Childhood tuberculosis (TB)

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Childhood Tuberculosis

Kyaw San Lin & Kay Yu SanFinal year, Part 2, M.B.B.S

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ContentsEpidemiologyPulmonary TB• pathophysiology• clinical features • investigations• treatment

Extrapulmonary TB (EPTB)• pathophysiology• clinical features• investigations• Treatment

Prevention

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EpidemiologyKyaw San Lin

Global tuberculosis report 2015. Geneva, World Health Organization, 2015 (WHO/HTM/TB/2015.22)

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Estimated TB Incidence Rates, 2014


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Mortality due to TB in Myanmar


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Prevalence of TB in Myanmar


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Incidence of TB in Myanmar


Among new and relapse cases, 26% of cases are aged under 15 years

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3 high burden countries (HBC) lists of 30 countries

Use of high burden country lists for TB by WHO in the post-2015 era. Geneva, World Health Organization, 2015 (WHO/HTM/TB/2015.29)

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Causal organisms•For immunocompetent hosts•Mycobacterium tuberculosis•Mycobacterium bovis

•For immunocompromised hosts•Mycobacterium avium intracellulare complex

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3 major clinical stages

Exposure

Infection

Disease

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Exposure• Significant contact with an adult or adolescent with infectious tuberculosis• Lacks proof of infection• TST, IGRA negative• CXR normal

Kliegman RM et al, Nelson Textbook of Pediatrics, 20th edn. Elsevier; 2016.

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Infection• inhales droplet nuclei containing M. tuberculosis• survives intracellularly within the lung and associated lymphoid tissue• Positive TST or IGRA• no signs or symptoms• Physical examination normal• CXR normal or reveals only granuloma or calcifications in the lung parenchyma


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Disease• signs or symptoms or radiographic manifestations caused by M. tuberculosis become apparent.• infected child younger than 1 yr of age has a 40% chance of developing disease within 9 mo.


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Risk factors for developing childhood tuberculosis

Childhood TB

Close contact

Age <5 years of

age

HIV infection

Severe malnutrition, measles

and immunosuppressive drugs or illnesses

Absence of BCG

vaccination

Adapted from Pediatrics for undergraduates, 2nd edn. Myanmar Pediatric Society.

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Risk of TB disease following infection by age

Childhood TB Training Toolkit, Geneva, World Health Organization, 2014. (WHO/HTM/TB/2014.14)

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Pulmonary TBKyaw San Lin

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Primary Complex

Parenchymal pul focus

Regional LN

Primary complex

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The natural history and spectrum of tuberculosis.

Adapted from a sketch provided by Prof R.K. Kumar, The University of New South Wales, School of Pathology, Sydney.Kumar V. Robbins and Cotran Pathologic Basis of Disease, Elsevir; 2015

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Ghon complex• The gray-white

parenchymal focus is under the pleura in the lower part of the upper lobe (red arrow). • Hilar lymph

nodes with caseation are seen on the left (blue arrow).

Kumar V. Robbins and Cotran Pathologic Basis of Disease, Elsevir; 2015

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Symptoms & Signs• Up to 50% with radiographically moderate to

severe pulmonary tuberculosisNo physical findings

• most commonNon-productive cough and mild dyspnea

• fever, night sweats, anorexia & decreased activity• less oftenSystemic complaints

• often does not improve significantly until several months of effective treatment have been taken.

Difficulty gaining weight or a true failure-to-thrive

syndrome• less commonPulmonary signs

• localized wheezing or decreased breath sounds that may be accompanied by tachypnea or, rarely, respiratory distress.

Bronchial obstruction

Adapted from Kliegman RM et al, Nelson Textbook of Pediatrics, 20th edn. Elsevier; 2016.

Perihilar lymphadenopathy • Obvious right

perihilar adenopathy with surrounding inflammatory changes. • Perihilar

lymphadenopathy is a common radiological finding in children with PTB


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• In a minority of cases, the diagnosis is simplified by the presence of a previous Ghon focus, which is calcified (see arrow). • Mediastinal

lymph gland enlargement with lung infiltration is seen on the left

Gie R. Diagnostic atlas of intrathoracic tuberculosis in children: a guide for low-income countries. Paris, International Union Against Tuberculosis and Lung Disease, 2003.

