a 32-year-old woman presented with a cough for several weeks and a 15-lb weight loss. she also had...
TRANSCRIPT
A 32-year-old woman presented with a cough for several weeks and a 15-lb weight loss. She also had night sweats and fevers and felt fatigued.
Despite erythromycin treatment for suspected pneumonia given by her family physician, her fever and cough got progressively worse. She complained about coughing blood-tinged sputum.
She had emigrated from Venezuela to the United States 3 years before her illness, but she frequently returned to Venezuela to visit relatives.
Physical examinationTemperature: 38.6˚CPulse: 96/minRespiration: 18/minBlood pressure: 112/60 mm HgExamination was remarkable for bilateral rales and
lymphadenopathyChest X-ray revealed right upper lobe infiltrates
Likely causes of illness
Actinomyces spp.Anaerobes (aspiration pneumonia)Endemic fungi (Histoplasma capsulatum)Legionella pneumophilaMycobacterium tuberculosisMycoplasma pneumoniaeNocardia spp.
MYCOBACTERIA
The captain of all the men of death that came against him to take him away, was the Consumption, for it was that that brought him down to his grave
John Bunyan (1628-1688)English author
MYCOBACTERIA
Died of tuberculosis:
ChopinPaganiniThoreauKeatsElizabeth Barrett BrowningEmily and Charlotte Bronte
MYCOBACTERIA
In the 19th Century, one quarter of the population of Europe is thought to have died of tuberculosis
MYCOBACTERIA
1.9 billion people infected with Mycobacterium tuberculosis
Tuberculosis kills about 2 million people and infects about 8 million others every year
Risk factors: poverty, malnutrition and poor housing
MYCOBACTERIA
May proceed toa generalizedinfection(“miliary”Tuberculosis)
Transmission electronmicrograph of
M. tuberculosis
Primarily a disease of the lungs
Mycobacteria stained with theZiehl-Neelsen stain
Acid-fast staining “Acid-fast bacteria”
M. tuberculosis colonies onLowenstein-Jensen agar
MYCOBACTERIA
Physiology and structure
Complex cell wall
Peptidoglycan layer linked with arabinose-galactose-mycolic acid (arabinogalactan mycolate)
Mycolic acidsMajor lipidsLong chain (C78-C90)
Mycobacterialcell wallstructure
MYCOBACTERIA
Physiology and structure
Free lipidsWaxes: wax D (Freund's adjuvant)
Helps withstand drying and thus increases survival
Mycosides: complex saturated glycolipids Cord factor: 6,6'-dimycolate of trehalose
Inhibits neutrophil migrationThought to mediate granuloma
Trehalose 6,6’-dimycolateRCO: mycolyl
MYCOBACTERIA
Physiology and structure
PolypeptidesAct as antigensUsed in skin testing (PPD)
MYCOBACTERIA
Physiology and structure
Runyon classification according to rate of growth and pigmentation
Photochromogens: Organisms that produce pigments after exposure to light
Scotochromogens: Produce pigments both in the light and dark
Photochromogenic M. kansasi colonieson Middlebrook agar
Pathogenesis
Infection via inhalation of infectious aerosols
Replicates in alveolar macrophages and destroys the cells
Infected macrophages migrate to the local (tracheobronchial) lymph nodes, the bloodstream and other tissues
Mycobacterium tuberculosis
Tubercle bacilli enter through the respiratory tract
Stealth invader:MTB in macrophages
Tubercle bacilli multiply in phagocytes and spread to lymph nodes and the circulation
Pathogenesis
No exotoxin or endotoxin
”Exported repetitive protein" prevents the phagosome from fusing with the lysosome
Mycobacterium tuberculosis
Pathogenesis
Two types of lesions
Exudative: Acute inflammatory response at the initial site of infection (usually lungs)
Granulomatous: A central area of infected giant cells (Langhans’cells) surrounded by epithelioid cells (tubercles)
Mycobacterium tuberculosis
Pathogenesis
TuberclesMay heal spontaneouslyMay become fibrotic or calcified
Caseous (cheesy) necrosis and cavitation in the center of the granuloma, due to:
Cellular immune responseEnzymes and reactive oxygen intermediates from
dying macrophages
Mycobacterium tuberculosis
Pathogenesis
The exudative lesion and the draining lymph nodes fibrose, and sometimes calcify, to produce theGhon complex seen in X-rays
Latent bacilli can be re-activated when the patient's immune system is weakened (malnutrition, alcoholism, diabetes, old age, emotional stress)
Mycobacterium tuberculosis
Pulmonary tuberculosis
MTB can cause devastating damage to the lungs
Pathogenesis and immunity
Intracellular replication stimulates helper and cytotoxic lymphocytes
T-cells release interferon- and other cytokines-> Macrophage activation -> MTB killing
Tuberculin skin test: purified protein derivative (PPD)Positive 4-6 weeks after infection
Mycobacterium tuberculosis
Pathogenesis and immunity
Localized activated macrophages can penetrate into small granulomas (< 3 mm) and kill all bacilli
Larger necrotic or caseous granulomas become encapsulated with fibrin that protects the bacilli
Mycobacterium tuberculosis
Pathogenesis and immunity
The pathogen population does not increase, but the immune system cannot get rid of the bacteria
It is not known how MTB can sit around in tissues for years or decades
MTB eats carbon from lipids via the glyoxylate pathwayIsocitrate lyase critical for this pathway
Mycobacterium tuberculosis
Epidemiology
Transmitted by aerosols
More common amongThe urban poorPatients with suppressed immune systems Immigrants from high-incidence areas
Health care workers are at risk for infection!
