February 24, 2020
Benjamin Speich, Anja Thomer, Soheila Aghlmandi, Hannah Ewald, Andreas Zeller and Lars G Hemkens
Cough is one of the most common reasons for seeking medical advice. Prolonged cough can be worrisome especially in the Philippine setting, where cough of more than 2 weeks is enough to suspect pulmonary tuberculosis. Treatment and diagnostic strategies for patients with prolonged cough are challenging, and the question of whether or not to prescribe antibiotics also frequently arises.
The American College of Chest Physicians (ACCP) defines subacute cough as cough that: ‘lasts no longer than 8 weeks; the chest radiography findings are negative ruling out pneumonia; and the cough eventually resolves, usually on its own’.
Subacute cough often follows non-specific viral infections causing protracted inflammation of the bronchial mucosa and extensive disruption of epithelial integrity without chronic underlying conditions. Although subacute cough usually improves spontaneously without treatment, a variety of treatments are proposed for alleviation but no no systematic review has evaluated all treatment options.
To provide a systematic overview of treatment options and outcomes evaluated in randomized clinical trials (RCTs).
Search strategy and inclusion criteria
Randomized Controlled Trials (RCTs) and systematic reviews from PubMed and Cochrane Library were obtained and reviewed. RCTs with a study population of age of 16y/o and above with a cough of 3- 8 weeks (subacute) and without known chronic respiratory diseases or other related diagnoses with overlapping symptoms were reviewed. Trials with slightly shorter or longer cough duration (that is a minimum of 2weeks to a maximum of 10 weeks) or with a less specific definition (no maximum duration reported) were also included.
Any drug or non-drug treatment, including traditional Western cough remedies or medicines, herbal or other natural products, and preparations with minimal processing from the European–North American region were considered (except Asian and Chinese herbal medicines).
The Six RCTs
The electronic search yielded 691publications but only 6 RCTs were considered eligible for this review which were conducted from 2000 to 2012. One of these is the study by Wang et al which had a population of 276 patients with a cough duration of 2 - 8 weeks (those experiencing the subacute type was not specified). Montelukast 10mg daily versus placebo was used as treatment. Cough specific quality of life using the LCQ score was measured at day 14 and 28. Other outcomes measured were overall cough severity, paroxysms of cough, cough cessation, cessation of exercise induced cough, further cough interventions and adverse events.
The study by Zanasi et al had a population of 92 patients with a cough duration of 3 to less than 4 weeks after upper respiratory tract infection or URTI (all categorized as subacute cough). Salbutamol 1.875 mg/0.5 ml plus ipratropium bromide 0.375 mg/0.5 ml or placebo was used as treatment. Cough severity (daytime and night- time separately) was measured at day 10 and day 20. Other outcomes measured were lung function and adverse events.
The study by Woodcock et al had a population of 91 patients with a cough duration of more than 2 weeks and less than 90 days after viral URTI (those experiencing the subacute type was not specified). NOP1 receptor agonist 100 mg twice daily versus codeine 30 mg twice daily versus placebo were used as treatment. Cough severity was measured at day 5. Other outcomes measured and obtained were cough frequency, Stanford sleepiness scores, patient diary, and adverse effects.
The study by Zolghadrasli et al had a population of 100 patients with a cough duration of more than 3 weeks (83% of those are categorized as subacute). Gelatin 5 cc (a teaspoon) given 3 times a day versus continuation of the previous antitussive medication were used as treatment. Subjective assessment of improvement and adverse events were obtained at day 3 to 5 and day 6 to 10.
The study by Ponsioen et al had a population of 135 patient with a cough duration of 3 to 8 weeks (67% of those are categorized as subacute). Five hundred microgram (μg) inhaled fluticasone propionate twice daily versus placebo was used as treatment. Daytime cough score was measured at day 14. Other outcomes measured and obtained were cough score improvement of more than 50%, perception of improvement, additional treatment required after 14 days, days off work, lung function, patient diary, and adverse events.
The study by Pornsuriyasak et al had a population of 30 patients with a cough duration of more than 3 weeks (those experiencing the subacute type was not specified). Four puffs of 100 μg budesonide twice daily versus placebo were used as treatment. Symptom score was measured at day 14 and 28 as well as lung function.
