Two childrenwith di¡ering outcomes after treatment for pulmonary tuberculosis diagnosed after allogeneic hematopoietic stemcell transplantation ppt

Case report
Two children with di¡ering outcomes after treatment
for pulmonary tuberculosis diagnosed after
allogeneic hematopoietic stem cell transplantation
J.W. Lee
1
, H J. Kwon
2
, P S. Jang
1
,
N G. Chung
1
, B. Cho
1
, D C. Jeong
1
,
J H. Kang
2
, H K. Kim
1
1
Division of Hematology and Oncology, Department of
Pediatrics,
2
Division 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.
Abstrac t: Tuberculosis (TB) is a rare infec tious complication af ter
hematopoietic stem cell transplantation (HSCT), but may be more
signi¢cant in areas where the disease is endemic. Here, we present the
clin i cal cours e o f 2 chi ld ren with ac u te lymph obl a stic leu kemi a w ho
were diagnosed with pulmonary TB after allogeneic HSCT. Both
patients were treated for either probabl e or possible invasive fungal
infection, as well as TB. One patient, diagnosed with TB 3 months af ter
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 1year of treatment with resolution of lung
lesions. C o-morbid opportunistic infec tions, profound host
immunosuppression early after transplantation, and p otential risk of
mult i-drug resistant-TB may act as major barriers to e¡ective treat ment
o f TB after HSCTdespite appropriate anti-TB medication.
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For recipients of allogeneic hematopoietic stem cell trans-
plantation (HS CT), Mycobacterium tuberculosi s may act as
a signi¢cant opportunistic pathogen in the early post-
transplantation period, especially in areas where tubercu-
los is (TB) i s en d emic .
Inc ide nc e and risk fac tor s for mycobacter i al infectio n
diagnosed in the post-HSCT period have been reviewed
previously in large cohort s of patients (1^ 6), with factors
such as matched unrelated and mismatched transplanta-
tions, treatment with total body irradiation, and graft-
versus-host d iseas e (GVHD) having a signi¢cant impact
on TB incidence. However, studies of TB diagnosed solely
in the pediatric HS CT p opulation are sc arce, and little is
known of prognostic factors after initi ation of anti-TB med-
ication . Most import a ntly, the severe immu nosup pressio n

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 pulmonaryTB diag-
nosed a fter allogen eic HSCT for acute lymphoblastic
leukem ia (A LL).
Case reports
Patient 1
The 17-year-old m al e patient had been diagnosed with Phil-
adelphia chro mosome-positive ALL a nd had received
matched unrelated bone marrow t ransplantation (BMT)
7 months af ter initial diagnosis. Myeloablative condition-
ing regimen consisted of total body irradiation, cytarabine,
cyclop hos ph a m ide (T BI-Ar a-Cy), and anti-thymoc y te
r 2011 John Wiley & Sons A/S
Transplant Infectious Disease . ISSN 1398-2273
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:
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
520

globulin (ATG). Neu trophil recovery was not delayed, with
ab s olute n e utrophi l c ou nt 40.5 Â 10
9
/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 cy tomegalovirus (CM V) DNAemia th at
was treated preemptively with ganciclovir.
Two months after t ransplantation he was readmitted for
fever and dyspn e a of 1 day’s dur ation. A che st co mputed to-
mography (CT) scan revealed nodular opacities consi stent
with fungal pneumonia, and broad-spectrum antibiotics
and intravenous amphotericin were started. Microbi ologi-
cal studies were negative, and fever persisted with pro-
gression of lung in¢ltrations despite changes to other
antifungal agents.
After a 6-day p eriod of defer vescence, fever started
again on d ay 32 of admission. Sputum study done at
this time stained positive for acid-fast bacilli (AFB) a nd
isoniazid, rifa mpin, pyrazinamide, and ethambutol were
started. A chest x-ray at this point showed signi ¢cant
aggr avation of in¢ltrations i n the left l ung ¢ eld (Fig. 1).
No tuberculous family or contact history was determ ined,
but sputum culture showed growth of M. tuberculosis.
Signs and symptoms of GVHD were not evident, and im-
munosup pressive medi cation 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 lymphocy tes. 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 med ications 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-dr ug reg-
imen. Sputum c ulture done 1 month after the initiation of
anti-TB medication showed the g rowth of yeast, and lipo-
so mal amphotericin was started. Throug hout the febrile
period, serial serum galactomannan (GM) assays were neg-
ative. Although follow-up sputum cultures for M. tuberculo-
sis were negative, fever and lung i n¢ltrations failed to abate
and the patient died of acute respiratory distress syndrome
(AR DS) 3 9 days af ter the start of anti-TB me dication, 136
days af ter t ransplantation. S ensitivity results repor ted
37 days afte r 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 remi ssion and
receive d granulocyte c olony-stimulating factor mobilized
peripheral blood stem cell (PBSC) transplantation from
her mother 4 months after initial diagnosis. Conditioning
regi m en i nclude d TBI-Ara-Cy and ATG. P rompt neut rophi l
engraftment occu rred, with absolute neutrophil count
40.5 Â 10
9
/L from day 11 of PB SC infusion. W|thin
day 1 10 0 of transplantation, the patient had bee n treated

