Brian Eley

Paediatric Infectious Diseases Unit, Red Cross War Memorial Children’s Hospital

Department of Paediatrics & Child Health, University of Cape Town

Aims:

To review the epidemiology

To understand definitions used in childhood TB

To understand common clinical & radiological manifestations

To identify diagnostic challenges

To review treatment

2012 WHO estimates: 8.6 million new cases of TB and 1.3 million deaths (HIV-negative:940,000; HIV-infected:320,000), worldwide

Childhood TB (global estimate, 2012): o 349,000 new TB notifications in children <15 years o TB incident case estimate: 530,000 cases (6% of total of 8.6

million incident cases)

HIV epidemic has had a profound influence on incidence of tuberculosis

TB risk in HIV-infected children

Hesseling A, et al. Clin Infect Dis 2009;48:108-114

Explain: Culture-confirmed TB versus unconfirmed TB

South Africa: TB incidence: 1000/100,000 population in 2012 South Africa: 50 474 TB cases in children <15 years in 2010

METRO WEST CHILDHOOD TB (age < 8 years) 2012

2012 Klipfontein Mitchells Plain Southern Western Metro West

Children 302 431 251 243 1227

% Children with TB 9% 11% 12% 8% 10%

Total TB 3337 3910 2047 2877 12171

302

431

251

243

Klipfontein

Mitchells Plain

Southern

Western

Courtesy of Dr F Conrad)

60-80% of children exposed to a smear-positive household contact will become infected

If source case is smear-negative: 30-40% of children become infected

The majority of children who become infected do so within 3 months of onset of symptoms in adult source. May be delayed in younger children

For many children >2 years of age, the contact is external to the household

Age at Primary infection (years)

Risk of disease after primary infection in immunocompetent children

<1 No disease: 50% PTB (Ghon focus ± lymph node): 30-40% TBM/miliary TB: 10-20%

1 - 2 No disease: 70-80% PTB (Ghon focus ± lymph node): 10-20% TBM/miliary TB: 2-5%

2 - 5 No disease: 95% PTB (lymph node): 5% TBM/miliary TB: 0.5%

5 - 10 No disease: 98% PTB (lymph node, pleural effusion or adult-type): 2% TBM/miliary TB: <0.5%

>10 No disease: 80-90% PTB (lymph node, pleural effusion or adult-type): 10-20% TBM/miliary TB: <0.5%

Ghon with / without cavitation

- Associated lymph node enlargement; cavitation (rare)

Lymph node disease

- Airway involvement

- Collapse / consolidation

- Bronchopneumonic consolidation

- Caseating consolidation: lobar consolidation ± volume (expansile)

Pleural disease

Adult-type disease - Homogenous shadow cavity formation (apical lung segments)

Haematogenous spread

- Miliary disease

Medical history ◦ History of TB contact

◦ Symptoms consistent with TB)

Clinical examination

Tuberculin skin testing (TST)

Other relevant investigations ◦ Suspected pulmonary TB: CXR

◦ Suspected extrapulmonary TB: depends on the disease site

Bacteriological confirmation whenever possible

HIV testing (in high HIV prevalence areas)

Newer TB diagnostic tests

Culture-confirmation 16% culture confirmation in a recent study

Evidence of M. tuberculosis Smear microscopy (1-6%)

Nucleic acid amplification tests e.g. Xpert MTB/RIF (70-75% culture-confirmed disease, 0-8.5% of culture-unconfirmed disease)

Evidence of the host response Tuberculin skin test (sensitivity, TB disease: 70-85%)

Interferon-gamma release assays (IGRAs): e.g. ELISPOT, QuantiFERON (sensitivity, TB disease: 60-80%)

Close contact: living in the same household or in frequent contact with a source case (e.g. caregiver) with sputum smear-positive TB.

