Friday, June 25, 2010

Tics, Tic Disorders, and TS

TS is a neurobiological condition characterized by vocal and motor tics that change over time and wax and wane in severity. TS is part of a spectrum of tic disorders, including transient tic disorder and chronic tic disorder ( Table 1 ).
Diagnosis is based on history and observation, with no specific diagnostic tests available (Bagheri, Kergeshian & Burd, 1999; Kiessling, 2001).
In reviewing family-genetic and epidemiological studies, some researchers suggest that there is little evidence to support the diagnostic distinction between, for example, chronic tics and TS (Peterson, Pine, Cohen & Brook, 2001).

Tics can be defined as "sudden, repetitive, stereotyped motor movements or phonic productions that involve discrete muscle groups" (Leckman, King, & Cohen, 1999, p. 24).
In contrast to other movement disorders, such as chorea or dystonia, tics are exaggerations and repetitions of normal movements (Bagheri et al., 1999; Leckman, Peterson, King, Scahill, & Cohen, 2001).
Primary tics such as TS have no identifiable cause or may be genetic in origin (Jankovic, 2001).
Conditions that could cause secondary tics include head trauma, encephalitis, and some medications.
There is an increased incidence of tics in children with pervasive developmental disorder (Kiessling, 2001).

Tics are commonly classified as simple or complex. Shoulder shrugging, neck twitching, and facial movements are examples of simple motor tics. Touching objects, skipping, and squatting in a rhythmic sequence (such as every four steps) are examples of complex motor tics. Simple vocal tics include sniffing, barking, coughing, yelling, and hiccupping. Complex vocal tics include repeating parts of words or phrases, talking to oneself, assuming different intonations, and uttering obscenities (Bagheri et al., 1999; Leckman et al., 1999).

There is a growing body of literature suggesting that tics are intentional responses to unwanted sensations or urges (Coffey & Park, 1997; Jankovic, 1997).
Up to 90% of older children and adults with TS report some premonitory sensations related to their tics, while children under 10 are more likely to view their tics as completely involuntary (Leckman et al., 1999).
Although many children are able to suppress their tics for some period of time, the urge to tic remains, and the tics must eventually be "released." Some children are able to remain relatively tic-free during school hours, only to engage in bouts of tics for several hours at home (Leckman et al.; Packer, 1997). Others report that tics are quiescent while they are engaged in an absorbing mental or physical task (Jankovic, 1997). Stress can exacerbate tics, but they can also increase when a child is in a relaxed state, such as watching television, and can be present during sleep (Jankovic, 1997). While this cycle of relative suppressibility and release is characteristic of tics in TS, it can lead to confusion and misguided attempts on the part of parents and teachers to use discipline or conditioning to stop the tics (Packer, 1997).

Presentation and Classification of Tic Disorders

As many as 10-20% of all school-age children have transient motor and, less commonly, vocal tics lasting less than 1 year (Bagheri et al., 1999; Zohar et al., 1999).
The majority of these children present with tics in the head, neck, or upper extremities (Leckman et al., 2001).
In children who are eventually diagnosed with TS, almost half report that eye blinking was their initial tic, followed by other head and facial tics. Others report vocal tics such as throat clearing and sniffing to be an early symptom of TS (Jankovic, 1997) and less commonly of transient tic disorder (Leckman et al., 2001). In many children with transient tic disorder, symptoms resolve before the family seeks medical attention (Leckman et al., 2001).

In 3-4% of school age children, symptoms of either motor or vocal tics, but not both, persist for more than 1 year (Leckman et al., 2001).
These children would be considered to have a chronic tic disorder, and they may or may not have associated behavioral and developmental conditions discussed below (Leckman et al., 2001). Children with both vocal and motor tics that persist for more than 1 year generally fulfill the criteria for TS.

The diagnostic criteria for TS have changed over time (Leckman et al., 2001). The DSM IV (APA, 1994, p. 103) criteria for TS are:

Both multiple motor and one or more vocal tics have been present at some time during the illness, although not necessarily concurrently.
The tics occur many times a day (usually in bouts), nearly every day or intermittently throughout a period of more than 1 year, and during this period there was never a tic-free period of more than 3 consecutive months.
The disturbance causes marked distress or significant impairment in social, occupational, or other important areas of functioning.
Onset is before age 18 years.
The disturbance is not due to the direct physiological effects of a substance (e.g., stimulants) or a general medical condition (e.g., Huntington's disease or post-viral encephalitis).

