- Email: [email protected]
Treatment of opportunistic infections in AIDS
both
copies of the gene while 54 had a mutation in an of a single copy. 34 (63%) of these "heterozygotes" were shown to have a DNA variant in a non-coding sequence of their other CFTR gene ("the 5T allele") which reduces the production of normal CFTR messenger RNA.6 Such mutations in non-coding regions of the gene may thus result in low levels of expression of normal CFTR protein, although the amount produced exon
may be sufficient to prevent or postpone disease in the organs classically affected by CF such as lungs and pancreas. These findings highlight the acute sensitivity of
deferens to CFTR dysfunction. Obstructive azoospermia has been proposed as a major diagnostic criterion in atypical patients with mild features of CF and normal or equivocal sweat chloride concentrations.3 Anecdotal reports of occasional fertile males with atypical CF were often regarded as unproven, sometimes with mention of a similar but distinct disease (phenocopy), until the advent of molecular genetic analysis revealed that some compound heterozygotes with CF gene mutations are unquestionably fertile.’ The Cleveland group who promoted the diagnostic value of azoospermia3 lately reported 4 adult male patients with CF and patency of the vas deferens. These individuals were all hemizygous for a splice mutation in an intron, 3849+lOkb C—/T. There is a further reference to semen analyses showing satisfactory sperm counts, and fertility, in patients with the same mutation.9 Although of the Cleveland patients had pancreatic none insufficiency, they had variable degrees of lung disease. Pancreatic insufficiency was present in 33% of patients with 3849+lOkb C-T and another "severe" mutation in an Israeli series.’° These observations add further support to the view that pancreatic insufficiency, bronchial infection, and lung damage in CF are determined not only by the level of expression and function of CFTR but also by environmental and perhaps other genetic factors.",12 Even for men with CBAVD there is now hope that they may be able to become fathers. After microsurgical epididymal sperm aspiration (MESA)’3 followed by intracytoplasmic sperm injection into oocytes in vitro, a man with CF fathered a healthy child." This case was the more remarkable because the female partner was a carrier of the A F508 mutation, and implantation of the fertilised ovum was carried out only after single-blastomere analysis of the embryo had shown it to be heterozygous. Other instances of successful pregnancies with sperm from CF men by the same technique have been reported.15 The high frequency of CF mutations and the 5T allele in men with CBAVD, together with the empirical carrier frequency of about 1 in 25 in their female partners, makes it essential that both partners should be screened for CF mutations before MESA and in-vitro fertilisation are contemplated. Sympathetic counselling of infertile couples requesting MESA and in-vitro fertilisation where the male partner has classic CF with lung disease should also address the likelihood that the potential father will have a reduced life expectancy, and that his partner may therefore have to cope with a dependent husband as well as a young child. In addition, in-vitro fertilisation has a high failure rate. Fortunately, two recent reports confirm continued and substantial improvements in CF survival’6 and the success of in-vitro fertilisation.17 Increasing
vas
588
numbers of affected couples will the new option for parenthood.
