Respiratory, Metabolic, and Acid-Base Disorders
L. V. Rao
Michael J. Mitchell
RESPIRATORY DISORDERSRespiratory diseases include diseases of the lung, pleural cavity, bronchial tubes, trachea, and upper respiratory tract and disorders 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 (PE). The symptoms of respiratory disease differ depending on the disease. Typical 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), lethargy, 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 illness 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 mainly 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, tuberculosis (TB) is a significant 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 (PCP). 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 significant 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 is 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
A 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 a 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. Estimating the duration of cough is the first step in narrowing the list of potential diagnosis and can be managed using evidence-based guidelines. A cough lasting <3 weeks is termed “acute,” between 3 and 8 weeks is “subacute,” and one lasting >8 weeks is defined as “chronic.”
common symptoms of pulmonary disease. Most cases of a 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. Estimating the duration of cough is the first step in narrowing the list of potential diagnosis and can be managed using evidence-based guidelines. 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
An 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 virusinduced, postnasal drip, throat clearing secondary to laryngitis or pharyngitis. It is frequently associated with acute exacerbations and hospitalizations with asthma and chronic obstructive pulmonary disease (COPD). Symptoms associated with an 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
Subacute cough is defined as a cough lasting 3-8 weeks. The gray area between 3 and 8 weeks of a cough is difficult to define etiologically since all chronic cough will have started as an acute cough, but the diagnostic group of a chronic cough is diluted by the patients with a postviral cough (a URTI cough lingering for >3 weeks). A cough after infection is the most common cause of a 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 a subacute cough that spontaneously resolves had a postinfection cough.
□ Chronic Cough
A 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 apparent etiology. Bronchoscopy should be undertaken in all patients with a chronic cough in whom inhalation of a foreign body is suspected. A cough can be dry or productive, depending on whether sputum is coughed up. A dry cough is a cough with no phlegm or mucus, is caused by a viral infection, cold/dry air or air pollutants such as cigarette smoke, smog, and dust. Productive coughs are coughs that produce phlegm and can be associated with TB, bacterial pneumonia, and bronchitis.
PULMONARY DISEASES ASSOCIATED WITH COUGHINFECTIOUS RESPIRATORY DISEASES
ACUTE BRONCHITIS
□ Definition
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, respiratory syncytial virus [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.
□ Diagnosis
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 two 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.
Suggested Reading
Wenzel RP, Fowler AA III. Acute bronchitis. N Engl J Med. 2006;355:2125-2130.
CROUP (LARYNGOTRACHEITIS)
□ Definition
Croup, or laryngotracheitis, refers to disease associated with symptoms related to inflammation of the larynx and subglottic airways. Croup is usually caused
by viral infection, especially parainfluenza virus and occasionally RSV and adenoviruses. Croup is occasionally caused by bacteria or an allergic reaction.
by viral infection, especially parainfluenza virus and occasionally RSV and adenoviruses. Croup is occasionally caused by bacteria or an allergic reaction.
□ Who Should Be Suspected?
Croup is most often clinically significant in children between 6 months and 3 years of age. Symptoms usually begin with nasal irritation, congestion, and coryza. Symptoms generally progress over 12-48 hours to include fever, hoarseness, barking cough, and stridor. Croup is usually a mild and self-limited illness, although significant upper airway obstruction, respiratory distress, and, rarely, death can occur. 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.
□ Diagnostic and Laboratory Findings
In young children, the degree of respiratory distress and state of hydration must be carefully evaluated. Other causes of airway obstruction and severe infection, like epiglottitis, should be ruled out.
Croup is primarily a clinical diagnosis. Laboratory studies are of limited diagnostic utility but may help guide management in more severe cases.
▼ CBC: Increased WBC and the presence of a large number of PMNs are suggestive of primary or secondary bacterial infection.
▼ Chemistry: There are no specific abnormalities.
▼ Microbiology: Specific diagnosis does not change the symptomatic treatment recommended for croup. Specific testing may be indicated for patients with severe symptoms or possibly for infection control/epidemiologic purposes.
▼ When needed, NAATs, in conjunction with viral cultures, are used for specific viral identification.
Suggested Reading
Cherry JD. Clinical practice. Croup. N Engl J Med. 2008;358(4):384-392.
