TB Intensive · 11/15/2011 1 TB Intensive San Antonio, Texas November 29-December 2 December 2,...

11/15/2011

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TB IntensiveSan Antonio, Texas

November 29 December 2 2011November 29-December 2, 2011

Pediatric TBAndrea Cruz, MD, MPH

December 2, 2011

Andrea Cruz, MD, MPH has thefollowing disclosures to make:

• No conflict of interests• No conflict of interests

• No relevant financial relationships with any commercial companies pertaining to this educational activityto this educational activity

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An Introduction to Childhood Tuberculosis

Andrea T Cruz MD/MPH

Pediatrics

Andrea T. Cruz, MD/MPH

Assistant Professor of Pediatrics

Sections of Emergency Medicine & Infectious Disease

Objectives

•To understand the definitions we use for childhood TB

•To know the common clinical and radiographic manifestations of childhood TB

•To understand the utility and limitations of available TB diagnostics

•To map out a plan of care (and know how to get

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To map out a plan of care (and know how to get help) for children with TB exposure, infection, and disease

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Population Distribution

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xxx00.#####.ppt 11/15/2011 1:02:20 PMPediatrics www.worldmapper.org

World map showing territory size as a proportion of the world’s population

Geography of TB

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World map showing territory size as a proportion of the world’s TB cases found there

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Famous People with TB

•JFK*

•Eleanor Roosevelt

•Bronte (x3)

•Fyodor Dostoyevsky

•Nelson Mandela

•Simon Bolivar

•King Tut

•Henry David Thoreau

•Ralph Waldo Emerson

•Franz Kafka

•John Keats

•Edgar Allan Poe*: possibly

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•Edgar Allan Poe

•R.L. Stevenson

•Frederic Chopin

www.dhss.delaware.gov/dph/dpc/tbfamouspeople

: possibly

National Epidemiology: 2010 Data

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MMWR 2011;60:333

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Texas Epidemiology

Harris County: •2005 – 379 cases•2005 – 379 cases•2006 – 402 cases •2007 – 394 cases•2008 – 398 cases•2009 – 396 cases•2010 – 341 cases

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http://www.dshs.state.tx.us/idcu/disease/tb/statistics

•4-5 times the average national incidence

Definitions we use for TB

Category Age Exam PPD/IGRA

CXR Contagious Treatment

Exposure < 5 ‐ ‐ ‐ Never 1 drug, usually for 2‐3 months (given by health department)

Infection All ‐ + ‐ Never Usually 1 drug, given 6‐9 months (given by family or health department)

Disease All ‐/+ +/‐ +/‐ Rarely Multiple drugs (3‐4), given 6‐12 months (always given by health

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months (always given by health department)

No patient with nontuberculous mycobacteria is contagious

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Childhood TB Disease Sites

Site* % of cases Median Age (years)

Pulmonary 77.5 6

Lymphatic 13.3 5

Pleural 3.1 16

Meningeal 1.9 2

Bone/joint 1.2 8

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Miliary 0.9 1

GU 0.8 16

Peritoneal 0.3 13*: United States (almost all are normal hosts)

Risk of Progression from TB Infection to Disease by Age

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Peds in Review 2010;31:13

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Signs and Symptoms of Pulmonary TB

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Available Diagnostic Tools

Tool Older

Generation

Newer

Generation

R di h CXR CT*Radiography CXR CT*

Immune response Skin test Interferon assay

Specimen collection

Gastric aspirates Induced sputa

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PCR Sputum Other body fluids

*CT is not the standard of care for the diagnosis of pulmonary TB, and is not necessary for the vast majority of children with pulmonary TB disease

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One difference between adults & kidsModality Adult

Studies*Pedi

Studies*∆ Ratio adult to

pediYear of 1st

publication

Culture: Solid

400 38 ‐362 11x 1967

Culture: Liquid

248 13 ‐235 19x 1966

MODS 37 7 ‐30 5x 2000

PPD/TST 6399 2031 ‐4368 3x 1907

IGRA 344 87 ‐257 4x 1999

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Xpert 7 1 ‐6 7x 2010

PCR, all 1831 187 ‐1644 10x 1990

*: PubMed Queries as of 7/27/11

CXR Findings in Pediatric TB

•Hilar or mediastinal adenopathy

•Segmental/lobar infiltrates

•Calcifications (seen in 75-80% of children with pulmonary TB)

•Miliary disease

•Pleural effusions

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15% of patients with TB disease will have normal CXRs

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Intrathoracic Lymphadenopathy

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N.O. 2008

Lobar Infiltrates

9mo M presents to TB clinic with 23mm PPD done after grandfather diagnosed with smear‐positive pulmonary TB. Baby is asymptomatic, normal vital signs, growing well.

