Tomasa‑Irriguible and Bielsa‑Berrocal Nutr J (2021) 20:66 https://doi.org/10.1186/s12937-021-00727-z SHORT REPORT Open Access COVID‑19: Up to 82% critically ill patients had low Vitamin C values Teresa Maria Tomasa‑Irriguible* and Lara Bielsa‑Berrocal Abstract There are limited proven therapeutic options for the prevention and treatment of COVID-19. We underwent an obser‑ vational study with the aim of measure plasma vitamin C levels in a population of critically ill COVID-19 adult patients who met ARDS criteria according to the Berlin definition. This epidemiological study brings to light that up to 82% had low Vitamin C values. Notwithstanding the limitation that this is a single-center study, it nevertheless shows an important issue. Given the potential role of vitamin C in sepsis and ARDS, there is gathering interest of whether sup‑ plementation could be beneficial in COVID-19. Keywords: COVID-19, SARS-CoV-2, Vitamin C, ARDS, ICU, Critically ill patient, Epidemiology Main text approved by the local Clinical Research Ethics Commit- There are limited proven therapeutic options for the pre- tee (PI-20–253). vention and treatment of COVID-19. Given the potential We included 67 patients from Mars to April. Median role of vitamin C in sepsis and ARDS, there is gathering age was 60 and 75% were male. The need of intubation interest of whether supplementation could be beneficial was high (73%) and more than 80% of them require prone in COVD-19 [1, 2]. However, first of all, we have to know position. Acute kidney Injury was registered in more if the incidence of vitamin C deficiency is high. than 30%, however only 7% require renal replacement We underwent an observational study with the aim of therapies. In-hospital mortality was around 22%. Main measure plasma vitamin C levels in a population of criti- characteristics of the population included are presented cally ill COVID-19 adult patients who met ARDS crite- in Table 1. ria according to the Berlin definition [3]. The patients Vitamin C was determined by high-performance liq- were admitted to hospital a median 10 days after onset uid chromatography (HPLC). Procedure: Once the blood of symptoms and the last intake was the day before hos- sample was drawn, it was quickly protected from light pital admission. We do not know if due to COVID-19 the and processed with maximum speed. Lab sequence: usual food intake was modified and, therefore, the vita- 1) separating the plasma (EDTA) in a 10 min, 3000 rev min C status was affected. The truth is that the overall and 14ºC centrifugation; 2) pipetting 1 ml of centri- intake had been reduced by half in most cases. fuged plasma into the supplied tube (1 ml homocyst- Vitamin C levels were measured within the first 24 h eine 0.7 mg/mL in 10% trichloroacetic acid) and mixing of ICU admission. The admission took place in ICU it repeatedly; 3) centrifuging again for 10 min at 3000 since first moment of hospitalization. The study was rev and 14ºC; and finally 4) separating and freezing the supernatant immediately at -80ºC, which was sent to the central laboratory. Vitamin C was determined by high- *Correspondence: teresatomasa@gmail.com; ttomasa.germanstrias@gencat. performance liquid chromatography. cat Intensive Care Department, Germ, ans Trias I Pujol Hospital, Germans Trias The range of normality of vitamin C plasma values I Pujol University Hospital, Autónoma de Barcelona University, Carretera are 0.4–2 mg/dL. Up to 82% had low Vitamin C values. del Canyet s/n, 08916 Badalona, , Barcelona, Spain The median value of vitamin C was 0.14 mg/dL with © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://crea‑ tivecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdo‑ main/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Tomasa‑Irriguible and Bielsa‑Berrocal Nutr J (2021) 20:66 Page 2 of 3 Table 1 Clinical characteristics of the COVID-19 patients Discussion included. Results of continuous variables are expressed as Vitamin C is an essential water-soluble nutrient, required median and minimum and maximum. Categorical variables are as a cofactor for a number of enzymatic reactions [4]. Its expressed as frequency (percentage). SOFA sequential organ effects on the immune system during infection include failure assessment, ICU