News

Hepatitis B Vaccine Recommended for Adults with Diabetes

Wed, 28 Dec 2011 17:31:00 GMT

On December 23, 2011, the U.S. Centers for Disease Control and Prevention released new recommendations on the use of hepatitis B vaccine for adults with diabetes mellitus. All previously unvaccinated adults aged 19 through 59 years with diabetes mellitus (type 1 and type 2) should be vaccinated against hepatitis B as soon as possible after a diagnosis of diabetes is made. Unvaccinated adults aged ≥60 years with diabetes may be vaccinated at the discretion of the treating clinician after assessing their risk and the likelihood of an adequate immune response to vaccination.

The Hepatitis Vaccines Work Group of the Advisory Committee on Immunization Practices (ACIP) evaluated the risk for HBV infection among all adults with diagnosed diabetes. The work group presented its findings at the October 25, 2011 meeting of the ACIP. Using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology, the recommendation for younger adults received an A grade. The recommendation for adults ≥60 received a B grade.

You can read more about the recommendations at:

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6050a4.htm?s_cid=mm6050a4_e

Swine-Origin Influenza A (H3N2) Virus Infection in Two Children

Fri, 09 Sep 2011 16:27:00 GMT

Centers for Disease Control and Prevention: MMWR; Morbidity and Mortality Weekly Report

Early Release / Vol. 60 September 2, 2011

Swine-Origin Influenza A (H3N2) Virus Infection in Two Children — Indiana and Pennsylvania, July–August 2011

Influenza A viruses are endemic in many animal species, including humans, swine, and wild birds, and sporadic cases of transmission of influenza A viruses between humans and animals do occur, including human infections with avian-origin influenza A viruses (i.e., H5N1 and H7N7) and swine-origin influenza A viruses (i.e., H1N1, H1N2, and H3N2) (1). Genetic analysis can distinguish animal origin influenza viruses from the seasonal human influenza viruses that circulate widely and cause annual epidemics. This report describes two cases of febrile respiratory illness caused by swine-origin influenza A (H3N2) viruses identified on August 19 and August 26, 2011, and the current investigations. No epidemiologic link between the two cases has been identified, and although investigations are ongoing, no additional confirmed human infections with this virus have been detected. These viruses are similar to eight other swine-origin influenza A (H3N2) viruses identified from previous human infections over the past 2 years, but are unique in that one of the eight gene segments (matrix [M] gene) is from the 2009 influenza A (H1N1) virus. The acquisition of the M gene in these two swine-origin influenza A (H3N2) viruses indicates that they are "reassortants" because they contain genes of the swine-origin influenza A (H3N2) virus circulating in North American pigs since 1998 (2) and the 2009 influenza A (H1N1) virus that might have been transmitted to pigs from humans during the 2009 H1N1 pandemic. However, reassortments of the 2009 influenza A (H1N1) virus with other swine influenza A viruses have been reported previously in swine (3). Clinicians who suspect influenza virus infection in humans with recent exposure to swine should obtain a nasopharyngeal swab from the patient for timely diagnosis at a state public health laboratory and consider empiric neuraminidase inhibitor antiviral treatment to quickly limit potential human transmission (4).

View Full Article Here

FDA Approves Boostrix Vaccine in People 65 and Older

Fri, 05 Aug 2011 14:18:00 GMT

On July 11, 2011, the FDA approved Boostrix vaccine to prevent tetanus, diphtheria, and pertussis (whooping cough) in people ages 65 and older.

Currently, there are vaccines approved for the prevention of tetanus and diphtheria that can be used in adults 65 and older. Now, Boostrix, which is given as a single-dose booster shot, is the first vaccine approved to prevent all three diseases in older people.

With this expansion, we are now able to recommend Tdap vaccine to all contacts of vulnerable infants. Additionally, please consider extending this protection to the elderly in assisted living, nursing homes, and hospitals.

For more information view the press release:

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm262390.htm

Latino Influenza Vaccination & Education

Mon, 04 Apr 2011 21:37:00 GMT

LIVE focuses on educating the Latino Community about the importance of the Influenza Vaccination.

LIVE's goals are to:

Increase knowledge on the importance of influenza immunizations (H1N1 education added in Year 2)
Increase influenza immunization rates Educate about the importance of personal hygiene in flu prevention
Educate about the benefits of establishing a medical home

Click below to view the wonderful graphic that includes a myriad of statistics and facts!

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APIC Position Paper

Thu, 31 Mar 2011 22:40:00 GMT

APIC Position Paper: Influenza Vaccination Should Be a Condition of Employment for Healthcare Personnel, Unless Medically Contraindicated

Influenza is a serious disease that is associated with high rates of morbidity and mortality. In the United States, an estimated 5% to 15% of the population is affected by the virus each year.¹ Influenza infections result in approximately 150,000 hospital admissions and 24,000 deaths annually.² A recent study estimated that annual influenza epidemics account for 610,660 life-years lost, 3.1 million days of hospitalization and 31.4 million outpatient visits.³

The most efficient method of preventing annual influenza epidemics and their associated morbidity and mortality, is through pre-exposure vaccination.⁴ In addition to their risk for exposure to influenza from community sources, healthcare personnel (HCP) are at an increased risk for acquiring influenza due to their exposure to ill patients. Conversely, those patients who are at greatest risk of developing severe complications of influenza are themselves more likely to be exposed to potentially infectious HCP. Therefore, one of the most important strategies to decrease influenza transmission to or from high risk persons is to immunize healthcare personnel.⁵

Despite long standing recommendations by the Association for Professionals in Infection Control and Epidemiology (APIC), the Centers for Disease Control and Prevention (CDC) and other national healthcare organizations, the response to voluntary programs has failed to increase immunization rates to acceptable levels required to substantially reduce healthcare-acquired influenza.^6,7 Annual influenza vaccination for HCP has been recommended by the CDC since 1981; however national survey data from 2010 demonstrated only marginal increases in HCP seasonal influenza vaccination coverage levels (61.9 %).⁸

As a profession dedicated to the prevention of infection, we have an ethical responsibility to protect those individuals entrusted to our care. We must do a better job of immunizing HCP every year to ensure patient safety and protect those individuals at high risk of developing complications of influenza.

Recommendation:

Therefore, APIC recommends that acute care hospitals, long term care, and other facilities that employ healthcare personnel* require annual influenza immunization as a condition of employment unless there are compelling medical contraindications. This requirement should be part of a comprehensive strategy which incorporates all of the recommendations for influenza vaccination of HCP of the Healthcare Infection Control Practices Advisory Committee (HICPAC) and the Advisory Committee on Immunization Practices (ACIP) for influenza vaccination of HCP.⁹ An essential part of this comprehensive strategy includes strict attention to important infection prevention practices such as hand hygiene and respiratory etiquette. Individuals exempted from annual vaccination due to medical contraindications must be educated on the importance of careful adherence to all of the non-vaccine related HICPAC prevention strategies, including hand hygiene and cough etiquette. Further, they may be required to wear a surgical mask when contact with patients or susceptible employees is likely. Additionally, strong leadership commitment that takes into account and collaboratively addresses concerns by employees and the organizations representing them is essential to providing the necessary support and resources to implement such a comprehensive program.

Rationale:

Multifaceted mandatory vaccination programs have been tried and tested and have been found to be the single most effective strategy to increase HCP vaccination rates, with multiple facilities and systems achieving vaccination coverage of more than 95%¹⁰
The vaccine is most effective in younger, healthier individuals. Patients at highest risk including the elderly and the immunocompromised are least likely to develop an adequate response to the vaccine.¹¹ Several studies now demonstrate that HCP influenza vaccination reduces patient mortality.¹² Therefore vaccination of those individuals who come in contact with our vulnerable population is the most effective strategy for prevention.
The virus can be transmitted to patients by both symptomatic and asymptomatic HCP. Multiple studies show that 70% or more of HCP continue to work despite being ill with influenza, thus exposing patients to the virus.¹³
Institutions that have implemented a mandatory policy have dramatically reduced employee absenteeism as well as healthcare associated influenza, thereby improving patient safety and reducing healthcare costs.¹⁴
Influenza vaccine is safe. The most common side effects of the injectable (inactivated) influenza vaccine include soreness, redness, or swelling at the site of the injection. These reactions are temporary and occur in 15%–20% of recipients.¹⁵
Immunization requirements are effective in increasing vaccination rates. HCP policies requiring demonstrable vaccination for measles, mumps and rubella have been successful in achieving near universal compliance. Requiring influenza vaccine should similarly be highly effective.¹⁶

Positions on mandatory vaccination have been endorsed by the Infectious Diseases Society of America (IDSA), the American Academy of Pediatrics (AAP), and the Society for Healthcare Epidemiology of America (SHEA).

Conclusion:

Seasonal influenza vaccination of HCP offers an important method for preventing transmission of influenza to high-risk patients. Evidence supports the fact that influenza vaccine is effective, cost efficient and successful in reducing morbidity and mortality. Evidence also demonstrates that the current policy of voluntary vaccination has not been effective in achieving acceptable vaccination rates. As healthcare providers, we have an obligation to ensure that all HCP are vaccinated against influenza. As a profession that relies on evidence to guide our decisions and actions, we can no longer afford to ignore the compelling evidence that supports requiring influenza vaccine for HCP. This is not only a patient safety imperative, but is a moral and ethical obligation to those who place their trust in our care.

“[T]he term HCP includes: all paid and unpaid persons working in health-care settings who have the potential for exposure to patients with influenza, infectious materials, including body substances, contaminated medical supplies and equipment, contaminated environmental surfaces or contaminated air. HCP might include (but are not limited to) physicians, nurses, nursing assistants, therapists, technicians, emergency medical service personnel, dental personnel, pharmacists, laboratory personnel, autopsy personnel, students and trainees, contractual staff not employed by the health-care facility, and persons (e.g., clerical, dietary, housekeeping, maintenance, and volunteers) not directly involved in patient care but potentially exposed to infectious agents that can be transmitted to and from HCP. The recommendations in this report apply to HCP in acute care hospitals, nursing homes, skilled nursing facilities, physician's offices, urgent care centers, and outpatient clinics, and to persons who provide home health care and emergency medical services.” [Source MMWR August 28, 2009)

¹ World Health Organization. Influenza (Seasonal). Available from: http://www.who.int/mediacentre/factsheets/fs211/en/. Accessed December 10, 2010.

² Estimates of Deaths Associated with Seasonal influenza—United States, 1976-2007. JAMA 2010; 304(16):1778- 1780.

³ Molinari NA, Ortega-Sanchez IR, Messonnier ML, Thompson WW, Wortley PM, Weintraub E, et al. The annual impact of seasonal influenza in the US: Measuring disease burden and cost. Vaccine 2007;25:5086-5096.

⁴ Poland, GA, Tosh P, Jacobson RM. Requiring influenza vaccination for health care workers: seven truths we must accept. Vaccine 2005;23:2251-2255.

⁵ Ibid.

⁶ Talbot TR, Dellit TH, Hebden J, Sama D, Cuny J. Factors associated with increased healthcare worker influenza vaccination rates: results from a national survey of university hospitals and medical centers. Infect Control Hosp Epidemiol 2010;31(5):456–462.

⁷ Bernstein HH, Starke JR. Policy Statement of the American Acedemy of Pediatrics: Recommendation for Mandatory Influenza Immunizatino of All Health Care Personnel. Pediatrics 2010;126:809-815.

⁸ Interim Results: Influenza A (H1N1) 2009 Monovalent and Seasonal Influenza Vaccination Coverage Among Health-Care Personnel -- United States, August 2009 --January 2010. MMWR 2010;59(12):357-362.

⁹ Pearson ML, Bridges CB, Harper, SA. Influenza vaccination of health-care personnel, recommendations of the Healthcare Infection Control Practices Advisory Committee (HICPAC) and the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2006;55(RR-2):1-16.

¹⁰ Talbot TR, Dellit TH, Hebden J, Sama D, Cuny J. Factors associated with increased healthcare worker influenza vaccination rates: results from a national survey of university hospitals and medical centers. Infect Control Hosp Epidemiol 2010;31(5):456–462.

¹¹Wilde JA, McMillan JA, Serwint J, Butta J, O’Riordan MA, Steinhoff MC, et al. Effectiveness of influenza vaccine in healthcare professionals. JAMA 1999;281(10):908-913.

¹² Talbot TR, Dellit TH, Hebden J, Sama D, Cuny J. Factors associated with increased healthcare worker influenza vaccination rates: results from a national survey of university hospitals and medical centers. Infect Control Hosp Epidemiol 2010;31(5):456–462.

¹³ Babcock H, Gemeinhart N, Jones M, Dunagan WC, Woeltje KF. Mandatory Influenza Vaccination of Health Care Workers: Translating Policy to Practice. Clin Infect Dis 2010;50:459-464.

¹⁴ Poland, GA. Mandating influenza vaccination for health care workers: Putting patients and professional ethics over personal preference. Vaccine 2010;28:5757-5759.

¹⁵ Belshe RB, Nichol KL, Black SB, Shinefield H, Cordova J, Walker J, et al. Safety, efficacy, and effectiveness of live, attenuated, cold-adapted influenza vaccine in an indicated population aged 5-49 Years. Clin Infect Dis 2004;39:920-927.

¹⁶ Poland, GA, Tosh P, Jacobson RM. Requiring influenza vaccination for health care workers: seven truths we must accept. Vaccine 2005;23:2251-2255. January 27, 2011

Treatment of periodontal disease in pregnancy

Mon, 04 Apr 2011 21:49:00 GMT

Treatment of periodontal disease in pregnancy does not improve pregnancy outcomes, but should still be part of routine preventive care

Epidemiological studies have shown that clinical and subclinical periodontal infections during pregnancy are associated with preterm birth. Infection is thought to result in the release of proinflammatory cytokines, which have downstream effects on other biological pathways and tissues. The association was first noted for bacterial vaginosis in the 1980s and 1990s, and randomised controlled trials were then performed to assess whether screening and treating the infection during pregnancy would improve pregnancy outcomes. Most of these trials found no benefit, and such screening is not currently recommended.¹ More recently, observational data have suggested that periodontal disease may also be linked to preterm birth and other adverse pregnancy outcomes.² Several large clinical trials have since been performed to assess whether pregnancy outcomes can be improved with treatment.

In the linked systematic review, Polyzos and colleagues assess whether treatment of periodontal disease with scaling and root planing during pregnancy is associated with a reduced rate of preterm birth.³ The meta-analysis pooled the results of 11 randomised controlled trials, five of which were of high quality. Low quality studies tended to be much smaller than higher quality ones (with one study enrolling only 15 subjects per arm) and tended to overestimate the effect of treatment.⁴ Given the large number of participants (2303 active treatment, 2290 placebo treatment) and lack of heterogeneity in the high quality studies, they deserve greater emphasis. The pooled results of the high quality studies do not a support a reduction in the risk of preterm birth (odds ratio 1.15, 95% confidence interval 0.95 to 1.40), low birth weight (1.07, 0.85 to 1.36), spontaneous abortions or stillbirths (0.79, CI 0.51 to 1.22), or overall adverse pregnancy outcome (1.09, 0.91 to 1.30) with treatment with scaling and root planing. The implications of this study are clear—scaling and root planing for the treatment of periodontal disease in pregnancy cannot be recommended.

