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Mycob acte ri u m tu b e rcu I osis I nfecti o n Trimethoprim sulfamethoxazole also has good tissue pen- KEY POI lITS etration and is a viable treatment option. Treatment dura- o Most Mycobacterium tuberculosis infections in the tion is typically 2 to 4 weeks (for further information, see United States occur in foreign-born persons; however, MKSAP 19 General Internal Medicine 2). Hospitalized others at high risk include those with alcohol use disor- patients should initially receive a broad-spectrum paren- der, urban poor, homeless persons, persons who inject teral antibiotic, such as an extended-spectrum penicillin or drugs, prison inmates, persons living in shelters, per- cephalosporin, with the possible addition of an aminogly- sons with HIV and older adults. coside. Imaging studies are not recommended unless a prostatic abscess is suspected. . Multidrug-resistant tuberculosis (MDR{B) accounts for 4.6% of new infections and 20% of relapsed infections; XEY POI ]ITS extensively drug-resistant tuberculosis accounts for o Gram-negative uropathogens account for about 80% of approximately 10% of all MDR-TB infections worldwide. acute prostatitis infections; in men 35 years or younger, sexually transmitted infections, including lVeisserio gonorrhoeae and Chlamgdia trachomotis, must be Pathophysiology considered. Most persons who become infected with M. tuberculosis . Fluoroquinolone antibiotics for 2to 4 weeks are the remain asymptomatic and develop latent tuberculosis. Specific preferred oral agents for treating acute bacterial prosta- risk factors for developing active tuberculosis among infected titis but should not be used if recent genitourinary persons are shown in Table 18. instrumentation was performed because most E. coli KEY POIilTS strains are resistant to fluoroquinolones. . Most persons who become infected with Mycobactenum tuberculosis remain asymptomatic and develop latent tuberculosis. Mycobacterium . Risk factors for developing active tuberculosis include tu be rcu I osis I nfecti o n recent infection, pulmonary fibrotic lesions, malnutri- tion, and comorbidities such as immunosuppression, Epidemiology tumor necrosis factor-a inhibitors, injection drug use, Tuberculosis remains one of the most common causes of silicosis, chronic kidney disease, and diabetes mellitus. death from an infectious disease worldwide. Rates of Mycobacterium tuberculosis infection remain relatively low in North America. However, approximately one quar- Clinical Manifestations ter of the world's population is infected with the bacteria. Tuberculosis is classified as pulmonary extrapulmonary or As of 2018, approximately 10 million new M. tuberculosis both; the two main forms are primary and secondary tubercu- infections are reported each year throughout the world, losis. Primary tuberculosis occurs soon after the initial and approximately 1.6 million deaths are documented each year. More than 5000 people per day die of tubercu- TABLE 1 8. Risk Factors for Developing Active losis throughout the world. More than 607, of infections M yco b acte ri u m tu be rculosis are reported from Southeast Asia, India, China, Micronesia, Recent infection (<1 year) Russia, and sub-Saharan Africa. Multidrug resistant Pul monary fibrotic lesions tuberculosis (MDR-TB) accounts for 4.6'/o of new infec Malnutrition tions and 20% of relapsed infections. Extensively drug- resistant tuberculosis (XDR-TB) accounts for approxi Comorbidities mately 10o1, of all MDR-TB infections worldwide. In 2018, HIV infection 9025 tuberculosis infections were reported in the United Silicosis States (Z.a per 100,000 persons). Infections in the United Chronic kidney disease States occur 15 times more frequently in foreign-born Diabetes mellitus persons than in U.S.-born p€rSons; however, others at high risk include those with alcohol use disorder, urban lnjection drug use poor, homeless persons, persons who inject drugs, prison I m munosuppressive therapy inmates, persons living in shelters, persons with HIV and Jejunoileal bypass older adults. Solid organ transplantation The burden of disease throughout the world and the rate Tu mor necrosis factor-cr i n h i bitors oftravel from country to country ensures a steady stream of Head and neck cancer active tuberculosis cases in the United States.

