Publications by authors named "Robert Orenstein"

66 Publications

Mild to moderate COVID-19 illness in adult outpatients: Characteristics, symptoms, and outcomes in the first 4 weeks of illness.

Medicine (Baltimore) 2021 Jun;100(24):e26371

Division of Infectious Diseases.

Abstract: Most patients with coronavirus disease 2019 (COVID-19) have mild to moderate illness not requiring hospitalization. However, no study has detailed the evolution of symptoms in the first month of illness.At our institution, we conducted remote (telephone and video) visits for all adult outpatients diagnosed with COVID-19 within 24 h of a positive nasopharyngeal polymerase chain test for SARS-CoV-2. We repeated regular video visits at 7, 14, and 28 days after the positive test, retrospectively reviewed the prospective data collected in the remote visits, and constructed a week by week profile of clinical illness, through week 4 of illness.We reviewed the courses of 458 symptomatic patients diagnosed between March 12, 2020, and June 22, 2020, and characterized their weekly courses. Common initial symptoms included fever, headache, cough, and chest pain, which frequently persisted through week 3 or longer. Upper respiratory or gastrointestinal symptoms were much shorter lived, present primarily in week 1. Anosmia/ageusia peaked in weeks 2 to 3. Emergency department visits were frequent, with 128 visits in the 423 patients who were not hospitalized and 48 visits among the 35 outpatients (7.6%) who were eventually hospitalized (2 subsequently died). By the fourth week, 28.9% said their illness had completely resolved. After the 4-week follow up, 20 (4.7%) of the 423 nonhospitalized patients had further medical evaluation and management for subacute or chronic COVID-19 symptoms.Mild to moderate outpatient COVID-19 is a prolonged illness, with evolving symptoms commonly lasting into the fourth week of illness.
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http://dx.doi.org/10.1097/MD.0000000000026371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213280PMC
June 2021

Association of a Remote Patient Monitoring (RPM) Program With Reduced Hospitalizations in Cancer Patients With COVID-19.

JCO Oncol Pract 2021 Jun 4:OP2100307. Epub 2021 Jun 4.

Division of Medical Oncology, Mayo Clinic, Rochester, MN.

Purpose: The goal of this study was to assess the impact of an interdisciplinary remote patient monitoring (RPM) program on clinical outcomes and acute care utilization in cancer patients with COVID-19.

Methods: This is a cross-sectional analysis following a prospective observational study performed at Mayo Clinic Cancer Center. Adult patients receiving cancer-directed therapy or in recent remission on active surveillance with polymerase chain reaction-confirmed SARS-CoV-2 infection between March 18 and July 31, 2020, were included. RPM was composed of in-home technology to assess symptoms and physiologic data with centralized nursing and physician oversight.

Results: During the study timeframe, 224 patients with cancer were diagnosed with COVID-19. Of the 187 patients (83%) initially managed in the outpatient setting, those who did not receive RPM were significantly more likely to experience hospitalization than those receiving RPM. Following balancing of patient characteristics by inverse propensity score weighting, rates of hospitalization for RPM and non-RPM patients were 2.8% and 13%, respectively, implying that the use of RPM was associated with a 78% relative risk reduction in hospital admission rate (95% CI, 54 to 102; = .002). Furthermore, when hospitalized, these patients experienced a shorter length of stay and fewer prolonged hospitalizations, intensive care unit admissions, and deaths, although these trends did not reach statistical significance.

Conclusion: The use of RPM and a centralized virtual care team was associated with a reduction in hospital admission rate and lower overall acute care resource utilization among cancer patients with COVID-19.
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http://dx.doi.org/10.1200/OP.21.00307DOI Listing
June 2021

Association of Intravenous Bamlanivimab Use with Reduced Hospitalization, Intensive Care Unit Admission, and Mortality in Patients with Mild to Moderate COVID-19.

medRxiv 2021 May 25. Epub 2021 May 25.

Background: Clinical data to support the use of bamlanivimab for the treatment of outpatients with mild to moderate coronavirus disease-19 (COVID-19) is needed.

Methods: 2,335 patients who received single-dose bamlanivimab infusion between November 12, 2020 to February 17, 2021 were compared with a propensity-matched control of 2,335 untreated patients with mild to moderate COVID-19 at Mayo Clinic facilities across 4 states. The primary outcome was the rate of hospitalization at days 14, 21 and 28.

Results: The median age of the population was 63; 47.3% of the bamlanivimab-treated cohort were ≥65 years; 49.3% were female. High-risk characteristics included hypertension (54.2%), body mass index ≥35 (32.4%), diabetes mellitus (26.5%), chronic lung disease (25.1%), malignancy (16.6%), and renal disease (14.5%). Patients who received bamlanivimab had lower all-cause hospitalization rates at days 14 (1.5% vs 3.5%; Odds Ratio [OR], 0.38), 21 (1.9% vs 3.9%; OR, 0.46), and 28 (2.5% vs 3.9%; OR, 0.61). Secondary exploratory outcomes included lower intensive care unit admission rates at days 14 (0.14% vs 1%; OR, 0.12), 21 (0.25% vs 1%; OR: 0.24) and 28 (0.56% vs 1.1%; OR: 0.52), and lower all-cause mortality at days 14 (0% vs 0.33%), 21 (0.05% vs 0.4%; OR,0.08) and 28 (0.11% vs 0.44%; OR, 0.01). Adverse events were uncommon with bamlanivimab, occurring in 19/2355, most commonly fever (n=6), nausea (n=5), and lightheadedness (n=3).

