- Email: [email protected]
Schistosoma japonicum: modern tools for an ancient disease
COMMENTARY
COMMENTARY
Schistosoma japonicum: modern tools for an ancient disease Egyptian mummies that are up to 7000 years old show evidence of infection with schistosomes.1,2 The causative agent of African schistosomiasis was identified by Theodor Bilharz in 1852,3 but scientific progress that could help infected people was scanty over the next 150 years. Antimonials were effective as a treatment,4 but it was only in the 1970s that safe single-dose oral drugs, such as oxamniquine and praziquantel, were introduced for human therapy.5 Progress in the war against schistosomiasis is badly needed, because the number of infected people is not decreasing and the available treatments are insufficient. Although socioeconomic progress has eliminated schistosomiasis from large areas of the world, the development of irrigation resources and population movements have spread the disease to previously non-endemic territories. Thus 200 million people are infected and 650 million are at risk. In 2002 there were 280 000 deaths from schistosomiasis.6 No new drugs are being developed, despite the pending threat of drug resistance, and it is unlikely that an effective vaccine will become available during the next decade.7 The infective agent is a waterborne larva (the cercaria) that penetrates intact human skin in contaminated freshwater. After penetration, the cercaria undergoes complex transformation and migration through the host tissues, until it settles in the mesenteric veins (Schistosoma mansoni and S japonicum) or in the perivesical veins (S haematobium). At this stage, the adult worms are sexually differentiated and can mate and produce eggs. About half the eggs traverse the intestinal or vesical wall and thus escape to the external environment via faeces or urine, hatch in contact with freshwater, and release a swimming larva (miracidium) that infects the intermediate host, an aquatic snail. The cercariae that emerge a month later from the snail are ready to infect humans and start the cycle again. Eggs retained in the human body are responsible for the clinical features of the disease. They accumulate in the liver or in the tissues of the urinary tract, where they elicit an immune reaction characterised by the formation of granulomas. One of the most fascinating—and harmful— features of schistosomes is their ability to survive and produce eggs for many years in the human body, surprisingly evading any immune rejection. Depending on the species, a schistosome pair can produce one egg every 1–10 min; hence the number of eggs and granulomas that accumulate in human tissues over the years is astounding. The pathological process is slow, and the infected person may stay free of serious symptoms for many years and perhaps for life, despite anaemia. However, a small and unpredictable proportion of individuals (generally less than 10%) develop serious problems that range from 180
bloody diarrhoea to portal hypertension and liver cirrhosis, or from haematuria to hydronephrosis. Ectopic localisation of eggs (eg, in the nervous system, genital tract, skin) can cause various symptoms, whereas, for S mansoni, the most common cause of death is the rupture of oesophageal varices after portal hypertension. Bladder cancer associated with S haematobium infection also contributes to the death toll. Two recent papers in Nature Genetics provide new impetus in practical schistosomiasis research. Sergio Verjovski-Almeida8 and Wei Hu9 and their respective colleagues describe two important bioinformatics resources that have been made freely available and which contain an impressive amount of new complementary DNA (cDNA) sequences from S mansoni8 and S japonicum.9 Both initiatives analyse the genetic information that is transcribed from genomic DNA to mRNA (the transcriptome) and which is instrumental for the synthesis of parasite proteins. The researchers used reverse transcription of mRNA extracted from schistosomes into cDNA and then, by random sequencing of a large number of individual cDNAs, generated partial sequences corresponding to the expressed proteins (expressed sequence tags). This information is not as complete as that obtained from the sequencing of the entire genomic DNA (which is in progress elsewhere and will be eventually available). Nevertheless, both groups have sequenced a number of transcripts that is close to the estimated number of total genes in the two organisms. This work means that a valuable tool is immediately available for those researchers hunting for candidate vaccine antigens or drug targets. Such extraordinary progress in the amount of information now available on the schistosome should ultimately benefit the 200 million people infected with these parasites. This progress in schistosome research comes essentially from two countries, Brazil and China, where the disease is endemic. Schistosomiasis is a disease of tropical and subtropical areas, often coinciding with the least developed countries. The geographical spread is one of the reasons why research progress has been slow. It is good news that less privileged countries now have both the expertise and the will to face such an important health problem, to offer substantial scientific advancement, and provide a stimulus to developed countries for a more intensive engagement in the battle against tropical diseases. We have no conflict of interest to declare.
