Antiandrogen agents in COVID-19: a meta-analysis of randomized trials.

INTRODUCTION: Antiandrogen therapy can reduce the expression of transmembrane protease 2, which is essential for severe acute respiratory syndrome coronavirus-2 to enter the host cells. Prior trials suggested the efficacy of antiandrogen agents in patients with COVID-19. We investigated whether antiandrogen agents reduce mortality compared to placebo or usual care. EVIDENCE ACQUISITION: We searched for randomized controlled trials comparing antiandrogen agents with placebo or usual care alone in adults with COVID-19 in PubMed, EMBASE, the Cochrane Library, the reference lists of retrieved articles, and publications by manufacturers of antiandrogen agents. The primary outcome was mortality at the longest follow-up available. The secondary outcomes included clinical worsening, the need for invasive mechanical ventilation, admission to the intensive care unit, hospitalization, and thrombotic events. We registered this systematic review and meta-analysis in PROSPERO International Prospective Register of Systematic Reviews (CRD42022338099). EVIDENCE SYNTHESIS: We included 13 randomized controlled trials enrolling 1934 COVID-19 patients. We found that antiandrogen agents reduced mortality at the longest follow-up available (91/1021 [8.9%] vs. 245/913 [27%]; risk ratio =0.40; 95% confidence interval, 0.25-0.65; P=0.0002; I2=54%). Antiandrogen therapy also reduced clinical worsening (127/1016 [13%] vs. 298/911 [33%]; risk ratio =0.44; 95% confidence interval, 0.27-0.71; P=0.0007; I2=70%) and hospitalization (97/160 [4.4%] vs. 24/165 [15%]; risk ratio =0.24; 95% confidence interval, 0.10-0.58; P=0.002; I2=44%). There was no significant difference in the other outcomes between the two treatment groups. CONCLUSIONS: Antiandrogen therapy reduced mortality and clinical worsening in adult patients with COVID-19.

Meta-Analysis of Glucocorticoids for Covid-19 Patients Not Receiving Oxygen

Background: Glucocorticoids reduce mortality in hospitalized patients with severe and critical coronavirus disease 2019 (Covid-19), although a possible harm was documented in patients with Covid-19 not requiring oxygen. Methods: We searched Embase, BioMed Central, medRxiv, bioRxiv, PubMed, and the Cochrane Central Register of Controlled Trials for any randomized trial or matched study ever performed on adult patients with Covid-19 not receiving oxygen therapy treated with intravenous or oral glucocorticoids versus any comparator (standard therapy or placebo);there were no restrictions on dose or time of administration. The primary end point was all-cause mortality at the longest available follow-up. Results: Five randomized trials and one propensity-matched study involving 6634 hospitalized patients not on oxygen were finally included (3704 received glucocorticoids and 2930 received standard treatment). The overall mortality of patients treated with glucocorticoids was significantly higher than the mortality of patients in the control group (509 of 3704 [14%] in the glucocorticoid group vs. 294 of 2930 [10%] in the control group;odds ratio, 1.56 [95% confidence interval, 1.27 to 1.92], with three articles reporting mortality events and contributing to the combined odds ratio;P<0.001;number needed to harm=27). Conclusions: Glucocorticoid use likely increases mortality in hospitalized patients with Covid-19 not receiving oxygen, with a number needed to harm of 27. (PROSPERO number CRD42022342996.)

Reparixin improves survival in critically ill and transplant patients: A meta-analysis.