JA
surely wish
to
explore
Dodge
Nuffield Department of Child Health, Queen’s University of Belfast, Belfast, UK Shwachman H, Perlmuter AD, Rule A, Khaw K-T, Holsclaw DS. Reproductive failure in males with cystic fibrosis. N Engl J Med 1968; 279: 65-69. 2 Landing BH, Wells TR, Wang CI. Abnormality of the epididymis and vas deferens in cystic fibrosis. Arch Pathol 1969; 88: 569-90. 3 Stern RC, Boat TF, Doershuk CF. Obstructive azoospermia as a diagnostic criterion for cystic fibrosis syndrome. Lancet 1983; i: 1401-04. 4 Anguiano A, Oates RD, Amos JA, et al. Congenital bilateral absence of the vas deferens: a primary genital form of cystic fibrosis. JAMA 1992; 267: 1794-97. 5 Augarten A,YahavY, Kerem B-S, et al. Congenital bilateral absence of vas deferens in the absence of cystic fibrosis. Lancet 1994; 344: 1473-74. 6 Chillon M, Casals T, Mercier B, Bassas L, et al. Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. N Engl J Med 1995; 332: 1475-80. 7 Barreto C, Marques Pinto L, Duarte A, Lavinha J, Ramsay M. A fertile male with cystic fibrosis: molecular genetic analysis. J Med Genet 1991; 28: 420-21. 8 Stern RC, Doershuk CF, Drumm M. 3849+10kb C→T mutation and disease severity in cystic fibrosis. Lancet 1995; 346: 274-76. 9 Highsmith WE, Burch LH, Zhou Z, et al. A novel mutation in the cystic fibrosis gene in patients with pulmonary disease but normal sweat chloride concentrations. N Engl J Med 1994; 331: 974-80. 10 Augarten A, Kerem B-S, Yahav Y, et al. Mild cystic fibrosis and normal or borderline sweat test in patient with the 3849+10kb C→T mutation. Lancet 1993; 342: 25-26. 11 Dean M, Santis G. Heterogeneity in the severity of cystic fibrosis and the role of CFTR gene mutations. Hum Genet 1994; 93: 364-68. 12 Veeze HJ, Halley DJJ, Bijman J, et al. Determinants of mild classical symptoms in cystic fibrosis patients: residual chloride secretion measured in rectal biopsies in relation to the genotype. J Clin Invest 1994; 93: 461-66. 13 Oates RD, Honig S, Berger MJ, Harris D. Microscopic epididymal sperm aspiration (MESA): a new option for treatment of the obstructive azoospermia associated with cystic fibrosis. J Assist Reprod Genet 1992; 9: 36-40. 14 Liu J, Lissens W, Silber SJ, et al. Birth after preimplantation diagnosis of the cystic fibrosis &Dgr;F508 mutation by polymerase chain reaction in human embryos resulting from intracytoplasmic sperm injection with epididymal sperm. JAMA 1994; 272: 1858-60. 15 Fogdestam I, Hamberger L, Ludin K, Sjögren A, Hjelte L, Strandvik B. Successful pregnancies after in vitro fertilization with sperm from men with cystic fibrosis. 19th European Cystic Fibrosis 1
Kaplan E,
Conference, Paris, 1994 (abstr). 16 UK Cystic Fibrosis Survey 1995 Report, June 1995. 17 Human Fertilisation and Embryology Authority. annual London: HFEA, 1994.
Treatment of AIDS
opportunistic
Report.
infections in
Opportunistic infections are responsible for much of the morbidity and mortality in AIDS patients and are mostly attributable to a small number of pathogens.’ Because these infections had previously been encountered in patients with other types of immune deficiency, effective had often been established before the onset of epidemic.’ Optimum therapy for AIDS-related opportunistic infections is frequently reviewed.3 A comparison of the treatments for these common opportunistic infections in 1981, when the AIDS epidemic was first identified, versus 1995 shows what has been achieved in the 14 year interval (table). Pneumocystis carinii pneumonia (PCP) was once the AIDS-defining infection in 60% of HIV-infected persons and occurred in up to 80% of individuals. With aggressive
treatments
the AIDS
At the
epidemic there were no drugs cytomegalovirus (CMV) end-organ infection. Two agents-ganciclovir and foscarnet-were subsequently approved, and are clearly effective in stabilising individuals with CMV disease. Relapses are frequent and usually occur 2-3 months into therapy. Both drugs have to be delivered intravenously. Oral ganciclovir seems to be a promising alternative for maintenance therapy in some start
of the AIDS
to treat
cases.
