ARncLEs ' Effect of subclinical infection on maintaining immunity against measles in vaccinated children in West Africa
Hilton C Whittle, Peter Aaby, Badara Samb, Henrick Jensen, John Bennett, Francois/Simondon
Summary . Introduction Background Despite a high coverage with measles Natural measles infection induces lifelong immunity as vaccines in parts of west Africa, epidemics of measles shown during an epidemic in the Faroe Islands when only inhabitants who had had measles in an epidemic 65 years occur with. reduced severity in an increasing proportion of earlier escaped infection.' However, the assumption that older children who .have been vaccinated. We examined' live measles vaccine also induces lifelong protectio? the effect of exposure to natural measles on immunity in or immunity against disease2 has been revised after vaccinated children. outbieaks among high school and university students in Methods .Our'stuhy was carried out in 1992 during an the USA during the 1980s who had been vaccinated ' epidemic of measles in Niakhar, a rural area of Senegal 15-20 years earlier.3" These observations' accord with with about 27'000 inhabitants who mostly live in evidence that although measles antibodies, persist for compounds that include several households; within each - . at least 16 years after vaccination2 concentratiöns may fall below the putative, protective concentration of household people !ive in'different huts. Vaccine coverage in ' , Niakhar was 81%at the time of our study. We measured 125 .mIU/mL in a few people,l which results in measles on exposure.*' Such a low concentration of antibodies is, haemagglutinin-inhibiting antibody at exposure and twice , however, now rare in the USA where live measles vaccine thereafter .(after 4-5 weeks and at 6 mdnths) in 36 is given at age' 15 months with a second dose vaccinated and 87 unvaccinated children. The frequency of recommended at school age.3 By contrast, in Senegal; me'asles and subclinical measles-defined as a four-fold or west Africa, where children are vaccinated in hifancyj we. greater. rise in antibody ,titre without clinical signs or found that during a measles. epidemic in 1987-90, the symptoms-was related to intensity'of exposure according proportion of vaccinated children with low antibody - to whether the index case was in the same hut, household, 'this . concentation was 13%; after exposure the attack rate in , . or compound., this group was 38%, compared with 82% in unvaccinated Findings Clinical measles occurred in 20 (56%) of 36 ~hildren.~In this region, although measles is common in unvaccinated .children and in one. (1%)of 87 vaccinated . vaccinated children, the case fatality rate is much lower children. Subclinical measles occurred in 39 (45%)of 86 than in children who have not been vaccinated: which ' vaccinated children who were exposed to measles and in suggests that residual cellular immunity, conferred by four (25%) of 16 unvaccinated children. The frequency was vaccination, still persists after antibody concentrations have waned. inversely .related to pre-exposure .antibody concentration' The role of natural measles in subclincal boosting of (p
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vaccine efficacy of only 71%1° and waning immunity, probable, possible, or no measles. With further follow-up, cases since previous data indicate that more than 95% of of possible measles were reclassified as either probable or no children respond to standard measles vaccination." measles. All children with a clinical diagnosis of probable Similarly, data from rural Senegal suggested waning measles had a typical morbilliform rash of acute measles, a immunity because vaccine efficacy declined from 100% typical desquamating rash of measles in the recovery phase, or both. A chid who developed measles more than 6 days after the first to 66% for standard Schwarz measles vaccine over 10 case (index case) in the same compound was classified as a secondary ca~e.~~"~Cases with an interval of less than 6 days were During an outbreak of measles in a part of Senegal with judged Co-index cases. As we have previously described,16 high vaccine coverage, we examined antibody changes in secondary cases and exposed children were classified according relation to vaccination status and to intensity of exposure. to the intensity of contact with a measles case: sleeping in the same hut (high), living in the same household but not sleeping Methods in same hut (intermediate), or living in the same compound but not in the same household (low). Study population The study was approved by the Senegalese Ministry of Health Our study took place between December, 1991, and August, and by the Gambia Govemment/Medical Research Council 1992, during an outbreak of measles in Niakhar, Senegal, a rural O00 (MRC) ethical committee. The purpose of the study was area with about 27 inhabitants who mostly belong to the explained to parents and guardians of the children before Sereer ethnic group and live in large compounds. Withm a consent was obtained for a blood sample. In West Africa compound there are several households, a self-defined social unit vaccination during epidemics is not standard practice. Since our with a household head and common storage and cooking project was designed to examine