ABSTRACT
Hypermutator lineages of Pseudomonas aeruginosa arise frequently during the years of lung infection seen in patients with cystic fibrosis and bronchiectasis but are rare in the absence of structural lung disease. Since the onset of the COVID-19 pandemic, large numbers of patients have remained mechanically ventilated for extended periods of time. These patients are prone to acquire bacterial pathogens that persist for many weeks and have the opportunity to evolve within the pulmonary environment. However, little is known about what types of adaptations occur in these bacteria and whether these adaptations mimic those described in chronic infections. We describe a COVID-19 patient with a secondary Pseudomonas aeruginosa lung infection in which the causative bacterium persisted for >90 days. During the course of this infection, a hypermutator lineage of P. aeruginosa emerged and co-existed with a non-hypermutator lineage. Compared to the parental lineage, the hypermutator lineage evolved to be more extensively resistant to antibiotics, to change its type III secretion profile, and to grow more slowly. Genomic analyses of the hypermutator lineage identified numerous mutations, including in the mismatch repair gene mutL and other genes frequently mutated in individuals with cystic fibrosis. Together, these findings demonstrate that hypermutator phenotypes can emerge when clearance of P. aeruginosa fails to occur in typically acute infections such as ventilator-associated pneumonia and suggest that hypermutator lineages can affect patient treatments and outcomes.
ABSTRACT
BackgroundRecent surges in coronavirus 2019 disease (COVID-19) is attributed to the emergence of more transmissible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs). However, the relative severity of SARS-CoV-2 VOCs in children is unknown. MethodsThis retrospective single-center cohort study was performed at the Ann & Robert H. Lurie Childrens Hospital of Chicago, academic free-standing childrens hospital. We included all children [≤] 18 years-old diagnosed with COVID-19 between October 15th, 2020 and August 31st, 2021 and whose SARS-CoV-2 isolate was sequenced using the Illumina platform. For each patient sample, we identified the SARS-CoV-2 lineage, which was assigned to one of the following groups: Non-VOC, alpha VOC, beta VOC, gamma VOC, or delta VOC. We measured frequency of 5 markers of COVID-19 severity: hospitalization; COVID-19 pharmacologic treatment; respiratory support; intensive care unit admission; and severe disease as classified by the COVID-19 World Health Organization (WHO) Clinical Progression Scale (severe disease; score [≥] 6). A series of logistic regression models were fitted to estimate odds of each severity marker with each VOC (in comparison to non-VOCs), adjusting for COVID-19 community incidence and demographic and clinical co-variates. ResultsDuring the study period, 2,025 patients tested positive for SARS-CoV-2; 1,422 (70.2%) had sufficient viral load to permit sequencing. Among the 499 (35.1%) patients whose isolate was sequenced, median (inter-quartile range) age was 7 (1,12) years; 256 (51.3%) isolates were a VOC: 96 (37.5%) alpha, 38 (14.8%) gamma, and 119 (46.5%) delta. After adjusting for age, Black race, Hispanic ethnicity, high-risk medical conditions, and COVID-19 community incidence, neither alpha nor delta was associated with severe COVID-19. Gamma was independently associated with hospitalization (OR 5.9, 95% CI 1.6-21.5, p=0.007), respiratory support (OR 8.3, 95% CI 1.5-56.3, p=0.02), and severe disease as classified by the WHO Clinical Progression Scale (OR 7.7, 95% CI 1.0-78.1, p=0.05). ConclusionsCompared to non-VOC COVID-19 infections, the gamma VOC, but not the alpha or delta VOCs, was associated with increased severity. These data suggest that recent increased in pediatric COVID-19 hospitalizations are related to increased delta COVID-19 incidence rather than increased delta virulence in children.
ABSTRACT
The global effort to vaccinate people against SARS-CoV-2 in the midst of an ongoing pandemic has raised questions about the nature of vaccine breakthrough infections and the potential for vaccinated individuals to transmit the virus. These questions have become even more urgent as new variants of concern with enhanced transmissibility, such as Delta, continue to emerge. To shed light on how vaccine breakthrough infections compare with infections in immunologically naive individuals, we examined viral dynamics and infectious virus shedding through daily longitudinal sampling in a small cohort of adults infected with SARS-CoV-2 at varying stages of vaccination. The durations of both infectious virus shedding and symptoms were significantly reduced in vaccinated individuals compared with unvaccinated individuals. We also observed that breakthrough infections are associated with strong tissue compartmentalization and are only detectable in saliva in some cases. These data indicate that vaccination shortens the duration of time of high transmission potential, minimizes symptom duration, and may restrict tissue dissemination.
