Neutrophil calprotectin identifies severe pulmonary disease in COVID-19

Shi, Hui; Zuo, Yu; Yalavarthi, Srilakshmi; Gockman, Kelsey; Zuo, Melanie; Madison, Jacqueline A; Blair, Christopher; Woodard, Wrenn; Lezak, Sean P; Lugogo, Njira L; Woods, Robert J.; Lood, Christian; Kanthi, Yogendra

doi:10.1101/2020.05.06.20093070

Cited by 24 publications

(28 citation statements)

References 65 publications

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“…COVID-19 is characterized by sudden respiratory deterioration in patients, and sIgA can induce an inflammatory response in the airway, including neutrophil activation, 46 and recent pre-prints suggest that systemic neutrophilic activation appears to be a marker of severity in pandemic flu 47 and COVID-19. 48 , 49 Thus, it may be desirable to look for correlations between clinical outcome and excess salivary IgA levels. If such a correlation is established, increased salivary IgA could serve as a biomarker to identify patients at an elevated risk of clinical deterioration in COVID-19, and perhaps candidates for early intervention with steroids, which have been shown to be effective in some ventilated patients.…”

Section: Discussionmentioning

confidence: 99%

Salivary anti-SARS-CoV-2 IgA as an accessible biomarker of mucosal immunity against COVID-19

Varadhachary¹,

Chatterjee²,

Garza³

et al. 2020

Preprint

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Background: Mucosal immunity, including secretory IgA (sIgA), plays an important role in early defenses against respiratory pathogens. Salivary testing, the most convenient way to measure sIgA, has been used to characterize mucosal immune responses to many viral infections including SARS, MERS, influenza, HIV, and RSV. However, its role has not yet been characterized in the COVID-19 pandemic. Here, we report development and validation of a rapid immunoassay for measuring salivary IgA against the SARS-CoV-2 virus, and report quantitative results in both pre-COVID-19 and muco-converted subjects. Methods: We developed and refined a specific test for salivary IgA against SARS-CoV-2 on the Brevitest platform, a rapid immunoassay system designed for point-of-care use. A qualitative test was validated as per FDA guidelines with saliva obtained from subjects prior to the emergence of COVID-19, and from PCR-confirmed COVID-19 patients. We also generated a quantitative measure of anti-SARS-CoV-2 salivary IgA. Time taken for saliva self-collection was measured and its ease-of-use assessed. Results: We successfully validated a qualitative salivary assay for SARS-CoV-2 IgA antibodies, with positive and negative predictive values of 92% and 97%, respectively, and no observable cross-reactivity with any of seven potential confounders. Pre-COVID-19 saliva samples showed an 8-fold range of IgA concentrations, suggesting a broad continuum of natural antibody resistance against the novel virus, though at levels lower than that observed in COVID-19 PCR-confirmed subjects. Samples from muco-positive subjects also shown a ~9-fold variation in salivary IgA levels, with elevated salivary IgA observed beyond three months after onset of symptoms. We observed a correlation (r=0.4405) between salivary IgA levels and COVID-19 disease severity. In anecdotal observations, we observed individuals who exhibited antibodies early in the course of their disease, contemporaneously with a positive PCR test, as well as individuals who muco-converted despite no known direct exposure to a COVID-19 patient, no symptoms, and negative molecular and/or serum antibody tests. Salivary collection took 5-10 minutes, and was reported as being easy (mean of 1.1 on a scale of 1 to 10). Implications: Mucosal immunity, including secretory IgA, plays an important role in host defense against respiratory pathogens, and our early data suggest it may do so in COVID-19. Salivary IgA, an accessible marker of mucosal immunity, may be a useful indicator of several key parameters including individual and community immune response, disease severity, clinical risk, and herd immunity. The non-invasive nature and ease of saliva collection facilitates its potential use as a biomarker for ongoing patient assessment and management, as well as a community surveillance tool. By measuring mucosal immune responses directly and systemic immune responses indirectly, salivary IgA could be useful in developing and deploying a vaccine(s) against COVID-19. Quantitative IgA assessment could also potentially serve as a tool to segment the population into different risk categories and inform individual and collective decisions relating to appropriate activities and vaccine prioritization/delivery. These data reinforce the importance of further investigation into the role of mucosal immunity and IgA in host responses against COVID-19.

