Primary Immunoglobulin Deficiency Research Articles

Limited Innovations After More Than 65 Years of Immunoglobulin Replacement Therapy: Potential of IgA- and IgM-Enriched Formulations to Prevent Bacterial Respiratory Tract Infections.

Patients with primary immunoglobulin deficiency have lower immunoglobulin levels or decreased immunoglobulin function, which makes these patients more susceptible to bacterial infection. Most prevalent are the selective IgA deficiencies (~1:3,000), followed by common variable immune deficiency (~1:25,000). Agammaglobulinemia is less common (~1:400,000) and is characterized by very low or no immunoglobulin production resulting in a more severe disease phenotype. Therapy for patients with agammaglobulinemia mainly relies on prophylactic antibiotics and the use of IgG replacement therapy, which successfully reduces the frequency of invasive bacterial infections. Currently used immunoglobulin preparations contain only IgG. As a result, concurrent IgA and IgM deficiency persist in a large proportion of agammaglobulinemia patients. Especially patients with IgM deficiency remain at risk for recurrent infections at mucosal surfaces, which includes the respiratory tract. IgA and IgM have multiple functions in the protection against bacterial infections at the mucosal surface. Because of their multimeric structure, both IgA and IgM are able to agglutinate bacteria efficiently. Agglutination allows for entrapment of bacteria in mucus that increases clearance from the respiratory tract. IgA is also important for blocking bacterial adhesion by interfering with bacterial adhesion receptors. IgM in its place is very well capable of activating complement, therefore, it is thought to be important in complement-mediated protection at the mucosal surface. The purpose of this Mini Review is to highlight the latest advances regarding IgA- and IgM-enriched immunoglobulin replacement therapy. We describe the different IgA- and IgM-enriched IgG formulations, their possible modes of action and potential to protect against respiratory tract infections in patients with primary immunoglobulin deficiencies.

Genetic screening of male patients with primary hypogammaglobulinemia can guide diagnosis and clinical management

The precise diagnosis of an immunodeficiency is sometimes difficult to assess, especially due to the large spectrum of phenotypic variation reported among patients. Common variable immunodeficiency disorders (CVID) do not have, for a large part, an identified genetic cause. The identification of a causal genetic mutation is important to confirm, or in some cases correct, the diagnosis. We screened >150 male patients with hypogammaglobulinemia for mutations in three genes involved in pediatric X-linked primary immunoglobulin deficiency: CD40LG, SH2D1A and BTK. The SH2D1A screening allowed to reclassify two individuals with an initial CVID presentation as XLP after mutations identification. All these mutations were associated with a lack of protein expression. In addition, 4 patients with a primary diagnosis of CVID and one with a primary IgG subclass deficiency were requalified as XLA after identifying BTK mutations. Interestingly, two out of these 5 patients carried a damaging coding BTK mutation associated with a lower, but detectable, BTK expression in monocytes, suggesting that a dysfunctional protein explains the disease phenotype in these patients. In conclusion, our results advocate to include SH2D1A and BTK in newly developed targeted NGS genetic testing, to contribute to providing the most appropriate medical treatment and genetic counselling.

Mucosal-associated invariant T cells are depleted and functionally altered in patients with common variable immunodeficiency

Common variable immunodeficiency (CVID) is a primary immunoglobulin deficiency characterized by recurrent infections and complications, including autoimmunity, enteropathy, polyclonal lymphocytic infiltration or lymphoid malignancy. Innate T cells can support B cell maturation and antibody production. We investigated the numbers, phenotypes and functions of circulating B cell, γδ T cell, invariant natural killer T (iNKT) cell and mucosal-associated invariant T (MAIT) cell subsets in 23 CVID patients and 27 healthy controls. Switched-memory B cells and plasmablasts were depleted in CVID patients (p<0.0001). γδ T cells were found at normal numbers, but iNKT and MAIT cells were depleted (p<0.0001 and p<0.002). MAIT cells were especially low in patients with complicated CVID (p<0.05). MAIT cells from patients appeared more activated and more frequently produced interleukin-17A, interleukin-22 and tumor necrosis factor-α than MAIT cells from healthy subjects in vitro. Thus, MAIT cell depletion and activation may contribute to immunodeficiency and complications associated with CVID.

