MSD’s Vaccine, ROTATEQ®, Reduced Severe Rotavirus Gastroenteritis in Infants in Asia and Africa

August 6, 2010

MSD’s Vaccine, ROTATEQ®, Reduced Severe Rotavirus Gastroenteritis in Infants in Asia and Africa

2010-08-06 01:23:02 –

In a study published today in The Lancet, ROTATEQ® (rotavirus vaccine, live, oral, pentavalent), MSD’s rotavirus vaccine, reduced the number of cases of severe rotavirus gastroenteritis by nearly half (48 percent) in infants evaluated in developing countries in Asia (Bangladesh and Vietnam) and by 39 percent in infants evaluated in developing countries in Africa (Ghana, Kenya, and Mali) through nearly two years of follow-up. This is the first study demonstrating efficacy for any rotavirus vaccine in developing countries in Asia and the first study to show efficacy for ROTATEQ in developing countries of Asia and Africa.

“We are encouraged by the data,” said study investigator Dr. Khalequz Zaman, International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh. “In this study, ROTATEQ prevented severe rotavirus gastroenteritis in infants in regions in Africa and Asia where the disease burden is quite high and rotavirus vaccines are needed the most.”

ROTATEQ is an oral pentavalent vaccine indicated for the prevention of rotavirus gastroenteritis in infants and children caused by the serotypes G1, G2, G3, G4, and G-serotypes that contain P1A[8] (e.g., G9). ROTATEQ may be administered as early as 6 weeks of age. The first dose should be administered at 6 to 12 weeks of age, with the subsequent doses administered at a minimum interval of four weeks between each dose.

ROTATEQ should not be administered to infants with a demonstrated history of hypersensitivity to any component of the vaccine. Infants with Severe Combined Immunodeficiency Disease (SCID) should not receive ROTATEQ. Cases of gastroenteritis associated with vaccine virus have been reported post-marketing in infants with SCID.

Rotavirus gastroenteritis is the leading cause of diarrheal disease mortality among children under 5 years of age, resulting in an estimated 527,000 deaths per year globally, mostly in Asia and Africa. It is highly prevalent and highly contagious, infecting nearly all children by age 5, often more than once in both developed and developing countries.

“Given the impact of rotavirus gastroenteritis in the developing world, reduction in severe rotavirus disease represents a critically important public health goal,” said Mark Feinberg, M.D., Ph.D., vice president, Medical Affairs and Policy, Merck Vaccines. “Merck is committed to advancing global health by improving access to ROTATEQ in areas most affected by the severe consequences of rotavirus disease.”

In 2009, the World Health Organization’s (WHO) Strategic Advisory Group of Experts recommended to expand rotavirus vaccine use to all regions of the world. The efficacy data for ROTATEQ in Asia and Africa, along with effectiveness data in Nicaragua, helped inform the WHO’s recommendation for expansion of the rotavirus vaccine to all regions. This recommendation led to global WHO-pre-qualification of ROTATEQ, accelerating the availability of vaccines in the developing world.

About the Study

More than 7,500 infants between 4 and 12 weeks of age from five developing countries in Asia (Bangladesh and Vietnam) and Africa (Ghana, Kenya, and Mali) were enrolled in the two-year randomized, double-blind, placebo-controlled clinical trial. The trial was designed to evaluate the efficacy of three doses of ROTATEQ (n=3,751) against severe rotavirus gastroenteritis versus placebo (n=3,753) in low income countries with high incidence of diarrheal disease mortality.

The study was coordinated through a partnership between Merck and the Rotavirus Vaccine Program (RVP), a collaboration between PATH, an international non-profit organization, WHO and the U.S. Centers for Disease Control and Prevention. Clinical trial investigators in Asia and Africa partnered with Merck and RVP to conduct the trial. The Merck and RVP partnership was initiated by the GAVI Alliance in an effort to introduce rotavirus vaccine in the developing world. The study was funded by RVP with a grant from the GAVI Alliance and was co-sponsored by Merck.

