A 52-Year-Old Man With a Positive PPD

DR DELBANCO: Mr Z is a 52-year-old college professor with a dry, hacking cough. Born in India and raised in Bangladesh, Mr Z immigrated to the United States more than 20 years ago. He lives in Boston with his wife and daughter and has managed care insurance.

Mr Z had a negative purified protein derivative (PPD) test result 15 years ago. He recently traveled to Bangladesh for 3 weeks. Upon returning from his trip with a persistent hacking cough, he saw a primary care nurse practitioner who prescribed a steroid inhaler; the cough resolved slowly. A PPD test yielded 22 × 28 mm of induration. Results of a chest radiograph were normal. On his recent trip, he had no known contacts with tuberculosis (TB). His BCG vaccination status is unknown.

His past medical history is significant for borderline hypertension and adenomatous polyps of the colon. He was diagnosed as having diabetes 3 years ago but has no retinopathy, nephropathy, or neuropathy. Recent glycohemoglobin levels were 8.8% and 7.8%. Mr Z smoked from ages 14 to 18 years but has not smoked since. He does not drink alcohol.

On physical examination, Mr Z appeared well and was overweight, weighing 181 lb at 5 feet 8 inches. His blood pressure was 140/90 mm Hg. His lungs were clear, his liver was normal in span, and he had nontender submandibular lymphadenopathy. He had good peripheral pulses and sensation. His current medications were lisinopril, 10 mg/d (started months before his cough developed); metformin, 500 mg twice daily; and glipizide XL, 5 mg/d. He has no known drug allergies.

When I was in Bangladesh, I did not have this cough, but during the trip back on the plane, I developed a cough. Coming back here, I was coughing incessantly for at least the first 2 weeks. Because I came from one part of the world where there is heavy incidence of tuberculosis, I was tested for TB. Three days later, I came back and the test came out positive.

I know I can catch TB anytime, anywhere. It doesn't take 2 weeks. I can catch it in one day. I could have caught it over there, I could have caught it over here. I'm not fighting the whole concept that I have TB. If it is, it is. I have to deal with it.

As far as I'm concerned, if I need to take medication or if I have to go through other tests, I'll be happy to do it. I am open to whatever the doctor wants me to do.

With the strides in medicine at this point, I'm not really afraid of tuberculosis. It's not a life-threatening illness. It may curtail some of my life experiences or the way I live my life. But I know that it's not immediately life-threatening. It can be dealt with.

Mr Z regularly goes to Bangladesh to visit family. The most recent trip was somewhat complicated because he became sick when he was there with a persistent dry cough.

What to do with his positive PPD was tricky. It wasn't clear that the fact that it was positive now was any indication of acute exposure. In fact, to my mind, the odds were more likely that he had been exposed during a previous visit.

When we sorted out the downside of having to take medication and be monitored regularly for that, and incur risk of liver damage compared with what seemed like a relatively small chance that this was a new exposure, we elected not to treat him. In my mind, the guidelines were not perfectly explicit about what to do with somebody who may or may not have had a recent exposure, and clearly had exposure going back a long ways.

The American Thoracic Society (ATS) guidelines basically say, don't screen anybody you don't want to treat. But what happens when somebody is screened and we weren't sure what we wanted to do with treatment?

What is the epidemiology of TB in the United States and globally? How is the PPD test applied and read, and what is its significance? What are the current recommendations for TB screening and chemoprophylaxis? What role is there for BCG vaccination and other approaches toward vaccines? For someone who has received BCG vaccination and has a positive skin test result, what do you recommend for surveillance? What are the downsides and dangers of preventive measures? What does the future hold in screening and prevention for TB? What do you recommend for Mr Z?

