1. No category

Tuberculosis:
A Global Epidemic
International Health Seminar Series
April 27, 2010
Teresa Bleakly
Allison Hill
Sid Mahapatra
Epidemiology
 > 2 billion p
people
p infected ((1/3 world
population)
 14.4 million with active infection
 9.2 million new cases per year
 1.7 million deaths per year worldwide
 Global incidence peaked in 2003, declined
since
TB Notification Rates
WHO Report 2008
TB in children
 884,019 cases under age 15 in 2000 (11%
of total cases))
 US: 1.3/100,000 in 2007 (6% of total cases)
 Higher rates in children < 5 years
 Declining rate in the US
 Most born in the US
 Infected by household contacts
Primary TB Presentation
 Formerly mostly in children, now seen in
teens and adults due to INH therapy
py
 Fever (70%) – generally low grade, lasting
22-3
3 weeks
 Chest pain (±pleuritic) – retrosternal and
interscapular
 Fatigue, cough, athralgias, pharyngitis less
common
Primary TB CXR Findings
 Hilar
Hil adenopathy
d
th (65%) – as
early as 1 week after PPD+
andd within
ithi 2 months
th in
i all
ll
cases
 Pleural effusions (30%) –
within 4 months
 Pulmonary infiltrates (27%) –
pperihilar, right
g sided
 RML collapse
Reactivation TB
 90% of adult cases in non-HIV infected
population
 Cough, weight loss, fatigue (50-67%)
 Cough initially mild, in AM, non-productive
 Cough progresses to continuous, productive
 Fever, night
g sweats (50%)
(
)
 Chest pain, dyspnea (33%)
 Hemoptysis (25%)
Reactivation TB
 Usually normal labs
 Late disease: normocytic anemia, leukocytosis,
monocytosis,
t i SIADH,
SIADH hhypoalbuminemia,
lb i
i
hyerpgammaglobulinemia
 CXR
 Apical posterior segment of upper lobe infiltrate (80-90%)
 Atypical: hilar adenopathy, middle/lower infiltrates, pleural
effusions solitary nodules (13-30%)
effusions,
(13 30%)
 Normal (10%)
Extrapulmonary Manifestations
 GU: dysuria, hematuria, frequency, painful
scrotal p
pass,, prostatitis,
p
, orchitis
 Joints: osteoporosis, sclerosis, vertebral
(Pott disease)
 CNS: AMS, neck stiffness, increased ICP,
cranial nerve involvement  TB meningitis
or tuberculoma
 Other:
O h llymphadenopathy,
h d
h choroidal
h id l tubercle
b l
TB in children
 Pulmonary: most frequent manifestations
 Chronic cough
 Fever for > 2 weeks
 Weight loss,
loss FTT
 Extrapulmonary