In this study, infants received ROTATEQ or placebo at approximately 6, 10, and 14 weeks of age with routine infant vaccines. Infants between 4 and 12 weeks of age who were free of symptoms of active gastrointestinal disease and could be adequately followed for safety were eligible. The primary endpoint was rotavirus gastroenteritis, irrespective of serotype, occurring 14 days or more after the third dose of ROTATEQ or placebo until the end of the study. Gastroenteritis was defined as three or more watery or looser than normal stools within a 24 hour period or forceful vomiting. Severity of rotavirus gastroenteritis was defined by a 20 point clinical scoring system (modified Vesikari system), with those cases with a score of 11 or more being classified as severe.

In Asia, 1,018 infants were randomly assigned to receive ROTATEQ and 1,018 infants received placebo; median follow-up time in both groups, from 14 days after the third dose of vaccine or placebo until final disposition, was 498 days. Over the entire study period, there were 38 cases of severe rotavirus gastroenteritis in the vaccine group, compared with 71 cases reported in the placebo group, resulting in a vaccine efficacy of 48.3 percent (95 percent CI 22.3, 66.1 percent) at sites in Asia. Through nearly two years of follow up, vaccine efficacy was 42.7 percent (95 percent CI 10.4, 63.9 percent) in Bangladesh and 63.9 percent (95 percent CI 7.6, 90.9 percent) in Vietnam.

In Africa, 2,733 infants were randomly assigned to receive ROTATEQ and 2,735 infants received placebo; median follow-up time in both groups was 527 days starting 14 days after the third dose of vaccine or placebo.
Over the entire study period, there were 79 cases of severe rotavirus gastroenteritis reported in the vaccine group, compared with the 129 cases reported in the placebo group, resulting in a vaccine efficacy of 39.3 percent (95 percent CI 19.1, 54.7 percent) at sites in Africa.

Efficacy was 55.5 percent (95 percent CI 28.0, 73.1 percent) in Ghana, 63.9 percent (95 percent CI < 0, 89.8 percent) in Kenya, and 17.6 percent (95 percent CI < 0, 45.0 percent) in Mali through nearly two years of follow up.

In post-hoc analyses, overall efficacy against severe rotavirus gastroenteritis in Asian infants was 51 percent (95 percent CI 12.8, 73.3 percent) in the first year of life and 45.5 percent (95 percent CI 1.2, 70.7 percent) in the second year of life. Efficacy in Bangladesh was 45.7 percent (95 percent CI < 0, 71.8 percent) in the first year of life and 39.3 percent (95 percent CI < 0, 69.7 percent) in the second year of life. Efficacy in Vietnam was 72.3 percent (95 percent CI < 0, 97.2 percent) in the first year of life and 64.6 percent (95 percent CI < 0, 93.9 percent) in the second year of life.

Overall efficacy against severe rotavirus gastroenteritis in African infants was 64.2 percent (95 percent CI 40.2, 79.4 percent) in the first year of life and 19.6 percent (95 percent CI < 0, 44.4 percent) in the second year of life. Efficacy in Ghana was 65.0 percent (95 percent CI 35.5, 81.9 percent) in the first year of life and 29.4 percent (95 percent CI < 0, 70.7 percent) in the second year of life. Efficacy in Kenya was 83.4 percent (95 percent CI 25.5, 98.2 percent) in the first year of life and less than 0 percent (95 percent CI < 0, 82.3 percent) in the second year of life. Efficacy in Mali was 1.0 percent (95 percent CI < 0, 81.6 percent) in the first year of life and 19.2 percent (95 percent CI < 0, 47.3 percent) in the second year of life. The surveillance system in the study protocol was designed to detect participants presenting to healthcare facilities. However, in Mali, for cultural reasons, many cases of severe diarrhea were preferentially taken to traditional healers during the first year of the study. Strengthening of the surveillance system after the first year of the study resulted in a 12-fold increase in detection of severe rotavirus gastroenteritis in Mali in the second year of life, and a higher point estimate of efficacy in the second year than in the first year. The proportion of subjects with reported serious adverse events (SAEs) was comparable between the vaccine and placebo groups in Asia (2.5 percent in ROTATEQ group, 2.0 percent in placebo group) and Africa (1.5 percent in ROTATEQ group, 1.7 percent in placebo group). The most frequent serious adverse event was pneumonia in Asia (1.2 percent in ROTATEQ group, 1.5 percent in placebo group) and gastroenteritis in Africa (0.6 percent in either ROTATEQ or placebo group). One confirmed case of intussusception (in Vietnam), in the placebo group (at Day 97 post-Dose 3), was reported during the clinical trial. “This study provided insights into how vaccine immune responses and efficacy varied in developing countries,” said Max Ciarlet, Ph.D., associate director, Merck Research Laboratories. “Several factors may adversely affect immune response and efficacy of vaccines in these regions, including poor nutrition, the presence of other intestinal bacteria and viruses, and co-infections in the digestive system.” Select Safety Information about ROTATEQ No safety or efficacy data are available from clinical trials regarding the administration of ROTATEQ to immunocompromised patients such as individuals with malignancies or who are otherwise immunocompromised; individuals receiving immunosuppressive therapy; individuals infected with HIV; or individuals who received a blood transfusion or blood products, including immunoglobulins within 42 days. More than 71,000 infants were evaluated in three Phase 3, placebo-controlled clinical trials. Parents/guardians were contacted on days 7, 14, and 42 after each dose regarding intussusception and any other serious adverse events. In the Rotavirus Efficacy and Safety Trial (REST) of more than 69,000 infants, ROTATEQ did not increase the risk of intussusception relative to placebo. There were no confirmed cases of intussesception during the 42-day period after dose one and no clustering of cases among vaccine recipients at any time period after any dose. Four cases of intussusception were reported in children who had received placebo following the one-year safety follow-up period. In a subset of more than 11,000 infants in these trials, the presence of adverse events was reported for 42 days after each dose. The most commonly reported adverse experiences with ROTATEQ (frequency >1/10) include upper respiratory infection, diarrhea, vomiting, pyrexia, otitis media, irritability, and cough.

