Tuberculosis

Systemic miliary TB

infective foci in the lung seed the pulmonary venous return to the heart with dissemination throughout the entire arterial system involving many organs such as the spleen, kidney ,adrenals, liver etc

How does mycobacterium tuberculosis block fusion of lysosome and phagocytic vacuole in the macrophage?

inhibiting Ca2+ signals and blocking the recruitment and assembly of the proteins which mediate phagosome-lysosome fusion

Rifampin 600mg PO daily

inhibits RNA synthesis

Ethambutol 1200mg PO daily

inhibits cell wall synthesis but at a different site than Isoniazid

Standard Latent TB infection treatment

*Isoniazid 300mg PO daily for 6-9 months* follow liver function tests to check for liver tox. of drug. Patient must refrain from alcohol.

Cascade of events from exposure onward:

1. 70% of exposed persons do not become infected, 30% of exposed persons become infected. 2. Of that 30% that become infected, 10% become actively infected. 90% of the time the disease is quiescent 3. 10% of quiescent TB will become active sometime in the patient's life. And 20% of these patients will have non-infectious extra pulmonary TB.

Chest Xray

1. Airspace consolidation 2. Infiltrates are typically apical and posterior, often bilaterally as well (as compared to malignancy) 3. Cavitations 4. Volume loss 5. Pleural effusions-ipsilateral to TB 6. Linear opacities 7. Nodules 8. Hilar adenopathy 9. Ghon/Ranke complex

Initial diagnostic work up

1. Chest Xray 2. Tuberculin skin test and or IFN-gamma release blood test 3. Serial sputum smears and culture 4. Opt-out HIV testing due to high prevalence of both diseases at the same time.

Clinical features of primary TB, if a person goes onto to have progressive pulmonary disease where does the disease affect? What are some complications?

1. Most pts have a latent course while others go on to have progressive infection 2. Progressive infection can involve the *lower and middle lobes with consolidation*, *hilar adenopathy* and *pleural effusion* 3. Complications include *tuberculous meningitis* and *miliary tuberculosis*

Pathogenesis of TB The pathogenesis of TB in the previously *unexposed immunocompetent person* is centered on the development of a targeted cell-mediated immunity that confers *resistance* to the organism and results in development of *tissue hypersensitivity* to tubercular antigens. The pathologic features of TB, such as caseating granulomas and cavitation, are the result of the destructive tissue hypersensitivity that is part of parcel of the host immune response. Because of the effector cells for both processes are the same, the appearance of tissue hypersensitivity also signals the acquisition of immunity to the organism.

1. Once a virulent strain of mycobacteria gains entry into the macrophage endosomes, the organisms are able to inhibit normal microbicidal responses by preventing the fusion of lysosomes with the phagocytic vacuole. The preventing of phagolysosome formation allows unchecked mycobacterial proliferation. Thus, earliest phase of primary TB (first 3 weeks) in the non-sensitized patient is characterized by bacillary proliferation within the pulmonary alveolar macrophages and air spaces, with resulting bacteremia and seeding of multiple sites. *Despite the bacteremia, most persons at this stage are asymptomatic or have mild flu-like symptoms*. 2. The development of cell-mediated immunity occurs approx. 3 weeks after exposure. Processed mycobacterial antigens reach the draining lymph nodes and are presented to CD4 T cells by dendritic cells and macrophages. Under the influence of macrophage-secreted IL-12, CD4+ T cells of of the TH1 subset are generated that are capable of secreting IFN-gamma. 3. IFN-gamma released by the CD4+ T cells of the TH1 subset is crucial in activating macrophages. Activated macrophages in turn release a variety of mediators and up regulate expression of genes with important down stream effects: (1) TNF which is responsible for recruitment of monocytes, which in turn undergo activation and differentiation into the "epitheloid histiocytes" that characterize the granulomatous response (2) expression of the inducible NO synthase gene which results in elevated NO levels at the site of infection with excellent antibacterial activity (3) generation of reactive oxygen species which are also antibacterial. Defects in any of the steps of a TH1 response (including IL-12, IFN-gamma, TNF, or NO production) result in poorly formed granulomas, absence of resistance, and disease progression.

Latent TB infection, there is a 10% chance in lifetime that patient will progress to active TB. Characteristics of latent TB infection:

1. Positive Tuberculin skin test 2. Negative Chest Xray 3. asymptomatic 4. non-contagious 5. *Progression risk greatest in first 2 years after infection* Tx: classic regimen is *Isoniazid for 6-9 months*.

clinical features of primary TB, is the organism in primary TB endogenous or exogenous?