BACKGROUND: Reparixin, an anti-inflammatory drug that inhibits interleukin 8 (IL-8) activity, might be life-saving for high-risk in-hospital patients without increasing the risk of infection according to a previous meta-analysis. With the increasing availability of randomised data the aim of the current study is to update previous findings by including any randomised control trials (RCTs) investigating the impact of reparixin on survival of critically ill or transplant patients. METHODS: A search strategy was developed to identify all RCTs involving reparixin in critically ill or transplant patients, with the exclusion of oncological patients. Two trained and independent authors conducted a thorough search of relevant databases. In addition, backward snowballing was employed. Language restrictions were not imposed. RESULTS: Our analysis included a total of nine studies involving 733 patients: 437 received reparixin and 296 the comparator. The reparixin group had a significantly lower all-cause mortality rate compared to the control group [15/437 (3.4%) vs. 19/294 (6.4%), odds ratio = 0.47 (95% confidence interval 0.23-0.96), p-value for effect .04, I2 = 22%, number needed to treat = 33]. These findings had the same direction and magnitude of effect across COVID-19 patients (n = 325) and non-COVID-19 patients (n = 408). Furthermore, there were no significant differences in the rate of pneumonia, sepsis or non-serious infections between the two groups. CONCLUSIONS: The findings of this meta-analysis indicate that reparixin, an anti-inflammatory drug, improved survival in critically ill or transplant patients (including both COVID-19 and non-COVID-19 patients) without increasing the risk of infection.

Is Gastrointestinal Bleeding a Problem for COVID-19 Intensive Care Unit Patients?

The objective of this study was to describe the COVID-19 intensive care unit population and analyze the characteristics and outcomes of gastrointestinal bleeding patients. An observational prospective study design was used following the STROBE checklist. All patients admitted between February and April 2020 to the intensive care unit were included. Main outcome measures were first bleeding event timing, sociodemographic and clinical data before admission, and gastrointestinal symptoms. A total of 116 COVID-19 patients were included; 16 (13.8%) developed gastrointestinal bleeding, 15 were males (93.7%), and the median age was 65.64 ± 7.33 years. All 16 patients were mechanically ventilated, one (6.3%) already had gastrointestinal symptoms, 13 (81.3%) had at least one concomitant disease, and six (37.5%) died. Bleeding episodes occurred on a mean of 16.9 ± 9.5 days after admission. Nine cases (56.3%) had effects on their hemodynamics, hemoglobin levels, or transfusion requirements; six (37.5%) required diagnostic imaging; and two (12.5%) underwent endoscopy procedures. The Mann-Whitney test showed statistically significant differences between the two groups of patients concerning comorbidities. Gastrointestinal bleeding can occur in critically ill patients with COVID-19. Having a solid tumor or chronic liver disease seems to increase that risk. Nurses caring for COVID-19 patients are urged to individualize patients at higher risk in order to improve safety.

Biobanking for COVID-19 research.

BACKGROUND: Biobanks are imperative infrastructures, particularly during outbreaks, when there is an obligation to acquire and share knowledge as quick as possible to allow for implementation of science-based preventive, diagnostic, prognostic, and therapeutic strategies. METHODS: We established a COVID-19 biobank with the aim of collecting high-quality and well-annotated human biospecimens, in the effort to understand the pathogenic mechanisms underlying COVID-19 and identify therapeutic targets (COVID-BioB, NCT04318366). Here we describe our experience and briefly review the characteristics of the biobanks for COVID-19 that have been so far established. RESULTS: A total of 46,677 samples have been collected from 913 participants (63.3% males, median [IQR] age 62.2 [51.2-74.0] years) since the beginning of the program. Most patients (66.9%) had been admitted to hospital for COVID-19, with a median length of stay of 15.0 (9.0-27.0) days. A minority of patients (13.3% of the total) had been admitted for other reasons and subsequently tested positive for SARS-CoV-2. The remainder were managed at home after being seen at the Emergency Department. CONCLUSIONS: Having a solid research infrastructure already in place, along with flexibility and adaptability to new requirements, allowed for the quick building of a COVID-19 biobank that will help expand and share the knowledge of SARS-CoV-2.

Microvascular lung vessels obstructive thromboinflammatory syndrome in patients with COVID-19: Insights from lung intravascular optical coherence tomography.

