InternalMed_Harrison

InternalMed_Harrison. regard, three important considerations are relevant: an increased frequency of paradoxical reactions, interactions between ART components and rifamycins, and development of rifampin monoresistance with intermittent treatment. IRIS—i.e., the exacerbation of symptoms and signs of TB—has been described above. Rifampin, a potent inducer of enzymes of the cytochrome P450 system, lowers serum levels of many HIV protease inhibitors and some NNRTIs— essential drugs used in ART. In such cases, rifabutin, which has much less enzyme-inducing activity, has been used in place of rifampin. However, dosage adjustments for rifabutin and protease inhibitors are still being assessed. Several clinical trials have found that patients with HIV-associated TB whose degree of immunosuppression is advanced (e.g., CD4+ T cell counts of <100/μL) are prone to treatment failure and relapse with rifampin-resistant organisms when treated with “highly intermittent” (i.e., onceor twice-weekly) rifamycincontaining


InternalMed_Harrison

InternalMed_Harrison. CD4+ T cell counts of <100/μL) are prone to treatment failure and relapse with rifampin-resistant organisms when treated with “highly intermittent” (i.e., onceor twice-weekly) rifamycincontaining regimens. Consequently, it is recommended that all TB patients who are infected with HIV receive a rifampin-containing regimen on a daily basis. Because recommendations are frequently updated, consultation of the following websites is advised: www.who .int/hiv, www.who.int/tb, www.cdc.gov/hiv, and www.cdc.gov/tb.


InternalMed_Harrison

InternalMed_Harrison. Although comparative clinical trials of treatment for extrapulmonary TB are limited, the available evidence indicates that most forms of disease can be treated with the 6-month regimen recommended for patients with pulmonary disease. The WHO and the American Academy of Pediatrics recommend that children with bone and joint TB, tuberculous meningitis, or miliary TB receive up to 12 months of treatment. Treatment for TB may be complicated by underlying medical problems that require special consideration. As a rule, patients with chronic renal failure should not receive aminoglycosides and should receive ethambutol only if serum drug levels 1120 can be monitored. Isoniazid, rifampin, and pyrazinamide may be given in the usual doses in cases of mild to moderate renal failure, but the dosages of isoniazid and pyrazinamide should be reduced for all patients with severe renal failure except those undergoing hemodialysis. Patients with hepatic disease pose a special problem because of the


InternalMed_Harrison

InternalMed_Harrison. of isoniazid and pyrazinamide should be reduced for all patients with severe renal failure except those undergoing hemodialysis. Patients with hepatic disease pose a special problem because of the hepatotoxicity of isoniazid, rifampin, and pyrazinamide. Patients with severe hepatic disease may be treated with ethambutol, streptomycin, and possibly another drug (e.g., a fluoroquinolone); if required, isoniazid and rifampin may be administered under close supervision. The use of pyrazinamide by patients with liver failure should be avoided. Silicotuberculosis necessitates the extension of therapy by at least 2 months. The regimen of choice for pregnant women (Table 202-3) is 9 months of treatment with isoniazid and rifampin supplemented by ethambutol for the first 2 months. Although the WHO has recommended routine use of pyrazinamide for pregnant women, this drug has not been recommended in the United States because of insufficient data documenting its safety in pregnancy. Streptomycin


InternalMed_Harrison

InternalMed_Harrison. has recommended routine use of pyrazinamide for pregnant women, this drug has not been recommended in the United States because of insufficient data documenting its safety in pregnancy. Streptomycin is contraindicated because it is known to cause eighth-cranial-nerve damage in the fetus. Treatment for TB is not a contraindication to breast-feeding; most of the drugs administered will be present in small quantities in breast milk, albeit at concentrations far too low to provide any therapeutic or prophylactic benefit to the child. Medical consultation on difficult-to-manage cases is provided by the U.S. CDC Regional Training and Medical Consultation Centers (www.cdc.gov/tb/education/rtmc/).


InternalMed_Harrison

InternalMed_Harrison. The best way to prevent TB is to diagnose and isolate infectious cases rapidly and to administer appropriate treatment until patients are rendered noninfectious (usually 2–4 weeks after the start of proper treatment) and the disease is cured. Additional strategies include BCG vaccination and treatment of persons with LTBI who are at high risk of developing active disease.


InternalMed_Harrison

InternalMed_Harrison. BCG was derived from an attenuated strain of M. bovis and was first administered to humans in 1921. Many BCG vaccines are available worldwide; all are derived from the original strain, but the vaccines vary in efficacy, ranging from 80% to nil in randomized, placebo-controlled trials. A similar range of efficacy was found in recent observational studies (case–control, historic cohort, and cross-sectional) in areas where infants are vaccinated at birth. These studies and a meta-analysis also found higher rates of efficacy in the protection of infants and young children from serious disseminated forms of childhood TB, such as tuberculous meningitis and miliary TB. BCG vaccine is safe and rarely causes serious complications. The local tissue response begins 2–3 weeks after vaccination, with scar formation and healing within 3 months. Side effects—most commonly, ulceration at the vaccination site and regional lymphadenitis—occur in 1–10% of vaccinated persons. Some vaccine strains have


InternalMed_Harrison

InternalMed_Harrison. scar formation and healing within 3 months. Side effects—most commonly, ulceration at the vaccination site and regional lymphadenitis—occur in 1–10% of vaccinated persons. Some vaccine strains have caused osteomyelitis in ~1 case per million doses administered. Disseminated BCG infection (“BCGitis”) and death have occurred in 1–10 cases per 10 million doses administered, although this problem is restricted almost exclusively to persons with impaired immunity, such as children with severe combined immunodeficiency syndrome or adults with HIV infection. BCG vaccination induces TST reactivity, which tends to wane with time. The presence or size of TST reactions after vaccination does not predict the degree of protection afforded.


InternalMed_Harrison

InternalMed_Harrison. BCG vaccine is recommended for routine use at birth in countries with high TB prevalence. However, because of the low risk of transmission of TB in the United States and other high-income countries, the unreliable protection afforded by BCG, and its impact on the TST, the vaccine is not recommended for general use. HIV-infected adults and children should not receive BCG vaccine. Moreover, infants whose HIV status is unknown but who have signs and symptoms consistent with HIV infection or who are born to HIV-infected mothers should not receive BCG. Over the past decade, renewed research and development efforts have been made toward a new TB vaccine. In mid-2014, 16 candidates were in clinical trials and 12 were being field tested. The first new vaccine, for which results of a clinical trial became available in early 2013, is MVA85A/AERAS-485; unfortunately, this viral-vectored vaccine did not show clinical benefit as a booster to BCG.


InternalMed_Harrison

InternalMed_Harrison. It is estimated that about 2 billion people, or nearly one-third of the human population, have been infected with M. tuberculosis. Although only a small fraction of these infections will progress toward active disease, new active cases will continue to emerge from this pool of “latently” infected individuals. Unfortunately, there is no diagnostic test at present that can predict which individuals with LTBI will develop active TB. Treatment of selected persons with LTBI aims at preventing active disease. This intervention (also called preventive chemotherapy or chemoprophylaxis) is based on the results of a large number of randomized, placebo-controlled clinical trials demonstrating that a 6to 9-month course of isoniazid reduces the risk of active TB in infected people by up to 90%. Analysis of available data indicates that the optimal duration of treatment is ~9 months. In the absence of reinfection, the protective effect is believed to be lifelong. Clinical trials have shown that


InternalMed_Harrison

InternalMed_Harrison. of available data indicates that the optimal duration of treatment is ~9 months. In the absence of reinfection, the protective effect is believed to be lifelong. Clinical trials have shown that isoniazid reduces rates of TB among TST-positive persons with HIV infection. Studies in HIV-infected patients have also demonstrated the effectiveness of shorter courses of rifampinbased treatment.


InternalMed_Harrison

InternalMed_Harrison. Candidates for treatment of LTBI are listed in Table 202-5. They can be identified by TST or IGRA of persons in defined high-risk groups. For skin testing, 5 tuberculin units of polysorbate-stabilized PPD should be injected intradermally into the volar surface of the forearm (i.e., the Mantoux method). Multipuncture tests are not recommended. Reactions are read at 48–72 h as the transverse


InternalMed_Harrison

InternalMed_Harrison. Tuberculin Risk Group Reaction Size, mm aTuberculin-negative contacts, especially children, should receive prophylaxis for 2–3 months after contact ends and should then undergo repeat TST. Those whose results remain negative should discontinue prophylaxis. HIV-infected contacts should receive a full course of treatment regardless of TST results. bThese conditions include silicosis and end-stage renal disease managed by hemodialysis cThese settings include correctional facilities, nursing homes, homeless shelters, and hospitals and other health care facilities. dExcept for employment purposes where longitudinal TST screening is anticipated, TST is not indicated for these low-risk persons. A decision to treat should be based on individual risk/benefit considerations.


InternalMed_Harrison

InternalMed_Harrison. Source: Adapted from Centers for Disease Control and Prevention: TB elimination—treatment options for latent tuberculosis infection (2011). Available at http://www.cdc.gov/tb/ publications/factsheets/testing/skintestresults.pdf.


InternalMed_Harrison

InternalMed_Harrison. diameter (in millimeters) of induration; the diameter of erythema is not considered. In some persons, TST reactivity wanes with time but can be recalled by a second skin test administered ≥1 week after the first (i.e., two-step testing). For persons periodically undergoing the TST, such as health care workers and individuals admitted to long-term-care institutions, initial two-step testing may preclude subsequent misclassification of those who have boosted reactions as TST converters. The cutoff for a positive TST (and thus for treatment) is related both to the probability that the reaction represents true infection and to the likelihood that the individual, if truly infected, will develop TB. Table 202-5 suggests possible cutoff by risk group. Thus, positive reactions for persons with HIV infection, recent close contacts of infectious cases, organ transplant recipients, previously untreated persons whose chest radiograph shows fibrotic lesions consistent with old TB, and persons


InternalMed_Harrison

InternalMed_Harrison. HIV infection, recent close contacts of infectious cases, organ transplant recipients, previously untreated persons whose chest radiograph shows fibrotic lesions consistent with old TB, and persons receiving drugs that suppress the immune system are defined as an area of induration ≥5 mm in diameter. A 10-mm cutoff is used to define positive reactions in most other at-risk persons. For persons with a very low risk of developing TB if infected, a cutoff of 15 mm is used. (Except for employment purposes where longitudinal screening is anticipated, the TST is not indicated for these low-risk persons.) A positive IGRA is based on the manufacturers’ recommendations; however, good clinical practice requires that epidemiologic and clinical factors also guide the decision to implement treatment for LTBI and that active TB be definitively excluded before the initiation of chemoprophylaxis.


