Tuberculosis in Pediatrics - Duke UniversityThe tuberculin skin test is unreliable in school...
Transcript of Tuberculosis in Pediatrics - Duke UniversityThe tuberculin skin test is unreliable in school...
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13 June 2017Tony Moody MD
Duke Pediatric Infectious Diseases
Tuberculosisin Pediatrics
Image from the National Library of Medicine, “Profiles in Science” Collection.
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Disclosures
• Advisory board member for GSK (for belimumab pregnancy registry).
• Co-founder of Grid Therapeutics (formerly Cue Biologics).
• Chief Medical Officer, DHVI.
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Learning Objectives
• Choose appropriate diagnostic tests for suspected MTB disease.
• Apply proper techniques for application and reading of TSTs.
• Compare the utility of TSTs, IGRAs, and other tests.
• Use proper dosing of anti-tuberculosis drugs in pediatric patients.
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Image from the National Library of Medicine, “Profiles
in Science” Collection.
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Tuberculosis
first disease declaredGlobal Health Emergencyby WHO (1993)
estimated ⅓ of humans infected
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Image courtesy of the World Health Organization Global Health Observatory Map Gallery
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Image taken from the World Health Organization Global Tuberculosis Report 2015
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Image courtesy of the World Health Organization Global Health Observatory Map Gallery
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Image taken from the World Health Organization Global Tuberculosis Report 2015
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Image courtesy of the World Health Organization Global Health Observatory Map Gallery
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Image courtesy of the World Health Organization Global Health Observatory Map Gallery
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Tuberculosis
tuberculosis ndisease caused by
MTB complex organisms
derived fromthe Latin tuberculum (swelling) +the Greek -ωσις (condition)
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Image courtesy of
the Clendening History of Medicine Library,
University of Kansas Medical Center
Identification of
Mycobacterium DNA
in an Egyptian
Pott’s disease of
5 400 years old.
Crubézy É, Ludes B, Poveda J-D, Clayton J,
Crouau-Roy B, Montagnon D.
C R Acad Sci Paris, Life Sciences 321: 941-951 (1998).
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Tuberculosis
consumption
wasting illness
Pott’s disease
spinal osteomyelitis
King’s evil
scrofula / lymphadenitis
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Images courtesy of the Clendening History of Medicine Library, University of Kansas Medical Center
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Tuberculosis: Etiology?
cause
• hereditary
• punishment for sin
• bad air
• vampires
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Tuberculosis: Etiology?
cause cure
• hereditary evolve / you’re
screwed
• punishment for sin redemption
• bad air move
• vampires wooden stake
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Tuberculosis Complex
Mycobacterium bovis
Mycobacterium canetti
Mycobacterium microti
Mycobacterium tuberculosis
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Tuberculosis Complex
● fossils showing animal disease
● evidence of M bovis increase8000-4000 BCE
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Hieronymus Fracastorius(Girolamo Fracastoro)(1478-1553)
De contagione etde contagiosis morbiset curatione
1546 treatise
130 years beforeLeeuwenhoek firstsaw microorganisms
Image courtesy ofthe Clendening History of Medicine Library,
University of Kansas Medical Center
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Sylvius(Franciscus de le Boe)
defined tubercules,tuberculous cavities
Image courtesy ofthe Clendening History of Medicine Library,
University of Kansas Medical Center
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Heinrich Hermann Robert Koch (1843-1910)
1882: identifiedM tuberculosis,
established MTB role incause of tuberculosis
Image courtesy ofthe Clendening History of Medicine Library,
University of Kansas Medical Center
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MTB
Aerobicnon-spore-formingnon-motilebacillus
On Gram stain, weakly GP or ghosts
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MTB
Mycolic acidsvery long chain fatty acidswaxy surface
provide protection from hazards
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MTB
Cordingin liquid culture TB orient parallel
MOTT orient randomly
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MTB
Acid-fast
decolorization step done withacid-alcohol
bacilli retain stain
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MTB
For initial stains most labs use a fluorescent stain
auramine-rhodamine
KMnO4 counterstain
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MTB
Requires special media for culture
Middlebrook 7H11
Löwenstein-Jensen
BACTEC
MGIT
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MTB
MTB very slow growing
average replication time15-20 hours
E coli replicates in about 20 minutes
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MTB
Starting with one bacterium in ideal conditions
MTB E coli
1 hour 1 4-8
1 day 2 2.3 x 1021
1 week 1024 2.6 x 10151
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MTB—Clinical
Primary TB (childhood)
mid lung zonesregional lymphadenitispleurisy with effusionpersistent cough illnessrisk of hematogenous spread
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MTB—Clinical
Primary TB (childhood)
can look like anything
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MTB—Clinical
high risk of dissemination
miliary tuberculosis
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image obtained from Wikipedia
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image obtained from http://www.granuloma.homestead.com/index.html
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MTB—Clinical
high risk of dissemination
cerebral tuberculosis
insidious
difficult to diagnose
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MTB—Clinical
high risk of dissemination
cerebral tuberculosis
LP in any child < 3yo
LP if headache / signs
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MTB—Clinical
• How often is disease recurrent vs. reinfection?
