[CIS PIDD] [cis-pidd] Granulomatous disease in 64y patient with Bruton's disease

[Nacho Gonzalez]

The patient cleared the infection (disseminated) with levofloxacin for
three months. Unfortunately she developed severe entesitis and the
infection relapsed. Mycoplasma faucium is resistant to macrolides but still
sensitive to doxycycline and levo/moxi (I've been in contact with Ken
Waites, an expert on rare Mycoplasma strains). As moxi is somewhat
different she has been on combination therapy (moxi+doxycycline or moxi+
josamycin) and the patient has been stable (now trying again to grow that
Mycoplasma three weeks off therapy). We are planning BMT in order to try to
cure the underlying immune defect.
Regards,

Luis Ignacio Gonzalez-Granado
Immunodeficiencies
Hematology & Oncology Unit.
Pediatrics.
Hospital 12 octubre
Madrid. Spain

How do you know what it is sensitive to if you are not able to grow it?



*From:* bounce-44192481-183824398 at lists.clinimmsoc.org [mailto:
bounce-44192481-183824398 at lists.clinimmsoc.org] *On Behalf Of *Nacho
Gonzalez
*Sent:* Monday, December 02, 2013 12:58 PM
*To:* CIS-PIDD
*Subject:* Re: [cis-pidd] Granulomatous disease in 64y patient with
Bruton's disease



Dear Klaus,



I follow a patient with agammaglobulinemia and "sterile" abscesses around
the neck, resembling granulomas. By 16S rDNA PCR and sequencing from
"sterile" neck and abdominal abscesses I identified a rare Mycoplasma
subespecies only sensitive to levo/moxifloxacin. Perhaps it is the reason
for the antibiotic unresponsiveness. Has your patient CD4 lymphopenia as
well?



Hope this helps,



Luis Ignacio Gonzalez-Granado

Immunodeficiencies. Pediatrics

Hemato-Oncology.

Hospital 12 octubre.

Madrid .Spain



2013/12/2 Klaus Warnatz <klaus.warnatz at uniklinik-freiburg.de>

thanks that is very helpful, and you did not see any reactivation of any
infection? How long do you have her (meaning that she is a CVID patient not
gamma, correct?) on infliximab?



greetings



klaus

Prof. Dr. med. Klaus Warnatz



UNIVERSITÄTSKLINIKUM FREIBURG

University Medical Center Freiburg

Center for Chronic Immunodeficiency

Division of Rheumatology and Clinical Immunology



Tel: +49-761-270-77640 / FAX -71000 / Pager: 12-7100



Breisacher Str. 117, 79106 Freiburg, Germany

klaus.warnatz at uniklinik-freiburg.de

http://www.uniklinik-freiburg.de/cci



Am 02.12.2013 um 19:35 schrieb amalbran31:



   I had a similar patient, reported in JCI, that went into remission with
infliximab. She relapses every time I taper it. Best regards,



Alex Malbran





Enviado desde Samsung Mobile de Claro


Klaus Warnatz <klaus.warnatz at uniklinik-freiburg.de> escribió:

Dear all,
I would appreciate diagnostic help in a male patient born in 1959 with a
genetically proven M. Bruton who developed in 2011 a granulomatous skin
disease of unknown origin.

Short version:
The granulomatous disease was also identified in lymph node biopsy (PET CT
positive all LN, bone marrow and spleen) (atypcial) mycobacterial infection
was excluded on several occasions, pan fungal and eubacterial PCR were
negative. No improvement on short term steroids (40mg pred/day for 2 weeks)
which was stopped due to increasing cytopenia (thrombus 40.000-20.000 and
Leukocytes 2.000-1.200). Subsequent thorough work up did not identify any
pathogen or lymphoma. Azithromycin
therapy for 3 weeks without improvement. Additional remarkable lab result:
persistent eosinophilia of 10-15%.
Happy to send photos of the skin lesions if wished for (not possible
through the server).

Our Questions see below!

