Clin Chest Med 26 (2005) 143 158

Nonresolving Pneumonia
Cheryl M. Weyers, MD*, Kenneth V. Leeper, MD
Pulmonary Medicine, Emory University, 550 Peachtree Street Northeast, MOT 6th Floor, Atlanta, GA 30308, USA

Inapparent resolution of pulmonary infiltrates is a common consultative problem for the pulmonologist. Nonresolving and slowly resolving pneumonias pose a diagnostic challenge. Operationally, nonresolving pneumonia often represents a noninfectious process that mimics an infectious one. Slowly resolving pneumonia is usually the result of misadventures of antimicrobial therapy or inadequacies of host defense. Although the precise incidence is not well established, early studies report that as many as 25% of patients have slowly resolving or nonresolving disease [1,2]. More recent studies report that 10% of hospitalized patients with community-acquired pneumonia (CAP) [3 5] and as many as 60% of patients with nosocomial pneumonia have inadequate responses to empiric therapy [6] with the consequence of increased mortality [4,7]. Originally described by Amberson [8] in 1943, nonresolving pneumonia has been variably defined. There are several components to successful resolution, including clinical improvement, radiographic resolution, and microbiologic eradication. In 1991 Kirtland and Winterbauer [9] defined delayed radiographic resolution as less than 50% clearance at 2 weeks or complete clearance at 4 weeks. More recently, Fein and colleagues [10] combined clinical and radiographic indices and defined nonresolving pneumonia as slow resolution of radiographic infiltrates or clinical symptoms despite adequate antibiotic therapy. Arbitrarily defined, these investigators required at least 10 days of treatment. Although most reports have examined the time to radiographic improvement, common clinical vari-

* Corresponding author. E-mail address: Cherylweyers@hotmail.com (C.M. Weyers).

ables to assess resolution include fever, sputum purulence, leukocytosis, and oxygenation. Lehtomaki [11] reported the duration of several signs and symptoms of CAP in 55 previously healthy men. Depending on the etiologic diagnosis, the time to defervescence was 2.5 to 4 days. Cough persisted slightly longer, especially in the group with pneumococcal pneumonia; abnormalities on physical examination persisted longer than all symptoms. Combining clinical parameters and chest radiographs into a daily scoring system, Garrard and ACourt [12] evaluated 83 patients with nosocomial pneumonia. Using a modification of the Clinical Pulmonary Infection Score (CPIS) [13], they diagnosed pneumonia and followed its course. An increasing CPIS was observed in the 2 days before the initiation of antimicrobial therapy; if therapy was appropriate, a gradual reduction in the score occurred over the next several days. Use of the CPIS score to define resolution of nosocomial pneumonia was further explored by Luna et al [14]. These investigators prospectively evaluated 63 patients with microbiologically confirmed ventilator-associated pneumonia (VAP). CPIS scores were followed serially and were noted to improve by as early as the third day of therapy in the group of patients who eventually survived. Nonsurvivors failed to demonstrate any improvement in CPIS score. These findings suggest that a clinical scoring system for VAP may be useful in the early identification of patients who are unlikely to respond to therapy or likely to have delayed resolution. Resolution also can be defined microbiologically. Based on serial quantitative cultures from respiratory secretions, the eradication or persistence of an organism can be demonstrated. In the prospective series reported on by Garrard and ACourt [12], nonbronchoscopic lung lavage specimens also were obtained

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in the 83 patients with nosocomial pneumonia. Serial cultures correlated well with the scored clinical responses. Culture counts increased in the few days before the onset of therapy and fell dramatically after its initiation. In most cases, the culture counts decreased by 24 hours but fell no later than 72 hours in all cases of resolving pneumonia. Nonresolving pneumonia was equally well defined by clinical and microbiologic criteria, although clinical nonresponse required more time for its determination.

Pneumonia resolution Normal resolution of pneumonia is variable and depends on the causative agent and the host response to the invading pathogen. In as many as half of cases, the pathogen remains unidentified. In one large series of CAP, Marston et al [15] reported no etiologic diagnosis in 60% of patients despite extensive diagnostic testing. Similarly, Luna and colleagues [16] evaluated 132 patients by bronchoscopy within the first 24 hours of diagnosis. An etiology was found in 65 patients (49%). Most of the patients were receiving antibiotics before the procedure, potentially reducing the diagnostic yield. Difficulty performing sputum Gram stains and the insensitivity of noninvasive diagnostic techniques also contribute to underrecognition. This lack of identification of a causative pathogen greatly hampers the evaluation of slowly resolving and nonresolving pneumonia.

686 patients with CAP. In their prospective analysis, the time to resolution of vital signs was recorded. The group reported stabilization within 2 to 3 days in most cases, and noted that the time to resolution was influenced by disease severity, such that the most severe cases required longer times for recovery. Marrie and coworkers [21] evaluated an ambulatory cohort for 6 weeks to assess the time to symptom resolution. Among 535 patients, the majority had at least one persistent symptom of the disease 6 weeks after the discontinuation of therapy. Fatigue was the most common complaint, present in 67% and 45% of patients at 2 and 6 weeks, respectively. Cough was present in 93% at initial evaluation and remained to at least week 6 in 35%. Multivariate analysis identified younger age, the absence of chronic obstructive pulmonary disease (COPD) or asthma, and the use of levofloxacin as significant predictors of successful resolution. Nosocomial pneumonia Because most studies of resolution have been limited to patients with CAP, the normal resolution of nosocomial pneumonia is more uncertain. Nevertheless, several investigators have identified risk factors for poor outcomes, including death. By inference, the factors promoting a poor outcome can be linked to delayed resolution. Celis and Torres [22] identified prognostic factors for nosocomial pneumonia. They reported that respiratory failure, the presence of a fatal underlying condition, age greater than 60 years, and the presence of bilateral radiographic involvement were associated with a significantly increased risk of mortality. Additionally, infection with a high-risk organism, such as Pseudomonas aeruginosa, Staphylococcus aureus, gramnegative bacilli, candida, and aspergillus species, was associated with worse outcomes. In addition to observing longer resolution times with gram-negative infections, Graybill et al [23] noted the significance of certain host factors. In their 1973 study of 82 patients with nosocomial pneumonia, prolonged resolution was defined as radiographic abnormalities extending beyond 4 weeks. Mortality was higher among patients in whom pneumonia developed postoperatively, while on the ventilator, after aspiration, and while on antibiotic therapy. Other studies of nosocomial pneumonia have identified similar risk factors [24,25]. Montravers [25] was one of the first investigators to compare microbiologic data with clinical outcomes. Serial bronchoscopy and protective-specimen brush (PSB) samples were performed in 76 patients requir-

