Respiratory diseases include diseases of the lung, pleural cavity, bronchial tubes, trachea, and upper respiratory tract and diseases of the nerves and muscles of breathing. These conditions range from mild and self-limiting such as the common cold to life threatening such as bacterial pneumonia or pulmonary embolism. The symptoms of respiratory disease differ depending on the disease. Common symptoms are cough with or without the production of sputum, hemoptysis, and dyspnea, which usually occurs with exercise, chest pain, noisy breathing (either wheeze or stridor), somnolence, loss of appetite, weight loss, cachexia, and cyanosis. In some cases, respiratory disease is diagnosed in the absence of symptoms during the investigation of another disease or through a routine check.
Respiratory diseases can be classified in many different ways: by the organ involved, by the pattern of symptoms, or by the cause of the disease.
Obstructive lung diseases are diseases of the lung in which the bronchial tubes become narrowed, making it difficult to move air in and especially out of the lung.
Restrictive lung diseases (also known as interstitial lung diseases) are a category of respiratory diseases characterized by a loss of lung compliance, causing incomplete lung expansion and increased lung stiffness.
Respiratory tract infections can affect any part of the respiratory system. They are traditionally divided into upper respiratory tract infections (URTIs) and lower respiratory tract infections (LRTIs). The most common URTI is the common cold. However, infections of specific organs of the upper respiratory tract such as sinusitis, tonsillitis, otitis media, pharyngitis, and laryngitis are also considered URTIs. Streptococcus pneumoniae is the most common cause of severe, community-acquired bacterial pneumonia. Worldwide, TB is an important cause of pneumonia, usually presenting as a chronic infection. Other pathogens such as viruses and fungi can cause pneumonia, for example, severe influenza and Pneumocystis pneumonia. Tumors of the respiratory tract are either malignant or benign. Benign tumors are relatively rare causes of respiratory disease. Malignant tumors, or cancers of the respiratory system, particularly lung cancers, are a major health problem responsible for 15% of all cancer diagnoses and 29% of all cancer deaths. The majority of respiratory system cancers are attributable to smoking tobacco.
There are a wide range of symptoms due to the intrathoracic effects of various respiratory diseases, the most common of which are dyspnea, cough, and infections.
Cough is a forced expulsive maneuver, usually against a closed glottis and which is associated with a characteristic sound. It is a natural respiratory defense mechanism to protect the respiratory tract and one of the most common symptoms of pulmonary disease. Most cases of troublesome cough reflect the presence of an aggravating factor (asthma, drugs, environmental, gastroesophageal reflex, upper airway pathology) in a susceptible individual. A cough can be classified by its duration, character, quality, and timing and is somewhat arbitrary. A cough lasting <3 weeks is termed “acute,” between 3 and 8 weeks is “subacute,” and one lasting >8 weeks is defined as “chronic.”
Acute cough is defined as a cough lasting <3 weeks. Most frequently, it presents in primary care settings and is commonly associated with URTIs. In most cases, it is benign and self-limiting and most commonly related to virus induced, postnasal drip, throat clearing secondary to laryngitis or pharyngitis. It is frequently associated with acute exacerbations and hospitalizations with asthma and COPD. Symptoms associated with acute cough that require further investigation include hemoptysis, breathlessness, fever, chest pain, and weight loss. Common serious conditions presenting with isolated cough include neoplasms, infections (e.g., TB), foreign body inhalation, acute allergy–anaphylaxis, and interstitial lung disease.
Subacute cough is defined as a cough lasting 3−8 weeks. The gray area between 3 and 8 weeks of cough is difficult to define etiologically, since all chronic cough will have started as acute cough, but the diagnostic group of chronic cough is diluted by the patients with postviral cough (a URTI cough lingering for >3 weeks). Cough after infection is the most common cause of subacute cough (48%), postnasal drip is the second most common (33%), and cough variant asthma is the third most common (16%). In a significant percentage of patients, subacute cough (34%) is self-limited and will resolve without treatment. Most patients with subacute cough that spontaneously resolves had a postinfection cough.
Chronic cough is defined as a cough lasting >8 weeks. It is reported by 10–20% of adults and is common in women and obese people. Most patients present with a dry or minimally productive cough. The presence of significant sputum production usually indicates primary lung pathology.
Chest radiograph and spirometry are recommended. Bronchial provocation testing should be performed in patients without a clinically obvious etiology. Bronchoscopy should be undertaken in all patients with chronic cough in whom inhalation of foreign body is suspected. A cough can be dry or productive, depending on whether sputum is coughed up. Dry cough, that is, there is no “phlegm” and is caused by a virus infection, cold, or dry air or air pollutants such as cigarette smoke, smog, and dust. Productive coughs are coughs that produce phlegm and can be associated with tuberculosis, bacterial pneumonia, and bronchitis.
PULMONARY DISEASES ASSOCIATED WITH COUGH
INFECTIOUS RESPIRATORY DISEASES
Acute bronchitis is a disease caused by infection and inflammation of the bronchial mucosa. Acute bronchitis is caused by respiratory viruses (e.g., influenza virus, parainfluenza virus, rhinovirus, RSV, adenovirus, corona viruses). There is little evidence to implicate bacteria as a significant cause of acute bronchitis, though atypical respiratory bacterial pathogens (Bordetella pertussis, Mycoplasma pneumoniae, Chlamydophila pneumoniae) cause a small proportion of cases.
Who Should Be Suspected?
Patients initially present with cold symptoms but progress to cough that persists for more than 5 days. Purulent sputum may be described; purulent sputum alone is not a reliable indication of bacterial infection and should not be used as the sole indication for antibiotic treatment. Cough resolves within 2–3 weeks in most patients.
Wheezing and bronchospasm develop in some patients.
Fever and systemic symptoms are unusual in uncomplicated acute bronchitis; these symptoms may suggest pneumonia or influenza.
Pertussis should be ruled out for patients with suggestive clinical signs and symptoms. Acute bronchitis is a self-limited viral infection in the vast majority of patients and does not require testing for effective management. Influenza testing might be considered during “flu season” for patients at risk for complicated influenza.
Radiographic and laboratory testing may be considered in patients if clinical presentation suggests pneumonia (cough, fever, sputum production, and systemic symptoms) or chronic bronchitis (cough and sputum production on most days for at least 3 months during 2 consecutive years).
There is little evidence that outcome is improved by antibiotic therapy of M. pneumoniae or C. pneumoniae infection; specific diagnostic testing for these agents is not recommended.
Wenzel RP, Fowler AA III. Acute bronchitis. N Engl J Med. 2006;355:2125–2130.
Croup refers to inflammation of the upper airway below the glottis and has been used to describe a variety of upper respiratory conditions in children, including laryngitis, laryngotracheitis, laryngotracheobronchitis, bacterial tracheitis, or spasmodic croup. Croup is usually caused by viral infection, especially parainfluenza virus, but it is occasionally caused by bacteria or an allergic reaction. It typically occurs in children 6 months to 3 years of age, usually during winter and early spring. Epiglottitis may result in acute airway obstruction and should be considered a medical emergency. A stable airway should be assured prior to collection of diagnostic specimens. Bacterial causes of epiglottitis include type b Haemophilus influenzae, S. pneumoniae, and beta-hemolytic streptococci. The clinical picture in infectious mononucleosis or diphtheria may resemble epiglottitis. TB may cause chronic laryngitis.
Who Should Be Suspected?
The hallmark of croup in infants and young children is the barking cough. In older children and adults, hoarseness predominates. Croup is usually a mild and self-limited illness, although significant upper airway obstruction, respiratory distress, and, rarely, death can occur. Symptoms usually begin with nasal irritation, congestion, and coryza. Symptoms generally progress over 12–48 hours to include fever, hoarseness, barking cough, and stridor. Respiratory distress increases as upper airway obstruction becomes more severe. Rapid progression or signs of lower airway involvement suggest a more serious illness.
Symptoms typically persist for 3–7 days, with a gradual return to normal.
Usually caused by viruses (80%). Parainfluenza virus (type 1–3) is the most common etiology.
Diagnostic and Laboratory Findings
Laboratory studies are of limited diagnostic utility but may help guide management in more severe cases.
