Amy Karon

Fecal immunochemical testing with a low hemoglobin threshold for colonoscopy resembled one-time, primary colonoscopy for detecting advanced neoplasias in the first-degree relatives of colorectal cancer patients, investigators reported in the November issue of Gastroenterology.

Annual fecal immunochemical testing (FIT), followed by colonoscopy if hemoglobin levels met or exceeded 10 mcg per gram of feces, detected all cases of colorectal cancer (CRC) and 61% of advanced adenomas in the study population, said Dr. Enrique Quintero and Dr. Maria Carrillo at the Universidad de la Laguna in Spain and their associates.

But one-time colonoscopy was better than FIT for detecting all neoplasms as a whole in first-degree relatives of patients with CRC, the researchers reported. Based on the findings, initial screening with FIT should be considered when access to colonoscopy is limited, especially if patients are more likely to accept FIT than colonoscopy, the investigators said (Gastroenterology [doi: 10.1053/j.gastro.2014.08.004]).

Courtesy: American Gastroenterological Association

The trial included 1,918 first-degree relatives of patients with CRC. In all, 782 relatives were randomized to one-time colonoscopy, while 784 were assigned to annual FIT for 3 years, the researchers reported. Advanced neoplasia was detected in 3.9% of the FIT group and in 5.8% of the primary colonoscopy group, the investigators said (odds ratio, 1.56; 95% confidence interval, 0.95-2.56; P = .08). Rates of detection of advanced neoplasia also were similar between the FIT and primary colonoscopy groups when participants were stratified by age, sex, age of family member with CRC, type of familial relationship, and number of relatives with CRC, the researchers reported. However, primary colonoscopy identified significantly more nonadvanced adenomas (19.8%) than did FIT (5.4%), they added (OR, 4.71; 95% CI, 3.22-6.89; P less than .001).

Participants with negative FIT results were invited to undergo colonoscopy at the end of the study, the researchers said. Follow-up colonoscopies in these relatives showed that FIT had missed 39% of advanced adenomas but no cases of CRC, they reported. To detect one case of advanced CRC, only 4 relatives in the FIT group needed to undergo colonoscopy, compared with 18 members in the primary colonoscopy group, they added. “A potential benefit of FIT over primary colonoscopy in familial CRC screening is that it may save a substantial number of unnecessary colonoscopies, thus preventing harm and lowering costs,” the investigators concluded.

Ethical concerns prevented the researchers from assessing the efficacy of FIT for more than 3 years, they said. In addition, participants knew they could opt out of their assigned screening method before providing informed consent, which could have biased rates of detection of advanced CRC, the researchers noted. However, these rates did not significantly differ between diagnostic groups, they said. The study did not look at sessile serrated or traditional serrated polyps, because the study was designed when these polyps were still considered hyperplastic and nonmalignant, the investigators noted.

Future studies should evaluate the acceptance of FIT-based screening and its effects on mortality in familial CRC, the researchers concluded.

Their study was supported by grants from Fundación Canaria para la Investigación Sanitaria, Caja de Canarias, and Departmento de Medicina Interna de la Universidad de La Laguna. They reported having no conflicts of interest.

Fecal immunochemical testing with a low hemoglobin threshold for colonoscopy resembled one-time, primary colonoscopy for detecting advanced neoplasias in the first-degree relatives of colorectal cancer patients, investigators reported in the November issue of Gastroenterology.

Annual fecal immunochemical testing (FIT), followed by colonoscopy if hemoglobin levels met or exceeded 10 mcg per gram of feces, detected all cases of colorectal cancer (CRC) and 61% of advanced adenomas in the study population, said Dr. Enrique Quintero and Dr. Maria Carrillo at the Universidad de la Laguna in Spain and their associates.

But one-time colonoscopy was better than FIT for detecting all neoplasms as a whole in first-degree relatives of patients with CRC, the researchers reported. Based on the findings, initial screening with FIT should be considered when access to colonoscopy is limited, especially if patients are more likely to accept FIT than colonoscopy, the investigators said (Gastroenterology [doi: 10.1053/j.gastro.2014.08.004]).

Courtesy: American Gastroenterological Association

The trial included 1,918 first-degree relatives of patients with CRC. In all, 782 relatives were randomized to one-time colonoscopy, while 784 were assigned to annual FIT for 3 years, the researchers reported. Advanced neoplasia was detected in 3.9% of the FIT group and in 5.8% of the primary colonoscopy group, the investigators said (odds ratio, 1.56; 95% confidence interval, 0.95-2.56; P = .08). Rates of detection of advanced neoplasia also were similar between the FIT and primary colonoscopy groups when participants were stratified by age, sex, age of family member with CRC, type of familial relationship, and number of relatives with CRC, the researchers reported. However, primary colonoscopy identified significantly more nonadvanced adenomas (19.8%) than did FIT (5.4%), they added (OR, 4.71; 95% CI, 3.22-6.89; P less than .001).

Participants with negative FIT results were invited to undergo colonoscopy at the end of the study, the researchers said. Follow-up colonoscopies in these relatives showed that FIT had missed 39% of advanced adenomas but no cases of CRC, they reported. To detect one case of advanced CRC, only 4 relatives in the FIT group needed to undergo colonoscopy, compared with 18 members in the primary colonoscopy group, they added. “A potential benefit of FIT over primary colonoscopy in familial CRC screening is that it may save a substantial number of unnecessary colonoscopies, thus preventing harm and lowering costs,” the investigators concluded.

Ethical concerns prevented the researchers from assessing the efficacy of FIT for more than 3 years, they said. In addition, participants knew they could opt out of their assigned screening method before providing informed consent, which could have biased rates of detection of advanced CRC, the researchers noted. However, these rates did not significantly differ between diagnostic groups, they said. The study did not look at sessile serrated or traditional serrated polyps, because the study was designed when these polyps were still considered hyperplastic and nonmalignant, the investigators noted.

Future studies should evaluate the acceptance of FIT-based screening and its effects on mortality in familial CRC, the researchers concluded.

Their study was supported by grants from Fundación Canaria para la Investigación Sanitaria, Caja de Canarias, and Departmento de Medicina Interna de la Universidad de La Laguna. They reported having no conflicts of interest.

Fecal immunochemical testing with a low hemoglobin threshold for colonoscopy resembled one-time, primary colonoscopy for detecting advanced neoplasias in the first-degree relatives of colorectal cancer patients, investigators reported in the November issue of Gastroenterology.

Annual fecal immunochemical testing (FIT), followed by colonoscopy if hemoglobin levels met or exceeded 10 mcg per gram of feces, detected all cases of colorectal cancer (CRC) and 61% of advanced adenomas in the study population, said Dr. Enrique Quintero and Dr. Maria Carrillo at the Universidad de la Laguna in Spain and their associates.

But one-time colonoscopy was better than FIT for detecting all neoplasms as a whole in first-degree relatives of patients with CRC, the researchers reported. Based on the findings, initial screening with FIT should be considered when access to colonoscopy is limited, especially if patients are more likely to accept FIT than colonoscopy, the investigators said (Gastroenterology [doi: 10.1053/j.gastro.2014.08.004]).

Courtesy: American Gastroenterological Association

The trial included 1,918 first-degree relatives of patients with CRC. In all, 782 relatives were randomized to one-time colonoscopy, while 784 were assigned to annual FIT for 3 years, the researchers reported. Advanced neoplasia was detected in 3.9% of the FIT group and in 5.8% of the primary colonoscopy group, the investigators said (odds ratio, 1.56; 95% confidence interval, 0.95-2.56; P = .08). Rates of detection of advanced neoplasia also were similar between the FIT and primary colonoscopy groups when participants were stratified by age, sex, age of family member with CRC, type of familial relationship, and number of relatives with CRC, the researchers reported. However, primary colonoscopy identified significantly more nonadvanced adenomas (19.8%) than did FIT (5.4%), they added (OR, 4.71; 95% CI, 3.22-6.89; P less than .001).