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Primary Pulmonary Disease•Most cases – resolve fully with appropriate Tx•Occasionally – residual calcification (6-12 months)


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Progressive Primary Pulmonary Disease

Rare but serious

complication of

tuberculosis in a

child!Kliegman RM et al, Nelson Textbook of Pediatrics, 20th edn. Elsevier; 2016.

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primary focus enlarges steadily

develops a large caseous center

formation of a primary cavity associated with large numbers of tubercle bacilli

slough necrotic debris into the adjacent bronchus

further intrapulmonary dissemination


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Common symptoms• High fever, severe cough with sputum

production, weight loss, and night sweatsPhysical signs• diminished breath sounds and dullness

over the cavityPrognosis• excellent with appropriate therapy


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Reactivation Tuberculosis• rare in childhood but can occur in adolescence. • initial infection when > 7 yr of age – more common•most common pulmonary sites • original parenchymal focus• lymph nodes• apical seedings (Simon foci) established during the

hematogenous phase of the early infection. • usually remains localized in the lungs• immune response prevents further extrapulmonary spread.


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Clinical features•H/O•more likely to experience fever, anorexia, malaise, weight loss, night sweats, productive cough, hemoptysis, and chest pain • improve within several wks of starting effective Tx• cough can last for several months• highly contagious if there is significant sputum production and cough.

•P/E - findings minor or absent•Prognosis - excellent with appropriate therapy.Adapted from Kliegman RM et al, Nelson Textbook of Pediatrics, 20th edn. Elsevier; 2016.

Post-primary tuberculosis • A case of post-

primary tuberculosis in a 10-year-old boy who, until recently, had a normal chest radiograph. • Cavities are

present in the left upper lobe. • This patient was

sputum smear positive. • Arrow indicates

calcified lymph node due to previous primary infection. Gie R. Diagnostic atlas of intrathoracic tuberculosis in

children: a guide for low-income countries. Paris, International Union Against Tuberculosis and Lung Disease, 2003.

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Recommended approach to diagnose TB in children WHO Guidance for NTP on Mx of TB in children1. Careful history • includes history of TB contact • symptoms suggestive of TB

2. Clinical examination • includes growth assessment

3. Tuberculin skin test 4. Bacteriological confirmation whenever

possible 5. Ix relevant for suspected PTB or

suspected EPTB 6. HIV testing


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Symptoms suggestive of childhood TB

Cough for more than 3 weeks which

is not improving

Fever (>38°C) For >2 weeks

after exclusion of

common causes of fever (e.g. malaria)

Failure to gain

weight (Weight loss if known/see

weight chart)

Unexplained loss of

appetite


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Signs suggestive of childhood TB

Pulmonary TB

• Signs of persistent pneumonia after full course of appropriate antibiotics

Highly suggestive EPTB

• Pleural effusion• Acute vertebral

gibbus• Non-painful glands

with draining sinus

Suggestive EPTB

• Meningitis…• Pericardial effusion• Swollen non-painful

joints• Non-painful enlarged

LN >2 wks…• Distended abdo with

ascites• CF indicative of

Tuberculin hypersensitivity


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•It is difficult to confirm diagnosis of TB in many children but it is usually not so difficult to make a clinical diagnosis of TB in a child.


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General approach to Dx of TB in children

Symptoms with or without risk factors

Physical examination

Pulmonary TB EPTB

child <8 yrchild ≥8 yrs

Sputum examination

Sputum Sm+

Sputum Sm- CXR

CXR+ CXR-

Treat TB

Refer for expert opinion & follow up

Cervical TB glands Other EPTB

Biopsy/ FNAC

Pleural aspirateLPJt aspiratePericardial aspirate + CT scan/ X-ray/ US

Pediatrics for undergraduates, 2nd edn. Myanmar Pediatric Society.

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Diagnostic tests

CXR

Micro

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Microbiological confirmation

Sputum examination• Indicated in children > 8 yr• Sputum should be collected

spot, early morning & spot strategy

Gastric lavage (aspiration) • Indicated in children < 5 yr• Should be carried out after 4

hr of not eating or drinking (starvation)Adapted from Pediatric Management Guidelines, 2nd Ed. Myanmar Pediatric Society, 2011.