Background: Microvascular lung vessels obstructive thromboinflammatory syndrome has been proposed as a possible mechanism of respiratory failure in COVID-19 patients. However, it has only been observed in post-mortem studies and has never been documented in vivo, probably because of a lack of CT scan sensitivity in small pulmonary arteries. The aim of the present study was to assess the safety, tolerability, and diagnostic value of optical coherence tomography (OCT) for the assessment of patients with COVID-19 pneumonia for pulmonary microvascular thromboinflammatory syndrome. Methods: The COVID-OCT trial was a multicenter, open-label, prospective, interventional clinical study. Two cohorts of patients were included in the study and underwent pulmonary OCT evaluation. Cohort A consisted of patients with COVID-19 with a negative CT scan for pulmonary thrombosis and elevated thromboinflammatory markers (D-dimer > 10,000 ng/mL or 5,000 < D-dimer < 10,000 ng/mL and one of: C-reactive Protein > 100 mg/dL, IL-6 > 6 pg/mL, or ferritin > 900 ng/L). Cohort B consisted of patients with COVID-19 and a CT scan positive for pulmonary thrombosis. The primary endpoints of the study were: (i) to evaluate the overall safety of OCT investigation in patients with COVID-19 pneumonia, and (ii) to report on the potential value of OCT as a novel diagnostic tool for the diagnosis of microvascular pulmonary thrombosis in COVID-19 patients. Results: A total of 13 patients were enrolled. The mean number of OCT runs performed in each patient was 6.1 ± 2.0, both in ground glass and healthy lung areas, achieving a good evaluation of the distal pulmonary arteries. Overall, OCT runs identified microvascular thrombosis in 8 patients (61.5%): 5 cases of red thrombus, 1 case of white thrombus, and 2 cases of mixed thrombus. In Cohort A, the minimal lumen area was 3.5 ± 4.6 mm2, with stenosis of 60.9 ± 35.9% of the area, and the mean length of thrombus-containing lesions was 5.4 ± 3.0 mm. In Cohort B, the percentage area obstruction was 92.6 ± 2.6, and the mean thrombus-containing lesion length was 14.1 ± 13.9 mm. No peri-procedural complications occurred in any of the 13 patients. Conclusion: OCT appears to be a safe and accurate method of evaluating the distal pulmonary arteries in hospitalized COVID-19 patients. Here, it enabled the first in vivo documentation of distal pulmonary arterial thrombosis in patients with elevated thromboinflammatory markers, even when their CT angiogram was negative for pulmonary thrombosis. Clinical trial registration: ClinicalTrial.gov, identifier NCT04410549.

Two-year multidisciplinary follow-up of COVID-19 patients requiring invasive and noninvasive respiratory support.

BACKGROUND: COVID-19 patients frequently develop respiratory failure requiring mechanical ventilation. Data on long-term survival of patients who had severe COVID-19 are insufficient. We assessed and compared two-year survival, CT imaging, quality of life, and functional recovery of COVID-19 ARDS patients requiring respiratory support with invasive (IMV) versus noninvasive ventilation (NIV). METHODS: Patients with COVID-19 pneumonia admitted up to May 28th, 2020, who required IMV or NIV, and survived to hospital discharge were enrolled. Patients were contacted two years after discharge to assess vital status, functional, psychological, and cognitive outcomes using validated scales. Patients with persistent respiratory symptoms or high burden of residual lung damage at previous CT scan received a two-year chest CT scan. RESULTS: Out of 61 IMV survivors, 98% were alive at two-year follow-up, and 52 completed the questionnaire. Out of 82 survivors receiving NIV only, 94% were alive at two years, and 47 completed the questionnaire. We found no major differences between invasively and noninvasively ventilated patients, with overall acceptable functional recovery. Among the 99 patients completing the questionnaire, 23 have more than moderate exertional dyspnea. Chest CT scans showed that 4 patients (all received IMV) had fibrotic-like changes. CONCLUSIONS: Patients who received mechanical ventilation due to COVID-19 and were discharged from hospital had a 96% survival rate at the two-year follow-up. There was no difference in overall recovery and quality of life between patients who did and did not require IMV, although respiratory morbidity remains high.

