Mixed pneumonic plague and nosocomial MDR-bacterial infection of lung: a rare case report

Mixed pneumonic plague and nosocomial MDR-bacterial infection of lung: a rare case report Background: Plague is a life-threatening disease caused by the bacterium, Yersinia pestis. Madagascar is the leading country for human plague cases worldwide. Human plague is a serious disease, particularly in its septicaemic and pneumonic forms. We report a case of pneumonic plague co-infected by a MDR-Stenotrophomonas maltophilia. Case presentation: A 24 year-old man originated from Soavinandriana, a plague focus, felt uneasy and developed high fever with chills. He started treatment by himself, by private medical care and by a traditional healer for nine days moving several times from place to place. His condition had deteriorated when he presented to a district hospital with a syndrome of dyspnea, bronchial rale and altered state of consciousness. Two days later, plague diagnosis, performed as a last resort, revealed a positive F1 antigen on rapid diagnostic test. Additional tests (pla PCR and plague serology) evidenced a Y. pestis infection. However, streptomycin treatment did not achieve a complete recovery as the course of disease was complicated by the presence of MDR-S. maltophilia in his lung. This opportunistic infection could have been favored by an immunosuppression due to Y. pestis pulmonary infection and probably been acquired during his stay at a District Hospital. He was treated with a combination of ciprofloxacin and gentamycin and recovered fully. Conclusions: Pneumonic plague infection may promote another virulent or avirulent bacterial infection particularly when it is not initially suspected. However, coinfection is rarely described and its occurrence frequency is unknown. In middle or low resources areas, which is the case of most plague endemic countries, control and prevention of infections in health facilities is not optimal. Co-infection with an opportunistic pathogen agent, such as S. maltophilia, is a risk which must not be disregarded as demonstrated by this case report. When deciding of a national control strategy, it should be taken into account in the choice of the first line treatment. Keywords: Yersinia pestis, Stenotrophomonas maltophilia, Pneumonia, Madagascar Background untreated. Pneumonic plague severity is due to Y. pestis Plague is a rapidly progressing disease in humans caused ability to evade the host immune system and also to the by the bacterium, Yersinia pestis [1]. Transmission of rapid establishment, by Y. pestis infection, of a permis- bubonic plague to human occurs after the bite of an sive environment for microbial proliferation in the lung infectious flea. Less frequently, infection may also occur [2]. According to the World Health Organization by inhalation of infectious respiratory droplets spread (WHO), 3248 cases of human plague have been reported from a patient suffering from pneumonic plague. In that between 2010 and 2015 by 11 countries from Africa, the case, the fatality rate is almost 100% if the patient is left Americas and Asia. During this period, Madagascar accounted for 74% of all cases reported worldwide with 18% of case fatality rate, making this island the most * Correspondence: mino@pasteur.mg affected country in the world [3]. Since its introduction Plague Unit- Institut Pasteur de Madagascar, BP1274 Ambatofotsikely, 101 in Madagascar in 1898, plague is endemic within a large Antananarivo, Madagascar Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Andrianaivoarimanana et al. BMC Pulmonary Medicine (2018) 18:92 Page 2 of 6 area in the central and in the northern highlands above infections and pneumonia with considerable morbidity 800 m in elevation [4]. Although plague is mainly a rural in immunocompromised patients [7, 8]. disease, some sporadic cases may occur particularly in the urban setting [5]. In Madagascar, methods for plague Case presentation diagnosis includes F1 antigen RDT, serology, bacterio- On December 30, 2013, a 24 year-old man developed logical culture on selective media at 26–28 °C, and Y. high fever with chills and took self-medication of pestis identification by biochemical profile using API20E trimethoprim-sulfamethoxazole (2x80mg-2x400mg re- kit and by bacteriophage lysis test [3]. Antibiotics spectively) and antipyretic [9]. Later the same day, he susceptibility of each isolated strain is surveyed. Molecu- sought private medical care and received antimalarial lar biology is not used routinely. As per the Plague treatment (3 quinine injections). Two days earlier, he National Control Program (PNCP), specific treatment of transported on his motorcycle a sick person who died pneumonic plague requires streptomycin injection later for unknown reasons. He lived in the village of during 8 days. However, this therapeutic strategy may Ambohimanana within the District of Soavinandriana fail in presence of MDR- Y. pestis [6] or mixed infection (Fig. 1, Site 1), one of the plague foci of the central high- involving other MDR-pathogen. Here, we describe the lands of Madagascar. In the absence of improvement, he features and medical history of a case of pneumonic visited a traditional healer at Andoharanokely- Faratsiho plague complicated by a MDR-Stenotrophomonas malto- (Fig. 1, Site 2) on December 31, and received herbal philia co-infection in a patient who travelled in different medicines and massage for 5 days. His condition contin- locations before reaching the capital Antananarivo as ued to decline with severe asthenia and fever. The trad- well as the case-management. S. maltophilia is an itional healer authorized him to get a treatment by aerobic gram-negative bacillus which is an opportunistic modern medicine. On January 7, 2014, an agent of a and nosocomial pathogen causing blood-stream first-level health center (Fig. 1, Site 2) gave him primary Fig. 1 Map emphasizing on the patient’s itinerary. Site 1 Ambohimanana-Soavinandriana: patient’s village; Site 2 Andoharanokely-Faratsiho: Traditional healer’s village; Site 3 Miarinarivo District Hospital; Site 4 Military Hospital of Antananarivo; Site 5 Anti-Plague Hospital of Ambohimiandra-Antananarivo Andrianaivoarimanana et al. BMC Pulmonary Medicine (2018) 18:92 Page 3 of 6 available treatment (betalactam, antipyretic, bronchodila- sputum associated