◦ Children < 5 years in close contact with a smear-positive TB should be screened for symptoms of TB

◦ After TB is diagnosed in a child or adolescent, an effort should be made to detect the adult source cases

◦ If a child presents with TB, then other childhood contacts should be sought and screened for active TB, especially undiagnosed household contacts

Most children with symptomatic disease develop chronic symptoms.

◦ Unremitting, persistent cough for > 2 weeks. Fever

(>38°C) for 14 days after common causes e.g. pneumonia have been excluded.

◦

◦ Weight loss (>5%) or failure to thrive (growth faltering in the last 3 months, or WAZ / WHZ ≤ -2 in the absence of information about recent growth trajectory).

◦ Persistent unexplained lethargy / reduced playfulness

Signs of hypersensitivity Phlyctenular conjunctivitis, erythema nodosum, polyarthritis (Poncet arthritis)

PTB: no specific signs

Signs highly suggestive of EPTB Non-painful enlarged cervical adenopathy – matted ± fistula

formation Gibbus, especially recent onset

Signs requiring investigation to exclude EPTB Non-painful enlarged lymph nodes without fistula formation Pleural effusion Pericardial effusion Unexplained hepatomegaly, splenomegaly, hepatosplenomegaly Distended abdomen with ascites Papable abdominal lymphadenopathy Meningitis not responding to antibiotic treatment, with sub-acute onset or raised

intracranial pressure non-painful monarthritis Cutaneous manifestations e.g. Papulonecrotic-type TB

Phlyctenular conjunctivitis / erythema nodosum

Tuberculin skin test (TST) 5 TU of PPD or 2 TU of RT23 (0.1ml) Intradermal administration Position: left forearm, palm-side up Read between 48-72 hours after administration Measure horizontal diameter of induration using a clear flexible ruler

Young child, 20mm induration; courtesy Dr Candyce Levin, August 2013 TU=tuberculin units; PPD=purified protein derivative

Positive TST induration ≥ 5 mm in HIV and severely malnourished children; ≥ 10 mmin all other

children Infection vs disease

Negative TST Never rules out a diagnosis of TB

False-positive TST Incorrect interpretation of test BCG vaccination Infection with nontuberculous mycobacteria

False-negative TST Incorrect administration or interpretation HIV infection Improper storage of tuberculin Severe TB Viral infection (e.g. measles, varicella) Vaccinated with live virus vaccines (within 6 weks) Malnutrition Immunosuppresives (e.g. glucocorticosteroids) Neonatal period Primary immunodeficeincy diseases Low protein states Diseases of lymphoid tissue (e.g. Hodgkin disease, lymphoma, leukemia, sarcoidosis)

Sputum: ◦ Spontaneously expectorated

◦ Induced after 3% NaCl nebulisation (MSF video:

http://www.youtube.com/watch?v=sbGITrNP8j8)

Gastric aspirate / gastric lavage aspirate

Nasopharyngeal aspirate

Fine needle aspirate

Lymph node biopsy

Bronchoalveolar lavage

Ear swab

Other extrapulmonary specimens

Smear microscopy

Fluorescence microscopy (FM) Detects 10% more TB cases than LM FM requires 25% of the time taken to

read a ZN stained smear

Bactec MGIT 960 culture system

Liquid culture versus solid culture Average time to growth detection: 10-14

days (LC) versus 4-6 weeks (SC)

LC 20% more sensitive than SC

Infection site Diagnostic approach

Peripheral lymph nodes (especially cervical)

Fine needle aspiration (FNA) or lymph node biopsy

TB meningitis Lumber puncture(opening pressure, biochemical analysis, microscopy & culture), CT scan, air encephalogram to determine whether hydrocephalus is communicating

Miliary TB Chest radiograph, lumber puncture, eye examination for choroidal tubercles

Pleural effusion Chest radiograph, pleural tap for biochemical analysis, microscopy & culture

Abdominal TB Abdominal ultrasound, ascitic tap for biochemical analysis, microscopy & culture, laparoscopy and peritoneal biopsy, other histological tissue

