Clinical characteristics and outcomes of immunocompromised critically ill patients with cytomegalovirus end-organ disease: a multicenter retrospective cohort study.

Humans Retrospective Studies Male Female Cytomegalovirus Infections / immunology Middle Aged Immunocompromised Host Aged Critical Illness Spain / epidemiology Cohort Studies Intensive Care Units / statistics & numerical data France / epidemiology Adult Israel / epidemiology Hospital Mortality Cytomegalovirus / immunology Risk Factors

Cytomegalovirus Hematologic malignancy Immunocompromised host Intensive care Transplantation

Journal

Critical care (London, England)

ISSN: 1466-609X

Titre abrégé: Crit Care

Pays: England

ID NLM: 9801902

Informations de publication

Date de publication:
16 Jul 2024

Historique:

received: 18 05 2024

accepted: 08 07 2024

medline: 17 7 2024

pubmed: 17 7 2024

entrez: 16 7 2024

Statut: epublish

Résumé

Cytomegalovirus (CMV) infection in patients with cellular immune deficiencies is associated with significant morbidity and mortality. However, data on CMV end-organ disease (CMV-EOD) in critically ill, immunocompromised patients are scarce. Our objective here was to describe the clinical characteristics and outcomes of CMV-EOD in this population. We conducted a multicenter, international, retrospective, observational study in adults who had CMV-EOD and were admitted to any of 18 intensive care units (ICUs) in France, Israel, and Spain in January 2010-December 2021. Patients with AIDS were excluded. We collected the clinical characteristics and outcomes of each patient. Survivors and non-survivors were compared, and multivariate analysis was performed to identify risk factors for hospital mortality. We studied 185 patients, including 80 (43.2%) with hematologic malignancies, 55 (29.7%) with solid organ transplantation, 31 (16.8%) on immunosuppressants, 16 (8.6%) with solid malignancies, and 3 (1.6%) with primary immunodeficiencies. The most common CMV-EOD was pneumonia (n = 115, [62.2%] including 55 [47.8%] with a respiratory co-pathogen), followed by CMV gastrointestinal disease (n = 64 [34.6%]). More than one organ was involved in 16 (8.8%) patients. Histopathological evidence was obtained for 10/115 (8.7%) patients with pneumonia and 43/64 (67.2%) with GI disease. Other opportunistic infections were diagnosed in 69 (37.3%) patients. Hospital mortality was 61.4% overall and was significantly higher in the group with hematologic malignancies (75% vs. 51%, P = 0.001). Factors independently associated with higher hospital mortality were hematologic malignancy with active graft-versus-host disease (OR 5.02; 95% CI 1.15-27.30), CMV pneumonia (OR 2.57; 95% CI 1.13-6.03), lymphocytes < 0.30 × 10 Mortality was high in critically ill, immunocompromised patients with CMV-EOD and varied considerably with the cause of immunodeficiency and organ involved by CMV. Three of the four independent risk factors identified here are also known to be associated with higher mortality in the absence of CMV-EOD. CMV pneumonia was rarely proven by histopathology and was the most severe CMV-EOD.

Sections du résumé

BACKGROUND BACKGROUND

METHODS METHODS

We conducted a multicenter, international, retrospective, observational study in adults who had CMV-EOD and were admitted to any of 18 intensive care units (ICUs) in France, Israel, and Spain in January 2010-December 2021. Patients with AIDS were excluded. We collected the clinical characteristics and outcomes of each patient. Survivors and non-survivors were compared, and multivariate analysis was performed to identify risk factors for hospital mortality.

RESULTS RESULTS

We studied 185 patients, including 80 (43.2%) with hematologic malignancies, 55 (29.7%) with solid organ transplantation, 31 (16.8%) on immunosuppressants, 16 (8.6%) with solid malignancies, and 3 (1.6%) with primary immunodeficiencies. The most common CMV-EOD was pneumonia (n = 115, [62.2%] including 55 [47.8%] with a respiratory co-pathogen), followed by CMV gastrointestinal disease (n = 64 [34.6%]). More than one organ was involved in 16 (8.8%) patients. Histopathological evidence was obtained for 10/115 (8.7%) patients with pneumonia and 43/64 (67.2%) with GI disease. Other opportunistic infections were diagnosed in 69 (37.3%) patients. Hospital mortality was 61.4% overall and was significantly higher in the group with hematologic malignancies (75% vs. 51%, P = 0.001). Factors independently associated with higher hospital mortality were hematologic malignancy with active graft-versus-host disease (OR 5.02; 95% CI 1.15-27.30), CMV pneumonia (OR 2.57; 95% CI 1.13-6.03), lymphocytes < 0.30 × 10

