Long-standing COVID-19 Disease in Immunocompromised and Immunocompetent Patients; Case Reports and Literature Review
-
Esmaeil Mortaz
,
Neda Dalil Roofchayee
,
Hamidreza Jamaati
,
Mohammad Varaham
,
Zahra Abtahian
,
Babak Afshar
,
Mahsa Rekabi
,
Ian M. Adcock
,
Payam Tabarsi
Abstract
Patients with immunodeficiency are at higher risk of severe disease and death following SARS-CoV-2 infection compared to the general population. Here, we describe humoral and cellular immune responses in 5 patients with immunodeficiency, 2 patients with multiple sclerosis, 1 patient with chronic lymphocytic leukemia (CLL), 1 patient with Good’s syndrome, and 1Human Immunodeficiency Virus (HIV) positive with developed Acquired immunodeficiency syndrome (AIDS)- patient.
T-cell responses were evaluated using the QuantiFERON SARS-CoV-2 assay following incubation with the SARS-CoV-2 Ag1, Ag2, and Ag3 viral antigens. Immunophenotyping of CD4+ and CD8+ T cells and CD19+ and CD20+ B cells was determined by flow cytometry.
All studied immunocompromised patients or those with acquired immune dysregulation patients showed reduced cellular immune responses (release of interferon (IFN)-g) to SARS-CoV-2 antigens than healthy controls [patients; Ag1, Ag2 and Ag3 and Nil (Median 5-95% percentile) (12 (1-95), 12 (1.5-78), 13.5 (12-95) and 3 (1-98) U/mL)], controls; Ag1, Ag2 and Ag3 and Nil (Median 5-95% percentile) 24.5 (7-89), 65 (31-173), 53.5 (13-71.5) and 3 (1-14) U/mL)]. The frequency of peripheral blood B cells was also reduced in these patients compared to healthy control subjects.
T-cell-dependent antibody responses require the activation of B cells by helper T cells. Reduced B cell numbers in immunocompromised patients infected with SARS-CoV-2 indicate the need for these patients to take additional precautions to prevent COVID-19 infection.
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2. Melenotte C, Silvin A, Goubet A-G, Lahmar I, Dubuisson A, Zumla A, et al. Immune responses during COVID-19 infection. Oncoimmunology. 2020;9(1):1807836.
3. Rezaei M, Mahmoudi S, Mortaz E, Marjani M. Immune cell profiling and antibody responses in patients with COVID-19. BMC Infect Dis. 2021;21(5):1-9.
4. Ahmadpoor P, Rostaing L. Why the immune system fails to mount an adaptive immune response to a Covid-19 infection. Transpl Int. 2020;33(7):824-5.
5. NICE. COVID-19 rapid guideline: managing the long-term effects of COVID-19. [Internet]. 2020 Dec 18 [cited 2021 ]. Available from https://www.nice.org.uk /guidance/ng188.
6. Davis HE, McCorkell L, Vogel JM, Topol EJ. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21(3):133-46.
7. Dioverti V, Salto-Alejandre S, Haidar G. Immunocompromised Patients with Protracted COVID-19: a Review of "Long Persisters". Curr Transplant Rep. 2022;9(4):209-18.
8. Chen Z, John Wherry E. T cell responses in patients with COVID-19. Nat Rev Immunol. 2020;20(9):529-36.
9. Liu L, Wei Q, Lin Q, Fang J, Wang H, Kwok H, et al. Anti–spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection. JCI Insight. 2019;4(4).
10. Adcock I, Alipoor S, Mortaz E, Jamaati H, Tabarsi P, Bayram H. COVID-2019: Molecular and cellular response. Front Cell Infect Microbiol. 2021:11:563085.
11. Zhang Q, Bastard P, Liu Z, Le Pen J, Moncada-Velez M, Chen J, et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science. 2020;370(6515):eabd4570.
12. Bastard P, Rosen LB, Zhang Q, Michailidis E, Hoffmann H-H, Zhang Y, et al. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science. 2020;370(6515):eabd4585.
13. Lucas C, Wong P, Klein J, Castro TB, Silva J, Sundaram M, et al. Longitudinal analyses reveal immunological misfiring in severe COVID-19. Nature. 2020;584(7821):463-9.
14. Mortaz E, Tabarsi P, Jamaati H, Dalil Roofchayee N, Dezfuli NK, Hashemian SM, et al. Increased serum levels of soluble TNF-α receptor is associated with ICU mortality in COVID-19 patients. Front Immunol. 2021;12(5):592727.
