pulmonolgy2 Flashcards
pneumonia
is an infection of the lung parenchyma. Clinically, pneumonia is classified a community- acquired (CAP), which refers to an infection acquired outside of hospitals or extended-care facilities. Health-care associated (HCAP) includes patients who have recently been hospitalized within 90 days of the infection, resided in a nursing home or long-term care facility, or received parenteral antimicrobial therapy, chemotherapy, or wound care within 30 days of pneumonia. Despite the multiplicity of antibiotics available for treat the disease, pneumonia remains a leading cause of death in the United States (7th). Hospital-acquired (HAP) pneumonia is defined as pneumonia that occurs 48 hours or more after hospital admission and that was not present at the time of admission. Ventilator Associated pneumonia (VAP) refers to pneumonia that occurs 48 hours or more after endotracheal intubation. The incidence of CAP is 4-5million/year with nearly 25% requiring hospital admission. Health-care and hospital acquired pneumonias are estimated to occur in 250,000 persons/year and represent 15-20% of all nosocomial infections. The term HAP is often used to represent both VAP and HCAP. For practical purposes, most principles for HAP, VAP, and HCAP overlap.
Pathogenesis of Pneumonia
Mechanisms have been identified in the pathogenesis of pneumonia in immunocompetent adults include inhalation of infectious particles, inhalation of oropharngeal or gastric contents, hematogenous spread, infection from adjacent or contiguous structures, direct inoculation and reactivation. Inhalation of infectious particles is probably the most important pathogenic mechanism in the development of community-acquired pneumonia, with particular importance of pneumonia caused by Legionella species and M. tuberculosis. Pneumonia occurs when the host’s ability to fight against invading microbial pathogens is compromised. The reduced state of the immune system could be due to interplay amongst different host factors, including underlying comorbidities, immunosuppressive medications, and a depressed level of consciousness leading to impaired mechanical (ciliated epithelium and mucus), humoral, and cellular host defenses.
Clinical evaluation of pneumonia
Initial evaluation involves history, physical exam and radiographic testing. Diligent history taking can direct the differential diagnosis of infectious agents. Clinical diagnosis of pneumonia requires clinical evidence of pulmonary parenchymal inflammation due to infection (bacterial, fungal, viral) in which purulence develops and fills the alveoli. Common clinically signs and symptoms include fever, chills, pleuritic chest pain, dyspnea and cough that can productive of sputum (bacterial infections) or with minimal sputum (atypical vs viral). Other clinical features include anorexia, nausea+/- vomiting, diarrhea, mental status changes. On physical exam, patients are typically febrile (>80%), with tachypnea and tachycardia. Lung exam can reveal crackles, rhonchi and bronchial breath sounds. If there is evidence of consolidation, patients will have egophony and dullness to percussion. The absence of these physical exam findings does not exclude pneumonia. The vast majority of patients will have leukocytosis with a left shift. Leucopenia, if concurrent with a diagnosis of pneumonia, portends a poor prognosis
Radiographic Evaluation of pneumonia
The presence of infiltrates on a plain chest x-ray with the appropriate clinical and microbiologic features is considered the gold standard for diagnosis. Chest x-ray should be obtained on all patients for which pneumonia is suspected. The radiographic features of pneumonia include: Lobar consolidation, Interstitial infiltrates, and caviation. Radiographic features alone cannot differentiate etiology of pneumonia and radiographic abnormalities is not sufficient to confirm the diagnosis of pneumonia by itself. In the absence of clinical or microbiologic supportive evidence of pneumonia the differential
diagnosis includes: Pulmonary edema, Pulmonary or diffuse alveolar hemorrhage, Pulmonary embolism, Malignancy, Drug induced lung disease, Inflammation secondary to non-infectious causes. Alternatively, if plain x-ray does not support the clinical suspicion, advanced radiographic testing can be ordered (CT chest), as CT is clearly superior to plain radiographs are detecting lesions and defining the anatomical position of pneumonia. Clinical situation in which plain radiographs may be initially negative include volume depletion and patients who are immunocompromised. CT scan to diagnosis pneumonia is not generally recommended as it incurs higher cost and has not been shown to improve outcomes.
Initial Management
Once pneumonia is diagnosed, the next critical decision includes determining indication for hospital admission. The Patient Outcome Research Team (PORT) study determined an validated a risk scale, Pneumonia Severity Index to help guide decision making regarding severity of CAP and indications for admission (risk class IV and V).
Diagnostic Testing
In patients who are not severely ill and have few risk factors, consensus guidelines from the IDSA/ATS recommend empiric treatment without additional testing. At minimum, all patients with suspected pneumonia should have the following: chest radiograph, complete blood count, complete metabolic profile, and blood gas or pulse oximetry. Advanced testing is reserved for individual clinical situations. Blood cultures can also shed light on a pathogen, and samples should be drawn in severely ill or immunocompromised patients. Pleural or cerebrospinal fluid should be sampled when infections in these spaces are suspected.
Gram staining for pneumonia
Gram-stained sputum specimen can help focus empiric antibiotic therapy. Sputum samples can be difficult to obtain from older patients because of a weak cough, obtundation, and dehydration. Nebulized saline treatments might help mobilize secretions. Nasotracheal suctioning can sample the lower respiratory tract directly but risks oropharyngeal contamination. A sputum specimen reflects lower respiratory secretions when more than 25 white blood cells (WBCs) and fewer than 10 epithelial cells are seen in a low-powered microscopic field. Other stains, such as the acid-fast stain for mycobacteria, modified acid-fast stain for Nocardia, or toluidine blue and Gomori’s methenamine silver stains should be used when directed by the history or clinical presentation. Direct fluorescent antibody (DFA) staining of sputum, bronchoalveolar lavage fluid, or pleural fluid can help identify bacterial infections (Legionella species) as well as rapid diagnosis of viral infections (nasopharyngeal DFA swab for influenza types A and B), as well as other common respiratory viruses such as respiratory syncytial virus, adenovirus, and parainfluenza virus. The sputum culture can be used to help tailor therapy
in certain clinical situations (admission to ICU, failure of
antibiotic therapy, cavitary lesions, alcohol abuse, structural
lung disease, immunocompromised host, pleural effusion,
epidemic pneumonia). Culture is particularly helpful for identifying organisms of epidemiologic significance, either for patterns of transmission or resistance. Expectorated morning sputum specimens should be sent for mycobacterial culture when the history is suggestive.
Bronchoscopy for diagnosis of pneumonia
When these procedures fail to yield a microbiologic diagnosis and when the patient does not respond to empirical antibiotic therapy, more-invasive diagnostic techniques may be indicated. Fiberoptic bronchoscopy allows the use of several techniques for the diagnosis of pneumonia. Bronchoalveolar lavage with saline can obtain deep respiratory specimens for the gamut of stains and cultures mentioned earlier. Transbronchial biopsy of lung parenchyma can reveal alveolar or interstitial pneumonitis, viral inclusion bodies, and fungal or mycobacterial elements. The protected brush catheter is used to distinguish quantitatively between tracheobronchial colonizers and pneumonic pathogens. A more substantial amount of lung tissue may be obtained for culture and histologic examination by thoracoscopic or open lung biopsy. Because these procedures can carry considerable morbidity, they are usually reserved for the deteriorating patient with a pneumonia that defies diagnosis by less-invasive techniques.
Serologic Testing
Serologic testing for such pathogens as Legionella species, Mycoplasma species, and C. pneumoniae should include sera drawn in the acute and convalescent phases for comparison. A fourfold increase in the immunoglobulin G (IgG) titer suggests recent infection with these organisms. An IgM microimmunofluorescence titer of more than 1:16 is considered diagnostic of C. pneumoniae infection. Infection with SARS-associated coronavirus is most often diagnosed by antibody testing and polymerase chain reaction (PCR) testing. A sensitive enzyme immunoassay has been developed for the detection of L. pneumophila type 1 antigen in urine, however, the antigen can persist for up to 1 year after infection, making it difficult to differentiate between past and current infections when using this assay. A urinary assay is also available for detecting S. pneumoniae cell wall polysaccharide. This assay may offer some advantage for the rapid diagnosis of pneumococcal pneumonia in culture-proven or unknown cases, but assay specificity is an ongoing question.
Molecular Techniques for pneumonia diagnosis
Powerful molecular techniques are now being applied to the early diagnosis of pneumonia. DNA probes have been used to detect Legionella species, M. pneumoniae, and M. tuberculosis in sputum. These probes have excellent sensitivity and specificity but can yield false-positive results. The PCR assay has been used for the early detection of various pathogens that are difficult or slow to culture from sputum specimens, including atypical bacteria, viruses (e.g., influenza), and mycobacteria. Given the large percentage of pneumonia cases for which no microbial cause is identified, it is likely that molecular tools will eventually be applied to the identification and antimicrobial susceptibility testing of almost all causative agents of pneumonia.
Procalcitonin
a peptide precursor of the hormone calcitonin. It is produced parecnchymal cells in response to bacterial toxins. The level of procalcitonin in the blood stream of healthy individuals is below the limit of detection (10pg/mL) of clinical assays. The level of procalcitonin rises in a response to a proinflammatory stimulus, especially of bacterial origin, and is produced mainly by the cells of the lung and the intestine. It does not rise significantly with viral or non-infectious inflammations. In serum, procalcitonin has a half-life of 25 to 30 hours. Remarkably the high procalcitonin levels produced during infections are not followed by a parallel increase in calcitonin or a decrease in serum calcium levels. In severe infection with clinical evidence of severe sepsis, the blood levels of procalcitonin may rise to 100 μg/L and has a sensitivity of 76% and specificity of 70%. In a Cochrane meta-analysis, procalcitonin level was found to be helpful in guiding when to use antibiotic therapy, use of antibiotics was more or less discouraged (
Antibiotic Treatment for pneumonia
Antibiotic therapy for CAP should be directed using patient characteristics, severity of disease and epidemiologic traits. Concerns about antimicrobial overuse, health care costs, and bacterial resistance increasing, therapy should follow confirmation of the diagnosis of pneumonia and should always be accompanied by a diligent effort to identify a causative agent. When a specific pathogen is identified, pathogen- specific therapy can be used. Most cases of pneumonia are adequately treated with 10 to 14 days of antibiotics. Longer courses may be required for certain organisms that cause tissue necrosis, (e.g., Legionella spp., S. aureus, Pseudomonas aeruginosa), organisms that live intracellularly (e.g., C. pneumoniae), or comorbidities that compromise local (COPD) or systemic (hematologic malignancy) immunity.
Pneumonia Prevention
Immunization against influenza and increasingly resistant pneumococci can play a critical role in preventing pneumonia, particularly in immunocompromised and older adults. The influenza vaccine is formulated and administered annually. The Centers for Disease Control and Prevention (CDC) recommends that vaccines be offered to persons older than 50 years, residents of extended-care facilities, and patients who have chronic heart and lung disorders, chronic metabolic diseases (including diabetes mellitus), renal dysfunction, hemoglobinopathies, or immunosuppression. The pneumococcal vaccine has been shown to be 60% to 70% effective in immunocompetent patients. Side effects are rarely serious and consist of local pain and erythema, which occur in up to 50% of recipients. The CDC recommends that vaccines be offered to all persons 65 years of age or older, those at increased risk for illness and death from pneumococcal disease because of chronic illness, those with functional or anatomic asplenia, and immunocompromised persons. Patients who are immunosuppressed by chronic disease or treatment might not have sustained titers of protective antibody and should be considered for revaccination after 6 years.
Residual immunity against Bordetella pertussis wanes over time, leading to transmission from older adults to other adults and infants. Because secondary bacterial pneumonia occurs in a significant number of cases of pertussis, the ACIP (Advisory Committee on Immunization Practices) has recommended that the tetanus-diphtheria-acellular pertussis (Tdap) vaccine replace the tetanus-diphtheria (Td) vaccine in the adult immunization schedule.
Influenza
An acute respiratory illness that is caused by either influenza A or B virus. Occurs as outbreaks and epidemics in a seasonal variation (winter season). Signs and symptoms of active infection include systemic illness (i.e. headache, myalgias, weakness) and upper and lower respiratory tract involvement. In the general population, influenza is a self-limiting though debilitating disease; however in certain at risk populations, it is associated with increased morbidity and morality.
Epidemiology of Influenza
Distinct outbreaks occur yearly with a seasonal distribution (winter) and reflect the changing nature of the antigenic properties of the virus. Mutliple strains of IFN typically ciruculate during a season. Of the IFN viruses, IFN A virus easily undergoes changes in the antigenic characteristics of their envelope glycoproteins. Outbreaks occur over a 2-3 week time period and last 2-3 months. Most outbreaks affect between 10-20% of the general population, but high rates can be seen in at risk persons.
Pathogenesis of Influenza
Transmission requires close contact with an infected individual via exposure to respiratory secretions (sneezing, cough). Close contact is required as the virus is large (>5 microns) and does not remain airborn for distances greater than 6 feet. IFN viral incubation period is 1-4 days with onset of illness occurring within 3-4 days. The virus can ‘shed’ from infected individuals 24-48 hours prior to onset of illness and continue for as long as 10 days, though the titers drop dramatically during symptomatic illness. At risk populations (children, aged adults, patients with chronic illness and immunocompromised hosts) have been shown to shed for up to 3 weeks. The pathogenic nature of influenza is related to the antigenic changes in it’s hemagglutinin, which is a surface glycoprotein that binds to sialic acid residues on respiratory epithelial cell surface glycoproteins and starts the infection. As the virus reproduces, the virions are also bound to the host cell. Neuraminidase cleaves these links and liberates the new virions; it also counteracts hemagglutinin-mediated self-aggregation entrapment in respiratory secretions. Among influenza A viruses that infect humans, three major subtypes of hemagglutinins (H1, H2, and H3) and two subtypes of neuraminidases (N1 and N2) have been described. Influenza B viruses have a lesser propensity for antigenic changes, and only antigenic drifts in the hemagglutinin have been described.
Clinical Features of Influenza
Uncomplicated Influenza occurs as an abrupt onset of fever, headache, myalgias and malaise. It can be associated with URI symptoms such as cough, nasal congestion and sore throat. Physical exam findings are include pharyngeal hyperemia and lymphadenopathy. This constellation of signs/symptoms are often confused with the common cold. Treatment is supportive.
Several complications can follow influenza viral infection
Pneumonia: The most common complication and occurs in patients who are high risk. The types of pneumonia that are encountered are
categorized as primary viral pneumonia, secondary bacterial
pneumonia, or a mixture of both. Primary influenza
pneumonia is the most clinically severe, but the least
common, of the pneumonic complications of influenza. It has
an apparent predilection for individuals who have elevated
left atrial pressures, although it has also been described in
patients with chronic pulmonary disorders and rarely in apparently otherwise healthy young adults. Secondary bacterial pneumonia contributes substantially to morbidity and mortality, and is common in individuals ≥65 years of age. The clinical hallmark of the clinical presentation in patients with secondary bacterial pneumonia recurrence of pulmonary symptoms after initial improvement in the symptoms of acute influenza. Mouse models of synergism between influenza virus and S. pneumoniae, the level of activity of neuraminidase correlated with increased adherence and invasion of S. pneumonia. The most common bacterial pathogen is Streptococcus pneumonia, Staphylococcus aureus, and Haemophilus influenza.
