links header

email icon printer icon

Emerging Infectious Threats in Cystic Fibrosis Patients
Undergoing Lung Transplantation


Shahid Husain, MD, MS
University Health Network/University of Toronto


shahid.husain@uhn.ca



sept linksIntroduction

Cystic fibrosis (CF) is a devastating disease that affects young individuals. With advancements in management and the introduction of newer therapies, the average survival in CF patients is around 38 years1; however, respiratory failure is a known complication in these individuals often requiring lung transplantation. According to the recent ISHLT registry data, 27% of bilateral lung transplantations across the world are performed in patients with CF. Of these patients, 50% will survive greater than 7.4 years post transplant. Infection following transplantation continues to be a moving target and is complicated by the pre-transplant microbiological profile of patients. Burkholderia cepacia complex (BCC) infection is well known to increase mortality after transplantation in these patients and there is new data on this old foe. Recently however, other pathogens have also gained more prominence.


Burkholderia cepacia complex (BCC)

Zlonisk et al looked into the correlation of phenotype of the BCC isolated to that of poor outcomes. They noticed that patients infected exclusively with the non-mucoid BCC had more rapid decline in lung function (annual FEV1 -8.51±2.41%) than those infected with mucoid bacteria (-3.01±1.09%; p<0.05). In vitro incubation of BCC with ceftazidime and ciprofloxacin caused conversion of BCC from mucoid to non mucoid type thus increasing the virulence, while use of meropenem did not result in phenotypic switch.2 Although to date no study has looked into the proportion of mucoid vs. nonmucoid infected patients undergoing lung transplantation, it is plausible that most of the CF patients undergoing lung transplant belong in the non mucoid group.

IMPLICATIONS FOR LUNG TRANSPLANTATION. Identification of non mucoid strains in patients prior to transplantation and refraining from the use of certain antibiotics post-transplant may prove helpful.


Methicillin resistant Staphylococcus aureus (MRSA)

The prevalence of MRSA in North America among CF patients had risen dramatically. The prevalence rate is around 20%.1 Persistent colonization with MRSA has been previously reported to be associated with decline in FEV1.3 The same group has recently reported higher mortality associated with presence of MRSA in the respiratory tract. Among those with MRSA, the attributable risk percentage of death associated with MRSA was 34.0% (95% CI, 26.7-40.4) and adjusted hazard ratio of MRSA associated with death was 1.27(95% CI, 1.11-1.45).1

IMPLICATIONS FOR LUNG TRANSPLANTATION. The higher rate of MRSA is the CF population is alarming especially in North America. CF patients with persistent MRSA colonization at the time of transplantation may require empiric therapy with anti-staphylococcal agents. However, it is still unknown whether those patients who had colonization once with MRSA prior to transplantation are at higher risk of developing MRSA pneumonia following transplantation.


Transmissible strains of Pseudomonas aeruginosa

Pseudomonas is the most common organism infecting CF patients. Recently Shawn and colleagues described two transmissible strains of P. aeruginosa infecting patients with CF in Canada and United Kingdom (Liverpool epidemic strain /strain A). The incidence rate of new infections with these strains was low (7.0 per 1000 person-years; 95% confidence interval [CI], 1.8-12.2 per 1000 person-years). The rate of decline of lung function was comparable to unique Pseudomonas strains. However, the 3 year death rate or lung transplantation was greater with the Liverpool epidemic strain (18.6%) compared with those infected with unique strains (8.7%) (Adjusted hazard ratio, 3.26 [95% CI, 1.41 to 7.54]; P=.01).4

IMPLICATIONS FOR LUNG TRANSPLANTATION. These strains should ideally be reported to the transplant team for the application of appropriate infection control measures following lung transplantation.


Non-Tuberculous Mycobacteria (NTM) and M. abscessus

Two large epidemiological studies have highlighted the rise in the incidence of NTM over time. Olivier et al initially reported the rate of 12.8% in the late 1990's.5 Levy et al from Israel reported the rate of 22.6%.6 More astonishing was the fact that a higher rate of M. abcessus was also noted in both studies. M. abcessus constituted 16-31% of NTM isolates. Renna et al in their seminal paper linked this increase to the excessive use of azithromycin in the CF population. They noted that the escalating use of azithromycin over the last 5 years mirrored an increase in patients colonized or infected with NTM in their adult CF center. This was not explicable by changes in sputum sampling or microbial culture methods. In their analysis, long-term azithromycin use was associated with developing infection with NTM, particularly M. abscessus (P = 0.0009). When adjusted for age, azithromycin use remained significantly associated with NTM disease (P=0.00046; odds ratio 9.80, 95% CI 2.09-45.87).7

IMPLICATION FOR LUNG TRANSPLANTATION. M. abcessus is a relative contraindication for lung transplantation in most of the centers across the world while NTM colonization prior to transplantation is not. However, one centre had reported higher mortality in patients colonized with NTM prior to transplantation. This study was not specific for CF patients and the true impact of this remains to be seen.

Conclusions

Newer organisms continue to emerge and pose significant challenges in managing CF patients undergoing lung transplantation. These emerging trends need to be monitored systematically and stress should be placed in devising appropriate therapeutic strategies to improve outcome.


Disclosure Statement: The author receives research grants from Pfizer, Astellas, and Merck.


References:

  1. Dasenbrook EC, Checkley W, Merlo CA, et al. Association between respiratory tract methicillin-resistant Staphylococcus aureus and survival in cystic fibrosis. JAMA 2010; 303(23):2386-2392.
  2. Zlosnik JE, Costa PS, Brant R, et al. Mucoid and nonmucoid Burkholderia cepacia complex bacteria in cystic fibrosis infections. Am J Respir Crit Care Med 2011; 183(1):67-72.
  3. Dasenbrook EC, Merlo CA, Diener-West M, et al. Persistent methicillin-resistant Staphylococcus aureus and rate of FEV1 decline in cystic fibrosis. Am J Respir Crit Care Med 2008; 178(8):814-821.
  4. Aaron SD, Vandemheen KL, Ramotar K, et al. Infection with transmissible strains of Pseudomonas aeruginosa and clinical outcomes in adults with cystic fibrosis. JAMA 2010; 304(19):2145-2153.
  5. Olivier KN, Weber DJ, Wallace RJ, Jr., et al. Nontuberculous mycobacteria. I: multicenter prevalence study in cystic fibrosis. Am J Respir Crit Care Med 2003; 167(6):828-834.
  6. Levy I, Grisaru-Soen G, Lerner-Geva L, et al. Multicenter cross-sectional study of nontuberculous mycobacterial infections among cystic fibrosis patients, Israel. Emerg Infect Dis 2008; 14(3):378-384.
  7. Renna M, Schaffner C, Brown K, et al. Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection. J Clin Invest 2011; 121(9):3554-3563.