Many questions about periodontal disease and pregnancy outcomes still warrant further research, however. Firstly, how should periodontal disease be defined? Interestingly, no real consensus exists, and even among high quality studies the definition varies. However, treatment was not effective in any of the studies regardless of the definition used. Secondly, does completely eliminating periodontal disease during pregnancy (most studies do not look at how effective the treatment was) improve pregnancy outcomes? A recent secondary analysis of one high quality randomised clinical trial supports this notion, but further study is needed.⁵ Thirdly, would treatment at a different time—for example, before conception or very early in pregnancy—yield different results? Although an attractive theory, it may not be possible in everyday care because many women do not have interpregnancy care or even register for prenatal care early in pregnancy. Fourthly, would adjuvant treatment with antibiotics enhance the efficacy of scaling and root planing? So far, we have little evidence on adjuvant treatment during and outside of pregnancy. Fifthly, are specific oral bacterial pathogens often linked to preterm birth? Selective treatment of specific pathogens may be more effective. Lastly, is it possible, as shown in one randomised controlled trial, that treatment of periodontal disease can worsen some pregnancy outcomes?⁶ This phenomenon was also seen in a randomised trial of screening and treating asymptomatic trichomoniasis in pregnancy.⁷ Clearly, there are many avenues for future research on periodontal disease in pregnancy.

Disappointingly, despites years of basic, clinical, and translational research, no robust data support the treatment of any infection to reduce preterm birth or improve pregnancy outcomes. This includes bacterial vaginosis, periodontal disease, trichomoniasis, and sexually transmitted diseases. It may be time to re-examine some basic assumptions about the cause of adverse pregnancy outcomes and explore new mechanisms and treatments. What should clinicians tell their patients about periodontal disease, oral health, and pregnancy? The maintenance of oral health is an important part of routine preventive care, and should be encouraged during and outside of pregnancy. But it should be done as part of routine preventive care, rather than specifically to improve pregnancy outcomes.

Provenance and peer review: Commissioned; not externally peer reviewed.

McDonald H, Brocklehurst P, Gordon A. Antibiotics for treating bacterial vaginosis in pregnancy. Cochrane Database Syst Rev 2007;1:CD000262.
Vergnes J, Sixou M. Preterm low birthweight and maternal periodontal status: a meta-analysis. Am J Obstet Gynecol 2007;196:135.e1-7. 3 Polyzos NP, Polyzos IP, Zavos A, Valachis A, Mauri D, Papanikolaou EG, et al. Obstetric outcomes after treatment of periodontal disease during pregnancy: systematic review and meta-analysis. BMJ 2010;341:c7017.
Sadatmansouri S, Sedighpoor N, Aghaloo M. Effects of periodontal treatment phase I on birth term and birth weight. J Indian Soc Pedod Prev Dent 2006;24:23-6.
Jeffcoat M, Parry S, Sammel M, Clothier B, Catlin A, Macones G. Periodontal infection and preterm birth: successful periodontal therapy reduces the risk of preterm birth. BJOG 2010; online 14 September; doi:10.1111/j.1471-0528.2010.02713.x.
Macones GA, Parry S, Nelson DB, Strauss JF, Ludmir J, Cohen AW, et al. Treatment of localized periodontal disease in pregnancy does not reduce the occurrence of preterm birth: results from the Periodontal Infections and Prematurity Study (PIPS). Am J Obstet Gynecol 2010;202:147.e1-8.
Klebanoff M, Carey JC, Hauth JC, Hillier SL, Nugent RP, Thom EA, et al. Failure of metronidazole to prevent preterm delivery among pregnant women with asymtomatic Trichomonas vaginalis infection. N Engl J Med 2001;345:487-93.

Prevention of Leishmania donovani infection Vector control is key to the success of the global elimination strategy

Visceral leishmaniasis, the most severe form of leishmaniasis, is usually fatal in the absence of treatment. Together India, Nepal, and Bangladesh represent the biggest focus of visceral leishmaniasis in the world. Human to human transmission occurs through the bite of an infected sandfly, with no animal reservoir, a phenomenon known as anthroponotic transmission. Deadly epidemics occur periodically. The two main strategies to control the disease are case management and vector control. In the linked randomised controlled trial, Picado and colleagues assess the effect of the large scale distribution of longlasting insecticide treated nets on the incidence of visceral leishmaniasis in India and Nepal.¹

Randomised controlled trials have shown that insecticide treated bed nets and curtains prevent anthroponotic cutaneous leishmaniasis in Afghanistan, Iran, and Syria.^{2 4} Observational studies in Bangladesh and Nepal found a significantly reduced risk of visceral leishmaniasis in residents who used untreated nets nightly during the hot season.^{5 6} However, an observational study in Bangladesh found that bed nets had no effect on asymptomatic leishmanial seroconversion.⁷

Picado and colleagues report the first large scale randomised controlled trial of the effectiveness of a comprehensive distribution programme of longlasting insecticide treated nets in an anthroponotic focus of visceral leishmaniasis. They found no significant difference in the risk of seroconversion (relative risk 0.90, 95% confidence interval 0.49 to 1.65) or clinical visceral leishmaniasis (0.99, 0.46 to 1.40) between groups who received treated nets and those who used usual preventive interventions (irregular indoor residual spraying and use of untreated nets) over 24 months. In addition, the distribution of treated nets did not reduce the annual incidence of visceral leishmaniasis below 18.8/10 000, which is much higher than the target for elimination in the region (1/10 000).

Although studies in Nepal and Bangladesh showed sustained decreases in sandfly density of 89% and 60.5%, respectively, with the use of insecticide treated bed nets,^{8 9} in Picado and colleagues' trial longlasting insecticide treated nets had a limited effect (25% decrease) on the indoor density of the vector Phlebotomus argentipes. In addition, the Kalanet pilot study found no decrease in indoor density of this vector with the use of treated nets.¹⁰ This could explain the lack of effect on the incidence of visceral leishmaniasis. In addition, the authors suggest that the lack of effect may be explained by transmission occurring outdoors.

The limited impact of indoor residual spraying on the density of P argentipes, as reported in Picado and colleagues' study and elsewhere,¹¹ should be a signal to programme managers to check key factors in the process. These factors include the quality of DDT (dicophane), storage conditions, maintenance of equipment, staff performance, bioavailability of the insecticide in the treated nets, World Health Organization susceptibility test results (to check that the treated nets are actually killing sandflies), the level of acceptability by communities, geographic coverage, and the impact on indoor sandfly density. Randomised trials that compare indoor residual spraying with longlasting insecticidal nets, and indoor residual spraying plus longlasting insecticidal bed nets are needed.

It is important that the negative results of this trial do not derail the current efforts to eliminate visceral leishmaniasis in South Asia. The factors responsible for the lack of efficacy of nets in the study should be identified and analysed to guide vector control strategies and policies.

The results were obtained from two areas: three districts in Nepal and one district in India. They could theoretically be extrapolated to Bangladesh, where the epidemiology is similar (anthroponotic transmission, same vector, and same Leishmania species). However, a complementary trial in Bangladesh would be advisable because the experience in vector control is limited, the susceptibility of P argentipes is unknown, the incidence of post-kala-azar dermal leishmaniasis is high, and yearly floods may have an effect on breeding sites.

The results cannot be generalised to countries in east Africa where visceral leishmaniasis is endemic because the epidemiology is very different in those countries (different vectors—P orientalis and P martini; presence of L donovani and L infantum; transmission is mainly anthroponotic but areas of zoonotic transmission also exist; incidence of post-kala-azar dermal leishmaniasis is high; and, in Ethiopia, coinfection with leishmania and HIV is common.)

Field research is needed in India, Nepal, and Bangladesh to answer several important questions and to optimise vector control: What is the current susceptibility of P argentipes to insecticides (DDT and pyrethroids) in each country? Does P argentipes bite indoors (endophagic) or outdoors (exophagic), and does it rest inside (endophilic) or outside (exophilic). Existing data support the view that P argentipes is endophilic and endophagic, ¹² but work is needed to test whether it might also be exophagic. What are its host feeding preferences, resting and breeding sites, and flight range? What reduction in the density of P argentipes is needed to decrease the incidence of visceral leishmaniasis significantly? Are cattle protective or a risk factor? Because cattle are never infected by leishmaniasis, the spread of infection may be reduced by sandflies biting cows instead of humans. On the other hand, cattle dung provides a good breeding site for the maturation of sandfly eggs. What environmental measures can help reduce transmission? People with post-kala-azar dermal leishmaniasis and coinfection with HIV are thought to be highly infectious, so should they be priority targets for the use of treated bed nets?

India, Nepal, and Bangladesh have embarked on a programme to eliminate visceral leishmaniasis in 2005. Vector control is a key element of the global strategy to eliminate this disease. If it does not receive the level of attention it deserves, the current elimination programme will fail and a unique opportunity will have been lost.

Competing interests: The author has completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declares: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Provenance and peer review: Commissioned; not externally peer reviewed.

Picado A, Singh SP, Rijal S, Sundar S, Ostyn B, Chappuis F, et al. Longlasting insecticidal nets for prevention of Leishmania donovani infection in India and Nepal: paired cluster randomised trial. BMJ 2010;341:c6760.
Jalouk L, Al Ahmed M, Gradoni L, Maroli M. Insecticide-treated bednets to prevent anthroponotic cutaneous leishmaniasis in Aleppo Governorate, Syria: results from two trials. Trans R Soc Trop Med Hyg 2007;101:360-7.
Moosa-Kazemi SH, Yaghoobi-Ershadir MR, Akhavan AA, Abdoli H, Zahraei-Ramazani AR, Jafari R, et al. Deltamethrin-impregnated bed nets and curtains in an anthroponotic cutaneous leishmaniasis control program in northeastern Iran. Ann Saudi Med 2007;27:6-12.
Reyburn H, Ashford R, Mohsen M, Hewitt S, Rowland M. A randomized controlled trial of insecticide-treated bednets and chaddars or top sheets, and residual spraying of interior rooms for the prevention of cutaneous leishmaniasis in Kabul, Afghanistan. Trans R Soc Trop Med Hyg 2000;94:361-6.
Bern C, Joshi AB, Jha SN, Das ML, Hightower A, Thakur GD, et al. Factors associated with visceral leishmaniasis in Nepal: bed-net use is strongly protective. Am J Trop Med Hyg 2000;63:184-8.
Bern C, Hightower AW, Chowdhury R, Ali M, Amann J, Wagatsuma Y, et al. Risk factors for kala-azar in Bangladesh. Emerg Infect Dis 2005;11:655-62.
Bern C, Haque R, Chowdhury R, Ali M, Kurkjian KM, Vaz L, et al. The epidemiology of visceral leishmaniasis and asymptomatic leishmanial infection in a highly endemic Bangladeshi village. Am J Trop Med Hyg 2007;76:909-14.
Das ML, Roy L, Rijal S, Paudel IS, Picado A, Kroeger A, et al. Comparative study of kala-azar vector control measures in eastern Nepal. Acta Trop 2010;113:162-6.
Mondal D, Chowdhury R, Huda MM, Maheswary NP, Akther S, Petzold M, et al. Insecticide-treated bed nets in rural Bangladesh: their potential role in the visceral leishmaniasis elimination programme. Trop Med Int Health 2010;15:1382-9.
Dinesh DS, Das P, Picado A, Davies C, Speybroeck N, Ostyn B, et al. Long-lasting insecticidal nets fail at household level to reduce abundance of sandfly vector Phlebotomus argentipes in treated houses in Bihar (India). Trop Med Int Health 2008;13:953-8.
Picado A, Das ML, Kumar V, Kesari S, Dinesh DS, Roy L, et al. Effect of village-wide use of long-lasting insecticidal nets on visceral leishmaniasis vectors in India and Nepal: a cluster randomized trial. PLoS Negl Trop Dis 2010;4:e587.
12 Dinesh DS, Ranjan A, Palit A, Kishore K, Kar SK. Seasonal and nocturnal landing/biting behaviour of Phlebotomus argentipes (Diptera: Psychodidae). Ann Trop Med Parasitol 2001;95:197-202.

Is estimating lifetime cardiovascular risk useful? No, but forecasting short term risk throughout life is

One of the exercises we set our medical students when introducing clinical epidemiology is to present the risk profile of a middle aged man and ask them to estimate his risk of death. Eventually someone works out the answer—100%. Death is inevitable, it is when and how the patient dies that are important. So does the QRISK lifetime cardiovascular risk model described in the linked study by Hippisley-Cox and colleagues have any more clinical relevance than the lifetime risk of death?¹

The QRISK lifetime cardiovascular risk model was derived from the QResearch database, an ongoing extract of clinical and administrative data from electronic general practice records in England and Wales, dating back to 1994. The database has generated the world's largest cardiovascular risk prediction cohort study, which now includes more than three million people aged 30-84 years. The linked study reports that one in two British women have an estimated lifetime cardiovascular risk of over 30% and one in 10 have a risk of 50% or more. For men the equivalent risks are 40% and almost 65%.

Would this information help clinicians tailor treatment any differently for patients at the 50th centile of risk compared with those at the 90th centile? Both risks are substantial because cardiovascular disease is the main cause of morbidity and mortality in Britain. Therefore, the whole population, whatever their individual predicted lifetime risk, should be informed of the high "national" lifetime risk of cardiovascular disease and receive general advice about how to reduce it. Indeed, the major value of lifetime risk calculations is to inform health policy and planning rather than personalised healthcare.

From a clinical perspective, another problem with a personal lifetime cardiovascular risk estimate is how to determine the optimum value to aim for. Counterintuitively, the ideal is probably 100%, with the first cardiovascular event being sudden death while sleeping, some time after making it to 100 years of age. Furthermore, some groups at high risk of premature death, like smokers, may have a lower lifetime risk of cardiovascular disease than non-smokers because cancer kills them first.²

So what information about cardiovascular risk would best inform clinical decisions? The clinician's main role here is to identify those patients at highest risk who will benefit most from specific individualised interventions and to determine when these interventions should be started. We now have a wide range of relatively cheap safe drugs that can more than halve the risk of a cardiovascular event within about five years.³ However, the absolute benefits of these drugs, and their cost effectiveness, are directly proportional to the patient's risk of having a cardiovascular event during the same period.⁴ The QRISK research group is already a world leader in developing the short term cardiovascular risk prediction tools that clinicians need to identify these high risk patients (www.qintervention.org/index.php).⁵ So why do clinicians continue to ask for information about their patients' longer term risk?

