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Short-term follow-up studies in amoebic dysentery
765 TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE.
Vol. 61. No. 6.
1967.
COMM[~NICATIONS SHORT-TERM FOLLOW-UP STUDIES IN AMOEBIC DYSENTERY
S. J. POWELL The Amoebiasis Research Unit and Department of Medicine, University of Natal, Durban, South Africa Acute amoebic dysentery, associated with rectal ulceration and the passage of haematophagous trophozoites of Entamoeba histolytica, can be converted by inadequate treatment to an asymptomatic state in which cysts are passed sporadically. In other instances, despite the apparent disappearance of amoebae and the absence of symptoms, some degree of rectal ulceration may persist. Such incomplete cure, which may be responsible for the notable tendency of the disease to relapse, is well known to be more common with some forms of treatment than with others. However, there seems to be an impression that, despite stringent criteria of immediate cure, relapse is more frequent after treatment with the indirectly acting antibiotics than after the use of directly acting amoebicides. Consequently there is a tendency to subject patients who have responded to broad-spectrum antibiotics with healing of rectal ulcers and disappearance of amoebae, to additional courses of direct-acting amoebicides. Conversely, doubt may be cast on a correct original diagnosis of amoebic dysentery because of the recurrence of symptoms after the use of a trusted direct-acting amoebicide. Although clinical trials comparing the efficacy of direct-acting amoebicides with that of antibiotics have been reported, they yield little information on relapse after apparent cure, and less on the significance of the persistence of cysts or of ulceration in patients rendered symptom-free. This information can only be obtained by comparison of the follow-up state in groups of patients who have attained a similar stage of cure after initial treatment with one or other of these forms of therapy. During the past 20 years the Amoebiasis Research Unit has undertaken therapeutic trials in amoebic dysentery, using standardized criteria. As the disease is endemic in Durban, distinction between relapse and reinfection is not possible during long-term follow-up. Nevertheless, recurrence of amoebic dysentery within one month of discharge is highly suggestive of relapse. The aim of the present study is comparison of such short-term follow-up with the state on discharge in groups of patients. The numbers who underwent trial of individual preparations are insufficient to provide The Amoebiasis Research Unit is sponsored by the following bodies :The South African Council for Scientific and Industrial Research. The Natal Provincial Administration The University of Natal The United States Public Health Service (Grant AI 01592). I am indebted m my colleagues Professor A. J. Wilmot and Drs. T. G. Armstrong, I. MacLeod and R. Elsdon-Dew who have shared in many of the trials on which this study was based. I also wish to thank Dr. H. Wannenburg, Medical Superintendent, King Edward VIII Hospital for providing facilities for these trials. a*
766
SHORT-TERM F O L L O W - U P STUDIES IN AMOEBIC DYSENTERY
information regarding specific drugs but significant comparisons can be made by combining the results of trials of all direct-acting amoebicides in one group and those obtained with broad-spectrum antibiotics in a second group. Material and methods 583 African male patients were classified into the following 3 categories according to the treatment they received: Direct-acting amoebicides: These, consisting predominantly of emetine preparations and quinoline derivatives, were given to 276 patients. Broad-spectrum antibiotics: These, comprising chiefly the tetracyclines, were received by 215 patients. Combined regimen: 92 patients, who received direct-acting amoebicides in c°mbinati°n with antibiotics, are included for comparison with the preceding two groups. At the commencement of treatment all patients had dysenteric stools containing haematophagous trophozoites of E. histolytica together with rectal ulceration demonstrable at sigmoidoscopy. Daily stool examinations by direct saline smears and zinc sulphate flotation were done throughout their stay in hospital and sigmoidoscopy was performed on admission and on the 5th, 10th, 15th, 20th and 27th days after beginning treatment. In the vast majority treatment was completed on the 10th day but the immediate results were not assessed until discharge on the 27th day. All patients reattended one month later for follow-up re-assessment by sigmoidoscopic and stool examination. The findings on discharge and at subsequent follow:up were classified as follows:
Cure: Symptom-free, rectal ulcers healed and E. histolytica absent. Doubtful: Symptom-free but rectal ulceration present although amoebae not demonstrable in stools or ulcer scrapings. Asymptomatic cyst-passers: Symptom-free and rectal ulcers healed but cysts of E. histolytica present. Relapse: Recurrence of dysentery, with trophozoites of E. histolytica present, at •follow-up. Results Table I summarizes the findings at one month follow-up in patients discharged as cured. TABLE I.
