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2.
Eur Clin Respir J ; 10(1): 2174640, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36815942

RESUMO

Background: Patients hospitalized with COVID-19 are at significant risk for superimposed bacterial pneumonia. However, diagnosing superinfection is challenging due to its clinical resemblance to severe COVID-19. We therefore evaluated whether the immune biomarker, procalcitonin, could facilitate the diagnosis of bacterial superinfection. Methods: We retrospectively identified 185 patients hospitalized with severe COVID-19 who underwent lower respiratory culture; 85 had evidence of bacterial superinfection. Receiver operating characteristic curve and area under the curve (AUC) analyses were performed to assess the utility of procalcitonin for diagnosing superinfection. Results: This approach demonstrated that procalcitonin measured at the time of culture was incapable of distinguishing patients with bacterial infection (AUC, 0.52). The AUC not affected by exposure to antibiotics, treatment with immunomodulatory agents, or timing of procalcitonin measurement. Conclusion: Static measurement of procalcitonin does not aid in the diagnosis of superinfection in severe COVID-19.

3.
Artigo em Inglês | MEDLINE | ID: mdl-36483405

RESUMO

Among 124 older adults with advanced cancer who were hospitalized with pneumonia, 7.3% met criteria for postobstructive pneumonia. There were no differences in antibiotic duration, antibiotic spectrum, 30-day and 90-day readmissions, or mortality between those with and without postobstructive pneumonia. Bacteria were identified in 5 patients with postobstructive pneumonia.

4.
bioRxiv ; 2022 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-35665001

RESUMO

Acute respiratory distress syndrome (ARDS) is a life-threatening clinical condition defined by rapid onset respiratory failure following acute lung injury (ALI). Its increased incidence due to COVID-19 and high mortality rate (∻40%) make the study of ARDS pathogenesis a crucial research priority. CRTH2 is a G protein-coupled receptor with established roles in type 2 immunity and well-characterized inhibitors. Prior studies have shown it also promotes neutrophilic inflammation, indicating that CRTH2 inhibition may be a potential therapeutic strategy for ARDS. To test this hypothesis, we first examined the expression pattern of CRTH2 on murine neutrophils. We found it is expressed on neutrophils, but only after extravasation into the lung. Next, we showed that extravasated lung neutrophils generate inflammatory responses upon stimulation with the CRTH2-specific agonist DK-PGD2, as demonstrated by reactive oxygen species (ROS) production. This response was abrogated in CRTH2 KO neutrophils. Inhibition of CRTH2 with fevipiprant suppressed baseline ROS production, indicating an autocrine PGD2-CRTH2 signaling loop. We then evaluated the role of CRTH2 in vivo using a murine model of LPS-induced ALI. Despite the pro-inflammatory effects of CRTH2 on neutrophils in vitro, we observed worsening of lung injury in CRTH2-deficient mice in terms of neutrophilic inflammation, vascular leak, and survival. Bulk RNAseq of lung tissue indicated an impairment in type 2 immune signaling; qPCR and ELISA confirmed downregulation of the key type 2 effector cytokine, IL-4. Thus, CRTH2 appears to play a dual role in ALI, directly promoting neutrophil effector responses, but indirectly suppressing lung injury and neutrophilic inflammation through type 2 immunity. These findings reveal a novel protective function for CRTH2 during lung injury and argue against the use of CRTH2 inhibitors in ARDS.

5.
medRxiv ; 2022 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-35411344

RESUMO

Patients hospitalized with COVID-19 are at significant risk for superimposed bacterial pneumonia. However, diagnosing superinfection is challenging due to its clinical resemblance to severe COVID-19. We therefore evaluated whether the immune biomarker, procalcitonin, could facilitate the diagnosis of bacterial superinfection. To do so, we identified 185 patients with severe COVID-19 who underwent lower respiratory culture; 85 had superinfection. Receiver operating characteristic curve analysis showed that procalcitonin at the time of culture was incapable of distinguishing patients with bacterial infection (AUC, 0.52). We conclude that static measurement of procalcitonin does not aid in the diagnosis of superinfection in severe COVID-19.

