- Email: [email protected]
Risk of asthma in children with exposure to mite and cat allergens
COMMENTARY
PMR and 39 in countries with a high PMR. Thus the resource implications of the NNT are greatest in countries with fewer resources, something which is also likely to limit the generalisability of the trial findings to countries with a low PMR. The Term Breech Trial has shown how, by choosing a clinical question relevant to thousands of people, summarising the existing evidence and developing a consensus about the options and the clinical uncertainty, and convincing other researchers to collaborate in answering the question, management of a common clinical condition can be clarified, at least for a large proportion of cases. The next step is rapid dissemination of the current findings to pregnant women, their families, and all clinicians involved in maternity care. Judith Lumley Centre for the Study of Mothers’ and Children’s Health, La Trobe University, Melbourne, Victoria 3153, Australia 1
2
3
4
Collea JV, Chein C, Quilligan EJ. A randomised management of term frank breech presentation: a study of 208 cases. Am J Obstet Gynecol 1980: 137: 235–244. Gimovsky ML, Wallace RL, Schifrin BS, Paul RH. Randomised management of the non-frank breech presentation at term: a preliminary report. Am J Obstet Gynecol 1983: 146: 34–40. Hannah ME, Hannah WJ, Hellman KJ, et al. Induction of labor as compared with serial antenatal monitoring in postterm pregnancy: a randomised controlled trial. N Engl J Med 1992; 326: 1587–92. Hannah WJ, Allardice J, Amankwah K, et al. The Canadian consensus on breech management at term. JSOGC 1994; 16: 1839–58.
Risk of asthma in children with exposure to mite and cat allergens See page 1392 Allergic sensitisation has been identified as a risk factor for persistent asthma. But it is unclear whether the onset of asthma is increased by exposure to allergens early in life or prevented by avoidance. Pearce and colleagues1 recently reviewed the studies on this topic and concluded that there is no evidence that allergen exposure in early life is a major risk factor for the development of asthma in children. Two longitudinal studies had been carried out, both among children with a family history of atopy. One study, by Sporik and colleagues,2 showed non-significant associations between early allergen exposure and active wheezing and airways hyper-responsiveness (surrogates for asthma). The other3 showed no association between early allergen exposure and the development of doctordiagnosed asthma. There have been no reports of
Relation between sensitisation, exposure to allergens, and development of asthma Sensitisation Established Not confirmed
Exposure to allergens
THE LANCET • Vol 356 • October 21, 2000
Asthma
longitudinal studies among a cohort selected from the general population. The longitudinal study by Susanne Lau and colleagues in this issue of The Lancet is important in that 62% of the cohort were randomly selected from a population not at high risk of atopy. Children were enrolled as newborns, were seen frequently during the first 2 years of life, then annually till age seven. Information was collected about symptoms of atopic disease, about environmental exposures, family history of atopy, family size, and social status. Carpet dust was collected at 6, 18, and 36 months of age and analysed for presence of dust-mite and cat allergens. Sensitisation to specific foods and inhaled allergen was assessed by RAST, and bronchial hyper-responsiveness was measured by histamine challenge. A significant association was found, from age 3 onward, between sensitisation to mite and/or cat allergens and wheezing. Furthermore, at age 7, sensitised individuals showed a greater response than non-sensitised individuals to histamine, which indicated that they had a higher degree of bronchial hyper-responsiveness. Although exposure to indoor allergens was related to sensitisation, it was not related to any of the asthma indicators that were