Selective IgM Deficiency Research Articles

IPINeT Ped-unPAD Study: Goals, Design, and Preliminary Results.

Background: An unclassified primary antibody deficiency (unPAD) is a widely heterogeneous clinical entity, recently identified within the spectrum of Inborn Errors of Immunity (IEIs). Since unPAD has been traditionally considered as a mild condition, it has incorrectly received little attention, resulting in the paucity of extensive and comparable studies describing its natural history. To address the gaps in characterizing, understanding, and managing pediatric unPAD patients, the Italian Primary Immunodeficiency Network (IPINet) Ped-unPAD study has recently been launched. Methods: Seventeen IPINeT Centers have expressed interest to participate, and data collection is still on-going. Hereby, we anticipate preliminary key issues emerging from the first 110 enrolled patients, attending three IPINet Centers. Results: A proportion of unPAD patients have experienced a severe infectious phenotype, which required hospitalization in a quarter of patients and antibiotic prophylaxis or Immunoglobulin Replacement Therapy in approximately 10% of patients. In this partial cohort, a mean follow-up (FU) of 5 years confirmed unPAD diagnosis in fifty percent of cases, with the remaining being reclassified as the Transient Hypogammaglobulinemia of Infancy (25%) and other IEIs (25%), such as a Common Variable Immunodeficiency, Selective IgA deficiency, Selective IgM deficiency, and IgG3 subclass deficiency. Conclusions: Despite a phenotype overlap at diagnosis, clinicians should be aware that unPAD is a mutable condition that deserves comprehensive evaluation and long-term monitoring to dissect the final diagnosis for optimal treatment.

The prevalence of immunodeficiency in a special population: intern doctors

Background: This study analyzes the immune system parameters of intern doctors working actively during the COVID-19 pandemic. When an intern doctor failed to respond to the treatment during a severe COVID-19 condition, the immune system panel was examined and as a result, it revealed an underlying immunodeficiency. The death of the intern doctor caused several concerns among other intern doctors, and for this reason, their immune systems were also considered to be examined. This study aims to demonstrate that immunodeficiencies might be more common than is known among the general population. Methods: In this single-center study, the demographic characteristics and European Society for Immunodeficiencies (ESID) diagnostic criteria of 92 intern doctors have been examined retrospectively. For the study, immune system parameters (complete blood count, serum immunoglobulins and subgroup levels, specific vaccine responses, isohemagglutinin titers, lymphocyte subgroups, and class-switched memory B cell (cSMB) levels have been evaluated. Results: When the demographic characteristics have been analyzed it is seen that the median age is 23.6 (21-28) years, and 64 (70%) of the intern doctors are female. In immune system parameters, one or more are found to be low in 51.08% of the doctors. Among the immunoglobulin subgroups, low IgG4 has been the most common. Selective IgA deficiency has been detected in 2.17% and selective IgM deficiency has been detected in also 2.17% of them. Low B cells (CD19+) are detected in 10.9% and low levels of class-switched memory B cells are found in 35.7% of them. Conclusion: This study reveals that deficient immunological parameters, especially selective Ig A, selective IgM deficiency, and low IgG4, might be more frequent than known. Depending on the data, it can be concluded that immunodeficiency might be more common than it is known among the general population; however, low immunological parameters alone do not lead to immunodeficiency.

Selective IgM Deficiency: Evidence, Controversies, and Gaps.

Selective Immunoglobulin M deficiency (SIgMD) has been recently included in the inborn errors of immunity (IEI) classification by the International Union of Immunological Societies Expert Committee. The understanding of SIgMD is still extremely limited, especially so in cases of SIgMD in the pediatric population. The epidemiology of SIgMD in the pediatric population is still unknown. The pathogenesis of SIgMD remains elusive, and thus far no genetic nor molecular basis has been clearly established as a definitive cause of this primary immunodeficiency. Recurrent respiratory infections represent the main clinical manifestations in children, followed by allergic and autoimmune diseases. No conclusive data on the correct therapeutic management of SIgMD are available. Although, for most SIgMD patients, Ig replacement therapy is not required, it may be recommended for patients with significantly associated antibody deficiency and recurrent or severe infections. Prophylactic antibiotics and the prompt treatment of febrile illness are crucial. There is insufficient evidence on the prognosis of this condition. Therefore, further studies are required to define the disease trajectories and to increase our understanding of the molecular mechanisms underlying SIgMD in order to facilitate a better clinical, immunological, and prognostic characterization of the condition and develop tailored therapeutic management strategies.

