COVID-19 Severity and Waning Immunity After up to 4 mRNA Vaccine Doses in 73 608 Patients With Cancer and 621 475 Matched Controls in Singapore: A Nationwide Cohort Study.

Importance: Despite patients with cancer being at risk of poor outcomes from COVID-19, there are few published studies for vaccine efficacy in this group, with suboptimal immunogenicity and waning vaccine efficacy described in small studies being a concern. Objective: To assess the incidence rate of severe COVID-19 disease outcomes associated with the number of vaccine doses received and the waning of protection over time. Design, Setting, and Participants: A prospective multicenter observational cohort study was carried out over 2 time periods (September 15, 2021, to December 20, 2021 [delta wave], and January 20, 2022, to November 11, 2022 [omicron wave]) predominated by SARS-CoV-2 delta and omicron variants, respectively. Overall, 73 608 patients with cancer (23 217 active treatment, 50 391 cancer survivors) and 621 475 controls matched by age, sex, race and ethnicity, and socioeconomic status were included. Exposure: Vaccine doses received, from zero to 4 doses, and time elapsed since last vaccine dose. Outcomes: Competing-risk regression analyses were employed to account for competing risks of death in patients with cancer. Main outcomes were incidence rate ratios (IRRs) of COVID-19 infection, hospitalization, and severe disease (defined as requirement for supplemental oxygen, intensive care, or death). The IRRs stratified by time from last vaccine dose served as indicators of waning of vaccine effectiveness over time. Results: The mean (SD) age of actively treated patients with cancer, cancer survivors, and controls were 62.7 (14.7), 62.9 (12.6), and 61.8 (14.7) years, respectively. Of 73 608 patients with cancer, 27 170 (36.9%) were men; 60 100 (81.6%) were Chinese, 7432 (10.1%) Malay, 4597 (6.2%) Indian, and 1479 (2.0%) were of other races and ethnicities. The IRRs for the 3-dose and 4-dose vs the 2-dose group (reference) for COVID-19 hospitalization and severe disease were significantly lower during both the delta and omicron waves in cancer and control populations. The IRRs for severe disease in the 3-dose group for active treatment, cancer survivors, and controls were 0.14, 0.13, and 0.07 during the delta wave and 0.29, 0.19, and 0.21 during omicron wave, respectively. The IRRs for severe disease in the 4-dose group during the omicron wave were even lower at 0.13, 0.10 and 0.10, respectively. No waning of vaccine effectiveness against hospitalization and severe disease was seen beyond 5 months after a third dose, nor up to 5 months (the end of this study's follow-up) after a fourth dose. Conclusion: This cohort study provides evidence of the clinical effectiveness of mRNA-based vaccines against COVID-19 in patients with cancer. Longevity of immunity in preventing severe COVID-19 outcomes in actively treated patients with cancer, cancer survivors, and matched controls was observed at least 5 months after the third or fourth dose.

Clinical efficacy and long-term immunogenicity of an early triple dose regimen of SARS-CoV-2 mRNA vaccination in cancer patients.

INTRODUCTION: Three doses of SARS-CoV-2 mRNA vaccines have been recommended for cancer patients to reduce the risk of severe disease. Anti-neoplastic treatment, such as chemotherapy, may affect long-term vaccine immunogenicity. METHOD: Patients with solid or haematological cancer were recruited from 2 hospitals between July 2021 and March 2022. Humoral response was evaluated using GenScript cPASS surrogate virus neutralisation assays. Clinical outcomes were obtained from medical records and national mandatory-reporting databases. RESULTS: A total of 273 patients were recruited, with 40 having haematological malignancies and the rest solid tumours. Among the participants, 204 (74.7%) were receiving active cancer therapy, including 98 (35.9%) undergoing systemic chemotherapy and the rest targeted therapy or immunotherapy. All patients were seronegative at baseline. Seroconversion rates after receiving 1, 2 and 3 doses of SARS-CoV-2 mRNA vaccination were 35.2%, 79.4% and 92.4%, respectively. After 3 doses, patients on active treatment for haematological malignancies had lower antibodies (57.3%±46.2) when compared to patients on immunotherapy (94.1%±9.56, P<0.05) and chemotherapy (92.8%±18.1, P<0.05). SARS-CoV-2 infection was reported in 77 (28.2%) patients, of which 18 were severe. No patient receiving a third dose within 90 days of the second dose experienced severe infection. CONCLUSION: This study demonstrates the benefit of early administration of the third dose among cancer patients.

