International BEAT-PCD consensus statement for infection prevention and control for primary ciliary dyskinesia in collaboration with ERN-LUNG PCD Core Network and patient representatives

BEAT-PCD suggestions concerning monitoring and indications for treatment of bacterial airway infections

A general concern for chronic P. aeruginosa infection in PCD is rational. A substantial prevalence of P. aeruginosa has been reported in PCD cohorts [5, 23–25], and there are indications of worse CT scan scores in chronically infected patients with PCD [11, 20] and a risk of further decline of lung function when chronically infected with P. aeruginosa [11]. Still, the evidence from studies including patients with PCD and P. aeruginosa infection are sparse and hence our presented suggestions for treating P. aeruginosa infections were additionally based on the indications of CF and PCD parallelism in airway susceptibility and bacterial adaptation, as the underlying genetic defects in these two diseases result in impaired mucociliary clearance [36]. Both diseases lead to increased susceptibility to airway infections, e.g. H. influenzae, S. aureus and P. aeruginosa. The infections are characterised by adaptation of the bacterial populations to the site of infection.

In two studies using whole genome sequencing of longitudinally collected P. aeruginosa isolates from patients with CF and PCD, evidence was found for phenotypic and genotypic parallelism in the evolution of P. aeruginosa across infected patients. The parallel changes and convergent adaptation and evolution are believed to be caused by similar selective forces such as the intensive antibiotic treatment and the inflammatory response, which drive the evolutionary processes [12, 22]. In a selected cohort of 34 CF patients and 12 patients with PCD similar convergent evolution was identified in eight genes related to antibiotic resistance, quorum sensing, motility, Type III secretion and mucoidity [12, 22].

All in all, the concern of clinical impact together with the predicted parallelism in bacterial behaviour in CF and PCD patients justified a well-founded concern of P. aeruginosa infection and is now reflected in the present BEAT-PCD consensus statement for close airway secretion monitoring, indication for treatment and segregation of patients infected with P. aeruginosa to limit its spread. Parallel suggestions for treatment of B. cepacia were proposed, primarily due to a concern derived from CF experience, as B. cepacia has only been rarely described in PCD and no studies on PCD and B. cepacia infection were identified in our literature search.

For the treatment of NTM, BEAT-PCD agreed to adopt the criteria from the ATS/ERS/ESCMID/IDSA guideline [27] as described in table 1. In alignment with these treatment criteria, BEAT-PCD also suggests culturing for NTM at least annually [37] and at the time of any unexplained deterioration of lung function.

Consensus was not reached on suggesting indication for treatment or segregation of patients with a positive culture for A. xylosoxidans, the main argument for rejection being the rarity of documented A. xylosoxidans infection in PCD, no published studies on A. xylosoxidans infection in PCD and overall lack of experience within the expert panel group. In CF, chronic infection with A. xylosoxidans has been associated with lung function decline [38, 39] and patient-to-patient transmission [40, 41], which raises the concern that A. xylosoxidans infection may also play an ignored but significant role in PCD. Future studies to investigate the impact of A. xylosoxidans in PCD are certainly warranted.

BEAT-PCD suggestions concerning adoption of Leeds criteria for defining chronicity of P. aeruginosa

The most commonly used definition for P. aeruginosa status in CF epidemiological research is that from the Leeds criteria [7], and although it may not be optimal in all circumstances and may, in some cases, lead to the misinterpretation of a chronic infection for an intermittent infection [42, 43], these criteria were considered as the most suitable definition at present.

The expert panel decided to adopt a modified version [5] of the original Leeds criteria established for CF [7] to define chronicity of P. aeruginosa in the current IP&C statement for PCD. The original Leeds criteria [7] define “chronic infection” when >50% of the preceding 12 months’ cultures are positive for the specific pathogen and “intermittent infection” when 50% or less of the preceding 12 months’ cultures have been positive for the specific pathogen and “free of infection” when no growth has occurred in the lungs in the previous 12 months. According to the modification of these criteria used in the current statements, the patient should provide at least four samples of airway secretion per year [5].

Within the expert panel concerns were raised for not being able to diagnose chronic infections due to poor quality of airway secretion samples or due to infrequent and inconsistent sampling of airway secretion. An additional concern was that the sinuses in patients with PCD can function as a bacterial reservoir for recurrent lung infection, including hosting P. aeruginosa [21]. The suggested requirement of four annual samples of airway secretion is in alignment with previous recommendations for pulmonary care and monitoring for PCD [10]. Although it may seem difficult to achieve, the expert panel believes that regular monitoring is the only way to detect, for example, P. aeruginosa at the earliest timepoint possible and have chosen to keep the bar at this higher level in recognition that an even more frequent monitoring is certainly further optimal, but probably difficult to implement.

BEAT-PCD suggestions concerning segregation inside and outside hospital settings

The BEAT-PCD IP&C consensus statement suggests segregation inside and outside hospital settings if the patient has a known infection with P. aeruginosa, B. cepacia, NTM or MRSA even at first positive isolate.

At present there is no clear evidence for patient-to-patient transmission of P. aeruginosa between patients with PCD. However, transmission of non-susceptible strains of P. aeruginosa between CF patients has been a well-known problem since first described in 1986 [44]. From the experience in CF, it is also known that some clone types have the potential to spread to other patients, e.g. patients with COPD. Therefore, all direct contact between individuals with CF is generally suggested to be avoided whether inside or out of the hospital [45, 46].

