Assessment of Broadly Reactive Responses in Patients With MERS-CoV Infection and SARS-CoV-2 Vaccination

Importance: In the ongoing COVID-19 pandemic, there remain unanswered questions regarding the nature and importance of the humoral immune response against other coronaviruses. Although coinfection of the Middle East respiratory syndrome coronavirus (MERS-CoV) with the SARS-CoV-2 has not been documented yet, several patients previously infected with MERS-CoV received the COVID-19 vaccine; data describing how preexisting MERS-CoV immunity may shape the response to SARS-CoV-2 following infection or vaccination are lacking. Objective: To characterize the cross-reactive and protective humoral responses in patients exposed to both MERS-CoV infection and SARS-CoV-2 vaccination. Design, Setting, and Participants: This cohort study involved a total of 18 sera samples collected from 14 patients with MERS-CoV infection before (n = 12) and after (n = 6) vaccination with 2 doses of COVID-19 mRNA vaccine (BNT162b2 or mRNA-1273). Of those patients, 4 had prevaccination and postvaccination samples. Antibody responses to SARS-CoV-2 and MERS-CoV were assessed as well as cross-reactive responses to other human coronaviruses. Main Outcomes and Measures: The main outcomes measured were binding antibody responses, neutralizing antibodies, and antibody-dependent cellular cytotoxicity (ADCC) activity. Binding antibodies targeting SARS-CoV-2 main antigens (spike [S], nucleocapsid, and receptor-binding domain) were detected using automated immunoassays. Cross-reactive antibodies with the S1 protein of SARS-CoV, MERS-CoV, and common human coronaviruses were analyzed using a bead-based assay. Neutralizing antibodies (NAbs) against MERS-CoV and SARS-CoV-2 as well as ADCC activity against SARS-CoV-2 were assessed. Results: A total of 18 samples were collected from 14 male patients with MERS-CoV infection (mean [SD] age, 43.8 [14.6] years). Median (IQR) duration between primary COVID-19 vaccination and sample collection was 146 (47-189) days. Prevaccination samples had high levels of anti-MERS S1 immunoglobin M (IgM) and IgG (reactivity index ranging from 0.80 to 54.7 for IgM and from 0.85 to 176.3 for IgG). Cross-reactive antibodies with SARS-CoV and SARS-CoV-2 were also detected in these samples. However, cross-reactivity against other coronaviruses was not detected by the microarray assay. Postvaccination samples showed significantly higher levels of total antibodies, IgG, and IgA targeting SARS-CoV-2 S protein compared with prevaccination samples (eg, mean total antibodies: 8955.0 AU/mL; 95% CI, -5025.0 to 22936.0 arbitrary units/mL; P =.002). In addition, significantly higher anti-SARS S1 IgG levels were detected following vaccination (mean reactivity index, 55.4; 95% CI, -9.1 to 120.0; P =.001), suggesting potential cross-reactivity with these coronaviruses. Also, anti-S NAbs were significantly boosted against SARS-CoV-2 (50.5% neutralization; 95% CI, 17.6% to 83.2% neutralization; P <.001) after vaccination. Furthermore, there was no significant increase in antibody-dependent cellular cytotoxicity against SARS-CoV-2 S protein postvaccination. Conclusions and Relevance: This cohort study found a significant boost in cross-reactive NAbs in some patients exposed to MERS-CoV and SARS-CoV-2 antigens. These findings suggest that isolation of broadly reactive antibodies from these patients may help guide the development of a pancoronavirus vaccine by targeting cross-reactive epitopes between distinct strains of human coronaviruses..This work was supported by internal funds from the Biomedical Research Center of Qatar University. Dr Nasrallah received funding from The WHO Eastern Mediterranean Regional Office (WHO-EMRO) Special Grant for COVID-19 Research

Coronavirus Disease 2019 Disease Severity in Children Infected With the Omicron Variant

