Dyspnea Due to Respiratory Causes, an Overview

Dyspnea Due to Respiratory Causes, an Overview

Summary

Dyspnea is a subjective feeling of difficulty breathing, also known as shortness of breath. It is a common symptom among patients and can be mild or severe in intensity. It can affect patients of all ages. It is caused by various respiratory, cardiovascular, psychogenic, and neuromuscular diseases. (1) To avoid morbidity and mortality associated with this presentation, it should be investigated properly and treated accordingly. This article will focus on the etiology, epidemiology, pathophysiology, evaluation, and management of dyspnea due to respiratory diseases.

Introduction

According to The American Thoracic Society, dyspnea is defined as a subjective feeling of breathing difficulty and sensations that vary in intensity which only the patient can distinctly qualify (2). It is an unusual sensation as it has no defined receptors. There is no definite area in the brain that represents this sensation (3). However, substantial evidence has proved that there are particular mechanisms and afferent pathways associated with sensations, such as effort, air hunger, and chest tightness.

As distinct sensations do not occur mostly in isolation, a combination of these pathways may result in the unpleasant sensation of dyspnea (2). It is also being emphasized here that dyspnea is a subjective feeling and can only be perceived by the patient. So, proper assessment and management also depend upon self-report (2). The sensation of dyspnea usually depends upon oxygen delivery to the patient, as oxygen is necessary for oxidative phosphorylation. Oxygen delivery is measured by the following formula (4):

Oxygen delivery= Q x (Hb x SaO2 x 1.39 + 0.003 x PaO2)

• Q is the cardiac output (amount of blood pumped by the heart in liter per minute).
• Hb is the hemoglobin concentration in the blood expressed as grams per liter.
• SaO2 is the oxygen saturation of hemoglobin expressed as a fraction.
• 1.39 is the oxygen binding capacity of hemoglobin per gram.
• 0.003 x PaO2 is the amount of oxygen dissolved in the blood in milliliters.

Epidemiology

Dyspnea is a common symptom affecting millions of people worldwide. According to population-based studies, it has a prevalence of 9%-13% in adults below 40 years of age (2). Above this age, the prevalence rises to 15%-18%, with older patients (>70 years of age) having the highest prevalence of 25%-37% (2). Also, the U.S. National Hospital Ambulatory Medical Care Survey has shown that dyspnea has a prevalence of 8.4% among 15 to 64-year-old patients presenting in emergency departments with a high mortality of 9.4% (5). It makes up to 3 to 4 million emergency department visits annually in the United States (2).

It is also important to mention that dyspnea is prevalent in many end-stage and chronic diseases. 50%-70% of cancer patients experience dyspnea, with prevalence rising to 90% in lung cancer (6). In other diseases like heart failure, end-stage renal disease (ESRD), HIV, and advanced age, dyspnea is often frequent, severe, and troublesome. The frequency and severity rise with age; up to 90% of patients have dyspnea in the last three days of life (6).

Etiology

Dyspnea is not a disease but a symptom that may arise from different diseases. These diseases can involve cardiovascular, respiratory, psychogenic, neuromuscular systems, or a combination of those. As we are discussing the respiratory causes only, these include both acute and chronic diseases as follows: (3, 7)

Acute Dyspnea

• Inhaled foreign body (especially in children).
• Acute exacerbation of chronic obstructive pulmonary disease (COPD).
• Acute exacerbation of asthma.
• Pneumonia.
• Pneumothorax.
• Pulmonary embolism.
• Laryngeal edema (as in anaphylaxis).

Chronic Dyspnea

• Chronic obstructive pulmonary disease (COPD).
• Interstitial lung disease (e.g., fibrosis, pneumoconiosis, sarcoidosis, allergic and fibrosing alveolitis).
• Chronic asthma.
• Pleural effusion.
• Lung carcinoma.

