Respiration 8 Pulmonary Tuberculosis

Pulmonary Tuberculosis Tuberculosis is one of the world's most widespread and deadly illnesses. M tuberculosis, the organism that causes tuberculosis infection and disease

Tuberculosis, the White Plague, kills an estimated 3 million people every year Unlike some more dramatic diseases like cholera, which can kill in hours, tuberculosis kills a person over a period of months or years. While TB can infect any organ, pulmonary tuberculosis is the only infectious form

A typical TB patient gives the disease to as many as 20 people a year. People need to inhale large doses of live bacteria in order to become infected so it means the disease is spread among people living in close proximity to one another

Microscopic examination of a specimen from a tuberculosis patient showing red, rod shaped tuberculosis bacilli

Mycobacterium tuberculosis. Acid-fast stain

Source of Infection and Transmission • Patient is the major source of infection • M. Tuberculosis is transmitted from person to person via the respiratory route mainly during speaking, sneezing, or singing • Tuberculosis is spread by droplet infection, through respiratory secretions • Infectiousness is dependant on the bacillary load

Predisposing Factors • Malnourishment • Homeless • Living in overcrowded and substandard housing and prisons • HIV-positive individuals • Associated diseases e.g. Type I Diabetes, Chronic renal failure, Malignancies (lymphoma, leukemias), Silicosis

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Pathology and Pathogenesis Primary tuberculosis Infection with M tuberculosis begins when a susceptible person inhales airborne droplet nuclei containing viable organisms

• Tubercle bacilli that reach the alveoli are ingested by alveolar macrophages • Infection follows if the inoculum escapes alveolar macrophage microbicidal activity • Once infection is established, lymphatic and hematogenous dissemination of tuberculosis typically occurs before the development of an effective immune response • This stage of infection, primary tuberculosis,

• In most persons with intact cell-mediated immunity, T cells and macrophages surround the organisms in granulomas that limit their multiplication and spread • Classical tuberculous granulomas display central caseous necrosis • The mass of Granulomas surrounding area of caseous necrosis forms a primary lesion called “ GHON FOCUS” • Primary lesion and regional lymph nodes involved make up the “ GHON COMPLEX”

Histological slide of a caseating granuloma

Necrotizing granulomas are prominent (left) and giant cells of the Langerhans type are also observed (right)

Gross specimen of a lung with Gohn lesions

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Latent tuberculosis infection The infection is contained but not eradicated, since viable organisms may lie dormant within granulomas for years to decades

• Individuals with this latent tuberculosis infection do not have active disease and cannot transmit the organism to others • Reactivation of disease may occur if the host's immune defenses are impaired

• In a small number of cases, the macrophage-activating response is weak, in this case, the lesion enlarges, the caseous material at its center liquefies, bronchial walls and blood vessels are invaded by bacteria and destroyed and cavities are formed in the lungs • Active tuberculosis will develop in approximately 10% of individuals with latent tuberculosis infection who are not given preventive therapy; half of these cases occur in the 2 years following primary infection

Progressive primary tuberculosis

• If the immune response is inadequate the host develops progressive primary tuberculosis • It is accompanied by both pulmonary and constitutional symptoms • 90% of tuberculosis in adults represents activation of latent disease

Clinical Findings Symptoms • Slowly progressive constitutional symptoms of malaise, anorexia, weight loss, fever, and night sweats • Chronic cough is the most common pulmonary symptom. It may be dry at first but typically becomes productive of purulent sputum as the disease progresses • Blood-streaked sputum is common, but significant hemoptysis is rarely a presenting symptom; lifethreatening hemoptysis may occur in advanced disease • Dyspnea is unusual unless there is extensive disease • Rarely, the patient is asymptomatic

Signs • On physical examination, the patient appears chronically ill and malnourished • On chest examination, there are no physical findings specific for tuberculosis infection • The examination may be normal or may reveal classic findings such as post-tussive apical rales • Large areas of exudative or caseous lesions may present signs of pulmonary consolidation

• Fibrotic changes will give rise to deviation of trachea, dullness on percussion, reduced breath sounds and moist rales. • Tuberculosis pleural effusion will show physical findings like dullness to percussion, decreased breath sounds etc. • Lab findings show anemia and leukocytosis