Mycobacterium tuberculosis
Annualincidenceof MTB inthe US1981-1995
In 2005:14,093 cases4.8 per 100,000
California:2,900 cases8 per 100,000
Epidemiology
An estimated 10-15 million people in the US are infected with M. tuberculosis without displaying symptoms
1 in 10 of these individuals will develop active TB at some time in their lives
Mycobacterium tuberculosis
Epidemiology
What caused TB to return?HIV/AIDS epidemicImmigration from countries with many TB casesIncreased poverty, injection drug use, homelessnessFailure to take antibiotics as prescribedIncreased number of people in long-term care
Mycobacterium tuberculosis
Clinical syndromes
Primary tuberculosismild and asymptomatic in 90% of cases does not proceed further
In the remaining 10%malaise, weight loss, productive cough, night
sweatsBloody and purulent sputum
Mycobacterium tuberculosis
Clinical syndromes
Reactivation of latent bacilli years later when the patient's immunologic responsiveness wanes:
Old ageImmunosuppressive disease or therapyMalnutritionAlcoholismDiabetesStress
Mycobacterium tuberculosis
Clinical syndromes
Necrosis may erode blood vessels -> hemorrhage
Most infections in the lungs
Can disseminate to the lymph nodes, pleura, the liver, genitourinary tract, bone marrow, spleen, kidneys,central nervous system
M. tuberculosis can also cause meningitis
Mycobacterium tuberculosis
Acutemiliarytuberculosisleading tomeningitis
Latin:milium, milletseed
Each tubercleresemblesa millet seed
Laboratory diagnosis
Skin test: "purified protein derivative" injected into the intradermal layer of the skin. Induration of 10 mm or more 48 hours later indicates exposure to MTB
Microscopy: Clinical specimen stained with carbolfuchsin (Ziehl-Neelsen and Kinyoun stains) or fluorochrome dyes (Truant auramine-rhodamine), de-colorized with acid-alcohol solution, and counterstained
Mycobacterium tuberculosis
Acid-fast stain(carbolfuchsin)of Mycobacteriumtuberculosis
M. tuberculosis stainedwith the fluorescentdyes auramine andrhodamine
Laboratory diagnosis
Culture: After treatment of specimen with 2% NaOH(to kill rapidly growing bacteria) MTB is grown on Lowenstein-Jensen (egg-based) medium, or Middlebrook (agar-based) medium
BACTEC measures the metabolism of 14C-palmitic acid to 14CO2
Mycobacterium tuberculosis
Laboratory diagnosis
Biochemical tests: The production of niacin, and nitrate reductase. Analysis of cell wall lipids Nucleic acid probes and nucleic acid sequencing
PCR
Mycobacterium tuberculosis
Treatment and control
Isoniazid: inhibits mycolic acid biosynthesis (used for prophylaxis)
Rifampin Pyrazinamide (active at low pH; mechanism unknown)Ethambutol (inhibits arabinogalactan synthesis)
American Thoracic Society recommendations:Initial treatment with these 4 drugs for 2 months, followed by INH/RIF for 4-6 months
Mycobacterium tuberculosis
Treatment and control
Multiple-drug-resistant (MDR) strains
Mutations in genes formycolic acid synthesiscatalase-peroxidase
required to activate isoniazid
Need in vitro susceptibility testing
Mycobacterium tuberculosis
Treatment and control
Noncompliance -> emergence of MDR strains
Directly observed therapy (DOT)
BCG: Bacille Calmette-Guérin (attenuated M. bovis)Used in most developing countries to reduce the severe consequences in infants and children Variable efficacy in adults
Mycobacterium tuberculosis
Treatment and control
PA-824 New drug in clinical trials(“nitroimidazopyran”)
Active against both actively dividing and slow growing MTB
Mycobacterium tuberculosis
Pathogenesis
Asymptomatic colonization: immunocompetent patients
Localized pulmonary disease: patients with chronic bronchitis
Disseminated disease: immunocompromised individuals
Organ dysfunction due to abundance of bacteria and host response to infection
Mycobacterium avium-intracellulare
M. avium-intracellulareinfected tissue froman AIDS patient
M. avium-intracellulare in fixed-tissue macrophages in a bone marrow biopsy from a patient with AIDS
(anti-mycobacterial Ab immunoperoxidase stain)
Epidemiology
Ingestion of contaminated food or water
Found in soil and water, and infected poultry and swine
Inhalation of infectious aerosols: minor role
