[CIS PIDD] [cis-pidd] 45 yoF with chronic candidiasis & neurologic deficits

[Seppänen Mikko]

Dear Brant,

both CMC and CAEBV can be seen at least in WASP, STK4, TRAC and different forms of hypomorphic SCIDs. Considering her age, if this indeed turns out to be a monogenic PIDD , a hypomorphic mutation would be required...? Also, all different forms of NK deficiencies are worth considering, there are multiple good recent reviews out there on these (at least by JL Casanova et al. &  by J Orange et al.).

If the patient has been in NIH, Sarah Browne probably has checked anti-cytokine Abs (?), if not - again considering her age - I would certainly check. And considering her other AI-like features, this would be my first bet.

Of the five Good syndromes whom I have treated over the years, I have never seen any involution of thymic tissue during IgGRT (since they were all operated with thymectomy). However, this would probably be my second bet - and first and second can coexist.

I would thus first check for anti-cytokineAbs, and if negative, probably biopsy (and definitely would biopsy if anticytokineAbs are positive, would certainly point towards possible Good and benign thymoma) and then if no dg, WES her (am I repeating myself? ;=) ).

Hope this helps?

Mikko

dos Mikko Seppänen, LKT
Immuunipuutosv-o, HYKS

Mikko Seppänen, MD, PhD, Associate professor/Senior Lecturer
Specialist in Internal Medicine and Infectious Diseases
Senior Consultant, Physician in charge (PIDD)
Immunodeficiency Unit
Division of Infectious Diseases
Department of Medicine
Helsinki University Central Hospital
Hospital District of Helsinki and Uusimaa
Aurora Hospital, Ward 4-2 and Outpatient Clinic
P.O.Box 348
FI-00029 HUS, Helsinki
FINLAND
phone +358 9 47175923, fax +358 9 47175945




Lähettäjä: Brant R Ward [mailto:bward at mcvh-vcu.edu]
Lähetetty: 18. kesäkuuta 2014 0:55
Vastaanottaja: CIS-PIDD
Aihe: [cis-pidd] 45 yoF with chronic candidiasis & neurologic deficits

Hello, all.  It's a long history (sorry), but I'm hoping someone might have some comments or suggests on what to do next...

I was recently asked to see a 45yo F with h/o chronic candidiasis, "MS-like" neurologic features, and ? of recurrent EBV.
History:
- 1987: Hospitalized for fever, splenomegaly, and neutropenia; diagnosed with "mono" due to elevated EBV titers.
- 1989: Diagnosed with MS due to muscle weakness (exacerbated by exertion).  CSF, evoked potentials, MRI were normal.
- 1990-2000: Treated with bursts of corticosteroids during bad flares; MTX, cytoxan, cellcept, IFN-B, and copaxone also tried (latter 2 made things worse).
- 2000: Started on IVIG (eventually SCIg) by neurology in 2000 -> significant improvement in symptoms.
- 2000: Developed chronic, treatment-resistant thrush and vaginal candidiasis.  Problematic even during long (months to years) periods off immunosuppression.  Currently taking fluconazole 400 mg daily to control the thrush, up to 600 mg if she needs to take antibiotics.

Other info:
- Denies cutaneous viral infections or invasive bacterial infections
- Previously had 2-3 sinus infections per year, improved after endoscopic sinus surgery
- Several periodic episodes of elevated EBV IgM (persistently IgG+), most recently 10/13.  EBV IgM and DNA by PCR negative since I've seen her.
- Mild hypothyroidism, treated, and isolated low cortisol when she was taking prednisone; no other endocrine abnormalities
- No persistent lymphadenopathy or "B" symptoms

Notable workup:
- Normal immunoglobulins on several occasions (off Ig replacement)
- Normal lymphocyte enumeration on several occasions
- Negative anti-thyroid, anti-adrenal, and anti-islet Ab workup
- Negative extensive autoimmune workup
- 2006: Decreased lymphocyte proliferation to mitogens, candida; normal to tetanus, PPD (possibly on immunosuppression at the time)
- 2012: Extensive work-up at NIH -> Sequencing negative for STAT1 mutation, lymph proliferation normal (off immunosuppression), flow notable for low CD20/27/IgD-/Igm- B cells (4 per ul, 0.2%)
- 2014: Nerve biopsy shows small fiber neuropathy. Thought likely autoimmune by neurology.
- 2014: Normal Th17 panel

With myasthenic/autoimmune neuro symptoms and chronic candidiasis, we considered Good syndrome (despite her age and normal Ig levels). In fact, CT scans from 2003 showed likely thymic tissue greater than would be expected for her age.  However, the mediastinal tissue has decreased in size, becoming minimal, stable, and without discrete mass over the last 2-3 years.  Also, we vaccinated her 2 months after a lapse in her Ig replacement for insurance reasons (was the longest she was willing to wait without Ig) -> protein and CHO titers all increased after another 2 months (all off Ig).  But recent peripheral blood lymphocyte clonality testing showed a mono/oligoclonal population of T cells (no clonal B cells).

Could this population be related to a thymoma?  Has anyone seen thymoma involute with IVIG and/or immune suppression?  Is it worth trying to biopsy the mediastinal tissue?  Or would looking for other causes of candidiasis be higher yield (dectins, CARD9, etc.)?

Cheers,


Brant Ward, MD, PhD
Division of Rheumatology, Allergy, and Immunology
Virginia Commonwealth University
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