There is some controversy about this definition, which has significant changes from the DSM-III-R (APA, 1987) and from the TS Classification Study Group (1993). The primary concern is that the DSM-IV definition relies on an undefined and subjective criterion of "distress," rather than a more objective measure of symptom severity (Erenberg & Fahn, 1996; Leckman et al., 2001).
Many researchers and clinicians in the field continue to use DSM III-R criteria in order to maintain a more uniform definition of TS (Bawden, Stokes, Camfield, Camfield & Salisbury, 1998; Carter et al., 2000; Coffey et al., 2000; Sherman, Shepard, Joschko & Freeman, 1998; Spencer et al., 1998). For a child who fulfills all criteria except psychological dysfunction or distress, an ICD-9 code can be used instead of a DSM diagnosis (Leckman et al., 2001).

Etiology, Course, and Prognosis of TS

First documented in the 19th century and named after a French neurologist, Gilles de la Tourette, TS was thought for a long time to have psychiatric origins (Coffey & Park, 1997). Contemporary research on dopamine receptors and the limbic system evolved after it was noticed that empiric treatment with neuroleptics such as haloperidol reduced tic severity (Coffey & Park, 1997). It is currently felt that there is an underlying defect of either excess dopamine or hypersensitivity of postsynaptic dopamine receptors (Bagheri et al., 1999).

Recent studies suggest that basal ganglia dysfunction may be involved in TS (Sherman et al., 1998). According to Leckman and Cohen (1999), some of the circuits that convey information from the cortex throughout the basal ganglia are selectively disinhibited in both TS and OCD, making them unusually sensitive to alterations in the environment. In this conceptual model, TS is seen as a disorder in which individuals are unable to inhibit premonitory sensory urges, leading to the emergence of motor and phonic behavior. In OCD, individuals are unable to inhibit specific innate worries, leading to the emergence of intense obsessions and compulsions.

In a cross-sectional study of 36 children with TS who were contacted 7 years after diagnosis, Leckman et al. (1998) found that the mean onset of tics at 5.6 years of age was followed by progressive worsening of tics, peaking at age 10.
While 22% of the sample had tics that were severe enough to jeopardize or prevent their functioning in school at the peak of tic symptoms, the tics steadily declined during adolescence, with 50% of the individuals virtually tic-free by age 18.
Most of the remaining 18-year-olds experienced minimal to mild symptoms, while only 10% reported moderate or marked tics.

TS and Genetics

Several studies have reported a risk for TS of 11.5% in brothers and 4.8% in sisters of children with TS (Tourette Syndrome Association International Consortium for Genetics, 1999). Based on extended family studies, most researchers associate TS, chronic tics, OCD, and OCS as part of a spectrum of expression of the same underlying genetic disorder (Alsobrook & Pauls, 1997). They suggest an autosomal dominant model with sex-specific penetrance, accounting for the higher incidence of TS among boys, but cannot rule out a multifactorial or intermediate mode of inheritance (Alsobrook & Pauls, 1997; Haasstedt, Leppert, Filloux, van de Wetering, & McMahon, 1995). While some researchers have suggested possible locations for the "TS gene," their findings have not been replicated (Alsobrook & Pauls, 1997).

Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcus (PANDAS)
There has been some research into the association of TS and OCD with streptococcal infections, noting that Sydenham's chorea, which involves abnormal movements, OCD-like symptoms, and emotional lability, is felt to be caused by a reaction between antibodies to Group A Beta hemolytic streptococcus and neuronal tissue (Müller et al., 2001; Perlmutter et al., 1999). In some children, infection with streptococcus, borrelia burgdorfi (Lyme's disease), and mycoplasma appear to exacerbate TS symptoms (Müller et al., 2001). These researchers hypothesize that a subset of children with TS belong to a category known as PANDAS (Müller et al., 2001). Criteria that would suggest PANDAS include abrupt onset of symptoms associated with a streptococcal infection, periods of remission, and exacerbations after additional streptococcal infections (Perlmutter et al., 1999). Müller et al. (2001) noted that adults with TS have higher levels of specific antibodies to streptococcus than controls without TS. Perlmutter et al. (1999) found that children with TS who fit the PANDAS criteria had their TS and OCD symptoms significantly reduced after being treated with either intravenous immune globulin or plasma exchange. At the moment, identification and treatment of PANDAS remains experimental, with many questions left unanswered (Hollenbeck, 2000).

Thursday, June 24, 2010

HPV Vaccine - Questions & Answers

Why are HPV vaccines needed?

