TABLE IV-114 Risk Factors for Active Tuberculosis Among Persons Who Have Been Infected With Tubercle Bacilli 14 page

Crackles (or rales) are predominantly heard during inspiration and are considered a sign of alveolar or interstitial lung disease. A variety of diseases cause crackles including pneumonia, pulmonary edema, and any cause of interstitial lung fibrosis. Some clinicians attempt to distinguish between the “wet” crackles of pulmonary edema or pneumonia compared to the “dry” crackles of interstitial lung disease. However, this is not a reliable finding. A better way to differentiate between the alveolar and interstitial causes of crackles is to test for the presence of egophony. When alveolar filling is present, the “EEE” sound will be heard as a “AH” sound; however, in interstitial lung disease the “EEE” sound will be preserved. Whispered pectoriloquy will also be intensified in alveolar filling processes, but not interstitial lung disease.

The lack of breath sounds is important to note, but can be caused by many factors including severe bullous lung disease, emphysema, pneumothorax, or pleural effusion.

VI-2. The answer is B. (Chap. 251) This patient presents with subacute-onset dyspnea and an examination consistent with pleural effusion. Dullness to percussion can be seen with consolidation, atelectasis, and pleural effusion. With consolidation, voice transmission is increased during expiration so that one may hear whispered pectoriloquy or egophony. However, in both pleural effusion and atelectasis, breath sounds are diminished and there is no augmentation of voice transmission. Although this patient could have either atelectasis or pleural effusion, the lack of tracheal deviation points to pleural effusion. Atelectasis would have to be of many segments to account for these findings, and such significant airway collapse would generally cause ipsilateral tracheal deviation. The clinician would expect to find pleural effusion on chest film, and the most appropriate next management step would be thoracentesis to aid in the diagnosis of the etiology and for symptomatic relief. With a lack of symptoms to suggest infection, antibiotics are not indicated. Similarly, in the absence of wheezing or significant sputum production, bronchodilators and deep suctioning are unlikely to be helpful. Bronchoscopy may be indicated ultimately in the management of this patient, particularly if malignancy is suspected;

however, the most appropriate first attempt at diagnosis is by means of thoracentesis.

VI-3. The answer is B. (Chap. 252) The functional residual capacity of the lung refers to the volume of air that remains in the lung following a normal tidal respiration. This volume of air represents the point at which the outward recoil of the chest wall is in equilibrium with the inward elastic recoil of the lungs. The lungs would remain at this volume if not for the actions of the respiratory muscles. The functional residual capacity is comprised of two lung volumes: the expiratory reserve volume and the residual volume. The expiratory reserve volume represents the additional volume of air that can be exhaled from the lungs when acted upon by the respiratory muscles of exhalation. The residual volume is the volume of air that remains in the lung following a complete exhalation and is determined by the closing pressure of the small airways.

VI-4. The answer is D. (Chap. 252) This patient presents with subacute dyspnea, stridor, and airflow obstruction, which are consistent with a diagnosis of subglottic stenosis related to his prior prolonged mechanical ventilation. This is confirmed by the finding of fixed airflow obstruction on the flow-volume loop. Flow-volume loops are derived from spirometry. Following a maximum inspiratory effort from residual volume, an individual forces the maximum volume of air from the lungs, and the resultant flows are plotted against the volume. By convention, inspiration is shown on the lower portion of the curve and expiration is on the top. There are characteristic patterns of airflow obstruction that can be evaluated by examining this curve. A fixed central airflow obstruction results in flattening of the flow-volume loop in both inspiration and expiration, yielding the characteristic boxlike effect in this patient. Examples of fixed airflow obstruction include tracheal stenosis and an obstructing central airway tumor. Other patterns of large airway obstruction are a variable intrathoracic obstruction and variable extrathoracic obstruction. In these situations, flattening of the flow-volume curve occurs on only one limb of the flow-volume loop, and the pattern of flattening can be explained by the dynamic changes in pressure that affect the trachea. A variable intrathoracic obstruction causes flattening of the flow-volume curve only on expiration. During inspiration the pleural pressure is more negative than the tracheal pressure, and the trachea remains unimpeded to flow. However, when pleural pressure rises on expiration relative to tracheal pressure, there is collapse of the trachea and flattening of the flow-volume curve. An example of a variable intrathoracic obstruction is tracheomalacia. In contrast, the variable extrathoracic defect leads to flattening of the flow-volume loop on inspiration but not expiration. The relevant pressure acting on airflow in the trachea in an extrathoracic obstruction is atmospheric pressure. During inspiration, the tracheal pressure drops below atmospheric pressure, leading to compromised airflow and the characteristic flattening of the flow-volume loop. However, tracheal pressure rises above atmospheric pressure during expiration, leading to a normal expiratory curve.

