Avni Y. Joshi

Incidence and Temporal Trends of Primary Immunodeficiency: A Population-Based Cohort Study

OBJECTIVE: To determine the incidence and temporal trends of primary immunodeficiency diseases (PIDs) and examine whether an association exists between delayed diagnosis and increased morbidity. PATIENTS AND METHODS: We performed a historical cohort study to describe the epidemiology of PIDs in Olmsted County, Minnesota, during a 31-year period from January 1, 1976, through December 31, 2006, using the Rochester Epidemiology Project. Incidence and trends over time, presence of comorbid conditions, and trends in management were determined. RESULTS: During the 31-year study period, 158 new cases of PIDs were diagnosed, with an overall incidence rate of 4.6 per 100,000 person-years. The rate of PIDs from 2001 through 2006 (10.3 per 100,000 person-years) was nearly 5 times higher than that from 1976 through 1980 (2.4 per 100,000 person-years). The associations between continuous variable(s) and categorical outcome(s) were assessed by using the Wilcoxon rank sum test. Longer delay in diagnosis was significantly associated with recurrent sinusitis (P<.001), recurrent pneumonia (P=.03), and subsequent treatment with immunoglobulins (P<.001). On the basis of Kaplan-Meier survival estimates, the proportion of patients surviving at 10 years after diagnosis was 93.5% (95% confidence interval, 85.9%-97.1%). However, older age at diagnosis was significantly associated with mortality (P=.01). CONCLUSION: This is one of the first population-based studies to examine the temporal trends of PIDs. The incidence of PIDs increased markedly between 1976 and 2006. In this cohort, a delay in diagnosis was common and was associated with increased morbidity. Despite substantial morbidity, most patients with PIDs can expect a normal life span.

Spontaneous Pneumomediastinum: Analysis of 62 Consecutive Adult Patients

OBJECTIVE To clarify the clinical presentation and course of patients with spontaneous pneumomediastinum (SP) and to determine the usefulness of diagnostic testing in these patients. PATIENTS AND METHODS We conducted a retrospective review of 62 consecutive adult patients (age ≥18 years) diagnosed as having SP during an 11-year period from July 1, 1997, to June 30, 2008. The study cohort included 41 men and 21 women (median age, 30 years; interquartile range, 20-69 years). RESULTS Among the 62 study patients, the most common presenting symptoms were chest pain (39 patients [63%]), cough (28 [45%]), and dyspnea (27 [44%]). Preexisting lung diseases were identified in 27 patients (44%) and included interstitial lung disease, asthma, lung malignancies, bronchiolitis obliterans syndrome, chronic obstructive pulmonary disease, bronchiectasis, and cystic lung lesions. The initial diagnosis of SP was achieved by chest radiography in 52 patients (84%); the remaining cases were diagnosed by computed tomography. Forty-seven patients (76%) were hospitalized for a median duration of 2.5 days. Additional diagnostic procedures were performed in 27 patients (44%) and included contrast esophagography, bronchoscopy, and esophagogastroduodenoscopy; however, they did not yield a pathologic cause in any patient. Pneumothorax was identified in 20 patients (32%), but less than one-third of these patients underwent chest tube thoracostomy. No episodes of mediastinitis or sepsis occurred. Recurrence of SP was seen in 1 patient, and thoracoscopic surgery was performed in 1 patient for persistent air leak (pneumothorax). CONCLUSION Spontaneous pneumomediastinum was associated with a relatively benign clinical course; however, pneumothorax was seen in 32% of cases. Diagnostic testing to determine a pathologic cause yielded little clinically relevant information in these patients.

Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency

Patients with mutations of the recombination-activating genes (RAG) present with diverse clinical phenotypes, including severe combined immune deficiency (SCID), autoimmunity, and inflammation. However, the incidence and extent of immune dysregulation in RAG-dependent immunodeficiency have not been studied in detail. Here, we have demonstrated that patients with hypomorphic RAG mutations, especially those with delayed-onset combined immune deficiency and granulomatous/autoimmune manifestations (CID-G/AI), produce a broad spectrum of autoantibodies. Neutralizing anti-IFN-α or anti-IFN-ω antibodies were present at detectable levels in patients with CID-G/AI who had a history of severe viral infections. As this autoantibody profile is not observed in a wide range of other primary immunodeficiencies, we hypothesized that recurrent or chronic viral infections may precipitate or aggravate immune dysregulation in RAG-deficient hosts. We repeatedly challenged Rag1S723C/S723C mice, which serve as a model of leaky SCID, with agonists of the virus-recognizing receptors TLR3/MDA5, TLR7/-8, and TLR9 and found that this treatment elicits autoantibody production. Altogether, our data demonstrate that immune dysregulation is an integral aspect of RAG-associated immunodeficiency and indicate that environmental triggers may modulate the phenotypic expression of autoimmune manifestations.

