Bilateral spontaneous pneumothorax as a late complication of COVID-19, a case report (preprint)

The first case of sever pneumonia caused by coronavirus (COVID-19) was detected in Wuhan, China in December 2019 and spread rapidly around the world. Pneumothorax has been reported as an uncommon complication following COVID-19 infection which caused by alveolar rupture, air leakage and interstitial emphysema after alveolar damages. Bilateral pneumothorax is also an uncommon life threatening complication induced by COVID-19 which has to be considered in patients present with late sudden dyspnea after Coronavirus infection. In this case report, we are presenting a patient with mild COVID-19 pneumonia with a left massive pneumothorax following a late sudden dyspnea in third week of the disease, during the hospitalization, in addition to aggravating the respiratory condition, right pneumothorax was also added.

Improving Fairness of Automated Chest X-ray Diagnosis by Contrastive Learning (preprint)

Purpose: Limited studies exploring concrete methods or approaches to tackle and enhance model fairness in the radiology domain. Our proposed AI model utilizes supervised contrastive learning to minimize bias in CXR diagnosis. Materials and Methods: In this retrospective study, we evaluated our proposed method on two datasets: the Medical Imaging and Data Resource Center (MIDRC) dataset with 77,887 CXR images from 27,796 patients collected as of April 20, 2023 for COVID-19 diagnosis, and the NIH Chest X-ray (NIH-CXR) dataset with 112,120 CXR images from 30,805 patients collected between 1992 and 2015. In the NIH-CXR dataset, thoracic abnormalities include atelectasis, cardiomegaly, effusion, infiltration, mass, nodule, pneumonia, pneumothorax, consolidation, edema, emphysema, fibrosis, pleural thickening, or hernia. Our proposed method utilizes supervised contrastive learning with carefully selected positive and negative samples to generate fair image embeddings, which are fine-tuned for subsequent tasks to reduce bias in chest X-ray (CXR) diagnosis. We evaluated the methods using the marginal AUC difference ($\delta$ mAUC). Results: The proposed model showed a significant decrease in bias across all subgroups when compared to the baseline models, as evidenced by a paired T-test (p<0.0001). The $\delta$ mAUC obtained by our method were 0.0116 (95\% CI, 0.0110-0.0123), 0.2102 (95% CI, 0.2087-0.2118), and 0.1000 (95\% CI, 0.0988-0.1011) for sex, race, and age on MIDRC, and 0.0090 (95\% CI, 0.0082-0.0097) for sex and 0.0512 (95% CI, 0.0512-0.0532) for age on NIH-CXR, respectively. Conclusion: Employing supervised contrastive learning can mitigate bias in CXR diagnosis, addressing concerns of fairness and reliability in deep learning-based diagnostic methods.

Isolated renal mucormycosis masquerading as emphysematous pyelonephritis.

Mucormycosis is an acute, life-threatening infection and isolated renal involvement is rare. Due to the angioinvasive nature of the disease, it is rapidly progressive and can be lethal if not managed expeditiously. In patients with underlying conditions of immunosuppression, diabetes mellitus, transplantation, COVID-19, intravenous drug and substance use and pyelonephritis, which is unable to be controlled via regular antibiotics, mucormycosis must be considered on the differential and antifungals must be empirically started. Most cases are often diagnosed on histopathology, which causes delayed treatment and resolution. We present a case of emphysematous pyelonephritis diagnosed on imaging and was later found to have mucormycosis on histopathological examination.

Ventilator management and risk of air leak syndrome for patients with COVID-19 pneumonia: a single-center, retrospective, observational study (preprint)

