Investigating Viral Involvement in Immunocompromised Patients Using Comprehensive Infectious Disease Testing Including FilmArray Respiratory Panel 2.1 on Bronchoscopy: A Retrospective Study.

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.

Does High Flow Nasal Cannula avoid intubation and improve the mortality of adult patients in acute respiratory failure in the intensive care setting, when compared to others methods as Conventional Oxygen Therapy or Non-Invasive Ventilation? A narrative review

High-flow oxygen therapy via nasal cannula (HFNC) has been used for many years to oxygenate patients in respiratory failure. However, scientific data in literature are divergent about its value to prevent invasive mechanical ventilation and mortality. The use of HFNC has increased following the COVID-19 pandemic. Our review considers the impact of HFNC on intubation rates and mortality compared with conventional oxygen therapy (COT) and noninvasive ventilation (NIV). HFNC would decrease the use of invasive mechanical ventilation compared to COT and would be equivalent to NIV. Combination of NIV and HFNC would have a benefit compared to NIV alone. Some etiologies of respiratory failure would benefit more from this technique as post-extubation critical ill patient or COVID-19 pneumonia. HFNC seems to reduce mortality in COVID-19 patients compared to NIV. Several clinical studies are needed to refine the indications of this technique.

Transcriptome in Human Mycoses

Mycoses are infectious diseases caused by fungi, which incidence has increased in recent decades due to the increasing number of immunocompromised patients and improved diagnostic tests. As eukaryotes, fungi share many similarities with human cells, making it difficult to design drugs without side effects. Commercially available drugs act on a limited number of targets and have been reported fungal resistance to commonly used antifungal drugs. Therefore, elucidating the pathogenesis of fungal infections, the fungal strategies to overcome the hostile environment of the host, and the action of antifungal drugs is essential for developing new therapeutic approaches and diagnostic tests. Large-scale transcriptional analyses using microarrays and RNA sequencing (RNA-seq), combined with improvements in molecular biology techniques, have improved the study of fungal pathogenicity. Such techniques have provided insights into the infective process by identifying molecular strategies used by the host and pathogen during the course of human mycoses. This chapter will explore the latest discoveries regarding the transcriptome of major human fungal pathogens. Further we will highlight genes essential for host–pathogen interactions, immune response, invasion, infection, antifungal drug response, and resistance. Finally, we will discuss their importance to the discovery of new molecular targets for antifungal drugs. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2014, 2022.

COVID-19 Adverse Outcomes in Immunocompromised Patients

Background: Coronavirus disease 2019 (COVID-19) is a devastating viral pandemic infecting millions of people with a wide range of symptoms from fever to death. It has been suggested that immunocompromised patients are at a higher risk of severe disease, poor clinical outcomes, and mortality. However, these patients' risk factors and COVID-19-related outcomes are not well characterized. Objective(s): We evaluated the COVID-19-related outcomes among immunocompromised patients ranging from solid tumors, hema-tological malignancies, and HIV to autoimmune disease and transplant recipients who received immunosuppressive agents. We also aimed at finding risk factors related to mortality among immunocompromised patients with COVID-19. Method(s): This cross-sectional study was conducted in Khansari Hospital, Iran between March and November 2021. We included immunocompromised patients with nasal swab positive SARS-CoV-2 polymerase chain reaction (PCR) results in the study. Patient outcomes, including hospitalization ward and the mortality rate, were assessed till three months after COVID-19 infection were evaluated in all patients. Moreover, the relation between risk factors and the rate of the mortality rate was analyzed in immuno-compromised patients with COVID-19. Result(s): A total number of 74 immunocompromised patients with solid tumors, hematologic malignancies, autoimmune diseases, acquired immunodeficiencies, and solid-organ transplant recipients were included in the study. Results indicated that the male gender and ICU hospitalization significantly increase the mortality risk. Surprisingly, chemotherapy is associated with a lower risk of mortality. Conclusion(s): Identifying the risk factors can improve the decision-making on cancer patients' management during the COVID-19 infection. A further large cohort of patients would be required to identify risk factors relating to poor clinical outcomes and mortality rates in immunocompromised patients with COVID-19.Copyright © 2023, Author(s).