Conclusions: Among high-risk patients with mild to moderate COVID-19, treatment with bamlanivimab was associated with a statistically significant lower rate of hospitalization compared with usual care.

Funding: Mayo Clinic.
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http://dx.doi.org/10.1101/2021.05.23.21257670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168391PMC
May 2021

LENZILUMAB EFFICACY AND SAFETY IN NEWLY HOSPITALIZED COVID-19 SUBJECTS: RESULTS FROM THE LIVE-AIR PHASE 3 RANDOMIZED DOUBLE-BLIND PLACEBO-CONTROLLED TRIAL.

medRxiv 2021 May 5. Epub 2021 May 5.

Background: Severe COVID-19 pneumonia results from a hyperinflammatory immune response (cytokine storm, CS), characterized by GM-CSF mediated activation and trafficking of myeloid cells, leading to elevation of downstream inflammatory chemokines (MCP-1, IL-8, IP-10), cytokines (IL-6, IL-1), and other markers of systemic inflammation (CRP, D-dimer, ferritin). CS leads to fever, hypotension, coagulopathy, respiratory failure, ARDS, and death. Lenzilumab is a novel Humaneered anti-human GM-CSF monoclonal antibody that directly binds GM-CSF and prevents signaling through its receptor. The LIVE-AIR Phase 3 randomized, double-blind, placebo-controlled trial investigated the efficacy and safety of lenzilumab to assess the potential for lenzilumab to improve the likelihood of ventilator-free survival (referred to herein as survival without ventilation, SWOV), beyond standard supportive care, in hospitalized subjects with severe COVID-19.

Methods: Subjects with COVID-19 (n=520), ≥18 years, and ≤94% oxygen saturation on room air and/or requiring supplemental oxygen, but not invasive mechanical ventilation, were randomized to receive lenzilumab (600 mg, n=261) or placebo (n=259) via three intravenous infusions administered 8 hours apart. Subjects were followed through Day 28 following treatment.

Results: Baseline demographics were comparable between the two treatment groups: male, 64.7%; mean age, 60.5 years; mean BMI, 32.5 kg/m ; mean CRP, 98.36 mg/L; CRP was <150 mg/L in 77.9% of subjects. The most common comorbidities were obesity (55.1%), diabetes (53.4%), chronic kidney disease (14.0%), and coronary artery disease (13.6%). Subjects received steroids (93.7%), remdesivir (72.4%), or both (69.1%). Lenzilumab improved the likelihood of SWOV by 54% in the mITT population (HR: 1.54; 95%CI: 1.02-2.31, p=0.041) and by 90% in the ITT population (HR: 1.90; 1.02-3.52, nominal p=0.043) compared to placebo. SWOV also relatively improved by 92% in subjects who received both corticosteroids and remdesivir (1.92; 1.20-3.07, nominal p=0.0067); by 2.96-fold in subjects with CRP<150 mg/L and age <85 years (2.96; 1.63-5.37, nominal p=0.0003); and by 88% in subjects hospitalized ≤2 days prior to randomization (1.88; 1.13-3.12, nominal p=0.015). Survival was improved by 2.17-fold in subjects with CRP<150 mg/L and age <85 years (2.17; 1.04-4.54, nominal p=0.040).

Conclusion: Lenzilumab significantly improved SWOV in hospitalized, hypoxic subjects with COVID-19 pneumonia over and above treatment with remdesivir and/or corticosteroids. Subjects with CRP<150 mg/L and age <85 years demonstrated an improvement in survival and had the greatest benefit from lenzilumab. NCT04351152.
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http://dx.doi.org/10.1101/2021.05.01.21256470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109186PMC
May 2021

A Framework for Outpatient Infusion of Antispike Monoclonal Antibodies to High-Risk Patients with Mild-to-Moderate Coronavirus Disease-19: The Mayo Clinic Model.

Mayo Clin Proc 2021 05 9;96(5):1250-1261. Epub 2021 Mar 9.

Division of Pediatric Infectious Diseases, Mayo Clinic, Rochester, MN.