1. Primary TB develops in a previously unexposed, unsensitized person 2. About 5% of newly infected people develop clinically significant disease 3. In primary TB the source of the organism in *exogenous*

Risk factors for TB

1. immune suppressed, particularly in HIV and cancer patients or those taking steroids 2. Occupational exposure: HCW and prison guards 3. Diabetes 4. Malnutrition 5. Location: endemic in certain areas 6. Silicosis: Silicosis impairs lungs ability to process and control TB once infection occurs.

Treatment

Active TB treatment- surgical intervention not typically indicated, use pharm. Use 4 drugs with different mechanisms of action for 2 months. Then stop Pyrazinamide and Ethambutol while continuing Isoniazid and Rifampin for 4-7 more months. Total therapy 6-9 months.

How is TB spread?

Although other routes may be involved, most infections are acquired by direct person to person transmission of airborne droplets of organisms from an active case to a susceptible host.

How is the host reaction in secondary TB different than primary TB?

Because of the pre-existence of hypersensitivity, the bacilli excite a prompt and marked tissue response that tends to wall off the focus. As a result of the localization, the regional lymph nodes are less prominently involved early in the disease than they are in primary TB. On the other hand cavitation occurs readily in the secondary form, leading to erosion into and dissemination along airways which can be coughed up or swallowed. Such changes become an important source of infectivity, because the patient now produces sputum containing bacilli.

Culture of sputum for acid fast bacilli

Can take as long as 4-6 weeks. Nucleic acid amplification of sputum smear can be performed if acid-fast bacilli sputum smear was positive. Can help to determine between mycobacterium tuberculosis and other acid-fast organisms.

Extensive Drug-Resistant TB (XDR-TB)

Definition: Resistant to Isoniazid and Rifampin plus any quinolone plus at least one injectable second-line agent. Approximately 5% of all multi-drug resistant TB is extensively drug-resistant. CDC reported 83 cases between 1993 and 2007. Extensively drug-resistant TB is a growing threat.

Multi-Drug Resistant TB (MDR TB) Definition: Resistant to Rifampin and Isoniazid. 4% of all active TB cases (440,000 cases in 2008) are multi-drug resistant. Require a special type of therapy, using more drugs for a longer period of time. Often require surgical treatment for resection of focal disease. Lung resection combined with anti-TB chemotherapy for multi-drug resistant TB has shown success rates of 89-96% Drug regimen

Definition: Resistant to Rifampin and Isoniazid. 4% of all active TB cases (440,000 cases in 2008) are multi-drug resistant. Require a special type of therapy, using more drugs for a longer period of time. Often require surgical treatment for resection of focal disease. Lung resection combined with anti-TB chemotherapy for multi-drug resistant TB has shown success rates of 89-96%. Drug regimen

Pyrazinamide 1500mg PO daily

Disrupts energy metabolism by disrupting plasma membrane

Quanti-FERON Gold

Does not distinguish current from past infection. Blood test for presence of IFN-gamma. If patient's lymphocytes have been exposed to TB antigen before they will release IFN-gamma in a test tube. Advantages: 1. No reader bias 2. Results in 24 hours 3. No BCG reaction and no amnestic response Disadvantages: 1. Questionable use in immunocompromised and children 2. Questionable use in predicting who will develop active TB.

Immune response to TB

Droplets are engulfed by lung dendritic cells and macrophages. Dendritic arm-like projections present TB to macrophages which subsequently release cytokines such as *IFN-gamma*. Phagocytosis leads to granuloma formation. Granuloma (aka tubercle) is the hallmark of protective immune mechanism of the host creating a low oxygen and low pH environment.

Endobronchial, endotracheal, and laryngeal tuberculosis

Endobronchial, endotracheal, and laryngeal tuberculosis may develop when infective material is spread either through lymphatic channels or from expectorated infectious material. The mucosal lining may be studded with minute granulomatous lesions, sometimes apparent only on microscopic examination.

What is the single most important risk factor for the development of TB?

HIV infection

Miliary pulmonary disease

If the treatment is inadequate, or if host defenses are impaired, the infection may spread by direct expansion by means of dissemination through airways, lymphatic channels, or within the vascular system. *Miliary Pulmonary Disease* occurs when organisms drain through the lymphatics into the lymphatic ducts, which empty into the venous system and return to the right side of the heart and then to the pulmonary arteries. Individual lesions are either microscopic or small, visible (2mm) foci of yellow/white consolidation scattered through the lung parenchyma (the word miliary is derived from the resemblance of these foci to millet seeds).

