Review

Respiratory infections in patients with cystic fibrosis undergoing lung transplantation Leonard J Lobo, Peadar G Noone

Cystic fibrosis is an inherited disease characterised by chronic respiratory infections associated with bronchiectasis. Lung transplantation has helped to extend the lives of patients with cystic fibrosis who have advanced lung disease. However, persistent, recurrent, and newly acquired infections can be problematic. Classic cystic fibrosis-associated organisms, such as Staphylococcus aureus and Pseudomonas aeruginosa, are generally manageable post-transplantation, and are associated with favourable outcomes. Burkholderia cenocepacia poses particular challenges, although other Burkholderia species are less problematic. Despite concerns about non-tuberculous mycobacteria, especially Mycobacterium abscessus, post-transplantation survival has not been definitively shown to be less than average in patients with these infections. Fungal species can be prevalent before and after transplantation and are associated with high morbidity, so should be treated aggressively. Appropriate viral screening and antiviral prophylaxis are necessary to prevent infection with and reactivation of Epstein-Barr virus and cytomegalovirus and their associated complications. Awareness of drug pharmacokinetics and interactions in cystic fibrosis is crucial to prevent toxic effects and subtherapeutic or supratherapeutic drug dosing. With the large range of potential infectious organisms in patients with cystic fibrosis, infection control in hospital and outpatient settings is important. Despite its complexity, lung transplantation in the cystic fibrosis population is safe, with good outcomes if the clinician is aware of all the potential pathogens and remains vigilant by means of surveillance and proactive treatment.

Introduction Cystic fibrosis is an inherited, chronic disease that affects roughly 30 000 children and adults in the USA and about 80 000 individuals worldwide. Although life expectancy has increased with new treatments, improved access to care, and improvements in the delivery of care, lung transplantation remains an important intervention to prolong survival. International data show survival of 82% at 1 year, 69% at 3 years, 59% at 5 years, and 42% at 10 years post–transplantation.1 Post-transplantation survival for patients with cystic fibrosis is better than for transplant recipients with other lung diseases after the first year (figure 1). Nonetheless, patients with cystic fibrosis being considered for lung transplantation present several unique challenges compared with transplant candidates with other end-stage lung diseases. Apart from involvement of other organs besides the lung, persistent, recurrent, and newly acquired infections can be especially problematic. Whether in the setting of lung transplantation or not, our understanding of the microbiology of cystic fibrosis airways has changed over time with advances in clinical microbiology laboratory techniques and therapeutic strategies, and changes in patterns of infection. Initially, Staphylococcus aureus was thought to be the main pathogenic organism in cystic fibrosis, but Gramnegative bacteria such as Pseudomonas aeruginosa and Burkholderia cepacia species were implicated soon after. More recently, other Gram-negative organisms such as Stenotrophomonas maltophilia and Achromobacter xylosoxidans species have emerged as infectious pathogens in patients with the disease, as well as acidfast bacilli such as non-tuberculous mycobacteria. All of these organisms, and other environmental bacteria, fungi, and viruses, can cause problems in pretransplantation and post-transplantation patients. wwww.thelancet.com/respiratory Vol 2 January 2014

The cystic fibrosis microbiome and lung transplantation

Lancet Respir Med 2014; 2: 73–82 Published Online August 23, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70162-0 Division of Pulmonary and Critical Care Medicine, Duke University School of Medicine, Durham, NC, USA (L J Lobo MD); and Pulmonary Division, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA (P G Noone MD) Correspondence to: Dr Peadar G Noone, Pulmonary Division, Department of Medicine, UNC Chapel Hill, NC 27599, USA [email protected]

In the care of patients with cystic fibrosis, surveillance of airway secretions for the presence and burden of organisms in the airway has been the traditional method for directing—at least in part—the focus and intensity of treatment for pulmonary disease, in an effort to slow the progression of lung destruction and improve quality of life. Surveillance has relied on traditional laboratory culture methods, resulting in what has been described as a reductionist view, based on a list of organisms that usually inhabit the lung in cystic fibrosis.2 In support of such an approach, most patients respond to combined antimicrobial treatment that is based on either laboratory Key messages • Consideration of the infectious agents that can affect patients with cystic fibrosis remains important before, during, and after transplantation, with specific outcomes linked to specific organisms; targeted treatments are usually necessary • Staphylococcus aureus and Pseudomonas aeruginosa are generally associated with favourable post-transplantation outcomes • Concerns exist with respect to non-tuberculous mycobacteria, especially Mycobacterium abscessus, although post-transplantation survival has not been definitively shown to be less than average in patients with these infections; however, morbidity might be high because of recurrent infection and drug toxicity • Burkholderia cenocepacia poses a particular challenge in terms of reduced survival, and is regarded as an absolute contraindication for lung transplantation by most centres, although other Burkholderia species are less problematic • Fungal species can be quite prevalent before and after transplantation and are associated with high morbidity, so should be treated aggressively • Appropriate viral screening and prophylaxis is necessary to prevent infection with and reactivation of Epstein-Barr virus and cytomegalovirus and their associated complications

