Evidence of SARS-CoV-2 convergent evolution in immunosuppressed patients treated with antiviral therapies.

BACKGROUND: The factors contributing to the accelerated convergent evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are not fully understood. Unraveling the contribution of viral replication in immunocompromised patients is important for the early detection of novel mutations and developing approaches to limit COVID-19. METHODS: We deep sequenced SARS-CoV-2 RNA from 192 patients (64% hospitalized, 39% immunosuppressed) and compared the viral genetic diversity within the patient groups of different immunity and hospitalization status. Serial sampling of 14 patients was evaluated for viral evolution in response to antiviral treatments. RESULTS: We identified hospitalized and immunosuppressed patients with significantly higher levels of viral genetic diversity and variability. Further evaluation of serial samples revealed accumulated mutations associated with escape from neutralizing antibodies in a subset of the immunosuppressed patients treated with antiviral therapies. Interestingly, the accumulated viral mutations that arose in this early Omicron wave, which were not common in the patient viral lineages, represent convergent mutations that are prevalent in the later Omicron sublineages, including the XBB, BA.2.86.1 and its descendent JN sublineages. CONCLUSIONS: Our results illustrate the importance of identifying convergent mutations generated during antiviral therapy in immunosuppressed patients, as they may contribute to the future evolutionary landscape of SARS-CoV-2. Our study also provides evidence of a correlation between SARS-CoV-2 convergent mutations and specific antiviral treatments. Evaluating high-confidence genomes from distinct waves in the pandemic with detailed patient metadata allows for discerning of convergent mutations that contribute to the ongoing evolution of SARS-CoV-2.

Implementation evaluation of tiered tele-triage pathways for burn center consultations and transfers.

BACKGROUND: Early transfer to specialized centers improves trauma and burn outcomes; however, overtriage can result in unnecessary burdens to patients, providers, and health systems. Our institution developed novel burn triage pathways in 2016 to improve resource allocation. We evaluated the implementation of these pathways, analyzing trends in adoption, resource optimization, and pathway reliability after implementation. METHODS: Triage pathways consist of transfer nurses (RNs) triaging calls based on review of burn images and clinical history: green pathway for direct outpatient referral, blue pathway for discussion with the on-call provider, red pathway for confirmation of transfer as requested by referring provider, and black pathway for the rapid transfer of severe burns. We used the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework to evaluate implementation. These pathways affected all acute burn referrals to our center from January 2017 to December 2019 (reach). Outcomes of interest were pathway assignment over time (adoption), changes to burn provider call volume (effectiveness), and the concordance of pathway assignment with final disposition (implementation reliability). RESULTS: Transfer RNs triaged 5,272 burn referrals between 2017 and 2019. By January 2018, >98% of referrals were assigned a pathway. In 2018-2019, green pathway calls triaged by RNs reduced calls to burn providers by a mean of 40 (SD, 11) per month. Patients in green/blue pathways were less likely to be transferred, with >85% receiving only outpatient follow-up ( p < 0.001). Use of the lower acuity pathways increased over time, with a concordant decrease in use of the higher acuity pathways. Younger adults, patients referred from Level III to Level V trauma centers and nontrauma hospitals, and patients referred by APPs were less likely to be triaged to higher acuity pathways. CONCLUSION: Implementation of highly adopted, reliable triage pathways can optimize existing clinical resources by task-shifting triage of lower acuity burns to nursing teams. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level III.

Impact of Tele-Triage Pathways on Short-Stay Admission after Transfer to a Regional Burn Center for Acute Burn Injury.

