Importance of Atypical Pathogens of Community-Acquired Pneumonia

S35 Importance of Atypical Pathogens of Community-Acquired Pneumonia Joseph F. Plouffe Departments of Internal Medicine and Medical Microbiology and Immunology, Ohio State University College of Medicine, Columbus, Ohio The atypical clinical presentation of patients with community-acquired pneumonia (CAP) was first recognized and reported by astute clinicians 50 years ago. The cause of pneumonia in this group eventually was shown to be Mycoplasma pneumoniae. More recently, Chlamydia pneumoniae also has been recognized as a cause of CAP. Legionella has been lumped together with M. pneumoniae and C. pneumoniae because of its antimicrobial susceptibility pattern. This group of organisms is susceptible to the macrolides, tetracycline, and the newer fluoroquinolones. However, Legionnaires disease frequently presents a more acute clinical picture than either mycoplasmal or chlamydial infections. Recent data suggest that in the Medicare population hospitalized with pneumonia, morbidity and mortality can be decreased if initial therapy includes coverage for atypical pathogens (i.e., macrolides or fluoroquinolones). Unfortunately, few studies use culture methodology for atypical pathogens. Future studies of the efficacy of macrolide or fluoroquinolone therapy for CAP should include aggressive diagnostic studies for M. pneumoniae, C. pneumoniae, and Legionella species. The etiologic diagnosis of community-acquired pneumonia (CAP) is commonly based on both clinical and laboratory findings. A detailed patient history and a physician s understanding of etiologic factors can contribute to the diagnosis. In addition, a number of available noninvasive tests can be useful in selecting effective initial empirical therapy (table 1) [1]. Despite the availability of such tests, however, the etiology of CAP remains undetermined in a relatively high percentage of cases. Studies reported in the past several years indicate that no causative pathogen is identified in 25% 50% of CAP cases [2 6]. An even higher rate was reported recently by Fine et al. [7], who conducted a prospective observational study of CAP in the United States and Nova Scotia. In this study, only 29.7% of the outpatient population underwent 1 microbiological tests, and an etiologic agent was identified in a mere 5.7% of cases. Moreover, although 95.7% of hospitalized patients underwent 1 tests, an etiologic diagnosis was established only for 29.6% of patients. A major factor contributing to the unknown etiology of CAP is the difficulty of identifying atypical respiratory tract pathogens, which include Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella species. As discussed below, current perceptions about the lack of distinguishable clinical features, along with the unavailability of rapid and accurate laboratory tests, have contributed to the complexity of identifying these organisms. Nonetheless, recent studies of CAP report that up to 50% of cases may be due to 1 atypical pathogens [2 5, 8]. Reprints or correspondence: Dr. Joseph F. Plouffe, Division of Infectious Diseases, Ohio State University Medical Center, N-1135 Doan Hall, Columbus, OH 43210 (plouffe.1@osu.edu). Clinical Infectious Diseases 2000;31(Suppl 2):S35 9 2000 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2000/3102S2-0005$03.00 Clearly, although these organisms may be considered atypical, they are a major etiologic factor and are likely to have a significant impact on the treatment of CAP in both outpatient and inpatient settings. M. pneumoniae and C. pneumoniae In 1938, Reiman [9] described a series of cases in which patients had symptoms that differed from the classic symptoms of pneumococcal pneumonia. Differences included a longer duration of illness, upper and lower respiratory tract symptoms, lack of response to penicillin, and slightly dissimilar chest radiogram findings. No bacterial pathogens were detected in these patients, and atypical pneumonia was attributed to possible viral infections. Eventually, M. pneumoniae was identified as the cause of these cases of atypical pneumonia. Subsequently, atypical pneumonia became associated with other pathogens that caused similar clinical presentations. In 1986, C. pneumoniae was isolated by Grayston et al. [10] and Thom et al. [11] from students with clinical manifestations similar to those associated with M. pneumoniae infections. Although a number of studies have concluded that the clinical signs of M. pneumoniae, C. pneumoniae, and pneumococcal infections are indistinguishable [4, 12 14], a retrospective analysis conducted by the Community-Based Pneumonia Incidence Study (CBPIS) Group indicates that physicians are able to appropriately suspect M. pneumoniae infections based on clinical features alone (J. F. Plouffe et al., unpublished data). The analysis included 100 hospitalized patients with M. pneumoniae infection and 200 patients with pneumococcal bacteremia. Examination of the patient records showed that without knowing the results of serological testing, physicians were 3.3 times more likely to prescribe erythromycin to patients with M. pneumoniae

