Exacerbation Of Chronic Lung Disease Research Articles

Dietary Eicosapentaenoic Acid Improves Ozone-Induced Pulmonary Inflammation in C57/BL6 Mice

Ambient concentrations of the air pollutant, ozone, are rising with increasing global temperatures. Ozone is known to increase incidence and exacerbation of chronic lung diseases, which will increase as ambient ozone levels rise. Studies have identified diet as a variable able to modulate the pulmonary health effects associated with ozone exposure. Eicosapentaenoic Acid (EPA) is an n-3 polyunsaturated fatty acid (PUFA) consumed through diet that lowers inflammation through conversion to oxylipins including Hydroxy Eicosapentaenoic Acids (HEPEs). However, the role of dietary EPA in ozone-induced pulmonary inflammation is unknown. Therefore, we hypothesize increasing dietary EPA will decrease ozone-induced pulmonary inflammation and injury through the production of HEPEs. To test this, male C57BL/6J mice were fed a purified control diet or EPA-supplemented diet for 4 weeks and then exposed to filtered air (FA) or 1 part per million ozone for 3 hours. 24 or 48 hours post exposure, bronchoalveolar lavage (BAL) fluid was collected to assess airspace inflammation/injury and lung tissue was collected for targeted Liquid Chromatography-Mass Spectrometry (LC-MS/MS) lipidomics. Following ozone exposure, EPA supplementation did not alter markers of lung injury, but decreased ozone-induced airspace neutrophilia. LC-MS/MS targeted lipidomics reveal dietary EPA supplementation increased pulmonary EPA-derived metabolites including 5-HEPE and 12-HEPE. Additionally, EPA supplementation decreased pulmonary levels of pro-inflammatory Arachidonic Acid (AA)-derived metabolites. To evaluate if dietary EPA reduces ozone-induced pulmonary inflammation through increased pulmonary HEPEs, C57BL/6J mice were administered 5- and 12-HEPEs systemically prior to filtered air or ozone exposure. Pretreatment with 5- and 12-HEPEs reduced ozone-driven increases in airspace macrophages. Together, these data indicate that an EPA-supplemented diet protects against ozone-induced airspace inflammation which is, in part, due to increasing pulmonary concentrations of 5- and 12-HEPEs. These findings suggest that dietary EPA and/or increasing EPA-derived metabolites in the lung can reduce ozone-driven incidences and exacerbations of chronic pulmonary diseases.

A Qualitative Study Identifying the Potential Risk Mechanisms Leading to Hospitalization for Patients With Chronic Lung Disease

BackgroundCare management programs for chronic lung disease attempt to reduce hospitalizations, yet have not reliably attained this goal. A key limitation of many programs is that they target patients with characteristics associated with hospitalization risk but do not specifically modify the mechanisms that lead to hospitalization. Research QuestionWhat are the common mechanisms underlying known patient-level risk characteristics leading to hospitalizations for acute exacerbations of chronic lung disease? Study Design and MethodsWe conducted a qualitative study of patients admitted to the University of Pennsylvania Health system with acute exacerbations of chronic lung disease between January and September 2019. We interviewed patients, their family caregivers, and their inpatient and outpatient clinicians about experiences leading up to the hospitalization. We analyzed the interview transcripts using triangulation and abductive analytic methods. ResultsWe conducted 69 interviews focused on the admission of 22 patients with a median age of 66 years (interquartile range 60 to 70), of whom 16 (73%) were women and 14 (64%) were Black. We interviewed 22 patients, 14 caregivers, 19 inpatient clinicians, and 14 outpatient clinicians. We triangulated the available interview data for each patient admission and identified the underlying mechanisms of how several known patient characteristics associated with risk actually led to hospitalization. These mechanisms included limited capacity for home management of acute symptom changes, barriers to accessing care, chronic functional limitations, and comorbid behavioral health disorders. Importantly, many of the clinical, social, and behavioral mechanisms underlying hospitalizations were present for months or years prior to the symptoms that prompted inpatient care. InterpretationCare management programs should be built to target specific clinical, social, and behavioral mechanisms that directly lead to hospitalization. Upstream interventions that reduce hospitalization risk are possible given that many contributory mechanisms are present for months or years before the onset of acute exacerbations.

Cooperative interaction of interferon regulatory factor -1 and bromodomain-containing protein 4 on RNA polymerase activation for intrinsic innate immunity.

