An Overview of Lung Cancer

Lung CancerLung Cancer
Written by: M. Daniyal Haider
Dr. Muhammad Daniyal Haider is a general physician who continuously seeks for platforms to serve the community and utilize his knowledge and abilities to improve the health system. Dedication to the cure of diseases and, more importantly, prevention and awareness of people about these diseases is the goal. He is a general physician, author and a calligrapher. He is passionate about research projects, latest guidelines and techniques which can lead to a better approach to the patient’s condition.
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Summary

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Lung cancer is the second most commonly diagnosed cancer worldwide. It is associated with high mortality since it is commonly diagnosed in late stages.

Lung cancer is associated with genetic and environmental risk factors. Among the latter, tobacco exposure is a significant one, considering the wide use of tobacco smoking.

Diagnosis includes clinical parameters, diagnostic imaging (staging), and histopathology with immunohistochemistry (grading) obtained by different invasive procedures.

Treatment strategies include surgery, chemotherapy, immunotherapy, and Radiotherapy.

Introduction to An Overview of Lung Cancer

Lung cancer is a tumor that originates in the lung parenchyma or within the lining of the airways of the lung. It is the most common cause of cancer-related deaths worldwide, leading to 1.4 million deaths annually (1). In the United States, approximately 236,740 new cases of lung cancer are reported annually, and 130,180 people die due to this disease (2).

Tobacco use is considered the most significant and preventable cause of lung cancer. Unfortunately, over the past few decades, the use of tobacco has increased drastically both in men and women, leading to a concurrent increase in lung cancer patients and deaths. It should be mentioned here that lung cancer was a relatively rare diagnosis at the beginning of the 20th century, and now, it has become the second most commonly diagnosed cancer and the leading cause of cancer-related deaths. In contrast to other malignancies, the prognosis of lung carcinoma is poor as the 5-year survival rate in this disease varies from 4-17% depending upon the stage of carcinoma at the time of diagnosis and regional differences. (3)

Epidemiology of Lung Cancer

Lung cancer is the second most common malignancy in both males (after prostate cancer) and females (after breast cancer), accounting for 12.4% of all cancers worldwide (3). In the United States, the incidence rate of this disease is 71.3 per 100,000 patients in males and 52.3 per 100,000 patients in females (4). 

Lung cancer is one of the leading causes of death worldwide, reaching 1.4 million deaths annually (1, 5). The highest age-standardized incidence rates of lung cancer per 100,000 is seen in Micronesia and Polynesia, followed by Eastern Europe and Eastern Asia. In Africa, however, the incidence rates tend to remain low as compared to other regions. On the other hand, China shows high incidence rates, especially among females, despite less use of tobacco. This is considered to be due to the high prevalence of exposure to smoke caused by the burning of charcoal which is used in cooking and heating, leading to damage to the lung parenchyma. (5)

Etiology of Lung Cancer

Several factors play a role in the development of lung cancer. The intensity and duration of exposure are also important in determining the patient’s susceptibility and the prognosis of the disease. These risk factors are as follows:

Tobacco Smoking

Smoking is the most significant and preventable cause of all histological types of lung cancer. The carcinogenic effect of tobacco smoke on lung tissue has been shown by several studies. The causative effect of tobacco smoking is also justified by geographic distribution and temporal patterns of the disease. African-Americans have a higher rate of lung cancer compared to ethnic groups in the United States due to higher tobacco use. Meanwhile, a lower rate of the disease in Chinese and Japanese people is due to less tobacco smoking and the relatively recent introduction of regular and heavy tobacco smoking. However, the composition of tobacco products and genetic variations may also contribute to these differences. (6)

The duration of smoking is also a strong determinant of the risk of cancer development in smokers. The relative risk of lung carcinoma in continuous smokers is 20 to 50-fold when compared with never-smokers. On the other hand, there is a gradual fall in relative risk after smoking cessation, even later in life. But it will remain higher compared to the people who never smoked in their lifetime. (7)

Previously, it was also considered that the relative risk of lung cancer due to smoking is higher in females as compared to males, and females were considered more susceptible to carcinoma development. It was also backed by several studies, but recent research has shown similar risks in both males and females. However, these studies have certain limitations, and more evidence is needed. (8)

Genetic Factors and Family History

Studies have shown that patients with a positive family history of lung carcinoma are always at a higher risk despite careful adjustment for smoking. Chromosome 6q23-25 is found to be the major locus in genetic predisposition (9). That is why a patient with a positive family history should take all the preventive measures and should undergo regular screening and checkups.