PERTUSSIS (WHOOPING COUGH)
□ Definition
Pertussis, a syndrome characterized by prolonged and severe cough, is caused by the bacterium B. pertussis. Infection is highly communicable, with potential for epidemic spread. Infection is transmitted by the direct respiratory. 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. The incidence of pertussis continues to be highest among infants but continues in all age groups. 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 suspicion in patients presenting with frequent attacks of paroxysmal coughing. History should include vaccination status and questions about exposure to possible or confirmed pertussis patients. Clinical symptoms develop 1 to 3 weeks after exposure.
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), and posttussive vomiting. In the context of a pertussis epidemic, any patient with a prolonged cough illness, regardless of other symptoms, may be suspected.
Typical cases of pertussis demonstrate three phases:
▼ Catarrhal (7-10 days): Runny nose; mild cough; low-grade fever
▼ Paroxysmal (1-6 weeks): Severe, paroxysmal coughing spells; inspiratory whoop; cyanosis; posttussive vomiting
▼ Recovery (2-4 weeks): Decreasing severity of symptoms
□ Diagnostic and Laboratory Findings
See Chapter 3 for details of pertussis diagnostic testing. Pertussis is a reportable infection to local Departments of Health. Refer to CDC and DPH criteria for laboratory diagnosis. The burden of B. pertussis in respiratory secretions is highest in the catarrhal phase, during which culture and PCR are most sensitive for diagnosis.
Culture: Culture should be obtained as soon after onset as possible from all suspected cases of pertussis. Isolation of B. pertussis confirms the diagnosis, but cultures are frequently negative (sensitivity: 15-35%). 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, antibiotic therapy, and recent vaccination.
PCR: PCR methods have high sensitivity (93-95%) and specificity (97-99%) when performed on appropriate patients within 3 weeks after onset of cough. False-negative results may be caused by antibiotic treatment. False-positive results may be caused by non-pertussis Bordetella species. 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.
Serology: A single-point serologic assay has been developed by the CDC and FDA, and adopted by many state public health laboratories, for pertussis confirmation in selected patients. This assay cannot be used for vaccinated children <11 years old or in adults vaccinated within 2 years. Specimens may be collected up to 12 weeks after onset of cough, ideally at 2 to 8 weeks.
□ Interpretation of Test Results
Confirmed:
Clinical: Any cough illness. Lab: isolation of B. pertussis by culture
Clinical: Meets CDC clinical case definition and epidemiologic link to a case confirmed by culture or PCR
Suggested Reading
CDC Pertussis (Whooping Cough). https://www.cdc.gov/pertussis/index.html. Accessed August 27, 2018.
NONINFECTIOUS RESPIRATORY DISEASESSARCOIDOSIS
□ Definition
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 of 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 100,000 populations. The age-adjusted incidence for whites is 11 cases per 100,000 populations. Incidence is higher in African American (34/100,000) and seems to experience more severe and chronic disease. Also, in African Americans, siblings and parents of sarcoidosis cases have an about 2.5-fold increased risk for developing the disease.
Internationally, the incidence is 20 cases per 100,000 in Sweden, 1.3 cases per 100,000 in Japan, and low in China, Africa, India, and other developing countries and could be hidden and misdiagnosed as TB.
Incidence peaks in persons aged 25-35 years, and a second peak occurs for women aged 45-65 years. The male-to-female ratio is approximately 2:1. Morbidity, mortality, and extrapulmonary involvement are higher in affected females.
Several studies have reported on the 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, which include ship’s servicemen, navy, metalwork, 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 fifty percent 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 a sudden onset, more frequently seen in Caucasians and may part as Lofgren syndrome (bilateral hilar adenopathy, erythema nodosum, and ankle arthritis) and nonspecific constitutional 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%). The clinical course is very heterogeneous, with 2/3 patients show spontaneous remissions and can be chronic and progressive about 10-30% of patients destroying lung and permanent loss of lung function. Seventy-five percent of patients have bilateral lymphadenopathy.
Extrapulmonary: Almost always associated with the involvement of the lung. Can cause obstructive airway disease if it involves the entire length of respiratory tract airways and a broad spectrum of airway dysfunction. Mostly affects eyes, bone marrow, extrapulmonary lymph nodes, and skin. This is common in both African Americans than in Caucasians.
