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Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a significant health and financial issue in the current century. Despite significant attempts to manage the illness, the transmission routes of the virus and its widespread genomic mutations have led to an increasing number of new infections and mortality rates. In the absence of specific treatment for this new virus, identifying and managing factors affecting the prognosis of the disease is one of the critical strategies to reduce disease mortality. Patients with iron deficiency anemia (IDA), who account for an estimated half a billion people globally, are more prone to infections due to immune system disorders. Since they visit hospitals more frequently for follow-up care and diagnosis, they are more susceptible to becoming infected with SARS-CoV-2. Once infected with SARS-CoV-2, low hemoglobin (Hb) levels and compromised immune systems disrupt the restriction of infection in these individuals, ultimately leading to severe complications of COVID-19.
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The sudden onset of the 2019 SARS-CoV-2 pandemic required agile development of standards and efficient validation of assays to assess prevalence of infection as well as immune responses to infection and vaccination. Leveraging their experience in HPV serology and standards, the Vaccine, Immunity and Cancer Directorate (VICD) at the Frederick National Laboratory for Cancer Research (FNCLR) pivoted to address this unmet need in SARS-Co-V2 serology clinical testing and research. This standardization effort required the collection and processing of large volumes of blood from SARS-Co-V2 infected and uninfected individuals into serum and peripheral blood mononuclear cells (PBMCs). Collaborations with specimen collection sites across the United States were established. Following qualification for anti-SARS-CoV-2 IgG and IgM levels in independent laboratories, VICD assembled reference evaluation panels, which were used to assist the FDA's performance evaluation of commercial assays submitted for EUA approval. To date, 185 different shipments of the standard or validation panel have been sent to both domestic and international labs. These materials are also available to the SARS-CoV-2 serology community for assay calibration and performance evaluation which greatly facilitates assay data harmonization. In addition, the NCI Serological Sciences Network (SeroNet) was born from this initiative and expertise, resulting in the establishment of Capacity Building Centers (CBCs) for sample collection from different healthy, cancer and immunocompromised cohorts at Mount Sinai, Arizona State University, the University of Minnesota, and Northwell Feinstein. The NCI and FNLCR simultaneously collaborated to develop a network of investigators focused on advancing research on the immune response to SARS-CoV-2 infection and vaccination among diverse and vulnerable populations, including cancer patients. Their research has resulted in over 326 peer-reviewed publications. The CBC's have enrolled patients in longitudinal studies, resulting in a centralized collection of annotated, well characterized serum, PBMCs and clinical data. Numerous cancer cohorts, but predominantly Multiple Myeloma, are included. Furthermore, technology development was supported at the CBC's. Based upon this success, the VICD in collaboration with NCI is pursuing an even more innovative effort in pandemic preparedness to establish a Center for Serology and Data Emergency Preparedness (CESDEP);a global network able to activate and pivot to address pandemic-level threats, while continuing to expand the development of immunological assays that can inform clinical decisions for cancer and other immunocompromised patients.
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In recent times, numerous reports of systemic fungal infections have been a major concern. The angioinvasive fungal infection, mucormycosis has surged in patients with COVID-19 due to various factors, mainly uncontrolled diabetes and inappropriate corticosteroid use. The prevalence of this acute and fatal fungal infection caused by Mucorales-related fungal species has been highest in the Indian population. COVID-associated mucormycosis (CAM) has a propensity for contiguous spread, and exhibits high morbidity as well as mortality. Unless promptly detected and treated, it is associated with a poor prognosis. A high index of suspicion, aggressive surgical debridement and use of systemic antifungal agents continue to be the standard of care for CAM. Moreover, there is an imperative need to address this public health issue by increasing public awareness and education. This article provides a comprehensive overview on the emergence of CAM during the pandemic, the current burden, pathophysiology, diagnostic interventions and management of CAM in Indian clinical practice.
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Telemedicine is a modality which utilizes technology to provide and support health care across large distances. It has redefined the practices of medicine in many specialties and continues to be a boon for clinicians on many frontiers. Its role in the branch of anesthesia remains largely unexplored but has shown to be beneficial in all the three phases: pre-operative, intra-operative, and post-operative. Now time has come that anesthesiologists across the globe reassess their strategies and utilize the telemedicine facilities in the field of anesthesia.Copyright © 2021 EDP Sciences. All rights reserved.
