Francisco A. Bonilla

Recognition, Clinical Diagnosis and Management of Patients With Primary Antibody Deficiencies: A Systematic Review

Wood P, Stanworth S, Burton J, et al. Clin Exp Immunol. 2007;149(3):410–423 PURPOSE OF THE STUDY. To create an evidence-based literature review of clinical diagnosis and management of primary antibody deficiency. METHODS. Computer literature searches were conducted for randomized clinical trials in medical literature databases including the US National Library of Medicine (Medline), the Excerpta Medica database (EMBASE), the Cochrane Library, the Database of Abstracts of Reviews of Effects (DARE) of the Centre for Reviews and Dissemination (University of York), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) up to June 2006. Reports were rated on the basis of relevance and quality or type of evidence. Disease entities included were X-linked agammaglobulinemia, common variable immunodeficiency, hyper–immunoglobulin M (IgM) syndromes, IgG subclass deficiency with and without IgA deficiency, and specific antibody deficiency. Reports that involved only a limited number of patients were not included. RESULTS. Individuals who present with recurrent respiratory infections of all types, especially with excessive frequency and severity, should be screened for antibody deficiency. In children, common associations included growth delay and failure to thrive, recurrent fevers without a source, and poor school attendance or performance. Chronic diarrhea was found in 40% to 60% of the patients at all ages. The median delay in diagnosis was 1 year but ranged to >10 years. Delayed diagnosis led to increased risk of bronchiectasis, pulmonary hypertension, and cor pulmonale. Randomized trials of the efficacy of γ-globulin replacement versus placebo do not currently exist. Many observational studies have confirmed the benefit of IgG therapy for reducing infectious morbidity. Higher IgG doses are associated with reduced incidence and severity of infections. CONCLUSIONS. Delayed diagnosis was common as a result of lack of recognition of presenting symptoms and signs. Delay was less frequent when patients were referred to specialists. Delayed diagnosis led to delayed therapy (IgG) and a higher rate of infections and morbidity. Several areas for additional research were identified, including studies of efficacy and dose of IgG and adjunct therapies (antibiotics), microbiologic study of pathogens, identification of prognostic markers, and effective monitoring of disease (eg, lung function, other organs, cancer). Collaboration and pooling of data among centers nationally and internationally would likely lead to better data. REVIEWER COMMENTS. This study again points out the human cost of delayed or undiagnosed immunodeficiency and the difficulties in accumulating high-quality data on therapy and outcomes. Several initiatives are taking shape in the United States and abroad to collaborate to answer many of the remaining questions pointed out in this study.

Infants Presenting With Recurrent Infections and Low Immunoglobulins: Characteristics and Analysis of Normalization