Cutaneous disease: Skin lesions divided into specific and nonspecific by the presence or absence of granulomatous inflammation on histopathology. Erythema nodosum, lupus pernio, and violaceous rash on the cheek or other parts of the body 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 the 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 granulomatosis, 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 the 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 endstage 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 the 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 (PFT): 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, serum amyloid A (SAA), lysozyme, neopterin, soluble IL-2 receptor, soluble intercellular adhesion molecules (ICAM-1, IFN-8), or 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.
The levels of two circulating microRNAs (126 and 223) showed promise and can be served as biomarkers for cardiac sarcoidosis.
Suggested Reading
Dastoori M, et al. Sarcoidosis—a clinically oriented reviews. J Oral Pathol Med. 2013;42:281-289.
UPPER AIRWAY COUGH SYNDROME
□ Definition
Upper airway cough syndrome (UACS) is related to postnasal drip syndrome, referring to cough associated with upper airway conditions because it is unclear
whether the mechanism of a cough is a 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 a chronic cough. It includes a variety of diseases: allergic rhinitis (AR), 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.
whether the mechanism of a cough is a 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 a chronic cough. It includes a variety of diseases: allergic rhinitis (AR), 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 the nasopharyngeal or oropharyngeal examination is also suggestive of UACS. It is the most common cause of the chronic condition.
□ Diagnostic Findings
In patients with a chronic cough, the diagnosis of a UACS-induced cough are nonspecific, and there is no definitive criteria and should be determined by considering a combination of symptoms, physical examination, 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 a chronic cough is apparent; empiric therapy should be considered in the cough of unknown etiology.
Suggested Reading
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□ Definition
“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: PE, 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 and 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 dyspneas.
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 for the initial evaluation of a patient with dyspnea. Hemoglobin and hematocrit to exclude anemia, and ABG measurements may be a value in managing a 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 the ER, BNP or NT-pro BNP may be useful for the evaluation of heart failure as the cause of dyspnea.
Suggested Reading
Parshall MB, Schwartzstein RM, Adams L, et al. An Official American Thoracic Society Statement: Update on the Mechanisms, Assessment, and Management of Dyspnea. Am J Respir Crit Care Med. 2012;185:435-452.
PULMONARY DISEASES ASSOCIATED WITH DYSPNEAINFECTIOUS RESPIRATORY SYNDROMES ASSOCIATED WITH DYSPNEA
LOWER RESPIRATORY TRACT SYNDROMES
BRONCHIOLITIS
□ Definition
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. 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.
□ 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 respiratory failure.
Initially, there may be nonspecific findings of viral respiratory infection, like rhinitis, cough, and low-grade fever. Symptoms progress to include increased cough and wheezing with signs of increased respiratory efforts (increase respiratory rate, grunting, nasal flaring, chest retractions). Severely affected infants may be cyanotic. Fever is not a prominent feature.
In young children, the degree of respiratory distress and state of hydration/feeding must be carefully evaluated.
□ 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 specific 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.
Pathogen identification: Nasopharyngeal aspirates or swabs should be submitted for testing. Diagnosis may be made using viral culture, molecular, or antigen-specific tests. NAAT tests show the greatest sensitivity and broadest range of viruses detected.
Specific antigen testing, including DFA, may provide rapid diagnosis, but infection cannot be ruled out by antigen assays because of their limited sensitivity and the limited scope of viruses tested.
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.
LEGIONELLOSIS (LEGIONNAIRES DISEASE)
□ Definition
Legionella species have been documented as a relatively common cause of community-acquired and nosocomial pneumonia. Infection is usually caused by Legionella pneumophila serotype 1, a fastidious aerobic gramnegative bacillus. Respiratory infections are the primary manifestation of legionellosis.
□ Who Should Be Suspected?
Legionellosis should be considered in any patient with moderate to severe community-acquired pneumonia, especially during outbreaks or specific exposures. 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.
□ Laboratory Findings
Specific diagnosis is most reliably based on culture isolation and antigen detection. See Chapter 3 for details of testing.