High-titer post-vaccine COVID-19 convalescent plasma for immunocompromised patients during the first omicron surge.

BACKGROUND: Transplant and hematologic malignancy patients have high Coronavirus disease 2019 (COVID-19) mortality and impaired vaccination responses. Omicron variant evades several monoclonal antibodies previously used in immunocompromised patients. Polyclonal COVID-19 convalescent plasma (CCP) may provide broader neutralizing capacity against new variants at high titers. Vaccination increases severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) titer in convalescent donors. METHODS: We conducted a retrospective chart review of hospitalized immunocompromised patients with COVID-19 who received high-titer CCP during the first omicron surge, collected from vaccinated donors within 6 months of pre-omicron COVID-19. Data on safety and outcomes were extracted. RESULTS: A total of 44 immunocompromised patients were included, 59.1% with solid organ transplant, 22.7% with hematopoietic cell transplant, 11.4% with hematologic malignancy, and 6.8% with autoimmune disease. Overall, 95% of CCP units transfused were from recently recovered and vaccinated donors and had SARS-CoV-2 antibody results 8- to 37-fold higher than the Food and Drug Administration's cutoff for high-titer CCP. There were two mild transfusion reactions. A total of 30-day mortality was 4.5%. There were no differences in 100-day mortality by underlying diagnosis, levels of immunosuppression, and timing of CCP administration. Patients with higher immunosuppression had significantly higher mean World Health Organization clinical progression scores at 30-day post-CCP compared to those with lower immunosuppression. CONCLUSIONS: CCP is a safe, globally available treatment for immunocompromised patients with COVID-19. Mortality was lower in our cohort than that of COVID-19 patients with similar immunocompromising conditions. Post-vaccine CCP with very high titers should be prioritized for study in immunocompromised patients. Post-vaccine CCP has the potential to keep pace with new variants by overcoming mutations at sufficiently high titer.

Effectiveness of vaccination against SARS-CoV-2 and the need for alternative preventative approaches in immunocompromised individuals: a narrative review of systematic reviews.

INTRODUCTION: Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including administration of booster doses, continues to be the most effective method for controlling COVID-19-related complications including progression to severe illness and death. However, there is mounting evidence that more needs to be done to protect individuals with compromised immune function. AREAS COVERED: Here, we review the effectiveness of COVID-19 vaccination in immunocompromised patients, including those with primary immunodeficiencies, HIV, cancer (including hematological malignancies), solid organ transplant recipients, and chronic kidney disease, as reported in systematic reviews/meta-analyses published over a 12-month period in PubMed. Given the varied responses to vaccination in patients with compromised immune function, a major goal of this analysis was to try to identify specific risk-factors related to vaccine failure. EXPERT OPINION: COVID-19 remains a global problem, with new variants of concern emerging at regular intervals. There is an ongoing need for optimal vaccine strategies to combat the pandemic. In addition, alternative treatment approaches are needed for immunocompromised patients who may not mount an adequate immune response to current COVID-19 vaccines. Identification of high-risk patients and the introduction of newer antiviral approaches such as monoclonal antibodies will offer physicians therapeutic options for such vulnerable individuals.

Outcome of COVID-19 in allogeneic stem cell transplant recipients: Results from the EPICOVIDEHA registry.

Background: The outcome of COVID-19 in allogeneic hematopoietic stem cell transplantation (HSCT) recipients is almost uniformely considered poor. The aim of present study was to retrospectively analyse the outcome and risk factors for mortality in a large series of patients who developed COVID-19 infection after an allogeneic HSCT. Methods: This multicenter retrospective study promoted by the European Hematology Association - Infections in Hematology Study Working Group, included 326 adult HSCT patients who had COVID-19 between January 2020 and March 2022. Results: The median time from HSCT to the diagnosis of COVID-19 was 268 days (IQR 86-713; range 0-185 days). COVID-19 severity was mild in 21% of the patients, severe in 39% and critical in 16% of the patients. In multivariable analysis factors associated with a higher risk of mortality were, age above 50 years, presence of 3 or more comorbidities, active hematologic disease at time of COVID-19 infection, development of COVID-19 within 12 months of HSCT, and severe/critical infections. Overall mortality rate was 21% (n=68): COVID-19 was the main or secondary cause of death in 16% of the patients (n=53). Conclusions: Mortality in HSCT recipients who develop COVID-19 is high and largely dependent on age, comorbidities, active hematologic disease, timing from transplant and severity of the infection.

