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Assessing the effect of patient screening and isolation on curtailing Clostridium difficile infection in hospital settings
- Sara Maghdoori1Email author and
- Seyed M. Moghadas1
https://doi.org/10.1186/s12879-017-2494-6
© The Author(s). 2017
Received: 3 February 2017
Accepted: 25 May 2017
Published: 2 June 2017
Abstract
Background
Patient screening at the time of hospital admission is not recommended as a routine practice, but may be an important strategy for containment of Clostridium difficile infection (CDI) in hospital settings. We sought to investigate the effect of patient screening in the presence of asymptomatic carriers and in the context of imperfect patient isolation.
Methods
We developed and parameterized a stochastic simulation model for the transmission dynamics of CDI in a hospital ward.
Results
We found that the transmission of CDI in the hospital, either through asymptomatic carriers or as a results of ineffective implementation of infection control practices, at the time of hospital admission. The results show that, for a sufficiently high reproduction number of CDI, the disease can persist within a hospital setting in the presence of in-ward transmission, even when there are no asymptomatically colonized patients at the time of hospital admission.
Conclusions
Our findings have significant public health and clinical implications, especially in light of the emergence and community spread of hypervirulent CDI strains with enhanced transmission rates and toxin production. Rapid detection of colonized patients remains an important component of CDI control, especially in the context of asymptomatic transmission. Screening of in-hospital patients with potential exposure to colonized patients or contaminated environment and equipment can help reduce the rates of silent transmission of CDI through asymptomatic carriers.
Keywords
Background
Clostridium difficile infection (CDI) has become the leading cause of hospital acquired nosocomial diarrhea worldwide [1, 2], and remains among the top 10 infectious causes of death in the developed world [3–5], with alarming rates in terms of morbidity and mortality [6]. The severity of CDI ranges from asymptomatic and mild diarrhea to life-threatening conditions including toxic, megacolon, bowel perforation and sepsis [7]. The steady increase in the incidence of CDI along with prolonged hospital stays inflict a substantial impact on the healthcare systems in terms of costs and patient outcomes [8, 9]. The changing epidemiology of CDI [10], especially in the presence of hypervirulent strains [11], underscores the need for improved and strategically integrated infection control measures.
For many nosocomial infections including C. difficile, hospitals and other healthcare facilities are primary resources for disease control, but may also serve as ‘hot spots’ for disease transmission, with subsequent hospital-to-community spread. Therefore recommended measures and strategies for diagnosis and management of patients with CDI are mainly implemented in the healthcare facilities [12, 13]. In these settings, often several interventions are implemented simultaneously, making it difficult to estimate the importance and effectiveness of each intervention individually or relative to another [13]. A number of modelling studies on the transmission dynamics of C. difficile in hospital settings have evaluated the effects of various interventions, including screening of patients at the time of hospital admission and within-ward transmission reduction measures such as isolation [14–17]. While projecting the potential gains that can be achieved through these interventions, these models indicate different ranks for each intervention in terms of their importance and effectiveness on reducing the incidence of CDI [14–16]. A recent systematic review of mathematical models of CDI and colonization in healthcare settings shows a substantial variability in the natural history assumptions, outcome measures presented, and interventions examined in published studies, highlighting the challenge in identification of optimal intervention strategies to control and prevent CDI transmission [18].
In this study, we sought to develop a stochastic model of C. difficile transmission dynamics in a hospital setting, based on biological and epidemiological characteristics of this disease including its natural history [14, 15, 19], to investigate the effect of screening patients on reducing the prevalence and incidence of CDI. We included several key parameters into the model, representing the level of patient screening, effectiveness of isolation, treatment failure, and the level of susceptibility to infection. While the contribution of admitted patients who are colonized without presenting symptoms (referred to as asymptomatic carriers) to the spread of CDI has been recognized [14, 20], the effect of imperfect isolation (i.e., < 100% effective in preventing C. difficile transmission in the ward) and screening of in-hospital patients with exposure to CDI have not been accounted for. By inclusion of these factors in the model, we simulated various scenarios for detection and isolation of colonized patients, and ranked the model parameters in terms of their relative importance on the reduction of CDI incidence and prevalence.