Participants with negative FIT results were invited to undergo colonoscopy at the end of the study, the researchers said. Follow-up colonoscopies in these relatives showed that FIT had missed 39% of advanced adenomas but no cases of CRC, they reported. To detect one case of advanced CRC, only 4 relatives in the FIT group needed to undergo colonoscopy, compared with 18 members in the primary colonoscopy group, they added. “A potential benefit of FIT over primary colonoscopy in familial CRC screening is that it may save a substantial number of unnecessary colonoscopies, thus preventing harm and lowering costs,” the investigators concluded.

Ethical concerns prevented the researchers from assessing the efficacy of FIT for more than 3 years, they said. In addition, participants knew they could opt out of their assigned screening method before providing informed consent, which could have biased rates of detection of advanced CRC, the researchers noted. However, these rates did not significantly differ between diagnostic groups, they said. The study did not look at sessile serrated or traditional serrated polyps, because the study was designed when these polyps were still considered hyperplastic and nonmalignant, the investigators noted.

Future studies should evaluate the acceptance of FIT-based screening and its effects on mortality in familial CRC, the researchers concluded.

Their study was supported by grants from Fundación Canaria para la Investigación Sanitaria, Caja de Canarias, and Departmento de Medicina Interna de la Universidad de La Laguna. They reported having no conflicts of interest.

Fecal immunochemical testing with a low hemoglobin threshold for colonoscopy resembled one-time, primary colonoscopy for detecting advanced neoplasias in the first-degree relatives of colorectal cancer patients, investigators reported in the November issue of Gastroenterology.

Annual fecal immunochemical testing (FIT), followed by colonoscopy if hemoglobin levels met or exceeded 10 mcg per gram of feces, detected all cases of colorectal cancer (CRC) and 61% of advanced adenomas in the study population, said Dr. Enrique Quintero and Dr. Maria Carrillo at the Universidad de la Laguna in Spain and their associates.

But one-time colonoscopy was better than FIT for detecting all neoplasms as a whole in first-degree relatives of patients with CRC, the researchers reported. Based on the findings, initial screening with FIT should be considered when access to colonoscopy is limited, especially if patients are more likely to accept FIT than colonoscopy, the investigators said (Gastroenterology [doi: 10.1053/j.gastro.2014.08.004]).

Courtesy: American Gastroenterological Association

The trial included 1,918 first-degree relatives of patients with CRC. In all, 782 relatives were randomized to one-time colonoscopy, while 784 were assigned to annual FIT for 3 years, the researchers reported. Advanced neoplasia was detected in 3.9% of the FIT group and in 5.8% of the primary colonoscopy group, the investigators said (odds ratio, 1.56; 95% confidence interval, 0.95-2.56; P = .08). Rates of detection of advanced neoplasia also were similar between the FIT and primary colonoscopy groups when participants were stratified by age, sex, age of family member with CRC, type of familial relationship, and number of relatives with CRC, the researchers reported. However, primary colonoscopy identified significantly more nonadvanced adenomas (19.8%) than did FIT (5.4%), they added (OR, 4.71; 95% CI, 3.22-6.89; P less than .001).

Participants with negative FIT results were invited to undergo colonoscopy at the end of the study, the researchers said. Follow-up colonoscopies in these relatives showed that FIT had missed 39% of advanced adenomas but no cases of CRC, they reported. To detect one case of advanced CRC, only 4 relatives in the FIT group needed to undergo colonoscopy, compared with 18 members in the primary colonoscopy group, they added. “A potential benefit of FIT over primary colonoscopy in familial CRC screening is that it may save a substantial number of unnecessary colonoscopies, thus preventing harm and lowering costs,” the investigators concluded.

Ethical concerns prevented the researchers from assessing the efficacy of FIT for more than 3 years, they said. In addition, participants knew they could opt out of their assigned screening method before providing informed consent, which could have biased rates of detection of advanced CRC, the researchers noted. However, these rates did not significantly differ between diagnostic groups, they said. The study did not look at sessile serrated or traditional serrated polyps, because the study was designed when these polyps were still considered hyperplastic and nonmalignant, the investigators noted.

Future studies should evaluate the acceptance of FIT-based screening and its effects on mortality in familial CRC, the researchers concluded.

Their study was supported by grants from Fundación Canaria para la Investigación Sanitaria, Caja de Canarias, and Departmento de Medicina Interna de la Universidad de La Laguna. They reported having no conflicts of interest.

Fecal immunochemical testing with a low hemoglobin threshold for colonoscopy resembled one-time, primary colonoscopy for detecting advanced neoplasias in the first-degree relatives of colorectal cancer patients, investigators reported in the November issue of Gastroenterology.

Annual fecal immunochemical testing (FIT), followed by colonoscopy if hemoglobin levels met or exceeded 10 mcg per gram of feces, detected all cases of colorectal cancer (CRC) and 61% of advanced adenomas in the study population, said Dr. Enrique Quintero and Dr. Maria Carrillo at the Universidad de la Laguna in Spain and their associates.

But one-time colonoscopy was better than FIT for detecting all neoplasms as a whole in first-degree relatives of patients with CRC, the researchers reported. Based on the findings, initial screening with FIT should be considered when access to colonoscopy is limited, especially if patients are more likely to accept FIT than colonoscopy, the investigators said (Gastroenterology [doi: 10.1053/j.gastro.2014.08.004]).

Courtesy: American Gastroenterological Association

The trial included 1,918 first-degree relatives of patients with CRC. In all, 782 relatives were randomized to one-time colonoscopy, while 784 were assigned to annual FIT for 3 years, the researchers reported. Advanced neoplasia was detected in 3.9% of the FIT group and in 5.8% of the primary colonoscopy group, the investigators said (odds ratio, 1.56; 95% confidence interval, 0.95-2.56; P = .08). Rates of detection of advanced neoplasia also were similar between the FIT and primary colonoscopy groups when participants were stratified by age, sex, age of family member with CRC, type of familial relationship, and number of relatives with CRC, the researchers reported. However, primary colonoscopy identified significantly more nonadvanced adenomas (19.8%) than did FIT (5.4%), they added (OR, 4.71; 95% CI, 3.22-6.89; P less than .001).

Participants with negative FIT results were invited to undergo colonoscopy at the end of the study, the researchers said. Follow-up colonoscopies in these relatives showed that FIT had missed 39% of advanced adenomas but no cases of CRC, they reported. To detect one case of advanced CRC, only 4 relatives in the FIT group needed to undergo colonoscopy, compared with 18 members in the primary colonoscopy group, they added. “A potential benefit of FIT over primary colonoscopy in familial CRC screening is that it may save a substantial number of unnecessary colonoscopies, thus preventing harm and lowering costs,” the investigators concluded.

Ethical concerns prevented the researchers from assessing the efficacy of FIT for more than 3 years, they said. In addition, participants knew they could opt out of their assigned screening method before providing informed consent, which could have biased rates of detection of advanced CRC, the researchers noted. However, these rates did not significantly differ between diagnostic groups, they said. The study did not look at sessile serrated or traditional serrated polyps, because the study was designed when these polyps were still considered hyperplastic and nonmalignant, the investigators noted.

Future studies should evaluate the acceptance of FIT-based screening and its effects on mortality in familial CRC, the researchers concluded.

Their study was supported by grants from Fundación Canaria para la Investigación Sanitaria, Caja de Canarias, and Departmento de Medicina Interna de la Universidad de La Laguna. They reported having no conflicts of interest.

