1932

Abstract

Cytokine storm syndrome (CSS), which is frequently fatal, has garnered increased attention with the ongoing coronavirus pandemic. A variety of hyperinflammatory conditions associated with multiorgan system failure can be lumped under the CSS umbrella, including familial hemophagocytic lymphohistiocytosis (HLH) and secondary HLH associated with infections, hematologic malignancies, and autoimmune and autoinflammatory disorders, in which case CSS is termed macrophage activation syndrome (MAS). Various classification and diagnostic CSS criteria exist and include clinical, laboratory, pathologic, and genetic features. Familial HLH results from cytolytic homozygous genetic defects in the perforin pathway employed by cytotoxic CD8 T lymphocytes and natural killer (NK) cells. Similarly, NK cell dysfunction is often present in secondary HLH and MAS, and heterozygous mutations in familial HLH genes are frequently present. Targeting overly active lymphocytes and macrophages with etoposide and glucocorticoids is the standard for treating HLH; however, more targeted and safer anticytokine (e.g., anti-interleukin-1, -6) approaches are gaining traction as effective alternatives.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-med-042921-112837
2023-01-27
2024-06-16
Loading full text...

Full text loading...

/deliver/fulltext/med/74/1/annurev-med-042921-112837.html?itemId=/content/journals/10.1146/annurev-med-042921-112837&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Henderson LA, Canna SW, Schulert GS et al. 2020. On the alert for cytokine storm: immunopathology in COVID-19. Arthritis Rheumatol. 72:1059–63
    [Google Scholar]
  2. 2.
    Fajgenbaum DC, June CH. 2020. Cytokine storm. N. Engl. J. Med. 383:2255–73
    [Google Scholar]
  3. 3.
    Cron RQ, Caricchio R, Chatham WW. 2021. Calming the cytokine storm in COVID-19. Nat. Med. 27:1674–75
    [Google Scholar]
  4. 4.
    Henderson LA, Cron RQ. 2020. Macrophage activation syndrome and secondary hemophagocytic lymphohistiocytosis in childhood inflammatory disorders: diagnosis and management. Paediatr. Drugs 22:29–44
    [Google Scholar]
  5. 5.
    Henter JI, Horne A, Arico M et al. 2007. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr. Blood Cancer 48:124–31
    [Google Scholar]
  6. 6.
    Ravelli A, Minoia F, Davi S et al. 2016. 2016 classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation collaborative initiative. Arthritis Rheumatol. 68:566–76
    [Google Scholar]
  7. 7.
    Minoia F, Bovis F, Davi S et al. 2019. Development and initial validation of the MS score for diagnosis of macrophage activation syndrome in systemic juvenile idiopathic arthritis. Ann. Rheum. Dis. 78:1357–62
    [Google Scholar]
  8. 8.
    Gerstein M, Borgia RE, Dominguez D et al. 2021. Predicting macrophage activation syndrome in childhood-onset systemic lupus erythematosus patients at diagnosis. J. Rheumatol. 48:1450–57
    [Google Scholar]
  9. 9.
    Eloseily EMA, Minoia F, Crayne CB et al. 2019. Ferritin to erythrocyte sedimentation rate ratio: simple measure to identify macrophage activation syndrome in systemic juvenile idiopathic arthritis. ACR Open Rheumatol. 1:345–49
    [Google Scholar]
  10. 10.
    Fardet L, Galicier L, Lambotte O et al. 2014. Development and validation of a score for the diagnosis of reactive hemophagocytic syndrome (HScore). Arthritis Rheumatol. 66:2613–20
    [Google Scholar]
  11. 11.
    Canna SW, Cron RQ. 2020. Highways to hell: mechanism based management of cytokine storm syndromes. J. Allergy Clin. Immunol. 146:949–59
    [Google Scholar]
  12. 12.
    Lee DW, Santomasso BD, Locke FL et al. 2019. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol. Blood Marrow Transplant. 25:625–38
    [Google Scholar]
  13. 13.
