It’s been 10 years since the X-SCID Conference held in Bethesda, Maryland. Now plans are underway for another conference. Preparations are still in the early stages, but to find out what’s planned visit the SCID Conference 2008 website. The SCID Conferences are for SCID patients and their families. New information will be posted on the conference site as soon as it’s known. Check the site often for the latest information. Dates and location have already been announced: July 25th to 27th, 2008 at Wintergreen Resort and Spa in Wintergreen, Virginia. Registration will be open soon!
30 JANUARY 2008 ISSUE
The over-65s and children under five years have a disproportionate number of consultations with the GP relative to their proportion of the practice population. Young children most commonly present with infections and some children seem to have a particular body system most likely to be affected; “When he gets a cold it always goes to his chest [or ears, throat, etc].”
Most primary school teachers will tell you they rarely have a full class because one child, or more, is off with an infection, yet, by secondary school age, absence due to ill health is much less common. It is part of the maturing of the immune system as we grow. So, when should we think of an immune problem in the face of a normal developmental process?
Immunodeficiency was first described in 1952 but, over 50 years later, the diagnosis is delayed on average five years from presentation. The majority is seen initially in paediatric, ENT and chest clinics, but 60 per cent of patients do not have the diagnosis made in the first three hospital visits. Immunodeficiency causes children and adults to have infections that recur frequently and are usually hard to cure. The acronym SPUR – serious, persistent, unusual, recurrent – applied to infections will suggest if a patient’s immune function should be tested.
Red flag signs would include two episodes of meningitis, which would be both serious and recurrent and may suggest a deficiency of the complement system. Opportunistic infection such as persistent thrush, which is unusual, would suggest there may be a T-cell deficiency. Deep abscesses such as a liver abscess, which would be unusual, suggest investigation to look for a neutrophil deficiency.
The five types of immunoglobulin are IgG, IgM, IgD, IgA and IgE. IgG and IgM are part of the systemic immunity, with IgM production being triggered first in response to an infection followed by IgG, the latter acting as the immunological memory. IgA is part of the mucosal immune system.
Splenomegaly, abnormal white cell count, chronic diarrhoea and chronic sinusitis, while not sensitive as screening tools, should at least make one think of immunodeficiency. These features, together with failure to thrive, developmental difficulties, etc, particularly in a child whose parents are consanguineous, would also warrant a full investigation.
Investigations include a full blood count and a differential. Frequently, apart from the neutrophil count, the differential blood count is often overlooked. The lymphocyte count in children under two years should be above 2.7. A lymphocytopenia in a child under two years should make one think of severe combined immunodeficiency (SCID). Requesting the immunoglobulin count – quite a cheap test – will show up as three main subgroups, IgG, IgM and IgA.
Specific antibody levels can also be requested for vaccine-related antibody levels, in particular tetanus, diphtheria and pneumococcus. These act as a guide to the overall immune function. The child can be given these vaccines, even if they have had them before, and the antibody levels can be tested post vaccination. Although ideally one should test before and after antibody levels, on a practical basis, one often just takes a post immunisation blood test. Even though two years is quoted for a minimum age for a response to a polysaccharide vaccine, children may not respond to the Pneumovax immunisation even up to the age of five years.
Lastly, do not forget the HIV test. Although there is still concern about approaching the parents to discuss this because of the stigma, if it is not considered, it will never be discovered as a cause of some children’s recurrent infections and immune problems.
Charles Essex is a consultant neurodevelopmental paediatrician based in Coventry, UK.
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A FAMILY who moved to Newcastle when their baby became ill are preparing to come back to Bolton.
Logan Wilkieson, who is now 10-months-old, was diagnosed with a rare disease which affects his immune system.
Last October, he was admitted to a specialist unit at Newcastle General Hospital and was placed in a “bubble” of clean air because the slightest infection could have been fatal. He had a successful stem-cell transplant and blood transfusion in November. Now his parents, Ruth Lawrie and Gareth Wilkieson, from Horwich, are preparing to come home.
The family is currently living in a halfway house – a residence for patients who do not require complete hospitalisation but who need an intermediate degree of care – but with Logan recovering well from his treatment, they could be allowed to leave in two weeks.
During their time in the North Ruth stayed in temporary accommodation near to the hospital while Gareth has been working in Bolton midweek and travelling to Newcastle at weekends.
Ruth and Gareth have now applied for a council house in Horwich to be near friends and family. But they have been told none is suitable for them and are on a waiting list.
