It is currently estimated that about one third of the world’s population is infected with M. tuberculosis (tubercle bacillus), with 30 million people having active disease. The incidence of tuberculosis in the United States has declined for many years and is now at a historic low (Figure 1). In contrast to the decline of tuberculosis in the West, the incidence of the disease in some Asian and sub-Saharan African nations has dramatically increased. In some of these nations, nearly 50 percent of the HIV-infected population is co infected with M. tuberculosis.

Fig1. Incidence of new cases of tuberculosis (United States).

1. Epidemiology: Patients with active pulmonary tuberculosis shed large numbers of organisms by coughing, creating aerosol droplet nuclei. Because of resistance to dessication, the organisms can remain viable as droplet nuclei suspended in room air for at least 30 minutes. The principal mode of contagion is person-to-person transmission by inhalation of the aerosol. A single infected person can pass the organism to numerous people in an exposed group, such as a family, classroom, or hospital ward without proper isolation.

2. Pathogenicity: After being inhaled, mycobacteria reach the alveoli, where they multiply in the pulmonary epithelium or macrophages. Within 2 to 4 weeks, many bacilli are destroyed by the immune system, but some survive and are spread by the blood to extra pulmonary sites. The virulence of M. tuberculosis rests with its ability to survive and grow within host cells (Figure 2). Although the organism produces no demonstrable toxins, when engulfed by macrophages, bacterial sulfolipids inhibit the fusion of phagocytic vesicles with lysosomes. The ability of M. tuberculosis to grow even in immunologically activated macrophages and to remain viable within the host for decades is a unique characteristic of the pathogen.

Fig2. Progression of active tuberculosis infection.

 3. Immunity: M. tuberculosis stimulates both a humoral and a cell mediated immune response. Although circulating antibodies appear, they do not convey resistance to the organism. Instead, cellular immunity (CD4+ T cells) and the accompanying delayed hypersensitivity directed against a number of bacterial protein antigens, develop in the course of infection and contribute to both the pathology of and immunity to the disease.

4. Clinical significance: Primary tuberculosis occurs in a person who has had no previous contact with the organism. For the majority of cases (about 95 percent), the infection becomes arrested, and most people are unaware of this initial encounter. The only evidence of tuberculosis may be a positive tuberculin test. Figure 2 illustrates the course of tuberculosis infection either remaining dormant or progressing to clinical disease. A chest radiograph sometimes shows the initial pulmonary nodule (a healing tubercle, see below), and some fibrosis as shown in Figure 3. Approximately 10 percent of those with an arrested primary infection develop clinical tuberculosis at some later time in their lives.

Fig3. A chest radiograph showing some fibrosis—the classic Ghon complex.

a. Primary disease–initial phase: Because primary tuberculosis is usually acquired via the respiratory tract, the initial lesion occurs in a small bronchiole or alveolus in the midlung periphery. The organisms are engulfed by local mononuclear phagocytes, and their presence initiates an inflammatory reaction. However, because tubercle bacilli grow well in phagocytic cells, the bacteria proliferate and are carried by lymphatic drainage to the lymph nodes and beyond to set up additional foci. This initial phase of the infection is usually mild or asymptomatic and results in exudative lesions in which fluid and polymorphonuclear leukocytes accumulate around the bacilli. A specific immune response develops after about 1 month, and this changes the character of the lesions. Cell-mediated immunity to M. tuberculosis and hypersensitivity to its antigens (tuberculoproteins) not only confer an enhanced ability to localize the infection and curb growth of the organism, but also cause a greater capacity to damage the host. Macrophages, activated by specific T lymphocytes, begin to accumulate and destroy the bacilli.

 b. Primary disease–tubercle formation: The productive (granulomatous) lesion that develops is known as a tubercle (see Figure 2). It consists of a central area of large, multinucleate giant cells (macrophage syncytia) containing tubercle bacilli, a midzone of pale epithelioid cells, and a peripheral collar of fibroblasts and mononuclear cells. Tissue damage is produced by the destruction of both bacilli and phagocytes, which results in the release of degradative enzymes and reactive oxygen species such as superoxide radicals. The center of the tubercle develops a characteristic expanding, caseous (cheesy) necrosis (see Figure 2).

 c. Primary disease–course: Primary tuberculosis follows one of two courses: If the lesion arrests, the tubercle undergoes fibrosis and calcification, although viable but nonproliferating organisms may persist (Figure 4). Alternatively, if the lesion breaks down, the caseous material is discharged, and a cavity is created that can facilitate spread of the infection. The organisms are dispersed by the lymph and the bloodstream and can seed the lungs; regional lymph nodes; or various distant issues, such as liver, spleen, kidneys, bone, or meninges. In progressive disease, one or more of the resulting tubercles may expand, leading to destruction of tissue and clinical illness (for example, chronic pneumonitis, tuberculous osteomyelitis, and tuberculous meningitis). In the extreme instance, active tubercles develop throughout the body, a serious condition known as miliary (disseminated) tuberculosis.