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1A1D (n=2490) Cystic fibrosis (n=5608) COPD (n=11 948) IPF (n=7540) IPAH (n=1308) Sarcoidosis (n=849)

Survival (%)

80

60

40

20

0 0

1

2

3

4

5 6 7 8 9 Time since transplantation (years)

10

11

12

13

14

Figure 1: Kaplan-Meier analysis of survival after adult lung transplantation1 Graph shows survival after lung transplantation by disease type for an international population of all patients who underwent lung transplantation from January, 1986, through June, 2011. Survival for patients with cystic fibrosis was better than for other transplant recipients after roughly 1 year. Survival was calculated by the Kaplan-Meier method, which incorporates information from all transplantations for which any follow-up data are available. Since many patients were still alive at the time of analysis and some patients had been lost to follow-up, the survival rates are estimates. The half-life is the estimated timepoint at which 50% of all of the recipients have died (α1-antitrypsin deficiency [A1AD]=6·2 years; cystic fibrosis=7·5 years; chronic obstructive pulmonary disease [COPD]=5·3 years; idiopathic pulmonary fibrosis [IPF]=4·4 years; idiopathic pulmonary arterial hypertension [IPAH]=5·0 years; sarcoidosis=5·3 years). Reproduced by permission of the International Society for Heart and Lung Transplantation.

sensitivity patterns or a clinical response to empirical choices of antibiotics. Aggressive treatments directed at exacerbations seem quite justified, since recurrent infectious pulmonary exacerbations generally lead to progressive destruction of the lung, with declining lung function, systemic manifestations, and a poor quality of life (which can, ultimately, if appropriate, necessitate lung transplantation). In the past 5 years, new molecular techniques have been used to reveal the complexity of the microbiological environment of the cystic fibrosis lung, with the term “cystic fibrosis microbiome” used to emphasise the types and abundance of microbes in the lungs of people with the disease.2–4 Thus, in addition to P aeruginosa, S maltophilia, and other common Gram-negative organisms, many other species (bacterial phylotypes) are also present. For example, enteric bacteria such as Prevotella, Bacteroides, Fusobacterium, Mycoplasma, Ralsotonia, and Veillonella species—organisms not normally cultured in the laboratory—have been detected by use of messenger RNA and terminal restriction fragment length polymorphism detection techniques. Shifts occur in the cystic fibrosis microbiome over time that seem to be associated with a decline in lung function in patients with a wide age range, independent of antibiotic use.5 Similar research will hopefully be done with respect to lung transplantation to improve our understanding of what occurs in the transplanted airway, which is without the cystic fibrosis airway epithelial defect, but is dwelling in an immunosuppressed host and directly connected to the native infected sinus tract. In one early 74

