The impact of immune dysfunction on perioperative complications in surgical COVID-19 patients: an imperative for early immunonutrition
Patient Safety in Surgery volume 16, Article number: 14 (2022)
Surgical patients with coronavirus disease 2019 (COVID-19) are vulnerable to increased perioperative complications and postoperative mortality, independent of the risk for contracting COVID-19 pneumonia after endotracheal intubation for general anesthesia. The presumed root cause of postoperative infections, microvascular soft tissue injuries and thromboembolic complications is largely attributed to the profound immune dysfunction induced by COVID-19 as a result of complement activation and the “cytokine storm”. The empirical therapy with anti-inflammatory agents has been shown to attenuate some of the adverse effects of systemic hyperinflammation in COVID-19 patients. In addition, the proactive concept of “immunonutrition” may represent a new promising avenue for mitigating the complex immune dysregulation in COVID-19 and thereby reduce the rates of surgical complications and postoperative mortality. This letter provides a narrative summary of the current state-of-the-art in the field of immunonutrition as it pertains to surgical patient safety in COVID-19 patients.
Postoperative mortality rates of surgical patients with coronavirus disease 2019 (COVID-19) have been shown to be dramatically increased compared to COVID-19 negative patients who undergo surgical procedures [1,2,3,4]. The increased postoperative mortality rate in COVID-19 patients has been observed in symptomatic as well as asymptomatic patients and applies to both elective and urgent/emergent surgical procedures [5,6,7,8,9,10,11,12]. Current medical treatment options for COVID-19 are limited, prompting the necessity to explore alternative treatment strategies that are both effective and widely available [13,14,15,16]. The emerging field of immunonutrition provides a novel potential mechanism to decrease perioperative morbidity in COVID-19 patients and subsequently decrease the risk of surgical complications [17, 18].
The mechanism of cellular infection by SARS-CoV-2 is depicted schematically in Fig. 1. The complex immune dysfunction in patients with COVID-19 has been implicated in adverse outcomes due to uncontrolled hyperinflammation, hypercoagulability associated with thromboembolic complications, and ultimately to delayed organ failure and death [20,21,22]. The “cytokine storm” (or “cytokine release syndrome”) and the activation of the complement cascade have been identified as key mechanisms contributing to the immunopathology of COVID-19 [23,24,25]. A wide spectrum of empirical treatment modalities have been widely applied during the pandemic in off-label indications to attenuate the hyperinflammatory response to coronavirus infection. These include antirheumatic agents, cytokine inhibitors, corticosteroids, intravenous immunoglobulin, complement inhibitors, and other novel anti-inflammatory molecules [26,27,28,29]. However, there is a lack of effective and specific therapeutics that may help reduce the risk of immune dysfunction-associated surgical complications in COVID-19 patients . The benefit of immunonutrition in attenuating hyperinflammation and adverse outcomes in the setting of major surgery or major injuries has been established for many decades in the pertinent literature [30,31,32].
Immunonutrition in COVID-19
Immunonutrition is an evolving concept designed to improve the potential of modulating the immune system in at-risk patients by providing high-dose supportive nutrients during a phase of increased vulnerability, e.g. due to infection, trauma, or surgery [30,31,32,33,34]. Micronutrients, such as vitamin C, D3, zinc, and selenium have been shown to play important supportive roles in antioxidant, anti-inflammatory, antithrombotic, antiviral, and immuno-modulatory functions in COVID-19 patients [33,34,35,36,37]. The present letter was designed to provide a pragmatic rationale to consider immunonutrition as an adjunct in the perioperative management of the vulnerable cohort of COVID-19 patients who require surgical interventions.
Ascorbic acid, commonly known as vitamin C, plays a vital role in regulating immune function and has been shown to support the innate and the adaptive immune system . Vitamin C promotes neutrophil activation, recruitment, and phagocytosis, thereby contributing to anti-viral immune mechanisms [39, 40]. Importantly, Vitamin C also serves to prevent tissue damage by decreasing neutrophil necrosis and promoting subsequent clearance by macrophages and works on the skin level by promoting the epithelial barrier, enhancing protection against environmental strain . Current data has highlighted the importance of Vitamin C in combating infection and has shown that Vitamin C deficiency results in weakened immune function resulting in higher rates of infection . Intravenous (IV) supplementation of Vitamin C in patients with COVID-19 has resulted in a marked decrease of inflammatory markers including D-Dimer and ferritin and highlighted potential benefits including shortened recovery times, decreased length of mechanical ventilation, and time spent in the ICU . The use of IV vitamin C supplementation in COVID-19 patients continues to be of limited study, however early anecdotal evidence supports its beneficial mechanisms by reducing overall mortality rates in COVID-19 patients including those critically ill [39, 42, 43].
