Version May 2024
INTRODUCTION — Slow or incomplete resolution of pneumonia despite treatment is a common clinical problem, estimated to be responsible for approximately 15 percent of inpatient pulmonary consultations and 8 percent of bronchoscopies [1]. There are a variety of reasons that a case of pneumonia might resolve slowly or incompletely, including those relating to the etiology of the pneumonia (misdiagnosis of the pathogen or the presence of a resistant pathogen); those relating to the host, including mechanical processes; and the development of complications from the initial infection. In addition, noninfectious etiologies of pulmonary infiltrates can mimic infectious pneumonia, thus making it appear that resolution is not following the expected course. Approximately 20 percent of presumed nonresponding community-acquired pneumonia is due to noninfectious causes [2]. Despite the frequency of this problem, there has been a paucity of studies specifically addressing this issue.
In this review, we will use the term "nonresolving pneumonia" to include those cases of presumed pneumonia that progress, resolve slowly, or fail to achieve complete resolution despite what is thought to be appropriate therapy. We will first discuss those factors that normally affect the resolution of pneumonia, and we will then focus on specific causes of nonresolving pneumonia.
Aspiration pneumonia, community-acquired pneumonia, hospital-acquired pneumonia, ventilator-associated pneumonia, and the approach to fever and pulmonary infiltrates in the immunocompromised patient are discussed separately.
●(See "Aspiration pneumonia in adults".)
●(See "Epidemiology, pathogenesis, and microbiology of community-acquired pneumonia in adults".)
●(See "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults".)
●(See "Clinical presentation and diagnostic evaluation of ventilator-associated pneumonia".)
●(See "Approach to the immunocompromised patient with fever and pulmonary infiltrates".)
Persistent illness following COVID-19 is also discussed separately. (See "COVID-19: Evaluation and management of adults with persistent symptoms following acute illness ("Long COVID")".)
EXPECTED RESOLUTION OF PNEUMONIA — The rate of resolution of pneumonia is not easily defined and may vary depending upon the underlying cause. Patients typically note subjective improvement within three to five days of treatment; more specific clinical criteria for resolution include improvement in tachycardia and hypotension, which are expected to improve in two days; fever, tachypnea, and arterial oxygenation (PaO2), which are expected to improve within three days; and cough and fatigue, which may take 14 days or longer to improve (table 1) [3,4]. The 2009 British Thoracic Society guidelines for the management of community-acquired pneumonia suggest that chest radiograph and hospitalization be considered for outpatients with pneumonia who fail to improve after 48 hours of treatment [5].
Most studies on the natural history of pneumonia have focused upon the resolution of chest radiographic abnormalities, with "slow resolution" often being defined as the persistence of radiographic abnormalities for greater than one month in a clinically improved host [6,7].
Determining whether a patient has nonresolving or progressive pneumonia must also take into account several factors that affect the expected rate of resolution. These include:
●Comorbidities – Comorbid conditions often slow the resolution of pneumonia (table 2). Whereas patients without associated medical illnesses usually demonstrate clearing of radiographic infiltrates by four weeks, only 20 to 30 percent of patients with a comorbid condition will clear by four weeks [8,9].
●Age – Approximately 90 percent of patients younger than 50 years of age show radiographic resolution by four weeks, compared with only 30 percent of patients older than 50, even in the absence of concurrent disease [10].
●Severity – Radiographic resolution of severe pneumonia is estimated at 10 weeks, compared with three to four weeks for mild to moderate pneumonia.
●Infectious agent – The rate of radiographic and clinical improvement varies with the particular infectious agent causing the pneumonia. In general, resolution is more rapid with Mycoplasma pneumoniae, nonbacteremic Streptococcus pneumoniae, Chlamydia species, and Moraxella catarrhalis than with other organisms [11].
EVALUATION OF NONRESOLVING PNEUMONIA — Evaluation of patients with an apparent nonresolving pneumonia generally centers around more detailed imaging studies and obtaining material for microbiologic and pathologic analysis (algorithm 1). While there are many potentially useful, noninvasive techniques to clarify the initial diagnosis, these may be limited by the difficulty of obtaining sputum in frail or immunocompromised patients. These groups are likely to constitute a larger proportion of those whose pneumonia fails to resolve. For example, heavy growth on expectorated sputum of a dominant organism would be extremely helpful in narrowing the differential diagnosis but may be hampered by the difficulty of obtaining adequate sputum samples. Improved molecular and immunologic techniques for specific viral or bacterial pathogens have improved the diagnostic yield in patients with initial presentation of pneumonia [12] but have not been studied in slowly or nonresolving pneumonia.
