- Email: [email protected]
Improved survival among young patients with cystic fibrosis
IMPROVED SURVIVAL AMONG YOUNG PATIENTS WITH CYSTIC FIBROSIS MICHAL KULICH, PHD, MARGARET ROSENFELD, MD, MPH, CHRISTOPHER H. GOSS, MD, MS, AND ROBERT WILMOTT, MD
Objective To investigate age-specific trends in survival among US patients with cystic fibrosis between 1985 and 1999 and to assess whether survival in female patients with cystic fibrosis has improved relative to survival in male patients. Study design A retrospective cohort study of 31,012 subjects in the US Cystic Fibrosis Foundation National Patient Registry. Trends in survival outcome were evaluated by the Cox model. Results Between 1985 and 1999, mortality fell 61% (95% CI, 36-76) for patients age 2 to 5 years, 70% (60-88) for patients age 6 to 10 years, and 45% (32-66) for patients age 11 to 15 years. Improvements in mortality rates among patients older than 15 years were smaller. Female patients had poorer survival rates than male patients in the age range 2 to 20 years, and this gender gap did not narrow throughout time. Conclusions Survival rates of US patients with cystic fibrosis have improved remarkably since 1985. However, most of the improvement was limited to patients 2 to 15 years old. Although both genders benefitted from this trend, female patients have had consistently poorer survival rates than male patients in the age range 2 to 20 years. Further studies are needed to clarify why adult patients with cystic fibrosis had little improvement in survival rates. (J Pediatr 2003;142:631-6)
ultiple studies have shown dramatic improvements in survival during the past 30 years among patients with cystic fibrosis (CF) in the United States1,2 and elsewhere.3–7 This trend is generally thought to be a result of improvements in nutritional and pulmonary therapies and the establishment of specialized care centers. In the United States, median survival has improved from 14 years in 1969 to 32 years in 2000.8 Although improving survival in CF is widely quoted, previous studies have been limited by small sample sizes3,4,7 and lack of longitudinal observation of a cohort.1–3,7 Some studies have evaluated measures of survival unadjusted for the aging of the CF population (crude mortality rate,2 age at death5). Many studies report changes in median survival,1,8 which is a crude cross-sectional measure unsuited for capturing subtle longitudinal survival trends. Moreover, few studies have acknowledged or assessed selection bias as a potential contributor to their findings. The representation of patients with mild disease in patient registries is likely to increase throughout time as a result of either an increase in the diagnosis of CF in patients with mild disease or the increasing participation of these patients in centralized care. Accurate estimates of survival are important for planning future health care needs, counseling patients, and targeting therapies. Analysis of survival trends can also identify subsets of patients whose survival has lagged behind that of the cohort as a whole. Previous studies have not had as a primary focus the assessment of patient characteristics that may influence the degree to which survival has improved throughout time. We undertook this study to examine the changes in survival of US patients with CF from 1985 to 1999. The primary objective was to investigate age-specific trends in survival. A secondary aim was to assess whether the well documented poorer survival among female patients with CF rela-
M
CF CFF
Cystic fibrosis Cystic Fibrosis Foundation
See related articles, p 617and p 624.
From the Department of Biostatistics, University of Washington, Seattle; the Division of Pulmonary Medicine, Department of Pediatrics, Children’s Hospital and Regional Medical Center, Seattle; the Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington Medical Center, Seattle; and the Department of Pediatrics, Saint Louis University, Missouri. Supported by National Institutes of Health grants RR-00037-39 and K23 RR15529 and the Cystic Fibrosis Foundation. Submitted for publication July 2, 2002; revisions received Jan 17, 2003, and Feb 7, 2003; accepted Feb 17, 2003. Reprint requests: Michal Kulich, PhD, Department of Biostatistics, Box 357232, University of Washington, Seattle, WA 98195-7232. E-mail: kulich@u .washington.edu. Copyright © 2003, Mosby, Inc. All rights reserved. 0022-3476/2003/$30.00 + 0
10.1067/mpd.2003.197
631
tive to male patients9,10 has improved during the last 15 years. We took advantage of the Cystic Fibrosis Foundation (CFF) National Patient Registry, estimated to contain data on 85% of diagnosed patients with CF in the United States and >90% of deaths,1 to overcome some of the limitations of previous studies. Modern statistical methods were used that express survival changes in terms of relative risks and allow for complete adjustment for the changing age of the cohort. The potential impact of selection bias on our results was evaluated by careful subgroup analyses.
mortality functions and median survival were based on estimated increments of the cumulative hazard function from the Cox model, with calendar year, gender, and their interactions with grouped age as covariates.
RESULTS Subject Characteristics
The CFF has maintained a registry of all patients with CF receiving care at CFF-accredited centers in the United States since 1966.1 Each CF center submits standardized data forms annually for all patients seen during the previous calendar year, providing demographic, clinical, and mortality information. Subjects in the current study are all patients seen at least once at a CFF-accredited center between January 1, 1985, and December 31, 1999. This study was reviewed and approved by the institutional review board at Children’s Hospital and Regional Medical Center, Seattle, Washington.
The cohort consisted of 31,012 subjects seen at CFF care centers between January 1985 and December 1999. Fiftythree percent of subjects were male, 95.6% were white, 3.6% were black, and 0.8% were of other races. The mean age of the cohort increased from 12.1 years in 1985 to 15.6 years in 1999. The overall mean age was 14.8 years, with a median of 12.5 years and a range of 0 to 73 years. The median age at diagnosis was close to 0.5 years during the whole study period. However, the mean age at diagnosis increased from 2.6 years in patients who entered the study in 1985 to 4.5 years in patients who entered in 1999. The increasing mean age at diagnosis was a result of a growing proportion of patients diagnosed after age 15 years. This proportion rose from 3% to 4% of patients entering between 1985 and 1988 to 8% to 12% of patients entering between 1996 and 1999.