Vitamin D3 (cholecalciferol) is historically known for its roles in calcium homeostasis and bone health, and also influences the innate and adaptive immune system by supporting antiviral mechanisms and attenuating inflammation [44, 45]. Decreased serum levels of vitamin D3 have been shown to significantly correlate with increased morbidity and mortality in COVID-19 patients [18, 46,47,48]. From a therapeutic immunonutrition perspective, the supplementation with vitamin D3 has been demonstrated to improve outcomes in COVID-19 patients and to decrease ICU admissions and mortality .
The discovery of the interaction between zinc and immune function dates back to the 1960’s . Although the exact functions of zinc in the immune system remain to be further elaborated, it has shown to exhibit anti-inflammatory and antioxidant capacities and serves roles in immune cell maturation and differentiation [48, 51]. In COVID-19, the administration of zinc in high doses has been shown to suport the immune system’s antiviral activity and to inhibit coronavirus replication [41, 52, 53].
Glutamine is considered an essential amino acid in cases of catabolic disease and is the most abundant amino acid in the body and primarily found in skeletal muscle and the lungs [54, 55]. Glutamine serves as the fuel for various immune and intestinal cells including lymphocytes and macrophages, as well as aiding in the creation of proteins, glucose, and other amino acids . These functions allow Glutamine to mediate immunological function and support antioxidant effects . Other important functions of Glutamine include supporting gut mucosa, muscle growth, and nitrogen transport between organs . L-glutamine has been shown to have beneficial impacts on COVID-19 patients by inhibiting inflammatory processes resulting in decreased length of hospitalization and lower rates of ICU admissions . Based on the demonstrated disruption of the metabolism of amino acids, including glutamine, in COVID-19 patients, in conjunction with the proven immunomodulatory functions of glutamine, this amino acid may present an ideal nutrient as an adjunct for surgical patients with COVID-19 infections [32, 58].
Omega-3 fatty acids
Omega-3 fatty acids are polyunsaturated fatty acids consisting of both eicosapentaenoic (EPH) and docosahexaenoic (DHA) acids . Polyunsaturated fatty acids have long been known for antiviral properties and are associated with the gut microbiota and gut-brain axis . Recent studies have shown that high levels of polyunsaturated fatty acids (omega-3 or omega-6) decrease the susceptibility to coronavirus infections and are protective against developing severe COVID-19 disease [61,62,63,64]. A double-blind randomized clinical trial on critically ill patients with COVID-19 demonstrated that the nutritional omega-3 supplementation improved clinical outcomes including renal and respiratory function . However, the high-dose supplementary use of omega-3 fatty acids has also been cautioned, due to EPA and DHA causing cell membranes to become more susceptible to oxidative stress and related cellular toxicity .
In light of the limited specific treatment options for surgical COVID-19 patients who are at risk of high postoperative complication rates and adverse outcomes, supportive immunonutrition appears to represent a safe, feasible, cost-effective, and pragmatically intuitive concept to mitigate the perioperative inflammation and adverse effects related to immune dysfunction [30, 35]. The micronutrients described in this review (vitamin C, D3, zinc, glutamine, and omega-3 fatty acids) have all shown to have a positive influence on the immune system and boost immune function through various pathways and mechanisms. The recommended dosing ranges of these immunonutrients for COVID-19 patients are provided in Table 1. Preliminary insights from case studies and randomized trials support the notion that immunonutrition decreases the severity of disease and risk of complications in COVID-19 patients by attenuating the inflammatory response and supporting antiviral activity by the immune system [30, 34, 35].
Availability of data and materials
Please contact the authors for data requests.
Abate SM, Mantefardo B, Basu B. Postoperative mortality among surgical patients with COVID-19: a systematic review and meta-analysis. Patient Saf Surg. 2020;14:37.
Colosimo C, Bhuller S, Cornett B, Dziadkowiec O, Yon JR, Weaver J, et al. Perioperative mortality in SARS-CoV-2-positive surgical patients during the first wave of the novel coronavirus pandemic. Br J Surg. 2021;108(5):e201–2.
