Case Discussion FAU Erlangen 13.12.2002

1. A 54-Day-old Premature Girl with Respiratory Distress and Persistent Pulmonary Infiltrates Case Discussion FAU Erlangen 13.12.2002 Wolfgang Freisinger

2. Chief Complaint • A 54-day-old girl was admitted to the hospital because of recurrent respiratory distress and failure to gain weight

3. SH - Mother • 38-year old woman ( gravida 2, para 0 ) • Group B, Rhesus positive blood • Immune to rubella, negative serologic test for syphilis • Smoking during pregnancy • Less than 1 pack a day • Respiratory tract infection several weeks before delivery • Treatment with erythromycine was successfull

4. PMH - Child • Delayed fetal growth • Born at 35 ½ weeks gestation by urgent cesarean section, performed after detection of meconium on amniocentesis and increased fetal heart rate • Birth weight was 1520g Is she a high-risk-infant ? • Yes, because of underweight, premature birth, mother smoking, meconium stained fluid • APGAR: 7 after one minute, 8 at five minutes, no resuscitation was required

5. PMH - Child (2) • Stable during and after brief administration of supplemental oxygen • No evidence of meconium aspiration • Placenta was small and showed a small, healed infarct • Tests for CMV and toxoplasmosis were negative

6. 9.400 – 34.00054-623-5 25-333-71-30-0,75 1,500-3,000/mm³84,000-478,00048-69

7. HPI – 4th day of life • child was transferred elsewhere for feeding and growth

8. HPI – 8th day of life • Development of a diaper rash • No response to multiple measures • Alternatives to cow milk don‘t bring any benefit

10. HPI – 26th Day of Life • Child is in tachypnea, with intercostal retractions

11. CXR 26th day of life Anteroposterior Film of the Chest on the 26th Day of Life. The lungs are hyperinflated, with bilateral streaky opacities in a parahilar, peribronchial distribution. The heart appears normal, and the superior mediastinal contour is narrow. There is a bone-within-bone appearance of the vertebral bodies and anterior flaring of the ribs.

12. CXR 26th Day of Life Lateral Film of the Chest on the 26th Day of Life. The lungs are hyperinflated, with bilateral streaky opacities in a parahilar, peribronchial distribution. The heart appears normal, and the superior mediastinal contour is narrow. There is a bone-within-bone appearance of the vertebral bodies and anterior flaring of the ribs.

13. HPI – 26th Day of Life Management ? • Specimens were obtained for culture • Administration of Gentamicin and Ampicilline

15. CXR 30th day of life Air – space Disease in the right upper lobe, a finding consistent with the presence of atelectasis

16. HPI – 30th Day of Life • Blood cultures were positive for coagulase-negative streptococci • Administration of antibiotics for additional 11 days • Condition improved

17. HPI – 36th Day of Life • Radiographic findings had improved

18. HPI – 40th Day of Life • Three days after the end of the antibiotic treatment : tachypnea recurred • But : another radiograph still shows improvement What would you do? • Administration of Cefuroxime, Clindamycin and Cisapride • Baby‘s conditon improves again

19. HPI – 44th Day of Life • CXR again shows abnormalities • Infant ist transferred to hospital this day

20. PE • Axillary Temp. 36,2°C • Pulse: 99 • Respirations 70 / min while breathing oxygen by nasal cannula • BP: 105/90

21. PE • Length 41cm (below 2 SD of new born) • Weight 2100g (below 2 SD of new born) • Head circumference: 34.5 cm (1 SD below the mean) • Lungs: occasional wheezes and scattered fine crackles are heard bilaterally • Minimal subcostal retractions • Liver edge palpable 5mm below right costal margin

22. Assessment 44-day-old premature girl with recurrent respiratory distress, severe lymphopenia and failure to gain weight

26. Cultures and serologic studies • No evidence of • Chlamydia • RSV • Adenovirus • Influenza A Virus

27. Stool specimen • No ova or parasites

28. Initial Treatment • Erythromycine and multivitamin • Albuterol by nebulizer • Axillary temperature does not exceed 37.7° but is normal on most occasions

