TB, or NOT TB? A Tough Question in Kids!

TB, or NOT TB? A Tough Question in Kids! Brian Lee, MD Pediatric Tuberculosis Program Division of Infectious Diseases Ken Martin, MD Division of Radiology

Overview Illustrate the range of clinical scenarios that present to pediatric ID/TB specialists Highlight clinical and radiographic features that are unique to pediatric TB Highlight common mistakes in the reading of pediatric radiographs Exchange ideas about approaches to management

Children are not little adults Children Primary Any lobe Rare Common Paucity Low Low Disease Type Location Cavitation Adenopathy Symptoms AFB Load Contagion Adults/Teens Reactivation Apical Common Rare Consistent High High

Diagnosis of Active TB in Children is Tough Clinical & radiographic findings are often nonspecific (due to immune response rather than AFB load) so can overlap with other diagnoses Low yield on AFB smears and cultures so microbiologic confirmation is not the norm (negative AFB smears and cultures NEVER rule out active tuberculosis) Diagnosis often based on epidemiologic risk and ruling out other causes

2-year old boy Arrived from Guatemala 3 months ago and was referred to TB clinic because of positive PPD (10 mm) and CXR showing right hilar adenopathy No significant past medical history Family denies any TB contact Symptom review: negative Physical exam: normal

What would you do? A. Test household members for TB and then decide what to do based on these results B. Obtain IGRA on patient and then decide what to do based on this result C. Obtain gastric aspirates and start multidrug TB therapy D. Another approach?

What would you do? A. Treat patient for LTBI B. Obtain IGRA and base LTBI treatment decision on this result

Pearls To evaluate for TB disease in children, CXR should include both frontal and lateral views (lateral view helps with evaluation of the hilum) Expiratory films can give the appearance of adenopathy around the hilum or infiltrate in the parenchyma (in some cases, repeating CXR with better inspiration can be helpful)

5-year old boy Arrived from Yemen over a year ago and referred to TB clinic because of positive PPD (17 mm) and CXR showing right hilar adenopathy Patient and family (parents, 2 sisters) all PPD negative 1 year ago (3 month old brother not yet tested) Family denies any TB contact Symptom review: cough and rhinorrhea for 1-2 months Physical exam: normal

Evaluation of Household Members 3- and 7-year old sisters: PPD positive (conversion) Parents and 3-month old brother: PPD negative

What would you do? Gastric aspirates were obtained, and RIPE therapy was initiated No source case was identified and AFB cultures of gastric aspirates all negative after 8 weeks A. Stop treatment for active TB B. Change to INH/RIF and complete 4 more months of treatment for active TB C. Continue RIPE therapy for 4 more months

Pearls Negative AFB smears and cultures never rule out active TB In general, if there is enough concern to initiate treatment for active TB in a child, the full treatment course should be completed, unless an alternative diagnosis is identified Because of the paucibacillary nature of pediatric TB, many experts are comfortable with INH/RIF for the continuation phase of treatment in the setting of culture-negative disease

2-week old boy Admitted to the hospital because of right upper lobe consolidation noted on CXR (obtained because pediatrician noted right clavicular fracture in clinic) Born in US to Hmong family PPD negative Family denies any TB contact Symptom review: negative Physical exam: normal

Pearls In children, thymus often mistaken as a pathologic process Thymus has variable appearance in both size and shape Normally prominent in newborn Increases in size during the first few months of life Less prominent between 5-10 year of age

8-month old boy Admitted to hospital with cough, diffuse wheezing, and increased work of breathing no improvement with albuterol and corticosteroids History of reactive airway disease and multiple clinic/ed visits over past 2 months for asthma, bronchiolitis, and/or pneumonia Born in US but mother and multiple family members from Cambodia Family denies any TB contact but aunt on treatment for LTBI PPD positive (15 mm)

Evaluation of Household Members Mother: CXR with right lung infiltrates and pleural effusion Father: PPD positive (20 mm), CXR normal 2-year old brother: PPD positive (10 mm), CXR right hilar adenopathy 5-year old brother: PPD positive (12 mm), CXR normal

Pearl: Pediatric TB = Sentinel Event Active TB (and recent TB test conversion) in a young child represents recent infection and therefore active transmission in the community (usually due to a contagious adult)

Pearl: Pediatric TB Infection = High Risk of Active TB Healthy adults: 5-10% (over a lifetime) Children: age-related risk (over 24 months) Age Pulmonary CNS/Miliary <1 year 30-40% 10-20% 1-2 years 10% 2-5% 2-5 years 5% 0.5% 5-10 years 2% <0.5% >10 years 10-20% <0.5% Marais BJ et al. Int J Tuberc Lung Dis 2004; 8: 392-402. Powell DA, Hunt WG. Advances in Pediatrics 2006;53:279-322.

