Mycobacterium genavense as a cause of subacute pneumonia in patients with severe cellular immunodeficiency
© Rammaert et al; licensee BioMed Central Ltd. 2011
Received: 26 May 2011
Accepted: 5 November 2011
Published: 5 November 2011
Mycobacterium genavense is a rare nontuberculous mycobacteria (NTM). Human infections are mostly disseminated in the setting of the AIDS epidemic or the use of aggressive immunosuppressive treatments. M. genavense culture is fastidious, requiring supplemented media. Pulmonary involvement rarely occurs as a primary localization.
We report here two patients with pneumonia as the predominant manifestation of M. genavense infection: one kidney transplanted patient and one HIV-infected patient. Both patients were initially treated with anti-tuberculous drugs before the identification of M. genavense on sputum or broncho-alveolar lavage fluid culture. A four-drug regimen including clarithromycin and rifabutin was started. Gamma interferon has been helpful in addition to antimycobacterial treatment for one patient.
Clinicians should be aware that M. genavense could be the etiologic agent of sub-acute pneumonia mimicking tuberculosis in patients with cellular immunodeficiency status.
Host defenses against mycobacteria need an immune cellular response (Th1/Th17) activated by cytokines and chemokines produced by innate immunity cells . Consequently, non-tuberculous mycobacteria (NTM) could cause life threatening infection in immunocompromised patients with profound cellular immune deficiency in particular those who are HIV-infected . M. genavense, is a fastidious growing mycobacteria found in water  with birds and pets being occasionally infected . Human infections were initially described in HIV-infected patients . Thereafter, few cases have been observed in non-HIV immunocompromised hosts including only two reports in solid organ transplant recipients [6, 7]. M. genavense infection preferentially involves bowel and abdominal lymph nodes, a fact being ascribed to the presumed digestive contamination. Mortality of patients with disseminated M. genavense infection is high, ranging from 44% to 71% in 2 series [8, 9]. Herein we report two cases of M. genavense infected patients with pulmonary involvement as the main clinical manifestation, one kidney transplant recipient and one HIV-infected patient.
We here emphasize the predominant thoracic involvement that revealed severe M. genavense infection in two patients with cellular immune deficiency. Secondary dissemination occurred in one case. M. genavense infection has previously been reported in only two solid organ (kidney and heart) transplanted patients [10, 11]. Both had intestinal involvement leading to secondary dissemination and death in one case . In HIV-infected patients, disseminated M. genavense infection associates weight loss, fever, anemia, digestive manifestations and hepatosplenomegaly [9, 12, 13]. Pulmonary symptoms such as cough and dyspnea are rarely at the forefront. A retrospective multicenter French study of 25 patients with M. genavense infection (of whom 20 were HIV positive) reported five patients with pulmonary symptoms in combination with extra-respiratory symptoms in all cases . However, M. genavense remains a rare cause of NTM infection. In the Microbiology Department of Foch Hospital, Suresnes, our two cases were the only two patients with M. genavense isolation among 176 patients with NTM isolated from clinical specimens between 2005 and 2008. The other mycobacteria identified were: Mycobacterium avium complex: 56; M. gordonae: 42; M. xenopi: 37; M. kansasii: 21; M. fortuitum: 8; M. abscessus complex or M. chelonae: 7; M. celatum: 1; non-identified: 2.
M. genavense can be cultured from stools, sputum, urine and blood samples and tissue biopsy . However, culture of M. genavense is fastidious, making microbiological diagnosis frequently difficult, requiring mycobactin J supplementation for optimal recovery on culture. Culture must be prolonged up to 4 months with a median positive culture time of 43 days (min. 10 days- max. 6 months) depending on the culture medium [5, 9, 11, 13, 15–18]. Our observations are in agreement with these findings, In our first case, diagnosis was delayed because the time to positive culture was 70 days.
Molecular tools such as polymerase chain reaction (PCR) are of interest in two ways before cultures become positive. Firstly, M. genavense can eventually be detected on clinical specimens with PCR [19–21]. Secondly, a negative result for M. tuberculosis PCR on a positive AFB smear specimen is useful to exclude tuberculosis earlier. In case one, NTM treatment would have been considered if M. tuberculosis PCR had been performed on sputum. Furthermore, we think that M. genavense should be envisaged in immunocompromised patients with mycobacterial pulmonary disease and digestive involvement or negative mycobacterial culture lasting for more than one month.
Infection control requires decrease of the immunosuppressive regimen in patients who receive such treatment in combination with appropriate antimycobacterial treatment. Human and mouse models have pointed out the role of CD4+ and CD8+ T lymphocytes in M. genavense infection [22, 23]. Explaining the crucial role of T lymphocytes, the bacterial load was significantly higher in organs from athymic mice compared to normal mice . During HIV infection, the risk of M. genavense disease is correlated with CD4 cell count. Indeed M. genavense infection occurs in patients with profound CD4+ lymphopenia (50 cells/mm3 or less). However, CD4+ cell count is not a reliable marker of immunosuppression in non-HIV patients receiving immunosuppressive treatment. For example, Pneumocystis pneumonia is frequently observed in organ transplanted patients with more than 400 CD4+ cells/mm3 . In our patient, the CD4+ T cell count was moderately diminished (230/mm3). Thus, M. genavense infection may occur in non-HIV patients under an immunosuppressive regimen with a much higher CD4+ cell count than seen in HIV-infected patients.
The optimal anti-mycobacterial therapy in M. genavense infection is unknown. The high effectiveness of clarithromycin and rifabutin has been demonstrated in a murine model . Multidrug therapies including clarithromycin are recommended . Even with appropriate treatment, clinical evolution is long before resolution of symptoms, and patients have to be treated for at least 12 to 24 months . As recommended in ATS/IDSA guidelines for Mycobacterium avium intracellulare infection, treatment was continued 12 months after immune restoration was achieved for Case 1 . Concerning Case 2, antimycobacterial treatment cannot be withdrawn because of reinforcement of immunosuppressive therapy.
In the case of our first patient, despite HAART introduction and appropriate anti-mycobacterial treatment, the infection was not controlled. The administration of IFN-γ was temporally associated with a significant clinical improvement and bacteriological clearance of infection. IFN-γ is essential for the control of M. genavense. Indeed, mice deficient for IFN-γ are unable to clear M. genavense infection . In HIV-infected individuals the monocytes-macrophages phagocytic function is impaired. IFN-γ can restore deficient functions of HIV-infected macrophages and has already been used in the management of M. avium intracellulare complex infection . The classic pathway of IFN-γ-dependent activation of macrophages by T helper 1-type responses is a well-established feature of immune response to infection with intracellular pathogens, such as M. tuberculosis and NTM .
Finally clinicians should be aware 1) That the main clinical manifestation of M. genavense infection may be a slowly progressive pneumonia mimicking tuberculosis in patients with cellular immunodeficiency; 2) Thus, this diagnosis should be evoked in an immunosuppressed patient who receives empirical anti-tuberculous therapy without improvement; 3) Extra-thoracic manifestations can be absent; 4) the microbiological diagnosis requires prolonged cultures and may be helped by PCR analysis of bronchial and lung specimens; 5) IFN-γ may be useful to control M. genavense pneumonia in addition to the anti-mycobacterial regimen; 6) CD4+ T cell count is not a reliable marker of the risk of M. genavense infection in non-HIV imunocompromised patients.
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal
T helper lymphocyte
Highly active anti-retroviral therapy
Acid fast bacilli
Human immunodeficiency virus
Polymerase chain reaction
Non tuberculous mycobacteria
The authors thank Polly Gobin for English revision.
- Mortellaro A, Robinson L, Ricciardi-Castagnoli P: Spotlight on Mycobacteria and dendritic cells: will novel targets to fight tuberculosis emerge?. EMBO Mol Med. 2009, 1 (1): 19-29. 10.1002/emmm.200900008.View ArticlePubMedPubMed CentralGoogle Scholar
- Glassroth J: Pulmonary disease due to nontuberculous mycobacteria. Chest. 2008, 133 (1): 243-251. 10.1378/chest.07-0358.View ArticlePubMedGoogle Scholar
- Hillebrand-Haverkort ME, Kolk AH, Kox LF, Ten Velden JJ, Ten Veen JH: Generalized mycobacterium genavense infection in HIV-infected patients: detection of the mycobacterium in hospital tap water. Scand J Infect Dis. 1999, 31 (1): 63-68. 10.1080/00365549950161907.View ArticlePubMedGoogle Scholar
- Manarolla G, Liandris E, Pisoni G, Sassera D, Grilli G, Gallazzi D, Sironi G, Moroni P, Piccinini R, Rampin T: Avian mycobacteriosis in companion birds: 20-year survey. Vet Microbiol. 2009, 133 (4): 323-327. 10.1016/j.vetmic.2008.07.017.View ArticlePubMedGoogle Scholar
- Bessesen MT, Shlay J, Stone-Venohr B, Cohn DL, Reves RR: Disseminated Mycobacterium genavense infection: clinical and microbiological features and response to therapy. AIDS. 1993, 7 (10): 1357-1361. 10.1097/00002030-199310000-00009.View ArticlePubMedGoogle Scholar
- Lu KJ, Grigg A, Leslie D, Finlay M, Sasadeusz J: Mycobacterium genavense duodenitis following allogeneic peripheral blood stem cell transplantation. Transpl Infect Dis. 2009, 11 (6): 534-536. 10.1111/j.1399-3062.2009.00431.x.View ArticlePubMedGoogle Scholar
- Bogdan C, Kern P, Richter E, Tannapfel A, Rusch-Gerdes S, Kirchner T, Solbach W: Systemic infection with Mycobacterium genavense following immunosuppressive therapy in a patient who was seronegative for human immunodeficiency virus. Clin Infect Dis. 1997, 24 (6): 1245-1247. 10.1086/513634.View ArticlePubMedGoogle Scholar
- Charles P, Lortholary O, Dechartres A, Doustar F, Viard J-P, Lecuit M, Gutierrez MC, Group TFMgS: Mycobacterium genavense Infections: a retrospective Multicenter Study between 1996 and 2007 in France. Medicine. 2011, 90 (4): 223-30. 10.1097/MD.0b013e318225ab89.View ArticlePubMedGoogle Scholar
- Tortoli E, Brunello F, Cagni AE, Colombrita D, Dionisio D, Grisendi L, Manfrin V, Moroni M, Passerini Tosi C, Pinsi G, et al: Mycobacterium genavense in AIDS patients, report of 24 cases in Italy and review of the literature. Eur J Epidemiol. 1998, 14 (3): 219-224. 10.1023/A:1007401305708.View ArticlePubMedGoogle Scholar
- Nurmohamed S, Weenink A, Moeniralam H, Visser C, Bemelman F: Hyperammonemia in generalized Mycobacterium genavense infection after renal transplantation. Am J Transplant. 2007, 7 (3): 722-723. 10.1111/j.1600-6143.2006.01680.x.View ArticlePubMedGoogle Scholar
- de Lastours V, Guillemain R, Mainardi JL, Aubert A, Chevalier P, Lefort A, Podglajen I: Early diagnosis of disseminated Mycobacterium genavense infection. Emerg Infect Dis. 2008, 14 (2): 346-347. 10.3201/eid1402.070901.View ArticlePubMedPubMed CentralGoogle Scholar
- Pechere M, Opravil M, Wald A, Chave JP, Bessesen M, Sievers A, Hein R, von Overbeck J, Clark RA, Tortoli E, et al: Clinical and epidemiologic features of infection with Mycobacterium genavense. Swiss HIV Cohort Study. Arch Intern Med. 1995, 155 (4): 400-404. 10.1001/archinte.155.4.400.View ArticlePubMedGoogle Scholar
- Thomsen VO, Dragsted UB, Bauer J, Fuursted K, Lundgren J: Disseminated infection with Mycobacterium genavense: a challenge to physicians and mycobacteriologists. J Clin Microbiol. 1999, 37 (12): 3901-3905.PubMedPubMed CentralGoogle Scholar
- Dumonceau JM, Van Gossum A, Adler M, Van Vooren JP, Fonteyne PA, De Beenhouwer H, Portaels F: Detection of fastidious mycobacteria in human intestines by the polymerase chain reaction. Eur J Clin Microbiol Infect Dis. 1997, 16 (5): 358-363. 10.1007/BF01726363.View ArticlePubMedGoogle Scholar
- Delpire P, Farber CM, Portaels F, Struelens M, Clevenbergh P, Dargent JL, Delpace J, Mehdi A, Van Vooren JP: Splenectomy in a patients with AIDS, generalized Mycobacterium genavense infection and severe pancytopenia. Tuber Lung Dis. 1996, 77 (6): 569-570. 10.1016/S0962-8479(96)90059-3.View ArticlePubMedGoogle Scholar
- Krebs T, Zimmerli S, Bodmer T, Lammle B: Mycobacterium genavense infection in a patient with long-standing chronic lymphocytic leukaemia. J Intern Med. 2000, 248 (4): 343-348. 10.1046/j.1365-2796.2000.00730.x.View ArticlePubMedGoogle Scholar
- Leautez S, Boutoille D, Bemer-Melchior P, Ponge T, Raffi F: Localized Mycobacterium genavense soft tissue infection in an immunodeficient HIV-negative patient. Eur J Clin Microbiol Infect Dis. 2000, 19 (1): 51-52. 10.1007/s100960050010.View ArticlePubMedGoogle Scholar
- Trueba F, Fabre M, Saint-Blancard P: Rapid identification of Mycobacterium genavense with a new commercially available molecular test, INNO-LiPA MYCOBACTERIA v2. J Clin Microbiol. 2004, 42 (9): 4403-4404. 10.1128/JCM.42.9.4403-4404.2004.View ArticlePubMedPubMed CentralGoogle Scholar
- Ninet B, Rutschmann O, Burkhardt K, Metral C, Borisch B, Hirschel B: Detection of mycobacterial nucleic acids by polymerase chain reaction in fixed tissue specimens of patients with human immunodeficiency virus infection. Swiss HIV Cohort Study. Diagn Mol Pathol. 1999, 8 (3): 145-151. 10.1097/00019606-199909000-00007.View ArticlePubMedGoogle Scholar
- Chevrier D, Oprisan G, Maresca A, Matsiota-Bernard P, Guesdon JL: Isolation of a specific DNA fragment and development of a PCR-based method for the detection of Mycobacterium genavense. FEMS Immunol Med Microbiol. 1999, 23 (3): 243-252. 10.1111/j.1574-695X.1999.tb01245.x.View ArticlePubMedGoogle Scholar
- Albrecht H, Rusch-Gerdes S, Stellbrink HJ, Greten H, Jackle S: Disseminated Mycobacterium genavense infection as a cause of pseudo-Whipple's disease and sclerosing cholangitis. Clin Infect Dis. 1997, 25 (3): 742-743. 10.1086/516941.View ArticlePubMedGoogle Scholar
- Casanova JL, Abel L: Genetic dissection of immunity to mycobacteria: the human model. Annu Rev Immunol. 2002, 20: 581-620. 10.1146/annurev.immunol.20.081501.125851.View ArticlePubMedGoogle Scholar
- Matsiota-Bernard P, Vilde F, Nauciel C: Mycobacterium genavense infection in normal and immunodeficient mice. Microbes Infect. 2000, 2 (6): 575-580. 10.1016/S1286-4579(00)00369-5.View ArticlePubMedGoogle Scholar
- Catherinot E, Lanternier F, Bougnoux ME, Lecuit M, Couderc LJ, Lortholary O: Pneumocystis jirovecii Pneumonia. Infect Dis Clin North Am. 24 (1): 107-138.
- Vrioni G, Nauciel C, Kerharo G, Matsiota-Bernard P: Treatment of disseminated Mycobacterium genavense infection in a murine model with ciprofloxacin, amikacin, ethambutol, clarithromycin and rifabutin. J Antimicrob Chemother. 1998, 42 (4): 483-487. 10.1093/jac/42.4.483.View ArticlePubMedGoogle Scholar
- Griffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, Holland SM, Horsburgh R, Huitt G, Iademarco MF, et al: An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007, 175 (4): 367-416. 10.1164/rccm.200604-571ST.View ArticlePubMedGoogle Scholar
- Ehlers S, Richter E: Gamma interferon is essential for clearing Mycobacterium genavense infection. Infect Immun. 2000, 68 (6): 3720-3723. 10.1128/IAI.68.6.3720-3723.2000.View ArticlePubMedPubMed CentralGoogle Scholar
- Kedzierska K, Azzam R, Ellery P, Mak J, Jaworowski A, Crowe SM: Defective phagocytosis by human monocyte/macrophages following HIV-1 infection: underlying mechanisms and modulation by adjunctive cytokine therapy. J Clin Virol. 2003, 26 (2): 247-263. 10.1016/S1386-6532(02)00123-3.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/11/311/prepub
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.