29. Stained blood smear • Anisocytosis (+) • Poikilocytosis (+) • Polychromatophilia (+) • Hypochromia (+) • Many microcytes • Few macrocytes • Rare teardrop cells and schistocytes • 2 nucleated red cells per 100 white cells

31. Effect of the therapy • Infant‘s condition improves and remains stable for several days • Considerable mucus production and coughing • Moderate respiratory distress (50-60/min) • Axillary temp 36,4°C • Pulse 179 /min • SpO2: 89 %

32. ABG While breathing supplemental oxygen • Oxygen: 137 mmHg • Carbon Dioxide: 46 mmHg • pH 7.39 • Bicarbonate 28 mmol/l

33. CXR After Initial Treatment • Resolution of pulmonary abnormalities

34. Upper GI Series • Normal findings

35. DD • AIDS/ HIV Infection • Intestinal Lymphangiectasia • Severe Combined Immunodeficiency SCID

36. AIDS • Could explain this form of prolonged and profound lymphopenia in adults • But in this case • There is no evidence for HIV-Infection of the mother • No risk factors of the mother are known • CD4+ Lyomphopenia is manifested later in life • No clinical features or lymphadenopathy characterisic of pediatric AIDS

37. Intestinal lymphangiectasia • Leads to extensive lymphopenia and accumulation of lymphocytes in the gut • BUT: • Infants are immunocompetent and do not aquire early opportunistic infections • The absence of diarrhea makes this diagnosis unlikely

38. Forms of Severe Combined Immunodeficiency ( SCID ) • SCID with deficient T- cells and normal or high levels of B-cells • X-linked form (common -chain-deficiency) • Autosomal recessive form: Janus kinase 3 (JAK3) deficiency • SCID with deficient T-cells and B-cells • Adenosine deaminase (ADA) deficiency • Defect in Recombinase activating gene (RAG) 1 or 2 • Reticular dysgenesis

40. Red Cell Studies • Absence of adenosine deaminase activity and elevated levels of deoxyadenosine triphosphate • Levels of purine nucleoside phosphorylase normal

41. Peripheral blood lymphocytes • No proliferative response to phytohemagglutinin

42. SCID due to ADA-Deficiency • Autosomal - recessive form; 20% of all SCID patients • Due to various mutations in the ADA gene • Accumulation of adenosine, deoxyadenosine deoxyadenosine triphosphate and S-Adenosy-L-homocysteine are toxic to lymphocytes  this causes the immunodeficiency • ADA-SCID presents with a more severe lymphopenia than other forms of SCID (absol. counts < 500/mm³)

43. Clinical Presentation of SCID due to ADA • Lymphopenia with marked depletion of T and B lymphocytes • Normal or increased NK Cells • No corticomedullary demarcation of the thymus (Absence of Hassall‘s bodies and thymocytes) • Lymphnodes retain their normal architecture but contain only very few lymphocytes • Rib cage abnormalities similar to rachitic rosary, predominantly at the costochondral junctions, the apophyses of the iliac bones and in the vertebral bodies

44. Clinical Presentation of SCID due to ADA (2) • Circulating B-cells may present in some patients • Severity depends on the type of mutation in the ADA gene and the resulting degree of the ADA definciency • Growth and developmental abnormalities, including neurologic and osseous findings, have been observed

45. SCID Treatment of the Patient • Our patient was treated with polyethylene-glycol – modified adenosine intramuscularly, initially twice a week, guided by the levels of ADA and the toxic metabolites • She began smiling and interacting with the environment already after two doses of ADA • Suspected P. carinii infection was treated with Trimethoprim-Sulfamethoxazole i.v.

46. SCID Treatment • HLA identical or haploidentical bone marrow transplantation without chemotherapy • first perfomed in 1969 • graft-versus-host disease is uncommon • Survival ~100% for HLA identical and 78% for haploidentical graft • Gene therapy • Substitution of the enzyme

47. Follow Up • 500 mg immunoglobuline per kilogram every three or four weeks will give her enough protection • No live vaccinating agents • She is expected to grow and develop normally • The cartilaginous abnormalities should disappear • She can have a normal diet

48. Thank you for your attention