Gulinac M, Novakov IP, Antovic S, Velikova T. Surgical complications in COVID-19 patients in the setting of moderate to severe disease. World J Gastrointest Surg. 2021;13(8):788–95.
Nahshon C, Bitterman A, Haddad R, Hazzan D, Lavie O. Hazardous postoperative outcomes of unexpected COVID-19 infected patients: a call for global consideration of sampling all asymptomatic patients before surgical treatment. World J Surg. 2020;44(8):2477–81.
Knisely A, Zhou ZN, Wu J, et al. Perioperative morbidity and mortality of patients with COVID-19 who undergo urgent and emergent surgical procedures. Ann Surg. 2021;273(1):34–40.
Cerullo G, Negro M, Parimbelli M, Pecoraro M, Perna S, Liguori G, et al. The long history of vitamin C: from prevention of the common cold to potential aid in the treatment of COVID-19. Front Immunol. 2020;11:574029.
Hogan A. COVID-19 and emergency surgery. Br J Surg. 2020;107(7):e180.
Wright EV, Musbahi O, Singh A, Somashekar N, Huber CP, Wiik AV. Increased perioperative mortality for femoral neck fractures in patients with coronavirus disease 2019 (COVID-19): experience from the United Kingdom during the first wave of the pandemic. Patient Saf Surg. 2021;15(1):8.
Brown NJ, Wilson B, Szabadi S, et al. Ethical considerations and patient safety concerns for cancelling non-urgent surgeries during the COVID-19 pandemic: a review. Patient Saf Surg. 2021;15(1):19.
Mascarenhas RE, Pralhad S, Manaktala N. Pan-dent-emic: safety considerations for dental surgery in the era of COVID-19. Patient Saf Surg. 2021;15(1):16.
Prakash L, Dhar SA, Mushtaq M. COVID-19 in the operating room: a review of evolving safety protocols. Patient Saf Surg. 2020;14:30.
Myles PS, Maswime S. Mitigating the risks of surgery during the COVID-19 pandemic. Lancet. 2020;396(10243):2–3.
Moletta L, Pierobon ES, Capovilla G, Costantini M, Salvador R, Merigliano S, et al. International guidelines and recommendations for surgery during Covid-19 pandemic: a systematic review. Int J Surg. 2020;79:180–8.
Salvi R, Patankar P. Emerging pharmacotherapies for COVID-19. Biomed Pharmacother. 2020;128:110267.
Gavriatopoulou M, Ntanasis-Stathopoulos I, Korompoki E, Fotiou D, Migkou M, Tzanninis IG, et al. Emerging treatment strategies for COVID-19 infection. Clin Exp Med. 2021;21(2):167–79.
Menendez JC. Approaches to the potential therapy of COVID-19: a general overview from the medicinal chemistry perspective. Molecules. 2022;27(3):658.
Jovic TH, Ali SR, Ibrahim N, Jessop ZM, Tarassoli SP, Dobbs TD, et al. Could vitamins help in the fight against COVID-19? Nutrients. 2020;12(9):2550.
Borsche L, Glauner B, von Mendel J. COVID-19 mortality risk correlates inversely with vitamin D3 status, and a mortality rate close to zero could theoretically be achieved at 50 ng/mL 25(OH)D3: results of a systematic review and meta-analysis. Nutrients. 2021;13(10):3596.
Lebeau G, Vagner D, Frumence E, Ah-Pine F, Guillot X, Nobecourt E, et al. Deciphering SARS-CoV-2 virologic and immunologic features. Int J Mol Sci. 2020;21(16):5932.
Mahmudpour M, Roozbeh J, Keshavarz M, Farrokhi S, Nabipour I. COVID-19 cytokine storm: the anger of inflammation. Cytokine. 2020;133:155151.
Leisman DE, Deutschman CS, Legrand M. Facing COVID-19 in the ICU: vascular dysfunction, thrombosis, and dysregulated inflammation. Intensive Care Med. 2020;46(6):1105–8.
Teuben MPJ, Pfeifer R, Teuber H, De Boer LL, Halvachizadeh S, Shehu A, et al. Lessons learned from the mechanisms of posttraumatic inflammation extrapolated to the inflammatory response in COVID-19: a review. Patient Saf Surg. 2020;14:28.
Zanza C, Romenskaya T, Manetti AC, Franceschi F, La Russa R, Bertozzi G, et al. Cytokine storm in COVID-19: immunopathogenesis and therapy. Medicina (Kaunas). 2022;58(2):144.
