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.
Nonadrenergic, noncholinergic neurons of the respiratory tract
Via nitric oxide release produces bronchodilation
Respiratory Mucosa
Specialized membrane lining surfaces of the upper and lower respiratory tracts. Cells of respiratory mucosa include ciliated and non-ciliated epithelial, goblet, and basal cells and mucous-secreting glands. Glandular secretions include enzymes, immunoglobulins, and other
immunomodulatory factors. Double fluid layer covers the respiratory mucosa with the outermost, thick and sticky, layer trapping
foreign materials such as dust, bacteria, and viruses. The innermost, thin and more aqueous, layer
sweeps the outermost layer toward the larynx via the synchronous action of ciliated epithelial cells. Interstitial tissue contains lymphocytes, fibroblasts and mast cells, often located close to neurons and
blood vessels in the epithelium
Cough Reflex
Irritation to the respiratory tract will activate sensory receptors that transmit impulses to the medulla via vagal nerves to the medulla. The medullary “cough center” then coordinates the complex cough response that propels mucous, cellular debris, and foreign material from the lower respiratory system. Sneeze reflex is a similar response that takes place in the nasal passageways.
Synthesis-Storage and Release of Histamine
Formed by decarboxylation of the amino acid histidine, then either stored or rapidly inactivated. Found in most tissues, unevenly distributed. Especially rich at sites of potential injury: nose, mouth, feet, internal body surfaces (skin, lungs, GI mucosa) and blood vessels. Exists in bound form in granules located in mast cells (tissue) or basophils (blood). Many stimuli (associated with allergic and inflammatory conditions) can trigger release. Immunologic release (sensitized by IgE antibodies): Degranulate on exposure to antigen as a mediator of type I (immediate) allergic reactions. Substances from IgM/IgG immune reactions (complement cascade: C3a, C5a) also initiate release. Amine drugs (e.g., morphine, codeine) can displace histamine from storage but this action is not associated with degranulation (as with chemical and mechanical mast cell injury).
Pharmacodynamics of histamines
Mechanism of action: Agonist at membrane surface receptors (H1, H2, and H3 subtypes). Tissue / organ effects. Most actions are mediated through H1 receptors (↑ IP3 / DAG): Cardiovascular: [H1]: Vasodilation of arterioles via NO (decreased BP, reflex tachycardia); increased capillary permeability (hypovolemic shock, edema, urticaria /
hives). [H2 (↑ cAMP)]: direct cardiac stimulation and vasodilation (higher levels). GI tract: Contraction of smooth muscle (cramping) [H1]. H2 receptor-mediated increase
in gastric acid secretion. Bronchiolar smooth muscle [H1]: Bronchoconstriction (prominent in asthmatics due to
hyperactive neural response). Neurons [H1]: Stimulation of sensory nerve endings-> pain, itching. “Triple Response” (wheal and flare) [H1]: Initial reddening (vasodilation in vascular smooth muscle), puffy and pale “wheal” (edema via endothelial cell separation), then brighter red “flare” (nerve-mediated vasodilation – axon reflex). CNS: Largely presynaptic H3 (↓ cAMP); decreases neurotransmitter release. Anaphylactic reaction [H1]. 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. This necessitates treatment with the physiological antagonist, epinephrine; antihistamines, while effects are additive with epinephrine, are not sufficient alone
two basic types of respiratory failure
hypoxemic and hypercapneic, though in truth, respiratory failure is a spectrum of disease, and may well involve varying degrees of both types.
Hypoxemic respiratory failure
Hypoxemic respiratory failure, strictly speaking, is respiratory failure due to inadequate oxygenation. Any process that impairs oxygen transport across the alveolar/capillary barrier can cause hypoxemic respiratory failure. Examples include alveolar filling processes, such as left heart failure with pulmonary edema, pneumonia, alveolar hemorrhage, and ARDS, as well as extra-alveolar processes, such as pulmonary vascular disease and shunt. The management of extra-alveolar hypoxemic respiratory failure is often far more difficult than the management of alveolar hypoxemic respiratory failure, and the nuances and adjuvant therapies involved are beyond the scope of this discussion. However, common to all types of hypoxemic respiratory failure are two key mechanical ventilatory parameters that are used to correct hypoxemia. These will be discussed below.
Hypercapneic respiratory failure
Hypercapneic respiratory failure is due to inadequate ventilation, or more colloquially, inadequate CO2 removal. Any process that impairs ventilation, be it obstructive lung disease, restrictive lung disease or physiology, or central causes of hypoventilation can cause hypercapneic respiratory failure. We often speak of hypercapneic respiratory failure in terms of “can’t breathe” (physiological hypoventilation) versus “won’t breathe” (central hypoventilation). As with respiratory failure in general, patients with hypercapneic respiratory failure may fall anywhere on the spectrum between “can’t” and “won’t”.
Dead space
Another important consideration in terms of ventilator failure is dead space. As you should know from previous lectures, dead space is partitioned into anatomic (trachea, mainstem bronchi, and conducting airways that have no means by which to participate in gas exchange – a fixed volume, usually about 150 cc) and physiologic (lung parenchymal volume that is un- or underperfused). Any process that decreases perfusion to aerated lung increases physiologic dead space. Decreased blood flow may be caused by hypovolemia, low cardiac output, or vascular obstruction such as a pulmonary embolus. This may also occur in a patient who requires high ventilation pressures, such that in certain zones, the alveolar pressure exceeds the feeding arteriolar pressure, effectively obstructing blood flow. This is sometimes referred to as West Zone 1 lung.
West zones
Understanding that this is an ex-vivo model that may not completely accurately represent human physiology (though comes pretty close in the mechanically ventilated patient), West and his colleagues divided the lung into three functional zones. Zone 1, as described above, has no blood flow due to the fact that alveolar pressure exceeds arteriolar pressure, collapsing pulmonary capillaries and obstructing blood flow. Zone 3 is ideally perfused lung, where vascular pressures exceed alveolar pressures, and blood flow remains consistent. Zone 2 perfuses in an intermittent, pulsatile fashion, at times in the cardiac and respiratory cycle when the arterial and venous pressures exceed alveolar pressures.
Mixed respiratory failure
There are innumerable permutations of combinations of central and physiological hypoventilation, as are there for hypoxemic and hypercapneic respiratory failure. Emphysema may be the easiest to comprehend. As you will learn in further lectures, patients with emphysema lose alveolar tissue and diffusing surface area, resulting in hypoxemia. Alveolar tissue is also important for maintaining patency of small airways, and its loss may also result in hypercapnea due to airways obstruction. The respiratory centers of patients with emphysema often become conditioned to their disease process, leading them to be more “accepting” of chronic hypercapnea. This is an example of central hypoventilation, and these patients are referred to as “CO2 retainers.” A patient with emphysema who comes in with an acute respiratory infection and COPD exacerbation (see future lecture), may develop mixed respiratory failure, with acute hypoxemic respiratory failure due to worsening of their underlying diffusion limitation, acute hypercapneic respiratory failure due to worsened airflow obstruction, and chronic central hypoventilation exacerbated by CO2 narcosis.
Mechanical ventilation
We will consider the mechanical ventilator as a black box with four dials. Again, this is a gross oversimplification of the real world. However, knowledge of these four parameters is necessary to understand more advanced concepts in ventilation, and knowledge of only these four parameters is sufficient for managing the vast majority of patients on the ventilator. Your parameters are: 1. FIO2 - the fraction of inspired oxygen between 21% (room air) and 100% (pure oxygen. 2. PEEP - Positive end-expiratory pressure.
- Respiratory rate - hopefully self explanatory.
- Tidal volume - also hopefully self explanatory.
The two determinants of ventilation
are respiratory rate and tidal volume. In fact, minute ventilation is simply the respiratory rate times the tidal volume. The two determinants of oxygenation are FIO2 and PEEP. This may not be as intuitive as the determinants of ventilation. Hopefully, the role of FIO2 needs no explanation – the more oxygen you put in, the better the patient’s oxygenation should be. PEEP is used to achieve and maintain alveolar recruitment by limiting lung deflation at end-expiration. The more PEEP you use, the more recruitment you get - up to a point: you can only recruit every single recruitable alveolus, and more PEEP above this will not help and may hurt. What you need to know: to increase ventilation, increase tidal volume and/or respiratory rate; to increase oxygenation, increase FIO2 and/or PEEP.
ARDS
The Acute Respiratory Distress Syndrome (ARDS). ARDS was initially defined based on three criteria: 1. Diffuse bilateral radiographic infiltrates
2. PaO2:FIO2 ratio
The Berlin Defintion
- Diffuse bilateral radiographic infiltrates 2. PaO2:FIO2 ratio
Risk stratification of ARDS
PaO2:FIO2 201-300 is mild with 27% mortality. 101-200 is moderate with 32% survival. Less than 100 severe with 45% survival.
Pathophysiology of ARDS
ARDS is marked by intense alveolar inflammation with increased pulmonary capillary permeability. This results in neutrophil and inflammatory macrophage influx, epithelial cell damage and death, alveolar flooding, intra-alveolar accumulation of protein deposits known as hyaline membranes, and sometimes hemorrhage. ARDS is not a disease, but a syndrome, a collection of clinical findings that may be due to any of a variety of disease processes. Many different diseases can lead to ARDS, including inflammatory conditions such as parncreatitis or systemic infections with sepsis, direct toxic injury due to inhalation or aspiration, and a variety of conditions that probably have under-appreciated inflammatory components, such as trauma, transfusion, CNS processes like head trauma or stroke, amniotic fluid embolism, fat emboli syndrome, and acute renal failure. The most common causes of ARDS are sepsis, pancreatitis, trauma, aspiration, and transfusion.
The clinical course of ARDS
is varied. Patients who die early in their course (≤3 days) usually die of their underlying illness. Patients surviving into their second week of illness usually take one of two courses: near-complete resolution or development of fibroproliferative disease and chronic interstitial lung disease in those who survive to discharge. Interestingly, most patients who die in the first 28 days of their illness die of extrapulmonary organ failure, not of respiratory failure, indicating that ARDS is a systemic process. In a study of one-year survivors of ARDS, 80% had some measurable physiological or functional deficit, and only 49% had returned to work. Subsequent evaluation of this cohort
Treatment of ARDS
Many strategies to improve survival in ARDS have been studied, including drugs, fluid management, different monitoring strategies, and several ventilatory strategies. Of all of these, only ventilation with low tidal volumes has been successful. There are subtle nuances to the ventilation strategy, such as adjustment of tidal volume based on lung compliance (plateau pressure), that did not materially affect the average tidal volumes of each cohort, and are not important for you to know. The low tidal volume strategy was continued even if patients developed hypercapnea and respiratory acidosis, and the acidosis was corrected with sodium bicarbonate to maintain pH ≥ 7.15. This concept is referred to as “permissive hypercapnea.” Interestingly, systemic markers of inflammation were elevated in the high volume cohort, supporting the concept of ARDS as a systemic, and not just pulmonary, disease. Indeed the fact that mechanical ventilation can induce or worsen lung injury have been known and studied for decades, but this was the first and only large-scale clinical trial to demonstrate survival benefit with a low tidal volume strategy. The only other intervention in ARDS that reliably improves outcomes is prone positioning in severe disease– a PaO2:FIO2 ratio of 150 or less using the Berlin definition, to receive standard care (6 cc/kg, plateau pressure ≤ 30 cm H2O, permissive hypercapnea) in the supine position (with crossover to prone position only in cases of severe, refractory hypoxemia), or to standard care plus a protocolized mandatory proning strategy. Patients were kept prone for a minimum of 16 hours initially, after which specified clinical parameters governed timing of supination and reproning.
Apnea
Cessation of nasal and oral airflow for a duration of at least 10 seconds. There are three types of apnea, namely central, obstructive and mixed.
Hypopnea
Reduction of airflow or amplitude of thoraco-abdominal movement by at least 30% from baseline, for at least 10 seconds in duration, and accompanied by oxyhemoglobin desaturation of 4% or more
Respiratory event related arousal (RERA)
Reduction in airflow that does not meet the criteria for either apnea or hypopnea and is not associated with significant oxygen desaturation
Obstructive event
Cessation or reduction of airflow that occurs despite the persistence of ventilatory efforts
Central event
Cessation or reduction of airflow that occurs in association with the absence of ventilatory efforts
Mixed event
Cessation or reduction of airflow with an initial central component and a terminal obstructive component
Cheyne-Stokes respiration
Crescendo-decrescendo variability in respiratory rate and tidal volume
Apnea index (AI)
Number of apneas per hour of sleep time
Apnea-hypopnea index (AHI)
Number of apneas plus hypopneas per hour of sleep time
Respiratory disturbance index (RDI)
Number of apneas plus hypopneas plus RERAs per hour of sleep time
Severity of obstructive sleep apnea
mild is 5-15 apnea-hypopnea index. Moderate is 16-30. Severe is greater than 30.
Risk factors of obstructive sleep apnea
Patients with OSA often have a positive family history of the disorder. Risk of developing OSA is greater among offsprings and first-degree relatives of OSA patients. Male gender is a risk factor for the occurrence of adult OSA. OSA is relatively more common in childhood (ages 3 to 5 years) than during adolescence and early adulthood. Prevalence progressively increases in middle-aged individuals until the sixth and seventh decade of life. Although the risk of developing OSA increases with aging, no specific age-related anatomic or functional factors primarily account for this increased risk. Prevalence may be higher among African -Americans, Mexican -Americans and Pacific Islanders compared with Caucasians. Certain craniofacial and cervical anatomic features increase the risk of developing OSA. Excess body weight, endocrinology disorder, neurologic disorders, smoking, alcohol use, medication use, nasal congestion and amyloidosis.
Gender and OSA
Among women, menopause increases the predisposition for developing OSA. In contrast, there appears to be no gender difference in OSA prevalence among children. There are several factors that could possibly account for the gender differences in the predisposition for developing OSA, including variations in distribution of body fat (peripheral obesity in women and central obesity in men), upper airway anatomy (narrower oropharynx in men), hormones (female estrogen and progesterone stimulate respiration and upper airway muscle tone; male androgens inhibit them), and central ventilatory control systems.
