 4 HPV subtypes in the vaccine (6, 11, 16, and 18) found that it reduced them by 50% to 66% using an intention-to-treat protocol (TABLE^1-4).

Vaccination reduces AIN and persistent infection in MSM

The first RCT evaluated a subset of 602 MSM from the second, larger RCT for preventing AIN and persistent HPV infection.¹ The intention-to-treat population included men with 5 or fewer lifetime sexual partners who had engaged in insertive or receptive anal intercourse or oral sex within the last year, were not necessarily HPV-negative at enrollment, and received at least one dose of vaccine (or placebo).

The vaccine reduced AIN associated with the 4 HPV types (6.3 vs 12.6 events per 100 person-years; relative risk reduction [RRR]=50.3%; 95% confidence interval [CI], 25.7-67.2; number needed to treat [NNT]=16 to prevent one AIN case per year) and with HPV of any type (13 vs 17.5 events per 100 person-years; RRR=25.7%; 95% CI, -1.1 to 45.6). It also reduced the rate of persistent HPV infection with the 4 HPV vaccine subtypes (8.8 vs 21.6 events per 100 person-years; RRR=59.4%; 95% CI, 43%-71%; NNT=8 to prevent one persistent HPV infection per year).

Investigators in the study also evaluated vaccine efficacy in a smaller subset (194 men) using per-protocol analysis and found higher prevention rates (78% for AIN due to HPV types 6, 11, 16, and 18). Investigators followed these subjects every 6 months for 36 months with polymerase chain reaction testing for HPV DNA, high-resolution anoscopy with anal cytology, and anal biopsy and histology if there were atypia.

The vaccine decreases persistent HPV infection and external genital lesions

The second RCT, including both MSM and heterosexual men, found that qHPV vaccine reduced rates of persistent HPV infection by 48%, and external genital lesions (condylomata or intraepithelial neoplasia involving the penis, perineum, or perianal area) by 66% associated with HPV types 6, 11, 16, and 18 using the intention-to-treat protocol.²

Investigators used the same protocols used in the first RCT, and the per-protocol population again had higher prevention rates (84% for any HPV type, 90% against the 4 vaccine types). The only adverse effect of the vaccine was injection site pain (57% vs 51% with placebo; P<.001).

The vaccine also helps older MSM

A nonconcurrent cohort study that evaluated qHPV vaccination among older MSM with previously treated high-grade AIN found a 50% decrease in recurrence rates in the 2 years after vaccination.³ Investigators recruited HIV-negative men, some of whom chose vaccination (not randomized), and followed them for 2 years. Study limitations included using medical records for data collection and the predominance of white, nonsmoking men with private insurance.

A post-hoc analysis of older men without previous anal condylomata (210 men) or with treated condylomata and no recurrence in the year before vaccination (103 men) found that qHPV vaccination was associated with 55% lower rates of anal condylomata.⁴

RECOMMENDATIONS

The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices recommends routine use of qHPV vaccine in males ages 11 through 21 years, and optional use in unvaccinated men as old as 26 years.⁵

EVIDENCE SUMMARY

Two RCTs that evaluated qHPV in young men for preventing outcomes associated with the 4 HPV subtypes in the vaccine (6, 11, 16, and 18) found that it reduced them by 50% to 66% using an intention-to-treat protocol (TABLE^1-4).

Vaccination reduces AIN and persistent infection in MSM

The first RCT evaluated a subset of 602 MSM from the second, larger RCT for preventing AIN and persistent HPV infection.¹ The intention-to-treat population included men with 5 or fewer lifetime sexual partners who had engaged in insertive or receptive anal intercourse or oral sex within the last year, were not necessarily HPV-negative at enrollment, and received at least one dose of vaccine (or placebo).

The vaccine reduced AIN associated with the 4 HPV types (6.3 vs 12.6 events per 100 person-years; relative risk reduction [RRR]=50.3%; 95% confidence interval [CI], 25.7-67.2; number needed to treat [NNT]=16 to prevent one AIN case per year) and with HPV of any type (13 vs 17.5 events per 100 person-years; RRR=25.7%; 95% CI, -1.1 to 45.6). It also reduced the rate of persistent HPV infection with the 4 HPV vaccine subtypes (8.8 vs 21.6 events per 100 person-years; RRR=59.4%; 95% CI, 43%-71%; NNT=8 to prevent one persistent HPV infection per year).

Investigators in the study also evaluated vaccine efficacy in a smaller subset (194 men) using per-protocol analysis and found higher prevention rates (78% for AIN due to HPV types 6, 11, 16, and 18). Investigators followed these subjects every 6 months for 36 months with polymerase chain reaction testing for HPV DNA, high-resolution anoscopy with anal cytology, and anal biopsy and histology if there were atypia.

The vaccine decreases persistent HPV infection and external genital lesions

The second RCT, including both MSM and heterosexual men, found that qHPV vaccine reduced rates of persistent HPV infection by 48%, and external genital lesions (condylomata or intraepithelial neoplasia involving the penis, perineum, or perianal area) by 66% associated with HPV types 6, 11, 16, and 18 using the intention-to-treat protocol.²

Investigators used the same protocols used in the first RCT, and the per-protocol population again had higher prevention rates (84% for any HPV type, 90% against the 4 vaccine types). The only adverse effect of the vaccine was injection site pain (57% vs 51% with placebo; P<.001).

The vaccine also helps older MSM

A nonconcurrent cohort study that evaluated qHPV vaccination among older MSM with previously treated high-grade AIN found a 50% decrease in recurrence rates in the 2 years after vaccination.³ Investigators recruited HIV-negative men, some of whom chose vaccination (not randomized), and followed them for 2 years. Study limitations included using medical records for data collection and the predominance of white, nonsmoking men with private insurance.

A post-hoc analysis of older men without previous anal condylomata (210 men) or with treated condylomata and no recurrence in the year before vaccination (103 men) found that qHPV vaccination was associated with 55% lower rates of anal condylomata.⁴

RECOMMENDATIONS

The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices recommends routine use of qHPV vaccine in males ages 11 through 21 years, and optional use in unvaccinated men as old as 26 years.⁵

THE CASE

A 72-year-old woman came to our internal medicine department clinic for a follow-up appointment for her fibromyalgia. Thirteen months earlier, she had sought care at our facility not only for fibromyalgia, but for insomnia, anxiety, depression, and urinary incontinence. At the time, we prescribed amitriptyline 10 mg/d—for her pain and depression—as well as clonazepam 10 mg/d and paracetamol 650 mg, as needed.

When she came in for the follow-up, she indicated that for the past 8 months, she’d been experiencing urinary retention that required her to self-catheterize 2 to 3 times a day. She said she hadn’t used other medicines or herbal products during this time.

The patient had visited her family physician several times over the previous few months, and had been referred to a urologist. During an episode of acute urinary retention, she went to the emergency department (ED), where the ED physician performed urinary catheterization and referred her to the hospital’s Urology Department. After 48 hours, she was evaluated by a urologist, who diagnosed chronic urinary retention related to a hypercontractile bladder, without any particular cause. She was advised to continue to catheterize herself when needed. She was also prescribed pyridostigmine bromide, but she stopped taking it because of abdominal pain and bloating.

Two months prior to her visit with us, the patient suffered a second acute urinary retention episode and returned to the ED. Urinary catheterization was performed for 72 hours. At her next visit to her urologist, she was told to continue self-catheterization and was prescribed silodosin 8 mg/d.

THE DIAGNOSIS

Based on the patient’s history, we suspected the urinary retention was secondary to the anticholinergic effects of amitriptyline. We were able to determine that the patient’s urinary retention was likely the result of an adverse drug reaction (ADR) by using the causality algorithm of the Spanish Pharmacovigilance System, which suggests the following criteria:¹ a) a positive time sequence (ie, onset of symptoms closely followed administration of the medication), b) the existence of an ADR that is well known and consistent with the mechanism of action of the drug,² c) symptoms that resolve after suspending the drug; d) no repeat exposure (to the adverse effects of amitriptyline) due to ethical reasons; and e) the absence of an alternative explanation for the symptoms.³

DISCUSSION

Although indicated for depression, amitriptyline is also used for other conditions, including nocturnal enuresis and chronic neuropathic pain.⁴ Amitriptyline exhibits anticholinergic effects that can cause symptoms related to the nervous system (agitation, disorientation, sleepiness, delirium, cognitive impairment), ocular system (blurred vision, dry eye, accommodation disturbances, increased intraocular pressure), cardiovascular system (tachycardia), gastrointestinal tract (dry mouth, paralytic ileus, constipation), urinary system (urinary retention); and skin and mucosal membranes (dryness).^5,6 Anticholinergic effects can also induce hyperthermia or increase the risk of falls.^5,6

Four other physicians had seen our patient, and none had considered the possibility that this was an adverse drug effect.

Anticholinergic medications can cause ADRs in high-risk older patients and thus are usually considered inappropriate for this patient population.⁶ The Anticholinergic Risk Scale (ARS) can be used to categorize medications based on their potential for anticholinergic adverse effects (TABLE).⁷ Amitriptyline is included in the group with the highest risk of ADRs. Amitriptyline is also included in the list of drugs that should be avoided in older adults, according to the 2012 American Geriatrics Society Beers Criteria.⁸

Our patient. We instructed her to stop taking amitriptyline, and her urinary retention disappeared within 48 hours. Two months later, she remained asymptomatic.

THE TAKEAWAY

Although many medications are known to cause adverse events, they can be missed when clinicians fail to pinpoint exactly when a new sign, symptom, or health problem appeared. This often leads to a chain reaction of unnecessary explorations, harmful treatment, patient suffering, and unjustified costs.^9-11 Our patient had seen 4 different health care providers (a family physician, urologist, and 2 ED physicians) before we saw her and ultimately made the diagnosis. Family physicians can prevent anticholinergic ADRs by using a scale, such as the ARS, before prescribing a medication.

THE CASE

A 72-year-old woman came to our internal medicine department clinic for a follow-up appointment for her fibromyalgia. Thirteen months earlier, she had sought care at our facility not only for fibromyalgia, but for insomnia, anxiety, depression, and urinary incontinence. At the time, we prescribed amitriptyline 10 mg/d—for her pain and depression—as well as clonazepam 10 mg/d and paracetamol 650 mg, as needed.

When she came in for the follow-up, she indicated that for the past 8 months, she’d been experiencing urinary retention that required her to self-catheterize 2 to 3 times a day. She said she hadn’t used other medicines or herbal products during this time.

The patient had visited her family physician several times over the previous few months, and had been referred to a urologist. During an episode of acute urinary retention, she went to the emergency department (ED), where the ED physician performed urinary catheterization and referred her to the hospital’s Urology Department. After 48 hours, she was evaluated by a urologist, who diagnosed chronic urinary retention related to a hypercontractile bladder, without any particular cause. She was advised to continue to catheterize herself when needed. She was also prescribed pyridostigmine bromide, but she stopped taking it because of abdominal pain and bloating.