CBC: WBC counts can be low, normal, or elevated; WBC counts >10,000 cells/μL are common. CBC differential shows neutrophil or lymphocyte predominance. The presence of a large number of band-form neutrophils is suggestive of primary or secondary bacterial infection.
Chemistries: Not associated with any specific alterations in serum tests.
Microbiology: Confirmation of etiologic diagnosis is not necessary, as croup requires only symptomatic therapy. Identification of a specific viral etiology may be necessary to make decisions regarding isolation for patients requiring hospitalization, for initiation of antiviral therapy, or for epidemiologic monitoring purposes.
Culture: Diagnosis of a specific viral etiology may be made by viral culture of secretions from the nasopharynx or throat.
Cherry JD. Croup (Laryngitis, laryngotracheitis, spasmodic croup, laryngotracheobronchitis, bacterial tracheitis, and laryngotracheobronchopneumonitis). In: Feigin RD, Cherry JD, Demmler-Harrison GJ, et al. (eds). Textbook of Pediatric Infectious Diseases, 6th ed. Philadelphia, PA: Saunders; 2009.
Rihkanen H, Rönkkö EB, Nieminen T, et al. Respiratory viruses in laryngeal croup of young children. J Pediatr. 2008;152:661–665.
PERTUSSIS (WHOOPING COUGH)
Pertussis, a syndrome characterized by prolonged and severe cough, is usually caused by the bacterium B. pertussis; however, B. parapertussis, B. holmesii, and B. bronchiseptica may also cause a pertussis syndrome. Infection is highly communicable, with potential for epidemic spread. Infection is transmitted by the direct respiratory route through exposure to droplets generated by an infected individual. Historically, the association of pertussis as a significant cause of morbidity and mortality in infants and children is well described. Implementation of routine immunization resulted in a significant reduction in the incidence of pertussis. However, since a nadir in the 1970s (0.5 cases/100,000), the incidence of pertussis has been increasing (13.4 cases/100,000 in 2012); outbreaks continue to occur in the United States. This increased incidence is likely due to multiple factors, including waning immunity among vaccines, improved diagnostics, and improved reporting. The incidence of pertussis continues to be highest among infants, followed by older children and adolescents. Spread of infection is limited by vaccination, timely diagnosis and reporting to Public Health officials, antimicrobial therapy and prophylaxis, and measures to prevent further transmission by infected patients.
Who Should Be Suspected/Who Should Be Tested
The most important issue in pertussis diagnosis is clinical recognition. Typical cases of pertussis demonstrate three phases:
Catarrhal (7–10 days): Runny nose; mild cough; low-grade fever. The burden of B. pertussis is highest in the catarrhal phase.
Paroxysmal (1–6 weeks): Severe, paroxysmal coughing spells; inspiratory whoop; cyanosis; posttussive vomiting.
Recovery (2–4 weeks): Decreasing severity of symptoms.
Infants and patients who are unvaccinated, are immunocompromised, or have underlying medical conditions are more likely to have more severe symptoms.
Clinical case definition: Recognition of the pertussis syndrome is critical for diagnosis. A clinical case is defined as a cough illness lasting at least 2 weeks (without other cause), with at least one of the following features: paroxysms of coughing, inspiratory “whoop” (most common in infants), posttussive vomiting.
In the context of a pertussis epidemic, any patient with a prolonged cough illness, regardless of other symptoms, may be suspected.
Diagnostic and Laboratory Findings
A number of test methods are available for detection of B. pertussis infection.
Tests recognized by the CDC for confirmation of pertussis:
Culture: Culture should be obtained from all suspected cases of pertussis. Isolation of B. pertussis confirms the diagnosis (specificity: approximately 100%), but cultures are frequently negative (sensitivity: 15–35%). Nasopharyngeal aspirate or swab (not cotton) specimens should be collected in the first 2 weeks of illness. Specimens should be directly plated onto supportive media, like Regan-Lowe or Bordet-Gengou, or inoculated into supportive media, like half-strength Regan-Lowe charcoal–blood media, for immediate transport to the laboratory. Negative cultures may be due to a number of factors including collection of specimen >2 weeks after the onset of illness, improper collection (e.g., site, swab type), delayed or improper transport conditions, prior antibiotic therapy, and recent vaccination.
PCR: Though there is no FDA-approved test for B. pertussis, PCR is playing an increasingly important role in diagnosis. Testing performed by a Public Health Laboratory is recommended. PCR methods have high sensitivity (93–95%) and specificity (97–99%) when performed on appropriate patients. PCR testing should only be performed on patients with a clinical diagnosis of pertussis. PCR should not be performed on asymptomatic contacts or other asymptomatic patients. Nasopharyngeal aspirate or swab (Dacron, rayon, or nylon) should be collected within the first 3 weeks after the onset of illness. Antibiotic therapy may result in false-negative PCR results.
Tests not recognized by the CDC for confirmation of pertussis:
DFA: Though very specific (>95%), the sensitivity of DFA, compared to PCR, is low (10–50%). For initial clinical management, if timely PCR testing is not available, DFA may be considered.
Serology: Serologic testing has limited utility for the diagnosis or management of patients with suspected pertussis. Serologic responses in patients usually occurs 2 or more weeks after the onset of cough (after the time when antibiotic therapy may be useful). Performance characteristics of commercially available tests have not been well defined for diagnosis of pertussis, and Public Health officials do not accept them for confirmation of pertussis. However, a single-point test has been validated by the Massachusetts Public Health Laboratory and is accepted by the CDC for confirmation of pertussis. This assay cannot be used for vaccinated children <11 years old or in adults vaccinated within 2 years.
Interpretation of Test Results
Clinical: Any cough illness; lab: isolation of B. pertussis by culture
Clinical: Meets CDC Clinical Case Definition; lab: positive PCR for B. pertussis
Clinical: Meets CDC Clinical Case Definition and epidemiologic link to a case confirmed by culture or PCR
Clinical: Meets CDC Clinical Case Definition, but not confirmed by culture or PCR, and is not epidemiologically linked to a laboratory-confirmed case. Positive B. pertussis DFA or serology supports but does not confirm diagnosis.
Best Practices for Health Care Professionals on the Use of Polymerase Chain Reaction (PCR) for Diagnosing Pertussis. Atlanta, GA: Centers for Disease Control and Prevention; 2012. See: www.cdc.gov/pertussis/clinical/diagnostic-testing/diagnosis-pcr-bestpractices.html. Accessed July, 2013.
Faulkner A, Skoff T, Martin S, et al. Chapter 10: Pertussis. Centers for Disease Control and Prevention. Manual for the Surveillance of Vaccine-Preventable Diseases, 5th ed. Atlanta, GA: Centers for Disease Control and Prevention; 2012. See: www.cdc.gov/vaccines/pubs/surv-manual/index.html. Accessed July, 2013.
Loeffelholz MJ, Thompson CJ, Long KS, et al. Comparison of PCR, culture, and direct fluorescent-antibody testing for detection of Bordetella pertussis. J Clin Microbiol. 1999;37:2872–2876.
Tilley PAG, Kanchana MV, Knight I, et al. Detection of Bordetella pertussis in a clinical laboratory by culture, polymerase chain reaction, and direct fluorescent antibody staining; accuracy, and cost. Diagn Microbiol Infect Dis. 2000;37:17–23.
She RC, Billetdeaux E, Phansalkar AR, et al. Limited applicability of direct fluorescent-antibody testing for Bordetella sp. and Legionella sp. specimens for the clinical microbiology laboratory. J Clin Microbiol. 2007;45:2212–2214.
NONINFECTIOUS RESPIRATORY DISEASES
Sarcoidosis is a multiorgan disorder of unknown etiology, characterized by granuloma formation, predominantly in the lungs and intrathoracic lymph nodes. It can affect all individuals with any race, sex, and age, but commonly affects middle-aged adults.
In the United States, the incidence of sarcoidosis ranges from 5 to 40 cases for 10,0000 populations. The age-adjusted incidence for whites is 11 cases per 10,0000 population. Incidence is higher in African American (34/10,0000) and seems to experience more severe and chronic disease. Also, in African Americans, siblings and parents of sarcoidosis cases have about 2.5-fold increased risk for developing the disease.