A novel homozygous frameshift CCNO variant presenting with primary ciliary dyskinesia and selective IgM deficiency.

A novel homozygous frameshift CCNO variant presenting with primary ciliary dyskinesia and selective IgM deficiency.

SERUM IGM DEFICIENCY ASSOCIATED WITH CONNEXIN MUTATION IN AN 18-YEAR-OLD MALE

<h3>Introduction</h3> Selective IgM deficiency (SIGMD) is characterized by remarkably low serum levels of IgM with normal IgG and IgA levels. These patients clinically present with recurrent infections, autoimmune disorders, and malignancies. While unknown, the proposed mechanisms explain the pathophysiology as an issue due to impaired IgG antibody response. The connexin genes encode for gap junctional proteins where mutations can cause hearing deficits and immune dysregulation. We present an 18-year-old patient with recurrent sinusitis and diagnosed connexin-26 mutation and SIGMD. <h3>Case Description</h3> An 18-year-old male with chronic sinusitis, Marfanoid joint hypermobility syndrome, and sensorineural hearing loss due to connexin-26 deficiency with bilateral cochlear implants. This patient's mutation is a GJB2 deletion located on chromosome 13 which encodes for the connexin-26 protein. The patient experienced recurrent infections, and serum immunoglobulins showed a normal IgA (84 mg/dL; normal: 70-400 mg/dL), IgG (922 mg/dL; normal: 700-1600 mg/dL) and reduced IgM (26 mg/dL; normal: 40-230 mg/dL) levels. The patient was responsive to Mumps, Measles, Rubella, and Diphtheria vaccinations amongst others, consistent with SIGMD diagnoses. Antibody responses to polysaccharide antigens were absent. The leukocyte counts were within normal limits. His parents are connexin-26 deficient carriers, and his older brother was diagnosed with SIGMD. <h3>Discussion</h3> Connexin-26 has been identified with multiple immunological mechanisms. Although mutations of this gene have no direct tie to antibody formation in relation to IgM, the presence of these two pathologies in one patient is intriguing and may suggest a pathophysiologic connection. We describe the first case of connexin mutation with SIGMD in an 18-year-old male.

Rapidly Progressive Bronchiectasis and Pulmonary Fibrosis in Yellow Nail Syndrome with Possible Association with Selective IgM Deficiency.

A 67-year-old man with a history of IgM deficiency and pulmonary fibrosis and bronchiectasis was admitted for management of worsening symptoms. Investigations revealed exudative pleural effusion with rapidly progressive bronchiectasis. Although a potential trigger of bronchiectasis and pulmonary fibrosis was not identified despite extensive work-up by several physicians in the past, a bedside observation of yellow dystrophic nails on all extremities revealed the diagnosis. This case report helps to remind clinicians of a rare medical disorder of still uncertain aetiology and no available cure. This case is consistent with a few previous case reports that suggest a potential association with selective immunoglobulin deficiency.LEARNING POINTSYellow nail syndrome is a rare condition characterized by the classic triad of respiratory, nail and lymphatic involvement.Diagnosis remains clinical with no confirmatory tests available; the absence of yellow nails does not preclude the diagnosis.An association with selective IgM deficiency has been infrequently reported.

