Inflammatory Endotype-associated Airway Microbiome in Chronic Obstructive Pulmonary Disease Clinical Stability and Exacerbations: A Multicohort Longitudinal Analysis.

Rationale: Understanding the role of the airway microbiome in chronic obstructive pulmonary disease (COPD) inflammatory endotypes may help to develop microbiome-based diagnostic and therapeutic approaches. Objectives: To understand the association of the airway microbiome with neutrophilic and eosinophilic COPD at stability and during exacerbations. Methods: An integrative analysis was performed on 1,706 sputum samples collected longitudinally from 510 patients with COPD recruited at four UK sites of the BEAT-COPD (Biomarkers to Target Antibiotic and Systemic COPD), COPDMAP (Chronic Obstructive Pulmonary Disease Medical Research Council/Association of the British Pharmaceutical Industry), and AERIS (Acute Exacerbation and Respiratory Infections in COPD) cohorts. The microbiome was analyzed using COPDMAP and AERIS as a discovery data set and BEAT-COPD as a validation data set. Measurements and Main Results: The airway microbiome in neutrophilic COPD was heterogeneous, with two primary community types differentiated by the predominance of Haemophilus. The Haemophilus-predominant subgroup had elevated sputum IL-1ß and TNFα (tumor necrosis factor α) and was relatively stable over time. The other neutrophilic subgroup with a balanced microbiome profile had elevated sputum and serum IL-17A and was temporally dynamic. Patients in this state at stability were susceptible to the greatest microbiome shifts during exacerbations. This subgroup can temporally switch to both neutrophilic Haemophilus-predominant and eosinophilic states that were otherwise mutually exclusive. Time-series analysis on the microbiome showed that the temporal trajectories of Campylobacter and Granulicatella were indicative of intrapatient switches from neutrophilic to eosinophilic inflammation, in track with patient sputum eosinophilia over time. Network analysis revealed distinct host-microbiome interaction patterns among neutrophilic Haemophilus-predominant, neutrophilic balanced microbiome, and eosinophilic subgroups. Conclusions: The airway microbiome can stratify neutrophilic COPD into subgroups that justify different therapies. Neutrophilic and eosinophilic COPD are interchangeable in some patients. Monitoring temporal variability of the airway microbiome may track patient inflammatory status over time.

Microbiota in non-IgE-mediated food allergy.

PURPOSE OF REVIEW: To perform a nonsystematic review of the literature on the microbiota in the different types of non-IgE-mediated food allergy. RECENT FINDINGS: The commonest non-IgE-mediated disorders managed by allergists include: eosinophilic esophagitis, food protein-induced enteropathy, food protein-induced enterocolitis syndrome, and food protein-induced allergic proctocolitis. The review of the literature describes how at phylum level we observe an increase of Proteobacteria in eosinophilic esophagitis esophageal microbiota and in food protein-induced enterocolitis syndrome, and food protein-induced allergic proctocolitis gut microbiota, while we observe an increase of Bacteroidetes in healthy controls. Several studies endorse the concept that a bloom of Proteobacteria in the gut reflects dysbiosis or an unstable gut microbial community structure. In several studies, the type of diet, the use of probiotics and in a single experience the use of fecal microbiota transplantation has produced significant variations of the microbiota. SUMMARY: Genetic factors alone cannot account for the rapid rise in food allergy prevalence and the microbiome might be contributing to allergy risk. Our review showed that common features of the pathological microbiota among different types of non-IgE-mediated food allergy can be identified. These evidences suggest a possible role of the microbiota in the pathogenesis and non-IgE-mediated food allergies and the need to understand the effects of its modulation on the disorders themselves.

Lung Lavage Granulocyte Patterns and Clinical Phenotypes in Children with Severe, Therapy-Resistant Asthma.

