Download Pulmonary tuberculosis in children from family contacts Larissa

Fatma TRITAR
Dept of Respiratory Diseases C
Tuberculosis Multidrug Resistance Unit
Abderrahmen Mami Hospital, Ariana, Tunisia
The First annuel conference of LATA 24 March 2016- Beyrouth
Chilhood Tuberculosis (TB)
 Childhood
TB is an indication of failing TB control in
the community.
 It
allows disease persistence in the population.
 Mortality
and morbidity due to TB is high in children.
 HIV
co-infection and MDR diseases are as frequent in
children as in adults.
In most settings, children with TB continue to be given low
priority by national TB control programmes (NTP) because
they are less likely to transmit disease
Epidemiology

Childhood TB accounted for 3.5% of the global TB caseload in
high-burden countries

In 2013, WHO estimate that there a total of :
 550000 childhood tuberculosis cases
 80000 deaths in children due to TB

An estimate that only included human immunodeficiency
virus (HIV)-uninfected children

There are no data of the numbers of TB-related deaths in HIVinfected children, the greatly increased risks of TB and of TBrelated mortality
• Graham SM,. Importance of tuberculosis control to address child survival. Lancet 2014
• World Health Organization. Global tuberculosis report 2014. Geneva, Switzerland: WHO, 2014.
• Dodd PJ. Burden of childhood tuberculosis in 22 high-burden countries. Lancet Global Health 2014
Epidemiology
 TB
disease and latent TB infection (LTBI)
frequencies are dramatically underestimated :
1.
Paucibacillary disease in infants and children
2.
Difficulty of confirming the diagnosis of TB
Epidemiology

> 90% of TB disease progression in young children
occurred within 12 months of primary M. tuberculosis infection

Most TB cases occur in children under five year

Extra-pulmonary TB (mediastinal lymphadenopathy) and
severe and disseminated TB (TB meningitis and miliary)
occurs mostly in young children (< 3 years)
HIV co-infection