Methods
Biological and epidemiological assumptions
Clinical studies demonstrate that a significant fraction of colonized patients remain infectious and can transmit the bacterium with no apparent symptoms [12, 14, 21]. These individuals may develop immune responses against C. difficile [14, 21], and we assumed that only colonized patients without immune responses develop clinical symptoms. It is well documented that the use of antibiotics increases susceptibility to colonization of C. difficile, as a result of damage to gut flora [14, 22, 23]. High rates of treatment failure for the management of CDI have been reported [14, 24, 25], with the possibility of recurrence even after effective treatment [26, 27]. We considered timelines for detecting colonized patients in two types of laboratory diagnosis methods including (i) the real-time polymerase chain reaction (PCR), and (ii) other tests of enzyme immunoassays, stool culture, and nucleic acid amplification [28–30]. The average time to reportable results for rapid PCR (about 1.5 h) is significantly shorter compared to other testing assays that generally range from 1 to 3 days [28, 31, 32].
The model
Model structure with transitions between compartments, corresponding to the epidemiological statuses of individuals at the time of hospital admission and in-hospital patients
Recognizing the importance of asymptomatic carriers in the hospital transmission of CDI [14, 20], we extended the main structure to include screening of patients at the time of admission, and in-hospital patients. A fraction of patients at the time of hospital admission will be screened and isolated if diagnosed with colonization of C. difficile, including patients with apparent symptoms (Additional file 1: Figure S1). For diagnosis using PCR testing method, we omitted the short time-interval (approximately 1.5–2 h [31]) prior to the release of laboratory results. We therefore introduced two classes of patients who are isolated and treated upon screening, based on whether they develop immune responses (\( {C}_T^{+} \)) or not (\( {C}_T^{-} \)). For diagnosis using other testing methods, we accounted for the delay between the time of sample collection and the time when laboratory results are released. Considering such a time delay, we introduced two additional classes of patients under screening with immune responses (\( {D}_T^{+} \)) and without immune responses (\( {D}_T^{-} \)). We assumed that during the screening period before the laboratory results are released, patients are neither isolated nor treated for C. difficile [13]. The transition of these patients to \( {C}_T^{+} \) and \( {C}_T^{-} \) for treatment of C. difficile occurs after the release of positive laboratory testing. Screening of in-hospital patients is considered for those with potential exposure to CDI through colonized patients, staff, or contaminated environment and equipment. In this model, we assumed that the same laboratory testing method was used for screening of patients at the time of admission and in-hospital patients.
The effects of treatment, screening, and the development of immune responses upon colonization are included in the reduction of disease transmission and transitions between different model compartments. Considering a mass-action incidence for disease transmission with homogenous mixing, the model can be expressed by systems of differential equations (see Additional file 1).
The basic reproduction number
Description of model parameters and their associated values (ranges)
Parameter | Description | Value (range) | Source |
|---|---|---|---|
R 0 | basic reproduction number | 1.07 (0.55–1.99) 2.6 (1–7) | [14] [34] |
r | hospital admission rate | 0.17 day−1 | assumed to be the same as discharge rate |
δ | fraction of admitted patients with CDI symptoms | 1.2 × 10−4 | Calculated based on the rate of 6.9 per 10,000 patient-days estimated over 82 periods of 4 weeks [20] |
θ | fraction of admitted patients without CDI symptoms who are screened | 0.925 (0–1) | [20] |
b s | fraction of screened admitted patients who are susceptible | 0.952 (0–1) | [20] |
η | fraction of screened patients who are colonized and develop immune responses | 0.6 (0.45–0.75) | |
α | fraction of screened admitted patients who are susceptible and receive antibiotic treatment | 0.22 (0.15–0.29) | [14] |
σ | fraction of in-hospital patients who are screened following exposure to CDI | 0.9 (0–1) | assumed, varied in sensitivity analysis |
f | fraction of colonized patients who develop immune responses | 0.6 (0.45–0.75) | |
ε | rate of developing CDI symptoms in colonized patients | 0.2 (0.14–0.26) day−1 | |
τ + | recovery rate of damaged gut flora | 0.011 day−1 | [37] |
τ − | rate of antibiotic treatment damaging gut flora | 0.11 day−1 | [36] |
q | fraction of CDI patients who are successfully treated | 0.8 (0.56–1) | |
μ | discharge rate of hospital patients without symptomatic infection | 0.17 day−1 | |
μ I | CDI-caused death rate | 0.0012 (0.001–0.01) day−1 | |
ρ | rate of symptoms resolution for CDI patients under treatment | 0.25 (0.143–0.33) day−1 | [35] |