BACKGROUND: Regionalized care for burn-injured patients requires accurate triage. In 2016, we implemented a tele-triage system for acute burn consultations. We evaluated resource utilization following implementation, hypothesizing that this system would reduce short-stay admissions and prioritize inpatient care for those with higher burn severity. STUDY DESIGN: We conducted a retrospective study of all transferred patients with acute burn injuries from January 1, 2010 to December 31, 2015, and January 1, 2017 to December 31, 2019. We evaluated the proportions of short-stay admissions (discharges less than 24 hours without operative intervention, ICU admission, or concern for nonaccidental trauma) among patients transferred before (2010 to 2015) and after (2017 to 2019) triage system implementation. Multivariable Poisson regression was used to evaluate factors associated with short-stay admissions. Interrupted time series analysis was used to evaluate the effect of the triage system. RESULTS: There were 4,688 burn transfers (3,244 preimplementation and 1,444 postimplementation) in the study periods. Mean age was higher postimplementation (32 vs 29 years, p < 0.001). Median hospital length of stay (LOS) and ICU LOS were both 1 day higher, more patients underwent operative intervention (19% vs 16%), and median time to first operation was 1 day lower postimplementation. Short-stay admissions decreased from 50% (n = 1,624) to 39% (n = 561), and patients were 17% less likely to have a short-stay admission after implementation (adjusted relative risk [aRR], 0.83; 95% CI, 0.8 to 0.9). Pediatric patients younger than 15 years old composed 43% of all short-stay admissions and were much more likely than adult patients to have a short-stay admission independent of transfer timing (aRR, 2.36; 95% CI, 1.84 to 3.03). CONCLUSIONS: Tele-triage burn transfer center protocols reduced short-stay admissions and prioritized inpatient care for patients with more severe injuries. Pediatric patients remain more likely to have short-stay admission after transfer.

Reported HIV-related stigma according to race and ethnicity.

People living with HIV/AIDS (PLWHA) have long experienced structural, community, and personal stigma. We explored differences in experienced HIV-related stigma according to race/ethnicity using quantitative and qualitative measures. Sixty-four patients were enrolled in this study (22 White and 42 people of color [POC]). POC scored higher than White PLWHA on all 12 survey statements, with statistically significant differences in disclosure concerns and with one of the statements on public attitudes towards PLWHA. Common themes in the qualitative interview were HIV disclosure concerns and fear of rejection. These data demonstrate that stigma continues to be a significant concern for PLWHA, particularly POC, meaningfully impacting their lives. By acknowledging and working to reduce negative perceptions about PLWHA, physicians may improve care for their patients by developing more trusting relationships.

Disseminated Protothecosis Due to Prototheca zopfii and Literature Review.

ABSTRACT: Prototheca species are achlorophyllic algae that are a rare cause of infection in humans. It most commonly causes localized cutaneous disease and rarely disseminated infection. Immunocompromised patients have the highest risk of disseminated protothecosis, with a higher mortality rate than localized cutaneous infections. At the species level, infections caused by Prototheca zopfii are reported less frequently than those caused by Prototheca wickerhamii. The diagnosis can be made using histopathology, culture, and molecular testing. There is no definitive evidence for an effective treatment, which currently consists of antifungals (primarily amphotericin B). With only a handful of cases of disseminated protothecosis reported worldwide that are caused by P. zopfii , we herein present an additional case of a postbone marrow transplant patient in the Midwest of the United States.

Genetic Testing Among Patients with High-Risk Breast, Ovarian, Pancreatic, and Prostate Cancers.

BACKGROUND: The National Comprehensive Cancer Network recommends genetic testing in patients with potentially hereditary breast, ovarian, pancreatic, and prostate cancers (HBOPP). Knowledge of genetic mutations impacts decisions about screening and treatment. METHODS: A retrospective cohort study of 28,586 HBOPP patients diagnosed from 2013 to 2019 was conducted using a linked administrative-cancer database in the Seattle-Puget Sound SEER area. Guideline-concordant testing (GCT) was assessed annually according to guideline updates. Frequency of testing according to patient/cancer characteristics was evaluated using chi-squared tests, and factors associated with receipt of genetic testing were identified using multivariable logistic regression. RESULTS: Testing occurred in 17% of HBOPP patients, increasing from 9% in 2013 to 21% in 2019 (p < 0.001). Ovarian cancer had the highest testing (40%) and prostate cancer the lowest (4%). Age < 50, female sex, non-Hispanic White race, commercial insurance, urban location, family history of HBOPP, and triple negative breast cancer (TNBC) were associated with increased testing (all p < 0.05). GCT increased from 38% in 2013 to 44% in 2019, and was highest for early age at breast cancer diagnosis, TNBC, male breast cancer, and breast cancer with family history of HBOPP (all > 70% in 2019), and lowest for metastatic prostate cancer (6%). CONCLUSIONS: The frequency of genetic testing for HBOPP cancer has increased over time. Though GCT is high for breast cancer, there are gaps in concordance among patients with other cancers. Increasing provider and patient education, genetic counseling, and insurance coverage for testing among HBOPP patients may improve guideline adherence.

