Part 4 : Cf Predictions

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DISCUSSION

    This analysis takes advantage of the large number of sites

and patients

 reporting to the ESCF. It presents an opportunity to study outcomes

and

 practices in a comprehensive way. The approach was to compare CF care

sites

 based on an important index of lung health (ie, the percentage of

predicted

 FE[V.sub.1] values). Large differences in lung health across sites

were

 demonstrated. The sites reporting the highest values for median

 FE[V.sub.1]monitored patients, obtained measurements of lung

function, and

 obtained cultures for respiratory pathogens more frequently. The

differences in

 monitoring were most striking for spirometry testing and respiratory

cultures,

 and were less marked for visit frequency. Also at these sites, more

patients of

 all ages were prescribed inhaled cromolyn or nedocromil and oral

corticosteroids

 for all degrees of disease severity. Adult patients at these sites

were

 prescribed bronchodilator agents, dornase alfa, and inhaled

corticosteroids more

 frequently than their lower quartile counterparts. At upper quartile

sites, IV

 antibiotics were used more frequently and for longer duration. It is

possible

 that this increased use of antibiotics may have resulted in the

increase in

 prevalence of bacterial strains, including resistant strains that

were noted at

 the upper quartile sites. However, we have reported previously an

increase in

 the detection of organisms and resistance at sites that monitor more

frequently.

 (19) Data were presented only for the upper and lower quartile sites,

but the

 results are further supported by the fact that for the two middle

quartiles the

 results generally lie between those for the upper and lower

quartiles. There are

 exceptions to this generalization, but these are primarily in the

severely ill

 patients where the numbers are relatively small. It also should be

noted that

 the generalizability of these observations may be limited by the

exclusion of

 sites with < 50 patients. Also, the decision by a number of Canadian

sites not

 to participate in the study may have affected the interpretation of

the results.

    Possible explanations for the substantial differences in

lung function

 results between the upper and lower quartile sites include

differences in the

 patterns of practice, but they might also include genetic or other

differences

 in the local patient populations, differences in local conditions

including

 climate, the distance that patients live from the site, and

socioeconomic

 status. Data from the CF Foundation Registry indicate that in 1996

only 226 of

 the 19,570 patients (1.4%) reported a lack of insurance coverage, so

at least

 this aspect of socioeconomic status is not likely to be an important

factor.

 (20) Upper quartile sites were somewhat more likely to be located in

the

 northeastern region of the United States, and, in the pediatric age

groups only,

 there was a tendency toward larger sites in the upper quartile

compared to the

 lower quartile. Although the results of this study suggest that the

upper

 quartile sites were more likely to perform special assessments and

prescribe

 some therapies, another possible explanation that always exists in

observational

 studies is more thorough reporting of these events at upper quartile

sites. To

 guard against this possibility, each site received patient-specific

data reports

 and was requested to verify the accuracy of their data.

    The use of nonsteroidal anti-inflammatory drugs was not

considered because,

 at the time of this study, the ESCF did not distinguish high-dose

ibuprofen

 therapy (9) from the analgesic use of nonsteroidal anti-inflammatory

 medications.

    Oral nonquinolone antibiotics were extensively used for

treatment of

 patients across all age and severity groups. Those antibiotics were

used

 significantly less often in adolescent and adult patients at the

lower quartile

 centers than in those patients at the upper quartile centers. These

data are

 consistent with those from a study undertaken in the United Kingdom

(21)

 indicating improved outcomes for young CF patients who received

long-term

 antistaphylococcal therapy. Regarding the use of antibiotics to treat

pulmonary

 exacerbations, the most striking differences between upper and lower

quartile

 sites occurred in patients < 18 years of age, particularly in the

adolescent age

 group. Adolescents from upper quartile sites received more treatment

with IV and

 inhaled antibiotics, and less treatment with oral quinolones. For IV

and inhaled

 antibiotics, the differences were greater for patients with milder

lung disease,

 suggesting that these patients were treated more aggressively. The

duration of

 treatment with IV antibiotics was also greater in upper quartile

sites in

 adolescents, as well as in adults. More intensive use of IV and

inhaled

 antibiotics at upper quartile sites might account for the better lung

function

 observed in patients at these sites.

    The identification of a pulmonary exacerbation warranting

antibiotic

 therapy, particularly IV therapy, may be related to the frequency of

obtaining

 spirometry, since a fall in FE[V.sub.1] values commonly results in

treatment for

 a pulmonary exacerbation. Whatever leads to the decision to treat, it

appears

 that the upper quartile sites are treating patients more often,

particularly

 those considered to have mild lung disease. One possible conclusion

from these

 data is that the use of antibiotics contributes to the improved

outcomes seen in

 patients at upper quartile sites. Support for intensive antibiotic

therapy comes

 from data reported in a Danish study, (17) which have shown that a

program of

 quarterly hospital admissions for IV antipseudomonal therapy is

associated with

 improved survival. Further support for intensive antibiotic therapy

also comes

 from studies of inhaled, high-dose tobramycin. (10) However, other

factors in

 Denmark, such as attention to nutritional support and access to

state-supported

 health care facilities, also may play a role in improved outcomes.

    These data suggest a greater prevalence of multiply

resistant P aeruginosa,

 B cepacia, and S maltophilia at upper quartile sites. This could

represent an

 important and disturbing association between increased antibiotic use

and the

 emergence of resistant strains. It is possible that this results from

an

 ascertainment bias due to the higher frequency of cultures in the

upper quartile

 sites. We have shown previously (20) that increased frequency of

cultures and

 better culture techniques result in the increased identification of

resistant

 organisms. This observation highlights the need for continued

research into

 improved antimicrobial agents and a better understanding of the

mechanisms of

 colonization and infection of the lung and the development of

antibiotic

 resistance in CF.

    Both inhaled cromolyn or nedocromil and oral corticosteroids

were

 administered more often at upper quartile sites. The association

between poor

 outcomes in CF patients and a vigorous inflammatory response was

first noted by

 Wheeler et al (22) and led to a large multicenter trial (23) of oral

 corticosteroid use in CF patients. Although this study showed a clear

benefit in

 terms of the maintenance of pulmonary function, a 1996 review (4)

stated that

 the adverse effects on linear growth and glucose metabolism should

limit the

 long-term use of oral corticosteroids. This analysis demonstrates the

widespread

 use of both oral and inhaled corticosteroids but does not distinguish

between

 long-term and sporadic use.

    A surprising result of this analysis is the finding of an

increased

 administration of inhaled cromolyn or nedocromil at upper quartile

sites These

 agents are known to modulate the inflammatory response but are also

reported to

 block non-CF transmembrane receptor chloride channels. (24,25)

Cromolyn-mediated

 or nedocromil-mediated blocking of chloride channels would appear to

be

 counterproductive. The strength of the observed association warrants

 investigation into possible mechanisms that might explain this

paradox.

    In summary, this large observational study of CF

demonstrates significant

 and clinically relevant differences across sites in lung health as

measured by

 FE[V.sub.1] . The striking finding of this analysis is the

consistency with

 which the sites in the upper quartile, regardless of age and disease

severity,

 monitor and treat patients more frequently than do lower quartile

centers. This

 association is particularly strong for younger and relatively healthy

CF

 patients. These results suggest, but do not prove, the hypothesis

that frequent

 monitoring and more interventions, including the more frequent use of

IV

 antibiotics for longer duration, potentially result in better

outcomes for CF

 patients.

Becki

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