A modified Sequential Organ Failure Assessment score for dengue: development, evaluation and proposal for use in clinical trials

Angela McBride, Nguyen Lam Vuong, Nguyen Van Hao, Nguyen Quang Huy, Ho Quang Chanh, Nguyen Thi Xuan Chau, Nguyen Minh Nguyet, Damien K Ming, Nguyen Thanh Ngoc, Phung Tran Huy Nhat, Nguyen Thanh Phong, Luong Thi Hue Tai, Phan Vinh Tho, Dinh The Trung, Dong Thi Hoai Tam, Huynh Trung Trieu, Ronald Bertus Geskus, Martin J Llewelyn, C Louise Thwaites, Sophie Yacoub, Angela McBride, Nguyen Lam Vuong, Nguyen Van Hao, Nguyen Quang Huy, Ho Quang Chanh, Nguyen Thi Xuan Chau, Nguyen Minh Nguyet, Damien K Ming, Nguyen Thanh Ngoc, Phung Tran Huy Nhat, Nguyen Thanh Phong, Luong Thi Hue Tai, Phan Vinh Tho, Dinh The Trung, Dong Thi Hoai Tam, Huynh Trung Trieu, Ronald Bertus Geskus, Martin J Llewelyn, C Louise Thwaites, Sophie Yacoub

Abstract

Background: Dengue is a neglected tropical disease, for which no therapeutic agents have shown clinical efficacy to date. Clinical trials have used strikingly variable clinical endpoints, which hampers reproducibility and comparability of findings. We investigated a delta modified Sequential Organ Failure Assessment (delta mSOFA) score as a uniform composite clinical endpoint for use in clinical trials investigating therapeutics for moderate and severe dengue.

Methods: We developed a modified SOFA score for dengue, measured and evaluated its performance at baseline and 48 h after enrolment in a prospective observational cohort of 124 adults admitted to a tertiary referral hospital in Vietnam with dengue shock. The modified SOFA score included pulse pressure in the cardiovascular component. Binary logistic regression, cox proportional hazard and linear regression models were used to estimate association between mSOFA, delta mSOFA and clinical outcomes.

Results: The analysis included 124 adults with dengue shock. 29 (23.4%) patients required ICU admission for organ support or due to persistent haemodynamic instability: 9/124 (7.3%) required mechanical ventilation, 8/124 (6.5%) required vasopressors, 6/124 (4.8%) required haemofiltration and 5/124 (4.0%) patients died. In univariate analyses, higher baseline and delta (48 h) mSOFA score for dengue were associated with admission to ICU, requirement for organ support and mortality, duration of ICU and hospital admission and IV fluid use.

Conclusions: The baseline and delta mSOFA scores for dengue performed well to discriminate patients with dengue shock by clinical outcomes, including duration of ICU and hospital admission, requirement for organ support and death. We plan to use delta mSOFA as the primary endpoint in an upcoming host-directed therapeutic trial and investigate the performance of this score in other phenotypes of severe dengue in adults and children.

Keywords: Clinical trial endpoint; Delta SOFA; Dengue; Modified SOFA; SOFA; Shock; Vietnam.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Association between baseline mSOFA score and endpoints. In A, F, G, H and I the probability of having the endpoint is estimated from the binary logistic regression model with a predictor baseline mSOFA score; the blue curve represents the estimated probability and the gray region represents 95% confidence interval. In all plots (A–I), each point represents an individual measurement and is coloured by survivor (red) and non-survivor (blue)
Fig. 2
Fig. 2
Association between delta mSOFA score and endpoints. In A, F, G, H and I the probability of having the endpoint is estimated from the binary logistic regression model with a predictor delta mSOFA score; the blue curve represents the estimated probability and the gray region represents 95% confidence interval. In all plots (A–I), each point represents an individual measurement and is coloured by survivor (red) and non-survivor (blue)
Fig. 3
Fig. 3
A Distribution of each component of mSOFA score at baseline (red) and day 2 (blue), B Distribution of each component of delta mSOFA score between day 2 and baseline, C Distribution of total mSOFA score (blue) and original SOFA score (red) in all patients
Fig. 4
Fig. 4
A-K show the association between each component of mSOFA score and mortality. The probability of having the endpoint is estimated from the binary logistic regression model with a predictor delta mSOFA score; in all panels the blue curve represents the estimated probability and the gray region represents 95% confidence interval. Each point represents an individual measurement and is coloured by survivor (red) and non-survivor (blue). CNS central nervous system; CV cardiovascular

