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A 29‐year‐old man after the Fontan operation had a catastrophic intracranial hemorrhage associated with eosinophilic granulomatous polyangiitis. Despite combination therapy with cyclophosphamide and methylprednisolone, he was dead at 6 months after the onset. The clinical course was worse owing to underlying coagulopathy and endothelial dysfunction associated with congenital heart disease. Key Clnical Massage The majority of patients with complex congenital heart disease survive into adulthood. Potential endothelial dysfunction and coagulopathy can attribute to unexpected clinical manifestations of other extracardiac disease among them., The majority of patients with complex congenital heart disease survive into adulthood. Potential endothelial dysfunction and coagulopathy can attribute to unexpected clinical manifestations of other extracardiac disease among them.

Objective To estimate the annual incidence, prevalence, and mortality of antineutrophil cytoplasmic autoantibody (ANCA)–associated vasculitis (AAV) and its subsets, granulomatosis with polyangiitis (Wegener's) (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA), in a US-based adult population. Methods All medical records of patients with a diagnosis of, or suspicion of having, AAV in Olmsted County, Minnesota from January 1, 1996 to December 31, 2015 were reviewed. AAV incidence rates were age- and sex-adjusted to the 2010 US white population. Age- and sex-adjusted prevalence of AAV was calculated on January 1, 2015. Survival rates observed in the study cohort were compared with expected rates in the Minnesota population. Results Of the 58 incident cases of AAV in Olmsted County during the study period, 23 (40%) were cases of GPA, 28 (48%) were cases of MPA, and 7 (12%) were cases of EGPA. Overall, 28 (48%) of the patients with AAV were women and 57 (98%) were white. The mean ± SD age at diagnosis was 61.1 ± 16.5 years. Thirty-four patients (61%) had myeloperoxidase (MPO)–ANCAs, and 17 (30%) were positive for proteinase 3 (PR3)–ANCAs; 5 (9%) were ANCA-negative. The annual incidence of AAV was 3.3 per 100,000 population (95% confidence interval [95% CI] 2.4–4.1). The incidence rates of GPA, MPA, and EGPA were 1.3 (95% CI 0.8–1.8), 1.6 (95% CI 1.0–2.2), and 0.4 (95% CI 0.1–0.6), respectively. The overall prevalence of AAV was 42.1 per 100,000 (95% CI 29.6–54.6). The mortality rate among AAV patients overall, and among patients with EGPA, those with MPA, and those with MPO-ANCAs, was increased in comparison to the Minnesota general population (each P < 0.05), whereas mortality rates among patients with GPA, those with PR3-ANCAs, and ANCA-negative patients did not differ from that in the general population. Conclusion The annual incidence of AAV in Olmsted County, Minnesota over the 20 years of the study was 3.3 per 100,000, with a prevalence of 42.1 per 100,000, which is substantially higher than the rates reported in other areas worldwide. The incidence of GPA was similar to that of MPA. Patients with MPA and those with EGPA, but not patients with GPA, experienced higher rates of mortality than that in the Minnesota general population. MPO-ANCAs were a marker of poor survival in this population of patients with AAV.

Objective In most patients with nonsevere systemic necrotizing vasculitides (SNVs), remission is achieved with glucocorticoids alone, but one-third experience a relapse within 2 years. This study was undertaken to determine whether the addition of azathioprine (AZA) to glucocorticoids could achieve a higher sustained remission rate of newly diagnosed nonsevere eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA), microscopic polyangiitis (MPA), or polyarteritis nodosa (PAN). Methods All patients included in this double-blind trial received glucocorticoids, gradually tapered over 12 months, and were randomized to receive AZA or placebo for 12 months, with stratification according to SNV (EGPA or MPA/PAN). The primary end point was the combined rate of remission induction failures and minor or major relapses at month 24. Results Ninety-five patients (51 with EGPA, 25 with MPA, and 19 with PAN) met the inclusion criteria, were randomized, and received at least 1 dose of AZA (n = 46) or placebo (n = 49). At month 24, 47.8% of the patients receiving AZA versus 49% of the patients receiving placebo had remission induction failures or relapses (P = 0.86). Secondary end points were comparable between the AZA and placebo arms. These included initial remission rate (95.7% versus 87.8%), total relapse rate (44.2% versus 40.5%), and glucocorticoid use. Two patients in the placebo arm died; 22 patients in the AZA arm (47.8%) and 23 patients in the placebo arm (46.9%) experienced ≥1 severe adverse event. For EGPA patients, the primary end point (48% in the AZA arm versus 46.2% in the placebo arm) and the percent of patients who experienced asthma/rhinosinusitis exacerbations (24% in the AZA arm versus 19.2% in the placebo arm) were comparable between treatment arms. Conclusion Addition of AZA to glucocorticoids for the induction of remission of nonsevere SNVs does not improve remission rates, lower relapse risk, spare steroids, or diminish the EGPA asthma/rhinosinusitis exacerbation rate.

