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McCrory DC, Coeytaux RR, Yancy WS Jr, et al. Assessment and Management of Chronic Cough [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2013 Jan. (Comparative Effectiveness Reviews, No. 100.)

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Assessment and Management of Chronic Cough [Internet].

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Discussion

Key Findings and Strength of Evidence

In this comparative effectiveness review (CER), we reviewed 78 studies involving 5927 patients that evaluated instruments used to assess cough (Key Question [KQ] 1) and 48 studies involving 2923 patients that evaluate nonspecific (or symptomatic) therapies to treat patients with chronic cough (KQ 2). We hoped to evaluate the comparative effectiveness of these instruments and treatments both in adults and in children (< 14 years of age). The evidence—especially related to the effectiveness of nonpharmacological therapies and to children—was very limited.

KQ 1. Instruments Used To Assess Cough

Our findings suggest that selected cough-specific quality-of-life instruments are valid and reliable for assessing cough. The Leicester Cough Questionnaire (LCQ) and the Cough-specific Quality of Life Questionnaire (CQLQ, along with its predecessor, the Adverse Cough Outcome Survey [ACOS]), are the most widely studied cough-specific quality-of-life questionnaires in adults, with several studies showing fair to moderate correlation with other cough measurement tools such as cough frequency logs, tussigenic challenges, electronic recordings, or other quality-of-life questionnaires. The Parent Cough-specific Quality-of-Life questionnaire (PC-QOL) has been validated in the pediatric population and shows good internal consistency and strong correlation with other subjective and objective cough measurement tools. Other cough-specific quality-of-life questionnaires, such as the Chronic Cough Impact Questionnaire (CCIQ) and the Cough and Sputum Assessment Questionnaire (CASA-Q) show good internal consistency but have not been compared extensively with objective cough measures. Other disease-specific, health-related quality-of-life questionnaires may include questions about cough, but also assess noncough symptoms, and their focus on multiple symptoms leads them to be less valuable tools specifically for assessing cough.

Electronic recording devices correlate well with human cough counts. This suggests that recording devices are reliable for assessing cough frequency. Electronic recording devices, however, demonstrate variable and generally weak correlation with other cough measurement tools, and the validation studies of devices that recorded cough events for 24 hours or longer were validated against human cough counts for only a portion of the overall recording period. Furthermore, we did not identify studies that confirmed that recording devices and human counters identified exactly the same cough events. This may be because cough frequency is unidimensional, whereas the impact that cough may have on an individual's functional status, quality of life, or sense of wellbeing may depend on many other factors. Multidimensional quality-of-life assessments such as the LCQ, CQLQ, and other cough-specific instruments may therefore be more useful than simple cough frequency in assessing meaningful impact of cough.

Visual analog scales (VAS), on the other hand, can generally be considered to have face validity and are usually easy to administer, but we did not identify any formal validation studies of any cough-related VAS instrument. A variety of other cough scoring methods we identified used inconsistent scales and assessed diverse cough outcomes, making it difficult to draw comparisons. Such instruments, which include diaries and ordinal scales, show variable to poor correlation with other cough measurement tools when used as reference tests.

Tables 10–14 summarize the strength of evidence29 for the available outcomes of validity, internal consistency, reliability, and responsiveness for the various instruments. We did not identify any studies evaluating the comparative therapeutic efficacy or patient outcome efficacy of these tools; therefore, the current evidence base is insufficient for us to draw any conclusions about these outcomes. Among the quality-of-life questionnaires evaluated, only the LCQ. CQLQ/ACOS, and the PC-QOL were represented by four or more published studies; as such, they are they only three questionnaires for which we generated strength of evidence tables.

Table 10. Summary of the strength of evidence for KQ 1—Leicester Cough Questionnaire (LCQ)—cough severity/QOL.

Table 10

Summary of the strength of evidence for KQ 1—Leicester Cough Questionnaire (LCQ)—cough severity/QOL.

Table 11. Summary of the strength of evidence for KQ 1—Cough-specific Quality of Life Questionnaire (CQLQ) and Adverse Cough Outcome Survey (ACOS)—cough severity/QOL.

Table 11

Summary of the strength of evidence for KQ 1—Cough-specific Quality of Life Questionnaire (CQLQ) and Adverse Cough Outcome Survey (ACOS)—cough severity/QOL.