with a mean abundance of hemoptysis, tor and a prokinetic agent) and evacuated him to Miari- dyspnea, bilateral crackles and breath-sounds rales. The narivo District Hospital (MDH) (Fig. 1, Site 3) for a examination of lymph nodes was normal. Biological ana- syndrome of dyspnea, bronchial rale and altered state of lysis showed a rise in the level of C-reactive protein consciousness. On his admission to MDH on January 8, (12 mg/ml) revealing an inflammatory syndrome. In 2014, he had a temperature of 39.5 °C and a heart rate addition, the second sputum sample collected remained of 120 b/min. The chest radiograph showed right pleural positive for Y. pestis F1 antigen. In order to limit exposure effusion and left radio-opacities of the lower lobe to the disease, the patient was transferred to the (Fig. 2a). Rapid diagnostic test (RDT) for malaria and Anti-Plague Hospital of Ambohimiandra-Antananarivo Widal-Felix serology for typhoid fever were both (APHAA) (Fig. 1, Site 5) the same day at 01:00 p.m. Once negative. Acid-fast bacilli from two sputa cultures were admitted, he was isolated in an individual room. Given the also negative. Therefore, he was treated for pneumonia positive result of Y. pestis F1 antigen and the absence of with ceftriaxone (1 g) intravenously (IV). patient’s health improvement, another therapeutic scheme Considering the fact that he was living in a known was initiated and consisted of a combination of IV plague region, RDT for Y. pestis F1 antigen [10]was ciprofloxacin (400 to 600 mg twice per day for 6 days) and performed on sputum as a differential diagnosis the next IV gentamycin (3 mg/kg per day, for 6 days). day and was markedly positive, suggesting a pneumonic Bacteriological culture of the second sputum sample also plague infection. Intramuscular streptomycin treatment failed to isolate Y. pestis, however growing colonies on was immediately initiated after the diagnosis according cefsulodin-irgasan-novobiocin medium were identified as to the PNCP of the Malagasy Ministry of Health: 0,5 g S. maltophilia on API20E biochemical strip. Antibiotic every 3 h for 2 days followed by 0,5 g every 4 h for 2 days susceptibility test using a disk diffusion method as per the and 1 g twice a day for 4 days. This sputum sample was Clinical and Laboratory Standards Institute guidelines sent to the Central Laboratory for Plague at Institut showed that S. maltophilia isolate was sensitive to Pasteur de Madagascar for bacteriological confirmation trimethoprim-sulfamethoxazole, ciprofloxacin and chlor- [11] but did not yield Y. pestis strain; instead Citrobacter amphenicol, but was resistant to tetracycline, strepto- freundii was identified. After completing an 8-day course mycin, gentamycin and ampicillin. Strain Escherichia coli of streptomycin treatment, the patient’s condition ATCC®25,922 was used as control. Moreover, plague remained stable without signs of recovery. Therefore, on ELISA serology testing in paired serum samples January 17, 2014, he was discharged from the hospital by (Ethical Committee authorization 068- MSANPE of his family against medical advice and sought treatment July 29, 2011) performed at a 7-day interval showed at the Military Hospital of Antananarivo (MHA) (Fig. 1, a three-fold rise in anti-F1 immunoglobulin G titer Site 4). On his admission at MHA on January 18, 2014 [12]and PCRtesttargeting Y. pestis plasminogen at 11:30 a.m., a second chest radiograph revealed an activator (pla) gene [13] was positive on all sputum enlargement of left opacities and appearance of right samples. nodular opacity, but a decrease of right pleural effusion The suggested bi-therapy treatment led to the pa- (Fig. 2b). His status has still altered and marked with tient’s condition improvement and recovery. Upon asthenia, anorexia, weight loss, greyish complexion, discharge, on January 27, 2014, his third chest X-ray colored conjunctiva with a temperature of 38.5 °C. Dur- demonstrated a decrease of right opacity and left ing physical examination, he had a cough with purulent pleural effusion (Fig. 2c). Fig. 2 Chest X-ray of the pneumonic plague patient. a on admission at Miarinarivo District Hospital: chest X-ray image revealed right pleural effusion and radio-opacities of left lower lobe, (b) On presentation to the Military Hospital of Antananarivo (10 days after A): enlargement of left opacities and appearance of right nodular opacity, decrease of right pleural effusion, and (c) Upon discharge at Anti-plague Hospital of Ambohimiandra- Antananarivo (9 days after B), decrease of right opacity and left pleural effusion Andrianaivoarimanana et al. BMC Pulmonary Medicine (2018) 18:92 Page 4 of 6 Discussion establish a permissive environment for proliferation of Madagascar is one of the most active plague regions in usually nonpathogenic bacteria [2]. In middle or low the world and was the origin of a natural multi-drug resources areas, which is the case of most plague resistant strain of Y. pestis [6]. Incidence has declined in endemic countries, control and prevention of infec- the last 2 years but there has been an increase in the tions in health facilities is not optimal. Co-infection overall case-fatality rate (23% in 2015) associated with with an opportunistic pathogen agent is a risk which the high frequency of pneumonic form (23.3%) [3]. must not be disregarded. Indeed, S. maltophilia is an Within 24–36 h after the onset of symptoms, pneu- important emergent opportunistic pathogen, causing monic plague progresses to an irreversible and lethal lung colonization or pulmonary infections among syndrome that cannot be effectively treated [14]. Indeed, immunosuppressed patients. According to available most pneumonic plague patients succumb in less than clinical information, distinction between S. maltophi- 3 days without prompt and adequate treatment. For the lia colonization and infection can be confusing [20]. present case, which is most likely a primary pneumonic in- His chest X-ray, 10 days after MDH admission, fection, the early doses of trimethoprime-sulfamethoxazole showed right nodular opacity (Fig. 2b)and might be self-administered might have induced a latent phase in evocative of S. maltophilia colonization or infection pneumonic plague infection, a delayed infection course of a severely impaired host [21, 22]. which allowed the patient