DR ISEMAN: Mr Z's history is outlined clearly. Several months ago while returning from Bangladesh, he developed a relentless hacking cough that led him to seek medical attention. Because the Indian subcontinent is an area endemic for TB, his evaluation appropriately included chest radiography and a tuberculin skin test (TST). The review of systems for risk factors for TB included diabetes mellitus, but he has well-controlled type 2 diabetes, which lessens the likelihood that his diabetes puts him at special risk for active TB.^{1 - 2}

The critical issues confronting Mr Z and his medical team at this juncture were to rule out active TB and, that being done, to consider preventive chemotherapy for latent TB infection. The central questions in treatment of such infection are: (1) What risk is signaled by the positive TST? (2) What is the efficacy of the various regimens recommended for treatment of latent TB infection? (3) What are the risks of these same regimens? and (4) What steps can be taken to minimize the hazards of such treatment? But, before addressing these issues, we should consider the current global crisis involving TB.

The tubercle bacillus arguably is the most successfully adapted parasite of humankind. The organism, or its biologically similar antecedents, has been a pathogen for more than 5000 years, as evidenced by osseous remains from ancient Egypt, China, and South America.³

In this long relationship with humans, the mycobacterium has corrupted our immune responses to facilitate its transmission and survival. The mycobacteria belong to the order Actinomycetales, organisms of the soil. Genetic phylogeny suggests that the original mycobacterial infection of humans came via the alimentary canal, presumably through eating the flesh or drinking the milk of grass-eating (ruminant) animals when humans began cultivating plants and herding animals, roughly 15 000 years ago.⁴ But as the tubercle bacillus adapted to humans, it evolved the capacity to elicit cavitary pulmonary lesions. In these cavities, the mycobacteria enjoyed uniquely unchecked extracellular replication. Through this mechanism, diseased patients coughed immense numbers of mycobacteria into the air, resulting in airborne transmission to others. This route of infection was more efficient than the alimentary pathway, but it required that humans spend time together in closed spaces, since the infinite volume of air and UV irradiation from sunlight effectively precluded outdoor transmission.

Currently, the World Health Organization (WHO) calculates that one third of the world's population is infected with the tubercle bacillus.⁵ However, the infections are not uniformly distributed. While roughly 40% of persons residing in the Indian subcontinent, China, and Pacific Rim nations are infected, only 4% of the current US population is thought to harbor latent infection.

These differing rates of infection are reflected in disproportionate morbidity rates for these areas. Experts estimate that approximately 10 million new cases develop annually. Nearly 2 million of these infected individuals live in India, while the United States reported only 16 377 in 2000.^{6 - 7} Both India and Bangladesh have prevalence rates of TB greater than 500 per 100 000 population, while that of the United States is fewer than 10 per 100 000.

Especially in developing nations, major factors driving the global epidemic of TB include inadequate diagnostic services and the inability to provide or ensure appropriate drug therapy. Also, in Africa, Asia, the Indian subcontinent, and other selected regions, HIV (human immunodeficiency virus) infection is rapidly accelerating TB case and death rates.⁸ Drug resistance to the major medications (multidrug-resistant TB) has in some regions reached the point where it has compromised the predictable efficacy of the standard regimens.⁹ However, this factor is not yet a measurable element in global incidence rates.

Underlying this dismal situation is the fundamental failure of the TB vaccine, BCG (bacillus of Calmette and Guerin). Although a meta-analysis calculated that the vaccine was approximately 50% protective,¹⁰ the ongoing epidemic in the face of very high vaccine coverage rates in these areas calls into question the effectiveness of BCG vaccine. Indeed, many authorities now believe that while BCG vaccine is capable of protecting infants and children, it does little to alter the prevalence of communicable pulmonary disease in adults.¹¹

After Robert Koch's discovery of the tubercle bacillus in 1882, considerable interest focused on screening for TB. In the first half of the 20th century, screening was directed to the detection of active disease among the general population. Mobile chest radiography units, routine annual chest radiographs, or admission radiography for all those entering hospitals were the primary techniques used. As the prevalence of disease diminished, these methods have been generally abandoned, except in the case of particularly high-risk individuals, such as persons from endemic areas who apply for immigration to the United States, homeless males in urban shelters, or those entering correctional facilities.¹²

In the United States today, the goal of screening is to examine persons for the presence of latent TB infection, with the ultimate objective of offering them preventive chemotherapy.¹² The United States and the Netherlands were the only 2 nations historically to have rejected the strategy of BCG vaccination in favor of the preemptive treatment of latent infection. However, many nations have added preventive chemotherapy to their public health armamentaria.