γ | recovery rate of CDI patients under treatment after symptoms resolution | 0.2 (0.143–0.33) day−1 | |
κ | relative transmissibility of colonized patients without symptoms | 0.5 (0.3–0.7) | assumed, varied in sensitivity analysis |
ν | reduction of transmissibility due to immune responses | 0.5 (0.3–0.7) | assumed, varied in sensitivity analysis |
ξ | effectiveness of isolation for CDI patients | 0.8, 0.9, 1 (0.8–1) | assumed, varied in sensitivity analysis |
Ψ | reduced risk of CDI in patients without antibiotic exposure | 0.2 (0.06–0.55) | [24] |
π | time-interval between sample collection and release of laboratory results | 1 (1–3) days |
Stochastic model implementation
We implemented the model stochastically, and used the Gillespie direct algorithm to simulate the stochastic model within a (non-ICU) hospital ward with 50 beds (as the population size) within the range of previous studies for C. difficile [18]. To estimate the transition time between the two consecutive events in the stochastic process, we let dt = − log(n 1)/Δ, where n 1 is a random number drawn from the uniform distribution on the unit interval [0, 1], and Δ is equal to the sum of the rates for all possible events. We then ordered the events as an increasing fraction of Δ and generated another uniform number n 2 between 0 and 1 to determine the nature of the next event. We ran 500 independent simulations to calculate the average of sample realizations of the stochastic process in each scenario.
Parameterization
To simulate the stochastic model, we extracted a number of parameter values from the previous literature. The mean values of these parameters were used for the main results, and the estimated ranges were explored in the sensitivity analyses to investigate the relative influence of each parameter on CDI prevalence. We varied R 0 in the estimated ranges reported in two previous studies [14, 34]. Lanzas et al. [14] fitted a mathematical model to hospital data for patients between January and December 2008, during which C. difficile diagnosis was conducted by stool toxin, and estimated the mean reproduction number of 1.07 (range: 0.55–1.99). By linking the secondary cases to index cases using PCR ribotyping, Norén et al. [34] estimated the mean reproduction number of 2.6 (range: 1–7) for a single hospital ward data between February 1999 and January 2000. The transmission parameter was calculated based on a given R 0, while fixing other parameters of the model. The rate of disease transmission by asymptomatic carriers or colonized patients who mount immune responses may be lower than those with CDI symptoms. While quantification for this lower transmission rate is lacking, we assumed a relative transmissibility that is reduced by 50% on average and considered a range of 30%–70% in the sensitivity analyses. The fraction of colonized patients who mount immune responses was set to 0.6 within the estimated range 0.45–0.75 [14, 15]. We considered a mean period of 5 days for colonized patients to develop symptoms [14, 15]. The duration of CDI symptoms was assumed to have a mean of 4 days [35], with an average of 5 days for full recovery after the resolution of symptoms [14, 15]. Treatment is assumed to be successful in 80% of CDI patients [14, 15]. Based on reported cases [20], we assumed 4.8% of the screened patients admitted to the hospital were colonized [28], and therefore 95.2% were assumed to be susceptible. We used the rate of 6.9 per 10,000 patient-days estimated over 82 periods of 4 weeks each to calculate the daily fraction 1.22 × 10−4 of patients admitted to the hospital presenting CDI symptoms [20]. We assumed 22% of screened patients who are susceptible to colonization receive antibiotic treatment [14]. The rate of in-hospital antibiotic treatment damaging gut flora was set to 0.11 per day [36], and the rate of recovery was assumed to be 0.011 per day [37]. The risk of antibiotic-associated C. difficile colonization relative to no antibiotic exposure has been reported to vary in a wide range of 1.8–16.8 [24, 38]. We considered a 5-fold higher risk of C. difficile colonization for patients under antibiotic treatment. The discharge rate (including mortality) is assumed to be 0.17 per day for hospital patients without CDI symptoms, with a CDI-induced mortality rate of 0.0012 per day for patients with C. difficile symptoms [14, 15]. The discharge rate corresponds to an average of 5.9 days for the length of hospital stay. For scenario evaluation, the fraction of patients screened at the time of admission was set to 0.925 [20]. This fraction for screening in-hospital patients with potential exposure to CDI was assumed to be 0.9. The effectiveness of patient isolation, represented by the parameter ξ in the model, was varied in the range 0.8–1. To account for the effect of imperfect isolation, we multiplied the factor (1 − ξ) by the baseline transmission (β) in the model equations (See Additional file 1). Parameter values and their respective ranges are provided in Table 1.