*Donato Cioli, Piero Liberti Institute of Cell Biology, CNR, 00016 Monterotondo (Rome), Italy (e-mail: [email protected])
THE LANCET • Vol 363 • January 17, 2004 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
COMMENTARY
1
2 3 4 5 6
7
8
9
Ruffer MA Note on the presence of Bilharzia haematobia in Egyptian mummies of the twentieth dynasty (1250-1000 B.B.). BMJ 1910; 1: 16. Deelder AM, Miller RL, De Jonge N, Kruger FW. Detection of schistosome antigen in mummies. Lancet 1990; 1: 724–25. Bilharz T. Ein beitrag zur helminthographis humana. Zeitschr Wissenschaftl Zoo 1852; 4: 53–76. Christopherson JB. The successful use of antimony in bilharziosis. BMJ 1918; 2: 325–27. Cioli D, Pica-Mattoccia L, Archer S. Antischistosomal drugs: past, present . . . and future? Pharmacol Ther 1995; 68: 35–85. van der Werf MJ, de Vlas SJ, Brooker S, et al. Quantification of clinical morbidity associated with schistosome infection in sub-Saharan Africa. Acta Trop 2003; 86: 125–39. WHO. Prevention and control of schistosomiasis and soiltransmitted helminthiasis. Report of WHO Expert Committee, WHO Tech Rep Ser 912. Geneva: WHO, 2002. Verjovski-Almeida S, DeMarco R, Martins EA, et al. Transcriptome analysis of the acoelomate human parasite Schistosoma mansoni. Nat Genet 2003; 35: 148–57. Hu W, Yan Q, Shen DK, et al. Evolutionary and biomedical implications of a Schistosoma japonicum complementary DNA resource. Nat Genet 2003; 35: 139–47.
Treatment of Guillain-Barré syndrome with corticosteroids: lack of benefit? See page 192 Guillain-Barré syndrome is an acute inflammatory neuropathy thought to be due to an autoimmune disease that ought to respond to corticosteroid treatment. The puzzle is that it does not. In this issue of The Lancet, Rinske van Koningsveld and colleagues describe a highquality trial in which 233 patients were randomised to receive intravenous methylprednisolone 500 mg daily for 5 days or placebo, in addition to standard treatment with intravenous immunoglobulin. For the primary outcome measure, after 4 weeks, slightly more patients on the corticosteroid (68%) had improved one grade or more on a simple seven-point disability scale1 than patients on placebo (56%). This difference did not reach the significance level of p<0·03 required by the statistical design. After further analysis allowing for selected expected prognostic baseline variables, including age and disease severity, this result just reached statistical significance. However, the effect size was small and none of the secondary outcome measures were significantly different. The data from this new trial are unique because none of the previous trials used intravenous immunoglobulin as the standard treatment. However, there is no known synergy between intravenous immunoglobulin and steroids, and the new data need to be considered in the context of all the available evidence. When these new data are synthesised with those of the four other trials of corticosteroids in Guillain-Barré syndrome with relevant information,2 there were 569 participants and the relative rate of improvement by one grade or more after 4 weeks is 1·06 (95% CI 0·92 to 1·23) more in the corticosteroidtreated patients than in the controls, which is not statistically significant. Three of these trials used oral steroids and only one3 used the same regimen as van Koningsveld and colleagues. When the meta-analysis is confined to the two trials with the same intravenous methylprednisolone regimen, the relative rate of improvement is 1·13 (0·97 to 1·32) more in the corticosteroid group, still not significant. The primary outcome measure in the Cochrane systematic review2 was the weighted mean difference of the change in the same disability grade scale, which ought to be a more sensitive method of analysis. Incorporating the data from the new
trial gives a weighted mean difference of 0·06 (–0·14 to 0·27) of a grade more improvement in the corticosteroid group than the placebo group, a result that is far from being clinically or statistically significant. Meta-analysis of the two intravenous methylprednisolone trials alone shows 0·17 (0·06 to 0·39) more improvement in the corticosteroid than the placebo-treated patients. Because even with this most optimistic analysis the 95% CI does not include the possibility of 0·5 of a disability grade more improvement with corticosteroids than without, it would be inappropriate to revise the recent consensus recommendation not to use corticosteroids routinely in Guillain-Barré syndrome.4 This conclusion is strengthened by the negative results with the secondary outcome measures in van Koningsveld and colleagues’ trial and the Cochrane review.2 For instance, incorporating the data from the new trial in a meta-analysis