Trimethoprim sulfamethoxazole also has good tissue pen- KEY POI lITS etration and is a viable treatment option. Treatment dura- o Most Mycobacterium tuberculosis infections in the tion is typically 2 to 4 weeks (for further information, see United States occur in foreign-born persons; however, MKSAP 19 General Internal Medicine 2). Hospitalized others at high risk include those with alcohol use disor- patients should initially receive a broad-spectrum paren- der, urban poor, homeless persons, persons who inject teral antibiotic, such as an extended-spectrum penicillin or drugs, prison inmates, persons living in shelters, per- cephalosporin, with the possible addition of an aminogly- sons with HIV and older adults. coside. Imaging studies are not recommended unless a prostatic abscess is suspected. . Multidrug-resistant tuberculosis (MDR{B) accounts for 4.6% of new infections and 20% of relapsed infections; XEY POI ]ITS extensively drug-resistant tuberculosis accounts for o Gram-negative uropathogens account for about 80% of approximately 10% of all MDR-TB infections worldwide. acute prostatitis infections; in men 35 years or younger, sexually transmitted infections, including lVeisserio gonorrhoeae and Chlamgdia trachomotis, must be Pathophysiology considered. Most persons who become infected with M. tuberculosis . Fluoroquinolone antibiotics for 2to 4 weeks are the remain asymptomatic and develop latent tuberculosis. Specific preferred oral agents for treating acute bacterial prosta- risk factors for developing active tuberculosis among infected titis but should not be used if recent genitourinary persons are shown in Table 18. instrumentation was performed because most E. coli KEY POIilTS strains are resistant to fluoroquinolones. . Most persons who become infected with Mycobactenum tuberculosis remain asymptomatic and develop latent tuberculosis. Mycobacterium . Risk factors for developing active tuberculosis include tu be rcu I osis I nfecti o n recent infection, pulmonary fibrotic lesions, malnutri- tion, and comorbidities such as immunosuppression, Epidemiology tumor necrosis factor-a inhibitors, injection drug use, Tuberculosis remains one of the most common causes of silicosis, chronic kidney disease, and diabetes mellitus. death from an infectious disease worldwide. Rates of Mycobacterium tuberculosis infection remain relatively low in North America. However, approximately one quar- Clinical Manifestations ter of the world's population is infected with the bacteria. Tuberculosis is classified as pulmonary extrapulmonary or As of 2018, approximately 10 million new M. tuberculosis both; the two main forms are primary and secondary tubercu- infections are reported each year throughout the world, losis. Primary tuberculosis occurs soon after the initial and approximately 1.6 million deaths are documented each year. More than 5000 people per day die of tubercu- TABLE 1 8. Risk Factors for Developing Active losis throughout the world. More than 607, of infections M yco b acte ri u m tu be rculosis are reported from Southeast Asia, India, China, Micronesia, Recent infection (<1 year) Russia, and sub-Saharan Africa. Multidrug resistant Pul monary fibrotic lesions tuberculosis (MDR-TB) accounts for 4.6'/o of new infec Malnutrition tions and 20% of relapsed infections. Extensively drug- resistant tuberculosis (XDR-TB) accounts for approxi Comorbidities mately 10o1, of all MDR-TB infections worldwide. In 2018, HIV infection 9025 tuberculosis infections were reported in the United Silicosis States (Z.a per 100,000 persons). Infections in the United Chronic kidney disease States occur 15 times more frequently in foreign-born Diabetes mellitus persons than in U.S.-born p€rSons; however, others at high risk include those with alcohol use disorder, urban lnjection drug use poor, homeless persons, persons who inject drugs, prison I m munosuppressive therapy inmates, persons living in shelters, persons with HIV and Jejunoileal bypass older adults. Solid organ transplantation The burden of disease throughout the world and the rate Tu mor necrosis factor-cr i n h i bitors oftravel from country to country ensures a steady stream of Head and neck cancer active tuberculosis cases in the United States. 32