Intestinal TB

In years past, intestinal tuberculosis contracted by the drinking of contaminated milk was fairly common as a primary focus of tuberculosis. In developed countries today, intestinal tuberculosis is more often a complication of protracted advanced secondary tuberculosis, secondary to the swallowing of coughed-up infective material. Typically, the organisms are trapped in mucosal lymphoid aggregates of the small and large bowel, which then undergo inflammatory enlargement with ulceration of the overlying mucosa, particularly in the ileum.

Positive TB test

Infection with Mycobacterium Tuberculosis typically leads to the development of delayed hypersensitivty, which can be detected by the tuberculin test. About 2 to 4 weeks after the infection has begun, intracutaneous injection of 0.1 mL of PPD induces a visible and palpable induration that peaks at 48-72 hours. A positive tuberculin skin test result signifies cell-mediated hypsensitivity to tubercular antigens. *It does not differentiate between infection and disease* A well-recognized limitation of this test is that false-negative reactions (or skin test anergy) may be produced by certain viral infections, sarcoidosis, malnutrition, HL, immunosuppression, and overwhelming active TB disease. False positives may result from infection by atypical mycobacterium.

Isoniazid (INH) 300mg PO daily

Inhibits cell wall synthesis

Isolated organ TB

Isolated-organ tuberculosis may appear in any one of the organs or tissues seeded hematogenously and may be the presenting manifestation of tuberculosis. Organs typically involved include the meninges (tuberculous meningitis), kidneys (renal tuberculosis), adrenals, bones (osteomyelitis), and fallopian tubes (salpingitis). When the vertebrae are affected, the condition is referred to as Pott disease. Paraspinal "cold" abscesses may track along the tissue planes to present as an abdominal or pelvic mass.

latent TB infection and HIV

It is essential to prophylax these individuals. latent TB in HIV patients is treated with chemotherapy.

Infection of TB vs. the Disease of TB

It is important that infection be differentiated from disease. Infection implies seeding of a focus with organisms, which may or may not cause clinically significant tissue damage (disease). In most persons, an asymptomatic focus of pulmonary infection appears that is self-limited, although uncommonly, primary TB may result in the development of fever and pleural effusions. Generally, the only evidence of infection, if any remains, is a tiny, telltale fibrocalcific nodule at the site of the infection. Viable organisms may remain dormant in such loci for decades, and possibly for life of the host. Such persons are infected but do not have active disease and therefore cannot transmit organisms to others. Yet when their immune defenses are lowered, the infection may reactivate to produce communicable and potentially life threatening disease. Only a small fraction of those who contract an infection develop active disease.

Lymphadenitis

Lymphadenitis is the most frequent form of extrapulmonary tuberculosis, usually occurring in the cervical region ("scrofula"). Lymphadenopathy tends to be unifocal, and most patients do not have concurrent extranodal disease. HIV-positive patients, on the other hand, almost always have multifocal disease, systemic symptoms, and either pulmonary or other organ involvement by active tuberculosis.

Mycobacterium tuberculosis

Mycobacteria are slender rods that have a waxy cell wall composed of mycolic acid which makes them *acid fast*.

Mycobacterium Avium-intracellulare Complex

Nontuberculous mycobacteria most commonly cause chronic but clinically localized pulmonary disease in immunocompetent persons. In immunosuppressed persons (primarily those with HIV) Mycobacterium avium and M. intracellulare are two different organisms but have very similar infections. Mycobacterium avium complex infection manifests as disseminated disease. Pulmonary disease is often indistinguishable form TB in patients with AIDS. See abundant acid-fast bacilli in macrophages Enlargement of lymph nodes, liver and spleen.

Primary Tuberculosis

Primary TB is the form of the disease that develops in a previously unexposed and therefore unsensitized patient.

progressive secondary TB

Progressive pulmonary tuberculosis occurs when the apical lesion enlarges with expansion of the area of caseation. Erosion into the bronchus evacuates the caseous center, creating a ragged, irregular cavity lined by caseous material that is poorly walled off by fibrous tissue. Erosion of blood vessels results in *hemoptysis*. With adequate treatment, the process may be arrested, although healing by fibrosis often distorts the pulmonary architecture.

Progressive pulmonary secondary TB can occur in who?

