WEB APPENDIX
Cancer association with the emergence of tuberculosis
In table 1, we have included 16 representative case reports highlighting the
development of tuberculous (TB) infection after the detection of a malignant
tumor.1-15 Nine of the 14 studies referred to hematological malignancies
such as acute lymphoblastic leukemia,1, 2, 4, 5, 8, 9, 12, 15 4 of which were treated
with allogeneic bone marrow transplantation (BMT),2, 5, 8 and the remaining
5 with chemotherapy.1, 4, 9, 12, 15 Three case reports showed TB infection after
the detection of carcinoma in the gastrointestinal tract (stomach, colon),7, 11,
14
and another 3 studies referred to carcinomas of the neck.3, 6, 13 Possible
mechanisms facilitating the emergence of mycobacterial infection were the
host’s immunosuppression and the irradiation at the infection site. Both of
them may synergistically create the proper microenvironment for
reactivation of a latent mycobacterial infection or acquisition and
establishment of a new (primary) infection.
In table 2, we present 9 cohort or case-controlled studies,16-24 8
retrospective,16-18, 20-24 and 1 prospective,19 which evaluated the frequency of
TB infections in patients with malignancies or allogeneic BMT recipients.
Two of the retrospective studies were designed as case-controlled studies.20,
21
In all studies, malignancies or BMT acted as risk factors for reactivation
of latent TB or acquisition of primary TB infection. Four studies evaluated
the incidence of tuberculosis in BMT recipients which ranged between 0.491.4%.16, 17, 22, 23 No particular site of tuberculous infection was related with
the type of malignancy. In one study, chronic lymphoblastic leukemia,
malnutrition and use of a chemotherapeutic agent (fludarabine) were found
to be independent factors for the occurrence of TB in the multivariate
analysis.24
Table 1. Case reports referring to the emergence of tuberculosis on a background of malignancy
First Author,
Year of
Country of
Age, Sex
Malignancy background
origin
Type/Site of
TB
Therapy of
Possible mechanism of
TB
documentation
malignant tumors
TB development
Intracranial
Stereotactic brain
Chemotherapy
Opportunistic infection in
tuberculomas
biopsy
Postoperative
Histopathology of
Right
Immunosupression -
sinus
resected sinus tract
hemicolectomy
reactivation
publication
Ahn,
Korea
54, M
Acute myeloid leukemia
2007 1
Gopal,
India
50, M
Right colon adenocarcinoma
2007 7
epidemic country
Derangement of host’s
intestinal mucosal barrier secondary infection
Nishiike,
Japan
74, M
Laryngeal carcinoma
Larynx
Biopsy
Radiotherapy
2006 13
Takashima,
Immunosupression, radiation
- reactivation
Japan
64, M
2005 14
GIST with liver metastatic
Pulmonary
Sputum culture
disease
Transhepatic artery
Immunosuppression
embolization
Imatinib mesylate
Chan,
China
67, M
2004 3
Zheng,
2003 15
Undifferentiated carcinoma of Nasopharynx
Biopsy
Radiotherapy
nasopharynx
China
52, M
APL
Reactivation due to
irradiation
Liver and brain
Liver biopsy under
abscesses
U/S guidance
Chemotherapy
Immunosuppression
(Opportunistic or
reactivation)
Kindler,
Russia
34, M
Pre-B ALL
2001 8
Menon,
Malaysia
6, M
Acute myeloid leukemia
Pulmonary
Allogeneic BMT
Immunosuppression,
Multi-organ
GVHD prophylaxis
positive family history,
failure
GVHD treatment
endemic TB
Chemotherapy
Opportunistic primary
Disseminated
BAL culture
Endotracheal tube
secretions’ culture
2001 12
infection from sputumpositive father
Aljurf,
Saudi
40, F / 38,
1999 2
Arabia
M
AML
Paravertebral
Culture of needle
Allogeneic BMT
abscess /
aspirate
GVHD prophylaxis
meningitis
Aljurf,
Saudi
34, F / 31,
1999 2
Arabia
M
Chen,
Taiwan
10, M
CML
ALL
Pulmonary
Pulmonary
Immunosuppression
GVHD treatment
Sputum and BAL