Patterns of resolution Community-acquired pneumonia Data from patients with CAP reveal that the most carefully documented clinical response is the time to defervescence. Occurring most rapidly with infection owing to Streptococcus pneumoniae, the average duration of fever after the initiation of appropriate therapy is 2.5 days. The time to defervescence for cases owing to Haemophilus is 2.7 days, whereas Legionella commonly requires up to 6 days of therapy for a patient to become afebrile [17,18]. Bacteremic pneumonias may also require more time for clinical resolution, especially in elderly patients [18,19]. Other parameters used to evaluate clinical resolution include the white blood cell count, physical examination, and imaging. Leukocytosis usually resolves by day 4 of therapy, whereas abnormalities on examination may persist beyond 7 days in 20% to 40% of cases [17,20]. Halm et al [20] evaluated

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ing mechanical ventilation. The level of eradication of a pathogen was shown to correlate with subsequent clinical improvement. High-level growth (> 103) on follow-up PSB at 72 hours was more common among patients with persistent symptoms of pneumonia. Despite sterilization of the lung in 94% of patients, clinical resolution occurred in only 20% of cases. To further evaluate the relationship between clinical and microbiologic data, Dennesen [26] and colleagues performed a prospective study in 27 patients with VAP. Temperature, the white blood cell count, and PaO2:FiO2 ratios were scored daily. Semiquantitative cultures of endotracheal aspirates were also obtained at the day of admission and twice weekly thereafter. Unlike the Montravers data [25], persistent bacterial growth was more common with certain pathogens, including pseudomonas and enterobacteriaceae, despite significant clinical improvement. These findings suggest that bacterial eradication is an imperfect marker of clinical response in VAP.

multicenter study [30] of more than 400 individuals with pneumococcal bacteremia reported host factors predictive of mortality. These risk factors were age greater than 65 years, the presence of chronic pulmonary disease, residence in a nursing home, higher Acute Physiology and Chronic Health Evaluation (APACHE) scores, and the need for mechanical ventilation. Additionally, mortality was significantly higher in patents with pneumococcal pneumonia and multilobar involvement (19%) when compared with patients with single lobe involvement (7%). Haemophilus In a prospective multicenter study by Fang et al, [31] Haemophilus was the second most frequently isolated pathogen. Accounting for 2% to 11% of cases of CAP, its incidence has increased over the last decade. Infection with this organism is difficult to confirm, because it is a frequent colonizer of the upper respiratory tract and is readily cultured from the sputum of individuals without pneumonia [32]. The organism often affects immunocompromised patients and the elderly. Patients with advanced COPD are particularly vulnerable. As a result, resolution times may be delayed. Legionella Implicated in as many as 15% of CAPs, legionella was the third most commonly isolated pathogen in the Fang study [31]. Along with S pneumoniae, it is the most common pathogen in cases of severe CAP [31]. The organism now comprises more than 30 species and 50 serotypes. Only a few species are human pathogens; L pneumophila is the most prevalent. Often included with mycoplasma and chlamydia in the category of atypical pneumonias, several large series have revealed that these agents account for at least one third of all CAPs [15,33,34]. Risk factors for infection include smoking and underlying systemic illness, particularly diabetes, endstage renal disease, malignancy, and AIDS. The most severely affected individuals are often African American and tobacco smokers [15]. Given its predilection for the elderly and chronically ill, it is not surprising that prolonged radiographic resolution is common for legionella pneumonia. In fact, the organism is not only associated with the longest time to resolution but also the highest frequency of residual radiographic abnormalities. Macfarlane [28] found that only 50% of patients had normal chest radiographs at 10 weeks, and that residual scarring was present in 19%.

Resolution of pneumonia by pathogen Pneumococcus S pneumoniae is the most common cause of CAP and accounts for most cases of slowly resolving pneumonia. In an early review of slowly resolving infiltrates, Israel and colleagues [2] reported isolation of pneumococcus in 78 of 139 pneumonias attributable to specific organisms. Factors associated with delayed resolution included multilobar disease and bacteremia. Jay [27] monitored 72 patients who were hospitalized for bacteremic pneumococcal pneumonia. Radiographic resolution of the consolidation was achieved in all patients by 10 weeks; however, persistent pleural disease and volume loss were noted in 10% beyond 8 weeks. Delayed clearance was observed more frequently in patients aged more than 50 years and in those with COPD, alcoholism, and more extensive disease on chest radiography. In a similar study, Macfarlane [28] compared radiographic resolution among bacteremic patients and nonbacteremic patients with pneumococcal pneumonia. A higher incidence of initial radiographic deterioration (52% versus 26%), a slower rate of resolution (60% versus 30% unresolved at 8 weeks), and a higher incidence of residual atelectasis and pleural densities (26% and 37% versus 9%) were observed in the bacteremic group. Bacteremia is observed in as many as 40% of patients with pneumococcal pneumonia and is commonly associated with comorbid diseases such as chronic lung disease and diabetes mellitus [29]. A