The administration of spike monoclonal antibody treatment to patients with mild to moderate COVID-19 is very challenging. This article summarizes essential components and processes in establishing an effective spike monoclonal antibody infusion program. Rapid identification of a dedicated physical infrastructure was essential to circumvent the logistical challenges of caring for infectious patients while maintaining compliance with regulations and ensuring the safety of our personnel and other patients. Our partnerships and collaborations among multiple different specialties and disciplines enabled contributions from personnel with specific expertise in medicine, nursing, pharmacy, infection prevention and control, electronic health record (EHR) informatics, compliance, legal, medical ethics, engineering, administration, and other critical areas. Clear communication and a culture in which all roles are welcomed at the planning and operational tables are critical to the rapid development and refinement needed to adapt and thrive in providing this time-sensitive beneficial therapy. Our partnerships with leaders and providers outside our institutions, including those who care for underserved populations, have promoted equity in the access of monoclonal antibodies in our regions. Strong support from institutional leadership facilitated expedited action when needed, from a physical, personnel, and system infrastructure standpoint. Our ongoing real-time assessment and monitoring of our clinical program allowed us to improve and optimize our processes to ensure that the needs of our patients with COVID-19 in the outpatient setting are met.
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http://dx.doi.org/10.1016/j.mayocp.2021.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942148PMC
May 2021

Efficacy of oral vancomycin prophylaxis for prevention of infection: a systematic review and meta-analysis.

Therap Adv Gastroenterol 2021 23;14:1756284821994046. Epub 2021 Feb 23.

Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.

Background: Prevention of recurrent infection (CDI) is a challenge in clinical practice, particularly in patients who need systemic antimicrobial therapy. We aimed to evaluate the role of oral vancomycin prophylaxis (OVP) in prevention of primary or future CDI in patients on systemic antimicrobial therapy.

Methods: A systematic search of MEDLINE, Embase, and Web of Science was performed from 2000 to January 2020. We included case-control or cohort studies that included patients on systemic antimicrobial therapy who did or did not receive oral vancomycin prophylaxis (OVP) and were evaluated for development of CDI. Odds ratio (OR) estimates with 95% confidence intervals (CI) were calculated.

Results: Four studies including 1352 patients evaluated OVP for primary CDI prevention, with CDI occurring in 29/402 patients on OVP (7.4%) compared with 10.4% (99/950) without OVP. Meta-analysis revealed no significant decrease in risk of CDI in patients who received OVP (OR, 0.18; 95% CI, 0.03-1.03;  = 0.06). There was significant heterogeneity with  = 76%. Ten studies including 9258 patients evaluated OVP for secondary CDI prevention. Future CDI occurred in 91/713 patients on OVP (13.3%) compared with 21.9% (1875/8545) who did not receive OVP. Meta-analysis revealed a statistically significant decreased risk of future CDI (OR, 0.34; 95% CI, 0.20-0.59;  < 0.00001). Significant heterogeneity was seen with  = 59%.

Discussion: Based on observational data, OVP appears to decrease the risk of future CDI in patients with prior CDI who require systemic antimicrobial therapy. However, OVP was not effective for primary prevention of CDI.
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http://dx.doi.org/10.1177/1756284821994046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905721PMC
February 2021

Outcomes of COVID-19 With the Mayo Clinic Model of Care and Research.

Mayo Clin Proc 2021 03 26;96(3):601-618. Epub 2020 Dec 26.

Division of Infectious Diseases, Mayo Clinic, Rochester, MN.

Objective: To report the Mayo Clinic experience with coronavirus disease 2019 (COVID-19) related to patient outcomes.

Methods: We conducted a retrospective chart review of patients with COVID-19 diagnosed between March 1, 2020, and July 31, 2020, at any of the Mayo Clinic sites. We abstracted pertinent comorbid conditions such as age, sex, body mass index, Charlson Comorbidity Index variables, and treatments received. Factors associated with hospitalization and mortality were assessed in univariate and multivariate models.

Results: A total of 7891 patients with confirmed COVID-19 infection with research authorization on file received care across the Mayo Clinic sites during the study period. Of these, 7217 patients were adults 18 years or older who were analyzed further. A total of 897 (11.4%) patients required hospitalization, and 354 (4.9%) received care in the intensive care unit (ICU). All hospitalized patients were reviewed by a COVID-19 Treatment Review Panel, and 77.5% (695 of 897) of inpatients received a COVID-19-directed therapy. Overall mortality was 1.2% (94 of 7891), with 7.1% (64 of 897) mortality in hospitalized patients and 11.3% (40 of 354) in patients requiring ICU care.

Conclusion: Mayo Clinic outcomes of patients with COVID-19 infection in the ICU, hospital, and community compare favorably with those reported nationally. This likely reflects the impact of interprofessional multidisciplinary team evaluation, effective leveraging of clinical trials and available treatments, deployment of remote monitoring tools, and maintenance of adequate operating capacity to not require surge adjustments. These best practices can help guide other health care systems with the continuing response to the COVID-19 pandemic.
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http://dx.doi.org/10.1016/j.mayocp.2020.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831394PMC
March 2021

GM-CSF Neutralization With Lenzilumab in Severe COVID-19 Pneumonia: A Case-Cohort Study.

Mayo Clin Proc 2020 11 3;95(11):2382-2394. Epub 2020 Sep 3.

Division of Infectious Diseases, Mayo Clinic, Rochester, MN; Department of Molecular Medicine, Mayo Clinic, Rochester, MN.

Objective: To assess the efficacy and safety of lenzilumab in patients with severe coronavirus disease 2019 (COVID-19) pneumonia.

