135
Campylobacter Enteritis SEVEN years ago,
campylobacter infections
were
of human disease. Since regarded the first description by VINZENT et al. in 1947, only 111 cases had been reported, mostly from the U.S.A. (The name campylobacter, meaning curved rod, was coined in 1963 when SEBALD and VÉRON2 distinguished the organisms genetically, biochemically, and serologically, from the true vibrios such as Vibrio cholerae and V. parahaemolyticus.) In veterinary medicine, campylobacter infections are taken very seriously: Campylobacter fetus venerealis causes enzootic sterility in cattle and C. fetus intestinalis causes abortion in sheep and cattle. In man, C. fetus intestinalis (serotype A biotype II, and serotype B) is an opportunist-that is, most affected patients have some predisposing factor such as cirrhosis, immunosuppression, neoplasm, or damage to heart-valves.3 Pregnant women and infants are at risk. But a different group of campylobacters has now taken the stage, as a common cause of enteritis in otherwise healthy people. These organisms were first recognised by KING4 in 1957, who originally called them "related vibrios" because they had features in common with VINZENT’S organism but were antigenically different. VERON and CHATELAIN5 saw this group as represented by the two species C. jejuni and C. coli as a rare cause
(listed by SMIBERT in Bergey’s Manual as C. fetus ss jejuní); but later work suggests that the group is heterogeneous and made up of many serotypes, so there is much to be said for keeping the term "related campylobacters" till more is known. When KING did her work, only 12 patients with "related"-campylobacter infection had been reported. The most prominent symptom was diarrhoea, but in all cases the organism was isolated from blood: attempts to isolate it from fxces failed because of overgrowth by coliforms. Ten years were to pass before BuTZLER and his colleagues in Brussels overcame the problem of selecting campylobacters from mixed bacterial populations. They used a method that depended upon the ability of campylobacters, which are very small, to pass through a filter that retains most other bacteria. By 1.
Vinzent, R., Dumas, J., Picard, N. Bull. Acad.
nat.
Méd. Paris, 1947, 131,
90 2. Sehald, M., Véron, M. Ann Inst. Pasteur, 1963, 105, 897. 3. Butzler, J. P , Dereume, J. P., Barbier, P., Smekens, L., Dekeyser, Presse méd. 1977, 6, 1033. 4. King, EO. J. inject. Dis. 1957, 101, 119. 5. Veron, M., Chatelain, R. Int. J. system. Bact. 1973, 23, 122.
J.
Nouv.
this means they isolated campylobacters from the faeces of 5.1% of children with diarrhoea and 1.3% of children without diarrhoea.6 In 1977 SKIRROW7 isolated "related" campylobacters from the fseces of 57 (7.1%) of 803 unselected patients with diarrhoea. Experience in Britain,’-1° Sweden, 12 the Netherlands,13 and elsewhere shows that the incidence of "related"-campylobacter infection is highest in young children but that people of all ages may be affected, some of the most severely ill patients being adults. Reports from Africa suggest that the organism may be very common in the tropiCS.14 In Brussels the isolation-rate increases during the summer.15 In the United States a large outbreak (about 2000 cases) has just been reported, apparently associated with consumption of water from a public supply.16 As with all enteropathogenic bacteria, carriage is compatible with health. Something under 1% of the population are carriers, and commonly they are contacts of patients with enteritis. There have been several outbreaks in nurseries and other institutions. Campylobacter enteritis is usually an acute diarrhoeal illness which lasts several days, with or without fever.’The diarrhoea is often slight but sometimes it is frankly watery or mucosanguinous and accompanied by vomiting, dehydration and electrolyte disturbance. Apart from diarrhoea the outstanding symptom is abdominal pain, which can be severe and sometimes brings the patient to a surgical bed. The average incubation period is thought to be about 5 days but it probably ranges from 2 to 10 days. Specific agappear in most patients durglutinating antibodies 17 ing the illness. 7, The site of infection seems to be the jejunum and ileum: in affected children. CADRANEL et al. 18 isolated campylobacters from ileal, jejunal, and gastric aspirates, and acute inflammation of the jejunum and ileum has been seen at laparotomy. Invasion of the bowel has been seen in chickens fed with isolates from human beings.l9 Campylobacteriosis is transmitted by ingestion and carriage in the intestine. Sometimes the organisms enter the bloodstream, perhaps in a bout of diarrhoea or because of a change of intestinal flora or some immunological deficiency. 18 In campylobacter septicaemia, the treatment of choice is 6.
Butzler, J. P., Dekeyser, P., Lafontaine, Th. Antimicrob. Agents Chemother.
