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


Todd D Green
Children’s Hospital of Pittsburgh
November 4, 2007
                 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
                  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
             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
                                     Differential?

                                     Combined
                                      immunodeficiency
                                     SCID
10 month old male with               Omenn’s Syndrome
respiratory failure                  MHC I or II Antigen
                                      Deficiency
History chronic rhinorrhea, OM       p56 Lck deficiency
History eosinophilia and rash        DiGeorge Syndrome
                                     Hyper-IgM Syndrome
Tonsils and lymph nodes present      CGD
Lymphopenic                          CVID
                                     XLP
                                     XLA
                                     Others…
Further assessment:
   IgG 38 mg/dL, IgA 9 mg/dL,
    IgM 9 mg/dL, IgE ≤2 U/mL
                                         Clinical course:
   Abs lymph count 2046/mm3                Gradual recovery
    (3400-9000)                             No rash
      CD3+ 1550/mm3 (1900-                 300-2700/mm3
       5900)                                 eosinophils during 4
                                             wk admission
      CD4+ 500/mm3 (1400-4300)
                                            Bone marrow biopsy
      33% 4/45RA/62L (58-91)                nl trilineage
      CD8+ 1053/mm3 (500-1700)
                                             hematopoesis, no
                                             malignancy
      69% 8/45RA/62L (47-87)               Home on IVIG,
      CD19+ 308/mm3 (610-2600)              presumptive CVID
   Lymphocyte prolif normal to
    mitogens, absent antigens

                           Normals from Shearer et al., J Allergy Clin Immunol 2003
                     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
 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)
CD4:8        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
 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 Φx-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)
    Further Immunologic Workup
   ADA, PNP activity
   Common gamma chain sequencing (pt, mom)
   SH2D1A sequencing
   BTK sequencing
   CD40Ligand sequencing
   CH50
   Platelet size, number

   All normal
                      Summary
   Now 3 3/12 yo, h/o PCP
   Agammaglobulinemia with         Where to next?
    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

				
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