Rhinovirus C Infection Induces Type 2 Innate Lymphoid Cell Expansion and Eosinophilic Airway Inflammation.

Rhinovirus C (RV-C) infection is associated with severe asthma exacerbations. Since type 2 inflammation is an important disease mechanism in asthma, we hypothesized that RV-C infection, in contrast to RV-A, preferentially stimulates type 2 inflammation, leading to exacerbated eosinophilic inflammation. To test this, we developed a mouse model of RV-C15 airways disease. RV-C15 was generated from the full-length cDNA clone and grown in HeLa-E8 cells expressing human CDHR3. BALB/c mice were inoculated intranasally with 5 x 106 ePFU RV-C15, RV-A1B or sham. Mice inoculated with RV-C15 showed lung viral titers of 1 x 105 TCID50 units 24 h after infection, with levels declining thereafter. IFN-α, ß, γ and λ2 mRNAs peaked 24-72 hrs post-infection. Immunofluorescence verified colocalization of RV-C15, CDHR3 and acetyl-α-tubulin in mouse ciliated airway epithelial cells. Compared to RV-A1B, mice infected with RV-C15 demonstrated higher bronchoalveolar eosinophils, mRNA expression of IL-5, IL-13, IL-25, Muc5ac and Gob5/Clca, protein production of IL-5, IL-13, IL-25, IL-33 and TSLP, and expansion of type 2 innate lymphoid cells. Analogous results were found in mice treated with house dust mite before infection, including increased airway responsiveness. In contrast to Rorafl/fl littermates, RV-C-infected Rorafl/flIl7rcre mice deficient in ILC2s failed to show eosinophilic inflammation or mRNA expression of IL-13, Muc5ac and Muc5b. We conclude that, compared to RV-A1B, RV-C15 infection induces ILC2-dependent type 2 airway inflammation, providing insight into the mechanism of RV-C-induced asthma exacerbations.

A Case of Eosinophilic Pustular Folliculitis Associated With Herpes Zoster.

ABSTRACT: Patients with eosinophilic pustular folliculitis (EPF), a sterile eosinophilic infiltration of hair follicles, often present with papulopustules that tend to form annular plaques. Histopathologic examination revealed eosinophilic infiltration around the pilosebaceous units and eosinophilic microabscess formation. Although the pathogenesis of EPF is unknown, T-helper type 2 immune responses were suggested to be important based on their stimulating effect on the sebaceous glands. Here, we report the first case of EPF associated with herpes zoster, indicating that herpes zoster and EPF are correlated with T-helper type 2 immune responses.

Human Polyomavirus 6 Detected in Cases of Eosinophilic Pustular Folliculitis.

BACKGROUND: Human polyomaviruses (HPyVs) have been associated with several cutaneous inflammatory conditions. More investigation is needed to identify further presentations of cutaneous pathology associated with HPyVs. Our aim was to investigate the possible association of skin-tropic HPyVs with folliculitis, particularly eosinophilic pustular folliculitis (EPF). METHODS: This study included 55 Japanese patients, comprising 13 patients with EPF and 42 patients with suppurative folliculitis. HPyV DNAs were detected by quantitative polymerase chain reaction. Expression of viral antigen and geographically related viral genotypes were also assessed. RESULTS: Human polyomavirus 6 (HPyV6) DNA was found in 9 of 13 (69%) patients with EPF, a rate significantly higher than that found in suppurative folliculitis (1/42; 2%). Of the 7 HPyV6 DNA-positive EPF specimens analyzed, 4 were positive for HPyV6 small tumor antigen. All the HPyV6 strains detected in this study were of the Asian/Japanese genotype. CONCLUSIONS: The predominant detection of HPyV6 DNA and the expression of viral antigen suggest a possible association between HPyV6 infection and EPF in a subset of patients. Worldwide studies are warranted to determine whether Asian/Japanese genotype HPyV6 is associated preferentially with the incidence and pathogenesis of this eosinophil-related skin disease that has an ethnic predilection for the East Asian population.

Paniculitis eosinofílica secundaria a infección por COVID-19 / Eosinophilic Panniculitis Associated With COVID-19

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Herpes simplex virus type 2 meningitis as a manifestation of Good's syndrome.

Good's syndrome is a primary immunodeficiency phenocopy characterized for thymoma and immunodeficiency. The most frequent clinical presentation is recurrent or opportunistic infections, hematological alterations, and chronic diarrhea. We treated a 66-year-old man who consulted for 5 days of headache and diplopia with right sixth cranial nerve palsy at examination. Patient reported chronic diarrhea and prolonged febrile syndrome accompanied by weight loss of 23 kg in the last year. Exhaustive evaluation revealed Herpes simplex virus (HSV) type 2 meningitis, eosinophilic colitis, and type A thymoma. Severe antibody deficiency (hypogammaglobulinemia) associated with thymoma confirmed the diagnosis of Good's syndrome.