The unmet need for COVID-19 treatment in immunocompromised patients.

BACKGROUND: Immunocompromised (IC) patients are at increased risk of severe and/or prolonged COVID-19. MAIN TEXT: The recent study by Scaglione et al., addresses the issue of IC outpatients with SARS-CoV-2 infection. Authors describe the real-life use of SARS-CoV-2 antivirals and/or monoclonal antibodies and the clinical benefit in high-risk COVID-19 patients. The study supports the use of early combination therapy in a subgroup of extremely high risk patients, and considers the combined strategy as a gold standard regimen to both increase the effectiveness of early treatment, especially in IC individuals, and, reduce the emergence of SARS-CoV-2 escape mutants. CONCLUSION: A tailored and standardised therapeutic approach in case of IC out and inpatients with SARS-CoV-2 infection is needed.

A Case of Multiple Sclerosis with Protracted Course of COVID-19.

BACKGROUND: We reported a case of multiple sclerosis (MS) with persistent symptomatic COVID-19, which was complicated by new-appearing severe pneumonia 40 days after disease onset. CASE PRESENTATION: A 38-year-old man with a history of multiple sclerosis referred to our hospital with fever, shaking chills, cough, and dyspnea. In his history, the patient had developed mild COVID-19 from 40 days ago. After 7 days of disease onset, the COVID symptoms had been subsided partially, but fatigue, myalgia, intermittent fever, and loss of taste and smell had been continued. In physical examinations, his oral temperature was 39.4 °C. He had respiratory distress, and his blood oxygen saturation on the room air was 90%. The spiral chest CT scan was performed, which revealed bilateral ground-glass and alveolar opacities in favor of COVID-19 pneumonia. The result of the RT-PCR test for SARS-COV-2 was reported positive subsequently. His current MS medication was rituximab and he had received the last dose of rituximab two months before developing COVID-19. The patient was admitted to the COVID ward and put on Remdesivir, subcutaneous interferon-beta1b, and dexamethasone. He improved gradually and was discharged from the hospital with the favorable condition after 10 days. This patient had a rare protracted disease course. We presumed that prolonged high degree fever (above 38 °C) in our patient is beyond the diagnosis of the post-COVID-19 syndrome and is more compatible with persistent infection. CONCLUSION: Although most immunocompromised patients effectively clear SARS-CoV-2 infection, this case report highlights the risk of persistent infection associated with recurrence of the disease.

Neutralizing antibodies to Omicron after the fourth SARS-CoV-2 mRNA vaccine dose in immunocompromised patients highlight the need of additional boosters.

Introduction: Immunocompromised patients have been shown to have an impaired immune response to COVID-19 vaccines. Methods: Here we compared the B-cell, T-cell and neutralizing antibody response to WT and Omicron BA.2 SARS-CoV-2 virus after the fourth dose of mRNA COVID-19 vaccines in patients with hematological malignancies (HM, n=71), solid tumors (ST, n=39) and immune-rheumatological (IR, n=25) diseases. The humoral and T-cell responses to SARS-CoV-2 vaccination were analyzed by quantifying the anti-RBD antibodies, their neutralization activity and the IFN-γ released after spike specific stimulation. Results: We show that the T-cell response is similarly boosted by the fourth dose across the different subgroups, while the antibody response is improved only in patients not receiving B-cell targeted therapies, independent on the pathology. However, 9% of patients with anti-RBD antibodies did not have neutralizing antibodies to either virus variants, while an additional 5.7% did not have neutralizing antibodies to Omicron BA.2, making these patients particularly vulnerable to SARS-CoV-2 infection. The increment of neutralizing antibodies was very similar towards Omicron BA.2 and WT virus after the third or fourth dose of vaccine, suggesting that there is no preferential skewing towards either virus variant with the booster dose. The only limited step is the amount of antibodies that are elicited after vaccination, thus increasing the probability of developing neutralizing antibodies to both variants of virus. Discussion: These data support the recommendation of additional booster doses in frail patients to enhance the development of a B-cell response directed against Omicron and/or to enhance the T-cell response in patients treated with anti-CD20.