asked about or tested for (figure).The concentrations of dust-mite allergen encountered in the homes in Lau and colleagues’ study were substantially lower than those in the longitudinal study by Sporik and colleagues.2 However, this low concentration did not prevent allergic sensitisation from developing in some of the population. Thus, this study seems to put to rest the idea that the onset of asthma is caused by exposure to one or two allergens in early life. Nevertheless, as Lau and colleagues point out, allergen exposure will trigger symptoms in sensitised asthmatic people, hence allergen avoidance is important in preventing exacerbations of asthma. It must be remembered, however, that the environment is a veritable “stew” containing many substances, which may interact with each other and possibly affect the onset of the disease. A study from Sweden has shown that a highly synergistic interaction among exposures to high concentrations of cat allergen, environmental tobacco smoke, and window-pane condensation increases the risk of sensitisation to cats.4 Additionally, pollutants, such as nitrogen dioxide, may potentiate asthmatic responses to low doses of allergens.5 Other pollutants, such as those generated by coal or wood heating, might protect children from developing allergic sensitisation and bronchial hyper-responsiveness.6 Thus, interactions among pollutants and allergens might modulate allergen sensitisation and possibly the onset of asthma. However, the factors that affect allergen sensitisation probably differ from those influencing onset of asthma. This point is evident from a study of Chinese schoolchildren from Hong Kong, Kota Kinabalu (in Malaysia), and San Bu (in China),7 which showed that, although dust-mite allergy was a significant risk factor for asthma, the prevalence of asthma was significantly lower among children living in San Bu than those living in Hong Kong despite similar rates of allergic sensitisation. Few studies have examined interactions among environmental factors and the onset of asthma, and more are needed. Thus, the search must go on for answers to the important questions of what causes asthma and why the prevalence of the disease has increased so substantially over the past 30 years. A large, multicentre, longitudinal study of population-based cohorts of newborns selected from areas around the world with different rates of asthma may well be needed. Such a study will be very expensive, 1369
For personal use only. Not to be reproduced without permission of The Lancet.
COMMENTARY
but will undoubtedly cost less than what society spends on asthma, and the rewards are potentially great. Roni Grad Department of Pediatrics. University of Alabama School of Medicine, Birmingham, AL 35233, USA 1 2
3 4
5
6
7
Pearce N, Douwes J, Beasley R. Is allergen exposure the major primary cause of asthma? Thorax 2000; 55: 424–31. Sporik R, Holgate ST, Platts-Mills TAE, Cogswell JJ. Exposure to house-dust mite allergen (Der p I) and the development of asthma in childhood: a prospective study. N Engl J Med 1990; 323: 502–07. Burr ML. Limb ES, Maguire MJ, et al. Infant feeding, wheezing and allergy: a prospective study. Arch Dis Child 1993; 68: 724–28. Lindfors A, Van Hage-Hamsten M, Rietz H, Wickman M, Nordvall SL. Influence of interaction of environmental risk factors and sensitization in young asthmatic children. J Allergy Clin Immunol 1999; 104: 755–62. Strand V, Svartengren M, Rak S, Barck C, Bylin G. Repeated exposure to an ambient level of NO2 enhances asthmatic response to a nonsymptomatic allergen dose. Eur Respir J 1998; 12: 6–12. Von Mutius E, Illi S, Nicolai T, Martinez FD. Relation of indoor heating with asthma, allergic sensitisation, and bronchial hyperresponsiveness: survey of children in south Bavaria. BMJ 1996; 312: 1448–50. Leung R, Ho P, Lam CWK, Lai CKW. Sensitization to inhaled allergens as a risk factor for asthma and allergic diseases in Chinese population. J Allergy Clin Immunol 1997; 99: 594–99.