InternalMed_Harrison

InternalMed_Harrison. Some TSTand IGRA-negative individuals are also candidates for treatment. Once an appropriate clinical evaluation has excluded active TB, infants and children who have come into contact with infectious cases should be treated for presumed LTBI. HIV-infected persons who have been exposed to an infectious TB patient should receive treatment regardless of the TST result. Any HIV-infected candidate for LTBI treatment must be screened carefully to exclude active TB, which would necessitate full treatment. The use of a clinical algorithm based on four symptoms (current cough, fever, weight loss, and night sweats) helps to define which HIV-infected person is a candidate for LTBI treatment. The absence of all four symptoms tends to exclude active TB. The presence of one of the four symptoms, on the other hand, warrants further investigation for active TB before treatment of LTBI is started. Although administering a TST is prudent, this test is not an absolute requirement—given the logistical


InternalMed_Harrison

InternalMed_Harrison. other hand, warrants further investigation for active TB before treatment of LTBI is started. Although administering a TST is prudent, this test is not an absolute requirement—given the logistical challenges—among people living with HIV in high-TB-incidence and low-resource settings.


InternalMed_Harrison

InternalMed_Harrison. Before treatment of LTBI begins, it is mandatory to carefully exclude active TB. Several regimens can be used to treat LTBI. The most widely used is that based on isoniazid alone at a daily dose of 5 mg/kg (up to 300 mg/d) for 9 months. On the basis of cost-benefit analyses and concerns about feasibility, a 6-month period of treatment is currently recommended by the WHO, especially in highly TB-endemic countries. Isoniazid can be administered intermittently (twice weekly) at a dose of 15 mg/kg (up to 900 mg) but only as directly observed therapy. An alternative regimen for adults is 4 months of daily rifampin. A 3-month regimen of daily isoniazid and rifampin is used in some countries (e.g., the United Kingdom) for both adults and children who are known not to have HIV infection. A previously recommended regimen of 2 months of rifampin and pyrazinamide has been associated with serious or even fatal hepatotoxicity and now is generally not recommended. The rifampin-containing regimens


InternalMed_Harrison

InternalMed_Harrison. recommended regimen of 2 months of rifampin and pyrazinamide has been associated with serious or even fatal hepatotoxicity and now is generally not recommended. The rifampin-containing regimens should be considered for persons who are likely to have been infected with an isoniazid-resistant strain. A recent clinical trial showed that a regimen of isoniazid (900 mg) and rifapentine (900 mg) given once weekly for 12 weeks is as effective as the standard 9-month isoniazid regimen. This regimen was associated with higher treatment completion (82% vs 69%) and less hepatotoxicity (0.4% vs 2.7%) than isoniazid alone, although the rate of permanent discontinuation due to an adverse event was higher (4.9% vs 3.7%).


InternalMed_Harrison

InternalMed_Harrison. Currently, the isoniazid–rifapentine regimen is not recommended for children <2 years of age, people living with HIV infection who are receiving ART, or pregnant women. Rifampin and rifapentine are contraindicated in HIV-infected individuals receiv-1121 ing protease inhibitors and most NNRTIs. (Efavirenz is the safest agent in this class of antiretrovirals for simultaneous administration with a rifamycin.) Clinical trials to assess the efficacy of long-term isoniazid administration (i.e., for at least 3 years) among people living with HIV in high-TB-transmission settings have shown that this regimen can be more effective than 9 months of isoniazid and is therefore recommended under those circumstances. Isoniazid should not be given to persons with active liver disease. All persons at increased risk of hepatotoxicity (e.g., those abusing alcohol daily and those with a history of liver disease) should undergo baseline and then monthly assessment of liver function. All patients should be


InternalMed_Harrison

InternalMed_Harrison. risk of hepatotoxicity (e.g., those abusing alcohol daily and those with a history of liver disease) should undergo baseline and then monthly assessment of liver function. All patients should be carefully educated about hepatitis and instructed to discontinue use of the drug immediately should any symptoms develop. Moreover, patients should be seen and questioned monthly during therapy about adverse reactions and should be given no more than a 1-month supply of drug at each visit. Treatment of LTBI among persons likely to have been infected by a multidrug-resistant strain is a challenge because no regimens have yet been tested in clinical trials. Close observation for early signs of disease is one option; consultation with a TB expert is advised.


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InternalMed_Harrison. It may be more difficult to ensure compliance when treating persons with LTBI than when treating those with active TB. If family members of active cases are being treated, compliance and monitoring may be easier. When feasible, supervised therapy may increase the likelihood of completion. As in active cases, the provision of incentives may also be helpful.


InternalMed_Harrison

InternalMed_Harrison. The highest priority in any TB control program is the prompt detection of cases and the provision of short-course chemotherapy to all TB patients under proper case-management conditions, including directly observed therapy. In addition, screening of high-risk groups, including immigrants from high-prevalence countries, migratory workers, prisoners, homeless individuals, substance abusers, and HIVseropositive persons, is recommended. TST-positive high-risk persons should be treated for LTBI as described above. Contact investigation is an important component of efficient TB control. In the United States and other countries worldwide, a great deal of attention has been given to the transmission of TB (particularly in association with HIV infection) in institutional settings such as hospitals, homeless shelters, and prisons. Measures to limit such transmission include respiratory isolation of persons with suspected TB until they are proven to be noninfectious (at least by sputum AFB smear


InternalMed_Harrison

InternalMed_Harrison. homeless shelters, and prisons. Measures to limit such transmission include respiratory isolation of persons with suspected TB until they are proven to be noninfectious (at least by sputum AFB smear negativity), proper ventilation in rooms of patients with infectious TB, use of ultraviolet irradiation in areas of increased risk of TB transmission, and periodic screening of personnel who may come into contact with known or unsuspected cases of TB. In the past, radiographic surveys, especially those conducted with portable equipment and miniature films, were advocated for case finding. Today, however, the prevalence of TB in industrialized countries is sufficiently low that “mass miniature radiography” is not cost-effective.


InternalMed_Harrison

InternalMed_Harrison. In high-prevalence countries, most TB control programs have made remarkable progress in reducing morbidity and mortality since the mid-1990s by adopting and implementing the strategy promoted by the WHO. Between 2000 and 2013, 37 million lives were saved, and since 1995, 61 million TB cases have been successfully treated. The essential elements of good TB care and control (the DOTS strategy) are political commitment with increased and sustained financing; case detection through quality-assured bacteriology (starting with examination of sputum from patients with cough of >2–3 weeks’ duration); administration of standardized short-course chemotherapy, with direct supervision and patient support; (4) an effective drug supply and management system; and (5) a monitoring and evaluation system, with impact measurement (including assessment of treatment outcomes—e.g., cure, completion of treatment without bacteriologic proof of cure, death, treatment failure, and default—in all cases 1122


InternalMed_Harrison

InternalMed_Harrison. with impact measurement (including assessment of treatment outcomes—e.g., cure, completion of treatment without bacteriologic proof of cure, death, treatment failure, and default—in all cases 1122 registered and notified). In 2006, the WHO indicated that, although these essential elements remain the fundamental components of any Leprosy control strategy, additional steps must be undertaken to reach the


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InternalMed_Harrison. Robert H. Gelber 2015 international TB control targets set within the United Nations Millennium Development Goals. Thus, a new “Stop TB Strategy” with six components has been promoted since 2006: (1) Pursue high-quality DOTS expansion and enhancement. (2) Address HIV-associated TB, MDR-TB, and the needs of poor and vulnerable populations. (3) Contribute to health system strengthening. (4) Engage all care providers. (5) Empower people with TB and their communities. (6) Enable and promote research. As part of the fourth component, evidence-based International Standards for Tuberculosis Care— focused on diagnosis, treatment, and public health responsibilities— have been introduced for wide adoption by medical and professional societies, academic institutions, and all practitioners worldwide (http://www.who.int/tb/publications/ISTC_3rdEd.pdf?ua=1).


InternalMed_Harrison

InternalMed_Harrison. Care and control of HIV-associated TB are particularly challenging in developing countries because existing interventions require collaboration between HIV/AIDS and TB programs as well as standard services. While TB programs must test every patient for HIV in order to provide access to trimethoprim-sulfamethoxazole prophylaxis against common infections and ART, HIV/AIDS programs must regularly screen persons living with HIV/AIDS for active TB, provide treatment for LTBI, and ensure infection control in settings where people living with HIV congregate.


InternalMed_Harrison

InternalMed_Harrison. Early and active case detection is considered an important intervention not only among persons living with HIV/AIDS but also among other vulnerable populations, as it reduces transmission in a community and provides early effective care. For TB control efforts to succeed and for elimination to become a realistic target, programs must optimize their performance and include additional interventions as described. Moreover, the approach to TB control and care needs to become holistic and engage beyond dedicated programs. Therefore, the WHO’s “End TB” strategy has been designed and builds on three pillars for the post-2015 era of increased efforts by governments and national programs worldwide: (1) integrated, patient-centered care and prevention; (2) bold policies and supportive systems; and (3) intensified research and innovation. The first pillar incorporates all technological innovations, such as early diagnostic approaches (including universal drug-susceptibility testing and


InternalMed_Harrison

InternalMed_Harrison. and (3) intensified research and innovation. The first pillar incorporates all technological innovations, such as early diagnostic approaches (including universal drug-susceptibility testing and systematic screening of identified, setting-specific, high-risk groups); well-designed treatment regimens for all forms of TB; proper management of HIV-associated TB and other comorbidities; and preventive treatment of persons at high risk. The second pillar is fundamental and is normally beyond the control of dedicated programs, relying on policies forged by the highest-level health and governmental authorities: availability of adequate and well-identified human and financial resources; engagement of civil society organizations and all relevant public and private providers to facilitate care and prevention of all patients; a policy of universal health coverage (which implies avoidance of catastrophic expenditures caused by TB among the poorest); regulatory frameworks for case notifications,


InternalMed_Harrison

InternalMed_Harrison. prevention of all patients; a policy of universal health coverage (which implies avoidance of catastrophic expenditures caused by TB among the poorest); regulatory frameworks for case notifications, vital registration, quality and rational use of medicines, and infection control; social protection mechanisms; poverty alleviation strategies; and interventions on the broader determinants of TB. Finally, the third pillar of the new strategy emphasizes intensification of engagement in research and development of new tools and interventions as well as optimization of implementation and rapid adoption of new tools in endemic countries. In the end, besides specific clinical care and control interventions as described in this chapter, elimination of TB ultimately will require control and attenuation of the multitude of risk factors (e.g., HIV, smoking, and diabetes) and socioeconomic determinants (e.g., extreme poverty, inadequate living conditions and bad housing, alcoholism, malnutrition,


InternalMed_Harrison

InternalMed_Harrison. of the multitude of risk factors (e.g., HIV, smoking, and diabetes) and socioeconomic determinants (e.g., extreme poverty, inadequate living conditions and bad housing, alcoholism, malnutrition, and indoor air pollution) with clearly implemented policies within the health sector and other sectors linked to human development and welfare.