HPV vaccines prevent serious health problems, such as cervical cancer and other, less common cancers, which are caused by HPV (human papillomavirus). In addition to cancer, HPV can also cause other health problems, such as genital warts. HPV is a common virus that is easily spread by skin-to-skin contact during sexual activity with another person. It is possible to have HPV without knowing it, so it is possible to unknowingly spread HPV to another person. Safe, effective vaccines are available to protect females and males against some of the most common types of HPV and the health problems that the virus can cause.

How common are the health problems caused by HPV?

HPV is the main cause of cervical cancer in women. There are about 11,000 new cervical cancer cases each year in the United States. Cervical cancer causes about 4,000 deaths in women each year in the United States.

About 1 in 100 sexually active adults in the United States have genital warts at any one time.

What HPV vaccines are available in the United States?
Two HPV vaccines are licensed by the FDA and recommended by CDC. These vaccines are Cervarix (made by GlaxoSmithKline) and Gardasil (made by Merck).

How are the two HPV vaccines similar?

Both vaccines are very effective against HPV types 16 and 18, which cause most cervical cancers.
So both vaccines prevent cervical cancer and precancer in women.
Both vaccines are very safe.
Both vaccines are made with very small parts of the human papillomavirus (HPV) that cannot cause infection with HPV, so neither of the vaccines can cause HPV infection.
Both vaccines are given as shots and require 3 doses.

How are the two HPV vaccines different?
Only one of the vaccines (Gardasil) also protects against HPV types 6 and 11. These HPV types cause most genital warts in females and males.
The vaccines have different adjuvants—a vaccine adjuvant is a substance that is added to the vaccine to increase the body's immune response.

Who should get HPV vaccine?
Cervarix and Gardasil are licensed, safe, and effective for females ages 9 through 26 years.
CDC recommends that all girls who are 11 or 12 years old get the 3 doses (shots) of either brand of HPV vaccine to protect against cervical cancer and precancer. Gardasil also protects against most genital warts.
Girls and young women ages 13 through 26 should get all 3 doses of an HPV vaccine if they have not received all doses yet.

Gardasil is also licensed, safe, and effective for males ages 9 through 26 years. Boys and young men may choose to get this vaccine to prevent genital warts.

People who have already had sexual contact before getting all 3 doses of an HPV vaccine might still benefit if they were not infected before vaccination with the HPV types included in the vaccine they received.
The best way to be sure that a person gets the most benefit from HPV vaccination is to complete all three doses before sexual activity begins.

Why is Gardasil not on the immunization schedule for boys and men?

CDC did not add this vaccine to the recommended immunization schedules for males in these age groups because studies suggest that the best way to prevent the most disease due to HPV is to vaccinate as many girls and women as possible.
Parents of boys can decide if Gardasil is right for their sons by talking with their sons’ health care providers. Young men can also discuss this vaccine with their doctors.

Why is HPV vaccine recommended at ages 11 or 12 years?

For the HPV vaccine to work best, it is very important to get all 3 doses (shots) before being exposed to HPV.
Someone can be infected with HPV the very first time they have sexual contact with another person.
It is also possible to get HPV even if sexual contact only happens one time.

How does getting HPV vaccine at ages 11 or 12 fit with other health recommendations?
Doctors recommend health check-ups for preteens.
The first dose of an HPV vaccine should be given to girls aged 11 or 12 years during a pre-teen health check-up. The first dose of Gardasil can also be given to boys during their pre-teen check-ups. Two other vaccines are recommended for pre-teens. During one visit, either HPV vaccine can be given safely with these other pre-teen vaccines. A check-up in the pre-teen years is also a time when pre-teens and their parents can talk to their providers about other ways to stay healthy and safe.

What is the recommended schedule (or timing) of the 3 HPV doses (shots)?

For both females and males, 3 doses (shots) are needed. CDC recommends that the second dose be given one to two months after the first, and the third dose be given six months after the first dose.

Will someone be protected against HPV-related diseases if they do not get all 3 doses?
No studies so far have shown whether or not 1 or 2 doses protect as well as getting 3 doses, so it is very important to get all 3 doses.

Are the HPV vaccines safe and effective?
FDA has licensed the vaccines as safe and effective. Both vaccines were tested in thousands of people around the world. These studies showed no serious side effects. Common, mild side effects included pain where the shot was given, fever, headache, and nausea. As with all vaccines, CDC and FDA continue to monitor the safety of these vaccines very carefully.

Do people faint after getting HPV vaccines?

People faint for many reasons. Some people may faint after getting any vaccine, including HPV vaccines. Falls and injuries can occur after fainting. Sitting or lying down for about 15 minutes after a vaccination can help prevent fainting and injuries.