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Background & Aim: Despite the successful implementation of vaccines worldwide, COVID-19 remains a risk in patients with a compromised immune system. Emerging viral variants have also reduced the effectiveness of monoclonal antibody therapies in these patients. New treatment options are therefore required to improve clinical outcomes. Methods, Results & Conclusion(s): T cell immunotherapy has proven effective for the treatment of a number of refractory viral diseases in patients with a compromised immune system. We have now completed the manufacture of a bank of SARS-CoV-2 specific T cells and commenced an open-label phase I clinical trial at the Royal Brisbane and Women's Hospital, Australia. Patients enrolled in the study receive two doses of partially HLA-matched allogeneic T cells at a fortnightly interval. We have thus far recruited and treated three immune compromised patients with SARS-CoV-2 T cells. In two of the three patients treated thus far, the administration of T cell therapy was coincident with the clearance of viral load after 28 days. Viral clearance in these patients was also associated with an increase in circulating SARS-CoV-2 specific T cells. Our preliminary observations suggest that SARS-CoV-2 specific T cell therapy is well tolerated and has the potential to impact viral control in immune compromised patients.Copyright © 2023 International Society for Cell & Gene Therapy
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BackgroundVaccination against SARS-CoV2 had a critical role in the fight against COVID19 pandemic.A weaker humoral response to COVID19 vaccine has been found in rheumatic patients treated with Rituximab (RTX) or Mycophenolate Mofetil (MMF)[1]. Despite the evidence that anti-SARS-CoV-2 mRNA vaccines can elicit a T-cell response [2], some data show that even the cellular immunity could be impaired in rheumatic patients [3] but COVID19 serology is the only parameter that is feasible to measure in daily practice.Tixagevimab+cilgavimab are two human-derived monoclonal antibodies administered parenterally and authorized by regulatory agencies in February 2022 for pre-exposure prophylaxis (PrEP) against COVID19 from different virus variants in fragile patients.ObjectivesTo demonstrate safety and effectiveness of tixagevimab+cilgavimab.MethodsPatients with autoimmune rheumatic diseases undergoing immunosuppressive treatment with RTX or MMF during the vaccination campaign were enrolled between April and June 2022. All patients must have anti-spike antibody levels below the protective threshold (defined by anti-spike IgG titre <250 BAU/ml) after receiving at least 2 vaccine doses.Patients were monitored with a questionnaire every month about COVID19 symptoms (including respiratory and gastrointestinal symptoms, anosmia and ageusia, skin rash and potential contact with COVID19+ subjects) and were checked for anti-spike and anti-nucleocapside antibodies titres every 2 months for a total of a 6 month follow-up. MMF dose was reduced at 1 g/die at the time of vaccine administration.ResultsFifteen patients were enrolled: 9 participants had a connective tissue disease (CTD;1 dermatomyositis, 3 anti-syntethase syndrome, 4 systemic sclerosis, 1 systemic lupus erythematosus) and 6 had vasculitis (all granulomatosis with polyangiitis). 12 of them received RTX in the preceding 12 months and 3 were taking MMF.About safety, the therapy was very well tolerated and only 4 patients (26%) reported a non-severe adverse event in the 2 weeks following drug administration (2 myalgia, 1 headache, 1 fatigue), none of them requiring hospitalization nor pharmacologic treatment.Regarding effectiveness, 3/15 patients contracted SARS-Cov2 infection (20%) with mild symptoms and no need for hospitalization nor oxygen therapy. Only 1 of them received an antiviral drug (nirmatrelvir+ritonavir). All infected patients had a CTD diagnosis. No significant correlation was observed between the type of rheumatic disease and the risk of infection or response to tixagevimab+cilgavimab.ConclusionNone of our patients developed severe adverse events after tixagevimab+cilgavimab administration and, among the 3 SARS-CoV2 infected patients, none required hospitalization nor oxygen therapy.We conclude that in our experience tixagevimab+cilgavimab is a safe and useful complementary immunization strategy to vaccination for COVID19 prophylaxis.These data will be implemented in a larger study, comprehending various immunocompromised patients from several departments.References[1] Furer et al., Ann Rheum Dis, 2021[2] Mangalakumari et al., Nat Rev Immunol, 2020[3] Picchianti-Diamanti et al., Front Immunol, 2021Charateristic of the cohortIdentificativeAgeDiagnosisRTX/MMFSARS-CoV2 InfectionHospitalizationAntiviral drugs180SScMMF-//270ASSDRTX+nono370ASSDRTX+noyes452GPARTX-//551GPARTX-//649SSc+SSjRTX-//768SScMMF-//847LESRTX-//964ASSDRTX-//1068GPARTX-//1123GPARTX-//1258DMRTX+nono1361SScMMF-//1475GPARTX-//1569GPARTX-//Figure 1.