Rohan Ameratunga

New diagnostic criteria for common variable immune deficiency (CVID), which may assist with decisions to treat with intravenous or subcutaneous immunoglobulin

Common variable immune deficiency (CVID) is the most frequent symptomatic primary immune deficiency in adults. The standard of care is intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (scIG) therapy. The cause of CVID is currently unknown, and there is no universally accepted definition of CVID. This creates problems in determining which patients will benefit from IVIG/scIG treatment. In this paper, we review the difficulties with the commonly used European Society of Immune Deficiencies (ESID) and the Pan American Group for Immune Deficiency (PAGID) definition of CVID. We propose new criteria for the diagnosis of CVID, which are based on recent scientific discoveries. Improved diagnostic precision will assist with treatment decisions including IVIG/scIG replacement. We suggest that asymptomatic patients with mild hypogammaglobulinaemia are termed hypogammaglobulinaemia of uncertain significance (HGUS). These patients require long‐term follow‐up, as some will evolve into CVID.

Intravenous Immunoglobulin in Acute Rheumatic Fever A Randomized Controlled Trial

BackgroundAcute rheumatic fever (ARF) remains the leading cause of acquired heart disease in children worldwide. No therapeutic agent has been shown to alter the clinical outcome of the acute illness. Immunological mechanisms appear to be involved in the pathogenesis of ARF. Intravenous immunoglobulin (IVIG), a proven immunomodulator, may benefit cardiac conditions of an autoimmune nature. We investigated whether IVIG modified the natural history of ARF by reducing the extent and severity of carditis. Methods and ResultsThis prospective, double-blind, randomized, placebo-controlled trial evaluated IVIG in patients with a first episode of rheumatic fever, stratifying patients by the presence and severity of carditis before randomization. Patients were randomly allocated to receive 1 g/kg IVIG on days 1 and 2 and 0.4 g/kg on days 14 and 28, or they received a placebo infusion. Clinical, laboratory, and echocardiographic evaluation was performed at 0, 2, 4, 6, 26, and 52 weeks. Fifty-nine patients were treated, of whom 39 had carditis (including 4 subclinical) and/or migratory polyarthritis (n=39). There was no difference between groups in the rate of normalization of the erythrocyte sedimentation rate or acute-phase proteins at the 6-week follow-up. On echocardiography, 59% in the IVIG group and 69% in the placebo group had carditis at baseline. There was no significant difference in the cardiac outcome, including the proportion of valves involved, or in the severity of valvar regurgitation at 1 year. At 1 year, 41% of the IVIG and 50% of the placebo group had carditis. ConclusionsIVIG did not alter the natural history of ARF, with no detectable difference in the clinical, laboratory, or echocardiographic parameters of the disease process during the subsequent 12 months.

The simultaneous presentation of sarcoidosis and common variable immune deficiency

Summary Sarcoidosis and common variable immune deficiency can rarely present simultaneously in the same individual. We describe a child who presented with both disorders. The diagnosis of sarcoidosis was delayed because of the atypical appearances of the liver biopsy. She failed to respond to intravenous immunoglobulin but improved once cyclosporin and corticosteroids were added to her treatment regimen. It is important that the co‐existence of both disorders is recognised so that treatment with a combination of intravenous immunoglobulin and immunosuppression can be in instituted to treat both the immune deficiency as well as the granulomatous disorder. As illustrated here, patients may fail to respond if either modality is used alone.

Clinical variability of family members with the C104R mutation in transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI).

PurposeCommon Variable Immunodeficiency Disorder (CVID) is a complex disorder that predisposes patients to recurrent and severe infections. The C104R mutation in the transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) is the most frequent mutation identified in patients with CVID. We carried out a detailed immunological and molecular study in a family with a C104R mutation.MethodsWe have undertaken segregation analysis of a kindred with C104R mutations of the TACI gene. Detailed immunological and molecular investigations were carried out for this kindred and the clinical phenotype was compared to the genotype.ResultsSegregation analysis of our kindred showed that inheriting single or double copy of the C104R mutation does not consign an individual to CVID. All heterozygotes in the family were phenotypically different, ranging from asymptomatic to ill-health. A family member with a wild type TACI variant had CVID-related phenotype including IgA deficiency and type 1 diabetes. Interestingly, a family member with the homozygous C104R/C104R variant did not meet the criteria for CVID because he had excellent, albeit unsustained, vaccine responses to T cell dependent and T cell independent vaccine antigens despite profound hypogammaglobulinemia.ConclusionThe C104R mutation does not correlate with the clinical phenotypes in this family.

Analysis of Intragraft Gene and Protein Expression of the Costimulatory Molecules, CD80, CD86 and CD154, in Orthotopic Liver Transplant Recipients

CD40‐CD154 and/or CD28‐CD80/86 costimulatory blockade induces long‐term allograft survival in numerous animal models. Studies examining the expression of costimulatory molecules during acute cellular rejection (ACR) have been limited to renal and cardiac allografts.