Table 12. Summary of the strength of evidence for KQ 1—Parent Cough-specific Quality-of-Life questionnaire (PC-QOL)—cough severity/QOL.

Table 12

Summary of the strength of evidence for KQ 1—Parent Cough-specific Quality-of-Life questionnaire (PC-QOL)—cough severity/QOL.

Table 13. Summary of the strength of evidence for KQ 1—electronic recording devices—cough frequency.

Table 13

Summary of the strength of evidence for KQ 1—electronic recording devices—cough frequency.

Table 14. Summary of the strength of evidence for KQ 1—visual analog scales—cough severity/QOL.

Table 14

Summary of the strength of evidence for KQ 1—visual analog scales—cough severity/QOL.

KQ 2. Nonspecific Therapies for Chronic Cough

Our review of studies of nonspecific therapies for chronic cough found that a wide variety of pharmaceutical agents have been used to treat the symptom of chronic cough, including opioid, anesthetic, and nonopioid/nonanesthetic antitussives; expectorant and mucolytic protussives; antihistamines; antibiotics; inhaled corticosteroids; and inhaled anticholinergics. The opioid and certain nonopioid/nonanesthetic antitussives demonstrated the most promise for managing the symptom of chronic cough. In particular, codeine (with dose response and placebo-controlled data) and dextromethorphan have reasonably good data for reducing cough frequency and severity. However, due to inconsistency and imprecision of results, and small numbers of head-to-head comparisons, the overall strength of evidence is insufficient to draw firm conclusions about the comparative effectiveness of these agents. There were few high-quality studies focusing on chronic cough using reliable outcome measurements over durations of followup pertinent to chronic cough. Even when similar outcomes were assessed across studies, the instruments used were diverse and inconsistent, making comparison and interpretation difficult. Furthermore, tolerability was uncommonly reported; thus, although few adverse effects were identified in the included studies, these data likely reflect the observed underreporting rather than assurance about the safety of these agents. In addition, other outcomes of interest (e.g., number of emergency department visits) have been evaluated in relation to over-the-counter cold and cough products, and this type of downstream impact of nonspecific therapies was not assessed in our review.145 Finally, the evidence exploring the effectiveness of treatments in patients with truly unexplained cough was minimal. We considered the vast majority of study populations to have unresponsive chronic cough.146 Only three studies, including one of morphine, were clearly in patients with unexplained cough and required subjects to have gone through a diagnostic evaluation to exclude most causes of cough.80,93,143 Interestingly, therapy in each of these studies was associated with a reduction in cough severity, suggesting that chronic unexplained cough can respond to nonspecific therapies aimed at the symptom and not the underlying etiology.

Controlled studies on nonpharmacological therapies for chronic cough were few. For all treatment categories, studies evaluating management of unidentified or refractory chronic cough in children were extremely limited. We identified two studies of one therapy (oral ketotifen) which is not currently available in the United States.130,138 A third study looked at an antibiotic, amoxicillin clavulanate, in children with more than 3 weeks of wet cough, but its applicability was limited in terms of its sample size and the description of the diagnostic evaluation of cough.

Tables 15–19 summarize the strength of evidence for the most commonly used classes of therapies and evaluated outcomes. Those comparisons for which evidence was based on mixed treatment meta-analyses were considered indirect. Evidence for other comparisons was too sparse to construct such summary tables.

Table 15. Summary of the strength of evidence for KQ 2—antitussive (anesthetic) versus antitussive (opiate).

Table 15

Summary of the strength of evidence for KQ 2—antitussive (anesthetic) versus antitussive (opiate).

Table 16. Summary of the strength of evidence for KQ 2—antitussive (opiate) versus antitussive (other).

Table 16

Summary of the strength of evidence for KQ 2—antitussive (opiate) versus antitussive (other).

Table 17. Summary of the strength of evidence for KQ 2—protussive (mucolytic) versus antitussive (other).

Table 17

Summary of the strength of evidence for KQ 2—protussive (mucolytic) versus antitussive (other).

Table 18. Summary of the strength of evidence for KQ 2—protussive (mucolytic) versus antitussive (opiate).

Table 18

Summary of the strength of evidence for KQ 2—protussive (mucolytic) versus antitussive (opiate).

Table 19. Summary of the strength of evidence for KQ 2—active therapies versus placebo.

Table 19

Summary of the strength of evidence for KQ 2—active therapies versus placebo.

