Serum IFN-γ and Electrolyte Dysregulation as Independent Predictors of COVID-19 Severity: A Cross-Sectional Study in Iraqi Patients
,
Abstract
COVID-19 pandemic has caused a significant mortality and morbidity in Iraq. Evidence is mounting that immune dysfunction and electrolyte derangements are key factors in disease progression and clinical outcome. The aim of this study was to assess the diagnostic utility of serum interferon gamma (IFN-gamma) along with electrolyte levels (potassium, sodium, chloride and calcium) as markers for the severity of the COVID-19 disease using ROC curve analysis. This cross-sectional study included 200 confirmed COVID-19 (severe, 100 patients; non-severe, 100 patients) admitted to Dar Al-Salam Hospital in Baghdad during January to December 2023. Severity was determined at admission according to the criteria set by the WHO. The level of serum IFN-gamma was measured by sandwich ELISA and electrolytes (Na, K, Ca and Cl) were estimated by biochemical assays with standard chemicals. Mann-Whitney U, chi-square, Spearman correlation, and ROC curve analyses were carried out using SPSS version 26 (IBM Corp., Chicago, IL, USA). Median serum IFN-gamma was significantly higher in non-severe patients than in severe patients (30.71 vs 7.81 pg/ml; P<0.001). Sodium levels were lower in severe cases (139.95 vs 146.80 mmol/L; P<0.001), while calcium was elevated (10.27 vs 9.37 mg/dL; P<0.001). Chloride and potassium were significantly higher in severe patients (P<0.001). ROC analysis demonstrated excellent discriminatory ability for IFN-gamma (AUC=0.917, 95% CI: 0.876-0.957), good ability for calcium (AUC=0.857) and chloride (AUC=0.848), and good ability for sodium (AUC=0.827). Potassium showed fair discriminatory ability (AUC=0.702), with elevated levels associated with disease severity. Elevated IFN-gamma in non-severe cases indicates its association with reduced inflammation and recovery, while low levels correlate with disease progression. Electrolyte imbalance plays a pivotal role in COVID-19 severity. IFN-gamma, calcium, and chloride demonstrate excellent to good predictive performance for disease severity.
1. Salih AM, Al-Kelaby KKA, Al-Zaidi JR. Review on therapeutic trials for coronavirus disease-19. Med J Babylon 2021;18:155-9.
2. Cuesta-Llavona E, Gómez J, Albaiceta GM, Amado-Rodríguez L, García-Clemente M, Gutiérrez-Rodríguez J, et al. Variant-genetic and transcript-expression analysis showed a role for the chemokine-receptor CCR5 in COVID-19 severity. Int Immunopharmacol 2021;98:107825.
3. Khudhair AM, Abdulsatar DM, Hatif ST, Ridha DJ, Ali MR, Ali JAAF. Molecular characterization and genomic diversity of SARS-CoV-2 spike gene variants circulating in Iraq: mutational impact on ACE2 affinity, RBD immune escape, and viral transmission. Adv Virol 2025;2025:9916617.
4. Lippi G, South AM, Henry BM. Electrolyte imbalances in patients with severe coronavirus disease 2019 (COVID-19). Ann Clin Biochem 2020;57:262-5.
5. Scibior A, Wnuk E. Elements and COVID-19: a comprehensive overview of studies on their blood/urinary levels and supplementation with an update on clinical trials. Biology (Basel) 2022;11:215.
6. Robinson CM, O’Dee D, Hamilton T, Nau GJ. Cytokines involved in interferon-gamma production by human macrophages. J Innate Immun 2010;2:56-65.
7. Patterson BK, Seethamraju H, Dhody K, Corley MJ, Kazempour K, Lalezari JP, et al. Disruption of the CCL5/RANTES-CCR5 Pathway Restores Immune Homeostasis and Reduces Plasma Viral Load in Critical COVID-19. medRxiv [Preprint] 2020
8. Yin K, Gribbin E, Wang H. Interferon-gamma inhibition attenuates lethality after cecal ligation and puncture in rats: implication of high mobility group box-1. Shock 2005;24:396-401.
9. Alwaaeely FA, Alsaadi MA, Madlum KN. Immunomodulatory effect of propolis on IFN-γ, IL-17A and IL-23 production in human peripheral blood mononuclear cells treated with Pseudomonas aeruginosa Ag. J Chem Health Risk 2021;11:143-51.
