Pneumonia. Introduction. The Different Faces of Pneumonia. Immunocompetent Host. Elisa Franquet, MD

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1 Pneumonia Elisa Franquet, MD Introduction Pneumonia continues to be a significant global health problem, remaining among the top 10 causes of death globally and in the US, 1 especially among elderly patients. 2 The diagnosis of pneumonia relies mainly on clinical symptoms and imaging findings. Despite imaging studies playing an important role in early diagnosis, laboratory confirmation can be obtained in only 30%-70% of cases even after a full microbial battery is performed. 3 Invasive procedures, such as bronchoscopy with lavage and biopsy, are limited to hospital-associated infections and immunocompromised patients. Imaging Modalities Chest radiography (CR) is considered the modality of choice for detecting new infiltrates in clinically suspected pneumonia. 4,5 This modality provides information about localization, extent, and prognosis, as well as excluding other causes of disease and at times even suggesting an etiologic agent. 5 However, the specificity of CR is low, and interpretation agreement among readers depends on their levels of expertise. 6-8 In immunocompromised patients (including smokers and diabetic patients), the appearance of signs of infection on CR may be delayed. In neutropenic fever, for example, CR may appear normal for up to 72 hours, though signs of underlying pneumonia may be apparent on computed tomography (CT). However, in patients who are immune competent, the early stages of pneumonia are usually visible on CR within hours. 3,9,10 Therefore, the appropriate timing for obtaining CR is crucial when diagnosing lung infections, particularly in immunocompromised patients. CT has higher sensitivity and specificity than CR and is indicated when there is a strong suspicion of pneumonia with normal or nonspecific CR (especially in immunosuppressed hosts), failure of medical treatment in an immunocompetent patient, recurrent pulmonary opacities, assessment of suspected complications, or suspicion of an underlying obstructive lesion CT is also superior in detecting associated findings, such as mediastinal lymphadenopathy in patients Beth Israel Deaconess Medical Center, Boston, MA. Address reprint requests to Elisa Franquet, MD, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA e.franquetelia@ gmail.com with suspected tuberculosis (TB) and parenchymal abnormalities in up to 50% of neutropenic patients with normal CR and persistent fever refractory to empiric treatment. 10,13-15 Nevertheless, CR is still the initial diagnostic imaging procedure because of its widespread availability and its low cost and radiation exposure. The Different Faces of Pneumonia The classic radiological patterns of pneumonia are lobar consolidation, bronchopneumonia, and interstitial consolidation. The radiological findings on CR and CT and the most common organisms for each pattern are summarized in Table 1. 10,16,17 The nodular pattern refers to the presence of multiple rounded opacities (2-10 mm) in a widespread but not necessarily uniform distribution. 18 In an acute clinical setting, centrilobular nodules of soft tissue attenuation are likely due to infection. The most common cause is endobronchial spread of bacterial, mycobacterial, or fungal organisms, and this appearance represents an early manifestation of bronchopneumonia. Centrilobular nodules of ground-glass opacity are more characteristic of infections associated with a peribronchiolar inflammation without bronchiolar impaction, such as viral (varicella zoster) and atypical bacterial (Chlamydia and Mycoplasma pneumoniae) infections. The dilatation of centrilobular bronchi filled with mucus, pus, or fluid resembling a budding tree ( tree-in-bud pattern ) is highly suspicious for infection (especially bacterial and mycobacterial). 18,19 Small nodules (o2 mm in diameter) in a random distribution are highly suggestive of miliary TB (Fig. 2), nontuberculous mycobacteria, or fungal infections (histoplasmosis, coccidioidomycosis, cryptococcosis; Fig. 3). Large nodules (41 cm) and cavities commonly reflect an infectious etiology, most likely septic embolism, bacterial lung abscess, and fungal and mycobacterial infections. In the immunocompromised host, Nocardia, Actinomyces, Mycobacteria, and Aspergillus frequently present as large nodules or cavities or both. An air-fluid level within a cavitary nodule or mass suggests bacterial infection. Immunocompetent Host In general, approaching pneumonia from the host perspective is clinically valuable, as each clinical setting has different X/& 2017 Elsevier Inc. All rights reserved.