Myositis and rhabdomyolysis
an important complications of and occurs most frequently in children. Although myalgias are a prominent feature of most cases of influenza, true myositis is uncommon. The pathogenesis of the myositis is not well understood. The hallmark of acute myositis is extreme tenderness of the affected muscles, most commonly in the legs. In the most severe cases, swelling and bogginess of the muscles may be noted. Markedly elevated serum creatine phosphokinase concentrations can be seen.
Central nervous system
may be associated with influenza, including encephalopathy, transverse myelitis, aseptic meningitis, and Guillain-Barré syndrome. However, the pathogenesis of the CNS illnesses associated with influenza remains poorly understood.
Cardiac complications
include electrocardiographic changes, increased risk of MI, myocarditis and pericarditis. The latter two are rare.
Treatment of Influenza
Indications include illness requiring hospitalization; progressive, severe or complicated illness; and those at risk (see Table 7). Treatment should be given within 48 hours of illness. Treatment includes neuroaminidase inhibitor (oseltamivir or zanamivir). Assess risk of oseltamivir resistance by reviewing the state influenza data as H1N1 IFN A has been reported. The adamantanes are no longer indicated given the high rates of resistance.
Restrictive disease
the complement of obstructive disease. The compliance of the lung is reduced, while the airway resistance is reduced. Gas exchange abnormalities may result from both ventilation-perfusion (V/Q) mismatch and diffusion abnormalities. Remember that the total pressure to begin airflow in the respiratory system is: Ptot = Pel + Pr. Ptot = the total pressure. Pel = pressure required to overcome elastic recoil of the lung. Pr = pressure required to overcome the resistance to airflow. Obstructive disease primarily increases resistive pressure, Pr. Restrictive disease increases the work required to distend the lung, the Pel. The respiratory system is composed of both the lung and the chest wall in series.
compliance (C)
is the (change in volume)/(change in pressure). (This is the inverse of elastance.) 1/Ctot = 1/Clung + 1/Ccw. Ctot = Compliance of the total system. Clung = Compliance of the lung. Ccw = Compliance of the chest wall. The compliance of the lung and chest wall separately is about 0.2L/cmH20. But combined the compliance is half that: 0.1 L/cm H20. This occurs because of the counterbalancing recoil forces of the chest wall and lung. The principle is that compliance of the respiratory system may be affected by changes in compliance of either the chest wall or lung (or both). Also keep in mind that the pressure-volume (P-V) curve is not linear, and thus compliance represents a point estimate for any given lung volume. This is the reason that the curve is shown for values across the patient’s vital capacity. Clinically, the pressure volume curve is measured by inserting an esophageal pressure monitor that is a surrogate for pleural pressure. This allows for measurement of the difference that transpulmonary pressure has on lung volume. Transpulmonary pressure is the difference between the pressure applied to the airway and the pressure in the pleural space. The result is a pressure volume curve for the lung alone.
Mechanisms that change lung compliance
A decrease in lung compliance can occur via 3 mechanisms: 1. Increased thickness of the lung interstitium. 2. Increased lung water. 3. Increased alveolar surface tension. Increases in the thickness of the interstitium can occur from many causes. There is increased deposition of elastic/connective tissue in many forms of chronic interstitial lung disease. In response to an injury, lung fibroblasts produce excessive collagen and elastin in the alveolar walls. This abnormal proliferation causes an increase in interstitial matrix which increases the elastic recoil of the lung and essentially stiffens the lungs. An increase in inflammatory cells in the interstitium can similarly stiffen the lung. Increased lung water is most commonly seen with congestive heart failure: initially fluid escapes the capillary and fills the interstitium (which thickens the interstitium and increases elasticity. Next, fluid fills the alveoli which disrupts the surfactant and increases surface tension.
Respiratory distress syndrome
Increases in alveolar surface tension tend to cause alveoli to collapse and remain closed which reduces compliance. Dilution of the normal surfactant via cardiogenic or noncardiogenic pulmonary edema (increased lung water) can increase surface tension. Abnormalities in surfactant production or functionality can also increase surface tension. Respiratory distress syndrome (formerly, hyaline membrane disease) in premature infants is a result of inadequate surfactant production due to immature lung development. In adults, a form of acute lung injury called acute respiratory distress syndrome (ARDS) results in dysfunctional surfactant due to injury to type 2 alveolar cells; furthermore noncardiogenic pulmonary edema in this disorder dilutes the surfactant that is present. ARDS also results in inflammation and injury in the interstitium that decreases compliance.
Pressure volume curve of normal and diseased states
TLC, FRC and RV are all decreased in pure restrictive lung disease. The PV curve is flatter and shifted down (reflecting lower lung volumes) as shown by this curve for pulmonary fibrosis. In patients with acute pulmonary edema (either due to heart failure or ARDS) P-V curves are usually not measured but would look the same as for fibrosis. Static compliance is easily measured in mechanically ventilated patients by measuring the pressure required to inflate a patient’s lung to a certain volume.
Supranormal airflow
Remember that peak expiratory lung flow is determined by lung volume. Airflows in pulmonary fibrosis and other forms of interstitial lung diseases are supranormal for a given lung volume because the airways are dilated due to traction applied from adjacent parenchyma. This phenomenon is termed traction bronchiectasis. For any given lung volume, the airflows will be higher than expected. The figure at left shows typical flow volume loops. Note that lung volumes must be measured to plot this graph. Spirometry will show a normal or elevated FEV1/FVC ratio. Resistance = 8nl/(πr4), where n = viscosity, l = length, r = radius.
Diffusion abnormalities
Restrictive disease due to various interstitial lung diseases results in impaired gas-exchange. This results from a decrease in lung volumes with subsequent decrease in alveolar capillary surface area. Diffusion can also be impaired as the thickness of the alveolar-capillary wall increases. The diffusion abnormality becomes more pronounced with exercise as the transit time across a capillary decreases from an average of 0.75 seconds to as short as 0.25 seconds. Symptoms with exercise are usually the earliest manifestation of interstitial lung disease. Ventilation-perfusion abnormalities also contribute to gas exchange abnormalities in restrictive disease. A decrease in diffusing capacity (DLCO) is often the first abnormality in patients with restrictive disease. DLCO can be corrected for alveolar volume (VA) to account for the decrease in diffusing capacity that results from reduced lung volumes. Be careful: many restrictive diseases result in lower lung volumes AND impair the function of the alveolar capillary membrane. A decreased DLCO that normalizes for VA should not suggest the absence of parenchymal lung disease.
Mechanisms that change chest wall compliance
Disease in any compartment of the chest wall from the skin to the pleura can result in decreased compliance of the chest wall system and a restrictive pattern. Some examples: burns: third degree burns form a thick eschar that limits chest wall excursion obesity- increases soft tissue mass and decreased ability of the chest wall to move kyphoscoliosis- deformity of the spine (lateral and anterior displacement) ankylosing spondylitis- inflammatory disease which causes ossification of the ligamentous structures of the spine (the bamboo spine). This restricts movement of the ribs respiratory muscle weakness - paralysis of the muscles, neuromuscular disease pleural fibrosis/thickening- restricts expansion of the lung within the thoracic cavity. pleural effusion - fluid in pleural cavity limits lung expansion
Abnormalities of the chest wall
Abnormalities of the chest wall lead to decreased lung volumes (including FRC) and normal airflow. Restrictive disease due to chest wall or pleural disease does not alter the function of the gas-exchange at the alveolar capillary membrane. As noted above, a mild reduction in lung volumes reduces the DLCO because the total surface area of the alveolar capillary membrane is reduced, but this corrects when DLCO is corrected for alveolar volume (DLCO /VA). At lower lung volumes, however, the lung develops regional atelectasis and other V/Q mismatch that can occur with ventilation at low lung volumes.
Pulmonary problems due to muscular weakness
In patients with muscular weakness, the effort dependent PFT measurements are affected but FRC is normal (low TLC and increased RV). This pattern is also seen in persons who put forth a poor effort (either on purpose or do not understand what they are supposed to do). The P-V curve of the lung can help distinguish between chest wall and muscular disease from restrictive lung diseases (fibrosis, edema). In patients with chest wall and/or muscular diseases, the slope of the P-V curve will be normal but the lung volumes (TLC) will be lower.
How do you determine whether restrictive physiology is due to obesity (chest wall) or due to interstitial lung disease?
Restrictive physiology caused by intrinsic lung disease can be distinguished from that caused by chest wall pathology by history, physical exam, chest radiograph, diffusing capacity, and pressure-volume curve. Pressure-volume curves can be used to assess the compliance of the lung without the effects of the chest wall. To review, a manometer is passed into the mid-esophagus which gives a close estimation of pleural pressure. In the body box a patient exhales slowly from TLC and lung volumes are measured periodically using Boyle’s Law. The volume is correlated to the pleural pressure as determined by the esophageal manometer. Since the manometer is inside the chest wall and (almost) directly measuring pleural pressure any restrictive effects of the chest wall are eliminated. Above are examples of P-V curves in these states. Obesity moves the curve down and to the right, but the shape of the curve (aka. the slope of the curve) mirrors that of the normal. Fibrosis flattens the curve (i.e. decreased the slope) and shows that increases in pressure result in decreased changes in volume compared to normal. People can have obstructive disease, restrictive disease, or a combination of both.
Examples of patients with a mixed disorder
An obese patient with asthma, Combined pulmonary fibrosis and emphysema, A construction worker with interstitial lung disease from asbestos or silica exposure who also has α1- antitrypsin deficiency. These people can have various PFT’s, but a classic scenario would be a decrease in TLC or FRC (restrictive) with a decreased FEV1/FVC (obstructive). Usually the combination of disorders combines to markedly decrease DLCO.
Clinical Aspects of Interstitial Lung Diseases (ILD)
ILD is a generic term that describes a heterogeneous group of disorders (also called diffuse parenchymal lung diseases) that are grouped together because of similar clinical, radiographic, physiologic, or pathologic manifestations. The terminology is confusing in part because of continued revisions to the classification system. ILD may result from a known cause or it may be idiopathic.
Causes of interstitial lung disease
Known causes of ILD may be grouped into one of four groups:1. Autoimmune disease 2. Exposure to inorganic dusts (typically occupational dusts such as silica or asbestos)3. Exposure to organic molecules that result in hypersensitivity pneumonitis 4. Drug effect
Idiopathic diseases
include sarcoidosis and the idiopathic interstitial pneumonias (IIPs)—this is a group of clinical diagnoses that correlate to a specific pattern of lung injury. The six major IIPs are shown below along with the pattern of injury observed (either radiographic or pathologic).
Diagnosis of interstitial lung disease
The current approach to diagnosis of ILD uses a clinical-radiologic-pathologic approach to diagnosis. Clinical information from the history and physical looks for evidence of a known cause of interstitial lung disease (autoimmune disease, exposures to drugs, organic or inorganic dusts). A radiographic pattern of disease is described by the radiologist. A pathologic pattern of lung involvement may be needed from a lung biopsy. These three streams of information are combined to come up with the best unifying clinical- radiologic-pathologic diagnosis. A specific diagnosis is important because of differences in prognosis and treatment response.
Presentation of ILD
The presentation of most forms of ILD is the insidious onset of dyspnea on exertion. Nonproductive cough is common. Rarely, the disease may be sudden in onset (examples include acute hypersensitivity pneumonitis, acute interstitial pneumonitis, acute eosinophilic pneumonia). PFTs typically show a restrictive pattern with reduced diffusing capacity.
Therapy of ILD
Therapy for many forms of ILD involves immunosuppression, although there is wide variability in response to therapy. Removal of inciting drugs or exposures is important.
Idiopathic pulmonary fibrosis (IPF)
has no response to anti-inflammatory therapy and seems be a disease of disordered alveolar epithelial repair. Two drugs were recently approved to slow the progression of IPF: nintedanib and pirfenidone.
Pulmonary fibrosis
is a generic term that refers to lung scarring. Many other forms of ILD have pulmonary fibrosis besides just IPF. Other forms of pulmonary fibrosis generally have a better prognosis than IPF.
Sarcoidosis
Sarcoid is a systemic granulomatous disease of unknown etiology that is characterized pathologically by noncaseating granulomas. Sarcoid can affect people of all racial and ethnic groups and can occur at all ages. It most frequently presents in young patients (between age 10-40 in 70-90% of cases) and usually has some degree of lung involvement. Racial/ethnic groups with increased risk include those of Scandinavian and Irish descent; African Americans have a three-fold increase risk of disease compared to Caucasian Americans; furthermore, they tend to have more severe disease and more extrapulmonary manifestations.
Granulomas
are compact collections of macrophages and epithelioid cells surrounded by lymphocytes. Macrophages combing to form multinucleated giant cells. CD4+ T cells interact with antigen-presenting cells to form and maintain granulomas. Granulomas may persist, resolve, or contribute to the development of fibrosis.
Pulmonary findings with sarcoidosis
The most frequent pulmonary finding is mediastinal and bilateral hilar lymphadenopathy (LAD). This is generally asymptomatic. Interstitial infiltrates and nodules may develop. Patients may develop pulmonary fibrosis
Symptoms of sarcoidosis
Constitutional symptoms (fevers, chills, fatigue) are common. Respiratory symptoms include dyspnea, wheezing, cough, and chest pain.
Extrapulmonary findings with sarcoidosis
Derm: Many different types: erythema nodosum (panniculitis); maculopapular rash; waxy nodules; hyperpigmented plaques especially on the face (lupus pernio). Ophthalmologic: anterior or posterior uveitis; vasculitis; keratoconjunctivitis; periorbital masses. Cardiac: related to infiltration of myocardium and/or conduction system. May result in arrhythmia or complete heart block; sudden death; heart failure. Pulmonary hypertension: this may be due to pulmonary fibrosis or due to pulmonary vascular granulomatous inflammation. Neurologic: May include granulomatous meningitis which may result in hypothalamic or pituitary involvement, or cranial nerve palsies; peripheral nerve involvement may be a late finding. Reticuloendothelial involvement: peripheral lymphadenopathy; hepatitis; splenomegaly. Metabolic: hypercalcemia occurs in up to 50% of patients due to calcitriol (1,25- dihydroxyvitamin D2) production in granulomas.