Statistical Analysis
Follow-up, Deaths, and Crude Mortality Rates
Survival was analyzed by using the Cox proportional hazards model with age as the time scale. The Cox model estimates relative risks of death associated with a unit change in a covariate. Patients contributed to the analysis only at ages at which they were at risk and under observation during the study period. The at-risk period began at the age on January 1 of the year during the study period in which a subject was first recorded in the CFF Registry. For patients diagnosed during the year they entered the registry, the at-risk period started at the age at diagnosis. The at-risk period ended at age at death, loss to follow-up, or end of the study (December 31, 1999), whichever occurred first. Patients were assumed to be lost to follow-up if they were not seen for 2 or more consecutive years without later visits recorded in the registry. All results are based on a single Cox model relating agespecific mortality to gender, age at diagnosis, and calendar year at which the given age was reached. Calendar year was modeled as a linear time-dependent variable. Thus, even though the results are presented as differences in mortality between 1999 and 1985, the data collected during the whole study period contribute to estimating the difference. To relax the assumption of proportional hazards, interactions of each of the three covariates with age were included in the model to estimate and test for potentially different effects at different ages. For this purpose, age was divided into eight groups based on age on January 1 of each calendar year. Covariate effects and interactions were tested by partial likelihood ratio tests. Cubic polynomial splines were used with the Cox model to obtain smooth curves of age-specific effects on mortality. The number of parameters in the spline model was the same as the number for grouped age. Estimates of
Subjects were followed for a mean duration of 8.7 years. A fifth of subjects were followed for all 15 years. There were 5234 deaths during the study period (16.9% of the cohort). The primary causes of death were respiratory-related, 82.0%; lung transplant-related, 6.6%; and unknown, 5.6%. Median age at death was 21.9 years. Whereas the number of subjects under observation grew markedly during the study period in the older age groups, it remained relatively constant in the younger patients (Table I). The crude overall mortality rate increased slightly from 18.1 deaths per 1000 person-years in 1985 to 20.8 deaths per 1000 person-years in 1999 (Table I). However, these rates are not adjusted for the increasing age of the study cohort. Crude agespecific mortality rates decreased during the study period in the age groups 2 to 5 years, 6 to 10 years, 11 to 15 years, and >40 years. The sharpest decline was observed in the age group 2 to 5 years, but the estimated crude rates in that group are based on a very small number of deaths.
METHODS Study Population
632 Kulich et al
Survival Model Survival among patients with CF was strongly associated with calendar time, gender, and age at diagnosis (P < .001 for each covariate). The effects of calendar time, gender, and age at diagnosis varied significantly with age (P < .001 for each interaction term). However, there was no interaction among calendar time, gender, and age at diagnosis.
Age-specific Mortality Age-specific mortality adjusted for gender and diagnosis age improved dramatically between 1985 and 1999, with the greatest improvements observed in patients younger than 16 The Journal of Pediatrics • June 2003
Table I. Number of person-years, deaths, and crude mortality rate by age group for 3 selected years and for the whole study period 1985
1992
1999
All years
Age, y
PY
n
Rate
PY
n
Rate
PY
n
Rate
PY
n
Rate
0–1 2–5 6–10 11–15 16–20 21–30 31–40 >40 All
999 2573 2680 2208 1713 1857 473 47 12549
4 8 30 46 46 67 23 3 227
4.0 3.1 11.2 20.8 26.9 36.1 48.6 64.1 18.1
1104 3071 4092 3303 2432 3186 1260 255 18702
8 9 24 52 53 128 63 14 351
7.2 2.9 5.9 15.7 21.8 40.2 50.0 54.9 18.8
1004 2759 4036 3977 3133 3380 1666 678 20632
10 1 25 49 83 155 78 29 430
10.0 0.4 6.2 12.3 26.5 45.9 46.8 42.8 20.8
15275 44476 57232 48848 37252 44731 17707 4648 270169
117 138 466 685 1010 1763 812 243 5234
7.7 3.1 8.1 14.0 27.1 39.4 45.9 52.3 19.4
n, Number of deaths; PY, Person-years; Rate, crude mortality rate per 1000 person-years.
Table II.Adjusted age-specific relative risks Year 1999 relative to 1985 Age, y
RR*
0–1 2–5 6–10 11–15 16–20 21–30 31–40 >41
1.27 0.39 0.30 0.55 0.97 0.86 0.80 0.71
95% CI† (0.75–2.17) (0.24–0.64) (0.22–0.40) (0.44–0.68) (0.80–1.16) (0.73–1.00) (0.63–1.01) (0.43–1.17)
Female patients relative to male patients
1-y Increase in diagnosis age
P value‡
RR*
95% CI†
P value‡
RR*
95% CI†
P value‡
.38 .0002 < .0001 < .0001 .71 .04 .06 .18
0.84 1.76 1.67 1.62 1.27 1.09 1.08 0.94
(0.60–1.18) (1.30–2.39) (1.40–2.00) (1.40–1.87) (1.13–1.43) (0.99–1.19) (0.94–1.25) (0.71–1.23)
.32 .0002 < .0001 < .0001 .0001 .09 .30 .65
0.69 0.64 0.84 0.90 0.93 0.96 0.98 0.98
(0.34–1.38) (0.51–0.81) (0.78–0.90) (0.87–0.93) (0.91–0.95) (0.95–0.97) (0.98–0.99) (0.98–0.99)
.29 .0002 < .0001 < .0001 < .0001 < .0001 .0002 .001
*Estimated relative risk based on a Cox model with each covariate adjusted for the remaining two. †95% CI for adjusted relative risk. ‡For the hypothesis of no difference in mortality because of the covariate (relative risk = 1).
years (Table II). The risk of death in 1999 expressed as a percentage of 1985 mortality was 39% for patients 2 to 5 years old, 30% for patients 6 to 10 years old, and 55% for patients 11 to 15 years old. These improvements were all highly significant. Among patients <2 years of age, there was no improvement in survival throughout time, although there were few deaths in this age group. In patients older than 16 years, the improvements in survival were far less striking. Among patients age 16 to 20 years, there was no indication of improving survival. There was a 15% to 20% decline in mortality rate among subjects age 21 to 40 years, with marginal statistical significance. In the Figure, A, the age profile of mortality changes from 1985 to 1999 is displayed with a smooth spline fit.
Sex Differences Female patients had significantly poorer survival than male patients, though poorer female survival was confined to patients age 2 to 20 years (Table II, Figure, B). Outside this age range male and female survival did not differ significantly. Improved Survival Among Young Patients With Cystic Fibrosis
The age-specific relative risk of death for female patients compared with male patients remained constant during the study period. Median survival (derived from a Cox model not including age at diagnosis) among female patients increased from 31.5 years in 1985 to 34.9 years in 1999 and among male patients from 34.5 years in 1985 to 37.1 years in 1999.
Effect of Age at Diagnosis Later age at diagnosis was associated with improved survival; the magnitude of this association decreased with increasing age (Table II, Figure, C). For example, the risk of death for a 5-year-old diagnosed at age 3 years was 36% lower than that for a 5-year-old diagnosed at age 2 years. However, for two 35-year-old patients diagnosed a year apart, the risk of death of the patient diagnosed later was only 2% lower.