Results
We ran the stochastic simulations for 200 days, with the introduction of two initial asymptomatic infections C +(0) = 1 and C −(0) = 1. We considered two different reproduction numbers (R 0 = 1.07, 2.6) in the estimated ranges of previous studies [14, 34]. The results for R 0 = 1.07 are described here. The corresponding simulation results for R 0 = 2.6 are summarized in the Additional file 1.
Model with rapid laboratory testing
Prevalence of C. difficile with R 0 = 1.07 over 200 days in the model with rapid testing, without screening (a-c) and with screening (d-f) 92.5% of patients at the time of hospital admission. Curves represent the prevalence of undiagnosed colonized patients (black), and isolated patients (grey) under CDI treatment. Total prevalence is the sum of black and grey curves. The effectiveness of CDI patient isolation in preventing in-ward transmission was 100% (a, d), 90% (b, e), and 80% (c, f)
Model with time-delay in laboratory testing
Prevalence of C. difficile with R 0 = 1.07 over 200 days in the model with time delay between sample collection and the release of laboratory results, without screening (a-c) and with screening (d-f) 92.5% of patients at the time of hospital admission. Curves represent the prevalence of undiagnosed colonized patients (black), and isolated patients (grey) under CDI treatment. Total prevalence is the sum of black and grey curves. The effectiveness of CDI patient isolation in preventing in-ward transmission was 100% (a, d), 90% (b, e), and 80% (c, f)
Disease persistence without admission of colonized patients
Prevalence of C. difficile with R 0 = 1.8 (grey curves) and R 0 = 2.6 (black curves) over 200 days with no admission of colonized patients (b s = 1). The effectiveness of patient isolation in preventing hospital transmission was 80% (ξ = 0.8; solid curves) and 90% (ξ = 0.9; dashed curves)
Relative reduction of CDI incidence
Percentage reduction in the number of new C. difficile infection with R 0 = 1.07 over 200 days in the model with rapid testing (a, b) and the model with time delay between sample collection and the release of laboratory results (c, d). Curves in panels (a) and (c) represent the reduction achieved with screening 92.5% of patients at the time of hospital admission, where the effectiveness of patient isolation in preventing infection transmission in hospital is: 100% (black); 90% (red); and 80% (grey). Curves in panels (b) and (d) represent the reduction achieved with screening 92.5% of patients at the time of hospital admission, where the effectiveness of patient isolation in preventing infection transmission is: 90% (red); and 80% (grey). Screening 90% of in-hospital patients with exposure to CDI started on day 100 (shaded area)
For the model with an average time-delay of 2 days between sample collection and the release of laboratory results, the relative reduction of incidence is significantly lower at 16.3% [95% CI: 15.1% – 17.4%], 10.2% [95% CI: 9.0% – 11.5%], and 10.1% [95% CI: 9.4% – 11.2%] when the effectiveness of patient isolation is 100%, 90%, and 80%, respectively (Fig. 5c).
