EuropeanJoumalof
Eur. J. Pediatr. 131, 147--153 (1979)
Pediatrics 9 by Springer-Verlag 1979
Original Investigations A Double-Blind Pediatric Evaluation of Levamisole in the Prevention of Recurrent Upper Respiratory Tract Infections M. Van Eygen ~*, F. Dils 2, J. Gillerot 3, and E. Verschueren 4 Drafstraat 29, B-8800 Roeselare, Belgium 2Braamstraat 2, B-3745 Eigenbilzen, Belgium 3Rue de la C6te 69, B-6090 Couillet, Belgium 4Zuidervest 24, B-3570 Peer, Belgium
Abstract. Levamisole was tested double-blind in 106 children with recurrent upper respiratory tract infections. They received either levamisole (n = 53) or placebo (n--53) 0.5 m l / k g bodyweight b.i.d, for two consecutive days each week for six months. A control examination was performed every two months. Both groups were compared by means of the Fisher-test and the Mann-Whitney U-test (two-tailed probability each). Improvement was observed more frequently in the levamisole group with regard to the number of episodes of infection, and the total duration and severity of the infections. No side-effects, except for some stomach complaints in one levamisole patient, were reported. Key words: E.N.T. infections - Levamisole - Winter infections.
Introduction A wide variety of agents and treatments have been tried with varying success in recurrent upper respiratory tract infections in children. The newest and probably most promising agent is levamisole, a drug which has been used for many years as an anthelminthic and which was found to possess immunotropic properties in the early seventies [2]. Since then it has become evident that levamisole is an antianergic chemotherapeutic agent which restores deficiencies of the T-lymphocytes and phagocyte-mediated defense mechanisms and which shares several properties with thymic hormones [7]. One of u s has already co-operated in a multicenter pediatric study on the use of this drug in the treatment of recurrent upper respiratory tract infections. The study produced very promising results and demonstrated that levamisole was well tolerated by this type of patient [8]. The * Corresponding author
0340-6199/79/0131/0147/$ 01.40
148
M. Van Eygen et al.
p r e s e n t e v a l u a t i o n was d e s i g n e d to c o n f i r m the results o f t h e first s t u d y in a s i m i l a r g r o u p o f c h i l d r e n , u s i n g a sufficiently h i g h d o s e (as d e f i n e d b y the p r e v i o u s trial) o f a n e w p h a r m a c e u t i c a l p r e p a r a t i o n , i.e. l e v a m i s o l e syrup.
Material and Methods
Patients One hundred and six children were selected for the trial. All had been suffering previously from chronically recurrent upper respiratory tract infections, particularly during the winter. Since no particular virus or bacterium is known to be typically involved in this condition, the main criterion for selection was a clinical one i.e. the reported presence of recurrent upper respiratory tract (mainly ENT) infections of sufficient severity to make the parents consult a pediatrician. If, however, an underlying disease appeared to cause the infections, the disease was treated and th~ patient was not considered for the present trial. Table l gives the main characteristics of the patients and Table 2 summarizes data about their previous infections and treatment.
Experimental Design and Medication The trial started early in October 1975 and lasted for six months. Before treatment a hematological examination was performed: hemoglobin, erythrocytes, leukocytes, platelets, ESR, IgG and IgE were determined. The patients were randomly allocated to one of the two double-blind medications, levamisole or a placebo. Both medications were supplied in identical bottles of 100 ml syrup, containing either 5 mg levamisole per ml or placebo. The bottles were
Table 1. Patients: Parameter
Sex~ male female
Levamisole patients (n = 53)
Placebo patients (n = 53)
Total population (n = 106)
32
34
66
21
19
40
Age'~ (years)
6.6 (2--16)
6.0 (0.6--13)
6.0 (0.6--16)
Weightb (kg)
21
20
20.5
(7.5--58)
(6.5--49)
(6.5--58)
Tonsils~ present removed no data
44 8 1
44 8 1
88 16 2
Adenoids" present removed no data
41 11 1
38 14 1
79 25 2
a Number of patients b Median value (and range)
clinical characteristics
149
Double-Blind Levamisole in Recurrent Upper Respiratory Tract Infections Table 2. Patients: previous infections and treatments Parameter
Levamisole patients (n = 53)
Placebo patients (n = 53)
Total population (n = 106)
11
11
22
4
4
adenoids tonsils larynx + trachea
10 10 6
9 9 6
8 19 19
bronchi
12
14
26
Site of infection~ nose sinuses
12
Severity of infectiona severe
18
19
37
moderate
34
33
67
1
1
2
9
12
21
44
41
85
26
2O
46
27
33
6O
slight Frequency of episodes of infectiona almost continuous at intervals Period of infections a throughout the year autumn + winter 9
.