The main reason is the challenge of managing younger patients with multiple cardiovascular risk factors, like the 40 year old male "ticking time bomb" who smokes, is overweight, has a blood pressure of 150/90 mm Hg, and a total cholesterol to high density lipoprotein cholesterol ratio of six, yet has a 10 year cardiovascular risk, according to QRISK's short term risk calculator, of only 5% (www.qintervention.org/index.php). The 10 year risk is unhelpful for informing this patient what his future may hold, because short term cardiovascular risk is strongly age dependent and does not capture the importance of younger patients' longer term risk. However, does this patient's predicted lifetime cardiovascular risk—the risk of having a cardiovascular event if he lives to 95—provide any more useful information?

His lifetime cardiovascular risk, based on a new QRISK lifetime risk calculator, is about 50%, and if he stops smoking, loses 10 kg, drops his systolic blood pressure by 10 mm Hg and his lipid ratio by one unit, this risk will fall to 40%. Unfortunately, this adds little to the predicted 10 year risk. Of far more relevance is the graphic display (www.qrisk.org/lifetime/index.php), included as part of the calculator's output (examples for two other patients are shown in boxes 1 and 2 in the linked paper). The graphs present a continuous prediction of patients' cumulative cardiovascular risk throughout their lifetime, based on both current risk profiles and if their risk profiles improve. The most important risk related factor—time—is incorporated into the graph, and it is simple to read off the predicted risk for any time period from a few years to a lifetime.

The new QRISK cumulative cardiovascular risk graph is similar to the heart age forecast tool (www.knowyournumbers.co.nz/heart-age-forecast.aspx),6 although the latter includes an additional metric—the patient's estimated "heart age"—to help with risk communication. Cardiovascular risk forecast calculators incorporate both short and longer term risk in one simple display and so have important advantages over separate 10 year and lifetime cardiovascular risk calculators.

Provenance and peer review: Commissioned; not externally peer reviewed.

Hippisley-Cox J, Coupland C, Robson J, Brindle P. Derivation, validation, and evaluation of a new QRISK model to estimate lifetime risk of cardiovascular disease: cohort study using QResearch database. BMJ 2010;341:c6624.
Lloyd-Jones DM, Leip EP, Larson MG, D'Agostino R, Beiser A, Wilson PWF, et al. Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age. Circulation 2006;113:791-8.
Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003;326:1419.
Jackson R, Lawes C, Bennett D, Milne R, Rodgers A. Treatment with drugs to lower blood pressure and blood cholesterol based on an individual's absolute cardiovascular risk. Lancet 2005;365:434-41.
Hippisley-Cox J, Coupland C, Vinogradova Y, Robson J, Minhas R, Sheikh A, et al. Predicting cardiovascular risk in England and Wales: prospective derivation and validation of QRISK2. BMJ 2008;336:a332.
Wells S, Kerr A, Eadie S, Wiltshire C, Jackson R. "Your heart forecast": a new approach for describing and communicating cardiovascular risk? Heart 2010;96:708-13.

Treating inflammatory arthritis early Sustained remission depends on rapid diagnosis and intensive treatment

Inflammatory arthritis is a major healthcare problem. It spans rheumatoid arthritis, seronegative arthritis, and childhood arthritis. Three linked articles outline its clinical and personal effects.^{1 3} Two clinical reviews challenge traditional management approaches, and a patient's personal testimony highlights the limitations of traditional care. The past decade saw major improvements in managing inflammatory arthritis, captured in guidelines from the National Institute for Health and Clinical Excellence (NICE) and other European and North American groups.^4–7 Despite such advances, far more is needed to overcome the long term effects of inflammatory arthritis on patients and carers.

Rapid diagnosis and treatment are crucial.^{1 4–7} Patients need early effective treatment with disease modifying antirheumatic drugs (DMARDs). Traditional, cautious, symptom relieving approaches have become untenable for early inflammatory arthritis. A brief "window of opportunity" exists when effective treatment radically improves long term outcomes.1 ^4–7 Delaying the start of DMARDs by more than three months since onset of symptoms perpetuates joint inflammation. The consequences are substantial joint damage and disability and lost independence.1 ^4–7 It is therefore important to identify and treat inflammatory arthritis at the earliest opportunity. Intensive early suppressive treatment should target remission and prevent joint damage.1 ^4–7

Currently, many patients with inflammatory arthritis present late. The National Audit Office surveyed practice in the United Kingdom in 2009. They found that most people with symptoms suggesting inflammatory arthritis wait for three months before consulting their general practitioner. A fifth wait for more than 12 months.⁸ One priority is to raise public awareness of arthritis so that people seek prompt medical advice. The UK Rheumatology Futures Group, Arthritis Research UK, and general practitioners are promoting public knowledge through the "S factor" campaign—stiffness, swelling, and the squeezing of joints causing pain mean that medical help is needed.

Diagnosing early inflammatory arthritis challenges both general practitioners and specialists. Low levels of clinical suspicion are essential because no ideal diagnostic tests exist. Patients often have normal inflammatory markers when first seen. The National Audit Office reported that people with inflammatory arthritis visit their general practitioner more than four times before specialist referral.⁸ A second priority is for healthcare commissioners, the Department of Health, and the royal colleges to ensure that general practitioners receive ongoing training to help them recognise early inflammatory arthritis. Clinicians seeing patients with potential inflammatory arthritis should have low diagnostic thresholds and refer patients urgently. If squeezing across the metacarpophalangeal or metatarsophalangeal joints causes pain, this should trigger concern. Clinical features are more important than tests. New criteria will make diagnosis less demanding.9 Referral must not be delayed until test results are available.1 4 General practitioners need rapid access to expert multidisciplinary teams working together in specialist centres who can follow up patients regularly to achieve rapid disease control.^{1 4}

Early, intensive DMARD treatment with regular follow-up—a key NICE guideline recommendation—has substantial implications for resources.⁴ However, by reducing morbidity and disability it will eventually save money. The National Audit Office calculated that rapid specialist access with early intensive treatment and follow-up would increase NHS costs by £11m (€13m; $17m) over five years. Thereafter it would be cost neutral. It would also reduce sick leave and limit unemployment, thereby achieving £31m in gained productivity for the UK economy.⁸ Long term extension studies of randomised controlled trials show that early DMARDs enable more patients to remain employed.¹⁰ Evidence from a systematic review showed that poorly controlled inflammatory arthritis has large societal costs.¹¹ We cannot afford suboptimal treatment for inflammatory arthritis.

When DMARDs fail to control rheumatoid arthritis patients need biological treatments, such as tumour necrosis factor inhibitors. These are both highly effective and expensive (£8000-£10 000/patient/year). Treating all patients with biologicals is clearly unaffordable. However, undertreating inflammatory arthritis also has high personal and societal costs. When biologicals were first introduced, large numbers of patients had very active disease. Times have now changed and clinical remission is achievable. In most of western Europe and North America biologicals can be used when patients have failed DMARDs and have ongoing active disease. Existing NICE guidelines mean that in the UK many patients with active arthritis do not fulfil the eligibility criteria to receive evidence based biological treatment. The UK should adopt more universal Western criteria.¹²

Limiting access to effective treatments is never defensible, whether based on UK postcodes or European country. The final priority is to make remission a UK quality standard when treating inflammatory arthritis. The challenge for rheumatologists, regulators, and commissioners is to ensure that patients get the treatment they need to achieve long term remission in ways that are deliverable and affordable.

Modern intensive treatments enable many patients with inflammatory arthritis to achieve sustained remission. Ailsa Bosworth's personal story, which shows what can be achieved in the face of personal adversity, highlights the limitations of treating arthritis too little and too late.3 General practitioners, specialists, and healthcare commissioners must work together to ensure that patients receive both early and effective care.

Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; CD was clinical adviser to the NICE rheumatoid arthritis management guideline group and until recently chairman of the clinical affairs committee of the British Society for Rheumatology; DS was a member of the NICE rheumatoid arthritis management guideline development group and is president of the British Society for Rheumatology and an NIHR senior investigator.

Provenance and peer review: Commissioned; not externally peer reviewed.

Klarenbeek NB, Kerstens PJSM, Huizinga TWJ, Dijkmans BAC, Allaart CF. Recent advances in the management of rheumatoid arthritis. BMJ 2010;341:c6942.
Prince FHM, Otten MH, van Suijlekom-Smit LWA. Diagnosis and management of juvenile idiopathic arthritis. BMJ 2010;341:c6434.
Bosworth AM, Steuer A. Rheumatoid arthritis. BMJ 2010;341:c7095. 4 National Institute for Health and Clinical Excellence. Rheumatoid arthritis: NICE guideline. 2009. http://guidance.nice.org.uk/CG79/NICEGuidance/pdf/English.
Smolen JS, Landewé R, Breedveld FC, Dougados M, Emery P, Gaujoux-Viala C, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis 2010;69:964-75.
American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis 2002 update. Arthritis Rheum 2002;46:7328-46.
Saag KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum 2008;59:762-84.
National Audit Office. Services for people with rheumatoid arthritis. Stationery Office, 2009.
Aletaha D, Neogi T, Silman A, Funovits J, Felson D, Bingham C, et al. The 2010 American College of Rheumatology/European League against Rheumatism classification criteria for rheumatoid arthritis. Arthritis Rheum 2010;62:2582-91.
Puolakka K, Kautiainen H, Möttönen T, Hannonen P, Korpela M, Hakala M, et al Early suppression of disease activity is essential for maintenance of work capacity in patients with recent-onset rheumatoid arthritis: five-year experience from the FIN-RACo trial. Arthritis Rheum 2005;52:36-41.
Schoels M, Wong J, Scott DL, Zink A, Richards P, Landewé R, et al. Economic aspects of treatment options in rheumatoid arthritis: a systematic literature review informing the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis 2010;69:995-1003.
Deighton C, Hyrich K, Ding T, Ledingham J, Lunt M, Luqmani R, et al. BSR and BHPR rheumatoid arthritis guidelines on eligibility criteria for the first biological therapy. Rheumatol (Oxford) 2010;49:1197-9.

Wakefield's article linking MMR vaccine and autism was fraudulent Clear evidence of falsification of data should now close the door on this damaging vaccine scare

"Science is at once the most questioning and . . . sceptical of activities and also the most trusting," said Arnold Relman, former editor of the New England Journal of Medicine, in 1989. "It is intensely sceptical about the possibility of error, but totally trusting about the possibility of fraud."¹ Never has this been truer than of the 1998 Lancet paper that implied a link between the measles, mumps, and rubella (MMR) vaccine and a "new syndrome" of autism and bowel disease.

Authored by Andrew Wakefield and 12 others, the paper's scientific limitations were clear when it appeared in 1998.^{2 3} As the ensuing vaccine scare took off, critics quickly pointed out that the paper was a small case series with no controls, linked three common conditions, and relied on parental recall and beliefs.⁴ Over the following decade, epidemiological studies consistently found no evidence of a link between the MMR vaccine and autism.^5–8 By the time the paper was finally retracted 12 years later,⁹ after forensic dissection at the General Medical Council's (GMC) longest ever fitness to practise hearing,¹⁰ few people could deny that it was fatally flawed both scientifically and ethically. But it has taken the diligent scepticism of one man, standing outside medicine and science, to show that the paper was in fact an elaborate fraud.

In a series of articles starting this week, and seven years after first looking into the MMR scare, journalist Brian Deer now shows the extent of Wakefield's fraud and how it was perpetrated. Drawing on interviews, documents, and data made public at the GMC hearings, Deer shows how Wakefield altered numerous facts about the patients' medical histories in order to support his claim to have identified a new syndrome; how his institution, the Royal Free Hospital and Medical School in London, supported him as he sought to exploit the ensuing MMR scare for financial gain; and how key players failed to investigate thoroughly in the public interest when Deer first raised his concerns.¹¹

Deer published his first investigation into Wakefield's paper in 2004.¹² This uncovered the possibility of research fraud, unethical treatment of children, and Wakefield's conflict of interest through his involvement with a lawsuit against manufacturers of the MMR vaccine. Building on these findings, the GMC launched its own proceedings that focused on whether the research was ethical. But while the disciplinary panel was examining the children's medical records in public, Deer compared them with what was published in the Lancet. His focus was now on whether the research was true.

The Office of Research Integrity in the United States defines fraud as fabrication, falsification, or plagiarism.¹³ Deer unearthed clear evidence of falsification. He found that not one of the 12 cases reported in the 1998 Lancet paper was free of misrepresentation or undisclosed alteration, and that in no single case could the medical records be fully reconciled with the descriptions, diagnoses, or histories published in the journal.

Who perpetrated this fraud? There is no doubt that it was Wakefield. Is it possible that he was wrong, but not dishonest: that he was so incompetent that he was unable to fairly describe the project, or to report even one of the 12 children's cases accurately? No. A great deal of thought and effort must have gone into drafting the paper to achieve the results he wanted: the discrepancies all led in one direction; misreporting was gross. Moreover, although the scale of the GMC's 217 day hearing precluded additional charges focused directly on the fraud, the panel found him guilty of dishonesty concerning the study's admissions criteria, its funding by the Legal Aid Board, and his statements about it afterwards.¹⁴

Furthermore, Wakefield has been given ample opportunity either to replicate the paper's findings, or to say he was mistaken. He has declined to do either. He refused to join 10 of his coauthors in retracting the paper's interpretation in 2004,¹⁵ and has repeatedly denied doing anything wrong at all. Instead, although now disgraced and stripped of his clinical and academic credentials, he continues to push his views.¹⁶

Meanwhile the damage to public health continues, fuelled by unbalanced media reporting and an ineffective response from government, researchers, journals, and the medical profession.^{17 18} Although vaccination rates in the United Kingdom have recovered slightly from their 80% low in 2003-4,¹⁹ they are still below the 95% level recommended by the World Health Organization to ensure herd immunity. In 2008, for the first time in 14 years, measles was declared endemic in England and Wales.²⁰ Hundreds of thousands of children in the UK are currently unprotected as a result of the scare, and the battle to restore parents' trust in the vaccine is ongoing.

Any effect of the scare on the incidence of mumps remains in question. In epidemics in the UK, the US, and the Netherlands, peak prevalence was in 18-24 year olds, of whom 70-88% had been immunised with at least one dose of the MMR vaccine.^{21 22} Any consequence of a fall in uptake after 1998 may not become apparent until the cohorts of children affected reach adolescence. One clue comes from an outbreak in a school in Essen, Germany, attended by children whose parents were opposed to vaccinations. Of the 71 children infected with mumps, 68 had not been immunised.23

But perhaps as important as the scare's effect on infectious disease is the energy, emotion, and money that have been diverted away from efforts to understand the real causes of autism and how to help children and families who live with it.²⁴

There are hard lessons for many in this highly damaging saga. Firstly, for the coauthors. The GMC panel was clear that it was Wakefield alone who wrote the final version of the paper. His coauthors seem to have been unaware of what he was doing under the cover of their names and reputations. As the GMC panel heard, they did not even know which child was which in the paper's patient anonymised text and tables. However, this does not absolve them. Although only two (John Walker-Smith and Simon Murch) were charged by the GMC, and only one, the paper's senior author Walker-Smith, was found guilty of misconduct, they all failed in their duties as authors. The satisfaction of adding to one's CV must never detract from the responsibility to ensure that one has been neither party to nor duped by a fraud. This means that coauthors will have to check the source data of studies more thoroughly than many do at present—or alternatively describe in a contributor's statement precisely which bits of the source data they take responsibility for.