    Reiff DD, Cron RQ. 2021. Performance of cytokine storm syndrome scoring systems in pediatric COVID-19 and multisystem inflammatory syndrome in children. ACR Open Rheumatol. 3:820–26
    [Google Scholar]
  14. 14.
    Reiff DD, Cron RQ. 2022. Who would have predicted multisystem inflammatory syndrome in children?. Curr. Rheumatol. Rep. 24:1–11
    [Google Scholar]
  15. 15.
    Schulert GS, Cron RQ. 2020. The genetics of macrophage activation syndrome. Genes Immun. 21:169–81
    [Google Scholar]
  16. 16.
    Jordan MB, Hildeman D, Kappler J, Marrack P. 2004. An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon γ are essential for the disorder. Blood 104:735–43Reveals that the host immune response was responsible for murine familial HLH mortality.
    [Google Scholar]
  17. 17.
    Jenkins MR, Rudd-Schmidt JA, Lopez JA et al. 2015. Failed CTL/NK cell killing and cytokine hypersecretion are directly linked through prolonged synapse time. J. Exp. Med. 212:307–17Demonstrates that prolonged interaction between perforin-deficient lymphocytes and APCs yields increased numbers of proinflammatory cytokines.
    [Google Scholar]
  18. 18.
    Locatelli F, Jordan MB, Allen C 2020. Emapalumab in children with primary hemophagocytic lymphohistiocytosis. N. Engl. J. Med. 382:1811–22Demonstrates a notable survival benefit to infants with familial HLH.
    [Google Scholar]
  19. 19.
    Zhang M, Bracaglia C, Prencipe G et al. 2016. A heterozygous RAB27A mutation associated with delayed cytolytic granule polarization and hemophagocytic lymphohistiocytosis. J. Immunol. 196:2492–503Shows that a partial dominant-negative mutation in RAB27A decreased cytolysis contributing to CSS in two unrelated teenagers.
    [Google Scholar]
  20. 20.
    Spessott WA, Sanmillan ML, McCormick ME et al. 2015. Hemophagocytic lymphohistiocytosis caused by dominant-negative mutations in STXBP2 that inhibit SNARE-mediated membrane fusion. Blood 125:1566–77Shows that two novel complete dominant-negative mutations in STXBP2 disrupted cytolytic granule membrane fusion in CSS patients.
    [Google Scholar]
  21. 21.
    Strippoli R, Caiello I, De Benedetti F. 2013. Reaching the threshold: a multilayer pathogenesis of macrophage activation syndrome. J. Rheumatol. 40:761–67
    [Google Scholar]
  22. 22.
    Schulert GS, Zhang M, Fall N et al. 2016. Whole-exome sequencing reveals mutations in genes linked to hemophagocytic lymphohistiocytosis and macrophage activation syndrome in fatal cases of H1N1 influenza. J. Infect. Dis. 213:1180–88
    [Google Scholar]
  23. 23.
    McElroy AK, Erickson BR, Flietstra TD et al. 2014. Ebola hemorrhagic fever: novel biomarker correlates of clinical outcome. J. Infect. Dis. 210:558–66
    [Google Scholar]
  24. 24.
    Cron RQ, Behrens EM, Shakoory B et al. 2015. Does viral hemorrhagic fever represent reactive hemophagocytic syndrome?. J. Rheumatol. 42:1078–80
    [Google Scholar]
  25. 25.
    Chen G, Wu D, Guo W et al. 2020. Clinical and immunological features of severe and moderate coronavirus disease 2019. J. Clin. Investig. 130:2620–29
    [Google Scholar]
  26. 26.
    Huang C, Wang Y, Li X et al. 2020. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395:497–506
    [Google Scholar]
  27. 27.
    Santaniello M, Matucci-Cerinic C, Natoli V et al. 2022. Childhood multisystem inflammatory syndrome associated with COVID-19 (MIS-C): distinct from Kawasaki disease or part of the same spectrum?. Pediatr. Allergy Immunol. 33:Suppl. 27102–4
    [Google Scholar]
  28. 28.
