[CIS PIDD] [cis-pidd] 22m F with Intermitternt fever, rash, stroke and autoimmune hepatitis
CIS-PIDD
cis-pidd at lists.clinimmsoc.org
Tue Jul 19 04:42:16 EDT 2016
Looks / smells / quacks like Omenn syndrome.
Do people agree / disagree? (Gigi?)
- Karl
Karl O. A. Yu, M.D., Ph.D., F.A.A.P.
Instructor of Pediatrics (Pediatric Infectious Diseases)
University of Chicago - Comer Children's Hospital
5841 S Maryland Ave, MC 6054, Chicago IL 60637
Pager: 773-702-6800 x1744
Fax: 773-702-1196
Lab phone (Bubeck Wardenburg laboratory): 773-834-6976
________________________________
From: CIS-PIDD [cis-pidd at lists.clinimmsoc.org]
Sent: Monday, July 18, 2016 7:21 PM
To: CIS-PIDD
Subject: [cis-pidd] 22m F with Intermitternt fever, rash, stroke and autoimmune hepatitis
Hi All,
I am currently taking care of a 22 month old female of Burmese ethnicity with the following summarized problems and workup below; further detailed information below that. Has anyone seen a case like this and have any experience in management and/or possible genetic causes?
1. Admission at 5 weeks of life with sepsis 2/2 disseminated CMV treated with valganciclovir with resolution (CMV PCR negative at discharge. HIV negative.) Immune workup showed T cell lymphopenia (30% Memory). Low TRECs and poor mitogen response.
2. 7 months of age with diagnosis of autoimmune hepatitis. Started Prednisolone/6-MP. Noted to have an erythema multiforme like rash. Continued T-cell lymphopenia with elevated IGG.
3. 9 months of age ETEC treated with azithromycin. Taper of steroids.
4. 12 months of age rash flares and admitted with respiratory failure (no infection found). HLH evaluation negative though pancytopenic during this time. T cell lymphopenia with poor mitogen response. IL-18 elevated so trialled Anakinra, stopped after 1 week due to elevated transminases.
5. At 15 months admission for bacterial thumb infection and 17 months admission for FUO which improved on steroid increase.
6. 18 months of age on steroid wean admitted for L sided stroke and rash flare. ADA2 testing was normal. Increased steroids and improved.
7. 22 months of age admitted for rash flare on steroid wean; improved on increased steroids (rash flared on 0.3mg/kg Prednisolone).
8. Other co-morbid problems: Gross motor delay, verbal delay, Pulmonary HTN, Hypertension, GJ Tube fed.
9. Current immune workup shows Profound T (low TRECs, poor repotoire), B ( though normal B cell profile) and NK cell lymphopenia. Normal Immunoglobulins (absent IgA) and normal titers to pneumococcus, CMV, EBV, Parvovirus, Tetanus.
10. SCID Panel, NLRP3, and Whole exome sequencing reveal no candidates other then 1 pathogenic variant of DNA Ligase IV (though western blot shows normal expression and radiation sensitivity testing pending).
11. Most recent skin biopsy: Interface dermatitis and dermal mucin without evidence of vasculitis
Extensive history below with laboratory data:
Admission #1 (5 weeks old)
• Admitted at 5 wks for sepsis (fever, respiratory distress, hepatomegaly) 2/2 disseminated CMV with CMV hepatitis. Transaminitis trended down, but still present upon discharge.
• Treated with 12-week course of valganciclovir. Additional infectious workup negative, including HIV (dad HIV+). CMV PCR undetectable upon discharge.
• MRI with nonspecific findings, thought possibly areas of evolving blood/mineralization/calcification of uncertain etiology – not c/w congenital CMV and/or any mitochondrial or metabolic disorder.
• Hearing tests showed mild to moderate hearing loss in both ears, f/u showed mild L conductive loss.