An estimated 2.5 million children <15 years were infected
with HIV
•
Majority living in sub-Saharan Africa
•
HIV prevalence in countries with moderate-to-high prevalence
= 10% to 60%.
•
In the absence of ART, more than 20% of HIV-infected
children living in high-burden areas would develop TB
disease, leading to a three- to six-fold higher mortality
Drug-resistant TB
•
Among children living with drug-resistant patients, an overall
high prevalence of TB was observed : 7.5%
•
In Thailand, 5.7% of specimens from children were MDR-TB in
2012 revealing a drastic increase in a few years
•
Recent Indian survey, half of the children with drug sensitivity
tests (DSTs) harboured drug-resistant strains, of which 50%
were MDR-TB.
1. Amanullah F. High tuberculosis prevalence in children exposed at home to drugresistant tuberculosis.
Int J Tuberc Lung Dis 2014
2. Lapphra K. Drug-resistant tuberculosis in children in Thailand. Int J Tuberc Lung Dis 2013
3. Jain SK, Ordonez A, Kinikar A, et al. Pediatric tuberculosis in young children in India: a prospective
study. Biomed Res Int 2013
Management of childhood TB
Why Difficult ?
 Difficulty
of establishing a definitive diagnosis :
1. TB pauci-bacillary
2. Excavations formation is relatively rare (6% ) in
children aged under 13 years
3. Challenges of obtaining respiratory samples
4. Presence of extra-pulmonary disease
5. Wide spectrum of disease manifestations and
severity that often overlap with other common
childhood conditions (pneumonia, HIV associated
lung disease, malnutrition)
 Lower
priority to public health
In current practice ….
•
The mother of two children (2 and 4 years)
•
Very worried, consult because their grand
mother is treated for one week for pulmonary TB
•
They are vaccinated with BCG
•
They sleep with their grandparents once a week,
in the same room as their grandmother.
Question : What are we doing ?
1. Search and treat TB disease
2. Manage latent infection TB
Diagnosis of TB in children
•
Symptoms of childhood TB are nonspecific, and up to 50%
of children may be asymptomatic in the early stage
•
The diagnosis of tuberculosis in children is challenging,
especially in infants and young children (<5 years), who
are at particular risk for disease and adverse outcomes
from tuberculosis
1. Zar HJ. Diagnosis of pulmonary tuberculosis in children. Exp Rev Anti-infect Therapy 2010
2. Oliwa JN KJ. Tuberculosis and childhood pneumonia in tuberculosis endemic settings-common, cause or
consequence? A review of the evidence. Lancet Resp Med 2015.
Diagnosis of TB in children
•
It is important to always take into account:
 Age
 Nutritional status
•
Risk factors for TB infection:
 History of contact with a TB patient
Generally, children develop TB within 2 years of exposure or
even a year in most cases (90%)
 Evolution of risk factors to active TB disease:
young, HIV infection, malnutrition, recent measles
Clinical Examination
•
BCG scar
•
Break of the growth curve
•
Peripheral lymphadenopathy
Tuberculous lymphadenopathy
•
Most common form of EPT in children
•
10% of cases of childhood TB.
•
The age of onset is usually between
2 and 10 years
•
The most commonly affected are the
cervical nodes
•
TB lymph node may be associated with
other symptoms of TB.
•
Spontaneous perforation (fistula)
and a flow may occur.
Chest radiography
 70% of infected children < 5 years
 Chest RX is abnormal :
•
•
•
•
Mediastino-pulmonary opacity
Condensations systematized, nodules
Alveolar opacities
Isolated lymphadenopathy
Boloursaz MR. Acta Med Iran. 2010 ;48:244-9.
Severe forms
Mediastinal lymphadenopathy rights in a child
ventilation disorder top right in an infant
ventilation disorder left lung in an infant
Pericardial tuberculosis effusion
Computed tomography (CT)
•
More sensitive than chest radiography (< 4 years)
•
Adenopathies or a pathological infiltrate in 60-85%
of children with normal chest radiography
.
Nodules, infiltrating
Condensations
Delacourt C. Rev Mal Respir 2011; 28: 529–541
Garrido JB. PediatrPulmonol. 2012 ;47:895-902.
Computed tomography (CT)
•
In infants, chest CT scans revealed extensive parenchymal
lesions and hilar/mediastinal lymph node enlargement
•
Airway complications are frequently missed by chest RX
•
CT scan sensitivity for prediction of severe bronchial
involvement = 100% (specificity 72%)
Lymphadenopathy with tracheobronchial Complications
Arlaud K. Arch Dis Child 2010; 95: 125-129.
Extensive TB
 Multivisceral
disease
 Lymph node cervical,
Mediastinal, abdominal
 Lung and hepatic TB
Miliary tuberculous
Bacteriological confirmation
•
Younger children rarely produce good quality respiratory
specimens, and TB is associated with a low bacillary burden
in children.
•
The diagnosis of childhood TB is mostly presumptive.
•
TB suspicion should be confirmed whenever possible, using
new available tools, particularly in case of pulmonary and
lymph node TB.
1. Zar HJ. Diagnosis of pulmonary tuberculosis in children: new advances. Exp Rev Anti-infect Therapy
2010
2. Nicol MP. New specimens and laboratory diagnostics forchildhood pulmonary TB: progress and
prospects. Paediatr Resp Rev 2011
3. World Health Organization. Policy update: Xpert MTB/RIF assay for the diagnosis of pulmonary and
extrapulmonary TB in adults and children. Available at: December 2014.
Bacteriological diagnosis

Sample collection: Sputum and GLA
Smear microscopy performs poorly in both sputum and GLA

Alternative methods of sample collection
o
Hypertonic saline-induced sputum collection (> 30%)
o
Nasopharyngeal aspiration (NPA)
(easy to perform and more sensitive than GLA)
o
Endoscopy with broncho-alveolar lavage
o
lymph node fine-needle aspiration biopsy (FNAB).
(60% diagnostic confirmation (histo / Bacteriology)
* Multiply the samples to increase rentability GLA+ induced sputum
* Check DST of contaminating +
Bacteriological diagnosis
•
Depending on the study setting and resources,
microbiological confirmation is established by
culture in only 15%-50% of pediatric cases.
•
Although the recently endorsed Xpert MTB/RIF assay is
more sensitive and specific than smear microscopy
in children with tuberculosis, it only has a sensitivity of
approximately 66% on respiratory specimens compared
with culture
1. Zar HJ. Diagnosis of pulmonary tuberculosis in children: new advances. Exp Rev Anti-infect Therapy
2010
2. Nicol MP. New specimens and laboratory diagnostics forchildhood pulmonary TB: progress and
prospects. Paediatr Resp Rev 2011
3. World Health Organization. Policy update: Xpert MTB/RIF assay for the diagnosis of pulmonary and
extrapulmonary TB in adults and children. Available at: December 2014.
Molecular biology
The Xpert MTB/RIF assay
•
The most popular molecular
diagnosis test
•
Improve the rentability of
bacteriological diagnosis
•
Using two induced sputum
specimens detected twice as many
cases (75.9%) compared with
sputum smear (38%)
•
Rapid detection of possible
resistance
•
Confirmation yet recommended
conventional DST
GeneXpert real-time PCR detection of DNA
Tortoli E, EurRespir J. 2012; 40:442-7.
Molecular biology
The Xpert MTB/RIF assay
•
Pulmonary TB :
 Sensitivity (sputum and GLA)
 96% in smear-positive children
 55% in smear-negative children
 Specificity = 98%
•
Extra-pulmonary TB :
 Sensitivity = 87%
 pleural fluid (100%)
 peripheral lymph nodes (86%)
 CSF (75%)
 Specificity = 81%-99%
WHO recommendations
Xpert MTB/RIF should be used rather than
conventional microscopy and culture as the initial
diagnostic test in children suspected of having
multidrug-resistant (MDR)-TB or HIV-associated
TB, or in cases of TB meningitis testing CSF
Bronchoscopy
•
Bronchoscopy showed airway anomalies in half of
the children with lymphadenopathy on chest
radiography.
•
Early detection and effective treatment of
endobronchial TB is essential in order to decrease
secondary bronchial stenosis and bronchiectasis
Bronchi complications
Chun-Mei Hu, J Thor Dis 2013, 5(4)
S Eren, Turkish thoracic journal 2009.
Bronchoscopy




