Factors associated with IgG levels in adults with IgG subclass deficiency.

BACKGROUND: Factors associated with IgG levels in adults with IgG subclass deficiency (IgGSD) are incompletely understood. We studied adults with IgGSD with subnormal IgG1 only, subnormal IgG1/IgG3, or subnormal IgG3 only without other subnormal IgG subclasses, IgA, or IgM. We compiled: age; sex; autoimmune condition(s) (AC); atopy; IgG, IgG subclasses, IgA, IgM; IgGsum (IgG1 + IgG2 + IgG3 + IgG4); and D (percentage difference between IgGsum and IgG). We compared attributes of patients with/without subnormal IgG (< 7.00 g/L; subnormal IgG1 subclass groups only) and analyzed IgGsum and IgG relationships. We performed backward stepwise regressions on IgG using independent variables IgG subclasses, age, and sex and on D using independent variables age and sex. RESULTS: There were 39 patients with subnormal IgG1 only (89.7% women), 53 with subnormal IgG1/IgG3 (88.7% women), and 115 with subnormal IgG3 only (91.3% women). Fifteen patients (38.5%) and 32 patients (60.4%) in the respective subnormal IgG1 subclass groups had subnormal IgG. Attributes of patients with/without IgG < 7.00 g/L were similar, except that AC prevalence was lower in patients with subnormal IgG1 only and IgG < 7.00 g/L than ≥ 7.00 g/L (p = 0.0484). Mean/median IgG1 and IgG2 were significantly lower in patients with IgG < 7.00 g/L in both subnormal IgG1 subclass groups (p < 0.0001, all comparisons). Regressions on IgG in three subclass groups revealed positive associations with IgG1 and IgG2 (p < 0.0001 each association). Regressions on D revealed no significant association. IgG1 percentages of IgGsum were lower and IgG2 percentages were higher in patients with subnormal IgG1 subclass levels than subnormal IgG3 only (p < 0.0001 all comparisons). CONCLUSIONS: We conclude that both IgG1 and IgG2 are major determinants of IgG in patients with subnormal IgG1, combined subnormal IgG1/IgG3, or subnormal IgG3 and that in patients with subnormal IgG1 or combined subnormal IgG1/IgG3, median IgG2 levels are significantly lower in those with IgG < 7.00 g/L than those with IgG ≥ 7.00 g/L.

Clinical and laboratory associations of mannose-binding lectin in 219 adults with IgG subclass deficiency.

BACKGROUND: Mannose-binding lectin (MBL) deficiency may increase risk of respiratory tract infection in adults unselected for IgG or IgG subclass levels. In a retrospective study, we sought to determine associations of serum MBL levels with clinical and laboratory characteristics of unrelated non-Hispanic white adults at diagnosis of IgG subclass deficiency (IgGSD). We computed the correlation of first and second MBL levels expressed as natural logarithms (ln) in a patient subgroup. We compared these characteristics of all adults with and without MBL ≤50 ng/mL: age; sex; body mass index; upper/lower respiratory tract infection; diabetes; autoimmune condition(s); atopy; other allergy; corticosteroid therapy; and subnormal serum IgG subclasses, IgA, and IgM. We performed logistic regression on MBL ≤50 ng/mL (dichotomous) using the three independent variables with the lowest values of p in univariate comparisons. RESULTS: There were 219 patients (mean age 51 ± 13 y; 82.5% women). Thirty-six patients (16.4%) had MBL ≤50 ng/mL. Two MBL measurements were available in 14 patients. The median interval between the first and second measurements was 125 d (range 18-1031). For ln-transformed data, we observed adjusted r2 = 0.9675; Pearson correlation coefficient 0.9849; and p < 0.0001. Characteristics of patients with and without MBL ≤50 ng/mL did not differ significantly in univariate comparisons. We performed a regression on MBL ≤50 ng/mL using: subnormal IgM (p = 0.0565); upper respiratory tract infection (p = 0.1094); and body mass index (p = 0.1865). This regression revealed no significant associations. CONCLUSIONS: We conclude that the proportion of the present IgGSD patients with serum MBL ≤50 ng/mL is similar to that of healthy European adults. MBL ≤50 ng/mL was not significantly associated with independent variables we studied.