10. Qian GQ, Yang NB, Ding F, Ma AHY, Wang ZY, Shen YF, et al. Epidemiologic and clinical characteristics of 91 hospitalized patients with COVID-19 in Zhejiang, China: a retrospective, multi-centre case series. QJM 2020;113:474-81.
11. de Carvalho H, Richared MC, Chouihed T, Goffinet N, Le Bastard Q, Freund Y, et al. Electrolyte imbalance in COVID-19 patients admitted to the emergency department: a case-control study. Intern Emerg Med 2021;16:1945-50.
12. Gálvez-Barrón C, Arroyo-Huidobro M, Miñarro A, Añaños G, Chamero A, Martin M, et al. COVID-19: clinical presentation and prognostic factors of severe disease and mortality in the oldest-old population: a cohort study. Gerontology 2022;68:30-43.
13. Post A, Dullaart RPF, Bakker SJL. Is low sodium intake a risk factor for severe and fatal COVID-19 infection? Eur J Intern Med 2020;75:109.
14. Kai H, Kai M. Interactions of coronaviruses with ACE2, angiotensin II, and RAS inhibitors-lessons from available evidence and insights into COVID-19. Hypertens Res 2020;43:648-54.
15. Kunutsor SK, Laukkanen JA. Renal complications in COVID-19: a systematic review and meta-analysis. Ann Med 2020;52:345-53.
16. Robbins-Juarez SY, Qian L, King KL, et al. Outcomes for patients with COVID-19 and acute kidney injury: a systematic review and meta-analysis. Kidney Int Rep 2020;5:1149-60.
17. Pfortmueller CA, Uehlinger D, von Haehling S, Schefold JC. Serum chloride levels in critical illness-the hidden story. Intensive Care Med Exp 2018;6:10.
18. Neyra JA, Canepa-Escaro F, Li X, et al. Association of hyperchloremia with hospital mortality in critically ill septic patients. Crit Care Med 2015;43:1938-44.
19. Bellocq A, Suberville S, Philippe C, Bertrand F, et al. Low environmental pH is responsible for the induction of nitric oxide synthase in macrophages: evidence for involvement of nuclear factor-kappaB activation. J Biol Chem 1998;273:5086-92.
20. Li C, He Q, Qian H, Liu J. Overview of the pathogenesis of COVID-19. Exp Ther Med 2021;22:1011.
21. Berend K, van Hulsteijn LH, Gans RO. Chloride: the queen of electrolytes? Eur J Intern Med 2012;23:203-11.
22. Filis C, Vasileiadis I, Koutsoukou A. Hyperchloraemia in sepsis. Ann Intensive Care 2018;8:43.
23. Pamart D, Otekpo M, Asfar M, Duval G, Gautier J, Annweiler C. Hypercalcemia as a biomarker of poor prognosis in frail elderly patients with COVID-19. J Nutr Health Aging 2021;25:1140-4.
24. Straus MR, Tang T, Lai AL. Ca2+ ions promote fusion of Middle East respiratory syndrome coronavirus with host cells and increase infectivity. J Virol 2020;94:e00426-20.
25. Sun JK, Zhang WH, Zou L. Serum calcium as a biomarker of clinical severity and prognosis in patients with coronavirus disease 2019. Aging (Albany NY) 2020;12:11287-95.
26. Singh VP, Khatua B, El-Kurdi B, Rood C. Mechanistic basis and therapeutic relevance of hypocalcemia during severe COVID-19 infection. Endocrine 2020;70:461-2.
27. Zhou Y, Frey TK, Yang JJ. Viral calciomics: interplays between Ca2+ and virus. Cell Calcium 2009;46:1-17.
28. Abdul W, Yasamine A, Al-Shireefy HMM. Incidence of acute kidney injury in hospitalized COVID-19 patients. Med J Babylon 2022;19:589-94.
29. Chen X, Cao R, Zhong W. Host calcium channels and pumps in viral infections. Cells 2020;9:94.
30. Ibtehal MS, Ahmad NF. Epidemiology and clinical characteristics of COVID-19 patients in Al-Shaikh Zayed Hospital in Baghdad in 2020. Iraqi New Med J 2022;8:1-9.