History of Chronic Inflammatory Diseases

The risk of lung cancer development also increases with a positive history of chronic inflammatory conditions and infections. Chronic obstructive pulmonary disease (COPD) is associated with an increased risk of lung cancer (9). A relative risk of 1.8 for lung cancer is seen in patients with asthma, even in never-smokers, as seen in meta-analysis studies of lung cancer (10). A study on tuberculosis patients in Shanghai, China, has also shown the increased relative risk (1.5-2.0) of lung cancer along with the correlation of tuberculosis lesions (11). These are important while evaluating the risk and prognosis in patients and should be kept in mind.

Occupational Exposure

Asbestos, silica, radon, and polyacrylic hydrocarbon exposure can also contribute to the development of lung cancer.

Asbestos has been associated with lung cancer in all forms and affects the patient in a dose-dependent manner. Sailors are the most affected group due to the use of asbestos in ship construction. Due to this, a permissible exposure limit (PEL) has also been advised to prevent carcinoma and lung diseases among workers. (12, 13)

Radon exposure is also associated with lung cancer. It is especially prevalent in uranium miners. The effect of radon may be small but is significant. Even in homes, radon may also be produced automatically by the decay of radium and uranium. It is thought to be the cause of 2% of all deaths from lung cancer in Europe. (14, 15)

Silicosis can be caused by inhalation of silica dust and is usually prevalent in people working in the ceramics industry, earth mining, stone cutting, and bricklayers. Increased risk of lung cancer was reported in these people by some studies, but not much evidence is present. (16)

Polycyclic aromatic hydrocarbon exposure is an important factor as it has both occupational and non-occupational effects. Diesel engine exhausts, automobile exhausts, coal industries, tar distillation, roofing, and chimney exhaust are the major source of polycyclic aromatic hydrocarbon pollution and may lead to an increased risk of lung cancer in workers. (9, 17)

Pathophysiology

The mechanism of lung cancer development is complex and is not completely understood. One of the hypotheses is that continuous exposure of the lungs to inflammatory substances and carcinogens (for example, tobacco smoke or asbestos) causes dysplasia of the epithelium of the lung. Moreover, it may also result in genetic mutations, changes in DNA repair mechanisms, and defective protein synthesis. This may affect the cell cycle and promote carcinogenesis due to impaired DNA repair mechanisms. As the process continues, the defective cells may enter a vicious cycle leading to an increase in the number of malignant cells resulting in lung carcinoma. Common mutations that are responsible for lung carcinoma include RB1 tumor suppressor gene, MYC, BCL2, and TP53 (p53) for small cell lung cancer (SCLC) and KRAS, p16, and EGFR for non-small cell lung cancer (NSCLC). (18, 19, 20)

Lung cancer can be classified based on histopathology and is also essential in the diagnosis and management of lung cancer. According to World Health Organization (WHO) classification system for lung tumors, the following subtypes are described: (18)

  • Squamous cell carcinomas (35%);
  • Adenocarcinomas (30%);
  • Small cell carcinoma (20%);
  • Large cell carcinomas (15%).
  • Adenosquamous carcinomas;
  • Squamous precursor lesions;
  • Precursor glandular lesions;
  • Sarcomatoid carcinomas;
  • Salivary gland-type tumors;
  • Neuroendocrine carcinomas;
  • And other epithelial tumors.

Squamous Cell Carcinoma

Squamous cell carcinoma is characterized by the production of keratin by tumor cells, and intercellular desmosomes may also be present in cytology. Immunohistochemistry (IHC) can also be done for diagnosis, which shows expression of CK5, CK5/6, p40, p63, or desmoglein. Squamous cell carcinoma exhibits central necrosis leading to cavitation. Squamous cell carcinoma can be further divided into subtypes as keratinizing, non-keratinizing, and basaloid. (18, 20)

