Bone Marrow Transplantation (2014) 49, 1347–1348 © 2014 Macmillan Publishers Limited All rights reserved 0268-3369/14 www.nature.com/bmt
LETTER TO THE EDITOR
Report of disseminated Mycobacterium haemophilum infection after double cord blood allo-SCT Bone Marrow Transplantation (2014) 49, 1347–1348; doi:10.1038/ bmt.2014.144; published online 14 July 2014
Allo-SCT predisposes recipients to opportunistic infections, including various Mycobacterium species. Whereas M. tuberculosis is the most common Mycobacterium species associated with infections, nontuberculous Mycobacterium infections have been reported at an estimated incidence of 0.16–2.8% among transplant recipients.1 M. haemophilum is a slow-growing organism first identified in 1978. Since that time, it has emerged as an unusual pathogen, but increasingly identified, and mainly involving immunocompromised patients.2 Here, we report a case of M. haemophilum infection occurring after double cord blood (CB) allo-SCT. A 54-year-old man was diagnosed in July 2012 with AML with normal karyotype and without duplication of FLT3-ITD or mutation of NPM1 and CEBPα. He received one course of induction with a combination of idarubicin, etoposide and cytarabine allowing achievement of first cytological remission. Then, he received two courses of consolidation with idarubicin and high-dose cytarabine. Induction and consolidation courses were well tolerated without any significant infectious complication. According to local guidelines, he proceeded to allo-SCT in January 2013 with a myeloablative conditioning regimen including thiotepa (5 mg/ kg/d × 2 days), i.v. BU (3.2 mg/kg/d × 3 days), fludarabine (40 mg/ m2/d × 4 days) and rabbit antithymocyte globulin (2.5 mg/kg/ d × 2 days). The stem cell source was two unrelated CB units (matched 4/6 with the patient and with each other, TNC = 4.6 × 107/kg recipient body weight). GVHD prophylaxis consisted of CsA and mycophenolate mofetil. Early after allo-SCT (day +15) the patient developed cutaneous and digestive grade II acute GVHD treated with 2 mg/kg/d steroids and an additional two courses of 3 mg/m2/infusion i.v. MTX. At day +20, the patient also presented a CMV reactivation treated successfully by valganciclovir. At day +60, he also developed hemorrhagic cystitis linked to BK virus, which was treated with Igs and hyperhydration. The medullar evaluation on day 100 showed no excess of blasts and chimerism was full donor (one of the engrafted CB units). However, the patient had a persistently poor hematological reconstitution. Laboratory data showed pancytopenia with a WBC count at 1.5 × 109/L, neutrophils at 0.7 × 109/L and lymphocytes at 0.26 × 109/L, Hb at 9 g/dL and plts of 33 × 109/ L. He was transfused weekly with red blood units and plts. Electrolytes, measures of renal function, and liver enzymes were within normal limits, a C-reactive protein level of 79 mg/L and hyperferritinemia (3590 ng/mL). CD4 T-cell count was 41/mm3 at day +90. Around day +100, the patient presented several persistent s.c. nodules on the upper and lower limbs, predominantly on the thighs, and on the lower abdomen. These painless nodules, reaching 4 cm diameter for the biggest ones, were swollen, tender, erythematous and violaceous (Figure 1). Of note, no corresponding regional adenopathy was present. At this time, the patient had intermittent low-grade fever and dry cough with rough voice. Chest computed tomography scan showed bilateral multiple pulmonary nodules suggesting atypical pneumonia.
Otolaryngologic investigations diagnosed a small inflammatory vocal cord nodule. The first biopsy of one of these skin nodules identified multisensitive Staphylococcus aureus. However, because of persistent fever and worsening of symptoms despite prystinamycin treatment for 2 weeks, a treatment with imipenem, vancomycin and amphotericin B was initiated and a second skin biopsy of a thigh lesion was performed. Morphologic examination of this biopsy showed s.c. granulomatous inflammatory infiltrate with many epithelioid histiocytes but no well-formed epithelioid and giganto-cellular granulomas (Figure 2a). Numerous intracellular acid-fast bacilli were observed on Ziehl–Neelsen stain (Figure 2b). The anti-infective drugs were switched to imipenem and amikacin. After 10 days of treatment, due to occurrence of novel skin lesions and the persistence of fever, we chose to switch for the combination clarithromycin, rifabutin and ethambutol initially. Identification of M. haemophilum was finally performed by GenoType Mycobacterium CM/AS (Hain Diagnostika, Nehren, Germany) based on DNA strip technology on this biopsy specimen. Mycobacterial culture of the skin biopsy tissue was also positive after 10 weeks in a culture medium with addition of hemin at 30 °C. Within a few weeks, the fever disappeared and skin lesions were regressive. Besides, an important improvement of hematopoiesis was observed. The patient was doing well at the last follow-up (9 months post allo-SCT). M. haemophilum has emerged as a pathogen that can cause a wide range of diseases.3 The incidence of infection related to this
Figure 1. Erythematous nodule on hips caused by M. haemophilum in an allograft patient.