Approach to diagnosis — The diagnostic evaluation of treatment failure in pneumonia begins with a careful history, physical examination, and review of the medical record.
Whether or not the rate of resolution is within the range of expected norms, takes the patient's underlying host factors, comorbidities, severity of illness, and suspected pathogen into account. In stable or slowly improving pneumonia, especially in the presence of comorbidities or host factors that are known to delay the resolution of pneumonia, careful observation with or without therapy is warranted for four to eight weeks. If there is no resolution or progression of disease, a more aggressive diagnostic approach is appropriate [13,14].
If further evaluation is necessary, it should include appropriate basic laboratory studies as used in initial diagnosis and a chest computed tomography (CT) to look for sequestered areas of infection or for findings that suggest an alternative diagnosis. When pneumonia fails to resolve or when there is clinical progression, bronchoscopy should be considered. Patients with a negative bronchoscopic examination have a good chance of merely having a slowly resolving pneumonia, particularly if they are smokers or over age 55. Diseases not readily or typically diagnosed with bronchoscopy include pulmonary vasculitis syndromes, cryptogenic organizing pneumonia, and diffuse alveolar damage of various etiologies. With a worsening chest radiograph and progressive symptoms accompanied by a negative bronchoscopy, further evaluation with thoracoscopic or open lung biopsy may be necessary (algorithm 1).
Imaging studies — The initial diagnosis of pneumonia will generally have been made on a chest radiograph. Three general patterns can be seen: (1) focal segmental or lobar, (2) multifocal, and (3) focal or diffuse interstitial changes, each with a different differential diagnosis [15].
CT can more accurately define areas of ground glass opacity, consolidation, and air bronchograms and is the primary radiographic tool for assessing treatment failure of a presumed pneumonia. Compared with conventional chest radiography, high-resolution chest CT allows superior detection of underlying parenchymal abnormalities, including emphysema, airspace disease, interstitial disease, and nodules. Such findings may narrow the differential diagnosis or suggest reasons for resolution failure. Chest CT also detects sequestered foci of infection, such as lung abscess and empyema, and helps direct biopsy procedures. (See "High resolution computed tomography of the lungs".)
Bronchoscopy — The relative ease and low risk of bronchoscopy make this the primary diagnostic procedure to obtain specimens from patients with a wide spectrum of possible infectious and noninfectious etiologies of nonresolving or progressive pneumonia. However, despite the frequency of its use for this indication, there are few studies that document the diagnostic yield of bronchoscopy for nonresolving pneumonia.
Objective data suggest that bronchoscopy with bronchoalveolar lavage and transbronchial biopsy can successfully diagnose approximately 90 percent of patients who eventually have a specific diagnosis established [16]. It is most likely to be useful in younger nonsmoking patients with multilobar involvement and prolonged disease, whereas older adult patients, smokers, and those with immunodeficiency are more likely to have a nondiagnostic bronchoscopy and to have a slowly resolving pneumonia [16]. In a study in an Indian population, bronchoscopy found pyogenic infection to be the most common cause of nonresolving pneumonia (53 percent), followed by bronchogenic cancer (27 percent), and tuberculosis (17 percent) [17]. However, causes of nonresolving pneumonia vary considerably with geography. Bronchoscopy is particularly useful to exclude mycobacteria or fungi if not detected with expectorated sputum [14]. Bronchoalveolar lavage may be useful in identifying noninfectious cause of nonresolving pneumonia, such as acute or chronic eosinophilic pneumonia. Similarly, if there is concurrent mediastinal lymphadenopathy and sarcoidosis is in the differential diagnosis, endobronchial ultrasound guided transbronchial needle aspiration will be useful [18] (algorithm 1).
Thoracoscopic or open lung biopsy — Several factors need to be considered when deciding to proceed to a more invasive biopsy procedure, such as thoracoscopic or open lung biopsy. A previous nondiagnostic bronchoscopy, concern about the specific patient's risk or ability to tolerate bronchoscopy, or the need for obtaining larger specimens of tissue for certain diagnoses may all support the need for proceeding to thoracoscopic or open lung biopsy (algorithm 1).