Whelan MA, Hwan WH, Beausoleil J, Hauck WW, McGeady SJ. J Clin Immunol. 2006;26:7–11 PURPOSE OF THE STUDY. To determine the outcomes of infants and young children with recurrent infections found to have low levels of ≥1 immunoglobulin (Ig) class (IgG, IgA, or IgM) without other screening laboratory indicators of immunodeficiency. STUDY POPULATION. Forty-nine infants who presented for evaluation at <24 months of age and had IgG, IgA, or IgM levels of <2 SD below the age-adjusted mean, intact antibody response to tetanus and diphtheria, intact cellular immunity, and no other immunodeficiency diagnoses. METHODS. Retrospective review of medical charts at a single institution from 1977 to 2005. RESULTS. Boys accounted for 70% of the patients. Recurrent otitis media was the predominant presentation (78%). Significant associated features were recurrent wheezing with infection (61%) and atopy (27%). Multiple isotypes were reduced in 65% of the patients; low IgA was most prevalent (96%). Only half of the patients had achieved normalization of Ig levels at the end of the observation period. Of these, 84% had become normal by 5 years of age. Of the patients who had not yet normalized at the end of the study, 54% were >5 years old. Two met criteria for selective IgA deficiency. Higher levels of Igs at presentation were associated with shorter times to normalization. Boys who presented at younger ages normalized more quickly than those who presented later. The opposite was true for girls. On average, the time to normalization for girls was 10-fold longer than the time for boys. Serious infections or death were not observed. CONCLUSIONS. Most patients with this phenotype are boys with recurrent otitis media, wheezing episodes, and atopy. Girls with this presentation may be at greater risk for prolonged immunodeficiency. A “definitive” diagnosis of transient hypogammaglobulinemia can only be conferred retrospectively (ie, after Ig levels have normalized). REVIEWER COMMENTS. There were several interesting new observations in this group of patients. In particular, the gender differences in time to normalization stand out; the immunologic significance of this finding is not known. The authors correctly pointed out that patients must be followed at least until clinical resolution, if not actual normalization, of Ig values. Only half of the patients normalized during the observation period. It is possible that other specific immunodeficiency diagnoses may be conferred on some of the patients who are still hypogammaglobulinemic. The authors did not comment on whether some patients who initially presented in this way subsequently developed additional clinical and/or laboratory features leading to the diagnosis of other immunodeficiencies. Without knowing this, it is impossible to estimate the predictive value of intact vaccine responses in this setting (ie, how often do we “miss” a different specific immunodeficiency diagnosis if we stop after this initial evaluation). However, these and other reports suggest that the majority of these patients follow a relatively benign course.

Memory Switched B Cell Percentage and Not Serum Immunoglobulin Concentration Is Associated With Clinical Complications in Children and Adults With Specific Antibody Deficiency and Common Variable Immunodeficiency

Alachkar H, Taubenheim N, Haeney MR, Durandy A, Arkwright PD. Clin Immunol. 2006;120:310–318 PURPOSE OF THE STUDY. To compare the associations of clinical complications of antibody deficiency with (1) measures of memory B-cell development and (2) serum immunoglobulin (Ig) concentrations. STUDY POPULATION. Twenty-seven children (aged 2–16 years) and 28 adults (aged 22–65 years) with diagnoses of specific antibody deficiency defined as having normal Ig levels and impaired responses to pneumococcal immunization (specific antibody deficiency [SAD], 21 patients) or common variable immunodeficiency defined as hypogammaglobulinemia with more generally impaired vaccine responses (common variable immunodeficiency [CVID]; 34 patients) were studied. Nineteen patients who underwent evaluation and were found to have normal Ig levels and fully intact vaccine responses served as a “control” group. METHODS. Serum Ig levels were measured by standard clinical laboratory methods; memory B-cell populations were assessed by flow cytometry using labeled monoclonal antibodies to detect cell-surface CD19, CD27, and IgD. (CD19 is a marker for all B cells. CD27 is a marker for the memory subset of cells. Cells that do not express IgD have undergone class-switching and express IgG, IgA, or IgE. CD19+CD27+IgD− cells are called “switched” memory B cells and are indicators of normal B-cell activation and development in germinal centers in lymph nodes or other secondary lymphoid tissues.) These laboratory findings were separately correlated with clinical characteristics. RESULTS. The only significant laboratory differences between the SAD and CVID groups were the serum concentrations of IgG and IgA, which was expected because of the laboratory definitions of these entities. There were no differences in memory B-cell populations nor the occurrence of splenomegaly, bronchiectasis, and autoimmune disease (enteropathy, cytopenias, arthritis, diabetes) between the groups with SAD and CVID. However, when patients with each of these complications (without regard to immunodeficiency diagnosis) were compared with those without, a significantly (P < .01) lower percentage and number of switched memory B cells was found in the affected patients. The statistical significance was unchanged after adjustment for age. Serum Ig levels were not different in patients with or without each of these complications, even after adjusting for age. CONCLUSIONS. Measurement of switched memory B cells is a more accurate predictor of clinical complications of humoral immunodeficiency than is the classification of SAD and CVID or measurement of serum Ig. REVIEWER COMMENTS. Measurement of memory B-cell populations has emerged in the past 5 years as a potentially clinically useful predictor of complications for patients with CVID, with reports of findings similar to those in this article. This study extends this observation to another diagnosis: SAD. This study was also the first to compare children and adults with these 2 diagnoses with respect to clinical and laboratory features. Although the numbers are relatively small, neither the diagnostic assignment nor measurement of serum Ig concentration (related by the clinical/laboratory definitions of these syndromes) allows one to predict the occurrence of the complications studied. Even across diagnoses, the determination of switched memory B-cell percentage emerges as a robust indicator of associated complications. This laboratory test is likely to become a part of the routine evaluation of humoral immunodeficiency.

