Etiologies of Nonresolving Pneumonia

Infectious Etiologies

If the initial diagnosis of an infectious etiology is correct, factors that can lead to a progressive or nonresolving pneumonia need to be assessed. These factors include those associated with the:

• Pathogen
• Host
• Therapy.

Pathogen Factors

Alternative or unusual pathogens need to be considered in the patient who fails to respond to treatment. Although there is a potentially unlimited number of unusual pathogens that may cause nonresolving pneumonia, several warrant special attention (Table 10-1). Among these, the most important to consider are:

• TB or other mycobacteria, including MAI and Mycobacterium abscessus
• Fungi
• Nocardia and Actinomyces spp.

In addition, the possibility of a relatively common pathogen with resistance needs to be considered. The role of methicillin-resistant Staphylococcus aureus (MRSA) is becoming increasingly important, even in community-acquired pneumonia (CAP).

Tuberculosis

There has been an increase in the incidence of tuberculosis (TB) recently, and in certain populations, The suspicion of TB should be particularly high in:

• Recent immigrant populations
• Unhoused individuals
• Incarcerated individuals
• Patients with a history of IV drug abuse
• Patients with HIV and acquired immunodeficiency syndrome (AIDS).

In the years since the COVID-19 pandemic began, the proportion of TB cases in immigrants to the United States (US) has increased; this may reflect increased migration from regions where the incidence of TB is higher. In addition, elderly patients should also be considered at higher risk for TB, since these patients still represent one of the largest repositories of TB in the United States. Infections in the elderly will usually represent reactivation disease, since the majority were infected 60 to 80 years ago. However, studies of epidemic spread in nursing homes indicate that new infections are also possible, so a high index of suspicion is necessary. The use of chronic (>1 month) therapeutic anti-TNF monoclonal antibodies and Janus kinase (JAK) inhibitors (e.g., for rheumatoid arthritis, inflammatory bowel disease, and psoriatic arthritis) has been linked to increased risk of TB.

The clinical presentation of TB as a cause of nonresolving pneumonia will often be subtle, especially in elderly patients. Atypical findings, such as nonspecific mid-lobe or lower-lobe changes, are common. Similarly, up to one third of adult patients with newly diagnosed TB have atypical findings, irrespective of age. Thus, the classic presentation of a cavitary infiltrate in the apical or posterior segments of one or both upper lobes may not always be present.

In this setting, the diagnosis of TB may be difficult. Tuberculin testing and QuantiFERON may be negative in 10% to 20% of patients with active disease and in an even higher percentage of elderly patients and patients with acquired immunodeficiency syndrome (AIDS). Gamma interferon production by macrophages in blood has compared favorably with tuberculin testing has generally supplanted this venerable test in routing screening and case finding. Sputum acid-fast cultures are positive in up to 80% of cases, but sputum is not always easy to obtain, especially in elderly patients. Because culture results may take up to 6 weeks, newer methods, including the BAC-TEC culture system, are recommended to decrease the time needed to establish a diagnosis. Polymerase chain reaction testing has been approved for smear-positive specimens to allow confirmation of tuberculous disease, but its role in smear-negative patients is increasing and may allow diagnosis from remote sites where organism load is low, such as pleura and colony-stimulating factor (CSF).

Fungi

Both opportunistic as well as endemic fungi may mimic bacterial pneumonia. Of the opportunistic fungi, Aspergillus is the most important. The spectrum of pulmonary Aspergillus infections includes:

• Benign mycetomas
• Chronic necrotizing aspergillosis or subacute invasive aspergillosis
• Invasive pulmonary aspergillosis.

Of these various forms, it is the chronic necrotizing/subacute invasive forms that are most likely to be mistaken for bacterial pneumonia.

Chronic necrotizing aspergillosis represents a semi-invasive form of infection and is most commonly seen in the setting of preexisting chronic lung disease, often with ongoing corticosteroid use. It may also be seen at the interface of a mycetoma and the normal lung. This syndrome represents the result of a host immune response that is not completely able to hold the infection in check but which is not strong enough to eradicate it. The radiographic infiltrate is persistent and progressive, affecting the upper lobes more frequently.

Invasive aspergillosis is classically described as affecting neutropenic patients who have been on multiple antibiotics for several days. However, it is important to realize that aspergillosis is being increasingly recognized in two new groups of patients. The first group is elderly patients with chronic lung disease who are on corticosteroids. In these cases, aspergillosis may mimic a bacterial infection, leading to significant delays in therapy. In one series, patients with invasive aspergillosis were treated an average of 18 days with multiple antibiotics before the diagnosis was made. In many of these cases, the diagnosis was only established postmortem.

The second new group at risk for Aspergillus infection are patients with AIDS. Patients with advanced AIDS are at increased risk for invasive aspergillosis. In addition, patients with less advanced disease (infection with HIV) may develop one of three different patterns of tracheobronchitis that may mimic nonresolving pneumonia. These three patterns are:

• Obstructive bronchial aspergillosis
• Ulcerative tracheobronchitis
• Pseudomembranous tracheobronchitis.

Obstructive bronchial disease is characterized by thick mucous plugs filled with Aspergillus with little mucosal involvement. Ulcerative tracheobronchitis is characterized by additional mucosal and cartilaginous involvement. Pseudomembranous tracheobronchitis develops when there is extensive inflammation and invasion of the tracheobronchial tree with formation of a pseudomembrane of hyphae and necrotic debris. Thus in addition to the traditional neutropenic patient, the diagnosis of Aspergillus as a cause of nonresolving pneumonia should be considered in the elderly immunocompromised patient and in those with advanced AIDS.