Ascertainment of Selection Bias To assess the potential impact of selection bias on our results, we performed analyses of survival among the follow633
Figure. Covariate effects on age-specific mortality. Solid lines, estimates based on age groups; dashed lines, smooth spline fits. A, Effect of calendar time (relative risk of death in 1999 compared with 1985). B, Effect of sex (relative risk of female patients vs male patients). C, Effect of diagnosis age (relative risk associated with 1-year increase in diagnosis age).
ing subgroups of patients: (1) subjects entering the study within 6 months of CF diagnosis (~1/3 of the cohort); (2) subjects from four large CF care centers that consistently diagnosed and enrolled a large proportion of patients at birth (n = 1451); (3) subjects in the registry at any time between 1985 and 1992; and (4) subjects in the registry at any time between 1993 and 1999. These subgroups were chosen because they should be subject to less selection bias throughout time than the cohort as a whole. Results for each of these subgroups were similar to results for the entire cohort, with large improvements in survival between 1985 and 1999 and the most dramatic decline in mortality rates among patients <16 years old.
DISCUSSION We have shown that the survival rates of US patients with CF have improved dramatically during the past 15 years, but that most of the improvement has been concentrated in patients 2 to 15 years old. Furthermore, we have demonstrated that, although both male and female patients have benefitted from improving survival trends, female survival remains consistently poorer than male survival in the age range 2 to 20 years. Improving survival has often been assessed by comparing the annual median survival,1,8 the mortality rate based on the general population2 or median age at death5 across successive years. The assessment of median survival assumes that older patients were, and recently diagnosed infants will be, subject to the same risk of death at a given age as the patients who were that age during the observation period.11 The very fact that CF survival is improving throughout time clearly challenges this assumption. The assessment of crude mortality rate or median age at death cannot adjust for the changing age distribution of a cohort, such as the aging of the CF patient population as a result of improving survival. Median age at death is a limited surrogate for mortality rates because it lacks the denominator of the number of persons under observation and at 634 Kulich et al
risk of death. In contrast, the Cox proportional hazards model used in the current study provides age-specific relative risks of death and makes no assumptions about the shape of the underlying mortality function. It therefore offers complete adjustment for age in a cohort with changing age distributions. By including calendar time as a time-dependent covariate, we avoided the assumption (made when assessing median survival by the life table method) that all patients at a given age are subject to the same risk of death, regardless of calendar time. One previous study assessed the effect of age on improvements in CF survival. Halliburton et al2 found a significant decline from 1979 to 1991 in the CF mortality rate among patients 1 to 14 years old, with no change among patients 15 to 24 years old. Thus, the trends described in the current study could have begun as early as 1979. Interestingly, Halliburton et al2 found that the mortality rate of patients younger than 1 year also declined, whereas we found no decline in the mortality rate of infants younger than 2 years during the period 1985 to 1999. The most likely reason for the different findings in the youngest age range is the different study periods. Substantial progress in the care of infants with CF during the 1970s and early 1980s, particularly improvements in the surgical management of meconium ileus,3,12 is the likely reason for improved infant mortality in the earlier study. The fact that Halliburton et al2 obtained results similar to ours using entirely different data sources and methodology reinforces the conclusions of both studies. They used US death certificates rather than CFF Registry data to obtain mortality data, leading to more complete ascertainment of CF deaths but also introducing greater potential for misclassification. Rather than following a cohort of patients with CF longitudinally, they calculated annual mortality based on US census data (ie, CF deaths per million US population). Assessing repeated cross-sectional annual mortality rather than assessing the survival of a cohort of patients followed longituThe Journal of Pediatrics • June 2003
dinally increases the potential for selection bias. In addition, they were unable to estimate the statistical significance of the observed improvements in survival by using their methods. The poorer survival of female patients relative to male patients has been documented in multiple previous studies.1,5,6,9,10 Thanks to the overall improvement in survival, the absolute difference between female and male mortality diminished, though the relative difference remained unchanged. It is perhaps noteworthy that the largest improvement in survival throughout time and the greatest relative risk of death for female patients compared with male patients were both in the age range 2 to 20 years. Until the cause of poorer female survival is understood, it seems unlikely that it will improve. Our finding that later age at diagnosis is associated with improved survival agrees with previous studies.9,13 Our study demonstrates that the size of this effect diminishes markedly with increasing age. It should be noted that the association of age at diagnosis and survival is based on the conventional diagnosis of CF (because of signs and symptoms); CF was diagnosed by newborn screening, which may alter the association between age at diagnosis and survival, in <3% of the study cohort. Selection bias should always be considered the explanation for the observed results in a cohort from which persons are continuously entering and exiting, such as the CFF Registry. Could selection bias explain our findings? The number of patients in the CFF Registry increased from 15,103 in 1985 to 21,588 in 1999. If patients with milder disease were more likely to be represented in the registry throughout time, a large part of any observed improvement in survival may be a result of changes in the CF population captured in the registry rather than a result of a real decrease in mortality. However, the registry did not grow equally in all age groups (Table I). There was very little increase during the last 15 years in the number of patients 0 to 5 years old, an ~50% increase in the number of patients ages 6 to 10 years old, and more than a fourfold increase in patients >30 years old. Provided that highrisk patients are as likely to be represented in the registry in 1999 as they were in 1985 and that ascertainment of deaths is not deteriorating throughout time, selection bias cannot possibly account for the whole observed improvement in survival among patients 2 to 15 years old. This conclusion was confirmed by our subgroup analyses. However, the estimated mortality change in the older age groups could have been more seriously affected by selection bias, and the true survival trends in CF patients older than 16 years remain unclear. We were unable to analyze directly the cause of the observed improving survival of patients with CF or to assess the changes in the CFF Registry population by using clinical or microbiologic data from the CFF Registry because of significant selection bias in the recording of these data. These data are recorded on a subset of patients that is not representative even of the CFF Registry cohort and, more importantly, that dramatically changes throughout time. The selection bias incurred by restricting the analysis to the subset of patients with completely observed covariates would render all conclusions meaningless. The analysis of the association of these characImproved Survival Among Young Patients With Cystic Fibrosis