The choice of the preventive therapy strategy for the United States (known initially as "chemoprophylaxis" and most recently as "treatment of latent TB infection") reflects the logic represented in Figure 1.¹³ Epidemiological data¹³ suggested that in a country such as the United States, most cases occurred from endogenous reactivation of infections that were remote (many years) in time. In contrast, BCG vaccination aims at persons not yet infected with TB (as identified by nonreactivity to the TST). Hence, even if the vaccine were highly efficacious, it would have a minimal effect on total morbidity. Rather, it was reasoned that if persons at higher risk for reactivation took chemotherapy, case rates would decrease significantly.

Because it was the most active agent then available, isoniazid was studied in 2 major trial programs. In 5 US Public Health Service trials in the 1960s, 72 000 persons were randomized to either isoniazid or placebo daily for 12 months.¹⁴ The overall protective efficacy of isoniazid in the study groups was approximately 60% to 65%. For instance, in the Alaskan Village trial, case rates in the placebo group after 5 years of observation were approximately 4.7% while they were in the range of 1.6% to 1.8% among isoniazid recipients.¹⁵ In eastern Europe, approximately 27 000 persons with positive TST results and upper lobe fibronodular shadows consistent with "healed" TB were randomized to isoniazid or placebo.¹⁶ In this 5-year study, efficacy ranged from 60% to 90%, depending on duration of therapy. Case rates for placebo recipients were 1.5%; by contrast, those who were compliant with 12 months of isoniazid therapy had a 0.11% attack rate. Analysis of one of the groups studied in the US trials, Alaskan villagers, indicated that protection persisted for 15 years and—possibly—for life.¹⁵

To screen for latent infection, the only tool is the TST. A brief history demonstrates how truly primitive and limited this test is. In 1890, 8 years after Koch's description of the tubercle bacillus, he cryptically announced that he had come upon a substance, a glycerine-extract of a broth culture of the mycobacteria, that would both cure and prevent TB.¹⁷ Known originally as Koch's Lymph, it was given to thousands of patients, with widely variable results including highly morbid, even lethal outcomes. By 1907, von Pirquet concluded that this material—by then called "old tuberculin"—was of no therapeutic utility but might best be used as a diagnostic tool.¹⁸

Refined in the 1930s and 1940s, this material was then designated as PPD. Routes of delivery included the multipuncture (tine or Heaf) devices, which have largely been supplanted by the intradermal needle (Mantoux) technique. After considerable study and debate, consensus has evolved regarding the appropriate amount of tuberculin to be delivered. Referred to as tuberculin units (TUs), 2 to 5 such quanta are to be given by standard WHO or ATS protocol.^{19 - 20} The potency of various batches is supposed to be quantified by human testing, but such standardization has proven problematic.^{21 - 23}

Current understanding of the biology of the TST is as follows. Persons infected with mycobacteria develop delayed-type hypersensitivity to constituents of the bacterial cell wall. Following the primary infection of a new patient, delayed-type hypersensitivity typically develops between 4 and 16 weeks. Then, when the tuberculoprotein is injected intradermally, an indurated response develops between 48 and 120 hours later.

Interpreting the results has proven vexing. Since induration, not erythema, is the end point, clinicians try to measure swelling in the skin of the forearm where the test was applied. Abundant literature documents discouraging variability, both interreader and intrareader.²⁴ Aids such as the ball-pen method (induration is said to impede the progress of the pen as it rolls up against the edge of the swelling) may help. However, contemporaneous to the Human Genome Project, to interpret this important diagnostic study with a sense of touch is an embarrassing indictment of modern TB research.

