- Email: [email protected]
The course of fever during treatment of pulmonary tuberculosis
Tube&e (1987) 68, 0 Longman Group
255-260 UK Ltd. 1987
THE COURSE OF FEVER DURING TREATMENT OF PULMONARY TUBERCULOSIS Peter F. Barnes,* Departments
of Medicine
Linda S. Chan and Sandra F. Wong
and Pediatrics,
LAGUSC
Medical
Center,
Los Angeles,
California,
USA
Summary We studied 161 patients with pulmonary tuberculosis: 55 (34 %) were afebrile and 106 (66 %) were febrile at presentation. Febrile patients were younger and more symptomatic than afebrile individuals. Fever was also associated with a higher incidence of lymphopenia, hyponatraemia, hypoalbuminaemia and many acid-fast bacilli on sputum smear. Most patients were treated with isoniazid, rifampicin and pyrazinamide. Of 83 individuals who became afebrile while in hospital, 74 (89 %I did so within a week and 77 (93 %) in 2 weeks. Prolonged fever was associated with alcoholism, hyponatraemia and hypoalbuminaemia. A therapeutic trial of anaemia, antituberculosis drugs may be more useful than has been previously thought, since in most patients the temperature falls to normal within 2 weeks.
R&urn6 L’auteur a etudie 161 malades qui presentaient une tuberculose pulmonaire: 55 (34 %I etaient apyretiques et 106 (66 %I etaient febriles au moment de I’examen. Les malades febriles etaient plus jeunes et avaient davantage de symptomes que ceux apyretiques. La fievre etait associee egalement a une incidence elevee de lymphopenie, hyponatremie, hypoalbuminemie et a la presence d’un nombre important de bacilles alcool-acido-resistants dans les frottis d’expectoration. La plupart des malades ont ete trait& par isoniazide, rifampicine et pyrazinamide. Quatre-vingt trois (83) sujets sont devenue apyretiques pendant leur sejour a I’hbpital: 74 (89 %) pendant la premiere semaine et 77 (93 %I 8 la fin de la deuxieme semaine. La fievre prolongee etait associee a I’alcoolisme, I’amemie, I’hyponatremie et I’hypoalbuminemie. Un traitement d’epreuve avec des medicaments antituberculeux est peut-etre plus utile qu’on ne le pensait auparavant puisque chez la plupart des malades, la temperature devient alors normale dans les deux premieres semaines.
Resumen Estudiamos 161 pacientes con tuberculosis pulmonar: 55 (34 %I eran afebriles y 106 (66 %) febriles al primer examen. Los pacientes febriles eran m&s jovenes y m&s sintomaticos que 10s afebriles. La fiebre estaba asociada ademas a una incidencia elevada de linfopenia, hiponatremia, hipoalbuminemia y a un numero importante de bacilos acido-alcoholresistentes en 10s frotis de expectoration. La mayoria de 10s enfermos fueron tratados con isoniacida, rifampicina y pirazinamida. Ochenta y tres (83) sujetos se hicieron afebriles durante su estadia en *Correspondence to: Dr Peter F. Barnes, Room 7900, Department State Street, Los Angeles, CA 90033, USA.
of Medicine,
LAC-USC
Medical Center,
1200 North
256
Barnes
and others
el hospital: 74 (89 %I en la primera semana y 77 al final de la segunda semana. La fiebre prolongada estaba asociada a alcoholismo, anemia, hiponatremia e hipoalbuminemia. La prueba terapeutica con medicamentos antituberculosos puede ser mas util de lo que se pensaba previamente, puesto que en la mayoria de 10s pacientes la temperatura se normaliza dentro de las dos primeras semanas.
Introduction Fever is a common manifestation of pulmonary tuberculosis. However, few investigators have systematically evaluated the significance of fever and its duration after initiation of chemotherapy [I-61. In the most recent report, Kiblawi noted that in 36 % of patients the fever persisted for over 2 weeks after antituberculosis therapy was begun, usually with isoniazid (INH), ethambutol (EMB) and streptomycin (SM) [l]. Many tuberculous patients with persistent fever undergo extensive evaluation for bacterial superinfections, though none are usually found [I I. If one could identify the variables that predict a prolonged febrile course, unnecessary investigations could be avoided. We decided to evaluate the course of fever in hospitalised patients with pulmonary tuberculosis, and to determine if clinical and laboratory variables obtained on admission were predictive of its duration.
