“Illness is the night side of life, a more onerous citizenship. Everyone who is born holds dual citizenship, in the kingdom of the well and in the kingdom of the sick. Although we all prefer to use the good passport, sooner or later each of us is obliged, at least for a spell, to identify ourselves as citizens of that other place.”
– Susan Sontag (Illness as a metaphor, 1978)
Counting an additional grey-hair in the mirror is the last thing most of us want in the morning and yet, for the Cystic Fibrosis (CF) patient community, there exists the celebratory ‘grey hair club’. The online club is for those with CF looking forward to greying, being grey or a loved one being so. Median life expectancy, for patients with CF, is today 44 years. In the first half of the 20th century CF carried a life expectancy of 6 months. Early enzymatic treatments and antistaphyloccals and antipseudomonals, that mitigate and even clear deadly airway infections, progressively increased life expectancy from the mid-1950s until today. A variety of bacteria present a fatal threat to CF patients and still are the leading cause of mortality overall with Staphyloccocus aureus, Haemophilus influenzae and worst of all, Pseudomonas aeruginosa. The hope is through greater understanding this progress in outcomes may continue and be protected against reversals, such as from antibiotic resistance.
Cystic Fibrosis is caused by mutation-derived alterations to the Cystic Fibrosis transmembrane conductance regulator (CFTR) protein. Fully functional, the CFTR protein transports chloride and sodium across epithelial cell membranes. Dysfunction results in ion imbalances and resultant dysregulation of water in and out of cells. This results in thick hard-to-move mucus in the lungs and gastrointestinal tract. Though clinical descriptions, that appear to refer to CF, were recorded in the 18th century, it would be at Babies Hospital Columbia-Presbyterian Medical Centre, New York in 1938 that it was properly identified. Assistant attending paediatrician and assistant pathologist, Dorothy H. Andersen, noticed a pancreatic lesion during a routine autopsy. Dissatisfied with this singular anomalous finding in a ‘celiac’ patient autopsy, Dr. Andersen scoured the autopsy records and medical literature. She would continue to contribute important knowledge in the post-war period, including collaboratively engineering the sweat chloride test, a non-invasive and accurate diagnostic that could be used on new-borns.
Most infections with P. aeruginosa come from different environmental variants of the bacteria. Coined opportunistic pathogens, these are better thought of as accidental pathogens. They are not ‘meant’ to be pathogenic and outside of certain patient pathologies, such as those with compromised immune systems, burn-wounds or CF, are not. Diverse variants are well adapted to many environments and may be further adapted to soil, pond or plant-root environments to name a few. Once in the CF lung environment, a comparatively hostile and microbiologically competitive environment, the replicating lineage must quickly adapt. There will be variety in the evolutionary pathways followed by distinct variants but also some commonality. This commonality, or convergent evolution, is directly analogous to distantly related bats and birds gaining flight independently or Artic and Antarctic fish species each developing bloodstream anti-freeze proteins. What this means in practice is that a chronic P. aeruginosa lung infections in a patient in Cardiff or Wroclaw can be expected to adapt in some of the same, non-trivial, ways.
For all opportunistic pathogens a major component of adjusting to a mammalian host environment is metabolic remodelling, particularly switching how they acquire iron in this iron-limited environment. Some of these adjustments are communal, rather than individual. Individuals in the population may acquire antibiotic resistance for example, or they may indirectly achieve it together by contributing to a new, communitarian lifestyle. One such lifestyle is achieved by biofilm formation, generating a mucoid glob that the bacteria thrive in and is impenetrable by many antibiotics. As always, evolution is reactionary and opportunistic rather than far-sighted. In moves that can be predicted by game-theoretic principles, individuals in the community can become cheaters. These cheats stop making the expensive-to-produce exopolysaccharide, primary components, of their shared biofilm while continuing to benefit from residency. Inevitably, these cheaters have a reproductive advantage over contributors and will come to comprise an unsustainable subpopulation. When this happens, everyone is deprived of the biofilm’s protection in a classic tragedy of the commons.