Can HPV vaccines treat HPV infections, cancers, or warts?

HPV vaccines will not treat or get rid of existing HPV infections. Also, HPV vaccines do not treat or cure health problems (like cancer or warts) caused by an HPV infection that occurred before vaccination.

Are there other HPV diseases that the two vaccines may prevent?

Studies have shown that Gardasil prevents cancers of the vagina and vulva, which like cervical cancer, can be caused by HPV types 16 and 18. Studies of Cervarix have not specifically looked at protection against vaginal and vulvar cancers.

Published studies have not looked at other health problems that might be prevented by HPV vaccines. It is possible that HPV vaccines will also prevent cancers of the head and neck, penis, and anus due to HPV 16 or 18. Gardasil might prevent recurrent respiratory papillomatosis (RRP), a rare condition caused by HPV 6 or 11 in which warts grow in the throat.

Are kids getting too many vaccines?
Vaccines strengthen the body’s immune system—they do not overload it. No reputable science shows that getting recommended vaccines hurts the immune systems of healthy kids. The HPV vaccines are important tools to prevent cervical cancer and genital warts. As with all vaccines, the benefits outweigh potential risks.

Why aren’t HPV vaccines recommended for people older than 26?
Both vaccines were studied in thousands of people from 9 through 26 years old and found to be safe and effective for these ages. The FDA will consider licensing HPV vaccines for other ages if new studies show that this would also be safe and effective.

Should pregnant women be vaccinated?
Pregnant women are not included in the recommendations for HPV vaccines. Studies show neither vaccine caused problems for babies born to women who got the HPV vaccine while they were pregnant. Getting the HPV vaccine when pregnant is not a reason to consider ending a pregnancy. But, to be on the safe side until even more is known, a pregnant woman should not get any doses of either HPV vaccine until her pregnancy is completed.

What should a woman do if she realizes she received HPV vaccination while pregnant?
If a woman realizes that she got any shots of an HPV vaccine while pregnant, she should do two things:

Wait until after her pregnancy to finish the remaining HPV vaccine doses.
Report the vaccination to the appropriate pregnancy registry. There are pregnancy registries to help us learn more about how pregnant women respond to each of the vaccines. So, if a woman realizes that she got any shots of either HPV vaccine while pregnant, she should work with her health care provider to report it to the appropriate pregnancy registry:
The toll-free number for Gardasil is 800-986-8999
The toll-free number for Cervarix is 888-452-9622

Will HPV vaccination be covered by health insurance?
Most health insurance plans cover recommended vaccines. But there may be a lag time after a vaccine is recommended before it gets added to insurance plans. Some insurance plans may not cover any or all vaccines. Check with your insurance provider to see if the cost of the vaccine is covered before going to the doctor.

How can my child get an HPV vaccine if I don’t have insurance?
The Vaccines for Children (VFC) program helps families of eligible children who might not otherwise have access to vaccines. The program provides vaccines at no cost to doctors who serve eligible children. Children younger than 19 years of age are eligible for VFC vaccines if they are Medicaid-eligible, American Indian, or Alaska Native or have no health insurance. "Underinsured" children who have health insurance that does not cover vaccination can receive VFC vaccines through Federally Qualified Health Centers or Rural Health Centers. Parents of uninsured or underinsured children who receive vaccines at no cost through the VFC Program should check with their health care providers about possible administration fees that might apply. These fees help providers cover the costs that result from important services like storing the vaccines and paying staff members to give vaccines to patients. For more information about the VFC program, visit

Brain Tumour Risk in Relation to Mobile Telephone Use: Results of the INTERPHONE

From International Journal of Epidemiology
International Case–Control Study
The INTERPHONE Study Group

Posted: 06/17/2010; International Journal of Epidemiology. 2010;39(3):675-694. © 2010 Oxford University Press

Background The rapid increase in mobile telephone use has generated concern about possible health risks related to radiofrequency electromagnetic fields from this technology.

Methods An interview-based case–control study with 2708 glioma and 2409 meningioma cases and matched controls was conducted in 13 countries using a common protocol.