Prevention of acute and recurrent otitis media See page 1398 Epidemiological studies of acute otitis media during the past decade have shown that acute otitis media is developing at an earlier age and that the proportion of children having multiple episodes before age 1 year has been increasing over the past decade. Concerns about a delay in language development and altered behaviour remain paramount among both professionals and parents. Parents of children with recurrent otitis media report anxiety about the unpredictable nature of their child’s illness, excess time lost from work, and frustration with ineffective treatment.1 Current strategies to prevent acute otitis media include use of prophylactic antibiotics, immunoprophylaxis, and tympanostomy tubes. Antibiotic prophylaxis, although effective, places selective pressure on bacterial ecology and contributes to the increase in resistance among respiratory pathogens. Pneumococcal polysaccharide vaccine is not sufficiently immunogenic in the target population (age under 2 years), and conjugate pneumococcal vaccine, albeit immunogenic, targets only the seven most common pneumococcal serotypes. A one-third reduction in pneumococcal otitis media has been observed in infants immunised with conjugate pneumococcal vaccine, but the decrease in episodes due to any organism was modest (<10%).2 Although this reduction has a substantial impact on a population basis, the benefit that accrues to an individual child is more limited. Tympanostomy tubes facilitate the drainage of the middle-ear cavity and reduce the duration of middle-ear effusions, but do not significantly decrease the frequency of acute episodes. In this week’s issue of The Lancet Pentti Ukkonen and colleagues describe an alternative approach to the prevention of acute otitis media. The pathophysiology of acute otitis media is such that it is preceded by nasopharyngeal colonisation with otopathogenic bacteria and in many cases a concomitant viral respiratory infection. The viral upper-respiratory infection enhances the likelihood of contiguous spread of nasopharyngeal pathogens to the middle ear by increasing the bacterial burden in the nasopharynx, impairing eustachian tube 1370
function, or altering host defences. Strategies that decrease colonisation with both Streptococcus pneumoniae and Haemophilus influenzae would probably be associated with a significant reduction in the frequency of acute otitis media. The use of oligosaccharides as competitive inhibitors of membrane receptors is well founded, and in-vitro studies have shown that sialylated glycoconjugates are adherence targets of both S pneumoniae and H influenzae. One potential limitation is that bacteria could use other membrane receptors, such as C3 (for S pneumoniae) when epithelial cells are activated during viral co-infection or inflammation.3 Nevertheless, in-vitro studies suggest that, even in the presence of activated epithelial cells, certain oligosaccharides are capable of reducing the adherence of S pneumoniae.4 Ukkonen and colleagues did not find a decrease in nasopharyngeal colonisation with otopathogens or a decline in episodes of acute otitis media after twice-daily intranasal application of NE-1530, a sialylated pentasaccharide. Potential explanations for these results include low potency of the compound, inadequate dose, failure to affect a persistent reservoir, or the presence of other membrane receptors not susceptible to competition with sialylated oligosaccharides. In vitro, xylitol, a five-carbon sugar alcohol, reduces binding of S pneumoniae and H influenzae to epithelial cells.5 The effect seems greatest when the concentration of xylitol is high (5%) and when both cells and bacteria are exposed. In a clinical study, children who used xylitol chewing gum had fewer episodes of acute otitis media than those who used sucrose-containing chewing gum.6 These results provide for the possibility that a different dose or regimen of NE-1530 may prove more successful. The fact that S pneumoniae and H influenzae are commonly cultured from oropharyngeal swabs also suggests why intranasal administration may not be effective. Bacterial adherence is a complex issue. For instance, in chinchilla tracheal cultures, pretreatment with lacto-Nneotetraose inhibited epithelial adherence of S pneumoniae; however, when neuraminidase was added, adherence increased—presumably because additional receptors were exposed.7 Another example of the complexity of bacterial adherence is that in non-typable Haemophilus influenzae at least three non-pilus proteins (HMW1, HMW2, HIA) have essential roles in the attachment process.8 HMW1 seems to recognise a sialylated glycoprotein, but HMW2 and HIA receptors have different specificities. Thus a mixture of competitive inhibitors may be necessary to reduce nasopharyngeal colonisation. The concept of reducing nasopharyngeal colonisation and episodes of bacterial otitis media through competitive inhibition remains “cutting-edge” medicine. The failure of NE-1530 to achieve those goals highlights the challenges in both understanding the complexities of bacterial adherence and the practicality of delivering a drug with enough potency to a large mucosal surface. Stephen Pelton Division of Pediatric Infectious Diseases, Boston Medical Center, Boston, MA 02118, USA
1
2
3
Asmussen L, Olson LM, Sullivan SA. “You have to live it to understand it . . . ”. Family experiences with chronic otitis media in children. Ambulatory Child Health 1999; 5: 303–12. Eskola J, Kilpi T. Efficacy of a heptavalent pneumococcal conjugate vaccine (PnnCRM) against serotype-specific, culture-confirmed pneumococcal acute otitis media (AOM) in infants and children. Thirty-ninth Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), San Francisco CA, Sept 27–29, 1999. LB-13 (abstr). Smith BL, Hostetter M. C3 as a substrate for adhesion of Streptococcus pneumoniae. J Infect Dis 2000; 182: 497–508.
THE LANCET • Vol 356 • October 21, 2000
For personal use only. Not to be reproduced without permission of The Lancet.