The human orthopneumovirus, Respiratory Syncytial Virus (RSV), is the causative agent of severe lower respiratory tract infections (LRTI) and exacerbations of chronic lung diseases. In immune competent hosts, RSV productively infects highly differentiated epithelial cells, where it elicits robust anti-viral, cytokine and remodeling programs. By contrast, basal cells are relatively resistant to RSV infection, in part, because of constitutive expression of an intrinsic innate immune response (IIR) consisting of a subgroup of interferon (IFN) responsive genes. The mechanisms controlling the intrinsic IIR are not known. Here, we use human small airway epithelial cell hSAECs as a multipotent airway stem cell model to examine regulatory control of an intrinsic IIR pathway. We find hSAECs express patterns of intrinsic IIRs, highly conserved with pluri- and multi-potent stem cells. We demonstrate a core intrinsic IIR network consisting of Bone Marrow Stromal Cell Antigen 2 (Bst2), Interferon Induced Transmembrane Protein 1 (IFITM1) and Toll-like receptor (TLR3) expression are directly under IRF1 control. Moreover, expression of this intrinsic core is rate-limited by ambient IRF1• phospho-Ser 2 CTD RNA Polymerase II (pSer2 Pol II) complexes binding to their proximal promoters. In response to RSV infection, the abundance of IRF1 and pSer2 Pol II binding is dramatically increased, with IRF1 complexing to the BRD4 chromatin remodeling complex (CRC). Using chromatin immunoprecipitation in IRF1 KD cells, we find that the binding of BRD4 is IRF1 independent. Using a small molecule inhibitor of the BRD4 acetyl lysine binding bromodomain (BRD4i), we further find that BRD4 bromodomain interactions are required for stable BRD4 promoter binding to the intrinsic IIR core promoters, as well as for RSV-inducible pSer2 Pol II recruitment. Surprisingly, BRD4i does not disrupt IRF1-BRD4 interactions, but disrupts both RSV-induced BRD4 and IRF1 interactions with pSer2 Pol II. We conclude that the IRF1 functions in two modes- in absence of infection, ambient IRF1 mediates constitutive expression of the intrinsic IIR, whereas in response to RSV infection, the BRD4 CRC independently activates pSer2 Pol II to mediates robust expression of the intrinsic IIR. These data provide insight into molecular control of anti-viral defenses of airway basal cells.

Effectiveness of Drip Infusion of Lascufloxacin, a Novel Fluoroquinolone Antibiotic, for Patients with Pneumonia Including Chronic Lung Disease Exacerbations and Lung Abscesses.

Lascufloxacin (LSFX), a novel fluoroquinolone antibacterial agent, has recently been used as a drip infusion for treating pneumonia, apparently with good effectiveness against various bacteria, including anaerobes, and good intrapulmonary penetration. The clinical effectiveness of LSFX was retrospectively investigated for the 55 patients admitted to our hospital with pneumonia, including chronic lung disease exacerbations and lung abscesses, from May 2021 to July 2023. The median age of the 55 patients was 76.1 (34.1-93.1) years, 45 (81.8%) were male, and 48 (87.5%) patients had underlying disease. Community-acquired pneumonia was seen in 47 (85.5%) patients, including 9 (16.4%) with lung abscess, and the other 8 (14.5%) had nursing and healthcare-associated pneumonia/hospital-acquired pneumonia. Moderate pneumonia was present in 33 (61.8%) of 55 patients, and LSFX was used as a second-line treatment for 28 (50.9%) patients in whom first-line antibiotics were ineffective. The median duration of intravenous LSFX administration was 9 (2.0-49) days. Streptococcus pneumoniae and methicillin-susceptible Staphylococcus aureus were isolated from 3 (7.1%) and 2 (4.8%) patients, respectively. Of the 55 patients, 45 (81.5%) improved clinically with intravenous LSFX administration; 20 (95.2%) of 21 community-acquired pneumonia cases, including 9 (100.0%) of 9 bacterial pneumonia cases, were improved by LSFX as first-line treatment, and 8 (88.9%) of 9 lung abscess patients also showed clinical improvement with LSFX as a second-line treatment. There were no severe adverse effects in any of the 55 patients. Based on these data, intravenous administration of LSFX seems effective for bacterial pneumonia, including chronic lung disease exacerbations and lung abscesses, and it appears to have broad antimicrobial activity and good tissue penetration into the lung.

Nanoparticle-Exposure-Triggered Virus Reactivation Induces Lung Emphysema in Mice.