Clinical use of Macklin-like radiological sign (Macklin effect): A systematic review.

INTRODUCTION: Recent studies suggested that Macklin sign is a predictor of barotrauma in patients with acute respiratory distress syndrome (ARDS). We performed a systematic review to further characterize the clinical role of Macklin. METHODS: PubMed, Scopus, Cochrane Central Register and Embase were searched for studies reporting data on Macklin. Studies without data on chest CT, pediatric studies, non-human and cadaver studies, case reports and series including <5 patients were excluded. The primary objective was to assess the number of patients with Macklin sign and barotrauma. Secondary objectives were: occurrence of Macklin in different populations, clinical use of Macklin, prognostic impact of Macklin. RESULTS: Seven studies enrolling 979 patients were included. Macklin was present in 4-22% of COVID-19 patients. It was associated with barotrauma in 124/138 (89.8%) of cases. Macklin sign preceded barotrauma in 65/69 cases (94.2%) 3-8 days in advance. Four studies used Macklin as pathophysiological explanation for barotrauma, two studies as a predictor of barotrauma and one as a decision-making tool. Two studies suggested that Macklin is a strong predictor of barotrauma in ARDS patients and one study used Macklin sign to candidate high-risk ARDS patients to awake extracorporeal membrane oxygenation (ECMO). A possible correlation between Macklin and worse prognosis was suggested in two studies on COVID-19 and blunt chest trauma. CONCLUSIONS: Increasing evidence suggests that Macklin sign anticipate barotrauma in patients with ARDS and there are initial reports on use of Macklin as a decision-making tool. Further studies investigating the role of Macklin sign in ARDS are justified.

Impact of Remdesivir on SARS-CoV-2 Clearance in a Real-Life Setting: A Matched-Cohort Study.

Background: Evidence regarding the impact of remdesivir (RDV) on SARS-CoV-2 viral clearance (VC) is scarce. The aim of this study was to compare VC timing in hospitalized COVID-19 patients who did or did not receive RDV. Methods: This was a matched-cohort study of patients hospitalized with pneumonia, a SARS-CoV-2-positive nasopharyngeal swab (NPS) at admission, and at least one NPS during follow-up. Patients who received RDV (cases) and those who did not (controls) were matched in a 1:2 ratio by age, sex, and PaO2/FiO2 (P/F) values at admission. NPSs were analyzed using real-time polymerase chain reaction. Time to VC (within 30 days after hospital discharge) was estimated using the Kaplan-Meier curve. A multivariable Cox proportional hazard model was fitted to determine factors associated with VC. Results: There were 648 patients enrolled in the study (216 cases and 432 controls). VC was observed in 490 patients (75.6%), with a median time of 25 (IQR 16-34) days. Overall, time to VC was similar between cases and controls (p = 0.519). However, time to VC was different when considering both RDV treatment status and age (p = 0.007). A significant finding was also observed when considering both RDV treatment status and P/F values at admission (p = 0.007). A multivariate analysis showed that VC was associated with a younger age (aHR = 0.990, 95% CI 0.983-0.998 per every 10-year increase in age; p = 0.009) and a higher baseline P/F ratio (aHR=1.275, 95% CI 1.029-1.579; p=0.026), but not with RDV treatment status. Conclusion: Time to VC was similar in cases and controls. However, there was a benefit associated with using RDV in regard to time to VC in younger patients and in those with a P/F ratio ≤200 mmHg at hospital admission.

Efficacy of Cetylpyridinium Chloride mouthwash against SARS-CoV-2: A systematic review of randomized controlled trials.

