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Assessment and diagnosis of chronic dyspnoea: a literature review

Assessment and diagnosis of chronic dyspnoea: a literature review www.nature.com/npjpcrm REVIEW ARTICLE OPEN Assessment and diagnosis of chronic dyspnoea: a literature review 1,4✉ 2,3 1 1,4 1 1,4,5✉ Anthony Paulo Sunjaya , Nusrat Homaira , Kate Corcoran , Allison Martin , Norbert Berend and Christine Jenkins Dyspnoea or breathlessness is a common presenting symptom among patients attending primary care services. This review aimed to determine whether there are clinical tools that can be incorporated into a clinical decision support system for primary care for efficient and accurate diagnosis of causes of chronic dyspnoea. We searched MEDLINE, EMBASE and Google Scholar for all literature published between 1946 and 2020. Studies that evaluated a clinical algorithm for assessment of chronic dyspnoea in patients of any age group presenting to physicians with chronic dyspnoea were included. We identified 326 abstracts, 55 papers were reviewed, and eight included. A total 2026 patients aged between 20–80 years were included, 60% were women. The duration of dyspnoea was three weeks to 25 years. All studies undertook a stepwise or algorithmic approach to the assessment of dyspnoea. The results indicate that following history taking and physical examination, the first stage should include simply performed tests such as pulse oximetry, spirometry, and electrocardiography. If the patient remains undiagnosed, the second stage includes investigations such as chest x-ray, thyroid function tests, full blood count and NT-proBNP. In the third stage patients are referred for more advanced tests such as echocardiogram and thoracic CT. If dyspnoea remains unexplained, the fourth stage of assessment will require secondary care referral for more advanced diagnostic testing such as exercise tests. Utilising this proposed stepwise approach is expected to ascertain a cause for dyspnoea for 35% of the patients in stage 1, 83% by stage 3 and >90% of patients by stage 4. npj Primary Care Respiratory Medicine (2022) 32:10 ; https://doi.org/10.1038/s41533-022-00271-1 INTRODUCTION in a study using questionnaires and spirometry to estimate the burden of obstructive lung disease in urban and regional Australia, Dyspnoea or breathlessness is a complex symptom deriving from 29% of people who said a doctor had diagnosed COPD, interactions of physiological, psychological, social and environ- mental factors and can only be perceived “by the person emphysema or chronic bronchitis, actually had no evidence of 1,2 experiencing it” . It has many causes and may present as sudden airflow limitation . This apparent over-diagnosis was matched by onset or more sub-acutely, with many years of progressively similar levels of under-diagnosis. In this same study, the 3–5 worsening symptoms . Among this latter group, the most prevalence of shortness of breath when hurrying or climbing a common diagnoses have a respiratory or cardiac origin and slight hill was 25.2% (95% CI, 22.7–27.6%) demonstrating the high include diseases such as asthma, chronic obstructive pulmonary prevalence of dyspnoea in Australians aged over 40 years. disease (COPD) and heart failure (HF). As populations become Similarly, in Italy, it was reported that only one-third (30.7%) of more sedentary and overweight, and retirement age increases, participants with daily respiratory symptoms had undergone any dyspnoea may increase in frequency and impact productivity, lung function tests. Moreover, the prevalence of self-reported healthcare usage, independence and demand for community physician diagnosis was 1.4%, far lower than the 9.1% to 11.7% 7,8 services . prevalence based on spirometry . Environmental effects are an emerging area of interest In addition to wasted opportunity to prevent morbidity and contributing to dyspnoea. Changes to the biosphere and address lifestyle issues, inappropriate prescription of medication environment due to climate change will likely lead to an increased and expensive testing is often undertaken to exclude serious 9,10 frequency of extreme weather events such as bushfires , disease . Conversely, if accurate diagnosis and appropriate heatwaves and colder winters, all of which negatively affect management of dyspnoea could be hastened, the risk of cardiopulmonary health . Furthermore, the yet unknown long- untreated disease and comorbid illness would be reduced, and term sequelae of coronavirus disease 2019 (COVID-19) for the hence healthcare costs . More accurate, systematic evaluation millions that have been affected, are expected to further increase and management of patients with chronic breathlessness has the the burden of dyspnoea and presentations to healthcare potential to improve quality of life and reduce work absenteeism, professionals . premature retirement, healthcare costs and productivity loss. Many of the medical and lifestyle problems which contribute to This narrative review aims to provide a comprehensive overview dyspnoea are treatable. However, misdiagnosis or incorrect of validated clinical algorithms for chronic dyspnoea and to assess attribution of cause can result in suboptimal symptom control, overuse of pharmaceuticals, potentially serious side effects, and how accurate and efficient they have been in determining a excessive cost to patients and the health system . As an example, diagnosis. We undertook this review to inform the need for a 1 2 Respiratory Group, The George Institute for Global Health, Sydney, NSW, Australia. Discipline of Paediatrics, School of Women’s and Children’s Health, Faculty of Medicine, 3 4 UNSW Sydney, Sydney, NSW, Australia. Respiratory Department, Sydney Children’s Hospital, Randwick, Sydney, NSW, Australia. Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia. Department of Thoracic Medicine, Concord Hospital, Concord, Sydney, NSW 2139, Australia. email: asunjaya@georgeinstitute.org.au; christine.jenkins@sydney.edu.au Published in partnership with Primary Care Respiratory Society UK 1234567890():,; AP Sunjaya et al. validated clinical algorithm incorporated into a Clinical Decision abstracts and excluded irrelevant studies. The full-length relevant Support System (CDSS) designed for use in primary care. articles were retrieved and examined to further determine if they met inclusion criteria. Conflicts were resolved through discussion with all investigators. Data were extracted to a specifically METHODS designed form that included details on the patient cohort, clinical Inclusion and exclusion criteria algorithm and investigations utilised and accuracy of the Only full-length peer-reviewed studies (randomised controlled algorithms. Results were analysed descriptively and presented in trials, cohort, case-control, cross-sectional studies and systematic a narrative format. reviews) published in English from 1946 to November 2020 were included in this review. We excluded abstracts for which a full- length paper was not available. Study participants were patients of RESULTS any age who presented to a primary, secondary or tertiary care The initial search identified 326 abstracts with another 18 papers services with unknown causes of chronic dyspnoea (duration were extracted from the reference search of the included papers, ≥1 month). The main outcome of interest was the use and diagnostic accuracy of an algorithmic approach to the assessment after removing 10 duplicates there were 316 abstracts for initial review. C.J., N.B., N.H. and A.P.S. independently reviewed all the of dyspnoea. abstracts. Thirty-seven abstracts were included for full-text review. Another 18 papers were extracted from the reference search of Search strategy, study selection and analysis the included papers, making a total of 55 articles reviewed in full A comprehensive MEDLINE search using the MESH terms length. After further review of the full articles, eight studies were “dyspnea/laboured breath/breath short/breathlessness” and “deci- included in the final analyses. (Fig. 1) The primary reasons for sion support system, clinical/diagnosis computer-assisted/decision exclusion were that the average duration of dyspnoea was of support techniques/medical decision making” was conducted. shorter duration than one month, there was an inadequate Secondary searches were performed using EMBASE using the description of the CDSS or algorithm, the algorithm was not same keywords. Additional literature was identified by searching validated and/or there was no quantification of outcome after its the citation list of the identified articles. We also looked for use. One study (Pratter et al. ) included patients with dyspnoea relevant literature using Google Scholar. All the searched results were merged into one single Endnote Library and all duplicates from >3 weeks but reported a mean dyspnoea duration of 2.9 years (range 3 weeks to 25 years), hence it was decided to include were removed. Once duplicates were removed, the investigators (C.J., N.B., N.H. and A.P.S.) independently reviewed the title and it as part of the review. Fig. 1 Study selection flow diagram. npj Primary Care Respiratory Medicine (2022) 10 Published in partnership with Primary Care Respiratory Society UK 