to survive despite a delay of S. maltophilia infection/colonization management is plague treatment. It was demonstrated that the most com- often problematic due to its inherent resistance to mul- mon indications for self-medication were pain, fever and tiple broad-spectrum antibiotic agents [21]. Thus, for cough [9]. In addition, antibiotic medication rapidly clears the presenting case, the initial streptomycin treatment the sputum of plague bacilli, so that a patient is generally was effective for Y. pestis infection but not for S. malto- not infective within hours after initiation of effective anti- philia. The use of ciprofloxacin in secondary bi-therapy biotic treatment [15]. In this report, clinical presentation allowed the recovery of the patient and this antibiotic is and epidemiological evidence (residence in a plague also recommended as an alternative treatment for S. endemic area) are consistent with a pneumonic plague maltophilia infection [23]. Indeed, recent study also infection. Additionally, laboratory results met the criterion supported the broader use of oral ciprofloxacin for treat- of the WHO standard case definition for a “Confirmed ment of human plague including pneumonic form. Its plague case” [5]. It is noteworthy that F1 antigen is specific bactericidal activity is comparable to that of strepto- to Y. pestis [16], temperature-stable and is excreted in large mycin, and its mode of administration is less restrictive; amount in samples from plague infected people [10]. The more acceptable for exposed population [24]. In failure of Y. pestis isolation by bacterial culture is not addition, a wide range of antibiotics was already in vitro uncommon if antibiotic treatment was administered before tested for their susceptibility to geographically diverse sampling [17, 18]. Positive results of F1 antigen RDT on all strains of Y. pestis which provide alternatives for plague sputum samples showed that Y. pestis F1 antigen could treatment [25]. Another study had also investigated the persist and be detected several days after the beginning of susceptibility patterns of Y. pestis strains from diverse treatment, when the plague bacillus is no longer sources to 12 antimicrobial agents and showed that a viable [10, 17, 19]; for this case, F1 antigen persisted large panel of Y. pestis remained susceptible not only to for 10 days after the beginning of treatment and drugs traditionally used to treat plague (streptomycin, 20 days after disease onset. Due to the failure of the doxycycline and chloramphenicol), but also to newer culture, sensitivity of Y. pestis to streptomycin was agents (broad-spectrum cephalosporins and quinolones). not tested; however a resistance is doubtful because The most active compounds against Y. pestis included the patient would have likely succumbed to pneu- ceftriaxone and trimethoprim-sulfamethoxazole, quino- monic plague infection if the complete streptomycin lones [26]. treatment was not effective. The isolation of MDR-S. The severe pneumonic plague outbreak which oc- maltophilia from his sputum collected at MDH sug- curred in urban context in Madagascar recently [27] gested that the patient had a mixed infection with Y. questioned the pertinence of maintaining strepto- pestis and S. maltophilia. This nosocomial infection mycin as the first line treatment. The challenge of the has probably been acquired during his stay at this clinical diagnosis in the context of an urban outbreak hospital and may have been favored by patient associated to the intense circulation of other potential immunocompromised condition. Without other med- causes of pneumonia could justify the choice of an ical information, his immune response maybe attenu- antibiotic with a broader spectrum. This case report ated by the courseof his diseaseorbymalnutrition suggests that the possibility of mixed infection, espe- with a notable weight loss. However, it has been cially in a nosocomial context, must be part of this shown that pulmonary infection by Y. pestis may strategic discussion. Andrianaivoarimanana et al. BMC Pulmonary Medicine (2018) 18:92 Page 5 of 6 To date, coinfection involving pneumonic plague and Consent for publication Written informed consent was obtained from the patient for publication of other pulmonary infections has been rarely described. this Case report and any accompanying images. A copy of the signed Indeed, Quan et al. reported the recovery of Y. pestis consent is available to the Editors on request. and other respiratory pathogens from mammals and Competing interests ectoparasites but not in human during plague investiga- The authors declare that they have no competing interests. tions [28]. However in 2004, two cases of confirmed infection for plague and leptospirosis have been ob- Publisher’sNote served in the Democratic Republic of Congo, both of Springer Nature remains neutral with regard to jurisdictional claims in which can cause severe pulmonary manifestations [29]. published maps and institutional affiliations. To our knowledge, this study is the first describing a Author details co-infection with Y. pestis and S. maltophilia in 1 Plague Unit- Institut Pasteur de Madagascar, BP1274 Ambatofotsikely, 101 Madagascar and emphasizes on the complicated man- Antananarivo, Madagascar. Department of Infectious Hazard Management, World Health Organization, Avenue Appia 20, CH-1211, 27 Geneva, agement of such pneumonic infections. Switzerland. Centre Hospitalier Anti-pesteux d’Ambohimiandra, 101 Antananarivo, Madagascar. Centre Hospitalier de District de Miarinarivo, Antananarivo, Madagascar. Institut Pasteur de Madagascar, BP1274 Conclusion 6 Ambatofotsikely, 101 Antananarivo, Madagascar. Present address: Service de In conclusion, although mixed infection of lung with Y. Santé des Armées, Direction Centrale, Division Expertise et Stratégie Santé de Défense, 60 Boulevard du Général Martial Valin – CS21623, 75509 Paris Cedex pestis and S. maltophilia is rare, a combined therapy 15, France. should be discussed when the condition of a plague patient does not improve under an appropriate treat- Received: 16 August 2017 Accepted: 18 May 2018 ment with streptomycin. The availability of plague alter- native treatments is also crucial to improve the patient’s References outcome and need to be implemented in the PNCP of 1. Stenseth NC, Atshabar BB, Begon M, Belmain SR, Bertherat E, Carniel E, et al. Plague: past, present, and future. PLoS Med. 2008;5:e3. the Malagasy Ministry of Health thus a new plague 2. Price PA, Jin J, Goldman WE. Pulmonary infection by Yersinia pestis rapidly therapeutic scheme is currently under evaluation. establishes a permissive environment for microbial proliferation. Proc Natl This situation has been considered to be an important Acad Sci U S A. 2012;109:3083–8. 