An Allergist's Perspective

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Crianças com sibilância recorrente: estudo de função respiratória, avaliação imunológica e polimorfismos genéticos

RESUMO Nos últimos anos têm sido identificados vários factores de risco para asma brônquica em crianças com sibilância recorrente, não se encontrando clara a importância da avaliação funcional respiratória nestas crianças. De igual modo, têm sido documentados resultados contraditórios na avaliação imunológica das populações de células reguladoras bem como na expressão de polimorfismos para a asma. O objectivo deste estudo consistiu na avaliação e comparação de parâmetros de avaliação funcional respiratória, imunológica e de polimorfismos genéticos em crianças entre 8 e 20 meses de idade, com três ou mais episódios de sibilância (n=50), sem qualquer terapêutica anti-inflamatória prévia, diagnosticados por um médico, com e sem factores de risco para asma brônquica (história de asma parental ou história pessoal de eczema ou pelo menos dois dos seguintes: história pessoal de rinite alérgica, sibilância fora do contexto infeccioso e contagem de eosinófilos no sangue periférico > 4%), comparados com um grupo controlo (n=30). Nestas crianças foram efectuadas provas de função respiratória em volume corrente e em volume aumentado através de técnicas de compressão torácica, avaliação de populações celulares por citometria de fluxo, expressão de citocinas por mARN em culturas de células estimuladas com PMA (leitura às 24 horas) e com extractos de ácaros do pó doméstico (leitura ao 7º dia) e expressão de polimorfismos para alguns genes associados a asma (ADAM 33, DPP10, GPRA). Na comparação entre as crianças com sibilância recorrente em relação ao grupo controlo foram observadas reduções significativas nos Z-scores para FVC (diferença média [95% IC]: -0,7 [-1,2; -0,1], p=0,01), FEV0.5 (-1,0 [-1,5; -0,5], p=0,0001), FEF75 (-0,6 [-1,0; -0,2], p=0,0001) e FEF25-75 (-0,8 [-1,2; -0,4], p=0,0001), bem como valores significativamente mais baixos para a quantificação do número absoluto de CD4+CD25forte (-47,9 [-89,6; -6,1], p=0,03), do número absoluto e percentual de CD4+CD25+CTLA-4 (p=0,0001) e da expressão de CTLA-4 (p=0,03) e IFN- (p=0,04) nas culturas com extractos de ácaros. As crianças sibilantes com alto risco para asma tinham, em relação ao grupo sem factores de risco, Z-scores significativamente mais baixos para FVC (-0,7 [-1,4; -0,04], p=0,04) e FEF25-75 (-0,6 [-1,2; -0,1], p=0,03),2 valores significativamente inferiores do número absoluto das populações CD4+CD25+ (-118,8 [-210,0; -27,5], p=0,01) e CD4+CD25forte (-56,2 [-109,9; -2,5], p=0,04) e ainda uma expressão diminuída de IFN- (p=0,03) em culturas de células estimuladas com extractos de ácaros. Foram encontradas diferenças na expressão de polimorfismos para os genes GPRA e ADAM 33, não sendo possível tecer extrapolações pelo reduzido número de crianças em estudo. As crianças com sibilância recorrente e alto risco de asma apresentavam alterações na avaliação funcional respiratória, bem como no número absoluto de populações celulares com função reguladora e na expressão de IFN- em culturas celulares estimuladas com extractos de ácaros. Estes resultados realçam a eventual importância da avaliação das provas de função respiratória e de parâmetros imunológicos, em crianças com sibilância recorrente e alto risco clínico para asma, nos primeiros dois anos de vida, apesar da sua controversa aplicabilidade individual. O seguimento prospectivo destas crianças poderá aferir o seu valor preditivo para asma em idade escolar

