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Coughing Children in Family Practice and Primary Care – A Systematic Review On Prevalence, Aetiology and Prognosis


 Background: For evidence-based decision-making general practitioners need setting specific knowledge on the pre-test probabilities of underlying diseases and a symptom’s course. We performed a systematic review on symptom evaluating studies in primary care to give evidence on the prevalence, aetiologies and prognosis of coughing children who consult primary care settings. Methods: Following a pre-defined algorithm and independent double reviewer ratings we searched MEDLINE and EMBASE. We included data from all quantitative original research articles in English, French or German assessing unselected study populations of children consulting for cough in primary care. We used the random effects model for meta-analysis in eligible subgroups if comprehensive in terms of heterogeneity. Results: We identified 14 eligible studies on prevalence, five on aetiology and one on prognosis. Prevalence estimates varied between 4.7% and 23.3% of all reasons for encounter or up to estimates of 60% when related to patients or consultations. Cough in children is more frequent than in adults with lowest prevalences in adolescents and in summer. Acute cough is mostly caused by upper respiratory tract infections (62.4%) and bronchitis (33.3%); subacute or chronic cough by recurrent respiratory tract infection (27.7%), asthma (3% in cough of all durations to 50.4% in more than 3 weeks cough), and pertussis (37.2%). Potentially serious diseases like croup, pneumonia or tuberculosis are scarce. In children with subacute and chronic cough the total duration of cough ranged from 24 to 192 days. About 62.3% of children suffering from prolonged cough are still coughing two months after the beginning of symptoms. We found strong heterogeneity across studies and only five studies with an overall low risk of bias. Conclusion: Cough is one of the most frequent reasons of encounter in primary care. Our findings on aetiologies and prognosis fit in with current guideline recommendations supporting a thoughtful wait-and-see approach in acute cough and a special awareness of asthma in chronic cough. There is a remarkable high pre-test probability of pertusssis in children with cough of more than two weeks’ duration. To develop primary-care cough guidelines symptom-evaluating studies assessing setting and age specific aetiologies and prognosis of cough are needed.


Background
Cough is a frequent reasons for encounter for both children 1,2 and adults 3 in ambulatory care. It often gives serious concern to parents 4,5 .
Especially when prolonged, cough impairs daily activities or sleep and children's and caregivers' quality of life 2,6,7 . Therefore, 30% to 40% of coughing children consult a physician 8 .
General practitioners (GPs), family physicians or paediatricians triage self-limiting, prolonged, and potential life-threatening courses. In this respect assumed or research based pre-test probabilities and prognosis drive GPs' decision making and action.
Current guideline recommendations are mainly based on secondary or tertiary care studies 9,10 , which not necessarily conform with the situation in primary care. We therefore aimed for a systematic literature review on studies evaluating the prevalence, aetiologies and prognosis of cough in children consulting primary care settings.

Methods
We performed a systematic review of symptom-evaluating studies. Methods -based on the PRISMA statement 11 and the recommendation of Donner-Banzhoff 12 et al. -were pre-speci ed in a protocol. Our working group applied the same methods on abdominal pain, tiredness, chest pain, dizziness and dyspnoea [13][14][15][16][17] .

Data sources and search strategy
We searched MEDLINE in June 2012, updated 2019, and EMBASE in January 2015, updated 2020. The reference lists of all relevant papers were screened (snowball search). Our search was limited to publications in English, French, and German. The search syntax comprised the term "cough" in all possible wordings in title/abstract OR as MeSH Term, and the term "primary care" in all possible wordings in title/abstract OR in mail address or name of the authors's institute OR as MeSH Term OR a journal representing primary care research. For the entire search syntax see Additional le 1.