The other major group of fungal infections that need to be considered as a cause of nonresolving pneumonia are the endemic fungi. The endemic fungi share many common clinical characteristics. A careful history is important since each fungus can be found in certain geographic areas. H capsulatum can be found in the Mississippi River valley, C immitis in the southwestern United States, and B dermatitidis in the southeast and midwest United States. In the case of both histoplasmosis and coccidioidomycosis, most inhabitants will have immunologic evidence of prior exposure. Each of these fungi can cause a nonspecific acute febrile illness, which is usually self-limited and may easily be confused with CAP.

The more difficult cases involve those patients who develop chronic and progressive disease. This usually involves the upper lobes and may be cavitary, often leading to a misdiagnosis of TB. Although blastomycosis is classically described as being mass-like and coccidioidomycosis is described as producing thin-walled cavities, none of these fungi can be reliably separated on the basis of chest radiograph findings.

In general, when the chest radiograph suggests TB but smears are negative for acid-fast organisms, these fungal infections should be considered. In addition, patients with HIV infection are at particularly high risk for disseminated infection with both histoplasmosis and coccidioidomycosis. Early consideration of these possibilities is essential in this group.

A combination of potassium hydroxide smear and culture of sputum may provide the diagnosis. Serology is generally not useful for histoplasmosis and blastomycosis. IgM antibodies for coccidioidomycosis may be clinically useful and typically rise in the first 2 weeks, disappearing by the end of 1 month. Skin testing is available for histoplasmosis but is not useful since active infection cannot be distinguished from prior exposure and 90% of inhabitants in an endemic area can be expected to test positive. Although many experts believe skin testing is useful for coccidioidomycosis, a single skin test is not enough to document the onset of infection. It is therefore more useful to use skin testing as an epidemiologic tool rather than a specific diagnostic test in individual patients.

Nocardia and Actinomyces

Although Nocardia and Actinomyces are classified as higher order bacteria, both behave in a fashion more consistent with the pulmonary mycoses. Both result in a chronic pulmonary disease that is difficult to diagnose because of the difficulty in isolating these pathogens. Nocardia can only be grown aerobically if cultures are examined for up to 4 weeks, while Actinomyces requires strict anaerobic conditions with enriched media. Both are gram-positive organisms with branching filamentous pseudohyphae. Nocardia frequently stains positive on acid-fast smear, but Actinomyces is rarely positive. Because these organisms have relatively specific culture requirements and are difficult to stain, communication with the microbiology laboratory is essential when there is clinical suspicion of disease caused by either.

Patients with Nocardia infection present with a subacute or chronic condition, including cough, purulent sputum, and night sweats. Infection frequently occurs in the setting of underlying malignancy or pulmonary alveolar proteinosis (PAP). Disseminated infection may occur, with the most serious consequence being central nervous system involvement with brain abscess. The most common radiographic presentation is that of a localized alveolar infiltrate that is usually homogenous, nonsegmental, and often cavitary. Infection with Actinomyces has similar clinical and radiographic features, with the exception being the propensity of actinomycosis to extend across fissures and to involve the chest wall.

Resistant Pathogens

An important consideration in the approach to any pneumonia is the possibility of antibiotic resistance. In particular, the possibility of multidrug-resistant Streptococcus

pneumoniae (MDRSP) must be considered when evaluating patients with nonresolving pneumonia. MDRSP was first described in the 1960s in Australia and New Guinea. In surveys from some European regions, up to 60% of pneumococci demonstrate intermediate-level (MIC 0.12–1.0 mg/mL) or high-level (MIC >2 mg/mL) resistance. In the United States, resistance rates are lower but are rising, mimicking the trends seen previously in Europe.Despite concerns about increasing resistance, the clinical significance of MDRP strains remains uncertain and nonsusceptibility remains uncommon, although local patterns can vary considerably. Likewise, there is little evidence pointing to significant increases in macrolide, tetracycline, or quinolone resistance although these can factor in specific cases of poorly responding pneumonia. In patients with nonresolving pneumonia, it is reasonable to investigate the possibility of drug resistance as a contributing factor. The suspicion of penicillin-resistant Streptococcus pneumoniae (PRSP) should be especially high in cases of nonresolving pneumonia associated with risk factors for drug resistance. The risk factors for infection with PRSP include:

• Prior antibiotic therapy within 6 months
• Pneumonia within 1 year
• Hospitalization in the prior 3 months
• Hospital-acquired infection
• Immunosuppression
• Alcoholism
• Age <6 years or >70 years
• Contact with child in day care.

Of these factors, the most significant in univariate and multivariate analyses is prior β-lactam use, especially cephalosporins.

Once MDRSP is either suspected or isolated, it becomes important to determine the level of penicillin resistance and the sensitivity pattern of the organism. The majority of MDRSP strains have intermediate resistance to penicillin, defined as an MIC >0.1 and <2.0 mg/mL. In the setting of intermediate resistance to penicillin, increasing the dose of penicillin to 12 to 18 million units per day is effective. Isolates with an MIC >2 mg/mL are defined as having high-level resistance and these cases should be treated with agents other than penicillin, based upon their susceptibility testing.

Alternative agents include cefotaxime, ceftriaxone, imipenem, newer fluoroquinolones (levofloxacin, moxifloxacin, delafloxacin) and vancomycin. Importantly, sensitivity patterns for cephalosporins do not necessarily follow penicillin-susceptibility patterns. Pneumococcal isolates that have intermediate resistance to penicillin may have high-level resistance to cephalosporins. Therefore, sensitivity to cephalosporins and carbapenem agents should be confirmed in cases of PRSP. Similarly, since macrolide resistance is less prevalent, these drugs may be useful alternatives, but their use still requires confirmation of sensitivity. If erythromycin resistance is demonstrated, clarithromycin, azithromycin, and clindamycin should not be used, since there is significant cross-resistance. Newer fluoroquinolones, including levofloxacin, moxifloxacin, and delafloxacin have demonstrated activity against PRSP and may be considered in cases of PRSP. Finally, vancomycin is the most reliable treatment for infection with PRSP since resistance to vancomycin has not yet been reported in the United States. Vancomycin should be used in combination in all cases of MDRSP meningitis. Although MRSA is considered primarily a hospital pathogen, it is increasingly recognized as a community pathogen. MRSA pneumonia is associated with a more prolonged course and higher mortality in ventilator-associated pneumonia (VAP) (Table 10-2).

