The results of this single-center prospective study demonstrate that a longer delay from the onset of dyspnea until evaluation at a tertiary care center is associated with a higher rate of death from IPF independent of disease severity. This finding did not appear to be explained by differences in the rate of lung transplantation, third-party payer, socioeconomic status, comorbidities, or functional status. In addition, delay was not associated with the rate of lung transplantation. These findings are noteworthy in that they persisted even after accounting for measures of lead time and the effect of transplantation.
This is the first study to examine the effect of delays in accessing subspecialty care in ILD. King and colleagues reported a median delay of 2 years from the onset of symptoms in IPF until initial evaluation at their center (2
), a finding similar to ours. We previously reported higher mortality rates among non-Hispanic black and Hispanic adults with IPF (16
) and ILD (17
) compared with non-Hispanic white subjects, a finding that might be rooted in racial and ethnic variation in accessing care. In the current study, however, we found that non-Hispanic white subjects tended to have similar delays compared with non-Hispanic black and Hispanic subjects, suggesting that delayed access might not explain these differences, at least among those with IPF. The impact of other barriers to accessing care, including social, economic, provider-level, and healthcare system–level factors, should be explored in this patient population with an eye toward improving access for all patients with ILD.
It is not immediately clear why those with longer delays in accessing subspecialty care have higher mortality rates. Differences in disease severity, the rate of lung transplantation, type of health insurance, socioeconomic status, prednisone use, oxygen use, comorbidities, and New York Heart Association functional class did not appear to explain this finding. However, we did find that those with coronary artery disease, diabetes, and gastroesophageal disease tended to have longer (albeit generally nonsignificant) delays in accessing care than those without these comorbidities. Although these comorbidities did not explain our findings, it is possible that dyspnea and cough were falsely attributed to these underlying conditions in some cases, thereby delaying referral for care. Alternatively, it may be that those who are referred later are less healthy in ways that are not readily apparent. For example, differences in physical fitness, frailty, and body composition (such as adiposity or sarcopenia) might be important explanatory factors that should be explored in future studies. It is also possible that misclassification of disease severity or functional status may have limited our ability to identify the factors responsible for our findings. Right heart catheterization was not routinely performed in our study, making it difficult to determine whether pulmonary vascular disease (i.e., pulmonary hypertension) contributed to the differences in survival time; however, the similar DlCO across categories of delay suggests that pulmonary vascular disease may not have been an important factor.
Our results suggest that the recognition (or suspicion) of IPF should prompt early referral to a specialty center. However, the symptoms of early IPF are often subtle, and an accurate diagnosis of even established IPF may not be feasible for community-based physicians (18
). Early access would be facilitated by improved methods of early detection. At present, ILD screening efforts are limited to those with known risk factors for ILD or those with a history of familial IPF. Innovative studies of circulating biomarkers and quantitative imaging methods may hold the key to more accurately identifying early disease (20
There were several limitations to our study. First, lead-time bias may have contributed to our findings if the higher observed mortality rate observed among those with longer delays was simply due to enrollment in the cohort at a later stage of the disease. However, disease severity (and age) were similar across quartiles of delay and our findings did not change substantially when we accounted for lead time by adjusting for age and FVC, the most widely accepted measure of disease severity in IPF (2
). Second, we started study follow-up at the time of evaluation at a tertiary care center even if it occurred before enrollment in our study. In order for these study participants to enroll in our study, they therefore must have survived from the time of evaluation until enrollment. We accounted for this “immortal time” in three ways: by left-truncating survival time, by performing a sensitivity analysis in which we started all observation times at the time of study enrollment, and by adjusting for site of initial visit. Because our findings are similar in each analysis, bias due to inclusion of immortal time seems unlikely. Third, this was an observational study; therefore, our findings cannot be considered causal. Residual and unmeasured confounders may be responsible for our findings. Fourth, we relied on recall of the timing of the onset of symptoms to ascertain delay, which may have misclassified exposure in some cases, particularly if the timing of symptom onset varied by baseline activity level. Our effect estimates, however, would be falsely inflated only if the inaccuracy of recall varied by the risk of death, a situation that appears unlikely. Fifth, by design, we enrolled only those referred to a tertiary care center. The outcome of those never referred was not examined, and might be better than those referred. Last, the results of this single center study could have been influenced by selection bias, and should be applied only cautiously to other centers.
In summary, we have shown an association between a longer delay in accessing a tertiary care center and a higher risk of death in IPF. Our findings should prompt primary care providers and pulmonologists to consider a diagnosis of ILD for unexplained dyspnea and to involve centers with expertise in diagnosing and managing ILD early in the course of disease.