teristics with survival during shorter periods of time6,9,14 is not subject to the same degree of selection bias. We have shown that the risk of death in younger patients with CF declined significantly between 1985 and 1999. Was the rate of decline in mortality constant during the study period? Our model indicates that the percent decline between any two consecutive years was the same, so that on the absolute scale, mortality decreased faster in the earlier years than in the later years. This pattern in rate of decline was induced by the fact that calendar time was modeled as a linear variable in the Cox model, in which the relative risk of death changes exponentially with each unit increase in the value of a covariate. We investigated several possible transformations of calendar time, leading to different patterns of rate of improvement in survival. However, none of them led to any improvement in model fit. Thus, the constant percent change in mortality agrees well with the data. Potential contributors to the improved survival of US patients with CF include improved nutritional management and dietary recommendations15 and the introduction during the last decade of new pulmonary therapies, including dornase-α, high-dose ibuprofen, new airway clearance techniques, and new antipseudomonal antibiotics such as tobramycin for inhalation.16 Why the survival of young adults with CF has not improved is unclear. One reason may be, paradoxically, the improved survival in the younger age groups. In 1985, many high-risk patients did not survive to age 15 years. During the next 15 years, mortality in patients 2 to 15 years old dramatically improved so that many of the patients who would have died at young ages in 1985 were surviving longer and dying at ages older than 15 years. This phenomenon could actually cause a transient increase in mortality in older age groups, especially those 16 to 20 years old, in whom we found the least improvement in survival. Another explanation is that new therapies may have less impact on survival when initiated in older patients with more established pulmonary disease. Alternatively, perhaps there is a time lag between the introduction of new therapies and their impact on adult survival. The improvement in survival among children with CF during the past 15 years has been dramatic and is resulting in a growing number of adult patients with CF. To date, adults with CF do not appear to be benefitting as much as children from these improving survival trends. It will be important to continue to monitor changes in survival during the next decade to assess whether therapies introduced in the 1990s will ultimately improve adult survival. In addition, research needs to continue into the cause of poorer female survival among patients with CF. Ideally, investigational therapies such as immunomodulatory drugs, correction of the membrane lipid imbalance found in CF, manipulation of electrolyte transport, and gene therapy will contribute to improvements in survival among adult and female patients with CF in the near future.16 We are indebted to the CFF and Preston Campbell, III, MD, Executive Vice President of Medical Affairs, CFF, for their support of this project and for making the CFF National Patient Registry data available to us. 635
REFERENCES 1. Fitzsimmons SC. The changing epidemiology of cystic fibrosis. J Pediatr 1993;122:1–9. 2. Halliburton CS, Mannino DM, Olney RS. Cystic fibrosis deaths in the United States from 1979 through 1991: an analysis using multiple-cause mortality data. Arch Pediatr Adolesc Med 1996;150:1181–5. 3. Elborn JS, Shale DJ, Britton JR. Cystic fibrosis: current survival and population estimates to the year 2000. Thorax 1991;46:881–5. 4. Frederiksen B, Lanng S, Koch C, Hoiby N. Improved survival in the Danish center-treated cystic fibrosis patients: results of aggressive treatment. Pediatr Pulmonol 1996;21:153–8. 5. Fogarty A, Hubbard R, Britton J. International comparison of median age at death from cystic fibrosis. Chest 2000;117:1656–60. 6. Corey M, Farewell V. Determinants of mortality from cystic fibrosis in Canada, 1970–1989. Am J Epidemiol 1996;143:1007–17. 7. Hill DJ, Martin AJ, Davidson GP, Smith GS. Survival of cystic fibrosis patients in South Australia: evidence that cystic fibrosis centre care leads to better survival. Med J Aust 1985;143:230–2. 8. Cystic Fibrosis Foundation National Patient Registry Annual Data Report 2000. Bethesda (MD): Cystic Fibrosis Foundation; 2001.
9. Rosenfeld M, Davis R, FitzSimmons S, Pepe M, Ramsey B. Gender gap in cystic fibrosis mortality. Am J Epidemiol 1997;145:794–803. 10. Demko CA, Byard PJ, Davis PB. Gender differences in cystic fibrosis: Pseudomonas aeruginosa infection. J Clin Epidemiol 1995;48:1041–9. 11. Corey M. Survival estimates in cystic fibrosis: snapshots of a moving target. Pediatr Pulmonol 1996;21:149–50. 12. Wesley AW, Smith PA, Elliott RB. Experience with neonatal screening for cystic fibrosis in New Zealand using measurement of immunoreactive trypsinogen. Aust Paediatr J 1989;25:151–5. 13. Hudson I, Phelan PD. Are sex, age at diagnosis, or mode of presentation prognostic factors for cystic fibrosis? Pediatr Pulmonol 1987; 3:288–97. 14. Liou TG, Adler FR, Fitzsimmons SC, Cahill BC, Hibbs JR, Marshall BC. Predictive 5-year survivorship model of cystic fibrosis. Am J Epidemiol 2001;153:345–52. 15. Corey M, McLaughlin FJ, Williams M, Levison H. A comparison of survival, growth, and pulmonary function in patients with cystic fibrosis in Boston and Toronto. J Clin Epidemiol 1988;41:583–91. 16. Tonelli MR, Aitken ML. New and emerging therapies for pulmonary complications of cystic fibrosis. Drugs 2001;61:1379–85.
50 Years Ago in The Journal of Pediatrics SYNDROME OF ANOMALOUS LEFT CORONARY ARTERY Kelly VC,Wilkins WS, Scott RB. J Pediatr 1953;42:731-3 In June 1953, when this report of the death of a 3-month-old infant with anomalous origin of the left coronary artery from the pulmonary artery (ALCA) was published, corrective surgery for congenital cardiac anomalies with cardiopulmonary bypass had not yet been done successfully. Thus, the discussion in 1953 focused on the typical clinical, electrocardiographic, and roentgenographic features of ALCA, suggesting that the diagnosis could be made before death. A brief mention of a possible closed heart surgical approach, based on the Potts-Smith shunt procedure is made. The uniformly fatal outcome in the 40 cases reported by 1953 in symptomatic infants was emphasized. An intriguing feature of the report is left ventricular rupture and death secondary to the tamponade induced by accumulation of pericardial blood. This complication still occurs in adults with myocardial infarction, albeit rarely. In the intervening 50 years, a remarkable transformation in outcome for ALCA has occurred. Early treatment of ALCA by ligation of the anomalous vessel at the pulmonary arterial connection, with the goal of interrupting the flow of poorly oxygenated blood at low pressure to the myocardium, did improve outcome, reducing mortality to ~50%. Other procedures based on coronary bypass experience to re-establish flow to the ALCA via venous or aortico-ALCA shunts had modest success because of the small size of the bypass grafts or vessels. Anatomical correction of ALCA by reimplantation of the left coronary artery to the aorta has become the standard surgical approach over the last 10 to 15 years, as experience with coronary reimplantation for other congenital anomalies, such as transposition of the great vessels, has become common and successful. The results are quite amazing, with more than 90% perioperative survival in many institutions and good long-term outcomes despite the severe and extensive infarction that occurs before diagnosis. It is truly remarkable that a disorder with 100% mortality 50 years ago now results in nearly 100% early survival. This incredible change in outcome parallels the progress in surgical correction of many congenital cardiac anomalies in the same time span. Arnold Strauss, MD Department of Pediatrics Vanderbilt University Medical Center Nashville, TN 37232-2574 YMPD255 10.1067/mpd.2003.255