Allogeneic BMT
culture
GVHD prophylaxis
Lung biopsy
GVHD treatment
Open lung biopsy
Allogeneic BMT
1999 5
Immunosuppression
Immunosuppression
GVHD prophylaxis
GVHD treatment
Chua,
Singapore
NR
Nasopharyngeal carcinoma
Nasopharynx
1998 6
Chan,
Posterior nasal
Radiotherapy
Radiation
Chemotherapy
Immunosuppression -
space biopsy
USA
15, F
ALL
Pulmonary
BAL culture
1997 4
Kornreich,
reactivation
Israel
15, F
ALL
Pulmonary
Open lung biopsy
Chemotherapy
Immunosuppression -
1995 9
Kutteh,
primary infection
USA
62, F
1992 10
Markman,
1985 11
Vaginal squamous cell
Vaginal
Biopsy
Radiotherapy
Radiation
Peritonitis
Cultures of
Subtotal
Immunosuppression
transbronchial
gastrectomy
Malnutrition
biopsy
Chemotherapy
carcinoma
Japan
32, F
Gastric adenocarcinoma and
peritoneal carcinomatosis
Abbreviations: ALL: acute lymphoblastic leukemia, AML: acute myelogenous leukemia, APL: acute promyelocytic leukemia, BAL: bronchoalveolar
lavage, BMT: bone marrow transplantation, CML: chronic myelogenous leukemia, F: female, GIST: gastrointestinal stromal tumor, GVHD: graft-versushost disease, LN: lymph node, M: male, NP: nasopharynx, NR: not reported, TB: tuberculosis
Table 2. Studies referring to the emergence of tuberculosis after the diagnosis of a malignant tumor
First author,
Country of
Year of
origin
Study type
Study population
Retrospective
Case-control
Study aim
Outcome measures
Results
1,809 cancer patients Solid organ
Newly developed TB (%)
11 (0.6) vs 5 (0.03)
1,809 controls
Old healed TB (CXR) (%)
10 (90.9) vs 5 (100)
publication
Kim,
2008 21
Korea
malignancy as a
risk factor for TB Incidence (IRR)
Pulmonary TB (%)
4.69 (1.52-14.46) (adjusted)
9 (81.8) vs 4 (80.0)
Risk factors for active TB development
(IRR)
4.35 (1.27-14.89)
Ex- or current smokers
Chronic renal failure
Multivariate analysis
Old healed TB on CXR
Multivariate analysis
Chemotherapy
19.72 (2.47-157.38)
9.91 (1.17-83.60)
49.08 (6.28-383.44)
45.05 (5.74-353.88)
3.45 (0.91-13.06)
4.32 (1.10-16.89)
Multivariate analysis
Old healed TB on CXR (-)
Anticancer chemotherapy (+)
3.39 (0.89-12.98)
Old healed TB on CXR (+)
Al-Anazi,
2007
16
Saudi
Arabia
Retrospective
Chemotherapy (+)
168.36 (14.48-1957.79)
477 patients with
Infections caused
Mycobacterial infections (%)
18/477 (3.8)
hematological
by TB in patients
AML, CML, MDS, AA, HCL, essential
4/128 (3.1), 3/51 (5.9),
disorders
with
thrombocythemia, polycythemia rubra
3/41(7.3), 1/25 (4), 1/10 (10),
hematological
vera, multiple myeloma, Hodgkin's
1/12 (8.3),
disorders and in
lymphoma, thrombocytopenic purpura
1/13 (7.7), 1/14 (7.1), 1/16 (6.3),
recipients of
(%)
1/36 (2.8)
BMT
TB diagnosis (%)
Positive cultures: 10/18 (55.5)
Empirical basis: 8/18 (44.5)
Anti-TB treatment (%)
Success/compliant (%)
16/18 (88.9)
15/16 (93.8), 13/16 (81.3)
Cytotoxic chemotherapy (IV and oral)
11/18 (61.1)
(%)
5/18 (27.8)
Steroid therapy (%)
3/18 (16.7)
Radiotherapy (%)
3/18 (16.7)
Hematopoietic stem cell transplant (%)
3/18 (16.7)
Graft-versus-host disease (%)
2/18 (11.1)
Other illnesses causing reduced
immunity (%)
Kim,
2005 20
Korea
Retrospective
24 patients with TB
Case-control
Pulmonary TB (%)
21/24 (87.5) vs 38/48 (79.2)
during chemotherapy characteristics of
Extrapulmonary TB (%)
p=0.63
or < 1 month after
TB in patients
Diagnosis bacteriological
completion of
with malignancy
Diagnosis clinical
17/24 (70.8) vs 41/48 (85.4)
Healed scars suggesting old TB
p=0.21
chemotherapy
Clinical
48 patients with TB
Healed scars
but without
TB in same lobe as a
3/24 (12.5) vs 10/48 (20.8)
7/24 (29.2) vs 7/48 (14.6)
malignancy serving
healed scar
16/24 (66.7) vs 21/48 (43.8)
as controls
Radiographic severity
p=0.07
Cavitary lesion
14/16 (87.5) vs 17/21 (81)
Lesions involving > 2
p=0.68
