1. Original Article
Epidemiological, Clinical, Laboratory Findings,
and Outcomes of Disseminated Tuberculosis in
Tehran, Iran
Mehrdad Hasibi, MD, Mehrnaz Rasoulinejad, MD, Seyed-Mahmoud Eshagh Hosseini, MD,
Parastoo Davari, MD, Azadeh Sahebian, MD, and Patricia Khashayar, MD
seeds on the lung; it may simultaneously involve multiple
Background: Disseminated tuberculosis (TB) accounts for 1 to 3% organs. This pattern is seen in 1 to 3% of all TB cases.1 TB
of all TB cases. This retrospective study reviews the clinical, radio- incidence has increased recently due to several factors, such
logical, laboratory findings and outcome in patients with dissemi- as the expansion of the human immunodeficiency virus (HIV)
nated tuberculosis in an endemic area. pandemic and the wide application of immunosuppressive
Methods: Medical records were reviewed for patients with dissem- drugs.2
inated TB admitted to two tertiary centers in Tehran, Iran between Disseminated TB may occur in several organs or through-
1999 and 2006. out the whole body, including the brain. Up to 25% of pa-
tients with disseminated TB may have meningeal involve-
Results: Fifty patients were found to have disseminated TB. A ment.3 Disseminated TB is associated with a high mortality
miliary pattern was documented in the chest x-ray of 34 patients. rate,4 and it may mimic many diseases.5 Therefore, a high
Hematologic abnormalities including anemia, leukopenia, and index of clinical suspicion is important for early diagnosis
thrombocytopenia were frequently observed. Death occurred in nine and further improvement of clinical outcomes. In this retro-
of the cases. The mortality rate was significantly higher in diabetic spective study, we reviewed the clinical, radiological, labo-
patients, injection drug users, and patients with hematologic abnor- ratory findings and outcomes in patients with disseminated
malities; however, steroid usage and human immunodeficiency virus TB in an endemic area.
infection were not significantly associated with a higher mortality
rate. Clinical improvement occurred in 41 patients following treat-
ment.
Materials and Methods
A review was done of the medical records of the patients
Conclusion: Disseminated TB could have different manifestations. admitted to Amir-Alam and Imam Hospitals between 1999
Hematologic abnormalities are common and are considered poor and 2006 with a TB diagnosis, in order to identify any evi-
prognostic signs in these patients. dence of disseminated TB. As all patients did not receive the
same workup, those with either of the following criteria were
Key Words: complication, disseminated tuberculosis, miliary tu-
included in the study: a miliary pattern on chest x-ray (CXR)
berculosis, mortality, outcome
with positive smear for acid-fast bacillus; or any presentation
indicating TB involvement in at least two nonadjacent or-
gans, confirmed by biopsy, smear or culture.6 Tuberculosis
D isseminated tuberculosis (TB) is caused by the hema-
togenous spread of Mycobacterium tuberculosis. Previ-
ously, this disease has been referred to as miliary tuberculosis
patients with sole organ involvement were excluded from the
study. Epidemiological, clinical, laboratory, and radiological
because the bacilli, at approximately 2 mm look like millet
Key Points
From the Amir-Alam Hospital, Medical Sciences/University of Tehran, • Different manifestations of disseminated tuberculosis
Tehran, Iran; and Imam Khomeini Hospital, Medical Sciences/University
of Tehran, Tehran, Iran. make diagnosis difficult.
Reprint requests to Patricia Khashayar, MD, Sina Hospital, Iman Khomeini • Mortality was significantly related to hematologic ab-
St., Tehran, Iran. Email: patricia.kh@gmail.com normalities.
Accepted December 18, 2007. • No correlation was found between mortality and ste-
Copyright © 2008 by The Southern Medical Association roid usage and human immunodeficiency virus.