Radiographic stages of Sarcoid
Stage 1: Bilateral hilar LAD without infiltration Stage 2: Bilateral hilar LAD with infiltration. Stage 3: Infiltration without LAD Stage 4: Fibrotic disease
Lofgren’s syndrome
- Inflammatory arthritis 2. Erythema nodosum 3. Bilateral hilar lymphadenopathy. Lofgren’s syndrome often has constitutional symptoms without respiratory symptoms. It is usually self-limited and does not require treatment in most cases.
Diagnosis of Lofgren’s syndrome
Diagnosis relies on compatible clinical findings and the finding of well-formed granulomas in involved tissue. Other causes of granulomas must be excluded—especially infection. Affected tissue should be biopsied. For the lung, bronchoscopy with transbronchial biopsy is usually diagnostic; mediastinoscopy to excise a lymph node is frequently performed if the bronchoscopy is nondiagnostic. A surgical lung biopsy is occasionally required. The angiotensin-converting enzyme test may be elevated, but is not useful due to its low sensitivity and specificity. Bronchioloalveolar lavage shows a lymphocyte predominance. PFTs are usually normal in patients with stage 1 disease. More than half of all patients with sarcoid have evidence of airflow limitation with reduced FEV/FVC ratio; they may have a bronchodilator response. Patients with infiltrative disease have a restrictive pattern with reduced diffusing capacity (DLCO). Mixed obstructive and restrictive disease is relatively common.
Treatment of Lofgren’s syndrome
Most patients do not require therapy for sarcoidosis. Progressive organ involvement is treated with corticosteroids or other cytotoxic drugs (e.g. methotrexate). PFTs should be regularly followed to assess the course of disease and to guide therapy.
Differential diagnosis of granulomatous lung disease
Infection (esp Mycobacterial (TB) and fungi), Sarcoid, Hypersensitivity pneumonitis, Hot tub lung, Granulomatosis with polyangiitis, Aspiration, Talc granulomatosis, Chronic beryllium disease, Common variable immunodeficiency (CVID)
Chronology of the TB pathogenesis
stage 1: ingestion by resident alveolar macrophages. Then the cell can either kill MTB through phagosome-lysosome fusion or apoptotic death of macrophages. But if the MTB multiplies and leads to necrotic death of macrophages than the MTB survives and are released extracellularly and are taken up by other macrophages. Stage 2: symbiotic stage- MTB multiplies and macrophages accumulate. Blood monocytes migrate into the lung and differentiate into macrophages. Continued ingestion but no destruction of MTB occurs. MTB multiplies within inactivated macrophages. Formation of early primary tubercle occurs. Stage 3: migration of t cell to site of infection. T-cells begin to activate macrophages to kill or prevent spread of MTB. Granulomas form (MTB is unable to multiply within the solid caseous material). In AIDS patients, CD4+ lymphopenia results in granuloma breakdown, resulting in the inability to control the primary infection or in reactivation of latent infection. The Granuloma contains infection. Stage 4a: latent tuberculosis infection at a cellular level. Solid caseous center remains intact. Any bugs that escape the caseous edge are ingested by highly activated macrophages. LTBI is established if the caseation remains solid and does not liquefy. Stage 4b: decline in immunity leads to reactivation of TB. Immunosuppression due to AIDS, cancer, anti-TBF alpha, aging, malnutrition, etc. This leads to loss of intergrity of granuloma and liquefaction of caseous material (caseous necrosis), which provides a favorable medium for multiplication of MTB. Cavity forms and ruptures and spread to other parts of the lung and to other individuals.
Ghon complex
a lesion seen in the lung that is caused by tuberculosis. The lesions consist of a calcified focus of infection and an associated lymph node. These lesions are particularly common in children and can retain viable bacteria, so are sources of long-term infection and may be involved in reactivation of the disease in later life.
Ranke complex
is seen in ‘healed’ primary pulmonary tuberculosis comprised of two parts: Ghon lesion: calcified parenchymal tuberculoma and ipsilateral calcified hilar node
Interferon-γ release assays (IGRA)
are medical tests used in the diagnosis of some infectious diseases, especially tuberculosis. Interferon-γ (IFN-γ) release assays rely on the fact that T-lymphocytes will release IFN-γ when exposed to specific antigens. These tests are mostly developed for the field of tuberculosis diagnosis, but in theory, may be used in the diagnosis of other diseases which rely on cell-mediated immunity, e.g. cytomegalovirus and leishmaniasis. For example, in patients with cutaneous adverse drug reactions, challenge of peripheral blood lymphocytes with the drug causing the reaction produced a positive test result for half of the drugs tested.
Tram-tracks
or the tram-track sign, are medical signs that bear some resemblance to tramway tracks. When found in the lungs, tram-tracks are radiologic signs that are usually accompanied by pulmonary edema in cases of congestive heart failure and bronchiectasis. Tram-tracks are caused by bronchial wall thickening, and can be detected on a lateral chest X-ray.
The finger in glove sign
can be seen on either chest radiograph or CT chest and refers to the characteristic sign of a bronchocoele.In bronchial obstruction, the portion of the bronchus distal to the obstruction is dilated with the presence of mucous secretions (mucus plugging).
Lung hysteresis
is evident when observing the compliance of a lung on inspiration versus expiration. The difference in compliance (volume/pressure) is due to the additional energy required during inspiration to recruit and inflate additional alveoli. The transpulmonary pressure vs Volume curve of inhalation is different from the Pressure vs Volume curve of exhalation, the difference being described as hysteresis. Lung volume at any given pressure during inhalation is less than the lung volume at any given pressure during exhalation.
Spine sign
paradoxically increased density of lower spine seen on lateral chest x-ray indicative of a lower lobe process such as pheumonia.
Kerley B lines
These are short parallel lines at the lung periphery. These lines represent interlobular septa, which are usually less than 1 cm in length and parallel to one another at right angles to the pleura. They are located peripherally in contact with the pleura, but are generally absent along fissural surfaces. They may be seen in any zone but are most frequently observed at the lung bases at the costophrenic angles on the PA radiograph, and in the substernal region on lateral radiographs. Causes of Kerley B lines include; pulmonary edema, lymphangitis carcinomatosa and malignant lymphoma, viral and mycoplasmal pneumonia, interstital pulmonary fibrosis, pneumoconiosis, sarcoidosis. They can be an evanescent sign on the CXR of a patient in and out of heart failure.
Two types of reasoning in differential diagnosis
Two types of reasoning are used: (1) mental short cuts called heuristics and (2) analytical reasoning. Heuristics use pattern recognition and rely on previous experience to reach a diagnosis. They are quick, but predisposed to various biases that may result in error. Analytic reasoning is a more systematic approach that is more time- consuming, but may result in less error. Physicians employ both of these strategies in their clinical reasoning. A useful process is to consider which data elements support a suspected diagnosis and which argue against it.
What is amyotrophic lateral sclerosis?
Amyotrophic lateral sclerosis (aka Lou Gehrig’s disease) is a relentlessly progressive neurodegenerative disease that causes weakness. Progressive muscle weakness causes upper and lower motor neuron dysfunction. Patients may develop dysphagia due to uncoordinated pharyngeal muscle movement resulting in aspiration of fluids and food. Rare (1-3 cases/100,000 incidence). No racial or ethnic predilection. May occur in 3rd decade, incidence peaks in 7th or 8th
Pulmonary Manifestations of ALS
Chronic aspiration due to uncoordinated pharyngeal muscle movement (“bulbar dysfunction”). Recurrent pneumonia. Respiratory muscle weakness: Inadequate ventilation, Nocturnal hypoventilation, Weak cough. PFTs with neuromuscular diseases
Restrictive pattern
reduced FEV1, FVC; normal ratio; reduced TLC. Reduced FVC in supine position. Reduced maximal inspiratory pressure (MIP) and reduced maximal expiratory pressure (MEP). Reduced maximum voluntary ventilation. Generally normal DLCO initially; prolonged hypoventilation results in atelectasis and shunt. Elevated PCO2 or hypercarbia in arterial blood gas
Treatment of lung involvement with neuromuscular disease
noninvasive positive pressure ventilation. Aspiration precautions. Cough assistance.
Other neuromuscular disease that can affect the lung
guillain- barre syndrome can affect lungs acutely. Multiple sclerosis (MS) has a relapsing affect on the lungs. ALS is chronic and progressive. MS, infarct, trauma, tetanus, transverse myelitis, and tumors can affect the spinal cord. ALS, poliom GBS, phrenic nerve injury can affect motor nerves. Botulism, MG, lambert eaton, organophosphates can affect neuromuscular junctions. Hypokalemia, hypophos, muscular dystrophy, polymyositis, thyroid disease can affect the muscles,
Rheumatoid Arthritis (RA)
is an autoimmune disease with a hallmark of symmetric, inflammatory arthritis. Relatively common: incidence is 40/100,000. Prevalence of 1% in Caucasians. 2-3 times more common in women. Inflammatory arthritis is distinguished from mechanical arthritis (osteoarthritis) by prolonged morning stiffness. The exam may demonstrate synovitis with tender, swollen, boggy joints. The distribution in RA is usually symmetric small (MCP/PIP/MTP) and large joints (wrists, shoulders). Labs show a positive rheumatoid factor and an anti- cyclic citrullinated peptide (a more specific test). Treated with anti-inflammatory drugs and disease modifying immunosuppressive drugs.
Pulmonary Manifestations of Rheumatoid Arthritis
Pleuritis. Pleural Effusion. Pleural Thickening. Pneumothorax. Upper airway obstruction (cricoarytenoid arthritis). Small airway obstruction (bronchiolitis, bronchiectasis). Interstitial Lung Disease (UIP > NSIP). Organizing pneumonia. Nodules. Pulmonary Hypertension. Vasculitis. Drug reactions (esp methotrexate, sulfasalazine). Pulmonary infections due to immunosuppression
Pleural fluid in RA
culture is negative and cytology is negative. Total protein 4 g/dL (ratio 0.6). LDH 1100 IU/L (ratio (1.8). Glucose 12 mg/dL. pH 7.05. WBC 3000/mm3 (60% lymphs)
Connective tissue diseases with prominent pulmonary manifestations
Systemic lupus erythematosus. Rheumatoid arthritis • Systemic sclerosis (scleroderma). Sjogren’s disease. Dermatomyositis/polymyositis. Mixed connective tissue disease. Ankylosing spondylitis
Differential for hemoptysis
Alveolar hemorrhage syndrome includes Pulmonary capillaritis (Vasculitis, Connective tissue disease, Drugs), Bland hemorrhage (CTD, Anticoagulants, and Mitral stenosis), Diffuse alveolar damage (Infection leading to ARDS, Viral pneumonia, Drugs). Localized infection includes Pneumonia, abscess. Airways problems include Bronchitis, Bronchiectasis, Cancer, Foreign body. Vascular disease includes Pulmonary embolism and Pulmonary AVM, Elevated PCWP (Mitral stenosis and LHF).
Differential for acute kidney injury
Pre-renal: poor perfusion due to Hypovolemia or Decompensated HF, cirrhosis. Intrinsic issues can involve Vascular, Glomerular, or Tubular/Interstitial issues. Post renal/obstructive. Vascular problems may include Microangiopathy and hemolytic anemia, Renal infarction, Renal vein thrombosis. Glomerular problems may include Nephrotic pattern or Nephritic pattern. Tubular/Interstitial problems may include Acute tubular necrosis, Acute interstitial nephritis, Tumor lysis syndrome.
Systemic diseases associated with diffuse alveolar hemorrhage and renal disease
Granulomatosis with polyangiitis (formerly Wegener’s). Microscopic polyangiitis. Churg-Strauss Syndrome. Goodpasture’s Syndrome (Anti-GBM disease). Systemic Lupus Erythematosus. Systemic Sclerosis (Scleroderma). Henoch-Schonlein Purpura. Cryoglobulinemia
Goodpasture’s Syndrome
Goodpasture’s syndrome is an idiopathic disease that manifests as diffuse alveolar hemorrhage and rapidly progressive glomerulonephritis. The disease is thought to be mediated by antibodies directed against glomerular basement membrane
Pulmonary Manifestations of Inflammatory Bowel Disease
Tracheobronchitis. Subglottic stenosis. Bronchiectasis. Bronchiolitis. Pleural Effusion. Interstitial Lung Disease. Pulmonary embolism. Drug complications. Infections
Sickle Cell Disease
Abnormal hemoglobin S forms polymers in RBCs that distort normal shape of cells when HbS deoxygenated. Results in occlusion of capillaries with subsequent tissue injury and pain; vaso-occlusive crises. Distorted RBCs are removed from circulation. Spleen autoinfarcts. Autosomal recessive due to single codon mutation. HbS protective against malaria.
Pulmonary Manifestations of Sickle Cell Disease
Infection. Embolic phenomena due to bone marrow infarction and fat emboli. Infarction caused by in-situ thrombosis. Hypoventilation due to rib and sternal infarctions. Pulmonary Edema due to excessive hydration. Pulmonary hypertension. Chronic lung disease
The acute chest syndrome
is a vaso-occlusive crisis of the pulmonary vasculature commonly seen in patients with sickle cell anemia. This condition commonly manifests with pulmonary infiltrate on a chest x-ray. The crisis is a common complication in sickle-cell patients and can be associated with one or more symptoms including fever, cough, excruciating pain, sputum production, shortness of breath, or low oxygen levels. Broad spectrum antibiotics to cover common infections like strep pneumoniae and mycoplasma, pain control, and blood transfusion. Acute chest syndrome is an indication for exchange transfusion.
Pulmonary complications in HIV
infections include bacterial pneumonia, tuberculosis, pneumocystis jirovecii (PCP), fungal pneumonia, and viral pneumonia. Noninfectious issues include kaposi’s sarcoma, non-hodgkin’s lymphoma, lung cancer, emphysema, ILD: LIP, org, pna, NSIP, pulmonary HTN, and effusions (parapneumonic, TB, and malignant—especially lymphoma). CD4 count is indicative of immunosuppression.
Asthma
a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. The chronic inflammation is associated with airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing particularly at night or in the early morning. These episodes are usually associated either with widespread, but variable airflow obstruction with in the lung that is often reversible spontaneously or with treatment.
Asthma
has classically been divided into two basic types - intrinsic and extrinsic. Extrinsic asthma is initiated by a type I hypersensitivity reaction induced by exposure to an outside agent. Subtypes include atopic or allergic asthma, occupational asthma, and allergic bronchopulmonary aspergillosis. Intrinsic asthma is initiated by diverse, non- immune mechanisms, including ingestion of aspirin, infection (viral), cold, inhaled irritants, stress, and/or exercise. In patient care, these divisions are not that meaningful as patients overlap categories.
Factors that influence the development of asthma
Host factors including a genetic predisposition to atopy or airway hyperresponsiveness, obesity, and sex. Environmental factors such as exposure to allergens (dogs, cats, mice, cockroach allergen, fungi, mold, pollen), infection (viral), occupational exposures (isocyanates), tobacco smoke, air pollution, and diet.
