Original Article

Ind. J. Tub. 2001,48, 147

PROLONGED FEVER OCCURRING DURING TREATMENT OF
PULMONARY TUBERCULOSIS - AN INVESTIGATION OF 40 CASES
Deepak Rosha*
(Received on 22.8.2000; Accepted on 6.2.2001)
Summary : A study that investigated the causes of prolonged fever or onset of fever during anti-tuberculosis treatment
(ATT) in sputum smear positive, HIV negative patients admitted in a TB sanatorium is reported. A total of 40 patients
were studied. All were males with ages ranging between 22 and 55 years (mean 43 years). There were 28(70%) patients who
had evidence of extra-pulmonary disease. It was found that fever occurred because of direct complications of tuberculosis
in 22.5%, tuberculous cold abscess in 12.5%, drug resistance in 10% and drug reaction in 22.5%. Other diseases were the
cause of fever in 32.5%. These included superaddcd lung infection, malaria, filariasis and amoebic liver abscess.
Key Words : Pulmonary Tuberculosis, Prolonged Fever, Treatment
INTRODUCTION
Fever occurs in 60-85% of patients afflicted
with tuberculosis. As a rule, every case of active
pulmonary tuberculosis may exhibit some degree of
pyrexia because it is one of the important signs of
disease activity
2
. Fever usually resolves by the
second week of starting chemotherapy
3
. Modern day
chemotherapy can achieve cure in virtually all
compliant patients
4
. However, there are patients who
remain febrile beyond a reasonable period of time or
develop fever during treatment. Such cases raise
issues such as quality of diagnosis, development of
drug resistance or associated cryptic disease
5
. This
study has been carried out to investigate the causes
of fever in such patients.
MATERIAL AND METHODS
The study was carried out in a tuberculosis
sanatorium where only male patients are admitted.
Only fresh sputum positive cases were eligible for
entry into the study, if they remained febrile for more
than 2 weeks after starting chemotherapy or if they
developed fever for 7 days while on treatment. Fever
was defined as mouth temperature >100 degrees
Fahrenheit at least once in 24 hours. The study
commenced on 1 December 1999 and ended on 30
September 2000. All patients were given standard
chemotherapy (2SHRZ/2EHRZ + 4HR), modified as
recommended
6
(for patients above 40 years of age
Ethambutol containing regimen, for those below 40
ears the Streptomycin regimen). All dosages were y

standardised for weight, as recommended
7
. Once
inducted into the study, the patients were examined
at least 3 times a week for development of any fresh
clinical finds, recorded weekly. Clinical examination
included palpation of liver, spleen, all sites of lymph
nodes, caecal area, spine, and fundoscopy. A high
calorie diet was provided (50 Kcal/kg) along with
high proteins (2g/kg) and vitamin supplements to all.
Sputum smears were examined once a week, serial
review of chest X-rays (CXR) and laboratory tests
as indicated in Table 1 carried out.
All the patients were classified according to
radiological extent of disease , evidence of extra-
pulmonary involvement and presence of toxemia as
follows:
1. Radiological extent:
a) Focal disease, minimal, where less than one
zone involved with non-cavitary disease on
CXR or severe if cavitation present.
b) Moderate disease, where more than one but
.less than 3 zones involved with non-cavitary
disease.
c) Extensive disease, where cavitation involved
more than one zone or non-cavitary disease
involving more than three zones.
2. Disseminated disease:
Defined as showing clinical, sonological,
radiological and/or laboratory evidence of
*Classified Specialist (Medicine & Respiratory Medicine) Military Hospital, Namkum. Ranchi, Jharkhand
Correspondence : Dr. Deepak Rosha, A-1/167. Safdarjung Enclave. New Delhi 110029
The Indian Journal of Tuberculosis