1234567890():,; AP Sunjaya et al. Profile of the studies and the study participants The initial evaluation provided objective evidence of a clear 18–25 diagnosis in 65% of patients, primarily identifying COPD, asthma, All eight studies included were primary studies. Patients were interstitial lung disease (ILD) or cardiomyopathy. Almost half the final recruited from general practice for only one of the eight primary diagnoses were non-respiratory. Physicians’ provisional diagnoses studies, and from tertiary care services for the other seven 18–21,23–25 following history, physical examination and chest X-ray were accurate studies . The age range of the study participants was 20 66% of the time compared with final diagnoses. Even so, this to 80 years, and 60% of the study participants were women (1234 accuracy varied, reaching an 81% accuracy when the cause was women vs 792 men). The duration of dyspnoea was 3 weeks to 25 asthma, COPD, ILD or cardiomyopathy but falling to 33% for less years (Table 1). common causes. In relation to the respiratory diagnoses, broncho- provocation challenge testing with methacholine had a 95% positive Clinical algorithms for assessment of dyspnoea predictive value and a 100% negative predictive value for the In addition to history and physical examination, 32 different types of diagnosis of asthma. A history of smoking in combination with diagnostic examinations were reported in the studies (Table 2). They spirometry was useful in assessing dyspnoea due to COPD, and in ranged from less invasive tests such as spirometry and electro- this study ,nonever-smokerhad a final diagnosis of COPD. The cardiography to bronchoscopy and open lung biopsy. Furthermore, presence of crackles on physical examination and chest roentgen- evaluation by psychiatrist, cardiologist and post-disease-specific ogram had a high positive predictive value for ILD (79%) and the therapy were included as steps in the assessment process. absence of crackles had a high negative predictive value (98%). Lung The studies found can be classified as three types—those volume measurement was not helpful in reaching a diagnosis of ILD reporting a step-wise assessment process, those advocating a in this study. CPET with measurement of gas exchange was minimum package of tests for all dyspnoea patients followed by particularly helpful in identifying dyspnoea with a psychogenic clinical judgement in the provision of testing, and another group component or if determined to be due to deconditioning. reporting the utility of cardiopulmonary exercise testing (CPET) for In another study undertaken by DePaso and colleagues in routine assessment of unexplained dyspnoea cases. patients with unexplained chronic dyspnoea, an alternative logical diagnostic approach was assessed. The assessment started with taking a targeted history and including age at onset of dyspnoea, Step-by-step assessment 20,22,23 duration, pattern and intensity and physical examination. Seventy- Three of the included studies used a three-step clinical review two patients with dyspnoea unexplained by a pulmonologist’s processtoassessdyspnoea. Allpatientsunderwent the first stage of repeat history and physical examination, chest X-ray and screening assessment which comprises history and physical exam- 20,23 spirometry made up the final study group and underwent a ination , and initial non-invasive or routine tests. If a cause of second more focused history. Those with a negative history had dyspnoea was not established in Stage 1 then patients were assessed routine biochemistry along with serum thyroxine and arterial using more specialised investigations (Stage 2). Patients for whom blood gas (ABGs) assessment at rest breathing room air. The the cause of dyspnoea was not ascertained after completion of Stage remaining patients underwent more non-invasive testing, at the 2 were then moved to Stage 3 investigations. In each proposed specialist physician’s discretion and testing stopped when a algorithm, Stage 3 included more invasive and expensive investiga- diagnosis that explained the dyspnoea was reached. This tier of tions. Apart from history and physical examination, the tests that tests included single-breath carbon monoxide diffusion capacity were commonly used for the first stage across the three studies were (DLCO), repeat spirometry, inspiratory flow-volume loop, measure- spirometry, electrocardiography, chest x-ray, thyroid function tests ment of maximal inspiratory and expiratory pressures, ventilation- and full blood count (Table 2). Echocardiogram and cardiac exercise/ perfusion lung scan, a two-dimensional echocardiogram, cardiac stress test were used commonly in Stage 2, while bronchoscopy and exercise treadmill examination, Holter monitoring, methacholine cardiac catheterisation would be undertaken in Stage 3. or exercise bronchoprovocation test, computed tomographic At the end of Stage 1, a cause for dyspnoea was ascertained for scanning of the thorax (thoracic CT), upper gastrointestinal series, 35% of the patients. Stage 1 and Stage 2 in combination 24-h oesophageal pH monitoring and CPET. diagnosed 65% of the patients with dyspnoea, and more than In this study, the diagnosis of the cause of dyspnoea was based 90% of the dyspnoea cases were diagnosed by a combination of on accepted diagnostic criteria , the attributed diseases had to be stages one, two and three. a known cause of dyspnoea, and treatment of the cause had to result in improvement in dyspnoea. Additionally, determination of Package of tests followed by clinical judgement cause was verified by a minimum 1 year follow-up period, which Two of the studies used a logical flow of investigations based on failed to reveal any additional diseases known to be associated the discretion of the study pulmonologist. The first by Pratter et al. with dyspnoea. Out of the 72 patients assessed for unexplained in 85 patients (median age 52 years) included an initial evaluation dyspnoea, the cause of dyspnoea was explained by respiratory comprised of extensive history taking, physical examination, tract diseases in 26 (36%) patients, cardiac diseases in 10 (14%), assessment of the severity of dyspnoea and chest roentgen- hyperventilation syndrome in 14 (19%), gastroesophageal reflux in ogram . Following this, more advanced investigations included 3 (4%), thyroid disease in 2 (3%), poor conditioning in 2 (3%) and spirometry, lung volume measurement, flow volume loops, renal diseases in 1 patient. The cause of dyspnoea could not be bronchial provocation, single-breath diffusing capacity, metabolic established in 14 (19%) patients. The duration and intensity of exercise test, radionuclide ventriculography and cardiac scan, 24-h dyspnoea offered no diagnostic insight. oesophageal pH monitoring and CPET. A final diagnostic decision Age at onset of <40 years had 81% positive predictive value and was made by agreement between two expert clinicians, based on 77% negative predictive value for hyperventilation or bronchial these results, which represented the “true” diagnosis. Additionally, hyperactivity assessed by methacholine bronchoprovocation tests . the degree of physiologic dysfunction demonstrated on objective In addition, age of onset <40 years with P(A-a) O ≤ 20 mmHg had testing had to be consistent with the patient’s functional 89% positive predictive value and 71% negative predictive value for limitation and could not be attributed to another disorder. hyperventilation or airways disease characterised by bronchial Response to specific treatment was not required as a diagnostic hyperreactivity. The positive predictive value and the negative criterion in those conditions for which specific therapy was predictive value reached 100% and 67% respectively when age at unavailable at the time, but for treatable responsive conditions onset of <40 years with P(A-a) O ≤ 20 mmHg was combined with such as asthma, positive treatment response was an additional intermittent dyspnoea. The authors concluded that patients with mandatory criterion. unexplained dyspnoea and symptom onset aged under 40 years, Published in partnership with Primary Care Respiratory Society UK npj Primary Care Respiratory Medicine (2022) 10 1234567890():,; AP Sunjaya et al. npj Primary Care Respiratory Medicine (2022) 10 Published in partnership with Primary Care Respiratory Society UK Table 1. Characteristics of the included study population and final diagnoses. Reference Study population Sample size Study setting Mean (SD)/ Dyspnoea Mean duration of Respiratory Cardiac Other Remain median score/severity dyspnoea in months final diagnosis final diagnosis unexplained b b b (min–max) (%) diagnosis (%) (%) age in years (%) DePaso Patients with 72 Pulmonary and critical Not Not mentioned Not mentioned 40 (54) 10 (13) 8 (11) 14 (19) et al. unexplained care unit of the clinic mentioned dyspnoea for >1 month Gumus Patients with 462 (M Outpatient 53 ± 17 Not mentioned Not mentioned 101 (22) 184 (40) 177 (38) et al. dyspnoea for 172, F 290) Department University >1 month Pulmonary Practice Unit Huang Patients with 530 (M University 57 (44–68) Not mentioned Not mentioned, 89 131 (25) 187 (35) 300 (57) et al. unexplained 174, F 356) Multidisciplinary patients (16.8%) have dyspnoea for Dyspnoea