SHORT SUMMARY: Severe acute respiratory syndrome coronavirus 2 infection from the Omicron variant in children/adolescents is less severe than infection from the Delta variant. Those 6 to <18 years also have less severe disease than those <6 years old. BACKGROUND: There are limited data assessing coronavirus 2019 (COVID-19) disease severity in children/adolescents infected with the Omicron variant. METHODS: We identified children and adolescents <18 years of age with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with Delta and propensity score-matched controls with Omicron variant infection from the National COVID-19 Database in Qatar. Primary outcome was disease severity, determined by hospital admission, admission to the intensive care unit (ICU), or mechanical ventilation within 14 days of diagnosis, or death within 28 days. RESULTS: Among 1735 cases with Delta variant infection between 1 June and 6 November 2021, and 32 635 cases with Omicron variant infection between 1 January and 15 January 2022, who did not have prior infection and were not vaccinated, we identified 985 propensity score-matched pairs. Among those who were Delta infected, 84.2% had mild, 15.7% had moderate, and 0.1% had severe/critical disease. Among those who were Omicron infected, 97.8% had mild, 2.2% had moderate, and none had severe/critical disease (P < .001). Omicron variant infection (vs Delta) was associated with significantly lower odds of moderate or severe/critical disease (adjusted odds ratio [AOR], 0.12; 95% confidence interval [CI], .07-.18). Those aged 6-11 and 12 to <18 years had lower odds of developing moderate or severe/critical disease compared with those younger than age 6 years (aOR, 0.47; 95% CI, .33-.66 for 6-11 year olds; aOR, 0.45; 95% CI, .21-.94 for 12 to <18 year olds). CONCLUSIONS: Omicron variant infection in children/adolescents is associated with less severe disease than Delta variant infection as measured by hospitalization rates and need for ICU care or mechanical ventilation. Those 6 to <18 years of age also have less severe disease than those <6 years old

COVID-19 infection in adult patients with hematological malignancies: a European Hematology Association Survey (EPICOVIDEHA)

Background: Patients with hematological malignancies (HM) are at high risk of mortality from SARS-CoV-2 disease 2019 (COVID-19). A better understanding of risk factors for adverse outcomes may improve clinical management in these patients. We therefore studied baseline characteristics of HM patients developing COVID-19 and analyzed predictors of mortality. Methods: The survey was supported by the Scientific Working Group Infection in Hematology of the European Hematology Association (EHA). Eligible for the analysis were adult patients with HM and laboratory-confirmed COVID-19 observed between March and December 2020. Results: The study sample includes 3801 cases, represented by lymphoproliferative (mainly non-Hodgkin lymphoma n = 1084, myeloma n = 684 and chronic lymphoid leukemia n = 474) and myeloproliferative malignancies (mainly acute myeloid leukemia n = 497 and myelodysplastic syndromes n = 279). Severe/critical COVID-19 was observed in 63.8% of patients (n = 2425). Overall, 2778 (73.1%) of the patients were hospitalized, 689 (18.1%) of whom were admitted to intensive care units (ICUs). Overall, 1185 patients (31.2%) died. The primary cause of death was COVID-19 in 688 patients (58.1%), HM in 173 patients (14.6%), and a combination of both COVID-19 and progressing HM in 155 patients (13.1%). Highest mortality was observed in acute myeloid leukemia (199/497, 40%) and myelodysplastic syndromes (118/279, 42.3%). The mortality rate significantly decreased between the first COVID-19 wave (March–May 2020) and the second wave (October–December 2020) (581/1427, 40.7% vs. 439/1773, 24.8%, p value < 0.0001). In the multivariable analysis, age, active malignancy, chronic cardiac disease, liver disease, renal impairment, smoking history, and ICU stay correlated with mortality. Acute myeloid leukemia was a higher mortality risk than lymphoproliferative diseases. Conclusions: This survey confirms that COVID-19 patients with HM are at high risk of lethal complications. However, improved COVID-19 prevention has reduced mortality despite an increase in the number of reported cases.EPICOVIDEHA has received funds from Optics COMMITTM (COVID-19 Unmet Medical Needs and Associated Research Extension) COVID-19 RFP program by GILEAD Science, United States (Project 2020-8223)

Phylogenetic analysis reveals two genotypes of the emerging fungus <i>Mucor indicus,</i> an opportunistic human pathogen in immunocompromised patients

Mucormycosis is a rare fungal infection caused by Mucor indicus. Phylogenetic analysis of many M. indicus isolates, mainly sampled from different clinical and environmental specimens collected worldwide, revealed two genotypes, I and II, based on ITS and D1/D2 LSU rDNA sequences. A retrospective review of the literature revealed 13 cases. Eight (76.9 patients had disseminated infections, and the overall mortality rate was 30.7 A pulmonary infection caused by M. indicus genotype I in a liver transplant recipient was disseminated to include the skin and was successfully treated with liposomal amphotericin B and aggressive surgery. M. indicus can infect a wide variety of patients with no real preference for the site of infection. We concluded that M. indicus has emerged as a significant cause of invasive mycosis in severely immunocompromised patients worldwide. Early diagnosis and initiation of appropriate therapy could enhance survival in these immunocompromised patient populations

Fatal Coronavirus Disease 2019-associated Pulmonary Aspergillosis; A Report of Two Cases and Review of the Literature

