Predictors of poor outcome in covid-19 infection, in a cohort of pediatric cancer patients, during the second wave in India. (preprint)

The second wave of COVID 19, far outnumbered the first, in cases and deaths. We report outcome of pediatric cancer patients with COVID-19 during the second wave, from a tertiary center in India. Out of 41 patients who tested positive; 51% were asymptomatic, 36% had mild symptoms, 12 required admissions in ward and 4 in intensive care. Mechanical ventilation, systemic steroids, Remdesivir and IVIG were required in those admitted to intensive care unit. Out of 4 deaths (9.7%), 3 occurred in adolescent age and 2 had superimposed bacterial/viral infections. Other contributors to mortality were: cachexia, airway obstruction, disease relapse.

Immune Resilience to SARS-CoV-2 Infection by Shifting Risk Within Normal and Disease Populations (preprint)

ABSTRACT: The idea of a Common Mucosal Immune system (CMS) is 50 years old. Its relevance to immune protection at mucosal sites and its potential to modulate the impact of vaccination-induced protection against infection of the airway, has been poorly understood. The consequent failure of current SARS-CoV-2 vaccination to satisfy expectations with respect to prevention of infection, viral transmission, duration of protection and pattern of clinical protection, led to public health and medical decisions now under review. This review summarises knowledge of the CMS in man, including the powerful role it plays in immune protection and lessons with respect to what can and can not be achieved by systemic and mucosal vaccination for prevention of airway infection. The powerful impact in both health and disease of optimising delivery of immune protection using selected isolates from the respiratory microbiome, is demonstrated through review of randomised controlled trials (RCT’s) in subjects with chronic airway disease, and in otherwise healthy individuals with risk factors, in whom the idea of mucosal immune resilience is introduced.

[A CASE OF INDUCIBLE LARYNGEAL OBSTRUCTION UNSUCCESSFULLY TREATED AS SEVERE ASTHMA WAS WELL CONTROLLED AFTER APPROPRIATE DIAGNOSIS AND INSTRUCTION OF THERAPEUTIC BREATHING MANEUVERS].

BACKGROUND: Inducible laryngeal obstruction (ILO) refers to respiratory disorders caused by airflow limitation in the larynx, including vocal cord dysfunction, and may sometimes be misdiagnosed as bronchial asthma (BA). Here, we report the case of an 11-year-old boy diagnosed with BA in infancy. He was referred to our Allergy Center and was taking a high dose of inhaled corticosteroids (ICS) due to frequent coughing from the age of 10 years and persistent coughing following COVID-19 infection at the age of 11. However, the patient continued to experience frequent coughing attacks and repeated visits to the emergency department after inhalation of ß2-stimulants failed to improve his cough. We admitted him to the allergy center for examinations to assess the BA severity. In the airway hypersensitiveness test, saline inhalation performed prior to methacholine inhalation caused expiratory stridor and respiratory distress in the larynx, which worsened with ß2-stimulant inhalation. Based on these results, we ruled out BA and diagnosed ILO. We instructed him on breathing maneuvers, and he was able to respond appropriately when symptoms appeared. We then started reducing his ICS dose.

Is abestos exposure a risk factor for small airways obstruction?

SUMMARY: To the editor, during these pandemic years, COVID-19 is taking away focus from other respiratory diseases such as pneumoconiosis, which should not be overlooked. We would like to emphasize the possible role of small airways in subjects with asbestos exposure. In a very interesting study, Yang et al (1) investigated the relation between increased small airway obstruction and asbestos exposure in patients with asbestosis. The authors evaluated lung function in a cohort of 281 patients with newly diagnosed asbestosis during an eight-year period, evidencing that patients with asbestosis have small airway obstructive defects that are significantly associated with asbestos exposure (1). These results are very consistent and in line with our previous study, in which we showed that a population of 655 long-term residents in an environmental asbestos (tremolite)-exposed area had a higher prevalence of smallairways disease compared to a group of 653 individuals living in areas not tremolite-exposed (2). Odds Ratio for small-airways obstruction was 3.46, irrespective of smoking status (2). To date, our knowledge on the role of small airways in pulmonary diseases is still matter of debate. Although small airways have a minor contribution to airway resistance in healthy subjects, it has been shown that small airways are the major site of airflow limitation in diseases such as asthma and Chronic Obstructive Pulmonary Disease (3). Taken these data together, we warmly encourage clinicians and researchers to always consider small airways parameters when performing lung function on asbestosexposed subjects. Moreover, long-term investigations are warranted to explore the decline in airflow over time in patients with either occupational or environmental asbestos exposure and with asbestosis.