Mycob a cte ri u m tu b e rcu I osis I nfection false-negative TST result may occur in patients with recent be positive in 65% of persons. If available, a NAAT assay that tuberculosis infection, overwhelming active tuberculosis also detects rifampin resistance is recommended for timely infection, recent viral infections, or severe immunocompro- identification. Although the NAAT assays are quick and sensi mise (e.g., AIDS) and in those younger than 6 years. Patients tive, mycobacterial cultures are still recommended so that in with remote exposure to M. tuberculosis may initially have a vitro susceptibilities can be obtained. A negative NAAT result negative TST result that can become positive several weeks cannot be used to exclude pulmonary tuberculosis; however, later after a second TST, known as the "booster effect." The NAAT can confirm the presence of M. tuberculosis in 507, to second test is recommended in health care workers 7 to B0% of AFB smear-negative, culture-positive specimens. 21 days after initial testing and should be performed on the Moreover, NAAT can facilitate earlier decision making regard- opposite forearm; it is not required if IGRA is used. IGRAs are ing whether to initiate tuberculosis therapy. recommended in nearly all clinical settings in which TST is If signs of extrapulmonary infection are present, sam recommended; one exception is children younger than ples from those areas should be obtained and sent for 5 years, for whom experts recommend both tests to increase AFB stain, mycobacterial culture, and histopathology. specificity. Histopathologz may be beneficial by demonstrating caseat- Recent guidelines by the CDC do not recommend annual ing granulomas, which are suggestive for but not exclusive to tuberculosis testing for health care personnel unless a known or diagnostic of tuberculosis. In disseminated tuberculosis, exposure or ongoing transmission is identified in the facility. blood cultures for mycobacteria using isolator methodology are helpful. KEY POIl{TS HVC o An interferon-y release assay is preferred to tuberculin t(EY POt ltTS skin testingfor Mycobocterium tuberculosis except for . The gold standard for the diagnosis of active those younger than 5 years. My cob acter ium tub ercu los is infection remains the o Latent tuberculosis infection is diagnosed when an mycobacterial culture;when a sputum smear result is positive for acid-fast bacilli, nucleic acid amplification asymptomatic patient has a positive tuberculin skin test or interferon-yrelease assay result with no clinical or testing is highly recommended to verify the presence of radiographic manifestations of active tuberculosis. M. tuberculosis. o If signs of extrapulmonary tuberculosis infection are present, samples from those areas should be obtained Diagnosis of Active Tuberculosis lnfection and sent for acid-fast bacilli staining, mycobacterial cul- The CDC recommends AFB smear microscopy in all patients ture, and histopatholory. suspected of having active pulmonary tuberculosis. In vitro fluorescence microscopy of sputum is the preferred method- Radiographic Findings ology. Testing three specimens is highly recommended The classic radiographic finding in pulmonary tuberculosis is because false-negative results from a single specimen are not that of upper lobe disease with air space disease and cavities uncommon. However, false-positive results are also not (Figure 17). However, any radiographic pattern can be seen. uncommon, thus a positive smear result requires mycobacte- rial culture confirmation. At least 3 mL of sputum should be submitted, although 5 to 10 mL is preferred. Serial specimens must be obtained at least 8 hours apart, and one must be an early morning specimen. Sputum induction is preferable to bronchoscopy as the sample methodologz because of its greater sensitivity in patients who are unable to expectorate sputum. The gold standard for diagnosis of active infection remains the mycobacterial culture. Whether AFB staining results are positive or negative, liquid and solid cultures should be per- formed for every specimen obtained. Liquid culture allows for faster growth and more rapid identification of organisms (z-+ weeks). When a sputum smear result is positive for AFB, nucleic acid amplification testing (NAAT) for M. tuberculosis is highly recommended to verify the organism. The positive predictive value of a NAAT on a smear-positive sputum sample is 95%. In FIGURE 17. Posteroanterior(PA)chest radiograph of a patientwith reactivation patients with an intermediate to high level of suspicion for tuberculosis showing bilateral upper lobe cavitary infiltrates. A left pleural effusion active disease who have a negative smear, the NAAT result will is also present.