Nanoparticles (NPs) released from engineered materials or combustion processes as well as persistent herpesvirus infection are omnipresent and are associated with chronic lung diseases. Previously, we showed that pulmonary exposure of a single dose of soot-like carbonaceous NPs (CNPs) or fiber-shaped double-walled carbon nanotubes (DWCNTs) induced an increase of lytic virus protein expression in mouse lungs latently infected with murine γ-herpesvirus 68 (MHV-68), with a similar pattern to acute infection suggesting virus reactivation. Here we investigate the effects of a more relevant repeated NP exposure on lung disease development as well as herpesvirus reactivation mechanistically and suggest an avenue for therapeutic prevention. In the MHV-68 mouse model, progressive lung inflammation and emphysema-like injury were detected 1 week after repetitive CNP and DWCNT exposure. NPs reactivated the latent herpesvirus mainly in CD11b+ macrophages in the lungs. In vitro, in persistently MHV-68 infected bone marrow-derived macrophages, ERK1/2, JNK, and p38 MAPK were rapidly activated after CNP and DWCNT exposure, followed by viral gene expression and increased viral titer but without generating a pro-inflammatory signature. Pharmacological inhibition of p38 activation abrogated CNP- but not DWCNT-triggered virus reactivation in vitro, and inhibitor pretreatment of latently infected mice attenuated CNP-exposure-induced pulmonary MHV-68 reactivation. Our findings suggest a crucial contribution of particle-exposure-triggered herpesvirus reactivation for nanomaterial exposure or air pollution related lung emphysema development, and pharmacological p38 inhibition might serve as a protective target to alleviate air pollution related chronic lung disease exacerbations. Because of the required precondition of latent infection described here, the use of single hit models might have severe limitations when assessing the respiratory toxicity of nanoparticle exposure.

Population-level trends in asthma and chronic obstructive pulmonary disease emergency department visits and hospitalizations before and during the coronavirus disease 2019 pandemic in the United States

BackgroundPrevious studies have identified reductions in exacerbations of chronic lung disease in many locales after onset of the coronavirus disease 2019 (COVID-19) pandemic. ObjectiveTo evaluate the population-level impacts of COVID-19 on asthma and chronic obstructive pulmonary disease (COPD) exacerbations—with a focus on disadvantaged communities—in the United States. MethodsWe analyzed 2016 to 2020 county-level data on asthma and COPD acute care use, with myocardial infarction hospitalizations as a comparator condition. We linked this with county-level lower respiratory disease mortality data. We calculated rates of emergency department (ED) visits, hospitalizations, and deaths and evaluated changes using linear regressions adjusted for year and county-fixed effects.For a supplementary analysis, we calculated ED visit rates nationwide for asthma, COPD, or any diagnosis using the 2016 to 2020 National Hospital Ambulatory Medical Care Survey. ResultsOur county-level data included 685 counties in 13 states. Rates of each outcome fell in 2020. In adjusted analyses, we found large reductions in asthma and COPD ED visit rates (eg, a 21.5 per 10,000-person reduction in COPD ED visits; 95% confidence interval, −23.8 to −19.1), with smaller reductions in hospitalizations and chronic lower respiratory mortality. Disadvantaged communities had mostly higher baseline rates of respiratory morbidity and larger absolute reductions in some outcomes.Among 90,808 ED visits in the National Hospital Ambulatory Medical Care Survey, asthma ED visits/y fell 33% during the pandemic and COPD visits by 51%; overall ED visits fell by only 7%. ConclusionOnset of the COVID-19 pandemic coincided with reductions in acute care utilization for asthma and COPD. Understanding the mechanism of this reduction might inform future efforts to prevent exacerbations.

Rhinovirus, When Is It More Than Just a Cold? Rhinovirus as a Cause of Organizing Pneumonia in Two Patients With Hematological Cancer

Abstract Human rhinoviruses are pathogens that cause significant morbidity and economic strain from upper respiratory infections. Rhinovirus has also been associated with exacerbations of chronic lung disease. Less understood is the role of rhinovirus in organizing pneumonia (OP). Organizing pneumonia is a certain lung pattern of injury that occurs after injury to the pulmonary parenchyma, with infection being the most studied etiology. It typically presents with similar symptoms to pneumonia, and patients are often treated with antibiotics to lack of improvement. However, OP is more subacute in presentation, and the treatment, systemic glucocorticoids, differs from bacterial pneumonia. Recognition of rhinovirus as a significant pathogen in immunocompromised patients is important because it tends to cause more severe disease in this group. Here, we present a case series of 2 hematological malignancy patients with a long-standing rhinovirus infection and lung disease unresponsive to antibiotics, later found on biopsy to be OP. Both patients survived the infection, and both patients had documented rhinovirus shedding for greater than 9 months. Both patients had lymphoma and were being actively treated with a monoclonal antibody that targeted cluster of differentiation 20. Both patients reported fever and dyspnea. Both patients had multiple superimposed bacterial infections, with both patients eventually developing Pseudomonas aeruginosa pneumonia. In the immunocompromised, rhinovirus may cause morbidity through a primary infection, a secondary bacterial infection, or OP. Novel treatment strategies and increased awareness are needed not only for rhinovirus-induced OP but also for rhinovirus as an important pathogen in immunocompromised patients.