COVID-19 and Speech-Language Pathology Clinical Practice of Voice and Upper Airway Disorders.

Purpose Evaluation and management of voice and upper airway disorders in adults and children, by speech-language pathologists worldwide, have been significantly altered by the COVID-19 pandemic. Secondary to the pathogenic nature of the virus in the respiratory tract and upper airway, it is essential that speech-language pathologists who specialize in these disorders are knowledgeable of current practices to provide evidence-based care while minimizing viral transmission. Understanding how and when SARS-CoV-2 spreads is critical to the development of effective infection prevention within clinical practices. Method We established an evidence-based clinical practice guide for clinicians working with voice and upper airway through a comprehensive evaluation of peer-reviewed journals, non-peer-reviewed manuscripts on preprint servers, national health guidelines, and published and online consensus statements and emerging data. Emphasis was placed on risk mitigation for viral transmission via safe clinical practices, including evaluative procedures, therapy including telehealth, personal protective equipment, room, staffing, and distancing considerations. Results/Conclusions While knowledge relevant to viral transmission of SARS-CoV-2 is rapidly evolving, there is a paucity of literature specific to the evaluation and treatment of voice and upper airway disorders. Within these confines and given the potentially significant high risk of infection secondary to the nature of COVID-19, we summarize current considerations and recommend best practices that maximize risk mitigation whereby ensuring patient and provider safety.

Acute upper airway disease in children with the omicron (B.1.1.529) variant of SARS-CoV-2: a report from the National COVID Cohort Collaborative (N3C) (preprint)

Background: Reports of SARS-CoV-2 causing laryngotracheobronchitis (commonly known as croup) have been limited to small case series. Early reports suggest the Omicron (B.1.1.529) strain of SARS-CoV-2 (the dominant circulating US strain since the week of 12/25/2021) replicates more efficiently in the conducting airways. This may increase the risk of a croup phenotype in children as they have smaller airway calibers. Methods: Description of the incidence, change over time, and characteristics of children with SARS-CoV-2 and upper airway infection (UAI) diagnoses within the National COVID Cohort Collaborative (N3C) before and during the rise of the Omicron variant. We compare the demographics, comorbidities, and clinical outcomes of hospitalized SARS-CoV-2 positive children with and without UAI. Results: SARS-CoV-2 positive UAI cases increased to the highest number per month (N = 170) in December 2021 as the Omicron variant became dominant. Of 15,806 hospitalized children with SARS-CoV-2, 1.5% (234/15,806) had an UAI diagnosis. Those with UAI were more likely to be male, younger, white, have asthma and develop severe disease as compared to those without UAI. Conclusions: Pediatric acute UAI cases have increased during the Omicron variant surge with many developing severe disease. Improved understanding of this emerging clinical phenotype could aid in therapeutic decision-making and healthcare resource planning.

Fibrin airway cast obstruction: Experience, classification, and treatment guideline from Denver.

BACKGROUND AND OBJECTIVES: Plastic bronchitis (PB) is a condition characterized by the formation of thick airway casts leading to acute and often life-threatening airway obstruction. PB occurs mainly in pediatric patients with congenital heart disease (CHO) who have undergone staged surgical palliation (Glenn, Fontan), but can also occur after chemical inhalation, H1N1, severe COVID-19, sickle cell disease, severe asthma, and other diseases. Mortality risk from PB can be up to 40%-60%, and no treatment guideline exist. The objectives herein are to develop a standardized evaluation, classification, and treatment guideline for PB patients presenting with tracheobronchial casts, based on our experience with PB at the Children's Hospital of Colorado in Denver. METHODS: We describe 11 patients with CHO-associated PB (post-Fontan [n = 9], pre-Fontan [n = 2]) who presented with their initial episodes. We utilized histopathological analysis of tracheobronchial casts to guide treatment in these patients, utilizing our hospital-wide guideline document and classification system. RESULTS: We found that 100% of post-Fontan PB patients had fibrinous airway casts, while pre-Fontan PB casts were fibrinous only in one of two patients (50%). Utilizing histopathology as a guide to therapy, PB patients with fibrin airway casts were treated with airway-delivered fibrinolytics and anticoagulants, as well as aggressive airway clearance and other supportive care measures. These therapies resulted in successful cast resolution and improved survival in post-Fontan PB patients. CONCLUSION: We have shown an improved outcome in PB patients whose treatment plan was based on Denver's PB classification schema and standardized treatment guideline based on tracheobronchial cast histopathology.

