TB Intensive :: Childhood Tuberculosis :: San Antonio, TX :: … · 11/24/2015 1 EXCELLENCE EXPERTISE INNOVATION Childhood Tuberculosis Andrea T. Cruz, MD, MPH November 19, 2015 Tuberculosis

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EXCELLENCE EXPERTISE INNOVATION

ChildhoodTuberculosisAndreaT.Cruz,MD,MPHNovember19,2015

Tuberculosis IntensiveNovember 17‐20, 2015

San Antonio, TX

• No conflict of interests

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

AndreaT.Cruz,MD,MPHhasthefollowingdisclosurestomake:

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Pediatrics

Childhood Tuberculosis

Andrea T. Cruz, MD/MPH

Associate Professor of Pediatrics

Sections of Infectious Diseases & Emergency Medicine

November 19, 2015

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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 help) for children with TB exposure, infection, and disease

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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 department)

No patient with nontuberculous mycobacteria is contagious

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xxx00.#####.ppt 11/24/2015 5:07:45 PMPediatrics 2014: http://www.who.int/tb/publications/global_report/en/

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MDR: resistant to at least INH and rifampicin

2014: http://www.who.int/tb/publications/global_report/en/

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MMWR 2014;64:265

US TB Epidemiology: 2014

•9412 cases

•3/100,000

•67% in the foreign-born

•Compared to whites:

‐Asians: 29x higher

‐Hispanics, Blacks: 8x higher

•4 states (CA, FL, TX, NY): 50% of US cases

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xxx00.#####.ppt 11/24/2015 5:07:46 PMPediatrics 9November 24, 2015 Baylor College of Medicine

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xxx00.#####.ppt 11/24/2015 5:07:46 PMPediatrics MMWR 2013;62:201

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

TB Epidemiology: Texas (1269 in ’14)

Harris County: •2009 – 393 cases•2010 – 339 cases•2011 – 318 cases•2012 – 267 cases•2013 – 287 cases•2014 – 320 cases

•4-5 times the average national incidence

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TB Risk Factors, Texas

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TB Disease

Adult TB Disease Pediatric TB Disease

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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

Miliary 0.9 1

GU 0.8 16

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

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Risk of Progression from TB Infection to Disease by Age

Peds in Review 2010;31:13

Age at infection (y) No disease (%) Pulmonary TB(%)

CNS TB (%)

<1 50 30‐40 10‐20

1‐2 75‐80 10‐20 2.5

2‐5 95 5 0.5

5‐10 98 2 <0.5

>10 80‐90 10‐20 <0.5

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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

15% of patients with TB disease will have normal CXRs

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Intrathoracic Lymphadenopathy

N.O. 2008

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Lobar Infiltrates

D.T. 2011

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. Admitted for LP (normal), gastric aspirates (smear‐negative), started on multidrug therapy for TB disease

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Collapse/Consolidation Pattern

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

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Calcifications

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

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Isolated Calcification

•Calcifications <2cm in diameter can be treated the same way as a normal CXR

•Represent old granulomatous disease, not active disease

Red Book 2012

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Cavitary Lesions

W.C. 2005

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Cavitary Lesions

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

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

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Miliary Disease

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

C.A. 2004

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Miliary TB with Tension Pneumothorax

D.M. 2008

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Miliary TB in Spleen, Liver

D.M. 2008

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Pleural Effusions

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

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Tuberculomas

At initiation of therapyAfter 2 months of therapy

W.C. 2005

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Tuberculous Pericarditis

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Lymphadenopathy + Scrofuloderma

Paed Resp Rev 2007;8:107

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Initial Presentation

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Pre/Immediately post drainage

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Comparison: Nontuberculous Mycobacterial lymphadenopathy

T.O. 2010A.J. 2009

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Cutaneous TB: Lupus vulgaris

M.R. 2010

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Skeletal TB

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Pott’s Disease

Clin Infect Dis 2005;41:515

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

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Immune System Recognition

•Tuberculin skin tests (PPD)

•Interferon gamma release assays (IGRA)

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Positive PPDs

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?

