Tuberculosis in the Child as an Orphaned Disease

David NadalDivision of Infectious diseases and Hospital EpidemiologyUniversity Children‘s Hospital of Zurich

Notification Rates of New Smear-Positive Tuberculosis Cases among Children 0-14 Years

Swaminathan S, Rekha B. Clin Infect Dis 2010;50 (S3):S184-S194

Primary Lung Tuberculosis in the Child Leading Infectious Killers (WHO 1999)

3.5

2.5

2.0

1.5

1.0

0.5

0

3.0

Dea

ths

in m

illion

s

Age > 5 yearsAge < 5 years

3.5

2.3 2.2

1.51.1

0.9

Acute respiratory infections

AIDS* Diarrhea TB Malaria Measles

* HIV-positive due to TB succumbed individuals are counted in the AIDS deaths

Millions deaths, worldwide, all age classes, 1998

** Chintu C et al. Lancet 2002;360:985-90

26 %TB**

Distribution of Tuberculosis, 2005

No notification0–2425–4950–99> 100

Notified tuberculosis cases/ 100,000 population

• 2 billion infected

• 1,6 million died

• 8,8 million new cases

Tuberculosis notification rates, 1995-2005(Countries with rates < 10 per 100,000 in 2005)

0

3

6

9

12

15

18

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

Cases / 100,000

Switzerland

Germany

Tuberculosis cases in immigrants

No data 0 – 4 % 5 – 19 % 20 – 49 % >49%

Tuberculosis in Switzerland, 2000-2004

Pathogenesis of Tuberculosis

Infection Calcified primary complex

Disease

Lymphogenous dissemination 85-90%

Primary tuberculosis 10-15%

Miliarytuberculosis

Extrapulmonarytuberculosis:CNS, joints, bones, lymh nodes

M. tuberculosis

Primary immune response to M. tuberculosis

Alveolar-Mφ

Cytokine / chemokine-storm

TNF-α IL-8CXCL9,10 IL-1

CCL2,3,4,5IL-15IL-12

Intracellularkilling

Regional lymph node

Monocyte/MφDendritic cell

Memory CD4+ T-Cell

Lungs

Antigen-specific CD4+ T-cll

Secondary Immune Responses: Lymphatic Tissue and Metastatic Foci

Dendritic cell

CD40

Memory CD4+ T-cell

γ2δ2 T cell Macrophage

CD40LCD1

Mycolic acid LAM

CD4-CD8-T-cell

Infected cell

Cytolysis

IsoprenylPO4

IFN-γ

CD8+ T cell

TNF-α↑ Killing

Activated macrophage

IFN-γ↑ Killing

Cytolysis

Memory CD4+T-cell

MHC II

CD40CD40L

TCR

IL-2

IL-12↑ IFN-γ

Tuberculosis: Child versus Adult

1. Innate immunity• Alveolar macrophage Killing ↓• Monocyte Chemotaxis↓

Cytokines ↓• Surfactant Amount ↓

2. Acquired Immunity• Antigen presentation Lower

MHC/CD40LExpression

• Lymphocytes Subpopu-lations Δ

• Cytokines Synthesis ↓Extrapulmonary tuberculosis

Atypical manifestations

Mortality of Tuberculosis Diseasein Relation to Age

AlcaisA et al. J E

xp Med

2005;212:1617-21

Mor

talit

y pe

r 100

,000

Years

Disseminated tuberculosis

Pulmonary tuberculosis

Pulmonary Tuberculosis:Tuberculous Primary Complex

Miliary Tuberculosis

Sharma SK et al. Lancet Infect Dis 2005;5:431-9

• One of the most severe forms of tuberculosis that has an unfavorable prognosis even following adequate treatment

• Preferentially in young children, older persons, and immunodeficientindividuals

• Signs and symptoms are often unspecific and the typical radiographic finding may be missing until late in the illness

Pathogenesis of Tuberculous Meningitis

BRAIN

Tubercle

Gohn complex

Bacilli in CSF tuberculin reaction in meninges meningitis adhesions neural and vascular lesions

Superficial tubercle brakes into subarach-noidal space Subarachnoidal space

LUNGs

Primary lesion

Regional lymph node VEIN

Bacilli in blood

THORACIC DUCT

Bacilli in lymph vessel

Necrotic (caseous) tubercle

Diagnosis of Tuberculosis in the Child

(Indirect)

Mantoux

Inter-feron-γ

ELISPOT

(Direct)

Ziehl-Neelsen

Culture

Moleculardetection

Diagnosis of Tuberculosis in the Child

• Sputum• Gastric fluid• Other body fluids• Tuberculin skin test, IGRA*• Imaging: radiography, CT scan, echography,

MRI/MRS*limited sensitivity in HIV-infected patients and

children younger than 4 years of age

Staining, culture, molecular detection

( )

Diagnosis of Tuberculosis: Indirect Detection of Infection: in-vivo and in-vitro Tests

Andersen P et al. Lancet 2000;356:1099-104

ESAT-6CFP-10

PPD

Vaccine: Bacille Calmette-Guérin (BCG)

1863-1933 1872-1961

High Rate of Indeterminate Results of IGRA in Children < 4 Years of Age

Bergamini BM et al. Pediatrics 2009;123:e419-24

n = 181 n = 315 n = 154

> 4 years< 4 years

Transmission of Mycobacterium tuberculosis

Adult Child

Untreated to 10-15

persons/year

Tuberculosis Classification and Initial Therapy

Classification Initial-Therapy Duration

TB Exposure: Age > 4 years and immuncompetent

Age < 4 years andimmuncompromised

Infant

Keine

INH2. Choice: Rifampicin

INH2. Choice: Rifampicin

--

2-3 months

> 2-3 months

TB Infection INH2. Choice: Rifampicin

9 months2. Choice: 6 months

TB Disease Multiple Drugs 6 months, except meningitis, miliaris and cavern 9-12

Chemotherapy: The Mitchison Hypothesis

Fast

Rate of Bacterial Growth

Slow

Pyrazinamide

Isoniazid Rifampin Streptomycin

Rifampin

Continuous Growth

AcidicpH

Spurts of Metabolism

Dormant Persisters

McKinney JD. Nat Med 2000; 6: 1330-3

Mechanisms of Action for Tuberculosis Drugs

Sasetti CM

, Rubin EJ. N

at Med 2007;7:13:279-80

Imaging: Monitoring of the Course

Russel D

G et al. S

cience2010;318:852-6

Proportion of MDR TB Among new Cases of TB

Nathanson E et al. NEJM 2010;363:1050-8

Summary: Transmission, progression and diagnosis

NE

JM2001;345:189-200

Summary

• Diagnosis of tuberculosis in the child remains a problem:– Clinical signs and symptoms are often not specific– Imaging is often not unequivocal as in adults– Indirect diagnostic in children < 4 years of age not reliable– Indirect diagnostic does not discern active from latent– Direct diagnostic is obstacled by specimen sampling

• Therapy of tuberculosis in the child remains a problem:– Studies on activity of new compounds are hampered by

hurdles of microbiologic diagnostics and monitoring• Vaccine against tuberculosis is enigmatic:

– Available vaccine induces no sterile immunity