Fig4. Stages in the pathogenesis of tuberculosis (TB).

 d. Secondary disease–reactivation: This is usually caused by M. tuberculosis that has survived in a dormant primary tubercle lesion (see Figure 4). Any of the preexisting tubercles may be involved, but pulmonary sites are most common, particularly the lung apices where high oxygen tension favors mycobacterial growth. The resulting pathology is known as "caseation necrosis." Destruction of the lung tissue leads to air-filled cavities where the bacteria replicate actively. Bacterial populations in such lesions often become quite large, and many organisms are shed (for example, in sputum). The patient again becomes capable of exposing others to the disease. Reactivation is apparently caused by an impairment in immune status, often associated with malnutrition, alcoholism, advanced age, or severe stress. Immunosuppressive medication or diseases (such as diabetes and, particularly, AIDS) are common preconditions leading to reactivation.

5. Tuberculin reaction: The tuberculin reaction test is a manifestation of delayed hypersensitivity to protein antigens of M. tuberculosis. Although such tests can be used to document contact with the tubercle bacillus, they do not confirm that the patient currently has active disease. In the Mantoux test, purified protein derivative (PPD) is prepared from culture filtrates of the organism and bio logically standardized. Activity is expressed in tuberculin units. In the routine procedure (Mantoux test), a measured amount of PPD is injected intradermally in the forearm (Figure 5). It is read 48 to 72 hours later for the presence and size of an area of induration (hardening) at the site of injection, which must be observed for the test to be positive (Figure 6). A positive reaction usually develops 4 to 6 weeks after initial contact with the organism. It remains positive for life, although it may wane after some years or in the presence of immunosuppression by medications or disease.

Fig5. Mantoux skin test for tuberculosis. [Note: For some people, determination of a positive reaction may be interpreted more stringently (see Figure 6).] PPD = purified protein derivative

Fig6. Interpretations of the Mantoux skin test for tuberculosis.

6. Laboratory identification: Diagnosis of active pulmonary tuberculosis includes demonstration of clinical symptoms and abnormal chest radiographs and confirmation by isolation of M. tuberculosis from relevant clinical material.

a. Identification in clinical specimens: A microscopic search for acid-fast bacilli using techniques such as the Ziehl-Neelsen stain is the most rapid test for mycobacteria. However, M. tuberculosis cannot be reliably distinguished on morphologic grounds from other pathogens in the genus, from some saprophytic mycobacterial species that may contaminate glassware and reagents in the laboratory, or from those mycobacteria that may be part of the normal flora. Therefore, a definitive identification of M. tuberculosis can only be obtained by culturing the organism or by using one of the newer molecular methods described below. Although 2 to 8 weeks are required to culture the tubercle bacillus because of its slow growth on laboratory media, such cultures can detect small numbers of organisms in the original sample. Figure 7 shows a culture of M. tuberculosis. Isolation of the organism is essential for determining its antibiotic sensitivity, in addition to confirming the specific identity of the bacillus by growth and biochemical characteristics.

Figure 7. Mycobacterium tuberculosis colonies grown on Lowenstein Jensen medium

 b. Nucleic acid amplification: Molecular techniques are increasingly important in the diagnosis of tuberculosis because they have the potential to shorten the time required to detect and identify M. tuberculosis in clinical specimens. For example, the amplified M. tuberculosis direct test uses enzymes that rapidly make copies of M. tuberculosis 16S ribosomal RNA, which can be detected using genetic probes. The sensitivity of the test ranges from 75 to 100 percent, with a specificity of 95 to 100 percent, and it is used for patients whose clinical smears are positive for acid-fast bacilli and whose cultures are in progress. A second technique, the polymerase chain reaction (PCR), amplifies a small portion of a predetermined target region of the M. tuberculosis DNA. Using human sputum, commercial PCR kits can confirm the diagnosis of tuberculosis within 8 hours, with a sensitivity and specificity that rivals culture techniques. In addition, PCR analysis facilitates DNA fingerprinting of specific strains, allowing studies of the progress of epidemics.

 7. Treatment: Several chemotherapeutic agents are effective against M. tuberculosis. Because strains of the organism resistant to a particular agent emerge during treatment, multiple drug therapy is employed to delay or prevent emergence. Isoniazid, rifampin, ethambutol, streptomycin, and pyrazinamide are the principal or “first-line” drugs because of their efficacy and acceptable degree of toxicity.

 a. Drug resistance: Mutants resistant to each of these agents have been isolated even prior to drug treatment. Therefore, the standard procedure is to begin treatment with two or more drugs to prevent outgrowth of resistant strains. Sensitivity tests, administered as soon as sufficient cultured organisms are available, are an important guide to modifying treatment. In most parts of the United States, 8 to 14 percent of M. tuberculosis strains are resistant to one or more of the primary drugs when initially isolated from new cases of tuberculosis. The higher incidence of multiple drug–resistant strains (MDR-TB) in some locations and patient populations (for example, prisons) is a cause for great concern.

