Establishment of diagnostic criteria for feline nonflea-induced hypersensitivity dermatitis

Hypersensitivity dermatitides (HD) are commonly seen in cats, and they are usually caused by environmental, food and/or flea allergens. Affected cats normally present with one of the following clinical reaction patterns: head and neck excoriations, usually symmetrical self-induced alopecia, eosinophilic skin lesions or miliary dermatitis. Importantly, none of these clinical presentations is considered to be pathognomonic for HD skin diseases, and the diagnosis of HD is usually based on the exclusion of other pruritic diseases and on a positive response to therapy. The objectives of this study were to propose sets of criteria for the diagnosis of nonflea-induced HD (NFHD). We recruited 501 cats with pruritus and skin lesions and compared clinical parameters between cats with NFHD (encompassing those with nonflea, nonfood HD and those with food HD), flea HD and other pruritic conditions. Using simulated annealing techniques, we established two sets of proposed criteria for the following two different clinical situations: (i) the diagnosis of NFHD in a population of pruritic cats; and (ii) the diagnosis of NFHD after exclusion of cats with flea HD. These criteria sets were associated with good sensitivity and specificity and may be useful for homogeneity of enrolment in clinical trials and to evaluate the probability of diagnosis of NFHD in clinical practice. Finally, these criteria were not useful to differentiate cats with NFHD from those with food HD.

Clinical characteristics and causes of pruritus in cats: a multicentre study on feline hypersensitivity-associated dermatoses

Hypersensitivity dermatitides (HD) are often suspected in cats. Cats with HD are reported to present with one or more of the following patterns: miliary dermatitis, eosinophilic dermatitis, self-induced symmetrical alopecia or head and/or neck excoriations. Previous reports on feline HD included small numbers of animals, took place in geographically restricted areas or did not compare these conditions with other causes of pruritus. The goal of the present study was to analyse 72 parameters covering signalment, clinical, laboratory and treatment characteristics from a large group of pruritic cats from different geographical areas. Of the 502 cats, the following diagnoses were made: flea HD (29% of cases), food HD (12%) nonflea/nonfood HD (20%) and other diseases in which pruritus was a feature (24%). Cats with signs consistent with a HD but which did not complete a food trial were not analysed further (15% of cases). Most cats with nonflea HD exhibited signs compatible with one or more of the four typical lesional patterns, but none of these patterns was found to be pathognomonic for any specific diagnosis. Food HD and nonflea/nonfood HD were found to be clinically undistinguishable. Young adult, purebred and female cats appeared predisposed to nonflea/nonfood HD. As many diagnoses presented with similar lesional patterns, a thorough clinical work-up is required for establishment of a specific diagnosis.

Comparison of genotypes and antibiotic resistance of Campylobacter jejuni isolated from humans and slaughtered chickens in Switzerland

AIMS: To get an overview of genotypes and antibiotic resistances in Swiss Campylobacter jejuni implicated in human gastroenteritis and to examine the association with isolates from chickens. METHODS AND RESULTS: Multilocus sequence typing (MLST) and flaB typing were applied to 136 human clinical isolates. Phenotypic resistance to 12 antimicrobials and genotypic resistance to macrolides and quinolones were determined. MLST resulted in 35 known and six new sequence types (ST). The flaB analysis revealed 35 different types, which - in combination with MLST - increased the resolution of the typing approach. Resistance to quinolones, tetracycline and ampicillin was found in 37.5, 33.1 and 8.1% of the isolates, respectively, whereas macrolide resistance was found only once. Genotypic and phenotypic resistance correlated in all cases. A comparison to Camp. jejuni isolated from slaughtered chickens was performed. While 86% of the quinolone-sensitive human isolates showed overlapping MLST-flaB types with those of chicken origin, resistant strains showed only 39% of matching types. CONCLUSION: Mainly quinolone-sensitive Camp. jejuni strains implicated in human campylobacteriosis showed matching genotypes with isolates originating from chickens. SIGNIFICANCE AND IMPACT OF THE STUDY: A large proportion of human cases in Switzerland are likely to originate from domestic chickens, confirming that prevention measures in the poultry production are important.

Eosinophils in the gastrointestinal tract: friends or foes?

