This retrospective cohort analysis reviewed the institutional EHR of patients with subacute or chronic cough referred to allergy and asthma specialist clinics at a tertiary care hospital between January 2010 and August 2018. A structured CRF has been used to collect baseline information of new referrals. This form includes the chief complaint and duration, present illness, concomitant symptoms, past medical history, and demographics. The CRF was completed by trained nurses and specialist physicians at the clinics.
Target populations in this analysis were newly referred patients with subacute (3–8 weeks in duration) or chronic cough (>8 weeks in duration) [6, 7]. Cough cases were first identified using the text search for the chief complaint indicating “cough” or “coughing” (either in English or Korean) in the CRF field. Then, data field for the duration of the chief complaint was retrieved to identify cases with subacute or chronic cough. Subjects were excluded if 1) cough duration was not described, 2) cough duration was less than 3 weeks, or 3) other symptoms, such as hemoptysis, fever, chest discomfort, or pain, were reported as co-chief complaints. Participant selection is presented in Figure 1A. Medical records during the first year since the baseline visit were retrieved for analysis, including diagnostic tests, drug prescriptions, and the date of subsequent outpatient visits or hospitalizations (Figure 1B). The study protocol was approved by the institutional review board of Asan Medical Center (IRB No. 2019-0511).
Baseline clinical information
Baseline parameters were retrieved from the structured CRF at baseline visits. A total of 12 concurrent symptoms were recorded in a dichotomous fashion (yes or no), including sputum, rhinorrhea, nasal obstruction, sneeze, postnasal drip (PND)/throat clearing, abnormal throat sensation (globus, tickling, or dryness), hoarseness, throat pain, dyspnea, wheeze, heartburn, and acid regurgitation. Sputum characteristics and amount were further collected if a patient responded yes to sputum. Productive cough (vs. non-productive cough) was defined as positive if sputum was purulent (or abnormal in color) or the daily amount was greater than a spoonful.
Cigarette smoking was classified into never, former, or current. A physician-diagnosed history defined past medical history. It included allergic rhinitis, chronic rhinosinusitis, asthma, COPD, bronchiectasis, pulmonary tuberculosis, interstitial lung disease (ILD), gastroesophageal reflux disease (GERD), heart failure, malignancy, hypertension, and diabetes mellitus (DM). The use of an angiotensin-converting enzyme inhibitor (ACEi) was also recorded.
Baseline diagnostic work-ups included chest X-rays, spirometry (with bronchodilator testing), and T2 marker tests (such as induced sputum eosinophils, blood eosinophils, or fractional exhaled nitric oxide [FeNO]) conducted since the baseline visit, and their results were retrieved for analyses. Chest X-rays were defined as abnormal if the patient had bronchiectasis, tuberculosis, malignancy, or any other grossly abnormal parenchymal lesion in the radiologist’s formal interpretation. Airflow obstruction was defined as positive if the ratio of forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) was less than 0.7 . T2 inflammation marker was defined as positive if induced sputum eosinophils ≥3%, a blood eosinophil count ≥300 cells/µl, or FeNO level ≥30 ppb .
Healthcare utilization during the first year of management
Healthcare utilization was assessed during the first year since the index date (baseline visit). It included additional diagnostic work-ups, prescribed medications, and the number of outpatient visits and hospitalizations. As additional diagnostic tests for cough, we retrieved the information of diagnostic tests prescribed by physicians at the allergy and asthma clinics: methacholine bronchial challenge, nasal endoscopy, laryngoscopy, and chest computed tomography (CT) scan.
Drug records were retrieved for the following prescriptions: inhaled bronchodilators, inhaled corticosteroids (ICS), anti-leukotrienes, H1-antihistamines, pseudoephedrine, proton pump inhibitors (PPIs), codeine (or codeine-containing drugs), amitriptyline, gabapentin, pregabalin, antibiotics, and oral corticosteroids (OCS). Drug exposure was defined as positive if a drug or drugs were prescribed at least once during the first year since the index date. However, in the case of OCS, cumulative dose (prednisolone equivalent) was further calculated, as the risk of corticosteroid complications can increase in a dose-dependent manner .
To quantify the proportion of patients who need repeated outpatient visits over a period, we arbitrarily defined “long-term healthcare utilization” by using the number and timing of subsequent outpatient visits during the first 1 year. It was defined positive if a patient had one or more outpatient visits during the first 6 months since the baseline visit and had at least one more visit during the next 6 months (Additional file 1: Fig. S1). The definition is based on our usual clinical practice pattern.
Descriptive data were calculated as mean ± standard deviation, median with, or percentages, depending on the type of distribution of each parameter. Group differences were assessed using t-tests or chi-square tests. Multiple correspondence analyses were used to visualize and explore inter-relationships between concomitant symptoms. All calculations were performed with Stata 15.1 software (Stata Corp, College Station, TX, USA). A two-sided p-value <0.05 was considered statistically significant. The jvenn was used to draw a Venn diagram (http://jvenn.toulouse.inra.fr/app/example.html).