Background: Coronavirus disease 2019 (COVID-19) pneumonia is reportedly associated with air leak syndrome (ALS), including mediastinal emphysema and pneumothorax, and has a high mortality rate. In this study, we compared values obtained every minute from ventilators to clarify the relationship between ventilator management (VM) and risk of developing ALS. Methods This single-center, retrospective, observational study took place at a tertiary care hospital in Tokyo, Japan, over a 21-month period. Patient background, ventilator data, and outcomes were collected from adult patients with COVID-19 pneumonia on VM. Patients who developed ALS within 30 days of VM initiation (ALS group) were compared with those who did not (non-ALS group). Results: Of the 105 patients, 14 (13%) developed ALS. The mean positive-end expiratory pressure (PEEP) difference was 0.33 cmH2O (95% confidence interval [CI], 0.31 to 0.33), and was higher in the ALS than in the non-ALS group (9.18 ± 2.20 vs. 8.85 ± 2.63, respectively). For peak pressure, the mean difference was − 0.18 cmH2O (95% CI, -0.20 to -0.15) (20.70 ± 5.30 in ALS vs. 20.87 ± 5.65 in non-ALS group) and the mean pressure difference of -0.05 cmH2O (95% CI, -0.04 to -0.07) (12.80 ± 3.13 vs. 12.85 ± 3.55, respectively) was also higher in the non-ALS group. The difference in single ventilation volume per ideal body weight was 0.65 mL/kg (95% CI, 0.63 to 0.66) (7.83 ± 3.16 vs. 7.18 ± 2.96, respectively), and the difference in dynamic lung compliance was 8.57 mL/cmH2O (95% CI, 8.43 to 8.70) (50.32 ± 31.68 vs. 49.68 ± 15.16, respectively); both were higher in the ALS group. Conclusions: There was no association between higher ventilator pressures and the development of ALS. The ALS group had higher dynamic lung compliance and higher tidal volumes, which may indicate a pulmonary contribution to ALS. VM that limits tidal volume may prevent the development of ALS.

Alpha-1 antitrypsin protects against phosgene-induced acute lung injury by activating the ID1-dependent anti-inflammatory response (preprint)

Phosgene, a highly dangerous chemical warfare agent, is widely used as an industrial chemical. Phosgene inhalation causes acute lung injury (ALI), which may further progress into pulmonary edema. Currently, there is no known antidote for phosgene poisoning. Alpha-1 antitrypsin (α1-AT) is a protease inhibitor that has been used to treat emphysema patients, who are deficient in α1-AT, for decades. Recent studies have shown that α1-AT has both anti-inflammatory and anti-SARS-CoV-2 effects. In this study, we aimed to investigate the role of α1-AT in phosgene-induced ALI. We observed a time-dependent increase in α1-AT expression and secretion in the lungs of rats exposed to phosgene. Interestingly, α1-AT was derived from neutrophils, but not from macrophages or alveolar type II cells, and α1-AT knockdown aggravated phosgene- and lipopolysaccharide (LPS)-induced inflammation and cell death in human bronchial epithelial cells (BEAS-2B). Conversely, α1-AT administration suppressed the inflammatory response and prevented death in LPS- and phosgene-exposed BEAS-2B cells. Furthermore, α1-AT treatment increased the expression of the inhibitor of DNA binding (ID1) gene, which suppressed NF-κB pathway activation, reduced inflammation, and inhibited cell death. These data demonstrate that neutrophil-derived α1-AT protects against phosgene-induced ALI by activating the ID1-dependent anti-inflammatory response. This study may provide novel strategies for the treatment of patients with phosgene-induced ALI.

Objective dyspnea evaluation on COVID-19 patients learning from exertion-induced dyspnea scores (preprint)

Objective: Dyspnea is one of the most common symptoms for many pulmonary diseases including COVID-19. Clinical assessment of dyspnea is mainly performed by subjective self-report, which has limited accuracy and is challenging for continuous monitoring. The objective of this research study is to determine if dyspnea progression in COVID patients can be assessed using a non-invasive wearable sensor and if the findings are comparable to a learning model of physiologically induced dyspnea on healthy subjects. Methods: Non-invasive wearable respiratory sensors were employed to retrieve continuous respiratory characteristics with user comfort and convenience. Overnight (~16h) respiratory waveforms were collected on 12 COVID-19 patients, and a benchmark on 13 healthy subjects with exertion-induced dyspnea were also performed for blind comparison. The learning model was built from the respiratory features with self report on 32 healthy subjects under exertion and airway blockage. Results: High similarity between dyspnea on COVID patients and physiologically induced dyspnea on healthy subjects was established. COVID patients have consistently high objective dyspnea scores in comparison with normal breathing of healthy subjects. We also exhibited continuous dyspnea scoring capability for 12-16 hours on patients. Conclusion: This paper validates the viability to use our objective dyspnea scoring for clinical dyspnea assessment on COVID patients. Significance: The proposed system can help the identification of dyspneic exacerbation in conditions such as COVID, leading to early intervention and possibly improving their outcome. This approach can be potentially applied to other pulmonary disorders such as asthma, emphysema, and pneumonia.