Clinical features: Pulmonary Disease

Primary Pulmonary TB • Infection of a previously uninfected individual. Disease only occurs if progressive infection during initial illness or after latent period of weeks or months

• Infection: 4-8 weeks Infuenza like illness Skin test conversion Primary complex

• Disease: Lymphadenopathy Collapse, consolidtion, Obstructive emphysema, Cavitation

Pleural effusion Endobronchial Miliary Meningitis Pericarditis • Hypersensitivity Erythema nodosum Phlyctenular conjunctivitis Dactylitis

Miliary TB • Blood borne dissemination • Acute presentation but may have 2-3 weeks of fever, night sweats, anorexia, dry cough • Hepatospleenomegally • Ausculation: normal or wide spread crackles • Fundoscopy: Choroidal tubercle • Chest X-ray: 1-2 mm ;millet seed’ lesions distributed throughout the lung fields • Elderly : Cryptic TB ( confirmation by biopsy of liver or bone marrow)

Autopsy specimen showing miliary lesions on the lungs

Miliary tuberculosis

Post-Primary Pulmonary TB Pulmonary TB is the must frequent form • • Insidious onset with chronic cough and hemoptysis • Pyrexia of unknown origin • Unresolved pneumonia • Exudative pleural effusion • Asymptomatic • Weight loss, general debility • Spontaneous pneumothorax • Chest X-ray: Ill-defined opacity located in the upper lobe • Consolidation, collapse, cavitation, miliary pattern

Clinical Features: Extra pulmonary Disease More common in HIV-Positive indiviuals Lymphadenitis • Lymph nodes are the most common extrapulmonary site • Cervical and mediastinal glands affected frequently, then axillary and inguinal • Nodes are painless, initially mobile but later become matted together • If caseation and liquefaction occurs, the swelling becomes fluctulant and discharges through skin with ‘collar stud ‘ abscess and sinus formation • Tuberculin test is strongly positive • Surgical excision is rarely required

Hilar adenopathy in tuberculosis

Current chest radiograph demonstrates a mediastinal mass (arrows) without pulmonary infiltrates

Gastrointestinal Tuberculosis

• Upper GI involvement is rare • Ileocaecal disease occurs in more than half of the cases • Fever, night sweats, anorexia, weight loss with palpable right iliac fossa • Ultrasound or CT shows thickened wall, abdominal lymphadenopathy, mesenteric thickening or acities • Barium enema shows narrowing, shortening and distortion of the bowel • Diagnosis: Biopsy by colonoscopy or mini-laprotomy • Laproscopy: White ‘tubercles’ over the peritoneal and omental surfaces • Miliary disease : hepatic dysfunction, and biopsy reveals granulomas

Pericardial Disease • Two forms: Pericadial effusion and Constrictive pericarditis • Insiduous onset with breathlessness and abdominal swelling • Signs: Pulsus paradoxus, raised JVP, hepatosplenomagally, ascities and absence of peripheral edema • Pericardial effusion: Globular heart on Chest X-ray • Constriction: Raised JVP, atrial fibrillation, third hear sound and pericardial calcification • Diagnosis: Clinical, Radiological and echocardiographic grounds • Treatment: Anti –TB drugs and corticosteroids

Tuberculous pericarditis

CNS Diseases • TB Meningitis is the most important form of CNS involvement • If unrecognized or untreated it can be fatal

Bone and Joint Disease • Bony TB of the spine is Pott’s disease • Presentation: Chronic back pain in lower thoracic and lumbar spine • Causes angulation of the vertebrae with subsequent kyphosis • Paravertebral and psoas abscesses are common • Important Differential diagnosis is malignancy

MRI of a patient with Pott's disease showing destruction of vertebral bodies and intervertebral disks

• TB in other joints e.g. hip and knee causes reduction in joint space and errosions

Genitourinary disease • Renal TB patients are mildly symptomatic with hematuria, frquency and dysuria • In men genitourinary TB presents with epididmitis or prostitis • In women Genitourinary TB may present with endometritis, salpingitis or tubo-ovarian abscess

Investigations Laboratory Findings • Definitive diagnosis depends on recovery of M tuberculosis from cultures or identification of the organism by DNA or RNA amplification techniques