Pneumococcal vaccination responses in adults with subnormal IgG subclass concentrations.

BACKGROUND: We sought to compare Pneumovax®23 responses in adults with subnormal IgG subclass concentrations. We studied adults with normal total IgG, frequent/severe respiratory infection, and subnormal IgG1, IgG3, or IgG1 + IgG3 before and after Pneumovax®23. We defined response as serotype-specific IgG > 1.3 µg/mL and aggregate response as IgG > 1.3 µg/mL for ≥70% of all serotypes tested. We compared patients with and without serotype-specific responses and performed logistic regression on aggregate responses using: age; male sex; body mass index; autoimmune condition(s); atopy; other allergies; subnormal IgGSc immunophenotypes; IgA; and IgM. RESULTS: There were 59 patients (mean age 44 ± 13 (SD) years; 83.1% women). Median days between pre- and post-Pneumovax®23 testing was 33 (range 19-158). The median post-vaccination summated concentration of serotype-specific IgG was higher in patients with subnormal IgG1 than subnormal IgG3 (responders and non-responders). All subnormal IgG1 + IgG3 non-responders responded to serotypes 8, 9 and 26, unlike other non-responders. Subnormal IgG3 responders had lower responses to serotypes 1, 4, 12, 23, 26, and 51. Subnormal IgG3 non-responders had higher responses to serotypes 1, 3, 8, 9, 12, 14, 19, 51, and 56. Response rates decreased with increasing age. Aggregate responders were: subnormal IgG1, 54%; IgG3, 46%; and IgG1 + IgG3, 46%. Regression on aggregate response revealed lower response with male sex (odds ratio 0.09 [95% CI 0.01, 0.77]) and atopy (0.17 [0.03, 0.83]). CONCLUSIONS: Serotype-specific IgG responses to Pneumovax®23 were greater in patients with subnormal IgG1 than subnormal IgG3. Male sex and atopy were associated with lower aggregate responses.

Pagophagia in men with iron-deficiency anemia.

Few case series of pagophagia and iron deficiency include men. We performed a retrospective study of non-Hispanic white men with iron-deficiency anemia whose anemia and pagophagia, thrombocytosis, and thrombocytopenia (if present) resolved after iron replacement. Iron-deficiency anemia was defined as transferrin saturation (TS) <15%, serum ferritin (SF) <30 µg/L, and hemoglobin (Hb) <13.0 g/dL. We excluded men with: anemia, thrombocytosis, or thrombocytopenia due to non-iron-deficiency causes; malignancy; chronic inflammatory conditions; hemochromatosis; or creatinine >1.1 mg/dL. We computed univariate and multivariable pagophagia associations with: age; gastrointestinal bleeding; TS; SF; Hb; red blood cell (RBC) count; mean corpuscular volume (MCV); RBC distribution width (RDW); and platelet count. Median age of 41 men was 54 y (range 18-81). Fourteen men (34.1%) had pagophagia. Thirty-six men (87.8%) had gastrointestinal bleeding. Mean Hb was 9.4 ±â€¯2.2 g/dL. Six men (14.6%) had thrombocytosis; two (4.9%) had thrombocytopenia. Logistic regression on pagophagia revealed: age (p = 0.0158; odds ratio 0.92 [95% confidence interval: 0.85, 0.99]) and platelet count (p = 0.0187; 0.98 [0.97, 1.00]) (41.4% of pagophagia occurrence; ANOVA p = 0.0053). We conclude that pagophagia occurred in 34% of men with iron-deficiency anemia and was negatively associated with age and platelet count, after adjustment for other variables.

Authentic IgM Fc Receptor (FcµR).

Since the bona fide Fc receptor for IgM antibody (FcµR) was identified eight years ago, much progress has been made in defining its biochemical nature, cellular distribution, and effector function. However, there are clearly conflicting results, especially about the cellular distribution and function of murine FcµR. In this short article, we will discuss recent findings from us and other investigators along with our interpretations and comments that may help to resolve the existing puzzles and should open new avenues of investigation.