The following adverse experiences have been spontaneously reported during post-approval use of ROTATEQ: urticaria and gastroenteritis with vaccine viral shedding in infants with SCID. Because these experiences were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or to establish a causal relationship to vaccine exposure.

In a prospective post-marketing observational study conducted using a large medical claims database, the risks of intussusception or Kawasaki disease resulting in emergency department visits or hospitalizations during the 30 days following any dose of vaccine were analyzed among 85,150 infants receiving one or more doses of ROTATEQ.

During the 0-30 day follow-up period after vaccination, there were no statistically significant differences in the rates of intussusception or Kawasaki disease compared with the expected background rates. In addition, there was no statistically significant increased risk of these adverse events during the 0-30 day follow-up period when comparing the 17,433 person-years of follow-up among infants receiving ROTATEQ (n equals 85,150) with the 12,339 person-years of follow up among a concurrent control group of infants who received DTaP, but not ROTATEQ (n equals 62,617).

There were six confirmed cases of intussusception among infants vaccinated with ROTATEQ compared with five among the concurrent controls vaccinated with DTaP (relative risk equals 0.8, 95 percent CI 0.22-3.52). There was one chart-confirmed case of Kawasaki disease identified among infants vaccinated with ROTATEQ and one chart-confirmed case of Kawasaki disease among concurrent DTaP controls (relative risk equals 0.7, 95 percent CI 0.01-55.56). In the general safety analyses, the Safety Monitoring Committee did not identify any specific safety concerns.

ROTATEQ® is a registered trademark of Merck & Co. Inc., Whitehouse Station, N.J., USA

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CDC: SCID is Contraindication for Rotavirus Vaccine

June 10, 2010

CDC: SCID is Contraindication for Rotavirus Vaccine

By Todd Neale, Staff Writer, MedPage Today
Published: June 10, 2010

ATLANTA — Rotavirus vaccine should not be given to infants with severe combined immunodeficiency (SCID), according to new CDC guidance.

The makers of the two live rotavirus vaccines — GlaxoSmithKline Biologicals (Rotarix) and Merck (RotaTeq) — had revised their labels in line with the change in December and February, respectively, with FDA approval.

The CDC announced the addition of severe combined immunodeficiency to the list of contraindications for the vaccines in the June 11 issue of Morbidity and Mortality Weekly Report, following consultations with members of the former Rotavirus Vaccine Work Group of the Advisory Committee on Immunization Practices (ACIP) and a review of the data.

Furthermore, “consultation with an immunologist or infectious disease specialist is advised for infants with known or suspected altered immunocompetence before rotavirus vaccine is administered,” the agency said.