dyspnoea complaints >4 >1 month Intolerance Center years 511 days (292–1095 days) Martinez Patients with 50 (M Pulmonary and critical 55 (26–82) Not mentioned Not mentioned 17 (34) 7 (14) 24 (48) 7 (14) et al. unknown cause of 23, F 27) care unit of the clinic diagnosed dyspnoea, mean of as normal 23 months (range 3–240 months) Ocal Patients with 250 (M Pulmonary Clinic 59.4 ± 13.2 Not mentioned Not mentioned 148 (59.2) 155 (62) 42 (17) et al. unexplained 124, F 126) dyspnoea for >1 month Pedersen Patients aged 60–79 129 (M General practice 71.5 (60–79) Mean grade 2 Not mentioned 68 (53) 27 (21) 49 (38) 15 (12) et al. years with dyspnoea 40, F 89) grade ≥1 as per WHO for >1 month Pratter Patients with 85 (M University pulmonary 52 (17–86) 2.93 (BMRC 2.9 years 56 (66) 9 (10.6) 21 (25) et al. dyspnoea for at least 48, F 37) practice unit Index), 5.74 (3 weeks–25 years) 3 weeks (Mahler dyspnoea index), 2.56 (patient self- rating) Pratter Patients with 123 (M University hospital 60.2 ± 15.1 6 ± 2.3 24.5 ± 33.9 78 (53) 23 (16) 46 (31) 1 (1) et al. dyspnoea for 48, F 75) >8 weeks M male, F female. Gender proportions not reported. It must be noted that an individual can be classified as having more than one diagnosis. AP Sunjaya et al. Table 2. List of investigations used in the studies and the order in which they are utilised for assessment of dyspnoea when available. Tests Pedersen Gumus Pratter Pratter DePaso Martinez Huang Ocal 22 20 23 18 19 21 25 24 et al. et al. et al. et al. 1989 et al. et al. et al. et al. History Stage 1 Stage 1 Initial Initial Initial Initial Initial evaluation evaluation evaluation evaluation evaluation Physical examination Stage 1 Stage 1 Initial Initial Initial Initial Initial evaluation evaluation evaluation evaluation evaluation Spirometry Stage 1 Stage 1 Stage 1 Second Initial Initial Initial Second evaluation in all evaluation evaluation evaluation evaluation patients Flow volume loop As needed As needed Lung volume Stage 3 Stage 3 Stage 1 As needed Lung diffusion capacity Stage 2 Stage 2 Stage 1 As needed As needed Electrocardiogram Stage 1 Stage 1 Initial evaluation Chest X-ray Stage 3 Stage 1 Stage 1 Initial Initial Initial evaluation evaluation evaluation Sinus X-ray As needed Full blood count Stage 1 Stage 1 Serum haemoglobin Stage 2 Thyroid function test/TSH; Stage 2 Stage 1 Stage 1 Second free T4 evaluation in all patients Basic chemistries Stage 1 Second evaluation in all patients Brain natriuretic peptide Stage 1 Oxygen saturation using pulse Stage 1 oximetry Bronchial provocation test Stage 2 Stage 1 As needed As needed Echocardiogram/stress Stage 2 Stage 2 Stage 3 As needed As needed Initial Second echocardiography evaluation evaluation Cardiac MRI Stage 3 Cardiopulmonary exercise test Stage 3 Stage 2 Stage 2 As needed As needed Only Second evaluation evaluation CT angiogram Stage 3 Stage 2 Chest CT scan Stage 3 As needed Ventilation/perfusion scan Stage 2 Stage 3 As needed Bronchoscopy Stage 3 Stage 3 As needed Open lung biopsy As needed Left cardiac catheterisation Stage 3 Stage 3 Right cardiac catheterisation Stage 3 Stage 3 Arterial blood gas Stage 3 Second evaluation in all patients Scintigraphy Stage 2 As needed Thoracentesis Stage 3 Upper GI endoscopy Stage 3 Barium swallow As needed 24 h oesophageal pH probe As needed Sinus CT Stage 3 Polysomnography As needed Maximal inspiratory pressure As needed (MIP) and maximal expiratory pressure (MEP)/respiratory muscle strength Evaluation by psychiatrist Stage 2 Evaluation by cardiologist Stage 2 Response to disease-specific As needed therapy Published in partnership with Primary Care Respiratory Society UK npj Primary Care Respiratory Medicine (2022) 10 AP Sunjaya et al. with P(A-a) O < 20, were most likely to have hyperventilation or dyspnoea assessment that starts with simple and then more airway hyperresponsiveness. Therefore, the most useful, single non- expensive or invasive tests only as the initial steps fail, could invasive test when the diagnosis of dyspnoea was uncertain in a achieve an accurate diagnosis in the majority of patients . young adult, was a bronchial challenge. With the exception of Our review suggests detailed history taking, physical examina- bronchial challenge, the diagnostic value of any other single non- tion, full blood count along with spirometry, chest X-ray and invasive test was poor in this study. electrocardiogram are the most appropriate initial clinical assess- On the other hand, Ocal and colleagues in a retrospective review ments to establish a cause of dyspnoea (>30%). While history of 250 patients with chronic dyspnoea (mean age 59.4 ± 13.2 years) taking and physical examination were reported to be essential which remained unexplained following clinical evaluation (history components in all studies, no study aimed to validate a high yield and physical examination) by specialists reported the utility of approach to it which is important considering the time constraints in primary care. Even so, several expert reviews on history taking spirometry and transthoracic echocardiography. They showed that and physical examination for chronic breathlessness such as the 83% of these patients can be diagnosed as having either heart and/ 30 31 Breathing SPACE framework , IMPRESS framework and a review or lung disease using only both tests. Importantly, they showed that by Baxter et al. from the Primary Care Respiratory Society are 95 patients (38%) had a multimorbid cause of dyspnoea wherein available as references for clinical practice. they had both heart and lung disease concomitantly. Asthma and History taking and physical examination may help direct initial COPD, and diastolic heart failure were the most common lung and investigations if the clinical presentation aligns with well- heart diseases respectively. recognised clinical diagnoses; however, spirometry, full blood Another study from a multi-disciplinary dyspnoea centre count or electrocardiogram, easily arranged within a primary care reported the utility of CPET in 864 patients with chronic dyspnoea setting, can readily inform a less clear presentation. Full blood (median age 57 years). After an initial evaluation using a suite of counts can not only support elucidating the various causes of pulmonary function tests, chest imaging, electrocardiogram, anaemia but also myeloproliferative disorders and other pathol- echocardiogram and historical data, 36% of patients received a ogies. The Tefferi et al. review for interpreting and pursuing diagnosis of the underlying cause of their dyspnoea. The abnormal full blood counts provided greater depth in describing remaining 554 unexplained patients underwent a CPET examina- these various possible combinations of full blood count results tion, although complete details were available for only 530 and its potential pathologies. patients who were included in the analysis. The study reported Subsequent appropriately directed tests include an echocardio- that the underlying explanation for dyspnoea was successfully gram, thoracic CT, lung volumes and DLCO. When combined with determined in all patients post CPET. Ultimate diagnoses included other more specialised tests such as CPET, CT angiogram, ABGs pulmonary arterial hypertension, heart failure with preserved and bronchoscopy it was reported that a diagnosis can be ejection fraction, dysautonomia, oxidative (mitochondrial) myo- established in the majority of patients presenting with dyspnoea pathy and primary hyperventilation. A median time of 27 days (13 (~90–100%). We note that some of these investigations are only to 53 days) was reported to obtain this final diagnosis post referral available in secondary and tertiary care with specific use cases. to the multidisciplinary clinic which contrasted to the median of ABGs for example were used in the two studies that reported 511 days (292 to 1095 days) with dyspnoea prior to referral. them only in patients with concomitant hypoxia (oxygen saturation <95%) or utilised to measure the alveolar to arterial Potential role of CPET in assessing unexplained dyspnoea (A-a) oxygen gradient which was found to support diagnosis of One of the identified studies investigated only the role of graded, functional dyspnoea in patients aged <40 years. It is, however, comprehensive CPET in assessing the cause of unexplained worth noting that since several of these studies were published, dyspnoea (median age 55 years). Patients with dyspnoea on several tests investigations have become much more practical in exertion with no suggestive findings on routine blood examina- primary care (e.g. oxygen saturation measurements), or very tion and chest radiograph and with normal flow-volume loop, an readily accessed (e.g. thoracic CT imaging with reports). FEV > 80% predicted, FVC > 80% predicted and FEV /FVC > 0.7; 1 1 A stepwise approach to assess dyspnoea based on a summary and the ability to complete an adequate symptom-limited CPET of the general consensus from included studies, possible utility in were included in the study . In this study CPET results were primary care and their possible diagnostic yield could be found in compared with final clinical diagnosis in 50 patients. In the Fig. 2. majority of patients (n = 24) the CPET study was suggestive of As a symptom