This study describes the characteristics of individuals with chronic cough, their underlying cough-related diseases and their treatments using a Japanese claims database. We devised an original algorithm to define the population of patients managed for chronic cough. This enabled us to identify a total of 6,038 such patients over the 26-month selection period.
Chronic cough is not explicitly defined in the current (2021) international classification of diseases of the World Health Organization and there is thus no single specific ICD-10 code which can be used to capture the entire chronic cough population, nor any established algorithm to identify patients with chronic cough in insurance claims databases. For these reasons, a major challenge of this study was to create original algorithms to identify these patients within the constraints of the coding conventions used in the Japanese healthcare system. The algorithm used took into account a combination of the ICD-10 codes and the more specific standard disease names in Japanese vernacular (which are a particular feature of the Medi-Scope® database) documented for each physician visit, and the frequency of visits with a cough diagnosis code. As well as including patients with chronic cough identified by the standard disease name in Japanese, the algorithm also selected patients with other cough diagnoses that were documented at least three times over a six-month period. Due to the particularity of the Japanese insurance claims system, whereby consultations are documented on a monthly (rather than daily) basis, it was not possible to document the exact date of consultation within each month and, for this reason, the algorithm used the more stringent criterion of multiple consultations over at least three months in order to ensure that the eight-week criterion was met. While antitussive use for > 8 weeks could be considered a straightforward marker for a chronic cough population, we chose not take into account this criterion in the selection algorithm, because of the risk of false positives due to potential use of certain medications as central antitussives or analgesics.
It should also be noted that many patients with chronic cough do not regularly consult a physician for their cough. In an internet survey of patients with cough performed in Japan in 2011, over 60% of interviewees were not being treated for their cough and 44% did not envisage consulting a physician about it [11]. For this reason, our selection algorithm may have led to the identification of only the more severe patients who were actively seeking treatment for their cough symptoms and thus carry a high disease burden.
The 6,038 patients with chronic cough identified represent 0.15% of all the patients in the Medi-Scope® database who made an insurance claim during the selection period. However, this proportion should not be considered as a true prevalence rate since patients in the database not making claims or not consulting a physician are not visible and the true number of individuals with chronic cough is thus not known. A recent general population web-based survey in Japan reported a point prevalence of self-reported chronic cough in adults of 2.9% and a 12-month prevalence of 4.3% [14], consistent with a previous survey reporting a point prevalence of 2.4% [11]. Recent data from Europe and North America suggest a similar prevalence of about 4 to 5% [15–17], although higher rates have been reported in earlier studies [23]. Compared to these prevalence rates, the proportion of patients in our sample fulfilling the criteria for chronic cough is low, which may reflect the fact that our sample is restricted to those patients actively seeking treatment for their coughs from a physician and does not include patients who treat themselves or seek help from other healthcare professionals such as pharmacists. In addition, it is possible that patients with cough due to underlying disease are documented in the Medi-Scope® database by the code of the underlying disease rather than a cough code, and these patients will not be captured by our algorithm. Identifying patients who have a claim of such underlying disease together with cough medication prescribing more than 8 weeks could provide us another degree of evidences for chronic cough study, however, this definition would carry a risk of including many false positives due to noise from the prescription of antitussives for other diseases. We have no established algorithms to eliminate that noise so that we prioritised fidelity rather than uncertainty.
Study participants with chronic cough were more frequently women than men, consistent with previous reports from other countries [10, 13, 15, 16, 24], but surprisingly not with two internet surveys from Japan, which both reported a higher prevalence in men [11, 14]. The mean age of our population (44 years in Population ‘All’) is rather low compared to that reported in previous studies (> 50 years) [10, 14, 16, 24], but this difference is probably to be explained by the age structure of the Medi-Scope® database, which insures employees and their families, so the number of retired people in the database aged > 65 years is low. With regard to underlying cough-related diseases, their relative proportion was similar to that reported in the previous internet survey of patient self-report in the Japanese general population [14], although absolute proportions were higher in the present study. This difference may be explained by the fact that our population is actively seeking care for their chronic cough and may thus have more severe disease. The proportion of patients presenting these cough-related diseases remained relatively stable over the course of the present study.
