Respiratory failure in a 10monthold: Pursuing a diagnosis

1
Respiratory failure in a 10-month-old Pursuing
a diagnosis

• Todd D Green
• Childrens Hospital of Pittsburgh
• November 4, 2007

2
Case Presentation

• 10 mo male transferred from outside hospital
• Admission 8 months for bilat pneumonia,
  pneumothorax
• WBC 4.4 k/ul, ALC 1628/mm3, ANC 2288/mm3, AEC
  308/mm3
• Resp failure, intubation, ECMO
• BAL unremarkable (including Pneumocystis, fungal)
• ET sputum Klebsiella, Stenotrophomonas, Serratia
• Urine negative for CMV, adenovirus
• EBV PCR negative
• Negative molecular testing for CF
• Macular rash with eosinophilia (2500/mm3)
• Skin biopsy contact dermatitis, resolved with
  steroids

3
Case Presentation

• PMH
• Chronic clear rhinorrhea since 1-2 months
• Recurrent otitis media beginning 4 months
• PE tubes placed 7 months, continued infections
• Rashes with azithromycin and amoxicillin
• No chronic thrush, diarrhea, failure to thrive
• FH
• 4 yo brother with JRA, mat first cousin with CF
• No consanguinity, PID, early childhood deaths

4
Case Presentation

• Medications on admission
• Bactrim, Zosyn, Vancomycin
• Prednisolone
• Methadone, diuretics, sedatives
• Exam Ht 5th ile, Wt 5th ile, HC 25th ile
• HEENT intubated (tonsils later visualized)
• Nodes 2 mm node rt axilla, 3 mm node lt groin
• Liver 4-5 cm below rcm
• No murmur, rash

5

• Differential?
• Combined immunodeficiency
• SCID
• Omenns Syndrome
• MHC I or II Antigen Deficiency
• p56 Lck deficiency
• DiGeorge Syndrome
• Hyper-IgM Syndrome
• CGD
• CVID
• XLP
• XLA
• Others

10 month old male with respiratory
failure History chronic rhinorrhea, OM History
eosinophilia and rash Tonsils and lymph nodes
present Lymphopenic
6

• Further assessment
• IgG 38 mg/dL, IgA 9 mg/dL, IgM 9 mg/dL, IgE 2
  U/mL
• Abs lymph count 2046/mm3 (3400-9000)
• CD3 1550/mm3 (1900-5900)
• CD4 500/mm3 (1400-4300)
• 33 4/45RA/62L (58-91)
• CD8 1053/mm3 (500-1700)
• 69 8/45RA/62L (47-87)
• CD19 308/mm3 (610-2600)
• Lymphocyte prolif normal to mitogens, absent
  antigens

• Clinical course
• Gradual recovery
• No rash
• 300-2700/mm3 eosinophils during 4 wk admission
• Bone marrow biopsy nl trilineage hematopoesis, no
  malignancy
• Home on IVIG, presumptive CVID

Normals from Shearer et al., J Allergy Clin
Immunol 2003
7
Follow-Up

• Continued recurrent OM, mult sets PE tubes
• Recurrent rhinorrhea, diarrhea, slow wt gain
• Resolution eosinophilia, no further rash
• Developed PCP at 15 months
• LE thromboses during hospitalization, diagnosed
  with MTHFR gene mutation (1p36.3)
• Generally well since
• Recurrent nephrolithiasis with ammonium urate
  stones (unusual in US) at 31 months

8
Follow-up Immunologic Parameters

• 19 months 31 months
• ALC 4320 (3600-8900) 2695 (2300-5400)
• CD3 2458 (2100-6200) 1730 (1400-3700
• CD4 760 (1300-3400) 507 (700-2200)
• CD8 1659 (620-2000) 1145 (490-1300)
• CD48 0.46 0.44
• CD16/56 151 (180-920) 137 (130-720)
• CD19 1581 (720-2600) 776 (390-1400)
• CD45RA/62L 53 of T-cells 70 of T-cells
• Normals from Shearer et al., J Allergy Clin
  Immunol 2003

9
Follow-up Immunologic Studies

• 19 months 31 months
• Mitogen Prolif Normal Normal
• Antigen Prolif Absent Absent
• IgA 0 mg/dL 0 mg/dL
• IgM 0 mg/dL 0 mg/dL
• IgE 4 IU/mL 5 IU/mL
• Bacteriophage Fx-174 immunization response
  abnormal
• No detectable antibody after primary
  immunization, but with phage clearance,
  suggesting presence of neutralizing antibody
• Very low antibody titer after second (no IgG
  isotype)

10
Further Immunologic Workup

• ADA, PNP activity
• Common gamma chain sequencing (pt, mom)
• SH2D1A sequencing
• BTK sequencing
• CD40Ligand sequencing
• CH50
• Platelet size, number
• All normal

11
Summary

• Now 3 3/12 yo, h/o PCP
• Agammaglobulinemia with normal B-cells
• Abnormal response to bacteriophage immunization
• Low CD4 , o/w normal lymphocyte populations,
  including CD45RA/62L
• T-cell fxn with nl mitogen prolif, absent antigen

• Where to next?