Fecal immunochemical testing with a low hemoglobin threshold for colonoscopy resembled one-time, primary colonoscopy for detecting advanced neoplasias in the first-degree relatives of colorectal cancer patients, investigators reported in the November issue of Gastroenterology.

Annual fecal immunochemical testing (FIT), followed by colonoscopy if hemoglobin levels met or exceeded 10 mcg per gram of feces, detected all cases of colorectal cancer (CRC) and 61% of advanced adenomas in the study population, said Dr. Enrique Quintero and Dr. Maria Carrillo at the Universidad de la Laguna in Spain and their associates.

But one-time colonoscopy was better than FIT for detecting all neoplasms as a whole in first-degree relatives of patients with CRC, the researchers reported. Based on the findings, initial screening with FIT should be considered when access to colonoscopy is limited, especially if patients are more likely to accept FIT than colonoscopy, the investigators said (Gastroenterology [doi: 10.1053/j.gastro.2014.08.004]).

Courtesy: American Gastroenterological Association

The trial included 1,918 first-degree relatives of patients with CRC. In all, 782 relatives were randomized to one-time colonoscopy, while 784 were assigned to annual FIT for 3 years, the researchers reported. Advanced neoplasia was detected in 3.9% of the FIT group and in 5.8% of the primary colonoscopy group, the investigators said (odds ratio, 1.56; 95% confidence interval, 0.95-2.56; P = .08). Rates of detection of advanced neoplasia also were similar between the FIT and primary colonoscopy groups when participants were stratified by age, sex, age of family member with CRC, type of familial relationship, and number of relatives with CRC, the researchers reported. However, primary colonoscopy identified significantly more nonadvanced adenomas (19.8%) than did FIT (5.4%), they added (OR, 4.71; 95% CI, 3.22-6.89; P less than .001).

Participants with negative FIT results were invited to undergo colonoscopy at the end of the study, the researchers said. Follow-up colonoscopies in these relatives showed that FIT had missed 39% of advanced adenomas but no cases of CRC, they reported. To detect one case of advanced CRC, only 4 relatives in the FIT group needed to undergo colonoscopy, compared with 18 members in the primary colonoscopy group, they added. “A potential benefit of FIT over primary colonoscopy in familial CRC screening is that it may save a substantial number of unnecessary colonoscopies, thus preventing harm and lowering costs,” the investigators concluded.

Ethical concerns prevented the researchers from assessing the efficacy of FIT for more than 3 years, they said. In addition, participants knew they could opt out of their assigned screening method before providing informed consent, which could have biased rates of detection of advanced CRC, the researchers noted. However, these rates did not significantly differ between diagnostic groups, they said. The study did not look at sessile serrated or traditional serrated polyps, because the study was designed when these polyps were still considered hyperplastic and nonmalignant, the investigators noted.

Future studies should evaluate the acceptance of FIT-based screening and its effects on mortality in familial CRC, the researchers concluded.

Their study was supported by grants from Fundación Canaria para la Investigación Sanitaria, Caja de Canarias, and Departmento de Medicina Interna de la Universidad de La Laguna. They reported having no conflicts of interest.

A mutation in the hepatitis E virus might contribute to ribavirin treatment failure in transplant recipients with chronic HEV infection, according to a small study published in the November issue of Gastroenterology.

The study is the first to find in vitro evidence for a virulence mutation in HEV, said Dr. Yannick Debing at the University of Leuven in Belgium, Dr. Annett Gisa at the Hanover Medical School in Germany, and their associates.

Courtesy: American Gastroenterological Association

The researchers studied 15 solid-organ transplant recipients who received ribavirin monotherapy for chronic HEV infection. Thirteen patients were successfully treated, but two with genotype 3c infections failed therapy. Viral RNA levels in both of these patients initially dropped and then rose, suggesting emerging resistance to ribavirin therapy, the investigators said (Gastroenterology 2014 Aug. 30 [doi: 10.1053/j.gastro.2014.08.040]).

When the researchers sequenced HEV genomes from the nonresponders, they found a G1634R mutation in HEV viral polymerase that conferred greater replication capacity compared with wild-type HEV, even after in vitro ribavirin treatment, they reported. “It may be interesting to assess the possible use of position 1634 as a prognostic marker, and accordingly to adjust the dose and duration of ribavirin therapy based on the presence of the G1634R variant,” Dr. Debing and his associates said.

The mutation consisted of a G-to-A nucleotide substitution in the C-terminal region of viral polymerase, the investigators said. By comparing HEV sequences in GenBank (an open-access collection of publicly available nucleotide sequences and their proteins), they found that G1634 was the most common amino acid sequence in genotype 3 HEV, while the K1634 sequence predominated in genotypes 1 and 4.

A subgenomic replicon of genotype 3 HEV with the 1634R mutation showed no increase in ribavirin sensitivity, compared with the wild-type replicon (50% effective concentration [EC50] values, 5.1 ± 4.1 mcM and 5.1 ± 3.7 mcM, respectively), the investigators said. But when they tested the 1634R variant in human hepatoma cells, they observed a 3.4-fold increase in luminescence signaling, compared with cells transfected with capped replicon RNA from wild-type HEV (P = .04). Greater luminescence indicated that the 1634R mutation increased viral replication, they said.

In addition, an HEV replicon with the K1634 mutation showed 2.7 times more luminescence compared with cells transfected with wild-type viral RNA (P = .07), the researchers reported.

The investigators next studied the effects of the 1634 R/K mutations on the full-length HEV genome. They introduced HEV with the two variants into human hepatoma cells, measured the amounts of viral RNA released, and found that both variants replicated at higher levels than did wild-type virus. When they treated these cells with 10- or 25-mcM ribavirin, replication levels dropped for the 1634 R/K variants and for wild-type virus, but remained at least twice as high for the variants, they said.

“The increased replication capacity of the mutant may have contributed to the persistent disease courses despite [ribavirin] treatment, although other patient- and virus-related factors could have contributed as well,” the investigators said.

The research was supported by the Research Foundation–Flanders, KU Leuven University, the Robert Koch Institute, Geconcerteerde Onderzoeksactie, the German Federal Ministry for Education and Research, and EU FP7 project SILVER. The authors reported having no conflicts of interest.

A mutation in the hepatitis E virus might contribute to ribavirin treatment failure in transplant recipients with chronic HEV infection, according to a small study published in the November issue of Gastroenterology.

The study is the first to find in vitro evidence for a virulence mutation in HEV, said Dr. Yannick Debing at the University of Leuven in Belgium, Dr. Annett Gisa at the Hanover Medical School in Germany, and their associates.

Courtesy: American Gastroenterological Association

The researchers studied 15 solid-organ transplant recipients who received ribavirin monotherapy for chronic HEV infection. Thirteen patients were successfully treated, but two with genotype 3c infections failed therapy. Viral RNA levels in both of these patients initially dropped and then rose, suggesting emerging resistance to ribavirin therapy, the investigators said (Gastroenterology 2014 Aug. 30 [doi: 10.1053/j.gastro.2014.08.040]).

When the researchers sequenced HEV genomes from the nonresponders, they found a G1634R mutation in HEV viral polymerase that conferred greater replication capacity compared with wild-type HEV, even after in vitro ribavirin treatment, they reported. “It may be interesting to assess the possible use of position 1634 as a prognostic marker, and accordingly to adjust the dose and duration of ribavirin therapy based on the presence of the G1634R variant,” Dr. Debing and his associates said.

The mutation consisted of a G-to-A nucleotide substitution in the C-terminal region of viral polymerase, the investigators said. By comparing HEV sequences in GenBank (an open-access collection of publicly available nucleotide sequences and their proteins), they found that G1634 was the most common amino acid sequence in genotype 3 HEV, while the K1634 sequence predominated in genotypes 1 and 4.

