The study identified some characteristics of WAP and compared them to those of AEP and summer-type HP. The duration from symptom appearance to hospital visit and BALF findings on bronchoscopic examination were useful for distinguishing among the patients with WAP, AEP, and summer-type HP. Between patients with WAP and HP, there were many different features, such as age, sex, smoking habit, dyspnea, and laboratory findings (WBC, CRP level, and serum KL–6 level). However, the features of WAP were similar to those of AEP. Therefore, we thought that asking patients about their history of exposure to waterproofing spray, determining the disease progression, and performing a bronchoscopic examination are very important steps.
The three diseases (WAP, AEP, and HP) are common acute pulmonary inflammatory diseases [10,38,39]. In our study, WAP had the fastest progression of the three diseases, and the WBC and CRP level of patients with WAP and AEP were higher than those of patients with HP. Similar to our report, Daubert GP et al. reported that the symptoms of patients with WAP appear rapidly within three hours after exposure [5], and Hays HL et al. demonstrated that patients with WAP have high WBCs and CRP levels as characteristic laboratory findings [40]. AEP is a severe, rapidly progressive lung disease due to exposure to inhalational agents, such as cigarette smoke. The onset of symptoms in patients with AEP is within a few weeks and often only days [10]. Summer-type HP, the most prevalent type of HP in Japan, is caused by seasonal mold contamination in the home environment, often by T. cutaneum (T. asahii) [38]. The symptom duration of acute HP is usually a few weeks or months [9]. The disease progression of WAP, AEP, and HP typically occurs within a few hours, days, or weeks/months, respectively, similar to the results in our report. In addition, the three diseases have alveolitis in common; however, only summer-HP had granulomas in our report. Generally, HP is a granulomatous lung disease that is caused by the repeated inhalation of antigens [41,42]. The granulomas are defined as chronic inflammation [43]; therefore, it is reasonable that patients with HP have a slower disease progression than patients with WAP and AEP.
We suggest that the cellular analysis of BALF is the best examination for distinguishing WAP from AEP and HP because the dominant cells in the BALF are different for each disease. The BALF of patients with WAP, AEP, and HP is dominated by macrophages, eosinophils, and lymphocytes, respectively. We thought that the BALF findings are the result of the different mechanisms underlying the three diseases. Generally, patients with AEP have eosinophil infiltration into the alveolar interstitium, which induces respiratory failure [44]. In addition, patients with HP have lymphocytes and plasma cells with interstitial infiltration [41]. Therefore, the BALF findings in patients with AEP and HP show dominant eosinophils and lymphocytes, respectively [10,41]. In our study, patients with WAP had alveolitis and/or alveolar hemorrhage on histopathological examination, and macrophages constituted the dominant cell type in the BALF. In a past report, the mechanism underlying WAP, namely, the inhalation of fluororesin in a waterproof spray, induces macrophage infiltration and thickening of the alveolar septum, increased airway resistance, and reduced expiratory flow rate in mice [45,46]. These mechanisms might induce the macrophage domination in the BALF findings of patients with WAP.
We demonstrated that serum KL–6 levels were also able to distinguish WAP from HP. Conversely, there was no significant difference in serum KL–6 levels between WAP and AEP patient in our report. However, no report has discussed serum KL–6 levels in patients with WAP. Serum KL–6 is a mucinous high molecular weight glycoprotein classified as human MUC1 mucin, which has been reported to serve as a sensitive marker for interstitial lung diseases [47,48]. Generally, serum KL–6 levels were highly elevated in patients with HP (median 2700 U/mL, IQR 1510–5710 U/mL) [49]. On the other hand, serum KL–6 levels in patients with AEP were reported to be within the normal range (median 161±74 U/mL) [48] because nonfibrotic interstitial lung diseases do not demonstrate elevated serum KL–6 levels [47]. In our study, the serum KL–6 levels of patients with WAP were also within the normal range. This might be because WAP does not induce lung fibrosis. Two patients with WAP in our study had not improved after more than a month of follow-up despite treatment with steroids. Follow-up CT scan and a histopathologic examination by TBLB or a video-assisted thoracoscopic lung biopsy a month after starting steroid therapy in those patients did not indicate fibrotic findings [8,26]. Therefore, WAP can be considered a respiratory disease with alveolitis, alveolar hemorrhage, and no fibrosis.
This investigation had several limitations. The study was conducted retrospectively in a single center, and some medical data were not recorded. Only two patients with WAP participated from our hospital. There might be publication bias because of the limited number of cases with WAP included from published reports. Some medical data such as the duration from symptom appearance to hospital visit were not described in careful detail.