Fibromyalgia in 300 adult index patients with primary immunodeficiency.

OBJECTIVES: We sought to determine the prevalence and clinical and laboratory associations of fibromyalgia in adults with primary immunodeficiency (immunoglobulin (Ig) G subclass deficiency (IgGSD) and common variable immunodeficiency (CVID). METHODS: We performed a retrospective analysis of these observations in 300 non-Hispanic white adult index patients with recurrent/severe respiratory tract infections and IgGSD or CVID: age; sex; IgGSD; fibromyalgia; chronic fatigue; autoimmune conditions (ACs); interstitial cystitis (IC); diabetes; body mass index; serum Ig isotypes; blood lymphocytes and subsets; and human leukocyte antigen (HLA)-A and -B types and haplotypes. We performed univariate comparisons, logistic multivariable regressions, and an analysis of covariance. RESULTS: Mean age was 49 ± 12 (standard deviation) y. There were 246 women (82.0%). IgGSD was diagnosed in 276 patients (92.0%). Fifty-six patients had fibromyalgia (18.7%; female:male 13:1). Other characteristics included: chronic fatigue, 63.0%; aggregate ACs, 35.3%; Sjögren's syndrome, 8.0%; IC, 3.0%; diabetes, 10.3%; and HLA-A*29, B*44 positivity, 9.7%. Prevalences of female sex; chronic fatigue; IC; and HLA-A*29, B*44 positivity were greater in patients with fibromyalgia. Logistic regression on fibromyalgia revealed three positive associations: chronic fatigue (p=0.0149; odds ratio 2.6 [95% confidence interval 1.2, 5.6]); Sjögren's syndrome (p=0.0004; 5.2 [2.1, 13.2]); and IC (p=0.0232; 5.7 [1.3, 25.7]). In an analysis of covariance, there were significant interactions of chronic fatigue, Sjögren's syndrome, and interstitial cystitis on fibromyalgia. CONCLUSIONS: Fibromyalgia is common in non-Hispanic white adult index patients with primary immunodeficiency, especially women. Chronic fatigue, Sjögren's syndrome, and IC are significantly associated with fibromyalgia after adjustment for other independent variables.

Selective subnormal IgG3 in 121 adult index patients with frequent or severe bacterial respiratory tract infections.

We characterized 121 adults with frequent or severe bacterial respiratory tract infections at diagnosis of selective subnormal IgG3. Mean age was 47 ± 13 (SD)y; 87.6% were women. Associated disorders included: autoimmune conditions 33.1%; hypothyroidism 14.9%; atopy 29.8%; and other allergy manifestations 41.3%. In 34.1%, proportions of protective Streptococcus pneumoniae serotype-specific IgG levels did not increase after polyvalent pneumococcal polysaccharide vaccination. Blood CD19+, CD3+/CD4+, CD3+/CD8+, and CD56+/CD16+ lymphocyte levels were within reference limits in most patients. In regression analyses, independent variables age; sex; autoimmune conditions; hypothyroidism; atopy; allergy manifestations; corticosteroid therapy; and lymphocyte subsets were not significantly associated with IgG subclass, IgA, or IgM levels. Frequencies of HLA haplotypes A*01, B*08; A*02, B*14; A*02, B*15; A*02, B*44; A*02, B*57; and A*03, B*07 were greater in 80 patients than 751 controls. We conclude that subnormal IgG3 and non-protective S. pneumoniae IgG levels contribute to increased susceptibility to respiratory tract infections.

Serum immunoglobulins in 28 adults with autoimmune sensorineural hearing loss: increased prevalence of subnormal immunoglobulin G1 and immunoglobulin G3.