Airway Inflammation in Asthma
the airway inflammation in asthma is persistent even though symptoms may be intermittent. The inflammation affects all airways but its physiologic effects are most pronounced in the medium sized bronchi. The following are inflammatory cells involved in asthmatic airways: mast cells, eosinophils, T lymphocytes (Th2), dendritic cells, macrophages and neutrophils.
Mast cells involvement in asthma
activated mucosal mast cells release bronchoconstrictive mediators including histamine, leukotrienes, and prostaglandin D2. Mast cells are activated by allergen via IgE receptors.
Eosinophils involvement in asthma
found in large numbers in the airways. Can release proteins that
damage epithelial cells
T lymphocytes (Th2) involvement in asthma
found in large numbers in the airways and release
cytokines including IL-4, IL-5, IL-9 and IL-13 causing IgE production by B-
lymphocytes.
Dendritic cells involvement in asthma
sample allergens
Macrophage involvement in asthma
can be activated by allergens and release inflammatory cytokines
Neutrophils involvement in asthma
increased in airways and sputum in patients with severe asthma.
Structural airway changes in asthma
Increase in airway smooth muscle cells due to hypertrophy and hyperplasia. Blood vessel proliferation. Mucus hyper-secretion in the context of increased number of goblet cells and
increase size of submucosal glands.
Airway narrowing is the final common pathway to symptoms and physiologic change in asthma and is due to airway smooth muscle contraction, airway edema, airway thickening or remodeling, and mucus hyper-secretion or plugging.
Increased tone of bronchial smooth muscle in asthma
Most agents that exert an effect on airway smooth muscle (ASM) act through specific surface receptors. A contractile substance (agonist) such as acetylcholine or histamine binds to a specific receptor to initiate a cascade of biochemical events that ultimately leads to an increase in smooth muscle contraction. The agonist’s effects may be negated by blocking the receptor with an antagonist (e.g. anti-cholinergic or anti-histamine).
Neural regulation of the airway diameter
a) Cholinergic (parasympathetic) motor neurons innervate the airways via the vagus nerve, synapsing near airway smooth muscle. The parasympathetic system provides the most important neural mechanism of bronchoconstriction. These neurons release the neurotransmitter, acetylcholine (ACH), which is a potent stimulator of ASM contraction. b) Sympathetic neurons seem to have little direct effect in determining airway caliber. c) Neurogenic inflammation refers to the inflammatory responses caused by tachykinins that activate specific receptors as part of the Nonadrenergic noncholinergic (NANC). Excitatory NANC (eNANC) effects are mediated by release of tachykinins such as neurokinin A and substance P acting on NK1 and NK2 receptors. NK1 mediate gland secretion, vasodilation, and leukocyte adhesion. NK2 mediates contraction of airway smooth muscle. Inhibitory NANC (iNANC) are thought to be mediated by vasoactive intestinal peptide and nitric oxide.
Beta-Adrenergic system regulation of the airway diameter
This is an important regulatory pathway in ASM. Beta-adrenergic agents such as isoproterenol or metaproterenol increase intracellular cAMP by activating G proteins. Beta-adrenergic agents cause ASM relaxation and are a cornerstone of the treatment of reactive airway disease.
Ion Channels regulation of the airway diameter
Primarily calcium and potassium channels. Inhaled anesthetics can have some effects on these channels, but ion channel blockers and activators are not a key part of treating asthma.
Physiologic Consequences of Airflow obstruction
During an asthma attack there is increased resistance to airflow, which is accentuated in expiration, causing air trapping and an increase in FRC and other lung volumesà hyperinflation. Hyperinflation, noted on the chest radiograph as flattening of the diaphragm, results in an increase in the work of breathing. Muscle fibers of the flattened (shortened) diaphragm cannot generate adequate tension and are operating at a suboptimal point on their length-tension curve. Remember that as the diaphragm flattens the radius of curvature increases, so based on LaPlace’s law, less pressure is generated for each corresponding increment of tension. Therefore, hyperinflation decreases tension generated and decreases pressure for that tension. Hence, in addition to overcoming increased airway resistance, the asthmatic must use less efficient respiratory muscles to inflate their lungs. Furthermore, these pathophysiologic effects increase oxygen consumption and carbon dioxide production by the diaphragm (and other respiratory muscles).
Interview questions for asthma patients
Have you ever been intubated for an asthma exacerbation? In the past six /twelve months, have you been in the hospital or
the emergency room? Are you now or have you been on oral corticosteroids for your
asthma? Have you had an increase in use of your inhalers in the past
day/week? Do you frequently awake at night because of your asthma?
Alterations in spirometry and lung volumes in asthma
In patients experiencing an exacerbation of their disease, PFT’s show an obstructive pattern. Between attacks, patients often have normal or near normal pulmonary function, although their airways remain hyperreactive (sensitive to cold air, allergens, smoke, perfume, pollutants, exercise, etc.). During an asthma attack airway obstruction leads to a decrease in FEV1/FVC. Usually this can be reversed (or improved) with a beta-adrenergic agent. An improvement of FEV1 or FVC of greater than 12% (and an absolute increase of > 200mL) is considered a positive bronchodilator response and is evidence of reversibility. Because of the air trapping, TLC, RV and FRC are increased as well and may be reversed with treatment. Peak expiratory flows (PEF; measured in liters per minute and compared to expected values) are used as an easy measurement of airflow limitation. They can be measured by patients at home.
Natural History of Asthma
The clinical course is variable. Childhood asthma patients experience complete remission more frequently than adults do. Progression to severe disease is rare in all age groups. In many asthmatics, the clinical course of the disease is characterized by exacerbations followed by complete remissions. Under treatment may result in structural changes with airway narrowing that may become irreversible: airway remodeling, and the airflow limitation similarly fixed with a progressive decline in FEV1 over time. Treatment may also change over time.
Bronchoprovocation
Useful in patients in whom the diagnosis of asthma is suspected but not definitely established. The patient performs serial spirometry after inhaling progressively higher concentrations of nebulized methacholine (or histamine) which stimulate airway obstruction in both healthy and asthmatic subjects. In asthmatics the concentration required to lower airflow (FEV1) by 20% (PC20) is several orders of magnitude lower than in healthy subjects without hyperresponsive airways. Therefore measurement of the PC20 can help diagnose asthma in patients with normal PFT’s. Bronchoprovocation can also be tested in response to exercise. Spirometry is performed, then then the patient vigorously exercises and then serial spirometry is performed after exercise to look for the development of airflow limitation.
General Triggers of Asthma
The presentation of asthma can
range from cough variant asthma, to mild exercise induced asthma to chronic respiratory disease and finally acute respiratory arrest. Asthmatics exacerbate following many different stimuli (including exercise, cold, viral infection, house mites, dust, chemicals, air pollution, etc.) but many exacerbations cannot be traced to a specific event. Coexisting conditions such as allergic rhinitis, sinusitis, postnasal drip, and gastroesophageal reflux can exacerbate asthma and should be searched for in patients with refractory symptoms. A personal or family history of atopic disease (atopic dermatitis, allergic rhinitis) is common in many patients. Obesity is a likely risk factor.
Therapy of Asthma
The emphasis of treatment is to control airway inflammation–primarily with inhaled steroids. Reducing increased airway tone also provides symptomatic benefit.
Reduce airway tone for treatment of asthma
beta-agonists (short-acting: albuterol; long-acting: salmeterol, formoterol) to stimulate beta receptors and cause ASM relaxation. anti-cholinergics (ipratoprium, tiotropium) to reduce ACH mediated ASM
contraction. leukotriene inhibitors (montelukast; zileuton) to reduce the vasoconstricting
effects of leukotriene which are released by activated mast cells. methylxanthines (theophylline) are phosphodiesterase inhibitors that increase
intracellular cAMP concentrations
Reduce inflammation for treatment of asthma
corticosteroids: oral, inhaled, or intravenous are effective and are thought to act
by 3 mechanisms (not acute):
1. reducing the number of inflammatory cells (eosinophils, neutrophils,
lymphocytes)
2. inhibiting the release of leukotrienes and prostaglandins by effector
cells.
3. decreasing airway edema. mast cell stabilizers (cromolyn; nedocromil inhibit the release of pro-inflammatory agents. leukotriene inhibitors (montelukast; zileuton) reduce number of inflammatory cells (particularly eosinophils) and reduce vasoconstricting effects of leukotrienes released from activated mast cells. Anti-Ig E therapy (omalizumab) decreases IgE binding to basophils and mast cells in patients with allergies and severe asthma
Chronic treatments choices for asthma
are determined based on the severity of asthma. If asthma is not controlled, step-up therapy should be used; if asthma is well controlled, a trial of step-down therapy may be appropriate.
Treatment of acute asthma exacerbations
Acute exacerbations are treated with systemic corticosteroids to decrease inflammation. Inhaled bronchodilators (SABA, anticholinergics) are used to treat acute symptoms. Supportive care for severe cases may include noninvasive positive pressure ventilation or, rarely, invasive mechanical ventilation.
Churg–Strauss syndrome
(CSS, also known as eosinophilic granulomatosis with polyangiitis [EGPA] or allergic granulomatosis) is an autoimmune condition that causes inflammation of small and medium-sized blood vessels (vasculitis) in persons with a history of airway allergic hypersensitivity (atopy).
Intermittent asthma
symptoms less than twice per week and asymptomatic between episodes. Nighttime awakenings less than twice per month. Treatment is SABA PRN.
Mild persistent asthma
symptoms between than twice per week and once daily. Nighttime awakenings greater than twice per month.
Moderate persistent asthma
daily symptoms, multiple exacerbations per week. Nighttime awakenings more than once per week.
Severe persistent asthma
continual symptoms, constant limitations of activity, frequent exacerbations and nightly awakenings.
Chronic obstructive pulmonary disease (COPD)
COPD is a common disease defined by irreversible airflow limitation (FEV/FVC
Chronic Bronchitis
Chronic bronchitis is an airway disease defined clinically as a productive cough present for three months per year over a two-year period without another identified medical cause such as bronchiectasis. Although the definition is clinical, a number of pathologic characteristics of chronic bronchitis have been described. Submucosal glands are hypertrophied and increased in number with an increase in the ratio of gland to bronchial wall thickness (the Reid index). Goblet cell frequency is increased and smooth muscle cell size and number may be increased. The overall result of these changes is to narrow the airway lumen and increase airflow resistance. Unlike asthma there is not a (acutely) reversible component; although it is important to reiterate that overlap between chronic bronchitis and asthma occurs relatively frequently. Often the airway epithelium, which is normally pseudo-stratified columnar epithelium, is transformed into squamous metaplasia, which can be a precursor of malignant transformation. Note that chronic bronchitis is a disease of the airways. This differentiates it from emphysema which is a parenchymal disease caused by loss of tissue elastic recoil.
Emphysema
Emphysema is characterized by abnormal, permanent enlargement of the air spaces distal to terminal bronchioles accompanied by destruction of their walls without obvious fibrosis. Note two things: it is not reversible and it is not a disease of the airway - it is primarily a disease of the air spaces. Airflow obstruction occurs due to airway collapse during expiration not due to edema or to an increased in smooth muscle tone. Emphysema is thought to occur primarily because of an excess of proteases relative to the protective anti-proteases in the lung. The most common cause of emphysema in the U.S. is cigarette smoking. Emphysema can also occur because of a deficiency of the enzyme alpha 1-antitrypsin. This enzyme neutralizes harmful proteases and protects the elastic lung from degradation. This disease is autosomal recessive. Patients present in their 50’s with emphysema - in their 30’s if they are smokers.Two major subtypes of emphysema are centriacinar and panacinar emphysema
centriacinar emphysema
begins in the respiratory bronchiole. Scarring and focal dilatation of the bronchioles and adjacent alveoli result in the development of enlarged air spaces in the center of the secondary lobule. This occurs most commonly because of cigarette smoking.
panacinar emphysema
occurs in older patients and patients with alpha1-anti-trypsin deficiency. The entire respiratory bronchioles (i.e. down to the alveoli) are involved.
Pathophysiology of emphysema
The hallmark of chronic bronchitis and emphysema is a limitation in airflow rates, particularly expiratory airflow. In chronic bronchitis the integrity of the alveolar-capillary surface is maintained. Airway resistance occurs because of excessive mucous secretion and bronchial wall inflammation and thickening. In emphysema the physiologic alterations occur because of the loss of the alveolar-capillary surface area with loss of elastic recoil. With exacerbations there is increased work of breathing above baseline. Similar to asthma there is hyperinflation with flattening of the diaphragm. This moves the lung higher on the pressure-volume curve and increases FRC. This places the diaphragm at a mechanical disadvantage (you have heard this before). As in asthma the work of breathing is again increased due to poor diaphragm function and increased airway resistance. On PFT’s the FEV1/FVC is decreased and RV, FRC, and TLC are all increased. In emphysema there is destruction of the alveolar-capillary bed and therefore there is a reduction of DLCO. Since chronic bronchitis does not involve the alveolar-capillary bed, DLCO is normal or only mildly reduced.
Clinical Presentation of COPD
The presentation of patients with COPD can be varied. Frequently the presenting complaint is dyspnea on exertion. Cough, wheezing, and chronic sputum production are also common initiating complaints. On exam mild cases may be difficult to detect. Once airway obstruction has become significant, evidence of hyperinflation can be found. The anterior-posterior diameter of the thorax appears to be enlarged, because the chest is near the position of full inspiration. The diaphragm is low and limited in motion. The accessory muscles of respiration may be used during breathing. To assist breathing some patients spontaneously use purse- lipped breathing. Others fix their arms on a chair or support (tripod position). This fixes the accessory respiratory muscles and improves the diaphragm function. With development of severe emphysema breath sounds and heart sounds are generally diminished. The forced expiratory time is prolonged. Exacerbations of disease are often noted to have increased cough with purulent sputum, wheezing and worsening dyspnea. Chest radiograph shows a flattened (shortened) diaphragm due to air trapping (hyperinflation).