2012 Red Book

≥ 5mm ≥ 10mm ≥15mm

HIV‐infected Children < 4 years of age Anyone, even without risk factors

Contact to a TB case Children exposed to high‐risk adults†

Child in whom you suspect TB disease

Immigrants from high‐prevalence regions*

Children with diabetes or other immunocompromising conditions

† HIV‐infected, incarcerated, IV drug use*Low prevalence regions: US, Canada, Scandinavia, Western Europe, Australia, New Zealand

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PPD Limitations

False positives:

•Exposure to mycobacteria other than TB

•BCG vaccine

False negatives:

•Corticosteroid usage

•Other immunocompromise

•Viral suppression: measles, mumps, influenza

•Inter-observer variability

•Sliding scale for what is considered positive can be confusing

•Until very recently, lack of any confirmatory tests

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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

‐QuantiFERON Gold In-Tube

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

MMWR 2010;59(No.RR‐5):1‐14

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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 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 persons

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IGRA: Limitations

•Indeterminate results: decrease the utility of a screening 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

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

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TB Risk Questionnaire

positive?

Age < 5 years?

BCG Vaccinated?

Screening Complete

TST Preferred

IGRA Preferred

TST or IGRA Acceptable

No

No

Yes

No

Yes

Yes

Algorithm for TB Testing in Children

Consider•Cost•Confidence in test •Ability to return

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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 positive

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

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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%

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 cases for our patients (cultures by proxy)

•Try new methods of obtaining cultures

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Gastric Aspirates

•Inpatient procedure

•Overnight fasting

•Lavage with NS if volume < 20cc

•Generally done qAM x3

•Inpatient costs substantial

•AFB smear yield: minimal

•AFB Culture yield: 20-30%

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Induced Sputum

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

•Nasopharynx suctioned

•One specimen sufficient•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-out 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

•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

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When do we worry about it?

•Older adolescents

•Children with certain findings on CXR

•Producing sputum

•Any draining skin lesions

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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Treatment

•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 TB

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

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

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Why Do We Do This?To Prevent This:

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

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

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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”

Red Book 2009, p691

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Treatment: LTBIRegimen Pros Cons

INH x9m ~20% benefit over INHx 6m

Adherence (<50% completion)

INH x 6m Adherence better than 9m

Slightly reduced benefit compared with 9m (assuming both taken as indicated)

RIF x 4m Adherence, availability Cost if uninsured; drug interactions

INH/Rifapentine x 12 doses

Adherence Availability; requirement for DOPT

INH/RIF x 3-4m Adherence Slightly increased risk of side effects compared to monotherapy

RIF/PZA x 2m Adherence Hepatotoxicity; recommended for patients initially suspected of having disease

Curr Opin Pediatr 2014;26:106

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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%; 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

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

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Notes on TB DrugsDrug Side Effects Other notes

INH Peripheral neuropathy; seizures in overdose

B6 helps prevent neuropathy and is only 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

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

Peds in Review 2010;31:13

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CNS PenetranceDrug CNS Penetrance

Isoniazid Good

Rifampin Inflamed meninges only

Pyrazinamide Good

Ethambutol Inflamed meninges only

Ethionamide Good

Aminoglycosides Inflamed meninges only

Fluoroquinolones Good except for ciprofloxacin

My routine empiric treatment of TB meningitis (in addition to steroids):• Inpatient: INH, RIF, PZA, amikacin• Outpatient: INH, RIF, PZA, ethionamide (need to transition kids to this

while they are still hospitalized to make sure they don’t start vomiting with addition of ethionamide)

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Expected Clinical Course for TB Disease in ChildrenSite Course

Pulmonary TB (parenchymal) 60‐70% abnormal CXR at conclusion of therapy

Intrathoracic adenopathy Takes > 1 year to resolve radiographically in many cases

Cervical lymphadenitis Often paradoxically worsen with onset of therapy; can see spontaneous fistulae formation. Resolution over months

TB meningitis Inflammation and symptoms often increase initially with therapy (hence use of systemic corticosteroids)