Methods Patient
population
The Los Angeles County-University of Southern California Medical Centre is a 1900-bed general hospital serving a predominantly indigent population. From June 1 1984 to March 27 1985, 192 consecutive hospitalised patients over the age of 15 years were found to have pulmonary tuberculosis, defined as the growth of Mycobacterium tuberculosis from sputum, bronchial washings or pulmonary tissue. Of 192 cases, 161 fit our inclusion criteria, which were: (i) hospitalisation prior to the initiation of antituberculosis therapy; (ii) availability of temperature recordings for at least 48 hours; (iii) absence of an extrapulmonary source of fever. Thirty-one patients were excluded: one patient and his chart could not be located, two had been treated before admission, nine were hospitalised for under 48 hours and 19 had extrapulmonary sources of fever (alcohol withdrawal, alcoholic hepatitis, cellulitis, perirectal abscess, bacteraemia, bacterial meningitis, empyema and Addison’s disease). Data collection One of us (PB) prospectively obtained a standardised history from all patients whose sputum smears revealed acid-fast bacilli (AFB), as well as individuals in whom tuberculosis was strongly suspected (149 patients). Twelve individuals with smear-negative disease were interviewed retrospectively. Historical data were obtained from the hospital chart or patient’s family when the patient could not provide a reliable history. Patients were questioned specifically about the following symptoms: fever, chills, night sweats, fatigue, cough, sputum production, haemoptysis, chest pain, shortness of breath and involuntary weight loss of over 5 lb. Individuals with any of these complaints were said to be symptomatic. Since most patients underestimate their own alcohol intake, we arbitrarily defined alcoholism as the achnowledged consumption of the equivalent of at least two cans of beer daily or 12 cans of beer per weekend up to the time of illness onset. In our experience, patients at our hospital who acknowledge this degree of alcohol intake usually have other stigmata of alcoholism, such as chronic liver disease.
Fever during
treatment
of tuberculosis
257
The admission chest X-ray was reviewed by a staff radiologist in standardised fashion. Each lung was divided into four zones. The area above the clavicle was considered the apex, and the remainder of the lung was divided into thirds. The total number of zones involved by alveolar infiltrate was noted and considered to be a rough measure of the radiographic extent of disease. The presence or absence of cavitation was also noted. Sputum smears for AFB were graded on a scale of 0 to 3+, 3+ signifying the presence of at least IO AFB in over 50 % of the oil immersion fields. Oral temperatures were recorded three times daily in afebrile patients, and every 4-6 hours when the temperature was over 37.8 “C (100.0 “F). Patients were considered afebrile if their temperatures remained under 37.8 “C prior to the institution of chemotherapy. After treatment was initiated, the temperature was said to have fallen to normal on the day the maximum temperature was below 37.8 “C, and remained so for a minimum of 48 hours. Statistical
analysis
The variables evaluated in the study were: 1. Age, sex, race, alcoholism, diabetes, presence of symptoms. 2. Anaemia, leucocytosis, percentage and absolute number of neutrophils, lymphocytes and monocytes. 3. Hyponatremia, hypoalbuminemia. 4. Cavitation, extent of alveolar infiltrate, 3+ sputum smear for AFB. 5. Concomitant extrapulmonary tuberculosis. 6. Death or respiratory failure requiring intubation. Each continuous variable was divided into groups that were clinically useful and provided an adequate number of cases in each group for analysis. The presence or absence of fever on admission was correlated with each of the variables previously mentioned, using the chisquare or Fisher’s exact test. All the variables noted were also correlated with duration of fever after therapy was begun, using the same statistical tests. Three additional variables evaluated were (iI initial temperature greater than 38.8 “C, (ii) mycobacterial resistance to INH or rifampin (RIF) and (iii) treatment regimens. In this analysis, patients were arbitrarily divided into those who were febrile for 7 days or less and those whose fever persisted for longer periods.
Results Fever
at presentation
Several variables were associated with the presence of fever (Table II. Febrile patients were more often symptomatic, lymphopenic, hyponatremic and hypoalbuminemic. They were also more likely to have many AFB on sputum smear. Fever was almost invariably present in hyponatremic individuals, occurring in 41 of 43 patients (95 %I. The mean age of afebrile patients was 44.3 years, compared to 38.1 years in febrile ones. (p=O.O2, Student’s t-test). Eight per cent of febrile individuals suffered death or respiratory failure, compared to 7 % of afebrile cases (p=O.64). Duration
of fever
with
therapy
Of the 106 patients who were febrile on admission, two became afebrile prior to the initiation of therapy. Thus, 104 febrile patients were treated with antituberculosis drugs. Twenty-one individuals were discharged while still febrile I-14 days (median 4) after treatment was begun. Of the remaining 83 cases, the cumulative percentage of patients who
258
Barnes
and
others
became afebrile at various times after initiation of therapy is shown in Table II: 89 % in 1 week or less, and 93 % within 2 weeks. The longest duration of fever was 87 days. In evaluating duration of fever, we found that 74 patients became afebrile within 7 days after the start of chemotherapy. Fourteen individuals took over 1 week to become Table
I.
