Neutrophil-mediated oxidative stress and albumin structural damage predict COVID-19-associated mortality

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Abstract

Human serum albumin (HSA) is the frontline antioxidant protein in blood with established anti-inflammatory and anticoagulation functions. Here we report that COVID-19-induced oxidative stress inflicts structural damages to HSA and is linked with mortality outcome in critically ill patients. We recruited 39 patients who were followed up for a median of 12.5 days (1-35 days), among them 23 had died. Analyzing blood samples from patients and healthy individuals (n=11), we provide evidence that neutrophils are major sources of oxidative stress in blood and that hydrogen peroxide is highly accumulated in plasmas of non-survivors. We then analyzed electron paramagnetic resonance (EPR) spectra of spin labelled fatty acids (SLFA) bound with HSA in whole blood of control, survivor, and non-survivor subjects (n=10-11). Non-survivor' HSA showed dramatically reduced protein packing order parameter, faster SLFA correlational rotational time, and smaller S/W ratio (strong-binding/weak-binding sites within HSA), all reflecting remarkably fluid protein microenvironments. Following loading/unloading of 16-DSA we show that transport function of HSA maybe impaired in severe patients. Stratified at the means, Kaplan–Meier survival analysis indicated that lower values of S/W ratio and accumulated H₂O₂ in plasma significantly predicted in-hospital mortality (S/W≤0.15, 81.8% (18/22) vs. S/W>0.15, 18.2% (4/22), p=0.023; plasma [H₂O₂]>8.6 mM, 65.2% (15/23) vs. 34.8% (8/23), p=0.043). When we combined these two parameters as the ratio ((S/W)/[H₂O₂]) to derive a risk score, the resultant risk score lower than the mean (< 0.019) predicted mortality with high fidelity (95.5% (21/22) vs. 4.5% (1/22), logrank c² = 12.1, p=4.9x10^-4). The derived parameters may provide a surrogate marker to assess new candidates for COVID-19 treatments targeting HSA replacements and/or oxidative stress.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Raw data collected and used to produce all figures and tables are available on Dyrad (https://doi.org/10.5061/dryad.cnp5hqc4q).

The following data sets were generated

1. Ali SS
2. et al
(2021) Data from: Biophysical Data Pertaining to COVID-19 caused human serum albumin damage
Dryad Digital Repository, doi:10.5061/dryad.cnp5hqc4q.

https://doi.org/10.5061/dryad.cnp5hqc4q

Article and author information

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Mohamed A Badawy

Research Department, Children's Cancer Hospital Egypt 57357, Cairo, Egypt

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The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-1691-0167
Basma A Yasseen

Research Department, Children's Cancer Hospital Egypt 57357, Cairo, Egypt

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The authors declare that no competing interests exist.
Riem M El-Messiery

Faculty of Medicine, Cairo University, Cairo, Egypt

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The authors declare that no competing interests exist.
Engy A Abdel-Rahman

Research Department, Children's Cancer Hospital Egypt 57357, Cairo, Egypt

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The authors declare that no competing interests exist.
Aya A Elkhodiry

Research Department, Children's Cancer Hospital Egypt 57357, Cairo, Egypt

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"This ORCID iD identifies the author of this article:" 0000-0001-5684-0242
Azza G Kamel

Research Department, Children's Cancer Hospital Egypt 57357, Cairo, Egypt

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The authors declare that no competing interests exist.
Hajar El-sayed

Research Department, Children's Cancer Hospital Egypt 57357, Cairo, Egypt

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The authors declare that no competing interests exist.
Asmaa M Shedra

Research Department, Children's Cancer Hospital Egypt 57357, Cairo, Egypt

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The authors declare that no competing interests exist.
Rehab Hamdy

Research Department, Children's Cancer Hospital Egypt 57357, Cairo, Egypt

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The authors declare that no competing interests exist.
Mona Zidan

Research Department, Children's Cancer Hospital Egypt 57357, Cairo, Egypt

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The authors declare that no competing interests exist.
Diaa Al-Raawi

Research Department, Children's Cancer Hospital Egypt 57357, Cairo, Egypt

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The authors declare that no competing interests exist.
Mahmoud Hammad

Pediatric Oncology Department, Children's Cancer Hospital Egypt 57357, Cairo, Egypt

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The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-1677-0360
Nahla Elsharkawy

Clinical pathology department, Children's Cancer Hospital Egypt 57357, Cairo, Egypt

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The authors declare that no competing interests exist.
Mohamed El Ansary

Department of Intensive Care, Faculty of Medicine, Cairo University, Cairo, Egypt

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The authors declare that no competing interests exist.
Ahmed Al-Halfawy

Department of Pulmonary Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt

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The authors declare that no competing interests exist.
Alaa Elhadad

Pediatric Oncology Department, Children's Cancer Hospital Egypt 57357, Cairo, Egypt

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The authors declare that no competing interests exist.
Ashraf Hatem

Department of Chest Diseases, Faculty of Medicine, Cairo University, Cairo, Egypt

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The authors declare that no competing interests exist.
Sherif Abouelnaga

Pediatric Oncology Department, Children's Cancer Hospital Egypt 57357, Cairo, Egypt

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The authors declare that no competing interests exist.
Laura L Dugan

Division of Geriatric Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, United States

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The authors declare that no competing interests exist.
Sameh Saad Ali

Research Department, Children's Cancer Hospital Egypt 57357, Cairo, Egypt

For correspondence
sameh.ali@57357.org

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The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-0339-6106

Funding

The Association of Friends of the National Cancer Institute (COVID-SA)

Sameh Saad Ali

The Children's Cancer Hospital Egypt (SA-Start up)

Sameh Saad Ali

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: Written informed consents were obtained from participants in accordance with the principles of the Declaration of Helsinki. For COVID-19 and control blood/plasma collection, Children's Cancer Hospital's Institutional Review Board (IRB) has evaluated the study design and protocol, IRB number 31-2020 issued on July 6, 2020.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.