3. World Health Organization. Plague around the world, 2010–2015. Wkly alert and allowed the establishment of a contingency Epidemiol Rec. 2016;91:89–93. plan to counteract plague epidemics, particularly the 4. Brygoo ER. Epidemiologie de la peste à Madagascar. Arch Inst Pasteur occurrence of the pneumonic form in urban areas where Madagascar. 1966;35:9–147. 5. World Health Organization. International meeting on preventing and the transmission risk at national and international levels controlling plague: the old calamity still has a future. Wkly Epidemiol Rec. is high. 2006;81:278–84. 6. Galimand M, Guiyoule A, Gerbaud G, Rasoamanana B, Chanteau S, Carniel E, et al. Multidrug resistance in Yersinia pestis mediated by a transferable Abbreviations plasmid. N Engl J Med. 1997;337:677–80. APHAA: Anti-Plague Hospital of Ambohimiandra-Antananarivo; 7. Khardori N, Elting L, Wong E, Schable B, Bodey GP. Nosocomial infections MDH: Miarinarivo District Hospital; MHA: Military Hospital of Antananarivo; due to Xanthomonas maltophilia (Pseudomonas maltophilia) in patients with PNCP: Plague National Control Program cancer. Rev Infect Dis. 1990;12:997–1003. 8. Looney WJ, Narita M, Mühlemann K. Stenotrophomonas maltophilia:an Acknowledgements emerging opportunist human pathogen. Lancet Infect Dis. 2009;9:312–23. We thank all the health workers involved in the care of this patient, the staff 9. Sendrasoa FA, Razanakoto NH, Ranaivo IM, Andrianasolo RL, Randria MJDD, of the Plague Unit for technical assistance, and Dr. Tendro Tondrasoa Antibiotic RRA. Antimalarial Selfmedication in Antananarivo, Madagascar. Int Ramaharitra for the patient’s itinerary mapping. Sincere thanks to Prof. J Infect Dis Ther. 2016;1:1–5. Michel Simonet for critical review of the manuscript. 10. Chanteau S, Rahalison L, Ralafiarisoa L, Foulon J, Ratsitorahina M, Ratsifasoamanana L, et al. Development and testing of a rapid diagnostic test for bubonic and pneumonic plague. Lancet. 2003;361:211–6. Funding 11. Rasoamanana B, Rahalison L, Raharimanana C, Chanteau S. Comparison of This work was supported by the Institut Pasteur de Madagascar. There was Yersinia CIN agar and mouse inoculation assay for the diagnosis of plague. no role of the funding body in the writing of the manuscript. Trans R Soc Trop Med Hyg. 1996;90:651. 12. Rasoamanana B, Leroy F, Boisier P, Rasolomaharo M, Buchy P, Carniel E, et al. Field evaluation of an immunoglobulin G anti-F1 enzyme-linked Authors’ contributions immunosorbent assay for serodiagnosis of human plague in Madagascar. VA analyzed clinical data, literature search, wrote the manuscript, EB Clin Diagn Lab Immunol. 1997;4:587–91. provided advice on the management of the event and reviewed the 13. Hinnebusch J, Schwan TG. New method for plague surveillance using manuscript, RR and TR collected and interpreted data, CR provided advice polymerase chain reaction to detect Yersinia pestis in fleas. J Clin Microbiol. on the management of the event, literature search, reviewed the manuscript, 1993;31:1511–4. MR analyzed clinical data, investigated the case and wrote the manuscript. 14. Pechous RD, Sivaraman V, Stasulli NM, Goldman WE. Pneumonic plague: the All authors read and approved the final version of the report. darker side of Yersinia pestis. Trends Microbiol. 2016;24:190–7. 15. Butler TC. Plague and other Yersinia infections. In: Greenough WB, editor. Ethics approval and consent to participate Current topics in infectious disease. New York: Plenum Medical Book Blood collection was approved by the National Ethics Committee of the Company; 1983. Malagasy Ministry of Health (ref 068- MSANPE of July 29, 2011). 16. Perry RD, Fetherston JD. Yersinia pestis–etiologic agent of plague. Clin See consent for publication below. Microbiol Rev. 1997;10:35–66. Andrianaivoarimanana et al. BMC Pulmonary Medicine (2018) 18:92 Page 6 of 6 17. Bertherat E, Thullier P, Shako JC, England K, Koné ML, Arntzen L, et al. Lessons learned about pneumonic plague diagnosis from two outbreaks, Democratic Republic of the Congo. Emerg Infect Dis. 2011;17:778–84. 18. Begier EM, Asiki G, Anywaine Z, Yockey B, Schriefer ME, Aleti P, et al. Pneumonic plague cluster, Uganda, 2004. Emerg Infect Dis. 2006;12:460–7. 19. Ratsitorahina M, Chanteau S, Rahalison L, Ratsifasoamanana L, Boisier P. Epidemiological and diagnostic aspects of the outbreak of pneumonic plague in Madagascar. Lancet. 2000;355:111–3. 20. Nicodemo AC, Garcia Paez JI. Antimicrobial therapy for Stenotrophomonas maltophilia infections. Eur J Clin Microbiol Infect Dis. 2007;26:229–37. 21. Fujita J, Yamadori I, Xu G, et al. Clinical features of Stenotrophomonas maltophilia pneumonia in immunocompromised patients. Respir Med. 1996; 90:35–8. 22. Pathmanathan A, Waterer GW. Significance of positive Stenotrophomonas maltophilia culture in acute respiratory tract infection. EurRespir J. 2005;25: 911–4. 23. Samonis G, Karageorgopoulos DE, Maraki S, Levis P, Dimopoulou D, Spernovasilis NA, et al. Stenotrophomonas maltophilia infections in a general hospital: patient characteristics, antimicrobial susceptibility, and treatment outcome. PLoS One. 2012;7:e37375. 24. Apangu T, Griffith K, Abaru J, Candini G, Apio H, Okoth F, et al. Successful treatment of human plague with oral ciprofloxacin. Emerg Infect Dis. 2017; 23(3):553–55. 25. Heine HS, Hershfield J, Marchand C, Miller L, Halasohoris S, Purcell BK, et al. In vitro antibiotic susceptibilities of Yersinia pestis determined by broth microdilution following CLSI methods. Antimicrob Agents Chemother. 2015; 59:1919–21. 26. Wong JD, Barash JR, Sandfort RF, Janda JM. Susceptibilities of Yersinia pestis strains to 12 antimicrobial agents. Antimicrob Agents Chemother. 2000;44: 1995–6. 27. Roberts L. Echoes of Ebola as plague hits Madagascar. Science. 2017;358:430–1. 28. Quan TJ, Tsuchiya KR, Carter LG. Isolation of pathogens other than Yersinia pestis during plague investigations. J Wildl Dis. 1979;15:505–10. 29. Bertherat E, Mueller MJ, Shako JC, Picardeau M. Discovery of a leptospirosis cluster amidst a pneumonic plague outbreak in a miners’ camp in the Democratic Republic of the Congo. Int J Environ Res Public Health. 2014;11: 1824–33. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Pulmonary Medicine Springer Journals