Jiang Y, Rubin L, Peng T, Liu L, Xing X, Lazarovici P, et al. Cytokine storm in COVID-19: from viral infection to immune responses, diagnosis and therapy. Int J Biol Sci. 2022;18(2):459–72.
Gubernatorova EO, Gorshkova EA, Polinova AI, Drutskaya MS. IL-6: relevance for immunopathology of SARS-CoV-2. Cytokine Growth Factor Rev. 2020;53:13–24.
Stahel PF, Barnum SR. Complement inhibition in coronavirus disease (COVID)-19: a neglected therapeutic option. Front Immunol. 2020;11:1661.
Thomas G, Frederick E, Hausburg M, Goldberg L, Hoke M, Roshon M, et al. The novel immunomodulatory biologic LMWF5A for pharmacological attenuation of the "cytokine storm" in COVID-19 patients: a hypothesis. Patient Saf Surg. 2020;14:21.
Rangappa P. Cytokine storm and immunomodulation in COVID-19. Indian J Crit Care Med. 2021;25(11):1288–91.
Boretti A, Banik B. Modulation of Covid-19 cytokine storm by tocilizumab. J Med Virol. 2021; (Oct 7, online ahead of print).
Deana C. Immunonutrition in perioperative care of COVID-19 patients: an old weapon for a new disease? Braz J Anesthesiol. 2021;71(2):197.
Probst P, Ohmann S, Klaiber U, Huttner FJ, Billeter AT, Ulrich A, et al. Meta-analysis of immunonutrition in major abdominal surgery. Br J Surg. 2017;104(12):1594–608.
Hasenboehler E, Williams A, Leinhase I, Morgan SJ, Smith WR, Moore EE, et al. Metabolic changes after polytrauma: an imperative for early nutritional support. World J Emerg Surg. 2006;1:29.
Di Renzo L, Gualtieri P, Pivari F, et al. COVID-19: is there a role for immunonutrition in obese patient? J Transl Med. 2020;18(1):415.
Caccialanza R, Laviano A, Lobascio F, et al. Early nutritional supplementation in non-critically ill patients hospitalized for the 2019 novel coronavirus disease (COVID-19): rationale and feasibility of a shared pragmatic protocol. Nutrition. 2020;74:110835.
Pimentel RFW, Silva AP, Santana AIC, et al. Effect of immunonutrition on serum levels of C-reactive protein and lymphocytes in patients with COVID-19: a randomized, controlled, double-blind clinical trial. Nutr Hosp. 2022;39(1):20–6.
Abulmeaty MMA, Aljuraiban GS, Shaikh SM, et al. The efficacy of antioxidant oral supplements on the progression of COVID-19 in non-critically ill patients: a randomized controlled trial. Antioxidants (Basel). 2021;10(5):804.
Pedrosa LFC, Barros A, Leite-Lais L. Nutritional risk of vitamin D, vitamin C, zinc, and selenium deficiency on risk and clinical outcomes of COVID-19: a narrative review. Clin Nutr ESPEN. 2022;47:9–27.
Carr AC, Maggini S. Vitamin C and immune function. Nutrients. 2017;9(11):1211.
Hemila H, Chalker E. Vitamin C as a possible therapy for COVID-19. Infect Chemother. 2020;52(2):222–3.
Junaid K, Ejaz H, Abdalla AE, Abosalif KOA, Ullah MI, Yasmeen H, et al. Effective immune functions of micronutrients against SARS-CoV-2. Nutrients. 2020;12(10):2992.
Shakoor H, Feehan J, Al Dhaheri AS, Ali HI, Platat C, Ismail LC, et al. Immune-boosting role of vitamins D, C, E, zinc, selenium and omega-3 fatty acids: could they help against COVID-19? Maturitas. 2021;143:1–9.
Waqas Khan HM, Parikh N, Megala SM, Predeteanu GS. Unusual early recovery of a critical COVID-19 patient after administration of intravenous vitamin C. Am J Case Rep. 2020;21:e925521.
Hiedra R, Lo KB, Elbashabsheh M, Gul F, Wright RM, Albano J, et al. The use of IV vitamin C for patients with COVID-19: a case series. Expert Rev Anti-Infect Ther. 2020;18(12):1259–61.
Aranow C. Vitamin D and the immune system. J Investig Med. 2011;59(6):881–6.