S36 Plouffe CID 2000;31 (Suppl 2) Table 1. Advantages and disadvantages of noninvasive tests for community-acquired pneumonia (CAP). Noninvasive test Advantages Disadvantages Chest radiograph Distinguishes CAP from bronchitis Not available in office, expensive Blood culture High specificity for S. pneumoniae, isolate for susceptibility tests Low sensitivity, 24 h for results Gram stain of sputum Rapid; defines quality of specimen, type of inflammatory response, presence of Does not reveal organisms that do not stain predominant pathogen, absence of gram negatives, absence of staphylococci Culture of sputum Isolate for susceptibility tests 24 48 h for results, can be contaminated by oropharyngeal flora Acid-fast stain, fluorochrome Rapid; identifies mycobacteria Culture for AFB High specificity Results not available for weeks Influenza antigen detection Rapid; high specificity, assists with isolation precautions Not readily available, doesn t exclude secondary pathogen RSV antigen detection Rapid; high specificity Not readily available, low probability Cryptococcal antigen High specificity Low probability Legionella urinary antigen High specificity Only identifies L. pneumophila sg 1 Histoplasma urinary antigen High specificity Low probability Cold agglutinins Heightens suspicion of Mycoplasma infection Nonspecific Serologies IgM Helpful in some series for Legionella, Mycoplasma, Chlamydia Unknown specificity IgG Sensitivity and specificity well defined, epidemiologic studies Results not available for weeks PCR for Mycoplasma, Chlamydia, Legionella, pneumococcus Potentially rapid (research tool at this time) Not readily available, unknown sensitivity and specificity NOTE. AFB, acid-fast bacilli; PCR, polymerase chain reaction; RSV, respiratory syncytial virus; sg, serogroup. Adapted from [1], with permission. infections than to those with pneumococcal pneumonia. Approximately two-thirds of the M. pneumoniae infected patients were treated with a macrolide on the day of admission. Accurate and expedient diagnostic tests for M. pneumoniae and C. pneumoniae have not been available. Isolation of these pathogens from respiratory sites requires specialized techniques and materials that are not often available in clinical laboratories. Although rapid and sensitive testing techniques that use PCR are being developed, these methods are still not widely accessible to primary care clinics [15]. Currently, serological methods are often used to report the incidence of M. pneumoniae and C. pneumoniae. Use of such methods, however, often varies in the strictness of criteria. In studies conducted by the CBPIS Group [8], convalescent-phase and acute-phase serum samples from patients with CAP were tested by the Centers for Disease Control and Prevention (CDC; Atlanta, GA). CF testing was used to detect antibodies to M. pneumoniae, and a microimmunofluorescence technique was used to detect IgG and IgM antibodies to C. pneumoniae. A definite M. pneumoniae infection was defined as a 4-fold increase in paired antibody titers to 1:64; a possible diagnosis was defined as single antibody titer of 1:64. Both the definite and possible criteria used by the CBPIS Group were higher than the 1:32 titer that is commonly used to determine M. pneumoniae infection. A definite C. pneumoniae infection was defined as a 4-fold rise in paired antibody titers of 1:32. A possible infection was defined as an IgG titer of 1:512 or IgM titer of 1:16 to C. pneumoniae [8]. A community surveillance study by the CBPIS Group demonstrates the effect of using different breakpoints in reporting the incidence of pathogens of CAP (table 2) [8, 16]. When definite diagnosis breakpoints were used, the incidences of M. pneumoniae infection and C. pneumoniae infection in Franklin and Summit Counties, Ohio, were 6.3 and 2.8 cases per 100,000 population, respectively. In contrast, when less stringent criteria were used, incidences were 38.2 and 16.5 cases per 100,000 population, respectively. These rates are similar to the rate of 14.8 cases per 100,000 population for bacteremic pneumococcal pneumonia. Understanding local etiologic data for CAP, therefore, requires careful consideration of the methodologies and breakpoints that are used to report the incidence of atypical pathogens. Legionella Species Compared with M. pneumoniae and C. pneumoniae infections, Legionnaires disease has clinical features that are more like those of typical pyogenic (bacterial) pneumonia [17]. In addition, a number of studies have concluded that Legionella infections cannot be distinguished from pneumococcal pneumonia on the basis of clinical manifestations alone [12, 14, 18, 19]. A multivariate analysis by the CBPIS Group, however, found that certain factors, especially when considered as a constellation of clinical signs, were more likely to be associated with Legionnaires disease than with infections due to M. pneumoniae, C. pneumoniae, or Streptococcus pneumoniae [20]. Significant variables associated with Legionella infection included high-grade fever (temperature, 139 C; P p.03), elevated serum lactate dehydrogenase levels (1700 U/L; P p.002), hyponatremia (serum sodium level,!130 mg/dl; P!.001), and headache ( P p.02). In addition, a retrospective analysis, similar to the one conducted with M. pneumoniae, revealed that physicians appropriately treated Legionella infections based on clinical information alone (J. F. Plouffe et al., unpublished data). With an odds ratio of 3.5, physicians were more likely to prescribe erythromycin at admission to patients with Legionella infections than to patients with typical bacterial pneumonia. In the surveillance study of CAP that was conducted by the