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InternalMed_Harrison. The contributions of Richard J. O’Brien to this chapter in previous editions are gratefully acknowledged.


InternalMed_Harrison

InternalMed_Harrison. Leprosy, first described in ancient Indian texts from the sixth century b.c., is a nonfatal, chronic infectious disease caused by Mycobacterium leprae, the clinical manifestations of which are largely confined to the skin, peripheral nervous system, upper respiratory tract, eyes, and testes. The unique tropism of M. leprae for peripheral nerves (from large nerve trunks to microscopic dermal nerves) and certain immunologically mediated reactional states are the major causes of morbidity in leprosy. The propensity of the disease, when untreated, to result in characteristic deformities and the recognition in most cultures that the disease is communicable from person to person have resulted historically in a profound social stigma. Today, with early diagnosis and the institution of appropriate and effective antimicrobial therapy, patients can lead productive lives in the community, and deformities and other visible manifestations can largely be prevented.


InternalMed_Harrison

InternalMed_Harrison. M. leprae is an obligate intracellular bacillus (0.3–1 μm wide and 1–8 μm long) that is confined to humans, armadillos in certain locales, and sphagnum moss. The organism is acid-fast, indistinguishable microscopically from other mycobacteria, and ideally detected in tissue sections by a modified Fite stain. Strain variability has been documented in this organism. M. leprae produces no known toxins and is well adapted to penetrate and reside within macrophages, yet it may survive outside the body for months. In untreated patients, only ~1% of M. leprae organisms are viable. The morphologic index (MI), a measure of the number of acid-fast bacilli (AFB) in skin scrapings that stain uniformly bright, correlates with viability. The bacteriologic index (BI), a logarithmic-scaled measure of the density of M. leprae in the dermis, may be as high as 4–6+ in untreated patients and falls by 1 unit per year during effective antimicrobial therapy; the rate of decrease is independent of the


InternalMed_Harrison

InternalMed_Harrison. of the density of M. leprae in the dermis, may be as high as 4–6+ in untreated patients and falls by 1 unit per year during effective antimicrobial therapy; the rate of decrease is independent of the relative potency of therapy. A rising MI or BI suggests relapse and perhaps—if the patient is being treated— drug resistance. Drug resistance can be confirmed or excluded in the mouse model of leprosy, and resistance to dapsone and rifampin can be documented by the recognition of mutant genes. However, the availability of these technologies is extremely limited.


InternalMed_Harrison

InternalMed_Harrison. As a result of reductive evolution, almost half of the M. leprae for proteins, and 1439 genes are shared with Mycobacterium tuberculosis. In contrast, M. tuberculosis uses 91% of its genome to encode for 4000 proteins. Among the lost genes in M. leprae are those for catabolic and respiratory pathways; transport systems; purine, methionine, and glutamine synthesis; and nitrogen regulation. The genome of M. leprae provides a metabolic rationale for its obligate intracellular existence and reliance on host biochemical support, a template for targets of drug development, and ultimately a pathway to cultivation. The finding of strain variability among M. leprae isolates has provided a powerful tool with which to address anew the organism’s epidemiology and pathobiology and to determine whether relapse represents reactivation or reinfection. The bacterium’s complex cell wall contains large amounts of an M. leprae–specific phenolic glycolipid (PGL-1), which is detected in serologic tests.


InternalMed_Harrison

InternalMed_Harrison. relapse represents reactivation or reinfection. The bacterium’s complex cell wall contains large amounts of an M. leprae–specific phenolic glycolipid (PGL-1), which is detected in serologic tests. The unique trisaccharide of M. leprae binds to the basal lamina of Schwann cells; this interaction is probably relevant to the fact that M. leprae is the only bacterium to invade peripheral nerves.


InternalMed_Harrison

InternalMed_Harrison. Although it was the first bacterium to be etiologically associated with human disease, M. leprae remains one of the few bacterial species that still has not been cultivated on artificial medium or tissue culture. The multiplication of M. leprae in mouse footpads (albeit limited, with a doubling time of ~2 weeks) has provided a means to evaluate antimicrobial agents, monitor clinical trials, and screen vaccines. M. leprae grows best in cooler tissues (the skin, peripheral nerves, anterior chamber of the eye, upper respiratory tract, and testes), sparing warmer areas of the skin (the axilla, groin, scalp, and midline of the back). Demographics Leprosy is almost exclusively a disease of the developing world, affecting areas of Asia, Africa, Latin


InternalMed_Harrison

InternalMed_Harrison. Demographics Leprosy is almost exclusively a disease of the developing world, affecting areas of Asia, Africa, Latin America, and the Pacific. While Africa has the highest disease prevalence, Asia has the most cases. More than 80% of the world’s cases occur in a few countries: India, China, Myanmar, Indonesia, Brazil, Nigeria, Madagascar, and Nepal. Within endemic locales, the distribution of leprosy is quite uneven, with areas of high prevalence bordering on areas with little or no disease. In Brazil the majority of cases occur in the Amazon basin and two western states, while in Mexico leprosy is mostly confined to the Pacific coast. Except as imported cases, leprosy is largely absent from the United States, Canada, and northwestern Europe. In the United States, ~4000 persons have leprosy and 100–200 new cases are reported annually, most of them in California, Texas, New York, and Hawaii among immigrants from Mexico, Southeast Asia, the Philippines, and the Caribbean.


InternalMed_Harrison

InternalMed_Harrison. The comparative genomics of single-nucleotide polymorphisms support the likelihood that four distinct strains exist, having originated in East Africa or Central Asia. A mutation spread to Europe and subsequently underwent two separate mutations that were then followed by spread to West Africa and the Americas.


InternalMed_Harrison

InternalMed_Harrison. The global prevalence of leprosy is difficult to assess, given that many of the locales with high prevalence lack a significant medical or public health infrastructure. Estimates range from 0.6 to 8 million affected individuals. The lower estimate includes only persons who have not completed chemotherapy, excluding those who may be physically or psychologically damaged from leprosy and who may yet relapse or develop immune-mediated reactions. The higher figure includes patients whose infections probably are already cured and many who have no leprosy-related deformity or disability. Although the figures on the worldwide prevalence of leprosy are debatable, incidence is not falling; there are still an estimated 500,000 new cases annually.


InternalMed_Harrison

InternalMed_Harrison. Leprosy is associated with poverty and rural residence. It appears not to be associated with AIDS, perhaps because of leprosy’s long incubation period. Most individuals appear to be naturally immune to leprosy and do not develop disease manifestations after exposure. The time of peak onset is in the second and third decades of life.


InternalMed_Harrison

InternalMed_Harrison. The most severe lepromatous form of leprosy is twice as com mon among men as among women and is rarely encountered in children. The frequency of the polar forms of leprosy in different countries varies widely and may in part be genetically determined; certain human leukocyte antigen (HLA) associations are known for both polar forms of leprosy (see below). Furthermore, variations in 1123 immunoregulatory genes are associated with an increased susceptibility to leprosy, particularly the multibacillary form. In India and Africa, 90% of cases are tuberculoid; in Southeast Asia, 50% are tuberculoid and 50% lepromatous; and in Mexico, 90% are lepromatous. (For definitions of disease types, see Table 203-1 and “Clinical, Histologic, and Immunologic Spectrum,” below.)


InternalMed_Harrison

InternalMed_Harrison. Transmission The route of transmission of leprosy remains uncertain, and transmission routes may in fact be multiple. Nasal droplet infection, contact with infected soil, and even insect vectors have been considered the prime candidates. Aerosolized M. leprae can cause infection in immunosuppressed mice, and a sneeze from an untreated lepromatous patient may contain >1010 AFB. Furthermore, both IgA antibody to M. leprae and genes of M. leprae—demonstrable by polymerase chain reaction (PCR)—have been found in the nose of individuals from endemic areas who have no signs of leprosy and in 19% of occupational contacts of lepromatous patients. Several lines of evidence implicate soil transmission. (1) In endemic countries such as India, leprosy is primarily a rural and not an urban disease. (2) M. leprae products reside in soil in endemic locales. (3) Direct dermal inoculation (e.g., during tattooing) may transmit M. leprae, and common sites of leprosy in children are the buttocks and


InternalMed_Harrison

InternalMed_Harrison. (2) M. leprae products reside in soil in endemic locales. (3) Direct dermal inoculation (e.g., during tattooing) may transmit M. leprae, and common sites of leprosy in children are the buttocks and thighs, suggesting that microinoculation of infected soil may transmit the disease. Evidence for insect vectors of leprosy includes the demonstration that bedbugs and mosquitoes in the vicinity of leprosaria regularly harbor


InternalMed_Harrison

InternalMed_Harrison. M. leprae and that experimentally infected mosquitoes can transmit the infection to mice. Skin-to-skin contact generally is not considered an important route of transmission. In endemic countries, ~50% of leprosy patients have a history of intimate contact with an infected person (often a household member), while, for unknown reasons, leprosy patients in nonendemic locales can identify such contact only 10% of the time. Moreover, household contact with an infected lepromatous case carries an eventual risk of disease acquisition of ~10% in endemic areas as opposed to only 1% in nonendemic locales. Contact with a tuberculoid case carries a very low risk. Physicians and nurses caring for leprosy patients and the coworkers of these patients are not at risk for leprosy. able variability among isolates, highly similar and even identical VNTR results have been obtained with isolates from a limited number


InternalMed_Harrison

InternalMed_Harrison. able variability among isolates, highly similar and even identical VNTR results have been obtained with isolates from a limited number TABLE 203-1 CLInICAL, BACTERIOLOgIC, PATHOLOgIC, And IMMunOLOgIC sPECTRuM OF LEPROsy Feature Tuberculoid (TT, BT) Leprosy Borderline (BB, BL) Leprosy Lepromatous (LL) Leprosy Skin lesions One or a few sharply defined annular Intermediate between BTand LL-type Symmetric, poorly marginated, asymmetric macules or plaques with a lesions; ill-defined plaques with an multiple infiltrated nodules and tendency toward central clearing, elevated occasional sharp margin; few or many plaques or diffuse infiltration; borders in number xanthoma-like or dermatofibroma Nerve lesions Skin lesions anesthetic early; nerve Hypesthetic or anesthetic skin Hypesthesia a late sign; nerve pal-near lesions sometimes enlarged; nerve lesions; nerve trunk palsies, at times sies variable; acral, distal, symmetric abscesses most common in BT symmetric anesthesia common


InternalMed_Harrison

InternalMed_Harrison. Acid-fast bacilli (BIa) 0–1+ 3–5+ 4–6+ Lymphocytes 2+ 1+ 0–1+ Macrophage differentiation Epithelioid Epithelioid in BB; usually undifferenti-Foamy change the rule; may be ated but may have foamy changes undifferentiated in early lesions in BL Langerhans giant cells 1–3+ — — Lepromin skin test +++ — — Lymphocyte transformation test Generally positive 1–10% 1–2% CD4+/CD8+ T cell ratio in lesions 1.2 BB: NT; BL: 0.48 0.50 M. leprae PGL-1 antibodies 60% 85% 95% aSee text. Abbreviations: BB, mid-borderline; BL, borderline lepromatous; BT, borderline tuberculoid; TT, polar tuberculoid; LL, polar lepromatous; BI, bacteriologic index; NT, not tested; PGL-1, phenolic glycolipid 1. 1124 of families with multiple cases. Moreover, VNTR results have been similar for isolates within certain geographic locales and divergent for isolates within others. These findings suggest that genomic analyses may prove useful in the future for defining M. leprae transmission patterns.