Evaluation of tracheobronchial lesions
LBA: bacteriology
Transbronchial needle aspiration (TBNA)
Endoscopic treatment
caseum
Inflammation
Compression of the bronchus
adenomegaly fistulized
Chun-Mei Hu, J Thor Dis 2013, 5(4)
Arlaud K. Arch Dis Child. 2010 ;95:125-9.
Bronchoscopy
•
Mediastinal lymph nodes may be sampled safely using
transbronchial needle aspiration (TBNA) through flexible
bronchoscopy .
•
A prospective study in 28 children with large subcarinal
lymphadenopathy reported that TBNA provided a
definitive diagnosis of mycobacterial infection in
50% of patients.
Goussard P. The diagnostic value and safety of transbronchial needle aspiration biopsy in children
with mediastinal lymphadenopathy. Pediatr Pulmonol 2010.
Immunoassays :
Control of exposure and infection !
Tuberculin skin test (TST)

TST positive is useful to indicate TB infection when there is no
known exposure to TB clinical evaluation (no contact history)

Useful to enhance the diagnosis of TB in children with
clinical features are suggestive of TB but whose sputum
smear is negative or who can not produce sputum

Level of positivity?
 in any child, regardless of BCG immunization : TST ≥ 10 mm
 in children severely malnourished : TST ≥ 5 mm
 TST positive does not distinguish TB infection to active TB disease
 TST negative does not rule out active TB disease
Immunoassays?
Control of exposure and infection!
Test for production of gamma interferon: IGRA
Quantiferon, Spot TB test :
•
In both active and presumed latently infected young children, the
immune system is immature, and is the likely cause of lower
cytokine release and compromised IGRA performance
•
Poor sensitivity before the age of 5 years
 There is no evidence to support the use of IGRA over TST in young
children under five
 Therefore, IGRAs should not replace the TST in TB diagnosis in this
age group.
 Nevertheless, they could add sensitivity to the results of the TST
testing.
Clinical Case Definitions for Classification of
Intrathoracic Tuberculosis in Children: An Update
Stephen M. Graham Clinical Infectious Diseases 2015
Evaluation of data from active case-finding studies have
reported that 12% and 65% of children with confirmed
tuberculosis did not have clinical features consistent with
the standardized “clinical signs/symptoms suggestive of
tuberculosis” used to categorize clinical, unconfirmed cases.
1. Beneri C. Understanding NIH clinical case definitions for pediatric intrathoracic TB by applying them to
a clinical trial. Int J Tuberc Lung Dis 2015.
1. WisemanCA.NovelapplicationofNIH case definitions in a paediatric tuberculosis contact investigation study.
Int J Tuberc Lung Dis 2015
Intrathoracic tuberculosis
diagnostic criteria
1. Microbiological confirmation
Addition of WHO-endorsed NAAT (eg, Xpert/RIF MTBassay)
2. Clinical signs/symptoms suggestive of tuberculosis
Well-defined symptoms/signs that are highly suggestive of TB
3. Interpretation of chest radiographs
4. Tuberculosis exposure
Time-window reduced to “within the past 12 months.”
5. Mycobacterium tuberculosis infection
TST and/or IGRA positive; methods and cutoffs used must be specified
6. Response to treatment
2010
Treatment of
Chilhood Tuberculosis (TB)

Children require higher drugs dosages than adults .

