pulmonology3 Flashcards
Group 1 pulmonary hypertension
this is pulmonary arterial hypertention causes include: Idiopathic PAH, Heritable PAH, Drug and toxin induced and can be Associated with: Connective tissue disease, HIV infection, Portal hypertension, Congenital heart diseases, and Schistosomiasis
Group 2 pulmonary hypertension
this is pulmonary hypertension due to left heart disease and can be caused by: left ventricular systolic dysfunction, Left ventricular diastolic dysfunction, Valvular disease, and Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies.
Group 3 pulmonary hypertension
this is pulmonary hypertension due to lung disease and/or hypoxia and includes: Chronic obstructive pulmonary disease, Interstitial lung disease, Other pulmonary diseases with mixed restrictive and obstructive pattern, Sleep-disordered breathing, Alveolar hypoventilation disorders, Chronic exposure to high altitude, and Developmental lung diseases
Group 4 pulmonary hypertension
Chronic thromboembolic pulmonary hypertension (CTEPH)
Group 5 pulmonary hypertension
Pulmonary hypertension with unclear multifactorial mechanisms and includes: Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy, Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis, Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders, and Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH
UIP – Usual Interstitial Pneumonitis (or Pneumonia)
The histopathologic pattern seen in Idiopathic Pulmonary Fibrosis (and other diseases).
IPF – Idiopathic Pulmonary Fibrosis
a clinical diagnosis of idiopathic (or unexplained) usual interstitial pneumonia.
Inexorable progression, 2-3 year survival, unresponsive to therapy. Smoking is a risk factor. More common in elderly. Radiographic findings include Basilar and peripheral predominant reticular abnormality, traction bronchiectasis, volume loss, honeycombing, paucity of ground glass. Histopathological findings of Spatially and temporally heterogeneous fibrosis with fibroblast foci and little inflammation (UIP pattern)
NSIP – Nonspecific Interstitial Pneumonitis (or Pneumonia)
Better prognosis than IPF, the more cellular, the more steroid responsive. Radiographic findings include basilar and peripheral predominant reticular abnormality, traction bronchiectasis, volume loss, usually with associated ground glass. Histopathological findings include spatially and temporally homogeneous fibrosis. Cellular and fibrotic variants.
RB-ILD – Respiratory Bronchiolitis
Interstitial Lung Disease. Smoking related; responds to smoking cessation, variably steroid responsive. Radiographic findings include airway thickening with centrilobular nodules, gas trapping, and patchy ground glass opacity. Histopathological findings include bronchiolocentric accumulation of “dusty brown” macrophages with peribronchiolar lymphocitic and monocytic infiltrates and peribronchiolar fibrosis.
DIP – Desquamative Interstitial Pneumonitis (or Pneumonia)
a misnomer based on the incorrect initial hypothesis that the cells filling the alveolar spaces were desquamated epithelial cells; these are actually alveolar macrophages (also a misnomer in that it is not a purely interstitial process. alveolar filling is the primary process, though there is also expansion of the alveolar septa and pulmonary interstitium). Smoking related; maybe on a spectrum with RB- ILD, responds to smoking cessation and variably to corticosteroids. Radiographic findings include patchy, basilar predominant ground glass opacity, sometimes with irregular reticular abnormality. Histopathological findings include thickened alveolar septa with “dusty brown” macrophages filling distal airspaces
DAD – Diffuse Alveolar Damage
the histopathologic pattern seen in AIP (and in other processes such as ARDS and some drug toxicities). Also called “acute lung injury.”
AIP – Acute Interstitial Pneumonitis (or Pneumonia)
similar to DIP, the primary process in AIP - and other entities marked by DAD - is alveolar filling. Rapid progression to respiratory failure and death, poorly responsive to therapy. Radiographic findings include diffuse alveolar filling with patchy ground glass, septal thickening, and traction bronchiectasis. Histological findings include alveolar edema, neutrophils, hemorrhage, hyaline membranes (similar pattern as ARDS). Diffuse alveolar damage (DAD) pattern of injury
COP – Cryptogenic Organizing Pneumonia
(of note, Organizing Pneumonia may also be seen in non-cryptogenic processes such as collagen-vascular disease and drug toxicity – COP refers specifically to Organizing Pneumonia without an evident precipitant). Subacute presentation, may be associated with collagen vascular dz, malignancy, infection, exposures, or idiopathic. Steroid responsive. Radiographic findings include bilateral peripheral alveolar opacities (fuzzy nodules) with preserved lung volumes. May be migratory. Thickened airways. Histopathological findings include intraluminal plugs of granulation tissue with peribronchiolar inflammation and sometimes intra- alveolar neutrophils.
LIP – Lymphoid (or Lymphocytic) Interstitial Pneumonitis (or Pneumonia)
Associated with immunodeficiency, Sjögren’s, lymphoma, or idiopathic. Radiographic findings include centrilobular nodules, ground glass sometimes, cyst formation in end stage disease. Histopathological findings include lymphocytic peribronchial and alveolar septal infiltrates, sometimes with germinal centers
AEP – Acute Eosinophilic Pneumonitis (or Pneumonia)
Presentation indistinguishable from DAD or pulmonary edema. Often febrile prodrome. AEP, however responds to steroids. Can mimic ARDS. Radiographic findings include diffuse bilateral alveolar infiltrates, indistinguishable from pulmonary edema, DAD, or ARDS. Histopathological findings is similar to DAD, though with intra-alveolar and septal eosinophilic infiltrates
CEP – Chronic Eosinophilic Pneumonitis (or Pneumonia)
Subacute presentation, constitutional sx, more in nonsmokers and women, steroid responsive. Radiographic findings are described as “Photographic negative” of pulmonary edema. Peripheral ground glass and reticular opacity. Histopathological findings include alveolar septal thickening, with eosinophilic infiltrates, fibrosis, macrophages
LCH – Langerhans Cell Histocytosis
formerly (and sometimes still) referred to as Eosinophilic Granuloma (but no eosinophils and no granulomas!) or EG. Smoking-related, younger patients, spontaneous pneumothorax in 25%. Radiographic findings include irregular cysts and nodules, upper zone predominant, spares costophrenic angles. Histopathological findings show Infiltration of Langerhans cells
LAM – Lymphangioleiomyomatosis
Women only, may respond to anti-estrogen therapy. Obstructive PFTs; pleural effusion (chylothorax) and spontaneous pneumothax common. Radiographic findings cysts and nodules, in a more random shape, size and distribution than in LCH. Pleural effusions and PTX common. Histopathological findings show peribronchovascular proliferation of smooth muscle cells, lymphatic occlusion
HP—Hypersensitivity pneumonitis
An immunologic response to inhaled organic antigen (mold, bird proteins most common). May be acute or chronic. Chronic disease is often fibrotic. Antigen avoidance key. Radiographic findings: Acute: centrilobular ground glass
Chronic: reticular pattern with fibrosis
Both are often upper-lobe predominant with mosaic attenuation. Histopathological findings show inflammation +/- fibrosis with poorly formed granulomas
“Interstitial” lung diseases with a prominent alveolar filling component
DIP, AIP, Organizing Pneumonia, AEP, CEP
Silhouette sign
is somewhat of a misnomer and in the true sense actually denotes the loss of a silhouette, thus it is sometimes also known asloss of silhouette signorloss of outlinesign. The differential attenuation of x-ray photons by two adjacent structures defines the silhouette, e.g. heart borders against the adjacent lung segments and it is the pathological loss of this differentiation, which the silhouette sign refers to.
Air bronchogram
refers to thephenomenonofair-filled bronchi (dark) being made visible by the opacification of surrounding alveoli (grey/white). It is almost always caused by a pathologic airspace/alveolar process, in which something other than air fills the alveoli.Air bronchograms will not be visible if the bronchi themselves are opacified(e.g. by fluid) and thus indicate patent proximal airways.
Subcutaneous emphysema
strictly speaking, refers to air in the subcutaneous tissues. But the term is generally used to describe any soft tissue emphysema of the body wall or limbs, since the air often dissects into the deeper soft tissue and musculature along fascial planes.
Producing a chest radiographic image
X-rays are produced by bombarding a rotating tungsten target with a focused electron beam. Even though x-rays are in the non-visible high-energy electromagnetic spectrum, the x-rays emit a divergent beam much like a flashlight from a focal point in the direction of the radiograph detector. The patient casts a shadow on the detector that becomes the radiograph. Thoracic anatomy has better resolution as it becomes farther away from the focal point (radiation source). As well, there is less magnification of the various anatomy when it is located further away from the focal point. This concept can be reproduced when taking a flashlight and making hand shadows at various distances between the flashlight and the wall. Therefore, anatomy such as the heart will appear larger on the radiograph if it is closer to the source and further from the detector (as in the source is anterior and the detector is posterior to the chest, termed “AP view.”). For this reason, ideal positioning of the patient for standard two-view chest radiographs places their anterior chest against the detector for the frontal view and the left chest against detector for the lateral view. The divergent beam/magnification also affects the appearances of other anatomy in the chest, such as ribs.
Attenuation
reduction of intensity of an x-ray beam as it traverses matter.
Density
ability of a structure to attenuate the x-ray beam (highest -> lowest:metal, calcium, bone, soft tissue, fat, air.)