15. Mrak D, Tobudic S, Koblischke M, Graninger M, Radner H, Sieghart D, et al. SARS-CoV-2 vaccination in rituximab-treated patients: B cells promote humoral immune responses in the presence of T-cell-mediated immunity. Ann Rheum Dis. 2021;80(10):1345-50.
16. Mortaz E, Bassir A, Roofchayee ND, Dezfuli NK, Jamaati H, Tabarsi P, et al. Serum cytokine levels of COVID-19 patients after 7 days of treatment with Favipiravir or Kaletra. Int Immunopharmacol. 2021;93(18):107407.
17. Notarbartolo S, Ranzani V, Bandera A, Gruarin P, Bevilacqua V, Putignano AR, et al. Integrated longitudinal immunophenotypic, transcriptional, and repertoire analyses delineate immune responses in patients with COVID-19. Sci Immunol. 2021;6(62):eabg5021.
18. Bergamaschi L, Mescia F, Turner L, Hanson AL, Kotagiri P, Dunmore BJ, et al. Longitudinal analysis reveals that delayed bystander CD8+ T cell activation and early immune pathology distinguish severe COVID-19 from mild disease. Immunity. 2021;54(6):1257-75.e8.
19. Lucas C, Klein J, Sundaram ME, Liu F, Wong P, Silva J, et al. Delayed production of neutralizing antibodies correlates with fatal COVID-19. Nat Med. 2021;27(7):1178-86.
20. Wu H-S, Hsieh Y-C, Su I-J, Lin T-H, Chiu S-C, Hsu Y-F, et al. Early detection of antibodies against various structural proteins of the SARS-associated coronavirus in SARS patients. J Biomed Sci. 2004;11(3):117-26.
21. Jalil M, Pietras J, Ahmed SN, Daniels P, Hostoffer R. COVID-19 infection in patients with humoral immunodeficiency: A case series and literature review. Allergy Rhinol. 2022;13(7):21526575221096044.
22. Zabalza A, Cárdenas‐Robledo S, Tagliani P, Arrambide G, Otero‐Romero S, Carbonell‐Mirabent P, et al. COVID‐19 in multiple sclerosis patients: susceptibility, severity risk factors and serological response. Eur J Neurol. 2021;28(10):3384-95.
23. Baker D, Amor S, Kang AS, Schmierer K, Giovannoni G. The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic. Mult Scler Relat Disord. 2020;43(8):102174.
24. Safavi F, Nourbakhsh B, Azimi AR. B-cell depleting therapies may affect susceptibility to acute respiratory illness among patients with multiple sclerosis during the early COVID-19 epidemic in Iran. Mult Scler Relat Disord. 2020;43(5):102195.
25. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-62.
26. WHO. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected. Interim guidance. Paediatr Fam Med. 2020;16(1):9.
27. Nogués X, Sánchez-Martinez F, Castells X, Díez-Pérez A, Sabaté RA, Petit I, et al. Hospital-at-Home expands hospital capacity during COVID-19 pandemic. J Am Med Dir Assoc. 2021;22(5):939-42.
28. Jaganathan S, Stieber F, Rao SN, Nikolayevskyy V, Manissero D, Allen N, et al. Preliminary evaluation of QuantiFERON SARS-CoV-2 and QIAreach anti-SARS-CoV-2 total test in recently vaccinated individuals. Infect Dis Ther. 2021;10(4):2765-76.
29. Pozzi MR, Baronio M, Janetti MB, Gazzurelli L, Moratto D, Chiarini M, et al. Fatal SARS-CoV-2 infection in a male patient with Good's syndrome. Clin Immunol (Orlando, Fla). 2021;223(41):108644.
30. Kräutler NJ, Suan D, Butt D, Bourne K, Hermes JR, Chan TD, et al. Differentiation of germinal center B cells into plasma cells is initiated by high-affinity antigen and completed by Tfh cells. J Exp Med. 2017;214(5):1259-67.
31. Kaneko N, Kuo H-H, Boucau J, Farmer JR, Allard-Chamard H, Mahajan VS, et al. Loss of Bcl-6-expressing T follicular helper cells and germinal centers in COVID-19. Cell. 2020;183(1):143-57.e13.
32. Blixt L, Bogdanovic G, Buggert M, Gao Y, Hober S, Healy K, et al. Covid-19 in patients with chronic lymphocytic leukemia: clinical outcome and B-and T-cell immunity during 13 months in consecutive patients. Leukemia. 2022;36(2):476-81.