Secondly, research ethics committees should not only scrutinise proposals but have systems to check that what is done is what was permitted (with an audit trail for any changes) and work to a governance procedure that can impose sanctions where an eventual publication proves this was not the case. Finally, there are lessons for the Royal Free Hospital, the Lancet, and the wider scientific community. These will be considered in forthcoming articles.

What of Wakefield's other publications? In light of this new information their veracity must be questioned. Past experience tells us that research misconduct is rarely isolated behaviour.²⁵ Over the years, the BMJ and its sister journals Gut and Archives of Disease in Childhood have published a number of articles, including letters and abstracts, by Wakefield and colleagues. We have written to the vice provost of UCL, John Tooke, who now has responsibility for Wakefield's former institution, to ask for an investigation into all of his work to decide whether any more papers should be retracted.

The Lancet paper has of course been retracted, but for far narrower misconduct than is now apparent. The retraction statement cites the GMC's findings that the patients were not consecutively referred and the study did not have ethical approval, leaving the door open for those who want to continue to believe that the science, flawed though it always was, still stands. We hope that declaring the paper a fraud will close that door for good. Competing interests: All authors have completed the

All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years. HM chairs GMC fitness to practise panels. He had no association with the Wakefield hearings and the views expressed in this article are his own and do not represent those of the GMC.

Provenance and peer review: Commissioned; not externally peer reviewed.

Schechter AN, Wyngaarden JB, Edsall JT, Maddox J, Relman AS, Angell M, et al. Colloquium on scientific authorship: rights and responsibilities. FASEB J 1989;3:209-17.
Wakefield AJ, Murch SH, Anthony A, Linnell, Casson DM, Malik M, et al. Ileal lymphoid nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children [retracted]. Lancet 1998;351:637-41.
Chen RT, DeStefano F. Vaccine adverse events: causal or coincidental? Lancet 1998;351:611-2.
Payne C, Mason B. Autism, inflammatory bowel disease, and MMR vaccine. Lancet 1998;351:907.
Black C, Kaye JA, Jick H. Relation of childhood gastrointestinal disorders to autism: nested casecontrol study using data from the UK General Practice Research Database. BMJ 2002;325:419-21.
Taylor B, Miller E, Lingam R, Andrews N, Simmons A, Stowe J. Measles, mumps, and rubella vaccination and bowel problems or developmental regression in children with autism: population study. BMJ 2002;324:393-6.
Madsen KM, Hviid A, Vestergaard M, Schendel D, Wohlfahrt J, Thorsen P, et al. A population-based study of measles, mumps, and rubella vaccination and autism. N Engl J Med 2002;347:1477-82.
Honda H, Shimizu Y, Rutter M. No effect of MMR withdrawal on the incidence of autism: a total population study. J Child Psychol Psychiatry 2005;46:572-9.
The editors of the Lancet. Retraction—Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet 2010;375:445.
Transcripts of hearings of fitness to practise panel (misconduct) in the case of Wakefield, Walker-Smith, and Murch, 16 July 2007 to 24 May 2010. GMC; 2010.
Deer B. Secrets of the MMR scare: how the case against the MMR vaccine was fixed. BMJ 2011;342:c5347.
Deer B. Revealed: MMR research scandal. Sunday Times 2004 February 22. www.timesonline.co.uk/tol/life_and_style/health/article1027636.ece.
Office of Research Integrity. Definition of research misconduct. http://ori.hhs.gov/misconduct/definition_misconduct.shtml.
GMC. Andrew Wakefield: determination of serious professional misconduct 24 May 2010. www.gmc-uk.org/Wakefield_SPM_and_SANCTION.pdf_32595267.pdf.
Murch SH, Anthony A, Casson DH, Malik M, Berelowitz M, Dhillon AP, et al. Retraction of an interpretation. Lancet 2004;363:750.
Shenoy R. Controversial autism researcher tells local Somalis disease is solvable. Minnesota Public Radio 2010 December 17. http://minnesota.publicradio.org/display/web/2010/12/17/somali-autism.
Hilton S, Hunt K, Langan M, Hamilton V, Petticrew M. Reporting of MMR evidence in professional publications: 1988–2007. Arch Dis Child 2009;94:831-3.
Bedford HE, Elliman DAC. MMR vaccine and autism. BMJ 2010 Feb 2;340:c655.
Health Protection Agency. Completed primary course at two years of age: England and Wales, 1966-1977, England only 1978 onwards. http://www.hpa.org.uk/web/HPAweb&HPAwebStandard/HPAweb_C/1195733819251.
Health Protection Agency. Confirmed cases of measles, mumps and rubella 1996-2009. http://www.hpa.org.uk/web/HPAweb&HPAwebStandard/HPAweb_C/1195733833790
Jick H, Chamberlin DP, Hagberg KW. The origin and spread of a mumps epidemic: United Kingdom, 2003-2006. Epidemiology 2009;20:656-61.
Kutty PK, Kruszon-Moran DM, Dayan GH, Alexander JP, Williams NJ, Garcia PE, et al. Seroprevalence of antibody to mumps virus in the US population, 1999-2004. J Infect Dis 2010;202:667-74.
Roggendorf H, Mankertz A, Kundt R, Roggendorf M. Spotlight on measles 2010: measles outbreak in a mainly unvaccinated community in Essen, Germany, March-June 2010. Euro Surveill 2010;15:2. http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19605.
Oakley GP, Johnstone RB. Balancing the benefits and harms in public health prevention programmes mandated by governments. BMJ 2004;329:41-3.
Rennie D. Misconduct and journal peer review. In: Godlee F, Jefferson T eds. Peer review in health sciences, 2nd ed. BMJ Books; 2003. p 118-129.

How the Case Against the MMR Vaccine was Fixed

Mon, 04 Apr 2011 22:05:00 GMT

How The Case Against The MMR Vaccine Was Fixed

The MMR Vaccine

In the first part of a special BMJ series, Brian Deer exposes the bogus data behind claims that launched a worldwide scare over the measles, mumps, and rubella vaccine, and reveals how the appearance of a link with autism was manufactured at a London medical school

Brian Deer

When I broke the news to the father of child 11, at first he did not believe me. "Wakefield told us my son was the 13th child they saw," he said, gazing for the first time at the now infamous research paper which linked a purported new syndrome with the measles, mumps, and rubella (MMR) vaccine.¹ "There's only 12 in this."

That paper was published in the Lancet on 28 February 1998. It was retracted on 2 February 2010.² Authored by Andrew Wakefield, John Walker-Smith and 11 others from the Royal Free Hospital and School of Medicine, London, it reported on 12 developmentally challenged children, and triggered a decade long public health scare.

John Walker-Smith

"Onset of behavioural symptoms was associated by the parents with measles, mumps, and rubella vaccination in eight of the 12 children," began the paper's "findings." Adopting these claims as fact, its results section added: "In these eight children the average interval from exposure to first behavioural symptoms was 6.³ days (range 1-14)."

Mr 11, an American engineer, looked again at the paper: a five page case series of 11 boys and one girl, aged between 3 and 9 years. Nine children, it said, had diagnoses of "regressive" autism, while all but one were reported with "non-specific colitis." The "new syndrome" brought these together, l ink ing brain and bowel diseases. Child 11 was the penultimate case.

Running his finger across the paper's tables, over coffee in London, Mr 11 seemed reassured by his anonymised son's age and other details. But then he pointed at table 2—headed "neuropsychiatric diagnosis"— and for a second time objected. "That's not true." Child 11 was among the eight whose parents apparently blamed MMR. The interval between his vaccination and the first "behavioural symptom" was reported as 1 week. This symptom was said to have appeared at age 15 months. But his father, whom I had tracked down, said this was wrong.

"From the information you provided me on our son, who I was shocked to hear had been included in their published study," he wrote to me, after we met again in California, "the data clearly appeared to be distorted."

He backed his concerns with medical records, including a Royal Free discharge summary. Although the family lived 5000 miles from the hospital, in February 1997 the boy (then aged 5) had been flown to London and admitted for Wakefield's project, the undisclosed goal of which was to help sue the vaccine's manufacturers.

Wakefield's "syndrome"

Unknown to Mr 11, Wakefield was working on a lawsuit,3 for which he sought a bowel-brain "syndrome" as its centrepiece. Claiming an undisclosed £150 (€180; $230) an hour through a Norfolk solicitor named Richard Barr, he had been confidentially put on the payroll for two years before the paper was published, eventually grossing him £435 643, plus expenses.⁴ Curiously, however, Wakefield had already identified such a syndrome before the project that would reputedly discover it. "Children with enteritis/ disintegrative disorder [an expression he used for bowel inflammation and regressive autism⁵ form part of a new syndrome," he and Barr explained in a confidential grant application to the UK government's Legal Aid Board,6 before any of the children were investigated. "Nonetheless the evidence is undeniably in favour of a specific vaccine induced pathology."

The two men also aimed to show a sudden onset "temporal association"—strong evidence in product liability. "Dr Wakefield feels that if we can show a clear time link between the vaccination and onset of symptoms," Barr told the legal board, "we should be able to dispose of the suggestion that it's simply a chance encounter."7 But child 11's case must have proved a disappointment. Records show his behavioural symptoms started too soon. "His developmental milestones were normal until 13 months of age," notes the discharge summary. "In the period 13-18 months he developed slow speech patterns and repetitive hand movements. Over this period his parents remarked on his slow gradual deterioration."

That put the first symptom two months earlier than reported in the Lancet, and a month before the boy had MMR. And this was not the only anomaly to catch the father's eye. What the paper reported as a "behavioural symptom" was noted in records as a chest infection.

"Please let me know if Andrew W has his doctor's license revoked," wrote Mr ¹¹, who is convinced that many vaccines and environmental pollutants may be responsible for childhood brain disorders. "His misrepresentation of my son in his research paper is inexcusable. His motives for this I may never know." The father need not have worried. My investigation of the MMR issue exposed the frauds behind Wakefield's research. Triggering the longest ever UK General Medical Council fitness to practise hearing, and forcing the Lancet to retract the paper, last May it led to Wakefield and Walker-Smith being struck off the medical register.^8–10 Wakefield, now 54, who called no witnesses, was branded "dishonest," "unethical," and "callous."^8–10 Walker-Smith, now 74, the senior clinician in the project, was found to have presided over "high risk" ¹¹ research without clinical indication or ethical approval. The developmentally challenged children of often vulnerable parents were discovered to have been treated like the doctors' guinea pigs.¹⁰

Lawsuit test case

But Mr 11 was not the first parent with a child in the study whom I interviewed during my investigation. That was Mrs 2: the first of the parents to approach Wakefield. She was sent to him by an anti-vaccine campaign called JABS. Her son had regressive autism,¹² longstanding problems with diarrhoea,¹³ and was the prime example of the purported bowel and brain syndrome—still unsubstantiated 14 years later.¹⁴ This boy would appear in countless media reports, and was one of the four "best" cases in Barr's lawsuit. I travelled to the family home, 80 miles northeast of London, to hear about child 2 from his mother. That was in September 2003, when the lawsuit fell apart after counsel representing 1500 families said that, on the evidence, Barr's autism claims would fail.¹⁵ By that time, Mrs 2 had seen her son's medical records and expert reports, written for her case at trial.

Her concerns about MMR had been noted by her general practitioner when her son was 6 years old. But she told me the boy's troubles began after his vaccination, which he received at 15 months.

"He'd scream all night, and he started head banging, which he'd never done before," she explained.

"When did that begin, do you think?" I asked.

"That began after a couple of months, a few months afterward, but it was still, it was concerning me enough, I remember going back."

"Sorry. I don't want to be, like, massively pernickety, but was it a few months, or a couple of months?"

"It was more like a few months because he'd had this, kind of, you know, slide down. He wasn't right. He wasn't right. Before he started."

"Not quicker than two months, but not longer than how many months? What are we talking about here?"

"From memory, about six months, I think."

The next day, she complained to my editors. She said my methods "seemed more akin to the gutter press." But I was perplexed by her story, since there was no case in the Lancet that matched her careful account. According to the paper, child 2 had his "first behavioural symptom" two weeks, not six months, after MMR. This was derived from a Royal Free medical history (citing "head banging" and "screaming" as the start) taken by Mark Berelowitz, a child psychiatrist and a coauthor of the paper. He saw Mrs 2 during the boy's admission, at age 8, after she had discussed her son's story with Wakefield.¹⁰ As I later discovered, each family in the project was involved in such discussions before they saw the hospital's clinicians. Wakefield phoned them at home, and must have at least suggestively questioned them, potentially impacting on later history taking. But I knew little of such things then, and shared my confusion with Walker-Smith, who I met shortly after Mrs 2.

"There is no case in the paper that is consistent with the case history [Mrs 2] has given me," I told him. "There just isn't one."

"Well that could be true," the former professor of paediatric gastroenterology replied, disarmingly. He knew the case well, having admitted the boy for the project and written reports for Barr, who paid him £23 000.¹⁶

"Well, so either what she is telling me is not accurate, or the paper's not accurate."

"Well I can't really comment," he said. "You really touch on an area which I don't think should be debated like this. And I think these parents are wrong to discuss such details, where you could be put in a position of having a lot of medical details and then try to match it with this, because it is a confidential matter."

It was not merely medically confidential, it was also legally protected: a double screen against public scrutiny. But responding to my first MMR reports in the Sunday Times, in February 2004,¹⁷ the GMC decided to investigate the cases and requisitioned the children's records. The regulator's main focus was whether the research was ethical. Mine was whether it was true. So as a five member disciplinary panel trawled through the records, with five Queen's counsel and three defendant doctors, I compared them with what was published in the journal.¹⁸

Multiple discrepancies

The paper gave the impression that the authors had been scrupulous in documenting the patients' cases. "Children underwent gastroenterological, neurological, and developmental assessment and review of developmental records," it explained, specifying that Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) criteria were used for neuropsychiatric diagnoses. "Developmental histories included a review of prospective developmental records from parents, health visitors, and general practitioners."

When the details were dissected before the panel, however, multiple discrepancies emerged. A syndrome necessarily requires at least some consistency, but, as the records were laid out, Wakefield's crumbled. First to crack was "regressive autism," the bedrock of his allegations.3 "Bear in mind that we are dealing with regressive autism in these children, not of classical autism where the child is not right from the beginning," he later explained, for example, to a United States congressional committee.¹⁹

But only one—child 2—clearly had regressive autism.²⁰ Three of nine so described clearly did not. None of these three even had autism diagnoses, either at admission or on discharge from the Royal Free.