INFLUENCE OF SPECIFIC BACTERIAL PATHOGENS — The rate of clinical and radiologic resolution of bacterial pneumonia varies depending on the specific bacterial pathogen. It should be noted that the empiric approach to treatment of community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP) suggested by most guidelines can result in failure to treat appropriately when pneumonia is the result of less common pathogens, like anaerobes and fungi.
Streptococcus pneumoniae — Because pneumococcal pneumonia represents the most common cause of CAP, it also is responsible for most cases of nonresolving pneumonia syndromes that are due to infection. In normal individuals without predisposing illness, clinical improvement is relatively rapid and precedes radiographic improvement. (See "Pneumococcal pneumonia in patients requiring hospitalization".)
Risk factors for delayed resolution of auscultatory findings and fever include more severe presentation, multilobar disease, and infection with drug-resistant organisms. (See 'Resistant bacterial pathogens' below and "Treatment of community-acquired pneumonia in adults in the outpatient setting" and "Treatment of community-acquired pneumonia in adults who require hospitalization".)
Radiographic improvement is often much slower, with 20 to 30 percent of patients demonstrating no radiographic improvement after one week. Initial worsening of the chest radiograph is common. Risk factors for delayed radiographic resolution include bacteremia, persistent fever or leukocytosis beyond six days, advanced age, chronic obstructive pulmonary disease, alcoholism, and HIV.
Radiographic clearing occurs by one to three months in nonbacteremic cases and three to five months in bacteremic cases. Residual radiographic abnormalities are rare in nonbacteremic cases but are present in up to 35 percent of bacteremic cases [19].
Legionella infection — Many of the risk factors for development of Legionella are also risk factors for delayed resolution. These include cigarette smoking, alcoholism, age greater than 65 years, immunosuppression (especially glucocorticoid use), chronic kidney disease, and hematopoietic stem cell and solid organ transplantation. As a result, the rate of resolution for Legionella infection is usually slower than for other organisms [20]. (See "Clinical manifestations and diagnosis of Legionella infection".)
Radiographic, but not necessarily clinical, deterioration despite treatment is common, occurring in up to two-thirds of patients with Legionella, compared with 4 percent of patients with nonbacteremic pneumococcal pneumonia. In addition, after this initial deterioration, resolution is slow, with clearing beginning only after two to three weeks and approximately one-half of patients demonstrating residual abnormalities at 10 weeks. Resolution may take as long as 6 to 12 months, and residual fibrosis may be evident in up to 25 percent of patients.
In addition to the slowly resolving or residual radiographic abnormalities, patients may experience generalized weakness and fatigue for months. Residual abnormalities on pulmonary function testing may be seen as long as two years later.
Mycoplasma pneumoniae — M. pneumoniae is a common cause of respiratory tract infection but a rare cause of severe pneumonia. Resolution is typically rapid and faster than that with other types of pneumonia [1]. Significant clinical improvement usually occurs within the first two weeks, which may in part reflect the predominantly young and otherwise healthy population affected.
Radiographic deterioration after treatment is rare, occurring in less than 25 percent of cases. The average duration of radiographic abnormalities is two to four weeks, depending upon the use of antibiotics. Forty percent have complete radiographic resolution at four weeks and 90 percent at eight weeks. Residual radiographic abnormalities are distinctly unusual. (See "Mycoplasma pneumoniae infection in adults".)
Chlamydia pneumoniae — Chlamydia pneumoniae infection is an uncommon cause of pneumonia, but it has been implicated in outbreaks of pneumonia in residents of long-term care facilities and military recruits. It is a relatively mild disease, and mortality is rare [21]. Prompt resolution is the rule in younger patients. (See "Pneumonia caused by Chlamydia pneumoniae in adults".)
Radiographic deterioration is uncommon, with clearing typically occurring in less than three months. Fifty percent of chest radiographs clear within four weeks, while up to 20 percent take longer than nine weeks. Residual radiographic abnormalities persist in 10 to 20 percent of cases. Much information regarding Chlamydia resolution is derived from observations of patients with psittacosis [9].
Haemophilus influenzae — Haemophilus influenzae is commonly considered a cause of pneumonia, especially in older adults, in cigarette smokers, and in patients with chronic obstructive lung disease. However, several large series following the widespread use of conjugate vaccines against H. influenzae type b in children have shown a decreasing incidence of infection and a shift to nontypeable strains compared with the more invasive type b infection [22,23]. (See "Epidemiology, clinical manifestations, diagnosis, and treatment of Haemophilus influenzae".)