Adenocarcinoma

This type consists of either neoplastic gland formation, intracytoplasmic mucin, or pneumocyte marker expression, i.e., thyroid transcription factor 1 (TTF-1), either with or without the expression of napsin. It can be either mucinous or non-mucinous (further divided into acinar, lepidic, solid, papillary, and micropapillary) based on the neoplastic gland formation architecture and extent. These subtypes are important as they may affect the prognosis of the disease. (18, 20)

Small Cell Carcinoma

Small cell carcinoma (SCLC) consists of round or oval-shaped cells having a size almost that of a lymphocyte. A small amount of cytoplasm is seen, while no distinct nucleoli can be appreciated. Small cell carcinomas are highly necrotic and usually have a positive stain for synaptophysin and chromogranin. RB1 and TP53 (17p13) tumor suppressor genes are involved in the mutations leading to SCLC. SCLC usually involves shortened arm of chromosome 3p containing the FHIT tumor suppressor gene. (18, 19)

Large Cell Carcinoma

Large cell carcinoma (LCC) is mostly diagnosed on exclusion criteria as it does not have characteristic features. It is poorly differentiated and may demonstrate features of glandular or neuroendocrine differentiation but are not consistent enough to be diagnosed as glandular, squamous, or neuroendocrine cancers. Markers such as p40 and TTF-1 are not expressed in immunohistochemistry. Cells are large, round to polygonal in shape with abundant cytoplasm and lack any defining features. (18, 20)

History and Clinical Features

History should include all the risk factors evaluation, duration of symptoms, any previous history of lung disease, and family history. It is especially important in patients with their second or third visit for the same complaints that are not being relieved by medications. It also gives an insight to the clinician to consider lung carcinoma as a differential diagnosis along with other possibilities.

Lung cancer does not exhibit any characteristic signs and symptoms. Usually, the patient remains asymptomatic for a long period and becomes symptomatic at an advanced stage when most lung carcinomas are diagnosed. Symptoms of lung cancer are caused by four main mechanisms. It can be due to the primary tumor, the intrathoracic spread of the tumor, distant metastases, and associated paraneoplastic syndromes. (18, 21)

Symptoms Due to the Primary Tumor

Cough, hemoptysis, chest pain, dyspnea, and dysphagia are the symptoms that are mainly caused by the primary tumor. These usually manifest due to the mass effect of the primary tumor or when the bronchus or esophagus is being pushed by the tumor. The frequency of these symptoms is as follows: (18)

Cough50-75%
Dyspnea25-40%
Chest pain20-40%
Hemoptysis15-30%

Symptoms Due to Intra-thoracic Spread

Lung cancer may spread to intra-thoracic regions and manifest different conditions such as pleural effusion, Horner syndrome, and superior vena cava obstruction.

Pleural effusion is usually present in 10 to 15% of patients during the course of the disease. It can be unilateral or bilateral. Bronchogenic carcinoma with ipsilateral malignant pleural effusion is challenging for the clinician as, in this case, the tumor is unresectable. That is why cytology is recommended to check the malignant potential of pleural effusion before surgery, and surgical thoracoscopy or medical pleuroscopy is also done before resectioning the primary tumor. (22, 23, 24)

Lung cancer, especially Pancoast tumor, can also damage the nervous bundle due to compression and present as Horner syndrome or Villaret syndrome. Horner syndrome is caused by compression of the thoracic sympathetic nervous ganglion and may present with symptoms of ptosis, miosis, enophthalmos, and anhydrosis. While Villaret syndrome is caused by affection of the last four cranial nerves; glossopharyngeal (IX), vagus (X), accessory (XI), and hypoglossal (XII) nerve, and may also be associated with ipsilateral Horner syndrome. (25, 26)

Superior vena cava obstruction is also a manifestation of the intra-thoracic spread of lung cancer. It presents as dilated neck veins and edema of the upper extremities, face, and neck, along with dyspnea and cough. It is also more common in Pancoast tumors and might be the primary presentation of the disease. (27)

Symptoms Due to Distant Metastases

Lung carcinoma can metastasize to different organs such as the brain, bones, liver, and adrenals. Each of these presents with its own set of symptoms which are as follows: (21)

Site of metastasisSymptoms
BrainHeadache, seizures, nausea, and vomiting, focal neurological signs
BonePain, fracture, and raised alkaline phosphatase
LiverWeight loss, anorexia, and hepatomegaly
Adrenal glandsAdrenal insufficiency
LymphaticsLymphadenopathy