Progressive secondary TB can occur in elderly and immunocompromised

Tuberculin Skin Test (PPD)

Purified protein derivative (PPD). Injected intradermal will react if antigen was seen before. Positive 8-10 weeks after exposure. 5mm= positive if you have HIV, contact with TB patients, fibrotic changes in chest Xray, or if patient is immunocompromised. 10mm= positive for most individuals (USE FOR ALL PRACTICAL PURPOSES) Those who are recent immigrants, IV drug users, employees of high risk congregate settings, mycobacteriology lab personnel, and persons with clinical conditions that put them at risk for TB. Greater than 15mm is positive for persons with absolutely NO risk factors for TB. can get false positive with BCG-vaccinated individuals.

Secondary TB is clinically localized to where?

Secondary TB is clinically *localized to the apex of one or both upper lobes*. The reason is obscure but may relate to high oxygen tension in the apices which promote growth.

Secondary TB

Secondary TB is the pattern of the disease that arises in a previously sensitized host. It may follow shortly after primary TB, but more commonly it arises from reactivation of dormant primary lesions many decades after initial infection, particularly when host resistance is weakened.

*In summary, immunity to a tubercular infection is primarily mediated by TH1 cells, which stimulate macrophages to kill bacteria*. This immune response, while largely effective, comes at the cost of hypersensitivity and the accompanying tissue destruction. Reactivation of the infection or reexposure to the bacilli in a previously sensitized host results in rapid mobilization of a defensive reaction but also increased tissue necrosis. Just as hypersensitivity and resistance appear in parallel, so, too, the loss of hypersensitivity (indicated by tuberculin negativity in a tuberculin-positive patient) may be an ominous sign that resistance to the organism has faded.

Sequence of events in the natural history of primary pulmonary tuberculosis. This sequence commences with inhalation of virulent strains of Mycobacterium and culminates in the development of immunity and delayed hypersensitivity to the organism. A, Events occurring in the first 3 weeks after exposure. B, Events thereafter. The development of resistance to the organism is accompanied by conversion to a positive result on tuberculin skin testing. Cells and bacteria are not drawn to scale. IFN-γ, interferon γ; iNOS, inducible nitric oxide synthase; MHC, major histocompatibility complex; MTB, Mycobacterium tuberculosis; NRAMP1, gene encoding natural resistance-associated macrophage protein 1; TNF, tumor necrosis factor.

Who gets TB?

TB flourishes under conditions of poverty, crowding, and chronic debilating illness. Similarly, elderly persons, with their weakened defenses, are vulnerable. In the US, TB is a disease of the elderly, urban poor, patients with AIDS, and members of the minority communities.

Morphology of the initial lesion in secondary TB

The inital lesion usually is a small focus of consolidation, less than 2cm in diameter, within 1 to 2 cm of the apical pleura. In favorable cases, the initial focus undergoes progressive fibrous encapsulation, leaving only fibrocalcific scars. Histologically, the active lesions show characteristic coalescent tubercles with central caseation. Bacilli may be found in early lesions but rarely in late ones.

What does acid fast mean?

They have a high content of complex lipids that readily bind the Ziehl-Neelsen stain and subsquently stubbornly resist decolorization. Acid fast allows them to retain stains even after treatment with a mixture of acid and alcohol. Note: Mycobacterium stain weakly with Gram stain

What is TB?

Tuberculosis is a communicable chronic granulomatous disease caused by *mycobacterium tuberculosis*. It usually involves the lungs but may affect any organ or tissue in the body. Typically, the centers of the tubercular granulomas undergo *caseous necrosis*.

Ghon complex and ranke complex

Typically, inhaled bacilli implant int he distal air spaces or the lower part of the upper lobe or the upper part of the lower lobe, usually close to the pleura. As sensitization occurs, a 1-1.5 cm area of gray/white inflammatory consolidation emerges called the *ghon focus*. In most cases the center of this ghon focus undergoes caseous necrosis. Tubercle bacilli, either free or within phagocytes, travel in lymph drainage to the regional lymph nodes, which also caseate. This combination of parenchymal lesion (ghon focus) and nodal involvement is referred to as the *ghon complex*. In 95% of cases, development of cell mediated immunity controls the infection. Hence, the ghon complex undergoes progressive fibrosis, often followed by radiologically detectable calcification called the *ranke complex*.

Acid-fast bacilli sputum smear

can be used to presumptively treat a patient for TB before the cultures come back (takes 24 hours)

Recommendations for preventative therapy for PPD positive persons:

less than 35: should get isoniazid treatment because likely hood of developing hepatitis is so low. greater than 35: greater fear of toxicities, the older the patient the more likely they are to get Isoniazid toxicity specifically hepatotoxicity. Consider prophylactic treatment for: 1. recent converters: someone who has converted within 2 years 2. close contact with active disease, HIV positive, IV drug user, Diabetes, silicosis, steroids, malnutrition...