BACKGROUND: Our informal observations suggested that some patients with acute sensorineural hearing loss (ASNHL) have subnormal serum immunoglobulin (Ig) levels. We evaluated 28 consecutive adults (18 men, 10 women) at ASNHL diagnosis using: antibodies to 68 kD protein, 30 kD protein, and type II collagen; and serum total IgG, IgG subclasses, total IgA, and IgM. Reference ranges for Ig levels were mean ± 2 SD. We compared prevalences of subnormal IgG subclasses to those in 275 healthy European adults in previous reports. We also reviewed charts of consecutive adult index patients with primary Ig deficiency (35 common variable immunodeficiency, 406 IgG subclass deficiency) to identify other patients with probable ASHNL. RESULTS: Mean age was 53 ± 10 (SD) y. Six patients (21.4%) had other autoimmunity manifestations. Antibodies to 68 kD protein, 30 kD protein, and type II collagen were detected in 21.4% (6/28), 21.1% (4/19) and 18.8% (3/16), respectively. Three patients (10.7%) had subnormal IgG1, six (21.4%) had subnormal IgG3, and four (14.3%) had subnormal IgG1 and IgG3. Some had subnormal IgG2, IgG4, IgA, and IgM (n = 1, 2, 3, and 1, respectively). Prevalences of subnormal IgG1 or IgG3 were greater in ASNHL patients (25.0% and 35.7%) than 275 controls (2.1% and 3.3%), respectively (p < 0.0001, each comparison). Relative risks of subnormal IgG1 and IgG3 in ASNHL were 11.5 [95% CI: 4.1, 31.7] and 10.9 [4.8, 25.6], respectively. Hearing improved after initial therapy in 17 patients (60.7%). Multiple regressions on Ig levels revealed no significant associations with other available variables. Logistic regressions on initial therapy response revealed a positive association with men (p = 0.0392) and a negative association with IgA (p = 0.0274). Our estimated prevalence of probable ASNHL in 35 patients with common variable immunodeficiency during a follow-up interval of 8 ± 4 y was 0% [95% CI: 0, 12.3]). Prevalence of probable ASNHL in 406 patients with IgG subclass deficiency during the same interval was 0.74% [0.19, 2.33]. CONCLUSIONS: Serum levels of IgG1 or IgG3 were subnormal in 46.4% of 28 patients with ASNHL. Among adults who present with primary Ig deficiency, some may have or later develop ASNHL.

The long elusive IgM Fc receptor, FcµR.

IgM exists as both a monomer on the surface of B cells and a pentamer secreted by plasma cells. Both pre-immune "natural" and antigen-induced "immune" IgM antibodies are important for protective immunity and for immune regulation of autoimmune processes by recognizing pathogens and self-antigens. Effector proteins interacting with the Fc portion of IgM, such as complement and complement receptors, have thus far been proposed but fail to fully account for the IgM-mediated protection and regulation. A major reason for this deficit in our understanding of IgM function seems to be lack of data on a long elusive Fc receptor for IgM (FcµR). We have recently identified a bona fide FcµR in both humans and mice. In this article we briefly review what we have learned so far about FcµR.

IgG subclass levels in referred hemochromatosis probands with HFE p.C282Y/p.C282Y.

BACKGROUND: IgG subclass levels in hemochromatosis are incompletely characterized. METHODS: We characterized IgG subclass levels of referred hemochromatosis probands with HFE p.C282Y/p.C282Y (rs1800562) and human leukocyte antigen (HLA)-A and -B typing/haplotyping and compared them with IgG subclass levels of eight published cohorts of adults unselected for hemochromatosis. RESULTS: There were 157 probands (82 men, 75 women; mean age 49±13 y). Median serum ferritin, mean body mass index (BMI), median IgG4, and median phlebotomy units to achieve iron depletion were significantly higher in men. Diabetes, cirrhosis, and HLA-A*03,-B*44, -A*03,B*07, and -A*01,B*08 prevalences and median absolute lymphocyte counts in men and women did not differ significantly. Mean IgG subclass levels [95% confidence interval] were: IgG1 5.31 g/L [3.04, 9.89]; IgG2 3.56 g/L [1.29, 5.75]; IgG3 0.61 g/L [0.17, 1.40]; and IgG4 0.26 g/L [<0.01, 1.25]. Relative IgG subclasses were 54.5%, 36.6%, 6.3%, and 2.7%, respectively. Median IgG4 was higher in men than women (0.34 g/L [0.01, 1.33] vs. 0.19 g/L [<0.01, 0.75], respectively; p = 0.0006). A correlation matrix with Bonferroni correction revealed the following positive correlations: IgG1 vs. IgG3 (p<0.01); IgG2 vs. IgG3 (p<0.05); and IgG2 vs. IgG4 (p<0.05). There was also a positive correlation of IgG4 vs. male sex (p<0.01). Mean IgG1 was lower and mean IgG2 was higher in probands than seven of eight published adult cohorts unselected for hemochromatosis diagnoses. CONCLUSIONS: Mean IgG subclass levels of hemochromatosis probands were 5.31, 3.56, 0.61, and 0.26 g/L, respectively. Median IgG4 was higher in men than women. There were positive associations of IgG subclass levels. Mean IgG1 may be lower and mean IgG2 may be higher in hemochromatosis probands than adults unselected for hemochromatosis.