Pathophysiology

• The sensation of dyspnea is produced by multiple signal interactions with different receptors. These receptors are also responsible for normal breathing patterns and include the brain’s respiratory center, mechanoreceptors, and chemoreceptors (central and peripheral).
• The respiratory center consists of the dorsal medullary group, ventral medullary group, and pontine grouping. The dorsal medullary group controls inhalation, while the ventral medullary group controls exhalation. The pontine grouping further consists of two centers: pneumotaxic and apneustic. They control the intensity and frequency of respiration by modulating medullary signals. The pneumotaxic center decreases inhalation, while the apneustic center supports inhalation. These groups work together to make a unified response and control breathing. (8)
• Mechanoreceptors are present in respiratory airways and pulmonary vessels. They perform their function by sending sensory signals to the respiratory center about the volume of lung space. Slow-adapting stretch receptors and rapid-adapting irritant receptors are the two types of mechanoreceptors. As the name indicates, slow-adapting stretch receptors respond to “stretch” on the lungs (corresponding to the volume of air present in the lungs), while rapid-adapting irritant receptors give information about the volume of the lung as well as irritants, if present in the airway, to initiate coughing patterns. Both mechanoreceptors’ signals are carried by the vagus nerve (cranial nerve X) to the brain. (1, 3, 9)
• Central chemoreceptors work by monitoring the pH changes in the central nervous system. They have major control over the respiratory drive of a person. They are located in the ventral surface of the medulla and the retrotrapezoid nucleus. Increased or decreased carbon dioxide levels lead to pH changes in cerebrospinal fluid (CSF). These pH changes are sensed by central chemoreceptors.
• If pH becomes acidic, signals are generated by the receptors to stimulate hyperventilation which clears the excess carbon dioxide from the body and brings pH back to the normal range. Similarly, when pH is in the alkaline range, hypoventilation is stimulated, and carbon dioxide levels increase due to decreased ventilation. In this way, central chemoreceptors control the ventilation rate by responding to pH and carbon dioxide levels. (1, 3, 9)
• Peripheral chemoreceptors include both carotid and aortic bodies. The carotid bodies are present at the bifurcation of common carotid arteries, while the aortic bodies are located within the aortic arch. These receptors function to detect the partial pressure of oxygen in the arterial blood and primarily respond to hypoxemia (low oxygen levels). Hypercapnia (high levels of carbon dioxide) and acidosis (low pH) increase the sensitivity of peripheral chemoreceptors and help in functioning.
• Signals from these receptors are carried to the brain by the glossopharyngeal nerve (from carotid bodies) and the vagus nerve (from aortic bodies). They play an important role in breathing patterns. Still, in healthy people, the respiratory center is more sensitive to high carbon dioxide levels perceived by central chemoreceptors than low oxygen levels. Although, an oxygen-derived response is vital in cases of severe hypoxemia. (9)
• The respiratory centers of the medulla oblongata and pons control the normal breathing pattern. However, it is modified by peripheral and central chemoreceptors in response to oxygen levels in arterial blood and pH and carbon dioxide levels in CSF, respectively. So, these receptors and respiratory centers work in a combined manner to create a unified signal. This signal is sent to respiratory muscles and the diaphragm.

History and Associated Signs and Symptoms

Detailed history and thorough examination of the patient are necessary for evaluation. First, the involved system (cardiovascular, respiratory, neuromuscular, or psychogenic) is inferred, narrowing down the number of differentials, and the practitioner could arrive at the possible diagnoses. In the case of respiratory system involvement, the following history and examination points are essential:

• The new onset of dyspnea in children and middle age patients associated with fever and cough is usually due to lower respiratory infections (LRTI) such as pneumonia. On auscultation of the chest, new crepitations also support pneumonia. Pneumonia in elderly patients may present with less evident symptoms, such as an altered state of consciousness, and fever may be absent. New pulmonary infiltrates on chest radiograph is required for a definite diagnosis. (10) If the chest is clear on auscultation and the chest radiograph is normal, upper respiratory tract infections (URTI) should be suspected. Sore throat with fever and cough can lead to the suspicion of epiglottitis, croup, and tonsillitis. (7)
• Asthma is suspected in patients with recurrent episodes of dyspnea and signs of atopy. A detailed history is essential, including respiratory symptoms in previous episodes, triggers for exacerbation, previous treatments if any, response to treatment, and any associated family history of atopy. Bilateral Ronchi on chest auscultation is a meaningful physical sign. (11) It may also be associated with the presence of nasal polyps. Spirometry with pre and post-bronchodilator therapy is the next best option for evaluating respiratory volumes, which helps to confirm the diagnosis. (7, 11)
• Chronic obstructive pulmonary disease (COPD) is usually associated with tobacco use and smoking history. It presents mainly in case of acute exacerbation with symptoms of cough with sputum, dyspnea, and wheezing. Clinical COPD questionnaire (CCQ) and COPD assessment test (CAT) scores are also used to evaluate patients properly. (11) The chest is barrel-shaped with diminished breathing sounds. The patient usually sits in a tripod position to use accessory muscles of respiration and has pursed lip breathing. (12) Spirometry and exercise tests are used to grade the severity of the disease.
• Dyspnea with a history of blunt trauma or stab wound to the chest points towards the suspicion of pneumothorax which is further confirmed on chest radiograph. (12)
• Pleural effusion can also present with dyspnea associated with co-morbidities leading to effusion (such as heart failure, renal failure, or pneumonia). Basal crepitations with decreased breath sounds and dullness on percussion may also be present. (13)
• Dyspnea is also associated with inhaled foreign bodies, especially in children. They present with a history of inhalation, dyspnea, respiratory obstruction, wheezing, and diminished breath sounds (may be one-sided or bilateral according to the position of obstruction) on auscultation. Chest X-ray and CT-scan chest are important for determining the position, and removal is done according to the suitable approach. (14)
• Lung cancer can also present with dyspnea in advanced stages. There is no specific presentation for it. Most patients have advanced cancer stages at the time of diagnosis. The symptoms are due to the mass effect of the tumor, metastasis, and paraneoplastic syndromes. (15)
• Other respiratory diseases such as idiopathic pulmonary fibrosis, fibrosing alveolitis, and sarcoidosis may also present with dyspnea but usually a less evident presentation. Therefore, proper investigations and systemic evaluation are further needed.

Differential Diagnosis

All diseases that can present with dyspnea should be suspected and ruled out with proper evidence. These include:

• Asthma;
• Chronic obstructive pulmonary disease (COPD);
• Pneumonia;
• Inhaled foreign body (especially in children);
• Pneumothorax;
• Pleural effusion;
• Interstitial lung diseases (fibrosing alveolitis, sarcoidosis);
• Lung carcinoma.

Investigations

Investigations are important as they help to reach the final diagnosis. The selection of investigations is made according to the associated history and physical examination. The following studies are relevant to respiratory diseases:

Pneumonia

In cases of suspected pneumonia, Chest X-ray is the most important investigation. The presence of new pulmonary infiltrates, along with symptoms of fever, cough, and dyspnea, is sufficient to establish the diagnosis of pneumonia.

Chest CT scan can also be done and is more sensitive but is costly and implies more radiation exposure. Furthermore, the clinical significance of a CT scan in cases of normal chest X-ray is unclear and is not advised but only in selected cases such as pulmonary embolism. (16) Chest ultrasound can also be done and is helpful in evaluating complications (such as parapneumonic effusion, consolidation, or empyema), especially in children, but has observer variability. Complete blood count and leukocyte count are also used for assessment. Blood and sputum cultures are not routinely done as they are costly and time-consuming but may prove helpful in cases at risk for antimicrobial resistance. (17)