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
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Background & Aim: Immunocompromised patients are susceptible to high-risk opportunistic infections and malignant diseases. If available, most antiviral and antifungal drugs are quite toxic, relatively ineffective, and induce resistance in the long term. Methods, Results & Conclusion(s): We have previously demonstrated the safety of adoptive cell therapy for COVID-19 patients with CD45RA negative cells containing SARS-CoV-2-specific T cells from a donor, chosen based on HLA compatibility and cellular response to SARS-CoV-2 peptide pools. After finishing a Phase 2 randomized multicenter clinical trial (RELEASE, NCT04578210), we concluded that the infusion is safe, effective, accelerates lymphocyte recovery and shows hallmarks of an immune response. To use adoptive cell therapy to treat COVID-19 it would be necessary to develop a biobank of living drugs. For that, we examined the immune evolution performing a longitudinal analysis from previously SARS-CoV-2 infected and infection- naive individuals covering 21 months from infection. Cellular responses were maintained over time while humoral responses increased after vaccination but were gradually lost. Therefore, the best donors would be recovered individuals and two months after vaccination. We also evaluated the effect of dexamethasone (current standard of care treatment for COVID-19 and other infections involving lymphopenia) and Interleukin-15 (cytokine involved in T-cell maintenance and survival) on CD45RA negative. Dexamethasone did not alter cell functionality, proliferation or phenotype at a clinical-practice concentration, while interleukin-15 increased the memory T-cell and T-regulatory cell activation state, and interferon gamma release. Furthermore, we applied the adoptive passive transfer of CD45RA negative cells containing pathogen-specific memory T-cells to other infectious diseases characterized by sustained lymphopenia. We infused six immunocompromised patients with Cytomegalovirus, BK virus, Aspergillus, and Epstein-Barr virus lymphoproliferative disease. Patients experienced pathogen clearance, resolution of symptoms and lymphocyte increase. Transient microchimerism was detected in three patients. The use of CD45RA negative cells containing specific memory T cells of a third-party donor for treating severe pathogenic diseases in immunocompromised patients is feasible, safe, and effective, and has an advantage over other cell therapies such as lower costs and a less complex regulatory environment.Copyright © 2023 International Society for Cell & Gene Therapy
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Breakthrough infection (BI) after coronavirus disease 2019 (COVID-19) vaccination has exploded owing to the emergence of various SARS-CoV-2 variants and has become a major problem at present. In this study, we analyzed the epidemiological information and possession status of neutralizing antibodies in patients with BI using SARS-CoV-2 pseudotyped viruses (SARS-CoV-2pv). Analysis of 44 specimens diagnosed with COVID-19 after two or more vaccinations showed high inhibition of infection by 90% or more against the Wuhan strain and the Alpha and Delta variants of pseudotyped viruses in 40 specimens. In contrast, almost no neutralizing activity was observed against the Omicron BA.1 variant. Many cases without neutralizing activity or BI were immunosuppressed individuals. The results of this study show that contact with an infected person can result in BI even when there are sufficient neutralizing antibodies in the blood. Thus, even after vaccination, sufficient precautions must be taken to prevent infection.