1974, 5, 86. 7. Skirrow, M. B. Br. med. J. 1977, ii, 9. 8. Dale, B. ibid. p. 318. 9. Tanner, E. I. ibid. p. 579. 10. Pearson, A. D., Suckling, W. G., Ricciardi, I. D , Knill, M., Ware, E. ibid.
p.955. 11. Telfer Brunton, W. A., Heggie, D. ibid. p. 956. 12. Landquist, B., Kjellander, J., Kosunen, T. ibid. 1978, i, 303. 13. Severin, W. P. J. Ned. T. Geneesk 1978, 122, 499. 14. De Mol, P., Bosmans, E. Lancet, 1978, i, 604. 15. Lauwers, S., De Boeck. M., Butzler, J. P. ibid. 16. Morbid. Mortal. wkly Rep. 1978, 27, 207. 17. Butzler, J. P. Lancet, 1973, ii, 858. 18. Cadranel, S., Rodesch, P., Butzler, J. P., Dekeyser, P. Am.
J. Dis. Child. 1973, 126, 152. 19. Butzler, J. P., Dekegel, D., Hubrechts, J. M., Lauwers, S., Zissis, G. Proc. int. Congr. Chemother. 1977, p. 174.
136
it
arise years after
In enteritis, the infection responds to furazolidone or erythromycin, but isolation of campylobacters from the stools is not necessarily an in-
gentamicin.
dication for antibiotic treatment. Although man-toman transmission is a common mode of spread, the infection is undoubtedly a zoonosis. As with salmonellosis, many species, including birds,2O harbour these organisms. Some human infections have been traced to contact with poultry (live and dressed) and to young dogs with diarrhoea. We do not yet know to what extent animals contribute to the pool of human infection.
Testicular Infiltrates in Childhood Leukaemia: Harbour or Harbinger? TREATMENT of acute lymphoblastic leukaemia (A.L.L) has revealed latent features of the disease. Meningeal leukaemia thus became a major problem in the 1960s, supposedly because the blood/brain barrier makes the meninges a sanctuary from chemotherapy. Eradication of occult meningeal disease has greatly improved prognosis, but new troubles have arisen. The prognosis for boys is now substantially worse than that for girls (see p. 128). Could this be related to testicular infiltration? Testicular involvement in childhood leukaemia was seldom recognised before 1960. It is rarely present at diagnosis, usually being seen in association with disease recurrence. Most of the patients have A.L.L., but in less common forms of leukaemia the risk may be higher.2 Testicular leukaemia is primarily a disease of prepubertal boys, though the fact that it does occur in young men treated for leukaemia and T-cell lymphoma4 suggests that it may be seen increasingly in older patients as survival improves. In 162 males treated at one hospital between 1962 and 1971,5 the incidence of testicular relapse was 14%. Testicular infiltration in necropsy series varies from 29% to 92%.6 Clinically, testicular involvement tends to be related to ominous features such as high initial white count,33 organomegaly, and age at diagnosis of under 2 or over 8. The symptomless swelling is seldom drawn to the doctor’s attention by patient or parents, and
_
20. Peckham, M. C. Diseases of Poultry. Ames Iowa State University, 1972. 1. Pinkel, D. Cancer, 1971, 27, 247. 2. Sullivan, M. P., Hrgovcic, M. in Clinical Pediatric Oncology (edited by W. W. Sutow and others); p. 371. St Louis, 1977. 3. Nies, B. A., Bodey, G. P., Thomas, L. B., Brecher, G., Freireich, E. J. Blood,
1965, 26, 133. Bloomfield, D. D., Frizzera, G., Gajl-Peczalska, K., Brunning, R., Kersey, J. Proc.Am. Soc. clin. Oncol. 1978, 19, 378. 5. Prieto, C., Hustu, O., Aur, R. J. A., Simone, J. Proc. Am. Ass. Cancer Res. 1975, 16, 178. 6. Stoffel, T. J., Nesbit, M. E., Levitt, S. H. Cancer, 1975, 35, 1203. 7. Steinfield, A. D. Radiology, 1976, 120, 681.