The current state of laboratory mycology in Asia/Pacific: A survey from the European Confederation of Medical Mycology (ECMM) and International Society for Human and Animal Mycology (ISHAM).

INTRODUCTION: Invasive fungal infections (IFIs) in Asia/Pacific are a particular threat to patients with malignancies, uncontrolled diabetes mellitus or undiagnosed/untreated human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS). Adequate and early access to diagnostic tools and antifungals is essential for IFI clinical management and patient survival. METHODS: Details on institution profile, self-perception on IFI, and access to microscopy, culture, serology, antigen detection, molecular testing, and therapeutic drug monitoring for IFI were collected in a survey. RESULTS: As of June 2022, 235 centres from 40 countries/territories in Asia/Pacific answered the questionnaire. More than half the centres were from six countries: India (25%), China (17%), Thailand (5%), Indonesia, Iran, and Japan (4% each). Candida spp. (93%) and Aspergillus spp. (75%) were considered the most relevant pathogens. Most institutions had access to microscopy (98%) or culture-based approaches (97%). Furthermore, 79% of centres had access to antigen detection, 66% to molecular assays, and 63% to antibody tests. Access to antifungals varied between countries/territories. At least one triazole was available in 93% of the reporting sites (voriconazole [89%] was the most common mould-active azole), whereas 80% had at least one amphotericin B formulation, and 72% had at least one echinocandin. CONCLUSION: According to the replies provided, the resources available for IFI diagnosis and management vary among Asia/Pacific countries/territories. Economical or geographical factors may play a key role in the incidence and clinical handling of this disease burden. Regional cooperation may be a good strategy to overcome shortcomings.

Dominant Negative TRAF3 Variant With Recurrent Mycobacterium abscessus Infection and Bronchiectasis.

Host factors leading to pulmonary nontuberculous mycobacteria (PNTM) disease are poorly understood compared with disseminated NTM disease, which is linked to the interleukin 12-interferon gamma signaling pathway. We investigated the tumor necrosis factor receptor associated factor 3 (TRAF3) R338W variant in a patient with recurrent PNTM infection, demonstrating TRAF3- and TNF-α-deficient phenotypes via ex vivo immune and cloning-transfection cellular studies.

Booster doses of COVID-19 vaccines for patients with haematological and solid cancer: a systematic review and individual patient data meta-analysis.

IMPORTANCE: Patients with cancer have an increased risk of severe disease and mortality from COVID-19, as the disease and antineoplastic therapy cause reduced vaccine immunogenicity. Booster doses have been proposed to enhance protection, and efficacy data are emerging from several studies. OBJECTIVE: To evaluate the proportion of COVID-19 primary vaccination non-responders with cancer who seroconvert after a booster dose. METHODS: PubMed, EMBASE, CENTRAL and medRxiv were searched from 1st January 2021 to 10th March 2022. Quality was assessed using the Joanna Briggs Institute Critical Appraisal checklist. RESULTS: After the eligibility assessment, 22 studies were included in this systematic review and 17 for meta-analysis of seroconversion in non-responders, pooling a total of 849 patients with haematological cancer and 82 patients with solid cancer. Haematological cancer non-responders exhibited lower seroconversion at 44% (95% CI 36-53%) than solid cancer at 80% (95% CI 69-87%). Individual patient data meta-analysis found the odds of having a meaningful rise in antibody titres to be significantly associated with increased duration between the second and third dose (OR 1.02, 95% CI 1.00-1.03, P ≤ 0.05), age of patient (OR 0.960, 95% CI 0.934-0.987, P ≤ 0.05) and cancer type. With patients with haematological cancer as a reference, patients with lung cancer had 16.8 times the odds of achieving a meaningful increase in antibody titres (OR 16.8, 95% CI 2.95-318, P ≤ 0.05) and gastrointestinal cancer patients had 25.4 times the odds of achieving a meaningful increase in antibody titres (OR 25.4, 95% CI 5.26-492.21, P ≤ 0.05). CONCLUSIONS: administration of a COVID-19 vaccine booster dose is effective in improving seroconversion and antibody levels. Patients with haematological cancer consistently demonstrate poorer response to booster vaccines than patients with solid cancer.