Absorption
is the object’s ability to “absorb” the x-ray beam, preventing it from getting to the detector. This varies on both density and thickness of the object.
Penetration
Absorption is inversely proportional to penetration, which is when x-ray beams readily reach the detector. Therefore, a radiograph that is “over penetrated” means that it is too “black”, which reduces the contrast between structures of varying density interfaces.
Silhouette sign and air bronchogram sign
If there are adjacent structures with the same density, they cannot be distinguished on radiograph. For example, a right middle lobe pneumonia (water density) can obscure the right heart border (also water density). Compare this to the air bronchogram sign: in normal lung, we cannot detect the small bronchi in a lobe, but if the alveoli around the bronchus are filled with pus or aspiration, we can see the bronchial contours because air and water densities are different.
Air fluid level
This occurs when a cavity contains both air and fluid (such as a lung abscess or when air is introduced into the plueral space containing a pleural effusion or empyema). It appears as a superior lucency and an inferior opacity separated by a discrete, well delineated line at their
disease states that are associated with an increased risk of lung cancer
patients who develop COPD (defined as chronic bronchitis or emphysema with pulmonary function testing showing at least mild airflow limitation, FEV1
Bat’s wing
or butterfly pulmonary opacities refer to a pattern of bilateral perihilar shadowing.
The deep sulcus sign
on a supine chest radiograph is an indication of a pneumothorax. In a supine film (common in the ICU), it may be the only indication of a pneumothorax because air collects anteriorly and basally, within the nondependent portions of the pleural space, as opposed to the apex when the patient is upright.The costophrenic angle is abnormally deepened when the pleural air collects laterally, producing the deep sulcus sign.
The Golden S sign
is seen on both PA chest radiographs and on CT scans. It is named because this sign resembles a reverse S shape, and is therefore sometimes referred to as the reverse S sign of Golden. Although typically seen with right upper lobe collapse, the S sign can also be seen with the collapse of other lobes. It is created by a central mass obstructing the upper lobe bronchus and should raise suspicion of a primary bronchogenic carcinoma. It can also be caused by other central masses, such as: metastasis, primary mediastinal tumour, or enlarged lymph nodes.
Cephalization
The antigravitational redistribution of pulmonary blood flow that occurs with heart failure, caused by increased vascular resistance in the dependent part of the lung, a consequence of pulmonary venous hypertension; usually described on the basis of relative vascular size on chest radiography. Vessels in upper chest is more prominent as a manifestation of pulmonary venous hypertension.
miliary opacities
refers to innumerable, small 1-4 mmpulmonary nodules scattered throughout the lungs.It is useful to divide these patients into those who are febrile and those who are not. Additionally, some miliary opacities are very dense, narrowing the differential
Lung parenchyma
is that portion of the lung involved in gas transfer—the alveoli, alveolar ducts and respiratory bronchioles.
Lung cancer pathogenesis
Cancer develops in a multi-step fashion in which cells become malignant by the accumulation of genetic alterations affecting cellular growth, differentiation, and survival. This can include mutation of tumor suppressor genes (for example p53), the activation of oncogenes (for example MYC, JUN, FOS), and transformation of apoptotic genes. Growth factors and growth factor receptors are also involved in the pathogenesis and progression of both small cell (SCLC) and non-small cell lung cancer (NSCLC).
EML4-Alk
newly diagnosed adenocarcinoma should be tested for mutations in Kras, EGFR (epidermal growth factor receptor), EML4-Alk (a fusion protein) and Braf.
Differential therapy for NSCLC
There is also differential therapy (aka targeted therapy that is directed against specific genetic mutations) approved for non-squamous cell NSCLC. Many of these factors or receptors are preferentially produced by the tumor cells and they induce cell specific growth. Many of these targeted treatments have proven to be more efficacious than standard platinum-based treatment for NSCLC.
Paraneoplastic syndromes and lung cancer
Paraneoplastic syndromes are remote effects of the primary tumor leading to organ dysfunction. Up to 20% of lung cancer patients develop paraneoplastic syndromes but these syndromes may not necessarily indicate metastatic disease. Classic SCLC has a neuroendocrine origin accounting for many of the paraneoplastic syndromes, which can be seen at presentation or during disease progression. Paraneoplastic syndromes are also seen in NSCLC patients due to accumulated genetic alterations in tumor cells.
Classification of lung cancer
Lung cancer is classified into two main categories, non-small cell (NSCLC) and small cell (SCLC). Within these two major categories are four basic histologic types that account for over 90% of the cases. NSCLC has three main types: squamous cell carcinoma (25% of cases) arising from the bronchial epithelium and typically more central in location; adenocarcinoma (40% of cases) arising from mucous glands and typically more peripheral in location; and large cell carcinoma (10% of cases), a heterogeneous group of poorly differentiated tumors that do not have features of adenocarcinoma, squamous cell, or SCLC. One subtype of adenocarcinoma is the newly named adenocarcinoma in-situ (previously known as bronchoalveolar cell [BAC} - 2% of all cases) that arises from distal airway epithelial cells and typically presents as an unresolving infiltrate or as multiple nodules. Small cell carcinoma (13% of cases) is of bronchial origin and typically begin as central lesions that can often narrow or obstruct bronchi. Hilar and mediastinal adenopathy, as well as evidence of metastatic disease, are often present on initial presentation. For staging and treatment purposes, NSCLC and SCLC are viewed very differently.
Signs and symptoms of lung cancer
In its earliest stages, lung cancer is asymptomatic. Primary lung cancers can reach a large size without causing any symptoms, although careful history and physical examinations reveal that only about 5% of lung cancer presentations are truly asymptomatic. Cough, anorexia, weakness and weight loss are the most common presenting symptoms in patients with undiagnosed lung cancer. Other common presenting symptoms include: 1. new cough or a change in a chronic cough (60+%) ; 2. Hemoptysis (10-25%); 3. Pain, either at the local thoracic site or secondary to metastatic disease (25-35%).
Associated syndromes with lung cancer
Presentation also depends on tumor location, for example, endobronchial obstruction can lead to post-obstructive pneumonia, atelectasis, and pleural effusions. Enlarging tumor size and/or lymph node involvement can lead to hoarseness (secondary to recurrent laryngeal nerve injury), superior vena cava syndrome (i.e. supraclavicular venous engorgement, much more common in SCLC), Horner’s syndrome (ptosis, anhidrosis, and miosis from inferior cervical ganglion and sympathetic chain involvement), and dysphagia (secondary to esophageal obstruction from bulky mediastinal adenopathy). The Pancoast syndrome is characterized by shoulder and upper chest wall pain caused by a tumor in the apex of the lung that can involve the brachial plexus. Tumor in this location can also be accompanied by Horner’s syndrome and reflex sympathetic dystrophy. Adenocarcinoma in-situ (formerly bronchoalveolar cell) tumors may induce copious amounts of ‘salty’ sputum (a condition termed bronchorrhea).
Symptoms of metastatic disease with lung cancer
are also relatively common presentations. Lung cancer commonly spreads to the adrenal glands, liver, brain, and bone. CNS spread may lead to headache, nausea, altered mental status, and possibly seizures. SCLC typically metastasizes at a much earlier time point than NSCLC.
Laboratory Findings with lung cancer
The diagnosis of lung cancer is completely dependent on a tissue sample containing confirmatory malignant cells. There are a variety of ways to obtain diagnostic tissue, including: sputum cytology (best for central airway lesions); bronchoscopy with endobronchial or transbronchial biopsies; thoracentesis with cytologic examination of the cellular component; and fine needle aspiration (CT guided or transbronchial during bronchoscopy) of intrathoracic masses, lymph nodes, or metastatic foci. The sensitivity of bronchoscopy in making the diagnosis is variable and depends on the size and location of the lesion. The development of electromagnetic navigational bronchoscopy (ENMB) has allowed for improved sampling of more peripheral lesions and thoracic adenopathy. Transbronchial needle aspiration, video-assisted thoracoscopic surgery (VATS), mediastinoscopy, and thoracotomy may also be needed to adequately diagnose and stage patients. Other laboratory abnormalities may be present due to the paraneoplastic syndromes (listed in Table 2).
Imaging Studies with lung cancers
Virtually all patients with lung cancer have abnormal chest x-rays or chest CT scans. Patients may present with a solitary pulmonary nodule and this particular clinical scenario is discussed at length later in the chapter.
Staging of lung cancer
Correctly staging patients with lung cancer is crucial in determining the proper therapeutic approach. One of the most important parts of staging is a thorough history and physical. These components directly determine blood work and further imaging. All patients need electrolyte testing, liver function tests (including alkaline phosphatase and LDH) and a chest X-ray. Elevated alkaline phosphatase suggests bone metastases. In the past, patients routinely had head CTs and radionuclide bone scans as part of the diagnostic workup, but large studies have shown that these tests should only be ordered based on the patient’s signs and symptoms. For example, CNS symptoms or an abnormal neurologic exam necessitates a brain CT with contrast. NSCLC and SCLC are staged differently. Due to the high incidence of micrometastases early in the disease state, small cell lung cancer is divided into two stages: limited disease (25-30%), tumor is limited to ipsilateral hemithorax (including contralateral mediastinal nodes); and extensive disease (70-75%), tumor extends beyond the hemithorax (including pleural effusions). SCLC is typically treated with chemotherapy and radiation therapy. NSCLC is staged using the TNM staging system (T-tumor size, N-nodal involvement, M-presence or absence of metastases).