Immunoglobulin A Deficiency in Celiac Disease

To determine the prevalence and significance of immunoglobulin A (IgA) deficiency and partial deficiency in patients with celiac disease (CD). Selective IgA deficiency is a common primary immunoglobulin deficiency and has a higher prevalence in patients with CD. The prevalence and significance of IgA deficiency and partial deficiency in patients with CD in the United States has not previously been examined. A retrospective, cohort study of 1498 adults and 317 children seen in a University Medical Center was conducted. There were 26 patients (22 adults, 4 children) with CD who were IgA deficient and 11 (9 adults, 2 children) with CD who were partially IgA deficient. The prevalence of IgA deficiency/partial deficiency was similar among adults and children (2.1% and 1.9%, respectively, P=0.99). Among adults, concomitant autoimmune disease was present in 29% of IgA-deficient/partially deficient patients versus 12% of CD patients with normal IgA levels (P=0.0081). All 4 IgA-deficient patients who had persistently positive IgG celiac serologies while adherent to a gluten-free diet and were rebiopsied had a normal repeat biopsy. Both positive tissue transglutaminase IgG and antigliadin IgG were found in these patients. Selective IgA deficiency/partial deficiency is present in 2% of CD patients at this referral center and is equally prevalent among adults and children. IgA-deficient/partially deficient adults had a higher prevalence of concomitant autoimmune disease than those without IgA deficiency. In patients who are IgA deficient, IgG serologies may be persistently elevated despite histologic recovery.

Protective effect of IgM against colonization of the respiratory tract by nontypeable Haemophilus influenzae in patients with hypogammaglobulinemia

Primary immunoglobulin deficiencies lead to recurrent bacterial infections of the respiratory tract and bronchiectasis, even with adequate immunoglobulin replacement therapy. It is not known whether patients able to secrete IgM (eg, those with hyper-IgM [HIgM] syndrome) are as susceptible to these infections as patients who lack IgM production (eg, those with panhypogammaglobulinemia [PHG]). This study is aimed at identifying specific microbiological and clinical (infections) characteristics that distinguish immunoglobulin-substituted patients with PHG from patients with HIgM syndrome. A cohort of patients with HIgM syndrome (n= 25) and a cohort of patients with PHG (n= 86) were monitored prospectively for 2 years while receiving similar polyvalent immunoglobulin replacement therapies. Regular bacterial analyses of nasal swabs and sputum were performed, and clinical events were recorded. In parallel, serum and saliva IgM antibody concentrations were measured. When compared with patients with PHG, patients with HIgM syndrome were found to have a significantly lower risk of nontypeable Haemophilus influenzae carriage in particular (relative risk, 0.39; 95% CI, 0.21-0.63). Moreover, patients with HIgM syndrome (including those unable to generate somatic hypermutations of immunoglobulin genes) displayed anti-nontypeable H influenzae IgM antibodies in their serum and saliva. Also, patients with HIgM syndrome had a lower incidence of acute respiratory tract infections. IgM antibodies appear to be microbiologically and clinically protective and might thus attenuate the infectious consequences of a lack of production of other immunoglobulin isotypes in patients with HIgM syndrome. Polyvalent IgG replacement therapy might not fully compensate for IgM deficiency. It might thus be worth adapting long-term antimicrobial prophylactic regimens according to the underlying B-cell immunodeficiency phenotype.

Longitudinal decline in lung function in patients with primary immunoglobulin deficiencies