Two months prior to her visit with us, the patient suffered a second acute urinary retention episode and returned to the ED. Urinary catheterization was performed for 72 hours. At her next visit to her urologist, she was told to continue self-catheterization and was prescribed silodosin 8 mg/d.

THE DIAGNOSIS

Based on the patient’s history, we suspected the urinary retention was secondary to the anticholinergic effects of amitriptyline. We were able to determine that the patient’s urinary retention was likely the result of an adverse drug reaction (ADR) by using the causality algorithm of the Spanish Pharmacovigilance System, which suggests the following criteria:¹ a) a positive time sequence (ie, onset of symptoms closely followed administration of the medication), b) the existence of an ADR that is well known and consistent with the mechanism of action of the drug,² c) symptoms that resolve after suspending the drug; d) no repeat exposure (to the adverse effects of amitriptyline) due to ethical reasons; and e) the absence of an alternative explanation for the symptoms.³

DISCUSSION

Although indicated for depression, amitriptyline is also used for other conditions, including nocturnal enuresis and chronic neuropathic pain.⁴ Amitriptyline exhibits anticholinergic effects that can cause symptoms related to the nervous system (agitation, disorientation, sleepiness, delirium, cognitive impairment), ocular system (blurred vision, dry eye, accommodation disturbances, increased intraocular pressure), cardiovascular system (tachycardia), gastrointestinal tract (dry mouth, paralytic ileus, constipation), urinary system (urinary retention); and skin and mucosal membranes (dryness).^5,6 Anticholinergic effects can also induce hyperthermia or increase the risk of falls.^5,6

Four other physicians had seen our patient, and none had considered the possibility that this was an adverse drug effect.

Anticholinergic medications can cause ADRs in high-risk older patients and thus are usually considered inappropriate for this patient population.⁶ The Anticholinergic Risk Scale (ARS) can be used to categorize medications based on their potential for anticholinergic adverse effects (TABLE).⁷ Amitriptyline is included in the group with the highest risk of ADRs. Amitriptyline is also included in the list of drugs that should be avoided in older adults, according to the 2012 American Geriatrics Society Beers Criteria.⁸

Our patient. We instructed her to stop taking amitriptyline, and her urinary retention disappeared within 48 hours. Two months later, she remained asymptomatic.

THE TAKEAWAY

Although many medications are known to cause adverse events, they can be missed when clinicians fail to pinpoint exactly when a new sign, symptom, or health problem appeared. This often leads to a chain reaction of unnecessary explorations, harmful treatment, patient suffering, and unjustified costs.^9-11 Our patient had seen 4 different health care providers (a family physician, urologist, and 2 ED physicians) before we saw her and ultimately made the diagnosis. Family physicians can prevent anticholinergic ADRs by using a scale, such as the ARS, before prescribing a medication.

THE CASE

A 72-year-old woman came to our internal medicine department clinic for a follow-up appointment for her fibromyalgia. Thirteen months earlier, she had sought care at our facility not only for fibromyalgia, but for insomnia, anxiety, depression, and urinary incontinence. At the time, we prescribed amitriptyline 10 mg/d—for her pain and depression—as well as clonazepam 10 mg/d and paracetamol 650 mg, as needed.

When she came in for the follow-up, she indicated that for the past 8 months, she’d been experiencing urinary retention that required her to self-catheterize 2 to 3 times a day. She said she hadn’t used other medicines or herbal products during this time.

The patient had visited her family physician several times over the previous few months, and had been referred to a urologist. During an episode of acute urinary retention, she went to the emergency department (ED), where the ED physician performed urinary catheterization and referred her to the hospital’s Urology Department. After 48 hours, she was evaluated by a urologist, who diagnosed chronic urinary retention related to a hypercontractile bladder, without any particular cause. She was advised to continue to catheterize herself when needed. She was also prescribed pyridostigmine bromide, but she stopped taking it because of abdominal pain and bloating.

Two months prior to her visit with us, the patient suffered a second acute urinary retention episode and returned to the ED. Urinary catheterization was performed for 72 hours. At her next visit to her urologist, she was told to continue self-catheterization and was prescribed silodosin 8 mg/d.

THE DIAGNOSIS

Based on the patient’s history, we suspected the urinary retention was secondary to the anticholinergic effects of amitriptyline. We were able to determine that the patient’s urinary retention was likely the result of an adverse drug reaction (ADR) by using the causality algorithm of the Spanish Pharmacovigilance System, which suggests the following criteria:¹ a) a positive time sequence (ie, onset of symptoms closely followed administration of the medication), b) the existence of an ADR that is well known and consistent with the mechanism of action of the drug,² c) symptoms that resolve after suspending the drug; d) no repeat exposure (to the adverse effects of amitriptyline) due to ethical reasons; and e) the absence of an alternative explanation for the symptoms.³

DISCUSSION

Although indicated for depression, amitriptyline is also used for other conditions, including nocturnal enuresis and chronic neuropathic pain.⁴ Amitriptyline exhibits anticholinergic effects that can cause symptoms related to the nervous system (agitation, disorientation, sleepiness, delirium, cognitive impairment), ocular system (blurred vision, dry eye, accommodation disturbances, increased intraocular pressure), cardiovascular system (tachycardia), gastrointestinal tract (dry mouth, paralytic ileus, constipation), urinary system (urinary retention); and skin and mucosal membranes (dryness).^5,6 Anticholinergic effects can also induce hyperthermia or increase the risk of falls.^5,6

Four other physicians had seen our patient, and none had considered the possibility that this was an adverse drug effect.

Anticholinergic medications can cause ADRs in high-risk older patients and thus are usually considered inappropriate for this patient population.⁶ The Anticholinergic Risk Scale (ARS) can be used to categorize medications based on their potential for anticholinergic adverse effects (TABLE).⁷ Amitriptyline is included in the group with the highest risk of ADRs. Amitriptyline is also included in the list of drugs that should be avoided in older adults, according to the 2012 American Geriatrics Society Beers Criteria.⁸

Our patient. We instructed her to stop taking amitriptyline, and her urinary retention disappeared within 48 hours. Two months later, she remained asymptomatic.

THE TAKEAWAY

Although many medications are known to cause adverse events, they can be missed when clinicians fail to pinpoint exactly when a new sign, symptom, or health problem appeared. This often leads to a chain reaction of unnecessary explorations, harmful treatment, patient suffering, and unjustified costs.^9-11 Our patient had seen 4 different health care providers (a family physician, urologist, and 2 ED physicians) before we saw her and ultimately made the diagnosis. Family physicians can prevent anticholinergic ADRs by using a scale, such as the ARS, before prescribing a medication.

THE CASE

A 25-year-old G2P2 woman came to our family practice clinic because she had multiple positive home pregnancy test results despite having undergone a sterilization procedure 4 years earlier. She said that 9 months ago, she had begun to experience hot flashes and night sweats that were getting progressively worse. Her menstrual cycles had been regular until 6 months earlier, when her bleeding became very light and irregular (2- to 6-week cycles with only one day of menstruation). Then 3 months ago, she stopped menstruating.

She’d had 2 uncomplicated pregnancies with normal vaginal deliveries 3 and 4 years ago, and had undergone a transcervical sterilization procedure after delivering her second child. Her medical history included hypothyroidism diagnosed at age 15, moderate persistent asthma, and seasonal allergies. She was taking levothyroxine 250 mcg/d, inhaled fluticasone/salmeterol, albuterol, and intranasal mometasone.

Transvaginal ultrasound failed to identify an intrauterine or ectopic pregnancy, and the patient’s ovaries were not visualized (uterine anatomy was normal with an endometrial stripe of 5.7 mm). The result of a serum human chorionic gonadotropin (hCG) test was 6.73 mIU/ mL. (In a nonpregnant, premenopausal woman, hCG is typically undetectable.) Subsequent serial hCG measurements remained low (6.72-7.09 mIU/mL), but persistent. Given these low hCG levels, it was imperative to rule out an intrauterine or ectopic pregnancy. A urine hCG was negative.

THE DIAGNOSIS

Because of our patient’s vasomotor symptoms, we ordered additional laboratory studies, which revealed an elevated follicle-stimulating hormone (FSH) level (66.08 mIU/mL and 42.2 mIU/mL taken one year apart; normal, 1.98-9.58 mIU/mL in a premenopausal female), an elevated luteinizing hormone (LH) level (46.1 mIU/mL; normal, 2.58-15.5 mIU/mL in a premenopausal female), a low thyroid-stimulating hormone (TSH) level (0.445 mIU/mL; normal, 0.465-4.65 mIU/mL), and a normal prolactin level (12.5 mIU/mL). Based on these results, we diagnosed primary ovarian insufficiency (POI).

DISCUSSION

POI, formerly known as premature ovarian failure, is defined as 4 to 6 months of amenorrhea or oligomenorrhea in a woman younger than 40 with an elevated FSH on 2 occasions, at least 4 weeks apart.^1-3

The etiology of POI is broad. It can be caused by a failure of the pituitary gland or hypothalamus to secrete regulating hormones to stimulate the ovaries. Possible genetic causes include Turner’s syndrome, fragile X permutation, and other autosomal disorders that cause follicle dysfunction or destruction.¹ Infections such as mumps, varicella, and tuberculosis are known to affect ovary function, as well.^1,4 In addition, women who are exposed to chemotherapy or radiation are at higher risk for developing POI.¹

Because POI and autoimmune disorders tend to occur together, consider screening any patient with POI for disorders such as hypothyroidism and Addison’s disease. A serum analysis to evaluate for autoantibodies against steroid-producing cells may be a potential marker for POI in patients with an autoimmune disease that affects the adrenal glands or thyroid. However, patients with isolated Addison’s disease, autoimmune hypothyroidism, or diabetes mellitus in the absence of POI do not appear to have steroid-specific antibodies.² In our patient’s case, her hypothyroidism may have placed her at higher risk of having a second organ system adversely affected by her immune system.

What causes a false-positive pregnancy test? This case is unique because our patient reported multiple positive home pregnancy test results and had persistently low serum hCG levels. While she had symptoms that suggested menopause (hot flashes, oligomenorrhea that progressed to amenorrhea), she believed these symptoms were related to pregnancy. In addition to pregnancy, an elevated serum hCG measurement can be due to various malignancies, molar pregnancy, pituitary production of hCG, elevated LH, cross-reactivity with multiple animal exposures (due to the production of human anti-animal antibodies that react with testing), and recent mononucleosis infection.⁵

Other potential causes for false-positive urine pregnancy test results include tuboovarian abscess,⁶ adenomyosis,⁷ and cancers that produce hCG, such as colon, pancreatic, lung, liver, and urothelial bladder carcinoma.^8,9 Urine with significant proteinuria can also cause a positive pregnancy test result.¹⁰

Our patient likely had a false-positive hCG due to elevated LH, secondary to POI, that demonstrated cross-reactivity on the hCG assay. The similarity in the chemical structure of the beta subunits of hCG and LH have been reported as false-positive tests in the absence of pregnancy.⁵

Hormone therapy and supplemental calcium and vitamin D are recommended for women with primary ovarian insufficiency to help prevent loss of bone density and other negative effects of low estrogen.

