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Pseudomonas cepacia—more than a harmless commensal?
1385
EDITORIALS
Pseudomonas cepacia—more than a harmless commensal? Fears of Pseudomonas cepacia cross-infection and the clinical outcome of colonisation have caused patients with cystic fibrosis (CF) and their doctors to take drastic measures. What scientific evidence underlies their actions? Until lately, the bacterial pathogens largely responsible for pulmonary exacerbations in CF
patients
were
Staphylococcus
aureus,
Haemophilus
and Pseudomonas aeruginosa. In the early 1980s there were reports from North American clinics of a disturbing increase in the prevalence of P cepacia from CF sputa.12 Between 1986 and 1989, surveillance studies in the UK indicated a maximum prevalence of 7% but isolations have now risen in some CF centres to equal the 40 % prevalence noted in the latest report from a North American centre, the Hospital for Sick Children in Toronto, Canada.6The increased isolations cannot be attributed solely to the use of selective culture media and reliable identification systems. Clinically, P cepacia colonisation can be symptomless or it can be associated with slowly declining lung function. More alarming, some colonised patients who previously have been mildly affected by their disease unexpectedly succumb to an accelerated and fatal deterioration in pulmonary function with fever, necrotising pneumonia, and in some cases septicaemia; this syndrome is not observed with other CF pathogens and females previously in
influenzae,
good clinical condition seem to be at special risk.2 In early studies, P cepacia colonisation was largely restricted to young adults; colonisation in children remains low, but even so the first reported death in the UK associated with P cepacia was in an eight-year-old CF patient? P cepacia, an environmentally ubiquitous plant pathogen, takes its name from its role as the cause of soft rot of onions. Paradoxically, this organism also produces antibiotic compounds that play an important part in the biological control of plant infections such as tobacco wilt and fungal spoilage of fruit.8 P cepacia is nutritionally versatile-it can grow in disinfectants and antiseptics and can even use penicillin G as a nutrient. The pathogen is naturally resistant to most antibiotics, and, even if individual strains show in-vitro susceptibility to an antibiotic, there is little clinical response and so the patient is denied effective therapy. Human infections with P cepacia are uncommon and tend to occur in immunocompromised patients and in those who have acquired the organism in hospital from contaminated equipment.9 Although CF patients are often heavily infected with P cepacia, with sputum colony counts of 108 CFU/ml, a direct pathogenic role for the organism is not proven. P cepacia is virtually non-pathogenic in healthy human beings and does not synthesise alginate or elastase, key virulence determinants associated with P aeruginosa colonisation in CF patients.5 Some strains of P cepacia synthesise iron-chelating siderophores1O and exhibit variable degrees of binding to human respiratory mucin;6 these observations led to speculation that such factors contribute to morbidity and mortality and may explain why some strains colonise patients transiently whereas other strains, once acquired, are never lost. Similarly, variations in virulence may explain the clinical spectrum observed in CF patients. The role of host factors in determining clinical outcome is probably important. The manner by which the organism evades host immunity remains to be determined, synergy with other pathogens is a possibility. With the exception of a non-protective IgG antibody response to P cepacia surface antigens," little is known about the host immune response and pathophysiology of P cepacia infection. The reasons for the susceptibility of CF adults to P cepacia colonisation are unclear. A case-control study12 showed that, apart from increasing age, colonisation was associated with severity of underlying disease, a colonised sibling, and previous hospital admission. Moreover, colonisation was associated with increased morbidity. Inhaled colistin-to which the organism is invariably resistant-is another possible risk factor; however, there is little evidence to support this hypothesis and the role of other antibiotics is unclear.12 Cross-infection with P cepacia is the cause of widespread concern. An epidemiological study13