Characteristics
of febrile
and
Characteristics
Male sex Symptoms Alcoholism Anaemia’ Lymphopenia’ Hyponatremia3 Hypoalbuminemia4 Cavitation 3+ AFB ‘Hgb 3<134
Table
Table
II.
III.
26 49 59 67 74 77 79 83
with
Alcoholism Temperature >38.8 Anaemia’ Lymphopenia’ Hyponatremia3 Hypoalbuminemia4 Cavitation
C
(%I
(%I
84 83 46 69 23 4 44 39 40
84 103/105 46/l 03 85/105 42/l 05 41/105 88 52/105 66
79 98 45 81 40 39 83 50 62
to normal
1 2 3 4 7 14 28 87
g/L
in
p value
females;
with
0.65 0.001 0.99 0.12 0.05 10.0001 10.0001 0.27 0.01 2<1000/cLl
treatment
number afebrile
llL;
in pulmonary
Cumulative percentage
31 59 71 81 89 93 95 100
prolonged Fever t7 (n= 74) Number
patients Febrile (n= 106) Number
~120
Cumulative of patients
Characteristic
‘d
46 45154 23/50 37/54 12/52 2154 24154 21154 22
Number of days after initiation of therapy
associated
Resistance or’RIF
Afebrile (n-551 Number
~140 g/L in males, meq/L; 4<39 g/L.
Rate of fall of temperature
Features
afebrile
fever.
days
p value
f%)
Fever >7 days in= 14) Number 1%)
23171 33 54173 26173 22173 54173 37
33 45 74 36 30 74 50
IO 10 14 7 9 14 10/13
71 71 100 50 64 100 77
0.006 0.007 0.002 0.31 0.02 0.002 0.07
6
8
1
7
0.69
to INH
See footnote
to Table
I.
tuberculosis.
Fever during
treatment
of tuberculosis
259
afebrile-nine became afebrile in the hospital, and five were febrile when discharged after more than a week of treatment. Sixteen patients were febrile at discharge, l-7 days after beginning therapy, and were excluded from analysis as their duration of fever was uncertain. Table III compares the clinical characteristics of patients with prolonged fever and those who became afebrile more rapidly. Alcoholism, anaemia, hypoalbuminemia and hyponatremia were markers of delayed defervescence. Among 33 alcoholics, 10 (30 %) took over 7 days to become afebrile, compared to only 8 % (4/52) of non-alcoholics. All patients with normal haemoglobin or albumin values became afebrile within a week. In contrast, 21 % (14/68) of those with anaemia or hypoalbuminemia had prolonged fevers. The most common treatment regimen was INH, rifampicin (RIF) and pyrazinamide (PZA) (62 cases). EMB was given as well in eight cases, SM in three and para-amino salicylic acid (PAS) in one. Six patients received INH, RIF and EMB, seven took INH and RIF, and one was given INH alone. We found no difference in duration of fever between patients receiving INH, RIF and PZA, with or without additional agents (74 cases), and those treated with all other combinations (14 cases).
Discussion Fever
at presentation
There is remarkably little data on the significance of fever in pulmonary tuberculosis and its duration with appropriate therapy. Our study is the first prospective evaluation of this problem in a large number of patients. In a retrospective investigation, Kiblawi noted fever to be associated with male sex and acute alcoholism [I], but we were unable to confirm this finding in our patients (Table I). There are no theoretical reasons to expect a difference between the febrile responses of the sexes to tuberculosis. Acute alcoholism in Kiblawi’s series may have been associated with fever because of concomitant alcohol withdrawal, which commonly causes temperature elevation. If most of their alcoholic patients were men, this would explain the association of fever with male sex that was observed. We excluded all patients with alcohol withdrawal from our population in order to eliminate this confounding effect. We conclude that male sex and alcoholism are not specially associated with fever in pulmonary tuberculosis. The mean age of our febrile patients was 38 years, compared to 44 years in afebrile individuals (p=O.O2). Older patients often do not mount a fever in response to bacterial infections. It is not surprising, therefore, that youth is associated with a febrile response in pulmonary tuberculosis. In Kiblawi’s series, febrile individuals were younger than afebrile ones, although the difference did not reach statistical significance. Kiblawi found febrile patients to be more often symptomatic, with a higher incidence of cavitation, and numerous AFB on sputum smear. Our findings were similar (Table I), though we noted no statistically significant correlation between cavitation and fever. Prior to 1950, several investigators found lymphopenia to indicate advanced tuberculosis [7-g]. Hyponatremia and anaemia have also been associated with extensive disease [IO, 1 I], and hypoalbuminemia is generally regarded as a sign of disease chronicity. Thus, compared to the afebrile group, febrile patients have clinical and laboratory markers of advanced tuberculosis. Duration
of fever
with
therapy
Tuberculosis may cause prolonged fever, even after appropriate therapy has been instituted [I, 2, 41. Berger treated 44 patients with INH and PAS, with or without SM, and found that 34 % took over 2 weeks to become afebrile. Kiblawi noted resolution of fever in only 64 % of 59 individuals after 2 weeks of therapy, most patients receiving INH, EMB and SM.