Anatomic features and OSA
Increasing neck circumference (> 17 inches in men and > 16 inches in women) is
correlated with greater apnea hypopnea indices (however, not independent of body
mass index [BMI]). Nasal features (nasal narrowing, deviated septum, polyps, prominent turbinates, or
chronic congestion). Lingual features (macroglossia or posteriorly displaced tongue). Palatal features (large broad uvula, low-lying soft palate). Enlarged tonsils and adenoids (especially in children). Restricted oropharyngeal size (generally narrowest at the level of the velopharynx),
especially its lateral dimensions. Maxillomandibular features (midface hypoplasia, retrognathia, micrognathia, or
mandibular hypoplasia). Hereditary syndromes (Down, Pierre-Robin sequence, achondroplasia, Crouzon, Apert,
Treacher-Collin, and Cornelia De Lange)
Excess body weight and OSA
(overweight defined as a BMI ≥ 25 kg/m2 and obese as BMI ≥ 30–40 kg/m2) is a major risk factor for OSA. The prevalence of OSA increases with greater excess body weight and is especially high among morbidly obese persons. Other factors influencing the risk of OSA include fat skin-fold thickness, intra-abdominal fat, and percentage of body fat. Excess body weight may be particularly important in persons without any apparent craniofacial or oropharyngeal features that would predispose them to developing OSA. Distribution of fat is important because central or nuchal obesity (increased waist-hip ratio and neck circumference) appears to correlate better with OSA severity than obesity in general (ie, body weight). The apnea hypopnea index is correlated with leptin levels.
Excess body weight can contribute to the development of OSA either by fatty deposition in the upper airways leading to reduced airway size and decreased muscle tone, or by reducing lung volumes, which, in turn, decreases upper airway size.
Aside from obesity, increased fat deposition in the upper airways can be seen in patients with acromegaly or myxedema.
Endocrine disorders and OSA
Untreated hypothyroidism (myxedema) can precipitate or exacerbate existing OSA, possibly secondary to upper airway narrowing, macroglossia (due to deposits of mucoproteins), upper airway myopathy, or impairment of ventilatory control systems. (Note: Routine screening for hypothyroidism in patients presenting with OSA is not warranted unless other clinical features suggestive of hypothyroidism are present.) Acromegaly is also associated with a greater risk of OSA.
Neurologic disorders and OSA
OSA and central sleep apnea (CSA) may develop following strokes. OSA has also been described in association with several neuromuscular conditions, such as Duchene muscular dystrophy, myotonic dystrophy, postpolio syndrome, neuropathies, and myopathies.
Smoking and OSA
Smoking can induce edema in the upper airways and increases risk for the development of OSA.
Alcohol use and OSA
Ingestion of alcohol close to bedtime can aggravate OSA. Alcohol inhibits the activity of the upper airway muscles and increases airway collapsibility. In addition, it can diminish arousal responses to airway obstruction, prolong apnea duration, and worsen oxygen desaturation.
Medication use and OSA
Several medications, including muscle relaxants, sedative -hypnotics (benzodiazepines and barbiturates), narcotics, and anesthetics can induce OSA by reducing upper airway dilator muscle tone. Some studies, but not all, have demonstrated that administration of benzodiazepines is associated with an increase in the frequency and duration of apneas as well as greater nocturnal oxygen desaturation. Morphine, an opioid analgesic, can depress ventilatory drive and give rise to obstructive and central apneas. Neither zolpidem, zaleplon nor eszopiclone, nonbenzodiazepine benzodiazepine receptor agonist hypnotic agents used for the treatment of insomnia, appear to significantly affect the AHI.
Nasal congestion and OSA
Nasal congestion, due to allergic or nonallergic chronic rhinitis, can worsen snoring and OSA.
Clinical features of OSA
Attention deficit (in children) Awakenings with a sensation of gasping or choking Behavioral disorders Changes in mood (eg, depression) or personality Daytime sleepiness or fatigue Decline in performance at work or school Dry mouth/throat sensation on awakening Excessive body movements during sleep Gastroesophageal reflux Hearing impairment Hyperactivity (in children) Impaired cognition (memory and concentration) Impotence or diminished libido Insomnia Morning headaches Mouth breathing (in children) Nocturia or enuresis Nocturnal diaphoresis Nonrestorative or unrefreshing sleep or naps “Restless” sleep with frequent movements Snoring Witnessed apneas, gasping, or choking
Associated features with OSA
Cardiac arrhythmias Congestive heart failure Ischemic heart disease Nocturnal seizures Parasomnias (eg, confusional arousals, sleep-related eating disorder) Pulmonary hypertension and cor pulmonale (severe disease) Systemic hypertension. Type 2 diabetes mellitus
Physical features of OSA
Crowded posterior pharyngeal space. Dental malocclusion
Enlarged tonsils and adenoids; prominent tonsillar pillars (especially among children) High, narrow hard palate Large neck circumference Large uvula. Low-lying soft palate
Lower extremity edema Macroglossia
Narrow oropharynx (maxilla and mandible)
Nasal septal deviation
Nasal turbinate hypertrophy Obesity (body mass index > 25) Retro- or micrognathia
Consequences of obstructive sleep apnea
Decrease in SaO2 and PaO2. Severity of oxygen desaturation is dependent on baseline oxygen saturation prior to the apnea, lung volume, and duration of apnea; thus, oxygen desaturation is more severe with lower baseline oxygen levels, lesser lung volumes and longer apneic episodes. Increase in PaCO2. Increase in systemic and pulmonary artery pressure. Decrease in left and right ventricular output. Increased vascular resistance secondary to heightened sympathetic nervous system activity. Disturbances in sleep continuity, consolidation, and architecture. Arousal occurs at the termination of the apneic-hypopneic event. Increase in mortality among young and middle-age adults. Systemic hypertension (independent of obesity). Pulmonary hypertension and cor pulmonale. Coronary artery disease (CAD). Congestive heart failure (CHF). Cardiac arrhythmias. Cerebrovascular disease. Excessive daytime sleepiness. Depression. Anxiety. “Irritable” mood. Changes in personality. Diminished quality of life. Decreased alertness. Impairment of cognitive performance. Deterioration of learning and memory. Gastroesophageal reflux is secondary to significant negative intrathoracic pressures prior to resumption of breathing at the termination of apnea. Nocturia, Erectile dysfunction, Decreased libido, Poor sexual function. Insulin resistance.
Treatment of obstructive sleep apnea
general measures include Avoidance of alcohol, muscle relaxants and sedative agents Correction of precipitating factors (eg, hypothyroidism) Smoking cessation. Weight reduction. Positional therapy. Oxygen therapy, pharmacotherapy. Positive airway pressure. Oral devices, and upper airway surgery.
Continuous positive airway pressure
Provides a constant pressure throughout the respiratory cycle
Bi-level positive airway pressure
Provides two pressure levels during the respiratory cycle: a higher level during inspiration and a lower pressure during expiration
Autotitrating positive airway pressure
Provides variable pressures using device-specific diagnostic and therapeutic algorithms
Nocturnal noninvasive positive pressure ventilation
Provides two pressure levels at a set rate to assist ventilation
Problems in host defense
host defects due to alcoholism or genetic abnormalities and diversity. Lung defects including problems in the conducting airways such as with the cilia and cystic fibrosis and with gas exchange portions of the lung such as with surfactant and surfactant proteins. Environmental agents such as air pollution, viral infections, and cigarette smoking.
Effects of chronic alcohol consumption
some of the effects of alcohol on pulmonary host defenses include: altered oropharyngeal flora and increased colonization by gram negative organisms; blunted cough and gag reflexes, predisposing to aspiration; decreased mucociliary clearance; impaired alveolar macrophage and epithelial function. Effects on the epithelium cells include increased apoptosis, decrease surfactant production, increase permeability, and decreased net liquid clearance. The effect on macrophages include decreased phagocytosis, cytokine production, surfactant recycling, and activation of adaptive immune response
How does alcohol impair pulmonary defenses?
In the oropharynx, it changes bacterial colonization and causes poor dentition. In the glottis, it decreases cough and increases aspiration. In the airways, decreases muccociliary function. In the innate immunity, decreases macrophage function and neutrophil function. With adaptive immunity, causes a decrease in T cell and cytokine production, and decreases B cells and airspace IgG.
Airway clearance mechanisms
Air turbulence created by nasal passages, trachea and large airways. Large particles (>10 μm) deposited on mucous-coated surfaces of these airways. Mucous is projected towards the pharynx by the beating of cilia on epithelial cell. Cleared by coughing, sneezing and/or swallowing
Ciliary function
10-15 beats per second. 200 cilia per cell. Coordinated movement. Particle movement: Small airways 0.5-1.0 mm/min and Large airways 5-20 mm/min. Examples of reduced clearance: Air pollution/ozone, Viral infection, Cigarette smoke
Genetic disorders associated with abnormal ciliary function
Primary ciliary dyskinesia (immotile ciliary syndrome). Autosomal recessive. Due to defects in dynein arms. Sinusitis, bronchiectasis, situs inversus, infertility. Kartagener’s syndrome - combination of situs inversus, chronic sinusitis, and bronchiectasis
Constituents of airway epithelial fluid
Antimicrobial peptides and proteins (e.g., β defensins, cathelicidin, lysozyme and lactoferrin). Antioxidants. Antiproteases. IgA. Contribute to maintenance of airway structure and function
Innate immunity
Provides early host defense against virus, fungi, and bacteria. Relies on recognition of pathogen-associated molecular patterns (PAMPs). PAMPs are recognized by secreted, cell surface, or intracellular pattern recognition receptors (PRRs). Engagement of PRRs results in recruitment of phagocytes, killing of microbes, and inflammation
Adaptive immunity
B and T cells. Provides antigen specificity. Upon re-exposure, immunological memory allows for a more rapid and augmented secondary immune response
Role of macrophages in host defense
Suppression of adaptive immune responses. Clearance of particles, bugs and cell debris. Clearance of apoptotic cells. Elicit an inflammatory response. Transport particles and bugs to lymph nodes. Clear alveolar surfactant
Bronchoalveolar Lavage (BAL)
Normal cell differential: 90-95% macrophages,
Which of the following is the predominant cell type in the bronchoalveolar lavage of normal subjects?
Macrophages
Overview of Innate Immune Protection in the Lung
when harmless particles enter the node, it can bind to dendritic cells, which travel to the regional lymph nodes leading to tolerance. Alveolar macrophages clear the particles. There is tonic suppression of inflammation and of adaptive immunity. When a particle with PAMPs enters the lung, it binds to dendritic cells, which travel to regional lymph nodes causing T-cell activation. Inflammation is intiated leading to cytokine and chemokine production, PMN recruitment, microbial killing, DC maturation, and monocyte recruitment.
What does TLR stimulation do?
Generally speaking induce proinflammatory response. Bridge between innate and adaptive immunity. Activates/ enhances oxidative burst from macrophage, neutrophils, eosinophils. Induces cytokines from tissue monocyte/Mø: IL-8, MIP-1 α/β, IL-6, IL-1α/β, IFN-γ, MCP-1, IL-10, IP-10, IFN-αβ. Enhances NK cell activation for killing and IFN-γ production. Activation of epithelial cells. Activation of DCs leading to Cytokine production, Expression of activation markers, and Migration to T cell areas of lymphoid tissue. Induction of type 1 IFN from either infection itself or from TLR stimulation
Resident macrophage of the lung
Suppression of adaptive immunity. Suppression of unwanted inflammation. Phagocytosis of inhaled particulates. Activation by PAMPs
Monocytes of the lung
Differentiation into inflammatory macrophages. Differentiation into inflammatory DCs. Patrolling vascular endothelium. Activation by PAMPs
Resident dendritic cells of the lung
Phagocytosis of inhaled particulates. Migrate to regional lymph nodes. Maintain tolerance in the steady state. Activate adaptive immunity in presence of PAMPs
Initiation of the Granulomatous Response
Inhalation of a stimulus (e.g. Mycobacterium tuberculosis). Development of an alveolitis is an essential initial step in the generation of the granuloma. Two major cell types include activated T cells and macrophages. Cytokine secretion (e.g. IL-1 and IL-2) by activated T cells and macrophages recruit additional cells to the site of inflammation. Step 1-triggering of CD4+ T cells by APCs. Step 2-release of Th1-type cytokines (IL-2, IFN-g, and TNF-a). Step 3-accumulation of immunocompetent cells at the site of disease activity. Granuloma formation can lead to lung injury and possibly eventually fibrosis.
How Do DCs Translate Stimuli Detected in Inhaled Air into a Specific Immune Response?
A harmless antigen binding to a DC causes release of IL-10 and TGF-beta leads to T-regulatory differentiation. Bacteria or viruses in the lungs lead to TLR stimulation leading to amplified migration of DC and expresses IL-12, IFN-gamma, and TNF-beta lead to T-helper 1 differentiation. Allergens causes GM-CSF and PGE2 production leading to amplified migration of DC leading to IL-4, IL-5, and IL-13 and T-helper 2 differentiation.
bronchoalveolar lavage (BAL) in Sarcoidosis
Dramatic increase in the number of CD4+ and/or CD8+ T cells in the lungs of patients with granulomatous lung disease. Percentage of lymphocytes can range from 5- 95% of alveolar cells, depending on the severity of the alveolitis. CD4:CD8 (help ratio>3-15:1. In sarcoidosis the majority of cases have an increased number of lymphocytes and a normal amount of eosinophils and neutrophils. Disease presentation or activity at the time the BAL is performed as well as the smoking status is crucial for interpretation of individual BAL fluid analysis results. In severe cases the number of neutrophils can be increased as well. For an individual case the CD4:CD8 ratio is of less importance because it can be increased, normal, and even decreased.
In subjects with sarcoidosis, a dramatic increase in which cell type in the bronchoalveolar lavage occurs
Lymphocytes
Activated T Cells
Following presentation of Ag by APCs, T cells are activated and express IL-2R. IL-1 and IL-2 attract blood T cells to the site of inflammation. T cells in the lung are increased by 2 potential mechanisms: Influx of Ag-specific T cells from the blood and Local T cell proliferation
Activation of Th1 cell
activated by IL-12 and IFN-gamma. It secretes IFN-gamma, lymphotoxin, and TNF-alpha. They are in charge of cell mediated immunity and intracellular pathogens
Activation of Th 17 cells
activated by IL-23/IL-6 and TGF-beta. Secrets IL-17 and IL-22. Is responsible for clearance of bacterial pathogens and autoimmunity.