To conduct the first and only systematic review of the existing literature on head and neck manifestations of eosinophilic granulomatosis with polyangiitis to guide clinical decision making for the otolaryngologist.PubMed, Cochrane Library, Scopus, and LILACS.A systematic review of the aforementioned sources was conducted per the PRISMA guidelines.From an initial 574 studies, 28 trials and reports were included, accounting for a total of 1175 patients with eosinophilic granulomatosis with polyangiitis. Among clinical and cohort studies, 48.0% to 96.0% of all included patients presented with head and neck manifestations. In a distinct group of patients detailed in case reports describing patients presenting with head and neck manifestations, patients on average fulfilled 4.6 diagnostic criteria per the American College of Rheumatology. Furthermore, 95.8% of reported cases were responsive to steroids, and 60% required additional therapy.Otolaryngologists are in a unique position for the early diagnosis and prevention of late complications of eosinophilic granulomatosis with polyangiitis. The American College of Rheumatology criteria should be relied on in the diagnostic workup. Close surveillance of these patients in a multidisciplinary fashion and with baseline complete blood counts, chest radiographs, and autoimmune laboratory tests is often necessary. Such patients with head and neck manifestations of the disease are nearly always responsive to steroids and often require additional immunosuppressive therapy or surgical intervention in cases of cranial neuropathies, temporal bone involvement, and refractory symptoms.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic vasculitis characterized by asthma and blood eosinophilia, with the lung being the organ most frequently affected. Oral glucocorticoids and/or immunosuppressive drugs are the mainstay therapy of EGPA. Occasional reports suggest that EGPA patients can be treated with omalizumab in addition to conventional therapy to achieve asthma control. In patients with EGPA and moderate to severe allergic asthma, omalizumab can be beneficial and safe. It enables corticosteroid tapering while decreasing eosinophilia and improving asthma symptoms.

A 42-year-old Japanese man developed Churg–Strauss syndrome 7 years after being diagnosed with chronic eosinophilic pneumonia. Prominent eosinophilia, subcutaneous nodules, and neuropathy in the left leg were seen. A pathological diagnosis of necrotizing vasculitis was determined by a biopsy of a subcutaneous nodule. The leg pain was severe and there was prominent atrophy of the thigh and calf, but the muscle weakness was mild. Serum anti-myeloperoxidase anti-neutrophil cytoplasmic antibody was positive. Because the initial treatment with an intravenous methylprednisolone pulse at 1 g/day for 3 days was not sufficient, a onetime treatment with intravenous cyclophosphamide at 15 mg/kg and intravenous immunoglobulin therapy (IVIG) at 400 mg/kg/day for 5 days were administered. Peripheral eosinophilia improved and the leg pain significantly improved. IVIG was repeated 1 month later and symptoms gradually improved further. The early diagnosis of Churg–Strauss syndrome and the early initiation of IVIG with cyclophosphamide were thought to be important.

Aim Many patients with systemic necrotizing vasculitis (SNV) satisfy classification criteria of different disease entities when different classification systems are used. A new classification algorithm has been proposed recently by using the American College of Rheumatology criteria, Chapel Hill Consensus Criteria (CHCC) and Sorensen surrogate markers for a more uniform classification of patients suffering from these rare disorders. Methods We applied this algorithm to patients diagnosed as having systemic vasculitis between 2007 and 2011. We also analyzed the data using this algorithm by incorporating the recently proposed revised CHCC nomenclature of vasculitis in place of the older criteria. Results Seventy-nine patients with SNV were studied. One patient diagnosed as microscopic polyangiitis (MPA) had to be excluded from analysis as she had previously been diagnosed as having Behcet's disease. All patients of eosinophilic granulomatosis with polyangiitis (EGPA), granulomatosis with polyangiitis (GPA) and MPA were reclassified to the same diagnostic subcategory after application of the algorithm. Three (16.7%) of 18 polyarteritis nodosa patients were unclassifiable after application of the consensus algorithm while two (11.1%) were reclassified as MPA. All previously unclassifiable patients could be classified either as MPA or GPA after application of the new algorithm. There was no difference in the results when the CHCC 2012 nomenclature was used instead of the older CHCC in the consensus algorithm. Conclusion The new classification algorithm is a reliable method for classification of SNV for epidemiological purposes in our population.

Background Wells syndrome has been described as an inflammatory disorder based on typical clinical appearance combined with the histopathological presence of eosinophilic infiltrates and flame figures in the absence of vasculitis. Churg–Strauss syndrome, on the other hand, is primarily a diffuse, necrotizing vasculitis but is also typically displaying eosinophils and flame figures. Despite several parallels, the present understanding of these two diseases excludes any pathogenetic relationship. Methods We describe the clinical course and histopathological appearance of three patients who had initially been diagnosed with Wells syndrome that developed into Churg–Strauss syndrome during the course of their disease. Results The clinical presentation of all three patients led to the diagnosis of Wells syndrome by independent specialists. Histopathology showed an eosinophilic infiltrate and flame figures next to features of leukocytoclastic vasculitis. Detailed examination revealed asthma bronchiale and additional symptoms indicating Churg–Strauss syndrome. The initial diagnosis of Wells syndrome had to be revised to Churg–Strauss syndrome. Conclusion We conclude that Wells syndrome could be the starting point of a pathogenetic process that might reach its maximum in Churg–Strauss syndrome. As a clinical consequence, patients with Wells syndrome should be evaluated and followed for Churg–Strauss syndrome.

Eosinophilic granulomatosis with polyangiitis (EGPA), also known as Churg-Strauss syndrome, is an antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis characterized by a history of asthma, hypereosinophilia. The prevalence of ANCA in EGPA is less common than in other ANCA-associated vasculitis. Increasing evidence of complement activation in the pathogenesis of ANCA-associated vasculitis has been provided by studies in animal models. We examined EGPA patients with cutaneous manifestations as an initial sign and investigated the correlations among clinical, serological and histopathological findings. We focused on differences among ANCA, blood urea nitrogen and complement levels such as complement 3 (C3), C4 and total complement hemolytic activity (CH50). We retrospectively investigated the records of 22 patients (11 male and 11 female) with EGPA admitted to our hospital from 1997-2012. Ten of the 22 patients (46%) were positive for serum myeloperoxidase (MPO)-ANCA. In contrast, all the patients were negative for serum proteinase 3 ANCA. There was a significantly positive correlation between serum CH50 and C4 levels in patients with EGPA. Serum blood urea nitrogen (BUN) levels differed significantly between MPO-ANCA-positive and -negative patients. Serum CH50 levels were higher in MPO-ANCA-positive patients compared to negative patients. Serum BUN levels were higher in elevated CH50 patients compared to normal and low CH50-negative patients. We propose that positive findings for MPO-ANCA with CH50 high activity may be a risk factor for developing renal insufficiency. Assuming there are correlations between the presence of ANCA and complements, earlier diagnosis based on initial efficacious treatment for EGPA.