Furthermore, the TST—even if correctly read—is neither sensitive nor specific in the diagnosis of TB infection or disease. Among persons with active disease, false-negative TST results occur in up to 25% of patients.²⁵ The rate of false-negatives is much higher in persons with AIDS, up to 76%.²⁶ Because the TST is the tool that defines latent TB infection, we cannot determine what percentage of those infected are unreactive or anergic. Based on negative TST results in persons who have active TB, we reason that some persons with latent TB infection should also have false-negative TSTs. But, we have only 1 test to identify latent infection—the TST. Thus, we can only infer that "some" (unknown percentage) with latent infection will be missed by the TST.

Even more problematic are false-positive results: TST reactions that reflect either prior BCG vaccination or infection due to environmental mycobacteria such as Mycobacterium avium complex. Cross-reactivity for these factors substantially compromises the positive predictive value of the TST, especially in low-risk groups. Indeed, when used in groups with a low prior probability of TB infection, the TST will generate significantly more false-positive than true-positive reactions.²⁷

Among immigrants, history of BCG vaccination has proven confusing. Because of the high risk for TB in their first 2 years in the United States, the Centers for Disease Control and Prevention (CDC) considers screening such individuals for latent infection a high priority.¹² Unfortunately, prior vaccination may confound the interpretation of the TST through cross-reactivity. However, authorities generally disregard the potential effects of BCG vaccination in analyzing tuberculin reactivity among immigrants from high-risk regions.²⁸ The rationale is the demonstrably high rates of TB in these groups, despite BCG vaccination. Also, this policy reflects willingness to give preventive treatment to a few persons whose TST reactivity is due to BCG vaccination to offer effective prevention to many at high risk for TB.

Because the risk of developing disease is relatively higher in the first 2 years after new infection, the ATS and CDC have placed considerable importance on identifying newly infected persons as candidates for preventive chemotherapy or treatment of latent TB infection.²⁹ This provides the epidemiological justification for serial TSTs in health care workers or others at high risk of TB exposure. Were Mr Z's TST results shown to have become positive within the last 2 to 3 years, he clearly would have been a candidate for preventive chemotherapy. This policy is based on the observation that following new infection, roughly 5% to 7% of adults will manifest active TB in the next 2 years (for preschool infants and children or persons 70 years or older—groups with naturally reduced resistance to TB—disease rates following new infections are considerably higher).²⁹ If individuals get through this period without TB and they have no other special risk factors, their annual risk of disease falls to significantly less than 1% annually. Hence, for groups at higher risk for exposure to TB, tests are recommended annually, or even more frequently. But, in some persons, repeated TSTs cause recall or boosting of prior tuberculin reactivity that had waned over time. Here, the initial TST may be negative, but the subsequent TST becomes positive—not due to intercurrent TB infection but to "boosting."³⁰ To lessen the likelihood of this misleading scenario, authorities suggest that persons who are to have serial TSTs should have a second test done 1 to 4 weeks after an initial negative test result.¹² A positive reaction after this short interval is deemed to reflect recalled delayed-type hypersensitivity, not recent infection. Although the boosted test may truly reflect prior TB infection, it does not have the same prognostic implications as a true recent conversion.

Before leaving this topic, we should discuss the implication of Mr Z's large tuberculin reaction. In general, studies indicate that persons with larger responses, eg, 20 mm of induration, are at greater risk for subsequent TB than those with lesser reactions, eg, 10 mm, even though both responses are considered positive. This pattern is presumably related to the effects of cross-reactivity from nontuberculous mycobacterial infections: a 10-mm tuberculin reaction is relatively more likely to reflect prior infection with an environmental organism like M avium than is the 20-mm response, which has a great likelihood of reflecting an encounter with Mycobacterium tuberculosis.³¹

In view of the changing epidemiology of TB in the United States, the guidelines for TB screening and prevention were revised one year ago.²⁹ This new document advocates more focused uses of tuberculin testing, summarized by the philosophy that "the decision to test is the decision to treat." If the TST is positive, we should be prepared to offer treatment ( Article ).

