PEDIATRICS Vol. 118 No. 3 September 2006, pp. 888-895 (doi:10.1542/peds.2004-2599)
ARTICLE |
Neonatal Screening for Cystic Fibrosis Does Not Affect Time to First Infection With Pseudomonas aeruginosa
a Cancer Epidemiology Unit, CPO Piemonte, CeRMS, University of Turin, Turin, Italy
b Pediatric Cystic Fibrosis Regional Reference Unit, ASO OIRM-Sant’Anna, Turin, Italy
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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OBJECTIVE. Newborn screening for cystic fibrosis was introduced in the Piedmont region of Italy in the year 2000. Our aim with this study was to estimate the effect of newborn screening on the risk of Pseudomonas aeruginosa infection at the regional cystic fibrosis pediatric reference center.
METHODS. The time to first infection with P aeruginosa within the historical cohort of cystic fibrosis children diagnosed between January 1, 1997, and June 30, 2004, was investigated, comparing survival functions and the adjusted hazard ratio of children diagnosed before and after newborn screening introduction. The role of pancreatic insufficiency was also concurrently investigated.
RESULTS. Overall, 71 children diagnosed with cystic fibrosis were identified, 27 cases were clinically diagnosed before newborn screening introduction, and 5 of them presented with meconium ileus, whereas 44 were identified by newborn screening. Among them 35 needed pancreatic enzyme supplementation, whereas 34 children were infected with P aeruginosa. Both the nonparametric and semiparametric survival estimates failed to show any significant increase in the risk of P aeruginosa infection among screened children compared with historical controls. However, the median time from cystic fibrosis diagnosis to P aeruginosa infection among screened children was significantly shorter (183 vs 448 days). Children with impaired pancreatic function were at high risk of P aeruginosa infection.
CONCLUSIONS. The results of the study suggest that health authorities should regard newborn screening for cystic fibrosis as an opportunity to improve care and outcomes among affected children and shift the focus from whether it is appropriate to screen to how to optimize biomedical and psychosocial outcomes of screening.
Key Words: cystic fibrosis • screening • infection
Abbreviations: CF—cystic fibrosis • NBS—newborn screening • RRCCF—Regional Reference Centre for Cystic Fibrosis • IRT—immunoreactive trypsinogen • MI—meconium ileus • HR—hazard ratio • AR-Pa—annual rate of first infection with Pseudomonas aeruginosa • CI—confidence interval
Since the introduction of cystic fibrosis (CF) newborn screening (NBS), the benefits and risks of the procedure have been debated.1–3 In 1992, the American Society of Human Genetics did not recommend CF NBS unless individuals had a positive family history of CF.4 In 1997, a systematic review of the scientific evidence on CF NBS led the Centers for Disease Control and Prevention to draw up recommendations on pilot screening programs, which were approached and promoted both as research activities and as community intervention programs referring patients to specialized centers.5 More recently it has been observed that evidence is accumulating in support of the beneficial role of CF NBS to patients with CF and their families. It has, therefore, been suggested that public health authorities should shift their attention from the legitimacy of screening procedures to optimizing the screening outcomes.6–10
The most significant concerns about routine screening practice are focused on the biomedical and psychosocial long-term impact on children's health. In particular, special attention has been devoted to investigating improvements in CF patient survival and nutritional and lung function status, as well as the quality of life evaluated according to a multidimensional approach examining physical, psychological, and social functioning.11 Recent systematic reviews of observational studies and randomized trials conducted in the United States and Europe have shown that substantial evidence supports the conclusion that CF NBS prevents early CF-related deaths and leads to a significant and prolonged health gain for patients with CF.8,10 The assessment of the benefits in the quality of life of patients with CF and their families still remains a debated issue, and the evidence available is not uniformly favorable to the CF NBS.
The diagnosis of CF by screening anticipates diagnosis by more than a year in 50% of cases.7 In microbiologic terms, this anticipation may translate into the exposure of asymptomatic children to nosocomial transmission of respiratory infections, unless infection control policies are strictly implemented.12 Because early infection with Pseudomonas aeruginosa is associated with a progressive deterioration of pulmonary function13,14 and increased mortality risk,15 it is critical to evaluate the role of CF NBS as a risk factor for the transmission of P aeruginosa infection. Unfortunately, until now the estimation of the microbiologic impact of NBS among children with CF has not been straightforward,16 and no conclusive evidence has been obtained in favor of or against the screening procedures. For instance, in the Wisconsin study,17 benefits from NBS were offset by earlier acquisition of P aeruginosa infection, whereas recently in the United Kingdom, Sims et al18 found that children <4 years who underwent NBS had fewer episodes of P aeruginosa infection than the clinically diagnosed CF cases.