Ruth, aged 20, said: “These last few months have been very difficult for us, having to give up our home to be with Logan in hospital.
“The one thing that kept us going was the thought that we would one day be able to return home to Bolton and be near our friends and family.
“We are upset that it is now looking in doubt.”
Logan suffers from severe combined immunodeficiency (SCID) which affects one in 100,000 babies.
A council spokesman said: “We awarded the family priority status on medical grounds last month through the Homes for You service and are monitoring their preferred area to see if a suitable house, preferably near relatives, becomes vacant.
“The family are also looking in a neighbouring council’s area where they also have relatives, and we have spoken to that authority on their behalf.”
2:47pm Saturday 26th January 2008
By Amanda Smith
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New Rochelle, NY, January 22, 2008—Can a patient who agrees to participate in a safety study of a gene therapy protocol give truly informed consent and understand the risks involved when the consent forms are highly technical and the physician or institution seeking their consent has a stake in the study and its outcome? The continuing debate over informed consent and the acknowledgement of risk and responsibility in gene therapy trials are the focus of a series of probing and provocative commentaries published in the January 2008 issue (Volume 19, Number 1) of Human Gene Therapy, a peer-reviewed journal published by Mary Ann Liebert, Inc. The commentaries are available free online.
In the Editorial, James M. Wilson, MD, PhD, Editor-in-Chief and Head of the Gene Therapy Program, Department of Pathology and Laboratory Medicine, at the University of Pennsylvania School of Medicine, in Philadelphia, calls on the gene therapy, regulatory, and research communities to re-explore the issue of informed consent as it relates to the safety of viral vector-based gene transfer therapies and the appropriateness of having physicians and others with an interest in the trials and their outcomes recruit patients and obtain the necessary informed consent.
“I encourage the professional gene therapy societies and various related foundations to work together in the new year to undertake a critical review of the conduct of our clinical trials…it behooves us to get ahead of this issue and put in place more effective ways to assure that research subjects who courageously give of themselves can do so with a full and unbiased understanding of the risks and benefits of their participation,” writes Dr. Wilson.
This issue of the Journal also includes five stimulating commentaries that discuss the key controversies related to patient recruitment and trial management. They explore the question of whether patients are able to comprehend the lengthy and often highly technical study descriptions and consent forms to the extent needed to make an informed decision about enrolling in a trial. The authors also present suggestions and innovative strategies for improving the recruitment and informed consent process.
Dr. Arthur Caplan, Professor of Bioethics, Chair of the Department of Medical Ethics, and Director of the Center for Bioethics at the University of Pennsylvania, authored a commentary entitled, “If It Is Broken Shouldn’t it Be Fixed? Informed Consent and Initial Clinical Trials of Gene Therapy.” Another, entitled, “Case of Leukaemia Associated with X-Linked Severe Combined Immunodeficiency Gene Therapy Trial in London,” was prepared by the Board of the European Society of Gene and Cell Therapy, Executive Committee of the Clinigene Network of Excellence, and Executive of the Consort Integrated Project. Dr. Jeffrey Kahn, Director and Professor, Center for Bioethics, at the University of Minnesota Medical School, presents his perspectives in, “Informed Consent in Human Gene Transfer Clinical Trials.” Also contributing a commentary is Dr. Tomas Jose Silber, Chair of the Institutional Review Board and Director of the Office of Ethics at Children’s National Medical Center, in Washington, D.C. It is entitled, “Human Gene Therapy, Consent, and the Realities of Clinical Research: Is It Time for a Research Subject Advocate? ” Ms. Suzanne Pattee, Vice President of Regulatory and Patient Affairs for the Cystic Fibrosis Foundation authored, “Protections for Participants in Gene Therapy Trials: A Patient’s Perspective.”
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By VICTORIA MACCHI
Wednesday, January 16, 2008
The second-grade Corkscrew Elementary student hasn’t spent time with his mother like he used to since Adam, now 9 months old, was diagnosed in August with Severe Combined Immunodeficiency.
The once-healthy baby boy needs to see doctors on the east coast two to three times a week to manage the condition that makes him extremely susceptible to infectious diseases.
“Adam is doing good overall. We just take it one day at a time,” Amy said from her car after two doctors’ visits.
The pair leaves for Miami at 5 a.m. on appointment days.
“Adam sleeps all the way there and back,” describes the mother of two and Collier County social worker. “He’s so happy even though we poke and prod him all the time.”
From August to November, Adam was confined to Jackson Memorial Hospital; now he is back in Naples, and the Saadas spent his first holidays – in between doctors’ visits – as a family.
