- Email: [email protected]
RSV and chronic asthma
those required for neuromuscular blockade. The debate about the value of magnesium has been protracted, and proper testing of its efficacy was long overdue. The magnesium saga also illustrates the folly of assuming that general medical principles apply in pregnancy-specific conditions. For example, the widespread introduction of a therapy on theoretical grounds (ie, phenytoin) without comparative studies against existing treatments should not be repeated. At a practical level, clinicians unfamiliar with magnesium may be worried about the potential for toxicity and overdose. However, magnesium is in many ways the ideal drug, with rapid onset of action, a nonsedative effect on mother and baby, a wide safety margin, and a readily available antidote in the form of calcium
gluconate. Serum magnesium can be measured to ensure therapeutic concentrations, although many practitioners with experience of the drug are happy to omit biochemical monitoring. Both intramuscular and intravenous methods of administration have been used successfully. The intramuscular regimen is more painful but seems to achieve therapeutic concentrations more rapidly.1O In practice, there is little to choose between these routes. About 10% of eclamptics will experience a further convulsion after receiving a loading dose of magnesium, and for these patients a further 2-4 g given intravenously over 5 min is usually effective. If magnesium concentrations exceed the therapeutic range, patients may complain of warmth, flushing, nausea, double vision, slurred speech, and muscular weakness." Patellar reflexes should be tested frequently during treatment; loss of reflex indicates overdosage, a problem which is more likely if there is renal impairment. There are no real contraindications to magnesium therapy other than perhaps myasthenia gravis, but there may be interaction with calcium-channel blockers or anaesthetic drugs that affect neuromuscular transmission,
in which case dose reduction may be required. Although Lucas and co-workers" showed that prophylactic magnesium therapy significantly reduces the risk of eclampsia in their population of pregnant hypertensive patients, only about 1 % of such patients would have been expected to have a fit if preventive therapy had not been given. In turn, the mortality rate of eclampsia is around 2%.’ Thus prophylactic magnesium therapy may prevent one eclamptic maternal death for every 5000 women treated. For this risk-benefit analysis to favour prophylaxis, magnesium therapy will need to be very safe indeed. As clinicians in the UK switch to magnesium sulphate for the treatment of eclampsia they will find it as safe and easy to use as do their US colleagues, but at this point in the learning curve full scale prophylactic use may not be appropriate.
Nigel Saunders,
Beth
Hammersley
Princess Anne Hospital, Southampton, UK 1 Goodwin JS, Goodwin JM. The tomato effect: rejection of highly efficacious therapies. JAMA 1984; 251: 2387-90. 2 Hutton JD, James DK, Stirrat GM, Douglas KA, Redman CWG. Management of severe pre-eclampsia and eclampsia by UK consultants. Br J Obstet Gynaecol 1992; 99: 554-56. 3 Pritchard JA, Cunningham FG, Pritchard SA. The Parkland Memorial Hospital protocol for treatment of eclampsia: evaluation of 245 cases. Am J Obstet Gynecol 1984; 148: 951-63. 4 Sibai BM. Eclampsia VI: maternal-perinatal outcome in 254 consecutive cases. Am J Obstet Gynecol 1990; 163: 1049-55.
The
5
Eclampsia Trial Collaborative Group. Which anticonvulsant for with eclampsia? Evidence from the Collaborative Eclampsia
women
Trial. Lancet 1995; 345: 1445-63. Lucas MJ, Leveno KJ, Cunningham FG. A comparison of magnesium sulfate with phenytoin for the prevention of eclampsia. N Engl J Med 1995; 333: 201-06. 7 Sadeh M. Action of magnesium sulfate in the treatment of preeclampsia-cclampsia. Stroke 1989; 20: 1273-75. 8 Belfort MA, Moise KJ. Effect of magnesium sulfate on maternal brain blood flow in preeclampsia: a randomised, placebo controlled study. Am J Obstet Gynecol 1992; 167: 661-66. 9 Cotton DB, Janusz CA, Berman RF. Anticonvulsant effects of magnesium sulfate on hippocampal seizures: therapeutic implications in preeclampsia-eclampsia. Am J Obstet Gynecol 1992; 166: 1127-36. 10 Sibai BM, Graham JM, McCubbin JH. A comparison of intravenous and intramuscular magnesium sulfate regimes in preeclampsia. Am J Obstet Gynecol 1984; 150: 728-33. 11 Sibai BM, Ramanthan J. The case for magnesium sulfate in preeclampsia. Int J Obstet Anesth 1992; 1: 167-75. 12 Douglas KA, Redman CWG. Eclampsia in the United Kingdom. BMJ
6
1994; 309: 1395-400.