false-negative TST result may occur in patients with recent be positive in 65% of persons. If available, a NAAT assay that tuberculosis infection, overwhelming active tuberculosis also detects rifampin resistance is recommended for timely infection, recent viral infections, or severe immunocompro- identification. Although the NAAT assays are quick and sensi mise (e.g., AIDS) and in those younger than 6 years. Patients tive, mycobacterial cultures are still recommended so that in with remote exposure to M. tuberculosis may initially have a vitro susceptibilities can be obtained. A negative NAAT result negative TST result that can become positive several weeks cannot be used to exclude pulmonary tuberculosis; however, later after a second TST, known as the "booster effect." The NAAT can confirm the presence of M. tuberculosis in 507, to second test is recommended in health care workers 7 to B0% of AFB smear-negative, culture-positive specimens. 21 days after initial testing and should be performed on the Moreover, NAAT can facilitate earlier decision making regard- opposite forearm; it is not required if IGRA is used. IGRAs are ing whether to initiate tuberculosis therapy. recommended in nearly all clinical settings in which TST is If signs of extrapulmonary infection are present, sam recommended; one exception is children younger than ples from those areas should be obtained and sent for 5 years, for whom experts recommend both tests to increase AFB stain, mycobacterial culture, and histopathology. specificity. Histopathologz may be beneficial by demonstrating caseat- Recent guidelines by the CDC do not recommend annual ing granulomas, which are suggestive for but not exclusive to tuberculosis testing for health care personnel unless a known or diagnostic of tuberculosis. In disseminated tuberculosis, exposure or ongoing transmission is identified in the facility. blood cultures for mycobacteria using isolator methodology are helpful. KEY POIl{TS HVC o An interferon-y release assay is preferred to tuberculin t(EY POt ltTS skin testingfor Mycobocterium tuberculosis except for . The gold standard for the diagnosis of active those younger than 5 years. My cob acter ium tub ercu los is infection remains the o Latent tuberculosis infection is diagnosed when an mycobacterial culture;when a sputum smear result is positive for acid-fast bacilli, nucleic acid amplification asymptomatic patient has a positive tuberculin skin test or interferon-yrelease assay result with no clinical or testing is highly recommended to verify the presence of radiographic manifestations of active tuberculosis. M. tuberculosis. o If signs of extrapulmonary tuberculosis infection are present, samples from those areas should be obtained Diagnosis of Active Tuberculosis lnfection and sent for acid-fast bacilli staining, mycobacterial cul- The CDC recommends AFB smear microscopy in all patients ture, and histopatholory. suspected of having active pulmonary tuberculosis. In vitro fluorescence microscopy of sputum is the preferred method- Radiographic Findings ology. Testing three specimens is highly recommended The classic radiographic finding in pulmonary tuberculosis is because false-negative results from a single specimen are not that of upper lobe disease with air space disease and cavities uncommon. However, false-positive results are also not (Figure 17). However, any radiographic pattern can be seen. uncommon, thus a positive smear result requires mycobacte- rial culture confirmation. At least 3 mL of sputum should be submitted, although 5 to 10 mL is preferred. Serial specimens must be obtained at least 8 hours apart, and one must be an early morning specimen. Sputum induction is preferable to bronchoscopy as the sample methodologz because of its greater sensitivity in patients who are unable to expectorate sputum. The gold standard for diagnosis of active infection remains the mycobacterial culture. Whether AFB staining results are positive or negative, liquid and solid cultures should be per- formed for every specimen obtained. Liquid culture allows for faster growth and more rapid identification of organisms (z-+ weeks). When a sputum smear result is positive for AFB, nucleic acid amplification testing (NAAT) for M. tuberculosis is highly recommended to verify the organism. The positive predictive value of a NAAT on a smear-positive sputum sample is 95%. In FIGURE 17. Posteroanterior(PA)chest radiograph of a patientwith reactivation patients with an intermediate to high level of suspicion for tuberculosis showing bilateral upper lobe cavitary infiltrates. A left pleural effusion active disease who have a negative smear, the NAAT result will is also present. 34