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Chest X-ray

Unequivocal hilar

lymph gland

enlargement with or without

parenchyma opacificatio

n

Miliary mottling (especially in HIV non-

infected host)

Large pleural effusion (≥1/3 of pleural

cavity) in children >5

years

Apical opacificati

on with cavitation (common in adolescents

)


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Tuberculin skin tests (TST)

http://www.webmd.com/skin-problems-and-treatments/measurement-of-a-tuberculin-skin-test-reaction Healthwise Staff, Current as of November 14, 2014

Guidance for national tuberculosis programmes on the management of tuberculosis in children –2nd ed. Geneva, World Health Organization, 2014 (WHO/HTM/TB/2014.03)

http://www.webmd.com/skin-problems-and-treatments/measurement-of-a-tuberculin-skin-test-reaction



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Causes of false-negative TST

Incorrect administration or interpretation of testHIV infectionImproper storage of tuberculinViral infections (e.g. measles, varicella)Vaccinated with live viral vaccines (within 6 weeks)MalnutritionBacterial infections (e.g. typhoid, leprosy, pertussis)Immunosuppressive medications (e.g. corticosteroids)Neonatal patientPrimary immunodeficienciesDiseases of lymphoid tissue (e.g. Hodgkin disease, lymphoma, leukaemia, sarcoidosis)Low protein statesSevere TB


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Causes of false-positive TST• Incorrect interpretation of test• BCG vaccination• Infection with non-tuberculous mycobacteria


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TST positive• Induration >10 mm is considered positive irrespective of whether BCG has been administered• Induration >5 mm is considered positive in HIV positive children•Negative TST never rule out TB in children

Pediatric Management Guidelines, 2nd Ed. Myanmar Pediatric Society, 2011.

Interferon-gamma release assays (IGRA)

• detect IFN-γ generation by the patient’s T cells in response to specific M. tuberculosis antigens (ESAT-6, CFP-10, and TB7.7). • T-SPOT.TB test -

the no. of lymphocytes/ monocytes producing IFN- γ. • QuantiFERON-TB

test - whole blood concentrations of IFN-γ

Brian R.W. et al. Davidson’s Principles & Practice of Medicine, 22nd edn. Elsevier; 2014. 46

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Interferon-gamma release assays (IGRA)• Test antigens not present on M. bovis–BCG and Mycobacterium avium complex•Higher specificity, fewer false-positive results. • need for only 1 patient encounter (vs 2 with the TST)• lack of crossreaction with BCG vaccination and most other mycobacteria.• cannot differentiate between TB infection and disease.


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However…•IGRAs should not replace TST in low- and middle-income countries for the diagnosis of latent TB infection in children or for the diagnostic work-up of children (irrespective of HIV status) suspected of TB disease in these settings.


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Recommendations for HIV testing•Miliary TB• Clinical signs suggestive of HIV disease•Mother known to be HIV positive or either parent suspected of being HIV infected• Relapse or treatment failure


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Recommended doses of first line anti TB drugs for children

Streptomycin should be avoided whenever possible in children because the injections are painful and irreversible auditory nerve damage may occur


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Recommended treatment regimens

Direct observation of drug administration (DOT) is recommended during the initial phase of treatment.Pediatric Management Guidelines, 2nd Ed. Myanmar Pediatric Society, 2011.

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Recommended treatment regimens for new cases of TB in children


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Indications to hospitalize• Respiratory distress in any form of TB• Severe adverse events (e.g. hepatoxicity)• TB meningitis•Miliary TB• Spinal TB


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Follow up• 2 weeks after treatment initiation, then at 2nd, 5th and 6th month• At every follow up assess symptoms, treatment adherence, adverse events and body weight• At 2nd, 5th and 6th month after treatment initiation→ collect sputum sample for smear microscopy only for the child smear positive at diagnosis• Follow up chest radiographs• Not routinely required in children• Indications for follow up CXR

• Extensive pulmonary involvement• Continued symptoms• Treatment failure regardless of smear positivity


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Extrapulmonary TB

Kay Yu San

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CNS TB

TB lymphadenopathy

TB pleural effusion

Pott’s spineTB intestine

Genital TB

TB pericardial effusion

Renal TB

TB peritoneum

TB arthritis

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Natural history of untreated primary TB

Brian R.W. et al. Davidson’s Principles & Practice of Medicine, 22nd edn. Elsevier; 2014.