Eosinophils play an important role in the mucosal immune system of the gastrointestinal tract under resting and under inflammatory conditions. Under steady-state conditions, the mucosa of the digestive tract is the only organ harboring a substantial number of eosinophils, which, if need be, get activated and exert several effector and immunoregulatory functions. The precise function of these late-phase inflammatory cells is not yet completely understood. Nevertheless, it has recently been demonstrated that lipopolysaccharides from gram-negative bacteria activate eosinophils to rapidly release mitochondrial DNA in the extracellular space. Released mitochondrial DNA and eosinophil granule proteins form extracellular structures able to bind and inactivate bacteria. These findings suggest a novel mechanism of eosinophil-mediated innate immune responses that might be important in maintaining the intestinal barrier function. Moreover, eosinophils also play a crucial role in several inflammatory conditions, such as intestinal infections, immune-mediated inflammations and hypersensitivity reactions. Under chronic inflammatory conditions, the ability of the eosinophils to induce repair can lead to pathological sequelae in the tissue, such as esophageal remodeling in eosinophilic esophagitis. It is established that the uncontrolled eosinophilic inflammation induces fibrosis, esophageal wall thickening and strictures leading to damage that results in a loss of esophageal function. One potential mechanism of this remodeling is so-called 'epithelial mesenchymal transition', which is triggered by eosinophils and is potentially reversible under successful anti-eosinophil treatment. Therefore, eosinophils may act either as friends or as foes, depending on the microenvironment.

Eosinophil extracellular DNA traps: molecular mechanisms and potential roles in disease

Eosinophil extracellular traps (EETs) are part of the innate immune response and are seen in multiple infectious, allergic, and autoimmune eosinophilic diseases. EETs are composed of a meshwork of DNA fibers and eosinophil granule proteins, such as major basic protein (MBP) and eosinophil cationic protein (ECP). Interestingly, the DNA within the EETs appears to have its origin in the mitochondria of eosinophils, which had released most their mitochondrial DNA, but were still viable, exhibiting no evidence of a reduced life span. Multiple eosinophil activation mechanisms are represented, whereby toll-like, cytokine, chemokine, and adhesion receptors can all initiate transmembrane signal transduction processes leading to the formation of EETs. One of the key signaling events required for DNA release is the activation of the NADPH oxidase. Here, we review recent progress made in the understanding the molecular mechanisms involved in DNA and granule protein release, discuss the presence of EETs in disease, speculate on their potential role(s) in pathogenesis, and compare available data on other DNA-releasing cells, particularly neutrophils.

Thymic stromal lymphopoietin stimulates the formation of eosinophil extracellular traps

Thymic stromal lymphopoietin (TSLP) that is released by epithelial cells upon certain environmental triggers activates cells of the innate and adaptive immune system resulting in a preferential T helper 2 immune response. By releasing eosinophil extracellular traps (EETs), eosinophils achieve an efficient extracellular bacterial killing. Eosinophil extracellular traps release, however, has been observed in both infectious and noninfectious eosinophilic diseases. Here, we aim to investigate whether eosinophils generate functional EETs as a direct response to TSLP, and further to study the extra- and intracellular mechanisms involved in this process as well as TSLP receptor (TSLPR) expression by eosinophils in vitro and in vivo.

cIAP-2 and survivin contribute to cytokine-mediated delayed eosinophil apoptosis

The exact molecular mechanisms leading to delayed apoptosis, a phenomenon frequently observed in eosinophil inflammatory responses, remain largely unknown. Here, we show that cultured eosinophils purified from blood of hypereosinophilic syndrome (HES) patients exhibit delayed spontaneous death and relative resistance towards ceramide- but not CD95-mediated death. The subsequent investigation of members of the inhibitor of apoptosis (IAP) family revealed that HES but not normal eosinophils expressed high levels of cellular IAP-2 (cIAP-2) and survivin. The eosinophil hematopoietins IL-3, IL-5, and GM-CSF increased the expression of cIAP-2 and survivin in normal eosinophils in vitro. In the blood of HES patients, we observed increased concentrations of IL-3 and/or IL-5, suggesting that these cytokines are, at least partially, responsible for the elevated levels of cIAP-2 and survivin in the eosinophils of these patients. Utilizing a cell-free system in which caspase-3 was activated in eosinophil cytosolic extracts by addition of cytochrome c and immunodepletion of cIAP-2 or survivin resulted in accelerated caspase activation. These data suggest that some members of the IAP family including survivin are regulated by survival cytokines and inhibit the caspase cascade in HES eosinophils. The cytokine-dependent mechanism of delayed eosinophil apoptosis described here may also apply to other eosinophilic diseases.