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D.T. 2011

o a ta s g s, g o g eAdmitted for LP (normal), gastric aspirates (smear‐negative), started on multidrug therapy for TB disease

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Collapse/Consolidation Pattern

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Lymph node collapses a bronchus, leading to distal atelectasis M.A. 2009

Calcifications

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Usually indicates disease present for 2‐6 months W.C. 2005

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Cavitary Lesions

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W.C. 2005

Cavitary Lesions

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Uncommon in children, but if see cavities, treat the child as contagious and take appropriate infection control precautions M.N. 2007

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Cavitary Lesion

•16yo M with very poorly controlled IDDM

•2 months of productive cough, weight loss

• Smear-positive TB

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Int J Tuberc Lung Dis 2011;15:179

* DM is single most common predisposing medical condition in TX adults with TB disease

J.A. 2010

Miliary Disease

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P.K. 2008

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2003: 17yo WM with Crohn’s, on anti‐TNFα therapy, negative baseline TST, developed miliary TB after 2 months

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C.A. 2004

Miliary TB with Tension Pneumothorax

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D.M. 2008

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Miliary TB in Spleen, Liver

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D.M. 2008

Pleural Effusions

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Often, children are very well‐appearing (vs. Staph empyemas) J.G. 2007

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Tuberculomas

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At initiation of therapyAfter 2 months of therapy

W.C. 2005

Tuberculous Pericarditis

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Lymphadenopathy + Scrofuloderma

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Comparison: Nontuberculous Mycobacterial lymphadenopathy

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T.O. 2010A.J. 2009

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Cutaneous TB: Lupus vulgaris

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M.R. 2010

Skeletal TB

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Pott’s Disease

J.M. 1/2011. 3yo F with 1yr of worsening ‘hunchback’ (gibbous deformity). T5 destruction. Culture: M. bovis

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Clin Infect Dis 2005;41:515

Immune System Recognition

•Tuberculin skin tests (PPD)

•Interferon gamma release assays (IGRA)

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PPD Placement

No controls

Need to see a wheal raised

No controls

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Positive PPDs

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Generally, skin test conversion occurs within 2 months of contact

Measure only induration, and record millimeters of induration (never record “+” or “‐”)

Any induration seen only in the first 24 hours should be ignored

Induration after 72 hours counts; blistering also counts

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What is a Positive PPD?

•≥ 5 mm:‐HIV+ or other immunocompromise‐Contact with suspected source caseSuspected TB disease‐Suspected TB disease

•≥ 10 mm: ‐Immigrants from high-prevalence areas‐Children under 4 years of age‐Children exposed to adults in high-risk categories‐Other immunocompromising conditions

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•≥ 15 mm: ‐anyone, even without risk factors

2009 Red Book

Who does AAP Recommend Skin Testing? •Universal skin testing is NOT recommended•Initial PPD should be done before initiation of immunosuppressive therapy (including prolongedimmunosuppressive therapy (including prolonged steroid usage, TNF-α antagonists)

•Annual PPDs: HIV+ or incarcerated•Q2-3yr testing should be considered: high-risk•Immediate PPD should be placed:

‐As part of contact investigation

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p g‐CXR or clinical findings consistent with TB‐Children emigrating from endemic countries‐Children with travel history to or contact with persons from endemic countries

2009 Red Book

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Validated Questions to Determine LTBI Risk•Has a relative or contact had TB disease?

•Has a family member had a positive TB skin test?

•Was the child born in a high-risk country?

•Has your child traveled to a high-risk country for > 1 week?

•Should consider screening for risk factors at the

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Should consider screening for risk factors at the initial visit and every 6 months thereafter in first 2 years of life

Pediatrics 2001;107:e54; Red Book 2009

PPD Limitations

False positives:

•Exposure to mycobacteria other than TB

•Inter-observer variability

•Sliding scale for what is considered positive can beother than TB

•BCG vaccine

False negatives:

•Corticosteroid usage

Other immunocompromise

considered positive can be confusing

•Until very recently, lack of any confirmatory tests

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•Other immunocompromise

•Viral suppression: measles, mumps, influenza

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PPD: Myths surrounding BCG

•Myth: PPDs will be positive in all patients who received BCG vaccination

R lit 50% f i f t i i BCG d t t t ki‐Reality: 50% of infants receiving BCG do not react to skin tests, and most of the rest stop reacting within 5 years

•Myth: PPDs can be neither placed nor interpreted in BCG recipients

‐Reality: different cut-off points for the skin test are not

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y precommended based upon a child’s BCG status

So, What Are Alternatives?

