- Email: [email protected]
Low-density-lipoprotein apheresis
Titres
are expressed as geometric mean titres, except for rose bengal test which is expressed as proportion of positives. Table: Antibody responses after vaccination with WC/rBS or natural infection with Vibrio cholerae 01
toxin (anti-CT) of IgA and IgG classes by GM1-ELISA method were determined as described.’ Brucella done the method were standard slide by agglutination assays and the rose bengal test.5 was As shown in the table, a significant increase (p<0-05) noted in the geometric mean titres of vibriocidal, CT IgA and IgG antibodies after vaccination with the WC/rBS. Brucella antibodies, on the other hand, did not vary between specimens before and after vaccination. Titres of 25 in four subjects and 50 in one subject were noted in the prevaccination specimens, the rest being negative (<25). After vaccination, no change occurred among the negative sera, and the same or decreased titres were noted among the positive sera. Sera were negative by rose bengal test for all specimens before and after vaccination. For comparison, paired sera from six patients (12-68 years old) naturally infected with V cholerae 01 were also tested. Again, a significant increase in all three V cholerae antibodies was noted. Initially, they all were negative for brucella antibodies by the slide and rose bengal test, but 2 weeks later, four patients developed titres of 25, 50, 100, and 800, the last three with concomitant positivity in the rose
bengal test.
Based on these findings, we conclude that vaccination with WC/rBS is not a source of false-positive brucella antibody, as observed following natural infection with V cholerae 01. *Rodolfo E
Begue,
Alfredo Guillen, Rina Meza
*Division of Pediatric Infectious Diseases, Children’s Hospital, Louisiana State University, New Orleans, LA 70112, USA; Instituto Nacional de Salud, Lima, Peru; and US Navy Medical Research Institute, Lima
1 2
3 4
5
Centers for Disease Control. Update: cholera-western hemisphere 1992. MMWR 1993; vol 42, no 5: 89-91. Gotuzzo E, Alarcon GS, Bocanegra TS, et al. Articular involvement in human brucellosis: a retrospective analysis of 304 cases. Semin Arthritis Rheum 1982; 12: 245-55. Eisele CW, McCullough NB, Beal GA. Brucella antibodies following cholera vaccination. Ann Intern Med 1948; 28: 833-37. Jetborn M, Svennerholm A-M, Holmgren J. Safety and immunogenicity of an oral recombinant cholera B subunit: whole cell vaccine in Swedish volunteers. Vaccine 1992; 10: 130-32. Moyer NP, Holcomb LA, Hausler WJ Jr. Brucella. In: Balows A, Hausler WJ Jr, Herrmann KL, Isenberg HD, Shadomy HJ, eds. Manual of clinical microbiology, 5th ed, Washington, DC: American Society for Microbiology, 1991: 457-62.
Low-density-lipoprotein apheresis SIR—In
the
Familial
Hypercholesterolaemia Regression Study (FHRS) (April 1, p 811) Thompson and co-workers compared suboptimal lipid-lowering therapy (simvastatin 40 low-densitymg daily) supplemented by half-strength lipoprotein (LDL) apheresis at one plasma volume fortnightly with optimal lipid-lowering drug therapy (simvastatin 40 mg + colestipol 20 g daily) in patients with 116
LDL-cholesterol above 8 mmol/L. Most patients with familial hypercholesterolaemia and an LDL-cholesterol around 8 mmol/L respond to combined drug therapy with a "statin" plus colestipol or cholestyramine, LDL-cholesterol falling by 50-60%.’ The patients in FHRS had initial LDLcholesterol values of about 8 mmol/L and there was no reason to suspect that they would not respond sufficiently to combined drug therapy. This notion is supported by the 54% decrease in LDL-cholesterol in the group treated with alone. The world-wide consensus is to apply LDL apheresis only in patients whose LDL-cholesterol remains despite very high maximal lipid-lowering therapy with diet and drugs. LDL apheresis, given weekly, reduces time-averaged LDLcholesterol in these patients by 40-60%.2-4 The key question is whether the reduction achieved induces regression or stops the progression of atherosclerosis. This question can be answered by a controlled study, and Thompson et al are right to note that all published studies on atherosclerosis during LDL apheresis have been uncontrolled.’ The first controlled one (FHRS) is in patients without indication for LDL apheresis, and the apheresis was fortnightly instead of weekly. This is not the study we needed.
drugs
C J Olbricht Nephrology,
Division of
Medical School Hannover, D30625 Hannover,
Germany
Hoeg JM, Brewer HB. 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors in the treatment of hypercholesterolaemia. JAMA
1
2
3
4
1987; 258: 3532-36. Olbricht CJ. Extracorporeal treatment of hypercholesterolaemia. Nephrol Dial Transplant 1993; 8: 814-20. Lane DM, McConathy WH, Laughlin LO, et al. Weekly treatment of diet/drug-resistant hypercholesterolaemia with the heparin-induced extracorporeal low-density lipoprotein precipitation (HELP) system by selective plasma low-density lipoprotein removal. Am J Cardiol 1993; 71: 816-22. Gordon BR, Saal SD. Advances in LDL-apheresis for the treatment of severe hypercholesterolaemia. Curr Opin Lipidol 1994; 5: 69-73.