CONCLUSIONS CONCLUSIONS

Mortality was high in critically ill, immunocompromised patients with CMV-EOD and varied considerably with the cause of immunodeficiency and organ involved by CMV. Three of the four independent risk factors identified here are also known to be associated with higher mortality in the absence of CMV-EOD. CMV pneumonia was rarely proven by histopathology and was the most severe CMV-EOD.

Identifiants

DOI: 10.1186/s13054-024-05029-4 PMID: 39014504

pubmed: 39014504

doi: 10.1186/s13054-024-05029-4

pii: 10.1186/s13054-024-05029-4

doi:

Types de publication

Journal Article Multicenter Study Observational Study

Langues

eng

Sous-ensembles de citation

Pagination

243

Informations de copyright

Références

Melendez-munoz R, Marchalik R, Jerussi T, Dimitrova D, Nussenblatt V, Beri A, et al. Cytomegalovirus infection incidence and risk factors across diverse hematopoietic cell transplantation platforms using a standardized monitoring and treatment approach: a comprehensive evaluation from a single institution. Biol Blood Marrow Transplant. 2019;25(3):577–86.

doi: 10.1016/j.bbmt.2018.10.011 pubmed: 30342913

Manuel O, Husain S, Kumar D, Zayas C, Mawhorter S, Levi ME, et al. Assessment of cytomegalovirus-specific cell-mediated immunity for the prediction of cytomegalovirus disease in high-risk solid-organ transplant recipients: a multicenter cohort study. Clin Infect Dis. 2013;56(6):817–24.

doi: 10.1093/cid/cis993 pubmed: 23196955

Alonso-Álvarez S, Colado E, Moro-García MA, Alonso-Arias R. Cytomegalovirus in haematological tumours. Front Immunol. 2021;12:703256.

doi: 10.3389/fimmu.2021.703256 pubmed: 34733270 pmcid: 8558552

Takizawa Y, Inokuma S, Tanaka Y, Saito K, Atsumi T, Hirakata M, et al. Clinical characteristics of cytomegalovirus infection in rheumatic diseases: multicentre survey in a large patient population. Rheumatology. 2008;47(9):1373–8.

doi: 10.1093/rheumatology/ken231 pubmed: 18577548

Limaye AP, Kirby KA, Rubenfeld GD, Leisenring WM, Bulger EM, Neff MJ, et al. Cytomegalovirus reactivation in critically ill immunocompetent patients. JAMA. 2008;300(4):413–22.

doi: 10.1001/jama.300.4.413 pubmed: 18647984 pmcid: 2774501

Chiche L, Forel JM, Roch A, Guervilly C, Pauly V, Allardet-Servent J, et al. Active cytomegalovirus infection is common in mechanically ventilated medical intensive care unit patients. Crit Care Med. 2009;37(6):1850–7.

doi: 10.1097/CCM.0b013e31819ffea6 pubmed: 19384219

Walton AH, Muenzer JT, Rasche D, Boomer JS, Sato B. Reactivation of multiple viruses in patients with sepsis. PLoS ONE. 2014;9(2): e98819.

doi: 10.1371/journal.pone.0098819 pubmed: 24919177 pmcid: 4053360

Li X, Huang Y, Xu Z, Zhang R, Liu X, Li Y, et al. Cytomegalovirus infection and outcome in immunocompetent patients in the intensive care unit: a systematic review and meta-analysis. BMC Infect Dis. 2018;18(1):1–10.

doi: 10.1186/s12879-018-3195-5

Emery VC, Sabin CA, Cope AV, Gor D, Hassan-Walker AF, Griffiths PD. Application of viral-load kinetics to identify patients who develop cytomegalovirus disease after transplantation. Lancet. 2000;355(9220):2032–6.

doi: 10.1016/S0140-6736(00)02350-3 pubmed: 10885354

Yong MK, Ananda-Rajah M, Cameron PU, Morrissey CO, Spencer A, Ritchie D, et al. Cytomegalovirus reactivation is associated with increased risk of late-onset invasive fungal disease after allogeneic hematopoietic stem cell transplantation: a multicenter study in the current era of viral load monitoring. Biol Blood Marrow Transplant. 2017;23(11):1961–7.