Serum markers of B cell activation in pregnant women with atopic asthma

PROBLEM: As maternal atopy represents a risk factor for the development of atopy in offspring, we aimed to assess how pregnancy affects B cell activation markers in women with atopic asthma and whether they correlate with risk manifestations for allergy in newborns from mothers with atopic asthma. METHOD OF STUDY: Pregnant women with atopic asthma (AP) in the third trimester of gestation and nonpregnant women with atopic asthma (ANP) were prospectively recruited and compared to respective healthy counterparts (HP and HNP). All pregnant women were also assessed during the postpartum period until 6 weeks after delivery (HP/PP and AP/PP). Newborns were clinically evaluated at the age of 6 months. Peripheral blood samples were taken from each woman at each time point. Soluble CD23 (sCD23), B cell activating factor (BAFF), IgA, IgG, IgM, kappa (κ) and lambda (λ) free light chains (FLC) were quantified in serum samples. RESULTS: The AP group presented increased sCD23 (P <0.05) and BAFF (P <0.001) levels compared to the ANP group and even higher levels of sCD23 during the postpartum period (P <0.001). Moreover, the cut-offs of 6.74 g/L for IgG (sensitivity 90.9%, specificity 77.8%) and of 11.30 mg/L for λ FLC (sensitivity 81.8%, specificity 88.9%) in the AP group were predictive factors for the manifestation of allergy in their offspring. CONCLUSIONS: After delivery, the dynamics of sCD23 and BAFF changed significantly in the AP group. Furthermore, we found novel predictive factors for allergy manifestations in the children of these women, with potential clinical application.publishersversionpublishe

Da fisiologia à patologia

Histamine is one of the main mediators involved in immune homeostasis, presenting a myriad of functions. Four histamine receptors (HR) are currently known, being HR1 the best characterized and recognized for its association with allergic diseases pathophysiology. HR2 is known for its involvement in gastric pathology, HR3 for its neuromodulatory role and, more recently, HR4, considered to be involved also in allergic pathology, as well as in autoimmunity and cancer. There are several drugs available on the market that block H1 receptors, as well as H2 receptors. Recently, anti-H3 drugs have been described, with therapeutic potential in neurological diseases. There are several molecules in study, blocking HR4, in monotherapy or in combination with blocking HR1, with therapeutic potential in allergic disease, in some neoplasms and autoimmune pathologies.publishersversionpublishe

Correlation between hyperglycemia and glycated albumin with retinopathy of prematurity

Funding Information: The present publication was funded by Fundação Ciência e Tecnologia, IP national support through CHRC (UIDP/04923/2020).To determine the association between hyperglycemia, glycated albumin (GlyA) and retinopathy of prematurity (ROP). Prospective study of all infants under ROP screening from March 2017 to July 2019. All demographic, clinical and laboratory data were collected. Glucose was measured at birth and every 8 h for the first week and serum GlyA was evaluated at birth, 1st, 2nd and 4th weeks after birth. Reference range for GlyA was obtained. Univariate logistic regression was used to examine risk factors for ROP followed by multivariate regression. A total of 152 infants were included in the study. Median gestational age was 30 weeks and median birth weight 1240 g. Thirty-three infants (21.7%) had ROP. Hyperglycemia was present in 24 (72.7%) infants diagnosed with any ROP versus 6 (0.05%) in those without ROP. Median GlyA at birth, 1st, 2nd and 4th and respective reference ranges were 8.50% (6.00–12.65), 8.20% (5.32–11.67), 8.00% (5.32–10.00) and 7.90% (5.30–9.00) respectively. After multivariate logistic regression, hyperglycemia but not GlyA, remained a significant risk factor for ROP overpowering the other recognized risk factors (Exp (B) 28.062, 95% CI for Exp(B) 7.881–99.924 p < 0.001). In our cohort, hyperglycemia but not GlyA, remained a significant risk factor for ROP overpowering the other recognized risk factors.publishersversionpublishe

Urticária Colinérgica Associada a Hipohidrose Generalizada Adquirida: Dois Casos Clínicos e Revisão da Literatura