• How risky are biologics?
• Why is there a summer peak in Dx?
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ResultRecurrence mostcommon in first year,reinfection morecommon thereafter.
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ResultMycobacterial OIsare the mostassociated; fungalsecond.
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CohortResidents of a Peruvianshantytown
MeasuresVitamin D, TST, IGRA
ResultsInfections occur duringwinter months, but symptomsdon’t appear until the summer
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MTB—Testing
the gold standard
biopsy / specimen with culture
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MTB—Testing
PPD (purified protein derivative)
Mantoux test
must be placed intradermal
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Clemens Peter von Pirquet(1874-1929)
developed one ofthe first non-culturetests for TB
tuberculin applied tosuperficial abrasionon arm
Image courtesy ofthe Clendening History of Medicine Library,
University of Kansas Medical Center
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image courtesy of the Public Health Image Library of the CDC
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Tuberculosis
Pirquet test
Moro test
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Tuberculosis
Calmette-Wolff-Eisner test
Mendel-Mantoux test
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Felix Mendel (1862-1925)
Zur endevenöse Applikation der MedikamenteII. Die kombinirte Arsen-Tuberkulinbehandlung
Therapeutische Monatshefte, Berlin 17: 177-188 (1903)
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Charles Mantoux (1877-1947)
Comptes rendus de l’Académie des Sciences, Paris147: 355-357 (1908)
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MTB—Testing
PPD (purified protein derivative)
Mantoux test
must be placed intradermal
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image courtesy of the CDC
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MTB—Testing
PPD
read 48-72 hours after placement
can be read up to 1 week later with accuracy
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image courtesy of the Public Health Image Library of the CDC
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MTB—Testing
PPD
erythema is meaningless
induration is the key
Sokol method (ball-point pen)
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Problems with TST
• requires specialized trainingfor both placement and reading
• requires two provider visits
• false positives and negatives
• vaccine confounding
• booster phenomenon
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Problems with TST
• requires specialized trainingfor both placement and reading
• requires two provider visits
• false positives and negatives
• vaccine confounding
• booster phenomenon
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Tuberculin Skin Testing in Patients withHIV Infection: Limited Benefit of ReducedCutoff Values.Cobelens FG, Egwaga SM, van Ginkel T, Muwinge H, Matee MI, Borgdorff MW.Clin Infect Dis 43: 634-639 (2006).
result
Adult study.
Lower cutoff doesn’t capturemany more.
Seems to be an all or nothingphenomenon.
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Problems with TST
• requires specialized trainingfor both placement and reading
• requires two provider visits
• false positives and negatives
• vaccine confounding
• booster phenomenon
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The tuberculin skin test is unreliable inschool children BCG-vaccinated in infancyand at low risk of tuberculosis infection.Jacobs S, Warman A, Richardson R, Yacoub W, Lau A, Whittaker D, Cockburn S, Verma G,
Boffa J, Tyrrell G, Kunimoto D, Manfreda J, Langlois-Klassen D, Long R.Pediatr Infect Dis J 30: 754-758 (2011).
result
Canadian study. BCG-vaccinated children more likely to have apositive TST.
Concludes test unreliable in 6-12 yo children.