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Box 1. Risk factors for infection with enteric gram-negative organisms Nursing home residence Cardiopulmonary disease Multiple medical comorbidities Recent antibiotic use

Additionally, Macfarlane [28] reported that most patients had radiographic deterioration in the first 2 weeks despite adequate antibiotic therapy. Mild abnormalities in pulmonary function may persist even after resolution [35]. Mycoplasma Mycoplasma was first identified in the 1940s and is implicated in 9% to 29% of CAPs [36]. It commonly affects a younger population, and rapid radiographic and clinical resolution is the rule. Frequently manifesting as patchy interstitial infiltrates, multilobar disease is common; however, residual scarring is infrequent. In one prospective study [28], mycoplasma infections resolved faster than other identifiable causes of pneumonia, with 50% of patients having normal chest radiographs at 4 weeks and nearly 90% at 8 weeks. Chlamydia Identified in 1998 as a significant respiratory pathogen, chlamydia is now known to cause a significant number of CAPs. Prevalence rates range from 3% to 22% [28,31], and it has been reported in as many as 10% of pneumonias requiring hospitalization [15]. Both Chlamydia psittaci and Chlamydia pneumoniae are responsible organisms. Infection occurs in all age groups and may be complicated by bacterial superinfection, bronchiectasis, and interstitial fibrosis. Macfarlane [28] reported that psittacosis resolution rates fell between that for mycoplasma and legionella. In 50% of cases, chest radiographs remained abnormal at 4 weeks. Frequently, chlamydia is implicated in infections with multiple pathogens [29]. Kauppinen and colleagues [37] found that these mixed infections were associated with longer resolution times and a worse prognosis overall. Gram-negative bacilli Colonization of the upper respiratory tract with enteric gram-negative organisms is common in hos-

pitalized patients, occurring in as many as 60% of critically ill patients, 40% of chronically hospitalized patients, and 23% of nursing home residents. Fagon and colleagues [38] reported that Pseudomonas was the most common organism recovered from patients requiring mechanical ventilation. One prospective series of patients with nosocomial pneumonia reported that lack of clinical and microbiologic resolution was most frequently due to infection with P aeruginosa [12]. Implicated in a minority of patients with CAP as well, the organism has been recovered in 2% to 4% of cases [15,16]. Although an infrequent CAP pathogen, most reports suggest higher mortality rates in cases caused by gram-negative bacilli. In one study [39], the mortality rate for severe CAP owing to P aeruginosa was nearly 100%. Colonization and the development of pneumonia are strongly associated with underlying systemic disease, particularly COPD [16]. Other known risk factors for infection with enteric gram-negative organisms and P aeruginosa, in particular, are listed in Boxes 1 and 2 [40]. Resolution of these pneumonias is most likely delayed in comparison with that of most CAPs, although specific data are lacking [41,42]. Staphylococcus Most frequently considered a nosocomial pathogen, staphylococcal pneumonia has been implicated in 3% to 14% of CAPs [31]. Commonly preceded by influenza or other viral illnesses, Woodhead and colleagues [43] have reported that S aureus is most likely to be present in CAP requiring intensive care unit admission. Resistance among S aureus organisms has been shown to affect mortality and resolution times adversely. Rello and colleagues [44] compared a group of patients with methicillin-resistant S aureus (MRSA) VAP with another group with methicillin-susceptible S aureus (MSSA). Patients with resistant strains were more likely to be greater than 25 years of age, to have pre-existing lung disease, to require mechanical ventilation greater than 6 days, and to have received prior steroid and anti-

Box 2. Risk factors for infection with P aeruginosa Structural lung disease Corticosteroid therapy (> 10 mg/d) Use of broad-spectrum antibiotics Malnutrition Leukopenic immunosuppression

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Box 3. Risk factors for MRSA infection Burns Surgical wounds Dialysis Indwelling intravenous catheters Tertiary care centers Acute care or nursing home residence Advanced age Prior antibiotic administration Proximity to other patients with MRSA

biotic therapy. The investigators noted an increased mortality among the MRSA group. Risk factors for infection with MRSA are listed in Box 3.

Risk factors for delayed resolution Host abnormalities A variety of abnormalities in host defense may result in delayed resolution of pneumonia. The most common conditions associated with a delayed resolution are advanced age, COPD, and alcoholism [27]. When these factors are present, the infection may be expected to take longer than usual to clear. Advanced age Several studies have demonstrated that prolonged radiographic abnormalities are more common in the elderly. Mittl and colleagues [45] prospectively examined 81 individuals with CAP at The Hospital of the University of Pennsylvania. Outpatients (n = 44) and hospitalized patients (n = 37) were included in the study. The radiographic clearance correlated inversely with age and the number of pulmonary lobes involved. Similarly, Van Meter [46] found that the likelihood of prolonged consolidation increased progressively with age. In 358 cases of pneumococcal pneumonia, consolidation persisted beyond 4 weeks in 27% of patients older than 50 years compared with 18% of younger patients. In a review of patients from Philadelphia General Hospital, Israel et al [2] stated that age alone was the most striking influence affecting the occurrence of abnormal resolution. In their series of 100 consecutive patients, delayed resolution was observed in 24.5% of patients aged more than 50 years compared with 6.6% of individuals less than 50 years old. Although older patients accounted for only one third of all patients in