BACKGROUND: Children with severe asthma have frequent exacerbations despite guidelines-based treatment with high-dose corticosteroids. The importance of refractory lung inflammation and infectious species as factors contributing to poorly controlled asthma in children is poorly understood. OBJECTIVE: To identify prevalent granulocyte patterns and potential pathogens as targets for revised treatment, 126 children with severe asthma underwent clinically indicated bronchoscopy. METHODS: Diagnostic tests included bronchoalveolar lavage (BAL) for cell count and differential, bacterial and viral studies, spirometry, and measurements of blood eosinophils, total IgE, and allergen-specific IgE. Outcomes were compared among 4 BAL granulocyte patterns. RESULTS: Pauci-granulocytic BAL was the most prevalent granulocyte category (52%), and children with pauci-granulocytic BAL had less postbronchodilator airflow limitation, less blood eosinophilia, and less detection of BAL enterovirus compared with children with mixed granulocytic BAL. Children with isolated neutrophilia BAL were differentiated by less blood eosinophilia than those with mixed granulocytic BAL, but greater prevalence of potential bacterial pathogens compared with those with pauci-granulocytic BAL. Children with isolated eosinophilia BAL had features similar to those with mixed granulocytic BAL. Children with mixed granulocytic BAL took more maintenance prednisone, and had greater blood eosinophilia and allergen sensitization compared with those with pauci-granulocytic BAL. CONCLUSIONS: In children with severe, therapy-resistant asthma, BAL granulocyte patterns and infectious species are associated with novel phenotypic features that can inform pathway-specific revisions in treatment. In 32% of children evaluated, BAL revealed corticosteroid-refractory eosinophilic infiltration amenable to anti-TH2 biological therapies, and in 12%, a treatable bacterial pathogen.

Allergic conversion of protective mucosal immunity against nasal bacteria in patients with chronic rhinosinusitis with nasal polyposis.

BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is characterized by eosinophilic inflammation and polyposis at the nose and paranasal sinus and a high concentration of IgE in nasal polyps (NPs). The causative antigen and pathogenesis of CRSwNP remain unknown. OBJECTIVE: We aimed to identify reactive allergens of IgE antibodies produced locally in NPs of patients with CRSwNP. We also attempted to unravel the differentiation pathway of IgE-producing B cells in NPs. METHODS: IgE reactivity of patients with CRSwNP was investigated by characterizing single cell-derived mAbs. T-cell response against identified allergens was investigated in vitro. NP-infiltrating lymphocytes were characterized by using flow cytometry. Immunoglobulins expressed in NPs were analyzed by using high-throughput DNA sequencing for immunoglobulin. RESULTS: About 20% of isolated IgE antibodies derived from NP-residing plasmablasts specifically recognized surface determinants of nasal bacteria, such as Staphylococcus aureus, Streptococcus pyogenes, and Haemophilus influenzae. A TH2 response against S pyogenes was observed in patients with CRSwNP. Flow cytometric analysis revealed sizable germinal center B-like cell and plasmablast subsets expressing IgE on the cell surface in NPs. High-throughput DNA sequencing immunoglobulin analysis highlighted the clonal connectivity of IgE with IgG and IgA1. The Iε-Cα1 circle transcript was detected in NPs. CONCLUSIONS: In patients with CRSwNP, nasal bacteria-reactive B cells differentiate into IgE-producing B cells through IgG/IgA1-IgE class switching, suggesting that allergic conversion of the mucosal response against nasal bacteria underlies disease pathogenesis.

Diagnosing and Understanding Angiostrongyliasis, A Zoonotic Cause of Meningitis.

Eosinophilic meningitis caused by Angiostrongylus cantonensis is spreading worldwide, and it can manifest as a severe neurological disease. Angiostrongyliasis is a food- and water-borne parasitosis that usually exhibits a seasonal and circumscribed geographical distribution. To improve control and treatment of these infections, further studies of transmission dynamics under natural conditions and the development of better diagnostic tools and treatment options are needed.