Rationale Churg–Strauss syndrome (CSS) and hypereosinophilic syndrome (HES) overlap considerably in clinical presentation. A reliable means of distinguishing between these groups of patients is needed, especially in the setting of glucocorticoid therapy. Methods A retrospective chart review of 276 adult subjects referred for evaluation of eosinophilia > 1500/μl was performed, and subjects with a documented secondary cause of eosinophilia or a PDGFR -positive myeloproliferative neoplasm were excluded. The remaining subjects were assessed for the presence of American College of Rheumatology (ACR) criteria. Laboratory and clinical parameters were compared between subjects with biopsy-proven vasculitis (CSS; n = 8), ≥4 ACR criteria (probable CSS; n = 21), HES with asthma and/or sinusitis without other CSS-defining criteria (HESwAS; n = 20), HES without asthma or sinusitis (HES; n = 18), and normal controls (n = 8). Serum biomarkers reported to be associated with CSS were measured using standard techniques. Results There were no differences between the subjects with definite or probable CSS or HES with respect to age, gender, or maintenance steroid dose. Serum CCL17, IL-8, and eotaxin levels were significantly increased in eosinophilic subjects as compared to normal controls, but were similar between the eosinophilic groups. Serum CCL17 correlated with eosinophil count (P

Background: Heart is frequently involved in Churg-Strauss syndrome (CSS). However, the mechanics of left ventricular (LV) dysfunction in CSS has not been studied. Objective: To assess the mechanics of LV function and to characterize the contribution of longitudinal, circumferential and rotational deformation to LV dysfunction in CSS. Methods: We enrolled 22 CSS patients (eight males, mean age 43.2 ± 9.5 years) in remission of their disease and 22 sex- and age-matched healthy subjects. All patients underwent conventional and two-dimensional speckle-tracking echocardiography. Global longitudinal, circumferential and rotational deformation parameters were calculated. Results: CSS subjects demonstrated lower LV ejection fraction (EF) than controls (56.6 ± 15.0% vs 63.8 ± 3.4%; P < 0.05). When compared to those with LVEF ≥ 50% (n = 14), CSS patients with LVEF < 50% (n = 7) had decreased global peak-systolic longitudinal and circumferential strain/strain rate (all P < 0.001) and tended to have lower global peak-systolic radial strain (P = 0.05). There were no differences between these two subgroups in global peak-systolic radial strain rate and LV twist/torsion. When comparing individual systolic and diastolic parameters early diastolic longitudinal and circumferential strain rate demonstrated the highest correlation with corresponding global longitudinal and circumferential peak-systolic strain/strain rate (r < −0.80, P < 0.001 for all correlations). Conclusions: In CSS LV systolic dysfunction strongly correlates with longitudinal and circumferential, but not radial or rotational systolic components, indicating that impaired LV systolic function may result predominantly from impaired contraction of inner and middle, but not outer myocardial fiber layers. The spatial correspondence between systolic and diastolic deformation parameters suggests the similar impact of pathologic process on systolic and diastolic function in CSS. (Echocardiography 2012;29:568-578)

Objective Microscopic polyangiitis (MPA) is necrotizing vasculitis of unknown etiology. We analyzed the serum peptide profile of MPA to find a biomarker for this disease. Methods Serum peptides from 33 patients with MPA, 7 with granulomatosis with polyangiitis (Wegener's), 7 with Churg-Strauss syndrome, 6 with giant cell arteritis, and 25 with systemic lupus erythematosus (SLE) were comprehensively analyzed by mass spectrometry. Peptide function on human microvascular endothelial cells (HMVECs) was examined by enzyme-linked immunosorbent assay and real-time polymerase chain reaction. Results A total of 102 serum peptides were detected from the 78 patients. One of the peptides, peptide 1,523, showed significantly higher ion intensity in MPA (mean ± SD 46.8 ± 39.3 arbitrary units [AU]) than in the other systemic vasculitides (14.1 ± 12.2 AU) (P < 0.05) or in SLE (17.0 ± 12.1 AU) (P < 0.05). In MPA, peptide 1,523 showed significantly higher ion intensity before treatment than 1 week (P < 0.05) and 6 weeks (P < 0.05) after the initiation of treatment. Peptide 1,523 was identified as 13 C-terminal amino acid residues of apolipoprotein A-I (Apo A-I) and was designated “AC13.” Validation of AC13 ion intensity using another MPA cohort (n = 14) similarly showed significantly higher ion intensity (90.1 ± 167.9 AU) compared to 14 patients with rheumatoid arthritis (8.6 ± 5.4 AU) (P < 0.01) and 14 healthy subjects (11.8 ± 6.1 AU) (P < 0.01). Serum concentrations of Apo A-I and high-density lipoprotein cholesterol were down-regulated in MPA before treatment and returned to their normal ranges 6 weeks after the initiation of treatment (both P < 0.01). Stimulation of HMVECs with AC13 significantly up-regulated secretion of interleukin-6 (IL-6) (P < 0.05) and IL-8 (P < 0.01). Conclusion AC13, a candidate biomarker for MPA, may be useful for monitoring disease activity and may exacerbate vascular inflammation through up-regulation of proinflammatory cytokines.