PMR and 39 in countries with a high PMR. Thus the resource implications of the NNT are greatest in countries with fewer resources, something which is also likely to limit the generalisability of the trial findings to countries with a low PMR. The Term Breech Trial has shown how, by choosing a clinical question relevant to thousands of people, summarising the existing evidence and developing a consensus about the options and the clinical uncertainty, and convincing other researchers to collaborate in answering the question, management of a common clinical condition can be clarified, at least for a large proportion of cases. The next step is rapid dissemination of the current findings to pregnant women, their families, and all clinicians involved in maternity care. Judith Lumley Centre for the Study of Mothers’ and Children’s Health, La Trobe University, Melbourne, Victoria 3153, Australia 1
2
3
4
Collea JV, Chein C, Quilligan EJ. A randomised management of term frank breech presentation: a study of 208 cases. Am J Obstet Gynecol 1980: 137: 235–244. Gimovsky ML, Wallace RL, Schifrin BS, Paul RH. Randomised management of the non-frank breech presentation at term: a preliminary report. Am J Obstet Gynecol 1983: 146: 34–40. Hannah ME, Hannah WJ, Hellman KJ, et al. Induction of labor as compared with serial antenatal monitoring in postterm pregnancy: a randomised controlled trial. N Engl J Med 1992; 326: 1587–92. Hannah WJ, Allardice J, Amankwah K, et al. The Canadian consensus on breech management at term. JSOGC 1994; 16: 1839–58.
Risk of asthma in children with exposure to mite and cat allergens See page 1392 Allergic sensitisation has been identified as a risk factor for persistent asthma. But it is unclear whether the onset of asthma is increased by exposure to allergens early in life or prevented by avoidance. Pearce and colleagues1 recently reviewed the studies on this topic and concluded that there is no evidence that allergen exposure in early life is a major risk factor for the development of asthma in children. Two longitudinal studies had been carried out, both among children with a family history of atopy. One study, by Sporik and colleagues,2 showed non-significant associations between early allergen exposure and active wheezing and airways hyper-responsiveness (surrogates for asthma). The other3 showed no association between early allergen exposure and the development of doctordiagnosed asthma. There have been no reports of
Relation between sensitisation, exposure to allergens, and development of asthma Sensitisation Established Not confirmed
Exposure to allergens
THE LANCET • Vol 356 • October 21, 2000
Asthma
longitudinal studies among a cohort selected from the general population. The longitudinal study by Susanne Lau and colleagues in this issue of The Lancet is important in that 62% of the cohort were randomly selected from a population not at high risk of atopy. Children were enrolled as newborns, were seen frequently during the first 2 years of life, then annually till age seven. Information was collected about symptoms of atopic disease, about environmental exposures, family history of atopy, family size, and social status. Carpet dust was collected at 6, 18, and 36 months of age and analysed for presence of dust-mite and cat allergens. Sensitisation to specific foods and inhaled allergen was assessed by RAST, and bronchial hyper-responsiveness was measured by histamine challenge. A significant association was found, from age 3 onward, between sensitisation to mite and/or cat allergens and wheezing. Furthermore, at age 7, sensitised individuals showed a greater response than non-sensitised individuals to histamine, which indicated that they had a higher degree of bronchial hyper-responsiveness. Although exposure to indoor allergens was related to sensitisation, it was not related to any of the asthma indicators that were asked about or tested for (figure).The concentrations