In July 2000, based on promising results observed both abroad16 and in other Italian regions,19 where the overall estimated CF prevalence is 
1 in 4700 newborns, the public health authorities of the Piedmont region of northwestern Italy introduced NBS for CF.20 According to the regional legislation, a dried blood spot sample was obtained from every newborn in the region and sent to the Regional Reference Centre for Cystic Fibrosis (RRCCF) for serum immunoreactive trypsinogen (IRT) and DNA investigation. In the region, NBS has been adopted as an investigational procedure, and the impact of the screening program is periodically assessed according to regional protocol principles.21
The aim of this study was to provide public health authorities with the necessary evidence to be able to make a judgment about the possible increased risk of early P aeruginosa infection among screened children. Therefore, we have investigated the cohort of children diagnosed with CF, before (historical controls) and after (screened children) the introduction of CF NBS, who were followed up for 
1 year at the RRCCF of the Piedmont region of Italy.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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The Piedmont region is a highly industrialized area of northwestern Italy. According to the last national census performed in 2001, the total resident population of the region was 4214677 people,22 with the annual birth-rate ranging between 8.1 and 8.7 per 1000 population between 1997 and 2004. According to the local legislation, for the last 2 decades, children with suspected CF have been referred, through a network of community and hospital-based pediatricians, to the RRCCF for diagnostic confirmation.21
This study was conducted on the cohort of children born and diagnosed with CF between January 1, 1997, and June 30, 2004, and followed-up at the RRCCF until September 30, 2005. The RRCCF regularly follows up >90% of pediatric CF cases born after 1997 who are resident in the region (National CF Registry, unpublished data, 2006). Children with 1 year of follow-up were included in the study, whereas those lost to follow-up were considered censored at the last routine checkup appointment. To rule out a reverse causal relationship between P aeruginosa infection and CF diagnosis based on respiratory tract clinical features, those children with a microbiologically confirmed P aeruginosa infection of the respiratory tract occurring within 60 days after the CF diagnosis were excluded from the study as prevalent cases of P aeruginosa infection. Children with false-negative results to the CF NBS were also excluded from the study because of the likelihood of underlying peculiarities in the natural history and pattern of morbidity of the disease. The overall process of the CF case selection from the historical cohort is shown in Fig 1. The cohort was collected at the same chest unit of the regional reference pediatric hospital. During the period under investigation, no major environmental, organizational, preventive, or therapeutic changes were introduced. Microbiologic segregation policies were already adopted and were not modified during this interval of time. The periodicity of follow-up visits was unaltered, and the screening protocol did not change. Microbiologically confirmed P aeruginosa infection was defined by the identification of the microorganism from the pharyngeal swab or aspirate.
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In the RRCCF, health status of the patient with CF is assessed monthly on a routine basis. On this occasion, the occurrence of lower tract respiratory infections is checked, and more detailed investigations are performed whenever clinically relevant. Moreover, a complete checkup of the patients, including imaging and laboratory investigations, is regularly performed yearly.
Before the introduction of the NBS, the suspicion of CF diagnosis was based on clinical criteria (summarized in Table 1) or family history and confirmed by sweat chloride testing. Children diagnosed through the CF NBS program were tested as follows: dried blood spot samples obtained from a newborn heel-stick procedure found to have an elevated serum IRT level underwent DNA testing using the oligonucleotide ligation assay polymerase chain reaction procedure (PE Applied Biosystems, Foster City, CA).23 Detection of 1 copy of a CF mutation prompted sweat testing. If the IRT level was above the cutoff but no mutations were detected, the IRT test was repeated, and children were referred for sweat testing to account for the possibility that DNA mutations may be present but not included in the mutation panel used for the CF NBS. The diagnostic procedures of the Piedmont region are centralized and performed only in the RRCCF. The diagnostic pathways are schematized in Fig 2.
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We investigated the relationship between the risk of first infection with P aeruginosa and the performance of CF NBS, pancreatic insufficiency,
F508 homozygous genotype status, occurrence of meconium ileus (MI), gender, and age of the child at CF diagnosis. Pancreatic insufficiency was defined as the need for enzyme supplementation treatment. For children diagnosed through screening, the date of result disclosure was the date of the CF diagnosis, usually at end of the sixth week of life. Conversely, for children whose diagnosis was based on clinical suspicion, the date of sweat test confirmation was the date of CF diagnosis.