33. Langerbeins P, Eichhorst B. Immune dysfunction in patients with chronic lymphocytic leukemia and challenges during COVID-19 pandemic. Acta Haematol. 2021;144(5):508-18.
34. Freeman JA, Crassini KR, Best OG, Forsyth CJ, Mackinlay NJ, Han P, et al. Immunoglobulin G subclass deficiency and infection risk in 150 patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2013;54(1):99-104.
35. Weeks JC, Tierney MR, Weinstein MC. Cost effectiveness of prophylactic intravenous immune globulin in chronic lymphocytic leukemia. N Engl J Med. 1991;325(2):81-6.
36. Danwang C, Noubiap JJ, Robert A, Yombi JC. Outcomes of patients with HIV and COVID-19 co-infection: a systematic review and meta-analysis. AIDS Res Ther. 2022;19(1):1-12.
37. Mascolo S, Romanelli A, Carleo MA, Esposito V. Could HIV infection alter the clinical course of SARS‐CoV‐2 infection? When less is better. J Med Virol. 2020;92(10):1777.
38. Sormani MP, De Rossi N, Schiavetti I, Carmisciano L, Cordioli C, Moiola L, et al. Disease‐modifying therapies and coronavirus disease 2019 severity in multiple sclerosis. Ann Neurol. 2021;89(4):780-9.
39. Sahraian MA, Azimi A, Navardi S, Ala S, Moghadasi AN. Evaluation of the rate of COVID-19 infection, hospitalization and death among Iranian patients with multiple sclerosis. Mult Scler Relat Disord. 2020;46(9):102472.
40. Soong R-S, Song L, Trieu J, Lee SY, He L, Tsai Y-C, et al. Direct T cell activation via CD40 ligand generates high avidity CD8+ T cells capable of breaking immunological tolerance for the control of tumors. PLoS One. 2014;9(3):e93162.
41. Chen S, Guan F, Candotti F, Benlagha K, Camara NOS, Herrada AA, et al. The role of B cells in COVID-19 infection and vaccination. Front Immunol. 2022;13:988536.
42. Song H, Cerny J. Functional heterogeneity of marginal zone B cells revealed by their ability to generate both early antibody-forming cells and germinal centers with hypermutation and memory in response to a T-dependent antigen. J Exp Med. 2003;198(12):1923-35.
43. Martin F, Oliver AM, Kearney JF. Marginal zone and B1 B cells unite in the early response against T-independent blood-borne particulate antigens. Immunity. 2001;14(5):617-29.
44. Liu Y, Wu Y, Ramarathinam L, Guo Y, Huszar D, Trounstine M, et al. Gene-targeted B-deficient mice reveal a critical role for B cells in the CD4 T cell response. Int Immunol. 1995;7(8):1353-62.
45. Lund FE, Randall TD. Effector and regulatory B cells: modulators of CD4+ T cell immunity. Nat Rev Immunol. 2010;10(4):236-47.
46. Tay C, Kanellakis P, Hosseini H, Cao A, Toh B-H, Bobik A, et al. B cell and CD4 T cell interactions promote development of atherosclerosis. Front Immunol. 2020;10:3046.
2. Melenotte C, Silvin A, Goubet A-G, Lahmar I, Dubuisson A, Zumla A, et al. Immune responses during COVID-19 infection. Oncoimmunology. 2020;9(1):1807836.
3. Rezaei M, Mahmoudi S, Mortaz E, Marjani M. Immune cell profiling and antibody responses in patients with COVID-19. BMC Infect Dis. 2021;21(5):1-9.
4. Ahmadpoor P, Rostaing L. Why the immune system fails to mount an adaptive immune response to a Covid-19 infection. Transpl Int. 2020;33(7):824-5.
5. NICE. COVID-19 rapid guideline: managing the long-term effects of COVID-19. [Internet]. 2020 Dec 18 [cited 2021 ]. Available from https://www.nice.org.uk /guidance/ng188.
6. Davis HE, McCorkell L, Vogel JM, Topol EJ. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21(3):133-46.
7. Dioverti V, Salto-Alejandre S, Haidar G. Immunocompromised Patients with Protracted COVID-19: a Review of "Long Persisters". Curr Transplant Rep. 2022;9(4):209-18.
8. Chen Z, John Wherry E. T cell responses in patients with COVID-19. Nat Rev Immunol. 2020;20(9):529-36.
9. Liu L, Wei Q, Lin Q, Fang J, Wang H, Kwok H, et al. Anti–spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection. JCI Insight. 2019;4(4).