One-month follow-up findings in patients discharged as cured. in brackets On discharge
Percentages
At one-month follow-up
No. of patients
Cured
Doubtful
Cysts
Relapse
Direct acting amoebicides
199
158 (79)
5 (3)
5 (3)
31 (16)
Antibiotics
187
154 (82)
1 (1)
5 (3)
27 (14)
80
70 (88)
1 (1)
1 (1)
8 (10)
Treatment
Combined regimen
S. J. POWELL
767
Table II summarizes the findings at one month follow-up in patients who at discharge were classified as doubtful. TABLEII.
One-month follow-up findings in patients discharged as doubtful. Percentages in brackets On discharge
At one-month follow-up ,
i
No. of patients
Cured
Doubtful
Cysts
Relapse
Direct acting amoebicides
39
25 (64)
5 (13)
1 (3)
8 (21)
Antibiotics
13
2 (15)
3 (23)
1 (8)
7 (54)
Combined regimen
11
10 (91)
0
0
1 (9)
Treatment
Table III summarizes the findings at one month in patients discharged as asymptomatic cyst-passers. TABLE III.
One-month follow-up findings in patients discharged as asymptomatic cyst-passers. Percentages in brackets On discharge
At one-month follow-up
No. of patients
Cured
Doubtful
Cysts
Relapse
Direct acting amoebicides
38
14 (37)
1 (3)
6 (16)
17 (45)
Antibiotics
15
8 (53)
0
1 (7)
6 (40)
0
0
0
Treatment
Combined regimen
1
1
Discussion
Among the patients discharged as cured the incidence of relapse, conversion to cyst-passing and recurrence of rectal ulceration were similar in the groups who received direct-acting amoebicides and those given antibiotics. It appears that these groups of drugs do not differ in their ability to maintain cure if carefully performed sigmoidoscopy shows holing of ulcers, and stool examinations are normal, after the initial course of treatment. It should, however, be borne in mind that certain direct-acting amoebicides, notably emetine preparations, niridazole and metronidazole, are systemically effective and have the advantage of protecting the liver from invasion while cure of the bowel infection is taking place. Although the numbers of patients classified as doubtful or as asymptomatic cystpassers on discharge are relatively small, certain differences are apparent. Among those in whom rectal ulceration was still present on discharge relapse occurred in more than half and cure in but 15% of the patients treated with antibiotics. In contrast, cure resulted in 64% of the equivalent group who had received direct-acting amoebicides.
