Acute Lower Respiratory Disease Research Articles

Activated Leukocyte Cell Adhesion Molecule Regulates the Expression of Interleukin-33 in RSV Induced Airway Inflammation by Regulating MAPK Signaling Pathways.

The respiratory syncytial virus (RSV) is a common respiratory virus that causes acute lower respiratory tract infectious diseases, particularly in young children and older individuals. Activated leukocyte cell adhesion molecule (ALCAM) is a membrane glycoprotein expressed in various cell types, including epithelial cells, and is associated with inflammatory responses and various cancers. However, the precise role of ALCAM in RSV-induced airway inflammation remains unclear, and our study aimed to explore this gap in the literature. C57BL/6 wild-type, ALCAM knockout mice and airway epithelial cells were infected with RSV and the expression of ALCAM and inflammatory cytokines were measured. We also conducted further experiments using Anti-ALCAM antibody and recombinant ALCAM in airway epithelial cells. The expression levels of ALCAM and inflammatory cytokines increased in both RSV-infected mice and airway epithelial cells. Interestingly, IL-33 expression was significantly reduced in ALCAM-knockdown cells compared to control cells following RSV infection. Anti-ALCAM antibody treatment also reduced IL-33 expression following RSV infection. Furthermore, the phosphorylation of ERK1/2, p38, and JNK was diminished in ALCAM-knockdown cells compared to control cells following RSV infection. Notably, in the control cells, inhibition of these pathways significantly decreased the expression of IL-33. In vivo study also confirmed a reduction in inflammation induced by RSV infection in ALCAM deficient mice compared to wild-type mice. These findings demonstrate that ALCAM contributes to RSV-induced airway inflammation at least partly by influencing IL-33 expression through mitogen-activated protein kinase signaling pathways. These results suggest that targeting ALCAM could be a potential therapeutic strategy for alleviating IL-33-associated lung diseases.

The implication of infection with respiratory syncytial virus in pediatric recurrent wheezing and asthma: knowledge expanded post-COVID-19 era.

Respiratory syncytial virus (RSV) infection has been identified to serve as the primary cause of acute lower respiratory infectious diseases in children under the age of one and a significant risk factor for the emergence and development of pediatric recurrent wheezing and asthma, though the exact mechanism is still unknown. In this study, we discuss the key routes that lead to recurrent wheezing and bronchial asthma following RSV infection. It is interesting to note that following the coronavirus disease 2019 (COVID-19) epidemic, the prevalence of RSV changes significantly. This presents us with a rare opportunity to better understand the associated mechanism for RSV infection, its effects on the respiratory system, and the immunological response to RSV following the COVID-19 epidemic. To better understand the associated mechanisms in the occurrence and progression of pediatric asthma, we thoroughly described how the RSV infection directly destroys the physical barrier of airway epithelial tissue, promotes inflammatory responses, enhances airway hyper-responsiveness, and ultimately causes the airway remodeling. More critically, extensive discussion was also conducted regarding the potential impact of RSV infection on host pulmonary immune response. In conclusion, this study offers a comprehensive perspective to better understand how the RSV infection interacts in the control of the host's pulmonary immune system, causing recurrent wheezing and the development of asthma, and it sheds fresh light on potential avenues for pharmaceutical therapy in the future.

NURSING CARE OF AIRWAY CLEARANCE INEFFECTIVE IN CHILDREN WITH PNEUMONIA: A CASE REPORT

Introduction: pneumonia is one of the acute lower respiratory tract infectious diseases with symptoms of cough and accompanied by shortness of breath caused by infectious agents such as viruses, bacteria, mycoplasma and aspiration of foreign substances , in the form of pneumonia accompanied by exudation and consultation. Airway clearance is not effective in many pneumonia patients. The aim of the study to get an overview and experience in providing pediatric nursing care with airway clearance is not effective in pneumonia. Methods: this research uses qualitative method type case study with nursing process approach. The subjects in this study amounted to 3 patients diagnosed with pneumonia with nursing problems of ineffective airway clearance in the Orchid Room of RSUD Ibnu Sina Gresik in research data collection techniques, namely interviews, observations and documentation studies. Results: based on the main assessment of the three patients, it was found that the patient had a cough and shortness of breath The nursing diagnosis that emerged was that airway clearance was ineffective associated with retained secretions. The focus intervention carried out is teaching effective cough 822and doing chest physiotherapy. After 3 days of nursing action by the researcher each obtained an evaluation on the third day of cases 1, 2 and 3 the problem was partially resolved. Conclusions: The selection of intervention is an important factor when conducting airway clearance nursing care is not effective to prevent contraindications so as to speed up the patient's recovery.