study6 that used these molecular techniques, for example, the association between recurrence of the cystic fibrosis microbiome in the transplanted lung and bronchiolitis obliterans syndrome was investigated, with the results suggesting that recurrence of P aeruginosa could be clinically beneficial, possibly by means of a protective effect against other more pathogenic organisms.6 A key question centres on the issue of whether particular pretransplantation infections are associated with poor post-transplantation outcomes. Despite early concern about chronic pretransplantation infections in the context of post-transplantation immunosuppression, these infections turned out to be manageable.7 Nonetheless, the issue arises periodically for many pathogens, especially emerging ones. Several years after the start of large-scale use of lung transplantation for patients with cystic fibrosis, data showed that patients with the disease, particularly those infected with P aeruginosa, had more post-transplantation respiratory infections than did other transplant recipients, but, importantly, with no appreciable difference in survival.8,9 In a retrospective study10 at two large North American centres, patients infected with panresistant bacteria (excluding Burkholderia species) had slightly reduced survival compared with other patients with cystic fibrosis.10 The caveat in interpreting these data is that survival in patients from these centres was better than the US national survival data1 for all lung transplant patients; thus, although survival in patients with resistant organisms was worse than that of the study-internal controls, it was still excellent when compared with national survival data. These findings of acceptable outcomes for patients with cystic fibrosis, even in those with resistant Gram-negative bacteria, are congruent with earlier data reported from other centres.8,11 Nevertheless, concerns remain. Although the idea of removing the burden of infection at the time of transplantation is attractive, microbes can persist in the recipient, leading to infections at the surgical anastomosis sites, in the allograft, and systemically.12,13 In this context, more sophisticated studies that take advantage of molecular techniques will probably shed more light on the pathogenesis of the cystic fibrosis microbiome on the transplanted lung. Although few microbiome-focused data exist in relation to cystic fibrosis and lung transplantation, some data have been reported for other lung diseases post-transplantation. For example, Borewicz and colleagues,14 used bronchoalveolar lavage to compare the microbiome of patients with emphysema post-transplantation with that of healthy lungs, noting that the transplanted organs showed substantial microbial diversity, including the presence of Burkholderiaceae species. Most of the post-transplantation microbes were transient, with only a small percentage persisting for an extended amount of time.14 The authors of a 2011 review15 noted that positive bacterial cultures are reported in up to 80% of lung-transplant recipients. Notably, antibiotic prophylaxis and targeted antibiotics www.thelancet.com/respiratory Vol 2 January 2014

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based on specific isolates were able to reduce the frequency of bacterial pneumonia. These authors also reported an association between pneumonia and a faster progression through the stages of bronchiolitis obliterans syndrome. Consistent with the findings of Borewicz and colleagues’ study,14 the review authors also noted the change in the natural microbiota, which changed over time to protect the lungs from infections through substantial interactions with the immune system, with the hypothesis that this change could lead to dysregulation of the immune system, and thus increase the risk of bronchiolitis obliterans syndrome.15 Data about the microbiomes of both the cystic fibrosis lung and the post-transplantation lungs of patients with and without the disease seem likely to add to our understanding of the associations between infections, the immune system, and graft damage of various types. Experience during two decades of lung transplantation in cystic fibrosis has shown that although recurrent infections with typical organisms occur posttransplantation, such infections are usually manageable, with favourable survival outcomes. However, the situation is more problematic with respect to the B cepacia family of organisms and non-tuberculous mycobacteria. One important issue is that many reports are from single centres or based on small datasets. Additionally, many transplantation programmes have developed internal protocols to deal with their own populations of patients, including those with cystic fibrosis, sometimes with little general validation. However, consensus about how to deal with most organisms has been achieved, either via reasonably sized reports, consistent reports from several centres, or on the basis of supportive long-term clinical experience.

negative effect on post-transplantation outcomes. In a large, single-centre, 5-year retrospective study19 of all lung-transplant recipients (of which patients with cystic fibrosis comprised 11% [67] the 596 patients studied), S aureus infections within the first 90 days of transplantation were associated with an increased longterm mortality and more frequent episodes of acute cellular rejection. Similarly, another reasonably sized retrospective study examined 163 lung-transplant recipients for 5 years and showed that de-novo acquisition of MRSA after transplantation, including the non-toxinproducing strains, resulted in increased mortality compared with transplant patients without MRSA infections.20 Only one of the patients infected posttransplantation had cystic fibrosis, however, so these findings should be interpreted with caution. Despite these data from mixed populations with and without cystic fibrosis, at most lung transplantation centres neither sensitive nor resistant S aureus infection in patients with cystic fibrosis is regarded as a contraindication for lung transplantation. Generally, the approach taken in patients with MRSA, as with most bacterial infections in cystic fibrosis, is to use extended courses of antibiotics in the immediate post-transplantation recovery phase, guided by the appearance of the airways and secretions on bronchoscopic examination, alongside serial microbial surveillance. In addition to standard antimicrobials of varying durations, new approaches have been tried. For example, minimisation of toxic effects with enhanced local delivery via inhaled vancomycin resulted in successful eradication of MRSA in a post-transplantation patient with cystic fibrosis (after failure of systemic vancomycin and linezolid).21