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InternalMed_Harrison. M. leprae causes disease primarily in humans. However, in Texas and Louisiana, 15% of nine-banded armadillos are infected, and armadillo contact occasionally results in human disease. Armadillos develop disseminated infection after IV inoculation of live M. leprae. CLINICAL, HISTOLOGIC, AND IMMuNOLOGIC SPECTRuM


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InternalMed_Harrison. The incubation period prior to manifestation of clinical disease can vary between 2 and 40 years, although it is generally 5–7 years in duration. This long incubation period is probably, at least in part, a consequence of the extremely long doubling time for M. leprae (14 days in mice versus in vitro doubling times of 1 day and 20 min for M. tuberculosis and Escherichia coli, respectively). Leprosy presents as a spectrum of clinical manifestations that have bacteriologic, pathologic, and immunologic counterparts. The spectrum from polar tuberculoid (TT) to borderline tuberculoid (BT) to mid-borderline (BB, which is rarely encountered) to borderline lepromatous (BL) to polar lepromatous (LL) disease is associated with an evolution from asymmetric localized macules and plaques to nodular and indurated symmetric generalized skin manifestations, an increasing bacterial load, and loss of M. leprae–specific cellular immunity (Table 203-1). Distinguishing dermatopathologic characteristics


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InternalMed_Harrison. and indurated symmetric generalized skin manifestations, an increasing bacterial load, and loss of M. leprae–specific cellular immunity (Table 203-1). Distinguishing dermatopathologic characteristics include the number of lymphocytes, giant cells, and AFB as well as the nature of epithelioid cell differentiation. Where a patient presents on the clinical spectrum largely determines prognosis, complications, reactional states, and the intensity of antimicrobial therapy required.


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InternalMed_Harrison. Tuberculoid Leprosy At the less severe end of the spectrum is tuberculoid leprosy, which encompasses TT and BT disease. In general, these forms of leprosy result in symptoms confined to the skin and peripheral nerves. TT leprosy is the most common form of the disease encountered in India and Africa but is virtually absent in Southeast Asia, where BT leprosy is frequent.


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InternalMed_Harrison. The skin lesions of tuberculoid leprosy consist of one or a few hypopigmented macules or plaques (Fig. 203-1) that are sharply demarcated and hypesthetic, often have erythematous or raised borders, and are devoid of the normal skin organs (sweat glands and hair follicles) and thus are dry, scaly, and anhidrotic. AFB are generally absent or few in number. Tuberculoid leprosy patients may have asymmetric enlargement of one or a few peripheral nerves. Indeed, leprosy and certain rare hereditary neuropathies are the only human diseases associated with peripheral-nerve enlargement. Although any peripheral nerve may be enlarged (including small digital and supraclavicular nerves), those most commonly affected are the ulnar, posterior auricular, peroneal, and posterior tibial nerves, with associated hypesthesia and myopathy. FIGuRE 203-1 Tuberculoid (TT) leprosy: a well-defined, hypopigmented, anesthetic macule with anhidrosis and a raised granular margin (arrowhead).


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InternalMed_Harrison. FIGuRE 203-1 Tuberculoid (TT) leprosy: a well-defined, hypopigmented, anesthetic macule with anhidrosis and a raised granular margin (arrowhead). In tuberculoid leprosy, T cells breach the perineurium, and destruction of Schwann cells and axons may be evident, resulting in fibrosis of the epineurium, replacement of the endoneurium with epithelial granulomas, and occasionally caseous necrosis. Such invasion and destruction of nerves in the dermis by T cells are pathognomonic for leprosy.


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InternalMed_Harrison. Circulating lymphocytes from patients with tuberculoid leprosy readily recognize M. leprae and its constituent proteins, patients have positive lepromin skin tests (see “Diagnosis,” below), and—owing to a type 1 cytokine pattern in tuberculoid tissues—strong T cell and macrophage activation results in a localized infection. In tuberculoid leprosy tissue, there is a 2:1 predominance of helper CD4+ over CD8+ T lymphocytes. Tuberculoid tissues are rich in the mRNAs of the pro-inflammatory TH1 family of cytokines: interleukin (IL) 2, interferon γ (IFN-γ), and IL-12; in contrast, IL-4, IL-5, and IL-10 mRNAs are scarce.


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InternalMed_Harrison. Lepromatous Leprosy Lepromatous leprosy patients present with symmetrically distributed skin nodules (Fig. 203-2), raised plaques, or diffuse dermal infiltration, which, when on the face, results in leonine facies. Late manifestations include loss of eyebrows (initially the lateral margins only) and eyelashes, pendulous earlobes, and dry scaling skin, particularly on the feet. In LL leprosy, bacilli are numerous in the skin (as many as 109/g), where they are often found in large clumps (globi), and in peripheral nerves, where they initially invade Schwann cells, resulting in foamy degenerative myelination and axonal degeneration and later in Wallerian degeneration. In addition, bacilli are plentiful in circulating blood and in all organ systems except the lungs and the central nervous system. Nevertheless, patients are afebrile, and there is no evidence of major organ system dysfunction.


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InternalMed_Harrison. Found almost exclusively in western Mexico and the Caribbean is a form of lepromatous leprosy without visible skin lesions but with diffuse dermal infiltration and a demonstrably thickened dermis, termed diffuse lepromatosis. In lepromatous leprosy, nerve enlargement and damage tend to be symmetric, result from actual bacillary invasion, and are more insidious but ultimately more extensive than in tuberculoid leprosy. Patients with LL leprosy have acral, distal, symmetric peripheral neuropathy and a tendency toward symmetric nerve-trunk enlargement. They may also have signs and symptoms related to involvement of the upper respiratory tract, the anterior chamber of the eye, and the testes.


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InternalMed_Harrison. In untreated LL patients, lymphocytes regularly fail to recognize either M. leprae or its protein constituents, and lepromin skin tests are negative (see “Diagnosis,” below). This loss of protective cellular immunity appears to be antigen-specific, as patients are not unusually susceptible to opportunistic infections, cancer, or AIDS and maintain delayed-type hypersensitivity to Candida, Trichophyton, mumps virus, tetanus toxoid, and even purified protein derivative of tuberculin. At times, M. leprae–specific anergy is reversible with effective chemotherapy. In LL tissues, there is a 2:1 ratio of CD8+ to CD4+ T lymphocytes. LL patients have a predominant TH2 response and hyperglobulinemia, and LL tissues demonstrate a TH2 cytokine profile, being rich in mRNAs for IL-4, IL-5, and IL-10 and poor in those for IL-2, IFN-γ, and IL-12. It appears that cytokines mediate a protective tissue response in leprosy, as injection of IFN-γ or IL-2 into lepromatous lesions causes a loss of AFB and


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InternalMed_Harrison. poor in those for IL-2, IFN-γ, and IL-12. It appears that cytokines mediate a protective tissue response in leprosy, as injection of IFN-γ or IL-2 into lepromatous lesions causes a loss of AFB and histopathologic conversion toward a tuberculoid pattern. Macrophages of lepromatous leprosy patients appear to be functionally intact; circulating monocytes exhibit normal microbicidal function and responsiveness to IFN-γ.


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InternalMed_Harrison. FIGuRE 203-2 Lepromatous (LL) leprosy: advanced nodular lesions. Reactional States Lepra reactions comprise several common immunologically mediated inflammatory states that cause considerable morbidity. Some of these reactions precede diagnosis and the institution of effective antimicrobial therapy; indeed, these reactions may precipitate presentation for medical attention and diagnosis. Other reactions follow the initiation of appropriate chemotherapy; these reactions may cause patients to perceive that their leprosy is worsening and to lose confidence in conventional therapy. Only by warning patients of the potential for these reactions and describing their manifestations can physicians treating leprosy patients ensure continued credibility.


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InternalMed_Harrison. type 1 lepra reactions (downgrading and reversal reactions) Type 1 lepra reactions occur in almost half of patients with borderline forms of leprosy but not in patients with pure lepromatous disease. Manifestations include classic signs of inflammation within previously involved macules, papules, and plaques and, on occasion, the appearance of new skin lesions, neuritis, and (less commonly) fever—generally low-grade. The nerve trunk most frequently involved in this process is the ulnar nerve at the elbow, which may be painful and exquisitely tender. If patients with affected nerves are not treated promptly with glucocorticoids (see below), irreversible nerve damage may result in as little as 24 h. The most dramatic manifestation is foot-drop, which occurs when the peroneal nerve is involved.


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InternalMed_Harrison. When type 1 lepra reactions precede the initiation of appropriate antimicrobial therapy, they are termed downgrading reactions, and the case becomes histologically more lepromatous; when they occur after the initiation of therapy, they are termed reversal reactions, and the case becomes more tuberculoid. Reversal reactions often occur in the first months or years after the initiation of therapy but may also develop several years thereafter. Edema is the most characteristic microscopic feature of type 1 lepra lesions, whose diagnosis is primarily clinical. Reversal reactions are typified by a TH1 cytokine profile, with an influx of CD4+ T helper cells and increased levels of IFN-γ and IL-2. In addition, type 1 reactions are associated with large numbers of T cells bearing γ/δ receptors—a unique feature of leprosy.