Results A reduced odds ratio (OR) related to ever having been a regular mobile phone user was seen for glioma [OR 0.81; 95% confidence interval (CI) 0.70–0.94] and meningioma (OR 0.79; 95% CI 0.68–0.91), possibly reflecting participation bias or other methodological limitations. No elevated OR was observed ≥10 years after first phone use (glioma: OR 0.98; 95% CI 0.76–1.26; meningioma: OR 0.83; 95% CI 0.61–1.14). ORs were <1.0 for all deciles of lifetime number of phone calls and nine deciles of cumulative call time. In the 10th decile of recalled cumulative call time, ≥1640 h, the OR was 1.40 (95% CI 1.03–1.89) for glioma, and 1.15 (95% CI 0.81–1.62) for meningioma; but there are implausible values of reported use in this group. ORs for glioma tended to be greater in the temporal lobe than in other lobes of the brain, but the CIs around the lobe-specific estimates were wide. ORs for glioma tended to be greater in subjects who reported usual phone use on the same side of the head as their tumour than on the opposite side.

Conclusions Overall, no increase in risk of glioma or meningioma was observed with use of mobile phones. There were suggestions of an increased risk of glioma at the highest exposure levels, but biases and error prevent a causal interpretation. The possible effects of long-term heavy use of mobile phones require further investigation.

Mobile phone use has increased dramatically in many countries since its introduction in the early-to-mid 1980s. The expanding use of this technology has been accompanied by concerns about health and safety. In the late 1990s, several expert groups critically reviewed the evidence on health effects of low-level exposure to radiofrequency (RF) electromagnetic fields, and recommended research into the possible adverse health effects of mobile telephony.[1–4] As a result, the International Agency for Research on Cancer (IARC) coordinated a feasibility study in 1998 and 1999, which concluded that an international study of the relationship between mobile phone use and brain tumour risk would be feasible and informative.[5,6]

INTERPHONE was therefore initiated as an international set of case–control studies focussing on four types of tumours in tissues that most absorb RF energy emitted by mobile phones: tumours of the brain (glioma and meningioma), acoustic nerve (schwannoma) and parotid gland. The objective was to determine whether mobile phone use increases the risk of these tumours and, specifically, whether RF energy emitted by mobile phones is tumourigenic.

This article presents the results of analyses of brain tumour risk in relation to mobile phone use in all INTERPHONE study centres combined. Analyses of brain tumours in relation to mobile phone use have been reported from a number of cohort[7–9] and case–control studies, including several of the national components of INTERPHONE.[10–25] No studies, however, have included as many exposed cases, particularly long-term and heavy users of mobile phones, as this study.

Wednesday, June 23, 2010

Breast-Feeding Until 4 Months May Protect Infants From Respiratory, GI Infections

From Medscape Medical News

Laurie Barclay, MD

June 21, 2010 — Breast-feeding until age 4 months is linked to lower rates of respiratory and gastrointestinal (GI) infection morbidity, according to the results of a population-based, prospective, cohort study reported online June 21 in Pediatrics.

"Exclusive breastfeeding seems to decrease the risk of infectious diseases in infancy," Liesbeth Duijts, MD, PhD, from Erasmus Medical Center in Rotterdam, the Netherlands. "However, the World Health Organization has called for more research regarding the benefits for 6 months instead of 4 months of exclusive breastfeeding."

The goal of this study, which was embedded in the Generation R Study, a study from fetal life onward in the Netherlands, was to evaluate the associations of duration of exclusive breast-feeding with upper respiratory tract infections (URTI), lower respiratory tract infections (LRTI), and GI tract infections in infancy.

There were 4164 subjects who completed questionnaires on rates of breast-feeding during the first 6 months (never; partial for < 4 months, not thereafter; partial for 4 - 6 months; exclusive for 4 months, not thereafter; exclusive for 4 months, partial thereafter; and exclusive for 6 months) and doctor-attended URTI, LRTI, and GI infections until age 12 months.

Risks for URTI, LRTI, and GI tract infection until age 6 months were lower in infants who were breast-fed exclusively until age 4 months and partially thereafter vs infants who were never breast-fed. Adjusted odds ratios (ORs) were 0.65 (95% confidence interval [CI], 0.51 - 0.83) for URTI, 0.50 (95% CI, 0.32 - 0.79) for LRTI, and 0.41 (95% CI, 0.26 -0.64) for GI tract infection. The adjusted OR for LRTIs in infants between the ages of 7 and 12 months was 0.46 (95% CI, 0.31 - 0.69).

For infants who were exclusively breast-fed for at least 6 months, trends were similar. However, partial breast-feeding, even for 6 months, was not associated with significantly lower risks for these infections.

"Exclusive breastfeeding until the age of 4 months and partially thereafter was associated with a significant reduction of respiratory and gastrointestinal morbidity in infants," the study authors write. "Our findings support health policy strategies to promote exclusive breastfeeding for at least 4 months, but preferably 6 months, in industrialized countries."