Cefotaxime: A Reappraisal in Lower Respiratory Tract Infections

Lower respiratory Tract Infection (LRTI) is one of the fourth most common cause of mortality across the globe, and constitutes to be a major portion in critically ill patients associated with prolonged hospitalisation. Apart from age factor, other risk factors which predispose to the LRTI include poor sanitization, severe malnutrition, and lack of breast feeding for infants, HIV infection, lack of immunization, chronic illness, family history of LRTI and exposure to tobacco smoke/air pollutants. The third generation cephalosporins are used in management and treatment of gram-negative and gram-positive organism. Common bacteria implicated in these infections include S. pneumoniae, H. influenzae, Chlamydia pneumoniae, and Staphylococcus aureus. Third generation cephalosporins also target respiratory ailments like acute bronchitis, pneumonia, acute exacerbation of chronic lung diseases (such as COPD or bronchiectasis). Cefotaxime and ceftriaxone have been widely recommended in guidelines to be used for many infections and diseases, but, some serious adverse effects have been seen in past few years with ceftriaxone like cholelithiasis, encephalopathy, memory impairment, tonic- clonic seizures, neurotoxicity and auto-immune haemolytic anaemia. This fact compels us to revisit the clinically safer and efficacious drug Cefotaxime which have been used since decades but have not developed any resistance till date. Cefotaxime has been found to be well tolerated and not associated with hypo-prothrombinemia/coagulopathies, disulfiram-like reactions, as with other cephalosporins. It can readily cross the blood-brain barrier when administered intravenously and may treat gram-negative infections resistant to previous generations of cephalosporins. Cefotaxime, demonstrates good efficacy and safety in the management of LRTIs including CAP, hospital acquired/nosocomial acquired pneumonia, acute exacerbation of pneumonia and acute bronchitis caused by both gram positive as well as gram negative bacteria. Keywords: LRTI, Cefotaxime, cephalosporins, CAP, pneumonia, respiratory tract

Systemic corticosteroid use and cardiovascular risk in patients hospitalized for pneumonia

BackgroundLimited data are available concerning cardiovascular risk with respect to adjunctive corticosteroid use in patients with pneumonia. We aimed to assess the associations between systemic corticosteroid use and the occurrence of major adverse cardiovascular events (MACEs) in patients hospitalized for pneumonia. MethodsAmong study participants enrolled via surveillance for severe acute respiratory infection from July 2016 to January 2017, the clinical course of patients with pneumonia was retrospectively investigated until December 2019. We evaluated the occurrence of in-hospital and after-discharge MACEs according to steroid use during hospitalization. ResultsOf the 424 patients hospitalized for pneumonia, 118 (28.8%) received systemic corticosteroids during hospitalization. The most common reason for steroid use was acute exacerbation of chronic lung disease (75.4%). Systemic steroid use was significantly associated with an increased risk of in-hospital MACEs; it was not associated with after-discharge MACEs. The risk of in-hospital MACEs was significantly greater in patients with more comorbidities, more severe pneumonia, and a higher inflammatory marker level; moreover, it was positively associated with duration and cumulative dose of steroid treatment. ConclusionSystemic corticosteroid use was associated with an increased risk of in-hospital MACEs in patients hospitalized for pneumonia.