To assess the effect of the NBS, pancreatic insufficiency, the occurrence of MI, gender, and age at CF diagnosis on the occurrence of respiratory infection with P aeruginosa, we compared the time to the first infection with P aeruginosa. The survival function was estimated using the nonparametric Kaplan-Meier approach, the equality of survivor functions was tested using the log-rank method, and the hazard ratios (HRs) were estimated using both univariate and multivariate semiparametric Cox regression analysis, after having tested for the proportional hazard assumption. Because the time when children diagnosed with CF on a clinical basis became at risk of P aeruginosa infection (birth) and the time when they came under observation (CF diagnosis) did not necessarily coincide, we performed a late-entry survival analysis assuming that late entry was noninformative.24 Two multivariate semiparametric models, assessing the relationship between NBS performance and pancreatic insufficiency and the occurrence of respiratory infection with P aeruginosa, were fitted. The former model accounted for the occurrence of MI, whereas the latter accounted also for the F508 homozygous genotype status. Finally, we estimated a posteriori the study power for detecting significant differences between screened and nonscreened children.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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At the end of June 2004, 175 children with CF attended the RRCCF. Between January 1, 1997, and June 30, 2004, 84 children were diagnosed with CF at the RRCCF, 1 moved to another center for follow-up, whereas 3 were lost to follow-up (follow-up <1 year): all of the children lost to follow-up had been diagnosed by NBS. Moreover, according to the National CF Registry, 4 of the CF cases resident in Piedmont were diagnosed and followed up at reference centers outside of the Piedmont region (National CF Registry, unpublished data, 2006). Among those children diagnosed since January 1, 1997, 5 were excluded because they were diagnosed with P aeruginosa within 60 days of diagnosis with CF, and another 5 were excluded because they proved to be false-negatives to the screening. Overall, 71 children were included in the study (Fig 1); 44 (62.0%) were diagnosed through the screening procedure, whereas 27 (38.0%) had been diagnosed before CF NBS introduction. The gender distribution was balanced with 36 boys and 35 girls. The infection with P aeruginosa was diagnosed in 34 cases (20 cases among screened and 14 among nonscreened children), pancreatic insufficiency occurred in 35 children (49.3%), whereas CF presented with MI in 12 cases (16.9%). Some 17 children (24.2%) were homozygous for the
F508 homozygous genotype. The main characteristics of the children with CF included in the study are shown in Table 2.
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Children diagnosed through NBS had a significantly shorter median time to infection with P aeruginosa than the historical controls (Mann-Whitney test P = .05): 183 (range: 35–951) versus 448 (range: 53–2170) days, respectively. The median age at first infection with P aeruginosa was 201 (range: 63–921) and 511 (range: 61–2858) days, respectively. Figure 3 summarizes the observed distribution of time intervals between CF diagnosis and P aeruginosa infection. The introduction of the CF NBS has significantly lowered the median age of diagnosis from 323 (range: 8–2295) to 42 (range: 8–42). The overall annual rate of first infection with P aeruginosa (AR-Pa) was 21.5 (95% confidence interval [CI]: 15.4–30.1) cases per 100 persons (%) and did not significantly differ between screened (AR-Pa: 23.1%; 95% CI: 14.9–35.8) and nonscreened (AR-Pa: 19.6%; 95% CI: 11.6–33.1) children.
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The nonparametric estimates of the survival functions (Fig 4) did not underscore a significant difference (log rank test: P = .24) in the time to first infection with P aeruginosa between screened and nonscreened children. Similarly, both the univariate and multivariate Cox regression models (Table 3) failed to show a significant association between the performance of CF NBS and the occurrence of respiratory tract infection with P aeruginosa. On the other hand, the semiparametric analyses have consistently shown that the need for pancreatic enzyme supplementation treatment was significantly associated with a raised HR for infection with P aeruginosa. The univariate model estimated an HR of 2.5 (95% CI: 1.2–5.3), whereas the 2 multivariate models estimated pretty similar HRs of 2.3 (95% CI: 1.0–5.2) for the model accounting for the occurrence of MI and 2.8 (95% CI: 1.2–6.9) for the model accounting also for adjusted
F508 homozygous genotype status. The present study also failed to confirm that female gender and the F508 homozygous genotype are risk factors for initial acquisition of P aeruginosa reported by Maselli et al.25 Nevertheless, the F508 homozygous genotype was significantly associated with pancreatic insufficiency (risk ratio: 2.6; 95% CI: 1.8–3.8).