of dust-mite allergen encountered in the homes in Lau and colleagues’ study were substantially lower than those in the longitudinal study by Sporik and colleagues.2 However, this low concentration did not prevent allergic sensitisation from developing in some of the population. Thus, this study seems to put to rest the idea that the onset of asthma is caused by exposure to one or two allergens in early life. Nevertheless, as Lau and colleagues point out, allergen exposure will trigger symptoms in sensitised asthmatic people, hence allergen avoidance is important in preventing exacerbations of asthma. It must be remembered, however, that the environment is a veritable “stew” containing many substances, which may interact with each other and possibly affect the onset of the disease. A study from Sweden has shown that a highly synergistic interaction among exposures to high concentrations of cat allergen, environmental tobacco smoke, and window-pane condensation increases the risk of sensitisation to cats.4 Additionally, pollutants, such as nitrogen dioxide, may potentiate asthmatic responses to low doses of allergens.5 Other pollutants, such as those generated by coal or wood heating, might protect children from developing allergic sensitisation and bronchial hyper-responsiveness.6 Thus, interactions among pollutants and allergens might modulate allergen sensitisation and possibly the onset of asthma. However, the factors that affect allergen sensitisation probably differ from those influencing onset of asthma. This point is evident from a study of Chinese schoolchildren from Hong Kong, Kota Kinabalu (in Malaysia), and San Bu (in China),7 which showed that, although dust-mite allergy was a significant risk factor for asthma, the prevalence of asthma was significantly lower among children living in San Bu than those living in Hong Kong despite similar rates of allergic sensitisation. Few studies have examined interactions among environmental factors and the onset of asthma, and more are needed. Thus, the search must go on for answers to the important questions of what causes asthma and why the prevalence of the disease has increased so substantially over the past 30 years. A large, multicentre, longitudinal study of population-based cohorts of newborns selected from areas around the world with different rates of asthma may well be needed. Such a study will be very expensive, 1369
For personal use only. Not to be reproduced without permission of The Lancet.
COMMENTARY
but will undoubtedly cost less than what society spends on asthma, and the rewards are potentially great. Roni Grad Department of Pediatrics. University of Alabama School of Medicine, Birmingham, AL 35233, USA 1 2
3 4
5
6
7
Pearce N, Douwes J, Beasley R. Is allergen exposure the major primary cause of asthma? Thorax 2000; 55: 424–31. Sporik R, Holgate ST, Platts-Mills TAE, Cogswell JJ. Exposure to house-dust mite allergen (Der p I) and the development of asthma in childhood: a prospective study. N Engl J Med 1990; 323: 502–07. Burr ML. Limb ES, Maguire MJ, et al. Infant feeding, wheezing and allergy: a prospective study. Arch Dis Child 1993; 68: 724–28. Lindfors A, Van Hage-Hamsten M, Rietz H, Wickman M, Nordvall SL. Influence of interaction of environmental risk factors and sensitization in young asthmatic children. J Allergy Clin Immunol 1999; 104: 755–62. Strand V, Svartengren M, Rak S, Barck C, Bylin G. Repeated exposure to an ambient level of NO2 enhances asthmatic response to a nonsymptomatic allergen dose. Eur Respir J 1998; 12: 6–12. Von Mutius E, Illi S, Nicolai T, Martinez FD. Relation of indoor heating with asthma, allergic sensitisation, and bronchial hyperresponsiveness: survey of children in south Bavaria. BMJ 1996; 312: 1448–50. Leung R, Ho P, Lam CWK, Lai CKW. Sensitization to inhaled allergens as a risk factor for asthma and allergic diseases in Chinese population. J Allergy Clin Immunol 1997; 99: 594–99.