Lymphadenopathy, adenitis
g (neonates
(
with highest
g
risk))
Meningitis
Pleural/pericardial effusion
Ascites, unexplained chronic diarrhea
Nontender joint effusion
Vertebral gibbus deformity
Warty lesions
Sterile pyuria, hematuria
Iritis, optic neuritis, phlyctenular conjunctivitis
Gibbus Deformity
Perinatal TB
 Mortality of congenital/neonatal TB 50%
 Congenital TB
 Associated with TB endometritis or
disseminated TB in mothers
 Acquired hematogenously via placenta or by
aspiration
asp
at o of
o amniotic
a
ot c fluid
ud
 Resp distress, fever, HSM, poor feeding,
lethargy,
gy, irritability,
y, LBW
Risk Factors
 Substance abuse
 Nutritional status
 Underwt,
U d
Vi
Vit D ddeficiency,
fi i
Fe deficiency
 Systemic diseases
 Silicosis, malignancy, DM,
renal dz, gastric surgery,
celiac dz
 Immune
I
compromise
i
 HIV, steroids, TNF
inhibitors, transplant
 Age
 Developing world = young
adults
 Developed world = elderly
 Gender
 Male>Female
 Socioeconomic status
 Ethnic minority
TB and HIV
 Increased risk of TB with HIV infx
 Risk doubles w/in 1st year, then progressively increases
with decreasing CD4 count
 HIV accelerates progression of TB
 Increased risk of AIDS or death
 TB --> generalized immune activation --> increase CD4 cell
circulation --> targeted by HIV
 Increased CCR5 and CXCR4 (HIV coreceptors) with TB
coinfection
 TB associated with increased HIV viremia
 Viremia
Vi
i usually
ll declines
d li
with
ith successful
f l TB treatment
t t
t
TB and
d HIV
V
Clinical Manifestations
 Early HIV: present similar to HIV neg pts
 Risk of extrapulmonary and disseminated
TB greater with increased
immunosuppression
 Lymph nodes, pleura
TB and HIV
Diagnosis
 PPD
 CD4 count >350: PPD + strongly suggestive of TB
 CD4 count <350: PPD not reliable
li bl
 Not useful for diagnosing active TB where prevalence
is high
g
 Most important test: repeated sputum samples for
smear andd culture,
l
andd lymph
l
h node
d aspiration
i i
 Normal CXR does not eliminate possibility of TB
QuickTime™ and a
Diagnosis of TB
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
 CXR
 In HIV-positive patients
 As CD4 count drops, more likely to have atypical CXR
findings
 Non-cavitary
y ppulmonary
y infiltrates
 No preference for upper lung fields
 Normal CXR
 More common when CD4 <200
 Chest CT - more sensitive
 Gastric aspiration
Diagnosis of TB
 Sputum smear: sensitivity 45-80%
 HIV: Smear-negative pulmonary TB common d/t lower
likelihood of pulmonary cavities
 A positive AFB is very specific for M. tuberculosis
 Sputum culture: sensitivity 85
85-100%
100%
 Lymph Node Biopsy
 FNA + in 75% of cases, bx with cx --> 96%
 Bronchoscopy
 To be avoided; aerosols of infectious droplets
 BUT it is a sensitive diagnostic technique
 AFB smears + in 50% of pts, culture + in ~100%
Diagnosis of TB
 Fluorescence microscopy (FM)
 Comparable specificity to smears,
smears but ~10%
greater sensitivity
 FM (vs. smears) may be more cost-effective and
expedite
dit dx
d in
i resource poor areas
 Urine culture
 77% of HIV pos pts w/ extrapulmonary TB grew
M. tuberculosis
 CSF, pleural, pericardial, and peritoneal fluid
 High protein, low glucose, lymphocytosis,
(elevated ADA)
 PCR
 Sensitive for rapid detection in blood, sputum, or
urine
Treatment of Latent TB
I f i
Infection
 Indications for treatment
 PPD > 5mm





HIV
Recent contacts of a TB case
Persons with fibrotic changes on CXR consistent with old TB
Transplant patients
Immunosuppressed
 PPD > 10mm
 Recent arrivals (< 5 years) from high-prevalence countries
 IV drug users
 Residents and employees of high-risk congregate settings (e.g.,
correctional facilities, nursing homes, homeless shelters, hospitals,
and other health care facilities)
 Mycobacteriology laboratory personnel
 Children < 4 years of age, or children and adolescents exposed to
adults in high-risk categories
 PPD > 15 mm (none of the above risk factors)
 Treatment – Daily INH for 9 months
Treatment of Active Disease

Initial Phase (8 weeks)


Daily INH, RIF, PZA, and EMB for 56 doses
Continuous phase (18 weeks)
 Daily INH and RIF for 126 doses
or
 Twice-weekly INH and RIF for 36 doses

Monthly sputum specimens




Monthly intervals until two consecutive specimens are negative on culture
Monitor for adverse effects
At end of initial phase to determine length of continuous phase
Directly observed therapy (DOT)


Health care worker or another designated person watches the TB patient swallow each dose of
the anti-TB drugs.
All patients taking drugs fewer than 7 days per week (e.g., 1, 2, 3, or 5 days a week) must
receive DOT.