Host Factors

The effect of various host factors, including comorbidities such as alcoholism, diabetes, chronic obstructive pulmonary disease (COPD), and age on the normal rate of resolution of pneumonia, has been discussed previously (see Natural History of Pneumonia). Most host factors cannot be altered and therefore do not necessarily impact directly on treatment. However, certain disorders of immune function warrant special attention because the underlying defect can be at least partially treated if recognized. These include AIDS and syndromes associated with deficiencies of humoral immunity.

Acquired Immunodeficiency Syndrome

With the experience gained from the HIV epidemic, most physicians are aware of P carinii pneumonia (PCP) as a cause of respiratory compromise in the HIV-infected patient. PCP was among the most common diseases associated with AIDS, being the initial manifestation in approximately two thirds of cases in older series. With the use of widespread prophylaxis, the dominance of PCP among the pulmonary pathogens associated with HIV has decreased, but it remains an important consideration. Bacterial pneumonia is now the most common initial lower respiratory tract infection in AIDS patients. Because of this, it is important to consider the possibility of HIV infection in patients with nonresolving pneumonia. If the diagnosis of unrecognized HIV is made, the spectrum of possible pathogens changes dramatically. The Infectious Disease Society of America (IDSA) recommends routine testing for HIV infection in patients with CAP between the ages of 15 and 54 occurring in hospitals where the rate of newly diagnosed HIV infection exceeds one case per 1000 discharges. Conditions that are much more likely in this setting and need to be considered in these cases include cryptococcal pneumonia, endemic fungi, TB and PCP.

Primary Humoral Immune Deficiencies

Primary humoral immune deficiencies are due to inherited defects in antibody production. While there is a large number of diseases associated with secondary disorders of humoral or cellular immunity, the importance of identifying primary humoral immune deficiency syndromes lies in the fact that treatment with IV immune globulin (IVIG) has an effect on the incidence and resolution of pneumonia. The disorders most commonly associated with hypogamma­globulinemia in which IVIG is indicated include X-linked agammaglobulinemia, common variable immune deficiency (CVID), selective IgG subset deficiency, and hypogammaglobulinemia with IgM.

All of these disorders are characterized by defects in the steps necessary for production of immunoglobulins, from intrinsic defects within the B cell itself to problems with B-cell/T-cell interactions. The resulting deficiencies in immunoglobulin production lead to impaired opsonization and complement activation. Thus patients with relative or absolute hypogamma­globulinemia are prone to recurrent and refractory sinopulmonary tract infections with encapsulated organisms, leading to nonresolving pneumonias. Infections typically begin in infancy or early childhood so that most cases are recognized by the time patients reach adulthood. Importantly, certain disorders, most notably CVID and IgG subclass deficiency, may present in an atypical fashion at a later age. The most common pathogens in these patients include S pneumoniae and H influenzae, with Mycoplasma and P carinii being less common.

Monthly IVIG maintenance therapy markedly reduces the incidence and severity of pneumonia in these patients. Currently, protocols require maintenance infusions every 2 to 4 weeks to maintain a trough level of >400 mg/dL. When patients with primary humoral immune deficiencies develop pneumonia, additional supplemental IVIG is warranted for treatment of the acute disease and facilitates resolution and decreases severity.

Therapy-Related Factors

When pneumonia fails to respond appropriately to treatment, certain aspects related to therapy need to be considered. These include consideration of possible medication errors as well as assuring adequate concentrations of antibiotics at the site of infection.

With respect to medication errors, it is especially important to carefully check dosing schedules, compliance and when appropriate, drug levels. If intermediate-level multidrug-resistant Streptococcus pneumoniae (MDRSP) is present, higher doses of penicillin will be required as previously discussed. Similarly, if Pneumocystis carinii pneumonia (PCP) is suspected, higher doses of trimethoprim/sulfamethoxazole (TMP/SMX) will be required. When aminoglycosides are used, it is important to check levels and adjust the dosing regimen accordingly. Similarly, as renal function changes, drug doses may require readjustment. In addition, since aminoglycosides do not penetrate the lung well, when utilizing a traditional dosing regimen it may be necessary to aim for higher peak concentrations, especially when treating infection caused by Pseudomonas. The effect of decreased pulmonary penetration on aminoglycoside efficacy using a once-daily dosing regimen has not yet been studied for pneumonia and remains unclear.

Inhaled aminoglycosides allow for increased local antibiotic concentration but have been used primarily in cystic fibrosis (CF) with poorly controlled Pseudomonas infections.

The other aspect of therapy is to guarantee that adequate levels of drug are reaching the site of infection by ruling out sequestered foci of infection. The two main forms of sequestered foci that may prevent adequate resolution of pneumonia are:

• Empyema
• Lung abscess.

Empyema evaluation can be facilitated by a variety of imaging techniques, including chest computed tomography (CT) and ultrasound. In the patient with nonresolving pneumonia, demonstration of any significant amount of pleural fluid should lead to consideration of a diagnostic thoracentesis to rule out empyema. Although the exact criteria for defining empyema remain controversial, in the setting of a nonresolving or progressive pneumonia, it is prudent to aggressively evaluate all effusions for possible chest tube drainage. A pH <7.20, positive Gram’s stain, positive culture, or demonstration of grossly purulent fluid should prompt drainage.

