Synchronous tuberculosis, Epstein-Barr virus-associated lymphoproliferative disorder and cytomegalovirus infection in an allogeneic transplant recipient: a case report
1 Department of Hematology, Oncology and Tumor Immunology,
Charité University Medicine, Augustenburger Platz 1, 13353 Berlin, Germany
2 Department of Radiology, Charité University Medicine, Berlin, Germany
3 Institute of Pathology, Charité University Medicine, Berlin, Germany
2 Department of Radiology, Charité University Medicine, Berlin, Germany
3 Institute of Pathology, Charité University Medicine, Berlin, Germany
SpringerPlus
2014, 3:278 doi:10.1186/2193-1801-3-278
The electronic version
of this article is the complete one and can be found online at: http://www.springerplus.com/content/3/1/278
| Received: | 13 December 2013 |
| Accepted: | 23 May 2014 |
| Published: | 2 June 2014 |
© 2014 Ostendorf et al.; licensee Springer.
This is an Open Access
article distributed under the terms of the Creative Commons Attribution License
( http://creativecommons.org/licenses/by/2.0),
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provided the original work is properly credited.
Abstract
Background
Allogeneic stem cell transplant recipients are
prone to infections by various organisms. Tuberculosis (TB) represents a rare
infectious complication, especially in countries non-endemic for TB.
Case report
Here, we report the case of a German patient with
exposure to TB decades before he was diagnosed with disseminated TB as well as
synchronous Epstein-Barr virus associated lymphoproliferative disorder and
cytomegalovirus infection after allogeneic stem cell transplantation for
refractory acute myeloid leukemia. Tuberculostatic and virostatic therapy was
administered and the patient could be discharged with no apparent signs of
infection two weeks after initiation of therapy.
Conclusion
This case illustrates the need for awareness of
mycobacterial infections in patients from non-endemic regions undergoing stem
cell transplantation even if other reasons for fever are present.
Keywords:
Allogeneic stem cell transplantation; Cytomegalovirus; Epstein-Barr virus; Post-transplant lymphoproliferative disorder; TuberculosisBackground
Infections are a major reason for morbidity and mortality in
patients undergoing allogeneic hematopoietic stem cell transplantation (ASCT).
Tuberculosis (TB) remains a major health threat in many parts of the world.
However, TB is rare in non TB-endemic countries, including immunocompromised
patients after ASCT with reported rates ranging between less than 1% in the US
and up to 16% in Pakistan (Russo et al. 2010). For Europe,
mycobacterial infections in ASCT recipients have been reported at a rate of
0.79% (Cordonnier et al. 2004). Usually, TB
affecting transplant patients in countries with low TB prevalence is confined to
foreign-born patients (Garces Ambrossi et al. 2005).
Diagnosis of TB has traditionally relied on
microscopic detection of acid-fast bacilli and bacterial cultures. Nowadays,
genomic amplification of mycobacterial nucleic acids has improved sensitivity.
The diagnosis is difficult because TB infection can present with clinical and
radiological signs resembling infections caused by other, more frequent
pathogens, such as fungi. In addition, TB is not often considered in the initial
differential diagnosis in febrile patients after ASCT due to its low incidence
in this population. Here, we report the case of a German man who underwent ASCT
and developed pulmonary and nodular TB in addition to pulmonary cytomegalovirus
(CMV) infection and Epstein Barr-virus (EBV)-associated lymphoproliferation.
Case description
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 μg/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 ×
106 CD34+ cells/kg and 76.8 × 106 CD3+ cells/kg. From day
+5 granulocyte-stimulating factor (5 μg/kg/day) was given intravenously until
the absolute leukocyte count exceeded 1 × 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 14×15 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 2001). 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.
Figure 1. Histological diagnosis of
synchronous nodular tuberculosis and EBV-associated lymphoproliferative
disorder. Biopsy of a cervical lymph node performed on day +36 showed
effacement of the architecture due to numerous granulomas (low magnification
(a), which were composed of epithelioid cells
(b). Between the granulomas a polymorphous lymphoid infiltrate
was noted containing blasts as well as plasma cells (c). The
blasts were latently EBV-infected as shown in the immunohistochemical
demonstration of EBNA2 (d). 
Figure 2. Radiological diagnosis of
disseminated tuberculosis. CT scan of the thorax on day +43 after
allogeneic stem cell transplantation revealed a borderline sized mediastinal
lymph node with central necrosis (a) as well as multiple
pulmonary nodules (b).
Discussion
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 Rom 1998). 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 Woo 2002). 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 Woo 2002).
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.
Competing interests
The authors declare that they have no competing
interests.
Authors’ contributions
BNO and IA wrote the article. CFJ, LGV, HN, PGH,
BG, OP, and IWB critically revised the manuscript. RA had the original idea and
critically revised the manuscript. All authors read and approved the final
manuscript.
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