VI-5. The answer is B. (Chap. 252) Pregnancy is a known risk factor for the development of venous thromboembolic disease and should be suspected in any pregnant patient presenting with acute dyspnea. Determining the need for further testing in a pregnant patient should take into account the potential risks of radiation exposure on the fetus. Unfortunately, the signs and symptoms of pulmonary embolism are often nonspecific. Most chest x-rays are normal, and sinus tachycardia may be the only finding on electrocardiogram. In addition, in the pregnant patient dyspnea is common due to a variety of factors including increased size of the uterus and the effects of progesterone as a central respiratory stimulant. The normal arterial blood gas in pregnancy shows a chronic respiratory alkalosis with a pH ranging as

high as 7.47 and PaCO₂ between 30 and 32 mmHg. Calculation of the alveolar-arterial gradient (A-a

gradient) can be helpful in this situation. It is easy to be fooled by the presence of a normal oxygen saturation and partial pressure of oxygen on arterial blood gas, but the A-a gradient may still be elevated in the presence of respiratory alkalosis. To calculate the A-a gradient, one first must calculate the alveolar oxygen tension with the alveolar gas equation shown below:

Pa0₂ = PiO_: - (PaC<X/R) where,

PiO₂ = inspired partial pressure of oxygen = ^Fi°₂ * (^pw - P_H*0, and

R = respiratory quotient = carbon dioxide production/oxygen consumption = ∼0.8

In this patient, calculation of the ^Pa°= = [°-²¹ * ⁽-⁷⁶⁰ " ⁴⁷>] ~ (²<>/0.8) = 117.23 mmHg At the same time the measured arterial partial pressure of oxygen was 85. Thus, the A-a gradient is elevated at 32 mmHg and should prompt the physician to perform further workup for pulmonary embolism The choice of test for diagnosis of pulmonary embolism in pregnant patients is most commonly CT pulmonary angiography, although ventilation-perfusion scanning may also be used.

VI-6. The answers are 1. C; 2. B; 3. D; 4. A. (Chap. 252) Ventilatory function can be easily measured with lung volume measurement and the FEV1/FVC ratio. A decreased FEV1/FVC ratio diagnoses

obstructive lung disease. Alternatively, low lung volumes, specifically decreased TLC, and occasionally decreased RV diagnose restrictive lung disease. With extensive air trapping in obstructive lung disease, TLC is often increased and RV may also be increased. VC is proportionally decreased. MIP measures respiratory muscle strength and is decreased in patients with neuromuscular disease. Thus, myasthenia gravis will produce low lung volumes and decreased MIP, whereas patients with idiopathic pulmonary fibrosis will have normal muscle strength and subsequently a normal MIP, but decreased TLC and RV In some cases of pulmonary parenchymal restrictive lung disease, the increase in elastic recoil results in an increased FEV1/FVC ratio.

VI-7. The answer is C. (Chap. 252) In this patient presenting with multilobar pneumonia, hypoxemia is present that does not correct with increasing the concentration of inspired oxygen. The inability to overcome hypoxemia or the lace of a notable increase in PaO₂ with increasing fraction of inspired

oxygen to 1.0 physiologically defines a shunt. A shunt occurs when deoxygenated blood is transported to the left heart and systemic circulation without having the capability of becoming oxygenated. Causes of shunt include alveolar collapse (atelectasis), intra-alveolar filling processes, intrapulmonary vascular malformations, or structural cardiac disease leading to right-to-left shunt. In this case, the patient has multilobar pneumonia leading to alveoli that are being perfused but are unable to participate in gas exchange because they are filled with pus and inflammatory exudates. Acute respiratory distress syndrome is another common cause of shunt physiology. Ventilation-perfusion mismatch is the most common cause of hypoxemia and results when there are some alveolar units with low ratios (low ventilation to perfusion) that fail to fully oxygenate perfused blood. When blood is returned to the left heart, the poorly oxygenated blood admixes with blood from normal alveolar units. The resultant

hypoxemia is less severe than with shunt and can be corrected with increasing the inspired oxygen concentration. Hypoventilation with or without other causes of hypoxemia is not present in this case as the PaCO₂ is less than 40 mmHg, indicating hyperventilation. The acidosis present in this case is of a

metabolic rather than a pulmonary source. Because the patient is paralyzed, she is unable to increase her respiratory rate above the set rate to compensate for the metabolic acidosis.

