GM-CSF: Orchestrating the Pulmonary Response to Infection

This review summarizes the structure and function of the alveolar unit, comprised of alveolar macrophage and epithelial cell types that work in tandem to respond to infection. Granulocyte-macrophage colony-stimulating factor (GM-CSF) helps to maintain the alveolar epithelium and pulmonary immune system under physiological conditions and plays a critical role in restoring homeostasis under pathologic conditions, including infection. Given the emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and global spread of coronavirus disease 2019 (COVID-19), with subsequent acute respiratory distress syndrome, understanding basic lung physiology in infectious diseases is especially warranted. This review summarizes clinical and preclinical data for GM-CSF in respiratory infections, and the rationale for sargramostim (yeast-derived recombinant human [rhu] GM-CSF) as adjunctive treatment for COVID-19 and other pulmonary infectious diseases.

Covid Adult Mortality in Brazil: An Analysis of Multiple Causes of Death

ObjectiveThis study aimed to analyze the chain of events and contributing causes associated with COVID-19 adult mortality (30–69 years old), based on qualified data on CoD from three Brazilian capitals cities, Belo Horizonte, Salvador, and Natal, in 2020.MethodsData of all deaths among residents in the three capitals in 2020 were provided by these municipalities' routine Mortality Information System (SIM). Mentions B34.2 with the markers U07.1 and U07.2 in the death certificate identified COVID-19 deaths. We used a multiple-cause-of-death approach better to understand the complexity of the morbid process of COVID-19. Conditions that appeared more frequently in the same line or above the COVID-19 mentions in the death certificate were considered a chain-of-event. Conditions that occurred more often after the codes for COVID-19 were considered as contributing.ResultsIn 2020, 7,029 records from COVID-19 as the underlying cause of death were registered in SIM in the three capitals. Among these, 2,921 (41.6%) were deceased between 30 and 69 years old, representing 17.0% of deaths in this age group. As chain-of-events, the most frequent conditions mentioned were sepsis (33.4%), SARS (32.0%), acute respiratory failure (31.9%), unspecified lower respiratory infections (unspecified pneumonia) (20.1%), and other specified respiratory disorders (14.1%). Hypertension (33.3%), diabetes unspecified type (21.7%), renal failure (12.7%), obesity (9.8%), other chronic kidney diseases (4.9%), and diabetes mellitus type 2 (4.7%) were the most frequent contributing conditions. On average, 3.04 conditions were mentioned in the death certificate besides COVID-19. This average varied according to age, place of death, and capital.ConclusionThe multiple-cause analysis is a powerful tool to better understand the morbid process due to COVID-19 and highlight the importance of chronic non-communicable diseases as contributing conditions.

First-Response ABCDE Management of Status Epilepticus: A Prospective High-Fidelity Simulation Study

Respiratory infections following status epilepticus (SE) are frequent, and associated with higher mortality, prolonged ICU stay, and higher rates of refractory SE. Lack of airway protection may contribute to respiratory infectious complications. This study investigates the order and frequency of physicians treating a simulated SE following a systematic Airways-Breathing-Circulation-Disability-Exposure (ABCDE) approach, identifies risk factors for non-adherence, and analyzes the compliance of an ABCDE guided approach to SE with current guidelines. We conducted a prospective single-blinded high-fidelity trial at a Swiss academic simulator training center. Physicians of different affiliations were confronted with a simulated SE. Physicians (n = 74) recognized SE and performed a median of four of the five ABCDE checks (interquartile range 3–4). Thereof, 5% performed a complete assessment. Airways were checked within the recommended timeframe in 46%, breathing in 66%, circulation in 92%, and disability in 96%. Head-to-toe (exposure) examination was performed in 15%. Airways were protected in a timely manner in 14%, oxygen supplied in 69%, and antiseizure drugs (ASDs) administered in 99%. Participants’ neurologic affiliation was associated with performance of fewer checks (regression coefficient −0.49; p = 0.015). We conclude that adherence to the ABCDE approach in a simulated SE was infrequent, but, if followed, resulted in adherence to treatment steps and more frequent protection of airways.

Reducing Unnecessary Respiratory Viral Testing to Promote High-Value Care

BACKGROUND AND OBJECTIVES: Viral respiratory infections are common in children, and practice guidelines do not recommend routine testing for typical viral illnesses. Despite results often not impacting care, nasopharyngeal swabs for viral testing are frequently performed and are an uncomfortable procedure. The aim of this initiative was to decrease unnecessary respiratory viral testing (RVT) in the emergency department (ED) and the pediatric medicine wards (PMWs) by 50% and 25%, respectively, over 36 months. METHODS: An expert panel reviewed published guidelines and appropriate evidence to formulate an RVT pathway using plan-do-study-act cycles. A multifaceted improvement strategy was developed that included implementing 2 newer, more effective tests when testing was deemed necessary; electronic order modifications with force functions; audit and feedback; and education. By using statistical process control charts, the outcomes analyzed were the percentage of RVT ordered in the ED and the rate of RVT ordered on the PMWs. Balancing measures included return visits leading to admission and inpatient viral nosocomial outbreaks. RESULTS: The RVT rate decreased from a mean of 3.0% to 0.5% of ED visits and from 44.3 to 30.1 per 1000 patient days on the PMWs and was sustained throughout the study. Even when accounting for the new rapid influenza test available in the ED, a 50% decrease in overall ED RVT was still achieved without any significant impact on return visits leading to admission or inpatient nosocomial infections. CONCLUSIONS: Through implementation of a standardized, electronically integrated RVT pathway, a decrease in unnecessary RVT was successfully achieved. Audit and feedback, reminders, and biannual education all supported long-term sustainability of this initiative.