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Signs suggestive of childhood TB

Pulmonary TB

• Signs of persistent pneumonia after full course of appropriate antibiotics

Highly suggestive EPTB

• Pleural effusion• Acute vertebral

gibbus• Non-painful glands

with draining sinus

Suggestive EPTB

• Meningitis…• Pericardial effusion• Swollen non-painful

joints• Non-painful enlarged

LN >2 wks…• Distended abdo with

ascites• CF indicative of

Tuberculin hypersensitivity

Adapted from Pediatric Management Guidelines, 2nd Ed. Myanmar Pediatric Society, 2011.

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Diagnosis of EPTBTB Site Type of TestCervical/other lymph glands

Biopsy/FNAC

Meningitis LP, CT brain scanArthritis Aspiration, biopsyAbdomen/Ascites USG, aspirationVertebra Vertebral X-ray


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Pleural effusion•Due to discharge of bacilli into pleural space from a subpleural pulmonary focus or caseated LN. • Asymptomatic, so common in primary tuberculosis that it is considered as part of the primary complex. •months to yrs after primary inf - larger and clinically significant effusions • usually unilateral but can be bilateral.


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Clinical features•H/O• often sudden• low to high fever• shortness of breath• chest pain on deep inspiration• fever and other symptoms can last for several wks

after the start of anti-TB• P/E - ….. • Prognosis • excellent, but radiographic resolution often takes

months. • Scoliosis is a rare complication from a long-standing

effusion.


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InvestigationsExamination of pleural fl & pleural membrane (important)• usually yellow and only occasionally tinged with blood. • specific gravity - 1.012-1.025• protein - 2-4 g/dL • glucose conc - low-normal range (20-40 mg/dL)• WBC - several hundred to several thousand per microliter, early

predominance of polymorphonuclear cells followed by a high percentage of lymphocytes.

• Acid-fast smears - rarely positive • Cultures - positive (<30%) Biopsy of the pleural membrane• positive acid-fast stain or culture• granuloma formation can be demonstrated.

TST• positive (70-80%)


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Diagnostic features for TB pleural effusion• Large pleural effusion (≥1/3 of pleural cavity) in children >5 years• Pleural tap indicates a lymohocyte rich exudates• Clinical picture suggestive of TB


Pleural effusion • Uncomplicated

right sided pleural effusion with no other radio-logical signsof primary TB visible.


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Often the radiographic abnormality is more extensive than would be suggested by physical findings or symptoms

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CNS Disease

Primary infection• Lymphohematoge

nous dissemination

cerebral cortex or meninges• metastatic caseous

lesion• increases in size• discharges small

numbers of tubercle bacilli

subarachnoid space• gelatinous exudate• interferes with the

normal flow of CSF in and out of the ventricular system at the level of the basilar cisterns

• Communicating hydrocephalus

corticomeningeal blood vessels• inflammation,

obstruction

cerebral cortex• Infarction

Brain stem• site of greatest

involvement• Dysfunction of CN

III, VI, and VII


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Clinical Features

• Alteration in level of consciousness

• Stupor to coma• decerebrate or decorticate posture

Stage 3 (Stage of Coma)

• Appearance of neurological signs & symptoms

• Increased irritability• Headache• Neck stiffness• Kernig and Brudzinski signs

• cranial nerve palsies• aphasia• Slurred speech• disorientation• Slurred speech• Hemiplegia• Ataxia• Involuntary movement

• Convulsion• Features of increased ICP

Stage 2 (Stage of meningitis)

• Nonsp symp• Apathy• Mood changes• Declining school performance

• Loss of appetite• Nausea• Vomiting• Low grade fever

Stage 1 (Prodromal Stage)

Adapted from Pediatrics for undergraduates, 2nd edn. Paediatric Society, MMA.