that manifests in many different diseases across poor conditioning but could not exclude a cardiac cause. Of these, respiratory, cardiovascular, musculoskeletal, mental health and 14 patients responded to exercise training and/or weight loss, 3 metabolic conditions, dyspnoea can be particularly difficult and had cardiac disease, 7 had airway hyperresponsiveness, and 4 had time consuming to assess in primary care, where it typically first psychogenic dyspnoea. In 13 patients with normal CPET results, presents. It is also low on the radar of many people and their the cause of dyspnoea was assessed as gastroesophageal reflux in health providers despite its serious impact on quality of life & 1, hyperactive airway disease in 2, psychogenic dyspnoea in 4, and wellbeing. Additionally, patients have their own explanations for no identifiable disease in 6. The authors concluded that CPET is it, often blaming themselves for lack of fitness, sedentary lifestyle, useful in identifying a cardiac or a pulmonary cause but has smoking or obesity. Nihilism and lack of vigilance on a clinician’s limited sensitivity in distinguishing cardiac cause from decondi- part can also delay diagnosis and the implementation of effective 6–8 24 tioning. Subsequent studies, however, suggest that cardiac treatment . As Ocal and colleagues had also noted, multi- disease and deconditioning can be distinguished more readily morbid causes of dyspnoea are common in practice and must be with CPET . When dyspnoea is unexplained after clinical history taken into account during evaluation. Even where the chronic and examination, lung function testing, chest X-ray and echo- heart and/or lung disease is present, dyspnoea was strongly cardiogram, CPET remains a highly informative test . associated with preventable, addressable lifestyle factors such as 34,35 physical inactivity, obesity, anxiety and depression . As presented in Fig. 2, spirometry plays one of the most DISCUSSION important roles in elucidating the cause of dyspnoea after history This literature review revealed the scarce research that has been and physical examination in practice. Although it is non-invasive undertaken to help clinicians develop an accurate and efficient and can be readily performed in primary care, many previous approach to the diagnosis of dyspnoea. The research we report studies have shown that spirometry is not routinely utilised in here has, however, demonstrated that a stepwise approach to primary care or is performed with sub-optimal technical quality npj Primary Care Respiratory Medicine (2022) 10 Published in partnership with Primary Care Respiratory Society UK AP Sunjaya et al. Fig. 2 A summary of the stepwise approach for dyspnoea assessment and the probability of elucidating the causal diagnosis based on the included studies. DLCO diffusing capacity of the lungs for carbon monoxide. 14,15 and interpretation .White andcolleaguesinanobservational that CDSS are effective at reducing these evidence-practice gaps study of spirometry in 6 general practices in the United Kingdom in various chronic conditions such as diabetes and cardiovascular 41–43 (UK) reported that 15% of spirometry test results were incomplete risk factor management , and hence could be well suited to and 40% of those complete were unacceptable by specialist assessing and diagnosing dyspnoea. standards . In a more recent validation study in the UK on the Our review is limited by the very few studies that have been validity and interpretation of spirometry recordings in primary care undertaken over a 30-year period, and in different secondary care for diagnosing COPD it was reported that while 98.6% of spirometry settings that already represent a decision that the problem is most recordings were of adequate quality according to chest physicians, likely cardiac or respiratory. Additionally, over this period, access only 72.5% of spirometry traces labelled as COPD were consistent to imaging and sophisticated testing has evolved rapidly. Ease of with obstruction .InAustralia,astudyinNew SouthWales reported access, however, can result in a battery of tests being undertaken, even lower values with only 57.8% of COPD patients diagnosed with rather than a systematic approach that maximises efficiency and no prior testing in primary care having had post-bronchodilator minimises costs. spirometry results consistent with COPD or asthma .These studies The results suggest that a simple, inexpensive and evidence- demonstrate that not only is the quality of recording a problem in based approach to dyspnoea assessment reachable to primary some sites but even when of technically adequate quality, care physicians can lead to an accurate diagnosis in most patients. interpretation may be inaccurate. This is a situation where a decision When dyspnoea remains unexplained, the results also suggest support system can help by providing support in both performing that a specialist referral for further testing can elucidate the causal the spirometry and its automated interpretation. diagnosis in almost all patients. Incorporating a validated In a randomised controlled trial on the validity of remote diagnostic algorithm into a CDSS could facilitate a “fast track” spirometry performed online via teleconference, it was reported to diagnosis and avoid unnecessary tests and consultations. If that there were no significant differences in quality found tested and implemented in primary care and linked to an between the online and conventional spirometry values evidence-based approach to management, diagnostic delays recorded . A study in Italy of 937 GPs on the use of tele- could be avoided, and patient outcomes enhanced. spirometry (diagnosis is performed by a remote specialist) demonstrated that during 2 years in over 20,000 tests, 70% of DATA AVAILABILITY patients met the criteria for good or partial cooperation and the The authors declare that all data supporting the findings of this study are available rate of tele-spirometries that could not be evaluated was low at within the paper. 9.2% . Although in both these studies there was remote real-time hospital support to guide spirometry taking and interpretation, Received: 1 February 2021; Accepted: 22 December 2021; they illustrate the potential of remote support to improve spirometry performance and interpretation in primary care. Similar systems guided by an automated CDSS system can be developed. 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Pratter, M. R., Curley, F. J., Dubois, J. & Irwin, R. S. Cause and evaluation of chronic AUTHOR CONTRIBUTIONS dyspnea in a pulmonary disease clinic. Arch. Intern. Med. 149, 2277–2282 (1989). The study was conceived by C.J., N.H. and A.P.S. The search was conducted by A.P.S. 19. DePaso, W. J., Winterbauer, R. H., Lusk, J. A., Dreis, D. F. & Springmeyer, S. C. and K.C. Abstract and full-text screening were completed by A.P.S., N.H., C.J. and N.B. Chronic dyspnea unexplained by history, physical examination, chest roentgen- Data extraction, analysis and interpretation of findings were completed by A.P.S. and ogram, and spirometry analysis of a seven-year experience. Chest 100, N.H. and subsequently reviewed by C.J. and A.M. The first draft was completed by A.P. 1293–1299 (1991). S. and N.H. and reviewed by all the authors. All authors read and approved the final 20. Gumus, A. et al. An evaluation of chronic dyspnea in a chest disease clinic. J. manuscript. Pulmon. Respir. Med. https://doi.org/10.4172/2161-105x.1000173 (2014). 21. Martinez, F. J. et al. Graded comprehensive cardiopulmonary exercise testing in the evaluation of dyspnea unexplained by routine evaluation. Chest 105, COMPETING INTERESTS 168–174 (1994). 22. Pedersen, F. et al. Evaluation of dyspnoea in a sample of elderly subjects The authors declare no competing interests. recruited from general practice. Int. J. Clin. Pract. 61, 1481–1491 (2007). 23. Pratter, M. R., Abouzgheib, W., Akers, S., Kass, J. & Bartter, T. An algorithmic approach to chronic dyspnea. Respir. Med. 105, 1014–1021 (2011). ADDITIONAL INFORMATION 24. Ocal, S. et al. The coexistence of heart and lung diseases in patients with chronic Correspondence and requests for materials should be addressed to Anthony Paulo dyspnoea that is unexplained by clinical evaluation. Erciyes Med. J. 35,63–67 Sunjaya or Christine Jenkins. (2013). 25. Huang, W. et al. Invasive cardiopulmonary exercise testing in the evaluation of Reprints and permission information is available at http://www.nature.com/ unexplained dyspnea: Insights from a multidisciplinary dyspnea center. Eur. J. reprints Prev. Cardiol. 24, 1190–1199 (2017). 26. Mahler, D. A. Evaluation of clinical methods for rating dyspnea. Chest J. 93, 580 Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims (1988). in published maps and institutional affiliations. 