2 28 E. Franquet Figure 1 Mycoplasma pneumoniae pneumonia. CT image shows a focal consolidation in the lingula with air bronchogram (arrows). associated comorbidities, risk of drug-resistance, treatment approaches, and outcomes. The imaging presentation of pneumonia tends to be different in these various situations. Community-Acquired Pneumonia Pneumonia acquired in the community setting, unrelated to a hospital encounter, predominantly affects individuals at the extremes of life 3,20 and is a leading cause of hospitalizations, particularly in elderly. 2,21 Community-acquired pneumonia (CAP) remains an important economic burden in the United States despite the pneumococcal vaccine 20,22 and the availability and adherence to treatment guidelines. 23 Streptococcus pneumoniae is the most common pathogen responsible for CAP (up to 40%), 22 followed by Haemophilus influenzae, M. pneumoniae, Moraxella catarrhalis, Chlamydia, and Legionella. Ps. aeruginosa can also cause CAP in patients with chronic obstructive pulmonary disease (COPD) or bronchiectasis, especially those undergoing steroid therapy. During flu outbreaks, influenza virus becomes a major cause of CAP and increases the risk of Staphylococcus aureus superinfection. 24 Other agents causing CAP are respiratory syncytial virus and adenovirus. Non-TB Mycobacteria and fungi such as Histoplasma and Coccidioides (endemic in the central and southwestern parts of the United States) may cause subacute pulmonary infections. An acute atypical pneumonia caused by Coxiella burnetii is common in patients who have had contact with animals. Nevertheless, the causative agent for CAP is only found in 50% of cases Lobar consolidation is the most frequent presentation of CAP, with S. pneumoniae being the most common etiologic micro-organism. Consolidation may be unilateral, bilateral, and involve multiple lobes. Although small parapneumonic pleural effusions are frequent, empyema is uncommon. 29 Klebsiella also causes lobar consolidation (although is the offending agent in o5% of cases of CAP). 30 It commonly affects mildly immunocompromised men in their 50s who are chronic alcoholics, smokers, or diabetics. 9,29 Klebsiella is an aggressive organism that presents as a rapidly progressive exudative reaction leading to a lobar consolidation with characteristic bulging fissures ( heavy pneumonia ). 31 Margins are sharp, and early abscess formation and cavitation often is observed. 9,11,32 Although frequent in children, round pneumonia is an uncommon presentation of CAP in adults, with S. pneumoniae the most frequent causative organism. It morphologically presents as a round or oval consolidation ( coin lesion ) of variable size, which is thought to be due to centrifugal spread of infection. Radiographically, round pneumonia is most commonly located in the lower lobes and typically presents with smooth or mildly irregular margins (Fig. 4), although lobulations and spicules may occur. 33 On CT, round pneumonia appears as a heterogeneous mass of soft tissue attenuation that may be associated with coarse spicules, air bronchograms, pleural thickening, and satellite lesions. 33,34 Therefore, a solitary pulmonary nodule with rapid growth (over 2-6 weeks) and signs of infection should raise the possibility of round pneumonia. 35 Legionella pneumophila pneumonia is a rapidly progressive and often fatal lung infection that commonly presents as unilateral or bilateral, segmental peripheral opacifications that may rapidly enlarge and spread to additional lobes. On CT, consolidations with associated areas of GGO are frequently observed. 36 Bronchopneumonia is most commonly caused by H. influenzae and S. aureus, with anaerobes and S. pneumoniae less likely. H. influenzae infections usually have a seasonal variation, being most common in winter and spring. S. aureus, which is found on the skin or nasopharyngeal mucosa in 20%- 30% of the population, leads to pyogenic exudates and lung abscesses, which may be complicated by pleural effusion, empyema, and pneumatocele formation. M. pneumoniae, often coexisting with Chlamydophila pneumoniae, and viruses present as diffuse bilateral interstitial or mixed interstitial-alveolar infiltrates (Fig. 5). Pulmonary nodules or masses (with or without cavitation) are often caused by bacteria such as Legionella, C. burnetii,and M. tuberculosis. In patients with COPD, cavitation is most commonly