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Hepatitis E is a zoonosis caused by hepatitis E virus (HEV), which was first discovered 40 years ago. Twenty million HEV infections worldwide are estimated each year. Most hepatitis E cases are self-limiting acute hepatitis, but the virus has been recognized to cause chronic hepatitis. Following the first case report of chronic hepatitis E (CHE) in a transplant recipient, CHE has recently been identified as associated with chronic liver damage induced by HEV genotypes 3, 4, and 7-usually in immunocompromised patients such as transplant recipients. In addition, patients infected with HIV and those receiving chemotherapy for malignancy, along with patients with rheumatic disease and COVID-19, have recently been reported as having CHE. CHE can be easily misdiagnosed by usual diagnostic methods of antibody response, such as anti-HEV IgM or IgA, because of the low antibody response in the immunosuppressive condition. HEV RNA should be evaluated in these patients, and appropriate treatments-such as ribavirin-should be given to prevent progression to liver cirrhosis or liver failure. While still rare, cases of CHE in immunocompetent patients have been reported, and care must be taken not to overlook these instances. Herein, we conduct an overview of hepatitis E, including recent research developments and management of CHE, in order to improve our understanding of such cases. The early diagnosis and treatment of CHE should be performed to decrease instances of hepatitis-virus-related deaths around the world.
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Background: Individuals who are immunocompromised (IC) are at high risk for severe coronavirus disease 2019 (COVID-19). Methods: Post hoc analyses of a double-blind trial conducted prior to Omicron (June 2020-April 2021), in hospitalized patients with COVID-19 assessed viral load, clinical outcomes, and safety of casirivimab plus imdevimab (CAS + IMD) versus placebo in IC versus overall study patients. Results: Ninety-nine of 1940 (5.1%) patients were IC. IC versus overall patients were more frequently seronegative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies (68.7% vs 41.2%) and had higher median baseline viral loads (7.21 vs 6.32 log10 copies/mL). On placebo, IC versus overall patients had slower viral load declines. CAS + IMD reduced viral load in IC and overall patients; least-squares mean difference versus placebo in time-weighted average change from baseline viral load at day 7 was -0.69 (95% confidence interval [CI], -1.25 to -.14) log10 copies/mL for IC patients and -0.31 (95% CI, -.42 to -.20) log10 copies/mL for overall patients. For IC patients, the cumulative incidence of death or mechanical ventilation at day 29 was lower with CAS + IMD (11.0%) versus placebo (17.2%), consistent with overall patients (15.7% CAS + IMD vs 18.3% placebo). IC and overall patients receiving CAS + IMD exhibited similar rates of treatment-emergent adverse events (30.4% and 26.6%, respectively), grade ≥2 hypersensitivity or infusion-related reactions (1.4% and 2.5%), and deaths (8.7% and 12.2%). Conclusions: IC patients were more likely to exhibit high viral loads and be seronegative at baseline. For susceptible SARS-CoV-2 variants, CAS + IMD reduced viral load and resulted in fewer death or mechanical ventilation events in IC and overall study patients. There were no new safety findings among IC patients. Clinical Trials Registration. NCT04426695.
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Probiotics are microorganisms, typically bacteria, similar to beneficial microbiota found in the human gut, usually consumed as dietary supplements or fermented foods. Although probiotics are generally safe, several cases of bacteremia, sepsis, and endocarditis associated with probiotics have been reported. Here we report a rare case of Lactobacillus casei endocarditis in a 71-year-old female, immunocompromised due to chronic steroid intake, who presented with a productive cough and low-grade fever. Blood cultures grew L. casei resistant to vancomycin and meropenem. Transesophageal echocardiography showed mitral and aortic vegetations; valve replacement was done after successfully removing vegetations. She was treated with a six-week course of daptomycin and recovered.
