Download M. tuberculosis - Yeditepe University

Tuberculosis & other
mycobacterial infections II
Assoc Prof Meral Sönmezoğlu
Division of Infectious Diseases
Yeditepe University Hospital
Tuberculosis
• Important new findings at the global level are:
•
The absolute number of TB cases has been falling
since 2006 (rather than rising slowly as indicated in
previous global reports);
•
TB incidence rates have been falling since 2002 (two
years earlier than previously suggested);
•
Estimates of the number of deaths from TB each year
have been revised downwards;
•
In 2009 there were almost 10 million children who
were orphans as a result of parental deaths caused by
TB.
Tuberculosis
• Of the 8.6 million (range, 8.3‒9 million) incident
cases of TB estimated to have occurred in 2012,
•
less than one third of the reported TB patients
estimated to have MDR-TB (and about one-fifth
of estimated incident cases) were actually
detected in 2012 .
• An estimated 1.1 million (13%) of the 8.6
million people who developed TB in 2012 were
HIV-positive.
• About 75% of these cases were in the African
Region.
•
•
Globally in 2012, an estimated 450 000
people developed MDR-TB and there were an
estimated 170 000 deaths from MDR-TB .
• Most TB cases and deaths occur among men,
but TB remains among the top three killers of
women worldwide.
• There were an estimated 410 000 TB deaths
among women in 2012, including 160 000
among HIV-positive women.
• Half of the HIV-positive people who died from
TB in 2012 were women. Of the estimated 8.6
million new TB cases worldwide in 2012, 2.9
million were women.
•
• There were an estimated 530 000 TB cases
among children (under 15 years of age) and
74 000 TB deaths (among HIV-negative
children) in 2012 (6% and 8% of the global
totals, respectively).
•
The majority of cases worldwide in 2012 were
in the South-East Asia (29%), African (27%)
and Western Pacific (19%) regions. India and
China alone accounted for 26% and 12% of
total cases, respectively.
Tuberculosis: current problems
• About 3.8 million cases per year; 90%
(and 98% of the 3 million deaths) are in
developing countries
• Multidrug resistance (“MDR-TB”)
• AIDS: atypical presentations and
distribution
• Nosocomial spread
• Foreign-born
Millennium Development Goals set for 2015
Goal : Combat HIV/AIDS, malaria and other diseases
Target: Halt and begin to reverse the incidence of
malaria and other major diseases
Indicator: Incidence, prevalence and death rates associated with
TB
Indicator: Proportion of TB cases detected and cured under
DOTS
Stop TB Partnership targets set for 2015 and 2050
By 2015: Reduce prevalence and death rates by 50%, compared with their levels in
1990
By 2050: Reduce the global incidence of active TB cases to <1 case per 1 million
population per year
History of TB
Scientific Discoveries in 1800s
• Until mid-1800s, many
believed TB was
hereditary
• 1865 Jean AntoineVillemin proved TB was
contagious
• 1882 Robert Koch
discovered M.
tuberculosis, the
bacterium that causes
TB
Mycobacterium tuberculosis
STOP TB
World TB Day 24th March
1882 when Dr Robert Koch astounded the scientific
community by announcing that he had discovered the
cause of tuberculosis, the TB bacillus
Robert Koch, discoverer of the tubercle bacillus,
concluded his Nobel Lecture on December 12, 1905
Treatment
22 millionlives were saved through the
Stop TB Strategy, 1995-2012.
Fact sheet on tuberculosis
MDR-TB cases
450 000people developed multidrugresistant tuberculosis (MDR-TB) in the
world in 2012.
Q&A on MDR-TB
Funding
2 billionUS dollars per year needed to fill
resource gap for implementing existing TB
interventions.
Prevalence of MDR Tuberculosis among New Cases of Tuberculosis, 2007, and Countries with at
Least One Reported Case of XDR Tuberculosis as of December 2008
Donald P and van Helden P. N Engl J Med 2009;360:2393-2395
Tuberculosis
Tuberculosis
Tuberculosis
Tuberculosis
Tuberculosis
Tuberculosis
Tuberculosis
Tuberculosis
Mycobacterium tuberculosis
• MTB is a bacterium belonging to the
Mycobacterium genus
• Its identification is based on the following
characteristics:shape of the colonies, growth
rate, and biochemical reactivity.