Inpatients screening
For the scenarios in which patient isolation was less than 100% effective in preventing in-ward transmission, we implemented screening of inpatients with exposure to C. difficile in addition to screening of patients at the time of admission (Fig. 5b, d). For the model with rapid diagnostic testing, Fig. 5b shows the percentage reduction of the incidence of C. difficile, when screening 90% of in-hospital patients started on day 100. This resulted in an increasing trend in the percentage reduction of C. difficile incidence over time, reaching levels over 76% and comparable to those achieved with screening patients only at the time of hospital admission when the effectiveness of patient isolation is assumed to be 100% (Fig. 5a, black curve). However, simulating the model with a 2-day delay in release of laboratory results indicates little additional benefits, achieving only 6% increase in the relative reduction of CDI incidence by inpatient screening (Fig. 5d). When the effectiveness of patient isolation is lower at 80%, the effect of inpatient isolation becomes more pronounced (Fig. 5b, grey curve) in the model with rapid testing.
Similar results were obtained for the prevalence of CDI. Additional file 1: Figure S2 shows that, in the model with rapid testing, the prevalence of CDI reduces and stabilizes at a lower level compared to the level achieved prior to 100 days with screening patients only at the time of hospital admission (Additional file 1: Figure S2A,B). However, for the model with time delay in laboratory testing, we observed virtually no change in the prevalence of CDI after implementing inpatients screening (Additional file 1: Figure S2C,D).
Sensitivity analysis
Relative influence of the model parameters on the response (i.e., CDI prevalence) based on their PRCC indices and p-values below the significance level in the sensitivity analyses with R 0 = 1.07
Model | relative influence | |||||
|---|---|---|---|---|---|---|
rapid laboratory testing | time-delay in laboratory testing | |||||
Parameter | Strong | Moderate | Weak | Strong | Moderate | Weak |
f | • | • | ||||
κ | • | • | ||||
ν | • | • | ||||
Ψ | • | • | ||||
σ | • | • | ||||
θ | • | • | ||||
q | • | • | ||||
ρ | • | • | ||||
γ | • | • | ||||
ξ | • | • | ||||
b s | • | • | ||||
η | • | • | ||||
π | • | |||||
Discussion
Our results show that the transmission of C. difficile within the hospital remains a key epidemiological parameter that can significantly influence the disease dynamics. We evaluated various scenarios in the presence of screening of patients at the time of hospital admission and in-hospital patients with potential exposure to C. difficile that may be due to person-to-person contacts or contaminated environment and equipment. For a relatively low reproduction number, we observed that when the effectiveness of CDI interventions was less than 100%, screening of in-hospital patients can lead to a reduction of C. difficile incidence over time, which may be comparable to that achieved with screening of patients only at the time of hospital admission when isolation is 100% effective in blunting disease transmission in the ward. However, the additional benefits of inpatient screening become negligible for a sufficiently high reproduction number. Furthermore, the silent transmission of C. difficile from asymptomatic carriers is an important pathway for the spread of CDI, especially among individuals with an increased risk of susceptibility to colonization.
Despite lower transmission rate for asymptomatic carriers, our results indicate that asymptomatic transmission in the hospital should be accounted for when designing and evaluating control interventions. Recent studies have evaluated the effectiveness of various intervention measures in healthcare facilities, including infection control practices [3, 12, 18, 40, 41]. A large population-based retrospective cohort study of all patients admitted to acute care hospitals between April 2011 and March 2012 in Ontario, Canada, found that selected hospital prevention strategies had limited effectiveness or were ineffectively implemented [3]. A controlled quasi-experimental study in the province of Quebec, Canada, evaluated the effect of identification and isolation of asymptomatic carriers on the incidence of healthcare associated CDI over a 15-month period. The findings showed that screening of admitted patients and isolating asymptomatic carriers decreased the incidence of CDI by 62.4% [20]. Collectively, these studies suggest that the effective implementation of measures to block the silent transmission of CDI by asymptomatically colonized patients remain essential components of containment strategies within healthcare facilities.