Treatment of disseminated Mycobacterium avium complex (MAC) has improved greatly in the past 14 infection for which the treatment was as disabling as the illness, MAC has been shown to respond to several newer agents, especially the macrolides (azithromycin and clarithromycin), the quinolones (eg, ciprofloxacin), and the rifamycins (rifabutin). With treatment, symptoms are sometimes controlled for a year
years. What
was once an
longer. Fungal infections, including cryptococcosis, mucosal candidosis, histoplasmosis, and coccidioidomycosis, continue to cause serious illness. Amphotericin B was established in the 1960s as effective therapy for these
or
MAC=Mycobacterium avium complex. 1 Macrolides mclude clanthromycin and azithromycin. 2 includes cryptococcosis, histoplasmosis, and coccidioidomycosis. 3 First-line agent for mucosal infections. 4 First-line agent for maintenance therapy and second-line
agent for acute therapy. of treatment of for Table: Comparison choice opportunistic infection, 1981 versus 1995 (new first4ine agents are under-
lined) of prophylaxis these rates have decreased, although in 1992 PCP still accounted for 42% of AIDS-indicator diseases reported to the CDC.’ The repertoire of agents for prophylaxis of PCP expanded in the 1980s, with dapsone and aerosol pentamidine, as well as cotrimoxazole, proving effective. However, the best drugs for the treatment of acute PCP in 1995 are the best drugs of 1981-co-trimoxazole and intravenous pentamidine. with dapsone Clindamycin with primaquine, are and trimetrexate trimethoprim, atovoquone, perhaps alternatives in the treatment of mild-toacceptable moderate PCP in patients intolerant of first-line therapy, and corticosteroids are a useful adjunct for severe disease. None of these agents is reliably effective for treatment of severe PCP and none is a first-line agent. Drugs such as eflornithine (DFMO) have been studied but are too toxic or ineffective or both. Treatment of toxoplasmosis with sulfadizine and pyrimethamine was shown to be effective in the 1950s and in 1995 remains clearly better than other therapies. Clindamycin with pyrimethamine is a reliable alternative for individuals intolerant of sulfa drugs. Neither azithromycin nor atovoquone seems to be predictably effective, although trials are still in progress. Trimetrexate has also been studied but is both toxic and ineffective. There is no effective therapy of cryptosporidiosis. bovine Spiramycin, azithromycin, paromomycin, immunoglobulin, diclazuril, and letrazuril are among the drugs tested, and none has emerged as reliably effective. Tuberculosis is increasingly common among AIDS patients, yet the repertoire of effective antituberculosis antibiotics has expanded very little since the 1970s. The quinolones, particularly ofloxacin and its L-isomer levofloxacin, look promising.
use
infections. In the 1980s fluconazole and itraconazole were introduced, and both have an established role in maintenance therapy of fungal infections. However, except for treatment of mucosal candida infections, amphotericin B remains the treatment of choice for acute infection. Despite the lack of new agents, survival from these opportunistic infections has improved. This is mostly due to earlier disease diagnosis and to the attenuating effect on acute infection of prophylaxis and antiretroviral therapy. Perhaps with further improvements in prophylaxis the need to treat many acute infections will be obviated. Meanwhile, it is sobering to review fourteen years of intensive effort and find few real advances in the treatment of opportunistic infections. Above all, this underlines the need for caution when new agents are introduced for the treatment of opportunistic infections. Too often, after the dust has settled, we see that the pathogen and not the antibiotic has prevailed. Kent A
Sepkowitz, Donald Armstrong
Infectious Disease Service, Memorial Sloan-Kettering Cancer Center and New York Hospital-Cornell Medical Center, New York, NY, USA 1 2
3
Centers for Disease Control and Prevention. HIV/AIDS surveillance report: year-end edition Atlanta: CDC, February, 1993. Brown AE, Armstrong D, eds. Infectious complications of neoplastic disease, 1st ed. New York: Yorke Medical Books, 1985. Glatt AE (ed). Management of infection in HIV disease. In: Infect Dis Clin N Am, 1994; 8.