The natural history of H. influenzae infection has not been well studied, but there do not appear to be any unique features regarding its resolution. Based on the propensity for the organism to infect the immunocompromised and older adults, resolution is often slow, with many patients having prolonged hospitalization. Only 50 percent of patients return to their previous level of function by six weeks [22].
COVID-19 — Persistent illness following COVID-19 is also discussed separately. (See "COVID-19: Evaluation and management of adults with persistent symptoms following acute illness ("Long COVID")".)
MISDIAGNOSIS OF PATHOGENS — Alternative pathogens in addition to the usual bacterial causes of pneumonia need to be considered in the patient who fails to respond to treatment (table 3). Particularly important pathogens in this category include mycobacteria (either Mycobacterium tuberculosis or atypical mycobacteria), fungi, Nocardia, and Actinomyces.
Tuberculosis — Tuberculosis is of significant concern, especially in older adult patients and in those who have immigrated within the past five years, those who have a history of intravenous drug use, and those who have other risk factors for AIDS.
The clinical presentation of tuberculosis as a cause of nonresolving pneumonia is often atypical, especially in diabetics and in older adult patients, who commonly have radiographic findings in the middle or lower lung zones. Diagnosis may be difficult as sputum is not always available and culture results take weeks after the specimen is obtained. Polymerase chain reaction testing has been approved for smear-positive specimens to allow confirmation of tuberculous disease, but its role in smear-negative cases is uncertain. (See "Pulmonary tuberculosis: Clinical manifestations and complications" and "Diagnosis of pulmonary tuberculosis in adults".)
Fungi — Both opportunistic and endemic fungal infections can mimic bacterial pneumonia [24]. These infections may present with "rounded" or mass-like densities with or without cavitation. In the patient with an apparent nonresolving pneumonia, Aspergillus is a particularly important pathogen, presenting either as chronic necrotizing or as invasive aspergillosis. Patients with advanced AIDS are at increased risk of invasive aspergillosis, while patients with less advanced disease may develop tracheobronchitis (image 1).
Although invasive aspergillosis classically occurs in neutropenic patients who have been on multiple antibiotics for several days, it is increasingly recognized in older adult patients with chronic lung disease who are on corticosteroids. Aspergillus in this setting may mimic a bacterial infection, and one series demonstrated that patients with invasive aspergillosis were treated for an average of 18 days with multiple antibiotics before the diagnosis was established [19]. (See "Epidemiology and clinical manifestations of invasive aspergillosis".)
Endemic fungal infections such as histoplasmosis, coccidioidomycosis, blastomycosis, and cryptococcosis should be considered as a cause of nonresolving pneumonia in the appropriate endemic areas (image 2) [25]. These include the Mississippi River Valley for histoplasmosis, the southwestern United States for coccidioidomycosis, and the southeast and Midwest for blastomycosis. Each of these fungi can cause a nonspecific acute febrile illness, which may be confused with community-acquired pneumonia. Histoplasmosis has worldwide distribution and should be considered in travelers to high-prevalence countries.
Nocardia and Actinomyces — Although Nocardia and Actinomyces are higher-order bacteria, the clinical presentation of infection due to these organisms is more consistent with a fungal etiology. Nocardia infection presents most commonly on chest radiograph as a localized alveolar infiltrate that is usually homogeneous, nonsegmental, and cavitary. Infection due to Actinomyces has a similar appearance but with a propensity to extend across fissures and invade the chest wall. (See "Treatment of nocardiosis".)
RESISTANT BACTERIAL PATHOGENS — The presence of a resistant pathogen is an important consideration for any pneumonia that is not responding appropriately to antibiotic therapy. Although penicillin-resistant Streptococcus pneumoniae (pneumococcus) is the organism of most concern, multidrug-resistant H. influenzae and Pseudomonas aeruginosa as well as methicillin-resistant Staphylococcus aureus are increasingly recognized in the community setting as possible causes of a nonresolving or recurrent pneumonia. (See "Resistance of Streptococcus pneumoniae to beta-lactam antibiotics" and "Epidemiology, clinical manifestations, diagnosis, and treatment of Haemophilus influenzae" and "Pseudomonas aeruginosa pneumonia" and "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of bacteremia".)