Staging NSCLC
In general, patients with NSCLC at an earlier stage with disease amenable to surgery have the best chance to be cured. Patients being considered for surgery must be thoroughly evaluated to determine if they have resectable disease and this routinely involves sampling nodes and other imaging detected lesions to determine if metastatic cancer is present. The decision for surgical resection is largely based on tumor invasion and lymph node status, along with underlying medical comorbidities. CT imaging, and to a larger extent positron emission tomography (PET) scanning, are important staging modalities.
CT scanning and staging of lung cancer
Chest CT scanning is performed with contiguous sections through the liver and adrenal glands to aid in staging. The latest generation of scanners combine CT and PET. Lymph nodes larger than 1 cm in diameter are concerning for tumor involvement and should surgically sampled at the time of resection, or in procedures to help determine the stage (i.e. ENMB, mediastinoscopy, trans- bronchial needle aspiration, or VATS). CT scanning does have limitations, for instance, determination of chest wall invasion has a sensitivity of 38-87% and a specificity of 40-90%. CT also has difficulties accurately determining mediastinal invasion. Patients should not be denied surgery based on unproven CT findings. In fact, many patients have their stage altered based on surgical pathology. A comprehensive discussion of staging can be found in the staging reference listed below.
PET and staging of lung cancer
One new addition to many staging algorhythms is FDG-PET scanning. PET scans exploit differences between normal and neoplastic tissue. Transformed cells exhibit increased glucose metabolism resulting in increased accumulation of FDG (18F-2-fluoro-2-deoxyglucose). Sensitivity and specificity of PET for detecting mediastinal metastases is superior to CT scans, and PET also is often used to evaluate patients with multiple nodules. PET does have limitations in resolution for nodules
Pulmonary Function Testing with lung cancer
Many patients with NSCLC have concomitant chronic lung disease that increases the risk of thoracic surgery. All patients considered for surgery need complete pulmonary function testing. A predicted post-resection FEV1 > 800 ml (or > 40% predicted FEV1) is typically used as a lower limit of those who should have decreased post-operative complications. A quantitative lung perfusion scan (Q scan) can be used to improve the estimate of the patient’s post-operative FEV1. Those patients who would have a post-operative FEV1
Screening for lung cancer
Advances in imaging technology also are being applied to lung cancer screening. Recently, there has been considerable interest in using low-dose, helical CT (spiral CT) as a lung cancer screening modality. Low dose CT is a more sensitive test than chest x-ray and can be used to accurately identify pulmonary nodules. The NLST trial (reported in NEJM August 4, 2011) showed a 20% decrease in lung cancer mortality in the CT screening group. The NSLT criteria have now been accepted by major cancer organizations (including the American Cancer Society) and CT screening is now recommended by the US Preventive Task Force and is covered by Medicare. The screening groups is those aged 55-77, current or former smoker with 30 pack years of tobacco exposure, former smokers had to have quit within the prior 15 years. A visit for counseling and shared decision making must occur prior to the LDCT being completed. Improved understanding of the distinct morphologic and genetic changes that occur in the airways will also allow for identification of the highest risk patients and those who may benefit from chemoprevention. The best populations for targeted screening and chemoprevention may ultimately be based on a variety of factors (tobacco exposure, family history, occupational history, pulmonary function testing, sputum cytology).
Treatment of Small Cell Lung Cancer
SCLC is classically treated with cisplatin and etoposide, with responsive rates directly related to disease stage. Two-year survival is around 20% in limited disease and 5% in extensive disease. Remissions tend to be relatively short, with a median duration of 7-9 months. Once SCLC recurs, survival is 3-4 months. Radiation therapy improves survival in patients with limited stage disease. Also, radiation therapy is used to treat symptomatic metastases, such as those in bone and the CNS. Patients with SCLC are not treated surgically, although there are rare patients who have solitary pulmonary nodules resected that turn out to have SCLC. These patients tend to have an improved survival compared to patients with limited disease SCLC. Newer targeted agents are being developed for SCLC.
Treatment of Non-Small Cell Lung Cancer
Surgical resection provides the best opportunity for cure. Many features will preclude resection, including: extrathoracic metastases; malignant pleural effusions; tumor involving contralateral mediastinal nodes; and tumor invading the heart, great vessels, pericardium, esophagus, trachea, or within 2 cm of the main carina. Medical comorbidities (typically advanced heart or lung disease) may also deem patients inoperable. For those proceeding to surgery, the type of surgery does affect the outcome. For example, trials comparing lobectomy to ‘limited resection’ found a higher incidence of local recurrence in the limited resection group, along with a trend toward mortality benefit at 5 years in the lobectomy cohort (44% vs. 27% survival, P = 0.09).
Neoadjuvant therapy of NSCLC
Neoadjuvant therapy, the administration of chemotherapy or radiation prior to surgery, is gaining favor in the initial therapy of NSCLC. Studies suggest there may be improved survival in patients with stage IB and II disease who receive chemotherapy prior to surgery. In general, neoadjuvant therapy is being studied in earlier stage disease (in combination with surgery) and may be one important avenue to improve the survival rates.
adjuvant therapy of NSCLC
Adjuvant chemotherapy, the administration of chemotherapy after radiation or surgery, is commonly used in NSCLC. Lung cancer treatment has been at the forefront of precision medicine, and NSCLC specimens (particularly adenocarcinoma) should be tested for specific mutations as this will direct treatment. In patients with stage IIIA disease and node positive stage II disease, adjuvant chemotherapy probably improves survival, but mostly in those with a good performance status. Patients with advanced stage disease (IIIA and IIIB), which comprises the majority of patients diagnosed with lung cancer, who are not surgical candidates do have an improved survival when treated with chemotherapy and radiation, particularly with the targeted agents that have been developed for adenocarcinoma. Patients with advanced disease (stage IIIB and IV) have an increased survival at one year with such treatments, provided they exhibit a good performance status on presentation. Overall, multiple trials have shown that patients with stage IIIB and stage IV disease treated with chemotherapy and/or radiation have better symptom control and performance when compared to palliative care alone. Newer chemotherapeutic agents are continually being evaluated and survival may show some improvements. Genetic testing is now routinely performed for patients with adenocarcinoma, particularly adenocarcinoma in situ and NSCLC in never smokers. This testing is considered standard of care and should be routinely ordered. It is imperative that patients placed on newer regimens do so as part of organized, multi-center protocols that act to best evaluate efficacy.
Prognosis of lung cancer
The cumulative 5-year survival rate for lung cancer is 16% based largely in part on the large percentage of patients who present with late stage (IIIA or greater) disease. Survival best correlates with surgical-pathologic stage of disease, and can vary from 74% 5-year survival in stage IA NSCLC, to roughly 5% 5-year survival in stage IIIB NSCLC. Most large studies have failed to find a significant difference in prognosis of the variety of NSCLC types when adjusted for stage and performance status.
Benign Causes of Solitary Pulmonary Nodules
Infectious granulomas: tuberculosis, coccidiodomycosis, histoplasmosis, blastomycosis Viral infections: measles, CMV. Pneumocystis carinii. Round pneumonia. Lung abscess. Hamartoma. Chondroma. Pulmonary infarct. A-V fistula or malformations. Pulmonary amyloidosis. Sarcoidosis. Pseudotumors (collections of fluid in the lung fissures).
Malignant Causes of Solitary Pulmonary Nodules
Bronchogenic carcinoma. Bronchial carcinoid tumors. Other primary lung tumors – carcinosarcoma, lymphoma, hemangioendothelioma. Metastatic tumors – most commonly colorectal, breast, renal cell, testicular, malignant melanoma, sarcoma
Symptoms & Signs of Solitary Pulmonary Nodules
Many patients are truly symptomatic when the SPN is discovered if a careful history and physical are performed. Additional clinical and radiographic data can assist in assessing the likelihood of malignancy. Key historical findings include: age; smoking history; environmental exposures; potential infectious exposures; residence or travel to areas with endemic pulmonary mycoses, history of malignancy (particularly lung or head and neck cancer); and any coexisting lung disease. For example, in those patients younger than 35 years of age and without a history of smoking or previous malignancy, the probability of primary bronchogenic carcinoma is less than 1%. Above the age of 35, likelihood of malignancy increase with age and tobacco exposure. Occupational exposure to asbestos, silica, radon, or uranium, particularly in smokers, increases the risk of lung cancer.
Other pertinent historical information about solitary pulmonary nodules
includes residence or travel in areas of endemic mycoses. In the United States, histoplasmosis and coccidiodomycosis are major concerns. Coccidiodomycosis is a soil organism endemic to the desert southwest, southern California, and northern Mexico. Case series from Arizona have determined that 60% of SPNs were due to coccidiodomycosis exposure. Histoplasmosis is a fungus that lives in soil fertilized by bird or bat droppings and is commonly found in the central and south-central United States. History of previous malignancy is also very important, as these may metastasize to the lungs. In patients with a prior history of cancer, pulmonary nodules represent metastasis from an extrathoracic primary in about 60%. These patients should expeditiously undergo further imaging. A tissue diagnosis is mandatory to differentiate between metastatic disease, a second primary cancer, and a benign etiology.