260
Barnes
and
others
Our results are strikingly different from those of previous reports. Eighty-nine per cent of our patients became afebrile within a week, and 93 % after 2 weeks of treatment. All but one patient received INH and RIF, most receiving PZA in addition. These three bactericidal drugs rapidly reduce the bacillary load. Regimens used in the past consisted of INH in combination with EMB, PAS or SM. EMB and PAS are bacteriostatic and do not eliminate mycobacteria as effectively as do RIF and PZA. Though SM is bactericidal, it is ineffective against intracellular organisms, unlike RIF and PZA 1131. Thus, the relatively rapid fall of temperature that we observed probably reflects the effectiveness of modern antituberculosis therapy. Since the diagnosis of tuberculosis is occasionally elusive, a therapeutic trial of specific chemotherapy is sometimes used to distinguish it from other diseases. Such a trial has been said to be of limited value because a third of patients with tuberculosis remain febrile for over 2 weeks [21. However, our data suggest that a therapeutic trial with present-day regimens is very likely to be helpful, since 93 % of tuberculous patients became afebrile within 2 weeks. Prolonged fevers after initiation of therapy have been associated with admission temperatures of over 38.8 “C, radiographically advanced disease and anaemia [I, 21. In our series, alcoholism, high initial temperatures, anaemia, hyponatremia and hypoalbuminemia were markers of delayed fall of temperature (Table Ill). Alcoholism is associated with multiple defects in host cell-mediated immunity [14], which is crucial in eliminating mycobacterial pathogens. It is thus not surprising that alcohol abusers have prolonged fever as a manifestation of their relatively slow response to antituberculosis therapy. As previously discussed, anaemia, hyponatremia and hypoalbuminemia may be clinical markers of extensive tuberculosis, in part accounting for the delayed fall in temperature noted among individuals with these characteristics. Thus, in cases of diagnostic uncertainty, a trial of antituberculosis chemotherapy is most helpful in non-alcoholic patients and in those with normal haemoglobin or serum albumin values. They almost invariably become afebrile within a week if tuberculosis is present. If fever is persistent, other diagnoses should be pursued. References 1 Kiblawi, S. S. 0.. Jay, S. J., Stonehill, R. B., Norton, J. (1981). Fever response of patients on therapy for pulmonary tuberculosis. American Review of Respiratory Disease, 123, 20. 2 Berger, H. W., Rosenbaum, I. (1968). Prolonged fever in patients treated for tuberculosis. American Review of Respiratory Disease, 97, 140. 3 Feingold, A. 0. (1975). Tuberculosis without fever. Southern Medical Journal, 69, 751. 4 Witkind, E., Willner, I. (1953). Clinical experience with isonicotinic acid hydrazide in tuberculosis. Diseases of the Chest, 23, 16. 5 Selikoff, I. J., Robitzek, E. l-i. (1952). Tuberculosis chemotherapy with hydrazine derivatives of isonicotinic acid. Diseases of the Chest, 21, 385. 6 Selikoff, I. J. (1956). The chemotherapy of tuberculosis. Journal of the Mount Sinai Hospital, 23, 331. 7 Muller, G. L. (1943). Clinical significance of the blood in tuberculosis, The Commonwealth Fund, New York. 8 Medlar, E. M. (1929). An evaluation of the leucocytic reaction in the blood as found in cases of tuberculosis. American Review of Tuberculosis, 20, 312. 9 Flinn, J. W. (1929). A study of the differential blood count in one thousand cases of active pulmonary tuberculosis. Annals of /n&%na/ Medicine, 2, 622. 10 Westwater. J. O., Stiven, D., Garry, R. C. (1939). A note on the serum sodium level in patients suffering from tuberculosis. Clinical Science, 4, 73. 11 Tani, P. (1970). Infectious anemia caused by pulmonary tuberculosis. Scandinavian Journal of Respiratory Disease, 72 (Suppl), 84. 12 Committee on Chemotherapy of Tuberculosis (1986). Standard therapy for tuberculosis 1985. Chest, 87 (SuppI). 117s. 13 Dutt, A. K., Stead, W. W. (1982). Present chemotherapy for tuberculosis. Journal oflnfectious Diseases, 146,698. 14 MacGregor, B. R. (1986). Alcohol and immune defense. Journal of the American Medical Association, 256, 1474.
