UACS is widely recognized as a cause of chronic cough. However, its prevalence is considered low in Japan [3, 11]. As it is unlikely that Japan constitutes the only exception, this study was conducted to examine the actual UACS prevalence in Japan. In this study, UACS was the most common cause of chronic cough. It was effectively treated by nasal corticosteroids. Some interview and examination items were useful for UACS diagnosis.
According to the ACCP guidelines, antihistamines/decongestants are recommended for UACS treatment, and the diagnosis should be based on the response to antihistamines in addition to symptoms and examinations [1]. The concept of "silent UACS" without nasal symptoms, diagnosed only by the efficacy of antihistamine treatment was also presented [20, 25]. First-generation antihistamines are recommended for UACS treatment [1]. The mechanism of action is considered to be mainly anticholinergic (suppression of cholinergic vagal reflex); the binding affinity of histamine receptors may not be highly correlated, but no definite conclusion has been reached [26]. This medicine may have strong sedative–hypnotic side effects, which can cause antitussive activity [6]. Therefore, instead of first-generation antihistamines, nasal corticosteroids were administered, as recommended by the European and American guidelines for rhinosinusitis, in this study [27–32]. Because UACS and rhinosinusitis share the same pathophysiological status, treatment with nasal corticosteroids for UACS is appropriate and has been previously reported [33, 34]. In this study, in 110 (75.3%) of the 146 patients with a final UACS-only diagnosis, cough scores significantly improved (from 10 to ≤ 2) within only 2 weeks with nasal corticosteroid administration. Although ERS cough guidelines state that there is no evidence of localised treatment being effective against UACS [10], this finding indicates that inflammation in the nasal cavity plays a central role in the pathophysiology of UACS. Compared with antihistamines, nasal corticosteroids constitute a potent therapeutic option for UACS in terms of efficacy, side effects, and clarification of the location of the primary pathophysiology. The efficacy and mechanism of action of herbal medicines used for treating rhinosinusitis have been demonstrated in Japan, China, and Korea [35–42].
UACS is described only briefly in the Japanese cough guideline [3] and is poorly recognised [11]. It would be interesting to examine why this is the case. The Japanese Cough Guidelines state that CVA, SBS, AC, and GERD are the major causes of chronic cough [3]. SBS, which is defined as chronic recurrent neutrophilic inflammation of the upper and lower airways, is described as a cause of chronic cough only in the Japanese guidelines. Macrolides are effective in treating SBS, and the therapeutic effect is determined based on improvements within 4–8 weeks after administration [3]. Although the concept of SBS differs from that of UACS in that it defines the presence of lower-airway as well as upper-airway lesions (rhinosinusitis), its clinical status largely overlaps with that of UACS [25]. In other words, rhinosinusitis as a cause of chronic cough has been incorporated into the SBS concept and is not recognized as a separate causative disease in Japan. AC had been reported mostly from Japan [43–45]. The condition has been defined as dry cough that can be effectively treated with inhaled corticosteroids or antihistamines and is characterised by eosinophilic central airway inflammation [3, 43, 44]. The concept of AC pathophysiologically overlaps with those of CVA and non-asthmatic eosinophilic bronchitis, and whether AC is an independent disease remains controversial [2, 11, 25, 46]. Niimi and Yu noted that AC may overlap with silent UACS, which is not associated with nasal symptoms and the associated cough symptoms can be improved in this case with antihistamine administration [11, 25]. Additionally, UACS associated with allergic rhinitis that can be ameliorated by antihistamines may overlap with AC. As these diseases overlapping with UACS are recognized as causes of chronic cough, UACS may not be recognized as a cause in itself in Japan.
ACCP reported that “the symptoms and signs of UACS are nonspecific, definitive diagnosis cannot be made from the medical history and physical examination alone” [1]. Several interview and examination items associated with rhinosinusitis were useful in diagnosing UACS in this study. The questions shown in Table 1 refer to common cough-related patient complaints and the major rhinosinusitis guidelines in the United States and Europe [27–32]. These guidelines utilise both clinical symptoms and objective findings for rhinosinusitis diagnosis. Given that UACS shares the same status with rhinosinusitis, it is reasonable to refer to the features of rhinosinusitis for the diagnosis of UACS. All guidelines recommend computed tomography, but echography might be a useful diagnostic tool, as it is economical, convenient, and does not involve radiation exposure [47–49].
More than half of patients presenting with chronic cough were excluded because they did not revisit the clinic for various reasons, and their clinical course could not be followed up. Many of them did not visit the clinic because their symptoms improved. On the other hand, some patients may not have been able to visit the clinic because their symptoms did not improve. There are no data on the extent and duration of cough improvement in these cases. Nevertheless, patients who did not return should have been followed up over the phone or by other means. More patients were diagnosed with UACS than with BA in this study. In general, outpatients often consult a physician before their cough becomes chronic. CVA is generally recognised among general practitioners because the Japanese guidelines specify CVA as the major cause of chronic cough [3]. Therefore, in many cases, inhaled corticosteroids had been empirically administered before the patients visited my clinic (data not shown). Thus, the possibly high number of cases that had not improved with inhaled corticosteroid use may have inflated the prevalence UACS over CVA as a cause of chronic cough. In addition, most patients with BA presented with nasal symptoms or abnormal echography findings and received UACS treatment. Although some patients should have been diagnosed with BA only, they may have been over-diagnosed with complicated UACS. The diagnosis of BA and UACS should have been separated. However, even when all these patients were diagnosed with BA only, the prevalence of UACS in patients with chronic cough was 63.5%. This result indicates that UACS remained the most common cause of chronic cough. The large difference in the number of patients with UACS-only and those without UACS may have biased the statistical results regarding the diagnostic items. This bias may be avoided by equalising the number of patients. This correction may lead to more accurate identification of diagnostic items for UACS. The interview and examination items were limited, and there might be additional items that could be useful for diagnosis. In this study, nine patients were diagnosed with cough of unknown aetiology. In 2016, a systematic review of randomized controlled trials of unexplained chronic cough showed that gabapentin was the only recommended treatment [50]; hence, gabapentin should have been considered to treat cough of unknown aetiology in this study.