I've had to move this blog over to Wordpress because I've had so many problems posting to this site. Seems I only get a post to upload about one out of every 3 times I try. I've written support, but didn't get any useful help. So, I've moved the site. You can click on http://scidstuff.wordpress.com to find newer entries.
Phoenix talk to focus on immunodeficiency diseases
Apr. 11, 2007 12:00 AM
Physician Ralph Shapiro of Midwest Immunology Clinic in Plymouth, Minn., will talk about primary immunodeficiency diseases at a session for patients.
The Immune Deficiency Foundation, which is hosting the session, says the diseases are disorders in which part of the body's immune system is missing or does not function properly. Severe combined immune deficiency, known as boy-in-the-bubble disease, is one of them.
In secondary immune deficiency disease, the immune system is compromised by outside factors, such as viruses and chemotherapy.
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The meeting will include information about administration of the antibody immunoglobulin G, insurance reimbursement and a question-and-answer session.
Details: 11 a.m.-3 p.m. Saturday at Chevy's, 2650 E. Camelback Road, Phoenix. Free, includes lunch. Reservations required by Thursday. 1-(520)-270-2654 or vohnout1@comcast.net.
linkback url: http://www.azcentral.com/arizonarepublic/arizonaliving/articles/
0411healthbriefs0411.html
Specialists Treat Primary Immunodeficiency Diseases More Aggressively Than Other Clinicians: Presented at AAAAI
By Bryan DeBusk
SAN DIEGO, CA -- February 26, 2007 -- A survey of academy members suggests that specialists in primary immunodeficiency diseases (PID) prescribe more aggressive therapies than their non-expert colleagues, according to findings presented here at the 2007 American Academy of Asthma, Allergy, and Immunology (AAAAI) annual meeting.
"The objectives of this survey were to identify clinical practice as applied to primary immunodeficiency disease patients, especially where there is little existing clinical evidence, to identify expert practices, and identify questions to fuel future clinical research in PID," said Jordan Orange, MD, PhD, assistant professor of paediatrics, division of allergy and immunology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States.
In a presentation on February 24th, Dr. Orange related the results of a web-based survey of AAAAI members on behalf of the AAAAI-PID committee and the Immune Deficiency Foundation. of 3,000 members invited to participate in the survey, 408 responded.
While 80% of respondents reported treating patients with PID, the majority reported that PID patients comprised less than 10% of their practices. The committee labelled physicians as PID experts if more than 10% of their patients had a PID. Both non-experts and experts reported seeing about 100 patients per week, and non-experts tended to see patients in solo practice while experts tended to operate in a hospital outpatient setting.
The survey responses indicated a number of differences in the way experts and non-experts treat patients with PID. Dr. Orange noted that while 87% of physicians with PID patients prescribe intravenous (IV) immunoglobulin (IG) therapy to prevent infection, experts are 6 times more likely to prescribe this therapy for their PID patients than non-experts.
Both experts and non-experts prescribed IVIG for all patients with X-linked agammaglobulinemia (XLA), but prescription patterns for other diseases were less consistent. Experts were more likely to prescribe IVIG for patients with ataxia telangiectasia, hyper-IgM syndrome, severe combined immunodeficiency, Wiskott-Aldrich syndrome, and X-linked lymphoproliferation.
Additionally, 63% of experts said they aim for trough IgG levels >600mg/dL while non-experts were more likely to aim for lower levels. No difference in the therapy schedule was reported between experts and non-experts, and 87.1% of respondents said they prescribe IVIG every 4 weeks while 10.6% prescribe every 3 weeks.
Prophylactic antibiotics are prescribed by 55% of respondents for at least some patients, and there was a trend toward experts using them more frequently, while some respondents prescribe them in addition to IVIG.
Reflecting on the importance of the survey results, Dr. Orange said, "I think it is important to have rigorous standards upon which the use of IVIG is based for PID …. Hopefully these data can be used to fuel pertinent questions."
[Presentation title: Specialist Physician Perspectives on Primary Immunodeficiency Diseases: A 2006 Survey of the AAAAI Membership. Abstract 279]
Linkback URL: http://www.docguide.com/news/content.nsf/news/852571020057CCF68525728E00545185
Human disease clues riding on horse genome research
By Bryn Nelson
Newsday
Associated Press
Scientists have found more than 80 genetically linked diseases that are common to both horses and humans.
Scientists have assembled the genetic blueprint of a thoroughbred mare, a rough draft of its entire DNA sequence that may point the way toward a better understanding of equine evolution, physiology and the dozens of diseases found in both horses and humans.
Claire Wade, a lead member of the sequencing team and a senior research scientist at the Broad Institute in Cambridge, Mass., said the assembled genome still contains sizable gaps and has yet to be thoroughly analyzed. Nevertheless, she and other researchers said its estimated 2.7 billion units, or letters, of DNA should provide a wealth of new information.
“It takes us from the relative Dark Ages of genetics to the relative forefront,” said Dr. Doug Antczak, a professor of equine medicine at Cornell University in Ithaca, N.Y.