636 Kulich et al
The Journal of Pediatrics • June 2003
Objective To investigate age-specific trends in survival among US patients with cystic fibrosis between 1985 and 1999 and to assess whether survival in female patients with cystic fibrosis has improved relative to survival in male patients. Study design A retrospective cohort study of 31,012 subjects in the US Cystic Fibrosis Foundation National Patient Registry. Trends in survival outcome were evaluated by the Cox model. Results Between 1985 and 1999, mortality fell 61% (95% CI, 36-76) for patients age 2 to 5 years, 70% (60-88) for patients age 6 to 10 years, and 45% (32-66) for patients age 11 to 15 years. Improvements in mortality rates among patients older than 15 years were smaller. Female patients had poorer survival rates than male patients in the age range 2 to 20 years, and this gender gap did not narrow throughout time. Conclusions Survival rates of US patients with cystic fibrosis have improved remarkably since 1985. However, most of the improvement was limited to patients 2 to 15 years old. Although both genders benefitted from this trend, female patients have had consistently poorer survival rates than male patients in the age range 2 to 20 years. Further studies are needed to clarify why adult patients with cystic fibrosis had little improvement in survival rates. (J Pediatr 2003;142:631-6)
ultiple studies have shown dramatic improvements in survival during the past 30 years among patients with cystic fibrosis (CF) in the United States1,2 and elsewhere.3–7 This trend is generally thought to be a result of improvements in nutritional and pulmonary therapies and the establishment of specialized care centers. In the United States, median survival has improved from 14 years in 1969 to 32 years in 2000.8 Although improving survival in CF is widely quoted, previous studies have been limited by small sample sizes3,4,7 and lack of longitudinal observation of a cohort.1–3,7 Some studies have evaluated measures of survival unadjusted for the aging of the CF population (crude mortality rate,2 age at death5). Many studies report changes in median survival,1,8 which is a crude cross-sectional measure unsuited for capturing subtle longitudinal survival trends. Moreover, few studies have acknowledged or assessed selection bias as a potential contributor to their findings. The representation of patients with mild disease in patient registries is likely to increase throughout time as a result of either an increase in the diagnosis of CF in patients with mild disease or the increasing participation of these patients in centralized care. Accurate estimates of survival are important for planning future health care needs, counseling patients, and targeting therapies. Analysis of survival trends can also identify subsets of patients whose survival has lagged behind that of the cohort as a whole. Previous studies have not had as a primary focus the assessment of patient characteristics that may influence the degree to which survival has improved throughout time. We undertook this study to examine the changes in survival of US patients with CF from 1985 to 1999. The primary objective was to investigate age-specific trends in survival. A secondary aim was to assess whether the well documented poorer survival among female patients with CF rela-
M
CF CFF
Cystic fibrosis Cystic Fibrosis Foundation
See related articles, p 617and p 624.
From the Department of Biostatistics, University of Washington, Seattle; the Division of Pulmonary Medicine, Department of Pediatrics, Children’s Hospital and Regional Medical Center, Seattle; the Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington Medical Center, Seattle; and the Department of Pediatrics, Saint Louis University, Missouri. Supported by National Institutes of Health grants RR-00037-39 and K23 RR15529 and the Cystic Fibrosis Foundation. Submitted for publication July 2, 2002; revisions received Jan 17, 2003, and Feb 7, 2003; accepted Feb 17, 2003. Reprint requests: Michal Kulich, PhD, Department of Biostatistics, Box 357232, University of Washington, Seattle, WA 98195-7232. E-mail: kulich@u .washington.edu. Copyright © 2003, Mosby, Inc. All rights reserved. 0022-3476/2003/$30.00 + 0
10.1067/mpd.2003.197
631
tive to male patients9,10 has improved during the last 15 years. We took advantage of the Cystic Fibrosis Foundation (CFF) National Patient Registry, estimated to contain data on 85% of diagnosed patients with CF in the United States and >90% of deaths,1 to overcome some of the limitations of previous studies. Modern statistical methods were used that express survival changes in terms of relative risks and allow for complete adjustment for the changing age of the cohort. The potential impact of selection bias on our results was evaluated by careful subgroup analyses.
mortality functions and median survival were based on estimated increments of the cumulative hazard function from the Cox model, with calendar year, gender, and their interactions with grouped age as covariates.
RESULTS Subject Characteristics
The CFF has maintained a registry of all patients with CF receiving care at CFF-accredited centers in the United States since 1966.1 Each CF center submits standardized data forms annually for all patients seen during the previous calendar year, providing demographic, clinical, and mortality information. Subjects in the current study are all patients seen at least once at a CFF-accredited center between January 1, 1985, and December 31, 1999. This study was reviewed and approved by the institutional review board at Children’s Hospital and Regional Medical Center, Seattle, Washington.
The cohort consisted of 31,012 subjects seen at CFF care centers between January 1985 and December 1999. Fiftythree percent of subjects were male, 95.6% were white, 3.6% were black, and 0.8% were of other races. The mean age of the cohort increased from 12.1 years in 1985 to 15.6 years in 1999. The overall mean age was 14.8 years, with a median of 12.5 years and a range of 0 to 73 years. The median age at diagnosis was close to 0.5 years during the whole study period. However, the mean age at diagnosis increased from 2.6 years in patients who entered the study in 1985 to 4.5 years in patients who entered in 1999. The increasing mean age at diagnosis was a result of a growing proportion of patients diagnosed after age 15 years. This proportion rose from 3% to 4% of patients entering between 1985 and 1988 to 8% to 12% of patients entering between 1996 and 1999.
