Atypical Pneumonia Updates on Legionella, Chlamydophila, and Mycoplasma Pneumonia Lokesh Sharma, PhDa,1, Ashley Losier, MDb,1, Thomas Tolbert, MDc,1, Charles S. Dela Cruz, MD, PhDa, Chad R. Marion, DO, PhDa,* KEYWORDS Community-acquired pneumonia (CAP) Walking pneumonia Legionella Legionnaires’ disease Pontiac fever Chlamydophila Mycoplasma KEY POINTS The clinical diagnosis of atypical pneumonia remains elusive but recent advances in rapid diag- nostic platforms show promise of earlier identification of the infectious organism. Macrolides and respiratory fluoroquinolones remain the antibiotics of choice for atypical pneu- monia but there are several new antibiotics currently under development or clinical trials. Both Chlamydophila and Mycoplasma have been associated with chronic diseases, but Legionella seems to occur sporadically and is not associated with chronic diseases. INTRODUCTION controversies surrounding the diagnosis and treat- ment of atypical CAP. Pneumonia is a common cause of hospital admis- sion and mortality and is categorized based on the clinical context in which a patient develops symp- LEGIONELLA PNEUMOPHILA toms of infection. These categories include Clinical Presentation community-acquired pneumonia (CAP), CAP with Legionella infections are manifested mainly in 2 risk factors of resistant organisms, hospital- forms: acquired pneumonia, and ventilator-associated events. CAP is defined as contracting pneumonia 1. Legionnaires’ disease, which is a severe form of with minimal or no recent contact with the health- pneumonia due to infection with Legionella. Le- care system CAP is one of the most common in- gionnaires’ disease can manifest as a multi- fectious diseases and is caused by various system disease most commonly involving the infectious pathogens, including viruses, typical lungs and gastrointestinal tract and is associ- bacteria, and atypical pathogens. This article re- ated with significant mortality.1 views the clinical considerations of atypical 2. Pontiac fever, which is a mild and self-resolving causes of CAP that include Legionella, Myco- flu-like disease. The characteristics of Pontiac plasma, and Chlamydophila and discusses current fever are mild fever, chills, myalgia, and a Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, 300 Cedar Street, TAC S440, New Haven, CT 06510, USA; b Department of Internal Medicine, Norwalk Hospital, 34 Maple Street, Norwalk, CT 06856, USA; c Department of Internal Medicine, Yale University School of Medicine, 330 Cedar Street, New Haven, CT 06510, USA 1 Contributed equally to this article. * Corresponding author. E-mail address: [email protected] Clin Chest Med 38 (2017) 45–58 http://dx.doi.org/10.1016/j.ccm.2016.11.011 0272-5231/17/Ó 2016 Elsevier Inc. All rights reserved. chestmed.theclinics.com 46 Sharma et al headache that lasts 2 to 5 days and often re- (FDA). Other tools, such as direct immunostaining, solves itself without significant mortality.2 are used to detect the presence of bacterium but frequently require invasive procedures to collect Legionella mostly affects people above 50 years tissue for testing.11 of age but cases have been reported in infants and neonates.3 Legionnaires’ disease is hard to distin- Prognosis guish from pneumonia caused by other pathogens because it presents similar clinical symptoms; Legionnaires’ disease has significant mortality however, presence of diarrhea and elevated creat- rates if untreated or if there is delay in adminis- inine kinase levels can be indicators of infection by trating appropriate antibiotic therapy. The risk fac- Legionella.4 Pneumonia due to Legionella is usu- tors associated with mortality are acquiring the ally found in clusters that are not associated with infection in nosocomial settings, diabetes, immu- 12,13 person-to-person transmissions but is related to nosuppression, and malignancies. Complete exposure to the same source of infection. Most recovery from the infection in these susceptible of the Legionella infections are acquired by populations might be prolonged and signs of 14 contaminated water or soil. Rainfall, high humidity, stress and trauma might persist for years. and work in gardens with compost are risk factors Treatment for acquiring Legionella disease.5–7 Most of the cases of legionnaires’ disease are associated Antibiotics are the first-line therapy for Legionella with Legionella pneumophila, but many other bac- pneumonia. Failure to administer appropriate anti- terial species have been found to cause Legionella microbial therapies at early stage of infection is lung infections.7,8 associated with high mortality rates.15,16 The cor- rect choice of antibiotic depends not only on its in vitro bactericidal or bacteriostatic activity but