Identification of factors impairing exercise capacity after severe COVID-19 pulmonary infection: a 3-month follow-up of prospective COVulnerability cohort.

BACKGROUND: Patient hospitalized for coronavirus disease 2019 (COVID-19) pulmonary infection can have sequelae such as impaired exercise capacity. We aimed to determine the frequency of long-term exercise capacity limitation in survivors of severe COVID-19 pulmonary infection and the factors associated with this limitation. METHODS: Patients with severe COVID-19 pulmonary infection were enrolled 3 months after hospital discharge in COVulnerability, a prospective cohort. They underwent cardiopulmonary exercise testing, pulmonary function test, echocardiography, and skeletal muscle mass evaluation. RESULTS: Among 105 patients included, 35% had a reduced exercise capacity (VO2peak < 80% of predicted). Compared to patients with a normal exercise capacity, patients with reduced exercise capacity were more often men (89.2% vs. 67.6%, p = 0.015), with diabetes (45.9% vs. 17.6%, p = 0.002) and renal dysfunction (21.6% vs. 17.6%, p = 0.006), but did not differ in terms of initial acute disease severity. An altered exercise capacity was associated with an impaired respiratory function as assessed by a decrease in forced vital capacity (p < 0.0001), FEV1 (p < 0.0001), total lung capacity (p < 0.0001) and DLCO (p = 0.015). Moreover, we uncovered a decrease of muscular mass index and grip test in the reduced exercise capacity group (p = 0.001 and p = 0.047 respectively), whilst 38.9% of patients with low exercise capacity had a sarcopenia, compared to 10.9% in those with normal exercise capacity (p = 0.001). Myocardial function was normal with similar systolic and diastolic parameters between groups whilst reduced exercise capacity was associated with a slightly shorter pulmonary acceleration time, despite no pulmonary hypertension. CONCLUSION: Three months after a severe COVID-19 pulmonary infection, more than one third of patients had an impairment of exercise capacity which was associated with a reduced pulmonary function, a reduced skeletal muscle mass and function but without any significant impairment in cardiac function.

Application of Precise Positioning for Sputum Expectoration in ICU Patients with Pulmonary Infection.

OBJECTIVE: To determine the application value of precise positioning for sputum expectoration in intensive care unit (ICU) hospitalized patients with pulmonary infection (PI). METHODS: A total of 183 patients with PI treated in the ICUs of Shengjing Hospital of China Medical University from June 2019 to June 2020 were divided into a control group (n = 91) and an observation group (n = 92), all of whom received conventional drug therapy. The control group was given routine nursing intervention, based on which, the observation group was supplemented with precise positioning for sputum expectoration. The 24-hour sputum volume, respiratory rate (RR), blood gas analysis indexes, inflammatory indicators, Clinical Pulmonary Infection Score (CPIS), Modified Medical Research Council (mMRC) dyspnea scale score, and quality of life (36-Item Short-Form Health Survey, SF-36) were observed in both arms before and after intervention. The incidence of adverse reactions was counted. RESULTS: The observation group showed better mMRC scores than the control group (P < 0.05). Compared with the control group, the sputum volume, RR, and CPIS score were lower, and the SF-36 score was higher in the observation group 7 days after intervention (P < 0.05). After intervention, the oxygen saturation (SaO2) and partial pressure of oxygen (PaO2) were higher, while the carbon dioxide partial pressure (PaCO2), C-reactive protein (CRP), procalcitonin (PCT), and leukocyte count were lower in the observation group compared with the control group (P < 0.05). There was no significant difference in the incidence of complications between the two arms (P > 0.05). CONCLUSION: The application of precise positioning for sputum expectoration in nursing intervention of ICU patients with PI can alleviate the severity of PI and dyspnea, reduce inflammatory reaction, and improve the quality of life of patients.

LAIR-1 acts as an immune checkpoint on activated ILC2s and regulates the induction of airway hyperreactivity.

