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.

Systemic Bacillus Calmette-Guerin Infection One Year After Intravesical Immunotherapy Mimicking Sarcoidosis.

A patient presented with pancytopenia and hypercalcemia after intravesical immunotherapy with Bacillus Calmette-Guerin (BCG) for bladder cancer. Bone marrow biopsy performed six months later revealed noncaseating granulomas with negative stains for AFB. He was diagnosed with sarcoidosis and treated with prednisone. Hypercalcemia resolved, but mild pancytopenia persisted. One year later, he developed sepsis. Blood cultures six weeks later grew Mycobacterium tuberculosis complex, ultimately identified as Mycobacterium bovis. Despite triple antibiotic therapy, the patient progressively declined and expired.

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.

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.

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.

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.

Human papillomavirus infection in solid organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice.

These guidelines from the American Society of Transplantation Infectious Diseases Community of Practice update the epidemiology and management of human papillomavirus (HPV) infections in organ transplant recipients. HPV is one of the most common sexually transmitted infections and is associated with cancers of the anogenital region. Increasing evidence suggests an association with head and neck cancers as well. Solid organ transplant recipients have a higher risk of HPV infection than the general population. Infection manifests as premalignant lesions, warts, or cancer of the cervix, penis, vulva, scrotum, and anal canal. Most are asymptomatic initially, so diagnosis can be difficult without screening. A vaccine is available though not effective in preventing all cancer-causing strains. Organ transplant recipients should be screened for HPV-associated cancers and appropriate therapy initiated in a timely manner. Further studies are warranted to delineate the most effective screening methods and therapeutic modalities, including whether changes in immunosuppression are effective in attenuating disease.

Update in the treatment of non-influenza respiratory virus infection in solid organ transplant recipients.

INTRODUCTION: Despite the improved outcomes in solid organ transplantation with regard to prevention of rejection and increased patient and graft survival, infection remains a common cause of morbidity and mortality. Respiratory viruses are a frequent and potentially serious cause of infection after solid organ transplantation. Furthermore, clinical manifestations of respiratory virus infection (RVI) may be more severe and unusual in solid organ transplant recipients (SOTRs) compared with the non-immunocompromised population. Areas covered: This article reviews the non-influenza RVIs that are commonly encountered in SOTRs. Epidemiologic and clinical characteristics are highlighted and available treatment options are discussed. Expert opinion: New diagnostic tools, particularly rapid molecular assays, have expanded the ability to identify specific RVI pathogens in SOTRs. This is not only useful from a treatment standpoint but also to guide infection control practices. More data are needed on RVIs in the solid organ transplant population, particularly regarding their effect on rejection and graft dysfunction. There is also a need for new antiviral agents active against these infections as well as markers that can identify which patients would most benefit from treatment.

Herpesvirus Respiratory Infections in Immunocompromised Patients: Epidemiology, Management, and Outcomes.

Among immunocompromised individuals, members of the human Herpesviridae family are frequently encountered pathogens. Cytomegalovirus, herpes simplex virus 1 and 2, varicella zoster virus, Epstein-Barr virus, and human herpesvirus-6, -7, and -8 all establish latency after infection and can reactivate during periods of immunosuppression, leading to both direct and indirect adverse effects on the host including severe organ dysfunction as well as allograft rejection and loss after transplantation. While not all herpesviruses are primary respiratory pathogens, many of their manifestations include involvement of the respiratory tract. This article discusses the individual viruses, their epidemiology, and clinical manifestations as well as recommended treatment and preventive strategies.

Treatment of MDR urinary tract infections with oral fosfomycin: a retrospective analysis.

OBJECTIVES: Limited options for treating MDR organisms have led clinicians to turn to older antimicrobial agents that may display activity against such infections. One such agent is fosfomycin, an oral drug with activity against a variety of Gram-positive and -negative bacteria, but only approved for use in the USA for urinary tract infection (UTI) due to Escherichia coli and Enterococcus faecalis. The purpose of this study was to assess the efficacy of fosfomycin treatment of MDR UTI and identify predictors of outcome. PATIENTS AND METHODS: A retrospective review was performed of patients treated for MDR UTI at a large quaternary medical centre between 1 January 2010 and 30 September 2014. Sixty patients received 69 courses of fosfomycin in the inpatient or outpatient setting for UTIs due to Enterobacteriaceae, Pseudomonas aeruginosa or VRE. RESULTS: In the 58 patients for whom follow-up data were available, the treatment success rate (no persistent or recurrent infection) was 55%. Chronic kidney disease was associated with persistent infection (OR = 3.56, 95% CI = 1.02-12.40, P = 0.04). No other factors, including comorbidities, infecting organism, fosfomycin MIC or number of doses of fosfomycin received, were associated with recurrent infection or treatment failure. CONCLUSIONS: This study supports the use of fosfomycin as an oral option for treating MDR UTIs. Additional studies are required to assess the optimal dosing and utility of combination therapy to decrease the incidence of treatment failure.

Acinetobacter baumannii infection in solid organ transplant recipients.

INTRODUCTION: Acinetobacter baumannii can cause serious infection in susceptible patients, but little has been published regarding risk factors for infection and outcomes in solid organ transplant (SOT) recipients. METHODS: We identified A. baumannii infection among adult SOT recipients that occurred between January 2001 and March 31, 2008 at a Chicago transplant center and evaluated characteristics of these infections and outcomes. RESULTS: Thirty-three individuals developed A. baumannii infection during the study period. Seventy-nine percent had healthcare-associated infection with respiratory tract as the most common site of infection (64%). Eighty-two percent of patients had received antibiotics within two wk prior to A. baumannii infection and multidrug resistance (MDR) or extensive resistance (XDR) occurred in 85%. The median time to onset of infection was five months after transplant. The 30-d mortality was 24% and was associated with XDR. Administration of an appropriate antibiotic within three d was associated with lower 30-d mortality (OR 0.16, p = 0.047). All isolates tested against colistin were susceptible. CONCLUSION: SOT recipients with A. baumannii infection had high mortality associated with delay in appropriate antibiotic therapy and XDR organisms. The use of colistin-containing treatment regimens should be considered in these patients when A. baumannii infection is suspected or identified in patients who have received prior antibiotics.