• subdivided in two main groups based on their
growth rates (fast vs. slow)
Mycobacterium tuberculosis
Mycobacterium tuberculosis
• The rapidly growing Mycobacterium species
(Mycobacterium abscessus, M. fortuitum, M.
porcinum), whereas the majority are
nonpathogenic
• Majority of the slowly growing Mycobacterium
species are pathogenic for humans and/or
animals (e.g., all the species of the MTB complex
[MTBC], M. leprae, M. ulcerans, M. avium), and
only a few of them are nonpathogenic (e.g., M.
terrae, M. gordonae).
• MTB complex: MTB (Koch,1882), M. bovis
(Karlsen and Lessel, 1970), M. africanum [25], M.
microti (Reed, 1957),“M. canettii’
Mycobacterium tuberculosis
• rod-shaped bacteria (0.2–0.6 m wide, 1–10 m
long), nonmotile, nonencapsulated,
Grampositive,
• aerobes (growing most successfully in tissues
with a high oxygen content such as lungs), or
facultative anaerobes.
• They are facultative intracellular pathogens,
usually infecting mononuclear phagocytes
(e.g., macrophages).
Mycobacterium tuberculosis
• An obligate aerobe: prefers P02 of 130
torr
• Replicates every 20 hours
• Natural resistance to one drug is one in
every 105 to 107 cells
• Natural resistance to two or more drugs
is 1 in every 109 to 1012 cells
Tuberculosis: the basics
• The Mycobacterium tuberculosis complex:
M. tuberculosis, M. bovis, M. africanum
• Transmitted primarily by airborne droplet nuclei
• Persons with positive AFB sputum smears are
especially effective transmitters
• Between 5% and 15% of infected persons will
develop active disease (involving any organ)
within two years
Tuberculosis: the basics (2)
• Populations at increased risk of infection:
medically-underserved, low-income groups;
immigrants; residents of long-term care or
correctional facilities
• Infected persons with increased risk of active
disease: close contacts of cases; children < 5
years old; persons with chronic diseases (renal
failure; silicosis; diabetes); immunosuppressed;
HIV-positive persons
Immunology of tuberculosis
• Tubercle bacillus + macrophages --> processed
antigen
• Antigen recognition by lymphocytes --> activated
lymphocytes --> lymphokines
• Lymphokines--> attraction, stimulation, and
retention of macrophages at antigen site
• Activated macrophages--> lytic enzymes with
mycobactericidal but also tissue-necrosing
capacity
Mycobacterium tuberculosis
(MTB) enters the host within inhaled droplets.
Immunology of tuberculosis (2)
• Interferon-gamma probably stimulates
macrophages to produce interferon-alfa
and 1,25-dihydroxyvitamin D, both of
which are mycobacterial inhibitors
• Cytokines secreted by alveolar
macrophages: interleukin 1 (fever);
interleukin 6 (hyperglobulinemia), and
tumor necrosis factor alpha (killing of
organisms, granuloma formation, fever and
weight loss)
Primary tuberculous infection
• Inhalation leads to infection at
periphery of middle lung zone
• Pneumonia 2 to 6 weeks after infection
followed by lymphohematogenous
dissemination
• Cell-mediated immunity (manifested by
positive PPD) usually contains the
infection
• Some organisms remain viable
Pathogenesis of tuberculosis
Reactivation of tuberculosis
• Occurs most often in persons > 50
years of age; more common in men
• Higher risk in elderly persons and in
those with malnutrition, diabetes
mellitus, post-gastrectomy,
immunocompromise, alcoholism, HIV
infection, or corticosteroid therapy
Residua of primary infection
• Ghon complex (after Anton Ghon, German
bacteriologist): calcified peripheral focus of
tuberculous infection with calcified regional
(hilar) lymph node (also called Ranke complex)
• Simon focus (after Georg Simon, German
pediatrician): focus at apex of lung, containing
viable organisms and manifested on x-ray as
“fibrous cap”
Axioms on Simon foci
• “If humans did not have apices to their
lungs, the tubercle bacillus would not
have survived as a human pathogen.”