Atherosclerosis in the ascending aorta and risk of ischaemic stroke Arterial disease in the carotid vasculature is closely related to the incidence of cerebrovascular events. Moreover, about two-thirds of patients with large-vessel disease leading to ischaemic strokes and transient ischaemic attacks have significant (> 70%) stenoses at the bifurcation of the common carotid artery.’ In the remaining one-third of cases, in the absence of obvious cardiac sources of emboli (eg, atrial fibrillation, valvular heart disease, or acute myocardial infarction), disease elsewhere in the arterial tree has to be considered in the aetiology of
589
copies of the gene while 54 had a mutation in an of a single copy. 34 (63%) of these "heterozygotes" were shown to have a DNA variant in a non-coding sequence of their other CFTR gene ("the 5T allele") which reduces the production of normal CFTR messenger RNA.6 Such mutations in non-coding regions of the gene may thus result in low levels of expression of normal CFTR protein, although the amount produced exon
may be sufficient to prevent or postpone disease in the organs classically affected by CF such as lungs and pancreas. These findings highlight the acute sensitivity of
deferens to CFTR dysfunction. Obstructive azoospermia has been proposed as a major diagnostic criterion in atypical patients with mild features of CF and normal or equivocal sweat chloride concentrations.3 Anecdotal reports of occasional fertile males with atypical CF were often regarded as unproven, sometimes with mention of a similar but distinct disease (phenocopy), until the advent of molecular genetic analysis revealed that some compound heterozygotes with CF gene mutations are unquestionably fertile.’ The Cleveland group who promoted the diagnostic value of azoospermia3 lately reported 4 adult male patients with CF and patency of the vas deferens. These individuals were all hemizygous for a splice mutation in an intron, 3849+lOkb C—/T. There is a further reference to semen analyses showing satisfactory sperm counts, and fertility, in patients with the same mutation.9 Although of the Cleveland patients had pancreatic none insufficiency, they had variable degrees of lung disease. Pancreatic insufficiency was present in 33% of patients with 3849+lOkb C-T and another "severe" mutation in an Israeli series.’° These observations add further support to the view that pancreatic insufficiency, bronchial infection, and lung damage in CF are determined not only by the level of expression and function of CFTR but also by environmental and perhaps other genetic factors.",12 Even for men with CBAVD there is now hope that they may be able to become fathers. After microsurgical epididymal sperm aspiration (MESA)’3 followed by intracytoplasmic sperm injection into oocytes in vitro, a man with CF fathered a healthy child." This case was the more remarkable because the female partner was a carrier of the A F508 mutation, and implantation of the fertilised ovum was carried out only after single-blastomere analysis of the embryo had shown it to be heterozygous. Other instances of successful pregnancies with sperm from CF men by the same technique have been reported.15 The high frequency of CF mutations and the 5T allele in men with CBAVD, together with the empirical carrier frequency of about 1 in 25 in their female partners, makes it essential that both partners should be screened for CF mutations before MESA and in-vitro fertilisation are contemplated. Sympathetic counselling of infertile couples requesting MESA and in-vitro fertilisation where the male partner has classic CF with lung disease should also address the likelihood that the potential father will have a reduced life expectancy, and that his partner may therefore have to cope with a dependent husband as well as a young child. In addition, in-vitro fertilisation has a high failure rate. Fortunately, two recent reports confirm continued and substantial improvements in CF survival’6 and the success of in-vitro fertilisation.17 Increasing
vas
588
numbers of affected couples will the new option for parenthood.
