Cat leukemia and the cluster controversy JAMES E. PARKER, MB, FRCP[C]
Two short communications by Jarrett and associates1'1 in Nature in 1964 describing transmission experiments with leukemia (lymphosarcoma) and the isolation of an associated virus-like particle may mark an important milestone in leukemia research. The stimulus to these experiments had been the occurrence of a space and time cluster of eight cases of leukemia in a household of about 30 unrelated cats. In the interim remarkable advances have been made in the understanding of etiologic, epidemiologic and immunologic aspects of cat leukemia.3'4 Since the cat, as with man, is a social, outbred species - as distinct from mice, an inbred species - consideration of the feline leukemia situation is in order. Feline leukemia virus is a ribonucleic acid C-type virus, transmitted horizontally from cat to cat through saliva and other secretions. The virus is infective and can be detected by electron microscopy in the recipient's platelets 3 or 4 weeks after infection. The recipient cat may produce antibodies and become immune or may become chronically infected and excrete virus. Immunity, which develops in a large proportion of infected cats, is directly related to the development of antibodies to feline oncornavirus membrane-associated antigens. Chronically infected cats become immunosuppressed, and hematologic malignant diseases - leukemias or sarcomas - develop in a substantial proportion. The latent period from infection to the development of the tumour can be up to 4 years. Other conditions associated with feline leukemia virus are runting syndrome, aregenerative anemia, fetal abortion, glomerulonephritis and infectious peritonitis. The proportion of cats exposed to feline leukemia virus has been noted Reprint requests to: Dr. James E. Parker, 2151 McCallum Rd., Ste. 302, Abbotsford, BC V2S 3N8
to vary from one area to another: in Boston 63% of cats had antibodies to this virus, in Glasgow 40%, in Detroit 47% and in New York 3%.' Accurate population denominators are not known for cats in many countries, so the overall incidences of the diseases caused by this virus have not been calculated. In California. however, an incidence of 438 cases of leukemia per million cats has been estimated, from two counties.5 While the horizontal transmission of leukemia virus had been demonstrated by Jarrett and colleagues in the laboratory, its occurrence in field situations was a matter of controversy as late as June 1974.0 Prevention of the development of diseases associated with feline leukemia virus in pet cats by a test and removal program, as Hardy and colleagues7 outlined in 1976, would seem, however, to resolve this dilemma. In their study infected cats were removed from 51 of 76 households that contained more than one cat. In the remaining 25 households serving as controls infected cats were not removed. After 3 months only 0.46% of infected cats in the 51 households had become infected whereas in the control households the figure was 19.3%. This trend continued over a 2-year observation period. Clustering of leukemia (lymphosarcoma) cases and isolation of virus particles have also been noted in cattle, another outbred species. Increased lymphocyte counts have been found to persist for many years before overt lymphosarcoma develops. Lymphocytosis and ultimately lymphosarcoma develop in young calves mixed with such animals.' As in other species horizontal transmission of leukemia seems possible in man. Leukemic transformation of engrafted marrow cells has been documented,'-" and leukemia-associated antigens and antibodies cytotoxic to
550 CMA JOURNAL/MARCH 4, 1978/VOL. 118