Physical examination of solitary pulmonary nodule
also can provide clues as the etiology of an SPN. Lymphadenopathy, particularly supraclavicular or scalene nodes, suggests malignancy, and generalized lymphadenopathy raises concern for lymphoma or an infectious process. A fixed or localized wheeze suggests an endobronchial location and raises the suspicion for a tumor (particularly in current and former smokers with COPD). Clubbing and joint tenderness (hypertrophic pulmonary osteoarthropathy) may also be found in association with bronchogenic carcinoma. Unexplained hypoxemia may signify pulmonary AVMs, and one such disease (HHT, hereditary hemorrhagic telangectasia; Osler-Weber-Rendu syndrome) is characterized by telangectasias or angiomata on the face, nasopharyngeal mucous membranes, skin, lips and nail beds.
Laboratory Findings of solitary pulmonary nodule
There are no specific laboratory findings in patients with solitary pulmonary nodules other than those listed above in the section on lung cancer. Rarely patients with bronchogenic carcinoma will present with manifestations of a paraneoplastic syndrome.
Imaging Studies of solitary pulmonary nodule
The most critical step in evaluating pulmonary nodules is reviewing old CXRS/CTs to determine nodule stability. The presence and pattern of calcification within a nodule can be a marker of benignity. Characteristic benign patterns have been described and include: lamination or a ‘bull’s eye’ pattern characteristic of granulomas; chondroid or “popcorn” pattern occurring in hamartomas; or a dense, central core of calcification. The likelihood of a cancer diagnosis rises significantly in SPNs lacking calcification. Most lesions which lack calcification are termed indeterminate until a tissue diagnosis is obtained. Malignant lesions can contain calcium, but it is usually eccentrically located and does not conform to the patterns listed above.
Computed tomography (CT) for solitary pulmonary nodule
is the most accepted way to further evaluate SPNs. CT is better than chest radiography in detecting calcification patterns and nodule density. Nodules must remain stable is size over at least 2 years to be considered benign. Malignant lesions typically have eccentric calcification patterns on CT, while the presence of fat density within a nodule is pathognomonic of hamartomas. Cavitary lesions with thick walls (>16 mm) are much more common in malignancies. One CT technique which can better define nodules is a nodule enhancement study (the differential enhancement following the injection of i.v. contrast). After injection of contrast, malignant nodules exhibit greater enhancement due to qualitative and quantitative differences in blood supply. This also allows for identification of vascular lesions.
Other imaging modalities of SPNs
Positron emission tomography (PET scanning) can be used to characterize and stage lesions. PET exploits the biochemical differences between normal and neoplastic tissue and can evaluate lesions which are indeterminate in nature. Transformed cells exhibit increased glucose metabolism resulting in accumulation of 18F-2-fluoro-2-deoxyglucose (FDG). The intensity of accumulation in the nodule is then compared with the background activity. Increases in activity raise the concern for malignancy. For SPNs, PET has reported sensitivities of 85-95% and specificities of 75- 85%. PET scans do have limitations, including: lack of resolution below 1 cm, high cost, and limited availability (PET scanners are not universally available at this time in the United States). Overall, PET has also been proven to be cost-effective in the staging of patients with non-small cell lung cancer because it reduces the number of surgical procedures in patients with unresectable disease. Magnetic resonance imaging is of little benefit in diagnosis, but can aid in determining chest wall or mediastinal invasion, such as in the evaluation of superior sulcus tumors.
Multiple Pulmonary Nodules
There will be times when the evaluation of a patient with an SPN reveals multiple nodules. The more common etiologies of multiple nodules are contained in table 3. The time course of the nodules appearance and the calcification patterns are important as they may represent independent disease processes. The most common cause is metastatic disease, which occurs more often than all of the other causes combined. Benign tumors of the lung, infectious nodules, and noninfectious granulomas comprise the other causes. CT scans are the most commonly employed imaging modality, and transthoracic needle aspiration (TTNA) under CT or ultrasound guidance is often the safest and simplest method to obtain tissue for diagnosis. Nondiagnostic TTNA should be followed by thoracoscopic open lung biopsy. Rapid diagnosis is essential in immunocompromised individuals to allow for appropriate treatment of opportunistic infections.
Benign Causes of Multiple Pulmonary Nodules
Infectious- granulomas, septic emboli, parasites. Non-infectious granulomas- Wegener’s granulomatosis, sarcoidosis, rheumatoid arthritis. Pulmonary AVMs. Silicosis. Vasculitis. Broncholithiasis
Malignant Causes of Multiple Pulmonary Nodules
Metastatic cancer. Lymphoma. Metastatic bronchogenic carcinoma. Kaposi’s sarcoma. Synchronous primary bronchogenic carcinomas
Treatment of multiple pulmonary nodules
Based on the clinical and radiographic data, the clinician must then decide which nodules should be biopsied, and the best method to obtain a tissue diagnosis. This decision is based on each unique clinical situation, and the discussion below will focus on guidelines. There are a variety of biopsy techniques to establish the benignity of an SPN or to establish malignancy in high-risk patients, including bronchoscopy, TTNA, and surgical resection. The efficacy of bronchoscopy depends on nodule size and location. If CT imaging shows a bronchus entering the nodule then bronchoscopy has a higher diagnostic yield. TTNA is usually carried out under ultrasound, fluoroscopic, or CT guidance. TTNA is diagnostic in 80-95% of malignancies, although the false negative rate has been reported to be as high as 29%. The indications for TTNA are controversial, but include: SPNs in patients with a history of a non-pulmonary tumor to establish it is the same tumor type; to establish a diagnosis in high-risk surgical patients; and to aid in tissue diagnosis in presumed benign lesions. Tumor dissemination along the needle track is extremely rare.
Video-assisted thoracoscopic surgery (VATS) or exploratory thoracotomy for resection of SPNs
are the most definitive diagnostic procedures. CT scans, besides evaluating the nodule, also may reveal hilar or mediastinal lymphadenopathy (a finding which is present in about 20% of SPN patients). If the CT scan fails to detect lymphadenopathy then thoracotomy can occur without mediastinoscopy. Surgical mortality for malignant nodules may be as high as 4%, and can rise to 9% in patients over the age of 70. For benign lesions, the mortality is 0.3%, mainly because these patients are less likely to have a history of heavy tobacco abuse with concomitant COPD and coronary artery disease. For patients with an intermediate probability of malignancy, VATS is likely the best treatment. During these procedures, if malignancy is revealed on the frozen sections the surgical procedure can be extended to a lobectomy with lymph node sampling for staging. In some patients lobectomy can be accomplished via VATS. The increased use of VATS will likely decrease morbidity secondary to nodule resection and has been used successfully in patients with severely compromised pulmonary function.
The larynx
is organized into 3 major regions: 1) The vestibuleis between the entrance to the larynx and the vestibular folds (i.e. “false vocal cords”).
The vestibular folds contain the vestibular ligaments which are the thickened inferior edges of the quadrangular membrane. 2) Theventriclesare the portion between the false vocal cords (superiorly) and the true vocal folds (inferiorly).
The vocal folds contain the vocal ligaments which are thickenings of the superior edge of the conus elasticus.
Vibration of the adducted vocal ligaments with expiration produces sound (see section on muscles below for more on movement of the vocal ligaments). 3) The infraglottic cavityis the portion of the larynx inferior to the vocal folds. It communicates distally with the lumen of the trachea. The larynx is composed of a cartilaginous skeleton
Superior laryngeal nerve
Divides into internal and external laryngeal nerves.
Internal laryngeal nerve: Enters thyrohyoid membrane with superior laryngeal artery. Provides sensory innervation to mucosa superior to vocal folds.
External laryngeal nerve: Travels with superior thyroid artery and provides motor innervation to the cricothyroid muscle.
Recurrent laryngeal nerves
Right: Loops under subclavian artery
- Left: Loops under arch of aorta
Both ascend posterior to the esophagus and enter the larynx at the level of the cricothyroid articulation.
Motor innervation to ALL muscles of the larynx (except the cricothyroids, as noted above) and provides sensory innervation to the mucosa of the larynx inferior to the vocal folds.
The trachea
is a highly cartilaginous structure composed of C-shaped cartilage surrounding the airway. Compression of the trachea may result from thyroid enlargement (tumor or goiter) or aortic arch aneurysm. In the case of aortic arch aneurysm, the pulse can then be felt through the trachea. The trachea is lined by pseudostratified, ciliated columnar epithelium. The ciliated epithelium facilitates the clearance of inhaled debris from the airway. This is an important innate defense mechanism, preventing the passage of microbes, irritants, or systemic toxins into the lungs. The wall of the trachea is lined with smooth musclethat is located predominantly on theposterioraspect of the trachea (where the cartilaginous rings are incomplete). Smooth muscle is continuouslypresent in the walls of theairway distally down to theterminal bronchioles.
Atracheostomy
is the placement of a tube between the second and third tracheal cartilage rings for long term ventilation support.