The paper did not reveal that two of this trio were brothers, living 60 miles south of the hospital. Both had histories of fits and bowel problems recorded before they received MMR. The elder, child 6, aged 4 years at admission, had Asperger's syndrome,²¹ which is distinct from autism under DSM-IV, is not regressive,²² and was confirmed on discharge.¹⁰ His brother, child 7, was admitted at nearly 3 years of age without a diagnosis,¹⁰ and a post-discharge letter from senior paediatric registrar and Lancet coauthor David Casson summarised: "He is not thought to have features of autism."

The third of this trio, child 12, was enrolled on the advice of the brothers' mother—reported in media as a JABS activist, who had herself "only relatively recently" blamed the vaccine. Child 12 was aged 6 at admission and had previously been assessed for possible Asperger's syndrome at Guy's Hospital, London, by a renowned developmental paediatrician. She diagnosed "an impairment in respect of language"—an opinion left undisturbed by Berelowitz.¹⁰

Mrs 12 was a GMC witness at its mammoth hearing, which between July 2007 and May 2010 ran for 217 days. She explained that the brothers' mother had made her suspicious of MMR and gave her Barr's and Wakefield's names. Mrs 12 approached them and filed a statement for legal aid before her son was referred. "It was like a jigsaw puzzle—it suddenly seemed to fit into place," she told the panel, describing how she concluded, four years after the boy was vaccinated, that MMR was to blame for his problems. "I had this perfectly normal child who, as I could see, for no apparent reason started to not be normal."

The 12 children were admitted between July 1996 and February 1997, and others had connections not revealed in the paper, almost as striking as the trio's. The parents of child 9 and child 10 were contacts of Mrs 2, who ran a group that campaigned against MMR. And child 4 and child 8 were admitted—without outpatient appointments¹⁰—for ileocolonoscopy and other invasive procedures, from one Tyneside general practice, 280 miles from the Royal Free, after advice from anti-MMR campaigners.

Pre-existing problems

Both child 4 and child 8 were among the eight whose parents were reported to have blamed the vaccine. But although the paper specified that all 12 children were "previously normal," both had developmental delays, and also facial dysmorphisms, noted before MMR vaccination.

In the case of child 4, who received the vaccine at 4 years, Wakefield played down problems, suggesting that early issues had resolved. "Child four was kept under review for the first year of life because of wide bridging of the nose," he reported in the paper. "He was discharged from follow-up as developmentally normal at age 1 year." But medical records, presented by the GMC, give a different picture for this child. Reports from his pre-MMR years were peppered with "concerns over his head and appearance," "recurrent" diarrhoea, "developmental delay," "general delay," and restricted vocabulary. And although before his referral to Wakefield his mother had inquired about vaccine damage compensation, his files include a report of a "very small deletion within the fragile X gene," and a note of the mother's view that her concerns about his development began when he was 18 months old.

"In general, his mother thinks he developed normally initially and subsequently his problems worsened, and he lost some of his milestones, but he subsequently improved on a restrictive exclusion diet," wrote his general practitioner, William Tapsfield, referring the boy, then aged 9, after a phone conversation with Wakefield. "The professionals who have known [child 4] since birth don't entirely agree with this, however, and there is a suggestion that some of his problems may have started before vaccination."

Similarly with child 8, who was also described in the Lancet as having overcome problems recorded before MMR. "The only girl . . . was noted to be a slow developer compared with her older sister," the paper said. "She was subsequently found to have coarctation of the aorta. After surgical repair of the aorta at the age of 14 months, she progressed rapidly, and learnt to talk. Speech was lost later."

But Wakefield was not a paediatrician. He was a former trainee gastrointestinal surgeon with a non-clinical medical school contract.¹⁰ And his interpretation differed from that of local consultants (including a developmental paediatrician and a geneticist) who had actually looked after the girl. Her doctors put the coarctation side by side with the developmental delay and dysmorphism, and noted of her vocabulary that, before MMR at 18 months, she "vocalised" only "two or three words."

"[Child 8's] mother has been to see me and said you need a referral letter from me in order to accept [child 8] into your investigation programme," the general practitioner, Diana Jelley, wrote to Wakefield at referral, when the girl was aged 3 and a half years. "I would simply re-iterate . . . that both the hospital and members of the primary care team involved with [child 8] had significant concerns about her development some months before she had her MMR."

The girl's general practice notes also provide insight into the background to the 12 children's referrals. After person(s) unknown told Mrs 8 that her daughter may have inflammatory bowel disease, Jelley wrote: "Mum taking her to Dr Wakefield, Royal Free hospital for CT scans/gut biopsies ?Crohn's—will need ref letter—Dr Wakefield to phone me. Funded through legal aid."

The child was "pale"

The remaining five children served Wakefield's claims no better. There was still no convincing MMR syndrome. Child 1, aged 3 years when he was referred to London, lived 100 miles from the Royal Free and had an older brother who was diagnosed as autistic. Child 1's recorded story began when he was aged 9 months, with a "new patient" note by general practitioner Andrea Barrow. One of the mother's concerns was that her son could not hear properly—which might sound like a hallmark presentation of classical autism, the emergence of which is often insidious. Indeed, a Royal Free history, by neurologist and coauthor Peter Harvey, noted "normal milestones" until "18 months or so."

This boy was vaccinated at 12 months of age, however. Thus neither 9 nor 18 months helped Wakefield's case. But in the Lancet, the "first behavioural symptom" was reported to have occurred "1 week" after the injection, holding the evidence for the lawsuit on track.

Step 1 to achieve this: two and a half years after the child was vaccinated, Walker-Smith took an outpatient history. Although the mother apparently had no worries following her son's vaccination, the professor elicited that the boy was "pale" 7-10 days after the shot. He also elicited that the child "possibly" had a fever, and "may" have been delirious, as well as pale.

"It's difficult to associate a clear historical link with the MMR and the answer to autism," Walker-Smith wrote to the general practitioner, with a similar letter to Wakefield, "although [Mrs 1] does believe that [child 1] had an illness 7-10 days after MMR when he was pale, ?fever, ?delirious, but wasn't actually seen by a doctor." Step 2: for the Lancet Wakefield dropped the question marks, turning Walker-Smith's queries into assertions. And, although Royal Free admission and discharge records refer to "classical" autism, step 3, the former surgeon reported "delirium" as the first "behavioural symptom" of regressive autism, with, step 4, a "time to onset" of 7 days.

So here—behind the paper—is how Wakefield evidenced his "syndrome" for the lawsuit, and built his platform to launch the scare.

"It is significant that this syndrome only appeared with the introduction of the polyvalent MMR vaccine in 1988 rather than with the monovalent measles vaccine introduced in 1968," he claimed in one of a string of patents he filed for businesses to be spun from the research.²³ "This indicates that MMR is responsible for this condition rather than just the measles virus." Three of the four remaining children were seen in outpatients on the same day—in November 1996. None of their families were reported in the paper as blaming the vaccine. Child 5, from Berkshire, aged 7 at admission, had received MMR at 16 months. The paper reported concerns at 18 months, but the medical records noted fits and parental worries at 11 months. Child 9, aged 6, from Jersey, also had MMR at 16 months. His mother dated problems from 18-20 months. Child 10, aged 4, from south Wales, contracted a viral infection, which was suspected by parents and doctors to have caused his disorder, four months after his vaccination.

"Behavioural changes included repetitive behaviour, disinterest in play or head banging," said a question and answer statement issued by the medical school, concerning the Lancet 12, on the day of the paper's publication.

Another discrepancy to emerge during the GMC hearing concerned the number of families who blamed MMR. The paper said that eight families (1, 2, 3, 4, 6, 7, 8, and 11) linked developmental issues with the vaccine. But the total in the records was actually 11. The parents of child 5, 9, and 12 were also noted at the hospital as blaming the vaccine, but their stated beliefs were omitted from the journal.

Case selection

The frequency of these beliefs should not have surprised Wakefield, retained as he was to support a lawsuit. In the month that Barr engaged him—two years before the paper was published—the lawyer touted the doctor in a confidential newsletter to his MMR clients and contacts. "He has deeply depressing views about the effect of vaccines on the nation's children," Barr said.²⁴ "He is also anxious to arrange for tests to be carried out on any children . . . who are showing symptoms of possible Crohn's disease. The following are signs to look for. If your child has suffered from all or any of these symptoms could you please contact us, and it may be appropriate to put you in touch with Dr Wakefield."

The listed symptoms included pain, weight loss, fever, and mouth ulcers. Clients and contacts were quickly referred. Thus, an association between autism, digestive issues, and worries about MMR—the evidence that launched the vaccine scare—was bound to be found by the Royal Free's clinicians because this was how the children were selected. Moreover, through the omission from the paper of some parents' beliefs that the vaccine was to blame, the time link for the lawsuit sharpened. With concerns logged from 11 of 12 families, the maximum time given to the onset of alleged symptoms was a (forensically unhelpful) four months. But in a version of the paper circulated at the Royal Free six months before publication, reported concerns fell to nine of 12 families but with a still unhelpful maximum of 56 days.²⁵ Finally, Wakefield settled on 8 of 12 families, with a maximum interval to alleged symptoms of 14 days.

Between the latter two versions, revisions also slashed the mean time to alleged symptoms—from 14 to 6.3 days. "In these children the mean interval from exposure to the MMR vaccine to the development of the first behavioural symptom was six days, indicating a strong temporal association," he emphasised, in a patent for, among other things, his own measles vaccine,²⁶ eight months before the Lancet paper. This leaves child 3. He was 6½ and lived on Merseyside: 200 miles from the hospital. He received MMR at 14 months, with the first concerns recorded in his GP notes 15 months after that. His mother— who 4 years later contacted Wakefield on the advice of JABS²⁷—told me that her son had become aggressive towards a brother, and records say that his vocabulary had not developed.

"We both felt that the MMR needle had made [child 3] go the way he is today," the parents wrote to a local paediatric neurologist, Lewis Rosenbloom, 18 months before their son's referral to London. They told him they wanted "justice" from the vaccine's manufacturer and that they had been turned down for legal aid. "Although it is said that the MMR has never been proven to make children to be autistic, we believe that the injection has made [child 3] to be mentally delayed, which in turn may have triggered off the autism." I visited this family twice. Their affected son was now a teenager and a challenge both to himself and to others. His mother said his diagnosis was originally "severe learning difficulties with autistic tendencies," but that she had fought to get it changed to autism. As for a connection with MMR, there was only suspicion. I don't think his family was sure, one way or the other. When I asked why they took him to the Royal Free, his father replied: "We were just vulnerable, we were looking for answers."

What was unquestionably true was that child 3 had serious bowel trouble: intractable, lifelong, constipation. This was the most consistent feature among the 12 children's symptoms and signs²⁸ but, being the opposite of an expected finding in inflammatory bowel disease,²⁹ was nowhere mentioned in the paper. This young man's symptoms were so severe that he was dosed at his special school, his mother said, with up to five packets of laxative a day. "You always knew when his stomach was hard," she told me, in terms echoed over the years by many parents involved with Wakefield. "He would start headbutting, kicking, breaking anything in the house. Then he would go to the toilet and release it."

For the Royal Free team, however, when reporting on these patients, such motility symptoms³⁰ were sidelined in the hunt for Wakefield's syndrome. In almost all the children, they noted commonly swollen glands in the terminal ileum, and what was reported as "non- specific colitis."^{31 32} In fact, as I revealed in the BMJ last April,³³ the hospital's pathology service found the children's colons to be largely normal, but a medical school "review" changed the results. In this evolution of the gut pathology to what was published in the Lancet, child 3's case was a prime example. After ileocolonoscopy (which GMC prosecution and defence experts agreed was not clinically indicated), the hospital's pathologists found all colonic samples to be "within normal histological limits." But three months after the boy was discharged, Walker-Smith recalled the records and changed the diagnosis to "indeterminate ileocolitis."³⁴

"I think, sadly, this was the first child who was referred, and the long-term help we were able to give in terms of dealing with constipation was not there," he told the GMC panel. "However, we had excluded Crohn's disease and we had done our best to try and help this child, but in the end we did not."

So that is the Lancet ¹²: the foundation of the vaccine scare. No case was free of misreporting or alteration. Taken together, the NHS records cannot be reconciled with what was published, to such devastating effect, in the journal (table). Wakefield, however, denies wrongdoing, in any respect whatsoever.³⁵ He says he never claimed the children had regressive autism, nor that he said they were previously normal. He never misreported or changed any findings in the study, and never patented a vaccine for measles. None of the children were Barr's clients before referral to the hospital, and he never received huge payments from the lawyer. There were no conflicts of interest. He is the victim of a conspiracy. ^{36 37} He never linked autism with MMR.

"Mr Deer's implications of fraud against me are claims that a trained physician and researcher of good standing had suddenly decided he was going to fake data for his own enrichment," he said in a now abandoned complaint against me to the UK Press Complaint s Commission. " The o the r authors generated and 'prepared' all the data that was reported in the Lancet. I merely put their completed data in tables and narrative form for the purpose of submission for publication."

But, despite signing up to claim credit for a paper in the Lancet, his co-authors Walker- Smith and Murch did not even know which case was which. Walker-Smith said he had "trusted" Wakefield. "When I signed that paper, I signed with good intent," he told the GMC panel. Denying any wrongdoing, he argued that the published report was not even about MMR, but merely described a new "clinico-pathological entity". He said that the admissions to the Royal Free were "entirely related to gastroenterological illness" and how the children were sourced was "irrelevant" and "immaterial." His lawyers said that he was appealing against the panel's decision and on these grounds they had advised him not to respond to my questions.

The journal, meanwhile, took 12 years to retract the paper, by which time its mischief had been exported. As parents' confidence slowly returned in Britain, the scare took off around the world, unleashing fear, guilt, and infectious diseases—and fuelling suspicion of vaccines in general. In addition to measles outbreaks, other infections are resurgent, with Mr 11's home state of California last summer seeing 10 babies dead from whooping cough, in the worst outbreak since 1958.³⁸ Wakefield, nevertheless, now apparently self employed and professionally ruined, remains championed by a sad rump of disciples. "Dr Wakefield is a hero," is how one mother caught their mood in a recent Dateline NBC television investigation, featuring the story of the doctor and me. "I don't know where we would be without him."³⁹

Brian Deer journalist, London, UK

Funding: Brian Deer's investigation, which led to the General Medical Council inquiry, was funded by the Sunday Times of London and the Channel 4 television network. Reports by Deer in the BMJ were commissioned and paid for by the journal. No other funding was received, apart from legal costs paid to Deer by the Medical Protection Society on behalf of Andrew Wakefield.

