[CIS PIDD] [cis-pidd] Input please - 2yo boy with respiratory failure and ulcerative skin lesions
CIS-PIDD
cis-pidd at lists.clinimmsoc.org
Wed Nov 18 10:17:14 EST 2015
Dear Joanne,
It sounds like that is your answer. There are several cases series of MDA5-associated lung disease/skin disease, although most are in adults, and interestingly many are from China (as is your patient).
We had one patient with very severe disease and I can share our group's experience. Our patient initially presented at 19 months of age with refusal to walk, weakness, and rash and was started on methotrexate and steroids. About 6 months after diagnosis he acutely developed respiratory failure and required oscillatory ventilation. His respiratory course was very severe, with several near-death episodes, and we did not expect him to survive. He was found to have anti-MDA5 antibodies and we treated him with high-dose methylprednisolone, 5 cycles of plasmapheresis (every other day), followed by rituximab and azathioprine. We also gave him high-dose IVIG after the rituximab to both support his immune system and for potential immunomodulation. He made quite an amazing recovery, although he did require a tracheostomy and home ventilator due to lung damage. At discharge (nearly 5 months later), he was maintained on azathioprine and monthly IVIG. He received a 2nd course of rituximab ~6 months later. His lungs very slowly recovered, and he was off of his home ventilator completely within ~9 months and was decanulated approximately 16 months after his initial presentation. Today, 2.5 years after his initial respiratory failure, he is a well-grown and thriving 4 year old starting pre-school and developmentally normal with the exception of requiring some physical therapy. He continues on daily azathioprine and his IVIG was recently stopped. Of note, his MDA5 antibody took quite a while to resolve, and was still listed as "indeterminate" on the last measure. We did not use resolution of MDA5 antibodies as a treatment goal for his plasmapheresis, in part because the turnaround time is relatively slow here in the US.
I hope this is helpful, please feel free to contact me offline if you have any questions.
Best,
Megan
Megan A. Cooper, MD, PhD
Assistant Professor, Department of Pediatrics
Division of Rheumatology
Washington University School of Medicine
Cooper_m at kids.wustl.edu<mailto:Cooper_m at kids.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 [mailto:cis-pidd at lists.clinimmsoc.org]
Sent: Wednesday, November 18, 2015 2:31 AM
To: CIS-PIDD
Cc: Jane Munro; Roger Allen
Subject: Re: [cis-pidd] Input please - 2yo boy with respiratory failure and ulcerative skin lesions
Dear Megan,
BINGO!
The MDA -5 antibodies are in fact positive.
He was given 2g/kg IVIG in the last 24hrs and has already had 1 course of pulse methyl pred. This is being repeated tonight. He remains very unwell on HFOV in PICU with no significant improvement to date. At what point would you initiate plasmapheresis and rituximab. In your experience is this lung pathology reversible?
What a fabulous resource this CIS PID list is. What out for more cases from Melbourne.
Thanks again for your input
Joanne
From: CIS-PIDD <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>>
Reply-To: CIS-PIDD <cis-pidd at lyris.dundee.net<mailto:cis-pidd at lyris.dundee.net>>
Date: Wednesday, 18 November 2015 2:29 am
To: CIS-PIDD <cis-pidd at lyris.dundee.net<mailto:cis-pidd at lyris.dundee.net>>
Subject: RE:[cis-pidd] Input please - 2yo boy with respiratory failure and ulcerative skin lesions
Dear Joanne,
In addition to interferonopathies, I would also consider JDM-associated lung disease with the skin ulcerations. You could check a myositis antibody panel and specifically MDA-5 antibodies (associated with amyopathic JDM with rapidly progressive lung disease and skin ulceration). Do you have any further history of "developmental regression" - we sometimes see this in children with weakness from JDM. Treatment for this (if ab positive) might include plasmapheresis, high dose steroids, and rituximab. This wouldn't fit with absent NK cells, but as you know sometimes NK numbers can fluctuate with medication and acute illness (not sure how many times this was checked).
Best,
Megan
Megan A. Cooper, MD, PhD
Assistant Professor, Department of Pediatrics
Division of Rheumatology
Washington University School of Medicine
Cooper_m at kids.wustl.edu<mailto:Cooper_m at kids.wustl.edu>
Lab website: http://research.peds.wustl.edu/Default.aspx?alias=research.peds.wustl.edu/Labs/Cooper_M
From: CIS-PIDD [mailto:cis-pidd at lists.clinimmsoc.org]
Sent: Tuesday, November 17, 2015 5:46 AM
To: CIS-PIDD
Subject: [cis-pidd] Input please - 2yo boy with respiratory failure and ulcerative skin lesions
Dear CIS members,
Please offer any suggestions about possible diagnosis and further investigation and management for this 2yo boy currently in PICU on oscillator ventilatory support at The Royal Children's Hospital Melbourne Australia
2 years old boy
No previous infections. No significant chest infections
Background of developmental regression and global developmental delay
Possible food allergies to milk, egg, soy, wheat. Mild eczema
? history of previous viral wheeze
History of low grade fevers for six months 37.5-37.8
Since Feb, has had history of ulceration of the hands, ears, underarms, also has digital ulcers and dystrophic nails. One photo shows small digital infarct. (no vesicles or boils)
No family history, non-consanguineous Chinese parents. 4 y/o older sister, currently well
Born Bendigo.