768
SHORT-TERM F O L L O W - U P STUDIES IN AMOEBIC DYSENTERY
This (significant) difference perhaps accounts for the view that relapse is prone to occur after treatment with antibiotics alone. In therapeutic trials over the past 20 years we have used the term "probable failure" for the group classified as doubtful in this study because we have been uncertain of the significance of some degree of persisting rectal ulceration despite the apparent disappearance of amoebae and symptomatic cure. The numbers discharged in this state have been so small that only the present retrospective study has yielded sufficient data from which to draw conclusions. It appears that, particularly when antibiotics alone are used, sigmoidoscopic evidence of healing of ulcers is an important criterion of successful treatment. Many clinical trials in Durban have given the impression that, despite eradication of amoebae, healing of ulcers is frequently slower when only direct-acting amoebicides are used. This was also noted in a combined trial of direct-acting amoebicides with suboptimal doses of tetracycline (POWELL et al., 1960). When used alone, presumably, antibiotics encourage healing of ulcers by reducing secondary bacterial infection but, should ulceration persist, relapse is liable to occur owing to the persistence of undetected amoebae. Nevertheless, when combined in adequate dosage with direct-acting amoebicides, antibiotics not only powerfully reinforce amoebicidal activity but also hasten the healing of ulcers. It is noteworthy that the relapse rate among patients discharged as asymptomatic cyst-passers was as high after direct-acting amoebicides as after antibiotics. The high relapse rate on either form of treatment confirms the importance of eradicating the parasite during initial therapy. In this respect it is significant that, of 92 patients who received a combined regimen, there was but a single instance of conversion to cystpassing immediately after treatment. This serves to emphasize the view, which is still insufficiently appreciated, that amoebic dysentery should be treated by the combination of an effective direct-acting amoebicide (which should also be active systemically) and a broad-spectrum antibiotic. On such a regimen healing of ulcers is hastened, the prospect of initial cure excellent and the likelihood of relapse relatively small.
Summary The findings at discharge and at one-month follow-up were compared in groups of patients with acute amoebic dysentery who had received ekher direct-acting amoebicides or broad-spectrum antibiotics or a combination of these drugs. Among patients discharged as cured, follow-up revealed no significant difference between those who had received direct-acting amoebicides and those treated with antibiotics in the incidence of relapse, conversion to cyst-passing and recurrence of rectal ulceration. There was, however, a high relapse rate among patients treated with antibiotics and rendered symptom-free with disappearance of amoebae, but with persistent rectal ulceration on discharge. Among patients who had become asymptomatic cyst-passers there was a similar and high relapse rate in both those who had received direct-acting amoebicides and in those treated with antibiotics. Amoebic dysentery should be treated with the combination of a direct-acting, systemically effective amoebicide and a broad'spectrum antibiotic. REFERENCE POWELL, S. J., WILMOT,A. J. & ELSDON-DEw,R. (1960).
Lancet, 1, 76.
Vol. 61. No. 6.
1967.
COMM[~NICATIONS SHORT-TERM FOLLOW-UP STUDIES IN AMOEBIC DYSENTERY
S. J. POWELL The Amoebiasis Research Unit and Department of Medicine, University of Natal, Durban, South Africa Acute amoebic dysentery, associated with rectal ulceration and the passage of haematophagous trophozoites of Entamoeba histolytica, can be converted by inadequate treatment to an asymptomatic state in which cysts are passed sporadically. In other instances, despite the apparent disappearance of amoebae and the absence of symptoms, some degree of rectal ulceration may persist. Such incomplete cure, which may be responsible for the notable tendency of the disease to relapse, is well known to be more common with some forms of treatment than with others. However, there seems to be an impression that, despite stringent criteria of immediate cure, relapse is more frequent after treatment with the indirectly acting antibiotics than after the use of directly acting amoebicides. Consequently there is a tendency to subject patients who have responded to broad-spectrum antibiotics with healing of rectal ulcers and disappearance of amoebae, to additional courses of direct-acting amoebicides. Conversely, doubt may be cast on a correct original diagnosis