31. Wu Y, Hou B, Liu J, Chen Y, Zhong P. Risk factors associated with long-term hospitalization in patients with COVID-19: a single-center retrospective study. Front Med (Lausanne) 2020;7:315.
32. Legrand M, Bell S, Forni L, Joannidis M, Koyner JL, Liu K, et al. Pathophysiology of COVID-19-associated acute kidney injury. Nat Rev Nephrol 2021;17:751-64.
33. Chen G, Wu D, Guo W, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest 2020;130:2620-9.
34. Di Filippo L, Formenti AM, Doga M, Frara S, Rovere-Querini P, Bosi E, et al. Hypocalcemia is a distinctive biochemical feature of hospitalized COVID-19 patients. Endocrine 2021;71:9-13.
35. Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat Rev Immunol 2020;20:355-62.
36. Taha DA, Mahfouz ER, Bibars MA, Hassan NA, Othman OE. Cytokine genes expression in uteri of Bubalus bubalis associated with endometritis infection. Jordan J Biol Sci 2021;14:245-51.
37. Wynn TA. IL-13 effector functions. Annu Rev Immunol 2003;21:425-56.
38. Al-Khero ZF, Yousif ZA, Salman HA, Thanoon AH. The consequences of severe acute respiratory syndrome coronavirus-2 on acute kidney injury among Iraqi patients. Biomed Biotechnol Res J 2023;7:48-51.
39. Amin A, Menon S, Moussa O, et al. COVID-19 in patients with and without hyperkalemia. Am J Med Sci 2022;364:401-8.
40. Nieto-Torres JL, Verdiá-Báguena C, Jimenez-Guardeño JM, Regla-Nava JA, Castaño-Rodriguez C, Fernandez-Delgado R, et al. Severe acute respiratory syndrome coronavirus E protein transports calcium ions and activates the NLRP3 inflammasome. Virology 2015;485:330-9.
41. Malieckal DA, Muhsin SA, et al. Electrolyte abnormalities in patients hospitalized with COVID-19. Clin Kidney J 2021;14:1704-7.
42. Cremoni M, Allouche J, Graça D, Zorzi K, Fernandez C, Teisseyre M, et al. Low baseline IFN-γ response could predict hospitalization in COVID-19 patients. Front Immunol 2022;13:953502.
43. Hoca TN, Berktaş BM. Baseline electrolyte disorders predict disease severity and mortality in patients with COVID-19. Medicine (Baltimore) 2022;101:e32397.
44. Yasari F. The role of electrolyte imbalances in predicting the severity of COVID-19 in hospitalized patients: a cross-sectional study. Sci Rep 2022;12:14732.
45. Asgharnia M, Yarmohamadi M, Ziari A, Izadi A. Comparison of serum electrolyte levels at admission in COVID-19 patients based on outcomes: a retrospective study during the Delta variant outbreak. Middle East J Rehabil Health Stud 2025;12:e159350.
2. Cuesta-Llavona E, Gómez J, Albaiceta GM, Amado-Rodríguez L, García-Clemente M, Gutiérrez-Rodríguez J, et al. Variant-genetic and transcript-expression analysis showed a role for the chemokine-receptor CCR5 in COVID-19 severity. Int Immunopharmacol 2021;98:107825.
3. Khudhair AM, Abdulsatar DM, Hatif ST, Ridha DJ, Ali MR, Ali JAAF. Molecular characterization and genomic diversity of SARS-CoV-2 spike gene variants circulating in Iraq: mutational impact on ACE2 affinity, RBD immune escape, and viral transmission. Adv Virol 2025;2025:9916617.
4. Lippi G, South AM, Henry BM. Electrolyte imbalances in patients with severe coronavirus disease 2019 (COVID-19). Ann Clin Biochem 2020;57:262-5.
5. Scibior A, Wnuk E. Elements and COVID-19: a comprehensive overview of studies on their blood/urinary levels and supplementation with an update on clinical trials. Biology (Basel) 2022;11:215.
6. Robinson CM, O’Dee D, Hamilton T, Nau GJ. Cytokines involved in interferon-gamma production by human macrophages. J Innate Immun 2010;2:56-65.