b. Course of treatment: Clinical tuberculosis requires a long course of treatment because of the characteristics of the organisms and the lesions they produce. For example, as intracellular pathogens, the bacilli are shielded from drugs that do not penetrate host cells, and large cavities with avascular centers are penetrated by drugs with difficulty. Further, in chronic or arrested tubercles, the organisms are nonproliferating and, therefore, not susceptible to many antimicrobial agents. Until recently, 12 to 18 months of drug administration was thought to be required for a clinical cure. In recent years, short courses of 6 months, beginning with a daily dose of a combination of drugs and later by twice-weekly doses, have been successful in curing uncomplicated tuberculosis (Figure 8). If the drugs are effective in the pulmonary form of tuberculosis, sputum acid-fast bacteria smears become negative, and the patient becomes noninfectious in 2 to 3 weeks.

Fig8. Duration of treatment for tuberculosis

 c. Directly observed therapy: Patient compliance is often low when multiple drug schedules last for 6 months or longer. One successful strategy for achieving better treatment completion rates is “directly observed therapy,” in which patients take their medication while being supervised and observed. Some healthcare providers have embraced the concept of directly observed therapy, whereas others regard the strategy as expensive and intrusive, suitable only for individuals who have a history of noncompliance.

 8. Prevention: Public health measures, such as tuberculin tests, chest radiographs, case registries, and contact tracing have done much to control tuberculosis at the population level.

a. Latent disease chemotherapy: For individuals who are tuberculin-positive but asymptomatic, chemotherapy is indicated in several situations, usually with the single antibiotic isoniazid. For example, people in whom a recent skin test conversion is documented or tuberculin-positive patients who need immunosuppressive therapy for another illness can be protected from active tuberculosis by this treatment.

b. Vaccines: A vaccine against tuberculosis has been available since early in the 20th century. It is produced from Bacille Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis. When injected intradermally, it can con fer tuberculin hypersensitivity and an enhanced ability to activate macrophages that kill the pathogen. This vaccine is about 80 percent protective against serious forms of tuberculosis, such as meningitis in children, and has been used in mass immunization campaigns by the World Health Organization and in several European countries. However, public health officials in the United States recommend that vaccination be considered only for tuberculin-negative individuals under sustained heavy risk of infection, such as special groups of healthcare workers and those at high risk in areas where MDR-TB is common (Figure 9). Vaccination results in con version from PPD negative to PPD positive, thus obviating the utility of the only available surveillance method.

Fig9. Bacille Calmette-Guérin (BCG) vaccine is used throughout the world, but seldom in the United States.

اخر الاخبار

اخبار العتبة العباسية المقدسة

العتبة العباسية المقدسة تنشر لافتات الحزن والعزاء بذكرى شهادة الإمام الحسن المجتبى (عليه السلام)

كلية التمريض في جامعة العميد تحصل على الاعتماد البرامجي الكامل من وزارة التعليم

العتبة العباسية المقدسة تعلن تهيئة مساحات جديدة قرب الحرم الطاهر استعدادًا لزيارة الأربعين

ملاكات العتبة العباسة المقدسة تواصل أعمال تهيئة صحن أمّ البنين (عليها السلام) استعدادًا لزيارة الأربعين

المزيد

الآخبار الصحية

ماذا يحدث لضغط الدم مع تناول بذور الشيا؟

الأولى من نوعها.. حقنة ثورية تنهي معاناة فقدان السمع نهائيا !

7 علامات تدل على نقص معدن مهم في الجسم.. تعرف عليها

الجسم يستعيد الوزن الذي فقده بعد أسابيع من وقف أدوية التنحيف

المزيد

الآخبار التكنلوجية

أمواج تسونامي تصل إلى هاواي بعد زلزال كامتشاتكا !

تشات جي بي تي يتجاوز اختبار "أنا لست روبوتا" المرعب ؟!

أستراليا تعتزم حظر استخدام "يوتيوب" لهذه الفئة العمرية

دراسة تكشف تأثير استخدام الهواتف بسن مبكرة على الصحة النفسية

المزيد

مواضيع ذات صلة

Actinomyces israelii

Mycobacterium leprae

Bacterial Virulence Factors : Toxins

Laboratory Diagnosis of Vibrio, Aeromonas, Chromobacterium, and Related Organisms

Pathogenesis and Spectrum of Disease of Vibrio, Aeromonas, Chromobacterium, and Related Organisms

Laboratory Diagnosis of Alcaligenes, Bordetella (Non-pertussis), Comamonas, and Similar Organisms

Antimicrobial Susceptibility Testing and Therapy of Rhizobium, Ochrobactrum, and Similar Organisms

Laboratory Diagnosis of Rhizobium, Ochrobactrum, and Similar Organisms

Antimicrobial Susceptibility Testing and Therapy of Pseudomonas, Burkholderia, and Similar Organisms

Chlamydia trachomatis

Mycoplasma Pneumonia

Leptospira interrogans