Lived in China June 2014-June 2015
Current admission:
? Presented 1/11 - 1/52 fever & cough. Diagnosed with LLL pneumonia on CXR
o IV fluclox & gentamicin, azithromycin added
? 3/11 - ICU transfer - for 24 hours requiring high-flow oxygen.
? Transferred back to ward (~ 36 hours on ward)
? 5/11 - desaturation and increasing oxygen requirement
o CXR: bilateral patchy changes
o CPAP then intubation 6/11
o IV ceftriaxone added
? 11/11 - respiratory deterioration. HFOV
o IV tazocin, vancomycin, Bactrim, amphotericin & acyclovir
o Pulsed IV methylprednisolone 30mg/kg x 3/7 with ongoing 2mg/kg
? 13/11
o Lung biopsy taken. Anakinra commenced post biopsy
* Remains on HFOV fluctuating fio2 70-90% - may require ECMO
Investigations:
Rheumatological
Immunological
Infectious
ANA - Strong positive
Nucleolar (no titre)
C3, C4 normal levels
Ferritin 5/11 460
11/11 2542
17/11 794
ESR 50
CRP 28
RF negative
Opthalmology review: no uveitis
IgG, IgM, IgA normal
Complement function pending
Soluble CD25 - 6959 (normal)
Absent NK cells
Normal naïve T cells
B & T cells normal
Neutrophil function normal
HIB response > 9
Normal SAP/XIAP
Urine culture negative, mixed growth No blood no protein
Sputum culture negative
PCT < 0.9 persistently ( could be inflammatory or viral)
Blood cultures neg
Swab axilla neg
Herpes PCR swab negative
Enterovirus PCR negative
Quantiferon not interpretable
Respiratory virus PCR negative
Pertussis negative
7/11 BAL: VZV, mycoplasma, HHV6, EBV, CMV, adeno, HSV, enterovirus negative
Mycobacterial PCR neg
WB: VZV, HSV, EBV, CMV, adeno negative
Serum: HHV6 negative
13/11 Lung biopsy: EBV, CMV, HSV PCR neg
PJP negative
HIV negative
Hep A, B , C negative
Biopsy
Skin Biopsy:
The clinical differential diagnosis is noted. Histologic evidence of lupus erythematosus is not seen. The cutaneous histologic features associated with interferonopathy are not well described and include panniculitis and lipoatrophy. The main finding in this sample is fat necrosis and the cause of this is unclear. The histologic features are insufficient for diagnosis of panniculitis.
Lung Biopsy:
Section shows lung with extensive necrosis of the alveolar lining epithelium and numerous hyaline membranes. The alveolar septa shows prominent congestion and oedema. Occasional capillaries are lined by neutrophils. There is mild focal infiltration of lymphocytes with occasional eosinophils. Small areas are lined by cuboidal epithelium, possibly type II pneumocytes. Prominent fibrosis is not seen. The features suggest diffuse alveolar damage, the cause of which is not clear. Obvious infective organisms and granulomas are not seen
Looking forward to hearing your thoughts
Regards
Jo
Joanne Smart
Paediatric Allergist/Immunologist
Department of Allergy and Immunology
Royal Children's Hospital
Melbourne
Australia
From: CIS-PIDD <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>>
Reply-To: CIS-PIDD <cis-pidd at lyris.dundee.net<mailto:cis-pidd at lyris.dundee.net>>
Date: Wednesday, 4 November 2015 1:53 am
To: CIS-PIDD <cis-pidd at lyris.dundee.net<mailto:cis-pidd at lyris.dundee.net>>
Subject: RE:[cis-pidd] PLEVA AND HLH?
That is a great thought. Thanks Sharat.
Viral stains and EBER were reported negative, but will review that and all other considerations with pathology.
Blachy
From: CIS-PIDD [mailto:cis-pidd at lists.clinimmsoc.org]
Sent: Monday, November 02, 2015 2:54 PM
To: CIS-PIDD
Subject: RE:[cis-pidd] PLEVA AND HLH?