255-260 UK Ltd. 1987
THE COURSE OF FEVER DURING TREATMENT OF PULMONARY TUBERCULOSIS Peter F. Barnes,* Departments
of Medicine
Linda S. Chan and Sandra F. Wong
and Pediatrics,
LAGUSC
Medical
Center,
Los Angeles,
California,
USA
Summary We studied 161 patients with pulmonary tuberculosis: 55 (34 %) were afebrile and 106 (66 %) were febrile at presentation. Febrile patients were younger and more symptomatic than afebrile individuals. Fever was also associated with a higher incidence of lymphopenia, hyponatraemia, hypoalbuminaemia and many acid-fast bacilli on sputum smear. Most patients were treated with isoniazid, rifampicin and pyrazinamide. Of 83 individuals who became afebrile while in hospital, 74 (89 %I did so within a week and 77 (93 %) in 2 weeks. Prolonged fever was associated with alcoholism, hyponatraemia and hypoalbuminaemia. A therapeutic trial of anaemia, antituberculosis drugs may be more useful than has been previously thought, since in most patients the temperature falls to normal within 2 weeks.
R&urn6 L’auteur a etudie 161 malades qui presentaient une tuberculose pulmonaire: 55 (34 %I etaient apyretiques et 106 (66 %I etaient febriles au moment de I’examen. Les malades febriles etaient plus jeunes et avaient davantage de symptomes que ceux apyretiques. La fievre etait associee egalement a une incidence elevee de lymphopenie, hyponatremie, hypoalbuminemie et a la presence d’un nombre important de bacilles alcool-acido-resistants dans les frottis d’expectoration. La plupart des malades ont ete trait& par isoniazide, rifampicine et pyrazinamide. Quatre-vingt trois (83) sujets sont devenue apyretiques pendant leur sejour a I’hbpital: 74 (89 %) pendant la premiere semaine et 77 (93 %I 8 la fin de la deuxieme semaine. La fievre prolongee etait associee a I’alcoolisme, I’amemie, I’hyponatremie et I’hypoalbuminemie. Un traitement d’epreuve avec des medicaments antituberculeux est peut-etre plus utile qu’on ne le pensait auparavant puisque chez la plupart des malades, la temperature devient alors normale dans les deux premieres semaines.
Resumen Estudiamos 161 pacientes con tuberculosis pulmonar: 55 (34 %I eran afebriles y 106 (66 %) febriles al primer examen. Los pacientes febriles eran m&s jovenes y m&s sintomaticos que 10s afebriles. La fiebre estaba asociada ademas a una incidencia elevada de linfopenia, hiponatremia, hipoalbuminemia y a un numero importante de bacilos acido-alcoholresistentes en 10s frotis de expectoration. La mayoria de 10s enfermos fueron tratados con isoniacida, rifampicina y pirazinamida. Ochenta y tres (83) sujetos se hicieron afebriles durante su estadia en *Correspondence to: Dr Peter F. Barnes, Room 7900, Department State Street, Los Angeles, CA 90033, USA.
of Medicine,
LAC-USC
Medical Center,
1200 North
256
Barnes
and others
el hospital: 74 (89 %I en la primera semana y 77 al final de la segunda semana. La fiebre prolongada estaba asociada a alcoholismo, anemia, hiponatremia e hipoalbuminemia. La prueba terapeutica con medicamentos antituberculosos puede ser mas util de lo que se pensaba previamente, puesto que en la mayoria de 10s pacientes la temperatura se normaliza dentro de las dos primeras semanas.
Introduction Fever is a common manifestation of pulmonary tuberculosis. However, few investigators have systematically evaluated the significance of fever and its duration after initiation of chemotherapy [I-61. In the most recent report, Kiblawi noted that in 36 % of patients the fever persisted for over 2 weeks after antituberculosis therapy was begun, usually with isoniazid (INH), ethambutol (EMB) and streptomycin (SM) [l]. Many tuberculous patients with persistent fever undergo extensive evaluation for bacterial superinfections, though none are usually found [I I. If one could identify the variables that predict a prolonged febrile course, unnecessary investigations could be avoided. We decided to evaluate the course of fever in hospitalised patients with pulmonary tuberculosis, and to determine if clinical and laboratory variables obtained on admission were predictive of its duration.