Pathogens that complicate pretransplantation and post-transplantation care

Pseudomonas aeruginosa and other Gram-negative organisms

Staphylococcus aureus

P aeruginosa is the most common pathogen cultured from the adult cystic fibrosis population.22 Patients infected with P aeruginosa generally have worse clinical outcomes than do those without the infection, independent of transplantation. Although P aeruginosa does not seem to have an effect on post-transplantation survival, its presence in the allograft (figure 2) has been associated with the early development of bronchiolitis obliterans syndrome.23,24 Contamination can occur from the native airways, since the bacteria can persist in the upper airways despite removal of the vast burden of infection in the lower airways and parenchyma.13 Because of this risk of infection seeding the allograft, regular assessment of the upper airways is generally recommended, and active disease is treated with sinonasal rinses, as well as topical and systemic antimicrobials (although no strong evidence exists to support this strategy). No definitive protocols have been established for early post-transplantation antipseudomonal treatment, but most transplantation programmes use antipseudomonal antibiotics, with

S aureus is the bacterial pathogen most frequently cultured in the paediatric cystic fibrosis population and remains an important pathogen throughout adulthood, with varying rates of meticillin-resistant S aureus (MRSA) in different centres. Some data suggest slightly worse clinical outcomes in patients with chronic MRSA infections than in those with meticillin-sensitive S aureus infections, because of greater airflow obstruction, increased hospital admissions, and extended courses of antibiotics.16 Other data, from the US Cystic Fibrosis Foundation patient registry, identifies S aureus infections as a possible marker for improved survival.17 Thus, the data are inconclusive, although rigorous infection control, as with all cystic fibrosis-related organisms, is recommended.18 Few reports exist on which to base a solid conclusion as to the risk posed for lung transplantation candidates with cystic fibrosis who are infected with S aureus, resistant or not, compared with reports about the risk posed by Gram-negative organisms. S aureus might have a www.thelancet.com/respiratory Vol 2 January 2014

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Figure 2: Excised right lung from a patient with cystic fibrosis Right lung excised during transplantation of a 20-year-old man with cystic fibrosis (homozygous for the Phe508del CFTR mutation). The conducting airways have been dissected away to reveal widespread bronchiectasis and cystic change, with airways and cysts filled with mucopurulent material. Previous sputum samples were positive for oxacillin-sensitive Staphylococcus aureus and mucoid Pseudomonas aeruginosa. Image courtesy of Scott H Randell (University of North Carolina, Chapel Hill, NC, USA).

course duration dependent on bronchoscopic airway appearance, quantity and quality of secretion, and quantitative microbiological data.25 Despite these concerns about contamination, studies have shown similar posttransplantation survival irrespective of pretransplantation infection with multidrug-resistant P aeruginosa, with an actuarial survival of patients with multidrug-resistant P aeruginosa better than that of non-cystic fibrosis patients in the US national data registry.8,10,26 Overall, most programmes accept that the presence of P aeruginosa, whether resistant or not, is not a contraindication for lung transplantation in cystic fibrosis. For other Gram-negative organisms such as A xylosoxidans and S maltophilia, few data are available for their effect on post-transplantation survival.10,22 Data from a single-centre study in Canada suggested a decrease in survival in patients with S maltophilia, so caution is warranted. Local practice at most centres is to regard these organism in the same way as multidrugresistant P aeruginosa—ie, to maintain close surveillance and treat active infection with extended courses of highdose antibiotics.27

Burkholderia cepacia complex Phenotypically similar to P aeruginosa, the B cepacia complex consists of at least 17 different species of Burkholderia (table; the genomovar nomenclature has been largely dropped).28 Currently, the most prevalent strain in patients with cystic fibrosis is Burkholderia multivorans.22 76