27. Corrà, U. et al. Role of cardiopulmonary exercise testing in clinical stratification in heart failure. A position paper from the Committee on Exercise Physiology and Training of the Heart Failure Association of the European Society of Cardiology. Eur. J. Heart Fail. 20,3–15 (2018). Open Access This article is licensed under a Creative Commons 28. Rocha, A. et al. Heart or lungs? Uncovering the causes of exercise intolerance in a Attribution 4.0 International License, which permits use, sharing, patient with chronic cardiopulmonary disease. Ann. Am. Thorac. Soc. 15, adaptation, distribution and reproduction in any medium or format, as long as you give 1096–1104 (2018). appropriate credit to the original author(s) and the source, provide a link to the Creative 29. Hawkins, N. M. et al. Heart failure and chronic obstructive pulmonary disease: Commons license, and indicate if changes were made. The images or other third party diagnostic pitfalls and epidemiology. Eur. J. Heart Fail. 11, 130–139 (2009). material in this article are included in the article’s Creative Commons license, unless 30. Hopkinson, N. S., Baxter, N. & London Respiratory, N. Breathing SPACE-a practical indicated otherwise in a credit line to the material. If material is not included in the approach to the breathless patient. NPJ Prim. Care Respir. Med. 27, 5 (2017). article’s Creative Commons license and your intended use is not permitted by statutory 31. British Thoracic Society & Primary Care Respiratory Society UK. Breathlessness regulation or exceeds the permitted use, you will need to obtain permission directly Algorithm (IMPRESS LSE Health Foundation, 2014). from the copyright holder. To view a copy of this license, visit http://creativecommons. 32. Baxter, N. & Lonergan, T. The differential diagnosis of the breathless patient. org/licenses/by/4.0/. Primary Care Respiratory Update. 21,7–11 (2020). 33. Tefferi, A., Hanson, C. A. & Inwards, D. J. How to interpret and pursue an abnormal complete blood cell count in adults. Mayo Clin. Proc. 80, 923–936 (2005). © The Author(s) 2022 npj Primary Care Respiratory Medicine (2022) 10 Published in partnership with Primary Care Respiratory Society UK http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png npj Primary Care Respiratory Medicine Springer Journals

Assessment and diagnosis of chronic dyspnoea: a literature review

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www.nature.com/npjpcrm REVIEW ARTICLE OPEN Assessment and diagnosis of chronic dyspnoea: a literature review 1,4✉ 2,3 1 1,4 1 1,4,5✉ Anthony Paulo Sunjaya , Nusrat Homaira , Kate Corcoran , Allison Martin , Norbert Berend and Christine Jenkins Dyspnoea or breathlessness is a common presenting symptom among patients attending primary care services. This review aimed to determine whether there are clinical tools that can be incorporated into a clinical decision support system for primary care for efficient and accurate diagnosis of causes of chronic dyspnoea. We searched MEDLINE, EMBASE and Google Scholar for all literature published between 1946 and 2020. Studies that evaluated a clinical algorithm for assessment of chronic dyspnoea in patients of any age group presenting to physicians with chronic dyspnoea were included. We identified 326 abstracts, 55 papers were reviewed, and eight included. A total 2026 patients aged between 20–80 years were included, 60% were women. The duration of dyspnoea was three weeks to 25 years. All studies undertook a stepwise or algorithmic approach to the assessment of dyspnoea. The results indicate that following history taking and physical examination, the first stage should include simply performed tests such as pulse oximetry, spirometry, and electrocardiography. If the patient remains undiagnosed, the second stage includes investigations such as chest x-ray, thyroid function tests, full blood count and NT-proBNP. In the third stage patients are referred for more advanced tests such as echocardiogram and thoracic CT. If dyspnoea remains unexplained, the fourth stage of assessment will require secondary care referral for more advanced diagnostic testing such as exercise tests. Utilising this proposed stepwise approach is expected to ascertain a cause for dyspnoea for 35% of the patients in stage 1, 83% by stage 3 and >90% of patients by stage 4. npj Primary Care Respiratory Medicine (2022) 32:10 ; https://doi.org/10.1038/s41533-022-00271-1 INTRODUCTION in a study using questionnaires and spirometry to estimate the burden of obstructive lung disease in urban and regional Australia, Dyspnoea or breathlessness is a complex symptom deriving from 29% of people who said a doctor had diagnosed COPD, interactions of physiological, psychological, social and environ- mental factors and can only be perceived “by the person emphysema or chronic bronchitis, actually had no evidence of 1,2 experiencing it” . It has many causes and may present as sudden airflow limitation . This apparent over-diagnosis was matched by onset or more sub-acutely, with many years of progressively similar levels of under-diagnosis. In this same study, the 3–5 worsening symptoms . Among this latter group, the most prevalence of shortness of breath when hurrying or climbing a common diagnoses have a respiratory or cardiac origin and slight hill was 25.2% (95% CI, 22.7–27.6%) demonstrating the high include diseases such as asthma, chronic obstructive pulmonary prevalence of dyspnoea in Australians aged over 40 years. disease (COPD) and heart failure (HF). As populations become Similarly, in Italy, it was reported that only one-third (30.7%) of more sedentary and overweight, and retirement age increases, participants with daily respiratory symptoms had undergone any dyspnoea may increase in frequency and impact productivity, lung function tests. Moreover, the prevalence of self-reported healthcare usage, independence and demand for community physician diagnosis was 1.4%, far lower than the 9.1% to 11.7% 7,8 services . prevalence based on spirometry . Environmental effects are an emerging area of interest In addition to wasted opportunity to prevent morbidity and contributing to dyspnoea. Changes to the biosphere and address lifestyle issues, inappropriate prescription of medication environment due to climate change will likely lead to an increased and expensive testing is often undertaken to exclude serious 9,10 frequency of extreme weather events such as bushfires , disease . Conversely, if accurate diagnosis and appropriate heatwaves and colder winters, all of which negatively affect management of dyspnoea could be hastened, the risk of cardiopulmonary health . Furthermore, the yet unknown long- untreated disease and comorbid illness would be reduced, and term sequelae of coronavirus disease 2019 (COVID-19) for the hence healthcare costs . More accurate, systematic evaluation millions that have been affected, are expected to further increase and management of patients with chronic breathlessness has the the burden of dyspnoea and presentations to healthcare potential to improve quality of life and reduce work absenteeism, professionals . premature retirement, healthcare costs and productivity loss. Many of the medical and lifestyle problems which contribute to This narrative review aims to provide a comprehensive overview dyspnoea are treatable. However, misdiagnosis or incorrect of validated clinical algorithms for chronic dyspnoea and to assess attribution of cause can result in suboptimal symptom control, overuse of pharmaceuticals, potentially serious side effects, and how accurate and efficient they have been in determining a excessive cost to patients and the health system . As an example, diagnosis. We undertook this review to inform the need for a 1 2 Respiratory Group, The George Institute for Global Health, Sydney, NSW, Australia. Discipline of Paediatrics, School of Women’s and Children’s Health, Faculty of Medicine, 3 4 UNSW Sydney, Sydney, NSW, Australia. Respiratory Department, Sydney Children’s Hospital, Randwick, Sydney, NSW, Australia. Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia. Department of Thoracic Medicine, Concord Hospital, Concord, Sydney, NSW 2139, Australia. email: asunjaya@georgeinstitute.org.au; christine.jenkins@sydney.edu.au Published in partnership with Primary Care Respiratory Society UK 1234567890():,; AP Sunjaya et al. validated clinical algorithm incorporated into a Clinical Decision abstracts and excluded irrelevant studies. The full-length relevant Support System (CDSS) designed for use in primary care. articles were retrieved and examined to further determine if they met inclusion criteria. Conflicts were resolved through discussion with all investigators. Data were extracted to a specifically METHODS designed form that included details on the patient cohort, clinical Inclusion and exclusion criteria algorithm and investigations utilised and accuracy of the Only full-length peer-reviewed studies (randomised controlled algorithms. Results were analysed descriptively and presented in trials, cohort, case-control, cross-sectional studies and systematic a narrative format. reviews) published in English from 1946 to November 2020 were included in this review. We excluded abstracts for which a full- length paper was not available. Study participants were patients of RESULTS any age who presented to a primary, secondary or tertiary care The initial search identified 326 abstracts with another 18 papers services with unknown causes of chronic dyspnoea (duration were extracted from the reference search of the included papers, ≥1 month). The main outcome of interest was the use and diagnostic accuracy of an algorithmic approach to the assessment after removing 