Internationally, the incidence is 20 cases per 10,0000 in Sweden, 1.3 cases per 10,0000 in Japan, and low in China, Africa, India, and other developing countries and could be hidden and misdiagnosed as tuberculosis.
Incidence peaks in persons aged 25–35 years, and a second peak occurs for women aged 45–65 years. Male-to-female ratio is approximately 2:1. Morbidity, mortality, and extrapulmonary involvement are higher in affected females.
Several studies have reported on association between environmental factors and occurrence of sarcoidosis. These include wood-burning stoves, tree pollen, soil exposures, inorganic particles, insecticides, and moldy environment. Also, several occupational associations are also observed, that include ship’s servicemen, navy, metal work, building supplies, fire workers, hardware, and gardening materials.
Who Should Be Suspected?
Clinical presentation of sarcoidosis is variable and depends on ethnicity, duration of illness, site and extent of organ involvement, and activity of the granulomatous process.
Sarcoidosis typically presents with bilateral hilar lymphadenopathy, pulmonary infiltration, and skin and ocular lesions.
Sarcoidosis can be clinically classified as
Asymptomatic sarcoidosis: Incidentally detected on chest imaging. Thirty to 50% of patients found to be asymptomatic at the time of diagnosis.
Sarcoidosis with nonspecific constitutional symptoms: Observed more frequently in African Americans and Asian Indians. The nonspecific symptoms include fever (39–40°C), weight loss (2–6 kg), fatigue, and malaise.
Sarcoidosis with symptoms related to specific organ involvement: Acute sarcoidosis has sudden onset, more frequently seen in Caucasians and may part as Lofgren syndrome (bilateral hilar adenopathy, erythema nodosum, and ankle arthritis) and constitutional nonspecific symptoms. Organ-related symptoms, often related to pulmonary infiltration (cough and dyspnea).
Pulmonary sarcoidosis: Asymptomatic (30–60%), but chest radiograph abnormalities are high (85–95%). Clinical course is very heterogenous, with 2/3 patients show spontaneous remissions and can be chronic and progressive about 10–30% of patients causing destruction of lung and permanent loss of lung function. Seventy-five percent of patients have bilateral lymphadenopathy.
Extrapulmonary: Common but is almost always associated with lung involvement. May involve entire length of respiratory tract airways causing obstructive airway disease and broad spectrum of airway dysfunction. Common in African Americans than in Caucasians, and in addition, the eyes, bone marrow, extrapulmonary lymph nodes, and skin are more frequently involved.
Cutaneous disease: Skin lesions can be divided into specific and nonspecific on the basis of the presence or absence of granulomatous inflammation on histopathology. Erythema nodosum, lupus pernio, and violaceous rash on the cheek or more are common.
Ocular disease: Most common ocular manifestation is anterior uveitis, which can manifest with blurred vision, red, painful eyes, and photophobia. Conjunctiva can be affected in 6–40% of cases. Optic neuropathy is rare but can cause rapid, permanent loss of vision or color vision.
Hepatic disease: Hepatic sarcoidosis is usually asymptomatic, but the common features are abdominal pain, pruritus, fever, weight loss, and jaundice. Biopsy-based studies showed presence of granulomas is 50–65% of patients and serology-based studies showed abdominal liver function tests in 35% of patients.
Cardiac disease: Known to give rise to heart failure, arrhythmias, sudden cardiac death, and granulomatoses, inflammation in the heart is present in 25% of patients.
Renal disease: Common, although clinically important involvement is occasional. Glomerular involvement is rare. Most patients remain asymptomatic, but nephrolithiasis (1–14%), nephrocalcinosis (observed in half of patients with renal insufficiency), and polyuria are potential complications. Hypercalciuria and hypercalcemia due to hyperabsorption of dietary calcium are most often responsible for renal involvement, but granulomatous interstitial nephritis, glomerular disease, obstructive uropathy, and rarely end-stage renal disease may occur.
Diagnostic and Laboratory Findings
Diagnosis requires biopsy in most cases. Endobronchial biopsy via bronchoscopy is often done.
Routine laboratory evaluation is often unrevealing, but possible abnormalities include hypercalcemia, hypercalciuria, and elevated alkaline phosphatase and angiotensin-converting enzyme (ACE) levels.
Kveim-Siltzbach test: This is a skin test specially designed for the diagnosis of sarcoidosis. It involves intradermal injection of sarcoid tissue preparation resulting in a specific localized granulomatous response (firm red papules) in patients with sarcoidosis. This test is poorly standardized and rarely used.
Pulmonary function test: Spirometry and diffusing capacity of the lung for the carbon monoxide (DLCO) are commonly used.
Serologic tests: A variety of laboratory and biologic markers are available such as ACE, lysozyme, neopterin, soluble IL-2 receptor, soluble intercellular adhesion molecules (ICAM-1, IFN-8), or in bronchoalveolar lavage (BAL) fluid, such as high lymphocytes, activation of marker expression on T cells, CD4/CD8 ratio, macrophages, TNF-alpha release, collagen III peptide, vitronectin, fibronectin, and hyaluronan. None of the mentioned markers are clinically recommended as routine assessment, except for serum ACE.
Serum ACE is elevated in 40% of patients who have clinically active disease. It has limited value in the diagnosis, but useful in monitoring the course of disease and treatment.
Dastoori M. et al. Sarcoidosis—a clinically oriented review. J Oral Pathol Med. 2013;42:281–289.
UPPER AIRWAY COUGH SYNDROME
Upper airway cough syndrome (UACS) is the newly recommended term to replace postnasal drip syndrome, referring to cough associated with upper airway conditions, because it is unclear whether the mechanism of cough is postnasal drip, direct irritation, or inflammation of the cough receptors in the upper airway. Postnasal drip is the drainage of secretions from the nose or paranasal sinuses into the pharynx. UACS, which is secondary to a variety of rhinosinus conditions, is the most common cause of chronic cough. It includes a variety of diseases: allergic rhinitis, perennial nonallergic rhinitis, nonallergic rhinitis with eosinophilia (NARES), bacterial sinusitis, and allergic fungal sinusitis, rhinitis due to anatomic abnormalities, rhinitis due to physical or chemical irritants, and occupational rhinitis.
Who Should Be Suspected?
Clinically, the diagnosis depends on the reporting of the patient of a sensation of having something drip down into the throat, nasal discharge, or frequent throat clearing. The presence of mucoid, mucopurulent secretions, or cobblestoning of the mucosa during nasopharyngeal or oropharyngeal examination is also suggestive of UACS. It is the most common cause of the chronic condition.
In patients with chronic cough, the diagnosis of UACS-induced cough should be determined by considering a combination of criteria, including symptoms, physical examination findings, radiographic findings, specific allergen testing (to check whether acquired hypogammaglobulinemia is present) and, ultimately, the response to specific therapy. Because UACS is a syndrome, no pathognomonic findings exist.
Specific therapy is instituted when the cause of chronic cough is apparent; empiric therapy should be considered in cough of unknown etiology.
Pratter MR. Chronic upper airway cough syndrome secondary to rhinosinus diseases (previously referred to as postnasal drip syndrome): ACCP evidence-based clinical practice guidelines. Chest. 2006;129(1 Suppl): 63S–71S.
“Dyspnea” is a term used to characterize a subjective experience of breathing discomfort that comprises qualitatively distinct sensations that vary in intensity (American Thoracic Society guidelines, 2012). The experience derives from interactions among multiple physiologic, psychological, social, and environmental factors and may induce secondary physiologic and behavioral responses. It is a common symptom that afflicts millions of patients with pulmonary disease.
The majority of patients with chronic dyspnea of unclear etiology have one of four diagnoses: asthma, COPD, interstitial lung disease, or myocardial dysfunction. Mild dyspnea is common. Dyspnea is a common chief complaint among patients who come to the emergency department. The majority of life-threatening causes of dyspnea are classified below.
