Respiratory, Metabolic, and Acid-Base Disorders

Respiratory, Metabolic, and Acid-Base Disorders

L. V. Rao

Michael J. Mitchell


Respiratory 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.


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.”

□ 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.




□ 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.

Suggested Reading

Wenzel RP, Fowler AA III. Acute bronchitis. N Engl J Med. 2006;355:2125-2130.


□ 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.


□ 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.

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. DFA testing is not accepted as a diagnostic criterion by the CDC.

□ 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.

Suggested Reading

CDC Pertussis (Whooping Cough). Accessed August 27, 2018.



□ 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.


□ 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.


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.





□ 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.


□ 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.


□ 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.


□ 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 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.

Core laboratory: Elevated LDH is useful in HIV-infected patients, but less specific in HIV noninfected patients; the degree of LDH elevation and increasing LDH despite therapy are poor prognostic signs.

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.


□ 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.

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.


□ 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.

  • 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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Mar 20, 2021 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Respiratory, Metabolic, and Acid-Base Disorders

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