Diagnosing Dyspneic Older Adult Emergency Department Patients: A Pilot Study.

Abstract

Dyspnea is the second leading cause of U.S. emergency department (ED) visits and an independent predictor of morbidity and mortality1 in older adult patients aged ≥ 65 years. Unfortunately, the diagnosis of the cause of dyspnea presents diagnostic challenges to emergency physicians2-4 that disproportionately affects older adults.5 One in five dyspneic older adults experience missed diagnosis in the ED2 and 21% are treated for one or more of pneumonia, acute exacerbation of chronic obstructive pulmonary disease (COPD), and acute exacerbation of heart failure (HF).5 Importantly, some may have multiple causes of their dyspnea but accurate diagnosis remains critical. Accurately differentiating pneumonia from COPD and congestive HF in older adults is particularly challenging to emergency physicians due to atypical presentations, decreased sensation of dyspnea,6 inaccuracy of chest radiographs (60% sensitivity, 76% specificity),7 comorbidities that are potential etiologies of symptoms, overlap of symptoms between pneumonia and other conditions, and inaccuracy of available biomarkers (e.g., procalcitonin8). Emergency physician diagnostic inaccuracy is associated with increased admission rate, longer hospital length of stay, and death or rehospitalization within 1 year.9 Further, current diagnostic criteria rely on symptoms and radiographic findings that, as described, are unreliable in this population. As a result of all these factors, diagnostic uncertainty may be as high as 45% of older adults diagnosed with pneumonia, HF, and/or COPD.5 Antimicrobial peptides (AMPs), innate immune system proteins that respond within minutes to bacterial, viral, and fungal infections, have shown promise in the ED older adult population for diagnosing other infections.10 AMPs have been studied in bronchoalveolar lavage (BAL) samples and demonstrated promise in the diagnosis of patients with dyspnea, but data on more readily available biologic fluids such as serum levels are more practical because BAL is not available in the ED. Serum AMP testing is fast and would be easily implemented in the ED. Because pneumonia, COPD, and HF are common,2, 3, 5 frequently misdiagnosed,3-5 and associated with high morbidity/mortality,9 the primary goal of this prospective pilot study was to build on previous national database work and describe diagnoses in dyspneic older adults. We performed an exploratory analysis to determine whether serum AMP levels should be studied further to improve pneumonia diagnostic accuracy of elderly ED patients; we hypothesize that AMP levels could be higher in the presence of infection. This pilot was a prospective, observational cohort study of ED patients ≥ 65 years of age who presented with dyspnea. Dyspnea was defined as either a chief complaint consistent with dyspnea or shortness of breath or as two measured respiratory rates (RR) ≥ 20 breaths per minute (breaths/min) within 4 hours of presentation. RR was used as the sensation of dyspnea can be decreased in older adults,6 and a cutoff RR of ≥ 20 breaths/min is used in the validated Emergency Severity Index. Patients were excluded if they had active cancer, immunosuppression, trauma activation, incarceration, or suicidal ideation. Informed consent was obtained from all patients. We allowed for consent by appropriate proxy to prevent selection bias. This study was approved by the institutional review board at our institution. Patients were enrolled by trained research assistants in a single, U.S. academic ED with more than 80,000 annual visits, 20% older adults. Data were collected from the patient in the ED via a patient survey and by chart review by trained abstractors. Blood samples were collected in the ED and centrifuged and then serum was stored at –80oC until analyzed using enzyme-linked immunosorbent assays. AMPs included in this pilot study were chosen based on our prior experience in older adult infections.10 We obtained serum leukocyte and procalcitonin in our facility’s clinical laboratory. The presence or absence of the three diagnoses of interest (pneumonia, COPD, HF) at the time of ED evaluation were determined by criterion standard reviewers by review of the electronic medical record (entirety of the patient chart including ED visit, inpatient visit [if applicable and all testing including imaging, pathogen identification, etc.] and subsequent outpatient visits) and patient survey.2 The criterion standard reviewers were board-certified physicians with expertise in geriatrics, emergency medicine, cardiology, heart failure, infectious diseases, and pulmonology. Two reviewers adjudicated each patient chart with review by a third reviewer if there was disagreement on the diagnoses of interest. This criterion standard was compared to ED physician impression collected by research assistants via physician survey at ED disposition. Sample size was calculated based on our primary analyses. Because it was not powered to evaluate the differences between AMPs, this was an exploratory analysis. We report