A NEW APPROACH TO CHILDHOOD

TUBERCULOSIS

Artur Sulik, Kacper Toczylowski

Department of Pediatric Infectious Disease

INTRODUCTION

TB - A WORLDWIDE PANDEMIC

The highest rates per capita are in Africa(28% of all TB cases)

Two billion people are infected with TB bacilli (about 1/3 of the world’s population!).

One in every 10 of those people will become sick with active TB in his/her lifetime.

TB ranks as the second leading cause of death from a single infectious agent ,

after the human immunodeficiency virus (HIV)

People living with HIV are at a much greater risk.

In 2013 48% TB patients globally were co-infected with HIV.

TB infected

TB IN POLAND

National Tuberculosis and Lung

Disease Research Institute

Warsaw, 2015

TB IN POLAND IN 2014 YR

Bacteriologicallyconfirmed cases

Clinicalmanifestation

Cases in children<14 yr

Total no of cases 6698

70

pulmonary

44

14

extrapulmonary

26

9

National Tuberculosis and Lung

Disease Research Institute

Warsaw, 2015

REASONS TO LEARN ABOUT PEDIATRIC TB

About 500 000 children (0-14 yrs) fell ill with

TB and 80 000 (HIV-neg) died in 2013

Children <4yr are more likely to develop TB

once infected and are more vulnerable to

disseminated TB

Children serve as indicators of contagious

adolescents or adults with TB

ABOUT THE BACTERIA

Tuberculosis is caused by acid-fast bacillus

Mycobacterium tuberculosis

Human disease caused by Mycobacterium bovis(the cause of bovine tuberculosis) may occur in children who

drink unpasteurized milk products.

Mycobacterium bovis Bacille Calmette–Guérin (BCG) is an

attenuated strain of M. bovis

NONTUBERCULOUS MYCOBACTERIA (NTM)

Many NTM species are ubiquitous in the nature (found in soil, food, water animals)

Most infections remain localized at the portal of entry (eg skin, oropharyngeal mucosa, respiratory tract) or in regional lymph nodes

In children the most common is cervical lymphadenitis

The species most commonly cultured in children is MAC

Symptoms of MAC diseases are reminiscent of tuberculosis. They include fever, fatigue, and weight loss.

Disseminated MAC infection in immunocompromised people (consider HIV/AIDS)

MAC

Mycobacterium avium complex

M avium

M intracellulare

COURSE OF TB

COURSE OF TUBERCULOSIS

exposed treated

diagnosedinfected

Susceptible

individual Cured child

TB disease

s i c k

SUSCEPTIBILITY TO TB INFECTION

Susceptible

individual The impact of BCG vaccine

Although developed years ago (1921)

BCG's clinical and immune effects remain unclear.

Is it efficient?

Does it protect from tuberculosis ???

Does it protect from disseminated tuberculosis in children ??

How long does the immunity last after vaccination?

How many doses are needed?

BCG = Bacillus Calmette Guerin

TB EXPOSURE

Exposure means that the child has had

significant contact with a contagious adult

(untreated primary pulmonary tuberculosis)

Tuberculosis (TB) spreads through the air.

If not treated, each person with active TB can infect on

average 10 to 15 people a year.exposed

Susceptible

individual

Consider treatment in young children (< 5 yr) exposed to TB

to prevent the rapid development of disseminated tuberculosis

TB TRANSMISSION IN CHILDREN

UNLIKELY !!!

TB Child < 10 y.TB adult

Small pulmonary lesions

Cough is not productive

Few/no bacilli expulsed

Contagiousness usually lasts

a few days to weeks

after initiation

of effective drug therapy

CHILD

TB TRANSMISSION

exposed

infected

Infected individuals does not

necessarily develop TB disease

Latent tuberculosis infection (LTBI)

positive TST test

no physical findings

normal CXR

primary TB

infection

NATURAL HISTORY

postprimary infection

CNS lymph nodes joins&bones otherMILIARY TB

Pulmonary TB

Extrapulmonary TB

Bacilli entering

child’s bodyLatent tuberculosis infection

20% of untreated children

RISK OF TUBERCULOSIS AFTER INFECTION IN IMMUNE

COMPETENT CHILDREN

Age at primary infection

Risk of pulmonary disease

or mediastinal lymphatic

disease %

Risk of meningeal or

disseminated tuberculosis

%

<12 mo 30–40 10–20

12–24 mo. 10–20 2–5

2–4 yr 5 0.5

5–10 yr 2 <0.5

>10 yr 10–20 <0.5

Eur Respir J. 2010 Oct;36(4):925-49

TIMETABLE OF TUBERCULOSIS

JR Starke, KC Smith. Tuberculosis in: Textbook of Pediatric Infectious Diseases, Saunders 2004