Mixed pneumonic plague and nosocomial MDR-bacterial infection of lung: a rare case report

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Abstract

Background: Plague is a life-threatening disease caused by the bacterium, Yersinia pestis. Madagascar is the leading country for human plague cases worldwide. Human plague is a serious disease, particularly in its septicaemic and pneumonic forms. We report a case of pneumonic plague co-infected by a MDR-Stenotrophomonas maltophilia. Case presentation: A 24 year-old man originated from Soavinandriana, a plague focus, felt uneasy and developed high fever with chills. He started treatment by himself, by private medical care and by a traditional healer for nine days moving several times from place to place. His condition had deteriorated when he presented to a district hospital with a syndrome of dyspnea, bronchial rale and altered state of consciousness. Two days later, plague diagnosis, performed as a last resort, revealed a positive F1 antigen on rapid diagnostic test. Additional tests (pla PCR and plague serology) evidenced a Y. pestis infection. However, streptomycin treatment did not achieve a complete recovery as the course of disease was complicated by the presence of MDR-S. maltophilia in his lung. This opportunistic infection could have been favored by an immunosuppression due to Y. pestis pulmonary infection and probably been acquired during his stay at a District Hospital. He was treated with a combination of ciprofloxacin and gentamycin and recovered fully. Conclusions: Pneumonic plague infection may promote another virulent or avirulent bacterial infection particularly when it is not initially suspected. However, coinfection is rarely described and its occurrence frequency is unknown. In middle or low resources areas, which is the case of most plague endemic countries, control and prevention of infections in health facilities is not optimal. Co-infection with an opportunistic pathogen agent, such as S. maltophilia, is a risk which must not be disregarded as demonstrated by this case report. When deciding of a national control strategy, it should be taken into account in the choice of the first line treatment. Keywords: Yersinia pestis, Stenotrophomonas maltophilia, Pneumonia, Madagascar Background untreated. Pneumonic plague severity is due to Y. pestis Plague is a rapidly progressing disease in humans caused ability to evade the host immune system and also to the by the bacterium, Yersinia pestis [1]. Transmission of rapid establishment, by Y. pestis infection, of a permis- bubonic plague to human occurs after the bite of an sive environment for microbial proliferation in the lung infectious flea. Less frequently, infection may also occur [2]. According to the World Health Organization by inhalation of infectious respiratory droplets spread (WHO), 3248 cases of human plague have been reported from a patient suffering from pneumonic plague. In that between 2010 and 2015 by 11 countries from Africa, the case, the fatality rate is almost 100% if the patient is left Americas and Asia. During this period, Madagascar accounted for 74% of all cases reported worldwide with 18% of case fatality rate, making this island the most * Correspondence: mino@pasteur.mg affected country in the world [3]. Since its introduction Plague Unit- Institut Pasteur de Madagascar, BP1274 Ambatofotsikely, 101 in Madagascar in 1898, plague is endemic within a large Antananarivo, Madagascar Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Andrianaivoarimanana et al. BMC Pulmonary Medicine (2018) 18:92 Page 2 of 6 area in the central and in the northern highlands above infections and pneumonia with considerable morbidity 800 m in elevation [4]. Although plague is mainly a rural in immunocompromised patients [7, 8]. disease, some sporadic cases may occur particularly in the urban setting [5]. In Madagascar, methods for plague Case presentation diagnosis includes F1 antigen RDT, serology, bacterio- On December 30, 2013, a 24 year-old man developed logical culture on selective media at 26–28 °C, and Y. high fever with chills and took self-medication of pestis identification by biochemical profile using API20E trimethoprim-sulfamethoxazole (2x80mg-2x400mg re- kit and by bacteriophage lysis test [3]. Antibiotics spectively) and antipyretic [9]. Later the same day, he susceptibility of each isolated strain is surveyed. Molecu- sought private medical care and received antimalarial lar biology is not used routinely. As per the Plague treatment (3 quinine injections). Two days earlier, he National Control Program (PNCP), specific treatment of transported on his motorcycle a sick person who died pneumonic plague requires streptomycin injection later for unknown reasons. He lived in the village of during 8 days. However, this therapeutic strategy may Ambohimanana within the District of Soavinandriana fail in presence of MDR- Y. pestis [6] or mixed infection (Fig. 1, Site 1), one of the plague foci of the central high- involving other MDR-pathogen. Here, we describe the lands of Madagascar. In the absence of improvement, he features and medical history of a case of pneumonic visited a traditional healer at Andoharanokely- Faratsiho plague complicated by a MDR-Stenotrophomonas malto- (Fig. 1, Site 2) on December 31, and received herbal philia co-infection in a patient who travelled in different medicines and massage for 5 days. His condition contin- locations before reaching the capital Antananarivo as ued to decline with severe asthenia and fever. The trad- well as the case-management. S. maltophilia is an itional healer authorized him to get a treatment by aerobic gram-negative bacillus which is an opportunistic modern medicine. On January 7, 2014, an agent of a and nosocomial pathogen causing blood-stream first-level health center (Fig. 1, Site 2) gave him primary Fig. 1 Map emphasizing on the patient’s itinerary. Site 1 Ambohimanana-Soavinandriana: patient’s village; Site 2 