In July 2012 a 51-year-old German male patient was diagnosed with acute myeloid leukemia with maturation. The disease proved refractory after administration of two cycles of induction chemotherapy and ASCT from a non-related donor with human leukocyte antigen-A mismatch (9/10 antigens matched) was performed as salvage therapy in December 2012. Conditioning consisted of the FLAMSA-RIC regimen (fludarabine 120 mg/m2, cytarabine 8,000 mg/m2, amsacrine 400 mg/m2, total body irradiation 4 Gy, cyclophosphamide 120 mg/kg and anti-thymocyte globulin (ATG, Fresenius, 60 mg/kg). Graft-versus-host disease (GVHD) prophylaxis was cyclosporine A from day -2 (target serum trough level of 180-220 mug/l) and mycophenolate mofetil from day 0 (2 g/day). Ciprofloxacin, acyclovir, voriconazole and monthly pentamidine inhalations were administered as anti-infective prophylaxis. Pre-transplant X-ray of the lungs did not show any pathologic findings and polymerase chain reactions (PCR) for CMV and EBV genomes in the peripheral blood were negative. The patient reported exposure to TB in an affected classmate decades ago but denied previous infection. BCG vaccination status was unknown. Tuberculin skin test is not routinely performed at our institution. The patient tolerated the conditioning regime well and received a non T-cell-depleted peripheral blood stem cell allograft containing 4.9 x 106 CD34+ cells/kg and 76.8 x 106 CD3+ cells/kg. From day +5 granulocyte-stimulating factor (5 mug/kg/day) was given intravenously until the absolute leukocyte count exceeded 1 x 109/l.
On day +1 after transplantation the patient developed fever of up to 38.5 C and the antibiotic treatment was switched to meropenem. After detection of Staphylococcus haemolyticus in a blood culture, vancomycin was added and the fever subsequently subsided. On day +8 fever recurred and vancomycin was exchanged for linezolid. Computer tomography (CT) of the lungs revealed micronodular lesions suspicious of calcified granulomas but did not show signs of acute pulmonary infection. Subsequently, the fever ceased and engraftment of neutrophils was achieved on day +19.
On day +26 fever was noted again and antibiotic treatment was re-initiated with piperacillin/tazobactam, which was exchanged for meropenem/vancomycin and then meropenem/linezolid after persistence of fever. Thoracic CT-scan showed multiple small pulmonary nodules and due to the morphology of the lesions pulmonary mycosis and extramedullary leukemia were primarily considered. On day +34 right cervical lymphadenopathy was noted and ultrasonography confirmed three enlarged, inhomogeneous and echopenic lymph nodes with a maximum size of 14x15 mm. Histological analysis of one extirpated lymph node showed complete effacement of its architecture due to multiple epithelioid cell granulomas with only occasional necrosis (Figure  1a,b). In addition, focal polymorphous lymphoid infiltrates (Figure  1c) composed of blastic activated B cells expressing CD20 and CD30 were identified, which were accompanied by plasma cells with polytypic expression of the immunoglobulin light chains. Further immunohistological investigations revealed that the activated B-blasts expressed the EBV encoded latent membrane protein-1 and the nuclear antigen EBNA2, both of which are involved in EBV-induced B cell activation and proliferation (Figure  1d) (Thorley-Lawson ). As a sign of a transition of the latent to the lytic EBV infection phase several lymphoid cells expressed the BamHI Z fragment leftward open reading frame 1 (BZLF1)-protein of the virus. Gene rearrangement analysis of the immunoglobulin heavy chains detected the presence of a monoclonal B-cell population. These findings led to the diagnosis of an EBV-associated polymorphic post-transplantation lymphoproliferative disorder combined with granulomatous lymphadenitis. Cultures remained sterile and microscopic examination revealed no acid-fast bacilli. However, PCR analysis of the lymph node revealed presence of Mycobacterium tuberculosis (M. tuberculosis) consensus sequences. Repeated thoracic CT showed mediastinal and hilar lymphadenopathy of up to 20 mm and unchanged pulmonary nodules (Figure  2a,b). Bronchoalveolar lavage was performed and PCR revealed presence of both M. tuberculosis and CMV (191,000 CMV copies/ml). Additionally, sputum samples were found positive for both microscopic and cultural detection of M. tuberculosis. Tuberculostatic therapy consisting of isoniazid, rifampicin, ethambutol and pyrazinamide was initiated. EBV and CMV replication was also detected in the peripheral blood by quantitative PCR (99,300 and 53,800 copies/ml, respectively). Intravenous ganciclovir was initiated and rituximab was administered three times (375 mg/m2/dose) with subsequent dropping of copy numbers of EBV and CMV below the detection limits. Two weeks after initiation of TB therapy the patient had completely recovered from all infectious symptoms and sputum samples turned negative for M. tuberculosis. The patient was subsequently discharged from the hospital for outpatient continuation of tuberculostatic therapy. Unfortunately, bone marrow examination on day +77 revealed fulminant relapse of the leukemia without signs of infection. Palliative cytoreduction using hydroxyurea was initiated and the patient was transferred to a hospice, where he died three weeks later. The patient's next of kin consented to the publication of this report.