General Approach to the Patient with a Respiratory Infection

What every physician needs to know:

Respiratory tract infections are major contributors to morbidity, mortality, and economic burden throughout the world. Upper respiratory tract infections account for the majority of the infections, including conditions like “the common cold”, sinusitis, epiglottitis, croup, and pharyngitis. Most of these upper respiratory tract infections are usually mild and self-limiting with symptoms lasting up to two weeks.

The remainder of the respiratory tract infections occur within the lower respiratory tract including the common conditions of bronchitis and pneumonia. Pneumonia is defined as infection of the lung parenchyma and remains a remarkably common problem and major healthcare burden in the U.S. Although the term “pneumonia” is often used to describe a chronic interstitial, non-infectious process (e.g. the idiopathic interstitial pneumonias), this chapter refers only to acute infection.

Classification:

Pneumonia has traditionally been categorized into two main categories: community-acquired (CAP) and hospital-acquired (HAP) pneumonias, the latter also referred to as nosocomial pneumonias. The distinction between CAP and HAP evolved based on the observation that patients with HAP were infected with a set of pathogens distinct from those noted in CAP and that it occurred after at least 48 hours of hospitalization. CAP infections are caused predominantly by Streptococcus pneumoniae, Haemophilus influenzae, Legionella sp., Mycoplasma sp., and others. However, HAP is most often due to pathogens like Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA). A further sub-type of HAP occurs in patients maintained on mechanical ventilation, where a new pneumonia evolves after at least 48 hours of mechanical ventilation, termed ventilator-associated pneumonia (VAP).

In recent years, the American Thoracic Society (ATS) and Infectious Disease Society of America (IDSA) guidelines defined an entity known as healthcare-associated pneumonia (HCAP). Patients with certain risk factors, such as hospitalization within 90 days or residing in an extended care facility, were considered at risk for a broader array of pathogens consistent with the bacteria generally associated with HAP. The updated 2016 ATS and IDSA guidelines recommend the removal of the term “health-care associated pneumonia” given its poor sensitivity and specificity to identify those at increased risk for infection with multi-drug resistant organisms after increasing evidence demonstrated that many patients considered HCAP were not at increased risk for these organisms.

An additional subtype of pneumonia includes aspiration pneumonia, described as a bacterial infection resulting from inhalation of oropharyngeal and gastric contents into the lower respiratory tract. Aspiration pneumonia primarily occurs in patients who are predisposed to aspiration because of altered mental status or oropharyngeal/esophageal dysfunction. By contrast, aspiration pneumonitis is a chemical pneumonitis due to introduction of acidic gastric contents into the lung causing acute inflammation without subsequent infection. Aspiration pneumonitis can mimic pneumonia with similar symptoms of fever and shortness of breath; however, symptoms and imaging findings resolve rapidly.

Viral pneumonia frequently causes community acquired pneumonias and commonly isolated pathogens include influenza, parainfluenza, human metapneumovirus, adenovirus, respiratory syncytial virus (RSV) amongst others. Many viruses have seasonal variations and affect young children and elderly adults with the greatest severity. Amongst viruses, influenza, RSV, and human metapneumovirus have increased prevalence in both children and elderly patients and have been associated with respiratory failure in the elderly population. The seasonal nature of these viruses prompted the development of vaccinations to help in preventing severe outbreaks of infection.

While infections with bacteria and viruses remain the most common causes leading to infectious pneumonia, additional infections with fungal and parasitic organisms become increasingly relevant in immunosuppressed patients. In immunosuppressed patients, opportunistic organisms like Actinomyces sp., Nocardia sp, Aspergillus sp., Pneumocystis jiroveci, and non-tuberculous Mycobacterium sp, may occur. Such a broad differential for infectious causes highlights the importance of history and physical exam in guiding potential diagnostic testing.

Are you sure your patient has pneumonia? What should you expect to find?

Clinical manifestations of pneumonia include a broad array of systemic signs and symptoms all closely linked to the local effects of the pathogens causing infection and injury within the lung parenchyma. Irrespective of the causative agent or subtype, patients affected by pneumonia classically present with symptoms of fever, cough, and dyspnea. Variations from this presentation are common and typically include changes in sputum quantity and quality, hypothermia instead of fever, and variable degrees of leukocytosis with bandemia.