CID 2000;31 (Suppl 2) Atypical Pathogens of CAP S37 Table 2. Incidence and projected numbers of community-acquired pneumonia associated with Mycoplamsma pneumoniae, Chlamydia pneumoniae, and Legionella spp. in Franklin and Summit Counties, Ohio, 1991. Pneumonia etiology, diagnosis Incidence (no. of cases per 100,000 population) Unadjusted Adjusted a Range Projected no. of cases per year in US M. pneumoniae b Definite 6.3 15.5 10.3 20.7 18,700 37,700 Any diagnosis 38.2 54.0 48.6 59.3 88,400 108,000 C. pneumoniae c Definite 2.8 7.4 3.2 11.6 5890 21,100 Any diagnosis 16.5 23.8 20.2 27.3 36,700 49,700 Legionella spp. d Definite 4.4 7.0 4.4 8.0 8,000 14,500 Any diagnosis 6.0 7.9 5.9 9.9 10,800 18,000 NOTE. Adapted from [16], with permission. a Adjusted incidence, ratio of infection estimates from those tested and applying ratio to entire population. b Definite M. pneumoniae infection was defined by the Community-Based Pneumonia Incidence Study (CBPIS) as a 4-fold increase in paired antibody titers to 1:64; possible infection was defined as a single antibody titer of 1:64. c Definite C. pneumoniae infection was defined by the CBPIS as a 4-fold rise in antibody titers to 1:32; possible infection was defined as an IgG titer of 1:512 or IgM titer of 1:16 to C. pneumoniae. d Definite Legionella infection was defined by the CBPIS as a 4-fold increase in paired antibody titers to 1:128, isolation of Legionella, or presence of a urinary antigen with a ratio of 3; possible infection was defined as a single antibody titer of 1:1024. CBPIS Group [8], serum samples were tested by the CDC for antibodies to Legionella pneumophila serogroup 1, which accounts for 70% 80% of Legionnaires disease. Definite Legionella infection was defined as a 4-fold increase in paired antibody titers to 1:128, isolation of Legionella, or presence of a urinary antigen with a ratio of 3. A possible infection was defined as a single antibody titer of 1:1024. As with M. pneumoniae and C. pneumoniae infections, the incidence of Legionnaires disease depended upon which breakpoint was used (table 2). Another useful diagnostic tool for detecting Legionnaires disease is the urinary antigen test [21]. The test is both highly sensitive and specific for L. pneumophila serogroup 1. A positive urinary antigen test on the day of admission to the hospital indicates Legionnaires disease. A negative test, however, does not exclude the possibility of infection. Patients with Legionnaires disease who are not infected with L. pneumophila serogroup 1 or those with mild disease due to L. pneumophila serogroup 1 may have a negative urinary antigen test. Mixed Infections Differential diagnoses of CAP are complicated by the possibility of mixed infections that include either 2 or more atypical pathogens or an atypical pyogenic pathogen. Mixed infections can occur either concurrently or sequentially and can be difficult to confirm. However, recent studies using serological evidence of either definite or presumed infections have reported an incidence of mixed infections of up to 48% among hospitalized patients with CAP [22, 23]. Currently, the clinical implications of mixed infections are still undetermined. The question remains whether infection with 1 pathogen simply facilitates penetration of a second or whether both organisms cause acute respiratory symptoms. It is therefore unclear whether treatment directed only toward the pyogenic pathogen is adequate or whether empirical treatment that covers other pathogens would decrease the length of treatment or hospitalization. Treatment of Atypical CAP Although there is a growing awareness of the potential prevalence of atypical pathogens causing CAP, a strictly pathogendirected approach to therapy is still not possible. Results from serological testing are not immediately available, and prompt initiation of effective therapy has been shown to reduce morbidity and mortality, particularly in the case of Legionella infections [24]. Other investigators suggest that infections with atypical pathogens do not need to be treated as they could not define any deaths in the small number of patients infected with atypical pathogens in Baltimore [25]. As empirical therapy for CAP, the b-lactam agents alone do not cover the atypical pathogens. Recently, Laurichesse et al. [26] from France reported that 75% of their patients with CAP received outpatient treatment with b-lactam agents. However, the duration of therapy (13.7 days) as well as the days of work missed (14.8 days) appeared prolonged. No randomized studies have been designed to compare therapy with and without