Andrew Wakefield

Competing interests: The author has completed the unified competing interest form at www.icmje.org/coi_ disclosure.pdf (available on request from him) and declares no support from any organisation for the submitted work; no financial relationships with any organisation that might have an interest in the submitted work in the previous three years; BD's investigation led to the GMC proceedings referred to in this report, including the charges. He made many submissions of information but was not a party or witness in the case, nor involved in its conduct.

Learning without patients

A device that simulates injection of fluid in the spinal cord

How far can medical simulation replace clinical experience? Toby Reynolds and Ming-Li Kong report

Medicine has traditionally approached the problem of the learning curve by supervising trainees' first attempts at new tasks and otherwise relying on them to call for help when they feel overwhelmed. But a growing movement within medical education argues that a better approach is to practise new skills in a realistic simulated environment before they are needed in a critical situation. "The huge benefit of simulation is that it shifts the steep and dangerous part of the learning curve away from patients," says Ian Curran, consultant anaesthetist and clinical director of the Simulation Technology-enhanced Learning Initiative (STeLI), a workforce development project funded by the UK National Health Service's London Deanery.

"There always has to be a first time with a real patient so we must do all we can to ensure that these early encounters with real patients are as safe as possible." Simulation ranges from task trainer models that teach a particular skill in isolation to full immersion in a replicated environment with manikins that mimic the physiological responses of real patients and are able to develop, for example, laryngeal oedema, pupillary dilation, or cyanosis. Use of simulation is growing worldwide. A database maintained by the Bristol Medical Simulation Centre lists more than 1500 dedicated manikin simulation facilities.¹ In Israel, for example, internship doctors are required to attend a five day workshop simulating a variety of challenging scenarios. It has a simulation based exam for anaesthetists, and certification exams for paramedics and all advanced nursing specialties also include simulation. In the United States, anaesthetists who gained board certification after 2000 are now required to do a day of simulation training for recertification. And last year the UK government's chief medical officer recommended that simulation be integrated into British postgraduate training.²

Sleepy start

Simulation in medicine has its roots in anaesthesia. The first computer controlled manikin simulator, SimOne, was developed in the 1960s by an anaesthetist and an engineer. They subsequently published a trial showing its effectiveness in teaching anaesthetic trainees.³ However, SimOne was expensive and proved to be a little ahead of its time. Only one was built, and activity in the field slowed until the 1980s, when separate groups interested in improving teamwork and preventing anaesthetic errors again took up the idea, recalls Jeffrey Cooper, a biomedical engineer and professor of anaesthesia at Harvard Medical School.

Professor Cooper was involved in awarding funding for some of this early work, which resulted in the parallel development of two computer controlled realistic manikin simulators, both of which formed the basis for commercially produced models. Task trainer simulators are also becoming more sophisticated, with models produced for learning interventional cardiology, endoscopy, and laparoscopic surgery, among others.

Wider environment

Regulatory bodies and healthcare commissioners are starting to agree that using simulation, particularly full immersion techniques, is better for both training and patient safety. A World Health Organization patient safety guide for medical schools also made extensive reference to simulation.⁴ Realistic replication of clinical situations not only helps teach technical skills but can also give important insights into how individuals and teams behave and communicate, areas that have been repeatedly identified as common sources of clinical errors.

Simulators are widely used in aviation, and the chief medical officer's report notes how trainee pilots are able to use the technology to recreate difficult situations and how established pilots must also fly regular simulator flights. But one of the key elements in the aviation industry's remarkable reduction in air crashes in the second half of the 20th century was the introduction of mandatory training in teamwork and human behavioural factors.⁵

"Other performance critical industries such as aviation, energy, and the military have made great strides in improving quality and safety by adopting a systems based approach to human factors and crisis management," says Dr Curran. "Healthcare has much to learn from their insights." Roger Kneebone, reader in surgical education at London's Imperial College, says that there is an important distinction to be drawn between physical simulators and the broader concept of simulation, which tries to create a recognisable clinical environment in which trainees can learn.

"The discourse has been dominated by simulators, by machines, by kit, which has taken away sometimes from the bigger picture," he says. He notes that simulation has so far mostly evolved for specific job roles, such as surgery or anaesthesia. He believes it needs to balance developing specialty specific skills with teaching different professionals to work better together.

This, Dr Kneebone says, requires a level of realism and sophistication in the environment, not just a manikin. You need to be able to make people feel that they are really doing what is being simulated, he says. "In the surgeon's case that involves having organs and an operation that seem realistic, a situation that doesn't require a superhuman level of suspension of disbelief in order to get into it." Some simulation centres are complete replicas or real clinical environments. But Dr Kneebone notes that a fully simulated operating theatre may cost up to a million pounds. The high costs limit access and make it harder for training to match the realities of clinical work.

Dr Kneebone's work on simulation has included the development of a portable simulated operating theatre⁶ that does not try to replicate the real thing but instead includes those elements that trainees need to see, hear, or feel in order to engage with the simulation.

Efficient training

There is evidence that simulation works. For instance, doctors with simulation training performed better in managing both simulated respiratory arrest⁷ and, more importantly, actual cardiac arrest.⁸ So now one of the main questions is not whether simulation is a good idea but how to best integrate it into clinical training. Making training more efficient is a key challenge in the UK, where the European Working Time Directive has cut clinical hours and limited the scope for achieving competence through clinical experience alone.

"The more traditional experiential and perhaps less efficient methods of learning need to be reviewed," says Dr Curran. "It is clear that every training hour needs to pack its educational punch."

Amitai Ziv, founder and director of Israel's MSR simulation centre, has overseen the integration of simulation training into a variety of national courses and exams for many healthcare professions. Dr Ziv is a former military pilot and was shockedby how aviation training was much more structured and accountable than that in medicine. He sees a wider role for simulation in medicine, such as in selecting candidates for medical training, as already happens in two of Israel's medical schools.

"Our vision was not only to train on simulators but rather to push it to its ultimate application—mandatory courses, screening, licensing, and certification," he says.

"We want to make it part of the routine accountable training of health professionals on the vertical axis, from screening into medical school up to the heads of departments."

He adds that simulation brings a new way to approach training, not just a new technology, with courses concentrating on hands-on application rather than accumulation of knowledge in isolation from the environment in which it will be used. Professor Cooper also sees simulation techniques changing healthcare education more widely. He thinks that reduced access to clinical learning for nurses and allied health professions such as emergency medical technicians (EMT) will be a powerful driver moving simulation training forward.

"It is harder and harder for an EMT to get practise in an operating room intubating because the risk is greater, there are more and more insurance issues, but the more sophisticated the simulators get, the cheaper and faster it is for him or her to learn everything outside of working on a patient," he says.

"They can get good enough that the first time they do it on a patient they need much less supervised training," he adds. "I don't think there is any question that all of these forms of simulation will become deeply integrated into the process of training all healthcare practitioners."

Advocates agree that simulation training cannot entirely replace clinical experience. "I think simulation can only ever be an adjunct to clinical practice," says Dr Kneebone. One area he notes that is difficult to recreate is how people respond when real disasters happen. Another difficulty is the sheer complexity of the human body, particularly for simulating surgery. "There are clearly limitations that affect the simulation of human beings that you don't get in aircraft cockpits or other more restricted environments where you can control everything," he says.

"There is something about the complexity and the contingency of real life clinical practice that defies copying." "We do need to look critically and conceptually at what simulation can do and can't do," he adds. "As clinicians and educators we need to decide what it is that is most important for people to learn and use simulation to construct environments that allow people to learn those things."

Nonetheless, it looks as if simulation can reduce the amount of time needed to be spent under supervision and is set to play an important part in healthcare education in the future, Professor Cooper says.

"In the medical education world it is starting to be felt that simulation is a tool for developing better educators, not just for safety, but to educate healthcare providers better and faster . . . and it is clearly doing that," he says. "You talk to an anaesthesia resident and ask them if they would take care of a patient without a pulse oximeter. That is the way we will think about simulation in the not too distant future," he adds.

Toby Reynolds FY2 doctor, Royal London Hospital, London, UK toby.reynolds@gmail.com

Ming-Li Kong specialist registrar in anaesthesia and intensive care medicine, Royal London Hospital, London, UK Competing interests: All authors have completed the unified competing interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from any organisation for the submitted work; M-LK was a fellow in medical education funded by the London Deanery from 2008-9; and no other relationships or activities that could appear to have influenced the submitted work. Provenance and peer review: Commissioned; not externally peer reviewed.

The Lancet's Two Days to Bury Bad News

Mon, 04 Apr 2011 22:16:00 GMT

The Lancet's Two Days to Bury Bad News

In the third part of a special BMJ series, Brian Deer reveals what happened when he reported misconduct in Andrew Wakefield's MMR research to the medical journal that published it

Preparing to give evidence in London to a UK General Medical Council fitness to practise panel, Richard Horton, editor of the Lancet, nodded in turn to three accused doctors, seated among their lawyers to his left. First, Simon Murch, almost close enough to touch. Next, John Walker-Smith, more distant. Finally, Andrew Wakefield, at the far end of the hearing room. Each smiled thinly and nodded back.

The four had last met together three and a half years before, at the Lancet's offices, nearly two miles north. There they had begun the journey that now brought their reunion in this, the longest medical disciplinary inquiry ever. Running for 217 days, between July 2007 and May 2010, it would probe the research and a paper that launched the MMR vaccine scare, and would lead to Wakefield and Walker-Smith being struck off. ^{1 2}

Their previous encounter was in 2004, on the afternoon of Wednesday 18 February. They had gathered in Horton's office to deal with an approach from me concerning a four month Sunday Times investigation. For five hours that morning, I had briefed the Lancet's senior staff about a now notorious 1998 paper in their journal.³ It reported on 12 children seen at the Royal Free hospital, north London, and claimed to have discovered a possible "new syndrome" involving regressive autism, inflammatory bowel disease, and MMR.

The Royal Free Hospital, north London

Mostly I had stood, occasionally pulling documents, as Horton, with five editors, took notes. I told them that the paper's first author, Wakefield, was retained by a lawyer and was funded to help sue vaccine manufacturers. Admissions criteria for the study had been manipulated and ethical safeguards flouted. A group of developmentally challenged children of parents who blamed MMR had been brought to the hospital to create a case against the vaccine. I said I thought that the study was "rigged."

At one point, I drew a diagram of a cluster of complaints, which had been used to link autism with the vaccine.⁴ "In the paper, the parents of eight of 12 children apparently said words to the effect of 'It was the MMR, doctor,'" I told the meeting, convened around the journal's boardroom table. "But when the series was extended to 30 children, only the parents of three more made that claim. So, why would the allegations bunch together at the start?"

I had assumed that when I finished Horton would say that an investigation was needed to untangle these complex matters. There were at least three strands: possible research fraud, unethical treatment of vulnerable children, and Wakefield's conflict of interest through the lawyer. But within 48 hours, and working with the paper's three senior authors, the journal was to publish a 5000 word avalanche of denials, in statements, unretracted to this day.^5–9

Years later, in the witness chair at the GMC hearing, Horton recalled that morning. "These were three sets of allegations which went to the heart of the credibility of the paper, and were clear allegations of research misconduct," he told Sally Smith, Queen's Counsel for the doctors' regulator, on 7 August 2007. "We contacted Dr Wakefield, Professor Walker-Smith and Dr Murch, and asked the three of them to come to the Lancet's offices so that we could discuss these allegations."

The General Medical Council, London

During the 2004 meetings—first with me, and then with the authors—Horton was caught in a bind. Facing public alarm over MMR and professional scepticism towards the research, for years he had championed his former colleague. "I do not regret publishing the original Wakefield paper," he said in a 2003 book, at the height of the UK scare. "Progress in medicine depends on the free expression of new ideas. In science, it was only this commitment to free expression that shook free the tight grip of religion on the way human beings understood their world." ¹⁰

Raising Galileo's ghost, he could not have then known how much of Wakefield's research was free expression. As I revealed in the BMJ two weeks ago, in not one case in the series of 12 children could the now retracted¹¹ paper be reconciled with National Health Service records.¹² And last week, I reported on Wakefield's secret business scheme, intended to harvest millions from the scare.¹³

Horton, moreover, was a crusader for integrity and had pressed for tough action against research fraud. As a force behind both the International Committee of Medical Journal Editors and the Committee on Publication Ethics, he had campaigned with Richard Smith, then the BMJ's editor, for a statutory watchdog on research misconduct. Despite their efforts, however, nothing had come of this, and Horton would now adopt a different approach.

Impropriety denied

"In this particular case," he told the GMC tribunal of three doctors and two lay members, seated to his right at the hearing, "we went to the vice-dean of the Royal Free, laid out the nature of the problem, and asked him to investigate and come back to us, as best he could, with his own judgment of the veracity or not of the allegations. In addition to that, we would look at the documentation as best we could and try and form our view as to whether those allegations were true."

March 2010, after the panel's findings¹⁴ fully endorsed what I had told him. "We asked the institution where the work was conducted—the Royal Free hospital—to complete an investigation," he submitted in a written statement to the journalists' magazine Press Gazette. "They did, and they cleared Wakefield of wrongdoing." ¹⁵

Horton was caught in a bind. Facing public alarm over MMR and professional scepticism towards the research, for years he had championed his former colleague

But documents, emails, and replies obtained under the Freedom of Information Act reveal no formal investigation. What emerges is merely a scramble to discredit my claims during the 48 hours after I disclosed the information. They show the journal's editor, the paper's senior authors, and the Royal Free medical school, frantically mobilising against me. Were it not for the GMC case, which cost a rumoured £6m (€7m; $9m), the fraud by which Wakefield concocted fear of MMR would forever have been denied and covered up.

The denial began as soon as I left the Lancet on that Wednesday in February 2004. Seated around a circular table in Horton's private office, the four doctors shared their thoughts and devised a strategy. Wakefield admitted only being retained for a lawsuit and denied receiving money himself. His legal role, he said, was to perform "quite separate" viral research, not the clinical study that appeared in the journal.

His claims were false. He was personally paid more than £435 000 through the lawyer, according to accounts I later obtained.¹⁶ And a corresponding "clinical and scientific study,"¹⁷ with the same protocol and principal authors as the paper, had been submitted to the UK Legal Aid Board for funding before the first of the 12 children was admitted. He had hired himself out explicitly to make a case against the vaccine, as a secret grant application revealed.

"The objective," he and his retaining solicitor had written in the application to the legal board, "is to seek evidence which will be acceptable in a court of law of the causative connection between either the mumps, measles and rubella vaccine or the measles/rubella vaccine and certain conditions which have been reported with considerable frequency by families of children who are seeking compensation."¹⁸

At their meeting with Horton, the paediatric gastroenterologists Walker-Smith and Murch also denied impropriety. I had claimed that some children were solicited, rather than spontaneously referred. This was denied. I said there was no ethical approval. Denied. In short, there was nothing wrong, apart from Wakefield's conflict of interest. They agreed to issue statements through the journal to make things clear.