associated with Mycobacterium tuberculosis, Aspergillus species, gram-negative bacilli, and S. aureus. Hospital-Acquired Pneumonia Hospital-acquired pneumonia (HAP), which develops at least 48 hours after admission, is the leading cause of mortality due to hospital-acquired infections. Patients in the intensive care unit and those with mechanical ventilation (ventilator-associated pneumonia) are more susceptible. HAP is usually acquired by aspiration or inhalation of micro-organisms, by direct implantation into the respiratory tract (by devices such as bronchoscopy), or through hematogenous spread (endocarditis or septic emboli). Although the most common pathogens in HAP are gramnegative bacilli and S. aureus, pathogens such as S. pneumoniae, M. catarrhalis, and H. influenzae also can be involved. Enterobactericeae species, such as Escherichia coli and Klebsiella, are

3 Pneumonia 29 Table Patterns of Pneumonia and Their Causes Lobar/alveolar consolidation Bronchopneumonia Interstitial pattern Target Air-space Airways (bronchitis or bronchiolitis or both) Interstitium Spread Alveoli through the pores of Kohn and channels of Lambert in the alveolar walls until it reaches the fissures (fills space) Along the airway walls and into adjacent alveoli (causes ulcers in the walls and fibropurulent membrane formation) Septal interstitium Limits Fissures No limits No limits Radiograph Opacity Patchy, inhomogeneous consolidation Reticular, reticulonodular opacities or nodular, patchy, alveolar densities, and areas of groundglass opacities Findings Begins peripherally and spreads centrally Nonsegmental, sublobar or lobar Can be multilobar Air bronchogram may be present (Fig. 1) Silhouette sign Lobular, subsegmental, segmental Usually multilobar and bilateral Air bronchogram usually absent Diffuse and bilateral CT findings Opacification with attenuation equal to the vessels and airways (hampering the visualization of such structures) Ground-glass opacities Pleural extension CT angiogram sign (opacified vessels within the consolidation after the infusion of IV contrast) Centrilobulillar nodules Tree-in-bud opacities Bronchial wall thickening Airway impaction and dilatation Ground-glass opacities Septal thickening Most frequent organisms S. pneumoniae Pseudomonas aeruginosa M. pneumoniae K. pneumoniae S. aureus Virus Legionella Escherichia coli Mycobacterium tuberculosis Moraxella catarrhalis Anaerobes Haemophilus influenzae Haemophilus influenzae C. pneumoniae PCP Figure 2 Miliary tuberculosis. CT image at the level of the aortic arch shows numerous randomly distributed nodules, 1-2 mm in diameter, throughout both lungs (miliary pattern). the most common micro-organisms after 5 days of hospital admission. 4,9,11,28,35,37,38 The diagnosis of HAP is challenging because of lack of classic symptoms, difficulties in identifying a causative agent, and a high rate of associated acute respiratory distress syndrome. 9 The radiographic findings usually appear during the first hours following the onset of clinical symptoms. Thus, the acquisition of CR soon after the onset of symptoms often results in a falsely normal appearance. 39 CT should be considered if there is a strong suspicion of pneumonia. 12,13,15 Bronchopneumonia is the most frequent presentation of HAP. 9 Although uncommon, air bronchograms and air-space consolidation abutting a fissurearethemostspecificsigns. Ps. aeruginosa infectionshouldbeconsideredinpatients with COPD, as well as those who have received corticosteroids

4 30 E. Franquet Figure 3 Cryptococcal pneumonia in a 50-year-old immunosuppressed male after hematopoietic stem cell transplant (HSCT). Magnified PA chest radiograph shows multiple poorly defined small nodules in the right upper lobe (multinodular pattern). PA, posteroanterior. or broad-spectrum antibiotics, had a prolonged stay in the intensive care unit, or show bronchiectasis. This possibly fatal pneumonia is a cause of chronic airways colonization in patients with cystic fibrosis. Radiologically, it presents as bronchopneumonia that predominantly involves the lower lobes. Less frequently, it produces lobar consolidation (at times with a bulging fissure), multiple nodular opacities, or a reticular pattern. Complications include cavitation, pneumatocele, unilateral or bilateral pleural effusion, and empyema. Aspiration Pneumonia The major complication of aspiration is pulmonary infection. Aspiration can lead to the development of lobar or segmental pneumonia, bronchopneumonia, lung abscess, and empyema. The posterior segment of the upper lobes and the superior segment of the lower lobes are the most commonly involved sites. 