Activation of Th2 cells
activated by IL-4. Produces IL-4, IL-5, IL-13. Responsible for humoral immunity, helminth infections, atopy, allergic disease
Th1 Vs. Th2 Vs. Th17 Development
Depends on: Type of antigen/microorganism invading the host (either Intracellular pathogens -Th1 or Helminth infections-Th2). Genetic background of the host. Cytokines present when T cells are first activated. Dose and route of immunization of antigen. Type of dendritic cell presenting to T cells
Proinflammatory and Profibrotic Mediators in the Initiation and Maintenance of Fibrosis
irritants and ROS cause inflammation in epithelial cells leading to IL1beta and TNG-alpha production. Irritants are also engulfed by macrophages, also leading to the release of to IL1beta and TNG-alpha. Inflammation leads to entry and activation of neutrophils and Th17 cells. Th17 cells release IL-17. IL1beta, TNG-alpha, and IL-17 lead to TGF-beta productions which cause epithelial to mesenchyme transition, creating myofribroblasts. Fibroblasts also proliferate and differentiate into myofibroblasts. Myofibroblasts produce extracellular matrix.
Airways diseases
occupational asthma, reactive airways dysfunction syndrome (RADS), chronic obstructive pulmonary disease (COPD), constrictive/obliterative bronchiolitis
Interstitial lung diseases
asbestos-related lung diseases (asbestosis), silicosis, coal worker’s pneumoconiosis, hypersensitivity pneumonitis, chronic beryllium disease
Tools to determine presence of an occupational/environmental lung disease
History: Where do you work? What is your job title? What are your job duties? What are you exposed to? Physical Exam: Findings usually nonspecific. Diagnostics: Pulmonary function testing (PFTs), cardio-pulmonary exercise tolerance test, bronchial challenge testing, chest imaging (chest x-ray, high resolution chest CT), blood tests (eg, BeLPT or tests for antigen-specific antibodies), occasionally lung biopsy. Exposure assessment: Review of MSDS, OSHA reports, exposure sampling
Major determinations of site and severity of lung disease
Dose: duration X concentration. Solubility: more water-soluble agents deposit in the upper airway (i.e. nasopharyngeal mucosa, eg, chlorine); less water-soluble agents affect the distal airways/bronchioles (eg, nitrogen oxides). Particle size: particles > 10 microns are filtered in the upper airway, particles
Occupational Asthma (OA)
Disease characterized by variable airflow obstruction,
airway hyperresponsiveness, and airway inflammation attributable to a particular
occupational exposure. Caused by agents with immunologic/sensitizing properties. OA and asbestos-related lung disease are the most common occupational lung disease
in developed countries. OA accounts for up to 15% of adult asthma.
Causes & Mechanism of occupational asthma
High-molecular weight compounds – eg, animal proteins, baking flours and enzymes that trigger a specific IgE immunologic reaction. Low-molecular weight compounds – eg, isocyanates, plicatic acid (found in western red cedar), epoxy resins, platinum compounds – probably combine with endogenous proteins to create new antigenic determinants
Summary of possible mechanisms in occupational asthma
causal agents of OA are categorized into high-molecular weight and low molecular weight agents. Exposure to high levels of respiratory irritants can induce irritant induced asthma. HMW agents are recognized by antigen presenting cells and mount a CD4 type 2 immunologic response leading to productions of specific IgE antibodies IL-4/IL-13 stimulated B cells. Certain LMW agents also induce specific IgE antibodies, probably acting as haptens and combining with a body protein to form functional antigens. However, most LMW agents do not consistently induce specific IgE antibodies. In this type of OA, a mixed CD4/CD8 type 2/type1 immunologic response or gamma/delta specific CD8 may play a role. Inhalation of high levels of irritants may damage airway epithelium. In subjects who develop irritant-induced asthma, alarm signals form damaged epithelial cells might in turn activate immunocompetent cells. Binding of IgE to their receptors, Th2 (IL-5) and Th1 (IFN-gamma) induce recruitment and activation of inflammatory cells. These cells (mast cells, eosinophils, macrophages and sometimes neutrophils) characterize airway inflammation, which contributes to the functional alterations of OA, that is, airway hyperresponsiveness and airflow obstruction. Subepithelial fibrosis due to thickening of the reticular basement membrane is considered a histopathologic feature of OA. However, the role of this remodeling of the airway in lung function is obscure.
History of occupational asthma
Asthma with Latency – onset months to years after initial exposure. Temporal pattern of symptoms – often, improvement in symptoms on weekends & holidays and decline with return to work. Work history – exposure to a known sensitizer, presence of similar symptoms in co-workers
Diagnostic testing for occupational asthma
confirm the presence of asthma. PFTs/spirometry demonstrate airflow limitation (best assessed
by FEV1 – most repeatable value). Methacholine challenge – demonstrates non-specific bronchial
hyperresponsiveness. Lung imaging – findings are nonspecific and may include
hyperinflation, bronchial wall thickening
Treatment of occupational asthma
Removal from causal exposure. Standard pharmacologic treatment for asthma. Medical follow up and assistance with worker’s compensation, other
benefits programs
Prognosis of occupational asthma
Symptomatic asthma may persist in about 70% of affected workers (especially with delay in recognition and exposure removal).
Case Study of occupational asthma
Auto body worker
Reactive Airways Dysfunction Syndrome (RADS) & irritant induced asthma
Airway epithelial injury from exposure to inhalants with irritant properties, leading to persistent bronchial hyperresponsiveness and airflow obstruction
Causes of RADS
exposure to noxious irritant gas/vapor/dusts (eg, World Trade Center workers exposed to high pH alkaline dust)
Mechanism of RADS
denudation of the mucosa with fibrinohemorrhagic exudates in the submucosa, followed by proliferation of basal cells and subepithelial edema. May expose airway c-fibers, triggering cough and bronchospasm.
Presentation of RADS
No Latency – symptom onset within 24-48 hours of exposure
Diagnosis of RADS
History – Irritant exposure followed temporally by symptoms. PFTs, MCC, chest imaging – airflow limitation and/or bronchial hyperresponsiveness
Treatment of RADS
Pharmacologic asthma management, appropriate workplace restrictions/accomodations
Prognosis of RADS
Majority have persistent asthma
Case Study of RADS
Chlorine exposure
Chronic Obstructive Pulmonary Disease (COPD)
15% of COPD due to occupational causes including biomass combustion,
respirable silica and coal mine dusts (mining), vanadium, organic dusts. Mechanism: probably similar to tobacco-smoke induced COPD – oxidant injury,
imbalance of proteases and anti-proteases. Presentation: symptoms of cough, sputum, wheezing, chest tightness and
dyspnea. Diagnosis: PFTs – fixed airflow limitation (may have component of reversibility with bronchodilator), hyperinflation (elevated residual volume) and decreased diffusion capacity (DLCO). Chest imaging – hyperinflation, emphysema, airway wall thickening. Treatment/Prognosis: Removal from exposure, conventional pharmacologic
management of COPD. Case Study: Coal mining
Constrictive / Obliterative Bronchiolitis
Pathologic injury of small airways (eg, less than 2 mm in diameter), with extrinsic or intrinsic bronchiolar narrowing.
Causes: Exposure to some noxious gases (eg, oxides of nitrogen and sulfur), dusts (combustion products), and chemicals (eg, diacetyl flavoring in buttered popcorn).
Mechanism: Injury to the bronchiolar epithelium results in excessive proliferation of granulation tissue, leading to narrowing or obliteration of the airway. Submucosal or peribronchiolar fibrosis may lead to extrinsic narrowing or obliteration of the bronchiolar lumen.
Presentation: Usually subtle onset of cough, dyspnea, chest tightness. Diagnosis: History: symptoms nonspecific, often insidious – have to probe for relevant exposure. PFTs: fixed airflow limitation, often with air trapping. Chest CT: mosaic air trapping, best seen in expiratory images. CXR is
usually normal. May need surgical lung biopsy if diagnosis is in doubt. Treatment: removal from causal exposure to prevent accelerated lung function decline.
Prognosis for recovery is poor.
Case Study: Flavor workers lung disease
Asbestos-related Lung Diseases
Asbestos fibers – group of naturally-occurring hydrated magnesium silicates that when crushed, break into fibers (friable). Have great tensile strength and flexibility, heat and acid resistance. Two major mineralogic types: serpentine (chrysotile) and amphibole
fibers (crocidolite, amosite, tremolite, anthophyllite, actinolite). Shape and size of fibers (aspect ratio) confer disease risk.
Who is exposed to asbestos?
OSHA developed permissible exposure limit (PEL) for asbestos in 1970’s. Asbestos use, however, is not completely prohibited. Remote exposures: Construction trade workers (e.g boilermakers, sheet metal workers), shipyard and dock workers from early-mid 20th century, painters. Current exposures: construction demolition/remodels, commercial brake mechanics
Mechanism of Asbestos-related Lung Diseases
Direct toxic effects of fibers on pulmonary parenchymal cells, with release of various mediators (reactive oxygen species, proteases, cytokines, and growth factors) by inflammatory cells. Free radicals react with and damage a variety of cellular macromolecules and may disrupt DNA, increasing risk for malignancy.
Non-malignant asbestos-related lung diseases
includes benign asbestos pleural effusion, pleural thickening/calcification/plaque, asbestosis, and rounded atelectasis.
Benign asbestos pleural effusion
Latency – 10-20 years after first exposure. Simple pleural effusion – inconsequential unless large and causing symptoms (shortness of breath) which may prompt thoracentesis; pleural fluid usually exudative with normal glucose
Pleural thickening/calcification/plaque
Latency – 20-40 years after first exposure. Discrete, circumscribed areas of pleural thickening and calcification; unique patterns on CXR (sometimes described as “holly leaf” or “candle wax”); commonly a marker of previous asbestos exposure. Diffuse pleural thickening involving the costophrenic angle can cause chest wall restriction with symptoms and decreased lung capacity.
Rounded Atelectasis
Latency – similar to pleural plaques, 20-40 years. Pleural thickening that curls inward/invaginates into the lung parenchyma in a “comet tail” pattern.
Asbestosis
Latency ~ 20+ years. Bilateral reticular fibrosis (irregular septal lines) affecting lower lung zones preferentially.
Malignant asbestos-related lung disease
Lung Cancer: Latency – 15-30 years; Synergy with cigarette smoking – Risk from smoking (10x) x
Risk from asbestos (5x) = 50x increased risk of lung cancer
compared to non-smokers with no asbestos exposure! All histologic lung cancer cell types can be seen in those
with asbestos exposure. Mesothelioma (pleural, peritoneal): Latency – typically ~40 years. NO increased risk with smoking. A sentinel cancer for asbestos exposure.
Diagnosis of asbestos-related lung diseases
Exposure history, with focus on early occupations (due to long disease latencies). PFTs - classically restricted. Chest imaging – look for plaques, lower lung zone scarring
Treatment of asbestos-related lung diseases
Benign asbestos related lung disease: No specific treatment, but
supportive measures if needed (oxygen supplementation,
pulmonary rehabilitation, immunizations, etc). Lung cancer and Mesothelioma: Conventional oncology care. Removal from exposure. Assistance with benefits programs. Case Study: Libby, Montana
Silicosis
Types and sources of silica: Crystalline silica (quartz, cristobalite, tridamite)
Who is exposed to silica?
Workers who blast, cut, grind with/on respirable silica containing materials. Hard rock miners (gold, silver, etc), foundry workers (often silica sand in huge foundry molds), sandblasters, stone-washed jeans manufacturers
Mechanism of silicosis
Generation of oxygen radicals that injure target pulmonary cells such as alveolar macrophages. Resultant generation of inflammatory cytokines (eg, interleukin-1 and tumor necrosis factor beta) by target cells leads to cytokine networking between inflammatory cells and resident pulmonary cells, resulting in inflammation and fibrosis.
Forms of Silicosis Disease
- Simple silicosis – Upper lobe predominant nodular interstitial lung disease, can progress to diffuse fibrotic lung disease. Sometimes see calcified mediastinal lymph nodes (classic “egg shell calcification” on chest imaging) 2. Complicated silicosis (Progressive Massive Fibrosis) – progression from simple silicosis, with formation of conglomerate masses in the upper lobes causing architectural distortion and lung volume loss. 3. Acute silicoproteinosis (secondary Pulmonary Alveolar Proteinosis) – Lungs fill with proteinaceous fluid caused by high dose inhalation of freshly fractured crystalline silica, eg, during sandblasting. Chest CT shows thickening of the interlobular septae known as “crazy paving”. 4. Accelerated silicosis – Like simple silicosis, just happens faster. 5. Associated conditions: Increased risk for autoimmune renal disease, infection with tuberculous and nontuberculous mycobacteria , lung cancer, chronic bronchitis/emphysema.
Diagnosis of Silicosis
Complete occupational exposure history (long latency of diseases). PFTs – classically restricted, but may be mixed or obstructed. Chest imaging – typically upper lobe predominant nodular disease; silicoproteinosis looks like pneumonia. Biopsy – usually not needed if careful exposure history is obtained.
Treatment of Silicosis
No specific pharmacologic treatment is available. For silicoproteinosis, whole lung lavage may be considered. Removal from exposure and assistance with worker’s compensation/other benefits programs
Case Study of Silicosis
Foundry worker
Coal Workers Pneumoconiosis (Black Lung)
Cause: inhalation of coal mine dust , underground > surface. Mechanism: similar to silica toxicity. Diagnosis: Occupational exposure history is key. PFTs – may be normal, may show obstruction or restriction. Imaging: typical shows upper lobe small rounded nodular opacities. Pathologic feature = “dust macule”. Treatment: Remove from exposure, No specific treatment (except good pulmonary care), Assist with Dept. of Labor Black Lung benefits
Causes of Chronic Beryllium Disease (CBD)
Beryllium (Be) is a lightweight, strong metal used in aerospace engineering, nuclear bomb manufacturing, nuclear reactors, high-tech electronics, etc. When inhaled (i.e. from machining/grinding on Be), may trigger an immune response known as Beryllium Sensitization, BeS (identified by abnormal Beryllium Lymphocyte Proliferation Test, BeLPT, in peripheral blood lymphocytes). Workers with positive BeLPT may develop CBD, a chronic granulomatous lung disease.
Mechanism of Chronic Beryllium Disease (CBD)
Immune response to beryllium, often leading to granulomatous lung inflammation. Some workers have a genetic susceptibility to beryllium’s effects, but there is a dose-response relationship as well that does not require genetic susceptibility.
Presentation of Chronic Beryllium Disease (CBD)
Latency around 10-20 years. Subtle onset of dyspnea, cough. May affect lungs, lymph nodes and skin.