To the Editor: Common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA) are 2 primary immunoglobulin deficiency (PID) disorders in which immunoglobulin replacement is indicated.1Orange J.S. Hossny E.M. Weiler C.R. Ballow M. Berger M. Bonilla F.A. et al.Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology.J Allergy Clin Immunol. 2006; 117: S525-S553Abstract Full Text Full Text PDF PubMed Scopus (553) Google Scholar Despite treatment, sinopulmonary infection remains a major cause of morbidity and early mortality in these patients.2Gathmann B. Grimbacher B. Beaute J. Dudoit Y. Mahlaoui N. Fischer A. et al.The European internet-based patient and research database for primary immunodeficiencies: results 2006-2008.Clin Exp Immunol. 2009; 157: 3-11Crossref PubMed Scopus (168) Google Scholar Lung function declines with normal aging, and accelerated decline is a major risk factor for adverse outcomes in healthy people, smokers, and patients with bronchiectasis.3Loebinger M.R. Wells A.U. Hansell D.M. Cinyanganya N. Devaraj A. Meister M. et al.Mortality in bronchiectasis: a long-term study assessing the factors influencing survival.Eur Respir J. 2009; 34: 843-849Crossref PubMed Scopus (285) Google Scholar, 4Kerstjens H.A. Rijcken B. Schouten J.P. Postma D.S. Decline of FEV1 by age and smoking status: facts, figures and fallacies.Thorax. 1997; 52: 820-827Crossref PubMed Scopus (225) Google Scholar, 5Kohansal R. Martinez-Camblor P. Agustí A. Buist A.S. Mannino D.M. Soriano J.B. The natural history of chronic airflow obstruction revisited: an analysis of the Framingham Offspring cohort.Am J Respir Crit Care Med. 2009; 180: 3-10Crossref PubMed Scopus (442) Google Scholar The rate of decline of lung function in patients with PID treated with intravenous immunoglobulin (IVIG) therapy is currently unknown but is likely a prognostic indicator. The aim of this study was to ascertain the rate of decline in FEV1 and forced vital capacity (FVC) in patients with XLA and CVID receiving IVIG. Our secondary aim was to identify clinical variables predictive of lung function decline. We undertook a retrospective study in a tertiary hospital in Melbourne, Australia. All patients age 18 years or older who satisfied stringent diagnostic criteria for CVID or XLA1Orange J.S. Hossny E.M. Weiler C.R. Ballow M. Berger M. Bonilla F.A. et al.Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology.J Allergy Clin Immunol. 2006; 117: S525-S553Abstract Full Text Full Text PDF PubMed Scopus (553) Google Scholar and who were receiving IVIG therapy during the years 2008 to 2009 were identified. For each patient, all available lung function tests (LFTs) were collected, including weight and height at first LFT and age at diagnosis. Factors likely to influence decline in lung function were also recorded, including hospital admissions, pack-years of smoking (20 cigarettes per day for 1 year = 1 pack-year), Pseudomonas aeruginosa airway colonization, the presence of bronchiectasis on chest imaging, and duration of IVIG therapy. Immunoglobulin dose was calculated as grams per kilogram of body weight (g/kg) per month. Serum IgG measurements were taken before infusions, and a weighted mean level was calculated for each patient. Continuous variables were summarized and reported as mean ± SD or median (interquartile range) and categoric variables as number (proportion). Outcome variables FEV1 and FVC were assessed for normality and found to be well approximated by a normal distribution. We used linear regression to estimate slopes and SEs of FEV1 and FVC for each patient. We calculated decline in lung function by using predicted normal values from Knudson et al.6Knudson R.J. Lebowitz M.D. Holberg C.J. Burrows B. Changes in the normal maximal expiratory flow-volume curve with growth and aging.Am Rev Respir Dis. 1983; 127: 725-734PubMed Google Scholar We performed weighted linear regression analyses to examine the association of clinical factors with change in lung function with weights derived by using the inverse variance method7Senn S. Stevens L. Chaturvedi N. Repeated measures in clinical trials: simple strategies for analysis using summary measures.Stat Med. 2000; 19: 861-877Crossref PubMed Scopus (92) Google Scholar and presented results as parameter estimates (PEs) with SEs. A 2-sided P value of .05 was considered statistically significant. Analyses were performed with SAS 9.1 (SAS