0038-4348/0 2000/10100-0910
910 © 2008 Southern Medical Association

2. Original Article
findings and details of followup were obtained from the med- Table 1. The frequency of involved organs in our
ical records. Anemia was defined as a hemoglobin level lower study
than 13 g/dL in men and lower than 12 g/dL in women;
thrombocytopenia was defined as a platelet level lower than Involved organ Frequency (%)
150,000/ L; and leukopenia was considered to be a leuko-
Lung
cyte count lower than 4000/ L.
Miliary pattern 34 (68)
It should be noted that, similar to pulmonary TB, four-
Other pattern 7 (14)
drug regimens (consisting of isoniazid, rifampin, pyrazin-
Bone and joint
amide and ethambutol) had been applied in all the patients
Vertebral column 3 (6)
enrolled in this study. Pyrazinamide and ethambutol were
Wrist 3 (6)
discontinued after two months; isoniazid and rifampin were
Shoulder 2 (4)
used for the maximum period of 12 months, depending on
Sternoclavicular 1 (2)
the patient and on the physician’s decision. Corticosteroids
Elbow 1 (2)
were prescribed in patients with disseminated TB with
Knee 1 (2)
pericardial or meningeal involvement, as well as in those
Sacroiliac 1 (2)
with marked constitutional symptoms. The databases were
Rib 1 (2)
analyzed by SPSS® v.13 (SPSS Inc., Chicago, IL). The chi-
Ankle 1 (2)
square test was used for the categorical variables, and the
Reticuloendothelial system
Mann-Whitney U test was used for the contentious ones.
Lymph node 8 (16)
Spleen 6 (12)
Bone marrow 5 (10)
Results
Liver 3 (6)
Fifty patients were found to have disseminated TB dur-
Serosal membranes
ing the study period. Nineteen (38%) patients were female
Peritoneum 5 (10)
and thirty-one (62%) were male, with a mean age of 39 17
Pleura 3 (6)
years (range: 9 to 87 years). Thirty-nine patients (78%) were
Pericardium 2 (4)
Iranian, and the others were from Afghanistan. None of the
Skin (cutaneous abscess) 3 (6)
patients had a previous history of TB, while six had a positive
Meninges 2 (4)
family history for TB. Twenty-seven patients (54%) had a
Muscle 2 (4)
history of predisposing factors including diabetes mellitus,
Paravertebral 1 (2)
intravenous drug abuse, long-term corticosteroid therapy, and
Psoas 1 (2)
HIV infection.
Intestine (ileocecal area) 1 (2)
The mean duration of symptoms before presentation was
Epiglottis 1 (2)
3.1 months, and the mean time from hospitalization to diag-
Kidney 1 (2)
nosis was reported to be 7 days. Fever, fatigue and malaise,
loss of appetite, and weight loss were reported in all of the
patients. The involved organs are shown in Table 1. Hema-
tologic abnormalities including anemia, leukopenia, and years; six (66.7%) were male; seven (77.8%) were Iranian;
thrombocytopenia were frequent in our cases. Leukopenia and five (54%) had underlying predisposing factors. The com-
and thrombocytopenia were both reported in 13 (26%) of the parison of gender, nationality, predisposing factors, and he-
patients. Mean hemoglobin, white blood cell and platelet lev- matologic abnormality between living and deceased patients
els in our patients were 9.2 g/dL, 3100/ L, and 65,000/ L, is shown in Table 2. The mortality rate was significantly
respectively. associated with the presence of pancytopenia (P 0.001),
A typical miliary pattern was observed on the CXR of 34 diabetes mellitus (P 0.03), and idoxuridine (IDU)(P
patients (68%). Nine patients had a normal CXR. Paraverte- 0.04); however, steroid use and HIV were not significantly
bral abscess with involvement of the rib, elbow, and thoracic associated with a greater mortality rate (P 0.05). Logis-
vertebrae were observed in one case. One patient suffered tic regression revealed diabetes mellitus as a confounding
from several abscesses in the psoas, paravertebral, thigh, and factor, pancytopenia as a protective factor (P 0.001; OR:
ankle region. Unilateral pleural effusion and pericardial ef- 0.03), and IDU as a predictive factor (P 0.04; odds ratio
fusion were simultaneously reported in one patient. Medias- [OR]: 4.66).
