24b Mycobacterium TB from Notes then NTM Flashcards by Jonathan Burgess

What are the general properties of mycobacteria?
Gram status?
Shape?
Capsule status?
Motility?
Spore status?
O2 status?
Intra or Extra cellular status?

Gram + non-encapsulated rod
Not motile
Non-spore forming
Obligate aerobe
Intracellular

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What is the host response to Mycobacterium tuberculosis (MTB)?
Name the cells involved and their cytokines.

Macrophages ingest MTB >> present to CD4 cells >> Th cells release IL-2 to clonally expand CD4 cells and release IFNg activate Macrophages.
Activated macrophages release TNFa to self-induce phagolysosomal fusion and kill intracellular MTB
Activated macrophages (epithelioid cells) have enhanced cidal activity against MTB

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What does the gene NRAMP1 do for MTB susceptibility?

What does “tt” vitamin D receptor polymorphism do for MTB susceptibility?

NRAMP1 makes more susceptible (regulates phagolysosomes)

tt vit D receptor makes less susceptible

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Epidemiology of MTB…
How many cases? How many deaths?
In the US, which groups are more susceptible?
Transmission?
Spread… If one person is untreated, how many new cases does tha person spread MTB to?

6-8 million cases, 2-3 million deaths
Minorities and people living in close proximity
Respiratory droplets
1 untreated person spreads to 10 people

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What is the distinction between infection and disease in MTB?
What is the steps from infection to disease?

Organism inhaled&raquo_space; macrophages&raquo_space; transient bacteremia&raquo_space; granuloma formation in organs

Infection is detected by PPD skin test
Disease is identified by culture of MTB from granuloma

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Detail: Among the 100 newly Dx cases of TB each year in the U.S. some are truly new infections and others are reactivated latent infections.
Most are reactivated infections.

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What is a Ghon lesion?

What is a Ranke Complex?

Ghon lesion is cell-mediated and contained MTB infection

Ranke complex is a further development of the Ghon lesion that has become calcified

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What is difference between cavitary pulmonary TB and disseminated miliary TB?

Cavitary Pulmonary TB is localized in the lung with one or more granulomas

Disseminated miliary TB is an infection that spreads to many organs with many small granulomas. It is fatal, even with treatment.

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What are common locations that TB spreads to?

Note: this can be either “pulmonary” or miliary TB.

Lymphatics aka scrofula
Skeletal aka Pott’s disease
Genitourinary
CNS and Menigitis

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What is the relationship between HIV and Mycobacterium tuberculosis?

HIV weakens CD4 cells and so if a person is infected, they are more likely to develop tuberculosis disease

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What techniques are used to Dx active tuberculosis?

Acid-Fast Bacillus (AFB) smear of sputum
Culture on Lowenstein Jensen egg
Nucleic acid amplification (PCR?) then confirm with TB-specific probe

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What are the advantages and disadvantages to…

1) Acid-Fast Bacillus (AFB)?
2) Culture on Lowenstein Jensen egg?
3) Nucleic acid amplification?

1) Same day results, but needs at least 10^5 organisms in sputum for detection
2) Standard practice. More senstive than AFB and allows for testing sensitivity to antibiotics, but takes 2 to 8 weeks and is costly.
3) Same day results, but is high tech

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How is Multidrug Resistant (MDR) defined with Mycobacterium tuberculosis?

Resistance to Isoniazide and Rifampin.

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What are risk factors for Multidrug Resistance in Mycobacterium tuberculosis?
What mechanism increases risk of MDR?
What illnesses increase risk of MDR?
What populations are at increased risk of MDR?

Prior exposure, especially inadequate treatment, with drugs (eg, monotherapy or incomplete Rx)
HIV and Cavitary TB
Low SES populations, incarcerated people, and people from certain geographical locations (like Russia, Dominican Republic, and others)

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In terms of numbers of TB organisms in an infected person, why are more severe infections more drug resistant?
What is the purpose of multidrug therapy as a first line of Tx?

Persons with cavitary disease may have 10^9 organisms
In terms of numbers, 1 in 10^8 organims is INH resistant, 1 in 10^9 organisms is rifampin resistant, and 1 in 10^16 organisms is INH and rifampin resistant.
Multidrug therapy is there to wipe out as many organisms as possible the first time, so that resistant lines are not selected for by incomplete Tx

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What is XDR-TB?