A subgenomic replicon of genotype 3 HEV with the 1634R mutation showed no increase in ribavirin sensitivity, compared with the wild-type replicon (50% effective concentration [EC50] values, 5.1 ± 4.1 mcM and 5.1 ± 3.7 mcM, respectively), the investigators said. But when they tested the 1634R variant in human hepatoma cells, they observed a 3.4-fold increase in luminescence signaling, compared with cells transfected with capped replicon RNA from wild-type HEV (P = .04). Greater luminescence indicated that the 1634R mutation increased viral replication, they said.

In addition, an HEV replicon with the K1634 mutation showed 2.7 times more luminescence compared with cells transfected with wild-type viral RNA (P = .07), the researchers reported.

The investigators next studied the effects of the 1634 R/K mutations on the full-length HEV genome. They introduced HEV with the two variants into human hepatoma cells, measured the amounts of viral RNA released, and found that both variants replicated at higher levels than did wild-type virus. When they treated these cells with 10- or 25-mcM ribavirin, replication levels dropped for the 1634 R/K variants and for wild-type virus, but remained at least twice as high for the variants, they said.

“The increased replication capacity of the mutant may have contributed to the persistent disease courses despite [ribavirin] treatment, although other patient- and virus-related factors could have contributed as well,” the investigators said.

The research was supported by the Research Foundation–Flanders, KU Leuven University, the Robert Koch Institute, Geconcerteerde Onderzoeksactie, the German Federal Ministry for Education and Research, and EU FP7 project SILVER. The authors reported having no conflicts of interest.

A mutation in the hepatitis E virus might contribute to ribavirin treatment failure in transplant recipients with chronic HEV infection, according to a small study published in the November issue of Gastroenterology.

The study is the first to find in vitro evidence for a virulence mutation in HEV, said Dr. Yannick Debing at the University of Leuven in Belgium, Dr. Annett Gisa at the Hanover Medical School in Germany, and their associates.

Courtesy: American Gastroenterological Association

The researchers studied 15 solid-organ transplant recipients who received ribavirin monotherapy for chronic HEV infection. Thirteen patients were successfully treated, but two with genotype 3c infections failed therapy. Viral RNA levels in both of these patients initially dropped and then rose, suggesting emerging resistance to ribavirin therapy, the investigators said (Gastroenterology 2014 Aug. 30 [doi: 10.1053/j.gastro.2014.08.040]).

When the researchers sequenced HEV genomes from the nonresponders, they found a G1634R mutation in HEV viral polymerase that conferred greater replication capacity compared with wild-type HEV, even after in vitro ribavirin treatment, they reported. “It may be interesting to assess the possible use of position 1634 as a prognostic marker, and accordingly to adjust the dose and duration of ribavirin therapy based on the presence of the G1634R variant,” Dr. Debing and his associates said.

The mutation consisted of a G-to-A nucleotide substitution in the C-terminal region of viral polymerase, the investigators said. By comparing HEV sequences in GenBank (an open-access collection of publicly available nucleotide sequences and their proteins), they found that G1634 was the most common amino acid sequence in genotype 3 HEV, while the K1634 sequence predominated in genotypes 1 and 4.

A subgenomic replicon of genotype 3 HEV with the 1634R mutation showed no increase in ribavirin sensitivity, compared with the wild-type replicon (50% effective concentration [EC50] values, 5.1 ± 4.1 mcM and 5.1 ± 3.7 mcM, respectively), the investigators said. But when they tested the 1634R variant in human hepatoma cells, they observed a 3.4-fold increase in luminescence signaling, compared with cells transfected with capped replicon RNA from wild-type HEV (P = .04). Greater luminescence indicated that the 1634R mutation increased viral replication, they said.

In addition, an HEV replicon with the K1634 mutation showed 2.7 times more luminescence compared with cells transfected with wild-type viral RNA (P = .07), the researchers reported.

The investigators next studied the effects of the 1634 R/K mutations on the full-length HEV genome. They introduced HEV with the two variants into human hepatoma cells, measured the amounts of viral RNA released, and found that both variants replicated at higher levels than did wild-type virus. When they treated these cells with 10- or 25-mcM ribavirin, replication levels dropped for the 1634 R/K variants and for wild-type virus, but remained at least twice as high for the variants, they said.

“The increased replication capacity of the mutant may have contributed to the persistent disease courses despite [ribavirin] treatment, although other patient- and virus-related factors could have contributed as well,” the investigators said.

The research was supported by the Research Foundation–Flanders, KU Leuven University, the Robert Koch Institute, Geconcerteerde Onderzoeksactie, the German Federal Ministry for Education and Research, and EU FP7 project SILVER. The authors reported having no conflicts of interest.

Patients with inflammatory bowel disease who took thiopurines for at least a year had an almost sixfold greater rate of lymphoma than did the general population, researchers reported in the November issue of Clinical Gastroenterology and Hepatology.

But lymphoma risk appeared to return to baseline after patients stopped taking thiopurines, suggesting that immunosuppression – not DNA damage – was the root cause of cancer in these patients, said Dr. David Kotlyar at the National Cancer Institute and his associates (Clin. Gastroenterol. Hepatol. [doi:10.1016/j.cgh.2014.05.015]). The researchers carried out a meta-analysis of 18 cohort studies of IBD that they identified by querying MEDLINE, Embase, the Cochrane databases, and other sources. In all, the studies identified 91 patients with lymphoma that occurred after a median of 18 months of exposure to azathioprine or 6-mercaptopurine (range, 1-109 months), the investigators reported.

In a subanalysis of eight population studies, patients who were currently taking thiopurines had a 5.7-fold greater incidence of lymphoma compared with the general population (95% confidence interval, 3.22-10.1), the researchers said. In contrast, patients who had never used thiopurines or who no longer used the drugs did not have an increased lymphoma risk, they said. In addition, standardized incidence ratios (SIRs) in referral center studies were as high as 9.16 (95% CI, 5.03-17.6), the investigators reported. The IBD seen in referral centers tends to be more severe than that in the population overall, which could explain the discrepancy in SIRs between referral and population studies, they said.

The study also found that men who took thiopurines had a more than threefold greater incidence of lymphoma, compared with the general population (SIR, 3.60; 95% CI, 2.68-4.83), while women had an almost twofold increase in estimated risk (SIR, 1.76; 95% CI, 1.08-2.87). Results of age stratifications varied depending on how the researchers defined age groups, but the absolute risk of lymphoma in men under 30 years of age was substantially higher than expected, they said. However, only two studies included raw data on age, and findings should be interpreted with caution, they added.

“It is important to emphasize that although the relative risks of lymphoma in active users are moderate, there remains a very low absolute risk of lymphoma for any given patient,” said Dr. Kotlyar and his associates. “For patients of all ages and genders, the risk of lymphoma needs to be weighed against the potential benefits of therapy. Further work is needed to understand how this trade-off of potential benefit and harm varies by age, particularly in the era of combination immunosuppression therapy.”

Dr. Kotlyar is funded by the National Institutes of Health. Four of the coauthors reported financial relationships with Pfizer, Centocor, Shire Pharmaceuticals Group, AstraZeneca, GlaxoSmithKline, and many others. The remaining authors reported no conflicts of interest.

Patients with inflammatory bowel disease who took thiopurines for at least a year had an almost sixfold greater rate of lymphoma than did the general population, researchers reported in the November issue of Clinical Gastroenterology and Hepatology.