doi: 10.1016/j.bbmt.2017.07.025 pubmed: 28797778

Garcia-Vidal C, Upton A, Kirby KA, Marr KA. Epidemiology of invasive mold infections in allogeneic stem cell transplant recipients: Biological risk factors for infection according to time after transplantation. Clin Infect Dis. 2008;47(8):1041–50.

doi: 10.1086/591969 pubmed: 18781877

Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients-guidelines of the American society of transplantation infectious disease community of practice. Clin Transplant. 2019;33(9): e13512.

doi: 10.1111/ctr.13512 pubmed: 30817026

Ljungman P, de la Camara R, Robin C, Crocchiolo R, Einsele H, Hill JA, et al. Guidelines for the management of cytomegalovirus infection in patients with haematological malignancies and after stem cell transplantation from the 2017 European conference on Infections in Leukaemia (ECIL 7). Lancet Infect Dis. 2019;19(8):e260–72.

doi: 10.1016/S1473-3099(19)30107-0 pubmed: 31153807

Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the working group on sepsis-related problems of the European society of intensive care medicine. Intens Care Med. 1996;22(7):707–10.

doi: 10.1007/BF01709751

Fryer JF, Heath AB, Kessler H, Rawlinson W, Boivin G, Preiksaitis J, et al. A collaborative study to establish the 1st WHO International Standard for human cytomegalovirus for nucleic acid amplification technology. Biologicals. 2016;44(4):242–51.

doi: 10.1016/j.biologicals.2016.04.005 pubmed: 27179913

Chemaly RF, Yen-Lieberman B, Castilla EA, Reilly A, Arrigain S, et al. Correlation between viral loads of cytomegalovirus in blood and bronchoalveolar lavage specimens from lung transplant recipients determined by histology and immunohistochemistry. J Clin Microbiol. 2004;42(5):2168–72.

doi: 10.1128/JCM.42.5.2168-2172.2004 pubmed: 15131185 pmcid: 404658

Green ML, Leisenring W, Xie H, Mast C, Cui Y, Sandmaier BM, et al. CMV viral load and mortality after hematopoietic cell transplantation: a cohort study in the era of preemptive therapy. Lancet Haematol. 2016;176(5):139–48.

Manuel O, Kralidis G, Mueller NJ, Hirsch HH, Garzoni C, Van Delden C, et al. Impact of antiviral preventive strategies on the incidence and outcomes of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant. 2013;13(9):2402–10.

doi: 10.1111/ajt.12388 pubmed: 23914796

Ong DSY, Spitoni C, Klein Klouwenberg PMC, Verduyn Lunel FM, Frencken JF, Schultz MJ, et al. Cytomegalovirus reactivation and mortality in patients with acute respiratory distress syndrome. Intensive Care Med. 2016;42(3):333–41.

doi: 10.1007/s00134-015-4071-z pubmed: 26415682 pmcid: 4747999

Al-Omari A, Aljamaan F, Alhazzani W, Salih S, Arabi Y. Cytomegalovirus infection in immunocompetent critically ill adults: literature review. Ann Intensive Care. 2016;6(1):110.

Papazian L, Hraiech S, Lehingue S, Roch A, Chiche L, Wiramus S, et al. Cytomegalovirus reactivation in ICU patients. Intensive Care Med. 2016;42(1):28–37.

doi: 10.1007/s00134-015-4066-9 pubmed: 26424680

Westall GP, Michaelides A, Williams TJ, Snell GI, Kotsimbos TC. Human cytomegalovirus load in plasma and bronchoalveolar lavage fluid: a longitudinal study of lung transplant recipients. J Infect Dis. 2004;190(6):1076–83.

doi: 10.1086/422327 pubmed: 15319856

Suárez-Lledó M, Marcos MÁ, Cuatrecasas M, Bombi JA, Fernández-Avilés F, Magnano L, et al. Quantitative PCR is faster, more objective, and more reliable than immunohistochemistry for the diagnosis of cytomegalovirus gastrointestinal disease in allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2019;25(11):2281–6.

doi: 10.1016/j.bbmt.2019.07.016 pubmed: 31325586

Lengliné E, Chevret S, Moreau AS, Pène F, Blot F, Bourhis JH, et al. Changes in intensive care for allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transplant. 2015;50(6):840–5.