Persons at Risk for Recent Infection

Persons Most Likely to Develop Active Disease

Looking specifically at Mr Z, his 28-mm tuberculin reaction following a 3-week visit to Bangladesh does not, per se, constitute an indication for treatment of latent TB infection. Although his PPD was nonreactive in 1986, this new test does not represent a recent conversion, since that is limited to a 2-year interval. And, he does not have biological risk factors such as HIV infection, type 1 diabetes mellitus, or end-stage renal disease. However, his PPD was strongly positive.

The clinical illness that Mr Z experienced while in Bangladesh compels us to consider the possibility of acutely acquired TB infection during the visit. However, the persistent hacking cough that he developed while traveling is not typical of primary TB in adults. And, the normal chest radiograph argues strongly against acute TB of the lungs. Nonetheless, there are instances of endobronchial TB with "normal" chest radiography but positive sputum smears and cultures. Sputa for mycobacterial smear and culture may be helpful in this situation.

Mr Z was treated with inhaled steroids for his refractory cough. Anecdotal observations from India have linked temporally the use of such therapy with the development of active pulmonary TB.³² Although it is improbable that inhaled corticosteroids exert systemic effects on immunity, it is conceivable that local or regional effects could prove deleterious.

Finally, Mr Z had lymphadenopathy noted on his return. In CDC surveys, TB of the neck and supraclavicular lymph nodes is relatively common among immigrants from the Indian subcontinent.³³ However, acute lymphadenitis is uncommon in primary TB, except in persons with AIDS. The nature of Mr Z's lymphadenitis is not characteristic of TB: M tuberculosis more commonly involves the supraclavicular, anterior, or posterior cervical nodes (chains that drain from the thorax) than the submandibular nodes, as in this case. And, in most instances, tuberculous adenitis is not bilateral.

Deciding to offer preventive therapy or treatment of latent TB infection requires a calculation of potential benefit vs risk, tempered by considerations of cost-effectiveness. Although the efficacy of isoniazid preventive therapy is beyond doubt, concerns over the potential risk of serious, even lethal, hepatitis have dampened enthusiasm for this practice.^{34 - 36} Early experience indicated isoniazid was benign, but around 1970 cases of fatal drug-induced hepatitis were reported in modest yet chilling numbers of patients.^{34 ,37} In retrospect, this increase in drug-induced hepatitis likely stemmed from the appearance or increased incidence in the United States of viral hepatitis C, then called non-A, non-B hepatitis. A recent report from Florida demonstrated that those with viral hepatitis C infection are at a 5-fold increased risk of hepatitis from anti-TB drugs.³⁸ It seems plausible that when this virus was introduced into the United States, it acted as a cofactor, potentiating both the frequency and severity of isoniazid-induced liver injury.

To calculate accurate benefit-risk ratios, good evidence is needed regarding the frequency of toxicity. One early survey indicated death in 8 of 13 800 recipients of isoniazid.³⁷ Pooled data from large trials in which monitoring for hepatitis was not done showed an average fatality rate of 1 in 10 000.³⁹ An influential decision analysis that used these risks for lethal hepatitis concluded that isoniazid preventive therapy for young adults with a positive TST result was not justified.⁴⁰ Comprehensive studies performed in an era with better awareness and monitoring suggest that the overall risk is roughly in the range of 1 in 100 000 and the risk for those older than 35 years is approximately 2 in 100 000.³⁹ The CDC and other authorities now believe that the benefit-risk profile clearly justifies the isoniazid preventive therapy strategy in the groups noted in the Article .²⁹