the study, they represented two thirds of all cases of nonresolving pneumonia. In a more recent study [47], radiographic clearance among 74 elderly patients was prospectively evaluated. Radiographic clearance at 3 weeks, 6 weeks, and 12 weeks was 35%, 60%, and 84%, respectively. It was concluded that a period of 12 to14 weeks should pass before considering pneumonia to be slowly resolving in elderly patients. The cause of slower resolution of pneumonia in the elderly is multifactorial [48]. An age-related impairment of several components of host defenses, including T cell mediated and humoral responses, is suspected. Additionally, as the lung ages, it loses elasticity, respiratory muscles weaken, and the strength of the cough is diminished. Sputum samples are frequently unobtainable or contaminated in the elderly, and determination of an etiologic diagnosis is impaired. Clinton and colleagues [49] reported that an etiology was obtained in less than one third of cases of CAP in their elderly population. Delayed recognition of pneumonia is another contributing factor in the elderly. Classic signs and symptoms of pneumonia are frequently absent. In one report, more than 50% of patients older than 65 years of age were afebrile [50]. Comorbidity Gleichman et al [1] studied 198 veterans with delayed resolution of CAP. A systemic disease was present in nearly all of the patients (96%) in whom the pneumonia failed to resolve within 30 days. Emphysema, chronic bronchitis, and asthma were the most prevalent. Eller et al [51] reported that patients who had chronic bronchitis and less advanced pulmonary disease, defined as an FEV1 greater than 50% predicted, were most commonly infected with gram-positive organisms such as pneumococcus. In contrast, the patients with severely compromised pulmonary function more often had gram-negative organisms isolated. Immunosuppression Steroid-treated patients with COPD are at greater risk for opportunistic infections. Rodrigues et al [52] performed a retrospective review of autopsy-proven cases of opportunistic infections at a teaching hospital in the United States. In 8 of the 30 cases, the only identifiable risk factor was corticosteroid therapy for COPD. Four of the cases were community-acquired infections, whereas the others were nosocomial. All of the patients had multilobar infiltrates that progressed despite broad-spectrum antibiotic therapy. Aspergillus species were recovered in six cases, Can-

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dida albicans in one individual, and cytomegalovirus (CMV) in another individual. Only one patient had the diagnosis established antemortem. Based on this study, nonresolving pneumonia in steroid-treated patients with COPD should prompt an early evaluation for opportunistic infections. Chronic alcohol abuse also imparts a risk for delayed resolution of pneumonia. There are several mechanisms by which it may exert a deleterious effect, including adverse effects on alveolar neutrophils and macrophages. Acute intoxication has been shown to impede recruitment of these inflammatory mediators and to interfere with their ability to adhere to endothelial surfaces [53]. Fernandez-Sola et al [54] examined a cohort of 50 alcoholic patients with CAP. Multilobar involvement, pleural effusions, and longer resolution times were associated with high alcohol intake, defined as more than 80 to100 g per day in women and men, respectively. Similarly, a review [55] of pneumonia outcomes linked alcoholism with increased costs of care, lengths of stay, and intensive care unit use.

hospital length of stay among patients infected with these pathogens. Pseudomonas and Acinetobacter organisms comprised 44% of cases of VAP but were implicated in 57% of all pneumonia deaths. Bronchoscopy with bronchoalveolar lavage (BAL) or PSB quantitative culture results were used to confirm the diagnosis. The mortality rate among cases of VAP owing to these organisms was 71% (attributable mortality, 44%) versus 41% for pneumonia owing to other organisms and 26% for paired controls. A larger prospective study by Heyland et al [59] subsequently revealed similar results. Additionally, pneumonia owing to high-risk organisms was associated with longer lengths of stay. The attributable length of stay in the intensive care unit was 9.1 days for these organisms versus 2.9 days for all others. In a prospective study, Trouillet et al [60] found three variables that were independently associated with infection by these pathogens: a duration of mechanical ventilation greater than or equal to 7 days, prior use of antibiotics, and prior use of broad-spectrum antibiotics. Drug-resistant S pneumoniae

Limitations of antimicrobial therapy General antimicrobial resistance Although numerous factors affect the outcome in pneumonia, the rapid institution of effective antibiotics is known to reduce mortality [22,56]. In a retrospective review of 111 patients, Dupont and coworkers [57] found that 50% of empiric therapy for VAP was inappropriate. Among these cases, 55% were due to infection by resistant organisms. The past decade has witnessed a dramatic increase in this prevalence. Resistance is a common concern when a patient with presumed pneumonia does not improve as expected. Arancibia et al [4] found that persistent infection was usually caused by antimicrobial resistance. In their evaluation of 49 patients with nonresolving CAP, infectious etiologies, including highly drug-resistant nosocomial pathogens, were most common. Similarly, Montravers [25] found that the causative organism determined by PSB culture persisted at low levels in 7% of cases and was most commonly associated with resistance. In fact, all of the patients with significant colony counts on repeat PSB samples had pathogens that were resistant to previous antibiotic therapy. Failure of eradication is most common among infections with high-risk organisms, such as Pseudomonas, Acinetobacter, and MRSA. Fagon and colleagues [58] reported an increased mortality and