Because home pregnancy tests are designed to detect pregnancy as early as possible, they typically feature a high sensitivity by detecting very low levels of hCG, which leads to more frequent false-positive results. It is possible that different assay methods could account for the discrepancy between our patient’s positive home pregnancy tests and our negative laboratory urine pregnancy test.

Our patient and her husband were both counseled regarding her POI diagnosis. We conducted further studies to establish a possible etiology. She was found to have a normal karyotype of 46, XX, which ruled out Turner’s syndrome. Testing for permutations of the FMR1 gene was negative for fragile X syndrome, and antibody testing for thyroid and adrenal glands was negative for autoimmune disease.

Hormone therapy and supplemental calcium and vitamin D are recommended for women with POI to help prevent bone loss and other negative effects of low estrogen.¹¹ We did not take this tack with our patient, however, because she decided she wanted to pursue a tubal ligation reversal in order to get pregnant. So instead, we decreased her dose of levothyroxine to 150 mcg (since her TSH was low) and we referred her to the Reproductive Endocrinology Department.

THE TAKEAWAY

Although many cases of POI have no discernible etiology, it is important to rule out malignancies, failure of pituitary production, genetic causes, infections, and other possible causes. Hormone therapy and prophylactic doses of calcium and vitamin D are recommended for patients diagnosed with POI.

THE CASE

A 25-year-old G2P2 woman came to our family practice clinic because she had multiple positive home pregnancy test results despite having undergone a sterilization procedure 4 years earlier. She said that 9 months ago, she had begun to experience hot flashes and night sweats that were getting progressively worse. Her menstrual cycles had been regular until 6 months earlier, when her bleeding became very light and irregular (2- to 6-week cycles with only one day of menstruation). Then 3 months ago, she stopped menstruating.

She’d had 2 uncomplicated pregnancies with normal vaginal deliveries 3 and 4 years ago, and had undergone a transcervical sterilization procedure after delivering her second child. Her medical history included hypothyroidism diagnosed at age 15, moderate persistent asthma, and seasonal allergies. She was taking levothyroxine 250 mcg/d, inhaled fluticasone/salmeterol, albuterol, and intranasal mometasone.

Transvaginal ultrasound failed to identify an intrauterine or ectopic pregnancy, and the patient’s ovaries were not visualized (uterine anatomy was normal with an endometrial stripe of 5.7 mm). The result of a serum human chorionic gonadotropin (hCG) test was 6.73 mIU/ mL. (In a nonpregnant, premenopausal woman, hCG is typically undetectable.) Subsequent serial hCG measurements remained low (6.72-7.09 mIU/mL), but persistent. Given these low hCG levels, it was imperative to rule out an intrauterine or ectopic pregnancy. A urine hCG was negative.

THE DIAGNOSIS

Because of our patient’s vasomotor symptoms, we ordered additional laboratory studies, which revealed an elevated follicle-stimulating hormone (FSH) level (66.08 mIU/mL and 42.2 mIU/mL taken one year apart; normal, 1.98-9.58 mIU/mL in a premenopausal female), an elevated luteinizing hormone (LH) level (46.1 mIU/mL; normal, 2.58-15.5 mIU/mL in a premenopausal female), a low thyroid-stimulating hormone (TSH) level (0.445 mIU/mL; normal, 0.465-4.65 mIU/mL), and a normal prolactin level (12.5 mIU/mL). Based on these results, we diagnosed primary ovarian insufficiency (POI).

DISCUSSION

POI, formerly known as premature ovarian failure, is defined as 4 to 6 months of amenorrhea or oligomenorrhea in a woman younger than 40 with an elevated FSH on 2 occasions, at least 4 weeks apart.^1-3

The etiology of POI is broad. It can be caused by a failure of the pituitary gland or hypothalamus to secrete regulating hormones to stimulate the ovaries. Possible genetic causes include Turner’s syndrome, fragile X permutation, and other autosomal disorders that cause follicle dysfunction or destruction.¹ Infections such as mumps, varicella, and tuberculosis are known to affect ovary function, as well.^1,4 In addition, women who are exposed to chemotherapy or radiation are at higher risk for developing POI.¹

Because POI and autoimmune disorders tend to occur together, consider screening any patient with POI for disorders such as hypothyroidism and Addison’s disease. A serum analysis to evaluate for autoantibodies against steroid-producing cells may be a potential marker for POI in patients with an autoimmune disease that affects the adrenal glands or thyroid. However, patients with isolated Addison’s disease, autoimmune hypothyroidism, or diabetes mellitus in the absence of POI do not appear to have steroid-specific antibodies.² In our patient’s case, her hypothyroidism may have placed her at higher risk of having a second organ system adversely affected by her immune system.

What causes a false-positive pregnancy test? This case is unique because our patient reported multiple positive home pregnancy test results and had persistently low serum hCG levels. While she had symptoms that suggested menopause (hot flashes, oligomenorrhea that progressed to amenorrhea), she believed these symptoms were related to pregnancy. In addition to pregnancy, an elevated serum hCG measurement can be due to various malignancies, molar pregnancy, pituitary production of hCG, elevated LH, cross-reactivity with multiple animal exposures (due to the production of human anti-animal antibodies that react with testing), and recent mononucleosis infection.⁵

Other potential causes for false-positive urine pregnancy test results include tuboovarian abscess,⁶ adenomyosis,⁷ and cancers that produce hCG, such as colon, pancreatic, lung, liver, and urothelial bladder carcinoma.^8,9 Urine with significant proteinuria can also cause a positive pregnancy test result.¹⁰

Our patient likely had a false-positive hCG due to elevated LH, secondary to POI, that demonstrated cross-reactivity on the hCG assay. The similarity in the chemical structure of the beta subunits of hCG and LH have been reported as false-positive tests in the absence of pregnancy.⁵

Hormone therapy and supplemental calcium and vitamin D are recommended for women with primary ovarian insufficiency to help prevent loss of bone density and other negative effects of low estrogen.

Because home pregnancy tests are designed to detect pregnancy as early as possible, they typically feature a high sensitivity by detecting very low levels of hCG, which leads to more frequent false-positive results. It is possible that different assay methods could account for the discrepancy between our patient’s positive home pregnancy tests and our negative laboratory urine pregnancy test.

Our patient and her husband were both counseled regarding her POI diagnosis. We conducted further studies to establish a possible etiology. She was found to have a normal karyotype of 46, XX, which ruled out Turner’s syndrome. Testing for permutations of the FMR1 gene was negative for fragile X syndrome, and antibody testing for thyroid and adrenal glands was negative for autoimmune disease.

Hormone therapy and supplemental calcium and vitamin D are recommended for women with POI to help prevent bone loss and other negative effects of low estrogen.¹¹ We did not take this tack with our patient, however, because she decided she wanted to pursue a tubal ligation reversal in order to get pregnant. So instead, we decreased her dose of levothyroxine to 150 mcg (since her TSH was low) and we referred her to the Reproductive Endocrinology Department.

THE TAKEAWAY

Although many cases of POI have no discernible etiology, it is important to rule out malignancies, failure of pituitary production, genetic causes, infections, and other possible causes. Hormone therapy and prophylactic doses of calcium and vitamin D are recommended for patients diagnosed with POI.

THE CASE

A 25-year-old G2P2 woman came to our family practice clinic because she had multiple positive home pregnancy test results despite having undergone a sterilization procedure 4 years earlier. She said that 9 months ago, she had begun to experience hot flashes and night sweats that were getting progressively worse. Her menstrual cycles had been regular until 6 months earlier, when her bleeding became very light and irregular (2- to 6-week cycles with only one day of menstruation). Then 3 months ago, she stopped menstruating.

She’d had 2 uncomplicated pregnancies with normal vaginal deliveries 3 and 4 years ago, and had undergone a transcervical sterilization procedure after delivering her second child. Her medical history included hypothyroidism diagnosed at age 15, moderate persistent asthma, and seasonal allergies. She was taking levothyroxine 250 mcg/d, inhaled fluticasone/salmeterol, albuterol, and intranasal mometasone.

Transvaginal ultrasound failed to identify an intrauterine or ectopic pregnancy, and the patient’s ovaries were not visualized (uterine anatomy was normal with an endometrial stripe of 5.7 mm). The result of a serum human chorionic gonadotropin (hCG) test was 6.73 mIU/ mL. (In a nonpregnant, premenopausal woman, hCG is typically undetectable.) Subsequent serial hCG measurements remained low (6.72-7.09 mIU/mL), but persistent. Given these low hCG levels, it was imperative to rule out an intrauterine or ectopic pregnancy. A urine hCG was negative.

THE DIAGNOSIS

Because of our patient’s vasomotor symptoms, we ordered additional laboratory studies, which revealed an elevated follicle-stimulating hormone (FSH) level (66.08 mIU/mL and 42.2 mIU/mL taken one year apart; normal, 1.98-9.58 mIU/mL in a premenopausal female), an elevated luteinizing hormone (LH) level (46.1 mIU/mL; normal, 2.58-15.5 mIU/mL in a premenopausal female), a low thyroid-stimulating hormone (TSH) level (0.445 mIU/mL; normal, 0.465-4.65 mIU/mL), and a normal prolactin level (12.5 mIU/mL). Based on these results, we diagnosed primary ovarian insufficiency (POI).

DISCUSSION

POI, formerly known as premature ovarian failure, is defined as 4 to 6 months of amenorrhea or oligomenorrhea in a woman younger than 40 with an elevated FSH on 2 occasions, at least 4 weeks apart.^1-3

The etiology of POI is broad. It can be caused by a failure of the pituitary gland or hypothalamus to secrete regulating hormones to stimulate the ovaries. Possible genetic causes include Turner’s syndrome, fragile X permutation, and other autosomal disorders that cause follicle dysfunction or destruction.¹ Infections such as mumps, varicella, and tuberculosis are known to affect ovary function, as well.^1,4 In addition, women who are exposed to chemotherapy or radiation are at higher risk for developing POI.¹

Because POI and autoimmune disorders tend to occur together, consider screening any patient with POI for disorders such as hypothyroidism and Addison’s disease. A serum analysis to evaluate for autoantibodies against steroid-producing cells may be a potential marker for POI in patients with an autoimmune disease that affects the adrenal glands or thyroid. However, patients with isolated Addison’s disease, autoimmune hypothyroidism, or diabetes mellitus in the absence of POI do not appear to have steroid-specific antibodies.² In our patient’s case, her hypothyroidism may have placed her at higher risk of having a second organ system adversely affected by her immune system.

