Akkerman, Onno W

Almesned, Mohammad A M

Eskandari, Siawosh K

Gan, Christiaan Tji-Joong

Jonkers, Sterre Y

Verschuuren, Erik A M

English

ARTS repository - University of Groningen

   University of GroningenRecurrent fever three years post lung transplantationEskandari, Siawosh K; Jonkers, Sterre Y; Almesned, Mohammad A M; Akkerman, Onno W;Verschuuren, Erik A M; Gan, Christiaan Tji-JoongPublished in:Transplant Infectious DiseaseDOI:10.1111/tid.13741IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2021Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Eskandari, S. K., Jonkers, S. Y., Almesned, M. A. M., Akkerman, O. W., Verschuuren, E. A. M., & Gan, C.T-J. (2021). Recurrent fever three years post lung transplantation: a Treacherous Case of Mycobacteriumgenavense. Transplant Infectious Disease, 23(6), Article e13741. Advance online publication.https://doi.org/10.1111/tid.13741CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 10-09-2023Received: 11 September 2021 Revised: 15 September 2021 Accepted: 18 September 2021DOI: 10.1111/tid.13741C L I N I C A L CORR E S POND ENC ERecurrent fever 3 years post-lung transplantation: Atreacherous case ofMycobacterium genavenseSiawosh K. Eskandari1,2 Sterre Y. Jonkers1 MohammadA.M. Almesned1OnnoW. Akkerman1,3 Erik A.M. Verschuuren1 Christiaan Tji-Joong Gan11 Department of Pulmonary Disease and Tuberculosis, UniversityMedical Center Groningen, University of Groningen, Groningen, Netherlands2 Transplantation Research Center, Brigham andWomen’s Hospital, HarvardMedical School, Boston, Massachusetts, USA3 Tuberculosis Center Beatrixoord, UniversityMedical Center Groningen, University of Groningen, Haren, NetherlandsCorrespondenceSiawoshK. Eskandari andChristiaanTji-JoongGan,DepartmentofPulmonaryDiseaseandTuberculosis,UniversityMedicalCenterGroningen,University ofGroningen,Hanzeplein1, 9713GZGroningen,NetherlandsEmail: s.eskandari@umcg.nl; c.t.gan@umcg.nlKEYWORDSlung transplantation,Mycobacterium genavense, nontuberculous lung diseaseTo The Editor,A 71-year-old man presented with a 9-month history of decreasedappetite, asthenia, weight loss, intermittent syncope, and recurrentfever up to 40◦C, having received a right-sided lung transplant 3 yearsprior for idiopathic pulmonary fibrosis (IPF). Physical examination pro-vided a blood pressure of 136 over 84 mm Hg, heart rate of 75 perminute, temperature of 36.9◦C (98.4◦F), and oxygen saturation of 99%on room air. Cardiac, abdominal, and neurological examinations werenormal, while lung examination showed decreased breath sounds withbasal crepitations on the left and normal breath sounds on the right.Subsequent laboratory work-up provided no infectious or splanchnicfocus for the fever or other symptoms. Chest X-rays similarly showedno anomalies compared to previous X-rays: Specifically, no indicationsof infiltrates or a pneumothorax (Figure 1A). Lung function was alsounremarkable, with an unchanged but known decreased FEV1 andforced vital capacity (FVC) (Figure 1B) and a lowered, yet normal,FEV1/FVC ratio (Figure 1C) in line with established left-sided IPF.An fluorodeoxyglucose positron emission tomography/computedtomography (FDG-PET/CT)-scan was subsequently made to rule outmalignancy, showing multiple FDG-avid, anatomically enlarged lymphnodes (Figure 1D), both above and below the diaphragm. A diag-nostic biopsy of the left supraclavicular lymph node presented non-necrotizing granulomas consisting of epithelioid histiocytes. Auraminestaining of this biopsy then revealed numerous acid-fast microor-ganisms with a histochemical profile characteristic of mycobacterialinfections (Ziehl-Neelsen +++, Wade-Fite +, Periodic Acid Schiff, +,Grocott-Gömöri+).Mycobacterium genavensewas ultimately identifiedas the causative pathogen using a nucleic acid amplification test.The patient was started on oral azithromycin (6.25 mg/kg, 1/d),ethambutol (15 mg/kg, 1/d), and rifampicin (7.5 mg/kg, 1/d). Addition-ally, to encourage endogenous immune responses againstM. genavense,the patient’s mycophenolate mofetil (500 mg, 2/d) was discontinued,while the prednisolone (5 mg, 1/d) and tacrolimus (1 mg, 2/d) weremaintained.In an admission that spanned over 2 months, the patient developedsevere hepatic and renal function failure—interpreted as medication-dependent toxicities. The antibiotic treatment was nonetheless sus-tained, and an FDG-PET/CT-scan was obtained 3 months post-treatment onset to monitor disease progression. The scan showedunchanged lymphadenopathy, with increased metabolic activity in thepericlavicular lymph nodes and moderately decreased activity in themediastinal lymph nodes. A new biopsy of the left supraclavicularlymph node showed abundant M. genavense coccobacilli without thepresence of alternative pathology.Based on the severity of the drug-based side-effects, the antibiotictreatment was finally discontinued. Despite the patient’s short-termclinical improvement, the intermittent bouts of fever soon recurred.Due to the relapsing, refractory fever, the lack of clinical response tothe antimycobacterial agents coupled with their toxic side-effects, andthe risk ofmultidrug-resistant substrainswith long-term therapy, alter-native drug regimens were not explored. The patient ultimately optedfor palliative treatment of his symptoms.Transpl Infect Dis. 2021;e13741. © 2021Wiley Periodicals LLC 1 of 4wileyonlinelibrary.com/journal/tidhttps://doi.org/10.1111/tid.137412 of 4 ESKANDARI ET AL.F IGURE 1 Chest X-rays (A); Lung function tests with FEV1 and FVC (B), and FEV1/FVC ratios (C); FDG-PET/CT-scan (D);M. genavenseinfection therapeutic dilemma (E). (A) The chest X-rays between January and September 2020 show a known small lung volume left characterizedby interstitial changes, with otherwise no indications of infiltrates or a pneumothorax. (B–C) Functional analyses of the patient’s lungs 3 years afterunilateral, right-sided lung transplantation in 2017 show (B) largely unaltered FEV1 and FVC parameters and (C) normal FEV1/FVC ratiosthroughout. The shaded areas in the graphs represent the reference ranges of eachmetric for healthy controls. (D) The FGD-PET/CT-scan fromSeptember 2020 shows relatively intense bilateral FDG uptake supraclavicularly, while showing intense FDG uptakemediastinally (paratracheallyESKANDARI ET AL. 3 of 41 DISCUSSIONIn 1990, a previously unidentified, fatal nontuberculous mycobacterial(NTM) infection was described in a patient with acquired immunodefi-ciency syndrome (AIDS) from Geneva, Switzerland.1 This later provedto be the first description ofMycobacterium genavense, soon detected inanother eighteen patients with advanced AIDS.2 Since then, this NTMis known to cause lethal opportunistic infections in AIDS patients andthose taking immunosuppressive drugs, such as for sarcoidosis.2–4 Thetypical symptoms of an M. genavense infection include fever, abdom-inal pain, weight loss, diarrhea, and anemia.5 Patients experience anextensive infection of the intestines and liver, although necropsiesof infected subjects have also shown involvement of the lungs, bonemarrow, and lymph nodes.2 M. genavense infections can spur mas-sive mesenteric lymphadenopathy and lead to hepatosplenomegaly.6These relatively nonspecific symptoms and the lack of a pathog-nomonic hallmark for the disease, however, make it hard to distinguishM. genavense from more prevalent NTM infections such as fromMycobacterium avium complex (MAC) and more common infectious orneoplastic diseases due to overlapping symptomatology. This vaguepresentation prevents physicians from actively performing diagnosticsfor M. genavense or similarly atypical NTMs—despite atypical NTMsconstituting ∼20% of all NTM infections.7Notably, experience regardingM. genavense infections in transplan-tation is limited as almost all relevant knowledge has been gleanedfrom AIDS patients.5,8–11 There are only sporadic accounts in renaland cardiac transplant recipients,5,10,11 with just one report of anM. genavense infected lung transplant patient.12 In that patient, theinfection was detected in a disseminated phase, and while there was alengthy resolution of the chief complaints, the recurrent infection ulti-mately caused fatal multiorgan failure.12In particular, the disease progression of M. genavense infections isunpredictable, which leads to diagnostic delays when coupled with thelimited clinical awareness of NTM pathology. Our patient experienceda 9-month history of vague subfebrile complaints before his diagnosis.This delay canbeascribed to the successive screeningsby cardiologists,geriatric specialists, and neurologists for his chief complaints, includ-ing intermittent syncope, asthenia, weight loss, and even parkinsonism,prior to his pulmonology work-up.Strikingly, all tuberculous diseases experience diagnostic delay,includingM. tuberculosis infections.13 This delay may be attributable tolow disease prevalence.13 For context, the NTM prevalence in a popu-lation of United States veterans was 41.1 cases per 100,000 patientsbetween 2008–2012, with 81% of these beingMAC infections and therest 32 other NTM strains.7 Among all NTMs infections, M. genavenseconstituted 0.05% of the total.7 Timely diagnosis of atypical NTMswillbecomemore important in the coming 20 yearswith estimates that theoverall NTM prevalence will quadruple,14 especially in individuals>65who aremore susceptible to NTM infections.15Upon M. genavense diagnosis, our patient was treated withazithromycin, ethambutol, and rifampicin. Ethambutol and rifampicinare commonly used to treat M. tuberculosis and M. genavenseinfections.5,8–11 Additionally, a recent case series demonstrated suc-cessful treatment with combinations of clarithromycin, ethambutol,rifabutin, and quinolones.10 Nonetheless, the experience in treatingM.genavense infections remains limited. Often, a broad-spectrum antibi-otic regimen is empirically selected.11 Due to the severe side-effects oftuberculostatics, the regimen predominantly depends on the patient’stolerance to the drug toxicity profiles.8 For transplant patients, thehepatic and renal side-effects caused by interactions between theantimycobacterials and the patients’ immunosuppressants are mostcritical. In light thereof, reducing immunosuppression can potentiallydecrease drug interactions and even have antimycobacterial effects.Finally, an additional factor that impedes the curative treatment ofNTMs such as M. genavense is insufficient tissue penetration of theantibiotics—causing systemic side-effects before curative drug levelscan be attained in local infection foci (Figure 1E).The inherent damage caused by M. genavense and the therapy-related side-effects tie into the highmortality among infected patients.Since the early 1990s, AIDS patients with M. genavense show highmortality,8,9 while the mortality rate among non-AIDS patients is like-wise high, ranging between 25% and 44%.10,112 CONCLUSIONM. genavense is an NTM that mimics inflammatory and neoplastic dis-eases and can cause lethal infections in immunosuppressed patients.Due to its low prevalence, the diagnosis is often missed by clini-cians, and even when it is diagnosed, there is much doubt regardingthe best therapy. Many patients eventually succumb to the infectiondespite treatment initiation due to the disseminated stage in which itis detected. As such, increased awareness among clinicians regardingatypical NTMs such asM. genavense is warranted to diminish diagnos-tic delay.AUTHOR CONTRIBUTIONSSiawosh K. Eskandari, Sterre Y. Jonkers, and Mohammad A.M.Almesned conducted patient care, while OnnoW. Akkerman, Erik A.M.Verschuuren, and Christiaan Tji-Joong Gan conducted and supervisedright and left, high ventrally right, and ventral of the right main bronchus). These FDG-avid foci correspondwith enlarged lymph nodes on the CTmodality. Intrapulmonally, there are diffusely FDG-avid nodules, andmesenterially and retroperitoneally, there aremultiple small intenseFDG-positive foci, including the bilateral paraaortic lymph nodes. The FDG uptake in the liver, spleen, and digestive tract is physiological, as well asthe FDG excretion via the kidneys to the bladder. (E) OnceM. genavensewas detected in our patient, the antibiotic treatment was initiated with theprimary goal of resolving themycobacterial proliferation in the lymph nodes. Parallel to the treatment of the infection, however, life-threateninghepatic and renal function failure occurred as a direct side-effect of the antibiotics. As such, the bacterial load was too high to eradicate theM.genavense coccobacilli without endangering the patient’s life4 of 4 ESKANDARI ET AL.patient care. All authors critically revised the manuscript. Siawosh K.Eskandari and Christiaan Tji-Joong Gan wrote the original draft andfinalized themanuscript for publication.CONFLICT OF INTERESTSAll authors declare that they have no competing interests.ORCIDSiawoshK. Eskandari https://orcid.org/0000-0003-4867-4170OnnoW.Akkerman https://orcid.org/0000-0001-5638-9260ErikA.M.Verschuuren https://orcid.org/0000-0002-6807-6744ChristiaanTji-JoongGan https://orcid.org/0000-0002-1310-4189REFERENCES1. Hirschel B, Chang HR, Mach N, et al. Fatal infection with a novel,unidentified mycobacterium in a man with the acquired immunodefi-ciency syndrome.N Engl J Med. 1990;323:109-113.2. Böttger EC, Teske A, Kirschner P, et al. Disseminated “Mycobacteriumgenavense” infection in patients with AIDS. Lancet. 1992;340:76-80.3. Bessesen MT, Shlay J, Stone-Venohr B, Cohn DL, Reves RR. Dissemi-nated Mycobacterium genavense infection: clinical and microbiologi-cal features and response to therapy. AIDS. 1993;7:1357-1361.4. Dumouchel-Champagne H, Charlier-Woerther C, Boibieux A, et al.Disseminated nontuberculous infections with Mycobacteriumgenavense during sarcoidosis. Eur Respir Rev. 2009;18:299-301.5. Santos M, Gil-Brusola A, Escandell A, Blanes M, GobernadoM. Mycobacterium genavense infections in a tertiary hospi-tal and reviewed cases in non-HIV patients. Patholog Res Int.2014;2014:371370.6. Monill JM, Franquet T, Sambeat MA, Martínez-Noguera A, Villalba J.Mycobacterium genavense infection in AIDS: imaging findings in eightpatients. Eur Radiol. 2001;11:193-196.7. Jones MM,Winthrop KL, Nelson SD, et al. Epidemiology of nontuber-culous mycobacterial infections in the U.S. Veterans Health Adminis-tration. PLoS One. 2018;13:e0197976.8. Shafran SD, Taylor GD, Talbot JA. Disseminated Mycobacteriumgenavense infection in Canadian AIDS patients. Tuber Lung Dis.1995;76:168-170.9. Thomsen VO, Dragsted UB, Bauer J, Fuursted K, Lundgren J. Dis-seminated infection with Mycobacterium genavense: a challenge tophysicians and mycobacteriologists. J Clin Microbiol. 1999;37:3901-3905.10. Charles P, Lortholary O, Dechartres A, et al. Mycobacteriumgenavense infections: a retrospective multicenter study in France,1996–2007.Medicine (Baltimore). 2011;90:223-230.11. Hoefsloot W, van Ingen J, Peters EJ, et al. Mycobacterium genavensein the Netherlands: an opportunistic pathogen in HIV and non-HIVimmunocompromised patients. An observational study in 14 cases.Clin Microbiol Infect. 2013;19:432-437.12. Lhuillier E, Brugière O, Veziris N, et al. Relapsing Mycobacteriumgenavense infection as a cause of late death in a lung transplant recip-ient: case report and review of the literature. Exp Clin Transplant.2012;10:618-620.13. El Halabi J, Palmer N, McDuffie M, et al. Measuring health-caredelays among privately insured patients with tuberculosis in theUSA: an observational cohort study. Lancet Infect Dis. 2021;21:1175-1183.14. Ratnatunga CN, Lutzky VP, Kupz A, et al. The rise of non-tuberculosismycobacterial lung disease. Front Immunol. 2020;11:303.15. Lake MA, Ambrose LR, Lipman MC, Lowe DM. “Why me, why now?”Using clinical immunology and epidemiology to explain who getsnontuberculous mycobacterial infection. BMC Med. 2016;14:54-016-0606-0606.How to cite this article: Eskandari SK, Jonkers SY, AlmesnedMAM, AkkermanOW, Verschuuren EAM, Gan CT-J. Recurrentfever 3 years post-lung transplantation: A treacherous case ofMycobacterium genavense. Transpl Infect Dis. 2021;:e13741.https://doi.org/10.1111/tid.13741

Recurrent fever three years post lung transplantation:a Treacherous Case of <i>Mycobacterium genavense</i>

Siawosh K. Eskandari

Sterre Y. Jonkers

Mohammad A.M. Almesned

Onno W. Akkerman

Erik A.M. Verschuuren

Christiaan Tji‐Joong Gan

Crossref

NARCIS 

Recurrent fever three years post lung transplantation: a Treacherous Case of Mycobacterium genavense

University of Groningen

University of GroningenRecurrent fever three years post lung transplantationEskandari, Siawosh K; Jonkers, Sterre Y; Almesned, Mohammad A M; Akkerman, Onno W;Verschuuren, Erik A M; Gan, Christiaan Tji-JoongPublished in:Transplant Infectious DiseaseDOI:10.1111/tid.13741IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2021Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Eskandari, S. K., Jonkers, S. Y., Almesned, M. A. M., Akkerman, O. W., Verschuuren, E. A. M., & Gan, C.T.-J. (2021). Recurrent fever three years post lung transplantation: a Treacherous Case of Mycobacteriumgenavense. Transplant Infectious Disease, 23(6), Article e13741. https://doi.org/10.1111/tid.13741CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 31-12-2025Received: 11 September 2021 Revised: 15 September 2021 Accepted: 18 September 2021DOI: 10.1111/tid.13741C L I N I C A L CORR E S POND ENC ERecurrent fever 3 years post-lung transplantation: Atreacherous case ofMycobacterium genavenseSiawosh K. Eskandari1,2 Sterre Y. Jonkers1 MohammadA.M. Almesned1OnnoW. Akkerman1,3 Erik A.M. Verschuuren1 Christiaan Tji-Joong Gan11 Department of Pulmonary Disease and Tuberculosis, UniversityMedical Center Groningen, University of Groningen, Groningen, Netherlands2 Transplantation Research Center, Brigham andWomen’s Hospital, HarvardMedical School, Boston, Massachusetts, USA3 Tuberculosis Center Beatrixoord, UniversityMedical Center Groningen, University of Groningen, Haren, NetherlandsCorrespondenceSiawoshK. Eskandari andChristiaanTji-JoongGan,DepartmentofPulmonaryDiseaseandTuberculosis,UniversityMedicalCenterGroningen,University ofGroningen,Hanzeplein1, 9713GZGroningen,NetherlandsEmail: s.eskandari@umcg.nl; c.t.gan@umcg.nlKEYWORDSlung transplantation,Mycobacterium genavense, nontuberculous lung diseaseTo The Editor,A 71-year-old man presented with a 9-month history of decreasedappetite, asthenia, weight loss, intermittent syncope, and recurrentfever up to 40◦C, having received a right-sided lung transplant 3 yearsprior for idiopathic pulmonary fibrosis (IPF). Physical examination pro-vided a blood pressure of 136 over 84 mm Hg, heart rate of 75 perminute, temperature of 36.9◦C (98.4◦F), and oxygen saturation of 99%on room air. Cardiac, abdominal, and neurological examinations werenormal, while lung examination showed decreased breath sounds withbasal crepitations on the left and normal breath sounds on the right.Subsequent laboratory work-up provided no infectious or splanchnicfocus for the fever or other symptoms. Chest X-rays similarly showedno anomalies compared to previous X-rays: Specifically, no indicationsof infiltrates or a pneumothorax (Figure 1A). Lung function was alsounremarkable, with an unchanged but known decreased FEV1 andforced vital capacity (FVC) (Figure 1B) and a lowered, yet normal,FEV1/FVC ratio (Figure 1C) in line with established left-sided IPF.An fluorodeoxyglucose positron emission tomography/computedtomography (FDG-PET/CT)-scan was subsequently made to rule outmalignancy, showing multiple FDG-avid, anatomically enlarged lymphnodes (Figure 1D), both above and below the diaphragm. A diag-nostic biopsy of the left supraclavicular lymph node presented non-necrotizing granulomas consisting of epithelioid histiocytes. Auraminestaining of this biopsy then revealed numerous acid-fast microor-ganisms with a histochemical profile characteristic of mycobacterialinfections (Ziehl-Neelsen +++, Wade-Fite +, Periodic Acid Schiff, +,Grocott-Gömöri+).Mycobacterium genavensewas ultimately identifiedas the causative pathogen using a nucleic acid amplification test.The patient was started on oral azithromycin (6.25 mg/kg, 1/d),ethambutol (15 mg/kg, 1/d), and rifampicin (7.5 mg/kg, 1/d). Addition-ally, to encourage endogenous immune responses againstM. genavense,the patient’s mycophenolate mofetil (500 mg, 2/d) was discontinued,while the prednisolone (5 mg, 1/d) and tacrolimus (1 mg, 2/d) weremaintained.In an admission that spanned over 2 months, the patient developedsevere hepatic and renal function failure—interpreted as medication-dependent toxicities. The antibiotic treatment was nonetheless sus-tained, and an FDG-PET/CT-scan was obtained 3 months post-treatment onset to monitor disease progression. The scan showedunchanged lymphadenopathy, with increased metabolic activity in thepericlavicular lymph nodes and moderately decreased activity in themediastinal lymph nodes. A new biopsy of the left supraclavicularlymph node showed abundant M. genavense coccobacilli without thepresence of alternative pathology.Based on the severity of the drug-based side-effects, the antibiotictreatment was finally discontinued. Despite the patient’s short-termclinical improvement, the intermittent bouts of fever soon recurred.Due to the relapsing, refractory fever, the lack of clinical response tothe antimycobacterial agents coupled with their toxic side-effects, andthe risk ofmultidrug-resistant substrainswith long-term therapy, alter-native drug regimens were not explored. The patient ultimately optedfor palliative treatment of his symptoms.Transpl Infect Dis. 2021;e13741. © 2021Wiley Periodicals LLC 1 of 4wileyonlinelibrary.com/journal/tidhttps://doi.org/10.1111/tid.137412 of 4 ESKANDARI ET AL.F IGURE 1 Chest X-rays (A); Lung function tests with FEV1 and FVC (B), and FEV1/FVC ratios (C); FDG-PET/CT-scan (D);M. genavenseinfection therapeutic dilemma (E). (A) The chest X-rays between January and September 2020 show a known small lung volume left characterizedby interstitial changes, with otherwise no indications of infiltrates or a pneumothorax. (B–C) Functional analyses of the patient’s lungs 3 years afterunilateral, right-sided lung transplantation in 2017 show (B) largely unaltered FEV1 and FVC parameters and (C) normal FEV1/FVC ratiosthroughout. The shaded areas in the graphs represent the reference ranges of eachmetric for healthy controls. (D) The FGD-PET/CT-scan fromSeptember 2020 shows relatively intense bilateral FDG uptake supraclavicularly, while showing intense FDG uptakemediastinally (paratracheallyESKANDARI ET AL. 3 of 41 DISCUSSIONIn 1990, a previously unidentified, fatal nontuberculous mycobacterial(NTM) infection was described in a patient with acquired immunodefi-ciency syndrome (AIDS) from Geneva, Switzerland.1 This later provedto be the first description ofMycobacterium genavense, soon detected inanother eighteen patients with advanced AIDS.2 Since then, this NTMis known to cause lethal opportunistic infections in AIDS patients andthose taking immunosuppressive drugs, such as for sarcoidosis.2–4 Thetypical symptoms of an M. genavense infection include fever, abdom-inal pain, weight loss, diarrhea, and anemia.5 Patients experience anextensive infection of the intestines and liver, although necropsiesof infected subjects have also shown involvement of the lungs, bonemarrow, and lymph nodes.2 M. genavense infections can spur mas-sive mesenteric lymphadenopathy and lead to hepatosplenomegaly.6These relatively nonspecific symptoms and the lack of a pathog-nomonic hallmark for the disease, however, make it hard to distinguishM. genavense from more prevalent NTM infections such as fromMycobacterium avium complex (MAC) and more common infectious orneoplastic diseases due to overlapping symptomatology. This vaguepresentation prevents physicians from actively performing diagnosticsfor M. genavense or similarly atypical NTMs—despite atypical NTMsconstituting ∼20% of all NTM infections.7Notably, experience regardingM. genavense infections in transplan-tation is limited as almost all relevant knowledge has been gleanedfrom AIDS patients.5,8–11 There are only sporadic accounts in renaland cardiac transplant recipients,5,10,11 with just one report of anM. genavense infected lung transplant patient.12 In that patient, theinfection was detected in a disseminated phase, and while there was alengthy resolution of the chief complaints, the recurrent infection ulti-mately caused fatal multiorgan failure.12In particular, the disease progression of M. genavense infections isunpredictable, which leads to diagnostic delays when coupled with thelimited clinical awareness of NTM pathology. Our patient experienceda 9-month history of vague subfebrile complaints before his diagnosis.This delay canbeascribed to the successive screeningsby cardiologists,geriatric specialists, and neurologists for his chief complaints, includ-ing intermittent syncope, asthenia, weight loss, and even parkinsonism,prior to his pulmonology work-up.Strikingly, all tuberculous diseases experience diagnostic delay,includingM. tuberculosis infections.13 This delay may be attributable tolow disease prevalence.13 For context, the NTM prevalence in a popu-lation of United States veterans was 41.1 cases per 100,000 patientsbetween 2008–2012, with 81% of these beingMAC infections and therest 32 other NTM strains.7 Among all NTMs infections, M. genavenseconstituted 0.05% of the total.7 Timely diagnosis of atypical NTMswillbecomemore important in the coming 20 yearswith estimates that theoverall NTM prevalence will quadruple,14 especially in individuals>65who aremore susceptible to NTM infections.15Upon M. genavense diagnosis, our patient was treated withazithromycin, ethambutol, and rifampicin. Ethambutol and rifampicinare commonly used to treat M. tuberculosis and M. genavenseinfections.5,8–11 Additionally, a recent case series demonstrated suc-cessful treatment with combinations of clarithromycin, ethambutol,rifabutin, and quinolones.10 Nonetheless, the experience in treatingM.genavense infections remains limited. Often, a broad-spectrum antibi-otic regimen is empirically selected.11 Due to the severe side-effects oftuberculostatics, the regimen predominantly depends on the patient’stolerance to the drug toxicity profiles.8 For transplant patients, thehepatic and renal side-effects caused by interactions between theantimycobacterials and the patients’ immunosuppressants are mostcritical. In light thereof, reducing immunosuppression can potentiallydecrease drug interactions and even have antimycobacterial effects.Finally, an additional factor that impedes the curative treatment ofNTMs such as M. genavense is insufficient tissue penetration of theantibiotics—causing systemic side-effects before curative drug levelscan be attained in local infection foci (Figure 1E).The inherent damage caused by M. genavense and the therapy-related side-effects tie into the highmortality among infected patients.Since the early 1990s, AIDS patients with M. genavense show highmortality,8,9 while the mortality rate among non-AIDS patients is like-wise high, ranging between 25% and 44%.10,112 CONCLUSIONM. genavense is an NTM that mimics inflammatory and neoplastic dis-eases and can cause lethal infections in immunosuppressed patients.Due to its low prevalence, the diagnosis is often missed by clini-cians, and even when it is diagnosed, there is much doubt regardingthe best therapy. Many patients eventually succumb to the infectiondespite treatment initiation due to the disseminated stage in which itis detected. As such, increased awareness among clinicians regardingatypical NTMs such asM. genavense is warranted to diminish diagnos-tic delay.AUTHOR CONTRIBUTIONSSiawosh K. Eskandari, Sterre Y. Jonkers, and Mohammad A.M.Almesned conducted patient care, while OnnoW. Akkerman, Erik A.M.Verschuuren, and Christiaan Tji-Joong Gan conducted and supervisedright and left, high ventrally right, and ventral of the right main bronchus). These FDG-avid foci correspondwith enlarged lymph nodes on the CTmodality. Intrapulmonally, there are diffusely FDG-avid nodules, andmesenterially and retroperitoneally, there aremultiple small intenseFDG-positive foci, including the bilateral paraaortic lymph nodes. The FDG uptake in the liver, spleen, and digestive tract is physiological, as well asthe FDG excretion via the kidneys to the bladder. (E) OnceM. genavensewas detected in our patient, the antibiotic treatment was initiated with theprimary goal of resolving themycobacterial proliferation in the lymph nodes. Parallel to the treatment of the infection, however, life-threateninghepatic and renal function failure occurred as a direct side-effect of the antibiotics. As such, the bacterial load was too high to eradicate theM.genavense coccobacilli without endangering the patient’s life4 of 4 ESKANDARI ET AL.patient care. All authors critically revised the manuscript. Siawosh K.Eskandari and Christiaan Tji-Joong Gan wrote the original draft andfinalized themanuscript for publication.CONFLICT OF INTERESTSAll authors declare that they have no competing interests.ORCIDSiawoshK. Eskandari https://orcid.org/0000-0003-4867-4170OnnoW.Akkerman https://orcid.org/0000-0001-5638-9260ErikA.M.Verschuuren https://orcid.org/0000-0002-6807-6744ChristiaanTji-JoongGan https://orcid.org/0000-0002-1310-4189REFERENCES1. Hirschel B, Chang HR, Mach N, et al. Fatal infection with a novel,unidentified mycobacterium in a man with the acquired immunodefi-ciency syndrome.N Engl J Med. 1990;323:109-113.2. Böttger EC, Teske A, Kirschner P, et al. Disseminated “Mycobacteriumgenavense” infection in patients with AIDS. Lancet. 1992;340:76-80.3. Bessesen MT, Shlay J, Stone-Venohr B, Cohn DL, Reves RR. Dissemi-nated Mycobacterium genavense infection: clinical and microbiologi-cal features and response to therapy. AIDS. 1993;7:1357-1361.4. Dumouchel-Champagne H, Charlier-Woerther C, Boibieux A, et al.Disseminated nontuberculous infections with Mycobacteriumgenavense during sarcoidosis. Eur Respir Rev. 2009;18:299-301.5. Santos M, Gil-Brusola A, Escandell A, Blanes M, GobernadoM. Mycobacterium genavense infections in a tertiary hospi-tal and reviewed cases in non-HIV patients. Patholog Res Int.2014;2014:371370.6. Monill JM, Franquet T, Sambeat MA, Martínez-Noguera A, Villalba J.Mycobacterium genavense infection in AIDS: imaging findings in eightpatients. Eur Radiol. 2001;11:193-196.7. Jones MM,Winthrop KL, Nelson SD, et al. Epidemiology of nontuber-culous mycobacterial infections in the U.S. Veterans Health Adminis-tration. PLoS One. 2018;13:e0197976.8. Shafran SD, Taylor GD, Talbot JA. Disseminated Mycobacteriumgenavense infection in Canadian AIDS patients. Tuber Lung Dis.1995;76:168-170.9. Thomsen VO, Dragsted UB, Bauer J, Fuursted K, Lundgren J. Dis-seminated infection with Mycobacterium genavense: a challenge tophysicians and mycobacteriologists. J Clin Microbiol. 1999;37:3901-3905.10. Charles P, Lortholary O, Dechartres A, et al. Mycobacteriumgenavense infections: a retrospective multicenter study in France,1996–2007.Medicine (Baltimore). 2011;90:223-230.11. Hoefsloot W, van Ingen J, Peters EJ, et al. Mycobacterium genavensein the Netherlands: an opportunistic pathogen in HIV and non-HIVimmunocompromised patients. An observational study in 14 cases.Clin Microbiol Infect. 2013;19:432-437.12. Lhuillier E, Brugière O, Veziris N, et al. Relapsing Mycobacteriumgenavense infection as a cause of late death in a lung transplant recip-ient: case report and review of the literature. Exp Clin Transplant.2012;10:618-620.13. El Halabi J, Palmer N, McDuffie M, et al. Measuring health-caredelays among privately insured patients with tuberculosis in theUSA: an observational cohort study. Lancet Infect Dis. 2021;21:1175-1183.14. Ratnatunga CN, Lutzky VP, Kupz A, et al. The rise of non-tuberculosismycobacterial lung disease. Front Immunol. 2020;11:303.15. Lake MA, Ambrose LR, Lipman MC, Lowe DM. “Why me, why now?”Using clinical immunology and epidemiology to explain who getsnontuberculous mycobacterial infection. BMC Med. 2016;14:54-016-0606-0606.How to cite this article: Eskandari SK, Jonkers SY, AlmesnedMAM, AkkermanOW, Verschuuren EAM, Gan CT-J. Recurrentfever 3 years post-lung transplantation: A treacherous case ofMycobacterium genavense. Transpl Infect Dis. 2021;:e13741.https://doi.org/10.1111/tid.13741

   University of GroningenRecurrent fever three years post lung transplantationEskandari, Siawosh K; Jonkers, Sterre Y; Almesned, Mohammad A M; Akkerman, Onno W;Verschuuren, Erik A M; Gan, Christiaan Tji-JoongPublished in:Transplant Infectious DiseaseDOI:10.1111/tid.13741IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2021Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Eskandari, S. K., Jonkers, S. Y., Almesned, M. A. M., Akkerman, O. W., Verschuuren, E. A. M., & Gan, C.T-J. (2021). Recurrent fever three years post lung transplantation: a Treacherous Case of Mycobacteriumgenavense. Transplant Infectious Disease, 23(6), [e13741]. https://doi.org/10.1111/tid.13741CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 08-06-2022Received: 11 September 2021 Revised: 15 September 2021 Accepted: 18 September 2021DOI: 10.1111/tid.13741C L I N I C A L CORR E S POND ENC ERecurrent fever 3 years post-lung transplantation: Atreacherous case ofMycobacterium genavenseSiawosh K. Eskandari1,2 Sterre Y. Jonkers1 MohammadA.M. Almesned1OnnoW. Akkerman1,3 Erik A.M. Verschuuren1 Christiaan Tji-Joong Gan11 Department of Pulmonary Disease and Tuberculosis, UniversityMedical Center Groningen, University of Groningen, Groningen, Netherlands2 Transplantation Research Center, Brigham andWomen’s Hospital, HarvardMedical School, Boston, Massachusetts, USA3 Tuberculosis Center Beatrixoord, UniversityMedical Center Groningen, University of Groningen, Haren, NetherlandsCorrespondenceSiawoshK. Eskandari andChristiaanTji-JoongGan,DepartmentofPulmonaryDiseaseandTuberculosis,UniversityMedicalCenterGroningen,University ofGroningen,Hanzeplein1, 9713GZGroningen,NetherlandsEmail: s.eskandari@umcg.nl; c.t.gan@umcg.nlKEYWORDSlung transplantation,Mycobacterium genavense, nontuberculous lung diseaseTo The Editor,A 71-year-old man presented with a 9-month history of decreasedappetite, asthenia, weight loss, intermittent syncope, and recurrentfever up to 40◦C, having received a right-sided lung transplant 3 yearsprior for idiopathic pulmonary fibrosis (IPF). Physical examination pro-vided a blood pressure of 136 over 84 mm Hg, heart rate of 75 perminute, temperature of 36.9◦C (98.4◦F), and oxygen saturation of 99%on room air. Cardiac, abdominal, and neurological examinations werenormal, while lung examination showed decreased breath sounds withbasal crepitations on the left and normal breath sounds on the right.Subsequent laboratory work-up provided no infectious or splanchnicfocus for the fever or other symptoms. Chest X-rays similarly showedno anomalies compared to previous X-rays: Specifically, no indicationsof infiltrates or a pneumothorax (Figure 1A). Lung function was alsounremarkable, with an unchanged but known decreased FEV1 andforced vital capacity (FVC) (Figure 1B) and a lowered, yet normal,FEV1/FVC ratio (Figure 1C) in line with established left-sided IPF.An fluorodeoxyglucose positron emission tomography/computedtomography (FDG-PET/CT)-scan was subsequently made to rule outmalignancy, showing multiple FDG-avid, anatomically enlarged lymphnodes (Figure 1D), both above and below the diaphragm. A diag-nostic biopsy of the left supraclavicular lymph node presented non-necrotizing granulomas consisting of epithelioid histiocytes. Auraminestaining of this biopsy then revealed numerous acid-fast microor-ganisms with a histochemical profile characteristic of mycobacterialinfections (Ziehl-Neelsen +++, Wade-Fite +, Periodic Acid Schiff, +,Grocott-Gömöri+).Mycobacterium genavensewas ultimately identifiedas the causative pathogen using a nucleic acid amplification test.The patient was started on oral azithromycin (6.25 mg/kg, 1/d),ethambutol (15 mg/kg, 1/d), and rifampicin (7.5 mg/kg, 1/d). Addition-ally, to encourage endogenous immune responses againstM. genavense,the patient’s mycophenolate mofetil (500 mg, 2/d) was discontinued,while the prednisolone (5 mg, 1/d) and tacrolimus (1 mg, 2/d) weremaintained.In an admission that spanned over 2 months, the patient developedsevere hepatic and renal function failure—interpreted as medication-dependent toxicities. The antibiotic treatment was nonetheless sus-tained, and an FDG-PET/CT-scan was obtained 3 months post-treatment onset to monitor disease progression. The scan showedunchanged lymphadenopathy, with increased metabolic activity in thepericlavicular lymph nodes and moderately decreased activity in themediastinal lymph nodes. A new biopsy of the left supraclavicularlymph node showed abundant M. genavense coccobacilli without thepresence of alternative pathology.Based on the severity of the drug-based side-effects, the antibiotictreatment was finally discontinued. Despite the patient’s short-termclinical improvement, the intermittent bouts of fever soon recurred.Due to the relapsing, refractory fever, the lack of clinical response tothe antimycobacterial agents coupled with their toxic side-effects, andthe risk ofmultidrug-resistant substrainswith long-term therapy, alter-native drug regimens were not explored. The patient ultimately optedfor palliative treatment of his symptoms.Transpl Infect Dis. 2021;e13741. © 2021Wiley Periodicals LLC 1 of 4wileyonlinelibrary.com/journal/tidhttps://doi.org/10.1111/tid.137412 of 4 ESKANDARI ET AL.F IGURE 1 Chest X-rays (A); Lung function tests with FEV1 and FVC (B), and FEV1/FVC ratios (C); FDG-PET/CT-scan (D);M. genavenseinfection therapeutic dilemma (E). (A) The chest X-rays between January and September 2020 show a known small lung volume left characterizedby interstitial changes, with otherwise no indications of infiltrates or a pneumothorax. (B–C) Functional analyses of the patient’s lungs 3 years afterunilateral, right-sided lung transplantation in 2017 show (B) largely unaltered FEV1 and FVC parameters and (C) normal FEV1/FVC ratiosthroughout. The shaded areas in the graphs represent the reference ranges of eachmetric for healthy controls. (D) The FGD-PET/CT-scan fromSeptember 2020 shows relatively intense bilateral FDG uptake supraclavicularly, while showing intense FDG uptakemediastinally (paratracheallyESKANDARI ET AL. 3 of 41 DISCUSSIONIn 1990, a previously unidentified, fatal nontuberculous mycobacterial(NTM) infection was described in a patient with acquired immunodefi-ciency syndrome (AIDS) from Geneva, Switzerland.1 This later provedto be the first description ofMycobacterium genavense, soon detected inanother eighteen patients with advanced AIDS.2 Since then, this NTMis known to cause lethal opportunistic infections in AIDS patients andthose taking immunosuppressive drugs, such as for sarcoidosis.2–4 Thetypical symptoms of an M. genavense infection include fever, abdom-inal pain, weight loss, diarrhea, and anemia.5 Patients experience anextensive infection of the intestines and liver, although necropsiesof infected subjects have also shown involvement of the lungs, bonemarrow, and lymph nodes.2 M. genavense infections can spur mas-sive mesenteric lymphadenopathy and lead to hepatosplenomegaly.6These relatively nonspecific symptoms and the lack of a pathog-nomonic hallmark for the disease, however, make it hard to distinguishM. genavense from more prevalent NTM infections such as fromMycobacterium avium complex (MAC) and more common infectious orneoplastic diseases due to overlapping symptomatology. This vaguepresentation prevents physicians from actively performing diagnosticsfor M. genavense or similarly atypical NTMs—despite atypical NTMsconstituting ∼20% of all NTM infections.7Notably, experience regardingM. genavense infections in transplan-tation is limited as almost all relevant knowledge has been gleanedfrom AIDS patients.5,8–11 There are only sporadic accounts in renaland cardiac transplant recipients,5,10,11 with just one report of anM. genavense infected lung transplant patient.12 In that patient, theinfection was detected in a disseminated phase, and while there was alengthy resolution of the chief complaints, the recurrent infection ulti-mately caused fatal multiorgan failure.12In particular, the disease progression of M. genavense infections isunpredictable, which leads to diagnostic delays when coupled with thelimited clinical awareness of NTM pathology. Our patient experienceda 9-month history of vague subfebrile complaints before his diagnosis.This delay canbeascribed to the successive screeningsby cardiologists,geriatric specialists, and neurologists for his chief complaints, includ-ing intermittent syncope, asthenia, weight loss, and even parkinsonism,prior to his pulmonology work-up.Strikingly, all tuberculous diseases experience diagnostic delay,includingM. tuberculosis infections.13 This delay may be attributable tolow disease prevalence.13 For context, the NTM prevalence in a popu-lation of United States veterans was 41.1 cases per 100,000 patientsbetween 2008–2012, with 81% of these beingMAC infections and therest 32 other NTM strains.7 Among all NTMs infections, M. genavenseconstituted 0.05% of the total.7 Timely diagnosis of atypical NTMswillbecomemore important in the coming 20 yearswith estimates that theoverall NTM prevalence will quadruple,14 especially in individuals>65who aremore susceptible to NTM infections.15Upon M. genavense diagnosis, our patient was treated withazithromycin, ethambutol, and rifampicin. Ethambutol and rifampicinare commonly used to treat M. tuberculosis and M. genavenseinfections.5,8–11 Additionally, a recent case series demonstrated suc-cessful treatment with combinations of clarithromycin, ethambutol,rifabutin, and quinolones.10 Nonetheless, the experience in treatingM.genavense infections remains limited. Often, a broad-spectrum antibi-otic regimen is empirically selected.11 Due to the severe side-effects oftuberculostatics, the regimen predominantly depends on the patient’stolerance to the drug toxicity profiles.8 For transplant patients, thehepatic and renal side-effects caused by interactions between theantimycobacterials and the patients’ immunosuppressants are mostcritical. In light thereof, reducing immunosuppression can potentiallydecrease drug interactions and even have antimycobacterial effects.Finally, an additional factor that impedes the curative treatment ofNTMs such as M. genavense is insufficient tissue penetration of theantibiotics—causing systemic side-effects before curative drug levelscan be attained in local infection foci (Figure 1E).The inherent damage caused by M. genavense and the therapy-related side-effects tie into the highmortality among infected patients.Since the early 1990s, AIDS patients with M. genavense show highmortality,8,9 while the mortality rate among non-AIDS patients is like-wise high, ranging between 25% and 44%.10,112 CONCLUSIONM. genavense is an NTM that mimics inflammatory and neoplastic dis-eases and can cause lethal infections in immunosuppressed patients.Due to its low prevalence, the diagnosis is often missed by clini-cians, and even when it is diagnosed, there is much doubt regardingthe best therapy. Many patients eventually succumb to the infectiondespite treatment initiation due to the disseminated stage in which itis detected. As such, increased awareness among clinicians regardingatypical NTMs such asM. genavense is warranted to diminish diagnos-tic delay.AUTHOR CONTRIBUTIONSSiawosh K. Eskandari, Sterre Y. Jonkers, and Mohammad A.M.Almesned conducted patient care, while OnnoW. Akkerman, Erik A.M.Verschuuren, and Christiaan Tji-Joong Gan conducted and supervisedright and left, high ventrally right, and ventral of the right main bronchus). These FDG-avid foci correspondwith enlarged lymph nodes on the CTmodality. Intrapulmonally, there are diffusely FDG-avid nodules, andmesenterially and retroperitoneally, there aremultiple small intenseFDG-positive foci, including the bilateral paraaortic lymph nodes. The FDG uptake in the liver, spleen, and digestive tract is physiological, as well asthe FDG excretion via the kidneys to the bladder. (E) OnceM. genavensewas detected in our patient, the antibiotic treatment was initiated with theprimary goal of resolving themycobacterial proliferation in the lymph nodes. Parallel to the treatment of the infection, however, life-threateninghepatic and renal function failure occurred as a direct side-effect of the antibiotics. As such, the bacterial load was too high to eradicate theM.genavense coccobacilli without endangering the patient’s life4 of 4 ESKANDARI ET AL.patient care. All authors critically revised the manuscript. Siawosh K.Eskandari and Christiaan Tji-Joong Gan wrote the original draft andfinalized themanuscript for publication.CONFLICT OF INTERESTSAll authors declare that they have no competing interests.ORCIDSiawoshK. Eskandari https://orcid.org/0000-0003-4867-4170OnnoW.Akkerman https://orcid.org/0000-0001-5638-9260ErikA.M.Verschuuren https://orcid.org/0000-0002-6807-6744ChristiaanTji-JoongGan https://orcid.org/0000-0002-1310-4189REFERENCES1. Hirschel B, Chang HR, Mach N, et al. Fatal infection with a novel,unidentified mycobacterium in a man with the acquired immunodefi-ciency syndrome.N Engl J Med. 1990;323:109-113.2. Böttger EC, Teske A, Kirschner P, et al. Disseminated “Mycobacteriumgenavense” infection in patients with AIDS. Lancet. 1992;340:76-80.3. Bessesen MT, Shlay J, Stone-Venohr B, Cohn DL, Reves RR. Dissemi-nated Mycobacterium genavense infection: clinical and microbiologi-cal features and response to therapy. AIDS. 1993;7:1357-1361.4. Dumouchel-Champagne H, Charlier-Woerther C, Boibieux A, et al.Disseminated nontuberculous infections with Mycobacteriumgenavense during sarcoidosis. Eur Respir Rev. 2009;18:299-301.5. Santos M, Gil-Brusola A, Escandell A, Blanes M, GobernadoM. Mycobacterium genavense infections in a tertiary hospi-tal and reviewed cases in non-HIV patients. Patholog Res Int.2014;2014:371370.6. Monill JM, Franquet T, Sambeat MA, Martínez-Noguera A, Villalba J.Mycobacterium genavense infection in AIDS: imaging findings in eightpatients. Eur Radiol. 2001;11:193-196.7. Jones MM,Winthrop KL, Nelson SD, et al. Epidemiology of nontuber-culous mycobacterial infections in the U.S. Veterans Health Adminis-tration. PLoS One. 2018;13:e0197976.8. Shafran SD, Taylor GD, Talbot JA. Disseminated Mycobacteriumgenavense infection in Canadian AIDS patients. Tuber Lung Dis.1995;76:168-170.9. Thomsen VO, Dragsted UB, Bauer J, Fuursted K, Lundgren J. Dis-seminated infection with Mycobacterium genavense: a challenge tophysicians and mycobacteriologists. J Clin Microbiol. 1999;37:3901-3905.10. Charles P, Lortholary O, Dechartres A, et al. Mycobacteriumgenavense infections: a retrospective multicenter study in France,1996–2007.Medicine (Baltimore). 2011;90:223-230.11. Hoefsloot W, van Ingen J, Peters EJ, et al. Mycobacterium genavensein the Netherlands: an opportunistic pathogen in HIV and non-HIVimmunocompromised patients. An observational study in 14 cases.Clin Microbiol Infect. 2013;19:432-437.12. Lhuillier E, Brugière O, Veziris N, et al. Relapsing Mycobacteriumgenavense infection as a cause of late death in a lung transplant recip-ient: case report and review of the literature. Exp Clin Transplant.2012;10:618-620.13. El Halabi J, Palmer N, McDuffie M, et al. Measuring health-caredelays among privately insured patients with tuberculosis in theUSA: an observational cohort study. Lancet Infect Dis. 2021;21:1175-1183.14. Ratnatunga CN, Lutzky VP, Kupz A, et al. The rise of non-tuberculosismycobacterial lung disease. Front Immunol. 2020;11:303.15. Lake MA, Ambrose LR, Lipman MC, Lowe DM. “Why me, why now?”Using clinical immunology and epidemiology to explain who getsnontuberculous mycobacterial infection. BMC Med. 2016;14:54-016-0606-0606.How to cite this article: Eskandari SK, Jonkers SY, AlmesnedMAM, AkkermanOW, Verschuuren EAM, Gan CT-J. Recurrentfever 3 years post-lung transplantation: A treacherous case ofMycobacterium genavense. Transpl Infect Dis. 2021;:e13741.https://doi.org/10.1111/tid.13741

   University of GroningenRecurrent fever three years post lung transplantationEskandari, Siawosh K; Jonkers, Sterre Y; Almesned, Mohammad A M; Akkerman, Onno W;Verschuuren, Erik A M; Gan, Christiaan Tji-JoongPublished in:Transplant Infectious DiseaseDOI:10.1111/tid.13741IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2021Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Eskandari, S. K., Jonkers, S. Y., Almesned, M. A. M., Akkerman, O. W., Verschuuren, E. A. M., & Gan, C.T-J. (2021). Recurrent fever three years post lung transplantation: a Treacherous Case of Mycobacteriumgenavense. Transplant Infectious Disease, 23(6), [e13741]. https://doi.org/10.1111/tid.13741CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 29-04-2023Received: 11 September 2021 Revised: 15 September 2021 Accepted: 18 September 2021DOI: 10.1111/tid.13741C L I N I C A L CORR E S POND ENC ERecurrent fever 3 years post-lung transplantation: Atreacherous case ofMycobacterium genavenseSiawosh K. Eskandari1,2 Sterre Y. Jonkers1 MohammadA.M. Almesned1OnnoW. Akkerman1,3 Erik A.M. Verschuuren1 Christiaan Tji-Joong Gan11 Department of Pulmonary Disease and Tuberculosis, UniversityMedical Center Groningen, University of Groningen, Groningen, Netherlands2 Transplantation Research Center, Brigham andWomen’s Hospital, HarvardMedical School, Boston, Massachusetts, USA3 Tuberculosis Center Beatrixoord, UniversityMedical Center Groningen, University of Groningen, Haren, NetherlandsCorrespondenceSiawoshK. Eskandari andChristiaanTji-JoongGan,DepartmentofPulmonaryDiseaseandTuberculosis,UniversityMedicalCenterGroningen,University ofGroningen,Hanzeplein1, 9713GZGroningen,NetherlandsEmail: s.eskandari@umcg.nl; c.t.gan@umcg.nlKEYWORDSlung transplantation,Mycobacterium genavense, nontuberculous lung diseaseTo The Editor,A 71-year-old man presented with a 9-month history of decreasedappetite, asthenia, weight loss, intermittent syncope, and recurrentfever up to 40◦C, having received a right-sided lung transplant 3 yearsprior for idiopathic pulmonary fibrosis (IPF). Physical examination pro-vided a blood pressure of 136 over 84 mm Hg, heart rate of 75 perminute, temperature of 36.9◦C (98.4◦F), and oxygen saturation of 99%on room air. Cardiac, abdominal, and neurological examinations werenormal, while lung examination showed decreased breath sounds withbasal crepitations on the left and normal breath sounds on the right.Subsequent laboratory work-up provided no infectious or splanchnicfocus for the fever or other symptoms. Chest X-rays similarly showedno anomalies compared to previous X-rays: Specifically, no indicationsof infiltrates or a pneumothorax (Figure 1A). Lung function was alsounremarkable, with an unchanged but known decreased FEV1 andforced vital capacity (FVC) (Figure 1B) and a lowered, yet normal,FEV1/FVC ratio (Figure 1C) in line with established left-sided IPF.An fluorodeoxyglucose positron emission tomography/computedtomography (FDG-PET/CT)-scan was subsequently made to rule outmalignancy, showing multiple FDG-avid, anatomically enlarged lymphnodes (Figure 1D), both above and below the diaphragm. A diag-nostic biopsy of the left supraclavicular lymph node presented non-necrotizing granulomas consisting of epithelioid histiocytes. Auraminestaining of this biopsy then revealed numerous acid-fast microor-ganisms with a histochemical profile characteristic of mycobacterialinfections (Ziehl-Neelsen +++, Wade-Fite +, Periodic Acid Schiff, +,Grocott-Gömöri+).Mycobacterium genavensewas ultimately identifiedas the causative pathogen using a nucleic acid amplification test.The patient was started on oral azithromycin (6.25 mg/kg, 1/d),ethambutol (15 mg/kg, 1/d), and rifampicin (7.5 mg/kg, 1/d). Addition-ally, to encourage endogenous immune responses againstM. genavense,the patient’s mycophenolate mofetil (500 mg, 2/d) was discontinued,while the prednisolone (5 mg, 1/d) and tacrolimus (1 mg, 2/d) weremaintained.In an admission that spanned over 2 months, the patient developedsevere hepatic and renal function failure—interpreted as medication-dependent toxicities. The antibiotic treatment was nonetheless sus-tained, and an FDG-PET/CT-scan was obtained 3 months post-treatment onset to monitor disease progression. The scan showedunchanged lymphadenopathy, with increased metabolic activity in thepericlavicular lymph nodes and moderately decreased activity in themediastinal lymph nodes. A new biopsy of the left supraclavicularlymph node showed abundant M. genavense coccobacilli without thepresence of alternative pathology.Based on the severity of the drug-based side-effects, the antibiotictreatment was finally discontinued. Despite the patient’s short-termclinical improvement, the intermittent bouts of fever soon recurred.Due to the relapsing, refractory fever, the lack of clinical response tothe antimycobacterial agents coupled with their toxic side-effects, andthe risk ofmultidrug-resistant substrainswith long-term therapy, alter-native drug regimens were not explored. The patient ultimately optedfor palliative treatment of his symptoms.Transpl Infect Dis. 2021;e13741. © 2021Wiley Periodicals LLC 1 of 4wileyonlinelibrary.com/journal/tidhttps://doi.org/10.1111/tid.137412 of 4 ESKANDARI ET AL.F IGURE 1 Chest X-rays (A); Lung function tests with FEV1 and FVC (B), and FEV1/FVC ratios (C); FDG-PET/CT-scan (D);M. genavenseinfection therapeutic dilemma (E). (A) The chest X-rays between January and September 2020 show a known small lung volume left characterizedby interstitial changes, with otherwise no indications of infiltrates or a pneumothorax. (B–C) Functional analyses of the patient’s lungs 3 years afterunilateral, right-sided lung transplantation in 2017 show (B) largely unaltered FEV1 and FVC parameters and (C) normal FEV1/FVC ratiosthroughout. The shaded areas in the graphs represent the reference ranges of eachmetric for healthy controls. (D) The FGD-PET/CT-scan fromSeptember 2020 shows relatively intense bilateral FDG uptake supraclavicularly, while showing intense FDG uptakemediastinally (paratracheallyESKANDARI ET AL. 3 of 41 DISCUSSIONIn 1990, a previously unidentified, fatal nontuberculous mycobacterial(NTM) infection was described in a patient with acquired immunodefi-ciency syndrome (AIDS) from Geneva, Switzerland.1 This later provedto be the first description ofMycobacterium genavense, soon detected inanother eighteen patients with advanced AIDS.2 Since then, this NTMis known to cause lethal opportunistic infections in AIDS patients andthose taking immunosuppressive drugs, such as for sarcoidosis.2–4 Thetypical symptoms of an M. genavense infection include fever, abdom-inal pain, weight loss, diarrhea, and anemia.5 Patients experience anextensive infection of the intestines and liver, although necropsiesof infected subjects have also shown involvement of the lungs, bonemarrow, and lymph nodes.2 M. genavense infections can spur mas-sive mesenteric lymphadenopathy and lead to hepatosplenomegaly.6These relatively nonspecific symptoms and the lack of a pathog-nomonic hallmark for the disease, however, make it hard to distinguishM. genavense from more prevalent NTM infections such as fromMycobacterium avium complex (MAC) and more common infectious orneoplastic diseases due to overlapping symptomatology. This vaguepresentation prevents physicians from actively performing diagnosticsfor M. genavense or similarly atypical NTMs—despite atypical NTMsconstituting ∼20% of all NTM infections.7Notably, experience regardingM. genavense infections in transplan-tation is limited as almost all relevant knowledge has been gleanedfrom AIDS patients.5,8–11 There are only sporadic accounts in renaland cardiac transplant recipients,5,10,11 with just one report of anM. genavense infected lung transplant patient.12 In that patient, theinfection was detected in a disseminated phase, and while there was alengthy resolution of the chief complaints, the recurrent infection ulti-mately caused fatal multiorgan failure.12In particular, the disease progression of M. genavense infections isunpredictable, which leads to diagnostic delays when coupled with thelimited clinical awareness of NTM pathology. Our patient experienceda 9-month history of vague subfebrile complaints before his diagnosis.This delay canbeascribed to the successive screeningsby cardiologists,geriatric specialists, and neurologists for his chief complaints, includ-ing intermittent syncope, asthenia, weight loss, and even parkinsonism,prior to his pulmonology work-up.Strikingly, all tuberculous diseases experience diagnostic delay,includingM. tuberculosis infections.13 This delay may be attributable tolow disease prevalence.13 For context, the NTM prevalence in a popu-lation of United States veterans was 41.1 cases per 100,000 patientsbetween 2008–2012, with 81% of these beingMAC infections and therest 32 other NTM strains.7 Among all NTMs infections, M. genavenseconstituted 0.05% of the total.7 Timely diagnosis of atypical NTMswillbecomemore important in the coming 20 yearswith estimates that theoverall NTM prevalence will quadruple,14 especially in individuals>65who aremore susceptible to NTM infections.15Upon M. genavense diagnosis, our patient was treated withazithromycin, ethambutol, and rifampicin. Ethambutol and rifampicinare commonly used to treat M. tuberculosis and M. genavenseinfections.5,8–11 Additionally, a recent case series demonstrated suc-cessful treatment with combinations of clarithromycin, ethambutol,rifabutin, and quinolones.10 Nonetheless, the experience in treatingM.genavense infections remains limited. Often, a broad-spectrum antibi-otic regimen is empirically selected.11 Due to the severe side-effects oftuberculostatics, the regimen predominantly depends on the patient’stolerance to the drug toxicity profiles.8 For transplant patients, thehepatic and renal side-effects caused by interactions between theantimycobacterials and the patients’ immunosuppressants are mostcritical. In light thereof, reducing immunosuppression can potentiallydecrease drug interactions and even have antimycobacterial effects.Finally, an additional factor that impedes the curative treatment ofNTMs such as M. genavense is insufficient tissue penetration of theantibiotics—causing systemic side-effects before curative drug levelscan be attained in local infection foci (Figure 1E).The inherent damage caused by M. genavense and the therapy-related side-effects tie into the highmortality among infected patients.Since the early 1990s, AIDS patients with M. genavense show highmortality,8,9 while the mortality rate among non-AIDS patients is like-wise high, ranging between 25% and 44%.10,112 CONCLUSIONM. genavense is an NTM that mimics inflammatory and neoplastic dis-eases and can cause lethal infections in immunosuppressed patients.Due to its low prevalence, the diagnosis is often missed by clini-cians, and even when it is diagnosed, there is much doubt regardingthe best therapy. Many patients eventually succumb to the infectiondespite treatment initiation due to the disseminated stage in which itis detected. As such, increased awareness among clinicians regardingatypical NTMs such asM. genavense is warranted to diminish diagnos-tic delay.AUTHOR CONTRIBUTIONSSiawosh K. Eskandari, Sterre Y. Jonkers, and Mohammad A.M.Almesned conducted patient care, while OnnoW. Akkerman, Erik A.M.Verschuuren, and Christiaan Tji-Joong Gan conducted and supervisedright and left, high ventrally right, and ventral of the right main bronchus). These FDG-avid foci correspondwith enlarged lymph nodes on the CTmodality. Intrapulmonally, there are diffusely FDG-avid nodules, andmesenterially and retroperitoneally, there aremultiple small intenseFDG-positive foci, including the bilateral paraaortic lymph nodes. The FDG uptake in the liver, spleen, and digestive tract is physiological, as well asthe FDG excretion via the kidneys to the bladder. (E) OnceM. genavensewas detected in our patient, the antibiotic treatment was initiated with theprimary goal of resolving themycobacterial proliferation in the lymph nodes. Parallel to the treatment of the infection, however, life-threateninghepatic and renal function failure occurred as a direct side-effect of the antibiotics. As such, the bacterial load was too high to eradicate theM.genavense coccobacilli without endangering the patient’s life4 of 4 ESKANDARI ET AL.patient care. All authors critically revised the manuscript. Siawosh K.Eskandari and Christiaan Tji-Joong Gan wrote the original draft andfinalized themanuscript for publication.CONFLICT OF INTERESTSAll authors declare that they have no competing interests.ORCIDSiawoshK. Eskandari https://orcid.org/0000-0003-4867-4170OnnoW.Akkerman https://orcid.org/0000-0001-5638-9260ErikA.M.Verschuuren https://orcid.org/0000-0002-6807-6744ChristiaanTji-JoongGan https://orcid.org/0000-0002-1310-4189REFERENCES1. Hirschel B, Chang HR, Mach N, et al. Fatal infection with a novel,unidentified mycobacterium in a man with the acquired immunodefi-ciency syndrome.N Engl J Med. 1990;323:109-113.2. Böttger EC, Teske A, Kirschner P, et al. Disseminated “Mycobacteriumgenavense” infection in patients with AIDS. Lancet. 1992;340:76-80.3. Bessesen MT, Shlay J, Stone-Venohr B, Cohn DL, Reves RR. Dissemi-nated Mycobacterium genavense infection: clinical and microbiologi-cal features and response to therapy. AIDS. 1993;7:1357-1361.4. Dumouchel-Champagne H, Charlier-Woerther C, Boibieux A, et al.Disseminated nontuberculous infections with Mycobacteriumgenavense during sarcoidosis. Eur Respir Rev. 2009;18:299-301.5. Santos M, Gil-Brusola A, Escandell A, Blanes M, GobernadoM. Mycobacterium genavense infections in a tertiary hospi-tal and reviewed cases in non-HIV patients. Patholog Res Int.2014;2014:371370.6. Monill JM, Franquet T, Sambeat MA, Martínez-Noguera A, Villalba J.Mycobacterium genavense infection in AIDS: imaging findings in eightpatients. Eur Radiol. 2001;11:193-196.7. Jones MM,Winthrop KL, Nelson SD, et al. Epidemiology of nontuber-culous mycobacterial infections in the U.S. Veterans Health Adminis-tration. PLoS One. 2018;13:e0197976.8. Shafran SD, Taylor GD, Talbot JA. Disseminated Mycobacteriumgenavense infection in Canadian AIDS patients. Tuber Lung Dis.1995;76:168-170.9. Thomsen VO, Dragsted UB, Bauer J, Fuursted K, Lundgren J. Dis-seminated infection with Mycobacterium genavense: a challenge tophysicians and mycobacteriologists. J Clin Microbiol. 1999;37:3901-3905.10. Charles P, Lortholary O, Dechartres A, et al. Mycobacteriumgenavense infections: a retrospective multicenter study in France,1996–2007.Medicine (Baltimore). 2011;90:223-230.11. Hoefsloot W, van Ingen J, Peters EJ, et al. Mycobacterium genavensein the Netherlands: an opportunistic pathogen in HIV and non-HIVimmunocompromised patients. An observational study in 14 cases.Clin Microbiol Infect. 2013;19:432-437.12. Lhuillier E, Brugière O, Veziris N, et al. Relapsing Mycobacteriumgenavense infection as a cause of late death in a lung transplant recip-ient: case report and review of the literature. Exp Clin Transplant.2012;10:618-620.13. El Halabi J, Palmer N, McDuffie M, et al. Measuring health-caredelays among privately insured patients with tuberculosis in theUSA: an observational cohort study. Lancet Infect Dis. 2021;21:1175-1183.14. Ratnatunga CN, Lutzky VP, Kupz A, et al. The rise of non-tuberculosismycobacterial lung disease. Front Immunol. 2020;11:303.15. Lake MA, Ambrose LR, Lipman MC, Lowe DM. “Why me, why now?”Using clinical immunology and epidemiology to explain who getsnontuberculous mycobacterial infection. BMC Med. 2016;14:54-016-0606-0606.How to cite this article: Eskandari SK, Jonkers SY, AlmesnedMAM, AkkermanOW, Verschuuren EAM, Gan CT-J. Recurrentfever 3 years post-lung transplantation: A treacherous case ofMycobacterium genavense. Transpl Infect Dis. 2021;:e13741.https://doi.org/10.1111/tid.13741

   University of GroningenRecurrent fever three years post lung transplantationEskandari, Siawosh K; Jonkers, Sterre Y; Almesned, Mohammad A M; Akkerman, Onno W;Verschuuren, Erik A M; Gan, Christiaan Tji-JoongPublished in:Transplant Infectious DiseaseDOI:10.1111/tid.13741IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2021Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Eskandari, S. K., Jonkers, S. Y., Almesned, M. A. M., Akkerman, O. W., Verschuuren, E. A. M., & Gan, C.T-J. (2021). Recurrent fever three years post lung transplantation: a Treacherous Case of Mycobacteriumgenavense. Transplant Infectious Disease, 23(6), [e13741]. https://doi.org/10.1111/tid.13741CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 20-11-2022Received: 11 September 2021 Revised: 15 September 2021 Accepted: 18 September 2021DOI: 10.1111/tid.13741C L I N I C A L CORR E S POND ENC ERecurrent fever 3 years post-lung transplantation: Atreacherous case ofMycobacterium genavenseSiawosh K. Eskandari1,2 Sterre Y. Jonkers1 MohammadA.M. Almesned1OnnoW. Akkerman1,3 Erik A.M. Verschuuren1 Christiaan Tji-Joong Gan11 Department of Pulmonary Disease and Tuberculosis, UniversityMedical Center Groningen, University of Groningen, Groningen, Netherlands2 Transplantation Research Center, Brigham andWomen’s Hospital, HarvardMedical School, Boston, Massachusetts, USA3 Tuberculosis Center Beatrixoord, UniversityMedical Center Groningen, University of Groningen, Haren, NetherlandsCorrespondenceSiawoshK. Eskandari andChristiaanTji-JoongGan,DepartmentofPulmonaryDiseaseandTuberculosis,UniversityMedicalCenterGroningen,University ofGroningen,Hanzeplein1, 9713GZGroningen,NetherlandsEmail: s.eskandari@umcg.nl; c.t.gan@umcg.nlKEYWORDSlung transplantation,Mycobacterium genavense, nontuberculous lung diseaseTo The Editor,A 71-year-old man presented with a 9-month history of decreasedappetite, asthenia, weight loss, intermittent syncope, and recurrentfever up to 40◦C, having received a right-sided lung transplant 3 yearsprior for idiopathic pulmonary fibrosis (IPF). Physical examination pro-vided a blood pressure of 136 over 84 mm Hg, heart rate of 75 perminute, temperature of 36.9◦C (98.4◦F), and oxygen saturation of 99%on room air. Cardiac, abdominal, and neurological examinations werenormal, while lung examination showed decreased breath sounds withbasal crepitations on the left and normal breath sounds on the right.Subsequent laboratory work-up provided no infectious or splanchnicfocus for the fever or other symptoms. Chest X-rays similarly showedno anomalies compared to previous X-rays: Specifically, no indicationsof infiltrates or a pneumothorax (Figure 1A). Lung function was alsounremarkable, with an unchanged but known decreased FEV1 andforced vital capacity (FVC) (Figure 1B) and a lowered, yet normal,FEV1/FVC ratio (Figure 1C) in line with established left-sided IPF.An fluorodeoxyglucose positron emission tomography/computedtomography (FDG-PET/CT)-scan was subsequently made to rule outmalignancy, showing multiple FDG-avid, anatomically enlarged lymphnodes (Figure 1D), both above and below the diaphragm. A diag-nostic biopsy of the left supraclavicular lymph node presented non-necrotizing granulomas consisting of epithelioid histiocytes. Auraminestaining of this biopsy then revealed numerous acid-fast microor-ganisms with a histochemical profile characteristic of mycobacterialinfections (Ziehl-Neelsen +++, Wade-Fite +, Periodic Acid Schiff, +,Grocott-Gömöri+).Mycobacterium genavensewas ultimately identifiedas the causative pathogen using a nucleic acid amplification test.The patient was started on oral azithromycin (6.25 mg/kg, 1/d),ethambutol (15 mg/kg, 1/d), and rifampicin (7.5 mg/kg, 1/d). Addition-ally, to encourage endogenous immune responses againstM. genavense,the patient’s mycophenolate mofetil (500 mg, 2/d) was discontinued,while the prednisolone (5 mg, 1/d) and tacrolimus (1 mg, 2/d) weremaintained.In an admission that spanned over 2 months, the patient developedsevere hepatic and renal function failure—interpreted as medication-dependent toxicities. The antibiotic treatment was nonetheless sus-tained, and an FDG-PET/CT-scan was obtained 3 months post-treatment onset to monitor disease progression. The scan showedunchanged lymphadenopathy, with increased metabolic activity in thepericlavicular lymph nodes and moderately decreased activity in themediastinal lymph nodes. A new biopsy of the left supraclavicularlymph node showed abundant M. genavense coccobacilli without thepresence of alternative pathology.Based on the severity of the drug-based side-effects, the antibiotictreatment was finally discontinued. Despite the patient’s short-termclinical improvement, the intermittent bouts of fever soon recurred.Due to the relapsing, refractory fever, the lack of clinical response tothe antimycobacterial agents coupled with their toxic side-effects, andthe risk ofmultidrug-resistant substrainswith long-term therapy, alter-native drug regimens were not explored. The patient ultimately optedfor palliative treatment of his symptoms.Transpl Infect Dis. 2021;e13741. © 2021Wiley Periodicals LLC 1 of 4wileyonlinelibrary.com/journal/tidhttps://doi.org/10.1111/tid.137412 of 4 ESKANDARI ET AL.F IGURE 1 Chest X-rays (A); Lung function tests with FEV1 and FVC (B), and FEV1/FVC ratios (C); FDG-PET/CT-scan (D);M. genavenseinfection therapeutic dilemma (E). (A) The chest X-rays between January and September 2020 show a known small lung volume left characterizedby interstitial changes, with otherwise no indications of infiltrates or a pneumothorax. (B–C) Functional analyses of the patient’s lungs 3 years afterunilateral, right-sided lung transplantation in 2017 show (B) largely unaltered FEV1 and FVC parameters and (C) normal FEV1/FVC ratiosthroughout. The shaded areas in the graphs represent the reference ranges of eachmetric for healthy controls. (D) The FGD-PET/CT-scan fromSeptember 2020 shows relatively intense bilateral FDG uptake supraclavicularly, while showing intense FDG uptakemediastinally (paratracheallyESKANDARI ET AL. 3 of 41 DISCUSSIONIn 1990, a previously unidentified, fatal nontuberculous mycobacterial(NTM) infection was described in a patient with acquired immunodefi-ciency syndrome (AIDS) from Geneva, Switzerland.1 This later provedto be the first description ofMycobacterium genavense, soon detected inanother eighteen patients with advanced AIDS.2 Since then, this NTMis known to cause lethal opportunistic infections in AIDS patients andthose taking immunosuppressive drugs, such as for sarcoidosis.2–4 Thetypical symptoms of an M. genavense infection include fever, abdom-inal pain, weight loss, diarrhea, and anemia.5 Patients experience anextensive infection of the intestines and liver, although necropsiesof infected subjects have also shown involvement of the lungs, bonemarrow, and lymph nodes.2 M. genavense infections can spur mas-sive mesenteric lymphadenopathy and lead to hepatosplenomegaly.6These relatively nonspecific symptoms and the lack of a pathog-nomonic hallmark for the disease, however, make it hard to distinguishM. genavense from more prevalent NTM infections such as fromMycobacterium avium complex (MAC) and more common infectious orneoplastic diseases due to overlapping symptomatology. This vaguepresentation prevents physicians from actively performing diagnosticsfor M. genavense or similarly atypical NTMs—despite atypical NTMsconstituting ∼20% of all NTM infections.7Notably, experience regardingM. genavense infections in transplan-tation is limited as almost all relevant knowledge has been gleanedfrom AIDS patients.5,8–11 There are only sporadic accounts in renaland cardiac transplant recipients,5,10,11 with just one report of anM. genavense infected lung transplant patient.12 In that patient, theinfection was detected in a disseminated phase, and while there was alengthy resolution of the chief complaints, the recurrent infection ulti-mately caused fatal multiorgan failure.12In particular, the disease progression of M. genavense infections isunpredictable, which leads to diagnostic delays when coupled with thelimited clinical awareness of NTM pathology. Our patient experienceda 9-month history of vague subfebrile complaints before his diagnosis.This delay canbeascribed to the successive screeningsby cardiologists,geriatric specialists, and neurologists for his chief complaints, includ-ing intermittent syncope, asthenia, weight loss, and even parkinsonism,prior to his pulmonology work-up.Strikingly, all tuberculous diseases experience diagnostic delay,includingM. tuberculosis infections.13 This delay may be attributable tolow disease prevalence.13 For context, the NTM prevalence in a popu-lation of United States veterans was 41.1 cases per 100,000 patientsbetween 2008–2012, with 81% of these beingMAC infections and therest 32 other NTM strains.7 Among all NTMs infections, M. genavenseconstituted 0.05% of the total.7 Timely diagnosis of atypical NTMswillbecomemore important in the coming 20 yearswith estimates that theoverall NTM prevalence will quadruple,14 especially in individuals>65who aremore susceptible to NTM infections.15Upon M. genavense diagnosis, our patient was treated withazithromycin, ethambutol, and rifampicin. Ethambutol and rifampicinare commonly used to treat M. tuberculosis and M. genavenseinfections.5,8–11 Additionally, a recent case series demonstrated suc-cessful treatment with combinations of clarithromycin, ethambutol,rifabutin, and quinolones.10 Nonetheless, the experience in treatingM.genavense infections remains limited. Often, a broad-spectrum antibi-otic regimen is empirically selected.11 Due to the severe side-effects oftuberculostatics, the regimen predominantly depends on the patient’stolerance to the drug toxicity profiles.8 For transplant patients, thehepatic and renal side-effects caused by interactions between theantimycobacterials and the patients’ immunosuppressants are mostcritical. In light thereof, reducing immunosuppression can potentiallydecrease drug interactions and even have antimycobacterial effects.Finally, an additional factor that impedes the curative treatment ofNTMs such as M. genavense is insufficient tissue penetration of theantibiotics—causing systemic side-effects before curative drug levelscan be attained in local infection foci (Figure 1E).The inherent damage caused by M. genavense and the therapy-related side-effects tie into the highmortality among infected patients.Since the early 1990s, AIDS patients with M. genavense show highmortality,8,9 while the mortality rate among non-AIDS patients is like-wise high, ranging between 25% and 44%.10,112 CONCLUSIONM. genavense is an NTM that mimics inflammatory and neoplastic dis-eases and can cause lethal infections in immunosuppressed patients.Due to its low prevalence, the diagnosis is often missed by clini-cians, and even when it is diagnosed, there is much doubt regardingthe best therapy. Many patients eventually succumb to the infectiondespite treatment initiation due to the disseminated stage in which itis detected. As such, increased awareness among clinicians regardingatypical NTMs such asM. genavense is warranted to diminish diagnos-tic delay.AUTHOR CONTRIBUTIONSSiawosh K. Eskandari, Sterre Y. Jonkers, and Mohammad A.M.Almesned conducted patient care, while OnnoW. Akkerman, Erik A.M.Verschuuren, and Christiaan Tji-Joong Gan conducted and supervisedright and left, high ventrally right, and ventral of the right main bronchus). These FDG-avid foci correspondwith enlarged lymph nodes on the CTmodality. Intrapulmonally, there are diffusely FDG-avid nodules, andmesenterially and retroperitoneally, there aremultiple small intenseFDG-positive foci, including the bilateral paraaortic lymph nodes. The FDG uptake in the liver, spleen, and digestive tract is physiological, as well asthe FDG excretion via the kidneys to the bladder. (E) OnceM. genavensewas detected in our patient, the antibiotic treatment was initiated with theprimary goal of resolving themycobacterial proliferation in the lymph nodes. Parallel to the treatment of the infection, however, life-threateninghepatic and renal function failure occurred as a direct side-effect of the antibiotics. As such, the bacterial load was too high to eradicate theM.genavense coccobacilli without endangering the patient’s life4 of 4 ESKANDARI ET AL.patient care. All authors critically revised the manuscript. Siawosh K.Eskandari and Christiaan Tji-Joong Gan wrote the original draft andfinalized themanuscript for publication.CONFLICT OF INTERESTSAll authors declare that they have no competing interests.ORCIDSiawoshK. Eskandari https://orcid.org/0000-0003-4867-4170OnnoW.Akkerman https://orcid.org/0000-0001-5638-9260ErikA.M.Verschuuren https://orcid.org/0000-0002-6807-6744ChristiaanTji-JoongGan https://orcid.org/0000-0002-1310-4189REFERENCES1. Hirschel B, Chang HR, Mach N, et al. Fatal infection with a novel,unidentified mycobacterium in a man with the acquired immunodefi-ciency syndrome.N Engl J Med. 1990;323:109-113.2. Böttger EC, Teske A, Kirschner P, et al. Disseminated “Mycobacteriumgenavense” infection in patients with AIDS. Lancet. 1992;340:76-80.3. Bessesen MT, Shlay J, Stone-Venohr B, Cohn DL, Reves RR. Dissemi-nated Mycobacterium genavense infection: clinical and microbiologi-cal features and response to therapy. AIDS. 1993;7:1357-1361.4. Dumouchel-Champagne H, Charlier-Woerther C, Boibieux A, et al.Disseminated nontuberculous infections with Mycobacteriumgenavense during sarcoidosis. Eur Respir Rev. 2009;18:299-301.5. Santos M, Gil-Brusola A, Escandell A, Blanes M, GobernadoM. Mycobacterium genavense infections in a tertiary hospi-tal and reviewed cases in non-HIV patients. Patholog Res Int.2014;2014:371370.6. Monill JM, Franquet T, Sambeat MA, Martínez-Noguera A, Villalba J.Mycobacterium genavense infection in AIDS: imaging findings in eightpatients. Eur Radiol. 2001;11:193-196.7. Jones MM,Winthrop KL, Nelson SD, et al. Epidemiology of nontuber-culous mycobacterial infections in the U.S. Veterans Health Adminis-tration. PLoS One. 2018;13:e0197976.8. Shafran SD, Taylor GD, Talbot JA. Disseminated Mycobacteriumgenavense infection in Canadian AIDS patients. Tuber Lung Dis.1995;76:168-170.9. Thomsen VO, Dragsted UB, Bauer J, Fuursted K, Lundgren J. Dis-seminated infection with Mycobacterium genavense: a challenge tophysicians and mycobacteriologists. J Clin Microbiol. 1999;37:3901-3905.10. Charles P, Lortholary O, Dechartres A, et al. Mycobacteriumgenavense infections: a retrospective multicenter study in France,1996–2007.Medicine (Baltimore). 2011;90:223-230.11. Hoefsloot W, van Ingen J, Peters EJ, et al. Mycobacterium genavensein the Netherlands: an opportunistic pathogen in HIV and non-HIVimmunocompromised patients. An observational study in 14 cases.Clin Microbiol Infect. 2013;19:432-437.12. Lhuillier E, Brugière O, Veziris N, et al. Relapsing Mycobacteriumgenavense infection as a cause of late death in a lung transplant recip-ient: case report and review of the literature. Exp Clin Transplant.2012;10:618-620.13. El Halabi J, Palmer N, McDuffie M, et al. Measuring health-caredelays among privately insured patients with tuberculosis in theUSA: an observational cohort study. Lancet Infect Dis. 2021;21:1175-1183.14. Ratnatunga CN, Lutzky VP, Kupz A, et al. The rise of non-tuberculosismycobacterial lung disease. Front Immunol. 2020;11:303.15. Lake MA, Ambrose LR, Lipman MC, Lowe DM. “Why me, why now?”Using clinical immunology and epidemiology to explain who getsnontuberculous mycobacterial infection. BMC Med. 2016;14:54-016-0606-0606.How to cite this article: Eskandari SK, Jonkers SY, AlmesnedMAM, AkkermanOW, Verschuuren EAM, Gan CT-J. Recurrentfever 3 years post-lung transplantation: A treacherous case ofMycobacterium genavense. Transpl Infect Dis. 2021;:e13741.https://doi.org/10.1111/tid.13741

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Recurrent fever three years post lung transplantation:a Treacherous Case of <i>Mycobacterium genavense</i>

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