Letter to the Editor
1348
a
b
Figure 2. Microscopic examination of the skin biopsy. (a) Hematoxilyn–eosin stain, x200. S.c. granulomatous inflammatory infiltrate with many epitheliod histiocytes but no well-formed epithelioid and giganto-cellular granulomas. (b) Ziehl–Neelsen stain, x1000. Numerous intracellular acid-fast bacilli.
microorganism seems to increase, possibly due to the growing number of immune-compromised patients (with HIV/AIDS, solidorgan transplantation4 and allo-SCT), and to better identification by laboratories.5 M. haemophilum is presumed to be ubiquitous but its exact habitat has not yet been defined.6 This fastidious organism grows best at 30–32 °C and in the presence of iron or hemin, which is a unique feature. Molecular detection of mycobacterial DNA by PCR has been used successfully to identify this organism.7 The identification can also be made by HPLC. In allo-SCT, 16 cases have been described in the literature thus far. To date, the largest series of M. haemophilum comes from one center in New York City.5 In a series of 23 infections with M. haemophilum, 14 developed in patients who underwent allo-SCT with BM as stem cell source. Most of these patients had cutaneous disease, four had pulmonary infiltrates, two had synovitis and one had osteomyelitis. In addition, two case reports have been published on catheter-related infections8 and filamentous keratopathy9 after allo-SCT. There are no current guidelines regarding antibiotic management of M. haemophilum in immunocompromised patients. In vitro, M. haemophilum appears to be susceptible to ciprofloxacin, clarithromycin, rifabutin and clofazimine but resistant to isoniazid and ethambutol.5 Nevertheless, most experts would recommend a three-drug regimen associating macrolide, rifamycin and quinolone during at least 12 months.2 Whenever possible, immunosuppressive therapy should be tapered. In conclusion, the present case suggests that physicians must be aware of this particular pathogen that requires special culture techniques. They should have a high index of suspicion in the setting of high-infectious risk allo-SCT such as CB allo-SCT in patients who develop chronic skin, pulmonary, bone or joint lesions but also in any other heavily immunocompromised patients in whom acid-fast bacilli or/and atypical granulomas are identified in any pathological specimen. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS We thank the nursing staff for providing excellent care for our patients, the transplant coordination nurses and the following physicians: M Buffet, P Coppo, JP Marie, J Gay, NC Gorin, M Aoudjhane, L Garderet, J Voswinkel, MP Lemonnier, E Corre, P Hirsch, A Vekhoff, Z Marjanovic, R Adaeva, H Benredouane, M Labopin and R Belhocine for their dedicated patient care. EB was supported by educational grants from the
Bone Marrow Transplantation (2014) 1347 – 1348
‘Association for Training, Education and Research in Hematology, Immunology and Transplantation’ (ATERHIT). Our group is supported by several grants from the French National Cancer Institute (PHRC, INCa to MM).