Diagnostic Considerations also on its ability to penetrate the cell membrane Because many manifestations of Legionella are of host tissues because Legionella resides within similar to other typical and atypical pneumonias, host tissue cells. Fluoroquinolones and macrolides clinical symptoms or radiologic evidences are of are the 2 most commonly used and highly effective little value for diagnostic purposes. The Centers antibiotics to treat patients with legionnaires’ dis- for Disease Control and Prevention defines confir- ease. Including these agents in initial treatment mation of infection if Legionella can be cultured regimen is prudent if Legionella infection is sus- from sputum or bronchoalveolar lavage, a positive pected based on an ongoing outbreak in the area, urine antigen test, or a 4-fold increase in anti- travel history, or extrapulmonary symptoms.17 bodies specific to Legionella.9,10 Details about It was found during the first reported outbreak of these tests are summarized in Table 1. Polymer- legionnaires’ disease that tetracycline and erythro- ase chain reaction (PCR)-based diagnostic tests mycin are more effective than other antibiotics, are being tested and some of them show speci- such as b-lactam antibiotics, whereas the use of ficity and sensitivity, although these tests are yet steroids has been associated with unfavorable to be approved by Food and Drug Administration outcome.1 Erythromycin has been the antibiotic Table 1 Diagnostic tests for Legionella species Test Sensitivity (%) Advantages Limitations Culture 20–80 Detects all the Takes technical Legionella species expertise, longer duration >5 d Urinary antigen 70–100 Quick, same-day results, Kits available are limited not affected by mostly to Legionella antibiotic treatment pneumophila; other species may go undetected Serology 80–90 Little effect of antibiotic Paired samples are treatment required Direct fluorescence 25–75 Performed on Technically difficult assay pathologic tissue Atypical Pneumonia 47 of choice for the treatment of legionnaires’ disease Table 2 that is highly effective but has been associated Antibiotic therapy for Legionella, with significant side effects, especially when Chlamydophila, and Mycoplasma community- 16,18–20 used intravenously. Azithromycin, another acquired pneumonia macrolide, has been shown highly effective in treating patients with Legionella infection, with mi- Medication Dose 21 nor side effects. Azithromycin has been suc- Azithromycin 1.5 g over 5 d (500 mg on cessfully used to treat Legionella infection not day 1 followed by 250 mg responding to erythromycin and is frequently cho- for 4 d) 22 sen to treat patients infected with Legionella. Clarithromycin 500 mg PO bid for 10 d Other antibiotics that are effective against Legion- Doxycycline 100 mg bid for 7–21 d ella are clarithromycin, rifampin, ciprofloxacin, and Tetracycline 250 mg qid for 7–21 d doxycycline, and these are used either alone or with erythromycin.18 In a prospective study, it Levofloxacin 750 mg PO/IV for 5–10 d or has been shown that fluoroquinolones are at least 500 mg PO/IV daily for 7–14 d as effective as erythromycin in treating patients with legionnaires’ disease.23 Levofloxacin, either Moxifloxacin 400 mg daily for 10 d a 500 mg for 10 days or 750 mg for 5 days, can Nemonoxacin 500 mg daily for 7 d or cure most of the patients (>95%) and is becoming 750 mg daily for 7 d the antibiotic of choice for legionnaires’ disease.24 Slorithromycina 800 mg on day 1 followed Use of levofloxacin is increasing to treat Legionella by 400 mg daily for 4 d infection and is associated with early clinical a Nemonoxacin and slorithromycin remain in the trial 25 response and shorter hospital stay. A meta- phase and are not yet FDA approved. Nemonoxacin treat- analysis by Burdet and colleagues26 revealed ment was associated with clinical in all patients with C quinolones may be superior to macrolides in treat- pneumoniae identified as etiologic pathogen between 5 ing the Legionella infection. 22 phase II clinical trials (n 9). Slorithromycin shows in vitro activity against C pneumoniae but has not been The usual duration of therapy for most of the an- specifically tested in vivo. tibiotics is 5 to 10 days and is often sufficient to Data from Refs.60,62,66 completely treat patients with Legionella infection, but duration of therapy up to 3 weeks may be considered in immunocompromised patients.17 as multiplex PCR assays, and may be more effica- The route of administration used for the antibiotics cious than detection of Legionella pneumophila depends on the severity of the infection, with serotype-1 antigen in patients’ urine.11,30 parenteral therapy preferred for severe infections. To date, there are few reported cases