Severity of COPD
Just like in asthma, the severity of COPD can be categorized as mild, moderate and severe based on the severity of the physiologic impairment (namely the FEV1). This is known as the GOLD classification. Survival is associated with the FEV1 as well. The lower the FEV1, the poorer the survival. Other contributors to severity include severity of symptoms, risk of exacerbations and comorbid conditions. Zero to one exacerbation per year is considered low risk for exacerbations, while >= 2 per year is considered high risk for future exacerbations. GOLD Classification of COPD Severity (by postbronchodilator FEV1)
COPD Treatment
Treatment is directed to relieving symptoms and reducing the severity and frequency of exacerbations. No therapy has been proven to convincingly alter the progression of the disease. Since there is a fair degree of overlap with asthma many of the treatments are the same. Agents to relax increased airway smooth muscle tone: Inhaled anticholinergics, Inhaled beta2-adrenergic agonists, and theophylline (maybe). Agents to decrease airway inflammation/edema: corticosteroids (inhaled, oral, or IV). Based on physiology you might expect that pure emphysema would not respond to the above agents given that the primary defect is a loss of elastic recoil and structure. In pure emphysema this is correct. Usually there is some degree of overlap of emphysema with bronchitis, however. Use of PFT’s can help assess whether these agents are effective (i.e. acute response to inhaled bronchodilators). Long-acting beta agonists are commonly combined with inhaled corticosteroids for ease of administration. Chronic macrolide antibiotic therapy may reduce exacerbations. Smoking cessation is very important to successful treatment. Supplemental oxygen therapy, physical rehabilitation, lung volume reduction surgery, and lung transplant have a role in therapy for advanced disease.
Conditions associated with Bronchiectasis
Infection, Bronchial obstruction, Primary Ciliary, Dyskinesia, Cystic Fibrosis, Allergic bronchopulmonary aspergillosis, Immunodeficiency, Alpha-1 antitrypsin deficiency, Bronchopulmonary sequestration, Unilateral hyperlucent lung (Swyer-James Syndrome), Congenital cartilage deficiency (Williams Campbell Syndrome), Tracheobronchomegaly (Mounier-Kuhn Syndrome), Yellow nail syndrome, Inflammation, and Autoimmune diseases
Bronchiectasis
refers to an abnormal dilation of the proximal medium-sized bronchi (i.e. cartilage-containing airways) due to destruction of the muscular and elastic components of their walls. This dilation commonly is associated with chronic bacterial infection and frequently with production of large quantities of foul-smelling sputum. A major cause of bronchiectasis is chronic inflammation in the airway walls usually because of recurring bacterial infections. Inflammation of the bronchial walls leads to a destruction of their elastic and muscular components; the surrounding undamaged lung tissue exerts a contractile force that expands the bronchi and creates the characteristic dilation observed on chest radiograph. The most important consequence of bronchiectasis is impaired tracheobronchial clearance, which in time predisposes to airway colonization and infection with pathogenic organisms. Bronchial arteries enlarge to supply the inflamed airways. Consequently hemoptysis is a frequent complication of bronchiectasis.
Characterization of bronchiectasis
Bronchiectasis is characterized by destruction of airway integrity and by poor airway clearance of pathogens and is manifest by: airflow obstruction—which may be partly reversible and recurrent infections requiring antibiotics
Causes of bronchiectasis
Severe pulmonary infection (frequently in childhood) causing extensive airway epithelial damage from which the airway never completely recovers: pertussis, Staph Aureus, Klebsiella, mycoplasm among others etiologic agents. Bronchial obstruction causes pooling of secretions behind the obstruction leading to local inflammation/destruction of airway walls (tumors, bronchiolithiasis, bronchial stenosis, aspirated foreign bodies). Abnormalities in airway clearance due to the absence or defect of mucociliary transport leads to pooling of secretions and colonization of airway with bacteria. Inflammation and infection lead to wall damage (leading to diffuse bronchiectasis). primary ciliary dyskinesia (Kartagener’s syndrome). Congenital or acquired defects of cartilage yield airways that lack structure (Williams- Cambell’s syndrome, Mounier-Kuhn’s disease). Congenital or acquired immunodeficiency states due to decreases in IgG level or activity are frequently associated with bronchiectasis and other chronic sinus/pulmonary infections. The most common syndrome is Common Variable Immunodeficiency- a defect in B cell maturation with resulting hypogammaglobulinemia.
Treatment of bronchiectasis
should start with treating the underlying condition. Prevention of exacerbations include routine chest physical therapy to promote clearance of retained secretions and antibiotics as necessary to control infections.
Cystic Fibrosis
a multi-system disorder present in approximately 1 in 2000 - 3000 live births among Caucasians in the United States. It is an autosomal- recessive trait resulting from mutations at a single gene locus. The gene encodes a membrane protein called the cystic fibrosis trans-membrane regulator (CFTR). Mutations in this gene (many different mutations have been identified) lead to dysfunctional chloride transport across epithelial surfaces which is thought to be responsible for its pathologic effect on a number of organs. The most clinically apparent organs involved are the lung and pancreas. Recurrent sinus and pulmonary infections (initially staph aureus and haemophilus influenza, later mucoid Pseudomonas aeruginosa) are prominent. Recruitment of neutrophils into the lung leads to widespread airway inflammation and destruction of airway walls leading to bronchiectasis. Children may present with meconium ileus (obstruction of the bowel in a newborn with meconium), respiratory symptoms or failure to thrive. Patients have recurrent infections, development of bronchiectasis and gradual onset of respiratory failure due to bronchiectasis and destruction of lung parenchyma. Pancreatic insufficiency, pancreatitis, and CF-related diabetes may develop. Male infertility is common because of defects in sperm transport. The diagnosis of CF can be made by demonstrating an elevated sweat chloride test (abnormally elevated levels of chloride in sweat) or by genetic testing to identify the mutation. Patients develop airflow obstruction with hyperinflation. A bronchodilator response is common. As bronchiectasis and airflow limitation progresses, V/Q mismatch may lead to hypoxemia.
Treatment of cystic fibrosis
CFTR Modulators: Ivacaftor (VX-770) has been designed to treat patients who have a G551D mutation in at least one of their CFTR genes. Ivacaftor is the first approved CF therapy that restores the function of a mutant CF protein rather than trying to target one or more downstream consequences of the mutation. G551D mutation occurs in approximately 4% of patients with CF and impairs the regulated activation of the ion channel that is formed by CFTR. Antibiotics to treat infections. Bronchodilators. Nebulized hypertonic saline can improve hydration of airways with improved mucus clearance. Inhaled DNase I decreases the viscosity of purulent CF sputum by cleaving long strands of denatured DNA released by degenerating neutrophils. Chest Physiotherapy. Exercise. Lung transplantation
Bronchiolitis
inflammation of the membranous bronchioles. These represent the peripheral airways. The auscultatory hallmark of bronchiolitis is the inspiratory squeak, which is probably due to shear stress developed upon late opening of inflamed bronchioles.
Bronchiolitis in children
Infectious bronchiolitis can be a serious problem in children resulting in long-term pulmonary disease particularly airflow obstruction. In children this begins as a viral illness and progresses to fever, cough, and dyspnea. Common agents include mycoplasma pneumoniae, adenovirus, and respiratory syncytial virus (RSV). Severe infections can denude the airway epithelium and in some cases lead to significant long-term airway obstruction. Severe pulmonary infections in children (before the airways are totally mature) can lead to significant long-term pulmonary impairment.
Bronchiolitis in adults
In adults bronchiolitis more frequently is caused by non- infectious etiologies and when the changes are progressive and irreversible this is called bronchiolitis obliterans. Examples include: inhalation of toxic gases (chlorine, nitrogen dioxide, etc), immunologic mechanisms (rheumatoid arthritis, scleroderma), drugs (gold, penicillamine), and transplant rejection (solid organ or bone marrow). These changes are usually irreversible and lead to progressive airway obstruction and respiratory failure.
The upper airway
defined as the portion of the airway extending from the mouth to the lower trachea. The upper airway is divided into the intra- and extrathoracic components by the thoracic inlet, which projects 1-3 com above the suprasternal notch on the anterior of the chest at the level of the first thoracic vertebra. Flow-volume loops can be used to detect obstructing lesions of the upper airway and occur in three patterns: variable extrathoracic obstruction, variable intrathoracic obstruction, and fixed obstruction.
Paradoxical vocal fold motion (Vocal Cord Dysfunction)
The inappropriate adduction of the focal folds on inspiration is commonly confused with asthma. Presentation to the emergency room is often wheeze, stridor, or apparent upper airway obstruction. Diagnosis is made with laryngoscopy. Treatment includes behavioral speech and voice therapy.
Communicating Severity of Obstructive Disease
Communication is a crucial part of medicine. It is important to ask the right questions and look in the chart for the right data when you admit a patient with obstructive disease. The information in the will allow you to quickly communicate how severe a patient’s disease. 1. Give the patient’s FEV1, FVC and FEV1/FVC ratio. 2. Give baseline arterial blood gas
- The patient is/is not steroid dependent.
- The patient is/is not oxygen dependent. 5. The patient has/has not been intubated for an exacerbation. 6. The patient’s exercise tolerance. - one mile on level ground- one flight of stairs before resting - SOB with combing his hair.
Overview of Asthma Management
Goals of therapy are to
o Reduce the frequency and intensity of asthma symptoms. Reduce cough, chest tightness, wheezing, dyspnea. Decease use of rescue medications including short acting beta
agonists (SABA). Reduce night-time symptoms and awakenings. Improve quality of live and allow patient to work, attend school, and
exercise. Prevent exacerbations. Prevent long term consequences of poorly controlled asthma. Loss of lung function. Side effect of chronic medications (oral steroids)
Components of Asthma Management
well-controlled asthma is characterized by symptoms no more than twice per week and nighttime symptoms no more than twice per month. SABA should be used less than twice weekly (with the exception of routine use prior to exercise). Peak flow near normal. Oral steroid no more than once per year. Urgent care visit no more than once per year. Routine monitoring of lung function and symptoms. Patient education - therapeutic partnership between patient and physician. Control environmental factors and triggers. Medications
Symptom Assessment
Has your asthma awakened you at night or in the early morning? How often do you use your rescue inhaler? How often to you get urgent care for you asthma including calls into the office? Has your asthma limited your ability to participate in activities? Are you having side effects from your medications?
Risk assessment
Have you been on oral steroids in the last year? Have you been hospitalized - how many times? Have you been admitted to the ICU or intubated? Do you smoke? Do you get increased symptoms with aspirin or NSAIDs
Controlling Asthma Triggers
Identify and avoid triggers: Allergens, Irritants – Smoke, Medications – beta-blockers, Aspirin, NSAIDS, Viral infections
Allergen immunotherapy
potential therapy to modify disease by inducing
specific allergen tolerance; tends to be more effective in managing allergic rhinitis
and conjunctivitis than asthma
Tiotropium
anticholinergic; approved for COPD but not asthma
Symptoms of
Acute Exacerbation
Symptoms include dyspnea, wheeze, cough, and chest tightness. Peak flow decrease greater than 20% from normal or patient’s personal best.
Management of Acute Exacerbation
SABA. Inhaled anticholinergics. Systemic steroids when peak flow 40% but
ß-adrenergic agonists
Clinical pharmacology: albuterol, terbutaline, salmeterol, formoterol. Used to treat asthma and COPD. Administered by the inhaled, injectable and oral route. Rapid onset of action: minutes for albuterol and formoterol (slightly longer for
salmeterol)
Duration of action of ß-adrenergic agonists
Rapid: 4 - 6 hours (albuterol, terbutaline, pirbuterol and levalbuterol) – used to relieve asthma symptoms and as a pre-treatment to prevent exercise-induced asthma. (levalbuterol is the active bronchodilator stereoisomer of albuterol – benefit is proposed as less risk of adverse effects due to extraction of the complementary stereoisomer associated with adverse effects). Sustained: long acting ß-agonists last approximately 12 hours (salmeterol, formoterol); used to prevent asthma symptoms.
Mechanism of action of ß-adrenergic agonists
ß-adrenergic receptor stimulation. Beneficial effect -bronchodilation via smooth muscle relaxation inhibits production of respiratory secretions. Caution: has “black box” warning associated with increased risk regarding asthma-related deaths. FDA recommends adding only if patient inadequately controlled on low to medium dose inhaled corticosteroids and to discontinue when asthma is well controlled.
mechanism of action of Anticholinergics
cholinergic receptor inhibition. beneficial effect
bronchodilation via smooth muscle relaxation inhibits production of respiratory secretions
Systemic Glucocorticoids
Clinical pharmacology: hydrocortisone, prednisone, prednisolone, methylprednisolone. Used to treat acute exacerbations of asthma. administered by the oral or parenteral route. onset of action: 30 - 60 minutes. metabolism: half-life 2 -3 hours. peak of action: approximately 8 hours duration of action. hydrocortisone - 12-24 hours. prednisolone, methylprednisolone - 36-48 hours
mechanism of action of systemic glucoccorticoid steroids
phospholipase inhibition; inhibition of cytokine synthesis. beneficial effect: anti-inflammatory - reduces cellular infiltration, particularly eosinophils, mast cells, lymphocytes. vasoconstrictor - reduces edema
Step 1 of asthma treatment
SABA PRN
Step 2 of asthma treatment
low dose ICS
Step 3 of asthma treatment
low dose ICS plus LABA or medium dose ICS
Step 4 of asthma treatment
medium dose ICS plus LABA
Step 5 of asthma treatment
high dose ICS plus LABA and consider omalizumab for patients who have allergies.
Step 6 of asthma treatment
high dose ICS plus LABA plus oral corticorsteroid and consider omalizumab for patients who have allergies.
Inhaled glucocorticoids
Clinical pharmacology: beclomethasone dipropionate, triamcinolone acetonide, flunisolide, budesonide, fluticasone propionate, mometasone and ciclesonide. Used as the preferred long-acting control agent to treat asthma and for the treatment of COPD, if repeated COPD exacerbations noted. administered by the inhaled route. onset of action: 30 - 60 minutes.
Metabolism of Inhaled glucocorticoids
half-life 2 -3 hours for most except fluticasone (7 hours). peak of action: approximately 8 hours for single dose; approximately 4 weeks for continued administration. duration of action: requires once to twice daily administration to maintain effect.
mechanism of action of Inhaled glucocorticoids
phospholipase inhibition; inhibition of cytokine synthesis. beneficial effect. anti-inflammatory - reduces cellular infiltration, particularly eosinophils, mast cells, lymphocytes; vasoconstrictor - reduces edema
Long acting ß-adrenergic agonists (LABA)
Salmeterol and formoterol - Clinical pharmacology. administered by the inhaled route. onset of action: 15 minutes. duration of action: 8 -12 hours after single dose. mechanism of action: ß-adrenergic receptor stimulation. beneficial effect: bronchodilator effect
adverse effect of Long acting ß-adrenergic agonists (LABA)
has Black Box warning due to an observed increase in
asthma-related deaths noted in a post-marketing study. Therefore, it should not be used as monotherapy for asthma since long-acting ß-adrenergic agonists (LABA) do not reduce inflammation. LABA should be combined with an inhaled corticosteroid to control inflammation component.
Combination Therapy with Long acting ß-adrenergic agonists (LABA)
Inhaled products are now available that combine an inhaled corticosteroid plus long acting ß-adrenergic agonist for benefits of both in the same delivery device.