Enhanced levels of both the membrane-bound and soluble forms of IgM Fc receptor (FcµR) in patients with chronic lymphocytic leukemia.

The association of an IgM-Fc receptor (FcµR) with chronic lymphocytic leukemia (CLL) was suggested more than 30 years ago, but its authenticity has never been formally addressed. We examined the expression of the recently identified FcµR by B and T cells in CLL patients using receptor-specific monoclonal antibodies. CLL B cells (CD5(+)/CD19(+)) expressed much higher levels of FcµR on their cell surface than B cells from healthy donors. Such enhanced expression was more evident in immunoglobulin heavy chain variable region (IGHV)-mutated, CD38(-) or early Rai-stage CLL than in IGHV-unmutated, CD38(+), or advanced Rai-stage CLL. Intriguingly, surface FcµR levels also were significantly elevated in the non-CLL B cells (CD5(-)/CD19(+)) and T cells (CD5(+)/CD19(-)), especially in IGHV-mutated CLL. CLL patients also had high serum titers of FcµR compared with healthy donors, and serum FcµR levels correlated significantly with circulating lymphocyte numbers but not with the IGHV mutation status or Rai stage. The serum FcµR was resolved as an ∼ 40-kDa protein, distinct from the cell surface FcµR of ∼ 60 kDa, and it was produced by both CLL B and non-CLL B cells. Mass spectrometric analysis revealed that the serum FcµR is a soluble form of the receptor encoded by an alternatively spliced FcµR transcript. These findings indicate enhanced levels of both membrane-bound and soluble forms of FcµR in CLL patients.

Hydroxychloroquine Therapy and Serum Immunoglobulin Levels in Women with IgG Subclass Deficiency and Systemic Lupus Erythematosus, Sjögren Syndrome, and Rheumatoid Arthritis: A Retrospective Study.

Hydroxychloroquine (HCQ) therapy decreased immunoglobulin (Ig) levels in patients with Sjögren syndrome (SS) and rheumatoid arthritis (RA) in previous studies. We found no report of Ig levels of women with IgG subclass deficiency (IgGSD) and systemic lupus erythematosus (SLE), SS, or RA treated with HCQ. We retrospectively evaluated IgG, IgG subclass, IgA, and IgM levels and other characteristics of women at IgGSD diagnosis who did and did not take HCQ for SLE, SS, or RA. There were 132 women (48 subnormal IgG1 only, 49 combined subnormal IgG1/IgG3, and 35 subnormal IgG3 only). Mean age was 49 ± 13 years. Twenty-two women with SLE, SS, RA, or combination thereof reported HCQ ≥ 200 mg/day ≥ 6 months. In each IgGSD subtype, median Ig levels of women who took HCQ were not significantly lower than those of women who did not take HCQ. Women with combined subnormal IgG1/IgG3 who took HCQ had greater median IgG2 than women who did not take HCQ (4.89 g/L (range 4.43, 4.94) vs. 2.57 g/L (1.21, 6.44), respectively; p = 0.0123). Regressions on IgG1, IgG2, and IgG3 revealed positive associations with HCQ therapy (p = 0.0043, 0.0037, and 0.0139, respectively). There were no significant Ig associations with age, SLE, SS, or RA as independent variables. HCQ therapy of SLE, SS, or RA in women with IgGSD was not associated with significantly lower IgG, IgG subclass, IgA, or IgM levels. IgG1, IgG2, and IgG3 were positively associated with HCQ therapy, after adjustment for other variables.