HEADACHE AS AN ADVERSE EFFECT OF IMMUNOGLOBULIN ADMINISTRATION FOR SELECTIVE IMMUNOGLOBULIN G DEFICIENCY

INTRODUCTION: IgG subclass deficiency was described by William Terry in a patient with recurrent infections. Selective IgG subclass is defined as a significant decrease in serum concentration of 1 or more IgG subclasses with normal total IgG, IgA and IgM levels. Persistent low serum levels of one or more immunoglobulin G (IgG) subclasses may be found in a high proportion of adult patients with increased susceptibility to infections (17). This deficiency has been described in association with other primary immunodeficiencies, including: selective IgA deficiency, selective IgM deficiency and Ataxia-Telangiectasia, growth hormone deficiency, Down syndrome, cystic fibrosis, among others (1). CLINICAL CASE:We present the clinical case of a 28-year-old female patient with a history of selective immunodeficiency to IgG immunoglobulin, repeated urinary tract infections, repeated vaginal infections and herpes simplex II infection, all of which have been treated, She went to a hospital in Morona Santiago three days ago for presenting, as the apparent cause, administration of immunoglobulin for a basic illness, a mild holocranial headache that evolved into a severe headache, accompanied by nausea that led to vomiting on one occasion, for which she was admitted to the hospital for pain management. Complementary examinations showed that there was no metabolic alteration or neurological deterioration, which is why she was classified as an adverse effect of the administration of immunoglobulin 3 days earlier. EVOLUTION:The patient was admitted for pain management due to severe headaches, multiple analgesics were administered without adequate response, so it was decided to start a tramadol infusion pump. During the following hours of hospitalization she remained with a feeling of nausea and weakness, however, the headache gradually subsided and it was decided to discontinue analgesic medication to assess the response of the clinical picture, and she was discharged 24 hours after admission with a favorable evolution. CONCLUSIONS: IgG subclass deficiency is a pathology characterized by the fact that it occurs in women over 16 years of age, with a very low prevalence; the presence of respiratory pathologies gives rise to the suspicion of this disease. The treatment of this pathology is based solely on the intravenous or subcutaneous administration of Immunoglobulin G, together with the concomitant treatment of the infections that the patient presents. Adverse effects should always be taken into account, as they are temporary, but quite disabling. KEYWORDS: Headache, Immunoglobulin G, Urinary Tract Infections, Herpes Simplex

Protocol for the unclassified primary antibody deficiency (unPAD) study: Characterization and classification of patients using the ESID online Registry.

BackgroundPrimary antibody deficiencies (PADs) without an identified monogenetic origin form the largest and most heterogeneous group of primary immunodeficiencies. These patients often remain undiagnosed for years and many present to medical attention in adulthood after several infections risking structural complications. Not much is known about their treatment, comorbidities, or prognosis, nor whether the various immunological forms (decreased total IgG, IgG subclass(es), IgM, IgA, specific antibody responses, alone or in combination(s)) should be considered as separate, clearly definable subgroups. The unclassified primary antibody deficiency (unPAD) study aims to describe in detail all PAD patients without an identified specific monogenetic defect regarding their demographical, clinical, and immunological characteristics at presentation and during follow-up. In constructing these patterns, the unPAD study aims to reduce the number of missed and unidentified PAD patients in the future. In addition, this study will focus on subclassifying unPAD to support the identification of patients at higher risk for infection or immune dysregulation related complications, enabling the development of personalized follow-up and treatment plans.Methods and analysisWe present a protocol for a multicenter observational cohort study using the ESID online Registry. Patients of all ages who have given informed consent for participation in the ESID online Registry and fulfill the ESID Clinical Working Definitions for ‘unclassified antibody deficiency’, ‘deficiency of specific IgG’, ‘IgA with IgG subclass deficiency’, ‘isolated IgG subclass deficiency’, ‘selective IgM deficiency’, ‘selective IgA deficiency’ or ‘common variable immunodeficiency’ will be included. For all patients, basic characteristics can be registered at first registration and yearly thereafter in level 1 forms. Detailed characteristics of the patients can be registered in level 2 forms. Consecutive follow-up forms can be added indefinitely. To ensure the quality of the collected data, all data will be fully monitored before they are exported from the ESID online Registry for analysis. Outcomes will be the clinical and immunological characteristics of unPAD at presentation and during follow-up. Subgroup analyses will be made based on demographical, clinical and immunological characteristics.

An unusual association of disseminated staphylococcal infection in dengue fever

Dengue fever is an important mosquito-borne disease with a highly variable clinical spectrum, ranging from self-limiting mild illness to expanded dengue syndrome (EDS). While the immune-pathogenesis of dengue virus (DENV) infection had been studied thoroughly, the exact mechanism remains elusive. The transient suppression of host innate immunity by DENV might be the likely reason for dengue-associated co-infections and/or superinfections. In addition, the dual infection can worsen the clinical outcome of Dengue fever. We are reporting a case of disseminated staphylococcal infection in a 31-year-old healthy male with a recent dengue infection. Blood culture showed methicillin-sensitive Staphylococcus aureus. Selective IgM deficiency has been proved in this patient, which might explain, the occurrence of disseminated staphylococcal septicemia. This case report highlights the importance of early detection of atypical features and the emerging entity called EDS

Selective IgM deficiency: Follow-up and outcome.