Pulmonary abscesses are the other sequestered infectious foci that can lead to nonresolving pneumonia. Predisposing factors that should raise the suspicion of abscess formation include:

• Alcoholism
• Seizures
• Poor oral hygiene
• Previous aspiration.

A chest radiograph typically will demonstrate an air-fluid level, but a chest CT scan is more sensitive and can confirm the diagnosis in difficult cases. Because most patients with lung abscesses do well with conservative management and a prolonged course of antibiotics, it is important to identify those factors associated with increased abscess-related mortality that may warrant a more aggressive approach. Factors that adversely affect the prognosis in patients with lung abscess include:

• Advanced age
• Pediatric age
• Large cavity size
• Longer duration of symptoms prior to therapy
• Lower lobe location
• Association with malignant disease
• Multiple abscesses
• Alcoholism
• Immunosuppression.

Intrabronchial aspiration is a contributing factor in fatal cases of lung abscess and has led to the recommendation that controlled drainage and improved physical measures be used to avoid intrabronchial spread. Thus although routine drainage is not necessary in all patients, in those at high risk and in those with nonresolving pneumonia, drainage should be considered.

A variety of techniques have been utilized to drain abscesses. These include:

• Bronchoscopic aspiration
• CT-guided aspiration
• Ultrasound-guided aspiration.

However, some attempts at bronchoscopic aspiration have actually led to intrabronchial aspiration and acute respiratory distress syndrome (ARDS). Thus if bronchoscopic aspiration is considered, it should probably be limited to carefully selected patients where there is a high level of local expertise.

Noninfectious Etiologies

Many noninfectious diseases may mimic pneumonia by presenting with persistent pulmonary infiltrates. The major categories of disease that warrant consideration as mimics of pneumonia include diseases that are (Table 10-3):

• Neoplastic
• Immunologic
• Drug induced
• Vascular.

Neoplastic

Neoplasms may cause a nonresolving pneumonia syndrome in one of two ways:

• By causing a postobstructive pneumonia or abscess
• By appearing as infiltrative processes with air bronchograms.

Neoplasms that cause postobstructive pneumonias and abscesses are most commonly bronchogenic carcinomas. Those that present as alveolar infiltrates include lymphoma and adenocarcinoma.

Bronchogenic Carcinoma

In cases of postobstructive pneumonia, the tumor occludes the bronchi either by endobronchial involvement or extrinsic compression. Bronchoscopy remains the method of choice for detecting endobronchial obstruction, since it allows for the simultaneous collection of biopsy and cytology specimens that are over 95% sensitive and specific for endobronchial malignancies. However, the overall frequency of endobronchial carcinoma as a cause of nonresolving pneumonia is surprisingly low, ranging from 0% to 8%. Despite this low prevalence, the relatively low risk of bronchoscopy makes it an appropriate consideration in those at especially high risk for lung cancer (e.g., cigarette smokers older than 50 years of age).

Adenocarcinoma

Various sub types of adenocarcinoma of the lung may be slow growing and frequently involve the small peripheral airways and alveolar spaces. Adenocarcinoma may present as a focal alveolar infiltrate, often with air bronchograms, mimicking the radiographic appearance of pneumonia. Consolidation occurs in up to one third of cases, involving both segmental and lobar areas. Other radiographic appearances include pulmonary nodules and diffuse or multicentric alveolar infiltrates. The local form has a good prognosis, while the diffuse and multicentric forms have a worse prognosis.

Lymphoma

Lymphoma in the lung may present with focal alveolar infiltrates with air bronchograms, mimicking the radiographic appearance of pneumonia. When lymphoma affects the lung parenchyma, it may occur either as part of a systemic disease or as a true primary pulmonary lymphoma. Although lymphoma may initially present with radiographic evidence of pulmonary parenchymal involvement, it is rare, with only 10% of Hodgkin’s and 4% of non-Hodgkin’s lymphomas presenting with initial parenchymal pulmonary involvement. However, in both cases, as the disease progresses, lung involvement becomes progressively more common, rising to 38% of Hodgkin’s and 24% of non-Hodgkin’s cases. If pulmonary Hodgkin’s is suspected, a CT scan of the chest may be especially useful, since mediastinal lymphadenopathy is almost invariably present. Importantly, in cases of non-Hodgkin’s lymphoma as well as Hodgkin’s associated with HIV, mediastinal lymphadenopathy may be absent in up to 50% of cases.

Immunologic Diseases

Many immunologic diseases can be associated with some pulmonary manifestations, and it would be impossible to review each possible presentation that might mimic pneumonia. This discussion will focus on those that can present with an acute onset, have frequent pulmonary manifestations, and be manifested with a paucity of extrapulmonary symptoms. These include:

• Systemic vasculitis
• Cryptogenic organizing pneumonia (COP)
• Eosinophilic pneumonia syndromes
• AIP/nonspecific interstitial pneumonia (NSIP)
• PAP (Pulmonary Alveolar Proteinosis)
• Sarcoidosis.

Systemic Vasculitis

Fever, dyspnea and pulmonary infiltrates may be the initial manifestation of systemic vasculitis or a connective tissue disorder and may be easily mistaken for CAP. In most patients, extrapulmonary symptoms will be prominent and a prior history of vasculitis will be present. However, when extrapulmonary symptoms are lacking, differentiating pulmonary vasculitis from severe CAP may be difficult. Furthermore, patients with a previously established diagnosis of vasculitis are frequently on immunosuppressive agents for their vasculitis and are therefore prone to opportunistic infections. Distinguishing a nonresolving infectious process from worsening vasculitis or alveolar hemorrhage can be especially difficult in these immunocompromised patients (Table 10-4).