Pulmonary Obstructive Disease

If there is a history of recurrent episodes of dyspnea with cough and a family history of atopy, asthma should be suspected. To confirm the diagnosis, spirometry is done, which calculates lung volumes. The FEV1/FVC ratio (forced expiratory volume in one second/Forced Vital Capacity) has a value of less than 0.7, showing the obstructive nature of lung disease. Furthermore, the reversibility of FEV1 with bronchodilators confirms the diagnosis of asthma and rules out COPD. (18)

If asthma patients have a smoking history, a subacute reversibility test with systemic steroids (such as prednisolone) should be done, in addition to an acute reversibility test to eliminate any suspicion of COPD. Total eosinophil count in peripheral blood and identification of allergens by skin prick or allergen-specific IgE antibodies measurement can be made. (18)

A patient with a chronic history of dyspnea and smoking should be investigated for COPD. Pulmonary function testing (PFT) and spirometry are essential for diagnosing and assessing severity. The patient’s long history, age, and nature of the symptoms are useful to differentiate it from asthma. Chest radiography is also relevant. Chest X-ray shows hyperinflated lungs and flattening of the diaphragm. CT imaging is usually done to rule out malignancy or if planning for surgery. (19)

Pleural Disease

Pneumothorax and pleural effusion can also be diagnosed using a chest X-ray. 2.5 cm of air space in the lung field on chest X-ray is diagnostic for pneumothorax. Chest ultrasonography can also be used. (13)

In the case of patients with inhaled foreign bodies, a chest X-ray is the first investigation according to the ENT guidelines. But the investigation of choice is flexible bronchoscopy as it is more likely to locate and remove the foreign body. CT scan is also used to avoid invasive procedures. (14)

Interstitial Lung Disease and Lung Cancer

Pulmonary fibrosis and lung carcinomas are rare, and other diseases should be excluded first. To assess these diseases, imaging techniques such as CT scan can be used. Idiopathic pulmonary fibrosis shows a “ground-glass appearance” on a CT scan. In comparison, carcinoma may appear as a mass or diffuse metastatic picture. Biomarkers such as LDH can be used for follow-up cases as it is simple and sensitive. (20)

Treatment

Treatment of dyspnea should be according to the underlying cause. Each disease has its treatment approach and guidelines. The treatment options are as follows:

• Pneumonia is treated with antibiotics and antipyretics. The choice of antibiotic depends upon the severity and resistance shown by the patients. CURB-65 is the criteria that are generally used for the assessment of the severity of pneumonia.
  In children and low-severity cases, amoxicillin is usually used in the outpatient department (OPD), but resistance has developed in most areas. The next option is therapy with beta-lactam drugs and macrolides in atypical pneumonia cases. Fluoroquinolones are also an alternative. In severe cases, beta-lactams plus either a macrolide or fluoroquinolone can be used. In admitted patients, intravenous antibiotics are used, and the antibiotic of choice is a combination of piperacillin and tazobactam. (21)
• Asthma should be treated according to its severity and the patient’s condition. In cases of acute exacerbation of asthma presenting with dyspnea in the emergency department, systemic steroids, and inhaled beta-agonists are used.
  Once the acute phase is over, maintenance therapy can be started. This includes inhaled and systemic corticosteroids, inhaled beta-agonists (both short-acting and long-acting), and inhaled muscarinic antagonists. The choice of drugs can range from inhaled corticosteroids (ICS) and short-acting beta-agonists (SABA) to systemic corticosteroids with long-acting beta-agonists (LABA) with or without muscarinic antagonists depending on the severity. The goal of this therapy should be good control of asthma while avoiding any exacerbations and with the minimum number of drugs at their lowest dose possible. (18, 22)
• COPD is also presented in the emergency department in case of acute exacerbation. The treatment for COPD depends upon the availability of medications, severity, patient preferences, and response. The steps include inhaled corticosteroids (ICS), long-acting beta-agonists (LABA), and long-acting muscarinic antagonists (LAMA). In case of a severe acute episode, intravenous and systemic medications can also be used.
  Antibiotics are also used to treat any underlying infectious disease. (23) The role of healthy exercise is also important as it helps prevent exacerbations and improve patients’ overall response. (23, 24) According to the German Society for Pneumology and Respiratory Medicine, NIV (non-invasive ventilation) is recommended in cases of acute respiratory failure as it improves respiratory function and symptoms measured by respiratory rate, blood gases and dyspnea improvement. But more evidence is required on this approach. (24)
• Pneumothorax can be treated in emergency settings by needle decompression and thoracostomy tube insertion, relieving dyspnea and other respiratory symptoms of the patient. (13) Surgical pleurodesis can also be done and is recommended in recurrent pleural effusion and pneumothorax cases. (25)
• In the case of inhaled foreign body, bronchoscopy is the treatment of choice for removal. Both flexible and rigid bronchoscopy can be done, but rigid bronchoscopy is considered to have more use compared to the flexible type. A rigid bronchoscope allows the ability to ventilate, provides improved visualization, and can accommodate various sizes of optical and suctioning forceps. First, the position of a foreign body is determined, and then it is removed by bronchoscopy. (26)
• Interstitial diseases such as idiopathic pulmonary fibrosis (IPF), fibrosing alveolitis, cystic fibrosis, and sarcoidosis should be treated accordingly. The treatment for acute exacerbation of IPF, as recommended by Japanese IPF treatment guidelines, includes systemic corticosteroids with pulse therapy.
  Appropriate titration of steroid dosage is required as therapy may be complicated by opportunistic infections. Once the acute phase is over, maintenance therapy with immunosuppressants such as intravenous cyclophosphamide can be initiated. The patient should be counseled about compliance with therapy and the prognosis of the disease. (20)
• Lung carcinomas should be entirely investigated before starting any treatment. The type of carcinoma is determined, and staging and grading are done. The treatment depends upon the stage of carcinoma. Surgery, chemotherapy, and radiotherapy are the treatment options, and palliative care is given. (27)

Complications

• Dyspnea itself could be harmless and may resolve in most cases without any complications. It also depends upon the underlying disease.
• Acute exacerbations of asthma and COPD usually resolves with no complications, but frequent episodes of acute exacerbation may prove dangerous.
• Pneumonia usually resolves with appropriate antibiotic coverage in most cases. But it may lead to complications such as parapneumonic effusion, empyema, or lung abscess.
• Inhaled foreign bodies may cause complete obstruction and hypoxia.
• Interstitial diseases and lung carcinoma usually have associated complications at the time of presentation (such as fibrosis, lung collapse, or even respiratory failure) and should be given proper attention. (7, 11, 16, 18, 20)

Prognosis

The prognosis of dyspnea also depends upon the underlying diseases. Most acute presentations have a good prognosis.

• Pneumonia resolves with proper antibiotic treatment without any complications in most cases.
• Pneumothorax is usually benign and resolves with treatment. But there are chances of its recurrence. Pneumothorax in patients with COPD and HIV can prove to be lethal.
• Acute exacerbations of asthma and COPD respond well to treatment, but long-term medication and lifestyle modification are necessary to avoid future episodes.
• Interstitial lung diseases and carcinomas are usually associated with complications at the time of presentation and have a poor prognosis. (11, 16, 18, 20)

Disclosures

The author does not report any conflict of interest.

Disclaimer

This information is for educational purposes and is not intended to treat disease or supplant professional medical judgment. Physicians should follow local policy regarding the diagnosis and management of medical conditions.