Health risk assessment for particulate matter: application of AirQ+ model in the northern Caribbean region of Colombia

Air pollution is considered the world’s most important environmental and public health risk. The annual exposure for particulate matter (PM) in the northern Caribbean region of Colombia between 2011 and 2019 was determined using PM records from 25 monitoring stations located within the area. The impact of exposure to particulate matter was assessed through the updated Global Burden of Disease health risk functions using the AirQ+ model for mortality attributable to acute lower respiratory disease (in children ≤ 4 years); mortality in adults aged > 18 years old attributable to chronic obstructive pulmonary disease, ischaemic heart disease, lung cancer, and stroke; and all-cause post-neonatal infant mortality. The proportions of the prevalence of bronchitis in children and the incidence of chronic bronchitis in adults attributable to PM exposure were also estimated for the population at risk. Weather Research and Forecasting-California PUFF (WRF-CALPUFF) modeling systems were used to estimate the spatiotemporal trends and calculate mortality relative risk due to prolonged PM2.5 exposure. Proportions of mortality attributable to long-term exposure to PM2.5 were estimated to be around 11.6% of ALRI deaths in children ≤ 4 years of age, 16.1% for COPD, and 26.6% for IHD in adults. For LC and stroke, annual proportions attributable to PM exposure were estimated to be 9.1% and 18.9%, respectively. An estimated 738 deaths per year are directly attributed to particulate matter pollution. The highest number of deaths per year is recorded in the adult population over 18 years old with a mean of 401 events. The mean risk in terms of the prevalence of bronchitis attributable to air pollution in children was determined to be 109 per 100,000 inhabitants per year. The maximum RR values for mortality (up 1.95%) from long-term PM2.5 exposure were predicted to correspond to regions downwind to the industrial zone.

Patterns of Emergency Room Visits for Respiratory Diseases in New York State in Relation to Air Pollution, Poverty and Smoking.

We have explored differences in rates of emergency room (ER) visits for respiratory diseases in the counties of New York State (NYS) in relation to levels of air pollution, poverty, and smoking. Air pollution information was derived from the National Emissions Inventory, which provides information on road, non-road, point, and non-point sources of 12 different air pollutants. This information is only available at the county level. Four types of respiratory diseases were considered: asthma, chronic obstructive pulmonary disease (COPD), acute lower respiratory diseases, and acute upper respiratory diseases. Asthma ER visits were elevated in counties with greater total air pollution. All forms of respiratory diseases were elevated in counties with a greater rate of poverty, although this may reflect the fact that poor people often use ERs for routine care. There was a very strong association between rates of smoking for COPD and acute lower respiratory diseases. There was an apparent negative association between smoking and asthma ER visits, but this must reflect the fact that smoking was much more common in upstate counties while asthma was more common in the New York City area, where air pollution is high. Air pollution was much greater in urban than in rural areas. Our evidence indicates that air pollution is the greatest risk factor for asthma attacks, whereas smoking is the greatest risk factor for chronic obstructive pulmonary disease (COPD) and lower respiratory disease. Poor people are more vulnerable to all forms of respiratory diseases.

Estimating the health burden of ambient fine particulate matter in Korea

Korea has been making efforts to reduce the PM2.5 concentration through policy intervention but the PM2.5 level still belongs to a lower group among OECD countries. The aim of this study is to thus to evaluate the cases of premature deaths due to PM2.5 levels in Korea using AirQ+ model. We also examined the effect of reducing the burden of disease according to the current level of PM2.5 and future reduction targets in Korea. The burden of disease analysis of PM2.5 was based on cases of premature death of chronic obstructive pulmonary disease (COPD), stroke, ischemic heart disease (IHD), acute lower respiratory disease (ALRI), and lung cancer (LC). For the scenario, the current PM2.5 conc. of 25㎍/㎥, and the future reduction targets of 17㎍/㎥ and 15㎍/㎥ were applied. Also, Statistics Korea’s population and baseline mortality data by disease were used. The premature deaths of the five diseases due to the current and future PM2.5 scenarios in Korea were calculated as 12826, 12808, and 13223, respectively. The increase of premature deaths cases due to aging in the future population offset the effect of improving PM2.5, and thus the actual number of deaths did not decrease. However, the contribution rates of PM2.5 to the premature death cases decreased to 15.8%, 12.2%, and 11% as the concentration improved. In particular, the concentration rate of PM2.5 in ALRI, COPD, and LC decreased by more than 5%. In conclusion, it could be more effective to estimate the contribution rate rather than the absolute death case for the health improvement effect due to the reduction of PM2.5 in the case of countries where aging is expected in the future. In addition, this study showed that the reduction of PM2.5 in Korea was slightly more effective in reducing premature death of respiratory disease than cardiovascular disease.

