Recurrent otitis may be linked to neonate-like immune response in young children

Could recurrent acute otitis media be related to a neonate-like antibody response in children as old as 24 months? Dr. Michael E. Pichichero believes so.

He and his colleagues have found data indicating the existence of what may be a new immunodeficiency that they are calling prolonged neonatal immune deficiency, Dr. Pichichero, director of the Rochester (N.Y.) General Hospital Research Institute, said in an interview.

Dr. Pichichero and his team started tracking children from his suburban Rochester, N.Y., private practice and collected blood samples from 600 patients who had not experienced acute otitis media by the age of 6 months. Between the ages of 6 and 30 months, 34 of those children (5.7%) experienced recurrent AOM and were classified as "stringently otitis prone," defined as having had three AOM episodes within 6 months, or four within 12 months, despite optimal diagnosis and treatment. These children were age-matched with 34 children from the same cohort, who experienced few or no episodes of AOM.**

Children in both groups received primary vaccinations according to the approved immunization schedule; each had blood drawn at 6, 9, 12, 15, 18, and 24 months of age.

Among samples from the stringently otitis-prone children, the investigators noted weak immune responses, including poor B and T cell memory after natural exposure to nontypeable Haemophilus influenzae and Streptococcus pneumoniae nasal colonization and AOM.

They measured antibody levels for diphtheria, tetanus, pertussis, pertussis filamentous hemagglutinin, polio, hepatitis B, H. influenzae type b, and S. pneumoniae pneumococcal polysaccharides.

When compared with children in the control group, stringently otitis-prone children at all ages had nonprotective levels of antibody for diphtheria (odds ratio, 8.59), tetanus (OR greater than 1), pertussis pertactin (OR, 5.09), and hepatitis B (OR greater than 10*). While these children more often had nonprotective levels of antibody for pertussis filamentous hemagglutinin, polio 3, and S. pneumoniae 23, the group effect varied with age (Pediatr. Infect. Dis. J. 2013 June 18; published ahead of print [doi: 10.1097/INF.0b013e31829e887e]).

Antibody responses also were measured in both groups at age 15 months, before the children received booster shots. Stringently otitis-prone children had "nondetectable or below protection titers," the investigators found. Specifically, 74% of the children had 1 or more antibodies below protection; 56% had 2 or more; 44% had 3 or more; and 27% had 5 or more. Among the age-matched controls, 47% had 1 or more; 27% had 2 or more; 12% had 3 or more; and 0% had 5 or more.

Stringently otitis-prone children may "have immune responses to otopathogens ... resembling a neonatal-like immune profile during at least the first 18-24 years of life," Dr. Pichichero said. Based on these findings, "a child with recurrent AOM should be considered a possible low vaccine responder, and vaccine-induced antibody levels may need to be evaluated."

The findings aren’t without controversy. "Not everyone has accepted the results as meaningful," Dr. Stephen I. Pelton, an epidemiologist at Boston Medical Center, said in an interview. "I think the issue relates to the fact that most children – virtually all – who have recurrent AOM do not have any other infectious diseases. Vaccine failures for PCV7 have been few, and as far as I am aware, pertussis is not more common in children with [recurrent AOM]."

Dr. Pelton also said that "children with AOM are more likely to be colonized with otopathogens early in life, and develop disease early in life as well."

"There is not that much pertussis or tetanus or diphtheria or polio around in the United States, so we did not see an increase in those diseases among otitis-prone kids," Dr. Pichichero noted. "However, we show in a paper that is forthcoming, that [stringently otitis-prone children] don’t respond to influenza vaccine, and correspondingly the kids do get flu more often. They don’t make good immunity to [respiratory syncytial virus] infections, and they get RSV more often. They also get pneumococcal infections more often."

Dr. Mark Sawyer, a pediatric infectious disease specialist at Rady Children’s Hospital in San Diego, pointed out that the question is, why don’t these children respond well to vaccines? "What is it about their immune system? That needs to be uncovered, and then if they identify those kids with some kind of simple questions, then maybe you would immunize them differently."