Respiratory viral infections, SARS-СoV-2 and chronic obstructive pulmonary disease

Further study of the distribution, pathogenesis of viral infection, the role of respiratory viruses in the formation and exacerbation of chronic lung diseases will allow the development of new methods of protection, the creation of modern pharmaceutical approaches for the treatment and prevention of COVID-19.The aim. The article presents an analytical review of the scientific literature in PubMed, Google Scholar, medRxiv, bioRxiv which was conducted to study and evaluate the mechanisms, pathogenesis, and clinical picture of respiratory viral infections, including Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-СoV-2).Conclusion. Understanding the specific mechanisms of the development of the host’s immune response to respiratory viruses allows a better understanding of the course of a new coronavirus infection, including in patients with COPD, since respiratory tract infections are closely associated with the formation and exacerbation of COPD. Respiratory viruses activate immune responses and exacerbate underlying inflammation in COPD. SARS-СoV-2 leads to a dysregulated immune response and, in severe cases, an overactive immune response, causing the development of a cytokine storm and acute respiratory distress syndrome (ARDS). Unlike seasonal respiratory viruses, SARS-СoV-2 circulates throughout the year and can be a source of frequent and severe exacerbations in patients with COPD which require further monitoring and research.

Noninvasive Oxygenation in Patients with Acute Respiratory Failure: Current Perspectives.

Purpose of ReviewHigh-flow nasal oxygen and noninvasive ventilation are two alternative strategies to standard oxygen in the management of acute respiratory failure.DiscussionAlthough high-flow nasal oxygen has gained major popularity in ICUs due to its simplicity of application, good comfort for patients, efficiency in improving oxygenation and promising results in patients with acute hypoxemic respiratory failure, further large clinical trials are needed to confirm its superiority over standard oxygen. Non-invasive ventilation may have deleterious effects, especially in patients exerting strong inspiratory efforts, and no current recommendations support its use in this setting. Protective non-invasive ventilation using higher levels of positive-end expiratory pressure, more prolonged sessions and other interfaces such as the helmet may have beneficial physiological effects leading to it being proposed as alternative to high-flow nasal oxygen in acute hypoxemic respiratory failure. By contrast, non-invasive ventilation is the first-line strategy of oxygenation in patients with acute exacerbation of chronic lung disease, while high-flow nasal oxygen could be an alternative to non-invasive ventilation after partial reversal of respiratory acidosis. Questions remain about the target populations and non-invasive oxygen strategy representing the best alternative to standard oxygen in acute hypoxemic respiratory failure. As concerns acute on-chronic-respiratory failure, the place of high-flow nasal oxygen remains to be evaluated.

Severe Acute Respiratory Infection Surveillance during the Initial Phase of the COVID-19 Outbreak in North India: A Comparison of COVID-19 to Other SARI Causes.

IntroductionWorld Health Organization proposes severe acute respiratory infection (SARI) case definition for coronavirus disease 2019 (COVID-19) surveillance; however, early differentiation between SARI etiologies remains challenging. We aimed to investigate the spectrum and outcome of SARI and compare COVID-19 to non-COVID-19 causes.Patients and methodsA prospective cohort study was conducted between March 15, 2020, to August 15, 2020, at an adult medical emergency in North India. SARI was diagnosed using a “modified” case definition—febrile respiratory symptoms or radiographic evidence of pneumonia or acute respiratory distress syndrome of ≤14 days duration, along with a need for hospitalization and in the absence of an alternative etiology that fully explains the illness. COVID-19 was diagnosed with reverse transcription-polymerase chain reaction testing.ResultsIn total, 95/212 (44.8%) cases had COVID-19. Community-acquired pneumonia (n = 57), exacerbation of chronic lung disease (n = 11), heart failure (n = 11), tropical febrile illnesses (n = 10), and influenza A (n = 5) were common non-COVID-19 causes. No between-group differences were apparent in age ≥60 years, comorbidities, oxygenation, leukocytosis, lymphopenia, acute physiology and chronic health evaluation (APACHE)-II score, CURB-65 score, and ventilator requirement at 24-hour. Bilateral lung distribution and middle-lower zones involvement in radiography predicted COVID-19. The median hospital stay was longer with COVID-19 (12 versus 5 days, p = 0.000); however, mortality was similar (31.6% versus 28.2%, p = 0.593). Independent mortality predictors were higher mean APACHE II in COVID-19 and early ventilator requirement in non-COVID-19 cases.ConclusionsCOVID-19 has similar severity and mortality as non-COVID-19 SARI but requires an extended hospital stay. Including radiography in the SARI definition might improve COVID-19 surveillance.How to cite this articlePannu AK, Kumar M, Singh P, Shaji A, Ghosh A, Behera A, et al. Severe Acute Respiratory Infection Surveillance during the Initial Phase of the COVID-19 Outbreak in North India: A Comparison of COVID-19 to Other SARI Causes. Indian J Crit Care Med 2021;25(7):761–767.