Antibiotic Use and Stewardship Practices in a Pediatric Community-based Cohort Study in Peru: Shorter Would be Sweeter.

There is a need to evaluate antibiotic use, duration of therapy, and stewardship in low- and middle-income countries to guide the development of appropriate stewardship programs that are global in scope and effectively decrease unnecessary antibiotic use. We prospectively collected information on illness occurrence and antibiotic use from a cohort of 303 children. We evaluated the incidence, duration of therapy, and appropriateness of antibiotic prescriptions by 5 main antibiotic prescribers (physicians and nurses, pharmacists, nursing assistants, self-prescriptions, and neighbors or family members). Ninety percent of children received an antibiotic during follow-up, and on average, by the end of follow-up a child had spent 4.3% of their first 5 years of life on antibiotics. The most frequent prescribers were physicians/nurses (79.4%), followed by pharmacists (8.1%), self-prescriptions (6.8%), nursing assistants (3.7%), and family or neighbors (1.9%). Of the 3702 courses of antibiotics prescribed, 30.9% were done so for the occurrence of fever, 25.3% for diarrhea, 2.8% for acute lower respiratory disease, 2.7% for dysentery, and 38.2% for an undetermined illness. Courses exceeding the recommended duration were common for the principal diseases for which treatment was initiated, with 27.3% of courses exceeding the recommended length duration, representing a potential reduction in 13.2% of days on which this cohort spent on antibiotics. Stewardship programs should target medical personnel for a primary care stewardship program even in a context in which antibiotics are available to the public with little or no restrictions and appropriate duration should be emphasized in this training.

Inhibition of NF-κB/IL-33/ST2 Axis Ameliorates Acute Bronchiolitis Induced by Respiratory Syncytial Virus.

Background/Aim Bronchiolitis is a common acute lower respiratory tract infectious disease in infants. Respiratory syncytial virus (RSV) infection is one of the main causes. Bronchiolitis can lead to a significant increase in the incidence of asthma in young children, but the mechanism of bronchiolitis transforming into asthma is still unclear. The study was aimed at investigating the role of NF-κB/IL-33/ST2 axis on RSV-induced acute bronchiolitis. Methods A total of 40 infants diagnosed with acute bronchiolitis infected by RSV, and 20 normal infants were included in this study. BALB/c mice (6-8 weeks old, 20 ± 1.1 g) were used as study models. Enzyme-linked immunosorbent assay (ELISA), quantitative real time PCR, western blot analysis, immunohistochemical staining, and flow cytometry analysis were performed to examine relevant indicators. Results IL-33 level was significantly elevated, and Th1/Th2 ratio is imbalance after in infants with acute bronchiolitis. In vivo study, we found that NF-κB/IL-33/ST2 axis is mediated the Th2 cytokine levels and BAL cell number induced by RSV. Acute bronchiolitis induced by RSV in a mouse model is attenuated after inhibition of NF-κB/IL-33/ST2 pathway. Moreover, we also confirmed that macrophages are important sources of IL-33 and are regulated by NF-κB pathway in RSV-induced mice. Conclusion We confirmed that inhibition of NF-κB/IL-33/ST2 axis could attenuate acute bronchiolitis by RSV infected. Our findings not only demonstrate the potential role of IL-33 antibody in attenuating RSV-induced lung damage but also provide a new insight into better prevention of RSV-induced asthma by mediating NF-κB/IL-33/ST2 axis.