vaccine efficacy, we ensured facilities; within a household people sleep in different huts. that all cases received adequate treatment. Niakhar has three dispensaries-two public and a private one by the Catholic church. From 1984 to 1990, infant and run Measurement of measles antibody titres childhood mortality in Niakhar was 112 per 1000 and 253 per 1000, respectively, most infant mortality was due to diarrhoea, We tested blood samples for measles haemagglutinin-inhibiting antibodies at the MRC Laboratories, the Gambia." The malaria, respiratory infections, measles, and malnutrition. In a survey camed out in 1990, 3% of the children aged 2-4 years sensitivity of this test was 15.62 mIU per rd. Since the test z started with a 112 dilution, the minimum detectable titre was were wasted (weight-for-height of less than -2 on scores) and mIU 36% were stunted (height for age less than -2 z scores). The 31.25 per mL. We defined acute infection as a four-fold surveillance system in Niakhar is based weekly visits by 12 increase in titre together with clinical features of measles. on Children who had a €our-fold or greater increase in titre between fieldworkers to all the 1800 compounds to obtain information on bds, migrations, marriages, "deaths, and infections.'4 There exposure and convalescence but who did not have clinical were measles vaccination campaigns in Niakhar in 1986-87 measles according to the physician were judged to have had subclinical measles. during the accelerated phase of the Expanded Programme on 7 Immunisation @Pl). From July, 1987, BCG, diphtheria, This analysis was limited to children aged from months to pertussis, tetanus, poliomyelitis, measles, and yellow fever 6 years at the time of exposure, since younger children could vaccines were offered systematically in immunisation sessions .have been protected by matemal antibodies. We excluded seven organised once a month at each of Niakhar's three health centres children who had a four-fold or greater decrease in titre between as part of measles and pertussis vaccine The coverage exposure and convalescence because they may have an early for measles vaccine among children aged 1-2 years bom in increase in antibody titre with a subsequent decline in antibody. Niakhar increased from 36% in 1986 to 81% in 1992. Children with a history of measles were also excluded.
Measles surveillance and exposure Statistical'analysis The study we report here, which examines household contacts of We used EPI-INFO (version 6) to calculate Mantel-Haenszel known cases, was part of a larger study to assess the long-term relative risks and to test for trend. Multiple samples from the efficacy and effect on mortality of high-titre measles vaccine same individuals were compared with a paired t test. Logistic given during a trial undertaken in Niakar between 1987 and regression analysis was done with SAD '(version 6.12) for 1990. The mal began active surveillance for acute cases of Windows. No child was entered in the analysis more than once. measles in Niakhar. When a fieldworker was told about a case of suspected measles, the project physician was called to examine Results the child. During the visit, information was sought on how the Study population case had contracted measles and contacts were traced. Thus, We identified 55 index cases in 51 compounds and 161 new cases of measles were found by routine surveillance and time . through active follow-up of contacts by the physician. At the first contacts who had a blood sample collected at the of visit to a compound, a census was made of all children aged exposure. 123 (76%) of the contacts had a second sample younger than 15 years. If parents gave their consent, a blood collected about, 1 mÒÁth after exposure and 90 (73%) sample was taken by finger prick from cases and. from exposed had another sample collected 6-9 months after exposure. children aged younger than 7 years who had no history of Of the 123 children who had a blood sample taken both measles infection. Samples were also taken kom children who at exposure and 1 month later, 21 (17%) developed developed measles and from uninfected contacts 4-5 weeks after clinical measles. All children with clinical measles had a the onset of symptoms and again 6 months later. significant increase in titre between the samples taken at exposure and thereafter, apart from one child who Clinical examination and case definition already had a high titre when tested after the onset of Compounds with suspected cases of measles were visited at least symptoms. Of: the 102 children with paired samples who twice a week for the first 4 weeks to observe the development of did not develop clinical measles, 43 (42%) had symptoms, to detect new cases as soon as possible, and to - provide treatment. During each visit, the presence and severity subclinical measles as indicated by a four-fold or greater of the following symptoms were recorded Koplik. spots, rash, increase in haemagglutitli-inhibiting antibody and no desquamation, conjunctivitis, stomatitis, cough, respiratory clinical symptoms. symptoms, diarrhoea, and temperature. At the end of each The 55 index cases and the 123 contacts with serial examination, the clinician assessed whether the child had antibody measurements had a similar sex distribution.