Statistical Analysis
Follow-up, Deaths, and Crude Mortality Rates
Survival was analyzed by using the Cox proportional hazards model with age as the time scale. The Cox model estimates relative risks of death associated with a unit change in a covariate. Patients contributed to the analysis only at ages at which they were at risk and under observation during the study period. The at-risk period began at the age on January 1 of the year during the study period in which a subject was first recorded in the CFF Registry. For patients diagnosed during the year they entered the registry, the at-risk period started at the age at diagnosis. The at-risk period ended at age at death, loss to follow-up, or end of the study (December 31, 1999), whichever occurred first. Patients were assumed to be lost to follow-up if they were not seen for 2 or more consecutive years without later visits recorded in the registry. All results are based on a single Cox model relating agespecific mortality to gender, age at diagnosis, and calendar year at which the given age was reached. Calendar year was modeled as a linear time-dependent variable. Thus, even though the results are presented as differences in mortality between 1999 and 1985, the data collected during the whole study period contribute to estimating the difference. To relax the assumption of proportional hazards, interactions of each of the three covariates with age were included in the model to estimate and test for potentially different effects at different ages. For this purpose, age was divided into eight groups based on age on January 1 of each calendar year. Covariate effects and interactions were tested by partial likelihood ratio tests. Cubic polynomial splines were used with the Cox model to obtain smooth curves of age-specific effects on mortality. The number of parameters in the spline model was the same as the number for grouped age. Estimates of
Subjects were followed for a mean duration of 8.7 years. A fifth of subjects were followed for all 15 years. There were 5234 deaths during the study period (16.9% of the cohort). The primary causes of death were respiratory-related, 82.0%; lung transplant-related, 6.6%; and unknown, 5.6%. Median age at death was 21.9 years. Whereas the number of subjects under observation grew markedly during the study period in the older age groups, it remained relatively constant in the younger patients (Table I). The crude overall mortality rate increased slightly from 18.1 deaths per 1000 person-years in 1985 to 20.8 deaths per 1000 person-years in 1999 (Table I). However, these rates are not adjusted for the increasing age of the study cohort. Crude agespecific mortality rates decreased during the study period in the age groups 2 to 5 years, 6 to 10 years, 11 to 15 years, and >40 years. The sharpest decline was observed in the age group 2 to 5 years, but the estimated crude rates in that group are based on a very small number of deaths.
METHODS Study Population
632 Kulich et al
Survival Model Survival among patients with CF was strongly associated with calendar time, gender, and age at diagnosis (P < .001 for each covariate). The effects of calendar time, gender, and age at diagnosis varied significantly with age (P < .001 for each interaction term). However, there was no interaction among calendar time, gender, and age at diagnosis.
Age-specific Mortality Age-specific mortality adjusted for gender and diagnosis age improved dramatically between 1985 and 1999, with the greatest improvements observed in patients younger than 16 The Journal of Pediatrics • June 2003
Table I. Number of person-years, deaths, and crude mortality rate by age group for 3 selected years and for the whole study period 1985
1992
1999
All years
Age, y
PY
n
Rate
PY
n
Rate
PY
n
Rate
PY
n
Rate
0–1 2–5 6–10 11–15 16–20 21–30 31–40 >40 All
999 2573 2680 2208 1713 1857 473 47 12549
4 8 30 46 46 67 23 3 227
4.0 3.1 11.2 20.8 26.9 36.1 48.6 64.1 18.1
1104 3071 4092 3303 2432 3186 1260 255 18702
8 9 24 52 53 128 63 14 351
7.2 2.9 5.9 15.7 21.8 40.2 50.0 54.9 18.8
1004 2759 4036 3977 3133 3380 1666 678 20632
10 1 25 49 83 155 78 29 430
10.0 0.4 6.2 12.3 26.5 45.9 46.8 42.8 20.8
15275 44476 57232 48848 37252 44731 17707 4648 270169
117 138 466 685 1010 1763 812 243 5234
7.7 3.1 8.1 14.0 27.1 39.4 45.9 52.3 19.4
n, Number of deaths; PY, Person-years; Rate, crude mortality rate per 1000 person-years.
Table II.Adjusted age-specific relative risks Year 1999 relative to 1985 Age, y
RR*
0–1 2–5 6–10 11–15 16–20 21–30 31–40 >41
1.27 0.39 0.30 0.55 0.97 0.86 0.80 0.71
95% CI† (0.75–2.17) (0.24–0.64) (0.22–0.40) (0.44–0.68) (0.80–1.16) (0.73–1.00) (0.63–1.01) (0.43–1.17)
Female patients relative to male patients
1-y Increase in diagnosis age
P value‡
RR*
95% CI†
P value‡
RR*
95% CI†
P value‡
.38 .0002 < .0001 < .0001 .71 .04 .06 .18
0.84 1.76 1.67 1.62 1.27 1.09 1.08 0.94
(0.60–1.18) (1.30–2.39) (1.40–2.00) (1.40–1.87) (1.13–1.43) (0.99–1.19) (0.94–1.25) (0.71–1.23)
.32 .0002 < .0001 < .0001 .0001 .09 .30 .65
0.69 0.64 0.84 0.90 0.93 0.96 0.98 0.98
(0.34–1.38) (0.51–0.81) (0.78–0.90) (0.87–0.93) (0.91–0.95) (0.95–0.97) (0.98–0.99) (0.98–0.99)
.29 .0002 < .0001 < .0001 < .0001 < .0001 .0002 .001
*Estimated relative risk based on a Cox model with each covariate adjusted for the remaining two. †95% CI for adjusted relative risk. ‡For the hypothesis of no difference in mortality because of the covariate (relative risk = 1).
years (Table II). The risk of death in 1999 expressed as a percentage of 1985 mortality was 39% for patients 2 to 5 years old, 30% for patients 6 to 10 years old, and 55% for patients 11 to 15 years old. These improvements were all highly significant. Among patients <2 years of age, there was no improvement in survival throughout time, although there were few deaths in this age group. In patients older than 16 years, the improvements in survival were far less striking. Among patients age 16 to 20 years, there was no indication of improving survival. There was a 15% to 20% decline in mortality rate among subjects age 21 to 40 years, with marginal statistical significance. In the Figure, A, the age profile of mortality changes from 1985 to 1999 is displayed with a smooth spline fit.
Sex Differences Female patients had significantly poorer survival than male patients, though poorer female survival was confined to patients age 2 to 20 years (Table II, Figure, B). Outside this age range male and female survival did not differ significantly. Improved Survival Among Young Patients With Cystic Fibrosis
The age-specific relative risk of death for female patients compared with male patients remained constant during the study period. Median survival (derived from a Cox model not including age at diagnosis) among female patients increased from 31.5 years in 1985 to 34.9 years in 1999 and among male patients from 34.5 years in 1985 to 37.1 years in 1999.
Effect of Age at Diagnosis Later age at diagnosis was associated with improved survival; the magnitude of this association decreased with increasing age (Table II, Figure, C). For example, the risk of death for a 5-year-old diagnosed at age 3 years was 36% lower than that for a 5-year-old diagnosed at age 2 years. However, for two 35-year-old patients diagnosed a year apart, the risk of death of the patient diagnosed later was only 2% lower.