Efficacy of covid-19 vaccines in immunocompromised patients: systematic review and meta-analysis.

OBJECTIVE: To compare the efficacy of covid-19 vaccines between immunocompromised and immunocompetent people. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, Embase, Central Register of Controlled Trials, COVID-19 Open Research Dataset Challenge (CORD-19), and WHO covid-19 databases for studies published between 1 December 2020 and 5 November 2021. ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were searched in November 2021 to identify registered but as yet unpublished or ongoing studies. STUDY SELECTION: Prospective observational studies comparing the efficacy of covid-19 vaccination in immunocompromised and immunocompetent participants. METHODS: A frequentist random effects meta-analysis was used to separately pool relative and absolute risks of seroconversion after the first and second doses of a covid-19 vaccine. Systematic review without meta-analysis of SARS-CoV-2 antibody titre levels was performed after first, second, and third vaccine doses and the seroconversion rate after a third dose. Risk of bias and certainty of evidence were assessed. RESULTS: 82 studies were included in the meta-analysis. Of these studies, 77 (94%) used mRNA vaccines, 16 (20%) viral vector vaccines, and 4 (5%) inactivated whole virus vaccines. 63 studies were assessed to be at low risk of bias and 19 at moderate risk of bias. After one vaccine dose, seroconversion was about half as likely in patients with haematological cancers (risk ratio 0.40, 95% confidence interval 0.32 to 0.50, I2=80%; absolute risk 0.29, 95% confidence interval 0.20 to 0.40, I2=89%), immune mediated inflammatory disorders (0.53, 0.39 to 0.71, I2=89%; 0.29, 0.11 to 0.58, I2=97%), and solid cancers (0.55, 0.46 to 0.65, I2=78%; 0.44, 0.36 to 0.53, I2=84%) compared with immunocompetent controls, whereas organ transplant recipients were 16 times less likely to seroconvert (0.06, 0.04 to 0.09, I2=0%; 0.06, 0.04 to 0.08, I2=0%). After a second dose, seroconversion remained least likely in transplant recipients (0.39, 0.32 to 0.46, I2=92%; 0.35, 0.26 to 0.46), with only a third achieving seroconversion. Seroconversion was increasingly likely in patients with haematological cancers (0.63, 0.57 to 0.69, I2=88%; 0.62, 0.54 to 0.70, I2=90%), immune mediated inflammatory disorders (0.75, 0.69 to 0.82, I2=92%; 0.77, 0.66 to 0.85, I2=93%), and solid cancers (0.90, 0.88 to 0.93, I2=51%; 0.89, 0.86 to 0.91, I2=49%). Seroconversion was similar between people with HIV and immunocompetent controls (1.00, 0.98 to 1.01, I2=0%; 0.97, 0.83 to 1.00, I2=89%). Systematic review of 11 studies showed that a third dose of a covid-19 mRNA vaccine was associated with seroconversion among vaccine non-responders with solid cancers, haematological cancers, and immune mediated inflammatory disorders, although response was variable in transplant recipients and inadequately studied in people with HIV and those receiving non-mRNA vaccines. CONCLUSION: Seroconversion rates after covid-19 vaccination were significantly lower in immunocompromised patients, especially organ transplant recipients. A second dose was associated with consistently improved seroconversion across all patient groups, albeit at a lower magnitude for organ transplant recipients. Targeted interventions for immunocompromised patients, including a third (booster) dose, should be performed. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021272088.

Manipulating NK cellular therapy from cancer to invasive fungal infection: promises and challenges.