HOST FACTORS — A variety of host factors may be associated with delayed resolution of pneumonia, including alcoholism, older age, and the presence of comorbid diseases, such as diabetes and chronic obstructive lung disease. In addition, disorders of immune function, particularly AIDS and syndromes associated with deficient humoral immunity, can be associated with delayed resolution of pneumonia.
AIDS — Although unrecognized Pneumocystis jirovecii (formerly P. carinii) pneumonia remains an important diagnostic consideration in patients with AIDS and a CD4 count <200 cells/mm3, the most common initial lower respiratory tract infection in this patient population remains bacterial pneumonia, especially pneumococcal pneumonia. It is important to consider the possibility of underlying HIV infection in patients with nonresolving or progressive pneumonia. The Infectious Disease Society of America recommends routine testing for HIV infection in patients with community-acquired pneumonia between the ages of 15 and 54 occurring in hospitals in which the rate of newly diagnosed HIV infection exceeds 1 case per 1000 discharges. (See "Bacterial pulmonary infections in patients with HIV".)
Primary humoral immune deficiencies — It is important to identify primary humoral immune deficiency as an underlying risk factor for pneumonia because of the effect of treatment with intravenous immune globulin (IVIG) on the incidence and resolution of pneumonia. Specific disorders commonly associated with hypogammaglobulinemia include X-linked agammaglobulinemia, common variable immune deficiency, and selective immunoglobulin (Ig)G subset deficiency. The most common pathogens in these patients include S. pneumoniae and H. influenzae, with M. pneumoniae and P. jirovecii being less common. (See "Primary humoral immunodeficiencies: An overview" and "Severe combined immunodeficiency (SCID): An overview".)
DEVELOPMENT OF COMPLICATIONS FROM THE INITIAL PNEUMONIA — Sequestered foci of infection may prevent adequate concentrations of antibiotic agents from reaching the site of infection. The two main forms of sequestered focus preventing adequate resolution of pneumonia are empyema and lung abscess.
Empyema — Empyema is now a rare complication of community-acquired pneumonia (CAP). This was illustrated in a review of 3675 patients with CAP in which empyema was diagnosed by the attending physician in 1.3 percent and by strict laboratory criteria in 0.7 percent [26]. The patients with empyema were more likely to be younger and to use illicit drugs. The most common cultured pathogen was Streptococcus milleri, suggesting a role for aspiration. (See "Infections due to the Streptococcus anginosus (Streptococcus milleri) group", section on 'Thoracic infections'.)
Evaluation of a possible empyema is initially facilitated by imaging techniques such as computed tomography (CT) and ultrasound. In a patient with nonresolving pneumonia, demonstration of any significant amount of pleural fluid should prompt consideration of a diagnostic thoracentesis to rule out empyema. (See "Epidemiology, clinical presentation, and diagnostic evaluation of parapneumonic effusion and empyema in adults".)
Lung abscess — Anaerobes are the dominant flora of the upper airways and common pathogens in aspiration pneumonia and its sequelae: necrotizing pneumonia and lung abscess. The major pathogens are Peptostreptococcus spp, Bacteroides melaninogenicus, and Fusobacterium nucleatum. These infections are often subtle in onset and relatively slow in progression. Patients typically present with fever, night sweats, weight loss, cough, dyspnea, and putrid sputum with or without pleurisy.
Predisposing factors that should raise the suspicion of abscess formation include alcoholism, seizures, poor oral hygiene, and previous aspiration. Chest radiography typically demonstrates an air-liquid level in a dependent segment (posterior segment of an upper lobe or posterior segment of a lower lobe), but chest CT is more sensitive and can confirm the diagnosis in difficult cases.
Most patients with lung abscess do well with conservative management and a prolonged course of antibiotics. However, several factors are associated with increased abscess-related mortality and may warrant a more aggressive approach. These include age-related factors (pediatric or older adult populations), large cavity size, longer duration of symptoms prior to therapy, lower lobe location, association with malignant disease, and the presence of multiple abscesses. The development of infection in pre-existing bullae may be mistaken for lung cancer. (See "Lung abscess in adults".)