leukemia cells have been detected in close relatives of persons with leukemia and in others.'2-14 A C-type virus similar to that in cats has been isolated from humans with leukemia'5" and from bone marrow cells of humans before the development of leukemia or malignant histiocytosis.'7 The clustering of leukemia and lymphoma cases in humans has intrigued physicians for many years, there being descriptions in the literature as far back as 1905." Many of the clusters described have represented isolated aggregations of cases or communities where the observed incidence exceeded the expected incidence.1' It seemed strange to Knoxw that parents of children with leukemia had known of other families with this disease, the expected incidence of leukemia being 4 per 100 000 per year. He devised the formula "time x distance" as a standard test of clustering.20 The long latent period observed in cats, however, negates the value of this test in cats. An association between clustering of cases of leukemia in children and an increased incidence of congenital cardiac malformations has been noted in two places21 and perhaps indicates widespread infection within the community. More recently there have been attempts to document case-to-case contact with a long latent period between the appearance of each case.". Perhaps it is time for an intensive, prospective epidemiologic survey of these diseases as a group in man. Such a study might involve notification to central registers at the time of diagnosis. Follow-up might be done by means of a suitable questionnaire completed by, or with the assistance of, the family physician. Because of the postulated long latent period before the development of overt disease, as suggested in other animals, such a study would be lengthy. The principal stumbling blocks to compliance would be
the problem of patient confidentiality and the understandable negative feelings generated by the suggestion of communicability. In cats, however, the incidence of leukemia is so low that only immunologically incompetent animals or those receiving a high dose of virus are at risk. It has been suggested that in cats leukemia represents only the tip of an epidemiologic iceberg.'. A similar situation in man might imply a major public health problem. References 1. JARRETr WFH, MARTIN WB, CRIGHTON G.,
et al: Leukaemia in the cat: transmission experiments with Ieukaemia (lymphosarcoma). Nature (Lond) 202: 566, 1964 2. JARRETr WF, CRAWFORD EM, MARTIN WB,
et al: A virus-like particle associated with leukaemia (lymphosarcoma). Ibid, p 567 3. JARRETT W: Feline Ieukaemia. I Clin Pathol 6 (suppi 25): 43, 1972 4. HARDY .D JR, OLD U, Hass PW, et al: Horizontal transmission of feline leukaemia virus. Nature 244: 266. 1973
5. JARRETF W: Cat leukemia and its viruses, in Advances in Veterinary Science and Comparative Medicine, vol 19, BRANDLY CA, Ct al (eds), New York, Acad Pr, 1975, pp 165-93 6. SCHNEIDER R: Status report: feline leukaemia (C). J Am Vet Med Assoc 164: 1070, 1974 7. HARDY WD JR, McCLELLAND AJ, ZUCKERMAN EE, et al: Prevention of the contagious spread of feline leukaemia virus and the development of leukaemia in pet cats. Nature 263: 326, 1976 8. Advance in leukaemia virus research (E). Vet Rec 96: 49, 1975 9. FIALKOW PJ, THOMAS ED, BRYANT IT, et al: Leukaemic transformation of engrafted human marrow cells in vivo. Lancet 1: 251, 1971 10. THOMAS ED, BRYANT II, BUCKNER CD, et al: Leukaemic transformation of engrafted marrow cells in vivo. Lancet 1: 1310, 1972 10. GOit KO: Cytogenetic evidence of in-vivo leukaemic transformation of engrafted marrow cells. Lancet 1: 1338, 1975 12. BIAS WB, SANTOs GW, Buana PJ, et al: Cytotoxic antibody in normal human serums reactive with tumor cells from acute lymphocytic leukemia. Science 178: 304, 1972 13. PENDERORASS TW, STOLLER RG, MANN DL, et al: Acute myelocytic leukaemia and leukaemia-associated antigens in sisters. Lancet 2: 429, 1975 14. ScHwArrz SO, GREENSPAN I, BROWN ER: Leukemia cluster in Niles, Ill. Immunologic data on families of leukemic patients and others. JAMA 186: 106, 1963 15. GALLAGHER RE, GALLO RC: Type C RNA tumor virus isolated from cultured human acute myclogenous leukemia cells. Science 187: 350. 1975 16. MAK TW,
Kuwrz
5,
MANASTER 3,
et al:
17.
18. 19.
20. 21.
22. 23. 24. 25.