Helmintosis y eosinofilia en España (1990-2015) / Helminthosis and eosinophilia in Spain (1990-2015)

La detección de eosinofilia periférica es un motivo relativamente frecuente para la remisión de un paciente a una Unidad/Servicio de Enfermedades Infecciosas. En general, se pretende descartar una enfermedad parasitaria, tanto en personas autóctonas como en viajeros o inmigrantes. Excepcionalmente la eosinofilia relacionada con parásitos corresponde a una protozoosis, siendo los helmintos los principales agentes causales de este hallazgo hematológico. La eosinofilia puede ser el único hallazgo anormal o formar parte del cuadro clínico-biológico del paciente. Por otro lado, no todas las helmintosis se asocian de forma sistemática a eosinofilia, y el grado de la misma difiere entre las fases de la infección y el tipo de helminto. El propósito de esta revisión es un estudio sistemático de la relación entre helmintosis y eosinofilia en la literatura española, distinguiendo los casos autóctonos e importados, así como la relación con situaciones de inmunodepresión (AU)

The finding of blood eosinophilia in a patient is a relatively frequent reason to refer him/her to a Clinical Department of Infectious Diseases. The doctor usually intends to rule out a parasitic disease in the autochthonous population, travelers or immigrants. It is uncommon for an eosinophilia to be produced by protozoa infection, whereas helminth parasites are more frequently associated with an increase of eosinophil counts in the infected patient. Eosinophilia can be the only abnormal finding, or it could be part of more complex clinical manifestations suffered by the patient. Furthermore, many, but not all, helminth infections are associated with eosinophilia, and the eosinophil level (low, high) differs according to parasite stages, helminth species, and worm co-infections. The purpose of the present article is to carry out a systematic review of cases and case series on helminth infections and eosinophilia reported in Spain from 1990 to 2015, making a distinction between autochthonous and imported (immigrants and travelers) cases, and studying their relationship with immunodepression situations (AU)

Strongyloides stercoralis en un hospital comarcal del Levante español: una enfermedad no solo importada / Strongyloides stercoralis infection in a Spanish regional hospital: Not just an imported disease

Introducción: La infestación por Strongyloides stercoralis es más prevalente en regiones tropicales, pero existen casos autóctonos en España, principalmente en La Safor (Valencia). Nuestro objetivo era estudiar los casos de un hospital de la provincia de Alicante y conocer si existían casos autóctonos. Procedimiento: Estudio retrospectivo de los casos diagnosticados de estrongiloidiasis en el Hospital Vega Baja (Orihuela, Alicante) entre enero de 1999 y marzo de 2016. Resultados: Se registraron 10 casos, 4 de ellos autóctonos, presentando 2 de ellos un cuadro de hiperinfestación con desenlace fatal. Todos los casos autóctonos fueron en personas ≥69años con síntomas digestivos, cutáneos y/o respiratorios. La serología fue positiva en los 8casos en los que se realizó. En 3 casos se visualizaron larvas en el estudio histopatológico. Conclusiones: Comunicamos los primeros casos autóctonos de estrongiloidiasis en la región Vega Baja. Se deben implantar programas de cribado principalmente en pacientes inmunosuprimidos o en tratamiento corticoideo (AU)

Introduction: Strongyloides stercoralis infection is more prevalent in tropical regions but autochthonous cases have been reported in Spain, mainly in La Safor (Valencia). The objective is to describe the strongyloidiasis cases registered in a regional hospital of Alicante province (Spain) and to determine if they were autochthonous cases. Methods: Retrospective study of all diagnosed cases of strongyloidiasis in Vega Baja Hospital (Orihuela, Alicante) between January 1999 and March 2016. Results: A total of 10 cases were found, four of which were autochthonous cases. Two of them presented with a hyper-infection syndrome, with a fatal outcome. All autochthonous cases were in patients ≥69years old with gastrointestinal, cutaneous, and/or respiratory symptoms. Serology was positive in the 8 cases studied. Larvae were found in histopathological samples of the gastrointestinal tract of three patients. Conclusions: We communicate the first autochthonous cases of strongyloidiasis in the region of Vega Baja. Screening programs should be implemented, especially in immunosuppressed patients or patients under chronic corticosteroid treatment (AU)

