Time Is Lung: Inpatient Transbronchial Lung Cryobiopsy Decreases Wait Time to Treatment Initiation for Newly Diagnosed Interstitial Lung Disease

Patients with ILD often wait a prolonged time between the initial presentation, the establishment of a diagnosis, and the initiation of medical therapy [1,2]. Therefore, it is important to identify opportunities to improve efficiency in the diagnostic process. With the development of more data supporting the efficacy of TBLC for diagnosing ILD, acutely ill, hospitalized inpatients with ILD may benefit from an expedited diagnosis to guide treatment. Our initial results evaluating wait times for newly identified ILD inpatients and outpatients show that inpatients have a significantly decreased wait time from initial consultation to lung biopsy and to changes in medical therapy. A potential concern when performing TBLC on inpatients is the severity of the illness that warranted their hospitalization. SLB has been shown to be potentially prohibitive for hospitalized patients due to higher mortality compared to elective, ambulatory patients [16,17,18]. In contrast, initial studies on inpatients undergoing TBLC have shown that while they are more acutely ill as measured by ASA score, supplemental oxygen need, and comorbidities, complication rates are not higher compared to outpatients for pneumothorax, bleeding, need for a higher level of care, or mortality [19,20]. While the size of these studies is limited (n = 17 inpatients [19] and n = 22 inpatients [20]), these findings are supported by other studies comparing inpatients and outpatients for other bronchoscopic procedures, such as endobronchial ultrasound-guided transbronchial needle aspiration [21] and flexible bronchoscopy with bronchoalveolar lavage on intubated patients [22]. Although the indications for these various procedures and patient populations are certainly different, the safety profiles further support performing bronchoscopic procedures on inpatients. Thus, consideration of inpatient TBLC to facilitate a diagnosis of ILD and treatment initiation appears reasonable. HRCT is a crucial component in the diagnostic algorithm for ILD [23]. The positive predictive value of an HRCT diagnosis of UIP is at least 90% in studies looking at patients with biopsy-proven diagnoses [6]. While overt radiographic abnormalities are regularly recognized, subtle imaging changes are more challenging to identify, demonstrating the complexity of HRCT interpretation [24]. This potential for conflicting data between imaging and biopsy results presents another concern regarding inpatient TBLC. While there are limited data looking at ILD resolution on serial imaging, it is possible that hospitalized patients with newly identified ILD could have short interval follow up imaging that refutes the possibility of ILD similar to incidentally found pulmonary parenchymal nodules [25] and airway nodules of the tracheobronchial tree [26]. In our study population, ten patients (six outpatients, four inpatients, Figure 1) received an alternative diagnosis despite the presence of what appeared to be ILD on imaging, further reflecting this potential discordance between radiographic and histopathologic diagnoses. However, we were able to establish an alternative diagnosis for these patients that guided their treatment, supporting the benefit of the biopsy procedure in their overall management. To mitigate the risk of an unnecessary procedure, it will be imperative to ensure that all alternative explanations for an ILD pattern on imaging, such as infection, interstitial edema, or malignancy, amongst others, are thoroughly examined before proceeding. Optimizing this process will be an area of future discussion. ILD is uncommon in younger patients, with the mean age at diagnosis for IPF being 68 [27]. Unfortunately, older age at diagnosis is associated with worse outcomes for patients with IPF [4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28], other progressive fibrosing interstitial lung diseases [29], and rheumatoid arthritis associated with ILD [5]. Because establishing a diagnosis of ILD is often delayed and exposes patients to unneeded procedures [1,2], years may pass before starting a treatment plan [1,2], potentially missing the opportunity to intervene earlier in the disease course before inflammation evolves into fibrosis. Interestingly, in our study, inpatients (59.4 ± 9.5 years) presented at a significantly earlier age than outpatients (65.9 ± 11.3 years; p = 0.02, Table 1) for TBLC. Although we are limited by our small sample size, this finding potentially suggests that these patients may be able to take advantage of a diagnosis at a significantly earlier age than outpatients, further supporting the finding of significant delays that outpatients with ILD experience. It is possible that the worse outcomes associated with advancing age may reflect the negative impact of a prolonged delay from symptoms to diagnosis and treatment. Thus, improving the efficiency of the diagnostic process may have the potential to impact morbidity and mortality. A portion of ILD patients will develop chronic, fibrosing, and progressive disease. While IPF is the