The main histopathological features in the cutaneous lesions of Churg-Strauss syndrome (CSS) are dermal leukocytoclastic vasculitis with a variable eosinophilic infiltrate and non-vasculitic tissue eosinophilia with granuloma formation. This wide histopathological spectrum may account for the various skin manifestations of CSS. However, the unique histopathological combination of dermal eosinophilic vasculitis and subcutaneous granulomatous phlebitis accompanied by bulla formation has not been previously described. We report an unusual CSS case showing dermal necrotizing eosinophilic vasculitis and granulomatous phlebitis in purpuric lesions coupled with subepidermal blistering. The blisters showed dermal granulomatous dermatitis and eosinophilia without evidence of vasculitis. Dermal necrotizing eosinophilic vasculitis was characterized by fibrinoid alteration of the vessel wall, a prominent perivascular eosinophilic infiltrate, a few infiltrating histiocytes along the affected vessel wall, and the absence of neutrophilic infiltration. The underlying subcutaneous granulomatous phlebitis was characterized by an angiocentric histiocytic infiltrate surrounded by marked eosinophilic infiltrate. Deposition of cytotoxic proteins and radicals derived from eosinophils in the vessel walls and papillary dermis followed by a secondary granulomatous response may account for the unique clinical and histopathological features in this case.

Objective To compare the criteria for Wegener's granulomatosis (WG) of the American College of Rheumatology (ACR) with those of the European League Against Rheumatism/Pediatric Rheumatology European Society (EULAR/PRES) in a cohort of children with WG and other antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides (AAVs), and to describe the interval to diagnosis, presenting features, and initial treatment for WG. Methods Eligible patients had been diagnosed by site rheumatologists (termed the “MD diagnosis”) since 2004. This diagnosis was used as a reference standard for sensitivity and specificity testing of the 2 WG classification criteria. Descriptive analyses were confined to ACR-classified WG patients. Results MD diagnoses of 117 patients (82 of whom were female) were WG (n = 76), microscopic polyangiitis (n = 17), ANCA-positive pauci-immune glomerulonephritis (n = 5), Churg-Strauss syndrome (n = 2), and unclassified vasculitis (n = 17). The sensitivities of the ACR and EULAR/PRES classification criteria for WG among the spectrum of AAVs were 68.4% and 73.6%, respectively, and the specificities were 68.3% and 73.2%, respectively. Two more children were identified as having WG by the EULAR/PRES criteria than by the ACR criteria. For the 65 ACR-classified WG patients, the median age at diagnosis was 14.2 years (range 4–17 years), and the median interval from symptom onset to diagnosis was 2.7 months (range 0–49 months). The most frequent presenting features by organ system were constitutional (89.2%), pulmonary (80.0%), ear, nose, and throat (80.0%), and renal (75.4%). Fifty-four patients (83.1%) commenced treatment with the combination of corticosteroids and cyclophosphamide, with widely varying regimens; the remainder received methotrexate alone (n = 1), corticosteroids alone (n = 4), or a combination (n = 6). Conclusion The EULAR/PRES criteria minimally improved diagnostic sensitivity and specificity for WG among a narrow spectrum of children with AAVs. Diagnostic delays may result from poor characterization of childhood WG. Initial therapy varied considerably among participating centers.

Churg Strauss syndrome (CSS) is a rare syndrome of vasculitis of the small to medium vessels, characterized by a triad of asthma, eosinophilia and atopic sinusitis. Although asthma is the most common manifestation, it is rarely associated with poor prognosis. Severe gastrointestinal tract manifestations are associated with worse outcomes. Patients with CSS at initial presentation, like our patient, may not meet all four American College of Rheumatology criteria to establish a diagnosis; however, clinicians should have a high index of suspicion to recognize the disease early in its course and treat aggressively, thereby decreasing the mortality and morbidity associated with this disease.

Summary Background Omalizumab (Xolair®) is a recombinant humanized monoclonal anti-IgE antibody with proven efficacy in patients with moderate-to-severe and severe persistent allergic (IgE-mediated) asthma. Objective To review clinical study data to assess the safety profile of omalizumab. Methods We analysed the safety of omalizumab using data from completed clinical studies (up to 1 year) involving more than 7500 patients with asthma, rhinitis or related conditions and up to 4 years in one study of patients with severe allergic asthma, as well as post-marketing safety data. Analysis focuses on the risk of immune-system effects, hypersensitivity reactions, malignant neoplasia, parasitic infections and thrombocytopenia. Results Omalizumab exhibited a good safety and tolerability profile that was maintained up to 4 years in one study. The incidence of anaphylaxis was 0.14% in omalizumab-treated patients and 0.07% in control patients. No omalizumab-treated patient developed measurable anti-omalizumab antibodies. Post-marketing, based on estimated exposure of 57 300 patients (June 2003–December 2006), the frequency of anaphylaxis attributed to omalizumab use was estimated to be at least 0.2% of patients. Current clinical trial data do not support an increased risk of malignant neoplasia or thrombocytopenia with omalizumab. Conclusion Data indicate that the proven efficacy of add-on omalizumab in patients with moderate-to-severe or severe allergic asthma is accompanied by a favourable safety and tolerability profile.

