Tuberculosis

Tuberculosis



Octavian C. Ioachimescu, J. Walton Tomford




Man must want to achieve more than he is able to achieve. … If we do not reach for the impossible, we shall never reach far enough to discover the possible. Our wishes should be boundless.


Dr. Gerhard Domagk (1947 Nobel Prize in medicine for the discovery of the first antimicrobial drug)


Over the last century, tuberculosis (TB) has killed more than 100 million people and this has continued relatively unchanged over the last 50 years, despite the development of effective antituberculous drugs. This chapter summarizes the current status of the epidemiology, pathogenesis, diagnosis, treatment, and control of pulmonary tuberculosis. We have excluded nontuberculous mycobacterial disorders and the various forms of extrapulmonary disease, except pleural TB.



HISTORICAL OVERVIEW



• Egyptian mummies with severe skeletal deformities suggest that TB has existed since antiquity (Pott’s disease).

• After the plague devastated Europe during the Middle Ages, TB (the “white plague”) began to take its heavy toll.

• TB affected famous kings and political figures (e.g., King Edward VI, King Louis VIII of France, John Calvin, Cardinal Richelieu, Napoleon II).

• TB, also called writer’s or artist’s disease, killed, among others, Nicolo Paganini, Robert Louis Stevenson, Franz Kafka, George Orwell, all five Brontë sisters, Thomas Mann, Albert Camus, and Igor Stravinsky.

• The Nobel Prize for Medicine for TB-related work was given to the following:

• Dr. Robert Koch (Fig. 1) for the discovery of TB bacillus (1905)

• Dr. Gerhard Domagk for the discovery of the first antibacterial drug (Prontosil); also pioneered anti-TB drug development (1947)

• Dr. Selman Waksman for the development of streptomycin as an anti-TB drug (1952)

• In 1993, the World Health Organization (WHO) declared TB a global emergency, the only disease ever so designated. In 2003, WHO reported a continued TB pandemic.

image

Figure 1 Robert Koch, 1843-1910.


(Reproduced with permission from the College of Physicians of Philadelphia).



PREVALENCE AND RISK FACTORS



Tuberculosis Worldwide


About one third of the world’s population is infected with Mycobacterium tuberculosis. Among the communicable diseases, TB is the second leading cause of death worldwide after HIV-AIDS, killing nearly two million people each year. Approximately 13% of TB patients have coexistent HIV infection. There were an estimated eight million to nine million new cases of TB in 2000, but fewer than one half were actually reported. Most cases (5 million to 6 million) occur in those aged 15 to 49 years, with significant socioeconomic impact. More than 50% of TB cases occur in the largest Asian countries (India, China, Indonesia, Bangladesh, Philippines, and Pakistan). Sub-Saharan Africa has the highest incidence rate (approximately 300/100,000 population/year). Even though TB has declined steadily in western Europe and North America, the global TB burden appears on the rise, especially in the former Soviet Union, Eastern Europe, and Africa. HIV infection accounts for much of the recent increase in the global TB incidence.



Tuberculosis in the United States


In the 1900s, TB was one of the leading causes of death in the United States. Here, the most important risk factors for the development of TB are immigration from or travel to an endemic area, close contact with a TB patient, exposure to untreated cases in crowded living facilities, advanced age, residing in an inner city, and host immunodeficiency. Although the TB incidence was already decreasing in the first half of the 20th century because of better nutrition and housing conditions, the introduction of effective chemotherapy produced a steep decline in mortality and an accelerated drop in incidence, reaching an average of a 5.5% decline per year of TB case rates between 1953 and 1983. Between 1985 and 1992, however, the incidence of TB unexpectedly increased by about 20%. The responsible factors were increased immigration from high-prevalence countries, the emergence of the HIV-AIDS epidemic, an increased number of medically underserved persons (e.g., homeless, drug abusers, low-income persons), emergence of drug-resistant TB cases and, most importantly, deterioration of the public health infrastructure for the control of TB.


In 2005, a total of 14,093 TB cases (4.8 cases/100,000 population) was reported in the United States, representing a 3.8% decline in the rate from 2004. These findings indicated that although the 2005 TB rate was the lowest recorded since national reporting began in 1953, the decline has slowed from an average of 7.1% per year (1993-2000) to an average of 3.8% per year (2001-2005). In 2005, the TB rate in foreign-born persons in the United States was 8.7 times that of U.S.-born persons. Hispanics, African Americans, and Asians had TB rates 7.3, 8.3, and 19.6 times higher than whites, respectively. Moreover, the number of multidrug-resistant (MDR) TB cases in the United States increased by 13.3%, with 128 cases of MDRTB in 2004, the most recent year for which complete drug-susceptibility data are available. Effective TB control and prevention in the United States require adequate resources, sustained collaborative measures with other countries to reduce the incidence of TB worldwide, and interventions targeted to populations with the highest TB rates.1