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 urine antigen detection: Urine antigen testing is an important method for diagnosis of Legionnaires diseases caused by L. pneumophila serotype 1 (approximately 90% of community-acquired and approximately 60% of nosocomial respiratory Legionella respiratory infections). Antigen may be detected in urine for several days after the initiation of antimicrobial therapy. 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%.
Molecular testing: PCR-based assays have been described, but FDA-approved tests are not available. Molecular assays detect all relevant Legionella species and serotypes and may be superior to culture for the diagnosis of Legionella infection.
Other: Serology and DFA testing are generally not useful for diagnosis and management of patients with suspected legionellosis.
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); C-reactive protein >100 mg/L.
Suggested Reading
Chen DJ, Procop GW, Vogel S, et al. Utility of PCR, culture, and antigen detection methods for diagnosis of legionellosis. J Clin Microbiol. 2015;53:3474-3477.
BACTERIAL PNEUMONIA
□ Definition
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. S. 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 Haemophilus 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.
or aspiration, or by hematogenous seeding from a distal site of infection. S. 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 Haemophilus 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, rhonchi, and diminished breath sounds.
□ Diagnostic and Laboratory Findings
Pneumonia is generally diagnosed on the basis of clinical signs and symptoms and CXR. Most patients can be successfully managed without specific microbiologic testing.
Diagnostic microbiologic testing should be performed on patients who require hospitalization or who may be at risk for unusual or resistant pathogens. For these patients, CBC, blood culture, sputum Gram stain, and routine culture are recommended. Specialized cultures, like Influenza testing or Legionella culture, are recommended based on presenting signs, symptoms, and risk factors. High-resolution CT scanning may be requested in patients with negative CXR.
The diagnosis of TB should be considered and ruled out as appropriate.
Lower respiratory culture: The value of culture is limited by the quality of the specimen submitted. Sputum specimens should be collected prior to initiation of antibiotic treatment. Patients should be instructed how to produce a “deep” cough specimen and how to avoid mixing saliva with the sputum. Abstaining from eating for several hours and rinsing the mouth prior to collection may improve the quality of expectorated sputum specimens.
Criteria for accepting sputum, based on the presence of PMN and bacteria, and the absence of SECs are used 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.
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 community-acquired pneumonia that requires hospitalization.
Other: Blood culture is positive in approximately 20% of patients; pneumococcal urinary antigen is positive in approximately 50%; antigen may be detectable for days after initiation of antibiotic treatment. PCR may demonstrate improved sensitivity, but the impact on patient management has not been demonstrated.
Core laboratories: Procalcitonin is not particularly useful in establishing a diagnosis of CAP, but serial testing may be useful in determining duration of treatment for patients diagnosed by standard testing. 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.
Suggested Readings
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.
Musher DM, Thorner AR. Community-acquired pneumonia. N Engl J Med. 2014;371:1619-1628.
Reimer LG, Carroll KC. Role of the microbiology laboratory in the diagnosis of lower respiratory tract infections. Clin Infect Dis. 1998;26:742-748.
PNEUMOCYSTIS PNEUMONIA
□ Definition
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. In HIV noninfected patients, primary immunodeficiency, rheumatologic or inflammatory diseases, malignancy (usually hematologic), organ transplantation (hematopoietic or solid organ), and other immunosuppressive therapy predispose to PCP.
□ 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.
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 other types of acquired or primary immunodeficiency states, cancer, hematopoietic cell or solid organ transplantation, etc.
□ Diagnostic Testing
Definitive diagnosis of P. jirovecii depends on the demonstration of organisms in respiratory specimens taken from patients at risk for PCP.
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 BAL for PCP diagnosis approaches 100%. The sensitivity of lung biopsy is very high, but biopsy is rarely needed unless other disease is suspected. The sensitivity of detection may be reduced in non-HIV patients or patients on antifungal prophylaxis. Organisms are rarely detected in routine expectorated sputum or bronchial wash specimens.
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 and/or troph forms (like calcofluor white, Gomori silver, toluidine blue Wright-Giemsa or Papanicolaou) of Pneumocystis. A commercially available fluorescein-conjugated monoclonal antibody is available that provides more sensitive and specific detections compared to these nonspecific stains.
Nucleic acid amplification: Methods have been developed for PCP diagnosis, but none are FDA approved. 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. 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 at-risk patients. Markedly elevated levels have sensitivity as high as 90% for detection of PCP. The specificity is limited by reactivity in infections caused by other fungi.