NONINFECTIOUS ETIOLOGIES — A variety of noninfectious etiologies of pulmonary infiltrates can mimic pneumonia and therefore represent causes of presumed nonresolving pneumonia. These generally fall into the categories of neoplastic, inflammatory, drug-induced, and vascular disease (table 4). Some of these noninfectious etiologies may also be associated with nonresolving pneumonia through other pathophysiologic mechanisms, such as endobronchial obstruction by bronchogenic carcinoma.
Neoplastic disorders — Neoplasms may be associated with nonresolving pneumonia either by compromise of the airway lumen and secondary postobstructive pneumonia or abscess or by mimicking an infiltrative process. Bronchogenic carcinoma and carcinoid tumors are the most common cause of endobronchial obstruction leading to pneumonia, whereas bronchioloalveolar cell carcinoma (adenocarcinoma in situ) and lymphoma are the most common causes of an alveolar infiltrate mimicking pneumonia.
●Bronchogenic carcinoma compromises the airway lumen either through endobronchial involvement or extrinsic compression. However, the frequency of endobronchial carcinoma as a cause of nonresolving pneumonia is relatively low, ranging from 0 to 8 percent in most series [16].
●Endobronchial obstruction by a carcinoid tumor is an important predisposing factor for a postobstructive pneumonia and should be considered as a possible etiology for endobronchial obstruction in a young or nonsmoking patient. (See "Lung neuroendocrine (carcinoid) tumors: Epidemiology, risk factors, classification, histology, diagnosis, and staging", section on 'Clinical features'.)
●Lung adenocarcinoma may present as a focal infiltrate, often with air bronchograms, and ground-glass infiltrates with a "subsolid" appearance, thus mimicking the radiographic appearance of pneumonia. Patients with bronchioloalveolar cell carcinoma may present with a discrepancy between the size of the infiltrate and the paucity of systemic symptoms [27].
●Lymphoma in the lung may also present with focal alveolar infiltrates with air bronchograms, mimicking the radiographic appearance of pneumonia. Lymphoma affecting the lung parenchyma may occur either as part of a systemic disease or as primary pulmonary lymphoma. Three categories of clonal lymphoid proliferation are now recognized as producing pulmonary parenchymal involvement: low-grade B cell lymphoma arising from mucosal tissue (MALT), high-grade B cell lymphoma, and lymphomatoid granulomatosis. Primary pulmonary lymphoma is unusual, with only 10 percent of Hodgkin lymphoma and 4 percent of non-Hodgkin lymphomas presenting with an alveolar infiltrate. As the disease progresses, lung involvement becomes more common, occurring in 38 percent of patients with Hodgkin lymphoma and 24 percent with non-Hodgkin lymphoma. Chest CT may be particularly useful in patients with suspected Hodgkin lymphoma, since mediastinal lymphadenopathy is common [28]. (See "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)" and "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma" and "Pulmonary lymphomatoid granulomatosis".)
In a prospective study in which 30 hospitalized patients with postobstructive pneumonia due to malignancy were compared with 60 patients with bacterial pneumonia, those with postobstructive pneumonia due to malignancy had a longer duration of symptoms (14 versus 5 days) and were more likely to have weight loss and cavitary lesions but were less likely to have leukocytosis [29].
Inflammatory disorders — Numerous inflammatory disorders can mimic and be misdiagnosed as pneumonia. Because these disorders do not respond to antibiotics, they should be considered in the evaluation of patients with an apparently nonresolving pneumonia.
●Systemic vasculitis or rheumatic diseases may cause fever, dyspnea, and pulmonary infiltrates and therefore can be easily mistaken for pneumonia. Granulomatosis with polyangiitis and the alveolar hemorrhage syndromes are the most frequent vasculitides to mimic pneumonia. Bronchoscopy and bronchoalveolar lavage are useful to establish the diagnosis of alveolar hemorrhage (image 3). (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Respiratory tract involvement" and "The diffuse alveolar hemorrhage syndromes".)
●Cryptogenic organizing pneumonia (previously called bronchiolitis obliterans organizing pneumonia) presents typically with a subacute onset, with 75 percent of patients having symptoms less than two months at the time of diagnosis. Idiopathic BOOP usually begins with a flu-like illness mimicking an atypical (community-acquired) pneumonia, with fever, malaise, fatigue, dyspnea, and dry cough. Patients may have an elevated sedimentation rate and leukocytosis. Patchy alveolar infiltrates are typically present on chest radiograph, often mimicking a pneumonia. (See "Cryptogenic organizing pneumonia".)