• “Once a Simon focus has formed, one
will eventually die of tuberculosis if
something else doesn’t cause death
first.”
TB Pathogenesis (1)
Pathogenesis is defined as how an infection or
disease develops in the body.
TB Pathogenesis (2)
Latent TB Infection (LTBI)
• Occurs when tubercle bacilli are in the body, but
the immune system is keeping them under control
• Detected by the Mantoux tuberculin skin test (TST)
or by blood tests such as interferon-gamma
release assays (IGRAs) which include:
– QuantiFERON®-TB Gold test (QFT-G)
– QuantiFERON®-TB Gold In-Tube (QFT-GIT)
– T-Spot®.TB test (T-SPOT)
TB Pathogenesis (3)
TB Disease
• Develops when immune system cannot keep
tubercle bacilli under control
– May develop very soon after infection or many
years after infection
• About 10% of all people with normal immune
systems who have LTBI will develop TB disease
at some point in their lives
• People with TB disease are often infectious
TB Pathogenesis (4)
Droplet nuclei containing tubercle bacilli are
inhaled, enter the lungs, and travel to small air
sacs (alveoli)
TB Pathogenesis (5)
2
bronchiole
blood vessel
tubercle bacilli
alveoli
Tubercle bacilli multiply in alveoli, where
infection begins
TB Pathogenesis (6)
3
brain
bone
lung
kidney
A small number of tubercle bacilli enter
bloodstream and spread throughout body
TB Pathogenesis (7)
LTBI
4
special
immune cells
form a barrier
shell (in this
example,
bacilli are
in the lungs)
• Within 2 to 8 weeks the immune system produces
special immune cells called macrophages that
surround the tubercle bacilli
• These cells form a barrier shell that keeps the bacilli
contained and under control (LTBI)
TB Pathogenesis (8)
TB Disease
5
shell breaks
down and
tubercle
bacilli escape
and multiply
(in this example,
TB disease
develops in
the lungs)
• If the immune system CANNOT keep tubercle bacilli under
control, bacilli begin to multiply rapidly and cause TB
disease
• This process can occur in different places in the body
LTBI vs. TB Disease
Latent TB Infection (LTBI)
TB Disease (in the lungs)
Inactive, contained tubercle bacilli Active, multiplying tubercle bacilli
in the body
in the body
TST or blood test results usually
positive
TST or blood test results usually
positive
Chest x-ray usually normal
Chest x-ray usually abnormal
Sputum smears and cultures
negative
Sputum smears and cultures may
be positive
No symptoms
Symptoms such as cough, fever,
weight loss
Not infectious
Often infectious before treatment
Not a case of TB
A case of TB
Caseous necrosis of tuberculosis
• This walled-off, friable,
cheesy nodule in the
subapical region (a Simon
focus) develops from
organisms spread
hematogenously from the
initial focus of infection in the
lower half of the lung.
Reactivation of this lesion
would probably destroy the
capsule, and the caseous
material would be
expectorated leaving a
cavity.
Tuberculous pleuritis
non-necrotizing granulomas
the Langhans' giant cells, the
epithelioid cells, and
the lymphocytes.
Progression to active tuberculosis
• One year after infection: approximately 5%
• Thereafter: approximately 5% (lifetime)
• It now seems that many people eventually
outlive their tubercle bacilli and are
consequently vulnerable to reinfection
(Stead, studies in Arkansas, early 1980s)
• Tuberculin-positive persons with HIV
infection: risk is 7% to 10% per year
Insights from genotyping of
M. tuberculosis isolates
(N Engl J Med 2003; 349: 1149-1155)
• Previously, it was thought that 90% of
TB cases in industrialized nations
resulted from reactivation of infection
acquired in remote past.
• It now seems that recent transmission
causes 40% to 50% of TB cases in
urban areas.
The cavity (1)
• Formation of the cavity is the pivotal
event in the evolution of pulmonary
tuberculosis.
• Mortality of cavitary pulmonary
tuberculosis without treatment
approaches 90%.
• All therapies prior to 1948 were aimed
at closing cavities.
The cavity (2)
• Even healed, cavities are unstable.
• The walls of cavities contain extensive
sheets of bacilli (up to 1011
bacilli/gram).
• The cavity is thinnest at the point of
penetration of bronchi.