Serology: Testing does not play a role in PCP diagnosis.
Suggested Readings
Roux A, Canet E, Valade S, et al. Pneumocystis jirovecii pneumonia in patients with or without AIDS, France. Emerg Infect Dis. 2014;20(9):1490-1497.
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.
VIRAL PNEUMONIA
□ Definition
A large number of viral respiratory pathogens are implicated in LRTI. The etiology depends somewhat on the age and the patient’s state of immunocompetence. Viral pneumonia is most important in patients younger than 5 years. Clinically significant, purely viral pneumonia is uncommon in immunocompetent older children and adults.
□ Who Should Be Suspected?
The clinical presentation is variable and depends on the patient’s age, immunocompetence, underlying medical conditions, and specific viral pathogen. Pneumonia is often preceded by nonspecific symptoms of URI. The presenting findings in viral pneumonia include acute illness with fever, showing signs of hypoxemia in severe cases. 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 (ARS). In immunocompetent hosts, disease is usually selflimited and mild, with resolution of symptoms within 7-10 days. Viral pneumonia, however, may present clinically with life-threatening disease, especially in high-risk patients.
□ Diagnosis
The activity of viruses circulating in the community should be considered in the patient’s initial assessment and diagnostic strategy. 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. Other respiratory viral pathogens include adenovirus, corona viruses, measles, HSV, and VZV. CMV is a common, clinically significant cause of viral pneumonia in immunocompromised patients.
Immunocompetent patients with mild disease can usually be diagnosed clinically and managed without laboratory or imaging studies.
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.
▼ Imaging studies typically demonstrate diffuse, bilateral interstitial infiltrates, although the spectrum of abnormalities is broad and nonspecific.
▼ Molecular testing: FDA-approved assays are available for respiratory viral pathogens and are considered the gold standard for diagnosis. These assays provide high sensitivity and specificity, a broad range of detectable viruses, and short turnaround time.
▼ 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.
▼ 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.
▼ 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.
▼ 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.
Suggested Reading
Treanor JJ. Chapter 2: Respiratory infections. In: Richman DD, Whitley RJ, Hayden FG, eds. Clinical Virology, 3rd ed. Washington, DC: ASM Press; 2009.
TUBERCULOSIS
□ Definition
Tuberculosis (TB) typically refers to pulmonary disease caused by infection with Mycobacterium tuberculosis (Mtb) or, rarely, related mycobacterial species. TB 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. See Chapter 13, Infectious Diseases, for a further discussion of mycobacteria and mycobacterial diseases.
□ Who Should Be Suspected?
Factors associated with increased risk of acquisition and transmission of TB are related to close contact with infected individuals. This includes living in, or emigration from, a region with a high prevalence of TB, personal history of TB,
poverty and homelessness, crowded living conditions, AIDS, and intravenous drug abuse. Typical signs and symptoms of TB depend on the age and state of immunocompetence of the patient.
poverty and homelessness, crowded living conditions, AIDS, and intravenous drug abuse. Typical signs and symptoms of TB depend on the age and state of immunocompetence of the patient.
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 (>2 weeks) with sputum production, hemoptysis, or pleuritic chest pain.
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.
More aggressive disease, with risk for extrapulmonary infection, is common in young children (<5 years) and the elderly. In adolescents and adults, infection may not be clinically obvious. Disease may first be suspected by observation of a characteristic abnormality on CXR, performed for other reasons, or a positive screening test for TB.
□ Diagnosis and Laboratory Findings
Definitive diagnosis of TB, using chest radiography and laboratory testing, should be attempted for all patients with a clinical presentation and relevant risk factors for TB. See Chapter 3 for details of specific testing.
Screening tests for tuberculosis: Screening for TB is recommended for patients at high risk of TB on the basis of clinical signs and symptoms or significant epidemiologic risk factors. These tests support a diagnosis of TB, but additional testing is needed to establish active TB (positive tests) or rule out TB (negative tests); they cannot distinguish between latent and active TB.
▼ 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. Test interpretation is based on immune status and exposure history. BCG vaccination may cause false-positive TST, especially if 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 M. 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 and 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 for whom TST is recommended.
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