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Attack rate Attack rate (number cases/number exwsed) (number wes/number exposed) Clinical Subclinical* Clinical Subclinical* - Age (months) of unvaccinatedchildren Intensity of exposure In unvacclnated chlldren In compound 7-23 36% (4/11) 29% (2/7) In 25% (2/8) 33% (2/6) 24-59 65% (13/20) 29% (2/7) household 64% (9/14) 20% (l/5) 60-83 60% (3/5) 0%(0/2) In hut 64% (9/14) 20% (1/5) Total 56% (20/36) 25% (4/16) Total 56% (20/36) 25% (4/16) Age (months) vaccinated chlldren Intensity of exposure In Vaccinated chllden 7-23 39% 19/23) In compound 0%(0/23) 17% (4/23) 24-59 47% (26/55) In household 0% (0/19) 47% (9/19) 60-83 50% (4/8) In hut 2% (1/45) 59% (26/44) Total 45% (39/86) Total 1% (1/87) 45% (39/86) *Excludes cases of measles. *Excludes cases of measles. Table 1: Clinical and subclinical measles after exposure by age Table 3: Clinical and subclinical measles after exposure by at exposure and vaccination status intensity of exposure and vaccination status
The mean age of the index cases was older than that 'of Antibody concentration at exposure contacts: 51 (SD 27) versus 36 (18) months (p=0-009). Table 2 shows that clinical attack rates were highest in Ten (18%) of the 55 index cases had been vaccinated, unvaccinated children with no detectable antibody; the compared with 87 (71 %) of the 123 contacts (relative risk presence of antibody in unvaccinated children probably 0.27 [95% CI 0.11-0.661, p 100 THE LANCET Vol 353 -January 9,1999 . ,._. .-_ ...... - ...... ~ .. .- -. ._.. . -_ .-. .. -. - i ARTICLES f (p for odds ratio <0*05) to 'a low pre-exposure antibody subclinical cases. A reasonable assumption is that the titre, absence of vaccinatioxi, intensity of exposure, and increase in antibody titre during subclinical measles is age. Children younger than 2 years had a significantly the result of systemic replication of the virus, which is lower attack rate than older children. Subclinical greatest among those with low pre-exposure antibody infection was significantly related to low pre-exposure concentrations who then encounter a high degree of antibody titre, history of vaccination, and the intensity of exposure. Whether this event is associated with shedding exposure, but not to age. In neither clinical nor of infectious virus is unknown and of obvious importance subclinical infection was ,sex or the delay between if measles is to be eradicated. exposure and the blood sample a signficant variable. We also examined the magnitude and duration of the increase in antibody titre after exposure in children who Duration of antibody response after exposure had and had not been immunised. Children with clinical Table 4 shows that antibody in subclinical measles was measles had a large increase that was sustained for 6 months. Subclinical measles in vaccinated children boosted on average by 45-fold to concentrations similar boosted antibody to similar concentrations, although to those of children who had had measles and that this increase in antibody persisted for at least 6 months after these fell by four-fold over 5 months. We have no local exposure. Although antibody titres fell over time, the data on the concentration and duration of measles mean titre in the 29 children with sub-cliical measles 6 antibody in children who were revaccinated. In Bin and months after exposure was still log, 2-8 (2.7) higher than colleagues' study in China: children were revaccinated the mean titre at exposure @<0.001, paired t test). 3, 5, LO years after primary immunisation and the increase in haemagglutinin-inhibiting antibody after Discussion reimmunisation was low, irrespective of the time between doses and the antibody concentration at vaccination. We found that clinical attacks of measles occurred mostly They also reported that the boosting effect was short lived among children who had not been vaccinated and lived in since antibody dropped to original concentrations within the household or hut of the index case (high degree of 1-2 years; decay was particularly rapid in those whose exposme). These &-dings accord with data obtained from primary response to the fist immunisation was poor.6 In Guinea Bi~sau'~and the situation in Niakhar in 1983-86 that study, like ours, vaccinated children exposed to when vaccine coverage was inadequate and the case natural measles had a substantial rise in antibody that fatality rate was 6.5% and dependent on the intensity of lasted for at least 3 years.6 Thus, exposure to natural exposure. During 1983-86, secondary cases in the measles that leads to subclinical measles may be a more compound were 1-9 times more likely to die than the effective way