Is atypical pneumonia becoming ... more typical? Molecular testing may help to answer that question, and enhance diagnosis and management of a challenging set of diseases.
In the United States, bacterial-and viral-related respiratory diseases are leading causes of morbidity and mortality, and they disproportionately impact the very young and older members of our population. According to the Centers for Disease Control and Prevention (CDC), in 2010 more than 120,000 deaths were attributable to some form of bacterial or viral respiratory infection, (1) constituting the eighth-leading cause of death in the United States. While approximately 80% of non-cancer/non-emphysema related respiratory disease is attributed to influenza and pathogens causing typical pneumonia, the apparent increasing incidence of atypical pneumonia is presenting clinicians with a potentially concerning trend. (1) (2)
Atypical pneumonia is a form of pneumonia not caused by one of the more traditional pathogens, and it presents clinically in a manner that is inconsistent with typical pneumonia. (2-4) The term was originally introduced in the 1930s3 and was contrasted with the bacterial pneumonia caused by Streptococcus pneumoniae, which at the time was the best known and most commonly occurring form of pneumonia. (4)
As its name suggests. "atypical pneumonia" is caused by atypical organisms. (4), (5) These atypical organisms include special bacteria, viruses, fungi, and protozoa. In addition, this form of pneumonia is atypical in presentation, with only moderate amounts of sputum, limited consolidation, only small increases in white cell counts, and no alveolar exudate. (5), (6 ) At the time that atypical pneumonia was first described, organisms like Mycoplastna, Chlamplophila, and Legionella still were not recognized as bacteria due to their small size, previously uncharacterized structure, and in some cases obligate reproductive lifecycles, and instead were considered to be viruses. (7)
Fast facts--atypical pneumonia
Atypical pneumonia affects nearly one in five people who contract pneumonia and is a significant source of morbidity for patients and costs to healthcare providers. The causative agents of atypical pneumonia may not respond to standard antibiotic therapy. Therefore accurate and rapid identification are essential for proper clinical management and positive clinical outcome. (8)
Clinical presentations of atypical pneumonia are most commonly caused by six organisms: three zoonotic organisms--Chthmydia psittaci (psittacosis), Francisella tularensis (tularemia), and Coxiella bunzetii (Q fever), and three non-zoonotic pathogens--Chlarnydia pneunzoniae. Mycoplasma pnetnoniae. and Legionella species. The latter three organisms account for more than 85% of atypical pneumonia cases. (9) The main characteristic that differentiates atypical from typical pneumonia pathogens is the presence or absence of extrapulmonary findings. In addition to pulmonary presentation, all atypical pneumonia pathogens cause systemic infectious disease, with each pathogen having a preference for certain extrapulmonary organ systems. Pneumonias caused by Streptococcus pnetunoniae, Haentophilus infhtenzae, or Moraxella catarrhalis are typical community-acquired pneumonias (CAPs) with clinical and laboratory findings that are limited to the lungs. (9-14)
Chlamydia pneumoniae is a species of Chlamydophila, an obligate intracellular bacteria. It exists as a non-biologically active elementary body (EB) in between hosts that is resistant to environmental stresses and can survive outside a host for extended periods. The biologically active reticulate bodies use the host cellular machinery to complete its replication. The reticulate bodies then convert back to elementary bodies, and are released back into the lung after causing the death of the host ce11. (15-19)
Mycoplasma pneumonia is a very small bacterium in the class Mollicutes and is related to cold agglutinin disease. This species lacks a peptidoglycan cell wall and instead has a cell membrane that incorporates sterol compounds obtained from the host serum. These organisms are resistant to the effects of penicillins and other beta-lactam antibiotics, which act by disrupting the bacterial cell wall. (20-21)
Legionella is a thin, aerobic, pleomorphic, flagellated, nonspore forming, Gram-negative bacterium of the genus Legionella. L. pnettmophila is the primary human pathogenic bacterium in this group and is the causative agent of legionellosis or Legionnaires' disease. L. pneumophila invades and replicates in macrophages. Once internalized, the bacteria surround themselves in a membranebound vacuole that does not fuse with lysosomes that would otherwise degrade the bacteria. (22-24)
Chlamydia psittaci is a lethal intracellular bacterial species that may cause endemic avian chlamydiosis, epizootic outbreaks in mammals, and respiratory psittacosis in humans. It exists as a nonbiologically active elementary body (EB) in between hosts that is resistant to environmental stresses and can survive outside a host for extended periods. The biologically active reticulate bodies use the host cellular machinery to complete their replication. The reticulate bodies then convert back to elementary bodies, and are released back into the lung after causing the death of the host ce11. (25-27)