VI-8. The answer is D. (Chap. 253) This patient presents with a slowly progressive illness manifested by dyspnea on exertion, dry cough, clubbing, and the presence of crackles on examination. In addition, the pulmonary function tests demonstrate restrictive lung disease. This scenario is characteristic of an individual with interstitial lung disease, most commonly idiopathic pulmonary fibrosis in individuals at this age. A more thorough history should be obtained to determine if there are any other exposures or symptoms that could identify other causes of interstitial lung disease. The next step in the evaluation of this patient is to perform a high-resolution computed tomography scan (HRCT) of the chest. The high-resolution technique for CT imaging employs thinner cross-sectional images at approximately 1–2 mm rather than the usual 7–10 mm. This creates more visible details and is particularly useful for recognizing subtle changes of the interstitium and small airways including interstitial lung disease, bronchiolitis, and bronchiectasis. Bronchoscopy with transbronchial biopsy typically does not provide the detail required to adequately diagnose interstitial lung disease. It may be considered if there are specific features on HRCT that would suggest an alternative diagnosis. However, in most instances, the pathologic diagnosis of interstitial lung disease requires a surgical lung biopsy to provide a definitive diagnosis. This patient’s symptoms do not suggest coronary artery disease or congestive heart failure. Thus, echocardiography and nuclear stress testing are not indicated.

CT scanning has evolved over the years to offer several different techniques that are useful in a variety of circumstances. Standard CT imaging is most useful for the evaluation and staging of lung masses. Helical CT scanning requires only a single breath hold and provides continuous collection of data with improved contrast enhancement and thinner collimation. Once the data are obtained, the images can be reconstructed into other views including sagittal and coronal planes as well as 3D volumetric representations. A recent use of this technology is employed in the setting of “virtual bronchoscopy” to aid in the planning and performance of bronchoscopy. Multidetector CT scans can obtain multiple slices in a single rotation that are thinner than the usual cuts. Multidetector CT scanners are used in the performance of the CT pulmonary angiogram.

VI-9. The answer is E. (Chap. 254) The patient in this clinical scenario presents with symptoms typical of asthma, including shortness of breath and wheezing. She also manifests evidence of atopy, the most common risk factor for developing asthma, with sensitivity to outdoor allergens and cats. In addition, the patient has a history of allergic rhinitis and eczema, both of which are commonly seen in individuals with asthma. Indeed, over 80% of asthma patients have a concomitant diagnosis of allergic rhinitis. Atopy is present in 40–50% of the population of affluent countries, but only a small proportion of these individuals develop asthma. Many studies have shown a genetic predisposition via family history and recent genome-wide screens, but no single genetic profile has show high positive predictive value. Overall, the prevalence of asthma in developed countries has increased over the past 30 years, but recently has leveled off with a prevalence of about 15% in children and 10–12% in adults. Asthma deaths remain rare and have decreased in recent decades. In the 1960s, asthma deaths did increase with an overuse of short-acting beta-agonist medications. However, since the introduction of inhaled corticosteroids as maintenance therapy, deaths have declined. Risk factors for fatal asthma include

frequent use of rescue inhalers, lack of therapy with inhaled corticosteroids, and prior hospitalizations for asthma. Interestingly, the overall disease severity does not vary significantly within a given patient over the course of the disease. Individuals who have mild asthma typically continue to have mild asthma, whereas as those with severe disease present with severe disease. Diagnosis of asthma can be made by demonstrating airflow obstruction with significant reversibility on bronchodilator administration. In this case, the FEV₁/FVC ratio is decreased to 70%, which is low. In addition, the FEV₁ increases by 12.4% and 230 mL. This meets the criteria for bronchodilator reversibility of an

increase of at least 200 mL and 12%. Bronchopro-vocation testing with methacholine may be considered in individuals who have suspected asthma but have normal pulmonary function tests.