"It was a difficult but useful meeting today," Walker-Smith wrote that evening as he minuted their discussion, in one of a flurry of emails among the doctors. "I have been asked to write something about referral for our combined statement to the Lancet . . . Simon I believe you will answer in detail the charge of deception in relation to the Ethical Committee, the most serious charge of all and indeed for us all. Andy you will deal with the legal issues."

At 13.16 Thursday, I emailed my agreement, and Harris bounced this forward to the journal. "Please see below for authorisation to send me Brian's papers on the research ethics," he wrote to Horton, 13 minutes later, planning to rely on the same material as the editor. "He wants me to give him an opinion and I explained I needed the papers. Hope they can be faxed forthwith under authority of one of your colleagues as you are out."

Horton, at the time, was at the Royal Free with Walker-Smith, Murch, and Humphrey Hodgson, the vice-dean. In Hodgson's basement office they "reviewed the allegations," Horton told the GMC panel, and "decided on a course of action." Then "we all went up to the department of paediatric gastroenterology," where the doctors "investigated" the children's records. He explained that Walker-Smith went to look at a biopsy book "to establish questions about referral patterns." Then "a view was formed about the evidence in support of, or not, the allegations."

In short, the accused were investigating themselves—an investigation that Horton would say "cleared Wakefield."¹⁵

"I think you said Professor Walker-Smith looked back at the biopsy book," Sally Smith asked him.

"He looked back at the biopsy book, as I recall," replied Horton, editor of the journal since 1995. "Dr Murch and Professor Walker-Smith together looked at the case notes. I will be honest and say I cannot remember whether Dr Wakefield did or did not look at the case notes himself."

not invited on to the Royal Free's campus, having been constructively dismissed from the school two years previously. But only he knew all the names of the paper's 12 anonymised children, and from home he faxed a list for the others to use.

No doctor interviewed

Horton paused to gather his thoughts. "It is customary for the institution to lead an investigation and to gather the data which will inevitably involve those who took part in the investigation," he replied. "It is then the responsibility of the institution to make sure that there is some kind of separation between its interpretation of those findings and those who are involved in the investigation who are being in some sense accused of a set of allegations, and once that interpretation by the institution has taken place and has been conveyed to whoever has brought the allegations to them then we can go forward. So there certainly should be some separation, which is why in the first instance I wanted to get the reaction from Dr Wakefield, Professor Walker-Smith, and Dr Murch, but after that my duty was to go to the head of the institution, the vice-dean, in this case Professor Hodgson."

But there had been no separation and no independent inquiry—as both the hospital and medical school later confirmed. No doctor was interviewed, and no documents were generated. There was only the "informal process" just described. This, I was told, involved "discussion with clinicians," their "review of the relevant clinical papers," and study of an ethics committee file. "The written outcome of this process was the statements made by clinicians concerned and the Medical School published in the Lancet."¹⁹

The shallowness of this process was exposed at the GMC hearing, where the panel read the children's hospital records. The pages were thick with evidence of orchestrated referrals and indications that the prime purpose was research. One child's notes contained a legal aid letter, and the ethics committee file was a scorcher.

Evan Harris (left) and Brian Deer outside the GMC

Even the patients' referral circumstances might have alerted a dispassionate investigator to the need to dig deeper into the cases. The panel would notice that child 2 and child 9 in the paper were solicited by Walker-Smith, at Wakefield's behest. Children 1, 5, 9, and 10, meanwhile, were referred to the Royal Free gastroenterologists without mention of any history of bowel problems. And child 4 and child 8 were referred directly to Wakefield, whose contract forbade clinical work.

"Thank you for asking to see this young boy," child 3's referral letter began.

"This 7¾ year autistic child's parents have been in contact with Dr Wakefield and have asked me to refer him," said child 5's.

"[Child 8's] mother has been to see me and said you need a referral letter from me in order to accept [child 8] into your investigation programme."

Meanwhile, ethics documents, reviewed by Hodgson, did not square with what was published in the journal. The hospital's file referred to a study of 25 children with disintegrative disorder, an exceptionally rare and serious degenerative brain condition.²⁰ This affects school age children, and Walker-Smith had told the ethics committee that the prognosis for such patients was "hopeless."²¹

But none of the 12 children was diagnosed with this disorder: they were a heterogeneous group, mostly reported with autism. And one patient—child 7—was referred to the hospital with no developmental diagnosis.

The ethics file, which I was shown, also included correspondence generated after the Lancet publication. David Hull, a former president of the British Paediatric Association, had noted the extraordinary battery of tests endured by the children. This included ileocolonoscopy, magnetic resonance imaging brain scans, electroencephalography and evoked potentials, lumbar punctures, and barium meal and follow throughs. The paper said that these "investigations were approved" by the ethics committee, which he thought might clash with codes requiring tests on children to be clinically indicated.²²

In order to respond to Hull, the committee chair, Michael Pegg, had been consulted. He advised that the paper was wrong. "In his letter Professor Hull states: 'I see that the investigations were approved by the Ethical Practices Committee,'" wrote Pegg in a memo on the file studied by Hodgson. "This is, of course, incorrect. We did not approve the investigations. We approved data collection from clinically indicated investigations. It is not, at present, the role of an ethics committee to question clinicians' judgment as to what are and what are not clinically indicated investigations."

Nevertheless, to deal with me, the doctors—now five—pressed on with preparing their statements. Wakefield, Walker-Smith, and Murch would cover their allocated topics, while Hodgson would respond solely on the ethics. Horton would collate and form judgments on the material and publish their explanations through his journal. They would be issued to the media on that Friday afternoon. They were to deny what the GMC would later prove.

"Before I go on to the statements by the doctors, which were published in the Lancet, and by the Royal Free," Sally Smith said to Horton at the hearing, "can I ask you, have there been other occasions when you have had to investigate allegations made about a research paper and its propriety, in general terms?"

"Frequently."

"Is it customary to discuss and take the word of those against whom the allegations are made?"

"It is."

Back in February 2004, the email traffic documented how that custom panned out. At 10.27 on the Friday morning, Wakefield issued "an updated version of my response." He circulated this to his publicist Hadden, plus Walker-Smith, Murch, Hodgson, and Richard Horton. "Richard, you have an earlier version," he commented in the text. "This cuts out repetition to the last allegation and puts the argument more succinctly."

At 12.24, Horton faxed Hodgson six pages of "draft statement docs." And at 14.12 he sent the vice-dean another fax, with 13 pages of statements. All would be read aloud to the GMC panel, with many key paragraphs repeated.

"On February 18 2004, serious allegations of research misconduct concerning an article by Dr Andrew Wakefield and colleagues published in the Lancet in February, 1998, were brought to the attention of senior editorial staff," Horton's said. "The . . . allegations of alleged research misconduct have been answered by clarifications provided by the senior authors of this work . . . We do not judge that there was any intention to conceal information or deceive editors, reviewers, or readers about the ethical justification for this work and the nature of patient referral."

Andrew Wakefield and his wife Carmel

Hodgson's said: "We are entirely satisfied that the investigations performed on the children reported in the Lancet paper had been subjected to appropriate and rigorous ethical scrutiny."

Media firestorm

Listening to these statements, years after they were issued, brought back my memories of those days. I had approached the Lancet on the instructions of John Witherow, editor of the Sunday Times. He had told his executives that I should speak to "god" on the subject matter, to be sure we were getting it right. My first attempt was with Richard Smith, the former BMJ editor. But he was on holiday. So I telephoned Horton.

I had discussed my findings at the Wednesday meeting in confidence. I expected guidance and at least a quote. I thought Horton would say that an investigation was required, and I assumed this might take some time. My inquiries at that stage had consumed four months of research, accumulated key documents in five lever arch files, and had taken from 9 am to 2 pm to present.

But Horton would say nothing. He left the room to meet the authors and released the statements without speaking to me again. He released them, moreover, first to everyone but me. Even the vice-dean formed a view of why this was.

"The Lancet editor's actions have been to regard the allegations . . . as allegations of research misconduct, and following the medical editorial code has carried out an investigation according to agreed guidelines, and intends to publish the result of the investigation pre-emptively," Hodgson told his UCL superiors in a memo that Friday. "No doubt one—but I believe only one—motive is to safeguard the Lancet's reputation by getting the riposte in first, and 'spoiling' the story."

But if this was Horton's aim, it proved a mistake. His actions sparked a media firestorm. Although denying all of the most serious of my findings (now proved), he conceded that Wakefield had a conflict of interest—and that weekend was what journalists call "slow."

The BBC was on the story within half an hour of the statements' release. Independent Television News called Harris. And all of Fleet Street knew the thrust of an impending splash in the Sunday Times, the UK's market leading Sunday broadsheet.

The furore blazed from Friday until Wednesday. The triple vaccine was on the agenda once again. This time, however, it was not Wakefield's campaign, which for years had exploited parents' fears. "Misconduct inquiry for doctor in MMR scare," shouted the Independent on Sunday's front page. "GMC to investigate 'conflict of interest.'" My paper's contribution was a front page and inside spread,The BBC was on the story within half an hour of the statements' release. Independent Television News called Harris. And all of Fleet Street knew the thrust of an impending splash in the Sunday Times, the UK's market leading Sunday broadsheet. The furore blazed from Friday until Wednesday. The triple vaccine was on the agenda once again. This time, however, it was not Wakefield's campaign, which for years had exploited parents' fears. "Misconduct inquiry for doctor in MMR scare," shouted the Independent on Sunday's front page. "GMC to investigate 'conflict of interest.'" My paper's contribution was a front page and inside spread,

"Revealed: MMR research scandal."²³ And, with the Daily Mail backing Wakefield, public uproar raged as the implications of that scandal were debated. The secretary of state for health and the chief medical officer issued statements. Tony Blair, the prime minister, told breakfast television: "I hope— now that people see that the situation is somewhat different from what they were led to believe— they will have the triple jab because it is important to do it."²⁴

Wakefield attempted to brazen it out, issuing a further statement to media. "It has been proposed that my role in this matter should be investigated by the General Medical Council," he said on the Monday. "I not only welcome this, I insist on it, and I will be making contact with the GMC personally in the forthcoming week."

The same day, a caseworker for the regulator called me from Manchester. Did I have any further information? And two days later, at 12.16 Wednesday, I emailed him the conclusions of my research. I summarised what I had said to the Lancet's senior staff and pledged my cooperation, in the public interest.

Over the following weeks and months, email traffic trickled on, especially at the Royal Free's campus. The former dean, Arie Zuckerman, who had known about the lawyer, said he was being advised by the Medical Defence Union. Walker- Smith, whom the GMC was to clear of dishonesty, said he had learnt of Wakefield's "financial details" from me. A press officer who in 1997 had proposed a press conference for the paper, issued statements for the hospital and school, brushing me off.

"I suppose we could say if you have any concerns about Brian Deer's conduct you could consult the Press Complaints Commission," she suggested to managers fielding grievances from Wakefield supporters about my access to the ethics committee file.

There was also a stream of internal documents, aimed at dealing with me, not the doctors. "Briefing note re Brian Deer's e-mail 12th March 2004—limited to issues of substance," one report was headed. "Line 8 . . . Line 16-19 . . . Line 20 . . . Line 22 . . . Line 28 . . . Line 30-35 . . . Lines 30-36 . . . With respect to the specific questions that Brian Deer now asks, the issues are (a) . . . (b) . . . (c) . . . (d) . . . (e) . . ."

But there was no change of stance over the substance of the scandal, either at the institution or at the journal. Although it would be another eight months before the GMC approached the accused, three years before a formal "notice of inquiry" was issued, and newspapers dismissed the prospect of any charges,^{25 26} the key players remained frozen in the positions they had agreed in February 2004.

In the end, the mammoth hearing got to the bottom of the matters that I had raised six years before. In a 143 page raft of findings against the three authors, the panel, chaired by general practitioner Surendra Kumar, ruled the research to have been unethical and falsely reported in the paper, which was retracted by the Lancet four days later. Murch, who during the hearing repudiated his 2004 statement, was found to have shown "insight" and was not struck off. But Wakefield was found guilty on four counts of dishonesty, and Walker- Smith was found to have ordered invasive procedures on children without clinical grounds or ethical approval.

In his later statement to Press Gazette, Horton (who did not respond to our request for comment) said he welcomed the outcome. "We are very happy with the result," he said. "Despite much past debate, this is the first time an official, independent investigation by a recognised regulatory body has proven these allegations. They are welcome because they gave us full authority to retract Dr Wakefield's paper."¹⁵

But this was not the editor's mood before the hearing began. Electronic chatter, once again, tells the tale. "The role of Brian Deer mystifies me," he sent from his Blackberry to the mother of two children in the paper, two and a half years before he took the witness chair. "My own view is that the GMC is no place to continue this debate. But the process has started and it will be impossible to stop."

Brian Deer journalist, London, UK briandeer.com

Competing interests: The author has completed the unified competing interest form at www.icmje.org/ coi_disclosure.pdf (available on request from him) and declares no financial relationships with any organisation that might have an interest in the submitted work; BD's investigation led to the GMC proceedings referred to in this report, including the charges. He made many submissions of information, but was not a party or witness in the case, nor involved in its conduct.

Provenance and peer review: Commissioned; not externally peer reviewed.

Why Southern Sudan needs your help

BMJ readers have so far raised £5318 for Save the Children health projects. You still have just over a week to donate to the appeal. The money raised is to be invested in projects in countries such as Sudan, which has some of the world's worst health indicators. Peter Moszynski, who has just returned from the region, reports

If (or more likely, when) Southern Sudan becomes the world's newest country, depending on the results of the independence referendum, it will have some of the world's worst health indicators. According to Save the Children, one of the main agencies working to rebuild the region's shattered health services, one in seven children die before their 5th birthday and less than 2% complete primary school.¹

Anthony Lodiong, Save the Children's communications officer in Southern Sudan, says the region was "the scene of Africa's longest running civil war, which took the lives of an estimated two million people and forced four million more from their homes. The wreckage of war has been exacerbated by natural disasters, civil and tribal conflicts, and political instability." The peace agreement has encouraged some two million displaced people to return, "yet they find few resources in a region that has had no development for nearly a half century."

Despite the government's efforts to strengthen the health system, a lack of resources and insecurity impede recovery efforts, and the ministry of health continues to struggle to meet basic health needs. As a result, 85% of health facilities are run by aid agencies.

Roughly the size of France, the region has only 50 km of tarmac roads, making access to remote rural communities impossible in the rainy season. Only one in four people can get to a functioning health facility—a proportion that has not increased since the signing of the Comprehensive Peace Agreement six years ago.

Southern Sudan has some of the world's highest maternal and infant mortality rates; one in seven women die from pregnancy related complications, and only 10% of births are attended by a skilled health professional. Early marriage and pregnancy are common, "making it more likely for a teenage girl to die in childbirth than to finish primary education."¹

These facilities treat children (predominantly with diarrhoea, malaria, and respiratory infections) and provide women with prenatal care, labour, and delivery services as well as postnatal care. They also offer immunisations and distribute insecticide treated bed nets and vitamin A. Other health projects create and rehabilitate water supplies and educate families on hygiene and sanitation.