    Naoi T, Morita M, Kawakami T, Fujimoto S. 2018. Hemophagocytic lymphohistiocytosis associated with scrub typhus: systematic review and comparison between pediatric and adult cases. Trop. Med. Infect. Dis. 3:19
    [Google Scholar]
  29. 29.
    Otrock ZK, Gonzalez MD, Eby CS. 2015. Ehrlichia-induced hemophagocytic lymphohistiocytosis: a case series and review of literature. Blood Cells Mol. Dis. 55:191–93
    [Google Scholar]
  30. 30.
    Poornachandra Wotiye AB, Ayele BA 2022. Hemophagocytic lymphohistiocytosis: an unusual presentation of disseminated tuberculosis. A case report and literature review. J. Clin. Tuberc. Other Mycobact. Dis. 27:100313
    [Google Scholar]
  31. 31.
    Mouhoub B, Bensalah M, Berhili A et al. 2021. Visceral leishmaniasis associated with macrophage activation syndrome: case report and literature review. IDCases 26:e01247
    [Google Scholar]
  32. 32.
    Jorgensen SE, Christiansen M, Host C et al. 2020. Systemic juvenile idiopathic arthritis and recurrent macrophage activation syndrome due to a CASP1 variant causing inflammasome hyperactivation. Rheumatology 59:3099–105
    [Google Scholar]
  33. 33.
    Ruscitti P, Ursini F, Berardicurti O et al. 2022. Cytokine profile, ferritin, and multi-visceral involvement characterise macrophage activation syndrome during adult-onset Still's disease. Rheumatology. In press
    [Google Scholar]
  34. 34.
    Shiga T, Nozaki Y, Tomita D et al. 2021. Usefulness of interleukin-18 as a diagnostic biomarker to differentiate adult-onset Still's disease with/without macrophage activation syndrome from other secondary hemophagocytic lymphohistiocytosis in adults. Front. Immunol. 12:750114
    [Google Scholar]
  35. 35.
    Wafa A, Hicham H, Naoufal R et al. 2022. Clinical spectrum and therapeutic management of systemic lupus erythematosus–associated macrophage activation syndrome: a study of 20 Moroccan adult patients. Clin. Rheumatol. 41:2021–33
    [Google Scholar]
  36. 36.
    Sato S, Uejima Y, Arakawa Y et al. 2019. Clinical features of macrophage activation syndrome as the onset manifestation of juvenile systemic lupus erythematosus. Rheumatol. Adv. Pract. 3:rkz013
    [Google Scholar]
  37. 37.
    Go E, van Veenendaal M, Manlhiot C et al. 2021. Kawasaki disease and systemic juvenile idiopathic arthritis—two ends of the same spectrum. Front. Pediatr 9:665815
    [Google Scholar]
  38. 38.
    Machaczka M, Vaktnas J, Klimkowska M, Hagglund H. 2011. Malignancy-associated hemophagocytic lymphohistiocytosis in adults: a retrospective population-based analysis from a single center. Leuk. Lymphoma 52:613–19
    [Google Scholar]
  39. 39.
    Parikh SA, Kapoor P, Letendre L et al. 2014. Prognostic factors and outcomes of adults with hemophagocytic lymphohistiocytosis. Mayo Clin. Proc. 89:484–92
    [Google Scholar]
  40. 40.
    Riviere S, Galicier L, Coppo P et al. 2014. Reactive hemophagocytic syndrome in adults: a retrospective analysis of 162 patients. Am. J. Med. 127:1118–25
    [Google Scholar]
  41. 41.
    Shen Z, Jin Y, Sun Q et al. 2022. A novel prognostic index model for adult hemophagocytic lymphohistiocytosis: a multicenter retrospective analysis in China. Front. Immunol. 13:829878
    [Google Scholar]
  42. 42.
    Sano H, Kobayashi R, Tanaka J et al. 2014. Risk factor analysis of non-Hodgkin lymphoma–associated haemophagocytic syndromes: a multicentre study. Br. J. Haematol. 165:786–92
    [Google Scholar]
  43. 43.