These summary tables highlight that across outcomes and comparisons, although the included evidence was from RCTs with an overall low risk of bias, the findings were inconsistent; the evidence was indirect, being mostly based on placebo-controlled trials; and the findings, when available, were imprecise. There was insufficient evidence to support conclusions about comparative effectiveness of the interventions for any of our key outcomes.

Findings in Relationship to What Is Already Known

Our results are generally consistent with previous systematic reviews and clinical guidelines. A recent systematic review of cough measurement tools by Leconte et al.147 analyzed some of the same data included in this CER. This previous review included 34 articles and also focused on electronic recording devices, quality-of-life questionnaires, and subjective cough measurements such as visual analog scales and cough diaries. In our review, we included additional studies that were excluded in the previous study, including studies that used human cough count as a reference test,35,36,40,47,65,71,73-75,78,98,102 and studies that evaluated disease-specific, health-related quality-of-life questionnaires.32 Our review summarized 60 studies involving 5,430 subjects and over 36 distinct instruments. The previous systematic review concluded that both quality-of-life scales and electronic recording devices were accurate and useful clinical tools. Our findings corroborate those from the previous systematic review, while providing additional, recently-published evidence that further supports the validity of the LCQ in adult populations. As in the previous review, we found no validation studies of visual analog scales and found enough variability in correlation of these scores with other cough measurement tools that no recommendation could be made regarding their usefulness as cough measurement tools. Our review included similar numbers of studies evaluating electronic recording devices and subjective score scales, but included more studies evaluating quality-of-life questionnaires, specifically the LCQ, which allowed us to be more comprehensive in our evaluation of this widely used tool.

Previous reviews of the effectiveness of antitussive and protussive drugs for cough have been broader in scope, but have drawn conclusions similar to those reached in this review. A recent review of cough suppressant and protussive drug treatment in the American College of Chest Physicians (ACCP) 2006 clinical practice guideline on cough addressed acute as well as chronic cough;146 our review identified a few more trials of codeine116,125 and dextromethorphan,125,129,131 as well as trials of other opiates,80,132 glaucine116,131 and benzonatate.134,135 Recommendations in the ACCP guidelines for use of peripheral cough suppressants (levodropropizine and moguisteine, neither available in the United States) were based on reduced cough frequency relative to placebo; similarly, a recommendation of short-term use of central cough suppressants (codeine and dextromethorphan) in chronic bronchitis cited placebo-controlled studies. None of the few extant head-to-head comparisons were cited; neither were comparative effectiveness comparisons or recommendations in selecting between drug classes made. Another review from the same guideline evaluated nonpharmacological treatments, noting that most studies of these therapies were conducted exclusively in patients with cystic fibrosis.148 The recommendations therefore focused exclusively on populations outside the scope of our review, namely on patients with respiratory muscle weakness, cystic fibrosis, and bronchiectasis.

Applicability

The effects of interventions, as determined in clinical trials, do not always translate well to usual practice, where patient characteristics, clinical training, diagnostic workup, and resources may differ importantly from trial conditions. In addition, the availability of interventions studied in our review may differ from those easily available to patients within the United States.

For our analysis of instruments for the assessment of cough (KQ 1), overall, the study instruments were generally adequately described. The main study reporting issue affecting applicability was the description of the study population. Sociodemographic and clinical characteristics of the study populations were often inadequately described. Of the studies with an adequate description of the study population, there was marked variability within and between studies in terms of the etiology and duration of cough symptoms, the age of patients, and severity of illness. It is reasonable to assume that the utility, performance, reliability, and validity of cough instruments may differ between children and adults, between acute and chronic cough conditions, and between underlying etiologies such as asthma, chronic bronchitis, acute rhinitis, lung cancer, and chronic refractory cough. More consistent reporting of patient characteristics such as age, underlying etiology, duration of symptoms and/or illness, overall medical comorbidity, and prior treatment would facilitate evaluations of various cough instruments in important subgroups. As far as geographical location of studies is concerned, 41 studies (53%) were conducted in Europe, with 32 of those conducted exclusively in the UK. Nineteen (24%) studies were conducted in the United States or Canada. Location of study was not, however, obviously related to design, patient, outcome, or analytic characteristics.