Mr Lodiong points out that delivering care is extremely difficult given the poor infrastructure, widespread insecurity, and large geographical area.

One of the most badly affected areas was Akobo county, which last year saw malnutrition rates three times above the emergency threshold.2 As a result of Save the Children's therapeutic feeding programme and the World Food Programme emergency food distributions, global acute malnutrition went down from 47% in February to 17.2% in November.

Save the Children's representative in Akobo, Jamal Seid, said: "This is still a worrying level but a tremendous improvement on before, and demonstrates the need to continue therapeutic infant feeding, and also for further general food distributions, which have recently been halted due to budgetary constraints."

Peter Moszynski freelance journalist, Juba and London globewisecom@hotmail.com

Competing interests: None declared.

Provenance and peer review: Commissioned; not externally peer reviewed.

References are in the version on bmj.com Cite this as: BMJ 2011;342:d176

2011 - 2012 Influenza Vaccine Recommendations

Tue, 24 May 2011 20:38:00 GMT

February 2011

The World Health Organization (WHO) convenes technical consultations1 in February and September each year to recommend viruses for inclusion in influenza vaccines2 for the northern and southern hemispheres, respectively. This recommendation relates to the influenza vaccines for the forthcoming influenza season in the northern hemisphere (2011-2012). A recommendation will be made in September 2011 relating to vaccines that will be used for the influenza season in the southern hemisphere (2012). For countries in equatorial regions, epidemiological considerations influence which recommendation (February or September) individual national and regional authorities consider more appropriate.

Influenza activity, September 2010 – January 2011

Between September 2010 and January 2011, influenza activity was reported in Africa, the Americas, Asia, Europe and Oceania. Pandemic 2009 influenza A(H1N1) [A(H1N1)pdm09]3 viruses predominated in Asia and Europe while influenza A(H3N2) viruses predominated in the Americas. Influenza B viruses co-circulated in many countries in the northern hemisphere and was the predominant virus in some countries. The former seasonal influenza A(H1N1) viruses were detected sporadically in very few countries.

In the northern hemisphere, widespread outbreaks of A(H1N1)pdm09 were reported in most European countries and the United States of America as well as some countries in Asia and north Africa. In Europe, A(H1N1)pdm09 activity occurred early in the United Kingdom of Great Britain and Northern Ireland (United Kingdom) and western Europe where it reached peaks or declined by January, whereas A(H1N1)pdm09 activity continues to increase in some countries in central and south eastern Europe. In Asia, regional and widespread A(H1N1)pdm09 influenza activity was reported during this period. In Canada and the United States of America activity due to A(H1N1)pdm09 was low but increased in January.

Influenza A(H3N2) activity resulted in regional outbreaks in the Americas. Activity increased in Canada and the United States of America in December and became widespread in January. In Cambodia and China Hong Kong Special Administrative Region (Hong Kong SAR) regional influenza A(H3N2) activity was reported during September and October while localized and sporadic activity was reported in some countries in north Africa and Europe.

Influenza B activity increased in Canada, the United States of America and many European countries in December and January. Influenza B was the predominant virus in Norway, the Russian Federation and Ukraine. Regional or widespread outbreaks were reported by Algeria and Israel in December and January. Localized and sporadic activity was also reported by several African countries.

The former seasonal influenza A(H1N1) virus was very rarely detected (reported by China, Malaysia, the Russian Federation, Tunisia and the United States of America).

In the southern hemisphere, influenza activity in general was low during this period with the exception of some South American countries where widespread activity was reported. A(H1N1)pdm09 was reported at low levels in a few countries in southern Africa, South America and Oceania. Influenza A(H3N2) was the predominant virus in many countries in South America with widespread outbreaks occurring in September in Chile. Localized and sporadic activity was also reported in southern Africa, South America and Oceania.

In tropical areas, many countries experienced outbreaks of varying intensity of influenza A(H1N1)pdm09, A(H3N2) and B viruses.

Sporadic human cases of avian influenza A(H5N1) were reported from Cambodia, China Hong Kong SAR, Egypt and Indonesia. No human cases of influenza A(H9N2) were reported during the period of September 2010 to January 2011.

The extent and type of influenza activity worldwide are summarized in Table 1.

Zoonotic influenza infections caused by A(H5N1), A(H9N2), and swine A(H1N1) and swine A(H3N2) viruses

From 27 September 2010 to 9 February 2011, 14 confirmed human cases of A(H5N1), 6 of which were fatal, were reported from Cambodia, China Hong Kong SAR, Egypt and Indonesia, where highly pathogenic avian influenza A(H5N1) is present in poultry or wild birds. Since December 2003, a total of 520 cases with 307 deaths have been confirmed in 15 countries4. To date there has been no evidence of sustained human-to-human transmission.

No human cases of influenza A(H9N2) were reported during the period September 2010 to January 2011.

Since September 2010, a total of 8 zoonotic infections caused by swine A(H1N1) and swine A(H3N2) viruses were detected in China (1), Switzerland (1) and the United States of America (6).

Antigenic and genetic characteristics of recent virus isolates Influenza A(H1N1) viruses

Between September 2010 and January 2011, the vast majority of A(H1N1) viruses detected worldwide were A(H1N1)pdm09. Haemagglutination inhibition (HI) tests using postinfection ferret antisera indicated that A(H1N1)pdm09 viruses remained antigenically homogeneous and closely related to the vaccine virus A/California/7/2009. Sequence analysis of the HA genes of A(H1N1)pdm09 viruses indicated that the viruses fell into three genetic subgroups which were antigenically indistinguishable. A small number of viruses showed reductions in reactivity with some ferret antisera in HI assays.

Only six former seasonal A(H1N1) viruses were detected: in China, Malaysia, the Russian Federation, Tunisia and the United States of America. Of those tested, most were antigenically and genetically closely related to A/Brisbane/59/2007 and belonged to clade 2B.

Influenza A(H3N2) viruses

The majority of A(H3N2) viruses collected from September 2010 to January 2011 were antigenically closely related to A/Perth/16/2009, the vaccine virus for the 2010-2011 northern hemisphere and 2011 southern hemisphere seasons. Antigenic characteristics were assessed with panels of postinfection ferret antisera in HI and virus neutralization assays. The HA genes of recent viruses fell into two phylogenetic clades represented by A/Perth/16/2009 and A/Victoria/208/2009, with the majority falling within the A/Victoria/208/2009 clade. Phylogenetic subgroups within both clades have emerged but viruses within these subgroups were antigenically similar to A/Perth/16/2009.

Influenza B viruses

Influenza B viruses of both the B/Victoria/2/87 and the B/Yamagata/16/88 lineages circulated with B/Victoria/2/87 lineage viruses continuing to predominate globally. However, in China, B/Yamagata/16/88 lineage viruses predominated from September 2010 to January 2011 and have continued to co-circulate with B/Victoria/2/87 lineage viruses at a low level.

In HI tests with postinfection ferret antisera, the majority of the B/Victoria/2/87 lineage viruses were antigenically closely related to the vaccine virus B/Brisbane/60/2008. A small number of viruses from several countries were antigenically and genetically distinguishable from B/Brisbane/60/2008-like viruses; most of them belonged to the subgroup represented by B/Singapore/616/2008 and B/Philippines/1617/2010. Most recent B/Yamagata/16/88 lineage viruses were antigenically and genetically distinguishable from the previous vaccine virus B/Florida/4/2006 and were more closely related to B/Bangladesh/3333/2007, B/Hubei-Wujiagang/158/2009 and B/Wisconsin/1/2010.

Resistance to influenza antiviral drugs Neuraminidase inhibitors

The vast majority of A(H1N1)pdm09 viruses were sensitive to oseltamivir. Of the small number of oseltamivir-resistant A(H1N1)pdm09 viruses detected, most were linked to the use of this drug for prophylaxis or treatment. However, in some countries e.g. Japan and United Kingdom, there were a few cases with no known exposure to oseltamivir. In all cases, resistance was due to a histidine to tyrosine substitution at amino acid 275 (H275Y) in the neuraminidase. There were no reports of oseltamivir-resistant A(H3N2) or B viruses. No zanamivir-resistant viruses were detected. Updates are available on the WHO website.

M2 inhibitors

All A(H1N1)pdm09 and A(H3N2) viruses tested were resistant to the M2 inhibitors, amantadine and rimantadine. Resistance to these antiviral drugs was associated with a serine to asparagine substitution at amino acid 31 (S31N) of the M2 protein.

Studies with inactivated influenza virus vaccines

HI assays were used to measure the presence of antibodies to the HA of recent virus isolates in 12 panels of sera from children, adults and elderly adults who had received seasonal trivalent inactivated vaccines. The trivalent vaccines contained the antigens of A/California/7/2009 (H1N1)-like, A/Perth/16/2009 (H3N2)-like and B/Brisbane/60/2008 viruses.

Vaccines containing A/California/7/2009-like antigens stimulated anti-HA antibodies of similar geometric mean HI titres to the vaccine virus and recent A(H1N1)pdm09 viruses.

Vaccines containing influenza A/Perth/16/2009-like antigens stimulated anti-HA antibodies of similar geometric mean HI titres to the vaccine virus and the majority of representative recent A(H3N2) viruses. Similar results were obtained in micro-neutralization tests using a subset of sera.

Vaccines containing influenza B/Brisbane/60/2008 antigens stimulated anti-HA antibodies of similar geometric mean HI titres to the vaccine virus and recent B/Victoria/2/87 lineage viruses. Geometric mean HI titres were lower to recent B/Yamagata/16/88 lineage viruses than to the most recent B/Victoria/2/87 lineage vaccine virus (average reductions: adults, 44%; elderly adults, 45%; children, 75%).

Recommended composition of influenza virus vaccines for use in the 2011-2012 influenza season

A(H1N1)pdm09 viruses co-circulated in varying proportions with A(H3N2) and B viruses during the period of September 2010 to January 2011. A(H1N1)pdm09 viruses were antigenically and genetically similar to A/California/7/2009. Vaccines containing A/California/7/2009 antigens stimulated anti-HA antibodies of similar titres against the vaccine virus and recent A(H1N1)pdm09 viruses.

Very few former seasonal influenza A(H1N1) viruses were reported. Most of those analysed were antigenically and genetically similar to the previous vaccine virus A/Brisbane/59/2007.

Influenza A(H3N2) viruses were detected in many parts of the world with widespread activity reported in several countries. The majority of recent viruses were antigenically and genetically similar to the vaccine virus A/Perth/16/2009. Vaccines containing A/Perth/16/2009-like antigens stimulated anti-HA antibodies of similar titres against the vaccine virus and recently circulating A(H3N2) viruses.

Influenza B activity was reported in many countries. B/Victoria/2/87 lineage viruses predominated in many parts of the world but B/Yamagata/16/88 lineage viruses predominated in China. The majority of recent B/Victoria/2/87 lineage viruses were antigenically and genetically closely related to B/Brisbane/60/2008. Most recently isolated B/Yamagata/16/88 lineage viruses were antigenically distinguishable from the previous vaccine virus B/Florida/4/2006 and were more closely related to B/Bangladesh/3333/2007, B/Hubei-Wujiagang/158/2009 and B/Wisconsin/1/2010 viruses. Current vaccines containing B/Brisbane/60/2008 antigens stimulated anti-HA antibodies that had similar titres against the vaccine viruses and recent viruses of the B/Victoria/2/87 lineage; however, titres were lower to recent viruses of the B/Yamagata/16/88 lineage.

It is expected that A(H1N1)pdm09, A(H3N2) and B viruses will co-circulate in the 2011-2012 northern hemisphere season.

It is recommended that the following viruses be used for influenza vaccines in the 2011-2012 influenza season (northern hemisphere):

an A/California/7/2009 (H1N1)-like virus;
an A/Perth/16/2009 (H3N2)-like virus;
a B/Brisbane/60/2008-like virus.

Candidate influenza vaccine viruses that are available or under development and reagents for vaccine standardization can be found on WHO website6. The website includes information of candidate vaccine viruses for the above recommendation. In addition, candidate vaccine viruses for the B/Yamagata/16/88 lineage and A(H5N1) viruses are also listed on the same website.

As in previous years, national or regional control authorities approve the composition and formulation of vaccines used in each country. National public health authorities are responsible for making recommendations regarding the use of the vaccine. WHO has published recommendations on the prevention of influenza7.

Candidate vaccine viruses (including reassortants) and reagents for use in the laboratory standardization of inactivated vaccine may be obtained from: Immunobiology, Office of Laboratory and Scientific Services, Monitoring and Compliance Group, Therapeutic Goods Administration, P.O. Box 100, Woden ACT, 2606 Australia (fax: +61 2 6232 8564, email: influenza.standards@tga.gov.au; web site: http://www.tga.gov.au); Division of Virology, National Institute for Biological Standards and Control, Health Protection Agency, Blanche Lane, South Mimms, Potters Bar, Hertfordshire, EN6 3QG UK (fax: +44 1707 641050, e-mail: enquiries@nibsc.hpa.org.uk, web site: http://www.nibsc.ac.uk/spotlight/influenza_resource_centre/reagents.aspx); or Division of Product Quality, Center for Biologics Evaluation and Research, Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 20892, United States (fax: +1 301 480 9748). Center for Influenza Virus Research, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashi-Murayama, Tokyo 208-0011, Japan (fax: +81 42 561 6156).

Requests for reference viruses for antigenic analysis should be addressed to the WHO Collaborating Centre for Reference and Research on Influenza, VIDRL, 10 Wreckyn Street, North Melbourne, Victoria 3051, Australia (fax: +61 3 9342 3939, web site: http://www.influenzacentre.org); the WHO Collaborating Centre for Reference and Research on Influenza, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashi-Murayama, Tokyo 208-0011, Japan (fax: +81 42 561 6149 or +81 42 565 2498, web site: http://www.nih.go.jp/niid/index.html); the WHO Collaborating Center for Surveillance, Epidemiology and Control of Influenza, Centers for Disease Control and Prevention, 1600 Clifton Road, Mail Stop G16, Atlanta, GA 30333, United States (fax: +1 404 639 0080, web site: http://www.cdc.gov/flu/); the WHO Collaborating Centre for Reference and Research on Influenza, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK (fax: +44 208 906 4477, web site: http://www.nimr.mrc.ac.uk/wic/) or the WHO Collaborating Center for Reference and Research on Influenza, National Institute for Viral Disease Control and Prevention, China CDC, 155 Changbai Road, Changping District, 102206, Beijing, P.R. China. (tel: +8610 58900851, fax: +8610 58900851, email: whocc-china@cnic.org, website: http://www.cnic.org.cn/eng/ )

Influenza surveillance information is updated on the WHO web site8.