Leukotriene modifiers
Clinical pharmacology: administered by the oral route. onset of action: 30 - 60 minutes. metabolism: half-life 6 hours; hepatic metabolism. duration of action: 12-24 hours
mechanism of action of Leukotriene modifiers
leukotriene D4 antagonist – montelukast, zafirlukast. 5-lipoxygenase inhibition – zileuton. beneficial effect: bronchodilator effect, anti-inflammatory effect due to leukotriene blocking effect, attenuates exercise-induced asthma
Immunomodulator
Anti-IgE (omalizumab) approved for allergic asthma, requires parenteral (subcutaneous) administration; binds to IgE to reduce likelihood of allergic response by inhibiting binding of IgE to mast cells. An adverse effect associated with anti-IgE is anaphylaxis, which may occur shortly after or several hours after administration.
Clinical pharmacology of Cromolyn/nedocromil
administered by the inhaled route. half-life: 20 minutes; excreted unchanged. mechanism of action: inhibition of mast cell mediator release. beneficial effect: preventative therapy for exercise-induced asthma and can prevent allergen-induced pulmonary response
Theophylline
administered by the oral or intravenous route • onset of action: 30 - 60 minutes. metabolism: half-life 7 hours; hepatic metabolism. duration of action: 12 - 24 hours after single dose
mechanism of action of Theophylline
inhibition of phosphodiesterase. beneficial effect: bronchodilator effect and some anti-inflammatory activity
adverse effect of Theophylline
“caffeine-like effects such as irritability, gastrointestinal distress. Also has very narrow therapeutic range and requires blood level monitoring to individualize dose. Significant adverse effects can include seizures and irreversible neurologic damage. Other disadvantages include multiple drug interactions. For example, certain macrolide antibiotics (such as clarithromycin but not azythromycin) can inhibit metabolism, and certain medications (such as anticonvulsants, phenytoin and carbamazepine, and rifampin) can increase metabolism, Thus, use of theophylline has diminished over the years with the introduction of safer and more effective medications.
GOLD 1: Mild of COPD
FEV1 > 80% predicted
GOLD 2: Moderate of COPD
50%
GOLD 3: Severe of COPD
30%
GOLD 4: Very Severe of COPD
FEV1
Assess Risk of exacerbation of COPD
To assess risk of exacerbations use history of exacerbations and spirometry: Two or more exacerbations within the last year or an FEV1
Patient A classification of COPD
low risk less symptoms. Gold 1-2 with less than 1 exacerbations per year. 0-1 on the MMRC Dyspnea scale. Less than ten on the COPD Assessment Test (CAT). Treatment is SAMA or SABA prn
Patient B classification of COPD
low risk more symptoms. Gold 1-2 with less than 1 exacerbations per year. Greater than 2 on the MMRC Dyspnea scale. Greater than ten on the COPD Assessment Test (CAT). Treatment is LAMA or LABA
Patient C classification of COPD
High risk less symptoms. Gold 3-4 with greater than 2 exacerbations per year. 0-1 on the MMRC Dyspnea scale. Less than ten on the COPD Assessment Test (CAT). Treatment is ICS + LABA or LAMA
Patient D classification of COPD
High risk more symptoms. Gold 3-4 with greater than 2 exacerbations per year. Greater than 2 on the MMRC Dyspnea scale. Greater than ten on the COPD Assessment Test (CAT). Treatment is ICS + LABA and/or LAMA
Non-pharmacologic management of stable COPD
Essential treatment includes smoking cessation (can include pharmacologic treatment). Pulmonary rehabilitation for patient B, C, D. Physical activity is recommended. Depending on local guidelines, should consider flu vaccination, pneumococcal vaccination. Oxygen. Lung volume reduction surgery (LVRS) is more efficacious than medical therapy
among patients with upper-lobe predominant emphysema and low exercise
capacity. Lung transplantation has been shown to improve quality of life and functional
capacity.
Medications for treatment of COPD
beta-agonists, anticholinergics, combination of the two. Emthlxanthines, inhaled corticosteroids, combination of LABA and corticosteroids in one inhaler, systemic corticosteroids, phosphodiesterase-4 inhibitors. Long-acting formulations of beta2-agonists and anticholinergics are preferred
over short-acting formulations. Based on efficacy and side effects, inhaled
bronchodilators are preferred over oral bronchodilators. Long-term treatment with inhaled corticosteroids added to long-acting
bronchodilators is recommended for patients with high risk of exacerbations.
Acute Exacerbations of COPD
an acute event characterized by a worsening of the patient’s respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medication. The most common causes of COPD exacerbations are viral upper respiratory tract infections and infection of the tracheobronchial tree. Diagnosis relies exclusively on the clinical presentation of the patient complaining of an acute change of symptoms that is beyond normal day-to-day variation. The goal of treatment is to minimize the impact of the current exacerbation and to prevent the development of subsequent exacerbations.
Management of Acute Exacerbation of COPD
Short-acting inhaled beta2-agonists with or without short-acting anticholinergics are usually the preferred bronchodilators for treatment of an exacerbation. Systemic corticosteroids and antibiotics can shorten recovery time, improve lung function (FEV1) and arterial hypoxemia (PaO2), and reduce the risk of early relapse, treatment failure, and length of hospital stay.
Airways
Composed of: mucus glands, smooth muscle and ciliated columnar respiratory epithelium
Major Histologic Changes in Acute bronchitis
Neutrophils in the airway lumen and infiltrating the wall of the airway. Usually infectious
Major Histologic Changes in Chronic bronchitis
Chronic inflammation (mostly lymphocytes) in the airway wall. Squamous metaplasia of the epithelium (transformation of the ciliated columnar type cells to flattened polygonal squamous cells). Mucus gland hypertrophy (too many glands making too much mucus)
Major Histologic Changes in Bronchiectasis
Dilation of the airway compared to the neighboring vessel (should be roughly the same size). Often the result of long-standing infection/inflammation
Major Histologic Changes in Asthma
Thickened subbasal lamina Eosinophilic inflammation Mucus hypersecretion
Major Histologic Changes in Chronic bronchiolitis
Inflammation in the wall of small airways that do not contain cartilage. Most common type of inflammation is chronic inflammation (lymphocyte predominate)
Major Histologic Changes in Follicular bronchiolitis
lymphoid aggregates with germinal centers. It is defined as lymphoid hyperplasia of the bronchus and is histologically characterised by hyperplastic polyclonal lymphoid follicles with reactive germinal centers principally distributed alongbronchioles.
Major Histologic Changes in Constrictive/obliterative bronchiolitis
Fibrosis squeezing the airway lumen shut. May cause severe airtrapping in the downstream lung. Bronchiolitis obliterans is a lung disease characterized by fixed airway obstruction. Inflammation and scarring occur in the airways of the lung, resulting in severe shortness of breath and dry cough.
Major Histologic Changes in Granulomatous bronchiolitis
Granulomas composed of clustered histiocytes and multinucleated giant cells. May be centrally necrotizing or nonnecrotizing Necrotizing cases are usually infectious. Nonnecrotizing cases may be infection, sarcoid or chronic beryllium disease. The airspaces lined by the alveolar septa (normally empty). A pathological type of bronchiolitis (not an imaging classification) characterised by an underling granulomatous reaction involving the small airways (bronchioles).
Major Histologic Changes in Acute pneumonia
Neutrophils, macrophages and fibrin within airspaces. Usually infectious
Major Histologic Changes in Aspiration pneumonia
Airspace foreign material (food). Multinucleated giant cells
Major Histologic Changes in Eosinophilic pneumonia
Eosinophils, macrophages and fibrin within airspaces. It is an idiopathic condition and is characterised by chronic and progressive clinical features.
Major Histologic Changes in Organizing pneumonia (OP)
Plugs of loose myxoid fibroblastic tissue plugs in airspaces and small airways. Usually patchy and may have densely consolidated areas May have a small amount of intermixed pink fibrin. A relatively non-specific finding consistent with an element of sub-acute lung injury. Also known as Bronchiolitis Obliterans Organizing Pneumonia (BOOP) or Cryptogenic Organizing Pneumonia (COP). Organising pneumonia (OP) is a histologic pattern of alveolar inflammation with varied aetiology (including pulmonary infection). The idiopathic form of OP is calledcryptogenic organising pneumonia(COP) and it belongs toidiopathic interstitial pneumonias(IIP’s).
Major Histologic Changes in Diffuse Alveolar Damage (DAD)
Hyaline membranes (fibrin ribbons in the airspaces lining the alveolar septa). Alveolar septa may be expanded by inflammation and fibroblastic tissue. The histologic pattern that corresponds to ARDS. Diffuse alveolar damage (DAD) is a common manifestation of drug-induced lung injury that results from necrosis of type II pneumocytes and alveolar endothelial cells.
Major Histologic Changes in Emphysema
Enlarged airspaces
Broken alveolar septa (irreversible damage). Subpleural blebs – may become very large and cause a pneumothorax if ruptured. Smoking-related emphysema is worse in the upper lobes and around bronchioles (centrilobular emphysema). Alpha-1-antitrypin deficiency related emphysema is worse in the lower lobes and is NOT worse around the airways (panlobular emphysema)
Major Histologic Changes in Respiratory Bronchiolitis (RB)
Brown pigmented macrophages in small bronchioles and surrounding airspaces
Major Histologic Changes in Desquamative Interstitial Pneumonia (DIP)
Similar brown pigmented airspace macrophages as RB, but found diffusely in the airspaces, not just around small airways. Desquamative interstitial pneumonia (DIP) is an interstitial pneumonia closely related to, and thought to represent the end stage of respiratory bronchiolitis interstitial lung disease (RB-ILD). It is associated with heavy smoking.
Major Histologic Changes in Diffuse Alveolar Hemorrhage (DAH)
Blood and iron-containing macrophages within airspaces. Alveolar septa may be mildly thickened by inflammation and fibroblastic tissue. May be associated with capillaritis (neutrophils attacking the capillaries of the alveolar septa). Diffuse alveolar haemorrhage (DAH) is a subset of diffuse pulmonary haemorrhage when bleeding is diffuse and directly into the alveolar spaces. It can occur in a vast number of clinical situations and at time can be life threatening.
Major Histologic Changes in Pulmonary Alveolar Proteinosis (PAP)
Airspaces filled with pink fluid and macrophages. Pulmonary alveolar proteinosis (PAP) is a lung disease characterised by abnormal intra-alveolar accumulation of surfactant-like lipoproteinaceous material.
Alveolar Septa
Thin structure containing small blood vessels (capillaries) and lined by epithelial cells (pneumocytes). Should normally be free of both inflammation and fibrosis.
Usual interstitial pneumonia (UIP)
refers to a morphological pattern of interstitial lung disease. In the past the term UIP was used synonymously with idiopathic pulmonary fibrosis(IPF) while more lately the termidiopathic pulmonary fibrosis is applied solely to the clinical syndrome associated with the morphologic pattern of UIP and specifically excludes entities such as non specific interstitial pneumonia (NSIP) and desquamative interstitial pneumonia DIP.
Major Histologic Changes in Usual Interstitial Pneumonia (UIP)
Patchy heterogeneous fibrosis of the septa by mature collagen. Fibroblastic foci (compact collections of fibroblasts and myxoid stroma buldging into the airspaces). Honeycomb cystic change (end-stage lung remodeling with mucus filled cysts lined by airway-type epithelium and surrounded by fibrosis)
Major Histologic Changes in NonSpecific Interstitial Pneumonia (NSIP)
Uniform homogenous inflammation, fibrosis or a mixture of both Few if any fibroblastic foci
Little if any honeycombing. Nonspecific interstitial pneumonia (NSIP) is one type of idiopathic interstitial pneumonia (IIP).
Major Histologic Changes in Hypersensitivity Pneumonia (HP)
Airway-centered chronic inflammation (lymphocytes and histiocytes) Nonnecrotizing granulomas
Focal organizing pneumonia
Variable fibrosis by mature collagen. A response to foreign antigens (birds, mold, hot-tub mycobacterial antigens, etc.). Hypersensitivity pneumonitis (HP; also called extrinsic allergic alveolitis, EAA) is an inflammation of the alveoli within the lung caused by hypersensitivity to inhaled organic dusts.
Major Histologic Changes in Thromboembolic disease
Organizing fibrin clots within pulmonary arteries. May form in situ (thrombus) or move to the lung from elsewhere (embolism)
Major Histologic Changes in Talc embolism
Polarizable crystals around vessels. May include foreign-body giant cells. Usually from intravenous drug use. Talc (Magnesium trisilicate)pulmonary embolism is a rare cause of non thrombotic pulmonary embolism. It tends to me more prevalent in patients with narcotic abuse.
Major Histologic Changes in Pulmonary hypertension
Muscular hypertrophy of pulmonary arteries
Muscularization of arterioles (normally should not contain smooth muscle). Some forms have plexiform lesions (the artery lumen replaced by endothelial proliferation with numerous tangled slit-like lumens)
Major Histologic Changes in Vasculitis
Inflammation of the vessel wall Often results in alveolar hemorrhage May be autoimmune or infectious
Major Histologic Changes in Sarcoid / Chronic beryllium disease (same appearance on pathology)
Well-formed coalescing nonnecrotizing granulomas (must exclude infectious etiology). Variable concentric collagen deposition around granulomas. “lymphatic distribution” = found next to blood vessels, airways and in the pleura
Pulmonary Langerhans cell histiocytosis
(previously histiocytosis X or eosinophilic granuloma) is a rare form of interstitial lung disease that primarily affects young adults. 90% of affected are cigarette smokers. Langerhans cells express CD1A and S100and possess large cytoplasmic “tennis-racket” Bierbeck granules. Pulmonary Langerhans cell histiocytosis (PLCH)most often presents in a young patients withdyspnea and non-productive cough. May cause spontaneous pneumothorax or diabetes insipidusare two complications seen in patients with pulmonary Langerhans cell histiocytosis (PLCH). High-resolution CT is the imaging study of choice in patients with suspected pulmonary Langerhans cell histiocytosis.The finding of multiple cysts and nodules in the middle to upper lung zones (vs. lower lung zone predominance in idiopathic pulmonary fibrosis) on CTin a young smoker is considered diagnostic for the disease. Stellate lesionsextending into the lung parenchyma is the characteristic histopathologic lesion characteristic of pulmonary Langerhans cell histiocytosis. Treatment of pulmonary Langerhans cell histiocytosis (PLCH) revolves aroundsmoking cessationas corticosteroids and cytotoxic agents have proven to have limited value.
