Fever in patients after allogeneic stem cell transplantation can develop due to various pathogens, including bacteria, viruses, fungi and protozoa. Tuberculosis constitutes a rare infectious complication in patients receiving hematopoietic stem cell transplantation in developed countries. More frequently, active EBV replication occurs in immunocompromised hosts, potentially leading to post-transplant lymphoproliferative disorders (PTLDs), comprising a spectrum from polyclonal B-cell expansion to malignant lymphoma (Swerdlow et al.2008). Here, we describe a rare case of a German man developing pulmonary and nodular TB as well as EBV-associated polymorphic PTLD and CMV infection after ASCT.
This case features several remarkable issues. TB in ASCT is usually confined to patients from endemic areas (Garces Ambrossi et al.2005). This case illustrates that TB should be included in an extended differential diagnosis in patients with fever even if from a non-endemic background and if other reasons explaining pyrexia are present. While it is not possible to definitely determine the route of infection in this patient, reactivation of latent TB seems the most likely scenario, because calcified pulmonary granulomas could be noted weeks before clinical onset of symptoms. In addition, the patient reported exposure to TB decades earlier, TB prevalence is low in Germany and reverse isolation measures were observed during neutropenia, making de novo infection less probable. This patient is the first to be diagnosed with TB in a total of 906 patients transplanted at our institution between 2001 and 2012. This low number is likely attributable to the low incidence of TB in Germany. However, fluoroquinolones have proven active in TB and have even been used as TB-prophylaxis by other centers in certain cases (Ip et al.1998). Therefore, the use of ciprofloxacin as anti-bacterial prophylaxis at our institution could have contributed to the low TB incidence in patient transplanted at our center. However, ciprofloxacin should generally not be considered as first-line tuberculostatic therapy as drug-resistant strains may be encouraged to emerge. Instead, isoniazid is generally considered first choice for empiric prophylaxis of TB in patients undergoing ASCT (Garces Ambrossi et al.2005).
Several risk factors are associated with TB infection in ASCT patients. Conditioning in our patient included 4 Gy total body irradiation, which has been shown to interfere with alveolar macrophage function besides its immunosuppressive effect on the host in general (Schluger and Rom1998). In addition, our patient received a graft mismatched at one human leukocyte antigen locus, which has been shown to be associated with higher incidence of TB (Cordonnier et al.2004). Another frequent risk factor predisposing for TB is GVHD, as it is associated with a delay in T-cell subset recovery. It is likely that therapy for GVHD further increases TB rates, although some controversy remains as to whether the treatment effect on GVHD outweighs its immunosuppressive effect in this regard (Yuen and Woo2002). However, our patient did not show any signs of GVHD. Increased rates of TB in ASCT patients have also been reported in patients receiving T-cell depleted grafts (Garces Ambrossi et al.2005). While T-cell depletion was only performed in vivo by administration of ATG, this patient received a relatively low T-cell count, possibly contributing to reactivation of several infections usually prevented by cellular immunity.
Onset of TB related symptoms took place on day +26 after transplantation after recovery of neutrophils. This is in line with previous reports that describe the vast majority of cases to occur after engraftment (Russo et al.2010), likely due to slow replication times of M. tuberculosis with symptoms developing only after partial immune reconstitution (Yuen and Woo2002).
There is controversy as to whether and how pre-transplantation screening for latent tuberculosis infection should be performed (Cordonnier et al.2004). As the tuberculin skin test lacks sensitivity in immunocompromised patients, T-cell-based interferon-gamma release assays have been proposed for ASCT patients (Moon et al.2012). However, more studies are warranted to establish the role of such assays in the context of ASCT. In addition, screening is only effective in TB endemic areas. Thus, we currently propose not to routinely perform TB screening prior to ASCT in countries not endemic for TB while considering and searching for mycobacterial disease in patients with persistent fever.
In summary, we describe a case of a German male patient developing synchronous TB, EBV-associated lymphoproliferative disorder and CMV pneumonia after ASCT for refractory acute myeloid leukemia. To our knowledge, this is the first case with such a combination of findings. In times of increasing population migration and increased use of T-cell depleted strategies it will be important to bear a high level of suspicion of mycobacterial disease in febrile patients even in countries with traditionally low TB prevalence.