10 duplicates there were 316 abstracts for initial review. C.J., N.B., N.H. and A.P.S. independently reviewed all the of dyspnoea. abstracts. Thirty-seven abstracts were included for full-text review. Another 18 papers were extracted from the reference search of Search strategy, study selection and analysis the included papers, making a total of 55 articles reviewed in full A comprehensive MEDLINE search using the MESH terms length. After further review of the full articles, eight studies were “dyspnea/laboured breath/breath short/breathlessness” and “deci- included in the final analyses. (Fig. 1) The primary reasons for sion support system, clinical/diagnosis computer-assisted/decision exclusion were that the average duration of dyspnoea was of support techniques/medical decision making” was conducted. shorter duration than one month, there was an inadequate Secondary searches were performed using EMBASE using the description of the CDSS or algorithm, the algorithm was not same keywords. Additional literature was identified by searching validated and/or there was no quantification of outcome after its the citation list of the identified articles. We also looked for use. One study (Pratter et al. ) included patients with dyspnoea relevant literature using Google Scholar. All the searched results were merged into one single Endnote Library and all duplicates from >3 weeks but reported a mean dyspnoea duration of 2.9 years (range 3 weeks to 25 years), hence it was decided to include were removed. Once duplicates were removed, the investigators (C.J., N.B., N.H. and A.P.S.) independently reviewed the title and it as part of the review. Fig. 1 Study selection flow diagram. npj Primary Care Respiratory Medicine (2022) 10 Published in partnership with Primary Care Respiratory Society UK 1234567890():,; AP Sunjaya et al. Profile of the studies and the study participants The initial evaluation provided objective evidence of a clear 18–25 diagnosis in 65% of patients, primarily identifying COPD, asthma, All eight studies included were primary studies. Patients were interstitial lung disease (ILD) or cardiomyopathy. Almost half the final recruited from general practice for only one of the eight primary diagnoses were non-respiratory. Physicians’ provisional diagnoses studies, and from tertiary care services for the other seven 18–21,23–25 following history, physical examination and chest X-ray were accurate studies . The age range of the study participants was 20 66% of the time compared with final diagnoses. Even so, this to 80 years, and 60% of the study participants were women (1234 accuracy varied, reaching an 81% accuracy when the cause was women vs 792 men). The duration of dyspnoea was 3 weeks to 25 asthma, COPD, ILD or cardiomyopathy but falling to 33% for less years (Table 1). common causes. In relation to the respiratory diagnoses, broncho- provocation challenge testing with methacholine had a 95% positive Clinical algorithms for assessment of dyspnoea predictive value and a 100% negative predictive value for the In addition to history and physical examination, 32 different types of diagnosis of asthma. A history of smoking in combination with diagnostic examinations were reported in the studies (Table 2). They spirometry was useful in assessing dyspnoea due to COPD, and in ranged from less invasive tests such as spirometry and electro- this study ,nonever-smokerhad a final diagnosis of COPD. The cardiography to bronchoscopy and open lung biopsy. Furthermore, presence of crackles on physical examination and chest roentgen- evaluation by psychiatrist, cardiologist and post-disease-specific ogram had a high positive predictive value for ILD (79%) and the therapy were included as steps in the assessment process. absence of crackles had a high negative predictive value (98%). Lung The studies found can be classified as three types—those volume measurement was not helpful in reaching a diagnosis of ILD reporting a step-wise assessment process, those advocating a in this study. CPET with measurement of gas exchange was minimum package of tests for all dyspnoea patients followed by particularly helpful in identifying dyspnoea with a psychogenic clinical judgement in the provision of testing, and another group component or if determined to be due to deconditioning. reporting the utility of cardiopulmonary exercise testing (CPET) for In another study undertaken by DePaso and colleagues in routine assessment of unexplained dyspnoea cases. patients with unexplained chronic dyspnoea, an alternative logical diagnostic approach was assessed. The assessment started with taking a targeted history and including age at onset of dyspnoea, Step-by-step assessment 20,22,23 duration, pattern and intensity and physical examination. Seventy- Three of the included studies used a three-step clinical review two patients with dyspnoea unexplained by a pulmonologist’s processtoassessdyspnoea. Allpatientsunderwent the first stage of repeat history and physical examination, chest X-ray and screening assessment which comprises history and physical exam- 20,23 spirometry made up the final study group and underwent a ination , and initial non-invasive or routine tests. If a cause of second more focused history. Those with a negative history had dyspnoea was not established in Stage 1 then patients were assessed routine biochemistry along with serum thyroxine and arterial using more specialised investigations (Stage 2). Patients for whom blood gas (ABGs) assessment at rest breathing room air. The the cause of dyspnoea was not ascertained after completion of Stage remaining patients underwent more non-invasive testing, at the 2 were then moved to Stage 3 investigations. In each proposed specialist physician’s discretion and testing stopped when a algorithm, Stage 3 included more invasive and expensive investiga- diagnosis that explained the dyspnoea was reached. This tier of tions. Apart from history and physical examination, the tests that tests included single-breath carbon monoxide diffusion capacity were commonly used for the first stage across the three studies were (DLCO), repeat spirometry, inspiratory flow-volume loop, measure- spirometry, electrocardiography, chest x-ray, thyroid function tests ment of maximal inspiratory and expiratory pressures, ventilation- and full blood count (Table 2). Echocardiogram and cardiac exercise/ perfusion lung scan, a two-dimensional echocardiogram, cardiac stress test were used commonly in Stage 2, while bronchoscopy and exercise treadmill examination, Holter monitoring, methacholine cardiac catheterisation would be undertaken in Stage 3. or exercise bronchoprovocation test, computed tomographic At the end of Stage 1, a cause for dyspnoea was ascertained for scanning of the thorax (thoracic CT), upper gastrointestinal series, 35% of the patients. Stage 1 and Stage 2 in combination 24-h oesophageal pH monitoring and CPET. diagnosed 65% of the patients with dyspnoea, and more than In this study, the diagnosis of the cause of dyspnoea was based 90% of the dyspnoea cases were diagnosed by a combination of on accepted diagnostic criteria , the attributed diseases had to be stages one, two and three. a known cause of dyspnoea, and treatment of the cause had to result in improvement in dyspnoea. Additionally, determination of Package of tests followed by clinical judgement cause was verified by a minimum 1 year follow-up period, which Two of the studies used a logical flow of investigations based on failed to reveal any additional diseases known to be associated the discretion of the study pulmonologist. The first by Pratter et al. with dyspnoea. Out of the 72 patients assessed for unexplained in 85 patients (median age 52 years) included an initial evaluation dyspnoea, the cause of dyspnoea was explained by respiratory comprised of extensive history taking, physical examination, tract diseases in 26 (36%) patients, cardiac diseases in 10 (14%), assessment of the severity of dyspnoea and chest roentgen- hyperventilation syndrome in 14 (19%), gastroesophageal reflux in ogram . Following this, more advanced investigations included 3 (4%), thyroid disease in 2 (3%), poor conditioning in 2 (3%) and spirometry, lung volume measurement, flow volume loops, renal diseases in 1 patient. The cause of dyspnoea could not be bronchial provocation, single-breath diffusing capacity, metabolic established in 14 (19%) patients. The duration and intensity of exercise test, radionuclide ventriculography and cardiac scan, 24-h dyspnoea offered no diagnostic insight. oesophageal pH monitoring and CPET. A final diagnostic decision Age at onset of <40 years had 81% positive predictive value and was made by agreement between two expert clinicians, based on 77% negative predictive value for hyperventilation or bronchial these results, which represented the “true” diagnosis. Additionally, hyperactivity assessed by methacholine bronchoprovocation tests . the degree of physiologic dysfunction demonstrated on objective In addition, age of onset <40 years with P(A-a) O ≤ 20 mmHg had testing had to be consistent with the patient’s functional 89% positive predictive value and 71% negative predictive value for limitation and could not be attributed to another disorder. hyperventilation