Limitations of this study include questionnaires with breast-feeding data available for only 65% of eligible participants of the Generation R Study and possible misclassification related to questionnaire use.

"Biological, cultural, and social constraints related to breastfeeding habits need to be studied more extensively," the study authors write. "The effects of prolonged and exclusive breastfeeding on infectious diseases at older ages in industrialized countries remain to be studied."

Exclusive breast-feeding until age 4 months and partially thereafter was associated with a significant reduction of respiratory and GI morbidity rates in infants.

The first phase of the Generation R Study was funded by Erasmus Medical Center, Erasmus University Rotterdam, and Netherlands Organization for Health Research and Development (Zon Mw). The present study was supported by an additional grant from Stichting W. H. Kröger (00–048) and AGS Kinderstichting. The study authors have disclosed no relevant financial relationships.

Pediatrics. Published online June 21, 2010.

Monday, June 14, 2010

Conflicts of interest and pandemic flu

Published 3 June 2010, doi:10.1136/bmj.c2947
Cite this as: BMJ 2010;340:c2947
WHO must act now to restore its credibility, and Europe should legislate

The world should of course be thankful that the 2009 influenza A/H1N1 pandemic proved such a damp squib. With so many fewer lives lost than had been predicted, it almost seems ungrateful to carp about the cost. But carp we must because the cost has been huge. Some countries—notably Poland—declined to join the panic buying of vaccines and antivirals triggered when the World Health Organization declared the pandemic a year ago this week. However, countries like France and the United Kingdom who have stockpiled drugs and vaccines are now busy unpicking vaccine contracts, selling unused vaccine to other countries, and sitting on huge piles of unused oseltamivir.Meanwhile drug companies have banked vast profits—$7bn (£4.8bn; 5.7bn) to $10bn from vaccines alone according to investment bank JP Morgan.1 Given the scale of public cost and private profit, it would seem important to know that WHO’s key decisions were free from commercial influence.

An investigation by the BMJ and the Bureau of Investigative Journalism, published this week (doi:10.1136/bmj.c2912 ), finds that this was far from the case.2 As reported by Deborah Cohen and Philip Carter, some of the experts advising WHO on the pandemic had declarable financial ties with drug companies that were producing antivirals and influenza vaccines. As an example, WHO’s guidance on the use of antivirals in a pandemic was authored by an influenza expert who at the same time was receiving payments from Roche, the manufacturer of oseltamivir (Tamiflu), for consultancy work and lecturing. Although most of the experts consulted by WHO made no secret of their industry ties in other settings, WHO itself has so far declined to explainto what extent it knew about these conflicts of interest or how it managed them.

This lack of transparency is compounded by the existence of a secret "emergency committee," which advised the director general Margaret Chan on when to declare the pandemic—a decision that triggered costly pre-established vaccine contracts around the world. Curiously, the names of the 16 committee members are known only to people within WHO.

Cohen and Carter’s findings resonate with those of other investigations, most notably an inquiry by the Council of Europe, which reports this week and is extremely critical of WHO.1 It concludes that decision making around the influenza A/H1N1 crisis has been lacking in transparency.

One of its chief protagonists is Paul Flynn, a UK member of parliament and a member of the council’s Parliamentary Assembly. He and others raised concerns last year about the lack of evidence to justify the scale of the international response to H1N1 (as also covered in the BMJ in December3 ), and the lack of transparency around the decision making process for declaringthe pandemic.1

WHO’s response to these concerns has been disappointing. Although Margaret Chan has ordered an inquiry and WHO has stressed its commitment to transparency, her office has turned down requests to clear up concerns about potential conflicts of interest.2 And at a hearing of the Council of Europe’s Parliamentary Assembly in January, WHO denied any industry influence on the scientific advice it received.1 Such a knee jerk defence beforethe facts were known may come to haunt the organisation.

This response is also disappointing given WHO’s track record of standing up to industry. In the late 1970s WHO sparked two iconic clashes with multinational companies over the marketing of breast milk substitutes in the developing world and the setting up of the Essential Drugs Programme.4 Both issues set WHO at loggerheads with the United States where these industries had major holdings. Partly in response to WHO’s position, America withdrew contributions to WHO’s budget.