ETIOLOGY


Tuberculosis is caused by a group of five closely related species, which form the Mycobacterium tuberculosis complex: M. tuberculosis, M. bovis, M. africanum, M. microti, and M. canettii. M. tuberculosis (Koch’s bacillus) is responsible for the vast majority of TB cases in the United States. The main defining characteristic of the genus Mycobacterium is the property called acid-fastness, which is the ability to withstand decolorization with an acid-alcohol mixture after staining with carbolfuchsin or auramine-rhodamine. Mycobacteria are primarily intracellular pathogens, have slow growth rates, are obligate aerobes, and produce a granulomatous reaction in normal hosts. In cultures, M. tuberculosis does not produce significant amounts of pigment, has a buff-colored, smooth surface appearance, and biochemically produces niacin. These characteristics are useful in differentiating M. tuberculosis from nontuberculous mycobacteria. One characteristic but not distinctive morphologic property of M. tuberculosis is the tendency to form cords, or dense clusters of bacilli, aligned in parallel (Fig. 2). The biochemical background of cording is called cord factor (a trehalose dimycolate), and its contribution to bacterial virulence is still unclear.


image

Figure 2 Ziehl-Neelsen stain of a sputum specimen showing acid-fast bacilli in cords (red; × 1000).



PATHOPHYSIOLOGY AND NATURAL HISTORY


TB transmission occurs almost exclusively from human to human; a prerequisite is having contact with a source case. More than 80% of new TB cases result from exposure to sputum smear-positive cases, although smear-negative, culture-positive cases can be responsible for up to 17% of new cases. Tuberculosis is spread by airborne droplet nuclei, which are 1- to 5-µm particles containing 1 to 400 bacilli each. They are expelled in the air by, for example, coughing, sneezing, singing, laughing, or talking, and remain suspended in the air for many hours. They can be inhaled and subsequently entrapped in the distal airways and alveoli. There, bacilli are ingested by local macrophages, multiply within the cells and, within 2 weeks, are transported through the lymphatics to establish secondary sites (lymphohematogenous spread). The development of an immune response, heralded by a delayed-type hypersensitivity reaction over the next 4 weeks, leads to granuloma formation, with a subsequent decrease in the number of bacilli. Some of them remain viable, or dormant, for many years. This stage is called latent TB infection (LTBI), which is generally an asymptomatic, radiologically undetected process in humans. Sometimes, a primary complex (Ghon complex) can be seen radiographically, mostly in the lower and middle lobes, and comprises the primary lesion, hilar lymphadenopathy, with or without a lymphangitic track. Later, the primary lesion tends to become calcified and can be identified on chest radiographs for decades. Most commonly, a positive tuberculin test result remains the only proof of LTBI, and therefore does not signify active disease.


Under certain conditions of immature or disregulated immunity, alveolar macrophages and the subsequent biologic cascade could fail in limiting the mycobacterial proliferation, leading to primary progressive tuberculosis; this is seen mostly in children younger than 5 years or in HIV-positive or profoundly immunosuppressed individuals. Factors known to influence this unfavorable course are patient’s age, nutritional status, host immunity, and bacterial infective load.


Once infected with M. tuberculosis, 3% to 5% of immunocompetent persons develop active disease (i.e., secondary progressive tuberculosis) within 2 years and an additional 3% to 5% later on during their lifetime. Overall, there is a lifetime risk of re-activation of 10%, with one half occurring during the first 2 years after infection—hence, the necessity to treat all tuberculin skin test converters. The lifetime re-activation rate is approximately 20% for most persons with purified protein derivative (PPD) induration of more than 10 mm and either HIV infection or evidence of old, healed tuberculosis; it is between 10% and 20% for recent PPD skin test converters, adults younger than 35 years with an induration of more than 15 mm or on therapy with infliximab (a tumor necrosis factor α [TNF-α] receptor blocker), and children younger than 5 years and a skin induration of more than 10 mm.


Studies performed in New York City and San Francisco using DNA fingerprinting have indicated that recent transmission (exogenous reinfection), especially among HIV patients, could account for up to 40% of new TB cases. This is significantly different from older studies, which have shown that approximately 90% of new TB cases are the result of endogenous re-activation.


After inhalation, the pathogenic bacilli start to replicate slowly and continuously and lead to the development of a cellular immunity in about 4 to 6 weeks. T lymphocytes and local (pulmonary and lymphatic node) macrophages represent key players in limiting further spread of bacilli in the host. This can be seen at the pathologic level, where the bacilli are in the center of necrotizing (caseating) and non-necrotizing (noncaseating) granulomas, surrounded by lymphocytes and macrophages. The infected macrophages release interleukins 12 and 18 (IL-12 and IL-18), which stimulate CD4-positive T lymphocytes to secrete IFN-γ (interferon gamma), which in turn activate the macrophage phagocytosis of M. tuberculosis and the release of TNF-α. TNF-α has an important role in granuloma formation and the control of infection.


