Tuberculosis remains a leading cause of infectious morbidity and mortality worldwide. In 1993, the World Health Organization (WHO) called tuberculosis a "global emergency." There are an estimated 8 million new cases of tuberculosis each year. Tuberculosis is a slow-growing disease that primarily affects the pulmonary system. In 15% of patients it manifests as an extrapulmonary disease, including lymphadenitis, pleurisy, and meningitis as well as renal, genitourinary, thyroid (rarely), and bone and joint involvement. Tuberculosis is most frequently transmitted via airborne droplets expelled when an infected person coughs, sneezes, or talks. When these droplets evaporate, the desiccated bacilli remain airborne, finding their way to the distal alveoli of a new host. There is typically a prolonged latency period between initial infection and overt disease.

The incidence of tuberculosis peaked in the United States in the early 1900s. With the advent of antibiotics, the number of cases steadily declined from the early 1950s to 1984. In 1985, the trend reversed. This increase has been attributed both to the premature abatement in government control programs and to the human immunodeficiency virus (HIV) epidemic. Since that time, effective public health programs have once again reversed this trend; since 1993, tuberculosis has declined.

Miliary tuberculosis is a systemic version of TB affecting many organ systems due to hematogenous spread.

• Mycobacterium tuberculosis—the major etiologic agent worldwide; humans are the sole reservoir
• M. bovis—transmitted from milk of infected cows; rare since institution of pasteurization
• M. africanum—rare; only in Africa

• Occupational: healthcare workers—airborne transmission, infection from extrapulmonary disease such as draining an abscess, autopsies; embalmers—from body fluids generating infectious aerosols
• Contact with infected person
• Location of birth: Asia, Africa, Latin America
• HIV infection
• Residence in a long-term care facility
• Immunosuppressive therapy
• Tuberculosis infection: increases likelihood of developing active disease within two years
• Low income, medically underserved individuals
• In areas with a high incidence of TB, exogenous re-infection is a major cause of recurrence after effective treatment.

• Asymptomatic—especially from initial infection
• Mild fever, headache, chills, night sweats
• Malaise, fatigue
• Anorexia, weight loss
• Cough—nonproductive or mucopurulent
• Hemoptysis
• Pleuritic chest pain
• Dyspnea
• Adenopathy
• Children—asymptomatic and extrapulmonary manifestations are more frequent than in adults; look for signs of meningitis, adenopathy

• Bacterial pneumonia
• Other nontubercular mycobacterial infections
• Lymphomas
• Sarcoidosis
• Lung abscess

With pulmonary disease, post-tussive rales or amphoric breath sounds may be heard. Keratoconjunctivitis may be apparent. Marked general ill health and possibly pallor from anemia are the most common general findings. Positive tuberculin skin test such as purified protein derivative (PPD).

• Acid-fast bacillus microscopy—sputum (take three specimens from three different days) or smear mycobacteriologic studies with stains; 10,000 bacilli/mL yields a positive microscopy result; negative result does not rule out tuberculosis.
• M. tuberculosis culture—more sensitive than sputum; radiometric culture permits detection in 7 to 14 days; also tests for drug resistance of the M. tuberculosis

• M. tuberculosis droplets are engulfed by an alveolar macrophage (phagocytized) and destroyed by a resistant host (95% of cases), or progress in an immunocompromised host.
• Macrophage lyses from replicating bacilli; circulating monocytes differentiate into macrophages, which ingest but cannot inhibit the logarithmic growth of the bacilli; infected macrophages are transported by lymphatics to the bloodstream.
• Infected macrophages release cytokines that attract T cells.
• CD4 helper T cells secrete various cytokines (cell-mediated immunity), activating the macrophages to kill the bacilli; local tissue also destroyed.
• Tubercle bacilli can survive dormant and walled off by epithelioid cells for years—cell walls contain high concentrations of lipids or waxes (resistant to standard staining); may be evidenced by a positive PPD 4 to 6 weeks after infection.
• Primary tuberculosis—uncontrolled tubercles and disseminated M. tuberculosis; granulomatous lung foci
• Liquefaction and cavity formation may occur from reactivation of dormant M. tuberculosis foci causing bronchopneumonia.
• Extrapulmonary—relative paucity of bacilli; giant cell granulomas with caseating necrosis

• Chest X ray—upper lobe with fibronodular shadowing, infiltrates, and cavities; may be normal even with active M. tuberculosis; hilar lymphadenopathy often seen in children
• CT or MRI—for meningitis