All patients require a detailed history and physical exam before being diagnosed with pneumonia. History should include questions concerning the duration of symptoms, their progression, occupational/environmental exposures, and the presence of risk factors for multi-drug resistant organisms. A careful assessment of the patient’s immune status (e.g. HIV, recent chemotherapy) is also needed. The physician must integrate the obtained clinical information with results from objective testing to determine whether the patient has pneumonia. Oftentimes diagnostic testing in pneumonia is unrevealing, and ultimately the diagnosis is made clinically.

The appearance of someone with pneumonia can range from mildly ill to a rapidly progressive severe course with shock and acute respiratory failure. Vital signs can correlate with disease severity and can suggest local effects of the infection. An increased respiratory rate and/or hypoxemia are reflective of the effects of the infection on the lung. Inflammation and infection within the lung parenchyma lead to impaired diffusion of oxygen and ultimately mismatches between ventilation and perfusion. Additional vital sign abnormalities including tachycardia and hypotension require close monitoring as these can suggest distributive shock resulting from the original infection. Ultimately, if these respiratory derangements progress and hypoxemic respiratory failure occurs, mechanical ventilation may be required.

Clinical support tools aid in making the diagnosis of pneumonia more objective and assist in stratifying its severity. These tools include the clinical pulmonary infection score (CPIS), pneumonia severity index (PSI) and CURB-65. The CPIS integrates various aspects of the clinical presentation and objective testing into a score which if higher, portends a higher likelihood of pneumonia and guides the initiation of antimicrobial treatment. A limitation of CPIS is that it has not been evaluated outside of VAP. Even within the arena of VAP, the diagnostic value of the CPIS appears to be limited.

PSI and CURB-65 integrate various aspects of clinical presentation and laboratory data to assist in predictions of disease severity. The reference standard for risk stratification of severity of illness in CAP remains PSI. Scores of 3 or more for CURB-65 and classes IV and V for PSI have significantly increased mortality risk at 30 days and likelihood of ICU treatment. In comparison to CURB-65, PSI’s predictive value is modestly superior.

Additional clinical tools have been developed recently to aide in further treatment decisions. Serum procalcitonin, a calcitonin precursor secreted by C cells of the thyroid and K cells of the lung, identifies subjects likely to have a bacterial infection and thus has a role in supporting antibiotic treatment decisions. Since its initial introduction, the procalcitonin assay has proved useful to guide de-escalation antibiotics in the intensive care unit.

Beware: there are other diseases that can mimic pneumonia.

Many diseases can cause the signs, symptoms, and imaging findings often attributed to pneumonia. At present, there is no objective gold standard for the diagnosis of pneumonia, and it remains a clinical diagnosis. Specific patterns of signs and symptoms and/or imaging findings were once thought to implicate a particular pathogen, but this observation remains unverified. Clinicians should avoid this approach when making treatment decisions.

The differential diagnosis for patients who present with an acute respiratory syndrome along with radiographic evidence of an infiltrate is broad. Apart from the diagnoses discussed above, additional considerations include:

• Acute lung injury/acute respiratory distress syndrome

• Aspiration pneumonitis/inhalation injury

• Congestive heart failure

• Connective tissue diseases with pulmonary manifestations

• Diffuse alveolar hemorrhage

• Adverse pulmonary drug reaction

• Diffuse parenchymal lung disease (e.g., idiopathic pulmonary fibrosis, non-specific interstitial pneumonia, organizing pneumonia)

• Malignancy

• Radiation pneumonitis

• Transfusion-related acute lung injury

• Trauma (pulmonary contusion)

In most instances, the clinical history excludes many of these possibilities. In some cases, several of these syndromes may co-exist with an acute pneumonia.

How and/or why did the patient develop pneumonia?

Not applicable.

Which individuals are at greatest risk of developing pneumonia?

While a particular population at greatest risk for developing pneumonia has not been clearly established, certain patient populations are more susceptible. These particular populations often have impairments in their host defenses and innate immunity that make them more prone to developing pneumonia. Among those at increased risk are the elderly, critically ill, patients with alcohol use disorders, malnutrition, cardiac disease, underlying lung parenchymal or airway disorders, and any others with an immunosuppressed or immunocompromised state.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Laboratory testing focuses on identifying the causative organism, which may involve nasopharyngeal aspirates, sputum and blood cultures, and occasionally pleural fluid analyses. Blood cultures are recommended for patients with HAP and VAP; in some cases, the blood culture may be the only way that the pathogen is identified. In CAP, the evidence supporting routine blood cultures is limited; except for critically ill patients with CAP, blood cultures are more likely to grow a contaminant than a true pathogen.