Ao T, Kikuta J, Ishii M. The effects of vitamin D on immune system and inflammatory diseases. Biomolecules. 2021;11(11):1624.
Saeed MAM, Mohamed AH, Owaynat AH. Cholecalciferol level and its impact on COVID-19 patients. Egypt J Intern Med. 2022;34(1):23.
Dror AA, Morozov N, Daoud A, et al. Pre-infection 25-hydroxyvitamin D3 levels and association with severity of COVID-19 illness. PLoS One. 2022;17(2):e0263069.
Chiodini I, Gatti D, Soranna D, et al. Vitamin D status and SARS-CoV-2 infection and COVID-19 clinical outcomes. Front Public Health. 2021;9:736665.
Varikasuvu SR, Thangappazham B, Vykunta A, Duggina P, Manne M, Raj H, et al. COVID-19 and vitamin D (co-VIVID study): a systematic review and meta-analysis of randomized controlled trials. Expert Rev Anti-Infect Ther. 2022:1–7.
Wessels I, Maywald M, Rink L. Zinc as a gatekeeper of immune function. Nutrients. 2017;9(12):1286.
Haase H, Rink L. Multiple impacts of zinc on immune function. Metallomics. 2014;6(7):1175–80.
Pal A, Squitti R, Picozza M, Pawar A, Rongioletti M, Dutta AK, et al. Zinc and COVID-19: basis of current clinical trials. Biol Trace Elem Res. 2021;199(8):2882–92.
Hemila H, Chalker E. Vitamin C and zinc lozenges for COVID-19? J Am Pharm Assoc (2003). 2021;61(5):e39.
Newsholme P, Procopio J, Lima MM, Pithon-Curi TC, Curi R. Glutamine and glutamate--their central role in cell metabolism and function. Cell Biochem Funct. 2003;21(1):1–9.
Miller AL. Therapeutic considerations of L-glutamine: a review of the literature. Altern Med Rev. 1999;4(4):239–48.
McRae MP. Therapeutic benefits of glutamine: an umbrella review of meta-analyses. Biomed Rep. 2017;6(5):576–84.
Cengiz M, Borku Uysal B, Ikitimur H, Ozcan E, Islamoglu MS, Aktepe E, et al. Effect of oral l-glutamine supplementation on Covid-19 treatment. Clin Nutr Exp. 2020;33:24–31.
Masoodi M, Peschka M, Schmiedel S, et al. Disturbed lipid and amino acid metabolisms in COVID-19 patients. J Mol Med (Berl). 2022; (Jan 22, online ahead of print).
Hathaway D, Pandav K, Patel M, et al. Omega 3 fatty acids and COVID-19: a comprehensive review. Infect Chemother. 2020;52(4):478–95.
Costantini L, Molinari R, Farinon B, Merendino N. Impact of omega-3 fatty acids on the gut microbiota. Int J Mol Sci. 2017;18(12):2645.
Sun Y, Chatterjee R, Ronanki A, Ye K. Circulating polyunsaturated fatty acids and COVID-19: a prospective cohort study and Mendelian randomization analysis. medRxiv. 2022; (Feb 8, online ahead of print).
Asher A, Tintle NL, Myers M, Lockshon L, Bacareza H, Harris WS. Blood omega-3 fatty acids and death from COVID-19: a pilot study. Prostaglandins Leukot Essent Fatty Acids. 2021;166:102250.
Chang JP, Pariante CM, Su KP. Omega-3 fatty acids in the psychological and physiological resilience against COVID-19. Prostaglandins Leukot Essent Fatty Acids. 2020;161:102177.
Baral PK, Amin MT, Rashid MMO, Hossain MS. Assessment of polyunsaturated fatty acids on COVID-19-associated risk reduction. Rev Bras Farmacogn. 2021:1–15.
Doaei S, Gholami S, Rastgoo S, et al. The effect of omega-3 fatty acid supplementation on clinical and biochemical parameters of critically ill patients with COVID-19: a randomized clinical trial. J Transl Med. 2021;19(1):128.
There were no external funding sources.
Ethics approval consent for participation
Consent for publication
The authors declare no conflicts of interest related to this letter to the editor.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Stahel, V.P., Blum, S.D. & Anand, P. The impact of immune dysfunction on perioperative complications in surgical COVID-19 patients: an imperative for early immunonutrition. Patient Saf Surg 16, 14 (2022). https://doi.org/10.1186/s13037-022-00323-y