In terms of our evaluation of therapies for the treatment of unexplained or refractory chronic cough (KQ 2), by restricting inclusion to trials of patients with unexplained or refractory cough, we improved the applicability of our findings to this population but also decreased the availability of evidence that could be reviewed. Expanding our evidence to include patients with acute cough would have substantially increased the evidence base but greatly reduced the applicability of the findings to the unexplained or refractory chronic cough population. We identified only 48 studies involving 2,923 patients (median number of patients per study=55). Few studies directly reported assembling patients fitting our intended population of idiopathic or refractory chronic cough. More often patients were selected from persons with chronic cough (of variable duration) with a variety of diseases associated with cough. While we tried to apply criteria to improve applicability (e.g., excluding cystic fibrosis and bronchiectasis), the studies we ultimately included contained more diversity than we intended. In particular, studies with mixed etiologies (including, e.g., patients with tuberculosis or lung cancer) and studies from different eras and geographic locations challenge the usefulness of data on treatment. The majority of studies took place in Europe, with 9 in the UK and 17 in other countries in Europe (total of 54%); only 9 (19%) took place within the United States or Canada. Location of study was not, however, obviously related to design, patient, outcome, or analytic characteristics.

We were only able to identify three studies of children eligible for inclusion in our review. Unfortunately, these studies have limited applicability to today's management of children with chronic cough. Two studies evaluated the same drug, oral ketotifen, which is not available in the United States and is used for children who likely had asthma in a manner inconsistent with current asthma management guidelines. The management of asthma has significantly changed since these studies were conducted (1989 and 1992), and today a greater emphasis is placed on the role of controller medicines (e.g., inhaled corticosteroids, leukotriene inhibitors) to reduce the chronic symptoms associated with poorly controlled asthma. In addition, it is unclear whether findings regarding ketotifen are generalizable to the other available medications in its class. A third study was a randomized, placebo-controlled trial of an antibiotic, amoxicillin clavulanate, in 50 children with more than 3 weeks of wet cough. Cough resolution was 48 percent in the treatment group and 16 percent in the placebo group (p=0.0016). This study was rated as good quality, although it had a small sample size and the description of diagnostic evaluation of cough was minimal. The strength of evidence based on these three studies regarding treatment of chronic cough in the pediatric population is insufficient.

For the studies focusing on the adult population, many of the drug treatment trials we identified included drugs that are not currently available in the United States (12 studies, 25%). While we excluded drugs that had been withdrawn from the U.S. market (e.g., for safety issues), we retained studies of drugs that were marketed elsewhere, in part because we believed that such studies would help with the assessment of the effect of a class of cough treatments. However, we believe that the within-class similarities were greater among opiate antitussives, compared with nonopiate antitussives or protussive mucolytic or protussive expectorant groupings. The applicability of the included studies was also reduced given the age of much of the evidence, and therefore of the corresponding interventions and underlying clinical management of the patients. Publication dates ranged from 1953 to 2012, with 32 (76%) of the articles being published before 2000. Given the changes in both available therapies and the diagnosis and treatment of underlying etiologies, more recent studies of contemporary therapies are needed.

Implications for Clinical and Policy Decisionmaking

The availability of strong evidence for validity of cough-related quality-of-life questionnaires is probably more important for future research than for clinical care. Despite some newer valid measures, evaluating the benefit from efficacy data in the clinical literature is based mostly on unvalidated symptom measurement tools for which the minimum clinically important benefit has not been well-defined. This deficiency in the literature complicates comparisons of efficacy and evaluation of the net benefit of therapeutic alternatives; therefore, the further development, validation, and use of these measures would help with future evaluations of the comparative effectiveness of available therapies. Consensus amongst researchers in terms of a reference standard test would be helpful for filling existing evidence gaps and future research needs.

The relatively low strength of the evidence summarized in this CER related to treatment of chronic cough provides limited guidance to clinical or policy decisionmaking. Despite the clinical and economic burden of chronic cough, continued insufficient evidence suggests that little needs to be changed regarding recommendations for symptomatic treatment of chronic cough from the major clinical practice guideline for cough diagnosis and management (ACCP 2006146). Greater differentiation in guideline recommendations between patients with unexplained and refractory cough from known causes would not seem to be supportable. The subjective nature of cough symptoms, combined with uncertainty about benefits and low reporting of adverse events, makes determining the net benefit of treatment somewhat uncertain even for those symptomatic cough treatments in which relevant studies have been performed. The lack of well-controlled scientific studies in children prompted recommendations against use of codeine and dextromethorphan in children from the American Academy of Pediatrics,149 as well as slightly broader recommendations against prescription cough suppressants and OTC cough-cold products by the ACCP. The U.S. Food and Drug Administration (FDA) issued a Public Health Advisory in January 2008 recommending against the use of over-the-counter cough-cold preparations in children under 2 years of age, citing poor data on efficacy in children as well as adverse event data from the FDA's Adverse Event Reporting database and recent data on the way these products have actually been used by parents and children.150 This example illustrates how policymakers have dealt with low-quality evidence in children, concerns about the applicability of efficacy data from adults, and current data from adverse event reporting.