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Introduction Reports are rare on the usefulness of the FilmArray Respiratory Panel 2.1 (FARP) using lower respiratory tract specimens. This retrospective study assessed its use, as part of a comprehensive infectious disease panel, to detect the viral causes of pneumonia using bronchoalveolar lavage samples from immunosuppressed patients. Methods This study included immunocompromised patients who underwent bronchoalveolar lavage or bronchial washing by bronchoscopy between April 1, 2021, and April 30, 2022. The collected samples were submitted for comprehensive testing, including FARP test; reverse transcription polymerase chain reaction (RT-PCR) for cytomegalovirus, varicella-zoster virus DNA, and herpes simplex virus; PCR for Pneumocystis jirovecii DNA; antigen testing for Aspergillus and Cryptococcus neoformans; and loop-mediated isothermal amplification method for Legionella. Results Out of 23 patients, 16 (70%) showed bilateral infiltrative shadows on computed tomography and three (13%) were intubated. The most common causes of immunosuppression were anticancer drug use (n=12, 52%) and hematologic tumors (n=11, 48%). Only two (9%) patients tested positive for severe acute respiratory syndrome coronavirus 2 and adenovirus by FARP. Four patients (17%) tested positive for cytomegalovirus by RT-PCR, but no inclusion bodies were identified cytologically. Nine (39%) patients tested positive for Pneumocystis jirovecii by PCR, but cytology confirmed the organism in only one case. Conclusions Comprehensive infectious disease testing, performed using bronchoalveolar lavage samples collected from lung lesions in immunosuppressed patients, showed low positive detection by FARP. The viruses currently detectable by FARP may be less involved in viral pneumonia diagnosed in immunocompromised patients.
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SARS-CoV-2 dynamics across different COVID-19 waves has been unclear in immunocompromised children. We aimed to compare the dynamics of SARS-CoV-2 RNA viral load (VL) during the first and third waves of COVID-19 in immunocompromised children. A retrospective and longitudinal cohort study was conducted in a pediatric referral hospital of Argentina. The study included 28 admitted immunocompromised children with laboratory confirmed SARS-CoV-2 infection. Thirteen acquired the infection during COVID-19 first wave (May to August 2020, group 1 (G1)) and fifteen in the third wave (January to March 2022, group 2 (G2)). RNA viral load measure and its dynamic reconstruction were performed in nasopharyngeal swabs by validated quantitative, real time RT-PCR, and linear mixed-effects model, respectively. Of the 28 children included, 54% were girls, most of them had hemato-oncological pathology (57%), and the median age was 8 years (interquartile range (IQR): 3-13). The dynamic of VL was similar in both groups (P = 0.148), starting from a level of 5.34 log10 copies/mL (95% confidence interval (CI): 4.47-6.21) in G1 and 5.79 log10 copies/mL (95% CI: 4.93-6.65) in G2. Then, VL decayed with a rate of 0.059 (95% CI: 0.038-0.080) and 0.088 (95% CI: 0.058-0.118) log10 copies/mL per day since diagnosis and fell below the limit of quantification at days 51 and 39 after diagnosis in G1 and G2, respectively. Our results evidenced a longer viral RNA persistence in immunocompromised pediatric patients and no difference in VL dynamic between COVID-19 first wave-attributed to ancestral infections-and third wave-attributed to Omicron infections.
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Objectives Immunocompromised patients, specifically those with solid organ transplants or cancer on chemotherapy, are at particularly high risk of severe pneumonia and opportunistic infections. In select patients, bronchoalveolar lavage (BAL) is performed to provide high-quality samples for analysis. We compare BioFire® FilmArray® Pneumonia Panel (BioFire Diagnostics, Salt Lake City, Utah, United States), a multiplex polymerase chain reaction (PCR) assay, with standard of care diagnostics in BAL samples from immunocompromised patients to identify opportunities for this test to affect clinical decision making. Methods Patients hospitalized with pneumonia based on clinical and radiographic findings who underwent evaluation with bronchoscopy between May 2019 to January 2020 were reviewed. Among those patients undergoing bronchoscopy, those who were immunocompromised were selected for inclusion in the study. BAL specimens submitted to the microbiology laboratory were chosen based on as part of the internal validation of the panel in comparison with sputum culture at our hospitals. We compared the outcomes of the multiplex PCR assay with traditional culture methods and evaluated the role of PCR assay in de-escalating antimicrobial therapy. Results Twenty-four patients were identified for testing with the multiplex PCR assay. Of the 24 patients, 16 were immunocompromised, all with solid or hematological malignancy or a history of organ transplant. Seventeen individual BAL samples from the 16 patients were reviewed. BAL culture results and the multiplex PCR assay were in agreement in 13 samples (76.5%). In four cases, the multiplex PCR assay identified a possible causative pathogen not detected by standard workup. The median time to de-escalation of antimicrobials was three days (interquartile range (IQR) 2-4) from the day of collection of the BAL samples. Conclusions Studies have established the additive role of multiplex PCR testing in addition to traditional diagnostic tools like sputum culture in diagnosing the etiology of pneumonia. Limited data exist specifically looking at immunocompromised patients, in whom a timely and accurate diagnosis is particularly important. There is a potential benefit for performing multiplex PCR assays as an additive diagnostic tool in BAL samples for these patients.