VI-10. The answer is B. (Chap. 254) The pathology of asthma has largely been determined by examining bronchial biopsies of patients with asthma as well as the lungs of individuals who die from asthma. These pathologic changes are centered around the airways with sparing of the alveolar spaces. The airways are infiltrated by eosinophils, activated T lymphocytes, and activated mucosal mast cells. However, the degree of inflammation does not correlate with the severity of asthma. Another common finding in all asthmatics and individuals with eosinophilic bronchitis is thickening of the basement membrane due to collagen deposition in the subepithelium. The airway smooth muscle is hypertrophied as well. Overall, this leads to thickening of the airway wall, which may also exhibit edematous fluid, particularly in those with fatal asthma. In cases of fatal asthma, it is also common to find multiple airways that are occluded by mucous plugs. However, the disease is limited to the airways, and infiltration of the alveolar spaces by inflammatory cells is not seen.

VI-11. The answer is E. (Chap. 254) A step up in asthma therapy should be considered when a patient continues to have symptoms after 3 months on appropriate therapy. Symptoms to consider when determining whether asthma therapy should be increased include presence of daily symptoms, nocturnal awakening more than once weekly, and limitations in daily activity. Physicians should also review the use of rescue inhalers and lung function when making decisions to step up therapy. In addition, the use of standard asthma severity questionnaires such as the Asthma Control Score may be helpful. When stepping up therapy in mild persistent asthma, the preferred next step in therapy is increasing to medium-dose inhaled corticosteroids or adding a long-acting beta-agonist. However, an alternate therapy that can be considered is adding a leukotriene antagonist, low-dose theophylline, or the leukotriene synthesis inhibitor zileuton to low-dose inhaled corticosteroids.

VI-12. The answer is C. (Chap. 254) The preferred method for diagnosing asthma is demonstration of airflow obstruction on spirometry that is at least partially reversible. This is demonstrated in option C with a decreased FEV₁/FVC ratio, decreased FEV₁, and a significant increase in FEV₁ following administration of albuterol. For an individual to be considered responsive to a bronchodilator, the individual should experience an increase in either FEV₁ or FVC of at least 200 mL and 12%. Option A

describes someone with postviral cough syndrome, which can persist for several weeks following a viral upper respiratory infection. Option B describes someone with exercise-induced bronchoconstriction (EIB), which, in the absence of other symptoms to suggest asthma, should not be diagnosed as asthma. Isolated EIB lacks the characteristic airway inflammation of asthma and does not progress to asthma. While it is estimated that 80–90% of individuals with asthma experience EIB, many individuals who have EIB do not also have asthma. EIB is caused by hyperventilation with inhalation of cool, dry air that leads to bronchospasm. Option D describes someone with occupational asthma that

has occurred after working with animals in the medical laboratory for many years. Symptoms that are characteristic of occupational asthma are symptoms only while at work that improve on the weekends and during holidays. Option E describes a patient with chronic obstructive pulmonary disease (COPD). In COPD, 25–48% of individuals can demonstrate bronchial hyperresponsiveness in response to methacholine.

VI-13. The answer is D. (Chap. 254) A step-down in asthma therapy can be considered when an individual has been clinically stable for 3–6 months. Factors demonstrating appropriate asthma control include daytime symptoms 2 or fewer times weekly, nighttime symptoms 2 or fewer times monthly, use of rescue inhaler 2 or fewer times weekly, FEV₁ or peak expiratory flow rate at least 80% of personal

best, or appropriate control by validated asthma control questionnaires such as the Asthma Control Test or Asthma Therapy Assessment Questionnaire. When stepping down therapy, it is important to review the medications and their dosages. This patient is currently being managed with low-dose inhaled corticosteroids plus a long-acting beta-agonist. At this point, the best course of therapy is to stop the long-acting beta-agonist salmeterol. Since the dose of fluticasone the patient is receiving is already at a low dose, it would not be recommended to decrease it further, and it is never appropriate to treat with a long-acting beta-agonist alone without inhaled corticosteroids. In a large clinical trial, asthma mortality increased in individuals treated with long-acting beta-agonists in the absence of therapy with inhaled corticosteroids. Adding another medication is not indicated as the patient is demonstrating good asthma control.