Over the post-index follow-up period, diagnostic cough codes were frequently no longer documented during the post-index period. For example, in Population 1, of the 3,500 participants with the diagnostic cough code (chronic cough) at inclusion, only 470 retained the same code at Months 10–12. For 1,026 participants with a code for cough-variant asthma at inclusion, 427 retained the code at Months 10–12. Very few participants are reassigned a different cough code between inclusion and Months 10–12 (Table 4). Several factors could explain this limited persistence of the chronic cough diagnosis. Firstly, the cough could have resolved during the post-index period, either spontaneously or following treatment. Alternatively, certain participants may no longer consult for their cough and manage it with non-prescription medication. Thirdly, the cause of the cough may have been identified though appropriate diagnostic work-up, and the participants documented with the disease code for the underlying disease (instead of the cough itself) at Months 10–12 of follow-up. Consistent with this, there was some increase in the proportion of participants with a diagnostic code for allergic rhinitis/nasal inflammation, and to a lesser extent for GERD, over the post-index period (Table 5). Nonetheless, there remained a significant minority of participants whose cough persisted for a year. However, the proportion is lower in our study (36.6% in Population 1) than that reported in a recent study from the USA, in which 41% of patients with chronic cough retained their cough diagnosis twelve months later [3]. However, the populations of the two studies were different, with almost half of the US population having GERD, compared to 17% in the present study. In addition, in the US study, the specialty of the physicians consulted at baseline was significantly associated with the reported persistence of chronic cough. In particular, an allergist visit was associated with lower persistence and a pulmonologist visit associated with higher persistence [3]. The relationship between physician speciality and persistence of chronic cough would be of interest to evaluate in the present study population.
With regard to treatment, the proportion of participants prescribed a central antitussive alone during the index month was very low. This is consistent with the Japanese respiratory society guidelines for the management of cough [18], which recommend treating the underlying disease rather than prescribing central antitussives. These recommendations appear to have been followed, since the proportion of participants prescribed these medications without central antitussives was 51.3% for antiallergic agents, 42.2% for corticosteroids (a sum of 14.7% of corticosteroids, 21.6% of ICS + LABA and 7.5% of bronchodilators) and 18.4% for peptic ulcer treatments (including 4.2% of drugs for improvement of gastrointestinal mobility); these numbers are consistent with the 51.9% of participants with allergic rhinitis/nasal inflammation, 41.7% with asthma and 13.7% with GERD (Tables 3 and 6 in Population `All`). Antiallergic agents and ICS + LABA were frequently used in patients in the cough-variant asthma subgroup as well as in the atopic/allergic cough subgroup, suggesting that the same combination of treatments was frequently used for two diseases with distinct disease mechanisms. In addition, these prescriptions were in general not renewed over the post-index follow-period, with very few participants still being prescribed antitussives six or twelve months later. Again, this is consistent with practice guidelines which discourage the long-term use of these agents due to the risk of dependence.
Medications to treat underlying diseases were sometimes prescribed together with central antitussives at the index month; however, this only concerned > 20% of participants in the case of bronchodilators (including ICS + LABA), corticosteroids and antimicrobials. The proportion of participants co-prescribed a central antitussive fell over the course of the study. Expectorants represented the other class of peripheral antitussive medication that was widely prescribed, to 48% of participants during the index month and to around 33% each month during the post-index period. This indicates that sputum control is an important element of the standard care of chronic cough in Japan, consistent with practice guidelines.
The limitations are principally related to the information in the database. Firstly, patients who do not consult a physician and make a claim are not captured, nor is use of non-prescription medications. Secondly, the database only covers employees and their families, so retired people over 65 years of age are under-represented. Thirdly, the total number of insurees in the database varies over time as individuals move into and out of the health insurance scheme. The only information available on the size of the source population is the number of beneficiaries making a claim in over a given period. For this reason, an accurate estimate of cough prevalence is not possible. In addition, patients who do not make a claim cannot be distinguished from those who leave the database for whatever reason (for example if they die or change employment), and it cannot be excluded that certain participants who were identified during the index month may leave the database during the post-index period because they changed their insurance plan. The database provider has estimated that around 14% of patients with an insurance plan documented in the database are transferring outside within a one-year time period.
In conclusion, in this comprehensive claim database study, we were able to identify a population of patients seeking treatment for chronic cough and describe their characteristics, underlying cough-related diseases and drug utilisation patterns. The present study noted a generally good adherence to the standard of care for chronic cough patients recommended in JRS guideline. However, despite adequate treatments, chronic cough may persist for a year, suggesting the presence of unmet medical needs. Studies to identify the characteristics of patients with chronic cough and their care trajectory, as well as medical education about chronic cough would be further required in this therapeutic area in Japan.