Prevalencia de la eosinofilia y factores relacionados en los viajeros e inmigrantes de la red +REDIVI / Eosinophilia prevalence and related factors in travel and immigrants of the network +REDIVI

Algunas enfermedades infecciosas han adquirido más relevancia por el aumento de los movimientos poblacionales. La eosinofilia es un hallazgo frecuente en inmigrantes y en viajeros. Una de las causas más frecuentes de eosinofilia es la infección por helmintos y algunos protozoos intestinales. El objetivo de este trabajo es describir las características epidemiológicas de los casos con eosinofilia y su asociación con la presencia de parásitos en la red de datos REDIVI. Se trata de un estudio observacional multicéntrico prospectivo, donde se incluyen los casos diagnosticados de eosinofilia registrados en la Red cooperativa para el estudio de las infecciones importadas por viajeros e inmigrantes (+REDIVI) desde enero de 2009 hasta diciembre de 2012. Se registraron en la red un total de 5.255 episodios durante el periodo de estudio, y la eosinofilia fue un hallazgo en el 8,1 al 31,3% de los casos (dependiendo del tipo migratorio). Fueron hombres el 60,2%, con una mediana de 31,0años, inmigrantes el 72,4% y asintomáticos el 81,2%. Los parásitos más frecuentemente identificados fueron S.stercoralis(34,4%), Schistosoma sp. (11,0%) y uncinarias (8,6%). Existía asociación entre eosinofilia y presencia de parásitos para todos los helmintos (excepto para larva migrans cutánea). La sintomatología y la duración del viaje no determinaron significativamente la presencia de eosinofilia. Ante una eosinofilia en una persona que ha vivido en zonas endémicas de helmintiasis es aconsejable realizar estudios dirigidos para su diagnóstico, independientemente del tipo migratorio, la duración de la estancia o la presencia de sintomatología (AU)

The population movements during the last decades have resulted in a progressively increasing interest in certain infectious diseases. Eosinophilia is a common finding in immigrants and travelers. One of the most common causes of eosinophilia is helminth infection, and some intestinal protozoa. The aim of this paper is to describe the epidemiological characteristics of cases with eosinophilia and its association with the presence of parasites in the REDIVI data network. This is a multicenter prospective observational study that includes patients diagnosed with eosinophilia registered in the cooperative network for the study of infectious diseases in travelers and immigrants (+REDIVI) from January 2009 to December 2012. A total of 5,255 episodes were recorded in the network during the study period, and eosinophilia was observed in 8.1-31.3% of cases (depending on the immigration group). There were 60.2% men, with a median age of 31years. There were 72.4% immigrants, and 81.2% were asymptomatic. The most commonly identified parasites were S.stercoralis (34.4%), Schistosoma sp. (11.0%), and hookworm (8.6%). The relationship between eosinophilia and parasite infection was significant for all helminths (except for cutaneous larva migrans). The symptoms and duration of the journey did not significantly determine the presence of eosinophilia. In the case of eosinophilia in a person who has lived in helminth endemic areas, it is advisable to carry out targeted studies to diagnose the infection, regardless of immigration type, length of stay, or the presence of symptoms (AU)

Eosinophilic airway inflammation in asthmatic patients is associated with an altered airway microbiome.