Diagnosis of Chronic Beryllium Disease (CBD)
History of exposure. PFTs, Cardiopulmonary exercise tolerance test, CXR or Chest CT. Peripheral blood BeLPT. Lung biopsy showing granulomas OR BAL with lymphocytosis + positive BAL BeLPT
Treatment and Prognosis of Chronic Beryllium Disease (CBD)
Removal from exposure (medically prudent, but not proven). Inhaled steroids for mild cases; oral steroids for more severe cases. 6-8% per year of BeS patients go on to develop CBD. Assistance with obtaining applicable benefits
Causes of Hypersensitivity Pneumonitis
(HP, also known as Extrinsic Allergic Alveolitis). Some animal proteins (mainly birds) – parrots, cockatiels, cockatoos, finches (Bird fancier’s lung). Microbial aerosols: fungi, bacteria inhaled from contaminated hay (Farmer’s Lung), hot tubs & indoor pools (due to non-tuberculous mycobacteria and gram-negative organisms), humidifiers, machining/metal-working fluids. A few low molecular weight chemicals: isocyanates
Mechanism of Hypersensitivity Pneumonitis
T-cell-mediated immune response, with antigen-specific antibodies
Presentation of Hypersensitivity Pneumonitis
Acute HP: flu-like (fevers, chills, myalgias) respiratory illness (with dyspnea, cough, chest tightness) occurring 6-12 hours after acute, high dose antigen exposure. Subacute/chronic HP: Insidious onset of non-specific respiratory and systemic (loss of appetite, myalgias) symptoms
Diagnosis of Hypersensitivity Pneumonitis
Exposure history. PFTs: classically restricted, but may look normal or obstructed. CT more sensitive than CXR: classically described as an upper-lobe predominant pattern with centrilobular nodularity, ground glass opacities, air trapping, cystic lesions. Biopsy: poorly-formed, non-necrotizing granulomas
Case study of Hypersensitivity Pneumonitis
hot tub lung disease
High Altitude Physiology
There are many potential risks to humans exposed to extreme altitudes (or even modest altitude as seen in some parts of Colorado). Though illness related to hypoxia is the focus of this section, other factors may be dominant at high altitude such as hypothermia, low humidity, and sun exposure. Thus, high altitude visitors and residents require protection from the elements beyond their need for acute and chronic adaptations to hypoxia. Climbers often perish on Mt. Everest from exposure and trauma, not just from hypoxia.
Acclimatization to hypoxia
is a subacute to chronic physiologic process that
permits more efficient function at
altitude. Acclimatization happens to everyone who goes to high altitude, though individuals vary in their responses. Examples are the increase in lung minute ventilation (VE) that occurs over minutes, and the increased erythropoietin (EPO) secretion after days at altitude. Increased VE increases PaO2, while increased serum EPO eventually leads to more red cells (more O2 carrying capacity).
Adaptation to hypoxia
Adaptation, in contrast, is a genetic event and thus occurs only in populations over generations. This form of natural selection increases fitness at altitude – such as in Tibetans whose increase in pulmonary artery pressure to hypoxia is minimal compared to that seen in unadapted Han Chinese lowlanders who migrate to Tibet. The goal of adaptive processes is to maximize delivery of oxygen to (often exercising) tissues. If acute hypoxia is severe in the unacclimatized, the person rapidly becomes unconscious. Thus, unacclimatized air passengers and pilots that suffer cabin decompression at 29,000 ft (9,000 meters) will rapidly lose consciousness and die without emergency 02, yet many climbers summit Mt. Everest (same altitude) without 02, an event possible by gradual acclimatization over 2 months. Likewise, an Iowa lacrosse team that lands at DIA and trains for 1-2 days in the intermediate altitude of Denver before going to the Vail Lacrosse Shootout will have less altitude sickness than a team that flies directly from Iowa to the Eagle county airport for this event.
Cardiac Mechanisms that Increase Oxygen Delivery
02 delivery depends on the oxygen content of blood and its flow. One of the earliest physiological changes that occurs when humans are exposed to acute hypoxia is to increase blood flow (cardiac output). Cardiac output (CO) is determined by heart rate (HR) x stroke volume (SV). An increase in HR occurs within minutes of hypoxia exposure (likely sympathetic). Additionally, since the systemic circulation responds to hypoxia by vasodilating, afterload is decreased and thus SV increases. The net result is an increase in CO and thus in 02 delivery, far in advance of any changes in Hb/red cell mass. However, this increased CO is only an acute adaptive response (likely too “expensive”) and within days CO returns to normal.
Ventilation mechanisms that increase oxygen delivery
Another rapid way to increase 02 delivery is to increase 02 content by increasing arterial Pa02 via increased minute ventilation (VE). Hypoxemia is sensed mainly by the carotid bodies, which then increase
afferent stimulatory signals to the brainstem respiratory centers. This hyperventilation increases Hb 02 saturation. This increased VE can last for days and weeks, and is thus the most useful short term adaptive response to high altitude exposure. Most humans increase their VE (both RR and tidal volume) when their PaO2 falls less than 55 mmHg. An increase in VE due to hypoxemia results in a decrease in both arterial PaCO2 and its surrogate - exhaled (alveolar) PCO2. This occurs as partial pressures (Pp) of all gases in the alveolus must equal one sum – if the Pp of one gas decreases, another gas’s Pp must increase. Based on this principle, one common prevention technique for high altitude illness is the use the oral diuretic acetazolamide, which causes a metabolic acidosis through renal bicarbonate loss. This acidosis triggers a reflexive increase in VE to lower arterial PaCO2 and thus increase pH back toward normal. A parallel increase in arterial Pa02 follows and this is homeostatic too. It is easy to see why patients with diseases or conditions that limit the ability to increase VE (eg pulmonary fibrosis, COPD, morbid obesity) will struggle with travel to ski resort altitudes or mountain passes.
the alveolar gas equation
any decrease in the arterial PaCO2 must increase the PaO2 when percentage of inspired oxygen, barometric pressure, and the A-a gradient are constant. Relatively small increases in PaO2 may lead to a significant increase in saturation based on the oxygen- hemoglobin saturation curve. Thus the best initial way to increase hemoglobin saturation (and thus tissue oxygen delivery) is to hyperventilate. If a person stays at altitude longer, other adaptive mechanisms become important (eg. Increased red cell mass/polycythemia) and augment the sustained increase in VE.
Chronic Compensatory Mechanisms to High Altitude Residence
The chronic adaptation to altitude again includes mechanisms to maximize the O2 delivery to the tissues. An increase in CO is energetically an expensive chronic change, so populations living at high altitude have adopted other strategies to increase O2 content in the blood and its delivery to tissues. Remember that blood O2 content is determined by hemoglobin (Hb) and saturation. Over weeks, the Hb content of the circulating blood increases due to an increase in erythropoietin secreted from the kidneys. The overall effect is to increase hemoglobin and red cell mass, while decreasing plasma volume. The net result is a small increase in total blood volume. However, this is only part of the equation. Increasing hemoglobin saturation is also important to maximize oxygen content.
the Hb-O2 dissociation curve
multiple factors determine the saturation status of Hb. One adaptation to life at high altitude occurs through structural changes in Hb that alter its affinity for O2. A “left shift” in the O2-Hb dissociation curve occurs due to respiratory alkalosis (hyperventilation/decreased PaCO2), which increases O2 saturation of Hb at any given PaO2. Note that decreased blood temperature is an unlikely chronic change. A decrease in 2,3- DPG would left-shift the curve too, but life at high altitude actually increases 2,3-DPG a little - this effect is overcome by the respiratory alkalosis. Thus, chronic respiratory alkalosis ends up increasing Hb saturation both acutely and chronically at high altitude. Even at Denver altitude, average arterial PaCO2 levels in healthy residents are 3-4 mmHg less than at sea level.
Acclimatized people
In persons that have acclimatized to high altitude, the ventilatory responses to both hypoxia and to higher PaCO2 are exaggerated. For example, a person that has acclimatized has an increased VE at a given PaCO2 compared to the VE of a person just arrived to the same high altitude – a PaCO2 higher than 32 mmHg is simply stamped out at high altitude in order to keep Pa02 levels up. For hypoxic ventilatory responses, a newly arrived person will increase VE only when the PaO2 falls to 55 mmHg or less in the first day at high altitude, whereas VE will start increasing when the PaO2 falls below 63 mmHg in those who have spent a few days at high altitude. These compensatory ventilatory responses to hypoxia and higher PaCO2 appear to be due to changes in expression of various genes in the carotid body, aortic body, and brainstem that change “set-points” for PaO2 and PaCO2.
So how can anyone climb to
extremely high altitudes without
supplemental O2?
First, most climbers who summit Mt. Everest and similar peaks are likely genetically gifted in their physiology. Secondly, acclimatization allows the gradual tolerance to conditions that acutely would cause a quick death; these acclimatization changes must occur in brain, muscle, and most organs. Blood gases measured in 2007 in climbers just below Mt. Everest’s summit (off supplemental oxygen) reveal dramatic hypoxemia but also a profound respiratory alkalosis, with average blood gas values of: pH 7.53 PaCO2 13 PaO2 25. While humans at sea level can easily achieve and maintain a similar respiratory alkalosis for days (e.g. diabetic ketoacidosis), they couldn’t tolerate this PaO2 > a few minutes.
A-a gradient in extreme hypoxia
We have thus far employed the alveolar gas equation presuming the A-a gradient is normal. At most levels of alveolar O2 encountered by humans, the diffusion of O2 across the alveolar-capillary membrane is dependent on its thickness and the concentration of Hb (Hb is the “sink” that draws O2 across) in capillaries. However in extreme hypoxia, the diffusion of O2 across the alveolar-capillary membrane may be limited by the severity of hypoxia. in severe hypoxia, the concentration gradient for oxygen (the raw difference in mmHg between mixed venous PO2 or entering lung capillaries and alveolar PO) is lessened leading to diffusion limitation for oxygen. This is worse at a higher CO (RBCs transit the lung capillaries faster) such as during climbing. Thus in extreme high altitude exercise, the A-a gradient may be increased in the absence of any lung disease. Importantly, persons with gas exchange problems causing borderline or low PaO2 at baseline (COPD, pulmonary fibrosis, emphysema, obesity hypoventilation) should avoid exposure to high altitude (> 10,000 ft; especially with exertion); or else they should have their O2 needs at the destination altitude calculated and met by provision of supplemental O2 for travel. Patients with significant lung disease on supplemental O2 in Colorado often find that they don’t need O2 on a California vacation. Those with a borderline low PaO2 at home often find that air travel (cabin pressures average 8,000 ft equivalent) or a Rocky Mountain vacation are poorly tolerated.
Other adaptive mechanisms to chronic hypoxemia
include skeletal muscle adaptations: myoglobin increases in both amount and in its affinity for O2 (another “left shift”) to improve muscle O2 utilization, and muscle increases the density of capillaries by angiogenesis, thus O2 has less diffusion distance between capillaries and myocytes.
train low, sleep high
Recent attention has been focused on the effect of altitude on elite athlete training. One philosophy is to “train low, sleep high.” Athletes that train at altitude may perform worse due to excessive lactic acid generation in hypoxic muscles leading to decreased training intensity. However, the other benefits of altitude exposure (increased red cell mass, increased muscle capillary density, increased myoglobin, etc.) when not exercising may improve performance. Note that the desired effect of illegal blood doping in elite athletes is to increase red cell mass/Hb; some illegally use recombinant erythropoietin injections to achieve this. Other elite athletes have begun sleeping in commercial hypoxic chambers for home use (“sleep high”), but the efficacy of this practice is unclear.
High altitude-related illnesses
Both acute and chronic altitude exposures are associated with a variety of illnesses; some are deadly. Many of us or our family members have experienced an altitude related illness. High altitude-related illness is a spectrum of severity where individual risk varies.
Acute Mountain Sickness (AMS)
AMS is the mildest form of acute altitude illness, but also the most common. AMS is manifest as headache (near universal), nausea, malaise, insomnia, and anorexia. Its incidence is rare below 6,000 ft, is about 25% at typical Summit County resort altitudes (9-10,000 feet), is 50% at Himalayan trekking altitudes of 16,000 ft, and is almost universal above 18,000 feet. Symptoms usually start after 6 hours at altitude and peak by 1 days. A quick rate of ascent increases AMS risk (eg driving to the top of Pike’s Peak in Summer, vs. hiking up). Living at an intermediate altitude (eg Denver) allows partial acclimatization and decreases AMS risk, but if you go to sea level for weeks-months, acclimatization is lost. The mechanism leading to AMS is not certain, but most evidence suggests that AMS is caused by an increase in brain volume in response to hypoxia; this may be due to cerebral edema and/or increased cerebral blood flow/intravascular volume. This theory is called the “tight box” theory, as the skull represents a tight box that impedes expansion of a swollen brain – an appealing mechanism to explain the headache and other prominent neurologic symptoms of AMS. Moreover, cerebral edema clearly occurs in the most severe form of AMS - termed High Altitude Cerebral Edema (see below) which is likely related to increased gene expression of hypoxia-induced proteins that increase capillary permeability. Some persons with AMS have a blunted hypoxic ventilatory drive; a higher PaCO2 and hypoxia both increase cerebral blood flow.
AMS Treatment
Symptoms usually resolve in uncomplicated AMS even without treatment, but simple measures such as analgesics help the headache. Most subjects do not get a specific treatment for AMS, but they may seek prevention measures before a future visit to high altitude as persons who develop AMS are likely to have it again at the same altitude. In more symptomatic cases of AMS, treatment with oral dexamethasone (a corticosteroid) OR oral acetazolamide (a diuretic that causes a respiratory alkalosis) will hasten resolution of AMS symptoms.
AMS prevention
Dexamethasone and acetazolamide find their greatest high-altitude utility in AMS Prevention when started the day before and continued 1-2 days after ascent to high altitude (based on clinical trial data). Dexamethasone blunts hypoxic induction of brain vessel permeability-inducing proteins (proven in rodent models of HACE), and acetazolamide increases minute ventilation (as discussed above). Ibuprofen used similarly, while not mechanistic in effect (it likely just decreases the headache) is very effective in AMS prevention – just as effective as acetazolamide in a large randomized clinical trial. Spending a few days acclimatizing in Denver, or visiting a lower altitude resort (Squaw Valley, Steamboat) are other strategies for preventing recurrent AMS.