Clinical characteristics and outcome of immunocompromised patients with COVID-19 caused by the Omicron variant: a prospective observational study.

BACKGROUND: In the general population, illness after infection with the SARS-CoV-2 Omicron variant is less severe compared with previous variants. Data on the disease burden of Omicron in immunocompromised patients are lacking. We investigated the clinical characteristics and outcome of a cohort of immunocompromised patients with COVID-19 caused by Omicron. METHODS: Solid organ transplant recipients, patients on anti-CD20 therapy, and allogenic hematopoietic stem cell transplantation recipients on immunosuppressive therapy infected with the Omicron variant, were included. Patients were contacted regularly until symptom resolution. Clinical characteristics of consenting patients were collected through their electronic patient files. To identify possible risk factors for hospitalization, a univariate logistic analysis was performed. RESULTS: A total of 114 consecutive immunocompromised patients were enrolled. Eighty-nine percent had previously received three mRNA vaccinations. While only one patient died, 23 (20%) required hospital admission for a median of 11 days. A low SARS-CoV-2 IgG antibody response (<300 BAU/mL) at diagnosis, higher age, being a lung transplant recipient, more comorbidities and a higher frailty were associated with hospital admission (all p < 0.01). At the end of follow-up, 25% had still not fully recovered. Of the 23 hospitalized patients, 70% had a negative and 92% a low IgG (<300 BAU/mL) antibody response at admission. Sotrovimab was administered to 17 of them, of which one died. CONCLUSIONS: While the mortality in immunocompromised patients infected with Omicron was low, hospital admission was frequent and the duration of symptoms often prolonged. Besides vaccination, other interventions are needed to limit the morbidity from COVID-19 in immunocompromised patients.

Long-Term Accuracy of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Interferon-γ Release Assay and Its Application in Household Investigation.

BACKGROUND: An immunodiagnostic assay that sensitively detects a cell-mediated immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is needed for epidemiological investigation and for clinical assessment of T- cell-mediated immune response to vaccines, particularly in the context of emerging variants that might escape antibody responses. METHODS: The performance of a whole blood interferon-gamma (IFN-γ) release assay (IGRA) for the detection of SARS-CoV-2 antigen-specific T cells was evaluated in coronavirus disease 2019 (COVID-19) convalescents tested serially up to 10 months post-infection and in healthy blood donors. SARS-CoV-2 IGRA was applied in contacts of households with index cases. Freshly collected blood in the lithium heparin tube was left unstimulated, stimulated with a SARS-CoV-2 peptide pool, and stimulated with mitogen. RESULTS: The overall sensitivity and specificity of IGRA were 84.5% (153/181; 95% confidence interval [CI]: 79.0-89.0) and 86.6% (123/142; 95% CI: 80.0-91.2), respectively. The sensitivity declined from 100% (16/16; 95% CI: 80.6-100) at 0.5-month post-infection to 79.5% (31/39; 95% CI: 64.4-89.2) at 10 months post-infection (P < .01). The IFN-γ response remained relatively robust at 10 months post-infection (3.8 vs 1.3 IU/mL, respectively). In 14 households, IGRA showed a positivity rate of 100% (12/12) and 65.2% (15/23), and IgG of 50.0% (6/12) and 43.5% (10/23) in index cases and contacts, respectively, exhibiting a difference of + 50% (95% CI: +25.4 to +74.6) and +21.7% (95% CI: +9.23 to +42.3), respectively. Either IGRA or IgG was positive in 100% (12/12) of index cases and 73.9% (17/23) of contacts. CONCLUSIONS: The SARS-CoV-2 IGRA is a useful clinical diagnostic tool for assessing cell-mediated immune response to SARS-CoV-2.