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InternalMed_Harrison. type 2 lepra reactions: erytHema nodosUm leprosUm Erythema nodosum leprosum (ENL) (Fig. 203-3) occurs exclusively in patients near the lepromatous end of the leprosy spectrum (BL/LL), affecting nearly 50% of this group. Although ENL may precede leprosy diagnosis and the initiation of therapy (sometimes, in fact, prompting the diagnosis), in 90% of cases it follows the institution of chemotherapy, generally within 2 years. The most common features of ENL are crops of painful erythematous papules that resolve spontaneously in a few days to a week but may recur; malaise; and fever that can be profound. However, patients may also experience symptoms of neuritis, lymphadenitis, uveitis, orchitis, and glomerulonephritis and may develop anemia, leukocytosis, and abnormal liver function tests (particularly increased aminotransferase levels). Individual patients may have either a single bout of ENL or chronic recurrent manifestations. Bouts may be either mild or severe and generalized; in rare


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InternalMed_Harrison. increased aminotransferase levels). Individual patients may have either a single bout of ENL or chronic recurrent manifestations. Bouts may be either mild or severe and generalized; in rare instances, ENL results in death. Skin biopsy of ENL papules reveals vasculitis or panniculitis, sometimes with many lymphocytes but characteristically with polymorphonuclear leukocytes as well.


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InternalMed_Harrison. FIGuRE 203-3 Moderately severe skin lesions of erythema nodosum leprosum, some with pustulation and ulceration. Elevated levels of circulating tumor necrosis factor (TNF) have been demonstrated in ENL; thus, TNF may play a central role in the pathobiology of this syndrome. ENL is thought to be a consequence of immune complex deposition, given its TH2 cytokine profile and its high levels of IL-6 and IL-8. However, in ENL tissue, the presence of HLA-DR framework antigen of epidermal cells—considered a marker for a delayed-type hypersensitivity response—and evidence of higher levels of IL-2 and IFN-γ than are usually seen in polar lepromatous disease suggest an alternative mechanism.


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InternalMed_Harrison. lUcio’s pHenomenon Lucio’s phenomenon is an unusual reaction seen exclusively in patients from the Caribbean and Mexico who have the diffuse lepromatosis form of lepromatous leprosy, most often those who are untreated. Patients with this reaction develop recurrent crops of large, sharply marginated, ulcerative lesions—particularly on the lower extremities—that may be generalized and, when so, are frequently fatal as a result of secondary infection and consequent septic bacteremia. Histologically, the lesions are characterized by ischemic necrosis of the epidermis and superficial dermis, heavy parasitism of endothelial cells with AFB, and endothelial proliferation and thrombus formation in the larger vessels of the deeper dermis. Like ENL, Lucio’s phenomenon is probably mediated by immune complexes.


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InternalMed_Harrison. Complications • tHe eXtremities Complications of the extrem ities in leprosy patients are primarily a consequence of neu ropathy leading to insensitivity and myopathy. Insensitivity affects fine touch, pain, and heat receptors but generally spares position and vibration appreciation. The most commonly affected nerve trunk is the ulnar nerve at the elbow, whose involvement results in clawing of the fourth and fifth fingers, loss of dorsal interosseous musculature in the affected hand, and loss of sensation in these distributions. Median nerve involvement in leprosy impairs thumb opposition and grasp; radial nerve dysfunction, although rare in leprosy, leads to wristdrop. Tendon transfers can restore hand function but should not be performed until 6 months after the initiation of antimicrobial therapy and the conclusion of episodes of acute neuritis.


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InternalMed_Harrison. Plantar ulceration, particularly at the metatarsal heads, is probably the most common complication of leprous neuropathy. Therapy requires careful debridement; administration of appropriate antibiotics; avoidance of weight-bearing until ulcerations are healed, with slowly progressive ambulation thereafter; and wearing of special shoes to prevent recurrence. Footdrop as a result of peroneal nerve palsy should be treated with a simple nonmetallic brace in the shoe or with surgical correction attained by tendon transfers. Although uncommon, Charcot’s joints, particularly of the foot and ankle, may result from leprosy.


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InternalMed_Harrison. The loss of distal digits in leprosy is a consequence of insensitivity, trauma, secondary infection, and—in lepromatous disease—a poorly understood and sometimes profound osteolytic process. Conscientious 1126 protection of the extremities during cooking and work and the early institution of therapy have substantially reduced the frequency and severity of distal digit loss in recent times. tHe nose In lepromatous leprosy, bacillary invasion of the nasal mucosa can result in chronic nasal congestion and epistaxis. Saline nose drops may relieve these symptoms. Long-untreated LL leprosy may further result in destruction of the nasal cartilage, with consequent saddle-nose deformity or anosmia (more common in the preantibiotic era than at present). Nasal reconstructive procedures can ameliorate significant cosmetic defects.


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InternalMed_Harrison. tHe eye Owing to cranial nerve palsies, lagophthalmos and corneal insensitivity may complicate leprosy, resulting in trauma, secondary infection, and (without treatment) corneal ulcerations and opacities. For patients with these conditions, eyedrops during the day and ointments at night provide some protection from such consequences. Furthermore, in LL leprosy, the anterior chamber of the eye is invaded by bacilli, and ENL may result in uveitis, with consequent cataracts and glaucoma. Thus leprosy is a major cause of blindness in the developing world. Slit-lamp evaluation of LL patients often reveals “corneal beading,” representing globi of M. leprae.


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InternalMed_Harrison. tHe testes M. leprae invades the testes, while ENL may cause orchitis. Thus males with lepromatous leprosy often manifest mild to severe testicular dysfunction, with an elevation of luteinizing and follicle-stimulating hormones, decreased testosterone, and aspermia or hypospermia in 85% of LL patients but in only 25% of BL patients. LL patients may become impotent and infertile. Impotence is sometimes responsive to testosterone replacement. amyloidosis Secondary amyloidosis is a complication of LL leprosy and ENL that is encountered infrequently in the antibiotic era. This complication may result in abnormalities of hepatic and particularly renal function.


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InternalMed_Harrison. nerve abscesses Patients with various forms of leprosy, but particularly those with the BT form, may develop abscesses of nerves (most commonly the ulnar), with a cellulitic appearance of adjacent skin. In such conditions, the affected nerve is swollen and exquisitely tender. Although glucocorticoids may reduce signs of inflammation, rapid surgical decompression is necessary to prevent irreversible sequelae.


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InternalMed_Harrison. Leprosy most commonly presents with both characteristic skin lesions and skin histopathology. Thus the disease should be suspected when a patient from an endemic area has suggestive skin lesions or peripheral neuropathy. The diagnosis should be confirmed by histopathology. In tuberculoid leprosy, lesional areas—preferably the advancing edge— must be biopsied because normal-appearing skin does not have pathologic features. In lepromatous leprosy, nodules, plaques, and indurated areas are optimal biopsy sites, but biopsies of normal-appearing skin also are generally diagnostic. Lepromatous leprosy is associated with diffuse hyperglobulinemia, which may result in false-positive serologic tests (e.g., Venereal Disease Research Laboratory, rheumatoid arthritis, and antinuclear antibody tests) and therefore may cause diagnostic confusion. On occasion, tuberculoid lesions may not (1) appear typical, (2) be hypesthetic, and (3) contain granulomas (instead containing only nonspecific


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InternalMed_Harrison. tests) and therefore may cause diagnostic confusion. On occasion, tuberculoid lesions may not (1) appear typical, (2) be hypesthetic, and (3) contain granulomas (instead containing only nonspecific lymphocytic infiltrates). In such instances, two of these three characteristics are considered sufficient for a diagnosis. It is preferable to overdiagnose leprosy rather than to allow a patient to remain untreated.


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InternalMed_Harrison. IgM antibodies to PGL-1 are found in 95% of patients with untreated lepromatous leprosy; the titer decreases with effective therapy. However, in tuberculoid leprosy—the form of disease most often associated with diagnostic uncertainty owing to the absence or paucity of AFB—patients have significant antibodies to PGL-1 only 60% of the time; moreover, in endemic locales, exposed individuals without clinical leprosy may harbor antibodies to PGL-1. Thus PGL-1 serology is of little diagnostic utility in tuberculoid leprosy. Heat-killed M. leprae (lepromin) has been used as a skin test reagent. It generally elicits a reaction in tuberculoid leprosy patients, may do so in individuals without leprosy, and gives negative results in lepromatous leprosy patients; consequently, it is likewise of little diagnostic value. Unfortunately, PCR of the skin for


InternalMed_Harrison

InternalMed_Harrison. M. leprae, although positive in LL and BL disease, yields negative results in 50% of tuberculoid cases, again offering little diagnostic assistance. Included in the differential diagnosis of lesions that resemble leprosy are sarcoidosis, leishmaniasis, lupus vulgaris, dermatofibroma, histiocytoma, lymphoma, syphilis, yaws, granuloma annulare, and various other disorders causing hypopigmentation (notably pityriasis alba, tinea, and vitiligo). Sarcoidosis may result in perineural inflammation, but actual granuloma formation within dermal nerves is pathognomonic for leprosy. In lepromatous leprosy, sputum specimens may be loaded with AFB—a finding that can be incorrectly interpreted as representing pulmonary tuberculosis.


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InternalMed_Harrison. ANTIMICROBIAL THERAPY Active Agents Established agents used to treat leprosy include dapsone (50–100 mg/d), clofazimine (50–100 mg/d, 100 mg three times weekly, or 300 mg monthly), and rifampin (600 mg daily or monthly; see “Choice of Regimens,” below). Of these drugs, only rifampin is bactericidal. The sulfones (folate antagonists), the foremost of which is dapsone, were the first antimicrobial agents found to be effective for the treatment of leprosy and are still the mainstays of therapy. With sulfone treatment, skin lesions resolve and numbers of viable bacilli in the skin are reduced. Although primarily bacteriostatic, dapsone monotherapy results in a resistance-related relapse rate of only 2.5%; after ≥18 years of therapy and subsequent discontinuation, only another 10% of patients relapse, developing new, usually asymptomatic, shiny, “histoid” nodules. Dapsone is generally safe and inexpensive. Individuals with glucose-6-phosphate dehydrogenase deficiency who are treated with


InternalMed_Harrison

InternalMed_Harrison. relapse, developing new, usually asymptomatic, shiny, “histoid” nodules. Dapsone is generally safe and inexpensive. Individuals with glucose-6-phosphate dehydrogenase deficiency who are treated with dapsone may develop severe hemolysis; those without this deficiency also have reduced red cell survival and a hemoglobin decrease averaging 1 g/dL. Dapsone’s usefulness is limited occasionally by allergic dermatitis and rarely by the sulfone syndrome (including high fever, anemia, exfoliative dermatitis, and a mononucleosis-type blood picture). It must be remembered that rifampin induces microsomal enzymes, necessitating increased doses of medications such as glucocorticoids and oral birth control regimens. Clofazimine is often cosmetically unacceptable to light-skinned leprosy patients because it causes a red-black skin discoloration that accumulates, particularly in lesional areas, and makes the patient’s diagnosis obvious to members of the community.


