Daniel E. Maddox

Common variable immunodeficiency: a new look at an old disease

Primary immunodeficiencies comprise many diseases caused by genetic defects primarily affecting the immune system. About 150 such diseases have been identified with more than 120 associated genetic defects. Although primary immunodeficiencies are quite rare in incidence, the prevalence can range from one in 500 to one in 500 000 in the general population, depending on the diagnostic skills and medical resources available in different countries. Common variable immunodeficiency (CVID) is the primary immunodeficiency most commonly encountered in clinical practice, and appropriate diagnosis and management of patients will have a significant effect on morbidity and mortality as well as financial aspects of health care. Advances in diagnostic laboratory methods, including B-cell subset analysis and genetic testing, coupled with new insights into the molecular basis of immune dysfunction in some patients with CVID, have enabled advances in the clinical classification of this heterogeneous disease.

Systemic reactions to allergy skin tests.

BACKGROUND Skin testing is a common diagnostic tool in allergy. It is considered a safe procedure, although systemic reactions have been reported. OBJECTIVE To identify the systemic reaction rates of allergy skin tests and to determine the clinical outcome of such reactions. METHOD This retrospective study used a computerized database at the Mayo Clinic to identify patients who developed systemic reactions to skin tests. Altogether 497,656 skin tests were performed on 18,311 patients from January 1992 to June 1997. Skin puncture tests were performed on 16,505 patients. Skin puncture and intradermal skin tests were performed on 1,806 patients. Systemic reactions were evaluated and treated by physicians. RESULTS There were 6 systemic reactions, an overall rate of 33 systemic reactions per 100,000 skin tests. All six patients had asthma. The systemic reaction rates for latex skin testing was 152 or 228 reactions per 100,000 latex skin tests, to penicillin and antibiotics 72 reactions per 100,000 penicillin and antibiotics skin tests, and to aeroallergens 15 or 23 reactions per 100,000 aeroallergen skin tests. The systemic reaction rate for skin puncture test was 30 reactions per 100,000 skin puncture tests, for skin puncture and intradermal skin tests, the rate was 55 reactions per 100,000 skin puncture and intradermal skin tests. All 6 patients were treated and dismissed within 1 hour after treatment. CONCLUSION The systemic reaction rate to skin tests was very low. Systemic reactions were mild and all patients recovered fully within 1 hour.

Maintenance dosing for sublingual immunotherapy by prominent European allergen manufacturers expressed in bioequivalent allergy units

BACKGROUND Sublingual immunotherapy (SLIT) has become established in Europe, and its efficacy is being evaluated in the United States. The doses used for SLIT in Europe today are difficult to evaluate, because each manufacturer expresses the potency of its extracts differently. OBJECTIVES To compare in vitro European SLIT maintenance solutions against US licensed standardized allergenic extract concentrates and to determine the monthly SLIT doses delivered expressed in bioequivalent allergy units ([B]AU). METHODS We studied Dermatophagoides pteronyssinus, timothy grass pollen, cat (hair) and short ragweed pollen allergen extracts. The SLIT maintenance solutions of 4 leading European manufacturers and standardized concentrate extracts of 3 US manufacturers were analyzed with the following assays: protein content, relative potency (immunoglobulin E [IgE]-binding enzyme-linked immunosorbent assay [ELISA] inhibition) and major allergen content. The relative monthly allergen dose in (B)AU was calculated for each recommended SLIT schedule. RESULTS Relative potency was approximately 10 times higher for US concentrate standardized extracts-which are meant to be diluted-than for European SLIT maintenance solutions of D pteronyssinus and timothy grass pollen. For cat (hair) and short ragweed pollen, the difference was less. Measurements of relative potency and major allergen content correlated well. In our assays, European mite extracts contain a very low quantity of Der p 2 compared with US mites. CONCLUSION Recommended SLIT doses in Europe vary widely among the manufacturers, but are consistently lower (Eur1) or higher (Eur4) over all four allergens tested. SLIT efficacy probably depends on additional factors apart from the exact dose. SLIT dose finding studies should be done for each product.

Vaccine allergy: diagnosis and management.

