Bronchiectasis is associated with delayed diagnosis and adverse outcomes in the New Zealand Common Variable Immunodeficiency Disorders cohort study.

Common variable immunodeficiency disorders (CVID) are multi-system disorders where target organ damage is mediated by infective, autoimmune and inflammatory processes. Bronchiectasis is probably the most common disabling complication of CVID. The risk factors for bronchiectasis in CVID patients are incompletely understood. The New Zealand CVID study (NZCS) is a nationwide longitudinal observational study of adults, which commenced in 2006. In this analysis, the prevalence and risk factors for bronchiectasis were examined in the NZCS. After informed consent, clinical and demographic data were obtained with an interviewer-assisted questionnaire. Linked electronic clinical records and laboratory results were also reviewed. Statistical methods were applied to determine if variables such as early-onset disease, delay in diagnosis and increased numbers of infections were associated with greater risk of bronchiectasis. One hundred and seven adult patients with a diagnosis of CVID are currently enrolled in the NZCS, comprising approximately 70% of patients known to have CVID in New Zealand. Fifty patients (46·7%) had radiologically proven bronchiectasis. This study has shown that patients with compared to those without bronchiectasis have an increased mortality at a younger age. CVID patients with bronchiectasis had a greater number of severe infections consequent to early-onset disease and delayed diagnosis. Indigenous Maori have a high prevalence of CVID and a much greater burden of bronchiectasis compared to New Zealand Europeans. Diagnostic latency has not improved during the study period. Exposure to large numbers of infections because of early-onset disease and delayed diagnosis was associated with an increased risk of bronchiectasis. Earlier diagnosis and treatment of CVID may reduce the risk of bronchiectasis and premature death in some patients.

Comparison of Diagnostic Criteria for Common Variable Immunodeficiency Disorders (CVID) in the New Zealand CVID Cohort Study.

Common variable immunodeficiency disorders (CVID) are the most frequent symptomatic primary immune deficiencies in adults and children. In addition to recurrent and severe infections, patients with CVID are susceptible to autoimmune and inflammatory complications. The aetiologies of these uncommon conditions are, by definition, unknown. When the causes of complex disorders are uncertain, diagnostic criteria may offer valuable guidance to the management of patients. Over the last two decades, there have been four sets of diagnostic criteria for CVID in use. The original 1999 European Society for Immunodeficiencies and Pan-American Society for Immunodeficiency (ESID/PAGID) criteria are less commonly used than the three newer criteria: Ameratunga et al (Clin Exp Immunol 174:203-211, 2013), ESID (J Allergy Clin Immunol Pract, 2019) and ICON (J Allergy Clin Immunol Pract 4:38-59, 2016) criteria. The primary aim of the present study was to compare the utility of diagnostic criteria in a well-characterised cohort of CVID patients. The New Zealand CVID cohort study (NZCS) commenced in 2006 and currently comprises one hundred and thirteen patients, which represents approximately 70% of all known CVID patients in NZ. Many patients have been on subcutaneous or intravenous (SCIG/IVIG) immunoglobulin treatment for decades. Patients were given a clinical diagnosis of CVID as most were diagnosed before the advent of newer diagnostic criteria. Application of the three commonly used CVID diagnostic criteria to the NZCS showed relative sensitivities as follows: Ameratunga et al (Clin Exp Immunol 174:203-211, 2013), possible and probable CVID, 88.7%; ESID (J Allergy Clin Immunol Pract, 2019), 48.3%; and ICON (J Allergy Clin Immunol Pract 4:38-59, 2016), 47.1%. These differences were mostly due to the low rates of diagnostic vaccination challenges in patients prior to commencing SCIG/IVIG treatment and mirror similar findings in CVID cohorts from Denmark and Finland. Application of the Ameratunga et al (Clin Exp Immunol 174:203-211, 2013) CVID diagnostic criteria to patients on SCIG/IVIG may obviate the need to stop treatment for vaccine studies, to confirm the diagnosis.

Perspective: Evolving Concepts in the Diagnosis and Understanding of Common Variable Immunodeficiency Disorders (CVID).

Common variable immunodeficiency disorders (CVID) are the most frequent symptomatic primary immune deficiency in adults. At this time, the causes of these conditions are unknown. Patients with CVID experience immune system failure consequent to late onset antibody failure. They have increased susceptibility to infections and are also at risk of severe autoimmune and inflammatory disorders as a result of immune dysregulation. An increasing number of monogenic causes as well as a digenic disorder have been described in patients with a CVID phenotype. If a causative mutation is identified, patients are removed from the umbrella diagnosis of CVID and are reclassified as having a CVID-like disorder, resulting from a specific mutation. In non-consanguineous populations, next-generation sequencing (NGS) identifies a genetic cause in approximately 25% of patients with a CVID phenotype. It is six years since we published our diagnostic criteria for CVID. There is ongoing debate about diagnostic criteria, the role of vaccine responses and genetic analysis in the diagnosis of CVID. There have been several recent studies, which have addressed some of these uncertainties. Here we review this new evidence from the perspective of our CVID diagnostic criteria and speculate on future approaches, which may assist in identifying and assessing this group of enigmatic disorders.

Defining Common Variable Immunodeficiency Disorders in 2020.