Wegener’s granulomatosis (WG) and the alveolar hemorrhage syndromes are the most frequent vasculitides to mimic pneumonia. Elevated serum antineutrophil cytoplasmic antibodies, acute renal insufficiency, rapidly filling hemoglobin, or hemoptysis should suggest possible vasculitis, but in many cases biopsy is necessary to confirm the diagnosis.

Cryptogenic-Organizing Pneumonia

Cryptogenic-Organizing Pneumonia (COP) is characterized by the proliferation of granulation tissue in the respiratory bronchioles and alveolar ducts associated with chronic inflammation in the adjacent alveoli. COP may occur in association with a variety of other disorders, in which case it is a secondary form of COP. It may also occur in an isolated form, in which case it is idiopathic COP. This discussion will focus on the idiopathic form.

COP typically occurs in the fifth or sixth decade of life, with men and women being equally affected. The onset is typically subacute, with 75% of patients having symptoms <2 months in duration at the time of diagnosis. The typical presentation begins with a flu-like illness mimicking CAP, with fever, malaise, fatigue, dyspnea and dry cough. Rales are common, being present in approximately 75% of patients, but wheezes are rare as is clubbing. Laboratory tests are nonspecific, with the most common findings being an elevated sedimentation rate and leukocytosis.

The chest radiograph demonstrates bilateral, diffuse alveolar infiltrates, often with a peripheral distribution. Up to half of all patients will have recurrent or migratory infiltrates. Linear, interstitial and cavitary lesions are rare, as are pleural effusions and pleural thickening. CT scan typically reveals patchy, alveolar infiltrates with consolidation, ground-glass changes, and bronchial wall thickening. Rarely, patients may progress rapidly to respiratory failure.

The diagnosis requires demonstration of the characteristic histologic pattern in the absence of other concurrent disease. Transbronchial biopsy is often insufficient to establish this diagnosis, since the histologic features of bronchiolitis obliterans-organizing

Pneumonia (BOOP) can be seen with a variety of other disorders. Therefore, surgery remains the gold standard for diagnosis, although clinical diagnosis is often employed.

Eosinophilic Pneumonia Syndromes

The common pathologic feature of the eosinophilic pneumonia syndromes is the collection of eosinophils in the interstitial and alveolar spaces. Other pathologic findings that may be present to varying degrees include lymphocytic interstitial pneumonia, COP, and usual interstitial pneumonia. Only two syndromes within this category are rapidly progressive and limited to the pulmonary system such that they are frequently mistaken for pneumonia. These are CEP and AEP.

Chronic Eosinophilic Pneumonia

Chronic Eosinophilic Pneumonia (CEP) may often present as a subacute illness with cough, fever, dyspnea, weight loss, wheezing, night sweats and radiographic infiltrates. With this constellation of findings, it is frequently mistaken for an infectious pneumonia or TB.

CEP occurs most commonly in middle-aged adults, although it can occur at any age. Women are affected twice as often as men. Atopy is common, occurring in up to 50% of patients. Asthmatic symptoms occur in 30% to 50% of patients and are usually of recent onset. The onset is insidious and the course variable, with symptoms present for weeks prior to the time of diagnosis. Peripheral blood eosinophilia is present in >80% of patients and may be very high. Other nonspecific laboratory abnormalities include an elevated sedimentation rate, IgE levels, thrombocytosis and iron deficiency anemia.

The chest radiograph demonstrates patchy, nonsegmental, alveolar infiltrates that tend to spare the central and basilar regions, resulting in a pattern termed “the photographic negative of pulmonary edema.” CT scan sometimes better delineates this peripheral pattern of disease, but the pattern is not pathognomonic and is not always present. This photonegative pulmonary edema pattern should at least prompt consideration of the diagnosis of CEP. Other radiographic patterns that can be seen in CEP include diffuse bilateral infiltrates and lobar consolidation.

The diagnosis of CEP is usually suspected on clinical grounds based on the chest radiograph pattern, blood eosinophilia and clinical history. However, examination of tissue is still necessary to confirm the diagnosis. The distinctive feature of CEP is elevated bronchoalveolar lavage (BAL) eosinophilia, typically in the 20% to 70% range. Transbronchial biopsy usually demonstrates interstitial and alveolar eosinophils and histiocytes. Multinucleated giant cells with a granulomatous component may be present as well. The sensitivity of BAL eosinophilia and transbronchial lung biopsy is such that open-lung biopsy is rarely needed to establish the diagnosis.

Fewer than 10% of patients will improve without treatment. Corticosteroids are the mainstay of therapy, with complete remission being the rule. Radiographic and clinical improvement can be expected within 2 to 3 days, with radiographic resolution by 3 weeks. Lack of a prompt response to corticosteroids should prompt reevaluation and consideration of other alternative diagnosis.

Acute Eosinophilic Pneumonia

Although acute eosinophilic pneumonia (AEP) is characterized by eosinophilic infiltration of the lung parenchyma similar to that seen in CEP, the two syndromes seem to be distinct clinical entities.

AEP occurs most commonly from the ages of 20 to 40, although it can occur at any age. Men are affected twice as often as women. An outbreak of severe AEP was recently reported in military personnel serving in the Middle East. There is no relationship to smoking, and unlike CEP, most patients do not have a history of asthma or atopy. In contrast to CEP, the onset of AEP is rapid, usually manifesting in <7 days. AEP typically presents with the onset of fever, nonproductive cough, dyspnea and pleuritic chest pain. Constitutional symptoms are common, including malaise, myalgia and night sweats. The most common findings on physical examination are fever, tachypnea, occasional rhonchi and bibasilar crackles. Laboratory findings are similarly nonspecific. The peripheral eosinophil count usually becomes markedly elevated during the course of disease, but may be normal at presentation. Respiratory failure with ARDS may occur.