The ideal strategy to fight an infection involves both (i) weakening the invading pathogen through conventional antimicrobial therapy, and (ii) strengthening defense through the augmentation of host immunity. This is even more pertinent in the context of invasive fungal infections whereby the majority of patients have altered immunity and are unable to mount an appropriate host response against the pathogen. Natural killer (NK) cells fit the requirement of an efficient, innate executioner of both tumour cells and pathogens - their unique, targeted cell killing mechanism, combined with other arms of the immune system, make them potent effectors. These characteristics, together with their ready availability (given the various sources of extrinsic NK cells available for harvesting), make NK cells an attractive choice as adoptive cellular therapy against fungi in invasive infections. Improved techniques in ex vivo NK cell activation with expansion, and more importantly, recent advances in genetic engineering including state-of-the-art chimeric antigen receptor platform development, have presented an opportune moment to harness this novel therapeutic as a key component of a multipronged strategy against invasive fungal infections.

A Novel X-Linked Inhibitor of Apoptosis Deficient Variant Showing Attenuated Epstein-Barr Virus Response.

We report on 2 Asian siblings with X-linked inhibitor of apoptosis deficiency that arose from a novel deletion that presented with Epstein-Barr virus disease and hemophagocytic lymphohistiocytosis. This disease is ascribed to dysfunction in the nucleotide binding and oligomerization domain receptor pathway, tested using a modified muramyl dipeptide-mediated assay.

Using Expanded Natural Killer Cells as Therapy for Invasive Aspergillosis.

Invasive aspergillosis (IA) is a major opportunistic fungal infection in patients with haematological malignancies. Morbidity and mortality rates are high despite anti-fungal treatment, as the compromised status of immune system prevents the host from responding optimally to conventional therapy. This raises the consideration for immunotherapy as an adjunctive treatment. In this study, we evaluated the utility of expanded human NK cells as treatment against Aspergillus fumigatus infection in vitro and in vivo. The NK cells were expanded and activated by K562 cells genetically modified to express 4-1BB ligand and membrane-bound interleukin-15 (K562-41BBL-mbIL-15) as feeders. The efficacy of these cells was investigated in A. fumigatus killing assays in vitro and as adoptive cellular therapy in vivo. The expanded NK cells possessed potent killing activity at low effector-to-target ratio of 2:1. Fungicidal activity was morphotypal-dependent and most efficacious against A. fumigatus conidia. Fungicidal activity was mediated by dectin-1 receptors on the expanded NK cells leading to augmented release of perforin, resulting in enhanced direct cytolysis. In an immunocompromised mice pulmonary aspergillosis model, we showed that NK cell treatment significantly reduced fungal burden, hence demonstrating the translational potential of expanded NK cells as adjunctive therapy against IA in immunocompromised patients.

Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial.

Importance: Remdesivir demonstrated clinical benefit in a placebo-controlled trial in patients with severe coronavirus disease 2019 (COVID-19), but its effect in patients with moderate disease is unknown. Objective: To determine the efficacy of 5 or 10 days of remdesivir treatment compared with standard care on clinical status on day 11 after initiation of treatment. Design, Setting, and Participants: Randomized, open-label trial of hospitalized patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and moderate COVID-19 pneumonia (pulmonary infiltrates and room-air oxygen saturation >94%) enrolled from March 15 through April 18, 2020, at 105 hospitals in the United States, Europe, and Asia. The date of final follow-up was May 20, 2020. Interventions: Patients were randomized in a 1:1:1 ratio to receive a 10-day course of remdesivir (n = 197), a 5-day course of remdesivir (n = 199), or standard care (n = 200). Remdesivir was dosed intravenously at 200 mg on day 1 followed by 100 mg/d. Main Outcomes and Measures: The primary end point was clinical status on day 11 on a 7-point ordinal scale ranging from death (category 1) to discharged (category 7). Differences between remdesivir treatment groups and standard care were calculated using proportional odds models and expressed as odds ratios. An odds ratio greater than 1 indicates difference in clinical status distribution toward category 7 for the remdesivir group vs the standard care group. Results: Among 596 patients who were randomized, 584 began the study and received remdesivir or continued standard care (median age, 57 [interquartile range, 46-66] years; 227 [39%] women; 56% had cardiovascular disease, 42% hypertension, and 40% diabetes), and 533 (91%) completed the trial. Median length of treatment was 5 days for patients in the 5-day remdesivir group and 6 days for patients in the 10-day remdesivir group. On day 11, patients in the 5-day remdesivir group had statistically significantly higher odds of a better clinical status distribution than those receiving standard care (odds ratio, 1.65; 95% CI, 1.09-2.48; P = .02). The clinical status distribution on day 11 between the 10-day remdesivir and standard care groups was not significantly different (P = .18 by Wilcoxon rank sum test). By day 28, 9 patients had died: 2 (1%) in the 5-day remdesivir group, 3 (2%) in the 10-day remdesivir group, and 4 (2%) in the standard care group. Nausea (10% vs 3%), hypokalemia (6% vs 2%), and headache (5% vs 3%) were more frequent among remdesivir-treated patients compared with standard care. Conclusions and Relevance: Among patients with moderate COVID-19, those randomized to a 10-day course of remdesivir did not have a statistically significant difference in clinical status compared with standard care at 11 days after initiation of treatment. Patients randomized to a 5-day course of remdesivir had a statistically significant difference in clinical status compared with standard care, but the difference was of uncertain clinical importance. Trial Registration: ClinicalTrials.gov Identifier: NCT04292730.