Although in vitro resistance is long-standing, clinical resistance of streptococcus was not observed until 1967 when an intermediately resistant strain was isolated in Australia [61]. The first infection in the United States was in 1974. During the 1980s, national surveillance studies revealed a persistently low prevalence of penicillin-resistant strains (2% to 8%) [62,63]. An abrupt change in pneumococcal sensitivity patterns occurred in the 1990s, with many US cities reporting rates in excess of 20%. Today, it is not uncommon to find rates greater than 30% in some regions [64]. Current definitions of resistance include intermediate-level resistance with penicillin minimal inhibitory concentration (MIC) values of 0.12 to 1.0 mg/mL and high-level resistance with values greater than or equal to 2.0 mg/mL. Recently, the Drug Resistant Streptococcus pneumoniae Therapeutic Working Group of the Centers for Disease Control recommended that these susceptibility patterns be changed for cases of CAP [65]. The proposal suggests that strains be considered susceptible if MIC values are no greater than 1 mg/mL, intermediate if values are 2 mg/mL, and resistant if greater than 4 mg/mL. The rationale for the change is based on studies that have not shown poorer outcomes among adults with pneumonia owing to resistant strains. Unlike for MRSA, the outcome seems to be adversely affected only when MIC values exceed 4 mg/mL [66]. Although one study reported [67] an increased

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Box 4. Risk factors for infection with penicillin-resistant pneumococcus Age <6 years or >70 years Recent antibiotic use Immunosuppression Recent or current hospitalization Family of a child attending day care Alcoholism

incidence of suppurative complications, most investigations have found no mortality difference with less resistant (< 4 mg/mL) strains [68 70]. Outside of the central nervous system, parenteral therapy achieves serum concentrations of antibiotic far in excess of these MIC values, and penicillin-resistant pneumococcus does not seem to be a significant problem in the patient with pneumonia [71]. Several surveillance studies have noted an increased prevalence of these highly resistant strains [72,73]. One study reported that 17% of all isolates from 2000 to 2001 had penicillin MICs of at least 2 mg/mL as compared with 3% in 1996 to 1997. Current data estimate the prevalence of even more resistant strains (MICs of at least 4 mg/mL) to be 6% to 7% [74]. Not every patient should be considered at risk for drug-resistant S pneumoniae (DRSP). Clinical risk factors have been identified [83] and are listed in Box 4.

Unusual infections Pathogens other than the most common bacterial ones must be considered in cases of pneumonia that fail to resolve. Additional testing, often invasive, is frequently performed. Serial bronchoscopy has been used to identify unusual or resistant organisms in such situations. In one prospective series of patients with nosocomial pneumonia, the lack of response to initial therapy was usually the result of infection with P aeruginosa [12]. Similarly, Arancibia et al [4] evaluated 49 patients with CAP that failed to resolve. Etiologies were discovered in 65% of cases; most were infectious in origin. Persistent infection with the originally isolated organism was usually caused by antimicrobial resistance, whereas new infections were primarily the result of nosocomial or unusual pathogens. A high index of suspicion for unusual organisms is required. Mycobacterium is an organism not adequately treated with standard therapy for CAP.

In fact, antibiotic therapy may cause the disease to wax and wane, further obscuring an accurate diagnosis. The incidence of tuberculosis declined until 1986, when the number of cases once again increased, most likely secondary to the AIDS epidemic. Persons most likely to develop the disease are those with a high rate of co-infection with HIV. Drug abusers, HIV-infected immigrants from countries where tuberculosis is endemic, poor inner-city dwellers, and close contacts of individuals with tuberculosis are at greatest risk [75]. Tuberculosis may mimic the clinical and radiographic appearance of CAP. Primary tuberculosis may occur anywhere in the lung and may appear disseminated or present as a lobar pneumonia. Post primary (reactivation) tuberculosis is classically associated with a cavitary lesion in the posterior segment of one or both upper lobes. Less frequently, the superior segments of the lower lobes are involved [76]. Unusual radiographic appearances and the presence of extrapulmonary disease are more common in immunocompromised individuals, such as persons with HIV infection and the elderly. In one review of unsuspected tuberculosis in a community hospital, 92% of all patients were elderly [77]. In that series, 60% of cases were reported after the patients death. A compatible chest radiograph must raise suspicion for tuberculosis, especially if accompanied by a positive tuberculin skin test. Eighty percent of patients with active disease will have a positive test. Recent infection, anergy due to immunosuppression, malnutrition, or chronic disease may result in a falsely negative test. Primary or reactivation fungal infections should be suspected in individuals in endemic areas. The endemic mycoses include infection with Blastomyces dermatitidis, Histoplasma capsulatum, and Coccidioides immitis. These infections are often asymptomatic but may present as protracted illnesses with fever and wasting [78]. Extrapulmonary disease occurs in as many as 25% of patients [79], and dissemination to the skin and central nervous system is common. Lymphadenopathy and splenomegaly may also be seen, especially in histoplasmosis. Among the viruses, CMV occurs predominantly in immunocompromised individuals. A recent review [80] of 86 intensive care unit patients with presumed VAP reported a histologically confirmed diagnosis of CMV in 25 of them. Clinical features alone were unable to differentiate these cases from bacterial infection, but a longer duration of mechanical ventilation was observed in the CMV group. Other viruses have been reported in nosocomial pneumonia and CAP. The importance of these pathogens relative to

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the more common ones is unclear. Nevertheless, viral infection should be included in the differential diagnosis of nonresolving pneumonia.