The carina
is the cartilaginous ridge within the trachea that runs anteroposteriorly between the left and right main bronchi. Displacement of the carina from its usual anatomical position can have several possible causes: Metastasis of bronchogenic carcinoma intotracheobronchial lymph nodes; Enlargement of the left atrium; Conditions causingtracheal deviation (ex:tension pneumothorax)
5 layers covering vocal folds
Epithelium. Superficial Lamina Propria, Intermediate Lamina Propria. Deep Lamina propria. Vocalis muscle (medial thyroarytenoid)
Abdominal Support System for vocal function
Maintains efficient, constant power source. Inspiratory – expiratory mechanism
Musculoskeletal System and vocal function
Small change in posture or stance can be significant. Body tension in any muscle group can make larynx compensate
Psychoneurologic system and vocal function
ANS plays role in mucus production, voice stability. Fine muscular control at risk with sympathetic stimulation or a neurological condition exists
Infrahyoid muscles
Thyrohyoid. Sternothyroid. Sternohyoid. Omohyoid
Suprahyoid muscles
Digastric. Mylohyoid. Geniohyoid. Stylohyoid
Anatomy of Laryngeal Skeleton
Most important cartilages are Thyroid, Cricoid, and Paired Arytenoids. Connected by soft tissue allows change in angles/distances/shape/ tension. Such membranes include the Thyrohyoid membrane and Cricothyroid ligament.
Vocal Fold Central Innervation
includes the cerebral cortex, vagus nerve, and superior laryngeal nerve.
Cerebral cortex
Speech area of temporal cortex. Voice area of precentral gyrus. Corticobulbar tract. Nucleus ambiguous. Cranial nerve X and spinal cord. Coordinates laryngeal muscles, sensation, abdominal musculature
Vagus Nerve
longest of the cranial nerves, Latin = “wandering”. Medulla to Jugular Foramen (IX, X, XI)
Superior Laryngeal Nerve
Internal Branch = Sensation. External Branch = Motor to Cricothyroid Muscle (CT)
Recurrent Laryngeal Nerve
all intrinsic muscles but CT Laryngeal Developmental Anatomy and Innervation
Cervical levels of vocal folds
Birth C3-C4. 5 years C6. 15-20 years C7. Descent leads to lower vocal pitch. With aging, more descent. Laxity of musculature, etc.
Resonator
We can tune to our frequencies by changing the shape of our vocal tract, including The jaw, The tongue, The lips, The nasopharynx. Vocal tract length effects formant frequencies. Shorter tract=higher fundamental frequencies. Adult male 17-20cm. Children frequencies 40% higher. Adult females 15% higher
Hoarseness
abnormal voice changes, breathy, raspy, strained, weak
Dysphonia
general alteration of voice quality. Usually a laryngeal source
Dysarthria
defect in rhythm, enunciation, articulation. Usually a neurological or
muscular source
Stridor
large airway noise from obstruction
Stertor
snoring sound from nose, nasopharynx, throat
Wheezing
pulmonary from smaller airways
Stridor
Inspiratory – supraglottic, extrathoracic. Expiratory – tracheal, large bronchi intrathoracic. Biphasic – laryngeal, immediate subglottis
Causes of Hoarseness
Viral laryngitis – acute. Reflux – chronic. Vocal abuse. Allergies, PND. Chronic cough. Nodules. Polyps. Trauma. Age. Neurological disorders. Smoking without malignancy. Malignancies of thyroid, larynx, lungs. Others
When should a patient see an otolaryngologist?
If hoarseness lasts longer than 2-3 weeks. If hoarseness is associated with: Pain, note ear radiation possible, Coughing up blood, Difficulty swallowing, A lump in the neck, Complete loss or severe change in voice lasting longer than a few days
Vocal fold cysts
are collections of fluid in sac-like formations on the vocal folds. Cysts can deteriorate the quality of human speech production, causing diplophonia, a condition where the vocal cords produce multiple tones at the same time, or dysphonia, an impaired quality of voice typically involving hoarseness or a breathy sound. Etiology: Trauma, previous injury. Can be hemorrhagic or mucous. Treatment: Therapy, can require surgery. Reactive masses can occur on the other side. Often resolves with therapy
Vocal Fold Polyps
Polyps may occur at the mid third of the membranous cords and are more often unilateral. They frequently result from an initiating acute phonatory injury. Polyps may have several other causes, including gastroesophageal reflux, untreated hypothyroid states, chronic laryngeal allergic reactions, or chronic inhalation of irritants, such as industrial fumes or cigarette smoke. Polyps tend to be larger and more protuberant than nodules and often have a dominant surface blood vessel. Etiology
– Trauma, predisposition. Hemorrhagic verses fibrotic
– affects how likely it is to resolve on own. Treatment
– Usually requires surgical intervention for resolution
Granulomas
occur in the posterior glottis against the vocal processes. They can be bilateral or unilateral. They usually result from intubation trauma but may be aggravated by reflux disease. Contact verses vocal process. Etiology– Reflux, Vocal Abuse. Treatment– Correct abuses, Surgery /Botox
Reinke’s edema
also known as polypoid degeneration, is the swelling of the vocal folds due to fluid collection (edema) in superficial lamina propria of vocal folds (Reinke’s space). It is named after Friedrich B. Reinke. Reinke’s edema causes the vocal folds to swell giving them an uneven, sac-like appearance. They appear pale and translucent. Individuals with Reinke’s Edema typically have low-pitched, husky voices because the vocal cords are thickened. Common causes of Reinke’s edema include smoking, gastroesophageal reflux, hormonal changes such as hypothyroidism and chronic voice abuse. The first course of treatment is to remove the source of the irritant (e.g. smoking cessation, vocal rest, etc.). This can be effective if done soon after development of the edema. Surgery is also an option and can result in some restoration of the voice but is ineffective in complete restoration of the voice to its original state. Decortication of the vocal folds, i.e. removal of a strip of epithelium, is done first on one side and 3–4 weeks later on the other side. Speech therapy is given for proper voice production.
A vocal cord hemorrhage
occurs when blood collects within the layers of the vocal cord after a blood vessel breakes. Vocal cord hemorrhages are essentially bruises of the vocal cord. Singers and others who use their voices often who experience a sudden change in the voice should be concerned for a hemorrhage, and evaluated immediately to prevent long term damage. Vocal cord hemorrhages occur after a traumatic voice event such as: Screaming or yelling, Singing loudly, Coughing, Voice overuse or misuse. Treatment– Strict Voice Rest. Resolution depends on technique and individual healing and is usually complete. Vocal fold tear has the same etiology and treatment.
The term sulcus vocalis
a groove or infolding of mucosa along the surface of the vocal fold. In the area of the sulcus, the mucosa is scarred down to the underlying vocal ligament, giving it a retracted appearance. Sulcus vocalis may be congenital or secondary to vocal trauma, infection, degeneration of benign lesions, or surgery. Can be asymptotic. Treatment– Difficult surgical problems if symptomatic. Vocal fold webs are the same except is due to anterior fusing of VF.
