Tuberculosis In Children

Haim Bibi

Barzilai Medical Center

Ashkelon

Epidemilogy

• WHO estimates globally over 10 years

– 90X106 new TB cases worldwide

(13x106 pediatric cases)

– 30x106 death cases worldwide

– (5X106 pediatric cases)

• As of today 1/3 of the world population is infected with TB

World wide prevalence TB

Pediatric Tuberculosis Incidence in Israel, by Sex, and Comparison to the Overall Incidence Rate, 1999-2010

Pediatric Tuberculosis and Their Proportion of all Tuberculosis Cases in

Israel, 1999-2014

%from all TB cases ex-pulmonary pulmonary year

10.3 17 37 1999

11.8 12 51 2000

7.8 10 30 2001

8.7 10 30 2002

7.6 9 26 2003

7.2 4 28 2004

8.9 7 25 2005

10.3 2 32 2006

7.7 3 26 2007

5.4 5 12 2008

5.9 5 15 2009

6.1 4 16 2010

5.7 4 20 2011

3.9 2 18 2012

5.5 3 14 2013

8.9 6 27 2014

8.4 103 407 Total

Rates of Pediatric Tuberculosis in Israel by Age Groups, 1999-2010

Country of Birth and Citizenship of Pediatric Tuberculosis in Israel, 1999-2010

Diagnosis by origin and time after immigration 1990-99

Ethiopia FSU Ethiopia + FSU Israel Total

No. (%) No. (%) No. (%)

Same year208 (60.1) 15 (37.5) 223 (57.8) - 223

0-2 81 (23.5) 6 (15.0) 87 (22.6) - 87

2-5 24 (6.9) 9 (22.5) 33 (8.5) - 33

5+ 33 (9.5) 10 (25.0) 43 (11.1) - 43

Total 346 (100) 40 (100) 386 (100) 93 479

One infant born in Israel died.

Pediatric Tuberculosis in Children Migrants in Israel, by Years After Arrival in Israel

1999-2010.

Epidemiology

• Children usually are infected by an adult or an adolescent in the immediate household

• Children with TB rarely, if ever, infect other children

Transmission

Factors that increase transmission:

• Number of organisms in the air

• Length of exposure-and close contact

• Immune status

Transmission

• Spread through the air by droplet nuclei containing 2-3 organisms

• Droplet nuclei are air born for long periods

• Droplet nuclei are small enough to reach the alveoli

Prevention of Transmission Needs Only Simple Means

Transmission

• One third of contacts with open TB (AFB positive smear) will become infected

• Not all infected individuals have the same risk of developing disease.

Infection

•An immunocompetent adult with untreated

tuberculosis infection has approximately a

•5-10% lifetime risk of developing disease.

•, an infected child younger In contrast

than 1 year of age has a 40% chance of

developing disease within 9 mo.

•

Resistance and Immunity

• Genetic factors influence susceptibility

• Females are more susceptible during adolescence

• Viral infections like measles and influenza lower resistance for TB infection

Incubation Period

• From time of inhalation to time of development of cutaneous sensitivity and IGRA 1-3 weeks at least

• Tissue reaction intensifies in the primary complex which may become visible on CXR

Wallgren’s Timetable of Tuberculosis Feigin Textbook of Ped. Inf. Dis.

0 1 2 3 6 9 12 mo 1-5 yr

RENAL

SKELETAL

1O COMPLEX

PLEURAL EFFUTION

MILIARY & MENINGEAL

INITIAL FEVER

HYPER- SENSITIVITY

Wallgren’s Timetable of Tuberculosis

Time of development of chronic pulmonary TB is extremely variable

The Risk of Disease The risk of disease in the first two years

following infection is age dependent. The decline of risk with increasing age reflects greater innate and acquired immunity

• Infants (ages ≤1): 50 percent

• Children (ages 1 to 2): 12 to 25 percent

• Children (ages 2 to 5): 5 percent

• Children (ages 5 to 10): 2 percent

• Age >10 years : 10 to 20 percent

Wallgren’s Timetable of Tuberculosis

Symptomatic, massive lymph-hematogenous spread, that is miliary or acute meningeal TB, is seen in 0.5-3% of infected children, onset is 2-6 mo after initial infection. Mainly at the young age group. Acute hydrocephalus cam be marker of TB meningitis

Wallgren’s Timetable of Tuberculosis

• Endobronchial TB develops slightly later

• Metastatic bone and joint lesions develop in untreated children beyond a year later

• Renal lesions come 5-25 yr after initial

infection

Clinical Forms of TB in Children: Asymptomatic Infection

(LTBI Latent TB Infection)

• Associated with tuberculin hypersensitivity

• No clinical manifestations

• Positive PPD (or + IGRA)

• Negative CXR

• Investigation of contacts must be undertaken

• Therapy must be started with follow-up

Clinical Forms of TB in Children Endothoracic Primary Complex

• The primary complex first described by Ghon include three elements:

– primary focus

– lymphangitis

– regional lymphadenitis

• All parts of the lung are at equal risk for infection

• 70-85% of primary infection are initiated by one focus

Clinical forms of TB in children Endothoracic primary complex

As tuberculin sensitivity develops the hilar lymph nodes enlarge and caseous foci appear within them

Large nodes can compress neighboring airway leading to: hyperinflation or atelectasis.

