Terry Harville

Use and interpretation of diagnostic vaccination in primary immunodeficiency: a working group report of the Basic and Clinical Immunology Interest Section of the American Academy of Allergy, Asthma & Immunology.

A major diagnostic intervention in the consideration of many patients suspected to have primary immunodeficiency diseases (PIDDs) is the application and interpretation of vaccination. Specifically, the antibody response to antigenic challenge with vaccines can provide substantive insight into the status of human immune function. There are numerous vaccines that are commonly used in healthy individuals, as well as others that are available for specialized applications. Both can potentially be used to facilitate consideration of PIDD. However, the application of vaccines and interpretation of antibody responses in this context are complex. These rely on consideration of numerous existing specific studies, interpolation of data from healthy populations, current diagnostic guidelines, and expert subspecialist practice. This document represents an attempt of a working group of the American Academy of Allergy, Asthma & Immunology to provide further guidance and synthesis in this use of vaccination for diagnostic purposes in consideration of PIDD, as well as to identify key areas for further research.

Rapid reduction in donor-specific anti-human leukocyte antigen antibodies and reversal of antibody-mediated rejection with bortezomib in pediatric heart transplant patients.

Background. High titer donor-specific antibodies (DSA) and positive crossmatch in cardiac transplant recipients is associated with increased mortality from antibody-mediated rejection (AMR). Although treatment to reduce anti-human leukocyte antigen antibodies using plasmapheresis, intravenous immunoglobulin, and rituximab has been reported to be beneficial, in practice these are often ineffective. Moreover, these interventions do not affect the mature antibody producing plasma cell. Bortezomib, a proteasome inhibitor active against plasma cells, has been shown to reduce DSA in renal transplant patients with AMR. We report here the first use of bortezomib for cardiac transplant recipients in four pediatric heart recipients with biopsy-proven AMR, hemodynamic compromise, positive crossmatch, and high titer class I DSA. Methods. Patients received four intravenous dose of bortezomib (1.3 mg/m2) over 2 weeks with plasmapheresis and rituximab. DSA specificity and strength (mean fluorescence intensity) was determined with Luminex. All had received previous treatment with plasmapheresis, intravenous immunoglobulin, and rituximab that was ineffective. Results. AMR resolved in all patients treated with bortezomib with improvement in systolic function, conversion of biopsy to C4d negative in three patients and IgG negative in one patient, and a prompt, precipitous reduction in DSAs. In three patients who received plasmapheresis before bortezomib, plasmapheresis failed to reduce DSA. In one case, DSA increased after bortezomib but decreased after retreatment. Conclusions. Bortezomib reduces DSA and may be an important adjunct to treatment of AMR in cardiac transplant recipients. Bortezomib may also be useful in desensitization protocols and in prevention of AMR in sensitized patients with positive crossmatch and elevated DSA.

Update on the use of immunoglobulin in human disease: A review of evidence.

&NA; Human immunoglobulin preparations for intravenous or subcutaneous administration are the cornerstone of treatment in patients with primary immunodeficiency diseases affecting the humoral immune system. Intravenous preparations have a number of important uses in the treatment of other diseases in humans as well, some for which acceptable treatment alternatives do not exist. We provide an update of the evidence‐based guideline on immunoglobulin therapy, last published in 2006. Given the potential risks and inherent scarcity of human immunoglobulin, careful consideration of its indications and administration is warranted.

Efficacy of the Detection of the α1-Antitrypsin “Z” Deficiency Variant by Routine Serum Protein Electrophoresis

Deficiency of alpha1-antitrypsin (AAT) is a common but underdiagnosed genetic disorder. Severe AAT deficiency may be detected by the absence of alpha1-globulin protein fraction by serum protein electrophoresis (SPEP). Routine SPEP may represent an underused resource for the identification of AAT deficiency. Total alpha1-globulin protein was measured in 47 MM, 24 MZ, and 19 ZZ phenotype serum samples by a Sebia CAPILLARYS (Norcross, GA) capillary electrophoresis system. Measured serum AAT concentrations by immunoassay exhibited moderate correlation with measured SPEP alpha1-globulin fraction concentrations. In this sample set, 16 (84%) of the ZZ, 7 (29%) of the MZ, and none of the MM sample phenotypes exhibited alpha1-globulin concentrations of less than 0.21 g/dL. From estimates of MZ and ZZ phenotype prevalence, it can be calculated that 1 ZZ phenotype should be present in approximately every 31 samples with alpha1-globulin concentrations of less than 0.21 g/dL. Clinicians should consider investigation of potential AAT deficiency in patients who exhibit low alpha1-globulin protein levels by routine SPEP.

Quantification, identification, and relevance of anti-human leukocyte antigen antibodies formed in association with the berlin heart ventricular assist device in children.

Background Ventricular assist devices (VADs) are increasingly being used in pediatric patients to provide long-term cardiac support. One potential complication of VAD therapy is the development of antibodies directed against human leukocyte antigens (HLA). This phenomenon has not been well described with the Berlin Heart EXCOR VAD, the most commonly used VAD in pediatric patients. Methods The records of all pediatric patients undergoing VAD support using the Berlin Heart device at our institution between April 2005 and August 2011 were reviewed retrospectively. Demographic and clinical data regarding the VAD course were collected. Assessment of anti-HLA antibodies was performed using Luminex, and antibodies were quantified using mean fluorescence intensity (MFI). Assessment for anti-HLA antibodies was performed before VAD implantation and in serial fashion after VAD implantation. Clinically significant anti-HLA antibodies (sensitization) were defined by an MFI of more than 1000. Results Thirty-six patients were supported with the Berlin Heart VAD; 13 met inclusion criteria. The majority (85%) carried the diagnosis of dilated cardiomyopathy. Evidence of sensitization pre-VAD was found in 69%; new-onset sensitization (the development of new antibodies on VAD) occurred in 69%. All patients survived to transplantation. In two patients, the retrospective crossmatch was positive, but only in one patient was the crossmatch positive for antibodies formed while on VAD. Conclusions Using Luminex and MFI quantification, anti-HLA antibodies are common before VAD implantation in pediatric patients. While on VAD support, new anti-HLA antibodies formed in a majority, but the immediate impact of these antibodies appears to be limited.