Scientists isolated the DNA from Twilight, a mare housed at Cornell and bred to help Antczak understand how horse fetuses and placentas can successfully evade or defend against the mother’s immune system. Far beyond his own studies, however, Antczak said Twilight’s DNA may lay the foundation for research efforts around the world.
Like humans, for example, horses are susceptible to the West Nile virus and must contend with allergies and arthritis. Some suffer from neurological or muscular disorders. And Arabian horses can inherit a form of severe combined immunodeficiency, more commonly called “bubble boy” disease.
So far, researchers have found more than 80 genetically linked diseases common to both horses and humans.
Wade said racing horses may grant a better understanding of physiology, perhaps allowing veterinarians to help them and other breeds more easily recover from injuries. And because, like us, horses have been preyed upon by bears, wolves and predatory cats, they may teach us a thing or two about the biological basis of caution.
“Horses do get anxious,” she said. “Because they’re prey animals, they do have to be very aware.”
The $15 million sequencing effort, funded by the National Human Genome Research Institute, suggests we share about 85 percent of our genetic information with horses. Like us, they are thought to possess fewer than 20,000 genes, although their 64 chromosomes – half inherited from each parent – easily bests our 46.
The new genome may also allow researchers to peer into the evolutionary past of a mammalian group that includes tapirs, rhinoceroses and zebras.
linkback url: http://www.fortwayne.com/mld/journalgazette/living/
16680370.htm?source=rss&channel=journalgazette_living
Web-posted Thursday, January 25, 2007
Spin doctors
Plasma bank contributes $1.2 million to local economy
By Jim McBride
jim.mcbride@amarillo.com
Donors pack the lobby at Biomat USA's plasma donor center almost daily in Amarillo, waiting to trade their blood plasma for a few dollars.
Biomat is a subsidiary of Grifols, a Spanish holding company specializing in the hospital and pharmaceutical industries. It collects blood plasma from donors at its Amarillo facility at 520 S.W. 10th Ave.
Spokesman Chris Healey said Biomat relies on repeat donors who provide blood plasma and carefully tracks them to make sure its blood products are safe.
If a donor comes in only once and doesn't come in for another appointment, that donor's plasma is tossed out.
"These people who donate plasma and who work at the centers are life-saving, life-changing."
Kathy Antilla, director of education for the Immune Deficiency Foundation
"We don't pay for their plasma. We compensate them for the time they spend in our facility. If they are donating plasma on a regular basis, we compensate them for that time," he said.
Biomat's plasma donors must fill out a detailed form and answer a series of questions about their health and personal history. They also must have a physical exam, follow special dietary regimens and comply with other instructions before they can donate.
Most donations take about 45 minutes. A staffer inserts a needle into the donor's arm, which is hooked up to sterile, disposable tubing and a centrifuge.
"It will take out a volume of roughly a coffee cup of the blood, spin it down, we collect what we want and it returns the red blood cells through the same needle line back to the individual, pulls it out again, separates and does that process until we accumulate the weight that we need," said Facility Manager Gordon Woods Jr.
The center has about 25 employees and pumps about $1.2 million a year in donor fees, taxes and employee salaries into the Amarillo economy, Woods said.
Biomat USA facilities nationwide generate about 1.5 million liters of plasma every year, enough to fill nearly two Olympic-size swimming pools.
The plasma can be turned into several products.
Biomat also tests donations for viruses and other impurities before its products are frozen and shipped to anywhere from California to Spain.
"The donor is actually paid cash at the end of their donation for their time. It's very simple, quick, and we have the purity and the safety to follow it up and make sure that that product that's going into another human being is the best on the market," he said.
A donor can give plasma up to twice a week and can earn up to $240 a month.
Healey said paying people to donate ensures they come back and gives them an incentive to remain healthy.
It also helps keep adequate blood products in supply.
"If there weren't compensated donors, there wouldn't be enough plasma therapies for sick people who need them," he said.
Human plasma is used to make life-saving medicines to treat rare diseases, such as hemophilia, primary immune deficiencies, genetic emphysema and shock, trauma or burns.
A major plasma product is known as IVIG, or intravenous immune globulin. It's a blood product that helps patients with immune deficiencies.
"That product is extracted from the plasma that we collect at the plasma centers like the one in Amarillo. It's one of the main medicines we take out of the plasma," Healey said. "Without this medicine, patients get sick; they get all kinds of infections, and they can die."
Kathy Antilla, director of education for the Immune Deficiency Foundation in Maryland, said plasma products that come from facilities like Biomat in Amarillo help patients whose bodies cannot make antibodies needed to fight off disease.
Antilla said her son, now 15, first began receiving intravenous plasma products about 10 years ago. He receives an intravenous infusion of plasma about every two weeks that replaces certain blood cells and gives him the antibodies he needs.
"As parents, we saw the change in him from the first infusion. All of a sudden he stopped coughing all night long, stopped vomiting when he ran, and there was a sparkle in his eye," she said. "These people who donate plasma and who work at the centers are life-saving, life-changing."
LinkBack URL: http://www.amarillo.com/stories/012507/bus_6505309.shtml
Stem Cells Discovered in Amniotic Fluid
By PAUL ELIAS
AP Biotechnology Writer
They reported they were able to extract the stem cells from the fluid, which cushions babies in the womb, without harm to mother or fetus and turn their discovery into several different tissue cell types, including brain, liver and bone.