Life-threatening upper airway causes: tracheal foreign objects, angioedema, anaphylaxis, infections of the pharynx, and neck and airway trauma
Life-threatening pulmonary causes: pulmonary embolism, COPD, asthma, pneumothorax, pulmonary infections, ARDS, direct pulmonary injury, and pulmonary hemorrhage
Life-threatening cardiac causes: ACS, flash pulmonary edema, high-output heart failure, cardiomyopathy, cardiac arrhythmia, valvular dysfunction, and cardiac tamponade.
Life-threatening neurologic causes: stroke, neuromuscular disease
Life-threatening toxic and metabolic causes: poisoning, salicylate poisoning, carbon monoxide poisoning, DKA, sepsis, anemia, and acute chest syndrome
Other miscellaneous causes include lung cancer, pleural effusion, ascites, pregnancy, hyperventilation, anxiety, and massive obesity.
The combination of all historical elements and physical examination findings is helpful in diagnosing the cause of both acute and chronic dyspnea.
Advanced cardiopulmonary exercise testing is the most accurate way to diagnose dyspnea. Many standard diagnostic tests for shortness of breath, including noninvasive cardiopulmonary testing, EKG, CT, and pulmonary function testing, provide inconclusive results or misdiagnosis.
There are relatively few blood tests that are necessary in the initial evaluation of a patient with dyspnea. Hemoglobin and hematocrit to exclude anemia, and ABG measurements may be a value in managing severe underlying cardiopulmonary disease. D-Dimer is a component of the evaluation of patients with suspected PE. For patients with acute dyspnea, especially those who come to ER, BNP or NT-pro BNP may be useful for the evaluation of heart failure as the cause of dyspnea.
PULMONARY DISEASES ASSOCIATED WITH DYSPNEA
INFECTIOUS RESPIRATORY SYNDROMES ASSOCIATED WITH DYSPNEA
LOWER RESPIRATORY TRACT SYNDROMES
Bronchiolitis is an inflammatory disease of the small airways and may be caused by a variety of infectious or noninfectious conditions. Infectious bronchiolitis is usually caused by viral pathogens and is primarily a disease of infants and young children. Respiratory syncytial virus (RSV) is the primary cause of bronchiolitis (approximately 75%), especially severe bronchiolitis that requires medical attention or hospitalization. Rhinovirus and other respiratory viral pathogens may causes bronchiolitis, including parainfluenza virus (type 3), human metapneumovirus, influenza virus, and adenovirus. Monoclonal antibody therapy or antiviral therapies may be considered for infants with severe RSV infection.
Who Should Be Suspected?
Bronchiolitis usually occurs in the fall and winter, during the peak times of circulation of seasonal respiratory viruses. The peak incidence is in children 2–6 months of age. Children with cardiac or pulmonary disease, immunodeficiency, and history of premature birth are at increased risk for serious disease.
There may be nonspecific findings of viral respiratory infection, like rhinitis. The major clinical manifestation is air trapping due to expiratory obstruction. Wheezing is common.
Infants present with an increased respiratory rate and obvious difficulty breathing marked by nasal flaring. Severely affected infants may be cyanotic. Fever is not a prominent feature.
Diagnostic and Laboratory Findings
Diagnostic studies are not required for the management of most infants with clinical signs and symptoms of bronchiolitis; testing should be reserved for patients for whom results are likely to affect management decisions, like decisions regarding the need for antibiotic therapy.
Chest radiograph: May be indicated to rule out pneumonia.
Core labs: ABGs may be monitored in infants with severe disease. Core laboratory tests are usually normal, although fluid status must be monitored carefully because of the risk of dehydration due to tachypnea.
Molecular tests: Commercially available assays, which include testing for a panel of respiratory viruses, are recommended for establishing a specific diagnosis. These assays show improved sensitivity and specificity compared to viral culture or antigen testing; they also enable detection of a broader range viruses.
Antigen detection: Detection of specific antigen in nasopharyngeal secretions is available for several relevant viruses, like influenza viruses A and B, RSV, and human metapneumovirus. Assays based on DFA staining are useful for evaluation of specimen quality and have shown improved sensitivity compared to IFA assays. Because of the rapid turnaround time and reasonable specificity, antigen detection assays may be helpful in establishing a diagnosis. Infection cannot be ruled out by antigen assays because of their limited sensitivity and the limited scope of viruses tested.
Culture: Most of the relevant viruses may be isolated by viral culture, but turnaround time is slow. Therefore, viral culture is usually not helpful for acute clinical management.
LEGIONELLA INFECTION (LEGIONNAIRES DISEASE)
Legionella species have been documented as a relatively common cause of communityacquired and nosocomial pneumonia. Infection is usually caused by Legionella pneumophila, a fastidious aerobic gram-negative bacillus, but several other species may also cause disease. Respiratory infections are the primary manifestation of legionellosis.
Who Should Be Suspected?
The pulmonary signs and symptoms of Legionella pneumonia are fairly nonspecific and are characterized by progressive respiratory distress (dyspnea, cough, and minimal sputum production). Symptoms outside the respiratory tract may increase the likelihood of legionellosis. GI symptoms, including diarrhea, nausea and vomiting, hepatic dysfunction, and abdominal pain, occur frequently and may be prominent. Patients often develop confusion or other neurologic findings. Hyponatremia occurs more frequently in legionellosis and in other types of pneumonia.
Specific diagnosis is most reliably based on culture isolation and antigen detection.
Culture: Isolation requires the use of special media, usually a combination of selective and nonselective buffered charcoal yeast extract (BCYE) agars. Using pleural fluid, lung biopsy, or transtracheal or bronchial aspirate, organisms may require 3–7 days’ incubation for isolation.
Direct antigen detection and serology: Urine antigen testing is an important method for diagnosis of Legionnaires diseases caused by L. pneumophila serogroup 1 (approximately 90% of community-acquired and approximately 60% of nosocomial respiratory Legionella respiratory infections). The specificity of the urine antigen test is approximately 99%. Antigen may be detected in urine for several days after the initiation of antimicrobial therapy. The sensitivity of urine antigen testing depends on the probability of infection with L. pneumophila serogroup 1 and the severity of infection. About 90% of patients with severe legionellosis that requires hospitalization should show a positive urine antigen test, whereas only about 50% of outpatients with milder legionellosis will yield a positive urine antigen test. The specificity of the urine antigen test is approximately 99%.
Serologic testing may be a useful adjunct to diagnostic testing, but serologic testing plays a limited role in acute patient management because of the time required to provide definitive results. Serum IFA testing is recommended and allows detection of immunoglobulin subclasses. Testing for total antibody as well as specific IgM and IgG is recommended. Seroresponse may not be detectable for weeks to months after acute infection. Only half of infected patients will seroconvert at 2 weeks. Therefore, testing paired acute and multiple convalescent (2, 4, 6, 8, and 12 weeks) serum samples is recommended. A diagnosis is supported by detection of specific IgM or by a fourfold or greater change in titer between acute and convalescent specimens. Specificity depends on the antigen preparation used in the assay. Tests that use L. pneumophila serogroup 1 demonstrate the best specificity (approximately 99%), while assays that use polyvalent antigen preparations demonstrate somewhat lower (90–95%) specificity.
Direct detection: Gram stain of sputum is of little use for detection because the faintly staining organisms are frequently masked by the proteinaceous background. Patient specimens show few to moderate number of PMNs. Stains with enhanced staining of Legionella, like silver or Gimenez staining, also show poor overall sensitivity for detection of legionellosis. DFA staining is very specific but shows variable sensitivity (25–75%). Therefore, a negative DFA test result cannot rule out legionellosis and does not substitute for culture.
Molecular testing: PCR-based assays have been described, but FDA-approved tests are not available. Molecular assays have not been shown to be superior to culture for the diagnosis of Legionella infection.
Published assays show moderate to high sensitivity, depending on the type of specimen tested, and high specificity. An advantage of most molecular diagnostic tests, compared to the urine antigen assay, is their ability to detect all Legionella species, rather than being limited to L. pneumophila serogroup 1.
Core laboratory findings: WBC count is increased (10,000–20,000/μL) in 75% of cases (leukopenia is a bad prognostic sign); thrombocytopenia is common. Hypophosphatemia; hyponatremia; hypoalbuminemia (<2.5 g/dL); proteinuria (approximately 50% of patients); microscopic hematuria; and abnormal LFTs (mild to moderate increase of serum AST, ALP, LD, or bilirubin is found in approximately 50% of patients).