Major Histologic Changes in Pulmonary Langerhans’ Cell Histiocytosis (PLCH) / Eosinophilic Granuloma (EG)
Cellular phase. Langhans histiocytes (S100, CD1a positive). Variable inflammation including eosinophils. Fibrotic/burnt-out phase. Stellate scar around airway. Usually smoking-related if limited to lung
Major Histologic Changes in Carcinoid
Nests and ribbons of neuroendocrine cells with powdery salt-and-pepper chromatin. Stain positive for neuroendocrine markers (chromogranin, synaptophysin, CD56). Usually indolent, but may act in a malignant fashion particularly if there is nuclear atypia, high mitotic rate or regions of necrosis
Major Histologic Changes in Small cell carcinoma
Small blue easily-crushed cells with scant cytoplasm. Stain positive for neuroendocrine markers (chromogranin, synaptophysin, CD56). High mitotic rate and abundant necrosis
Major Histologic Changes in Squamous cell carcinoma
Large polygonal cells with hyperchromatic (dark) nuclei and abundant cytoplasm Rarely have prominent nucleoli May be keratinizing and form ‘keratin pearls’
Major Histologic Changes in Adenocarcinoma
Cells with large nuclei, large nucleoli and variable amounts of cytoplasm. Form gland-like structures. If cells only line the alveolar septa but do not invade, considered adenocarcinoma in situ (formally known as bronchioloalveolar cell carcinoma)
Major Histologic Changes in Large cell carcinoma
Large, sometimes bizarre-appearing, malignant cells that lack the typical features of either squamous cell carcinoma or adenocarcinoma
General considerations of diseases of the mediastinum and pleura
Most mediastinal abnormalities are found incidentally. Mediastinal abnormalities may be found on a radiograph obtained as part of the evaluation of an unrelated clinical issue (e.g. suspected pneumonia) or may be recognized on a study obtained to evaluate a specific complaint, symptom or sign directly referable to potential mediastinal pathology (e.g. swallowing difficulty) or after chest trauma (e.g. risk of dissection of the thoracic aorta). When present, symptoms are related either to direct effects of the mass or system effects of the illness. Thus, a symptom or sign referable to a particular organ system may not be indicative of primary disease in that system. For example dysphagia may result from either esophageal pathology or an extrinsic compressing mass.
Although there are no reliable estimates of prevalence, abnormalities of structures within the mediastinum are varied and common. Many abnormalities, such as courses or dilatations of otherwise normal blood vessels, are benign structural variants, which are of no pathologic significance. Many non-malignant lesions occur including pericardial or bronchogenic cysts, aneurysmic dilatations of the aorta and great vessels, benign tumors and substernal goiters. Such lesions are generally, but not always, asymptomatic. Malignant lesions may be either primary or metastatic, and are equally likely to be symptomatic or asymptomatic. Symptomatic lesions are most often malignant. Thymoma, germ cell tumors, lymphoma and neurinoma are the most common tumors of the mediastinum.
mediastinum
is the region of the body bounded by the thoracic inlet superiorly, the diaphragm inferiorly, the sternum anteriorly, the vertebral column posteriorly and the pleura bilaterally. Core elements of the respiratory, digestive and cardiovascular systems are located in this central area as are elements of the neurologic, lymphatic and endocrine systems The mediastinum is separated in to anatomic subdivisons, anterior, superior, middle and posterior, although not arbitrary, is somewhat misleading in that there are no clear boundaries
that separate one division from another (e.g. there
are no fascial planes that define these compartments). Further, the location of the mediastinum within the chest may vary as processes
in either hemithorax (e.g. tension pneumothorax or
pleural effusion) may cause mediastinal deviation
and shift of its contents to one side or the other. Of
note, combining the anterior and superior divisions
for description as the anterior-superior mediastinum is sometimes clinically useful as processes often extend from one to the other.
Adult vs. children abnormalities of the mediastinum
There are marked differences between children and adults regarding the relative frequency of abnormalities in the various mediastinal subdivisions. In adults approximately 65% of lesions are found in the anterior mediastinum, 25% in the posterior mediastinum and 10% in the middle mediastinum. In children only about 25% of lesions are in the anterior mediastinum and the majority (65%) are in the posterior mediastinum. Most mass lesions in adults are benign (75%) while slightly more than half in children are malignant.
The Anterior Mediastinum
The anterior and anterior-superior mediastinum contains several important structures including the great vessels and aortic root, the thymus gland, inferior aspects of the trachea and esophagus. In addition, a substernal thyroid and parathyroids are common variants. Lymphatic tissue is also present. The most common mass in the superior mediastinum is a substernal thyroid (goiter). The most common masses in the anterior mediastinum are germ cell tumors, Hodgkin’s disease, and non-Hodgkin’s lymphoma. The tumors of the anterior mediastinum are referred to collectively as the “terrible T’s”: thymoma, teratoma/GCT, (terrible) lymphoma and thyroid tissue.
Thymic masses
arise from the third pharyngeal pouch during the 6th week of gestation. The thymus regresses in both mass and size after the first year of life until middle age. They account for approximately 50% of all anterior mediastinal masses and include both benign and malignant disease processes.
Thymic cancer
incidence peaks between 40-60 years with an equal gender distribution and can be associated with paraneoplastic syndromes. The most commonly associated paraneoplastic syndrome that occurs with thymoma is myasthenia gravis (30%). All patients with thymic mass found incidentally on imaging should be evaluated for myasthenia gravis and should be tested for anti-acetylcholine receptor antibodies. Histologically they appear benign, are composed of epithelial and lymphoid cells and may be difficult to distinguish from thymic lymphoma. Of note, benign appearing, well-encapsulated thymoma may be invasive in 30% of patients. “Invasive” or “malignant” thymoma is usually locally invasive and affects adjacent mediastinal structures and pleura, but does not metastasize. Only 10% of well-encapsulated thymomas recur, but invasive thymoma recurs much more commonly. Locally invasive disease is associated with a 67% five-year survival after treatment.
Treatment for thymoma
usually requires surgical resection, sometimes followed by post-operative radiation and chemotherapy. Most recurrences occur locally but many patients (20%) subsequently develop second malignancies. Patients who are unresectable or poor surgical candidates may benefit from chemotherapy. A needle biopsy for tissue is not sufficient thymomas can difficult to distinguish histopathologically from lymphomas and the diagnosis, prognosis and treatment plans can be quite different. Upwards of 15% of all thymomas are malignant. The Masaoka staging system, utilizes the radiographic appearance of a thymic mass, is used for treatment planning and prognostication.
Benign thymic masses
are cysts and require surgical treatment only if compression of neighboring anatomic structures has occurred.
Germ cell tumors
can be benign (teratomas or dermoid cysts) or malignant (seminomas and non seminomatous GCTs). The mediastinum is the most common location for GCTs to occur. Teratomas have equal gender distribution. They can contain elements of fat, fluid and bone. Rarely, they are associated with paraneoplastic encephalitis due to anti-N-methyl-D-aspartate receptor antibodies in patients ovarian or mediastinal teratomas. Treatment is surgical resection as they have a high rate of malignant degeneration. Malignant GCTs typically occur in males in the third decade of life. All patients should undergo a full physical exam including a scrotal ultrasound to rule out the mediastinal mass is not related to a metastatic primary testicular malignancy. An abdominal CT should follow the chest CT. Tumor markers (alpha fetal protein and beta-HCG) are helpful at supporting the diagnosis and following for treatment response. Seminomas are more common than non-seminomatous GCTs and are managed with chemotherapy alone most commonly. Non- seminomatous GCTs have residua of yolk sac carcinoma, embryonal cell carcinoma and/or choriocarcinoma. Occur most frequently in males between the ages of 20-40 years. Upwards of 80% have metastatic disease at time of diagnosis. Treatment is a combination of chemotherapy and surgical for residual disease.
Lymphoma
typically presents with fevers, weight loss, night sweats and symptoms associated compression of mediastinal structures. The most common types of lymphoma include nodular sclerosing Hodgkin’s lymphoma and primary mediastinal B-cell lymphoma.
Thyroid mass or goiter
that enters into the thoracic typically present with shortness of breath or dysphagia. Treatment is surgical resection. Large goiters can cause significant airway obstruction thus careful surgical and anesthetic planning should be performed.
The Middle Mediastinum
The middle mediastinum, which includes that space bounded by the pericardium anteriorly, the vertebral bodies posteriorly, diaphragm inferiorly and pleura laterally contains within its confines the only true mediastinal compartment, the pericardial sac. Lymphatics, proximal airways, the esophagus, the vagus (including the recurrent laryngeal branch) and phrenic nerves, and blood vessels including the pulmonary arteries, superior and inferior vena cava is also present.
Lymphadenopathy
is the most common mass presenting in the middle mediastinum. The most commonly associated causes include lymphoma, sarcoid and metastatic lung cancer. Surgical biopsy and resection occurs via a mediastinoscopy.
Cystic mass lesions
can also occur in the middle mediastinum and include bronchogenic cysts, enteric cysts and pericardial cysts. In general, cysts are always surgically resected in order to establish a diagnosis, decrease risk of infection and prevent malignant transformation. Bronchogenic cysts are the most common and arise from an abnormally developed foregut. They occur with a male predominance with right-sides cysts occurring more frequently than left. Often present with substernal chest pain, cough and recurrent infection symptoms. Treatment is surgical resection of the cyst, or lobectomy in extreme cases. Enteric cysts are benign and typically asymptomatic. Diagnosis requires evidence of attachment to the esophagus, presence of 2 layers of muscularis propira and gastric epithelium. Pericardial cysts occur rarely and have an anatomic predisposition to develop at the right cardiophrenic angle. Symptoms include shortness of breath, right heart failure secondary to compression, infection and bleeding.
The Posterior Mediastinum
The posterior mediastinum interfaces with the paravertebral sulci and anterior vertebral column and includes the spinal nerve roots, which combine to form the intercostal nerves, the sympathetic chain and the thoracic duct as well as the inferior portion of the descending aorta. Neurinomas, tumors of peripheral nerves, which are almost always benign, are the most common mass lesions found in this compartment, >60% of all masses.
Schwannomas and neurofibromas
are benign and arise from the intercostal nerve sheath.
Neuroblastomas and ganglioneuroblastomas
are malignant and arise from the sympathetic ganglia and most commonly present during childhood.
Ganglioneuromas
are also benign and arise from the sympathetic ganglia.
DIAGNOSTIC EVALUATION OF THE MEDIASTINUM
After history and physical examination, routine chest radiography with frontal and lateral projections is the first step in identifying a mediastinal mass. Projection in two views allows for localization to a particular mediastinal compartment and a more focused differential diagnosis. Chest-CT is now routinely employed as the next diagnostic test for suspected mediastinal masses. It provides an excellent means to specifically localize lesions anatomically, to separate cystic from solid lesions, to identify fatty structures (e.g. pericardial fat pad), and with intravenous contrast, to differentiate lymphadenopathy and vascular abnormalities. Masses that are not diagnosed definitively on chest CT require further study. CT or ultrasound guided needle biopsy is a useful approach that often obviates the need for more invasive strategies. If surgery is required for further characterization or treatment, chest CT is useful in guiding the selection of approach. Chest MRI is useful for patients who cannot tolerate intravenous contrast because of contrast allergy or renal insufficiency or for those with suspected vascular, chest wall or extra-thoracic invasion.
Trans-thoracic or trans-esophageal echocardiography
can be very useful in assessment of cardiac structures, the pericardium and aortic root. It may also characterize a mass as cystic. Trans-thoracic or endoscopic ultrasound may also be used to guide needle biopsy. Radionuclide scintigraphy is useful for the evaluation of substernal goiter (131I or 123I), pheochromocytoma (131I metaiodobenzylguanine) or lymphoma (Gallium). The role of Positron Emission Tomography (PET) scanning has yet to be determined, but will likely prove useful in the evaluation of metastatic and inflammatory lesions.
Measurement of serum biochemical markers
is useful in several conditions. Serum determinations of AFP and beta-HCG should be done in patients suspected of having germ cell tumors. Urinary catecholamines, vanillylmandelic acid and homovanillic acid may be elevated with pheochromocytoma or neurogenic tumors.
Biopsy of malignancy
Decisions to biopsy for suspected malignancy must be individualized. Relevant considerations include the presence of symptoms, clinical status of the patient, elevation of serum markers, evidence of invasion on imaging studies, and presence of extrathoracic disease, which may offer alternative sites for biopsy. Full resection is favored over tissue biopsy if pheochromocytoma is likely as tumor manipulation may precipitate a hypertensive crisis. Resection is also favored with suspected thymoma as FNA may cause tumor spread.
Tissue specimens may be obtained via CT or ultrasound guided FNA prior to a definitive surgery. CT guided FNA is well tolerated and is diagnostic in 75%. Biopsy of hilar or mediastinal lymph nodes may also be done transbronchially. Surgical approaches that may be used to provide for either tissue biopsy or possible resection of a mediastinal mass include anterior mediastinoscopy, cervical mediastinoscopy and videothoracoscopy.
COMPLICATIONS OF MEDIASTINAL DISEASE
Complications of mediastinal pathology reflect both the primary pathology and the relationship of anatomic structures within the mediastinum. Tumors or infection within the mediastinum may produce complications through direct extension and involvement of adjacent structures, by compression of adjacent structures, by causing paraneoplastic syndromes or by metastasis elsewhere. Four dreaded complications of mediastinal disease are (1) tracheal obstruction, (2) SVC syndrome (3) vascular invasion and catastrophic hemorrhage (4) esophageal rupture.
TREATMENT OF MEDIASTINAL DISEASE
Treatment recommendations regarding mediastinal disease in most cases are predicated upon a specific clinical and pathologic diagnosis as well as knowledge of a particular patient’s overall medical and functional status. Thus, imaging and tissue biopsy precede treatment; there is only a limited role for empiric therapies. In general, malignant disease of the mediastinum due to lymphoma, germ cell tumor or thymoma responds well to aggressive therapy, which may be multimodal involving surgery, radiation and chemotherapy. Acute necrotizing infection most often requires surgical intervention and broad-spectrum intravenous antibiotics. Chronic infections may respond to antibiotic therapy alone. Benign disease may sometimes be managed expectantly if the patient is asymptomatic. Bronchogenic cysts should generally be removed despite their benign nature. Patients with mediastinal masses are at significant risk of airway collapse or obstruction and hemodynamic compromise when undergoing general anesthesia and may require preoperative bronchoscopy as a component of their perioperative assessment.
PROGNOSIS OF MEDIASTINAL DISEASES
The prognosis of benign mediastinal disease is good, particularly if the patient is asymptomatic. The outlook for patients with malignant disease is variable depending upon specific diagnosis, stage of illness and other patient specific characteristics. Most mediastinal malignancies respond well to conventional therapies. Most patients with infectious disease do well with timely institution of broad-spectrum antibiotics and surgical intervention when indicated. Modern vascular surgical techniques are very effective at treating many vascular lesions. There is, however, great individual variation owing to the broad spectrum of pathology present.
Pneumothorax
is defined as the presence of air within the pleural space and is classified as either spontaneous or traumatic. Spontaneous pneumothorax occurs without obvious case and is subclassified as either primary or secondary. Primary spontaneous pneumothorax occurs in the absence of underlying lung disease, whereas secondary spontaneous pneumothorax occurs as a complication of underlying lung disease. The incidence is similar, both conditions occur more commonly in younger males, with a peak incidence in the third decade of life. Secondary spontaneous pneumothorax can be associated with severe respiratory compromise due to lack of respiratory reserve.