Risk factors of pulmonary complications in the patients with COVID-19: A case-control study (preprint)

Background Pneumothorax (PTX), pneumomediastinum (PM), and emphysema (EM) are complications of SARS-CoV-2 infections. Studying these situations' risk factors, complications, and prognosis is essential for early diagnosis during a pandemic. Methods We performed a case-control study of patients diagnosed with coronavirus pneumonia complicated with PTX, PM, and EM compared with patients without these complications to evaluate the risk factors for the incidence and prognosis of patients with pulmonary complications of COVID-19. We used parametric, non-parametric, and regression tests to analyze the data. Results We enrolled 162 patients (81 complicated, 81 uncomplicated). A past medical history of diabetes mellitus (DM), hyperlipidemia (HLP), lung disease, and ischemic heart disease (IHD) was not associated with PTX, PM, and EM in COVID 19 pneumonia (p-value > 0.05). The mortality rate was higher in the case group (69% vs. 15%). Among ventilator modes, 46.2% of intubated patients in the case group had synchronized intermittent mandatory ventilation (SIMV) for their ventilation. ESR, CRP, D-dimer, LDH, WBC, and troponin significantly increased, and lymphocytes decreased in complicated COVID compared to control groups (p-value < 0.05). Conclusion The nature of SARS-CoV-2 predisposes patients to PTX and other pulmonary complications. In practice, we could predict the complications and severity of COVID-19 pneumonia from some specific laboratory data.

Bilateral Emphysematous Pyelonephritis Associated with COVID Pneumonia: A Case Report.

BACKGROUND 0ptviral pneumonia and bilateral emphysematous pyelonephritis create a rapid acute respiratory distress syndrome. CASE REPORT A 59-year-old diabetic man with altered awareness was admitted as an emergency due to fever, shivering, and pain in the lap. Based on the accurate diagnosis, we concluded that the patient had bilateral emphysematous pyelonephritis, as well as inflammatory changes in the lung parenchyma caused by coronavirus infection (SARS-CoV-2). Active therapy - nephrectomy - was ruled out due to the late detection of the gas collection in the kidneys, as well as the general condition caused by respiratory symptoms. With symptomatic, supportive, and antimicrobial therapy, such as percutaneous renal drainage, renal abnormalities improved. Unfortunately, the virus-induced parenchymal inflammation progressed and proved fatal. The inflammatory process in the urothelial cell is most likely where the linkage and potentiation of COVID-19 infection and emphysematous pyelonephritis begins. Local inflammation that obstructs the movement of the generated gas is one of the hypothesized processes of emphysematous pyelonephritis. The renal and urothelial tubular cells contain the angiotensin-converting enzyme II (ACE2) receptor, which is used by the SARS-CoV-2 virus to enter human cells and may be a risk factor for simultaneous and direct viral injury to urinary tract cells. Sepsis was most likely caused by viral pneumonia, based on the resolution of changes in the kidneys. CONCLUSIONS The combination of EPN and COVID-19 is difficult to treat. Despite multidisciplinary treatment, it has been linked to a worse prognosis and fatal outcome.

Emphysematous cystitis with bilateral pyelonephritis in a pediatric patient with COVID-19.

A 15-year-old female adolescent with a medical history of recurrent urinary tract infections and grade 1 left-sided vesicoureteral reflux presented to the emergency room with abdominal and back pain. Labs revealed a haemoglobin A1c (HbA1c) of 9.1% and a random blood glucose of 200 mg/dL, consistent with new-onset diabetes mellitus. Nasopharyngeal COVID-19 PCR test returned positive. A CT scan of the abdomen and pelvis revealed bilateral attenuation of the kidneys and air in the bladder, which was confirmed by pelvic ultrasound. Gas subsequently resolved 2 days later after treatment with antibiotics, and a diagnosis of emphysematous cystitis was made. Emphysematous cystitis in the paediatric population is an extremely rare condition with four cases reported in the literature. Furthermore, there has been a reported association between COVID-19, cystitis and non-typical course of urinary symptoms. Local inflammation obstructing transportation of formed gas is one of the proposed mechanisms underlying emphysematous cystitis, and so COVID-19 may be yet another predisposing factor.