Sequencing during Times of Change: Evaluating SARS-CoV-2 Clinical Samples during the Transition from the Delta to Omicron Wave.

The pandemic of SARS-CoV-2 is characterized by the emergence of new variants of concern (VOCs) that supplant previous waves of infection. Here, we describe our investigation of the lineages and host-specific mutations identified in a particularly vulnerable population of predominantly older and immunosuppressed SARS-CoV-2-infected patients seen at our medical center in Chicago during the transition from the Delta to Omicron wave. We compare two primer schemes, ArticV4.1 and VarSkip2, used for short read amplicon sequencing, and describe our strategy for bioinformatics analysis that facilitates identifying lineage-associated mutations and host-specific mutations that arise during infection. This study illustrates the ongoing evolution of SARS-CoV-2 VOCs in our community and documents novel constellations of mutations that arise in individual patients. The ongoing evaluation of the evolution of SARS-CoV-2 during this pandemic is important for informing our public health strategies.

Disseminated Nocardia paucivorans Infection Resembling Metastatic Disease in a Kidney Transplant Recipient.

Recipients of solid-organ transplants (SOT) or hematopoietic stem-cell transplants are prone to various complications, including serious infections. Nocardiosis is an opportunistic bacterial infection that primarily affects the lung. It may also cause skin and soft-tissue infection, cerebral abscess, bloodstream infection, or infection involving other organs. We present a case of an immunocompromised kidney transplant recipient who experienced a prolonged history of unexplained indolent constitutional symptoms without a fever. Initial radiographic findings were suggestive of metastatic disease at multiple sites. However, metagenomic next-generation sequencing of microbial cell-free DNA in blood revealed disseminated Nocardia paucivorans infection, and organisms consistent with Nocardia were identified on histopathology of a lung biopsy. It is crucial for healthcare providers to be aware of unusual opportunistic infections to provide appropriate workups and interventions for immunocompromised SOT recipients.

Infections Due to Acinetobacter baumannii-calcoaceticus Complex: Escalation of Antimicrobial Resistance and Evolving Treatment Options.

Bacteria within the genus Acinetobacter (principally A. baumannii-calcoaceticus complex [ABC]) are gram-negative coccobacilli that most often cause infections in nosocomial settings. Community-acquired infections are rare, but may occur in patients with comorbidities, advanced age, diabetes mellitus, chronic lung or renal disease, malignancy, or impaired immunity. Most common sites of infections include blood stream, skin/soft-tissue/surgical wounds, ventilator-associated pneumonia, orthopaedic or neurosurgical procedures, and urinary tract. Acinetobacter species are intrinsically resistant to multiple antimicrobials, and have a remarkable ability to acquire new resistance determinants via plasmids, transposons, integrons, and resistance islands. Since the 1990s, antimicrobial resistance (AMR) has escalated dramatically among ABC. Global spread of multidrug-resistant (MDR)-ABC strains reflects dissemination of a few clones between hospitals, geographic regions, and continents; excessive antibiotic use amplifies this spread. Many isolates are resistant to all antimicrobials except colistimethate sodium and tetracyclines (minocycline or tigecycline); some infections are untreatable with existing antimicrobial agents. AMR poses a serious threat to effectively treat or prevent ABC infections. Strategies to curtail environmental colonization with MDR-ABC require aggressive infection-control efforts and cohorting of infected patients. Thoughtful antibiotic strategies are essential to limit the spread of MDR-ABC. Optimal therapy will likely require combination antimicrobial therapy with existing antibiotics as well as development of novel antibiotic classes.

Antibody Response to SARS-CoV-2 Infection and Vaccination in COVID-19-naïve and Experienced Individuals.