Early in AEP, the chest radiograph may only show subtle reticular or ground-glass infiltrates. High-resolution CT (HRCT) is more sensitive, demonstrating progressive, bilateral, patchy, ground-glass infiltrates, often located along the bronchovascular bundles. As the disease progresses, bilateral diffuse alveolar and reticular changes are seen. Unlike CEP, the infiltrates are not localized to the periphery. Small effusions occur in up to two thirds of patients and are frequently bilateral. If thoracentesis is done, these effusions typically demonstrate a high pH with marked eosinophilia.

The distinctive feature of AEP is the markedly elevated number of eosinophils in the BAL fluid. Typically >25% of BAL cells are eosinophils, along with an increased proportion of BAL lymphocytes and neutrophils. Transbronchial biopsy usually demonstrates extensive eosinophilic parenchymal involvement, frequent diffuse alveolar damage, an organizing fibrinous exudate, hyaline membranes, type II cell hyperplasia and the absence of granulomas or hemorrhage.

Response to corticosteroids is frequently dramatic, occurring within 48 hours, and failure to respond should prompt the consideration of an alternative diagnosis. In contrast to CEP, there should be no further episodes of relapse during long-term follow-up.

Acute Interstitial Pneumonia

Acute interstitial pneumonia (AIP) is a rare, idiopathic form of diffuse alveolar damage. Hamman and Rich described AIP in 1935 and classified it with idiopathic pulmonary fibrosis. However, it is now recognized that AIP is separate and distinct from idiopathic pulmonary fibrosis and probably corresponds to a subset of idiopathic ARDS.

AIP typically occurs in young healthy adults. There are no known risk factors and both sexes are affected equally. The median age is 43, with a range of 7 to 83 years of age. AIP typically presents after a prodromal period of up to 14 days with the abrupt onset of fever, cough and dyspnea. Chest radiographs usually demonstrate bilateral airspace disease. CT scan of the chest typically reveals patchy or diffuse areas of ground-glass attenuation. The disease is similar to ARDS, but unlike ARDS, there are none of the usual risk factors such as sepsis, shock, trauma, or pneumonitis. Unlike idiopathic pulmonary fibrosis, the onset and progression of the disease is very rapid. Most patients develop hypoxic respiratory failure, and mechanical ventilation is often required. Mortality is high, ranging from 60% to 100% in several series, with an average of approximately 70%. It is unclear whether corticosteroids are beneficial in AIP, although most clinicians would favor a trial of corticosteroids once infectious etiologies have been ruled out. The most common findings on biopsy are those of a proliferative picture of diffuse alveolar damage. Importantly, these features of diffuse alveolar damage are nonspecific and other diagnoses must be ruled out. Open or thoracoscopic biopsy may be necessary to rule out other etiologies.

PAP

PAP, also known as pulmonary alveolar phospholipoproteinosis, is a rare diffuse lung disease characterized by the abnormal accumulation of lipoproteinaceous fluid in the distal airspaces. PAP probably represents a histopathologic syndrome caused by multiple etiologies. Histopathologic findings similar to PAP can be found in cases of silicoproteinosis, aluminum dust exposure, titanium exposure, hematologic malignancies, immunosuppressive disorders and opportunistic infections. However, despite these associations, the majority of cases of PAP are not associated with any of these risk factors and fall into the category of idiopathic PAP.

PAP typically presents with the insidious onset of dyspnea, fatigue, weight loss and low-grade fever. Most patients have a nonproductive cough, but occasionally a history of producing chunky or gelatinous material may be obtained. The age at presentation is usually 30 to 50 years, with men outnumbering women 2 to 1. Physical examination is remarkably normal in most patients, often with normal lung exams despite marked alveolar filling. Laboratory findings are nonspecific, with polycythemia and elevated LDH being common.

Tests that can help differentiate PAP from other causes of nonresolving pneumonia include chest radiography, HRCT, serum surfactant proteins, BAL fluid analysis, and either open-lung biopsy or transbronchial biopsy. Chest radiographs typically demonstrate nonspecific central alveolar opacities in the lower-lung and mid-lung zones with marked sparing of the areas adjacent to the diaphragm and heart. HRCT will often reveal a ground-glass appearance with thickening of the intralobular and interlobular septa in a pattern of polygonal shapes, frequently referred to as a “crazy-paving” appearance. Elevated serum levels of surfactant proteins A and D have been demonstrated in PAP. These are not specific to PAP and can also be found in idiopathic pulmonary fibrosis. While none of these findings are diagnostic of PAP, they should raise the suspicion of PAP and can narrow the diagnostic possibilities.

BAL, transbronchial biopsy, or open biopsy can confirm the diagnosis. BAL demonstrates characteristic findings of PAP, including milky appearing, periodic acid–Schiff (PAS)-positive fluid, macrophages filled with PAS-positive material, and acellular eosinophilic granules. Transbronchial biopsy is distinctive for preserved alveolar architecture with minimal thickening of the septa and scant inflammatory infiltrates. Terminal bronchioles and alveoli are flooded with a PAS-positive lipoproteinaceous fluid consisting of phospholipids.

In contrast to many of the other noninfectious mimics of pneumonia, there is no role for immuno­suppressives or corticosteroids in PAP. Indeed, PAP may exist with concurrent infections and predisposes to superinfections with Nocardia, opportunistic fungi, and MAI. It is therefore critical to rule out concurrent infection, and corticosteroids should be avoided since there have been reports that they may increase mortality. More recent work has shown that, in ~90% of patients, PAP is an autoimmune process affecting granulocyte monocyte colony-stimulating factor (GM-CSF) and some patients will respond to administration of this agent.

