MD, FIACM, FICP - APIDSC · pericardial calcification ... Male genital tract TB ² acute epidydymitis or epidydmoorchitis -may cause caseation and fistula, chronic prostatitis and
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1
Dr MPS Chawla
MD, FIACM, FICP
•An astute clinician, a keen academician and a popular teacher.
Several Publications in Indexed journals
•Associate Editor of API Medicine Update 2009
•Associate Editor of Clinical Medicine Update 2013
•Associate Editor, journal of Indian Association of Clinical
Medicine
•Hon Gen Secretary, API Delhi State Chapter
•Member. Governing Body, API
Senior Internist PGIMER, Dr RML Hospital
New Delhi
Photogr
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Challenges and Perspectives in The
Diagnosis of Extrapulmonary TB
Dr MPS Chawla
MD, FIACM, FICP
Senior Internist
PGIMER, Dr RML Hospital, New Delhi
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Tuberculosis
One of the world’s deadliest communicable disease, 2nd
biggest killer among infectious agents
In 2014, an estimated 9.6 million people developed
TB(5.4 m men,3.2 m women and 1 m children ) and 1.5
million died from the disease, 360 000 of whom were
HIV-positive, 37% of new cases remained undiagnosed
or not reported. 4,80,000 cases of MDR TB
1/3 rd of world’s population infected with MTB
India—highest burden country
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Case Definitions
Pulmonary tuberculosis (PTB) refers to a case of TB involving the lung
parenchyma.
Extrapulmonary tuberculosis (EPTB) refers to a case of TB involving
organs other than the lungs
Diagnosis should be based on at least one specimen with confirmed
M. tuberculosis or histological or strong clinical evidence consistent
with active EPTB, followed by decision by clinician to treat with full
course of TB chemotherapy
Can/should still treat presumptively if strong clinical evidence
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Case Definitions
If several sites affected, case definition of an EPTB case depends on
the site representing the most severe form of disease.
Miliary tuberculosis is classified as pulmonary TB because there are
lesions in the lung parenchyma.
Tuberculous intrathoracic lymphadenopathy (mediastinal and/or hilar)
or tuberculous pleural effusion, without radiographic abnormalities in
the lungs, constitutes a case of EPTB.
A patient with both pulmonary and extrapulmonary TB should be
classified as a case of pulmonary TB.
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Overview
TB can occur in any site, including:
– Lymph Nodes (most common)
– Pleura
– Bones and joints
– CNS (usually meningitis, but can occur in brain or spine)
– Larynx
– Pericardium
– Abdominal sites; Kidneys
– Genitourinary tract
– Disseminated (miliary)
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Extrapulmonary TB
Especially common in children and people living with HIV
EPTB occurs ~15-20 % in HIV(-)
But in HIV(+), ≥ 50 %
– 33% with extrapulmonary alone
– 33% with pulmonary alone
– 33% both pulmonary and extrapulmonary
(many with negative CXRs)
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Diagnostic Challenges
Often more difficult to diagnose EPTB--
Variable clinical presentation
Pauci-bacillary
Often occurs in inaccessible body sites
Lack of diagnostic facilities in resource-limited settings
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Transmission of EPTB
usually not infectious, unless person has:
Concomitant pulmonary disease,
disease in the oral cavity or larynx, or
disease with open site, especially with aerosolized fluid
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Clinical Clues to Prompt Suspicion of EPTB
Ascites with lymphocyte predominance and negative bacterial cultures
Chronic lymphadenopathy (especially cervical)
CSF lymphocytic pleocytosis with elevated protein and low glucose
Differential diagnosis of Crohn’s disease and amebiasis
Exudative pleural effusion with lymphocyte predominance, negative
bacterial cultures, and pleural thickening
HIV infection
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Clinical Clues to Prompt Suspicion of EPTB
Joint inflammation (monoarticular) with negative bacterial
cultures
Persistent sterile pyuria
Unexplained pericardial effusion, constrictive pericarditis, or
pericardial calcification
Vertebral osteomyelitis involving the thoracic spine
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EPTB Symptoms
Can have the same symptoms as in pulmonary TB:
– fever, night sweats, fatigue, loss of appetite, wt loss.