Study selection and inclusion/exclusion criteria
We rst screened titles and abstracts with respect to (1) original research article, (2) primary care as study setting, and (3) reason for encounter "cough" (primary or secondary reason for consultation).
The full text publications were assessed for our inclusion criteria as above plus (4) an unselected study population regarding the likelihood of the underlying aetiology, and (5) data available on incidence, prevalence, underlying diagnoses or prognosis of cough. All criteria had to be ful lled. We excluded qualitative studies, case reports, reviews, studies without available full text, and studies recruiting in secondary or tertiary care, emergency departments/out-of-hours-services or population-based settings. No studies with patients systematically asked about cough were included. To avoid pre-selection, we did not consider studies that excluded patients with chronic diseases; studies, which recruited patients with an increased probability for a particular diagnosis or with cough being part of a required symptom combination (e.g. cough plus fever or expectoration). We only included studies on children. Reasons for exclusion were documented.
The selection process was performed by two independently working reviewers: MB/DB or MB/SS (except the search update 2019/2020). In case of disagreement, reviewers discussed their ratings or, secondly, consulted a third reviewer (AB).

Data extraction
For each publication, we extracted bibliographic information (author, publication year, title, journal), country, inclusion/exclusion criteria, de nition of cough, characteristics of physicians and practices, type of recruitment, information on study population (sample size, age, gender distribution) and study duration.
For prevalence/incidence data, we extracted the number of cough cases and the number and type of the reference study sample. For aetiology we registered all diagnostic categories with their relative and absolute frequencies, and we extracted any kind of prognostic data. We analysed all available publications of each study, and in doubt contacted the authors personally (n=7).

Assessment of methodical quality and risk of bias
Our working group developed a literature based tool for evaluation of risk of bias and clinical heterogeneity in symptom studies 12,18 . A validation study is still running. Two reviewers (KH, MB) assessed independently 16 items in four key domains (Additional le 2 a) and rated the risk of bias in patient selection, data collection/patient ow, and in diagnostic and prognostic work-up. The risk of substantial variation/clinical heterogeneity was judged.

Statistics
Proportions on prevalence/incidence and underlying aetiologies plus 95% con dence interval were calculated. Study outcomes refer to different reference parameters as denominators (e.g. consultations, reasons for encounters or patients), We grouped studies by these denominators, by duration of cough (pre-speci ed) and regional characteristics (post hoc). Aetiological and prognostic outcomes were analysed descriptively. Probability estimates and between-study-variation are visualized with forest plots. For meta-analysis, we used the random-effects model (for distribution across studies) 19 .
Study outcomes vary due to methodical (study design and bias) and clinical heterogeneity (study population, inclusion criteria, health care system, diagnostic work-up) 19 . We used χ 2 , p-value and I 2 :: A heterogeneity beyond chance is characterized by high values of χ 2 and low pvalues; the portion of variability that is not due to chance is marked by I 219 .
We used the software R (R Foundation for statistical Computing, Vienna, Austria, version 3.4.4) and RStudio V (RStudio, Inc., version 1.1.442).

Results
We identi ed 5704 records (2985 in MEDLINE and 2719 in EMBASE) after removal of duplicates plus 19 records from snowballing, 73 papers ful lled our inclusion criteria after full text screening, only 19 studies focussed on children. Of these, 14 studies provided data on the cough prevalence, ve on underlying aetiologies and one study on prognostic outcomes (see Fig. 1).

Included studies
Most studies were conducted in Europe (n=10), followed by North America (n=3), Australia (n=1), Africa (n=4), and Asia (n=1). Studies were published between 1971 and 2019. Mostly, data was assessed prospectively. The study populations consisted of 121 to 5100 patients, 188 to 92888 consultations, 1196 to 70489 reasons for encounters and 3371 episodes of care. Female patients ranged from 45% to 54%, mean age varied from 18.4 months to 9.8 years. Only three studies included children of all age groups (one study including some adults consulting paediatric o ces). Solely children <5/<6/<7 years were included in ve studies, solely children ≥5 years in two studies. Nine studies excluded children >11/>14/>15 years of age. Data was accrued by 1-209 primary care paediatricians or GPs in 1-57 paediatric or general practices. Further details on the included studies are given in Table 1.