to boost antibody than reimmunisation, index cases, and children in the same-hut were 3-8times which may have a short-lived response, especially in more likely to die than index cases. By contrast, in 1992 children who have had their primary immunisation in with increased coverage and improved treatment in the infancy.24 home, the case fatality rate *ras 1.6%. The fall in the case Little is known about antibody persistence after fatality rate is unlikely to reflect a change in vitamin A vaccination in west Africa where malaria and other status, since such supplementation was not part off infections are rife. Cohen and co-workers25found a rapid treatmema A change in thk virulence of the virus is an turnover of y-globulin in Gambian adults with synthesis unlikely explanation, because although genetic analysis rates seven times higher than in Europeans. We found has revealed variability the haemagglutinin2O and measles antibody concentrations 5-7 years after nucleoprotein genes:' the virus behaves in a monotypic Vaccination to be higher when taken in the rainy season way in relation to infectivity and pathogenicity.22 than in the dry Perhaps malaria and other We showed that subclinical measles was common in infections cause fluctuations in antibody responses to immunised children and the frequency of the attacks was vaccines with an overall acceleration of decay. related to post-vaccination antibody titres. Thus, 88% of A possible criticism of our small study is that vaccine vaccinated children with haemagglutinin-inhibiting titres efficacy against clinical disease was high and that there is of 1/2 or less showed a boost in antibody, which fell to little cause for concern. This argument ignores data from 60% in those with pre-exposure titres between 1/4 and the 1997 outbreak in the Gambia and previous data from 1/32, and to zero in those with high titres above 1/128. As Senega113 and Guinea BissauLgwhere vaccine efficacy in the case of clinical meades, subclinical episodes were ranged from 65% to 70%. Moreover, our main focus was probably related to exposure, with lowest exposure in the to examine young children vaccinated within the previous compound (17%) and hiaest exposure in the same hut 3 years who had high antibody concentrations. A as the index case (58%). Other less likely explanations are decrease in antibody concentrations and decline in a familial trend towards similar antibody concentrations vaccine efficacy will mainly occur among older children. or that nutritional state, which varied according to family, If we compare vaccinated and unvaccinated children with was the underlying deneminant. This explanation seems no antibodies, the vaccine efficacy was 91%. In a improbable because antibody responses to measles vaccines previous study, we found the vaccine efficacy for this are normal in children with moderate maln~trition.2~ group of older children was about 50% and the secondary We have no data to suggwt that minor symptoms such attack rate was 48%.5 These findings contrast with as fever and headache were common in subclinical reports fro.m developed countries where long-term attacks, as reported by Chen and colleagues3in Boston. efficacy remains Perhaps young age at Similarly, we could not answer the important issue of vaccination, a high intensity of exposure, and a more whether clinical and subclinical attacks follow exposure to rapid decline in antibody concentration account for the subclinical measles since au contacts had blood samples differences in west Africa. collected immediately after the identification of the fist The Gambia .was one of the first countries to interrupt clinical case in the compound and not after the measles transmission through the introduction of yearly THE LANCET - Vol 353 'January 9,1999 101 ARTICLES campaigns to immunise children aged 6 months to 6 7 Markowia LE, Preblud SR, Fine PEM, Orenstein WA. Duration of years?” Strategies have evolved to interrupt transmission live measles vaccine induced immunity. Pedian Infecc DisJ 1990; 9: and eventually eliminate measles by keeping the number 101-10. 8 Samb B, Aaby P, Whittle H, Coll-Seck AM, Simondon F. Dediein of susceptible people below a critical minimum, which in measles case fatality rano after the introduction of measles some populations may be as low as 3%. The basic plan immunisation in rural Senegal. AmJ Epidemwl1997; 145: consists of three phases. The catch-up phase involves one 51-57. immunisation of children aged 1-14 years. The keep-up 9 Mulholland K. Measles and pertussis in developing counmes with phase involves routine immunisation at age 12 months. good vaccine coverage. Lancer 1995; 345: 305-07. 