10. Adcock I, Alipoor S, Mortaz E, Jamaati H, Tabarsi P, Bayram H. COVID-2019: Molecular and cellular response. Front Cell Infect Microbiol. 2021:11:563085.
11. Zhang Q, Bastard P, Liu Z, Le Pen J, Moncada-Velez M, Chen J, et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science. 2020;370(6515):eabd4570.
12. Bastard P, Rosen LB, Zhang Q, Michailidis E, Hoffmann H-H, Zhang Y, et al. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science. 2020;370(6515):eabd4585.
13. Lucas C, Wong P, Klein J, Castro TB, Silva J, Sundaram M, et al. Longitudinal analyses reveal immunological misfiring in severe COVID-19. Nature. 2020;584(7821):463-9.
14. Mortaz E, Tabarsi P, Jamaati H, Dalil Roofchayee N, Dezfuli NK, Hashemian SM, et al. Increased serum levels of soluble TNF-α receptor is associated with ICU mortality in COVID-19 patients. Front Immunol. 2021;12(5):592727.
15. Mrak D, Tobudic S, Koblischke M, Graninger M, Radner H, Sieghart D, et al. SARS-CoV-2 vaccination in rituximab-treated patients: B cells promote humoral immune responses in the presence of T-cell-mediated immunity. Ann Rheum Dis. 2021;80(10):1345-50.
16. Mortaz E, Bassir A, Roofchayee ND, Dezfuli NK, Jamaati H, Tabarsi P, et al. Serum cytokine levels of COVID-19 patients after 7 days of treatment with Favipiravir or Kaletra. Int Immunopharmacol. 2021;93(18):107407.
17. Notarbartolo S, Ranzani V, Bandera A, Gruarin P, Bevilacqua V, Putignano AR, et al. Integrated longitudinal immunophenotypic, transcriptional, and repertoire analyses delineate immune responses in patients with COVID-19. Sci Immunol. 2021;6(62):eabg5021.
18. Bergamaschi L, Mescia F, Turner L, Hanson AL, Kotagiri P, Dunmore BJ, et al. Longitudinal analysis reveals that delayed bystander CD8+ T cell activation and early immune pathology distinguish severe COVID-19 from mild disease. Immunity. 2021;54(6):1257-75.e8.
19. Lucas C, Klein J, Sundaram ME, Liu F, Wong P, Silva J, et al. Delayed production of neutralizing antibodies correlates with fatal COVID-19. Nat Med. 2021;27(7):1178-86.
20. Wu H-S, Hsieh Y-C, Su I-J, Lin T-H, Chiu S-C, Hsu Y-F, et al. Early detection of antibodies against various structural proteins of the SARS-associated coronavirus in SARS patients. J Biomed Sci. 2004;11(3):117-26.
21. Jalil M, Pietras J, Ahmed SN, Daniels P, Hostoffer R. COVID-19 infection in patients with humoral immunodeficiency: A case series and literature review. Allergy Rhinol. 2022;13(7):21526575221096044.
22. Zabalza A, Cárdenas‐Robledo S, Tagliani P, Arrambide G, Otero‐Romero S, Carbonell‐Mirabent P, et al. COVID‐19 in multiple sclerosis patients: susceptibility, severity risk factors and serological response. Eur J Neurol. 2021;28(10):3384-95.
23. Baker D, Amor S, Kang AS, Schmierer K, Giovannoni G. The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic. Mult Scler Relat Disord. 2020;43(8):102174.
24. Safavi F, Nourbakhsh B, Azimi AR. B-cell depleting therapies may affect susceptibility to acute respiratory illness among patients with multiple sclerosis during the early COVID-19 epidemic in Iran. Mult Scler Relat Disord. 2020;43(5):102195.
25. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-62.
26. WHO. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected. Interim guidance. Paediatr Fam Med. 2020;16(1):9.
27. Nogués X, Sánchez-Martinez F, Castells X, Díez-Pérez A, Sabaté RA, Petit I, et al. Hospital-at-Home expands hospital capacity during COVID-19 pandemic. J Am Med Dir Assoc. 2021;22(5):939-42.
28. Jaganathan S, Stieber F, Rao SN, Nikolayevskyy V, Manissero D, Allen N, et al. Preliminary evaluation of QuantiFERON SARS-CoV-2 and QIAreach anti-SARS-CoV-2 total test in recently vaccinated individuals. Infect Dis Ther. 2021;10(4):2765-76.