or airways disease characterised by bronchial Response to specific treatment was not required as a diagnostic hyperreactivity. The positive predictive value and the negative criterion in those conditions for which specific therapy was predictive value reached 100% and 67% respectively when age at unavailable at the time, but for treatable responsive conditions onset of <40 years with P(A-a) O ≤ 20 mmHg was combined with such as asthma, positive treatment response was an additional intermittent dyspnoea. The authors concluded that patients with mandatory criterion. unexplained dyspnoea and symptom onset aged under 40 years, Published in partnership with Primary Care Respiratory Society UK npj Primary Care Respiratory Medicine (2022) 10 1234567890():,; AP Sunjaya et al. npj Primary Care Respiratory Medicine (2022) 10 Published in partnership with Primary Care Respiratory Society UK Table 1. Characteristics of the included study population and final diagnoses. Reference Study population Sample size Study setting Mean (SD)/ Dyspnoea Mean duration of Respiratory Cardiac Other Remain median score/severity dyspnoea in months final diagnosis final diagnosis unexplained b b b (min–max) (%) diagnosis (%) (%) age in years (%) DePaso Patients with 72 Pulmonary and critical Not Not mentioned Not mentioned 40 (54) 10 (13) 8 (11) 14 (19) et al. unexplained care unit of the clinic mentioned dyspnoea for >1 month Gumus Patients with 462 (M Outpatient 53 ± 17 Not mentioned Not mentioned 101 (22) 184 (40) 177 (38) et al. dyspnoea for 172, F 290) Department University >1 month Pulmonary Practice Unit Huang Patients with 530 (M University 57 (44–68) Not mentioned Not mentioned, 89 131 (25) 187 (35) 300 (57) et al. unexplained 174, F 356) Multidisciplinary patients (16.8%) have dyspnoea for Dyspnoea dyspnoea complaints >4 >1 month Intolerance Center years 511 days (292–1095 days) Martinez Patients with 50 (M Pulmonary and critical 55 (26–82) Not mentioned Not mentioned 17 (34) 7 (14) 24 (48) 7 (14) et al. unknown cause of 23, F 27) care unit of the clinic diagnosed dyspnoea, mean of as normal 23 months (range 3–240 months) Ocal Patients with 250 (M Pulmonary Clinic 59.4 ± 13.2 Not mentioned Not mentioned 148 (59.2) 155 (62) 42 (17) et al. unexplained 124, F 126) dyspnoea for >1 month Pedersen Patients aged 60–79 129 (M General practice 71.5 (60–79) Mean grade 2 Not mentioned 68 (53) 27 (21) 49 (38) 15 (12) et al. years with dyspnoea 40, F 89) grade ≥1 as per WHO for >1 month Pratter Patients with 85 (M University pulmonary 52 (17–86) 2.93 (BMRC 2.9 years 56 (66) 9 (10.6) 21 (25) et al. dyspnoea for at least 48, F 37) practice unit Index), 5.74 (3 weeks–25 years) 3 weeks (Mahler dyspnoea index), 2.56 (patient self- rating) Pratter Patients with 123 (M University hospital 60.2 ± 15.1 6 ± 2.3 24.5 ± 33.9 78 (53) 23 (16) 46 (31) 1 (1) et al. dyspnoea for 48, F 75) >8 weeks M male, F female. Gender proportions not reported. It must be noted that an individual can be classified as having more than one diagnosis. AP Sunjaya et al. Table 2. List of investigations used in the studies and the order in which they are utilised for assessment of dyspnoea when available. Tests Pedersen Gumus Pratter Pratter DePaso Martinez Huang Ocal 22 20 23 18 19 21 25 24 et al. et al. et al. et al. 1989 et al. et al. et al. et al. History Stage 1 Stage 1 Initial Initial Initial Initial Initial evaluation evaluation evaluation evaluation evaluation Physical examination Stage 1 Stage 1 Initial Initial Initial Initial Initial evaluation evaluation evaluation evaluation evaluation Spirometry Stage 1 Stage 1 Stage 1 Second Initial Initial Initial Second evaluation in all evaluation evaluation evaluation evaluation patients Flow volume loop As needed As needed Lung volume Stage 3 Stage 3 Stage 1 As needed Lung diffusion capacity Stage 2 Stage 2 Stage 1 As needed As needed Electrocardiogram Stage 1 Stage 1 Initial evaluation Chest X-ray Stage 3 Stage 1 Stage 1 Initial Initial Initial evaluation evaluation evaluation Sinus X-ray As needed Full blood count Stage 1 Stage 1 Serum haemoglobin Stage 2 Thyroid function test/TSH; Stage 2 Stage 1 Stage 1 Second free T4 evaluation in all patients Basic chemistries Stage 1 Second evaluation in all patients Brain natriuretic peptide Stage 1 Oxygen saturation using pulse Stage 1 oximetry Bronchial provocation test Stage 2 Stage 1 As needed As needed Echocardiogram/stress Stage 2 Stage 2 Stage 3 As needed As needed Initial Second echocardiography evaluation evaluation Cardiac MRI Stage 3 Cardiopulmonary exercise test Stage 3 Stage 2 Stage 2 As needed As needed Only Second evaluation evaluation CT angiogram Stage 3 Stage 2 Chest CT scan Stage 3 As needed Ventilation/perfusion scan Stage 2 Stage 3 As needed Bronchoscopy Stage 3 Stage 3 As needed Open lung biopsy As needed Left cardiac catheterisation Stage 3 Stage 3 Right cardiac catheterisation Stage 3 Stage 3 Arterial blood gas Stage 3 Second evaluation in all patients Scintigraphy Stage 2 As needed Thoracentesis Stage 3 Upper GI endoscopy Stage 3 Barium swallow As needed 24 h oesophageal pH probe As needed Sinus CT Stage 3 Polysomnography As needed Maximal inspiratory pressure As needed (MIP) and maximal expiratory pressure (MEP)/respiratory muscle strength Evaluation by psychiatrist Stage 2 Evaluation by cardiologist Stage 2 Response to disease-specific As needed therapy Published in partnership with Primary Care Respiratory Society UK npj Primary Care Respiratory Medicine (2022) 10 AP Sunjaya et al. with P(A-a) O < 20, were most likely to have hyperventilation or dyspnoea assessment that starts with simple and then more airway hyperresponsiveness. Therefore, the most useful, single non- expensive or invasive tests only as the initial steps fail, could invasive test when the diagnosis of dyspnoea was uncertain in a achieve an accurate diagnosis in the majority of patients . young adult, was a bronchial challenge. With the exception of Our review suggests detailed history taking, physical examina- bronchial challenge, the diagnostic value of any other single non- tion, full blood count along with spirometry, chest X-ray and invasive test was poor in this study. electrocardiogram are the most appropriate initial clinical assess- On the other hand, Ocal and colleagues in a retrospective review ments to establish a cause of dyspnoea (>30%). While history of 250 patients with chronic dyspnoea (mean age 59.4 ± 13.2 years) taking and physical examination were reported to be essential which remained unexplained following clinical evaluation (history components in all studies, no study aimed to validate a high yield and physical examination) by specialists reported the utility of approach to it which is important considering the time constraints in primary care. Even so, several expert reviews on history taking spirometry and transthoracic echocardiography. They showed that and physical examination for chronic breathlessness such as the 83% of these patients can be diagnosed as having either heart and/ 30 31 Breathing SPACE framework , IMPRESS framework and a review or lung disease using only both tests. Importantly, they showed that by Baxter et al. from the Primary Care Respiratory Society are 95 patients (38%) had a multimorbid cause of dyspnoea wherein available as references for clinical practice. they had both heart and lung disease concomitantly. Asthma and History taking and physical examination may help direct initial COPD, and diastolic heart failure were the most common lung and investigations if the clinical presentation aligns with well- heart diseases respectively. recognised clinical diagnoses; however, spirometry, full blood Another study from a multi-disciplinary dyspnoea centre count or electrocardiogram, easily arranged within a primary care reported the utility of CPET in 864 patients with chronic dyspnoea setting, can readily inform a less clear presentation. Full blood (median age 57 years). After an initial evaluation using a suite of counts can not only support elucidating the various causes of pulmonary function tests, chest imaging, electrocardiogram, anaemia but also myeloproliferative disorders and other pathol- echocardiogram and historical data, 36% of patients received a ogies. The Tefferi et al. review for interpreting and pursuing diagnosis of the underlying cause of their dyspnoea. The abnormal full blood counts provided greater depth in describing remaining 554 unexplained patients underwent a CPET examina- these various possible combinations of full blood count results tion, although complete details were available for only 530 and its potential pathologies. patients who were included in the analysis. The study reported Subsequent appropriately directed tests include an echocardio- that the underlying explanation for dyspnoea was successfully gram, thoracic CT, lung volumes and DLCO. When combined with determined in all patients post CPET. Ultimate diagnoses included other more specialised tests such as CPET, CT angiogram, ABGs pulmonary arterial hypertension, heart failure with preserved and bronchoscopy it was reported that a diagnosis can be ejection fraction, dysautonomia, oxidative (mitochondrial) myo- established in the majority of patients presenting with dyspnoea pathy and primary