1386
mentioned previous failures to recover P cepacia from extensive surveillance cultures of respiratory equipment and environmental surfaces, and the researchers concluded that direct person-to-person transmission of the organism might be the primary means by which transmission occurs. A subsequent prospective study14 with reliable selective media and typing systems showed that colonised patients can their contaminate environment-ie, indirect transmission might occur via contaminated surfaces. Although there is no scientific evidence to confirm that skin contact, respiratory aerosols, sharing food, kissing, or other forms of intimacy increase the risk of acquiring P cepacia, doctors who care for CF patients have come round to the view that kissing and having a colonised sibling probably present special risks. There are calls for policies to reduce the risk of acquisition of P cepacia and to reassure non-colonised patients. Segregation of colonised from non-colonised patients effectively creates "microbiological outcasts". The social effects of segregation on older patients are devastating since their lives often revolve around CF contacts. Meanwhile, non-colonised patients become increasingly anxious about "getting cepacia". Finally, segregation imposes a considerable burden on medical staff in large clinics and needs to be accompanied by advice that social contacts should also be restricted.’s Attitudes to P cepacia are evolving rapidly and it is difficult to give firm guidance about the risks and consequences of colonisation. However, several centres in Europe and North America segregate colonised from non-colonised patients, and a British CF association has produced interim guidelines to reduce the risk of cross-infection.16 An indication of the impact of these recommendations can be appreciated from this section alone: "P cepacia colonised CF individuals should avoid kissing and intimacy with non-colonised CF individuals. They should also refrain from sleeping, exercising or performing physiotherapy in the same room as non-colonised CF individuals. Contact between colonised CF individuals and CF children should be avoided. On current evidence, colonised CF individuals should probably not attend CF conference/holiday camps." For patients and all concerned in their care, the stigma and problems of P cepacia colonisation are very hard to accept. Nevertheless, the risks cannot be ignored. A, Macluskey I, Corey M, et al. Pseudomonas cepacia infection in cystic fibrosis: an emerging problem. J Pediatr 1984; 104: 206-10. 2. Thomassen MJ, Demko CA, Klinger JD, Stern RC. Pseudomonas cepacia colonization among patients with cystic fibrosis: a new opportunist. Am Rev Respir Dis 1985; 131: 791-96. 3. Simmonds EJ, Conway SP, Ghoneim ATM, Ross H, Littlewood JM. Pseudomonas cepacia: a new pathogen in patients with cystic fibrosis referred to a large centre in the United Kingdom. Arch Dis Child 1990; 1. Isles
65: 874-77. 4. Gladman G, Connor PJ, Williams RF, David TJ. Controlled study of Pseudomonas cepacia and Pseudomonas maltophilia in cystic fibrosis. Arch Dis Child 1992; 67: 192-95. 5. Govan JRW, Glass S. The microbiology and therapy of cystic fibrosis lung infections. Rev Med Microbiol 1990; 11: 19-28.
Sajjan US, Corey M, Karmali MA, Forstner JF. Binding of Pseudomonas cepacia to normal human intestinal mucin and respiratory mucin from patients with cystic fibrosis. J Clin Invest 1992; 89: 648-56. 7. Glass S, Govan JRW. Psendomonas cepacia: fatal pulmonary infection in a patient with cystic fibrosis. J Infect 1986; 13: 157-58. 8. Aoki M, Uehara K, Koseki K, et al. An antimicrobial substance produced by Pseudomonas cepacia B5 against the bacterial wilt disease pathogen Pseudomonas solanacearum. Agric Biol Chem 1991; 55: 715-22. 9. Holmes B. The identification of Pseudomonas cepacia and its occurrence in clinical material. J Appl Bact 1986; 61: 299-314. 10. Sokol PA, Lewis CJ, Dennis JJ. Isolation of a novel siderophore from Pseudomonas cepacia. J Med Microbiol 1992; 35: 184-89. 11. Aronoff SC, Lewis FJ, Stern RC. Longitudinal serum IgG response to Pseudomonas cepacia surface antigens in cystic fibrosis. Pediatr 6.