n (%) for categorical variables and mean (95% confidence intervals [CIs]) for continuous variables. T-tests were used to compare laboratory values with log transformation where appropriate. Agreement between adjudicators was measured by Cohen’s kappa. Data management was completed in SAS 9.4 (SAS Institute Inc., Cary, NC) and data analyses in STATA 15 (StataCorp, College Station, TX). Patients were enrolled from October 2017 to June 2018. A total of 391 patients were screened, 140 were eligible, 81 were enrolled, and 79 with blood samples were included in final study analyses. The most common reason eligible patients did not enroll was patient/family refusal (95.0%). The majority of enrolled patients were eligible by chief complaint only (79.8%) and few were eligible by both criteria (7.6%). Eligible patients who did not enroll were similar in age to patients who did enroll (76.6 years [95% CI = 74.3 to 79.0] vs. 73.0 years [95% CI = 71.4 to 74.5]). Characteristics of enrolled patients are shown in Table 1. At least one of the three diagnoses of interest was present in 42 (53.2%) patients as determined by criterion standard reviewers. Pneumonia was diagnosed in 10 (12.7%), COPD in nine (11.4%), and HF in 31 (39.2%). Pneumonia diagnosis agreement between criterion reviewers occurred in 96.2% (κ = 0.85), for COPD 91.1% (κ = 0.54), and for HF 88.6% (κ = 0.76). Codiagnosis was present in 10.1%. (Table 1). Considering all diagnoses for dyspnea determined by the criterion standard reviewers, HF, pneumonia, and COPD remained the most common (Table 1). The emergency medicine attending physician diagnosed pneumonia in 16 (20.3%), COPD in 12 (15.2%), and HF in 30 (38.0%) with a codiagnosis rate of 15.2%. Emergency physicians agreed with the criterion reviewer in 89.9% of pneumonia, 91.1% COPD, and 73.4% HF diagnoses. Underdiagnosis rates were 10.0, 22.2, and 35.5% for pneumonia, COPD, and HF respectively, and overdiagnosis rates were 10.0, 7.1, and 20.8%. Leukocyte count was significantly higher in patients diagnosed with pneumonia (mean = 11.5 × 109 vs. 7.8 × 109/L; p < 0.01) but procalcitonin was not (0.18 ng/mL vs. 0.11 ng/mL; p = 0.42). Among the novel AMPs studied, DEFA5 (mean [±SD] = 428.7 [±186.5] pg/mL vs. 342.0 [±104.4] pg/mL, p = 0.0873; median [IQR] = 362.9 [131.6] vs. 325.1 [244.2]) and DEFB2 (mean [±SD] = 1072.1 [±840.5] pg/mL vs. 609.9 [±738.2] pg/mL, p = 0.077; median [IQR] = 890.9 [548.4] vs. 287.7 [1503.0]) were higher in patients with pneumonia and trended toward significance. This study describes a prospective cohort of dyspneic older adult ED patients, redemonstrates the diagnostic challenge facing emergency medicine physicians, and identifies two AMPs that may help differentiate patients with and without pneumonia in this population. Consistent with previous literature,2 HF, pneumonia, and COPD were the most common causes of dyspnea in our population and codiagnosis occurred in 10.1%. Compared to prior studies, our study benefits from adjudication of presence of HF, pneumonia, and COPD by experts rather than relying on chart review. Emergency physicians regularly care for very ill patients with limited information and time, leading to diagnostic inaccuracy2, 4 as confirmed in this study. Therefore, a quantitative test that can be applied quickly and accurately in the older adult population, such as an AMP, or a quantitative test that is part of a decision rule, similar to the use of a D-dimer with the Well’s criteria for pulmonary embolism, would be well suited to the ED. Improving diagnostic accuracy in the ED would also be expected to improve the inpatient care and long-term outcomes of these patients.9 Our study demonstrates that two AMPs, DEFB2 and DEFA5, may help identify older adult ED patients with pneumonia. This is the first step in the evaluation of new biomarkers; the next steps will include prospective validation and determination of incremental value and clinical utility. Although benefiting from a prospective approach with complete symptom data from patients rather than chart review and a criterion standard of experts to establish diagnoses, this study has several limitations. First, these results describe a preliminary cohort of dyspneic older adults in one academic ED, potentially limiting generalizability to other US EDs. Related, this sample was limited and not all possible etiologies of dyspnea were captured due to chance. The specificity of emergency physician diagnosis is artificially elevated in this population because it was clear that some patients’ dyspnea was due to other diagnoses (for example, atrial fibrillation with rapid ventricular response). Finally, we cannot comment on cost and cost-effectiveness of AMPs if used in clinical practice. This prospective preliminary study demonstrates that emergency physicians continue to have poor diagnostic accuracy in dyspneic older adult ED patients when a criterion standard is used to establish the diagnosis. Two novel biomarkers (DEFB2 and DEFA5) are elevated in pneumonia and may ultimately be useful diagnostic markers to help improve diagnostic accuracy.