Understanding the magnitude of responses to vaccination during the ongoing SARS-CoV-2 pandemic is essential for ultimate mitigation of the disease. Here, we describe a cohort of 102 subjects (70 COVID-19-naïve, 32 COVID-19-experienced) who received two doses of one of the mRNA vaccines (BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna)). We document that a single exposure to antigen via infection or vaccination induces a variable antibody response which is affected by age, gender, race, and co-morbidities. In response to a second antigen dose, both COVID-19-naïve and experienced subjects exhibited elevated levels of anti-spike and SARS-CoV-2 neutralizing activity; however, COVID-19-experienced individuals achieved higher antibody levels and neutralization activity as a group. The COVID-19-experienced subjects exhibited no significant increase in antibody or neutralization titer in response to the second vaccine dose (i.e., third antigen exposure). Finally, we found that COVID-19-naïve individuals who received the Moderna vaccine exhibited a more robust boost response to the second vaccine dose (p = 0.004) as compared to the response to Pfizer-BioNTech. Ongoing studies with this cohort will continue to contribute to our understanding of the range and durability of responses to SARS-CoV-2 mRNA vaccines.

Systemic antifungal therapy with isavuconazonium sulfate or other agents in adults with invasive mucormycosis or invasive aspergillosis (non-fumigatus): A multicentre, non-interventional registry study.

BACKGROUND: Isavuconazole, administered as isavuconazonium sulfate (ISAVUSULF), is a broad-spectrum triazole agent for the treatment of invasive fungal disease. In phase 3 studies, ISAVUSULF showed comparable efficacy to voriconazole and amphotericin B for the treatment of invasive aspergillosis (IA) and invasive mucormycosis (IM), respectively. OBJECTIVES: The objective of this study is to determine all-cause mortality and safety outcomes among adults with IM and/or IA non-fumigatus (nf) treated with ISAVUSULF or other antifungal therapies (AFT). PATIENTS AND METHODS: This multicentre, non-interventional registry enrolled patients aged ≥18 years with IM or IA-nf who received systemic AFT from January 2016 to November 2018. Patients received primary ISAVUSULF, non-primary ISAVUSULF, or other AFT, as monotherapy or combination therapy. The primary end point was all-cause mortality at Days 42 and 84; safety outcomes were adverse drug reactions (ADRs) to ISAVUSULF. RESULTS: Of 204 patients enrolled, 74 received primary ISAVUSULF, 30 non-primary ISAVUSULF, and 100 other AFT. All-cause mortality through Day 42 was numerically lower in the non-primary ISAVUSULF group than in the primary ISAVUSULF and other AFT groups, for patients with IM (20.0% vs. 33.3% and 41.3%, respectively) or IA-nf (0% vs. 14.8% and 17.8%, respectively). All-cause mortality tended to be lower with combination therapy than with monotherapy, except for patients with IM receiving primary ISAVUSULF. Of 111 patients receiving ISAVUSULF, 14 (12.6%) reported ADRs, of whom three (2.7%) developed serious ADRs. There were no drug-related deaths. CONCLUSIONS: This study supports the effectiveness and tolerability of ISAVUSULF in clinical practice. Further research is required to confirm the value of ISAVUSULF combination therapy over monotherapy.

Breakthrough Infections with Multiple Lineages of SARS-CoV-2 Variants Reveals Continued Risk of Severe Disease in Immunosuppressed Patients.

The pandemic of COVID-19 caused by SARS-CoV-2 infection continues to spread around the world. Vaccines that elicit protective immunity have reduced infection and mortality, however new viral variants are arising that may evade vaccine-induced immunity or cause disease in individuals who are unable to develop robust vaccine-induced responses. Investigating the role of viral variants in causing severe disease, evading vaccine-elicited immunity, and infecting vulnerable individuals is important for developing strategies to control the pandemic. Here, we report fourteen breakthrough infections of SARS-CoV-2 in vaccinated individuals with symptoms ranging from asymptomatic/mild (6/14) to severe disease (8/14). High viral loads with a median Ct value of 19.6 were detected in the nasopharyngeal specimens from subjects regardless of disease severity. Sequence analysis revealed four distinct virus lineages, including alpha and gamma variants of concern. Immunosuppressed individuals were more likely to be hospitalized after infection (p = 0.047), however no specific variant was associated with severe disease. Our results highlight the high viral load that can occur in asymptomatic breakthrough infections and the vulnerability of immunosuppressed individuals to post-vaccination infections by diverse variants of SARS-CoV-2.

