Use of whole genomic sequencing to detect New Delhi metallo-B-lactamase (NDM)-producing Escherichia coli outbreak associated with endoscopic procedures.

BACKGROUND: Whole-genome sequencing (WGS) has emerged as an alternative genotyping tool for outbreak investigations in the healthcare setting. We describe the investigation and control of a New Delhi metallo-B-lactamase (NDM)-producing Escherichia coli cluster in Southeast Michigan. METHODS: Michigan Bureau of Laboratories identified several closely related NDM-producing E. coli isolates with WGS. An epidemiologic investigation, including case-control study, assessment of infection control practices, and endoscope culturing, was performed to identify source of transmission. Targeted screening of potentially exposed patients was performed following identification of probable source. RESULTS: Between July 2021 and February 2023, nine patients were identified. Phylogenetic analysis confirmed the isolates were closely related with less than 26 single nucleotide polymorphism (SNP) differences between isolates, suggesting an epidemiological link. Eight (89%) patients had a duodenoscope and/or gastroscope exposure. Cases were compared with 23 controls. Cases had significantly higher odds of exposure to duodenoscopes (odds ratio 15.0; 95% CI, 1.8-142.2; P = .015). The mean incubation period, estimated as date of procedure to positive index culture, was 86 days (range, 1-320 days). No lapses in endoscope reprocessing were identified; NDM-producing E. coli was not recovered from reprocessed endoscopes or during targeted screening. No additional cases were identified after removal of implicated gastroscopes and replacement of duodenoscope with disposable end caps. CONCLUSIONS: In this investigation, WGS was utilized to identify transmission of an NDM-producing E. coli outbreak associated with endoscope exposure. Coupled with epidemiologic data, WGS can facilitate outbreak investigations by rapidly identifying linked cases and potential sources to prevent further transmission.

Outcomes associated with SARS-CoV-2 reinfection in individuals with natural and hybrid immunity.

BACKGROUND: Studies comparing SARS-CoV-2 reinfection outcomes among individuals with previous infection (natural immunity) and previous infection plus vaccination (hybrid immunity) are limited. METHODS: Retrospective cohort study comparing SARS-CoV-2 reinfection among patients with hybrid immunity (cases) and natural immunity (controls) from March 2020 to February 2022. Reinfection was defined as positive PCR> 90 days after initial laboratory-confirmed SARS-CoV-2 infection. Outcomes included time to reinfection, symptom severity, COVID-19-related hospitalization, critical COVID-19 illness (need for intensive care unit, invasive mechanical ventilation, or death), length of stay (LOS). RESULTS: A total of 773 (42%) vaccinated and 1073 (58%) unvaccinated patients with reinfection were included. Most patients (62.7%) were asymptomatic. Median time to reinfection was longer with hybrid immunity (391 [311-440] vs 294 [229-406] days, p < 0.001). Cases were less likely to be symptomatic (34.1% vs 39.6%, p = 0.001) or develop critical COVID-19 (2.3% vs 4.3%, p = 0.023). However, there was no significant difference in rates of COVID-19-related hospitalization (2.6% vs 3.8%, p = 0.142) or LOS (5 [2-9] vs 5 [3-10] days, p = 0.446). Boosted patients had longer time to reinfection (439 [IQR 372-467] vs 324 [IQR 256-414] days, p < 0.001) and were less likely to be symptomatic (26.8% vs 38%, p = 0.002) compared to unboosted patients. Rates of hospitalization, progression to critical illness and LOS were not significantly different between the two groups. CONCLUSIONS: Natural and hybrid immunity provided protection against SARS-CoV-2 reinfection and hospitalization. However, hybrid immunity conferred stronger protection against symptomatic disease and progression to critical illness and was associated with longer time to reinfection. The stronger protection conferred by hybrid immunity against severe outcomes due to COVID-19 should be emphasized with the public to further the vaccination effort, especially in high-risk individuals.

Vaccine coverage and factors associated with vaccine adherence in persons with HIV at an urban infectious disease clinic.