Clinical Forms of TB in Children Endothoracic Primary Complex

• Calcification occurs more in children

• Calcifications may persist or start resorb after five years until they disappear

• extensive calcifications are uncommon in Western world because lesions treated with INH rarely caseate

Clinical Forms of TB in Children Pleural Effusion

• May be localized or generalized, uni or bilateral, symptomatic or asymptomatic

• Very often accompanies the primary complex

• Rare in children under 2 yr and uncommon under 5 yr.

Clinical Forms of TB in Children Pleural Effusion

• The exudate has high protein level, low glucose, cells: predominantly T lymph.

• Due to small numbers of bacilli in the fluid:

– Smears are almost always negative

– Cultures are positive in less than 30%.

– Gene MTB/RIF-Low sensitivity for pleural fluid samples

• Prognosis in children is good

Clinical Forms of TB in Children Progressive Pulmonary TB

• A complication of the primary complex

• High fever, cough, malaise, weight loss

• DD: simple tuberculous focus with a superimposed acute bacterial pneumonia

Clinical Forms of TB in Children Extrathoracic Spread - CNS

• Distributed to CNS during lymph-hemat. spread

• Can affect CNS in various ways:

– tuberculous meningitis

– Tuberculoma

– brain abscess

Clinical Forms of TB in Children Extrathoracic Spread - Other

• Skeletal

• Renal

• Cutaneous

• Scrofula: as an integral part of primary complex, or, as first sign of reactivation of prior infection

– Ocular

% Cases of Tuberculosis of Pulmonary and Extra Pulmonary Origin (Starke-USA)

30

10

80

60

50

40

20

100

90

70

All cases All extra pulmonary cases

Pulmonary 84%

Extra-pul 16%

Lymphatic 28%

Pleural 23%

Genitourinary 13%

Miliary 10%

Bone/Joint 9%

Other 9%

Peritoneal 4% Meningeal 5%

Site of Extra Pulmonary Tuberculosis in

Israel, Cumulative Data, 1999-2010

How Children with TB

are Discovered?

• In the developing world:

– with profound illness

– (2 weeks cough + FTT)

• In the developed world:

– symptomatic illness

– during contact investigation of an adult with TB

– During screening process

Diagnosis

• Absolute diagnosis: positive culture for M. Tuberculosis

• Due to difficulties associated with obtaining adequate samples for culture, the diagnosis of TB is confirmed by positive culture in less than half of the cases (10 - 75%)

Diagnosis

Even in developed countries the triad of

1. Positive PPD (IGRA -+ ?)

2. Abnormal CXR

3. Exposure to an infectious adult

Remains the most effective method for diagnosis

Diagnosis

• In adults the diagnosis of TB disease is mainly bacteriologic

• In children it is usually epidemiologic and thus indirect

Diagnosis

90% of TB cases in adults were bacteriologically confirmed

compared with 28% in children

CRITERIA FOR DIAGNOSIS OF TB

Culture of M. Tuberculosis from body fluid or tissue

OR

two or more of the following:

1. Cough lasting longer than 2 weeks

2. Radiographic findings compatible with TB

3. History of close contact with known or suspected infectious case of TB

CRITERIA FOR DIAGNOSIS OF TB Cont.

4. Positive PPD (positive IGRA)

5. Positive acid fast stain of sputum and gastric aspirate (Positive Gene MTB/RIF)

6. Positive response to anti- TB treatment:

– increase in body weight

– decrease in symptoms

– improving CXR (can be after years)

Diagnosis:

Culture

Clinical samples for culture:

• Common: sputum (may be induced with hypertonic saline inhalation)

• gastric fluid

• Less common: BAL, CSF, blood, urine, pleural fluid, biopsy material

Gastric Aspiration (GLA)

• Is the recommended method for children who cannot produce sputum

• Aspiration should be done early in the morning, after a fast of at least 8 hours

Gastric Aspiration

• Gastric aspiration for three consecutive days was better than BAL for bacteriological diagnosis

• Gene MTB/RIF + results

• Induced sputum better than Gastric aspirate.