JA
surely wish
to
explore
Dodge
Nuffield Department of Child Health, Queen’s University of Belfast, Belfast, UK Shwachman H, Perlmuter AD, Rule A, Khaw K-T, Holsclaw DS. Reproductive failure in males with cystic fibrosis. N Engl J Med 1968; 279: 65-69. 2 Landing BH, Wells TR, Wang CI. Abnormality of the epididymis and vas deferens in cystic fibrosis. Arch Pathol 1969; 88: 569-90. 3 Stern RC, Boat TF, Doershuk CF. Obstructive azoospermia as a diagnostic criterion for cystic fibrosis syndrome. Lancet 1983; i: 1401-04. 4 Anguiano A, Oates RD, Amos JA, et al. Congenital bilateral absence of the vas deferens: a primary genital form of cystic fibrosis. JAMA 1992; 267: 1794-97. 5 Augarten A,YahavY, Kerem B-S, et al. Congenital bilateral absence of vas deferens in the absence of cystic fibrosis. Lancet 1994; 344: 1473-74. 6 Chillon M, Casals T, Mercier B, Bassas L, et al. Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. N Engl J Med 1995; 332: 1475-80. 7 Barreto C, Marques Pinto L, Duarte A, Lavinha J, Ramsay M. A fertile male with cystic fibrosis: molecular genetic analysis. J Med Genet 1991; 28: 420-21. 8 Stern RC, Doershuk CF, Drumm M. 3849+10kb C→T mutation and disease severity in cystic fibrosis. Lancet 1995; 346: 274-76. 9 Highsmith WE, Burch LH, Zhou Z, et al. A novel mutation in the cystic fibrosis gene in patients with pulmonary disease but normal sweat chloride concentrations. N Engl J Med 1994; 331: 974-80. 10 Augarten A, Kerem B-S, Yahav Y, et al. Mild cystic fibrosis and normal or borderline sweat test in patient with the 3849+10kb C→T mutation. Lancet 1993; 342: 25-26. 11 Dean M, Santis G. Heterogeneity in the severity of cystic fibrosis and the role of CFTR gene mutations. Hum Genet 1994; 93: 364-68. 12 Veeze HJ, Halley DJJ, Bijman J, et al. Determinants of mild classical symptoms in cystic fibrosis patients: residual chloride secretion measured in rectal biopsies in relation to the genotype. J Clin Invest 1994; 93: 461-66. 13 Oates RD, Honig S, Berger MJ, Harris D. Microscopic epididymal sperm aspiration (MESA): a new option for treatment of the obstructive azoospermia associated with cystic fibrosis. J Assist Reprod Genet 1992; 9: 36-40. 14 Liu J, Lissens W, Silber SJ, et al. Birth after preimplantation diagnosis of the cystic fibrosis &Dgr;F508 mutation by polymerase chain reaction in human embryos resulting from intracytoplasmic sperm injection with epididymal sperm. JAMA 1994; 272: 1858-60. 15 Fogdestam I, Hamberger L, Ludin K, Sjögren A, Hjelte L, Strandvik B. Successful pregnancies after in vitro fertilization with sperm from men with cystic fibrosis. 19th European Cystic Fibrosis 1
Kaplan E,
Conference, Paris, 1994 (abstr). 16 UK Cystic Fibrosis Survey 1995 Report, June 1995. 17 Human Fertilisation and Embryology Authority. annual London: HFEA, 1994.
Treatment of AIDS
opportunistic
Report.
infections in
Opportunistic infections are responsible for much of the morbidity and mortality in AIDS patients and are mostly attributable to a small number of pathogens.’ Because these infections had previously been encountered in patients with other types of immune deficiency, effective had often been established before the onset of epidemic.’ Optimum therapy for AIDS-related opportunistic infections is frequently reviewed.3 A comparison of the treatments for these common opportunistic infections in 1981, when the AIDS epidemic was first identified, versus 1995 shows what has been achieved in the 14 year interval (table). Pneumocystis carinii pneumonia (PCP) was once the AIDS-defining infection in 60% of HIV-infected persons and occurred in up to 80% of individuals. With aggressive
treatments
the AIDS
At the
epidemic there were no drugs cytomegalovirus (CMV) end-organ infection. Two agents-ganciclovir and foscarnet-were subsequently approved, and are clearly effective in stabilising individuals with CMV disease. Relapses are frequent and usually occur 2-3 months into therapy. Both drugs have to be delivered intravenously. Oral ganciclovir seems to be a promising alternative for maintenance therapy in some start
of the AIDS
to treat
cases.