Noninfectious etiologies of nonresolving pneumonia The reported incidence of noninfectious conditions mimicking pneumonia is variable, depending on the study and the type of patient evaluated. Timsit and colleagues [81] reviewed a large number of studies and concluded that two-thirds of suspected pneumonias in intubated patients were caused by unrelated conditions, including atelectasis and pulmonary edema. In another retrospective series of 130 intensive care unit patients [82], BAL fluid was used to exclude pneumonia in the absence of a microbiologic pathogen. Nineteen percent of cases were found to be noninfectious. The etiologies included pulmonary embolism, drug-induced pneumonitis, acute respiratory distress syndrome (ARDS), lung contusion, and pulmonary edema. In addition, one case of lymphangitic carcinomatosis was diagnosed by BAL cytology. Meduri and colleagues [83] at the University of Tennessee performed a similar study. Fifty patients with presumed VAP underwent extensive diagnostic testing to identify specific etiologies. Noninfectious causes for fever and pulmonary infiltrate were identified more often in patients with ARDS than in patients without the disease. There are several possible explanations for this finding, but clinical and radiographic features are often more difficult to interpret in the patient with ARDS. Additionally, Meduri et al [84] revealed that the fibroproliferative phase of ARDS was associated with many of the typical signs and symptoms of an infectious process, such as fever, leukocytosis, and radiographic infiltrates. Several autopsy studies have reported underdiagnosis and overdiagnosis of pneumonia in the setting of acute lung injury [85]. In the nonintubated patient, several studies have suggested that the most common cause of nonresolving pneumonia is primary, persistent, or nosocomial infection. In one series, only 7 of 35 patients had noninfectious etiologies, including one patient with chronic eosinophilic pneumonia, one patient with Wegeners granulomatosis, one patient with bronchitis obliterans with organized pneumonia (BOOP), and four patients with carcinomas [86]. Open lung biopsy was required for the diagnoses of Wegeners granulomatosis and BOOP. Arancibia and colleagues [4] observed a similarly low incidence of

noninfectious processes. In their series of 49 hospitalized patients, noninfectious causes were discovered in only eight individuals. Despite the low incidence, a noninfectious etiology should be considered when a patient fails to respond to antibiotic therapy. As mentioned previously, the time until which pneumonia is considered nonresolving is arbitrary and depends on the severity of the patients condition. For example, a presumed CAP in an outpatient may allow more observation time than in a hemodynamically unstable individual in the intensive care unit where 48 to 72 hours of observation is common [87]. Knowledge of the natural history of pneumonia, including the expected duration of symptoms and radiographic and physical examination abnormalities, avoids an exhaustive search for alternative etiologies. The number of true cases of pneumonia is vastly outnumbered by the noninfectious possibilities. Failure to recognize this fact may lead to an inappropriately extensive and expensive evaluation. Pronounced extrapulmonary manifestations are rare in community and hospital-acquired pneumonias and should raise suspicion for a noninfectious etiology. Similarly, peripheral eosinophilia is occasionally seen in fungal and mycobacterial diseases but is otherwise uncommon. An elevated eosinophil count should raise concern for an immunologic process, vasculitis, or rheumatologic disease. The eosinophilic pulmonary diseases, including chronic eosinophilic pneumonia (CEP) and allergic bronchopulmonary aspergillosis (ABPA), should also be considered. Mediastinal adenopathy is an uncommon finding in CAP and should prompt an evaluation for alternative etiologies. Sarcoidosis may present with clinical and radiographic manifestations that are suggestive of infection. Although symptoms are generally insidious, an acute form (Lofgrens syndrome) exists, and fever may be present. One series [88] found that more than 40% of patients were febrile, 50% experienced night sweats, and nearly one third complained of chills. Pulmonary involvement is the hallmark of the disease, and adenopathy is present in the most cases at presentation. Other diagnostic considerations include tuberculosis and endemic fungal infections. The clinician often considers malignancy when pneumonia fails to resolve; however, several studies [1,86] have reported it to be an infrequent cause of nonresolving pneumonia. In their series of 115 patients with nonresolving and chronic pneumonia, Kirtland et al [89] reported an incidence of 19%. This value is much higher than that reported in other series, and the inclusion of chronic pneumonias may explain the discrepancy. In a smaller series, Feinsilver

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and colleagues reported only four cases of carcinoma among 35 patients undergoing bronchoscopy [86]. Malignancies that may present with pulmonary infiltrates include bronchioloalveolar cell carcinoma (BAC), lymphoma, leukemia, Kaposi sarcoma, and lymphangitic carcinomatosis. BAC is most notorious for mimicking a pneumonic process, but infrequently presents with diffuse infiltrates. Hill [90] reviewed the chest radiographs of 136 patients with BAC and found that most had a single mass or nodule (43%) at the time of diagnosis. Thirty percent had an area of consolidation, and a pleural effusion was present in 32%. Diffuse infiltrates, the radiographic pattern most likely to be confused with CAP, were present in only 23%. Lymphoma is rarely confused with pneumonia. Primary pulmonary involvement is uncommon in Hodgkins disease but present in 50% of cases of non-Hodgkins lymphoma at diagnosis. Similarly, lung involvement is frequent in Kaposi sarcoma, and most patients have bilateral interstitial or alveolar infiltrates [91]. Characteristic endobronchial lesions occur in as many as 45% of cases. Drug-induced pneumonitis may resemble an infectious process with high fevers and pulmonary infiltrates. A thorough review of a patients current and former medications may elicit a potential etiology. The number of implicated medications is extensive, and a detailed summary is beyond the scope of this review. Two of the more frequently encountered drugs are mentioned herein. Amiodarone causes pulmonary disease in as many as 10% of patients; those at greatest risk have preexisting lung disease [92]. The clinical presentation is generally indolent but may be acute and fulminant in one third of cases. The diagnosis is suggested in the appropriate clinical setting, but the histopathologic features are distinctive, including abundant foamy macrophages and dense lamellar bodies that can be seen on electron microscopy. Biopsy is seldom performed, because a reduction in the diffusion capacity of carbon monoxide is a sensitive indicator of pulmonary toxicity. Nitrofurantoin causes two distinct pulmonary syndromes, an acute form and a chronic one, in 1% of patients. The acute toxicity is most common and more likely to be confused with pneumonia. Symptoms such as fever, dyspnea, and cough are generally evident within 1 month of ingestion. Bibasilar infiltrates and a peripheral eosinophilia frequently occur. A clinicopathologic syndrome, BOOP has been linked to a variety of systemic illnesses, including drug reactions [93]. The most common radiographic

abnormality, bilateral airspace consolidation, may be confused with pneumonia. In fact, the diagnosis is rarely entertained before failure of antibiotic therapy. A preceding viral-like illness occurs in up to one third of patients, but extrapulmonary involvement does not occur, and sputum production is uncommon. The diagnosis is suggested by restrictive pulmonary function tests and a reduced diffusion capacity, but biopsy is often required, and thoracotomy remains the gold standard.