Fatal Pneumonia Associated With a Novel Genotype of Human Coronavirus OC43

Since its first discovery in 1967, human coronavirus OC43 (HCoV-OC43) has been associated with mild self-limiting upper respiratory infections worldwide. Fatal primary pneumonia due to HCoV-OC43 is not frequently described. This study describes a case of fatal primary pneumonia associated with HCoV-OC43 in a 75-year-old patient with good past health. The viral loads of the respiratory tract specimens (bronchoalveolar lavage and endotracheal aspirate) from diagnosis to death were persistently high (3.49 × 106–1.10 × 1010 copies/ml). HCoV-OC43 at a 6.46 × 103 copies/ml level was also detected from his pleural fluid 2 days before his death. Complete genome sequencing and phylogenetic analysis showed that the present HCoV-OC43 forms a distinct cluster with three other HCoV-OC43 from United States, with a bootstrap value of 100% and sharing 99.9% nucleotide identities. Pairwise genetic distance between this cluster and other HCoV-OC43 genotypes ranged from 0.27 ± 0.02% to 1.25 ± 0.01%. In contrast, the lowest pairwise genetic distance between existing HCoV-OC43 genotypes was 0.26 ± 0.02%, suggesting that this cluster constitutes a novel HCoV-OC43 genotype, which we named genotype I. Unlike genotypes D, E, F, G, and H, no recombination event was observed for this novel genotype. Structural modeling revealed that the loop with the S1/S2 cleavage site was four amino acids longer than other HCoV-OC43, making it more exposed and accessible to protease, which may have resulted in its possible hypervirulence.

Patients’ and clinicians’ perspectives on the primary care consultations for acute respiratory infections during the first wave of the COVID-19 pandemic: an eight-country qualitative study in Europe

BackgroundThe impact of the COVID-19 pandemic on patients’ and clinicians’ perceptions of healthcare-seeking behaviour and delivery of care is unclear. The pandemic accelerated the use of remote care and understanding its benefits and drawbacks may inform its implementation during this and future healthcare emergencies.AimTo explore patients’ and primary care professionals’ (PCPs) experiences of primary care delivery in the first wave of the pandemic.Design & settingQualitative study using semi-structured interviews in primary care in eight European countriesResultsWe conducted 146 interviews with 80 PCPs and 66 patients consulting for respiratory tract infection (RTI) symptoms, in eight European countries (England, Ireland, Belgium, the Netherlands, Greece, Poland, Sweden and Germany). Data was collected between April and July 2020 and analysed using thematic analysis. We found that patients accepted telemedicine when PCPs spent time to understand and address their concerns, but a minority preferred in-person consultations. PCPs felt that remote consultations created emotional distance between themselves and patients, and they reported having to manage diverse COVID-19-related medical and social concerns.ConclusionRemote consultations for RTI symptoms may be acceptable long-term if both groups are happy to use this format but it is important that PCPs take time to address patients’ concerns and provide safety-netting advice.

An open-label, pilot study to evaluate the benefits of using lyophilized human milk-derived nutritional product (NeoLact 70 – 1.55 g) as an immune-nutritional supplement in premature infants discharged from NICU

Background: Premature and low birth weight (LBW) infants are at increased risk of having inadequate growth in post-discharge periods. In this study, lyophilized human milk was used as an immune-nutrition supplement along with breastfeeding for a period of 1 month in preterm infants discharged from neonatal intensive care unit (NICU). Objectives: Primary objective was to assess the percentage change in serum immunoglobulins for the duration of supplementation, and secondary objectives were to correlate changes in immunoglobulins to number of episodes of infections including respiratory infections and diarrhea, requirement of antibiotics, weight gain, and episodes of feed intolerance during the study period. Methods: A total of 10 preterm and LBW infants were included in the study at the time of discharge from NICU after satisfying the inclusion and exclusion criteria. The serum immunoglobulins were estimated at baseline and at end of the study, other parameters such as episodes of infections, feed intolerance, and weight gain were recorded on the weekly follow-up visits. All the infants received supplementation with NeoLact 70 – 1.55 g on a TID frequency along with the regular breastfeeding for a period of 1-month post-discharge from NICU and were followed up on a weekly basis. Results: Ten infants completed the study, mean birth weight and gestational age were 1779.4±576 gm and 33.5±4.9 weeks, respectively. There was increase in immunoglobulins IgA, IgE, IgG, and IgM by 38.29%, 85.36%, 17.45%, and 48.25%, respectively, from baseline to end of study. None of the infants experienced feeding intolerance, diarrhea, abdominal distension, fever, respiratory infections, or rehospitalizations, none of the infants required antibiotics or probiotics during the study period. The average weight gain in the 1st, 2nd, 3rd, and 4th week of supplementation was 28.42 g/day, 31.57 g/day, 35.17 g/day, and 39.24 g/day, respectively, with a mean weight gain of 30.4 g/day achieved for the entire duration of the study. Conclusion: The immune-nutritional supplementation with lyophilized human milk (NeoLact 70 – 1.55 g) helps to ensure exclusive human milk diet post-discharge and reduce the risk of infections, diarrhea, and rehospitalization through the enhancement of immunoglobulins and ensuring optimal weight gain. However, these results should be confirmed through multicentric studies with larger sample size. Supplementation with NeoLact 70 – 1.55 g can clinically benefit premature and LBW infants post-discharge.