Assessing Health Impact of Air Pollutants in Five Iraqi Cities Using AirQ+ Model

Concentration of air pollutants CO, NO2, SO2, O3, PM10, PM2.5 in four Iraqi cities (Al-Najaf, Al-Muthanna, Maysan, Kirkuk) and PM2.5 in Baghdad city were monitored and analysed for the period September 1, 2019 to August 31, 2020. The results showed that the daily mean concentration of CO, NO2 for the four cities are well below the WHO air quality standard. In general, PM2.5 and PM10 concentrations are the factors that govern the air quality index in Iraqi cities under consideration. It is clear that, for all the cities under consideration, the daily AQI is mostly “Moderate” and to a less extent “Unhealthy for sensitive groups”. However, there are 53 days for Al-Muthanna (mainly due to PM10) and 58 days for Baghdad (due to PM2.5 alone) in which the AQI is “Unhealthy”. Moreover, there are another 53 days for Al-Muthanna in which the AQI is “Hazardus”. So, the air quality in Al-Muthanna and Baghdad can be considered lower than that in other cities. Indeed, this is attributed to dust storms in Al-Muthanna and high population of Baghdad city and consequently higher air pollutants emissions due to their industrial, transportation and electric generation activities. AirQ+ software was used to assess public health consequences of long term exposure to PM2.5 in terms of relative risk (RR). RR of acute lower respiratory disease, chronic obstructive pulmonary, mortality by lung cancer, ischemic heart disease, mortality by stroke for the five cities were assessed. RR of mortality by lung cancer due to exposure to PM2.5 in Baghdad is the highest among the cities under consideration. RRLC = 1.25 (95% CI = 1.14 – 1.4).

A Survey on Smart Monitoring System of Environment Based on IoT

This paper introduces different topics about Air pollution monitoring based on IoT (internet of things). It describes different methods used for monitoring and measuring Air pollution using different techniques. Some papers discussed Air pollution monitoring using (Arduino uno, Raspberry or ESP8266, PIC microcontroller). All would be presented to improve air monitoring efficiently and to clarify the tools used in each technique giving the differences between one technique and another. Reducing air pollution is necessary for the future, and cities around the world are using technology and smart city initiatives to take on the problem because it is considered as the major environmental risk factor for human health. Air pollution causes heart disease, stroke, chronic obstructive pulmonary disease, lung cancer and acute lower respiratory disease. Therefore, it is important to reduce traffic and output from factories to decrease pollution

Respiratory Diseases as Risk Factors for Seropositive and Seronegative Rheumatoid Arthritis and in Relation to Smoking.

The link and interplay between different airway exposures and rheumatoid arthritis (RA) risk are unclear. This study was undertaken to determine whether respiratory disease is associated with development of RA, and specifically to examine this relationship by RA serostatus and smoking exposure. Using data from the Epidemiological Investigation of Rheumatoid Arthritis study, this analysis included 1,631 incident RA cases and 3,283 matched controls recruited from 2006 to 2016. Linking these individuals to the National Patient Register provided information on past acute or chronic, upper or lower respiratory disease diagnoses. For each disease group, we estimated adjusted odds ratios (ORadj ) with 95% confidence intervals (95% CI) for RA, using logistic regression models adjusted for age, sex, residential area, body mass index, and education both overall and stratified by anti-citrullinated protein antibody (ACPA)/rheumatoid factor (RF) status and by smoking status. Respiratory disease diagnoses were associated with risk of RA, with an ORadj of 1.2 for acute upper respiratory disease (95% CI 0.8-1.7), 1.4 for chronic upper respiratory disease (95% CI 1.1-1.9), 2.4 for acute lower respiratory disease (95% CI 1.5-3.6), and 1.6 for chronic lower respiratory disease (95% CI 1.5-3.6). These associations were present irrespective of RF or ACPA status, though the association was somewhat stronger for ACPA/RF-positive than ACPA/RF-negative RA. The association between any respiratory disease and RA was stronger for nonsmokers (ORadj 2.1 [95% CI 1.5-2.9]) than for smokers (ORadj 1.2 [95% CI 0.9-1.5]). Respiratory diseases increase the risk for both seropositive and seronegative RA, but only among nonsmokers. These findings raise the hypothesis that smoking and airway disease are associated with RA development through partly different mechanisms.

Acute effects of ambient air pollution on outpatients with chronic rhinitis in Xinxiang, China.