Information on vaccination rates and factors associated with adherence in persons with HIV (PWH) is limited. We report vaccine adherence in 653 adult PWH attending an urban Infectious Disease Clinic from January 2015 to December 2021. Vaccines evaluated included influenza, pneumococcal, tetanus, hepatitis A virus (HAV) and hepatitis B virus (HBV), human papillomavirus (HPV), and zoster vaccines. Vaccine reminders were triggered at every visit, and all vaccines were accessible in the clinic. The mean age was 50 y (±SD 13), male gender was 78.6%, and black race was 74.3%. The overall adherence to all recommended vaccines was 63.6%. Vaccine adherence was >90% for influenza, pneumococcal, and tetanus, >80% for HAV and HBV, and ≥60% for HPV and zoster vaccines. The main predictor of adherence to all vaccines was ≥2 annual clinic visits (odds ratio [OR] 3.45; 95% confidence interval [CI] 2.36-5.05; p < .001). Other predictors included an assigned primary care provider within the system (OR 2.89 [95% CI 1.71-5.00, p < .001]) and CD4 >200 cell/mm3 at entry into care (OR 1.91 [95% CI 1.24-2.94, p = .0003]). Retention in care combined with vaccine reminders and accessibility of vaccines in the clinic can achieve high vaccine uptake in PWH.

Role of diagnostic stewardship in reducing healthcare-facility-onset Clostridioides difficile infections.

We describe the implementation of an electronic medical record "hard stop" to decrease inappropriate Clostridioides difficile testing across a 5-hospital health system, effectively reducing the rates of healthcare-facility-onset C. difficile infection. This novel approach included expert consultation with medical director of infection prevention and control for test-order override.

Bezlotoxumab for Prevention of Recurrent Clostridioides difficile Infection With a Focus on Immunocompromised Patients.

Objectives: Approximately 25% of patients with Clostridioides difficile infection (CDI) will experience recurrence, which is greater in immunocompromised patients. We report experience with an institutional guideline targeting high-risk immunocompromised patients. Methods: This was a retrospective cohort of consecutive patients with CDI who met institutional criteria for bezlotoxumab due to high risk for recurrent CDI between June 1, 2017, and November 30, 2018. The primary endpoint of recurrent CDI within 12 weeks was compared between patients who received the standard of care (SoC) plus or minus bezlotoxumab. Results: Twenty-three patients received bezlotoxumab infusion plus SoC and were compared to 30 SoC patients. 84% of patients were immunocompromised and 54.7% were transplant recipients. The primary endpoint occurred in 13% of bezlotoxumab patients compared to 23.3% of SoC patients. No serious adverse effects were identified. Conclusion: Bezlotoxumab was associated with a meaningful reduction in recurrent CDI in this cohort largely comprising immunocompromised and transplant patients. Larger studies are warranted to evaluate bezlotoxumab in this population.

Utility of microbiologic testing in surveillance bronchoscopy following lung transplantation: A retrospective cohort study.

BACKGROUND: The utility of surveillance bronchoscopy (SB) for the clinical management of lung transplant recipients (LTRs) is undefined. This study evaluates the role of SB in the monitoring and care of LTRs. METHODS: We retrospectively analyzed all LTRs who had SB at Henry Ford Hospital in Detroit, Michigan between August 2014 and August 2019. Bronchoscopies performed for clinical symptoms, new radiographic abnormalities, and to assess stents or acute rejection were excluded. A total of 107 LTRs and 449 bronchoscopies were analyzed. The primary outcome was the rate of change in clinical care based on microbiologic and pathologic test results. Secondary outcomes were rates of microbiologic and pathologic test positivity and rates of adverse effects. RESULTS: The most common microbiologic tests performed on bronchoalveolar lavage were bacterial (96.9%), fungal (95.3%), and acid-fast bacillus (95.1%) stains and cultures. Of 2560 microbiologic tests, 22.0% were positive and resulted in therapy changes for 2.9%. Positive galactomannan, acid-fast bacillus tests, and Pneumocystis jirovecii antigen/polymerase chain reaction did not result in therapy changes. Of the 370 transbronchial biopsies performed, 82.2% were negative for acute rejection and 13% were positive for A1/A2 rejection. Immunosuppressive therapy changes occurred after 15.8% with reduction in immunosuppression due to positive microbiologic tests in 16.9%. Adverse events occurred in 8.0% of patients. CONCLUSION: Diagnostic stewardship is warranted when performing SB in LTRs.

Bridging the gap: An approach to reporting antimicrobial stewardship metrics specific to solid organ transplant recipients.