Vocal fold bowing or Presbyphonia
a condition that occurs in patients of advanced age. The combination of a thinned vocal fold cover and a decrease in underlying muscle bulk lead to incomplete closure of the vocal folds. Patients typically have a weak and breathy voice, which translates into difficulty being heard in background noise. Superior Laryngeal paralysis can be a cause. Treatment– Increase VF bulk (therapy, surgery). Prevention– Good techniques, exercise
Laryngeal Trauma
Skeleton Injuries. Arytenoid Dislocations. Etiology: Intubation, trauma. Treatment: Quick diagnosis critical. Cricothyroid Joint Injuries
Vocal cord paresis (or paralysis)
is weakness of one or both vocal folds. Symptoms of paresis include hoarseness; vocal fatigue; mild to severe reduction in vocal volume; pain in the throat when speaking; shortness of breath; aspiration (food or liquids going down the trachea) with frequent resultant coughing, and in extreme cases may cause death. Some causes of paresis include viral infection; cancer or tumor compressing the recurrent laryngeal nerve; intramuscular tumor limiting vocal fold movement; trauma; compression of the recurrent laryngeal nerve[1] from intubation, or laryngopharyngeal reflux. Cardiac surgery represents a risk to normal voice function as the nerves serving the larynx are routed near the heart. Damage to this nerve during open heart surgery is not uncommon. The recurrent laryngeal nerve also runs in close proximity to the thyroid gland making hoarseness of voice due to partial paralysis an important side effect of thyroid surgery. Neurological diseases such as Parkinson’s can deteriorate vocal functions. Paresis may occur from an unknown cause (idiopathic). w/u includes CT scan of skull base through aortic arch with contrast. Laryngeal EMG. Intubation Trauma -> dislocation. Rheumatoid Arthritis. Relapsing Polychondritis. Most reliable method of differentiating between paralysis and fixation is laryngeal electromyography (LEMG). Normal implies fixation. Abnormal implies paralysis
Laryngopharyngeal reflux (LPR)
retrograde flow of gastric contents to the upper aero-digestive tract, which causes a variety of symptoms, such as cough, hoarseness, and asthma, among others.Although heartburn is a primary symptom among people with gastroesophageal reflux disease (GERD), heartburn is present in fewer than 50% of the patients with LPR. Extraesophageal symptoms are the result of exposure of the upper aerodigestive tract to the gastric juice. This causes a variety of symptoms, including hoarseness, postnasal drip, sore throat, difficulty swallowing, indigestion, wheezing, chronic cough, globus pharyngis and chronic throat-clearing. Some people with LPR have heartburn, while others have little or none of this symptom. This is because the material that refluxes does not stay in the esophagus for very long. In other words, the acid does not have enough time to irritate the esophagus. Hoarseness. Chronic cough. Foreign Body sensation (globus). Tracheal Stenosis. Chronic ear disease? Chronic sinusitis? Treatment:
elevation of the head of the bed (3-6 inches), antacids after meals and at bedtime, avoidance of eating 3-4 hours before bedtime, avoidance of alcohol and caffeine, prescription medications may be necessary, aparoscopic Nissen
Symptoms of reflux
bad breath or bitter taste in a.m. a.m. hoarseness or after meals. sensation of a lump in the throat (globus). sensation of post-nasal drip but no nasal issues. heartburn not always present
Human Papilloma Viruses (HPV)
are a group of non-enveloped icosahedral circular double-stranded DNA (dsDNA). HPV clinically presents acutely as warts or chronically as carcinomas (cervical, squamous cell, laryngeal). HPV 6 and 11 cause condyloma acuminata (genital warts) and laryngeal papillomas in children. Laryngeal papillomas can cause airway swelling, hoarseness, and secondary bacterial pneumonia. HPV 6 and 11 cause condyloma acuminata (genital warts) and laryngeal papillomas in children. Laryngeal papillomas can cause airway swelling, hoarseness, and secondary bacterial pneumonia. Treatment– Lifelong disease. Transformation to cancer occurs in some
Precancerous and Cancerous Lesions
Smoker/ Drinker, but not always. Early treatment important. Stage and type important. Treatment
– Conservative Surgery, Radiation
The Cough Mechanism
Cough defends the body by clearing pathogens, particulates, foreign bodies, and accumulated secretions from the lung airways, larynx and pharynx. Normal children and adults cough every day. The vagus nerve is the major afferent pathway in the cough reflex arc. Within the vagus nerve, three main subtypes of afferent nerves regulate cough: rapidly adapting receptors (RARs), slowly adapting stretch receptors (SARs), and C-fibers. RARs and SARs are highly sensitive to mechanical stimuli (bronchial obstruction, lung inflation), while C- fibers are highly sensitive to noxious chemical stimuli. From an anatomical perspective, cough is initiated in areas supplied by the vagus nerve, including the ear (via the auricular branch of the vagus), pharynx, lungs and trachea, heart, and esophagus. Cough may also be initiated voluntarily, via the cerebral cortex. This is sometimes handy in social situations (e.g., attracting attention of medical students before a lecture).
The efferent pathway of the cough reflex
consists of 4 phases: 1. Inspiratory Phase: inhalation ends before closure of the glottis. 2. Compressive Phase: thoracic and abdominal muscles contract against a fixed diaphragm (modified Valsalva maneuver); intrathoracic pressure increases (≤ 300 mm Hg). 3. Expiratory Phase: glottis opens; air is rapidly (≤ 500 miles/hr!) expelled. 4. Relaxation Phase: chest wall and abdominal muscles relax
Conditions associated with impaired cough
In order for cough to clear the airways effectively, both the afferent and efferent pathways of the cough reflex must be intact. Conditions associated with impaired cough include general anesthesia, sedation, intoxication, use of certain medications (particularly narcotics), neuromuscular diseases (e.g., spinal cord injury), and the inability to close the glottis properly (e.g. following stroke or laryngeal surgery). Patients with these conditions are more likely to aspirate oral or gastric contents into the lungs, resulting in pneumonia or chronic airway disease (e.g., bronchiectasis). Inability to clear airways secretions also predisposes to atelectasis (partial collapse of the lung), which also can lead to pneumonia.
Complications of cough
Complications of cough result from the increase in intrathoracic pressure during the compressive and expiratory phases of cough, which can be transmitted to the central nervous system, mediastinum, and abdomen. From a patient’s perspective, cough can have a profoundly detrimental effect on quality of life. Patients with chronic cough may develop hoarseness, headaches, insomnia, retching, and vomiting. They are often embarrassed by their cough and may shy away from social activities. They may worry that they have a disease like tuberculosis or lung cancer.
Approach to the Diagnosis of Cough in Adults
History: key elements include the duration of cough (8 weeks), frequency and timing of cough (day/night), relationship to exposures (e.g., sick grandkids, allergens, dust, chemicals), ameliorating or exacerbating factors (e.g., meals, medications, diet), and quality (e.g., dry, productive of blood or sputum). The review of systems should include questions about nasal/sinus disease, esophageal disease (including heartburn frequency), and other respiratory symptoms. Inquire about occupation and workplace exposures. Physical: look at vital signs for clues to a life-threatening cause. Focus in on areas that have vagal afferents for cough—ears, nose, throat, neck, chest, heart, upper abdomen.
Acute Cough in Adults
Acute cough is defined as cough lasting less than 3 weeks in duration. The key step is to determine whether cough is likely to be a symptom of a life-threatening or, as is usually the case, a non-life-threatening condition. Life-threatening conditions include: Upper respiratory tract infection; Lower respiratory tract infection, or acute bronchitis; Exacerbation of a pre-existing condition, e.g. asthma, bronchiectasis, upper airways cough syndrome (UACS) (see below), COPD; Environmental/ occupational exposures.
Upper respiratory tract infection
“the common cold”, is the single most common cause of acute cough. The clinical syndrome of nasal congestion, nasal discharge, postnasal drip, throat clearing, sneezing and cough is familiar to all. Virus-induced post-nasal drainage irritates the larynx, and inflammatory mediators from the upper airway increase sensitivity of sensory afferent nerves in the upper airway. Antibiotics should not be prescribed, because these are viral infections.
Lower respiratory tract infection, or acute bronchitis
A respiratory tract infection, usually (>90%) viral in etiology, manifested predominantly by cough, with or without sputum production. Acute bronchitis should be distinguished from pneumonia, either using clinical data (vital signs, chest exam) or with an x- ray (no infiltrates are seen in bronchitis). Routine treatment with antibiotics is not justified. Short-term treatment with antitussives (e.g. dextromethorphan, codeine) is occasionally helpful. Bacterial causes (and antibiotic therapy) should be considered in certain settings, such as patients with exposure to Bordetella pertussis (whooping cough) or adolescents/ young adults living in group situations (Mycoplasma pneumoniae, Chlamydophila pneumoniae).
Environmental/ occupational exposures
Acute exposure to allergens (e.g. pollens, fungi) and irritants (e.g. dusts, certain chemicals) may precipitate cough or exacerbate a pre-existing condition (asthma, UACS, COPD).
Subacute Cough in Adults
Subacute cough is defined as cough lasting 3-8 weeks in duration. The key step in evaluation is to determine whether the cough follows an obvious preceding upper or lower respiratory infection. In postinfectious cough, cough is stimulated by persistent postnasal drainage, mucus accumulation in the sinuses or lung airways, extensive upper and/or lower airway inflammation, or increased bronchial hyperresponsiveness. In most cases of postinfectious cough, antibiotic therapy is not indicated. Postinfectious cough may exacerbate other conditions, including UACS, asthma, GERD, and COPD. It is important to consider pneumonia and bacterial bronchitis as causes of subacute cough, as these conditions would be treated with antibiotics. The cough associated with B. pertussis bronchitis can be particularly long- lasting (“the hundred day cough”). If the subacute cough does not appear to be related to a respiratory infection, it is evaluated as if it were a chronic cough.
Chronic Cough in Adults
Chronic cough is defined as cough lasting more than 8 weeks in duration. The three most common causes of chronic cough in immunocompetent adults with normal chest x-rays are, in descending order of frequency, UACS, asthma, and GERD. In one prospective study in 1990(2), UACS, asthma, and GERD accounted for 86% of all cases of chronic cough in a pulmonary outpatient clinic. More recently, NAEB has been added to the list of common etiologies. NAEB is probably less common than GERD. It is important to remember that chronic cough may result from more than one condition. Twenty-six percent of chronic cough was caused by more than one disease in this same study (2). Common causes of chronic cough in the adult patient in whom the chest x-ray does not reveal a potential cause of chronic cough include the following: Upper airway cough syndrome (UACS); Asthma; Gastroesophageal reflux disease (GERD); Non-asthma eosinophilic bronchitis (NAEB); Neuropathic Cough (Chronic Cough Hypersensitivity Syndrome)
Upper airway cough syndrome (UACS)
the most common cause of chronic cough, sometimes referred to as postnasal drip syndrome. Mechanism: stimulation of upper airway cough receptors by secretions from the nose or paranasal sinuses, or direct irritation or inflammation of upper airway cough receptors. Symptoms: sensation of “tickle” or something in throat, throat clearing, hoarseness, nasal congestion and drainage. Some patients with UACS (20%) will have cough as their only symptom. Signs: cobblestone appearance of oropharyngeal mucosa, mucus in nasal passages or oropharynx. Possible underlying causes of nasal and sinus inflammation, including: allergic rhinitis, non-allergic rhinitis, postinfectious rhinitis, bacterial sinusitis, rhinitis medicamentosa (persistent nasal drainage associated with over-use of topical alpha-agonists nasal sprays or cocaine). Diagnostic/therapeutic trial: first generation anti-histamine/decongestant combination medication for ≥ 2 weeks. Improvement or resolution of cough is consistent with UACS.