Myristoylated rhinovirus VP4 protein activates TLR2-dependent proinflammatory gene expression.

Asthma exacerbations are often caused by rhinovirus (RV). We and others have shown that Toll-like receptor 2 (TLR2), a membrane surface receptor that recognizes bacterial lipopeptides and lipoteichoic acid, is required and sufficient for RV-induced proinflammatory responses in vitro and in vivo. We hypothesized that viral protein-4 (VP4), an internal capsid protein that is myristoylated upon viral replication and externalized upon viral binding, is a ligand for TLR2. Recombinant VP4 and myristoylated VP4 (MyrVP4) were purified by Ni-affinity chromatography. MyrVP4 was also purified from RV-A1B-infected HeLa cells by urea solubilization and anti-VP4 affinity chromatography. Finally, synthetic MyrVP4 was produced by chemical peptide synthesis. MyrVP4-TLR2 interactions were assessed by confocal fluorescence microscopy, fluorescence resonance energy transfer (FRET), and monitoring VP4-induced cytokine mRNA expression in the presence of anti-TLR2 and anti-VP4. MyrVP4 and TLR2 colocalized in TLR2-expressing HEK-293 cells, mouse bone marrow-derived macrophages, human bronchoalveolar macrophages, and human airway epithelial cells. Colocalization was absent in TLR2-null HEK-293 cells and blocked by anti-TLR2 and anti-VP4. Cy3-labeled MyrVP4 and Cy5-labeled anti-TLR2 showed an average fractional FRET efficiency of 0.24 ± 0.05, and Cy5-labeled anti-TLR2 increased and unlabeled MyrVP4 decreased FRET efficiency. MyrVP4-induced chemokine mRNA expression was higher than that elicited by VP4 alone and was attenuated by anti-TLR2 and anti-VP4. Cytokine expression was similarly increased by MyrVP4 purified from RV-infected HeLa cells and synthetic MyrVP4. We conclude that, during RV infection, MyrVP4 and TLR2 interact to generate a proinflammatory response.

Interferon lambda receptor 1 (IFNL1R) transcript is highly expressed in rhinovirus bronchiolitis and correlates with disease severity.

BACKGROUND: As the expression of type III IFN receptor is restricted to the mucosal surfaces, its evaluation could be crucial to characterize the role of IFNλs during bronchiolitis. OBJECTIVES: This study was designed to investigate airway type III IFN receptor (IFNLR1/IL10RB) expression during respiratory syncytial virus (RSV) or human rhinovirus (HRV) bronchiolitis. STUDY DESIGN: Seventy-one 1-6 month old infants hospitalized with their first episode of acute RSV or HRV bronchiolitis were selected for this study. Expression of IFNLR1, IL10RB and IFN-stimulated genes (ISGs) MxA and ISG56 in cells of nasopharyngeal washings taken within the first 48 h of admission were determined by a real-time hydrolysis probe RT-PCR assay. The ability of types I and III IFNs to induce the expression of both IFNLR1 and IL10RB in vitro was also evaluated. RESULTS: Airway IFNLR1 transcript levels were significantly higher in HRV bronchiolitis infants compared to those with RSV bronchiolitis. No differences were recorded for IL10RB-mRNA between RSV or HRV infection. IFNLR1 mRNA levels increased significantly in infants infected with the C species of HRV and in those with a higher clinical score index and with an eosinophil count >3%. There were no correlations in vivo between type III IFN receptors and those of ISGs and neither IFNLR1 nor IL10RB were induced in vitro by IFNs. CONCLUSIONS: These results suggest that IFNLR1 are increased in HRV-infected infants with more severe bronchiolitis and blood eosinophilia and in those infected with the HRVC species.

Characteristics associated with clinical severity and inflammatory phenotype of naturally occurring virus-induced exacerbations of asthma in adults.