Cholinergic urticaria is a relatively common condition defined by itching, redness and whealing induced by exercise and passive warming. In turn, acquired idiopathic generalized anhidrosis is a rare disorder of unknown pathogenesis, characterized by an impairment in total body sweating despite exposure to heat or exercise. We report two cases of this extremely rare association of cholinergic urticaria and acquired generalized hypohidrosis, and briefly review current knowledge with regard to classification, ethiopathogenesis and therapeutic options.A urticária colinérgica é uma patologia relativamente comum definida por máculo-pápulas eritematosas e pruriginosas induzidas por aumento da temperatura corporal, passivo ou induzido por exercício físico. Pelo contrário, a anidrose generalizada idiopática adquirida é uma doença rara de patogénese desconhecida, caraterizada por um comprometimento da capacidade de sudação, apesar da exposição a calor ou exercício. Descrevem-se dois casos desta associação extremamente rara de urticária colinérgica e hipohidrose generalizada adquirida, e procede-se a uma breve revisão do conhecimento atual no que respeita à classificação, etiopatogenia e opções terapêuticas

Characteristic Immune Dynamics in COVID-19 Patients with Cardiac Dysfunction

Funding Information: Type of funding sources: Foundation—015_595935779—Foundation for Science and Technology (FCT), in collaboration with the Agency for Clinical Research and Biomedical Innovation (AICIB) opened special funding, “RESEARCH 4 COVID-19”, to R&D projects and initiatives that respond to the needs of the National Health Service (SNS) as a response to this and future pandemics in a very short time Horizon. Project: “Early recognition of cardiac injury associated with COVID-19 and clinical outcomes”.Background: We aimed to explore immune parameters in COVID-19 patients admitted to the intensive care unit (ICU) to identify distinctive features in patients with cardiac injury. Methods: A total of 30 COVID-19 patients >18 years admitted to the ICU were studied on days D1, D3 and D7 after admission. Cardiac function was assessed using speckle-tracking echocardiography (STE). Peripheral blood immunophenotyping, cardiac (pro-BNP; troponin) and inflammatory biomarkers were simultaneously evaluated. Results: Cardiac dysfunction (DYS) was detected by STE in 73% of patients: 40% left ventricle (LV) systolic dysfunction, 60% LV diastolic dysfunction, 37% right ventricle systolic dysfunction. High-sensitivity cardiac troponin (hs-cTn) was detectable in 43.3% of the patients with a median value of 13.00 ng/L. There were no significant differences between DYS and nDYS patients regarding mortality, organ dysfunction, cardiac (including hs-cTn) or inflammatory biomarkers. Patients with DYS showed persistently lower lymphocyte counts (median 896 [661–1837] cells/µL vs. 2141 [924–3306] cells/µL, p = 0.058), activated CD3 (median 85 [66–170] cells/µL vs. 186 [142–259] cells/µL, p = 0.047) and CD4 T cells (median 33 [28–40] cells/µL vs. 63 [48–79] cells/µL, p = 0.005), and higher effector memory T cells (TEM) at baseline (CD4%: 10.9 [6.4–19.2] vs. 5.9 [4.2–12.8], p = 0.025; CD8%: 15.7 [7.9–22.8] vs. 8.1 [7.7–13.7], p = 0.035; CD8 counts: 40 cells/µL [17–61] vs. 10 cells/µL [7–17], p = 0.011) than patients without cardiac dysfunction. Conclusion: Our study suggests an association between the immunological trait and cardiac dysfunction in severe COVID-19 patients.publishersversionpublishe

Cytokine profiles in the peripheral blood and aqueous humor of patients with herpetic uveitis

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Association between EBV serological patterns and lymphocytic profile of SjS patients support a virally triggered autoimmune epithelitis