Viral Population Heterogeneity and Fluctuating Mutational Pattern during a Persistent SARS-CoV-2 Infection in an Immunocompromised Patient.

Literature offers plenty of cases of immunocompromised patients, who develop chronic and severe SARS-CoV-2 infections. The aim of this study is to provide further insight into SARS-CoV-2 evolutionary dynamic taking into exam a subject suffering from follicular lymphoma, who developed a persistent infection for over 7 months. Eight nasopharyngeal swabs were obtained, and were analyses by qRT-PCR for diagnostic purposes. All of them were considered eligible (Ct < 30) for NGS sequencing. Sequence analysis showed that all sequences matched the B.1.617.2 AY.122 lineage, but they differed by few mutations identifying three genetically similar subpopulations, which evolved during the course of infection, demonstrating that prolonged replication is paralleled with intra-host virus evolution. These evidences support the hypothesis that SARS-CoV-2 adaptive capacities are able to shape a heterogeneous viral population in the context of immunocompromised patients. Spill-over of viral variants with enhanced transmissibility or immune escape capacities from these subjects is plausible.

An Impact of COVID-19 on Cancer Care: An Update.

The world has been affected socioeconomically for the last two years due to the emergence of different variants of the COVID-19 virus. Vaccination is the major and most efficient way to prevent the widening of this pandemic. Those who are having comorbidities are more vulnerable to serious infections due to their immunocompromised state. Additionally, cancer patients could be at significant risk for COVID-19. In this pandemic era, the diagnosis and treatment of cancer were significantly affected. Clinical trials at the initial stage were performed on healthy or COVID-19 infected patients. This produces a greater level of hesitancy in cancer patients. This review article provide an update regarding the vaccination and treatment for COVID-19 in patients with cancer and future directions.

Translation suppression underlies the restrained COVID-19 mRNA vaccine response in the high-risk immunocompromised group.

Background: Immunocompromised (IC) patients show diminished immune response to COVID-19 mRNA vaccines (Co-mV). To date, there is no 'empirical' evidence to link the perturbation of translation, a rate-limiting step for mRNA vaccine efficiency (VE), to the dampened response of Co-mV. Materials and methods: Impact of immunosuppressants (ISs), tacrolimus (T), mycophenolate (M), rapamycin/sirolimus (S), and their combinations on Pfizer Co-mV translation were determined by the Spike (Sp) protein expression following Co-mV transfection in HEK293 cells. In vivo impact of ISs on SARS-CoV-2 spike specific antigen (SpAg) and associated antibody levels (IgGSp) in serum were assessed in Balb/c mice after two doses (2D) of the Pfizer vaccine. Spike Ag and IgGSp levels were assessed in 259 IC patients and 50 healthy controls (HC) who received 2D of Pfizer or Moderna Co-mV as well as in 67 immunosuppressed solid organ transplant (SOT) patients and 843 non-transplanted (NT) subjects following three doses (3D) of Co-mV. Higher Co-mV concentrations and transient drug holidays were evaluated. Results: We observed significantly lower IgGSP response in IC patients (p<0.0001) compared to their matched controls in 2D and 3D Co-mV groups. IC patients on M or S showed a profound dampening of IgGSP response relative to those that were not on these drugs. M and S, when used individually or in combination, significantly attenuated the Co-mV-induced Sp expression, whereas T did not exert significant influence. Sirolimus combo pretreatment in vivo significantly attenuated the Co-mV induced IgMSp and IgGSp production, which correlated with a decreasing trend in the early levels (after day 1) of Co-mV induced Sp immunogen levels. Neither higher Co-mV concentrations (6µg) nor withholding S for 1-day could overcome the inhibition of Sp protein levels. Interestingly, 3-days S holiday or using T alone rescued Sp levels in vitro. Conclusions: This is the first study to demonstrate that ISs, sirolimus and mycophenolate inhibited Co-mV-induced Sp protein synthesis via translation repression. Selective use of tacrolimus or drug holiday of sirolimus can be a potential means to rescue translation-dependent Sp protein production. These findings lay a strong foundation for guiding future studies aimed at improving Co-mV responses in high-risk IC patients.