But lymphoma risk appeared to return to baseline after patients stopped taking thiopurines, suggesting that immunosuppression – not DNA damage – was the root cause of cancer in these patients, said Dr. David Kotlyar at the National Cancer Institute and his associates (Clin. Gastroenterol. Hepatol. [doi:10.1016/j.cgh.2014.05.015]). The researchers carried out a meta-analysis of 18 cohort studies of IBD that they identified by querying MEDLINE, Embase, the Cochrane databases, and other sources. In all, the studies identified 91 patients with lymphoma that occurred after a median of 18 months of exposure to azathioprine or 6-mercaptopurine (range, 1-109 months), the investigators reported.

In a subanalysis of eight population studies, patients who were currently taking thiopurines had a 5.7-fold greater incidence of lymphoma compared with the general population (95% confidence interval, 3.22-10.1), the researchers said. In contrast, patients who had never used thiopurines or who no longer used the drugs did not have an increased lymphoma risk, they said. In addition, standardized incidence ratios (SIRs) in referral center studies were as high as 9.16 (95% CI, 5.03-17.6), the investigators reported. The IBD seen in referral centers tends to be more severe than that in the population overall, which could explain the discrepancy in SIRs between referral and population studies, they said.

The study also found that men who took thiopurines had a more than threefold greater incidence of lymphoma, compared with the general population (SIR, 3.60; 95% CI, 2.68-4.83), while women had an almost twofold increase in estimated risk (SIR, 1.76; 95% CI, 1.08-2.87). Results of age stratifications varied depending on how the researchers defined age groups, but the absolute risk of lymphoma in men under 30 years of age was substantially higher than expected, they said. However, only two studies included raw data on age, and findings should be interpreted with caution, they added.

“It is important to emphasize that although the relative risks of lymphoma in active users are moderate, there remains a very low absolute risk of lymphoma for any given patient,” said Dr. Kotlyar and his associates. “For patients of all ages and genders, the risk of lymphoma needs to be weighed against the potential benefits of therapy. Further work is needed to understand how this trade-off of potential benefit and harm varies by age, particularly in the era of combination immunosuppression therapy.”

Dr. Kotlyar is funded by the National Institutes of Health. Four of the coauthors reported financial relationships with Pfizer, Centocor, Shire Pharmaceuticals Group, AstraZeneca, GlaxoSmithKline, and many others. The remaining authors reported no conflicts of interest.

Patients with inflammatory bowel disease who took thiopurines for at least a year had an almost sixfold greater rate of lymphoma than did the general population, researchers reported in the November issue of Clinical Gastroenterology and Hepatology.

But lymphoma risk appeared to return to baseline after patients stopped taking thiopurines, suggesting that immunosuppression – not DNA damage – was the root cause of cancer in these patients, said Dr. David Kotlyar at the National Cancer Institute and his associates (Clin. Gastroenterol. Hepatol. [doi:10.1016/j.cgh.2014.05.015]). The researchers carried out a meta-analysis of 18 cohort studies of IBD that they identified by querying MEDLINE, Embase, the Cochrane databases, and other sources. In all, the studies identified 91 patients with lymphoma that occurred after a median of 18 months of exposure to azathioprine or 6-mercaptopurine (range, 1-109 months), the investigators reported.

In a subanalysis of eight population studies, patients who were currently taking thiopurines had a 5.7-fold greater incidence of lymphoma compared with the general population (95% confidence interval, 3.22-10.1), the researchers said. In contrast, patients who had never used thiopurines or who no longer used the drugs did not have an increased lymphoma risk, they said. In addition, standardized incidence ratios (SIRs) in referral center studies were as high as 9.16 (95% CI, 5.03-17.6), the investigators reported. The IBD seen in referral centers tends to be more severe than that in the population overall, which could explain the discrepancy in SIRs between referral and population studies, they said.

The study also found that men who took thiopurines had a more than threefold greater incidence of lymphoma, compared with the general population (SIR, 3.60; 95% CI, 2.68-4.83), while women had an almost twofold increase in estimated risk (SIR, 1.76; 95% CI, 1.08-2.87). Results of age stratifications varied depending on how the researchers defined age groups, but the absolute risk of lymphoma in men under 30 years of age was substantially higher than expected, they said. However, only two studies included raw data on age, and findings should be interpreted with caution, they added.

“It is important to emphasize that although the relative risks of lymphoma in active users are moderate, there remains a very low absolute risk of lymphoma for any given patient,” said Dr. Kotlyar and his associates. “For patients of all ages and genders, the risk of lymphoma needs to be weighed against the potential benefits of therapy. Further work is needed to understand how this trade-off of potential benefit and harm varies by age, particularly in the era of combination immunosuppression therapy.”

Dr. Kotlyar is funded by the National Institutes of Health. Four of the coauthors reported financial relationships with Pfizer, Centocor, Shire Pharmaceuticals Group, AstraZeneca, GlaxoSmithKline, and many others. The remaining authors reported no conflicts of interest.

SAN DIEGO – Extended-release dexmethylphenidate combined with guanfacine caused no adverse cardiovascular effects among children with attention-deficit/hyperactivity disorder, according to results from a double-blind, randomized trial of 207 patients presented at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

Amy Karon/Frontline Medical News

On electrocardiography, a QTc interval prolongation of more than 500 ms raises concerns about arrhythmia and sudden death, “but this study showed that this did not happen with combination treatment,” lead investigator Dr. Gregory Sayer said in an interview. “In fact, there were no clinically meaningful cardiovascular effects.

“The take-home message is that combination therapy with dexmethylphenidate extended release and guanfacine immediate release is a cardiovascularly safe option for patients who might require dual therapy.”

Stimulants for ADHD were previously thought to carry the risk of sudden cardiac death, noted Dr. Sayer, a third-year psychiatry resident at the University of California, Los Angeles. Although further analyses revealed that these concerns were unfounded, clinicians have continued to question the milder cardiovascular effects of stimulants for ADHD, as well as the effects of combining stimulants with alpha-2 agonists such as guanfacine, which can improve cognitive function in ADHD, he said.

Therefore, Dr. Sayer and his associates monitored pulse, blood pressure, and electrocardiograms in children with ADHD who were 7-14 years old and had been randomized in a double-blinded fashion to immediate-release guanfacine (1-3 mg/day), extended-release dexmethylphenidate (5-20 mg/day), or both. They measured vital signs and ECGs at baseline, at the end of the 8-week dose-optimization period, and then monthly during a 12-month, open-label maintenance phase, they reported.

Guanfacine and dexmethylphenidate had “opposing cardiovascular effects,” although none of these effects were clinically significant, the researchers said. During titration, guanfacine monotherapy lowered children’s pulse and blood pressure; dexmethylphenidate increased pulse, blood pressure, and QTc interval; and combination therapy increased diastolic blood pressure alone, they said. “The combination group’s parameters fell between the ranges for both monotherapy groups, and there were no significant QTc changes in the combination therapy group,” Dr. Sayer added.

“Combination treatment may buffer long-term cardiovascular effects of guanfacine and stimulant monotherapy, possibly reducing risk from the small but significant changes resulting from either single treatment,” he and his associates concluded.

During the yearlong maintenance phase, cardiovascular measures remained stable except for a borderline significant increase in pulse in the guanfacine group (P = .06) and a decrease in systolic blood pressure in the dexmethylphenidate group (P < .0001, the researchers reported.

The study is part of a larger trial that is examining the effects of combination therapy on ADHD symptoms and cognitive effects, such as working memory, Dr. Sayer noted. In the current study, the researchers did not continuously monitor vital signs, such as with a Holter monitor, so they could not eliminate the possibility of cardiac phenomena occurring between monitoring points, he added.

The National Institute of Mental Health funded the study. Dr. Sayer declared having no conflicts of interest. Two coauthors reported financial or advisory relationships with Akili Interactive Labs, Sunovion, and other companies.