Selective IgM deficiency (sIgMD) is classified under primary immunodeficiencies (PID). This study aimed to define the clinical and immunologic features of sIgMD. We assessed a retrospective medical record of patients who fulfilled the diagnostic criteria for sIgMD in a pediatric immunology department. There were 55 patients with sIgMD. Out of 55 patients, 13 (23.6%) patients, diagnosed with a well-defined PID disease, and nine, evaluated as transient hypogammaglobulinemia, were excluded in the follow-up. The ratio of the sIgMD was %0.12 in the outpatient clinic of pediatric immunology (33/27,000). Out of 33 patients, eight (24,2%) were asymptomatic during the follow-up period. Fifteen (45.4%) patients presented with upper/lower respiratory and skin infections. Six patients (18%) had chromosomal anomaly, or syndrome (trisomy 21, 22q11.2 deletion 1p deletion, CHARGE syndrome, and Cohen syndrome). Six (18%) had autoimmune/inflammatory diseases, such as Behcet's disease, immune thrombocytopenic purpura, Crohn's disease, Guillain-Barre syndrome, and diabetes mellitus. Five (15%) had allergic disorders. Three patients (9%) developed malignancy. The PID diagnoses were combined immunodeficiency, common variable immunodeficiency, chronic granulomatous disease, adenosine deaminase deficiency, and congenital neutropenia. Genetic disorders, autoimmune/inflammatory, and allergic diseases may accompany sIgMD. Approximately 25% of the patients were asymptomatic in our series. Patients had increased malignancy risk. We diagnosed about 25% of the patients having low IgM with a specific PID in the follow-up period. Thus, patients with sIgMD should be followed up regularly in immunology clinics.

Novel coronavirus disease 2019 and combined autoimmune neutropenia and thrombocytopenia: a case report

Background: Combined autoimmune neutropenia (AIN) and immune thrombocytopenia (ITP) is a rare disease that can present as extremely low neutrophil count and platelet count, respectively [1]. Case Presentation: We describe the first case, to the authors’ knowledge, of the novel SARS CoV-2 infection and combined AIN and ITP in a healthy 27-year-old male. Conclusion: Viruses have been known to trigger autoimmune diseases in people with genetic predisposition. We speculate that the patient’s selective IgM deficiency predisposed him to have autoimmune cytopenia, and SARS-COV-2 triggered him to acquire combined AIN and ITP. Our hypothesis is supported by a lack of evidence of malignancy, a normal morphology on the smear, and an immediate response to IVIG infusion with significant improvement in platelet and neutrophilic count.

Phenotypic analysis of T follicular helper and T follicular regulatory cells in primary selective IgM deficiency

Selective IgM deficiency (SIgMD) is a rare immunodeficiency characterized by serum IgM below two standard of mean, and normal IgG and IgA levels. Both in human and mice with selective IgM deficiency, germinal centers cells are decreased. The development of germinal center and humoral immunity are regulated in part by follicular helper T (TFH) and follicular regulatory T (TFR) cells. However, the analysis of circulating TFH (cTFH) and TFR (cTFR) cells in the pathogenesis of SIgMD has not been explored. We observed lower percentage of cTFR cells in SIgMD patients than in control group. However, we did not observe any significant difference in the percentage of cTFH cells and their subsets between both experimental groups. When data were analyzed according to specific antibody response to pneumococcal polysaccharide, we observed a higher percentage of cTFH cells in SIgMD patients with specific antibody deficiency than in SIgMD patients with normal specific antibody response. Our results suggest that cTFH cells and their subsets are preserved in SIgMD patients. However, the role of lower percentage of cTFR cells in the pathogenesis of this immunodeficiency is not clear.

Challenges in investigating patients with isolated decreased serum IgM: The SIMcal study.