SiR-Why in FHRS have procedures that resulted in nearly identical LDL-cholesterol concentrations been compared? Intervention studies with drugs (colestipol, cholestyramine, lovastatin, simvastatin, niacin), life-style modification, or partial ileal bypass have shown that it is not the way LDLcholesterol is lowered but the LDL-cholesterol concentration reached that is important for the effect on coronary heart disease. In our opinion most of the patients treated by LDL apheresis plus simvastatin did not have an indication for the extracorporeal procedure; drug therapy alone would be sufficient. Furthermore, LDL apheresis is not acceptable if given every 14 days. The patients had LDL-concentrations above 3-2 mmol/L for 10 of those 14 days. To conclude that apheresis has no additional benefit it would have been necessary to investigate weekly extracorporeal LDL-elimination. The question is whether in severe familial hypercholesterolaemia an LDL-cholesterol lowering by LDL apheresis to 2-6 mmol/L is superior in its effects on coronary heart disease than lipid-lowering drug therapy alone with LDL-cholesterol concentrations of 3-5-5 mmol/L. This question has already been answered because patients with LDL-cholesterol around 2-5 mmol/L have a better prognosis than those with concentrations above 4 mmol/L.1- From the slight decrease of lipoprotein(a) reported (the geometric mean was still high) a positive effect on the course of coronary heart disease cannot be expected. No prospective study has shown that such a difference is associated with change in risk for coronary heart disease. *Werner O Richter, Peter Schwandt Ludwig-Maximilians-Universitat,
Medizinische Klinik II,
81377 München,
Germany
1 Brown G, Albers J, Fisher LD, et al. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med 1990; 323: 1289-98. 2 Watts GF, Lewis B, Brunt JNH, et al. Effects of coronary artery disease of lipid-lowering diet, or diet plus cholestyramine, in the St Thomas’ Atherosclerosis Regression Study (STARS). Lancet 1992; 339: 563-69. 3 Kane JP, Malloy MJ, Ports TA, et al. Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens. JAMA 1990; 264: 3007-12. 4 MAAS Investigators. Effect of simvastatin in coronary atheroma: the Multicentre Anti-Atheroma Study (MAAS). Lancet 1994; 344: 633-38.
Author’s reply SIR—Olbricht’s contention that there is a world-wide consensus that LDL apheresis be used only in patients with very high LDL-cholesterol concentrations is misleading. In Germany Thiery and Seidel’ recommend its use in patients with coronary artery disease whose LDL-cholesterol is above 3-5 mmol/L despite maximal drug therapy, whereas in the USA Gordon et al2 stipulate an LDL-cholesterol above 4-9 mmol/L under similar circumstances. The question of whether LDL reduction by apheresis induces regression was answered by our study, which showed it to be similarly beneficial to combination drug therapy in this respect. Angiographic benefit was derived solely from the reduction in LDL but not lipoprotein(a). Had we used weekly LDL apheresis, the greater LDL-lowering thereby achieved might have obscured our being able to answer this equally
important question. Richter and Schwandt query the rationale of our comparing LDL apheresis with drug therapy on the grounds that it is the extent of lipid-lowering rather than the means by which this is achieved that determines outcome. That may be so for life-style modification, drug therapy, and partial ileal bypass but ours was the first trial to compare in a randomised manner the efficacy of continuous versus intermittent LDL reduction. Richter and Schwandt’s preference for weekly rather than biweekly procedures would double the time and expense but does not double the efficacy of apheresis, with time-averaged reductions in LDL cholesterol of 39% and 33%, respectively.3 Their proposition that the lower the LDL cholesterol the better is not borne out by angiographic trials, which show that change in % diameter stenosis correlates better with % reduction in LDL-cholesterol than with its concentration during treatment.4This conclusion is supported by the findings in our study (FHRS) where both treatment groups showed a decrease in % diameter stenosis, in contrast with five other studies (FATS, STARS, MARS, CCAIT, and MAAS) where mean % diameter stenosis increased despite treatment. In those five trials LDL-cholesterol on treatment was 3-0 mmol/L (-30%) compared with 3-2 mmol/L (-53%) and 3-4 mmol/L (-44%) in the apheresis and drug groups, respectively, in our study. The better angiographic response in FHRS presumably reflected greater % reductions in LDL despite LDL levels higher than those in the other trials. Gilbert R Thompson,
on
behalf of FHRS
investigators
MRC Lipoprotein Team, Hammersmith Hospital, London W12 0HS, UK
1
2
Thiery J, Seidel D. LDL-apheresis: clinical experience and indications in the treatment of severe hypercholesterolaemia. Transfus Sci 1993; 14: 249-59. Gordon BR, Stein E,
Jones P, Illingworth DR. Indications for low-density lipoprotein apheresis. Am J Cardiol 1994; 74: 1109-12.
3
4
Lane DM, McConathy WJ, Laughlin LO, et al. Selective removal of plasma low density lipoprotein with the HELP system: biweekly versus weekly therapy. Atherosclerosis 1995; 114: 203-11. Waters DD. Stabilization of coronary atherosclerosis. London: Science Press, 1994.