Mycob a cte ri u m tu b e rcu I osis I nfection infection, most frequently in children and immunosuppressed Diagnosis persons. Often, the lesions heal spontaneously. Secondary or The key to the diagnosis of tuberculosis is a high index of sus- reactivation tuberculosis results from endogenous reactivation picion in patients at high risk. of a latent infection. Most cases of active tuberculosis are caused by reactivation of latent tuberculosis in the setting of immunosuppression. Seventy-five percent of secondary infec- Diagnosis of Latent Tuberculosis lnfection tions are pulmonary except in those infected with HIY in The goal of diagnosing latent tuberculosis infection (LIBI) is to whom two thirds of patients have pulmonary and extrapul- identiff and treat persons at increased risk for reactivation monary infection. tuberculosis. The lifetime risk of developing active infection in Frequent manifestations of active infection include patients with UIBI is 5% to 10'2,, with half of active disease fever, night sweats, weight loss, productive cough (occa- manifesting within 2 years of infection. The risk of developing sionally blood tinged), anorexia, malaise, and pleuritic active tuberculosis is considerably higher in patients who are chest pain. Hemoptysis occurs in 10% to 20% of patients immunocompromised. The estimated global frequency of LIBI with positive acid-fast bacilli (AFB) smear results. In is about 25%. Testing methods include interferon-y release immunosuppressed patients, the infection may also spread assay (IGRA) performed on a blood sample or tuberculin skin hematogenously, producing miliary (progressive, widely dis- testing (TST). LIBI is diagnosed when an asymptomatic patient seminated) tuberculosis, which can result in a systemic has a positive TST or IGRA result with no clinical or radio- inflammatory response syndrome, septic shock, and ulti- graphic manifestations of active tuberculosis. mately death if not diagnosed and treated early. Additionally, The CDC recommends performing an IGRA rather than a patients with disseminated infection may present with TST in persons 5 years or older who are likely to have M. atypical clinical manifestations and chest radiographs. tuberculosis infection, have a low or intermediate risk of dis- Extrapulmonary disease may be the result of hematogenous ease progression, have a history of bacille Calmette-Gudrin dissemination and may be seen in up to 30% of patients with (BCG) vaccination, or are unlikely to return to have their TST active tuberculosis. It may involve almost any organ system, result interpreted. IGRAs are in vitro assays that measure including the pleura, lymph nodes, central nervous system, T-cell release of interferon-y in response to stimulation with skeletal system, pericardium, larynx, peritoneum, and geni- highly tuberculosis-specific antigens ESAT-6 and CFP-10 tourinary system. (QuantiFERON-TB Gold In-Tube and T-SPOT.TB test). IGRAs rEY POITTS are more specific than TST because they have less cross- o Clinical manifestations of active tuberculosis include reactivity resulting from BCG vaccination and sensitization by nontuberculous mycobacteria. Although not used to diagnose fever, night sweats, weight loss, productive cough (occa- active tuberculosis, IGRAs appear to be at least as sensitive as sionally blood tinged), anorexia, malaise, and pleuritic TST in patients with active tuberculosis. chest pain. TST has become the alternative diagnostic test if IGRA is . In immunosuppressed patients, tuberculosis infection not feasible or available. The purified protein derivative is may spread hematogenously, resulting in widely dis- injected intradermally and interpreted after 48to72 hours by seminated progressive tuberculosis, which can result in measuring the transverse diameter of induration, not ery- a systemic inflammatory response syndrome, septic thema. The criteria for a positive TST result are based on shock, and ultimately death if not treated early. the patient's risk factors for tuberculosis (Table 19). A

infection, most frequently in children and immunosuppressed Diagnosis persons. Often, the lesions heal spontaneously. Secondary or The key to the diagnosis of tuberculosis is a high index of sus- reactivation tuberculosis results from endogenous reactivation picion in patients at high risk. of a latent infection. Most cases of active tuberculosis are caused by reactivation of latent tuberculosis in the setting of immunosuppression. Seventy-five percent of secondary infec- Diagnosis of Latent Tuberculosis lnfection tions are pulmonary except in those infected with HIY in The goal of diagnosing latent tuberculosis infection (LIBI) is to whom two thirds of patients have pulmonary and extrapul- identiff and treat persons at increased risk for reactivation monary infection. tuberculosis. The lifetime risk of developing active infection in Frequent manifestations of active infection include patients with UIBI is 5% to 10'2,, with half of active disease fever, night sweats, weight loss, productive cough (occa- manifesting within 2 years of infection. The