As a group, vaccines provide a safe and effective way of preventing infectious and allergic illness. Allergic reactions to vaccines and drug products have become important and common features of practice and demand heightened awareness. Serious adverse effects of vaccines are rare but have been reported to various components of different vaccines. Although there are few precise diagnostic tests available, patients usually can be diagnosed accurately after careful attention to the history and physical findings. Better understanding of these reactions can lead to proper vaccine selection and can improve immunization acceptance rates in the community. Prevention, avoidance, use of alternative agents, desensitization, and premedication remain the mainstays of therapy, even as more refined diagnostic and management tools are developed. VAERS data, in addition to the traditional uses (signal detection, large registry of rare vaccine adverse events), can serve as a source of cases for epidemiologic (eg, case-control) studies that evaluate biologic factors that may be related to vaccine-related adverse reactions. Additional studies that are aimed at identifying other causes of immediate hypersensitivity after immunization with live virus vaccines are warranted.

Adult-onset manifestation of idiopathic T-cell lymphopenia due to a heterozygous RAG1 mutation

To the Editor: We would like to share a relevant and interesting immunodeficiency case that would be of interest to the readers of the Journal of Allergy and Clinical Immunology. This report describes an adult-onset idiopathic T-cell lymphopenia due to recombinase activating gene 1 (RAG1) deficiency in an HIV-negative male patient with no recurrent or opportunistic infections presenting at the age of 38 years with chronic dermatitis, pruritus, and hyperkeratosis. Clinical and immunologic examination revealed eosinophilia with modestly elevated IgE (747 kU/L), normal IgG, IgA, and IgM, profound pan–T-cell lymphopenia, high normal total B cells, and slightly reduced natural killer cells. Genetic analysis revealed a heterozygous frameshift mutation in the RAG1 gene, resulting in a truncated RAG1 protein. This is a late clinical presentation of an idiopathic T-cell lymphopenia secondary to a heterozygous hypomorphic RAG1 mutation and has important implications for the considerable phenotypic variability related to molecular defects in genes typically associated with severe combined immunodeficiency or Omenn syndrome (OS). A 38-year-old man presented with significant pruritic skin rash on his legs and eosinophilia that had been present for 2 years with poor resolution using over-the-counter topical treatments. Medical history revealed a healthy childhood and adulthood until 2 years earlier when the skin rash first appeared on the lower extremities. Gross examination of the skin revealed a generalized dermatitis with hyperkeratosis without histologic evidence of granulomas (Fig 1, A). There was also keratoderma of the feet and onychodystrophy. Skin biopsy of the lesions on the leg revealed a chronic dermatitis with eosinophilia, which was negative for IgG, IgM, or IgA with weak, discontinuous granular deposition of C3 along the basement membrane zone. Complete blood cell count with differential revealed significant lymphopenia, which on detailed lymphocyte subset evaluation by flow cytometry revealed profound pan–T-cell lymphopenia (Table I). There was a relative increase in the frequency of activated T cells (CD4+CD25+ and HLA-DR+ CD4 and CD8 T cells). Thymic function was significantly impaired for age, with almost absent CD4 recent thymic emigrants and TREC. Genetic analysis revealed the following heterozygous frameshift mutation (c.256_257delAA, K86VfsX33) in exon 2 of the gene encoding RAG1 that has been previously reported to be associated with SCID and OS, when present as a homozygous or compound heterozygous mutation.1 No other pathogenic genetic variations were found in either the known coding or promoter regions of the RAG1 gene or in any of the following SCID-associated genes: RAG2, JAK3, IL7R, ADA, CD3D, CD3E, DCLRE1C, and IL2RG. Genetic analysis for the above RAG1 mutation was performed not only on DNA extracted from whole blood but also from PBMCs and buccal brushing. In all 3 sample types, the same heterozygous mutation was identified, indicating that this was not a somatic mutation but a germline variation in the RAG1 gene. Genetic testing for this specific RAG1 mutation was performed on PBMCs isolated from whole blood of both parents of this patient, and the father was shown to have the same heterozygous mutation as the patient; however, the father was clinically, phenotypically, and immunologically normal with normal T, B, and natural killer cell counts. A second mutation was not identified in the patient or the mother. The patient has a single older male sibling who was not evaluated but was negative for relevant clinical history. FIG 1 A, Photograph showing skin rash. Diffuse skin rash was present on the extremities and, to a lesser extent, on the trunk of this patient with a heterozygous RAG1 mutation. B, Determination of recombinase activity level of wild-type and mutant RAG1. Stable ... TABLE I Lymphocyte subset quantitation by flow cytometry Further immunologic analysis revealed robust antibody responses to vaccine antigens such as tetanus and diphtheria toxoids, but significantly abnormal lymphocyte proliferation to mitogens (PHA, PWM) and antigens (Candida and tetanus toxoid) and stimulation