Similar challenges exist with applying data on short-term outcomes to longer term or frequent symptomatic treatment of chronic cough, and applying data from historical populations that may have undergone inadequate diagnostic evaluation to present-day patients. Although the current systematic review does not add much to aid clinical and policy decisionmaking, it does help identify numerous gaps in the evidence base and areas of needed future research.

Limitations of the Comparative Effectiveness Review Process

Our findings have limitations related to the literature and our approach. Important limitations of the literature include: (1) few studies exploring the clinical population of interest (unexplained or refractory chronic cough) and in specific patient subgroups of interest (e.g., children, women, immunocompromised patients); (2) variable definitions of chronic cough; (3) diverse etiologies of cough that might respond differently to different therapies; (4) incomplete reporting of patient characteristics, study design, or outcomes; (5) small sample sizes and short duration of followup; (6) lack of gold standard outcomes to assess efficacy and tolerability; and (7) inconsistent reporting of comparative statistical analyses.

In addition, most of the studies were comparatively old, and as such the evidence base suffers from age because of advances in clinical trial methodology, improved diagnostic evaluation of cough, and development of valid and reliable measures for cough and cough-specific quality of life. The relative lack of newer therapeutic trials in nonspecific or symptomatic treatment for chronic cough may reflect more focus on disease-specific treatment to the exclusion of nonspecific treatments. Specific to KQ 1, we found no studies evaluating the impact of cough assessment instruments on therapeutic or patient outcome efficacy. In addition, many of the cough instrument validation studies were based on reference instruments not previously validated for cough, which may introduce measurement error and which decreases our confidence in the reported results. An analytical synthesis of the literature was not possible in the current study of cough instruments due to the heterogeneity of included study instruments and methods, but would be a useful goal for future research given additional evidence. For KQ 2, the variability in treatment class and specific drug comparisons, and the scarcity of studies that reported similar outcome measures, inhibited the quantitative synthesis of the evidence and limited our conclusions based on this evidence.

Our review methods also had limitations. Our study was limited to English-language publications. It was the opinion of the investigators and the Technical Expert Panel that the resources required to translate non-English articles were not justified. With this exclusion our search still returned over 15,000 citations. Unfortunately, although the literature on cough is quite large, much of it focuses on acute cough. In addition, much of the chronic cough literature relates to specific populations that were outside the scope of this CER: bronchiectasis and cystic fibrosis. In addition, even within patients with chronic cough, the target population of patients with unexplained chronic cough or refractory chronic cough with a known underlying etiology was difficult to identify. Few studies assembled populations consistent with these goals. Rarely was a thorough negative diagnostic evaluation performed to assemble a group with unexplained chronic cough; in the case of studies of patients with a known underlying etiology, seldom was previously tried therapy described well enough to determine whether patients were treatment-refractory. Many decisions regarding these criteria were resolved through investigator discussion. In general, we considered use of a symptomatic treatment in a population with a known underlying etiology to imply refractory cough unless patients were noted to be treatment-naïve; certain etiologies, however, were considered differently, for example, most studies of cough-variant asthma, a common cause of chronic cough in children, which is usually highly responsive to appropriate asthma management, were excluded.

It is possible that our a priori definition of chronic cough in childhood (i.e., persisting at least 4 weeks if < 14 years of age, or 8 weeks if 14 years or older) was too long and did not reflect care delivery. However, our decision to include studies that described their population as suffering with chronic cough regardless of time cut-off may have mitigated this problem.