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InternalMed_Harrison. Other antimicrobial agents active against M. leprae in animal models and at the usual daily doses used in clinical trials include ethionamide/prothionamide; the aminoglycosides streptomycin, kanamycin, and amikacin (but not gentamicin or tobramycin); minocycline; clarithromycin; and several fluoroquinolones, particularly ofloxacin. Next to rifampin, minocycline, clarithromycin, and ofloxacin appear to be most bactericidal for M. leprae, but these drugs have not been used extensively in leprosy control programs. Most recently, rifapentine and moxifloxacin have been found to be especially potent against M. leprae in mice. In a clinical trial in lepromatous leprosy, moxifloxacin was profoundly bactericidal, matched in potency only by rifampin.


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InternalMed_Harrison. Choice of Regimens Antimicrobial therapy for leprosy must be individualized, depending on the clinical/pathologic form of the disease encountered. Tuberculoid leprosy, which is associated with a low bacterial burden and a protective cellular immune response, is the easiest form to treat and can be cured reliably with a finite course of chemotherapy. In contrast, lepromatous leprosy may have a higher bacillary load than any other human bacterial disease, and the absence of a salutary T cell repertoire requires prolonged or even lifelong chemotherapy. Hence, careful classification of disease prior to therapy is important.


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InternalMed_Harrison. In developed countries, clinical experience with leprosy classification is limited; fortunately, however, the resources needed for skin biopsy are highly accessible, and those for pathologic interpretation are readily available. In developing countries, clinical expertise is greater but is now waning substantially as the care of leprosy patients is integrated into general health services. In addition, access to dermatopathology services is often limited. In such instances, skin smears may prove useful, but in many locales access to the resources needed for their preparation and interpretation also may be unavailable. Use of skin smears is no longer encouraged by the World Health Organization (WHO) and is often replaced by mere counting of lesions, which, together with a lack of capacity for histopathologic assessment, may negatively affect decisions about chemotherapy, increase the potential for reactions, and worsen the ultimate prognosis. A reasoned approach to the treatment of


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InternalMed_Harrison. for histopathologic assessment, may negatively affect decisions about chemotherapy, increase the potential for reactions, and worsen the ultimate prognosis. A reasoned approach to the treatment of leprosy is confounded by these and several other issues: 1.


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InternalMed_Harrison. Even without therapy, TT leprosy may heal spontaneously, and prolonged dapsone monotherapy (even for LL leprosy) is generally curative in 80% of cases. 2. In tuberculoid disease, it is common for no bacilli to be found in the skin prior to therapy, and thus there is no objective measure of therapeutic success. Furthermore, despite adequate treatment, TT and particularly BT lesions often resolve minimally or incompletely, while relapse and late type 1 lepra reactions can be difficult to distinguish. 3. LL leprosy patients commonly harbor viable persistent M. leprae organisms after prolonged intensive therapy; the propensity of these organisms to initiate clinical relapse is unclear. Because relapse in LL patients after discontinuation of rifampin-containing regimens usually begins only after 7–10 years, follow-up over the very long term is necessary to assess ultimate clinical outcomes. 4.


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InternalMed_Harrison. 4. Even though primary dapsone resistance is exceedingly rare and multidrug therapy is generally recommended (at least for lepromatous leprosy), there is a paucity of information from experimental animals and clinical trials on the optimal combination of antimicrobial agents, dosing schedule, and duration of therapy.


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InternalMed_Harrison. In 1982, the WHO made recommendations for leprosy chemotherapy administered in control programs. These recommendations came on the heels of the demonstration of the relative success of long-term dapsone monotherapy and in the context of concerns about dapsone resistance. Other complicating considerations included the limited resources available for leprosy care in the very areas where it is most prevalent and the frustration and discouragement of patients and program managers with the previous requirement for lifelong therapy for many leprosy patients. Thus, for the first time, the WHO advocated a finite duration of therapy for all forms of leprosy and—given the prohibitive cost of daily rifampin treatment in developing countries—encouraged the monthly administration of this agent as part of a multidrug regimen. Over the ensuing years, the WHO recommendations have been broadly implemented, and the duration of therapy required, particularly for lepromatous leprosy, has been


InternalMed_Harrison

InternalMed_Harrison. as part of a multidrug regimen. Over the ensuing years, the WHO recommendations have been broadly implemented, and the duration of therapy required, particularly for lepromatous leprosy, has been progressively shortened. For treatment purposes, the WHO classifies patients as paucibacillary or multibacillary. Previously, patients without demonstrable AFB in the dermis were classified as paucibacillary and those with AFB as multibacillary. Currently, in light of the perceived unreliability of skin smears in the field, patients are classified as multibacillary if they have six or more skin lesions and as paucibacillary if they have fewer. (Unfortunately, this classification method has been found wanting, as some patients near the lepromatous pole have only one or a few skin lesions.) The WHO recommends that paucibacillary adults be treated with 100 mg of dapsone daily and 600 mg of rifampin monthly (supervised) for 6 months (Table 203-2). For patients with single-lesion paucibacillary


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InternalMed_Harrison. recommends that paucibacillary adults be treated with 100 mg of dapsone daily and 600 mg of rifampin monthly (supervised) for 6 months (Table 203-2). For patients with single-lesion paucibacillary leprosy, the WHO recommends as an alternative a single dose of rifampin (600 mg), ofloxacin (400 mg), and minocycline (100 mg). Multibacillary adults should be treated with 100 mg of dapsone plus 50 mg of clofazimine daily (unsupervised)


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InternalMed_Harrison. Form of More Intensive WHO-Recommended Regimen Leprosy Regimen (1982) Tuberculoid Dapsone (100 mg/d) for Dapsone (100 mg/d, unsuper month, supervised) for 6 months (multibacillary) for 3 years plus dapsone mine (50 mg/d), unsupervised; Note: See text for discussion and comparison of the WHO recommendations with the more intensive approach as well as the alternative WHO regimen for single-lesion paucibacillary leprosy. and with 600 mg of rifampin plus 300 mg of clofazimine monthly (supervised). Originally, the WHO recommended that lepromatous patients be treated for 2 years or until smears became negative (generally in ~5 years); subsequently, the acceptable course was reduced to 1 year—a change that remains especially controversial in the absence of supporting clinical trials.


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InternalMed_Harrison. Several factors have caused many authorities to question the WHO recommendations and to favor a more intensive approach. Among these factors are—for multibacillary patients—a high (double-digit) relapse rate in several locales (reaching 20–40% in one locale, with the rate directly related to the initial bacterial burden) and—for paucibacillary patients—demonstrable lesional activity for years in fully half of patients after the completion of therapy. The more intensive approach (Table 203-2) calls for tuberculoid leprosy to be treated with dapsone (100 mg/d) for 5 years and for lepromatous leprosy to be treated with rifampin (600 mg/d) for 3 years and with dapsone (100 mg/d) throughout life.


InternalMed_Harrison

InternalMed_Harrison. With effective antimicrobial therapy, new skin lesions and signs and symptoms of peripheral neuropathy cease appearing. Nodules and plaques of lepromatous leprosy noticeably flatten in 1–2 months and resolve in 1 year or a few years, while tuberculoid skin lesions may disappear, ameliorate, or remain relatively unchanged. Although the peripheral neuropathy of leprosy may improve somewhat in the first few months of therapy, rarely is it significantly alleviated by treatment.


InternalMed_Harrison

InternalMed_Harrison. Despite the drawbacks of the WHO’s recommendations for multidrug therapy, these regimens have been used almost exclusively worldwide. Although two of the three recommended drugs (dapsone and clofazimine) are only bacteriostatic against M. leprae and bactericidal agents have been identified since the WHO formulated its recommendations, significant studies employing the available alternatives in newly designed regimens have not been initiated. Given the recent findings that moxifloxacin, like rifampin, is profoundly bactericidal in leprosy patients and that short-course chemotherapy for tuberculosis is possible only when two or more bactericidal agents are used, a moxifloxacin/rifamycin-based regimen including either minocycline or clarithromycin appears promising; such a regimen may prove to be more reliably curative than WHO-recommended multidrug therapy for lepromatous leprosy and may allow a considerably shorter course of treatment.


InternalMed_Harrison

InternalMed_Harrison. THERAPY FOR REACTIONS Type 1 Type 1 lepra reactions are best treated with glucocorticoids (e.g., prednisone, initially at doses of 40–60 mg/d). As inflammation subsides, the glucocorticoid dose can be tapered, but steroid therapy must be continued for at least 3–6 months lest recurrence supervene. Because of the myriad toxicities of prolonged glucocorticoid therapy, the indications for its initiation are strictly limited to lesions whose intense inflammation poses a threat of ulceration; lesions at cosmetically important sites, such as the face; and cases in which neuritis is present. Mild to moderate lepra reactions that do not meet these criteria should be tolerated and glucocorticoid treatment withheld. Thalidomide is ineffective against type 1 lepra 1128 reactions. Clofazimine (200–300 mg/d) is of questionable benefit but in any event is far less efficacious than glucocorticoids.


InternalMed_Harrison

InternalMed_Harrison. Type 2 Treatment of ENL must be individualized. If ENL is mild (i.e., if it occurs without fever or other organ involvement and with occasional crops of only a few skin papules), it may be treated with antipyretics alone. However, in cases with many skin lesions, fever, malaise, and other tissue involvement, brief courses (1–2 weeks) of glucocorticoid treatment (initially 40–60 mg/d) are often effective. With or without therapy, individual inflamed papules last for <1 week. Successful therapy is defined by the cessation of skin lesion development and the disappearance of other systemic signs and symptoms. If, despite two courses of glucocorticoid therapy, ENL appears to be recurring and persisting, treatment with thalidomide (100–300 mg nightly) should be initiated, with the dose depending on the initial severity of the reaction. Because even a single dose of thalidomide administered early in pregnancy may result in severe birth defects, including phocomelia, the use of this drug in


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InternalMed_Harrison. on the initial severity of the reaction. Because even a single dose of thalidomide administered early in pregnancy may result in severe birth defects, including phocomelia, the use of this drug in the United States for the treatment of fertile female patients is tightly regulated and requires informed consent, prior pregnancy testing, and maintenance of birth control measures. Although the mechanism of thalidomide’s dramatic action against ENL is not entirely clear, the drug’s efficacy is probably attributable to its reduction of TNF levels and IgM synthesis and its slowing of polymorphonuclear leukocyte migration. After the reaction is controlled, lower doses of thalidomide (50–200 mg nightly) are effective in preventing relapses of ENL. Clofazimine in high doses (300 mg nightly) has some efficacy against ENL, but its use permits only a modest reduction of the glucocorticoid dose necessary for ENL control.