Lymphopenic on admission (ALC 600s – low 1000s). Immune workup at that time:
Ref. Range
IGG
Latest Range: 425-1150 mg/dL
564
Ref. Range
TOTAL T LYMPHS(CD3+)%
Latest Range: 53-75 %
40 (L)
ABS TOTAL T LYMPHS (CD3+)
Latest Range: 2100-6200 CELLS/UL
684 (L)
HELPER T CELLS (CD3+CD4+) %
Latest Range: 32-51 %
13 (L)
CD3+CD4+MEMORY%
Latest Range: 4-36 %
31.0 (H)
CD3+CD4+TRANSITIONAL%
Latest Range: 5-28 %
9.6
CD3+CD4+NAIVE%
Latest Range: 46-83 %
60.2
ABS HELPER T CELLS (CD3+CD4+)
Latest Range: 1300-3400 CELLS/UL
227 (L)
SUPPRESSOR T CELLS (CD3+CD8+) %
Latest Range: 14-30 %
27
ABS SUPPRESSOR T CELLS (CD3+CD8+)
Latest Range: 620-2000 CELLS/UL
452 (L)
CD4/CD8
Latest Range: 1.2-6.6
0.50 (L)
TOTAL B CELLS (CD19+) %
Latest Range: 16-35 %
52 (H)
ABS TOTAL B CELLS (CD19+)
Latest Range: 720-2600 CELLS/UL
877
NK CELLS (CD3-CD56+CD16+) %
Latest Range: 3-15 %
7
ABS NK CELLS (CD3-CD56+CD16+)
Latest Range: 180-920 CELLS/UL
127 (L)
Ref. Range
TOTAL T LYMPHS(CD3+)%
Latest Range: 53-75 %
54
ABS TOTAL T LYMPHS (CD3+)
Latest Range: 2100-6200 CELLS/UL
1668 (L)
HELPER T CELLS (CD3+CD4+) %
Latest Range: 32-51 %
10 (L)
ABS HELPER T CELLS (CD3+CD4+)
Latest Range: 1300-3400 CELLS/UL
299 (L)
SUPPRESSOR T CELLS (CD3+CD8+) %
Latest Range: 14-30 %
39 (H)
ABS SUPPRESSOR T CELLS (CD3+CD8+)
Latest Range: 620-2000 CELLS/UL
1219
CD4CD8 RATIO
Latest Range: 1.20-6.60
0.25 (L)
TOTAL B CELLS (CD19+) %
Latest Range: 16-35 %
24
ABS TOTAL B CELLS (CD19+)
Latest Range: 720-2600 CELLS/UL
733
NK CELLS (CD3-CD56+CD16+) %
Latest Range: 3-15 %
18
ABS NK CELLS (CD3-CD56+CD16+)
Latest Range: 180-920 CELLS/UL
563
TREC (44 days of life):
CD3 T Cells L 739 cells/mcL 1484-5327
CD4 T Cells L 248 cells/mcL 733-3181
CD8 T Cells 465 cells/mcL 370-2555
TREC Copies L 2561 per 10(6) CD3
Tcells >4168
Cellular immune profile (44 days of life):
NORM CTL PHA 74489 [25000-350000] CPM
PATIENT PHA L 10465 [25000-350000] CPM
NORM CTL CON A 27678 [8830-350000] CPM
PATIENT CON A L 4247 [8830-350000] CPM
NORM CTL PWM 35063 [3500-200000] CPM
PATIENT PVM 14743 [3500-200000] CPM
NORMAL CTL CANDIDA 128.6 [5-500] SI
PATIENT CANDIDA L 1.0 [5-500] SI
NORM CTL TETANUS 9.8 [5-500] SI
PATIENT TETANUS L 1.1 [5-500] SI
Admission #2 (7 months of age)
• Findings c/w Autoimmune Hepatitis, so started prednisolone, as well as Diflucan for esophageal candidiasis. Subsequent addition of 6MP.
• EGD/liver bx results:
1. Duodenum, Biopsy: - Severe chronic active duodenitis with organizing ulcer
2. Stomach, Biopsy: - Fundic type gastric mucosa with moderate-to-severe chronic active gastritis with a significant component of eosinophilic gastritis - No H. Pylori-like organisms identified by Diff-Quik stain
3. Esophagus, Biopsy: - Mild epithelial hyperplasia consistent with mild reflux esophagitis, - Candidal colonization also noted
4. Liver, Biopsy: - Chronic acute hepatitis (Grade 3/4) with lobular activity (Grade 2) and portal and bridging fibrosis (Stage 3)
• Dermatology consulted d/t diffuse skin rash in most likely atypical erythema multiforme.