tinal adenopathy was seen in two patients. One had a pattern Meningitis was the cause of death in one patient; other
of diffuse bronchopneumonia on CXR. deaths were reported to be secondary to disseminated intra-
Of the nine patients who died, six (67%) had a typical vascular coagulation (DIC), acute respiratory distress syn-
miliary pattern on CXR; three (33.3%) were between 60 to 69 drome (ARDS) and massive hemoptysis. Clinical improve-
Southern Medical Journal • Volume 101, Number 9, September 2008 911

3. Hasibi et al • Disseminated Tuberculosis in Iran
Table 2. The comparison of different characteristics between living and deceased patients
Characteristics Deceased patients Living patients P value OR (95% CI)
Male:female 6:3 25:16 0.75 0.78 (0.71–3.57)
Nationality (Iranian:Afghanian) 7:2 32:9 0.98 0.98 (0.17–5.59)
Diabetes mellitus (%) 3 (33.3) 3 (7.3) 0.03 6.33 (1.02–38.98)
Corticosteroid usage (%) 0 (0) 3 (7.3) 0.40 1.07 (0.99–1.17)
Injection drug user (%) 4 (44.4) 6 (14.6) 0.04 4.66 (0.96–22.52)
HIV infection (%) 2 (22.2) 6 (14.6) 0.57 1.66 (0.27–10.02)
Anemia (%) 8 (88.9) 12 (29.3) 0.001 19.33 (2.17–171.89)
Leukopenia (%) 6 (66.7) 7 (17.1) 0.002 9.74 (1.95–48.45)
Thrombocytopenia (%) 6 (66.7) 7 (17.1) 0.002 9.74 (1.95–48.45)
Pancytopenia (%) 6 (66.7) 3 (7.3) 0.001 0.03 (0.00–0.24)
Miliary pattern (%) 6 (66.7) 28 (68.3) 0.014 0.161 (0.34–0.77)
HIV, human immunodeficiency virus; OR, odds ratio; CI, confidence interval.
ment (disappearance of fever, recovery of appetite, and sense ranging from 80 –100%. Kidney (60%) and bone marrow
of well being) occurred in 41 patients following the treat- (roughly 25 to 75%) were the next most consistently involved
ment. However, hepatotoxicity occurred in 4 patients, and all organs.15
of their symptoms and signs subsided after proper manage- Hematologic abnormalities in disseminated TB are well
ment. recognized. Anemia, leukopenia and thrombocytopenia are
common; however, pancytopenia is quite rare. Pancytopenia,
Discussion leukopenia and thrombocytopenia are considered poor prog-
The worldwide incidence of TB has increased recently nostic signs in disseminated tuberculosis.4,16 Our findings
after the decreasing trend observed during the years 1985 and confirmed the relation between these findings and increasing
1992. Many studies have reported this increase to be parallel mortality rate.
to the HIV epidemic.7 Moreover, since the advent of HIV Predisposing conditions such as long-term steroid usage,
infection, the pattern of TB has been changed, and extrapul- diabetes mellitus, neoplasm, chronic renal failure, pregnancy,
monary involvement has become more common.1 In the and alcohol consumption were present in 30 – 66% of the
present study, disseminated TB was more prevalent among cases in previous reports.10,11 In the present study, more than
the 60 – 69 year age group. A study conducted in Saudi Ara- half of the cases had a predisposing factor, neither of which
bia reported that 68% of their patients were over 60 years of was related to mortality. Similarly, Mert et al5 found no sig-
age. The underlying reason may be because this age group nificant relation between mortality and any of the predispos-
did not receive the bacille Calmette-Guerin (BCG) vaccine,
´ ing factors of their study.