• Three consecutive morning sputum specimens are advised. • Sputum induction may be helpful in patients who cannot voluntarily produce satisfactory specimens • Fluorochrome staining with rhodamine-auramine of concentrated, digested sputum specimens is performed initially as a screening method, with confirmation by the Kinyoun or Ziehl-Neelsen stains • Cultures on solid media (L-J medium, Middlebrook) to identify M tuberculosis may require 12 weeks. Liquid medium culture (BACTEC)systems allow detection of mycobacterial growth in several days

• In patients thought to have tuberculosis despite negative sputum smears, fiberoptic bronchoscopy can be considered • Bronchial washings are helpful • Transbronchial lung biopsies increase the diagnostic yield • Early morning aspiration of gastric contents after an overnight fast is an alternative to bronchoscopy but is suitable only for culture and not for stained smear • M tuberculosis may be cultured from blood in up to 15% of patients with tuberculosis.

Colonies of Mycobacterium tuberculosis on LowensteinJensen medium

Other Lab tests Blood tests: • ESR, CRP, Hemoglobin, TLC with differential • Tuberculin skin test

Imaging Radiographic abnormalities in primary tuberculosis include: • Small homogeneous infiltrates, hilar and paratracheal lymph node enlargement, and segmental atelectasis • Pleural effusion may be present • Cavitation may be seen with progressive primary tuberculosis • Ghon (calcified primary focus) and Ranke (calcified primary focus and calcified hilar lymph node) complexes are sometimes

This AP X-ray of the chest reveals the presence of bilateral pulmonary infiltrate, and “cavity formation” present in the right apical region. The diagnosis is far-advanced tuberculosis

Chest radiograph showing bilateral upper lobe cavitary infiltrates (arrows), indicating active pulmonary tuberculosis

Tuberculous pleural effusion

Pulmonary tuberculosis

Pulmonary tuberculosis with cavity

Pyopneumothorax in tuberculosis

Reactivation tuberculosis is associated with: • Fibrocavitary apical disease • Nodules • Pneumonic infiltrates • The usual location is in the apical or posterior segments of the upper lobes or in the superior segments of the lower lobes

Special Examinations The tuberculin skin test Identifies individuals who have been infected with M tuberculosis but does not distinguish between active and latent infection The test is used to evaluate: • A person who has symptoms of tuberculosis • An asymptomatic person who may be infected with M tuberculosis (eg, after contact exposure) • Establish the prevalence of tuberculous infection in a population

• The Mantoux test is the preferred method: • 0.1 mL of purified protein derivative (PPD) containing 5 tuberculin units is injected intradermally on the volar surface of the forearm using a 27-gauge needle on a tuberculin syringe • The transverse width in millimeters of induration at the skin test site should be measured after 48–72 hours

Mantoux-test

The test is considered positive: • If the diameter of the resulting lesion is 10 mm or greater • The lesion is characterized by erythema (redness) and swelling and induration (raised and hard) • 90% of people that have a lesion of 10 mm or greater are currently infected with M.TB or have been previously exposed to M.TB • 100% of people that have a lesion of 15 mm or greater are currently infected with M.TB. or have been previously exposed to M.TB

Swellings arising from Mantoux Tests should be measured within 2 to 3 days, when swellings greater than 5 to 10 mm  in size are considered positive

Strongly positive Mantoux test in a patient with active tuberculosis. Intradermal injection of M. tuberculosis antigen has induced a florid type IV hypersensitivity reaction with some blistering

• In general, it takes 2–10 weeks after tuberculosis infection for an immune response to PPD to develop • Both false-positive and false-negative results occur • False-positive tuberculin skin test reactions occur in persons previously vaccinated against M tuberculosis with bacillus Calmette-Guérin (BCG) and in those infected with non-tuberculous mycobacteria • False-negative tuberculin skin test reactions may result from improper testing technique, concurrent infections, malnutrition, advanced age, immunologic disorders, corticosteroid therapy, chronic renal failure, HIV infection, and fulminant tuberculosis

Prevention BCG Vaccine Two French scientists Albert Calmette and Camille Guerin developed a vaccine against tuberculosis from an attenuated form of the bovine bacillus in 1921. BCG stands for BacillusCalmette‑Guerin. It is the only vaccine we have for the prevention of TB. It should be given to children at birth. BCG protects children from meningial and milliary TB