High Altitude Cerebral Edema (HACE)
HACE is considered to be the most extreme form of AMS and is a medical emergency. Without appropriate and timely therapy, the patient may die. HACE is uncommon: the incidence of diagnosed HACE at typical Colorado ski resort altitudes in
Treatment of HACE
Treatment is supportive (oxygen, descent, mechanical ventilation for coma), followed by administration of intravenous dexamethasone (based on retrospective case series and animal data). HACE can recur so anyone with HACE needs to avoid a future return to the same altitude. No prevention studies have been done for HACE due to its rarity and the ethical difficulties of its study.
High Altitude Pulmonary Edema (HAPE)
HAPE is a life threatening complication of altitude exposure that is less common than AMS; in Colorado its incidence is 0.1-1% of visitors to typical ski resort altitudes. Symptom onset is usually on the 2nd day and is manifest as cough (occasionally pink frothy sputum), shortness of breath, and fatigue. Signs include hypoxia, lung rales, and infiltrates on chest X-ray. Some HAPE patients also have AMS. The predispositions to AMS and to HAPE are different – not all HAPE- susceptible subjects are susceptible to AMS, and few AMS-susceptible subjects get HAPE. When measured in several studies, the pulmonary capillary wedge pressure is normal during HAPE – HAPE is thus a noncardiogenic pulmonary edema (diuretics to decrease intravascular volume won’t help). In HAPE a main feature is exuberant pulmonary hypertension (PHTN) in response to acute hypoxia. Indeed, HAPE-susceptible subjects demonstrate a marked increase in pulmonary arterial pressure (PAP) even at sea level if breathing a hypoxic gas mixture, and PAP increases even more in these subjects with hypoxic exercise. Accentuated hypoxic PHTN causes uneven vasoconstriction thoughout the lung, leading to scattered lung capillary breakdown with plasma/blood leakage into alveoli. As proof of this mechanism, medications that blunt the hypoxia-related increase in PAP (nifedipine) have been proven to both prevent HAPE and to hasten its resolution. Healthy sea level residents will increase their resting mean PAP from 12 mmHg to 24 mmHg in response to 1 month of residence at 14,000 feet; but their PAP will return to normal when they return home. In adapted populations that have lived at this altitude for centuries, the increase in PAP due to high altitude residence is blunted – in fact at these altitudes Tibetans have a normal mean PAP of 13 mmHg (while Peruvian Indians, less adapted, have slightly higher PAPs). Such adaptations are necessary for population fitness, and likely explain why Tibetans make the best Sherpas. HAPE typically recurs with a similar hypoxic exposure.
Treatment of HAPE
like all altitude illnesses, common sense efforts dictate immediate descent to a lower altitude when safe, and provision of supplemental oxygen. Realistically, at moderate altitudes such as Summit County, mild-moderate HAPE patients are discharged from the ER and sent back to their hotel with an O2 tank and rest for a few days, unless the HAPE is severe. Medications that are useful in HAPE treatment are all vasodilator medications that lower pulmonary artery pressures – the best studied is oral nifedipine (a calcium channel blocker used in treatment of systemic hypertension).
HAPE prevention
Pulmonary vasodilators such as nifedipine and tadalafil are useful in HAPE prevention, as is one inhaled medication that increases the clearance rate of water out of alveoli (salmeterol, a bronchodilator used in asthma care that also increases activity of the Na-K ATPase). Dexamethasone was effective for HAPE prevention in one study, likely (a theme here) due to effects on genes that improve water resorption out of the alveolus (Na-K ATPase). Acetazolamide, though useful in AMS prevention/treatment, does not seem to be useful in HAPE treatment. Given the fact that HAPE can kill, HAPE susceptible individuals should avoid recreational and occupational activities that expose them to hypoxia unless they are close to advanced medical care and accept use of preventative medications.
Chronic Mountain Sickness
High altitude residence leads to multiple complications and illnesses. Infants born at high altitude have on average lower birth weights and higher mortality than those born at sea level. Mothers at high altitude also have higher rates of pre-eclampsia. In many high altitude populations (i.e. Andeans) the pregnant mother moves to lower altitude for the pregnancy and birth. Interestingly, even the average birth weight in Denver is about 250 grams less than the national average; in Leadville it is even lower. Tibetans (the best-adapted) have less problems with this than Andeans at the same altitude. Polycythemia and PHTN due to high altitude residence together denote Chronic Mountain Sickness (CMS, aka Monge’s Disease); with an increased risk of stroke and heart failure. Isolated right ventricular failure due to PHTN can occur, but again is less for Tibetans. A minority of residents in Leadville (10,000 ft) will develop CMS; though evidence of hypoxemia should be sought and treated by either a move to a lower altitude or supplemental oxygen and periodic phlebotomy.
Physics of diving
Atmospheric (or barometric) pressure increases by 1 atmosphere (atm) for every 10 meters of depth in sea water. This translates into tremendous pressure applied to the body of a diver. How is one not crushed while diving? We would be - if it were not for generation of equal but opposite pressure through the use of an underwater breathing apparatus to keep airway pressure equal to the surrounding water column. If we didn’t equilibrate airway pressure with diving (i.e. breath holding), our lungs would be crushed as the outside pressure would compress the lower pressure gas trapped in the lung. While the presence of increased airway pressure keeps us from being crushed at depth, the cost is the increased density of the gas (due to compression). This increased density of the gas increases resistive work of breathing - but for healthy persons this is not prohibitive. For persons with existing airflow limitation (i.e. COPD, moderate asthma) this may translate to significant problems and thus such patients may not tolerate diving. Also, immersion has important effects on lung volumes (abdominal compression upward) and perfusion (increased venous return). Improper management of the physical changes associated with diving can result in significant injuries and death.
Airflow at depth
As the density of gas increases, so does the resistance to flow. The reasons for this depend on understanding complex fluid dynamics but the end result is a decrease in flow rates in the lung. This results in a significant increase in the work of breathing. Adding to the increased work of breathing is the resistance to flow through the tubing and mouthpiece as well as pressure effects on the extrathoracic trachea. The most commonly asked question in the “medical clearance” of divers is a history of asthma. Previously, a history of asthma was a contraindication to diving as the increased viscosity of the gas could result in a poorly tolerated increased work of breathing. Asthma is no longer an absolute contraindication to diving, it just needs to be well controlled. Clearly, someone on vacation who is having even a mild asthma exacerbation should not dive.
Lung Volumes at Depth
Diving and the resultant pressure increase also have important effects on lung volumes. Remembering Boyle’s law, the volume of a gas is proportional to the pressure exerted on the gas; if the pressure is increased by a factor of 2, the volume of the gas decreases by half. This also explains why changes in depth in shallower water result in greater changes in volume than changes in depth in deeper waters. This is the explanation for the phenomenon known as “squeeze” where tissues are displaced into the space the gas occupied at surface conditions. For example, the air in the diver’s mask compresses as the pressure increases with diving at deeper depths. The tissues of the face (especially periorbital) can then get “squeezed” into the mask (resulting in ‘raccoon eyes’ bruising). Clearing the mask underwater by equilibrating it with gas helps. Organs can be subjected to “squeeze”, including the lung. Inner and middle ear trauma, “tooth squeeze”, and “sinus squeeze” also occur. In recreational diving, this usually doesn’t occur because the diver is breathing pressurized gas which keeps the airways and lungs from compressing. Theoretically, for a breath-holding free diver, lung squeeze could happen (since they aren’t filling the lung with pressurized gas) but in reality this doesn’t happen too much since the blood volume in the lung is also increased. Immersion is associated with increased intra-thoracic vascular volume due to increased venous return (legs and arms squeezed) resulting in an increase in CO and central filling pressures. This also results in decreased lung capacity via decreased lung compliance, magnifying the effects of compression. It is thus easy to see why patients with heart failure should avoid diving.
Pulmonary barotrauma
can occur even at shallow depths (
Decompression sickness
Consider the effects of diving on properties of a dissolved gas in blood. O2 and CO2 are dissolved in the blood, representing the PaO2 and PaCO2 measured on arterial blood gases. At equilibrium, the dissolved arterial gases have the same partial pressure (Pp) as the gas dissolved in tissues (such as muscles). For O2 and CO2, the Pp in tissues and blood is usually low and does not easily supersaturate into cause gas bubbles. This is however not true for inert gasses such as nitrogen (79% content in regular air, whether compressed or not) and helium. As pressure increases with increased depth, the Pp of the inert gases increases in blood in tissues. Equilibrium with the tissues takes some time so the longer and deeper the dive, the more concern for decompression sickness (the “bends”) during ascent (the tissues will have had more time to become supersaturated). Decompression sickness (“bends”) occurs with too rapid of an ascent. Gas in supersaturated tissues can form bubbles as pressure decreases with surfacing, these bubbles expand in the tissues and blood causing organ dysfunction. Clinical features range from confusion, musculoskeletal pain, dyspnea, stroke, coma, seizures, paralysis, and death. Recompression (hyperbaric chamber) may drive gases back into the dissolved state - the treatment of choice. Prevention of decompression sickness by graded surfacing is key. Even with careful resurfacing, divers should avoid returning to higher altitude (e.g. getting on the plane home) for several days. Vacationers returning home to Colorado may get decompression sickness in this way.
Nitrogen narcosis
occurs when a diver breathes compressed air (about 75% nitrogen) at depths greater than 100 ft and can cause clumsiness, bizarre behavior (giving his regulator to fish, euphoria (like the effects of nitrous oxide at the dentist), and unconsciousness. The incidence magnifies with increasing depth owing to the narcotic effect of nitrogen. This is why helium is used at dives of > 100 ft. Shallow water blackout is a problem for free divers and for athletes trying to swim a maximal distance without surfacing (ie trying to get into the Navy SEALs). During apneic swims or dives (breath holding), subjects hyperventilate to increase PaO2 before submerging; as the PaO2 progressively falls with time and activity hypoxemia can cause unconsciousness in this setting before any dyspnea occurs. PaCO2 is the major trigger of dyspnea (more than hypoxemia) and PaCO2 rises only 3-5 mmHg for each minute of apnea. If a person hyperventilates to a PaCO2 of 15 mmHg before submerging, a PaCO2 of 45-50 mmHg (that would normally cause dyspnea) may not occur before the PaO2 falls enough to cause unconsciousness (the brain prioritizes the PaCO2 signal over the PaO2). Such persons drown unless a rescuer is present; another reason to never swim/dive alone.
Pediatric lung disease
Pediatric pulmonary disease accounts for almost 50% of deaths in children younger than 1 year and 20% of hospitalizations of children younger than 15 years old. Approximately 7% of children have a chronic disorder of the lower respiratory system. This handout will expose the student to the breath of pediatric lung disease, of which a few diseases will be covered in the lecture. Understanding the pathophysiology of many pediatric pulmonary diseases requires an appreciation of the normal growth and development of the lung.
Growth & development of the lung
The lung has its origins from an outpouching of the foregut during the fourth week of gestation. The development of the lung is divided into five overlapping stages. Abnormalities during the various stages can result in pediatric pulmonary disease. Abnormalities during the embryonic stage result in congenital abnormalities such as lung aplasia, tracheoesophageal fistula, and congenital pulmonary cysts. Abnormalities during the pseudoglandular stage lead to pulmonary sequestration, cystic adenomatoid malformation, and congenital diaphragmatic hernia.
Abnormalities of development during the canalicular stage include
neonatal respiratory distress syndrome (RDS) and lung hypoplasia. Abnormalities during the alveolar stage lead to lung hypoplasia and can result in the development of bronchopulmonary dysplasia.
Lung at birth
At birth, the lung assumes the gas-exchanging function served by the placenta in utero, placing immediate stress on all components of the respiratory system. Abnormalities in the lung, respiratory muscles, chest wall, airway, respiratory controller, or pulmonary circulation may therefore be present at birth. Survival after delivery depends, for example, on the development of the surfactant system to maintain airspace stability and allow gas exchange.
Differences between pediatric and adult airway
- Infant’s larynx and trachea are significantly smaller than an adult.
- The narrowest part of the pediatric airway is just below the vocal cords at the level of the cricoid cartilage, the first (and only complete) ring of cartilage that is the first part of the trachea. In contrast, the narrowest part of the adult airway is the vocal cords.
- Given the small diameter of the pediatric airway the equivalent decrease in airway radius results in a significant increase in resistance and reduction in the cross sectional area of the pediatric airway as compared to the adult.
Extrathoracic airway obstruction
Extrathoracic airway obstruction usually causes stridor or a barking cough. The history should include the following: 1. Age at onset
- Precipitating factors (eg, agitation, positioning, sleeping, eating) 3. Course—acute onset vs. chronic
- Presence and nature of cough
- Production of viral symptoms. Physical examination should include growth measurements and vital signs. The examiner should look for cyanosis or pallor, work of breathing including respiratory rate, retractions, level of consciousness, and evidence of lower respiratory track involvement. The presence of the four D’s of upper airway obstruction indicates danger and the possibility of significant airway obstruction. The four D’s are: Dyspnea, Drooling, Dysphagia, and Distress.
Laryngomalacia
most common congenital disorder of the extrathoracic airway. Key Feature: Presentation from birth or within the first few months of life. Laryngomalacia is a benign congenital disorder in which the cartilaginous support for the supraglottic structures is underdeveloped. It is the most common cause of persistent stridor in infants and usually is seen in the first 6 weeks of life. Stridor has been reported to be worse in the supine position, with increased activity, with upper respiratory infections, and during feeding; however, the clinical presentation can be variable.
Croup Syndromes
Key feature: Patients can present with acute or subacute symptoms.
Croup syndrome describes acute inflammatory diseases of the larynx, including viral croup (laryngotracheobronchitis), epiglottitis (supraglottitis), and bacterial tracheitis. These are the main entities in the differential diagnosis for patients presenting with acute stridor.
Viral Croup
Viral croup generally affects younger children in the fall and early winter months and is most often caused by parainfluenza virus serotypes. Although inflammation of the entire airway is usually present, edema formation in the subglottic space accounts for the predominant signs of upper airway obstruction.
Clinical Findings of Croup
Symptoms and Signs: Usually a prodrome of upper respiratory tract symptoms is followed by a barking cough and stridor. Fever is usually absent or low-grade. Patients with mild disease may have stridor when agitated. As obstruction worsens, stridor occurs at rest, accompanied in severe cases by retractions, air hunger, and cyanosis. On examination, the presence of cough and the absence of drooling favor the diagnosis of viral croup over epiglottitis.