Letermovir treatment of cytomegalovirus infection or disease in solid organ and hematopoietic cell transplant recipients.

BACKGROUND: Few options are available for cytomegalovirus (CMV) treatment in transplant recipients resistant, refractory, or intolerant to approved agents. Letermovir (LET) is approved for prophylaxis in hematopoietic cell transplant (HCT) recipients, but little is known about efficacy in CMV infection. We conducted an observational study to determine the patterns of use and outcome of LET treatment of CMV infection in transplant recipients. METHODS: Patients who received LET for treatment of CMV infection were identified at 13 transplant centers. Demographic and outcome data were collected. RESULTS: Twenty-seven solid organ and 21 HCT recipients (one dual) from 13 medical centers were included. Forty-five of 47 (94%) were treated with other agents prior to LET, and 57% had a history of prior CMV disease. Seventy-seven percent were intolerant to other antivirals; 32% were started on LET because of resistance concerns. Among 37 patients with viral load < 1000 international units (IU)/ml at LET initiation, two experienced >1 log rise in viral load by week 12, and no deaths were attributed to CMV. Ten patients had viral load > 1000 IU/ml at LET initiation, and six of 10 (60%) had a CMV viral load < 1000 IU/ml at completion of therapy or last known value. LET was discontinued in two patients for an adverse event. CONCLUSIONS: Patients treated with LET with viral load < 1000 IU/ml had good virologic outcomes. Outcomes were mixed when LET was initiated at higher viral loads. Further studies on combination therapy or alternative LET dosing are needed.

Escalating antimicrobial resistance among Enterobacteriaceae: focus on carbapenemases.

Introduction: Over the past few decades, antimicrobial resistance (AMR) has skyrocketed globally among bacteria within the Family Enterobacteriaceae (i.e. Enterobacter spp, Klebsiella spp, Escherichia coli, Proteus spp, Serratia marcescens, Citrobacter spp, and others). Enterobacteriaceae are intestinal flora and are important pathogens in nosocomial and community settings. Enterobacteriaceae spread easily between humans and may acquire AMR via plasmids or other mobile resistance elements. The emergence and spread of multidrug resistant (MDR) clones have greatly limited therapeutic options. Some infections are untreatable with existing antimicrobials.Areas covered: The authors discuss the escalation of CRE globally, the epidemiology and outcomes of CRE infections, the optimal therapy, and the potential role of several new antimicrobials to combat MDR organisms. An exhaustive search for literature related to Enterobacteriaceae was performed using PubMed, using the following key words: antimicrobial resistance; carbapenemases; Enterobacterales; Enterobacteriaceae; Klebsiella pneumoniae; Escherichia coli; global epidemiology; metallo-ß-lactamases; multidrug resistance; New Delhi Metalloproteinase-1 (NDM-1); plasmidsExpert opinion: Innovation and development of new classes of antibacterial agents are critical to expand effective therapeutic options. The authors encourage the judicious use of antibiotics and aggressive infection-control measures are essential to minimize the spread of AMR.

Nocardia spp.: A Rare Cause of Pneumonia Globally.

Members of the Nocardia genus are ubiquitous in the environment. These aerobic, gram-positive organisms can lead to life-threatening infection, typically in immunocompromised hosts such as solid organ transplant recipients or those receiving immunosuppressive medications for other reasons. This current review discusses the microbiology of nocardiosis, risk factors for infection, clinical manifestations, methods for diagnosis, and treatment. Nocardiosis primarily affects the lung but may also cause skin and soft tissue infection, cerebral abscess, bloodstream infection, or infection involving other organs. Although rare as a cause of community-acquired pneumonia, Nocardia can have severe morbidity and mortality, particularly in patients with comorbidities or compromised immunity. Early diagnosis and timely initiation of therapy are critical to optimizing patient outcomes. Species identification is important in determining treatment, as is in vitro susceptibility testing. Sulfonamide therapy is usually indicated, although a variety of other antimicrobials may be useful, depending on the species and susceptibility testing. Prolonged therapy is usually indicated, for 6 to 12 months, and in some cases surgical debridement may be required to resolve infection.