Merck and GlaxoSmithKline Biologicals made the labeling changes in response to eight reports of vaccine-acquired rotavirus infection in infants with severe combined immunodeficiency since the 2006 approval of RotaTeq. Seven were related to the pentavalent RotaTeq and the last was related to the monovalent Rotarix, which was approved in 2008.

Five of the cases — four in the U.S. and one in Australia — were reported in the literature and another three — two in the U.S. and one from outside the U.S. — were reported to the Vaccine Adverse Event Reporting System.

All of the infants, who were diagnosed with severe combined immunodeficiency at between 3 and 9 months of age and had received at least one dose of the vaccine before diagnosis, had diarrhea from the rotavirus infection.

In all eight cases, vaccine-acquired rotavirus infection was confirmed by reverse-transcription-polymerase chain reaction and nucleotide sequencing.

Prolonged shedding of the virus was documented in at least six cases with a duration of up to 11 months.

For infants in whom it is not contraindicated, rotavirus vaccination is recommended by ACIP in three doses at ages 2, 4, and 6 months for RotaTeq and in two doses at ages 2 and 4 months for Rotarix.

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FDA says Healthcare Providers Can Resume Use of Rotarix (Rotavirus Vaccine, Live, Oral)

May 14, 2010

Children should be screened for SCID BEFORE being given this LIVE vaccine!!!

FDA says Healthcare Providers Can Resume Use of Rotarix (Rotavirus Vaccine, Live, Oral)

Press Release Source: GlaxoSmithKline On Friday May 14, 2010, 3:51 pm EDT

PHILADELPHIA, May 14 /PRNewswire-FirstCall/ — GlaxoSmithKline (NYSE:GSKNews) announced that the Food and Drug Administration (FDA) has determined that U.S. healthcare practitioners can resume the use of Rotarix® (Rotavirus Vaccine, Live, Oral), effective immediately. This action supersedes the FDA’s recommendation from March 22, 2010 and reflects the agency’s assessment that the presence of porcine circovirus type 1 (PCV-1) in the vaccine poses no safety risk.

The FDA stated that the benefits of rotavirus vaccination are substantial, and include prevention of death in some parts of the world and hospitalization for severe rotavirus disease in the United States. The FDA further concluded that these benefits outweigh the risk, which is theoretical.

Barbara Howe, MD, Vice President, Director, North American Vaccine Development, GlaxoSmithKline stated: “We appreciate the swift and thorough review conducted by both the FDA and an expert advisory committee into the recent findings related to PCV-1 and the benefit/risk profile of Rotarix. We will continue to work with the FDA and other regulatory authorities on next steps as we maintain our commitment to helping protect infants from rotavirus disease in the U.S. and around the world.”

Notes to Editors

About PCV-1

Porcine circovirus 1 (PCV-1) is a small circular virus composed of a single strand of DNA. According to scientific literature, PCV-1 is a common virus that has been found in pork products. This is consistent with the body of literature that has not shown any evidence of PCV-1 infection in humans, or any other animals, including pigs.

About Rotarix®

Rotarix is a two-dose, orally-administered vaccine that offers protection against rotavirus to infants and children. More than 69 million doses of the vaccine have been distributed globally, with 2.5 million in the United States.

In the U.S., Rotarix is indicated for the prevention of rotavirus gastroenteritis caused by G1 and non-G1 types (G3, G4, and G9). It is approved for use in infants 6 weeks to 24 weeks of age.

The safety profile of Rotarix is based on extensive clinical data from the largest vaccine clinical trial program conducted by GSK, enrolling more than 90,000 participants in Europe, Latin America, Asia, Africa, and the U.S.

Important Safety Information Based on the Rotarix US Prescribing Information

  • In clinical studies, common adverse events were fussiness/irritability, cough/runny nose, fever, loss of appetite, and vomiting.
  • Contraindications include a history of any of the following: Hypersensitivity to any component of the vaccine including latex rubber (contained in the oral applicator), uncorrected congenital malformation of the gastrointestinal tract, or Severe Combined Immunodeficiency Disease (SCID).

  • Administration in infants suffering from acute diarrhea or vomiting should be delayed.
  • Safety and effectiveness in infants with chronic gastrointestinal disorders, or with known primary or secondary immunodeficiencies, have not been evaluated.
  • Vaccination may not provide 100% protection to all recipients.

