Prevalence of Methicillin-Resistant Staphylococcus Aureus (MRSA) infection in patients with Cystic Fibrosis: a meta-analysis

Methicillin-resistant staphylococcus aureus (MRSA) infection is increasingly being reported among patients with cystic fibrosis (CF) and contributes to pulmonary morbidity in CF, with poorer prognosis. The aim of this study was to assess the prevalence of MRSA infection in patients with CF. We conducted this study according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Databases of MEDLINE/PubMed, WHO-Virtual Health Library (VHL), ScienceDirect, Google Scholar and OpenGrey were searched to recruit the relevant articles. Pooled prevalence with the corresponding 95% confidence interval (CI) was calculated using OpenMeta Analyst software, and heterogeneity among studies was estimated using the I2 statistics. to our 27 studies a of 47,413 patients were The pooled prevalence of MRSA was (95% CI Subgroup analyses and showed that prevalence geographical obtaining source


Introduction
Cystic fibrosis (CF) is an autosomal recessive multisystem genetic disease, and one of the commonest life-threatening disorders caused by mutations in the CF transmembrane conductance regulator (CFTR) gene on chromosome 7, leading to production of thick secretions that predispose to chronic pulmonary infections, digestive tract disorders, as well as other systems impairment [1][2]. Most of patients with CF develop respiratory failure brought on by recurrent and chronic bacterial infection leading to persistent lung infections & obstructive lung disease, which is the most common cause of death in this population [3]. Respiratory tract colonization by these pathogenic microorganisms in patients with CF represents a serious health problem and it is considered a major cause of morbidity and mortality [4][5].
Patients with cystic fibrosis are susceptible to respiratory tract colonization and infections by different microorganisms due to their thick viscid secretions and impaired mucociliary clearance mechanism [6]. Classic organisms isolated from patients with cystic fibrosis include methicillin-sensitive staphylococcus aureus (MSSA), methicillin-resistant staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and Burkholderia capacia [3]. MRSA is considered among pathogens of the highest prevalence, and a significant cause of increased morbidity and mortality among patients with CF [7]. Methicillin resistance seriously compromises the choice of antibiotic treatment in these patients [8]. Recent epidemiologic studies have evaluated the role of MRSA as contributor to clinical outcomes in patients with CF, 5 and a risk factor for failure to recover lung function after an acute pulmonary exacerbation [9][10].
Studies have demonstrated that patients with MRSA detected in their sputum cultures and bronchial secretions had more hospital admissions per year as well as increased length of hospitalization and impaired pulmonary function tests than in patients without MRSA even after hazard ratios adjustment. Thus, it greatly impairs the quality of life of the affected patients. Furthermore, it has been linked with poor survival [11][12][13].
Several studies assessed the prevalence of MRSA in patients with CF and reported a progressive increase in the prevalence. However, these studies remain inconsistent with wide variation in the data obtained from these studies, and to the best of our knowledge, there is no meta-analysis of existing contemporary evidence on the prevalence of MRSA in patients with CF. The systematic measurements of the prevalence of MRSA will show the magnitude of this problem and the results of this study can provide a comprehensive view of MRSA prevalence in this susceptible population and may contribute to its control and management.

Methods
Search strategy and inclusion criteria: The methodology was developed from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [14]. Medline/PubMed, WHO-Virtual Health Library (VHL), Google Scholar, ScienceDirect and OpenGrey were searched for all studies on association between MRSA infection and CF. We performed a systematic literature search of the database up to February 2019 using the search 6 terms "methicillin-resistant staphylococcus aureus", "MRSA", "cystic fibrosis", and "CF" to ensure maximal coverage of possible literature.
The criteria for paper inclusion were any study published in English that presented the prevalence estimates of MRSA in patients with CF or sufficient data for estimation. If two or more studies shared the same patient population, the study with more complete data or a larger sample size was included to avoid duplication.
Infection was defined as the presence of this microorganism as detected by isolation from the specimens obtained from patients with CF, weather it was described as intermittent or persistent colonization in the included studies. Study exclusion criteria included the following: case reports, case series, editorial letters, reviews, abstracts, and studies lacking the data of interest.
The titles and abstracts of all papers retrieved from this search were screened for potential inclusion in this review. Then, potentially relevant studies were reviewed for inclusion according to the defined eligibility criteria. Any disparity was resolved by discussion and consensus. Quality of the studies was assessed using a quality assessment tool for prevalence studies suggested by Hoy et al, which is a tool that addresses internal and external validity issues of prevalence studies based on combined criteria [15]. Data extraction form was developed to extract the relevant information, and the following data were extracted: authors, study region, data collection method, samples' sources, year of publication, gender, patients' age group, number of patients with CF and number of patients with MRSA.

Statistical analysis:
Pooled prevalence from the random effects model with the corresponding 95% confidence interval (CI) was calculated using OpenMeta Analyst software version 10.10 for analysis [16]. Heterogeneity among studies was estimated using the I 2 7 statistics and publication bias was estimated by visual examination of the funnel plot. We detected a substantial level of heterogeneity (I 2 = 99.7%) in estimated effect size between the included studies. Therefore, factors associated with the studies themselves (study area, data collection methods, sampling source, publication year and sample size) may have a moderating effect on the overall results. We therefore conducted subgroup analyses and meta-regression to determine the extent to which these variables moderated the overall results. Chisquare (X 2 ) test was used to assess the differences between the categorical subgroups and the significance level was set at 0.05.

Results
The schematic flow of study identification and selection process is presented in The discrepancy between prevalence rates reported from the reviewed studies might be attributable to several factors. In this meta-analysis, we have found that the prevalence of MRSA showed regional epidemiological differences. This finding was also reported by previous review done Christopher H. Goss et al [9]. While rates of MRSA have been reported to be considerably lower in most European CF centres, the prevalence tends to be a little higher in other countries where there is overcrowded living condition and inadequate implementation of infection control measures.
MRSA poses a concern because of its rising prevalence and its rapidly growing antibiotic resistance attributed to its resilience and different molecular properties that facilitate the acquisition of different antibiotic resistance genes [42]. In this meta-analysis, we found that the prevalence of MRSA infection has climbed up over years. This increase is in line with previous reviews done by LiPuma, Kahl and Jennings et al [3,10,43]. They reported that MRSA infection among CF population has demonstrated a notable increase in prevalence over the last decades. Analysis of data from the Cystic Fibrosis Foundation Patient Registry in the United States indicates that the prevalence of MRSA infection in CF patients increased steadily during the last years [3]. Also, this observation has been noted in a reference centre for the treatment of CF patients in Buenos Aires, Argentina, where the prevalence of MRSA has climbed from 23% in 1995 up to 32% in 2011 [34].
Sputum specimen is a common and readily available method for clinical evaluation of the lung microorganisms in patients with CF. It is less sensitive than other more invasive procedures such as bronchoalveolar lavage, but it remains an accurate indicator of lower airway microbiology [44]. Most of the included studies data came from the results of sputum samples. This meta-analysis showed that the colonization prevalence of MRSA from sputum culture alone was lower than that from specimens obtained from sputum with other more invasive sampling.
Other possible risk factors of MRSA infection in patients with CF have been assessed by a few of the included studies. Some of these studies had demonstrated that older age [22], MRSA detection in family members [17], occupational exposure [38], frequent hospitalization [21,34,37], CF-related diabetes [34], pancreatic insufficiency [21], pre-existing bronchiectasis [21], and Pseudomonas aeruginosa co-infection [17,31]  Availability of data and material: The dataset generated during this study are available from the corresponding author on reasonable request.

Competing interests:
The authors declare that they have no competing interests.