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Problems with TST
• requires specialized trainingfor both placement and reading
• requires two provider visits
• false positives and negatives
• vaccine confounding
• booster phenomenon
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Enhancing of Tuberculin Allergy byPrevious Tuberculin Testing
Narain R, Nair SS, Rao GR, Chandrasekhar P, Lal P.Bull Wld Hlth Org 34: 623-635 (1966).
cohorteight villages in India
resultthose with mild reactions,8-13 mm initially, had themost increases withboosting
testingTST using 1 TUon upper ⅓ of L forearm
some given 20 TU tests
2 mo laterTST w/ 1 TUon middle ⅓ of R forearm
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The Booster Effect in Two-StepTuberculin Testing amongYoung Adults in MontrealMenzies R, Vissandjee B, Rocher I, St. Germain Y.Ann Int Med 120: 190-198 (1994).
resultboosting seen in both BCG-V +ve and –ve groups
greater effect in BCG-V gp
correlation w/ age at BCG-V
most boosters reactive to PPD-B(I)
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Boosting
• CDC recommends two-step testingfor HCW at first screen
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Desirable Properties
• no special training
• single encounter
• reduced false positives and negatives
• distinguish between MTB and other mycobacteria
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IGRA
Interferon-Gamma Release Assay
• reduced cross-reactivity• lab-based test / quantitative answer• single patient contact• no boosting
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BOVIGAM
• testing of cattle
• licensed inAustralia & New Zealand
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Y
antigen
YYYγ γ
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Evaluation of the Tuberculin GammaInterferon Assay: Potential toReplace the Mantoux Skin TestPottumarthy S, Morris AJ, Harrison AC, Wells VC.J Clin Microbiol 37: 3229-3232 (1999).
cohortimmigrants, HCW, patients
result64-89% concordance71% +ve w/ smear +ve TB (Mantoux slightly better)
testingQuantiFERON usingPPDs for MTB, M bovis,M avium
TST
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humans are to chimpanzees
as
M tuberculosis is to M bovis
>98% genetic identity
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differences betweenM bovis and BCG
RD1 (region of difference)
encodes for ESAT-6 & CFP10
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IGRA
• relies on response to RD1 antigens
• can be negative in disease
• increasing studies in pediatrics
• multiple forms (ELISA, ELISpot)
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Performance of whole blood IFN-gtest for tuberculosis diagnosis basedon PPD or the specific antigensESAT-6 and CFP-10Brock I, Munk ME, Kok-Jensen A, Andersen P.Int J Tuberc Lung Dis 5: 462-467 (2001).
cohorthealthy volunteersknown TB +ve patients
result78% sensitive100% specific in non-BCG, 89% in BCG-V
testingQuantiFERON usingPPDs for MTB, M avium,ESAT-6, CFP-10
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Whole blood interferon-γ release assay is auseful tool for the diagnosis of tuberculosisinfection particularly among Bacille CalmetteGuèrin-vaccinated children.Tsolia MN, Mavrikou M, Critselis E, Papadopoulos NG, Makrinioti H, Spyridis NP, Metsou F,
Tsagaraki M, Koulouri M, Kafetzis DA.Pediatr Infect Dis J 29: 1137-1140 (2010).
result
High rates of concordance between TST and IGRA in non-vaccinatedchildren.
IGRA more predictive in BCG-vaccinated children.
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ResultIGRA reasonablyaccurate in Dx ofTB disease.
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Impact of targeted testing for latenttuberculosis infection using commerciallyavailable diagnostics.Mancuso JD, Tribble D, Mazurek GH, Li Y, Olsen C, Aronson NE, Geiter L, Goodwin D,
Keep LW.Clin Infect Dis 53: 234-244 (2011).
result
Testing in low incidencepopulations gives poorresults.
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result
In low risk college students,TST better than IGRA;for high risk, they arethe same.
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Other Diagnostic Options
• In-house PCR tests
• Xpert MTB/RIF
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ResultTB Xpert on NP aspirates perhaps useful, esp if induced sputum impractical. (Gastric aspirates better.)
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ResultVery small numbers, but results from stool and GA testing similar.
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What about vaccine?