What causes a false-positive pregnancy test? This case is unique because our patient reported multiple positive home pregnancy test results and had persistently low serum hCG levels. While she had symptoms that suggested menopause (hot flashes, oligomenorrhea that progressed to amenorrhea), she believed these symptoms were related to pregnancy. In addition to pregnancy, an elevated serum hCG measurement can be due to various malignancies, molar pregnancy, pituitary production of hCG, elevated LH, cross-reactivity with multiple animal exposures (due to the production of human anti-animal antibodies that react with testing), and recent mononucleosis infection.⁵

Other potential causes for false-positive urine pregnancy test results include tuboovarian abscess,⁶ adenomyosis,⁷ and cancers that produce hCG, such as colon, pancreatic, lung, liver, and urothelial bladder carcinoma.^8,9 Urine with significant proteinuria can also cause a positive pregnancy test result.¹⁰

Our patient likely had a false-positive hCG due to elevated LH, secondary to POI, that demonstrated cross-reactivity on the hCG assay. The similarity in the chemical structure of the beta subunits of hCG and LH have been reported as false-positive tests in the absence of pregnancy.⁵

Hormone therapy and supplemental calcium and vitamin D are recommended for women with primary ovarian insufficiency to help prevent loss of bone density and other negative effects of low estrogen.

Because home pregnancy tests are designed to detect pregnancy as early as possible, they typically feature a high sensitivity by detecting very low levels of hCG, which leads to more frequent false-positive results. It is possible that different assay methods could account for the discrepancy between our patient’s positive home pregnancy tests and our negative laboratory urine pregnancy test.

Our patient and her husband were both counseled regarding her POI diagnosis. We conducted further studies to establish a possible etiology. She was found to have a normal karyotype of 46, XX, which ruled out Turner’s syndrome. Testing for permutations of the FMR1 gene was negative for fragile X syndrome, and antibody testing for thyroid and adrenal glands was negative for autoimmune disease.

Hormone therapy and supplemental calcium and vitamin D are recommended for women with POI to help prevent bone loss and other negative effects of low estrogen.¹¹ We did not take this tack with our patient, however, because she decided she wanted to pursue a tubal ligation reversal in order to get pregnant. So instead, we decreased her dose of levothyroxine to 150 mcg (since her TSH was low) and we referred her to the Reproductive Endocrinology Department.

THE TAKEAWAY

Although many cases of POI have no discernible etiology, it is important to rule out malignancies, failure of pituitary production, genetic causes, infections, and other possible causes. Hormone therapy and prophylactic doses of calcium and vitamin D are recommended for patients diagnosed with POI.

“I have acute appendicitis,” I told my wife. “I need to go to the radiologist.”

A computed tomography (CT) scan of my abdomen confirmed my suspicion. After learning that I also had leukocytosis, we headed to the emergency department. The ED doctor was pleasantly surprised that someone had come to his facility completely evaluated. All he had to do was call the surgeon. But first he introduced me to a 4th-year medical student who was participating in a surgical rotation.

Prioritizing the EMR over the patient

The student wheeled his large computer to the side of my gurney and began to question me about my abdominal pain. Within 5 minutes, this unsupervised student had somehow acquired all the information he needed for my admission. He thanked me for my time and told me that he would see me in the operating room.

Unfortunately for him, I was not about to let him leave my cubicle without a redirect. I told him I have type 1 diabetes and several comorbidities. I wear an insulin pump and continuous glucose sensor that alerts me to impending hypoglycemia. I take 11 medications to successfully manage my metabolic disorders.

The student wheeled his machine back to the side of my gurney.

With his eyes fixed squarely on his computer and his finger on a mouse, he asked me to list all of my medications. He had never heard of a rapid-acting insulin analogue, nor was he familiar with my GLP-1 receptor agonist or SGLT2 inhibitor. And the pump and sensor? There were no check boxes for these devices in his electronic medical record (EMR).

He—like several of the doctors I met during my subsequent stay—suggested that I remove the pump and meter so that they could manage my diabetes.

Still in considerable pain, I suggested to the student and anyone else who would listen that my pump and sensor were off limits. As long as I was conscious, I would self-manage my diabetes.

I also told him that his history and physical exam were deficient. Although he did listen to my bowel sounds (or lack thereof) through a blanket and hospital gown, he overlooked examining my heart, lungs, eyes, mouth, and feet.

It frightens me to think what might have happened during my hospital stay if I hadn’t provided information that wasn’t required by the EMR.

“You failed to ask me about my medical history or my diabetes," I said. The student searched his EMR for the appropriate questions to ask, but to no avail. Stunned, he appeared to be at a loss of words. I suggested that he ask about the type of diabetes I had, the duration of the disease, how well my glucose levels were controlled, my most recent HbA1c, and if I had developed any long-term microvascular or macrovascular complications. He politely thanked me, moved the mouse around on his computer stand, and began to wheel his computer away.

“Wait!” I thought. “Don’t you think you should examine my eyes, mouth, and feet?” I reminded myself that this student hadn’t evaluated me for peritoneal signs. So why should I insist that he look at non-critical parts of my body?

My physical pain was increasing and I was becoming increasingly distressed. The student was more interested in inputting data into the EMR than learning about acute abdomens and type 1 diabetes.

Postop: From bad to worse

My postoperative course was dreadful. I nearly died from complications that included acute renal failure, dehydration, hypokalemia, and a postoperative ileus that persisted for 8 days. My blood glucose levels, however, were perfect. Still, the Attendings and the students blamed my complications on diabetes.

“Yeah, I see this all the time,” said the hospitalist who was caring for me. “Diabetes causes gastroparesis. What we should do is have you take off that pump and sensor device. We’ll have the pharmacist help you manage your diabetes.” The hospitalist who suggested this course of action was immediately relieved of his duties by my wife as I drifted in and out of consciousness in the intensive care unit (ICU).

Despite the state of my health, I began to provide professional guidance for my own care. I demanded that the nurse give me a 250 cc rider of normal saline and increase my IV flow rate from 50 cc to 150 cc. The nasogastric tube was removed and I began using IV erythromycin, which increases gastric motility. I received oral and IV potassium.

I suggested that the medical students needed to unplug their smart phones, computers, and iPads and spend a day or 2 with one of us “old-time docs.”

While in the ICU, I was questioned by physicians and medical students, but never examined. I am convinced that had I not been an experienced family physician, I would have suffered a fatal postoperative event. The medical students assigned to my care would not have known that I died, unless they received a notification via Twitter.

Providing care in a digital age

My experience as a patient was in stark contrast to the way I practice medicine.

I use an EMR only to e-prescribe, and have chosen not to participate in submitting meaningful use data to the government. Rather than spending 2 hours a day making eye contact with an EMR, I prefer to use that time to listen to my patients’ concerns about their health. I know how to conduct a review of systems and I touch my patients at each visit. I look at their feet, skin, and eyes, listen to their heart and lungs, and palpate their abdomen. I perform a rectal exam on every patient who presents with abdominal pain.

I have learned to communicate my suspicions and thoughts (both positive and negative) to all of my patients. I take notes on scratch paper, not on a computer, just as my grandfather and father used to do when they were practicing medicine. I only order tests to confirm a suspected diagnosis, not as a primary means of evaluating patients.

Could my hospital experience lead to change?

Upon my discharge from the hospital, I reached out to the director of clinical studies at the local medical school and explained the deficiencies I’d encountered. I explained that the 4th-year medical students were ill-equipped to perform an adequate history or physical exam. They lacked knowledge of basic pharmacology. And they failed to appropriately follow a patient during the perioperative period.

The director appreciated my concern and provided me with the details of a corrective action plan that she had been working on.

“We need to implement our patient simulation computer program designed to teach our students how to appropriately interact with their distressed patients,” she said.

Really?

I suggested that the medical students needed to unplug their smartphones, computers, and iPads. Let them spend a day or 2 with one of us “old-time docs” who still work with our hands—hands that are skilled at evaluating patients, rather than texting and data entry. We’ll show these students how to become caring, intelligent, and dedicated clinicians.

“I have acute appendicitis,” I told my wife. “I need to go to the radiologist.”

A computed tomography (CT) scan of my abdomen confirmed my suspicion. After learning that I also had leukocytosis, we headed to the emergency department. The ED doctor was pleasantly surprised that someone had come to his facility completely evaluated. All he had to do was call the surgeon. But first he introduced me to a 4th-year medical student who was participating in a surgical rotation.

Prioritizing the EMR over the patient

The student wheeled his large computer to the side of my gurney and began to question me about my abdominal pain. Within 5 minutes, this unsupervised student had somehow acquired all the information he needed for my admission. He thanked me for my time and told me that he would see me in the operating room.

Unfortunately for him, I was not about to let him leave my cubicle without a redirect. I told him I have type 1 diabetes and several comorbidities. I wear an insulin pump and continuous glucose sensor that alerts me to impending hypoglycemia. I take 11 medications to successfully manage my metabolic disorders.

The student wheeled his machine back to the side of my gurney.

With his eyes fixed squarely on his computer and his finger on a mouse, he asked me to list all of my medications. He had never heard of a rapid-acting insulin analogue, nor was he familiar with my GLP-1 receptor agonist or SGLT2 inhibitor. And the pump and sensor? There were no check boxes for these devices in his electronic medical record (EMR).

He—like several of the doctors I met during my subsequent stay—suggested that I remove the pump and meter so that they could manage my diabetes.

Still in considerable pain, I suggested to the student and anyone else who would listen that my pump and sensor were off limits. As long as I was conscious, I would self-manage my diabetes.

I also told him that his history and physical exam were deficient. Although he did listen to my bowel sounds (or lack thereof) through a blanket and hospital gown, he overlooked examining my heart, lungs, eyes, mouth, and feet.

It frightens me to think what might have happened during my hospital stay if I hadn’t provided information that wasn’t required by the EMR.

“You failed to ask me about my medical history or my diabetes," I said. The student searched his EMR for the appropriate questions to ask, but to no avail. Stunned, he appeared to be at a loss of words. I suggested that he ask about the type of diabetes I had, the duration of the disease, how well my glucose levels were controlled, my most recent HbA1c, and if I had developed any long-term microvascular or macrovascular complications. He politely thanked me, moved the mouse around on his computer stand, and began to wheel his computer away.

“Wait!” I thought. “Don’t you think you should examine my eyes, mouth, and feet?” I reminded myself that this student hadn’t evaluated me for peritoneal signs. So why should I insist that he look at non-critical parts of my body?