Alveolar cell fate selection and lifelong maintenance of AT2 cells by FGF signaling (preprint)

Summary The lung’s gas exchange surface comprises thin alveolar type 1 (AT1) cells and cuboidal surfactant-secreting AT2 cells that are corrupted in some of the most common and deadly diseases including adenocarcinoma, emphysema, and SARS/Covid-19. These cells arise from an embryonic progenitor whose development into an AT1 or AT2 cell is thought to be dictated by differential mechanical forces. Here we show the critical determinant is FGF signaling. FGF Receptor 2 (Fgfr2) is expressed in mouse progenitors then restricts to nascent AT2 cells and remains on throughout life. Its ligands are expressed in surrounding mesenchyme and can, in the absence of differential mechanical cues, induce purified, uncommitted E16.5 progenitors to form alveolus-like structures with intermingled AT2 and AT1 cells. FGF signaling directly and cell autonomously specifies AT2 fate; progenitors lacking Fgfr2 in vitro and in vivo exclusively acquire AT1 fate. Fgfr2 loss in AT2 cells perinatally results in reprogramming to AT1 fate, whereas loss or inhibition later in life immediately triggers AT2 apoptosis followed by a compensatory regenerative response. We propose Fgfr2 signaling directly selects AT2 fate during development, induces a cell non-autonomous secondary signal for AT1 fate, and stays on throughout life to continuously maintain healthy AT2 cells. One Sentence Summary FGF signaling induces and distinguishes the two cell types of the lung’s gas exchange surface, and the pathway remains on throughout life to maintain one that can be transformed into lung cancer or targeted in the deadly form of SARS/Covid-19.

Successful use of endobronchial valve for persistent air leak in a patient with COVID-19 and bullous emphysema.

Patients with SARS-CoV-2 pneumonia can suffer from pneumothorax and persistent air leak (PAL). The pneumothorax occurs with or without pre-existing lung disease. PAL refers to air leak lasting more than 5-7 days and arises due to bronchopleural or alveolopleural fistula. The management of PAL can be challenging as a standard management guideline is lacking. Here we present the case of a 42-year-old smoker with COVID-19 who presented to the hospital with fever, cough, acute left-sided chest pain and shortness of breath. He suffered from a large left-sided pneumothorax requiring immediate chest tube drainage. Unfortunately, the air leak persisted for 13 days before one-way endobronchial valve (EBV) was used with complete resolution of the air leak. We also review the literature regarding other cases of EBV utilisation for PAL in patients with COVID-19.

Severe COVID-19 pneumonia and barotrauma: From the frying pan into the fire. (preprint)

AimCOVID-19 pneumonia with ARDS (C-ARDS) has a high mortality. Preliminary reports indicate a higher incidence of barotrauma in patients with C-ARDS[1] both on invasive mechanical ventilation (iMV) and non-invasive ventilation (NIV) This study examines the incidence and risk factors for barotrauma and change in outcomes after barotrauma in patients with severe C-ARDS on positive pressure respiratory support (PPRS). Methods and materialsThis is a retrospective study of C-ARDS associated barotrauma over 5 months in patients on PPRS in a tertiary COVID care center. The type of barotrauma, intervention, related factors, such as type of respiratory support (iMV vs NIV), airway pressure prior to the occurrence of barotrauma, and post-barotrauma outcomes were analyzed. ResultsA total of 38/410 (9.3%) C-ARDS patients on PPRS [mean age 57.82 {+/-} 13.3 years, 32 males (84.2%)] developed barotrauma. Of these, 20 patients (52.6%) were on NIV and 18 (47.4%) patients were iMV on standard recommended settings. The median P/F ratio of patients on MV at the time of barotrauma was 116.4 (IQR 72.4, 193.25). The details of barotrauma were as follows: 24 patients had pneumothorax (PTX), 2 had pneumo-mediastinum and 12 had subcutaneous emphysema. Overall, 24/38 (63.2%) patients, including 15/18 (83.3%) on MV succumbed to their illness. The barotrauma happened a median of 6.5 days (IQR 4.75,13) after admission and 15 days (IQR 10.25,18.0) from symptom onset. The median duration from barotrauma to death was 7 days (IQR 2.25, 8.0) and barotrauma to discharge (for survivors) was 12.5 days (IQR 8.0, 21.25). All patients received steroids and 11/38 (28.9%) received additional immunosuppression with tocilizumab. ConclusionA high incidence of barotrauma was seen in this large series of severe C-ARDS patients on PPRS. Barotrauma led to further deterioration in the clinical status leading to a fatal outcome in the majority of the MV patients, despite prompt treatment.

