Review
Isolation measures for prevention of infection with respiratory pathogens in cystic fibrosis: a systematic review

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Summary

Respiratory infections are the most important cause of morbidity and mortality in patients with cystic fibrosis (CF). These infections are typically caused by a limited number of respiratory pathogens, particularly Burkholderia cepacia complex (BCC) and Pseudomonas aeruginosa (PA). Since the 1980s, several outbreaks of unique strains of PA and BCC among CF patients attending the same CF care centres have been described, leading to a sharp decline in the patients' health. One of the measures adopted in CF centres to interrupt ongoing outbreaks is the separation of patients with a respiratory tract culture that is positive for PA or BCC from patients who are not infected. This type of measure has been implemented routinely in many CF centres to prevent cross-transmission of PA and BCC. The aim of this review was to determine what evidence is available to support the efficacy of isolation (or segregation) practices in preventing, delaying or reducing the risk for CF patients of acquiring PA and BCC. A systematic review of scientific literature from 1980 to 31 December 2004 was performed. Existing guidelines regarding infection control in CF were also analysed. In total, 398 relevant papers were retrieved. Only 10 well-designed studies were found that evaluated the efficacy of isolation practices in preventing the transmission of respiratory pathogens in CF care centres (one prospective controlled study, one retrospective cohort study, five ‘before–after’ studies and three cross-sectional studies. No systematic reviews or randomized controlled trials exist on this subject. In the absence of studies with an experimental, controlled design, the efficacy of isolation practices in preventing the transmission of respiratory pathogens in CF remains unproven. However, notwithstanding the considerable limits represented by the study designs, which were mainly retrospective, the observational studies reviewed seem to support the implementation of isolation (or segregation) measures to reduce the risk of transmission of BCC and PA in CF patients.

Introduction

Cystic fibrosis (CF) is the most widespread genetic disease in the Caucasian population. The genetic defect causes an error in the synthesis of the CFTR protein responsible for ionic exchanges through the cell membrane. Clinically, the defect manifests with the presence of denser and more viscous secretions than normal, with progressive damage to the respiratory tract, despite a considerable diversity of clinical situations. The thick, dehydrated bronchial mucus stagnates in the lungs, creating a substratum that is fertile ground for the development of respiratory infections. The clinical history of CF patients is characterized by frequent episodes of pneumonia and bronchial pneumonia. Mucus stagnation, infections and inflammatory reactions tend to perpetuate a vicious circle that leads to progressive damage to the pulmonary parenchyma, deterioration of pulmonary function and, eventually, respiratory insufficiency in the more advanced stages.

Over the last three decades, thanks also to specific therapies in specialized centres, there have been improvements in survival; life expectancy has increased from 2 years in the post-war period to 40 years today.1 Currently, almost half of CF patients are adults and manage to maintain a much better quality of life than in the past. Nevertheless, the major causes of morbidity and mortality are still respiratory infections. The pathogens responsible for this are relatively limited in number, consisting mainly of Burkholderia cepacia complex (BCC), Pseudomonas aeruginosa (PA) and, to a lesser extent, Staphylococcus aureus, Stenotrophomonas maltophilia and Achromobacter xylosoxidans, the pathogenic role of which is not yet entirely clear. PA and BCC are Gram-negative bacteria that are very widespread in the external environment (stagnant fresh water) and in specific reservoirs of hospital environments (e.g. washbasin drains). They are usually innocuous for immunocompetent subjects; however, in hospital environments, they may turn into severe pathogens that usually affect patients with lowered defences (burns, immunodepressed and oncological patients; ventilated patients in intensive care).

Although the mechanism is not fully understood, the lungs of CF patients seem to have a specific affinity for these bacteria, which appear to be equipped with special adhesiveness with regard to CF respiratory mucosa, and also benefit from the chronic inflammatory condition that gradually builds up in the lungs.

Initially, the presence of this bacterium is intermittent and clinically silent. However, its presence tends to become stable and, over time, gives rise to episodes of acute infection (pneumonia), progressive clinical deterioration and worsening of the prognosis.

Although it is not fully understood how patients come into contact with the pathogens, the means of transmission seem to be represented by droplets (large particles expelled by patients from the respiratory tract colonized by the pathogen, usually within a distance of 1 m), and direct or indirect contact with the mucus of the respiratory tract. The latter mainly takes place via kissing, shaking hands, the operator's hands, the use of contaminated medical devices (aerosol devices, physiotherapy respiratory devices, spirometry devices), contact with inanimate surfaces in hospital environments, even when apparently uncontaminated by the pathogens (both PA and BCC are capable of surviving for several days on inanimate surfaces) and shared use of contaminated objects (toys, eating utensils). Airborne transmission of these pathogens does not seem to be supported by any studies.