Complaints specific to the body site infected with TB.
– Blood in the urine (TB of the kidney)
– Headache/confusion (TB meningitis)
– Back pain (TB of the spine)
– Hoarseness (TB of the larynx)
– Disseminated (miliary) TB may have no localizing signs,
may present with anemia, or low platelets
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Lymph Node TB
Most common—35% of cases, king’s Evil or scrofula
Predisposing factors– age under 14 yrs, Female gender, Asian ethnicity,
HIV
Commonest presentation—cervical lymphadenopathy (scrofula)—post
cervical and supraclavicular
Other common sites– mediastinal, axillary, mesentric, perihepatic and
inguinal
Classical triad of multiplicity, matting and caseation, FNA– esp useful in
HIV patients, excision biopsy
Complications—fistulisation and rupture, compression of adjacent
structures, secondary bacterial infections and local extension of TB to
skin or other organs
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Pleuritis and Pleural Effusion
2nd most common site of EPTB, can occur as sequel of
primary infection or as a manifestation of TB reactivation
Rupture of sub-pleural focus into the pleural space with
inflammatory response
Symptoms: pleuritic chest pain, SOB, fever
HIV-infected more likely to have +smear/culture and
+pleural biopsy
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Pleural TB
Resolves spontaneously, however patient at high risk of
reactivation (40-65 %)
Complications– bronchopleural fistula, empyema and fibrothorax
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Biomarkers
Adenosine deaminase (ADA) level
Several meta- analyses show sensitivity of ADA is around 91% and
specificity 89%
– Similar performance in HIV infected
ADA ≥ 70 IU/L is highly suggestive of TB pleuritis
≤ 40 IU/L virtually rules out TB
ADA 2 is predominant isoform in TB pleural fluid—90 % of ADA activity,
ADA 1: ADA 2 ratio less than 0.45 is highly suggestive of TB
Interferon gamma—produced by CD4 T lymphocytes, high levels≥ 200 pG/L suggestive of TB
Lysozyme—Higher levels in TB than in other causes of exudative pleural
effusion
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CNS Tuberculosis
TBM—commonest and most severe form of TB in terms of
morbidity and mortality, represents a medical emergency
Cranial nerve palsies, focal neurological deficits, impairment of
consciousness and seizures
Hydrocephalus, cerebral vasculitis and infarctions, inflammatory
encasement of nerves and direct damage to cerebral parenchyma
Crucial to suspect the disease on a clinical basis and to promptly
introduce ATT with steroids
Intracranial Tuberculomas, Spinal Tuberculous Arachnoiditis
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Coronal T1-weighted gadolinium-enhanced magnetic resonance image demonstrates characteristic abnormal leptomeningeal enhancement (short, thick, white arrow), with intensely enhancing walls of both lateral ventricles (black arrows). High signal within the left frontal lobe represents an enhancing tuberculoma (thin white arrow). Entrapment of the left temporal horn (long, thick, white arrow) and midline shift to the right are due to the ventricular mass lesion.