Methods Patient
population
The Los Angeles County-University of Southern California Medical Centre is a 1900-bed general hospital serving a predominantly indigent population. From June 1 1984 to March 27 1985, 192 consecutive hospitalised patients over the age of 15 years were found to have pulmonary tuberculosis, defined as the growth of Mycobacterium tuberculosis from sputum, bronchial washings or pulmonary tissue. Of 192 cases, 161 fit our inclusion criteria, which were: (i) hospitalisation prior to the initiation of antituberculosis therapy; (ii) availability of temperature recordings for at least 48 hours; (iii) absence of an extrapulmonary source of fever. Thirty-one patients were excluded: one patient and his chart could not be located, two had been treated before admission, nine were hospitalised for under 48 hours and 19 had extrapulmonary sources of fever (alcohol withdrawal, alcoholic hepatitis, cellulitis, perirectal abscess, bacteraemia, bacterial meningitis, empyema and Addison’s disease). Data collection One of us (PB) prospectively obtained a standardised history from all patients whose sputum smears revealed acid-fast bacilli (AFB), as well as individuals in whom tuberculosis was strongly suspected (149 patients). Twelve individuals with smear-negative disease were interviewed retrospectively. Historical data were obtained from the hospital chart or patient’s family when the patient could not provide a reliable history. Patients were questioned specifically about the following symptoms: fever, chills, night sweats, fatigue, cough, sputum production, haemoptysis, chest pain, shortness of breath and involuntary weight loss of over 5 lb. Individuals with any of these complaints were said to be symptomatic. Since most patients underestimate their own alcohol intake, we arbitrarily defined alcoholism as the achnowledged consumption of the equivalent of at least two cans of beer daily or 12 cans of beer per weekend up to the time of illness onset. In our experience, patients at our hospital who acknowledge this degree of alcohol intake usually have other stigmata of alcoholism, such as chronic liver disease.
Fever during
treatment
of tuberculosis
257
The admission chest X-ray was reviewed by a staff radiologist in standardised fashion. Each lung was divided into four zones. The area above the clavicle was considered the apex, and the remainder of the lung was divided into thirds. The total number of zones involved by alveolar infiltrate was noted and considered to be a rough measure of the radiographic extent of disease. The presence or absence of cavitation was also noted. Sputum smears for AFB were graded on a scale of 0 to 3+, 3+ signifying the presence of at least IO AFB in over 50 % of the oil immersion fields. Oral temperatures were recorded three times daily in afebrile patients, and every 4-6 hours when the temperature was over 37.8 “C (100.0 “F). Patients were considered afebrile if their temperatures remained under 37.8 “C prior to the institution of chemotherapy. After treatment was initiated, the temperature was said to have fallen to normal on the day the maximum temperature was below 37.8 “C, and remained so for a minimum of 48 hours. Statistical
analysis
The variables evaluated in the study were: 1. Age, sex, race, alcoholism, diabetes, presence of symptoms. 2. Anaemia, leucocytosis, percentage and absolute number of neutrophils, lymphocytes and monocytes. 3. Hyponatremia, hypoalbuminemia. 4. Cavitation, extent of alveolar infiltrate, 3+ sputum smear for AFB. 5. Concomitant extrapulmonary tuberculosis. 6. Death or respiratory failure requiring intubation. Each continuous variable was divided into groups that were clinically useful and provided an adequate number of cases in each group for analysis. The presence or absence of fever on admission was correlated with each of the variables previously mentioned, using the chisquare or Fisher’s exact test. All the variables noted were also correlated with duration of fever after therapy was begun, using the same statistical tests. Three additional variables evaluated were (iI initial temperature greater than 38.8 “C, (ii) mycobacterial resistance to INH or rifampin (RIF) and (iii) treatment regimens. In this analysis, patients were arbitrarily divided into those who were febrile for 7 days or less and those whose fever persisted for longer periods.
Results Fever
at presentation
Several variables were associated with the presence of fever (Table II. Febrile patients were more often symptomatic, lymphopenic, hyponatremic and hypoalbuminemic. They were also more likely to have many AFB on sputum smear. Fever was almost invariably present in hyponatremic individuals, occurring in 41 of 43 patients (95 %I. The mean age of afebrile patients was 44.3 years, compared to 38.1 years in febrile ones. (p=O.O2, Student’s t-test). Eight per cent of febrile individuals suffered death or respiratory failure, compared to 7 % of afebrile cases (p=O.64). Duration
of fever
with
therapy
Of the 106 patients who were febrile on admission, two became afebrile prior to the initiation of therapy. Thus, 104 febrile patients were treated with antituberculosis drugs. Twenty-one individuals were discharged while still febrile I-14 days (median 4) after treatment was begun. Of the remaining 83 cases, the cumulative percentage of patients who
258
Barnes
and
others
became afebrile at various times after initiation of therapy is shown in Table II: 89 % in 1 week or less, and 93 % within 2 weeks. The longest duration of fever was 87 days. In evaluating duration of fever, we found that 74 patients became afebrile within 7 days after the start of chemotherapy. Fourteen individuals took over 1 week to become Table
I.