SIR—Besides the implications discussed by Watts in his accompanying commentary on FHRS by Thompson and colleagues we would like to add two others that do not result directly from the published data but from the study design. LDL apheresis has a large effect on the coagulation system, and dextran sulphate adsorption in particular seems to bind some coagulation factors such as FVIII, von Willebrand factor, FIX, and FXI as avidly as LDLcholesterol and lipoprotein(a) (Lp[a]).’ The reduction of fibrinogen after apheresis is also pronounced, ranging from 20% to 30%.’-’ Fibrinogen and most other coagulation factors return to baseline after 24 h and the changes in haemostatic factor activity do not last longer than 3 days.3 Nevertheless, these repeated reductions do not seem to enhance the therapeutic efficacy of dextran sulphate LDL apheresis in promoting regression of coronary artery lesions over pharmacological reduction of LDL-cholesterol alone. The role of the coagulation system in the development of coronary atherosclerosis is under intense scrutiny, and results are often confounded by the fact that investigators do not distinguish between coronary atherosclerosis and coronary thrombosis. Although there is a definite link between the two, their respective pathogenetic mechanisms are not always the same. Thompson and co-workers primarily examined changes in coronary morphology that seem to be mainly determined by LDL-cholesterol concentration. The fact that the shortlived but repeated and important reductions in fibrinogen, FVIII, and other coagulation factors did not produce any additional benefit can be interpreted as an argument for a limited role of coagulation factors in the development of coronary atherosclerosis, whereas their role in coronary thrombosis remains undisputed. The same can also be postulated for Lp(a). Accordingly, it is noteworthy that the two myocardial infarctions took place in the drug treatment group, whereas none occurred in the LDL
apheresis group. The relative contribution of LDL-cholesterol, Lp(a), fibrinogen, and other coagulation factors in the pathogenesis of coronary atherosclerosis and coronary thrombosis are not yet clearly defined. However, Thompson and colleagues’ findings support the thesis that LDL-cholesterol is the prime enemy in the fight against coronary atherosclerosis, whereas other studies indicate that haemostatic factors are of greater relevance for coronary thrombosis.4 The clinical importance of Lp(a) remains to be clarified. The other implication is important for the evaluation and comparison of the different LDL apheresis procedures currently in use. The results of the FHRS refute the theory5 that the less selective methods, which additionally remove other plasma factors beside LDLcholesterol, can achieve better long-term results than the highly selective ones. However, when designing trials aiming to compare the different LDL apheresis procedures, it seems wise to include as endpoints not only angiographic changes but also clinical events. This inclusion would help to clarify whether reduction of fibrinogen and other coagulation factors confers increased protection against coronary thrombosis. *Ion S Jovin, Uwe Taborski, Kathrin Gert Müller-Berghaus
Heidinger,
*Department of Haemostaseology and Transfusion Medicine, Kerckhoff-Klinik GmbH, 61231 Bad Nauheim, Germany
117
1
Kojima S, Harada-Shiba M, Toyota Y, et al. Changes in coagulation factors by passage through a dextran sulfate cellulose column during low-density lipoprotein apheresis. Int J Artif Organs 1992; 15:
2
Schulzeck P, Olbricht CJ, Koch KM.
185-90.
Long-term experience with extracorporeal low-density lipoprotein cholesterol removal by dextran sulfate cellulose adsorption. Clin Invest 1992; 70: 99-104. Knisel W, Di Nicuolo A, Pfohl M, et al. Different effects of two methods of low-density lipoprotein apheresis on the coagulation and fibrinolytic systems. J Intern Med 1993; 234: 479-87.
3
4 5
Hamsten A. Hemostatic function and coronary artery disease. N Engl J Med 1995; 332: 677-78. Matsuda Y, Malchesky PS, Nosé Y. Assessment of currently available low-density lipoprotein apheresis systems. Artif Organs 1994; 18: 93-99.
We suggest that clinical presentation may be altered by chronic antifungal therapy. These cases raise some concern about the validity of systematic prophylaxis of fungal diseases with fluconazole in HIV-positive patients. We thank the Mycology Unit of the Pasteur Institute in Paris (Prof B Dupont) for in-vitro susceptibility testing.
*Jean-Paul Viard, Christophe Hennequin, Nicolas Fortineau, Nathalie Pertuiset, Chantal Rothschild, Hervé Zylberberg *Service d’Immunologie Clinique, Service de Microbiologie, and Centre de Traitement de ’Hémophilie, Hôpital Necker, 75743 Paris, France
1
Quagliarello VJ, Viscoli C, Horwitz RI. Primary prevention of cryptococcal meningitis by fluconazole in HIV-infected patients. Lancet
2
Powderly WG, Finkelstein DM, Feinberg J, et al. A randomized trial comparing fluconazole with clotrimazole troches for the prevention of fungal infections in patients with advanced human immunodeficiency virus infection. N Engl J Med 1995; 332: 700-05. Rex JH, Rinaldi MG, Pfaller MA. Resistance of Candida species to fluconazole. Antimicrob Agents Chemother 1995; 39: 1-8. Paugam A, Dupouy-Camet J, Blanche P, Gangneux JP,
1995; 345: 548-52.