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Pericardial Tuberculosis May result in acute pericarditis, chronic pericardial effusion, cardiac
temponade or pericardial constriction
Accounts for 2/3 rd of cases of constrictive pericarditis in India
Results from direct extension from mediastinal lymph nodes or
lymphohematogenous route from a focus elsewhere
Stages– dry, effusive, absortive and constrictive
May present with fever with no localisation
Cardiomegaly on CXR PA view may be the only clue
Low voltage and shifting axis on ECG
Echocardiography
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Characteristic Findings in Body Fluids in various forms
of EPTB Variable Pleural Fluid Pericardial Fluid CSF
Appearance Straw colored Straw colored or
serosanguinous
Clear early, turbid with
chronicity
pH 7.3-7.4, never more than 7.4 Not well described Not well described
Cell count
Total Count
Differential
1000-5000
50-90% lymphocytes, few
mesothelial cells
Not well described
Leucocyte count increased,
PMN preponderance early,
later mononuclear cells
predominate
100-500
PMN preponderance
early,Laterupto 95%
mononuclear
Protein Usually high
More than 2.5 g/dL
Usually high Ususally high(100-500
mg/dL), can be very high
with blockage or chronicity
Glucose Less than serum conc Low 50% of bld glucose
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Miliary TB
Miliary TB occurs when tubercle bacilli enter the bloodstream and are
carried to all parts of the body
Wide range of presentations
May include on one extreme ARDS and on the other extreme failure
to thrive without fever
Symptoms may be dominated by whatever organ system is primarily
involved
Typical patient has a febrile wasting syndrome of 2-4 months
duration
Fulminant disease esp in primary form—septic shock, ARDS and MOF
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Miliary Tuberculosis
Sputum smear is positive in about 25% of cases in both
HIV and non-HIV patients
In sputum smear negative miliary TB, bronchoscopy led to
an immediate diagnosis in 65% and this increased to 79%
with culture
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Bone TB
Pott’s spine-commonest site- thoracic spine and thoracolumbar junction
Occurs as a result of hematogenous transmission
Local pain, swelling and limitation of joint movement may precede
radiological changes by 4-8 wks
Structural damage to the skeleton may produce deformities and
compression of nerve roots and spinal cord
Affected bone may fracture and may produce spinal cord compression
Untreated TB may involve adjacent soft tissues and epidural space
Vertebral abscess may travel along psoas muscle- Psoas abscess
Extraspinal tuberculous osteomyelitis, Poncet’s
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Genitourinary Tuberculosis MTB reach kidneys, epidydimis or female genital organs via
hematogenous spread
Peak incidence in females of age 20-40 yrs
Risk factors– male gender, HIV infection, hemodialysis and ESRD,
recipients of renal transplant
Kidneys- most common site of GU TB
Renal TB—Symptoms—urinary frequency, urgency, dysuria and nocturia
Urine– classical triad of hematuria, proteinuria and sterile pyuria
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Urogenital Tuberculosis
Male genital tract TB—acute epidydymitis or
epidydmoorchitis-may cause caseation and fistula,
chronic prostatitis and extensive scarring of
epidydmus, ejaculatory ducts and seminal vesicles
leading to male infertility
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Female GU TB
May present with infertility, menstrual irregularities and chronic pelvic or
lower abdominal pain
Fallopian tubes—most commonly affected, followed by endometrium,
ovaries and cervix
Tubo-ovarian abscesses and adnexal masses mimicking ovarian cancer
mostly in presence of peritoneal involvement and when serum levels of
CA-25 marker are raised
Requires a high index of suspicion
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A 75-year-old woman with ureteric tuberculosis. (A) Retrograde pyelogram image demonstrates irregularity of the ureter and absence of contrast in the strictured distal portion (arrow). (B, C) Contrast-enhanced computed tomography image in the portal venous phase of the same patient demonstrates rightsided hydronephrosis (arrow, B) caused by stricturing and thickening of the distal ureter (arrow, C).
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A 30-year-old woman who presented with fever of unknown origin,later found to have tuberculous peritonitis and salpingitis. Contrast-enhanced computed tomography image in the portal venous phase demonstrates massive ascites (23 HU), diffuse peritoneal enhancement (black arrow), omental caking (thin white arrow), and nodular soft-tissue thickening (thick white arrow).
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Gastrointestinal TB
20-40 years age group
Slight female preponderance
Pain abdomen, abdominal distension, wt loss, diarrhea
constipation, bleeding P/R
Signs- anemia, malnutrition, abdominal
tenderness,ascitis,mass in right iliac fossa, intestinal
obstruction
Classic doughy abdomen– 5-10 %
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Peritoneal TB
Results often from the re-activation of latent peritoneal TB foci
Classical risk factors --HIV infection, cirrhosis and CAPD; diabetes
mellitus, underlying malignancy and therapy with anti-TNF agents
Ascitic fluid is exudative, with a SAAG ≤ 1.1 g/dl and leukocyte count
variable from 150 to 4000/mm3 with a lymphocytic predominance,
although neutrophyllic pleocytosis can be seen in cases undergoing
peritoneal dialysis
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investigations
Abdominal lymphadenopathy-retroperitoneal, peripancreatic, porta
hepatic and mesentric-on CT
Caseous lymph nodes appear as low attenuating necrotic centres with
thick enhancing inflammatory rim
Preferential thickening of medial caecal wall with exophytic mass
engulfing terminal ileum associated with massive lymphadenopathy—typical of TB
Short segments of mural thickening with normal intervening bowel
associated with ileo-caecal involvement
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Investigations
Colonoscopy- edematous, deformed ileocaecal valve
with both sides diseased, ulceration, girdle strictures
FNAC, Biopsy
Laproscopy—multiple yellowish white miliary nodules
over peritoneum, erythematous, thickened, hypremic
peritoneum
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TB of Adrenal Glands
5th most common site of EP TB, after the liver, spleen, kidneys, and bones
In 6% of patients with active TB and is nearly always b/L, The gland
becomes enlarged and demonstrates rim enhancement and central low
attenuation consistent with caseous necrosis.