Ascertainment of Selection Bias To assess the potential impact of selection bias on our results, we performed analyses of survival among the follow633
Figure. Covariate effects on age-specific mortality. Solid lines, estimates based on age groups; dashed lines, smooth spline fits. A, Effect of calendar time (relative risk of death in 1999 compared with 1985). B, Effect of sex (relative risk of female patients vs male patients). C, Effect of diagnosis age (relative risk associated with 1-year increase in diagnosis age).
ing subgroups of patients: (1) subjects entering the study within 6 months of CF diagnosis (~1/3 of the cohort); (2) subjects from four large CF care centers that consistently diagnosed and enrolled a large proportion of patients at birth (n = 1451); (3) subjects in the registry at any time between 1985 and 1992; and (4) subjects in the registry at any time between 1993 and 1999. These subgroups were chosen because they should be subject to less selection bias throughout time than the cohort as a whole. Results for each of these subgroups were similar to results for the entire cohort, with large improvements in survival between 1985 and 1999 and the most dramatic decline in mortality rates among patients <16 years old.
DISCUSSION We have shown that the survival rates of US patients with CF have improved dramatically during the past 15 years, but that most of the improvement has been concentrated in patients 2 to 15 years old. Furthermore, we have demonstrated that, although both male and female patients have benefitted from improving survival trends, female survival remains consistently poorer than male survival in the age range 2 to 20 years. Improving survival has often been assessed by comparing the annual median survival,1,8 the mortality rate based on the general population2 or median age at death5 across successive years. The assessment of median survival assumes that older patients were, and recently diagnosed infants will be, subject to the same risk of death at a given age as the patients who were that age during the observation period.11 The very fact that CF survival is improving throughout time clearly challenges this assumption. The assessment of crude mortality rate or median age at death cannot adjust for the changing age distribution of a cohort, such as the aging of the CF patient population as a result of improving survival. Median age at death is a limited surrogate for mortality rates because it lacks the denominator of the number of persons under observation and at 634 Kulich et al
risk of death. In contrast, the Cox proportional hazards model used in the current study provides age-specific relative risks of death and makes no assumptions about the shape of the underlying mortality function. It therefore offers complete adjustment for age in a cohort with changing age distributions. By including calendar time as a time-dependent covariate, we avoided the assumption (made when assessing median survival by the life table method) that all patients at a given age are subject to the same risk of death, regardless of calendar time. One previous study assessed the effect of age on improvements in CF survival. Halliburton et al2 found a significant decline from 1979 to 1991 in the CF mortality rate among patients 1 to 14 years old, with no change among patients 15 to 24 years old. Thus, the trends described in the current study could have begun as early as 1979. Interestingly, Halliburton et al2 found that the mortality rate of patients younger than 1 year also declined, whereas we found no decline in the mortality rate of infants younger than 2 years during the period 1985 to 1999. The most likely reason for the different findings in the youngest age range is the different study periods. Substantial progress in the care of infants with CF during the 1970s and early 1980s, particularly improvements in the surgical management of meconium ileus,3,12 is the likely reason for improved infant mortality in the earlier study. The fact that Halliburton et al2 obtained results similar to ours using entirely different data sources and methodology reinforces the conclusions of both studies. They used US death certificates rather than CFF Registry data to obtain mortality data, leading to more complete ascertainment of CF deaths but also introducing greater potential for misclassification. Rather than following a cohort of patients with CF longitudinally, they calculated annual mortality based on US census data (ie, CF deaths per million US population). Assessing repeated cross-sectional annual mortality rather than assessing the survival of a cohort of patients followed longituThe Journal of Pediatrics • June 2003
dinally increases the potential for selection bias. In addition, they were unable to estimate the statistical significance of the observed improvements in survival by using their methods. The poorer survival of female patients relative to male patients has been documented in multiple previous studies.1,5,6,9,10 Thanks to the overall improvement in survival, the absolute difference between female and male mortality diminished, though the relative difference remained unchanged. It is perhaps noteworthy that the largest improvement in survival throughout time and the greatest relative risk of death for female patients compared with male patients were both in the age range 2 to 20 years. Until the cause of poorer female survival is understood, it seems unlikely that it will improve. Our finding that later age at diagnosis is associated with improved survival agrees with previous studies.9,13 Our study demonstrates that the size of this effect diminishes markedly with increasing age. It should be noted that the association of age at diagnosis and survival is based on the conventional diagnosis of CF (because of signs and symptoms); CF was diagnosed by newborn screening, which may alter the association between age at diagnosis and survival, in <3% of the study cohort. Selection bias should always be considered the explanation for the observed results in a cohort from which persons are continuously entering and exiting, such as the CFF Registry. Could selection bias explain our findings? The number of patients in the CFF Registry increased from 15,103 in 1985 to 21,588 in 1999. If patients with milder disease were more likely to be represented in the registry throughout time, a large part of any observed improvement in survival may be a result of changes in the CF population captured in the registry rather than a result of a real decrease in mortality. However, the registry did not grow equally in all age groups (Table I). There was very little increase during the last 15 years in the number of patients 0 to 5 years old, an ~50% increase in the number of patients ages 6 to 10 years old, and more than a fourfold increase in patients >30 years old. Provided that highrisk patients are as likely to be represented in the registry in 1999 as they were in 1985 and that ascertainment of deaths is not deteriorating throughout time, selection bias cannot possibly account for the whole observed improvement in survival among patients 2 to 15 years old. This conclusion was confirmed by our subgroup analyses. However, the estimated mortality change in the older age groups could have been more seriously affected by selection bias, and the true survival trends in CF patients older than 16 years remain unclear. We were unable to analyze directly the cause of the observed improving survival of patients with CF or to assess the changes in the CFF Registry population by using clinical or microbiologic data from the CFF Registry because of significant selection bias in the recording of these data. These data are recorded on a subset of patients that is not representative even of the CFF Registry cohort and, more importantly, that dramatically changes throughout time. The selection bias incurred by restricting the analysis to the subset of patients with completely observed covariates would render all conclusions meaningless. The analysis of the association of these characImproved Survival Among Young Patients With Cystic Fibrosis