Outcomes from pandemic influenza A H1N1 infection in recipients of solid-organ transplants: a multicentre cohort study.

BACKGROUND: There are few data on the epidemiology and outcomes of influenza infection in recipients of solid-organ transplants. We aimed to establish the outcomes of pandemic influenza A H1N1 and factors leading to severe disease in a cohort of patients who had received transplants. METHODS: We did a multicentre cohort study of adults and children who had received organ transplants with microbiological confirmation of influenza A infection from April to December, 2009. Centres were identified through the American Society of Transplantation Influenza Collaborative Study Group. Demographics, clinical presentation, treatment, and outcomes were assessed. Severity of disease was measured by admission to hospital and intensive care units (ICUs). The data were analysed with descriptive statistics. Proportions were compared by use of chi(2) tests. We used univariate analysis to identify factors leading to pneumonia, admission to hospital, and admission to an ICU. Multivariate analysis was done by use of a stepwise logistic regression model. We analysed deaths with Kaplan-Meier survival analysis. FINDINGS: We assessed 237 cases of medically attended influenza A H1N1 reported from 26 transplant centres during the study period. Transplant types included kidney, liver, heart, lung, and others. Both adults (154 patients; median age 47 years) and children (83; 9 years) were assessed. Median time from transplant was 3.6 years. 167 (71%) of 237 patients were admitted to hospital. Data on complications were available for 230 patients; 73 (32%) had pneumonia, 37 (16%) were admitted to ICUs, and ten (4%) died. Antiviral treatment was used in 223 (94%) patients (primarily oseltamivir monotherapy). Seven (8%) patients given antiviral drugs within 48 h of symptom onset were admitted to an ICU compared with 28 (22.4%) given antivirals later (p=0.007). Children who received transplants were less likely to present with pneumonia than adults, but rates of admission to hospital and ICU were similar. INTERPRETATION: Influenza A H1N1 caused substantial morbidity in recipients of solid-organ transplants during the 2009-10 pandemic. Starting antiviral therapy early is associated with clinical benefit as measured by need for ICU admission and mechanical ventilation. FUNDING: None.

Early intra-abdominal infections associated with orthotopic liver transplantation.

BACKGROUND: Postoperative infections remain a significant problem among liver transplant recipients (LTRs). An early cause of morbidity after liver transplantation is intra-abdominal infection (IAI) about which there are limited data. METHODS: We report a retrospective review of 169 adult LTRs from January 1, 2002 to June 9, 2006, comparing those who developed early postoperative IAI (peritonitis, biliary tract infection, abdominal abscess, or enteritis) with those who did not to identify clinical features and risk factors, analyze epidemiology, and assess graft and patient survival. RESULTS: Sixty-eight patients (40%) had 104 infections, with 148 pathogens isolated. Leukocytosis (53%) and fever (34%) were the most common clinical features, and peritonitis (43%) was the most common manifestation. Enterococcus spp., the most frequent single pathogens, comprised 26% of organisms cultured. There were significant associations of IAI with pretransplant ascites (P=0.002), posttransplant dialysis (P=0.015), and non-IAI surgical complications (P<0.001). There was a trend toward graft failure in patients with IAI (P=0.051) but increased mortality was not associated with IAI. Use of pretransplant antibiotics was significantly associated with development of multiple drug-resistant organisms in IAI (P=0.032). CONCLUSION: IAI occurred at a relatively high rate in the early postoperative period, and fever was not a major indicator. In patients receiving antibiotics within 2 weeks before transplantation, multiple drug-resistant organisms often caused IAI. In addition, the presence of pretransplant ascites, posttransplant dialysis, and wound infection or reoperation after transplant should alert one to the increased risk of IAI in LTRs.

Rapid development of Acinetobacter baumannii resistance to tigecycline.

A 53-year-old woman experienced a multidrug-resistant (MDR) Acinetobacter baumannii urinary tract infection 5 months after undergoing kidney and liver transplantation. The tigecycline minimum inhibitory concentration (MIC) for her A. baumannii isolate was 1.5 microg/ml; the patient received 2 weeks of therapy with intravenous tigecycline as a 100-mg loading dose followed by 50 mg every 12 hours, with no lapses in treatment and with resolution of the infection. Three weeks later, MDR A. baumannii was isolated from her sputum in the setting of clinical evidence of pneumonia, and tigecycline was restarted; the tigecycline MIC for the A. baumannii isolate was 2 microg/ml. At approximately the same time, the patient was found to have a paraspinal abscess and spinal osteomyelitis. Cultures of the abscess fluid grew A. baumannii with a tigecycline MIC of 24 microg/ml. A follow-up sputum culture again yielded A. baumannii, but with a tigecycline MIC of 24 microg/ml. Urine culture at that time also grew A. baumannii with a tigecycline MIC of 24 microg/ml. Clinicians should be aware that tigecycline MICs for A. baumannii isolates may increase during therapy with tigecycline after only brief exposure to the drug. Patients receiving tigecycline for Acinetobacter should be monitored for the development of clinical resistance, and isolates should be monitored for evidence of microbiologic resistance.