Sjögren's syndrome (SjS) is characterized by lymphocytic infiltration of exocrine glands, i.e. autoimmune epithelitis. Lymphocytes are central in SjS pathogenesis, with B-cell hyperactivity mediated by T-cells. B-cells are main targets of Epstein-Barr virus (EBV) infection, a frequently-suggested trigger for SjS. We aimed to evaluate how the EBV infection modulates B and T-cell subsets in SjS, including as controls Rheumatoid arthritis patients (RA) and healthy participants (HC). SjS patients presented decreased CXCR5+T-cells, although IL21-secreting Tfh and Tfc cells were increased. Tfc were positively correlated with ESSDAI scores, suggesting their relevant role in SjS pathogenesis. As previously described, SjS patients showed expanded circulating naïve B-cell compartments. SjS patients had a higher incidence of EBV-EA-D-IgG+ antibodies, characteristic of recent EBV-infection/reactivation. SjS patients with past infection or recent infection/reactivation showed increased CXCR3+Th1 and CXCR3+Tfh1 cells compared to those without active infection. SjS patients with a recent infection/reactivation profile presented increased transitional B-cells compared to patients with past infection and increased plasmablasts, compared to those without infection. Our results suggest EBV-infection contributes to B and T-cell differentiation towards the effector phenotypes typical of SjS. Local lymphocyte activation at ectopic germinal centres, mediated by Tfh and Tfc, can be EBV-driven, perpetuating autoimmune epithelitis, which leads to gland destruction in SjS.publishersversionpublishe

Novel genomic approach to decode syphilis

A sífilis é uma doença sexualmente transmissível causada pela bactéria Treponema pallidum e constitui um problema de saúde pública mundial, em parte devido à ausência de uma vacina para prevenção da sua transmissão. A investigação desta doença tem sido atrasada pela incapacidade histórica de cultivar T. pallidum in vitro, dificultando por exemplo o desenvolvimento de estudos genómicos. De facto, há uma grande lacuna no conhecimento da epidemiologia molecular deste agente patogénico, assim como da base molecular que medeia a patogénese da sífilis. No estudo aqui apresentado, foi possível implementar uma abordagem inovadora para capturar o genoma de T. pallidum no contexto de infeção humana, evitando-se, assim, a necessidade da cultura da bactéria em modelo animal. Esta estratégia permitiu estudar, pela primeira vez, como é que este agente patogénico vai alterando o seu genoma para se adaptar e sobreviver como agente infecioso humano. Nomeadamente permitiu descodificar os principais mecanismos genéticos pelos quais a bactéria T. pallidum evade o sistema imunitário e se adapta ao Homem nesta complexa e multifásica doença. A aplicação desta estratégia inovadora de monitorização da interação Homem-bactéria poderá ser importante para o desenvolvimento de novas medidas profiláticas e/ou terapêuticas. Acresce que esta abordagem constitui também um ponto de viragem para o aperfeiçoamento de metodologias de diagnóstico e de epidemiologia molecular, o que permitirá aumentar o conhecimento da distribuição geográfica, das vias de transmissão e das propriedades de virulência deste agente patogénico para bem da saúde pública.Syphilis, a sexually transmitted disease caused by the bacterium T. pallidum, remains a global problem with an estimated 6 million people infected each year, which is in part attributed to the absence of a vaccine to prevent infection and transmission. Despite its tremendous public health impact, research in syphilis has been considerable hampered due to the historical inability to culture T. pallidum in vitro, which has hampered, for instance, the acquisition of consistent genomic data. As such, there is a strong lack of knowledge on the molecular epidemiology of this important human pathogen as well as on the molecular mechanisms underlying syphilis pathogenesis. In the work presented here, we have bypassed the culture bottleneck by means of a targeted strategy never applied to uncultivable bacterial human pathogens to directly capture whole-genome T. pallidum data in the contex t of human infection. This strategy allowed, for the first time, to understand how this pathogen shapes its genome towards adaptation and sur vival during syphilis. While this work demonstrates the exceptional power of monitoring the pathogen adaptability during human infection, it also provides critical data that may guide the development of novel treatments and prophylactic measures, such as a vaccine. In other perspective, it is anticipated that the implemented methodological approach constitutes a disruptive step towards the improvement of the current diagnostics and typing methodologies, which will enhance the knowledge on the geographic distribution of strains, its transmissibility and propensity to cause disease.Este estudo foi financiado pela Fundação para a Ciência e Tecnologia (EXPL/BIA-MIC/0309/2013).info:eu-repo/semantics/publishedVersio