any time-sometimes as late as 7 diagnosis, and after treatment has When the testes become involved during stopped. treatment the patient will usually have other poor prognostic features, and within a few months disease can be expected in bone-marrow, central nervous system, and elsewhere, with short survival thereafter.6 The most important group are those patients with an otherwise good prognosis in whom testicular leukaemia is the sole manifestation of relapse. In this group the condition is usually diagnosed in the first year after completion of chemotherapy. Almost half the patients in the latest M.R.C. report9 had testicular relapse as the sole initial recurrence. The overall incidence was 13%. However, if the testis is a sanctuary site like the meninges and is protected by a blood/testis barrier, then the actuarial risk to patients who might otherwise have achieved a long remission is 30%. There are difficulties in interpreting the data. An apparent excess of testicular relapse in those on the UKALL 11 schedule randomised to receive cyclocan
at
phosphamide could be due to the dropping of spinal radiotherapy as part of their central-nervous-system prophylaxis. More importantly, the results could also be due to a secular trend, since increasing awareness of the problem of testicular disease has changed the diagnostic threshold. Testicular relapse could easily have been overlooked when it occurred in association with haematological relapse, since new or more intensive chemotherapy will often cause shrinkage of the testicular swelling. Control of testicular infiltrates by chemotherapy is also evident from the clustering of cases in the first few months after treatment is stopped; whatever the duration of chemotherapy. This sensitivity to chemotherapy challenges the sanctuary theory. Are testicular infiltrates the source or merely a signal of further systemic disease? The question is critical to the planning of treatment. NIEs et a1. investigated 15 patients who died in apparent complete remission of their leukaemia and found extramedullary disease in 10. 3 of the 4 males had testicular infiltrates, but these 3 (all more than 20 years old) all had leukxmic infiltrates in other organs. MATHÉ et al. 10 found evidence of leukaemia in 12 of 31 patients apparently in complete remission. 4 had disease in at least one of the six bone-marrow sites biopsied, 4 had liver infiltrates, 4 had C.N.S. involvement, and 2 had renal involvement. Testicular disease was found in only 1 of the 13 males who had biopsies. SHARP et al. n 8.
Finklestein, J. Z., Dyment, P. G., Hammond, G. D. Pediatrics, 1969, 43,
9.
Report of M.R.C. Working Party on Childhood Leukæmia. Br. med. J. 1978,
10.
i, 334. Mathé, G., Scharwzenberg, L., Mery, A. M., Cattan, A., Scheider, M., Amiel, J. L., Schlumberger, J. R., Poisson, J., Wajcner, G. ibid. 1966, i,
11.
Sharp,
1042.
4.
640. H.
1403.
L., Nesbit, M. E., D’Angio, G. J., Krivit, W. Cancer, 1967, 20,
Campylobacter Enteritis SEVEN years ago,
campylobacter infections
were
of human disease. Since regarded the first description by VINZENT et al. in 1947, only 111 cases had been reported, mostly from the U.S.A. (The name campylobacter, meaning curved rod, was coined in 1963 when SEBALD and VÉRON2 distinguished the organisms genetically, biochemically, and serologically, from the true vibrios such as Vibrio cholerae and V. parahaemolyticus.) In veterinary medicine, campylobacter infections are taken very seriously: Campylobacter fetus venerealis causes enzootic sterility in cattle and C. fetus intestinalis causes abortion in sheep and cattle. In man, C. fetus intestinalis (serotype A biotype II, and serotype B) is an opportunist-that is, most affected patients have some predisposing factor such as cirrhosis, immunosuppression, neoplasm, or damage to heart-valves.3 Pregnant women and infants are at risk. But a different group of campylobacters has now taken the stage, as a common cause of enteritis in otherwise healthy people. These organisms were first recognised by KING4 in 1957, who originally called them "related vibrios" because they had features in common with VINZENT’S organism but were antigenically different. VERON and CHATELAIN5 saw this group as represented by the two species C. jejuni and C. coli as a rare cause
(listed by SMIBERT in Bergey’s Manual as C. fetus ss jejuní); but later work suggests that the group is heterogeneous and made up of many serotypes, so there is much to be said for keeping the term "related campylobacters" till more is known. When KING did her work, only 12 patients with "related"-campylobacter infection had been reported. The most prominent symptom was diarrhoea, but in all cases the organism was isolated from blood: attempts to isolate it from fxces failed because of overgrowth by coliforms. Ten years were to pass before BuTZLER and his colleagues in Brussels overcame the problem of selecting campylobacters from mixed bacterial populations. They used a method that depended upon the ability of campylobacters, which are very small, to pass through a filter that retains most other bacteria. By 1.
Vinzent, R., Dumas, J., Picard, N. Bull. Acad.
nat.
Méd. Paris, 1947, 131,
90 2. Sehald, M., Véron, M. Ann Inst. Pasteur, 1963, 105, 897. 3. Butzler, J. P , Dereume, J. P., Barbier, P., Smekens, L., Dekeyser, Presse méd. 1977, 6, 1033. 4. King, EO. J. inject. Dis. 1957, 101, 119. 5. Veron, M., Chatelain, R. Int. J. system. Bact. 1973, 23, 122.