But Dr. Anthony Atala, head of Wake Forest's regenerative medicine institute and the senior researcher on the project, said the scientists still don't know exactly how many different cell types can be made from the stem cells found in amniotic fluid. The scientists said preliminary tests in patients are years away.
The cells from amniotic fluid "can clearly generate a broad range of important cell types, but they may not do as many tricks as embryonic stem cells," said Dr. Robert Lanza, chief scientist at the stem cell company Advanced Cell Technology. "Either way, I think this work represents a giant step forward for stem cell research."
Dr. George Daley, a Harvard University stem cell researcher, said the finding raises the possibility that someday expectant parents can freeze amnio stem cells for future tissue replacement in a sick child without fear of immune rejection.
Nonetheless, Daley said, the discovery shouldn't be used as a replacement for human embryonic stem cell research.
"While they are fascinating subjects of study in their own right, they are not a substitute for human embryonic stem cells, which allow scientists to address a host of other interesting questions in early human development," said Daley, who began work last year to clone human embryos to produce stem cells.
Atala said the research reported in the scientific journal Nature Biotechnology expands far beyond similar work.
At a heart research conference in November, Swiss researcher Simon Hoerstrup said he managed to turn amniotic fluid stem cells into heart cells that could be grown into replacement valves. Hoerstrup has yet to publish his work in a scientific journal.
"Our hope is that these cells will provide a valuable resource for tissue repair and for engineered organs as well," Atala said.
It took Atala's team some seven years of research to determine the cells they found were truly stem cells that "can be used to produce a broad range of cells that may be valuable for therapy."
Atala said the new research has found even more promising stem cells with the potential to turn into many more medically useful replacement parts.
"We have other cell lines cooking," Atala said.
The hallmark of human embryonic stem cells, which are created in the first days after conception, is the ability to turn into any of the more than 220 cell types that make up the human body. Researchers are hopeful they can train these primordial cells to repair damaged organs in need of healthy cells.
However, many people, including President Bush, oppose the destruction of embryos for any reason. The Bush administration has restricted federal funding for the embryo work since 2001, leading many scientists to search for alternative stem cell sources.
The advance is the latest in the so-called regenerative medicine field that has sprung from Atala's lab in Winston-Salem, N.C.
In April, Atala and his colleagues rebuilt bladders for seven young patients using live tissue grown in the lab.
In the latest work, Atala's team extracted a small number of stem cells swimming among the many other cell types in the amniotic fluid.
One of the more promising aspects of the research is that some of the DNA of the amnio stem cells contained Y chromosomes, which means the cells came from the babies rather than the pregnant moms. ___
On the Net:
Wake Forest regenerative medicine institute: http://www.wfirm.org/
backlink url: http://www.newsday.com/news/health/
ats-ap_health10jan08,0,7632149.story?track=rss
AAP ENCOURAGES PUBLIC CORD BLOOD BANKING
Below is a news release on a policy statement appearing in the January issue of Pediatrics, the peer-reviewed, scientific journal of the American Academy of Pediatrics (AAP). To receive the full text of this report, please contact the AAP Department of Communications.
For Release: January 2, 2007, 12:01 am (ET)
CHICAGO - Cord blood stem cell banks can provide an invaluable service to those afflicted with leukemia and immune disorders. The American Academy of Pediatrics (AAP) encourages families to donate their newborn’s cord blood, which is normally discarded at birth, to cord blood banks (if accessible in their area) for use by other individuals in need. Storing cord blood at private banks for later personal or family use as a general “insurance policy” is discouraged.
According to the revised AAP policy statement, “Cord Blood Banking for Potential Future Transplantation,” the chances of a child needing his or her own cord blood stem cells in the future are estimated to range from one in 1,000 to one in 200,000. Private cord blood banks target parents at an emotionally vulnerable time when the reality is most conditions that might be helped by cord blood stem cells already exist in the infant’s cord blood. However, the AAP does recommend private cord blood banking for parents who have an older child with a condition that could potentially benefit from transplantation, such as a genetic immunodeficiency.
See: frequently asked questions about cord blood banking
The policy details recommendations for private or public cord blood banks, such as obtaining written permission for obtaining cord blood prior to the beginning of labor; refraining from collecting cord blood during complicated deliveries; complying with standards set by federal and state agencies; and actively recruiting minorities to donate cord blood.
Parents who decide to donate or store an infant’s cord blood should be informed that genetic and infectious disease testing will be performed on the cord blood and that they will be notified of any abnormalities that are found. Likewise, parents should notify cord blood banks if their child develops a genetic, immunologic or malignant condition so their cord blood is not used for transplants.
The American Academy of Pediatrics is an organization of 60,000 primary care pediatricians, pediatric medical subspecialists and pediatric surgical specialists dedicated to the health, safety and well being of infants, children, adolescents and young adults.
LinkBack URL: http://www.aap.org/advocacy/releases/jan07cordblood.htm
Get your Questions Answered about FluMist™
See our Q & A about the FluMist™ Influenza Vaccine
From the IDF Newsletter, Primary Immune Tribune, Volume 1 Issue 3
Q: What is FluMist™?
