Post on 09-May-2022
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.