Diagnostic evaluation of nonresolving pneumonia The initial consideration in a patient with nonresolving pneumonia should be re-evaluation of possible host-related factors (Fig. 1). If there are no factors associated with delayed resolution, such as advanced age or alcohol abuse, a thorough investigation for an alternative diagnosis should be entertained, particu-

Fig. 1. Diagnostic algorithm for evaluation of the patient with nonresolving pneumonia.

152 Table 1 Approach to nonresolving pneumonia Cause of nonresolution Antimicrobial failure Patient noncompliance Improper dosing regimen Resistant pathogen Unusual or unsuspected pathogen Infectious complications Empyema Endocarditis Superinfection

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Diagnostic considerations 1. Confirm compliance 2. Review microbiologic data 3. Review antibiotic sensitivities 4. Consider unusual pathogen (PPD) 1. Review/repeat CXR 2. Consider chest CT 3. Evaluate for other infection (echocardiography, sinus CT, empyema) 4. Consider superinfection 1. Review history (travel, exposure) 2. Review laboratory data (eosinophilia?) 3. Consider bronchoscopy

Incorrect diagnosis Malignancy Pulmonary embolism Other noninfectious etiologies

Abbreviations: CXR, chest radiography; PPD, purified protein derivative (of tuberculin).

larly in younger patients who are nonsmokers and who have multilobar disease [86]. The most common causes for lack of resolution include inadequate antimicrobial selection, complications such as ARDS and empyema, unusual pathogens, and noninfectious etiologies (Table 1). Although physical examination and laboratory data provide little insight to a specific etiology, the history is particularly important. Thorough travel, medication, and occupational histories should be elicited. Travel to an endemic area may suggest the possibility of fungal disease or certain infrequent bacterial or helminth infections. Similarly, history of exposure to one of many organic antigens may lead to the diagnosis of hypersensitivity pneumonitis. The diagnostic work-up should begin with reevaluation of initial culture results and antimicrobial susceptibility data. Repeat respiratory sampling may be performed if additional information is unavailable. Depending on the method of recovery, if repeated cultures remain negative, pneumonia with typical microorganisms is unlikely. If borderline thresholds are isolated on repeat sampling, one of two actions may be undertaken: (1) treatment with an alternative antimicrobial agent or (2) the discontinuation of all therapy followed by repeated sampling

within 48 to 72 hours [87]. Current literature suggests that this sampling may be performed sufficiently via invasive or noninvasive means. Wu and colleagues [94] evaluated 48 patients with presumed VAP who lacked clinical improvement at 72 hours of therapy. Each patient underwent quantitative cultures of endotracheal aspirate (QEA), BAL, and PSB. Cultures were positive in 58% of tracheal aspirates compared with 50% of BALs and 48% of PSBs. Overall, QEA at a cutoff point of 1 million cfu/mL revealed a sensitivity of 93% and a specificity of 80%, comparable with the more invasive approaches. Although a standardized threshold does not exist, other studies have revealed varying sensitivities and specificities with different diagnostic cutoff levels [95,96]. Sanchez-Nieto and colleagues [97] recently reported a 71% agreement among QEA, PSB, and BAL culture techniques. Fiberoptic bronchoscopy is invasive but allows direct visualization of the tracheobronchial tree and is often considered in the early evaluation of nonresolving pneumonia. Several investigators have reported that serial quantitative cultures correlate with clinical improvement [25]; however, if a patient is already receiving antibiotics before the procedure, the results must be interpreted cautiously. Sterile bronchoscopic cultures may indicate the absence of infection or the adequacy of antimicrobial coverage. Alternatively, persistence of an organism implies resistance and should prompt a change in therapy. Occasionally, a superinfection may be diagnosed. Occurring in 12% to 15% of VAP cases [24], superinfection was discovered in 9% of patients in the series reported on by Montravers [25] and was associated with reduced survival. Pereira-Gomes and colleagues [98] evaluated the impact of bronchoscopy on cases of nonresolving pneumonia. Testing was performed in 53 patients who failed to improve after at least 72 hours of therapy. The most frequently isolated organisms were Acinetobacter baumannii (38.7%), S aureus (19.3%), and P aeruginosa (17.7%). Consistent with other reports [39], nearly half of the cases (46.7%) were polymicrobial. The BAL cultures resulted in changes in antibiotic therapy in most patients and were associated with a nonstatistically significant reduction in mortality. Feinsilver and colleagues [86] reported that bronchoscopy was helpful in a minority of cases. They

Fig. 2. Slowly resolving pneumonia. (A) Posteroanterior and (B) lateral chest radiographs of a 62-year-old woman at initial presentation. A right middle lobe infiltrate is clearly visible and consistent with her symptoms of pneumonia. (C,D) Follow-up radiographs at 4 weeks. Only partial radiographic resolution occurred. Fiberoptic bronchoscopy was subsequently performed and revealed no endobronchial lesions. Advanced age was the risk factor for this patients delayed resolution.

