|Year : 2015 | Volume
| Issue : 2 | Page : 29-31
Challenges from atypical pathogens in diagnosis and treatment of community-acquired pneumonia
Department of Respiratory Diseases, The First Affiliated Hospital of China Medical University, Shenyang - 110 001, Liaoning Province, China
|Date of Web Publication||25-Jun-2015|
Department of Respiratory Diseases, The First Affiliated Hospital of China Medical University, Shenyang - 110 001, Liaoning Province
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Kang J. Challenges from atypical pathogens in diagnosis and treatment of community-acquired pneumonia. Community Acquir Infect 2015;2:29-31
|How to cite this URL:|
Kang J. Challenges from atypical pathogens in diagnosis and treatment of community-acquired pneumonia. Community Acquir Infect [serial online] 2015 [cited 2022 Aug 18];2:29-31. Available from: http://www.caijournal.com/text.asp?2015/2/2/29/159216
In 1920s when antibiotics were initially used, a new type of pneumonia was discovered in Europe. It is manifested with mild onset symptoms, without sputa, progressively developing into different degrees of pneumonia involving organs out of the lung and without responses to antibiotics, which is different from the typical pneumococcal pneumonia characterized by acute onset, fever and vomica.  In 1938, Reimann firstly used the "atypical pneumonia" to define this kind of infection in respiratory tract.  In 1970s, atypical pneumonia was introduced to medical literatures, indicating the pneumonia caused by Mycoplasmas, chlamydia, Legionellae, psittacosis and Rickett's organisms.  Currently, pathogens of atypical pneumonia are still not clearly defined,  generally referring to Mycoplasmas, chlamydia and Legionellae. Some researchers also included other nonpneumococcal pathogens such as viruses and Rickett's organisms which may also cause pneumonia. Mycoplasmas, chlamydia and Legionellae are considered as the important pathogens of community-acquired pneumonia (CAP) all over the world. , A study from 2001 to 2006 showed that the infections of these three pathogens accounted for 22%, 28%, 21% and 20% in patients with CAP in North America (USA and Canada), Europe, Latin America as well as Asia and Africa, respectively. Meanwhile, viral infection is also a great threat to the health of human beings. This editorial is focusing on the challenges from Mycoplasmas, chlamydia, Legionellae and viruses in diagnosis and/or treatment of CAP.
Drug resistance of Mycoplasma pneumoniae to macrolide antibiotics has attracted extensive attention of researchers. In 2001, mycoplasma with resistance to macrolide antibiotics were firstly found in children with CAP in Japan, and then it was also reported by researchers from other countries.  In recent years, the resistance rate of M. pneumoniae to macrolide antibiotics was dramatically increased in Asia, and the rate was even over 90% in some regions.  From the year 2008 to 2012, the resistance rates of M. pneumoniae to macrolide antibiotics were 68.9%, 90.0%, 98.4%, 95.4%, and 97.0% in CAP patients in Beijing, China, respectively;  the rates were 33.3%, 33.3%, 50.0%, and 60.0% in child CAP patients in Japan from the year 2008 to 2011, respectively, and 14.3%, 16.7%, 28.5%, and 37.5% in adult patients, respectively.  However, in regions out of Asia, the resistance rate was relatively low. For example, the rates were 0%, 2%, 8%, and 22% in The Netherlands, Denmark, France, and USA, and Israel, respectively. ,,,, Despite the resistance, infections of Mycoplasmas can also be cured in patients with the general condition by increasing the courses of treatments. As for severe cases caused by resistant mycoplasma, the efficacy of macrolide antibiotics is poor, and the disease deteriorates rapidly. Therefore, the treatment regimen should be modified right away, otherwise, prognosis will be impacted. Up to now, resistances of mycoplasma to quinolones have not been discovered. 