E Brissot1,2,3, A Gomez1,2,3, A Aline-Fardin2,4,5, V Lalande6, S Lapusan1, F Isnard1, O Legrand1,2,3, J-L Meynard7, M-T Rubio1,2,3 and M Mohty1,2,3 1 Service d’Hématologie clinique et Thérapie cellulaire, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; 2 Université Pierre et Marie Curie, UPMC Univ Paris 06, Paris, France; 3 INSERM, UMRs 938, Paris, France; 4 Laboratoire d’Anatomo-Cyto-Pathologie, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; 5 INSERM, UMR_S893, Paris, France; 6 Laboratoire de Bactériologie, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France and 7 Service des Maladies Infectieuses et Tropicales, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France E-mail: [email protected] REFERENCES 1 Doucette K, Fishman JA. Nontuberculous mycobacterial infection in hematopoietic stem cell and solid organ transplant recipients. Clin Infect Dis 2004; 38: 1428–1439. 2 Kelley CF, Armstrong WS, Eaton ME. Disseminated Mycobacterium haemophilum infection. Lancet Infect Dis 2011; 11: 571–578. 3 Lindeboom JA, Bruijnesteijn van Coppenraet LE, van Soolingen D, Prins JM, Kuijper EJ. Clinical manifestations, diagnosis, and treatment of Mycobacterium haemophilum infections. Clin Microbiol Rev 2011; 24: 701–717. 4 Lau SK, Curreem SO, Ngan AH, Yeung CK, Yuen KY, Woo PC. First report of disseminated Mycobacterium skin infections in two liver transplant recipients and rapid diagnosis by hsp65 gene sequencing. J Clin Microbiol 2011; 49: 3733–3738. 5 Shah MK, Sebti A, Kiehn TE, Massarella SA, Sepkowitz KA. Mycobacterium haemophilum in immunocompromised patients. Clin Infect Dis 2001; 33: 330–337. 6 Saubolle MA, Kiehn TE, White MH, Rudinsky MF, Armstrong D. Mycobacterium haemophilum: microbiology and expanding clinical and geographic spectra of disease in humans. Clin Microbiol Rev 1996; 9: 435–447. 7 Giulieri S, Morisod B, Edney T, Odman M, Genne D, Malinverni R et al. Outbreak of Mycobacterium haemophilum infections after permanent makeup of the eyebrows. Clin Infect Dis 2011; 52: 488–491. 8 Ward MS, Lam KV, Cannell PK, Herrmann RP. Mycobacterial central venous catheter tunnel infection: a difficult problem. Bone Marrow Transplant 1999; 24: 325–329. 9 Millar MJ, Bulliard C, Balachandran C, Maloof AJ. Mycobacterium hemophilum infection presenting as filamentary keratopathy in an immunocompromised adult. Cornea 2007; 26: 764–766.
© 2014 Macmillan Publishers Limited
LETTER TO THE EDITOR
Report of disseminated Mycobacterium haemophilum infection after double cord blood allo-SCT Bone Marrow Transplantation (2014) 49, 1347–1348; doi:10.1038/ bmt.2014.144; published online 14 July 2014
Allo-SCT predisposes recipients to opportunistic infections, including various Mycobacterium species. Whereas M. tuberculosis is the most common Mycobacterium species associated with infections, nontuberculous Mycobacterium infections have been reported at an estimated incidence of 0.16–2.8% among transplant recipients.1 M. haemophilum is a slow-growing organism first identified in 1978. Since that time, it has emerged as an unusual pathogen, but increasingly identified, and mainly involving immunocompromised patients.2 Here, we report a case of M. haemophilum infection occurring after double cord blood (CB) allo-SCT. A 54-year-old man was diagnosed in July 2012 with AML with normal karyotype and without duplication of FLT3-ITD or mutation of NPM1 and CEBPα. He received one course of induction with a combination of idarubicin, etoposide and cytarabine allowing achievement of first cytological remission. Then, he received two courses of consolidation with idarubicin and high-dose cytarabine. Induction and consolidation courses were well tolerated without any significant infectious complication. According to local guidelines, he proceeded to allo-SCT in January 2013 with a myeloablative conditioning regimen including thiotepa (5 mg/ kg/d × 2 days), i.v. BU (3.2 mg/kg/d × 3 days), fludarabine (40 mg/ m2/d × 4 days) and rabbit antithymocyte globulin (2.5 mg/kg/ d × 2 days). The stem cell source was two unrelated CB units (matched 4/6 with the patient and with each other, TNC = 4.6 × 107/kg recipient body weight). GVHD prophylaxis consisted of CsA and mycophenolate mofetil. Early after allo-SCT (day +15) the patient developed cutaneous and digestive grade II acute GVHD treated with 2 mg/kg/d steroids and an additional two courses of 3 mg/m2/infusion i.v. MTX. At day +20, the patient also presented a CMV reactivation treated successfully by valganciclovir. At day +60, he also developed hemorrhagic cystitis linked to BK virus, which was treated with Igs and hyperhydration. The medullar evaluation on day 100 showed no excess of blasts and chimerism was full donor (one of the engrafted CB units). However, the patient had a persistently poor hematological reconstitution. Laboratory data showed pancytopenia with a WBC count at 1.5 × 109/L, neutrophils at 0.7 × 109/L and lymphocytes at 0.26 × 109/L, Hb at 9 g/dL and plts of 33 × 109/ L. He was transfused weekly with red blood units and plts. Electrolytes, measures of renal function, and liver enzymes were within normal limits, a C-reactive protein level of 79 mg/L and hyperferritinemia (3590 ng/mL). CD4 T-cell count was 41/mm3 at day +90. Around day +100, the patient presented several persistent s.c. nodules on the upper and lower limbs, predominantly on the thighs, and on the lower abdomen. These painless nodules, reaching 4 cm diameter for the biggest ones, were swollen, tender, erythematous and violaceous (Figure 1). Of note, no corresponding regional adenopathy was present. At this time, the patient had intermittent low-grade fever and dry cough with rough voice. Chest computed tomography scan showed bilateral multiple pulmonary nodules suggesting atypical pneumonia.