Andoharanokely-Faratsiho: Traditional healer’s village; Site 3 Miarinarivo District Hospital; Site 4 Military Hospital of Antananarivo; Site 5 Anti-Plague Hospital of Ambohimiandra-Antananarivo Andrianaivoarimanana et al. BMC Pulmonary Medicine (2018) 18:92 Page 3 of 6 available treatment (betalactam, antipyretic, bronchodila- sputum associated with a mean abundance of hemoptysis, tor and a prokinetic agent) and evacuated him to Miari- dyspnea, bilateral crackles and breath-sounds rales. The narivo District Hospital (MDH) (Fig. 1, Site 3) for a examination of lymph nodes was normal. Biological ana- syndrome of dyspnea, bronchial rale and altered state of lysis showed a rise in the level of C-reactive protein consciousness. On his admission to MDH on January 8, (12 mg/ml) revealing an inflammatory syndrome. In 2014, he had a temperature of 39.5 °C and a heart rate addition, the second sputum sample collected remained of 120 b/min. The chest radiograph showed right pleural positive for Y. pestis F1 antigen. In order to limit exposure effusion and left radio-opacities of the lower lobe to the disease, the patient was transferred to the (Fig. 2a). Rapid diagnostic test (RDT) for malaria and Anti-Plague Hospital of Ambohimiandra-Antananarivo Widal-Felix serology for typhoid fever were both (APHAA) (Fig. 1, Site 5) the same day at 01:00 p.m. Once negative. Acid-fast bacilli from two sputa cultures were admitted, he was isolated in an individual room. Given the also negative. Therefore, he was treated for pneumonia positive result of Y. pestis F1 antigen and the absence of with ceftriaxone (1 g) intravenously (IV). patient’s health improvement, another therapeutic scheme Considering the fact that he was living in a known was initiated and consisted of a combination of IV plague region, RDT for Y. pestis F1 antigen [10]was ciprofloxacin (400 to 600 mg twice per day for 6 days) and performed on sputum as a differential diagnosis the next IV gentamycin (3 mg/kg per day, for 6 days). day and was markedly positive, suggesting a pneumonic Bacteriological culture of the second sputum sample also plague infection. Intramuscular streptomycin treatment failed to isolate Y. pestis, however growing colonies on was immediately initiated after the diagnosis according cefsulodin-irgasan-novobiocin medium were identified as to the PNCP of the Malagasy Ministry of Health: 0,5 g S. maltophilia on API20E biochemical strip. Antibiotic every 3 h for 2 days followed by 0,5 g every 4 h for 2 days susceptibility test using a disk diffusion method as per the and 1 g twice a day for 4 days. This sputum sample was Clinical and Laboratory Standards Institute guidelines sent to the Central Laboratory for Plague at Institut showed that S. maltophilia isolate was sensitive to Pasteur de Madagascar for bacteriological confirmation trimethoprim-sulfamethoxazole, ciprofloxacin and chlor- [11] but did not yield Y. pestis strain; instead Citrobacter amphenicol, but was resistant to tetracycline, strepto- freundii was identified. After completing an 8-day course mycin, gentamycin and ampicillin. Strain Escherichia coli of streptomycin treatment, the patient’s condition ATCC®25,922 was used as control. Moreover, plague remained stable without signs of recovery. Therefore, on ELISA serology testing in paired serum samples January 17, 2014, he was discharged from the hospital by (Ethical Committee authorization 068- MSANPE of his family against medical advice and sought treatment July 29, 2011) performed at a 7-day interval showed at the Military Hospital of Antananarivo (MHA) (Fig. 1, a three-fold rise in anti-F1 immunoglobulin G titer Site 4). On his admission at MHA on January 18, 2014 [12]and PCRtesttargeting Y. pestis plasminogen at 11:30 a.m., a second chest radiograph revealed an activator (pla) gene [13] was positive on all sputum enlargement of left opacities and appearance of right samples. nodular opacity, but a decrease of right pleural effusion The suggested bi-therapy treatment led to the pa- (Fig. 2b). His status has still altered and marked with tient’s condition improvement and recovery. Upon asthenia, anorexia, weight loss, greyish complexion, discharge, on January 27, 2014, his third chest X-ray colored conjunctiva with a temperature of 38.5 °C. Dur- demonstrated a decrease of right opacity and left ing physical examination, he had a cough with purulent pleural effusion (Fig. 2c). Fig. 2 Chest X-ray of the pneumonic plague patient. a on admission at Miarinarivo District Hospital: chest X-ray image revealed right pleural effusion and radio-opacities of left lower lobe, (b) On presentation to the Military Hospital of Antananarivo (10 days after A): enlargement of left opacities and appearance of right nodular opacity, decrease of right pleural effusion, and (c) Upon discharge at Anti-plague Hospital of Ambohimiandra- Antananarivo (9 days after B), decrease of right opacity and left pleural effusion Andrianaivoarimanana et al. BMC Pulmonary Medicine (2018) 18:92 Page 4 of 6 Discussion establish a permissive environment for proliferation of Madagascar is one of the most active plague regions in usually nonpathogenic bacteria [2]. In middle or low the world and was the origin of a natural multi-drug resources areas, which is the case of most plague resistant strain of Y. pestis [6]. Incidence has declined in endemic countries, control and prevention of infec- the last 2 years but there has been an increase in the tions in health facilities is not optimal. Co-infection overall case-fatality rate (23% in 2015) associated with with an opportunistic pathogen agent is a risk which the high frequency of pneumonic form (23.3%) [3]. must not be disregarded. Indeed, S. maltophilia is an Within 24–36 h after the onset of symptoms, pneu- important emergent opportunistic pathogen, causing monic plague progresses to an irreversible and lethal lung colonization or pulmonary infections among syndrome that cannot be effectively treated [14]. Indeed, immunosuppressed patients. According to available most pneumonic plague patients succumb in less than clinical information, distinction between S. maltophi- 3 days without prompt and adequate treatment. For the lia colonization and infection can be confusing [20]. present case, which is most likely a primary pneumonic in- His chest X-ray, 10 days after MDH