Till today, studies on chlamydia are limited. Serologic evidence shows that 50% of youths and 75% of the elderly had a history of chlamydia infection, with the initial infection at the school age and the secondary infection mostly at the adult age. Chlamydia infection accounts for 3-10% of CAP in adults. , A large-scale study showed that 7% of CAP had been caused by chlamydia infection all over the world: 8% for North America, 7% for Europe, 6% for Latin America and 5% for Asia and Africa.  A study from China also showed that chlamydia infection accounted for some proportions of CAP pathogens.  Due to the limited attention to chlamydia infection in the past, there are no rapid, standardized, and accurate methods for its diagnosis currently. Therefore, we should strengthen the monitoring, improve its diagnostic methods and achieve early diagnosis and treatment. 
At present, diagnosis and treatment of Legionella infection are great challenges. Studies out of China reported that 90% of Legionnaires' diseases were caused by Legionella pneumophila, and its serogroup 1 (LP1) accounted for 84%.  In Europe and America, urinary antigen assay is the first-line method to detect Legionellae, and 70-80% cases were diagnosed by this assay. , It is simple and easy and can be used in early diagnosis of Legionella infection. But it can only be used in detecting the LP1-type Legionellae, because it is only sensitive to the mAb3 site positive of the LP1-type Legionellae with a sensitive rate as high as 80-90%. However, the sensitive rate of urinary antigen assay is <50% for Legionellae serotype LP1 with non-mAb3 positive and other Legionella species. , Therefore, missed diagnosis frequently occurs. In China, serologic antibody detection is used to determine Legionella infection in most hospitals. However, the antibodies of Legionellae appear 2-3 weeks after the onset of the disease,  and 20-30% of patients do not produce antibodies;  therefore, serologic method is limited to be used in early diagnosis and missed diagnosis easily happen if only one serum sample is detected; yet it is still superior in patients without sputa or with negative urinary antigens. Culture method is the gold standard to diagnose infection of Legionellae. In addition to LP1-type Legionellae, other kinds of Legionellae can also be detected. But special culture medium is required for this method, and it is difficult to be cultured. It also takes a long period of time. Polymerase chain reaction (PCR) is rapid and specific in detecting Legionella infection, but it is a complicated procedure with a long period of time. Special facility is also needed for the procedure which is now carried out only in professional researching laboratories. PCR is promising technique which can be carried out in the clinic. A variety of methods should be developed so as to detect Legionella infection more effectively.
Legionella pneumonia often develops into severe pneumonia, and about 50%  of the patients have to be admitted in intensive care unit with mortality rates of 12.8-33%. , Therefore, infection of Legionellae cannot be ignored in patients with severe CAP and treatments should cover Legionellae before pathogenic diagnosis is made in severe CAP patients. In some severe cases, the disease course still cannot be reversed although treatments with full coverage are performed, which may be associated with superinfection induced by Legionellae. A study has ever shown that non Legionella bacteria were isolated from the pulmonary and hepatic tissues of mice with acute stage Legionella pneumonia, suggesting the occurrence of superinfection.  Hence, we should pay attention to the possible occurrence of superinfection. Besides, inhalation of high-concentration oxygen aggravates acute injury during Legionella pneumonia,  and early extra-corporeal membrane oxygenation, continuous renal replacement therapy may benefit the prognosis of severe cases.
Great challenges exist in the diagnosis of virus-associated CAP. Due to the poor specificity of viral antibody detection and difficulties in implementation of PCR assay, it is difficult to diagnose the sporadic viral infection. Influenza virus infection often involves many regions with severe cases difficult to be treated; therefore much attention should be paid. At the end of the year 2002, an acute respiratory infectious disease caused by the severe acute respiratory syndrome (SARS) coronavirus broke out, that is, the outbreak of SARS. It started from Guangzhou, China and then spread to Vietnam, Singapore, Canada, etc. Finally, the disease covered the Five Continents involving >30 countries. There were 8096 patients infected, of whom 774 died, and the mortality rate was 9.5%.  In March 2009, influenza A H1N1 (H1N1pdm09) broke out in Mexico, and then it spread rapidly to the U.S., later involving Canada, Spain, United Kingdom, New Zealand, Israel, and Germany. Till August 2010, almost every country had patients with confirmed H1N1 infection.  It was estimated that about 123,000-203,000 died of H1N1pdm09 infection in 2009 all over the world, and moreover, the mortality rate of patients <65 years old was very high.  In March 2013, Chinese researchers reported a new fatal influenza virus H7N9. ,,, Till February 2014, there were 354 cases infected with H7N9 in China and 112 cases died at least, with a mortality rate as high as 32%. ,, Nowadays, the number of H7N9 infected cases is still increasing.