PPD skin test

• Induration ³5 mm is positive for patients with a close contact who is infected or a patient with HIV
• Induration ³10 mm is positive for high-risk, high-prevalence groups
• Induration ³ 15 mm is positive for anyone
• False negatives may occur with immunosuppression even in the presence of overwhelming disease
• False positives may occur in the case of bacilli Calmette-Guérin (BCG) vaccine recipient

DNA detection by polymerase chain reaction (PCR)

• Rapid; problems of false positives may be resolved; specimen preparation problems, though, still do exist 

In the case of hemoptysis, the patient must be treated emergently to prevent asphyxiation. Chest x-ray, sputum, and culture tests are administered when diagnosis is suspected. Patients are often treated presumptively until results of lab tests return. Multidrug, not single-drug, antituberculous agents are prescribed. The 1998 consensus statement of the Public Health Tuberculosis Guidelines Panel found that rates of treatment completion are most likely to exceed 90% with directly observed therapy (DOT). The more action that is taken to administer medications, the higher the completion rates. Directly observed therapy should be employed whenever possible.

The patient is tested for drug resistance to determine the most effective combination of medications. Multidrug regimens taken regularly and for a sufficient period of time are required to effectively eradicate M. tuberculosis. Drug therapy regimens last 6 to 9 months for most patients, 9 to 12 months for HIV-infected patients, and a minimum of 12 months with extrapulmonary tuberculosis. For patients with HIV, preventive therapy reduces incidence of active tuberculosis and decreases mortality rates for those with positive skin tests. Drug regimens are divided into an initial bactericidal phase followed by a sterilization phase.

Standard antibiotics for tuberculosis include:

• Isoniazid—adults 5 mg/kg/day, children 10 to 20 mg/kg/day, 300 mg maximum for both; side effects: hepatitis (risk increased with alcohol consumption), peripheral neuropathy, rash, fever; additional drug interactions and toxicity for patients with HIV
• Rifampin—adults 10 mg/kg/day, maximum 600 mg/day, children 10 to 20 mg/kg/day; side effects: gastrointestinal upset, hepatitis, orange discoloration of body fluids (and contact lenses); additional drug interactions and toxicity for patients with HIV
• Pyrazinamide—15 to 30 mg/kg/day, 2 g maximum; side effects: hepatitis, hyperuricemia possibly with polyarthralgias (both reduced by concurrent rifampin administration)
• Ethambutol—least potent against M. tuberculosis; 15 to 25 mg/kg/day for 2 months, then reduce to 15 mg/kg/day; side effects: retrobulbar optic neuritis and color perception problems, avoid with children
• Streptomycin—used least often because of toxicity; intramuscular or intravenous administration of 10 to 15 mg/kg/day, maximum 1 g/day, up to 5 times per week for adults, 20 to 40 mg/kg/day with 1 g/day maximum for children; side effects: ototoxicity (both hearing loss and vestibular dysfunction), nephrotoxicity, teratogenic
• Pyridoxine (vitamin B₆) added to regimen particularly in populations at risk for vitamin deficiency (e.g., malnourished, alcoholics, elderly, pregnant and nursing mothers) or at risk for neuropathy (diabetics, HIV, chronic renal failure)

Experimental drugs:

• Rifapentine—longer acting, allowing dosing twice a week
• Fluoroquinolones (e.g., ciprofloxacin)—antibacterial; concentrations higher in respiratory secretions than in serum; well tolerated, but insufficient data to use as standard treatment; less effective with HIV
• Rifabutin—as effective as rifampin with concurrent HIV, but reduces time to sputum conversion; 150 mg/day associated with fewest adverse effects; possible role with multidrug resistance

• Bone and joint: curettage and bone grafting of extra-articular lesions; joint or bone resection; excision of soft tissue abscess; amputation

The control of tuberculosis worldwide depends on the effectiveness of vaccination programs and antibiotic therapy. Recent studies have determined that dietary deficiencies of proteins, zinc, and vitamins A, C, and D are linked to multiple abnormalities in immune function; these abnormalities may result in a poor immunologic response to tuberculosis and to the BCG vaccine, especially among the elderly, children, alcoholics, the homeless, and HIV-infected individuals.

Although the antimicrobial properties of plant species are not comparable to the potency of antimicrobial agents produced by microorganisms, researchers continue to conduct in vitro studies in an effort to uncover effective plant compounds that will inhibit M. tuberculosis. A definitive review of this research was compiled by Newton and her colleagues (2000).

