162
likely that this method can be used as a predictive test in symptom-free individuals with the gene for Huntington’s chorea. Institute of Clinical Investigation and School of Bioanalysis,
ERNESTO BONILLA NELLY VARGAS-URRIBARRI FELIX NAVAS
Faculty of Medicine, University of Zulia, Maracaibo, Venezuela
ANAPHYLACTIC REACTION TO INTRALESIONAL B.C.G.
SIR,-Severe side-effects’and
two deaths3 have been in cancer patients treated with B.C.G. Among the severe side-effects is anaphylaxis or immediate hypersensitivity, and we report here what we believe to be the second instance in a cancer patient3 and the third after B.C.G. adminis-
reported
tration.4 The patient was a 74-year-old male who had had a nodular level v malignant melanoma excised from his left wrist in July, 1977. Left axillary lymph-node dissection in September, 1977, revealed a mass of lymph-nodes involved with metastatic melanoma. During the same hospital admission, a partial gastrectomy was performed because of adenocarcinoma of the stomach with 5 of 8 mesenteric lymph-nodes involved with adenocarcinoma. In October, 1977, chemotherapy was started; in addition, the patient agreed to active immunotherapy with low-dose B.c.G. (2-5 x 105 viable organisms/injection) mixed with a low number (2 x 107) of mitomycin-treated allogeneic melanoma cells. He tolerated his chemotherapy poorly and missed his third course of immunotherapy. In late December, 1977, 25 cutaneous metastases and a 6 x 6 cm axillary mass were identified in the left arm. He was reevaluated for systemic metastatic disease including bone, brain, and liver scans, and liver-function tests, which were normal. After each of his two previous B.c.G./tumour vaccinations an induration of 1-1.5cm, had developed 48 h after injection and there was a progressive decline in blocking activity . to his lymphocyte cytotoxicity against 3 of 4 melanoma lines. In January, a trial of intralesional B.c.G. was begun because the patient had 85 lesions, although no evidence of systemic disease, and he was reluctant to accept isolated limb perfusion chemotherapy. He had been P.P.D.-negative on two occasions, but the P.P.D. had been given on the same day as his immunotherapy for reasons of convenience (he lived 60 miles from the hospital during a bad winter), allowing for antigenic competition between the P.P.D. and B.c.G. A single 40 mg intramuscular injection of diphenhydramine was given 1 h before injection. 270 .g B.c.G. (Glaxo) (approximately 2.7x103 viable organisms) had been injected into four of the lesions, divided on the basis of their mean diameters, when the patient complained of dry mouth and feeling sick. Several seconds later he became apnoeic and cyanotic. Diphenhydramine, 35 mg, was given intravenously and a tourniquet was placed above the injection site. 30 s later spontaneous respiration and consciousness returned and blood-pressure was 60/40. The patient was given 0.22 ml adrenaline 1:10 00 0 intravenously and 0.5ml adrenaline 1:1000 subcutaneously. Blood-pressure returned to 120/80 several minutes later. Plasma volume was expanded with 1000 ml of normal saline solution and 25 g of ’Albumisol’. Minor expiratory rhonchi were observed at first but there was no definite evidence of bronchospasm at any time. The patient recovered uneventfully and had the expected pyrexia of 38-6°C 9 h after B.c.G. All of the injected lesions and several others became indurated and 1. 2.
Bluming, A. Z. New Eng. J. Med. 1973, 289, 860. Sparks, F. C., Silverstein, M. J., Hunt, J. S., Haskell,
C. M., Pilch, Y. H., Morton, D. L. ibid. 1973, 289, 827. 3. McKhann, C. F., Hendrickson, C. G., Spitler, L. E., Gunnarrsson, A., Banerjee, D., Nelson, W. R. Cancer, 1975, 35, 514. 4. Diamond, J. Lancet, 1968, ii, 875.