40 Aspiration pneumonia occurs more often in patients with loss of consciousness, chronic debilitating disease, Figure 5 Streptococcus pneumoniae pneumonia. CT image shows multifocal ill-defined areas of mixed interstitial-alveolar infiltrates. There is lobular consolidation seen in the right upper lobe and a segmental ground-glass opacity in the superior segment of the left lower lobe. structural abnormalities of the pharynx and esophagus, neuromuscular disorders, deglutition abnormalities, general anesthesia, and oropharyngeal or airway instrumentation. 41 Alcoholism is probably the most important predisposing factor for pulmonary aspiration in adults. 40 Anaerobic organisms are the offending pathogens in 90% of cases of aspiration pneumonia. The typical CR finding in aspiration pneumonia is bilateral, multicentric segmental opacities that are most common on the right, in the perihilar regions, and in the dependent portions of the lung, with the location depending on the position of the patient when the aspiration occurred (Fig. 6). The radiographic manifestations vary with the organism involved. Ps. aeruginosa infection typically results in bronchopneumonia, with lobar consolidation less common. Cavitation suggests S. aureus, gram-negative bacilli, anaerobes, or actinomycosis. Actinomyces israelii is a common anaerobic bacterium of low virulence found in patients with poor oral hygiene, periodontal disease, and excessive alcoholic intake. Aspiration of this organism produces a subacute localized or segmental pneumonia that, if untreated, can result in cavitation, pleural effusion, Figure 4 Chest radiograph shows a 6-cm diameter rounded consolidation with ill-defined margins in the right lung (round pneumonia). The patient was a 55-year-old woman. Figure 6 Aspiration bronchopneumonia. PA chest radiograph shows bilateral ill-defined, patchy areas of consolidation in the lower lobes. PA, posteroanterior.

5 Pneumonia 31 or empyema. The infection may invade the chest wall, mediastinum, or diaphragm. 10 Immunocompromised Host and AIDS The number of immunocompromised patients has increased considerably in the past 3 decades because of 3 main phenomena: the AIDS epidemic, advances in cancer chemotherapy, and expanding solid organ and hematopoietic stem cell transplantation (HSCT). In symptomatic patients, it is important to determine whether the cause of symptoms is infectious or noninfectious. The American Thoracic Society (ATS) guidelines recommend that when possible posteroanterior and lateral chest radiographs be obtained whenever pneumonia is suspected in adults. CR must be routinely undertaken in patients with presumptive pneumonia to make the diagnosis. However, a normal chest radiograph should not exclude the diagnosis of pneumonia, because the radiograph can lag behind the clinical findings by several days. CT is a useful adjunct to CR in unresolved cases or when complications of pneumonia are suspected. In solid organ transplantation, bacterial pneumonia is the most common respiratory infectious complication; cytomegalovirus (CMV) infection usually occurs within the first 3 months after transplantation. 42 Pulmonary complications following HSCT are common, occurring in about half the number of patients. In the early phase, bacterial infections are responsible for 90% of infections. The most likely presentations are consolidation (S. pneumoniae, Klebsiella) and bronchopneumonia (gram-negative bacteria, S. aureus). Fungi (mainly Aspergillus species) are the most frequent cause of pulmonary infection during the neutropenic phase (up to 3 weeks after transplantation), whereas CMV pneumonia typically occurs 3 weeks to 100 days after transplantation. 11,32,41,43-45 The characteristic CT findings of angioinvasive aspergillosis are air-space nodules (6-10 mm in diameter) and, less frequently, segmental consolidation or bronchopneumonia. In some cases, nodules may be associated with a halo of groundglass attenuation. In severely neutropenic patients, the halo sign is highly suggestive of angioinvasive aspergillosis 11,46,47 (Fig. 7). However, a similar appearance has been described in infections due to nontuberculous Mycobacteria, Mucorales, Candida, Herpes simplex virus,andcmv. 