ABSTRACT
BackgroundWhile several demographic and clinical correlates of Coronavirus Disease 2019 (COVID-19) outcome have been identified, they remain imprecise tools for clinical management of disease. Furthermore, there are limited data on how these factors are associated with virological and immunological parameters over time. Methods and FindingsNasopharyngeal swabs and blood samples were longitudinally collected from a cohort of 58 hospitalized adults with COVID-19 in Chicago, Illinois between March 27 and June 9, 2020. Samples were assessed for SARS-CoV-2 viral load, viral genotype, viral diversity, and antibody titer. Demographic and clinical information, including patient blood tests and several composite measures of disease severity, were extracted from electronic health records. All parameters were assessed for association with three patient outcome groups: discharge without intensive care unit (ICU) admission (n = 23), discharge with ICU admission (n = 29), and COVID-19 related death (n = 6). Higher age, male sex, and higher body mass index (BMI) were significantly associated with ICU admission. At hospital admission, higher 4C Mortality scores and lactate dehydrogenase (LDH) levels were likewise associated with ICU admission. Longitudinal trends in Deterioration Index (DI) score, Modified Early Warning Score (MEWS), and serum neutrophil count were also associated with ICU admission, though only the retrospectively calculated median DI score was predictive of death. While viral load and genotype were not significantly associated with outcome in this study, viral load did correlate positively with C-reactive protein levels and negatively with D-dimer, lymphocyte count, and antibody titer. Intra-host viral genetic diversity resulted in changes in viral genotype in some participants over time, though intra-host evolution was not associated with outcome. A stepwise-generated multivariable model including BMI, lymphocyte count at admission, and neutrophil count at admission was sufficient to predict outcome with a 0.82 accuracy rate in this cohort. ConclusionsThese studies suggest that COVID-19 disease severity and poor outcomes among hospitalized patients are likely driven by dysfunctional host responses to infection and underlying co-morbid conditions rather than SARS-CoV-2 viral loads. Several parameters, including 4C mortality score, LDH levels, and DI score, were ultimately predictive of participant outcome and warrant further exploration in larger cohort studies for use in clinical management and risk assessment. Finally, the prevalence of intra-host diversity and viral evolution in hospitalized patients suggests a mechanism for population-level change, further emphasizing the need for effective antivirals to suppress viral replication and to avoid the emergence of new variants.
ABSTRACT
The emergence of new SARS-CoV-2 variants with enhanced transmissibility or decreased susceptibility to immune responses is a major threat to global efforts to end the coronavirus disease 2019 (COVID-19) pandemic. Disparities in viral genomic surveillance capabilities and efforts have resulted in gaps in our understanding of the viral population dynamics across the globe. Nigeria, despite having the largest population of any nation in Africa, has had relatively little SARS-CoV-2 sequence data made publicly available. Here we report the whole-genome sequences of 74 SARS-CoV-2 isolates collected from individuals in Oyo State, Nigeria in January 2021. Most isolates belonged to either the B.1.1.7 Alpha "variant of concern" or the B.1.525 Eta lineage, which is currently considered a "variant of interest" containing multiple spike protein mutations previously associated with enhanced transmissibility and possible immune escape. Nigeria has the highest reported frequency of the B.1.525 lineage globally with phylogenetic characteristics consistent with a recent monophyletic origin and rapid expansion. Spike protein from the B.1.525 lineage displayed both increased infectivity and decreased neutralization by convalescent sera compared to Spike proteins from other clades. These results, along with indications that the virus is outpacing the B.1.1.7 lineage in Nigeria, suggest that the B.1.525 lineage represents another "variant of concern" and further underline the importance of genomic surveillance in undersampled regions across the globe.
ABSTRACT
BackgroundThe rapid spread of SARS-CoV-2, the causative agent of Coronavirus disease 2019 (COVID- 19), has been accompanied by the emergence of distinct viral clades, though their clinical significance remains unclear. Here, we aimed to investigate the phylogenetic characteristics of SARS-CoV-2 infections in Chicago, Illinois and assess their relationship to clinical parameters. MethodsWe performed whole-genome sequencing of SARS-CoV-2 isolates collected from COVID-19 patients in a Chicago healthcare system in mid-March, 2020. Using these and other publicly available sequences, we performed phylogenetic, phylogeographic, and phylodynamic analyses. Patient data was assessed for correlations between demographic or clinical characteristics and virologic features. FindingsThe 88 SARS-CoV-2 genome sequences in our study separated into three distinct phylogenetic clades. Clade 1 was most closely related to viral sequences from New York, and showed evidence of rapid expansion across the US, while Clade 3 was most closely related to those in Washington state. Clade 2 was localized primarily to the Chicago area with limited evidence of expansion elsewhere. At the time of diagnosis, patients infected with Clade 1 viruses had significantly higher average viral loads in their upper airways relative to patients infected with Clade 2 viruses, independent of time to symptom onset and disease severity. InterpretationThese results show that multiple variants of SARS-CoV-2 are circulating in the Chicago area that differ in their relative viral loads in patient upper airways. These data suggest that differences in virus genotype impact viral load and may in turn influence viral transmission and spread. FundingDixon Family Translational Research Award, Northwestern University Clinical and Translational Sciences Institute (NUCATS), National Institute of Allergy and Infectious Diseases (NIAID)