Objective Chronic disease affects both patients and spouses, yet the effect of vasculitis on the spouses of patients has not been systematically examined. We addressed this research gap by describing 8 dimensions of health-related quality of life (HRQOL) for antineutrophil cytoplasmic antibody–associated vasculitis (AAV) patients and their spouses and compared patients and spouses with norms for the general US population. We also determined whether the impact of AAV on HRQOL differs by sex for patients or their spouses. Methods Ninety-seven patients with AAV and their spouses completed a mailed questionnaire that included demographic information and a measure of HRQOL (Medical Outcomes Study Short Form 36.) Using the RAND method, we calculated 8 HRQOL dimensions: general health, physical functioning, emotional role limitations, physical role limitations, social functioning, mental health, bodily pain, and energy/vitality. Using norm-based scores, we compared the HRQOL of patients and spouses with the general US population. We then used multivariate analysis of covariance (MANCOVA) test for sex differences in HRQOL for patients and spouses. Results Patients with AAV scored lower than the US norm on all HRQOL subscales with the exception of bodily pain. In contrast, spouses scored similarly to national norms. When age, education, race, illness duration, and disease severity were controlled, there were no significant sex differences in HRQOL for patients or spouses. Conclusion AAV negatively impacts HRQOL for patients; whereas, spouses do not appear to be as negatively impacted. Long-term marriages may attenuate the effect of sex on HRQOL. Quality of life should be assessed throughout the disease course for both patients and spouses.

Objective Wegener's granulomatosis (WG) and Churg-Strauss syndrome (CSS) belong to the heterogeneous group of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides. Current understanding of their pathogenesis and genetic background is limited. Expression levels of interleukin-10 (IL-10), a potent and pleiotropic cytokine, are largely determined by variations in the gene encoding the IL-10 precursor. This study was undertaken to determine the impact of IL10 polymorphisms on the pathogenesis of both WG and CSS in large cohorts. Methods Three single-nucleotide polymorphisms (SNPs) tagging the promoter haplotypes of the IL10 gene (IL10 −3575, IL10 −1082, and IL10 −592) were analyzed in 403 patients with WG and 103 patients with CSS as well as 507 matched control subjects from Germany. In addition, 3 informative SNPs in other parts of IL10 were genotyped. Results None of the markers or their haplotypes was associated with WG or any of its subgroups classified according to ANCA status, sex, or presence of further WG genetic risk factors. In contrast, the IL10 −3575/−1082/−592 TAC haplotype, part of the extended ancient haplotype IL10.2, was highly significantly associated with ANCA-negative CSS (χ2 = 19.14, P = 0.000012, corrected P = 0.0003, odds ratio 2.16, 95% confidence interval 1.52–3.06). Conclusion These findings challenge those from previous studies of IL10 in WG and provide further evidence that CSS and WG have distinct genetic backgrounds. Because the IL10.2 haplotype has been correlated reproducibly with increased IL10 expression, the possible role of IL-10 in the pathogenesis of ANCA-negative CSS needs to be further elucidated.

Objectives: Churg-Strauss syndrome (CSS) is a systemic vasculitic disorder of unknown etiology that affects small-to-medium-size blood vessels. Patients affected by CSS frequently show ear, nose, and throat manifestations, which are often present at the time of disease onset. The purpose of this study was to determine the frequency of nasal polyposis in a series of 29 patients with CSS and to correlate the nasal findings to the total health situation of these patients. Study Design: Retrospective analysis. Setting: Department of Otolaryngology and Department of Clinical Medicine, Nephrology and Health Science, University of Parma. Methods: Twenty-nine patients with CSS were identified. Of the 29 patients, 17 (58.6%) had nasal polyposis and were enrolled in this study. The nasal polyps were graded according to the Lund and Mackay endoscopic and radiological classifications. Results: At diagnosis, endoscopic intranasal evaluation identified nasal polyposis of grade 3 in nine cases (52.9%), grade 2 in six cases (35.2%), and grade 1 in the remaining case (5.8%). After corticosteroid and immunosuppressive therapy, clinical remission was achieved in 14 patients (82.3%), whereas 3 patients experienced a relapse. Posttreatment endoscopic evaluation showed a permanent disappearance (grade 0) of nasal polyps in eight patients (47%). The other nine patients (52.92%) were found to have a small polyp situated in the middle meatus (grade 1). Conclusions: Nasal polyposis in patients with CSS may represent the initial phase of the syndrome, though patients often have concurrent pulmonary disease. Corticosteroid therapy either alone or combined with immunosuppressive drugs usually yielded improvement or stabilization.

The cytotoxic proteins released by activated eosinophils should play a role in the development of Churg-Strauss syndrome (CSS). Eighteen patients (15 males and 3 females, age 41 +/- 13.3 years) with CSS according to the American College of Rheumatology criteria were included in the study. Thirteen serum samples from 11 patients were obtained at the time of disease flare, and the sera from 6 of them were also obtained at the time of clinical remission. Sera from seven other patients were obtained in clinical remission. Anti-neutrophil cytoplasm antibodies were detected in four (22.2%) patients. Fifteen healthy individuals were used as controls. Mean eosinophil count differed significantly between CSS patients with active disease and patients in clinical remission (3,407/mm(3) vs. 258/mm(3); P < 0.01), between CSS patients with active disease and healthy individuals (3,407/mm(3) vs. 211/mm(3); P < 0.01). Mean serum ECP levels differed significantly between patients with active or inactive disease (219 microg/L vs. 56.8 microg/L; P < 0.0001), between patients with active disease and healthy individuals (219 microg/L vs. 26.2 microg/L; P < 0.0001), but not between patients with inactive disease and healthy individuals (ns). Peripheral blood eosinophils count correlated with serum ECP during CSS flares disease (R = 0.6264; P < 0.05) and during periods of remission (R = 0.4798; P < 0.05). Our results support that ECP might be used as a disease activity marker in CSS.