BACKGROUND: This study seeks to describe inpatient antimicrobial use (AU) utilizing the National Healthcare Safety Network-AU (NHSN-AU) framework among solid organ transplant recipients (SOTr) within 12 months after transplant. METHODS: This cross-sectional study included SOTr ≥ 18 years of age who underwent transplantation from January 2015 to December 2016 at a Midwestern US transplant center. Inpatient AU was followed for 12 months post-transplant. Hospital days present up to 12 months post-transplant, AU variables, and Clostridioides difficile infection (CDI) occurrences were analyzed. RESULTS: The cohort of 530 SOTr included 225 kidney (42.5%), 171 liver (32.3%), 45 lung (8.5%), 40 heart (7.5%), 39 multivisceral (7.4%), seven small bowel (1.3%), and three pancreas (0.6%) transplants. Total days of therapy (DOT) were 22 782 among the cohort, with a median of 5 days [interquartile range [IQR], 1-12]. Lung and liver transplants had the most total DOT (6571 vs. 5569 days), while lungs and small bowels had the highest median DOT (13 [IQR, 2-56] vs. 12 [IQR, 2-31]). The facility-wide DOT/1000 days were lowest in pancreas and highest in lung transplants (5.3 vs. 428.1). Small bowel transplants received the most resistant-Gram-positive infection and hospital-onset infection agents for facility-wide DOT/1000 days present. Pancreas and kidney transplants accounted for the most high-risk CDI agents. CDI occurred in 34 patients, with kidney and liver transplants experiencing 13 each. CONCLUSION: This study represents one of the first reports of AU in SOTr utilizing the NHSN-AU framework. More studies are needed for further peer-to-peer comparison of AU in this complex patient population.

Progression to Critical Illness and Death in Patients With Breakthrough Hospitalizations.

Background: Characterization of disease progression and outcomes after coronavirus disease 2019 (COVID-19)-related hospitalization in vaccinated compared with unvaccinated individuals is limited. Methods: This was a retrospective case-control study of symptomatic vaccinated (cases) and unvaccinated (controls) participants hospitalized for COVID-19 between December 30, 2020, and September 30, 2021, in Southeast Michigan. Hospitalized adult patients with lab-confirmed COVID-19 were identified through daily census report. Breakthrough infection was defined as detection of severe acute respiratory syndrome coronavirus 2 ≥14 days after completion of the primary vaccination series. The association between prior vaccination and critical COVID-19 illness (composite of intensive care unit [ICU] admission, invasive mechanical ventilation [IMV], 28-day mortality) was examined. Results: Two hundred ten (39%) fully vaccinated and 325 (61%) unvaccinated patients were evaluated. Compared with controls, cases were older, had more comorbidities (4 [3-7] vs 2 [1-4]; P < .001), and were more likely to be immunocompromised. Cases had less severe symptoms compared with controls (2 [1-2] vs 2 [2-3]; P < .001) and were less likely to progress to critical COVID-19 illness (33.3% vs 45.5%; P < .001); 28-day mortality was significantly lower in cases (11.0% vs 24.9%; P < .001). Symptom severity (odds ratio [OR], 2.59; 95% CI, 1.61-4.16; P < .001) and modified Sequential Organ Failure Assessment score on presentation (OR, 1.74; 95% CI, 1.48-2.06; P < .001) were independently associated with development of critical COVID-19 illness. Prior vaccination (OR, 0.528; 95% CI, 0.307-0.910; P = .020) was protective. Conclusions: COVID-19-vaccinated patients were less likely to develop critical COVID-19 illness and more likely to survive. Disease severity at presentation was a predictor of adverse outcomes regardless of vaccination status.

Real-world Experience of Sotrovimab in High-risk, Immunocompromised COVID-19 Patients.

We completed a real-world analysis of 498 consecutive high-risk nonimmunocompromised and immunocompromised patients who received sotrovimab during the B.1.1.529 surge. Emergency department visits/hospitalizations and 30-day all-cause mortality between the 2 groups were similar. When administered early, sotrovimab is effective at preventing coronavirus disease 2019 progression in immunocompromised and nonimmunocompromised patients.

SARS-CoV-2 neutralizing antibodies for COVID-19: Outcomes for bamlanivimab versus bamlanivimab-etesevimab combination in a racially diverse cohort of patients with significant comorbidities.