Imaging of Croup
Neck radiographs can be diagnostically supportive by showing subglottic narrowing- steeple sign. This is not done routinely in the child with a classic presentation.
Treatment of Croup
Treatment of viral croup is based on the symptoms. Mild croup, signified by a barking cough and no stridor at rest, requires supportive therapy with oral hydration and minimal handling. Mist therapy is used by some physicians. Conversely, patients with stridor at rest require active intervention. Nebulized epinephrine (2.25% solution; 0.05 mL/kg to a maximum of 1.5 mL diluted in sterile saline) is commonly used because it has a rapid onset of action within 10–30minutes. Glucocorticoids reduce the duration of hospitalizations and frequency of intubations, and permit earlier discharge from the emergency room.
Prognosis of Croup
Most children with viral croup have an uneventful course and improve within a few days. Some evidence suggests that patients with a history of croup associated with wheezing may have airway hyperreactivity.
Epiglottitis
Epiglottitis is a true medical emergency. In published case series, it is almost always caused by Haemophilus influenzae type B, although other organisms such as nontypable H influenzae, Streptococcus pneumoniae, groups A and C Streptococcus pyogenes, Neisseria meningitides, and staphylococci have been implicated. Resulting inflammation and swelling of the supraglottic structures (epiglottis and arytenoids) can develop rapidly and lead to life-threatening upper airway obstruction. The incidence has decreased dramatically since H influenzae conjugate vaccine was introduced, indicating that the best treatment strategy is prevention.
Symptoms and Signs of Epiglottitis
Typically, patients present with a sudden onset of high fever, dysphagia, drooling, muffled voice, inspiratory retractions, cyanosis, and soft stridor. They often sit in the so- called sniffing dog position, which gives them the best airway possible under the circumstances. Progression to total airway obstruction may occur and result in respiratory arrest.
Diagnosis of Epiglottitis
The best way to diagnosis epiglottitis is to visualize the airway.
Treatment of Epiglottitis
Once the diagnosis of epiglottitis is made, endotracheal intubation must be performed immediately. Most anesthesiologists prefer general anesthesia (but not muscle relaxants) to facilitate intubation. After an airway is established, cultures of the blood and epiglottis should be obtained and the patient started on appropriate intravenous antibiotics to cover H influenzae (ceftriaxone sodium or equivalent cephalosporin). Extubation can usually be accomplished in 24–48 hours, when direct inspection shows significant reduction in the size of the epiglottis. Intravenous antibiotics should be continued for 2–3 days, then oral antibiotics to complete a 10-day course.
Prognosis of Epiglottitis
Prompt recognition and appropriate treatment usually results in rapid resolution of swelling and inflammation. Recurrence is unusual.
Bacterial Tracheitis
Bacterial tracheitis (pseudomembranous croup) is a severe life-threatening form of laryngotracheobronchitis. The organism most often isolated is Staphylococcus aureus. The disease probably represents localized mucosal invasion of bacteria in patients with primary viral croup, resulting in inflammatory edema, purulent secretions, and pseudomembranes.
Symptoms and Signs of Bacterial Tracheitis
The early clinical picture is similar to that of viral croup. However, instead of gradual improvement, patients develop higher fever, toxicity, and progressive or intermittent severe upper airway obstruction that is unresponsive to standard croup therapy. The incidence of sudden respiratory arrest or progressive respiratory failure is high; in such instances, airway intervention is required. Aggressive medical treatment and debridement is needed. A high index of suspicion is required for this life-threatening condition.
Diagnosis of Bacterial Tracheitis
Bronchoscopy showing a normal epiglottis and the presence of copious purulent tracheal secretions and membranes confirm the diagnosis.
Treatment of Bacterial Tracheitis
Suspected bacterial tracheitis should be managed similar to epiglottitis. The incidence of respiratory arrest or progressive respiratory failure leading to intubation is high. Patients often have thick, purulent tracheal secretions requiring debridement, and frequent suctioning, and intensive care monitoring are required to prevent endotracheal tube obstruction. Intravenous antibiotics to cover Staphylococcus aureus.,
Differences between pediatric and adult airway
- Airways are smaller and the cross sectional area is lower 2. Infant chest walls have: a. Weak intercostal muscles
b. Ribs are horizontal (not slanted like in adults-see below). This means that infants rely mostly on their diaphragm for increased tidal volume.
c. Diaphragm is flat limiting the change in tidal volume and fatigues easily
Intrathoracic airway obstruction
Intrathoracic airway obstruction usually causes expiratory wheezing. The history should include the following: Age at onset. Precipitating factors (eg, exercise, upper respiratory illnesses, allergens, choking while eating). Course—acute (bronchiolitis, foreign body), chronic (vascular ring), or recurrent (asthma). Presence and nature of cough. Production of sputum. Previous response to bronchodilators. Symptoms with positional changes (airway compression such as vascular
rings). Involvement of other organ systems (trouble with feeds as in aspiration)
Physical examination for intrathoracic airway obstruction
should include growth measurements and vital signs. The examiner should look for cyanosis or pallor, barrel-shaped chest, retractions and use of accessory muscles, and clubbing. Auscultation should define the pattern and timing of respiration, detect the presence of crackles and wheezing, and determine whether findings are localized or generalized. Routine tests include plain chest radiographs and pulmonary function tests in older children. Other diagnostic studies are dictated by the history and physical findings. Treatment should be directed toward the primary cause of the obstruction but generally includes a trial of bronchodilators.
Congenital disorders of intrathoracic airway obstruction
- Tracheomalacia and bronchomalacia
. 2. Tracheoesophageal fistula
. 3. Vascular Rings, Pulmonary slings, and other vascular anomalies that can cause airway compression
Typical features of bronchiolitis
Characterized by acute onset tachypnea, labored breathing, and/or hypoxia. Irritability, poor feeding. Wheezing and crackles on chest auscultation.
Bronchiolitis
the most common serious acute respiratory illness in infants and young children. One to three percent of infants with bronchiolitis will require hospitalization, especially during the winter months. The typical presentation is acute onset of tachypnea, cough, rhinorrhea, and expiratory wheezing. Respiratory syncytial virus (RSV) is by far the most common viral cause of acute bronchiolitis. Human metapneumovirus, parainfluenza, influenza, adenovirus, Mycoplasma, Chlamydia, Ureaplasma, and Pneumocystis are other less common causes of bronchiolitis during early infancy. Major concerns include not only the acute effects of bronchiolitis but also the possible development of chronic airway hyperreactivity (asthma). Bronchiolitis due to RSV infection contributes substantially to morbidity and mortality in children with underlying medical disorders, including chronic lung disease of prematurity, cystic fibrosis, congenital heart disease, and immunodeficiency.
Symptoms and Signs Bronchiolitis
The usual course of RSV bronchiolitis is 1–2 days of fever, rhinorrhea, and cough, followed by wheezing, tachypnea, and respiratory distress. Typically the breathing pattern is shallow, with rapid respirations. Nasal flaring, cyanosis, retractions, and rales may be present, along with prolongation of the expiratory phase and wheezing, depending on the severity of illness. Some young infants present with apnea and few findings on auscultation but may subsequently develop rales, rhonchi, and expiratory wheezing.
Diagnosis of Bronchiolitis
The diagnosis is a clinical diagnosis in a child with upper respiratory track infection, tachypnea, and hypoxemia. Chest radiographic findings are generally nonspecific and typically include hyperinflation, peribronchial cuffing, increased interstitial markings, and subsegmental atelectasis.
Prevention & Treatment of Bronchiolitis
The most effective treatment of RSV is prevention. The best way to prevent RSV infections is to use proper hand-washing techniques and to reduce exposure. Prophylaxis with a monoclonal antibody (palivizumab or Synagis) has proven effective in reducing the rate of hospitalization and associated morbidities in high-risk premature infants and those with chronic cardiopulmonary conditions. Although most children with RSV bronchiolitis are readily treated as outpatients, hospitalization is frequently required in young infants (younger than 6 months of age) and in patients with hypoxemia on room air, a history of apnea, moderate tachypnea with feeding difficulties, marked respiratory distress with retractions, or underlying chronic cardiopulmonary disorders. Supportive strategies including frequent suctioning and providing adequate fluids to maintain hydration form the mainstays of treatment for bronchiolitis. If hypoxemia is present, supplemental oxygen should be administered. Corticosteroids and inhaled bronchodilators have no effect on length of illness or length of oxygen requirement.
Prognosis of Bronchiolitis
The prognosis for the majority of infants with acute bronchiolitis is very good. With improved supportive care and prophylaxis with palivizumab, the mortality rate among high-risk infants has decreased substantially.
Typical features of Asthma
Recurrent symptoms of airway obstruction (cough, shortness of breath, chest tightness). At least partial reversal of bronchospasm and symptom relief with a bronchodilator (e.g. a beta agonist such as albuterol). All other diagnoses ruled out
Asthma
the most chronic pediatric condition affecting more than 9.6 million children under the age of 18. Asthma is also a leading cause of pediatric emergency department visits and hospitalizations and the number one reason for missed school days (over 14 million per year). The costs of treating asthma skyrockets when a patient’s asthma is not well controlled resulting in Emergency Department visits (approximately $600 per visit) and hospitalizations (over $6,600 per stay) instead of controlled asthma treatment which costs approximately $1,800 per year.
Symptoms and Signs of asthma
Recurrent symptoms of cough, wheeze, shortness of breath, or chest tightness usually with specific triggers such as respiratory illness, exercise, or allergens (90% of pediatric asthma is allergic). Symptoms should also be at least partially relieved by a bronchodilator.
Diagnosis of asthma
The diagnosis is often clinical in pediatrics. Over the age of six, children who can perform spirometry may have pulmonary function testing that shows airway obstruction that is at least partially reversible with a bronchodilator. An important part of the diagnosis of asthma is ruling out other causes.
Differential diagnosis of no response to a bronchodilator, hypoxemia, failure to thrive, and/clubbing
Upper/Central Airways: Foreign body, Vascular ring or sling, Laryngo/tracheo/ bronchomalacia. Lower Airways: Bronchiolitis
, Cystic fibrosis
, Bronchopulmonary dysplasia, Heart disease
, Aspiration/GER
Prevention and treatment of Asthma
Asthma is caused by airway inflammation leading to increased mucous production, bronchial hyperreactivity, and airway edema. The treatment of a child with daytime or nighttime symptoms or with exercise intolerance is to control the airway edema and the associated bronchial hyperreactivity, mucus production. The acute, short term treatment for bronchial hyperreactivity is an inhaled beta-agonist. Multiple studies show that frequent symptoms and airway inflammation in children with persistent asthma is more responsive to corticosteroids than other therapeutic options and therefore the chronic treatment of choice is inhaled corticosteroids.
Prognosis of Asthma
Children who wheeze only with illness and children who are not atopic (allergic) are more likely to grow out of their symptoms by age 12. Those who are allergic and have a family history of asthma are more likely to continue wheezing.
Parenchymal pediatric lung disease
Parenchymal lung disease in children refers to disorders that affect the alveoli and associated structures and may also affect the airways. Parenchymal lung disease may present many different ways. The history should include the following: 1. Age at onset
- Course—acute (pneumonia, infection), chronic (BPD), or recurrent (cystic fibrosis)
- Presence and nature of cough
- Production of sputum
- Involvement of other organ systems and growth 6. Hypoxemia. Common acquired causes of parenchymal lung disease acutely includes viral or bacterial pneumonia and chronically bronchopulmonary dysplasia.
Physical examination of Parenchymal pediatric lung disease
should include growth measurements and vital signs. The examiner should look for cyanosis or pallor, barrel-shaped chest, retractions and use of accessory muscles, and clubbing. Auscultation should define the pattern and timing of respiration, detect the presence of crackles and wheezing, and determine whether findings are localized or generalized. Routine tests include plain chest radiographs and pulmonary function tests in older children. Other diagnostic studies are dictated by the history and physical findings. Treatment should be directed toward the primary cause.
Lower respiratory tract infections (LRTI)
are a major cause of childhood mortality in disadvantaged areas of the world. The infectious etiologies vary widely by geographic region and by the age of the child. In developed countries the majority of pneumonias are caused by viral agents and bacterial pneumonia is a less common cause. Discrimination between viral and bacterial pneumonia is challenging. Bacterial pneumonia usually follows a viral lower respiratory tract infection.
Symptoms and Signs of community associated pneumonia
The pathogen, severity of the infection, and age of the patient may cause substantial variations in the presentation of community-acquired pneumonia (CAP). Fevers (over 39°C), tachypnea, and cough are hallmarks of CAP. Chest auscultation may reveal crackles or decreased breath sounds in the setting of consolidation or an associated pleural effusion. Some patients may have additional extrapulmonary findings, such as meningismus or abdominal pain, due to pneumonia itself. Others may have evidence of infection at other sites due to the same organism causing their pneumonia: meningitis, otitis media, sinusitis, pericarditis, epiglottitis, or abscesses.
Treatment of community associated pneumonia
If a bacterial pneumonia is suspected, empiric antibiotic therapy should be considered. Children less than 4 weeks of age should be treated with ampicillin and an aminoglycoside. Infants 4-12 weeks of age should be treated with IV ampicillin for 7-10 days. Children 3 months – 5 years of age should be treated with oral amoxicillin (50-90mg/kg/dose) for 7-10 days. Children over 5 years should be treated with a macrolide antibiotic or amoxicillin or penicillin G depending on the suspected etiology. When possible, therapy can be guided by the antibiotic sensitivity pattern of the organisms isolated. Whether a child should be hospitalized depends on his or her age, the severity of illness, the suspected organism, and the anticipated reliability of adherence to the treatment regimen at home. All children younger than 3 months of age should be admitted for treatment.
Prognosis of community associated pneumonia
In developed countries, for the immunocompetent host in whom bacterial pneumonia is adequately recognized and treated, the survival rate is high. For example, the mortality rate from uncomplicated pneumococcal pneumonia is less than 1%. If the patient survives the initial illness, persistently abnormal pulmonary function following empyema is surprisingly uncommon, even when treatment has been delayed or inappropriate.
Typical features of bronchopulmonary dysplasia
Acute respiratory distress in the first week of life. Required oxygen therapy or mechanical ventilation, with persistent oxygen requirement at 36 weeks gestational age or 28 days of life. Persistent respiratory abnormalities, including physical signs and radiographic findings.