Samter's triad in childhood: a warning for those prescribing NSAIDs.

Aspirin‐exacerbated respiratory disease (AERD) has been recognized in adults with chronic asthma. Samters triad is a subset of AERD where adult patients develop nasal polyps, asthma, and sensitivity to aspirin. This condition is thought not to occur before the third decade of life. We report a 13‐year‐old boy with nasal polyps who suffered a life‐threatening exacerbation of asthma during a graded aspirin challenge. Resuscitation required positive pressure ventilation and inotropic support. Our observations confirm that classical Samters triad can occur in children. We suggest that graded aspirin challenges in children are undertaken in a facility with equipment and staff trained for resuscitation. Consideration should be given to this rare complication when prescribing nonsteroidal anti‐inflammatory drugs in the perioperative period. Suspicion of this condition merits referral to an immunologist for desensitization to aspirin.

The clinical utility of molecular diagnostic testing for primary immune deficiency disorders: a case based review

Primary immune deficiency disorders (PIDs) are a group of diseases associated with a genetic predisposition to recurrent infections, malignancy, autoimmunity and allergy. The molecular basis of many of these disorders has been identified in the last two decades. Most are inherited as single gene defects. Identifying the underlying genetic defect plays a critical role in patient management including diagnosis, family studies, prognostic information, prenatal diagnosis and is useful in defining new diseases. In this review we outline the clinical utility of molecular testing for these disorders using clinical cases referred to Auckland Hospital. It is written from the perspective of a laboratory offering a wide range of tests for a small developed country.

Evidence Refuting the Existence of Autoimmune/Autoinflammatory Syndrome Induced by Adjuvants (ASIA)

Autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA) was described in 2011. Over time the condition and its triggers have broadened to include several autoimmune disorders, the macrophagic myofasciitis syndrome, the Gulf war syndrome, the sick building syndrome, siliconosis, and the chronic fatigue syndrome. The aluminum-containing adjuvants in the hepatitis B vaccine and the human papillomavirus vaccine in particular have been stated to be the major causes of the disorder. Here, we review the specificity of the diagnostic criteria for ASIA. We also examine relevant human data, pertaining to causation, particularly from patients undergoing allergen-specific immunotherapy (IT). Patients undergoing allergen-specific IT receive 100 to 500 times more injected aluminum over 3 to 5 years, compared with hepatitis B and human papillomavirus vaccine recipients. In a large pharmacoepidemiological study, in contrast to case series of ASIA, patients receiving aluminum-containing allergen IT preparations were shown to have a lower incidence of autoimmune disease. In another clinical trial, there were no increases in exacerbations in a cohort of patients with systemic lupus erythematosus immunized with the hepatitis B vaccine. Current data do not support the causation of ASIA by vaccine adjuvants containing aluminum, which should be of reassurance to patients undergoing routine immunizations as well as to those undergoing allergen-specific IT.

Primary immune deficiency disorders in the South Pacific: the clinical utility of a customized genetic testing program in New Zealand

Primary immune deficiency disorders (PIDs) are a group of diseases associated with a genetic susceptibility to recurrent infections, malignancy, autoimmunity, and allergy. The molecular basis of many of these disorders has been identified in the last two decades. Most are inherited as single gene defects. As discussed in this paper, identifying the underlying genetic defect plays a critical role in many areas—including patient management, diagnosis, identifying atypical presentations, family studies, providing prognostic information, prenatal diagnosis, and defining new diseases. New Zealand is a geographically isolated, developed country in the South Pacific. We have introduced a dedicated customized genetic testing service for PID patients in New Zealand. This accredited diagnostic program offers rapid turnaround times for genetic tests and minimizes the risk of laboratory errors. Here we review the clinical indications for genetic testing for PIDs based on cases referred to the molecular immunology diagnostic service at Auckland City Hospital.

Polycythemia vera and water–induced pruritus: evidence against mast cell involvement

&NA; The mechanism of water‐induced pruritus in patients with polycythemia vera is unknown. Evidence has been presented previously that bathing or showering may trigger mast cell degranulation and that release of a mediator by mast cells may be responsible for the pruritus. Tryptase is a specific marker of human mast cell secretory granules and its presence in body fluids indicates mast cell degranulation. In this study, serum tryptase levels were measured both before and one hour after showering in 11 patients suffering from polycythemia vera and water‐induced pruritus. Tryptase was not found in the serum of any of the subjects one hour after showering, when levels would be expected to be near peak had significant mast cell degranulation occurred. These results argue against mass cell degranulation‐with systemic release of a mast cell product as the mechanism for water‐induced pruritus in patients with polycythemia vera.