Air pollution exposure leads to increased mortality and morbidity rates of respiratory diseases. Most of the evidence was founded on acute diseases such as acute lower respiratory diseases. However, limited studies have been conducted to evaluate the effects of air pollution on chronic respiratory diseases. This time-series study was conducted to examine the acute effects of 6 criteria ambient air pollutants on hospital outpatients with chronic rhinitis (CR) in Xinxiang, China. We retrieved 223,826 outpatient records of patients with respiratory diseases, of which 62,901 were those of patients with CR. Results showed that the current 10-μg/m3 increase in fine particulate matter (PM2.5), inhalable particulate matter (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2), and carbon monoxide (CO) corresponds to 0.67% (95% confidence interval [CI]: 0.15-1.18%), 0.58% (95% CI: 0.24-0.92%), 1.89% (95% CI: 0.52-3.27%), 3.01% (95% CI: 1.66-4.35%), and 0.06% (95% CI: 0.03-0.10%) increments in outpatients with CR, respectively. In addition, the effects in the male were stronger than those in the female. Higher effect estimates were observed in the old (≥ 65years of age) and younger (< 15years of age) groups. Our study confirmed the association between air pollution and outpatients with CR in Xinxiang, China. More stringent air pollution control measures must be implemented.

Efforts to control air pollution in the Asia-Pacific region.

Efforts to control air pollution in the Asia-Pacific region.

ВОИНА И СОСТОЯНИЯ ЗДОРОВЬЯ НАСЕЛЕНИЕ ИРАКА

Iraq, or the Republic of Iraq, lies in western Asia encircling the Mesopotamian plain, the northwestern part of the Zagros mountain range and the eastern branch of the Syrian desert. Syria lies on the northwest border of Iraq, Turkey is to the north, Iran is east, and Jordan is to the west. It has a narrow coastline of about 58km at the North Persian Gulf. More than 15 years ago, a war broke out in Iraq, which turned into a disaster for the entire region. Armed conflict entailed massive displacement in Iraq. The United Nations estimates that 1.8 million people have been displaced since early August, 850,000 of them in the north of the country. Large groups of people were forced to move up to 3 times - all this has caused serious health risks that the government and international agencies led by WHO seek to eliminate. Iraq is experiencing internal instability. On the one hand, it is caused by environmental conditions, including due to the fact that Turkey blocked all the water flowing into Iraq through the Euphrates River, as well as due to environmental pollution in Iraq itself. The Iraq War destroyed an estimated 12% of hospitals and Iraq's two main public health laboratories. The collapse of sanitation infrastructure in 2003 led to an increased incidence of cholera, dysentery, and typhoid fever. Malnutrition and childhood diseases. The people of Iraq face a mixture of health hazards associated with poverty. Children, adolescents, women, the elderly, disabled people and those who are chronically ill are at particular risk. 8 The primary causes of the high burden of communicable disease among children are acute lower respiratory infections, diarrheal diseases and measles. (see Children's health). Lack of adequate sanitation and clean drinking water lead to a high risk of diarrhoea outbreaks Major causes of death in children in Iraq The three major killers in children are acute lower respiratory infections, such as pneumonia; diarrheal diseases; and measles. Child death rates due to acute lower respiratory infections and diarrhoea have increased over the last decade. These conditions account for 70% of deaths in children under five years of age.

Feasibility of high-flow nasal cannula implementation for children with acute lower respiratory tract disease in rural Kenya

ABSTRACTBackground: High-flow nasal cannula (HFNC) is a well-established respiratory support device in high-income countries, but to our knowledge, its use in sub-Saharan Africa has not been reported. This feasability study describes the implementation process of HFNC in rural Kenya.Methods: HFNC was implemented in intensive care and high dependency units at Kijabe Hospital, Kenya for children with acute lower respiratory disease. Rate of intubation was compared with historical controls and challenges of implementation described.Results: Fifteen patients received HFNC between January and November 2016, and compared to 25 historical control patients. Both groups had many comorbidities, and control patients were significantly younger. There were no significant differences in clinical outcome between the groups: 5 (33%) HFNC vs 12 (48%) controls required intubation; 10 (67%) HFNC vs 22 (88%) controls survived to discharge; and the HFNC required 3 vs the controls’ 4 days on respiratory support. The greatest technical issues encountered were large pressure differences between air from a wall outlet (wall air) and oxygen and an inability to automatically refill humidifier water chambers.Conclusion: HFNC in limited-resource settings is feasible but there were technical challenges and concern about the increased workload. The small sample size, heterogeneous population, availability of oxygen and blending of wall air at the study site limit inferences for other sites in low- and middle-income countries.Abbreviations: ALRI, acute lower respiratory infection; CPAP, continuous positive airway pressure; ETAT, emergency triage, assessment and treatment; HDU, high dependency unit; HFNC, high-flow nasal cannula; HIC, high-income country; HR, heart rate; ICU, intensive care unit; LMIC, low- and middle-income countries; PSI, pounds per square inch; RR, respiratory rate; mRISC, modified Respiratory Index of Severity in Children.