INTRODUCTION: COVID-19 is a transmissible respiratory and multisystem disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Viral transmission occurs mainly through the spread of salivary droplets or aerosol from an infected subject. Studies suggest that salivary viral load is correlated with disease severity and probability of transmission. Cetylpyridinium chloride mouthwash has been found to be effective in reducing salivary viral load. The aim of this systematic review of randomized controlled trials is to evaluate the efficacy of the mouthwash ingredient cetylpyridinium chloride on salivary viral load in SARS-CoV-2 infection. METHODS: Randomized controlled trials comparing cetylpyridinium chloride mouthwash with placebo and other mouthwash ingredients in SARS-CoV-2 positive individuals were identified and evaluated. RESULTS: Six studies with a total of 301 patients that met the inclusion criteria were included. The studies reported the efficacy of cetylpyridinium chloride mouthwashes in reduction on SARS-CoV-2 salivary viral load compared to placebo and other mouthwash ingredients. CONCLUSION: Mouthwashes containing cetylpyridinium chloride are effective against salivary viral load of SARS-CoV-2 in vivo. There is also the possibility that the use of mouthwash containing cetylpyridinium chloride in SARS-CoV-2 positive subjects could reduce transmissibility and severity of COVID-19.

The Effect of Heparin Full-Dose Anticoagulation on Survival of Hospitalized, Non-critically Ill COVID-19 Patients: A Meta-analysis of High Quality Studies.

BACKGROUND: International COVID-19 guidelines recommend thromboprophylaxis for non-critically ill inpatients to prevent thrombotic complications. It is still debated whether full-dose thromboprophylaxis reduces all-cause mortality. The main aim of this updated systematic review and meta-analysis is to evaluate the effect of full-dose heparin-based thromboprophylaxis on survival in hospitalized non-critically ill COVID-19 patients. METHODS: A systematic review was performed across Pubmed/Medline, EMBASE, Cochrane Central Register of clinical trials, Clinicaltrials.gov, and medRxiv.org from inception to November 2022. We conducted a meta-analysis of randomized clinical trials (RCTs) comparing full-dose heparin-based anticoagulation to prophylactic or intermediate dose anticoagulation or standard treatment in hospitalized non-critically ill COVID-19 patients. The risk of bias was assessed using the Cochrane risk-of-bias tool for randomized trials and Grading of Recommendations Assessment, Development and Evaluation was applied. The primary outcome was all-cause mortality at the longest follow-up available. RESULTS: We identified 6 multicenter RCTs involving 3297 patients from 13 countries across 4 continents. The rate of all-cause mortality was 6.2% (103/1662) in the full-dose group vs 7.7% (126/1635) in the prophylactic or intermediate dose group (Risk Ratio [RR] = 0.76; 95% confidence interval [CI] = 0.59-0.98; P = 0.037). The probabilities of any mortality difference and of NNT ≤ 100 were estimated at 98.2% and 84.5%, respectively. The risk of bias was low for all included RCTs and the strength of the evidence was "moderate." CONCLUSION: Our meta-analysis of high-quality multicenter RCTs suggests that full-dose anticoagulation with heparin or low molecular weight heparin reduces all-cause mortality in hospitalized non-critically ill COVID-19 patients. STUDY REGISTRATION: PROSPERO, review no. CRD42022348993.

Testosterone in males with COVID-19: a 12-month cohort study.