Glycolysis and Oxidative Phosphorylation Play Critical Roles in Natural Killer Cell Receptor-Mediated Natural Killer Cell Functions.

Natural killer (NK) cells are innate lymphocytes that directly kill tumor and pathogen-infected cells upon activation by cytokines and NK cell receptors (NKRs) without previous sensitization. It is known that cell metabolism affects the differentiation and effector functions of immune cells. For instance, interleukin-2 and interleukin-15 treatment increases glycolysis and oxidative phosphorylation (OXPHOS) in NK cells to support their effector functions. However, little is known about the metabolic reprogramming of human NK cells upon their activation by NKRs. In this study, we investigated the metabolism of NK cells stimulated via NKRs. We found that NK cells upregulated glycolysis and OXPHOS in response to anti-CD16 antibody or NKG2D ligand engagement. Inhibition of either glycolysis or OXPHOS impaired NK cell production of interferon-γ. Interestingly, inhibition of glycolysis but not OXPHOS decreased NK cell killing and dampened NK cell degranulation and Fas ligand expression, suggesting that glycolysis is more critical for NKR-activated cell cytotoxicity. Thus, our study provides insight into understanding the metabolic requirements underlying different effector functions of human NK cells.

Immunomodulation as Therapy for Fungal Infection: Are We Closer?

Invasive fungal disease (IFD) causes significant morbidity in immunocompromised patients due to their weakened immune system. Immunomodulatory therapy, in synergy with existing antifungal therapy, is an attractive option to enhance their immune system and aid clearance of these opportunistic pathogens. From a scientific and clinical perspective, we explore the immunotherapeutic options to augment standard antifungal drugs for patients with an IFD. We discuss the range of immunomodulatory therapies being considered in IFD - from cytokines, including G-CSF, GM-CSF, M-CSF, IFN-γ, and cytokine agonists, to cellular therapies, consisting of granulocyte transfusion, adoptive T-cell, CAR T-cell, natural killer cell therapies, and monoclonal antibodies. Adjunct pharmaceutical agents which augment the immunity are also being considered. Lastly, we explore the likelihood of the use of probiotics and manipulation of the microbiome/mycobiome to enhance IFD treatment outcomes.

Network Meta-analysis and Pharmacoeconomic Evaluation of Fluconazole, Itraconazole, Posaconazole, and Voriconazole in Invasive Fungal Infection Prophylaxis.