Development of Population-Based Newborn Screening for Severe Combined Immunodeficiency

Purpose of the Study. To evaluate analysis of T-cell development as a potential population-screening method for severe combined immunodeficiency (SCID). Study Population. Twenty-three infants with SCID, 2 patients without SCID, 245 randomly selected infants, and several healthy adults. Methods. DNA was extracted from dried blood spots on standard newborn screening (Guthrie) cards. The DNA was subjected to polymerase chain reaction (PCR) to amplify and quantitate the number of T-cell receptor excision circles (TRECs), a marker of T-cell development in the thymus. For comparison, the β-actin gene was also amplified by PCR. Results. None of the SCID patients’ blood spots contained detectable TRECs, whereas the infants without SCID had normal TRECs. Healthy adults had normal TRECs, and intentional depletion of T cells led to the disappearance of TRECs in simulated blood spots. Approximately 3% of randomly collected blood spots did not contain measurable TRECs but did contain β-actin. Conclusions. Measurement of TRECs by PCR can accurately identify infants with SCID. The relatively high percentage (3%) of screened spots having the SCID profile indicates the need for further refinement of the method before a larger population study. Reviewer Comments. Newborn screening for SCID is desirable because of the rapidly fatal nature of this disease and because of the good outcomes that may be obtained with the earliest possible diagnosis. The minimum estimate of the incidence of SCID is >1 per 100 000 births, comparable to other diseases that are already part of newborn screening programs. Almost all patients with SCID lack detectable TRECs. The ability to accurately measure them in dried blood spots represents a tremendous advance toward the possibility of effective newborn screening for this genetically very heterogeneous group of disorders. If the specificity of the analysis can be improved, this may soon be implemented in newborn screening programs.