Patients may present with an Addisonian-type clinical picture.
A 60-year-old woman with adrenal tuberculosis. Contrast enhanced computed tomography image in the portal venous phase demonstrates right adrenal enlargement, rim enhancement and central low attenuation
consistent with caseous necrosis (arrow).
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Cutaneous Tuberculosis
Lupus vulgaris
Scrofuloderma
Tuberculous verrucosa cutis
Tuberculids- erythema nodosum,
erythema induratum
Prosector’s warts
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Ocular Tuberculosis
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TNF alpha Inhibitor Associated Tuberculosis
Seen in patients with RA or Crohn’s disease after t/t
with TNF alpha inhibitors, especially infliximab
EPTB in 52-57 %
Patients should be screened for latent tuberculosis
infection or active disease before initiation of therapy with
a TNF-alpha inhibitor.
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Microscopy
Direct visualization of AFB-- the first microbiological test to be performed
ZN staining/ Kinyoun staining, low sensitivity
Light emitting diode (LED) technology --cheaper and viable alternative to
Ziehl–Neelsen microscopy and to fluorescence microscopy based on
mercury vapor or halogen lamps, 10%more sensitive, 1/4th time
In some cases, concentration of large volumes of sampled fluid(CSF,
ascites, etc.) and repeated analyses can increase the diagnostic yield
Microscopy, as well as culture, may be affected by the rapid mycobacterial
killing operated by some antibiotic agents like fluoroquinolones, resulting
in false-negative results
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IGRAs
based on the assessment of the IFN-g released after stimulation of
sensitized T-cells by highly MTB-specific antigens, including ESAT 6 and
CFP10,
two commercially available IGRAs: QuantiFERON-TBGold In Tube assay
(QIAGEN corp., Hilden, Germany), which utilizes an ELISA technique to
measure the amount of IFN-g secreted, and the T.SPOT-TB (Oxford
Immunotec, Abingdon,UK), which uses an ELI Spot assay to quantify the
number of IFN-g-producing cells
cannot distinguish between latent infection and active TB; therefore, they
are not suited to diagnose active TB.
Next generation tests--Dual cytokines-Interferon gamma and IL 2
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Culture
Most sensitive diagnostic test, with a lower limit of detection of 10 bacilli/mL of
sputum
Liquid culture --mainstay for the diagnosis of EPTB., BACTEC MGIT 960 based
on modified Middlebrook 7H9 Broth with an oxygen-sensitive fluorescent
detection technology , Capilia TB—rapid speciation strip test-MPB 64 antigen,
15 min
Solid cultures on the egg-based Lo¨wenstein–Jensen medium
advantages of liquid culture --sensitivity, identification of Mycobacterium
species and to perform phenotypic DSTs as well as genotyping
Main drawback is the time needed for mycobacteria to grow
Samples from biopsy or FNA may be submitted for analyses in incorrect
media (e.g., formalin) or insufficient volume,
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Immunohistochemistry & Immunocytochemistry
Can detect degraded AFB
Can detect different mycobacterial antigens in formalin
fixed paraffin embedded tissue, tissue aspirate and body
fluids e.g. BCG, MPT64, Antigen 5 (38kDa), LAM, ESAT6,
HspX, Tb8.4, and the phospholipase C encoding A (PlcA)
protein
Can be applied to extrapulmonary specimens
High sensitivity (70-100%) & high specificity (65-100%)
Performs equally well in HIV co-infected patient
Results within 1 day, insensitive to contamination
Disadv—invasive tissue sample collection and preparation
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Nucleic Acid Amplification Tests
The Xpert Mycobacterium tuberculosis/rifampicin (MTB/RIF) assay is the first
automated and standardised NAAT assay
results within two hours and performs a RT PCR in a platform that is polyvalent
Xpert had 88% sensitivity against all cases of tuberculosis, ranging from 98%
in smear-positive to 68% in smear-negative culture-positive cases and 98%
specificity
The sensitivity in people with HIV was 80% identifying 30% more cases than
smear microscopy
WHO reviewed about 20 relevant studies concerning the use of the Xpert
MTB/RIF system for the diagnosis of EPTB-- for lymph nodes sensitivity was
84.9% and specificity 92.5%, for gastric fluid 83.8 and 98.1% respectively, for
tissue 81.2 and 98.1%, respectively, and for CSF 79.5 and 98.6%, respectively.