b
Duration of recurrent mfecnon (years) Mean monthly incidence of infections during previous winter b
2.0 (0.2--8) 1.3 (1.0--1.9)
2.6 (0.3--8) 1.3 (1.0--1.8)
2.0 (0.2--8) 1.3 (1.0--1.9)
Previous treatment and results Symptomatic drugs very good
0
0
good
3
3
doubtful
7
absent
6
I2 11
Anti-bacterial drugs very good good
2 3
0 7
2 10
doubtful
10
6
16
absent
14
17
31
no data
5
1
6
Vitamins and roborantia very good
0
good
0
doubtful absent
3 0
Number of patients b Median value (and range)
150
M. Van Eygen et al.
separately coded for each patient. During the entire trial the patients took 5 ml of syrup per 5 kg bodyweight twice a day for two consecutive days every week. Other medications were only taken if judged necessary by the treating physician. Assessments
The patients were asked to come for a control examination every two months in order to inform the investigator of the number, duration and severity of the episodes of infection which had occurred. Infections of the upper respiratory tract were only considered if fever, i.e. a body temperature of at least 38.5~ measured rectally or 38~ axillary, had been found. The assessment of the severity of the infection, based on the judgment of the patients' parents, was done by means of one of the following scoring possibilities: severe, moderate or slight. At the end of the trial the investigator also gave an overall appreciation, considering the incidence of infections during the trial period as compared with previous winters, and using one of the following terms: markedly better, better, similar, or worse. The occurrence of side-effects was registered throughout the entire trial period. Statistics
To evaluate the comparability of the two groups, the Fisher two-tailed probability test was used for sex, site of previous infections, their degree and frequency, effect of previous treatment and presence of tonsils and/or adenoids, whilst the Mann-Whitney U-test (two-tailed probability) was used for the other parameters mentioned in Table 1 and Table 2, and for the hematological data. The latter test was also used to assess the difference between the results of the two medications. The potential impact on the therapeutic effect of the patients' age (_ 6yr), the hematological parameters, and the presence or absence of tonsils and adenoids, was assessed by means of the G-test (two-tailed probability) [6].
Results B r e a k i n g the code r e v e a l e d t h a t 53 p a t i e n t s h a d been t r e a t e d with levamisole a n d an equal n u m b e r with the p l a c e b o . All the clinical d a t a (Tables 1 a n d 2) a n d h e m a t o l o g i c a l p a r a m e t e r s p r o v e d c o m p a r a b l e ( P > 0 . 0 5 ) in the two t r e a t m e n t g r o u p s at the start o f the trial. T a b l e 3 s u m m a r i z e s the results. T h e n u m b e r o f episodes o f infection d u r i n g each p e r i o d of two m o n t h s was significantly s m a l l e r in the l e v a m i s o l e - t r e a t e d p a t i e n t s t h a n in the c o n t r o l patients. If an incidence o f only one infection each winter is c o n s i d e r e d n o r m a l , 69.8% o f the levamisole p a t i e n t s against only 26.4% o f the controls, s h o w e d a n o r m a l defense a g a i n s t such infections. A l s o , the t o t a l d u r a t i o n o f infection d u r i n g each p e r i o d o f the trial was lowest in the levamisole g r o u p . If one week o f infection each winter is c o n s i d e r e d n o r m a l , the p e r c e n t a g e o f n o r m a l patients was 57.1% in the levamisole g r o u p a n d only 26.4% in the c o n t r o l g r o u p . M o r e o v e r , the severity of the infections d u r i n g the three p e r i o d s o f the study was significantly less in the levamisole g r o u p . F i n a l l y , the overall a p p r e c i a t i o n c o n f i r m e d the a b o v e findings as a m e l i o r a t i o n was o b s e r v e d m o r e f r e q u e n t l y in the l e v a m i s o l e - t r e a t e d patients (Table 4). T h e c o n t r o l g r o u p children o l d e r t h a n six years clearly s h o w e d m o r e episodes o f infection t h a n y o u n g e r children b u t there was no evidence ( P > 0 . 0 5 ) o f a