Bronchopulmonary dysplasia (BPD)
remains one of the most significant sequelae of acute respiratory distress in the neonatal intensive care unit, with an incidence of about 30% for infants with a birth weight of less than 1000 g. This disease was first characterized in 1967 when Northway and coworkers reported the clinical, radiologic, and pathologic findings in a group of premature newborns that required prolonged mechanical ventilation and oxygen therapy to treat hyaline membrane disease. The pathologic findings and clinical course of BPD in recent years have changed due to a combination of new therapies (artificial surfactant, prenatal glucocorticoids, and protective ventilatory strategies) and increased survival of infants born at earlier gestational ages. Although the incidence of BPD has not changed, the severity of the lung disease has decreased. Pathologically this “new” BPD is a developmental disorder characterized by decreased surface area for gas exchange, reduced inflammation, and dysmorphic vascular structure.
Pathogenesis of Bronchopulmonary dysplasia (BPD)
The precise mechanism that results in the development of BPD is unclear. The premature lung makes insufficient functional surfactant; furthermore, the antioxidant defense mechanisms are not sufficiently mature to protect the lung from the toxic oxygen metabolites, and lungs destined to develop BPD show early inflammation and hypercellularity followed by healing with fibrosis. Thus abnormal lung mechanics due to structural immaturity, surfactant deficiency, atelectasis, and pulmonary edema—as well as lung injury secondary to hyperoxia and mechanical ventilation—lead to further abnormalities of lung function, causing increases in ventilator and oxygen requirements and resulting in a vicious cycle of progressive lung injury. Although the exact mechanisms are not completely understood, BPD represents the consequences of lung injury caused by oxygen toxicity, barotrauma, and inflammation superimposed on the susceptible immature lung.
Clinical Findings of Bronchopulmonary dysplasia (BPD)
A 2003 summary of a National Institutes of Health workshop on BPD proposes a definition of the disease that includes oxygen requirement for more than 28 days, a history of positive pressure ventilation or continuous positive airway pressure, and gestational age. The new definition accommodates several key observations regarding the disease, as follows: (1) although most of these children were premature, full-term newborns with such disorders as meconium aspiration, diaphragmatic hernia, or persistent pulmonary hypertension can also develop BPD; (2) some extremely preterm newborns require minimal ventilator support yet subsequently develop a prolonged oxygen requirement despite the absence of severe acute manifestations of respiratory failure; (3) newborns dying within the first weeks of life can already have the aggressive, fibroproliferative pathologic lesions that resemble BPD; and (4) physiologic abnormalities (increased airway resistance) and biochemical markers of lung injury (altered protease-antiprotease ratios, and increased inflammatory cells and mediators), which may be predictive of BPD, are already present in the first week of life.
Differential Diagnosis of Bronchopulmonary dysplasia (BPD)
The radiologic appearance of BPD is changing, and severe chronic lung findings of fibrosis with infiltrate are less common. The changes in severe BPD necessitate ruling out meconium aspiration syndrome, congenital infection (e.g., cytomegalovirus or Ureaplasma), cystic adenomatoid malformation, recurrent aspiration, pulmonary lymphangiectasia, total anomalous pulmonary venous return, over-hydration, and idiopathic pulmonary fibrosis.
Clinical Course of Bronchopulmonary dysplasia (BPD)
The clinical course of infants with BPD ranges from a mild increased oxygen requirement that gradually resolves over a few months to more severe disease requiring tracheostomy and chronic mechanical ventilation for the first 2 years of life. In general, patients show slow, steady improvements in oxygen or ventilator requirements but can have frequent respiratory exacerbations leading to frequent and prolonged hospitalizations. Clinical management generally includes careful attention to growth, nutrition (caloric requirements of infants with oxygen dependence and respiratory distress are quite high), metabolic status, developmental and neurologic status, and related problems, along with the various cardiopulmonary abnormalities described in a later discussion.
Prognosis of Bronchopulmonary dysplasia (BPD)
Surfactant replacement therapy has had a significant effect on reducing morbidity and mortality from BPD. Infants of younger gestational age are surviving in greater numbers. Surprisingly, the effect of neonatal care has not significantly decreased the incidence of BPD, as 50% of survivors go on to develop this diagnosis. The disorder typically develops in the most immature infants, but the long-term outlook for most survivors is generally favorable. Follow-up studies suggest that lung function may be altered for life. Hyperinflation and damage to small airways has been reported in children 10 years after the first signs of BPD. In addition, these infants are at a higher risk for developing sequelae such as persistent hypoxemia, airway hyperreactivity, exercise intolerance, pulmonary hypertension, increased risk for chronic obstructive pulmonary disease, and abnormal lung growth. As smaller, more immature infants survive, abnormal neurodevelopmental outcomes become more likely. The incidence of cerebral palsy, hearing loss, vision abnormalities, spastic diplegia, and developmental delay is increased. Feeding abnormalities, behavior difficulties, and increased irritability have all been reported. A focus on good nutrition, prophylaxis against respiratory pathogens and airway hyperreactivity, and attention to school performance continue to provide the best outcomes. Patience, continued family support, attention to developmental issues, and speech and physical therapy help to improve the long-term outlook.
Typical features of Cystic Fibrosis
Greasy, bulky, malodorous stools; failure to thrive.
Recurrent respiratory infections.
Digital clubbing on examination. Bronchiectasis on chest imaging. Sweat chloride > 60 mmol/L.
Cystic fibrosis
CF, an autosomal recessive disease, results in a syndrome of chronic sinopulmonary infections, malabsorption, and nutritional abnormalities. It is one of the most common lethal genetic diseases in the United States, with an incidence of approximately 1:3000 among Caucasians and 1:9200 in the US Hispanic population. Although abnormalities occur in the hepatic, gastrointestinal, and male reproductive systems, lung disease is the major cause of morbidity and mortality. Most individuals with CF develop obstructive lung disease associated with chronic infection that leads to progressive loss of pulmonary function.
The cause of CF
a defect in a single gene on chromosome 7 that encodes an epithelial chloride channel called the CF transmembrane conductance regulator (CFTR) protein. The most common mutation is ΔF508, although approximately 1500 other disease- causing mutations in the CF gene have been identified. Gene mutations lead to defects or deficiencies in CFTR, causing problems in salt and water movement across cell membranes, resulting in abnormally thick secretions in various organ systems and critically altering host defense in the lung.
Clinical Findings of CF
Symptoms and Signs: All states in the US and many other countries now perform newborn screening for CF by measuring immunoreactive trypsin (IRT), a pancreatic enzyme, in blood with or without concurrent DNA testing. Most infants with CF have elevated IRT in the newborn period, although false negative results are possible. In newborns with positive newborn screen, the diagnosis of CF must be confirmed by sweat testing, mutation analysis, or both. Approximately 15% of newborns with CF present at birth with meconium ileus, a severe intestinal obstruction resulting from inspissation of tenacious meconium in the terminal ileum. Meconium ileus is virtually diagnostic of CF, so the infant should be treated presumptively as having CF until a sweat test or genotyping can be obtained.
Presentation of CF
During infancy and beyond, a common presentation of CF is failure to thrive due to malabsorption from exocrine pancreatic insufficiency.. These children fail to gain weight despite good appetite and typically have frequent, bulky, foul-smelling, oily stools. These symptoms are the result of severe exocrine pancreatic insufficiency, the failure of the pancreas to produce sufficient digestive enzymes to allow breakdown and absorption of fats and protein.
Clinical manifestations of CF
From a respiratory standpoint, clinical manifestations include productive cough, wheezing, recurrent pneumonias, progressive obstructive airways disease, exercise intolerance, dyspnea, and hemoptysis. Chronic airway infection with bacteria, including S aureus and H influenzae, often begins in the first few months of life, even in asymptomatic infants. Eventually, Pseudomonas aeruginosa becomes the predominant pathogen. Chronic infection with the mucoid phenotype of P aeruginosa is associated with a more rapid decline in pulmonary function. Chronic infection leads to airflow obstruction and progressive airway and lung destruction resulting in bronchiectasis. Methicillin-resistant S. aureus is increasingly prevalent in CF and may worsen lung disease. CF should also be considered in infants and children who present with severe dehydration and hypochloremic alkalosis. Other findings that should prompt a diagnostic evaluation for CF include unexplained bronchiectasis, rectal prolapse, nasal polyps, chronic sinusitis, and unexplained pancreatitis or cirrhosis.
Laboratory Findings and Imaging Studies of CF
The diagnosis of CF is made by a sweat chloride concentration greater than 60 mmol/L in the presence of one or more typical clinical features (chronic sinopulmonary disease, pancreatic insufficiency, salt loss syndromes) or an appropriate family history (sibling or first cousin who has CF). A diagnosis can also be confirmed by genotyping that reveals two disease-causing mutations.
Treatment for CF
The cornerstone of gastrointestinal treatment is pancreatic enzyme supplementation combined with a high calorie, high protein, and high fat diet. Persons with CF are required to take pancreatic enzyme capsules immediately prior to each meal and with snacks. Individuals should also take daily multivitamins that contain vitamins A, D, E, and K. Caloric supplements are often added to the patient’s diet to optimize growth. Daily salt supplementation also is recommended to prevent hyponatremia, especially during hot weather. Airway clearance therapy and aggressive antibiotic use form the mainstays of treatment for CF lung disease. Antibiotic therapy appears to be one of the primary reasons for the increased life expectancy of persons with CF.
Prognosis of CF
A few decades ago, CF was fatal in early childhood. Now the median life expectancy is around 35 years of age. The rate of lung disease progression usually determines survival. Lung transplantation may be performed in those with end-stage lung disease. In addition, new treatments, including gene therapy trials and agents that modulate CFTR protein function, are being developed based on improved understanding of the disease at the cellular and molecular levels.
What variables determine thoracic gas volume (TGV)?
Lung compliance. Chest wall compliance TGV represents the point when the inward recoil of the lung is exactly balanced by the outward recoil of the chest wall. This is measured at the end of a normal tidal volume. Anything that makes the lung stiffer (such as interstitial lung disease or loss of surfactant) without changing the chest wall compliance will decrease the TGV. Conversely anything that increases lung compliance (such as emphysema) will increase the TGV. Note that TGV and FRC both indicate the same thing but are measured differently. They should be the same in normal people, but can vary in disease.
What variables determine total lung capacity?
Lung compliance. Chest wall compliance Respiratory muscle strength Good effort TLC requires effort (whereas TGV does not) so it is more dependent on patient cooperation. Muscle weakness or reduced inspiratory effort (due to pain or other causes) will reduce TLC even if the chest wall and lung compliance are normal.
How is the diffusing capacity determined?
What factors determine diffusing capacity? Diffusing capacity is determined by measuring the transfer of carbon monoxide out of the gas-exchange units (most commonly done during a 10 second breath hold). The difference between the amount of CO inhaled and exhaled (10 seconds later) is the amount of gas transferred. Helium is used as a tracer gas (i.e. it is not transferred across the alveolar-capillary membrane) to determine the alveolar volume so gas transfer can be normalized to lung volume. Diffusing capacity is determined by alveolar surface area, thickness of the alveolar-capillary membrane, and the presence of passing hemoglobin to which the CO binds.
What does the increased TGV indicate about the respiratory system?
That either the compliance curve of the lung has increased or the compliance curve of the chest wall has increased (i.e. less pressure is required to effect a given change in volume). Increases in TGV almost always represent changes in the compliance curve of the lung. This increase in TGV can represent a permanent change in the compliance curve of the lung (as in severe emphysema) or a temporary increase during acute worsening of lung function (as in asthma).
Differential diagnosis of restrictive pulmonary process
This could be due to a decrease in lung compliance (in chronic disease this would usually indicate interstitial lung disease due to any number of possible causes) or a decrease in compliance of the chest wall. This could include pleural disease (fibrosis, effusion, pneumothorax) muscle weakness, skeletal wall abnormalities (scoliosis, kyphosis, ankylosing spondylitis) or excessive soft tissue (obesity). Any exposures that might lead to interstitial lung disease (asbestoes exposure, coal mining, birds in the house) or presence of joint pain, which can accompany collagen vascular disease. Past history of tuberculosis or pneumonia (pleural fibrosis), muscle weakness, back pain, weight gain is important information to obtain. The presence of crackles on auscultation would suggest interstitial lung disease, as would the presence of nail clubbing. The presence of obvious skeletal abnormalities or excessive weight would be helpful. Chest radiograph or chest CT would be helpful in distinguishing lung and pleural disease from chest wall disease. In terms of PFTs, the DLCO would be helpful in that it would (usually) be decreased in restrictive disease due to interstitial lung disease and normal in other causes. A PV curve (next question) would also be helpful.
Differential diagnosis for normal PFTs and reduced diffusing capacity
Pulmonary vascular disease: Chronic pulmonary emboli, Primary pulmonary hypertension, Scleroderma,Collagen vascular disease, Congenital heart disease, Anorectic drug induced pulmonary hypertension,HIV infection, and Severe anemia
What could explain the decreased DLCO?
The lung appears to be functioning properly based on lung volumes and airflow. Specifically there is no evidence of obstructive or restrictive disease. The primary abnormality is a decrease in diffusing capacity (DLCO). The diffusing capacity is determined by 3 things: 1. It is directly proportional to the surface area of the gas-exchange units (the alveolar-capillary interface) 2. It is inversely proportional to the distance through which it must diffuse, and 3. It requires hemoglobin to be passing through the capillaries to which carbon monoxide (in the test) and oxygen (ordinarily) can bind. Surface area is most commonly reduced in emphysema as the alveolar- capillary interface is destroyed (surface area can be decreased in late stage interstitial lung disease also due to scarring and fibrosis). However there is no evidence of airflow obstruction. Increased membrane thickness can be seen in interstitial lung disease, but there is no evidence of restrictive disease. A reduction in passing hemoglobin can occur if either severe anemia is present or if the blood vessels perfusing alveoli have been blocked or destroyed. Usually the DLCO is corrected for the degree of hemoglobin so it does not just become an expensive way to detect anemia. Therefore these PFTs are most commonly associated with pulmonary vascular disease such as chronic pulmonary emboli, primary pulmonary hypertension, scleroderma or a number of other causes. Any history of: pulmonary emboli or thrombosis, congenital heart disease, symptoms of collagen vascular disease, use of diet pills, HIV infection or family history of pulmonary disease. Clubbing (especially in congenital heart disease), elevated neck veins, loud second heart sound over the pulmonic valve, evidence of collagen vascular disease (telangiectasias, sclerodactyly, synovitis, malar rash, etc).