erythematous during the 48
h after injection. The patient was discharged 72 h after the apparent anaphylactic reaction. During the following 12 weeks all four injected lesions completely regressed. Four uninjected lesions also reduced very substantially in size, while in several others there was bullous formation after three weeks, followed by areas of necrosis and peripheral regrowth. During this time, no new lesions were identified in the arm, but his axillary mass proliferated rapidly and abundant new skin lesions developed on the chest wall,
presumably because of retrograde lymphatic dissemination. The prognosig of this patient was extremely poor and yet we justified the trial with intralesional B.C.G. with its risks of sideeffects because no other treatment was available and he had no evidence of systemic disease. Nevertheless, the episode might well have killed a less fit man of his age or at least produced more severe sequels. While anaphylaxis after B.C.G. is uncommon, particularly at the low dose we used with the Glaxo strain, in an immunocompetent patient who has been injected intradermally with B.C.G. previously the usual precautions should be exercised and an earlier and more sustained course of antihistaminics probably given beforehand. A potential solution to problems encountered with intralesional B.C.G. is suggested by the promising early response to the clinical use of glucan, a powerful non-immunogenic reticuloendothelial stimulant. This active component of zymosan can apparently resolve subcutaneous melanoma deposits6 which are generally regarded to be refractory to intralesional B.C.G. or vaccinia. A conclusion to the contrary’ can probably be discounted since it was based on the use of single-dose regimens of glucan in animal models of doubtful relevance to cancer in man. JULIAN W. PROCTOR BERNARD ZIDAR Divisions of Radiation Therapy, Medical Oncology, MARC POMERANTZ Internal Medicine and YASUHIRO YAMAMURA Cancer Research, CHEE PING ENG Allegheny General Hospital, DARIA WOODSIDE Pittsburgh, Philadelphia 15212, U.S.A.
VIRUS-ANTIBODY TITRES IN CHRONIC GLOMERULONEPHRITIS
SIR,-A role for virus infection has been postulated in systemic
lupus erythematosus (S.L.E.). This concept is supported by high antibody titres to measles, rubella, parainfluenza I’l-3 and parainfluenza III.4 In chronic glomerulonephritis (G.N.), the aetiology of which is usually unknown, there are similarities with lupus nephritis, but virus-antibody studies have not been reported. We studied antiviral activity in the sera from 60 patients with chronic G.N. (aged 16-64), 40 patients with S.L.E. (35 of them with lupus nephritis, aged 16-56), and 97 healthy age-matched blood-donors. Antibody titres to measles (100 patients), influenza A2 (82 patients), and parainfluenza i-in viruses (87 patients) were investigated by hxmagglutination inhibition test; antibody to adenovirus antigen (46 patients) was sought by complement fixation. In both patients and controls antibodies to measles were the most common. Titres above 1/100 were seen in only 6 of 97 controls (6%) but in 26 out of 60 G.N. patients (43%) and in 18 out of 40 patients with S.L.E. (45%). The mean antibody titre to measles was 1/41 in blood-donors, 1/471 in chronic 5. DiLuzio, N. R., Riggi, S. J. J. reticuloendothel. Soc. 1970, 8, 465. 6. Mansell, P. W. A., DiLuzio, N. R., McNamee, R., Rowden, G., Proctor, J. W. Ann N.Y. Acad. Sci. 1976, 277, 20. 7. Hunter, J. T., Meltzer, M. S., Ribi, E., Fidler, I. J., Zbar, B., Rapp, H. J. J. natn. Cancer Inst. 1978, 60, 419.
1. Phillips, P. E., Christian, L. Arthr. Rheum. 1969, 12, 688. 2. Hard, R. E , and others ibid 1970, 13, 324. 3. Nassonova, V. A., and other. Sov. Med. 1973, 5, 7. 4. Hollinger, T., and others. Arthr. Rheum. 1971, 14, 1.
163 MEAN ANTIBODY TITRES
(RECIPROCAL)
TO VIRAL ANTIGENS IN
G.N. AND S.L.E.
We think that measurement of
lactic acid, either by method (availenzymatic gas/liquid chromatography able in kit form), is a rapid method providing useful additional or
by
C.S.F.
an
information for the differential diagnosis of meningitis. In our experience, the lactic-acid level was of the greatest value in differentiating tuberculous from viral meningitis, since in most of our cases of M. tuberculosis infection, no organisms were seen in direct smears of the c.s.F., chemical and cellular parameters were not always helpful in diagnosis, and culture takes time.