risk of developing sionally blood tinged), anorexia, malaise, and pleuritic active tuberculosis is considerably higher in patients who are chest pain. Hemoptysis occurs in 10% to 20% of patients immunocompromised. The estimated global frequency of LIBI with positive acid-fast bacilli (AFB) smear results. In is about 25%. Testing methods include interferon-y release immunosuppressed patients, the infection may also spread assay (IGRA) performed on a blood sample or tuberculin skin hematogenously, producing miliary (progressive, widely dis- testing (TST). LIBI is diagnosed when an asymptomatic patient seminated) tuberculosis, which can result in a systemic has a positive TST or IGRA result with no clinical or radio- inflammatory response syndrome, septic shock, and ulti- graphic manifestations of active tuberculosis. mately death if not diagnosed and treated early. Additionally, The CDC recommends performing an IGRA rather than a patients with disseminated infection may present with TST in persons 5 years or older who are likely to have M. atypical clinical manifestations and chest radiographs. tuberculosis infection, have a low or intermediate risk of dis- Extrapulmonary disease may be the result of hematogenous ease progression, have a history of bacille Calmette-Gudrin dissemination and may be seen in up to 30% of patients with (BCG) vaccination, or are unlikely to return to have their TST active tuberculosis. It may involve almost any organ system, result interpreted. IGRAs are in vitro assays that measure including the pleura, lymph nodes, central nervous system, T-cell release of interferon-y in response to stimulation with skeletal system, pericardium, larynx, peritoneum, and geni- highly tuberculosis-specific antigens ESAT-6 and CFP-10 tourinary system. (QuantiFERON-TB Gold In-Tube and T-SPOT.TB test). IGRAs rEY POITTS are more specific than TST because they have less cross- o Clinical manifestations of active tuberculosis include reactivity resulting from BCG vaccination and sensitization by nontuberculous mycobacteria. Although not used to diagnose fever, night sweats, weight loss, productive cough (occa- active tuberculosis, IGRAs appear to be at least as sensitive as sionally blood tinged), anorexia, malaise, and pleuritic TST in patients with active tuberculosis. chest pain. TST has become the alternative diagnostic test if IGRA is . In immunosuppressed patients, tuberculosis infection not feasible or available. The purified protein derivative is may spread hematogenously, resulting in widely dis- injected intradermally and interpreted after 48to72 hours by seminated progressive tuberculosis, which can result in measuring the transverse diameter of induration, not ery- a systemic inflammatory response syndrome, septic thema. The criteria for a positive TST result are based on shock, and ultimately death if not treated early. the patient's risk factors for tuberculosis (Table 19). A TABLE 1 9. lnterpretation of Tuberculin Skin Test Results Criteria for Tuberculin Positivity by Risk Group >5 mm lnduration >10 mm Induration >15 mm lnduration HIV-positive persons Recent (<5 years) arrivals from high-prevalence countries All others with no risk factors for TB Recent contacts of persons with active TB Persons who inject drugs Persons with fibrotic changes on chest Residents or employees of high-risk congregate settings: prisons radiograph consistent with old TB and jails, nursing homes and other long-term facilities for the elderly, hospitals and other health care facilities, residential facilities Patients with organ transplants and other for patients with AIDS, homeless shelters immunosuppressive conditions (receiving the equivalent of 215 mg/d of Mycobacteriology la boratory person nel ; persons with cl nica i I

TABLE 1 9. lnterpretation of Tuberculin Skin Test Results Criteria for Tuberculin Positivity by Risk Group >5 mm lnduration >10 mm Induration >15 mm lnduration HIV-positive persons Recent (<5 years) arrivals from high-prevalence countries All others with no risk factors for TB Recent contacts of persons with active TB Persons who inject drugs Persons with fibrotic changes on chest Residents or employees of high-risk congregate settings: prisons radiograph consistent with old TB and jails, nursing homes and other long-term facilities for the elderly, hospitals and other health care facilities, residential facilities Patients with organ transplants and other for patients with AIDS, homeless shelters immunosuppressive conditions (receiving the equivalent of 215 mg/d of Mycobacteriology la boratory person nel ; persons with cl nica i I prednisone for >4 weeks) conditions that put them at high risk for active disease (silicosis, diabetes mellitus, severe kidney disease, certain types of cancer, some intestinal conditions); children aged <4 years or exposed to adults in high-risk categories TB = tuberculosis infection 33