Asthma
a chronic, inflammatory airway disorder characterized by variable airflow obstruction and airway hyperresponsiveness. Mechanism: stimulation of cough receptors by inflammatory mediators, mucus, bronchoconstriction.
Symptoms of asthma
classic asthma is characterized by a triad of intermittent wheezing, dyspnea, and cough. However, in a subgroup of asthmatics (6.5% to 57%, depending on the study), cough may be the only symptom of asthma. This condition is called cough-variant asthma.
Signs of cough- variant asthma
When present, bilateral, polyphonic expiratory wheezing supports the diagnosis, but it is often absent.
Diagnostic Tests for asthma
Pulmonary Function Testing: a ≥ 12% and 200 ml increase in FEV1 after administration of a short-acting bronchodilator (e.g. albuterol) supports a diagnosis of asthma. In patients with cough-variant asthma, pulmonary function testing may be normal, i.e.
Diagnostic/therapeutic trial of asthma
inhaled bronchodilator and an inhaled corticosteroid for ≥ 8 weeks, with avoidance of triggers (e.g. allergens), if appropriate. In some cases, oral corticosteroids are needed. Improvement or resolution of cough confirms the diagnosis of asthma.
Gastroesophageal reflux disease (GERD)
the backflow of stomach contents into the esophagus. Mechanism: stimulation of the afferent limb of the cough reflex by 1) irritation of the upper respiratory tract (e.g., the larynx); 2) irritation of the lower respiratory tract by aspiration of large or small amounts of gastric contents; or 3) an esophageal-bronchial cough reflex, in which refluxate in the distal esophagus alone triggers cough. Note that cough can increase GERD, resulting in a vicious cycle of cough and reflux. Symptoms: cough, with or without phlegm, may be the only symptom of GERD. Gastrointestinal symptoms (heartburn, regurgitation) may be absent in ≤ 75% of patients with GERD-related chronic cough. Some patients complain of hoarseness. Signs: there are no specific exam findings for GERD. Diagnostic Tests: 24-hour esophageal pH monitoring is the most sensitive and specific test for GERD-related cough. It shows an abnormal increase in acid reflux events and an association between reflux events and cough. Diagnostic/therapeutic trial: gastric acid suppression with a proton pump inhibitor (e.g. omeprazole) for ≥ 2 months, combined with diet and lifestyle modification. Improvement or resolution of cough confirms the diagnosis of GERD.
Non-asthma eosinophilic bronchitis (NAEB)
eosinophilic airway inflammation, similar to that seen in asthma, but without variable airflow limitation or airway hyperresponsiveness. NAEB may develop in response to environmental or occupational exposures (e.g. allergens, certain chemicals). Most often diagnosed by subspecialists. Mechanism: likely via stimulation of lower airway cough receptors by inflammatory mediators. Symptoms: cough without wheezing or dyspnea (indistinguishable from cough-variant asthma). Signs: No wheezing on chest examination. Diagnostic Tests: Pulmonary function testing is normal. Methacholine inhalation challenge is normal. Induced sputum analysis (patient inhales hypertonic saline, coughs up sputum, sputum cells are classified and counted) shows an increase (>3%) percentage of eosinophils. This test is not widely available. Diagnostic/therapeutic treatment trial: inhaled corticosteroid for ≥ 4 weeks.
Neuropathic Cough (Chronic Cough Hypersensitivity Syndrome)
Cough that is triggered by low level stimuli such as changes in ambient temperature, taking a deep breath, laughing, talking on the phone for more than a few minutes, cigarette smoke, aerosol sprays, perfumes, and eating crumbly dry food. Symptoms that patients can complain of include repeated throat clearing, chest tightness, hoarse voice and dysphonia, a globus sensation and dysphagia. Hypersensitivity caused by denervation of the upper airways (laryngeal sensory neuropathy) is usually induced by chronic irritation from post-nasal drip, gastroesophageaal reflux disease, environmental pollutants, vitamin B12 deficiency and also post-viral vagal neuropathy. The diagnosis is usually suspected after the other causes of chronic cough are excluded or managed and the cough persists. Treatment is aimed at eliminating or reducing the chronic irritation and with neuropathic medications such as amitryptyline and gabapentin.
An algorithm for diagnosing and treating chronic cough
Note that a chest x-ray is performed at the beginning of the algorithm. For patients in whom the chest x-ray, history and physical fail to pinpoint a cause for cough, UACS, asthma, NAEB, and GERD are the top diagnostic considerations, and empiric treatment, starting with UACS is implemented. If the cough resolves or partially improves with treatment of the condition, then it is concluded that the cough was caused by that condition. If the history, physical, or chest x-ray point to another probable cause of cough, then diagnostic evaluation and treatment would be immediately directed at that abnormality. For example, if the patient appears to have cough related to COPD, then bronchodilator therapy for COPD might be initiated. Or, if the chest x-ray revealed a lung mass, a bronchoscopy might be performed to obtain tissue for diagnosis.
Targets for pharmacotherapy in the upper airway
targets include bronchial smooth muscle, secretory cells, blood vessels, cough center, sensory pain afferents, inflammatory cell mediators (both synthesis and release pathways).
Bronchial smooth muscle pharmaceutical targets
muscarinic, leukotriene, histamine H1 receptors cause bronchoconstriction. beta-2 adrenergic receptors cause bronchodilation.
Secretory cells pharmaceutical targets
muscarinic receptors cause increased secretion.
Blood vessels pharmaceutical targets
alpha-1 adrenergic receptors cause vasoconstriction. Muscarinic, histamine H1, and bradykinin receptors causes vasodilation.
Cough center pharmaceutical targets
mu opiod receptors cause suppress cough reflex.
Sensory pain afferents pharmaceutical targets
bradykinin and histamine H1 receptors cause an increase in pain.
Pathophysiology of allergic disorders
Initial allergen exposure stimulates B cell mediated production of IgE antibodies
that attach to surface of mast cells. Subsequent exposure to the antigen (e.g., pollens and mold spores) will trigger the release of preformed inflammatory mediators from mast cells (histamine). Largely confined to the upper respiratory tract.
Symptoms of allergic disorders
Symptoms resulting from the interaction of histamine with H1 receptors predominate, including: itching, pain, vasodilation, and plasma exudation (profuse watery rhinorrhea, postnasal drip, and nasal congestion). An anaphylactic reaction is an extreme example of this response that occurs system wide and can be life-threatening. Symptoms include: urticaria, abdominal cramps, laryngospasm, bronchospasm, decreased blood pressure, shock.
[Leukotrienes, prostaglandins, platelet-activating factor (PAF), and kinins are also released from mast cells in Type I reactions necessitating treatment with the physiological antagonist, epinephrine. Antihistamines have additive effects with epi but are not sufficient alone.]
Pathophysiology of common cold
Rhinoviruses (> 100 serotypes) are responsible for majority of adult colds. Attachment of virus to respiratory epithelial cell surface receptor begins the infection, initiating a series of biochemical and immunologic events that generate inflammatory mediators, with bradykinins of especial importance. On the other hand, mast cell mediators such as histamine appear to have a smaller role in the viral inflammatory response.
Symptoms of common cold
Most common cold symptoms appear 1-3 days after infection and can be explained by the actions of bradykinins including: pain via activation of nociceptors, nasal stuffiness via dilation of blood vessels, nasal fluid hypersecretion via increased capillary permeability (also via parasympathetic reflex mechanisms), and cough via activation of irritant sensory receptors.
Therapeutic Strategies
Drugs that are used in the treatment of a number of respiratory conditions accomplish two broad therapeutic objectives: (1) Maintenance of airway patency and (2) Treatment of respiratory tract irritation and control of respiratory secretions. Specific drug categories include: Antihistamines [primary use in allergic rhinitis, minor role in viral cold infections] Decongestants [primary use in allergic rhinitis and viral cold infections] Antitussives [useful in coughs associated with viral cold infections, allergic rhinitis, asthma, COPD] Mucolytics [some utility in viral cold infections and COPD] Expectorants [some utility in viral cold infections and COPD]
Bronchodilators
(Beta-adrenergic agonists, Anticholinergic agents [primary use in asthma, also useful in COPD, some viral cold infections])
Anti-Inflammatory Agents
(Corticosteroids and Cromolyn sodium) [primary use in asthma, (variable efficacy in COPD), allergic rhinitis] [covered in asthma lecture]
Leukotriene Antagonists
[primary use in asthma, also in allergic rhinitis] [covered in asthma lecture]
Antihistamines
(H1 Receptor Antagonists) [drugs listed on page 4; see appendix for discussion of histamine physiology]. Agents are also available that prevent histamine release (cromolyn sodium) and physiologically antagonize histamine effects (epinephrine).
First generation agents have additional blocking actions at non H1-receptors (structurally similar
to antagonists of these receptors). Not generally seen with second generation agents.
H1 receptor blockade Pharmacodynamics
Reversible and competitive block, with neglible H2 blocking effects.