•Since 2005: 2 commercially available blood tests, interferon gamma release assays (IGRA) that offer more specificity than the skin test

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IGRAs•Interferon-γ release assays (IGRAs) detect host response to Mycobacterium tuberculosis-specific antigens

•Two main tests currently FDA-approved:

‐T-SPOT.TB

Q tiFERON G ld I T b

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‐QuantiFERON Gold In-Tube

•Offer several potential advantages over the tuberculin skin test (TST)

MMWR 2010;59(No.RR‐5):1‐14

Comparison of Skin Test & IGRA

Characteristic TST IGRA

Antigens studied Many -PPD ESAT-6, CFP-10, (TB-7.7)

Cross-reactivity with BCG Yes Unlikely

Cross-reactivity with NTM Yes Less Likely

Estimated sensitivity, TB in immunocompetent adults

75-90% 75-95%

Estimated specificity, TB inimmunocompetent adults

70-95% 90-100%

Distinguish between TB infection No No

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Distinguish between TB infectionand TB disease

No No

Boosting Yes No

Patient visits required Two One

Pediatr Infect Dis J 2006;25:941

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IGRAs: Advantages

•One visit: optimal if adherence issues

•Decreased confusion about interpretation: one cut-off irrespective of age, immune status, and TB risk factors

•Enhanced specificity: optimal for BCG-immunized

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persons

IGRA: Limitations

•Indeterminate results: decrease the utility of a screening toolscreening tool

•One cut-off: is this appropriate across risk strata?

•Unknown dynamics of when assays become positive

•Discordance: interpretation if TST and IGRA provide different results

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•Limited pediatric data: especially for the most vulnerable risk groups

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Sensitivity plummets with CD4 < 200

HIV-infected Children

with CD4 < 200

Sensitivity: TSPOT > QFN > TST

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We don’t know the dynamics of IGRAs in HIV+ kids

No association with QFN result and CD4 (but n=14 with + TST)

Malnourished Children

•251 malnourished children, of whom 47% had helminthic infection (Ascaris, Trichuris)

•Test agreement: κ = 0.55 between TST and QuantiFERON

•25% had indeterminate test results

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•Degree of malnutrition and helminth infection were associated with indeterminate IGRA results

Pediatrics 2010;126:e1522

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Cancer Center Patients•34 newly diagnosed children with cancer (S. Africa)

•TST vs. T-SPOT vs. QuantiFERON

7 ere (+) ith an test (less than e pected)•7 were (+) with any test (less than expected)

•IGRAs had 12-15% indeterminate results

‐ In 1/5 of cases, TSPOT could not be completed because of low cell counts (controls failed)

•Multiple discordances:

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‐Between TST and both IGRAs

‐Between the IGRAs

Conclusion: no stand-alone test helpful in this population


Renal Patients

•Conversions and reversions of IGRAs seen

‐Conversions: 22% and 27% for QFN and T-SPOT

‐Reversions: 16% and 30% for QFN and T-SPOT

•Most studies suggest QFN is better for this group

•Indeterminate results range from 3-15%

•Results can be dramatically different if blood b i d di l i

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obtained pre- or post-dialysis

‐ IGRA should be done pre-dialysis

Transpl Infect Dis 2009;11:28 / J Infect 2010;61:144

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Diabetics

•Adult type II diabetics with culture-positive TB*TB

•QFN: 70% sensitive

•T-SPOT: 93% sensitive

•Seemed to perform as

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pwell as TST


* DM is single most common predisposing medical condition in TX adults with TB disease

TST preferred, IGRA acceptable

•Children < 5 years of age

IGRA preferred, TST acceptable

•BCG recipients

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MMWR 2010;59:RR‐5

p•Groups with historically low rates of return for TST reading

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Either IGRA or TST can be used

•Contact investigations

•Surveillance programs for healthcare workers

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MMWR 2010;59:RR‐5

Both TST and IGRA should be consideredI iti l IGRA i d t i t b d li•Initial IGRA indeterminate or borderline

•When initial test (TST or IGRA) is negative and:

‐There exists clinical suspicion for TB disease

‐Risk of infection, progression, and poor outcome higher

•When initial test (TST or IGRA) is positive and:

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•When initial test (TST or IGRA) is positive and:

‐Need additional evidence to increase compliance

‐Healthy persons with low risk for both infection and disease progression

MMWR 2010;59:RR‐5

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What to do with discordant results?