Francisella tularensi s is a pathogenic species of Gram-negative bacteria and the causative agent of tularemia or rabbit fever. It is a fastidious, facultative intracellular bacterium that requires cysteine for growth. F. tularensis is easily spread by aerosol and is highly virulent. Tularemia is caused by contact with infected animals or vectors such as ticks, mosquitoes, and deer flies. Reservoir hosts of importance can include rabbits, rodents, birds, and deer. (24), (28) (29)
Coxiella burnetii is a small, obligate intracellular bacterial pathogen that is the causative agent of Q fever. C. burnetii is highly resistant to environmental stresses such as high temperature. osmotic pressure, and ultraviolet light. It can survive standard disinfectants, is resistant to many other environmental changes, and is one of the most infectious known organisms. (30), (31)
Epidemiology and clinical challenges
While six primary organisms have been described as causative agents in atypical pneumonia, C. pneumoniae and M. pneumoniae are the pathogens most commonly associated with it. They are not the organisms usually associated with pneumonia, and the conditions caused by these agents have different courses and respond to different treatments: hence, the identification of the specific causative pathogen is important to guide clinical practice. (32) C. pneumoniae and M. pneumoniae cause nearly 80% of all cases of atypical pneumonia and approximately 17% of all pneumonia among adults and young children, accounting for an estimated two to three million cases of pneumonia and 200,000 pneumonia-related hospitalizations in the United States each year. (6), (33-35)
In adults, M. pneumoniae and C. pneummilae may exacerbate or cause asthma. Because of the potential role of C. pneumoniae in coronary artery disease and multiple sclerosis (MS), and the role of M. pneumoniae and C. pneumoniae in causing or exacerbating asthma, atypical CAPs also have public health importance.38 The importance of the atypical pneumonias is not related to their frequency, but to difficulties in their diagnosis and to their nonresponsiveness to 13-lactam therapy. Clinical presentation is often indistinguishable from other pathogens that cause pneumonia. Culture identification of the organisms is technically demanding and time-consuming and has a low sensitivity, further complicating diagnosis and clinical disposition). (6), (36-38)
Infections may occur throughout the year and can cause periodic outbreaks within small communities. Transmission is by person-to-person contact, most often within closed populations such as hospital wards. childcare centers, schools, and intensive care units. Because diagnosis of acute infections remains a difficult and often time-consuming process, it is a significant contributor to morbidity in these populations, making prevention of secondary cases a high priority of infection control measures. Efforts to prevent secondary cases are diminished by external factors. The fluid medical insurance landscape and increasing costs are creating an environment where the adult working population is more often deferring medical expenses. And during times of economic uncertainty and a strained employment outlook, workers are less inclined to sc11iso1ate.
An expanding role for molecular diagnostics
Due to the rapid onset and progression of pneumonia symptoms and severity, clinicians want to accurately and rapidly detect. identify, and distinguish pathogens causing pneumonia to aid in the selection of appropriate antimicrobial therapy. In all cases traditional methodologies including chest X-ray, culture, staining, and serology can be challenging tinder even the best of circumstances. Unique structural or reproductive characteristics in some cases confer resistance or diminish the effectiveness of common antibiotic therapy. (6), (38)
Culture of the organism is technically demanding and time-consuming, further complicating diagnosis and clinical disposition. Because many of these pathogens are intracellular, diagnosis depends upon serological confirmation. Recently, however, it has become possible to make a diagnosis directly in these cases using DNA or protein microarrays. Hopefully, these will prove to be valuable tools for the rapid determination of patient status, allowing effective and efficient postexposure prophylaxis and treatment. (33), (38)
Because molecular diagnostic methods are rapid and accurate. detection methods that correctly identify C. pneumoniae and M. pnewnoniae can result in:
* Correct determination of the causative pathogen, which may lead to more accurate diagnoses.
* The prescription of appropriate antibiotic therapy(s) that are effective against C. pneumoniae and M. pneumoniae.
* Effective therapy(s) that may lead to a reduced disease course, significantly lower morbidity, and lower overall costs of care.
Is atypical pneumonia on the rise?