    Zoref-Lorenz A, Murakami J, Hofstetter L et al. 2022. An improved index for diagnosis and mortality prediction in malignancy-associated hemophagocytic lymphohistiocytosis. Blood 139:1098–110
    [Google Scholar]
  44. 44.
    El-Mallawany NK, Curry CV, Allen CE. 2022. Haemophagocytic lymphohistiocytosis and Epstein–Barr virus: a complex relationship with diverse origins, expression and outcomes. Br. J. Haematol. 196:31–44
    [Google Scholar]
  45. 45.
    Booth C, Gilmour KC, Veys P et al. 2011. X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease. Blood 117:53–62
    [Google Scholar]
  46. 46.
    Li FY, Chaigne-Delalande B, Su H et al. 2014. XMEN disease: a new primary immunodeficiency affecting Mg2+ regulation of immunity against Epstein–Barr virus. Blood 123:2148–52
    [Google Scholar]
  47. 47.
    Gayden T, Sepulveda FE, Khuong-Quang DA et al. 2018. Germline HAVCR2 mutations altering TIM-3 characterize subcutaneous panniculitis-like T cell lymphomas with hemophagocytic lymphohistiocytic syndrome. Nat. Genet. 50:1650–57
    [Google Scholar]
  48. 48.
    Clementi R, Locatelli F, Dupré L et al. 2005. A proportion of patients with lymphoma may harbor mutations of the perforin gene. Blood 105:4424–28
    [Google Scholar]
  49. 49.
    Gadoury-Levesque V, Dong L, Su R et al. 2020. Frequency and spectrum of disease-causing variants in 1892 patients with suspected genetic HLH disorders. Blood Adv. 4:2578–94
    [Google Scholar]
  50. 50.
    Setiadi A, Zoref-Lorenz A, Lee CY et al. 2022. Malignancy-associated haemophagocytic lymphohistiocytosis. Lancet Haematol. 9:e217–27
    [Google Scholar]
  51. 51.
    Delavigne K, Berard E, Bertoli S et al. 2014. Hemophagocytic syndrome in patients with acute myeloid leukemia undergoing intensive chemotherapy. Haematologica 99:474–80
    [Google Scholar]
  52. 52.
    Kobayashi R, Tanaka J, Hashino S et al. 2014. Etoposide-containing conditioning regimen reduces the occurrence of hemophagocytic lymphohistiocytosis after SCT. Bone Marrow Transplant. 49:254–57
    [Google Scholar]
  53. 53.
    Noseda R, Bertoli R, Müller L, Ceschi A. 2019. Haemophagocytic lymphohistiocytosis in patients treated with immune checkpoint inhibitors: analysis of WHO global database of individual case safety reports. J. Immunother. Cancer 7:117
    [Google Scholar]
  54. 54.
    Lichtenstein DA, Schischlik F, Shao L et al. 2021. Characterization of HLH-like manifestations as a CRS variant in patients receiving CD22 CAR T cells. Blood 138:2469–84
    [Google Scholar]
  55. 55.
    Teachey DT, Rheingold SR, Maude SL et al. 2013. Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood 121:5154–57
    [Google Scholar]
  56. 56.
    Tudesq J-J, Valade S, Galicier L et al. 2021. Diagnostic strategy for trigger identification in severe reactive hemophagocytic lymphohistiocytosis: a diagnostic accuracy study. Hematol. Oncol. 39:114–22
    [Google Scholar]
  57. 57.
    Gars E, Purington N, Scott G et al. 2018. Bone marrow histomorphological criteria can accurately diagnose hemophagocytic lymphohistiocytosis. Haematologica 103:1635–41
    [Google Scholar]
  58. 58.
    Schram AM, Campigotto F, Mullally A et al. 2015. Marked hyperferritinemia does not predict for HLH in the adult population. Blood 125:1548–52
    [Google Scholar]
  59. 59.
    La Rosée P, Horne A, Hines M et al. 2019. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood 133:2465–77
    [Google Scholar]
  60. 60.