7. Patterson BK, Seethamraju H, Dhody K, Corley MJ, Kazempour K, Lalezari JP, et al. Disruption of the CCL5/RANTES-CCR5 Pathway Restores Immune Homeostasis and Reduces Plasma Viral Load in Critical COVID-19. medRxiv [Preprint] 2020
8. Yin K, Gribbin E, Wang H. Interferon-gamma inhibition attenuates lethality after cecal ligation and puncture in rats: implication of high mobility group box-1. Shock 2005;24:396-401.
9. Alwaaeely FA, Alsaadi MA, Madlum KN. Immunomodulatory effect of propolis on IFN-γ, IL-17A and IL-23 production in human peripheral blood mononuclear cells treated with Pseudomonas aeruginosa Ag. J Chem Health Risk 2021;11:143-51.
10. Qian GQ, Yang NB, Ding F, Ma AHY, Wang ZY, Shen YF, et al. Epidemiologic and clinical characteristics of 91 hospitalized patients with COVID-19 in Zhejiang, China: a retrospective, multi-centre case series. QJM 2020;113:474-81.
11. de Carvalho H, Richared MC, Chouihed T, Goffinet N, Le Bastard Q, Freund Y, et al. Electrolyte imbalance in COVID-19 patients admitted to the emergency department: a case-control study. Intern Emerg Med 2021;16:1945-50.
12. Gálvez-Barrón C, Arroyo-Huidobro M, Miñarro A, Añaños G, Chamero A, Martin M, et al. COVID-19: clinical presentation and prognostic factors of severe disease and mortality in the oldest-old population: a cohort study. Gerontology 2022;68:30-43.
13. Post A, Dullaart RPF, Bakker SJL. Is low sodium intake a risk factor for severe and fatal COVID-19 infection? Eur J Intern Med 2020;75:109.
14. Kai H, Kai M. Interactions of coronaviruses with ACE2, angiotensin II, and RAS inhibitors-lessons from available evidence and insights into COVID-19. Hypertens Res 2020;43:648-54.
15. Kunutsor SK, Laukkanen JA. Renal complications in COVID-19: a systematic review and meta-analysis. Ann Med 2020;52:345-53.
16. Robbins-Juarez SY, Qian L, King KL, et al. Outcomes for patients with COVID-19 and acute kidney injury: a systematic review and meta-analysis. Kidney Int Rep 2020;5:1149-60.
17. Pfortmueller CA, Uehlinger D, von Haehling S, Schefold JC. Serum chloride levels in critical illness-the hidden story. Intensive Care Med Exp 2018;6:10.
18. Neyra JA, Canepa-Escaro F, Li X, et al. Association of hyperchloremia with hospital mortality in critically ill septic patients. Crit Care Med 2015;43:1938-44.
19. Bellocq A, Suberville S, Philippe C, Bertrand F, et al. Low environmental pH is responsible for the induction of nitric oxide synthase in macrophages: evidence for involvement of nuclear factor-kappaB activation. J Biol Chem 1998;273:5086-92.
20. Li C, He Q, Qian H, Liu J. Overview of the pathogenesis of COVID-19. Exp Ther Med 2021;22:1011.
21. Berend K, van Hulsteijn LH, Gans RO. Chloride: the queen of electrolytes? Eur J Intern Med 2012;23:203-11.
22. Filis C, Vasileiadis I, Koutsoukou A. Hyperchloraemia in sepsis. Ann Intensive Care 2018;8:43.
23. Pamart D, Otekpo M, Asfar M, Duval G, Gautier J, Annweiler C. Hypercalcemia as a biomarker of poor prognosis in frail elderly patients with COVID-19. J Nutr Health Aging 2021;25:1140-4.
24. Straus MR, Tang T, Lai AL. Ca2+ ions promote fusion of Middle East respiratory syndrome coronavirus with host cells and increase infectivity. J Virol 2020;94:e00426-20.
25. Sun JK, Zhang WH, Zou L. Serum calcium as a biomarker of clinical severity and prognosis in patients with coronavirus disease 2019. Aging (Albany NY) 2020;12:11287-95.
26. Singh VP, Khatua B, El-Kurdi B, Rood C. Mechanistic basis and therapeutic relevance of hypocalcemia during severe COVID-19 infection. Endocrine 2020;70:461-2.