SARS-CoV-2 Pre-Exposure Prophylaxis with Sotrovimab and Tixagevimab/Cilgavimab in Immunocompromised Patients-A Single-Center Experience.

Immunocompromised patients experience reduced vaccine effectiveness and are at higher risk for coronavirus disease 19 (COVID-19) death. Pre-exposure prophylaxis (PrEP) aims to protect these patients. So far, only tixagevimab/cilgavimab is authorized for use as PrEP. This paper aims to provide real-world data on the use of tixagevimab/cilgavimab and sotrovimab as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PrEP in immunocompromised patients, comparing the evolution of antibody levels and reporting the incidence of breakthrough infections. A retrospective, single-center analysis was conducted including 132 immunocompromised patients with inadequate vaccine response, who received COVID-PrEP at our clinic between January and June 2022. Initially, 95 patients received sotrovimab while 37 patients received tixagevimab/cilgavimab. Antibody levels after first PrEP with sotrovimab remain high for several months after infusion (median 10,058 and 7235 BAU/mL after 1 and 3 months, respectively), with higher titers than after tixagevimab/cilgavimab injection even 3 months later (7235 vs. 1647 BAU/mL, p = 0.0007). Overall, breakthrough infections were rare (13/132, 10%) when compared to overall infection rates during this period (over 30% of the Austrian population), with mild disease course and rapid viral clearance (median 10 days). Sotrovimab may be an additional option for SARS-CoV-2 PrEP.

Antibody response and intra-host viral evolution after plasma therapy in COVID-19 patients pre-exposed or not to B-cell-depleting agents.

Administration of plasma therapy may contribute to viral control and survival of COVID-19 patients receiving B-cell-depleting agents that impair humoral immunity. However, little is known on the impact of anti-CD20 pre-exposition on the kinetics of SARS-CoV-2-specific antibodies. Here, we evaluated the relationship between anti-spike immunoglobulin G (IgG) kinetics and the clinical status or intra-host viral evolution after plasma therapy in 36 eligible hospitalized COVID-19 patients, pre-exposed or not to B-cell-depleting treatments. The majority of anti-CD20 pre-exposed patients (14/17) showed progressive declines of anti-spike IgG titres following plasma therapy, contrasting with the 4/19 patients who had not received B-cell-depleting agents (p = 0.0006). Patients with antibody decay also depicted prolonged clinical symptoms according to the World Health Organization (WHO) severity classification (p = 0.0267) and SARS-CoV-2 viral loads (p = 0.0032) before complete virus clearance. Moreover, they had higher mutation rates than patients able to mount an endogenous humoral response (p = 0.015), including three patients with one to four spike mutations, potentially associated with immune escape. No relevant differences were observed between patients treated with plasma from convalescent and/or mRNA-vaccinated donors. Our study emphasizes the need for an individualized clinical care and follow-up in the management of COVID-19 patients with B-cell lymphopenia.

Third Early "Booster" Dose Strategy in France of bnt162b2 SARS-CoV-2 Vaccine in Allogeneic Hematopoietic Stem Cell Transplant Recipients Enhances Neutralizing Antibody Responses.

Immunocompromised individuals generally fail to mount efficacious immune humoral responses following vaccination. The emergence of SARS-CoV-2 variants of concern has raised the question as to whether levels of anti-spike protein antibodies achieved after two or three doses of the vaccine efficiently protect against breakthrough infection in the context of immune suppression. We used a fluorescence-based neutralization assay to test the sensitivity of SARS-CoV-2 variants (ancestral variant, Beta, Delta, and Omicron BA.1) to the neutralizing response induced by vaccination in highly immunosuppressed allogeneic HSCT recipients, tested after two and three doses of the BNT162b2 vaccine. We show that neutralizing antibody responses to the Beta and Delta variants in most immunocompromised HSCT recipients increased after three vaccine doses up to values similar to those observed in twice-vaccinated healthy adults and were significantly lower against Omicron BA.1. Overall, neutralization titers correlated with the amount of anti-S-RBD antibodies measured by means of enzyme immunoassay, indicating that commercially available assays can be used to quantify the anti-S-RBD antibody response as a reliable surrogate marker of humoral immune protection in both immunocompetent and immunocompromised individuals. Our findings support the recommendation of additional early vaccine doses as a booster of humoral neutralizing activity against emerging variants, in HSCT immunocompromised patients. In the context of Omicron circulation, it further emphasizes the need for reinforcement of preventive measures including the administration of monoclonal antibodies in this high-risk population.