Sarcoidosis

Sarcoidosis is a chronic granulomatous disease of unknown etiology that affects multiple organ systems, most frequently the lungs, skin and eyes. Because sarcoidosis usually has extrapulmonary organ system involvement, it is rarely confused with other causes of nonresolving pneumonias. Evidence of extrapulmonary disease that should raise the suspicion of sarcoidosis includes extrathoracic lymphadenopathy, skin lesions (e.g., erythema nodosum, lupus pernio, or sarcoid plaques) and uveitis. Clinically significant extrapulmonary involvement in other organ systems is much less common, with asymptomatic histologic evidence of involvement being the rule.

Chest radiographs typically demonstrate hilar adenopathy in >70% of cases, but parenchymal infiltrates in the absence of adenopathy may be present in up to 25% of cases. Histology typically demonstrates a nonspecific pattern of noncaseating granulomas with multinucleated giant cells and lymphocytes. In contrast to its use in many other interstitial lung diseases, bronchoscopy with transbronchial biopsy has an excellent diagnostic yield, in the range of 75% to 95%.

Since the finding of noncaseating granulomas is relatively nonspecific and may be found in other infectious and noninfectious granulomatous disorders, reserving therapy for those patients with severe or progressive disease is warranted. Therapy in such cases typically consists of corticosteroids given for several weeks to months.

Drug-Induced Pneumonitis

The number of drugs and therapeutic agents that may cause pulmonary toxicity is large and ever-growing. Mechanisms of injury include direct toxic effects, idiosyncratic reactions and immune-mediated mechanisms. With some exceptions, the diagnosis of drug-induced lung disease is one of exclusion. Clinical findings, histology, chest radiographs and even HRCTs are relatively nonspecific. Most reactions are not dose-related, but some reactions can occur weeks to years after the medication is discontinued. Effectively ruling out drug-induced lung disease in the setting of a nonresolving pneumonia thus requires careful evaluation of every drug that the patient is receiving or has recently received. A list of agents commonly associated with pulmonary toxicity that may mimic pneumonia is shown in Table 10-4. While it is impossible to review all of the drugs with pulmonary toxicity, this section will focus on agents that have unusual or characteristic findings that may mimic pneumonia. These include amiodarone, methotrexate and bleomycin. Many newer biologic modifiers and monoclonal antibodies, including the commonly used anti-TNF agents rituximab (Rituxan) and azacitidine (Vidaza), have been associated with variable lung pathologies. Immune checkpoint inhibitors (ICIs; CTLA-4, PD-1 and PD-L1 inhibitors), used widely in controlling malignancy, are associated with pulmonary syndromes that may be confused with infectious pneumonia.

Amiodarone

Amiodarone is associated with a wide variety of pulmonary presentations, including interstitial pneumonitis, mass lesions, COP, hypersensitivity pneumonitis, eosinophilic pneumonitis, DAH, asthma-like syndromes, pleural effusions and lymphocytic interstitial pneumonitis. One unusual association of amiodarone toxicity is the possible association with postoperative ARDS. There are a number of reports of ARDS occurring postsurgery in patients on amiodarone, typically within 18 to 72 hours. Some investigators have observed unilateral lung injury postoperatively, with only the ventilated lung being involved. Whether this represents potentiation of amiodarone toxicity by supplemental oxygen remains unclear.

The exact incidence of these complications is difficult to define, with most estimates being around 5% in the literature. There is no good way to identify those patients at particularly high risk for amiodarone toxicity. Men are affected more commonly than women, and pulmonary toxicity is more common in those with other pulmonary comorbidities. Most patients who develop toxicity are on 400 mg/day for ≥2 months; therefore, this toxicity has become less common. As with most forms of drug toxicity, clinical and radiographic findings are otherwise nonspecific. Symptoms may be acute or insidious in onset. Pleurisy is uncommon, occurring in 10% of cases, with pleural effusions also being uncommon but reported. Chest radiograph is nonspecific, ranging from focal alveolar infiltrates to peripheral infiltrates to mixed alveolar-interstitial patterns. Because amiodarone is an iodinated compound, its density on noncontrast high-resolution CT scan may be increased. While not sensitive, this is one of the few highly specific radiographic findings that, when present, can definitively establish a diagnosis.

Therapy for suspected amiodarone toxicity is corticosteroids and discontinuation of the drug. In those rare instances when there are no suitable alternative antiarrhythmic agents, corticosteroids combined with reducing amiodarone to the lowest possible dose may be effective.

Methotrexate

Methotrexate has been associated with many syndromes that may mimic pneumonia, including bronchospasm, COP, pleural effusions, eosinophilic pulmonary infiltrates, noncardiogenic pulmonary edema (from intrathecal methotrexate) and a hypersensitivity type of pneumonitis. Because opportunistic infection is a well-documented complication with even low-dose methotrexate, it is particularly important to rule out concurrent infection and to look for signs that may differentiate drug toxicity from infection. In patients receiving chemotherapeutic doses of methotrexate, there are well-described cases of a hypersensitivity pneumonitis-like reaction, with about half of patients reporting both lung and blood eosinophilia. Granulomas are also frequently associated with this reaction, and occasionally hilar adenopathy has been reported.

Patients receiving lower doses of methotrexate for anti-inflammatory purposes have a slightly different presentation. About 5% of patients receiving a chronic low dose of methotrexate develop a subacute interstitial process with fever, hypoxia, rales and cough. Eosinophilia in this syndrome is rare, but poorly formed granulomas are still seen on biopsy. Nitrofurantoin potentiates this syndrome and deaths have been reported. Treatment is drug withdrawal and corticosteroids.