Molecules involved in the regulation of eosinophil apoptosis

Apoptosis is the most common form of physiological cell death and a necessary process to maintain cell numbers in multicellular organisms. Eosinophils are constantly produced in the bone marrow and the same numbers die, under normal circumstances, within a relatively short time period. In many eosinophilic inflammatory diseases, reduced eosinophil apoptosis has been described. This mechanism may contribute to increased eosinophil numbers, a phenomenon called eosinophilia. Overexpression of interleukin-5 appears to be crucial for delaying eosinophil apoptosis in many allergic disorders. Survival factor withdrawal leads to the induction of apoptosis. Besides survival cytokines, eosinophil apoptosis is also regulated by death factors. Recent observations suggest a role for mitochondria in conducting eosinophil apoptosis, although the mechanisms that trigger mitochondria to release proapoptotic factors remain less clear. Drugs that specifically induce eosinophil apoptosis might be useful for triggering the resolution of unwanted eosinophilic inflammatory responses.

[Pemphigoid nodularis triggered by hypereosinophilic syndrome?]

Pemphigoid nodularis (PN) is a rare clinical variant of pemphigoid characterized by prurigo-like skin lesions and antibodies against BP180 and BP230 characteristic for bullous pemphigoid. Interestingly, most PN patients never develop blisters. This condition is often resistant to treatment. We describe a female patient who was initially diagnosed with hypereosinophilic dermatitis. Later on, in the presence of eosinophilic infiltrations in the gastrointestinal tract, obstructive ventilation disorder, pericardial and pleural effusions, the diagnosis of idiopathic hypereosinophilic syndrome was made. During the following 3 years she developed recalcitrant PN.

[Eosinophilia, diarrhea and asthma in a young woman]

We present the case of a young woman that was diagnosed with Churg-Strauss syndrome. The classical as well as the atypical symptoms, signs and findings are discussed in the context of clinically relevant differential diagnoses. The diagnostic criteria and the relevant aspects of pathogenesis, clinical course and treatment are reviewed. In addition, the similarities and differences with respect to the other idiopathic interstitial eosinophilic pneumopathies are described.

[A young child with acute abdomen and iron deficiency anemia]

The case of a 20 month-old girl that was admitted to the emergency ward because of worsening of her general condition in the setting of acute non-bloody gastroenteritis is reported. The clinical examination revealed signs of severe dehydration and a prominent tender abdomen. Laboratory evaluation showed leucocytosis, elevated C-reactive protein and severe hypochromic microcytic anemia. Abdominal X-ray revealed diffuse meteorism. The child underwent laparascopic evaluation. A perforated Meckel's diverticulum was found. Perforation and anemia due to occult bleeding are unusual presentations of Meckel's diverticulum. The differential diagnosis of children presenting with an acute abdomen with special focus on Meckel's diverticulum is discussed.

Population-based epidemiology of rotavirus hospitalisations in Switzerland

BACKGROUND: Rotaviruses (RV) are the most common cause of dehydrating gastroenteritis requiring hospitalisation in children <5 years of age. A new generation of safe and effective RV vaccines is available. Accurate data describing the current burden of RV disease in the community are needed to devise appropriate strategies for vaccine usage. METHODS: Retrospective, population-based analysis of RV hospitalisations in children <5 years of age during a 5-year period (1999-2003) in a both urban and rural area inhabited by 12% of the Swiss population. RESULTS: Of 406 evaluable cases, 328 were community-acquired RV infections in children <5 years of age. RV accounted for 38% of all hospitalisations for gastroenteritis. The overall hospitalisation incidence in the <5-year-old was 1.5/1000 child-years (peak incidence, 2.6/1000 child-years in children aged 13-24 months). The incidence of community-acquired RV hospitalisations was significantly greater in children of non-Swiss origin (3.0 vs. 1.1/1000 child-years, relative risk 2.7; 95% CI 2.2-3.4), who were younger, but tended to be less severely dehydrated on admission than Swiss children. In comparison with children from urban areas, RV hospitalisation incidence was significantly lower among those residing in the remote mountain area (0.71 vs. 1.71/1000 child years, relative risk 2.2, 95% CI 1.6-3.1). CONCLUSION: Population-based RV hospitalisation incidence was low in comparison with other European countries. Significantly greater hospitalisation rates among children living in urban areas and those from non-Swiss families indicate that factors other than the severity of RV-induced dehydration are important driving forces of hospital admission.

Langerhans cell histiocytosis as differential diagnosis of a mediastinal tumor

We describe the case of a 55-year-old man who presented with parasternal swelling. The chest CT scan showed a large tumor of the chest wall infiltrating the subcutaneous tissue. To assume histologic diagnosis an open biopsy was performed. Between the myofibrils a coarse, white tumor with infiltrative growth was noted. Histopathologic examination revealed expanded atrophic skeletal muscle that was infiltrated by histiocytic cells. Numerous eosinophilic granulocytes and lymphocytes CD20 and CD3 positive could be detected and immunohistochemical staining was also positive for S-100 proteins and CD1a. Histologic findings were characteristic of Langerhans cell histiocytosis (LCH). To the best of our knowledge a LCH originating from the mediastinum in an adult as presented has not been previously described.