Studies showed that early use (within 48 h from the onset) of antiinfluenza virus drugs such as neuraminidase inhibitors (Oseltamivir, etc.,) may improve the symptoms of patients and reduce the rates of severity. Therefore, in a pandemic period of influenza, diagnosis of influenza cannot be excluded, although rapid diagnosis showed a negative result in patients with flu symptoms. Antiinfluenza treatment should be performed immediately according to the clinical diagnosis. However, H1N1 and H7N9 virus resistant to Oseltamivir have been reported , and we must attach great importance to this situation.
In conclusion, atypical pathogens play important roles in CAP, and unsolved challenges still exist in diagnosis and treatment of atypical pneumonia. Especially, pandemic outbreak caused by influenza viruses threatens greatly the health of human beings. It will benefit prognosis of patients to improve diagnostic methods and perform early individualized treatments.
| References|| |
Basarab M, Macrae MB, Curtis CM. Atypical pneumonia. Curr Opin Pulm Med 2014;20:247-51.
Reimann HA. An acute infection of the respiratory tract with atypical pneumonia. J Am Med Assoc 1984;251:936-44.
Marrie TJ, Haldane EV, Noble MA, Faulkner RS, Martin RS, Lee SH. Causes of atypical pneumonia: Results of a 1-year prospective study. Can Med Assoc J 1981;125:1118-23.
van den Hoogen BG, de Jong JC, Groen J, Kuiken T, de Groot R, Fouchier RA, et al.
A newly discovered human pneumovirus isolated from young children with respiratory tract disease. Nat Med 2001;7:719-24.
Plouffe JF. Importance of atypical pathogens of community acquired pneumonia. Clin Infect Dis 2000;31 Suppl 2:S35-9.
Arnold FW, Summersgill JT, Lajoie AS, Peyrani P, Marrie TJ, Rossi P, et al.
A worldwide perspective of atypical pathogens in community-acquired pneumonia. Am J Respir Crit Care Med 2007;175:1086-93.
Okazaki N, Narita M, Yamada S, Izumikawa K, Umetsu M, Kenri T, et al.
Characteristics of macrolide-resistant Mycoplasma pneumoniae
strains isolated from patients and induced with erythromycin in vitro
. Microbiol Immunol 2001;45:617-20.
Zhao F, Liu G, Wu J, Cao B, Tao X, He L, et al.
Surveillance of macrolide-resistant Mycoplasma pneumoniae
in Beijing, China, from 2008 to 2012. Antimicrob Agents Chemother 2013;57:1521-3.
Miyashita N, Oka M, Atypical Pathogen Study Group, Kawai Y, Yamaguchi T, Ouchi K. Macrolide-resistant Mycoplasma pneumoniae
in adults with community-acquired pneumonia. Int J Antimicrob Agents 2010;36:384-5.
Spuesens EB, Meijer A, Bierschenk D, Hoogenboezem T, Donker GA, Hartwig NG, et al.
Macrolide resistance determination and molecular typing of Mycoplasma pneumoniae
in respiratory specimens collected between 1997 and 2008 in The Netherlands. J Clin Microbiol 2012;50:1999-2004.
Uldum SA, Bangsborg JM, Gahrn-Hansen B, Ljung R, Mølvadgaard M, Føns Petersen R, et al.