References

    1. Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, et al. The global distribution and burden of dengue. Nature. 2013;496(7446):504–507. doi: 10.1038/nature12060.
    1. Geneva: World Health Organization. Dengue: guidelines for diagnosis, treatment, prevention and control: new edition. Geneva; 2009. 1–144pp.
    1. Tricou V, Minh NN, Van TP, Lee SJ, Farrar J, Wills B, et al. A randomized controlled trial of chloroquine for the treatment of dengue in Vietnamese adults. PLoS Negl Trop Dis. 2010;4(8):e785. doi: 10.1371/journal.pntd.0000785.
    1. Nguyen NM, Tran CNB, Phung LK, Duong KTH, Huynh HA, Farrar J, et al. A randomized, double-blind placebo controlled trial of balapiravir, a polymerase inhibitor, in adult dengue patients. J Infect Dis. 2013;207(9):1442–1450. doi: 10.1093/infdis/jis470.
    1. Whitehorn J, Nguyen CVV, Khanh LP, Kien DTH, Quyen NTH, Tran NTT, et al. Lovastatin for the treatment of adult patients with dengue: a randomized, double-blind placebo-controlled trial. Clin Infect Dis. 2016;62(4):468–476.
    1. Tam DTH, Ngoc TV, Tien NTH, Kieu NTT, Thuy TTT, Thanh LTC, et al. Effects of short-course oral corticosteroid therapy in early dengue infection in Vietnamese patients: a randomized, placebo-controlled trial. Clin Infect Dis. 2012;55(9):1216–1224. doi: 10.1093/cid/cis655.
    1. Jaenisch T, Hendrickx K, Erpicum M, Agulto L, Tomashek KM, Dempsey W, et al. Development of standard clinical endpoints for use in dengue interventional trials: introduction and methodology. BMC Med Res Methodol. 2018;18(134):1–10.
    1. Tomashek KM, Wills B, See Lum LC, Thomas L, Durbin A, Leo YS, et al. Development of standard clinical endpoints for use in dengue interventional trials. PLoS Negl Trop Dis. 2018;12(10):e0006497. doi: 10.1371/journal.pntd.0006497.
    1. Lambden S, Laterre PF, Levy MM, Francois B. The SOFA score-development, utility and challenges of accurate assessment in clinical trials. Crit Care. 2019;23(1):374. doi: 10.1186/s13054-019-2663-7.
    1. Rudd KE, Seymour CW, Aluisio AR, Augustin ME, Bagenda DS, Beane A, et al. Association of the quick Sequential (sepsis-related) Organ Failure Assessment (qSOFA) score with excess hospital mortality in adults with suspected infection in low- and middle-income countries. JAMA. 2018;319(21):2202–2211. doi: 10.1001/jama.2018.6229.
    1. de Grooth HJ, Geenen IL, Girbes AR, Vincent JL, Parienti JJ, Oudemans-van Straaten HM. SOFA and mortality endpoints in randomized controlled trials: a systematic review and meta-regression analysis. Crit Care. 2017;21(1):38. doi: 10.1186/s13054-017-1609-1.
    1. Wills BA, Dung NM, Loan HT, Tam DTH, Thuy TTN, Minh LTT, et al. Comparison of three fluid solutions for resuscitation in dengue shock syndrome. N Engl J Med. 2005;353(9):877–889. doi: 10.1056/NEJMoa044057.
    1. Ngo NT, Cao XT, Kneen R, Wills B, Nguyen VM, Nguyen TQ, et al. Acute management of dengue shock syndrome: a randomized double-blind comparison of 4 intravenous fluid regimens in the first hour. Clin Infect Dis. 2001;32(2):204–213. doi: 10.1086/318479.