My physical pain was increasing and I was becoming increasingly distressed. The student was more interested in inputting data into the EMR than learning about acute abdomens and type 1 diabetes.

Postop: From bad to worse

My postoperative course was dreadful. I nearly died from complications that included acute renal failure, dehydration, hypokalemia, and a postoperative ileus that persisted for 8 days. My blood glucose levels, however, were perfect. Still, the Attendings and the students blamed my complications on diabetes.

“Yeah, I see this all the time,” said the hospitalist who was caring for me. “Diabetes causes gastroparesis. What we should do is have you take off that pump and sensor device. We’ll have the pharmacist help you manage your diabetes.” The hospitalist who suggested this course of action was immediately relieved of his duties by my wife as I drifted in and out of consciousness in the intensive care unit (ICU).

Despite the state of my health, I began to provide professional guidance for my own care. I demanded that the nurse give me a 250 cc rider of normal saline and increase my IV flow rate from 50 cc to 150 cc. The nasogastric tube was removed and I began using IV erythromycin, which increases gastric motility. I received oral and IV potassium.

I suggested that the medical students needed to unplug their smart phones, computers, and iPads and spend a day or 2 with one of us “old-time docs.”

While in the ICU, I was questioned by physicians and medical students, but never examined. I am convinced that had I not been an experienced family physician, I would have suffered a fatal postoperative event. The medical students assigned to my care would not have known that I died, unless they received a notification via Twitter.

Providing care in a digital age

My experience as a patient was in stark contrast to the way I practice medicine.

I use an EMR only to e-prescribe, and have chosen not to participate in submitting meaningful use data to the government. Rather than spending 2 hours a day making eye contact with an EMR, I prefer to use that time to listen to my patients’ concerns about their health. I know how to conduct a review of systems and I touch my patients at each visit. I look at their feet, skin, and eyes, listen to their heart and lungs, and palpate their abdomen. I perform a rectal exam on every patient who presents with abdominal pain.

I have learned to communicate my suspicions and thoughts (both positive and negative) to all of my patients. I take notes on scratch paper, not on a computer, just as my grandfather and father used to do when they were practicing medicine. I only order tests to confirm a suspected diagnosis, not as a primary means of evaluating patients.

Could my hospital experience lead to change?

Upon my discharge from the hospital, I reached out to the director of clinical studies at the local medical school and explained the deficiencies I’d encountered. I explained that the 4th-year medical students were ill-equipped to perform an adequate history or physical exam. They lacked knowledge of basic pharmacology. And they failed to appropriately follow a patient during the perioperative period.

The director appreciated my concern and provided me with the details of a corrective action plan that she had been working on.

“We need to implement our patient simulation computer program designed to teach our students how to appropriately interact with their distressed patients,” she said.

Really?

I suggested that the medical students needed to unplug their smartphones, computers, and iPads. Let them spend a day or 2 with one of us “old-time docs” who still work with our hands—hands that are skilled at evaluating patients, rather than texting and data entry. We’ll show these students how to become caring, intelligent, and dedicated clinicians.

“I have acute appendicitis,” I told my wife. “I need to go to the radiologist.”

A computed tomography (CT) scan of my abdomen confirmed my suspicion. After learning that I also had leukocytosis, we headed to the emergency department. The ED doctor was pleasantly surprised that someone had come to his facility completely evaluated. All he had to do was call the surgeon. But first he introduced me to a 4th-year medical student who was participating in a surgical rotation.

Prioritizing the EMR over the patient

The student wheeled his large computer to the side of my gurney and began to question me about my abdominal pain. Within 5 minutes, this unsupervised student had somehow acquired all the information he needed for my admission. He thanked me for my time and told me that he would see me in the operating room.

Unfortunately for him, I was not about to let him leave my cubicle without a redirect. I told him I have type 1 diabetes and several comorbidities. I wear an insulin pump and continuous glucose sensor that alerts me to impending hypoglycemia. I take 11 medications to successfully manage my metabolic disorders.

The student wheeled his machine back to the side of my gurney.

With his eyes fixed squarely on his computer and his finger on a mouse, he asked me to list all of my medications. He had never heard of a rapid-acting insulin analogue, nor was he familiar with my GLP-1 receptor agonist or SGLT2 inhibitor. And the pump and sensor? There were no check boxes for these devices in his electronic medical record (EMR).

He—like several of the doctors I met during my subsequent stay—suggested that I remove the pump and meter so that they could manage my diabetes.

Still in considerable pain, I suggested to the student and anyone else who would listen that my pump and sensor were off limits. As long as I was conscious, I would self-manage my diabetes.

I also told him that his history and physical exam were deficient. Although he did listen to my bowel sounds (or lack thereof) through a blanket and hospital gown, he overlooked examining my heart, lungs, eyes, mouth, and feet.

It frightens me to think what might have happened during my hospital stay if I hadn’t provided information that wasn’t required by the EMR.

“You failed to ask me about my medical history or my diabetes," I said. The student searched his EMR for the appropriate questions to ask, but to no avail. Stunned, he appeared to be at a loss of words. I suggested that he ask about the type of diabetes I had, the duration of the disease, how well my glucose levels were controlled, my most recent HbA1c, and if I had developed any long-term microvascular or macrovascular complications. He politely thanked me, moved the mouse around on his computer stand, and began to wheel his computer away.

“Wait!” I thought. “Don’t you think you should examine my eyes, mouth, and feet?” I reminded myself that this student hadn’t evaluated me for peritoneal signs. So why should I insist that he look at non-critical parts of my body?

My physical pain was increasing and I was becoming increasingly distressed. The student was more interested in inputting data into the EMR than learning about acute abdomens and type 1 diabetes.

Postop: From bad to worse

My postoperative course was dreadful. I nearly died from complications that included acute renal failure, dehydration, hypokalemia, and a postoperative ileus that persisted for 8 days. My blood glucose levels, however, were perfect. Still, the Attendings and the students blamed my complications on diabetes.

“Yeah, I see this all the time,” said the hospitalist who was caring for me. “Diabetes causes gastroparesis. What we should do is have you take off that pump and sensor device. We’ll have the pharmacist help you manage your diabetes.” The hospitalist who suggested this course of action was immediately relieved of his duties by my wife as I drifted in and out of consciousness in the intensive care unit (ICU).

Despite the state of my health, I began to provide professional guidance for my own care. I demanded that the nurse give me a 250 cc rider of normal saline and increase my IV flow rate from 50 cc to 150 cc. The nasogastric tube was removed and I began using IV erythromycin, which increases gastric motility. I received oral and IV potassium.

I suggested that the medical students needed to unplug their smart phones, computers, and iPads and spend a day or 2 with one of us “old-time docs.”

While in the ICU, I was questioned by physicians and medical students, but never examined. I am convinced that had I not been an experienced family physician, I would have suffered a fatal postoperative event. The medical students assigned to my care would not have known that I died, unless they received a notification via Twitter.

Providing care in a digital age

My experience as a patient was in stark contrast to the way I practice medicine.

I use an EMR only to e-prescribe, and have chosen not to participate in submitting meaningful use data to the government. Rather than spending 2 hours a day making eye contact with an EMR, I prefer to use that time to listen to my patients’ concerns about their health. I know how to conduct a review of systems and I touch my patients at each visit. I look at their feet, skin, and eyes, listen to their heart and lungs, and palpate their abdomen. I perform a rectal exam on every patient who presents with abdominal pain.

I have learned to communicate my suspicions and thoughts (both positive and negative) to all of my patients. I take notes on scratch paper, not on a computer, just as my grandfather and father used to do when they were practicing medicine. I only order tests to confirm a suspected diagnosis, not as a primary means of evaluating patients.

Could my hospital experience lead to change?

Upon my discharge from the hospital, I reached out to the director of clinical studies at the local medical school and explained the deficiencies I’d encountered. I explained that the 4th-year medical students were ill-equipped to perform an adequate history or physical exam. They lacked knowledge of basic pharmacology. And they failed to appropriately follow a patient during the perioperative period.

The director appreciated my concern and provided me with the details of a corrective action plan that she had been working on.

“We need to implement our patient simulation computer program designed to teach our students how to appropriately interact with their distressed patients,” she said.

Really?

I suggested that the medical students needed to unplug their smartphones, computers, and iPads. Let them spend a day or 2 with one of us “old-time docs” who still work with our hands—hands that are skilled at evaluating patients, rather than texting and data entry. We’ll show these students how to become caring, intelligent, and dedicated clinicians.

Family physicians are on the frontline for depression care, often being the first line of defense for diagnosis and management. This 1.25-hour, CME-certified activity will provide clinicians with a comprehensive review on the following:

• Clinical factors in the primary care setting that influence treatment outcomes in major depressive disorder
• Identification and management of residual symptoms
• Tools for effective monitoring of treatment outcomes
• Nonpharmacologic and pharmacologic therapies to treat patients to goal: remission and recovery
• Strategies to promote patient-focused, recovery-oriented care.

Click here to read the supplement.

After reading the supplement, click here to visit www.rapidcme.com/clinibriefs.aspx and complete the posttest and evaluation form for CME credit.

Family physicians are on the frontline for depression care, often being the first line of defense for diagnosis and management. This 1.25-hour, CME-certified activity will provide clinicians with a comprehensive review on the following:

• Clinical factors in the primary care setting that influence treatment outcomes in major depressive disorder
• Identification and management of residual symptoms
• Tools for effective monitoring of treatment outcomes
• Nonpharmacologic and pharmacologic therapies to treat patients to goal: remission and recovery
• Strategies to promote patient-focused, recovery-oriented care.

Click here to read the supplement.

After reading the supplement, click here to visit www.rapidcme.com/clinibriefs.aspx and complete the posttest and evaluation form for CME credit.

Family physicians are on the frontline for depression care, often being the first line of defense for diagnosis and management. This 1.25-hour, CME-certified activity will provide clinicians with a comprehensive review on the following:

• Clinical factors in the primary care setting that influence treatment outcomes in major depressive disorder
• Identification and management of residual symptoms
• Tools for effective monitoring of treatment outcomes
• Nonpharmacologic and pharmacologic therapies to treat patients to goal: remission and recovery
• Strategies to promote patient-focused, recovery-oriented care.

Click here to read the supplement.

After reading the supplement, click here to visit www.rapidcme.com/clinibriefs.aspx and complete the posttest and evaluation form for CME credit.

CASE 1 › Judy C is a newly employed 40-year-old health care worker who was born in China and received the bacille Calmette-Guérin (BCG) vaccination as a child. Her new employer requires her to undergo testing for tuberculosis (TB). Her initial tuberculin skin test (TST) is 0 mm, but on a second TST 2 weeks later, it is 8 mm. She is otherwise healthy, negative for human immunodeficiency virus (HIV), and has no constitutional symptoms. Does she have latent tuberculosis infection (LTBI)?