16.9
86.5 41.5
0--6 months
76.9 93.8 44.9
4--6 months
0--6 months
12.2
6.2
7.7
12.0
_< 1
18.4
--
9.6
20.0
1--2
11.3
3.8 1.9 3.9
2--4 months
4--6 months
0--6 months
13.2
0
3.8
13.2
3
29.4
7.7
9.4
26.9
3
6.1
--
3.9
2.0
2--3
7.5
--
--
--
4
43.2
86.5
75.5
51.9
4
18.4
--
1.9
12.0
>3
3.8
--
--
--
_>5
'~ M a n n - W h i t n e y U-test, two-tailed probability Scoring possibilities: 1 = severe; 2 = moderate; 3 = slight; 4 = no infection
23.5
3.9
17.3
2
3.9
1
Severity of the infection
54.0
2--4 months
0
0--2 months
0--2 months
5.7
2
3.8
7.6
2
N u m b e r of weeks with infection
28.3
11.5
75.5
2--4 months
4--6 months
1 28.3
0
N u m b e r of infectious episodes
Levamisole g r o u p
Percentage of patients
50.9
0--2 months
Period of trial
Table 3. Effect of treatment on infections
--
5.7
1.9
--
1
17.0
50.0
46.1
32.1
0
17.0
49.1
45.3
32.1
0
47.2
30.2
28.3
17.0
13.5
15.4
18.9
1--2
5.7
24.5
11.3
11.3
2
37.7
2
9.4
25.0
23.1
15.1
_< 1
9.4
17.0
18.9
11.3
1
Placebo g r o u p
11.3
--
--
--
4
35.8
15.1
24.5
7.5
11.5
7.7
11.3
2--3
30.2
3
20.8
9.4
24.5
45.3
3
17.0
49.0
45.3
32.1
4
49.1
--
7.7
22.6
>3
35.8
--
--
--
_>5
0.008
< 0.001
0.004
0.04
< 0.001
< 0.001
0.002
0.015
< 0.001
< 0.001
Eur. J. Pediatr. 131, 147--153 (1979)
Pediatrics 9 by Springer-Verlag 1979
Original Investigations A Double-Blind Pediatric Evaluation of Levamisole in the Prevention of Recurrent Upper Respiratory Tract Infections M. Van Eygen ~*, F. Dils 2, J. Gillerot 3, and E. Verschueren 4 Drafstraat 29, B-8800 Roeselare, Belgium 2Braamstraat 2, B-3745 Eigenbilzen, Belgium 3Rue de la C6te 69, B-6090 Couillet, Belgium 4Zuidervest 24, B-3570 Peer, Belgium
Abstract. Levamisole was tested double-blind in 106 children with recurrent upper respiratory tract infections. They received either levamisole (n = 53) or placebo (n--53) 0.5 m l / k g bodyweight b.i.d, for two consecutive days each week for six months. A control examination was performed every two months. Both groups were compared by means of the Fisher-test and the Mann-Whitney U-test (two-tailed probability each). Improvement was observed more frequently in the levamisole group with regard to the number of episodes of infection, and the total duration and severity of the infections. No side-effects, except for some stomach complaints in one levamisole patient, were reported. Key words: E.N.T. infections - Levamisole - Winter infections.
Introduction A wide variety of agents and treatments have been tried with varying success in recurrent upper respiratory tract infections in children. The newest and probably most promising agent is levamisole, a drug which has been used for many years as an anthelminthic and which was found to possess immunotropic properties in the early seventies [2]. Since then it has become evident that levamisole is an antianergic chemotherapeutic agent which restores deficiencies of the T-lymphocytes and phagocyte-mediated defense mechanisms and which shares several properties with thymic hormones [7]. One of u s has already co-operated in a multicenter pediatric study on the use of this drug in the treatment of recurrent upper respiratory tract infections. The study produced very promising results and demonstrated that levamisole was well tolerated by this type of patient [8]. The * Corresponding author
0340-6199/79/0131/0147/$ 01.40
148
M. Van Eygen et al.
p r e s e n t e v a l u a t i o n was d e s i g n e d to c o n f i r m the results o f t h e first s t u d y in a s i m i l a r g r o u p o f c h i l d r e n , u s i n g a sufficiently h i g h d o s e (as d e f i n e d b y the p r e v i o u s trial) o f a n e w p h a r m a c e u t i c a l p r e p a r a t i o n , i.e. l e v a m i s o l e syrup.