intensive care unit, ECMO extracorporeal the promotion of phagocytosis and chemotaxis of leu- membrane oxygenation, AKI acute kidney injury, CRRT cocytes and development and maturation of T-lympho- continuous renal replacement therapy, IRR intermittent renal replacement, CKD chronic kidney disease, ICU-LOS Length of ICU cytes. Animal studies support a beneficial role of vitamin stay, HOSP-LOS Length of hospital stay C. These positive effects include increased resistance of chick embryo tracheal organ cultures to infection and Clinical characteristics COVID-19 with ARDS protecting broiler chicks against avian coronavirus [5, (n = 67) 6]. Vitamin C had been shown to significantly decrease serum TNFα and IL-1β levels and increased superox- Age (median, min–max, years) 60 (31 – 76) ide dismutase, catalase, and glutathione levels in a rat Male (n, %) 50 (75) ARDS model supporting its antioxidant effect [7]. Addi- SOFA score (median, min–max, points) 9 (2 – 17) tionally, vitamin C also enhances lung epithelial barrier Intubation (n, %) 49 (73.1) function by promoting epigenetic and transcriptional Prone position (n, % respect of intubation) 40 (81.6) expression of protein channels at the alveolar capillary VV-ECMO (n, %) 3 (4.5) membrane that regulate alveolar fluid clearance, which VA-ECMO (n, %) 1 (1.5) include aquaporin-5, cystic fibrosis transmembrane con- Noradrenaline (n, %) 40 (59.7) ductance regulator, epithelial sodium channel, and the Dobutamine (n, %) 6 (9) Na + /K + -ATPase pump [8]. CKD (n, %) 6 (9) The present study has several limitations. It is an obser- AKI (n, %) 22 (32.8) vational study conducted in a single center with small CRRT (n, %) 3 (4.5) sample size of critically ill patients. We found almost 18% IRR (n, %) 2 (3) of undetectable Vitamin C values. However, vitamin C Bacterial superinfection (n, %) 23 (34.3) status could be affected by various confounding factors. ICU-LOS (median, min–max, days) 12 (1 -90) As we know, Vitamin C is very sensitive to light and to HOSP-LOS (median, min–max, days) 25 (1 – 101) oxidation, so that once the blood sample is drawn, it must Mortality (n, %) 15 (22.4) quickly be protected from light and processed with maxi- mum speed. It is possible that we had some trouble few vitamin C blood samples before processed. We would like a minimum value of < 0.10 mg/dL and a maximum of to address this issue because it is important. The recently 1.08 mg/dL; the mean value was 0.14 mg/dL and stand- published study by Chiscano-Camón et al. [9] described ard deviation was 0.05 mg/dL. There were 12 patients a 94.4% undetectable vitamin C levels for COVID-19 with a value below 0.10 mg/dL. Main results are shown patients. This data caught our attention. They included in Table 2. 18 patients with severe acute respiratory syndrome coro- navirus-2 (SARS-CoV-2) disease and Vitamin C was also determined by high-performance liquid chromatography Table 2 Vitamin C results in COVID-19 patients. Values are with photodiode detector. They hypothesized that several expressed as mean and standard deviation. Categorical values mechanisms may be involved, such as increased meta- are expressed as frequency (percentage) bolic consumption due to the enhanced inflammatory Vitamin C status n = 67 response, glomerular hyperfiltration, dialysis, decreased gastrointestinal absorption, or decreased recycling of Low values (0.1–0.4 mg/dL) dehydroascorbate to ascorbic acid. Nevertheless, we    N (%) 43 (64.2) think it is important to be aware with the fact that there   Mean (SD) 0.14 (0.05) might be a problem with blood samples and the measure- Undetectable values (< 0.1 mg/dL) ment method.   