One of the central issues is the age of the patient, something clearly relevant to Mr Z. Early studies suggested that the risk of isoniazid-induced hepatitis increased with age. A survey from Maryland,⁴¹ a CDC surveillance report,³⁷ the East Europe IUAT trial,⁴² and a survey in Seattle⁴³ all noted that the likelihood of hepatitis increased with age, generally from less than 1% in the third decade to 3% to 5% in the sixth decade. This observation led to the practice of advocating preventive therapy for persons with a positive TST result and no other risk factors only if they were aged 35 years or younger. But 2 decision analyses favor isoniazid preventive therapy in those without other risk factors up to age 45 years³⁶ and 50 years.³⁹ Furthermore, the other indications for treatment of latent TB infection ( Article ) are not constrained by age.

Also noteworthy is the change in recommendations for monitoring. Formerly, periodic observation of liver chemistries was advocated for early recognition of hepatic injury. However, the new guidelines primarily endorse monitoring for symptoms.²⁹ While up to 20% of those receiving isoniazid will experience elevations of their alanine aminotransferase values, virtually all cases of serious hepatitis have been marked by early symptoms.^{42 ,44 - 45}

Finally, the 2000 guidelines²⁹ offer clinicians new options for the treatment of latent infection. The 1994 recommendations identified 6 months of isoniazid as the standard regimen, with 12 months of isoniazid advocated for persons with HIV infection or fibrotic lesions on chest radiography.⁴⁶ The newer recommendations include different durations of isoniazid therapy, as well as a 4-month regimen of rifampin, or 2- or 3-month regimens of rifampin and pyrazinamide (Table 1). The use of alternative agents should overcome isoniazid resistance. Recent data suggest that drug resistance rates may range as high as 25% in regions of India, with isoniazid resistance being the most common pattern,⁹ so this is not a trivial issue for our case.

The 2- or 3-month regimens are intended to combat nonadherence by shortening the duration and permitting twice-weekly schedules. However, recent reports of liver injury with rifampin and pyrazinamide have prompted changes to the 2000 guidelines.⁴⁷ The 2-month course should be used with caution, especially in patients taking other medications that can cause liver injury and in patients with alcoholism. The guidelines also now recommend monitoring serum aminotransferase and bilirubin at baseline and every 2 weeks for the course of the 2-month therapy.⁴⁷

My choice in this case would be to offer preventive therapy to Mr Z, either with 9 months of isoniazid or 4 months of rifampin. I do so recognizing that he does not completely fulfill any of the current indications for treatment of latent TB infection. My decision is based on the amalgam of the size of his TST reaction, the recent decision analysis favoring such a strategy,³⁹ and a general sense that his diabetes and race⁴⁸ subtly increase his risk for TB.

Extrapolating from various animal model studies,⁴⁹ as well as its impact in therapeutic regimens, rifampin should be equal to or superior to isoniazid in terms of protection. A large meta-analysis suggests that the risk of hepatitis from rifampin is roughly two thirds that from isoniazid.⁵⁰ From an economic perspective, however, rifampin costs far more than isoniazid. The average wholesale price in the United States for 4 months of rifampin (600 mg/d) is $456.00, compared with $21.60 to $40.50 for 9 months of isoniazid (300 mg/d) (average wholesale price determined by the First Data Bank Inc; http://www.firstdatabank.com). A word of caution when using a rifampin-based regimen: this drug is a highly potent inducer of the hepatic cytochrome P450 pathways. This results in accelerated catabolism of many medications and endogenous hormones, including estrogens and cortisol. Clinicians must be alert to these interactions when treating patients. My reluctance to advocate the shorter rifampin-pyrazinamide regimen relates to concern for potentially increased adverse effects and hepatotoxicity from this combination.⁵¹