BACKGROUND: Asthmatic patients have higher microbiome diversity and an altered composition, with more Proteobacteria and less Bacteroidetes compared with healthy control subjects. Studies comparing airway inflammation and the airway microbiome are sparse, especially in subjects not receiving anti-inflammatory treatment. OBJECTIVE: We sought to describe the relationship between the airway microbiome and patterns of airway inflammation in steroid-free patients with asthma and healthy control subjects. METHODS: Bronchoalveolar lavage fluid was collected from 23 steroid-free nonsmoking patients with asthma and 10 healthy control subjects. Bacterial DNA was extracted from and subjected to Illumina MiSeq sequencing of the 16S rDNA V4 region. Eosinophils and neutrophils in the submucosa were quantified by means of immunohistochemical identification and computerized image analysis. Induced sputum was obtained, and airway hyperresponsiveness to mannitol and fraction of exhaled nitric oxide values were measured. Relationships between airway microbial diversity and composition and inflammatory profiles were analyzed. RESULTS: In asthmatic patients airway microbial composition was associated with airway eosinophilia and AHR to mannitol but not airway neutrophilia. The overall composition of the airway microbiome of asthmatic patients with the lowest levels of eosinophils but not asthmatic patients with the highest levels of eosinophils deviated significantly from that of healthy subjects. Asthmatic patients with the lowest levels of eosinophils had an altered bacterial abundance profile, with more Neisseria, Bacteroides, and Rothia species and less Sphingomonas, Halomonas, and Aeribacillus species compared with asthmatic patients with more eosinophils and healthy control subjects. CONCLUSION: The level of eosinophilic airway inflammation correlates with variations in the microbiome across asthmatic patients, whereas neutrophilic airway inflammation does not. This warrants further investigation on molecular pathways involved in both patients with eosinophilic and those with noneosinophilic asthma.

Beware the "red herring".

A young patient with relapsed diffuse large B-cell lymphoma presented with new onset respiratory symptoms and hypereosinophilia in the early stage post high-dose therapy/autologous stem cell rescue. Here, we present a step-wise practical approach to this unexpected laboratory finding for a not uncommon infective complication in the immunosuppressed patient.

Eosinophilia in Preterm Born Infants Infected with Chlamydia trachomatis.

A higher than 350 eosinophils/mm(3) is strongly associated with Chlamydia trachomatis in term born babies coursing with respiratory distress. However, in preterm newborns infected with this pathogen, the levels of eosinophils are unknown. Forty newborn infants with clinical data of respiratory problems and/or sepsis were analyzed. DNA of leukocytes from peripheral blood was used to identify C. trachomatis. Detection of chlamydial infection was performed by amplifying the ompA gene by an in-house PCR, and eosinophil levels were evaluated in an XT-2000-hematology analyzer. Eighteen infants showed chlamydial infection and 14 of them showed pneumonia (RR = 2.6; CI95% 1.03-6.5; p =.027). Their eosinophil levels were 719 ± 614 cells/mm(3). A significant association between eosinophilia ≥1250 cells/mm(3) and gestational age of less than 29 weeks (RR = 5.8; 1.35; CI95% [1.4-24.5], p <.008) was observed. The preterm infants with chlamydial infection did not show higher eosinophil levels than uninfected infants.

Eosinophilic airway inflammation is common in subacute cough following acute upper respiratory tract infection.

BACKGROUND AND OBJECTIVE: Patients presenting with refractory postinfectious cough may respond to glucocorticosteroids but it is unclear whether airway eosinophilic inflammation exists in those patients. We aimed to determine the airway inflammation and causes of subacute cough following acute upper respiratory tract infection (AURTI). METHODS: One hundred and sixteen patients with persistent cough lasting 3-8 weeks after upper respiratory tract infection were evaluated with differential cell count in induced sputum, spirometry and methacholine bronchial challenge testing. RESULTS: In patients with subacute cough, sputum eosinophilia (median 8.5%,3.0-73.0%) was identified in 35 (33.6%) patients, 22 (18.5%) without bronchial hyperresponsiveness (BHR) were diagnosed as non-asthmatic eosinophilic bronchitis (NAEB), 13 (14.3%) of whom with BHR were diagnosed as cough variant asthma (CVA). Cough in patients with sputum eosinophilia improved after treatment with corticosteroids. Compared with postinfectious cough (PIC) and NAEB, CVA had significantly higher median eosinophil count in induced sputum (0.5% vs 7.5% vs 20.0%, P < 0.01). MMEF in CVA was significantly lower than PIC and NAEB (P < 0.05). The common causes of subacute cough following acute upper respiratory tract infection (AURTI) were PIC (37.8%), NAEB (18.5%), CVA (14.3%) and upper airway cough syndrome (UACS) (10.1%). Atopic cough (AC) (5.2%) and gastroesophageal reflux-related cough (GERC) (3.4%) were less common in subacute cough following AURTI, while 9 (7.8%) patients had unexplained cough. CONCLUSION: Subacute cough following AURTI can be attributed to different entities, eosinophilic airway inflammation is common. Induced sputum should be considered when evaluating patients with subacute cough following acute upper respiratory tract infection.