Common variable immunodeficiency disorders (CVID) are the most frequent symptomatic primary immune deficiency in adults. Because there is no known cause for these conditions, there is no single clinical feature or laboratory test that can confirm the diagnosis with certainty. If a causative mutation is identified, patients are deemed to have a CVID-like disorder caused by a specific primary immunodeficiency/inborn error of immunity. In the remaining patients, the explanation for these disorders remains unclear. The understanding of CVID continues to evolve and the authors review recent studies, which have addressed some of these uncertainties.

The Natural History of Untreated Primary Hypogammaglobulinemia in Adults: Implications for the Diagnosis and Treatment of Common Variable Immunodeficiency Disorders (CVID).

Background: Adults with primary hypogammaglobulinemia are frequently encountered by clinicians. Where IgG levels are markedly decreased, most patients are treated with subcutaneous or intravenous immunoglobulin (SCIG/IVIG), because of the presumed risk of severe infections. The natural history of untreated severe asymptomatic hypogammaglobulinemia is thus unknown. Similarly, there are no long-term prospective studies examining the natural history of patients with moderate reductions in IgG. Methods: In 2006, we began a prospective cohort study of patients with symptomatic and asymptomatic reductions in IgG who were not immediately commenced on SCIG/IVIG. Over the course of 12 years, 120 patients were enrolled in the NZ hypogammaglobulinemia study (NZHS) including 59 who were asymptomatic. Results: Five patients with profound primary hypogammaglobulinemia (IgG < 3 g/l), who were not on regular SCIG/IVIG have remained well for a mean duration of 139 months. This study has also shown most asymptomatic patients with moderate hypogammaglobulinemia (IgG 3.0-6.9 g/l) have been in good health for a mean observation period of 96 months. We have only identified one asymptomatic patient with moderate hypogammaglobulinemia who experienced progressive decline in IgG levels to <3 g/l and was accepted for IVIG replacement. Prospective monitoring has shown that none have suffered catastrophic infections or any of the severe autoimmune or inflammatory sequelae associated with Common Variable Immunodeficiency Disorders (CVID). Unexpectedly, 18.1% of asymptomatic and 41.6% of symptomatic hypogammaglobulinemic patients spontaneously increased their IgG into the normal range (≥7.0 g/l) on at least one occasion, which we have termed transient hypogammaglobulinemia of adulthood (THA). In this study, vaccine challenge responses have correlated poorly with symptomatic state and long-term prognosis including subsequent SCIG/IVIG treatment. Conclusions: In spite of our favorable experience, we recommend patients with severe asymptomatic hypogammaglobulinemia are treated with SCIG/IVIG because of the potential risk of severe infections. Patients with moderate asymptomatic hypogammaglobulinemia have a good prognosis. Patients with symptomatic hypogammaglobulinemia are a heterogeneous group where some progress to SCIG/IVIG replacement, while many others spontaneously recover. This study has implications for the diagnosis and treatment of CVID.

Application of diagnostic and treatment criteria for common variable immunodeficiency disorder.

Common variable immunodeficiency disorder (CVID) is the most frequent symptomatic primary immune deficiency disorder in adults. It probably comprises a spectrum of polygenic disorders, with hypogammaglobulinemia being the overarching feature. While the majority of patients with CVID can be identified with relative ease, a significant proportion can present with minimal symptoms in spite of profound laboratory abnormalities. Here we discuss three patients who were presented to the Auckland Hospital immunoglobulin treatment committee to determine if they qualified for immunoglobulin replacement. Two were asymptomatic with profound laboratory abnormalities while the third patient was severely ill with extensive bronchiectasis. The third patient had less severe laboratory abnormalities compared with the two asymptomatic patients. We have applied four sets of published diagnostic and treatment criteria to these patients to compare their clinical utility. We have chosen these patients from the broad phenotypic spectrum of CVID, as this often illustrates differences in diagnostic and treatment criteria.

Comparison of diagnostic criteria for common variable immunodeficiency disorder.

Common variable immunodeficiency disorders (CVIDs) are the most frequent symptomatic primary immune deficiency condition in adults. The genetic basis for the condition is not known and no single clinical feature or laboratory test can establish the diagnosis; it has been a diagnosis of exclusion. In areas of uncertainty, diagnostic criteria can provide valuable clinical information. Here, we compare the revised European society of immune deficiencies (ESID) registry (2014) criteria with the diagnostic criteria of Ameratunga et al. (2013) and the original ESID/pan American group for immune deficiency (ESID/PAGID 1999) criteria. The ESID/PAGID (1999) criteria either require absent isohemagglutinins or impaired vaccine responses to establish the diagnosis in patients with primary hypogammaglobulinemia. Although commonly encountered, infective and autoimmune sequelae of CVID were not part of the original ESID/PAGID (1999) criteria. Also excluded were a series of characteristic laboratory and histological abnormalities, which are useful when making the diagnosis. The diagnostic criteria of Ameratunga et al. (2013) for CVID are based on these markers. The revised ESID registry (2014) criteria for CVID require the presence of symptoms as well as laboratory abnormalities to establish the diagnosis. Once validated, criteria for CVID will improve diagnostic precision and will result in more equitable and judicious use of intravenous or subcutaneous immunoglobulin therapy.