Immunocompromised patients (esp. AIDS) and those with long-standing pulmonary disease at greatest risk
Mycobacterium avium-intracellulare
Clinical syndromes
The most common mycobacterial isolate in AIDS patients
Disseminated disease: Tissues filled with MAC
Bacteremia: 100-1000/ml in blood
Mycobacterium avium-intracellulare
Treatment and control
Resistant to most antimycobacterial drugs
Combination therapyClarithromycin (or azithromycin) + Ethambutol +
Rifabutin
For prophylaxis in AIDS patients with low CD4 counts: Clarithromycin or Azithromycin
Mycobacterium avium-intracellulare
Pathogenesis
Causes leprosy or Hansen's disease
Tuberculoid leprosyStrong cellular immune reactionLymphocytes and granulomas, but relatively few
bacteriaProduction of interferon- and IL-2 -> macrophage
activation, phagocytosis and bacterial clearance
Mycobacterium leprae
A. TuberculoidleprosyMacules withhypo-pigmentation
B. Lepromatousleprosy withextensiveinfiltration,edema andcorrugation ofthe face
Pathogenesis
Lepromatous leprosy Specific defect in the cellular immune response to
M. leprae antigensBacilli populate dermal macrophages and
Schwann cells of peripheral nervesThe most infectious form of leprosy
Mycobacterium leprae
Tuberculoid leprosy
Lepromatous leprosy
Ziehl-Neelsen staining of Mycobacterium leprae
Clinical syndromes
Tuberculoid
Lepromatous leprosyMost infectious, with large numbers of bacilli in
infected tissuesCauses disfigurations in the skin
Mycobacterium leprae
Epidemiology
> 12 million cases of leprosy worldwide
250 cases annually in the U.S. ( California, Texas, Louisiana and Hawaii), mostly in immigrants
Spread by person-to-person contactInhalation of infectious aerosols, skin contact with respiratory secretions or wound exudates.
Arthropod vectors? Armadillos?
Mycobacterium leprae
ArmadillosandM. leprae?
Treatment and control
Tuberculoid leprosyDapsone (antifolate) + Rifampin (min 6 months)
Lepromatous leprosyClofazimine in addition to Dapsone and Rifampin (therapy extended to 12 months)
Controlled by prompt recognition and treatment of infected people
Mycobacterium leprae
Mycobacterium kansasii
Causes chronic pulmonary disease
Disseminated disease in immunocompromised patients
Mycobacterium marinum
Causes "swimming pool granulomas”nodular lesions along the lymphatics
-> ulceration
Fish tank granulomacaused byMycobacteriummarinum infectionof a lesion acquired while cleaning outa fish tank
NOCARDIA
Strict aerobic, Gram-positive bacilli
Form branched hyphae
The cell wall contains mycolic acids
"acid-fast” (in contrast to Actinomyces)
Nocardia
Nocardia asteroides causes bronchopulmonary disease that can spread to the skin and CNS
Nocardia brasiliensis causes cutaneous disease
Nocardia
Acid-fast stain of Nocardia asteroidesin expectorated sputum
Gram stain of Nocardia asteroidesin expectorated sputum
Pathogenesis
Found worldwide in organic-rich soil
Colonizes the oropharynx
Aspiration of oral secretions causes infection of the lower airways
Nocardia
Pathogenesis
Causes necrosis and abscess formation
Can survive in phagocytes
Traumatic introduction into subcutaneous tissue > Cutaneous nocardiosis
Nocardia
Epidemiology
Infections are exogenous (not caused by normal human flora)
Nocardia asteroides infections occur in patients with impaired cell-mediated immunity
Nocardia
Epidemiology
Immunocompetent patients with chronic pulmonary disease (bronchitis, emphysema)
Nocardia brasiliensis infections of the skin can occur in immunocompetent persons
Nocardia
Mycetoma caused by Nocardia brasiliensis
The foot is grosslyenlarged and coveredwith multiple drainingsinus tracts
Clinical syndromes
Bronchopulmonary infections: Cough, dyspnea (difficulty in breathing), fever
Cutaneous infections: Cellulitis (inflammation of the soft or connective tissue), pustula, pyoderma (purulent skin disease), chronic ulcerative lesions, subcutaneous abscesses
Nocardia
Clinical syndromes
Lymphocutaneous infections: Regional lymph nodes
Mycetoma: Chronic granulomatous disease; may involve bone, connective tissue and muscle
CNS: Single or multiple brain abscesses
Nocardia
Treatment
Proper wound care and trimethoprim-sulfamethoxazole for 6 weeks or more
Prognosis is poor for immunocompromised patients with disseminated disease
Nocardia