BACKGROUND: Male patients with COVID-19 have been found with reduced serum total testosterone (tT) levels and with more severe clinical outcomes. OBJECTIVES: To assess total testosterone (tT) levels and the probability of recovering eugonadal tT levels during a minimum 12-month timespan in a cohort of men who have been followed over time after the recovery from laboratory-confirmed COVID-19. MATERIALS AND METHODS: Demographic, clinical and hormonal values were collected for the overall cohort. Hypogonadism was defined as tT ≤9.2 nmol/l. The Charlson Comorbidity Index was used to score health-significant comorbidities. Descriptive statistics was used to compare hormonal levels at baseline versus 7-month (FU1) versus 12-month (FU2) follow-up, respectively. Multivariate cox proportional hazards regression model was used to identify the potential predictors of eugonadism recovery over time among patients with hypogonadism at the time of infection. RESULTS: Of the original cohort of 286 patients, follow-up data were available for 121 (42.3%) at FU1 and 63 (22%) patients at FU2, respectively. Higher median interquartile range (IQR) tT levels were detected at FU2 (13.8 (12.3-15.3) nmol/L) versus FU1 (10.2 [9.3-10.9] nmol/L) and versus baseline (3.6 [3.02-4.02] nmol/L) (all p < 0.0001), whilst both LH and E2 levels significantly decreased over the same time frame (all p ≤ 0.01). Circulating IL-6 levels further decreased at FU2 compared to FU1 levels (19.3 vs. 72.8 pg/ml) (p = 0.02). At multivariable cox regression analyses, baseline tT level (HR 1.19; p = 0.03 [1.02-1.4]) was independently associated with the probability of tT level normalization over time, after adjusting for potential confounders. CONCLUSIONS: Circulating tT levels keep increasing over time in men after COVID-19. Still, almost 30% of men who recovered from COVID-19 had low circulating T levels suggestive for a condition of hypogonadism at a minimum 12-month follow-up.

Combined plasma levels of IL-10 and testosterone, but not soluble HLA-G5, predict the risk of death in COVID-19 patients.

BACKGROUND: The identification of biomarkers correlated with coronavirus disease 2019 (COVID-19) outcomes is a relevant need for clinical management. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is characterized by elevated interleukin (IL)-6, IL-10, HLA-G, and impaired testosterone production. OBJECTIVES: We aimed at defining the combined impact of sex hormones, interleukin-10, and HLA-G on COVID-19 pathophysiology and their relationship in male patients. MATERIALS AND METHODS: We measured by chemiluminescence immunoassay, electrochemiluminescent assays, and enzyme-linked immunosorbent assay circulating total testosterone, 17ß-estradiol (E2 ), IL-10, and -HLAG5 as well as SARS-CoV-2 S1/S2 Immunoglobulin G from 292 healthy controls and 111 COVID-19 patients with different disease severity at hospital admission, and in 53 COVID-19 patients at 7-month follow-up. RESULTS AND DISCUSSION: We found significantly higher levels of IL-10, HLA-G, and E2 in COVID-19 patients compared to healthy controls and an inverse correlation between IL-10 and testosterone, with IL-10, progressively increasing and testosterone progressively decreasing with disease severity. This correlation was lost at the 7-month follow-up. The risk of death in COVID-19 patients with low testosterone increased in the presence of high IL-10. A negative correlation between SARS-CoV-2 Immunoglobulin G and HLA-G or IL-10 at hospitalization was observed. At the 7-month follow-up, IL-10 and testosterone normalized, and  HLA-G decreased. CONCLUSION: Our findings indicate that combined evaluation of IL-10 and testosterone predicts the risk of death in men with COVID-19 and support the hypothesis that IL-10 fails to suppress excessive inflammation by promoting viral spreading.

Impact of Remdesivir on SARS-CoV-2 Clearance in a Real-Life Setting: A Matched-Cohort Study

Background Evidence regarding the impact of remdesivir (RDV) on SARS-CoV-2 viral clearance (VC) is scarce. The aim of this study was to compare VC timing in hospitalized COVID-19 patients who did or did not receive RDV. Methods This was a matched-cohort study of patients hospitalized with pneumonia, a SARS-CoV-2-positive nasopharyngeal swab (NPS) at admission, and at least one NPS during follow-up. Patients who received RDV (cases) and those who did not (controls) were matched in a 1:2 ratio by age, sex, and PaO2/FiO2 (P/F) values at admission. NPSs were analyzed using real-time polymerase chain reaction. Time to VC (within 30 days after hospital discharge) was estimated using the Kaplan–Meier curve. A multivariable Cox proportional hazard model was fitted to determine factors associated with VC. Results There were 648 patients enrolled in the study (216 cases and 432 controls). VC was observed in 490 patients (75.6%), with a median time of 25 (IQR 16–34) days. Overall, time to VC was similar between cases and controls (p = 0.519). However, time to VC was different when considering both RDV treatment status and age (p = 0.007). A significant finding was also observed when considering both RDV treatment status and P/F values at admission (p = 0.007). A multivariate analysis showed that VC was associated with a younger age (aHR = 0.990, 95% CI 0.983–0.998 per every 10-year increase in age;p = 0.009) and a higher baseline P/F ratio (aHR=1.275, 95% CI 1.029–1.579;p=0.026), but not with RDV treatment status. Conclusion Time to VC was similar in cases and controls. However, there was a benefit associated with using RDV in regard to time to VC in younger patients and in those with a P/F ratio ≤200 mmHg at hospital admission.