• Immune labs during admission:
Ref. Range
TOTAL T LYMPHS(CD3+)%
Latest Range: 53-75 %
47 (L)
45 (L)
ABS TOTAL T LYMPHS (CD3+)
Latest Range: 2100-6200 CELLS/UL
930 (L)
561 (L)
HELPER T CELLS (CD3+CD4+) %
Latest Range: 32-51 %
19 (L)
19 (L)
CD3+CD4+MEMORY%
Latest Range: 4-36 %
59.4 (H)
CD3+CD4+TRANSITIONAL%
Latest Range: 5-28 %
14.3
CD3+CD4+NAIVE%
Latest Range: 46-83 %
26.9 (L)
ABS HELPER T CELLS (CD3+CD4+)
Latest Range: 1300-3400 CELLS/UL
368 (L)
236 (L)
SUPPRESSOR T CELLS (CD3+CD8+) %
Latest Range: 14-30 %
27 (H)
21
ABS SUPPRESSOR T CELLS (CD3+CD8+)
Latest Range: 620-2000 CELLS/UL
531 (L)
265 (L)
CD4CD8 RATIO
Latest Range: 1.20-6.60
0.69 (L)
0.89 (L)
TOTAL B CELLS (CD19+) %
Latest Range: 16-35 %
45 (H)
50 (H)
ABS TOTAL B CELLS (CD19+)
Latest Range: 720-2600 CELLS/UL
887
621
NK CELLS (CD3-CD56+CD16+) %
Latest Range: 3-15 %
7
4
ABS NK CELLS (CD3-CD56+CD16+)
Latest Range: 180-920 CELLS/UL
137 (L)
48 (L)
Ref. Range
IGA
Latest Range: 8-120 mg/dL
<8 (L)
IGG
Range: 225-1400 mg/dL
3190 (H)
IGM
Latest Range: 30-160 mg/dL
149
Total IgE
Latest Range: <30 kU/L
Admission #3 (9 months of age)
• Admitted to hepatology for fever, vomiting, and diarrhea. Stool positive for enterotoxigenic E Coli – treated with azithro.
• NLRP3 sent to evaluate for NOMID/CINCA.
o NLRP3 gene: no sequence variants that are likely to be a primary cause of disease.
Admission #4 (10 months of age) for GT placement
• Repeat EGD showed resolution of candida esophagitis and upper intestinal inflammation.
• Transaminases improving, so began tapering prednisolone, but continued 6MP; also stopped Difluccan.
• 12 months of age, continued tapering steroids. Skin rash reportedly worsened.
Admission #5 (12 months of age)
• Admitted with fever, URI sx’s, and hypoxemia.
• Ventilated, including period on HFOV and iNO. BAL negative, including PJP, except lipid-laden macrophages.
• Abdominal drain place d/t significant ascites.
• Ganciclovir started due to elevated CMV PCR; gradually improved.
• Abd U/S (9/20) showed new splenic infarcts.
• Initial concern for possible HLH, though heme/onc thought unlikely, so no treatment initiated. Soluble IL-2R 2326 (ref 334-3026). Pancytopenic during course, required multiple PRBC transfusions and G-CSF initiated. Counts gradually improved.
• Immune workup during hospitalization:
o XIAP/XLP2:
CD4 : 72 % L (>=92)
CD8 : 64 % L (>-=93)
CD56 : 89 % L (>= 94)
CD19 : 84 % L (>-=89)
Decreased XIAP expression. Recommended repeating assay or pursuing XIAP/BIRC4 sequencing if clinically indicated
o NK cell degranulation: Not reportable d/t limited number of NK cells in specimen.
o Interleukin 18: 3818 (ref range 89-540)
o Sap Protein: normal SAP expression
o C3/C4 complements wnl
o Cytokine Panel:
PROCEDURE RESULT UNITS REFERENCE RANGE
IL-1 beta <10 pg/mL [<=58]
IL-2 <5 pg/mL [<=91
IL-4 11 pg/mL [<=17]
IL-5 1 pg/mL [<=4]
IL-6 24 H pg/mL [<=7]
IL-8 542 H pg/mL [<=47]
IL-10 2 pg/mL [<=7]
IFNg 8 pg/mL [<=8]
TNFa 12 pg/mL [<=16]
GM-CSF <1 pg/mL [<=11]
o SCID panel: One copy of pathogenic variant in LIG4 gene. Second pathogenic variant not identified. Western blot shows DNA Ligase IV expression; radiation sensitivity testing is pending.