A Case Report of Silicosis: Culprit of Progressive Massive Fibrosis

Silicosis is a fibronodular lung disease secondary to the inhalation of crystalline silica dust. It had continued to cause significant morbidity and mortality worldwide. Here is a case of a 63-year-old woman, a lifelong non-smoker who complained of intermittent wheezing since retired 8 years ago. She had worked in the clay and piping industry for more than a decade. She wore only a simple 3-ply face mask at work without other protective devices. She had multiple hospital admissions for acute exacerbation of chronic lung disease for the past several years. Respiratory examinations revealed bilateral fine crepitations and occasional rhonchi on auscultation. Chest radiograph revealed ground glass changes. Pulmonary function testing showed an irreversible severe obstruction picture with an FEV1 of 45%. High resolution computed tomography thorax demonstrated hyperinflated lungs with emphysematous changes and multiple nodules over subpleural region, conglomerate mass with calcifications over bilateral lungs. Her imaging findings combined with a significant occupational history were suggestive of progressive massive fibrosis (PMF) due to silicosis. She is currently being treated with several inhalers and does not require home oxygen therapy. She is suffering from accelerated silicosis which may potentially progress to radiological deterioration, altered respiratory function and premature death. Therefore, it is essential to avoid any potential hazards that may predispose to silicosis.

Bones Versus Teeth

Introduction: A 200% increase in population growth among those over 85 is projected in the United States by 2050. Approximately half of women over 50 will experience an osteoporotic fracture in their lifetime. Osteoporosis disproportionately affects old-old adults (those between 85 and 95) as more than half of those admitted to the hospital for hip fracture are over 80 years of age. Older adults are also likely to need dental care. The American Dental Association guidelines offer preventive recommendations for those over 60 years of age but do not address the nuances of treatment options for nonagenarian persons. This case illustrates the treatment dilemma of nonagenarians wishing to optimize both bone and dental health. Case: We have a 95-year-old performance artist, who seeks to optimize bone health in the face of recommended dental work. She has been physically active her whole life and consumes adequate quantities of calcium and Vitamin D. She doesn’t smoke but has needed periodic glucocorticoids for exacerbations of chronic lung disease. At age 84 she began ibandronate but stopped due to worsening of esophageal reflux. She was then treated with teriparatide for 2 years. DEXA scans have shown declining hip T scores from -2.8 at age 88 to -3.5 at age 94 (osteoporotic bone density: T-score lower than -2.5). Her dentist recommended the extraction of several teeth before beginning zoledronate. She refused tooth extraction and sought treatment options to enhance her bone density. Discussion: Persons of advanced age are likely to have oral health problems requiring dental treatment. Bone health treatments such as bisphosphonates and denosumab are generally safe but can potentially cause osteonecrosis of the jaw even with simple tooth extraction in old-old population. Specific guidelines are lacking for treatment to maintain bone and dental health. The American Association of Oral and Maxillofacial Surgeons suggests that extractions and implants can be conducted as usual in patients who have been treated with oral bisphosphonates for less than four years and lack other clinical risk factors. A delay of two months is suggested for those who have been treated for more than four years or has taken glucocorticoids concomitantly. The approach is uncertain for old-old adults who are taking treatment but develop a need for dental surgery. More research is needed about options for optimizing dental health while enhancing bone density in aging population.

Impact of Long-Term Azithromycin Therapy on Carriage and Resistance of Respiratory Bacteria Among Children with HIV-Associated Chronic Lung Disease: A Randomised Controlled Trial