coverage for atypical pathogens. Gleason et al. [27] reported that initial therapy with a macrolide plus a third-generation cephalosporin without activity against Pseudomonas was more efficacious than cephalosporin alone. Stahl et al. [28] reported that using macrolides as part of the initial therapeutic regimen was associated with a shortened hospital stay. A number of recent surveillance studies have documented the increasing incidence of b-lactam resistance among both S. pneumoniae and Haemophilus influenzae, 2 of the most common respiratory pathogens that cause CAP [29 31]. Newer macrolides, such as clarithromycin and azithromycin, have demonstrated good activity in vitro against the atypical pathogens and have generally been better tolerated than erythromycin. Currently, such agents are being used either alone or in combination with b-lactam agents as empirical therapy for CAP. However, concerns about the appropriateness of macrolides as empirical therapy have been raised [32], particularly in light of studies that report increasing rates of macrolide resistance among S. pneumoniae [33]. Despite the increasing MICs, there have been few reports of failures of macrolide treatment of CAP, perhaps because of the high tissue concentration of the newer macrolides. Another possible alternative is treatment with one of the newer fluoroquinolones (gatifloxacin, levofloxacin, moxifloxacin, and grepafloxacin). These agents are generally more active

S38 Plouffe CID 2000;31 (Suppl 2) Table 3. Activity of fluoroquinolones against atypical pathogens in community-acquired pneumonia. Fluoroquinolone Mycoplasma pneumoniae Chlamydia pneumoniae Legionella pneumophila Gatifloxacin 0.125 0.25 0.004 0.03 Ciprofloxacin 2.0 1.0 0.12 0.5 Ofloxacin 2.0 1.0 0.06 0.25 Levofloxacin 0.5 0.5 0.125 Sparfloxacin 0.06 0.25 0.06 Grepafloxacin 0.25 0.5 0.016 Trovafloxacin 0.25 0.12 0.004 NOTE. Adapted from [16], with permission. Data on gatifloxacin are from Ishida et al. [34], Roblin and Hammerschlag [35], and Dubois and St.-Pierre [36]. than older fluoroquinolones (ciprofloxacin and ofloxacin) against the atypical pathogens [34 36] (table 3). In addition, the newer fluoroquinolones all demonstrate excellent activity against S. pneumoniae, even against strains that are penicillin resistant [37, 38]. Because of their strong coverage of both typical and atypical respiratory tract pathogens, these agents may prove to be an ideal choice for treating CAP, particularly in areas where high rates of macrolide resistance among pneumococci are suspected. In the report by Gleason et al. [27] that included hospitalized Medicare patients, therapy with a quinolone was associated with a lower mortality rate than was initial therapy with a third-generation cephalosporin without activity against Pseudomonas. Conclusion Although infections with M. pneumoniae, C. pneumoniae, and Legionella species may be somewhat difficult to diagnose, they are important etiologic factors in CAP. Because testing for these organisms is not often performed in the outpatient setting, the prevalence of atypical pathogens in the community may be underestimated. In the hospital setting, serological testing requires time, and immediate therapeutic decisions must often be made for acutely ill patients. Therefore, the treatment of infections due to atypical pathogens remains largely an empirical practice. Because they do not cover the potentially high percentage of CAP cases that are due to atypical pathogens or mixed infections, b-lactam agents alone are not ideal therapeutic options. In addition, resistance to these agents in such common respiratory pathogens as S. pneumoniae and H. influenzae continues to increase. The addition of a macrolide to b-lactam therapy may be useful, although reported increases in macrolide resistance may soon limit the effectiveness of such combination therapies. However, newer fluoroquinolones, such as levofloxacin, gatifloxacin, and moxifloxacin, offer expanded antipneumococcal activity and good coverage of atypical pathogens. Moreover, pneumococcal resistance to these agents remains very low [39]. The newer fluoroquinolones are already being considered by the Infectious Diseases Society of America as possible empirical therapy for CAP, and they are likely to become important additions to the antibacterial armamentarium [40]. As new diagnostic techniques, such as detection with PCR analysis, become available, the relative prevalence of atypical organisms in various settings and among patient populations can be better assessed. In addition, further research should clarify ongoing questions regarding the relationship between atypical and pyogenic organisms. It is to be hoped that as these techniques and data are offered, improvements will be made in the clinical approaches to CAP. References 1. Plouffe JF, McNally C, File TM Jr. Value of noninvasive studies in community-acquired pneumonia. Infect Dis Clin North Am 1998;12:689 99. 2. Ruiz-Gonzalez A, Falguera M, Nogues A, Rubio-Caballero M. Is Streptococcus pneumoniae the leading cause of pneumonia of unknown etiology? 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