A: FluMist™ is a live virus influenza vaccine. It was approved by the U.S. Food and Drug Administration in June 2003 and is the first nasally administered vaccine to be marketed in the United States. FluMist™ is approved to prevent influenza illness due to influenza A and B viruses in healthy children and adolescents, ages 5-17 and healthy adults, aged 18-49. FluMist™ is produced by MedImmune Vaccines and distributed by Wyeth.
Q: How is FluMist™different from the traditional flu shot?
A: FluMist™ is a live virus vaccine and administered through a nasal spray. The flu shot is an inactivated (killed virus) vaccine. Killed virus vaccines can be taken by individuals with primary immune deficiencies and their families.
Q: What is influenza?
A: Influenza, or "the flu", can cause serious respiratory illnesses in normal people. Those with primary immune deficiency diseases may be at an increased risk for the flu and experience more serious complications. There are two types of influenza virus that cause human disease, Type A and Type B. Each year these types undergo changes, which make individuals susceptible to infection even though they may have antibodies to other strains of influenza from prior infections or immunizations.
Q: How is influenza spread and what are its symptoms?
A: Influenza is spread by coughing and sneezing. After infection, there is an incubation period of one to four days. Infected individuals can infect others before symptoms begin and for about five days after symptoms begin. Symptoms include fever, cough, muscle aches, headache, sore throat, runny nose, and fatigue. The cough and fatigue can last a few weeks. Pneumonia and other complications can be very severe.
Q: Who should not receive the FluMist™ vaccine?
A: FluMist™ should not be given for any reason to the following:
* People with primary immune deficiency diseases or their close contacts
* People with weakened immune systems due to HIV infection, certain cancers, or immunosuppressive agents used to treat cancer or organ transplantation
* People with asthma or other reactive airway diseases
* Children younger than 5 years and adults older than 50 years
* People with a history of Guillan-Barre syndrome, chronic diseases of the cardiovascular or pulmonary system, or allergies to eggs
* Pregnant women
Q: What are the potential complications of the FluMist™ vaccine?
A: The most common adverse events associated with the vaccine in normal individuals were nasal congestion, runny nose, sore throat and a cough. Although there is no specific information available, it is anticipated that if a person with a primary immune deficiency receives FluMist™ (s)he would be more likely to develop complications. If a close contact is vaccinated, the resulting viral shedding could cause a person with a primary immune deficiency disease to become infected with the flu vaccine strains. (See A7 below)
Q: What is the risk to individuals with primary immune deficiency disorders if a close contact is vaccinated with FluMist™?
A: During a clinical trial with FluMist™ in a day care center, there was documented transmission from vaccinated children to unvaccinated children. Viral shedding following the administration of FluMist™ typically continues for about a week on the average, but may be as long as three weeks. The risk of transmission in the day care center setting was estimated at 2.4% or one in approximately 42 children. The risk could be higher if different children in the center receive the vaccine at different times over the fall.
Healthcare workers who receive FluMist™ may also present a possible way for a person with a primary immune deficiency disease to become infected with the flu vaccine strains. Although there is no data about transmission of the live vaccine virus from vacinees to immune compromised contacts and subsequent development of disease, the Centers for Disease Control and Prevention have stated that the inactivated vaccine (flu shot) is preferred over live, intranasal influenza vaccine (FluMist™) for physicians, nurses, family members, or anyone else coming in close contact with anyone with a weakened immune system.
Q: Is the killed virus flu vaccine (flu shot) recommended for those with primary immune deficiencies or their close contacts?
A: People with primary immune deficiency diseases may choose to receive the inactivated influenza vaccine shot. This is the killed version of the vaccine and will not cause the flu! The only risks of receiving the shot are soreness at the injection site, and less often fever, tiredness, muscle aches, and headache. Those allergic to eggs should not receive the vaccine shot, as there is a risk for more serious reactions. Even if you do not develop antibody titers high enough to prevent influenza, you still might benefit from receiving the shot every year. Receiving the shot may reduce your risk for hospitalization, pneumonia, and other complications. Your family members should seriously consider receiving the killed version of the flu vaccine to reduce the risk of bringing the flu virus home to their family member with primary immune deficiency.
Q: How can you reduce your risk of complications from the FluMist™ vaccine?
A: To reduce the risk of contracting the flu vaccine strains, the Immune Deficiency Foundation's Medical Advisory Committee has made the following recommendations:
* Because it is a live virus vaccine, people with primary immune deficiency diseases should NOT receive the FluMist™ vaccine.
* The FluMist™ vaccine is not recommended for close contacts of primary immune deficient patients.
* Primary immune deficient patients should talk to their doctors to see if it may be advisable to receive preventive medicine to avoid becoming infected with the FluMist™ strains of the flu.
* Primary immune deficient patients exposed through close contact to FluMist™, should see their doctor immediately, as (s)he may advise a treatment medicine.
* School authorities may want to advise their immune deficient pupils if FluMist™ is being administered in the school system. This information may be especially useful to those with T cell or combined T and B cell immune deficiencies.