BACKGROUND: Type 2 innate lymphoid cells (ILC2s) are relevant players in type 2 asthma. They initiate eosinophil infiltration and airway hyperreactivity (AHR) through cytokine secretion. Leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) is an inhibitory receptor considered to be an immune checkpoint in different inflammatory diseases. OBJECTIVE: Our aim here was to investigate the expression of LAIR-1 and assess its role in human and murine ILC2s. METHODS: Wild-type and LAIR-1 knockout mice were intranasally challenged with IL-33, and pulmonary ILC2s were sorted to perform an ex vivo comparative study based on RNA sequencing and flow cytometry. We next studied the impact of LAIR-1 deficiency on AHR and lung inflammation by using knockout mice and adoptive transfer experiments in Rag2-/-Il2rg-/- mice. Knockdown antisense strategies and humanized mice were used to assess the role of LAIR-1 in human ILC2s. RESULTS: We have demonstrated that LAIR-1 is inducible on activated ILC2s and downregulates cytokine secretion and effector function. LAIR-1 signaling in ILC2s was mediated via inhibitory pathways, including SHP1/PI3K/AKT, and LAIR-1 deficiency led to exacerbated ILC2-dependent AHR in IL-33 and Alternaria alternata models. In adoptive transfer experiments, we confirmed the LAIR-1-mediated regulation of ILC2s in vivo. Interestingly, LAIR-1 was expressed and inducible in human ILC2s, and knockdown approaches of Lair1 resulted in higher cytokine production. Finally, engagement of LAIR-1 by physiologic ligand C1q significantly reduced ILC2-dependent AHR in a humanized ILC2 murine model. CONCLUSION: Our results unravel a novel regulatory axis in ILC2s with the capacity to reduce allergic AHR and lung inflammation.

Comparison of the Epidemiological and Clinical Characteristics of Hospitalized Children With Pneumonia Caused by SARS-CoV-2, Influenza A, and Human Adenoviruses: A Case-Control Study.

Background. This case-control study aims to investigate the clinical characteristics in pediatric patients with pneumonia infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza A, and human adenoviruses (HAdVs). Methods. Hospitalized pediatric patients with pneumonia infected with SARS-CoV-2 at Wuhan Children's Hospital and pneumonia infected with influenza A, and HAdVs at Qilu Children's Hospital were compared. Clinical manifestations, laboratory examinations, and imaging characteristics were analyzed. Results. The proportions of hyperpyrexia (54.3%, 33.9%), cough (100%, 99.2%), wheezing (45.7%, 53.7%), diarrhea (31.4%, 14.9%), and fever (100%, 75.2%) in patients with influenza A and HAdVs were higher than those of patients with SARS-CoV-2 (9.4%, P < .001; 48.5%, P < .001; 0%, P < .001; 8.8%, P = .002; 41.5%, P < .001; respectively). Laboratory examinations revealed the proportions of leukocytosis (37.1%, 52.9%), abnormal rates of neutrophils (40%, 40.5%), and lymphocytosis (42.9%, 65.3%) in influenza A and HAdV pneumonia groups were significantly higher than coronavirus disease 2019 (COVID-19) group (0%, P < .001; 0%, P < .001; 0%, P < .001; respectively). The proportion of elevated procalcitonin (5.7%, 14%) in patients with influenza A and HAdVs was significantly lower than those in patients with SARS-CoV-2 (64%, P < .001). In chest computed tomography, ground-glass opacities near the pleura were more common in patients with COVID-19 than those in patients with influenza A and HAdVs (32.7% vs 0% vs 0%, P < .001). Conclusion. Fever, cough, and wheezing are more common in the influenza A and HAdVs groups, whereas procalcitonin and computed tomography findings are likely to be pronounced in COVID-19 pneumonia. It provides a variety of methods except polymerase chain reaction for differentiating COVID-19 pneumonia from influenza A and HAdVs pneumonia.