OBJECTIVE: To explore the association between HLA alleles and Churg-Strauss syndrome (CSS), and to investigate the potential influence of HLA alleles on the clinical spectrum of the disease. METHODS: Low-resolution genotyping of HLA-A, HLA-B, and HLA-DR loci and genotyping of TNFA -238A/G and TNFA -308A/G single-nucleotide polymorphisms were performed in 48 consecutive CSS patients and 350 healthy controls. RESULTS: The frequency of the HLA-DRB1*07 allele was higher in the CSS patients than in controls (27.1% versus 13.3%; chi(2) = 12.64, P = 0.0003, corrected P [P(corr)] = 0.0042, odds ratio [OR] 2.42, 95% confidence interval [95% CI] 1.47-3.99). The HLA-DRB4 gene, present in subjects carrying either HLA-DRB1*04, HLA-DRB1*07, or HLA-DRB1*09 alleles, was also far more frequent in patients than in controls (38.5% versus 20.1%; chi(2) = 16.46, P = 0.000058, P(corr) = 0.000232, OR 2.49, 95% CI 1.58-3.09). Conversely, the frequency of the HLA-DRB3 gene was lower in patients than in controls (35.4% versus 50.4%; chi(2) = 7.62, P = 0.0057, P(corr) = 0.0228, OR 0.54, 95% CI 0.35-0.84). CSS has 2 major clinical subsets, antineutrophil cytoplasmic antibody (ANCA)-positive, with features of small-vessel vasculitis, and ANCA-negative, in which organ damage is mainly mediated by tissue eosinophilic infiltration; analysis of HLA-DRB4 in patients categorized by different numbers of vasculitic manifestations (purpura, alveolar hemorrhage, mononeuritis multiplex, rapidly progressive glomerulonephritis, and constitutional symptoms) showed that its frequency strongly correlated with the number of vasculitis symptoms (P for trend = 0.001). CONCLUSION: These findings indicate that HLA-DRB4 is a genetic risk factor for the development of CSS and increases the likelihood of development of vasculitic manifestations of the disease.

Purpose Case reports suggest that leukotriene modifier use may be associated with the onset of Churg–Strauss syndrome (CSS). Using pooled data from two nested case-control studies, we examined the association between asthma drug use and the development of CSS. Methods The study was performed in three US managed care organizations and a US national health plan with chart access and complete electronic pharmacy data, with a covered population of 13.9 million. There were 47 cases of possible or definite CSS and 4700 asthma drug user controls identified between January 1, 1995 and December 31, 2002. We examined exposure to asthma drugs in cases and controls, including leukotriene modifiers (6 cases and 202 controls), in the two to 6 months prior to the onset of adjudicated CSS. Results While the crude association between use of leukotriene modifiers and CSS was strong (odds ratio (OR) 4.00, 95% confidence interval (CI): 1.49–10.60), in a multivariable analysis controlling for use of oral corticosteroids, inhaled corticosteroids, and number of categories of asthma drugs dispensed, there was no significant association (OR 1.32, 95% CI: 0.44–3.96). Use of inhaled and oral corticosteroids, evaluated as markers of asthma severity, were associated with CSS (OR 3.07, 95% CI: 1.34–7.03 and OR 5.36, 95% CI: 2.51–11.45, respectively). Conclusions No association was found between CSS and leukotriene modifiers after controlling for asthma drug use However, it is not possible to rule out modest associations with asthma treatments given CSS is so rare and so highly correlated with asthma severity, suggesting further investigation is warranted. Copyright © 2006 John Wiley & Sons, Ltd.

Churg-Strauss syndrome (CSS) is one of the rarest forms of vasculitis, and very rarely presents in the pediatric population. We present two cases of childhood CSS, both with hepatic and cardiac involvement. To our knowledge, these are the first two cases of CSS in the pediatric population described in Mexico.

The full expression of Churg-Strauss syndrome (CSS) is characterized by eosinophilia, a necrotizing vasculitis of small to medium blood vessels, and extravascular granuloma formation. The development of CSS typically occurs on a background of asthma, allergic rhinitis, or nasal polyps (1). A number of allergic, infectious, neoplastic, and idiopathic diseases may present with blood as well as tissue eosinophilia, sharing patterns of organ involvement and clinical features that are similar to those of CSS (2). Prompt distinction of CSS from these other entities is essential to the timely institution of appropriate treatment and the prevention of the potentially devastating complications of this disorder: congestive heart failure, severe gastrointestinal ischemia, central nervous system involvement, crippling vasculitic neuropathy (i.e., mononeuritis multiplex), glomerulonephritis, and others (3). In CSS, allergic manifestations and upper respiratory tract symptoms may occur anywhere frommonths to many years before the onset of systemic vasculitis. Empiric glucocorticoid treatment of the atopic features that characterize the disease’s early phase may suppress the emergence of vasculitis, at least temporarily. Conversely, the introduction of more effective inhaled agents for the management of asthma (e.g., the leukotriene inhibitors) is believed to unmask latent CSS in many patients by permitting reductions in the systemic glucocorticoids used to treat reactive airway disease (4). In the absence of pathologic evidence of destructive inflammation within blood vessel walls, distinguishing early CSS from other forms of eosinophilia is challenging. The pathologic diagnosis of CSS has traditionally been linked to the detection of necrotizing vasculitis accompanied by presence of eosinophilic granulomas (1). All of the patients described in 1951 by Churg and Strauss died from their conditions. Consequently, the clinical and pathologic features of the cases described in the original report of the disease were advanced. Moreover, complete postmortem examinations were available on all patients. In the current era, when awareness of CSS is higher, diagnostic testing is more facile, and the availability of effective therapy is widespread, the diagnosis of CSS is more likely to be suspected in the clinic than at postmortem. The authors describe a case of CSS in a patient with long-standing asthma and rhinitis who developed enlarged salivary glands, lymphadenopathy, pulmonary infiltrates, and respiratory distress. Identification of nonvasculitic eosinophilic tissue infiltrates within the salivary glands and skin in the context of the patient’s overall clinical picture led to the diagnosis of CSS at an early stage, the prompt institution of therapy, and a good outcome.