RSV and chronic asthma Childhood asthma, especially the more
chronic form seen in children of school age, usually occurs in association of immediate hypersensitivity to with evidence environmental allergens. Asthma induced by a certain allergen may suddenly become evident only after years of exposure to the substance. Clinicians often suspect that a singular event has triggered the onset of refractory asthma in such cases, and the darkest aspersions are frequently cast in the direction of respiratory viruses as precipitants. Viruses could theoretically induce a persistent asthmatic diathesis by altering the immune response to favour overproduction of IgE antibodies to allergens, by increasing airway reactivity, or by a combination of these mechanisms. Sigurs and colleagues’ lately reported a study in which children who had been admitted to hospital with respiratory syncytial virus (RSV) infection in infancy were followed to the age of 3 years. At 3 years they were more likely to have a diagnosis of asthma (three episodes of wheezing) and evidence of immediate
hypersensitivity to allergens (skin prick tests or serum IgE antibodies) than were a control group of children matched for sex, date of birth, and area of residence. RSV bronchiolitis was the most important risk factor for development of asthma as well as for the presence of IgE antibodies to foods and inhalants, and acted independently of each child’s heredity for asthma. The implication is that RSV infection somehow induced or permitted greater IgE responses to allergens, and therefore more asthma episodes. Has this study unmasked RSV as the trigger for an atopic diathesis in childhood? Unfortunately the evidence is still insufficient to support (or refute) the possibilty that RSV infection alters synthesis of allergen-specific IgE. Other prospective studies in children have not shown a temporal relation between the occurrence of common viral infections in the first 5 years of life and the onset of immediate hypersensitivity.2,3 In addition, there may be another explanation for the findings of Sigurs et al. Previous studies have suggested that the more severe forms of lower respiratory illness due to RSV (those studied by Sigurs et al) and parainfluenza viruses are associated with exaggerated virus-specific IgE responses at the time of infection.4-6 Using data provided in the Sigurs study, I calculate that asthma was present in 5 (23%) of 22 subjects with evidence of IgE-mediated hypersensitivity at age 3 years, and in only 7 (6-5%) of
789
participants without such hypersensitivity (p<0-005). Thus a predisposition to immediate hypersensitivity could have preceded (and provoked) episodes of both RSV bronchiolitis and recurrent wheezing, and could also have been responsible for the positive results of skin and serum IgE tests done at age 3 years. Viral infections could also contribute to asthma by causing increases in airway reactivity-eg, transient, symptomless increases in reactivity can accompany common colds.7 Experimental rhinovirus infection in subjects with allergic rhinitis induces late-phase asthmatic responses,8 which would be expected to result in more persistent airway hyperreactivity. However, similar responses are not induced in non-atopic individuals. Viral 107
infections may therefore promote immune responses along T-helper cell type 2 pathways, which are associated in late asthmatic responses, but this sequence of events seems to occur only in predisposed individuals and not as sole result of viral infection. Despite the intriguing data from Sigurs’ study, RSV infection cannot yet be regarded as a cause of persistent overproduction of IgE antibody to allergens. RSV infection serves as a marker for a tendency to wheeze at the time of infection with several respiratory viruses,9 but this tendency diminishes sharply at about 3 years of age and continues to decline thereafter. 10 One should not conclude that the 3-year-old children in Sigurs’ study will have persistent asthma. So, there is no clear association between RSV infection in infancy and the development of allergic asthma. By contrast, the onset of childhood allergic asthma seems to be induced by exposure to high concentrations of allergen early in life." Avoidance of such exposures may be important in reducing asthma morbidity, but it is unclear whether prevention of RSV infection in early life will have a similar effect. a
Robert C Welliver Department of Pediatrics, Division of Infectious Diseases, SUNY at Buffalo and Children’s Hospital, Buffalo, NY, USA 1
2
3
4
5
6
7 8
9
10
11
Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman B, Bjorksten B. Asthma and immunoglobulin E antibodies after respiratory syncytial virus bronchiolitis: a prospective cohort study with matched controls. Pediatrics 1995; 95: 500-05. Cogswell JJ, Mitchell EB, Alexander J. Parental smoking, breast feeding and respiratory infection in development of allergic diseases. Arch Dis Child 1987; 62: 338-44. Cogswell JJ, Halliday DF, Alexander JR. Respiratory infections in the first year of life in children at risk of developing atopy. BMJ 1982; 284: 1011-13. Welliver RC, Wong DT, Sun M, et al. The development of respiratory syncytial virus-specific IgE and the release of histamine in nasopharyngeal secretions after infection. N Engl J Med 1981; 305: 841-46. Bui RHD, Molinaro GA, Kettering JD, et al. Virus-specific IgE and IgG4 antibodies in serum of children infected with respiratory syncytial virus. J Pediatr 1987; 110: 87-90. Welliver RC, Wong DT, Middleton E Jr, et al. Role of parainfluenza virus-specific IgE in pathogenesis of croup and wheezing subsequent to infection. J Pediatr 1982; 101: 889-96. Stempel DA, Boucher RC. Respiratory infection and airway reactivity. Med Clin N Am 1981; 65: 1045-53. Lemanske RF, Dick EC, Swenson CA, Vrtis RF, Busse WW. Rhinovirus upper respiratory infection increases airway hyperreactivity and late asthmatic reactions. J Clin Invest 1989; 83: 1-10. Welliver RC, Wong DT, Sun M, McCarthy N. Parainfluenza virus bronchiolitis. Am J Dis Child 1986; 140: 34-40. Henderson FW, Stewart PW, Burchinal MR, et al. Respiratory allergy and the relationship between early childhood lower respiratory illness and subsequent lung function. Am Rev Respir Dis 1992; 145: 283-90. Sporik R, Holgate ST, Platts-Mills TAE, Cogswell JJ. Exposure to house-dust mite allergen (Derp p I) and the development of asthma in childhood. N Engl J Med 1990; 323: 502-07.
790
Towards the elimination of tuberculosis See pages 809, 836
The global burden of tuberculosis-an estimated 90 million new cases will occur during this decade alone-is no longer news. But the institutional inertia facing those charged with defending this mycobacterial attack on global public health does deserve wider and closer
scrutiny. Four impediments stand
in the way of progress. First, nations almost Individual governments. universally adopt a parochial view when setting research and budget priorities. Unless there is a clear and substantial immediate local need, long-term implications of transnational disease spread are rarely addressed. Second, science policy makers. Targets for research inquiry are often resisted by politicians, who consider ring-fenced budgets politically adverse, and by scientists, who prefer the notion of investigator-led to goal-directed science. These attitudes impair the development of potentially important research initiatives-eg, sequencing the genome of Mycobacterium tuberculosis. Third, the market. Commercial competition will not drive the development of new antituberculosis drugs as long as 95% of cases occur in resource-poor countries. Without subsidies, the incentives for pharmaceutical investment into tuberculosis research are small. And finally, national health infrastructures. No control and prevention programme will succeed if the country’s health srvice is unable to support its implementation. Still, there are reasons to be cautiously optimistic. The tuberculosis research community is small but vigorous. One example of such research is the work of Dr V Brahmajothi Mugulu and colleagues (Madurai Kamaraj University, India), whose study of the immunogenetic basis of treatment responses to a multidrug regimen won the investigator award at The Lancet’s conference on tuberculosis held in Washington, DC, last week. Those who hold the pursestrings of research budgets continue to show little commitment to basic research into M tuberculosis. Unless pharmaceutical companies and funding agencies recognise the fundamental role of research, the manifesto set out at our conference will become simply another embarrassing testimony to unrealised ambitions. To many physicians, scientists, and policy makers tuberculosis is seen as a disease of the immigrant, the economically dispossessed, or the individual with HIV. Such crude and reflexive thinking paralyses us all into displacing our collective responsibility onto others, and this is the greatest obstacle to those designing strategies to tackle tuberculosis. In this issue, we publish the final statement from participants at our conference. This document outlines a research and policy agenda that we hope will be seen as benchmark by which to judge future developments in tuberculosis prevention and control. Only by setting such a benchmark and revisiting it-as we will do in the pages of The Lancet-can the medical community prevent a recurrence of the U-shaped curve of concern which has long characterised the history of tuberculosis.