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Gene Expert MTB/RF RIF-positive assays need to be confirmed by another
method.
Requires stable electricity, a backup system and space for
storage of cartridges at temp below 28°C
Initial diagnostic test in individuals suspected of having
MDR-TB infection, in HIV-associated TB and as a follow-up
test in patients with negative smear-microscopy in
settings where MDR-TB and HIV are infrequent
GeneXpert Omni—smaller, lighter,less expensive, 4 hr
battery
Xpert Ultra—next generation cartridge, will replace culture
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MODS Assay
High sensitivity -- 92% to 97.5%
An inverted microscope with automated reader software
is used to see cording
faster results (7-10 days)and is considerably cheaper than
liquid culture
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loop-mediated isothermal amplification (LAMP) assay
Results available within two hours, and sensitivity and specificity is said to
range from 88% to 100% and 94% to 99%, respectively
A multipurpose platform, the NATeasy, is being developed in China and
integrates NAAT in disposable, contamination-proof devices .
A joint initiative of the Indian government, academia and industry is
developing TrueLab, which is a multipurpose platform for real-time PCR. The
platform is hand-held and battery-operated and combines a simplified sample
preparation device
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Line Probe Assays
LPAs use multiplex PCR amplification and reverse
hybridisation to identify M. tuberculosis complex and
mutations to genes associated with rifampicin and
isoniazid resistance.
In culture isolates, LPAs can attain high sensitivity and
specificity to detect rifampicin (≥ 97% and ≥ 99%) and isoniazid resistance (≥90% and ≥99%) and provide results
in one to two days
MTBDR and Genotype MTBDR plus
NTM+MDRTB Detection Kit 2 (Nipro Corporation,
Japan) and GenoType® MTBDRplus V2 assay
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Serological Tests
very poor sensitivity or specificity, and that they have no
clinical value.
Indian Govt has banned them.
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Lipoarabinomannan-Based Assays
(LAM) is a cell envelope glycolipid released from metabolically active
mycobacteria that can be detected and quantified in urine
LAM is excreted more readily in patients with advanced HIV infection, and that
the assay could be a rule-in test for adults with disseminated tuberculosis
WHO recommends to use it for diagnosis in people with HIV with low CD 4
counts and those who are seriously ill, not to be used for screening
Determine TB LAM 20 minutes to perform
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GBD TB REaD™ POC (Enzymatic detection M.
tuberculosis β-lactamase reporter assay)
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Pipeline of molecular diagnostics for tuberculosis, by level of deployment (ie, reference, intermediate, and peripheral microscopy laboratories).
Madhukar Pai, and Marco Schito J Infect Dis. 2015;211:S21-S28
© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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Take Home Points
EPTB-Not uncommon, especially in HIV-infected persons
High index of suspicion, always include in D/D
Difficult to diagnose as it can mimic many diseases, is paucibacillary
and limited diagnostics in some countries
Respiratory isolation key until PTB ruled out
Treat it like you would pulmonary TB, except:
– Steroids in meningeal and pericardial disease
– Longer treatment in bone/joint TB, TB meningitis, disseminated TB
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