6.
BMC Infect Dis ; 21(1): 47, 2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33430799

RESUMO

BACKGROUND: The spread of a highly pathogenic, novel coronavirus (SARS-CoV-2) has emerged as a once-in-a-century pandemic, having already infected over 63 million people worldwide. Novel therapies are urgently needed. Janus kinase-inhibitors and Type I interferons have emerged as potential antiviral candidates for COVID-19 patients due to their proven efficacy against diseases with excessive cytokine release and their direct antiviral ability against viruses including coronaviruses, respectively. METHODS: A search of MEDLINE and MedRxiv was conducted by three investigators from inception until July 30th 2020 and included any study type that compared treatment outcomes of humans treated with Janus kinase-inhibitor or Type I interferon against controls. Inclusion necessitated data with clearly indicated risk estimates or those that permitted their back-calculation. Outcomes were synthesized using RevMan. RESULTS: Of 733 searched studies, we included four randomized and eleven non-randomized trials. Five of the studies were unpublished. Those who received Janus kinase-inhibitor had significantly reduced odds of mortality (OR, 0.12; 95% CI, 0.03-0.39, p< 0.001) and ICU admission (OR, 0.05; 95% CI, 0.01-0.26, p< 0.001), and had significantly increased odds of hospital discharge (OR, 22.76; 95% CI, 10.68-48.54, p< 0.00001) when compared to standard treatment group. Type I interferon recipients had significantly reduced odds of mortality (OR, 0.19; 95% CI, 0.04-0.85, p< 0.05), and increased odds of discharge bordering significance (OR, 1.89; 95% CI, 1.00-3.59, p=0.05). CONCLUSIONS: Janus kinase-inhibitor treatment is significantly associated with positive clinical outcomes in terms of mortality, ICU admission, and discharge. Type I interferon treatment is associated with positive clinical outcomes in regard to mortality and discharge. While these data show promise, additional well-conducted RCTs are needed to further elucidate the relationship between clinical outcomes and Janus kinase-inhibitors and Type I interferons in COVID-19 patients.


Assuntos
Tratamento Farmacológico da COVID-19 , COVID-19/imunologia , Interferon Tipo I/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Humanos , Interferon Tipo I/imunologia , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Resultado do Tratamento
7.
Res Sq ; 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32869016

RESUMO

Background The spread of a highly pathogenic, novel coronavirus (SARS-CoV-2) has emerged as a once-in-a-century pandemic, having already infected over 17 million. Novel therapies are urgently needed. Janus kinase-inhibitors and Type I interferons have emerged as potential antiviral candidates for COVID-19 patients for their proven efficacy against diseases with excessive cytokine release and due to direct antiviral ability against viruses including coronaviruses, respectively. We conducted a systemic review and meta-analysis to evaluate the effect of Janus kinase-inhibitors and Type I interferons and their ability to produce positive patient outcomes in COVID-19 patients. Methods A search of MEDLINE and MedRxiv was conducted by three investigators from inception until July 30 th 2020, including any study type that compared treatment outcomes of humans treated with JAK-inhibitor or Type I interferon against controls. Inclusion necessitated data with clearly indicated risk estimates or those that permitted their back-calculation. Outcomes were synthesized using RevMan. Results Of 733 searched studies, we included four randomized and eleven non-randomized trials. Five of the studies were unpublished. Those who received Janus kinase-inhibitor had significantly reduced odds of mortality (OR, 0.12; 95% CI, 0.03 - 0.39, p<0.001) and ICU admission (OR, 0.05; 95% CI, 0.01 - 0.26, p<0.001), and had significantly increased odds of hospital discharge (OR, 22.76; 95% CI, 10.68 - 48.54, p<0.00001), when compared to standard treatment group. Type I interferon recipients had significantly reduced odds of mortality (OR, 0.19; 95% CI, 0.04 - 0.85, p<0.05), and increased odds of discharge bordering significance (OR, 1.89; 95% CI, 1.00 - 3.59, p=0.05). Conclusions Janus kinase-inhibitor treatment is significantly associated with positive clinical outcomes in terms of mortality, ICU admission, and discharge. Type I interferon treatment is associated with positive clinical outcomes in regard to mortality and discharge. While these data show promise, additional well-conducted RCTs are needed to further elucidate the relationship between clinical outcomes and Janus kinase-inhibitors and Type I interferons in COVID-19 patients.