Muscarinic receptor block
Pharmacodynamics
Sedation (CNS): Common effect, intensity varies among agents; also contribution from
H1 blockade. NOTE: Second generation agents (fexofenadine, cetirizine, and loratadine, desloratadine) are highly H1 selective (less antimuscarinic actions) and have less complete CNS penetration, both actions contribute to a significantly lower level of sedation. Prevention of nausea and vomiting (CNS): Several agents have good activity in preventing motion sickness and in treatment of nausea/vomiting of pregnancy. Antiemetic effects occur via block of both muscarinic cholinergic and histamine H1 receptors at multiple sites that are involved in the control of vomiting. NOTE: Second generation agents will not have this action. Block of secretions (ANS): These peripheral antimuscarinic drying actions may be of uncertain benefit in nonallergic rhinorrhea, but greater likelihood of problems with side effects such as blurred vision, dry mouth, and urinary retention. NOT seen with second generation agents.
Sodium channel blockade Pharmacodynamics
Effective local anesthetic agents via block of the Na+ channels involved in action potential
generation (diphenhydramine, promethazine). Actually more potent than procaine. Most often used topically for this effect.
Adrenergic receptor block Pharmacodynamics
(esp. the phenothiazine group [promethazine]). May cause orthostatic hypotension in susceptible individuals.
Clinical uses of antihistamines
Allergic reactions (rhinitis and urticaria) [H1 receptor block], most common use: Goal of therapy to minimize sedation; effects of different agents may vary among individuals. First generation antihistamines have considerable sedating properties (e.g., diphenhydramine, chlorpheniramine) and are available over-the-counter (OTC). Second generation antihistamines that are available OTC include loratadine and cetirizine. Chronic use may diminish clinical effectiveness, possibly due to increased metabolism (can try switch to different class). Cough suppression [Na+ channel block]: Direct antitussive effect (blocks both afferent and efferent pathways); questionable efficacy. Motion sickness and vestibular disturbances [H1 and muscarinic receptor block]: Diphenhydramine (in dimenhydrinate) and promethazine act to interrupt visceral afferent pathway to vestibular nuclei via receptor block. Nausea / vomiting of pregnancy [H1 and muscarinic receptor block]: Meclizine and dimenhydrinate have lowest risk for teratogenicity (category B). Sleep aid for insomnia [H1 and muscarinic receptor block]: Over-The Counter 1st generation agents are used for this purpose (diphenhydramine [Benadryl] and doxylamine [Sominex])
Side Effects of antihistamines
Sedation, prominent with 1st generation agents like diphenhydramine. Cetirizine is the most
sedating of second generation agents. Additive CNS depression possible with alcohol and
other CNS depressants. [Less with 2nd generation agents]. Antimuscarinic action is sometimes used therapeutically (inappropriately), but dry mouth
occurs with chronic use. [Less with 2nd generation agents]. Paradoxical excitation (disinhibition) at ordinary doses in children (occasionally) and adults
(rarely); convulsions and coma at toxic dose levels. Postural hypotension (more likely with phenothiazine agents). Some GI effects: Loss of appetite, nausea / vomiting, constipation (take with water or meals)
Mechanism of action for Topical Decongestants (available OTC)
Stimulate α1-adrenergic receptors of vascular smooth muscle resulting in constriction
of nasal blood vessels dilated by histamine or inflammatory response. Promotes drainage, improves breathing via decrease in local congestion in nasal passages. Produces prompt effect relative to oral decongestants which can lead to tendency to overuse.
Side effects of Topical Decongestants (available OTC)
Topical administration associated with rebound congestion (rhinitis medicamentosa) due to ischemia / local irritation (minimize by restricting use to 3-4 days). Individual agents: include phenylephrine and oxymetazoline. Primary difference is intensity and duration of action
Phenylephrine (Neosynephrine)
One of most effective agents; but may produce
marked irritation in some individuals. Shorter duration, up to 4 hours.
Oxymetazoline (Afrin) / Xylometazoline (Otrivin)
Longer acting agents (6-12 hr
duration); used only twice per day, limiting rebound congestion. Oral Decongestants (available OTC, some restrictions)
Mechanism of action for Oral Decongestants (available OTC, some restrictions)
Oral administration delivers drug via systemic circulation to nasal vascular bed,
NOT associated with rebound congestion. Advantage of longer duration of action, unaffected by
characteristic of mucus, but less intense vasoconstriction than topical agents.
Side effects of Oral Decongestants (available OTC, some restrictions)
Affects other vascular beds (not limited to nasal blood vessels) and can cause headaches, dizziness, nervousness, nausea, increased blood pressure / palpitations, but these effects are usually only apparent at higher doses or with chronic, excessive use. Still, use
cautiously if history of hypertension or arrhythmias.
Types of oral decongestants
pseudoephedrine, phenylephrine, and phenylpropanolamine.
Pseudoephedrine (Sudafed)
Effective vasoconstrictor, less vasopressor effect than ephedrine, little CNS stimulation. Probably safest and most effective of oral agents.
Phenylephrine (Sudafed PE)
Substrate for hepatic MAO, thus blood levels hard to predict due to interpatient differences in metabolism; usually present in OTC products
in inadequate doses. Duration up to 4 hours.
Phenylpropanolamine
(formerly in many combination cold preparations and as an
appetite suppressant): Resembles ephedrine, but more vasoconstriction and less CNS stimulation; peak effect in about 3 hours. [Withdrawn from market in 2000 due to increased incidence of hemorrhagic strokes in women patients].
Antitussives
(Cough Suppressants). Indicated when need to reduce frequency of cough, especially dry, non- productive cough as excessive coughing can be discomforting and self-perpetuating. Types of antitussives include codeine, hydrocodone, dextromethorphan, diphenhydramine, and benzonatate.
Mechanisms of action for Antitussives
Include both central and peripheral actions. The most effective agents are those that are agonists at endogenous opioid receptors that act to depress the cough center in brain stem (codeine, dextromethorphan, hydrocodone). Diphenhydramine is generally less effective, working through antihistaminic and/or local anesthetic actions.
Codeine, Hydrocodone (in Tussionex)
Opioid drugs (controlled substances); very effective antitussives, less physiological / psychological dependence when used as recommended; less effect on respiration. Most common adverse effects are nausea, drowsiness, constipation; allergic reactions (pruritus less common).
Dextromethorphan (in Robitussin DM, OTC)
Variable effectiveness. Opioid agonist, but does not depress respiration or predispose to addiction. Mild adverse effects including drowsiness, GI upset; but can produce phencyclidine (PCP)-like effects and coma at doses 50-100X therapeutic. Most commonly used OTC cough suppressant.
Diphenhydramine (Benylin, OTC)
Safe and effective antitussive; but greater propensity for side effects (sedation, antimuscarinic effects) than dextromethorphan.
Benzonatate (Tessalon Perles)
Tetracaine (local anesthetic) congener
Guidelines for Pharmacologic Treatment of Cough in Adults
Acute cough due to common cold: 1st generation antihistamine/decongestant (e.g., brompheniramine/pseudoephedrine). Naproxen (tid x 5 days): blocks inflammation that stimulates cough afferents. Comments: Antitussives show mixed results; zinc not recommended; 2nd generation
antihistamines ineffective. Cough due to upper airway cough syndrome (postnasal drip): 1st generation antihistamine/ decongestant (e.g., brompheniramine/pseudoephedrine)
Expectorants
Use is highly controversial because of doubts of therapeutic efficacy. Mechanism: Uncertain, proposed to ease expectoration by stimulating respiratory tract secretions, thus decreasing their viscosity. The decrease in viscosity of secretions enhances the normal mucociliary mechanism for removing these accumulated upper and lower respiratory tract secretions, thus encouraging ejection of phlegm and sputum. Increasing fluid intake (6-8 glasses/day, use of cool mist or steam vaporizer probably as or more effective. Side effects: No absolute contraindications to use; most common adverse effect is GI upset. Individual agents: Guaifenesin (Mucinex, Robitussin, OTC): Only expectorant approved as generally safe and effective by the FDA. Also causes reflex gastric stimulation; seldom associated with gastric upset or nausea.
Mucolytics (N-acetyl cysteine [Mucomyst])
Mechanism: Splits disulfide linkages between mucoproteins resulting in decreased viscosity of
pulmonary mucus secretions. Also possesses antioxidant properties. Generally administered directly (via inhalation) to the respiratory mucosa. Side effects: Major concern with use in COPD is the irritation associated with its administration
may trigger bronchospasm (should always be given with a bronchodilator). Other adverse effects include nausea, vomiting, stomatitis, and rhinorrhea.
Respiratory Tract Innervation
Rich supply of vagal afferent (carry sensory information to the CNS) and efferent fibers.
Cholinergic neurons of the respiratory tract
Provide the predominant neuronal tone to the respiratory tract (with exception of blood vessels). Activation of muscarinic cholinergic receptors (M3) by acetylcholine produces bronchoconstriction of smooth muscle, increases in respiratory glandular secretions, and dilation of blood vessels.
Adrenergic neurons of the respiratory tract
Adrenergic innervation of bronchial smooth muscle is sparse, although non- innervated β2-adrenergic receptors are present and subject to pharmacologic activation resulting in bronchodilation. Blood vessels are innervated and provide the predominant vasoconstrictor tone via norepinephrine interaction with α1-adrenergic receptors.