Fields BS, Benson RF, Besser RE. Legionella and Legionnaires’ disease: 25 years of investigation. Clin Microbiol Rev. 2002;15:506–526.
Newton HJ, Ang DKY, van Driel IR, et al. Molecular pathogenesis of infections caused by Legionella pneumophila. Clin Microbiol Rev. 2010;23:274–298.
Pneumonia describes infection of the pulmonary parenchyma. Bacteria most commonly gain access to lower respiratory tract directly, by inhalation or aspiration, or by hematogenous seeding from a distal site of infection. Streptococcus pneumoniae is the most common cause of serious community-acquired bacterial pneumonia. Viruses are implicated in about 30% of cases of communityacquired pneumonia. Other pathogens, like H. influenzae, Moraxella catarrhalis, M. pneumoniae, Legionella, and C. pneumoniae, are also significant pathogens. Staphylococcus aureus and gram-negative bacilli are often implicated in nosocomial pneumonias.
Who Should Be Suspected?
A broad range of conditions predispose to bacterial pneumonia, including underlying medical conditions (e.g., alcoholism, decreased level of consciousness, malnutrition, immune compromise, uremia), toxic exposure (e.g., inhalants, tobacco smoke, environmental pollutants), structural or functional defects of normal pulmonary defense mechanisms (e.g., COPD, cystic fibrosis, bronchiectasis, ciliary dysfunction), and age >65 years.
Common symptoms include dyspnea, shortness of breath, pleuritic chest pain, cough, and sputum production, typically purulent. Systemic signs include fever and malaise; a significant minority of patients report rigors.
Physical examination may demonstrate diffuse or localized abnormalities, including rales, ronchi, and diminished breath sounds.
Diagnostic and Laboratory Findings
Pneumonia is generally diagnosed on the basis of clinical signs and symptoms and CXR.
Diagnostic testing depends on the severity of disease and specific risk factors. Healthy outpatients may be managed without additional laboratory testing. For patients with significant infection or risk for complications of respiratory tract infection, CBC, blood culture, sputum Gram stain, and culture are recommended. High-resolution CT scanning may be requested in patients with negative CXR.
The diagnosis of tuberculosis should be considered and ruled out as appropriate. Special culture techniques (e.g., Legionella culture) or urine antigen testing (e.g., Legionella, S. pneumoniae) might be considered. Additional respiratory pathogens may be considered on the basis of epidemiologic risk and clinical presentation.
Sputum specimens should be collected prior to initiation of antibiotic treatment. Patients should be instructed on how to produce a “deep” specimen and avoid mixing saliva with the specimen. Abstaining from eating for several hours and rinsing the mouth prior to collection may improve the quality of expectorated sputum specimens.
The value of lower respiratory culture is limited by the quality of the specimen submitted, and results must be carefully interpreted. Criteria for accepting sputum, based on the presence of PMN and bacteria, and the absence of SECs should be established for routine bacterial cultures in order to avoid inoculation of contaminated specimens. Quantitative culture of BAL specimens may improve diagnosis for patients who are unable to provide a good-quality expectorated sputum sample or when unusual pathogens are suspected.
Informative cultures should show moderate to heavy growth of a bacterial pathogen as the predominant growth in culture. Cultures that yield growth of three or more species in comparable quantities are more likely to be contaminated and are of limited value for managing patients. A specific pathogen can only be identified by culture in about half of patients with communityacquired pneumonia that requires hospitalization. Blood culture is positive in approximately 20% of these patients; pneumococcal urinary antigen is positive in approximately 50%.
PCR may demonstrate improved sensitivity, but the impact on patient management has not been demonstrated.
Core laboratories: Leukocytosis (>15,000 with left shift) is typical for acute bacterial pneumonia. Leukopenia is associated with poor prognosis. Serial measurement of ABGs, electrolytes, and other analytes should be collected to monitor the respiratory and metabolic status of patients with severe infection. Abnormalities typical for underlying medical conditions or severity of disease should be evaluated.
Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44:S27–S72.
Reimer LG, Carroll KC. Role of the microbiology laboratory in the diagnosis of lower respiratory tract infections. Clin Infect Dis. 1998;26:742–748.
van der Eerden MM, Vlaspolder F, de Graaff CS, et al. Value of intensive diagnostic microbiological investigation in low- and high-risk patients with community-acquired pneumonia. Eur J Clin Microbiol Infect Dis. 2005;24:241–249.
PNEUMOCYSTIS PNEUMONIA (PCP)
Pneumocystis jirovecii (formerly Pneumocystis carinii) infection is almost exclusively restricted to pulmonary disease in immunocompromised patients. Its role as an opportunistic pathogen was described after World War II in malnourished children affected by atypical pneumonia and subsequently as a rare cause of pneumonia in patients with hematologic malignancies. The incidence of PCP increased dramatically in the 1980s in association with HIV infection. Though the incidence of P. jirovecii pneumonitis has decreased in recent years, due to the use of highly active antiretroviral therapy and prophylaxis in susceptible patients, PCP remains an important cause of pulmonary disease in immunocompromised patients. PCP is an opportunistic infection in patients with HIV infection and is an AIDS-defining illness in these patients. The incidence of PCP has fallen dramatically in patients compliant with highly active antiretroviral treatment.
Who Should Be Suspected?
Radiology: Most patients with Pneumocystis pneumonitis show bilateral, diffuse interstitial infiltrates on CXR. Some patients with PCP have no abnormality on CXR. In such patients, high-resolution CT scans have high sensitivity for detecting the characteristic ground-glass abnormalities of PCP.
HIV-infected patients: The onset of PCP is usually slowly progressive with fever, shortness of breath, tachypnea, and nonproductive cough. Fatigue, weight loss, and other symptoms are common. Chest x-rays most commonly demonstrate diffuse, bilateral abnormality usually consisting of interstitial infiltrates; other patterns may be seen. Gallium scanning shows intense diffuse uptake. The risk of PCP is inversely related to CD4 counts; patients with HIV infection are at highest risk when the CD4 count falls below 200 cells/mm3.
Non–HIV-infected patients: These patients typically present with acute onset of respiratory failure, fever, and nonproductive cough. Glucocorticoid use and defects in cell-mediated immunity are the most common predisposing factors for infection. Conditions associated with increased risk for PCP in patients without HIV infection include
Immunosuppressive drug therapy
Malignancy (usually hematologic)
Organ transplantation (hematopoietic or solid organ)
Rheumatologic or inflammatory diseases
The risk of PCP is reduced in patients taking effective prophylactic therapy.
Definitive diagnosis of P. jirovecii depends on the demonstration of organisms in respiratory specimens taken from patients at risk for PCP with typical signs, symptoms, and radiographic findings.
Specimens: It is critical to sample alveolar contents or lung tissue for sensitive diagnosis of PCP. Induced sputum (IS) samples are relatively noninvasive and sensitive (50–90%). The sensitivity of bronchoalveolar lavage (BAL) for PCP diagnosis approaches 100%. The sensitivity of lung biopsy is very high, but biopsy is rarely needed for diagnosis. Lung biopsy may be collected for diagnosis of other infections (e.g., fungi) or diseases (e.g., lymphoma) that may be in the differential diagnosis. Organisms are rarely detected in routine expectorated sputum or bronchial wash specimens. The sensitivity of detection may be reduced in non-HIV patients or patients on antifungal prophylaxis.
Direct detection: Definitive diagnosis is achieved by microscopic demonstration of organism in respiratory secretions or lung tissue. A variety of stains may be used to demonstrate characteristic cyst forms (like calcofluor white, Gomori silver, toluidine blue) or troph forms (like Wright-Giemsa or Papanicolaou) of Pneumocystis. A commercially available fluorescein-conjugated monoclonal antibody is available that provides sensitive detections of both cyst and troph forms.
Nucleic acid amplification: Methods have been developed for PCP diagnosis, but none are FDA approved. The increased sensitivity of PCR testing may allow for sensitive detection using noninvasively collected specimens, like saliva. However, the increased cost and turnaround time for PCR, and small (if any) incremental sensitivity compared to visual detection, are likely to limit wide implementation of PCR for PCP diagnosis. In addition, false-positive results have been reported for PCR.