CSF appearance• Colour – clear/

cloudy• Cob-web

coagulum on standing

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http://jeevankuruvilla.blogspot.com/2012/04/tuberculosis-continuing-to-ravage.html last assessed on 8th March 2016

http://jeevankuruvilla.blogspot.com/2012/04/tuberculosis-continuing-to-ravage.html



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Investigations (CSF examination & culture)•WBC - usually ranges from 10-500 cells/μL. Polymorph present initially, but lymphocytes predominate in the majority of cases. •Glucose - <40 mg/dL but rarely <20 mg/dL. • Protein - elevated and may be markedly high (400-5,000 mg/dL) secondary to hydrocephalus and spinal block. •During early stage 1, the CSF can resemble that of viral aseptic meningitis only to progress to the more-severe CSF profile over several wks. • acid-fast–stained CSF and mycobacterial culture (related to volume of CSF sample) • PCR testing of the CSF - can improve diagnosis.

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Tuberculomas•MRI of brain of a 3 yr old child showing multiple pontine tuberculomas.


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Tuberculoma with hydrocephalus• a 1.1 x 1.0 cm round hypodense lesion in the right frontal lobe. • There was dilatation of all the ventricles, basal cisterns. • The anterior fontanelle was bulging.Case contributed by A.Prof

Frank Gaillardhttp://radiopaedia.org/cases/tuberculoma-with-hydrocephalus last assessed on 7th March 2016

http://radiopaedia.org/users/frank

http://radiopaedia.org/users/frank

http://radiopaedia.org/cases/tuberculoma-with-hydrocephalus

http://radiopaedia.org/cases/tuberculoma-with-hydrocephalus

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TB leptomeningitis• View of the inferior surface of the brain demonstrating encasement of the base of the brain with thick white exudate, characteristic of TB leptomeningitis.

Image courtesy of Yale Rosen, M.Dhttp://radiopaedia.org/cases/tuberculous-leptomeningitis-gross-pathology-1 last assessed on 7th March 2016

http://radiopaedia.org/cases/tuberculous-leptomeningitis-gross-pathology-1



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Treatment• 2HRZE + 7HR + corticosteroid

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Corticosteroids• Indication• TB meningitis• TB glands causing airway obstruction• TB pericardial effusion• Severe Immune Reconstitution Inflammatory Syndrome (IRIS)

• Recommended drug• Prednisolone 2 mg/kg daily increased up to 4 mg/kg daily in the

case of most seriously ill children• Maximum dosage of 60 mg/day for 4 weeks• The dose should then be gradually tapered over 2-4 weeks before

stopping


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Miliary TB•widespread hematogenous dissemination to multiple organs. • The lesions are of roughly the same size as a millet seed, from which the name miliary is derived.

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Miliary TB

A. The cut surface of the lung reveals numerous uniform, white nodules. B. A low-power photomicrograph discloses many foci of granulomatous

inflammation.

AB

Klatt EC. Robbins and Cotran Atlas of Pathology, 2nd Edn. Elsevir; 2010.

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Clinical features• Fever• Fatigue •Malaise•Wt loss• Cyanosis• Coarse crepition•Hepatosplenomegaly• LN enlargement• BM involvement

Pediatrics for undergraduates, 2nd edn. Paediatric Society, MMA.

Miliary TB• Fine millet-

sized nodules typically seen in miliary TB. • The nodules are

all of similar size and spread through all the lung fields. • No other

radiological signs of primary TB are visible.


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PreventionKay Yu San

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Prevention

BCG vaccinat

ion

Contact screening & Mx

TB inf control

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Bacille Calmette-Guérin (BCG) vaccination

Original vaccine

• a strain of M. bovis attenuated by subculture every 3 wk for 13 yr

distributed to laboratories

• continued to subculture the organism on different media under various conditions

many BCG vaccines

• differ widely in morphology, growth characteristics, sensitizing potency, & animal virulence


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Meta-analysis on effect of BCG vaccination

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Extended Program of Immunization (EPI) in Myanmar•BCG at birth• If the child missed BCG at birth, BCG should be given at 2 months of age.

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Child immunization coverage on BCG

• Chin State stood behind other states and regions in all these doses.

• Magway was at first place of BCG coverage (94.5%)• Source: Public Health Statistics 2012, Ministry of Health, The Republic of

the Union of Myanmar, May 2014.

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Thank you for your attention!Any questions?

Childhood tuberculosis (TB)

Health & Medicine