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Section: Discussionmentioning

confidence: 99%

Salivary anti-SARS-CoV-2 IgA as an accessible biomarker of mucosal immunity against COVID-19

Varadhachary¹,

Chatterjee²,

Garza³

et al. 2020

Preprint

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“…Transcriptome analyses further demonstrated the downregulation of a number of important pro-inflammatory gene products, including IFNG, IL1B, IKBKB and STAT3B, which contribute to TH17 cell differentiation and IBD pathogenesis. Calprotectin, a heterodimer encompassing calgranulin A and calgranulin B, which are encoded by S100A8 and S100A9, respectively, was recently identified as a biomarker of severe COVID-19 disease and suggested to represent a trigger of cytokine release syndrome 81 . We observed no induction of S100A8 or All rights reserved.…”

Section: Discussionmentioning

confidence: 99%

Gastrointestinal involvement attenuates COVID-19 severity and mortality

Livanos

Jha

Cossarini

et al. 2020

Preprint

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Given that gastrointestinal (GI) symptoms are a prominent extrapulmonary manifestation of coronavirus disease 2019 (COVID-19), we investigated the impact of GI infection on disease pathogenesis in three large cohorts of patients in the United States and Europe. Unexpectedly, we observed that GI involvement was associated with a significant reduction in disease severity and mortality, with an accompanying reduction in key inflammatory proteins including IL-6, CXCL8, IL-17A and CCL28 in circulation. In a fourth cohort of COVID-19 patients in which GI biopsies were obtained, we identified severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) within small intestinal enterocytes for the first time in vivo but failed to obtain culturable virus. High dimensional analyses of GI tissues confirmed low levels of cellular inflammation in the GI lamina propria and an active downregulation of key inflammatory genes including IFNG, CXCL8, CXCL2 and IL1B among others. These data draw attention to organ-level heterogeneity in disease pathogenesis and highlight the role of the GI tract in attenuating SARS-CoV-2-associated inflammation with related mortality benefit.

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“…Furthermore, serum of COVID-19 patients requiring mechanical ventilation exhibited augmented cell-free DNA and MPO-DNA complexes, compared to patients breathing room air (Zuo et al, 2020). An additional NET marker, calprotectin, was found to be present at prominently elevated levels in the blood of 172 COVID-19 patients (H. Shi, Zuo, et al, 2020). PGs are reported to have inhibitory effect upon NET formation.…”

Section: Pge 2 On Net Releasementioning

confidence: 98%

Non‐steroidal anti‐inflammatory drugs, prostaglandins, and COVID‐19

Robb

Goepp

Rossi

et al. 2020

British J Pharmacology

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the novel coronavirus disease 2019 (COVID-19), a highly pathogenic and sometimes fatal respiratory disease responsible for the current 2020 global pandemic. Presently, there remains no effective vaccine or efficient treatment strategies against COVID-19. Non-steroidal anti-inflammatory drugs (NSAIDs) are medicines very widely used to alleviate fever, pain, and inflammation (common symptoms of COVID-19 patients) through effectively blocking production of prostaglandins (PGs) via inhibition of cyclooxyganase enzymes. PGs can exert either proinflammatory or anti-inflammatory effects depending on the inflammatory scenario. In this review, we survey the potential roles that NSAIDs and PGs may play during SARS-CoV-2 infection and the development and progression of COVID-19.

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Neutrophil calprotectin identifies severe pulmonary disease in COVID-19

Cited by 24 publications

References 65 publications

Salivary anti-SARS-CoV-2 IgA as an accessible biomarker of mucosal immunity against COVID-19

Salivary anti-SARS-CoV-2 IgA as an accessible biomarker of mucosal immunity against COVID-19

Gastrointestinal involvement attenuates COVID-19 severity and mortality

Non‐steroidal anti‐inflammatory drugs, prostaglandins, and COVID‐19

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