PROGRESSION FROM LTBI TO TB DISEASE

Risk factors for the progression from latent to active disease

Age (infants and postpubertal adolescents are at increased risk)

(5-15 years - favored age, primary focus usually resolves spontaneously)

Recent infection

Immunodeficiency (including HIV infection)

Intravenous drug use

Certain medical conditions diabetes mellitus, chronic renal failure

Use of immunosuppressive drugs (prolonged or high-dose corticosteroids or chemotherapy)

Treatment with TNF antagonists

TB AND HIV

TB is the most common opportunistic infection in HIV-infected people worldwide.

The diagnosis of TB can be difficult in HIV infected children:

TST is less likely to be positive

radiological changes caused by TB are difficult to distinguish from other lung disease found in HIV.

TB in this group of children tends to be moresevere and progress more rapidly

CONGENITAL TUBERCULOSIS

1) Skin lesions during the first week of life (including papular lesions or petechiae)

2) Documentation of TB infection of the placenta or the maternal genital tract

3) Presence of a primary hepatic complex

4) Exclusion of the possibility of postnatal transmission

DIAGNOSTIC CRITERIA: proven TB lesions + at least one of the following:

DIAGNOSIS

WHAT IS TUBERCULIN?

Tuberculin was discovered by German physician Robert Koch in 1890.

It was an extract of the tubercule bacilli, developed as a remedy for tuberculosis (finally found ineffective)

Purified protein derivative (PPD) tuberculin is a precipitate of non-species-specific molecules obtained from filtrates of sterilized, concentrated cultures

The Mantoux test is a delayed hypersensitivity reaction. 48-72 hours following the intradermal administration of tuberculin PPD, patients who have been exposed to the bacteria develop a delayed reaction manifested by inflammation and edema in the dermis.

TST ADMINISTRATION

Administering the Tuberculin Skin Test:

Inject intradermally 0.1 mL tuberculin into the volar

aspect of forearm

Produce wheal 6 mm to 10 mm in diameter.

Do not recap, bend, or break needles, or remove

needles from syringes

TST should be assessed 48-72 hours after

administration

The diameter of induration (not

erythema!) in mm is measured

transversely to the long axis of the forearm

and considered result

POSITIVE TUBERCULIN SKIN TEST (TST)

Induration ≥ 5 mm close contact with infectious cases

abnormal chest radiograph

HIV infection or other immunocompromise

Induration ≥ 10 mm medical risk factors (lymphoma, diabetes mellitus, chronic renal

failure)

children born/been to high-prevelance regions

exposure to drug users, adults who are HIV infected, homeless

children <4 yr

Induration ≥ 15 mm No risk factor

FALSE NEGATIVE TST TEST

improper administration of TST

young age

immunosuppresion

viral infections (especially measles, varicella, influenza)

poor nutrition

recent or disseminated tuberculosis disease

Advise family to return to clinic if induration increases in next few days. A positive TST can be read up to 7 days after placement

Negative TST does not exclude tuberculosis disease

FALSE POSITIVE TST TEST

nontuberculous mycobacteria infection

previous BCG

Distinguishing between a positive TST test caused by TB

infection and BCG vaccine can be difficult.

Consider: interval between BCG and TST, number of

doses of BCG received, frequency of previous TST

INTERFERON GAMMA RELEASE ASSAYS (IGRAS)

Test is positive if lymphocytes have recognized

mycobacterial proteins and produced gamma-

interferon

Better than TST at distinguishing true TB

infections from those caused by NTM or BCG

May be useful in BCG vaccinated children

Can be used in place of TST

Negative IGRA cannot rule out TB or LTBI

TB OR LTBI?