About Rotavirus

Rotavirus is the leading cause of severe gastroenteritis among children below five years of age and a major disease burden in developing countries. It is estimated that more than half a million children die of rotavirus gastroenteritis each year, a child a minute worldwide. Of these deaths, 90% occur in Asia and Africa. More than 100,000 deaths each year occur in India and sub-Saharan Africa and 35,000 in China. It is predicted that rotavirus vaccination could prevent more than 2 million rotavirus deaths globally over the next decade.

Globally, 25% to 55% of all children under the age of five hospitalized with diarrhoea or acute gastroenteritis are infected with rotavirus.

Before rotavirus vaccination was introduced in the U.S., each year an estimated 2.7 million children younger than five years of age experienced rotavirus disease, resulting in hundreds of thousands of emergency room visits and more than 55,000 hospitalisations.

GlaxoSmithKline Biologicals

GlaxoSmithKline Biologicals (GSK Biologicals), GlaxoSmithKline’s vaccines business, is one of the world’s leading vaccine companies and a leader in innovation. The company is active in the fields of vaccine research, development and production with over 30 vaccines approved for marketing and 20 more in development. For further information please visit

GlaxoSmithKline – one of the world’s leading research-based pharmaceutical and healthcare companies – is committed to improving the quality of human life by enabling people to do more, feel better and live longer.  For further information please visit

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Rotavirus vaccine effective in reducing pediatric deaths, illness in developing nations

January 28, 2010

Rotavirus vaccine effective in reducing pediatric deaths, illness in developing nations

Rotavirus vaccine use likely contributed to a reduction in pediatric deaths in Mexico and a reduction in severe gastroenteritis in vaccinated African infants, according to two studies published today in The New England Journal of Medicine. However, a brief report in the same journal also cautions against use of rotavirus vaccines in children with severe combined immunodeficiency.

Researchers from the National Center for Child and Adolescent Health, Ministry of Health, Mexico City and the CDC said that a rotavirus vaccination program introduced in Mexico in February 2006 led to a marked reduction in deaths from diarrhea among young children.

The researchers compared annual deaths from diarrhea before and after the immunization program began. The researchers noted that for the three years before the vaccination program began, the median annual number of diarrhea-related deaths among children younger than 5 was 1,793, for a mortality rate of 18.1 deaths per 100,000. That number dropped to 1,118 deaths in 2008, which yielded a mortality rate of 11.8 per 100,000 children. The researchers said diarrhea-related mortality was 29% lower for children between the ages of 12 and 23 months, few of whom were age-eligible for vaccination, but mortality among unvaccinated children between the ages of 24 and 59 months did not change significantly.

The researchers noted that their study findings were limited in that it was not possible to attribute the reduction in deaths to vaccination, because precise vaccine coverage information is lacking and other changes, like improved hand hygiene, may have affected the rates.

In the second study, researchers in South Africa and Malawi enrolled 4,939 infants in clinical trials examining the efficacy of GlaxoSmithKline’s rotavirus vaccine, Rotarix.

Healthy babies were randomly assigned (1:1:1) to receive placebo followed by two or three doses of vaccine, or three doses of placebo, respectively, at 6, 10 and 14 weeks of age with routine childhood vaccines including oral poliovirus vaccine.

The researchers in that study noted rotavirus-related gastroenteritis occurred in 4.9% of the placebo group and in 1.9% of the pooled vaccine group, yielding a statistically significant vaccine efficacy of 61.2%. The researchers said efficacy against all-cause severe gastroenteritis was 30.2%.

In a brief report accompanying the two journal articles, researchers from Baylor College of Medicine noted that it is important to remember that the rotavirus vaccines can actually cause the disease in infants born with severe combined immunodeficiency.

In the report, experts examined three cases in which infants developed rotavirus disease after receiving the live attenuated rotavirus vaccine.

“All three infants (in the study) were vaccinated before they were diagnosed with severe combined immunodeficiency,” Paula Hertel, MD, assistant professor of pediatrics-gastroenterology at BCM and Texas Children’s Hospital, and study researcher said in a press release. “If the children could have been caught in a screening test done within days of birth, they may not have received the vaccine.”

While current routine newborn screening does test for many diseases, severe combined immune deficiency is not one of them, the researchers in the brief report noted.