Ranke complex
Ghon complex + calcified regional hilar and/or mediastinal lymph nodes. Seen in TB
Ghon complex
calcified lung nodule (site of initial infection). Seen in TB
Latent TB infection
MTB is present in small numbers. Tuberculin skin test is positive. Tuberculin skin test is positive. Normal chest x-ray (may have a Gohn complex). Sputum smears and cultures are negative. There are no symptoms and are not infectious.
Active TB in the lungs
MTB is present in large numbers. Tuberculin skin test is positive. Abnormal chest x-ray with pneumonia with or without cavitary lesions. Sputum smears and cultures are positive. Symptomatic with cough, fever, night sweats and weight loss. Often infectious before treatment.
The criteria for a positive TST
depends on the risk for reactivation TB. Greater than 5mm if the patient has Recent close contact to an active case of TB, HIV-positive, Apical fibronodular disease consistent with old healed TB, Organ transplant, Anti-TNFa therapy. Greater than 10mm is positive if Recent tuberculin skin test converter, Immigrants from high prevalent regions for TB, Other high risk groups, and Certain predisposing medical conditions. Greater than 15mm are positive for all others, essentially those who are considered low risk; in essence, these individuals should not be tested in the first place
What are the advantages of IFNg-release assays (IGRA) over TST?
Fewer patient visits. More rapid turnaround time. Quantifying IFNg levels or counting number of “spots” is more objective than measuring diameter of the induration. Sensitivity for LTBI is probably as good or better than TST. In immunocompromised subjects, T-SPOT.TB® may be better than either Quantiferon® or TST. Specificity for LTBI is considered to be better than PPD. For example, in BCG-vaccinated individuals with low risk of exposure, specificity is 86-99% for T-SPOT.TB® and 96-99% for Quantiferon®. A positive test may be more predictive of progression to disease than TST.
Vitamin D and TB
1,25-(OH)2 D3 suppresses growth of MTB in macrophages. In a study of TB in Gujarati Hindus (strict vegans) in foggy London, vitamin D deficiency was a risk factor for TB. In general, African-Americans have lower vitamin D levels and this may account for increased susceptibility for TB. A vitamin D receptor polymorphism (tt genotype) was protective against TB. In contrast, three other vitamin D receptor polymorphism increased susceptibility to TB. Vit D induces expression of cathelicidin, an antimicrobial peptide that kills MTB
What is the treatment for LTBI?
9 months isoniazid (INH) (QD or BIW). A common alternative is rifampin daily for 4 months. Overwhelming evidence that treatment of LTBI with INH reduces reactivation risk by up to 70 to 90%. Risk of INH-associated hepatitis. Risk factors: Age, EtOH, pre-existing active liver disease, use of other hepatotoxic drugs. INH 900 mg + rifapentene 900 mg ONCE WEEKLY x 3 months (~12 doses) vs 9 months of INH could be in the future.
Usual interstitial pneumonia (UIP)/ Idiopathic pulmonary fibrosis histopathological presentation
changes in the lung is more often subpleural than central and in the bases than in apices. The fibrosis is temporally heterogenous. It can be ongoing with multiple cycles of injury. Fibroblastic foci in the subepithelial area of the septae is present. Honeycomb lung development over time is also present.
Non-specific interstitial pneumonia (NSIP) histopathological presentation
is both cellular (inflammatory) and fibrosing (fibrotic). There are diffuse changes in the lung; one area is not particularly worse than another. The fibrosis is temporally homogenous. Rarely has fibroblstic foci in the subepithelial area of the septae and honeycoming.
Phases of acute lung injury (ALI)/ acute respiratory distress syndrome (ARDS) diffuse alveolar damage (DAD)
acutely, there is exudative edema with fibrin deposition leading hyaline membrane formation in the alveoli. There is also edema/fibrin deposition also occurs in the interstitium and septum along with mild inflammation with mononuclear infiltration. The next phase is organizing and proliferative with type II hyperplasia in the alveoli and fibroblast proliferation in the interstitium/septum. The third phase is chronic and fibrotic. Hyaline membranes are mostly reabsorbed and focal fibrosis may occur in the alveoli. Fibrosis may also occur in the interstitum and septum.
Microscopic features of the bronchus
epithelium is ciliated columnar, pseudostratified, and there are no mucus producing cells. Beneath the basement membrane lies the submucosa, which is composed of connective tissues/ fibroblasts, inflammatory cells (normally only a few), smooth muscle, submucosal glands and cartilage.
Pink puffer physiology
predominatly emphysema without a prominent bronchititis component. Appearance is generally thin and cachectic with muscle wasting. They also appear pink and well perfused. Late in course there is scant sputum production. There is no toleration of hypoxia because patient increases respiratory rate to compensate. There is also hyperventilation and normal blood gases. Cardiac output is low compared to blue bloater physiology. There can be late onset of cor pulmonale if it develops.
Blue bloater physiology
is predominantly bronchitis. Appearance is generally overweight with cyanotic lips and nail beds. There is a productive cough due to greater overlay of bronchitis. They also can tolerate hypoxia. They also have decreased ventilation rate and lowered O2 saturation and increased cardiac output (faster pulse). Cor pulmonale with right heart failure is more likely to develop than in pink puffer physiology, which can lead to edema and hepatosplenomegaly.
Bronchitis
injury occurs in the bronchi and bronchiole lumen, which is reduced by mucus and changes in the bronchi. The cause of damage is persistant exposure to irritant (cigarette smoke).
Emphysema
area of injury is the alveoli. Alveolar wall damage leads to reduced elasticity and reduced elastic recoil, resulting in hyperinflation of the lungs
Anthracosis of the pleural surface
is caused by cigarette smoke. It is composed of accumulated carbonaceous material inhaled into the lungs
Distinguish between Blebs and Bulla
descriptors of dilated air spaces: Blebs: 1cm
Centriacinar vs. panacinar patteren in emphysema
Centriacinar pattern = Cigarette smoking; affects central or proximal parts of acini (spares distal alveoli). PAnacinar pattern = Alpha-1 antitrypsin deficiency; uniformly affects respiratory bronchiole to distal alveolus
3 components of the normal anatomy of a bronchiole
Ciliated columnar epithelial cells. Goblet cells are not seen in this image, but normally present Basement membrane: very thin. Smooth muscle. No cartilage or submucosal glands.
Histopathological findings of asthma
Submucosal glands hypertrophy/hyperplasia. Mucus plugs in airway. Goblet cell metaplasia of epithelium. Basement membrane thickened. Smooth muscle hypertrophy. Eosinophilic infiltrate in submucosa
Range of findings in Usual Interstitial Pneumonia
Normal: Patchy areas with relatively spared alveoli and septa. Not fibrotic / not inflamed. Acute to Subacute: Expansion of the septa, probably with inflammatory cells. Magnification is too low to check for fibroblastic foci, which are a subacute / repair type change. Chronic: dense fibrosis with admixed inflammatory cells (blue dots). Also note subpleural fibrosis. Chronic: End-stage fibrosis and dilated air spaces some with mucinous secretions: “Honeycomb changes”. Cystic spaces are lined by airway-type columnar epithelium = metaplasia. Mucus in lumens. Fibrosis of remaining septa surrounding the dilated spaces
Fibroblastic focus
loose interstitial fibroblast-rich ‘hump’. Fibroblastic foci do have some resemblance to organizing pneumonia (where alveolar fibrotic plugs are noted) but foci are subepithelial and organizing pneumonia would be in the airspace. Present in UIP.
What is expanding the interstitial areas in nonspecific interstitial pneumonia?
Uniform inflammatory cells admixed - mononuclear (need higher magnification to distinguish cell types). Uniform but scant collagen deposition appears to be present admixed with inflammatory cells expanding septae. There are no fibroblastic foci present in the subepithelial region of the septa
Histopathological findings of ARDS
Airspace / Alveolus = “Hyaline membranes”. A few neutrophils in alveoli. Reactive epithelial cell changes (prominent nucleoli). Septa =Mild increase in chronic inflammatory cells, Minimal fibroblast proliferation at this point … with organization, there would be more fibrosis. Restrictive Features. Histologic diagnosis would be diffuse alveolar damage
Acute response to ARDS injury in the alveolar
pro-inflammatory cytokines such as IL-8, IL-1, TNF (released by macrophages), cause neutrophils to adhere to pulmonary capillaries and extravasate into the alveolar space, where they undergo activation. Activated neutrophils release a variety of factors, such as leukotrienes, oxidants, proteases, and platelet activating factor (PAF), which contribute to local tissue damage, accumulation of edema fluid in the airspaces, surfactant inactivation, and hyaline membrane formation. Macrophage migration inhibitory factor (MIF) released into the local milieu sustains the ongoing pro-inflammatory response. Subsequently, the release of macrophage-derived fibrogenic cytokines such as transforming growth factor beta (TGF-beta) and platelet derived growth factor (PDGF) stimulate fibroblast growth and collagen deposition associated with the healing phase of injury. VEGF also released by macrophages causes vascular proliferation.
What are the most common disease processes that can progress to ALI / ARDS?
Infectious / Inflammatory Etiology: Sepsis, Pulmonary infections, Viral, Bacteria: mycoplasma (“atypical pneumonia”), Fungal: Pneumocystis jiroveci (immune compromise). Traumatic Etiology: Chemical Trauma: Aspiration of gastric contents, Physical Trauma: Head trauma or other trauma including chest trauma. There are multiple other associations (see Table) including - Intubation itself: ? oxygen toxicity
Adenocarcinoma
cell of origin is epithelial cells. Location in lung can be anywhere; often in the peripheral. There can be smoking or no smoking history. Most common lung cancer in non-smokers. With asbestos exposure – most common neoplasm is adenocarcinoma. Architecture: Neoplasm adjacent to normal appearing alveoli – gland formation (central white space). Size: Neoplastic cells are fairly large with prominent nuclei and also discernible cytoplasm. Cytology: Neoplastic cells show nuclear pleomorphism, high N:C ratio, mitotic activity (circle)
Squamous cell carcinoma
cell of origin is epithelial cells. More often found proximal than in the periphery. Mostly occurs in smokers; lacks definite adenocarcinoma and squamous cell carcinoma features. Often creates cavity.
Carcinoid
derived from neuroendocrine cells. Is a low grade malignant caner. Usually found around the bronchi or bronchioles; both proximal and peripheral. Smokers (60-80%) and Non- Smokers (20-40%)
Small cell carcinoma
derived from neuroendocrine cells (Kulchitsky cells). Neuroendocrine cells are most numerous in bronchi and large bronchioles (e.g. proximal in the airways). Hence small cell carcinomas tend to be proximal lesions, associated with large airways. Usually found proximal. >95% in smokers; Aggressive. Architecture: Sheets of cells without evidence of gland formation or other architectural features. Cytology: Highly atypical cells: “small round blue cell”, Nuclear atypia / hyperchromicity. Ovalor spindle-shaped nucleus (sometimes called “oatcell”), Some nuclear “molding”—compression by other neoplastic cells. Minimal cytoplasm – very high nuclear to cytoplasmic ratio. “Small” cells compared to lesion in Case 4. Mitotic rate: Increased. Small cell carcinoma is very aggressive . . . in many instances, considered non-curable. Likely to metastasize broadly – lymph nodes, other lung, liver, brain. Surgical excision is usually not indicated given aggressive nature of neoplasm and likelihood of metastasis. Generally, patients with small cell carcinoma have a very poor outcome and a short life expectancy.
Mesothelialioma
derived from mesothelial cells in the pleura. Found in the pleural, pericardial, or peritoneum. Asbestos exposure link in most cases (up to 90%).
Bronchopneumonia
Patchy, multifocal consolidations
Lobar pneumonia
consists of involvement of an entire lobe or a substantial portion of a lobe by fibrinopurulent exudate. Entire lower lobe is consolidated. Histology revealed extensive fibrinopurulent exudate with minimal organization. Less commonly seen today, in the age of antibiotics …which can truncate the progression to lobar pneumonia.
What are some complications of pneumonia?
Systemic spread: sepsis, Abscess formation: within lung parenchyma, Empyema formation: loculated inflammation in pleura
Abscess
loculated collection of fibrinopurulent material within organ parenchyma. Special stains for bacteria and fungus negative but patient had been treated with antibiotic. Not the same as empyema: Empyema is loculation of material within a space –e.g. within the pleural space
Causes of bronchiectasis
Bronchiectasis results from obstruction of airway-> damage of bronchi and bronchiole walls-> dilation. Developmental / Congenital: Cysticf ibrosis, Ciliary diseases. Trauma / Obstruction: Neoplasm, Foreign body. By definition, change ipermanents. The airway wall is damaged and cannot recover.
Military pattern
There is a multinodular appearance in the lungs as viewed through the pleura. There is a miliary pattern to the nodules (each is the size of millet seeds - 0.1 - 0.5 cm). often found in tuberculosis. Etiology could also be due to mycobacteria, fungus or an autoimmune process like sarcoidosis.
Histopathological findings of tuberculosis
Inflammation: Macrophages: “epithelioid” (spindled nucleus), foamy, multinucleated giant cell (inset). Lymphocytes: relatively scant. Central necrosis. Caseous necrosis. Necrotizing granulomatous inflammation may also be present.
Tuberculosus can affect which organs?
Active and Chronic TB lesions can be seen in the lung or any organ with abundant macrophages
(similar to Mycobacterium avium- intracellulare). Lung / Pulmonary: Lung parenchyma
, Thoracic and mediastinal lymph nodes, Pleura. Extrapulmonary: Lymph nodes
- Spleen
- Liver
- Bone and joints (“Pott disease” vertebral body and intervertebral disk involvement)
TTF-1: thyroid transcription factor-1
expression is seen in a majority of primary pulmonary neoplasms. Also seen in non-lung lesions (not specific)
Cytokeratin profile
is consistent with lung primary. Also seen in other body sites (not specific)
Identify the sequential steps to the metaplastic squamous epithelium that result in invasive carcinoma with repeated exposure to carcinogens
Repeated injury to bronchial and bronchiolar epithelium leads to: Squamous metaplasia, Dysplasia, Carcinoma in situ … constrained by basement membrane, and Invasive carcinoma … basement membrane breached. This process in the lung bears resemblance to the squamous metaplasia-> dysplasia-> carcinoma sequence in the uterine cervix and colon