Institute, Cary, NC). The study was approved by the Alfred Hospital Ethics Committee (Project 156/08). Thirty-seven patients (21 male; 57%) were included in the study, and 375 LFTs were collected, with 10.2 ± 8.6 pulmonary function tests per patient (range, 2-34) spanning a follow-up period of 7.6 ± 5.6 years. Demographic data are presented in Table I. The mean baseline FEV1 for the whole group was 2.83 ± 1.28 L (82% ± 25% predicted), and those for the CVID group and XLA group, 2.77 ± 1.16 L (82% ± 24% predicted) and 3.48 ± 1.39 L (81% ± 29% predicted), respectively. The mean FVC was 3.85 ± 1.35 L (88% ± 21% predicted). The average annual FEV1 decline for all patients with PID was 45 ± 6 mL/y. The XLA group was found to have a more rapid decline in FEV1 (65 ± 11 mL/y) compared with the CVID group (36 ± 7 mL/y; P = .034; Fig 1). The decline in FVC (mean ± SE) was 43 ± 9.0 mL, higher in XLA (58 ± 20 mL/y) compared with CVID (39 ± 10 mL/y. However, the difference between groups was not significant (P = .39; Fig 2).Table IDemographic characteristics of study groupClinical variableTotalCVIDXLASubjects (n)3729 (78%)8 (22%)Age (y)48.34 ± 15.9750.61 ± 16.6340.09 ± 10.29Male (n)21 (57%)13 (44%)8 (100%)Weight (kg)66.84 ± 16.0967.70 ± 17.6463.68 ± 8.52Height (cm)167.48 ± 9.75166.04 ± 9.98172.67 ± 7.15BMI (kg/m2)23.86 ± 5.8724.55 ± 6.3321.36 ± 2.75IVIG dose/mo (g/kg/mo)0.45 ± 0.120.43 ± 0.120.51 ± 0.10IgG trough level (g/L)7.73 ± 1.417.71 ± 1.487.79 ± 1.21Hospital admissions22 (59%)15 (52%)7 (87%)Age at diagnosis (y)34.72 ± 22.443.53 ± 16.753.87 ± 4.42Pack years of smoking0 (0-5)0 (0-2)3.5 (0-22.5)Bronchodilator responsiveness11 (30%)8 (27%)3 (37%)Bronchiectasis17 (46%)12 (41%)5 (63%)Pseudomonas colonization (n)5 (13%)5 (17%)0 (0%)FEV1 predicted (%) at start81.73 ± 25.0981.86 ± 24.3581.26 ± 29.40FVC predicted (%) at start87.83 ± 20.5086.07 ± 21.2894.19 ± 17.04BMI, Body mass index.Data are expressed as mean ± SD, median (interquartile range), or number (proportion). Open table in a new tab Fig 2Average decline in FVC (mL/y) for PID (total group), CVID, and XLA groups. Error bars represent estimates (SEs). Predicted decline is taken from predicted normal values at each time point for each patient.View Large Image Figure ViewerDownload Hi-res image Download (PPT) BMI, Body mass index. Data are expressed as mean ± SD, median (interquartile range), or number (proportion). Univariate analysis identified 3 variables associated with decline in lung function (Table II). These were as follows:1.Increased IVIG dose per kilogram was inversely associated with lung function decline (PE [SE] = –0.121 [0.039]; P = .004), indicating that higher dose per kilogram appeared to be protective of lung function. The related variables IVIG dose per month (g/kg/mo) and IVIG dose (g) were also inversely associated with lung function decline (Table II).2.Diagnosis of XLA compared with CVID was associated with a more rapid decline in lung function (PE [SE] = 0.028 [0.013]; P = .034).3.Younger age at diagnosis (PE [SE] = 0.001 [0.0002]; P = .005).Table IIFactors associated with decline in FEV1 (univariate analysis)VariablePESEP valueIVIG dose (g/kg)−0.1210.039.004Age at diagnosis (y)0.0010.0002.005IVIG dose/mo (g/kg/mo)−0.1380.052.01IVIG dose (g)−0.0020.001.03CVID0.0280.013.03Pack-years of smoking−0.0020.001.06IgG trough level (g/L)−0.0040.006.49PEs describe the effect on FEV1 decline in liters per year. Open table in a new tab PEs describe the effect on FEV1 decline in liters per year. Trough IgG level did not have a statistically significant association with FEV1 decline (P = .485) or FVC decline (P = .69). Similar significant associations with the IVIG dose/kg/mo and IVIG dose (g) were observed for FVC and FEV1. The normal rate of decline in FEV1 (and 95% CI) in healthy nonsmoking men in a population similar to ours is reported to be 19.6 mL (17.1-22.1), and for women, 17.6 mL (13.8-21.4).5Kohansal R. Martinez-Camblor P. Agustí A. Buist A.S. Mannino D.M. Soriano J.B. The natural history of chronic airflow obstruction revisited: an analysis of the Framingham Offspring cohort.Am J Respir Crit Care Med. 2009; 180: 3-10Crossref PubMed Scopus (442) Google Scholar The average decline of FEV1 in our group of 45 mL per year exceeds that associated with heavy smoking.5Kohansal R. Martinez-Camblor P. Agustí A. Buist A.S. Mannino D.M. Soriano J.B. The natural history of chronic airflow obstruction revisited: an analysis of the Framingham Offspring cohort.Am J Respir Crit Care Med. 2009; 180: 3-10Crossref PubMed Scopus (442) Google Scholar Although smoking was recorded as a variable, the average duration of smoking was small (3.5 pack-years), so the decline in lung function associated with smoking just failed to reach statistical significance (P = .06). Previous longitudinal reports of LFT in PID have used predicted normal values to indicate little change in LFT despite radiographic progression.8Haidopolou K. Calder A. Jones A. Jaffe A. Sonnappa S. Bronchiectasis secondary to primary immunodeficiency in children: longitudinal changes in structure and function.Pediatr Pulmonol. 2009; 44: 669-675Crossref PubMed Scopus (59) Google Scholar However cross-sectional data used to derive predicted normal equations overestimate lung function decline by as much as 35 mL/y in the under 50 years age group compared with longitudinal studies4Kerstjens H.A. Rijcken B. Schouten J.P. Postma D.S. Decline of FEV1 by age and smoking status: facts, figures and fallacies.Thorax. 1997; 52: 820-827Crossref PubMed Scopus (225) Google Scholar, 9Van Pelt W. Borsboom G.J. Rijcken B. Schouten J.P. van Zomeren B.C. Quanjer P.H. Discrepancies between longitudinal and cross-sectional change in ventilatory function in 12 years of follow-up.Am J Respir Crit Care Med. 1994; 149: 1218-1226Crossref PubMed Scopus (72) Google Scholar indicating that predicted normal values are inappropriate to monitor longitudinal LFT changes. In this study, higher monthly IVIG dose (g/kg) is significantly linked with decreased lung function decline (0.45 ± 0.12 [g/kg]; PE, –0.121 [0.039]; P = .004). This means that a 1 g per kg dose increase in IVIG was associated in these patients with a reduction in the decline of FEV1 by 121 mL per year. Although such a dose is well beyond a practical therapeutic range, our findings suggest that IVIG dose might be targeted to reduce lung function decline. This approach is supported by a recent publication from Lucas et al10Lucas M. Lee M. Lortan J. Lopez-Granados E. Misbah S. Chapel H. Infection outcomes in patients with common variable immunodeficiency disorders: relationship to immunoglobulin therapy over 22 years.J Allergy Clin Immunol. 2010; 125: 1354-1360Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar reporting that infection frequency was found to be unrelated to trough IgG levels. Taken together, these results indicate that maintaining a higher dose of IVIG, independent of trough level, may be associated with superior outcomes in PID. Obviously this hypothesis should be tested in prospective trials, but such an approach differs from currently recommended algorithms.1Orange J.S. Hossny E.M. Weiler C.R. Ballow M. Berger M. Bonilla F.A. et al.Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology.J Allergy Clin Immunol. 2006; 117: S525-S553Abstract Full Text Full Text PDF PubMed Scopus (553) Google Scholar One of the limitations of the study is the small number of patients. We were careful to ensure that this group met current definitions of XLA and CVID.1Orange J.S. Hossny E.M. Weiler C.R. Ballow M. Berger M. Bonilla F.A. et al.Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology.J Allergy Clin Immunol. 2006; 117: S525-S553Abstract Full Text Full Text PDF PubMed Scopus (553) Google Scholar The strength of this cohort lies in this diagnostic rigor and the large number of respiratory function tests performed. Larger cohorts of patients with PID are now available through international registries, and such data will enable measurement of lung function decline and provide a basis for comparison of treatment outcomes.2Gathmann B. Grimbacher B. Beaute J. Dudoit Y. Mahlaoui N. Fischer A. et al.The European internet-based patient and research database for primary immunodeficiencies: results 2006-2008.Clin Exp Immunol. 2009; 157: 3-11Crossref PubMed Scopus (168) Google Scholar This database also reveals reduced life expectancy in patients with PID, consistent with reduced lung function. To our knowledge, this is the first study to report longitudinal rate of decline in lung function in well characterized patients with PID. Our findings suggest that studies of the outcomes of immunoglobulin therapy in PID might use change in lung function as an indicator of treatment efficacy. Our study also supports higher doses of IVIG as protective of lung function decline.