Coronavirus Disease 2019 (COVID-19)-associated pulmonary aspergillosis is an emerging entity. We report two fatal cases of putative COVID-19-associated pulmonary aspergillosis. Both cases were diagnosed on the basis of respiratory tract cultures yielding Aspergillus species and otherwise unexplained clinical and radiological deterioration. Existing published literature on COVID-19-associated pulmonary aspergillosis indicate poor outcomes and high mortality. CAPA should be considered in patients with critical COVID-19 who have unexplained progressive respiratory failure despite optimized supportive care. Diagnostic work-up should be initiated as early as possible and should ideally include fungal cultures, galactomannan detection and Aspergillus PCR on tracheal aspirates or broncho-alveolar lavage fluid. Empiric systemic antifungal therapy may be justified in selected cases, pending diagnostic work up results. Large, multi-center studies are required to further understand the pathogenesis of invasive aspergillosis in COVID-19, and the optimal diagnostic and treatment strategies

The Emergence of Rare Clinical Aspergillus Species in Qatar: Molecular Characterization and Antifungal Susceptibility Profiles

Aspergillus are ubiquitous mold species that infect immunocompetent and immunocompromised patients. The symptoms are diverse and range from allergic reactions, bronchopulmonary infection, and bronchitis, to invasive aspergillosis. The aim of this study was to characterize 70 Aspergillus isolates recovered from clinical specimens of patients with various clinical conditions presented at Hamad general hospital in Doha, Qatar, by using molecular methods and to determine their in vitro antifungal susceptibility patterns using the Clinical and Laboratory Standards Institute (CLSI) M38-A2 reference method. Fourteen Aspergillus species were identified by sequencing β-tubulin and calmodulin genes, including 10 rare and cryptic species not commonly recovered from human clinical specimens. Aspergillus welwitschiae is reported in this study for the first time in patients with fungal rhinosinusitis (n = 6) and one patient with a lower respiratory infection. Moreover, Aspergillus pseudonomius is reported in a patient with fungal rhinosinusitis which is considered as the first report ever from clinical specimens. In addition, Aspergillus sublatus is reported for the first time in a patient with cystic fibrosis. In general, our Aspergillus strains exhibited low MIC values for most of the antifungal drugs tested. One strain of Aspergillus fumigatus showed high MECs for echinocandins and low MICs for the rest of the drugs tested. Another strain of A. fumigatus exhibited high MIC for itraconazole and categorized as non-wild type. These findings require further analysis of their molecular basis of resistance. In conclusion, reliable identification of Aspergillus species is achieved by using molecular sequencing, especially for the emerging rare and cryptic species. They are mostly indistinguishable by conventional methods and might exhibit variable antifungal susceptibility profiles. Moreover, investigation of the antifungal susceptibility patterns is necessary for improved antifungal therapy against aspergillosis

Epidemiology of candidemia in Qatar, the Middle East: performance of MALDI-TOF MS for the identification of Candida species, species distribution, outcome, and susceptibility pattern

Item does not contain fulltextINTRODUCTION: Bloodstream infections (BSIs) due to Candida spp. constitute the predominant group of hospital-based fungal infections worldwide. A retrospective study evaluated the performance of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) for the identification of BSI Candida isolates. The epidemiology, risk factors, demographic features, species distribution, and clinical outcome associated with candidemia in patients admitted to a single tertiary-care hospital in Qatar, were analyzed. METHODS: A single-center, retrospective analysis covering the period from January 1, 2004 to December 31, 2010 was performed. Molecular identification used sequence analysis of the D1/D2 domains of the large subunit ribosomal DNA (LSU rDNA) and the ITS1/2 regions of the rDNA. MALDI-TOF MS-based identification of all yeast isolates was performed with the ethanol/formic acid extraction protocol according to Bruker Daltonics (Bremen, Germany). The susceptibility profiles of 201 isolates to amphotericin B, itraconazole, fluconazole, voriconazole, anidulafungin, caspofungin, posaconazole, and isavuconazole were tested using CLSI standard broth microdilution method (M27-A3 and M27 S4) guidelines. Statistical analyses were performed with the statistical package SPSS 19.0. RESULTS: A total of 187 patients with 201 episodes of candidemia were identified. Candida albicans was the most common species isolated (33.8 %; n = 68), whereas non-albicans Candida species represented 66.2 % (n = 133) of the episodes. The species distribution and outcome of candidemia showed a difference in the crude mortality between patients infected with C. albicans (n = 30; 45.5 %) and non-albicans Candida species. For example, C. parapsilosis candidemia was associated with the lowest mortality rate (40.6 %), and patients with other non-albicans species had the highest mortality rate (68-71.4 %). High mortality rates were observed among pediatric (60 years of age). All strains showed low minimum inhibitory concentrations (MICs) (MIC90 of 0.063 mug/ml) to isavuconazole. The overall resistance to voriconazole in vitro antifungal activity was 2.5 %. C. glabrata (n = 38) had an MIC90 of 8 mug/ml for fluconazole. Most yeast isolates were susceptible to anidulafungin (>99.5 %) and 81.1 % to caspofungin. Resistance to anidulafungin was detected in 1/8 (12.5 %) isolates of C. orthopsilosis. According to new Clinical and Laboratory Standards Institute (CLSI) breakpoints, C. glabrata (n = 38) showed 100 % resistance, and 37/68 (54.4 %) C. albicans isolates were susceptible dose dependent (SDD) to caspofungin. Identification by MALDI-TOF MS was in 100 % concordance with molecular identification. CONCLUSION: The Middle East epidemiology of candidemia has a unique species distribution pattern distinct from other parts of the globe. High mortality rates were observed among pediatric (60 years of age). All strains were susceptible to isavuconazole. All isolates of C.glabrata were resistant to caspofungin based on M27 S4. MALDI-TOF MS is a highly useful method for the routine identification of yeast isolates in clinical setting to achieve successful therapeutic treatment