TB

•Metabolically active M. tuberculosis in somepart of the body

•Many children areasymptomatic

•Findings on physicalexam and/or chestradiograph

LTBI

•M. tuberculosis isdormant

•Children areasymptomatic

•Physical exam and radiograph are normal

POSITIVE TST

CHILDCHOOD TB DIAGNOSIS

Epidemiology (contact with infectious adult)

Symptoms and signs

Positive TST (tuberculin skin test)

CXR

Culture

Staining

PCR

CLINICAL MANIFESTATION

Most children are asymptomatic*(*in developed countries)

Nonspecific findings include: fever

growth delay

weight loss

poor weight gain

cough

night sweats

chills

CLINICAL MANIFESTATION

Pulmonary ExtrapulmonaryTB

PULMONARY TB

O/E: Rales

Decreased breath sound

Increased work of breathing

CXR: - difficult to distinguish from community acquired pneumonia. TB suspicion increase:

Intrathoracic lymphadenopathy (two-view CXR helpful)

Calcified granulomata

Findings relatively modest or even absent, even with abnormal CXR!

MILIARY TUBERCULOSIS

haematogenous spread of mycobacteria throughout the body (multiple foci in lungs, liver, spleen, brain and more)

CXR showing reticulonodular shadowing

nodules: size of millet seed (1-4mm)

grow if TB left untreated

sharply or poorly defined

diffuse, random distribution

CNS infection is the most severe complication of miliaryTB

EXTRAPULMONARY TB

M. tuberculosis can infect virtually

every part of the body

TUBERCULOUS LYMPHADENITIS

The most common extrapulmonary TB

Lymphadenopathy develops within 6 months of initial infection

Any nodes in the body may be involved (cervical, submandibular, subclavicular, supraclavicularmost often)

painless, slowly evolving lymph node enlargement if untreated nodes become rubbery, matted, adherent to overlying skin

BONE & JOINT TUBERCULOSIS

lymphohaematogenous spread from primary focus (mainly pulmonary)

lessions usually occurs within 1-3 years of primary TB

spinal tuberculosis accounts for 30-50% of bony TB disease.

severe destruction at early stage of disease unlikely M. tuberculosis does not produce proteolytic enzymes)

TB arthritis is rare

Radiography should be performed accompanied by standard TB investigation

CENTRAL NERVOUS SYSTEM TUBERCULOSIS

TB meningitisGradual onset (usually).

Three stages of the disease:

1) non-specific symptoms: fever,

anorexia, headache, vomiting

2) minor neurological signs (focal

neurology, cranial nerve palsies)

3) comatose with signs of severe

intracranial hypertension

TUBERCULOMAwithin brain tissue

small necrotic area enlarge to form

tuberculomas associate with

surrounding edema and leukocyte

infiltration

seizures and focal neurological signs

may be present

haematogenous spread to the brain or meninges

prompt diagnosis and early treatment is crucial for the favorable outcome !!

IDENTIFICATION OF BACTERIA

Culture (positive in 50% cases; takes 6-9 weeks with susceptibility testing some 3-6 weeks more)

gastric aspirates (Gastric aspiration using a nasogastric feeding tube can be performed on young children who are unable or unwilling to produce sputum. Samples are collected on each of three consecutive mornings.)

sputum

bronchial washings

pleural fluid

cerebrospinal fluid (CSF)

urine

Staining The Ziehl-Neelsen specific staining

Polymerase chain reaction (PCR) lack of sensitivity and specificity

SUMMARY: DIAGNOSIS

Exposure to TB

TST

IGRA

Clinicalevaluation

Identificationof bacteria

TREATMENT

TREATMENT TARGETS

TB EXPOSURE LTBI TB

All children with LTBI, as opposed to adults, deserve treatment!• LTBI treatment is less toxic in children than in adults

• Children are more likely to develop TB

In uncertain situations of TB diagnosis, it is OK to overtreat!

chemoprophylaxis chemoprevention

HISTORY OF TB MEDICATIONS

November 20th, 1944

Streptomycin first

administered to a

critically ill TB patient

Immediately impressive

results

Side effects

Resistance within a few

months!!!