of the three trials with available data, the relative risk of being dead or disabled after a year is 1·3 (0·91 to 1·92) more in the corticosteroid than the placebo patients, a non-significant result. A meta-analysis of individual patients’ data from existing trials, taking into account the prognostic variables selected by van Koningsveld and colleagues, would provide a more precise estimate of the effect (or lack of effect) of corticosteroids. The present metaanalysis does nothing to encourage further investigation of the previously tried corticosteroid regimens for Guillain-Barré syndrome. The lack of effect of corticosteroids in Guillain-Barré syndrome might be related to their adverse effects on denervated muscle or to their inhibition of macrophage function. In an animal model, treatment of denervated muscle with corticosteroids causes more severe necrosis of muscle fibres than denervation alone.5 The major underlying pathological process in Guillain-Barré syndrome is macrophage stripping of myelin sheaths, which blocks nerve conduction and causes weakness. So, interfering with the process ought to be helpful. Unfortunately macrophage stripping of myelin is ultimately a requirement for remyelination and its inhibition might delay or prevent recovery. In an animal model of Guillain-Barré syndrome, it has been difficult to show a beneficial effect of corticosteroids.6,7 GuillainBarré syndrome is not the only predominantly motor neuropathy not to respond to steroids; multifocal motor neuropathy does not respond and can even be made worse.8 Although plasma exchange and intravenous immunoglobulin are both effective in Guillain-Barré syndrome, recovery may be slow: about 15% of patients die or are left disabled and persistent fatigue is common.9,10 The need now is for a better understanding of the pathogenesis of Guillain-Barré syndrome and for immunological treatments that are specific for the underlying pathological processes. I was the prinicipal investigator in two trials that did not show significant benefit from corticosteroids in Guillain-Barré syndrome.
Richard A C Hughes Department of Clinical Neurosciences, Guy's, King's and St Thomas' School of Medicine, London SE1 1 UL, UK (e-mail: [email protected]) 1
2
Hughes RAC, Newsom-Davis JM, Perkin GD, Pierce JM. Controlled trial of prednisolone in acute polyneuropathy. Lancet 1978; 2: 750–53. Hughes RAC, van der Meché FGA. Corticosteroid treatment for Guillain-Barré syndrome (Cochrane Review). Chichester, UK: John Wiley & Sons Ltd, The Cochrane Library, Issue 4, 2003.
THE LANCET • Vol 363 • January 17, 2004 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
181
COMMENTARY
Schistosoma japonicum: modern tools for an ancient disease Egyptian mummies that are up to 7000 years old show evidence of infection with schistosomes.1,2 The causative agent of African schistosomiasis was identified by Theodor Bilharz in 1852,3 but scientific progress that could help infected people was scanty over the next 150 years. Antimonials were effective as a treatment,4 but it was only in the 1970s that safe single-dose oral drugs, such as oxamniquine and praziquantel, were introduced for human therapy.5 Progress in the war against schistosomiasis is badly needed, because the number of infected people is not decreasing and the available treatments are insufficient. Although socioeconomic progress has eliminated schistosomiasis from large areas of the world, the development of irrigation resources and population movements have spread the disease to previously non-endemic territories. Thus 200 million people are infected and 650 million are at risk. In 2002 there were 280 000 deaths from schistosomiasis.6 No new drugs are being developed, despite the pending threat of drug resistance, and it is unlikely that an effective vaccine will become available during the next decade.7 The infective agent is a waterborne larva (the cercaria) that penetrates intact human skin in contaminated freshwater. After penetration, the cercaria undergoes complex transformation and migration through the host tissues, until it settles in the mesenteric veins (Schistosoma mansoni and S japonicum) or in the perivesical veins (S haematobium). At this stage, the adult worms are sexually differentiated and can mate and produce eggs. About half the eggs traverse the intestinal or vesical wall and thus escape to the external environment via faeces or urine, hatch in contact with freshwater, and release a swimming larva (miracidium) that infects the intermediate host, an aquatic snail. The cercariae that emerge a month later from the snail are ready to infect humans and start the cycle again. Eggs retained in the human body are responsible for the clinical features