Most data concerning nutrients and tuberculosis are derived from animal studies and in vitro experiments using cultured macrophages infected with M. tuberculosis. Extrapolating relevant data for human subjects must therefore be done cautiously.

Protein Deficiency

Protein deficiency in guinea pigs resulted in (McMurray et al. 1990):

• Loss of protection from BCG vaccine
• Reduction in E rosette-forming T cells
• Loss of PPD-lymphocyte responses
• Altered production of interleukin-2 (IL-2)

A reversal of all immune dysfunction occurred after good nutrition was reestablished.

Vitamins B₁₂

The high incidence of tuberculosis among a vegetarian population was attributed to defective macrophage killing of M. tuberculosis secondary to vitamin B₁₂ (cyanocobalamin) deficiency. Levels of methylmalonic acid (MMA) tend to accumulate in cases of B₁₂ deficiency and MMA can be used by mycobacteria for constructing their cell walls. The authors hypothesized, therefore, that chronic vitamin B₁₂ deficiency may predispose individuals to infection by mycobacteria (Chanarin and Stephenson 1998).

Vitamin D Deficiency

Vitamin D deficiency results in (McMurray et al. 1990):

• Reduced tuberculin skin reactions
• Impaired PPD-induced lymphocyte proliferation
• Inability to control M. tuberculosis infection 

Results of a hospital-based, case-controlled study in Asia suggest that persons with tuberculosis who are vitamin D (25-hydroxycholecalciferol) deficient are more susceptible to tuberculosis. Undetectable levels of vitamin D were associated with the highest risk (Wilkinson 2000). In a previous study, an active metabolite of vitamin D (1,25-dihydroxyvitamin D₃) was reported to help mononuclear phagocytes restrict the intracellular growth of M. tuberculosis in vitro; the combination of 1,25-dihydroxyvitamin D₃ with gamma interferon appears to potentiate this growth inhibition further. These findings may help explain case reports of the value of vitamin D as adjunctive treatment for tuberculosis (Rook et al. 1986).

Zinc Deficiency

The results of studies concerning the role of zinc supplementation on immune cell function are somewhat controversial. Zinc deficiency is thought to result in (McMurray et al. 1990):

• Impaired thymic function
• Loss of T-cell mediated responses
• Subsequent increased susceptibility to infection

Respiratory infection with virulent M. tuberculosis in zinc-deficient guinea pigs led to:

• Tuberculin anergy 
• Decreased numbers of circulating E rosette-forming T cells
• Decreased response of peritoneal exudate cells to PPD in vitro 

In addition, recent human studies demonstrated that immune system function in patients with acute respiratory disease (e.g., tuberculosis, bacterial pneumonia) is dependent on zinc levels. Zinc has been shown to regulate the production of interleukin-1 alpha by alveolar macrophages in patients with tuberculosis and bacterial pneumonia. Zinc in concert with interleukin-1 (IL-1) is thought to stimulate other mediators that help regulate the host immune system, such as IL-2, IL-6, and IL-8 (Abul et al. 1995). However, the dose and stage of infection during which zinc is administered may be critical for determining whether immunologic responses to antigen are evoked or inhibited (Abul et al. 1995).

Essential Fatty Acids: Omega-3

Animal studies suggest that tuberculosis is more severe in guinea pigs fed omega-3 polyunsaturated fatty acids (e.g., eicosapentaenoic acid, docosahexaenoic acid) than in guinea pigs fed saturated fatty acids or omega-6 fatty acids (Paul et al. 1997). Omega-3 fatty acids impair the intracellular killing of mycobacteria in general, and this may account for the reduced resistance to M. tuberculosis (Rastogi and David 1988).

Vitamin A

A double-blind clinical trial sought to determine the effect of vitamin A repletion therapy in a pediatric population with pulmonary tuberculosis and vitamin A deficiency (<20 mcg/dL). The researchers found that while vitamin A therapy had no effect on the outcome of the tuberculosis, after 6 weeks the respiratory status of the placebo group had improved in significantly more children than in the treatment group, leading to the conclusion that there may be adverse effects to vitamin A therapy (Hanekom et al. 1997).