Material and Methods
Patients One hundred and six children were selected for the trial. All had been suffering previously from chronically recurrent upper respiratory tract infections, particularly during the winter. Since no particular virus or bacterium is known to be typically involved in this condition, the main criterion for selection was a clinical one i.e. the reported presence of recurrent upper respiratory tract (mainly ENT) infections of sufficient severity to make the parents consult a pediatrician. If, however, an underlying disease appeared to cause the infections, the disease was treated and th~ patient was not considered for the present trial. Table l gives the main characteristics of the patients and Table 2 summarizes data about their previous infections and treatment.
Experimental Design and Medication The trial started early in October 1975 and lasted for six months. Before treatment a hematological examination was performed: hemoglobin, erythrocytes, leukocytes, platelets, ESR, IgG and IgE were determined. The patients were randomly allocated to one of the two double-blind medications, levamisole or a placebo. Both medications were supplied in identical bottles of 100 ml syrup, containing either 5 mg levamisole per ml or placebo. The bottles were
Table 1. Patients: Parameter
Sex~ male female
Levamisole patients (n = 53)
Placebo patients (n = 53)
Total population (n = 106)
32
34
66
21
19
40
Age'~ (years)
6.6 (2--16)
6.0 (0.6--13)
6.0 (0.6--16)
Weightb (kg)
21
20
20.5
(7.5--58)
(6.5--49)
(6.5--58)
Tonsils~ present removed no data
44 8 1
44 8 1
88 16 2
Adenoids" present removed no data
41 11 1
38 14 1
79 25 2
a Number of patients b Median value (and range)
clinical characteristics
149
Double-Blind Levamisole in Recurrent Upper Respiratory Tract Infections Table 2. Patients: previous infections and treatments Parameter
Levamisole patients (n = 53)
Placebo patients (n = 53)
Total population (n = 106)
11
11
22
4
4
adenoids tonsils larynx + trachea
10 10 6
9 9 6
8 19 19
bronchi
12
14
26
Site of infection~ nose sinuses
12
Severity of infectiona severe
18
19
37
moderate
34
33
67
1
1
2
9
12
21
44
41
85
26
2O
46
27
33
6O
slight Frequency of episodes of infectiona almost continuous at intervals Period of infections a throughout the year autumn + winter 9
.
b
Duration of recurrent mfecnon (years) Mean monthly incidence of infections during previous winter b
2.0 (0.2--8) 1.3 (1.0--1.9)
2.6 (0.3--8) 1.3 (1.0--1.8)
2.0 (0.2--8) 1.3 (1.0--1.9)
Previous treatment and results Symptomatic drugs very good
0
0
good
3
3
doubtful
7
absent
6
I2 11
Anti-bacterial drugs very good good
2 3
0 7
2 10
doubtful
10
6
16
absent
14
17
31
no data
5
1
6
Vitamins and roborantia very good
0
good
0
doubtful absent
3 0
Number of patients b Median value (and range)
150
M. Van Eygen et al.
separately coded for each patient. During the entire trial the patients took 5 ml of syrup per 5 kg bodyweight twice a day for two consecutive days every week. Other medications were only taken if judged necessary by the treating physician. Assessments
The patients were asked to come for a control examination every two months in order to inform the investigator of the number, duration and severity of the episodes of infection which had occurred. Infections of the upper respiratory tract were only considered if fever, i.e. a body temperature of at least 38.5~ measured rectally or 38~ axillary, had been found. The assessment of the severity of the infection, based on the judgment of the patients' parents, was done by means of one of the following scoring possibilities: severe, moderate or slight. At the end of the trial the investigator also gave an overall appreciation, considering the incidence of infections during the trial period as compared with previous winters, and using one of the following terms: markedly better, better, similar, or worse. The occurrence of side-effects was registered throughout the entire trial period. Statistics
To evaluate the comparability of the two groups, the Fisher two-tailed probability test was used for sex, site of previous infections, their degree and frequency, effect of previous treatment and presence of tonsils and/or adenoids, whilst the Mann-Whitney U-test (two-tailed probability) was used for the other parameters mentioned in Table 1 and Table 2, and for the hematological data. The latter test was also used to assess the difference between the results of the two medications. The potential impact on the therapeutic effect of the patients' age (_ 6yr), the hematological parameters, and the presence or absence of tonsils and adenoids, was assessed by means of the G-test (two-tailed probability) [6].