Clinical outcomes in patients with COPD hospitalized with SARS-CoV-2 versus non- SARS-CoV-2 community-acquired pneumonia.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) have poor outcomes in the setting of community-acquired pneumonia (CAP) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The primary objective is to compare outcomes of SARS-CoV-2 CAP and non-SARS-CoV-2 CAP in patients with COPD. The secondary objective is to compare outcomes of SARS-CoV-2 CAP with and without COPD. METHODS: In this analysis of two observational studies, three cohorts were analyzed: (1) patients with COPD and SARS-CoV-2 CAP; (2) patients with COPD and non-SARS-CoV-2 CAP; and (3) patients with SARS-CoV-2 CAP without COPD. Outcomes included length of stay, ICU admission, cardiac events, and in-hospital mortality. RESULTS: Ninety-six patients with COPD and SARS-CoV-2 CAP were compared to 1129 patients with COPD and non-SARS-CoV-2 CAP. 536 patients without COPD and SARS-CoV-2 CAP were analyzed for the secondary objective. Patients with COPD and SARS-CoV-2 CAP had longer hospital stay (15 vs 5 days, p < 0.001), 4.98 higher odds of cardiac events (95% CI: 3.74-6.69), and 7.31 higher odds of death (95% CI: 5.36-10.12) in comparison to patients with COPD and non-SARS-CoV-2 CAP. In patients with SARS-CoV-2 CAP, presence of COPD was associated with 1.74 (95% CI: 1.39-2.19) higher odds of ICU admission and 1.47 (95% CI: 1.05-2.05) higher odds of death. CONCLUSION: In patients with COPD and CAP, presence of SARS-CoV-2 as an etiologic agent is associated with more cardiovascular events, longer hospital stay, and seven-fold increase in mortality. In patients with SARS-CoV-2 CAP, presence of COPD is associated with 1.5-fold increase in mortality.

Community-Acquired Pneumonia in Children: Rapid Evidence Review.

In the United States, pneumonia is the most common cause of hospitalization in children. Even in hospitalized children, community-acquired pneumonia is most likely of viral etiology, with respiratory syncytial virus being the most common pathogen, especially in children younger than two years. Typical presenting signs and symptoms include tachypnea, cough, fever, and anorexia. Findings most strongly associated with an infiltrate on chest radiography in children with clinically suspected pneumonia are grunting, history of fever, retractions, crackles, tachypnea, and the overall clinical impression. Chest radiography should be ordered if the diagnosis is uncertain, if patients have hypoxemia or significant respiratory distress, or if patients fail to show clinical improvement within 48 to 72 hours after initiation of antibiotic therapy. Outpatient management of community-acquired pneumonia is appropriate in patients without respiratory distress who can tolerate oral antibiotics. Amoxicillin is the first-line antibiotic with coverage for Streptococcus pneumoniae for school-aged children, and treatment should not exceed seven days. Patients requiring hospitalization and empiric parenteral therapy should be transitioned to oral antibiotics once they are clinically improving and able to tolerate oral intake. Childhood and maternal immunizations against S. pneumoniae, Haemophilus influenzae type b, Bordetella pertussis, and influenza virus are the key to prevention.

Combined exercise training improved exercise capacity and lung inflammation in rats with hepatopulmonary syndrome.

AIM: Physical exercise training attenuates pulmonary inflammation, but its effects on impaired respiratory function caused by hepatopulmonary syndrome (HPS) have not been evaluated. We determined if the combination of moderate intensity aerobic and resistance training during HPS development modifies exercise capacity, respiratory system mechanics, and lung inflammation responses. MAIN METHODS: Wistar rats were randomly divided into sham, HPS, and HPS + combined exercise training groups. Fifteen days after HPS induction, a moderate intensity aerobic plus resistance exercise training protocol was performed five times a week for 5 weeks on alternate days. Exercise capacity, respiratory system mechanics, lung inflammation, pulmonary morphology, and immunohistochemistry were evaluated. KEY FINDINGS: Overall, our findings indicated that combined exercise training efficiently increased the maximal running and resistance capacity of HPS animals. The training regimen reduced the expression of P2X7 in parenchymal leukocytes (P < 0.01), partially restored the expression of interleukin-10 in airway epithelium (P < 0.01), and increased the expression of TFPI in the airway epithelium (P < 0.01) as well as reduced its expression in parenchymal leukocytes (P < 0.01). However, exercise training did not attenuate HPS-induced respiratory mechanical derangements or lung tissue remodeling. SIGNIFICANCE: Combined exercise training can elicit adaptation with regard to both maximal running capacity and maximum strength and modify the expression of P2X7 and TFPI in parenchymal leukocytes and that of IL-10 in airway epithelium.

Based on improved deep convolutional neural network model pneumonia image classification.