Symptoms Due to Paraneoplastic Syndrome

Lung carcinoma is also present with paraneoplastic syndromes such as hypercalcemia, hyponatremia, Cushing’s syndrome, and hypertrophic osteoarthropathy. (21)

Investigations

History and clinical features are important in lung carcinoma evaluation, but most of the time, investigations are necessary to establish the diagnosis as well as for grading and staging of the tumor as treatment is done according to it. The following investigations are usually used in lung carcinoma evaluation:

Chest X-ray

Chest X-ray (CXR) is the initial investigation when a lung carcinoma is suspected. It is also used for screening purposes in high-risk patients. It is quick, cost-effective, and has no side effects due to low radiation exposure. A study was conducted in Japan, which showed a 25% reduction in mortality of lung cancer patients who were screened annually with chest X-rays. This shows the importance and effectiveness of chest radiography (28). It can also be used to rule out other causes of symptoms such as pneumonia, pleural effusion, tuberculosis, and pneumothorax.

CT-scan chest

When there is suspicion of lung cancer on CXR, a CT-scan chest with intravenous (IV) contrast should be done. It is useful in diagnosis as well as the staging of the tumor. It also helps to monitor the treatment response of the patient. An increase in the diameter of the lesion (which shows an increase in volume) is indicative of malignancy. Central tumors are more likely to be diagnosed using CT scan than peripheral tumors. It can also be used to check lymph node involvement by using dimensional criteria. If the short axis of the lymph node exceeds 10mm, it is characteristic of lymphadenopathy. (29)

CT-scan chest is often extended to the upper abdomen to look for distant metastasis in the liver and adrenal glands. It also helps in the staging of the tumor to check resectability. If the tumor is of a stage equal to or higher to IIIB, it is usually not resectable. (29)

A recent study in Japan has also shown the effectiveness of low-dose helical computed tomography (LDCT) in the screening of lung cancer. It also showed a reduction of 20% in mortality compared to traditional radiographic screening. (30)

Sputum Cytology

This is a traditional technique in which the sputum of the patient can be examined under a microscope to identify any malignant cells through aberrant cell morphology. The diagnostic significance of this technique depends upon the observer and the number of sputum samples examined. The sensitivity of sputum cytology is 60% and has not improved for many years. In developed countries, it is replaced by tumor biopsy, which is considered the gold standard but is more invasive and costly. However, in developing countries, it is still used as it is an easily available and affordable technique. (31)

PET Scan

It is the most advanced radiographic technique which shows the metabolic and pathologic processes of the tumor along with mediastinal involvement and distant metastases. It is a significant technique as it has reduced the number of thoracotomies and identifies distant metastasis with accuracy. The sensitivity and specificity of the PET scans are 80% and 88%, respectively, which is higher than CT scan chest. But a CT scan may still be needed for staging of the disease and surgical planning. (18)

Bronchoscopy

Bronchoscopy is one of the most important invasive techniques in lung cancer diagnosis. It also helps to identify the exact location of tumors, evaluation of tracheobronchial shaft, tumor lesions, and their mechanism of obstruction. Bronchoscopy can also be used to take samples for tissue biopsy. Lymph node biopsy can also be obtained for the staging of the disease. Different types of bronchoscopy techniques are available as follows: (18)

  • Convex probe-endobronchial ultrasound-guided (CP-EBUS);
  • Radial probe-EBUS (RP-EBUS);
  • Navigation bronchoscopy.

Mediastinoscopy

Previously, it was considered the gold standard test for the diagnosis and staging of lung cancer. The main purpose is to sample lymph nodes of the mediastinum, most commonly para-tracheal lymph nodes. Sub-aortic and para-aortic lymph nodes can also be accessed with the help of anterior mediastinoscopy (also known as the Chamberlain procedure). Mediastinoscopy is 78% sensitive and 100% specific, but it has some risks which should be weighed against the benefits. It is an invasive procedure; general anesthesia is required, and it also has a mortality rate of 0.08%. (32, 33)

Thoracoscopy

Originally, thoracoscopy was done by dividing the ribs and opening the chest cavity. It is used to treat different pulmonary and pleural conditions. Nowadays, video-assisted thoracoscopic surgery (VATS) has replaced traditional thoracoscopy and can be used for mediastinal lymph node sampling and full dissection during lung cancer resection. An advanced version of VATS is now introduced, known as RATS (robotic-assisted thoracoscopy). (18)

Tumor Grading and Staging

The grading of the tumor is the extent of differentiation of the malignant tissue. It can be graded as well-differentiated (grade 1 or low grade), moderately differentiated (grade 2), or poorly differentiated (grade 3 or high grade). This is confirmed by the histopathology of the specimen taken from malignant tissue.