SAN DIEGO – Extended-release dexmethylphenidate combined with guanfacine caused no adverse cardiovascular effects among children with attention-deficit/hyperactivity disorder, according to results from a double-blind, randomized trial of 207 patients presented at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

Amy Karon/Frontline Medical News

On electrocardiography, a QTc interval prolongation of more than 500 ms raises concerns about arrhythmia and sudden death, “but this study showed that this did not happen with combination treatment,” lead investigator Dr. Gregory Sayer said in an interview. “In fact, there were no clinically meaningful cardiovascular effects.

“The take-home message is that combination therapy with dexmethylphenidate extended release and guanfacine immediate release is a cardiovascularly safe option for patients who might require dual therapy.”

Stimulants for ADHD were previously thought to carry the risk of sudden cardiac death, noted Dr. Sayer, a third-year psychiatry resident at the University of California, Los Angeles. Although further analyses revealed that these concerns were unfounded, clinicians have continued to question the milder cardiovascular effects of stimulants for ADHD, as well as the effects of combining stimulants with alpha-2 agonists such as guanfacine, which can improve cognitive function in ADHD, he said.

Therefore, Dr. Sayer and his associates monitored pulse, blood pressure, and electrocardiograms in children with ADHD who were 7-14 years old and had been randomized in a double-blinded fashion to immediate-release guanfacine (1-3 mg/day), extended-release dexmethylphenidate (5-20 mg/day), or both. They measured vital signs and ECGs at baseline, at the end of the 8-week dose-optimization period, and then monthly during a 12-month, open-label maintenance phase, they reported.

Guanfacine and dexmethylphenidate had “opposing cardiovascular effects,” although none of these effects were clinically significant, the researchers said. During titration, guanfacine monotherapy lowered children’s pulse and blood pressure; dexmethylphenidate increased pulse, blood pressure, and QTc interval; and combination therapy increased diastolic blood pressure alone, they said. “The combination group’s parameters fell between the ranges for both monotherapy groups, and there were no significant QTc changes in the combination therapy group,” Dr. Sayer added.

“Combination treatment may buffer long-term cardiovascular effects of guanfacine and stimulant monotherapy, possibly reducing risk from the small but significant changes resulting from either single treatment,” he and his associates concluded.

During the yearlong maintenance phase, cardiovascular measures remained stable except for a borderline significant increase in pulse in the guanfacine group (P = .06) and a decrease in systolic blood pressure in the dexmethylphenidate group (P < .0001, the researchers reported.

The study is part of a larger trial that is examining the effects of combination therapy on ADHD symptoms and cognitive effects, such as working memory, Dr. Sayer noted. In the current study, the researchers did not continuously monitor vital signs, such as with a Holter monitor, so they could not eliminate the possibility of cardiac phenomena occurring between monitoring points, he added.

The National Institute of Mental Health funded the study. Dr. Sayer declared having no conflicts of interest. Two coauthors reported financial or advisory relationships with Akili Interactive Labs, Sunovion, and other companies.

SAN DIEGO – Extended-release dexmethylphenidate combined with guanfacine caused no adverse cardiovascular effects among children with attention-deficit/hyperactivity disorder, according to results from a double-blind, randomized trial of 207 patients presented at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

Amy Karon/Frontline Medical News

On electrocardiography, a QTc interval prolongation of more than 500 ms raises concerns about arrhythmia and sudden death, “but this study showed that this did not happen with combination treatment,” lead investigator Dr. Gregory Sayer said in an interview. “In fact, there were no clinically meaningful cardiovascular effects.

“The take-home message is that combination therapy with dexmethylphenidate extended release and guanfacine immediate release is a cardiovascularly safe option for patients who might require dual therapy.”

Stimulants for ADHD were previously thought to carry the risk of sudden cardiac death, noted Dr. Sayer, a third-year psychiatry resident at the University of California, Los Angeles. Although further analyses revealed that these concerns were unfounded, clinicians have continued to question the milder cardiovascular effects of stimulants for ADHD, as well as the effects of combining stimulants with alpha-2 agonists such as guanfacine, which can improve cognitive function in ADHD, he said.

Therefore, Dr. Sayer and his associates monitored pulse, blood pressure, and electrocardiograms in children with ADHD who were 7-14 years old and had been randomized in a double-blinded fashion to immediate-release guanfacine (1-3 mg/day), extended-release dexmethylphenidate (5-20 mg/day), or both. They measured vital signs and ECGs at baseline, at the end of the 8-week dose-optimization period, and then monthly during a 12-month, open-label maintenance phase, they reported.

Guanfacine and dexmethylphenidate had “opposing cardiovascular effects,” although none of these effects were clinically significant, the researchers said. During titration, guanfacine monotherapy lowered children’s pulse and blood pressure; dexmethylphenidate increased pulse, blood pressure, and QTc interval; and combination therapy increased diastolic blood pressure alone, they said. “The combination group’s parameters fell between the ranges for both monotherapy groups, and there were no significant QTc changes in the combination therapy group,” Dr. Sayer added.

“Combination treatment may buffer long-term cardiovascular effects of guanfacine and stimulant monotherapy, possibly reducing risk from the small but significant changes resulting from either single treatment,” he and his associates concluded.

During the yearlong maintenance phase, cardiovascular measures remained stable except for a borderline significant increase in pulse in the guanfacine group (P = .06) and a decrease in systolic blood pressure in the dexmethylphenidate group (P < .0001, the researchers reported.

The study is part of a larger trial that is examining the effects of combination therapy on ADHD symptoms and cognitive effects, such as working memory, Dr. Sayer noted. In the current study, the researchers did not continuously monitor vital signs, such as with a Holter monitor, so they could not eliminate the possibility of cardiac phenomena occurring between monitoring points, he added.

The National Institute of Mental Health funded the study. Dr. Sayer declared having no conflicts of interest. Two coauthors reported financial or advisory relationships with Akili Interactive Labs, Sunovion, and other companies.

SAN DIEGO – Children who parents describe as “always sick” often are immunologically normal, but knowing when to suspect otherwise is crucial, according to Dr. Meg Fisher.

“When parents tell you their child is sick all the time, they are. They’re literally just recovering from one thing when they pick up the next,” said Dr. Fisher, a pediatric infectious diseases specialist at Monmouth Medical Center in West Orange, N.J.

CDC/Janice Haney Carr

Children under 2 years of age typically acquire 4-10 symptomatic respiratory infections per year – and up to 13 if they are in day care, Dr. Fisher said. These children also normally develop one to four gastrointestinal infections per year, she added. And children older than 2 years average four to eight respiratory infections and up to two gastrointestinal infections annually, she said at the annual meeting of the American Academy of Pediatrics .

Certain types of infections always merit a closer look, Dr. Fisher emphasized. Invasive infections, recurrent meningitis, excessive episodes of respiratory disease, chronic diarrhea, recurrent urinary tract infections, and recurrent skin and soft tissue infections can indicate immunodeficient disorders, inherited diseases such as cystic fibrosis, or anatomic abnormalities that predispose children to serious infections, she said. “The site of recurrent infections is really going to help you determine which subspecialist you need,” she added.

Culture results also provide clues about underlying conditions. “If you ever recover Pseudomonas aeruginosa from the respiratory tract of a child, you should automatically think about cystic fibrosis,” Dr. Fisher said. Pseudomonas is often isolated from stool samples, but is not normally found in a child’s respiratory tract, she explained.

“Unusual organisms and abnormal laboratory results should always trigger a follow-up evaluation,” Dr. Stuart Abramson said in a related presentation. The most common primary immunodeficiency disorders include selective IgA deficiency – which affects 1 in 500 children – IgG₂deficiency, transient hypogammaglobulinemia of infancy, and DiGeorge anomaly, said Dr. Abramson, who is director of allergy and immunology services at Shannon Medical Center in San Angelo, Tex. Less common primary immunodeficiencies affect 1 in 50,000 to 1 in 200,000 children and include B-cell disorders, T-cell disorders, phagocytic disorders, and complement disorders, he said at the meeting.