admission, fection, the early doses of trimethoprime-sulfamethoxazole showed right nodular opacity (Fig. 2b)and might be self-administered might have induced a latent phase in evocative of S. maltophilia colonization or infection pneumonic plague infection, a delayed infection course of a severely impaired host [21, 22]. which allowed the patient to survive despite a delay of S. maltophilia infection/colonization management is plague treatment. It was demonstrated that the most com- often problematic due to its inherent resistance to mul- mon indications for self-medication were pain, fever and tiple broad-spectrum antibiotic agents [21]. Thus, for cough [9]. In addition, antibiotic medication rapidly clears the presenting case, the initial streptomycin treatment the sputum of plague bacilli, so that a patient is generally was effective for Y. pestis infection but not for S. malto- not infective within hours after initiation of effective anti- philia. The use of ciprofloxacin in secondary bi-therapy biotic treatment [15]. In this report, clinical presentation allowed the recovery of the patient and this antibiotic is and epidemiological evidence (residence in a plague also recommended as an alternative treatment for S. endemic area) are consistent with a pneumonic plague maltophilia infection [23]. Indeed, recent study also infection. Additionally, laboratory results met the criterion supported the broader use of oral ciprofloxacin for treat- of the WHO standard case definition for a “Confirmed ment of human plague including pneumonic form. Its plague case” [5]. It is noteworthy that F1 antigen is specific bactericidal activity is comparable to that of strepto- to Y. pestis [16], temperature-stable and is excreted in large mycin, and its mode of administration is less restrictive; amount in samples from plague infected people [10]. The more acceptable for exposed population [24]. In failure of Y. pestis isolation by bacterial culture is not addition, a wide range of antibiotics was already in vitro uncommon if antibiotic treatment was administered before tested for their susceptibility to geographically diverse sampling [17, 18]. Positive results of F1 antigen RDT on all strains of Y. pestis which provide alternatives for plague sputum samples showed that Y. pestis F1 antigen could treatment [25]. Another study had also investigated the persist and be detected several days after the beginning of susceptibility patterns of Y. pestis strains from diverse treatment, when the plague bacillus is no longer sources to 12 antimicrobial agents and showed that a viable [10, 17, 19]; for this case, F1 antigen persisted large panel of Y. pestis remained susceptible not only to for 10 days after the beginning of treatment and drugs traditionally used to treat plague (streptomycin, 20 days after disease onset. Due to the failure of the doxycycline and chloramphenicol), but also to newer culture, sensitivity of Y. pestis to streptomycin was agents (broad-spectrum cephalosporins and quinolones). not tested; however a resistance is doubtful because The most active compounds against Y. pestis included the patient would have likely succumbed to pneu- ceftriaxone and trimethoprim-sulfamethoxazole, quino- monic plague infection if the complete streptomycin lones [26]. treatment was not effective. The isolation of MDR-S. The severe pneumonic plague outbreak which oc- maltophilia from his sputum collected at MDH sug- curred in urban context in Madagascar recently [27] gested that the patient had a mixed infection with Y. questioned the pertinence of maintaining strepto- pestis and S. maltophilia. This nosocomial infection mycin as the first line treatment. The challenge of the has probably been acquired during his stay at this clinical diagnosis in the context of an urban outbreak hospital and may have been favored by patient associated to the intense circulation of other potential immunocompromised condition. Without other med- causes of pneumonia could justify the choice of an ical information, his immune response maybe attenu- antibiotic with a broader spectrum. This case report ated by the courseof his diseaseorbymalnutrition suggests that the possibility of mixed infection, espe- with a notable weight loss. However, it has been cially in a nosocomial context, must be part of this shown that pulmonary infection by Y. pestis may strategic discussion. Andrianaivoarimanana et al. BMC Pulmonary Medicine (2018) 18:92 Page 5 of 6 To date, coinfection involving pneumonic plague and Consent for publication Written informed consent was obtained from the patient for publication of other pulmonary infections has been rarely described. this Case report and any accompanying images. A copy of the signed Indeed, Quan et al. reported the recovery of Y. pestis consent is available to the Editors on request. and other respiratory pathogens from mammals and Competing interests ectoparasites but not in human during plague investiga- The authors declare that they have no competing interests. tions [28]. However in 2004, two cases of confirmed infection for plague and leptospirosis have been ob- Publisher’sNote served in the Democratic Republic of Congo, both of Springer Nature remains neutral with regard to jurisdictional claims in which can cause severe pulmonary manifestations [29]. published maps and institutional affiliations. To our knowledge, this study is the first describing a Author details co-infection with Y. pestis and S. maltophilia in 1 Plague Unit- Institut Pasteur de Madagascar, BP1274 Ambatofotsikely, 101 Madagascar and emphasizes on the complicated man- Antananarivo, Madagascar. Department of Infectious Hazard Management, World Health Organization, Avenue Appia 20, CH-1211, 27 Geneva, agement of such pneumonic infections. Switzerland. Centre Hospitalier Anti-pesteux d’Ambohimiandra, 101 Antananarivo, Madagascar. Centre Hospitalier de District de Miarinarivo, Antananarivo, Madagascar. Institut Pasteur de Madagascar, BP1274 Conclusion 6 Ambatofotsikely, 101 Antananarivo, Madagascar. Present address: Service de In conclusion, although mixed infection of lung with Y. Santé des Armées, Direction Centrale, Division Expertise et Stratégie Santé de Défense, 60 Boulevard du Général Martial Valin – CS21623, 75509 Paris Cedex pestis and S. maltophilia is rare, a combined therapy 15, France. should be discussed when the condition of a plague patient does not improve under an appropriate treat- Received: 16 August 2017 Accepted: 18 May 2018 ment with streptomycin. The availability of plague alter- native treatments is also crucial to improve the patient’s References outcome and need to be implemented in the PNCP of 1. Stenseth NC, Atshabar BB, Begon M, Belmain SR, Bertherat E, Carniel E, et al. Plague: past, present, and future. PLoS Med. 2008;5:e3. the Malagasy Ministry of Health thus a new plague 2. Price PA, Jin J, Goldman WE. Pulmonary infection by Yersinia pestis rapidly therapeutic scheme is currently under evaluation. establishes a permissive environment for microbial proliferation. Proc Natl This situation has been considered to be an important Acad Sci U S A. 2012;109:3083–8. 