Increased Adverse Drug Reactions to Cephalosporins in Penicillin Allergy Patients with Positive Penicillin Skin Test

Background: Cephalosporin administration in patients with a history of penicillin allergy is controversial. Studies looking at the safety of cephalosporin in patients with a history of penicillin allergy lacked a control group, had a small number of patients, and/or lacked confirmation of penicillin allergy by penicillin skin testing. The purpose of this study was to determine whether patients with penicillin allergy were at increased risk of adverse drug reactions when administered cephalosporin. Methods: A cohort study of patients with a history of penicillin allergy and a positive or negative penicillin skin test when administered cephalosporin was conducted. Charts were reviewed for adverse drug reactions to cephalosporin after penicillin skin testing. Results: Eighty-five patients with a history of penicillin allergy and positive penicillin skin test and 726 patients with a history of penicillin allergy and negative penicillin skin test were administered cephalosporin. Five (6%) of 85 cases had an adverse drug reaction to cephalosporin as compared to 5 (0.7%) of 726 of the referent population (p = 0.0019). The rate of presumed IgE-mediated adverse drug reactions to the cephalosporins amongst the cases was 2 (2%) of 85 compared to 1 (0.1%) of 726 amongst the referent population (p = 0.0304). Conclusion: A greater risk of an adverse drug reaction to cephalosporin exists in patients with penicillin allergy. We recommend penicillin skin testing if cephalosporin, especially a first-generation cephalosporin, is to be administered to patients with a history of penicillin allergy.

Effectiveness of inactivated influenza vaccine in children less than 5 years of age over multiple influenza seasons: A case―control study

The effectiveness of influenza vaccine over multiple influenza seasons in children less than 5 years of age has not been well studied. This is especially important to assess because of the recent recommendation for routine influenza vaccination in childhood. We conducted a matched case-control study to assess the vaccine effectiveness of Trivalent Inactivated Influenza Vaccine (TIV) against laboratory-confirmed, medically attended influenza among children 6-59 months of age at the start of each influenza season from 1999-2000 through 2006-2007 in Olmsted County, MN, USA. The children vaccinated against influenza accordingly to the 2007 ACIP guidelines had a lower risk of laboratory-confirmed medically attended influenza illness (Odds Ratio: 0.14, 95% Confidence Interval: 0.03-0.71) than the unvaccinated children. TIV provided strong protection against laboratory-confirmed medically attended influenza in children 6-59 months old in the fully vaccinated group. This trend continued in the partially vaccinated group (Odds Ratio: 0.27, 95% Confidence Interval: 0.07-0.97) but the protection provided maybe suboptimal.

Immune evaluation and vaccine responses in Down syndrome: Evidence of immunodeficiency?

BACKGROUND Patients with Down syndrome (DS) appear to be at a greater risk for serious infections, but it is unclear whether this is due to anatomic variations or intrinsic immune defects. OBJECTIVE We assessed a cohort of pediatric subjects with DS to determine if immunological abnormalities indeed account for the excess infections. METHODS We performed quantitative assessment of T-independent (type 2 - pneumococcal polysaccharide vaccine) and T-dependent Ab responses (with inactivated seasonal influenza vaccine) along with numerical quantitation of lymphocyte subpopulations and thymic output in a random population sample of children with DS (cases) along with family-matched sibling or community controls. RESULTS Median serum IgG levels were significantly higher in cases (1090 mg/dL) as compared with controls (808 mg/dL, P=0.02). Cases had significantly lower median CD4 T cell counts than the controls (636 cells/μL, P=0.01). Cases had reduced CD19 B cell counts and CD19% than the controls (P=0.009 and 0.006 respectively). Cases also showed decreased total memory (CD19+CD27+, P=0.002) and class-switched memory (CD19+CD27+IgM-IgD-, P=0.004) B cells. The median CD4 recent thymic emigrant (RTE) in females and males cases was lower than controls (P=0.007 and 0.07 respectively). Cases had a lower median T cell receptor excision circle (TREC) count of 2556 as compared to the controls count of 5216, P<0.006 although both the cases and controls were within the established reference range. There were no differences in the percentage of cases and controls who responded to inactivated influenza vaccine, but the response to polysaccharide pneumococcal vaccine was suboptimal in cases. CONCLUSIONS Our study suggests that there are subtle abnormalities in both humoral and cellular arms of the immune response in children with DS as compared to the control subjects.