Assessment of methodical quality and risk of bias
We found a high risk of substantial variation/clinical heterogeneity in the majority of studies (n=11), mostly because certain age groups per 1000 patients at risk (0-4 years) and 113 (female) resp. 160(male) for children aged 5-14 yeas 30 . Age subgroup analyses didn't minimize the high heterogeneity across studies. We did a subgroup analysis for regional characteristics which showed comparable estimates for consultations, reasons for encounters, and patients in Western countries (see Fig. 2).
Because only one study showed a low overall risk of bias and a low concern of clinical heterogeneity a subgrouping by quality was not possible 35 .

Aetiologies
Five studies presented prevalence data on aetiology. Except for Harnden 2006 who excluded children <5 years, the studies included all age groups. As outcomes referred to different durations of cough, we omitted meta-analysis and presented the data descriptively (see Table 2).
The most frequent aetiology is upper respiratory tract infection, followed by bronchitis in acute cough, and recurrent respiratory tract infection, asthma and pertussis in subacute and chronic cough. Estimates of frequencies are lower when related to episodes of care (Transition 37 ) compared to consultations (Krishnan 25 ), when patients may be counted more than once. There is a high prevalence of pertussis in children coughing for more than two weeks, con rmed by serological evidence 24 . In all other studies aetiologies based on GPs' working diagnoses 31,37,39 or the diagnostic work-up was unclear 25 , which is attended by a high or unclear risk of bias. No study presented with an overall low risk of bias.

Prognosis
Only one study reported prognostic outcomes.: In 18 practices in the United Kingdom, Harnden et al. recruited 179 children aged 5 to 16 years who had been coughing for 14 days or more 24 . Participants completed a daily cough diary for two weeks, then a weekly diary for its duration. The total duration of cough ranged from 24 to 192 days (median duration was 112 days/resp. 58 days for patients with a positive/resp. negative pertussis serology). After two months 62,3% of children were still coughing (positive pertussis serology: 85%, negative pertussis serology: 49%).

Summary
Our systematic review identi ed 19 eligible studies. Prevalence estimates varied widely between 12% (of reasons for encounter) and up to 45% (of patients) in Western countries. We found differential effects with lower prevalences in summer and in older children. Whereas acute cough is mostly caused by infectious diseases like upper respiratory tract infection (RTI) or bronchitis, up to every second case of subacute/chronic cough goes back on asthma. It is likely that there is a high number of unreported cases suffering from Pertussis in children with prolonged cough of at least 14 days. Potentially serious diseases like pneumonia or tuberculosis are scarce. Duration of cough varies widely, in subacute/chronic cough 62.3% of children are still coughing after two months.

Strengths and limitations
Sources of potential bias in systematic reviews are (1)  To control these factors, we performed a substantial search and stated clear inclusion and exclusion criteria. We omitted specialised paediatric journals or the term "paediatric practice" in our syntax, but we expect the misclassi cation to be low due to the comprehensive search on primary care settings including primary care paediatricians. We explicitly excluded studies from secondary/tertiary care or paediatric outpatient departments and did a double reviewer screening. Selection bias was minimized by considering only unselected study populations: In case of missing data regarding eligibility criteria we contacted study authors. Though, in some cases uncertainty remained.
We performed a strict and standardized assessment of methodical quality, clinical heterogeneity and risk of bias 12 . Given the small number of included studies, we didn't control for risk of bias across studies. Also publication bias is unlikely, since we suppose it improbable that prevalences, aetiologies or prognosis wouldn't be published.
We found substantial methodological and clinical heterogeneity across age groups, study settings, health care systems, duration of cough, outcomes and reference parameters. Furthermore, cultural variables or gate keeping in uence the threshold to consult the doctor which is why we included only studies recruiting in primary care settings. Still, age distribution in study samples may affect results: In German general practices over 50% of the study population were 15-19 years of age 35 , while in two Italian family paediatricians' o ces 61-73% of children were <6 years 21,22 . In fact, its impact seems to be low, since heterogeneity was not minimized by age related subgroups. The biggest limit to our study probably is the scarcity of high quality studies.