CASE 2 › A mom brings in her 3-year-old son, Patrick. She reports that a staff member at his day care center traveled outside the country for 3 months and was diagnosed with LTBI upon her return. She wants to know if her son should be tested.

More than 2 billion people—nearly one-third of the world’s population—are infected with Mycobacterium tuberculosis.¹ Most harbor the bacilli as LTBI, which means that while they have living TB bacilli within their bodies, these mycobacteria are kept dormant by an intact immune system. These individuals are not contagious, nor are they likely to become ill from active TB unless something adversely affects their immune system and increases the likelihood that LTBI will progress to active TB.

Two tests are available for diagnosing LTBI: the TST and the newer interferon gamma release assay (IGRA). Each test has advantages and disadvantages, and the best test to use depends on various patient-specific factors. This article describes whom you should test for LTBI, which test to use, and how to diagnose active TB.

Why test for LTBI?

LTBI is an asymptomatic infection; patients with LTBI have a 5% to 10% lifetime risk of developing active TB.² The risk of developing active TB is approximately 5% within the first 18 months of infection, and the remaining risk is spread out over the rest of the patient’s life.² Screening for LTBI is desirable because early diagnosis and treatment can reduce the activation risk to 1% to 2%,³ and treatment for LTBI is simpler, less costly, and less toxic than treatment for active TB.

Whom to test. Screening for LTBI should target patients for whom the benefits of treatment outweigh the cost and risks of treatment.⁴ A decision to screen for LTBI implies that the patient will be treated if he or she tests positive.³

The benefit of treatment increases in people who have a significant risk of progression to active TB—primarily those with recently acquired LTBI, or with co-existing conditions that increase their likelihood of progression (TABLE 1).⁵

Screening for latent TB infection is desirable because early diagnosis and treatment can reduce the activation risk to 1% to 2%.

All household contacts of patients with active TB and recent immigrants from countries with a high TB prevalence should be tested for LTBI.⁶ Those with a negative test and recent exposure should be retested in 8 to 12 weeks to allow for the delay in conversion to a positive test after recent infection.⁷ Health care workers and others who are potentially exposed to active TB on an ongoing basis should be tested at the time of employment, with repeat testing done periodically based on their risk of infection.^8,9

Individuals with coexisting conditions should be tested for LTBI as long as the benefit of treatment outweighs the risk of drug-induced hepatitis. Because the risk of drug-induced hepatitis increases with age, the decision to test/treat is affected by age as well as the individual’s risk of progression. Patients with the highest risk conditions would benefit from testing/treating regardless of age, while treatment may not be justified in those with lower-risk conditions. A reasonable strategy is as follows:¹⁰
• high-risk conditions: test regardless of age
• moderate-risk conditions: test those <65 years
• low-risk conditions: test those <50 years.

Children with LTBI are at particularly high risk of progression to active TB.⁵ The American Academy of Pediatrics (AAP) recommends assessing a child’s risk for TB at first contact with the child and once every 6 months for the first year of life. After one year, annual assessment is recommended, but specific TB testing is not required for children who don’t have risk factors.¹¹ The AAP suggests using a TB risk assessment questionnaire that consists of 4 screening questions with follow-up questions if any of the screening questions are positive (TABLE 2).¹¹

Use of TST is well established

To perform a TST, inject 5 tuberculin units (0.1 mL) of purified protein derivative (PPD) intradermally into the inner surface of the forearm using a 27- to 30-gauge needle. (In the United States, PPD is available as Aplisol or Tubersol.) Avoid the former practice of “control” or anergy testing with mumps or Candida antigens because this is rarely helpful in making TB treatment decisions, even in HIV-positive patients.¹²

To facilitate intradermal injection, gently stretch the skin taut during injection. Raising a wheal confirms correct placement. The test should be read 48 to 72 hours after it is administered by measuring the greatest diameter of induration at the administration site. (Erythema is irrelevant to how the test is interpreted.) Induration is best read by using a ballpoint pen held at a 45-degree angle pointing toward the injection site. Roll the point of the pen over the skin with gentle pressure toward the injection site until induration causes the pen to stop rolling freely (FIGURE). The induration should be measured with a rule that has millimeter measurements and interpreted as positive or negative based on the individual’s risk factors (TABLE 3).³

Watch for these 2 factors that can affect TST results

Bacille Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis, is (or has been) used as a routine childhood immunization in many parts of the world, although not in the United States.¹³ It is ordinarily given as a single dose shortly after birth, and has some utility in preventing serious childhood TB infection. The antigens in PPD and those in BCG are not identical, but they do overlap.

BCG administered after an individual’s first birthday resulted in false positive TSTs >10 mm in 21% of those tested more than 10 years after BCG was administered.¹⁴ However, a single BCG vaccine in infancy causes little if any change in the TST result in individuals who are older than age 10 years. When a TST is performed for appropriate reasons, a positive TST in people previously vaccinated with BCG is generally more likely to be the result of LTBI than of BCG.¹⁵ Current guidelines from the Centers for Disease Control and Prevention (CDC) recommend that previous BCG status not change the cutoffs used for interpreting TST results.¹⁶

Booster phenomenon. In many adults who have undiagnosed LTBI that they acquired in the distant past, or who received BCG vaccination as a child, immunity wanes after several decades. This can result in an initial TST being negative, but because the antigens in the PPD itself stimulate antigenic memory, the next time a TST is performed, it may be positive.

In people who will have annual TST screenings, such as health care workers or nursing home residents, a 2-step PPD can help discriminate this “booster” phenomenon from a new LTBI acquired during the first year of annual TST testing. A second TST is placed 1 to 2 weeks after the initial test, a time interval during which acquisition of LTBI would be unlikely. The result of the second test should be considered the person’s baseline for evaluation of subsequent TSTs. A subsequent TST would be considered positive if the induration is >10 mm and has increased by ≥6 mm since the previous baseline.¹⁷

IGRA offers certain benefits

IGRA uses antigens that are more specific for Mycobacterium tuberculosis than the TST, and as a result, this test is not influenced by previous BCG vaccination. It requires only one blood draw, and interpretation does not depend on the patient’s risk category or interpretation of skin induration. The primary disadvantage of IGRAs is high cost (currently $200 to $300 per test), and the need for a laboratory with adequate equipment and personnel trained in performing the test. IGRAs must be collected in special blood tubes, and the samples must be processed within 8 to 16 hours of collection, depending on the test used.⁵

Currently, 2 IGRAs are approved for use in the United States—the QuantiFERON-TB Gold In-Tube (QFT-GIT) and the T-SPOT.TB assay. Both tests may produce false positives in patients infected with Mycobacterium marinum or Mycobacterium kansasii, but otherwise are highly specific for Mycobacterium tuberculosis. IGRA results may be “boosted” by recent TST (ie, a TST given within the previous 3 months may cause a false positive IGRA result), and this effect may begin as early as 3 days after a TST is administered.¹⁸ Therefore, if an IGRA is needed to clarify a TST result, it should be drawn on the day the TST is read.¹⁹

CDC guidelines (2010) recommend that IGRAs may be used in place of—but not routinely in addition to—TSTs in all cases in which TST is otherwise indicated.²⁰ There are a few situations where one test may be preferred over the other.²¹

IGRA may be preferred over TST in individuals in one of 2 categories:
• those who have received BCG immunization. If a patient is unsure of their BCG status, the World Atlas of BCG Policies and Practices, available at www.bcgatlas.org,²² can aid clinicians in determining which patients likely received BCG as part of their routine childhood immunizations.
• those in groups that historically have poor rates of return for TST reading, such as individuals who are homeless or suffer from alcoholism or a substance use disorder.

Individuals in whom TST is preferred over IGRA include:
• children age <5 years, because data guiding use of IGRAs in this age group are limited.²³ Both TST and IGRA may be falsely negative in children under the age of 3 months.²⁴
• patients who require serial testing, because individuals with positive IGRAs have been shown to commonly test negative on subsequent tests, and there are limited data on interpretation and prognosis of positive IGRAs in people who require serial testing.²⁵

Individuals in whom performing both tests simultaneously could be helpful include:
• those with an initial negative test, but with a high risk for progression to active TB or a poor outcome if the first result is falsely negative (eg, patients with HIV infection or children ages <5 years who have been exposed to a person with active TB)
• those with an initial positive test who don’t believe the test result and are reluctant to be treated for LTBI.

TST and IGRA have comparable sensitivities—around 80% to 90%, respectively—for diagnosing LTBI. IGRAs have a specificity >95% for diagnosing LTBI. While TST specificity is approximately 97% in patients not vaccinated with BCG, it can be as low as 60% in people previously vaccinated with BCG.²⁶ IGRAs have been shown to have higher positive and negative predictive values than TSTs in high-risk patients.²⁷ A recent study suggested that the IGRAs might have a higher rate of false-positive results compared to TSTs in a low-risk population of health care workers.²⁸

Both the TST and IGRA have lag times of 3 to 8 weeks from the time of a new infection until the test becomes positive. It is therefore best to defer testing for LTBI infection until at least 8 weeks after a known TB exposure to decrease the likelihood of a false-negative test.³

Diagnose active TB based on symptoms, culture

The CDC reported 9412 new cases of active TB in the United States in 2014, for a rate of 3 new cases per 100,000 people.²⁹ This is the lowest rate reported since national reporting began in 1953, when the incidence in the United States was 53 cases per 100,000.

Who should you test for active TB? The risk factors for active TB are the same as those for LTBI: recent exposure to an individual with active TB, and other disease processes or medications that compromise the immune system. Consider active TB when a patient with one of these risk factors presents with:²
• persistent fever
• weight loss
• night sweats
• cough, especially if there is any blood.

Routine laboratory and radiographic studies that should prompt you to consider TB include:²
• upper lobe infiltrates on chest x-ray
• sterile pyuria on urinalysis with a negative culture for routine pathogens
• elevated levels of C-reactive protein or an elevated erythrocyte sedimentation rate without another obvious cause.

Active TB typically presents as pulmonary TB, but it can also affect nearly every other body system. Other common presentations include:³⁰
• vertebral destruction and collapse (“Pott's disease”)
• subacute meningitis
• peritonitis
• lymphadenopathy (especially in children).

IGRAs have been shown to have higher positive and negative predictive values than TSTs in high-risk patients.