Pneumonia remains the leading infectious cause of death in children under the age of five, killing about 700,000 children each year and affecting 7% of the world's population. X-ray images of lung become the key to the diagnosis of this disease, skilled doctors in the diagnosis of a certain degree of subjectivity, if the use of computer-aided medical diagnosis to automatically detect lung abnormalities, will improve the accuracy of diagnosis. This research aims to introduce a deep learning technology based on the combination of Xception neural network and long-term short-term memory (LSTM), which can realize automatic diagnosis of patients with pneumonia in X-ray images. First, the model uses the Xception network to extract the deep features of the data, passes the extracted features to the LSTM, and then the LSTM detects the extracted features, and finally selects the most needed features. Secondly, in the training set samples, the traditional cross-entropy loss cannot more balance the mismatch between categories. Therefore, this research combines Pearson's feature selection ideas, fusion of the correlation between the two loss functions, and optimizes the problem. The experimental results show that the accuracy rate of this paper is 96%, the receiver operator characteristic curve accuracy rate is 99%, the precision rate is 98%, the recall rate is 91%, and the F1 score accuracy rate is 94%. Compared with the existing technical methods, the research has achieved expected results on the currently available datasets. And assist doctors to provide higher reliability in the classification task of childhood pneumonia.

Ding Chuan Tang Attenuates Airway Inflammation and Eosinophil Infiltration in Ovalbumin-Sensitized Asthmatic Mice.

Asthma is a T helper 2 (Th2) cell-associated chronic inflammatory diseases characterized with airway obstruction, increased mucus production, and eosinophil infiltration. Conventional medications for asthma treatment cannot fully control the symptoms, and potential side effects are also the concerns. Thus, complement or alternative medicine (CAM) became a new option for asthma management. Ding Chuan Tang (DCT) is a traditional Chinese herbal decoction applied mainly for patients with coughing, wheezing, chest tightness, and asthma. Previously, DCT has been proved to improve children airway hyperresponsiveness (AHR) in a randomized and double-blind clinical trial. However, the mechanisms of how DCT alleviates AHR remain unclear. Since asthmatic features such as eosinophil infiltration, IgE production, and mucus accumulation are relative with Th2 responses, we hypothesized that DCT may attenuate asthma symptoms through regulating Th2 cells. Ovalbumin (OVA) was used as a stimulant to sensitize BALB/c mice to establish an asthmatic model. AHR was detected one day before sacrifice. BALF and serum were collected for immune cell counting and antibody analysis. Splenocytes were cultured with OVA in order to determine Th2 cytokine production. Lung tissues were collected for histological and gene expression analyses. Our data reveal that DCT can attenuate AHR and eosinophil accumulation in the 30-day sensitization asthmatic model. Histological results demonstrated that DCT can reduce cell infiltration and mucus production in peribronchial and perivascular site. In OVA-stimulated splenocyte cultures, a significant reduction of IL-5 and IL-13 in DCT-treated mice suggests that DCT may alleviate Th2 responses. In conclusion, the current study demonstrates that DCT has the potential to suppress allergic responses through the reduction of mucus production, eosinophil infiltration, and Th2 activity in asthma.

Anisakis pegreffii Extract Induces Airway Inflammation with Airway Remodeling in a Murine Model System.

Exposure of the respiratory system to the Anisakis pegreffii L3 crude extract (AE) induces airway inflammation; however, the mechanism underlying this inflammatory response remains unknown. AE contains allergens that promote allergic inflammation; exposure to AE may potentially lead to asthma. In this study, we aimed to establish a murine model to assess the effects of AE on characteristic features of chronic asthma, including airway hypersensitivity (AHR), airway inflammation, and airway remodeling. Mice were sensitized for five consecutive days each week for 4 weeks. AHR, lung inflammation, and airway remodeling were evaluated 24 h after the last exposure. Lung inflammation and airway remodeling were assessed from the bronchoalveolar lavage fluid (BALF). To confirm the immune response in the lungs, changes in gene expression in the lung tissue were assessed with reverse transcription-quantitative PCR. The levels of IgE, IgG1, and IgG2a in blood and cytokine levels in the BALF, splenocyte, and lung lymph node (LLN) culture supernatant were measured with ELISA. An increase in AHR was prominently observed in AE-exposed mice. Epithelial proliferation and infiltration of inflammatory cells were observed in the BALF and lung tissue sections. Collagen deposition was detected in lung tissues. AE exposure increased IL-4, IL-5, and IL-13 expression in the lung, as well as the levels of antibodies specific to AE. IL-4, IL-5, and IL-13 were upregulated only in LLN. These findings indicate that an increase in IL-4+ CD4+ T cells in the LLN and splenocyte resulted in increased Th2 response to AE exposure. Exposure of the respiratory system to AE resulted in an increased allergen-induced Th2 inflammatory response and AHR through accumulation of inflammatory and IL-4+ CD4+ T cells and collagen deposition. It was confirmed that A. pegreffii plays an essential role in causing asthma in mouse models and has the potential to cause similar effects in humans.