48 The reversed halo sign a focal rounded area of ground-glass opacity surrounded by a more or less complete ring of consolidation is much less common and associated with mucormycosis. 13 Both signs usually appear early during the course of infection. Following treatment, the nodules may cavitate. Eccentric cavitation produces the crescent sign, which has a good prognosis. In mildly immunocompromised hosts (diabetics, alcoholics, and those with COPD), aspergillosis presents as lobar consolidation (semi-invasive form). Diabetics are Figure 7 Angioinvasive aspergillosis. CT image in a 30-year-old neutropenic man shows a nodule in the posterior segment of the right upper lobe surrounded by a halo of ground-glass opacity ( halo sign )(arrow). especially at high risk for developing mucormycosis that tends to cross fissures or invade the chest wall and pulmonary arteries. CMV pneumonia on CT produces solitary or multiple areas of ground-glass attenuation, multiple small nodules surrounded by a halo of ground-glass attenuation, and areas of consolidation. Pneumocystis jiroveci (formerly Pneumocystis carinii) is a unique opportunistic fungal pathogen that causes pneumonia in immunocompromised individuals, such as patients with AIDS, organ transplants, or hematologic or solid organ malignancies who are undergoing chemotherapy, and in patients receiving immune-suppressive treatments, particularly systemic corticosteroids. PCP is relatively rare among HSCT patients, except in the setting of chronic graft-vs-host disease in the late phase following allogenic transplantation. 45 The classical imaging findings consist of extensive bilateral ground-glass opacities that typically involve the perihiliar regions or the middle and lower lungs 10,29 (Fig. 8). Other common organisms causing pulmonary infection in this group are gram-positive and gram-negative bacteria, M. tuberculosis,andmycobacterium Avium Complex (MAC). Cryptococcus and CMV are rarely seen in immunocompetent hosts, but they are often encountered in patients with AIDS. In the absence of symptoms, PCP or TB is most likely, and CT is the recommended imaging modality. Bacterial pneumonia and pyogenic bronchitis are the most common manifestations of pulmonary infection in patients with AIDS and are usually caused by S. pneumoniae, H. influenzae, Ps. aeruginosa, and S. aureus. Asin immunocompetent hosts, lobar consolidation is the typical presentation of bacterial CAP in patients with AIDS. Unilateral or bilateral bronchopneumonia are usually caused by Ps. aeruginosa, Staphylococcus, Klebsiella, Enterobacter, orhaemophilus infection. In AIDS, opportunistic lung infections usually occur in patients with CD4 counts less than 200 cell/mm 3 ; typical

6 32 E. Franquet Figure 8 Close-up view of a high-resolution CT at the level of the carina shows patchy ground-glass opacities in the right upper lung. Note associated interstitial emphysema (thick arrow) and pneumomediastinum (thin arrows). bacterial pneumonia is more common when the CD4 count is more than 500 cell/mm 3. In the last decade, the prevalence of opportunistic infections has decreased with the introduction of highly active retroviral therapy (HAART). The immunosuppressed state associated with AIDS predisposes to the reactivation of latent TB. MAC infection occurs in advanced stages of AIDS, when the CD4 count is lower than 50 cells/mm 3. The radiological findings of TB are similar in both immunocompromised and immunocompetent patients, although mediastinal lymph node and bronchogenic spread more frequently are seen in patients with HIV. 49 The characteristic CT findings consist of focal areas of consolidation, centrilobular nodules, and tree-in-bud opacities, mainly in the apical and posterior segments of the upper lobes. Other associated findings are bronchovascular distortion secondary to parenchymal destruction, cavitation, lymphadenopathy, and pleural effusion. In patients with severe lymphocytopenia, the findings are similar to those in primary infection, including focal, patchy, or mass-like heterogeneous consolidation in any lobe, poorly defined nodules, and linear opacities. Unilateral hilar or mediastinal lymphadenopathy or both can develop with lymphatic spread of the disease. The impaired lymphocytic response in patients with AIDS prevents granuloma formation, resulting in a higher