Pulmonol 1991; 11: 289-93. 12. Tablan OC, Martone WJ, Doershuk CF, et al. Colonization of the respiratory tract with Pseudomonas cepacia in cystic fibrosis: risk factors and outcomes. Chest 1987; 91: 527-32. 13. LiPuma JJ, Dasen SE, Nielson DW, Stern RC, Stull TL. Person-toperson transmission of P cepacia between patients with cystic fibrosis. Lancet 1990; 336: 1094-96. 14. Nelson JW, Doherty CJ, Brown PH, et al. Pseudomonas cepacia in inpatients with cystic fibrosis. Lancet 1991; 338: 1525. 15. Smith DL, Smith EG, Gumery LB, Stableforth DE. Pseudomonas cepacia infection in cystic fibrosis. Lancet 1992; 339: 252. 16. Newsletter of the Association of Cystic Fibrosis Adults (UK). April, 1992, no 30, p 2.
Heart disease: in the
beginning
Norway in the 1970s, Forsdhal was puzzled by the geographical distribution of cardiovascular mortality. Why were there substantial regional differences when the standard and mode of living was reasonably uniform throughout the country? Could these differences be related, he wondered, not to present circumstances but to poverty or deprivation in early life? More recently, Rose has pointed out that In
well-established risk factors for coronary heart
disease--cigarette smoking, high
serum
cholesterol,
and high blood pressure-have very limited ability to predict disease in adults.2 Could childhood influences explain this gap in our understanding of aetiology? Epidemiologists, notably Barker and colleagues in the UK Medical Research Council Environmental Epidemiology Unit at Southampton University, have taken up the challenge by exploring Forsdahl’s hypothesis on childhood deprivation.3 In a series of studies based mainly on national statistics in the UK, the USA, and Norway, adult cardiovascular mortality rates were shown to correlate with indicators of childhood deprivation in earlier years-ie, with infant mortality,4-7 and short adult and childhood height.8,9 There are also correlations with measures suggestive of intrauterine deprivation such as maternal and neonatal mortality.lO,l1 Not content with these statistical comparisons, Barker et al identified, by means of painstaking detective work, two populations that they were able to follow-up retrospectivelyP,13 In 5654 men born in Hertfordshire between 1911 and 1932, they found that the death rate from ischaemic heart disease was related inversely to weight at one year and was higher in men who had weighed less than 5-5 lb (2-5 kg) at birth.12 Furthermore, indicators of early deprivation were associated in the same cohort with cardiovascular risk factors in adult life-blood pressure, plasma
EDITORIALS
Pseudomonas cepacia—more than a harmless commensal? Fears of Pseudomonas cepacia cross-infection and the clinical outcome of colonisation have caused patients with cystic fibrosis (CF) and their doctors to take drastic measures. What scientific evidence underlies their actions? Until lately, the bacterial pathogens largely responsible for pulmonary exacerbations in CF
patients
were
Staphylococcus
aureus,
Haemophilus
and Pseudomonas aeruginosa. In the early 1980s there were reports from North American clinics of a disturbing increase in the prevalence of P cepacia from CF sputa.12 Between 1986 and 1989, surveillance studies in the UK indicated a maximum prevalence of 7% but isolations have now risen in some CF centres to equal the 40 % prevalence noted in the latest report from a North American centre, the Hospital for Sick Children in Toronto, Canada.6The increased isolations cannot be attributed solely to the use of selective culture media and reliable identification systems. Clinically, P cepacia colonisation can be symptomless or it can be associated with slowly declining lung function. More alarming, some colonised patients who previously have been mildly affected by their disease unexpectedly succumb to an accelerated and fatal deterioration in pulmonary function with fever, necrotising pneumonia, and in some cases septicaemia; this syndrome is not observed with other CF pathogens and females previously in
influenzae,
good clinical condition seem to be at special risk.2 In early studies, P cepacia colonisation was largely restricted to young adults; colonisation in children remains low, but even so the first reported death in the UK associated with P cepacia was in an eight-year-old CF patient? P cepacia, an environmentally ubiquitous plant pathogen, takes its name from its role as the cause of soft rot of onions. Paradoxically, this organism also produces antibiotic compounds that play an important part in the biological control of plant infections such as tobacco wilt and fungal spoilage of fruit.8 P cepacia is nutritionally versatile-it can grow in disinfectants and antiseptics and can even use penicillin G as a nutrient. The pathogen is naturally resistant to most antibiotics, and, even if individual strains show in-vitro susceptibility to an antibiotic, there is little clinical response and so the patient is denied effective therapy. Human infections with P cepacia are uncommon and tend to occur in immunocompromised patients and in those who have acquired