Characteristics
of febrile
and
Characteristics
Male sex Symptoms Alcoholism Anaemia’ Lymphopenia’ Hyponatremia3 Hypoalbuminemia4 Cavitation 3+ AFB ‘Hgb 3<134
Table
Table
II.
III.
26 49 59 67 74 77 79 83
with
Alcoholism Temperature >38.8 Anaemia’ Lymphopenia’ Hyponatremia3 Hypoalbuminemia4 Cavitation
C
(%I
(%I
84 83 46 69 23 4 44 39 40
84 103/105 46/l 03 85/105 42/l 05 41/105 88 52/105 66
79 98 45 81 40 39 83 50 62
to normal
1 2 3 4 7 14 28 87
g/L
in
p value
females;
with
0.65 0.001 0.99 0.12 0.05 10.0001 10.0001 0.27 0.01 2<1000/cLl
treatment
number afebrile
llL;
in pulmonary
Cumulative percentage
31 59 71 81 89 93 95 100
prolonged Fever t7 (n= 74) Number
patients Febrile (n= 106) Number
~120
Cumulative of patients
Characteristic
‘d
46 45154 23/50 37/54 12/52 2154 24154 21154 22
Number of days after initiation of therapy
associated
Resistance or’RIF
Afebrile (n-551 Number
~140 g/L in males, meq/L; 4<39 g/L.
Rate of fall of temperature
Features
afebrile
fever.
days
p value
f%)
Fever >7 days in= 14) Number 1%)
23171 33 54173 26173 22173 54173 37
33 45 74 36 30 74 50
IO 10 14 7 9 14 10/13
71 71 100 50 64 100 77
0.006 0.007 0.002 0.31 0.02 0.002 0.07
6
8
1
7
0.69
to INH
See footnote
to Table
I.
tuberculosis.
Fever during
treatment
of tuberculosis
259
afebrile-nine became afebrile in the hospital, and five were febrile when discharged after more than a week of treatment. Sixteen patients were febrile at discharge, l-7 days after beginning therapy, and were excluded from analysis as their duration of fever was uncertain. Table III compares the clinical characteristics of patients with prolonged fever and those who became afebrile more rapidly. Alcoholism, anaemia, hypoalbuminemia and hyponatremia were markers of delayed defervescence. Among 33 alcoholics, 10 (30 %) took over 7 days to become afebrile, compared to only 8 % (4/52) of non-alcoholics. All patients with normal haemoglobin or albumin values became afebrile within a week. In contrast, 21 % (14/68) of those with anaemia or hypoalbuminemia had prolonged fevers. The most common treatment regimen was INH, rifampicin (RIF) and pyrazinamide (PZA) (62 cases). EMB was given as well in eight cases, SM in three and para-amino salicylic acid (PAS) in one. Six patients received INH, RIF and EMB, seven took INH and RIF, and one was given INH alone. We found no difference in duration of fever between patients receiving INH, RIF and PZA, with or without additional agents (74 cases), and those treated with all other combinations (14 cases).
Discussion Fever
at presentation
There is remarkably little data on the significance of fever in pulmonary tuberculosis and its duration with appropriate therapy. Our study is the first prospective evaluation of this problem in a large number of patients. In a retrospective investigation, Kiblawi noted fever to be associated with male sex and acute alcoholism [I], but we were unable to confirm this finding in our patients (Table I). There are no theoretical reasons to expect a difference between the febrile responses of the sexes to tuberculosis. Acute alcoholism in Kiblawi’s series may have been associated with fever because of concomitant alcohol withdrawal, which commonly causes temperature elevation. If most of their alcoholic patients were men, this would explain the association of fever with male sex that was observed. We excluded all patients with alcohol withdrawal from our population in order to eliminate this confounding effect. We conclude that male sex and alcoholism are not specially associated with fever in pulmonary tuberculosis. The mean age of our febrile patients was 38 years, compared to 44 years in afebrile individuals (p=O.O2). Older patients often do not mount a fever in response to bacterial infections. It is not surprising, therefore, that youth is associated with a febrile response in pulmonary tuberculosis. In Kiblawi’s series, febrile individuals were younger than afebrile ones, although the difference did not reach statistical significance. Kiblawi found febrile patients to be more often symptomatic, with a higher incidence of cavitation, and numerous AFB on sputum smear. Our findings were similar (Table I), though we noted no statistically significant correlation between cavitation and fever. Prior to 1950, several investigators found lymphopenia to indicate advanced tuberculosis [7-g]. Hyponatremia and anaemia have also been associated with extensive disease [IO, 1 I], and hypoalbuminemia is generally regarded as a sign of disease chronicity. Thus, compared to the afebrile group, febrile patients have clinical and laboratory markers of advanced tuberculosis. Duration
of fever
with
therapy
Tuberculosis may cause prolonged fever, even after appropriate therapy has been instituted [I, 2, 41. Berger treated 44 patients with INH and PAS, with or without SM, and found that 34 % took over 2 weeks to become afebrile. Kiblawi noted resolution of fever in only 64 % of 59 individuals after 2 weeks of therapy, most patients receiving INH, EMB and SM.