VI-14. The answer is D. (Chap. 254) Omalizumab is a blocking antibody that binds to and neutralizes circulating immunoglobulin E (IgE) to inhibit IgE-mediated reactions. Omalizumab therapy can be considered for the outpatient treatment of severe, persistent asthma requiring high-dose inhaled corticosteroids in the presence of sensitivity to an aeroallergen. In clinical trials, treatment with omalizumab has been demonstrated to decrease the number of exacerbations in individual experiences and most individuals are also able to decrease the amount of oral or inhaled corticosteroids they are using. Elevations in serum IgE are frequently seen in asthmatic patients, and omalizumab can be considered in individuals whose IgE ranges from 30 to 700 IU/L. However, the manufacturer recommends not giving omalizumab therapy with marked elevations in IgE (>700 IU/L). Omalizumab is given as an injection every 2–4 weeks and must be given in an office setting because rare anaphylactic reactions can occur. If an individual is experiencing an acute exacerbation of asthma, omalizumab is typically held. However, it is not necessary to normalize lung function or discontinue oral steroids prior to initiating therapy with omalizumab.

VI-15. The answer is C. (Chap. 255) This patient has an acute presentation with pulmonary infiltrates and a pleural effusion, both of which have an increased percentage of eosinophils. In the United States, drug reactions are the most common cause of pulmonary infiltrates with eosinophilia (PIE syndrome), and among the drugs that can cause eosinophilia, nitrofurantoin is the most common. Nitrofurantoin is known to cause two types of pulmonary drug reaction. The acute drug reaction occurs within hours to days of starting nitrofurantoin. Patients present with dry cough, dyspnea, and fever. Chest radiograph demonstrates bilateral infiltrates. In a minority of cases, a pleural effusion is seen. Differential cell count demonstrates eosinophilia in both the pleural and bronchoalveolar lavage fluids. Treatment of nitrofurantoin-associated pulmonary eosinophilia consists primarily of stopping the medication. In severe cases, oral corticosteroids can be used as well, but this does not supersede the need to

discontinue the nitrofurantoin. High doses of steroids are typically not required for drug-related pulmonary eosinophilia. While pulmonary infections can cause pulmonary eosinophilia, this patient has a typical time course and presentation for nitrofurantoin-associated lung disease. Therefore, one would not wait for cultures before recommending stopping the nitrofurantoin. Multiple drugs have been associated with eosinophilic pulmonary reactions. In addition to nitrofurantoin, they include sulfonamides, NSAIDs, penicillins, thiazides, tricyclic antidepressants, hydralazine, and chlorpropamide, among others. Levothyroxine, however, is not known to cause any lung disease. Both hypo- and hyperthyroidism can be associated with pleural effusions from the primary disease or associated heart failure. However, they are not associated with eosinophilic lung disease, and adjusting the levothyroxine dose is not indicated.

VI-16 and VI-17. The answers are B and E, respectively. (Chap. 249) The patient has a subacute presentation of hypersensitivity pneumonitis related to exposure to bird droppings and feathers at work. Hypersensitivity pneumonitis is a delayed-type hypersensitivity reaction that has a variety of presentations. Some people develop acute onset of shortness of breath, fevers, chills, and dyspnea within 6–8 hours of antigen exposure. Others may present subacutely with worsening dyspnea on exertion and dry cough over weeks to months. Chronic hypersensitivity pneumonitis presents with more severe and persistent symptoms with clubbing. Progressive worsening is common with the development of chronic hypoxemia, pulmonary hypertension, interstitial pulmonary fibrosis, and respiratory failure. The diagnosis relies on a variety of tests. Peripheral eosinophilia is not a feature of this disease as the disease is mediated through T-cell inflammation. Other nonspecific markers of inflammation may be elevated, including the erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, and serum immunoglobulins. Neutrophilia and lymphopenia may be seen. If a specific antigen is suspected, serum precipitins directed toward that antigen may be demonstrated. However, these tests are neither sensitive nor specific for the presence of disease. Chest radiography may be normal or show a diffuse reticulonodular infiltrate. High-resolution chest CT is the imaging modality of choice and shows ground-glass infiltrates in the lower lobes. Centrilobular infiltrates are often seen as well. In the chronic stages, patchy emphysema is the most common finding. Histopathologically, interstitial alveolar infiltrates predominate, with a variety of lymphocytes, plasma cells, and occasional eosinophils and neutrophils being seen. Loose, noncaseating granulomas are typical.