Results B r e a k i n g the code r e v e a l e d t h a t 53 p a t i e n t s h a d been t r e a t e d with levamisole a n d an equal n u m b e r with the p l a c e b o . All the clinical d a t a (Tables 1 a n d 2) a n d h e m a t o l o g i c a l p a r a m e t e r s p r o v e d c o m p a r a b l e ( P > 0 . 0 5 ) in the two t r e a t m e n t g r o u p s at the start o f the trial. T a b l e 3 s u m m a r i z e s the results. T h e n u m b e r o f episodes o f infection d u r i n g each p e r i o d of two m o n t h s was significantly s m a l l e r in the l e v a m i s o l e - t r e a t e d p a t i e n t s t h a n in the c o n t r o l patients. If an incidence o f only one infection each winter is c o n s i d e r e d n o r m a l , 69.8% o f the levamisole p a t i e n t s against only 26.4% o f the controls, s h o w e d a n o r m a l defense a g a i n s t such infections. A l s o , the t o t a l d u r a t i o n o f infection d u r i n g each p e r i o d o f the trial was lowest in the levamisole g r o u p . If one week o f infection each winter is c o n s i d e r e d n o r m a l , the p e r c e n t a g e o f n o r m a l patients was 57.1% in the levamisole g r o u p a n d only 26.4% in the c o n t r o l g r o u p . M o r e o v e r , the severity of the infections d u r i n g the three p e r i o d s o f the study was significantly less in the levamisole g r o u p . F i n a l l y , the overall a p p r e c i a t i o n c o n f i r m e d the a b o v e findings as a m e l i o r a t i o n was o b s e r v e d m o r e f r e q u e n t l y in the l e v a m i s o l e - t r e a t e d patients (Table 4). T h e c o n t r o l g r o u p children o l d e r t h a n six years clearly s h o w e d m o r e episodes o f infection t h a n y o u n g e r children b u t there was no evidence ( P > 0 . 0 5 ) o f a
16.9
86.5 41.5
0--6 months
76.9 93.8 44.9
4--6 months
0--6 months
12.2
6.2
7.7
12.0
_< 1
18.4
--
9.6
20.0
1--2
11.3
3.8 1.9 3.9
2--4 months
4--6 months
0--6 months
13.2
0
3.8
13.2
3
29.4
7.7
9.4
26.9
3
6.1
--
3.9
2.0
2--3
7.5
--
--
--
4
43.2
86.5
75.5
51.9
4
18.4
--
1.9
12.0
>3
3.8
--
--
--
_>5
'~ M a n n - W h i t n e y U-test, two-tailed probability Scoring possibilities: 1 = severe; 2 = moderate; 3 = slight; 4 = no infection
23.5
3.9
17.3
2
3.9
1
Severity of the infection
54.0
2--4 months
0
0--2 months
0--2 months
5.7
2
3.8
7.6
2
N u m b e r of weeks with infection
28.3
11.5
75.5
2--4 months
4--6 months
1 28.3
0
N u m b e r of infectious episodes
Levamisole g r o u p
Percentage of patients
50.9
0--2 months
Period of trial
Table 3. Effect of treatment on infections
--
5.7
1.9
--
1
17.0
50.0
46.1
32.1
0
17.0
49.1
45.3
32.1
0
47.2
30.2
28.3
17.0
13.5
15.4
18.9
1--2
5.7
24.5
11.3
11.3
2
37.7
2
9.4
25.0
23.1
15.1
_< 1
9.4
17.0
18.9
11.3
1
Placebo g r o u p
11.3
--
--
--
4
35.8
15.1
24.5
7.5
11.5
7.7
11.3
2--3
30.2
3
20.8
9.4
24.5
45.3
3
17.0
49.0
45.3
32.1
4
49.1
--
7.7
22.6
>3
35.8
--
--
--
_>5
0.008
< 0.001
0.004
0.04
< 0.001
< 0.001
0.002
0.015
< 0.001
< 0.001