Viral-related information in oncornavirus-like particles isolated from cultures of marrow cells from leukemic patients in relapse and remission (human leukemic cells in culture! 705 RNA/hybridization/C-type virus). Proc Nati Acad Sc, USA 72: 623, 1975 Vosn. GJ, KrnvsT W, GERRARD 3M, et al: Oncornavirus-like particles from cultured bone marrow cells preceding leukemia and malignant histiocytosis (human leukemia/preleukemia/reverse transcriptase). Ibid, p 2804 ARNSPERGER L: Endemisches Aufreten von myeloider Leukamie. Munch Med Wochenschr 52: 9, 1905 HEATH CW: Epidemic leukaemia in man. Community patterns of leukaemia occurrence, in Proceedings of the XIth Congress of the International Society of Haematology, Sydney, Blight, 1966, pp 194-96 K.riox G: Epidemiology of childhood leukaemia in Northumberland and Durham. Br I Prey Soc Med 18: 17, 1964 HEATH CW JR, MANNING MD ZELKOWITZ L: Case clusters in the occurren.e of leukaemia and congenital malformations. Lancet 2: 136, 1964 PARKER JE: Horizontal transmission of leukaemia. Lancet 1: 210, 1974 KEMMOONA I: Direct-contact clusters of acute lymphatic leukaemia. Ibid, p 994 SCHIMPPF SC, SCHIMPFF CR, BRAGER DM, et al: Leukaemia and lymphoma patients interlinked by prior social contact. Lancet 1: 124, 1975 JARRE1-r W, Essex M, MACKEY L, et al: Antibodies in normal and leukemic cats to feline oncornavirus-associated cell membrane antigens. I Nati Cancer Inst 51: 261, 1973
Treatment of urinary tract infection with a single dose of trimethoprim*sulfamethoxazole Ross R. BAILEY, MD, CH B, FRACP, MRCP; GEORGE D. ABBOTT, MD, CH B, FRACP
The duration of antimicrobial therapy commonly prescribed for treating a urinary tract infection ranges from 5 to 21 days. However, there is no convincing evidence that a long course of therapy is more successful than a short course.1" We recently demonstrated that a single 3-g dose of amoxicillin taken orally was as successful in eradicating a urinary tract infection as a 5- to 7day course of the same antibiotic.3 This paper reports our experience in treating urinary tract infections with either a single oral dose or a conventional course of trimethoprim-sulfamethoxazole (TMP-SMX).
tion was considered cured 1 week after The dosage schedule was as follows: completion of treatment if urine ob* Single dose tained by suprapubic bladder aspiration - 1 to 2 years: 0.72 g was sterile or if a voided midstream - 2 to 5 years: 0.96 g urine specimen had a bacterial count - 5 to 12 years: 1.44 g of less than 10000 colonies/mL. * 7-day course Plasma creatinine concentration was - 1 to 2 years: 0.12 g ql2h measured with the use of an auto- 2 to 5 years: 0.24 g ql2h analyser. Standard intravenous uro- 5 to 12 years: 0.48 g ql2h graphy was performed in all patients, and micturating cystourethrography in Resul6 children less than 5 years of age. Forty women aged 17 to 55 years Women In both groups of women 17 of 20 were referred to a special outpatient clinic with asymptomatic bacteriuria, (85%) were cured (Table I). The cystitis (frequency and dysuria) or types of organisms were similar in the acute pyelonephritis (temperature of two groups. A new organism appeared more than 37.80C and loin pain or in the urine within 1 week of treatment tenderness). They were allocated at in all three patients in whom singleMethods and patlnts random to groups receiving TMP-SMX dose treatment failed. Of the patients Urinary tract infection was diagnosed orally in either a single 2.88-g dose who received 5 days of treatment two from the culture of a specimen of (trimethoprim, 0.48 g; sulfamethoxa- did not have the organisms eradicated urine obtained by suprapubic bladder zole, 2.4 g) or 0.96 g (trimethoprim, (Kiebsiella in one and Staphylococcus aspiration.4 Only patients with a urinary 0.16 g; sulfamethoxazole, 0.8 g) every epidermidis in the other) and one patient infected with Escherichia ccli betract pathogen sensitive to TMP-SMX 12 hours for 5 days. were included in the study. The infecTwenty children aged 14 months to came reinfected with Streptococcus fae11 years who were either asymptomatic calis. Only two women had impaired or had cystitis were seen in a special renal function as evidenced by a plasma From the department of renal medicine, pediatric clinic. (Children with acute creatinine concentration of more than Christchurch Hospital, and the department of pediatrics, Christchurch Clinical School, pyelonephritis were not included in the 1.4 mg/dL. One of these was a 37-yearChristchurch, New Zealand study.) They were allocated at random old woman with a renal transplant and Reprint requests to: Dr. Ross R. Bailey, to groups receiving TMP-SMX orally a plasma creatinine concentration of 2.5 Department of renal medicine, Christchurch Hospital, Christchurch, I, New Zealand in either a single dose or a 7-day course. mg/dL; her asymptomatic Kiebsiella CMA JOURNAL/MARCH 4, 1978/VOL. 118 551