Previous studies have concluded, using modelling and simulation scenarios, that the admission of colonized patients and asymptomatic carriers are the main impediments to the control of CDI in healthcare facilities [14–17]. Our results in evaluating the effect of interventions concur with this conclusion. However, contrary to previous findings [14], we have shown that transmission within the ward alone can sustain new C. difficile colonizations in the range estimated for the reproduction numbers, even in the absence of colonized patients at the time of hospital admission. Our findings indicate that if infection control measures are implemented inefficiently, within-ward transmission can potentially offset the benefits of patient screening. For patient screening, we implemented the model taking into account the possible time-interval for detecting C. difficile using various laboratory testing methods. When colonized patients are not isolated during the time-interval prior to the release of laboratory tests, we observed that the effect of screening on the incidence of CDI is substantially reduced, even when patient isolation is 100% effective in preventing in-ward transmission. In an exploratory analysis, we found that if screening of patients at the time of hospital admission and screening of in-hospital patients are implemented individually, then the former would always outperform the latter in terms of reducing the prevalence and incidence of CDI irrespective of the reproduction number, time-delay in the release of laboratory tests, or effectiveness of patient isolation. These findings harken back to the importance of transmission by asymptomatically colonized patients.
Previous work also shows that improving environmental cleaning and hand hygiene leads to a substantial reduction of colonization rates [15]. In our study, while we have not explicitly modelled the effect of these measures, we evaluated how their effectiveness (represented in the C. difficile transmission parameter) influences the incidence and prevalence of CDI. This evaluation was performed using parameter estimates extracted from the published literature, which is subject to parameter uncertainty. Although the relative transmissibility of C. difficile for asymptomatic carriers who mount immune responses (compared to symptomatic CDI patients) has not been quantified, our sensitivity analyses support the robustness of the model outcomes with variation in parameter space. However, our model has several limitations including the measures for sensitivity and specificity of C. difficile laboratory tests. While we did not consider the variability in these measures documented in the literature [29, 32, 42], other parameters of the model could be adjusted to account for their effects. For example, the parameter representing the fraction of patients who are screened can be tuned to account for the level of sensitivity of a test for C. difficile detection. We assumed the same risk of acquiring C. difficile for all patients as a result of exposure to antibiotics; yet, we understand that the relative risk varies across different classes of antibiotics. This variation was explored through sensitivity analysis. Furthermore, we did not consider the variability in CDI transmission from environmental factors compared with person-to-person, which is affected by contact patterns of individuals. A recent data-driven study of individual movements in a long-term care facility demonstrates that the network of contacts in healthcare facilities is highly structured and deviates from random mixing [43]; an assumption that underlies many models in the literature including the one presented here. The structure of contacts among patients and staff in these settings could significantly affect the identification of optimal intervention strategies and their outcomes for the control of nosocomial infections [43]. The modelling framework developed here could be translated into an agent-based computational model to include individual characteristics and environmental factors, and assess the likely outcomes of novel interventions.
Conclusions
Our findings indicate that the effective implementation of bundle strategies within hospital settings is critically important in the control of CDI even in the absence of asymptomatically colonized patients at the time of hospital admission. Furthermore, rapid detection of colonized patients can significantly affect the prevalence of CDI and its control, especially in the context of asymptomatic carriers and in-ward transmission. Further studies are required to quantify the effectiveness of current CDI interventions, and recurrent rates in hospital settings to parameterize decision models for the evaluation of preventive measures.
Abbreviations
- CDI:
-
Clostridium difficile infection
- PCR:
-
Polymerase chain reaction
Declarations
Acknowledgements
The authors would like to thank the reviewers for insightful comments that have greatly improved the paper.
Funding
This study was in part supported by the Natural Sciences and Engineering Research Council of Canada (NSERC), and the Mathematics of Information Technology and Complex Systems (Mitacs).
Availability of data and materials
No patient-level data were used in this study. The model was parameterized with previously published estimates. Computer simulation codes (developed in Matlab©) are available as Additional files 2 and 3.
Authors’ contributions
SM developed the model, performed the experiments, interpreted the results and contributed to the writing of the manuscript. SMM designed the study, contributed to the model development and writing the manuscript, and provided important intellectual content. Both authors have read the final version of this manuscript and approved it.
Competing interests
The authors declare that they have no competing interests.
Consent for publication
Not Applicable.
Ethics approval and consent to participate
Not Applicable.
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