A preliminary review of published data would seem to suggest that the incidence of lower-respiratory tract infections due to the pathogens that cause atypical pneumonia is increasing. However, evolving techniques in serology and culture, along with more sensitive molecular diagnostic methods, have given clinicians the tools to make more accurate identification and diagnosis of atypical pneumonia. So while the number of reported cases appears to have risen, it remains unclear if the incidence rates for these pathogens are actually on the rise.
While relatively new, molecular methods such as the polymerase chain reaction (PCR) and other nucleic acid amplification technologies are growing in popularity and importance as tools for the identification, diagnosis, and clinical management of atypical pneumonia. Undoubtedly, continued monitoring of atypical pneumonia and its clinical course with more specific and more sensitive molecular methods may soon offer epidemiologists an answer.
(1.) Minino AM, et al. Deaths: Final data for 2008. National Vital Statistics Report, Volume 59, Number 10, Dec 10, 2011.
(2.) Marston BJ, Plouffe JF, File TM, et al. Incidence of community-acquired pneumonia requiring hospitalization. Results of a population-based active surveillance Study in Ohio. The Community-Based Pneumonia Incidence Study Group. Arch Intern Med. 1997;157(15)1709-1718.
(3.) McCoy WC. Primary atypical pneumonia: a report of 420 cases with one fatality during twenty-seven month at Station Hospital, Camp Rucker, Alabama. Southern Med J. 1946;39(9):696.
(4.) Commission on Acute Respiratory Diseases, Fort Bragg, North Carolina. Primary Atypical Pneumonia. Am J of Public Health and the Nation's Health. 1944;34(0347-357. doi:10.2105/AJPH.34.4.347.
(5.) Memish ZA, Ahmed GA, Arabi YM, Shibl AM, Niederman MS. Microbiology of community-acquired pneumonia in the Gulf Corporation Council states. J of Chemotherapy. 2007;19(Suppl 1):17-23. PMID 18073166.
(6.) Schneeberger PM, Dorigo-Zetsma JW, van der Zee A, van Bon M, van Opstal JL. Diagnosis of atypical pathogens in patients hospitalized with community-acquired respiratory infection. Scandinavian J Infect Dis. 2004;36(4):269-273. dad 0.1080100365540410020127. PMID 15198183.
(7.) National Heart, Lung, and Blood Institute, U.S.A. What causes pneumonia? http://www.nhlbi.nih.gov/health/healthtopics/topics/pnu/. Accessed July 31, 2012.
(8.) Source: CDC, WHO, Internal ELITech Group Marketing.
(9.) Murray HW, Tuazon C. Atypical pneumonias. Med Clin North Am. 1980;64:507-527.
(10.) Martin RE, Bates JH. Atypical pneumonia. Infect Dis Clin North Am. 1991;5:585-601.
(11.) Blasi F Atypical pathogens and respiratory tract infections. Eur Respir J. 2004;24:171-181.
(12.) Marrie TJ, ed. Community-Acquired Pneumonia. New York: Kluwer Academic; 2001.
13. Karetzky M, Cunha BA, Brandstetter RD. The Pneumonias. New York: Springer-Verlag; 1993.
(14.) Cunha BA. Pneumonia Essentials. Royal Oak, ML Physicians Press; 2006. 15. Mayer G, et al. Bacteriology--Chapter Twenty, Chlamydia and Chlamydophila. Medical Microbiology, 6th ed. http://pathmicro.med.sc.edu/mayer/chlamyd.htm. Accessed July 31, 2012.
(16.) Grayston JT, Kuo CC, Campbell LA, Wang SR. Chlamydia pneumoniae sp-nov for Chlamydia sp strain TWAR. Int J Syst Bacteri. 1989;39:88-90.
(17.) Appelt DM, Roupas MR, Way DS, et al. Inhibition of apoptosis in neuronal cells infected with Chlamydophila (Chlamydia) pneumoniae. BMC Neurosci. 2008;9:13. doi:10.1186/1471-2202-9-13. PMC 2266938. PMID 18218130.
(18.) Lang BR. Chlamydia pneumoniae as a differential diagnosis? Follow-up to a case report on progressive pneumonitis in an adolescent, Patient Care. Sept 15, 1991.
(19.) Little L. Elusive pneumonia strain frustrates many clinicians. Medical Tribune. September 19, 1991:6.