* Family members and healthcare workers in close contact with immune deficient patients should be advised to receive the killed virus flu shot, rather than the FluMist™ vaccine.
Q: How do you evaluate the risk of FluMist™ vaccine complications for you or your family member?
A: The FluMist™ vaccine is not recommended for individuals with primary immune deficiency disorders and/or any of the above listed medical conditions (A5). It is best to consult with your physician when evaluating the risk of complications for you or your family members.
Q: Is treatment available for individuals who develop complications from the FluMist™ vaccine?
A: One antiviral agent, Tamiflu (Roche) has been approved by the FDA for prevention of Types A and B Influenza in those 13 years of age and older. It is given once daily for up to 42 days and may have benefit if given within 2 days of exposure to influenza strains. However, there are no studies of the use of Tamiflu in primary immune deficient patients exposed to FluMist™ influenza strains. If exposed to FluMist™ strains of influenza, a primary immune deficient patient should contact his or her physician immediately.
Q: How can I find out if FluMist™ is being given in my local community?
A: For information about FluMist™, contact your state or local health department and/or school system.
Q: Where can I find more information?
A: Please utilize the following websites:
* Centers for Disease Control and Prevention, National Immunization Program: www.cdc.gov/nip.
* Immune Deficiency Foundation: www.primaryimmune.org
* Clinical Focus on Primary Immune Deficiency Diseases: Immunization of the Immunocompromised Host: www.primaryimmune.org . Go to "Publications" and then to "Clinical Focus". It is the October 1998 issue.
* U.S. Food and Drug Administration, Center for Biologics Evaluation and Research: www.fda.gov/cber.
Original Article from the IDF Newsletter:
Linkback URL:
http://www.imakenews.com/idf/e_article000704177.cfm?x=b8y4wp9,b5TSrMPk,w
On another busy evening, a feverish 7-month-old boy is another failure to thrive
May 1, 2006
By: Mark Goldblatt, MD, William T. Basco, Jr, F.M. Schaffer, MD
Contemporary Pediatrics
ACKNOWLEDGMENT
Rochelle Hirschhorn, MD, professor of medicine, cell biology, and pediatrics at NYU Medical Center, New York, N.Y., provided invaluable assistance in determinations of adenosine deaminase (ADA) enzyme activity in specimens collected from the patient.
DR. GOLDBLATT is an attending physician in internal medicine and pediatrics at the Northern Navajo Medical Center, Shiprock, N.M.
DR. BASCO and DR. SCHAFFER are associate professors of pediatrics at The Medical University of South Carolina, Charleston.
DR. SIBERRY is an assistant professor of pediatrics in the divisions of general pediatric and adolescent medicine and pediatric infectious diseases at Johns Hopkins Hospital, Baltimore.
The authors and section editor have nothing to disclose in regard to affiliations with, or financial interests in, any organization that may have an interest in any part of this article.
On a Friday evening, in a tertiary care hospital, a pager that's been hotter than a Saharan mid-afternoon goes off, again. Seems like it's the hundredth call today. And, once again, it's all yours! You head to the nearest telephone. On the other end is a physician you know from a community hospital some 150 miles from your facility. She's requesting transfer of a 7-month-old boy who has been hospitalized for the past six weeks for failure to thrive, recurrent wheezing, and bilateral infiltrates refractory to antibiotics. You happily accept the patient and quickly relay the information you have to the on-call resident.
Despite the busy evening, there's time for your creative juices to begin to swirl as you await the transfer. A differential gathers. Respiration, you consider, can consume as much as two thirds of metabolic demand, resulting in failure to thrive. Will the baby's lungs be the key to a diagnosis? But what about the wheezing? As an "old doc" once told you, there are only a few general causes of wheezing: reactive airway disease (asthma, allergies, mastocytosis), infection (respiratory syncytial virus, human metapneumovirus), a foreign body, a structural defect (slings, rings, bronchiectasis), a genetic disorder (including cystic fibrosis), and heart failure.
Back to the business of fact-gathering
The patient arrives at your facility and the team begins its evaluation to gather a detailed understanding of his condition. His mother has accompanied him; she reports that he is the product of a full-term pregnancy that was complicated only by a case of genital warts. Delivery was vaginal. Birth weight was 3.3 kg.
The boy was hospitalized at 1 month of age for fever. A workup for sepsis was negative. He was seen by his pediatrician at 3 months of age for bronchiolitis. She reports that he had intermittent episodes of wheezing over following months.
During his sixth month, he was seen in the emergency department of the referring hospital three times for cough, low-grade fever, rhinorrhea, wheezing, thrush, and poor oral intake. The first two times, he was sent home on an antibiotic and an inhaled bronchodilator. At the third visit, he was admitted; over the course of one or two days before that hospitalization, the patient had a persistent fever (to 102° F), poor oral intake, increasing fatigue, and difficulty breathing—all despite nebulizer treatments, antipyretics, and multiple attempts to feed him. The chart from that admission notes desaturations in the 80% to 89% range while breathing room air; fever; bilateral infiltrates on a chest radiograph; and thrush.