hyperventilation. A median time of 27 days (13 (~90–100%). We note that some of these investigations are only to 53 days) was reported to obtain this final diagnosis post referral available in secondary and tertiary care with specific use cases. to the multidisciplinary clinic which contrasted to the median of ABGs for example were used in the two studies that reported 511 days (292 to 1095 days) with dyspnoea prior to referral. them only in patients with concomitant hypoxia (oxygen saturation <95%) or utilised to measure the alveolar to arterial Potential role of CPET in assessing unexplained dyspnoea (A-a) oxygen gradient which was found to support diagnosis of One of the identified studies investigated only the role of graded, functional dyspnoea in patients aged <40 years. It is, however, comprehensive CPET in assessing the cause of unexplained worth noting that since several of these studies were published, dyspnoea (median age 55 years). Patients with dyspnoea on several tests investigations have become much more practical in exertion with no suggestive findings on routine blood examina- primary care (e.g. oxygen saturation measurements), or very tion and chest radiograph and with normal flow-volume loop, an readily accessed (e.g. thoracic CT imaging with reports). FEV > 80% predicted, FVC > 80% predicted and FEV /FVC > 0.7; 1 1 A stepwise approach to assess dyspnoea based on a summary and the ability to complete an adequate symptom-limited CPET of the general consensus from included studies, possible utility in were included in the study . In this study CPET results were primary care and their possible diagnostic yield could be found in compared with final clinical diagnosis in 50 patients. In the Fig. 2. majority of patients (n = 24) the CPET study was suggestive of As a symptom that manifests in many different diseases across poor conditioning but could not exclude a cardiac cause. Of these, respiratory, cardiovascular, musculoskeletal, mental health and 14 patients responded to exercise training and/or weight loss, 3 metabolic conditions, dyspnoea can be particularly difficult and had cardiac disease, 7 had airway hyperresponsiveness, and 4 had time consuming to assess in primary care, where it typically first psychogenic dyspnoea. In 13 patients with normal CPET results, presents. It is also low on the radar of many people and their the cause of dyspnoea was assessed as gastroesophageal reflux in health providers despite its serious impact on quality of life & 1, hyperactive airway disease in 2, psychogenic dyspnoea in 4, and wellbeing. Additionally, patients have their own explanations for no identifiable disease in 6. The authors concluded that CPET is it, often blaming themselves for lack of fitness, sedentary lifestyle, useful in identifying a cardiac or a pulmonary cause but has smoking or obesity. Nihilism and lack of vigilance on a clinician’s limited sensitivity in distinguishing cardiac cause from decondi- part can also delay diagnosis and the implementation of effective 6–8 24 tioning. Subsequent studies, however, suggest that cardiac treatment . As Ocal and colleagues had also noted, multi- disease and deconditioning can be distinguished more readily morbid causes of dyspnoea are common in practice and must be with CPET . When dyspnoea is unexplained after clinical history taken into account during evaluation. Even where the chronic and examination, lung function testing, chest X-ray and echo- heart and/or lung disease is present, dyspnoea was strongly cardiogram, CPET remains a highly informative test . associated with preventable, addressable lifestyle factors such as 34,35 physical inactivity, obesity, anxiety and depression . As presented in Fig. 2, spirometry plays one of the most DISCUSSION important roles in elucidating the cause of dyspnoea after history This literature review revealed the scarce research that has been and physical examination in practice. Although it is non-invasive undertaken to help clinicians develop an accurate and efficient and can be readily performed in primary care, many previous approach to the diagnosis of dyspnoea. The research we report studies have shown that spirometry is not routinely utilised in here has, however, demonstrated that a stepwise approach to primary care or is performed with sub-optimal technical quality npj Primary Care Respiratory Medicine (2022) 10 Published in partnership with Primary Care Respiratory Society UK AP Sunjaya et al. Fig. 2 A summary of the stepwise approach for dyspnoea assessment and the probability of elucidating the causal diagnosis based on the included studies. DLCO diffusing capacity of the lungs for carbon monoxide. 14,15 and interpretation .White andcolleaguesinanobservational that CDSS are effective at reducing these evidence-practice gaps study of spirometry in 6 general practices in the United Kingdom in various chronic conditions such as diabetes and cardiovascular 41–43 (UK) reported that 15% of spirometry test results were incomplete risk factor management , and hence could be well suited to and 40% of those complete were unacceptable by specialist assessing and diagnosing dyspnoea. standards . In a more recent validation study in the UK on the Our review is limited by the very few studies that have been validity and interpretation of spirometry recordings in primary care undertaken over a 30-year period, and in different secondary care for diagnosing COPD it was reported that while 98.6% of spirometry settings that already represent a decision that the problem is most recordings were of adequate quality according to chest physicians, likely cardiac or respiratory. Additionally, over this period, access only 72.5% of spirometry traces labelled as COPD were consistent to imaging and sophisticated testing has evolved rapidly. Ease of with obstruction .InAustralia,astudyinNew SouthWales reported access, however, can result in a battery of tests being undertaken, even lower values with only 57.8% of COPD patients diagnosed with rather than a systematic approach that maximises efficiency and no prior testing in primary care having had post-bronchodilator minimises costs. spirometry results consistent with COPD or asthma .These studies The results suggest that a simple, inexpensive and evidence- demonstrate that not only is the quality of recording a problem in based approach to dyspnoea assessment reachable to primary some sites but even when of technically adequate quality, care physicians can lead to an accurate diagnosis in most patients. interpretation may be inaccurate. This is a situation where a decision When dyspnoea remains unexplained, the results also suggest support system can help by providing support in both performing that a specialist referral for further testing can elucidate the causal the spirometry and its automated interpretation. diagnosis in almost all patients. Incorporating a validated In a randomised controlled trial on the validity of remote diagnostic algorithm into a CDSS could facilitate a “fast track” spirometry performed online via teleconference, it was reported to diagnosis and avoid unnecessary tests and consultations. If that there were no significant differences in quality found tested and implemented in primary care and linked to an between the online and conventional spirometry values evidence-based approach to management, diagnostic delays recorded . A study in Italy of 937 GPs on the use of tele- could be avoided, and patient outcomes enhanced. spirometry (diagnosis is performed by a remote specialist) demonstrated that during 2 years in over 20,000 tests, 70% of DATA AVAILABILITY patients met the criteria for good or partial cooperation and the The authors declare that all data supporting the findings of this study are available rate of tele-spirometries that could not be evaluated was low at within the paper. 9.2% . Although in both these studies there was remote real-time hospital support to guide spirometry taking and interpretation, Received: 1 February 2021; Accepted: 22 December 2021; they illustrate the potential of remote support to improve spirometry performance and interpretation in primary care. Similar systems guided by an automated CDSS system can be developed. 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Uncovering the causes of exercise intolerance in a Attribution 4.0 International License, which permits use, sharing, patient with chronic cardiopulmonary disease. Ann. Am. Thorac. Soc. 15, adaptation, distribution and reproduction in any medium or format, as long as you give 1096–1104 (2018). appropriate credit to the original author(s) and the source, provide a link to the Creative 29. Hawkins, N. M. et al. Heart failure and chronic obstructive pulmonary disease: Commons license, and indicate if changes were made. The images or other third party diagnostic pitfalls and epidemiology. Eur. J. Heart Fail. 11, 130–139 (2009). material in this article are included in the article’s Creative Commons license, unless 30. Hopkinson, N. S., Baxter, N. & London Respiratory, N. Breathing SPACE-a practical indicated otherwise in a credit line to the material. If material is not included in the approach to the breathless patient. NPJ Prim. Care Respir. 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