Pica associated with iron deficiency or depletion: clinical and laboratory correlates in 262 non-pregnant adult outpatients.

BACKGROUND: There are many descriptions of the association of pica with iron deficiency in adults, but there are few reports in which observations available at diagnosis of iron deficiency were analyzed using multivariable techniques to identify significant predictors of pica. We sought to identify clinical and laboratory correlates of pica in adults with iron deficiency or depletion using univariable and stepwise forward logistic regression analyses. METHODS: We reviewed charts of 262 non-pregnant adult outpatients (ages ≥18 y) who required treatment with intravenous iron dextran. We tabulated their sex, age, race/ethnicity, body mass index, symptoms and causes of iron deficiency or depletion, serum iron and complete blood count measures, and other conditions at diagnosis before intravenous iron dextran was administered. We excluded patients with serum creatinine >133 µmol/L or disorders that could affect erythrocyte or iron measures. Iron deficiency was defined as both SF <45 pmol/L and TS <10%. Iron depletion was defined as serum ferritin (SF) <112 pmol/L. We performed univariable comparisons and stepwise forward logistic regression analyses to identify significant correlates of pica. RESULTS: There were 230 women (184 white, 46 black; ages 19-91 y) and 32 men (31 white, 1 black; ages 24-81 y). 118 patients (45.0%) reported pica; of these, 87.3% reported ice pica (pagophagia). In univariable analyses, patients with pica had lower mean age, black race/ethnicity, and higher prevalences of cardiopulmonary and epithelial manifestations. The prevalence of iron deficiency, with or without anemia, did not differ significantly between patients with and without pica reports. Mean hemoglobin and mean corpuscular volume (MCV) were lower and mean red blood cell distribution width (RDW) and platelet count were higher in patients with pica. Thrombocytosis occurred only in women and was more prevalent in those with pica (20.4% vs. 8.3%; p = 0.0050). Mean total iron-binding capacity was higher and mean serum ferritin was lower in patients with pica. Nineteen patients developed a second episode of iron deficiency or depletion; concordance of recurrent pica (or absence of pica) was 95%. Predictors of pica in logistic regression analyses were age and MCV (negative associations; p = 0.0250 and 0.0018, respectively) and RDW and platelet count (positive associations; p = 0.0009 and 0.02215, respectively); the odds ratios of these predictors were low. CONCLUSIONS: In non-pregnant adult patients with iron deficiency or depletion, lower age is a significant predictor of pica. Patients with pica have lower MCV, higher RDW, and higher platelet counts than patients without pica.

Characterization of adult patients with IgG subclass deficiency and subnormal IgG2.