Osteoarticular TB Radiographs, joint tap, and/or synovial biopsy

Pericardial TB Echocardiogram, pericardial tap for biochemical analysis, microscopy & culture

Chronic ear discharge (especially in HIV-infected children)

Pus swab for microscopy & TB culture

Presence of at least three the following is strongly suggestive of TB: Chronic symptoms suggestive of TB Physical signs highly suggestive of TB A positive TST Chest radiograph suggestive of TB

WHO, Int J Tuberc Lung Dis 2006;10(10): 1091-7

Evaluates frequency of INF-secreting peripheral lymphocytes in response to stimulation by M. tuberculosis-specific early secretory antigens (ESAT-6 & CFP-10)

IGRAs do not distinguish latent TB infection

from active disease WHO recommends that IGRAs should not

replace TST in LMICs. There is a shortage of tuberculin; IGRAs could be reconsidered

Newer tests: Xpert MTB/RIF

Diagnosis of M. tuberculosis complex disease

Detection of rifampicin and/or isonizid resistance

Detection of resistance to second-line anti-TB drugs (fluoroquinolones, amnioglycosides/cyclic peptides,

ethambutol)

Differentiation of M. tuberculosis complex (M. tuberculosis, M. africanum, M. microti, M bovis ssp. bovis, M. bovis BCG, M. bovis ssp. Caprae)

Differentiation of M. tuberculosis complex from NTM species (M. intracellulare, M. kansasii, M. malmoense, M. avium)

GenoType MTBDRplus ® V2 assay

KatG mutation: high-level INH resistance InhA mutation: low-level INH resistance

1. Treatment of infection (preventive therapy)

2. Treatment of disease

1. Combination therapy to which the bacillus is sensitive

2. Short-course regimens comprising both bactericidal and sterilizing activity

3. Start with an induction phase to achieve a rapid reduction of the organism load

4. Continuation phase: to ensure effective eradication of dormant and intermittently metabolizing (persistent) bacilli, thus preventing disease relapse

5. Optimise adherence & minimise adverse effects

Drug-susceptible TB: Aim to cure the child & prevent emergence of drug-resistant TB

Isoniazid (H) has high early bactericidal activity (EBA) that kills actively dividing bacteria, causing rapid decline in sputum bacilli

Rifampicin (R) is bactericidal; it is active against bacilli with spurts of metabolism and therefore a major sterilizing agent

Pyrazinamide (Z) kills dormant or slow-growing bacilli; has a remarkable sterilizing effect

Ethambutol (E) is bacteriostatic having some efficacy against actively replicating bacilli

Ethionimide (Eth) is bacteriostatic, targeting actively growing bacilli; high CSF penetration

TB diagnostic category Intensive phase

Continuation phase

New smear negative PTB (other than in next category) Less severe forms of EPTB: lymph node TB, pleural effusion

2HRZ 4HR

New smear-positive PTB New smear-negative PTB with extensive parenchymal involvement / cavitatory disease Severe forms of EPTB (other than TB meningitis)

2HRZE 4HR

TB meningitis and Miliary TB 6*HRZEth (all drugs administered at 2X Std dose) *Duration may be extended to 9 months by EDL guideline committee

H = Isoniazid, R = Rifampicin; Z = Pyrazinamide; E = Ethambutol; Eth = Ethionimide

Drug Daily dosage in mg/kg (range) [maximum]

Daily dosage in mg/kg (range) [maximum]

TBM/Miliary TB

Isoniazid 10 (10 – 15) [300 mg] 15 – 20 [400 mg]

Rifampicin 15 (10 – 20) [600 mg] 15 – 20 [600 mg]

Pyrazinamide 35 (30 – 40) [2000 mg] 30 – 40 [2000 mg]

Ethambutol 20 (15 – 25) [1200 mg]

Ethionimide 20 (15 – 25) [1200 mg]

Prednisolone 2 mg/kg/day (maximum 60 mg / day) for 4 weeks then taper over 2 weeks