Of the four stages of testing for primary immunodeficiencies, only the first stage needs to be done by the primary care pediatrician; testing at the first stage includes taking a history and physical examination, complete blood count and differential, and quantitative immunoglobulin levels for IgA, IgG, and IgM, said Dr. Fisher. A child who needs further testing “might be better served by an immunologist,” she added.

Pediatricians should consider first-stage testing if a patient presents with one or more warning signs of a primary immunodeficiency in children, Dr. Abramson said.

Those warning signs are:

• Four or more new ear infections within 1 year.

• Two or more serious sinus infections within 1 year.

• Two or more months on antibiotics with little effect.

• Two or more pneumonias within 1 year.

• Failure of an infant to gain weight or grow normally.

• Recurrent, deep abscesses of the skin or organs.

• Persistent oral thrush or cutaneous mycoses.

• Need for intravenous antibiotics to clear infections.

• Two or more deep-seated infections, including septicemia.

• A family history of primary immunodeficiency.

(This list was assembled by the Jeffrey Modell Foundation.)

Dr. Fisher and Dr. Abramson declared no relevant financial relationships.

SAN DIEGO – Children who parents describe as “always sick” often are immunologically normal, but knowing when to suspect otherwise is crucial, according to Dr. Meg Fisher.

“When parents tell you their child is sick all the time, they are. They’re literally just recovering from one thing when they pick up the next,” said Dr. Fisher, a pediatric infectious diseases specialist at Monmouth Medical Center in West Orange, N.J.

CDC/Janice Haney Carr

Children under 2 years of age typically acquire 4-10 symptomatic respiratory infections per year – and up to 13 if they are in day care, Dr. Fisher said. These children also normally develop one to four gastrointestinal infections per year, she added. And children older than 2 years average four to eight respiratory infections and up to two gastrointestinal infections annually, she said at the annual meeting of the American Academy of Pediatrics .

Certain types of infections always merit a closer look, Dr. Fisher emphasized. Invasive infections, recurrent meningitis, excessive episodes of respiratory disease, chronic diarrhea, recurrent urinary tract infections, and recurrent skin and soft tissue infections can indicate immunodeficient disorders, inherited diseases such as cystic fibrosis, or anatomic abnormalities that predispose children to serious infections, she said. “The site of recurrent infections is really going to help you determine which subspecialist you need,” she added.

Culture results also provide clues about underlying conditions. “If you ever recover Pseudomonas aeruginosa from the respiratory tract of a child, you should automatically think about cystic fibrosis,” Dr. Fisher said. Pseudomonas is often isolated from stool samples, but is not normally found in a child’s respiratory tract, she explained.

“Unusual organisms and abnormal laboratory results should always trigger a follow-up evaluation,” Dr. Stuart Abramson said in a related presentation. The most common primary immunodeficiency disorders include selective IgA deficiency – which affects 1 in 500 children – IgG₂deficiency, transient hypogammaglobulinemia of infancy, and DiGeorge anomaly, said Dr. Abramson, who is director of allergy and immunology services at Shannon Medical Center in San Angelo, Tex. Less common primary immunodeficiencies affect 1 in 50,000 to 1 in 200,000 children and include B-cell disorders, T-cell disorders, phagocytic disorders, and complement disorders, he said at the meeting.

Of the four stages of testing for primary immunodeficiencies, only the first stage needs to be done by the primary care pediatrician; testing at the first stage includes taking a history and physical examination, complete blood count and differential, and quantitative immunoglobulin levels for IgA, IgG, and IgM, said Dr. Fisher. A child who needs further testing “might be better served by an immunologist,” she added.

Pediatricians should consider first-stage testing if a patient presents with one or more warning signs of a primary immunodeficiency in children, Dr. Abramson said.

Those warning signs are:

• Four or more new ear infections within 1 year.

• Two or more serious sinus infections within 1 year.

• Two or more months on antibiotics with little effect.

• Two or more pneumonias within 1 year.

• Failure of an infant to gain weight or grow normally.

• Recurrent, deep abscesses of the skin or organs.

• Persistent oral thrush or cutaneous mycoses.

• Need for intravenous antibiotics to clear infections.

• Two or more deep-seated infections, including septicemia.

• A family history of primary immunodeficiency.

(This list was assembled by the Jeffrey Modell Foundation.)

Dr. Fisher and Dr. Abramson declared no relevant financial relationships.

SAN DIEGO – Children who parents describe as “always sick” often are immunologically normal, but knowing when to suspect otherwise is crucial, according to Dr. Meg Fisher.

“When parents tell you their child is sick all the time, they are. They’re literally just recovering from one thing when they pick up the next,” said Dr. Fisher, a pediatric infectious diseases specialist at Monmouth Medical Center in West Orange, N.J.

CDC/Janice Haney Carr

Children under 2 years of age typically acquire 4-10 symptomatic respiratory infections per year – and up to 13 if they are in day care, Dr. Fisher said. These children also normally develop one to four gastrointestinal infections per year, she added. And children older than 2 years average four to eight respiratory infections and up to two gastrointestinal infections annually, she said at the annual meeting of the American Academy of Pediatrics .

Certain types of infections always merit a closer look, Dr. Fisher emphasized. Invasive infections, recurrent meningitis, excessive episodes of respiratory disease, chronic diarrhea, recurrent urinary tract infections, and recurrent skin and soft tissue infections can indicate immunodeficient disorders, inherited diseases such as cystic fibrosis, or anatomic abnormalities that predispose children to serious infections, she said. “The site of recurrent infections is really going to help you determine which subspecialist you need,” she added.

Culture results also provide clues about underlying conditions. “If you ever recover Pseudomonas aeruginosa from the respiratory tract of a child, you should automatically think about cystic fibrosis,” Dr. Fisher said. Pseudomonas is often isolated from stool samples, but is not normally found in a child’s respiratory tract, she explained.

“Unusual organisms and abnormal laboratory results should always trigger a follow-up evaluation,” Dr. Stuart Abramson said in a related presentation. The most common primary immunodeficiency disorders include selective IgA deficiency – which affects 1 in 500 children – IgG₂deficiency, transient hypogammaglobulinemia of infancy, and DiGeorge anomaly, said Dr. Abramson, who is director of allergy and immunology services at Shannon Medical Center in San Angelo, Tex. Less common primary immunodeficiencies affect 1 in 50,000 to 1 in 200,000 children and include B-cell disorders, T-cell disorders, phagocytic disorders, and complement disorders, he said at the meeting.

Of the four stages of testing for primary immunodeficiencies, only the first stage needs to be done by the primary care pediatrician; testing at the first stage includes taking a history and physical examination, complete blood count and differential, and quantitative immunoglobulin levels for IgA, IgG, and IgM, said Dr. Fisher. A child who needs further testing “might be better served by an immunologist,” she added.

Pediatricians should consider first-stage testing if a patient presents with one or more warning signs of a primary immunodeficiency in children, Dr. Abramson said.

Those warning signs are:

• Four or more new ear infections within 1 year.

• Two or more serious sinus infections within 1 year.

• Two or more months on antibiotics with little effect.

• Two or more pneumonias within 1 year.

• Failure of an infant to gain weight or grow normally.

• Recurrent, deep abscesses of the skin or organs.

• Persistent oral thrush or cutaneous mycoses.

• Need for intravenous antibiotics to clear infections.

• Two or more deep-seated infections, including septicemia.

• A family history of primary immunodeficiency.

(This list was assembled by the Jeffrey Modell Foundation.)