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Invasive mould infections (IMIs), which are mostly caused by Aspergillus spp. and Mucormycetes, are opportunistic infections that impose a substantial threat to patients who are considered to be 'fragile'. There is no fixed definition for fragile patients; however, patients with cancer or acquired immunodeficiency syndrome (AIDS), patients who have undergone organ transplants, and patients being treated in the intensive care units (ICUs) were considered fragile. Management of IMIs in fragile patients is challenging, owing to their compromised immune status. The diagnostic challenges associated with IMIs due to insufficient sensitivity and specificity of the current diagnostic tests lead to delayed treatment. A widening demographic of at-risk patients and a broadening spectrum of pathogenic fungi have added to the challenges to ascertain a definite diagnosis. A recent surge of mucormycosis associated with SARS-CoV-2 infections and the resultant steroid usage has been reported. Liposomal amphotericin B (L-AmB) is the mainstay for treating mucormycosis while voriconazole has displaced amphotericin B as the mainstay for treating Aspergillus infection due to its better response, improved survival, and fewer severe side effects. The selection of antifungal treatment has to be subjected to more scrutiny in fragile patients owing to their comorbidities, organ impairment, and multiple ongoing treatment modalities. Isavuconazole has been documented to have a better safety profile, stable pharmacokinetics, fewer drug-drug interactions, and a broad spectrum of coverage. Isavuconazole has thus found its place in the recommendations and can be considered a suitable option for treating fragile patients with IMIs. In this review, the authors have critically appraised the challenges in ascertaining an accurate diagnosis and current management considerations and suggested an evidence-based approach to managing IMIs in fragile patients.
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We administered SARS-CoV-2 VST under emergency IND to 6 immunocompromised patients with persistent COVID-19 and characterized clinical and virologic responses: three patients had partial responses after failing other therapies but then died. Two patients completely recovered, but the role of VST in recovery was unclear due to concomitant use of other antivirals. One patient had not responded to two courses of remdesivir and experienced sustained recovery after VST. The use VST in immunocompromised patient with persistent COVID-19 requires further study.
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INTRODUCTION: Remdesivir (REM) and monoclonal antibodies (mAbs) could alleviate severe COVID-19 in at-risk outpatients. However, data on their use in hospitalized patients, particularly in elderly or immunocompromised hosts, are lacking. METHODS: All consecutive patients hospitalized with COVID-19 at our unit from 1 July 2021 to 15 March 2022 were retrospectively enrolled. The primary outcome was the progression to severe COVID-19 (P/F < 200). Descriptive statistics, a Cox univariate-multivariate model, and an inverse probability treatment-weighted (IPTW) analysis were performed. RESULTS: Overall, 331 subjects were included; their median (q1-q3) age was 71 (51-80) years, and they were males in 52% of the cases. Of them, 78 (23%) developed severe COVID-19. All-cause in-hospital mortality was 14%; it was higher in those with disease progression (36% vs. 7%, p < 0.001). REM and mAbs resulted in a 7% (95%CI = 3-11%) and 14% (95%CI = 3-25%) reduction in the risk of severe COVID-19, respectively, after adjusting the analysis with the IPTW. In addition, by evaluating only immunocompromised hosts, the combination of REM and mAbs was associated with a significantly lower incidence of severe COVID-19 (aHR = 0.06, 95%CI = 0.02-0.77) when compared with monotherapy. CONCLUSIONS: REM and mAbs may reduce the risk of COVID-19 progression in hospitalized patients. Importantly, in immunocompromised hosts, the combination of mAbs and REM may be beneficial.