260
Barnes
and
others
Our results are strikingly different from those of previous reports. Eighty-nine per cent of our patients became afebrile within a week, and 93 % after 2 weeks of treatment. All but one patient received INH and RIF, most receiving PZA in addition. These three bactericidal drugs rapidly reduce the bacillary load. Regimens used in the past consisted of INH in combination with EMB, PAS or SM. EMB and PAS are bacteriostatic and do not eliminate mycobacteria as effectively as do RIF and PZA. Though SM is bactericidal, it is ineffective against intracellular organisms, unlike RIF and PZA 1131. Thus, the relatively rapid fall of temperature that we observed probably reflects the effectiveness of modern antituberculosis therapy. Since the diagnosis of tuberculosis is occasionally elusive, a therapeutic trial of specific chemotherapy is sometimes used to distinguish it from other diseases. Such a trial has been said to be of limited value because a third of patients with tuberculosis remain febrile for over 2 weeks [21. However, our data suggest that a therapeutic trial with present-day regimens is very likely to be helpful, since 93 % of tuberculous patients became afebrile within 2 weeks. Prolonged fevers after initiation of therapy have been associated with admission temperatures of over 38.8 “C, radiographically advanced disease and anaemia [I, 21. In our series, alcoholism, high initial temperatures, anaemia, hyponatremia and hypoalbuminemia were markers of delayed fall of temperature (Table Ill). Alcoholism is associated with multiple defects in host cell-mediated immunity [14], which is crucial in eliminating mycobacterial pathogens. It is thus not surprising that alcohol abusers have prolonged fever as a manifestation of their relatively slow response to antituberculosis therapy. As previously discussed, anaemia, hyponatremia and hypoalbuminemia may be clinical markers of extensive tuberculosis, in part accounting for the delayed fall in temperature noted among individuals with these characteristics. Thus, in cases of diagnostic uncertainty, a trial of antituberculosis chemotherapy is most helpful in non-alcoholic patients and in those with normal haemoglobin or serum albumin values. They almost invariably become afebrile within a week if tuberculosis is present. If fever is persistent, other diagnoses should be pursued. References 1 Kiblawi, S. S. 0.. Jay, S. J., Stonehill, R. B., Norton, J. (1981). Fever response of patients on therapy for pulmonary tuberculosis. American Review of Respiratory Disease, 123, 20. 2 Berger, H. W., Rosenbaum, I. (1968). Prolonged fever in patients treated for tuberculosis. American Review of Respiratory Disease, 97, 140. 3 Feingold, A. 0. (1975). Tuberculosis without fever. Southern Medical Journal, 69, 751. 4 Witkind, E., Willner, I. (1953). Clinical experience with isonicotinic acid hydrazide in tuberculosis. Diseases of the Chest, 23, 16. 5 Selikoff, I. J., Robitzek, E. l-i. (1952). Tuberculosis chemotherapy with hydrazine derivatives of isonicotinic acid. Diseases of the Chest, 21, 385. 6 Selikoff, I. J. (1956). The chemotherapy of tuberculosis. Journal of the Mount Sinai Hospital, 23, 331. 7 Muller, G. L. (1943). Clinical significance of the blood in tuberculosis, The Commonwealth Fund, New York. 8 Medlar, E. M. (1929). An evaluation of the leucocytic reaction in the blood as found in cases of tuberculosis. American Review of Tuberculosis, 20, 312. 9 Flinn, J. W. (1929). A study of the differential blood count in one thousand cases of active pulmonary tuberculosis. Annals of /n&%na/ Medicine, 2, 622. 10 Westwater. J. O., Stiven, D., Garry, R. C. (1939). A note on the serum sodium level in patients suffering from tuberculosis. Clinical Science, 4, 73. 11 Tani, P. (1970). Infectious anemia caused by pulmonary tuberculosis. Scandinavian Journal of Respiratory Disease, 72 (Suppl), 84. 12 Committee on Chemotherapy of Tuberculosis (1986). Standard therapy for tuberculosis 1985. Chest, 87 (SuppI). 117s. 13 Dutt, A. K., Stead, W. W. (1982). Present chemotherapy for tuberculosis. Journal oflnfectious Diseases, 146,698. 14 MacGregor, B. R. (1986). Alcohol and immune defense. Journal of the American Medical Association, 256, 1474.