SARS-CoV-2 vaccine response and rate of breakthrough infection in patients with hematological disorders.

BACKGROUND: The clinical efficacy of SARS-CoV-2 vaccines according to antibody response in immunosuppressed patients such as hematological patients has not yet been established. PATIENTS AND METHODS: A prospective multicenter registry-based cohort study conducted from December 2020 to December 2021 by the Spanish transplant and cell therapy group was used to analyze the relationship of antibody response at 3-6 weeks after full vaccination (2 doses) with breakthrough SARS-CoV-2 infection in 1394 patients with hematological disorders. RESULTS: At a median follow-up of 165 days after complete immunization, 37 out of 1394 (2.6%) developed breakthrough SARS-CoV-2 infection at median of 77 days (range 7-195) after full vaccination. The incidence rate was 6.39 per 100 persons-year. Most patients were asymptomatic (19/37, 51.4%), whereas only 19% developed pneumonia. The mortality rate was 8%. Lack of detectable antibodies at 3-6 weeks after full vaccination was the only variable associated with breakthrough infection in multivariate logistic regression analysis (Odds Ratio 2.35, 95% confidence interval 1.2-4.6, p = 0.012). Median antibody titers were lower in cases than in non-cases [1.83 binding antibody units (BAU)/mL (range 0-4854.93) vs 730.81 BAU/mL (range 0-56,800), respectively (p = 0.007)]. We identified 250 BAU/mL as a cutoff above which incidence and severity of the infection were significantly lower. CONCLUSIONS: Our study highlights the benefit of developing an antibody response in these highly immunosuppressed patients. Level of antibody titers at 3 to 6 weeks after 2-dose vaccination links with protection against both breakthrough infection and severe disease for non-Omicron SARS-CoV-2 variants.

Mini Review: Risk Assessment, Clinical Manifestation, Prediction, and Prognosis of Mucormycosis: Implications for Pathogen- and Human-Derived Biomarkers.

Mucormycosis is a fungal disease caused by members of the fungal order Mucorales, which are abundantly found in terrestrial environments. The fungi propagate clonally via mitospores, which are transmitted to humans through the air and cause superficial or invasive infections. The disease has emerged in recent years and coincides generally with immunosuppression on the patient side. Mucormycosis is still rarely recognized in the clinical because of its unspecific symptoms which often triggers misdiagnosis with bacterial or viral infections leading to prolonged therapeutic cycles and loss of valuable time to manage mucormycosis properly. Infected patients develop various clinical forms, most notably ranging from rhinocerebral via pulmonary to gastrointestinal forms. Traditional diagnosis is based on culture and histopathologic examinations of the affected tissue. But, the achievement of a precise result is time-consuming, labor-intensive, requires mycological expertise and the finding appears often too late. A rapid and precise diagnosis is mandatory because symptoms are non-specific and the disease is rapidly progressing with often fatal outcome. Mucormycosis was increasingly associated with other infections and underlying conditions and risk factors causing comorbidities, which are difficult to successfully manage. This mini-review summarizes the current knowledge on the epidemiology and causative agents of mucormycosis, transmission, risk factors, clinical presentation, diagnosis, and highlights the lack of appropriate biomarkers on the pathogen and the host sides for rapid pathogen and host susceptibility detection, respectively. Fungal antigens and single nucleotide polymorphisms (SNPs) in human host genes are useful for the assessment of susceptibility. This mini-review addresses possibilities for early prediction of susceptibility to mucormycosis based on forecasting of the risk of infection with fungal pathogens other than Mucorales. The topic of early prediction and diagnosis of mucormycosis represents a current research gap and highlights the importance of potential future developments in the area of risk assessment, susceptibility prognosis in conjunction with early diagnosis to reduce mortality in patients suffering from mucormycosis.