Tuberculosis Flashcards
general characteristics of Mycobacterium tuberculosis
aerobic, non-spore forming, non-motile bacillus
high cell wall content of high-molecular-weight lipids
4.4 Mb circular genome - a very large proportion of genes encode enzymes involved in lipogenesis and lipolysis
slow growing - 22-24 hour generation time and visible growth takes 3-8 weeks on solid media
TB pathogenesis
airborne droplet nuclei
initial focus on subpleural in the midlung zone - ventillation greatest in the middle and lower lobes
ingested by alveolar macrophages
infected macrophages carried to regional lymph nodes
may spread hematogenously to lymph nodes, kidneys, epiphyses of long bones, vertebral bodies, meninges and the apical posterior areas of the lung
tuberculin reactivity
hypersensitivity to tuberculin appears 3-8 weeks after infection and makrs the development of cellular imunity an dtissue hypersensitivity
before this reaction, bacterial growth is uninhibited, both in the intial focus and in metastatic foci
Ghon complex
antigen concentration int he primarily complex after the acute TB infection
consists of the Ghon focus (pulmonary focus) and draining regional nodes
visible calcification on CXR
Ziehl-Neelsen stain
fixed smear covered with carbol-fuschin is heated, rinsed, decolorized with acid-alcohol, and counterstained with methylene blue
Kinyoun stain
modified Ziehl-Neelsen stain to make the heating step unnecessary
Fluorochrome stain (auramine-rhodamine)
slightly modified acid-alcohol decolorization step and potassium permanganate counterstaining - fluorescent mycobacteria can be easily seen with a x20 or x40 low-magnification objective
characteristic structure of granulomas
necrotic center (if caseating)
surrounded by macrophages
surrounded by T cells
caseating granuloma
cells within the ring of macrophages are lysed contributing to centralized necrosis
extracellular bacteria reside within necrosis
prevents bacteria from spreading
also prevents immune cells from reaching and eliminating those trapped bacteria
Langhans giant cell
consissts of fused macrophages oriented around tuberculosis antigen with the multiple nuclei in a peripheral position
represents the most successful type of host tissue response
What are the most important determinants of transmission of infection?
close contact and infectiousness of the source
source infectivity is a function of the number of TB in bacilli in respiratory secretions and frequency and magnitude of the cough
What does reactivation tuberculosis typically look like in chest x-rays in young people?
apical posterior infiltrates, often with cavitation
apical localization attributed to high oxygen content in the apices and the the aerobic nature of the tubercle bacillus
an alternate theory attributes it to deficient lymphatic flow at the lung apices, especially the posterior apices, wher ethe pumping effect of respiratory motion is minimal
latent TB
all bacteria are harbored within a few infected macrophages within the granuloma
diagnosis is traditionally by tuberculin skin testing - may cross reaction with BCG, have operator error, or be mistaken for other mycobaccteria
interferon-gamma release assays (IGRAs) are used today
reactivation TB
extracellular bacterial levels increase when the immune system is unable to control infection
limitations of PPD skin testing
requires follow-up visit for interpretation
“operator error” - application and interpretation
corss reactions with BCG and MAI
negative in ~25% with active disease
interferon-gamma release assays (IGRAs)
quantify release of the interferon-gamma from lymphocytes in the whole blood incubated overnight with specific M. tuberculosis antigens - early secretory antigen target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10)
as sensitive and more specific than tuberculin skin testing in identifying the latent TB infection
downside is that they are expensive
clinical presentation of TB
fever, night sweats, weight loss, shortness of breath, hemoptysis
cough > 2 weeks
history of exposure to infectious TB or positive TST
common CXR findings in TB
upper lobe infiltrate
cavitary infiltrate
hilar/paratracheal adenopathy
primary vs. reactivation active pulmonary tuberculosis
primary - more common in young children, elderly, and immunosuppressed hosts; presents as lower or middle lobe infiltrates, often with hilar or mediastinal adenopathy
reactivation - typical in adolescents and adults, presents with several weeks of malaise, fever, sweats, weight loss, cough; CXR shows apical posterior infiltrates - often cavitary
milliary tuberculosis
presents as diffuse reticulonodular infiltrates
reflects widespread dissemination of TB
can occur in almost any organ, especially the lymph nodes, vertebrae, and meninges
CXR findings may not suggest TB in 50% of individuals
tuberculous meningitis
untreated death ensues within 5-8 weeks of illness onset
early diagnosis often based on CSF formula - lymphocytic or mixed pleocytosis, high protein, low glucose, negative cultures
types of media used for culture of mycobacteria
egg-based (Lowenstein Jensen) and agar-based (Middlebrook 7H11) - 3-8 weeks of incubation
liquid broth (Middlebrook 7H12) - 1-3 weeks of incubation
Xpert MTB/RIF test
automatic nucleic acid amplification test for TB and rifampin resistant TB
very sensitive and specific
takes about an hour to get results
first-line drugs for TB treatment
isoniazid
rifampin
rifapentine
rifabutin
ethambutol
pyrazinamide
second-line drugs for TB
moxifloxacin
levofloxacin
streptomycin
amikacin/kanamycin
cycloserine
ethionamide
p-aminosalicylic acid
capreomycin
bedaquiline
treatment for latent TB
isoniazid x9 months
or
rifampin x 4 months
or
isoniazid plus rifapentine weekly x2 months (directly observed therapy)
treatment for active TB
standard regimen - 2 months of isoniazid, rifampin, thambutol, and pyrazinamide followed by 4 months of isoniazid plus rifampin
extended treatment is recommended for cavitary disease on initial CXR and positive sputum cultures at 2 months of treatment
What is multi-drug resistant TB? What are the categories of MDRTB?
TB that is resistant to at least INH and rifampin
primary - patient initially infected with MDR-TB
acquired - poor adherence to Rx, selection of resistant bacteria
Why does drug resistance emerg during therapy? What is the likelihood of this happening?
selection - resistant variants pre-exist in the bacterial population
about 108 bacteria in a cavity
1in 108 are rifampin resistant
1 in 106 are isoniazid resistant
1 in 105 are ethambutol resistant
overall resistance probability to isoniazid and rifampin is 10-14
extensively drug resistant TB (XDR-TB)
resistance to INH and rifampin plus any fluoroquinolone and any one of the second-line anti-TB injectable drugs
totally drug-resistant TB (TDR-TB)
resistant to all first and second-line agents
BCG (Bacillus Calmette-Guerin) vaccine
significant protection vs. fatal TB in children
>80% protective vs. TB meningitis
variable protection vs TB infection
not very effectve vs. adult TB
effective only for a limited period of time - benefit lasts no more than 10-20 years
booster doses ineffective