10-month old girl Referred to TB clinic because of exposure to the same family in the previous case (who was culture positive for pan-susceptible TB) No significant past medical history Symptom review: cough and fevers for 3-4 days Physical exam: normal PPD positive (12 mm)

Initial CXR (PA)

Initial CXR (Lateral)

What would you do? A. Obtain gastric aspirates and start multidrug TB therapy B. Forego gastric aspirates and start multidrug TB therapy C. Another approach?

2 months into 3-drug therapy

What would you do? A. Continue current 3-drug TB therapy B. Change to 4-drug TB therapy C. Obtain gastric aspirates and add 2 new TB drugs D. Another approach?

1-week after prednisolone

Pearls Hilar adenopathy can manifest in multiple ways, including airway compression and ball-valve obstruction Worsening adenopathy (paradoxical reaction) after start of TB therapy is not uncommon and does not necessarily indicate treatment failure or drug resistance Rarely, corticosteroid therapy may be indicated in TB, such as for airway compression/obstruction

11-year old girl Referred to TB clinic because of positive PPD (19 mm) and abnormal CXR Born and raised in Japan until age 7 (h/o BCG), though parents originally from Sweden Past medical history: pectus excavatum Family denies any TB contact Review of symptoms: negative Physical exam: normal except pectus excavatum

What would you do? A. Test household members for TB and then decide what to do based on these results B. Obtain IGRA on patient and then decide what to do based on this result C. Obtain induced sputum samples and start multidrug TB therapy D. Another approach?

Evaluation of Household Members Parents: PPD negative 10-year old brother: PPD positive in past (h/o BCG), CXR normal

Pearls Chest wall deformities can cause increased density on CXR that can be mistaken for parenchymal disease CT scan can at times provide additional information when CXR findings are equivocal, but risks/benefits must be weighed

16-year old male Referred to TB clinic with 1 week of fevers and productive cough, h/o positive PPD, and CXR showing right lung disease Born in China and arrived in US 4 years ago Past medical history: PPD positive with normal CXR 1 year ago, but completed <1 month of INH Family denies any TB contact Symptom review: night sweats Physical exam: crackles over right lung

Additional information Evaluation of household members: Parents: h/o positive PPDs, CXRs normal 9-year old sister: PPD negative Induced sputum samples: all AFB smear negative and TB PCR negative

What would you do? A. Treat for community-acquired pneumonia B. Start multidrug TB therapy C. Obtain IGRA and based decision on this result D. Another approach?

Pearls When symptoms are acute, trial of treatment for community-acquired pneumonia is reasonable as long as: Initial sputum studies do show evidence of tuberculosis Reliable follow up assured BUT avoid using fluoroquinolone Normalization of CXR without TB therapy provides good evidence against active TB

16-year old male Referred to TB clinic due to productive cough over 3 weeks (despite course of azithromycin and amoxicillin), positive PPD, and CXR with RML/RLL infiltrates Born in China and arrived in US 2 years ago Past medical history: unremarkable Family denies any TB contact Review of systems: fever, cough, fatigue Physical exam: rales at right lung base

Additional Information Evaluation of household members Father: PPD positive (15 mm), normal CXR Mother: PPD positive (10 mm), normal CXR Sputum samples AFB smear 2+ positive, TB PCR positive

Pearls When symptoms are more chronic and has not responded to treatment for common entities, TB must be considered higher on the differential diagnosis Teenagers, like adults with TB, are more likely than young children to have higher AFB load and contagion so early testing of sputum samples can be helpful

15-month old girl Admitted with cough and respiratory distress, marked weight loss, diffuse adenopathy, and hepatosplenomegaly Born in the US, no foreign travel Past medical history: bullous pemphigoid requiring chronic prednisone and mycophenalate therapy Family denies any TB contact PPD negative (0 mm)

What would you do? A. Obtain gastric aspirates B. Perform bronchoscopy C. Perform lymph node biopsy D. Perform urine studies E. Perform lumbar puncture F. All of the above

Results BAL fluid: AFB stain positive Lymph node pathology: caseating granulomas CSF: normal AFB cultures from gastric aspirates, BAL, lymph node, and urine all positive for M. tuberculosis

What later emerged Prior to her birth: Father diagnosed/treated for active pulmonary TB Contact investigation identified LTBI in mother and 3 siblings, all of whom completed INH 3 months after birth: Adult cousin diagnosed with active pulmonary TB Contact investigation never identified baby as a contact Prior to immunosuppression for skin condition, patient was never screened/tested for TB