Antibodies to flagellin indicate reactivity to bacterial antigens in IBS patients

One of the several possible causes of irritable bowel syndrome (IBS) is thought to be low-grade mucosal inflammation. Flagellin, the primary structural component of bacterial flagellae, was shown in inflammatory bowel disease patients to activate the innate and adaptive immunity. It has not yet been conclusively established if IBS patients show reactivity to luminal antigens. In 266 patients [112 IBS, 61 Crohn's disease (CD), 50 ulcerative colitis (UC) and 43 healthy controls (HC)], we measured antibodies to flagellin (FAB, types A4-Fla2 and Fla-X), anti-Saccharomyces cerevisiae antibodies (ASCA) (both ELISA), antipancreas antibodies (PAB) and perinuclear antineutrophil cytoplasmatic antibodies (p-ANCA) (both IF). All IBS patients had normal fecal calprotectin (mean 21 microg mL(-1), SD 6.6) and fulfilled the ROME II criteria. Frequencies of antibodies in patients with IBS, CD, UC and HC, respectively, are as follows (in per cent): antibodies against A4-Fla2: 29/48/8/7; antibodies against Fla-X: 26/52/10/7; ASCA: 6/59/0/2; p-ANCA: 0/10/52/0; and PAB: 0/28/0/0. Antibodies against A4-Fla2 and Fla-X were significantly more frequent in IBS patients than in HC (P = 0.004 and P = 0.009). Antibodies to A4-Fla2 and Fla-X were significantly more frequent in IBS patients with antecedent gastroenteritis compared to non-postinfectious IBS patients (P = 0.002 and P = 0.012). In contrast to ASCA, PAB and p-ANCA, antibodies against A4-Fla2 and Fla-X were found significantly more often in IBS patients, particularly in those with postinfectious IBS, compared to HC. This observation supports the concept that immune reactivity to luminal antigens has a putative role in the development of IBS, at least in a subset of patients.

Correlation of intravascular ultrasound findings with histopathological analysis of thrombus aspirates in patients with very late drug-eluting stent thrombosis

BACKGROUND: Intravascular ultrasound of drug-eluting stent (DES) thrombosis (ST) reveals a high incidence of incomplete stent apposition (ISA) and vessel remodeling. Autopsy specimens of DES ST show delayed healing and hypersensitivity reactions. The present study sought to correlate histopathology of thrombus aspirates with intravascular ultrasound findings in patients with very late DES ST. METHODS AND RESULTS: The study population consisted of 54 patients (28 patients with very late DES ST and 26 controls). Of 28 patients with very late DES ST, 10 patients (1020+/-283 days after implantation) with 11 ST segments (5 sirolimus-eluting stents, 5 paclitaxel-eluting stents, 1 zotarolimus-eluting stent) underwent both thrombus aspiration and intravascular ultrasound investigation. ISA was present in 73% of cases with an ISA cross-sectional area of 6.2+/-2.4 mm(2) and evidence of vessel remodeling (index, 1.6+/-0.3). Histopathological analysis showed pieces of fresh thrombus with inflammatory cell infiltrates (DES, 263+/-149 white blood cells per high-power field) and eosinophils (DES, 20+/-24 eosinophils per high-power field; sirolimus-eluting stents, 34+/-28; paclitaxel-eluting stents, 6+/-6; P for sirolimus-eluting stents versus paclitaxel-eluting stents=0.09). The mean number of eosinophils per high-power field was higher in specimens from very late DES ST (20+/-24) than in those from spontaneous acute myocardial infarction (7+/-10), early bare-metal stent ST (1+/-1), early DES ST (1+/-2), and late bare-metal stent ST (2+/-3; P from ANOVA=0.038). Eosinophil count correlated with ISA cross-sectional area, with an average increase of 5.4 eosinophils per high-power field per 1-mm(2) increase in ISA cross-sectional area. CONCLUSIONS: Very late DES thrombosis is associated with histopathological signs of inflammation and intravascular ultrasound evidence of vessel remodeling. Compared with other causes of myocardial infarction, eosinophilic infiltrates are more common in thrombi harvested from very late DES thrombosis, particularly in sirolimus-eluting stents, and correlate with the extent of stent malapposition.