G.N., and
1/325 in
The patterns for influenza A2 and B and parainfluenza m were the same (see tabled— namely, higher mean antibody titres in G.N. and S.L.E. The antibody titres to parainfluenza i and II in G.N. and S.L.E. were slightly higher, and antibodies titres to adenovirus lower, than in controls. Thus antibody titres to measles, influenza A2 and B, and parainfluenza in in chronic G.N. were significantly higher than in controls, as in s.L.E. I. E. TAREYEVA Laboratory of Nephrology, R. G. FILIMONOVA 1st Moscow Medical Setchenov Institute, M. MAKSUDOVA 119021 Moscow, U.S.S.R., E. CHOLETSKAYA and Institute of Virology, Moscow L. FADEEVA s.L.E.
Department of Microbiology, St Pierre Hospital, 1000 Brussels, Belgium
S. LAUWERS
patients.
LACTIC-ACID CONCENTRATION IN CEREBROSPINAL FLUID AND DIFFERENTIAL DIAGNOSIS OF MENINGITIS
Bf POLYMORPHISM AND ANKYLOSING
SPONDYLITIS
SIR,-Arnason et al. reported their findings of Bf (properdin factor B) polymorphism in anklosing spondylitis (A.s.). They studied 19 Icelandic A.s. patients, all B27-positive, with enough relatives for their HLA and Bf haplotypes to be derived. Surprisingly, all patients carried on the same chromosome the B27 marker and the BP allele. This strong association was not confirmed in 46 B27-positive healthy individuals, only 50% of whom showed this surprising B27/BP haplotype association. We have typed 44 Italian A.s. patients for Bf (all carried the B27 antigen, none were B27 homozygous): 27 had Bf SS, 14 SF, 2 SlS, and 1 FF (see table). Phenotype frequencies of the Bf PHENOTYPES
IN
B27-POSITIVE
A.S. PATIENTS
SIR,-c.s.F. lactic-acid determination is
a useful additional for the early detection of bacterial meningitis, in both untreated and partially treated cases.’-3 In our experience, the c.s.F. lactic acid was above 35 mg/dl in all initial’ c.s.F. specimens from patients with bacterial meningitis, whereas in specimens from patients with viral meningitis, lactic-acid levels have been consistently below 35mg/dl. We have measured c.s.F. lactic acid in all patients admitted to our hospital with a presumptive diagnosis of meningitis for the past two years. Using gas/liquid chromatography we have examined 174 c.s.F. specimens from 118 patients, including 46 cases of bacterial meningitis (16 due to Neisseria meningitidis, 8 to Haemophilus influenza, 7 to Streptococcus pneumoniae, 11 to Mycobacterium tuberculosis, 2 to Listeria monocytogenes, 1 to Strep. agalactiae, and 1 to Staphylococcus aureus; and 20 cases of viral meningitis, 11 of which were proven by C.S.F. culture or by antibody detection in c.s.F. None of these patients had been treated with antibiotics. 52 patients with normal c.s.F. acted as controls. All the controls and viral cases had c.s.F. lactic-acid values lower than 35 mg/dl and all bacterial cases had levels significantly higher than 35 mg/dl, except for 2 patients with meningococcoemia (N. meningitidis group B) with only minor involvement of C.S.F. where we found values of 29 and 31 mg/dl. Further, the c.s.F. lactic acid can be useful in evaluating the response to treatment. In all our cases of pyogenic meningitis with a favourable response to treatment the lactic-acid level fell almost to normal when the second sample of c.s.F. was taken on the 10th day of therapy, whereas in 1 patient who deteriorated clinically a high level persisted. In tuberculous meningitis the c.s.F. lactic acid took several weeks to return to normal. In 2 of these cases neurological complications were reflected by high levels of lactic acid.
diagnostic
1. Brook,
test
I, Bricknell, K. S., Overturf, G. D., Fmegold, S. M. J. infect. Dis. 1978, 137, 384. 2. Controni, G, Rodriguez, W. J., Hicks, J. M., Ficke, M., Ross, S., Friedman, G., Khan, W. J. Pediat. 1977, 91, 379. 3. Ferguson, I. R., Tearle, P. V. J. clin. Path. 1977, 30, 1163.