Staging of the tumor depends on three different factors; the size of the tumor, lymph node involvement, and metastasis. This involves radiological staging and invasive staging. TNM classification is used to determine the stage of the tumor. In the case of lung carcinoma, TNM classification of the tumor is done as follows: (34)

Tumor Size (T)

  • Tx: Tumor can’t be assessed on scans but malignant cells present in aspirate fluid or sputum.
  • T0: No tumor.
  • Tis: Carcinoma in situ.
  • T1a: Tumor is 1 cm or less.
  • T1b: Tumor is 1-2 cm in size.
  • T1c: Tumor is 2-3 cm in size.
  • T2: Tumor involves the main bronchus or visceral pleura.
  • T2a: Tumor is 3-4 cm in size.
  • T2b: Tumor is 4-5 cm in size.
  • T3: Tumor is 5-7 cm in size, or there is more than one tumor in the same lobe of the lung or the involvement of the chest wall, the parietal pleura, the phrenic nerve, or the pericardium.
  • T4: The tumor is larger than 7 cm, or it involves more than one lobe of the lung, or the tumor has spread to the diaphragm, mediastinum, heart, trachea, or esophagus.

Lymph Node Involvement (N)

  • Nx: Lymph nodes can’t be assessed.
  • N0:  No involvement of lymph nodes.
  • N1: Involvement of lymph nodes within the lung or lymph nodes of the hilum.
  • N2: Involvement of lymph nodes of mediastinum of the same side or near carina (the point where the trachea branches off into bronchi).
  • N3: Involvement of lymph nodes on the opposite side or above the clavicle.

Metastasis (M)

  • M0: No metastasis.
  • M1: Metastasis to other areas of the body.
  • M1a: Metastasis to the opposite lung or lining around the heart or malignant pleural or pericardial effusion.
  • M1b: Metastasis to organ or lymph node outside the chest.
  • M1c: Metastasis to more than one or more than one area of metastasis in the same organ. (35, 36)

Using this TNM classification, the staging of lung carcinoma is done as follows:

Non-Small Cell Lung Cancer Staging

  • Stage 0: Also known as carcinoma in situ, is an early stage in which the tumor is limited to the lining of the lung
  • Stage I: Tumor has not spread to lymph nodes or any other parts of the body.
  • Stage II: Tumor size is greater than that of stage I and may involve lymph nodes but no distant metastasis to other organs is present.
  • Stage III: The tumor is greater in size than stage II and involves lymph nodes in the mediastinum
  • Stage IV: Most advanced stage in which cancer has metastasized to other areas of the body with lymph node involvement. (36)

Small Cell Lung Cancer Staging

  • Limited stage: Cancer involves only one lung with or without the involvement of lymph nodes.
  • Extensive stage: Cancer has spread to the opposite lung or distant organs of the body. (36)

Staging of the tumor is important as the treatment and prognosis of the patient depend on the stage of the tumor.

Treatment of Lung Cancer

Non-Small Cell Lung Cancer (NSCLC)

  • Stage I:

Surgery is the mainstay of managing stage I NSCLC. Lobectomy or pneumonectomy are the two options for surgical intervention, along with a sampling of mediastinal lymph nodes. Segmentectomy or wedge resection can also be done if the pulmonary reserve is less and lobectomy or pneumonectomy are not possible. The 5-year survival rate is 78%, but there is a high chance of local recurrence. Adjuvant chemotherapy or radiotherapy is not useful in improving the outcome.

  • Stage II:

The treatment of choice is surgery in stage II, followed by adjuvant chemotherapy, with a survival rate of 36 to 46%. Pancoast tumor is a unique tumor of stage II and is treated with neoadjuvant chemotherapy and radiotherapy followed by surgical resection of the tumor. The prognosis also depends upon the presence or absence of microscopic disease in resected tissue.