of the disease. They accumulate in the liver or in the tissues of the urinary tract, where they elicit an immune reaction characterised by the formation of granulomas. One of the most fascinating—and harmful— features of schistosomes is their ability to survive and produce eggs for many years in the human body, surprisingly evading any immune rejection. Depending on the species, a schistosome pair can produce one egg every 1–10 min; hence the number of eggs and granulomas that accumulate in human tissues over the years is astounding. The pathological process is slow, and the infected person may stay free of serious symptoms for many years and perhaps for life, despite anaemia. However, a small and unpredictable proportion of individuals (generally less than 10%) develop serious problems that range from 180
bloody diarrhoea to portal hypertension and liver cirrhosis, or from haematuria to hydronephrosis. Ectopic localisation of eggs (eg, in the nervous system, genital tract, skin) can cause various symptoms, whereas, for S mansoni, the most common cause of death is the rupture of oesophageal varices after portal hypertension. Bladder cancer associated with S haematobium infection also contributes to the death toll. Two recent papers in Nature Genetics provide new impetus in practical schistosomiasis research. Sergio Verjovski-Almeida8 and Wei Hu9 and their respective colleagues describe two important bioinformatics resources that have been made freely available and which contain an impressive amount of new complementary DNA (cDNA) sequences from S mansoni8 and S japonicum.9 Both initiatives analyse the genetic information that is transcribed from genomic DNA to mRNA (the transcriptome) and which is instrumental for the synthesis of parasite proteins. The researchers used reverse transcription of mRNA extracted from schistosomes into cDNA and then, by random sequencing of a large number of individual cDNAs, generated partial sequences corresponding to the expressed proteins (expressed sequence tags). This information is not as complete as that obtained from the sequencing of the entire genomic DNA (which is in progress elsewhere and will be eventually available). Nevertheless, both groups have sequenced a number of transcripts that is close to the estimated number of total genes in the two organisms. This work means that a valuable tool is immediately available for those researchers hunting for candidate vaccine antigens or drug targets. Such extraordinary progress in the amount of information now available on the schistosome should ultimately benefit the 200 million people infected with these parasites. This progress in schistosome research comes essentially from two countries, Brazil and China, where the disease is endemic. Schistosomiasis is a disease of tropical and subtropical areas, often coinciding with the least developed countries. The geographical spread is one of the reasons why research progress has been slow. It is good news that less privileged countries now have both the expertise and the will to face such an important health problem, to offer substantial scientific advancement, and provide a stimulus to developed countries for a more intensive engagement in the battle against tropical diseases. We have no conflict of interest to declare.
*Donato Cioli, Piero Liberti Institute of Cell Biology, CNR, 00016 Monterotondo (Rome), Italy (e-mail: [email protected])
THE LANCET • Vol 363 • January 17, 2004 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
COMMENTARY
1
2 3 4 5 6
7
8
9
Ruffer MA Note on the presence of Bilharzia haematobia in Egyptian mummies of the twentieth dynasty (1250-1000 B.B.). BMJ 1910; 1: 16. Deelder AM, Miller RL, De Jonge N, Kruger FW. Detection of schistosome antigen in mummies. Lancet 1990; 1: 724–25. Bilharz T. Ein beitrag zur helminthographis humana. Zeitschr Wissenschaftl Zoo 1852; 4: 53–76. Christopherson JB. The successful use of antimony in bilharziosis. BMJ 1918; 2: 325–27. Cioli D, Pica-Mattoccia L, Archer S. Antischistosomal drugs: past, present . . . and future? Pharmacol Ther 1995; 68: 35–85. van der Werf MJ, de Vlas SJ, Brooker S, et al. Quantification of clinical morbidity associated with schistosome infection in sub-Saharan Africa. Acta Trop 2003; 86: 125–39. WHO. Prevention and control of schistosomiasis and soiltransmitted helminthiasis. Report of WHO Expert Committee, WHO Tech Rep Ser 912. Geneva: WHO, 2002. Verjovski-Almeida S, DeMarco R, Martins EA, et al. Transcriptome analysis of the acoelomate human parasite Schistosoma mansoni. Nat Genet 2003; 35: 148–57. Hu W, Yan Q, Shen DK, et al. Evolutionary and biomedical implications of a Schistosoma japonicum complementary DNA resource. Nat Genet 2003; 35: 139–47.