Comparison with existing literature
Indeed, reviews report coughing as one of the most common reasons for consultation in routine paediatric and family practice 2, 41. The majority of children experience 5 to 8 episodes of one week caught throughout the year 41 . But these studies are mostly based on secondary/tertiary care data 42,43 or population based 44 . Age in uences the development of the respiratory system in general 45 , which explains the change of prevalences over lifetime and distinctive age-related patterns 44 as shown in our study with lowest cough prevalences in studies on mainly older children (51,2% of children aged 15 to 19 years 35 ). This is in accordance with the guidelines of the American College of Chest Physicians who set the cut-off age to apply adult protocols at 14 years of age 11,46 .
The distinction between acute, subacute and chronic cough differs from that used in adults [46][47][48][49] . The US and Australian-New Zealand guidelines de ne acute cough in children to last <2 weeks, subacute cough 2-4 weeks and chronic cough >4 weeks. This is based on the natural course of upper RTI in children 9,50 differing to the one in adults (<3 weeks, 3-8 weeks and >8 weeks) 7 . Triaging patients according the duration of cough is the rst step in the diagnostic process, which is why aetiological data for both acute and chronic cough are required. Though, the categorizations in the identi ed studies differed from those suggested in the cough guidelines 24,31 .
Acute cough in children is mostly caused by upper RTI and bronchitis, which is con rmed by the current literature 2,7,51 . Its self-limiting course justi es a "wait-and-see" strategy, if no warning signs are present. This is different for chronic cough with a high prevalence of asthma and pertussis. Studies conducted in hospitals con rmed the importance of asthma in chronic cough 42,43,52 and current guidelines highlight asthma as frequent cause of disease. Our data suggest that the risk of asthma increases with the duration of cough. This explains why studies including patients with all durations of cough 27,37 show much lower rates than a sample with a minimum of a three weeks' symptom duration 31 . However, further studies are needed to provide the exact thresholds in time for clinical relevant increase of risk. The prevalence and consequently the two weeks' pre-test probability of pertussis turned out to be very high, found in a multicentre study in the UK with low rik of bias. Physicians should be aware of this.
We know from secondary care studies that acute cough caused by upper RTI lasts about 5.18 days (follow-up 6 days) in children 53 . For the primary care setting acute cough seems to resolve in half of children within one week, in 10-20% of children by three weeks 51,54 . The methodological quality of these studies is low. 51,54 . Terms like "acute cough", "acute bronchitis" or "chest infection" are often used simultaneously for different signs and symptoms 55 . Therefore, authors claim prognostic studies in primary care based on symptoms 54,55 with a su cient long follow-up period and an unselected patient population.

Conclusions
Prevalence of cough is higher in younger children than in adolescents and lowest in summer. The high prevalence of upper RTI as underlying disease and the low prevalence of potential serious illnesses justi es a "wait and see"-approach in acute cough. Evidence on prolonged cough is scarce, but the prevalence of asthma and pertussis seem to rise substantially up to every second child suffering from asthma (1in 5 from pertussis) in subacute or chronic cough. Other serious diseases like pneumonia or tuberculosis are less than 0.5%.
There is hardly any data on prognosis of cough of children. To ensure evidence-based decision-making there is a great need for further high quality studies. symptom evaluating studies on children's cough with a special focus on primary care.   1 = unless otherwise stated, aet = aetiology of the symptom cough in primary care, n.r.= not reported, pre = prevalence of the symptom cough in primary care, prog = prognosis of the symptom cough in primary care, resp.=respectively, RFE = reasons for encounter, =female, Ø=mean Table 2: Prevalences of selected aetiologies, referring to children in consultation for a cough in primary care / paediatric practices sorted by duration of cough