In Vitro Pharmacodynamic Analyses Help Guide the Treatment of Multidrug-Resistant Enterococcus faecium and Carbapenem-Resistant Enterobacter cloacae Bacteremia in a Liver Transplant Patient.

BACKGROUND: Infections due to multidrug-resistant pathogens are particularly deadly and difficult to treat in immunocompromised patients, where few data exist to guide optimal antimicrobial therapy. In the absence of adequate clinical data, in vitro pharmacokinetic (PK)/pharmacodynamic (PD) analyses can help to design treatment regimens that are bactericidal and may be clinically effective. METHODS: We report a case in which in vitro pharmacodynamic analyses were utilized to guide the treatment of complex, recurrent bacteremias due to vancomycin-, daptomycin-, and linezolid-resistant Enterococcus faecium and carbapenem-resistant Enterobacter cloacae complex in a liver transplant patient. RESULTS: Whole-genome sequencing revealed unique underlying resistance mechanisms and explained the rapid evolution of phenotypic resistance and complicated intrahost genomic dynamics observed in vivo. Performing this comprehensive genotypic and phenotypic testing and time-kill analyses, along with knowledge of institution and patient-specific factors, allowed us to use precision medicine to design a treatment regimen that maximized PK/PD. CONCLUSIONS: This work provides a motivating example of clinicians and scientists uniting to optimize care in the era of escalating antimicrobial resistance.

Mucormycosis.

Mucormycosis is an infection caused by a group of filamentous molds within the order Mucorales. Infections may result from ingestion of contaminated food, inhalation of spores into the nares or lungs, or inoculation into disrupted skin or wounds. In developed countries, mucormycosis occurs primarily in severely immunocompromised hosts (e.g., those with hematological malignancies, organ transplantation, neutropenia, autoimmune disorders, or other impairments in immunity). Only 6 to 10% of cases occur in subjects with no underlying disease. In contrast, in developing countries, most cases of mucormycosis occur in persons with poorly controlled diabetes mellitus or in immunocompetent subjects following trauma. Mucormycosis exhibits a marked propensity to invade blood vessels, leading to thrombosis, necrosis, and infarction of tissue. Mortality associated with invasive mucormycosis is high (> 30-50%), with 90% mortality associated with disseminated disease. Mortality rates are much lower, though still significant (10-30%), among patients with localized cutaneous disease.The diagnosis of mucormycosis relies upon histopathology and culture. Blood tests are of limited diagnostic value. Even with disseminated disease, blood cultures are usually negative. Mucorales have a distinct histological appearance, with irregular, nonseptate hyphae that branch at right angles. Cultures and/or polymerase chain reaction (PCR) are important to identify the genera.Based on anatomic localization, mucormycosis can be classified as one of six forms: (1) rhino-orbital-cerebral mucormycosis (ROCM), (2) pulmonary, (3) cutaneous, (4) gastrointestinal (GI), (5) disseminated, and (6) mucormycosis of uncommon sites. Among diabetics, ROCM is the most common clinical presentation, whereas lung involvement is uncommon. In contrast, among organ transplant recipients or patients with hematological malignancies (HemeM), pulmonary and disseminated diseases are most common. Mucormycosis can progress rapidly, and delay in initiation of treatment by even a few days markedly worsens outcomes.Due to the rarity of mucormycosis, randomized controlled therapeutic trials have not been performed. Lipid formulations of amphotericin B (LFAB) are the mainstay of therapy, but the newer triazoles, posaconazole (POSA) and isavuconazole (ISAV) (the active component of the prodrug isavuconazonium sulfate), may be effective in patients refractory to or intolerant of LFAB. Early surgical debridement or excision plays an important adjunctive role. Additional studies are required to assess the optimal duration of therapy as well as the specific roles of LFAB and the triazoles in the treatment of mucormycosis.