More recently, in 1999, when the forced disclosure of confidential tobacco industry documents alerted WHO to possible interference in its anti-tobacco activities, its then director general Gro Harlem Brundtland quickly set up an independent inquiry. She then published and press released its shocking findings—of an elaborate industry funded campaign to undermine WHO—without any attempt at interference or spin.5 The report recommended that all staff, consultants, temporary advisers, and members of expert committees should be required to declare their conflicts of interest, with well enforced penalties for those who failed to do so.6

As Cohen and Carter report, WHO subsequently published in 2003 new rules on managing conflicts of interest. These recommended that people with a conflict of interest should not be involved in the part of the discussion or the piece of work affected by that interest or, in certain circumstances, that they should not participate in the relevant discussion or work at all.7 WHO seems not to have followed its own rules for the decision making around the pandemic.

WHO will not be the only body to come under scrutiny for its handling of the pandemic. The coming months will see a spate of reports, from the European Commission, the European Parliament, and from national bodies including the French Senate, and the UK’s Cabinet Office. This soul searching takes place against a backdrop of hardening attitudes to conflicts of interest aroundthe world. Last year’s report from the Institute of Medicine8 has been followed by new guidance from groups such as the World Association of Medical Editors9 and the American College of Chest Physicians,10 which stress that declaration alone is no longer enough. To quote the Institute of Medicine report, "Disclosure is the essential though limited first step in identifying and responding to conflicts of interest." The big question is what to do about the conflicts.

On the basis of our own investigation and those of others, the answer is now inescapable. As Barbara Mintzes says in Cohen and Carter’s report, "No one should be on a committee developing guidelines if they have links to companies that either produce a product—vaccine or drug—or a medical device or test for a disease." The same, and more, must apply to committeesmaking major decisions on public health. Where entirely independent experts are hard to find, experts who are involved with industry could be consulted but should be excluded from decision making. The United States has made important progress with its Sunshine Act and other legislation. European legislation on managing conflicts of interest is long overdue.

As for WHO, its credibility has been badly damaged. Recovery will be fastest if it publishes its own report without delay or defensive comment; makes public the membership and conflicts of interest of its emergency committee; and develops, commits to, and monitors stricter rules of engagement with industrythat keep commercial influence away from its decision making.

In a briefing at the end of last year, a spokesperson for WHO said, "Given the discrepancy between what was expected [from the pandemic] and what has happened, a search for ulterior motives on the part of WHO and its scientific advisors is understandable, though without justification."11 The implication is that, had there been a huge death toll, the process behind WHO’s decision making would not have been subject to such scrutiny. This is almost certainly true. But it does not mean that we are wrong to ask hard questions. Neither does it make the answers we have found any less troubling. And nor does it remove from WHO the urgent need to restore its credibility and public trustbefore the next pandemic comes along.

Cite this as: BMJ 2010;340:c2947

Fiona Godlee, editor in chief

1 BMJ, London WC1H 9JP
Feature, doi:10.1136/bmj.c2912

Competing interests: The author has completed the Unified CompetingInterest form at (available on request from the corresponding author) and declares: (1) No financial support for the submitted work from anyone other than her employer; (2) No financial relationships with commercial entities that might have an interest in the submitted work; (3) No spouse, partner, or children with relationships withcommercial entities that might have an interest in the submitted work; (4) FG has written articles on the challenges faced by WHO, and on the influence of the drugs industry. She is in favour of a more assertive approach to conflict of interest and supports efforts to control the influence of the drugs industry on medical research, medical education, and health policy.

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

Saturday, June 12, 2010

Rotavirus Vaccine Contraindicated in Infants With Severe Combined Immunodeficiency

From Medscape Medical News
Brande Nicole Martin

June 11, 2010 — Rotavirus vaccine should not be administered to infants with severe combined immunodeficiency (SCID), according to the Centers for Disease Control and Prevention (CDC) and US Food and Drug Administration (FDA)-approved prescribing information and patient safety labeling.

Both monovalent (RV1) and pentavalent (RV5) rotavirus vaccines are contraindicated in infants diagnosed with SCID and can cause vaccine-acquired infection.

The CDC announced this new contraindication to rotavirus vaccine in the June 11 issue of Morbidity and Mortality Weekly Report.

SCID is a rare, life-threatening group of disorders caused by defects in several genes that is commonly diagnosed in infants after they have experienced a severe, potentially life-threatening infection from one or more pathogens. It occurs annually in about 40 to 100 new cases in the United States per year. Most infants commonly experience chronic diarrhea, failure to thrive, and early onset of infections.

In December 2009 and February 2010, Merck Co and GlaxoSmithKline Biologicals, the makers of the RV1 (RotaTeq) and RV5 (Rotarix) vaccines, respectively, updated their prescribing information and patient labeling with FDA approval to reflect this contraindication.

