CXCL17 is a Prognostic Biomarker That Distinguishes Severe Pandemic InfluenzaA(H1N1) from COVID-19 (preprint)

BackgroundCXCL17 is chemotactic for myeloid cells, exhibits broad-spectrum bactericidal activity, and is expressed in mucosal tissues. This chemokine is constitutively expressed in the respiratory tract, suggesting a role for CXCL17 in lung defenses. However, little is known about the possible participation of CXCL17 during respiratory infections in humans. Here, we evaluated the role of CXCL17 as a biomarker in patients with severe pandemic influenza A(H1N1) and coronavirus disease 2019 (COVID-19). MethodsWe conducted a prospective cohort study in hospitalized patients with severe influenza A(H1N1) and COVID-19 admitted to two national reference centers in Mexico City. Peripheral blood samples were obtained on admission for determinations of the serum levels of CXCL17 by enzyme-linked immunosorbent assay (ELISA). The expression of CXCL17 in lung autopsy specimens from patients that succumbed to both diseases was assessed by immunohistochemistry (IHQ). Serum CXCL17 levels were compared between patients grouped according to their disease and clinical outcome. The diagnostic and predictive value of serum CXCL17 levels was evaluated using machine-learning algorithms and regression analyses. ResultsA total of 92 patients were enrolled in the study, from which 68 were infected with influenza and 24 had COVID-19. Their clinical characteristics were similar, although dyspnea, rhinorrhea, and sputum production were more common during influenza, whereas dry cough and vomit were more frequent among COVID-19 patients. Both diseases induced the local expression of CXCL17 in the lung. However, serum levels of CXCL17 were increased only in patients with influenza but not COVID-19. CXCL17 not only differentiates influenza from COVID-19 but serves as a prognostic biomarker associated with mortality and renal failure in influenza patients. Using cell culture assays, we also identified that human alveolar A549 cells and peripheral blood monocyte-derived macrophages produce CXCL17 after influenza A(H1N1) pdm09 virus infection. ConclusionsOur results suggest a possible role for CXCL17 in the pathogenesis of influenza A(H1N1), supporting the use of this molecule as a prognostic biomarker. Future studies on the role of CXCL17 in COVID-19 are warranted.  

Clinical Risk Factors for Mortality Among Critically ill Mexican Patients With COVID-19 (preprint)

BackgroundLittle literature exists about the experience with critically ill COVID-19 patients from Latin America, despite this is the current epicenter of the pandemic. Here, we aimed to describe the clinical characteristics and risk factors for mortality in mechanically-ventilated COVID-19 patients from Mexico.  MethodsClinical data from sixty-seven consecutive, mechanically-ventilated COVID-19 patients were analyzed. Patients were grouped according to their clinical outcome (survival vs. death). Clinical risk factors for mortality were identified by machine-learning algorithms and traditional regression analyses. ResultsThe median age of study participants was 42 years and 65% were men. The most common comorbidity observed in our study was obesity (49.2%). Fever was the most frequent symptom of illness (88%), followed by dyspnea (84%), and cough (62%). Multilobe ground-glass opacities were observed in 76% of patients by thoracic CT scan. Fifty-two percent of study participants were ventilated in prone position, and 59% required cardiovascular support with norepinephrine. Furthermore, 49% of participants had a coinfection with a second pathogen. Two-thirds of COVID-19 patients developed acute kidney injury (AKIN). Thirty deaths occurred during the study (44.7%). Levels of uric acid, creatinine, bilirubin, and SOFA score, were significantly higher among deceased patients, whereas survivors showed higher PaO2/FiO2 values at admission. AKIN, uric acid, LDH, and a longitudinal increase in ventilatory ratio were associated with mortality. Baseline PaO2/FiO2 values and a longitudinal recovery of lymphocytes were protective factors against mortality.ConclusionsOur study provides reference data about the clinical phenotype and risk factors for COVID-19-assocaited mortality among mechanically-ventilated Mexican patients.

Clinical and immunological factors that distinguish COVID-19 from pandemic influenza A(H1N1) (preprint)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is a global health threat with the potential to cause severe disease manifestations in the lungs. Although clinical descriptions of COVID-19 are currently available, the factors distinguishing SARS-CoV-2 from other respiratory viruses are unknown. Here, we compared the clinical, histopathological, and immunological characteristics of patients with COVID-19 and pandemic influenza A(H1N1). We observed a higher frequency of respiratory symptoms, increased tissue injury markers, a histological pattern of alveolar pneumonia, and higher levels of IL-1RA, TNF-, CCL3, G-CSF, APRIL, sTNF-R1, sTNF-R2, sCD30, and sCD163 in influenza patients. Conversely, dry cough, gastrointestinal symptoms, interstitial lung pathology, increased Th1 (IL-12, IFN-{gamma}) and Th2 (IL-4, IL-5, IL-10, IL-13) cytokine levels, along with IL-1{beta}, IL-6, CCL11, VEGF, TWEAK, TSLP, MMP-1, and MMP-3, were observed in COVID-19 cases. We demonstrated the diagnostic potential of some clinical and immune factors to differentiate COVID-19 from pandemic influenza A(H1N1). Our data suggest that SARS-CoV-2 induces a dysbalanced polyfunctional inflammatory response that is different from the immune response against influenza. These findings might be relevant for the upcoming 2020-2021 influenza season, which is projected to be historically unique due to its convergence with COVID-19.

IFN signaling and neutrophil degranulation transcriptional signatures are induced during SARS-CoV-2 infection (preprint)

The novel virus SARS-CoV-2 has infected more than 14 million people worldwide resulting in the Coronavirus disease 2019 (COVID-19). Limited information on the underlying immune mechanisms that drive disease or protection during COVID-19 severely hamper development of therapeutics and vaccines. Thus, the establishment of relevant animal models that mimic the pathobiology of the disease is urgent. Rhesus macaques infected with SARS-CoV-2 exhibit disease pathobiology similar to human COVID-19, thus serving as a relevant animal model. In the current study, we have characterized the transcriptional signatures induced in the lungs of juvenile and old rhesus macaques following SARS-CoV-2 infection. We show that genes associated with Interferon (IFN) signaling, neutrophil degranulation and innate immune pathways are significantly induced in macaque infected lungs, while pathways associated with collagen formation are downregulated. In COVID-19, increasing age is a significant risk factor for poor prognosis and increased mortality. We demonstrate that Type I IFN and Notch signaling pathways are significantly upregulated in lungs of juvenile infected macaques when compared with old infected macaques. These results are corroborated with increased peripheral neutrophil counts and neutrophil lymphocyte ratio in older individuals with COVID-19 disease. In contrast, pathways involving VEGF are downregulated in lungs of old infected macaques. Using samples from humans with SARS-CoV-2 infection and COVID-19, we validate a subset of our findings. Finally, neutrophil degranulation, innate immune system and IFN gamma signaling pathways are upregulated in both tuberculosis and COVID-19, two pulmonary diseases where neutrophils are associated with increased severity. Together, our transcriptomic studies have delineated disease pathways to improve our understanding of the immunopathogenesis of COVID-19 to facilitate the design of new therapeutics for COVID-19.