• Open cavities may persist for years,
constantly draining bacilli into the rest
of the bronchial tree.
Complications of pulmonary tuberculosis
• Cough, fever, night sweats, weight loss,
anemia
• Massive hemoptysis (erosion of a vessel in
the wall of a cavity; a dilated vessel in a
cavity (Rasmussen’s aneurysm; or an
aspergilloma)
• Progressive pulmonary disease, rarely
ARDS
• Hyponatremia due to syndrome of inappropriate
secretion of antidiuretic hormone (SIADH)
Major syndromes of extrapulmonary
tuberculosis
• Disseminated (miliary) tuberculosis
• “Serosal” tuberculosis (anatomic
spaces or cavities): pleurisy,
pericarditis, meningitis, peritonitis,
arthritis
• Tuberculosis of solid organs: renal
(genitourinary), osteomyelitis, adrenal
glands (Addison’s disease), lymph
nodes
Miliary tuberculosis: diagnostic aids
• Repeat physical examination: choroidal
tubercles, palpable lymph nodes
• Repeat CXR and tuberculin test
• Cultures: sputum (up to 63% positive), urine,
bone marrow, CSF, gastric aspirate, pleural
fluid
• Biopsy: palpable nodes, marrow, liver
• Therapeutic trial
“Cryptic miliary tuberculosis”
• An occult illness with gradual decline in
general health
• Often no significant fever
• Non-reactive tuberculin skin test
• Normal chest x-ray
Frequency order of extrapulmonary sites
1. Lymph node
2. Pleura
3. Genitourinary tract
4. Bone and joints
5. Meninges
6. Peritoneum
Tuberculous pleurisy
• Subpleural focus ruptures into the pleural space
• Usually younger adults, 3 to 7 months after
primary tuberculous infection
• Abrupt or insidious onset. DDx: pneumonia,
pulmonary infarct, tumor, others
• Natural history untreated: 65% of 141 patients
developed active tbc (Roper & Waring)
Tuberculous meningitis
• Rupture of subependymal tubercle into
subarachnoid space (“Rich focus”; Rich and
McCormack, 1933)
• The intrathecal tuberculin reaction (instillation
of PPD material into CSF of PPD-positive
volunteers)
• Usually occurs within first 6 months of
infection; now seen in older adults
Tuberculous pericarditis
• Rupture of a tuberculous mediastinal lymph
node into the pericardial sac
• Mortality 80% to 90% without treatment. Major
problems even with appropriate Rx
• Diagnosis is difficult to make short of total
pericardiectomy
• Constrictive pericarditis
• Can extend into myocardium --> fiber atrophy
Tuberculous peritonitis
• Onset is usually insidious. Mortality 45% to
55% untreated but as low as 0% to 4% with
treatment
• Polar types: plastic or adhesive type
(“doughy abdomen”) and exudative or
serous peritonitis with ascites
• Presentations: debilitating FUO; chronic
abdominal pain; ascites of unknown origin
Tuberculous arthritis
• Tuberculous focus in bone ruptures into
joint space; trauma predisposes
• Adults: spine 50%, hips 15%
• Children: Knees 15%
• Insidious joint pain and swelling, most often
involving large weight-bearing joints
• Absence of proteolytic enzymes explains
preservation of joint space
Genitourinary tuberculosis
• Tubercle of the glomerulus ruptures into
the calyceal system
• May progress to involve the entire kidney
(“autonephrectomy”) and/or may spread
throughout the GU tract (prostatitis,
epididymitis, salpingitis)
• Insidious onset
Tuberculous osteomyelitis
 Subchondral osteoporosis with
surrounding ring of sclerosis
 Spine: anterior involvement of vertebral
bodies with disk collapse (Pott’s
disease)
 Suspect: Monoarticular arthritis of
insidious onset; paraspinous mass;
back pain
Tuberculosis of the adrenal glands
(Addison’s disease)
• Tuberculosis formerly the major
cause of the disease as described
by Thomas Addison (now rare;
most common cause is idiopathic
[autoimmune])
• Wasting, hyperpigmentation, low
blood pressure, hyponatremia,
hyperkalemia
Tuberculosis in HIV-positive patients
• Present in 5% to 35% of patients
diagnosed with AIDS