Multi-Drug
Multi
Drug Treatment
Rationale
Patient with extensive pulmonary TB has approximately 10
12
bacteria in his
bod
body.
 Frequency of spontaneous mutations conferring resistance to an individual
g
drug:
 1 in 107 for EMB
 1 in 108 for STM and INH
 1 in 1010 for RMP
 Chances of harboring a bacterium that is spontaneously resistant to both
INH and RMP is 1 in 106. Chances of harboring a bacterium that is
p
y resistant to all four drugs
g is 1 in 1015.
spontaneously
 Different drugs in the regimen have different modes of action.
 Using only single drugs result in rapid development of resistance and
treatment failure.
Resistant TB

Emergence
 Patients
P ti t who
h do
d nott complete
l t their
th i full
f ll course off treatment
t t
t
 Health-care providers prescribe the wrong treatment, the wrong dose, or wrong length of
time for taking the drugs
 Supply of drugs is not available
 Drugs are of poor quality

Drug-resistant tuberculosis (TB)
 M. tuberculosis resistant to at least one first-line anti-TB drug.
 Multidrug-resistant
M ltid
i t t TB (MDR TB) resistant
i t t to
t more than
th one anti-TB
ti TB drug
d
andd att least
l t
isoniazid (INH) and rifampin (RIF).
 Should be managed by or in close consultation with an expert.

D
Drug
resistance
it
proven by
b drug-susceptibility
d
tibilit testing
t ti




Can take weeks
Start with an empirical treatment regimen
When the testing results are known, the treatment regimen should be adjusted according
Di tl observed
Directly
b
d therapy
th
(DOT) always
l
should
h ld bbe used
d iin th
the ttreatment
t
t off drugd
resistant TB to ensure adherence.
Special Considerations
 Children
 Guided by the source-case susceptibility results.
 If source unknown and circumstances suggest an increased risk of drug
resistance, treat with standard four-drug initial-phase regimen until
susceptibility pattern known.
 Ethambutol (EMB) can be used safely (15-20 mg/kg per day), in the
likelihood of INH resistance. Streptomycin,
p
y , kanamycin,
y , or amikacin also
can be selected as the fourth drug.
 Long-term use of fluoroquinolones in children has not been approved.
However, most experts agree that these drugs should be considered for
children with MDR TB
TB.
 Consultation with a specialist in pediatric TB treatment is recommended
 HIV-positive
 ART dec
decreases
eases TB-related
e ated death
deat and
a d reduces
educes the
t e risk
s of
o developing
deve op g TB
 Risk of TB diminishes only when CD4 >500/microL
References








Bernardo, J, et al. Diagnosis of tuberculosis in HIV-seronegative patients. Up-To-Date.
Last literature review version 18.1: January 2010. Updated: December 1, 2009.
Cain, K, et al. An Algorithm for Tuberculosis Screening and Diagnosis in People with
g J Med 2010;; 362;8.
;
HIV. N Engl
David HL (November 1970). Probability distribution of drug-resistant mutants in
unselected populations of Mycobacterium tuberculosis. Applied Microbiology 20 (5):
810–4.
g Jr, CR, et al. Epidemiology
p
gy of tuberculosis. Up-To-Date.
p
Last literature
Horsburgh
review version 18.1: January 2010. Updated: Oct 6, 2009.
Horsburgh Jr, CR. Priorities for the treatment of latent tuberculosis infection in the
United States. N Engl J Med 2004; 350:2060.
g
of tuberculosis in HIV-infected
Maartens, G, et al. Clinical features and diagnosis
patients. Up-To-Date. Last literature review version 18.1: January 2010. Updated:
December 18, 2009.
Streptomycin treatment of pulmonary tuberculosis. British Medical Journal 2 (4582):
769–82. October 1948.
WHO 2009 Global Tuberculosis Report.
http://www.who.int/tb/publications/global_report/2009/annex_1/en/index.html
http://www.cdc.gov/tb/topic/treatment/default.htm
TB and HIV
Clinical Manifestations
 133 AIDS pts with TB at a single hosipital in NYC






Typical primary TB pattern: 36%
Reactivation TB pattern: 29%
Miliary pattern: 4%
Atypical TB pattern (diffuse infiltrates suggestive of PCP): 13%
Minimal change: 5%
Normal CXR: 14%
 More common when CD4 <200