BACKGROUND: Adults with IgG subclass deficiency (IgGSD) with subnormal IgG2 are inadequately characterized. METHODS: We retrospectively analyzed observations in unrelated adults with IgGSD evaluated in a single hematology clinic (1991-2019) and selected those with subnormal serum IgG2 (<117 mg/dL (<1.2 g/L)) without corticosteroid therapy to describe: age; prevalence of women; upper/lower respiratory infection; autoimmune condition(s); atopy; other allergy; frequent or severe respiratory tract infection in first-degree relatives; IgG, IgG subclasses, IgA, and IgM; blood lymphocyte subpopulations; human leukocyte antigen (HLA)-A and -B types and haplotypes; and 23-valent pneumococcal polysaccharide vaccination (PPSV23) responses. We determined the prevalence of subnormal IgG2 among unrelated adults with IgGSD without corticosteroid therapy and compared general characteristics of those with and without subnormal IgG2. RESULTS: There were 18 patients (94.4% women) with subnormal IgG2. Mean age was 52 ± 11 y. Upper/lower respiratory infection occurred in 94.4%/74.8%, respectively. Autoimmune condition(s), atopy, other allergy, and frequent or severe respiratory infection in first-degree relatives occurred in 44.4%, 44.4%, 61.1%, and 22.2%, respectively. Median IgG2 was 105 mg/dL (83, 116). Subnormal IgG, IgG1, IgG3, IgG4, IgA, and IgM was observed in 66.7%, 50.0%, 100.0%, 5.6%, 33.3%, and 0%, respectively. Lymphocyte subpopulations were normal in most patients. HLA frequencies were similar in patients and controls. Three of 4 patients had no protective S. pneumoniae serotype-specific IgG levels before or after PPSV23. These 18 patients represent 7.6% of 236 adults with IgGSD. Prevalence of subnormal IgG, subnormal IgG3, and subnormal IgA was significantly greater in 18 adults with subnormal IgG2 than 218 adults without subnormal IgG2. Prevalence of subnormal IgM was significantly lower in patients with subnormal IgG2. CONCLUSIONS: Characteristics of adults with IgGSD with subnormal IgG2 include female predominance, other immunologic abnormalities, subnormal IgG3 and/or IgG1, lack of HLA-A and -B association, and suboptimal PPSV23 response.

HLA-A and -B Type and Haplotype Frequencies in IgG Subclass Deficiency Subgroups.

We sought to determine whether HLA-A and -B type and haplotype frequencies differ between subgroups of adults with IgG subclass deficiency (IgGSD). We retrospectively compared type and haplotype frequencies of three subgroups of 269 unrelated adult IgGSD patients (70 subnormal IgG1; 121 subnormal IgG3; 78 subnormal IgG1/IgG3) and controls (1,321 for types; 751 for haplotypes). We selected types and haplotypes because their uncorrected frequencies differed significantly from controls in a previous adult IgGSD/common variable immunodeficiency cohort: A*24; B*14; B*35; B*40; B*49; B*50; B*58; B*62; A*01,B*08; A*02,B*44; A*02,B*60; A*03,B*07; A*03,B*14; A*03,B*44; A*31,B*40; and A*32,B*14. We used χ2 analysis (2 × 4 tables) to identify frequency differences across three subgroups and controls. If the null hypothesis was rejected (p < 0.05), we computed 2 × 2 χ2 tables to compare six combinations of subgroup and control frequencies [Bonferroni p < 0.0083 (< 0.05/6)]. Mean age was 48 ± 13 years; 82.2% were women. B*35 and B*40 frequencies were higher in subnormal IgG1 than subnormal IgG3 patients (0.1000 vs. 0.0248 and 0.0571 vs. 0.0083, respectively; p ≤ 0.0061). B*62 frequencies were lower in three IgGSD subgroups than controls (p < 0.0001, respectively). A*02, B*44 frequency was higher in subnormal IgG1/IgG3 patients than controls (0.1282 vs. 0.0632, respectively; p = 0.0024). A*02, B*60 frequency was lower in subnormal IgG3 patients than controls (0.0 vs. 0.0233, respectively; p = 0.0051). HLA-B*35 and -B*40 frequencies differ significantly between some IgGSD subgroups. B*62, A*02, B*44, and A*02, B*60 frequencies differ significantly between some IgGSD subgroups and controls.

Bilateral subdural hematomas in an adult with hereditary factor VII deficiency: A complication of sit-ups and inversion?

A 57-year-old man of northern Italian and Polish descent with a late-onset, mild form of hereditary factor VII deficiency developed bilateral intracranial subdural hematomas after performing sit-ups while he was in a head-down position on an inversion table. The pertinence of the Valsalva maneuver and increased intracranial venous and intraocular pressure associated with sit-ups and other exercises in the causation of subdural hematomas and other types of intracranial and ocular hemorrhage are discussed in this study.

Implanted ports in adults with primary immunodeficiency.