    Liang JH, Wang L, Zhu HY et al. 2020. Dose-adjusted EPOCH regimen as first-line treatment for non-Hodgkin lymphoma–associated hemophagocytic lymphohistiocytosis: a single-arm, open-label, phase II trial. Haematologica 105:e29–32
    [Google Scholar]
  61. 61.
    Nicholson MC, Naeije L, Hayden AR et al. 2020. Etoposide-based treatment of adult HLH is associated with high biochemical response but poor survival outcomes. eJHaem 1:277–80
    [Google Scholar]
  62. 62.
    Jin Z, Wang Y, Wei N, Wang Z 2020. Hodgkin lymphoma–associated hemophagocytic lymphohistiocytosis—a dangerous disease. Ann. Hematol. 99:1575–81
    [Google Scholar]
  63. 63.
    Wang Y, Huang W, Hu L et al. 2015. Multicenter study of combination DEP regimen as a salvage therapy for adult refractory hemophagocytic lymphohistiocytosis. Blood 126:2186–92
    [Google Scholar]
  64. 64.
    Chellapandian D, Das R, Zelley K et al. 2013. Treatment of Epstein Barr virus–induced haemophagocytic lymphohistiocytosis with rituximab-containing chemo-immunotherapeutic regimens. Br. J. Haematol. 162:376–82
    [Google Scholar]
  65. 65.
    Wang J, Wang Y, Wu L et al. 2020. Ruxolitinib for refractory/relapsed hemophagocytic lymphohistiocytosis. Haematologica 105:e210
    [Google Scholar]
  66. 66.
    Zhou L, Liu Y, Wen Z et al. 2020. Ruxolitinib combined with doxorubicin, etoposide, and dexamethasone for the treatment of the lymphoma-associated hemophagocytic syndrome. J. Cancer Res. Clin. Oncol. 146:3063–74
    [Google Scholar]
  67. 67.
    Bami S, Vagrecha A, Soberman D et al. 2020. The use of anakinra in the treatment of secondary hemophagocytic lymphohistiocytosis. Pediatr. Blood Cancer 67:e28581
    [Google Scholar]
  68. 68.
    Shah NN, Highfill SL, Shalabi H et al. 2020. CD4/CD8 T-cell selection affects chimeric antigen receptor (CAR) T-cell potency and toxicity: updated results from a phase I anti-CD22 CAR T-cell trial. J. Clin. Oncol. 38:1938–50
    [Google Scholar]
  69. 69.
    Liu C, Gao J, Liu J. 2022. Management of hemophagocytic lymphohistiocytosis in pregnancy: case series study and literature review. J. Obstet. Gynaecol. Res. 48:610–20
    [Google Scholar]
  70. 70.
    Zhou JY, Martinez JA, Shen JP. 2019. Lamotrigine-induced hemophagocytic lymphohistiocytosis with Takotsubo cardiomyopathy: a case report. J. Med. Case Rep. 13:345
    [Google Scholar]
  71. 71.
    Saper VE, Ombrello MJ, Tremoulet AH et al. 2022. Severe delayed hypersensitivity reactions to IL-1 and IL-6 inhibitors link to common HLA-DRB1*15 alleles. Ann. Rheum. Dis. 81:406–15
    [Google Scholar]
  72. 72.
    Silverman ED, Miller JJ 3rd, Bernstein B, Shafai T. 1983. Consumption coagulopathy associated with systemic juvenile rheumatoid arthritis. J. Pediatr. 103:872–76
    [Google Scholar]
  73. 73.
    Prahalad S, Bove KE, Dickens D et al. 2001. Etanercept in the treatment of macrophage activation syndrome. J. Rheumatol. 28:2120–24
    [Google Scholar]
  74. 74.
    Al-Fares A, Pettenuzzo T, Del Sorbo L. 2019. Extracorporeal life support and systemic inflammation. Intensive Care Med. Exp. 7:46
    [Google Scholar]
  75. 75.
    Thompson CP, Jagdale A, Walcott G et al. 2021. A perspective on the potential detrimental role of inflammation in pig orthotopic heart xenotransplantation. Xenotransplantation 28:e12687
    [Google Scholar]
  76. 76.
