Report of Disseminated Mycobacterium Haemophilum Infection After Double Cord Blood Allo-SCT

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/ Otolaryngologic investigations diagnosed a small inflammatory bmt.2014.144; published online 14 July 2014 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 prystina- Allo-SCT predisposes recipients to opportunistic infections, mycin treatment for 2 weeks, a treatment with imipenem, including various Mycobacterium species. Whereas M. tuberculosis vancomycin and amphotericin B was initiated and a second skin is the most common Mycobacterium species associated with biopsy of a thigh lesion was performed. Morphologic examination infections, nontuberculous Mycobacterium infections have been of this biopsy showed s.c. granulomatous inflammatory infiltrate reported at an estimated incidence of 0.16–2.8% among with many epithelioid histiocytes but no well-formed epithelioid transplant recipients.1 M. haemophilum is a slow-growing organ- and giganto-cellular granulomas (Figure 2a). Numerous intracel- ism first identified in 1978. Since that time, it has emerged as an lular acid-fast bacilli were observed on Ziehl–Neelsen stain unusual pathogen, but increasingly identified, and mainly invol- (Figure 2b). The anti-infective drugs were switched to imipenem ving immunocompromised patients.2 Here, we report a case of M. and amikacin. After 10 days of treatment, due to occurrence of haemophilum infection occurring after double cord blood (CB) novel skin lesions and the persistence of fever, we chose to switch allo-SCT. for the combination clarithromycin, rifabutin and ethambutol A 54-year-old man was diagnosed in July 2012 with AML with initially. Identification of M. haemophilum was finally performed by normal karyotype and without duplication of FLT3-ITD or mutation GenoType Mycobacterium CM/AS (Hain Diagnostika, Nehren, of NPM1 and CEBPα. He received one course of induction with a Germany) based on DNA strip technology on this biopsy combination of idarubicin, etoposide and cytarabine allowing specimen. Mycobacterial culture of the skin biopsy tissue was achievement of first cytological remission. Then, he received two also positive after 10 weeks in a culture medium with addition of courses of consolidation with idarubicin and high-dose cytarabine. hemin at 30 °C. Within a few weeks, the fever disappeared and Induction and consolidation courses were well tolerated without skin lesions were regressive. Besides, an important improvement fi any signi cant infectious complication. According to local guide- of hematopoiesis was observed. The patient was doing well at the lines, he proceeded to allo-SCT in January 2013 with a last follow-up (9 months post allo-SCT). myeloablative conditioning regimen including thiotepa (5 mg/ M. haemophilum has emerged as a pathogen that can cause a fl kg/d × 2 days), i.v. BU (3.2 mg/kg/d × 3 days), udarabine (40 mg/ wide range of diseases.3 The incidence of infection related to this 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 pancyto- penia 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 Figure 1. Erythematous nodule on hips caused by M. haemophilum multiple pulmonary nodules suggesting atypical pneumonia. 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 ‘Association for Training, Education and Research in Hematology, Immunology and number of immune-compromised patients (with HIV/AIDS, solid- Transplantation’ (ATERHIT). Our group is supported by several grants from the French organ transplantation4 and allo-SCT), and to better identification National Cancer Institute (PHRC, INCa to MM). by laboratories.5 M. haemophilum is presumed to be ubiquitous but its exact habitat has not yet been defined.6 This fastidious E Brissot1,2,3, A Gomez1,2,3, A Aline-Fardin2,4,5, V Lalande6, organism grows best at 30–32 °C and in the presence of iron or S Lapusan1, F Isnard1, O Legrand1,2,3, J-L Meynard7, M-T Rubio1,2,3 hemin, which is a unique feature. Molecular detection of and M Mohty1,2,3 mycobacterial DNA by PCR has been used successfully to identify 1Service d’Hématologie clinique et Thérapie cellulaire, Hôpital this organism.7 The identification can also be made by HPLC. Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), In allo-SCT, 16 cases have been described in the literature thus Paris, France; far. To date, the largest series of M. haemophilum comes from one 2Université Pierre et Marie Curie, UPMC Univ Paris 06, Paris, France; center in New York City.5 In a series of 23 infections with M. 3INSERM, UMRs 938, Paris, France; haemophilum, 14 developed in patients who underwent allo-SCT 4Laboratoire d’Anatomo-Cyto-Pathologie, Hôpital Saint-Antoine, with BM as stem cell source. Most of these patients had cutaneous Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; disease, four had pulmonary infiltrates, two had synovitis and one 5INSERM, UMR_S893, Paris, France; had osteomyelitis. In addition, two case reports have been 6Laboratoire de Bactériologie, Hôpital Saint-Antoine, Assistance published on catheter-related infections8 and filamentous Publique-Hôpitaux de Paris (AP-HP), Paris, France and keratopathy9 after allo-SCT. There are no current guidelines 7Service des Maladies Infectieuses et Tropicales, Hôpital regarding antibiotic management of M. haemophilum in immu- Saint-Antoine, Assistance Publique-Hôpitaux nocompromised patients. In vitro, M. haemophilum appears to be de Paris (AP-HP), Paris, France susceptible to ciprofloxacin, clarithromycin, rifabutin and clofazi- E-mail: [email protected] mine 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 REFERENCES Whenever possible, immunosuppressive therapy should be 1 Doucette K, Fishman JA. Nontuberculous mycobacterial infection in hematopoietic tapered. stem cell and solid organ transplant recipients. Clin Infect Dis 2004; 38: 1428–1439. In conclusion, the present case suggests that physicians must 2 Kelley CF, Armstrong WS, Eaton ME. Disseminated Mycobacterium haemophilum be aware of this particular pathogen that requires special culture infection. Lancet Infect Dis 2011; 11: 571–578. techniques. They should have a high index of suspicion in the 3 Lindeboom JA, Bruijnesteijn van Coppenraet LE, van Soolingen D, Prins JM, setting of high-infectious risk allo-SCT such as CB allo-SCT in Kuijper EJ. Clinical manifestations, diagnosis, and treatment of Mycobacterium patients who develop chronic skin, pulmonary, bone or joint haemophilum infections. Clin Microbiol Rev 2011; 24: 701–717. lesions but also in any other heavily immunocompromised 4 Lau SK, Curreem SO, Ngan AH, Yeung CK, Yuen KY, Woo PC. First report of dis- patients in whom acid-fast bacilli or/and atypical granulomas are seminated Mycobacterium skin infections in two liver transplant recipients and 49 – identified in any pathological specimen. rapid diagnosis by hsp65 gene sequencing. J Clin Microbiol 2011; : 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. CONFLICT OF INTEREST 6 Saubolle MA, Kiehn TE, White MH, Rudinsky MF, Armstrong D. Mycobacterium haemophilum: microbiology and expanding clinical and geographic spectra of The authors declare no conflict of interest. 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. ACKNOWLEDGEMENTS Clin Infect Dis 2011; 52:488–491. We thank the nursing staff for providing excellent care for our patients, the transplant 8 Ward MS, Lam KV, Cannell PK, Herrmann RP. Mycobacterial central venous catheter coordination nurses and the following physicians: M Buffet, P Coppo, JP Marie, J Gay, tunnel infection: a difficult problem. Bone Marrow Transplant 1999; 24:325–329. NC Gorin, M Aoudjhane, L Garderet, J Voswinkel, MP Lemonnier, E Corre, P Hirsch, 9 Millar MJ, Bulliard C, Balachandran C, Maloof AJ. Mycobacterium hemophilum A Vekhoff, Z Marjanovic, R Adaeva, H Benredouane, M Labopin and R Belhocine for infection presenting as filamentary keratopathy in an immunocompromised adult. their dedicated patient care. EB was supported by educational grants from the Cornea 2007; 26: 764–766.