Corrigendum: Case Series: Maraviroc and pravastatin as a therapeutic option to treat long COVID/Post-acute sequalae of COVID (PASC).

[This corrects the article DOI: 10.3389/fmed.2023.1122529.].

Case series: Maraviroc and pravastatin as a therapeutic option to treat long COVID/Post-acute sequelae of COVID (PASC).

Post-acute sequelae of COVID (PASC), or long COVID, is a multisystem complication of SARS-CoV-2 infection that continues to debilitate millions worldwide thus highlighting the public health importance of identifying effective therapeutics to alleviate this illness. One explanation behind PASC may be attributed to the recent discovery of persistent S1 protein subunit of SARS-CoV-2 in CD16+ monocytes up to 15 months after infection. CD16+ monocytes, which express both CCR5 and fractalkine receptors (CX3CR1), play a role in vascular homeostasis and endothelial immune surveillance. We propose targeting these receptors using the CCR5 antagonist, maraviroc, along with pravastatin, a fractalkine inhibitor, could disrupt the monocytic-endothelial-platelet axis that may be central to the etiology of PASC. Using five validated clinical scales (NYHA, MRC Dyspnea, COMPASS-31, modified Rankin, and Fatigue Severity Score) to measure 18 participants' response to treatment, we observed significant clinical improvement in 6 to 12 weeks on a combination of maraviroc 300 mg per oral twice a day and pravastatin 10 mg per oral daily. Subjective neurological, autonomic, respiratory, cardiac and fatigue symptoms scores all decreased which correlated with statistically significant decreases in vascular markers sCD40L and VEGF. These findings suggest that by interrupting the monocytic-endothelial-platelet axis, maraviroc and pravastatin may restore the immune dysregulation observed in PASC and could be potential therapeutic options. This sets the framework for a future double-blinded, placebo-controlled randomized trial to further investigate the drug efficacy of maraviroc and pravastatin in treating PASC.

COVID-19 pandemic impact on telehealth use and perceptions for atopic and respiratory disease: Survey results.

Background: Telehealth use increased during the coronavirus disease 2019 (COVID-19) pandemic to provide patient care while deferring to social distancing recommendations. Objective: Health-care provider and patient surveys were conducted to assess the impact of COVID-19 on the use and perception of telehealth visits for atopic and respiratory diseases. Methods: Health-care provider (N = 200) and patient (N = 200) surveys were conducted in the United States between September and October, 2020, and January, 2021. The participants were required to have used telehealth before or after March 1, 2020, the cutoff date selected to represent the start of the COVID-19 pandemic. Results: Before the pandemic, 40% of the health-care provider participants were conducting telehealth visits, which increased to 100% after the pandemic started. The average time spent per telehealth visit with patients increased from 13 to 16 minutes. A higher percentage of family medicine physicians/pediatricians had access to most monitoring tools than allergy/dermatology specialists both before the pandemic and after the pandemic started. Practice expenses reportedly increased after the pandemic started for 42% of participants. Before the pandemic, 27% of the patient participants used telehealth, which increased to 94% after the pandemic started. Ratings of "good" or "excellent" for the overall telehealth experience by the health-care provider participants improved from 44% before to 60% after the pandemic started, and by the patient participants improved from 77% to 88%. The willingness by the health-care provider participants to recommend telehealth to colleagues improved from 73% before to 83% after the pandemic started. The willingness by the patient participants to use telehealth again dropped slightly, from 94% to 89%. Conclusion: Telehealth visits for atopic and respiratory diseases increased during the COVID-19 pandemic. Telehealth experiences were overall positive, particularly for the patients.

Immune-Based Prediction of COVID-19 Severity and Chronicity Decoded Using Machine Learning.