27. Zhou Y, Frey TK, Yang JJ. Viral calciomics: interplays between Ca2+ and virus. Cell Calcium 2009;46:1-17.
28. Abdul W, Yasamine A, Al-Shireefy HMM. Incidence of acute kidney injury in hospitalized COVID-19 patients. Med J Babylon 2022;19:589-94.
29. Chen X, Cao R, Zhong W. Host calcium channels and pumps in viral infections. Cells 2020;9:94.
30. Ibtehal MS, Ahmad NF. Epidemiology and clinical characteristics of COVID-19 patients in Al-Shaikh Zayed Hospital in Baghdad in 2020. Iraqi New Med J 2022;8:1-9.
31. Wu Y, Hou B, Liu J, Chen Y, Zhong P. Risk factors associated with long-term hospitalization in patients with COVID-19: a single-center retrospective study. Front Med (Lausanne) 2020;7:315.
32. Legrand M, Bell S, Forni L, Joannidis M, Koyner JL, Liu K, et al. Pathophysiology of COVID-19-associated acute kidney injury. Nat Rev Nephrol 2021;17:751-64.
33. Chen G, Wu D, Guo W, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest 2020;130:2620-9.
34. Di Filippo L, Formenti AM, Doga M, Frara S, Rovere-Querini P, Bosi E, et al. Hypocalcemia is a distinctive biochemical feature of hospitalized COVID-19 patients. Endocrine 2021;71:9-13.
35. Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat Rev Immunol 2020;20:355-62.
36. Taha DA, Mahfouz ER, Bibars MA, Hassan NA, Othman OE. Cytokine genes expression in uteri of Bubalus bubalis associated with endometritis infection. Jordan J Biol Sci 2021;14:245-51.
37. Wynn TA. IL-13 effector functions. Annu Rev Immunol 2003;21:425-56.
38. Al-Khero ZF, Yousif ZA, Salman HA, Thanoon AH. The consequences of severe acute respiratory syndrome coronavirus-2 on acute kidney injury among Iraqi patients. Biomed Biotechnol Res J 2023;7:48-51.
39. Amin A, Menon S, Moussa O, et al. COVID-19 in patients with and without hyperkalemia. Am J Med Sci 2022;364:401-8.
40. Nieto-Torres JL, Verdiá-Báguena C, Jimenez-Guardeño JM, Regla-Nava JA, Castaño-Rodriguez C, Fernandez-Delgado R, et al. Severe acute respiratory syndrome coronavirus E protein transports calcium ions and activates the NLRP3 inflammasome. Virology 2015;485:330-9.
41. Malieckal DA, Muhsin SA, et al. Electrolyte abnormalities in patients hospitalized with COVID-19. Clin Kidney J 2021;14:1704-7.
42. Cremoni M, Allouche J, Graça D, Zorzi K, Fernandez C, Teisseyre M, et al. Low baseline IFN-γ response could predict hospitalization in COVID-19 patients. Front Immunol 2022;13:953502.
43. Hoca TN, Berktaş BM. Baseline electrolyte disorders predict disease severity and mortality in patients with COVID-19. Medicine (Baltimore) 2022;101:e32397.
44. Yasari F. The role of electrolyte imbalances in predicting the severity of COVID-19 in hospitalized patients: a cross-sectional study. Sci Rep 2022;12:14732.
45. Asgharnia M, Yarmohamadi M, Ziari A, Izadi A. Comparison of serum electrolyte levels at admission in COVID-19 patients based on outcomes: a retrospective study during the Delta variant outbreak. Middle East J Rehabil Health Stud 2025;12:e159350.
| Files | ||
| Issue | Vol 64 No 7 (2026) | |
| Section | Original Articles | |
| DOI | https://doi.org/10.18502/acta.v64i7.22413 | |
| Keywords | ||
| COVID-19 IFN-γ Hyperchloremia Hypercalcemia Hyponatremia Hyperkalemia Electrolytes ROC | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Alwaeely FA, Yousif ZAA-A. Serum IFN-γ and Electrolyte Dysregulation as Independent Predictors of COVID-19 Severity: A Cross-Sectional Study in Iraqi Patients. Acta Med Iran. 2026;64(7):460-469.