WHAT IS KNOWN AND OBJECTIVE: Anti-spike monoclonal antibodies (MAB) including bamlanivimab (BAM) and bamlanivimab/etesevimab (BAM/E) have shown reduced hospitalization rates for non-severe coronavirus disease 2019 (COVID-19) in clinical trials. Recent data have provided real-world hospitalization rates for high-risk patients treated with BAM, however, data on a similar cohort treated with BAM/E are lacking. METHODS: This retrospective cohort study evaluated outpatients ≥18 years with laboratory-confirmed mild/moderate COVID-19 who received MAB from 1 December 2020 to 19 April 2021. Use of BAM monotherapy changed to BAM/E combination on 27 March 2021. Primary outcome was overall rate of COVID-19 related-hospitalization, including comparison of hospitalization rates between MAB-formulation groups. Secondary outcomes were 30-day mortality and length of stay (LOS). RESULTS AND DISCUSSION: The population included 643 patients (BAM and BAM/E); median age was 58 years, 43% were male, median BMI was 33 kg/m2 , and 24% self-identified as Black. Patients in the BAM/E combination group were significantly younger with higher median BMI and a longer time from symptom onset to infusion. The incidence of 30-day COVID-19 related hospitalization was similar between patients receiving either BAM or BAM/E combination (7.8% and 7.2%, respectively). WHAT IS NEW AND CONCLUSION: This study represents the first such publication of real-world BAM/E hospitalization outcomes. Hospitalization rates utilizing BAM/E were comparable to BAM in our real-world study.

Risk Factors Associated With Hospitalization and Death in COVID-19 Breakthrough Infections.

Background: Characterizations of coronavirus disease 2019 (COVID-19) vaccine breakthrough infections are limited. We aim to characterize breakthrough infections and identify risk factors associated with outcomes. Methods: This was a retrospective case series of consecutive fully vaccinated patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a multicenter academic center in Southeast Michigan, between December 30, 2020, and September 15, 2021. Results: A total of 982 patients were identified; the mean age was 57.9 years, 565 (59%) were female, 774 (79%) were White, and 255 (26%) were health care workers (HCWs). The median number of comorbidities was 2; 225 (23%) were immunocompromised. BNT162b2 was administered to 737 (75%) individuals. The mean time to SARS-CoV-2 detection was 135 days. The majority were asymptomatic or exhibited mild to moderate disease, 154 (16%) required hospitalization, 127 (13%) had severe-critical illness, and 19 (2%) died. Age (odds ratio [OR], 1.14; 95% CI, 1.04-1.07; P < .001), cardiovascular disease (OR, 3.02; 95% CI, 1.55-5.89; P = .001), and immunocompromised status (OR, 2.57; 95% CI, 1.70-3.90; P < .001) were independent risk factors for hospitalization. Additionally, age (OR, 1.06; 95% CI, 1.02-1.11; P = .006) was significantly associated with mortality. HCWs (OR, 0.15; 95% CI, 0.05-0.50; P = .002) were less likely to be hospitalized, and prior receipt of BNT162b2 was associated with lower odds of hospitalization (OR, 0.436; 95% CI, 0.303-0.626; P < .001) and/or death (OR, 0.360; 95% CI, 0.145-0.898; P = .029). Conclusions: COVID-19 vaccines remain effective at attenuating disease severity. However, patients with breakthrough infections necessitating hospitalization may benefit from early treatment modalities and COVID-19-mitigating strategies, especially in areas with substantial or high transmission rates.

A center experience with lung transplantation for COVID-19 ARDS.

COVID-19 can cause irreversible lung damage from acute respiratory distress syndrome (ARDS), chronic respiratory failure associated with post COVID-19 de novo fibrosis or worsening of an underlying fibrotic lung disease. Pregnant women are at increased risk for invasive mechanical ventilation, extracorporeal membrane oxygenation, and death. The Centers for Disease Control and Prevention reported more than 22,000 hospitalizations and 161 deaths for COVID-19 in pregnant women. Between August 2020 and September 2021, five patients underwent bilateral lung transplant (LT) for COVID-19 ARDS at the Henry Ford Hospital in Detroit, Michigan. De-identified demographics data, clinical characteristics, perioperative challenges, explanted lung pathology, and post-transplant outcomes are described. In post-hospitalization follow-up (median survival 273 days), we see improving endurance and excellent lung function. One patient did not survive to hospital discharge and succumbed to complications 5 months after LT. We report the first cases of bilateral LT in two postpartum women.

Low- Versus High-Dose Methylprednisolone in Adult Patients With Coronavirus Disease 2019: Less Is More.