Expression of CCR5 and its cognate ligands have been implicated in COVID-19 pathogenesis, consequently therapeutics directed against CCR5 are being investigated. Here, we explored the role of CCR5 and its ligands across the immunologic spectrum of COVID-19. We used a bioinformatics approach to predict and model the immunologic phases of COVID so that effective treatment strategies can be devised and monitored. We investigated 224 individuals including healthy controls and patients spanning the COVID-19 disease continuum. We assessed the plasma and isolated peripheral blood mononuclear cells (PBMCs) from 29 healthy controls, 26 Mild-Moderate COVID-19 individuals, 48 Severe COVID-19 individuals, and 121 individuals with post-acute sequelae of COVID-19 (PASC) symptoms. Immune subset profiling and a 14-plex cytokine panel were run on all patients from each group. B-cells were significantly elevated compared to healthy control individuals (P<0.001) as was the CD14+, CD16+, CCR5+ monocytic subset (P<0.001). CD4 and CD8 positive T-cells expressing PD-1 as well as T-regulatory cells were significantly lower than healthy controls (P<0.001 and P=0.01 respectively). CCL5/RANTES, IL-2, IL-4, CCL3, IL-6, IL-10, IFN-γ, and VEGF were all significantly elevated compared to healthy controls (all P<0.001). Conversely GM-CSF and CCL4 were in significantly lower levels than healthy controls (P=0.01). Data were further analyzed and the classes were balanced using SMOTE. With a balanced working dataset, we constructed 3 random forest classifiers: a multi-class predictor, a Severe disease group binary classifier and a PASC binary classifier. Models were also analyzed for feature importance to identify relevant cytokines to generate a disease score. Multi-class models generated a score specific for the PASC patients and defined as S1 = (IFN-γ + IL-2)/CCL4-MIP-1ß. Second, a score for the Severe COVID-19 patients was defined as S2 = (IL-6+sCD40L/1000 + VEGF/10 + 10*IL-10)/(IL-2 + IL-8). Severe COVID-19 patients are characterized by excessive inflammation and dysregulated T cell activation, recruitment, and counteracting activities. While PASC patients are characterized by a profile able to induce the activation of effector T cells with pro-inflammatory properties and the capacity of generating an effective immune response to eliminate the virus but without the proper recruitment signals to attract activated T cells.

Persistence of SARS CoV-2 S1 Protein in CD16+ Monocytes in Post-Acute Sequelae of COVID-19 (PASC) up to 15 Months Post-Infection.

The recent COVID-19 pandemic is a treatment challenge in the acute infection stage but the recognition of chronic COVID-19 symptoms termed post-acute sequelae SARS-CoV-2 infection (PASC) may affect up to 30% of all infected individuals. The underlying mechanism and source of this distinct immunologic condition three months or more after initial infection remains elusive. Here, we investigated the presence of SARS-CoV-2 S1 protein in 46 individuals. We analyzed T-cell, B-cell, and monocytic subsets in both severe COVID-19 patients and in patients with post-acute sequelae of COVID-19 (PASC). The levels of both intermediate (CD14+, CD16+) and non-classical monocyte (CD14Lo, CD16+) were significantly elevated in PASC patients up to 15 months post-acute infection compared to healthy controls (P=0.002 and P=0.01, respectively). A statistically significant number of non-classical monocytes contained SARS-CoV-2 S1 protein in both severe (P=0.004) and PASC patients (P=0.02) out to 15 months post-infection. Non-classical monocytes were sorted from PASC patients using flow cytometric sorting and the SARS-CoV-2 S1 protein was confirmed by mass spectrometry. Cells from 4 out of 11 severe COVID-19 patients and 1 out of 26 PASC patients contained ddPCR+ peripheral blood mononuclear cells, however, only fragmented SARS-CoV-2 RNA was found in PASC patients. No full length sequences were identified, and no sequences that could account for the observed S1 protein were identified in any patient. That non-classical monocytes may be a source of inflammation in PASC warrants further study.

Synchronous Primary Pancreatic Ductal Carcinoma and Colonic Adenocarcinoma Present in a Patient With History of Skin Squamous Cell Carcinoma.

The synchronous diagnosis of two or more primary malignancies in a patient is overall rare. This is a case report of a 70-year-old female with a history of skin squamous cell carcinoma presenting with occult hematochezia. Colonoscopy and biopsy results confirmed a microsatellite stable (MMS) adenocarcinoma in the ascending colon, and subsequent computed tomography (CT) scans identified a 3.2 cm right colonic mass and a 5.0 cm mass in the pancreatic body. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) confirmed the presence of pancreatic ductal adenocarcinoma (PDAC). The patient underwent neo-adjuvant FOLFIRINOX (folinic acid, fluorouracil, irinotecan and oxaliplatin) chemotherapy prior to the simultaneous distal pancreatectomy and right hemicolectomy for both pancreatic and colonic tumors. The pathology diagnoses included moderately differentiated pancreatic ductal carcinoma (PDAC) with histiocyte-like features (tumor stage: ypT3N1M0) and moderately differentiated colonic adenocarcinoma, intestinal type (tumor stage: ypT3N0M0). To the best of our knowledge, this is the first documented case of synchronous primary colonic adenocarcinoma and PDAC in the English literature.

Long-term outcomes of patients with common bile duct injury following laparoscopic cholecystectomy.