“It was wonderful to be home for Christmas,” Amy Saada said.
Juggling medical trips, work, and the two boys’ schedules, “you just want to do something together as a family.”
Since Adam received a bone marrow transplant from his mother in September to help him develop an immune system, his T-cell count increased from zero to 500; the goal is 4,000 to 5,000.
“His cell counts are what’s expected. It’s just going to be slow-going…,” Amy Saada said.
Although he hasn’t had a severe rejection of the graft, “we just keep running into obstacles. He has an enlarged liver. (Then) it was vomiting,” his mother explained.
He is having eye trouble as well.
One cause doctors are monitoring is graft vs. host disease, a result of the transplant that can affect the skin, eyes, stomach and intestinal tract. It could take years for Adam’s body to clear the disease as his body accepts his mother’s cells.
Adam’s face is bloated from steroids; he takes them to control his body’s reaction to the graft, but Amy worries they also are stunting his growth.
When he was born on April 3, 2007, Adam was in the 90th percentile for height; he is now in the 30th.
One beam of light for the Saadas was talking to families of children who have the same affliction, which affects approximately one in 500,000 people.
“It’s good to know that there are kids doing fine, out playing baseball,” Amy said.
For now, Adam isn’t allowed out of the house much. When he is, he usually wears a surgical mask – which he would rather chew than keep on – to protect him from airborne germs. His immune system is so weak a cold could quickly turn into pneumonia.
“He’s on so much medicine,” Amy lamented with a frazzled sigh.
She and her husband, Hussam, are up every two to three hours a night to give Adam medication. The three share a bedroom in Amy’s father’s home.
“How do you do it? You just do it,” Amy said. “You do what you have to do for your kids.”
Donations can be made at http://cotaforadams.com.
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Contact Victoria Macchi at firstname.lastname@example.org
By Jocelyn Kaiser
ScienceNOW Daily News
10 January 2008
The announcement last month that a fifth child who received gene therapy for an immune system disease has developed leukemia was the latest blow to the field of gene therapy. But there’s new hope: The U.K. team running the trial reports this week that a safer formulation of the treatment can cure the disease in mice and should also work in people. Gene therapy’s clearest success to date has been restoring the health of about 40 children with severe combined immunodeficiency (SCID), also known as “bubble boy” disease because patients cannot fight off infections and are often isolated to protect them from germs. The treatment had a down side, however: Since 2002, four of 10 children in a French trial for a form of SCID involving a defect on the X chromosome (X-SCID) have developed leukemia, apparently because the retrovirus used to insert a curative gene into patients’ blood stem cells turned on a cancer gene (ScienceNOW, 7 March 2005). Researchers at the Institute of Child Health at Great Ormond Street Hospital in London were conducting a nearly identical X-SCID study without serious side effects, and some researchers suspected that their technique was somehow safer. But in mid-December, one of their patients also developed leukemia.
Now the U.K. team says it has found a better approach. The problem with the virus used in the U.K. and French studies seemed to be its powerful promoter, a stretch of DNA that regulates expression of the inserted gene, IL2RG. This promoter also apparently turned on a nearby cancer gene. To eliminate this problem, U.K. study leader Adrian Thrasher and colleagues replaced the promoter with one less likely to turn on other genes. This “self-inactivating” retrovirus also cannot make more copies of itself once it has stitched itself into the host genome. In vitro studies on self-inactivating vectors, including a recent paper by this group comparing the growth of cells treated with their new vector and the old one, are boosting confidence. “It’s very reasonable to think the [self-inactivating] vectors are going to be safer,” says Cynthia Dunbar of the U.S. National Heart, Lung, and Blood Institute in Bethesda, Maryland.
Although the new vector is less potent, it should be more than adequate, Thrasher notes. In a paper published online this week in the journal Molecular Therapy, Thrasher’s team and collaborators in Germany and the United States report that the new vector restored immune system function in a mouse model of X-SCID. “It’s probably going to work” in humans, says molecular virologist Frederic Bushman of the University of Pennsylvania School of Medicine in Philadelphia.
Thrasher’s group and collaborators now hope to start multisite trials in Europe and the United States with the new vector later this year. Donald Kohn of Children’s Hospital in Los Angeles, California, who is thinking about participating, says he’s optimistic that the safety issues will be solved and that gene therapy will eventually become the standard of care. If X-SCID can be cured with no serious side effects, that will ease concerns about the risks of using similar vectors to treat other blood diseases such as sickle cell disease, notes Dunbar.