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reported their findings in 35 patients undergoing fiberoptic bronchoscopy for nonresolving pneumonia. In 21 patients, the final diagnosis was simply slowly resolving disease. Seven patients were subsequently diagnosed with unusual infections, including Pneumocystis carinii pneumonia, tuberculosis, CMV, and actinomycosis, and four patients were found to have malignancy. One case of chronic eosinophilic pneumonia was noted. The diagnostic yield for bronchoscopy was greatest in young nonsmoking patients with multilobar disease. A longer period of observation may be warranted in patients who are older than 55 years, in smokers, and in patients with multiple comorbidities. Chest radiographs are seldom diagnostic but may suggest a group of diseases that produce such radiographic appearances (Fig. 2). For example, upper lobe cavitary disease is suggestive not only of tuberculosis but also of many fungal infections. Similarly, the propensity for pleural involvement is characteristic of infection with Nocardia asteroides, Actinomyces israelii, and Mycobacterium tuberculosis [99]. Comparison with old chest radiographs should always be performed and may allow recognition of benign changes associated with previous surgery or inflammatory diseases. CT scanning affords greater visualization of the lung and surrounding structures and may be especially helpful in excluding noninfectious etiologies. An unsuspected pulmonary embolus or obstructing endobronchial lesion can be readily identified and treated appropriately. An extrapulmonary infection should also be considered and may be evaluated further by CT scanning. For example, sinusitis is often confused with VAP because of the presence of purulent secretions. In fact, a prospective series of intubated patients reported an unusually high incidence of concomitant pneumonia and sinusitis [100]. Associated with nasotracheal intubation and nasogastric tubes, typical organisms are Pseudomonas, Acinetobacter, S aureus, and anaerobes [101]. The role of more invasive diagnostic testing in nonresolving pneumonia is poorly defined. Bulpa and coworkers [102] recently performed a retrospective review of transbronchial lung biopsy in mechanically ventilated patients. Causes for the respiratory failure were diverse, but diffuse unexplained pulmonary infiltrates were present in all. Thirty-eight patients, 16 of who were immunocompromised and 11 with ARDS, underwent the diagnostic procedure. A histologic diagnosis was obtained in 74% (n = 28), and a change in therapy, including the addition or withdrawal of antimicrobial agents and corticosteroids, occurred in 63% of cases. A few procedure-related

complications occurred, including pneumothorax (n = 9), hemorrhage (n = 4), and transient hypotension (n = 2). These results are similar to those in a previous review [103] and suggest that transbronchial biospy may be performed safely in mechanically ventilated patients with unexplained infiltrates. Although not routinely performed in this context, it may obviate the need for a more invasive procedure, such as open lung biopsy. In the nonimmunocompromised patient, open lung biopsy is rarely performed. In fact, most information in the literature refers to its use in immunocompromised individuals. Despite its consideration in many studies as the gold standard for the diagnosis of pneumonia, its primary indication in this setting is the exclusion of noninfectious etiologies. Dunn and colleagues [104] observed 26 patients undergoing open lung biopsy for progressive pneumonia. Eight of the patients were immunocompetent, and the invasive procedure led to an alternative diagnosis in three. BOOP, lipoid pneumonia, and CMV infection were subsequently diagnosed. Fig. 1 illustrates a diagnostic algorithm for the evaluation of the patient with nonresolving pneumonia. A common clinical scenario, nonresolving pneumonia often causes frustration among clinicians when considering the innumerable possibilities for delayed resolution. A systematic approach, such as the one shown in Fig. 1, will help the clinician decide whether additional testing or longer observation is required. The initial step involves re-evaluation of possible host-related factors. Older age, comorbid systemic diseases, and alcoholism are some of the risk factors for longer resolution. When present, a longer period of observation is warranted. At this point in the investigation, consideration of the causative agent and the expected resolution time also should occur. As mentioned previously, normal resolution is variable and depends on the etiology. A more prolonged course should be anticipated among patients with legionnaires disease, bacteremic pneumococcal pneumonia, and several other types of illness. After a consideration of host factors, microbiologic data should be reviewed, including previous culture results and antibiotic susceptibilities. Frequently, a pathogen that is not susceptible to the initial empiric therapy is recovered and, if the data are not reviewed, subsequently forgotten. This problem is easily solved but often overlooked and should be addressed early in the evaluation. At the next point in the algorithm, the clinician is confronted with a patient lacking risk factors for delayed resolution who is not improving with appropriate therapy. A repeat chest radiograph should be

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obtained at this time and carefully evaluated for new or persistent infiltrates. If a pleural effusion is present, thoracentesis may be performed to exclude empyema. Additionally, any suggestion of a mass or significant lymphadenopathy should prompt further evaluation with CT scanning. If the patient is hemodynamically stable, changes in empiric antimicrobial therapy should be deferred until repeat respiratory sampling is performed. Quantitative cultures of secretions can be obtained by bronchoscopy or through noninvasive means. The results will most likely direct the remainder of the investigation.

Summary Although common, a pneumonia that appears to be slowly resolving or nonresolving can be problematic. The sheer number of alternative diagnoses, both infectious and noninfectious, can overwhelm the clinician and lead to unnecessary testing. Knowledge of typical resolution patterns and risk factors for delayed resolution can aid the clinician and prevent an exhaustive search for alternative etiologies. In most cases, the illness is slow to resolve because of hostrelated factors, such as older age and concomitant pulmonary or other systemic diseases. Unusual or resistant pathogens and noninfectious etiologies should be considered after exclusion of these host and pathogen-specific factors. A systematic approach to the diagnostic evaluation is most likely to be fruitful.

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