A super multidrug resistant strain that is resistant to
Isonaizide
Rifampin
Fluouroquinolone
and other injectable Rx

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What are the 4 standard drugs for active Mycobacterium tuberculosis?
(Directly Observed Therapy = DOT)

R.I.P.E.
Rifampin
INH (Isoniazid)
Pyrazinamide
Ethambutol

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What are the mechanisms for...
Rifampin
INH (Isoniazid)
Pyrazinamide
Ethambutol

Name the Mechanism, whether it is Intracellular or Extracellular, and whether it is Static or Cidal.

R: blocks DNA-dependent RNA polymerase, works agains intracellular TB, Cidal
I: blocks Mycolic acid formation (the cell wall of TB), works against extracellular TB, Cidal
P: creates acidic intracellular environment for the TB bacilli, works against intracellular TB, both Static and Cidal
E: blocks Mycolic acid formation, doesn’t say intra or extracellular, helps prevent resistance, Static

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What are the side effects for...
Rifampin
INH (Isoniazid)
Pyrazinamide
Ethambutol

R: influenza syndrome, HEPATITIS, orange urine, drug interactions
I: HEPATITIS, neuropathy, mild CNS, B6 DEFICIENCY
P: GI, HEPATITIS, arthalgias, uric acid
E: optic neuritis, rash

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What is the length of drug Tx for active TB:

RIPE for two months
RI for four months
Adminsiter all drugs by Directly Observed Therapy (DOT)

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Detail: What is Directly Observed Therapy (DOT) in TB?

Contains five elements

1) Government commitment (including both political will at all levels, and establishing a centralized and prioritized system of TB monitoring, recording and training)
2) Case detection by sputum smear microscopy
3) Standardized treatment regimen directly observed by a healthcare worker or community health worker for at least the first two months
4) A regular drug supply
5) A standardized recording and reporting system that allows assessment of treatment results

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What is the Multdrug Resistant protocol for TB?

From RIPE to RIPF (think RIFE) for 12 months
Rifampin
Isoniazid (INH)
Pyrazinamide
Flouroquinolone
Plus one or more additional drugs

What is the Tx for TB with HIV?

At first, it is the same as standard tx
If response is slow, make the following changes…
1) Tx for 9 months or 4 months beyond negative TB cultures
2) Switch Rifampin to Rifabutin. Why? Rifampin cannon be used with the protease inhibitors used in HIV or (or switch to an HIV protocol without protease inhibitors)

What is a side effect that occurs in Tx for TB with HIV?

Immune Restoration Inflammatory Syndrome (IRIS)

Immune system restores, but inflammation increases making the symptoms worse than before

What is Immune Restoration Inflammatory Syndrome (IRIS)? | What illness is this seen in?

Immune system restores, but inflammation increases making the symptoms worse than before. Seen in HIV infections

What are techniques for Dx of latent TB infection?

PPD purified protein derivative TST Tuberculin Skin Test (check 3 days later) Interferon gamma Release Assays (IGRAs) aka Blood Assay for M. Tuberculosis (BAMT)

What is the basis for Tuberculin Skin Test PPD?

Delayed Type Hypersensitivity (DTH)

What is the basis for Interferon gamma Release Assays (IGRAs) aka Blood Assay for M. Tuberculosis (BAMT)?

Mononuclear cells from patients with TB infection and normal T cell immunity produce IFNa in response to TB specific antigens This test is better than and will replace intradermal testing

What are the cutoffs for PPD TB test for... 1) HIV patient, organ transplant, TB contact? 2) Immigrant, IV drug user, diabetics, heme disorders, gastrectomy patients? 3) Person without risk?

1) > 5mm 2) > 10mm 3) > 15mm

What are the Tx regimes for latent infections? | Detail: which is best for HIV?

INH for 9 months (best for HIV) INH for 6 months Rifampin for 4 months Rifapentine and INH once/week for 12 weeks

What is Px for TB control?

Dx and prompt isolation of patients | Healthcare workers should wear face masks or see patients in well-ventillated rooms

What is Mycobacterium bovis?

Similar to M. Tuberculosis, but causes TB in cows and large hoofed animals (vocab word: ungulates)

What is Bacille Calmette Guerin BCG?

Attenuated M. bovis that is used as a live vaccine against Mycobacterium

What is the efficacy of Bacille Calmette Guerin BCG? How long is vaccine effective? Is there a booster?

Reduces risk of childhood TB by 80% and all TB by 50% Especially beneficial against menengitis complications 15 years No booster has been successful

What are complications from Bacille Calmette Guerin (BCG)? | Name four from bad to worse.