BACKGROUND: In experimental studies viral infections have been shown to induce type 2 inflammation in asthmatics, but whether this is a feature of naturally occurring virus-induced asthma exacerbations is unknown. Thymic stromal lymphopoietin (TSLP) released from the airway epithelium in response to damage, has been suggested as a link between viral infection and type 2 inflammation, but the role of TSLP in asthma exacerbations is unknown. OBJECTIVE: To assess whether type 2 inflammation, as measured by sputum eosinophils and fractional exhaled nitric oxide (FeNO), is a feature of naturally occurring virus-induced exacerbations of asthma and whether TSLP is associated with this type 2 inflammation. METHODS: Patients presenting to hospital with acute asthma were examined during the exacerbation, and after 4 weeks recovery. The assessments included spirometry, FeNO and induced sputum for differential counts and TSLP mRNA levels. Nasal swabs were collected for viral detection. RESULTS: Sputum eosinophils and FeNO were similar between virus-positive (n = 44) and negative patients (n = 44). In virus-positive patients, TSLP expression was lower at exacerbation than follow-up (p = 0.03). High TSLP at exacerbation was associated with lower sputum eosinophils (p = 0.01) and higher FEV1 (p = 0.03). In virus-positive patients, %-predicted FEV1 negatively correlated with both FeNO and sputum eosinophils (p = 0.02 and p = 0.05, respectively). CONCLUSION: Our findings support that type 2 inflammation is present in patients during virus-induced asthma exacerbations, to the same degree as non-viral exacerbations, and correlate negatively with FEV1. However, in virus-positive patients, high TSLP expression during exacerbation was associated with low sputum eosinophils, suggesting that the effect of TSLP in vivo, in the setting of an asthma exacerbation, might be different than the type 2 inducing effects observed in experimental studies.

Virus-like nanoparticle and DNA vaccination confers protection against respiratory syncytial virus by modulating innate and adaptive immune cells.

Respiratory syncytial virus (RSV) is an important human pathogen. Expression of virus structural proteins produces self-assembled virus-like nanoparticles (VLP). We investigated immune phenotypes after RSV challenge of immunized mice with VLP containing RSV F and G glycoproteins mixed with F-DNA (FdFG VLP). In contrast to formalin-inactivated RSV (FI-RSV) causing vaccination-associated eosinophilia, FdFG VLP immunization induced low bronchoalveolar cellularity, higher ratios of CD11c(+) versus CD11b(+) phenotypic cells and CD8(+) T versus CD4(+) T cells secreting interferon (IFN)-γ, T helper type-1 immune responses, and no sign of eosinophilia upon RSV challenge. Furthermore, RSV neutralizing activity, lung viral clearance, and histology results suggest that FdFG VLP can be comparable to live RSV in conferring protection against RSV and in preventing RSV disease. This study provides evidence that a combination of recombinant RSV VLP and plasmid DNA may have a potential anti-RSV prophylactic vaccine inducing balanced innate and adaptive immune responses.

Eosinophilia and associated factors in a large cohort of patients infected with human immunodeficiency virus.

OBJECTIVES: To determine the prevalence of eosinophilia among antiretroviral therapy (ART)-naïve patients infected with human immunodeficiency virus (HIV) and to identify variables associated with eosinophilia. METHODS: We included all ART-naïve HIV-infected patients entering into care at the Thomas Street Health Center (Houston, Texas) between February 2007 and January 2009. Eosinophilia was defined as absolute eosinophil count ≥ 400 cells per cubic millimeter. Patients with eosinophilia (cases) at baseline were matched to patients without baseline eosinophilia (controls). Clinical and laboratory data were collected for cases and controls. Variables associated with eosinophilia were evaluated by univariate and multivariate analyses. RESULTS: Sixty-five (9.7%) of 671 ART-naïve patients had eosinophilia. There was no difference in age, sex, race, or baseline CD4 count between patients with and without eosinophilia; however, patients with eosinophilia were more likely to have higher HIV RNA viral loads (5.05 vs 4.82 log10 copies per milliliter; P = 0.019). A total of 52 (80%) of 65 patients with eosinophilia (cases) had at least two follow-up clinic visits. They were matched to 104 controls. Skin rash was the only variable associated with eosinophilia (odds ratio 2.16, 95% confidence interval 1.04-4.47) in our multivariate analysis. Of eight cases tested, only one, from Central America, had a parasitic infection (hookworm). Thirty-eight (73.1%) patients experienced resolution of their eosinophilia by the end of the study (mean follow-up 1019 days). Resolution of eosinophilia did not differ between patients with and without HIV viral suppression. CONCLUSIONS: Eosinophilia is not an infrequent occurrence among ART-naïve HIV-infected patients. Patients with eosinophilia are more likely than patients without eosinophilia to present with a skin rash. HIV RNA viral suppression did not necessarily result in the resolution of eosinophilia. Extensive workup for eosinophilia may not be necessary in most cases.

Eosinophilic dysplasia of the cervix associated with HPV 6 infection - case report and review of the literature.