California Pediatric TB Risk Assessment

Pearls Families not always forthcoming with regards to TB history/exposure Risk assessment must include current/planned immunosuppression, which was not emphasized in prior TB risk assessments

7-year old girl Referred to nephrology clinic because of several months of urinary discomfort and urinalysis showed Protein 100, WBC>2250, and RBC 360 with negative urine culture Born in US; family originally from China Past medical history: h/o positive PPD Review of systems: unremarkable except for urinary complaints Physical exam: normal CXR and renal imaging obtained

Additional information obtained after referral to ID/TB clinic History of exposure to uncle with active TB several years ago Patient had positive PPD at that time but never completed INH Urine AFB cultures obtained and positive for pansusceptible TB

After 9-months of TB therapy

What would you do? A. Stop TB treatment B. Continue 2-drug TB therapy C. Add 2 new drugs to TB therapy D. Recommend resection of nonfunctional kidney

After 16 months of TB therapy kidney was resected Upper pole kidney: 3+ AFB, TB PCR negative Lower pole kidney: AFB negative, TB PCR positive Ureter: 2+ AFB, TB PCR positive ALL AFB cultures negative Molecular beacon testing: no INH/rifampin resistance mutations detected What would you do?

Pearls I hope you can tell me some for this case

10-year old girl Admitted with fevers and severe abdominal pain and emesis Born in Philippines but arrived in US 3 years ago Past medical history: negative Review of systems: negative other than above Physical exam: acute abdomen Taken to OR due to concern for ruptured appendix

Hospital Course OR findings Cloudy peritoneal fluid Gross pus draining from mesenteric lymph nodes Periappendiceal inflammation Pathologic findings Necrotizing granulomatous inflammation AFB stain positive Additional testing PPD negative (0 mm) CXR normal

Evaluation of Household Members Mother: PPD negative Brother: PPD positive (15 mm), CXR normal

Pearls TB can mimic almost any disease Extrapulmonary involvement is not uncommon among children with active TB Extrapulmonary 22% Both 7% Pulmonary 71% Any extrapulmonary involvement* (totaling 29.5%) Extrapulmonary site (%) Lymphatic (18.8) Meningeal (3.6) Miliary (1.3) Bone & Joint (1.5) Other (4.3) https://www.cdc.gov/tb/publications/slidesets/pediatrictb/default.htm

Cavitary Lung Cases Case 1: 14-year old female with cough and fevers for 1 month despite course of azithromycin. Patient born in US and no foreign travel but met missionaries from Uruguay. PPD negative. Case 2: 16-year old male with fever, cough, and weight loss over 10 days. Born in US and no foreign travel but parents both from Liberia. PPD negative. Case 3: 17-year old female with fever, chest pain, and cough for 2-3 weeks despite course of azithromycin. Born in Ethiopia and arrived in US 3 months ago. PPD negative.

Case 1: 14-year old female

Case 2: 16-year old male

Case 3: 17-year old female

Who has TB? A. Case 1 B. Case 2 C. Case 3 D. Case 1 & 2 E. Case 2 & 3 F. Case 1 & 3 G. All of the above

Epidemiologic Risk? Case 1: Lives in Tuolumne, CA. Both parents PPD negative years ago, contact with visitors from Uruguay Case 2: Lives in Antioch, CA. Parents from Liberia. Father (medical transport) PPD negative. Mother (LVN) PPD positive but CXR normal. Case 3: Lives in San Leandro, CA. Born in Ethiopia. Parents and 2 siblings TB cleared for immigration 3 months prior.

Alternative Causes? Case 1: Induced sputums with negative AFB smears. Fevers and cough improved on IV Unasyn and then PO Augmentin. CXR normal 2 weeks later. Case 2: Induced sputums with negative AFB smears. Coccidioidomycosis suspected. Fever and cough improved with fluconazole. Case 3: Symptoms not improving on ceftriaxone/clindamycin. Induced sputums with positive AFB smears and positive TB PCR.

Pearls Early testing of sputum samples for AFB and TB PCR can be helpful in older children with adult-type disease When negative, there should be careful consideration of other causes of cavitary disease

Summary Abnormal radiographs should be reviewed carefully, ideally with a pediatric radiologist Consider what else could be causing CXR finding (overlying clothing/jewelry, nipple, poor inspiration, thymus, etc.) Consider repeat CXR (sometimes with additional views) In some cases, consider CT scan to provide better definition of the abnormality Consider treatment of common infections first (as long as no evidence of contagion risk) Use TB infection/disease around child as surrogate for risk this may require active investigation