Sputum Induction for the Diagnosis of Pulmonary Tuberculosis

in Infants and Young

Sputum induction with hypertonic saline (Saline 3%-7%)can be safely and effectively performed in infants and young children.

Sputum Induction for the Diagnosis of Pulmonary Tuberculosis

in Infants and Young

Induced sputum provides a satisfactory and more convenient specimen for bacteriological confirmation of pulmonary tuberculosis in HIV infected and uninfected children.

Gene-Xpert MTB/RIF

• Culture-positive tuberculosis was identified in 58 (6.2%) of 930 children: ten from sputum producers and 48 from GLA of non-sputum producers.

• The sensitivity and specificity of the Xpert MTB/RIF assay were similar

Chest X-RAY Compatible With TB

• Hilar adenopathy

• Bronchial stenosis, mainly in the RML-->leading to atelectasis and RML pneumonia

• Infiltrate

• Cavitary lesion

10 mo old infant with compressive RT hilar adenopathy with atelectasis and hyper-aeration of the RUL, 10 TB

0

10

20

30

40

50

60

70

80

0-4 yr 5-9 yr 10-14 yr 15-17 yr

lymph nodes

infiltrates

pleura

CXR Findings According to Age In Israel

CXR According to Origin

Immunodiagnosis of Tuberculosis: Tubeculin Skin Test

• The tuberculin skin test reflects recognition of M. TB antigens by T-lymphocytes

• Tuberculin reactivity appears 3 – 6 weeks, rarely up to 3 month, after initial infection

Immunodiagnosis of Tuberculosis: Tubeculin Skin Test

PPD – obligatory step in the diagnosis

False negative reactions are a major problem:

• Malnutrition

• Immunodeficiency states (HIV,steroids treatment, severe viral infections)

• Severe TB, or beginning of TB disease

• Technical problems ( material, injection, interpretation)

• Up to 20% of patients with TB

• Two step ( 2 weeks apart)

Immuno Diagnosis of Tuberculosis: Tuberculin Skin Test

• False positive results occur in people who have been infected with other mycobacteria including BCG vaccination (< 15 mm)

• In any population the likelihood that a positive response represent a true infection is influenced by the prevalence of infection with TB.

IGRA and LTBI

• There was no clear evidence that IGRAs should replace TST for detecting LTBI in children. Sensitivity of the IGRA for TB disease was no different from TST, and a significantly reduced IGRA sensitivity was found in high-burden TB settings compared with low-burden TB settings.

• IGRA can be positive post PPD test (JIA)

IGRA and TST

Routine testing with both TST and IGRA is NOT recommended. However, results from both tests might be useful in the following situation:

when the initial test is negative progression to and risk for poor outcome is high (e.g. HIV-infected individuals or children under five years of age who are exposed to a person with infectious TB)

Interpretation of the PPD Skin Test (irrespective of prior BCG vaccination)

5 – 9 mm 10 – 14 mm mm15 >

Contacts of infectious case

Children < 4 yrs., diabetes, renal failure

No personal or environmental risk factors

Suspected TB (CXR, symptoms)

Children of foreign born parents

HIV / immune-suppressive state

Travel to endemic areas

Bronchoscopy and BAL

Is indicated in infants and children with abnormal CXR (controversial)

Bronchoscopy and BAL

• Forty to 60% of whom will display endobronchial involvement:

– Airway narrowing by enlarged lymph node

– Granulation tissue

• Obstructive caseum

Bronchoscopy and BAL

• CXR may under-estimate endobronchial disease

• and Flexible bronchoscopy is safe and well-tolerate procedure

Bronchoscopy and BAL

• Flexible bronchoscopy has the advantage of viewing the airways in addition to obtaining BAL for culture

• But, gastric aspirates gives equal or better bacteriological results than BAL

Granulation tissue projecting into the lumen of

the RUL bronchus

Slit-like compression and granulation tissue of the RUL bronchus in a six yr old

Endoscopy in a case of laryngeal tuberculosis vegetation in the LT laryngeal ventricles

Laryngeal TB: pseudoneoplastic nodule

תיאור מקרה

ילד בן שנה וחצי יליד הארץ בן להורים • ילידי הארץ ממוצא צפון אפריקאי

הגיע לחדר מיון עם קוצר נשימה ושיעול•

כניסת אויר מופחתת לריאה : בבדיקה • ימנית

:צילום חזה•

חשד לגוף זר בדרכי הנשימה •

ברונכוסקופיה: –

תיאור מקרה

:אבחנה מבדלת

• Infection:M.tuberculosis ,Histoplasmosis

Coccidiomycosis, Syphilis,

Pneumocystis carinii in a patient with AIDS

• Tumors: Carcinoid, malignancy

• Congenital malformations

תיאור מקרה

תיאור מקרה

BALמיץ קיבה ונוזל •

• Ziehl-Neelsen (+)