The main sources of infection are represented by the external environment, other patients (whose lungs represent real reservoirs of the pathogen), and the care centre and hospital environments.

The acquisition of PA and BCC has been clearly associated with clinical deterioration and an increase in the mortality and morbidity of patients with CF.2, 3, 4 This acquisition and consequent deterioration were once considered to be inevitable at some point during the life of a CF patient. It is now known that it is at least possible to reduce the risk of acquisition or to delay chronic infection. In fact, besides therapeutic intervention, there are several possible measures to prevent contact with typical CF pathogenic micro-organisms. Prevention must first be enacted in specialized care centres and the wards where CF patients are hospitalized, and is therefore the direct responsibility of the care staff.

The problem of how to prevent infections with PA and BCC arose in the 1980s. From this period onwards, the literature describes numerous cases of epidemics from single strains of PA and BCC among CF patients in the same care centre. These epidemics of particularly virulent strains with multi-resistance against antibiotics brought about a sharp deterioration in clinical conditions and an increase in the mortality rate.5, 6, 7, 8

One of the measures used historically in CF centres to prevent the transmission of pathogens is the separation of patients with positive cultures for micro-organisms from patients without positive cultures (segregation). This measure has been adopted in numerous CF centres all over the world, often in ‘emergency’ situations, with the aim of interrupting any epidemics in progress. It was mainly based on a theoretical rationale derived from analogous experiences in diseases or circumstances considered to be similar or comparable to those of CF, or in situations where the same pathogens that are relevant for CF were involved, or on the basis of hygienic and preventive recommendations contained in general practice guidelines. Subsequently, segregation became a routine procedure in the prevention of infections with PA and BCC in numerous CF care centres. It is contemplated in the five existing specific guidelines pertaining to the problem of prevention of respiratory infections in CF.9, 10, 11, 12, 13

Section snippets

Objectives

The aim of this study was to analyse the existing scientific literature to determine what evidence is available in support of the efficacy of segregation (or isolation) of CF patients with positive respiratory cultures for BCC or PA from negative patients in order to prevent, delay or reduce the risk of acquisition of micro-organisms.

Methods and criteria for inclusion in the study

An analysis was made of the literature published from 1980 using PubMed, Embase, CINAHL and Central Register of Trials of Cochrane Library, and by hand searching some non-indexed journals and the proceedings of European, North American, Italian and other international CF conferences. MeSH terms and free-text words used for research on Pubmed are given in the supplementary data (see Appendix). No language limits were adopted, although a time limit was imposed with the inclusion of studies

Results

After the initial research in Pubmed, 398 articles were retrieved. No randomized controlled trials, case–control trials or systematic revisions were found. Ten studies investigating the efficacy of patient segregation on the basis of the bacteria present in their respiratory tracts were found. Only one of these studies had a controlled prospective design.14 This study examined the effect of non-participation at summer camps specifically designated for CF children, characterized by prolonged and

Analysis of the existing guidelines

As far as the existing guidelines are concerned, all agree on the need to segregate (or separate or isolate) patients with BCC from each other and from all other patients in both outpatient and inpatient systems. With PA, the indications are more diversified; the guidelines of the Cystic Fibrosis Foundation (CFF) only recommend the segregation of patients with multi-resistant PA,9 but the guidelines of the British and French CF Trusts and the European consensus also recommend the cohorting of

Discussion

Very few well-designed studies have investigated the efficacy of isolation in the prevention of transmission of respiratory pathogens in CF. As mentioned above, many of the measures introduced historically in CF centres to prevent the transmission of pathogens, including segregation, have been adopted in ‘emergency’ situations at the onset of epidemics that have provoked sharp increases in morbidity and mortality rates among CF patients. Data collected in the CF field that support the use of

Acknowledgements

This work is part of a systematic literature review conducted by the Infection Control and Prevention Study Group of the Italian Foundation for Research on Cystic Fibrosis. We gratefully acknowledge Ermanno Baldo, Fiorella Battistini, Serenella Bertasi, Gemma Braccini, Silvia Campana, Lia Myriam Cappelletti, Lisa Cariani, Diana Costantini, Ersilia Fiscarelli, Maria Lucia Furnari, Rolando Gagliardini, Bianca Grosso, Francesca Mangiantini, Paola Melotti, Anna Silvia Neri, Giovanna Pizzamiglio,

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