P-aminosalicylic acid

(1949)

Isoniazid (1952)

Pyrazinadmide (1952)

Cycloserine (1955)

Ethambutol (1961)

Rifampin (1966)

ANTITUBERCULOSIS DRUGS

First-line drugs

Isoniazid

Rifampin/Rifapentine/Rifabutin*

Ethambutol

Pyrazinamide

* Not FDA approved for TB

Second-Line drugs

Cycloserine

Ethionamide

Levofloxacin*

Moxifloxacin*

PAS

Streptomycin

Amikacin/Kanamycin

Capreomycin

Linezolid

Bedaquiline

ANTITUBERCULOSIS DRUGS

Isoniazid (CSF ok!) alters the pyridoxine metabolism. Vit B6 supplements might be

necessary for some individuals (eg. brest-fed infants, children with nutritional deficiencies - incl. HIV-infected children)

Rifampin (CSF ok!) causes orange urine, sweat, tears

Pyrazinamide (CSF ok!) use with caution in children with underlying liver disease

Ethambutol causes reversible or irreversible optic neuritis (monthly monitoring

for visual acuity)

Streptomycin intramuscular administration

CHEMOPROPHYLAXIS –

TREATMENT OF CONTACTS

Child contact to a TB case AND negative TST

Consider INH (isoniazid) if <4 yr

Repeat TST after 8-10 weeks (individualize the window period)

If (+)TST – complete 9 mo of INH

If (-) TST – stop INH

LTBI TREATMENT (CHEMOPREVENTION)

9 mo of isoniazid (270 doses)

6 mo of rifampin for isoniazid resistant strains

TREATMENT REGIMENS FOR DRUG-SUSCEPTIBLE TB

IN INFANTAS, CHILDREN & ADOLESCENTS

Pulmonary and extrapulmonary (exept meningitis)

2 mo of isoniazid, rifampin, pyrazinamide

followed by 4 mo of isoniazid & rifampin

TB meningitis

2 mo of isoniazid, rifampin, pyrazinamide and

aminoglycoside or ethionamide followed by

7-10 mo of isoniazid & rifampin

initially drugs given once a day or 2/3 times/wk in case of poor compliance

TUBERCULOSIS TREATMENT REGIMENS

DOT – DIRECTLY OBSERVED THERAPY

In case of poor adherence to prescribed

treatment regimens

DOT should be considered.

WHO and US guidelines recommend DOT for treatment of children

with tuberculosis diseases

MULTI-DRUG RESISTANT TUBERCULOSIS

Multidrug-resistant tuberculosis (MDR-TB) is a form of TB caused by bacteria that do not respond to, at least, isoniazid and rifampicin

The primary cause of MDR-TB is inappropriate or incorrect use of anti-TB drugs, or use of poor quality medicines

Extensively drug-resistant TB, XDR-TB, is a form of multi-drug resistant tuberculosis that responds to even fewer available medicines, including the most effective second-line anti-TB drugs.

WHO, Fact sheet N°104, March 2015

MULTI-DRUG RESISTANT TUBERCULOSIS

People diagnosed with MDR-TB tripled between 2009 and 2013 reaching 480 000 (350 000–610

000) new cases of MDR-TB worldwide, and approximately 210 000 (130 000–290 000) deaths

from MDR-TB.

Only 48% of MDR-TB patients had a successful treatment outcome.

(on comparison – first-line treatment success rate is 86%)

WHO, Fact sheet N°104, March 2015

LEARNING POINTS

Neither BCG, nor negative TST can exclude

TB

Possible fulminant course of TB in children

– prompt diagnosis is essential

BCG vaccine is of uncertain value

There are currently 15 vaccine candidates in clinical trials

KEY POINTS TO CHILDCHOOD TB

Children with TB usually acquire the disease from infectious adults.

In the majority of cases the infection is controlled by the immune system and the germ remain dormant (latent TB infection).

Young children are at greatest risk of disseminated disease

Tuberculin skin test and radiograph may initially be negative in most pediatric patients

KEY POINTS TO CHILDHOOD TB CONT.

The diagnosis is challenging. It is difficult to

diagnose TB on a microbiologic basis in

children. Symptoms, if present, are

nonspecific.

Poor adherence to drug therapy is the main

barrier to cure TB disease.

CNS TB infection has an insidious onset and is

related to serious sequelae, or death.