INTRODUCTION: Common bile duct (CBD) injury is a serious and dreaded complication of cholecystectomy. A paucity of data assessing long-term outcomes exists. This study aimed to determine long-term mortality and liver transplantation rates following CBD injury requiring operative intervention. METHODS: Patients were identified via the New York State (NYS) Planning and Research Cooperative System longitudinal administrative database which captures patient-level data from every inpatient and outpatient hospital discharge in NYS. In total, 125 patients with CBD injuries were identified following 156,958 laparoscopic cholecystectomies for cholelithiasis performed in NYS from 2005 to 2010. Patients were then tracked by unique identifier to obtain rate of liver transplantation. Follow-up ranged from 4 to 9 years from surgery. RESULTS: There were 125 patients with CBD injuries detected. No mortalities occurred within 30 days. All-cause mortality was 20.8 % (n = 26) with mean time to death 1.64 ± 1.08 years. One patient who underwent hepaticoenterostomy required a liver transplant 4.3 years after surgery. Significant factors predictive of all-cause mortality included: age >61, Medicare insurance, male gender, White race, diabetes, hypertension and pulmonary complications following surgery. Overall 30-day morbidity, timing to and type of operative intervention did not influence mortality. CONCLUSION: Considerable long-term mortality, 20.8 %, is associated with common bile duct injury requiring operative intervention. This was an increase of 8.8 % above the cohort's expected age-adjusted rate of death. The mortality rate is appreciably higher than quoted previously. No difference was demonstrated by type of repair required. Liver transplant rate was 0.8 %. These data have significant implications for patient and family counseling both prior to cholecystectomy and following CBD injury.

Beyond the learning curve: incidence of bile duct injuries following laparoscopic cholecystectomy normalize to open in the modern era.

BACKGROUND: Early reports of higher complication rates, specifically bile duct injuries, raised concerns over the safety of laparoscopy over open cholecystectomy. This study aims to ascertain the rate, management, and perioperative outcomes of bile duct injury in an era beyond the laparoscopic learning curve. METHODS: The New York State (NYS) Planning and Research Cooperative System longitudinal administrative database was used to identify patients. From 2005 to 2010, 156,315 patients were identified who had undergone laparoscopic cholecystectomy for symptomatic cholelithiasis or acute or chronic cholecystitis. Patients were then tracked with unique identifiers for common bile duct injury. Common bile duct injury was identified by ICD-9 and CPT diagnosis and procedure codes for patients who subsequently underwent hepatectomy, hepaticojejunostomy, or other bile duct surgery. RESULTS: From 2005 to 2010, 156,958 patients were identified who had undergone laparoscopic cholecystectomy for symptomatic cholelithiasis or acute or chronic cholecystitis. Of the total patients, 149 patients underwent a biliary duct procedure within a year. Twenty-four of them were diagnosed with gallbladder cancer and excluded, leaving 125 for further analysis. The biliary injuries were identified at a rate of 0.080 %. Thirty-one of those patients (24.8 %) underwent hepatectomy, 40 patients (32.0 %) underwent hepaticoenterostomy, and 54 patients (43.2 %) underwent primary repair of the bile duct. Thirty-two (26 %) patients were repaired on the same day of their initial procedure. Of the remaining 93 patients, 38 (30 %) were repaired within 10 days, seven (6 %) repaired between 11 and 20 days, and 48 (38 %) patients over 21 days from injury. CONCLUSION: In NYS, the rate of bile duct injury has now decreased to 0.08 % and mirrors the historical figures quoted for open cholecystectomy. This improvement likely reflects increased experience, improved instrumentation, and movement beyond the "learning curve."

Surgical management of pancreatic cancer--distal pancreatectomy.

Distal pancreatectomy is the standard procedure for tumors located in the body and tail of the pancreas. In the last three decades, significant progress has been made with regard to technical aspects as well as perioperative care so that excellent mortality and morbidity rates can be achieved. Recently, there is growing evidence that distal pancreatectomy may be performed laparoscopically in selected patients, offering the advantages of minimally invasive surgery. Unfortunately, the oncologic outcomes for pancreatic adenocarcinoma remain poor, in part due to the late stage of presentation in most patients. We review the history of distal pancreatectomy, discuss current indications for performing this procedure, compare operative techniques in performing distal pancreatectomy, and review both the early complications seen in patients who have undergone a distal pancreatectomy and the long-term metabolic and oncologic outcomes of these patients.

Relationship between urine dichlorophenol levels and asthma morbidity.