(20.) Eaton MD, Meiklejohn G, van Herrick W, Corey M. Studies on the etiology of primary atypical pneumonia: Ill. Specific neutralization of the virus by human serum. J Exp Med. 1945;82(5):329-342. doi:10.1084/ jem.82.5.329. PMC 2135563. PMID 19871504.
(21.) Marmion BR Eaton agentscience and scientific acceptance: a historical commentary. Rev Infect Dis. 1990;12(2):338-353. doi:10.1093/clinids/12.2.338. PMID 2109871.
(22.) Madigan M, Martinko J, eds. Brock Biology of Microorganisms. 11th ed. Prentice Hall; 2005. ISBN 0-13-144329-1.
(23.) Heuner K, Swanson M, eds. Legionella: Molecular Microbiology. Caister Academic Press; 2008. ISBN 978-1-904455-26-4.
(24.) Ryan KJ, Ray CG, eds. Sherds Medical Microbiology. 4th ed. McGraw Hill; 2004. ISBN 0-8385-8529-9.
(25.) Sareyyupoglu B, CantekinZ, Bas B. Chlamydophila psittaci DNA detection in the faeces of cage birds. Zoonoses Public Health. 2007;54(6-7):237242.
(26.) Andersen AA. Serotyping of US isolates of Chlamydophila psittaci from domestic and wild birds. J Vet Diagn Invest. 2005;17(5):479-482. doi:10.1177/104063870501700514. PMID 16312243.
(27.) Dorrestein GM, Wiegman LJ. [Inventory of the shedding of Chlamydia psittaci by parakeets in the Utrecht area using ELISA.I (in Dutch; Flemish). Ti(dschr Diergeheeskd. 1989;114424)1227-1236. PMID 2617495.
(28.) Oyston P, Sjostedt A, Titball R. Tularaemia: bioterrorism defence renews interest in Francisella tularensis. Nat Rev Microbiol. 2004;2(12):967-978. doi:10.1038/nrmicro1045. PMID 15550942.
(29.) Tarnvik A, Berglund L. Tularaemia. Eur Respir J. 2003;21:361-373.
(30.) Voth DE, Heinzen RA. Lounging in a lysosome: The intracellular lifestyle of Coxiella burnetii. Cellular Microbiol. 2007;9(4)1 829-840. doi:10.1111/j.1462-5822.2007.00901.x. PM I D 17381428.
(31.) Sankaran, N. Coxiella burnetii. In: Microbes and People: An A-Z of Microorganisms in Our Lives. Phoenix, AZ; The Oryx Press; 2000:72. ISBN 1-57356217-3. Cunha BA. The atypical pneumonias: clinical diagnosis and importance. Clin Microbial Infect. 2006;12(Suppl 3):12-24. doi:10.1111/j.1469-0691.2006.01393.x. PM ID 16669925.
(32.) Gouriet F, Drancourt M, Raoult D. Multiplexed serology in atypical bacterial pneumonia. Ann NY Acad Sci. 2006;1078:530-540. cloi:10.1196/annals.1374.104. PMID 17114771.
(33.) Hindiyeh M, Carroll KC. Laboratory diagnosis of atypical pneumonia. Semin Respir Infect. 2000;15(2)101-113. doi:10.1053/srin.2000.9592. PMID 10983928.
(34.) Kumar et al. Robbins and Cotran Pathologic Basis of Disease. 8th ed. Philadelphia; 2010;714.
(35.) Tang VW. Molecular diagnostics of atypical pneumonia. Acta Pharmacol Sin. 2003;24(12):1308--1313. PMID 14653964.
(36.) Murphy CG, van de Pol AC, Harper MB, Bachur RG. Clinical predictors of occult pneumonia in the febrile child. Acad Emerg Med. 2007;14(3):243-249. doi:10.1197/j.aem.2006.08.022. PMID 17242382.
(37.) Rutman MS, Bachur R, Harper MB. Radiographic pneumonia in young, highly febrile children with leukocytosis before and after universal conjugate pneumococcal vaccination. Pediatric Emerg Care. 2009;25(1):1-7. doi:10.1097/PEC.0b013e318191 dab2. PMID 19116501.
David DeBonville is the Product Marketing Manager for ELITech Molecular Diagnostics, NA. He has more than 25 years of IVD experience, both as a scientist/product developer and marketing manager. He has written extensively on molecular diagnostics and its role in laboratory testing, clinical endpoint analysis, and the advancement of personalized healthcare