Fulminant cryptococcal infections in HIVinfected patients on oral fluconazole 3
SIR—Case-control1 and prospective2 studies suggest that fluconazole prophylaxis protects against cryptococcal meningitis, one of the most severe opportunistic infections in HIV disease. However, the risk of fluconazole-resistant strains and modification of the clinical presentation of cryptococcosis must not be overlooked. Two cases illustrate this possible drawback to large-scale fluconazole prophylaxis. A 29-year-old patient with haemophilia was found to be HIV-1-infected in 1983. He did not develop major opportunistic infections but his CD4 count had been below 10/µL since 1993. He was treated with zidovudine and didanosine, and had been receiving oral fluconazole (50 mg daily) since 1993 for recurrent oral candidosis. In March, 1994, he was admitted to hospital with a headache that had started 10 days earlier. He was afebrile. Clinical examination and a cerebral computerised tomographic (CT) scan were normal. He died suddenly a few hours after admission. Blood cultures were positive for Cryptococcus neoformans serotype A. Fluconazole minimum inhibitory concentration (MIC) of the strain was 6-25 µg/mL (high resolution
5
Tourte-Schaefer C, Sicard D. Increased fluconazole resistance of Cryptococcus neoformans isolated from a patient with AIDS and recurrent meningitis. Clin Infect Dis 1994; 19: 975-76. Mitchell DH, Sorrell TC, Allworth AM, et al. Cryptococcal disease of the CNS in immunocompetent hosts: influence of cryptococcal variety on clinical manifestations and outcome. Clin Infect Dis 1995; 20: 611-16.
Treatment of Kaposi’s sarcoma and other manifestations of AIDS with human chorionic
gonadotropin SIR—At
the
1994
International
AIDS
Conference
(Yokohama, Japan), Robert Gallo and colleagues’ reported the injection of nude mice (immune deficient) with a human Kaposi’s sarcoma (KS) cell line; this resulted in massive KS in these mice. When these mice were subsequently treated with intramuscular human chorionic gonadotropin (HCG) dose of 50 000-100 000 international units of (IU) per 10 g mouse weight (three times per week), their KS went into remission. Based on this work, we elected to treat six HIV-infected human subjects with Kaposi’s sarcoma with intramuscular HCG. Patients were homosexual males between 29 years old and 45 years old; one was African-American; the remainder were white. T4 counts at initiation of therapy ranged from 4-442 cells/µL. T8 cell counts at initiation ranged from
medium). A 40-year-old homosexual man was found to be HIV-1positive in 1991. He was successively treated with Cerebral zidovudine, didanosine, and zalcitabine. toxoplasmosis was diagnosed at the end of 1991, and he had had a mild cutaneous Kaposi’s sarcoma since 1993. He had received oral fluconazole (100 mg daily) since November, 1993, for recurrent oral and oesophageal candidosis. In February, 1994, when his CD4 cell count was 5/µL, he was admitted because of nausea, headache, fever, and dizziness.
hormone
at a
465-970
Cerebral CT
cells/jjbL. Two patients had only one cutaneous patients had extensive cutaneous disease; two
lesion; patients had extensive visceral and cutaneous disease. One patient with a single cutaneous lesion underwent HCG therapy as primary therapy while the other had progressed
scan
was
normal.
He died
24
h
after Blood
admission, despite wide-spectrum antibiotherapy. cultures showed the presence of C neoformans (serotype A). The strain showed reduced sensitivity to fluconazole in vitro (MIC 16 µg/mL). These two cases emphasise that low-dose, long-term therapy with oral fluconazole does not always prevent
neoformans. This lack of response underlying immune deficiency or to the selection of less sensitive strains (the second patient), since suboptimum dosage of antifungal monotherapy is known to induce resistance in Candida spp.3 The frequency of the emergence of fluconazole-resistant C neoformans strains in fluconazole-treated HIV-positive patients should be established by carefully designed prospective studies. However, case reports’ suggest that C neoformans resistance may be clinically relevant, and in secondary prophylaxis. A high virulence could also be a factor in prophylaxis failure. For instance, C neoformans var gattii is more virulent in immunocompetent hosts presenting with cerebral mass clinical disease due
to
might be attributable
.
4
C
to
lesions.5 In our cases, however, serotype studies identified C neoformans var neoformans. 118
two
after
with 2500 rads external-beam radiation The two patients with massive skin disease underwent chemotherapy with vincristine sulphate, doxorubicin, and bleomycin sulphate for several months with minor improvement but significant toxicity. Of the two patients with visceral involvement, one was treated with HCG de novo and the other was treated with intralesional vinblastine sulphate at the time of limited disease and later with radiation therapy when disease disseminated to the sinuses and finally with high-dose HCG when disease became generalised. Since massive doses of HCG had never been given to human patients, we slowly escalated the dose in all patients to avoid toxicity. Patients then received between 150 000 IU and 700 000 IU HCG intramuscularly on Mondays, Wednesdays, and Fridays with marked tumour regression as defined by Krown et al. The only toxicity was a mild sensation of skin retraction around lesions and tolerable pain treatment
therapy.