Treatment of disseminated Mycobacterium avium complex (MAC) has improved greatly in the past 14 infection for which the treatment was as disabling as the illness, MAC has been shown to respond to several newer agents, especially the macrolides (azithromycin and clarithromycin), the quinolones (eg, ciprofloxacin), and the rifamycins (rifabutin). With treatment, symptoms are sometimes controlled for a year
years. What
was once an
longer. Fungal infections, including cryptococcosis, mucosal candidosis, histoplasmosis, and coccidioidomycosis, continue to cause serious illness. Amphotericin B was established in the 1960s as effective therapy for these
or
MAC=Mycobacterium avium complex. 1 Macrolides mclude clanthromycin and azithromycin. 2 includes cryptococcosis, histoplasmosis, and coccidioidomycosis. 3 First-line agent for mucosal infections. 4 First-line agent for maintenance therapy and second-line
agent for acute therapy. of treatment of for Table: Comparison choice opportunistic infection, 1981 versus 1995 (new first4ine agents are under-
lined) of prophylaxis these rates have decreased, although in 1992 PCP still accounted for 42% of AIDS-indicator diseases reported to the CDC.’ The repertoire of agents for prophylaxis of PCP expanded in the 1980s, with dapsone and aerosol pentamidine, as well as cotrimoxazole, proving effective. However, the best drugs for the treatment of acute PCP in 1995 are the best drugs of 1981-co-trimoxazole and intravenous pentamidine. with dapsone Clindamycin with primaquine, are and trimetrexate trimethoprim, atovoquone, perhaps alternatives in the treatment of mild-toacceptable moderate PCP in patients intolerant of first-line therapy, and corticosteroids are a useful adjunct for severe disease. None of these agents is reliably effective for treatment of severe PCP and none is a first-line agent. Drugs such as eflornithine (DFMO) have been studied but are too toxic or ineffective or both. Treatment of toxoplasmosis with sulfadizine and pyrimethamine was shown to be effective in the 1950s and in 1995 remains clearly better than other therapies. Clindamycin with pyrimethamine is a reliable alternative for individuals intolerant of sulfa drugs. Neither azithromycin nor atovoquone seems to be predictably effective, although trials are still in progress. Trimetrexate has also been studied but is both toxic and ineffective. There is no effective therapy of cryptosporidiosis. bovine Spiramycin, azithromycin, paromomycin, immunoglobulin, diclazuril, and letrazuril are among the drugs tested, and none has emerged as reliably effective. Tuberculosis is increasingly common among AIDS patients, yet the repertoire of effective antituberculosis antibiotics has expanded very little since the 1970s. The quinolones, particularly ofloxacin and its L-isomer levofloxacin, look promising.
use
infections. In the 1980s fluconazole and itraconazole were introduced, and both have an established role in maintenance therapy of fungal infections. However, except for treatment of mucosal candida infections, amphotericin B remains the treatment of choice for acute infection. Despite the lack of new agents, survival from these opportunistic infections has improved. This is mostly due to earlier disease diagnosis and to the attenuating effect on acute infection of prophylaxis and antiretroviral therapy. Perhaps with further improvements in prophylaxis the need to treat many acute infections will be obviated. Meanwhile, it is sobering to review fourteen years of intensive effort and find few real advances in the treatment of opportunistic infections. Above all, this underlines the need for caution when new agents are introduced for the treatment of opportunistic infections. Too often, after the dust has settled, we see that the pathogen and not the antibiotic has prevailed. Kent A
Sepkowitz, Donald Armstrong
Infectious Disease Service, Memorial Sloan-Kettering Cancer Center and New York Hospital-Cornell Medical Center, New York, NY, USA 1 2
3
Centers for Disease Control and Prevention. HIV/AIDS surveillance report: year-end edition Atlanta: CDC, February, 1993. Brown AE, Armstrong D, eds. Infectious complications of neoplastic disease, 1st ed. New York: Yorke Medical Books, 1985. Glatt AE (ed). Management of infection in HIV disease. In: Infect Dis Clin N Am, 1994; 8.
Atherosclerosis in the ascending aorta and risk of ischaemic stroke Arterial disease in the carotid vasculature is closely related to the incidence of cerebrovascular events. Moreover, about two-thirds of patients with large-vessel disease leading to ischaemic strokes and transient ischaemic attacks have significant (> 70%) stenoses at the bifurcation of the common carotid artery.’ In the remaining one-third of cases, in the absence of obvious cardiac sources of emboli (eg, atrial fibrillation, valvular heart disease, or acute myocardial infarction), disease elsewhere in the arterial tree has to be considered in the aetiology of
589