Open access Original research BMJ Open: first published as 10.1136/bmjopen-2019-036452 on 12 July 2020. Downloaded from Risk of invasive candidiasis with prolonged duration of ICU stay: a systematic review and meta- analysis Zhidan Zhang, Ran Zhu, Zhenggang Luan, Xiaochun Ma To cite: Zhang Z, Zhu R, ABSTRACT Strengths and limitations of this study Luan Z, et al. Risk of Objective This study aimed to evaluate the duration of invasive candidiasis with intensive care unit (ICU) stay prior to onset of invasive ► This meta- analysis is one of the few that investi- prolonged duration of ICU candidiasis (IC)/candidaemia. stay: a systematic review and gated the association of invasive candidiasis with Design Systematic review and meta- analysis. meta- analysis. BMJ Open length of intensive care unit (ICU) stay, using data Data sources PubMed, Cochrane, Embase and Web of 2020;10:e036452. doi:10.1136/ published worldwide and adhering to the Preferred Science databases were searched through June 2019 to bmjopen-2019-036452 Reporting Items for Systematic Reviews and Meta- identify relevant studies. Analyses guideline. ► Prepublication history and Eligibility criteria Adult patients who had been admitted ► Extensive subgroup analyses were performed and additional material for this to the ICU and developed an IC infection. paper are available online. To meta- regression was made to examine possible Data extraction and synthesis The following data were view these files, please visit causes of heterogeneity in the results. extracted from each article: length of hospital stay, length the journal online (http:// dx. doi. ► Although this meta-analysis was performed me- of ICU stay, duration of ICU admission prior to candidaemia org/ 10. 1136/ bmjopen- 2019- thodically, it lacked a prespecified protocol and pre- onset, percentage of patients who received antibiotics and 036452). liminary registration. duration of their antibiotic therapy prior to candidaemia ► Heterogeneity exists in some subgroup and overall Received 11 September 2019 onset, and overall mortality. In addition to the traditional analyses. Revised 12 March 2020 meta- analyses, meta- regression was performed to explore ► Due to a lack of sufficient published data, rela- Accepted 13 March 2020 possible mediators which might have contributed to the tionship between prolonged exposure to broad- heterogeneity. spectrum antibiotics and ICU-acquired candidaemia Results The mean age of patients ranged from 28 to could not be assessed. 76 years across selected studies. The pooled mean duration of ICU admission before onset of candidaemia http://bmjopen.bmj.com/ was 12.9 days (95% CI 11.7 to 14.2). The pooled mean duration of hospital stay was 36.3±5.3 days (95% CI incidence of IC has been gradually increasing 25.8 to 46.7), and the pooled mean mortality rate was in most regions,3 ranging from 0.5 to 32 cases 49.3%±2.2% (95% CI 45.0% to 53.5%). There was no per 1000 ICU admissions. It has been found significant difference in duration of hospital stay (p=0.528) or overall mortality (p=0.111), but a significant difference that there is a significant difference in the was observed in the mean length of ICU stay (2.8 days, incidence of IC among several countries in p<0.001), between patients with and without Candida Latin America and North America; however, on September 25, 2021 by guest. Protected copyright. albicans. Meta- regression analysis found that South data from Asia Pacific countries are still rela- American patients had longer duration of ICU admission tively rare.4 Candidaemia has been described prior to candidaemia onset than patients elsewhere, while as the most common manifestation of IC, those in Asia had the shortest duration. and further infection of the liver, spleen, Conclusions Patients with IC are associated with longer heart valves or eye might also occur after a ICU stay, with the shortest duration of ICU admission bloodstream infection.5 In the past, the main prior to the candidaemia onset in Asia. This shows a Candida species isolated from patients with IC © Author(s) (or their more proactive strategy in the diagnosis of IC should be employer(s)) 2020. Re- use considered in caring for ICU patients. was Candida albicans. However, non-C. albicans permitted under CC BY-NC. No species have seen a rising proportion and now commercial re- use. See rights account for approximately 50% of all cases of and permissions. Published by 1 6–8 BMJ. INTRODUCTION IC in the past two decades. Candida species account for approximately Diagnosis and management of IC remain Department of Critical Care 1 2 Medicine, The First Hospital 70%–90% of invasive fungal infections and challenging for physicians in the ICU. The of China Medical University, are the most frequent cause of fungal infec- early initiation of empiric antifungal treat- Shenyang, China tions in patients admitted to the intensive ment has been demonstrated to improve the 1 2 9 Correspondence to care unit (ICU). Invasive