Presenting Phenotype in 100 Children With the 22q11 Deletion Syndrome

Purpose of the Study. To describe the clinical presentations of individuals having deletion of the 22q11 region. Study Population. The first 100 individuals <20 years old presenting to the Queen Sylvia Children’s Hospital (Göteborg, Sweden) and found to have 22q11 deletion (from 1993–2002). Methods. All diagnoses were confirmed by fluorescence in situ hybridization. Clinical data collected at diagnosis included age and clinical findings in 8 categories (1, cardiac defects; 2, thymus size, infection history, autoimmune disease; 3, hypocalcemia; 4, feeding difficulties; 5, cleft lip/palate, speech/language impairment; 6, developmental delay, learning difficulties, behavioral abnormalities; 7, other malformations/deformities; 8, dysmorphic features). Those features that led (in particular) to the consideration of the diagnosis were distinguished. Results. The largest number was diagnosed by cardiologists (39) at a median age of 0.5 years old, with cleft palate or speech pathology specialists second (22) at a median age of 8 years, and neurologists or psychiatrists third (19) at a median age of 11.2. Note that 68 of the 74 children diagnosed after age 2 were born before the fluorescence in situ hybridization test was routinely available. The main findings are summarized in Table 1. TABLE 1 Clinical Features (Category) % Diagnosed at <2 yr (n = 26) % Diagnosed at >2 y (n = 74) Overall 1. Cardiac defects (eg, ventricular septal defect, tetralogy of Fallot, truncus arteriosus) 92a 54a 64a 2. Hypoplastic thymus 91a Unknown 2. Infections (mainly upper and lower respiratory tract bacterial infections) 8 85a 65 2. Autoimmunity 0 6 6 3. Hypocalcemia/hypoparathyroidism 58a 1a 16a 4. History of feeding difficulty (poor suck, nasal reflux) Not recorded 74 5. Cleftlip/palate 15a 28 25 5. Speech/language impairment N/A 85a 6. Developmental delay, learning difficulties, psychiatric problems N/A 96a 7. Other malformations (most common was inguinal or umbilical hernia; many others were noted) 42 45 44 8. Characteristic subtle dysmorphic features (mildly abnormal ears, broad nasal tip, small arched mouth, long slender fingers, etc) 100 100 100a Elements of the presentation that led to diagnosis. Conclusions. The authors offer diagnostic guidelines for testing for 22q11 deletion (for infants: any typical cardiac defect or 2 of the features in categories 2 through 5, 7, or 8; for preschool-aged children and adolescents: any 2 of the 8 categories either present currently or in the past medical history). Reviewer Comments. 22q11 deletion leads to a spectrum of phenotypes most commonly called velocardiofacial syndrome and/or DiGeorge syndrome. Occurring in ∼1 in 3000 to 4000 live births, it is among the most common syndromes associated with primary immunodeficiency. Serious infection occurs but is relatively rare. Early diagnosis is most desirable to prevent or mitigate morbidity arising from developmental and psychiatric complications in childhood and adolescence. Of the major clinical manifestations, the symptoms arising from velopharyngeal insufficiency (poor suck, nasal reflux) and various associated malformations seem to be significantly overlooked. The fact that all patients had subtle characteristic dysmorphisms that did not contribute very much to diagnosis shows how much our vision improves with the aid of molecular genetic glasses.

Health-Related Quality of Life of Children With Primary Immunodeficiency Disease: A Comparison Study

Zebracki K, Palermo TM, Hostoffer R, Duff K, Drotar D. Ann Allergy Asthma Immunol . 2004;93:557–561 To compare parental perceptions of health-related quality of life (HRQOL) in children with primary immunodeficiency (PI) with children with juvenile idiopathic arthritis (JIA) and healthy children. Thirty-six children in each of 3 groups (108 total): those with PI, those with JIA, and those who were healthy. Patients were matched for age, ethnicity, and parental marital status. The age ranged from 4 to 18 years, and 94% …

Autosomal Recessive Hyperimmunoglobulin E Syndrome: A Distinct Disease Entity

Renner ED, Puck JM, Holland SM, et al. J Pediatr . 2004;144:93–99 To describe the clinical and immunologic features of a distinct subgroup of patients with hyper-IgE syndrome (HIES) having autosomal recessive inheritance (AR-HIES) as distinct from the form having autosomal dominant inheritance (AD-HIES). Thirteen patients from 6 families having AR-HIES and 68 of their relatives. Patients were identified based on exhibiting a classic triad of features of HIES: recurrent skin abscesses, recurrent pneumonias, and elevated serum IgE. Medical records were reviewed, and patients and family members underwent uniform immunologic evaluations. All families were consanguineous. Five are from Turkey and 1 is …

Children and Adults With Primary Antibody Deficiencies Gain Quality of Life by Subcutaneous IgG Self-Infusions at Home

Gardulf A, Nicolay U, Math D, et al. J Allergy Clin Immunol . 2004;114:936–942 To determine the impact of a change from in-hospital infusion of intravenous immunoglobulin (IVIG) to in-home infusion of subcutaneous immunoglobulin (SCIG) on health-related quality of life (HRQOL) and treatment satisfaction. Fifty-eight patients between the ages of 2 and 75 years (17 patients <14 years old [“children” for the purposes of this study]; 41 patients ≥14 years old [“adults”]) with primary antibody deficiency. Thirty-seven patients were receiving IVIG, and 10 were receiving SCIG (a control group to compare for …