Short courses of steroids are associated with TB treatment in
case of respiratory distress

Fibroscopic desobstruction is proposed for severe airways
involvement

Antiretroviral therapy is mandatory in case of HIV infection.
Treatment of Chilhood
Tuberculosis (TB)
Combined Forms :
 HRZ 30/60/150 mg
 HR 30/60 mg
Treatment of Chilhood
Tuberculosis (TB)

Children with suspected or confirmed pulmonary TB or
tuberculous peripheral lymphadenitis who live in settings
with low HIV prevalence or low resistance to isoniazid

Children who are HIV-negative can be treated with :
o Three-drug regimen (HRZ) for 2 months
o Followed by two-drug (HR) regimen for 4 months
o Total duration of treatment being 6 months
Treatment of Chilhood
Tuberculosis (TB)
•
Children living in settings where the prevalence of HIV or
resistance to isoniazid is high
•
Children with extensive pulmonary disease
•
Should be treated with :
o Four-drug regimen (HRZE) for 2 months
o Two-drug regimen (HR) for 4 months
o Total duration of treatment being 6 months
Treatment of Chilhood
Tuberculosis (TB)

Addition of a fourth drug such as ethambutol is
necessary in complicated pulmonary TB or meningeal
involvement or oste-oarticular tuberculosis :
o Four-drug
o Followed
o Total

regimen (HRZE) for 2 months
by a two-drug regimen (HR) for 10 months
duration of treatment being 12 months .
For infants < 6 months of age with widespread
dissemination, ethionamide use was reported in place
of ethambutol considering its superior penetration
into the central nervous system*.
* American Academy of Pediatrics
Stop TB partnership childhood TB subgroup. Guidance for national tuberculosis programmes on the
management of tuberculosis in children. Int J Tuberc Lung Dis 2006
Additional medications
•
Steroid therapy is usually indicated in cases of
severe bronchial obstruction, meningeal
involvment, pericard.
•
Prednisone (1-2 mg/kg/day - maximum 60 mg/day)
for 4 weeks followed by reduction dose for 2 weeks
•
Combining 4 weeks of steroids and possibly
endoscopic resection demonstrated good results and
dramatically reduced the need for surgery.
•
In severe pulmonary TB, additional antibiotics may be
required for bacterial co-infections.
Management of LTBI
•
Post-exposure prophylaxis in children is a highly
effective strategy to reduce the risk of TB disease.
•
IPT is recommended for any HIV-positive child
with TB exposure, irrespective of the child’s age or
TST result, once active TB has been excluded
Treatment options for LTBI
The following treatment options are
recommended for the treatment
of LTBI:
•
6-month isoniazid,
•
9-month isoniazid,
•
3-month of weekly rifapentine plus isoniazid,
•
•
3-4 months isoniazid plus rifampicin,
3-4 months rifampicin alone
(Strong recommendation, moderate to high quality of evidence)
Treatment options for LTBI
Management of LTBI
A short-course regimen with isoniazid
and rifampicin for 3 months could be
better then 9 month course of isoniazid
monotherapy regarding compliance and
chest radiography evolution, and
showed a significant decrease in
childhood TB that persisted to 12 years
of follow-up
Preventive treatment
for contacts of
MDR-TB cases ?

The optimal therapy for treatment of latent infection
with a presumably multidrug-resistant Mycobacterium
tuberculosis strain is currently not known
•
•
MDR-TB prophylaxis is much more controversial.
We need urgent valuation of appropriate chemo-
prophylactic regimens for child contacts of patients with
MDR-TB
Van der Werf MJ .Lack of evidence to support policy development for management
of contacts of multidrug-resistant tuberculosis patients : two systematic reviews.
Int J Tuberc Lung Dis 2012
Prevention BCG
•
BCG remains the only available vaccine for TB worldwide
•
The global BCG efficacy is estimated to be 50%
•
BCG vaccination at birth halved neonatal mortality from
non-TB infections
Childhood tuberculosis
•
Childhood tuberculosis (TB) is a preventable and
curable infectious disease
•
Remains overlooked by public health authorities,
health policy makers and TB control programmes.
•
Despite being a major contributor to childhood
morbidity and mortality particularly in high TB-burden
settings and advocacy and scientific progress are still
insufficient.
•
Childhood TB contributes significantly to the burden of
disease and represents the failure to control
transmission in the community.
 The pool of infected children constitutes a
reservoir of infection for the future burden of TB.
Childhood tuberculosis
•
Guidelines for childhood TB management have been
developed and are already adopted by many countries
•
It is time to prioritise childhood TB, advocate for
addressing the challenges and grasp the opportunities
in its prevention and control.
Thank you