Background: Long-term azithromycin (AZM) therapy is increasingly used to prevent acute exacerbations of chronic lung diseases (CLD). However, selection for resistance to macrolides and other antibiotics remains a concern. We investigated the impact of 48 weeks of AZM therapy on the carriage and antibiotic resistance of common respiratory bacteria in children and adolescents with HIV-associated CLD. Methods: Nasopharyngeal (NP) swabs and sputa were collected at baseline, 48 and 72 weeks from children and adolescents with HIV-associated CLD randomised to receive weekly AZM or placebo for 48 weeks and followed post-intervention up to 72 weeks. The primary outcomes were the prevalence of Streptococcus pneumoniae (SP), Staphylococcus aureus (SA), Haemophilus influenzae (HI), and Moraxella catarrhalis (MC) and their antibiotic resistance between the trial arms at 48 and 72 weeks. Mixed-effects logistic regression and Fisher's exact test were used to compare carriage and resistance, respectively. Findings: Between June 2016, and September 2018, 347 participants (174 AZM, 173 placebo arm) were enrolled (median age, 15 years [IQR = 13–18], females, 49%). NP carriage was significantly lower in the AZM compared to placebo arm at 48 weeks for SP (18% [29/159] vs 41% [64/153], adjusted odds ratio (aOR) 0·2 [95% CI 0·1–0·4]), HI (7% [11/159] vs 16% [24/153], aOR 0·3 [0·1–0·8]), or MC (4% [7/159] vs 11% [17/153], aOR 0·3 [0·1–0·8]). SP resistance to AZM (62% [18/29] vs 13% [8/63], p <0·0001) or tetracycline (60% [18/29] vs 21% [13/63], p <0·0001) were higher in the AZM arm at 48 weeks. Although, carriage of SA did not differ between the two arms, carriage of SA resistant to AZM (NP= 91% [31/34] vs 3% [1/31], p <0·0001), tetracycline (NP= 35% [12/34] vs 13% [4/31], p = 0·05) or clindamycin (NP= 79% [27/34] vs 3% [1/31], p <0·0001) was significantly higher in the AZM arm at 48 weeks and persisted at 72 weeks. The above observations were mirrored in sputum samples. Interpretation: Long-term AZM reduced carriage of SP, HI and MC but promoted antibiotic resistance in SP and SA; antibiotic-resistant SA persisted at 72 weeks from randomisation. This risk of drug resistance should be taken into account when long-term AZM therapy is being considered. Trial Registration: The trial registration number is ClinicalTrials.gov Identifier: NCT02426112 Funding: The Global Health and Vaccination Research (GLOBVAC) Programme of the Medical Research Council of Norway Declaration of Interest: None declared. Ethical Approval: Approval for the main trial was obtained from local regulatory bodies at the study sites and the research ethics committees of the London School of Hygiene and Tropical Medicine, the University of Cape Town, and the Medical and Health Research in Norway. This sub-study was approved by the Human Research Ethics Committee of the University of Cape Town (HREC/REF: 092/2019).

Noninvasive ventilation and high-flow nasal oxygen for acute respiratory failure: is less more?

High-flow nasal oxygen and noninvasive ventilation (NIV) are two strategies representing an alternative to standard oxygen in the management of respiratory failure. Although high-flow nasal oxygen has shown promising results in patients with de-novo acute respiratory failure, further large clinical trials are needed to determine the best oxygenation strategy. As NIV may have deleterious effects, especially in patients generating strong inspiratory efforts, protective NIV using higher levels of positive-end expiratory pressure, more prolonged sessions and additional interfaces such as helmets should be assessed in the future. Whereas NIV is the first-line ventilation strategy in patients with acute exacerbation of chronic lung diseases, high-flow nasal oxygen could be an alternative to NIV after partial reversal of respiratory acidosis. To prevent severe hypoxemia during intubation of hypoxemic patients or to prevent postextubation respiratory failure in patients at high-risk of reintubation, NIV is the best strategy for preoxygenation or immediately after extubation in ICUs. New large-scale clinical trials are needed to compare high-flow nasal oxygen with standard oxygen in patients with de-novo acute respiratory failure to determine the reference treatment. After which, more protective NIV could be assessed among the more severe patients.

Influenza vaccine uptake and its effectiveness in preventing hospitalisations among Australian children with chronic lung diseases

Background: Influenza is one of the main viral aetiologies associated with exacerbations of chronic lung diseases (CLDs) in children. Under the Australian Government's Immunisation Program, influenza vaccine is recommended for people aged ≥6 months with chronic medical conditions. However, there are limited data on uptake of influenza vaccine and its effectiveness in Australian children with CLDs. The aim of this study was to determine influenza vaccine uptake and its effectiveness in preventing influenza hospitalisation in children with CLDs using routinely collected administrative data. Methods and materials: We performed a retrospective cohort study using population-based linked administrative data for all children aged ≤17 years with CLDs (including asthma, cystic fibrosis, bronchopulmonary dysplasia and other chronic/congenital lung diseases) born in New South Wales and Western Australia between 2001 and 2012 with follow-up data until 2013. The 10th edition of the International Classification of Disease, Australian Modification codes from hospital datasets were used to identify the study cohort. The main exposure variable was influenza vaccination status obtained from the linked national immunisation registry. The primary outcome was any influenza-coded hospitalisation at least 14 days after vaccination retrieved from the hospital dataset. Cox regression models were used to assess the effectiveness of influenza vaccination in preventing influenza hospitalisation. Results: Of the 1,407,182 children born during 2001 and 2012, 18,954 children (1.4%) had one or more CLDs; 2479 children (13%) with CLDs received one or more doses of influenza vaccine. In total 1,499 children (8%) with CLDs were hospitalised for influenza at least once during the study period. The adjusted incidence/1000 child-years (95% CI) of influenza-associated hospitalisation in vaccinated children with CLD was 54.38 (42.04–69.75) and for unvaccinated children was 30.45 (29.04–31.93). The adjusted hazard ratio of being hospitalised with influenza in vaccinated children compared to unvaccinated children with CLDs was 1.48 (1.14–1.93). Conclusion: This large population-based study has demonstrated low uptake of influenza vaccine in children with CLDs which limits our ability to generate precise vaccine effectiveness estimates. Strategies to improve influenza vaccine uptake and recording of influenza vaccination status may provide better estimates for vaccine effectiveness.