are expressed as geometric mean titres, except for rose bengal test which is expressed as proportion of positives. Table: Antibody responses after vaccination with WC/rBS or natural infection with Vibrio cholerae 01
toxin (anti-CT) of IgA and IgG classes by GM1-ELISA method were determined as described.’ Brucella done the method were standard slide by agglutination assays and the rose bengal test.5 was As shown in the table, a significant increase (p<0-05) noted in the geometric mean titres of vibriocidal, CT IgA and IgG antibodies after vaccination with the WC/rBS. Brucella antibodies, on the other hand, did not vary between specimens before and after vaccination. Titres of 25 in four subjects and 50 in one subject were noted in the prevaccination specimens, the rest being negative (<25). After vaccination, no change occurred among the negative sera, and the same or decreased titres were noted among the positive sera. Sera were negative by rose bengal test for all specimens before and after vaccination. For comparison, paired sera from six patients (12-68 years old) naturally infected with V cholerae 01 were also tested. Again, a significant increase in all three V cholerae antibodies was noted. Initially, they all were negative for brucella antibodies by the slide and rose bengal test, but 2 weeks later, four patients developed titres of 25, 50, 100, and 800, the last three with concomitant positivity in the rose
bengal test.
Based on these findings, we conclude that vaccination with WC/rBS is not a source of false-positive brucella antibody, as observed following natural infection with V cholerae 01. *Rodolfo E
Begue,
Alfredo Guillen, Rina Meza
*Division of Pediatric Infectious Diseases, Children’s Hospital, Louisiana State University, New Orleans, LA 70112, USA; Instituto Nacional de Salud, Lima, Peru; and US Navy Medical Research Institute, Lima
1 2
3 4
5
Centers for Disease Control. Update: cholera-western hemisphere 1992. MMWR 1993; vol 42, no 5: 89-91. Gotuzzo E, Alarcon GS, Bocanegra TS, et al. Articular involvement in human brucellosis: a retrospective analysis of 304 cases. Semin Arthritis Rheum 1982; 12: 245-55. Eisele CW, McCullough NB, Beal GA. Brucella antibodies following cholera vaccination. Ann Intern Med 1948; 28: 833-37. Jetborn M, Svennerholm A-M, Holmgren J. Safety and immunogenicity of an oral recombinant cholera B subunit: whole cell vaccine in Swedish volunteers. Vaccine 1992; 10: 130-32. Moyer NP, Holcomb LA, Hausler WJ Jr. Brucella. In: Balows A, Hausler WJ Jr, Herrmann KL, Isenberg HD, Shadomy HJ, eds. Manual of clinical microbiology, 5th ed, Washington, DC: American Society for Microbiology, 1991: 457-62.
Low-density-lipoprotein apheresis SIR—In
the
Familial
Hypercholesterolaemia Regression Study (FHRS) (April 1, p 811) Thompson and co-workers compared suboptimal lipid-lowering therapy (simvastatin 40 low-densitymg daily) supplemented by half-strength lipoprotein (LDL) apheresis at one plasma volume fortnightly with optimal lipid-lowering drug therapy (simvastatin 40 mg + colestipol 20 g daily) in patients with 116
LDL-cholesterol above 8 mmol/L. Most patients with familial hypercholesterolaemia and an LDL-cholesterol around 8 mmol/L respond to combined drug therapy with a "statin" plus colestipol or cholestyramine, LDL-cholesterol falling by 50-60%.’ The patients in FHRS had initial LDLcholesterol values of about 8 mmol/L and there was no reason to suspect that they would not respond sufficiently to combined drug therapy. This notion is supported by the 54% decrease in LDL-cholesterol in the group treated with alone. The world-wide consensus is to apply LDL apheresis only in patients whose LDL-cholesterol remains despite very high maximal lipid-lowering therapy with diet and drugs. LDL apheresis, given weekly, reduces time-averaged LDLcholesterol in these patients by 40-60%.2-4 The key question is whether the reduction achieved induces regression or stops the progression of atherosclerosis. This question can be answered by a controlled study, and Thompson et al are right to note that all published studies on atherosclerosis during LDL apheresis have been uncontrolled.’ The first controlled one (FHRS) is in patients without indication for LDL apheresis, and the apheresis was fortnightly instead of weekly. This is not the study we needed.
drugs
C J Olbricht Nephrology,
Division of
Medical School Hannover, D30625 Hannover,
Germany
Hoeg JM, Brewer HB. 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors in the treatment of hypercholesterolaemia. JAMA
1
2
3
4
1987; 258: 3532-36. Olbricht CJ. Extracorporeal treatment of hypercholesterolaemia. Nephrol Dial Transplant 1993; 8: 814-20. Lane DM, McConathy WH, Laughlin LO, et al. Weekly treatment of diet/drug-resistant hypercholesterolaemia with the heparin-induced extracorporeal low-density lipoprotein precipitation (HELP) system by selective plasma low-density lipoprotein removal. Am J Cardiol 1993; 71: 816-22. Gordon BR, Saal SD. Advances in LDL-apheresis for the treatment of severe hypercholesterolaemia. Curr Opin Lipidol 1994; 5: 69-73.