Obtaining respiratory cultures remains important to assist in identifying the pathogen causing pneumonia. Non-invasive techniques to obtain a culture include nasopharyngeal aspirates or brushings (used in viral testing), sputum cultures, as well as endotracheal aspirates in patients who are mechanically ventilated.

In mechanically ventilated patients, clinicians may consider obtaining lower airway cultures rather than endotracheal aspirates if the diagnosis remains uncertain. Invasive respiratory sampling techniques to obtain lower airway cultures have been thought to be more reliable than tracheal aspirates since they are less likely to be confounded by upper airway colonization; however, meta-analyses have shown no differences in clinical outcomes when using invasive versus non-invasive sampling techniques for obtaining cultures in the non-immunocompromised host. Lower airway cultures may be obtained through bronchoscopic and non-bronchoscopic techniques. Bronchoscopic approaches include bronchoalveolar lavage (BAL) and bronchial brushing. Mini-BAL and blind-brushing are alternative non-bronchoscopic options. Additional non-invasive sampling techniques include the mentioned endotracheal aspirate which remains the most sensitive but least specific method of obtaining cultures.

Other tools for identifying the pathogen include urinary antigen testing and serum antibody studies. Urinary antigen tests are commercially available for Streptococcus pneumoniae and selected Legionella species. The urinary antigen tests have limited sensitivity and specificity since they are positive only in the presence of select serotypes/species. Serologic studies using enzyme linked immunosorbent assays (ELISA) to quantify specific bacterial antibody titers have been used serially to determine the seroconversion of IgG in patients with suspected infections. Given the delay to allow for antibody production, serologic studies have little clinical use apart from retrospective epidemiological research.

Alternative novel laboratory studies have emerged for diagnosis, such as direct fluorescent antigens and real time polymerase chain reactions (RT-PCR). These studies are quickly becoming a mainstay in diagnosis given their ability to produce fast results with high sensitivity and specificity. Multiplex PCR respiratory panels can identify up to 17 of the most common viruses associated with respiratory tract infections as well as several of the common atypical bacterial infections including M. pneumoniae and C. pneumoniae. In addition to using these molecular studies to assess readily available nasopharyngeal aspirates in the clinical setting, studies have also shown that using them on sputum further increases the yield of identifying more than one pathogen causing infection.

Additional consideration should be taken in immunocompromised patients where special stains may be ordered to evaluate sputum, BAL and tissue specimens for opportunistic pathogens rarely identified in otherwise immunocompetent hosts. Pneumocystis jiroveci (PJP) is an opportunistic infection commonly identified in patients with HIV/AIDS when CD₄ counts decrease. PJP is identified by silver staining and BAL and tissue biopsy yields are higher in HIV patients compared to patients with other conditions such as hematologic malignancies. Immunocompromised patients should also be evaluated for organisms such as Actinomyces sp., Nocardia sp, Aspergillus sp., non-tuberculous Mycobacterium sp, and Strongyloides sp. These tests are of little value in otherwise immunocompetent hosts unless history warrants increased clinical concern.

Finally, in any patient population where tuberculosis is clinically suspected, acid fast stains and subsequent cultures are appropriate, along with airborne precautions.

What imaging studies will be helpful in making or excluding the diagnosis of pneumonia?

Pneumonia can be identified by the presence of an infiltrate on CXR. Infiltrates on CXR can be characterized as airspace opacities, lobar consolidation, or interstitial opacities usually without associated volume loss. Without evidence of direct parenchymal involvement, it is unlikely that an infectious pneumonia explains the patient’s syndrome. However, standard CXR has limitations: Portable AP films without an accompanying lateral image may miss up to 20% of acute infiltrates. Similarly, even a PA film with a lateral is less sensitive then a dedicated CT scan of the chest.

Approximately 10% of patients with pneumocystis pneumonia have normal chest films; the presence of infiltrates is detected only on a CT scan. Similarly, in immunosuppressed subjects, the CT is more sensitive than the CXR for the diagnosis of pneumonia.

Chest films should be the primary diagnostic imaging modality to rule out pneumonia; however, CT is appropriate if pneumonia is suspected and the standard CXR is unremarkable. CT is the preferred imaging modality for immunosuppressed patients with suspected pneumonia. In addition, if there is a question about the pattern of infiltrates or cavitary disease after reviewing a CXR or if further mediastinal evaluation is indicated, a CT is the appropriate next step.