Nodular lymphoid hyperplasia and histologic changes mimicking celiac disease, collagenous sprue, and lymphocytic colitis in a patient with selective IgA deficiency

Selective IgA deficiency is the most common primary immunoglobulin deficiency. The clinical manifestations of selective IgA deficiency, including gastrointestinal (GI) complications, are rare and typically milder than those seen with common variable immunodeficiency or X-linked agammaglobulinemia. We present a rare case of selective IgA deficiency that shows a number of interesting histological features in the GI tract, including diffuse nodular lymphoid hyperplasia involving the entire small and large intestine, celiac disease-like and collagenous sprue-like changes in the small intestine, as well as lymphocytic colitis pattern. However, this patient had no particular GI symptoms suggestive of celiac sprue or microscopic colitis. These findings suggest that the GI tract in patients with selective IgA deficiency can show peculiar histologic changes that mimic celiac disease, collagenous sprue, or lymphocytic colitis, which may be a pattern of injury related to infection or immunoglobulin immunodeficiency-associated autoimmune phenomena.

The clinical significance of immunoglobulin A deficiency

IgA deficiency is the most common primary immunoglobulin deficiency. The prevalence in Caucasians is around one in 500, whereas in some Asian populations it is very uncommon. Most individuals with IgA deficiency are clinically asymptomatic. Those with symptoms of immunodeficiency have predominantly sinopulmonary or gastrointestinal infections, which are more severe when associated with IgG2, IgG4 or specific antibody deficiency. IgA deficiency is believed to be one end of a spectrum of immunodeficiency with common variable immunodeficiency at the most severe end. Although primary IgA deficiency is the most commonly encountered form, secondary deficiencies due to drugs or viral infections are recognized. IgA deficiencies can be partial or transient. Primary IgA deficiency is caused by a defect of terminal lymphocyte differentiation, which leads to underproduction of serum and mucosal IgA; affected individuals have normal IgA genes. A number of non-immunoglobulin genes have been implicated in IgA deficiency. There have been many diseases reported in association with IgA deficiency, particularly autoimmune diseases. The most common association is with coeliac disease (CD), which has special significance since CD is usually diagnosed by detection of specific IgA antibodies that are obviously lacking in IgA deficiency. There is no specific treatment for patients with symptomatic IgA deficiency. Antibiotics are prescribed in those with acute infections. A significant proportion of IgA-deficient individuals are reported to have anti-IgA antibodies in their serum. Although blood or blood products given to IgA-deficient individuals can lead to severe, even fatal, transfusion reactions, such reactions are rare.

A prospective controlled crossover trial of a new presentation (10% vs. 5%) of a heat-treated intravenous immunoglobulin

Thirty-five patients with primary or secondary immunoglobulin deficiency were included in a crossover study to test the tolerance, clinical efficacy, and safety of a liquid pasteurized 10% concentrated intravenous gammaglobulin versus a 5% concentrated presentation. No statistically significant differences were found between these parameters. Total serum immunoglobulin-(Ig)G and IgG subclass levels were similar in both groups. No modifications in serum alanine transferase (ALT) levels and viral status (HBsAg, HCV-RNA, p24 antigen or RNA for HIV) were observed throughout treatment. Adverse reactions were reported in 3 out of 70 infusions (4.3%), 2 in the experimental group and 1 in the control group. The maximum recommended rate of infusion for the 10% gammaglobulin is the same as for the 5% gammaglobulin product (0.04 ml/kg/min); generally speaking, this means that infusion time is halved. We conclude that a 10% gammaglobulin product is a well-tolerated, clinically efficacious and safe intravenous preparation, and that it could be a short infusion time alternative for primary and secondary antibody deficiencies.