Rubella persistence in epidermal keratinocytes and granuloma M2 macrophages in patients with primary immunodeficiencies

To the Editor: Cutaneous granulomas are a well-recognized pathologic feature in patients with various primary immunodeficiency diseases (PIDs) and may be self-limited or can progress to a persisting granulomatous disorder. Rubella virus (RV) vaccine strain RA27/3 has been recently detected in disseminated cutaneous granulomas of 2 patients with ataxia telangiectasia (AT) and a patient with Simpson-Golabi-Behmel syndrome (who had combined immunodeficiency [CID]). However, a more detailed study of a larger series of granuloma cases in patients with different PIDs was required to confirm and extend this observation. Patients with cutaneous granulomas and with diverse PIDs were selected from the United States Immune Deficiency Network registry. Additional cases (cases 1 and 11) were recruited from the Clinical Immunology Society immune deficiency Listserv. Presence of RV in granuloma-containing tissue samples (Fig 1, A-C) was examined by immunofluorescence staining with 2 different RV capsid-specific antibodies (see this article’s Methods section in the Online Repository at www.jacionline.org) by a reader blinded to the diagnosis. Seven out of 14 patients (50%) exhibited positive RV antigen staining (Table I), whereas the tissue samples of 5 non-PID granuloma patients were negative. Staining intensity varied substantially between patients and did not correlate with the severity of granulomatous disease. RV immunostaining was typically observed in both epidermis and granulomas in dermis (Fig 1, D-F); however, staining only in granulomas (case 3) was seen (Table I). Multiple granulomas within a sample contained RV antigen with typically a few positive cells in the middle except cases 2 and 6, in which virtually all cells in the granulomas were positive. RV was found exclusively in patients with CIDs: CID cause unknown (n 5 2), AT (n5 4), and cartilage hair hypoplasia (n5 1). The immune deficiencies in which granulomas were not found to be positive for rubella were common variable immune deficiency (n 5 2), AT (n 5 2), X-linked agammaglobulinemia (n 5 1), MardenWalker syndrome (n 5 1), and nuclear factor kappa B essential modulator (n 5 1). None of the nonimmune deficient samples was positive. RV-positive cells in granulomas were positive for CD14 and CD68, markers of monocyte/macrophage cell lineage, and CD206 and CD163, activation markers for M2 macrophages, but negative for iNOS, an M1 macrophage marker (see this article’s Methods section; see Table E1 in this article’s Online Repository at www.jacionline.org; Fig 1, G-H). Endothelial cells (vWF), T cells (CD3), B cells (CD20), dermal Langerhans (CD1a), and dendritic (CD11c) cells were negative for RV antigen (see this article’s Results section in the Online Repository at www.jacionline.org; Table E1). These results demonstrate that M2 macrophages were the cell type harboring RV antigen in granulomas. There was a high production of cytokeratin in many RV-positive keratinocytes, suggesting that RV replication in keratinocytes can lead to dysregulation of keratin synthesis (Fig 1, I). Overexpression of keratin is known to alter the architecture of the epidermis and impact healing of ulcers. The RV-immunostaining patterns were unchanged in the 3 skin samples obtained within a 7-year period (case 1), indicating longterm persistence of RVantigen. Antigen persistence is a hallmark of granulomas. Biopsy specimens collected from different body sites contained both RV-positive and RV-negative specimens (case 3), indicating focal distribution of RVantigen-positive cells in patient tissues. In addition to the skin samples from case 6, a bone periosteum tissue (collected 5 years later) contained RVpositive M2 macrophages in the granulomas. PCR fragments covering the entire genome were amplified and sequenced from 1 patient. Phylogenetic analysis revealed that rubella virus of genotype 1a was present in the patient skin (RVs/ Oulu.FIN/22.15/PID; see Fig E1 in this article’s Online Repository at www.jacionline.org). The sequence was similar (97.4% identity) to that of the RA27/3 vaccine virus. In RVs/Oulu.FIN/ 22.15/PID, 2 out of 7 RA27/3-specific amino acid residues had reverted to the wild type (see this article’s Results section; see Table E2 in this article’s Online Repository at www.jacionline.org). There were 69 amino acid substitutions in RVs/Oulu.FIN/22.15/ PID compared with RA27/3; 52 of them were not found in wild-type RV genomes (see Table E3 in this article’s Online Repository at www.jacionline.org). Most neutralizing epitopes, which are located in the E1 protein, were conserved including the immunodominant epitope E1214-233, whereas each of 3 known CD8 T-cell epitopes (largely predicted to be A2 binding), all located in the capsid, contained single mutations (see this article’s Results section; see Table E4 in this article’s Online Repository at www.jacionline.org), suggesting a role for CD8 T-cell–selective pressure in viral evolution during chronic RA27/3 infection. Similar to the previous report, ATwas the most common single diagnosis among RV-positive patients. We have also identified additional PIDs (cartilage hair hypoplasia and CID) in which RV was found in granulomas. Thus, current data have clearly shown an association between defects in T-cell immunity, granulomas, and RV. One of the important findings of this study is the identification of RV-positive cells in granulomas as M2 macrophages. ProinflammatoryM1macrophages play an essential role in eliminating pathogens, whereas anti-inflammatory M2 macrophages are crucial for maintaining tissue homeostasis. RV can infect most cell types and can persistently infect a macrophage-like cell line, but it is currently unknown whether this occurs in vivo. Another novel finding is persisting RVantigen in epidermal keratinocytes, in all epidermal layers except the basal layer. In contrast, in acute postnatal rubella cases, rubella antigen was found only in the deep dermis (cell types not defined) in skin biopsies from rubella rashes, whereas the epidermis was negative. Wild-type RV can establish persistent infections and cause disease in immunologically normal individuals if infection occurs in immune-privileged sites, for example, Fuchs’ uveitis or fetal development. A role for vaccine virus in Fuchs’ uveitis is also suspected. Granulomas have been reported only once in CRS. We hypothesize that the immune deficiency allows persistence of the attenuated virus, polarization of macrophages to M2 occurs,

Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis.

Trichoderma longibrachiatum is an emerging pathogen in immunocompromised patients. We report a case of Trichoderma post-operative mediastinitis and peritonitis in a child with complex congenital cardiac disease and functional asplenia. The patient was treated unsuccessfully, initially with caspofungin alone followed by a combination of voriconazole (systemic and topical), caspofungin and intraperitoneal amphotericin B.

Elevated serum immunoglobulin E (IgE) : When to suspect hyper-IgE syndrome-A 10-year pediatric tertiary care center experience

Elevated serum immunoglobulin E(IgE) can be caused by allergies, infections and immune conditions including hyper IgE syndrome (HIES). HIES is a rare primary immunodeficiency disease most commonly characterized by a triad of findings, including increased serum IgE levels, recurrent skin abscesses, and pneumonias leading to pneumatocele formation. The objective of this study was to characterize the clinical profile of patients presenting with increased IgE levels (>or=2000 IU/mL) focusing specifically on HIES. A database search identified 70 patients in the pediatric age range (<or=18 yrs.) between January 1997 and December 2006 who had an IgE level of >or=2000 IU/mL. Charts were abstracted for clinical diagnosis, comorbidities, and laboratory parameters. Data were analyzed using the students t-test, Wilcoxon signed rank test, and univariate/multivariate regression models. Clinical diagnosis in 70 patients with elevated IgE levels were: atopic diseases (n = 54; 77%), parasitic diseases (n = 1; 1.5%), malignancy (n = 2; 3%), and HIES (n = 6; 8%), among other causes. There was a statistically significant association between IgE levels and the severity of eczema (p = 0.009). Ninety percent of the subjects with IgE level >or=2000 IU/mL did not have HIES. There was no correlation between IgE levels and the diagnosis of HIES (p = 0.5). A variety of clinical situations result in an elevated IgE level, with atopy being the most common cause. In the absence of typical clinical features, elevated serum IgE levels are not predictive of HIES.

Electronic cigarettes: navigating the vapor

Electronic cigarettes (e-Cigarettes) are novel nicotine delivery systems that have the potential to drastically change the landscape of nicotine addiction and tobacco use. Their increasing popularity has raised concerns that e-Cigarettes might undercut the gains associated with tobacco cessation efforts and limits on public use and advertising.1,2 Particularly worrisome is the increasing use of e-Cigarettes in youth. The goal of this piece is to (1) introduce the reader to e-Cigarettes, (2) describe safety concerns and the limited evidence supporting potential benefits, and (3) discuss pertinent regulatory issues. The authors conclude by suggesting proactive responses that medical professionals can take regarding this developing issue.