10 Orenstein WA, Bernier RH, Hinman AR. Assessing vaccine efficacy in The follow-up campaign is done every 4-5 years to the field. Epidemiol Rev 1988; 10: 21241. reduce the accumulation of susceptible ’ infants and 11 Whittle H, Hanlon P, O’Neill K, et al. Trial of high-dose Edmonston- children aged 1-4 years. This strategy has been successful Zagreb measles vaccine in The Gambia: antibody response and side in the elimination of measles in Cuba and the English effects. Lancet 1988; i? 811-14. 12 Samb B, Aaby P, Whittle H, Col1 Seck AM, Simondon F. Protective speaking Ca1ibbean.2~ However, in west Africa political efficacy of high-titre measles vaccines administered from the age of five instability and economic strictures has made it difficult to months in rural Senegal. Trans R Soc Trop Med Hyg 1993; 87: implicate or sustain all three components of the plan. 697-701. Thus, in countries with good routine immunisation, 13 Cisse B, Aaby P, Simondon F, Samb B, Soumare M, Whittle H. The but no catch-up phase or regular follow-up campaigns, role of schools in the transmission of measles in rural Senegal. Implications for measles control in developing countries. Am J measles still occurs in widely spaced epidemics. The EpiXemiol (in press). trigger may be an imported case of measles which 14 ,Chahnazarian A, Becker C, Delaunay V, et al. Population et sante à initiates infection in the pool of susceptible infants who Niakhar, 1984-1991. Dakar: ORSTOM, 1992. were only briefly protected by low concentrations of 15 Gareime M, Leroy O, Beau JI?, Sene I. Child mortality after high-titre antibody transferred from vaccinated mothers whose measles vaccines: prospective study in Senegal. Lancet 1991; 338: 903-07. antibodies are no longer boosted by natural exposure. 16 Garenne M, Aaby P. Pattem of exposure and measles mortality in Another large and growing group of susceptible people Senegal.JInfectDb 1990; 161: 1088-94. are older children who have missed immunisation or 17 Whittle HC, Mann G, Eccles M, et al. Effects of dose and strain of vaccinated children who, in the absence of boosting of vaccine on success of measles vaccination of infants aged 4-5 months. immunity by natural measles or by revaccination, become Lancet 1998; i: 866-963. 18 Bennett J, Whittle H, Samb B, Cisse B, Simondon F, Aahy P. infected in the face of intense exposure in crowded huts Seroconversions in unvaccinated infants: further evidence for sub- and household^.^^ clinical measles from vaccine trials in Niakhar, Senegal. Int3Epziiemiol Contributors (in press). The study was planned by all authors except Henrick Jensen and was 19 Aaby P, Knudsen K, Jensen TG, et al. Measles incidence, vaccine written by Hilton C Whittle who also supervised the laboratory work. efficacy, and mortality in two urban African areas with high Badara Samb did the fieldwork under the guidance of Peter Aaby and vaccination coverage. JInfect Dis 1990; 162: 1043-48. Francois Simondon. John Bennett advised on the design, analysis, and 20 Outlaw M, Jaye A, Whittle HC, Pringle CR. Clustering of presentation of the study. Henrick Jensen and Peter Aaby did the haemagglutinin gene sequences of measles viruses isolated in The statistical analyses. Gambia. VirusRes 1997; 48: 125-31. Acknowledgments 21 Rima BK, Earle JAP, Ye0 RP, et al. Temporal and geographical We thank Brian Greenwood for his support, Fulloe Kanteh for the distribution of measles vims genotypes. J Got Virol 1995; 76: antibody measurements, and Mansour Nyang and Awa Kinteh for the 1173-80. collection of data on the measles outbreak in the Gambia. 22 Norrby E. The paradigms of measles vaccinology. Cur Top Microbio1 This work was supported by grants from the UK’s Medical Research Immunoll995; 191: 167-80. Council; the Task Force for Child Survival, Atlanta, USA; the Expanded 23 McMurray DN, Loomis SA, Casazza LJ, Rey H. Muence of Programme on Immunization,WHO, Geneva, Switzerland; Science and moderate malnumtion on morbidity and antibody response following Technology for Development Programme of the European Community; vaccination with live attenuated measles virus vaccine. Bull Panam and Orstom, Dakar, Senegal. Hedch Organ 1979; 13: 52-57. 24 Stetler HC, Orenstein WA, Bernier RH. Impact of revaccinating References children who initially received measles vaccine before 10 months of age. Paediatrics 1986; 77: 471-76. .Parium PL. Observations made during the epidemic of measles in the 25 Cohen S, McGregor IA, Canington S. y-globulin and acquired Faroe Islands in the year 1846. New York New York Public Health immunity to human malaria. Nancre 1961; 192: 733-87. Association, 1940. 