‡ Pyridoxine supplementation: Malnutrition, HIV infection, high dose INH (>10 mg/kg/day)

Uncomplicated TB disease

Complicated TB disease

(excluding TB meningitis)

Intensive phase

2 months

Once daily

7 days a week

Continuation

phase

4 months

Once daily

7 days a week

Intensive phase

2 months

Once daily

7 days a week

Continuation

phase

4 months

Once daily

7 days a week

Target dose or

dose range

(mg/kg/dose)

RH

R: 10-20

H: 10-15

Z

30-40

RH

R: 10-20

H: 10-15

RH

R: 10-20

H: 10-15

Z

30-40

E

15-25

RH

R: 10-20

H: 10-15

Target dose or

dose range

(mg/kg/dose)

Formulation

Body weight

(kg)

RH 60/60mg

dissolvable

tablet

(scored)

Z 500mg

tablet

(scored)

RH 60/60mg

dissolvable

tablet

(scored)

RH 60/60mg

dissolvable

tablet

(scored)

Z 500mg

tablet

(scored)

E 400mg

tablet

(un-scored)

OR

400mg/8ml#

solution

RH 60/60mg

dissolvable

tablet

(scored)

Formulation

Body weight

(kg)

<2 Expert advice recommended <2

2-2.9 ½ 75mg (1/2 x

150mg tab)*

½ ½ 75mg (1/2 x

150mg tab)*

1ml ½ 2-2.9

3-3.9

¾

¼

¾

¾

¼

1.5ml

¾

3-3.9

4-5.9 1 ¼ 1 1 ¼ 2ml 1 4-5.9

6-7.9

11/2

½

11/2

11/2

½

3ml

11/2

6-7.9

8-11.9

2

½

2

2

½

½ tab

2

8-11.9

12-14.9

3

1

3

3

1

¾ tab

3

12-14.9

15–19.9

3 ½

1

3 ½

3 ½

1

1 tab

3 ½

15-19.9

20-24.9

4 ½

1 ½

4 ½

4 ½

1 ½

1 tab

4 ½

20-24.9

25-29.9

5

2

5

5

2

11/2 tab

5

25-29.9

TB dosing, children < 8 years (2013)

http://www.scah.uct.ac.za/sites/default/files/image_tool/images/38/TB_drug_dosing_chart_2013.pdf

1. TB meningitis (TBM)

2. TB pericarditis

3. Hilar adenopathy with compression of airways

Post-exposure INH prophylaxis prevents progression to disease

Indications:

HIV uninfected children aged 0-5 years

HIV-infected children irrespective of their age

Dosing instructions: INH 10 mg/kg body weight/day for 6 months

HIV-TB coinfection

History including contact history Important because of poor sensitivity of TST

Symptoms consistent with TB Lower specificity due to overlap between symptoms of TB & HIV High proportion of patients with short duration of symptoms

Examination including growth Lower specificity because malnutrition common in TB & HIV

Tuberculin skin testing Lower sensitivity; TST positivity with immunosuppression

Chest radiograph findings Lower specificity: overlap with HIV-related disease

Bacteriological confirmation Important but beyond capabilities of many clinicians, Lacks sensitivity

Investigations relevant for suspected PTB and EPTB

Wide range of diagnostic possibilities because of other HIV-related disease

Ref Country TB incidence rate / TB risk

1 SA n=1132

Pre-cART: 21.1 / 100 py vs on cART: 6.4 / 100 py a crude reduction of 70%

2 DRC n=6535

On-cART: 10.2 / 100 py vs not on-cART: 20.4 / 100 py Model-estimated TB Hazard ratio for cART: 0.51 [0.27-0.94]

3 Kenya n=364

On cART: 7.2 / 100 py vs not on-cART: 22.2 / 1– py; IRR for cART = 0.32 [0.26-0.40] Adjusted for other factors, cART was associated with marked reduction in TB risk; AHR: 0.15 [0.12-0.20]