Since at least four samples of airway secretion per year is also suggested, the last positive airway secretion culture could be 3 months old or more. Hence, there will be a potential risk for transmission of these unwanted pathogens if they were contracted more recently than the last airway secretion sample. A consideration to minimise this risk could be to ask patients to send their airway secretion sample a week before their outpatient appointment to allow any change of infection status to be known on the day of the patients’ appointments. It should, however, be noted that slow-growing pathogens in a sample may bias culture results owing to overgrowth of more fast-growing bacteria with the risk of not detecting the pathogenic bacteria if present in small amounts.

A 30-min gap between all PCD patient appointments regardless of infectious status that could otherwise minimise transmission did not reach consensus as it was perceived too difficult to adhere to due to logistics at various sites.

It has been suggested that non-CF bronchiectasis patients managed within a CF service centre should be managed according to the same strict infection control procedures as patients with CF, because of the risk of transmission from the CF patients to the non-CF bronchiectasis patients and vice versa [14]. This concern for transmission was not evaluated in the current BEAT-PCD IP&C statement. However, shared facilities between patients with CF and those with PCD do occur in some of the PCD centres, and adherence to the strict CF segregation rules should be considered in these centres.

The statements on segregation are more far-reaching based on a precautionary principle and more detailed with regard to both bacteria and viruses and in line with IP&C for CF [16] and clearly deviate from recommendations regarding bronchiectasis in general [47].

BEAT-PCD suggestions concerning cleaning procedures in hospital settings

Cleaning of the patient-room between appointments and at the end of the day with registered hospital-grade disinfectant/detergent was suggested to avoid the general spread of microorganisms to other patients. According to World Health Organization (WHO) guidelines, healthcare personnel must also perform hand hygiene before entering the room and when leaving the room of a patient, before or after direct contact with a patient, before putting gloves on and after removing gloves, for sterile and nonsterile procedures, after contact with a patient's skin, mucous membranes, respiratory secretions or other body fluids, and after contact with medical equipment near the patient that may be contaminated with respiratory secretions [48].

BEAT-PCD suggestions concerning wearing a mask and keeping a 2-m distance at outside hospital patient events

The overall concern for cross-infection of, for example, P. aeruginosa between patients with PCD led to this proposed statement. Use of face masks had previously been shown to be effective at reducing the release of potentially infective Pseudomonas-containing aerosols in patients with CF [49, 50], and wearing a face mask is suggested for CF in healthcare settings [51]. However, our PCD patient representatives raised concerns of stigmatisation by wearing masks and also that highly valued meetings between patients outside the hospital would be too difficult to organise, and therefore the opportunity for mutual support and face-to-face exchange of experiences could get lost. Partly due to this patient concern, the proposed statement was initially rejected but later accepted following the COVID-19 outbreak. Currently, during the COVID-19 pandemic, wearing a mask has become commonly suggested and widely used among most people in all daily life situations and hence stigmatism is currently not an issue. In addition, many larger patient meetings will currently not be possible due to the general assembly restrictions in most countries. It is, however, important to stress that this issue had been clearly controversial before the COVID-19 pandemic, since both PCD experts and patient's representatives were reluctant to accept the suggestion. Whether the suggestion should be removed from the statement once the COVID-19 pandemic is under full control remains open, and the board of PCD experts and patient's representatives should be consulted again when this time comes [52].

Limitations of the study

Members of the expert panel were mainly paediatric pulmonologists, whereas representation from physicians managing adult PCD was low, which could lead to the concern that adult patients were not appropriately represented. However, adult PCD care has traditionally been managed by paediatricians in many PCD centres for many years, and almost 75% of the medical experts in the present consensus panel have extensive experience in management of both children and adults with PCD.

Many of the consensus statements grew out of extrapolation of evidence based on CF because of the lack of current evidence in the field of PCD, although extrapolation from a whole different disease entity such as CF can never be optimal. Crafting evidence specifically for PCD is of extreme importance and will also be possible in the near future owing to currently growing PCD registries, more randomised controlled trials to come and further multicenter observational studies in PCD cohorts. In the current situation and for lack of anything better, we found that the Delphi method used was appropriate in achieving the presented statements concerning PCD.

There is currently no evidence regarding patient-to-patient transmission of NTMs and no evidence regarding the risk associated with infection of specific NTM species in PCD. However, from the experience across the expert panel it was clear that NTMs indeed are sometimes cultured and also in some cases cause clinical symptoms and radiological changes in patients with PCD. Based on these experiences, the expert panel chose to include statements suggesting indication of treatment as per ATS/ERS/ESCMID/IDSA 2020 guidelines [27], which include treatment strategies for a number of NTM species. In alignment with this and due to lack of evidence in PCD we chose not to differentiate between specific NTMs in the statements. Similarly, the expert panel chose to suggest segregation whenever any NTM species is cultured.

We consider these IP&C statements as a guide for all physicians who manage paediatric and adult patients with PCD, whether it takes place in a dedicated PCD centre, a centre where the experts in addition to CF also manage PCD or where PCD patients constitute a minority among larger numbers of patients with all sorts of other diagnoses within adult pulmonary medicine.

Conclusion

We here provide the first International BEAT-PCD IP&C consensus statement for PCD within COST Action and ERS Clinical Research Collaboration together with the ERN-LUNG PCD Core Network.

The consensus statement consists of 20 suggestions for IP&C intended specifically for patients with PCD in a number of settings. The statements are targetted at paediatric and adult PCD healthcare providers, microbiologists, PCD patient organisations and patients themselves. Patient representatives were included throughout the process of conducting the presented consensus statements. The statements include suggestions for microbial diagnostics, infection prevention for specific pathogens considered indicated for treatment, and segregation strategies for outpatient and inpatient settings as well as for non-healthcare settings.