Dr. Pichichero said that he aims to next investigate the question of whether or not at some point otitis-prone children ever reach antibody parity with non–otitis-prone children. "We will be studying dendritic cells, B cells, and T cells further in the future. What is the mechanism? That will be the key to unlock what we can do about it."

If the data in the current study are confirmed, Dr. Pichichero said, "at 9 months when we take a blood sample for anemia and lead, we may also take a sample for vaccine responses. We could give a booster if needed."

"I think it’s a long way from leading to a change in the vaccine schedule. I think the immediate next step is to get this reproduced in a larger number of kids that are more equally balanced, so we can find out if this is purely an immune problem, or does this relate to allergy or other things that set aside one group from another," said Dr. Sawyer, who previously served on the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices.

For now, Dr. Pichichero said the take-away for practicing pediatricians treating children with recurrent otitis media is that "you can explain to the parent that it may be the kid isn’t making immunity to the infection germ. We have strong hints that the ... immune system is immature."

Dr. Pichichero and his colleagues reported no relevant disclosures. The studies received funding from the Thrasher Foundation and the National Institute for Deafness and Communication Disorders.

[email protected]

*Correction, 10/3/2013: An earlier version of this story misstated the odds ratio for nonprotective levels of antibody in otitis-prone children with hepatitis B. In addition, the article misstated the name of Dr. Michael E. Pichichero.

**Updated, 10/5/2013.

Could recurrent acute otitis media be related to a neonate-like antibody response in children as old as 24 months? Dr. Michael E. Pichichero believes so.

He and his colleagues have found data indicating the existence of what may be a new immunodeficiency that they are calling prolonged neonatal immune deficiency, Dr. Pichichero, director of the Rochester (N.Y.) General Hospital Research Institute, said in an interview.

Dr. Pichichero and his team started tracking children from his suburban Rochester, N.Y., private practice and collected blood samples from 600 patients who had not experienced acute otitis media by the age of 6 months. Between the ages of 6 and 30 months, 34 of those children (5.7%) experienced recurrent AOM and were classified as "stringently otitis prone," defined as having had three AOM episodes within 6 months, or four within 12 months, despite optimal diagnosis and treatment. These children were age-matched with 34 children from the same cohort, who experienced few or no episodes of AOM.**

Children in both groups received primary vaccinations according to the approved immunization schedule; each had blood drawn at 6, 9, 12, 15, 18, and 24 months of age.

Among samples from the stringently otitis-prone children, the investigators noted weak immune responses, including poor B and T cell memory after natural exposure to nontypeable Haemophilus influenzae and Streptococcus pneumoniae nasal colonization and AOM.

They measured antibody levels for diphtheria, tetanus, pertussis, pertussis filamentous hemagglutinin, polio, hepatitis B, H. influenzae type b, and S. pneumoniae pneumococcal polysaccharides.

When compared with children in the control group, stringently otitis-prone children at all ages had nonprotective levels of antibody for diphtheria (odds ratio, 8.59), tetanus (OR greater than 1), pertussis pertactin (OR, 5.09), and hepatitis B (OR greater than 10*). While these children more often had nonprotective levels of antibody for pertussis filamentous hemagglutinin, polio 3, and S. pneumoniae 23, the group effect varied with age (Pediatr. Infect. Dis. J. 2013 June 18; published ahead of print [doi: 10.1097/INF.0b013e31829e887e]).

Antibody responses also were measured in both groups at age 15 months, before the children received booster shots. Stringently otitis-prone children had "nondetectable or below protection titers," the investigators found. Specifically, 74% of the children had 1 or more antibodies below protection; 56% had 2 or more; 44% had 3 or more; and 27% had 5 or more. Among the age-matched controls, 47% had 1 or more; 27% had 2 or more; 12% had 3 or more; and 0% had 5 or more.

Stringently otitis-prone children may "have immune responses to otopathogens ... resembling a neonatal-like immune profile during at least the first 18-24 years of life," Dr. Pichichero said. Based on these findings, "a child with recurrent AOM should be considered a possible low vaccine responder, and vaccine-induced antibody levels may need to be evaluated."