Autologous Graft versus Host Disease: An Emerging Complication in Patients with Multiple Myeloma

Autologous graft versus host disease (autoGVHD) is a rare transplant complication with significant morbidity and mortality. It has been hypothesized that patients with multiple myeloma might be predisposed to autoGVHD through dysregulation of the immune response resulting from either their disease, the immunomodulatory agents (IMiDs) used to treat it, or transplant conditioning regimen. Hematopoietic progenitor cell (HPC) products were available from 8 multiple myeloma patients with biopsy-proven autoGVHD, 16 matched multiple myeloma patients who did not develop autoGVHD, and 7 healthy research donors. The data on number of transplants prior to developing autoGVHD, mobilization regimens, exposure to proteasome inhibitors, use of IMiDs, and class I human leukocyte antigen types (HLA A and B) were collected. The HPC products were analyzed by flow cytometry for expression of CD3, CD4, CD8, CD25, CD56, and FoxP3. CD3+ cell number was significantly lower in autoGVHD patients compared to unaffected controls (P = 0.047). On subset analysis of CD3+ cells, CD8+ cells (but not CD4+ cells) were found to be significantly lower in patients with autoGVHD (P = 0.038). HLA-B55 expression was significantly associated with development of autoGVHD (P = 0.032). Lower percentages of CD3+ and CD8+ T-cells and HLA-B55 expression may be predisposing factors for developing autoGVHD in myeloma.

Early immunologic findings in omenn syndrome

Michelle M Montalbano*, Terry 0 Harville§, Laura L Dziadzio*, James E Gem* *University of Wisconsin, Madison, WI §University of Arkansas, Little Rock, AR First described in 1965, Omenn Syndrome is an autosomal recessive combined immunodeficiency characterized by recurrent, severe infections and chronic skin eruptions. An oligoclonal expansion of activated, ineffective T cells often results in normal or high T cell numbers. These dysfunctional T cells can cause an autoimmune-like infiltration of the skin, Gl tract, liver and spleen with resultant skin eruptions and chronic diarrhea. We describe prospective clinical and immunologic findings in a baby boy beginning at birth. AM was born at 37 weeks gestation to a family whose older son has Omenn Syndrome and is status post bone marrow transplant. At birth, AM exhibited some, but not all, features of Omenn Syndrome. For example, on physical exam, he had an exfoliating erythroderma but no adenopathy or hepatomegaly. Immunologic evaluation revealed eosinophilia (Eos) and increased CD45RO T cells; however, his absolute lymphocyte count (ALC), B cell numbers, and total IgE were normal (Table). By 2 months of age, AM had developed lymphadenopathy (LAD), hepatomegaly (HM), increased ALC, and decreased B cell numbers, as is expected with this disorder. AM was evaluated for an unrelated stem cell transplant, and a 5/6 HLA match with a molecular match at both DR antigens was found. He received ablative chemotherapy with busulfan, fludarabine, and ATG, followed by the transplant. The transplant was complicated by Grade I graft versus host disease and significant hypertension. Since the transplant, he has had resolution of the rash and normalization of his eosinophil count. In conclusion, although not all of the features associated with Omenn Syndrome were present at birth, our patient did exhibit a typical rash, eosinophilia, and increased CD45RO T cells. These distinctive clinical and immunologic features may make immediate postnatal or even prenatal diagnosis of Omenn Syndrome possible, which could lead to earlier definitive treatment and improved clinical outcomes for these individuals.

Could better categorization of pulmonary disease in common variable immunodeficiency ultimately allow for better treatment outcomes

Disclosure: Dr Harville serves on the advisory boards of Baxter, CSL Behring, and ARORA. [2] Wiggs B, Moreno R, James A, Hogg JC, Pare P. A model of the mechanics of airway narrowing in asthma. In: Kaliner MA, Barnes PJ, Persson CGA, eds. Asthma: Its Pathology and Treatment. New York: Marcel Dekker; 1991:84. [3] Miller RD, Hyatt RE. Obstructing lesions of the larynx and trachea: clinical and physiological characteristics. Mayo Clin Proc. 1969;44:145e161. [4] Juniper EF, Guyatt GH, Ferrie PJ, Griffith LE. Measuring quality of life in asthma. Am Rev Respir Dis. 1993;147:832e838. [5] Lavietes MH, Ameh J, Cherniack N. Dyspnea and symptom amplification in asthma. Respiration. 2008;75:158e162. [6] Wechsler ME, Kelley JM, Boyd IOE, et al. Active albuterol or placebo, sham acupuncture, or no intervention in asthma. N Engl J Med. 2011;365:119e126. [7] Foschino Barbaro MP, Lacedonia D, Palladino GP, et al. Dyspnea perception in asthma: role of airways inflammation, age and emotional status. Respir Med. 2011;105:195e203.