BACKGROUND: Chlorinated phenols are associated with atopic conditions, but it is not known whether they are associated with wheeze or asthma and whether atopy is involved in these associations. OBJECTIVES: To test the association between urine levels of 2 dichlorophenols (2,4- and 2,5-dichlorophenols) and asthma morbidity in atopic and nonatopic wheezers and between total serum immunoglobulin E (IgE) levels. METHODS: Data from a sample of 2,125 participants at least 6 years old from the US National Health and Nutrition Examination Survey 2005 to 2006 were analyzed. Asthma morbidity data were available for those participants who reported wheezing in the past year ("wheezers"; n = 250). This subsample was categorized as atopic or nonatopic. RESULTS: Atopic wheezers with higher 2,5-dichlorophenol levels were more frequently diagnosed with asthma by a physician (odds ratio [OR] 4.7 for highest vs lowest tertile, P < .001), required more prescriptions for asthma medications (OR 2.2, P = .046), and reported more exercise-induced wheezing (OR 5.8, P = .045) than atopic wheezers with low dichlorophenol levels. Atopic wheezers with higher 2,5- or 2,4-dichloropheonol levels also were more likely to miss work or school because of wheezing (OR 10.0, P < .001; OR 11.4, P < .01, respectively). In contrast, in nonatopic wheezers, there were no significant associations between dichlorophenol levels and asthma morbidity measurements. The 2 dichlorophenol metabolites were positively associated with increased serum IgE levels in the larger study sample. CONCLUSION: These findings indicate that in patients with atopy and a history of wheezing, asthma morbidity is associated with high urinary dichlorophenol levels. Increased urine dichlorophenol levels are associated with higher total serum IgE.

Discordance between aeroallergen specific serum IgE and skin testing in children younger than 4 years.

BACKGROUND: Atopic sensitization to aeroallergens in early life has been found to be a strong risk factor for the development of persisting asthma in young children with recurrent wheeze. OBJECTIVE: To assess the yield of skin prick test (SPT) compared with allergen specific serum IgE (sIgE) testing at identifying aeroallergen sensitization in atopic children younger than 4 years. METHODS: Concordance between SPT and allergen-specific sIgE testing for 7 common aeroallergens was analyzed in 40 atopic inner-city children 18 to 48 months of age (mean [SD], 36 [9] months) with recurrent wheezing and family history of asthma and/or eczema. RESULTS: In 80% of children one or more allergen sensitizations would have been missed if only SPT had been performed, and in 38% of children one or more sensitizations would have been missed if only sIgE testing had been performed. Agreement between the SPT and sIgE test was fair for most allergens (κ = -0.04 to 0.50), as was correlation between sIgE levels and SPT grade (ρ = 0.21 to 0.55). Children with high total sIgE (≥300 kU/L) were more likely to have positive sIgE test results, with negative corresponding SPT results (P = .02). CONCLUSION: Our study revealed a significant discordance between allergen-specific SPT and sIgE testing results for common aeroallergens, suggesting that both SPT and sIgE testing should be performed when diagnosing allergic sensitization in young children at high risk of asthma. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01028560.

Pancreatectomy risk calculator: an ACS-NSQIP resource.

BACKGROUND: The morbidity of pancreatoduodenectomy remains high and the mortality may be significantly increased in high-risk patients. However, a method to predict post-operative adverse outcomes based on readily available clinical data has not been available. Therefore, the objective was to create a 'Pancreatectomy Risk Calculator' using the American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP) database. METHODS: The 2005-2008 ACS-NSQIP data on 7571 patients undergoing proximal (n = 4621), distal (n = 2552) or total pancreatectomy (n = 177) as well as enucleation (n = 221) were analysed. Pre-operative variables (n = 31) were assessed for prediction of post-operative mortality, serious morbidity and overall morbidity using a logistic regression model. Statistically significant variables were ranked and weighted to create a common set of predictors for risk models for all three outcomes. RESULTS: Twenty pre-operative variables were statistically significant predictors of post-operative mortality (2.5%), serious morbidity (21%) or overall morbidity (32%). Ten out of 20 significant pre-operative variables were employed to produce the three mortality and morbidity risk models. The risk factors included age, gender, obesity, sepsis, functional status, American Society of Anesthesiologists (ASA) class, coronary heart disease, dyspnoea, bleeding disorder and extent of surgery. CONCLUSION: The ACS-NSQIP 'Pancreatectomy Risk Calculator' employs 10 easily assessable clinical parameters to assist patients and surgeons in making an informed decision regarding the risks and benefits of undergoing pancreatic resection. A risk calculator based on this prototype will become available in the future as on online ACS-NSQIP resource.