Bf locus are in the Hardy-Weinberg equilibrium and in good agreement with our control group (X2s=6.30, 0.25
likely that this method can be used as a predictive test in symptom-free individuals with the gene for Huntington’s chorea. Institute of Clinical Investigation and School of Bioanalysis,
ERNESTO BONILLA NELLY VARGAS-URRIBARRI FELIX NAVAS
Faculty of Medicine, University of Zulia, Maracaibo, Venezuela
ANAPHYLACTIC REACTION TO INTRALESIONAL B.C.G.
SIR,-Severe side-effects’and
two deaths3 have been in cancer patients treated with B.C.G. Among the severe side-effects is anaphylaxis or immediate hypersensitivity, and we report here what we believe to be the second instance in a cancer patient3 and the third after B.C.G. adminis-
reported
tration.4 The patient was a 74-year-old male who had had a nodular level v malignant melanoma excised from his left wrist in July, 1977. Left axillary lymph-node dissection in September, 1977, revealed a mass of lymph-nodes involved with metastatic melanoma. During the same hospital admission, a partial gastrectomy was performed because of adenocarcinoma of the stomach with 5 of 8 mesenteric lymph-nodes involved with adenocarcinoma. In October, 1977, chemotherapy was started; in addition, the patient agreed to active immunotherapy with low-dose B.c.G. (2-5 x 105 viable organisms/injection) mixed with a low number (2 x 107) of mitomycin-treated allogeneic melanoma cells. He tolerated his chemotherapy poorly and missed his third course of immunotherapy. In late December, 1977, 25 cutaneous metastases and a 6 x 6 cm axillary mass were identified in the left arm. He was reevaluated for systemic metastatic disease including bone, brain, and liver scans, and liver-function tests, which were normal. After each of his two previous B.c.G./tumour vaccinations an induration of 1-1.5cm, had developed 48 h after injection and there was a progressive decline in blocking activity . to his lymphocyte cytotoxicity against 3 of 4 melanoma lines. In January, a trial of intralesional B.c.G. was begun because the patient had 85 lesions, although no evidence of systemic disease, and he was reluctant to accept isolated limb perfusion chemotherapy. He had been P.P.D.-negative on two occasions, but the P.P.D. had been given on the same day as his immunotherapy for reasons of convenience (he lived 60 miles from the hospital during a bad winter), allowing for antigenic competition between the P.P.D. and B.c.G. A single 40 mg intramuscular injection of diphenhydramine was given 1 h before injection. 270 .g B.c.G. (Glaxo) (approximately 2.7x103 viable organisms) had been injected into four of the lesions, divided on the basis of their mean diameters, when the patient complained of dry mouth and feeling sick. Several seconds later he became apnoeic and cyanotic. Diphenhydramine, 35 mg, was given intravenously and a tourniquet was placed above the injection site. 30 s later spontaneous respiration and consciousness returned and blood-pressure was 60/40. The patient was given 0.22 ml adrenaline 1:10 00 0 intravenously and 0.5ml adrenaline 1:1000 subcutaneously. Blood-pressure returned to 120/80 several minutes later. Plasma volume was expanded with 1000 ml of normal saline solution and 25 g of ’Albumisol’. Minor expiratory rhonchi were observed at first but there was no definite evidence of bronchospasm at any time. The patient recovered uneventfully and had the expected pyrexia of 38-6°C 9 h after B.c.G. All of the injected lesions and several others became indurated and 1. 2.
Bluming, A. Z. New Eng. J. Med. 1973, 289, 860. Sparks, F. C., Silverstein, M. J., Hunt, J. S., Haskell,
C. M., Pilch, Y. H., Morton, D. L. ibid. 1973, 289, 827. 3. McKhann, C. F., Hendrickson, C. G., Spitler, L. E., Gunnarrsson, A., Banerjee, D., Nelson, W. R. Cancer, 1975, 35, 514. 4. Diamond, J. Lancet, 1968, ii, 875.