The findings aren’t without controversy. "Not everyone has accepted the results as meaningful," Dr. Stephen I. Pelton, an epidemiologist at Boston Medical Center, said in an interview. "I think the issue relates to the fact that most children – virtually all – who have recurrent AOM do not have any other infectious diseases. Vaccine failures for PCV7 have been few, and as far as I am aware, pertussis is not more common in children with [recurrent AOM]."

Dr. Pelton also said that "children with AOM are more likely to be colonized with otopathogens early in life, and develop disease early in life as well."

"There is not that much pertussis or tetanus or diphtheria or polio around in the United States, so we did not see an increase in those diseases among otitis-prone kids," Dr. Pichichero noted. "However, we show in a paper that is forthcoming, that [stringently otitis-prone children] don’t respond to influenza vaccine, and correspondingly the kids do get flu more often. They don’t make good immunity to [respiratory syncytial virus] infections, and they get RSV more often. They also get pneumococcal infections more often."

Dr. Mark Sawyer, a pediatric infectious disease specialist at Rady Children’s Hospital in San Diego, pointed out that the question is, why don’t these children respond well to vaccines? "What is it about their immune system? That needs to be uncovered, and then if they identify those kids with some kind of simple questions, then maybe you would immunize them differently."

Dr. Pichichero said that he aims to next investigate the question of whether or not at some point otitis-prone children ever reach antibody parity with non–otitis-prone children. "We will be studying dendritic cells, B cells, and T cells further in the future. What is the mechanism? That will be the key to unlock what we can do about it."

If the data in the current study are confirmed, Dr. Pichichero said, "at 9 months when we take a blood sample for anemia and lead, we may also take a sample for vaccine responses. We could give a booster if needed."

"I think it’s a long way from leading to a change in the vaccine schedule. I think the immediate next step is to get this reproduced in a larger number of kids that are more equally balanced, so we can find out if this is purely an immune problem, or does this relate to allergy or other things that set aside one group from another," said Dr. Sawyer, who previously served on the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices.

For now, Dr. Pichichero said the take-away for practicing pediatricians treating children with recurrent otitis media is that "you can explain to the parent that it may be the kid isn’t making immunity to the infection germ. We have strong hints that the ... immune system is immature."

Dr. Pichichero and his colleagues reported no relevant disclosures. The studies received funding from the Thrasher Foundation and the National Institute for Deafness and Communication Disorders.

[email protected]

*Correction, 10/3/2013: An earlier version of this story misstated the odds ratio for nonprotective levels of antibody in otitis-prone children with hepatitis B. In addition, the article misstated the name of Dr. Michael E. Pichichero.

**Updated, 10/5/2013.

Could recurrent acute otitis media be related to a neonate-like antibody response in children as old as 24 months? Dr. Michael E. Pichichero believes so.

He and his colleagues have found data indicating the existence of what may be a new immunodeficiency that they are calling prolonged neonatal immune deficiency, Dr. Pichichero, director of the Rochester (N.Y.) General Hospital Research Institute, said in an interview.

Dr. Pichichero and his team started tracking children from his suburban Rochester, N.Y., private practice and collected blood samples from 600 patients who had not experienced acute otitis media by the age of 6 months. Between the ages of 6 and 30 months, 34 of those children (5.7%) experienced recurrent AOM and were classified as "stringently otitis prone," defined as having had three AOM episodes within 6 months, or four within 12 months, despite optimal diagnosis and treatment. These children were age-matched with 34 children from the same cohort, who experienced few or no episodes of AOM.**

Children in both groups received primary vaccinations according to the approved immunization schedule; each had blood drawn at 6, 9, 12, 15, 18, and 24 months of age.

Among samples from the stringently otitis-prone children, the investigators noted weak immune responses, including poor B and T cell memory after natural exposure to nontypeable Haemophilus influenzae and Streptococcus pneumoniae nasal colonization and AOM.