Recently, there has been a surge of interest regarding the utility of point-of-care ultrasound (US) for the diagnosis of pneumonia. The appearance of a normal lung using US typically shows a “sliding lung” sign with “A-lines” which are findings of the visceral and parietal pleura sliding upon each other with the “A-line” representing a reverberated artifact of the parallel pleural line. In infected lung, consolidation has findings of “B-lines” which are characterized by hyperchoic rays arising from pleural line and radiating vertically through the lung. When the lung becomes consolidated it appears increasingly hyperechoic on US and may become difficult to distinguish from nearby organs including the liver and spleen. While US still has more validation to determine its full clinical utility, it has the advantages of no radiation and rapid bedside examination which can also exclude other pulmonary processes such as pneumothorax and pleural effusions. The use of US can have up to a 95% diagnostic accuracy with high precision that has been demonstrated amongst experienced users; however, there is a large degree of inter-observer variability.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of pneumonia?

None

What diagnostic procedures will be helpful in making or excluding the diagnosis of pneumonia?

Several diagnostic processes apart from imaging can be useful in the diagnosis of pneumonia and its related complications. In patients with pleural effusions, both chest imaging and US may be used to identify the effusion. Thoracentesis can be a helpful adjunct in diagnosing a complicated infection resulting in a parapneumonic effusion. Pleural analyses will show an exudative effusion based on Light’s criteria and additional studies looking at glucose and pH can help identify an empyema that may ultimately require chest tube drainage.

A bronchoscopy is often indicated when there is accompanying hemoptysis, an abnormality on imaging suggesting malignancy, non-resolving pneumonias, atypical clinical features and/or exposures, or an immunosuppressed patient. In patients who require mechanical ventilation, many clinicians perform bronchoscopy to obtain lower airway samples in suspected VAP due to its advantage of obtaining cultures that may have a higher yield for diagnosis in comparison to endotracheal aspirates. An advanced bronchoscopic technique known as endobronchial ultrasound may occasionally identify respiratory infections that involve the mediastinal lymph nodes but is not routinely used for the diagnosis of pneumonia.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of pneumonia?

None

If you decide the patient has pneumonia, how should the patient be managed?

The management of patients diagnosed with pneumonia can take place in many settings including outpatient practices, emergency departments, inpatient general medical floors, and medical intensive care units. Depending on the clinical setting, antimicrobial management is tailored to address likely organisms, severity of illness, immunocompromised state, adjunctive therapies, and care in the emergent or refractory settings.

The most common location for treatment of pneumonia remains the outpatient setting where pneumonia is diagnosed clinically and patients are subsequently managed with oral antibiotics for CAP. In patients with suspected CAP, it is crucial to utilize regimens against S. pneumoniae, the most common pathogen in this syndrome and common atypical bacteria such as Chlamydia pneumoniae and Mycoplasma pneumoniae. It should be noted that there has been increasing resistance of many strains of S. pneumoniae to penicillin- and/or macrolide therapies, frequently linked to local antibiotic resistance patterns. The current prevalence of these pathogens is not clearly established, and in some countries treatment for these organisms is not considered routine. If influenza A or B viruses are identified, then treatment with oseltamivir may be initiated if symptoms have persisted for no more than 48 hours. There are multiple guidelines that can aid in antibiotic decision making, including those from the ATS/IDSA and the British Thoracic Society. Typical regimens for coverage of S, pneumoniae and the aforementioned atypicals include oral formulations with moxifloxacin, azithromycin or tetracyclines; as well as IV formulations for inpatient admissions with ceftriaxone along with a macrolide or tetracycline. Compliance with national guidelines with respect to antibiotic decision making has also been shown to improve clinical outcomes.

For patients at risk of hospital-acquired microbial infections like P. aeruginosa, and MRSA, broader initial antimicrobial therapy is recommended. These pathogens are of particular concern in persons with HAP or VAP, and in those who are immunosuppressed. Broad spectrum antibiotic regimens are part of the initial empiric treatment regimen to ensure that at least one of the agents is active in vitro against what is eventually found to be the primary organism. It is important to de-escalate therapy when microbiology data become available in order to limit the development of resistance and minimize adverse effects of complications secondary to antimicrobial therapy.

Immunocompromised patients, while still most commonly affected by CAP and HAP associated organisms, may be at risk for opportunistic pathogens like cytomegalovirus, and various fungal infections such as PJP. In these patients, empiric treatment is recommended while awaiting cultures. Patients infected with HIV should be given empiric Pneumocystis treatment (e.g., TMP-SMX) along with traditional antibiotics.