Focusing on nonspecific or symptomatic treatments to the exclusion of treatments aimed at specific causes of chronic cough proved more complicated to implement than we had anticipated. Certain therapies that we classified as specific (e.g., antihistamines and decongestants for upper airway cough syndrome) are sometimes referred to as nonspecific.151 Furthermore, some other specific treatments (e.g., corticosteroids for eosinophilic bronchitis, antibiotics for chronic bronchitis) were occasionally tested as nonspecific treatments in populations that did not meet diagnostic criteria for conditions for which the specific treatment would be appropriate.

Finally, we grouped antitussive and protussive drugs into subsets that sometimes included pharmacologically diverse agents (e.g., glaucine, moguisteine) or even separate drugs with certain similarities (e.g., codeine and dextromethorphan). A physiological classification such as that used by Bolser et al.146 that classifies drugs as affecting mucociliary function, afferent limb of the cough reflex, and central mechanism for cough and efferent limb of the cough reflex, may be a better alternative; however, certain drugs that have pharmacological properties that span mechanisms still create uncertainty.

Research Gaps

Chronic cough is a common health problem that is associated with significant health complications and reduction in health-related quality of life. We found sufficient evidence to suggest that the LCQ and CQLQ (for adults) and the PC-QOL (for children) may be valid instruments for assessing severity/QOL of cough, and that electronic recording devices, in general, appear to be valid assessments of cough frequency compared with human cough counts. Unfortunately, however, the current evidence base is insufficient to provide conclusive findings related to the comparative effectiveness of available therapies for patients with unexplained or refractory chronic cough. There are, therefore, numerous areas of evidence gaps and areas for potential future research. We used the framework recommended by Robinson et al. to identify gaps in evidence and describe why these gaps exist.152 This approach considers PICOTS (population, intervention, comparator, outcomes, timing, and setting) to identify gaps and classifies gaps as due to (a) insufficient or imprecise information, (b) biased information; (c) inconsistency or unknown consistency, and (d) not the right information. Results are as follows:

KQ 1—Instruments used to assess cough:

  • Evidence establishing the responsiveness, validity, reliability, and consistency of available assessment instruments other than the LCQ and CQLQ, and building on available evidence for the LCQ and CQLQ instruments
  • Additional validation or measurement studies focusing on the pediatric population in addition to the limited studies that report on the PC-QOL
  • Development and validation of child/patient-completed, cough-specific quality-of-life instruments (as opposed to parent/proxy instruments such as the PC-QOL))
  • Feasibility of cough assessment instruments in usual care (outside of RCTs or validation studies)
    • Insufficient evidence curently exists; could be explored through observational studies
  • Uncertainty about the effects of patient self-reporting, parent reporting, or provider reporting in use of cough assessment tools
    • Insufficient evidence curently exists; could be explored through observational studies
  • Incomplete evidence regarding the minimally important difference of cough frequency or severity/QOL instruments
  • Impact of measurement tools on therapeutic efficacy or patient outcome efficacy

KQ 2—Nonspecific therapies for chronic cough:

  • Comparative effectiveness of pharmacological therapies in the adult population
    • Current evidence is both imprecise and inconsistent. Additional comparative RCTs of contemporary and available agents are needed.
  • Comparative effectiveness of pharmacological therapies in the pediatric population
    • Current evidence is insufficient and does not reflect available therapies. Comparative RCTs of contemporary and available agents specific to the pediatric population are needed.
  • Comparative effectiveness of nonpharmacological therapies in both adult and pediatric populations
    • Current evidence is insufficient. Comparative RCTs of contemporary and available agents specific in both adult and pediatric populations are needed.
    • Additional RCTs or potentially patient-level meta-analyses of existing and future RCTs focusing on subpopulations of interest including women, pregnant women, patients with specific underlying etiologies, immunocompromised patients, and patients with a history of substance abuse
  • Comparative effectiveness of available therapues in impacting health utilizationa and costs
    • Insufficient evidence curently exists; could be explored through observational studies
  • Comparative effectiveness of available therapies in impacting cough severity, frequency, and quality of life
    • Current evidence is both imprecise and inconsistent. Additional comparative RCTs using standardized instruments are needed.

For KQ 1, the primary research gaps include a paucity of validation studies for the pediatric population across all cough instruments and the lack of studies that address the feasibility of adminstration of cough measurement tools in the clinical setting or the impact of cough instruments on therapeutic or patient outcome efficacy. A major limitation to research assessing cough is that there is no consensus gold (or reference) standard. As such, many of the instruments were validated by reference standards that may be insufficient or have not themselves been validated to measure cough. As a result, we suggest that future cough validation studies use a common reference standard such as a validated clinical change instrument or the LCQ or CQLQ in adult populations. Based on our strength of evidence findings, electronic recording devices demonstrated high strength of evidence as an assessment of cough frequency, and as such may be appropriate reference standards for future validity research; such devices are, however, impractical for use by clinicans in real-world clinical practice.

For KQ 2, existing research examining therapies for chronic cough has a number of limitations, including variable definitions of chronic cough, diverse etiologies of cough that might respond differently to different therapies, small sample sizes, lack of power analyses, short duration of followup, lack of gold standard outcomes to assess efficacy and tolerability, and inconsistent reporting of comparative statistical analyses. Several of these limitations (e.g., diverse etiologies, lack of gold standard outcomes) may prove difficult to address. Future research recommendations, however, include:

  • Striving to employ commonly used definitions for chronic cough and report descriptive statistics on the duration of cough, as well as the etiology and pertinent comorbid conditions
  • Explicitly stating whether the aim of therapy is to treat the symptom of chronic cough or an underlying etiology; this will help clinicians understand how the study results might generalize to their individual patients
  • Using longer durations of followup (several weeks as opposed to a few hours or days)
  • Using a combination of objective cough frequency and patient-oriented outcome measures to provide the most meaningful information regarding the efficacy and effectiveness of therapies.
  • Assessing tolerability of therapies in order to improve comparisons among therapies.
  • Given the low efficacy of a number of commonly used cough therapies, stronger research designs would be traditional (parallel-group) randomized controlled trials (RCTs) or randomized crossover trials, and would include both an active comparator and a placebo. These studies should consider and report the sample size needed to detect differences in the primary outcome, and should use and report standard statistical techniques to examine for differences.

Over the past two decades there has been a marked increase in the medical literature on research of nonpharmacological interventions such as herbal remedies; dietary supplements; traditional approaches such as Ayurveda or traditional Chinese medicine; manual or energy-based interventions such as chiropractic and acupuncture; and mind-body approaches such as yoga, Tai Chi, and meditation, among others. This is especially true for clinical conditions that are characterized by symptoms such as low back pain, headache, fatigue, or gastrointestinal symptoms. Still, our systematic review of the literature identified only two studies of nonpharmacological interventions for chronic cough; one was published in 1988 and one in 2006, and neither involved complementary or alternative medical approaches that have recently garnered attention by patients, clinicians, researchers. Only one study included in our review involved such an approach.127

Specific to the evaluation of therapies for chronic cough in children, a future systematic review of studies of acute cough may be helpful. During the course of the review process, we observed more studies of acute than chronic cough in children, and we were only able to include three studies in our systematic review given our inclusion/exclusion criteria. A systematic review of the acute cough literature would be helpful in evaluating the comparative effectiveness of treatments for acute cough in children and might also provide some insight into the therapeutic options for chronic cough. It is likely, however, that our current limited findings reflect the general lack of high-quality evidence regarding medications in children.

Conclusions

Several instruments, including the LCQ, CQLQ, and the PC-QOL, show good internal consistency but variable correlation with other cough measurement tools. The lack of validated reference tests and the diverse number of instruments used among treatment evaluations also complicates comparisons across studies. We identified no evidence exploring the impact of cough assessment instruments on therapeutic efficacy or patient outcome efficacy.

A wide variety of pharmaceutical agents have been used to treat the symptom of chronic cough, including opioid, anesthetic, and nonopioid/nonanesthetic antitussives; expectorant and mucolytic protussives; antihistamines; antibiotics; inhaled corticosteroids; and inhaled anticholinergics. There were relatively few good-quality studies focusing on chronic cough using reliable outcome measurements over durations of followup pertinent to chronic cough. The opioid and certain nonopioid/nonanesthetic antitussives most frequently demonstrated efficacy for managing the symptom of chronic cough compared with placebo, but there were insufficient data to draw conclusions between therapies. Data on nonpharmacological therapies for chronic cough are extremely limited, as are data on the management of unidentified or refractory chronic cough in children.

Our systematic review highlights the clear need for further studies in patient populations with unexplained or refractory chronic cough as determined by current diagnostic and empiric treatment recommendations. Further, it shows the need for more systematic design and reporting of these studies and assessment of patient-centered outcomes.

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