BACKGROUND: Corticosteroids use in severe coronavirus disease 2019 (COVID-19) improves survival; however, the optimal dose is not established. We aim to evaluate clinical outcomes in patients with severe COVID-19 receiving high-dose corticosteroids (HDC) versus low-dose corticosteroids (LDC). METHODS: This was a quasi-experimental study conducted at a large, quaternary care center in Michigan. A corticosteroid dose change was implemented in the standardized institutional treatment protocol on November 17, 2020. All patients admitted with severe COVID-19 that received corticosteroids were included. Consecutive patients in the HDC group (September 1 to November 15, 2020) were compared to the LDC group (November 30, 2020 to January 20, 2021). High-dose corticosteroids was defined as 80 mg of methylprednisolone daily in 2 divided doses, and LDC was defined as 32-40 mg of methylprednisolone daily in 2 divided doses. The primary outcome was all-cause 28-day mortality. Secondary outcomes included progression to mechanical ventilation, hospital length of stay (LOS), discharge on supplemental oxygen, and corticosteroid-associated adverse events. RESULTS: Four-hundred seventy patients were included: 218 (46%) and 252 (54%) in the HDC and LDC groups, respectively. No difference was observed in 28-day mortality (14.5% vs 13.5%, P = .712). This finding remained intact when controlling for additional variables (odds ratio, 0.947; confidence interval, 0.515-1.742; P = .861). Median hospital LOS was 6 and 5 days in the HDC and LDC groups, respectively (P < .001). No differences were noted in any of the other secondary outcomes. CONCLUSIONS: Low-dose methylprednisolone had comparable outcomes including mortality to high-dose methylprednisolone for the treatment of severe COVID-19.

Outcomes of clinical decision support for outpatient management of Clostridioides difficile infection.

OBJECTIVE: To determine the impact of clinical decision support on guideline-concordant Clostridioides difficile infection (CDI) treatment. DESIGN: Quasi-experimental study in >50 ambulatory clinics. SETTING: Primary, specialty, and urgent-care clinics. PATIENTS: Adult patients were eligible for inclusion if they were diagnosed with and treated for a first episode of symptomatic CDI at an ambulatory clinic between November 1, 2019, and November 30, 2020. INTERVENTIONS: An outpatient best practice advisory (BPA) was implemented to notify prescribers that "vancomycin or fidaxomicin are preferred over metronidazole for C.difficile infection" when metronidazole was prescribed to a patient with CDI. RESULTS: In total, 189 patients were included in the study: 92 before the BPA and 97 after the BPA. Their median age was 59 years; 31% were male; 75% were white; 30% had CDI-related comorbidities; 35% had healthcare exposure; 65% had antibiotic exposure; 44% had gastric acid suppression therapy within 90 days of CDI diagnosis. The BPA was accepted 23 of 26 times and was used to optimize the therapy of 16 patients in 6 months. Guideline-concordant therapy increased after implementation of the BPA (72% vs 91%; P = .001). Vancomycin prescribing increased and metronidazole prescribing decreased after the BPA. There was no difference in clinical response or unplanned encounter within 14 days after treatment initiation. Fewer patients after the BPA had CDI recurrence within 14-56 days of the initial episode (27% vs 7%; P < .001). CONCLUSIONS: Clinical decision support increased prescribing of guideline-concordant CDI therapy in the outpatient setting. A targeted BPA is an effective stewardship intervention and may be especially useful in settings with limited antimicrobial stewardship resources.

Effect of a urine culture stewardship initiative on urine culture utilization and catheter-associated urinary tract infections in intensive care units.

OBJECTIVE: Urine cultures have poor specificity for catheter-associated urinary tract infections (CAUTIs). We evaluated the effect of a urine-culture stewardship program on urine culture utilization and CAUTI in adult intensive care units (ICUs). DESIGN: A quasi-interventional study was performed from 2015 to 2017. SETTING AND PATIENTS: The study cohort comprised 21,367 patients admitted to the ICU at a teaching hospital. INTERVENTION: The urine culture stewardship program included monthly 1-hour discussions with ICU house staff emphasizing avoidance of "pan-culture" for sepsis workup and obtaining urine culture only if a urinary source of sepsis is suspected. The urine culture utilization rate metric (UCUR; ie, no. urine cultueres/catheter days ×100) was utilized to measure the effect. Monthly UCUR, catheter utilization ratio (CUR), and CAUTI rate were reported on an interactive quality dashboard. To ensure safety, catheterized ICU patients (2015-2016) were evaluated for 30-day readmission for UTI. Time-series data and relationships were analyzed using Spearman correlation coefficients and regression analysis. RESULTS: Urine culture utilization decreased from 3,081 in 2015 to 2,158 in 2016 to 1,218 in 2017. CAUTIs decreased from 78 in 2015 to 60 in 2016 and 28 in 2017. Regression analysis over time showed significant decreases in UCUR (r, 0.917; P < .0001) and CAUTI rate (r, 0.657; P < .0001). The co-correlation between UCUR and CAUTI rate was (r, 0.625; P < .0001) compared to CUR and CAUTI rate (r, 0.523; P = .004). None of these patients was readmitted with a CAUTI. CONCLUSIONS: Urine culture stewardship program was effective and safe in reducing UC overutilization and was correlated with a decrease in CAUTIs. Addition of urine-culture stewardship to standard best practices could reduce CAUTI in ICUs.