Safety study of live, oral human rotavirus vaccine: A cohort study in United States health insurance plans

ABSTRACTAs part of a regulatory commitment for post-licensure safety monitoring of live, oral human rotavirus vaccine (RV1), this study compared the incidence rates (IR) of intussusception, acute lower respiratory tract infection (LRTI) hospitalization, Kawasaki disease, convulsion, and mortality in RV1 recipients versus inactivated poliovirus vaccine (IPV) recipients in concurrent (cIPV) and recent historical (hIPV) comparison cohorts. Vaccine recipients were identified in 2 claims databases from August 2008 – June 2013 (RV1 and cIPV) and January 2004 – July 2008 (hIPV). Outcomes were identified in the 0–59 days following the first 2 vaccine doses. Intussusception, Kawasaki disease, and convulsion were confirmed via medical record review. Outcome IRs were estimated. Incidence rate ratios (IRRs) were obtained from Poisson regression models. A post-hoc self-controlled case series (SCCS) analysis compared convulsion IRs in a 0–7 day post-vaccination period to a 15–30 day post-vaccination period. We identified 57,931 RV1, 173,384 cIPV, and 159,344 hIPV recipients. No increased risks for intussusception, LRTI, Kawasaki disease, or mortality were observed. The convulsion IRRs were elevated following RV1 Dose 1 (cIPV: 2.07, 95% confidence interval [CI]: 1.27 – 3.38; hIPV: 2.05, 95% CI: 1.24 – 3.38), a finding which is inconclusive as it was observed in only one of the claims databases. The IRR following RV1 Dose 1 in the SCCS analysis lacked precision (2.40, 95% CI: 0.73 – 7.86). No increased convulsion risk was observed following RV1 Dose 2. Overall, this study supports the favorable safety profile of RV1. Continued monitoring for safety signals through routine surveillance is needed to ensure vaccine safety.

Investigation into the causes of indwelling urethral catheter implementation and its effects on clinical outcomes and health care resources among dementia patients with pneumonia: A retrospective cohort study.

There is a possibility that unnecessary treatments and low-quality medical care, such as inappropriate indwelling urethral catheter use, are being provided to older Japanese individuals.The aim of this study was to investigate contextual effects relating to indwelling urethral catheters in older people with dementia and to clarify the effects of indwelling urethral catheter use on patients' mortality, length of stay (LOS), and health care spending. This retrospective cohort study involved 4501 male and female Japanese participants. Those who were aged 75 or older with dementia and had a primary diagnosis of acute lower respiratory disease with antibiotics administered during hospitalization were eligible for inclusion. Patient mortality, LOS, and total charge during hospitalization were the main study outcomes. This study showed that indwelling urethral catheter use was significantly associated with higher mortality, longer LOS, and higher total charge for hospitalization. The pattern of indwelling urethral catheter use was clustered by care facility level. Physician density was significantly associated with indwelling urethral catheter use; the relationship was not linear but U-shaped, such that the approximate median had the lowest rate of urethral catheter use and this increased gradually toward both lower and higher physician densities. Our study found considerable variation in indwelling urethral catheter use between care facilities in older people with dementia. Additionally, indwelling urethral catheter use was related to poor outcomes. Based on these findings, we consider there to be an urgent need for constructing a framework to measure, report on, and promote the improvement of care quality for older individuals in Japan.