●Eosinophilic pneumonias, including both chronic and acute forms, are characterized by collections of eosinophils in the interstitial and alveolar spaces [30,31]. Chronic eosinophilic pneumonia typically presents as a subacute illness with cough, fever, dyspnea, weight loss, wheezing, night sweats, and radiographic infiltrates appearing over weeks to months. Chest radiographs often demonstrate patchy, nonsegmental alveolar infiltrates that predominantly affect the periphery of the lungs, sparing the central and basilar regions. Patients typically have a rapid clinical and radiographic response to treatment with corticosteroids. (See "Chronic eosinophilic pneumonia".)
Acute eosinophilic pneumonia has a more rapid onset of fever, nonproductive cough, dyspnea, and pleuritic chest pain. Chest radiograph early in the course may show only subtle reticular or ground-glass infiltrates, which can progress to bilateral diffuse alveolar disease and acute respiratory distress syndrome (ARDS). As in chronic eosinophilic pneumonia, response to corticosteroids is often dramatic. Data suggest significant clinical overlap between eosinophilic pneumonia syndromes [32]. (See "Idiopathic acute eosinophilic pneumonia".)
●Acute interstitial pneumonia is a rare, idiopathic form of diffuse alveolar damage, thus corresponding to a clinical picture compatible with idiopathic ARDS [33,34]. Patients typically present after a prodromal period of up to 14 days with the onset of fever, cough, and dyspnea. Chest radiographs usually demonstrate bilateral airspace disease, and chest CT characteristically shows patchy or diffuse areas of ground-glass attenuation. The effectiveness of corticosteroids is not clear, and mortality is approximately 70 percent. (See "Acute interstitial pneumonia (Hamman-Rich syndrome)".)
●Pulmonary alveolar proteinosis (PAP) is a rare diffuse lung disease characterized by the abnormal accumulation of lipoproteinaceous fluid in the distal airspaces [35]. Patients typically present with the insidious onset of dyspnea, fatigue, weight loss, and low-grade fever. Chest radiographs often demonstrate nonspecific central alveolar opacities in the lower and mid-lung zones with sparing of the areas adjacent to the diaphragm and heart. High-resolution CT commonly has a "crazy paving" appearance, characterized by a ground-glass pattern with thickening of the intralobular and interlobular septa to produce polygonal shapes. (See "Causes, clinical manifestations, and diagnosis of pulmonary alveolar proteinosis in adults".)
●Sarcoidosis may be confused with a nonresolving pneumonia when patients have pulmonary parenchymal disease without intrathoracic adenopathy and in the absence of clinically apparent extrapulmonary involvement. (See "Clinical manifestations and diagnosis of sarcoidosis".)
Drug-induced lung disease — Drug-induced lung disease can be confused with an infectious pneumonia, and a careful evaluation of medication history should be done in patients with an apparent nonresolving pneumonia to rule out a drug-related etiology. Amiodarone toxicity is a particularly important mimic of nonresolving pneumonia as it may have an acute presentation with focal alveolar infiltrates (see "Amiodarone pulmonary toxicity"). Other drugs of concern include methotrexate (see "Methotrexate-induced lung injury"), nitrofurantoin (see "Nitrofurantoin-induced pulmonary injury"), bleomycin (see "Bleomycin-induced lung injury"), and systemic antineoplastic therapy (See "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment".)
In addition to traditional antineoplastic agents, many new, increasingly used biologic modifiers are associated with significant respiratory symptoms and radiograph abnormalities. Anti-tumor necrosis factor-alpha agents have been associated with an increased risk of tuberculosis as well as other bacterial and fungal infections. These may have unusual or atypical features. Tyrosine kinase inhibitors like erlotinib, now frequently used in advanced adenocarcinoma of the lung, may be associated with interstitial lung disease and acute lung injury. Everolimus, which is used to treat progressive renal cell carcinoma, has been associated with interstitial pneumonitis in up to one-third of patients (table 5) [36]. Although uncommon, persistent infiltrates resulting from newer antineoplastic checkpoint inhibitors is increasingly seen and may be confused with a prolonged resolution of an infectious pneumonia. Overlap of infectious and drug-induced pneumonitis is common in patients receiving chemotherapy and radiation [37].