See Also

Approach to Chest Pain

Acute Asthma Exacerbation

Lower Urinary Tract Infections

Acute Diarrhea in Adults

Acute Otitis

Acute Upper Respiratory Tract Infections

References

1. Sharma S, Hashmi MF, Badireddy M. Dyspnea on Exertion. 2022 Aug 18. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 29763022.
2. Parshall, M. B., Schwartzstein, R. M., Adams, L., Banzett, R. B., Manning, H. L., Bourbeau, J., Calverley, P. M., Gift, A. G., Harver, A., Lareau, S. C., Mahler, D. A., Meek, P. M., & O’Donnell, D. E. (2012b). An Official American Thoracic Society Statement: Update on the Mechanisms, Assessment, and Management of Dyspnea. American Journal of Respiratory and Critical Care Medicine, 185(4), 435–452. https://doi.org/10.1164/rccm.201111-2042st
3. Boon, N. A., Colledge, N. R., Walker, B. R., & Hunter, J. (2023). Davidson’s Principles and Practice of Medicine: with Online access + Interactive extras (Internation (20th ed.). Churchill Livingstone Elsevier.
4. Walsh, Brian & Smallwood, Craig. (2017). Pediatric Oxygen Therapy: A Review and Update. Respiratory Care. 62. 645-661. 10.4187/respcare.05245.
5. Viniol A, Beidatsch D, Frese T, Bergmann M, Grevenrath P, Schmidt L, Schwarm S, Haasenritter J, Bösner S, Becker A. Studies of the symptom dyspnoea: a systematic review. BMC Fam Pract. 2015 Oct 24;16:152. doi: 10.1186/s12875-015-0373-z. PMID: 26498502; PMCID: PMC4619993.
6. Baker Rogers J, Modi P, Minteer JF. Dyspnea in Palliative Care. 2022 May 1. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 30252378.
7. Hashmi MF, Modi P, Basit H, Sharma S. Dyspnea. 2022 Aug 18. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 29763140.
8. Alheid GF, McCrimmon DR. The chemical neuroanatomy of breathing. Respir Physiol Neurobiol. 2008 Dec 10;164(1-2):3-11. doi: 10.1016/j.resp.2008.07.014. PMID: 18706532; PMCID: PMC2701569.
9. Brinkman JE, Toro F, Sharma S. Physiology, Respiratory Drive. 2022 Jun 8. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 29494021.
10. Eshwara VK, Mukhopadhyay C, Rello J. Community-acquired bacterial pneumonia in adults: An update. Indian J Med Res. 2020 Apr;151(4):287-302. doi: 10.4103/ijmr.IJMR_1678_19. PMID: 32461392; PMCID: PMC7371062.
11. Jones PW, Watz H, Wouters EF, Cazzola M. COPD: the patient perspective. Int J Chron Obstruct Pulmon Dis. 2016 Feb 19;11 Spec Iss(Spec Iss):13-20. doi: 10.2147/COPD.S85977. PMID: 26937186; PMCID: PMC4764028.
12. Budhwar N, Syed Z. Chronic Dyspnea: Diagnosis and Evaluation. Am Fam Physician. 2020 May 1;101(9):542-548. PMID: 32352727.
13. McKnight CL, Burns B. Pneumothorax. 2022 Nov 26. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 28722915.
14. Mohsen F, Bakkar B, Melhem S, Altom R, Sawaf B, Alkhija I, Nahas LD. Foreign body aspiration in a tertiary Syrian centre: A 7-year retrospective study. Heliyon. 2021 Mar 17;7(3):e06537. doi: 10.1016/j.heliyon.2021.e06537. PMID: 33817384; PMCID: PMC8010408.
15. Siddiqui F, Vaqar S, Siddiqui AH. Lung Cancer. 2022 Dec 5. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 29493979.
16. Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, Dowell SF, File TM Jr, Musher DM, Niederman MS, Torres A, Whitney CG; Infectious Diseases Society of America; American Thoracic Society. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007 Mar 1;44 Suppl 2(Suppl 2):S27-72. doi: 10.1086/511159. PMID: 17278083; PMCID: PMC7107997.