Elastocapillary network model of inhalation (preprint)

The seemingly simple process of inhalation relies on a complex interplay between muscular contraction in the thorax, elasto-capillary interactions in individual lung branches, propagation of air between different connected branches, and overall air flow into the lungs. These processes occur over considerably different length and time scales; consequently, linking them to the biomechanical properties of the lungs, and quantifying how they together control the spatiotemporal features of inhalation, remains a challenge. We address this challenge by developing a computational model of the lungs as a hierarchical, branched network of connected liquid-lined flexible cylinders coupled to a viscoelastic thoracic cavity. Each branch opens at a rate and a pressure that is determined by input biomechanical parameters, enabling us to test the influence of changes in the mechanical properties of lung tissues and secretions on inhalation dynamics. By summing the dynamics of all the branches, we quantify the evolution of overall lung pressure and volume during inhalation, reproducing the shape of measured breathing curves. Using this model, we demonstrate how changes in lung muscle contraction, mucus viscosity and surface tension, and airway wall stiffness---characteristic of many respiratory diseases, including those arising from COVID-19, cystic fibrosis, chronic obstructive pulmonary disease, asthma, and emphysema---drastically alter inhaled lung capacity and breathing duration. Our work therefore helps to identify the key factors that control breathing dynamics, and provides a way to quantify how disease-induced changes in these factors lead to respiratory distress.

Computed Tomography-based determinants for predicting death and ICU requirement in patients suffering COVID-19 (preprint)

Background: What has received special attention in recent months is the use of a combination of clinical findings, laboratory markers, and, in addition, the findings of lung Computed Tomography (CT) scan in the design and delivery of risk scoring systems for Coronavirus Disease 2019 (COVID -19) patients. The present study aimed to determine main lung CT-related correlates of disease severity (Intensive Care Units (ICU) requiring) as well as death in COVID -19 patients.Methods: This cross-sectional study was performed on 515 consecutive patients with definitive diagnosis of COVID-19 admitted to one of the COVID -19 referral hospitals in Tehran. All patients' information was collected through a review of their archives. All patients were evaluated by CT scan of the lungs.Results: The mean follow-up of patients from the time of admission was 10.85±6.11 days between 1 and 30 days. During this period, a total of 29.1% were admitted to the ICU. Also, the mortality rate of patients was equal to 28.2%. According to multivariable logistic regression model with the presence of death-related correlates, crazy paving pattern, diffuse distribution of lesions, CT Severity Score (CTSS) score >12, the presence of plural effusion or emphysema were the main determinants of COVID -19 related death and should be considered for presenting new scoring system for predicting death following COVID -19 disease. In similar model, CTSS score >12 along with the presence of plural effusion, emphysema, or pulmonary hypertension were the main determinants of requiring ICU admission. Conclusion: The CT score higher than 12 along with observing the pattern of diffuse distribution of lesions especially accompanied with emphysema, pleural effusion or pulmonary hypertension can predict patient mortality or will determine the need for hospitalization in the ICU.