Summary Background In allergic diseases, eosinophils in affected tissues release granule proteins with cytotoxic, immunoregulatory, and remodelling-promoting properties. From recent observations, it may be assumed that eosinophils degranulate already in circulating blood. If degranulation occurs in the circulation, this could contribute to widespread systemic effects and provide an important marker of disease. Objective To determine the degranulation status of circulating eosinophils in common allergic diseases. Methods Using a novel approach of whole blood fixation and leucocyte preparation, the granule morphology of blood eosinophils from healthy subjects, non-symptomatic patients, symptomatic patients with asthma, asthma and Churg–Strauss syndrome, allergic rhinitis, and atopic dermatitis was evaluated by transmission electron microscopy (TEM) and eosinophil peroxidase (TEM) histochemistry. Plasma and serum levels of eosinophil cationic protein were measured by fluoroenzymeimmunoassay. Selected tissue biopsies were examined by TEM. Results Regardless of symptoms, circulating eosinophils from allergic patients showed the same granule morphology as cells from healthy subjects. The majority of eosinophil-specific granules had preserved intact electron-density (96%; range: 89–98%), while the remaining granules typically exhibited marginal coarsening or mild lucency of the matrix structure. Abnormalities of the crystalline granule core were rarely detected. Furthermore, granule matrix alterations were not associated with any re-localization of intracellular EPO or increase in plasma eosinophil cationic protein. By contrast, eosinophils in diseased tissues exhibited cytolysis (granule release through membrane rupture) and piecemeal degranulation (loss of granule matrix and core structures). Conclusion In symptomatic eosinophilic diseases, circulating blood eosinophils retain their granule contents until they have reached their target organ.

Objective To register all newly diagnosed patients with primary systemic vasculitides (PSV) in a large region in northern Germany. Methods Between January 1, 1998 and December 31, 2002 all newly diagnosed cases of PSV were identified in a large mixed rural/urban northern German region consisting of 2,777,275 habitants in a population-based prospective study. The following sources were used: departments of all hospitals, including their outpatient clinics; all departments of pathology; and the reference immunologic labs serving the catchment area. Results During 5 years, 642 PSV patients were identified. The incidence rates for all PSV were between 40 and 54 cases per 1 million and per year. People at age 50 years and older had a 3–5-fold higher risk of developing PSV compared with those younger than 50 years. The incidence rates of antineutrophil cytoplasmic antibody (ANCA)–associated PSV (Wegener's granulomatosis [WG], microscopic polyangiitis [MPA], Churg-Strauss syndrome [CSS]) were between 9.5 and 16/million/year. WG occured 2–3 times more frequently than MPA or CSS. Conclusion Results of a population-based vasculitis register over 5 years for the incidence of PSV among 2.78 million habitants in northern Germany revealed a stable incidence for all PSV. Compared with other European studies coming from small regions or referral centers, the incidence rates for ANCA-associated PSV were the same as in Norway, lower than those in United Kingdom, but higher than those in Spain.

We report an unusual association of multiple perforating and non-perforating pilomatricomas with Churg-Strauss syndrome, and a dysmorphic syndrome evocative of Rubinstein-Taybi syndrome. These syndromes may be independent, but these rare diseases and genetic abnormalities may be linked together.

Objective To estimate the prevalences of polyarteritis nodosa (PAN), microscopic polyangiitis (MPA), Wegener's granulomatosis (WG), and Churg-Strauss syndrome (CSS). Methods Cases were collected in Seine–St. Denis County, a northeastern suburb of Paris, which has 1,093,515 adults (≥15 years), 28% of whom are of non-European ancestry. The study period encompassed the entire calendar year 2000. Cases were identified by general practitioners, the departments of all the public hospitals and 2 large private clinics, and the National Health Insurance System. The Chapel Hill nomenclature was used to define MPA, and American College of Rheumatology criteria to define WG and CSS; PAN was diagnosed based on clinical laboratory, histological and/or angiographic findings. Three-source capture–recapture analysis was performed to correct for incomplete case ascertainment. Results A total of 75 cases were retained and capture–recapture analysis estimated that 23.8 cases had been missed by any 1 of the 3 sources. Accordingly, prevalences per 1,000,000 adults (95% confidence interval [95% CI]) were estimated to be 30.7 (95% CI 21–40) for PAN, 25.1 (95% CI 16–34) for MPA, 23.7 (95% CI 16–31) for WG, and 10.7 (95% CI 5–17) for CSS. The overall prevalence was 2.0 times higher for subjects of European ancestry than for non-Europeans (P = 0.01). Conclusions This study provides the first prevalence estimates for these 4 vasculitides for a multiethnic, urban population. The significantly higher prevalence observed for Europeans may infer a genetic susceptibility of Caucasians. Compared with previous estimates based mostly on rural populations, the higher frequency of PAN and the lower frequency of WG might suggest specific environmental etiologic factors.