Culture: Effective in vitro culture techniques are not available.
Serum beta-D-glucan assay: May be used as a sensitive test to screen for PCP in HIV-infected patients. The performance of the assay depends on the definition used for a positive result as well as the population studied, but sensitivity >90% for detection of PCP has been demonstrated. The specificity is limited by reactivity in infections caused by other fungi.
Serology: Testing does not play a role in PCP diagnosis.
Core laboratory: Elevated LDH is typical; the degree of LDH elevation and increasing LDH despite therapy are poor prognostic signs.
Azoulay E, Bergeron A, Chevret S, et al. Polymerase chain reaction for diagnosing pneumocystis pneumonia in non-HIV immunocompromised patients with pulmonary infiltrates. Chest. 2009;135:655–661.
Fischer S, Gill VJ, Kovacs J, et al. The use of oral washes to diagnose Pneumocystis carinii pneumonia: a blinded prospective study using a polymerase chain reaction-based detection system. J Infect Dis. 2001;184:1485–1488.
Sax PE, Komarow L, Finkelman MA, et al. Blood (1->3)-beta-D-glucan as a diagnostic test for HIV-related Pneumocystis jiroveci pneumonia. Clin Infect Dis. 2011;53:197–202.
Stringer JR. Pneumocystis carinii: what is it, exactly? Clin Microbiol Rev. 1996;9:489–498.
Thomas CF, Limper AH. Pneumocystis pneumonia. N Engl J Med. 2004;350:2487–2498.
Viral pneumonia is characterized by the development of abnormal alveolar gas exchange and inflammation of the lung tissue. May be caused by a number of viral respiratory pathogens. Pneumonia is often preceded by nonspecific symptoms of URI. The etiology depends somewhat on the age and the patient’s state of immunocompetence. In children, viral pneumonia is most important in patients younger than 5 years. Clinically significant, purely viral pneumonia is uncommon in immunocompetent older children and adults. The parainfluenza viruses, RSV, and human metapneumoviruses are relatively more common causes of viral pneumonia in children and infants compared to older children and adults. In older children and adults, influenza viruses, especially type A, are responsible for most cases of pneumonia. CMV is the most common, clinically significant cause of viral pneumonia in immunocompromised patients.
Etiology and Diagnosis
Specific identification may be required for optimal management of severely ill patients. Because the clinical and laboratory presentation of viral pneumonia is not specific, other etiologies, like bacteria, mycoplasmas, P. jirovecii, must be considered and ruled out by relevant laboratory and other evaluations.
Common causes include influenza (adults), parainfluenza (children), RSV (immunocompromised patients), human metapneumovirus (children), adenovirus, corona viruses, CMV (primarily in immunocompromised patients and children), HSV, measles virus, and VZV.
Who Should Be Suspected?
The clinical presentation is variable and depends on the patient’s age, immunocompetence, underlying medical conditions, and specific viral pathogen. Most patients have mild, self-limited disease, but viral pneumonia may present clinically with life-threatening disease, especially in high-risk patients. In immunocompetent hosts, disease is usually self-limited and mild, with resolution of symptoms within 7–10 days.
The activity of viruses circulating in the community should be considered in the patient’s initial assessment.
The presenting findings in viral pneumonia include acute illness with fever, showing signs of hypoxemia. Cough is usually nonproductive with scant mucoid sputum. Examination typically demonstrates tachypnea, rales, and wheezing. There may be signs of viral infection in other respiratory tract tissues, like conjunctivitis and acute rhinosinusitis. Underlying medical conditions may be exacerbated by viral pneumonia; the severity of viral pneumonia is often greater in patients with underlying illness.
Imaging studies typically demonstrate diffuse, bilateral interstitial infiltrates, although the spectrum of abnormalities is broad and nonspecific.
Bacterial superinfection is well described and represents a significant complication of viral pneumonia. Bacterial superinfection may be suspected in patients whose initial pneumonia resolves but develop fever, cough, and dyspnea 1–2 weeks later. Bacterial pathogens associated with superinfection of viral pneumonia include S. pneumoniae, H. influenzae, and S. aureus.
Diagnostic and Laboratory Findings
Most patients with viral pneumonia have a relatively benign, self-limited illness. Specific diagnosis is usually not required unless severe disease or complication of infection is present.
Culture: Most of the relevant viruses may be isolated by viral culture, but turnaround time is slow. Therefore, viral culture is usually not helpful for acute clinical management.
Direct antigen detection: Antigen detection kits are commercially available for a number of the relevant viruses, such as influenza viruses A and B, RSV, and human metapneumovirus. Although the specificity of these assays is usually high, sensitivity may be <80%; they may be used to confirm but cannot exclude any specific viral infection. The use of specific DFA staining is useful for evaluation of specimen quality and has shown improved sensitivity.
Molecular testing: FDA-approved assays are available for respiratory viral pathogens. These assays provide high sensitivity and specificity, a broad range of detectable viruses, and short turnaround time, but higher cost, compared to culture and antigen testing.
Serology: Serologic testing is not useful for the acute management of patients.
Core laboratory findings: ABGs, CBC, and other tests should be monitored in patients with severe or complicated viral pneumonia. Core laboratory tests are usually normal. In patients with severe respiratory distress, careful monitoring of ABGs is critical for patient management. Fluid status must be monitored carefully because of the risk of dehydration due to fever and tachypnea.
Treanor JJ. Chapter 2 Respiratory infections. In: Richman DD, Whitley RJ, Hayden FG (eds). Clinical Virology, 3rd ed. Washington, DC: ASM Press; 2009.
Diagnosis of tuberculosis is suspected on clinical presentation, screening tests (e.g., IGRAs), and imaging studies and is confirmed by acid-fast smear and culture and other laboratory findings. See Chapter 11, Infectious Diseases for a further discussion of mycobacteria and mycobacterial diseases.
Tuberculosis refers to disease caused by infection with Mycobacterium tuberculosis (Mtb), or, rarely, related mycobacterial species. Tuberculosis is usually transmitted by inhalation of respiratory droplets. Transmission is not efficient, typically requiring prolonged exposure on multiple occasions. Other organs may be infected by lymphohematogenous spread.
Who Should Be Suspected?
Typical signs and symptoms of tuberculosis depend on the age and state of immunocompetence of the patient.
More aggressive disease is common in young children (<5 years), with risk for extrapulmonary infection. CXR demonstrates prominent hilar and mediastinal lymphadenopathy; middle and lower lung field pneumonitis may be minimal.
In the elderly, tuberculosis is also more aggressive and may represent new infection, with mid-field pneumonitis and hilar adenopathy, or due to reactivation of latent infection, with typical apical cavitary disease.
In adolescents and adults, primary infection may not be clinically obvious. Apical abnormality may be seen coincidentally during latent infection or at the time of reactivation of disease.
Patients whose primary infection is controlled by their immunologic response enter a latent, asymptomatic phase of infection. Organisms, however, continue to multiply slowly in infected tissues, leading to ongoing risk of reactivation disease.
Common symptoms of active disease include nonspecific constitutional symptoms, like fever, anorexia, weight loss, and night sweats, and specific symptoms related to the respiratory tract or other infected organ systems, like cough with sputum production, hemoptysis, or pleuritic chest pain.
Factors associated with increased risk of acquisition and transmission of tuberculosis include living in, or emigration from, a region with a high prevalence of tuberculosis, poverty and homelessness, crowded living conditions, AIDS, and intravenous drug abuse. Patients usually become noninfectious within 2 weeks after initiation of effective therapy. Negative AFB smears for three specimens, taken at least 8 hours apart, are recommended to take patients out of respiratory isolation.
Screening tests for tuberculosis: Screening for tuberculosis is recommended for patients at high risk of tuberculosis on the basis of clinical signs and symptoms or epidemiologic factors.