The Effects of Heatwaves on Human Morbidity in Primary Care Settings: A Case-Crossover Study

Purpose: This study assesses the potential acute effects of heatwaves on human morbidities in primary care settings. Methods: We performed a time-stratified case-crossover study to assess the acute effects of heatwaves on selected morbidities in primary care settings in Flanders, Belgium, between 2000 and 2015. We used conditional logistic regression models. We assessed the effect of heatwaves on the day of the event (lag 0) and X days earlier (lags 1 to X). The associations are presented as Incidence Density Ratios (IDR). Results: We included 22,344 events. Heatwaves are associated with increased heat-related morbidities such as heat stroke IDR 3.93 [2.94–5.26] at lag 0, dehydration IDR 3.93 [2.94–5.26] at lag 1, and orthostatic hypotension IDR 2.06 [1.37–3.10] at lag 1. For cardiovascular morbidities studied, there was only an increased risk of stroke at lag 3 IDR 1.45 [1.04–2.03]. There is no significant association with myocardial ischemia/infarction or arrhythmia. Heatwaves are associated with decreased respiratory infection risk. The IDR for upper respiratory infections is 0.82 [0.78–0.87] lag 1 and lower respiratory infections (LRI) is 0.82 [0.74–0.91] at lag 1. There was no significant effect modification by age or premorbid chronic disease (diabetes, hypertesnsion). Conclusion: Heatwaves are associated with increased heat-related morbidities and decreased respiratory infection risk. The study of heatwaves’ effects in primary care settings helps evaluate the impact of heatwaves on the general population. Primary care settings might be not suitable to study acute life-threatening morbidities.

Indirect effects of the covid-19 pandemic on childhood infection in England: population based observational study

ObjectiveTo assess the impact of the covid-19 pandemic on hospital admission rates and mortality outcomes for childhood respiratory infections, severe invasive infections, and vaccine preventable disease in England.DesignPopulation based observational study of 19 common childhood respiratory, severe invasive, and vaccine preventable infections, comparing hospital admission rates and mortality outcomes before and after the onset of the pandemic in England.SettingHospital admission data from every NHS hospital in England from 1 March 2017 to 30 June 2021 with record linkage to national mortality data.PopulationChildren aged 0-14 years admitted to an NHS hospital with a selected childhood infection from 1 March 2017 to 30 June 2021.Main outcome measuresFor each infection, numbers of hospital admissions every month from 1 March 2017 to 30 June 2021, percentage changes in the number of hospital admissions before and after 1 March 2020, and adjusted odds ratios to compare 60 day case fatality outcomes before and after 1 March 2020.ResultsAfter 1 March 2020, substantial and sustained reductions in hospital admissions were found for all but one of the 19 infective conditions studied. Among the respiratory infections, the greatest percentage reductions were for influenza (mean annual number admitted between 1 March 2017 and 29 February 2020 was 5379 and number of children admitted from 1 March 2020 to 28 February 2021 was 304, 94% reduction, 95% confidence interval 89% to 97%), and bronchiolitis (from 51 655 to 9423, 82% reduction, 95% confidence interval 79% to 84%). Among the severe invasive infections, the greatest reduction was for meningitis (50% reduction, 47% to 52%). For the vaccine preventable infections, reductions ranged from 53% (32% to 68%) for mumps to 90% (80% to 95%) for measles. Reductions were seen across all demographic subgroups and in children with underlying comorbidities. Corresponding decreases were also found for the absolute numbers of 60 day case fatalities, although the proportion of children admitted for pneumonia who died within 60 days increased (age-sex adjusted odds ratio 1.71, 95% confidence interval 1.43 to 2.05). More recent data indicate that some respiratory infections increased to higher levels than usual after May 2021.ConclusionsDuring the covid-19 pandemic, a range of behavioural changes (adoption of non-pharmacological interventions) and societal strategies (school closures, lockdowns, and restricted travel) were used to reduce transmission of SARS-CoV-2, which also reduced admissions for common and severe childhood infections. Continued monitoring of these infections is required as social restrictions evolve.