[CIS PIDD] [cis-pidd] 2-y-o girl with h/o heart transplant, very sick x 1 year

Fri Apr 6 11:54:29 EDT 2018

We published the use of basiliximab in a young infant w heart transplant who developed severe, necrotizing GI enteropathy that was responsive only to high dose IV solumedrol 2-4 mg/kg/day.   Her ulcerating gut disease prevented us from using sirolimus. However, her gut healed on basiliximab given q 1-3 weeks (started weekly and then tapered to q 3wks) and we were able to eventually add sirolimus. We could never get her off the basiliximab without return of symptoms until we switched to infliximab (used basiliximab for 2 years or so). She is still not perfect on tacro/siro /infliximab but we are trying to maximize her infliximab without going back to the basiliximab. She has normal CD4 and CD8 counts now that she is off of basiliximab but <2% of CD4 are naïve, presumably related to thymectomy at 1mo w heart surgery.  It is a benign drug short term but we have no idea what the long term effects would be….
Puri K, Kocoshis S, Risma K, Perez L, Hart C, Chin C, Ryan TD, Jefferies JL, Schumacher KR, Castleberry C. Basiliximab treatment for autoimmune bowel disease in a pediatric heart transplant patient.<http://www.ncbi.nlm.nih.gov/pubmed/26374667> Pediatr Transplant. 2015 PubMed PMID: 26374667.

Kim
Kimberly Risma MD PhD
Associate Professor Pediatrics
Allergy/Immunology
Cincinnati Children's Hospital Medical Cener

From: cis-pidd at lyris.dundee.net [mailto:cis-pidd at lyris.dundee.net] On Behalf Of CIS-PIDD
Sent: Thursday, April 05, 2018 10:06 AM
To: CIS-PIDD <cis-pidd at lyris.dundee.net>
Subject: Re: [cis-pidd] 2-y-o girl with h/o heart transplant, very sick x 1 year

Thanks Megan and Karl,

Karl, yes, FISH was done on the intestinal biopsies and it was negative for XY (no donor cells). CD3 cell chimerism has not been looked.
We thought about Omenn syndrome, but wouldn't you expect some response to high dose steroids? Her symptoms continued to worsen on high dose steroids and IVIG.
Megan, does the fact that high dose steroids did not work suggest anything else?
HHV6 is still high (600,000 copies/ml). She has been treated with Foscarnet and Gancyclovir for a long time with no luck. I will discuss your suggestion about brincidofovir with our ID team.
Thanks a lot,
Yeshim

Yesim Demirdag

Columbia University Medical Center

New York, NY

On Wed, Apr 4, 2018 at 5:06 PM, CIS-PIDD <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>> wrote:
I have a few of these patients, thought not quite so severe, the enteritis can be severe and challenging to treat.  With the cardiac transplant team we have been shifting some of these patients to mTOR inhibitors as you have.  My patients with a challenging course have primarily been infants with very early heart transplant, perhaps due to the immunosuppression and thymectomy at that age.  I have not found any PID genes with sequencing.

I would be interested in what others recommend.  I know she wouldn’t qualify for the thymic tx clinical trial, but I do wonder if some of these patients might need that for their immune dysregulation and immunodeficiency.

Megan

Megan A. Cooper, MD, PhD
Assistant Professor, Department of Pediatrics, Division of Rheumatology
Director, Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies at St. Louis Children’s Hospital
Program Director, Pediatric Rheumatology Fellowship
Washington University School of Medicine
Cooper_m at wustl.edu<mailto:Cooper_m at wustl.edu>
Lab website: http://research.peds.wustl.edu/Default.aspx?alias=research.peds.wustl.edu/Labs/Cooper_M
(lab office) 314-286-0262
(lab fax) 314-286-2895

From: cis-pidd at lyris.dundee.net<mailto:cis-pidd at lyris.dundee.net> <cis-pidd at lyris.dundee.net<mailto:cis-pidd at lyris.dundee.net>> On Behalf Of CIS-PIDD
Sent: Wednesday, April 04, 2018 3:49 PM
To: CIS-PIDD <cis-pidd at lyris.dundee.net<mailto:cis-pidd at lyris.dundee.net>>
Subject: [cis-pidd] 2-y-o girl with h/o heart transplant, very sick x 1 year

Dear all,
I would like to ask your opinion about this difficult case.

Very short summary:
- 2-year-old girl with normal NBS and ALC at birth underwent heart trasnplantation at 1-month of age due to pulmonary atresia and intact ventricular septum. Placed on Tacro.
- She did well until 1-year of age. At 1 year, she developed PCP pneumonia and was treated with Bactrim and steroids. T cells were very low (< 50). She was sent home on Bactrim ppx.
- About 2 months later she was hospitalized with severe desquamative dermatitis, eosinophilia, and increased LFTs. She has been in the hospital (and in and out of ICU) since then (almost 1 year!!).
- She still has T-cell lymphopenia, and recurrent infections with staph, enterobacter, pseudomonas and candida.
- During her stay she also developed severe bloody diarrhea and hypogammaglobulinemia which resolved after diarrhea was controlled.
- She also developed chronic pancreatitis (could be medications)
- WES did not reveal anything that can explain her symptoms.
- Biopsy of the skin and intestine were suggestive of GVHD.  HLH could not be ruled out.