• Precedes diagnosis of AIDS in 67% of
patients
• Although most of these cases result from
reactivation, CXR often resembles
progressive primary tuberculosis
• Multiple drug resistance a major problem
AFB smears
• Three morning specimens
• Fluorescent methods are more
sensitive than traditional Kinyoun or
Ziehl-Neelsen method
• Predictive value of a positive test
decreases strikingly as prevalence of
the disease decreases (Bayes’ s
theorem)
Tuberculin skin test guidelines
• 5 mm for close contacts; for persons
with compatible chest x-rays; and for
HIV-infected persons
• 10 mm for recently-infected persons,
persons with high-risk medical
conditions, and high-risk patients
under 35 years of age
• 15 mm for low-risk persons under
age 35
Rapid laboratory confirmation
• Fluorochrome smear on concentrated
specimens
• Rapid methods of detection: Bactec system;
polymerase chain reaction
• Rapid mechanisms of identification: DNA
probes; HPLC
• Rapid methods of susceptibility testing
• Handle reports as critical laboratory values
Non tuberculos mycobacteria
• M. avium Complex
(MAC)
•
M. gordonae
•
M. haemophilum
•
M. immunogenum
•
M. malmoense
•
M. marinum
•
M. mucogenicum
• M. chelonae
•
M. nonchromogenicum
•
M. scrofulaceum
• M. fortuitum
•
M. simiae
•
M. smegmatis
•
M. szulgai
•
M. terrae complex
•
M. ulcerans
•
M. xenopi
• M. kansasii
• M. abscessus
• M. genavense
Nontuberculous mycobacteria (NTM)
• Synonyms: atypical mycobacteria,
mycobacteria other than tuberculosis
(MOTT), nontuberculous mycobacteria
(NTM)
• Numerous species; widespread
• Can be difficult to treat
• “MAC” = M. avium-intracelluare
complex
Pulmonary disease due to NTM in
immunocompetent persons
• Isolation of organism from sputum does
not necessarily imply disease
• M. avium-intracelluare (especially in the
Southeast) and M. kansasii (especially in
the west) cause disease resembling
tuberculosis (clinically milder but more
difficult-to-treat)
Mycobacterium avium-intracelluare
(“MAC”) in HIV disease
• Disseminated “MAC” infection with
or without pulmonary involvement
• Prolonged fever, weight loss,
hepatosplenomegaly, diarrhea,
abdominal pain
• Positive blood cultures; AFB also
found in bone marrow, liver, and
often stool
Lymphadenitis due to NTM
• Usually due to M. scrofulaceum or M.
avium-intracelluare
• “Scrofula”: cervical lymphadenitis,
usually in children
• Usual treatment of choice: surgical
excision without chemotherapy
Swimming pool and fish-tank granuloma
• Caused by Mycobacterium marinum
• Small violet nodule or pustule at the site
of minor trauma may evolve into crusted
ulcer or abscess
• Multiple lesions can resemble
lymphocutaneous sporotrichosis
Infections related to injections or
surgery
• “M. fortuitum complex”: Mycobacterium
fortuitum, M. chelonae, M. abscessus (all
“rapidly-growing mycobacteria”)
• Opportunistic pathogens causing wound
infections (which can be epidemic) and
skin infections
Leprosy (Hansen’s disease)
 A chronic granulomatous infection attacking
superficial tissues, especially the skin and
peripheral nerves
 M. leprae has not been successfully
cultured. It can be propagated in armadillos
and in the footpads of mice
 Phenolic glycolipid I binds to C3 which
mediates phagocytosis by macrophages
Tuberculoid leprosy
 Delayed hypersensitivity to M. leprae antigens
is present (in contrast to lepromatous leprosy)
 Large, erythematous, anesthetic plaques with
flat, dry, hairless centers and raised outer
edges
 Limited but severe involvement of peripheral
nerves
Lepromatous leprosy
 Anergy to M. leprae antigens
 B-cell over-activity: polyclonal
hyperimmunoglobulinemia with many unusual
antibodies (e.g., false-positive VDRL [RPR];
secondary amyloidosis)
 Massive infiltration of dermis--> leonine facies
 Nerve involvement is diffuse but less severe
than in tuberculoid form