SiR-Why in FHRS have procedures that resulted in nearly identical LDL-cholesterol concentrations been compared? Intervention studies with drugs (colestipol, cholestyramine, lovastatin, simvastatin, niacin), life-style modification, or partial ileal bypass have shown that it is not the way LDLcholesterol is lowered but the LDL-cholesterol concentration reached that is important for the effect on coronary heart disease. In our opinion most of the patients treated by LDL apheresis plus simvastatin did not have an indication for the extracorporeal procedure; drug therapy alone would be sufficient. Furthermore, LDL apheresis is not acceptable if given every 14 days. The patients had LDL-concentrations above 3-2 mmol/L for 10 of those 14 days. To conclude that apheresis has no additional benefit it would have been necessary to investigate weekly extracorporeal LDL-elimination. The question is whether in severe familial hypercholesterolaemia an LDL-cholesterol lowering by LDL apheresis to 2-6 mmol/L is superior in its effects on coronary heart disease than lipid-lowering drug therapy alone with LDL-cholesterol concentrations of 3-5-5 mmol/L. This question has already been answered because patients with LDL-cholesterol around 2-5 mmol/L have a better prognosis than those with concentrations above 4 mmol/L.1- From the slight decrease of lipoprotein(a) reported (the geometric mean was still high) a positive effect on the course of coronary heart disease cannot be expected. No prospective study has shown that such a difference is associated with change in risk for coronary heart disease. *Werner O Richter, Peter Schwandt Ludwig-Maximilians-Universitat,
Medizinische Klinik II,
81377 München,
Germany
1 Brown G, Albers J, Fisher LD, et al. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med 1990; 323: 1289-98. 2 Watts GF, Lewis B, Brunt JNH, et al. Effects of coronary artery disease of lipid-lowering diet, or diet plus cholestyramine, in the St Thomas’ Atherosclerosis Regression Study (STARS). Lancet 1992; 339: 563-69. 3 Kane JP, Malloy MJ, Ports TA, et al. Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens. JAMA 1990; 264: 3007-12. 4 MAAS Investigators. Effect of simvastatin in coronary atheroma: the Multicentre Anti-Atheroma Study (MAAS). Lancet 1994; 344: 633-38.
Author’s reply SIR—Olbricht’s contention that there is a world-wide consensus that LDL apheresis be used only in patients with very high LDL-cholesterol concentrations is misleading. In Germany Thiery and Seidel’ recommend its use in patients with coronary artery disease whose LDL-cholesterol is above 3-5 mmol/L despite maximal drug therapy, whereas in the USA Gordon et al2 stipulate an LDL-cholesterol above 4-9 mmol/L under similar circumstances. The question of whether LDL reduction by apheresis induces regression was answered by our study, which showed it to be similarly beneficial to combination drug therapy in this respect. Angiographic benefit was derived solely from the reduction in LDL but not lipoprotein(a). Had we used weekly LDL apheresis, the greater LDL-lowering thereby achieved might have obscured our being able to answer this equally
important question. Richter and Schwandt query the rationale of our comparing LDL apheresis with drug therapy on the grounds that it is the extent of lipid-lowering rather than the means by which this is achieved that determines outcome. That may be so for life-style modification, drug therapy, and partial ileal bypass but ours was the first trial to compare in a randomised manner the efficacy of continuous versus intermittent LDL reduction. Richter and Schwandt’s preference for weekly rather than biweekly procedures would double the time and expense but does not double the efficacy of apheresis, with time-averaged reductions in LDL cholesterol of 39% and 33%, respectively.3 Their proposition that the lower the LDL cholesterol the better is not borne out by angiographic trials, which show that change in % diameter stenosis correlates better with % reduction in LDL-cholesterol than with its concentration during treatment.4This conclusion is supported by the findings in our study (FHRS) where both treatment groups showed a decrease in % diameter stenosis, in contrast with five other studies (FATS, STARS, MARS, CCAIT, and MAAS) where mean % diameter stenosis increased despite treatment. In those five trials LDL-cholesterol on treatment was 3-0 mmol/L (-30%) compared with 3-2 mmol/L (-53%) and 3-4 mmol/L (-44%) in the apheresis and drug groups, respectively, in our study. The better angiographic response in FHRS presumably reflected greater % reductions in LDL despite LDL levels higher than those in the other trials. Gilbert R Thompson,
on
behalf of FHRS
investigators
MRC Lipoprotein Team, Hammersmith Hospital, London W12 0HS, UK
1
2
Thiery J, Seidel D. LDL-apheresis: clinical experience and indications in the treatment of severe hypercholesterolaemia. Transfus Sci 1993; 14: 249-59. Gordon BR, Stein E,
Jones P, Illingworth DR. Indications for low-density lipoprotein apheresis. Am J Cardiol 1994; 74: 1109-12.
3
4
Lane DM, McConathy WJ, Laughlin LO, et al. Selective removal of plasma low density lipoprotein with the HELP system: biweekly versus weekly therapy. Atherosclerosis 1995; 114: 203-11. Waters DD. Stabilization of coronary atherosclerosis. London: Science Press, 1994.