Corticosteroid therapy and airflow obstruction influence the bronchial microbiome, which is distinct from that of bronchoalveolar lavage in asthmatic airways.

BACKGROUND: The lung has a diverse microbiome that is modest in biomass. This microbiome differs in asthmatic patients compared with control subjects, but the effects of clinical characteristics on the microbial community composition and structure are not clear. OBJECTIVES: We examined whether the composition and structure of the lower airway microbiome correlated with clinical characteristics of chronic persistent asthma, including airflow obstruction, use of corticosteroid medications, and presence of airway eosinophilia. METHODS: DNA was extracted from endobronchial brushings and bronchoalveolar lavage fluid collected from 39 asthmatic patients and 19 control subjects, along with negative control samples. 16S rRNA V4 amplicon sequencing was used to compare the relative abundance of bacterial genera with clinical characteristics. RESULTS: Differential feature selection analysis revealed significant differences in microbial diversity between brush and lavage samples from asthmatic patients and control subjects. Lactobacillus, Pseudomonas, and Rickettsia species were significantly enriched in samples from asthmatic patients, whereas Prevotella, Streptococcus, and Veillonella species were enriched in brush samples from control subjects. Generalized linear models on brush samples demonstrated oral corticosteroid use as an important factor affecting the relative abundance of the taxa that were significantly enriched in asthmatic patients. In addition, bacterial α-diversity in brush samples from asthmatic patients was correlated with FEV1 and the proportion of lavage eosinophils. CONCLUSION: The diversity and composition of the bronchial airway microbiome of asthmatic patients is distinct from that of nonasthmatic control subjects and influenced by worsening airflow obstruction and corticosteroid use.

Cryptococcal eosinophilic meningitis in a patient with sarcoidosis.

A 51-year-old African-American man with underlying pulmonary, hepatic and splenic sarcoidosis, reported a 3-day history of headache, neck stiffness and photophobia. He was not using medication for chronic sarcoidosis. Physical examination was significant for nuchal rigidity. Lumbar puncture revealed marked eosinophilia in the cerebrospinal fluid, which, on further analysis, demonstrated a positive cryptococcal antigen. HIV antibody and PCR tests were negative. Bronchoscopy and fungal blood cultures were also negative. The patient was started on amphotericin B and flucytosine, with significant clinical improvement. He recovered well without any neurological sequelae and remained symptom-free at 2-week follow-up. Cryptococcal central nervous infections are uniformly fatal if left untreated. Prompt diagnosis and treatment is essential, to prevent the associated high morbidity and mortality.

Factors of Suppression of Immune Response in Patients with Pulmonary Tuberculosis and Eosinophilia.

We studied possible mechanisms of immunosuppression mediated by regulatory T cells that promotes suppression of antigen-specific immune response to Mycobacterium tuberculosis in patients with pulmonary tuberculosis and eosinophilia. It was shown that the number of CD4(+)CD25(+)Foxp3(+) regulatory T cells with immunosuppressive activity (Treg) increased in the peripheral blood of patients with disseminated destructive forms of pulmonary tuberculosis with multiple resistance of the causative agent to antituberculosis substances and eosinophilia. These changes were accompanied by imbalance in secretion of Treg-associated cytokines (in vitro) manifested in hyperproduction of TGFß and IL-10 and decreased production of IL-2.