Epidemic of Mycoplasma pneumoniae
infection in Denmark, 2010 and 2011. Euro Surveill 2012;17:pii: 20073.
Pereyre S, Touati A, Petitjean-Lecherbonnier J, Charron A, Vabret A, Bébéar C. The increased incidence of Mycoplasma pneumoniae
in France in 2011 was polyclonal, mainly involving M. pneumoniae
type 1 strains. Clin Microbiol Infect 2013;19:E212-7.
Yamada M, Buller R, Bledsoe S, Storch GA. Rising rates of macrolide-resistant Mycoplasma pneumoniae
in the central United States. Pediatr Infect Dis J 2012;31:409-10.
Pereyre S, Charron A, Hidalgo-Grass C, Touati A, Moses AE, Nir-Paz R, et al.
The spread of Mycoplasma pneumoniae
is polyclonal in both an endemic setting in France and in an epidemic setting in Israel. PLoS One 2012;7:e38585.
Hanada S, Morozumi M, Takahashi Y, Mochizuki S, Sato T, Suzuki S, et al.
Community-acquired pneumonia caused by macrolide-resistant Mycoplasma pneumoniae
in adults. Intern Med 2014;53:1675-8.
Chedid MB, Chedid MF, Ilha DO, Bozzetti MC, Chaves L, Griza D, et al.
Community-acquired pneumonia by Chlamydophila pneumoniae
: A clinical and incidence study in Brazil. Braz J Infect Dis 2007;11:75-82.
Reechaipichitkul W, Saelee R, Lulitanond V. Prevalence and clinical features of Chlamydia pneumoniae pneumonia at Srinagarind Hospital, Khon Kaen, Thailand. Southeast Asian J Trop Med Public Health 2005;36:151-5.
Zhong NS, Sun T, Zhuo C, D′Souza G, Lee SH, Lan NH, et al
. Ceftaroline fosamil versus ceftriaxone for the treatment of Asian patients with community-acquired pneumonia: A randomised, controlled, double-blind, phase 3, non-inferiority with nested superiority trial. Lancet Infect Dis 2014.
Burillo A, Bouza E. Chlamydophila pneumoniae
. Infect Dis Clin North Am 2010;24:61-71.
Benitez AJ, Winchell JM. Clinical application of a multiplex real-time PCR assay for simultaneous detection of Legionella species
, Legionella pneumophila
, and Legionella pneumophila
serogroup 1. J Clin Microbiol 2013;51:348-51.
European Centre for Disease Prevention and Control. Legionnaires′ disease in Europe, 2011. Stockholm: ECDC; 2013.
Centers for Disease Control and Prevention (CDC). Influenza vaccination coverage among health-care personnel - United States, 2010-11 influenza season. MMWR Morb Mortal Wkly Rep 2011;60:1073-7.
Helbig JH, Uldum SA, Bernander S, Lück PC, Wewalka G, Abraham B, et al.
Clinical utility of urinary antigen detection for diagnosis of community-acquired, travel-associated, and nosocomial Legionnaires′ disease. J Clin Microbiol 2003;41:838-40.
Svarrer CW, Lück C, Elverdal PL, Uldum SA. Immunochromatic kits Xpect Legionella
and BinaxNOW Legionella
for detection of Legionella pneumophila
urinary antigen have low sensitivities for the diagnosis of Legionnaires′ disease. J Med Microbiol 2012;61:213-7.
Elverdal PL, Svarrer CW, Jørgensen CS, Skovsted IC, Uldum SA. Development and validation of ELISA for detection of antibodies to Legionella pneumophila
serogroup 1, 3 and 6 in human sera. J Microbiol Methods 2011;86:298-303.
Fields BS, Benson RF, Besser RE. Legionella
and Legionnaires′ disease: 25 years of investigation. Clin Microbiol Rev 2002;15:506-26.