Evaluation of the selection of cerebrospinal fluid testing in suspected meningitis and encephalitis.

Diagnostic stewardship interventions can decrease unnecessary antimicrobial therapy and microbiology laboratory resources and costs. This retrospective cross-sectional study evaluated factors associated with inappropriate initial cerebrospinal fluid (CSF) testing in patients with suspected community-acquired meningitis or encephalitis. In 250 patients, 202 (80.8%) and 48 (19.2%) were suspected meningitis and encephalitis, respectively. 207 (82.8%) patients had inappropriate and 43 (17.2%) appropriate testing. Any inappropriate CSF test was greatest in the immunocompromised (IC) group (n = 54, 91.5%), followed by non-IC (n = 109, 80.1%) and HIV (n = 44, 80%). Ordering performed on the general ward was associated with inappropriate CSF test orders (adjOR 2.81, 95% CI [1.08-7.34]). Laboratory fee costs associated with excessive testing was close to $300,000 per year. A stepwise algorithm defining empiric and add on tests according to CSF parameters and patient characteristics could improve CSF test ordering in patients with suspected meningitis or encephalitis.

Nosocomial Fungal Infections: Epidemiology, Infection Control, and Prevention.

Invasive fungal infections are an important cause of morbidity and mortality in hospitalized patients and in the immunocompromised population. This article reviews the current epidemiology of nosocomial fungal infections in adult patients, with an emphasis on invasive candidiasis (IC) and invasive aspergillosis (IA). Included are descriptions of nosocomial infections caused by Candida auris, an emerging pathogen, and IC- and IA-associated with coronavirus disease 2019. The characteristics and availability of newer nonculture-based tests for identification of nosocomial fungal pathogens are discussed. Recently published recommendations and guidelines for the control and prevention of these nosocomial fungal infections are summarized.

T2Candida for the Diagnosis and Management of Invasive Candida Infections.

Invasive candidiasis is a common healthcare-associated infection with high mortality and is difficult to diagnose due to nonspecific symptoms and limitations of culture based diagnostic methods. T2Candida, based on T2 magnetic resonance technology, is FDA approved for the diagnosis of candidemia and can rapidly detect the five most commonly isolated Candida sp. in approximately 5 h directly from whole blood. We discuss the preclinical and clinical studies of T2Candida for the diagnosis of candidemia and review the current literature on its use in deep-seated candidiasis, its role in patient management and prognosis, clinical utility in unique populations and non-blood specimens, and as an antifungal stewardship tool. Lastly, we summarize the strengths and limitations of this promising nonculture-based diagnostic test.

COVID-19: disease pathways and gene expression changes predict methylprednisolone can improve outcome in severe cases.

MOTIVATION: COVID-19 has several distinct clinical phases: a viral replication phase, an inflammatory phase and in some patients, a hyper-inflammatory phase. High mortality is associated with patients developing cytokine storm syndrome. Treatment of hyper-inflammation in these patients using existing approved therapies with proven safety profiles could address the immediate need to reduce mortality. RESULTS: We analyzed the changes in the gene expression, pathways and putative mechanisms induced by SARS-CoV2 in NHBE, and A549 cells, as well as COVID-19 lung versus their respective controls. We used these changes to identify FDA approved drugs that could be repurposed to help COVID-19 patients with severe symptoms related to hyper-inflammation. We identified methylprednisolone (MP) as a potential leading therapy. The results were then confirmed in five independent validation datasets including Vero E6 cells, lung and intestinal organoids, as well as additional patient lung sample versus their respective controls. Finally, the efficacy of MP was validated in an independent clinical study. Thirty-day all-cause mortality occurred at a significantly lower rate in the MP-treated group compared to control group (29.6% versus 16.6%, P = 0.027). Clinical results confirmed the in silico prediction that MP could improve outcomes in severe cases of COVID-19. A low number needed to treat (NNT = 5) suggests MP may be more efficacious than dexamethasone or hydrocortisone. AVAILABILITY AND IMPLEMENTATION: iPathwayGuide is available at https://advaitabio.com/ipathwayguide/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.