The Short-Chain Fatty Acid Butyrate Attenuates Pulmonary Vascular Remodeling and Inflammation in Hypoxia-Induced Pulmonary Hypertension.

Pulmonary hypertension (PH) is a progressive cardiovascular disorder in which local vascular inflammation leads to increased pulmonary vascular remodeling and ultimately to right heart failure. The HDAC inhibitor butyrate, a product of microbial fermentation, is protective in inflammatory intestinal diseases, but little is known regarding its effect on extraintestinal diseases, such as PH. In this study, we tested the hypothesis that butyrate is protective in a Sprague-Dawley (SD) rat model of hypoxic PH. Treatment with butyrate (220 mg/kg intake) prevented hypoxia-induced right ventricular hypertrophy (RVH), hypoxia-induced increases in right ventricular systolic pressure (RVSP), pulmonary vascular remodeling, and permeability. A reversal effect of butyrate (2200 mg/kg intake) was observed on elevated RVH. Butyrate treatment also increased the acetylation of histone H3, 25-34 kDa, and 34-50 kDa proteins in the total lung lysates of butyrate-treated animals. In addition, butyrate decreased hypoxia-induced accumulation of alveolar (mostly CD68+) and interstitial (CD68+ and CD163+) lung macrophages. Analysis of cytokine profiles in lung tissue lysates showed a hypoxia-induced upregulation of TIMP-1, CINC-1, and Fractalkine and downregulation of soluble ICAM (sICAM). The expression of Fractalkine and VEGFα, but not CINC-1, TIMP-1, and sICAM was downregulated by butyrate. In rat microvascular endothelial cells (RMVEC), butyrate (1 mM, 2 and 24 h) exhibited a protective effect against TNFα- and LPS-induced barrier disruption. Butyrate (1 mM, 24 h) also upregulated tight junctional proteins (occludin, cingulin, claudin-1) and increased the acetylation of histone H3 but not α-tubulin. These findings provide evidence of the protective effect of butyrate on hypoxic PH and suggest its potential use as a complementary treatment for PH and other cardiovascular diseases.

Pulmonary function and six-minute-walk test in patients after recovery from COVID-19: A prospective cohort study.

OBJECTIVES: To study abnormality of spirometry, six-minute walk distance, and chest radiograph among patients recovered from Coronavirus Disease 2019 (COVID-19). METHODS AND STUDY DESIGN: A prospective cohort study was conducted in 87 COVID-19 confirmed cases who recovered and discharged from a medical school hospital in Thailand. At the follow-up visit on day 60 after onset of symptoms, patients underwent an evaluation by spirometry (FVC, FEV1, FEV1/FVC, FEF25-75, and PEF), a six-minute-walk test (6MWT), and a chest radiograph. RESULTS: There were 35 men and 52 women, with a mean age of 39.6±11.8 years and the mean body mass index (BMI) was 23.8±4.3 kg/m2. Of all, 45 cases had mild symptoms; 35 had non-severe pneumonia, and 7 had severe pneumonia. Abnormality in spirometry was observed in 15 cases (17.2%), with 8% of restrictive defect and 9.2% of obstructive defect. Among the patients with an abnormal spirometry, the majority of the cases were in the severe pneumonia group (71.4%), compared with 15.6% in the non-severe pneumonia group, and 10.2% in the mild symptom group (p = 0.001). The mean six-minute-walk distance (6MWD) in the mild symptom and non-severe pneumonia groups was 538±56.8 and 527.5±53.5 meters, respectively. Although the severe pneumonia group tended to have a shorter mean 6-min walking distance, but this was not statistically significant (p = 0.118). Twelve patients (13.8%) had abnormal chest radiographs that showed residual fibrosis. This abnormality was more common in the severe pneumonia group (85.7%) and in others (7.5%) (p<0.001). CONCLUSIONS: Abnormal spirometry was noted in 17.2% of COVID-19 survivors with both restrictive and obstructive defects. Severe COVID-19 pneumonia patients had higher prevalence rates of abnormal spirometry and residual fibrosis on the chest radiographs when compared to patients in the mild symptom and non-severe pneumonia groups.

