Case reportTwo children with di¡ering outcomes after treatment for pulmonary tuberculosis diagnosed after allogeneic hematopoietic stem cell transplantation J.W.. Two children with di¡er
Trang 1Case report
Two children with di¡ering outcomes after treatment for pulmonary tuberculosis diagnosed after
allogeneic hematopoietic stem cell transplantation
J.W Lee1, H.-J Kwon2, P.-S Jang1, N.-G Chung1, B Cho1, D.-C Jeong1, J.-H Kang2, H.-K Kim1
1 Division of Hematology and Oncology, Department of Pediatrics,2Division of Infectious Diseases, Department of Pediatrics, The Catholic University of Korea, Seoul, Republic
of Korea
J.W Lee, H.-J Kwon, P.-S Jang, N.-G Chung, B Cho, D.-C Jeong,
J.-H Kang, H.-K Kim Two children with di¡ering outcomes after
treatment for pulmonary tuberculosis diagnosed after allogeneic
hematopoietic stem cell transplantation
Transpl Infect Dis 2011: 13: 520^523 All rights reserved
Abstract: Tuberculosis (TB) is a rare infectious complication after
hematopoietic stem cell transplantation (HSCT), but may be more
signi¢cant in areas where the disease is endemic Here, we present the
clinical course of 2 children with acute lymphoblastic leukemia who
were diagnosed with pulmonary TB after allogeneic HSCT Both
patients were treated for either probable or possible invasive fungal
infection, as well as TB One patient, diagnosed withTB 3 months after
HSCT, showed remittent fever and symptoms that progressed to acute
respiratory distress syndrome and death, despite 3 modi¢cations to the
anti-TB regimen In contrast, another patient who was diagnosed with
TB 8 months after transplantation, responded well to anti-TB
medication and completed 1 year of treatment with resolution of lung
lesions Co-morbid opportunistic infections, profound host
immunosuppression early after transplantation, and potential risk of
multi-drug resistant-TB may act as major barriers to e¡ective treatment
of TB after HSCTdespite appropriate anti-TB medication
For recipients of allogeneic hematopoietic stem cell
trans-plantation (HSCT),Mycobacterium tuberculosis may act as
a signi¢cant opportunistic pathogen in the early
post-transplantation period, especially in areas where
tubercu-losis (TB) is endemic
Incidence and risk factors for mycobacterial infection
diagnosed in the post-HSCT period have been reviewed
previously in large cohorts of patients (1^6), with factors
such as matched unrelated and mismatched
transplanta-tions, treatment with total body irradiation, and
graft-versus-host disease (GVHD) having a signi¢cant impact
on TB incidence However, studies of TB diagnosed solely
in the pediatric HSCT population are scarce, and little is
known of prognostic factors after initiation of anti-TB
med-ication Most importantly, the severe immunosuppression
that characterizes the post-HSCT period may have a
delete-rious e¡ect on response to anti-TB treatment
In this study, we report on 2 children who showed a di¡er-ing clinical course after treatment for pulmonary TB diag-nosed after allogeneic HSCT for acute lymphoblastic leukemia (ALL)
Case reports
Patient 1 The 17-year-old male patient had been diagnosed with Phil-adelphia chromosome-positive ALL and had received matched unrelated bone marrow transplantation (BMT)
7 months after initial diagnosis Myeloablative condition-ing regimen consisted of total body irradiation, cytarabine, cyclophosphamide (TBI-Ara-Cy), and anti-thymocyte
Key words: tuberculosis; hematopoietic stem cell transplantation; children
Correspondence to:
Nak-Gyun Chung, MD, PhD, Department of Pediatrics, Seoul Saint Mary’s Hospital, Catholic University of Korea,
Seocho-gu, Banpo-dong 505, Seoul 137-701, Republic of Korea Tel: 82 2 2258 6188
Fax: 82 2 588 3589 E-mail: cngped@catholic.ac.kr Received 26 November 2010, revised 9 January 2011, accepted for publication 5 February 2011
DOI: 10.1111/j.1399-3062.2011.00641.x Transpl Infect Dis 2011
Trang 2globulin (ATG) Neutrophil recovery was not delayed, with
absolute neutrophil count 40.5 109
/L from day 13 of bone marrow infusion He did not experience acute GVHD,
and the immediate post-transplantation period was
un-eventful except for cytomegalovirus (CMV) DNAemia that
was treated preemptively with ganciclovir
Two months after transplantation he was readmitted for
fever and dyspnea of 1 day’s duration A chest computed
to-mography (CT) scan revealed nodular opacities consistent
with fungal pneumonia, and broad-spectrum antibiotics
and intravenous amphotericin were started
Microbiologi-cal studies were negative, and fever persisted with
pro-gression of lung in¢ltrations despite changes to other
antifungal agents
After a 6 -day period of defervescence, fever started
again on day 32 of admission Sputum study done at
this time stained positive for acid-fast bacilli (AFB) and
isoniazid, rifampin, pyrazinamide, and ethambutol were
started A chest x-ray at this point showed signi¢cant
aggravation of in¢ltrations in the left lung ¢eld (Fig 1)
No tuberculous family or contact history was determined,
but sputum culture showed growth of M tuberculosis
Signs and symptoms of GVHD were not evident, and