Engel MF, van Manen L, Hoepelman AI, Thijsen S, Oosterheert JJ. Diagnostic, therapeutic and economic consequences of a positive urinary antigen test for Legionella
spp. in patients admitted with community-acquired pneumonia: A 7-year retrospective evaluation. J Clin Pathol 2013;66:797-802.
von Baum H, Ewig S, Marre R, Suttorp N, Gonschior S, Welte T, et al.
pneumonia: New insights from the German competence network for community acquired pneumonia. Clin Infect Dis 2008;46:1356-64.
Arancibia F, Cortes CP, Valdés M, Cerda J, Hernández A, Soto L, et al.
Importance of Legionella pneumophila
in the etiology of severe community-acquired pneumonia in Santiago, Chile. Chest 2014;145:290-6.
Chen Y, Tateda K, Fujita K, Ishii T, Ishii Y, Kimura S, et al.
Sequential changes of Legionella
antigens and bacterial load in the lungs and urines of a mouse model of pneumonia. Diagn Microbiol Infect Dis 2010;66:253-60.
Tateda K, Deng JC, Moore TA, Newstead MW, Paine R 3 rd
, Kobayashi N, et al.
Hyperoxia mediates acute lung injury and increased lethality in murine Legionella
pneumonia: The role of apoptosis. J Immunol 2003;170:4209-16.
Cheng VC, Lau SK, Woo PC, Yuen KY. Severe acute respiratory syndrome coronavirus as an agent of emerging and reemerging infection. Clin Microbiol Rev 2007;20:660-94.
Fineberg HV. Pandemic preparedness and response - lessons from the H1N1 influenza of 2009. N Engl J Med 2014;370:1335-42.
Simonsen L, Spreeuwenberg P, Lustig R, Taylor RJ, Fleming DM, Kroneman M, et al.
Global mortality estimates for the 2009 Influenza Pandemic from the GLaMOR project: A modeling study. PLoS Med 2013;10:e1001558.
Gao R, Cao B, Hu Y, Feng Z, Wang D, Hu W, et al.
Human infection with a novel avian-origin influenza A (H7N9) virus. N Engl J Med 2013;368:1888-97.
Chen Y, Liang W, Yang S, Wu N, Gao H, Sheng J, et al.
Human infections with the emerging avian influenza A H7N9 virus from wet market poultry: Clinical analysis and characterisation of viral genome. Lancet 2013;381:1916-25.
Yang F, Wang J, Jiang L, et al
. A fatal case caused by novel H7N9 avian influenza A virus in China. Emerg Microbes Infect 2013;2:e19.
Jie Z, Xie J, He Z, Song Y, Hu Y, Li F, et al.
Family outbreak of severe pneumonia induced by H7N9 infection. Am J Respir Crit Care Med 2013;188:114-5.
European Centre for Disease Prevention and Control. Rapid Risk Assessment. Human Infection with Avian Influenza A viruses, China. Stockholm: ECDC; 2014.
To KK, Song W, Lau SY, Que TL, Lung DC, Hung IF, et al.
Unique reassortant of influenza A(H7N9) virus associated with severe disease emerging in Hong Kong. J Infect 2014;69:60-8.
Ho PL, Sin WC, Chan JF, Cheng VC, Chan KH. Severe influenza A H7N9 pneumonia with rapid virological response to intravenous zanamivir. Eur Respir J 2014;44:535-7.
Okomo-Adhiambo M, Fry AM, Su S, Nguyen HT, Elal AA, Negron E, et al.
Oseltamivir-resistant influenza A(H1N1)pdm09 viruses, United States, 2013-14. Emerg Infect Dis 2015;21:136-41.
Qi Y, Fan H, Qi X, Zhu Z, Guo X, Chen Y, et al.
A novel pyrosequencing assay for the detection of neuraminidase inhibitor resistance-conferring mutations among clinical isolates of avian H7N9 influenza virus. Virus Res 2014;179:119-24.