Ref. Range
TOTAL T LYMPHS(CD3+)%
Latest Range: 53-75 %
88 (H)
ABS TOTAL T LYMPHS (CD3+)
Latest Range: 2100-6200 CELLS/UL
685 (L)
HELPER T CELLS (CD3+CD4+) %
Latest Range: 32-51 %
5 (L)
ABS HELPER T CELLS (CD3+CD4+)
Latest Range: 1300-3400 CELLS/UL
40 (L)
SUPPRESSOR T CELLS (CD3+CD8+) %
Latest Range: 14-30 %
73 (H)
ABS SUPPRESSOR T CELLS (CD3+CD8+)
Latest Range: 620-2000 CELLS/UL
570 (L)
CD4CD8 RATIO
Latest Range: 1.20-6.60
0.07 (L)
TOTAL B CELLS (CD19+) %
Latest Range: 16-35 %
9 (L)
ABS TOTAL B CELLS (CD19+)
Latest Range: 720-2600 CELLS/UL
71 (L)
NK CELLS (CD3-CD56+CD16+) %
Latest Range: 3-15 %
2 (L)
ABS NK CELLS (CD3-CD56+CD16+)
Latest Range: 180-920 CELLS/UL
19 (L)
Ref. Range
10/2/2015 05:35
IGA
Latest Range: 8-120 mg/dL
18
IGG
Latest Range: 425-1150 mg/dL
1360 (H)
IGM
Latest Range: 40-159 mg/dL
88
Total IgE
Latest Range: <53 kU/L
1211 (H)
10/6/15 Cellular immune profile:
NORM CTL PHA 183480 [25000-350000] CPM
PATIENT PHA L 670 [25000-350000] CPM
NORM CTL CON A 83994 [8830-350000] CPM
PATIENT CON A L 356 [8830-350000] CPM
NORM CTL PWM 49231 [3500-200000] CPM
PATIENT PWM L 1680 [3500-200000] CPM
NORMAL CTL CANDIDA 6.5 [5-500] SI
PATIENT CANDIDA L 1.3 [5-500] SI
NORM CTL TETANUS L 4.2 [5-500] SI
PATIENT TETANUS L 0.7 [5-500] SI
COMMENT LYMPH STIM
MINIMAL RESPONSE TO MITOGENS AND NO RESPONSE TO ANTIGENS.
• Started Anakinra d/t elevated IL18, but stopped after 1 week d/t transaminitis.
• Liver biopsy on 11/10 showed steatosis, AIH, and mild (level 1-2) fibrosis. Restarted 6-MP and prednisolone.
Admission #6 (15 months)
• Concern for possible sepsis. Monitored in PICU on home O2.
• Broad-spectrum abx narrowed to Clinda for superficial thumb infection.
• Repeat steroid taper.
Admission #7 (17 months of age)
• Admitted for persistent FUO, cough, emesis and AKI with dehydration.
• EBV PCR elevated, so decreased steroid dose. EBV and CMV PCRs subsequently remained low.
• Drug fever from 6MP considered, so d/c’d and steroid dose increased.
• Fevers resolved on increased steroid dose.
• Pancytopenic, but improved with increased steroid dose.
18 months of age: Started on a slow steroid taper.
Admission #8 (19 months of age)
• Admitted for R-sided weakness 2/2 acute ischemic stroke.
