J ALLERGY CLIN IMMUNOL

FEBRUARY 2014

AB252 Abstracts

TUESDAY

871 Impaired T-Independent IgM Responses Due To Irak-4-,MyD88 Deficiency Or Splenectomy

Dr. Paul J. Maglione, MD, PhD1, Lin Radigan1, Sam Black1, Jessica

Overbey1, Dr. Emelia Bagiella1, Dr. Isabelle Meyts2, Prof. Jean-Laurent

Casanova, MD, PhD3,4, Dr. Capucine Picard, MD, PhD3, Dr. Charlotte

Cunningham-Rundles, MD, PhD, FAAAAI1; 1Mount Sinai Medical Cen-

ter, New York, NY, 2University Hospitals Leuven, Belgium, 3Hopital

Necker-Enfants Malades, Paris, France, 4Rockefeller University, New

York, NY.

RATIONALE: CD27+IgM+IgD+ B cells reside in the splenic marginal

zone and mount robust T-independent antibody responses against bacteria.

Human IRAK-4- or MyD88-deficiency, like splenectomy, are associated

with reduction of CD27+IgM+IgD+ B cells and susceptibility to bacteria,

mostly encapsulated. We investigated whether T-independent IgM against

bacterial antigens was impaired in patients with IRAK-4-MyD88 defi-

ciency or splenectomy.

METHODS: ELISA and carbohydrate array (functionalglycomics.org)

were used for antibody analysis. Immunoglobulin production and

CD27+IgM+IgD+ B cell expansion in culture after T-independent activa-

tion was measured. Antibodies from splenectomized subjects and controls

were measured before and after pneumococcal carbohydrate

immunization.

RESULTS: Patients with IRAK-4 or MyD88 deficiency have impaired

production of IgM against phosphorylcholine (p5 0.0009), S. pneumoniae

capsule (p5 0.002), teichoic acid from S. pneumoniae (p5 0.0032) and S.

aureus (p 5 0.0004), and array carbohydrates in total (p 5 0.0005) and

limited to S. pneumoniae or S. aureus expression (p < 0.0001) compared

to controls. In vitro, we observed that PBMCs from IRAK-4-deficient pa-

tients have inhibited IgM production and replication of CD27+IgM+IgD+

B cells. Secondly, boosting of T-independent IgM by pneumococcal immu-

nization was abated in splenectomized subjects, with anti-bacterial IgM

correlating with levels of CD27+IgM+IgD+ B cells.

CONCLUSIONS: Reduction of CD27+IgM+IgD+ B cells by IRAK-4-

MyD88 deficiency or splenectomy impairs T-independent IgM responses,

including those against bacteria. IRAK-4 and MyD88 appear vital for

optimal T-independent IgM responses and CD27+IgM+IgD+ B cell

replication in response to bacterial antigens in humans. Appreciation of

factors influencing T-independent IgM and marginal zone B cells may

provide useful insight into novel therapeutic or vaccine strategies.

872 Intestinal Perforation and Non-Tuberculous MycobacterialPeritonitis In a Patient With Interleukin-1 ReceptorAssociated Kinase 4 Deficiency

Dr. Hana B. Niebur, MD, Dr. Nathan Tang, MD, FAAAAI, Dr. Jennifer

Leiding, MD; University of South Florida, St. Petersburg, FL.

RATIONALE: Interleukin-1 receptor associated kinase 4 (IRAK-4)

deficiency is an autosomal recessive immunodeficiency associated with

recurrent invasive bacterial infections and impaired inflammatory response

due to abnormalities in Toll-like receptor signaling. Infection severity and

frequency typically decrease with age. Herein we describe a 16 year-old

female with IRAK-4 deficiency that developed intestinal perforations,

intra-abdominal abscesses, and non-tuberculous mycobacterial (NTM)

peritonitis.