Uso del péptido CIGB-258 en un paciente pediátrico con neumonía grave por SARS-CoV-2 / Use of CIGB-258 peptide in a pediatric patient with severe pneumonia due to SARS-CoV-2

Introducción: La presentación clínica de la enfermedad provocada por el SARS-CoV-2 es heterogénea. Los pacientes pueden ser asintomáticos o tener una enfermedad leve de las vías respiratorias superiores o desarrollar una neumonía grave que puede progresar al síndrome de dificultad respiratoria aguda y provocar la muerte. La fisiopatología de las formas graves de la enfermedad se caracteriza por una marcada hiperinflamación. Las terapias que modulan la respuesta inmunitaria pueden ser cruciales para tratar y prevenir este estado. El péptido CIGB-258, marca comercial Jusvinza, es una opción terapéutica para este propósito, por sus propiedades inmunomoduladoras. Objetivo: Describir la evolución clínica de un paciente pediátrico con neumonía grave por SARS-CoV-2, tratado con el péptido CIGB-258 Presentación del caso: Adolescente de 12 años con epilepsia refractaria, parálisis cerebral infantil y antecedentes epidemiológicos de contacto con paciente positivo a test confirmatorio de reacción en cadena de la polimerasa con transcriptasa inversa para SARS-CoV-2 que ocho días después del contacto, muestra evidencias clínicas, radiográficas y de laboratorio de neumonía grave por COVID-19. Dentro del protocolo terapéutico, recibió tratamiento con el péptido inmunomodulador CIGB-258, con una evolución favorable y egreso hospitalario. Conclusiones: El uso del péptido CIGB-258 en el tratamiento de la neumonía grave por COVID-19 en pediatría, podría contribuir a evitar la progresión hacia las etapas críticas de la enfermedad(AU)

Introduction: The clinical presentation of the disease caused by SARS-CoV-2 is heterogeneous. Patients may be asymptomatic or have mild upper respiratory tract disease, or develop severe pneumonia that can progress to acute respiratory distress syndrome and lead to death. The pathophysiology of severe forms of the disease is characterized by a marked hyperinflammation. Therapies that modulate the immune response can be crucial in treating and preventing this state. The CIGB-258 peptide, brand name Jusvinza, is a therapeutic option for this purpose, due to its immunomodulatory properties. Objective: Describe the clinical evolution of a pediatric patient with severe pneumonia due to SARS-CoV-2, and treated with the CIGB-258 peptide. Case Presentation: A 12-year-old adolescent with refractory epilepsy, infantile cerebral palsy, and an epidemiological history of contact with a patient positive to PCR confirmatory test for SARS-CoV-2 who, eight days after contact, shows clinical, radiographic, and laboratory evidence of severe pneumonia due to COVID-19. Within the therapeutic protocol, he received treatment with CIGB-258 immunomodulatory peptide, with a favorable evolution and hospital discharge. Conclusions: The use of CIGB-258 peptide in the treatment of severe pneumonia due to COVID-19 in pediatrics could contribute to prevent progression to the critical stages of the disease(AU)

Serum Micronutrients as related to Childhood Pneumonia Severity and Outcome in a Nigerian Health Facility.