the organism in hospital from contaminated equipment.9 Although CF patients are often heavily infected with P cepacia, with sputum colony counts of 108 CFU/ml, a direct pathogenic role for the organism is not proven. P cepacia is virtually non-pathogenic in healthy human beings and does not synthesise alginate or elastase, key virulence determinants associated with P aeruginosa colonisation in CF patients.5 Some strains of P cepacia synthesise iron-chelating siderophores1O and exhibit variable degrees of binding to human respiratory mucin;6 these observations led to speculation that such factors contribute to morbidity and mortality and may explain why some strains colonise patients transiently whereas other strains, once acquired, are never lost. Similarly, variations in virulence may explain the clinical spectrum observed in CF patients. The role of host factors in determining clinical outcome is probably important. The manner by which the organism evades host immunity remains to be determined, synergy with other pathogens is a possibility. With the exception of a non-protective IgG antibody response to P cepacia surface antigens," little is known about the host immune response and pathophysiology of P cepacia infection. The reasons for the susceptibility of CF adults to P cepacia colonisation are unclear. A case-control study12 showed that, apart from increasing age, colonisation was associated with severity of underlying disease, a colonised sibling, and previous hospital admission. Moreover, colonisation was associated with increased morbidity. Inhaled colistin-to which the organism is invariably resistant-is another possible risk factor; however, there is little evidence to support this hypothesis and the role of other antibiotics is unclear.12 Cross-infection with P cepacia is the cause of widespread concern. An epidemiological study13
1386
mentioned previous failures to recover P cepacia from extensive surveillance cultures of respiratory equipment and environmental surfaces, and the researchers concluded that direct person-to-person transmission of the organism might be the primary means by which transmission occurs. A subsequent prospective study14 with reliable selective media and typing systems showed that colonised patients can their contaminate environment-ie, indirect transmission might occur via contaminated surfaces. Although there is no scientific evidence to confirm that skin contact, respiratory aerosols, sharing food, kissing, or other forms of intimacy increase the risk of acquiring P cepacia, doctors who care for CF patients have come round to the view that kissing and having a colonised sibling probably present special risks. There are calls for policies to reduce the risk of acquisition of P cepacia and to reassure non-colonised patients. Segregation of colonised from non-colonised patients effectively creates "microbiological outcasts". The social effects of segregation on older patients are devastating since their lives often revolve around CF contacts. Meanwhile, non-colonised patients become increasingly anxious about "getting cepacia". Finally, segregation imposes a considerable burden on medical staff in large clinics and needs to be accompanied by advice that social contacts should also be restricted.’s Attitudes to P cepacia are evolving rapidly and it is difficult to give firm guidance about the risks and consequences of colonisation. However, several centres in Europe and North America segregate colonised from non-colonised patients, and a British CF association has produced interim guidelines to reduce the risk of cross-infection.16 An indication of the impact of these recommendations can be appreciated from this section alone: "P cepacia colonised CF individuals should avoid kissing and intimacy with non-colonised CF individuals. They should also refrain from sleeping, exercising or performing physiotherapy in the same room as non-colonised CF individuals. Contact between colonised CF individuals and CF children should be avoided. On current evidence, colonised CF individuals should probably not attend CF conference/holiday camps." For patients and all concerned in their care, the stigma and problems of P cepacia colonisation are very hard to accept. Nevertheless, the risks cannot be ignored. A, Macluskey I, Corey M, et al. Pseudomonas cepacia infection in cystic fibrosis: an emerging problem. J Pediatr 1984; 104: 206-10. 2. Thomassen MJ, Demko CA, Klinger JD, Stern RC. Pseudomonas cepacia colonization among patients with cystic fibrosis: a new opportunist. Am Rev Respir Dis 1985; 131: 791-96. 3. Simmonds EJ, Conway SP, Ghoneim ATM, Ross H, Littlewood JM. Pseudomonas cepacia: a new pathogen in patients with cystic fibrosis referred to a large centre in the United Kingdom. Arch Dis Child 1990; 1. Isles
65: 874-77. 4. Gladman G, Connor PJ, Williams RF, David TJ. Controlled study of Pseudomonas cepacia and Pseudomonas maltophilia in cystic fibrosis. Arch Dis Child 1992; 67: 192-95. 5. Govan JRW, Glass S. The microbiology and therapy of cystic fibrosis lung infections. Rev Med Microbiol 1990; 11: 19-28.