Antibody-Dependent Enhancement (ADE) and the role of complement system in disease pathogenesis

Antibody-dependent enhancement (ADE) has been associated with severe disease outcomes in several viral infections, including respiratory infections. In vitro and in vivo studies showed that antibody-response to SARS-CoV and MERS-CoV could exacerbate infection via ADE. Recently in SARS CoV-2, the in vitro studies and structural analysis shows a risk of disease severity via ADE. This phenomenon is partially attributed to non-neutralizing antibodies or antibodies at sub-neutralizing levels. These antibodies result in antigen-antibody complexes' deposition and propagation of a chronic inflammatory process that destroys affected tissues. Further, antigen-antibody complexes may enhance the internalization of the virus into cells through the Fc gamma receptor (FcγR) and lead to further virus replication. Thus, ADE occur via two mechanisms; 1. Antibody mediated replication and 2. Enhanced immune activation. Antibody-mediated effector functions are mainly driven by complement activation, and the first complement in the cascade is complement 1q (C1q) which binds to the virus-antibody complex. Reports say that deficiency in circulating plasma levels of C1q, an independent predictor of mortality in high-risk patients, including diabetes, is associated with severe viral infections. Complement mediated ADE is reported in several viral infections such as dengue, West Nile virus, measles, RSV, Human immunodeficiency virus (HIV), and Ebola virus. This review discusses ADE in viral infections and the in vitro evidence of ADE in coronaviruses. We outline the mechanisms of ADE, emphasizing the role of complements, especially C1q in the outcome of the enhanced disease.Qatar National LibraryOpen access funding is provided by the Qatar National Library.Scopu

Phylogenetic diversity of human pathogenic Fusarium and emergence of uncommon virulent species

OBJECTIVES: Fusarium species cause a broad spectrum of infections. However, little is known about the etiological agents to the species level. We identified Fusarium species isolated from clinical specimens including those of high risk patients to better understand the species involved in the pathogenesis. METHODS: A set of 44 Fusarium isolates were identified by two-locus sequence typing using partial sequences of the second largest subunit of RNA polymerase (RPB2) and translation elongation factor 1 alpha (TEF-1α). RESULTS: The identified species belonged to four species complexes (SC); the most common SC was Fusarium solani (FSSC) (75%), followed by Fusarium oxysporum (FOSC) (4.5%), Fusarium fujikuroi (FFSC) (13.6%), and Fusarium dimerum (FDSC) (6.8%). Sites of infections were nails (n = 19, 43.2%), skin (n = 7, 15.9%), cornea (n = 6, 13.6%), blood (n = 3, 9%), wound (n = 4, 6.8%), burn (n = 2, 4.5%), tissue (n = 2, 4.5%), and urine (n = 1, 2.27%). Fusarium acutatum was rare and seem restricted to the Middle East. Comorbidities associated with invasive infections were hematological malignancy and autoimmune disorders. CONCLUSIONS: Members of the FSSC predominantly caused cornea, nail and bloodstream infections. Less frequently encountered were the FOSC, FFSC and FDSC. More accurate molecular identification of Fusarium species is important to predict therapeutic outcome and the emergence of these species