From bad to worse... 1) Swelling, drainage, and scar 2) Local abscess with adenopathy aka BCG-itis 3) Osteomyelitis (inflammation of bone or marrow) 4) Disseminated BCG infection in the case of AIDS or other immune disorders

What is the difference between PPD skin test and IGRAs aka BAMT test with regard to the BCG vaccine?

PPD + with BCG vaccine | IGRAs aka BAMT is - with vaccine and can still detect TB infection

Non-tuberculous Mycobacteria (NTM) aka atypical mycobacteria... Details: found in soil, water, and animals. Some are pathogenic. Some colonize people. Some are lab contaminants.

List of examples is on page T-10

What is Myobacterium avium complex (MAC)?

Most common non-tuberculous mycobacterium (NTM) causing human infection water, soil, birds are natural habitat Note: it is a combo of 4 species

What are the clinical sydromes of Mycobacterium avium complex (MAC)?

Cervical adenitis in children (swollen lymph) Pulmonary disease in patients with lung disease and/or older women Disseminated infection in advanced AIDS

Note: skin tests suggests that 40% of adults have been infected with Mycobacterium avium complex.

Who is at risk for MAC?

``` Preexisting lung disease --Acquired bronchiectasis --Cigarette smokers --Cystic Fibrosis Chest wall abnormalities --Thin, elderly women, no previous lung disease >>>“Lady Windemere’s Syndrome” --Pectus excavatum --Scoliosis Hot tub users: hypersensitivity pneumonitis ```

What are environmental sources of MAC?

``` House dust Soil Birds (M. avium) Farm animals (M. intracellularae) Cigarette components Tobacco, filter, paper 25% of water samples on East coast Major source of infection is aerosolized water Hypothesis for increasing prevalence: increased use of showers rather than baths ```

``` Asymptomatic infection: 30-40% Acquired in childhood Epidemiologic data indicate prior infection with NTM protects against TB Symptomatic disease Localized cervical adenitis age 1-5 Localized pulmonary disease in adults Mimics TB, but slower and less virulent than TB (Disseminated disease in AIDS) ```

What aer the ATS definitions for NTM pulmonary disease?

Patient with symptoms, abnormal CXR or HRCT and no other explanation Sputum: 3 positive cultures Biopsy only: 1 positive culture plus histology BAL and sputum: 1 pos from each BAL only: 1 positive smear and/or growth

What is Tx for Mycobacterium Avium Complex (MAC)?

``` Combo therapy: Macrolide (clarithromycin or azithromycin) Ethambutol Rifamycin (rifabutin or rifampin) 18-24 Months!!! ```

Not testable... | What is the Runyon classification of NTM?

Runyon I photochromogens: slow growing, produce yellow-orange pigment only in light Runyon II scotochromogens: slow growing, produce yellow-orange pigment in either light or dark Runyon III nonchromogenic: slow growing, no pigment Runyon IV rapid growers: colonies in 5 days, no pigment

NTMs are common and geographically variable

Is there human to human transmission of NTM?

What are syndromes that NTM causes?

Pulmonary Cutaneous Disseminated Lymphatic

Detail: How do we distinguish NTM from TB?

``` Epidemiology: more common in Male smokers Middle-aged female nonsmokers (RML) Rarely radiographic features Growth characteristics and biochemicals Microscopic appearance Genetic probes ```

Infections due to Runyon IV Rapid Growers (very rare) do we need to know?

M. abscessus, M. chelonae, M. fortuitum Present in soil, water, animals Cutaneous, wound, pulmonary infections, and infections of prosthetic devices Organisms grow on standard media within 1 week Treatment of deep infections and pulmonary infections may be difficult

Tx for M. abscessus, M. chelonae, M. fortuitum

M. abscessus most common rapid grower and most difficult to treat Macrolides, linezolid may have some activity with goal of control rather than cure M. fortuitum responsible for 20% of infections with rapid growers: treatment is 6-12 mos with 2 oral agents based on susceptibility testing Macrolides, tetracyclines, quinolones, sulfonamides

Surgery for NTM when?

Rare indications: progressive, localized disease with drug failure, resistance or intolerance Experienced centers report 20-30% rate of bronchopleural fistula and significant operative mortality Higher rate of sputum conversion than medical therapy alone Caution: subclinical disease may exist in other lung regions, thus concern about long term outcome

Summary: Acid-fast staining is one of 5 common features of the genus mycobacterium Understanding the differences between LTBI and active TB is fundamental MAC pulmonary disease increasing in US, more common than TB Not person to person transmission MAC lymphadenitis is increasing in children