lobes
6/21 (28.6) vs 5/38 (13.6)
p=0.28
9/21 (42.9) vs 13/38 (34.2)
p=0.51
Silva,
2005 24
Brazil
Retrospective
917 patients with
Risk factors for
hematologic
and attributable
Positive blood culture (%)
14/24 pts (58.3)
malignancies
mortality from
Positive sputum culture (%)
4/24 pts (16.7)
2 risk groups
TB in patients
Clinical and radiological findings
6/24 pts (25)
with hematologic
TB diagnosis based on:
24/917 patients (2.6%)
(%)
malignances
(3.3), (1.1) OR 3.1 (0.9–10.4)
TB incidence (%) in high and low risk
p=0.06
patients
11 cases (3.5)
5 cases (6.9)
NHL-TB (%)
4 cases (3), (1.8)
CLL-TB (%)
2 cases (2.2), (0.9)
HD (MDS and MM)-TB
(%)
95.8 vs 75.7 p=0.02
CML, AML-TB (%)
Clinical signs (with or without TB) %
95.8 vs 40.9 p<0.01 OR 14.72
66.7 vs 29.3 p<0.01 OR 2.51
Fever
50 vs 29.7 p=0.04
Cough
75 vs 24.3 p<0.01
Shortness of breath
41.7 vs 14.9 p<0.01
Weight loss of >10%
16.7 vs 4.7 p=0.03
Productive cough
1.8 vs 59.4 p=0.49 OR 0.49
Chest pain
Hemoptysis
Neutropenia
Risk factors for TB
CLL
OR 3.24 (1.03-9.59) p=0.03
Malnutrition
OR 38.78 (2.35-6.39) p=0.05
After multivariate
analysis
OR 55.66 (2.47-1254.82) p=0.01
OR 5.18 (1.92-14.0) p<0.01
Use of corticosteroids
After multivariate
analysis
OR 5.32 (1.15-24.39) p=0.03
OR 8.03 (1.66-38.8) p=0.04
OR 6.08 (1.22-30.25) p=0.03
Use of fludarabine
After multivariate
OR 3.73 (1.09-12.76) p=0.04
75 vs 12.5 p<0.01
analysis
62.5 OR 21.00 (3.84-134.72)
Risk classification
6.00 (2.03-17.70)
Mortality rate for TB %
Attributable mortality rate %
Risk ratio
Karnak,
Turkey
Prospective
2002 19
73 patients with
Reactivation of
Primary lung carcinoma (%)
66/73 (90.4)
malignancy
pulmonary TB in
Lymphoma (%)
5/73 (6.8)
undergoing
malignancy
Metastatic breast adenocarcinoma (%)
1/73 (1.4)
diagnostic fiberoptic
Acute myelocytic leukemia (%)
1/73 (1.4)
bronchoscopy
Findings compatible with TB on
31/73 (42.5)
radiology (%)
Negative in 73/73 (100)
Sputa and bronchial washing specimens
6/73 (8)
(%)
4/73 (5.4)
Positive blood culture (%)
Positive radiology for TB (%)
George,
India
Retrospective
2001 17
217 patients
Mycobacterial
Mycobacterial infections
3/217 (1.4)
undergoing
infections
Diagnosis of TB (Days post-BMT)
13, 81, 445, respectively
allogeneic BMT
following BMT
Site of infection
in India
Cervical spine, Lymph node, Lung,
1/3 (33.3) respectively
Spleen
2/3 (66.7) respectively
Liver, Bone marrow
Jagarlamudi
, 2000 18
Inia
Retrospective
91 patients with
Infections in
acute leukemia
acute leukemia
Mycobacterial species
3/3 (100) M. tuberculosis
Mortality
0/3 (0)
TB infection (%)
2/91 (2.2)
Roy,
USA
Retrospective
1997 23
2,241 BMT
Mycobacterial
Mycobacterial infections (%)
11/2,241 (0.49)
recipients
infections
Type of BMT with infection (%)
9/11 (81.8) allogeneic
following BMT
2/11 (18.2) autologous
Site of infection CV catheter tunnel
5/11
Bacteremia
4/11
Bone marrow
2/11
Pulmonary, pleural
1/11, respectively
effusion
Navari,
1983 22
USA
Retrospective
682 BMT recipients
Mycobacterial species
2/11 M. tuberculosis
Mortality (%)
2/11 (18.2)
Mycobacterial
Mycobacterial infections (%)
7/682 (1.03)
infections
Site of infection
4/7 lung
following BMT
2/7 skin
1/7 liver
Mycobacterial species (%)
2/7 (28.6) M. tuberculosis
Infection outcome (%)
6/7 (85.7) resolved
Mortality (%)
3/7 (42.9) (CMV pneumonia)
Abbreviations: AA: aplastic anemia, AML: acute myelogenous leukemia, BMT: bone marrow transplantation, CLL: chronic lymphoblastic leukemia, CML:
chronic myeloid leukemia, CMV: cytomegalovirus, CV: central vein, HCL: hairy cell leukemia, HD: Hodgkin’s disease, M.: mycobacterial, MDS:
myelodysplastic syndrome, MM: multiple myeloma, NHL: non-Hodgkin’s lymphoma, TB: tuberculosis
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