[CIS PIDD] [cis-pidd] PIK3CD protocol/survey at NIH

Fri Aug 19 13:45:32 EDT 2016

Dear All,
I’m posting this message on behalf of my NIH colleague Koneti Rao.
This is related to a clinical trial using PIK3CD inhibitors in patients with PIK3CD GOF mutations.
If you have any questions, please contact Sharon Webster at phone number (301) 496-2771 or email: Webster, Sharon (NIH/NIAID) [C] sharon.webster at nih.gov<mailto:sharon.webster at nih.gov>.
Thanks,
Sergio

Immunology Service, DLM, CC, NIH
srosenzweig at cc.nih.gov<mailto:srosenzweig at cc.nih.gov>

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Draft survey questions

Dear investigators

APDS / PASLI ("Activated Phosphoinositide 3-kinase Delta Syndrome" /

"p110δ-activating mutation causing senescent T cells,

lymphadenopathy and immunodeficiency") is a genetic disease

identified in 2013 where a gain-of-function mutation in the PIK3CD

gene (encoding the p110δ subunit of PI3Kδ) manifests typically as

lymphoproliferative CVID with increased risk of lymphoma. While

APDS / PASLI is obviously a very rare, orphan disease, its prevalence

and age distribution are not known. The investigators at NIH/NIAID

and Novartis, conducting jointly a clinical research study in APDS /

PASLI (https://clinicaltrials.gov/ct2/show/NCT02435173), have

initiated this survey to get a more accurate estimate of the

prevalence. Your time to answer the short questions below (by

replying to this email) is greatly appreciated.

• How many patients with genetically confirmed APDS / PASLI do

you treat at your institution?

• Kindly provide us the gender, the current age (ideally the birth

dates) and the age of onset of symptoms (or diagnosis) of your

patients with PASLI / APDS.

Kind regards,

Investigators at NIAID and Novartis

If you have any questions, please contact Sharon Webster at phone number 301-4962771 or email: Webster, Sharon (NIH/NIAID) [C] sharon.webster at nih.gov<mailto:sharon.webster at nih.gov>.

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: Monday, May 23, 2016 at 1:09 PM
To: CIS-PIDD <cis-pidd at lyris.dundee.net<mailto:cis-pidd at lyris.dundee.net>>
Cc: "Ken B. Waites" <kwaites at uabmc.edu<mailto:kwaites at uabmc.edu>>
Subject: RE:[cis-pidd] neonatal spiroplasma infection

Hi Jan:

  Ken Waites, the UAB Diagnostic Mycoplasma Lab Director, agrees that a quinolone would be the best bet, but without MIC testing it’s just a guess.

I am assuming that your identification was made using 16S rRNA sequence.  Lorenz’s organism was apparently undescribed but most closely related to S. taiwanense, which was isolated from Culex mosquitoes in Taiwan.  Is your sequence identical to that in Lorenz et al?

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

From: CIS-PIDD [mailto:cis-pidd at lists.clinimmsoc.org]
Sent: Monday, May 23, 2016 11:49 AM
To: CIS-PIDD
Cc: Ken B. Waites
Subject: RE:[cis-pidd] neonatal spiroplasma infection

Hi Jan:

I work with the UAB Diagnostic Mycoplasma Lab here in Alabama – I have seen one other report of human infection by spiroplasma in addition to the ones you mention – also in an immunocompromised patient (lung transplant) – Mueller et al, 2015, American Journal of Transplantation 2015; XX: 1–6.   It is interesting, as reviewed by Lorenz et al,  that Spiroplasma mirum, originally isolated from rabbit ticks in the southeastern U.S., was first called suckling mouse cataract agent because of its effects in newborn mice.   It is also an interest coincidence that both your report and that of Lorenz et al describing congenital cataracts due to spiroplasma have occurred in Germany.