29. Pozzi MR, Baronio M, Janetti MB, Gazzurelli L, Moratto D, Chiarini M, et al. Fatal SARS-CoV-2 infection in a male patient with Good's syndrome. Clin Immunol (Orlando, Fla). 2021;223(41):108644.
30. Kräutler NJ, Suan D, Butt D, Bourne K, Hermes JR, Chan TD, et al. Differentiation of germinal center B cells into plasma cells is initiated by high-affinity antigen and completed by Tfh cells. J Exp Med. 2017;214(5):1259-67.
31. Kaneko N, Kuo H-H, Boucau J, Farmer JR, Allard-Chamard H, Mahajan VS, et al. Loss of Bcl-6-expressing T follicular helper cells and germinal centers in COVID-19. Cell. 2020;183(1):143-57.e13.
32. Blixt L, Bogdanovic G, Buggert M, Gao Y, Hober S, Healy K, et al. Covid-19 in patients with chronic lymphocytic leukemia: clinical outcome and B-and T-cell immunity during 13 months in consecutive patients. Leukemia. 2022;36(2):476-81.
33. Langerbeins P, Eichhorst B. Immune dysfunction in patients with chronic lymphocytic leukemia and challenges during COVID-19 pandemic. Acta Haematol. 2021;144(5):508-18.
34. Freeman JA, Crassini KR, Best OG, Forsyth CJ, Mackinlay NJ, Han P, et al. Immunoglobulin G subclass deficiency and infection risk in 150 patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2013;54(1):99-104.
35. Weeks JC, Tierney MR, Weinstein MC. Cost effectiveness of prophylactic intravenous immune globulin in chronic lymphocytic leukemia. N Engl J Med. 1991;325(2):81-6.
36. Danwang C, Noubiap JJ, Robert A, Yombi JC. Outcomes of patients with HIV and COVID-19 co-infection: a systematic review and meta-analysis. AIDS Res Ther. 2022;19(1):1-12.
37. Mascolo S, Romanelli A, Carleo MA, Esposito V. Could HIV infection alter the clinical course of SARS‐CoV‐2 infection? When less is better. J Med Virol. 2020;92(10):1777.
38. Sormani MP, De Rossi N, Schiavetti I, Carmisciano L, Cordioli C, Moiola L, et al. Disease‐modifying therapies and coronavirus disease 2019 severity in multiple sclerosis. Ann Neurol. 2021;89(4):780-9.
39. Sahraian MA, Azimi A, Navardi S, Ala S, Moghadasi AN. Evaluation of the rate of COVID-19 infection, hospitalization and death among Iranian patients with multiple sclerosis. Mult Scler Relat Disord. 2020;46(9):102472.
40. Soong R-S, Song L, Trieu J, Lee SY, He L, Tsai Y-C, et al. Direct T cell activation via CD40 ligand generates high avidity CD8+ T cells capable of breaking immunological tolerance for the control of tumors. PLoS One. 2014;9(3):e93162.
41. Chen S, Guan F, Candotti F, Benlagha K, Camara NOS, Herrada AA, et al. The role of B cells in COVID-19 infection and vaccination. Front Immunol. 2022;13:988536.
42. Song H, Cerny J. Functional heterogeneity of marginal zone B cells revealed by their ability to generate both early antibody-forming cells and germinal centers with hypermutation and memory in response to a T-dependent antigen. J Exp Med. 2003;198(12):1923-35.
43. Martin F, Oliver AM, Kearney JF. Marginal zone and B1 B cells unite in the early response against T-independent blood-borne particulate antigens. Immunity. 2001;14(5):617-29.
44. Liu Y, Wu Y, Ramarathinam L, Guo Y, Huszar D, Trounstine M, et al. Gene-targeted B-deficient mice reveal a critical role for B cells in the CD4 T cell response. Int Immunol. 1995;7(8):1353-62.
45. Lund FE, Randall TD. Effector and regulatory B cells: modulators of CD4+ T cell immunity. Nat Rev Immunol. 2010;10(4):236-47.
46. Tay C, Kanellakis P, Hosseini H, Cao A, Toh B-H, Bobik A, et al. B cell and CD4 T cell interactions promote development of atherosclerosis. Front Immunol. 2020;10:3046.
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How to Cite
1.
Mortaz E, Dalil Roofchayee N, Jamaati H, Varaham M, Abtahian Z, Afshar B, Rekabi M, Adcock I, Tabarsi P. Long-standing COVID-19 Disease in Immunocompromised and Immunocompetent Patients; Case Reports and Literature Review. Iran J Allergy Asthma Immunol. 2024;:1-10.