    Sandler RD, Tattersall RS, Schoemans H et al. 2020. Diagnosis and management of secondary HLH/MAS following HSCT and CAR-T cell therapy in adults; a review of the literature and a survey of practice within EBMT centres on behalf of the Autoimmune Diseases Working Party (ADWP) and Transplant Complications Working Party (TCWP). Front. Immunol. 11:524
    [Google Scholar]
  77. 77.
    Tomomasa D, Isoda T, Mitsuiki N et al. 2021. Successful ruxolitinib administration for a patient with steroid-refractory idiopathic pneumonia syndrome following hematopoietic stem cell transplantation: a case report and literature review. Clin. Case Rep. 9:e05242
    [Google Scholar]
  78. 78.
    Ehl S, Astigarraga I, von Bahr Greenwood T et al. 2018. Recommendations for the use of etoposide-based therapy and bone marrow transplantation for the treatment of HLH: consensus statements by the HLH Steering Committee of the Histiocyte Society. J. Allergy Clin. Immunol. Pract. 6:1508–17
    [Google Scholar]
  79. 79.
    Ravelli A, Grom AA, Behrens EM, Cron RQ. 2012. Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment. Genes Immun 13:289–98
    [Google Scholar]
  80. 80.
    Shankar-Hari M, Vale CL, Godolphin PJ et al. 2021. Association between administration of IL-6 antagonists and mortality among patients hospitalized for COVID-19: a meta-analysis. JAMA 326:499–518
    [Google Scholar]
  81. 81.
    Le RQ, Li L, Yuan W et al. 2018. FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell–induced severe or life-threatening cytokine release syndrome. Oncologist 23:943–47Reports that IL-6 blockade is FDA approved to treat CRS following CAR-T therapy for refractory cancer.
    [Google Scholar]
  82. 82.
    Kyriazopoulou E, Poulakou G, Milionis H et al. 2021. Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial. Nat. Med. 27:1752–60
    [Google Scholar]
  83. 83.
    Eloseily EM, Weiser P, Crayne CB et al. 2020. Benefit of anakinra in treating pediatric secondary hemophagocytic lymphohistiocytosis. Arthritis Rheumatol. 72:326–34Reveals that IL-1 blockade increased survival in patients with CSS.
    [Google Scholar]
  84. 84.
    Canna SW, Girard C, Malle L et al. 2017. Life-threatening NLRC4-associated hyperinflammation successfully treated with IL-18 inhibition. J. Allergy Clin. Immunol. 139:1698–701
    [Google Scholar]
  85. 85.
    Keenan C, Nichols KE, Albeituni S. 2021. Use of the JAK inhibitor ruxolitinib in the treatment of hemophagocytic lymphohistiocytosis. Front. Immunol. 12:614704
    [Google Scholar]
  86. 86.
    Tanaka Y, Luo Y, O'Shea JJ, Nakayamada S 2022. Janus kinase–targeting therapies in rheumatology: a mechanisms-based approach. Nat. Rev. Rheumatol. 18:133–45
    [Google Scholar]
  87. 87.
    Kalil AC, Patterson TF, Mehta AK et al. 2021. Baricitinib plus remdesivir for hospitalized adults with COVID-19. N. Engl. J. Med. 384:795–807Demonstrates JAKi increased survival of COVID-19 patients with CSS features.
    [Google Scholar]
  88. 88.
    Stockmann H, Thelen P, Stroben F et al. 2022. CytoSorb rescue for COVID-19 patients with vasoplegic shock and multiple organ failure: a prospective, open-label, randomized controlled pilot study. Crit. Care Med. 50:964–76
    [Google Scholar]
  89. 89.
    Behrens EM, Koretzky GA. 2017. Cytokine storm syndrome: looking toward the precision medicine era. Arthritis Rheumatol. 69:1135–43
    [Google Scholar]
/content/journals/10.1146/annurev-med-042921-112837
Loading
/content/journals/10.1146/annurev-med-042921-112837
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error