Troubling as fatal lung infections already were, at least they were not communicable. A pair of patients could, it was believed, be in repeated close contact, one with a chronic P. aeruginosa lung infection and one without and carry no risk to the latter. In 1986 it was first suggested in the scientific literature that this may not be the case. Clinicians at a paediatric CF clinic in Copenhagen observed that P. aeruginosa sampled from different patients were resistant to the same combination of antibiotics and further, isolation appeared to stop the suspected outbreak(1). In fact, it had been suggested epidemiologically in 1980, that the increased incidence in P. aeruginosa lung infection following holiday camp attendance was due to cross-infection(2). The holiday camps were first developed in the Netherlands in 1974 for children with CF, where a vacation was possible due to onsite health professionals. The CF microbiology research community, however, would soon redirect their attention toward an aggressive infectious threat. Cepacia syndrome, caused by a group of bacteria that make up the Burkholderia cepacia complex and in particular, outbreaks of Burkholderia cenocepacia through the 1990’s wrought catastrophic outcomes. A positive B. cenocepacia test would prognosticate an average shortening of life expectancy by a decade. Scientific and clinical investigations into cepacia syndrome culminated in highly successful isolation policies within CF clinics. Meanwhile, with no conclusive evidence of cross-infection of the main CF lung pathogen, P. aeruginosa quietly spread through clinics.
As in Copenhagen in 1986, clinicians and microbiologists noticed that infecting strains present in Liverpool’s Alder Hey children’s hospital had a shared pattern of antibiotic resistance in 1995. Suspicious of the possibility of cross-infection from the earlier Scandinavian studies and with what was learnt from Burkholderia infections, the bacteria were carefully investigated. Molecular typing confirmed, for the first time, that P. aeruginosa too had been cross-infecting patients. Named the Liverpool Epidemic Strain (LES), it was believed, as in 1986, that antibiotic treatment regimens in the clinic had provided the evolutionary pressure to generate this specialised variant(3). The LES would quickly be surveyed nationwide in the UK and transatlantically in Canadian clinics. Comparative genomics would later show that the strain had its origins, the other way around, in Canada and not as a result of the Alder Hey antibiotic policies(4). In fact, not only was the LES transmissible, but it could superinfect. Where no medical treatments could reverse a chronic P. aeruginosa lung infection, the LES can competitively replace it.
What the emergence of a strain capable of cross-infection represents, is a single chronic infection adapting out of isolation. Since the discovery of the LES it has become apparent, in the Australian Epidemic Strain, Danish Epidemic Strain, Prairie Epidemic Strain and more, that within the species this ability has materialised multiple times. Each of these strains would have begun with a single infection. It also means that as long as there are chronic infections with P. aeruginosa, we can expect new strains to emerge capable of person-to-person transmission. As these strains pass between patients, they gain decades more time to adapt to the lung environment. The oldest known transmissible isolate is of the LES and is from 1988. Stored in laboratory freezers prior to the 1995 discovery, it was in 2009 reanimated and whole-genome sequenced(5). While isolation policies and rapid molecular testing have greatly mitigated the spread of transmissible strains, continued adaptation and particularly, growing antibiotic resistance, threatens that progress.
Due in large part to a patient community highly engaged with research efforts, CF microbiology can be viewed as infectious disease and evolutionary science in microcosm. First, the benefits of antibiotic chemotherapy, the study of convergent host-adaptation across distinct variants, emergence of specialised lineages and next, growing antibiotic resistance. Forestalling, mitigation and ultimately, radical progress in this area will soon be needed to prevent a reversal to the clinical outcomes of 60 years ago.
1. Pedersen SS, Koch C, Heiby N, Rosendal K. An epidemic spread of multiresistant pseudomonas aeruginosa in a cystic fibrosis centre. J Antimicrob Chemother. 1986;
2. Hoogkamp-Korstanje JAA, van der Laag J. Incidence and risk of cross-colonization in cystic fibrosis holiday camps. Antonie Van Leeuwenhoek. 1980;
3. Cheng K, Smyth RL, Govan JRW, Doherty C, Winstanley C, Denning N, et al. Spread of beta-lactam-resistant Pseudomonas aeruginosa in a cystic fibrosis clinic. The Lancet. 1996;
4. Moore MP, Lamont IL, Williams D, Paterson S, Kukavica-Ibrulj I, Tucker NP, et al. Transmission, adaptation and geographical spread of the Pseudomonas aeruginosa Liverpool epidemic strain. Microbial Genomics. 2021;
5. Craig Winstanley, Morgan G.I. Langille, Joanne L. Fothergill, Irena Kukavica-Ibrulj, Catherine Paradis-Bleau, François Sanschagrin, Nicholas R. Thomson, Geoff L. Winsor, Michael A. Quail, Nicola Lennard, Alexandra Bignell, Louise Clarke, Kathy Seeger, D and RCL. Newly introduced genomic prophage islands are critical determinants of in vivo competitiveness in the Liverpool Epidemic Strain of Pseudomonas aeruginosa. Genome Research. 2009;
First posted on Medium.com (https://medium.com/@91mattmoore/pseudomonas-aeruginosa-outbreaks-in-cystic-fibrosis-forty-two-years-of-discovery-c05d41746ec3)
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