SIR—Besides the implications discussed by Watts in his accompanying commentary on FHRS by Thompson and colleagues we would like to add two others that do not result directly from the published data but from the study design. LDL apheresis has a large effect on the coagulation system, and dextran sulphate adsorption in particular seems to bind some coagulation factors such as FVIII, von Willebrand factor, FIX, and FXI as avidly as LDLcholesterol and lipoprotein(a) (Lp[a]).’ The reduction of fibrinogen after apheresis is also pronounced, ranging from 20% to 30%.’-’ Fibrinogen and most other coagulation factors return to baseline after 24 h and the changes in haemostatic factor activity do not last longer than 3 days.3 Nevertheless, these repeated reductions do not seem to enhance the therapeutic efficacy of dextran sulphate LDL apheresis in promoting regression of coronary artery lesions over pharmacological reduction of LDL-cholesterol alone. The role of the coagulation system in the development of coronary atherosclerosis is under intense scrutiny, and results are often confounded by the fact that investigators do not distinguish between coronary atherosclerosis and coronary thrombosis. Although there is a definite link between the two, their respective pathogenetic mechanisms are not always the same. Thompson and co-workers primarily examined changes in coronary morphology that seem to be mainly determined by LDL-cholesterol concentration. The fact that the shortlived but repeated and important reductions in fibrinogen, FVIII, and other coagulation factors did not produce any additional benefit can be interpreted as an argument for a limited role of coagulation factors in the development of coronary atherosclerosis, whereas their role in coronary thrombosis remains undisputed. The same can also be postulated for Lp(a). Accordingly, it is noteworthy that the two myocardial infarctions took place in the drug treatment group, whereas none occurred in the LDL
apheresis group. The relative contribution of LDL-cholesterol, Lp(a), fibrinogen, and other coagulation factors in the pathogenesis of coronary atherosclerosis and coronary thrombosis are not yet clearly defined. However, Thompson and colleagues’ findings support the thesis that LDL-cholesterol is the prime enemy in the fight against coronary atherosclerosis, whereas other studies indicate that haemostatic factors are of greater relevance for coronary thrombosis.4 The clinical importance of Lp(a) remains to be clarified. The other implication is important for the evaluation and comparison of the different LDL apheresis procedures currently in use. The results of the FHRS refute the theory5 that the less selective methods, which additionally remove other plasma factors beside LDLcholesterol, can achieve better long-term results than the highly selective ones. However, when designing trials aiming to compare the different LDL apheresis procedures, it seems wise to include as endpoints not only angiographic changes but also clinical events. This inclusion would help to clarify whether reduction of fibrinogen and other coagulation factors confers increased protection against coronary thrombosis. *Ion S Jovin, Uwe Taborski, Kathrin Gert Müller-Berghaus
Heidinger,
*Department of Haemostaseology and Transfusion Medicine, Kerckhoff-Klinik GmbH, 61231 Bad Nauheim, Germany
117
1
Kojima S, Harada-Shiba M, Toyota Y, et al. Changes in coagulation factors by passage through a dextran sulfate cellulose column during low-density lipoprotein apheresis. Int J Artif Organs 1992; 15:
2
Schulzeck P, Olbricht CJ, Koch KM.
185-90.
Long-term experience with extracorporeal low-density lipoprotein cholesterol removal by dextran sulfate cellulose adsorption. Clin Invest 1992; 70: 99-104. Knisel W, Di Nicuolo A, Pfohl M, et al. Different effects of two methods of low-density lipoprotein apheresis on the coagulation and fibrinolytic systems. J Intern Med 1993; 234: 479-87.
3
4 5
Hamsten A. Hemostatic function and coronary artery disease. N Engl J Med 1995; 332: 677-78. Matsuda Y, Malchesky PS, Nosé Y. Assessment of currently available low-density lipoprotein apheresis systems. Artif Organs 1994; 18: 93-99.
We suggest that clinical presentation may be altered by chronic antifungal therapy. These cases raise some concern about the validity of systematic prophylaxis of fungal diseases with fluconazole in HIV-positive patients. We thank the Mycology Unit of the Pasteur Institute in Paris (Prof B Dupont) for in-vitro susceptibility testing.
*Jean-Paul Viard, Christophe Hennequin, Nicolas Fortineau, Nathalie Pertuiset, Chantal Rothschild, Hervé Zylberberg *Service d’Immunologie Clinique, Service de Microbiologie, and Centre de Traitement de ’Hémophilie, Hôpital Necker, 75743 Paris, France
1
Quagliarello VJ, Viscoli C, Horwitz RI. Primary prevention of cryptococcal meningitis by fluconazole in HIV-infected patients. Lancet
2
Powderly WG, Finkelstein DM, Feinberg J, et al. A randomized trial comparing fluconazole with clotrimazole troches for the prevention of fungal infections in patients with advanced human immunodeficiency virus infection. N Engl J Med 1995; 332: 700-05. Rex JH, Rinaldi MG, Pfaller MA. Resistance of Candida species to fluconazole. Antimicrob Agents Chemother 1995; 39: 1-8. Paugam A, Dupouy-Camet J, Blanche P, Gangneux JP,
1995; 345: 548-52.