A novel p38 mitogen activated protein kinase (MAPK) specific inhibitor suppresses respiratory syncytial virus and influenza A virus replication by inhibiting virus-induced p38 MAPK activation

Respiratory syncytial virus (RSV) and influenza A virus are leading causes of acute lower respiratory infectious disease. Respiratory diseases caused by RSV and influenza A virus result in serious economic burden and life-threatening disease for immunocompromised people. With the revelation that p38 mitogen-activated protein kinase (MAPK) activity in host cells is crucial for infection and replication of RSV and influenza A virus, inhibition of p38 MAPK activity has been suggested as a potential antiviral therapeutic strategy. However, the low selectivity and high toxicity of the p38 MAPK inhibitors necessitate the development of better inhibitors. Herein, we report the synthesis of a novel p38 MAPK inhibitor, NJK14047, with high kinase selectivity. In this work, it was demonstrated that NJK14047 inhibits RSV- and influenza A-mediated p38 MAPK activation in epithelial cells. Subsequently, NJK14047 treatment resulted in decreased viral replication and viral mRNA synthesis. In addition, secretion of interleukin-6 from infected cells was greatly diminished by NJK14047, suggesting that it can ameliorate immunopathological responses to RSV and influenza A. Collectively, the results suggest that NJK14047 has therapeutic potential to treat respiratory viral infection through the suppression of p38 MAPK activation, which is suggested to be an essential step for respiratory virus infection.

Increased health service use for asthma, but decreased for COPD: Northumbrian hospital episodes, 2013-2014.

The burden of respiratory disease has persisted over the years, for both men and women. The aim of the present study was to investigate the hospital episode rates in respiratory disease and to understand whether and how the use of the health service for respiratory disease might have changed in recent years in the North-East of England. Hospital episode data covering two full calendar years (in 2013–2014) was extracted from the Northumbria Healthcare NHS Foundation Trust, which serves a population of nearly half a million. Hospital episode rates were calculated from admissions divided by annual and small area-specific population size by sex and across age groups, presented with per 100,000 person-years. The use of the health service for influenza and pneumonia, acute lower respiratory infections and chronic obstructive pulmonary disease (COPD) increased with an advancing age, except for acute upper respiratory infections and asthma. Overall, the use of the health service for common respiratory diseases has seemed to be unchanged, except for asthma. There were large increases in young adults aged 20–50 for both men and women and the very old aged 90+ in women. Of note, there were large increases in acute lower respiratory infections for both men and women aged 90+, whereas there was also a large decrease in COPD in women aged 80–90. This is the first study to examine health service use for respiratory diseases by calculating the detailed population size as denominator. Re-diverting funding to improve population health on a yearly basis may serve the changing need in local areas.

The Interferon Type I/III Response to Respiratory Syncytial Virus Infection in Airway Epithelial Cells Can Be Attenuated or Amplified by Antiviral Treatment.

Human respiratory syncytial virus (RSV) is a single-stranded RNA virus that causes acute, and occasionally fatal, lower respiratory illness in young infants, the elderly, and immunocompromised patients. Therapeutic interventions able to cut short viral replication and quickly return the airways to normal function are needed. An understanding of antiviral activities and their effects on host defense mechanisms is important for the design of safe and effective therapy. We targeted functionally and temporally distinct steps within the viral life cycle using small-molecule RSV inhibitors and studied their antiviral activities and their effects on innate interferon responses of airway epithelial cells in vitro. Antivirals acting upstream of RSV polymerase activity (i.e., compounds targeting the fusion protein or the nucleoprotein) reduced viral load immediately postinfection and partially attenuated interferon responses. In contrast, antivirals directed to the RSV polymerase demonstrated activity throughout the viral replication cycle and specifically modulated the RIG-I/mitochondrial antiviral signaling protein (MAVS)/TBK1/IRF3/interferon-stimulated gene (ISG) axis, causing either an upregulation or a downregulation of interferon responses, depending on the mechanism of polymerase inhibition. Notably, polymerase inhibition leading to the accumulation of abortive RNA products correlated with the amplification of interferon-stimulated genes to up to 10 times above normal infection levels. Understanding how antiviral activities and their modulation of innate immunity may affect recovery from RSV infection will help guide the development of safe and effective therapies. RSV circulates seasonally, causing acute lower respiratory disease. Therapeutic interventions with efficacy throughout the viral replication cycle, rapid viral clearance, and prevention of potentially harmful inflammatory responses are desirable. Compounds targeting the RSV polymerase inhibited virus replication late in the viral life cycle and, depending on the functional domain targeted, either attenuated or amplified RIG-I and downstream interferon pathways in infected cells. These data will help guide the development of safe and effective therapies by providing new molecular evidence that the mechanism of inhibition by an antiviral compound can directly impact innate antiviral immune responses in the airway epithelium.