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Despite the fact that we have included in the study virtually all cases of CF in the Piedmont region of Italy between 1997 and June 2004, the a posteriori estimate of the study power for detecting significant differences between the risk among screened and nonscreened children of being infected with P aeruginosa was <10%. The overall follow-up period for both groups was between 87 and 71 person-years, respectively. To reach a statistical power of 90%, the overall follow-up should be
1400 person-years in both groups. The collection of a cohort of this size would be a considerable task in Italy where 163 to 174 new CF cases have been recorded annually by the CF National Registry between 1997 and 2003 and where the standards of care and screening policies are not uniform throughout the country. |
DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Although on the one hand this study failed to show any significant relationship between the nature of the diagnostic approach to CF and the risk of the first respiratory infectious episode with P aeruginosa, on the other it revealed a relationship between the need for pancreatic enzyme supplementation and the occurrence of the P aeruginosa infection. However, when P aeruginosa infection occurred, the median time to infection among the screened children was significantly shorter than among the historical controls. Indeed, the practice, repeatedly adopted in the RRCCF, of mainstreaming infants into the chest clinic for additional diagnostic evaluation after a positive screening test may have exposed children with CF to an early risk of nosocomial P aeruginosa infection, which plays a major role as predictor of the long-term evolution of respiratory function in children with CF.13,15 At the RRCCF, 35 children (49.3%) among those included in the present study were brought into the hospital for evaluation. More specifically, 11 children (8 cases of P aeruginosa infection) among those diagnosed in the prescreening period and 24 (13 cases of P aeruginosa infection) among those screened were admitted for diagnostic and assessment purposes. It is biologically sensible to hypothesize that the incomplete maturation of the innate and adaptive immune defenses makes newborns and very young infants more susceptible to the respiratory tract infection.26 Therefore, given the younger age at diagnosis, screened children may be more rapidly infected by nosocomial P aeruginosa strains. In this case, the time interval between diagnosis and P aeruginosa infection should be reduced by improving the quality of hospital infection control measures. The evidence thus far collected on the role of CF NBS in increasing the risk of respiratory tract P aeruginosa infection suggests that the strict adoption of infection-transmission–control measures and the full implementation of the "NBS system" methodology, including education, screening, follow-up, diagnosis, management, and evaluation,27 are essential to making NBS a safe procedure.1 Therefore, late occurrence of P aeruginosa infection is considered as an accurate marker of good preventive and segregation practices in CF units.18,28,29
The results of this observational study should be interpreted cautiously, because 5 historical controls diagnosed with P aeruginosa infection within 60 days of diagnosis with CF were excluded from the study as prevalent cases of infection. When these cases are included in the analysis, the difference between median time to infection among the screened and nonscreened children becomes not statistically significant. Moreover, the late entry approach to the survival analysis assumes that individuals who present at a certain age are essentially comparable with those of the same age already being followed up; in other words, the late entry is noninformative.24 Nevertheless, these results may contribute toward a process of systematic revision of the existing evidence on the microbiologic consequences of the introduction of CF NBS.30
The observed relationship between pancreatic insufficiency and F508 homozygous genotype status and between pancreatic insufficiency and P aeruginosa infection is in agreement with previous findings showing that patients with CF who are homozygous for the F508 mutation generally have more severe diseases than patients with CF who have other genotypes and an increased risk of early detection of P aeruginosa.31,32 Finally, this investigation did not confirm the role of female gender as a risk factor for initial acquisition of P aeruginosa.25,33
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CONCLUSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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We think that this study supports the suggestion that public health authorities should focus on implementation methods of the NBS system in settings where infection-transmission–control practices are safely implemented, rather than on the legitimacy of the NBS program.6
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ACKNOWLEDGMENTS |
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We thank the "Associazione per la lotta alla Fibrosi Cistica, Piemonte e Valle d'Aosta" for their support for the research project and Susan Phillips, English reader at the University of Turin, for the language revision.
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FOOTNOTES |
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Accepted Mar 27, 2006.
Address correspondence to Iacopo Baussano, MD, MSc, Cancer Epidemiology Unit, Università di Torino, Via Santena 7, 10126 Torino, Italy. E-mail: iacopo.baussano{at}cpo.it
The authors have indicated they have no financial relationships relevant to this article to disclose.
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