N (%) 12 (17.9) Nonetheless, our study shows that most critically ill Low & Undetectable values COVID-19 patients have low Vitamin C values. Research   N (%) 55 (82) is ongoing with COVID-19 disease with a high-dose Normal values (normal range: 0.4–2 mg/dL) intravenous vitamin C (HDIVC) with a clinical trial   N (%) 12 (17.9) investigating vitamin C infusion for severe 2019-nCoV-   Mean (SD) 0.59 (0.18) infected pneumonia in Wuhan, China [10]. Tomasa‑Irriguible and Bielsa‑Berrocal Nutr J (2021) 20:66 Page 3 of 3 Conclusion Received: 6 October 2020 Accepted: 5 July 2021 In conclusion, in our cohort of patients with COVID- 19-associated ARDS, vitamin C status is very low. Fur- ther studies are needed to find out real incidence of References vitamin C deficiency and if treatment with vitamin C has 1. Fowler AA, Truwit JD, Hite RD, et al. Effect of Vitamin C Infusion on Organ any impact COVID-19 disease. Failure and Biomarkers of Inflammation and Vascular Injury in Patients with Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Rand‑ omized Clinical Trial. JAMA. 2019;322(13):1261–70. Abbreviations 2. Fujii T, Luethi N, Young PJ, et al. Effect of Vitamin C, Hydrocortisone, and SARS-CoV-2: Name of this novel coronavirus; COVID-19: Disease caused Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor by SARS-CoV-2; ARDS: Acute Respiratory Distress Syndrome; ICU: Intensive Support Among Patients with Septic Shock: The VITAMINS Randomized Care Unit; SOFA: Sequential organ failure assessment; ECMO: Extracorporeal Clinical Trial. JAMA. 2020. https://​doi.​org/​10.​1001/​jama.​2019.​22176. membrane oxygenation; AKI: Acute kidney injury; CRRT​: Continuous renal 3. ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, Thompson BT, Fer‑ replacement therapy; IRR: Intermittent renal replacement; CKD: Chronic kidney guson ND, Caldwell E, Fan E, Camporota L, Slutsky AS. Acute respiratory disease; ICU-LOS: Length of ICU stay; HOSP-LOS: Length of hospital stay. distress syndrome: the Berlin Definition. JAMA. 2012;307(23):2526–33. doi: https://​doi.​org/​10.​1001/​jama.​2012.​5669. PMID: 22797452. Acknowledgements 4. Padayatty, S.J.; Levine, M. Vitamin C: The known and the unknown and Not Applicable Goldilocks. Oral Dis. 2016, 22, 463–493. [CrossRef ] [PubMed] 5. Atherton, J.G.; Kratzing, C.C.; Fisher, A. The effect of ascorbic acid on Authors’ contributions infection of chick-embryo ciliated tracheal organ cultures by coronavirus. The author(s) read and approved the final manuscript. Lara Bielsa-Berrocal, Arch. Virol. 1978, 56, 195–199. [CrossRef ] [PubMed] MD. Contribution: This author collected the data and prepared the manu‑ 6. Davelaar, F.G.; Van Den Bos, J. Ascorbic acid and infectious bronchitis script. This author helped design the study and prepared the manuscript. This infections in broilers. Avian Pathol. 1992, 21, 581–589. [CrossRef ] author helped design the study and analysed the data. This manuscript was 7. Erol, N.; Saglam, L.; Saglam, Y.S.; Erol, H.S.; Altun, S.; Aktas, M.S.; Halici, M.B. handled by: Teresa M. Tomasa-Irriguible, Ph.D, M.D. The protection potential of antioxidant vitamins against acute respira‑ tory distress syndrome: A rat trial. Inflammation 2019, 42, 1585–1594. Funding [CrossRef ] Funding Support was provided solely from institutional and/or departmental 8. Fisher, B.J.; Kraskauskas, D.; Martin, E.J.; Farkas, D.; Wegelin, J.A.; Brophy, D.; sources. No funding was provided from any of the following organizations: Ward, K.R.; Voelkel, N.F.; Fowler, A.A.; Natarajan, R. Mechanisms of attenua‑ National Institutes of Health (NIH), Wellcome Trust, Howard Hughes Medical tion of abdominal sepsis induced acute lung injury by ascorbic acid. Am. Institute (HHMI). J. Physiol. Lung Cell. Mol. Physiol. 2012, 303, L20–L32. [CrossRef ] [PubMed] 9. Chiscano-Camón, L; Ruiz-Rodriguez, J.C.; Ruiz-Sanmartin, A; Roca O. and Availability of data and materials Ferrer R. Vitamin C levels in patients with SARS-CoV2-associated acute Not Applicable. respiratory distress syndrome. Critical Care (2020); 24:522. https://​doi.​org/​ 10.​1186/​s13054-​020-​03249-y 10. Liu F, Zhu Y, Zhang J, Li Y, Peng Z. Intravenous high-dose vitamin C for Declarations the treatment of severe COVID-19: study protocol for a multicentre randomised controlled trial. BMJ Open. 2020;10(7): e039519. https://​doi.​ Ethics approval and consent to participate org/​10.​1136/​bmjop​en-​2020-​039519.​PMID:​32641​343;​PMCID:​PMC73​48463. Clinical Research Ethical Committee approved the study.The Center’s Clini‑ cal Research Ethics Committee considered there was no need to request informed consent. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub‑ Consent for publication lished maps and institutional affiliations. Not Applicable. Competing interests The authors declare no competing interests. Ready to submit your research ? 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