First recognised in the UK and Canada in the 1980s, the first strain, Burkholderia cenocepacia (Edinburgh-Toronto ET-12 strain), was highly transmissible and very pathogenic, leading to many deaths. B cenocepacia carries the greatest risk of morbidity and mortality of all cystic fibrosis-associated organisms, and is associated with cepacia syndrome, a necrotising pneumonia with sepsis and death. The negative effect of B cenocepacia on the posttransplantation survival of patients with cystic fibrosis was recognised in the 1990s, and the infection is now regarded by most—although not all—centres as an absolute contraindication for lung transplantation.29–31 More recent data for B cenocepacia continue to show an adverse effect on survival. In a large UK study29 of 216 patients with cystic fibrosis (22 with B cepacia, including 12 with B cenocepacia) who received transplants, those with B cenocepacia pretransplantation had a high frequency of post-transplantation recurrence of the infection, leading to septicaemia and death, despite extended use of antimicrobial treatment (targeted by susceptibilities) before and after transplantation. As in the earlier study by Aris and colleagues,32 patients with B cepacia species other than B cenocepacia had no such adverse survival outcome, although B mulitvorans can cause additional morbidity.29,32 These findings also accord well with data from the US national registry,33 which showed excellent post-transplantation survival in patients with cystic fibrosis without B cenocepacia infections. The non-B cenocepacia population had rates of survival, rejection, and bronchiolitis obliterans syndrome similar to the general cystic fibrosis population. A study in France of 247 patients with cystic fibrosis (22 with B cepacia, including seven with B cenocepacia) showed similarly poor outcomes to those with B cenocepacia, adding to the evidence that this organism confers a very high risk of early death.30 Some centres (eg, in France and Canada) continue to offer lung transplants to patients with cystic fibrosis infected with B cenocepacia.30,31,34 With respect to Burkholderia species other than B cepacia complex organisms, Burkholderia gladioli might also carry an increased risk for patients undergoing lung transplantation, although some centres report no additional adverse outcomes; the numbers of patients for which data are available are too few to be certain.35,36 The negative effect of Burkholderia dolosa on survival in patients with cystic fibrosis has resulted in transplantation programmes being quite wary about putting these patients forward as candidates, even in the absence of any reported data.37 As with resistant P aeruginosa and other Gram-negative bacteria, treatment strategies are difficult to formulate scientifically, and local experience tends to dominate protocol development. Antibiotic selection can be directed by laboratory in-vitro susceptibility panels and synergy testing, and antibiotic courses are generally extended post-transplantation (sometimes with reduced immunosuppression), irrespective of airway sampling results, www.thelancet.com/respiratory Vol 2 January 2014

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although, as with many transplantation protocols, little or no supporting data are available.34 Various groups use their own internally developed protocols; for example, at the lung transplant unit at Freeman Hospital, Newcastle upon Tyne, UK, topical and inhaled antimicrobial drugs such as taurolidine (not licensed in the USA) have been added to the antibiotic regimens on the basis of synergy testing.38 One report39 has outlined the successful treatment of cepacia syndrome in a patient with cystic fibrosis after a liver and pancreas transplantation with intravenous meropenem and inhaled tobramycin.

Non-tuberculous mycobacteria Non-tuberculous mycobacteria are often cultured from patients with cystic fibrosis.40 Of these organisms, Mycobacterium abscessus might be the most clinically virulent.41 Treatment decisions can be difficult and the usefulness of antibiotic susceptibility testing is uncertain because clinical relation to treatment regimens is poorly defined.42 One of the first studies to address the issue of nontuberculous mycobacteria in cystic fibrosis43 used data from a large US centre and showed that isolation of nontuberculous mycobacteria before transplantation was common (19·7%), and that although prevalence after transplantation was low (3·4%), it was predicted most strongly by pretransplantation isolation. Additionally, no difference in post-transplantation morbidity or mortality was seen between patients with and without pretransplantation infection. However, those patients who had smear-positive disease at the time of transplantation had a higher mortality than those with smear-negative disease. In a more recent, large, 15-year cohort study44 of patients with and without cystic fibrosis at the Brigham and Women’s Hospital transplantation centre (Boston, MA, USA), isolation of non-tuberculous mycobacteria after transplantation was not associated with an increased mortality; however, patients with M abscessus had more persistent surgical-site infections. Smear positivity might be linked to an increased mycobacterial load in the airways, including the large airways, which probably predisposes to infection of the graft by contiguous spread.45 Many centres continue to regard the presence of any non-tuberculous mycobacterial species in cystic fibrosis as a contraindication for lung transplantation, and most guidelines raise special caution for M abscessus.46 A widely cited report47 of one patient with a poor outcome after a lung transplantation concluded that pretransplantation infection with M abscessus should be viewed as a strong relative, if not absolute, contraindication for lung transplantation. Certainly, of all the non-tuberculous mycobacteria, M abscessus is unpredictable. A survey48 of lung transplantation programmes examined data from patients (with and without cystic fibrosis) with either pretransplantation or post-transplantation infections with M abscessus. 31 of the 62 transplant centres affiliated with the International Society for Heart & Lung www.thelancet.com/respiratory Vol 2 January 2014

Relative distribution among pretransplant patients with cystic fibrosis in the USA*

Increased post-transplant risk?†

Burkholderia cepacia complex‡ 3%

Yes

B multivorans (II)

37%

Yes

B cenocepacia (III)

31%

Yes (highly pathogenic)

B stabilis (IV)

Respiratory infections in patients with cystic fibrosis undergoing lung transplantation.

Cystic fibrosis is an inherited disease characterised by chronic respiratory infections associated with bronchiectasis. Lung transplantation has helpe...
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