Characteristics of COVID-19 at a non-COVID tertiary pulmonary care centre in Delhi, India.

The pandemic of COVID-19 has emerged as a serious health crisis globally and India too has been extensively affected with 604,641 active cases reported, till date. The present study focuses on the demographic, clinical and laboratory profile of such patients from a tertiary level non-COVID respiratory care hospital. This is a retrospective observational study. Seventy-seven sick patients fulfilling COVID suspect criteria were admitted to the isolation area. Their RT-PCR test was done from the designated laboratory and 35 of them were confirmed to be COVID-19 patients. The detailed demographic, clinical and laboratory profile of these COVID-19 patients was studied. The mean age was 46±17 years with male predominance (57%). Majority of the cases (83%) were symptomatic. The most common symptom was cough (66%) followed by breathlessness and fever. Nineteen (54.3%) patients had one or the other co-morbidity and 16 (45.7%) had chronic lung diseases as one of the comorbidities. Nearly half of the patients (51%) required supplementary oxygen on presentation. Two patients were put on invasive mechanical ventilation while 4 patients required non-invasive ventilation before being shifted to the COVID hospital. Hence, it can be concluded that COVID-19 in patients of chronic respiratory diseases manifests with higher prevalence of symptoms and also higher severity of disease. Further, the symptomatology of COVID-19 closely mimics the acute exacerbation of chronic lung diseases, so cautious screening and testing should be done, especially at the pulmonary department.

Natural Killer Cells and Host Defense Against Human Rhinoviruses Is Partially Dependent on Type I IFN Signaling.

Rhinovirus (RV), the causative agent of the common cold, causes only mild upper respiratory tract infections in healthy individuals, but can cause longer lasting and more severe pulmonary infections in people with chronic lung diseases and in the setting of immune suppression or immune deficiency. RV-infected lung structural cells release type I interferon (IFN-I), initiating the immune response, leading to protection against viruses in conjunction with migratory immune cells. However, IFN-I release is deficient in some people with asthma. Innate immune cells, such as natural killer (NK) cells, are proposed to play major roles in the control of viral infections, and may contribute to exacerbations of chronic lung diseases, such as asthma. In this study, we characterized the NK cell response to RV infection using an in vitro model of infection in healthy individuals, and determined the extent to which IFN-I signaling mediates this response. The results indicate that RV stimulation in vitro induces NK cell activation in healthy donors, leading to degranulation and the release of cytotoxic mediators and cytokines. IFN-I signaling was partly responsible for NK cell activation and functional responses to RV. Overall, our findings suggest the involvement of NK cells in the control of RV infection in healthy individuals. Further understanding of NK cell regulation may deepen our understanding of the mechanisms that contribute to susceptibility to RV infections in asthma and other chronic lung diseases.

Oral or intravenous antibiotics?

SUMMARYIntravenous antibiotics are overused in hospitals. Many infections can be managed with oral antibioticsOral antibiotics avoid the adverse effects of intravenous administration. They are also usually less expensiveWhen intravenous antibiotics are indicated, it may be possible to switch to oral therapy after a short course. There are guidelines to aid the clinician with the timing of the switch so that there is no loss of efficacyInfections that may be suitable for a short course of intravenous antibiotic include pneumonia, complicated urinary tract infections, certain intra-abdominal infections, Gram-negative bacteraemia, acute exacerbations of chronic lung disease, and skin and soft tissue infectionsBone and joint infections and infective endocarditis are managed with prolonged courses of intravenous antibiotics. However, there is research looking at the feasibility of an earlier switch to oral antibiotics in these conditions