3. World Health Organization. Plague around the world, 2010–2015. Wkly alert and allowed the establishment of a contingency Epidemiol Rec. 2016;91:89–93. plan to counteract plague epidemics, particularly the 4. Brygoo ER. Epidemiologie de la peste à Madagascar. Arch Inst Pasteur occurrence of the pneumonic form in urban areas where Madagascar. 1966;35:9–147. 5. World Health Organization. International meeting on preventing and the transmission risk at national and international levels controlling plague: the old calamity still has a future. Wkly Epidemiol Rec. is high. 2006;81:278–84. 6. Galimand M, Guiyoule A, Gerbaud G, Rasoamanana B, Chanteau S, Carniel E, et al. Multidrug resistance in Yersinia pestis mediated by a transferable Abbreviations plasmid. N Engl J Med. 1997;337:677–80. APHAA: Anti-Plague Hospital of Ambohimiandra-Antananarivo; 7. Khardori N, Elting L, Wong E, Schable B, Bodey GP. Nosocomial infections MDH: Miarinarivo District Hospital; MHA: Military Hospital of Antananarivo; due to Xanthomonas maltophilia (Pseudomonas maltophilia) in patients with PNCP: Plague National Control Program cancer. Rev Infect Dis. 1990;12:997–1003. 8. Looney WJ, Narita M, Mühlemann K. Stenotrophomonas maltophilia:an Acknowledgements emerging opportunist human pathogen. Lancet Infect Dis. 2009;9:312–23. We thank all the health workers involved in the care of this patient, the staff 9. Sendrasoa FA, Razanakoto NH, Ranaivo IM, Andrianasolo RL, Randria MJDD, of the Plague Unit for technical assistance, and Dr. Tendro Tondrasoa Antibiotic RRA. Antimalarial Selfmedication in Antananarivo, Madagascar. Int Ramaharitra for the patient’s itinerary mapping. Sincere thanks to Prof. J Infect Dis Ther. 2016;1:1–5. Michel Simonet for critical review of the manuscript. 10. Chanteau S, Rahalison L, Ralafiarisoa L, Foulon J, Ratsitorahina M, Ratsifasoamanana L, et al. Development and testing of a rapid diagnostic test for bubonic and pneumonic plague. Lancet. 2003;361:211–6. Funding 11. Rasoamanana B, Rahalison L, Raharimanana C, Chanteau S. Comparison of This work was supported by the Institut Pasteur de Madagascar. There was Yersinia CIN agar and mouse inoculation assay for the diagnosis of plague. no role of the funding body in the writing of the manuscript. Trans R Soc Trop Med Hyg. 1996;90:651. 12. Rasoamanana B, Leroy F, Boisier P, Rasolomaharo M, Buchy P, Carniel E, et al. Field evaluation of an immunoglobulin G anti-F1 enzyme-linked Authors’ contributions immunosorbent assay for serodiagnosis of human plague in Madagascar. VA analyzed clinical data, literature search, wrote the manuscript, EB Clin Diagn Lab Immunol. 1997;4:587–91. provided advice on the management of the event and reviewed the 13. Hinnebusch J, Schwan TG. New method for plague surveillance using manuscript, RR and TR collected and interpreted data, CR provided advice polymerase chain reaction to detect Yersinia pestis in fleas. J Clin Microbiol. on the management of the event, literature search, reviewed the manuscript, 1993;31:1511–4. MR analyzed clinical data, investigated the case and wrote the manuscript. 14. Pechous RD, Sivaraman V, Stasulli NM, Goldman WE. Pneumonic plague: the All authors read and approved the final version of the report. darker side of Yersinia pestis. Trends Microbiol. 2016;24:190–7. 15. Butler TC. Plague and other Yersinia infections. In: Greenough WB, editor. Ethics approval and consent to participate Current topics in infectious disease. New York: Plenum Medical Book Blood collection was approved by the National Ethics Committee of the Company; 1983. Malagasy Ministry of Health (ref 068- MSANPE of July 29, 2011). 16. Perry RD, Fetherston JD. Yersinia pestis–etiologic agent of plague. Clin See consent for publication below. Microbiol Rev. 1997;10:35–66. Andrianaivoarimanana et al. BMC Pulmonary Medicine (2018) 18:92 Page 6 of 6 17. Bertherat E, Thullier P, Shako JC, England K, Koné ML, Arntzen L, et al. Lessons learned about pneumonic plague diagnosis from two outbreaks, Democratic Republic of the Congo. Emerg Infect Dis. 2011;17:778–84. 18. Begier EM, Asiki G, Anywaine Z, Yockey B, Schriefer ME, Aleti P, et al. Pneumonic plague cluster, Uganda, 2004. Emerg Infect Dis. 2006;12:460–7. 19. Ratsitorahina M, Chanteau S, Rahalison L, Ratsifasoamanana L, Boisier P. Epidemiological and diagnostic aspects of the outbreak of pneumonic plague in Madagascar. Lancet. 2000;355:111–3. 20. Nicodemo AC, Garcia Paez JI. Antimicrobial therapy for Stenotrophomonas maltophilia infections. Eur J Clin Microbiol Infect Dis. 2007;26:229–37. 21. Fujita J, Yamadori I, Xu G, et al. Clinical features of Stenotrophomonas maltophilia pneumonia in immunocompromised patients. Respir Med. 1996; 90:35–8. 22. Pathmanathan A, Waterer GW. Significance of positive Stenotrophomonas maltophilia culture in acute respiratory tract infection. EurRespir J. 2005;25: 911–4. 23. Samonis G, Karageorgopoulos DE, Maraki S, Levis P, Dimopoulou D, Spernovasilis NA, et al. Stenotrophomonas maltophilia infections in a general hospital: patient characteristics, antimicrobial susceptibility, and treatment outcome. PLoS One. 2012;7:e37375. 24. Apangu T, Griffith K, Abaru J, Candini G, Apio H, Okoth F, et al. Successful treatment of human plague with oral ciprofloxacin. Emerg Infect Dis. 2017; 23(3):553–55. 25. Heine HS, Hershfield J, Marchand C, Miller L, Halasohoris S, Purcell BK, et al. 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BMC Pulmonary MedicineSpringer Journals

Published: May 29, 2018

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