INTRODUCTION: Micronutrients are essential minerals and vitamins needed for optimal health. There are however conflicting reports about the roles of micronutrients in severity and outcomes of childhood pneumonia. This study aims to determine the socio-demographic and serum micronutrients - Zinc (Zn), Selenium (Se), Vitamins (Vit) A, C and E status of Nigerian children with or without pneumonia and relate these to pneumonia severity and outcome. METHODOLOGY: Children aged two months to 14 years with severe and non-severe pneumonia were recruited with age and sex-matched controls over 12 month period in a Nigerian tertiary health centre. Relevant history and serum micronutrients were compared in the two groups and related to pneumonia severity and length of hospitalisation (LOH). RESULTS: One hundred and forty-four children (72 for each group) were recruited with median (IQR) age 1.6 (0.6 - 4.0) years and fifty-six (38.8%) had severe pneumonia. Pneumonia incidence was associated with undernutrition, inappropriate immunisation and Zn deficiency (p < 0.05). Hypovitaminosis A [60.8(22.2)µg/dl vs. 89.5(34.7)µg/dl; p < 0.001], low serum Zn [71.6(32.5)µg/dl vs. 92.6(24.6)µg/dl; p=0.019] and indoor air pollution (IAP) were associated with pneumonia severity. However, only IAP (OR = 4.529; 95%CI 1.187-17.284; p=0.027) and Zn deficiency (OR=6.144; 95%CI 1.157-32.617; p=0.033) independently predicted severe pneumonia. No significant correlation between serum micronutrients and LOH. CONCLUSIONS: Exposure to IAP and low serum micronutrients particularly Zn and Vit A were associated with pneumonia incidence and severity in Nigerian children. Routine micronutrient supplementation may assist to reduce the burden of childhood pneumonia in developing countries.

Heteromeric TRP Channels in Lung Inflammation.

Activation of Transient Receptor Potential (TRP) channels can disrupt endothelial barrier function, as their mediated Ca2+ influx activates the CaM (calmodulin)/MLCK (myosin light chain kinase)-signaling pathway, and thereby rearranges the cytoskeleton, increases endothelial permeability and thus can facilitate activation of inflammatory cells and formation of pulmonary edema. Interestingly, TRP channel subunits can build heterotetramers, whereas heteromeric TRPC1/4, TRPC3/6 and TRPV1/4 are expressed in the lung endothelium and could be targeted as a protective strategy to reduce endothelial permeability in pulmonary inflammation. An update on TRP heteromers and their role in lung inflammation will be provided with this review.

Long-term endogenous acetylcholine deficiency potentiates pulmonary inflammation in a murine model of elastase-induced emphysema.

Acetylcholine (ACh), the neurotransmitter of the cholinergic system, regulates inflammation in several diseases including pulmonary diseases. ACh is also involved in a non-neuronal mechanism that modulates the innate immune response. Because inflammation and release of pro-inflammatory cytokines are involved in pulmonary emphysema, we hypothesized that vesicular acetylcholine transport protein (VAChT) deficiency, which leads to reduction in ACh release, can modulate lung inflammation in an experimental model of emphysema. Mice with genetical reduced expression of VAChT (VAChT KDHOM 70%) and wild-type mice (WT) received nasal instillation of 50 uL of porcine pancreatic elastase (PPE) or saline on day 0. Twenty-eight days after, animals were evaluated. Elastase instilled VAChT KDHOM mice presented an increase in macrophages, lymphocytes, and neutrophils in bronchoalveolar lavage fluid and MAC2-positive macrophages in lung tissue and peribronchovascular area that was comparable to that observed in WT mice. Conversely, elastase instilled VAChT KDHOM mice showed significantly larger number of NF-κB-positive cells and isoprostane staining in the peribronchovascular area when compared to elastase-instilled WT-mice. Moreover, elastase-instilled VAChT-deficient mice showed increased MCP-1 levels in the lungs. Other cytokines, extracellular matrix remodeling, alveolar enlargement, and lung function were not worse in elastase-instilled VAChT deficiency than in elastase-instilled WT-controls. These data suggest that decreased VAChT expression may contribute to the pathogenesis of emphysema, at least in part, through NF-κB activation, MCP-1, and oxidative stress pathways. This study highlights novel pathways involved in lung inflammation that may contribute to the development of chronic obstrutive lung disease (COPD) in cholinergic deficient individuals such as Alzheimer's disease patients.

Inhalation of particulate matter containing free radicals leads to decreased vascular responsiveness associated with an altered pulmonary function.