Background: Interferon (IFN)-α is a cytokine that possesses potent anti-viral and immunoregulatory activities. We aimed to assess clinical and immunological effects of low-dose IFN-α in patients with severe corticosteroid-resistant asthma with and without Churg–Strauss syndrome. There is currently no efficient pharmacological treatment available for this group of patients. Methods: We studied 10 patients with corticosteroid-resistant asthma, in which 3×106 IU/day IFN-α were administrated in addition to the prednisone dose given already before introduction of the cytokine therapy. The prednisone dose was gradually reduced dependent on the clinical situation and used as a clinical readout to evaluate the efficacy of the cytokine therapy. To distinguish between IFN-α- and prednisone-mediated immunological changes, the corticosteroid dose was kept constant for at least 2 weeks upon introduction of the cytokine therapy in seven patients. The effects of treatment on clinical and immunological parameters were measured at 2–4 weeks and 5–10 months depending on the availability of the patient. Results: Interferon-α treatment rapidly improved the clinical situation as assessed by lung function parameters and required prednisone dose. Important immunological changes included: decreased leukocyte numbers, increased relative numbers of CD4+ T cells, increased differentiation of T helper (Th)1 cells, and increased expression of interleukin (IL)-10 in peripheral blood mononuclear cells. Conclusion: Interferon-α treatment was associated with dramatic improvements in the condition of patients with corticosteroid-resistant asthma with and without Churg–Strauss syndrome. Potential mechanisms of action include the establishment of a correct Th1/Th2 balance and the induction of the anti-inflammatory IL-10 gene.

Objectives/Hypothesis To describe the clinical features, pathogenesis, and management of the otological complications in Churg-Strauss syndrome (CSS). Study Design Retrospective review of five patients with documented CSS who had otological manifestations in the later stages of CSS. Methods The history, treatment, and outcome were evaluated using office and hospital chart data in these five cases. Results In all cases, otological manifestations occurred during an advanced stage of CSS and was characterized by the presence of dense aural discharge, granulomatous eosinophilic infiltration into mastoid and middle ear, and subacute severe to profound hearing loss. In all cases, the recurrent aural discharge and granulomatous infiltrate was unresponsive to conventional treatment including repeated myringotomies and aggressive antibiotics. Systemic steroid administration resulted in a rapid, complete cessation of aural discharge and reversal or stabilization of hearing loss. Otological manifestations have been stable over a range of follow-up from 1 to 20 years on a maintenance regimen of steroids. Conclusions Temporal bone involvement in CSS is rare. Surgical intervention of the temporal bone is relegated to complications that may include infectious mastoiditis and intracranial involvement. Recognition of the association between CSS and otological disease is important because it is highly responsive to systemic steroids, and early steroid treatment may prevent progression to irreversible hearing loss, infectious otomastoiditis, or intracranial complications.

A 69-year-old Japanese man suffered from bronchial asthma, atrial fibrillation, general fatigue, high fever, and weight loss of about 5 kg within a month. He also had intermittent claudication, a tingling feeling in his fingers and toes, and an ulcer on his toe. His laboratory data revealed leukocytosis with absolute eosinophilia. The patient was treated with predonisolone 30 mg daily. Although the ulcers healed once, the lesions recurred with tapering predonisolone. The patient visited us because of the ulcer on his toe. Physical examination showed a 2 cm ulcer surrounded by slight erythema on his right fourth toe. Magnetic resonance angiography detected tapering stenosis of the medium-sized arteries in both legs. A biopsy from his myocardium showed the infiltration of eosinophils into the myocardium. The neuron conduction rate of his lower leg was slower than that of the normal control, demonstrating mononeuritis. From these findings, we diagnosed this patient as Churg-Strauss syndrome.

The mRNA levels of nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF), and interleukin-6 (IL-6) were examined in sural nerves of 22 patients with acute necrotizing vasculitic neuropathies. NGF, GDNF, and IL-6 mRNAs were upregulated and CNTF mRNA was downregulated in the lesioned nerves, but their up- and down-regulation levels were not correlated with each other, showing that these mRNAs were independently expressed. The expression of NGF and CNTF mRNAs was clearly correlated with the degree of infiltrated macrophages and T cells, and myelinated fiber density, respectively. These findings indicate that these neurotrophic factors are differentially expressed temporally and spatially in the vasculitic nerve lesion by an underlying pathology-related process.

Objective To examine the operating characteristics of the American College of Rheumatology (ACR) classification criteria for Churg-Strauss syndrome (CSS) and Wegener's granulomatosis (WG), and to develop and validate improved criteria for distinguishing CSS from WG. Methods The ACR classification criteria for WG and CSS were applied to 40 consecutive CSS patients age- and sex-matched with 40 patients with WG. Forty-three clinical, laboratory, and biopsy parameters were assessed. Artificial neural networks (ANNs) were trained and tested with all 43 parameters (set A) and with 15 solely clinical parameters documented at the initial manifestation of the disease (set B). The ANNs were trained with data from the first 27 CSS and 27 WG patients and validated with data from the next 13 consecutive CSS and 13 WG patients. To compare the ANNs with established methods, traditional format and classification tree criteria were generated using the same data sets. Results Fourteen of 40 CSS patients fulfilled the ACR criteria for WG, while 4 WG patients met the ACR criteria for CSS. The ANN, in contrast, reliably distinguished all CSS cases from WG cases (parameter set A, accuracy 100%). For parameter set B, the ANN achieved an accuracy of 100% in the training phase and 96% for validation. The newly formulated traditional format and classification tree criteria reached an accuracy of 81% and 88%, respectively. Conclusion The ACR criteria for WG do not reliably differentiate between CSS and WG (specificity 65%). An ANN, however, could be trained to correctly allocate all but 1 patient on the basis of clinical data. Indeed, the ANN applied in this study proved superior to established methods of classification. We suggest that an ANN may be effectively applied in the classification of systemic vasculitides.