Congenital Hairy Polyp Causing Severe Upper Airway Obstruction in a Newborn: A Case Report.

BACKGROUND Hairy polyps are rare tumors mainly comprising fatty tissues covered by skin and hair follicles, with varied localizations and sizes. Early excision of the polyps by surgery is an effective treatment resulting in a permanent cure. We present a case of successful management of severe obstruction of the oropharynx in a newborn who presented with a large mass of congenital hairy polyp. CASE REPORT A vaginally delivered infant, weighing 3 kg, presented immediately after birth with cyanosis symptoms, failure of the first cry, and respiratory distress signs. The newborn was born to a mother with an uneventful pregnancy. Screening tests during the pregnancy reported no congenital anomalies. The newborn's hematological and biochemical test results were normal. After presenting these symptoms, the newborn was immediately intubated and put on a nasogastric feeding tube, which revealed a small portion of a polyp-like mass. A computed tomography (CT) scan further confirmed a large pedunculated mass, measuring 3×2 cm, arising from the soft palate, and obstructing the oropharynx. Histopathological examination confirmed the presence of a hairy polyp. The polyp was wholly removed transorally using the Covidien LigaSure device without the need for endoscopy. This procedure allowed safe extubation, and the baby was discharged home without symptoms 4 days after birth. CONCLUSIONS This case sheds light on the importance of considering hairy polyp in the differential diagnosis of pharyngeal mass with respiratory distress in pediatric patients. This report also describes our experience using the LigaSure surgical device without needing endoscopic visualization to successfully resect the hairy polyp without complications.

Acute upper airway obstruction due to tonsillitis necessitating emergency cricothyroidotomy.

A 17-year-old man was admitted to Accident & Emergency out of hours with unilateral tonsillar enlargement covering more than 75% of his oropharyngeal inlet. He appeared calm and stable on initial presentation, but in a short span of time rapidly deteriorated, leading to near complete airway obstruction necessitating an emergency awake cricothyroidotomy. Tracheostomy and tonsillectomy were done after this, he was ventilated postoperatively in intensive therapy unit and discharged home in a week. This is a rare clinical scenario in a patient presenting with palatine tonsillitis. A few subtle points in the history and examination alerted the team and prevented a risky inter hospital transfer for ear, nose and throat review. This is the first reported case in UK of palatine tonsillitis not due to infectious mononucleosis presenting with acute upper airway obstruction in a patient with no airway anomalies. It may also have been a varied presentation of COVID-19.

Ventilation Monitoring.

Ventilation or breathing is vital for life yet is not well monitored in hospital or at home. Respiratory rate is a neglected vital sign and tidal volumes together with breath sounds are checked infrequently in many patients. Medications with the potential to depress ventilation are frequently administered, and may be accentuated by obesity causing airway obstruction in the form of sleep apnea. Sepsis may adversely affect ventilation by causing an increase in respiratory rate, often a very early sign of infection. Changes in ventilation may be early signs of deterioration in the patient.

VEGF receptor 2 (KDR) protects airways from mucus metaplasia through a Sox9-dependent pathway.

Mucus-secreting goblet cells are the dominant cell type in pulmonary diseases, e.g., asthma and cystic fibrosis (CF), leading to pathologic mucus metaplasia and airway obstruction. Cytokines including IL-13 are the major players in the transdifferentiation of club cells into goblet cells. Unexpectedly, we have uncovered a previously undescribed pathway promoting mucous metaplasia that involves VEGFa and its receptor KDR. Single-cell RNA sequencing analysis coupled with genetic mouse modeling demonstrates that loss of epithelial VEGFa, KDR, or MEK/ERK kinase promotes excessive club-to-goblet transdifferentiation during development and regeneration. Sox9 is required for goblet cell differentiation following Kdr inhibition in both mouse and human club cells. Significantly, airway mucous metaplasia in asthmatic and CF patients is also associated with reduced KDR signaling and increased SOX9 expression. Together, these findings reveal an unexpected role for VEGFa/KDR signaling in the defense against mucous metaplasia, offering a potential therapeutic target for this common airway pathology.

