Pulmonary Tuberculosis and Atypical Mycobacterial Infection
Fabio R. Tavora, M.D., Ph.D.
Allen P. Burke, M.D.
Mycobacterium Tuberculosis
Microbiology
Tuberculosis has been known as a human disease for several millennia. It is a pulmonary and systemic disease caused by Mycobacterium tuberculosis complex species. The M. tuberculosis complex consists of seven organisms: M. tuberculosis, M. bovis, M. africanum, M. microti, M. canetti, M. caprae, and M. pinnipedii. In humans, tuberculosis is overwhelmingly caused by M. tuberculosis, with a small fraction of disease cause by M. bovis and M. africanum.1
Epidemiology
In 2013, there were about 9 million new cases of active tuberculosis, and about 20% of those involve coinfection with HIV.2 In 2001, a total of 15,989 cases of TB were reported to the Centers for Disease Control and Prevention (CDC) from the 50 states and the District of Columbia, a number which decreased to 9,582 cases in 2013, a rate of 3.0 cases per 100,000 persons (http://www.cdc.gov/tb/statistics). Despite the overall decline in the number of cases of tuberculosis, the percentage of extrapulmonary disease and drug-resistant forms has remained constant or increased.3 Furthermore, despite advances in antimicrobial therapy, tuberculosis still accounts for millions of deaths worldwide, with an estimated annual death toll of 1.58 million.4,5
Clinical Features
In general terms, pulmonary infection by M. tuberculosis can be divided in latent and active infection (Table 40.1). Because of differences in treatment and prognosis, drug-resistant tuberculosis is often considered separately.
The clinical features of pulmonary tuberculosis include productive chronic cough, weight loss, intermittent fever, night sweats, and hemoptysis.6 About 5% of active cases may become resistant to regular regimens.
In 4% of cases, diagnosis is not made until death. These patients were more likely older, Caucasian, and drug addicts.7
Latent Tuberculosis
Latent infection is manifest only by a positive tuberculin skin test,8 which relies on measurement of host immune response.9
TABLE 40.1 Classifications of Clinical Tuberculosis | ||||||||||||||
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Newer tests relying on interferon-γ release assays have no crossreactivity with prior vaccine exposure and have a higher positive predictive value for the subsequent development of active disease.9 Overall, ˜2% of the population in the United States have a positive skin test, a rate that is higher in foreign born (from high-risk countries), intravenous drug addicts, homeless persons, and those with known contact with an infected individual.9 It has also been estimated (of particular interest to practicing pathologists) that the staff of laboratories and necropsy rooms are estimated to be between 100 and 200 times more likely than the general public to develop latent or active tuberculosis.10
Latent infection suggests an absence of prior active disease and therefore a normal chest radiograph. However, patients in the “latent” category often include those with abnormal chest x-rays indicative of healed, untreated tuberculosis placing them in a high-risk category for postprimary or reactivation tuberculosis.9 Any evidence of acute infection by clinical, radiologic, or microbiologic means indicates active disease in a patient with a positive skin test done for screening purposes.
Although it is often stated that M. tuberculosis organisms persist in an inactive state in granulomas in the latent phase, this fact has never been directly demonstrated.5 An autopsy study utilizing multiple molecular techniques (including in situ polymerase chain reaction [PCR]) showed nucleotide sequences specific for M. tuberculosis in the lungs, spleens, kidneys, and livers, all at about the same rate, of patients with presumed latent tuberculosis. Cells infected included endothelium, pneumocytes, macrophages, Bowman parietal cells, and proximal tubular cells. Interestingly, none was found in granulomas, inflammatory infiltrates, or fibrosis.11
Active Tuberculosis
Active disease has traditionally been classified into two groups: disease progressing from the initial infection (primary tuberculosis) and disease occurring years after initial infection, with reactivation. Since many patients do not neatly fall into either category, current clinical classifications separate patients into latent, active, and drug-resistant tuberculosis.12 Because, however, some pathologic differences have been espoused between primary tuberculosis and postprimary tuberculosis, they will be considered separately.