4 Uganda N=311

Pre-ART incidence: 10.0 per 100 py, 1st 100 days of ART risk of new TB was 2.7-fold higher; after 100 days TB incidence rate decline to below pre-ART level, RR=0.41, p=0.002

1 Martinson NA, et al. Int J Tuberc Lung Dis 2009;13(7):862-867; 3 Braitstein P et al. P Infect dis J 2009;28:626-632 2 Edmonds A, et al. Int J Epidemiol 2009;38:1612-1621 4 Bakeera-Kitaka S, et al. Int J Tuberc Lung Dis 2011;15:1082-1086

Drug interactions: rifampicin potent inducer of cytochrome P450 system reduces exposure to PIs & NNRTIs

Modification to ART regimens

- Kaletra-containing regimens: boost with additional ritonavir

- Efavirenz-containing regimens: no drug modifications necessary

Swinging fever

Worsening lymphadenitis

Worsening pulmonary infiltrates, respiratory failure

Worsening pleuritis, pericarditis, ascites

Intracranial tuberculomas, TBM

Disseminated skin lesions

Hepatosplenomegaly, soft tissue abscesses

Defined as resistance to at least INH & Rifampicin

Overall 5% in children with TB

Clinical, radiological presentation identical to drug-susceptible TB

Commonly identified through adult contacts infected with resistant isolates

Need specialist referral

Delay in inititing definitive treatment is common

Single drug should never be added to a failing treatment regimen

Use at least 4 drugs to which TB isolate is susceptible

One of drugs should be Injectable agent, administered for the 1st 4-6 months

Hospitalise for therapy or implement DOT

Continue INH 15-20 mg/kg/day as an additional drug especially if INH resistance due to inhA gene mutation

Treat for 12 – 18 months after first negative culture. However, children with paucibacilliary disease can be treated for a total of 12-15 months.

Group Drugs Adverse events

1. 1st line oral agents Isoniazid Hepatitis, peripheral neuropathy

Rifampicin Hepatitis, discolorarion of secretions

Ethambutol Optic neuritis

Pyrzinamide Hepatits, arthritis

2. Injectable agents Kanamycin Ototoxicity, nephrotoxicity

Amikacin As above

Capreomycin As above

Streptomycin As above

3. Fluoroquniolones Ofloxacin Sleep disturbance, git disturbance, arthritis, peripheral neuropathy

Ciprofloxacin As above

Levofloxacin As above

Moxifloxacin As above but includes prolonged QT interval

4. Oral bacteriostatic agents

Ethionimide Git disturbance, metallic taste, hypothyroidism

Terizidone Neurological and psychological effects

Para-aminosalicylic acid Git intolerence, hypothyroidism, hepatitis

5. Agents with unclear efficacy

Clofazimine Skin discoloration, xerosis, abdominal pain

Linezolid Diarrhoea, headache, nausea, myelosuppression, neurotoxicity, lactic acidosis, pancreatitis, optic neuropathy

Amoxycillin-clavulanic acid Git intolerance, hypersensitivity, seizures, liver & renal dysfunction

Imipenem/cilastatin As above

Thiacetazone Stevens Johnson syndrome in HIV-infected patients, git intolerance, hepatitis, skin reactions

Clarithromycin Git intolerance, rash, hepatitis, prolonged QT syndrome, ventricular arrythmias

High-dose isoniazid Hepatitis, peripheral neuropathy, neurological & psychological effects

Dheda K, et al. Lancet 2010;375:1798-1807

Outcome of XDR-TB in South African cohorts

INH mono-resistant contacts: Rifampicin 10-15 mg/kg/day x 4 months

Rifampicin mono-resistant contacts: INH 10 mg/kg/day x 6 months

MDR-TB: Levofloxacin 15-20 mg/kg/day, INH 15-20 mg/kg/day & Ethambutol 15-25 mg/kg/day x 6 months

Pre-XDR-TB or XDR-TB: INH 15-20 mg/kg/day x 6 months

Importance of follow-up to detect the development of active TB