Bleomycin

Bleomycin has been associated with a wide variety of complications, including pulmonary fibrosis, BOOP/COP, eosinophilic infiltrates, pulmonary veno-occlusive disease and an acute pneumonitis reaction similar to hypersensitivity. Up to 20% of patients on bleomycin develop pulmonary reactions and 1% die of pulmonary complications. Risk factors include age >70 years and dose >450 units. There is a marked synergy between bleomycin and high levels of inspired oxygen. This is often encountered after general anesthesia, typically manifesting about 18 hours later as ARDS. Other reported synergistic insults include the concurrent use of G-CSF. Treatment in all cases includes minimizing inspired oxygen content and corticosteroids. Lung toxicity and infiltrates have been reported with these recently introduced agents, including α-interferon and anti-TNF monoclonal antibodies.

Immune Checkpoint Inhibitors

Immune checkpoint inhibitors a class of drugs that inhibit the regulatory pathways that antagonize T-cell activation, which in healthy individuals is a mechanism of immune tolerance and functions to prevent the development of autoimmunity. Because ICIs enhance T-cell activation, in cancer patients they allow T cells to more effectively target tumor cells. Several ICIs have demonstrated good safety and efficacy for the treatment of many solid and hematologic cancers; to date, ICIs that have received FDA approval include a CTLA-4 inhibitor (ipilimumab), PD-1 inhibitors (pembrolizumab, nivolumab, cemiplimab) and PD-L1 inhibitors (atezolizumab, durvalumab, avelumab). However, because they inhibit the mechanisms that suppress autoimmunity, ICIs are also associated with a unique set of immune-related adverse events (irAEs). In contrast to chemotherapy, ICI-associated irAEs are often organ-specific; when ICI-mediated immune potentiation damages lung tissue, pneumonitis may occur.

Clinical presentations of ICI-associated pneumonitis are nonspecific and can range from asymptomatic cases to those with symptoms like dyspnea, cough and less frequently, fever and chest pain. Radiologically, the most common manifestations of ICI-associated pneumonitis include organizing pneumonia, nonspecific interstitial pneumonia and hypersensitivity pneumonitis. Bronchoalveolar lavage typically reveals increased lymphocyte levels and tissue biopsies show T-cell infiltration.

The incidence of pneumonitis among patients treated with ICIs has been estimated in several studies to range from 3% to 19%, depending on the population and the specific ICI used, but the overall incidence appears to be closer to 3%. The risk is particularly elevated in patients with preexisting lung disease, including COPD and interstitial lung disease (ILD); with ILD, the incidence can be as high as 31%. Other risk factors include a history of smoking, previous thoracic radiotherapy, non-small cell lung cancer (compared to melanoma), and the use of combination ICIs. Once pneumonitis develops, withholding or discontinuing ICI therapy depends on pneumonitis severity; for grade 1 (asymptomatic) pneumonitis, treatment may continue depending on clinical judgment, but ICIs should be withheld for grade 2 (symptomatic but not severe) pneumonitis until it is treated, and permanently discontinued for grade 3 and 4 (severe) pneumonitis.

The recommended treatment for ICI-related pneumonitis is corticosteroid therapy. For grade 1 pneumonitis, close monitoring or low-dose corticosteroids (0.5-1 mg/kg/day) are recommended, while for grade 2 and grade ≥3 pneumonitis, corticosteroids at 1-2 mg/kg/day or 2-4 mg/kg/day, respectively, are recommended. After symptoms improve, corticosteroids should be carefully tapered over the course of at least 6 weeks. Empiric antibiotic therapy should be considered for patients with grade 2 pneumonitis and administered to all patients with grade 3 and higher pneumonitis. Additional treatments for ICI-associated pneumonitis that are currently being investigated for safety and efficacy include pulsed corticosteroid therapy, the anti-IL-6 antibody tocilizumab and the tyrosine kinase inhibitor nintedanib.

Pulmonary Vascular Disease

Vascular conditions that may mimic pneumonia include pulmonary embolism (PE) and heart failure (HF). PE is a common problem, with radiographic and clinical findings that may easily be mistaken for pneumonia. There are no specific or typical clinical signs and symptoms. Dyspnea is observed in 80% of patients, pleuritic pain in up to 75%, hemoptysis in 20% and wheezing in 15%. Chest radiographs show infiltrates in up to 30% of cases, with effusions being present in 20%. Other radiographic findings include diaphragmatic elevation in 60%, focal oligemia in 10%, enlarged pulmonary arteries in 20% and normal radiographs in 30%. The classic Hampton’s Hump is rarely seen. Infiltrates from PE may take several weeks to resolve and thus are easily mistaken for slowly resolving pneumonia.

The possibility of PE as the cause of a nonresolving pneumonia syndrome should be raised when hypoxia is out of proportion to radiographic findings and fails to improve. PE is more common in patients presenting with CAP.

Although the diagnosis of HF is usually apparent, occasionally unusual radiographic patterns of cardiogenic pulmonary edema may mimic pneumonia. In particular, atypical pulmonary edema patterns have been well described in patients with bullous lung disease and in patients with mitral regurgitation. Because pulmonary edema principally develops in areas of maximal perfusion, patients with marked COPD may manifest asymmetric pulmonary edema patterns. Similarly, if the regurgitant jet associated with mitral valve insufficiency is directed at one of the pulmonary veins, unilateral and focal pulmonary edema patterns may occur. In this setting, echocardiography may be of help to identify the severity and direction of the mitral regurgitation. In borderline cases, transesophageal echocardiogram or catheterization may be necessary to further clarify the issue and is usually definitive.