Below is a longer summary :

A 2-year-old girl with history of pulmonary atresia and IVS s/p orthotopic heart transplant in March 2016 (at 1 month of age). Tacrolimus started after the transplantation. Her newborn screening revealed normal TREC, and ALC were normal before the transplantation.

She did well with only one ear infection until March 2017 (1 yr later).

In March 2017she developed PCP pneumonia, treated with Bactrim and steroids in PICU. Absolute T cell counts were 24 at that time. We thought it was secondary to medications (tacrolimus) and cardiac surgery (thymectomy). T cell counts increased to 250 and she was discharged 1 month later on Bactrim ppx.

In June 2017 she was re-admitted for fever and desquamative rash, eosinophilia, elevated liver enzymes with no atypical lymphocytes. DRESS vs GVHD-like syndrome were suspected. She was initially seen by dermatology and placed on high dose steroids. Bactrim was stopped. Skin biopsy showed superficial fragments of stratum corneum, not otherwise specifically diagnostic. There was no T cells in the skin, and FISH did not show any donor cells in the skin (donor was male).

During this time tacrolimus was stopped and cyclosporin was started.

HHV6 PCR was positive and has been positive with high counts since then.

In August 2017, she developed bloody diarrhea. IgG started to drop as well, and we thought it was due to intestinal loss. IVIG started and IgG levels stayed > 600 most of the time. Bloody diarrhea persisted. Sigmoidoscopy in September 2017 showed nodular, erythematous, friable mucosa with some rectal sparing possibly due to suppository use. Pathology appeared like grade 3 GVHD.

Skin symptoms (generalized erythema and desquamation) continued to persist for months. She still has generalized erythema, skin edema, and desquamation. She has been on systemic and topical steroids since August 2017.

On 10/28/17 and 11/10/17 she received vedolizumab which seemed to partially help with enteritis.

In December 2017: she underwent EGD/colonoscopy which showed severe gastritis with denudation and oozing blood. Duodenum and esophagus and terminal ileum were unremarkable. She had moderate to severe colitis, sigmoid to ascending rectum with some areas of sparing; friable, erythematous with ulcerations and loss of vasculatirty. Pathology with multiple denuded areas and apoptosis consistent with severe GVHD (grade IV) or drug reaction. CMV and HHV6 negative. H.pylori and HSV-1 negative.

On 12/20 cyclosporine was stopped and Sirolimus was started. Sirolimus was held on 3/2/18 for elevated lactate and mild acidosis.

In early March 2018, she developed subepithelial nodules on the neck and arm and underwent biopsy of the arm nodules that showed necrotic skin and thrombus. She became febrile again on 3/5 and blood returned in her stools on 3/7. It is unclear whether this is due to the stopping of sirolimus or ischemia to her gut.

Of note, she has persistently elevated triglycerides and recent CT showed chronic pancreatitis with a dilated pancreatic duct. She also has a new requirement for insulin. Thought is that pancreatitis may be due to hpyertriglyceridemia vs. inflammatory response. She remains intubated and edematous in the PICU and is NPO on TPN.

During the past year she had numerous episodes of fever. Cultures from various sites (skin, respiratory, urine, IV access site) grew various microorganisms including Staph epi, Enterobacter, Pseudomonas, and Candida).

LABS:

T cells increased to 1500s during an infection in September 2017 but they have been < 200 with normal B and NK cell counts since then.

Ferritin has been high up to 5000s, hematology thinks it is due to recurrent PRBC transfusions.

sIL2R has been very high (2200, normal < 1000)

Other cytokines at ARUP lab are normal.

CRP high

GENETICS:

WES, 207 gene immunodeficiency/autoinflammatory disease panel and microarray have not revealed an etiology.

Immunology panel shows variants of uncertain significance (VUS) in CR2, NLRP12, PTPRC and TERC genes. It was felt that the autosomal recessive variants of uncertain significance likely do not contribute to the patient's phenotype, because only one copy of each gene is affected. Mitochondrial DNA sequencing is negative for known pathogenic point mutations in mtDNA

Biopsy results:

Sigmoid biopsy 9/11: Colon, sigmoid, biopsy: Acute graft versus host disease (GVHD) Grade III (moderate to marked), with multifocal confluent crypt apoptosis and focal erosion with granulation tissue. There are mainly CD8 positive T-cells within the lamina propria with scattered CD4 positive T-cells. No B-cell lymphoid aggregates were sampled in the biopsy and by immunostaining only rare scattered CD20 B-cells are identified in the lamina propria.
Thanks,

Yeshim

Yesim Demirdag

Columbia University Medical Center

New York, NY

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