The CDC also has updated their list of contraindications to rotavirus vaccine after consulting with the Advisory Committee on Immunization Practices.

The addition of this contraindication was based on data from 8 reported cases of vaccine-acquired rotavirus infection in infants with SCID since 2006, when the rotavirus vaccine was first introduced in the United States. Five cases were reported in the literature — 4 in the United States and 1 in Australia. Two additional cases in the United States and another outside the United States were reported to the Vaccine Adverse Event Reporting System.

The 8 infants were between 3 and 9 months of age when diagnosed with SCID. All had received 1 to 3 doses of rotavirus vaccine before the diagnosis and presented with diarrhea. Most of the infants also had additional infections, such as Pneumocystis jirovecii, rhinovirus, adenovirus, Salmonella, Escherichia coli, and Giardia. The vaccine-acquired infection was confirmed using reverse transcription–polymerase chain reaction in all cases. In at least 6 cases, prolonged shedding of vaccine virus up to 11 months' duration was documented.

The rotavirus vaccine is recommended by the Advisory Committee on Immunization Practices to be given to infants at ages 2 and 4 months for RV1 and ages 2, 4, and 6 months for RV5. This timeframe for rotavirus vaccination overlaps with the median age of 4 to 7 months when infants are usually diagnosed with SCID.

Rotavirus vaccine is indicated for the prevention of rotavirus gastroenteritis in infants.

The CDC advises parents to consult with an immunologist or infectious disease specialists before rotavirus vaccine is administered to infants with confirmed or suspected altered immunocompetence.

Morb Mortal Wkly Rep. 2010;59:687-688.

Sunday, June 6, 2010

Breast-Feeding Linked to Lower Incidence of Fever After Immunizations

News Author: Laurie Barclay, MD
CME Author: Charles P. Vega, MD

May 19, 2010 — Breast-feeding is linked to a lower incidence of fever after immunizations, according to the results of a prospective cohort study reported online May 17 in Pediatrics.

"Immune response to some vaccines is different among breastfed infants compared with those who are not breastfed," write Alfredo Pisacane, MD, from Università Federico II in Napoli, Italy, and colleagues. "The objective of this study was to evaluate the effects of breastfeeding on the risk for fever after routine immunizations."

At a pediatric vaccination center in Naples, Italy, mothers of infants scheduled for routine vaccinations were told how to measure and record infant temperature on the evening that the immunization was administered and for the next 3 days. On the third day after vaccination, mothers were phoned to determine the incidence of fever. After adjustment for vaccine dose, maternal educational level and smoking status, and number of other children in the household, multivariate analyses allowed estimation of the relative risk for fever in relationship to the type of breast-feeding.

Of 460 infants recruited, outcome data were available for 450 (98%). Fever was reported in 30 (25%) of exclusively breast-fed infants, in 48 (31%) of partially breast-fed infants, and in 94 (53%) of infants who were not breast-fed at all (P < .01).
Among infants who were exclusively breast-fed, the relative risk for fever was 0.46 (95% confidence interval [CI], 0.33 - 0.66), and it was 0.58 (95% CI, 0.44 - 0.77) among partially breast-fed infants.

"The protection conferred by breastfeeding persisted even when considering the role of several potential confounders," the study authors write. "In this study, breastfeeding was associated with a decreased incidence of fever after immunizations."

Limitations of this study include body temperatures taken by the mothers rather than by health professionals and the possibility that fever after immunization could be an infective episode.

"Breastfeeding seems to be associated with a reduced risk for fever after immunization, but additional, well organized studies are needed," the study authors conclude. "The design of such studies should include more objective research methods, such as measurements taken by health care professionals at the same time of the day or night, and should evaluate the role of mild intercurrent infections by medical monitoring."

The study authors have disclosed no relevant financial relationships.

Pediatrics. Published online May 17, 2010.

Clinical Context

Breast-feeding can strengthen infants' immune systems, among other salutary effects. A previous study by Pabst and colleagues examined whether breast-fed infants experienced a more robust immune response to the conjugate H influenzae type b vaccine.
This research, which was published in the August 4, 1990, issue of The Lancet, did not find a difference in the immune response between breast-fed and formula-fed children at ages 2, 4, and 6 months. However, at ages 7 months and 12 months, the antibody levels against H influenzae were significantly higher among breast-fed vs formula-fed children.

Breast milk and the act of breast-feeding itself have properties that might reduce fever, particularly after vaccinations. The current study examines this hypothesis.