Methods: Hospitalized patients with COVID-19 pneumonia and risk factors for poor outcomes were treated with lenzilumab 600 mg intravenously for three doses through an emergency single-use investigational new drug application. Patient characteristics, clinical and laboratory outcomes, and adverse events were recorded. We also identified a cohort of patients matched to the lenzilumab patients for age, sex, and disease severity. Study dates were March 13, 2020, to June 18, 2020. All patients were followed through hospital discharge or death.

Results: Twelve patients were treated with lenzilumab; 27 patients comprised the matched control cohort (untreated). Clinical improvement, defined as improvement of at least 2 points on the 8-point ordinal clinical endpoints scale, was observed in 11 of 12 (91.7%) patients treated with lenzilumab and 22 of 27 (81.5%) untreated patients. The time to clinical improvement was significantly shorter for the lenzilumab-treated group compared with the untreated cohort with a median of 5 days versus 11 days (P=.006). Similarly, the proportion of patients with acute respiratory distress syndrome (oxygen saturation/fraction of inspired oxygen<315 mm Hg) was significantly reduced over time when treated with lenzilumab compared with untreated (P<.001). Significant improvement in inflammatory markers (C-reactive protein and interleukin 6) and markers of disease severity (absolute lymphocyte count) were observed in patients who received lenzilumab, but not in untreated patients. Cytokine analysis showed a reduction in inflammatory myeloid cells 2 days after lenzilumab treatment. There were no treatment-emergent adverse events attributable to lenzilumab.

Conclusion: In high-risk COVID-19 patients with severe pneumonia, granulocyte-macrophage colony-stimulating factor neutralization with lenzilumab was safe and associated with faster improvement in clinical outcomes, including oxygenation, and greater reductions in inflammatory markers compared with a matched control cohort of patients hospitalized with severe COVID-19 pneumonia. A randomized, placebo-controlled clinical trial to validate these findings is ongoing (NCT04351152).
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http://dx.doi.org/10.1016/j.mayocp.2020.08.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470718PMC
November 2020

Research Response to SARS-CoV-2/COVID-19.

Mayo Clin Proc 2020 09 7;95(9S):S52-S55. Epub 2020 Jul 7.

Division of Infectious Diseases, Mayo Clinic, Rochester, MN.

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http://dx.doi.org/10.1016/j.mayocp.2020.06.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340066PMC
September 2020

First Clinical Use of Lenzilumab to Neutralize GM-CSF in Patients with Severe COVID-19 Pneumonia.

medRxiv 2020 Jun 14. Epub 2020 Jun 14.

Background: In COVID-19, high levels of granulocyte macrophage-colony stimulating factor (GM-CSF) and inflammatory myeloid cells correlate with disease severity, cytokine storm, and respiratory failure. With this rationale, we used lenzilumab, an anti-human GM-CSF monoclonal antibody, to treat patients with severe COVID-19 pneumonia.

Methods: Hospitalized patients with COVID-19 pneumonia and risk factors for poor outcomes were treated with lenzilumab 600 mg intravenously for three doses through an emergency single-use IND application. Patient characteristics, clinical and laboratory outcomes, and adverse events were recorded. All patients receiving lenzilumab through May 1, 2020 were included in this report.

Results: Twelve patients were treated with lenzilumab. Clinical improvement was observed in 11 out of 12 (92%), with a median time to discharge of 5 days. There was a significant improvement in oxygenation: The proportion of patients with SpO2/FiO2 < 315 at the end of observation was 8% vs. compared to 67% at baseline (p=0.00015). A significant improvement in mean CRP and IL-6 values on day 3 following lenzilumab administration was also observed (137.3 mg/L vs 51.2 mg/L, p = 0.040; 26.8 pg/mL vs 16.1 pg/mL, p = 0.035; respectively). Cytokine analysis showed a reduction in inflammatory myeloid cells two days after lenzilumab treatment. There were no treatment-emergent adverse events attributable to lenzilumab, and no mortality in this cohort of patients with severe COVID-19 pneumonia.

Conclusions: In high-risk COVID-19 patients with severe pneumonia, GM-CSF neutralization with lenzilumab was safe and associated with improved clinical outcomes, oxygen requirement, and cytokine storm.
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http://dx.doi.org/10.1101/2020.06.08.20125369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310641PMC
June 2020

Efficacy of Fecal Microbiota Transplantation for Recurrent C. Difficile Infection in Inflammatory Bowel Disease.

Inflamm Bowel Dis 2020 08;26(9):1415-1420

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.

Background: Clostridioides difficile infection (CDI) is associated with poor outcomes in inflammatory bowel disease (IBD) patients. Data are scarce on efficacy of fecal microbiota transplant (FMT) for recurrent CDI in IBD patients.

Methods: We reviewed health records of IBD patients (18 years of age or older) with recurrent CDI who underwent FMT. Outcomes of FMT for CDI were assessed on the basis of symptoms and stool test results.