national
Richard Horton The Lancet, London, UK
gluconate. Serum magnesium can be measured to ensure therapeutic concentrations, although many practitioners with experience of the drug are happy to omit biochemical monitoring. Both intramuscular and intravenous methods of administration have been used successfully. The intramuscular regimen is more painful but seems to achieve therapeutic concentrations more rapidly.1O In practice, there is little to choose between these routes. About 10% of eclamptics will experience a further convulsion after receiving a loading dose of magnesium, and for these patients a further 2-4 g given intravenously over 5 min is usually effective. If magnesium concentrations exceed the therapeutic range, patients may complain of warmth, flushing, nausea, double vision, slurred speech, and muscular weakness." Patellar reflexes should be tested frequently during treatment; loss of reflex indicates overdosage, a problem which is more likely if there is renal impairment. There are no real contraindications to magnesium therapy other than perhaps myasthenia gravis, but there may be interaction with calcium-channel blockers or anaesthetic drugs that affect neuromuscular transmission,
in which case dose reduction may be required. Although Lucas and co-workers" showed that prophylactic magnesium therapy significantly reduces the risk of eclampsia in their population of pregnant hypertensive patients, only about 1 % of such patients would have been expected to have a fit if preventive therapy had not been given. In turn, the mortality rate of eclampsia is around 2%.’ Thus prophylactic magnesium therapy may prevent one eclamptic maternal death for every 5000 women treated. For this risk-benefit analysis to favour prophylaxis, magnesium therapy will need to be very safe indeed. As clinicians in the UK switch to magnesium sulphate for the treatment of eclampsia they will find it as safe and easy to use as do their US colleagues, but at this point in the learning curve full scale prophylactic use may not be appropriate.
Nigel Saunders,
Beth
Hammersley
Princess Anne Hospital, Southampton, UK 1 Goodwin JS, Goodwin JM. The tomato effect: rejection of highly efficacious therapies. JAMA 1984; 251: 2387-90. 2 Hutton JD, James DK, Stirrat GM, Douglas KA, Redman CWG. Management of severe pre-eclampsia and eclampsia by UK consultants. Br J Obstet Gynaecol 1992; 99: 554-56. 3 Pritchard JA, Cunningham FG, Pritchard SA. The Parkland Memorial Hospital protocol for treatment of eclampsia: evaluation of 245 cases. Am J Obstet Gynecol 1984; 148: 951-63. 4 Sibai BM. Eclampsia VI: maternal-perinatal outcome in 254 consecutive cases. Am J Obstet Gynecol 1990; 163: 1049-55.
The
5
Eclampsia Trial Collaborative Group. Which anticonvulsant for with eclampsia? Evidence from the Collaborative Eclampsia
women
Trial. Lancet 1995; 345: 1445-63. Lucas MJ, Leveno KJ, Cunningham FG. A comparison of magnesium sulfate with phenytoin for the prevention of eclampsia. N Engl J Med 1995; 333: 201-06. 7 Sadeh M. Action of magnesium sulfate in the treatment of preeclampsia-cclampsia. Stroke 1989; 20: 1273-75. 8 Belfort MA, Moise KJ. Effect of magnesium sulfate on maternal brain blood flow in preeclampsia: a randomised, placebo controlled study. Am J Obstet Gynecol 1992; 167: 661-66. 9 Cotton DB, Janusz CA, Berman RF. Anticonvulsant effects of magnesium sulfate on hippocampal seizures: therapeutic implications in preeclampsia-eclampsia. Am J Obstet Gynecol 1992; 166: 1127-36. 10 Sibai BM, Graham JM, McCubbin JH. A comparison of intravenous and intramuscular magnesium sulfate regimes in preeclampsia. Am J Obstet Gynecol 1984; 150: 728-33. 11 Sibai BM, Ramanthan J. The case for magnesium sulfate in preeclampsia. Int J Obstet Anesth 1992; 1: 167-75. 12 Douglas KA, Redman CWG. Eclampsia in the United Kingdom. BMJ
6
1994; 309: 1395-400.