Prevention of acute and recurrent otitis media See page 1398 Epidemiological studies of acute otitis media during the past decade have shown that acute otitis media is developing at an earlier age and that the proportion of children having multiple episodes before age 1 year has been increasing over the past decade. Concerns about a delay in language development and altered behaviour remain paramount among both professionals and parents. Parents of children with recurrent otitis media report anxiety about the unpredictable nature of their child’s illness, excess time lost from work, and frustration with ineffective treatment.1 Current strategies to prevent acute otitis media include use of prophylactic antibiotics, immunoprophylaxis, and tympanostomy tubes. Antibiotic prophylaxis, although effective, places selective pressure on bacterial ecology and contributes to the increase in resistance among respiratory pathogens. Pneumococcal polysaccharide vaccine is not sufficiently immunogenic in the target population (age under 2 years), and conjugate pneumococcal vaccine, albeit immunogenic, targets only the seven most common pneumococcal serotypes. A one-third reduction in pneumococcal otitis media has been observed in infants immunised with conjugate pneumococcal vaccine, but the decrease in episodes due to any organism was modest (<10%).2 Although this reduction has a substantial impact on a population basis, the benefit that accrues to an individual child is more limited. Tympanostomy tubes facilitate the drainage of the middle-ear cavity and reduce the duration of middle-ear effusions, but do not significantly decrease the frequency of acute episodes. In this week’s issue of The Lancet Pentti Ukkonen and colleagues describe an alternative approach to the prevention of acute otitis media. The pathophysiology of acute otitis media is such that it is preceded by nasopharyngeal colonisation with otopathogenic bacteria and in many cases a concomitant viral respiratory infection. The viral upper-respiratory infection enhances the likelihood of contiguous spread of nasopharyngeal pathogens to the middle ear by increasing the bacterial burden in the nasopharynx, impairing eustachian tube 1370
function, or altering host defences. Strategies that decrease colonisation with both Streptococcus pneumoniae and Haemophilus influenzae would probably be associated with a significant reduction in the frequency of acute otitis media. The use of oligosaccharides as competitive inhibitors of membrane receptors is well founded, and in-vitro studies have shown that sialylated glycoconjugates are adherence targets of both S pneumoniae and H influenzae. One potential limitation is that bacteria could use other membrane receptors, such as C3 (for S pneumoniae) when epithelial cells are activated during viral co-infection or inflammation.3 Nevertheless, in-vitro studies suggest that, even in the presence of activated epithelial cells, certain oligosaccharides are capable of reducing the adherence of S pneumoniae.4 Ukkonen and colleagues did not find a decrease in nasopharyngeal colonisation with otopathogens or a decline in episodes of acute otitis media after twice-daily intranasal application of NE-1530, a sialylated pentasaccharide. Potential explanations for these results include low potency of the compound, inadequate dose, failure to affect a persistent reservoir, or the presence of other membrane receptors not susceptible to competition with sialylated oligosaccharides. In vitro, xylitol, a five-carbon sugar alcohol, reduces binding of S pneumoniae and H influenzae to epithelial cells.5 The effect seems greatest when the concentration of xylitol is high (5%) and when both cells and bacteria are exposed. In a clinical study, children who used xylitol chewing gum had fewer episodes of acute otitis media than those who used sucrose-containing chewing gum.6 These results provide for the possibility that a different dose or regimen of NE-1530 may prove more successful. The fact that S pneumoniae and H influenzae are commonly cultured from oropharyngeal swabs also suggests why intranasal administration may not be effective. Bacterial adherence is a complex issue. For instance, in chinchilla tracheal cultures, pretreatment with lacto-Nneotetraose inhibited epithelial adherence of S pneumoniae; however, when neuraminidase was added, adherence increased—presumably because additional receptors were exposed.7 Another example of the complexity of bacterial adherence is that in non-typable Haemophilus influenzae at least three non-pilus proteins (HMW1, HMW2, HIA) have essential roles in the attachment process.8 HMW1 seems to recognise a sialylated glycoprotein, but HMW2 and HIA receptors have different specificities. Thus a mixture of competitive inhibitors may be necessary to reduce nasopharyngeal colonisation. The concept of reducing nasopharyngeal colonisation and episodes of bacterial otitis media through competitive inhibition remains “cutting-edge” medicine. The failure of NE-1530 to achieve those goals highlights the challenges in both understanding the complexities of bacterial adherence and the practicality of delivering a drug with enough potency to a large mucosal surface. Stephen Pelton Division of Pediatric Infectious Diseases, Boston Medical Center, Boston, MA 02118, USA
1
2
3
Asmussen L, Olson LM, Sullivan SA. “You have to live it to understand it . . . ”. Family experiences with chronic otitis media in children. Ambulatory Child Health 1999; 5: 303–12. Eskola J, Kilpi T. Efficacy of a heptavalent pneumococcal conjugate vaccine (PnnCRM) against serotype-specific, culture-confirmed pneumococcal acute otitis media (AOM) in infants and children. Thirty-ninth Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), San Francisco CA, Sept 27–29, 1999. LB-13 (abstr). Smith BL, Hostetter M. C3 as a substrate for adhesion of Streptococcus pneumoniae. J Infect Dis 2000; 182: 497–508.
THE LANCET • Vol 356 • October 21, 2000
For personal use only. Not to be reproduced without permission of The Lancet.