They measured antibody levels for diphtheria, tetanus, pertussis, pertussis filamentous hemagglutinin, polio, hepatitis B, H. influenzae type b, and S. pneumoniae pneumococcal polysaccharides.

When compared with children in the control group, stringently otitis-prone children at all ages had nonprotective levels of antibody for diphtheria (odds ratio, 8.59), tetanus (OR greater than 1), pertussis pertactin (OR, 5.09), and hepatitis B (OR greater than 10*). While these children more often had nonprotective levels of antibody for pertussis filamentous hemagglutinin, polio 3, and S. pneumoniae 23, the group effect varied with age (Pediatr. Infect. Dis. J. 2013 June 18; published ahead of print [doi: 10.1097/INF.0b013e31829e887e]).

Antibody responses also were measured in both groups at age 15 months, before the children received booster shots. Stringently otitis-prone children had "nondetectable or below protection titers," the investigators found. Specifically, 74% of the children had 1 or more antibodies below protection; 56% had 2 or more; 44% had 3 or more; and 27% had 5 or more. Among the age-matched controls, 47% had 1 or more; 27% had 2 or more; 12% had 3 or more; and 0% had 5 or more.

Stringently otitis-prone children may "have immune responses to otopathogens ... resembling a neonatal-like immune profile during at least the first 18-24 years of life," Dr. Pichichero said. Based on these findings, "a child with recurrent AOM should be considered a possible low vaccine responder, and vaccine-induced antibody levels may need to be evaluated."

The findings aren’t without controversy. "Not everyone has accepted the results as meaningful," Dr. Stephen I. Pelton, an epidemiologist at Boston Medical Center, said in an interview. "I think the issue relates to the fact that most children – virtually all – who have recurrent AOM do not have any other infectious diseases. Vaccine failures for PCV7 have been few, and as far as I am aware, pertussis is not more common in children with [recurrent AOM]."

Dr. Pelton also said that "children with AOM are more likely to be colonized with otopathogens early in life, and develop disease early in life as well."

"There is not that much pertussis or tetanus or diphtheria or polio around in the United States, so we did not see an increase in those diseases among otitis-prone kids," Dr. Pichichero noted. "However, we show in a paper that is forthcoming, that [stringently otitis-prone children] don’t respond to influenza vaccine, and correspondingly the kids do get flu more often. They don’t make good immunity to [respiratory syncytial virus] infections, and they get RSV more often. They also get pneumococcal infections more often."

Dr. Mark Sawyer, a pediatric infectious disease specialist at Rady Children’s Hospital in San Diego, pointed out that the question is, why don’t these children respond well to vaccines? "What is it about their immune system? That needs to be uncovered, and then if they identify those kids with some kind of simple questions, then maybe you would immunize them differently."

Dr. Pichichero said that he aims to next investigate the question of whether or not at some point otitis-prone children ever reach antibody parity with non–otitis-prone children. "We will be studying dendritic cells, B cells, and T cells further in the future. What is the mechanism? That will be the key to unlock what we can do about it."

If the data in the current study are confirmed, Dr. Pichichero said, "at 9 months when we take a blood sample for anemia and lead, we may also take a sample for vaccine responses. We could give a booster if needed."

"I think it’s a long way from leading to a change in the vaccine schedule. I think the immediate next step is to get this reproduced in a larger number of kids that are more equally balanced, so we can find out if this is purely an immune problem, or does this relate to allergy or other things that set aside one group from another," said Dr. Sawyer, who previously served on the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices.

For now, Dr. Pichichero said the take-away for practicing pediatricians treating children with recurrent otitis media is that "you can explain to the parent that it may be the kid isn’t making immunity to the infection germ. We have strong hints that the ... immune system is immature."

Dr. Pichichero and his colleagues reported no relevant disclosures. The studies received funding from the Thrasher Foundation and the National Institute for Deafness and Communication Disorders.

[email protected]

*Correction, 10/3/2013: An earlier version of this story misstated the odds ratio for nonprotective levels of antibody in otitis-prone children with hepatitis B. In addition, the article misstated the name of Dr. Michael E. Pichichero.

**Updated, 10/5/2013.