Otolaryngologic investigations diagnosed a small inflammatory vocal cord nodule. The first biopsy of one of these skin nodules identified multisensitive Staphylococcus aureus. However, because of persistent fever and worsening of symptoms despite prystinamycin treatment for 2 weeks, a treatment with imipenem, vancomycin and amphotericin B was initiated and a second skin biopsy of a thigh lesion was performed. Morphologic examination of this biopsy showed s.c. granulomatous inflammatory infiltrate with many epithelioid histiocytes but no well-formed epithelioid and giganto-cellular granulomas (Figure 2a). Numerous intracellular acid-fast bacilli were observed on Ziehl–Neelsen stain (Figure 2b). The anti-infective drugs were switched to imipenem and amikacin. After 10 days of treatment, due to occurrence of novel skin lesions and the persistence of fever, we chose to switch for the combination clarithromycin, rifabutin and ethambutol initially. Identification of M. haemophilum was finally performed by GenoType Mycobacterium CM/AS (Hain Diagnostika, Nehren, Germany) based on DNA strip technology on this biopsy specimen. Mycobacterial culture of the skin biopsy tissue was also positive after 10 weeks in a culture medium with addition of hemin at 30 °C. Within a few weeks, the fever disappeared and skin lesions were regressive. Besides, an important improvement of hematopoiesis was observed. The patient was doing well at the last follow-up (9 months post allo-SCT). M. haemophilum has emerged as a pathogen that can cause a wide range of diseases.3 The incidence of infection related to this
Figure 1. Erythematous nodule on hips caused by M. haemophilum in an allograft patient.
Letter to the Editor
1348
a
b
Figure 2. Microscopic examination of the skin biopsy. (a) Hematoxilyn–eosin stain, x200. S.c. granulomatous inflammatory infiltrate with many epitheliod histiocytes but no well-formed epithelioid and giganto-cellular granulomas. (b) Ziehl–Neelsen stain, x1000. Numerous intracellular acid-fast bacilli.