exemplar of this process, non-IPF ILDs may also evolve into a progressive pulmonary fibrosis (PPF) phenotype, which is characterized by worsening symptoms, radiographic progression, and physiological progression over the past year [10]. PPF leads to a decline in lung function, decreased quality of life, and early mortality [30]. Unfortunately, prognosticating which patients will develop this phenotype is challenging [31]. Because fibrosis is irreversible, treatment should be initiated as soon as a diagnosis is confirmed for IPF [32,33] and once evidence of PPF is confirmed based on established criteria [10]. In our study, inpatients undergoing TBLC waited significantly less time from IP consultation to biopsy (2.5 ± 4.4 days vs. 15.5 ± 16.1 days, p < 0.001), from biopsy to treatment (10.3 ± 7.9 days vs. 34.6 ± 37.0 days, p < 0.001), and most importantly from initial IP consult to treatment initiation (12.8 ± 10.8 days vs. 50.1 ± 38.5 days, p < 0.001) (Table 3) compared to outpatients. It is reasonable to hypothesize that these findings suggest a potential positive impact on patient outcomes if lung function and lung structure are preserved through a more expeditious and efficient diagnostic and management process. Longitudinal studies assessing this possibility will be an area of future research. While TBLC may present an efficient means to obtain an ILD diagnosis and establish a treatment plan, the need to obtain prior insurance authorization for certain medications may prevent patients from receiving their prescribed therapy. Studies from multiple medical specialties have shown that when prior insurance authorization is required, the time between medical therapy prescription and initiation of therapy is delayed, often due to denials for prior insurance authorization [34,35,36]. Delays in initiating medications may lead to worse outcomes, as seen in post-cardiac stent patients who are unable to obtain anti-platelet therapy in a timely manner [34]. Efforts to combat this barrier include the utilization of a centralized pharmacy [37] and identifying individuals or teams to champion the process [38]. Further efforts to accelerate the prior insurance authorization process will be needed to ensure that once a diagnosis is established and medical therapy is prescribed, patients will be able to begin their treatment quickly. Although not examined in this study, there may also be a role for TBLC in evaluating inpatients with known ILD admitted for an acute exacerbation or concern for disease progression. While guidelines recommend ruling out cardiac failure or volume overload as part of the diagnostic criteria for an acute exacerbation of IPF [39] or other ILDs [40], the role of bronchoscopy with bronchoalveolar lavage to evaluate for infection as the inciting event or TBLC to obtain histopathology in this evaluation requires additional investigation [39]. In lung transplant patients undergoing both surveillance bronchoscopy and those suspected of experiencing acute cellular rejection, TBLC, compared to the gold standard conventional transbronchial forceps biopsy [41], improved the diagnostic accuracy of acute cellular rejection and led to treatment changes with an acceptable safety profile [42,43]. Extrapolating from this population, it may be beneficial to understand if histopathology for ILD patients with a suspected acute exacerbation or progression shows a change from an inflammatory state that requires additional or alternative immunosuppression to a fibrotic state that would be better suited by treatment with anti-fibrotic therapy. The potential impact of the information gained by TBLC on altering treatment regimens will require formal studies in the future. Our study has limitations. These include its design as a single center and retrospective analysis with a small sample size, thus potentially impacting the rate of complications seen in our groups. Additionally, patients were not able to be randomized between the two groups, given the nature of their presentation for evaluation. However, it is strengthened by its inclusive nature of all patients with new ILD from both the inpatient and outpatient environments and the ability to obtain complete data points on all patients. We were able to show that inpatients with a new diagnosis of ILD present at a younger age (Table 1) and wait less time to initiate medical therapy and to obtain a treatment determining TBLC procedure (Table 3) compared to outpatients. Because patients with ILD experience significant delays in establishing a diagnosis and initiating treatment, efforts to improve this process are essential. TBLC is a guideline recommended option to obtain a tissue diagnosis for patients with ILD. Our study shows that inpatients undergoing TBLC have a significantly decreased wait time from initial consultation to biopsy and to medical therapy changes, including medication initiation, adjustment, or cessation. Accelerating this process has the potential to positively impact patients by preventing progressive lung loss due to prolonged wait times. Evaluating the clinical impact of using TBLC to expedite and ILD diagnosis will require future prospective, longitudinal studies.