Genetic defects are illustrated by different polymorphisms of the NRAMP-1 gene (natural resistance-associated macrophage protein-1); vitamin D receptors, and interleukin-1 have also been shown to be involved in TB pathogenesis. It can be difficult to differentiate between genetic predisposition and overwhelming bacteriologic load, as often seen in countries with a high prevalence of TB.


HIV coinfection is the greatest risk factor for progression to active disease in adults. The relation between HIV and TB has augmented the deadly potential of each disease. Other risk factors include diabetes mellitus, renal failure, coexistent malignancies, malnutrition, silicosis, immunosuppressive therapies (including steroids and anti-TNF drugs), and TNF-α receptor, IFN-γ receptor, or IL-12 β1 receptor defects.



DIAGNOSIS



Signs and Symptoms


A high index of suspicion is needed in countries with a high prevalence of infection or in patients with immunosuppression, although bacteriologic confirmation is required whenever possible. Persistent cough for more than 2 to 4 weeks should raise the possibility of pulmonary TB. Other common associated symptoms are hemoptysis, dyspnea, malaise, weight loss, night sweats, and chest pain. The symptoms are less pronounced in children, and any exposure to an active TB patient or a positive tuberculin test should raise more concerns about this disease. Box 1 shows the Centers for Disease Control and Prevention (CDC) recommendations for the clinical and laboratory criteria of TB diagnosis.



Box 1 Centers for Disease Control and Prevention (CDC) Case Definition of Tuberculosis



Laboratory Criteria



Isolation of M. tuberculosis from a clinical specimen or (when culture not obtained)

Demonstration of acid-fast bacilli in a clinical specimen


Clinical Elements (All of these are needed when not confirmed by laboratory test results.)



A positive skin tuberculin test

Signs and symptoms compatible with tuberculosis or an abnormal chest radiograph

Treatment with two or more antituberculous drugs

A complete diagnostic evaluation with exclusion of other, alternative diagnoses


Laboratory Tests


One inexpensive and rapid diagnostic test is the sputum smear, done by Ziehl-Neelsen (ZN) carbolfuchsin, Kinyoun carbolfuchsin, or fluorochrome staining methods. ZN stain identifies 50% to 80% of culture-positive TB cases and is a useful diagnostic and epidemiologic tool, because smear-positive TB patients are more infectious than smear-negative patients and have a higher fatality rate. Nevertheless, smear-negative cases may account for up to 20% of M. tuberculosis transmission. In countries with a high prevalence of TB, a positive smear signifies TB in 95% of ases. The lower limit of detection of ZN staining is 5 × 103 organisms/mL, whereas rhodamine-auramine fluorochrome staining tends to be more sensitive. In children, M. tuberculosis can be recovered from gastric aspirates, with yields varying from 30% to 50% in older children to 70% in infants for three consecutive specimens. The role of induced sputum or bronchoscopy in diagnosing TB is well established in patients unable to provide good-quality sputum specimens.


Culture media most often used for diagnosis include the following:


• Solid culture medium: egg-based Löwenstein-Jensen, or agar-based Middlebrook 7H10 or 7H11 (growth can take up to 6 weeks)

• Liquid culture medium (growth in 1-3 weeks)

The speciation can be done with biochemical tests or DNA probes. The direct specimen polymerase chain reaction assay is rapid (1-2 days), although it can lead to false-positive results and has been disappointing in its practicality.



Imaging Studies


Radiographic findings suggesting TB include upper lobe infiltrates, cavitary lesions, and hilar or paratracheal lymphadenopathy. In many patients with primary progressive disease and in HIV patients, radiographic findings can be subtle and include lower lobe opacities, a miliary pattern, or both. In a study done on HIV-infected pulmonary TB patients, 8% of cases had normal chest radiographs.



TREATMENT



Lifestyle Modifications


These include good nutrition, which is of paramount importance, and physical activity, which is strongly encouraged.



Treatment Options



• Drug treatment is an individual and public health measure.

• Regimens must contain multiple drugs to which organisms are susceptible, given for a sufficient period of time.

• Adherence to the drug regimen is critical for success. Directly observed therapy (DOT) is cost effective for patients at high risk for nonadherence, and should be used in all cases.

• Chemotherapy can be successful only within a health system infrastructure that addresses the clinical and social management of patients and their contacts.

• Surgery is indicated for TB abscesses or loculated foci of infection that are unresponsive to medical therapy.

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Jul 18, 2017 | Posted by in GENERAL SURGERY | Comments Off on Tuberculosis

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