לשחפת חיובית תרבית •

שלילי –מבחן מנטו •

PZI -ו INH ,RIFטופל ב •

סטרואידים + •

חודשי טיפול מבחן מנטו הופך לחיובי 6לאחר •

מ"מ 20•

תיאור מקרים ישראלי ממוצא ערבי מחלת חום עם –בן שנה וחצי

ניקור מתני דלקת קרום המוח –פרכוס לא פשוט

. ש עקרה"תרבית נוזל ע -טיפול עם רוצפין ללא שיפור

. ש"כלוריד מעט נמוך בנוזל ע

הפרכוס המשיך ההורים החליטו להעביר לבית חולים

בבית החולים –ניקור נוסף –גדול במרכז הארץ

CT –ממצא המתאים לדלקת קרום המוח –הגדול

MRI ספק ממצא בחומר הלבן

תיאור מקרים

• MRI נוסף כשבועיים וחצי לאחר האשפוז ממצא

.חיובי –מנטו . TBבקרומי המוח היכול להתאים ל

•Gene MTB Rif +

אבא מנטו חיובי: סקר מגעים•

. צילום חזה עם ממצא בפסגה הימנית•

.שחפת פעילה•

הילד כעת במצב של פגיעה נוירולוגית קשה•

תיאור מקרה o חודשים יליד ישראל להורים 6בן

, התקבל עקב מרפס בולט, מאריתריאה

חלבון , תאים לבנים 2–בוצע ניקור

100כלוריד מעט נמוך , מעט גבוה

.מוח תקין US. ליטר/מאק

o טיפול ברוצפין ללא שיפור 0תרבית .

0 –מנטו

.לאור המוצא הוחל טיפול נגד שחפת

תיאור מקרה

נשלח acute hydrocephalusתוך כדי אשפוז •

תאים לבנים 10נמצאו , בוצע ניקור -לנוירוכירורג

•GeneMTB Rif - שלילי

TBהמשך טיפול נוגד 0תרבית שחפת •

–מנטו בהמשך הפך לחיובי •

בריא לחלוטין –חודשים 9טיפול נוגד שחפת •

תיאור מקרה

בן להורים –פעוט בן כשנתיים ממוצא ישראלי •

.ללא קשר למדינה אנדמית. ילידי הארץ

RMLממצא קבוע באונה אמצעית מימין •

–לאחר תקופה ממושכת של ממצא קבוע •

ברונכסקופיה חסימה בברונכוס מימין

•geneMTB RIF + > מנטו +

LTBIבירור מגעים אבא •

על טיפול נוגד שחפת וסטרואידים •

Treatment of Childhood TB Disease

As in adults

• Including etambutol (Color blindness – optic neuritis).

• Quinolones – as indicated

Treatment of Childhood TB Disease

• DOT: 2-3 times/ week

• Specific indications for steroid use:

Meningeal, endobronchial with obstruction, pleural with mediastinal shift, pericardial.

Main Adverse Effect of Anti –TB Drugs

Isoniazid Neuropathy> hepatitis> rash

Rifampicin Hepatitis> rash Flu-like, thrombocytopenia, hemolysis Acute renal failure

PZA Rash> arthralgia> hepatitis

Streptomycin Rash> tinnitus> vertigo

Ethambutol Optic neuritis (rare)

Directly Observed Therapy (DOT)

ילדים מטופלים תחת השגחת גורם רפואי

DOT

(Direct Observed Therapy)

at least 3 times a week

LTBI Latent TB Infection treatment

9 months daily, 2-3 times a week INH

Or 4 months daily Rifampin

•Rifabutine and Isoniazide once a week 12

weeks

•The 12-dose regimen can be considered for

other groups on a case by case basis when it

offers practical advantages, such as

completion within a limited timeframe.

LTBI Latent TB Infection

•The 12-dose regimen is NOT recommended for the

•following individuals:

•Children younger than 2 years of age

•People with HIV/AIDS who are taking antiretroviral

therapy (ART)

•People presumed to be infected with INH or rifampin-

resistant M.tuberculosis

•Pregnant women, or women expecting to become

pregnant while taking this regimen

BCG Bacille Calmette-Guerin

• BCG vaccines are not an instrument for TB control

because

– They do not prevent infection with M. TB

– Their protective effect is short lived

– They do not prevent cases of contagious tuberculosis among adults in the community

• The role of vaccination is justified in areas where the annual tuberculin conversion is 0.5 – 1%

BCG-itis

• Manifestations: – Lymphadenopathy/ adenitis, local/ remote

– Abscess

• Can occur in a normal or immune compromised host

• Treatment – Drainage (needle aspiration) and cultue

– INH or RIF (and anti-staph)