17. Smith DK, Kuckel DP, Recidoro AM. Community-Acquired Pneumonia in Children: Rapid Evidence Review. Am Fam Physician. 2021 Dec 1;104(6):618-625. PMID: 34913645.
18. Lommatzsch M, Virchow JC. Severe asthma: definition, diagnosis and treatment. Dtsch Arztebl Int. 2014 Dec 12;111(50):847-55. doi: 10.3238/arztebl.2014.0847. PMID: 25585581; PMCID: PMC4357024.
19. Agarwal AK, Raja A, Brown BD. Chronic Obstructive Pulmonary Disease. 2022 Aug 8. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 32644707.
20. Kishaba T. Acute Exacerbation of Idiopathic Pulmonary Fibrosis. Medicina (Kaunas). 2019 Mar 16;55(3):70. doi: 10.3390/medicina55030070. PMID: 30884853; PMCID: PMC6473875.
21. Chou CC, Shen CF, Chen SJ, Chen HM, Wang YC, Chang WS, Chang YT, Chen WY, Huang CY, Kuo CC, Li MC, Lin JF, Lin SP, Ting SW, Weng TC, Wu PS, Wu UI, Lin PC, Lee SS, Chen YS, Liu YC, Chuang YC, Yu CJ, Huang LM, Lin MC; Infectious Diseases Society of Taiwan;; Taiwan Society of Pulmonary and Critical Care Medicine,; Medical Foundation in Memory of Dr. Deh-Lin Cheng;; Foundation of Professor Wei-Chuan Hsieh for Infectious Diseases Research and Education;; CY Lee’s Research Foundation for Pediatric Infectious Diseases and Vaccines,; 4th Guidelines Recommendations for Evidence-based Antimicrobial agents use in Taiwan (GREAT) working group. Recommendations and guidelines for the treatment of pneumonia in Taiwan. J Microbiol Immunol Infect. 2019 Feb;52(1):172-199. doi: 10.1016/j.jmii.2018.11.004. Epub 2018 Dec 6. PMID: 30612923.
22. Lommatzsch M, Buhl R, Korn S. The Treatment of Mild and Moderate Asthma in Adults. Dtsch Arztebl Int. 2020 Jun 19;117(25):434-444. doi: 10.3238/arztebl.2020.0434. PMID: 32885783; PMCID: PMC7490458.
23. Vogelmeier CF, Román-Rodríguez M, Singh D, Han MK, Rodríguez-Roisin R, Ferguson GT. Goals of COPD treatment: Focus on symptoms and exacerbations. Respir Med. 2020 May;166:105938. doi: 10.1016/j.rmed.2020.105938. Epub 2020 Mar 21. PMID: 32250871.
24. Lorenz J, Bals R, Dreher M, Jany B, Koczulla R, Pfeifer M, Randerath W, Steinkamp G, Taube C, Watz H, Windisch W. Expertentreffen COPD: Exazerbation der COPD [Exacerbation of COPD]. Pneumologie. 2017 May;71(5):269-289. German. doi: 10.1055/s-0043-106559. Epub 2017 May 15. PMID: 28505687.
25. Mendogni P, Vannucci J, Ghisalberti M, Anile M, Aramini B, Congedo MT, Nosotti M, Bertolaccini L; Collaborators of the Pneumothorax Working Group, on behalf of the Italian Society for Thoracic Surgery (endorsed by the Italian Ministry of Health) Collaborators of the Pneumothorax Working Group; D’Ambrosio AE, De Vico A, Guerrera F, Imbriglio G, Pardolesi A, Schiavon M, Russo E. Epidemiology and management of primary spontaneous pneumothorax: a systematic review. Interact Cardiovasc Thorac Surg. 2020 Mar 1;30(3):337-345. doi: 10.1093/icvts/ivz290. PMID: 31858124.
26. Cramer N, Jabbour N, Tavarez MM, Taylor RS. Foreign Body Aspiration. 2022 Aug 1. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 30285375.
27. Siddiqui F, Vaqar S, Siddiqui AH. Lung Cancer. 2022 Dec 5. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 29493979.