Mycoplasmal arthritis in patients with primary immunoglobulin deficiency: clinical features and outcome in 18 patients.

A survey of 358 patients with primary antibody deficiency shows that mycoplasmal infection is the commonest cause of severe chronic erosive arthritis. We review our experience with 18 patients with confirmed or probable mycoplasmal arthritis. There was a broad spectrum of severity from a monoarthritis rapidly responding to tetracyclines to severe debilitating polyarthritis, sometimes with antibiotic-resistant organisms which in two cases were eliminated following hyperimmune animal serum therapy. Most patients had very low serum 1gG levels at the onset of arthritis, suggesting that maintaining levels within the normal range with immunoglobulin replacement may prevent infection. The unique susceptibility of these patients to mycoplasmal arthritis shows that antibodies play a crucial role in protection against these organisms.

Decreased Number of CD73 (ecto‐5′‐Nucleotidase) Molecules on Lymphocytes from Patients with Primary Immunoglobulin Deficiencies. Correlation between Number of CD73 Molecules and T‐Lymphocyte Function In Vitro

CD73 is a bifunctional glycosyl phosphatidylinositol anchored leucocyte differentiation antigen which has specific ecto-5'-nucleotidase (ecto-5'-NT) activity and is an accessory T-lymphocyte activation molecule. The aim of the present study was to investigate the CD73 expression on blood mononuclear cells (BMC) from a group of patients with primary immunoglobulin deficiency (IGD). This group of patients had both significantly decreased levels of ecto-5'-NT on BMC (P = 0.002) and decreased numbers of CD73 molecules per CD73+ lymphocyte (P = 0.01). Five of the 10 patients had a decreased percentage of CD73+ lymphocytes. Among B-lymphocytes the patients had normal percentages of CD73+ cells but four of the 10 patients had numbers of CD73 molecules per CD73+ B-lymphocyte below the normal range. Among CD4-lymphocytes three out of 10 patients had percentages of CD73+ below the normal range and four out of 10 patients had decreased percentages of CD73+ CD8-lymphocytes. Significant correlations were found between in vitro proliferative responses to mitogens and the number of CD73 molecules per CD73+ lymphocyte (rs = 0.60, P < 0.01) and per CD73+ CD8-lymphocyte (rs = 0.64, P < 0.02). In addition, a positive correlation was found between ability to proliferate and level of ecto-5'-NT on BMC (rs = 0.53, P < 0.05). Furthermore the ability of BMC to synthesize ecto-5'-NT was studied. During 2 days culture ecto-5'-NT activity increased markedly on BMC from both patients and healthy donors. The level of activity on BMC from all patients attained levels higher than on freshly isolated BMC from healthy donors. This shows that the decreased levels of ecto-5'-NT found on freshly isolated BMC from patients with IGD is due to defective regulation of the enzyme activity in vivo.

Prevalence of gallstones in patients with primary immunoglobulin deficiency

In the early 1970s an increased prevalence of gallstones was reported in adults and children with immunoglobulin deficiency. As the advent of ultrasonography has largely changed the diagnostic approach to gallstones, we have reevaluated the prevalence of cholelithiasis in a group including 37 patients with common variable immunodeficiency and seven patients with other forms of primary immunodeficiency. All patients were receiving intravenous gammaglobulin replacement since 1983 or, in more recent cases, soon after the diagnosis was made, and therefore had relatively few infections. All patients underwent a hepatobiliary ultrasonogram and blood sampling. Data were compared, after age and sex standardization, with those obtained by the GREPCO in a free-living population of 1239 men and 1081 women. Only two women with immunoglobulin deficiency had gallstones. One of these was obese and had had one pregnancy. Both were asymptomatic. None of the patients studied had a history of cholecystectomy or evidence of biliary sludge. Thus, the observed prevalence rates of gallstone disease were 8.7% in women and 0% in males, respectively, against expected values of 9.5% and 3.2%. Immunodeficient patients expressed several putative risk factors for gallstones in the low range (body mass index, total and HDL cholesterol, and blood glucose in both sexes, and triglycerides in men). We conclude that gallstone disease is not more frequent in patients with immunodeficiency syndromes undergoing immunoglobulin therapy than in the general population.