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InternalMed_Harrison. Lucio’s Phenomenon Neither glucocorticoids nor thalidomide is effective against this syndrome. Optimal wound care and therapy for bacteremia are indicated. Ulcers tend to be chronic and heal poorly. In severe cases, exchange transfusion may prove useful. Vaccination at birth with bacille Calmette-Guérin (BCG) has proved variably effective in preventing leprosy: the results have ranged from total inefficacy to 80% efficacy. The addition of heat-killed M. leprae to BCG does not increase the effectiveness of the vaccine. Because whole mycobacteria contain large amounts of lipids and carbohydrates that have proved in vitro to be immunosuppressive for lymphocytes and macrophages, M. leprae proteins may prove to be superior vaccines. Data from a mouse model support this possibility.


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InternalMed_Harrison. Chemoprophylaxis with dapsone may reduce the number of tuberculoid leprosy cases but not the number of lepromatous cases and hence is not recommended, even for household contacts. In addition, single-dose rifampin prophylaxis is of doubtful efficacy. Because leprosy transmission appears to require close prolonged household contact, hospitalized patients need not be isolated.


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InternalMed_Harrison. In 1992, the WHO—on the basis of that organization’s treatment recommendations—launched a landmark campaign to eliminate leprosy as a public health problem by the year 2000 (goal, <1 case per 10,000 population). The campaign mobilized and energized nongovernmental organizations and national health services to treat leprosy with multiple drugs and to clean up outdated registries. In these respects, the effort has proved hugely successful, with >6 million patients completing therapy. However, the target of leprosy elimination has not yet been reached. In fact, the success of the WHO campaign in reducing the number of cases worldwide has been largely attributable to the redefinition of what constitutes a case of leprosy. Formerly calculated by disease prevalence, the count is now limited to cases not yet treated with multiple drugs. Worldwide, the annual incidence of leprosy has not fallen. Furthermore, after the completion of therapy, when a patient is no longer considered to represent


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InternalMed_Harrison. cases not yet treated with multiple drugs. Worldwide, the annual incidence of leprosy has not fallen. Furthermore, after the completion of therapy, when a patient is no longer considered to represent a “case,” half of all patients continue to manifest disease activity for years; relapse rates (at least for multibacillary patients) are unacceptably high; disabilities and deformities go unchecked; and the social stigma of the disease persists.


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InternalMed_Harrison. During most of the twentieth century, nongovernmental organizations, particularly Christian missionaries, provided a medical infrastructure devoted to the care and treatment of leprosy patients— the envy of those with other medical priorities in the developing world. With the public perception that leprosy is near eradication, resources for patient care are rapidly being diverted, and the burden of patient care is being transferred to nonexistent or overloaded national health services and to health workers who lack the tools and skills needed for the disease’s diagnosis and classification and for the selection of nuanced therapy (particularly in cases of reactional neuritis). Thus the prerequisites for a salutary outcome increasingly go unmet. Steven M. Holland


InternalMed_Harrison

InternalMed_Harrison. Steven M. Holland Several terms—nontuberculous mycobacteria (NTM), atypical mycobacteria, mycobacteria other than tuberculosis, and environmental mycobacteria—all refer to mycobacteria other than Mycobacterium tuberculosis, its close relatives (M. bovis, M. caprae, M. africanum, M. pinnipedii, M. canetti), and M. leprae. The number of identified species of NTM is growing and will continue to do so because of the use of DNA sequence typing for speciation. The number of known species currently exceeds 150. NTM are highly adaptable and can inhabit hostile environments, including industrial solvents.


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InternalMed_Harrison. NTM are ubiquitous in soil and water. Specific organisms have recurring niches, such as M. simiae in certain aquifers, M. fortuitum in pedicure baths, and M. immunogenum in metalworking fluids. Most NTM cause disease in humans only rarely unless some aspect of host defense is impaired, as in bronchiectasis, or breached, as by inoculation (e.g., liposuction, trauma). There are few instances of human-tohuman transmission of NTM, which occurs almost exclusively in cystic fibrosis. Because infections due to NTM are rarely reported to health agencies and because their identification is sometimes problematic, reliable data on incidence and prevalence are lacking. Disseminated disease denotes significant immune dysfunction (e.g., advanced HIV infection), whereas pulmonary disease, which is much more common, is highly associated with pulmonary epithelial defects but not with systemic immunodeficiency.


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InternalMed_Harrison. In the United States, the incidence and prevalence of pulmonary infection with NTM, mostly in association with bronchiectasis (Chap. 312), have for many years been several-fold higher than the corresponding figures for tuberculosis, and rates of the former are increasing among the elderly. Among patients with cystic fibrosis, who often have bronchiectasis, rates of clinical infection with NTM range from 3% to 15%, with even higher rates among older patients. Although NTM may be recovered from the sputa of many individuals, it is critical to differentiate active disease from commensal harboring of the organisms. A scheme to help with the proper diagnosis of pulmonary infection caused by NTM has been developed by the American Thoracic Society and is widely used. The bulk of nontuberculous mycobacterial disease in North America is due to M. kansasii, organisms of the M. avium complex (MAC), and M. abscessus.


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InternalMed_Harrison. In Europe, Asia, and Australia, the distribution of NTM in clinical specimens is roughly similar to that in North America, with MAC species and rapidly growing organisms such as M. abscessus encountered frequently. M. xenopi and M. malmoense are especially prominent in northern Europe. M. ulcerans causes the distinct clinical entity Buruli ulcer, which occurs throughout tropical zones, especially in western Africa. M. marinum is a common cause of cutaneous and tendon infections in coastal regions and among individuals exposed to fish tanks or swimming pools. The true international epidemiology of infections due to NTM is hard to determine because the isolation of these organisms often is not reported and speciation often is not performed for M. tuberculosis and NTM. The increasing ease of identification and speciation of these organisms is likely to have a major impact on the description of their international epidemiology in the next few years.


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InternalMed_Harrison. Because exposure to NTM is essentially universal and disease is rare, it can be assumed that normal host defenses against these organisms must be strong and that otherwise healthy individuals in whom significant disease develops are highly likely to have specific susceptibility factors that permit NTM to become established, multiply, and cause disease. At the advent of HIV infection, CD4+ T lymphocytes were recognized as key effector cells against NTM; the development of disseminated MAC disease was highly correlated with a decline in CD4+ T lymphocyte numbers. Such a decrease has also been implicated in disseminated MAC infection in patients with idiopathic CD4+ T lymphocytopenia. Potent inhibitors of tumor necrosis factor α (TNF-α), such as infliximab, adalimumab, certolizumab, golimumab, and etanercept, can neutralize this critical cytokine. The occasional result is severe mycobacterial or fungal infection; these associations indicate that TNF-α is a crucial element in


InternalMed_Harrison

InternalMed_Harrison. golimumab, and etanercept, can neutralize this critical cytokine. The occasional result is severe mycobacterial or fungal infection; these associations indicate that TNF-α is a crucial element in mycobacterial control. However, in cases without the above risk factors, much of the genetic basis of susceptibility to disseminated infection with NTM is accounted for by specific mutations in the interferon γ (IFN-γ)/interleukin 12 (IL-12) synthesis and response pathways.


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InternalMed_Harrison. Mycobacteria are typically phagocytosed by macrophages, which respond with the production of IL-12, a heterodimer composed of IL-12p35 and IL-12p40 moieties that together make up IL-12p70. IL-12 activates T lymphocytes and natural killer cells through binding to its receptor (composed of IL-12Rβ1 and IL-12Rβ2/IL-23R), with consequent phosphorylation of STAT4. IL-12 stimulation of STAT4 leads to secretion of IFN-γ, which activates neutrophils and macrophages to produce reactive oxidants, to increase expression of the major histocompatibility complex and Fc receptors, and to concentrate certain antibiotics intracellularly. Signaling by IFN-γ through its receptor (composed of IFN-γR1 and IFN-γR2) leads to phosphorylation of STAT1, which in turn regulates IFN-γ-responsive genes, such as those coding for IL-12 and TNF-α. TNF-α signals through its own receptor via a downstream complex containing the nuclear factor κB (NF-κB) essential modulator (NEMO). Therefore, the positive feedback loop


InternalMed_Harrison

InternalMed_Harrison. coding for IL-12 and TNF-α. TNF-α signals through its own receptor via a downstream complex containing the nuclear factor κB (NF-κB) essential modulator (NEMO). Therefore, the positive feedback loop between IFN-γ and IL-12/IL-23 drives the immune response to mycobacteria and other intracellular infections. These genes are known to be the critical ones in the pathway of mycobacterial control: specific Mendelian mutations have been identified in IFN-γR1, IFN-γR2, STAT1, GATA2, ISG15, IRF8, IL-12A, IL-12Rβ1, IL-12Rβ2, CYBB, and NEMO (Fig. 204-1). Despite the identification of genes associated with disseminated disease, only ~70% of cases of disseminated nontuberculous mycobacterial infections that are not associated with HIV infection have a genetic diagnosis; the implication is that more mycobacterial susceptibility genes and pathways remain to be identified.


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InternalMed_Harrison. In contrast to the recognized genes and mechanisms associated with disseminated nontuberculous mycobacterial infection, the best-recognized underlying condition for pulmonary infection with NTM is bronchiectasis (Chap. 312). Most of the well-characterized forms of bronchiectasis, including cystic fibrosis, primary ciliary dyskinesia, STAT3-deficient hyper-IgE syndrome, and idiopathic bronchiectasis, have high rates of association with nontuberculous mycobacterial infection. The precise mechanism by which bronchiectasis predisposes to locally destructive but not systemic involvement is unknown. Unlike disseminated or pulmonary infection, “hot-tub lung” represents pulmonary hypersensitivity to NTM—most commonly MAC organisms—growing in underchlorinated, often indoor hot tubs.