METHODS: Bacterial cultures were performed at All Children’s

Hospital, St. Petersburg, FL with molecular identification of NTM

performed by National Jewish Laboratories.

RESULTS: This patient is a female with IRAK-4 deficiency who

experienced life-threatening pneumonia, septic arthritis, pyelonephritis,

and sepsis from Staphylococcal aureus and Streptococcal pneumoniae and

colitis from Clostridium dificile, Candida albicans, and enterovirus from 5

weeks to 7 years. She received IVIG from 7 to 10 years; subsequent infec-

tions were limited to chronic erosive sinusitis due to Pseudomonas aerugi-

nosa. At age 16, she experienced 2 spontaneous bowel perforations which

led to recurrent intra-abdominal abscesses and peritonitis requiring

numerous surgical interventions and broad-spectrum antimicrobial therapy

over a 2-year period. Initial bacteria isolated included enteric flora and

Pseudomonas. She developed Mycobacterium abscessus-induced perito-

nitis associated with severe protein losing enteropathy and intra-abdominal

ascites.

CONCLUSIONS: Bowel perforations and gastrointestinal disease have

been reported in few cases suggesting this is an under recognized feature of

IRAK-4 deficiency. While NTM frequently causes peritoneal dialysis-

associated peritonitis, Mycobacterium abscessus has not previously been

described in IRAK-4 deficiency. This patient’s clinical course challenges

the previously reported natural history of IRAK-4 deficiency of less severe

invasive infections after puberty.

873 Suspected Non-Infectious Prosthetic Valve InflammatoryDehiscence In X-Linked Chronic Granulomatous Disease

Dr. Monica Bhagat, MD1, Dr. Joshua A. Steinberg, MD2, Dr. Frank

Silvestry, MD3, Dr. Lea Surrey, MD3, Dr. Andrea J. Apter, MD, MA,

MSc, FAAAAI1, Dr. Patricia A. Takach, MD, FAAAAI1, Dr. Benjamin

P. Soule, MD1; 1University of Pennsylvania, Philadelphia, PA, 2Medical

College of Wisconsin, Milwaukee, WI, 3UPENN, Philadelphia, PA.

RATIONALE: Chronic granulomatous disease (CGD) is characterized by

severe recurrent bacterial and fungal infections. Hyper-inflammation

leading to tissue dehiscence is observed. We present a case report of a

patient with CGD diagnosed with a valvular abscess requiring mechanical

prosthetic valve replacement, which was complicated by suspected sterile

inflammation and recurrent valvular dehiscence.

METHODS: Tissue culture, staining.

RESULTS: This patient presented with Serratia osteomyelitis and pneu-

monia by 23 months of age and was diagnosed with X-linked CGD. At

age 22 he was admitted with shortness of breath and chest imaging showed

lung nodules. Biopsy of nodule positive for Philaphora richardsiae.

Developed acute congestive heart failiure and echocardiogram showed

an aortic perivalvular abscess. Treated with caspofungin and vancomycin.

Underwent mechanical aortic valve replacement. Cardiac tissue cultures

negative for infection; blood cultures negative. A newmurmur was audible

and patient diagnosed with aortic root abscess with partial dehiscence of

prosthetic aortic valve. Underwent repeat aortic valve replacement and

aortic root repair. Developed fevers and a new murmur on antibiotics.

Echocardiogram demonstrated valvular and aortic root dehiscence.

High-risk salvage surgery was indicated but declined by patient.

Intensive consideration of corticosteroid therapy occurred but was

declined. The patient passed away from septic shock.

CONCLUSIONS: We believe this is the first case report suggestive of

recurrent endocarditis and peri-prosthetic valvular dehiscence in a XL-

CGD patient. We suspect this outcome was due to CGD-related sterile

hyper-inflammation, induced by surgical manipulation and/or the presence

of prosthetic material. This case highlights the need to consider steroid

therapy for such atypical sterile hyper-inflammatory pathology.