A recent report documented suboptimal performance of programs of contact investigations and treatment of latent TB infection in the United States.⁵² This consistent pattern is due in some measure to the cumbersome, poorly reliable performance of the current TST, aggravated by the extended duration and hazards of the drug regimen(s). The recent decline in TB case rates in the United States is arguably mainly due to improvements in treatment programs—notably, wholesale introduction of directly observed therapy (DOT) that rapidly and consistently renders patients noninfectious.⁵³ However, if the United States is to approach the goal of eliminating TB by 2010, new technologies must be developed to identify those with latent infection and devise shorter, safer, and more economical regimens for treatment of latent TB infection.⁵⁴

A PHYSICIAN: How do you factor in the fact that Mr Z was born in India in interpreting the PPD result and its size?

DR ISEMAN: The odds are very high that Mr Z—I believe his father was a physician—received BCG as a young man. If he received BCG as a young person, though, and then did not have a TST until age 37, there is a very low likelihood that his tuberculin would have been reactive from BCG. Could the first skin test 15 years ago have boosted him so that his second test was now positive? The answer is the interval between the first test and this is too great to invoke boosting. So, he likely was exposed recently. A 28-mm induration implies freshness of infection and, in my opinion, discounts the contribution of BCG.

A PHYSICIAN: Does the size of the PPD reaction relate to the likelihood of active disease vs latent disease?

DR ISEMAN: Individuals who have advanced, debilitating TB tend to become anergic. Thus, among patients with active TB we rarely see large, inflamed TST reactions. But, overall, the modes of TST size for patients with latent infection and active disease are roughly comparable.⁵⁵

A PHYSICIAN: When looking at the proposed regimens for treatment of latent infection, does the likelihood that the person might have been infected with multidrug-resistant organisms affect your choice?

DR ISEMAN: Researchers at WHO surveyed 35 countries in 1994-1997.⁵³ Overall, they found a median of 9.9% primary resistance to any drug, 7.3% to isoniazid. The only clear-cut justification for using other preventive agents is for a contact to a source case with known drug resistance. However, I think it is reasonable to infer that drug resistance could come into play in certain communities or areas where the prevalence of drug resistance is extraordinarily high.

A PHYSICIAN: I like the idea of rifampin, because I think we underestimated the toxicity of isoniazid. We probably underestimated it because patients were smart enough not to take it. In the 1970s, when the treatment changed from a 3-times-daily to a once-daily regimen, people actually began to swallow the pills. I saw an extraordinary amount of toxicity, including 2 very bad cases of hepatitis in a small panel of patients.

DR ISEMAN: It turns out that the distribution of serious hepatitis clearly is canted toward women. If you believe some of the behaviorists that women are more likely to be adherent to treatment, it would go along with your notion that they experience more toxicity because they take more of the pills. I believe in the strategy of the ATS and CDC, but I agree with your concerns about isoniazid. It is important to recognize that in a meta-analysis of thousands of individuals who have taken isoniazid or rifampin, the risk of hepatitis is about 1.5 times greater for isoniazid than it is for rifampin.⁴⁸

A PHYSICIAN: What is your sense of the risk of contracting TB from recirculated air in jet planes?

DR ISEMAN: What is the risk of jet planes being "exposure chambers"? The answer is, try to fly first class. In fact, there is a potential difference in risk. The older generation of jet planes averaged about 6 air changes per hour. Now, in the name of fuel economy, newer models are reducing the introduction of fresh air. Today some planes may have only 1 or 2 air changes per hour in coach class, but more frequent air changes in first class. Yet it turns out that even up to 6 air changes per hour may not be sufficient protection.⁵⁶ So, I think airplanes may pose the risk of TB transmission. However, from contact investigations relating to various flights, the CDC has concluded that domestic flights do not provide enough time for high-risk exposure.⁵⁷ The CDC recommends contact investigation only with international flights that are 8 hours or longer, because only in those settings have they seen transmission to other passengers.