Dear Blachy,
Her hx of PLEVA plus disconnect between soluble IL-2R and ferritin could favor a CNS T-cell Lympho-proliferative disorder (LPD). The T-cells driving the LPD are likely contributing to the HLH phenotype. Apart from looking for an underlying genetic predisposition, if not already done, would suggest characterizing the infiltrating T-cells further: determine clonality by immunophenotyping and TCR gene rearrangement studies, evaluate for any chromosomal aberrations, and stain for ALK. Also, would be important to see if there is a particular infectious agent that could be driving her LPD. Given her ancestry, EBV would need to be excluded - suggest EBER staining if not already done. Other infectious agents to consider in this setting not listed below - Toxo (in particular given her CNS presentation), HHV8 and HTLV-1. Toxo and HHV8 are known to be associated with PLEVA.
Sharat
Sharat Chandra, MD
Assistant Professor
Division of Bone Marrow Transplantation and Immune Deficiency
Cincinnati Children's Hospital Medical Center
Cincinnati, OH 45229
________________________________
From: CIS-PIDD [cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>]
Sent: Monday, November 02, 2015 10:22 AM
To: CIS-PIDD
Subject: [cis-pidd] PLEVA AND HLH?
Dear all;
I have a very puzzling case I was hoping to get your opinions on.
8 year old girl, adopted, of Korean ancestry.
-4 years ago: Acutely developed a severe rash. After path discussions amongst many centers in the US, final diagnosis was PLEVA (pityriasis lichenoides et varioliformis acuta), a very rare T cell driven skin disorder. Treated with methotrexate to resolution.
-1 month ago: One week of high fevers and lethargy, brought by ambulance to hospital with new onset seizures and altered mental status. Labs at the time:
WBC 2.09, ANC 490
Hgb 10.0
Plt 94k
Transaminitis AST 148, ALT 248
Fibrinogen 155
Trigs 451
Ferritin 616
Soluble IL2R 12882
Subsets (prior to any treatment, but during this acute episode): CD3 493, CD4 189. CD8 247. CD19 152. CD56 - 51.
NK Lytic Units 0.0 (note lymphopenia and low NK cell number above)
Brain MR: Multiple large, poorly marginated enhancing lesions scattered throughout the bilateral cerebral hemispheres, predominantly involving white matter.
LP: 27 WBC, with lymphocytic predominance. Protein mildly elevated (54), glucose normal. Fungal, aerobic, AFB cultures negative. HSV, entero, VZV, EBV, CMV, Tb PCR negative. JC negative. Crypto Ag, myelin basic protein negative.
Brain stereotactic biopsy: Marked perivascular cellular infiltrate comprised of lymphocytes, plasma cells and macrophages. CD3 and CD5 stains show increased numbers of T-lymphocytes. Sections show abundant macrophages, some of which demonstrate intracelullar material consistent with hemophagocytosis. There is a marked perivascular cellular infiltrate comprised of lymphocytes, plasma cells and macrophages. A CD68 stain highlights No abnormal cells. Viral stains negative.
Bone marrow: 60-70% cellularity. Increased amount of macrophages, showing occasional hemophagocytosis. No malignant cells noted by morphology or flow.
ID (blood): HIV, RPR negative. EBV, CMV, entero, HHV6 PCR neg. Crypto Ag neg. VZV, WNV, mycoplasma, Erlichia, R Typhi, RMSF, typhus, borrelia, Hep B, Hep C, Parvo negative by antibodies (IgG normal at 1004).
Immuno: ANA, RF, SSA/SSB, lupus anticoagulant, cardiolipin Ab negative. ASO titer normal. C3/C4 levels normal.
Our hematology service started her on HLH treatment (with intrathecals), which has improved both her systemic and CNS inflammation, and has now referred her to me for consideration of transplant. HLH genetic panel was negative for AP3B1, BLOC1SG, CD27, ITK, LYST, MAGT1, PRF1, RAB27a, SH2D1a, SLC7A7, STX11, STXBP2, UNC13D, XIAP. LRBA/CTLA4 studies are in process.
I am not sold this is "just HLH", especially given her previous history. However, I am very concerned about her severe CNS presentation, and agree with hematology BMT might be in her best interest even if I don't have a definitive diagnosis. Looks like we have a couple possible 9/10 donors.
So, with that in mind:
1. Any diagnostic considerations? She is on etoposide and steroids, so functional studies will likely not be very helpful.
2. Our standard is to condition "HLH" patients on RICHI (-14 campath/flu/mel). Would you consider alternate regimens for her given her history? Her functional status remains low from her CNS insult, so I don't think myeloablation is not in her best interest.
Thanks for your input.
Blachy
Blachy J. Dávila Saldaña, MD
Attending Physician, Division of Blood and Marrow Transplantation
Children's National Health System
Assistant Professor of Pediatrics
George Washington University School of Medicine and Health Sciences
111 Michigan Avenue, N.W.
Washington, DC 20010
Phone: 202-476-4561
Fax: 202-476-2280
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