Pulmonary embolism — Pulmonary embolism can rarely mimic pneumonia, based on the radiographic findings of pulmonary infiltrates in up to 30 percent and pleural effusions in approximately 20 percent of cases. Infiltrates, representing areas of pulmonary infarction, may take several weeks to resolve and are easily mistaken for slowly resolving pneumonia. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism".)
Hydrostatic pulmonary edema — Unusual or focal radiographic patterns of hydrostatic pulmonary edema can occasionally mimic pneumonia. Pulmonary edema can have a focal presentation limited to areas of increased perfusion, as in patients with bullous lung disease or mitral regurgitation. Because pulmonary edema appears most prominent in areas of maximal perfusion, patients with severe chronic obstructive pulmonary disease may manifest asymmetric patterns of pulmonary edema. Fluid may be trapped in a fissure and look like a mass (“pseudotumor”); this is more common in patients with pre-existing pleural abnormalities.
Congenital abnormalities — A pulmonary sequestration can mimic pneumonia, generally appearing as an area of consolidation, usually in a lower lobe. Extralobar sequestrations are more common in males than females and appear to be congenital. Intralobar consolidations may be acquired early in life. Either type may be asymptomatic and thus not discovered until adulthood.
Bronchogenic cysts are also usually asymptomatic and found incidentally on chest imaging. They are most common in the middle mediastinum and fluid density. Large cysts can lead to bronchial obstruction or can become infected.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Community-acquired pneumonia in adults".)
SUMMARY AND RECOMMENDATIONS
●Prevalence – Slow or incomplete resolution of pneumonia despite treatment is a common clinical problem, estimated to be responsible for approximately 15 percent of inpatient pulmonary consultations and 8 percent of bronchoscopies. (See 'Introduction' above.)
●Expected rate of resolution – Normal resolution of pneumonia is not easily defined and may vary depending upon the underlying cause. Patients typically note subjective improvement within three to five days of treatment; more specific clinical criteria for resolution include improvement in fever, cough, crackles, leukocytosis, arterial oxygenation (PaO2), and level of C-reactive protein (table 1). Determining whether a patient has nonresolving or progressive pneumonia must also take into account several factors that affect the expected rate of resolution, including comorbidities, age, severity, and etiology (table 2 and table 3). (See 'Expected resolution of pneumonia' above.)
●Evaluation of nonresolving pneumonia – Evaluation of patients with an apparent nonresolving pneumonia generally centers around more detailed imaging studies or obtaining material for microbiologic and pathologic analysis (algorithm 1). (See 'Evaluation of nonresolving pneumonia' above.)
●Influence of specific pathogens – Data are available regarding resolution of pneumonia caused by different etiologic agents, including factors that affect the course of particular types of pneumonia. (See 'Influence of specific bacterial pathogens' above.)
●Misdiagnosis – Alternative pathogens, in addition to the usual bacterial causes of pneumonia, need to be considered in the patient who fails to respond to treatment (table 3). Particularly important pathogens in this category include mycobacteria (either Mycobacterium tuberculosis or atypical mycobacteria), fungi, Nocardia, and Actinomyces. (See 'Misdiagnosis of pathogens' above.)
●Antimicrobial resistance – The presence of a resistant pathogen is an important consideration for any pneumonia that is not responding appropriately to antibiotic therapy. (See 'Resistant bacterial pathogens' above.)
●Host factors – A variety of host factors may be associated with delayed resolution of pneumonia, including alcoholism, older age, and the presence of comorbid diseases such as diabetes and chronic obstructive lung disease. In addition, disorders of immune function, particularly AIDS and syndromes associated with deficient humoral immunity, can be associated with delayed resolution of pneumonia. (See 'Host factors' above.)
●Complications – Sequestered foci of infection may prevent adequate concentrations of antibiotic agents from reaching the site of infection. The two main forms of sequestered focus preventing adequate resolution of pneumonia are empyema and lung abscess. (See 'Development of complications from the initial pneumonia' above.)
●Noninfectious causes – A variety of noninfectious etiologies of pulmonary infiltrates can mimic pneumonia and therefore represent causes of presumed nonresolving pneumonia. These fall into the categories of neoplastic, inflammatory, drug-induced, and vascular disease (table 4). (See 'Noninfectious etiologies' above.)
ACKNOWLEDGMENT — UpToDate gratefully acknowledges John G Bartlett, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.
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