Usually, experts recommend that children with severe combined immune deficiency not receive live vaccines. However, this vaccine must be given before most children are diagnosed with the immune disorder. The American College of Medical Genetics recently recommended that severe combined immunodeficiency be included as a part of the newborn screen.

Scientists analyzed the viral genetic material in stool specimens from the three children. This enabled them to determine that the rotavirus was of vaccine origin. This study led to a change in the vaccine exclusions listed on the vaccine manufacturer’s label to include a history of severe combined immunodeficiency.

The children did not successfully fight the infection until they underwent bone marrow transplantation or enzyme replacement therapy that gave them a functioning immune system, researchers noted.

The vaccine is very important for healthy infants, and in the United States, rotavirus cases decreased by 50% after the first season of vaccinations against the illness, said Hertel.

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AAAAI: Rotavirus Vaccine May Cause Infections in SCID Kids

March 19, 2009

AAAAI: Rotavirus Vaccine May Cause Infections in SCID Kids

By John Gever, Senior Editor, MedPage Today

Published: March 18, 2009

Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston.

WASHINGTON, March 17 — The rotavirus vaccine recommended for all infants can cause infection in babies with severe immunodeficiencies, a researcher said here.

Two infants receiving the first two of three scheduled doses of the live, attenuated-virus rotavirus vaccine (RotaTeq) developed infections traced to the product, according to Niraj C. Patel, M.D., of Baylor College of Medicine in Houston.

After the babies were hospitalized with diarrhea and other symptoms consistent with rotavirus infection, it was discovered that they had severe combined immunodeficiency syndrome (SCID).

These are the first reported cases of infection caused by the rotavirus vaccine, which was approved in 2006, Dr. Patel said in a late-breaking research session here at the American Academy of Allergy, Asthma, and Immunology meeting.

Dr. Patel said molecular analyses showed that the vaccine caused the infections. All the attenuated virus strains used in the vaccine contain two bovine genes that aren’t found in wild-type human rotavirus. Both were present in the rotavirus isolates obtained from the babies.

The CDC recommends that the vaccine be given to all infants at two, four, and six months of age. Both infants who developed infections received the first two doses on schedule.

One case involved a girl hospitalized for pneumonia and respiratory infection from two weeks to two months of age; SCID was not immediately recognized. About a month after the second dose, she was rehospitalized with diarrhea, acidosis, and failure to thrive.

The other case was a boy who developed diarrhea, dehydration, and shock six days after the second vaccination.

Dr. Patel noted that other live-pathogen vaccines — poliovirus, BCG, measles, and varicella — have also been found to cause infection in children with SCID.

The condition occurs in about one in 500,000 to 1 million births. The Immune Deficiency Foundation estimates that the median age at diagnosis is about 24 weeks — well after infant vaccinations are supposed to begin.

There is currently no standard, reliable screening test for SCID, Dr. Patel said. It is usually diagnosed when infants present with repeated and/or unusual infections. Lymphopenia is a warning sign, but “it is not very specific,” he said.

The molecular analysis of the infants’ viral isolates indicated that the vaccine strains underwent mutation to cause disease.

That may explain why the infections did not develop immediately after the first dose in either case. “[The virus] perhaps took some time to mutate before causing disease,” he said.

Session moderator A. Wesley Burks, M.D., of Duke University in Durham, N.C., commented that the clinical implications are still uncertain.

“We [still] have to understand what the right thing to do is,” he said.

“Immune deficiency is not common, but at the same time it happens. Children [with it] that get a live viral vaccine, they’re going to have trouble with it.”

Both he and Dr. Patel suggested that a reliable screening test for infant immunodeficiencies is needed to avert future infections associated with live-virus immunizations.

No external funding for the study was reported.

Dr. Patel reported no potential conflicts of interest. Dr. Burks reported relationships with Acto-GeniX NV, Allertein, Dannon Co. Probiotics, EpiPen/Dey L.P., Genentech, Novartis, Nutricia, McNeil Nutritionals, Mead Johnson, MastCell Inc., and Gerber.

Primary source: American Academy of Allergy, Asthma & Immunology
Source reference:
Patel N, et al “Vaccine-acquired rotavirus infection in two infants with severe combined immunodeficiency” AAAAI 2009; Abstract L29.

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On another busy evening, a feverish 7-month-old boy is another failure to thrive

May 1, 2006

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


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!


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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