Results: We included 145 patients (75 women [51.7%]; median age, 46 years). Median IBD duration was 8 (range, 0-47) years, 36.6% had Crohn disease, 61.4% had ulcerative colitis, and 2.1% had indeterminate colitis. Median number of prior CDI episodes was 3 (range, 3-20), and 61.4% had received vancomycin taper. Diarrhea resolved after FMT in 48 patients (33.1%) without further testing. Ninety-five patients (65.5%) underwent CDI testing owing to post-FMT recurrent diarrhea; 29 (20.0%) had positive results. After FMT, 2 patients received empiric treatment of recurrent CDI without symptom resolution, suggesting IBD was the cause of symptoms. The overall cure rate of CDI after FMT was 80.0%, without CDI recurrence at median follow-up of 9.3 (range, 0.1-51) months. Forty-three patients (29.7%) had planned IBD therapy escalation after CDI resolution; none de-escalated or discontinued IBD therapy. Overall, 7.6% had worsening IBD symptoms after FMT that were treated as new IBD flares. No clinical predictors of FMT failure were identified.

Conclusions: Few patients had new IBD flare after FMT. Fecal microbiota transplantation effectively treats recurrent CDI in IBD patients but has no apparent beneficial effect on the IBD course.
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http://dx.doi.org/10.1093/ibd/izz299DOI Listing
August 2020

Polyneuritis cranialis after acute tularemia infection: A case study.

Muscle Nerve 2020 01 7;61(1):E1-E2. Epub 2019 Nov 7.

Department of Neurology, Mayo Clinic, Scottsdale, Arizona.

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http://dx.doi.org/10.1002/mus.26725DOI Listing
January 2020

therapeutics: guidelines and beyond.

Ther Adv Infect Dis 2019 Jan-Dec;6:2049936119868548. Epub 2019 Aug 13.

Division of Infectious Diseases, Mayo Clinic Arizona, Phoenix, AZ, USA.

infection (CDI) has become an increasingly common infection both within and outside of the hospital setting. The management of this infection has been evolving as we learn more about the role of the human microbiota in protecting us from this gastrointestinal opportunist. For many years the focus of treatment had been on eradication of the vegetative, toxin-producing form of the organism, with little regard for its collateral impact on the host's microbiota or risk of recurrence. With the marked increase in disease, and, particularly, recurrent disease in the last decade, new guidelines are more focused on targeting and reducing collateral damage to the colonic microbiota. Immune-based strategies that manipulate the microbiota and provide a humoral response to toxins have now become mainstream. Newer strategies are needed to look beyond simply resolving the primary episode but are focused on delayed outcomes such as cure at 90 days, reduced morbidity and mortality, and patient quality of life. The purpose of this review is to familiarize readers with the most recent evidence-based guidelines for management, and to describe the role of newer antimicrobials, immunological-, and microbiota-based therapeutics to prevent recurrence and improve the outcomes of people with CDI.
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http://dx.doi.org/10.1177/2049936119868548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693025PMC
August 2019

Why Does Clostridium difficile Infection Recur?

J Am Osteopath Assoc 2019 May;119(5):322-326

Clostridium (or Clostridioides) difficile infection affects more than 500,000 people annually in the United States, one-third of whom have recurrent symptoms. The evolution of C difficile as a resilient pathogen has to do with its ability to persist in the environment and in the host, leading to recurrence and environmental spread. Understanding the mechanisms by which this microbe interacts with the environment, the host, and the gut microbiota are critical to solving this problem. This article presents a brief clinical vignette; discusses the current state of understanding of colonization, transmission, and recurrence; and considers the role the host plays in eliminating this infection. The understanding of these mechanisms and application of osteopathic principles has the potential to improve patient outcomes.
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http://dx.doi.org/10.7556/jaoa.2019.054DOI Listing
May 2019

The Art and Science of Osteopathic Medicine.

Authors:
Robert Orenstein

J Am Osteopath Assoc 2019 05;119(5):281

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http://dx.doi.org/10.7556/jaoa.2019.046DOI Listing
May 2019

Post-transplant primary central nervous system lymphoma after Epstein-Barr virus cerebellitis.

J Neurovirol 2019 04 3;25(2):280-283. Epub 2019 Jan 3.

Division of Neurology, Mayo Clinic Arizona, 13400 East Shea Boulevard, Scottsdale, AZ, 85259, USA.

Post-transplantation lymphoproliferative disorder (PTLD) is a complication of solid organ and hematopoietic stem cell transplantation. Cases with isolated central nervous system (CNS) disease are rare. Epstein-Barr virus (EBV) plays a causative role. We present a patient with EBV cerebellitis documented 5 months prior to development of primary CNS PTLD (PCNS-PTLD). This case report demonstrates progression from EBV CNS infection to lymphoproliferative disorder, highlighting the importance of serial clinical and imaging monitoring in transplant patients post-EBV CNS infection. PCNS-PTLD should always be considered in the differential diagnosis for transplant patients presenting with CNS symptoms, even in cases with no evidence of EBV viremia. Earlier diagnosis and appropriate treatment could result in improved outcomes.
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http://dx.doi.org/10.1007/s13365-018-0711-8DOI Listing
April 2019

Results From a Randomized, Placebo-Controlled Clinical Trial of a RBX2660-A Microbiota-Based Drug for the Prevention of Recurrent Clostridium difficile Infection.

Clin Infect Dis 2018 09;67(8):1198-1204

Edward Hines Jr. VA Hospital, Illinois.