Adjunctive therapies with corticosteroids may be considered in PJP infections when there is an increased arterial-alveolar gradient greater than 35mmHg with moderate hypoxemia, as steroids may prevent acute respiratory distress in patients with HIV. The role of corticosteroids in other settings in which pneumonia is a concern is controversial; routine corticosteroid administration is not recommended for CAP or HAP. The exception to this may be in severe CAP, where the addition of methylprednisolone was shown to decrease treatment failure but had no difference on mortality outcomes compared to prior standard of care.

In the setting of hypoxemic respiratory failure secondary to pneumonia, the patient should be managed in the emergency room setting. Rapid physician recognition of the severity of illness is important to help preserve clinical stability where a stable airway is needed to maintain adequate oxygenation and ventilation. For patients who are in septic shock from pneumonia, rapid fluid resuscitation is crucial and early initiation of empiric antibiotics have helped to improve outcomes. It should be noted that one of the most common causes of septic shock and acute respiratory distress syndrome resulting in ICU admissions is pneumonia.

Timeliness and appropriateness of antibiotics improves outcomes in every form of pneumonia so clinicians should strive to ensure that the patient receives treatment promptly (i.e. within six hours of symptom onset or presentation) with antibiotics that are active against the suspected pathogen. Standardized empiric regimens should be based on local susceptibility data for patients who present to the emergency room and for those who develop HAP. Failure to administer initially appropriate antibiotic therapy can significantly increase mortality. On average, patients in the ICU require three or four days to achieve clinical stability after initial antibiotic treatment for pneumonia.

Patients who progressively worsen or fail to respond to initial treatment, need a careful review of all cultures to ensure that a multidrug-resistant organism has not been missed. With treatment failure, clinical suspicion must remain high to evaluate for interval development of a complicated pleural effusion that would require drainage, or development of resistant bacteria. If the patient has developed diarrhea, he or she may have developed antibiotic-associated colitis. In cases in which the presentation was unclear, the clinical situation may provide additional insight as time progresses, and lead to an alternate diagnosis, such as hypoxemia secondary to pulmonary embolism or heart failure.

Given the diagnostic limitations of the approach to pneumonia, it is important to have a low threshold for questioning the original diagnosis. Repeat chest imaging is often part of the re-evaluation process to aid in assessing progression or resolution of infiltrates over several days. Ongoing pulmonary symptoms without clear evidence of pneumonia may also warrant additional imaging to rule out pulmonary embolism.

The recommended follow-up upon resolution of clinical symptoms varies based on the type of pneumonia. For CAP and HAP, guidelines recommend a follow-up radiograph at six to eight weeks after onset in order to ensure that the infiltrate has resolved and that there is no confounding malignancy. For VAP, no specific follow-up is recommended.

Ultimately the goal of treatment is prevention of further episodes of pneumonia; however, our current preventative strategies rely largely on avoidance of exposure and minimizing risk factors. Immunizations aid in prevention of only some types of pneumonia. There are several vaccines available for common respiratory pathogens, including pneumococcal and influenza vaccinations. The pneumococcal vaccines include the pneumococcal conjugate vaccine (PCV13) and pneumococcal polysaccharide vaccine (PPSV23). Both of these vaccines are given to select age groups unless deemed to have an increased risk factor predisposing the individual to pneumococcal pneumonia. The PCV13 vaccination is given to all children under age 2 and adults greater than age 65, and the PPSV23 is given to adults greater than age 65. A seasonal vaccination is available for influenza usually using an injectable inactivated virus format to help promote formation of antibodies against the influenza viruses. Finally, there is also a vaccination available for adenovirus containing live adenovirus types 4 and 7; however, this oral vaccine is only recommended for military personnel living in close-quarters, who are at high risk of adenovirus infections.

What is the prognosis for patients managed in the recommended ways?

Prognosis is best determined based on general measures of outcome prediction. The presence or absence of organ failure (e.g., respiratory failure, shock) is a major determinant of outcome. For both CAP and HAP, scoring tools that measure the severity of illness perform moderately well at predicting outcomes, but they have certain limitations. For CAP, the CURB-65 scoring tool, expanded CURB-65 and the Pneumonia Severity Index correlate with mortality. For HAP and VAP there are no well-validated scores uniquely developed to predict outcome.

For both HAP and CAP, most patients who will improve will do so by day three. Multiple biomarkers have been correlated with clinical outcomes, although these biomarkers have low specificity.

What other considerations exist for patients with pneumonia?

None

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