candidiasis (IC) is prognosis of IC. However, there is diffi- Dr Xiaochun Ma; associated with a high mortality rate (range: culty in the diagnosis of IC, which can delay XCMA2972@ sina. com 40%–60%).1 2 Over recent decades, the timely antifungal treatment.2 10 Blood culture Zhang Z, et al. BMJ Open 2020;10:e036452. doi:10.1136/bmjopen-2019-036452 1 Open access BMJ Open: first published as 10.1136/bmjopen-2019-036452 on 12 July 2020. Downloaded from remains the gold standard for the diagnosis of IC, but its sensitivity is variable (21%–71%).11 To improve the diagnosis of IC and to identify the patients who may best benefit from prophylactic, pre- emptive or empiric therapy prior to or at an early stage of ICU admission, several methods in predicting the development of IC based on their associated risk factors have been developed.12 13 The risk factors in the various predictive models include broad-spectrum antibiotic use, central venous catheter placement, total parenteral nutri- tion, haemodialysis (days 1–3 in the ICU), any surgery, immunosuppressive use, pancreatitis prior to ICU admis- sion and steroid use. However, different risk factors are included in different predictive models. In addition, potential risk factors such as Candida colonisation14 and mechanical ventilation15 have not been included in these models. Long- term ICU stay has been reported as a risk factor for IC.11 14–16 Only a few studies have examined the interval between ICU admission or initiation of broad- spectrum antibiotics and the diagnosis of IC. However, the specific duration of long- term ICU stays and the prolonged use of broad- spectrum antibiotics are often arbitrarily defined and inconsistent among studies.6 12 15 17–19 Furthermore, a large majority of severe candidiasis cases are caused Figure 1 PRISMA flow diagram of study selection. PRISMA, by endogenous colonisation. This may be the primary Preferred Reporting Items for Systematic Reviews and Meta- Analyses. reason for causing a delay of 7–10 days between exposure to risk factors and the development of IC.20 Thus, the objective of this systematic review was to editorials, case reports, proceedings, personal communi- evaluate several possible risk factors associated with the cations and case series were excluded. Studies in which development of candidaemia, including the length of patients were diagnosed with candidiasis prior to ICU hospitalisation and ICU stay, as well as regional differ- http://bmjopen.bmj.com/ admission were excluded. Studies that did not evaluate ences in these factors. the incidence of candidiasis as a primary objective or that were not designed to evaluate risk factors/prognostic factors of patients with candidiasis were also excluded. METHODS Search strategy Data extraction The study was performed in accordance with guidance The following information/data were extracted from from the Preferred Reporting Items for Systematic studies that met the inclusion criteria: name of the first Reviews and Meta- Analyses. PubMed, Cochrane, Embase author, year of publication, country, study design, type of on September 25, 2021 by guest. Protected copyright. and Web of Science databases were searched from incep- ICU, number of participants in each group, participants’ tion through June 2019 using the following terms: candi- age and gender, presence of C. albicans, presence of neut- diasis, candidemia, intensive care unit or ICU, and risk ropaenia and antifungal treatment (especially the use of factors (online supplementary table S1). Studies identi- broad- spectrum antibiotics). The following data were also fied by the search strategy were reviewed for inclusion extracted from each article: length of stay in hospital/ and data were extracted by two independent reviewers. ICU, length of stay prior to ICU admission, duration of Where there was uncertainty regarding study eligibility, ICU stay prior to candidaemia onset, antibiotic therapy a third reviewer was consulted. A flow chart of the study prior to candidaemia onset, duration of antibiotic therapy selection is shown in figure 1. prior to candidaemia onset and overall mortality. Study selection criteria Quality assessment Randomised controlled trials, cohort studies, case- We used the Risk of Bias In Non-randomized Studies of controlled and cross- sectional studies were included. All Interventions (ROBINS- I) tool to assess the quality of the studies included adult patients who were critically ill, included studies.21 ROBINS- I is based on the Cochrane who had been admitted to the ICU and who were tested Risk of Bias tool and is suited for evaluating non- positive for Candida species using blood culture analyses. randomised studies that compare the health effects of Studies had to have reported quantitative outcomes of different interventions. ROBINS-I covers seven different interest, and no author was contacted. Letters, comments, bias domains: bias due to confounding, bias in selection 2 Zhang Z, et al. BMJ Open 2020;10:e036452.