Risk of Bias Assessment
Five studies reported on cough severity scores at various time points. No treatment was associated with a clear clinically relevant improvement of cough scores. But two studies reported possible indications for beneficial treatment effects compared to placebo. Ponsioen reported a favorable effect of inhaled fluticasone. There was a statistically significant subgroup effect for smoking status (prespecified subgroup), showing an improvement only in non- smoking patients. Zanasi also reported more favorable effects with salbutamol plus ipratropium bromide. On the other hand, Pornsuriyasak found no steroidal benefits on cough outcomes at all.
Other Cough Related Outcomes
Montelukast was found to have no effect on overall cough severity, paroxysmal cough severity, the likelihood of cough cessation, and cessation of exercise- induced cough. There was also no association of treatment with a NOP1 agonist or with codeine on cough frequency when compared to placebo.
Zolghadrasli reported that there was patient’s perception of cough improvement. Ponsioen reported dichotomized success rates (>50% reduction of mean cough scores) of 80.4% (33 of 41 patients) for non-smokers treated with inhaled fluticasone versus 54% (23 of 43 patients) given placebo. The study also observed fewer requests for additional treatment after 14 days of fluticasone compared to placebo (28 of 65 patients, 43%, versus 42 of 67 patients, 63%). The same study also made a statement that after 14 days, patients perceived themselves to be ‘significantly better’ following treatment with fluticasone.
Both Ponsioen and Pornsuriyasak stated that there were no statistically significant differences in spirometric parameters (without providing specific outcome data).
Five studies reported adverse events. Across all studies and treatments, adverse events were reported for 98 of 694 analyzed patients (14% of patients across all study arms). Adverse events were typically described as rather mild symptoms (mucus production, nasal symptoms, dry mouth, chest or breast discomfort, fainting, headache, nausea, general gastrointestinal complaints, hoarseness, sore throat, and oropharyngeal candidiasis).
Ponsioen found no impact of fluticasone on days off work, nocturnal awakenings, and lower respiratory tract symptoms, but they reported lower sputum scores. Woodcock stated that there was no patient-reported impact on sleep or daytime activities but a ‘nonsignificant trend’ for higher Stanford sleepiness scores in patients who received NOP1 receptor agonist
Overall, there was no clear benefit associated with any of these treatments, even though two studies found some indications for favorable effects. One trial (Ponsioen) indicated a beneficial effect of inhaled steroids on cough recovery in the non-smoker subgroup. Potential benefit of salbutamol plus ipratropium bromide compared to placebo on cough severity scores 10 days after randomization was reported. These findings, however, were based on an analysis excluding 10% of patients with ‘increased cough’ or adverse events.
Strengths and Limitation
PubMed/ MEDLINE and the Cochrane Central Register of Controlled Trials were the only databases used. Chinese or Asian herbal medicine was not considered. The inclusion of these treatment options would have been beyond the scope of this project, which aimed to summarize the evidence for treatments that are commonly used by GPs and their patients in Europe and North America only. All RCTs except one included some patients with shorter or longer cough duration (then defined as acute or chronic cough), and did not report separate treatment effects for patients with a cough duration of 3–8 weeks. Improvement of cough severity as the most commonly assessed outcome was measured with cough scores that were different across trials.
Comparison with existing literature
These results are similar to those of a 2013 and 2014 Cochrane Review which evaluated inhaled corticosteroids for acute, subacute, and chronic cough. Both concluded that the data were too mixed to be able to draw any conclusions, and that there is insufficient evidence to recommend the routine use of inhaled corticosteroids.
Implications for Practice
This systematic review clearly emphasizes there is no beneficial treatment for subacute cough due to the limited available evidence on therapeutic options for subacute cough. However, it also shows that the symptoms diminish over time as a natural course of the self-limiting disease. Therefore, considering the problem of over treatment, spending time with the patient to explain the illness might be crucial for patient satisfaction.
Speich B. Et al. Treatments for Subacute Cough in Primary Care: Systematic Review and Meta-analyses of Randomized Clinical Trials. British Journal of General Practice: The Journal of the Royal College of General Practitioners. October 2018