J Infect Chemother xxx (2014) 1e3
Contents lists available at ScienceDirect
Journal of Infection and Chemotherapy journal homepage: http://www.elsevier.com/locate/jic
Case report
A case of community-acquired pneumonia due to influenza A virus and Nocardia farcinica co-infection Toyomitsu Sawai, MD, PhD a, *, Sumako Yoshioka, MD, PhD a, Nobuko Matsuo, MD, PhD a, Naofumi Suyama, MD, PhD a, Shigeru Kohno, MD, PhD b a b
Department of Respiratory Medicine, Nagasaki Municipal Hospital, Nagasaki, Japan Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 15 October 2013 Received in revised form 20 April 2014 Accepted 21 April 2014
Nocardia spp. has not been reported previously as a cause of post-influenza pneumonia. Here we present a first case of post-influenza bacterial pneumonia due to Nocardia farcinica. Initial reason for hospitalization of the 90 year old female patient was a pneumonia with the symptoms of fever and productive cough. A rapid test for influenza antigen was positive for influenza A virus. Treatment with Zanamivir and piperacillin was initiated. However, after 1 week of treatment, the infiltration shadows on chest X-ray had worsened. Because the expectorated sputum collected on admission for culture was found to be positive for Nocardia spp., piperacillin was replaced with trimethoprim/sulfamethoxazole, and a chest Xray showed some improvement. Although pulmonary nocardiosis with co-infection with influenza A is extremely rare, clinicians should be alert to the possibility. Ó 2014, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Keywords: Influenza Post-influenza bacterial pneumonia Nocardia farcinica Co-infection
1. Introduction Influenza is highly contagious and constitutes a significant public health problem due to its rapid transmission and the associated high morbidity and mortality. Two kinds of pneumonia associated with influenza are well-recognized: primary influenza viral pneumonia and secondary bacterial pneumonia. Secondary bacterial pneumonia is a well-described complication of influenza that continues to contribute significantly to the morbidity and mortality associated with both seasonal and pandemic influenza [1,2]. During previous influenza pandemics, bacterial co-infections caused by Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and group A Streptococcus spp. were identified frequently [3e6]. However, to our knowledge Nocardia spp. have not been reported previously as a cause of post-influenza pneumonia. Nocardia farcinica is a Gram-positive branching filamentous bacillus causing localized and disseminated infections in humans, including pulmonary infections [7], subcutaneous
* Corresponding author. Department of Respiratory Medicine, Nagasaki Municipal Hospital, 6-39 Shinchi-machi, Nagasaki 850-8555, Japan. Tel.: þ81 (95) 822 3251; fax: þ81 (95) 824 4030. E-mail address: [email protected] (T. Sawai).
infections [8], brain abscesses [9], and bacteremia [10]. Here we report what we believe to be the first reported case of postinfluenza pneumonia due to N. farcinica. This case illustrates that N. farcinica infection should be suspected in post-influenza pneumonia patients that do not respond to conventional antimicrobial therapy. 2. Case report A 90-year-old, female nonsmoker presented to our department with complaints of fever, cough and sputum production after 7 years of observation for Mycobacterium intracellulare pulmonary infection. These past several years, sputum examination was repeatedly negative for non tuberculous mycobacteria, the state of pulmonary mycobacteriosis was stable. Physical examination revealed fever of 39.9 C and an oxygen saturation of 84%, and the patient was admitted to the hospital. A chest X-ray showed infiltration shadows in the right upper and middle lung fields (Fig. 1). A computed tomography scan showed infiltration shadows and bronchiectasis in the right middle lobe and micro-nodular shadows in the right lower and left upper lobes (Fig. 2). A rapid test for influenza antigen (Espline Influenza A&BeN; Fujirebio Inc., Tokyo, Japan) was positive for influenza A virus. The white blood cell count and C-reactive protein were 10,220/ml and 13.44 mg/dl,
http://dx.doi.org/10.1016/j.jiac.2014.04.008 1341-321X/Ó 2014, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Sawai T, et al., A case of community-acquired pneumonia due to influenza A virus and Nocardia farcinica coinfection, J Infect Chemother (2014), http://dx.doi.org/10.1016/j.jiac.2014.04.008
2
T. Sawai et al. / J Infect Chemother xxx (2014) 1e3
3. Discussion
Fig. 1. Chest radiograph showed infiltration shadows in the right upper and middle lung fields.