Two short communications by Jarrett and associates1'1 in Nature in 1964 describing transmission experiments with leukemia (lymphosarcoma) and the isolation of an associated virus-like particle may mark an important milestone in leukemia research. The stimulus to these experiments had been the occurrence of a space and time cluster of eight cases of leukemia in a household of about 30 unrelated cats. In the interim remarkable advances have been made in the understanding of etiologic, epidemiologic and immunologic aspects of cat leukemia.3'4 Since the cat, as with man, is a social, outbred species - as distinct from mice, an inbred species - consideration of the feline leukemia situation is in order. Feline leukemia virus is a ribonucleic acid C-type virus, transmitted horizontally from cat to cat through saliva and other secretions. The virus is infective and can be detected by electron microscopy in the recipient's platelets 3 or 4 weeks after infection. The recipient cat may produce antibodies and become immune or may become chronically infected and excrete virus. Immunity, which develops in a large proportion of infected cats, is directly related to the development of antibodies to feline oncornavirus membrane-associated antigens. Chronically infected cats become immunosuppressed, and hematologic malignant diseases - leukemias or sarcomas - develop in a substantial proportion. The latent period from infection to the development of the tumour can be up to 4 years. Other conditions associated with feline leukemia virus are runting syndrome, aregenerative anemia, fetal abortion, glomerulonephritis and infectious peritonitis. The proportion of cats exposed to feline leukemia virus has been noted Reprint requests to: Dr. James E. Parker, 2151 McCallum Rd., Ste. 302, Abbotsford, BC V2S 3N8
to vary from one area to another: in Boston 63% of cats had antibodies to this virus, in Glasgow 40%, in Detroit 47% and in New York 3%.' Accurate population denominators are not known for cats in many countries, so the overall incidences of the diseases caused by this virus have not been calculated. In California. however, an incidence of 438 cases of leukemia per million cats has been estimated, from two counties.5 While the horizontal transmission of leukemia virus had been demonstrated by Jarrett and colleagues in the laboratory, its occurrence in field situations was a matter of controversy as late as June 1974.0 Prevention of the development of diseases associated with feline leukemia virus in pet cats by a test and removal program, as Hardy and colleagues7 outlined in 1976, would seem, however, to resolve this dilemma. In their study infected cats were removed from 51 of 76 households that contained more than one cat. In the remaining 25 households serving as controls infected cats were not removed. After 3 months only 0.46% of infected cats in the 51 households had become infected whereas in the control households the figure was 19.3%. This trend continued over a 2-year observation period. Clustering of leukemia (lymphosarcoma) cases and isolation of virus particles have also been noted in cattle, another outbred species. Increased lymphocyte counts have been found to persist for many years before overt lymphosarcoma develops. Lymphocytosis and ultimately lymphosarcoma develop in young calves mixed with such animals.' As in other species horizontal transmission of leukemia seems possible in man. Leukemic transformation of engrafted marrow cells has been documented,'-" and leukemia-associated antigens and antibodies cytotoxic to
550 CMA JOURNAL/MARCH 4, 1978/VOL. 118