rate of miliary TB than in normal hosts. Septic emboli caused by recurrent Staphylococcus infection are most likely encountered among intravenous drug abusers and present as multiple cavitary nodules on CT. Figure 9 Pneumocystis jirovecii pneumonia. Magnified PA chest radiograph in a 33-year-old man with AIDS shows a left upper lobe consolidation with an air-fluid level (arrows). PA, posteroanterior. made with certainty on radiologic grounds, but it may be possible on CT. 50 In a patient with pneumonia, the CT demonstration of pleural thickening associated with a pleural effusion and enhancement of both pleural layers after IV contrast ( split pleura sign) indicates the presence of an exudative effusion or empyema. 50,51 Aspiration can lead to the development of lobar or segmental pneumonia, bronchopneumonia, lung abscess, and empyema. Therefore, the posterior segment of the upper lobes and the superior segment of the lower lobes are the most commonly involved lung sites in aspiration disease. Lung abscess, a necrotic cavitary lesion 42 cm in diameter and containing pus, is most often related to S. aureus, gramnegative anaerobic bacteria, and fungi. On CT, it typically presents as a cavity (purulent necrosis), particularly in gravitydependent sites of the lung, with thickened walls, peripheral Common Complications of Pneumonia Parapneumonic effusion, often unilateral, is a common pulmonary complication in the setting of bacterial pneumonia. Progression to empyema occurs in 5%-10% of cases. Distinction of pleural transudate from pleural exudate cannot be Figure 10 Lung abscess. Enhanced CT image (same patient as in Fig. 9) confirms a large abscess in the superior segment of the left lower lobe, with thick nodular walls and an air-fluid level (arrow).

7 Pneumonia 33 drug reactions, cryptogenic organizing pneumonia, eosinophilic pneumonia, and nonspecific interstitial pneumonia. All suspected pneumonias must be followed with CR after 4 weeks to evaluate for clearing of the process. However, it is important to remember that resolution of a pneumonia often lags behind clinical improvement and might take up to 6 weeks to resolve on CR. Failure of antibiotic therapy to completely clear a pulmonary consolidation should suggest an alternative diagnosis. Figure 11 P. Jiroveci pneumonia in a 36-year-old HIV-positive male. Coronal CT image shows bilateral ground-glass opacities containing multiple cysts (pneumatoceles) (arrows). contrast enhancement, and sometimes an air-fluid level (Figs. 9 and 10). Necrotizing pneumonia (NP) may result as a sequela of severe CAP or TB. Common causes include S. pneumoniae, H. influenzae, and several gram-negative anaerobes. Radiographically, NP begins as a lobar consolidation, usually in the upper lobes, followed by development of lucencies that coalesce to form a cavity secondary to thrombosis of the pulmonary vessels. NP should be suspected in all severely ill patients with prolonged fever and significantly elevated serum inflammatory markers. Although not always necessary, CT may play an important role in showing necrotizing or cavitary lesions that are not visible on CR. NP is associated with a very high risk of local complications, such as empyema. Pneumatoceles manifest as single or multiple, thin-walled, air-cystic spaces within an area of consolidation, which usually increase in size over days or weeks (Fig. 11). Pneumatoceles occur most commonly in S. aureus and P. jiroveci pneumonia, but they also may occur in infections due to E. coli and S. pneumoniae Pneumothorax is a common complication, which occurs secondary to a ruptured pneumatocele or extensionofanair-filled lung abscess into the pleura (Fig. 8). Differential Diagnosis Unfortunately, the clinical data and radiographic findings often fail to lead to a definitive diagnosis of pneumonia, because there are many noninfectious processes associated with febrile pneumonitis. Pulmonary edema and the acute respiratory distress syndrome are the most common conditions that must be distinguished from bronchopneumonia when a generalized pulmonary abnormality is demonstrated radiographically. Localized pulmonary disease with a lobar or segmental distribution can be produced by bronchogenic carcinoma, lymphoma, pulmonary infarction, and vasculitis. Noninfectious inflammation can also be related to adverse References 1. 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