148
DI-EPAK ROSHA

involvement of extra-pulmonary organs excluding
pleura.
3. Toxemia:
Defined as presence of : (a) less than 90% of
expected body weight (b) serum albumin <3.5g%
(c) serum sodium <130 meqL (d) t uber cul i n
test(ITU) <5mm (e) normocytic normochromic
anemia with haemoglobin <8.0g%.
Table 1: Protocol for investigation of fever during
treatment for pulmonary tuberculosis
1. Complete blood counts done weekly
2. Peripheral blood smears for toxic granulation, type
of anemia, haemoparasites, abrormal cells etc.
3. Bone marrow studies*
4. Blood culture
5. Urine for pyogenic and M.tuberculosis cultures
6. Sputum smear examination
7. Tuberculin test (1TU)
8. Serial review of Chest X-Rays
9. Ultrasound of chest wall and abdomen
10. Anti-nuclear antibodies examination*
11. Cerebrospinal fluid examination*
12. CT Scan of chest and/or abdomen*
13. Bronchoscopy, bronchoalveolar lavage, biopsy*
14. Eliminate drug suspected of causing reaction
15. Repeated detailed clinical examination
* where indicated
RESULTS
A total of 40 patients were studied; all were
males, sputum smear positive for acid fast bacilli,
and HIV negative. Their ages ranged from 22 to 55
years with mean age, 43 years. Four patients had
diabetes mellitus, 2 had cirrhosis of liver and one
had dilated cardiomyopathy. There were 14 smokers
and 3 known cases of alcohol abuse.
There were 22 pat i ent s who had
radiologically extensive disease, 20 of these had
disease di ssemi nat i on to ot her organs and 12
had additional toxemia (Table 2). In all, 28(70%)
patients had extra-pulmonary involvement with the
disease.
Table 2: Classification of pulmonary tuberculosis cases
havi ng prolonged fever accordi ng to
radiological extent and di ssemination of
disease
Radiological
Not diss- Diss- Toxemia Total
extent eminated eminated &
disse-
mination
Extensive 2 8 12 22
Moderate 5 4 0 9
Focal Severe 2 2 0 4
Focal Minimal 3 2 0 5
12 16 12 40
The causes of fever as determined are given
in Table 3.
Table 3 : Causes of fever in patients of pulmonary
tuberculosis undergoing chemotherapy
Cause Number %

Direct complication of tuberculosis 9 22.5
Dissemination with toxemia alone 4
Potts disease with abscess 2
Loculatcd empyema 2
Tuberculous arthritis of hip with 1
abscess
Cold abscess 5 12.5
Mediastinal 2
Retroperitoneal 2
Retropectoral 1
Drug resistance 4 10.0
Drug reaction 9 22.5
Other illnesses 13 32.5
Pyogenic lung infection 6
Malaria 3
Others 4
It was seen that 9 patients had fever due to
direct complications of tuberculosis, i ncl udi ng
asymptomatic Potts disease wi t h para-spi nal
abscess in 2 patients and loculated empyema found
by ultra-sonography of the chest in 2 patients. One
patient had a minimally symptomatic tuberculous
arthritis of hip with peri-articular abscess. Cold
abscesses were seen in 5 patients, 2 mediastinal
abscesses detected by CT scan, and 2 retro pectoral
abscess by ultra sound. Drug resistance was seen
in 4 cases and these had multi drug resistance.
The Indian Journal of Tuberculosis
PROLONGED FEVER DURING TREATMFNT OF PULMONARY TUBERCULOSIS
149
Fever due to drug hypersensitivity reaction
was seen in 9 cases; perhaps Strepromycin associated
in 7 cases but without rash or eosinophilia and
Isoniazid induced lupus in 2 cases. There were 13
patients who had fever due to associated illnesses.
Of these, 6 patients had super-added pyogenic lung
infection and 3 patients had malaria.
DISCUSSION
The febrile response of body is to combat
infecting microbes. The response is generated by
the release of cytokines, notably interleukin-1 alpha
and tumor necrosis factor which are released in large
amounts in mycobacterial infections. Although short
term fevers may be beneficial, prolonged fevers cause
depletion of muscle mass and essentml nutrients
8
leading to malnutrition that ultimately weakens the
immune system. Thus, it is necessary to correctly
identify the underlying cause of fever and treat it
effectively.
When a patient of pulmonary tuberculosis
cont i nues to have fever despi t e t r eat ment or
developed fever during treatment, one has to consider
drug resistance and add second line drugs, or think
of hypersensitivity reaction producing fever and add
glucocorticoids. This study shows that both options
may be inappropriate since only 10% fevers were
due to dr ug resistance and 12.5% due to
hypersensitivity reaction (from cold abscess). The
more common cause of the fevers was concomitant
diseases (32.5%), of whi ch superadded l ung
infection formed the major part(15%). In such
situations, reliance has to be placed on sputum as
well as blood count studies. Search has to be made
for other causes diligently. Drug reaction was the
cause of fever in 22.5% of the cases as reported by
others
9
. In two patients (5%), Isoniazid induced
lupus was the cause of fever. These patients had
severe anaemia, hepatosplenomegaly and worsening
shadows on chest X-ray. Both the patients were
sputum negative, at this stage, and strongly positive
for anti-nuclear antibodies. There was marked
improvement after withdrawal of Isoniazid. This
phenomenon should be borne in mind as it might be
confused with drug resistance
10
.
There were 9(22.5%) fever cases due to
direct complications of tuberculosis. In 4 cases no
cause other than toxemia of tuberculosis could be
found and the fever resolved gradually. But in others,
a diligent search succeeded in locating the real cause.
This study shows that fevers developing
or persisting in patients undergoing treatment
for pulmonary tuberculosis require careful,
repeated clinical examination and detailed
investigations and should not be attributed to
tuberculosis alone, or the emergence of drug
resistance. Locally prevalent associated diseases
should be ruled out at first. Liberal use of
ultrasound should be made to detect pus
collections in the pleura, chest wall,
mediastinum, and retroperitoneal areas.
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