    1. Grissom CK, Brown SM, Kuttler KG, Boltax JP, Jones J, Jephson AR, et al. A modified sequential organ failure assessment score for critical care triage. Disaster Med Public Health Prep. 2010;4(4):277–284. doi: 10.1001/dmp.2010.40.
    1. Heinze G, Schemper M. A solution to the problem of separation in logistic regression. Stat Med. 2002;21(16):2409–2419. doi: 10.1002/sim.1047.
    1. Firth D. Bias reduction of maximum likelihood estimates. Biometrika. 1993;80(1):27–38. doi: 10.1093/biomet/80.1.27.
    1. R Core Team, R: A language and environment for statistical computing. 2021.
    1. Jog S, Prayag S, Rajhans P, Zirpe K, Dixit S, Pillai L, et al. Dengue infection with multiorgan dysfunction: SOFA score, arterial lactate and serum albumin levels are predictors of outcome. Intensive Care Med. 2015;41(11):2029–2030. doi: 10.1007/s00134-015-4024-6.
    1. John KJ, Gunasekaran K, Prasad JD, Mathew D, Das S, Sultan N, et al. Predictors of major bleeding and mortality in dengue infection: a retrospective observational study in a tertiary care centre in South India. Interdiscip Perspect Infect Dis. 2019;2019:4823791. doi: 10.1155/2019/4823791.
    1. Shastri P, Gupta P, Kumar R. A prospective 3 year study of clinical spectrum and outcome of dengue fever in ICU from a tertiary care hospital in North India. Indian J Anaesth. 2020;64(3):181–186. doi: 10.4103/ija.IJA_865_19.
    1. Padyana M, Karanth S, Vaidya S, Gopaldas JA. Clinical profile and outcome of dengue fever in multidisciplinary intensive care unit of a tertiary level hospital in India. Indian J Crit Care Med. 2019;23(6):270. doi: 10.5005/jp-journals-10071-23178.
    1. Juneja D, Nasa P, Singh O, Javeri Y, Uniyal B, Dang R. Clinical profile, intensive care unit course, and outcome of patients admitted in intensive care unit with dengue. J Crit Care. 2011;26(5):449–452. doi: 10.1016/j.jcrc.2011.05.007.
    1. Schmitz L, Prayag S, Varghese S, Jog S, Bhargav-Patil P, Yadav A, et al. Nonhematological organ dysfunction and positive fluid balance are important determinants of outcome in adults with severe dengue infection: a multicenter study from India. J Crit Care. 2011;26(5):441–448. doi: 10.1016/j.jcrc.2011.05.008.
    1. Amâncio FF, Heringer TP, de Oliveira CCHB, Fassy LB, de Carvalho FB, Oliveira DP, et al. Clinical profiles and factors associated with death in adults with dengue admitted to intensive care units, Minas Gerais, Brazil. PLoS ONE. 2015;10(6):e0129046–e0129046. doi: 10.1371/journal.pone.0129046.
    1. Chang WA, Tsai JR, Tsai MJ, Kuo CY, Sheu CC. SOFA Score Is a Good Predictor of ICU Mortality in Severe Dengue. In: A55 CRITICAL CARE: SIRS, QSOFA, SEPSIS - WHAT’S IN A NAME? American Thoracic Society; 2017. p. A1903–A1903. (American Thoracic Society International Conference Abstracts).
    1. Kan FK, Tan CC, Von Bahr GT, Khalid KE, Supramaniam P, Hed Myrberg I, et al. Dengue infection complicated by hemophagocytic lymphohistiocytosis: experiences from 180 patients with severe dengue. Clin Infect Dis. 2020;70(11):2247–2255. doi: 10.1093/cid/ciz499.
