[CIS PIDD] [cis-pidd] Renal Disease and CVID

Fri Mar 25 03:20:02 EDT 2016

Hi Prescott,

Have you considered STAT3 GOF in your patient?

ATB,

Mikko

Oyl Mikko Seppänen
Harvinaissairauksien yksikkö (HAKE)

Head, Rare Disease Center,
Helsinki University Hospital (HUH)
FINLAND

phone +358 947180201
GSM +358 50 4279606
fax +358 9 47174703

CIS-PIDD <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>> kirjoitti 24.3.2016 kello 23.46:

Hi Jason:

If infection is still under consideration, I would suggest sending BAL or preferably lung biopsy to the University of Washington for 16S PCR/NGS.  Mycoplasmas, of which there are a number of different species capable of causing prolonged slowly progressive infection in hypoimmunoglobulinemic patients, are only one possibility – very hard to culture and specific PCR testing will fail unless you know what you are looking for.  IgG replacement may not help if the organism is a from a non-human host – we are collaborating with another center in a case of a fatal infection in a CVID patient associated with M. arginini, a species usually found in cattle.

With regard to the renal disease and the poorly reconstituted B cells after rituximab (unfortunate that our hematology and rheumatology colleagues rarely seem to check flow cytometry prior to ritux), I am following a young adult male with similar features, minus the (potentially) infectious aspects.  He was very healthy in infancy and early childhood, developed ITP at age 10, received 1 dose of IVIG and it improved transiently, then returned.  He got several doses of IVIG and responded each time.  Steroids didn't help for more than a week.  About a year later he developed neutropenia and he got a full workup at a well-known center - this turned out to be also autoimmune.  ALPS testing showed ~2.5% double negative T cells on one panel, lower on later tests.  FAS sequence was normal.  He originally had generalized lymphadenopathy that developed in 2009 - biopsy was neg for malignancy or DNT cells.  He got Rituximab July 2009 (4 weekly doses) and his immunoglobulins have drifted down to very low levels since that time.  Lymphadenopathy resolved.  Starting about a year after rituximab he has been treated with regular IVIG/SCIG.  Since the ritux he has had some recurrent sinus problems and bronchitis that responded to increased dosing of his SCIG replacement.  He had a perirectal abscess while neutropenic - hospitalized briefly Nov 2008.

His creatinine was 1.3 when I initially checked it – he had no h/o renal problems – and I referred to nephrology.  I am pasting in his biopsy results below.  He seems to have suffered silent injury to his kidneys at some point in the past – perhaps related to his underlying disorder – which seems to be inactive now.  I discussed this case with Koneti Rao at NIH and he felt it was quite likely he had some type of ALPS originally. His current flow panel on his sparse B cell population shows very low CD27+ B cells and no excess DNT cells.

I have considered that he might have a defect in the CD19/CD81/CD21 complex, which has been associated with kidney disease, and am planning to get WGS when it gets a little cheaper.  This might be a more pertinent option for your patient since she has active renal inflammation.

Prescott

T. Prescott Atkinson, MD PhD, Professor and Director
Division of Pediatric Allergy, Asthma & Immunology
University of Alabama at Birmingham
Tel: 205-996-9582
Fax: 205-975-7080
Cell: 205-999-7688

Date Reported:  7/14/2012

FINAL PATHOLOGIC DIAGNOSIS:

KIDNEY, LEFT, BIOPSY:
     FOCAL GLOBAL SCLEROSIS AND MILD INTERSTITIAL FIBROSIS (SEE COMMENT).

pm/7/13/2012

COMMENT:
There is no evidence of immune complex-mediated glomerulopathy.  The renal biopsy findings of focal global sclerosis and mild interstitial fibrosis likely represent old injury that is currently inactive.  Clinical correlation is advised.  This case has been seen in consultation with Dr. XXXXX (UAB Nephropathology), who concurs with the diagnosis.

CLINICAL HISTORY:
Sixteen-year-old white male with a history of idiopathic thrombocytopenic purpura treated with IVIG and Rituximab, who presents with azotemia.  Biopsy of the left kidney was performed.

GROSS DESCRIPTION:
The specimen is received in a container labeled "Renal bx."  It consists of two cores of tan soft tissue measuring 1.3 x 0.1 x 0.1 cm and 1.0 x 0.1 x 0.1 cm.  Tissue is collected for immunofluorescence and for electron microscopy.
(Jar 0)

MICROSCOPIC DESCRIPTION:
The renal biopsy specimen consists of two portions of renal cortex.  Thirty glomeruli are available for examination on multiple sections.  Twelve glomeruli are globally sclerosed.  The remaining glomeruli are mildly enlarged but show no significant expansion of the mesangial matrix or increase in mesangial cellularity.  The capillary lumina are widely patent, and the glomerular basement membranes have a normal appearance by light microscopy.  An occasional glomerulus is surrounded by a thickened Bowman' s capsule.  A rare glomerulus shows dilatation of Bowman' s space.  There is mild irregular interstitial fibrosis with corresponding tubular atrophy accompanied by a sprinkling of lymphoid cells and plasma cells.  Rare tubules contain intraluminal hyaline and pigmented casts.  There are rare foci of tubulointerstitial calcification.  The blood vessels are histologically unremarkable.  There is no evidence of vasculitis.  The special stains have appropriately reactive controls.

ELECTRON MICROSCOPY:
(EMLABS 2012-706): Thirteen glomeruli are present on multiple plastic embedded, BFMB-stained sections.  Nine glomeruli are globally sclerosed.  The remaining glomeruli are mildly enlarged but show no significant expansion of the mesangial matrix or increase in mesangial cellularity.  The capillary lumina are widely patent, and the glomerular basement membranes have a normal appearance.  Ultrastructural examination shows widely patent capillaries.  The glomerular basement membranes are of normal thickness.  Minimal segmental foot process effacement of the visceral epithelial cells is present.  Rare paramesangial electron densities are seen; however, there are no electron dense deposits.

From: CIS-PIDD [mailto:cis-pidd at lists.clinimmsoc.org]
Sent: Thursday, March 24, 2016 3:23 PM
To: CIS-PIDD <cis-pidd at lyris.dundee.net<mailto:cis-pidd at lyris.dundee.net>>
Subject: RE:[cis-pidd] Renal Disease and CVID

All,
I have a complex patient that I would like to present.

This is a 24 year old white female with CVID.  She presented to me in 2012.  Prior to my seeing her she was followed by peds Hem/Onc and then adult Hem/Onc for ITP (now resolved).  Her treatment included IVIG and rituximab.  On my initial evaluation her main infection was recalcitrant sinus disease.  My initial work up showed her to be:
Agammaglobulinemic with undetectable IgG, IgA, and IgM
Titers:  No response to pneumovax, tetanus, or diphtheria
Current T and B cell numbers
B cell 1% and 30 cells/uL
CD3  96.7% and 2420 cells/uL
CD4  19.5% and 490 cells/uL
CD8 77.5% and 1940 cells/uL
CD4/CD8 0.3

CD27+ B cells < 1%.

T cell function normal at initial consult.

Comorbid conditions:
ITP (resolved)
Lymphoid hyperplasia
Hepatosplenomegaly
Granulomatous Skin Disease
FINAL PATHOLOGIC DIAGNOSIS
MICROSCOPIC EXAMINATION AND DIAGNOSIS

SKIN, RIGHT JAWLINE, BIOPSY:
Sparse dermatitis with immature granulomas..
Lung Disease (Considering further lung studies and GLILD)
CT OF THE CHEST, ABDOMEN AND PELVIS WITH INTRAVENOUS CONTRAST,
.
INDICATION: adenopathy
.
COMPARISON: CT abdomen and pelvis 1/10/2014
.
TECHNIQUE: After administration of intravenous contrast, axial images of the chest, abdomen and pelvis were obtained in the portal venous phase. Supplemental 2D reformatted images were generated and reviewed as needed.
.
CHEST:
. Chest wall/thoracic inlet: Within normal limits.
. Thyroid: Incompletely imaged 13 mm low-density lesion in the left thyroid lobe.
. Mediastinum/hila: Within normal limits.
. Heart/vessels: Within normal limits.
. Lungs: Multiple groundglass foci are present predominantly in the right middle and bilateral lower lobes. 9 mm right middle lobe nodule (series 4, image 58). Several additional groundglass nodules are present in the periphery of the right lower lobe. 12 mm groundglass nodule in the right lower lobe (image 76, series 4).
CONCLUSION:
No substantial change in appearance of upper abdominal ligament and retroperitoneal adenopathy.
Patchy enhancement of the kidneys, concerning for pyelonephritis. Correlation with urinalysis is recommended.
Several groundglass nodules are present in both lungs which may be infectious or inflammatory in etiology. Recommend continued attention on follow-up.

Current clinical issue:
                In 12/2015 she presented with fever and flank pain.  She was admitted, diagnosed and treated for  pyelonephritis.  At this time she was found to have a creatinine of 1.91 (her weight is only 46.7 kg).   She was thought to have acute renal failure, but unfortunately he elevated creatinine has persisted and increased to 2.1.  Nephrology became involved and she had a renal biopsy showing a CD3+ CD68+ diffuse infiltrate with near complete interstitial fibrosis(note:  The biopsy was very small and not optimal) . A laparoscopic renal  biopsy has been completed and shows: scattered and few B cells or plasma cells.  A predominant CD8 interstitial infiltrate (80%). The infiltrate is not represented of the entire kidney with the larger biopsy, but 1 of 15 glomeruli are fibrosed.
                An infectious work up is negative for: HIV, CMV, EBV, JC virus, BK virus, HSV and pending for a GI panel, TB gold, repeat CT of Chest, Ab, and Pelvis, and HHV-8.  Urine has always been negative.
                My search of the literature shows a paucity of CVID patients with renal involvement.  Most in fact are case reports.  This renal literature reports the use of corticosteroids for disease suppression for varying lengths of time and success.

  1.  Has anyone see this type of infiltrate in the kidneys?
  2.  What other comments or recommendations do you have?

Thank you in advance for your attention,

Jason

PS: For those who are interested, she has one health boy born in 2014.  She was treated and monitored on sub q IgG replacement throughout the pregnancy and the baby was follow for several months after birth.  He had normal IgG levels though out this period.

Jason W Caldwell DO FAAAAI
Associate Professor Internal Medicine & Pediatrics
Section of Pulmonary, Critical Care, Allergic and Immunological Diseases
Director of Allergy & Immunology
Program Director Allergy & Immunology Fellowship
Wake Forest School of Medicine
p 336.716.4843/f 336.716.7277
jcaldwel at wakehealth.edu<mailto:jcaldwel at wakehealth.edu> / WakeHealth.edu<http://wakehealth.edu>
<image001.jpg>

Jason W Caldwell DO FAAAAI
Associate Professor of Internal Medicine and Pediatrics
Section of Pulmonary, Critical Care, Allergic and Immunological Diseases
Director of Allergy/Immunology
Program Director of Allergy/Immunology Fellowship
Wake Forest University School of Medicine
Office: 336-716-5166
Administrative: 336-716-4843
Pager: 336-806-8330
jcaldwel at wakehealth.edu<mailto:jcaldwel at wfubmc.edu>
<image002.gif>

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