Tuberculin skin test (TST): TST is performed by intradermal injection of a standardized solution of a purified protein precipitate from Mtb. Induration (not erythema) at the injection site is assessed after 48–72 hours. A 5-mm cutoff is used for immunocompromised persons and other individuals with recent exposure to patients with active tuberculosis. A 10-mm cutoff is used for individuals in other risk groups. BCG vaccination is an unlikely cause of false-positive TST, unless the vaccination was administered in the prior several years. False-positive TST may also be seen in patients with infections caused by mycobacterial species other than Mycobacterium tuberculosis (NTM). False-negative TST reactions may occur in HIV-infected patients with advanced immunosuppression; retesting may be performed after immune recovery associated with effective antiretroviral therapy.
Interferon-γ release assays (IGRA): These assays measure the quantity of interferon-γ released from patient’s peripheral blood lymphocytes incubated with purified Mtb antigens. These assays have comparable sensitivity and specificity compared to TST assays. An advantage of IGRAs is that patients do not have to return for test interpretation; BCG vaccination does not cause false-positive IGRA reaction. The utility of IGRAs has not been established for young children (<5 years) or immunocompromised patients.
Specimens for AFB smear and culture:
Sputum samples: Sputum is most commonly submitted to the laboratory for analysis. First-morning specimens are recommended as most likely to yield positive results. Submission of two or three specimens, submitted at least 8 hours apart and including at least one first-morning specimen, has been recommended for evaluation of patients. Sputum specimens of at least 5-mL volume should be submitted for AFB studies; detection is decreased in lower volume specimens. Pooled sputum is not acceptable because of the high rate of culture contamination. Sputum induced by inhalation of hypertonic saline or specimens collected by bronchoalveolar lavage (BAL) are recommended for patients who are unable to provide a good quality expectorated sputum sample and for those with a continued high suspicion for tuberculosis even after negative AFB studies of expectorated sputum. First-morning gastric lavage specimens may be submitted on infants or other patients from whom sputum collection is not feasible.
Specimens from other potentially infected sources, like blood, pleural fluid, urine, or CSF, should be submitted in addition to respiratory specimens.
Respiratory specimens, and specimens from other sources typically contaminated with endogenous flora, are decontaminated and concentrated (centrifugation at 3,000× g for 15 minutes) for smear preparation and culture inoculation.
Culture: Isolation of Mtb by culture is the gold standard for diagnosis; cultures should be submitted for every patient.
Three types of media are commonly used for AFB culture: egg-based solid (e.g., Lowenstein-Jensen), agar-based solid (e.g., Middlebrook 7H11), and liquid media (e.g., Middlebrook 7H12). Cultures are incubated in 5–10% CO2 for up to 8 weeks.
Cultures should include liquid media and at least one type of solid media. Growth is more rapid in liquid media. Solid media may be more sensitive for isolation of mycobacteria and can also provide information about the quantity of growth, colony morphology, and purity of culture.
Broth systems have been used to develop automated systems for incubation and detection of growth. Automated systems have decreased turnaround time for positive cultures and are less labor intensive than traditional culture methods.
Direct detection (AFB smear):
The acid-fast smear is used for direct detection of mycobacteria in clinical specimens; Gram stains are not reliable for detection. AFB should be quantified (e.g., 1+ to 4+) for positive smears.
The sensitivity of AFB smears for detection of tuberculosis is variable (20– 80%), depending on factors like type of disease, specimen quality, laboratory procedures, and experience; overall, at least one AFB smear is positive in 60–80% of patients with active tuberculosis and positive cultures for Mtb.
Sensitivity of the AFB smear is directly related to the organism burden in the sample; detection is improved by evaluation of multiple specimens, examination of sputum samples of >5-mL volume, decontamination and concentration, use of fluorochrome staining, and following standardized methods for smear examination.
The predictive value of a positive AFB smear for tuberculosis is >90%.
Several FDA-approved nucleic acid amplification assays are available for the direct detection of Mtb in clinical specimens. Good performance depends on strict adherence to the manufacturer’s instructions.
The sensitivity for detection is intermediate between AFB smear and culture; assays are useful to provide presumptive diagnosis of Mtb infection in patients with positive AFB smears (sensitivity: 40–77% in smear-negative patients and >95% in smear-positive patients).
Testing should only be performed on patients with a high clinical suspicion for tuberculosis. Though the specificity is high (>95%), the clinical utility may be unacceptably low in low-prevalence populations because of falsepositive test results.
Nonamplified rRNA probes are available for preliminary identification of some mycobacterial species from positive cultures, including M. tuberculosis complex, M. avium and intracellulare, M. gordonae, and M. kansasii. Note: The M. tuberculosis complex includes Mtb, M. bovis, M. africanum, M. microti, and several other related species.
Susceptibility testing: Should be performed on all initial Mtb isolates and repeated if cultures remain positive after 3 months of appropriate treatment. Susceptibility testing for second-line agents should be performed on rifampin-resistant isolates, on isolates resistant to any two other primary drugs, or for patients in whom a second-line agent will be used for treatment.
Method: The agar proportion method, using organisms isolated in culture, is commonly used for susceptibility testing. Standardized inocula of the clinical isolate are inoculated onto Middlebrook plates containing a specific critical concentration of the drug tested, as well as drug-free control media. Antibiotics for which there is <99% reduction in organisms, compared to growth on the control media, are unlikely to be clinically effective. Susceptibility test methods adapted to use of liquid media have been developed using automated or manual methods. Testing methods have also been described for direct preparation of inocula from smear-positive specimens.
Primary panel: Isoniazid (INH), rifampin (RMP), ethambutol (EMB), and pyrazinamide (PZA).
Second-line panel: INH—high concentration, IMB—high concentration, amikacin, capreomycin, ethionamide, kanamycin, levofloxacin, ofloxacin, para-aminosalicylic acid, rifabutin, streptomycin.
Strains that are resistant to at least rifampin and INH are considered MDR (multiple drug resistant); strains resistant to at least rifampin, INH, a fluoroquinolone, and an aminoglycoside are considered XDR (extensively drug resistant).
Nonculture methods: Specific mutations have been identified that confer resistance to drugs used to treat tuberculosis. For example, >95% of rifampin resistance is caused by mutation of the rpoB gene. Various methods may be used to detect relevant mutations, and several are commercially available (e.g., LIPA, molecular beacons).
Common core laboratory findings in active tuberculosis:
CBC: normocytic, normochromic anemia; WBC and differential usually normal.
Chemistry: Hypoalbuminemia; hypogammaglobulinemia. Hyponatremia may occur due to SIADH or adrenal gland infection.
Barnes PF. Rapid diagnostic tests for tuberculosis: progress but no gold standard. Am J Respir Crit Care Med. 1997;155:1497–1498.
Forbes BA, Banaiee N, Beavis KG, et al. Laboratory Detection and Identification of Mycobacteria; Approved Guideline. CLSI Document M48-A. Wayne, PA: Clinical and Laboratory Standards Institute; 2008.
Mase SR, Ramsay A, Ng V, et al. Yield of serial sputum specimen examinations in the diagnosis of pulmonary tuberculosis: a systemic review. Int J Tuberc Lung Dis. 2007;11:485–495.
Pfyffer GE, Palicova F. Chapter 28: mycobacterium: general characteristics, laboratory detection, and staining procedures. In: Versalovic J (ed). Manual of Clinical Microbiology, 10th ed. Washington, DC: ASM Press; 2011.
Steingart KR, Henry M, Ng V, et al. Fluorescence versus conventional sputum smear microscopy for tuberculosis: a systemic review. Lancet Infect Dis. 2006;6:570–581.
Woods GL, Lin SG, Desmond EP. Chapter 73: susceptibility test methods: mycobacteria, nocardia, and other actinomycetes. In: Versalovic J. Manual of Clinical Microbiology, 10th ed. Washington, DC: ASM Press; 2011.
NONINFECTIOUS PULMONARY DISEASES ASSOCIATED WITH DYSPNEA
Aspiration pneumonia refers to pulmonary disease caused by abnormal entry of fluids into the lower respiratory tract. The fluid may be endogenous secretions (e.g., gastric contents, upper respiratory secretions) or exogenous. Development of disease usually requires defective protective mechanisms (e.g., cough reflex, glottis function, ciliary transport) and aspiration of “toxic” material (e.g., particulate matter, acidic fluid, heavy bacterial contamination). Conditions that predispose to aspiration include alcoholism, seizure, CVA, head trauma, general anesthesia, dysphagia, periodontal disease, neurologic disorder, protracted vomiting, and mechanical disruption of the usual defense barriers (nasogastric tube, endotracheal intubation, upper GI endoscopy, and bronchoscopy).