Culture is the gold standard. Neither TST or IGRA should ever be relied upon to make or exclude the diagnosis of active TB, as these tests are neither sensitive nor specific for diagnosing active TB.^31,32 Instead, the gold standard for the diagnosis of active TB remains a positive culture from infected tissue—commonly sputum, pleura or pleural fluid, cerebrospinal fluid, urine, or peritoneal fluid. Cultures are crucial not only to confirm the diagnosis, but to guide therapy, because of the rapidly increasing resistance to firstline antibiotics used to treat TB.³³

Culture results and drug sensitivities are ordinarily not available until 2 to 6 weeks after the culture was obtained. A smear for acid-fast bacilli as well as newer rapid diagnostic tests such as nucleic acid amplification (NAA) tests are generally performed on the tissue sample submitted for culture, and these results, while less trustworthy, are generally available within 24 to 48 hours. The CDC recommends that an NAA test be performed in addition to microscopy and culture for specimens submitted for TB diagnosis.³⁴

A single BCG vaccine in infancy causes little if any change in the TST result in individuals who are older than 10 years of age.

Since 2011, the World Health Organization has endorsed the use of a new molecular diagnostic test called Xpert MTB/RIF in settings with high prevalence of HIV infection or multidrug-resistant TB (MDR-TB).³⁵ This test is able to detect M. tuberculosis as well as rifampin resistance, a surrogate for MDR-TB, within 2 hours, with sensitivity and specificity approaching that of culture.³⁶

“Culture-negative” TB? A small but not insignificant proportion of patients will present with risk factors for, and clinical signs and symptoms of, active TB; their cultures, however, will be negative. In such cases, consultation with an infectious disease or pulmonary specialist may be warranted. If no alternative diagnosis is found, such patients are said to have “culture-negative active TB” and should be continued on anti-TB drug therapy, although the course may be shortened.³⁷ This highlights the fact that while cultures are key to diagnosing and treating active TB, the condition is—practically speaking—a clinical diagnosis; treatment should not be withheld or stopped simply because of a negative culture or rapid diagnostic test.

CASE 1 › Based on her risk factors (being a health care worker, born in a country with a high prevalence of TB), Ms. C’s cutoff for a positive test is >10 mm, so her TST result is negative and she is not considered to have LTBI. The increase to 8 mm seen on the second TST probably represents either childhood BCG vaccination or previous infection with nontuberculous Mycobacterium.

CASE 2 › Strictly speaking, 3-year-old Patrick does not need testing, because he was exposed only to LTBI, which is not infectious. However, because children under age 5 are at particularly high risk for progressing to active TB and poor outcomes, it would be best to confirm the mother’s story with the day care center and/or health department. If it turns out that Patrick had, in fact, been exposed to active TB, much more aggressive management would be required.

CORRESPONDENCE
Jeff Hall, MD, Family Medicine Center, 3209 Colonial Drive Columbia, SC 29203; jeff.hall@uscmed.sc.edu

CASE 1 › Judy C is a newly employed 40-year-old health care worker who was born in China and received the bacille Calmette-Guérin (BCG) vaccination as a child. Her new employer requires her to undergo testing for tuberculosis (TB). Her initial tuberculin skin test (TST) is 0 mm, but on a second TST 2 weeks later, it is 8 mm. She is otherwise healthy, negative for human immunodeficiency virus (HIV), and has no constitutional symptoms. Does she have latent tuberculosis infection (LTBI)?

CASE 2 › A mom brings in her 3-year-old son, Patrick. She reports that a staff member at his day care center traveled outside the country for 3 months and was diagnosed with LTBI upon her return. She wants to know if her son should be tested.

More than 2 billion people—nearly one-third of the world’s population—are infected with Mycobacterium tuberculosis.¹ Most harbor the bacilli as LTBI, which means that while they have living TB bacilli within their bodies, these mycobacteria are kept dormant by an intact immune system. These individuals are not contagious, nor are they likely to become ill from active TB unless something adversely affects their immune system and increases the likelihood that LTBI will progress to active TB.

Two tests are available for diagnosing LTBI: the TST and the newer interferon gamma release assay (IGRA). Each test has advantages and disadvantages, and the best test to use depends on various patient-specific factors. This article describes whom you should test for LTBI, which test to use, and how to diagnose active TB.

Why test for LTBI?

LTBI is an asymptomatic infection; patients with LTBI have a 5% to 10% lifetime risk of developing active TB.² The risk of developing active TB is approximately 5% within the first 18 months of infection, and the remaining risk is spread out over the rest of the patient’s life.² Screening for LTBI is desirable because early diagnosis and treatment can reduce the activation risk to 1% to 2%,³ and treatment for LTBI is simpler, less costly, and less toxic than treatment for active TB.

Whom to test. Screening for LTBI should target patients for whom the benefits of treatment outweigh the cost and risks of treatment.⁴ A decision to screen for LTBI implies that the patient will be treated if he or she tests positive.³

The benefit of treatment increases in people who have a significant risk of progression to active TB—primarily those with recently acquired LTBI, or with co-existing conditions that increase their likelihood of progression (TABLE 1).⁵

Screening for latent TB infection is desirable because early diagnosis and treatment can reduce the activation risk to 1% to 2%.

All household contacts of patients with active TB and recent immigrants from countries with a high TB prevalence should be tested for LTBI.⁶ Those with a negative test and recent exposure should be retested in 8 to 12 weeks to allow for the delay in conversion to a positive test after recent infection.⁷ Health care workers and others who are potentially exposed to active TB on an ongoing basis should be tested at the time of employment, with repeat testing done periodically based on their risk of infection.^8,9

Individuals with coexisting conditions should be tested for LTBI as long as the benefit of treatment outweighs the risk of drug-induced hepatitis. Because the risk of drug-induced hepatitis increases with age, the decision to test/treat is affected by age as well as the individual’s risk of progression. Patients with the highest risk conditions would benefit from testing/treating regardless of age, while treatment may not be justified in those with lower-risk conditions. A reasonable strategy is as follows:¹⁰
• high-risk conditions: test regardless of age
• moderate-risk conditions: test those <65 years
• low-risk conditions: test those <50 years.

Children with LTBI are at particularly high risk of progression to active TB.⁵ The American Academy of Pediatrics (AAP) recommends assessing a child’s risk for TB at first contact with the child and once every 6 months for the first year of life. After one year, annual assessment is recommended, but specific TB testing is not required for children who don’t have risk factors.¹¹ The AAP suggests using a TB risk assessment questionnaire that consists of 4 screening questions with follow-up questions if any of the screening questions are positive (TABLE 2).¹¹

Use of TST is well established

To perform a TST, inject 5 tuberculin units (0.1 mL) of purified protein derivative (PPD) intradermally into the inner surface of the forearm using a 27- to 30-gauge needle. (In the United States, PPD is available as Aplisol or Tubersol.) Avoid the former practice of “control” or anergy testing with mumps or Candida antigens because this is rarely helpful in making TB treatment decisions, even in HIV-positive patients.¹²

To facilitate intradermal injection, gently stretch the skin taut during injection. Raising a wheal confirms correct placement. The test should be read 48 to 72 hours after it is administered by measuring the greatest diameter of induration at the administration site. (Erythema is irrelevant to how the test is interpreted.) Induration is best read by using a ballpoint pen held at a 45-degree angle pointing toward the injection site. Roll the point of the pen over the skin with gentle pressure toward the injection site until induration causes the pen to stop rolling freely (FIGURE). The induration should be measured with a rule that has millimeter measurements and interpreted as positive or negative based on the individual’s risk factors (TABLE 3).³

Watch for these 2 factors that can affect TST results

Bacille Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis, is (or has been) used as a routine childhood immunization in many parts of the world, although not in the United States.¹³ It is ordinarily given as a single dose shortly after birth, and has some utility in preventing serious childhood TB infection. The antigens in PPD and those in BCG are not identical, but they do overlap.

BCG administered after an individual’s first birthday resulted in false positive TSTs >10 mm in 21% of those tested more than 10 years after BCG was administered.¹⁴ However, a single BCG vaccine in infancy causes little if any change in the TST result in individuals who are older than age 10 years. When a TST is performed for appropriate reasons, a positive TST in people previously vaccinated with BCG is generally more likely to be the result of LTBI than of BCG.¹⁵ Current guidelines from the Centers for Disease Control and Prevention (CDC) recommend that previous BCG status not change the cutoffs used for interpreting TST results.¹⁶

Booster phenomenon. In many adults who have undiagnosed LTBI that they acquired in the distant past, or who received BCG vaccination as a child, immunity wanes after several decades. This can result in an initial TST being negative, but because the antigens in the PPD itself stimulate antigenic memory, the next time a TST is performed, it may be positive.

In people who will have annual TST screenings, such as health care workers or nursing home residents, a 2-step PPD can help discriminate this “booster” phenomenon from a new LTBI acquired during the first year of annual TST testing. A second TST is placed 1 to 2 weeks after the initial test, a time interval during which acquisition of LTBI would be unlikely. The result of the second test should be considered the person’s baseline for evaluation of subsequent TSTs. A subsequent TST would be considered positive if the induration is >10 mm and has increased by ≥6 mm since the previous baseline.¹⁷

IGRA offers certain benefits

IGRA uses antigens that are more specific for Mycobacterium tuberculosis than the TST, and as a result, this test is not influenced by previous BCG vaccination. It requires only one blood draw, and interpretation does not depend on the patient’s risk category or interpretation of skin induration. The primary disadvantage of IGRAs is high cost (currently $200 to $300 per test), and the need for a laboratory with adequate equipment and personnel trained in performing the test. IGRAs must be collected in special blood tubes, and the samples must be processed within 8 to 16 hours of collection, depending on the test used.⁵

Currently, 2 IGRAs are approved for use in the United States—the QuantiFERON-TB Gold In-Tube (QFT-GIT) and the T-SPOT.TB assay. Both tests may produce false positives in patients infected with Mycobacterium marinum or Mycobacterium kansasii, but otherwise are highly specific for Mycobacterium tuberculosis. IGRA results may be “boosted” by recent TST (ie, a TST given within the previous 3 months may cause a false positive IGRA result), and this effect may begin as early as 3 days after a TST is administered.¹⁸ Therefore, if an IGRA is needed to clarify a TST result, it should be drawn on the day the TST is read.¹⁹

CDC guidelines (2010) recommend that IGRAs may be used in place of—but not routinely in addition to—TSTs in all cases in which TST is otherwise indicated.²⁰ There are a few situations where one test may be preferred over the other.²¹

IGRA may be preferred over TST in individuals in one of 2 categories:
• those who have received BCG immunization. If a patient is unsure of their BCG status, the World Atlas of BCG Policies and Practices, available at www.bcgatlas.org,²² can aid clinicians in determining which patients likely received BCG as part of their routine childhood immunizations.
• those in groups that historically have poor rates of return for TST reading, such as individuals who are homeless or suffer from alcoholism or a substance use disorder.