High Risk of Secondary Infections Following Thrombotic Complications in Patients With COVID-19.

Background: This study's primary aim was to evaluate the impact of thrombotic complications on the development of secondary infections. The secondary aim was to compare the etiology of secondary infections in patients with and without thrombotic complications. Methods: This was a cohort study (NCT04318366) of coronavirus disease 2019 (COVID-19) patients hospitalized at IRCCS San Raffaele Hospital between February 25 and June 30, 2020. Incidence rates (IRs) were calculated by univariable Poisson regression as the number of cases per 1000 person-days of follow-up (PDFU) with 95% confidence intervals. The cumulative incidence functions of secondary infections according to thrombotic complications were compared with Gray's method accounting for competing risk of death. A multivariable Fine-Gray model was applied to assess factors associated with risk of secondary infections. Results: Overall, 109/904 patients had 176 secondary infections (IR, 10.0; 95% CI, 8.8-11.5; per 1000-PDFU). The IRs of secondary infections among patients with or without thrombotic complications were 15.0 (95% CI, 10.7-21.0) and 9.3 (95% CI, 7.9-11.0) per 1000-PDFU, respectively (P = .017). At multivariable analysis, thrombotic complications were associated with the development of secondary infections (subdistribution hazard ratio, 1.788; 95% CI, 1.018-3.140; P = .043). The etiology of secondary infections was similar in patients with and without thrombotic complications. Conclusions: In patients with COVID-19, thrombotic complications were associated with a high risk of secondary infections.

The effect of reparixin on survival in patients at high risk for in-hospital mortality: a meta-analysis of randomized trials.

Introduction: A great number of anti-inflammatory drugs have been suggested in the treatment of SARS-CoV-2 infection. Reparixin, a non-competitive allosteric inhibitor of the CXCL8 (IL-8) receptors C-X-C chemokine receptor type 1 (CXCR1) and C-X-C chemokine receptor type 2 (CXCR2), has already been tried out as a treatment in different critical settings. Due to the contrasting existing literature, we decided to perform the present meta-analysis of randomized controlled trials (RCTs) to investigate the effect of the use of reparixin on survival in patients at high risk for in-hospital mortality. Methods: We created a search strategy to include any human RCTs performed with reparixin utilization in patients at high risk for in-hospital mortality, excluding oncological patients. Two trained, independent authors searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) for appropriate studies. Furthermore, references of review articles and included RCTs were screened to identify more studies. No language restrictions were enforced. To assess the risk of bias of included trials, the Revised Cochrane risk-of-bias tool for randomized trials (RoB 2) was used. Results: Overall, six studies were included and involved 406 patients (220 received reparixin and 186 received the comparator). The all-cause mortality in the reparixin group was significantly lower than that in the control group [5/220 (2.3%) in the reparixin group vs. 12/186 (6.5%) in the control group, odds ratio = 0.33 (95% confidence interval 0.12 to 0.96), p-value for effect 0.04, p for heterogeneity 0.20, I2 = 36%]. In addition, no difference in the rate of pneumonia, sepsis, or non-serious infections was shown between the two groups. Conclusion: Our meta-analysis of randomized trials suggests that short-term inhibition of CXCL8 activity improved survival in patients at high risk for in-hospital mortality without increasing the risk of infection. Meta-analysis registration: PROSPERO, identifier CRD42021254467.