im-munosuppressive medication administered at the time
of TB diagnosis was cyclosporine only Peripheral blood
lymphocyte study previous to the diagnosis showed 90%
NK cells, with few B and T lymphocytes Fever continued
with rapid aggravation of pneumonia despite treatment, prompting consideration of drug resistance of the TB strain to one or more of the anti-TB medications initially given Levo£oxacin was substituted for ethambutol, but fe-ver and pulmonary in¢ltrations failed to abate, and a sec-ond change was made to the anti-TB regimen, with cycloserine given instead of pyrazinamide Progressive disease led to the addition of ethambutol to the 4 -drug reg-imen Sputum culture done 1 month after the initiation of anti-TB medication showed the growth of yeast, and lipo-somal amphotericin was started Throughout the febrile period, serial serum galactomannan (GM) assays were neg-ative Although follow-up sputum cultures forM tuberculo-sis were negative, fever and lung in¢ltrations failed to abate and the patient died of acute respiratory distress syndrome (ARDS) 39 days after the start of anti-TB medication, 136 days after transplantation Sensitivity results reported
37 days after diagnosis of TB showed the strain to be sus-ceptible to isoniazid and rifampin
Patient 2 The 14 -year-old female patient had been diagnosed with T cell ALL, achieved delayed complete remission and received granulocyte colony-stimulating factor mobilized peripheral blood stem cell (PBSC) transplantation from her mother 4 months after initial diagnosis Conditioning regimen included TBI-Ara-Cy and ATG Prompt neutrophil engraftment occurred, with absolute neutrophil count 40.5 109/L from day 11 of PBSC infusion W|thin day 1 100 of transplantation, the patient had been treated for CMV DNAemia with ganciclovir, and had been admit-ted twice for probable invasive fungal infection (IFI), according to standard criteria (7 ) Four months after trans-plantation, the patient had been exposed to Patient 1 during inpatient care but prophylactic isoniazid was withdrawn after 1 week because of persistently elevated liver enzymes that were found concurrent with chronic skin and oral GVHD The patient was subsequently diagnosed with late-onset acute GVHD of skin, liver, and gastrointestinal tract that showed resolution with steroids
Eight months after transplantation, the patient was re-admitted for fever Chest CT imaging indicated in¢ltrations
of the left upper lung ¢eld and bronchoalveolar lavage (BAL) studies proved to be positive for AFB Immunosuppressive medication administered at the time included oral cyclospor-ine, as well as beclomethasone for previously diagnosed gut GVHD, with the latter stopped because of improved symp-toms The patient was started on isoniazid, rifampin, pyrazinamide, and levo£oxacin Relapse of fever and aggra-vation of chest in¢ltrations 2 weeks after starting anti-TB medication (Fig 2), concurrent with positive tests for serum
Fig 1 Patient 1 was a Philadelphia chromosome-positive acute
lymph-oblastic leukemia patient who was readmitted for fever and dyspnea
2 months after unrelated bone marrow transplantation Sputum smear
on day 36 of admission was acid-fast bacilli positive, and a chest x-ray at
the time showed left lung in¢ltrations (arrows).
Trang 3GM, led to the initiation of amphotericin B and a switch from
rifampin to cycloserine, which resulted in defervescence and
improvement of chest lesions The patient was discharged
with voriconazole, as well as the 4 -drug anti-TB regimen
The strain ofM tuberculosis cultured from BAL £uid proved
to be sensitive to both isoniazid and rifampin, as well as
other anti-TB medication administered The sensitivity
pro-¢le, however, was di¡erent from that of theTB strain isolated
in Patient 1, with sensitivity to aminoglycosides to which the
strain of Patient 1 was resistant
Five months after initiation of anti-TB
medica-tion, biopsy of a newly developed skin nodule showed
chronic granulomatous in£ammation with central caseous
necrosis, with positive results forM tuberculosis PCR, and
rifampin was reinstated instead of pyrazinamide and
cyclo-serine The patient maintained this regimen for 5 months
before cessation of anti-TB medication 1 year after
initia-tion, with most recent imaging showing signi¢cant
regres-sion of pulmonary TB
Discussion
Incidence of TB after allogeneic HSCT is signi¢cantly
higher in regions where TB is endemic, with reported rates
ranging from 1.7% to 3.0% (8, 9) However, studies on the clinical course of children diagnosed with TB during the post-HSCT period are few