so they were prone to contract disseminated TB.8 Chest x-ray has a high sensitivity in the early diagnosis
Disseminated TB is increasingly recognized as an im- of disseminated TB. In our study, 34 patients had a typical
portant cause of morbidity and mortality in developing coun- miliary pattern on their CXR; such a finding has been docu-
tries, especially among HIV-positive patients.9,10 However, mented in 40 to 100% of the patients with disseminated TB
only 16% of our patients were HIV positive. The clinical in other reports. Kwong et al observed the evidence of dis-
manifestations and laboratory findings of disseminated TB seminated disease in the CXR of 59 to 69% of their patients.
may be insidious and nonspecific. Syndromes ranging from a Normal CXR can be seen in a considerable number of dis-
fever of unknown origin to ARDS may be associated with seminated tuberculosis patients, especially in those with HIV
this disease.11 Major presenting symptoms and physical find- infection.17,18 Al Jahdali et al8 reported that 89% of their
ings in the present study were similar to those mentioned in cases had a miliary pattern.
other studies. Early reports noted choroidal tuberculoma in up In the previous studies, pneumothorax, small bowel per-
to 28% of the patients infected with disseminated TB12; how- foration and ARDS were the most common complications
ever, recent series report this finding as far less frequent (with reported during the treatment course.19,20 In the present study,
less than 2% of infected persons).4,13–15 We observed this hepatotoxicity was observed in four patients during the treat-
pathognomonic finding in only one of our patients. Following ment course. According to previous studies, the mortality rate
lungs, bones and joints were the second most frequently in- was related to age ( 40 years), delay in starting treatment
volved organs; other reports have indicated the most com- and the presence of meningitis.3,21 Mert et al5 have reported
monly involved organs to be the lungs, liver, and spleen, all mortality to be significantly related to the male sex, atypical
912 © 2008 Southern Medical Association

4. Original Article
miliary pattern, altered mental status and failure to treat TB. 6. Raviglione MC, O’Brien RT. Tuberculosis, in Kasper DL, Braunwald E,
However, in our study, we failed to find any relation between Fauci AS, et al (eds): Harrison’s Principles of Internal Medicine. New
York, McGraw Hill Companies, 2005, ed 16, pp 953–966.
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7. Maher D, Raviglione MC. The global epidemic of tuberculosis: a World
topenia were the sole factors significantly correlated with Health Organization perspective, in Sclossberg D (ed): Tuberculosis and
mortality rate in our study. Different mortality rates have Nontunberculosis Mycobacterial Infections. Philadelphia, WB, Saunders
been reported in different studies, ranging from 10 to 64%.4,21 Co, 1999, ed 4, pp 104 –115.
In Mert et al’s study, the mortality rate was similar to ours. In 8. Al Jahdali H, Al Zahrani K, Amene P, et al. Clinical aspects of miliary
our study, four patients died because of the discontinuation of tuberculosis in Saudi adults. Int J Tuberc Lung Dis 2000;4:252–255.
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community hospitals. Clin Infect Dis 1992;15:968 –973.
As disseminated tuberculosis may present with various
manifestations, it should always be kept in mind, especially in 12. Illingsworth RS, Wright T. Tubercles of the choroids. BMJ 1948;2:365–
368.
the presence of hematological derangements.
13. Milea D, Fardeau C, Lumbroso L, et al. Indocyanine green angiography
in choroidal tuberculomas. Br J Ophthalmol 1999;83:753.
Acknowledgment 14. Helm C, Holland GN. Ocular tuberculosis. Serv Ophthalmol 1993;38:
We are indebted to the Research and Development Cen- 229 –256.
ter of Amir-Alam Hospital for their support. 15. Iseman MD. A Clinician’s Guide to Tuberculosis. Philadelphia, Lippin-
cott Williams & Wilkins, 2000.
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“Everybody gets so much information all day long that
they lose their common sense.”
—Gertrude Stein
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