Background: Despite advancements, recurrent Clostridium difficile infections (CDI) remain an urgent public health threat with insufficient response rates to currently approved antibiotic therapies. Microbiota-based treatments appear effective, but rigorous clinical trials are required to optimize dosing strategies and substantiate long-term safety.

Methods: This randomized, double-blind, placebo-controlled phase 2B trial enrolled adults with 2 or more CDI recurrences to receive: 2 doses of RBX2660, a standardized microbiota-based drug (group A); 2doses of placebo (group B); or 1 dose of RBX2660 followed by 1 dose of placebo (group C). Efficacy was defined as prevention of recurrent CDI for 8 weeks following treatment. Participants who had a recurrence within 8 weeks were eligible to receive up to 2 open-label RBX2660 doses. The primary endpoint was efficacy for group A compared to group B. Secondary endpoints included the efficacy of group C compared to group B, combined efficacy in the blinded and open-label phases, and safety for 24 months.

Results: The efficacy for groups A, B, and C were 61%, 45%, and 67%, respectively. The primary endpoint was not met (P = .152). One RBX2660 dose (group C) was superior to placebo (group B; P = .048), and the overall efficacy (including open-label response) for RBX2660-treated participants was 88.8%. Adverse events did not differ significantly among treatment groups.

Conclusions: One, but not 2, doses of RBX2660 was superior to placebo in this randomized, placebo-controlled trial. These data provide important insights for a larger phase 3 trial and continued clinical development of RBX2660.

Clinical Trials Registration: NCT02299570.
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http://dx.doi.org/10.1093/cid/ciy259DOI Listing
September 2018

Low Risk of Primary Clostridium difficile Infection With Tetracyclines: A Systematic Review and Metaanalysis.

Clin Infect Dis 2018 02;66(4):514-522

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.

Background: The choice of antibiotics for systemic infections in patients with a high risk of Clostridium difficile infection (CDI) remains a clinical practice dilemma. Although some studies suggest that tetracyclines may be associated with a lower risk of CDI than other antibiotics, other results are conflicting. We conducted a systematic review and metaanalysis of studies that assessed the risk of CDI with tetracyclines compared to other antibiotics.

Methods: We conducted a systematic search of Medline, Embase, and Web of Science from January 1978 through December 2016 to include studies that assessed the association between tetracycline use and risk of CDI. Weighted summary estimates were calculated using generalized inverse variance with a random-effects model using RevMan 5.3. Study quality was assessed using the Newcastle-Ottawa scale.

Results: Six studies (4 case control, 2 cohort) with patient recruitment between 1993 and 2012 were included. Metaanalysis using a random-effects model, demonstrated that tetracyclines were associated with a decreased risk of CDI (odds ratio [OR], 0.62; 95% confidence interval [CI], 0.47-0.81; P < .001). There was significant heterogeneity, with an I2 of 53% with no publication bias. Subgroup analysis of studies that evaluated the risk of CDI with doxycycline alone also demonstrated a decreased risk of CDI (OR, 0.55; 95% CI, 0.40-0.75; P < .001).

Conclusions: Metaanalyses of existing studies suggest that tetracyclines may be associated with a decreased risk of CDI compared with other antimicrobials. It may be reasonable to use tetracyclines whenever appropriate to decrease CDI associated with antibiotic use.
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http://dx.doi.org/10.1093/cid/cix833DOI Listing
February 2018

Mini-Fecal Microbiota Transplantation for Treatment of Clostridium difficile Proctitis Following Total Colectomy.

Clin Infect Dis 2018 01;66(2):299-300

Colorectal Surgery, Mayo Clinic Arizona, Phoenix.

Rarely, in fulminant Clostridium difficile infection (CDI), the rectal stump is persistently infected following total abdominal colectomy. We report cure of a septic patient with proctitis by fecal microbiota transplant via rectal swabs (mini-FMT). This novel procedure offers a management option for recurrent CDI following total abdominal colectomy.
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http://dx.doi.org/10.1093/cid/cix736DOI Listing
January 2018

Vancomycin Taper and Risk of Failure of Fecal Microbiota Transplantation in Patients With Recurrent Clostridium difficile Infection.

Clin Infect Dis 2017 10;65(7):1214-1217

Division of Infectious Diseases.

We retrospectively analyzed a cohort of 109 subjects treated for recurrent Clostridium difficile infection with fecal microbiota transplantation (FMT) at a tertiary referral center between 2011 and 2014 to determine risk factors for FMT failure. In a multivariate analysis, failure to use an oral vancomycin taper preceding FMT was associated with a significant risk of FMT failure (odds ratio, 0.15; 95% confidence interval, .007-.40).
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http://dx.doi.org/10.1093/cid/cix511DOI Listing
October 2017

History of Osteopathic Medicine: Still Relevant?

Authors:
Robert Orenstein

J Am Osteopath Assoc 2017 03;117(3):148

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http://dx.doi.org/10.7556/jaoa.2017.027DOI Listing
March 2017

Antimicrobial Stewardship and Osteopathic Medicine: A Call to Action.