Comparing biomarkers for COVID-19 disease with commonly associated preexisting conditions and complications. (preprint)

Severe coronavirus disease 2019 (COVID-19) has been associated with certain preexisting health conditions and can cause respiratory failure along with other multi-organ injuries. However, the mechanism of these relationships is unclear, and prognostic biomarkers for the disease and its systemic complications are lacking. This study aims to examine the plasma protein profile of COVID-19 patients and evaluate overlapping protein modules with biomarkers of common comorbidities. Blood samples were collected from COVID-19 cases (n=307) and negative controls (n=78) among patients with acute respiratory distress. Proteins were measured by proximity extension assay utilizing next-generation sequencing technology. Its associations to COVID-19 disease characteristics were compared to that of preexisting conditions and established biomarkers for myocardial infarction (MI), stroke, hypertension, diabetes, smoking, and chronic kidney disease. Several proteins were differentially expressed in COVID-19, including multiple pro-inflammatory cytokines such as IFN-gamma, CXCL10, and CCL7/MCP-3. Elevated IL-6 was associated with increased severity, while baseline IL1RL1/ST2 levels were associated with a worse prognosis. Network analysis identified several protein modules associated with COVID-19 disease characteristics overlapping with processes of preexisting hypertension and impaired kidney function. BNP and NTpro-BNP, markers for MI and stroke, increased with disease progression and were positively associated with severity. MMP12 was similarly elevated and has been previously linked to smoking and inflammation in emphysema, along with increased cardiovascular disease risk. In conclusion, this study provides an overview of the systemic effects of COVID-19 and candidate biomarkers for clinical assessment of disease progression and the risk of systemic complications.

Clinical Characteristics of Severe Covid Pneumonia: Exploring New Trends in ICU (preprint)

Background: In late December 2019, Covid-19 emerged as clusters of pneumonia of unknown cause in a province of china, Wuhan. Etiological agent was identified as novel coronavirus that resembles severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East Respiratory syndrome coronavirus (MERS-CoV) and has zoonotic transmission. Covid pneumonia can remain asymptomatic, present as mild infection, severe pneumonia or respiratory failure. Diagnosis is based on rRT-PCR carried out on respiratory secretions. Covid related mortality exceeds 50% once patient requires ICU admission. Objective: To study the characteristics of ICU population admitted to ICU of Shifa International hospital.Results: we prospectively analysed 74 patients which included 43.3% females and 56.7% males. Commonest symptoms were shortness of breath (94.5%), fever (74.3%) and cough (74.3%). Most of our study population consisted of non-smokers (79.7%) and had hypertension (59.4%) followed by diabetes (47.2%). Hydroxychloroquine (HCQ) and azithromycin combination is superior to hydroxychloroquine and doxycycline in reducing mortality (p=0.023) whereas Doxycycline alone resulted in increased mortality (p=0.009). Those who did not require antibiotics or required only narrow spectrum antibiotics had increased survival and reduced requirement of invasive mechanical ventilation (p=< 0.0001). in our study population, (44.9%) developed acute kidney injury, 2.7% needed re-intubations 10.8% developed surgical emphysema and 2.7 % thromboembolic events despite full anticoagulation. ICU mortality was 41.8% and was higher in females (59.4%, p=0.008), those who had SOFA score > 3.5 at time of admission, raised D-Dimers > 931 ng/ml, NLR > 9.2. It was further high in those who required invasive mechanical ventilation and vasopressor support (58.1% mortality p=< 0.001). ICU stay was more prolonged in those requiring invasive mechanical ventilation as compared to those who did not. (23 days vs 6 days, p=0.001). Mean plateau pressure was 19.6 ± 7.6; mean Driving pressures 14.4 ± 4.6; mean PaO2/FiO2 150.7 ± 73.9; mean SPO2/FiO2 173.9 ± 106.9; mean PEEP was 8.2 ±4.33.Conclusion: We concluded that severe covid pneumonia is common amongst males, non-smokers those who had comorbid. HCQ and azithromycin combination is superior to combination of HCQ and doxycycline or doxycycline alone and QT prolongation is a rare complication. Baseline NLR, APACHI II, SOFA, SAPS II, NUTRIC scores, D-Dimers, invasive ventilation and vasopressor support are important tools to predict ICU mortality. Invasive mechanical ventilation carries higher mortality and associated with more prolonged ICU stay. AKI is most common complication followed by shock and surgical emphysema. CRP, Ferritin levels has no impact on outcome.