Assessment of the infectious threshold of SARS-CoV-2 in primary airway epithelial cells (preprint)

Comparison of virus isolation success from clinical samples across a range of viral loads inoculated in parallel on Vero E6 and human airway epithelia (HAE) showed lower success of virus isolation in HAE, suggesting an overestimation of actual infectiousness in humans using Vero E6 cell lines, commonly considered as reference.

ProLung™-budesonide Inhibits SARS-CoV-2 Replication and Reduces Lung Inflammation (preprint)

Background: Inhaled budesonide benefits patients with COVID 19. ProLung budesonide enables the sustained, low dose administration of budesonide within a delivery vehicle similar to lung surfactant. ProLung budesonide may offer anti-inflammatory and protective effects to the lung in COVID 19, yet its effect on SARS CoV 2 replication is unknown. Objective: To determine the efficacy of ProLung budesonide against SARS CoV 2 infection in vitro, evaluate its ability to decrease inflammation, and airway hyperresponsiveness in an animal model of lung inflammation. Methods: SARS CoV 2 infected Vero 76 cells were treated with ProLung budesonide ([0.03 to 100 ug/ml]) for 3 days, and virus yield in the supernatant was measured. Ovalbumin-sensitized C57BL/6 mice received aerosolized (a) ProLung budesonide weekly, (b) only budesonide, either daily or weekly, or (c) weekly empty ProLung carrier (without budesonide). All treatment groups were compared to sensitized untreated, or normal mice using histopathologic examination, electron microscopy (EM), airway hyperresponsiveness (AHR) to Methacholine (Mch) challenge, and eosinophil peroxidase activity (EPO) measurements in bronchioalveolar lavage (BAL). Results: ProLung budesonide showed significant inhibition on viral replication of SARS CoV 2 infected cells with the selectivity index (SI) value > 24. Weekly ProLung budesonide and daily budesonide therapy significantly decreased lung inflammation and EPO in BAL. ProLung budesonide localized in type II pneumocytes, and was the only group to significantly decrease AHR, and EPO in BAL with Mch challenge. Conclusions: ProLung budesonide significantly inhibited viral replication in SARS CoV 2 infected cells. It localized into type II pneumocytes, decreased lung inflammation, AHR and EPO activity with Mch challenge. This novel drug formulation may offer a potential inhalational treatment for COVID 19.

Positive end-expiratory pressure in COVID-19-related ARDS: Do not forget the airway closure.

Airway closure is a physiological phenomenon in which the distal airways are obstructed when the airway pressure drops below the airway opening pressure. We assessed this phenomenon in 27 patients with coronavirus disease 2019-related acute respiratory distress syndrome. Twelve (44%) patients had an airway opening pressure above 5 cmH2O. The median airway opening pressure was 8 cmH2O (interquartile range, 7-10), with a maximum value of 17 cmH2O. Three patients had a baseline positive end-expiratory pressure lower than the airway opening pressure.

Ventilated Patients With COVID-19 Show Airflow Obstruction.

OBJECTIVE: Many patients with coronavirus disease 2019 (COVID-19) need mechanical ventilation secondary to acute respiratory distress syndrome. Information on the respiratory system mechanical characteristics of this disease is limited. The aim of this study is to describe the respiratory system mechanical properties of ventilated COVID-19 patients. DESIGN, SETTING, AND PATIENTS: Patients consecutively admitted to the medical intensive care unit at the University of Iowa Hospitals and Clinics in Iowa City, USA, from April 19 to May 1, 2020, were prospectively studied; final date of follow-up was May 1, 2020. MEASUREMENTS: At the time of first patient contact, ventilator information was collected including mode, settings, peak airway pressure, plateau pressure, and total positive end expiratory pressure. Indices of airflow resistance and respiratory system compliance were calculated and analyzed. MAIN RESULTS: The mean age of the patients was 58 years. 6 out of 12 (50%) patients were female. Of the 21 laboratory-confirmed COVID-19 patients on invasive mechanical ventilation, 9 patients who were actively breathing on the ventilator were excluded. All the patients included were on volume-control mode. Mean [±standard deviation] ventilator indices were: resistive pressure 19 [±4] cmH2O, airway resistance 20 [±4] cmH2O/L/s, and respiratory system static compliance 39 [±16] ml/cmH2O. These values are consistent with abnormally elevated resistance to airflow and reduced respiratory system compliance. Analysis of flow waveform graphics revealed a pattern consistent with airflow obstruction in all patients. CONCLUSIONS: Severe respiratory failure due to COVID-19 is regularly associated with airflow obstruction.