J.
Nouv.
this means they isolated campylobacters from the faeces of 5.1% of children with diarrhoea and 1.3% of children without diarrhoea.6 In 1977 SKIRROW7 isolated "related" campylobacters from the fseces of 57 (7.1%) of 803 unselected patients with diarrhoea. Experience in Britain,’-1° Sweden, 12 the Netherlands,13 and elsewhere shows that the incidence of "related"-campylobacter infection is highest in young children but that people of all ages may be affected, some of the most severely ill patients being adults. Reports from Africa suggest that the organism may be very common in the tropiCS.14 In Brussels the isolation-rate increases during the summer.15 In the United States a large outbreak (about 2000 cases) has just been reported, apparently associated with consumption of water from a public supply.16 As with all enteropathogenic bacteria, carriage is compatible with health. Something under 1% of the population are carriers, and commonly they are contacts of patients with enteritis. There have been several outbreaks in nurseries and other institutions. Campylobacter enteritis is usually an acute diarrhoeal illness which lasts several days, with or without fever.’The diarrhoea is often slight but sometimes it is frankly watery or mucosanguinous and accompanied by vomiting, dehydration and electrolyte disturbance. Apart from diarrhoea the outstanding symptom is abdominal pain, which can be severe and sometimes brings the patient to a surgical bed. The average incubation period is thought to be about 5 days but it probably ranges from 2 to 10 days. Specific agappear in most patients durglutinating antibodies 17 ing the illness. 7, The site of infection seems to be the jejunum and ileum: in affected children. CADRANEL et al. 18 isolated campylobacters from ileal, jejunal, and gastric aspirates, and acute inflammation of the jejunum and ileum has been seen at laparotomy. Invasion of the bowel has been seen in chickens fed with isolates from human beings.l9 Campylobacteriosis is transmitted by ingestion and carriage in the intestine. Sometimes the organisms enter the bloodstream, perhaps in a bout of diarrhoea or because of a change of intestinal flora or some immunological deficiency. 18 In campylobacter septicaemia, the treatment of choice is 6.
Butzler, J. P., Dekeyser, P., Lafontaine, Th. Antimicrob. Agents Chemother.
1974, 5, 86. 7. Skirrow, M. B. Br. med. J. 1977, ii, 9. 8. Dale, B. ibid. p. 318. 9. Tanner, E. I. ibid. p. 579. 10. Pearson, A. D., Suckling, W. G., Ricciardi, I. D , Knill, M., Ware, E. ibid.
p.955. 11. Telfer Brunton, W. A., Heggie, D. ibid. p. 956. 12. Landquist, B., Kjellander, J., Kosunen, T. ibid. 1978, i, 303. 13. Severin, W. P. J. Ned. T. Geneesk 1978, 122, 499. 14. De Mol, P., Bosmans, E. Lancet, 1978, i, 604. 15. Lauwers, S., De Boeck. M., Butzler, J. P. ibid. 16. Morbid. Mortal. wkly Rep. 1978, 27, 207. 17. Butzler, J. P. Lancet, 1973, ii, 858. 18. Cadranel, S., Rodesch, P., Butzler, J. P., Dekeyser, P. Am.
J. Dis. Child. 1973, 126, 152. 19. Butzler, J. P., Dekegel, D., Hubrechts, J. M., Lauwers, S., Zissis, G. Proc. int. Congr. Chemother. 1977, p. 174.
136
it
arise years after
In enteritis, the infection responds to furazolidone or erythromycin, but isolation of campylobacters from the stools is not necessarily an in-
gentamicin.
dication for antibiotic treatment. Although man-toman transmission is a common mode of spread, the infection is undoubtedly a zoonosis. As with salmonellosis, many species, including birds,2O harbour these organisms. Some human infections have been traced to contact with poultry (live and dressed) and to young dogs with diarrhoea. We do not yet know to what extent animals contribute to the pool of human infection.