erythematous during the 48
h after injection. The patient was discharged 72 h after the apparent anaphylactic reaction. During the following 12 weeks all four injected lesions completely regressed. Four uninjected lesions also reduced very substantially in size, while in several others there was bullous formation after three weeks, followed by areas of necrosis and peripheral regrowth. During this time, no new lesions were identified in the arm, but his axillary mass proliferated rapidly and abundant new skin lesions developed on the chest wall,
presumably because of retrograde lymphatic dissemination. The prognosig of this patient was extremely poor and yet we justified the trial with intralesional B.C.G. with its risks of sideeffects because no other treatment was available and he had no evidence of systemic disease. Nevertheless, the episode might well have killed a less fit man of his age or at least produced more severe sequels. While anaphylaxis after B.C.G. is uncommon, particularly at the low dose we used with the Glaxo strain, in an immunocompetent patient who has been injected intradermally with B.C.G. previously the usual precautions should be exercised and an earlier and more sustained course of antihistaminics probably given beforehand. A potential solution to problems encountered with intralesional B.C.G. is suggested by the promising early response to the clinical use of glucan, a powerful non-immunogenic reticuloendothelial stimulant. This active component of zymosan can apparently resolve subcutaneous melanoma deposits6 which are generally regarded to be refractory to intralesional B.C.G. or vaccinia. A conclusion to the contrary’ can probably be discounted since it was based on the use of single-dose regimens of glucan in animal models of doubtful relevance to cancer in man. JULIAN W. PROCTOR BERNARD ZIDAR Divisions of Radiation Therapy, Medical Oncology, MARC POMERANTZ Internal Medicine and YASUHIRO YAMAMURA Cancer Research, CHEE PING ENG Allegheny General Hospital, DARIA WOODSIDE Pittsburgh, Philadelphia 15212, U.S.A.
VIRUS-ANTIBODY TITRES IN CHRONIC GLOMERULONEPHRITIS
SIR,-A role for virus infection has been postulated in systemic
lupus erythematosus (S.L.E.). This concept is supported by high antibody titres to measles, rubella, parainfluenza I’l-3 and parainfluenza III.4 In chronic glomerulonephritis (G.N.), the aetiology of which is usually unknown, there are similarities with lupus nephritis, but virus-antibody studies have not been reported. We studied antiviral activity in the sera from 60 patients with chronic G.N. (aged 16-64), 40 patients with S.L.E. (35 of them with lupus nephritis, aged 16-56), and 97 healthy age-matched blood-donors. Antibody titres to measles (100 patients), influenza A2 (82 patients), and parainfluenza i-in viruses (87 patients) were investigated by hxmagglutination inhibition test; antibody to adenovirus antigen (46 patients) was sought by complement fixation. In both patients and controls antibodies to measles were the most common. Titres above 1/100 were seen in only 6 of 97 controls (6%) but in 26 out of 60 G.N. patients (43%) and in 18 out of 40 patients with S.L.E. (45%). The mean antibody titre to measles was 1/41 in blood-donors, 1/471 in chronic 5. DiLuzio, N. R., Riggi, S. J. J. reticuloendothel. Soc. 1970, 8, 465. 6. Mansell, P. W. A., DiLuzio, N. R., McNamee, R., Rowden, G., Proctor, J. W. Ann N.Y. Acad. Sci. 1976, 277, 20. 7. Hunter, J. T., Meltzer, M. S., Ribi, E., Fidler, I. J., Zbar, B., Rapp, H. J. J. natn. Cancer Inst. 1978, 60, 419.
1. Phillips, P. E., Christian, L. Arthr. Rheum. 1969, 12, 688. 2. Hard, R. E , and others ibid 1970, 13, 324. 3. Nassonova, V. A., and other. Sov. Med. 1973, 5, 7. 4. Hollinger, T., and others. Arthr. Rheum. 1971, 14, 1.
163 MEAN ANTIBODY TITRES
(RECIPROCAL)
TO VIRAL ANTIGENS IN
G.N. AND S.L.E.
We think that measurement of
lactic acid, either by method (availenzymatic gas/liquid chromatography able in kit form), is a rapid method providing useful additional or
by
C.S.F.
an
information for the differential diagnosis of meningitis. In our experience, the lactic-acid level was of the greatest value in differentiating tuberculous from viral meningitis, since in most of our cases of M. tuberculosis infection, no organisms were seen in direct smears of the c.s.F., chemical and cellular parameters were not always helpful in diagnosis, and culture takes time.