  • Stage III:

This stage involves a wide range of tumor invasion, and lymph nodes at different levels may be involved. So, the treatment plan should be according to the presentation.

In stage IIIA with N1 lymph nodes, surgery can be done, but with N2/N3 lymph nodes, surgery may not be the best option. In that case, concurrent chemo-radiotherapy is considered the best option with a good outcome. However, it may not be tolerated by all patients and can cause severe esophagitis. The survival rate is 40% to 45% in the first two years and only 20% after five years.

T4 tumors with N0-1 can undergo surgery, while other T4 tumors are managed with exclusive chemo-radiotherapy. Stage IIIB and IIIA are usually unresectable and are treated with chemo-radiotherapy.

  • Stage IV:

If the tumor has advanced to stage IV, the survival rate declines and it is considered incurable. Only 10% to 30% respond to chemotherapy, and the 5-year survival rate is only 1% to 3%. Therapy is done for palliative purposes and to improve survival if possible. (18, 20)

Immunotherapy for NSCLC:

There have been some recent advances in the domain of immunotherapy for the treatment of NSCLC, and many FDA-approved drugs have been introduced for this purpose. One of the characteristics of these malignant cells is the ability to stimulate programmed-death receptors (PD-1). This receptor, when stimulated, leads to the inactivation of activated T-cells causing a decrease in immunity and longer survival of malignant cells. There are antibodies approved by FDA that inhibit the PD-1 receptor directly or through its ligand (PD-L1), thus preventing T-cell inactivation and, in turn, boosting immunity.

Nivolumab and pembrolizumab are FDA-approved IgG4 monoclonal antibodies against PD-1 used for squamous and non-squamous NSCLC, while ateozolizumab is an IgG1 antibody against PD-L1. These are also used following platinum-based chemotherapy and also in the pretreatment of metastatic NSCLC. (37, 38)

Targeted therapy for NSCLC:

In this type of therapy, the specific mutations which lead to cell growth and replication in NSCLC are targeted. This includes:

  • Epidermal growth factor receptor (EGFR) is a mutation in NSCLC that can be inhibited by tyrosine inhibitors such as gefitinib and afatinib. (39)
  • Anaplastic lymphoma kinase (ALK) is a similar mutation that can be inhibited by crizotinib, alectinib, and ceritinib.

Small Cell Lung Cancer (SCLC)

The treatment of small cell lung cancer is according to the stage of the disease as limited-stage or extensive-stage small cell lung cancer.

  • Limited-stage small cell lung carcinoma (LS-SCLC):

Small cell lung cancers that present as peripheral nodules without the involvement of mediastinal or hilar lymph nodes are usually treated with lobectomy followed by adjuvant chemotherapy. PET-CT and lymph node sampling should be done first to rule out lymph node involvement, as it may lead to recurrence and incomplete clearance of the tumor.

If mediastinal or hilar lymph nodes are involved, then the management plan is four to six cycles of chemotherapy followed by radiotherapy. Radiotherapy is important to prevent recurrence as chemotherapy alone results in recurrence in almost 80% of cases. In cases of recurrence, prophylactic whole-brain radiotherapy is done to reduce symptomatic brain metastasis which, in turn, improves the overall survival of the patient.

  • Extensive-stage small cell lung cancer (ES-SCLC):

This may include involvement of contralateral hilar or supraclavicular lymph nodes, malignant pleural or pericardial effusion, and distant metastasis. Treatment is done with platinum-based chemotherapy. In case of recurrence (which occurs in 50 to 60% of patients), radiotherapy is followed by prophylactic whole-brain irradiation. The prognosis of ES-SCLC is poor, only 8 to 13 months. While only five percent of patients survive two years after diagnosis.  (40, 41)

Prognosis of Lung Cancer

The prognosis of lung carcinoma depends on the TNM stage of the tumor. A higher TNM stage of the tumor is associated with a bad prognosis and poor outcome of treatment. Other prognostic factors include clinical status at the time of diagnosis (i.e., anorexia and weight loss) and the absence or presence of distant metastasis.

 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

Acute Pericarditis

What is Atherosclerosis?

Heart Failure with Preserved Ejection Fraction

Hypertensive Crisis

Dyspnea Due to Respiratory Causes

Approach to Chest Pain

Acute Asthma Exacerbation

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