The clinical consequences of isolated decreased serum immunoglobulin (Ig)M are not sufficiently known. Therefore, it is difficult to determine the clinical policy following such a finding. Only few reported IgM‐deficient patients fulfil the European Society for Immunodeficiencies (ESID) diagnostic criteria for selective IgM deficiency (true sIgMdef), or their diagnosis is uncertain due to insufficient laboratory data (possible sIgMdef). Decreased serum IgM is often incidentally found in asymptomatic adults. The objective of our study was to further characterize true sIgMdef and to compare the European data collected through the ESID Registry community (tertiary centres) to our previously published Dutch cohort (secondary centre). Fifteen centres (12 countries) participated with 98 patients. Patients were excluded if serum IgM was only determined once (n = 14), had normalized (n = 8), or if they also had other immunological abnormalities (n = 15). Ten patients (5 adults) completely fulfilled the ESID criteria for true sIgMdef. Age‐matched cut‐off values varied widely between centres; when using the ESID diagnostic protocol reference values, only six patients (five adults) had true sIgMdef. Because of these small numbers, further analyses were performed in patients with true or possible sIgMdef (13 adults, 48 children). Respiratory infections were commonly reported at presentation (adults 54%, children 60%). Symptomatic adults had lower serum IgM levels (mean 0.27 g/L, 95% CI 0.22‐0.31) than those without symptoms (mean 0.33 g/L, 95% CI 0.30‐0.36; P = 0.02). To be able to explore the clinical consequences of true sIgMdef, we should fully analyse and accurately describe those patients in whom a decreased serum IgM is found.

COMPREHENSIVE CLINICAL AND IMMUNOLOGICAL FEATURES OF ADULT SELECTIVE PRIMARY IGM DEFICIENCY: RESPONSE TO IMMUNOGLOBULIN THERAPY

Introduction Selective IgM Deficiency (SIGMD) is a recently incorporated primary immunodeficiency. Clinical and immunological features have been reported in a small number of cases. The aim of this study is to present comprehensive clinical immunological features in a large cohort of adult patients diagnosed with SIGMD, and to assess response to Ig therapy. Methods A retrospective EMR and chart review of 64 patients between 2009 and 2017 was performed. SIGMD is defined by serum IgM levels at least two standard deviations below the mean of controls. Immunological data, clinical presentations, associated features, and response to Ig therapy were collected. Results The mean value of IgM observed was 40 (±14) with 20% of the patients exhibiting IgM Conclusions Patients with SIGMD frequently present with sinopulmonary infections (68%). Autoimmune and allergic manifestations are common. Specific antibody deficiency is observed in almost 50% of patients. Immunoglobulin therapy is effective in a subset of patients with SIGMD. T cells, T cell subsets, and B cells are generally normal.

AN ATYPICAL PRESENTATION OF SELECTIVE IMMUNOGLUBULIN M (IGM) DEFICIENCY

Introduction Selective IgM deficiency (SIGMD) remains a poorly described primary immunodeficiency. The condition is frequently under-recognized and no genetic defect has been identified to date. Case Description We present two patients with gradually progressive chronic cough and dyspnea, unresponsive to multiple courses of antibiotics and steroids. Both were non-smokers with no significant past medical history, exposures or reflux. Chest radiographs and pulmonary function testing were unremarkable. Case 1: 60-year-old lady with a high-resolution chest computed tomographic (CT) scan revealing cylindrical bronchiectasis (Figure 1, panel A). Immunoglobulin assays revealed low IgM (9 mg/dL; ref 37-286 mg/dL). She has had one bronchiectasis flare since diagnosis. Case 2: 75-year-old gentleman with chest CT showing bronchiectasis (Figure 1, panel B) and low IgM (18mg/dL; ref 37-286 mg/dL). He too has had only one bronchiectasis flare in the last year. Both patients had IgA, IgG, and IgE levels within normal limits and protective titers against protein and polysaccharide vaccines. T, B, NK cell flow cytometry was unremarkable. Since diagnosis, they have been evaluated with immunoglobulin assays and screening for autoimmune disease and lymphoma twice yearly. Neither has required prophylactic antibiotics. Discussion SIGMD has a prevalence of 0.03 – 0.4% in the general population. SIGMD is not considered a classic etiologic factor for bronchiectasis and SIGMD diagnosis rates of around 14% have been reported in bronchiectasis patient cohorts. In prospective studies evaluating phenotypes of bronchiectasis patients, only 2 in 189 patients had SIGMD. However, lower IgM levels were noted consistently among these patients, raising the question of a potential association.