The course of illness at that hospital was marked by a range of therapeutics: three weeks of parenteral ceftriaxone; 10 days of amoxicillin-clavulanate; two courses of azithromycin; courses of fluconazole and econazole nitrate; a short course of parenteral nutrition; a scheduled multivitamin; and scheduled nebulized budesonide (Pulmicort), albuterol, and ipratropium bromide (Atrovent).
Despite your knowledgeable colleague's treatments and extensive work-up, the baby continues to have thrush, wheezing, and respiratory difficulties and hasn't gained weight. You review the initial history that was taken upon presentation at the referring hospital when the baby was 5 months old. The notes describe a male full-term, African-American infant with a maternal complaint that the baby has had a life-long history of "cold"-like symptoms. As already reported by the mother and documented in the hospital record, the patient had been seen in the ED twice in the month before the 5-month-old admission, for intermittent "rattling cough," wheezing, low-grade fever (to 101°F) and poor oral intake without nausea, vomiting, or diarrhea. At each ED visit, he was sent home with a prescription for a course of oral antibiotic, and his mother was encouraged to treat him with the home nebulizer.
Five days before the baby was admitted at 5 months of age, he was seen by his pediatrician, who prescribed a course of ocular antibiotic drops for bilateral conjunctivitis, which, his mother tells you, resolved with treatment.
You obtain more history. The patient lives with his mother, father, and an older sister; there are no pets. Immunizations are up to date. He does not attend day care. Domestic water supply is from a municipal source. He has reached the developmental milestones of only a 4-month-old.
The family history is significant only for systemic lupus erythematosus in his maternal grandmother. All other family members are in good health. The parents report no unusual or potentially hazardous occupational exposures.
The physical exam in your ED today revealed an ill-appearing infant with a rectal temperature of 102.3°F; respiratory rate, 44/min; heart rate, 200/min; and oxygen saturation, 97% breathing room air, with frequent desaturations into the 80% to 89% range. Weight is 5.9 kg (below the fifth percentile). Examination of the head, ears, eyes, nose, and throat (HEENT) was significant for bilaterally bulging, erythematous, and thickened tympanic membranes and purulent effusions, as well as white lacey plaques on the tongue and buccal mucosa without tonsillar hypertrophy.
The neck showed no evidence of lymphadenopathy, thyromegaly, or masses. The cardiovascular exam revealed regular rhythm with tachycardia but no murmurs, rubs, or gallops. Diffuse inspiratory rales and rhonchi, diminished bibasilar breath sounds, and a prolonged expiratory phase were noted on the pulmonary exam. The remainder of the physical exam was unremarkable.
A few moments away to think: What's the connection?
Later, sitting in your office, you begin to formulate a differential diagnosis that accounts for the failure to thrive, developmental delay, thrush, and refractory pulmonary process. Your focus is still on the lungs, and includes recurrent infections, caused by acquired pathogens or as a consequence of a congenital abnormality. Your explanations include hospital-acquired pneumonia, structural abnormalities such as rings and slings, cystic fibrosis, and reactive airway disease, among others. You've decided to extend your differential, however, to include inborn errors of metabolism; endocrine, immune, and autoimmune abnormalities; malignancy; and, although less likely, cardiac diseases and abnormalities. In fact, the differential seems limitless as you build it!
Fortunately—for you—the night passes quickly and you find yourself on rounds early Saturday morning.
The next morning, you examine the baby; he is afebrile. Heart rate is 140/min; respiratory rate, 27/min; and oxygen saturation, 100% on room air. He is visibly small—weight, height, and head circumference would be at the 50th percentile for a 2.5-month-old (but are proportional)—yet remains active and alert. Despite a careful exam, you cannot palpate any peripheral lymph nodes, and no tonsillar tissue is visible.
The abdomen is soft and non-tender, with active bowel sounds and without hepatomegaly or splenomegaly. The neurologic exam is remarkable for a diminished response to noise. Tone is only that of a 4-month-old child, and he still cannot sit unassisted.
Your pulmonary exam reveals intermittent scattered wheezes, rhonchi, and bilateral crackles that you can best describe as "Velcro-like." Examination of the skin reveals multiple hypopigmented patches on the arms, chest, and shoulders.
You consider that, despite six weeks of therapy, your young patient continues to have persistent pulmonary findings, failure to thrive, and thrush. Is it possible that these ailments are iatrogenic? One complicated scenario comes to mind: What if this baby aspirated a small object, such as a sunflower seed, given to him by his older sibling? That foreign body resulted in shifting infiltrates, wheezing, rhonchi, and a post-obstructive process; in the hospital, he contracted an RSV infection from another child, or a hospital-acquired pneumonia. The thrush is a result of inhaled corticosteroids or prolonged courses of antibiotics, or both, and the failure to thrive is caused by respiratory distress or antibiotic-induced diarrhea. It's time to test these possibilities, and others.
Show me!
You, and one of the residents, quickly review the referring hospital's work-up, including an extensive battery of laboratory tests: a basic metabolic profile, multiple blood and urine cultures, complete blood count, chest and abdominal radiographs, renal ultrasonography, thyroid function, sweat chloride assay for cystic fibrosis, ELISA for human immunodeficiency virus (HIV) infection, total hemolytic complement study (CH50), liver function, immunoglobulins, and the acyl-carnitine level. You note several important findings: persistent bilateral interstitial infiltrates on chest radiographs; a negative sweat chloride test for cystic fibrosis; a negative HIV ELISA study; normal renal function; a recent elevation of transaminases in the face of low albumin; low levels of complement, immunoglobulins, and acyl-carnitine; negative urine and blood cultures; mild anemia and leukopenia; and a normal level of thyroid-stimulating hormone.