leukemia cells have been detected in close relatives of persons with leukemia and in others.'2-14 A C-type virus similar to that in cats has been isolated from humans with leukemia'5" and from bone marrow cells of humans before the development of leukemia or malignant histiocytosis.'7 The clustering of leukemia and lymphoma cases in humans has intrigued physicians for many years, there being descriptions in the literature as far back as 1905." Many of the clusters described have represented isolated aggregations of cases or communities where the observed incidence exceeded the expected incidence.1' It seemed strange to Knoxw that parents of children with leukemia had known of other families with this disease, the expected incidence of leukemia being 4 per 100 000 per year. He devised the formula "time x distance" as a standard test of clustering.20 The long latent period observed in cats, however, negates the value of this test in cats. An association between clustering of cases of leukemia in children and an increased incidence of congenital cardiac malformations has been noted in two places21 and perhaps indicates widespread infection within the community. More recently there have been attempts to document case-to-case contact with a long latent period between the appearance of each case.". Perhaps it is time for an intensive, prospective epidemiologic survey of these diseases as a group in man. Such a study might involve notification to central registers at the time of diagnosis. Follow-up might be done by means of a suitable questionnaire completed by, or with the assistance of, the family physician. Because of the postulated long latent period before the development of overt disease, as suggested in other animals, such a study would be lengthy. The principal stumbling blocks to compliance would be
the problem of patient confidentiality and the understandable negative feelings generated by the suggestion of communicability. In cats, however, the incidence of leukemia is so low that only immunologically incompetent animals or those receiving a high dose of virus are at risk. It has been suggested that in cats leukemia represents only the tip of an epidemiologic iceberg.'. A similar situation in man might imply a major public health problem. References 1. JARRETr WFH, MARTIN WB, CRIGHTON G.,
et al: Leukaemia in the cat: transmission experiments with Ieukaemia (lymphosarcoma). Nature (Lond) 202: 566, 1964 2. JARRETr WF, CRAWFORD EM, MARTIN WB,
et al: A virus-like particle associated with leukaemia (lymphosarcoma). Ibid, p 567 3. JARRETT W: Feline Ieukaemia. I Clin Pathol 6 (suppi 25): 43, 1972 4. HARDY .D JR, OLD U, Hass PW, et al: Horizontal transmission of feline leukaemia virus. Nature 244: 266. 1973
5. JARRETF W: Cat leukemia and its viruses, in Advances in Veterinary Science and Comparative Medicine, vol 19, BRANDLY CA, Ct al (eds), New York, Acad Pr, 1975, pp 165-93 6. SCHNEIDER R: Status report: feline leukaemia (C). J Am Vet Med Assoc 164: 1070, 1974 7. HARDY WD JR, McCLELLAND AJ, ZUCKERMAN EE, et al: Prevention of the contagious spread of feline leukaemia virus and the development of leukaemia in pet cats. Nature 263: 326, 1976 8. Advance in leukaemia virus research (E). Vet Rec 96: 49, 1975 9. FIALKOW PJ, THOMAS ED, BRYANT IT, et al: Leukaemic transformation of engrafted human marrow cells in vivo. Lancet 1: 251, 1971 10. THOMAS ED, BRYANT II, BUCKNER CD, et al: Leukaemic transformation of engrafted marrow cells in vivo. Lancet 1: 1310, 1972 10. GOit KO: Cytogenetic evidence of in-vivo leukaemic transformation of engrafted marrow cells. Lancet 1: 1338, 1975 12. BIAS WB, SANTOs GW, Buana PJ, et al: Cytotoxic antibody in normal human serums reactive with tumor cells from acute lymphocytic leukemia. Science 178: 304, 1972 13. PENDERORASS TW, STOLLER RG, MANN DL, et al: Acute myelocytic leukaemia and leukaemia-associated antigens in sisters. Lancet 2: 429, 1975 14. ScHwArrz SO, GREENSPAN I, BROWN ER: Leukemia cluster in Niles, Ill. Immunologic data on families of leukemic patients and others. JAMA 186: 106, 1963 15. GALLAGHER RE, GALLO RC: Type C RNA tumor virus isolated from cultured human acute myclogenous leukemia cells. Science 187: 350. 1975 16. MAK TW,
Kuwrz
5,
MANASTER 3,
et al:
17.
18. 19.
20. 21.
22. 23. 24. 25.