Authors:
Robert Orenstein

J Am Osteopath Assoc 2016 09;116(9):564-6

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http://dx.doi.org/10.7556/jaoa.2016.112DOI Listing
September 2016

Coccidioidomycosis in Patients with Selected Solid Organ Cancers: A Case Series and Review of Medical Literature.

Mycopathologia 2016 Dec 4;181(11-12):787-798. Epub 2016 Aug 4.

Division of Infectious Diseases, Mayo Clinic Hospital, 5777 E Mayo Blvd, Phoenix, AZ, 85054, USA.

Coccidioidomycosis is a common infection in the desert southwestern USA; approximately 3 % of healthy persons in Arizona alone become infected annually. Coccidioidomycosis may be severe in immunocompromised persons, but experience among patients with solid organ cancer has not been fully described. Therefore, we aimed to describe the clinical courses of patients whose cancers were complicated by coccidioidomycosis at our institution, which is located in an area with endemic Coccidioides. To do so, we conducted a retrospective review from January 1, 2000, through December 31, 2014, of all patients with breast, colorectal, or ovarian cancer whose cancer courses were complicated by coccidioidomycosis. We identified 17,576 cancer patients; 14 (0.08 %) of these patients met criteria for proven or probable coccidioidomycosis diagnosed within the first 2 years after the cancer diagnosis. All of these patients had primary pulmonary coccidioidomycosis, none had relapsed prior infection, and 1 had possible extrapulmonary dissemination. Five had active coccidioidal infection during chemotherapy, 1 of whom was hospitalized for coccidioidal pneumonia. All were treated with fluconazole, and all improved clinically. Eleven did not require prolonged courses of fluconazole. There were no clearly demonstrated episodes of relapsed infection. In conclusion, coccidioidomycosis was not a common complication of breast, colorectal, or ovarian cancers in patients treated at our institution, and it was not commonly complicated by severe or disseminated infection.
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http://dx.doi.org/10.1007/s11046-016-0044-1DOI Listing
December 2016

Disseminated Varicella-Zoster Virus After Vaccination in an Immunocompetent Patient.

J Am Osteopath Assoc 2016 Jun;116(6):402-5

Severe adverse events associated with varicella-zoster virus (VZV) vaccination are rare. The authors describe a 53-year-old woman with no known immunodeficiency who presented with diffuse pruritic rash 17 days after receiving the varicella virus vaccine live. She had a low level of white blood cells and received a diagnosis of thrombocytopenia with elevated aminotransferase levels. Punch biopsy demonstrated positive VZV immunostaining and viral culture positive for VZV. After treatment with acyclovir, her rash improved and her white blood cell and platelet counts returned to normal. Mild reactions to vaccines including localized rash are well recognized. Disseminated infections have been reported in patients with congenital and acquired immunodeficiency, but systemic postvaccination infections are rare in immunocompetent adults. This case highlights the importance of recognizing adverse events associated with vaccination.
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http://dx.doi.org/10.7556/jaoa.2016.082DOI Listing
June 2016

ENGAGE Initiative: Showcasing Osteopathic Scholarly Activity.

Authors:
Robert Orenstein

J Am Osteopath Assoc 2016 May;116(5):276-7

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http://dx.doi.org/10.7556/jaoa.2016.054DOI Listing
May 2016

Preoperative risk prediction of surgical site infection requiring hospitalization or reoperation in patients undergoing vascular surgery.

J Vasc Surg 2016 07 27;64(1):177-84. Epub 2016 Feb 27.

Division of Infectious Diseases, Mayo Clinic, Scottsdale, Ariz.

Objective: The objective of this study was to develop a surgical site infection (SSI) prediction score for risk assessment before elective vascular surgery.

Methods: We conducted a nested case-control study among patients who underwent elective vascular (abdominal aortic and peripheral arterial) surgery from January 1, 2003, to December 31, 2007, at Mayo Clinic (Rochester, Minn) an academic tertiary surgical center. Cases were patients with SSI requiring hospitalization; controls (one or two per case) were matched on type of procedure and date of surgery. Clinical data were collected by chart review. A risk score based on preoperative variables was developed using multivariable logistic regression and bootstrap resampling. The C statistic, equivalent to the area under the receiver operating characteristic curve, was used to assess discrimination. Calibration was assessed by plotting percentile risk groups of model-predicted values against observed proportions of subjects with SSI.

Results: Eighty-four cases were compared with 160 controls. Preoperative variables independently associated with SSI risk were critical limb ischemia, previous SSI, prior revascularization procedure, and chronic obstructive pulmonary disease. A prediction model containing these variables was developed (model and risk score C statistic of 0.737 and 0.727, respectively). The calibration curve did not appear to deviate appreciably from the 45-degree line of identity.

Conclusions: We developed an SSI risk score based on noninvasive preoperative variables with acceptable discrimination and calibration. This tool needs prospective and external validation.
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http://dx.doi.org/10.1016/j.jvs.2016.01.029DOI Listing
July 2016

Safety and Durability of RBX2660 (Microbiota Suspension) for Recurrent Clostridium difficile Infection: Results of the PUNCH CD Study.

Clin Infect Dis 2016 Mar 12;62(5):596-602. Epub 2015 Nov 12.