Fulminant cryptococcal infections in HIVinfected patients on oral fluconazole 3
SIR—Case-control1 and prospective2 studies suggest that fluconazole prophylaxis protects against cryptococcal meningitis, one of the most severe opportunistic infections in HIV disease. However, the risk of fluconazole-resistant strains and modification of the clinical presentation of cryptococcosis must not be overlooked. Two cases illustrate this possible drawback to large-scale fluconazole prophylaxis. A 29-year-old patient with haemophilia was found to be HIV-1-infected in 1983. He did not develop major opportunistic infections but his CD4 count had been below 10/µL since 1993. He was treated with zidovudine and didanosine, and had been receiving oral fluconazole (50 mg daily) since 1993 for recurrent oral candidosis. In March, 1994, he was admitted to hospital with a headache that had started 10 days earlier. He was afebrile. Clinical examination and a cerebral computerised tomographic (CT) scan were normal. He died suddenly a few hours after admission. Blood cultures were positive for Cryptococcus neoformans serotype A. Fluconazole minimum inhibitory concentration (MIC) of the strain was 6-25 µg/mL (high resolution
5
Tourte-Schaefer C, Sicard D. Increased fluconazole resistance of Cryptococcus neoformans isolated from a patient with AIDS and recurrent meningitis. Clin Infect Dis 1994; 19: 975-76. Mitchell DH, Sorrell TC, Allworth AM, et al. Cryptococcal disease of the CNS in immunocompetent hosts: influence of cryptococcal variety on clinical manifestations and outcome. Clin Infect Dis 1995; 20: 611-16.
Treatment of Kaposi’s sarcoma and other manifestations of AIDS with human chorionic
gonadotropin SIR—At
the
1994
International
AIDS
Conference
(Yokohama, Japan), Robert Gallo and colleagues’ reported the injection of nude mice (immune deficient) with a human Kaposi’s sarcoma (KS) cell line; this resulted in massive KS in these mice. When these mice were subsequently treated with intramuscular human chorionic gonadotropin (HCG) dose of 50 000-100 000 international units of (IU) per 10 g mouse weight (three times per week), their KS went into remission. Based on this work, we elected to treat six HIV-infected human subjects with Kaposi’s sarcoma with intramuscular HCG. Patients were homosexual males between 29 years old and 45 years old; one was African-American; the remainder were white. T4 counts at initiation of therapy ranged from 4-442 cells/µL. T8 cell counts at initiation ranged from
medium). A 40-year-old homosexual man was found to be HIV-1positive in 1991. He was successively treated with Cerebral zidovudine, didanosine, and zalcitabine. toxoplasmosis was diagnosed at the end of 1991, and he had had a mild cutaneous Kaposi’s sarcoma since 1993. He had received oral fluconazole (100 mg daily) since November, 1993, for recurrent oral and oesophageal candidosis. In February, 1994, when his CD4 cell count was 5/µL, he was admitted because of nausea, headache, fever, and dizziness.
hormone
at a
465-970
Cerebral CT
cells/jjbL. Two patients had only one cutaneous patients had extensive cutaneous disease; two
lesion; patients had extensive visceral and cutaneous disease. One patient with a single cutaneous lesion underwent HCG therapy as primary therapy while the other had progressed
scan
was
normal.
He died
24
h
after Blood
admission, despite wide-spectrum antibiotherapy. cultures showed the presence of C neoformans (serotype A). The strain showed reduced sensitivity to fluconazole in vitro (MIC 16 µg/mL). These two cases emphasise that low-dose, long-term therapy with oral fluconazole does not always prevent
neoformans. This lack of response underlying immune deficiency or to the selection of less sensitive strains (the second patient), since suboptimum dosage of antifungal monotherapy is known to induce resistance in Candida spp.3 The frequency of the emergence of fluconazole-resistant C neoformans strains in fluconazole-treated HIV-positive patients should be established by carefully designed prospective studies. However, case reports’ suggest that C neoformans resistance may be clinically relevant, and in secondary prophylaxis. A high virulence could also be a factor in prophylaxis failure. For instance, C neoformans var gattii is more virulent in immunocompetent hosts presenting with cerebral mass clinical disease due
to
might be attributable
.
4
C
to
lesions.5 In our cases, however, serotype studies identified C neoformans var neoformans. 118
two
after
with 2500 rads external-beam radiation The two patients with massive skin disease underwent chemotherapy with vincristine sulphate, doxorubicin, and bleomycin sulphate for several months with minor improvement but significant toxicity. Of the two patients with visceral involvement, one was treated with HCG de novo and the other was treated with intralesional vinblastine sulphate at the time of limited disease and later with radiation therapy when disease disseminated to the sinuses and finally with high-dose HCG when disease became generalised. Since massive doses of HCG had never been given to human patients, we slowly escalated the dose in all patients to avoid toxicity. Patients then received between 150 000 IU and 700 000 IU HCG intramuscularly on Mondays, Wednesdays, and Fridays with marked tumour regression as defined by Krown et al. The only toxicity was a mild sensation of skin retraction around lesions and tolerable pain treatment
therapy.