Traumatic pneumothorax
results from direct or indirect trauma to the chest, is classified as iatrogenic or non-iatrogenic.
Tension pneumothorax
occurs then the intrapleural pressure exceeds atmospheric pressure throughout expiration and is associated with hemodynamic compromise and is considered a medical emergency.
Primary spontaneous pneumothorax
occurs when subpleural emphysematous blebs rupture. These blebs are commonly located in the lung apices. Risks factors that predispose patients to the development of blebs include tobacco use, body habitus (tall, thin males) and family history. Greater than 10% of patients with primary spontaneous pneumothorax have a family history. Associated anatomic risk factors include narrowed airways and missing or accessory bronchi, 90% of all patients with primary spontaneous pneumothorax have one or more risk factors. The inflammation associated with tobacco use, particularly heavy use, is thought to contribute to the development of emphysematous blebs. Taken together, both inflammation and genetic predisposition can contribute to the development of emphysematous blebs; however, inflammation likely has a larger pathogenic role.
Secondary spontaneous pneumothorax
can occur in nearly all types of lung disease.
Non-iatrogenic traumatic pneumothorax
results from both penetrating and blunt chest trauma. Pneumothorax from penetrating trauma can be caused by entry of atmospheric air into the pleural space through the chest wall, or intrapulmonic air from injury to the visceral pleura. The most common mechanism of injury is due to alveolar wall rupture from sudden increase in alveolar pressure from chest compression.
Prevention of pneumothorax
Prevent of pneumothorax is focused on reducing the risk of iatrogenesis and preventing recurrence of spontaneous pneumothorax. Prevention of iatrogenic pneumothorax emphasizes learning and training proper technique, avoidance of procedures if risk is too great, or modifying technique to minimize risk. The rate or recurrence following an initial primary spontaneous pneumothorax is ~30 – 50%, with risk increasing with each subsequent pneumothorax occurrence, with the majority occurring within the first year. Sclerosis of the pleural space using either chemical or surgical technique can prevent recurrence. There are several chemical pleurodesis agents available, though talc and tetracycline derivatives tend to be most efficacious. Talc is most efficacious, but talc should be used with caution as case reports of acute respiratory distress syndrome (ARDS) have been reported. Long term, talc can be associated with chronic pleural fibrosis and restrictive lung disease. Recurrence of pneumothorax following talc
Clinical findings & Diagnosis of pneumothorax
Signs and symptoms of primary and secondary pneumothorax are similar. Nearly all patients complain of acute onset chest pain and/or dyspnea. Dyspnea tends to be more common and more severe in patients with secondary pneumothorax and is more likely to be associated with respiratory distress, cyanosis and anxiety.
Physical signs on pneumothorax
are localized to the side of the pneumothorax and include decreased tactile and vocal fremitus, hyperresonant percussion, and decreased or absent breath sounds.
Tension pneumothorax is a medical emergency as these patients rapidly develop cardiopulmonary collapse and hemodynamic instability. This most commonly occurs in mechanically ventilated patients. Patients will present with sudden respiratory distress, “fighting the vent”. Physical exam findings include tachycardia, tachypnea, labored breathing, hypotension and cyanosis. Chest exam findings include hyperexpansion of the ipsilateral hemithorax with deviation of the trachea to the unaffected lung.
Laboratory findings of pneumothorax
are usually mild in primary spontaneous pneumothorax and include mild hypoxia, increased A-a gradient and respiratory alkalosis. These findings are exaggerated in secondary spontaneous pneumothorax.
Imaging studies of pneumothorax
including chest radiograph which will demonstrate a pleural line, relative lucency over upper abdominal quadrants, visualization of the anterior costophrenic sulcus, sharp definition of the diaphragm (deep sulcus sign), unilateral increase in hemithorax volume and relative lucency in one lung. Tension pneumothorax will show hyperexpansion of the ipsilateral hemithorax with tracheal and/or mediastinal shift toward the contralateral hemothorax or depression of the ipsilateral hemidiaphragm.
Differential Diagnosis for pneumothorax
Differential diagnosis includes conditions that present with acute onset of chest pain and dyspnea including rib fractures, costochondritis, pulmonary embolism, pneumonia, pleuritis, empyema, and myocardial infarction. Radiographic imaging should quickly diagnosis the presence of a pneumothorax.
Complications of pneumothorax
Complications following pneumothorax include bronchopleural fistula (BPF) and re-expansion pulmonary edema. BPF is a pleural leak that persists following the placement of tube thoracostomy. Initial management includes conservative treatment with tube thoracostomy drainage and most close spontaneously. If the BPF persists for more than 4-7 days, surgical intervention is indicated. Chemical pleurodesis for closure of BPF is reserved for patients who refuse or are unable to tolerate surgical intervention. Re-expansion pulmonary edema is uncommon and is characterized by unilateral pulmonary edema occurring within 24-48hrs after re-expansion of the collapsed lung. Pulmonary edema is due to increase in vascular permeability and oxidant mediated reperfusion injury. Risk factors include duration of pneumothorax prior to re-expansion, application of negative pressure to expand lung. Management is supportive, rarely mechanical ventilation for respiratory failure.
Treatment of pneumothorax
Treatment options run the spectrum of conservative observation, simply aspiration, tube thoracostomy, VATS or open thoracotomy. All patients with a diagnosis of pneumothorax should be placed on supplemental oxygen as it has been shown to increased rate of pleural absorption of air. If the pneumothorax is small, conservative management with supplemental oxygen and observation may be sufficient. Tube thoracostomy is indicated for large pneumothorax, physiologic impairment or enlarging pneumothorax. They can be placed by interventional radiology or by a trained physician. Thoracostomy tubes can be removed once pneumothorax has shown radiographic stability and no air leak is present.
Prognosis of pneumothorax
Death can occur in both primary and secondary pneumothorax if left untreated, and is most likely related to the degree of underlying pulmonary pathology. Thus, secondary spontaneous pneumothorax is more likely to result in death.
General considerations of pleural effusions
The visceral and parietal pleura are separated by a surfactant-containing, hypooncotic fluid that lubricates and allow for frictionless movement and apposition the pleural surfaces during the respiratory cycle. Normally, 0.2-0.3 mL/kg of pleural fluid is present in the pleural space. It is continuously produced by the systemic vessels of the pleural and removed by the pleural lymphatics. The rate of removal has been estimated to be between 0.01mL/kg/h and is governed by both hydrostatic and oncotic gradients across the pleural surfaces. The protein concentration of the pleural fluid is generally low (~1g/dL), slightly alkalotic to serum and is relatively hypocellular (2000 WBC/uL in a monocyte/macrophage predominance with 10-20% lymphocytes and few granulocytes and erythrocytes.
Pathogenesis of pleural effusion
Pleural effusion is an abnormal accumulation of fluid in the pleural space and cane arise from a wide variety of pathologic conditions. Effusions are first broadly classified, as transudative versus exudative in nature then further classified as empyematous, hemorrhage or chylous.
Clinical findings Signs and Symptoms of pleural effusion
The hallmark of pleural effusion on physical exam are attenuation of breath sounds, dullness to percussion, and decreased tactile fremitus over the area of effusion. These findings require fluid accumulation of > 300mL. Other exam findings may include a friction rub, egophony and crackles due to lung compression above the effusion. In massive fluid accumulation, signs of tension including tracheal shift past midline and bulging of the intercostal spaces may be present.
Symptoms of pleural effusion
may be absent to minimal in the setting of small effusions, but often include dyspnea, cough or pleuritic chest pain. Dyspnea is typically out of proportion to accompanying hypoxia and is related to the mechanical distortion placed on the muscles of respiration physical presence of the fluid.
Conventional Radiology with pleural effusions
As little as 5 mL of fluid is can be detected using the lateral decubitus position on chest radiography. The traditional posteroanterior and lateral view require more fluid, posteroanterior view; 175-200mL and lateral view; 50-75 mL. The appearance of a fluid meniscus along the chest wall or mediastinum should alert the clinician to the presence of an effusion. Fluid loculation and trapping may have the radiographic appearance of a pleural or parenchymal mass and will have a lenticular or rounded appearance with a smooth-contoured interface with the lung. These collections typically occur along the chest wall or within the fissures. Loculations are best identified by the use of ultrasound or CT.
Ultrasound with pleural effusions
Ultrasound is particularly useful in diagnosing and sampling loculated fluid collections and to guide sampling of small or difficult to tap fluid collections.
Computed tomography (CT) with pleural effusions
CT is the most sensitive of all radiographic studies for the detection and delineation of pleural fluid collections. Freely flowing collections appear as crescent-shaped opacity in the dependent regions of the thorax. Loculations remained in a fixed position, and typically appear as lenticular or rounded opacities. CT can be used for directed placement of catheters in complex fluid collections. CT is also extremely helpful in delineating between anatomic compartments and fluid densities. Use of other advanced imaging modalities (PET and MRI) are of limited use in pleural effusions and should only be utilized in specific occasions.
Laboratory Findings/Diagnosis with pleural effusions
Determining the cause of the fluid collection helps to facilitate diagnosis and directs management. Thoracentesis is a simple procedure that can be performed at the bedside that can be used for both diagnostic and therapeutic purposes. Indications for thoracentesis include; presence of new fluid collection to determine nature of the effusion and cause. Clues to the cause of the effusion can be gained by simple inspection of the fluid. Frank pus indicates infection, empyema, blood fluid should raise the concern of a hemothorax and fluid should be sent to the laboratory for a hematocrit, fluid hematocrit >50% of the measured peripheral blood hematocrit is diagnostic for hemothorax. Turbid fluid should be spun to remove cellular debris, if sample does not clear, this would indicate a chylous effusion and the diagnosis is confirmed by the presence of triglycerides and cholesterol in the fluid. Clear yellow fluid should be sent for creatinine to evaluate for the presence of a urinothorax.
Transudative vs. exudative effusion
Distinguishing between a transudative versus exudative effusion is necessary as it provides differential diagnosis. Transudative effusions occur in the setting of derangement of hydrostatic and oncotic forces within thorax in the setting of normal pleura, whereas, exudative effusions occur increased vascular permeability and/or decreased lymphatic drainage. This distinction is best made using Light’s criterion that utilizes serum and pleural fluid (PF) laboratory values. Pleural fluid is likely exudative if one or more of the following criteria is met. 1. PF protein/serum protein ratio > 0.5
- PF LDH/serum LDH ratio > 0.6
- PF LDH > two-thirds the upper limit of normal serum range. If criteria are consistent with an exudative effusion, then further studies should be pursued to identify the etiology. These studies should include fluid cell count and differential, glucose, gram stain and culture and cytology. Those diagnoses that can be established by pleural fluid analysis alone are listed in Table 3.
Varenicline
is the first designer drug for tobacco dependence and was recently approved by FDA for smoking cessation. It acts as a partial agonist at the nicotine receptor leading to the release of dopamine, thereby decreasing cravings. It also blocks the binding of exogenous nicotine, thereby decreasing feelings of reward from smoking. Dosing is titrated to 1 mg twice daily and started one week before the quit date. Patients can continue for 12 weeks safely (longer is probably safe but hasn’t been studied). Side effects of this drug include nausea (up to 40%) and nightmares.
Bupropion
is an antidepressant which inhibits reuptake of dopamine and norepinephrine. Use of this medicine in smoking cessation has been shown to reduce cravings and symptoms of withdrawal. This effect appears to be independent of anti- depressant activity.
Cytisine
is a partial agonist at the nicotine receptor. In one small non-blinded RCT, it was shown to be superior to NRT at 1 and 6 months in terms of abstinence rates. Side effects appear to be nausea and sleep disturbance. This drug has been available over- the-counter in Eastern Europe for 50 years and is significantly less expensive than NRT. More studies on this compound in the future may prompt FDA approval in the US.
Acid-base disturbances
The body will try to compensate when there are disturbances to try and normalize the pH. lungs can regulate CO2 levels (minutes) and kidneys can regulate bicarbonate (hours to days). Compensation will never completely correct to normal pH (nor will it over-compensate). There are 4 basic acid-base disturbances: respiratory acidosis, respiratory alkalosis, metabolic acidosis, metabolic alkalosis
Respiratory acidosis
Too much CO2 results in lower pH. Virtually always due to ineffective ventilation. Can be either acute (before kidneys can compensate) or chronic. Compensation rules: Acutely, for every 10 Torr increase in CO2, pH decreases by 0.08. Chronically, for every 1Torr increase in CO2, HCO3- increases about 0.4 meq/L
Acute causes of respiratory acidosis
CNS depressants (opiates, benzodiazepines, alcohol most common). Respiratory muscle fatigue (increased work of breathing)
Chronic causes of respiratory acidosis
Central hypoventilation (e.g. obesity hypo-ventilation syndrome). Neuromuscular disease (e.g. ALS). Chronic lung diseases (emphysema, bronchiectasis, etc). Hypothyroidism
Respiratory alkalosis
Too little CO2 results in higher pH. Due to increased ventilation. Can be either acute or chronic. Compensation rules: Acutely, for every 10 Torr decrease in CO2, pH increases by 0.08. Chronically, for every 1Torr decrease in CO2, HCO3- decreases about 0.4 meq/L
Acute causes of respiratory alkalosis
Pain, Anxiety/Panic attack, Fever, Mechanical Ventilation
Chronic causes of respiratory alkalosis
Living at altitude, Brain injury, Chronic salicylate toxicity, Pregnancy
Metabolic acidosis
Too much acid results in decreased HCO3- and lower pH. Respiratory compensation is quite rapid with increased ventilation resulting in decreased pCO2. Compensation rules: Expected pCO2 = 1.5[HCO3-] + 8 ± 2. Two categories of metabolic acidosis: Anion Gap and Non-Anion Gap
Causes of anion gap
Methanol, Uremia, DKA (and other ketoacids, namely EtOH and starvation), Propylene Glycol, INH, Lactate, Ethylene Glycol, Salicylates
Non-anion gap
GI losses (i.e. diarrhea), Renal losses (RTA), Too much IV saline (increases Cl- with loss of bicarb)
Metabolic alkalosis
Too much HCO3- results in higher pH. Respiratory compensation is quite rapid with decreased ventilation resulting in increased pCO2. Will not hypoventilate to point of hypoxemia, so is often incomplete. Compensation rules: Increase [HCO3-] of 1mEq/L increases PaCO2 by 0.7 Torr
Causes of metabolic alkalosis
Vomiting or NG tube suction (loss of gastric acid), Ingestion NaHCO3, Ingestion of other alkali (milk-alkali syndrome), Hypovolemia, so-called contraction alkalosis, Diuretics