Treatment of Guillain-Barré syndrome with corticosteroids: lack of benefit? See page 192 Guillain-Barré syndrome is an acute inflammatory neuropathy thought to be due to an autoimmune disease that ought to respond to corticosteroid treatment. The puzzle is that it does not. In this issue of The Lancet, Rinske van Koningsveld and colleagues describe a highquality trial in which 233 patients were randomised to receive intravenous methylprednisolone 500 mg daily for 5 days or placebo, in addition to standard treatment with intravenous immunoglobulin. For the primary outcome measure, after 4 weeks, slightly more patients on the corticosteroid (68%) had improved one grade or more on a simple seven-point disability scale1 than patients on placebo (56%). This difference did not reach the significance level of p<0·03 required by the statistical design. After further analysis allowing for selected expected prognostic baseline variables, including age and disease severity, this result just reached statistical significance. However, the effect size was small and none of the secondary outcome measures were significantly different. The data from this new trial are unique because none of the previous trials used intravenous immunoglobulin as the standard treatment. However, there is no known synergy between intravenous immunoglobulin and steroids, and the new data need to be considered in the context of all the available evidence. When these new data are synthesised with those of the four other trials of corticosteroids in Guillain-Barré syndrome with relevant information,2 there were 569 participants and the relative rate of improvement by one grade or more after 4 weeks is 1·06 (95% CI 0·92 to 1·23) more in the corticosteroidtreated patients than in the controls, which is not statistically significant. Three of these trials used oral steroids and only one3 used the same regimen as van Koningsveld and colleagues. When the meta-analysis is confined to the two trials with the same intravenous methylprednisolone regimen, the relative rate of improvement is 1·13 (0·97 to 1·32) more in the corticosteroid group, still not significant. The primary outcome measure in the Cochrane systematic review2 was the weighted mean difference of the change in the same disability grade scale, which ought to be a more sensitive method of analysis. Incorporating the data from the new
trial gives a weighted mean difference of 0·06 (–0·14 to 0·27) of a grade more improvement in the corticosteroid group than the placebo group, a result that is far from being clinically or statistically significant. Meta-analysis of the two intravenous methylprednisolone trials alone shows 0·17 (0·06 to 0·39) more improvement in the corticosteroid than the placebo-treated patients. Because even with this most optimistic analysis the 95% CI does not include the possibility of 0·5 of a disability grade more improvement with corticosteroids than without, it would be inappropriate to revise the recent consensus recommendation not to use corticosteroids routinely in Guillain-Barré syndrome.4 This conclusion is strengthened by the negative results with the secondary outcome measures in van Koningsveld and colleagues’ trial and the Cochrane review.2 For instance, incorporating the data from the new trial in a meta-analysis of the three trials with available data, the relative risk of being dead or disabled after a year is 1·3 (0·91 to 1·92) more in the corticosteroid than the placebo patients, a non-significant result. A meta-analysis of individual patients’ data from existing trials, taking into account the prognostic variables selected by van Koningsveld and colleagues, would provide a more precise estimate of the effect (or lack of effect) of corticosteroids. The present metaanalysis does nothing to encourage further investigation of the previously tried corticosteroid regimens for Guillain-Barré syndrome. The lack of effect of corticosteroids in Guillain-Barré syndrome might be related to their adverse effects on denervated muscle or to their inhibition of macrophage function. In an animal model, treatment of denervated muscle with corticosteroids causes more severe necrosis of muscle fibres than denervation alone.5 The major underlying pathological process in Guillain-Barré syndrome is macrophage stripping of myelin sheaths, which blocks nerve conduction and causes weakness. So, interfering with the process ought to be helpful. Unfortunately macrophage stripping of myelin is ultimately a requirement for remyelination and its inhibition might delay or prevent recovery. In an animal model of Guillain-Barré syndrome, it has been difficult to show a beneficial effect of corticosteroids.6,7 GuillainBarré syndrome is not the only predominantly motor neuropathy not to respond to steroids; multifocal motor neuropathy does not respond and can even be made worse.8 Although plasma exchange and intravenous immunoglobulin are both effective in Guillain-Barré syndrome, recovery may be slow: about 15% of patients die or are left disabled and persistent fatigue is common.9,10 The need now is for a better understanding of the pathogenesis of Guillain-Barré syndrome and for immunological treatments that are specific for the underlying pathological processes. I was the prinicipal investigator in two trials that did not show significant benefit from corticosteroids in Guillain-Barré syndrome.
Richard A C Hughes Department of Clinical Neurosciences, Guy's, King's and St Thomas' School of Medicine, London SE1 1 UL, UK (e-mail: [email protected]) 1
2
Hughes RAC, Newsom-Davis JM, Perkin GD, Pierce JM. Controlled trial of prednisolone in acute polyneuropathy. Lancet 1978; 2: 750–53. Hughes RAC, van der Meché FGA. Corticosteroid treatment for Guillain-Barré syndrome (Cochrane Review). Chichester, UK: John Wiley & Sons Ltd, The Cochrane Library, Issue 4, 2003.
THE LANCET • Vol 363 • January 17, 2004 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
181