You sift through all this information, struggling with how to make sense of the earlier test results and what you've learned from your history and physical exam. What do you know? Is it possible to make the definitive diagnosis with what you know already?
So whadda ya know?
You know that your patient is a 7-month-old male who began to fail to thrive two months ago despite a hospital stay that included supplemental and parenteral nutrition. He has recurrent infiltrates on a chest radiograph and persistent thrush. He has had low levels of immunoglobulins, complement, and acyl-carnitine; leukopenia; and anemia. At the moment, your differential diagnosis is broad and includes several categories of illness: congenital infection, immune deficiency, chronic lung disease, pulmonary malformation, metabolic and endocrine disorders, malignancy, autoimmune disease, and mechanical feeding difficulties.
Recurrent infections such as chronic gastroenteritis, recurrent thrush, and atypical severe infections (e.g., Pneumocystis carinii pneumonia), each in association with failure to thrive, are all histories consistent with a diagnosis of a combined immune deficiency (B and T cell) or a cellular (T cell) immune deficiency disorder.1 There is a relatively broad spectrum of immune deficiency states to consider in the differential; better-known disorders include severe combined immune deficiency (SCID), AIDS, DiGeorge anomaly, and the Wiskott-Aldrich syndrome (WAS).
With earlier test results in mind, you decide to order a basic metabolic panel, liver function tests, another chest radiograph, a CBC with a differential white count, and levels of ammonia, lactate, pyruvate, and serum amino acids. As the results slowly arrive, you note that serum electrolytes and renal function are normal and elevated transaminase levels have returned to normal. Leukopenia and anemia persist, however: The white blood cell count is 3.8 X 103/μL (normal, 6 to 14 X 103/μL) without evidence of granulocytopenia.
Surprisingly, however, the absolute lymphocyte count is 114 X 103/μL, with peripheral eosinophilia. You quickly return to the lab reports from the other hospital and find that the lymphocyte count did not exceed 400 X 103/μL on any CBC during the hospital stay. You call the hospital and the baby's pediatrician and request that all previous CBCs be sent to you. Upon reviewing additional ambulatory labs you realize the child has had lymphopenia since birth. Eureka!!!
You next order an immunology consult, an HIV polymerase chain reaction (PCR) study, and a test of serum immunoglobulin levels. The immunologist requests a repeat total hemolytic complement study, flow cytometric analysis, and in vitro lymphocyte mitogen stimulation studies. The consultant sends the child's blood and his mother's blood for evaluation of adenosine deaminase (ADA) activity.
Results begin to arrive the next day. Flow cytometric analysis demonstrates severe deficits in T, B and natural killer cell counts. ADA activity is abnormally low in the patient and only approximately 50% of normal in his mother.
Because the patient has been severely lymphopenic (on the basis of routine CBCs) throughout his life, with flow cytometry-documented low numbers of B and T lymphocytes and natural killer cells, his test results are most consistent with SCID. The diagnosis now reveals itself: Your patient has ADA-deficient SCID, corroborated by the results of in vitro lymphocyte stimulation studies—namely, minimal T cell responsiveness to the T cell mitogens of phytohemagglutinin and concanavalin A and minimal response to T cell-dependent B cell pokeweed mitogen.
You consider that the absence of lymphoid tissue on physical examination is noteworthy. This finding is characteristic of SCID and of X-linked agammaglobulinemia and severe cellular immune deficiency disorders.2 Because this patient does not show evidence of hypocalcemia and characteristic facies and cardiac anomalies, the diagnosis of DiGeorge anomaly is unlikely. And without a history or evidence of ecchymoses, spontaneous hemorrhage, thrombocytopenia, and small platelets, Wiskott-Aldrich syndrome is also unlikely. Last, HIV ELISA and PCR studies were negative, which, for all purposes, rules out AIDS as the cause of the immune deficiency state.
Shortly after the diagnosis is made, histocompatibility testing is performed on blood specimens from all immediate family members to determine the optimal potential bone marrow transplant donor. Transfer to a pediatric center that specializes in bone marrow transplantation for SCID is arranged.
Before transfer is possible, the baby develops rotavirus enteritis. In an attempt to lower the intestinal viral load, he is treated with enteral gamma globulin. Once that infection resolves, he undergoes bone marrow transplantation with marrow donated by his mother, a haplo-identical match.
The transplant fails to engraft. His hospital course is complicated by recurrent rotavirus infection, and he develops hepatoblastoma. During treatment for the malignancy, he is started on the remaining therapeutic option for his immune deficiency disorder: weekly injection of polyethylene glycol-conjugated bovine ADA (PEG-ADA), to which his response is good, with improved T cell function. The following winter, he weathers a bout of influenza.