doi: 10.1038/bmt.2015.55 pubmed: 25798675

Cantoni N, Hirsch HH, Khanna N, Gerull S, Buser A, Bucher C, et al. Evidence for a bidirectional relationship between cytomegalovirus replication and acute graft-versus-host disease. Biol Blood Marrow Transplant. 2010;16(9):1309–14.

doi: 10.1016/j.bbmt.2010.03.020 pubmed: 20353832

Erard V, Guthrie KA, Seo S, Smith J, Huang M, Chien J, et al. Reduced mortality of cytomegalovirus pneumonia after hematopoietic cell transplantation due to antiviral therapy and changes in transplantation practices. Clin Infect Dis. 2015;61(1):31–9.

doi: 10.1093/cid/civ215 pubmed: 25778751 pmcid: 4542910

Santos CAQ, Brennan DC, Yusen RD, Olsen MA. Incidence, risk factors and outcomes of delayed-onset cytomegalovirus disease in a large retrospective cohort of lung transplant recipients. Transplantation. 2015;99(8):1658–66.

doi: 10.1097/TP.0000000000000549 pubmed: 25675196 pmcid: 4534357

Meng XY, Fu HX, Zhu XL, Wang JZ, Liu X, Yan CH. Comparison of different cytomegalovirus diseases following haploidentical hematopoietic stem cell transplantation. Ann Hematol. 2020;99(11):2659–70.

doi: 10.1007/s00277-020-04201-4 pubmed: 32734550

Torres HA, Kontoyiannis DP, Bodey GP, Adachi JA, Luna MA, Tarrand JJ, et al. Gastrointestinal cytomegalovirus disease in patients with cancer: a two decade experience in a tertiary care cancer center. Eur J Cancer. 2005;41:2268–79.

doi: 10.1016/j.ejca.2005.07.011 pubmed: 16143517

Wetwittayakhlang P, Rujeerapaiboon N, Wetwittayakhlung P, Sripongpun P, Pruphetkaew N, Jandee S, et al. Clinical Features, endoscopic findings, and predictive factors for mortality in tissue-invasive gastrointestinal cytomegalovirus disease between immunocompetent and immunocompromised patients. Gastroenterol Res Pract. 2021;2021:8886525.

doi: 10.1155/2021/8886525 pubmed: 33897776 pmcid: 8052155

Randolph-habecker J, Iwata M, Torok-storb B. Cytomegalovirus mediated myelosuppression. J Clin Virol. 2002;25:51–6.

doi: 10.1016/S1386-6532(02)00092-6

Boeckh M, Hoy C, Torok-Storb B. Occult cytomegalovirus infection of marrow stroma. Clin Infect Dis. 1998;26(1):209–10.

doi: 10.1086/517022 pubmed: 9455550

Yong MK, Slavin MA, Kontoyiannis DP. Invasive fungal disease and cytomegalovirus infection: is there an association? Curr Opin Infect Dis. 2018;31(6):481–9.

doi: 10.1097/QCO.0000000000000502 pubmed: 30299361

Boeckh M, Stevens-Ayers T, Travi G, Huang ML, Cheng GS, Xie H, et al. Cytomegalovirus (CMV) DNA quantitation in bronchoalveolar lavage fluid from hematopoietic stem cell transplant recipients with CMV pneumonia. J Infect Dis. 2017;215(10):1514–22.

doi: 10.1093/infdis/jix048 pubmed: 28181657 pmcid: 5461426

Ljungman P, Boeckh M, Hirsch HH, Josephson F, Lundgren J, Nichols G, et al. Definitions of cytomegalovirus infection and disease in transplant patients for use in clinical trials. Clin Infect Dis. 2017;64(1):87–91.

doi: 10.1093/cid/ciw668 pubmed: 27682069

Baber A, Calvet L, Vissac C, Salmona M, Legoff J, De Jong A, et al. Cytomegalovirus infection in intensive care unit patients with hematological malignancies: characteristics and clinical outcomes. J Crit Care. 2024;82: 154766.

doi: 10.1016/j.jcrc.2024.154766 pubmed: 38479298

Rodrigues dos Santos SD, Bafi AT, Rezende de Freitas FG, Pontes de Azevedo LC, Machado FR. Prevalence of cytomegalovirus disease in kidney transplant patients in an intensive care unit. Rev Bras Ter Intensiva. 2017;29(4):436–43.