Eosinophilic dysplasia of the cervix is recently described unusual and somewhat obscure dysplastic lesion of squamous epithelium. We present histological features of a lesion in 41 years old woman. It was composed of cells with brightly eosinophilic cytoplasm contoured by a sharp and slightly broader cytoplasmic membrane, lacking maturation, with mild increase in nuclear-cytoplasmic ratio, slight chromatin clumping and uneven mild nuclear clearing. Electronmicroscopic study showed mild crevices of the nuclear membrane in some dysplastic cells. Tissue in situ hybridization study confirmed the presence of HPV 6 in the form of patchy dotted pattern of integrated type. Immunohistochemistry revealed diffuse positive expression of antigen p16, extraordinarily in this case focally sparing basal part of the epithelium. Underestimation of this lesion can be avoided by paying attention to strong eosinophilia of the cytoplasm and sharp cellular contouring of the examined epithelium in routine hematoxylin-eosin staining.

Case report of drug rash with eosinophilia and systemic symptoms demonstrating human herpesvirus-6 reactivation.

Drug rash with eosinophilia and systemic symptoms (DRESS) is a severe drug-induced hypersensitivity syndrome that presents with diffuse cutaneous eruptions, fever, and multiorgan involvement. Here we present a pediatric case of DRESS complicated by human herpesvirus (HHV)-6 reactivation. After 1 week of sulfasalazine, our patient developed a diffuse morbilliform eruption. Sulfasalazine was discontinued. The patient presented to the emergency department soon thereafter with worsening eruption, fever, rigors, facial edema, and lymphadenopathy. Methylprednisolone was initiated. Peripheral smear did not demonstrate eosinophilia but showed toxic granulation with atypical lymphocytes. Transaminase levels and white blood cell count quickly became elevated, with increased eosinophils, suggesting DRESS. During the methylprednisolone taper, our patient experienced symptom exacerbation, acute hepatitis, and HHV-6 seroconversion, indicating HHV-6 reactivation as the cause. As demonstrated by our patient, a decelerated methylprednisone taper is important because of potential symptom flaring during taper. Additionally, in the care of individuals with DRESS, HHV-6 is often tested for upon admission and not repeated. Delay in the rise of titers necessitates repeat testing.

Eosinophilia: clinical significance in HIV-infected individuals.

This study was conducted to determine the relationship between eosinophilia and parasitic infection in HIV-infected individuals. HIV-positive patients attending an HIV clinic in Birmingham were recruited and classified as either eosinophilic (>400 eosinophils/mm(3)) or non-eosinophilic. A demographic and parasitic risk history was taken and clinical examination was performed. Urine and stool were examined for parasites, and blood samples taken for parasite serology. A total of 266 patients (96 eosinophilic and 170 non-eosinophilic) were recruited. Of 64 eosinophilic patients who had a stool examination, one (1.6%) was positive for both Strongyloides larvae and schistosomal eggs. Urine microscopy was negative in the 245 patients (88 eosinophilic, 157 non-eosinophilic) from whom a sample was available. Two hundred and sixty-three patients underwent serological investigation (96 eosinophilic and 167 non-eosinophilic): 13 (4.9%) were positive for schistosomiasis and three (1.1%) positive for Strongyloides. A significant association between eosinophilia and positive schistosomal serology was found (P = 0.003): 11 (10.5%) were eosinophilic patients, while only four (2.3%) were non-eosinophilic patients. Eosinophilia was associated with a low nadir CD4 count (P = 0.021) and prior AIDS-defining illness (P = 0.041). In all, 7.8% of patients from a developing country and 5.3% of patients from a developed country with a travel history had positive parasitic serology. Eosinophilia in HIV-infected patients was significantly associated with positive serology for schistosomiasis, low nadir CD4 count and prior AIDS-defining illness. Geographical exposure is also an important determinant of positive parasitic serology.

Drug reaction with eosinophilia and systemic symptoms (DRESS): a complex interaction of drugs, viruses and the immune system.

The DRESS syndrome (drug reaction with eosinophilia and systemic symptoms), also known as DIHS (drug-induced hypersensitivity syndrome), presents clinically as an extensive mucocutaneous rash, accompanied by fever, lymphadenopathy, hepatitis, hematologic abnormalities with eosinophilia and atypical lymphocytes, and may involve other organs with eosinophilic infiltration, producing damage in several systems, especially kidney, heart, lungs, and pancreas. The pathogenesis is related to specific drugs (especially the aromatic anticonvulsants), altered immune response, sequential reactivation of herpes virus, and association with some HLA alleles. Glucocorticoids are the basis for the treatment of the syndrome, which may be given with intravenous immunoglobulin and, in selected cases, ganciclovir. This article reviews current concepts regarding the interaction of drugs, viruses and immune responses during this complex adverse-drug reaction.