Henry Ford Hospital System, Detroit, Michigan.

Background: Managing recurrent Clostridium difficile infection (CDI) presents a significant challenge for clinicians and patients. Fecal microbiota transplantation (FMT) is a highly effective therapy for recurrent CDI, yet availability of a standardized, safe, and effective product has been lacking. Our aim in this study was to assess the safety and effectiveness of RBX2660 (microbiota suspension), a commercially prepared FMT drug manufactured using standardized processes and available in a ready-to-use format.

Methods: Patients with at least 2 recurrent CDI episodes or at least 2 severe episodes resulting in hospitalization were enrolled in a prospective, multicenter open-label study of RBX2660 administered via enema. Intensive surveillance for adverse events (AEs) was conducted daily for 7 days following treatment and then at 30 days, 60 days, 3 months, and 6 months. The primary objective was product-related AEs. A secondary objective was CDI-associated diarrhea resolution at 8 weeks.

Results: Of the 40 patients enrolled at 11 centers in the United States between 15 August 2013 and 16 December 2013, 34 received at least 1 dose of RBX2660 and 31 completed 6-month follow-up. Overall efficacy was 87.1% (16 with 1 dose and 11 with 2 doses). Of 188 reported AEs, diarrhea, flatulence, abdominal pain/cramping, and constipation were most common. The frequency and severity of AEs decreased over time. Twenty serious AEs were reported in 7 patients; none were related to RBX2660 or its administration.

Conclusions: Among patients with recurrent or severe CDI, administration of RBX2660 via enema appears to be safe and effective.

Clinical Trials Registration: NCT01925417.
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http://dx.doi.org/10.1093/cid/civ938DOI Listing
March 2016

Coccidioidal Tenosynovitis of the Hand and Wrist: Report of 9 Cases and Review of the Literature.

Clin Infect Dis 2015 Nov 3;61(10):1514-20. Epub 2015 Aug 3.

Division of Infectious Diseases.

Background: Tenosynovitis is an uncommon manifestation of disseminated infection with Coccidioides fungal species. Most experts treat this infection with combined surgical debridement and antifungal medication. The aim of our study was to examine the outcomes of patients with coccidioidal tenosynovitis of the hand and wrist.

Methods: We retrospectively searched for the records of patients with coccidioidal tenosynovitis of the hand and wrist at our institution. between 1987 and 2013. We also conducted a review of the literature from 1950 to 2014 to identify additional cases.

Results: We identified 9 cases of coccidioidal tenosynovitis of the hand and wrist at our institution, along with 5 other cases found in a review of the literature. The relapse rate was high overall (50%) and was higher after discontinuation of antifungal therapy (71%) in both immunocompromised and immunocompetent patients. Results of serologic testing were not predictive of relapse.

Conclusions: A treatment strategy for coccidioidal tenosynovitis should focus on long-term administration of antifungal agents.
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http://dx.doi.org/10.1093/cid/civ642DOI Listing
November 2015

Prolonged use of a proton pump inhibitor reduces microbial diversity: implications for Clostridium difficile susceptibility.

Microbiome 2014 25;2:42. Epub 2014 Nov 25.

Division of Gastroenterology, Mayo Clinic, Scottsdale, AZ, USA.

Background: The role of the gut microbiome in arresting pathogen colonization and growth is important for protection against Clostridium difficile infection (CDI). Observational studies associate proton pump inhibitor (PPI) use and CDI incidence. We hypothesized that PPI use affected the distal gut microbiome over time, an effect that would be best explored by time-longitudinal study of healthy subjects on PPI in comparison to treatment-naïve CDI subjects. This study enrolled nine healthy human subjects and five subjects with treatment-naïve CDI. After random assignment to a low (20 mg/day) or high (2× 20 mg/day) dose group, fecal samples were collected from the nine healthy subjects before, during, and after 28 days of PPI use. This was done in conjunction with pre-treatment fecal collection from CDI subjects. High-throughput sequencing (16S rRNA) was performed on time-longitudinal samples to assess changes to the healthy gut microbiome associated with prolonged PPI usage. The healthy samples were then compared to the CDI subjects to explore changes over time to the gut microbiome associated with PPI use and potentially related to CDI.

Results: We report that PPI usage at low and high dosages, administered for 28 days, resulted in decreases to observed operational taxonomic unit (OTU) counts after both 1 week and 1 month. This decrease resulted in observed OTU levels that were similar to those found in treatment-naïve CDI patients, which was partly reversible after a 1 month recovery period. We did not detect a dose-dependent difference in OTU levels nor did we detect significant changes in taxa previously reported to be affected by PPI treatment.

Conclusion: While our observation of diminishing observed OTU counts during PPI therapy is a preliminary finding in a small cohort, our hypothesis that PPIs disrupt the healthy human gut microbiome is supported in this group. We conclude that decreases in observed species counts were reversible after cessation of PPI usage within 1 month. This finding may be a potential explanation for the association between prolonged PPI usage and CDI incidence.
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http://dx.doi.org/10.1186/2049-2618-2-42DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4242847PMC
November 2014