teristics with survival during shorter periods of time6,9,14 is not subject to the same degree of selection bias. We have shown that the risk of death in younger patients with CF declined significantly between 1985 and 1999. Was the rate of decline in mortality constant during the study period? Our model indicates that the percent decline between any two consecutive years was the same, so that on the absolute scale, mortality decreased faster in the earlier years than in the later years. This pattern in rate of decline was induced by the fact that calendar time was modeled as a linear variable in the Cox model, in which the relative risk of death changes exponentially with each unit increase in the value of a covariate. We investigated several possible transformations of calendar time, leading to different patterns of rate of improvement in survival. However, none of them led to any improvement in model fit. Thus, the constant percent change in mortality agrees well with the data. Potential contributors to the improved survival of US patients with CF include improved nutritional management and dietary recommendations15 and the introduction during the last decade of new pulmonary therapies, including dornase-α, high-dose ibuprofen, new airway clearance techniques, and new antipseudomonal antibiotics such as tobramycin for inhalation.16 Why the survival of young adults with CF has not improved is unclear. One reason may be, paradoxically, the improved survival in the younger age groups. In 1985, many high-risk patients did not survive to age 15 years. During the next 15 years, mortality in patients 2 to 15 years old dramatically improved so that many of the patients who would have died at young ages in 1985 were surviving longer and dying at ages older than 15 years. This phenomenon could actually cause a transient increase in mortality in older age groups, especially those 16 to 20 years old, in whom we found the least improvement in survival. Another explanation is that new therapies may have less impact on survival when initiated in older patients with more established pulmonary disease. Alternatively, perhaps there is a time lag between the introduction of new therapies and their impact on adult survival. The improvement in survival among children with CF during the past 15 years has been dramatic and is resulting in a growing number of adult patients with CF. To date, adults with CF do not appear to be benefitting as much as children from these improving survival trends. It will be important to continue to monitor changes in survival during the next decade to assess whether therapies introduced in the 1990s will ultimately improve adult survival. In addition, research needs to continue into the cause of poorer female survival among patients with CF. Ideally, investigational therapies such as immunomodulatory drugs, correction of the membrane lipid imbalance found in CF, manipulation of electrolyte transport, and gene therapy will contribute to improvements in survival among adult and female patients with CF in the near future.16 We are indebted to the CFF and Preston Campbell, III, MD, Executive Vice President of Medical Affairs, CFF, for their support of this project and for making the CFF National Patient Registry data available to us. 635
REFERENCES 1. Fitzsimmons SC. The changing epidemiology of cystic fibrosis. J Pediatr 1993;122:1–9. 2. Halliburton CS, Mannino DM, Olney RS. Cystic fibrosis deaths in the United States from 1979 through 1991: an analysis using multiple-cause mortality data. Arch Pediatr Adolesc Med 1996;150:1181–5. 3. Elborn JS, Shale DJ, Britton JR. Cystic fibrosis: current survival and population estimates to the year 2000. Thorax 1991;46:881–5. 4. Frederiksen B, Lanng S, Koch C, Hoiby N. Improved survival in the Danish center-treated cystic fibrosis patients: results of aggressive treatment. Pediatr Pulmonol 1996;21:153–8. 5. Fogarty A, Hubbard R, Britton J. International comparison of median age at death from cystic fibrosis. Chest 2000;117:1656–60. 6. Corey M, Farewell V. Determinants of mortality from cystic fibrosis in Canada, 1970–1989. Am J Epidemiol 1996;143:1007–17. 7. Hill DJ, Martin AJ, Davidson GP, Smith GS. Survival of cystic fibrosis patients in South Australia: evidence that cystic fibrosis centre care leads to better survival. Med J Aust 1985;143:230–2. 8. Cystic Fibrosis Foundation National Patient Registry Annual Data Report 2000. Bethesda (MD): Cystic Fibrosis Foundation; 2001.
9. Rosenfeld M, Davis R, FitzSimmons S, Pepe M, Ramsey B. Gender gap in cystic fibrosis mortality. Am J Epidemiol 1997;145:794–803. 10. Demko CA, Byard PJ, Davis PB. Gender differences in cystic fibrosis: Pseudomonas aeruginosa infection. J Clin Epidemiol 1995;48:1041–9. 11. Corey M. Survival estimates in cystic fibrosis: snapshots of a moving target. Pediatr Pulmonol 1996;21:149–50. 12. Wesley AW, Smith PA, Elliott RB. Experience with neonatal screening for cystic fibrosis in New Zealand using measurement of immunoreactive trypsinogen. Aust Paediatr J 1989;25:151–5. 13. Hudson I, Phelan PD. Are sex, age at diagnosis, or mode of presentation prognostic factors for cystic fibrosis? Pediatr Pulmonol 1987; 3:288–97. 14. Liou TG, Adler FR, Fitzsimmons SC, Cahill BC, Hibbs JR, Marshall BC. Predictive 5-year survivorship model of cystic fibrosis. Am J Epidemiol 2001;153:345–52. 15. Corey M, McLaughlin FJ, Williams M, Levison H. A comparison of survival, growth, and pulmonary function in patients with cystic fibrosis in Boston and Toronto. J Clin Epidemiol 1988;41:583–91. 16. Tonelli MR, Aitken ML. New and emerging therapies for pulmonary complications of cystic fibrosis. Drugs 2001;61:1379–85.
50 Years Ago in The Journal of Pediatrics SYNDROME OF ANOMALOUS LEFT CORONARY ARTERY Kelly VC,Wilkins WS, Scott RB. J Pediatr 1953;42:731-3 In June 1953, when this report of the death of a 3-month-old infant with anomalous origin of the left coronary artery from the pulmonary artery (ALCA) was published, corrective surgery for congenital cardiac anomalies with cardiopulmonary bypass had not yet been done successfully. Thus, the discussion in 1953 focused on the typical clinical, electrocardiographic, and roentgenographic features of ALCA, suggesting that the diagnosis could be made before death. A brief mention of a possible closed heart surgical approach, based on the Potts-Smith shunt procedure is made. The uniformly fatal outcome in the 40 cases reported by 1953 in symptomatic infants was emphasized. An intriguing feature of the report is left ventricular rupture and death secondary to the tamponade induced by accumulation of pericardial blood. This complication still occurs in adults with myocardial infarction, albeit rarely. In the intervening 50 years, a remarkable transformation in outcome for ALCA has occurred. Early treatment of ALCA by ligation of the anomalous vessel at the pulmonary arterial connection, with the goal of interrupting the flow of poorly oxygenated blood at low pressure to the myocardium, did improve outcome, reducing mortality to ~50%. Other procedures based on coronary bypass experience to re-establish flow to the ALCA via venous or aortico-ALCA shunts had modest success because of the small size of the bypass grafts or vessels. Anatomical correction of ALCA by reimplantation of the left coronary artery to the aorta has become the standard surgical approach over the last 10 to 15 years, as experience with coronary reimplantation for other congenital anomalies, such as transposition of the great vessels, has become common and successful. The results are quite amazing, with more than 90% perioperative survival in many institutions and good long-term outcomes despite the severe and extensive infarction that occurs before diagnosis. It is truly remarkable that a disorder with 100% mortality 50 years ago now results in nearly 100% early survival. This incredible change in outcome parallels the progress in surgical correction of many congenital cardiac anomalies in the same time span. Arnold Strauss, MD Department of Pediatrics Vanderbilt University Medical Center Nashville, TN 37232-2574 YMPD255 10.1067/mpd.2003.255
636 Kulich et al
The Journal of Pediatrics • June 2003