Long version:
He associated it with the sickness of his lovebird (but no chlamydia were
identified at that time, I don't think other pathogens were excluded). He
had presented with a polyarthritis of finger, wrists and knees in 6/2011,
as expected autoantibody negative, synovial fluid could not be obtained and
a course steroids was started. Under this treatment while slowly tapering
the steroids he developed the skin disease starting in the face, but also
involving extremities, less the corso.  At this point we saw him the first
time. Steroids had been stopped because of the skin reaction. For the
arthritis no pathogen could be identified (no synovial fluid on joint tap)
we nevertheless had started him on doxycycline was started but stopped
after 2 weeks due to skin reaction without significant improvement. M
Whipple was excluded subsequently  Afterwards we did not see him for one
year but meanwhile we had asked for skin biopsies, which  confirmed
granulomatous disease partly with  central necrosis. First attempts to
identify
 mycobacterial DNA were all negative for myc. tuberculosis as well as
atypical mycobacteria. Due to the central necrosis in the granulomatous
disease infectious origin was suspected but  cultures of skin biopsies were
negative. A PET CT was performed demonstrating increased metabolism in
nearly all lymph nodes, the enlarged spleen and the bone marrow. 5 lymph
inguinal nodes were removed and demonstrated granulomatous disease and in 1
of 5 the PCR for atypical mycobacteria was positive but could not be
further differentiated and the confirmative test was negative. the treating
physicians decided to call it sarcoidosis and restarted steroids (this is
about 1.5y after the
 first round) with 40mg/day. This led to improvement of the subfebrile
temperatures and the general feeling, but not of the granulomatous skin
lesions within the first two weeks. At this time we were contacted again
because the blood cell counts worsened. The patient was leucopenic around
2ooo/nl and thrombopenic(around 40.000/nl) but dropped to 1.200 leukocytes
and 20.000 thrombocytes. Steroids  were stopped and the patient referred
again to our  hospital. Here we basically rebiopsied the skin lesions and
the bone marrow. Histology was confirmed, all cultures negative
(mycobacterial cultures are currently in the third week), multiplex PCR for
eubacterial DNA, for fungal DNA, mycobacterial DNA, leishmania, chlamydia
psittaci all negative. Beta D Glucan negative. Markers for granulomatous
disease were elevated (sIl2R, ACE, Neopterin). We did not identify a
lymphoma although the last clonality analysis from the skin biopsies is
still pending.
 Lab results: Leucopenia: 49% neutrophils, 28% lymphocytes, 12% eosinophils
(this was a persisting finding over the last 1.5 years, LDH within the
normal range
 Bone marrow. regular differentiation of the white and red cells, normal
megakaryocytes, eosinophilia,no signs of malignancy, no increased
lymphocytic infiltration
Microbiology: BM and skin biopsies: eubacterial, fungal, macobacterial, M
Tub, Listeria, Bartonella, Toxoplasma PCRs all negative,
blood CMV and EBV PCR eng cryptococcal Ag neg.
 Immune status: Cd4 400/µl CD19 0, CD8 300/µl.
Skin histology: adnexotrope granulomatous, partially necrotising
inflammation (partiale with destruction of hair follicles) with increased
lymphocytic infiltrates (IHC still pending),  PAS, Gram, Ziehl-Nelsen
negative.
 Because of the reaction to the steroids and the suspicion of a pathogen
driven inflammation we decided to first put him on a course of
azithromycin. after 2 weeks the blood cell counts had improved (leucocytes

>3000 and thrombocytes > 70.000), but the patient is still having

subfebrile temperatures and there is no change of the skin (may be not to
be expected).

Our Questions are:
 1) what is the differential diagnosis of granulomatous skin disease in a
patient with Bruton's disease given the results mentioned above?
(eosinophilia, partly granulomatous disease with central necrosis, etc)
 1b) is there a potential link with the sick love bird?
 1c) is there a link to changing the patient from  octagam to privigen
(prolin?) a question asked by the patient?
  2) have we sufficiently excluded an infectious cause ? if not which other
examinations should we perform?
  3) what is the next therapeutic step? can we dare to put him on
etanercept? try steroids again  despite the primary manifestation under
steroid treatment and worsening of the blood cell counts  under this
treatment?
 4) any prophylactic treatment for xyz?

 we appreciate your input, thanks

 Klaus
Prof. Dr. med. Klaus Warnatz

UNIVERSITÄTSKLINIKUM FREIBURG
University Medical Center Freiburg
Center for Chronic Immunodeficiency
Division of Rheumatology and Clinical Immunology

Tel: +49-761-270-77640 / FAX -71000 / Pager: 12-7100

Breisacher Str. 117, 79106 Freiburg, Germany
klaus.warnatz at uniklinik-freiburg.de
http://www.uniklinik-freiburg.de/cci



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