The 2 patients presented here emphasize the major ob-stacles to e¡ective anti-TB treatment in the post-allogeneic HSCT period One impediment, common to both patients, is the presence of signi¢cant co-infections that may confound accurate interpretation of patient response to anti-TB treat-ment Our patients were diagnosed with either probable or possible IFI, and were administered antifungal agents con-comitant with the anti-TB regimen Continued fever, and persistence or aggravation of pulmonary in¢ltrates in both children that led to modi¢cations to anti-TB treatment may have been the result of unproven fungal infections Radio-logic signs more diagnostic of fungal infection, such as air-crescent sign or cavity formation, as outlined in the revised diagnostic criteria for IFI (7 ), may have aided in di¡erenti-ation of worsening fungal infection fromTB, but these were not evident in our patients Despite di⁄culties, diagnostic tests including bronchoscopy should be undertaken in order to isolate the cause of clinical aggravation in the post-HSCTsituation where multiple infections may coexist Second, the premature termination of isoniazid prophylaxis
in Patient 2 because of elevated liver enzymes underscores the di⁄culty of administering anti-TB medication post-HSCT when hepatotoxicity may have many causes, including he-patic GVHD, veno-occlusive disease, and CMV infection Despite treatment with an anti-TB regimen to which the
M tuberculosis strain proved to be susceptible, Patient 1 experienced a remittent fever course with productive cough, combined with gradual aggravation of pneumonia until death from ARDS Throughout this period, all other cultures and serum GM assay had been negative, with only
an unidenti¢ed yeast found on sputum culture toward the end of the patient’s clinical course The patient had under-gone 3 changes to the anti-TB regimen with consideration
of possible multi-drug resistant-TB (MDR-TB) Studies have con¢rmed a 12^13% incidence ofM tuberculosis strain resis-tant to any ¢rst-line anti-TB medication in Korea among newly diagnosed patients, with a 3^4% incidence of
MDR-TB (10, 11) MDR-MDR-TB diagnosed after allogeneic BMT has also been reported (12) As results of TB drug sensitivities are delayed considerably, anti-TB modi¢cation was deemed necessary in our patient to counter potential drug resistance
as a cause of clinical aggravation
One major di¡erence between Patient 1 and Patient 2, who showed resolution of TB, is that the former’s TB was diagnosed much earlier, within day 100 of transplantation One study reported 9 patients withTB resolution among 11 overall after BMT (1); 9 of these 11 patients had TB diag-nosed within 100 days post transplantation However,
2 other studies indicate that time to diagnosis after HSCT was much shorter among patients who died from TB, than
Fig 2 Patient 2, with underlying acute lymphoblastic leukemia, was
di-agnosed with tuberculosis 8 months after mismatched familial peripheral
blood stem cell transplantation Fever restarted 2 weeks after initiation of
anti-tuberculous medication, concurrent with serial positive results for
serum galactomannan, leading to amphotericin B administration
Fol-low-up imaging of Patient 2 at this time point showed persistent left
up-per lobe consolidation (arrow).
Trang 4among those who survived (2, 3) A rapidly progressive,
fa-tal case of sepsis due toM tuberculosis diagnosed within a
few months of HSCT has also been described (13) W|th
regards to infectious complications, the post-HSCT period
has been divided into the pre-engraftment period, and
intermediate ( day 100) and late (after day 100) recovery
periods, with di¡erent pathogens being more predominant
in each phase (14) Whether the T and B lymphocyte-based
immune de¢ciency that characterizes the time up till the
late recovery period renders TB slowly responsive or
re-fractory to appropriate anti-TB medication requires
fur-ther study Such immune de¢ciency characterized by poor
lymphocyte function may last beyond the intermediate
re-covery period, especially if the patient is diagnosed and
treated for GVHD, as in the case of Patient 2 Chronic
GVHD especially, which was not evident in either of the
pa-tients at time of TB diagnosis, may lead to prolonged
de¢-ciency of cell-mediated immunity Adjustments to the
anti-TB regimen may be done with greater caution if severely
impaired host immunity, rather than microbial resistance,
is more likely responsible for clinical deterioration
One pediatric HSCT-based study reported resolution of
TB in all 4 patients diagnosed (8) However, co-morbid
in-fections and severe host immune de¢ciency after HSCT
may act as major barriers to treatment despite appropriate
medication In summary, we present 2 children diagnosed
with TB after allogeneic HSCT, in whom the timing of TB
infection, as well as ¢nal outcome of treatment, were
di¡er-ent Further studies are necessary to con¢rm the poor
prognosis of TB diagnosed early after HSCT
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... response to anti-TB treatmentIn this study, we report on children who showed a di¡er-ing clinical course after treatment for pulmonary TB diag-nosed after allogeneic HSCT for acute lymphoblastic... Pulmonary tuberculosis in allogeneic hematopoietic stem cell transplantation Bone Marrow Transplant 2001; 27: 1293^1297.
4 Lee J, Lee MH, Kim WS, et al Tuberculosis in hematopoietic. .. immediate post -transplantation period was
un-eventful except for cytomegalovirus (CMV) DNAemia that
was treated preemptively with ganciclovir
Two months after transplantation