Treatment

General Measures The goals of therapy are to eliminate all tubercle bacilli from an infected individual while avoiding the emergence of clinically significant drug resistance

The basic principles of anti-tuberculous treatment: (1) to administer multiple drugs to which the organisms are susceptible (2) to add at least two new antituberculous agents to a regimen when treatment failure is suspected (3) to provide the safest, most effective therapy in the shortest period of time (4) to ensure adherence to therapy

Directly observed therapy (DOT) • Nonadherence to antituberculous treatment is a

major cause of treatment failure, continued transmission of tuberculosis, and the development of drug resistance

• Directly observed therapy (DOT), which requires that a health care worker physically observe the patient ingest antituberculous medications in the home, clinic, hospital, or elsewhere, also improves adherence to • The CDC recommends DOT for all patients with drug-resistant tuberculosis and for those receiving intermittent (twice- or thrice-weekly) therapy

Drug

Most Common Side Effects Tests for Side Effects

Isoniazid

Peripheral neuropathy, AST and ALT; hepatitis, rash, mild CNS neurologic effects examination

Rifampin

CBC, platelets, AST and Hepatitis, fever, rash, ALT Colors urine and flu-like illness, gastrointestinal upset, other body secretions bleeding problems, renal orange. Discoloring of contact lenses. failure.

Uric acid, AST, ALT Pyrazinami Hyperuricemia, hepatotoxicity, rash, de gastrointestinal upset, joint aches

color Ethambuto Optic neuritis (reversible Red-green with discontinuance of discrimination and l drug; rare at 15 mg/kg); visual acuity (difficult

Streptomy

rash.

to test in children under 3 years of age).

Eighth nerve damage,

Vestibular function

Treatment of Tuberculosis • Most patients with previously untreated pulmonary tuberculosis can be effectively treated with either a 6-month or a 9-month regimen, though the 6-month regimen is preferred • The initial phase of a 6-month regimen consists of 2 months of daily isoniazid, rifampin, pyrazinamide, and ethambutol

• Once the patient is determined to be isoniazid-sensitive, ethambutol may be discontinued • If the M tuberculosis isolate is susceptible to isoniazid and rifampin, the second phase of therapy consists of isoniazid and rifampin for a minimum of 4 additional months, with treatment to extend at least 3 months beyond documentation of conversion of sputum cultures to negative for M tuberculosis

• If susceptibility to isoniazid and rifampin is demonstrated or drug resistance is unlikely, ethambutol can be discontinued and isoniazid and rifampin may be given twice a week for a total of 9 months of therapy • If drug resistance is a concern, patients should receive isoniazid, rifampin, and ethambutol for 9 months

Treatment of Tuberculosis in HIV-Positive Persons • The basic approach to HIV-positive patients with tuberculosis is similar to that for patients without HIV disease • Additional considerations in HIV-positive patients include (1) longer duration of therapy (2) drug interactions between rifamycin derivatives such as rifampin and rifabutin, used to treat tuberculosis, and some of the protease inhibitors and nonnucleoside reverse transcriptase inhibitors (NNRTIs), used to treat HIV • DOT should be used for all HIV-positive tuberculosis patients • Pyridoxine (vitamin B6), 25–50 mg orally each day, should be administered to all HIV-positive patients being treated with isoniazid to reduce central and peripheral nervous system side effects

Treatment of Drug-Resistant Tuberculosis Multidrug-resistant tuberculosis (MDRTB) calls for •

an individualized daily directly observed treatment plan under the supervision of a clinician experienced in the management of this entity

• Most MDRTB isolates are resistant to at least isoniazid and rifampin and require a minimum of three drugs to which the organism is susceptible • These regimens are continued until culture conversion is documented, and then a two-drug regimen is then continued for at least another 12 months • Some experts recommend at least 18–24 months of a three-drug regimen.

Treatment of Extrapulmonary Tuberculosis

• In most cases, regimens that are effective for treating pulmonary tuberculosis are also effective for treating extrapulmonary disease • Experts recommend 9 months of therapy when miliary, meningeal, or bone and joint disease is present • Treatment of skeletal tuberculosis is enhanced by early surgical drainage and debridement of necrotic bone • Corticosteroid therapy has been shown to help prevent cardiac constriction from tuberculous pericarditis and to reduce neurologic complications from tuberculous meningitis.