    1. Hsieh CC, Cia CT, Lee JC, Sung JM, Lee NY, Chen PL, et al. A cohort study of adult patients with severe dengue in Taiwanese intensive care units: the elderly and APTT prolongation matter for prognosis. PLoS Negl Trop Dis. 2017;11(1):e0005270–e0005270. doi: 10.1371/journal.pntd.0005270.
    1. Vietnamese Ministry of Health Decision 3705/QĐ-BYT. Guidance on diagnosis and management of Dengue. 2019.
    1. Haniffa R, Isaam I, De Silva AP, Dondorp AM, De Keizer NF. Performance of critical care prognostic scoring systems in low and middle-income countries: a systematic review. Crit Care. 2018;22(1):18. doi: 10.1186/s13054-017-1930-8.
    1. Pandharipande PP, Shintani AK, Hagerman HE, St Jacques PJ, Rice TW, Sanders NW, et al. Derivation and validation of Spo2/Fio2 ratio to impute for Pao2/Fio2 ratio in the respiratory component of the Sequential Organ Failure Assessment score. Crit Care Med. 2009;37(4):1317–1321. doi: 10.1097/CCM.0b013e31819cefa9.
    1. Levick JR, Michel CC. Microvascular fluid exchange and the revised Starling principle. Cardiovasc Res. 2010;87(2):198–210. doi: 10.1093/cvr/cvq062.
    1. Aukland K, Reed RK. Interstitial-lymphatic mechanisms in the control of extracellular fluid volume. Physiol Rev. 1993;73(1):1–78. doi: 10.1152/physrev.1993.73.1.1.
    1. Halstead SB, Lum LC. Assessing the prognosis of dengue-infected patients. F1000 Med Rep. 2009;1:73. doi: 10.3410/M1-73.
    1. Lamia B, Chemla D, Richard C, Teboul JL. Clinical review: Interpretation of arterial pressure wave in shock states. Critical Care [Internet]. 2005;9(6):601. Available from: 10.1186/cc3891
    1. Koganti K, Thatavarthi U. Dengue Severity Index, a scoring system to detect severity of illness in dengue like Sequential Organ Failure Assessment (SOFA) in Sepsis. Int J Infect Dis. 2020;101:508–509. doi: 10.1016/j.ijid.2020.09.1321.
    1. Moskowitz A, Huang DT, Hou PC, Gong J, Doshi PB, Grossestreuer AV, et al. Effect of ascorbic acid, corticosteroids, and thiamine on organ injury in septic shock: the ACTS randomized clinical trial. JAMA. 2020;324(7):642–650. doi: 10.1001/jama.2020.11946.
    1. He H, Chi Y, Yang Y, Yuan S, Long Y, Zhao P, et al. Early individualized positive end-expiratory pressure guided by electrical impedance tomography in acute respiratory distress syndrome: a randomized controlled clinical trial. Crit Care. 2021;25(1):230. doi: 10.1186/s13054-021-03645-y.
    1. McBride A, Mehta P, Rivino L, Ramanan AV, Yacoub S. Targeting hyperinflammation in infection: can we harness the COVID-19 therapeutics momentum to end the dengue drugs drought? Lancet Microbe. 2021;2:e277–e278. doi: 10.1016/S2666-5247(21)00087-2.
    1. Rosenberger KD, Alexander N, Martinez E, Lum LCS, Dempfle CE, Junghanss T, et al. Severe dengue categories as research endpoints-results from a prospective observational study in hospitalised dengue patients. PLoS Negl Trop Dis. 2020;14(3):e0008076. doi: 10.1371/journal.pntd.0008076.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere