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Australasian Journal of Dermatology (2015) 56, 124–127
doi: 10.1111/ajd.12269
BRIEF REPORTS
Cutaneous non-tuberculous mycobacterial infection in patients with chronic graft-versus-host disease: A case series Gilberto Moreno-Bonilla,1 Bonita Choy1,2 and Pablo Fernandez-Peñas1,2 1
Department of Dermatology, Westmead Hospital, and 2Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
ABSTRACT We report the first case series of allogeneic haematopoietic stem-cell transplant patients with graft versus host disease who developed cutaneous non-tuberculous mycobacteria infection. A multidisciplinary approach, reduction of immunosuppressive medications, combination of antibiotics, close skin surveillance and excision of suitable lesions are recommended in this specific subgroup. Key words: graft versus host disease, hematopoietic stem cell transplantation, nontuberculous mycobacteria, transplantation.
INTRODUCTION Non-tuberculous mycobacteria (NTM) are ubiquitous in the environment and are resistant to eradication due to various complex mechanisms.1 Lung, skin and catheter-related sites are reportedly the most common sites of NTM infection in transplant recipients.2,3
REPORT OF CASES A total of 860 patients with allogeneic haematopoietic stemcell transplants (AHSCT) have been reviewed at Westmead Hospital graft versus host disease (GVHD) clinic between 1996 and 2014. Three patients with 6/6 human leukocyte
Correspondence: Dr Gilberto Moreno-Bonilla, Department of Dermatology, Westmead Hospital, Darcy Road, Westmead, NSW, 2145 Australia. Email: [email protected] Gilberto Moreno-Bonilla, MBBS. Bonita Choy, MBBS. Pablo Fernandez-Peñas, MD. Conflict of interest: none. Submitted 19 August 2014; accepted 24 September 2014. © 2014 The Australasian College of Dermatologists
antigen (HLA) matched sibling AHSCT developed a NTM skin infection, as captured by dermatology and microbiology files.
Case one In 2002 a 55-year-old man treated for acute myeloid leukaemia developed severe chronic GVHD involving the skin, oral mucosa, nails and liver. A conjunctival mass developed in 2006 while simultaneous violaceous nodules and plaques were noted on his face, arms, trunk and gluteal region. His immunosuppressive medications were prednisone 30 mg/day and tacrolimus 5 mg b.i.d. Skin biopsies showed granulomas, multiple acid-fast bacilli (AFB) (Fig. 1) and Mycobacterium haemophilum was identified by polymerase chain reaction (PCR). A conjunctival biopsy also revealed AFB.4 Further investigations were negative for systemic disease. He completed 12 months of oral clindamycin, clarithromycin and moxifloxacin plus a further 6 months of clarithromycin and moxifloxacin with favourable response. Skin and blood cultures showed a relapse of his infection in 2008. I.v. and oral antibiotics, with reduction of his immunosuppressive medications, did not prevent his death from an unrelated infection.
Case two A 50-year-old woman treated for acute myeloid leukaemia developed cutaneous and liver GVHD in 2007. Prednisone (15–30 mg daily), mycophenolate (2 g daily) and tacrolimus (2 mg daily) remained constant for 4 years after transplantation. Two erythematous nodules were noted over areas of previous insulin injections (Fig. 2a). A biopsy revealed marked
Abbreviations: AFB AHSCT GVHD NTM PCR
acid-fast bacilli allogeneic haematopoietic stem-cell transplant graft versus host disease non-tuberculous mycobacteria polymerase chain reaction
Cutaneous NTM infection in GVHD patients
(a)
125
(b)
Figure 1 (a) granulomatous reaction, HE ×20 and (b) multiple acid-fast bacilli, Ziehl–Neelsen stain ×40.
(a)
(b)
(c)
(d)
Figure 2 (a) Subcutaneous nodules right thigh pretreatment and (b) post-treatment; dermal and subcutaneous infiltrate with suppuration and fat necrosis (c) HE ×2 and (d) ×10.
suppuration, profuse neutrophil infiltration, focal fat necrosis and AFB (Fig. 2b). Ill-defined granulomas were noted. M. chelonae was isolated in 2010. Further investigations excluded systemic inflammation or disseminated infection. Surgical excision and i.v. antibiotics were followed by oral linezolid and clarithromycin for 8 weeks and clarithromycin alone for a further 6 months. Complete resolution was observed on regular reviews over the subsequent years (Fig. 2a).
Case three A 57-year-old man received an AHSCT for chronic lymphocytic leukaemia in 2008. Gastrointestinal and chronic mucocutaneous GVHD was documented 7 months later. Multiple firm nodules with purulent discharge over
the dorsum of hands, arms and thighs were identified in 2013 (Fig. 3). Immunosuppressive medications included only prednisone 30–40 mg daily. Two skin biopsies demonstrated necrotising and suppurative granulomas with AFB (Fig. 3), but no mycobacteria was isolated in culture. Tissue-based PCR for NTM and M. tuberculosis were negative. Two months later he presented with multilobar pneumonia and died of polymicrobial (viral/fungal/bacterial) septic shock. Investigations failed to isolate tuberculous and NTM from respiratory and blood cultures. His cutaneous NTM infection remained unresolved at the time of death.
DISCUSSION Although single case reports have been published, case series in AHSCT patients have described mostly non-skin © 2014 The Australasian College of Dermatologists
126
G Moreno-Bonilla et al.
(a)
(b)
(c)
(d)
Figure 3 (a,b). Fluctuant nodules on hands; (c) HE ×10 necrotizing granuloma and neutrophils; (d) acid-fast bacilli, Ziehl–Neelsen stain ×40.
disease.5,6 To our knowledge, this is the first case series of cutaneous NTM infection in patients with chronic GVHD. Statistically significant risk factors for NTM infection proposed by Au and colleagues include acute GVHD, relapse of leukaemia, a matched unrelated donor and a mismatched transplant.2 In contrast, our three patients with perfectly matched related donors and chronic GVHD still developed cutaneous infection. We found that routine inflammatory markers did not help to assess the degree of involvement in our three patients. On the other hand, from our seven tissue biopsies necrosis (6/7), AFB (6/7) and granuloma formation (5/7) were almost constant findings and were useful in diagnosis. Histology findings can be inconsistent or not species-specific.7,8 Although subcutaneous infiltrates with abscess formation were constant, granulomas were only noted in 60% of patients in one study.7 High-performance liquid chromatography analysis and PCR assays targeting 16SrRNA confirmed the presence of M. chelonae and M. haemophilum in two patients. Precise identification of the mycobacteria implicated in patient no. three was not possible. Although multiple attempts at culturing the organism failed, the low prevalence of tuberculosis in our community, a negative history of exposure and the clinical and histological presentation were consistent with NTM. The successful treatment of skin infection is based on experience. Combination antibiotic therapy has improved survival rates in recent years.9,10 Excision of suitable lesions and the reduction of immunosuppression have been recommended in transplant recipients.11 These recommendations helped only one of our patients. We noted that progressive and distant cutaneous infection was seen in those with worse immunosuppression and poorer prognosis. Also, the number of immunosuppressive medications used did not reflect the outcome. © 2014 The Australasian College of Dermatologists
Our centre covers the largest AHSCT population in the country, combined with the largest reference laboratory for mycobacterial disease in the state. Multicentre studies are required to establish and to validate risk factors and treatment in this population.
CONCLUSION Close skin surveillance, a high index of suspicion, serial skin biopsies for histopathology, cultures and PCR are required for the diagnosis of NTM. An integrated multidisciplinary approach with the reduction of immunosuppressive medications (when possible), a combination of antibiotics based on culture sensitivities, the excision of suitable lesions and the close monitoring of treatment progress are all essential components in the management of patients with GVHD.
ACKNOWLEDGEMENT All authors had full access to the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis. All authors participated in the development of the study concept and design, the acquisition and analysis of data and manuscript preparation.
REFERENCES 1.
2.
Primm TP, Lucero CA, Falkinham JO, 3rd. Health impacts of environmental mycobacteria. Clin. Microbiol. Rev. 2004; 17: 98–106. Au WY, Cheng VC, Ho PL et al. Nontuberculous mycobacterial infections in Chinese hematopoietic stem cell transplantation recipients. Bone Marrow Transplant. 2003; 32: 709–14.
Cutaneous NTM infection in GVHD patients 3.
4.
5.
6.
7.
Weinstock DM, Feinstein MB, Sepkowitz KA et al. High rates of infection and colonization by nontuberculous mycobacteria after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2003; 31: 1015–21. Millar MJM, Bulliard CM, Balachandran CMF et al. Mycobacterium hemophilum infection presenting as filamentary keratopathy in an immunocompromised adult. Cornea 2007; 26: 764–6. Gaviria JM, Garcia PJ, Garrido SM et al. Nontuberculous mycobacterial infections in hematopoietic stem cell transplant recipients: characteristics of respiratory and catheter-related infections. Biol. Blood Marrow Transplant. 2000; 6: 361–9. Roy V, Weisdorf D. Mycobacterial infections following bone marrow transplantation: a 20 year retrospective review. Bone Marrow Transplant. 1997; 19: 467–70. Bartralot R, Pujol RM, Garcia-Patos V et al. Cutaneous infections due to nontuberculous mycobacteria: histopathological
8.
9.
10.
11.
127
review of 28 cases. Comparative study between lesions observed in immunosuppressed patients and normal hosts. J. Cutan. Pathol. 2000; 27: 124–9. Busam KJ, Kiehn TE, Salob SP et al. Histologic reactions to cutaneous infections by Mycobacterium haemophilum. Am. J. Surg. Pathol. 1999; 23: 1379–85. Unal E, Yen C, Saiman L et al. A low incidence of nontuberculous mycobacterial infections in pediatric hematopoietic stem cell transplantation recipients. Biol. Blood Marrow Transplant. 2006; 12: 1188–97. Ingram CW, Tanner DC, Durack DT et al. Disseminated infection with rapidly growing mycobacteria. Clin. Infect. Dis. 1993; 16: 463–71. Doucette K, Fishman JA. Nontuberculous mycobacterial infection in hematopoietic stem cell and solid organ transplant recipients. Clin. Infect. Dis. 2004; 38: 1428–39.
© 2014 The Australasian College of Dermatologists
This document is a scanned copy of a printed document. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material.
Australasian Journal of Dermatology (2015) 56, 124–127
doi: 10.1111/ajd.12269
BRIEF REPORTS
Cutaneous non-tuberculous mycobacterial infection in patients with chronic graft-versus-host disease: A case series Gilberto Moreno-Bonilla,1 Bonita Choy1,2 and Pablo Fernandez-Peñas1,2 1
Department of Dermatology, Westmead Hospital, and 2Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
ABSTRACT We report the first case series of allogeneic haematopoietic stem-cell transplant patients with graft versus host disease who developed cutaneous non-tuberculous mycobacteria infection. A multidisciplinary approach, reduction of immunosuppressive medications, combination of antibiotics, close skin surveillance and excision of suitable lesions are recommended in this specific subgroup. Key words: graft versus host disease, hematopoietic stem cell transplantation, nontuberculous mycobacteria, transplantation.
INTRODUCTION Non-tuberculous mycobacteria (NTM) are ubiquitous in the environment and are resistant to eradication due to various complex mechanisms.1 Lung, skin and catheter-related sites are reportedly the most common sites of NTM infection in transplant recipients.2,3
REPORT OF CASES A total of 860 patients with allogeneic haematopoietic stemcell transplants (AHSCT) have been reviewed at Westmead Hospital graft versus host disease (GVHD) clinic between 1996 and 2014. Three patients with 6/6 human leukocyte
Correspondence: Dr Gilberto Moreno-Bonilla, Department of Dermatology, Westmead Hospital, Darcy Road, Westmead, NSW, 2145 Australia. Email: [email protected] Gilberto Moreno-Bonilla, MBBS. Bonita Choy, MBBS. Pablo Fernandez-Peñas, MD. Conflict of interest: none. Submitted 19 August 2014; accepted 24 September 2014. © 2014 The Australasian College of Dermatologists
antigen (HLA) matched sibling AHSCT developed a NTM skin infection, as captured by dermatology and microbiology files.
Case one In 2002 a 55-year-old man treated for acute myeloid leukaemia developed severe chronic GVHD involving the skin, oral mucosa, nails and liver. A conjunctival mass developed in 2006 while simultaneous violaceous nodules and plaques were noted on his face, arms, trunk and gluteal region. His immunosuppressive medications were prednisone 30 mg/day and tacrolimus 5 mg b.i.d. Skin biopsies showed granulomas, multiple acid-fast bacilli (AFB) (Fig. 1) and Mycobacterium haemophilum was identified by polymerase chain reaction (PCR). A conjunctival biopsy also revealed AFB.4 Further investigations were negative for systemic disease. He completed 12 months of oral clindamycin, clarithromycin and moxifloxacin plus a further 6 months of clarithromycin and moxifloxacin with favourable response. Skin and blood cultures showed a relapse of his infection in 2008. I.v. and oral antibiotics, with reduction of his immunosuppressive medications, did not prevent his death from an unrelated infection.
Case two A 50-year-old woman treated for acute myeloid leukaemia developed cutaneous and liver GVHD in 2007. Prednisone (15–30 mg daily), mycophenolate (2 g daily) and tacrolimus (2 mg daily) remained constant for 4 years after transplantation. Two erythematous nodules were noted over areas of previous insulin injections (Fig. 2a). A biopsy revealed marked
Abbreviations: AFB AHSCT GVHD NTM PCR
acid-fast bacilli allogeneic haematopoietic stem-cell transplant graft versus host disease non-tuberculous mycobacteria polymerase chain reaction
Cutaneous NTM infection in GVHD patients
(a)
125
(b)
Figure 1 (a) granulomatous reaction, HE ×20 and (b) multiple acid-fast bacilli, Ziehl–Neelsen stain ×40.
(a)
(b)
(c)
(d)
Figure 2 (a) Subcutaneous nodules right thigh pretreatment and (b) post-treatment; dermal and subcutaneous infiltrate with suppuration and fat necrosis (c) HE ×2 and (d) ×10.
suppuration, profuse neutrophil infiltration, focal fat necrosis and AFB (Fig. 2b). Ill-defined granulomas were noted. M. chelonae was isolated in 2010. Further investigations excluded systemic inflammation or disseminated infection. Surgical excision and i.v. antibiotics were followed by oral linezolid and clarithromycin for 8 weeks and clarithromycin alone for a further 6 months. Complete resolution was observed on regular reviews over the subsequent years (Fig. 2a).
Case three A 57-year-old man received an AHSCT for chronic lymphocytic leukaemia in 2008. Gastrointestinal and chronic mucocutaneous GVHD was documented 7 months later. Multiple firm nodules with purulent discharge over
the dorsum of hands, arms and thighs were identified in 2013 (Fig. 3). Immunosuppressive medications included only prednisone 30–40 mg daily. Two skin biopsies demonstrated necrotising and suppurative granulomas with AFB (Fig. 3), but no mycobacteria was isolated in culture. Tissue-based PCR for NTM and M. tuberculosis were negative. Two months later he presented with multilobar pneumonia and died of polymicrobial (viral/fungal/bacterial) septic shock. Investigations failed to isolate tuberculous and NTM from respiratory and blood cultures. His cutaneous NTM infection remained unresolved at the time of death.
DISCUSSION Although single case reports have been published, case series in AHSCT patients have described mostly non-skin © 2014 The Australasian College of Dermatologists
126
G Moreno-Bonilla et al.
(a)
(b)
(c)
(d)
Figure 3 (a,b). Fluctuant nodules on hands; (c) HE ×10 necrotizing granuloma and neutrophils; (d) acid-fast bacilli, Ziehl–Neelsen stain ×40.
disease.5,6 To our knowledge, this is the first case series of cutaneous NTM infection in patients with chronic GVHD. Statistically significant risk factors for NTM infection proposed by Au and colleagues include acute GVHD, relapse of leukaemia, a matched unrelated donor and a mismatched transplant.2 In contrast, our three patients with perfectly matched related donors and chronic GVHD still developed cutaneous infection. We found that routine inflammatory markers did not help to assess the degree of involvement in our three patients. On the other hand, from our seven tissue biopsies necrosis (6/7), AFB (6/7) and granuloma formation (5/7) were almost constant findings and were useful in diagnosis. Histology findings can be inconsistent or not species-specific.7,8 Although subcutaneous infiltrates with abscess formation were constant, granulomas were only noted in 60% of patients in one study.7 High-performance liquid chromatography analysis and PCR assays targeting 16SrRNA confirmed the presence of M. chelonae and M. haemophilum in two patients. Precise identification of the mycobacteria implicated in patient no. three was not possible. Although multiple attempts at culturing the organism failed, the low prevalence of tuberculosis in our community, a negative history of exposure and the clinical and histological presentation were consistent with NTM. The successful treatment of skin infection is based on experience. Combination antibiotic therapy has improved survival rates in recent years.9,10 Excision of suitable lesions and the reduction of immunosuppression have been recommended in transplant recipients.11 These recommendations helped only one of our patients. We noted that progressive and distant cutaneous infection was seen in those with worse immunosuppression and poorer prognosis. Also, the number of immunosuppressive medications used did not reflect the outcome. © 2014 The Australasian College of Dermatologists
Our centre covers the largest AHSCT population in the country, combined with the largest reference laboratory for mycobacterial disease in the state. Multicentre studies are required to establish and to validate risk factors and treatment in this population.
CONCLUSION Close skin surveillance, a high index of suspicion, serial skin biopsies for histopathology, cultures and PCR are required for the diagnosis of NTM. An integrated multidisciplinary approach with the reduction of immunosuppressive medications (when possible), a combination of antibiotics based on culture sensitivities, the excision of suitable lesions and the close monitoring of treatment progress are all essential components in the management of patients with GVHD.
ACKNOWLEDGEMENT All authors had full access to the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis. All authors participated in the development of the study concept and design, the acquisition and analysis of data and manuscript preparation.
REFERENCES 1.
2.
Primm TP, Lucero CA, Falkinham JO, 3rd. Health impacts of environmental mycobacteria. Clin. Microbiol. Rev. 2004; 17: 98–106. Au WY, Cheng VC, Ho PL et al. Nontuberculous mycobacterial infections in Chinese hematopoietic stem cell transplantation recipients. Bone Marrow Transplant. 2003; 32: 709–14.
Cutaneous NTM infection in GVHD patients 3.
4.
5.
6.
7.
Weinstock DM, Feinstein MB, Sepkowitz KA et al. High rates of infection and colonization by nontuberculous mycobacteria after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2003; 31: 1015–21. Millar MJM, Bulliard CM, Balachandran CMF et al. Mycobacterium hemophilum infection presenting as filamentary keratopathy in an immunocompromised adult. Cornea 2007; 26: 764–6. Gaviria JM, Garcia PJ, Garrido SM et al. Nontuberculous mycobacterial infections in hematopoietic stem cell transplant recipients: characteristics of respiratory and catheter-related infections. Biol. Blood Marrow Transplant. 2000; 6: 361–9. Roy V, Weisdorf D. Mycobacterial infections following bone marrow transplantation: a 20 year retrospective review. Bone Marrow Transplant. 1997; 19: 467–70. Bartralot R, Pujol RM, Garcia-Patos V et al. Cutaneous infections due to nontuberculous mycobacteria: histopathological
8.
9.
10.
11.
127
review of 28 cases. Comparative study between lesions observed in immunosuppressed patients and normal hosts. J. Cutan. Pathol. 2000; 27: 124–9. Busam KJ, Kiehn TE, Salob SP et al. Histologic reactions to cutaneous infections by Mycobacterium haemophilum. Am. J. Surg. Pathol. 1999; 23: 1379–85. Unal E, Yen C, Saiman L et al. A low incidence of nontuberculous mycobacterial infections in pediatric hematopoietic stem cell transplantation recipients. Biol. Blood Marrow Transplant. 2006; 12: 1188–97. Ingram CW, Tanner DC, Durack DT et al. Disseminated infection with rapidly growing mycobacteria. Clin. Infect. Dis. 1993; 16: 463–71. Doucette K, Fishman JA. Nontuberculous mycobacterial infection in hematopoietic stem cell and solid organ transplant recipients. Clin. Infect. Dis. 2004; 38: 1428–39.
© 2014 The Australasian College of Dermatologists
This document is a scanned copy of a printed document. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material.