Viral-related information in oncornavirus-like particles isolated from cultures of marrow cells from leukemic patients in relapse and remission (human leukemic cells in culture! 705 RNA/hybridization/C-type virus). Proc Nati Acad Sc, USA 72: 623, 1975 Vosn. GJ, KrnvsT W, GERRARD 3M, et al: Oncornavirus-like particles from cultured bone marrow cells preceding leukemia and malignant histiocytosis (human leukemia/preleukemia/reverse transcriptase). Ibid, p 2804 ARNSPERGER L: Endemisches Aufreten von myeloider Leukamie. Munch Med Wochenschr 52: 9, 1905 HEATH CW: Epidemic leukaemia in man. Community patterns of leukaemia occurrence, in Proceedings of the XIth Congress of the International Society of Haematology, Sydney, Blight, 1966, pp 194-96 K.riox G: Epidemiology of childhood leukaemia in Northumberland and Durham. Br I Prey Soc Med 18: 17, 1964 HEATH CW JR, MANNING MD ZELKOWITZ L: Case clusters in the occurren.e of leukaemia and congenital malformations. Lancet 2: 136, 1964 PARKER JE: Horizontal transmission of leukaemia. Lancet 1: 210, 1974 KEMMOONA I: Direct-contact clusters of acute lymphatic leukaemia. Ibid, p 994 SCHIMPPF SC, SCHIMPFF CR, BRAGER DM, et al: Leukaemia and lymphoma patients interlinked by prior social contact. Lancet 1: 124, 1975 JARRE1-r W, Essex M, MACKEY L, et al: Antibodies in normal and leukemic cats to feline oncornavirus-associated cell membrane antigens. I Nati Cancer Inst 51: 261, 1973
Treatment of urinary tract infection with a single dose of trimethoprim*sulfamethoxazole Ross R. BAILEY, MD, CH B, FRACP, MRCP; GEORGE D. ABBOTT, MD, CH B, FRACP
The duration of antimicrobial therapy commonly prescribed for treating a urinary tract infection ranges from 5 to 21 days. However, there is no convincing evidence that a long course of therapy is more successful than a short course.1" We recently demonstrated that a single 3-g dose of amoxicillin taken orally was as successful in eradicating a urinary tract infection as a 5- to 7day course of the same antibiotic.3 This paper reports our experience in treating urinary tract infections with either a single oral dose or a conventional course of trimethoprim-sulfamethoxazole (TMP-SMX).
tion was considered cured 1 week after The dosage schedule was as follows: completion of treatment if urine ob* Single dose tained by suprapubic bladder aspiration - 1 to 2 years: 0.72 g was sterile or if a voided midstream - 2 to 5 years: 0.96 g urine specimen had a bacterial count - 5 to 12 years: 1.44 g of less than 10000 colonies/mL. * 7-day course Plasma creatinine concentration was - 1 to 2 years: 0.12 g ql2h measured with the use of an auto- 2 to 5 years: 0.24 g ql2h analyser. Standard intravenous uro- 5 to 12 years: 0.48 g ql2h graphy was performed in all patients, and micturating cystourethrography in Resul6 children less than 5 years of age. Forty women aged 17 to 55 years Women In both groups of women 17 of 20 were referred to a special outpatient clinic with asymptomatic bacteriuria, (85%) were cured (Table I). The cystitis (frequency and dysuria) or types of organisms were similar in the acute pyelonephritis (temperature of two groups. A new organism appeared more than 37.80C and loin pain or in the urine within 1 week of treatment tenderness). They were allocated at in all three patients in whom singleMethods and patlnts random to groups receiving TMP-SMX dose treatment failed. Of the patients Urinary tract infection was diagnosed orally in either a single 2.88-g dose who received 5 days of treatment two from the culture of a specimen of (trimethoprim, 0.48 g; sulfamethoxa- did not have the organisms eradicated urine obtained by suprapubic bladder zole, 2.4 g) or 0.96 g (trimethoprim, (Kiebsiella in one and Staphylococcus aspiration.4 Only patients with a urinary 0.16 g; sulfamethoxazole, 0.8 g) every epidermidis in the other) and one patient infected with Escherichia ccli betract pathogen sensitive to TMP-SMX 12 hours for 5 days. were included in the study. The infecTwenty children aged 14 months to came reinfected with Streptococcus fae11 years who were either asymptomatic calis. Only two women had impaired or had cystitis were seen in a special renal function as evidenced by a plasma From the department of renal medicine, pediatric clinic. (Children with acute creatinine concentration of more than Christchurch Hospital, and the department of pediatrics, Christchurch Clinical School, pyelonephritis were not included in the 1.4 mg/dL. One of these was a 37-yearChristchurch, New Zealand study.) They were allocated at random old woman with a renal transplant and Reprint requests to: Dr. Ross R. Bailey, to groups receiving TMP-SMX orally a plasma creatinine concentration of 2.5 Department of renal medicine, Christchurch Hospital, Christchurch, I, New Zealand in either a single dose or a 7-day course. mg/dL; her asymptomatic Kiebsiella CMA JOURNAL/MARCH 4, 1978/VOL. 118 551