of amoebic dysentery because of the recurrence of symptoms after the use of a trusted direct-acting amoebicide. Although clinical trials comparing the efficacy of direct-acting amoebicides with that of antibiotics have been reported, they yield little information on relapse after apparent cure, and less on the significance of the persistence of cysts or of ulceration in patients rendered symptom-free. This information can only be obtained by comparison of the follow-up state in groups of patients who have attained a similar stage of cure after initial treatment with one or other of these forms of therapy. During the past 20 years the Amoebiasis Research Unit has undertaken therapeutic trials in amoebic dysentery, using standardized criteria. As the disease is endemic in Durban, distinction between relapse and reinfection is not possible during long-term follow-up. Nevertheless, recurrence of amoebic dysentery within one month of discharge is highly suggestive of relapse. The aim of the present study is comparison of such short-term follow-up with the state on discharge in groups of patients. The numbers who underwent trial of individual preparations are insufficient to provide The Amoebiasis Research Unit is sponsored by the following bodies :The South African Council for Scientific and Industrial Research. The Natal Provincial Administration The University of Natal The United States Public Health Service (Grant AI 01592). I am indebted m my colleagues Professor A. J. Wilmot and Drs. T. G. Armstrong, I. MacLeod and R. Elsdon-Dew who have shared in many of the trials on which this study was based. I also wish to thank Dr. H. Wannenburg, Medical Superintendent, King Edward VIII Hospital for providing facilities for these trials. a*
766
SHORT-TERM F O L L O W - U P STUDIES IN AMOEBIC DYSENTERY
information regarding specific drugs but significant comparisons can be made by combining the results of trials of all direct-acting amoebicides in one group and those obtained with broad-spectrum antibiotics in a second group. Material and methods 583 African male patients were classified into the following 3 categories according to the treatment they received: Direct-acting amoebicides: These, consisting predominantly of emetine preparations and quinoline derivatives, were given to 276 patients. Broad-spectrum antibiotics: These, comprising chiefly the tetracyclines, were received by 215 patients. Combined regimen: 92 patients, who received direct-acting amoebicides in c°mbinati°n with antibiotics, are included for comparison with the preceding two groups. At the commencement of treatment all patients had dysenteric stools containing haematophagous trophozoites of E. histolytica together with rectal ulceration demonstrable at sigmoidoscopy. Daily stool examinations by direct saline smears and zinc sulphate flotation were done throughout their stay in hospital and sigmoidoscopy was performed on admission and on the 5th, 10th, 15th, 20th and 27th days after beginning treatment. In the vast majority treatment was completed on the 10th day but the immediate results were not assessed until discharge on the 27th day. All patients reattended one month later for follow-up re-assessment by sigmoidoscopic and stool examination. The findings on discharge and at subsequent follow:up were classified as follows:
Cure: Symptom-free, rectal ulcers healed and E. histolytica absent. Doubtful: Symptom-free but rectal ulceration present although amoebae not demonstrable in stools or ulcer scrapings. Asymptomatic cyst-passers: Symptom-free and rectal ulcers healed but cysts of E. histolytica present. Relapse: Recurrence of dysentery, with trophozoites of E. histolytica present, at •follow-up. Results Table I summarizes the findings at one month follow-up in patients discharged as cured. TABLE I.
One-month follow-up findings in patients discharged as cured. in brackets On discharge
Percentages
At one-month follow-up
No. of patients
Cured
Doubtful
Cysts
Relapse
Direct acting amoebicides
199
158 (79)
5 (3)
5 (3)
31 (16)
Antibiotics
187
154 (82)
1 (1)
5 (3)
27 (14)
80
70 (88)
1 (1)
1 (1)
8 (10)
Treatment
Combined regimen
S. J. POWELL
767
Table II summarizes the findings at one month follow-up in patients who at discharge were classified as doubtful. TABLEII.
One-month follow-up findings in patients discharged as doubtful. Percentages in brackets On discharge
At one-month follow-up ,
i
No. of patients
Cured
Doubtful
Cysts
Relapse
Direct acting amoebicides
39
25 (64)
5 (13)
1 (3)
8 (21)
Antibiotics
13
2 (15)
3 (23)
1 (8)
7 (54)
Combined regimen
11
10 (91)
0
0
1 (9)
Treatment
Table III summarizes the findings at one month in patients discharged as asymptomatic cyst-passers. TABLE III.