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InternalMed_Harrison. Unlike disseminated or pulmonary infection, “hot-tub lung” represents pulmonary hypersensitivity to NTM—most commonly MAC organisms—growing in underchlorinated, often indoor hot tubs. CLINICAL MANIFESTATIONS Disseminated Disease Disseminated MAC or M. kansasii infections in patients with advanced HIV infection are now uncommon in North America because of effective antimycobacterial prophylaxis T/NK12NEMONRAMP1ISG15STAT1GATA2IL-15IL-2IL-2RAFBIFN˛Salm.M˜TNF°RTLRIRF8CD14IFN˛RIL-12IL-18?˝1˝2


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InternalMed_Harrison. FIGuRE 204-1 Cytokine interactions of infected macrophages (Mф) with T and natural killer (NK) lymphocytes. Infection of macrophages by mycobacteria (AFB) leads to the release of heterodimeric interleukin 12 (IL-12). IL-12 acts on its receptor complex (IL-12R), with consequent STAT4 activation and production of homodimeric interferon γ (IFNγ). Through its receptor (IFNγR), IFNγ activates STAT1, stimulating the production of tumor necrosis factor α (TNFα) and leading to the killing of intracellular organisms such as mycobacteria, salmonellae (Salm), and some fungi. Homotrimeric TNFα acts through its receptor (TNFαR) and requires nuclear factor κB essential modulator (NEMO) to activate nuclear factor κB, which also contributes to the killing of intracellular bacteria. Both IFNγ and TNFα lead to upregulation of IL-12. TNFα-blocking antibodies work either by blocking the ligand (infliximab, adalimumab, certolizumab, golimumab) or by providing soluble receptor (etanercept). Mutations in


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InternalMed_Harrison. to upregulation of IL-12. TNFα-blocking antibodies work either by blocking the ligand (infliximab, adalimumab, certolizumab, golimumab) or by providing soluble receptor (etanercept). Mutations in IFNγR1, IFNγR2, IL-12p40, IL-12Rβ1, IL-12Rβ2, STAT1, GATA2, ISG15, IRF8, CYBB, and NEMO have been associated with a predisposition to mycobacterial infections. Other cytokines, such as IL-15 and IL-18, also contribute to IFNγ production. Signaling through the Toll-like receptor (TLR) complex and CD14 also upregulates TNFα production. LPS, lipopolysaccharide; NRAMP1, natural resistance-associated macrophage protein 1.


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InternalMed_Harrison. and improved treatment of HIV infection. When such mycobacterial disease was common, the portal of entry was the bowel, with spread to bone marrow and the bloodstream. Surprisingly, disseminated infections with rapidly growing NTM (e.g., M. abscessus, M. fortuitum) are very rare in HIV-infected patients, even those with very advanced HIV infection. Because these organisms are of low intrinsic virulence and disseminate only in conjunction with impaired immunity, disseminated disease can be indolent and progressive over weeks to months. Typical manifestations of malaise, fever, and weight loss are often accompanied by organomegaly, lymphadenopathy, and anemia. Because special cultures or stains are required to identify the organisms, the most critical step in diagnosis is to suspect infection with NTM. Blood cultures may be negative, but involved organs typically have significant organism burdens, sometimes with a grossly impaired granulomatous response. In a child, disseminated


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InternalMed_Harrison. infection with NTM. Blood cultures may be negative, but involved organs typically have significant organism burdens, sometimes with a grossly impaired granulomatous response. In a child, disseminated involvement (i.e., involvement of two or more organs) without an underlying iatrogenic cause should prompt an investigation of the IFN-γ/IL-12 pathway. Recessive mutations in IFN-γR1 and IFN-γR2 typically lead to severe infection with NTM. In contrast, dominant negative mutations in IFN-γR1, which lead to overaccumulation of a defective interfering mutant receptor on the cell surface, inhibit normal IFN-γ signaling and thus lead to nontuberculous mycobacterial osteomyelitis. Dominant negative mutations in STAT1 and recessive mutations in IL-12Rβ1 can produce variable phenotypes consistent with their residual capacities for IFN-γ synthesis and response. Male patients who have disseminated nontuberculous mycobacterial infections along with conical, peg, or missing teeth and an abnormal hair


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InternalMed_Harrison. their residual capacities for IFN-γ synthesis and response. Male patients who have disseminated nontuberculous mycobacterial infections along with conical, peg, or missing teeth and an abnormal hair pattern should be evaluated for defects in the pathway 1130 that activates NF-κB through NEMO. These patients may have associated immune globulin defects as well. Patients with myelodysplasia and mycobacterial disease should be investigated for GATA2 deficiency. A recently recognized group of patients that often develops disseminated infections with rapidly growing NTM (predominantly M. abscessus) as well as other opportunistic infections has high-titer neutralizing auto-antibodies to IFN-γ. Thus far, this syndrome has been reported most frequently in East Asian female patients. IV catheters can become infected with NTM, usually as a consequence of contaminated water. M. abscessus and M. fortuitum sometimes infect deep indwelling lines as well as fluids used in eye surgery, subcutaneous


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InternalMed_Harrison. can become infected with NTM, usually as a consequence of contaminated water. M. abscessus and M. fortuitum sometimes infect deep indwelling lines as well as fluids used in eye surgery, subcutaneous injections, and local anesthetics. Infected catheters should be removed.


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InternalMed_Harrison. Pulmonary Disease Lung disease is by far the most common form of nontuberculous mycobacterial infection in North America and the rest of the industrialized world. The clinical presentation typically consists of months or years of throat clearing, nagging cough, and slowly progressive fatigue. Patients will often have seen physicians multiple times and received symptom-based or transient therapy before the diagnosis is entertained and samples are sent for mycobacterial stains and cultures. Because not all patients can produce sputum, bronchoscopy may be required for diagnosis. The typical lag between onset of symptoms and diagnosis is ~5 years in older women. Predisposing factors include underlying lung diseases such as bronchiectasis (Chap. 312), pneumoconiosis (Chap. 311), chronic obstructive pulmonary disease (Chap. 314), primary ciliary dyskinesia (Chap. 312), α1 antitrypsin deficiency (Chap. 367e), and cystic fibrosis (Chap. 313). Bronchiectasis and nontuberculous mycobacterial


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InternalMed_Harrison. pulmonary disease (Chap. 314), primary ciliary dyskinesia (Chap. 312), α1 antitrypsin deficiency (Chap. 367e), and cystic fibrosis (Chap. 313). Bronchiectasis and nontuberculous mycobacterial infection often coexist and progress in tandem. This situation makes causality difficult to determine in a given index case, but bronchiectasis is certainly among the most critical predisposing factors that are exacerbated by infection.


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InternalMed_Harrison. MAC organisms are the most common causes of pulmonary non-tuberculous mycobacterial infection in North America, but rates vary somewhat by region. MAC infection most commonly develops during the sixth or seventh decade of life in women who have had months or years of nagging intermittent cough and fatigue, with or without sputum production or chest pain. The constellation of pulmonary disease due to NTM in a tall and thin woman who may have chest wall abnormalities is often referred to as Lady Windermere syndrome, after an Oscar Wilde character of the same name. In fact, pulmonary MAC infection does afflict older nonsmoking white women more than men, with onset at ~60 years. Patients tend to be taller and thinner than the general population, with high rates of scoliosis, mitral valve prolapse, and pectus anomalies. Whereas male smokers with upper-lobe cavitary disease tend to carry the same single strain of MAC indefinitely, nonsmoking females with nodular bronchiectasis tend to carry


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InternalMed_Harrison. and pectus anomalies. Whereas male smokers with upper-lobe cavitary disease tend to carry the same single strain of MAC indefinitely, nonsmoking females with nodular bronchiectasis tend to carry several strains of MAC simultaneously, with changes over the course of their disease.


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InternalMed_Harrison. M. kansasii can cause a clinical syndrome that strongly resembles tuberculosis, consisting of hemoptysis, chest pain, and cavitary lung disease. The rapidly growing NTM, such as M. abscessus, have been associated with esophageal motility disorders such as achalasia. Patients with pulmonary alveolar proteinosis are prone to pulmonary nontuberculous mycobacterial and Nocardia infections; the underlying mechanism may be inhibition of alveolar macrophage function due to the autoantibodies to granulocyte-macrophage colony-stimulating factor found in these patients.


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InternalMed_Harrison. Cervical Lymph Nodes The most common form of nontuberculous mycobacterial infection among young children in North America is isolated cervical lymphadenopathy, caused most frequently by MAC organisms but also by other NTM. The cervical swelling is typically firm and relatively painless, with a paucity of systemic signs. Because the differential diagnosis of painless adenopathy includes malignancy, many children have infection with NTM diagnosed inadvertently at biopsy; cultures and special stains may not have been requested because mycobacterial disease was not ranked high in the differential. Local fistulae usually resolve completely with resection and/or antibiotic therapy. Likewise, the entity of isolated pediatric intrathoracic nontuberculous mycobacterial infection, which is probably related to cervical lymph node infection, is usually mistaken for cancer. In neither isolated cervical nor isolated intrathoracic infections with NTM have children with underlying immune defects been


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InternalMed_Harrison. related to cervical lymph node infection, is usually mistaken for cancer. In neither isolated cervical nor isolated intrathoracic infections with NTM have children with underlying immune defects been identified, nor do the affected children go on to develop other opportunistic infections.


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InternalMed_Harrison. Skin and Soft Tissue Disease Cutaneous involvement with NTM usually requires a break in the skin for introduction of the bacteria. Pedicure bath–associated infection with M. fortuitum is more likely if skin abrasion (e.g., during leg shaving) has occurred just before the pedicure. Outbreaks of skin infection are often caused by rapidly growing NTM (especially M. abscessus, M. fortuitum, and M. chelonae) acquired via skin contamination from surgical instruments (especially in cosmetic surgery), injections, and other procedures. These infections are typically accompanied by painful, erythematous, draining subcutaneous nodules, usually without associated fever or systemic symptoms.


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InternalMed_Harrison. M. marinum lives in many water sources and can be acquired from fish tanks, swimming pools, barnacles, and fish scales. This organism typically causes papules or ulcers (“fish-tank granuloma”), but the infection can progress to tendinitis with significant impairment of manual dexterity. Lesions appear days to weeks after inoculation of organisms by a typically minor trauma (e.g., incurred during the cleaning of boats or the handling of fish). Tender nodules due to M. marinum can advance up the arm in a pattern also seen with Sporothrix schenckii (sporotricoid spread). The typical carpal tendon involvement may be the first presenting manifestation and may lead to surgical exploration or steroid injection. The index of suspicion for M. marinum infections must be high to ensure that proper specimens obtained during procedures are sent for culture.


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InternalMed_Harrison. M. marinum infections must be high to ensure that proper specimens obtained during procedures are sent for culture. M. ulcerans, another waterborne skin pathogen, is found mainly in the tropics, especially in tropical areas of Africa. Infection follows skin trauma or insect bites that allow admission to contaminated water. The skin lesions are typically painless, clean ulcers that slough and can cause osteomyelitis. The toxin mycolactone accounts for the modest host inflammatory response and the painless ulcerations.