microorganism seems to increase, possibly due to the growing number of immune-compromised patients (with HIV/AIDS, solidorgan transplantation4 and allo-SCT), and to better identification by laboratories.5 M. haemophilum is presumed to be ubiquitous but its exact habitat has not yet been defined.6 This fastidious organism grows best at 30–32 °C and in the presence of iron or hemin, which is a unique feature. Molecular detection of mycobacterial DNA by PCR has been used successfully to identify this organism.7 The identification can also be made by HPLC. In allo-SCT, 16 cases have been described in the literature thus far. To date, the largest series of M. haemophilum comes from one center in New York City.5 In a series of 23 infections with M. haemophilum, 14 developed in patients who underwent allo-SCT with BM as stem cell source. Most of these patients had cutaneous disease, four had pulmonary infiltrates, two had synovitis and one had osteomyelitis. In addition, two case reports have been published on catheter-related infections8 and filamentous keratopathy9 after allo-SCT. There are no current guidelines regarding antibiotic management of M. haemophilum in immunocompromised patients. In vitro, M. haemophilum appears to be susceptible to ciprofloxacin, clarithromycin, rifabutin and clofazimine but resistant to isoniazid and ethambutol.5 Nevertheless, most experts would recommend a three-drug regimen associating macrolide, rifamycin and quinolone during at least 12 months.2 Whenever possible, immunosuppressive therapy should be tapered. In conclusion, the present case suggests that physicians must be aware of this particular pathogen that requires special culture techniques. They should have a high index of suspicion in the setting of high-infectious risk allo-SCT such as CB allo-SCT in patients who develop chronic skin, pulmonary, bone or joint lesions but also in any other heavily immunocompromised patients in whom acid-fast bacilli or/and atypical granulomas are identified in any pathological specimen. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS We thank the nursing staff for providing excellent care for our patients, the transplant coordination nurses and the following physicians: M Buffet, P Coppo, JP Marie, J Gay, NC Gorin, M Aoudjhane, L Garderet, J Voswinkel, MP Lemonnier, E Corre, P Hirsch, A Vekhoff, Z Marjanovic, R Adaeva, H Benredouane, M Labopin and R Belhocine for their dedicated patient care. EB was supported by educational grants from the
Bone Marrow Transplantation (2014) 1347 – 1348
‘Association for Training, Education and Research in Hematology, Immunology and Transplantation’ (ATERHIT). Our group is supported by several grants from the French National Cancer Institute (PHRC, INCa to MM).
E Brissot1,2,3, A Gomez1,2,3, A Aline-Fardin2,4,5, V Lalande6, S Lapusan1, F Isnard1, O Legrand1,2,3, J-L Meynard7, M-T Rubio1,2,3 and M Mohty1,2,3 1 Service d’Hématologie clinique et Thérapie cellulaire, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; 2 Université Pierre et Marie Curie, UPMC Univ Paris 06, Paris, France; 3 INSERM, UMRs 938, Paris, France; 4 Laboratoire d’Anatomo-Cyto-Pathologie, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; 5 INSERM, UMR_S893, Paris, France; 6 Laboratoire de Bactériologie, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France and 7 Service des Maladies Infectieuses et Tropicales, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France E-mail: [email protected] REFERENCES 1 Doucette K, Fishman JA. Nontuberculous mycobacterial infection in hematopoietic stem cell and solid organ transplant recipients. Clin Infect Dis 2004; 38: 1428–1439. 2 Kelley CF, Armstrong WS, Eaton ME. Disseminated Mycobacterium haemophilum infection. Lancet Infect Dis 2011; 11: 571–578. 3 Lindeboom JA, Bruijnesteijn van Coppenraet LE, van Soolingen D, Prins JM, Kuijper EJ. Clinical manifestations, diagnosis, and treatment of Mycobacterium haemophilum infections. Clin Microbiol Rev 2011; 24: 701–717. 4 Lau SK, Curreem SO, Ngan AH, Yeung CK, Yuen KY, Woo PC. First report of disseminated Mycobacterium skin infections in two liver transplant recipients and rapid diagnosis by hsp65 gene sequencing. J Clin Microbiol 2011; 49: 3733–3738. 5 Shah MK, Sebti A, Kiehn TE, Massarella SA, Sepkowitz KA. Mycobacterium haemophilum in immunocompromised patients. Clin Infect Dis 2001; 33: 330–337. 6 Saubolle MA, Kiehn TE, White MH, Rudinsky MF, Armstrong D. Mycobacterium haemophilum: microbiology and expanding clinical and geographic spectra of disease in humans. Clin Microbiol Rev 1996; 9: 435–447. 7 Giulieri S, Morisod B, Edney T, Odman M, Genne D, Malinverni R et al. Outbreak of Mycobacterium haemophilum infections after permanent makeup of the eyebrows. Clin Infect Dis 2011; 52: 488–491. 8 Ward MS, Lam KV, Cannell PK, Herrmann RP. Mycobacterial central venous catheter tunnel infection: a difficult problem. Bone Marrow Transplant 1999; 24: 325–329. 9 Millar MJ, Bulliard C, Balachandran C, Maloof AJ. Mycobacterium hemophilum infection presenting as filamentary keratopathy in an immunocompromised adult. Cornea 2007; 26: 764–766.
© 2014 Macmillan Publishers Limited