8.
medRxiv ; 2020 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-32817985

RESUMO

Background Novel coronavirus (SARS-CoV-2) has infected over 17 million. Novel therapies are urgently needed. Janus-kinase (JAK) inhibitors and Type I interferons have emerged as potential antiviral candidates for COVID-19 patients for their proven efficacy against diseases with excessive cytokine release and by their ability to promote viral clearance in past coronaviruses, respectively. We conducted a systemic review and meta-analysis to evaluate role of these therapies in COVID-19 patients. Methods MEDLINE and MedRxiv were searched until July 30th, 2020, including studies that compared treatment outcomes of humans treated with JAK-inhibitor or Type I interferon against controls. Inclusion necessitated data with clear risk estimates or those that permitted back-calculation. Results We searched 733 studies, ultimately including four randomized and eleven non-randomized clinical trials. JAK-inhibitor recipients had significantly reduced odds of mortality (OR, 0.12; 95%CI, 0.03-0.39, p=0.0005) and ICU admission (OR, 0.05; 95%CI, 0.01-0.26, p=0.0005), and had significantly increased odds of hospital discharge (OR, 22.76; 95%CI, 10.68-48.54, p<0.00001), when compared to standard treatment group. Type I interferon recipients had significantly reduced odds of mortality (OR, 0.19; 95%CI, 0.04-0.85, p=0.03), and increased odds of discharge bordering significance (OR, 1.89; 95%CI, 1.00-3.59, p=0.05). Conclusions JAK-inhibitor treatment is significantly associated with positive clinical outcomes regarding mortality, ICU admission, and discharge. Type I interferon treatment is associated with positive clinical outcomes regarding mortality and discharge. While these data show promise, additional randomized clinical trials are needed to further elucidate the efficacy of JAK-inhibitors and Type I interferons and clinical outcomes in COVID-19.

9.
Thorax ; 75(11): 974-981, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32826284

RESUMO

INTRODUCTION: Procalcitonin expression is thought to be stimulated by bacteria and suppressed by viruses via interferon signalling. Consequently, during respiratory viral illness, clinicians often interpret elevated procalcitonin as evidence of bacterial coinfection, prompting antibiotic administration. We sought to evaluate the validity of this practice and the underlying assumption that viral infection inhibits procalcitonin synthesis. METHODS: We conducted a retrospective cohort study of patients hospitalised with pure viral infection (n=2075) versus bacterial coinfection (n=179). The ability of procalcitonin to distinguish these groups was assessed. In addition, procalcitonin and interferon gene expression were evaluated in murine and cellular models of influenza infection. RESULTS: Patients with bacterial coinfection had higher procalcitonin than those with pure viral infection, but also more severe disease and higher mortality (p<0.001). After matching for severity, the specificity of procalcitonin for bacterial coinfection dropped substantially, from 72% to 61%. In fact, receiver operating characteristic curve analysis showed that procalcitonin was a better indicator of multiple indices of severity (eg, organ failures and mortality) than of coinfection. Accordingly, patients with severe viral infection had elevated procalcitonin. In murine and cellular models of influenza infection, procalcitonin was also elevated despite bacteriologic sterility and correlated with markers of severity. Interferon signalling did not abrogate procalcitonin synthesis. DISCUSSION: These studies reveal that procalcitonin rises during pure viral infection in proportion to disease severity and is not suppressed by interferon signalling, in contrast to prior models of procalcitonin regulation. Applied clinically, our data suggest that procalcitonin represents a better indicator of disease severity than bacterial coinfection during viral respiratory infection.


Assuntos
Biomarcadores/metabolismo , Pneumonia Viral/metabolismo , Pró-Calcitonina/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Coinfecção , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Pneumonia Bacteriana/metabolismo , Pneumonia Bacteriana/mortalidade , Pneumonia Viral/mortalidade , Estudos Retrospectivos , Índice de Gravidade de Doença
10.
Am J Physiol Lung Cell Mol Physiol ; 319(4): L661-L669, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32783617

RESUMO

The past two decades have witnessed a resurgence in neutrophil research, inspired in part by the discovery of neutrophil extracellular traps (NETs) and their myriad roles in health and disease. Within the lung, dysregulation of neutrophils and NETosis have been linked to an array of diseases including pneumonia, cystic fibrosis, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), and severe asthma. However, our understanding of pathologic neutrophil responses in the lung remains incomplete. Two methodologic issues have contributed to this gap: first, an emphasis on studying neutrophils from blood rather than the lung and second, the technical difficulties of interrogating neutrophil responses in mice, which has largely restricted basic murine research to specialized laboratories. To address these limitations, we have developed a suite of techniques for studying neutrophil effector functions specifically in the mouse lung. These include ex vivo assays for phagocytosis and NETosis using bronchoalveolar neutrophils and in situ evaluation of NETosis in a murine model of pneumonia. Throughout, we have prioritized technical ease and robust, quantitative readouts. We hope these assays will help to standardize research on lung neutrophils and improve accessibility to this burgeoning field.


Assuntos
Armadilhas Extracelulares/metabolismo , Neutrófilos/patologia , Fagocitose/fisiologia , Doença Pulmonar Obstrutiva Crônica/patologia , Animais , Modelos Animais de Doenças , Pulmão/patologia , Camundongos , Pneumonia/diagnóstico , Pneumonia/patologia , Síndrome do Desconforto Respiratório/diagnóstico , Síndrome do Desconforto Respiratório/patologia
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