Treatment requires removing the individual from exposure to the antigen. If this is not possible, the patient should wear a mask that prevents small-particle inhalation during exposure. In patients with mild disease, removal from antigen exposure alone may be sufficient to treat the disease. More severe symptoms require therapy with glucocorticoids at an equivalent prednisone dose of 1 mg/kg daily for 7–14 days. The steroids are then gradually tapered over 2–6 weeks.

VI-18. The answer is C. (Chap. 256) Mesothelioma is a rare malignancy of the pleura and peritoneum with almost all cases associated with asbestos exposure. It is notable that the exposure to asbestos could seem almost minimal, but still confer significant risk. Exposures of less than 1–2 years or those that have occurred more than 40 years in the past have been demonstrated to confer an increased risk of mesothelioma. While tobacco smoking in association with asbestos exposure increases the risk of lung cancer several fold, there is no additive or exponential risk of mesothelioma in those who smoke. Mesothelioma most often presents with a persistent unilateral pleural effusion that may mask the underlying pleural tumor. However, the pleura may be diffusely thickened. Even with large effusions, no mediastinal shift is seen on chest radiograph because the pleural thickening associated with the

disease leads to a fixed chest cavity size and thoracic restriction. The most difficult diagnostic dilemma in these patients is to differentiate mesothelioma from metastatic lung carcinoma (usually adenocarcinoma), as many patients are at risk for both tumors, and lung cancer is far and away the most common malignancy seen in those individuals with asbestos exposure and cigarette smoking. Pleural fluid cytology is not adequate for the diagnosis of most individuals with mesothelioma, with samples being positive for the disease in less than 50% of individuals. Most often video-assisted thoracoscopy is required to directly visualize the pleural surfaces and direct biopsy sampling. Unfortunately, there is no proven effective therapy for mesothelioma, and most patients die from local extension of the disease.

VI-19. The answer is E. (Chap. 256) Silicosis results from the inhalation of free silica (or crystalline quartz) and is associated with mining, stonecutting, foundry work, and quarrying. The chronic form of silicosis has been associated with an increased risk of a variety of diseases. Silica is known to be cytotoxic to alveolar macrophages and thus places patients at increased risk of pulmonary infections that rely on cellular immunity, including Mycobacterium tuberculosis, atypical mycobacteria, and fungus. In addition, silicosis is associated with the development of connective tissue disorders including rheumatoid arthritis with rheumatoid nodules (Caplan syndrome) and scleroderma. Finally, silica is listed as a probable lung carcinogen.

VI-20. The answer is D. (Chap. 256) Occupational lung diseases have been associated with a wide variety of organic and inorganic exposures in the workplace and clinically can range from primarily an airways disease to progressive pulmonary fibrosis. When evaluating a patient for a new pulmonary diagnosis, it is important to perform a detailed occupational history to determine if there is a possibility that the patient’s profession may be causing or perpetuating the disease process. Specific clinical syndromes are associated with well-defined clinical exposures. The inorganic dusts include asbestos, silica, coal dust, beryllium, and a variety of other metals. Asbestos and silica are among the most common exposures. Asbestos exposure is associated with mining, construction, and ship repair. In areas near where asbestos mining has occurred, the general population also has shown an increased risk of asbestos-related lung disease. Clinically, asbestos exposure is associated with a range of clinical syndromes including asbestosis, benign pleural plaques and pleural effusions, lung cancer, and mesothelioma. Silica exposure is common among miners, stone masons, and individuals involved in sand blasting or quarrying. A variety of clinical syndromes can occur with silica exposure, the most severe being progressive massive fibrosis with masslike upper-lobe consolidating nodules (>1 cm). Coal mining is also associated with a clinical picture similar to silicosis and progressive massive fibrosis. Beryllium is a lightweight metal that is highly conductive and is used in high-tech industries. The classic disease associated with beryllium exposure is a chronic granulomatous disease similar in clinical appearance to sarcoidosis. Other metals can produce any number of clinical syndromes. Welders of galvanized metal who utilize zinc oxide are susceptible to metal fume fever and present with an acute self-limited influenza-like illness.

Date: 2016-04-22; view: 977