respectively. Expectorated sputum smears were negative for bacteria and acid-fast bacilli (AFB). The Binax NOW S. pneumoniae and Legionella pneumophila urinary antigen tests (Binax, Inc., Portland, ME, USA) were negative. Although it was difficult to determine the causative bacteria, a presumptive diagnosis of influenza type A with post-influenza bacterial pneumonia was made, and treatment with zanamivir 10 mg inhaled twice daily and piperacillin 2 g intravenously twice daily was initiated. However, after 1 week of treatment, the symptoms and inflammatory reaction continued, and the infiltration shadows on chest X-ray had worsened. Expectorated sputum was negative for AFB; however, Gram staining revealed many neutrophils and Gram-positive rods with branching, filamentous hyphae (Fig. 3(A)). Moreover, the Gram-positive rods were stained with Kinyoun acid-fast stain (Fig. 3(B)), and the expectorated sputum collected on admission for culture was found to be positive for Nocardia spp., but mycobacteria was not isolated after 6 weeks of culture. Until now, we performed sputum examination semiannually, but cultures were negative for Nocardia spp.. On the basis of these findings, pulmonary nocardiosis was diagnosed, and piperacillin was replaced with intravenous trimethoprim/sulfamethoxazole (TMP/SMX) 80 mg/400 mg 3 times daily. The cultured strain was sent to the Research Center for Pathogenic Fungi and Microbial Toxicoses (Chiba University), where the identification of N. farcinica was confirmed by the 16S rRNA gene sequence. The isolate was susceptible to TMP/SMX and imipenem/cilastatin (IPM/ CS) but resistant to tobramycin (TOB), kanamycin, and ciprofloxacin (CPFX). The serum antibody titer against influenza A virus H3N2 and H1N1 on day 14 of hospitalization were 1280 and 40, respectively (The serum antibody titer on admission was not done). On day 21, fever, cough and sputum disappeared, and a chest X-ray showed some improvement. Unfortunately, the patient died on day 29 of hospitalization from urosepsis and Clostridium difficile-associated colitis.
Fig. 2. Computed tomography scan showed infiltration shadows and bronchiectasis in the right middle lobe and micro-nodular shadows in the right lower and left upper lobes.
Bacterial pneumonia is a well-described complication of influenza that can affect the nature and severity of clinical manifestations and disease outcome. It is an important contributor to morbidity and mortality during periods of seasonal influenza activity [1,2]. Susceptible individuals, such as young children, older adults, and persons of any age with certain underlying medical conditions, including chronic lung or cardiovascular disease and immunosuppressive conditions, are known to be at increased risk for influenza-associated complications. Potential mechanisms for synergies between viral and bacterial infection include the following: 1) virus-induced damage to the airway epithelium, which leads to increased colonization by bacteria [11]; 2) viral neuraminidase activity, which increases adhesion to airway epithelial cells [12]; 3) inflammatory responses to viral infection that may upregulate expression of molecules utilized as receptors by bacteria [13]; 4) virus-induced, immunosuppression-promoting bacterial superinfections [14]; and 5) synthesis of virus-activating bacterial proteases [15]. In this case, there may be two mechanisms at least. Firstly, in addition to bronchiectasis due to M. intracellulare pulmonary infection, influenza virus-induced epithelial injury may lead to not only the increased risk of bacterial colonization, but also enhanced invasion by bacteria [16]. Secondary, influenza virus infection has been shown to impair neutrophil function [17,18]. Nocardia spp. secrete superoxide dismutase and catalase, and organisms are relatively resistant to neutrophil-mediated killing [19,20]. As a result, a reduction in phagocytic capacity of neutrophils may be caused. To the best of our knowledge, this is the first reported case of community-acquired pneumonia due to influenza A virus and N. farcinica co-infection. We performed sputum examination semiannually, but until now cultures were negative for Nocardia spp.. However, routinely we did not perform sputum culture more than 1 week, and did not stain Kinyoun acid-fast stain. Moreover, this patient had bronchiectasis, Nocardia spp. was in condition to be easy to colonize in the respiratory tract [16]. Therefore, we can not completely deny the possibility that the colonization of the respiratory tract by N. farcinica existed. Before this hospitalization, white blood cell count, differentiation, C-reactive protein, and erythrocyte sedimentation rate were all within the normal ranges, and a chest X-ray did not show new shadows. Even if the colonization of the respiratory tract by N. farcinica existed from before, the organisms did not cause infectious disease. As intrinsic infection, N. farcinica caused community-acquired pneumonia associated with influenza A virus infection this time. Nocardia infections are rare but potentially fatal, typically more problematic in patients with cell-mediated immunosuppressive conditions [21], but occasionally inimmunocompetent patients as well [22]. N. farcinica is a ubiquitous, Gram-positive actinomycete saprophyte that lives in soil, organic matter and water. Human infection usually arises from direct inoculation of skin or by inhalation. It is considered an opportunistic pathogen that affects patients with impaired cell-mediated immunity. Most of the patients with Nocardia infection have predisposing factors, such as hematologic malignancies, treatment with corticosteroids, solid tumors, bone marrow or solid organ transplantation, HIV infection or chronic pulmonary or renal disease [23]. N. farcinica infection is potentially lethal because of its tendency to disseminate and its resistance to antibiotics. The most common clinical presentation is subacute pneumonia with nodules, necrosis, cavitatary disease, lung abscess, effusion and/or empyema [7,23]. Due to nonspecific clinical and radiologic manifestations including irregular nodules, cavitation, reticulonodular shadow, infiltration and pleural
Please cite this article in press as: Sawai T, et al., A case of community-acquired pneumonia due to influenza A virus and Nocardia farcinica coinfection, J Infect Chemother (2014), http://dx.doi.org/10.1016/j.jiac.2014.04.008
T. Sawai et al. / J Infect Chemother xxx (2014) 1e3
3
Fig. 3. (A) Gram stain of expectorated sputum ( 1000) showing a cluster of branching, filamentous Gram-positive rods. (B) Modified acid fast Kinyoun staining of expectorated sputum ( 1000) showing filamentous red-stained partially acid-fast rods.
effusion, pulmonary nocardiosis is easily misdiagnosed as bacterial pneumonia, tuberculosis, mycosis or actinomycosis. Moreover, the microbiological diagnosis of nocardiosis and the identification of Nocardia clinical isolates by conventional methods are difficult and time-consuming processes [24]. Culture of Nocardia spp. is difficult because of the slow growth of the bacteria and presence of normal flora in the culture. Because of the potentially long culture time, it is very important that the physicians notify the laboratory when Nocardia spp. is suspected in a clinical specimen. N. farcinica is an important and generally more antibiotic-resistant species. The antimicrobial resistance is considered responsible for the high mortality of N. farcinica infections [25]. The treatment for N. farcinica is complicated by its resistance to most b-lactam antibiotics, TOB, and tetracyclines. N. farcinica is susceptible to TMP/ SMX, linezolid, moxifloxacin, and amikacin and demonstrates variable susceptibility to IPM/CS and CPFX. The empiric gold standard of medical treatment is TMP/SMX. To the best of our knowledge, this is the first case of community-acquired pneumonia due to influenza A virus and N. farcinica co-infection. In managing influenza patients, empirical antibacterial therapy is needed in addition to antiviral medications when bacterial co-infection is suspected. N. farcinica infection may be suspected in post-influenza pneumonia patients that do not respond to initial empirical antibacterial therapy. N. farcinica should be kept in mind as a cause of postinfluenza pneumonia especially in immunosuppressed patients. Conflict of interest None. Acknowledgments The authors thank Dr. Yaguchi for 16S rRNA gene sequence analysis and antimicrobial susceptibility test. References [1] Guarner J, Paddock CD, Shieh WJ, Packard MM, Patel M, Montague JL, et al. Histopathologic and immunohistochemical features of fatal influenza virus infection in children during the 2003e2004 season. Clin Infect Dis 2006;43: 132e40. [2] Morens DM, Taubenburger JK, Fauci AS. Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness. J Infect Dis 2008;198:962e70. [3] Petersdorf RG, Fusco JJ, Harter DH, Albrink WS. Pulmonary infections complicating Asian influenza. AMA Arch Intern Med 1959;103:262e72. [4] Schwarzmann SW, Adler JL, Sullivan Jr RJ, Marine WM. Bacterial pneumonia during the Hong Kong influenza epidemic of 1968e1969. Arch Intern Med 1971;127:1037e41.
[5] Kallen AJ, Brunkard J, Moore Z, Budge P, Arnold KE, Fosheim G. Staphylococcus aureus community-acquired pneumonia during the 2006 to 2007 influenza season. Ann Emerg Med 2009;53:358e65. [6] Centers for Disease Control. Bacterial co-infections in lung tissue specimens from fatal cases of 2009 pandemic influenza A (H1N1) e United States, Maye August 2009. MMWR 2009;58:1071e4. [7] Bittar F, Stremler N, Audie JP, Dubus JC, Sarles J, Raoult D, et al. Nocardia farcinica lung infection in a patient with cystic fibrosis: a case report. J Med Case Rep 2010;4:84. [8] Schiff TA, McNeil MM, Brown JM. Cutaneous Nocardia farcinica infection in a nonimmunocompromised patient. Clin Infect Dis 1993;16:756e60. [9] Chung TT, Lin JC, Hsieh CT, Chen GJ, Ju DT. Nocardia farcinica brain abscess in an immunocompetent patient treated with antibiotics and two surgical techniques. J Clin Neurosci 2009;16:1675e7. [10] Christidou A, Maraki S, Scoulica E, Mantadakis E, Agelaki S, Samonis G. Fatal Nocardia farcinica bacteremia in a patient with lung cancer. Diagn Microbiol Infect Dis 2004;50:135e9. [11] Plotkowski MC, Puchelle E, Beck G, Jacquot J, Hannoun C. Adherence of type I Streptococcus pneumonia to tracheal epithelium of mice infected with influenza A/PR8 virus. Am Rev Respir Dis 1986;134:1040e4. [12] McCullers JA, Bartmess KC. Role of neuraminidase in lethal synergism between influenza virus and Streptococcus pneumonia. J Infect Dis 2003;187: 1000e9. [13] McCullers LA, Rehg JE. Lethal synergism between influenza virus and Streptococcus pneumonia: characterization of a mouse model and the role of platelet-activating factor receptor. J Infect Dis 2002;186:341e50. [14] Peltola VT, McCullers JA. Respiratory viruses predisposing to bacterial infections: role of neuraminidase. Pediatr Infect Dis 2004;23:S87e97. [15] Tashiro M, Ciborowski P, Klenk HD, Pulverer G, Rott R. Role of Staphylococcus protease in the development of influenza pneumonia. Nature 1987;325:536e 7. [16] Cremades MJ, Menendez R, Santos M, Gobernado M. Repeated pulmonary infection by Nocardia asteroids complex in a patient with bronchiectasis. Respiration 1998;65:211e3. [17] Larson HE, Parry RP, Tyrrell DA. Impaired polymorphonuclear leukocyte chemotaxis after influenza virus infection. Br J Dis Chest 1980;74:56e62. [18] Colamussi ML, White MR, Crouch E, Hartshorn KL. Influenza A virus accelerates neutrophil apoptosis and markedly potentiates apoptotic effects of bacteria. Blood 1999;93:2395e403. [19] Wu G, Nie L, Zhang W. Predicted highly expressed genes in Nocardia farcinia and the implication for its primary metabolism and nocardial virulence. Antonie Van Leeuwenhoek 2006;89:135e46. [20] Beaman BL, Black CM, Doughty F, Beaman L. Role of superoxide dismutase and catalase as determinants of pathogenicity of Nocardia asteroids: importance in resistance to microbicidal activities of human polymorphonuclear neutrophils. Infect Immun 1985;47:135e41. [21] Matulionyte R, Rohner P, Uckay I, Lew D, Garbino J. Secular trends of Nocardia infection over 15 years in a tertiary care hospital. J Clin Pathol 2004;57:807e 12. [22] Budzik JM, Hosseini M, Mackinnon Jr AC, Taxy JB. Disseminated Nocardia farcinica: literature review and fatal outcome in an immunocompetent patient. Surg Infect 2012;13:163e70. [23] Mari B, Monton C, Mariscal D, Lujan M, Sala M, Domingo C. Pulmonary nocardiosis: clinical experience in ten cases. Respiration 2001;68:382e8. [24] Severo CB, Oliveria F de M, Cunha L, Cantarelli V, Severo LC. Disseminated nocardiosis due to Nocardia farcinica: diagnosis by thyroid abscess culture. Rev Inst Med Trop Sao Paulo 2005;47:355e8. [25] Torres OH, Domingo P, Pericas R, Boiron P, Montiel JA, Vazquez G. Infection caused by Nocardia farcinica: case report and review. Eur J Clin Microbiol Infect Dis 2000;19:205e12.
Please cite this article in press as: Sawai T, et al., A case of community-acquired pneumonia due to influenza A virus and Nocardia farcinica coinfection, J Infect Chemother (2014), http://dx.doi.org/10.1016/j.jiac.2014.04.008
Contents lists available at ScienceDirect
Journal of Infection and Chemotherapy journal homepage: http://www.elsevier.com/locate/jic
Case report
A case of community-acquired pneumonia due to influenza A virus and Nocardia farcinica co-infection Toyomitsu Sawai, MD, PhD a, *, Sumako Yoshioka, MD, PhD a, Nobuko Matsuo, MD, PhD a, Naofumi Suyama, MD, PhD a, Shigeru Kohno, MD, PhD b a b
Department of Respiratory Medicine, Nagasaki Municipal Hospital, Nagasaki, Japan Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 15 October 2013 Received in revised form 20 April 2014 Accepted 21 April 2014
Nocardia spp. has not been reported previously as a cause of post-influenza pneumonia. Here we present a first case of post-influenza bacterial pneumonia due to Nocardia farcinica. Initial reason for hospitalization of the 90 year old female patient was a pneumonia with the symptoms of fever and productive cough. A rapid test for influenza antigen was positive for influenza A virus. Treatment with Zanamivir and piperacillin was initiated. However, after 1 week of treatment, the infiltration shadows on chest X-ray had worsened. Because the expectorated sputum collected on admission for culture was found to be positive for Nocardia spp., piperacillin was replaced with trimethoprim/sulfamethoxazole, and a chest Xray showed some improvement. Although pulmonary nocardiosis with co-infection with influenza A is extremely rare, clinicians should be alert to the possibility. Ó 2014, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Keywords: Influenza Post-influenza bacterial pneumonia Nocardia farcinica Co-infection
1. Introduction Influenza is highly contagious and constitutes a significant public health problem due to its rapid transmission and the associated high morbidity and mortality. Two kinds of pneumonia associated with influenza are well-recognized: primary influenza viral pneumonia and secondary bacterial pneumonia. Secondary bacterial pneumonia is a well-described complication of influenza that continues to contribute significantly to the morbidity and mortality associated with both seasonal and pandemic influenza [1,2]. During previous influenza pandemics, bacterial co-infections caused by Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and group A Streptococcus spp. were identified frequently [3e6]. However, to our knowledge Nocardia spp. have not been reported previously as a cause of post-influenza pneumonia. Nocardia farcinica is a Gram-positive branching filamentous bacillus causing localized and disseminated infections in humans, including pulmonary infections [7], subcutaneous
* Corresponding author. Department of Respiratory Medicine, Nagasaki Municipal Hospital, 6-39 Shinchi-machi, Nagasaki 850-8555, Japan. Tel.: þ81 (95) 822 3251; fax: þ81 (95) 824 4030. E-mail address: [email protected] (T. Sawai).
infections [8], brain abscesses [9], and bacteremia [10]. Here we report what we believe to be the first reported case of postinfluenza pneumonia due to N. farcinica. This case illustrates that N. farcinica infection should be suspected in post-influenza pneumonia patients that do not respond to conventional antimicrobial therapy. 2. Case report A 90-year-old, female nonsmoker presented to our department with complaints of fever, cough and sputum production after 7 years of observation for Mycobacterium intracellulare pulmonary infection. These past several years, sputum examination was repeatedly negative for non tuberculous mycobacteria, the state of pulmonary mycobacteriosis was stable. Physical examination revealed fever of 39.9 C and an oxygen saturation of 84%, and the patient was admitted to the hospital. A chest X-ray showed infiltration shadows in the right upper and middle lung fields (Fig. 1). A computed tomography scan showed infiltration shadows and bronchiectasis in the right middle lobe and micro-nodular shadows in the right lower and left upper lobes (Fig. 2). A rapid test for influenza antigen (Espline Influenza A&BeN; Fujirebio Inc., Tokyo, Japan) was positive for influenza A virus. The white blood cell count and C-reactive protein were 10,220/ml and 13.44 mg/dl,
http://dx.doi.org/10.1016/j.jiac.2014.04.008 1341-321X/Ó 2014, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Sawai T, et al., A case of community-acquired pneumonia due to influenza A virus and Nocardia farcinica coinfection, J Infect Chemother (2014), http://dx.doi.org/10.1016/j.jiac.2014.04.008
2
T. Sawai et al. / J Infect Chemother xxx (2014) 1e3
3. Discussion
Fig. 1. Chest radiograph showed infiltration shadows in the right upper and middle lung fields.
respectively. Expectorated sputum smears were negative for bacteria and acid-fast bacilli (AFB). The Binax NOW S. pneumoniae and Legionella pneumophila urinary antigen tests (Binax, Inc., Portland, ME, USA) were negative. Although it was difficult to determine the causative bacteria, a presumptive diagnosis of influenza type A with post-influenza bacterial pneumonia was made, and treatment with zanamivir 10 mg inhaled twice daily and piperacillin 2 g intravenously twice daily was initiated. However, after 1 week of treatment, the symptoms and inflammatory reaction continued, and the infiltration shadows on chest X-ray had worsened. Expectorated sputum was negative for AFB; however, Gram staining revealed many neutrophils and Gram-positive rods with branching, filamentous hyphae (Fig. 3(A)). Moreover, the Gram-positive rods were stained with Kinyoun acid-fast stain (Fig. 3(B)), and the expectorated sputum collected on admission for culture was found to be positive for Nocardia spp., but mycobacteria was not isolated after 6 weeks of culture. Until now, we performed sputum examination semiannually, but cultures were negative for Nocardia spp.. On the basis of these findings, pulmonary nocardiosis was diagnosed, and piperacillin was replaced with intravenous trimethoprim/sulfamethoxazole (TMP/SMX) 80 mg/400 mg 3 times daily. The cultured strain was sent to the Research Center for Pathogenic Fungi and Microbial Toxicoses (Chiba University), where the identification of N. farcinica was confirmed by the 16S rRNA gene sequence. The isolate was susceptible to TMP/SMX and imipenem/cilastatin (IPM/ CS) but resistant to tobramycin (TOB), kanamycin, and ciprofloxacin (CPFX). The serum antibody titer against influenza A virus H3N2 and H1N1 on day 14 of hospitalization were 1280 and 40, respectively (The serum antibody titer on admission was not done). On day 21, fever, cough and sputum disappeared, and a chest X-ray showed some improvement. Unfortunately, the patient died on day 29 of hospitalization from urosepsis and Clostridium difficile-associated colitis.
Fig. 2. Computed tomography scan showed infiltration shadows and bronchiectasis in the right middle lobe and micro-nodular shadows in the right lower and left upper lobes.
Bacterial pneumonia is a well-described complication of influenza that can affect the nature and severity of clinical manifestations and disease outcome. It is an important contributor to morbidity and mortality during periods of seasonal influenza activity [1,2]. Susceptible individuals, such as young children, older adults, and persons of any age with certain underlying medical conditions, including chronic lung or cardiovascular disease and immunosuppressive conditions, are known to be at increased risk for influenza-associated complications. Potential mechanisms for synergies between viral and bacterial infection include the following: 1) virus-induced damage to the airway epithelium, which leads to increased colonization by bacteria [11]; 2) viral neuraminidase activity, which increases adhesion to airway epithelial cells [12]; 3) inflammatory responses to viral infection that may upregulate expression of molecules utilized as receptors by bacteria [13]; 4) virus-induced, immunosuppression-promoting bacterial superinfections [14]; and 5) synthesis of virus-activating bacterial proteases [15]. In this case, there may be two mechanisms at least. Firstly, in addition to bronchiectasis due to M. intracellulare pulmonary infection, influenza virus-induced epithelial injury may lead to not only the increased risk of bacterial colonization, but also enhanced invasion by bacteria [16]. Secondary, influenza virus infection has been shown to impair neutrophil function [17,18]. Nocardia spp. secrete superoxide dismutase and catalase, and organisms are relatively resistant to neutrophil-mediated killing [19,20]. As a result, a reduction in phagocytic capacity of neutrophils may be caused. To the best of our knowledge, this is the first reported case of community-acquired pneumonia due to influenza A virus and N. farcinica co-infection. We performed sputum examination semiannually, but until now cultures were negative for Nocardia spp.. However, routinely we did not perform sputum culture more than 1 week, and did not stain Kinyoun acid-fast stain. Moreover, this patient had bronchiectasis, Nocardia spp. was in condition to be easy to colonize in the respiratory tract [16]. Therefore, we can not completely deny the possibility that the colonization of the respiratory tract by N. farcinica existed. Before this hospitalization, white blood cell count, differentiation, C-reactive protein, and erythrocyte sedimentation rate were all within the normal ranges, and a chest X-ray did not show new shadows. Even if the colonization of the respiratory tract by N. farcinica existed from before, the organisms did not cause infectious disease. As intrinsic infection, N. farcinica caused community-acquired pneumonia associated with influenza A virus infection this time. Nocardia infections are rare but potentially fatal, typically more problematic in patients with cell-mediated immunosuppressive conditions [21], but occasionally inimmunocompetent patients as well [22]. N. farcinica is a ubiquitous, Gram-positive actinomycete saprophyte that lives in soil, organic matter and water. Human infection usually arises from direct inoculation of skin or by inhalation. It is considered an opportunistic pathogen that affects patients with impaired cell-mediated immunity. Most of the patients with Nocardia infection have predisposing factors, such as hematologic malignancies, treatment with corticosteroids, solid tumors, bone marrow or solid organ transplantation, HIV infection or chronic pulmonary or renal disease [23]. N. farcinica infection is potentially lethal because of its tendency to disseminate and its resistance to antibiotics. The most common clinical presentation is subacute pneumonia with nodules, necrosis, cavitatary disease, lung abscess, effusion and/or empyema [7,23]. Due to nonspecific clinical and radiologic manifestations including irregular nodules, cavitation, reticulonodular shadow, infiltration and pleural
Please cite this article in press as: Sawai T, et al., A case of community-acquired pneumonia due to influenza A virus and Nocardia farcinica coinfection, J Infect Chemother (2014), http://dx.doi.org/10.1016/j.jiac.2014.04.008
T. Sawai et al. / J Infect Chemother xxx (2014) 1e3
3
Fig. 3. (A) Gram stain of expectorated sputum ( 1000) showing a cluster of branching, filamentous Gram-positive rods. (B) Modified acid fast Kinyoun staining of expectorated sputum ( 1000) showing filamentous red-stained partially acid-fast rods.
effusion, pulmonary nocardiosis is easily misdiagnosed as bacterial pneumonia, tuberculosis, mycosis or actinomycosis. Moreover, the microbiological diagnosis of nocardiosis and the identification of Nocardia clinical isolates by conventional methods are difficult and time-consuming processes [24]. Culture of Nocardia spp. is difficult because of the slow growth of the bacteria and presence of normal flora in the culture. Because of the potentially long culture time, it is very important that the physicians notify the laboratory when Nocardia spp. is suspected in a clinical specimen. N. farcinica is an important and generally more antibiotic-resistant species. The antimicrobial resistance is considered responsible for the high mortality of N. farcinica infections [25]. The treatment for N. farcinica is complicated by its resistance to most b-lactam antibiotics, TOB, and tetracyclines. N. farcinica is susceptible to TMP/ SMX, linezolid, moxifloxacin, and amikacin and demonstrates variable susceptibility to IPM/CS and CPFX. The empiric gold standard of medical treatment is TMP/SMX. To the best of our knowledge, this is the first case of community-acquired pneumonia due to influenza A virus and N. farcinica co-infection. In managing influenza patients, empirical antibacterial therapy is needed in addition to antiviral medications when bacterial co-infection is suspected. N. farcinica infection may be suspected in post-influenza pneumonia patients that do not respond to initial empirical antibacterial therapy. N. farcinica should be kept in mind as a cause of postinfluenza pneumonia especially in immunosuppressed patients. Conflict of interest None. Acknowledgments The authors thank Dr. Yaguchi for 16S rRNA gene sequence analysis and antimicrobial susceptibility test. References [1] Guarner J, Paddock CD, Shieh WJ, Packard MM, Patel M, Montague JL, et al. Histopathologic and immunohistochemical features of fatal influenza virus infection in children during the 2003e2004 season. Clin Infect Dis 2006;43: 132e40. [2] Morens DM, Taubenburger JK, Fauci AS. Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness. J Infect Dis 2008;198:962e70. [3] Petersdorf RG, Fusco JJ, Harter DH, Albrink WS. Pulmonary infections complicating Asian influenza. AMA Arch Intern Med 1959;103:262e72. [4] Schwarzmann SW, Adler JL, Sullivan Jr RJ, Marine WM. Bacterial pneumonia during the Hong Kong influenza epidemic of 1968e1969. Arch Intern Med 1971;127:1037e41.
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Please cite this article in press as: Sawai T, et al., A case of community-acquired pneumonia due to influenza A virus and Nocardia farcinica coinfection, J Infect Chemother (2014), http://dx.doi.org/10.1016/j.jiac.2014.04.008