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Edmond Isidore Etienne Nocard (1850-1903)
isolated virulentM bovis strain →‘lait Nocard’
1901: transferred strainto Institut Pasteur
Image obtained viaen.wikipedia.org
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Jean-Marie Camille Guérin(1872-1961)
student of Nocard
joined Institut Pasteurin 1897 under Calmette
together with Calmetteattenuated M bovis
Image obtained viaen.wikipedia.org
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Léon Charles Albert Calmette(1863-1933)
1908-1919: serial passageof ‘lait Nocard’ onglycerinated bile potatomedium (230 x)
continued attenuationfrom 1919-1929
Image courtesy ofthe Clendening History of Medicine Library,
University of Kansas Medical Center
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BCG Genealogy
BCG widely distributed (1924-1926)34 nations
1927: 26 other nations given BCG
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BCG Genealogy
BCG Moreau (Brazil)
BCG Tokyo (strain 172)
BCG Danish (2 transfers) (1331)
BCG Tice (BLP)
BCG Pasteur (1173P)
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BCG and vole bacillus vaccines in theprevention of tuberculosis inadolescence and early adult lifeFourth report to the Medical Research Council by its Tuberculosis VaccinesClinical Trials Committee.Medical Research Council. Bull WHO 46: 371-385 (1972).
BCG and vole bacillus vaccines in theprevention of tuberculosis inadolescence and early adult lifeFinal report to the Medical Research Council.Hart PD, Sutherland I. Br Med J 2: 293-295 (1977).
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BCG: World Experience
● > 2.5 billion immunizations
● given routinely to infants
● can be given PO
● quite heat stable
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ResultOverall case number notchanged, disseminatedcases reduced.
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ResultBCG given to LBW infantsreduced all-cause mortality.
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ResultBCG responses reducedin both HIV infection andHIV exposure.
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Image from the National Library of Medicine, “Profiles in Science”
Collection.
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MTB—Treatment
Isolation
MTB aerosolized into fine droplets
light enough to be suspended
air in room is infectious
1 cough = 5 min talking
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MTB—Treatment
Isolation
negative pressure room
N95 masks / PAPRs
Family should be isolated until tested
must wear masks outside of room
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MTB—Treatment
Isolation and drugs
streptomycin amikacin
isoniazid quinolones
pyrazinamide
rifampin
ethambutol
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MTB—Treatment
isoniazid
nicotinamide analog
primarily active against MTB
hepatic toxicity
neurotoxicity (slow-acetylators)prevented by giving pyridoxine
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MTB—Treatment
pyrazinamide
nicotinamide analog
good CNS penetration
hepatic toxicity(compounded by INH)
reduces uric acid excretion
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MTB—Treatment
rifampin
inhibits DNA-dependentRNA polymerase
dye
enhances metabolism ofsome drugs
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MTB—Treatment
ethambutol
bacteriostatic
affects mycobacterial cell wall
optic neuritis(needs careful monitoring
in children)
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MTB—Treatment
streptomycin
still an excellent drug
only available as an IM preparation
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MTB—Treatment
Drug Pediatric Dose Adult Dose Daily Maximum
Isoniazid 10 mg/kg(10-15)
5 mg/kg(4-6)
300 mg
Rifampin 15 mg/kg(10-20)
10 mg/kg(8-12)
600 mg
Pyrazinamide 35 mg/kg(30-40)
25 mg/kg(20-30)
—
Ethambutol 20 mg/kg(15-25)
15 mg/kg(15-20)
—
Streptomycin — 15 mg/kg(12-18)
1000 mg
Recommendations from the World Health Organization.
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Increasing adherence for latent tuberculosisinfection therapy with health department–administered therapy.Cruz AT, Starke JR.Pediatr Infect Dis J 31: 193-195 (2012).
result
Looked at multiple variables related to therapy completion.
Only variable associated was health department DOT(>90% completed vs. 50% for self administered; OR 7.7).
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Unexplained deterioration duringantituberculous therapy in children andadolescents: clinical presentation and risk factors.Thampi N, Stephens D, Rea E, Kitai I.Pediatr Infect Dis J 31: 129-133 (2012).
result
Canadian case series.
Some children deteriorated during therapy; hard to distinguishfrom clinical failure.
Corticosteroids seemed to help a subset.
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result
In children with Sx referable to TB (cough, wheeze, FTT) symptomstook ≥60 days to resolve on appropriate Tx.
Do not use response to Tx as proof of Dx.
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Image from the Library of Congress, WPA Posters
Collection.