Who Should Be Suspected?
The endogenous flora of the upper respiratory and gastrointestinal tract most commonly cause bacterial aspiration pneumonia. Polymicrobial infection, including anaerobes and less virulent streptococcal species found in gingival crevices, is typical.
Most patients present with subacute progression of symptoms over several weeks. Common symptoms include dyspnea, cough, and purulent (often putrid) sputum production, with associated fever and weight loss. Rigors are uncommon. Symptoms of complicated infection, like abscess or empyema, may be present.
Diagnostic and Laboratory Findings
Microbiology: Expectorated sputum is not reliable for diagnosis, except for possibly establishing an alternative diagnosis. Culture of specimens (e.g., transtracheal or transthoracic aspirates) collected using techniques for anaerobic isolation may be informative.
Fusobacterium nucleatum, Bacteroides, Peptostreptococcus, and Prevotella species are most commonly implicated anaerobes. Aerobic organisms, including S. aureus and gram-negative bacilli, are common, especially in nosocomial aspiration pneumonias.
Core laboratory: Anemia is typical. Laboratory abnormalities associated with underlying medical conditions should be investigated that includes ABGs.
Marik PE. Aspiration pneumonitis and aspiration pneumonia. N Engl J Med. 2001;344(9):665–671.
Asthma is a highly prevalent and chronic inflammatory disorder in which the airway smooth muscle undergoes exaggerated contractions and is abnormally responsive to external stimuli. The best defined and most commonly identified cause of this inflammation is inhalation of allergens.
Classification of bronchial asthma can be based on age, etiology-associated characteristics, or severity. The pattern of disease presenting at different ages is distinct. In the first 2 years of life, wheezing and bronchiolitis are not distinguishable, and the most common cause of these episodes is infection with the RSV. In older children and young adults, by far the most commonly identified cause of asthma is sensitization to one of the most common inhalant allergens, particularly those encountered indoors.
Asthma that presents after 20 years of age provides a complex problem, and there is a wider differential diagnosis. Major causes include simple allergic asthma in adults, intrinsic asthma associated with chronic hyperplastic sinusitis, allergic bronchopulmonary aspergillosis, and wheezing associated with chronic obstructive lung disease.
Among adults aged >40 years who develop severe asthma for the first time, almost 50% may have intrinsic asthma (negative skin tests to common allergens, no family history, persistent eosinophilia). Late-onset asthma, which is frequently not associated with atopy, may be linked to workplace (occupational exposure to sensitizing chemicals).
Who Should Be Suspected?
Classic symptoms of asthma are intermittent dyspnea, cough, and wheezing. These symptoms are nonspecific and sometimes difficult to distinguish from other respiratory diseases. Patients may present to clinics or the emergency department with acute symptoms of breathlessness, wheezing, and coughing. Alternatively, they may present between episodes with normal or nearnormal lungs. Asthma may develop at any age, although new-onset asthma is less frequent in elderly compared to other age groups. Seventy-five percent of the cases are diagnosed before the age 7.
Asthmatic symptoms characteristically come and go, with a time course of hours to days, resolving spontaneously with removal of triggering stimulus or in response to antiasthmatic medications. Characteristic triggers of asthma include cold air, exercise, and exposure to allergens. Allergens that typically trigger asthmatic symptoms include dust, molds, furred animals, cockroaches, and pollens. Viral infections are also common triggers.
The diagnostic tools should include history, physical examination, pulmonary function tests (PFTs), and other laboratory evaluations.
PFTs: Measurement of peak expiratory flow rate (PEFR) and spirometry are the two PFTs most often used in the diagnosis of asthma. Spirometry is used to measure the amount of air a person can breathe out and the amount of time taken to do so. Forced vital capacity (FVC): maximum volume of air that can be exhaled during a forced maneuver. Forced expired volume in 1 second (FEV1): volume expired in the first second of maximal expiration after a maximal inspiration. This is a measure of how quickly the lungs can be emptied. FEV1/FVC: FEV1 expressed as a percentage of the FVC gives a clinically useful index of airflow limitation. The ratio FEV1 /FVC is between 70% and 80% in normal adults; it is influenced by the age, sex, height, and ethnicity and is best considered as a percentage of the predicted normal value. Variability of >20% in PEFR, a reversible reduction in FEV1 and FEV1/FVC, and heightened sensitivity to bronchoprovocation are findings consistent with asthma.
Chest radiography: Almost always normal in patients with asthma. It is recommended in the evaluation of severe or difficult-to-control asthma and for the detection of comorbid conditions (e.g., allergic bronchopulmonary aspergillosis, eosinophilic pneumonia, or atelectasis due to mucous plugging).
Hematology: CBC with differential WBC analysis to screen for eosinophilia or significant anemia may be helpful in certain cases. Markedly elevated eosinophil percentages (>15%) may be due to allergic asthma but should prompt consideration of alternative diagnoses, including parasitic infections, drug reactions, and syndromes of pulmonary infiltrates with eosinophilia. An alpha-1 antitrypsin level is recommended in nonsmokers with persistent and irreversible airflow obstruction to exclude emphysema due to alpha-1 antitrypsin deficiency.
Allergy tests: Allergic sensitivity to specific allergens can be assessed by either skin tests or blood tests for allergen-specific IgE. Aeroallergens (house dust mite, cat or dog dander, cockroach, pollen, and mold spore antigens) are most commonly implicated in asthma. Food allergens rarely cause isolated asthmatic symptoms. Total IgE levels are sometimes helpful. A very high level (>1,000 IU/mL) suggests the associated conditions of eczema or allergic bronchopulmonary aspergillosis.
National Asthma Education and Prevention Program: Expert Panel Report III: Guidelines for the Diagnosis and Management of Asthma. Bethesda, MD: National Heart, Lung, and Blood Institute, 2007. (NIH publication no. 08–4051): Full text available online: www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm.
CARDIAC HEART FAILURE
See Chapter 3, Cardiovascular Disorders.
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Chronic bronchitis with emphysema, also known as chronic obstructive pulmonary disease (COPD), is in most cases a sequel of many years of active smoking. It refers to a group of diseases that cause airflow blockage and breathing-related problems. COPD results from complex interactions between clinical and genetic risk factors. Definite or possible risk factors for COPD include inhalational exposure (e.g., smoking), increased airway responsiveness, atopy, and antioxidant deficiency. Genetic risk factors for COPD include a variety of gene polymorphisms, antioxidant-related enzyme dysfunction, metalloproteinase dysregulation, and abnormalities that cause excess elastase.
The Global Initiative for Chronic Obstructive Lung Disease (GOLD)—a report produced by the National Heart, Lung, and Blood Institute (NHLBI) and the World Health Organization (WHO)—defines COPD as “a preventable and treatable disease with some significant extrapulmonary effects that may contribute to the severity in individual patients. Its pulmonary component is characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases.”
Classification of severity of COPD. An FEV1/FVC <70% indicates airflow limitation and the possibility of COPD.
Stage 0—at risk: normal spirometry; chronic symptoms (cough, sputum production); FEV1/FVC <70%.
Stage I—mild: with or without chronic symptoms (cough, sputum production); mild airflow limitation (FEV1/FVC1 >80% predicted).
Stage II—moderate: Worsening airflow limitation (FEV1/FVC <70%; 50% < FEV1 <80% predicted), with shortness of breath typically developing during exertion.
Stage III—severe: with or without chronic symptoms (cough, sputum production); further worsening of airflow limitation (FEV1/FVC <70%; 30% < FEV1 < 50% predicted).
Stage IV—very severe: with or without chronic symptoms (cough, sputum production); severe airflow limitation (FEV1/FVC <70%; FEV1 <30% predicted); or FEV1 <50% predicted plus chronic respiratory failure. Patients may have very severe (stage IV) COPD even if the FEV1 is >30% predicted, whenever this complication is present.