BACKGROUND: We sought to learn more about the utility and safety of implanted ports for monthly immunoglobulin G infusions in adults with primary immune deficiency. METHODS: We reviewed charts of adults who were referred to a single practice during the interval 2006-2016 for evaluation and management of frequent or severe upper and lower respiratory tract and other infections, subnormal total immunoglobulin G or immunoglobulin G subclasses, and suboptimal responses to polyvalent pneumococcal polysaccharide vaccinations; were diagnosed to have primary immune deficiency; and were advised to undergo immunoglobulin G therapy. RESULTS: Of 606 patients, 20 (19 women, 1 man; 16 immunoglobulin G subclass deficiency, 4 common variable immunodeficiency; 3.3%) needed implanted ports because they had inadequate upper extremity superficial venous access. Median age at diagnosis was 48 years (range: 32-65 years). In total, 17 of the 20 patients preferred monthly in-office intravenous immunoglobulin G treatment to weekly at-home subcutaneous immunoglobulin G. The other three patients could not be treated with subcutaneous immunoglobulin G (unfavorable self-treatment experiences and insurance limitations). Median duration of treatment via implanted ports was 73 months (range: 10-153 months). In the man, the first implanted port was replaced after 26 months due to catheter fracture of unknown cause. His second port has been used for 112 months. We observed no other port-related failure, infections, thrombosis, or other adverse events. CONCLUSION: The utility and safety of implanted ports in adults with primary immune deficiency for whom subcutaneous immunoglobulin G therapy is not desired or feasible are probably similar to those of ports in patients without primary immune deficiency.

Remission of porphyria cutanea tarda after anastrozole treatment of breast cancer.

Porphyria cutanea tarda (PCT) is sometimes precipitated or aggravated by increased exposure to estrogen, estrogen-like compounds, or tamoxifen. We report the case of a 37-year-old white woman who developed sporadic PCT after she took oral contraceptives for 10 years. She was heterozygous for the common H63D mutation of the hemochromatosis-associated HFE gene. The PCT responded partially to the cessation of oral contraceptives and to phlebotomy therapy to maintain low iron stores, but only remitted after she received anastrozole therapy for management of adenocarcinoma of the breast at age 59 years. The pertinence of HFE mutations, anastrozole and tamoxifen treatment, and chemotherapy to the development and management of PCT in women with breast cancer is discussed.

Intravenous Bevacizumab Therapy in a Patient with Hereditary Hemorrhagic Telangiectasia, ENG E137K, Alcoholic Cirrhosis, and Portal Hypertension.

Intravenous bevacizumab decreased mucosal bleeding in some patients with hereditary hemorrhagic telangiectasia (HHT). We treated a 47-year-old male who had HHT, severe epistaxis, and gastrointestinal bleeding, alcoholic cirrhosis, and portal hypertension with intravenous bevacizumab 2.5 mg/kg every 2 weeks. We tabulated these measures weekly during weeks 1-33 (no bevacizumab); 34-57 (bevacizumab); and 58-97 (no bevacizumab): hemoglobin (Hb) levels; platelet counts; units of transfused packed erythrocytes (PRBC units); and quantities of iron infused as iron dextran to support erythropoiesis. We performed univariate and multivariable analyses. We sequenced his ENG and ACVRL1 genes. Epistaxis and melena decreased markedly during bevacizumab treatment. He reported no adverse effects due to bevacizumab. Mean weekly Hb levels were significantly higher and mean weekly PRBC units and quantities of intravenous iron were significantly lower during bevacizumab treatment. We performed a multiple regression on weekly Hb levels using these independent variables: bevacizumab treatment (dichotomous); weekly platelet counts; weekly PRBC units; and weekly quantities of intravenous iron. There was 1 positive association: (bevacizumab treatment; p = 0.0046) and 1 negative association (PRBC units; p = 0.0004). This patient had the novel ENG mutation E137K (exon 4; c.409G→A). Intravenous bevacizumab treatment 2.5 mg/kg every 2 weeks for 24 weeks was well-tolerated by a patient with HHT due to ENG E137K and was associated with higher weekly Hb levels and fewer weekly PRBC units.