Mueller goes into some detail on the little that is known on antibiotic sensitivities of spiroplasmas, but these studies have been done mainly on plant and insect pathogens (tobramycin and fluoroquinolones are mentioned as effective).  Their patient responded to doxycycline and azithromycin,  but the best strategy of course would be to perform MIC testing in an experienced mycoplasma laboratory if you could obtain an isolate.  Lorenz’s patient was treated with erythromycin apparently with success; I wonder if the continued evolution of inflammation in your patient is due to the fact that macrolides are only bacteriostatic.

Regarding the question of underlying PID in the infant, I would agree that it should be explored.  However, although both Aquino’s and Mueller’s patients were immunocompromised adults, no mention is made of immune deficiency in Lorenz’s patient.  Since this is a slow-moving infection by an organism of low virulence, I would think judicious use of steroids at anti-inflammatory doses along with antibiotics would be a good idea.  Lorenz used topical steroids successfully in their patient.

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

From: CIS-PIDD [mailto:cis-pidd at lists.clinimmsoc.org]
Sent: Monday, May 23, 2016 5:42 AM
To: CIS-PIDD
Subject: [cis-pidd] neonatal spiroplasma infection

Dear colleagues,

I would appreciate your advice on the case of a now 6 months old, term-born male infant, who was noted to develop bilateral cataracts in the first months of life, requiring bilateral lentectomy. In addition, opthalmological examination revealed bilateral uveitis and persistant fetal retinal vascularization. Microbiological samples obtained during ophtalmological surgery on two different occasions yielded positive PCRs for Spiroplasma on both occasions.

All other microbiological studies performed on these samples (standard bacterial cultures, fungal PCR, CMV-PCR, Rubella-PCR, Bartonella-PCR, Toxoplasma gondii PCR, M. Tuberculosis PCR,) remained negative. In addition, serologies for CMV and Toxoplasma were negative, as were tests for lues, enterovirus (stool). Serologies for HSV and VZV yielded low titers which we believe to be due to maternal IgGs. ANA and pathergy tests were negative. The only positive findings were a positive throat swab for RSV – accompagnied by low level oxygen requirement for a few days - and a borderline tuberculine skin test (4 - 5 mm), yet no other clinical or radiological signs of TB.

Initial treatment consisted of prednison and – once microbiology results came back – erythromycin for 21 days. Follow-up examinations by the ophthalmologists revealed worsening uveitis about 4 weeks after discontinuation of the antibiotic treatment.

Upon screening the literature, I could find two case reports on Spiroplasma infection in humans: one linking Spiroplasma infection to cataract and anterior uveitis in an infant (Lorenz at al. 2002) and another describing a systemic spiroplasma infection in a patient with hypogammaglobulinemia (Aquilinio et al., 2015). Our little patient does have normal levels of IgA, IgM and IgG.

I do have two questions for which I would appreciate advice from the PAGID-listserver community:

‧         Has anyone seen spiroplasmosis in the context of an immunodeficiency ? In other words, would you be worried about an underlying immunodeficiency in an infant with bilateral Spiroplasma-uveitis that is otherwise well and thriving and does not have a family history of PID ? Beyond immunoglobulin levels (and maybe vaccine responses): are any other investigations warranted in this direction ?

‧         Given the observation that first-line therapy with erythromycin apparently did not prevent disease recurrence, what would be you next treatment choice ? We are thinking about combining clarithromycin with levofloxacin (as we are hesitant to give tetracycline to an infant). Would you consider adding steroids ? Any other suggestions ?
I would very much appreciate your advice in this matter.
Regards,
Jan

--
Dr. Jan Rohr

Center for Chronic Immunodeficiency (CCI)
University Medical Center Freiburg
Breisacher Str. 117
79106 Freiburg
Germany

phone (office): +49 (0)761 270-45295
phone (lab):    +49 (0)761 203-6550
e-mail:         jan.rohr at uniklinik-freiburg.de<mailto:jan.rohr at uniklinik-freiburg.de>

http://www.uniklinik-freiburg.de/cci/live/index.en.html

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