with soluble anti-CD3. RAG1 function was determined by recombinase activity (Fig 1, B), and the 256–257delAA mutant had only 2.67% ± 0.58% activity as compared with wild-type RAG1. Although overexpression experiments have shown that this mutation can induce the production of an N-terminal–truncated protein by using a second internal ATG1 (which might explain the residual recombination activity), we failed to detect the expression of the mutant RAG1 on retrovirus-mediated transduction of Rag1−/− pro–B cells. Detailed B-cell subset analysis revealed low total memory B cells with low class-switched memory and marginal zone B cells with a significant increase in naive B cells (CD27−) and transitional B cells (CD19+CD24++CD38++). Functional B-cell analysis revealed that the patient’s B cells were capable of plasmablast differentiation on stimulation with CD40L and IL-21 or CpG, though it was decreased than that in a healthy control (data not shown). B-cell proliferation in response to CD40L + IL-21 was lower than in control B cells, but almost comparable to that in control with CpG. Also, the distribution of immunoglobulin light chains (kappa/lambda) was normal, arguing against significant defects of receptor editing of B cells. Therefore, it would appear that patient’s B cells are capable of responding to helper T-cell signals, and the reduced frequency of memory B cells is likely related to the low numbers of such T cells. There was evidence of autoantibody production with high titer of ANA, double-stranded DNA and SS-A antigens in addition to antibodies to 14 other autoantigens. Although there was no clinical evidence of specific autoimmune disease or granulomatous disease and renal function was preserved,2,3 the diffuse skin rash, which was responsive to steroids, suggests that a clear inflammatory process was present (prior to treatment). Molecular T-cell receptor repertoire analysis (T-cell receptor Vb spectratyping) revealed an overall polyclonal T-cell repertoire for most T-cell receptor Vb families with oligoclonality of a few (family 2 was absent and families 3–1, 6–4, 13, and 16 were oligoclonal with limited diversity). There was a significant increase in peripheral levels of IL-7, which is related to the presence of T-cell lymphopenia. Clinically, the patient responded well to wet dressings with ammonium lactate topical (AmLactin), a keratolytic, and treatment with triamcinolone. He was treated with prophylactic antibiotics with no evidence of infection. In a mouse model of a hypomorphic Rag1 variant, progressive T-cell lymphopenia with age was demonstrated,4 suggesting that heterozygosity for RAG defects may lead to premature immune senescence and T-cell dysfunction. This case is unique and exemplifies the magnitude of phenotypic variations that can be seen in molecular defects typically associated with SCID, or hypomorphic mutations in genes that are associated with OS,2 but in this case represents an idiopathic T-cell lymphopenia, adding to the spectrum of previously reported mutations.5 What is remarkable is the apparent adult-onset presentation of eosinophilia, skin rash, and low T-cell counts in this patient with only a single copy of a frameshift variation in the 5′ open reading frame of the RAG1 gene that usually causes an autosomal-recessive disorder. There is evidence that frameshift mutations in the 5′ end of RAG1 can maintain V(D)J recombination activity,1 and this may partially explain the late onset of the phenotype and normal B-cell numbers in the context of T-cell lymphopenia. As seen in the mouse model of hypomorphic Rag1 mutation,4 it is possible that the T-cell lymphopenia is due to an age-related decline in immunocompensatory mechanisms that permit the phenotype to be revealed later than typical. There are several differences between OS and idiopathic T-cell lymphopenia, with the former typically being clinically severe and characterized by elevated eosinophils and IgE along with erythrodermia, hepatosplenomegaly, lymphadenopathy, T-cell counts that are variable but generally oligoclonal in diversity, absent B cells, and normal natural killer cells.6 Patients with OS usually present early in life with recurrent and opportunistic infections, and the clinical course is fulminant and typically managed with hematopoietic cell transplantation. Adult-onset patients with idiopathic T-cell lymphopenia may have an overall milder clinical phenotype and are unlikely to require hematopoietic cell transplantation; nonetheless, these patients require careful monitoring to control significant infections as well as the development of autoimmunity and subsequent end-organ damage. Adult-onset ADA deficiency is the only other SCID-associated defect that has been reported with delayed manifestations in the context of heterozygous mutations in the ADA gene,7 resulting in partial ADA deficiency and a milder phenotype. In the partial ADA deficiency, immune function has been shown to decline over time, resulting in an immunologic and clinical phenotype. This phenomenon appears to be reproduced in this patient with the heterozygous RAG1 mutation. The presence of severe T-cell lymphopenia with dysregulated B-cell responses raises intriguing questions about the impact of hypomorphic mutations on immune function, and further the lack of an immunologic or clinical phenotype in the parent who is a carrier for this mutation suggests that there is an underlying additional genetic, epigenetic, or environmental modulation of RAG1 function in this patient.