Invasive fungal infections (IFIs) are associated with high mortality rates and large economic burdens. Triazole prophylaxis is used for at-risk patients with hematological malignancies or stem cell transplants. We evaluated both the efficacy and the cost-effectiveness of triazole prophylaxis. A network meta-analysis (NMA) of randomized controlled trials (RCTs) evaluating fluconazole, itraconazole capsule and solution, posaconazole, and voriconazole was conducted. The outcomes of interest included the incidences of IFIs and deaths. This was coupled with a cost-effectiveness analysis from patient perspective over a lifetime horizon. Probabilities of transitions between health states were derived from the NMA. Resource use and costs were obtained from the Singapore health care institution. Data on 5,505 participants in 21 RCTs were included. Other than itraconazole capsule, all triazole antifungals were effective in reducing IFIs. Posaconazole was better than fluconazole (odds ratio [OR], 0.35 [95% confidence interval [CI], 0.16 to 0.73]) and itraconazole capsule (OR, 0.25 [95% CI, 0.06 to 0.97]), but not voriconazole (OR, 1.31 [95% CI, 0.43 to 4.01]), in preventing IFIs. Posaconazole significantly reduced all-cause deaths, compared to placebo, fluconazole, and itraconazole solution (OR, 0.49 to 0.54 [95% CI, 0.28 to 0.88]). The incremental cost-effectiveness ratio for itraconazole solution was lower than that for posaconazole (Singapore dollars [SGD] 12,546 versus SGD 26,817 per IFI avoided and SGD 5,844 versus SGD 12,423 per LY saved) for transplant patients. For leukemia patients, itraconazole solution was the dominant strategy. Voriconazole was dominated by posaconazole. All triazole antifungals except itraconazole capsule were effective in preventing IFIs. Posaconazole was more efficacious in reducing IFIs and all-cause deaths than were fluconazole and itraconazole. Both itraconazole solution and posaconazole were cost-effective in the Singapore health care setting.

Necrotizing Fasciitis in Hematological Patients: Enterobacteriaceae Predominance and Limited Utility of Laboratory Risk Indicator for Necrotizing Fasciitis Score.

Immune suppression is a recognized risk factor for necrotizing fasciitis. In patients with hematological malignancies, a profoundly immunocompromised group, the predominant causative organisms are Gram negative. Clinical presentation and outcomes in these patients are similar to the immunocompetent. The Laboratory Risk Indicator for Necrotizing Fasciitis score is not reliable for risk stratification of the disease.

Voriconazole or amphotericin B as primary therapy yields distinct early serum galactomannan trends related to outcomes in invasive aspergillosis.

An improved number of anti-fungal drugs are currently available for the treatment of invasive aspergillosis (IA). While serial galactomannan index (GMI) measurement can be used to monitor response to treatment, the extent to which different anti-fungal regimens can affect galactomannan levels is unknown. In 147 IA patients receiving either voriconazole (VCZ) or conventional amphotericin B (CAB) in a multicentre clinical trial, we performed post-hoc analyses of GMI trends in relation to outcomes. The generalized estimation equations approach was used to estimate changes in the effect size for GMI over time within patients. Patients who received VCZ primary therapy and had good treatment response 12 weeks later showed earlier decreases in GMI values at Week 1 and Week 2 (p = 0.001 and 0.046 respectively) as compared to patients who only received CAB. At end-of-randomized therapy (EORT), which was a pre-set secondary assessment point for all patients who switched from randomized primary (CAB or VCZ) to an alternative anti-fungal drug, treatment failure was associated with increasing GMI at Weeks 1 and 2 in CAB-primary treated patients (p = 0.022 and 0.046 respectively). These distinct trends highlight the variations in GMI kinetics with the use of different anti-fungal drugs and their implications in relation to IA treatment response.

Recent advances in invasive pulmonary aspergillosis.

PURPOSE OF REVIEW: This review highlights the most important and salient recent developments with regards to invasive pulmonary aspergillosis (IPA), currently the most common opportunistic fungal pneumonia in patients with hematological malignancies. RECENT FINDINGS: Besides patients in hematology units, other immunosuppressed and critically ill patients are also at risk of IPA. Identification of patients who possess specific polymorphisms of Toll-like receptor 4 and dectin-1, both of which are involved in the immune sensing of Aspergillus spp., may facilitate risk-stratification. The use of the galactomannan assay in bronchoalveolar fluid to improve diagnosis of IPA is undergoing validation. Trending galactomannan and other biomarker results may prognosticate clinical outcomes. During intensive chemotherapy for leukemia, posaconazole and aerosolized liposomal amphotericin B (L-AMB) have demonstrated efficacy as prophylaxis against invasive fungal infection. However, fluconazole remains an effective prophylactic agent in the setting of hematopoietic stem cell transplantation despite availability of newer antifungal agents. Although voriconazole is still the drug of choice for IPA, both caspofungin and L-AMB are viable alternatives. SUMMARY: Despite increasing knowledge of IPA and availability of newer antifungal agents, clinical management remains a challenge in the setting of a compromised host defense system that is unable to mount an appropriate immune response against the pathogen.