[CIS PIDD] [cis-pidd] Opinion on a challenging case of suspected primary immunodeficiency

Tue Oct 31 15:40:57 EDT 2017

Dr. Jindal:

I am sure others would have more insight in this case … but right off the top of my head …

#  Because of the severe lung involvement, I would like to know if cystic fibrosis has been ruled out

#  Because of the concern for immunodeficiency, I am left wondering if you have any evidence of proper anti-vaccine responses (antibody) before exogenous IgG was given (or, at best, several months after the last dose of IVIG was given), as well as some subanalysis for recent thymic emigrants (TREC count, CD45RA, checking for maternal T cell engraftment, etc.).  Abnormalities here would strongly suggest a primary immune defect, despite your negative whole exome.

Good luck with the case.

Karl

Karl O. A. Yu, M.D., Ph.D., F.A.A.P.
Scientist and Assistant Director, Center for Infectious Diseases and Immunology
RGH Research Institute | Rochester General Hospital | Rochester Regional Health
1425 Portland Ave., Room R-403, Rochester, NY   14621
Tel  585-922-3709  |  Fax  585-922-2415

From: cis-pidd at lyris.dundee.net [mailto:cis-pidd at lyris.dundee.net] On Behalf Of CIS-PIDD
Sent: Monday, October 30, 2017 12:56 AM
To: CIS-PIDD
Subject: [cis-pidd] Opinion on a challenging case of suspected primary immunodeficiency

Dear All

I need opinions on this difficult case of suspected primary immunodeficiency
Here is a summary of the case:
A 2-year-old, boy first born to non-consanguineous marriage (with three first trimester abortions and pregnancy induced hypertension in the mother) by emergency caesarean with birth weight of 3.5 kg with smooth perinatal transition.
Till 9 months of age he was doing well. At 9 months of age, he had exanthematous febrile illness (clinical diagnosis Hand Foot Mouth disease).
At age of 12 months, watery diarrhea followed by bloody diarrhea, treated for suspected food protein induced enterocolitis syndrome (? eosinophilic colitis) [Given milk protein free diet and oral prednisolone for total of 3 months and oral mesalamine for 5 months till the age of 18 months]. On this treatment, his symptoms improved.
At 19 months of age, similar GI symptoms. Investigation, showed elevated serum IgE, positive fecal calprotectin, persistent leukocytosis with thrombocytosis. He was given IVIG (intravenous immunoglobulin) in April 2017 in view of suspected immunodeficiency. Colonoscopy and biopsy showed lymphoid aggregates in colon with formation of lymphoid follicles in lamina propria, lymphoid cells infiltrating into the crypt (autoimmune colitis), moderately dense lymphomononuclear cell infiltrate admixed with eosinophils. No features suggestive of inflammatory bowel disease. A panel of exome sequencing for 200 genes (including STAT3, STAT1, STAT2, STAT4, STAT5b, DOCK8, complement components, PIK3R1, IL21, IL21R, common SCID genes, genes for MSMD, gene for ALPS, IRAK4 etc.) showed no mutation.
July 2017 (age 21 months), diarrhea and respiratory symptoms with consolidation on chest X ray with blood c/s showing growth of pseudomonas species. CT chest showed multiple small pulmonary nodules with cavitatory pneumonia. Pleural biopsies revealed subacute inflammation (no evidence of TB and nocardia). Azithromycin, Meropenem and oral amoxicillin-clavulinic acid for 25 days. Autoimmune workup ANCA, ANA, ds DNA, Anti MPO IgG, Anti PR3 IgG- were negative.
September 2017 (age 24 months), he presented to our institute with persistent fever spikes and respiratory symptoms without any bowel symptoms. Hemogram showed anemia, high leucocyte count and mild thrombocytosis (Hb – 81 gm/L, significant leukocytosis with neutrophilic predominance (Total leucocyte count 33.1 x109/L, DLC-P61, L26M11E02) and thrombocytosis Platelet count- 560 x109/L), high erythrocyte sedimentation rate (83mm/hr). Lung MRI showed multiple cavitatory nodules in bilateral lungs (increased in size and number when compared from CT chest at 21 months of age). Fine needle aspiration from these nodules showed gram positive cocci but no organism on culture. Stool for calprotectin is normal and autoimmune markers are all normal again.
Date

Investigation

Report

Normal range

29/09/2017

IgG

8.04 (gram/L)

3.7 to 15.8 gram /L

IgA

1.44 (gram/L)

3.0 to 1.30 gram /L

IgM

1.28(gram/L)

5.0 to 2.2 gram /L

29/09/2017

NBT

Normal

29/09/2017

DHR

Normal

03/10/2017

Ig G 1

5.35gram/L

3.33  to 7.29 gram/L

Ig G2

1.93gram/L

0.40 to 1.88 gram/L

Ig G4

0.01 gram/L

0.05 to 0.31 gm/L

29/09/2017

CD 3+ cells

63%

43 to 76%

CD 19+ cells

13.30%

14 to 44%

CD 56+ cells

18.00%

04 to 23%

CD 3+56+cells

01.15%

-

03/10/2017

CD3+CD4+

61.52%

33 to 58%

CD3+CD8+

31.91%

11 to 25 %

CD4/CD8 ratio

01.92

1.3 -6.3

His immunoglobulin profile as well as NBT/DHR, lymphocyte subset, naïve CD3+ T cells, CD40 ligand, CD18, CD4/CD8 ratio, pSTAT3 levels, HIV serology all are showing normal results. On further workup he was found to have Elevated Ig E – 677kU/L with reduced CD 4+ IFN gamma cells (1.9% as compared to 14.6% in control) and Th17 cells numbers (0.3% as compared to 1.3% in control) [He was given steroids in past but now off steroids for 6 months]. Tubercular workup with with gastric lavage, tuberculin skin test, Bronchoscopy lavage, pus from FNAC are all negative.
After multiple sterile blood cultures, culture on 13/10/17 showed methicillin resistant Staphylococcus aureus- MRSA which is being treated with Teicoplanin because patient is allergic to vancomycin. Bronchoalveolar lavage (BAL) culture grew MDR Klebsiella Pneumoniae sensitive to colistin, which has been initiated. BAL for fungal smear is negative but BAL for galactomann was 3.4 ( positive) and patient is being treated with amphotericin-B for that. BAL for CMV DNA is PCR positive. However CMV viral load from blood is negtaive. He has been given 2 gm /kg of IVIG. Despite all these measures for more last 3 weeks, he is running high grade fever along with persisting cough and chest infiltrates and elevated inflammatory markers.
My queries are-

1.     What could be the possible immunodeficiency here (Could this still be STAT3 deficiency or DOCK-8 deficiency)?

2.     What additional testing can be done?

3.     Significance of low Th17 cells and CD4+IFNgamma cells when a patient has received steroids in the past?

Thanks

--
Regards
Dr ANKUR JINDAL
Senior Resident (DM)
Pediatric immunology and rheumatology unit,
Advance Pediatrics Centre,
Post Graduate Institute of Medical Education and research,
Chandigarh

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