26 Whittle HC, Aaby P, Samb B, et al. Poor serological responses 5-7 Krugman S. Further attenuated measles vaccine: characteristicsand years after immunisation with high and standard titre measles use. Rev Infecc DiS 1983; 5: 477-81. vaccines. Pe&m Infect Dis J (in press). Chen RT, Markowitz LE, Albrecht P, et al. Measles antibody: re-evaluation of protective titres. Infecc Dis 1990; 162: 1036-62. 27 Anders JF,Jacobson RM, Poland GA, Jacobsen SJ, Wollan PC. 3 Secondary failure rates of measles vaccines: a meta analysis of Gustafson TL,Lievens AW, Brune11 PA, et al. Measles outbreak in a fully immunised secondary school population. N EnglJMed 1987; published studies. Pediam Infect DiSJ 1996; 15: 62-66. ! 316: 771-74. 28 Forster SO, Pifer JM. Mass measles control in West and Central Samb B, Aaby P, Whihle HC, et al. Serologic status and measles Africa. AfrJhedSci 1971; 2: 151-58. attack rates among vaccinated and unvaccinated children in rural 29 de Quadros CA, Olive JM, Hensh BS, et al. Measles elimination in the Senegal. Pediam Inqéct Dis J 1995; 14: 203-09. Americas. JAM 1996; 275: 224-29. Bin D, Zhihui C, Qichang L, et al. Duration of immunity following 30 Aaby P, Bukh J, Lisse IM, Smits AJ. Overcrowding and intensive immunisation with live measles vaccine: 15 years of observation in exposure as determinants of measles mortality. AmJEpidemioll984; Zheyiang Province, China. Bull WorldHeaIch Organ 1991; 69: 415-23. 120: 49-63. I 102’ THE LANCET * Vol 353 - January 9,1999 P THE..- LANCET $ Volume 353, Number 9147 Founded 1823 -,Published weekly Saturday 9 January 1999 EDITORIAL 81 First principles in cloning COMMENTARY NEWS 82 Lifetime-risk prediction: a complicated business Science & medicine G De Backer, D De BacqUer 125 Clues for anti-HIV strategies 83 Extracellular "calcistat" in health and disease No trials for South Africa's HIV drug S Pearce 126 How drugs damage young brains Tracking coronary artery disease 84 Nail-apparatus melanoma US cardiovascular disease rates J M Spencer 127 Two new genes for ovarian cancer 85 Treatment of multiple myeloma Toothsome restraint of S mutans G Gahrton Feature 86 Stiff-man syndrome and its variants 128 Tackling the taboo of urinary P J Shaw incontinence 87 Radiological assessment of hip osteoarthritis Dispatches D L Scott, P Gishen 129, Difficult new year for NHS US to fight antibiotic resistance ARTICLES Policy & people - 89 Lifetime iisk of developing coronary heart disease 130 Horror at death of South African activist D M Lloyd-Jones and others US military and anthrax vaccine 93 Prevention of falls in the elderly trial (PROFET) 131 Abortion in Ireland J Close and others FDA approves narcolepsy drug Invasive aspergillosis in Spain 98 Effect of subclinical infection on maintaining immunity against 132 Canada lifts ban on blood from people measles in vaccinated children in West Africa with CJD H C Whittle and others 111 health among Israel's children io3 Comparison of phenotypes of polycystic kidney disease types 1 and 2 NEW DRUG CLASSES N Hateboer and others, for the European PKDI-PKD2 Study Group 133 Endothelin antagonists A Benigni, G Remuzzi EARLY REPORTS io8 Concordancing: use of languagebased research in medical . HYPOTHESIS communication 139 Bacterial infection in the J,R Skelton, F D R Hobbs pathogenesis of variceal 112 A986S polymorphism of the calcium-sensing receptor and circulating bleeding calcium concentrations J Goulis and others D E C Cole and others ESSAY ,- CASE REPORT 143 Developing health in Africa 116 A man with diabetes and a swollen leg M Sagar and others J Decosas RESEARCH LETTERS ' Contents list continues inside 117 ProphyJactic potential of pentosan 120 Extracorporeal liver perfusion polysulphate ìn transmissible spongiform L P McChesney and others encephalopathies 121 Edentulism and worsening of C Faq-uhar and others obstructive sleep apnoea 117 Favourable prognosis in Lambert-Eaton C Bucca and others myasthenic syndrome and smallcell 122 Direct magnetic resonance imaging of lung carcinoma carotid artery thrombus in acute stroke P Maddison and others A R Moody and others 118 Effect Of statins on C-reactive protein in 123 An anatomical explanation for patients with coronary artery disease good-prognosis rheumatoid arthritis T E Strandberg and others D McGonagle and others 119 Two de-novo balanced autosomal 124 Primary persistent autoimmune disorder translocations after intracytoplasmic in a neonate sperm injection R Bergman and others D Lev and others 119 HIV-1 replication in patients with undetectable plasma virus receiving HAART V Natarajan and others PM All literary matter inThe Lancet is copyrig I istered as a newspaper. ISSN 0140-6736. J14.50 1 JAFI, 5999 .. . -...... , , . . . . ~ \ ...... -. -- j".-..- .,. . -