The forms and presentations of severe combined immune deficiency
SCID is one of more than 90 different primary immune deficiency states that have been described ("primary" meaning a heritable, not acquired, disorder). This class comprises heterogeneous rare genetic disorders that present in childhood and are generally fatal without treatment. It is estimated that approximately one in 100,000 live births in the US are affected by a primary immune deficiency disorder. All forms of SCID are characterized by absolute lymphopenia, which involves T, and often B, cells. Although B cell numbers may be preserved in some forms of SCID, they are nonfunctional in vivo. In some forms of SCID, a normal level of natural killer cell function is maintained.3
The presentation during the first year of life is predictable, particularly as passive immunity from transplacentally acquired maternal IgG wanes.4 Failure to thrive and recurrent infections—including thrush, chronic gastroenteritis, chronic lung disease, and atypical infections—should raise the question of whether a child has a combined immune deficiency with B and T cell deficits or a cellular immune deficiency with a T cell deficit solely.3
A child who has a T cell deficiency generally manifests clinical findings at 4 or 5 months of age. He may lack lymphoid tissue, and a thymic shadow may be absent on radiography. The deficiency results in recurrent infections with viral, fungal, mycobacterial, and parasitic pathogens. The child fails to develop immunity after routine childhood vaccinations—much like this patient—and a live vaccine, such as bacille Calmette-Guérin, can be fatal.3
Malignancy is common in SCID because the patient lacks tumor suppressor activity because of deficits of natural killer and T cells. Graft-versus-host disease (GVHD) may occur by various means: transplacental passage of competent maternal T cells, secondary to non-irradiated blood product transfusion (containing competent T cells), and after bone marrow transplantation. Early signs and symptoms are eosinophilia, rash, gastrointestinal symptoms, and elevated levels of liver transaminases.3
Pure B cell deficiencies are generally characterized by recurrent infection with encapsulated bacteria, which can result in recurrent sinopulmonary infection, lymphadenitis, meningitis, and osteomyelitis. Symptoms often do not develop until 7 to 9 months of age, when levels of transplacentally acquired maternal antibodies wane.1,4 Growth impairment is variable. Affected persons are at increased risk of autoimmune disorders; in some, lymphoid hyperplasia may be evident as hepatosplenomegaly.
Eosinophilia is seen in some SCID patients and in those who have one of the other primary immune deficiencies (e.g., Wiskott-Aldrich syndrome, hyper-IgE syndrome).3 Primary immune deficiency thereby adds an additional "P" to the mnemonic NAACP for eosinophilia: neoplasia, Addison disease, allergies and asthma, collagen vascular disease, cholesterol emboli, parasites, and primary immune deficiency.
The presence of eosinophilia in this patient may have been consistent with a parasitic infection, a developing neoplastic state, early developing GVHD, or Omenn syndrome. Highly unlikely here is Omenn syndrome: Reported cases are characterized by a recombinase-activating gene (RAG) deficiency, which results in SCID with minimal T and B cells but usually normal numbers of natural killer cells because RAG genes are not involved in natural killer cell ontogeny.3 Our patient, on the other hand, demonstrated a minimal presence of natural killer cells. In fact, this child was believed to have early GVHD—most likely, from transplacentally acquired competent maternal T cells; he had no prior transfusion of blood products or earlier evidence of a parasitic or neoplastic disorder. In fact, treatment to minimize GVHD was instituted before bone marrow transplantation.
An X-linked form and several autosomal-recessive forms of SCID have been well characterized. Although X-linked SCID accounts for nearly half of cases, the ADA-deficient form is one of the more common autosomal recessive forms. Absence of ADA leads to a buildup of intracellular lymphotoxic metabolic products.5 Providing a normal, functioning ADA gene through bone marrow transplantation or providing active, functioning enzyme with PEG-ADA allows for appropriate catabolism of these toxic metabolites.3
Because of the variable presentation of SCID and other primary immune deficiencies, they are often a challenge to the diagnostician: Subtle onset can delay diagnosis and treatment, thereby raising the risk and severity of morbidity and the risk of death. To avoid such consequences, always pay close attention to any lymphopenia, and always consider an immune deficiency in the presence of a combined clinical presentation, such as recurrent thrush, persistent sinopulmonary disease, unexplained rash, or recurrent diarrhea coupled with failure to thrive. Remember that connection, and you may very well "skid" into the right diagnosis!
REFERENCES
1. Schaffer FM, Ballow M: Immunodeficiency: Office work-up. J Resp Dis 1995;16:523
2. Ballow M, Schaffer FM: Molecular genetics of immunoglobulin genes and the generation of antibody diversity, in Levsin AL, Patterson Y (eds): Molecular and Cellular Immunology of the Allergic and Immune Response. New York, Marcel Dekker, 1994, pp 3-40
3. Buckly RH: Primary cellular immunodeficiencies. J Allergy Clin Immunol 2002;109:747
4. Schaffer FM, Newton JA: Intravenous gamma globulin administration to common variable immunodeficient women during pregnancy. Case report and review of the literature. J Perinatol 1994;14:114
5. Hirschlhorn R: Overview of biochemical abnormalities and molecular genetics of adenosine deaminase deficiency. Pediatr Res 1993;33(1suppl):S35
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