•In patients in whom disease is suspected or at high risk for progression from infection, treat if any test positivepositive

•For patients without risk factors, treat if the more specific test is positive

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Case: A.N. (2010)

•19mo M presents with fever, altered mentation. No medical history or known contacts with TB.

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Case: A.N. (2010)CSF Source

WBC RBC Protein Glucose Smear AFB Cx

EVD 15 17,315 58 35 ‐ ‐

•PPD: 0 mm

•QuantiFERON: indeterminate

•T-SPOT: ‘wicked positive’

LP 111 25 512 < 20 ‐ ‐

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T SPOT: wicked positive

•Mother’s (now former) boyfriend found to have pulmonary TB after contact investigation

Acid-Fast Culture Yield

Specimen Culture Yield

Sputum/gastric aspirate 30-40%

Lymphatic tissue 75%

Pleural fluid 20-40%

Cerebrospinal fluid 20-50%

Pericardial fluid 0-42%

Ascitic fluid 30%

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Skin biopsy 20-50%

Skeletal biopsy 75%

Paed Resp Rev 2007;8:107

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So, Our Culture Yield is Horrible; Now What?

•Great contact investigations to identify source g ycases for our patients (cultures by proxy)

•Try new methods of obtaining cultures

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•Try new methods of obtaining cultures

Gastric Aspirates

•Inpatient procedure

•Overnight fasting•Overnight fasting

•Lavage with NS if volume < 20cc

•Generally done qAM x3

•Inpatient costs substantial

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•AFB smear yield: minimal

•AFB Culture yield: 20-30%

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Induced Sputum

•Outpatient procedure•2-3h fasting periodg p•Pretreated with salmeterol; nebulized saline, then CPT given

•Nasopharynx suctioned

•One specimen sufficient

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•Minimal costs•AFB smear yield: 50%•AFB Culture yield: 25-30%

Lancet. 2005;365:130

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TB Infection Control

•In the mid-1990s, TCH began to require that adults and adolescents accompanying inpatient children with suspected tuberculosis undergo chest radiography to rule-p g g p yout infectious pulmonary TB

•A previous report from TCH [Muñoz et al. Infect Control Hosp Epidemiol 2002;23:568-572.] demonstrated that 15% of the adults accompanying hospitalized children with suspected tuberculosis had previously undiagnosed pulmonary TB

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pulmonary TB

•Results from this study also showed that no healthcare worker who cared for a child with tuberculosis became infected [conversion of the TST]

Infect Control Hosp Epidemiol 2002;23:568 and 2011;32:188

When do we worry about it?

•Older adolescents

•Children with certain findings on CXR

•Producing sputum

•Any draining skin lesions

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Infect Control Hosp Epidemiol 2011;32:188

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If we are worried, what do we do?

•N95 respirator for you

•Simple facemask (not N95) for patient

•Keep patient in room

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History of Drug-Resistant TB

Drug Year Introduced Year of 1st Documented Resistance

Streptomycin 1944 1948

Isoniazid 1952 1952

Pyrazinamide 1952 1964

Ethambutol 1960 1965

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Rifampin 1966 1968

Fluoroquinolones 1988 1992

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Total drugs to treat pan-susceptible TB

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Total drugs to treat 1 case of multidrug-resistant (MDR)* TB

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*MDR: resistant to at least INH and RifampinXDR (extensively drug‐resistant): MDR + resistance to fluoroquinolones + injectable agents

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DOTS (directly‐observed therapy, short‐course): administration of medications to persons with TB disease by dispassionate 3rd partySt d d f f TB di•Standard of care for TB disease in the United States

•Provided free of charge to patient•Removes some barriers to care•Increases adherence, thereby

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Photos courtesy of Manish Shah, MD

decreasing risk of selecting out for drug‐resistant organisms by sporadic medication usage

Treatment

TB•TB exposure

•TB infection

•TB disease

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TB Exposure

•Children < 5 years of age with a negative PPD, normal CXR and examination exposed to contact with suspected TBwith suspected TB

•Provide chemoprophylaxis in the window period (8-10 weeks) pending repeat skin testing

•Children > 4 yrs of age also need sequential skin

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Children > 4 yrs of age also need sequential skin testing, but no window chemoprophylaxis

Why Do We Do This?To Prevent This:

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E.Q. 2009

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Why do we treat TB infection?