• Immune workup this admission thus far:
Ref. Range
TOTAL T LYMPHS(CD3+)%
Latest Range: 53-75 %
81 (H)
83 (H)
ABS TOTAL T LYMPHS (CD3+)
Latest Range: 2100-6200 CELLS/UL
773 (L)
785 (L)
HELPER T CELLS (CD3+CD4+) %
Latest Range: 32-51 %
21 (L)
27 (L)
CD3+CD4+MEMORY%
Latest Range: 4-36 %
86 (H)
CD3+CD4+TRANSITIONAL%
Latest Range: 5-28 %
8
CD3+CD4+NAIVE%
Latest Range: 46-83 %
6 (L)
ABS HELPER T CELLS (CD3+CD4+)
Latest Range: 1300-3400 CELLS/UL
204 (L)
252 (L)
SUPPRESSOR T CELLS (CD3+CD8+) %
Latest Range: 14-30 %
51 (H)
48 (H)
ABS SUPPRESSOR T CELLS (CD3+CD8+)
Latest Range: 620-2000 CELLS/UL
487 (L)
450 (L)
CD4CD8 RATIO
Latest Range: 1.20-6.60
0.42 (L)
0.56 (L)
TOTAL B CELLS (CD19+) %
Latest Range: 16-35 %
14 (L)
13 (L)
ABS TOTAL B CELLS (CD19+)
Latest Range: 720-2600 CELLS/UL
129 (L)
127 (L)
NK CELLS (CD3-CD56+CD16+) %
Latest Range: 3-15 %
3
3
ABS NK CELLS (CD3-CD56+CD16+)
Latest Range: 180-920 CELLS/UL
31 (L)
33 (L)
Ref. Range
ANA Symphony
Latest Range: <0.70
0.40
dsDNA Antibody
Latest Range: <10.0 IU/mL
2.0
ANCA IFA
Latest Range: <1:20
<1:20
C3 COMPLEMENT
Latest Range: 83-152 mg/dL
115
C4 COMPLEMENT
Latest Range: 13-37 mg/dL
23
IGA
Latest Range: 8-120 mg/dL
<8 (L)
IGG
Latest Range: 425-1150 mg/dL
1020
IGM
Latest Range: 40-159 mg/dL
134
CD4CD8 RATIO
Latest Range: 1.20-6.60
0.56 (L)
Total IgE
Latest Range: <53 kU/L
73.2 (H)
IL18: 1022 (elevated)
ADA2/PNP/ADA: Normal
TREC (20 months of life):
CD3 T Cells L 537 cells/mcL 1484-5327
CD4 T Cells L 143 cells/mcL 733-3181
CD8 T Cells 334 cells/mcL 370-2555
TREC Copies L Below limits of detection of current assay per 10(6) CD3
Tcells >4168
B cell phenotyping is normal distribution though overall B cell lymphopenia
Ref. Range
20 months
Cytomegalovirus IgG
Latest Ref Range: <0.9 AI
>8.0 (H)
Epstein-Barr Virus Viral Capsid Ag IgG
Latest Ref Range: <0.9 AI
>8.0 (H)
Epstein-Barr Virus Viral Capsid Ag IgM
Latest Ref Range: <0.9 AI
0.5
Epstein-Barr Virus Early Ag IgG
Latest Ref Range: <0.9 AI
<0.2
Epstein-Barr Virus Nuclear Ag IgG
Latest Ref Range: <0.9 AI
0.5
TCR Repotoire: 1 with polyclonal, 1 with oligoclonal, 26 with polyclonal non Gaussian
13/14 Pneumococcal Serotypes >1.3
Ref. Range
22 months
CMV Qnty PCR IU/mL
Latest Units: IU/mL
<300
CMV Qnty PCR DNA Copies/mL
Latest Units: DNA Copies/mL
<250
EBV Qnty PCR IU/mL
Latest Units: IU/mL
818
EBV Qnty PCR DNA Copies/mL
Latest Units: DNA Copies/mL
265
Ref. Range
22 months
PARVOVIRUS B19 IGG AB
Latest Ref Range: <0.90 index
1.17 (H)
PARVOVIRUS B19 IGM AB
Latest Ref Range: <0.90 index
0.14
Thanks,
Kiran
__________________________________________________________
Kiran P. Patel, MD, MS
Associate Program Director Allergy/Immunology Fellowship
Assistant Professor of Pediatrics & Medicine
Emory University School of Medicine/Children's Healthcare of Atlanta
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