Selective IgM deficiency associated with adult-onset Still disease

Selective IgM deficiency associated with adult-onset Still disease

Metastatic Infection by Methicillin-Sensitive Staphylococcus aureus and its Potential Association to an Unusual Humoral Immunodeficiency

Multifocal metastatic infection by Staphylococcus aureus is severe and uncommon. We describe the case of a previously asymptomatic 63-year-old man diagnosed with complicated staphylococcal endocarditis of the mitral valve along with cervical and lumbar spondylodiscitis, and multiple pre/para-vertebral abscesses; establishing a persistent flaccid tetraparesis, neurogenic bladder and anal sphincter dysfunction. The patient overcame infection after an 8-week Cloxacillin/ Rifampicin treatment associated to multiple surgical procedures. Thereafter, immunological assessment was performed, driving to the diagnosis of selective IgM deficiency. We propose a physiopathological relationship between this rare dysgammaglobulinemia and such fulminant staphylococcal invasive infection; that would, perhaps, justify humoral immunity assessment in patients undergoing staphylococcemia.

Truly selective primary IgM deficiency is probably very rare.

Isolated decreased serum-immunoglobulin (Ig)M has been associated with severe and/or recurrent infections, atopy and autoimmunity. However, the reported high prevalence of clinical problems in IgM-deficient patients may reflect the skewed tertiary centre population studied so far. Also, many papers on IgM deficiency have included patients with more abnormalities than simply IgM-deficiency. We studied truly selective primary IgM deficiency according to the diagnostic criteria of the European Society for Immunodeficiencies (ESID) (true sIgMdef) by reviewing the literature (261 patients with primary decreased serum-IgM in 46 papers) and analysing retrospectively all patients with decreased serum-IgM in a large teaching hospital in 's-Hertogenbosch, the Netherlands [1 July 2005-23 March 2016; n=8049 IgM <0·4 g/l; n=2064 solitary (IgG+IgA normal/IgM<age-matched reference)]. A total of 359 of 2064 (17%) cases from our cohort had primary isolated decreased serum-IgM, proven persistent in 45 of 359 (13%) cases; their medical charts were reviewed. Our main finding is that true sIgMdef is probably very rare. Only six of 261 (2%) literature cases and three of 45 (7%) cases from our cohort fulfilled the ESID criteria completely; 63 of 261 (24%) literature cases also had other immunological abnormalities and fulfilled the criteria for unclassified antibody deficiencies (unPAD) instead. The diagnosis was often uncertain (possible sIgMdef): data on IgG subclasses and/or vaccination responses were lacking in 192 of 261 (74%) literature cases and 42 of 45 (93%) cases from our cohort. Our results also illustrate the clinical challenge of determining the relevance of a serum sample with decreased IgM; a larger cohort of true sIgMdef patients is needed to explore fully its clinical consequences. The ESID online Registry would be a useful tool for this.

P299 Plasma cell dyscrasia in primary selective IgM deficiency

There is an increased prevalence of autoimmunity and malignancies; however, no cases of plasma cell dycrasia have been described in selective IgM deficiency (SIGMD). We present two cases of SIGMD, one with multiple myeloma and secondary amyloidosis of the GI tract; and the second with IgAλ monoclonal gammopathy of undetermined significance (MGUS).

Selective IgM Deficiency-An Underestimated Primary Immunodeficiency.

Although selective IgM deficiency (SIGMD) was described almost five decades ago, it was largely ignored as a primary immunodeficiency. SIGMD is defined as serum IgM levels below two SD of mean with normal serum IgG and IgA. It appears to be more common than originally realized. SIGMD is observed in both children and adults. Patients with SIGMD may be asymptomatic; however, approximately 80% of patients with SIGMD present with infections with bacteria, viruses, fungi, and protozoa. There is an increased frequency of allergic and autoimmune diseases in SIGMD. A number of B cell subset abnormalities have been reported and impaired specific antibodies to Streptococcus pneumoniae responses are observed in more than 45% of cases. Innate immunity, T cells, T cell subsets, and T cell functions are essentially normal. The pathogenesis of SIGMD remains unclear. Mice selectively deficient in secreted IgM are also unable to control infections from bacterial, viral, and fungal pathogens, and develop autoimmunity. Immunological and clinical similarities and differences between mouse models of deficiency of secreted IgM and humans with SIGMD have been discussed. Patients with SIGMD presenting with recurrent infections and specific antibody deficiency responses appear to improve clinically on immunoglobulin therapy.