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

Sat Apr 7 13:09:10 EDT 2018

Hi Ellie,
Yes, the skin bipsy as well as gut biopsies were all performed while
patient was on steroids (she has been on steroids since August 2017).
There weren't any XY cells in either locations.
thanks,
Yeshim

On Thu, Apr 5, 2018 at 9:46 AM, CIS-PIDD <cis-pidd at lists.clinimmsoc.org>
wrote:

> Dear Yeshim,
> This discrepancy between the two biopsies (skin vs gut) is indeed
> interesting.
> Was the skin biopsy performed after steroids?
> In the gut biopsy, have you analyzed whether T cells were male or female,
> as you did for the skin biopsy?
> Elie
>
> Élie Haddad
> CHU Sainte-Justine, Montréal, QC
>
> On Apr 5, 2018, at 09:20, CIS-PIDD <cis-pidd at lists.clinimmsoc.org<mailto:
> cis-pidd at lists.clinimmsoc.org>> wrote:
>
>
> Hi, Dr. Demirdag:
>
> My 2 cents ...
>
> I'm trying to reconcile your pathologists' reads of GVHD versus the
> seeming absence of evidence for graft T cells in the biopsies.  For the
> skin lesions, you said they were not seen by FISH.  For the gut lesions,
> were they not seen also, or just not looked for?  Were there any peripheral
> blood CD3 cell chimerism studies done?
>
> 'Just my naive observation -- this phenotype almost sounds like Omenn
> syndrome, except with the "maternal graft lymphocytes" actually derived
> from the (male) solid organ graft.  (right??)
>
> My second thought -- you mentioned that HHV6 (blood) PCR's are high "since
> then", but not present in the gut biopsies.  Are they still high now?  I've
> always thought of viral studies in biopsies to be of medium/low sensitivity
> -- if it's positive, it is.  If negative, did the surgeon just poke the
> wrong place?  If the inflammation is indeed viral-driven (either HHV6 or
> CMV), brincidofovir/CMX001 may be worth a thought.  It certainly won't be
> the first case of an HLH phenotype being driven by something treatable by
> antibiotics/virals/fungals.
>
> Good luck with this difficult case.
>
>         - Karl
>
> Karl O. A. Yu, M.D., Ph.D., F.A.A.P.
> Scientist II and Assistant Director, Center for Infectious Diseases and
> Immunology
> RGH Research Institute | Rochester General Hospital | Rochester Regional
> Health
> 1425 Portland Ave., 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> [
> cis-pidd at lyris.dundee.net<mailto:cis-pidd at lyris.dundee.net>] on behalf of
> CIS-PIDD [cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.
> clinimmsoc.org>]
> Sent: Wednesday, April 04, 2018 5:06 PM
> To: CIS-PIDD
> Subject: RE: [cis-pidd] 2-y-o girl with h/o heart transplant, very sick x
> 1 year
>
>
> 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<https://urldefense.
> proofpoint.com/v2/url?u=http-3A__research.peds.wustl.edu_
> Default.aspx-3Falias-3Dresearch.peds.wustl.edu_Labs_Cooper-5FM&d=DwMGaQ&c=
> ZcS_IThVDLRgSnibLQVJ9vwqRPpc3RkFqvJL1VfvJu0&r=SS5WX_
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> MK95EsnBCqPEmk9nxrV0dc3zmqszBchQahpJng80j2I&e=>
> (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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