G.N., and
1/325 in
The patterns for influenza A2 and B and parainfluenza m were the same (see tabled— namely, higher mean antibody titres in G.N. and S.L.E. The antibody titres to parainfluenza i and II in G.N. and S.L.E. were slightly higher, and antibodies titres to adenovirus lower, than in controls. Thus antibody titres to measles, influenza A2 and B, and parainfluenza in in chronic G.N. were significantly higher than in controls, as in s.L.E. I. E. TAREYEVA Laboratory of Nephrology, R. G. FILIMONOVA 1st Moscow Medical Setchenov Institute, M. MAKSUDOVA 119021 Moscow, U.S.S.R., E. CHOLETSKAYA and Institute of Virology, Moscow L. FADEEVA s.L.E.
Department of Microbiology, St Pierre Hospital, 1000 Brussels, Belgium
S. LAUWERS
patients.
LACTIC-ACID CONCENTRATION IN CEREBROSPINAL FLUID AND DIFFERENTIAL DIAGNOSIS OF MENINGITIS
Bf POLYMORPHISM AND ANKYLOSING
SPONDYLITIS
SIR,-Arnason et al. reported their findings of Bf (properdin factor B) polymorphism in anklosing spondylitis (A.s.). They studied 19 Icelandic A.s. patients, all B27-positive, with enough relatives for their HLA and Bf haplotypes to be derived. Surprisingly, all patients carried on the same chromosome the B27 marker and the BP allele. This strong association was not confirmed in 46 B27-positive healthy individuals, only 50% of whom showed this surprising B27/BP haplotype association. We have typed 44 Italian A.s. patients for Bf (all carried the B27 antigen, none were B27 homozygous): 27 had Bf SS, 14 SF, 2 SlS, and 1 FF (see table). Phenotype frequencies of the Bf PHENOTYPES
IN
B27-POSITIVE
A.S. PATIENTS
SIR,-c.s.F. lactic-acid determination is
a useful additional for the early detection of bacterial meningitis, in both untreated and partially treated cases.’-3 In our experience, the c.s.F. lactic acid was above 35 mg/dl in all initial’ c.s.F. specimens from patients with bacterial meningitis, whereas in specimens from patients with viral meningitis, lactic-acid levels have been consistently below 35mg/dl. We have measured c.s.F. lactic acid in all patients admitted to our hospital with a presumptive diagnosis of meningitis for the past two years. Using gas/liquid chromatography we have examined 174 c.s.F. specimens from 118 patients, including 46 cases of bacterial meningitis (16 due to Neisseria meningitidis, 8 to Haemophilus influenza, 7 to Streptococcus pneumoniae, 11 to Mycobacterium tuberculosis, 2 to Listeria monocytogenes, 1 to Strep. agalactiae, and 1 to Staphylococcus aureus; and 20 cases of viral meningitis, 11 of which were proven by C.S.F. culture or by antibody detection in c.s.F. None of these patients had been treated with antibiotics. 52 patients with normal c.s.F. acted as controls. All the controls and viral cases had c.s.F. lactic-acid values lower than 35 mg/dl and all bacterial cases had levels significantly higher than 35 mg/dl, except for 2 patients with meningococcoemia (N. meningitidis group B) with only minor involvement of C.S.F. where we found values of 29 and 31 mg/dl. Further, the c.s.F. lactic acid can be useful in evaluating the response to treatment. In all our cases of pyogenic meningitis with a favourable response to treatment the lactic-acid level fell almost to normal when the second sample of c.s.F. was taken on the 10th day of therapy, whereas in 1 patient who deteriorated clinically a high level persisted. In tuberculous meningitis the c.s.F. lactic acid took several weeks to return to normal. In 2 of these cases neurological complications were reflected by high levels of lactic acid.
diagnostic
1. Brook,
test
I, Bricknell, K. S., Overturf, G. D., Fmegold, S. M. J. infect. Dis. 1978, 137, 384. 2. Controni, G, Rodriguez, W. J., Hicks, J. M., Ficke, M., Ross, S., Friedman, G., Khan, W. J. Pediat. 1977, 91, 379. 3. Ferguson, I. R., Tearle, P. V. J. clin. Path. 1977, 30, 1163.
Bf locus are in the Hardy-Weinberg equilibrium and in good agreement with our control group (X2s=6.30, 0.25