Airborne particulate matter (PM) is associated with an increased risk for cardiovascular diseases. Although the goal of thermal remediation is to eliminate organic wastes through combustion, when incomplete combustion occurs, organics chemisorb to transition metals to generate PM-containing environmentally persistent free radicals (EPFRs). Similar EPFR species have been detected in PM found in diesel and gasoline exhaust, woodsmoke, and urban air. Prior in vivo studies demonstrated that EPFRs reduce cardiac function secondary to elevations in pulmonary arterial pressures. In vitro studies showed that EPFRs increase ROS and cytokines in pulmonary epithelial cells. We thus hypothesized that EPFR inhalation would promote lung inflammation and oxidative stress, leading to systemic inflammation, vascular endothelial injury, and a decline in vascular function. Mice were exposed to EPFRs for either 4 h or for 4 h/day for 10 days and lung and vascular function were assessed. After a 4-h exposure, plasma nitric oxide (NO) was reduced while endothelin-1 (ET-1) was increased, however lung function was not altered. After 10 day, plasma NO and ET-1 levels were again altered and lung tidal volume was reduced. These time course studies suggested the vasculature may be an early target of injury. To test this hypothesis, an intermediate time point of 3 days was selected. Though the mice exhibited no marked inflammation in either the lung or the blood, we did note significantly reduced endothelial function concurrent with a reduction in lung tidal volume and an elevation in annexin V protein levels in the lung. Although vascular dysfunction was not dependent upon inflammation, it may be associated with an injury at the air-blood interface. Gene expression analysis suggested roles for oxidative stress and aryl hydrocarbon receptor (Ahr) signaling. Studies probing the relationship between pulmonary oxidative stress and AhR signaling at the air-blood interface with vascular dysfunction seem warranted.NEW & NOTEWORTHY Particulate matter (PM) resulting from the combustion of organic matter is known to contribute to cardiopulmonary disease. Despite hypotheses that cardiovascular dysfunction occurring after PM exposures is secondary to lung or systemic inflammation, these studies investigating exposures to PM-containing environmentally persistent free radicals (EPFRs) demonstrate that cardiovascular dysfunction precedes pulmonary inflammation. The cardiopulmonary health consequences of EPFRs have yet to be thoroughly evaluated, especially in healthy, adult mice. Our data suggest the vasculature as a direct target of PM exposure, and our studies aimed to elucidate the mechanisms contributing to EPFR-induced vascular dysfunction.

Effect of Immune-Related Adverse Events and Pneumonitis on Prognosis in Advanced Non-Small Cell Lung Cancer: A Comprehensive Systematic Review and Meta-analysis.

OBJECTIVE: The correlation between immune-related adverse events (irAEs) and prognosis remains controversial in advanced non-small cell lung cancer (NSCLC). The aim of this study was to systematically evaluate the effect of irAEs, especially checkpoint inhibitor pneumonitis (CIP), on the survival and treatment response in advanced NSCLC. METHODS: The primary outcomes were overall survival (OS) and objective response rate (ORR). Databases were searched for relevant studies, and meta-analysis was conducted with RevMan. RESULTS: A total of 51 studies involving 12,600 participants were included. The development of irAEs had an advantageous effect on OS and ORR in advanced NSCLC (OS: hazard ratio [HR], 0.56 [95% confidence interval [CI] 0.46 to 0.67]; ORR: odds ratio [OR], 3.13 [2.41 to 4.06]). The occurrence of endocrine and skin irAEs had advantageous effects on both OS and ORR (endocrine OS, HR, 0.47 [-0.37 to 0.59]; endocrine ORR: OR, 1.90 [1.27 to 2.84]; skin OS: HR, 0.48 [0.38 to 0.61]; skin ORR: OR, 4.30 [2.68 to 6.91]). Severe-grade irAEs resulted in shorter OS than low-grade irAEs (HR, 1.49 [1.06, 2.09]), and multiple irAEs resulted in better ORR compared with 1 irAE (OR, 2.04 [1.41 to 2.94]). The occurrence of CIP had no significant effect on OS (HR, 1.14 [0.70 to 1.86]), but it was associated with better ORR (OR, 2.12 [1.06 to 4.25]). Severe-grade CIP had no effect on OS or ORR, but CIP leading to treatment discontinuation resulted in shorter OS (HR, 2.35 [1.17 to 4.72]). CONCLUSION: The development of irAEs had advantageous effects on survival and response in advanced NSCLC. CIP had no effect on survival, but it predicted better response.