•Risk of developing TB disease with untreated + PPD:

‐5-10% lifetime risk in most patients

‐40% risk in infants

‐5-10% annual risk in HIV-infected patients

•½ of lifetime risk in 1st 1-2 yrs after PPD conversion

•Remainder of risk evenly spread over lifetime

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Remainder of risk evenly spread over lifetime

•We can reduce risk by 90-95% with INH

Red Book Statement on TB Infection

•“All infants, children, and adolescents who have a positive PPD result but no evidence of TB disease and who have never received antituberculosis therapy should be considered for INH unless resistance to INH is suspected or a specific contraindication exists”

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Red Book 2009, p691

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How is LTBI different in children?

•Risk of disease progression

•Identifying time of infection

•Identification of source case

•Medication tolerance

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Medication tolerance

Risk of Progression to Disease, Stratified by Patient Age

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Pediatrics in Review 2010;31:13NEJM 2011;364:15

Risk of disease progression in adults: 1‐13% lifetime risk

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Pinpointing time of infection

•Most young children are by definition ‘new’ converters

•So, this is best opportunity to prevent future disease:

‐½ of lifetime risk is in first 1-2 years after TST conversion

‐Risk substantively higher for infants

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•Children have circumscribed social networks•Often the person who infected the child is a caregiver/relative•Easier to identify source case, and child is unlikely to have > 1 source case

NEJM 2011;364:730

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Medication Tolerance•Pediatrics:

‐5% risk of side effects in children•Most minor – abdominal pain without elevation in LFTs

‐3 3% risk of elevated LFTs in 1970s with INH+RIF‐3.3% risk of elevated LFTs in 1970s with INH+RIF

•Adults:

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Pediatrics 2006;117:e148; Pediatrics 1983;72:491

NEJM 2011;364:15IJTLD 2010;14:1374

•Take home messages:

‐educate families on side effects

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‐ low threshold for checking LFTs if symptomatic

‐screen for LTBI judiciously

Pediatrics 2008;121:e1732

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TB Prevention

•Isoniazid (INH) = mainstay of therapy

‐10-15 mg/kg single daily dose if given by family

‐20-30 mg/kg twice weekly if given by health department

‐Duration: 9 months

•Alternative: rifampin x 6 months

‐ If person around child with TB is known to have INH-resistant

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pdisease or if child is INH-intolerant

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LTBI Treatment Pearls•Use INH suspension only in children < 5 kg

‐Otherwise, give tablets that can be crushed & mixed with food

•Compliance with 9 months of INH averages a bit over 50%; p g ;be skeptical

•Use health department to administer medications to high-risk patients: infants, immunocompromised children, recent contacts

•When children aren’t tolerating INH, the problem is more often with the parent than the child

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p

•Routine LFTs not indicated unless: concomitant administration of other hepatotoxic drugs; pre-existing liver disease; or signs/symptoms of hepatitis

Therapy for TB Disease•Start 4-drug therapy (a change from 2006 Red Book)

‐INH, rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB); INH/RIF are the backbone of therapy

•Use PZA only during 1st 2 months for susceptible TB

‐This is your ‘shortening agent’: consolidate from 9 to 6 months of therapy

•Stop EMB once culture results known, if have pan-susceptible TB

‐This is your insurance in case you have drug-resistant TB

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•Anticipate minimum 6 month therapy, and we often extend it to longer periods, especially for extrapulmonary disease

•Always administered by directly observed therapy (DOT)

2009 Red Book

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Notes on TB DrugsDrug Side Effects Other notes

INH Peripheral neuropathy; seizures in B6 helps prevent neuropathy and is p p yoverdose

p p p yonly treatment for INH seizures, but doesn’t prevent hepatotoxicity

RIF Orange discoloration of secretions; inactivates oral contraceptives; many drug interactions

Please warn of Longhorn‐orange urine!

PZA Can increase uric acid gout symptoms; rash

Of 1st‐line drugs, greatest association with hepatotoxicity

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EMB Optic neuritis, red‐green color blindness

Despite side effects, has very poor CNS penetrance and not used for meningitis

*All primarily hepatically metabolized, except EMB, which is also renally excreted


Conclusions

•Screen all children for TB risk factors via questionnaire•Traditional culture techniques are of much lower yield in

hild d ith d ltchildren as compared with adults•Newer diagnostic assays have recently become available, but are not without their own limitations

•IGRAs offer improved specificity, not sensitivity, compared to PPDs

•There is no substitute for a comprehensive history to elicit TB risk factors

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TB risk factors•It is impossible to effectively manage childhood TB without close cooperation with an effective public health infrastructure

TB Intensive · 11/15/2011 1 TB Intensive San Antonio, Texas November 29-December 2 December 2,...

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Transcript of TB Intensive · 11/15/2011 1 TB Intensive San Antonio, Texas November 29-December 2 December 2,...