Garlic

The antibacterial properties of garlic (Allium sativum) are well documented. The antimicrobial component of garlic oil is allicin (diallyl thiolsulfinate). In vitro studies have demonstrated that garlic extract inhibits the growth of 17 species of mycobacteria. However, high concentrations of garlic extract (1.34 to 2.68 mg/mL) were required to exert this effect on the various strains of M. tuberculosis tested. Such high serum levels could prove toxic to humans and animals. Further study is necessary to determine safe but efficacious levels of garlic extract for treatment of tuberculosis (Delaha and Garagusi 1985).

A recent animal study indicates that garlic oil also has an inhibitory effect on M. tuberculosis. In a study on guinea pigs inoculated with M. tuberculosis, the viscera of the inoculated animals showed markedly reduced tubercular lesions compared to controls (Jain 1998). It may be that a combination of garlic extract with antituberculous agents will prove to be an effective synergistic treatment for mycobacterial infections (Delaha and Garagusi 1985).

Other Herbs 

Other herbs that may be helpful include (Wagner 1999):

• Echinacea (Echinacea spp.)
• Tamarisk (Tinospora cordifolia)  

In vitro study of the following root extracts suggest that active fractions had a significant inhibitory effect against M. tuberculosis (Cantrell et al. 1999):

• Elecampane (Inula helenium); used by Native Americans for lung disorders including tuberculosis
• Sweet coneflower (Rudbeckia subtomentosa)

Analysis of the active fractions resulted in the identification of such known sesquiterpene lactones as alantolactone, isoalantolactone, alloalantolactone, 3-oxoalloalantolactone, and 11 alpha H,13-dihydroisoalantolactone.

• Adherence to treatment is essential—directly observed therapy (now the standard approach to drug administration in the United States for treating tuberculosis) insures compliance and reduces the possibility of drug-resistant strains.
• Sputum samples should be collected monthly; if still positive after 3 months, drug resistance and treatment failure is assumed.
• U.S. public health policy mandates patients with communicable tuberculosis be treated or quarantined; it is a reportable disease in all states.
• Isolation from any new contacts for at least 2 weeks is very important.
• Hospitalization is required for the elderly, acutely ill, and for those with drug-resistant tuberculosis for at least the first few days of treatment.
• Monitor patients carefully for adverse drug reactions.

• BCG vaccine from M. bovis—efficacy 0% to 80%; used at birth in high risk countries
• Isoniazid—used alone for preventive therapy (300 mg/day for 6 months for adults or 10 to 15 mg/kg/day for 9 months for children; 12 months with HIV, may extend survival time with HIV; supervised prophylactic dose is 900 mg two times per week)
• Rapid diagnosis and appropriate treatment
• Patient and health care worker education
• Surgical masks limit patients' transmission of M. tuberculosis; dust-mite respirators must be used by medical staff for high-risk procedures.
• Ultraviolet radiation tends to destroy M. tuberculosis.
• All patients with tuberculosis should be tested for HIV infection.

• Drug-resistant tuberculosis—defined as resistance to two or more antituberculous agents; occurs from inadequate treatment that may be due to irregular drug availability, inappropriate regimens, or poor compliance; also results from transmission of drug-resistant M. tuberculosis; potentially lethal; isolate patient; 96% cure rates with prompt recognition
• Extrapulmonary disease—increased at faster rate than pulmonary tuberculosis since 1984; frequently associated with HIV
• Tuberculosis meningitis in children—basilar meningitis, infarction, vasculitis; affects 1% to 2% of untreated cases
• Pneumothorax
• Massive hemoptysis—possibly caused by aspergilloma
• Lymph nodes that rupture into the pericardium

• Complete resolution with full course of therapy and lack of drug resistance
• Patients with miliary disease, drug-resistant strains, extrapulmonary disease, and HIV or the acquired immunodeficiency syndrome (AIDS) have less promising prognoses, as do the elderly.

• Tuberculosis does not alter the course of pregnancy with the exception of extrapulmonary tuberculosis that extends beyond the lymph nodes; most infants acquire infection postpartum.
• Infant of contagious mother should be separated until mother is not contagious; test infant at 4 to 6 weeks and 3 to 4 months.
• Noninfectious, compliant mother is not separated from infant.
• Treatment for tuberculosis is not contraindicated in pregnancy or when breast feeding; the mother must be treated; treatment of choice is isoniazid and rifampin for 9 months with ethambutol for the first 2 months. Streptomycin is contraindicated due to risk of congenital deafness for the fetus. Pyrazinamide should be avoided but may be necessary to take.

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