Sajjan US, Corey M, Karmali MA, Forstner JF. Binding of Pseudomonas cepacia to normal human intestinal mucin and respiratory mucin from patients with cystic fibrosis. J Clin Invest 1992; 89: 648-56. 7. Glass S, Govan JRW. Psendomonas cepacia: fatal pulmonary infection in a patient with cystic fibrosis. J Infect 1986; 13: 157-58. 8. Aoki M, Uehara K, Koseki K, et al. An antimicrobial substance produced by Pseudomonas cepacia B5 against the bacterial wilt disease pathogen Pseudomonas solanacearum. Agric Biol Chem 1991; 55: 715-22. 9. Holmes B. The identification of Pseudomonas cepacia and its occurrence in clinical material. J Appl Bact 1986; 61: 299-314. 10. Sokol PA, Lewis CJ, Dennis JJ. Isolation of a novel siderophore from Pseudomonas cepacia. J Med Microbiol 1992; 35: 184-89. 11. Aronoff SC, Lewis FJ, Stern RC. Longitudinal serum IgG response to Pseudomonas cepacia surface antigens in cystic fibrosis. Pediatr 6.
Pulmonol 1991; 11: 289-93. 12. Tablan OC, Martone WJ, Doershuk CF, et al. Colonization of the respiratory tract with Pseudomonas cepacia in cystic fibrosis: risk factors and outcomes. Chest 1987; 91: 527-32. 13. LiPuma JJ, Dasen SE, Nielson DW, Stern RC, Stull TL. Person-toperson transmission of P cepacia between patients with cystic fibrosis. Lancet 1990; 336: 1094-96. 14. Nelson JW, Doherty CJ, Brown PH, et al. Pseudomonas cepacia in inpatients with cystic fibrosis. Lancet 1991; 338: 1525. 15. Smith DL, Smith EG, Gumery LB, Stableforth DE. Pseudomonas cepacia infection in cystic fibrosis. Lancet 1992; 339: 252. 16. Newsletter of the Association of Cystic Fibrosis Adults (UK). April, 1992, no 30, p 2.
Heart disease: in the
beginning
Norway in the 1970s, Forsdhal was puzzled by the geographical distribution of cardiovascular mortality. Why were there substantial regional differences when the standard and mode of living was reasonably uniform throughout the country? Could these differences be related, he wondered, not to present circumstances but to poverty or deprivation in early life? More recently, Rose has pointed out that In
well-established risk factors for coronary heart
disease--cigarette smoking, high
serum
cholesterol,
and high blood pressure-have very limited ability to predict disease in adults.2 Could childhood influences explain this gap in our understanding of aetiology? Epidemiologists, notably Barker and colleagues in the UK Medical Research Council Environmental Epidemiology Unit at Southampton University, have taken up the challenge by exploring Forsdahl’s hypothesis on childhood deprivation.3 In a series of studies based mainly on national statistics in the UK, the USA, and Norway, adult cardiovascular mortality rates were shown to correlate with indicators of childhood deprivation in earlier years-ie, with infant mortality,4-7 and short adult and childhood height.8,9 There are also correlations with measures suggestive of intrauterine deprivation such as maternal and neonatal mortality.lO,l1 Not content with these statistical comparisons, Barker et al identified, by means of painstaking detective work, two populations that they were able to follow-up retrospectivelyP,13 In 5654 men born in Hertfordshire between 1911 and 1932, they found that the death rate from ischaemic heart disease was related inversely to weight at one year and was higher in men who had weighed less than 5-5 lb (2-5 kg) at birth.12 Furthermore, indicators of early deprivation were associated in the same cohort with cardiovascular risk factors in adult life-blood pressure, plasma