Primary immunoglobulin deficiency and haematological disorders.

Nine patients with immunoglobulin deficiency and various haematological disorders are presented. In all patients, recurrent infections had antedated the onset of the haematological disorder but, in most, the possibility of primary immunodeficiency had not been considered until after the haematological diagnosis had been established. The recognition of immunodeficiency is important since such patients may require steroids, immunosuppressive therapy or splenectomy. Gammaglobulin would appear to be the appropriate therapy in this situation. Infections were reduced in all 6 patients so treated.

Diffuse follicular lymphoid hyperplasia of the small intestine without primary immunoglobulin deficiency

Three cases of follicular lymphoid hyperplasia extending to the whole length of the small intestine are reported in three young adutt patients of low economic status. The disease was revealed by chronic diarrhea with malabsorption and/or protein-losing enteropathy. In one patient, all transitional patterns were found between the hyperplastic follicles and a small intestinal multicentric centrocytic-centroblastic lymphoma. No abnormalities in humoral or cellular immunity were found in the three patients. In particular, serum immunoglobulins (except IgG in one case) and plasma cell populations of small intestinal lamina propria were normal. Diffuse follicular iymphoid hyperplasia of the small intestine in the absence of primary immunoglobulin deficiency appears to be a rare condition associated with (or leading to) intestinal malignant lymphoma in most cases. Patients usually belong to the same populations as those suffering from α-chain disease.

Abnormalities of regulatory T-cell subpopulations in patients with primary immunoglobulin deficiencies

Lymphocyte subsets in 5 patients with X-linked hypogammaglobulinemia, in 13 with common variable hypogammaglobulinemia (CVH), and in 10 with selective IgA defect were studied with a panel of monoclonal antibodies of the OK series. Helper T lymphocytes, defined as OKT4 + cells, were reduced, and suppressor T cells, defined as OKT8 + cells, were increased in several patients. Moreover an inversion of the normal ratio between OKT4 + and T8 + cells was observed in 4 patients with CVH and in one with selective IgA defect. Such abnormalities may play an important role in the pathogenesis of these diseases.

Suppression of B-cell differentiation by leukocytes from hypogammaglobulinemic patients.

Leukocytes from patients with several forms of immunodeficiency characterized by apparently differing defects in B-lymphocyte maturation produced few or no plasmacytoid cells in vitro, and were capable of suppressing the generation of plasma cells in co-culture with cells of normal persons, in the presence of pokeweed mitogen. Such inhibition was commonly observed in cultures which included cells from patients with primary immunoglobulin deficiency, but was not seen to a significant degree in identical co-cultures of cells from normals. The suppression observed was not dependent upon mixed leukocyte culture reactivity. Both sheep erythrocyte-rosetting lymphocytes and adherent cells appeared to participate in these effects in some patients. In one patient with common variable immunodeficiency, but not in several others, removal of suppressing cells permitted the patient's remaining cells to differentiate into plasma cells in vitro. Because of the diverse syndromes in which suppression was observed, it is likely that, in at least some hypogammaglobulinemic patients, the suppression is secondary to the disease process rather than being the primary pathogenic mechanism.

Primary Immunoglobulin Deficiency with Recurrent Sinusitis and Prolonged Steatorrhoea

Primary Immunoglobulin Deficiency with Recurrent Sinusitis and Prolonged Steatorrhoea

[Differentiation of human blood lymphocytes using serologic and autoradiographic methods. II. Results in primary and symptomatic immunoglobulin deficiency conditions (author's transl)].

[Differentiation of human blood lymphocytes using serologic and autoradiographic methods. II. Results in primary and symptomatic immunoglobulin deficiency conditions (author's transl)].