RSV and chronic asthma Childhood asthma, especially the more
chronic form seen in children of school age, usually occurs in association of immediate hypersensitivity to with evidence environmental allergens. Asthma induced by a certain allergen may suddenly become evident only after years of exposure to the substance. Clinicians often suspect that a singular event has triggered the onset of refractory asthma in such cases, and the darkest aspersions are frequently cast in the direction of respiratory viruses as precipitants. Viruses could theoretically induce a persistent asthmatic diathesis by altering the immune response to favour overproduction of IgE antibodies to allergens, by increasing airway reactivity, or by a combination of these mechanisms. Sigurs and colleagues’ lately reported a study in which children who had been admitted to hospital with respiratory syncytial virus (RSV) infection in infancy were followed to the age of 3 years. At 3 years they were more likely to have a diagnosis of asthma (three episodes of wheezing) and evidence of immediate
hypersensitivity to allergens (skin prick tests or serum IgE antibodies) than were a control group of children matched for sex, date of birth, and area of residence. RSV bronchiolitis was the most important risk factor for development of asthma as well as for the presence of IgE antibodies to foods and inhalants, and acted independently of each child’s heredity for asthma. The implication is that RSV infection somehow induced or permitted greater IgE responses to allergens, and therefore more asthma episodes. Has this study unmasked RSV as the trigger for an atopic diathesis in childhood? Unfortunately the evidence is still insufficient to support (or refute) the possibilty that RSV infection alters synthesis of allergen-specific IgE. Other prospective studies in children have not shown a temporal relation between the occurrence of common viral infections in the first 5 years of life and the onset of immediate hypersensitivity.2,3 In addition, there may be another explanation for the findings of Sigurs et al. Previous studies have suggested that the more severe forms of lower respiratory illness due to RSV (those studied by Sigurs et al) and parainfluenza viruses are associated with exaggerated virus-specific IgE responses at the time of infection.4-6 Using data provided in the Sigurs study, I calculate that asthma was present in 5 (23%) of 22 subjects with evidence of IgE-mediated hypersensitivity at age 3 years, and in only 7 (6-5%) of
789
participants without such hypersensitivity (p<0-005). Thus a predisposition to immediate hypersensitivity could have preceded (and provoked) episodes of both RSV bronchiolitis and recurrent wheezing, and could also have been responsible for the positive results of skin and serum IgE tests done at age 3 years. Viral infections could also contribute to asthma by causing increases in airway reactivity-eg, transient, symptomless increases in reactivity can accompany common colds.7 Experimental rhinovirus infection in subjects with allergic rhinitis induces late-phase asthmatic responses,8 which would be expected to result in more persistent airway hyperreactivity. However, similar responses are not induced in non-atopic individuals. Viral 107
infections may therefore promote immune responses along T-helper cell type 2 pathways, which are associated in late asthmatic responses, but this sequence of events seems to occur only in predisposed individuals and not as sole result of viral infection. Despite the intriguing data from Sigurs’ study, RSV infection cannot yet be regarded as a cause of persistent overproduction of IgE antibody to allergens. RSV infection serves as a marker for a tendency to wheeze at the time of infection with several respiratory viruses,9 but this tendency diminishes sharply at about 3 years of age and continues to decline thereafter. 10 One should not conclude that the 3-year-old children in Sigurs’ study will have persistent asthma. So, there is no clear association between RSV infection in infancy and the development of allergic asthma. By contrast, the onset of childhood allergic asthma seems to be induced by exposure to high concentrations of allergen early in life." Avoidance of such exposures may be important in reducing asthma morbidity, but it is unclear whether prevention of RSV infection in early life will have a similar effect. a
Robert C Welliver Department of Pediatrics, Division of Infectious Diseases, SUNY at Buffalo and Children’s Hospital, Buffalo, NY, USA 1
2
3
4
5
6
7 8
9
10
11
Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman B, Bjorksten B. Asthma and immunoglobulin E antibodies after respiratory syncytial virus bronchiolitis: a prospective cohort study with matched controls. Pediatrics 1995; 95: 500-05. Cogswell JJ, Mitchell EB, Alexander J. Parental smoking, breast feeding and respiratory infection in development of allergic diseases. Arch Dis Child 1987; 62: 338-44. Cogswell JJ, Halliday DF, Alexander JR. Respiratory infections in the first year of life in children at risk of developing atopy. BMJ 1982; 284: 1011-13. Welliver RC, Wong DT, Sun M, et al. The development of respiratory syncytial virus-specific IgE and the release of histamine in nasopharyngeal secretions after infection. N Engl J Med 1981; 305: 841-46. Bui RHD, Molinaro GA, Kettering JD, et al. Virus-specific IgE and IgG4 antibodies in serum of children infected with respiratory syncytial virus. J Pediatr 1987; 110: 87-90. Welliver RC, Wong DT, Middleton E Jr, et al. Role of parainfluenza virus-specific IgE in pathogenesis of croup and wheezing subsequent to infection. J Pediatr 1982; 101: 889-96. Stempel DA, Boucher RC. Respiratory infection and airway reactivity. Med Clin N Am 1981; 65: 1045-53. Lemanske RF, Dick EC, Swenson CA, Vrtis RF, Busse WW. Rhinovirus upper respiratory infection increases airway hyperreactivity and late asthmatic reactions. J Clin Invest 1989; 83: 1-10. Welliver RC, Wong DT, Sun M, McCarthy N. Parainfluenza virus bronchiolitis. Am J Dis Child 1986; 140: 34-40. Henderson FW, Stewart PW, Burchinal MR, et al. Respiratory allergy and the relationship between early childhood lower respiratory illness and subsequent lung function. Am Rev Respir Dis 1992; 145: 283-90. Sporik R, Holgate ST, Platts-Mills TAE, Cogswell JJ. Exposure to house-dust mite allergen (Derp p I) and the development of asthma in childhood. N Engl J Med 1990; 323: 502-07.
790
Towards the elimination of tuberculosis See pages 809, 836
The global burden of tuberculosis-an estimated 90 million new cases will occur during this decade alone-is no longer news. But the institutional inertia facing those charged with defending this mycobacterial attack on global public health does deserve wider and closer
scrutiny. Four impediments stand
in the way of progress. First, nations almost Individual governments. universally adopt a parochial view when setting research and budget priorities. Unless there is a clear and substantial immediate local need, long-term implications of transnational disease spread are rarely addressed. Second, science policy makers. Targets for research inquiry are often resisted by politicians, who consider ring-fenced budgets politically adverse, and by scientists, who prefer the notion of investigator-led to goal-directed science. These attitudes impair the development of potentially important research initiatives-eg, sequencing the genome of Mycobacterium tuberculosis. Third, the market. Commercial competition will not drive the development of new antituberculosis drugs as long as 95% of cases occur in resource-poor countries. Without subsidies, the incentives for pharmaceutical investment into tuberculosis research are small. And finally, national health infrastructures. No control and prevention programme will succeed if the country’s health srvice is unable to support its implementation. Still, there are reasons to be cautiously optimistic. The tuberculosis research community is small but vigorous. One example of such research is the work of Dr V Brahmajothi Mugulu and colleagues (Madurai Kamaraj University, India), whose study of the immunogenetic basis of treatment responses to a multidrug regimen won the investigator award at The Lancet’s conference on tuberculosis held in Washington, DC, last week. Those who hold the pursestrings of research budgets continue to show little commitment to basic research into M tuberculosis. Unless pharmaceutical companies and funding agencies recognise the fundamental role of research, the manifesto set out at our conference will become simply another embarrassing testimony to unrealised ambitions. To many physicians, scientists, and policy makers tuberculosis is seen as a disease of the immigrant, the economically dispossessed, or the individual with HIV. Such crude and reflexive thinking paralyses us all into displacing our collective responsibility onto others, and this is the greatest obstacle to those designing strategies to tackle tuberculosis. In this issue, we publish the final statement from participants at our conference. This document outlines a research and policy agenda that we hope will be seen as benchmark by which to judge future developments in tuberculosis prevention and control. Only by setting such a benchmark and revisiting it-as we will do in the pages of The Lancet-can the medical community prevent a recurrence of the U-shaped curve of concern which has long characterised the history of tuberculosis.
national
Richard Horton The Lancet, London, UK