Individuals in whom TST is preferred over IGRA include:
• children age <5 years, because data guiding use of IGRAs in this age group are limited.²³ Both TST and IGRA may be falsely negative in children under the age of 3 months.²⁴
• patients who require serial testing, because individuals with positive IGRAs have been shown to commonly test negative on subsequent tests, and there are limited data on interpretation and prognosis of positive IGRAs in people who require serial testing.²⁵

Individuals in whom performing both tests simultaneously could be helpful include:
• those with an initial negative test, but with a high risk for progression to active TB or a poor outcome if the first result is falsely negative (eg, patients with HIV infection or children ages <5 years who have been exposed to a person with active TB)
• those with an initial positive test who don’t believe the test result and are reluctant to be treated for LTBI.

TST and IGRA have comparable sensitivities—around 80% to 90%, respectively—for diagnosing LTBI. IGRAs have a specificity >95% for diagnosing LTBI. While TST specificity is approximately 97% in patients not vaccinated with BCG, it can be as low as 60% in people previously vaccinated with BCG.²⁶ IGRAs have been shown to have higher positive and negative predictive values than TSTs in high-risk patients.²⁷ A recent study suggested that the IGRAs might have a higher rate of false-positive results compared to TSTs in a low-risk population of health care workers.²⁸

Both the TST and IGRA have lag times of 3 to 8 weeks from the time of a new infection until the test becomes positive. It is therefore best to defer testing for LTBI infection until at least 8 weeks after a known TB exposure to decrease the likelihood of a false-negative test.³

Diagnose active TB based on symptoms, culture

The CDC reported 9412 new cases of active TB in the United States in 2014, for a rate of 3 new cases per 100,000 people.²⁹ This is the lowest rate reported since national reporting began in 1953, when the incidence in the United States was 53 cases per 100,000.

Who should you test for active TB? The risk factors for active TB are the same as those for LTBI: recent exposure to an individual with active TB, and other disease processes or medications that compromise the immune system. Consider active TB when a patient with one of these risk factors presents with:²
• persistent fever
• weight loss
• night sweats
• cough, especially if there is any blood.

Routine laboratory and radiographic studies that should prompt you to consider TB include:²
• upper lobe infiltrates on chest x-ray
• sterile pyuria on urinalysis with a negative culture for routine pathogens
• elevated levels of C-reactive protein or an elevated erythrocyte sedimentation rate without another obvious cause.

Active TB typically presents as pulmonary TB, but it can also affect nearly every other body system. Other common presentations include:³⁰
• vertebral destruction and collapse (“Pott's disease”)
• subacute meningitis
• peritonitis
• lymphadenopathy (especially in children).

IGRAs have been shown to have higher positive and negative predictive values than TSTs in high-risk patients.

Culture is the gold standard. Neither TST or IGRA should ever be relied upon to make or exclude the diagnosis of active TB, as these tests are neither sensitive nor specific for diagnosing active TB.^31,32 Instead, the gold standard for the diagnosis of active TB remains a positive culture from infected tissue—commonly sputum, pleura or pleural fluid, cerebrospinal fluid, urine, or peritoneal fluid. Cultures are crucial not only to confirm the diagnosis, but to guide therapy, because of the rapidly increasing resistance to firstline antibiotics used to treat TB.³³

Culture results and drug sensitivities are ordinarily not available until 2 to 6 weeks after the culture was obtained. A smear for acid-fast bacilli as well as newer rapid diagnostic tests such as nucleic acid amplification (NAA) tests are generally performed on the tissue sample submitted for culture, and these results, while less trustworthy, are generally available within 24 to 48 hours. The CDC recommends that an NAA test be performed in addition to microscopy and culture for specimens submitted for TB diagnosis.³⁴

A single BCG vaccine in infancy causes little if any change in the TST result in individuals who are older than 10 years of age.

Since 2011, the World Health Organization has endorsed the use of a new molecular diagnostic test called Xpert MTB/RIF in settings with high prevalence of HIV infection or multidrug-resistant TB (MDR-TB).³⁵ This test is able to detect M. tuberculosis as well as rifampin resistance, a surrogate for MDR-TB, within 2 hours, with sensitivity and specificity approaching that of culture.³⁶

“Culture-negative” TB? A small but not insignificant proportion of patients will present with risk factors for, and clinical signs and symptoms of, active TB; their cultures, however, will be negative. In such cases, consultation with an infectious disease or pulmonary specialist may be warranted. If no alternative diagnosis is found, such patients are said to have “culture-negative active TB” and should be continued on anti-TB drug therapy, although the course may be shortened.³⁷ This highlights the fact that while cultures are key to diagnosing and treating active TB, the condition is—practically speaking—a clinical diagnosis; treatment should not be withheld or stopped simply because of a negative culture or rapid diagnostic test.

CASE 1 › Based on her risk factors (being a health care worker, born in a country with a high prevalence of TB), Ms. C’s cutoff for a positive test is >10 mm, so her TST result is negative and she is not considered to have LTBI. The increase to 8 mm seen on the second TST probably represents either childhood BCG vaccination or previous infection with nontuberculous Mycobacterium.

CASE 2 › Strictly speaking, 3-year-old Patrick does not need testing, because he was exposed only to LTBI, which is not infectious. However, because children under age 5 are at particularly high risk for progressing to active TB and poor outcomes, it would be best to confirm the mother’s story with the day care center and/or health department. If it turns out that Patrick had, in fact, been exposed to active TB, much more aggressive management would be required.

CORRESPONDENCE
Jeff Hall, MD, Family Medicine Center, 3209 Colonial Drive Columbia, SC 29203; jeff.hall@uscmed.sc.edu

CASE 1 › Judy C is a newly employed 40-year-old health care worker who was born in China and received the bacille Calmette-Guérin (BCG) vaccination as a child. Her new employer requires her to undergo testing for tuberculosis (TB). Her initial tuberculin skin test (TST) is 0 mm, but on a second TST 2 weeks later, it is 8 mm. She is otherwise healthy, negative for human immunodeficiency virus (HIV), and has no constitutional symptoms. Does she have latent tuberculosis infection (LTBI)?

CASE 2 › A mom brings in her 3-year-old son, Patrick. She reports that a staff member at his day care center traveled outside the country for 3 months and was diagnosed with LTBI upon her return. She wants to know if her son should be tested.

More than 2 billion people—nearly one-third of the world’s population—are infected with Mycobacterium tuberculosis.¹ Most harbor the bacilli as LTBI, which means that while they have living TB bacilli within their bodies, these mycobacteria are kept dormant by an intact immune system. These individuals are not contagious, nor are they likely to become ill from active TB unless something adversely affects their immune system and increases the likelihood that LTBI will progress to active TB.

Two tests are available for diagnosing LTBI: the TST and the newer interferon gamma release assay (IGRA). Each test has advantages and disadvantages, and the best test to use depends on various patient-specific factors. This article describes whom you should test for LTBI, which test to use, and how to diagnose active TB.

Why test for LTBI?

LTBI is an asymptomatic infection; patients with LTBI have a 5% to 10% lifetime risk of developing active TB.² The risk of developing active TB is approximately 5% within the first 18 months of infection, and the remaining risk is spread out over the rest of the patient’s life.² Screening for LTBI is desirable because early diagnosis and treatment can reduce the activation risk to 1% to 2%,³ and treatment for LTBI is simpler, less costly, and less toxic than treatment for active TB.

Whom to test. Screening for LTBI should target patients for whom the benefits of treatment outweigh the cost and risks of treatment.⁴ A decision to screen for LTBI implies that the patient will be treated if he or she tests positive.³

The benefit of treatment increases in people who have a significant risk of progression to active TB—primarily those with recently acquired LTBI, or with co-existing conditions that increase their likelihood of progression (TABLE 1).⁵

Screening for latent TB infection is desirable because early diagnosis and treatment can reduce the activation risk to 1% to 2%.

All household contacts of patients with active TB and recent immigrants from countries with a high TB prevalence should be tested for LTBI.⁶ Those with a negative test and recent exposure should be retested in 8 to 12 weeks to allow for the delay in conversion to a positive test after recent infection.⁷ Health care workers and others who are potentially exposed to active TB on an ongoing basis should be tested at the time of employment, with repeat testing done periodically based on their risk of infection.^8,9

Individuals with coexisting conditions should be tested for LTBI as long as the benefit of treatment outweighs the risk of drug-induced hepatitis. Because the risk of drug-induced hepatitis increases with age, the decision to test/treat is affected by age as well as the individual’s risk of progression. Patients with the highest risk conditions would benefit from testing/treating regardless of age, while treatment may not be justified in those with lower-risk conditions. A reasonable strategy is as follows:¹⁰
• high-risk conditions: test regardless of age
• moderate-risk conditions: test those <65 years
• low-risk conditions: test those <50 years.

Children with LTBI are at particularly high risk of progression to active TB.⁵ The American Academy of Pediatrics (AAP) recommends assessing a child’s risk for TB at first contact with the child and once every 6 months for the first year of life. After one year, annual assessment is recommended, but specific TB testing is not required for children who don’t have risk factors.¹¹ The AAP suggests using a TB risk assessment questionnaire that consists of 4 screening questions with follow-up questions if any of the screening questions are positive (TABLE 2).¹¹

Use of TST is well established

To perform a TST, inject 5 tuberculin units (0.1 mL) of purified protein derivative (PPD) intradermally into the inner surface of the forearm using a 27- to 30-gauge needle. (In the United States, PPD is available as Aplisol or Tubersol.) Avoid the former practice of “control” or anergy testing with mumps or Candida antigens because this is rarely helpful in making TB treatment decisions, even in HIV-positive patients.¹²

To facilitate intradermal injection, gently stretch the skin taut during injection. Raising a wheal confirms correct placement. The test should be read 48 to 72 hours after it is administered by measuring the greatest diameter of induration at the administration site. (Erythema is irrelevant to how the test is interpreted.) Induration is best read by using a ballpoint pen held at a 45-degree angle pointing toward the injection site. Roll the point of the pen over the skin with gentle pressure toward the injection site until induration causes the pen to stop rolling freely (FIGURE). The induration should be measured with a rule that has millimeter measurements and interpreted as positive or negative based on the individual’s risk factors (TABLE 3).³

Watch for these 2 factors that can affect TST results

Bacille Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis, is (or has been) used as a routine childhood immunization in many parts of the world, although not in the United States.¹³ It is ordinarily given as a single dose shortly after birth, and has some utility in preventing serious childhood TB infection. The antigens in PPD and those in BCG are not identical, but they do overlap.

BCG administered after an individual’s first birthday resulted in false positive TSTs >10 mm in 21% of those tested more than 10 years after BCG was administered.¹⁴ However, a single BCG vaccine in infancy causes little if any change in the TST result in individuals who are older than age 10 years. When a TST is performed for appropriate reasons, a positive TST in people previously vaccinated with BCG is generally more likely to be the result of LTBI than of BCG.¹⁵ Current guidelines from the Centers for Disease Control and Prevention (CDC) recommend that previous BCG status not change the cutoffs used for interpreting TST results.¹⁶