Perioperative angioedema: background, diagnosis, and management

Angioedema is a potentially life-threatening condition that may present at any point in the perioperative care of patients. It requires prompt recognition and diagnosis; the primary concern during acute attacks is airway management. The pathophysiology, various causes of angioedema, and treatment strategies according to underlying etiology are presented.

Premedication of patients for prior urticarial reaction to iodinated contrast medium

PurposeThe purpose of this study was to determine whether premedication of patients with a history of urticaria after low osmolality contrast media (LOCM) results in fewer subsequent reactions, and if a benefit is seen, to determine which premedication regimen results in the fewest reactions.Materials and methodsThe subsequent contrast enhanced studies of patients who experienced urticaria after intravenous LOCM between 2002 and 2009 were reviewed to determine whether an additional reaction occurred. Patients undergoing subsequent studies received either no premedication, or premedication with diphenhydramine alone, corticosteroid alone, or corticosteroid plus diphenhydramine. Reactions occurring without premedication were termed repeat reactions and reactions occurring after premedication were termed breakthrough reactions.ResultsFifty patients with a history of urticaria after LOCM met the inclusion criteria and underwent 133 subsequent contrast enhanced studies. Repeat reactions occurred in 7.6% (5/66) of subsequent studies in patients receiving no premedication. Breakthrough reactions occurred in 8% (2/25), 46% (12/26), and 44% (7/16) of subsequent studies in patients receiving premedication with diphenhydramine, corticosteroid, and corticosteroid plus diphenhydramine, respectively. All subsequent reactions consisted of urticaria as the most severe manifestation; no hemodynamic instability or respiratory compromise occurred. In multivariate analysis, premedication with corticosteroid was significantly associated with higher rate of breakthrough reaction relative to no premedication (OR 14.3, 95% CI: 4.1–50.4), as was premedication with corticosteroid plus diphenhydramine (OR 8.3, 95% CI: 1.8–37.9).ConclusionThe results suggest that premedication of patients with a history of urticaria after LOCM may not be necessary.

Acute Kidney Injury in Patients with Inactive Cytochrome P450 Polymorphisms

Medications are a major source of acute kidney injury, especially in critically ill patients. Medication-induced renal injury can occur through a number of mechanisms. We present two cases of acute kidney injury (AKI) where inactive cytochrome P450 (CYP) polymorphism may have played a role. The first patient developed a biopsy-proven allergic interstitial nephritis following urethrotomy. Genetic testing revealed the patient to be heterozygous for an inactivating polymorphism CYP2C9*3 and homozygous for an inactivating polymorphism CYP2D6*4. Patient had received several doses of promethazine, which is metabolized by CYP2D6*4. Another patient developed AKI on several occasions after exposure to lansoprazole and allopurinol. CYP testing revealed the patient to be homozygous for inactivating polymorphism CYP2C19*2, which is responsible for the metabolism of lansoprazole. These are the first two cases of AKI associated with non-functional polymorphisms of cytochrome P450 superfamily. While the exact mechanism has not been worked out, it introduced the possibility of a new source of kidney injury.

Successful rapid desensitization to temozolomide: A case series.

Clinical Implications Females (%) 8 (57) Desensitization for temozolomide: primary indication Oligodendroglioma (%) 4 (28) Glioblastoma (%) 3 (21) Glioma (%) 2 (14) Oligoastrocytoma (%) 2 (14) Temozolomide is a first-line therapy for primary brain tumors. Cutaneous hypersensitivity reactions are common and may preclude its use. A protocol for rapid oral desensitization is presented that when used in the correct setting may afford valuable therapy.