for CMV DNAemia wi th gancicl ovir, and had been admit-
ted t wice for probable invasive f ungal infec tion (IFI),
according to standard criteria (7). Four months after trans-
plantation, the patient had been exposedto Patient1during
inpatient ca re but prophylactic isoniazid was withdrawn
after 1week because of persistently elevated liver enzymes
thatwerefoundconcurrentwithchronicskinandoral
GVH D.The patient was subsequently diagnosed with late-
o nset acute GVHD of skin, liver, and gastrointestinal tract
that showed resoluti on with steroids.
Eight months a fter transplantation, th e patient was re-
admitted for fever. Chest CT imaging indicated in¢ltrations
of the lef t upper lung ¢ eld and bronchoalveolar lavage (BAL)
studies proved to be pos itive for AFB. Immunosuppressive
medication administered at the time included oral cyclo spor-
ine, as well as beclomethasone for previously diagnosed gut
GVHD, with the latter stopped because of improved symp-
toms. The patient was started on isonia zid, 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 Phil adelphia 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-f ast bacilli positive, and a ch es t x-r ay at
the time showed left lung in¢ ltrations (arrows).
Lee et al:TB in children after allogeneic HSCT
Transplant Infectious Disease 2011: 13: 520^523 521
GM, 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 of M. tuberculosis cultured from BAL £uid proved
to be sensitive to both ison iazid and rifampin, as well as
other anti-TB medication admin istered. The sensitivity pro-
¢le, however, was di¡erent from that of theTB strain isolated
in Patient 1, with sensitivity to aminoglyco sides to which the
strain of Patie nt 1was resistant.
Five months after initiation of anti-TB medica-
tion, biopsy of a newly developed skin nodule showed
chronic gr anu lom atous i n£ ammatio n wit h central ca seous
necrosis, with positive results for M. tube rculosis PCR, and
rifampinwas reinstated instead of pyrazinamide and cyclo-
serine. The patient maintained this regimen for 5 months
before cess ation of anti-TB m edication 1 year af ter initia-
tion, with most recent imaging showing signi¢cant regres-
sion of pulmonar yTB.
Discussion
Inc idenc e of T B a f te r alloge n e ic HS C T is sig n i ¢cantly
high e r in re g ions whereTB is endemic, with re p o rte d rates
ranging fro m 1.7% to 3.0% (8, 9). However, studies on the
clin ic al cour s e of c hi ldre n diagnos e d with TB du r ing 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, commonto bothpatients, is
the presence of signi¢ca nt co-infections that may confound
accurate interpretation of patient response to anti-TB treat-
ment. Ou r patients were diagnosed with either probable or

possible IFI, and were administered antifungal agents con-
co mitant with the anti-TB re gimen. Continued fever, and
persistence or aggravation of pulmonar y in¢ltrates in both
children that led to modi¢cations to anti-TB treatment may
have been the result of unproven fungal infections. Radio-
log i c sign s more diag nost i c 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 in fection fromTB, but these were
not evident in our patients. Despite di⁄culties, diagnostic
tests including bronchoscopy should b e undertaken in
order to isolate the cause of clinical aggravation in the
post-HSCTsituation where multiple infections may coexi st.
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 t o be susceptible, Patient 1
experi enced a remittent fever course with productive
co ugh, combined with gradual aggravation of pneumonia
until death from AR D S. Th roughout this pe rio d, all othe r
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 cou rse. The patient had u nder-
gone 3 changes to the anti-TB regimen with consideration
of possible multi-drug resistant-TB (MDR-TB). Stu dies have
con¢rmed a12^13% incidence of M. tuberculosis st rain 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-TB diagnosed after allogeneic BMT has
also been reported (12). As results of TB drug sensitivit ies
are delayed considerably, anti-TB modi¢cation was deemed
necess a r y in our patient to counter p otential drug resistance
as a cause of clinical aggravation.
One major di¡erence between Patient 1 and Patient 2,
wh o showed resolution of TB, is that the former’s TB was
diagnosed much earlier, within day10 0 of transplantation.
One study reported 9 patients withTB resolution among 11
overall a fter BMT (1); 9 of these 11 patients had TB diag-
nosed within 100 days post transplantation. However,
2otherstudiesindicatethattimetodiagnosisafterHSCT
was much sho r te r a mong patients who di e d f rom TB, th an
Fig. 2
. Patient 2, with underlying acute lymphoblastic leukemia , was di-
agnosed withtuberculosis 8 months after mismatched familial peripheral
blood stem cel l transplantation. Fever restarted 2 weeks after initiation of
anti-tuberculous medication, concurrent with serial positive results for
seru m galactom annan, leadi n g to ampho teric in B admin i s tr ati o n . Fol-
low-up imaging of Patient 2 at this time point showed persistent left up-
per lobe consolidation (arrow).
Lee et al:TB in children after allogeneic HSCT
522
Transplant Infectious Disease 2011: 13: 520^523
among those who survived (2, 3). A rapidly p rogress ive, fa-
tal case of sepsis due to M. tuberculosis diagnosed within a
few months of HS CT has also be en describe d (13). W|th
regards to infectious complications, th e post-HSCT period
ha s been divided into the pre -engraftment per iod , and

intermediate ( day 100) and late (after day 100) recovery
periods, wi th 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 per iod renders TB slowly responsive or re-
fractory to appropriate anti-TB medi cation requires fur-
ther study. Such immune de¢ciency characterized by poor
lymphocyte fun ction 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 deter ioration.
One pediatric HSCT-based s tudy 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 appropri ate
medication. In summar y, we present 2 children diagnosed
withTB after allogeneic HS CT, in whom the timing of TB
infection, as well as ¢nal ou tc ome of treatment, were di¡er-
ent. Fu rthe r studies are necess ary to con¢rm the poor
prognosis of TB di agnosed early after HSCT.
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Transplant Infectious Disease 2011: 13: 520^523 523