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Monitoring on Treatment

•Risk of drug toxicity very low

•Monitor clinically, as opposed to with laboratories

•Monitor/reinforce adherence

•Pulmonary TB and getting CXRs:

‐Baseline

‐At 2 months (before stopping EMB/PZA)

‐At end of therapy (if 2m CXR still abnormal)

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Ethambutol in Children

Adults:

•Risk of optic neuritis:‐Visual acuity

‐Color perception

‐Dose related

‐Usually reversible

‐Risk around 1-3% in adults

Children:

•Metabolize EMB far faster than adults

‐Need higher mg/kg dose to achieve same serum levels

•Risk of optic neuritis far less than for adults

•There is no child too young to get EMB

•Can use even in the pre-verbal child

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Ethambutol in Children

SM Graham. Arch Dis Child 1998;79:274‐278.

Age # Method of evaluation Length of f/u (months)

# with toxicity

3‐13y 47 Visual evoked responses 15‐18 0

4m‐16y 36 Acuity/field/color perception 24‐48 0

1‐15y 45 Acuity/field/color perception 9‐18 0

4‐5y 30 Acuity/field/color perception 6 0

5‐15y 27 Acuity/field/color perception 12‐36 0

9‐16y 6 Computerized visual field examination 9 0

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Fluoroquinolones in Children

•Initial clinical trials in children: not done

•Data from off-label use: cystic fibrosis, UTI, shigellosis, TB

•Most consider safe in children

‐Germany study, 1997: 2030 children treated, 1.5% had self-resolving arthralgia

•Consider risk/benefit:

‐Clearly beneficial for MDR-TB

‐Monitor for joint/tendon problems

Hampel et al. Pediatr Infect Dis J 1997;16:127

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Pediatrics

Pediatric TB Cases

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Lymphadenopathy

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Clinical CaseCervical Lymphadenopathy

•8 yr old with cervical lymphadenopathy

•History:• LAN for 3 months•PMHx: Healthy

• BCG vaccine at birth•TB skin test 10 mm

•Physical Exam:• 3 cm anterior cervical LAN•1.5 cm supraclavicular lymphadenopathy

•CXR:•Hilar LAN, no infiltrates

•Is this TB disease?•What else could it be?

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Hilar & Cervical Lymphadenopathy

•Differential Dx•Tuberculosis•Non TB mycobacteria (NTM)•Lymphoma/Leukemia•HIV•Other causes

•Diagnostic tests•Biopsy (FNA or surgical for culture and path)

•Interferon blood test for TB infection

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Results

•Fine needle aspirate of node:•Pathology: lymphoma, no TB by culture or microscopy

•Interferon Blood test for TB•Positive•Diagnostic for latent TB infection or disease

•Diagnoses:•LTBI• AND•Hodgkin’s Lymphoma

•Treatment:•Chemotherapy for lymphoma AND•INH daily for 9 months for LTBI

• consider prolonged treatment during immunosuppression

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Skin Test in Foreign Born

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Skin Test in Foreign Born

•6-year-old with positive TST for school entry

•Born in Taiwan

•BCG documented on vaccination records at birth and BCG scar present

•TST measures 12mm

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CXR normal

•How do you interpret the 12 mm skin test?

•Is this BCG effect or LTBI?

•Are there any other tests that may help?

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TB in Newborn Nursery

Pediatrics

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New Mother with Positive TST

•Newborn infant in hospital nursery•Mother with 15 mm TST•CXR: calcified granuloma no active disease•Not on treatment

‐What is mother’s diagnosis?‐Do mother or baby need isolation?‐May baby breast feed and room with mother?

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Maternal TB disease or LTBI during pregnancy

Is mother contagious?

Exposure to contagious household TB contact:• Window prophylaxis for

baby• Multivitamin for baby• Okay to breastfeed

If no exposure to contagious household TB contacts:• No treatment for baby• Okay to breastfeed

No Yes

TB Intensive :: Childhood Tuberculosis :: San Antonio, TX :: … · 11/24/2015 1 EXCELLENCE EXPERTISE INNOVATION Childhood Tuberculosis Andrea T. Cruz, MD, MPH November 19, 2015 Tuberculosis

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