Testicular Infiltrates in Childhood Leukaemia: Harbour or Harbinger? TREATMENT of acute lymphoblastic leukaemia (A.L.L) has revealed latent features of the disease. Meningeal leukaemia thus became a major problem in the 1960s, supposedly because the blood/brain barrier makes the meninges a sanctuary from chemotherapy. Eradication of occult meningeal disease has greatly improved prognosis, but new troubles have arisen. The prognosis for boys is now substantially worse than that for girls (see p. 128). Could this be related to testicular infiltration? Testicular involvement in childhood leukaemia was seldom recognised before 1960. It is rarely present at diagnosis, usually being seen in association with disease recurrence. Most of the patients have A.L.L., but in less common forms of leukaemia the risk may be higher.2 Testicular leukaemia is primarily a disease of prepubertal boys, though the fact that it does occur in young men treated for leukaemia and T-cell lymphoma4 suggests that it may be seen increasingly in older patients as survival improves. In 162 males treated at one hospital between 1962 and 1971,5 the incidence of testicular relapse was 14%. Testicular infiltration in necropsy series varies from 29% to 92%.6 Clinically, testicular involvement tends to be related to ominous features such as high initial white count,33 organomegaly, and age at diagnosis of under 2 or over 8. The symptomless swelling is seldom drawn to the doctor’s attention by patient or parents, and
_
20. Peckham, M. C. Diseases of Poultry. Ames Iowa State University, 1972. 1. Pinkel, D. Cancer, 1971, 27, 247. 2. Sullivan, M. P., Hrgovcic, M. in Clinical Pediatric Oncology (edited by W. W. Sutow and others); p. 371. St Louis, 1977. 3. Nies, B. A., Bodey, G. P., Thomas, L. B., Brecher, G., Freireich, E. J. Blood,
1965, 26, 133. Bloomfield, D. D., Frizzera, G., Gajl-Peczalska, K., Brunning, R., Kersey, J. Proc.Am. Soc. clin. Oncol. 1978, 19, 378. 5. Prieto, C., Hustu, O., Aur, R. J. A., Simone, J. Proc. Am. Ass. Cancer Res. 1975, 16, 178. 6. Stoffel, T. J., Nesbit, M. E., Levitt, S. H. Cancer, 1975, 35, 1203. 7. Steinfield, A. D. Radiology, 1976, 120, 681.
any time-sometimes as late as 7 diagnosis, and after treatment has When the testes become involved during stopped. treatment the patient will usually have other poor prognostic features, and within a few months disease can be expected in bone-marrow, central nervous system, and elsewhere, with short survival thereafter.6 The most important group are those patients with an otherwise good prognosis in whom testicular leukaemia is the sole manifestation of relapse. In this group the condition is usually diagnosed in the first year after completion of chemotherapy. Almost half the patients in the latest M.R.C. report9 had testicular relapse as the sole initial recurrence. The overall incidence was 13%. However, if the testis is a sanctuary site like the meninges and is protected by a blood/testis barrier, then the actuarial risk to patients who might otherwise have achieved a long remission is 30%. There are difficulties in interpreting the data. An apparent excess of testicular relapse in those on the UKALL 11 schedule randomised to receive cyclocan
at
phosphamide could be due to the dropping of spinal radiotherapy as part of their central-nervous-system prophylaxis. More importantly, the results could also be due to a secular trend, since increasing awareness of the problem of testicular disease has changed the diagnostic threshold. Testicular relapse could easily have been overlooked when it occurred in association with haematological relapse, since new or more intensive chemotherapy will often cause shrinkage of the testicular swelling. Control of testicular infiltrates by chemotherapy is also evident from the clustering of cases in the first few months after treatment is stopped; whatever the duration of chemotherapy. This sensitivity to chemotherapy challenges the sanctuary theory. Are testicular infiltrates the source or merely a signal of further systemic disease? The question is critical to the planning of treatment. NIEs et a1. investigated 15 patients who died in apparent complete remission of their leukaemia and found extramedullary disease in 10. 3 of the 4 males had testicular infiltrates, but these 3 (all more than 20 years old) all had leukxmic infiltrates in other organs. MATHÉ et al. 10 found evidence of leukaemia in 12 of 31 patients apparently in complete remission. 4 had disease in at least one of the six bone-marrow sites biopsied, 4 had liver infiltrates, 4 had C.N.S. involvement, and 2 had renal involvement. Testicular disease was found in only 1 of the 13 males who had biopsies. SHARP et al. n 8.
Finklestein, J. Z., Dyment, P. G., Hammond, G. D. Pediatrics, 1969, 43,
9.
Report of M.R.C. Working Party on Childhood Leukæmia. Br. med. J. 1978,
10.
i, 334. Mathé, G., Scharwzenberg, L., Mery, A. M., Cattan, A., Scheider, M., Amiel, J. L., Schlumberger, J. R., Poisson, J., Wajcner, G. ibid. 1966, i,
11.
Sharp,
1042.
4.
640. H.
1403.
L., Nesbit, M. E., D’Angio, G. J., Krivit, W. Cancer, 1967, 20,