Primary Tuberculosis
The initial infection (primary tuberculosis) begins when bacilli are inhaled into the lungs where they induce a granulomatous inflammatory response. The organisms rapidly spread from the lung to lymph nodes and hematogenously. The infection is typically self-limited with the development of effective cell-mediated immunity and resolves in 6 to 8 weeks, either leaving no trace or resulting in healed lesions on chest radiograph. In a small percentage of individuals, the initial infection progresses to pleuritis, if the granuloma ruptures into the pleura; extensive consolidative pneumonia; enlargement of mediastinal lymph nodes, causing bronchial obstruction and postobstructive pneumonia; rupture of a tuberculous focus into a bronchus, leading to extensive endobronchial spread; or rupture of a tuberculous focus into a pulmonary blood vessel with hematogenous spread.1,13 Primary tuberculosis is usually seen in children.13
Postprimary (Reactivation)
Reactivation tuberculosis occurs in patients previously sensitized to M. tuberculosis. Genetic studies suggest that susceptibility to primary and postprimary tuberculosis may be governed by different genes.14
It is believed that 80% of cases of tuberculosis in the United States are the result of reactivated latent infection.9 The diagnosis of reactivation depends on history of prior skin test, history or remote exposure, or findings on chest radiograph more typical of previous disease. In otherwise healthy patients with latent disease, there is a 5% to 10% chance over a lifetime of developing active disease,9 a number that is reduced to 1% with antimicrobial prophylaxis.15 In patients with HIV infection prior to effective therapy, there was a 7% yearly risk of developing tuberculosis.8
The fact that the risk of “reactivation” tuberculosis increases dramatically with acquired immune deficiency is at odds with the concept that reactivation requires a strong cellular immune response.13 For this reason, and because tuberculosis that results from reactivation of a latent infection is not always clinically distinguishable from tuberculosis that results from recent exposure,9 the distinction between reactivation and primary tuberculosis is not always made. The term “accelerated” tuberculosis has been substituted for “reactivation” in referring to disease developing in immunocompromised patients, in essence placing immunosuppression-related tuberculosis in a category of primary disease.13
In addition to immunosuppression, reactivation rates are increased if there is malnutrition, debilitation, alcoholism, poorly controlled diabetes mellitus, smoking, low body weight, silicosis, immunosuppression, the postpartum period, gastrectomy, chronic hemodialysis, and jejunoileal bypass surgery, although in most patients no predisposing factor can be identified.1,9,16 Evidence of untreated tuberculosis on chest x-ray and recent contact with an infected person imparts the greatest risk for reactivation.1
Postprimary tuberculosis in patients with normal immunity is generally confined to the lung, does not spread to lymph nodes or distant sites, and does not spontaneously regress. It is characterized by cavities in the lung that produce massive numbers of organisms resulting in high infectivity.17 It occurs more commonly in adults and usually involves the apical and posterior segments of the upper lung lobes and the superior segments of the lower lobes.16
Miliary Tuberculosis
Miliary tuberculosis occurs in 2% of tuberculosis. It is variably considered a form of primary (accelerated) or reactivation tuberculosis, depending on the patient’s exposure history and immune status.3 Risk factors overlap with reactivation disease and include prior infection with tuberculosis, coinfection with HIV, treatment with immunosuppressive agents, diabetes mellitus, and alcoholism. Unlike other types, miliary tuberculosis relatively frequently is misdiagnosed during life, and the diagnosis is first made at autopsy in 33% of patients.3 Once considered a disease of children, it is increasingly seen in adults. There is a bimodal distribution, with one peak in children and adolescents and the other in the elderly. The mortality is estimated at 18% to 30%.18
The tuberculin skin test has been reported to be almost always negative miliary tuberculosis.3 There is believed to be an inadequacy of effector T-cell response to the organism. The clinical manifestations are extremely variable and range from subtle, systemic symptoms to a fulminant process with adult respiratory distress syndrome (see Chapter 21).3 In a series from India, 5% of patients treated in intensive care for acute respiratory distress syndrome had tuberculosis as the underlying cause.19
Miliary tuberculosis represents a relatively large proportion of extrapulmonary disease (over 20%) and involves the liver, spleen, bone marrow, and meninges most frequently, in addition to the lungs.18
Immunocompromised Patients
The risk of developing tuberculosis is as high as 20% in patients with AIDS.7 In HIV disease, there are radiologic and pathologic differences compared to reactivation tuberculosis in immunocompromised patients. Imaging of the lung may show subtle or even absent findings. Small and diffuse opacities on lung imaging, pleural effusions, and hilar lymphadenopathy may be the only findings. Pulmonary cavities are uncommon, resulting in a lower likelihood for transmission of infection by aerosolization.13
In general, tuberculosis in HIV disease has a higher frequency of negative tuberculin skin tests than non-HIV-related tuberculosis (61% vs. 10%). Other clinical differences include a higher rate of extrapulmonary involvement (60% vs. 28%), a higher rate of diffuse or miliary infiltrates (60% vs. 32%), a higher rate of hilar lymphadenopathy (20% vs. <5%), a higher rate of normal chest radiographs despite pulmonary involvement (15% vs. <1%), a lower rate of focal infiltrates (35% vs. 68%), and a lower rate of cavities (18% vs. 67%).1 These differences corroborate the concept that reactivation tuberculosis is different from the accelerates disease seen in immunocompromised patients.17
Pathologically, compared to tuberculosis in immunocompetent individuals, there is more likely to be necrosis, organisms are more numerous, and giant cells, well-formed granulomas, and lymphocytes are less common.17,20
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