One-month follow-up findings in patients discharged as asymptomatic cyst-passers. Percentages in brackets On discharge
At one-month follow-up
No. of patients
Cured
Doubtful
Cysts
Relapse
Direct acting amoebicides
38
14 (37)
1 (3)
6 (16)
17 (45)
Antibiotics
15
8 (53)
0
1 (7)
6 (40)
0
0
0
Treatment
Combined regimen
1
1
Discussion
Among the patients discharged as cured the incidence of relapse, conversion to cyst-passing and recurrence of rectal ulceration were similar in the groups who received direct-acting amoebicides and those given antibiotics. It appears that these groups of drugs do not differ in their ability to maintain cure if carefully performed sigmoidoscopy shows holing of ulcers, and stool examinations are normal, after the initial course of treatment. It should, however, be borne in mind that certain direct-acting amoebicides, notably emetine preparations, niridazole and metronidazole, are systemically effective and have the advantage of protecting the liver from invasion while cure of the bowel infection is taking place. Although the numbers of patients classified as doubtful or as asymptomatic cystpassers on discharge are relatively small, certain differences are apparent. Among those in whom rectal ulceration was still present on discharge relapse occurred in more than half and cure in but 15% of the patients treated with antibiotics. In contrast, cure resulted in 64% of the equivalent group who had received direct-acting amoebicides.
768
SHORT-TERM F O L L O W - U P STUDIES IN AMOEBIC DYSENTERY
This (significant) difference perhaps accounts for the view that relapse is prone to occur after treatment with antibiotics alone. In therapeutic trials over the past 20 years we have used the term "probable failure" for the group classified as doubtful in this study because we have been uncertain of the significance of some degree of persisting rectal ulceration despite the apparent disappearance of amoebae and symptomatic cure. The numbers discharged in this state have been so small that only the present retrospective study has yielded sufficient data from which to draw conclusions. It appears that, particularly when antibiotics alone are used, sigmoidoscopic evidence of healing of ulcers is an important criterion of successful treatment. Many clinical trials in Durban have given the impression that, despite eradication of amoebae, healing of ulcers is frequently slower when only direct-acting amoebicides are used. This was also noted in a combined trial of direct-acting amoebicides with suboptimal doses of tetracycline (POWELL et al., 1960). When used alone, presumably, antibiotics encourage healing of ulcers by reducing secondary bacterial infection but, should ulceration persist, relapse is liable to occur owing to the persistence of undetected amoebae. Nevertheless, when combined in adequate dosage with direct-acting amoebicides, antibiotics not only powerfully reinforce amoebicidal activity but also hasten the healing of ulcers. It is noteworthy that the relapse rate among patients discharged as asymptomatic cyst-passers was as high after direct-acting amoebicides as after antibiotics. The high relapse rate on either form of treatment confirms the importance of eradicating the parasite during initial therapy. In this respect it is significant that, of 92 patients who received a combined regimen, there was but a single instance of conversion to cystpassing immediately after treatment. This serves to emphasize the view, which is still insufficiently appreciated, that amoebic dysentery should be treated by the combination of an effective direct-acting amoebicide (which should also be active systemically) and a broad-spectrum antibiotic. On such a regimen healing of ulcers is hastened, the prospect of initial cure excellent and the likelihood of relapse relatively small.
Summary The findings at discharge and at one-month follow-up were compared in groups of patients with acute amoebic dysentery who had received ekher direct-acting amoebicides or broad-spectrum antibiotics or a combination of these drugs. Among patients discharged as cured, follow-up revealed no significant difference between those who had received direct-acting amoebicides and those treated with antibiotics in the incidence of relapse, conversion to cyst-passing and recurrence of rectal ulceration. There was, however, a high relapse rate among patients treated with antibiotics and rendered symptom-free with disappearance of amoebae, but with persistent rectal ulceration on discharge. Among patients who had become asymptomatic cyst-passers there was a similar and high relapse rate in both those who had received direct-acting amoebicides and in those treated with antibiotics. Amoebic dysentery should be treated with the combination of a direct-acting, systemically effective amoebicide and a broad'spectrum antibiotic. REFERENCE POWELL, S. J., WILMOT,A. J. & ELSDON-DEw,R. (1960).
Lancet, 1, 76.