Dr. Fisher and Dr. Abramson declared no relevant financial relationships.

SAN DIEGO – Pediatricians should screen patients for hypertrophic cardiomyopathy if a first- or second-degree relative has been diagnosed with the condition or has a history of sudden death, said Dr. Kevin Shannon, a pediatric cardiologist at the University of California, Los Angeles, Medical Center.

“Anybody with a family history of HCM, including uncles, cousins, parents, and siblings, should be screened,” he emphasized. “Even if they don’t have obstructive HCM, they will often have a murmur, most commonly at the upper sternal border.” The murmur is typically late-peaking and worsens during Valsalva, he added.

HCM is the most common cause of sudden death in athletes and is the most common genetic cardiac disease, affecting about 1 in 500 young adults (Circulation 1995;92:785-9). The autosomal dominant inheritance pattern shows varying degrees of penetrance, translating to a range of phenotypes, Dr. Shannon said at the annual meeting of the American Academy of Pediatrics. “Even if your family member didn’t have hypertrophy until age 30, you can get it at age 5, and the opposite can also be true,” he noted.

HCM can be a silent disease until it causes sudden death. However, pediatricians should ask patients about exercise tolerance and should consider HCM in patients who describe a substantial drop in sports performance, Dr. Shannon said. An athlete with HCM might say that he or she always finished the field lap first and is now second to last, and a soccer player with a field position might say, “Now I finish the runs after the goalies,” he said.

A resting electrocardiogram is not sufficient to exclude HCM, Dr. Shannon emphasized. Because up to 10% of patients with HCM have normal ECGs, children whose parents or grandparents have HCM should have an echocardiogram every 5 years until puberty, and then every year until they turn 20 years old or finish growing, he said. But ECGs also are important because they may become abnormal before the echocardiogram does, Dr. Shannon said. If the ECG becomes abnormal, pediatricians should tell parents that the echocardiogram is likely to become abnormal and should advise them to steer the child away from competitive athletics, he said.

Twenty-four hour ambulatory (Holter) ECGs also are part of risk stratification in patients with HCM, Dr. Shannon said. The American College of Cardiology and the American Heart Association recommend Holter monitoring for the initial evaluation of patients with HCM and for patients with HCM who develop palpitations or lightheadedness (J. Am. Coll. Cardiol. 2011;58:2703-38).

Dr. Shannon reported no conflicts of interest.

SAN DIEGO – Pediatricians should screen patients for hypertrophic cardiomyopathy if a first- or second-degree relative has been diagnosed with the condition or has a history of sudden death, said Dr. Kevin Shannon, a pediatric cardiologist at the University of California, Los Angeles, Medical Center.

“Anybody with a family history of HCM, including uncles, cousins, parents, and siblings, should be screened,” he emphasized. “Even if they don’t have obstructive HCM, they will often have a murmur, most commonly at the upper sternal border.” The murmur is typically late-peaking and worsens during Valsalva, he added.

HCM is the most common cause of sudden death in athletes and is the most common genetic cardiac disease, affecting about 1 in 500 young adults (Circulation 1995;92:785-9). The autosomal dominant inheritance pattern shows varying degrees of penetrance, translating to a range of phenotypes, Dr. Shannon said at the annual meeting of the American Academy of Pediatrics. “Even if your family member didn’t have hypertrophy until age 30, you can get it at age 5, and the opposite can also be true,” he noted.

HCM can be a silent disease until it causes sudden death. However, pediatricians should ask patients about exercise tolerance and should consider HCM in patients who describe a substantial drop in sports performance, Dr. Shannon said. An athlete with HCM might say that he or she always finished the field lap first and is now second to last, and a soccer player with a field position might say, “Now I finish the runs after the goalies,” he said.

A resting electrocardiogram is not sufficient to exclude HCM, Dr. Shannon emphasized. Because up to 10% of patients with HCM have normal ECGs, children whose parents or grandparents have HCM should have an echocardiogram every 5 years until puberty, and then every year until they turn 20 years old or finish growing, he said. But ECGs also are important because they may become abnormal before the echocardiogram does, Dr. Shannon said. If the ECG becomes abnormal, pediatricians should tell parents that the echocardiogram is likely to become abnormal and should advise them to steer the child away from competitive athletics, he said.

Twenty-four hour ambulatory (Holter) ECGs also are part of risk stratification in patients with HCM, Dr. Shannon said. The American College of Cardiology and the American Heart Association recommend Holter monitoring for the initial evaluation of patients with HCM and for patients with HCM who develop palpitations or lightheadedness (J. Am. Coll. Cardiol. 2011;58:2703-38).

Dr. Shannon reported no conflicts of interest.

SAN DIEGO – Pediatricians should screen patients for hypertrophic cardiomyopathy if a first- or second-degree relative has been diagnosed with the condition or has a history of sudden death, said Dr. Kevin Shannon, a pediatric cardiologist at the University of California, Los Angeles, Medical Center.

“Anybody with a family history of HCM, including uncles, cousins, parents, and siblings, should be screened,” he emphasized. “Even if they don’t have obstructive HCM, they will often have a murmur, most commonly at the upper sternal border.” The murmur is typically late-peaking and worsens during Valsalva, he added.

HCM is the most common cause of sudden death in athletes and is the most common genetic cardiac disease, affecting about 1 in 500 young adults (Circulation 1995;92:785-9). The autosomal dominant inheritance pattern shows varying degrees of penetrance, translating to a range of phenotypes, Dr. Shannon said at the annual meeting of the American Academy of Pediatrics. “Even if your family member didn’t have hypertrophy until age 30, you can get it at age 5, and the opposite can also be true,” he noted.

HCM can be a silent disease until it causes sudden death. However, pediatricians should ask patients about exercise tolerance and should consider HCM in patients who describe a substantial drop in sports performance, Dr. Shannon said. An athlete with HCM might say that he or she always finished the field lap first and is now second to last, and a soccer player with a field position might say, “Now I finish the runs after the goalies,” he said.

A resting electrocardiogram is not sufficient to exclude HCM, Dr. Shannon emphasized. Because up to 10% of patients with HCM have normal ECGs, children whose parents or grandparents have HCM should have an echocardiogram every 5 years until puberty, and then every year until they turn 20 years old or finish growing, he said. But ECGs also are important because they may become abnormal before the echocardiogram does, Dr. Shannon said. If the ECG becomes abnormal, pediatricians should tell parents that the echocardiogram is likely to become abnormal and should advise them to steer the child away from competitive athletics, he said.

Twenty-four hour ambulatory (Holter) ECGs also are part of risk stratification in patients with HCM, Dr. Shannon said. The American College of Cardiology and the American Heart Association recommend Holter monitoring for the initial evaluation of patients with HCM and for patients with HCM who develop palpitations or lightheadedness (J. Am. Coll. Cardiol. 2011;58:2703-38).

Dr. Shannon reported no conflicts of interest.

SAN DIEGO– Pediatricians are at risk of misdiagnosing myocarditis despite its severity. That’s because children tend to present with abdominal symptoms and a history of a recent viral illness that lacked signs of cardiac involvement, Dr. Kevin Shannon said.

“Typically, they have a bout of flu, they seem to be getting better, and then they start vomiting or having stomach pain again,” he said at the annual meeting of the American Academy of Pediatrics.

Viruses ranging from adenovirus to varicella have been implicated in myocarditis in children (J. Clin. Microbiol. 2010;48:642-5; Pediatr. Cardiol. 2011;32:1241-3). Pediatricians should watch for patients who were recently ill and are now presenting with an apparent relapse and tachycardia that is worse than how they appear overall, said Dr. Shannon, a pediatric cardiologist at the University of California, Los Angeles, Medical Center. “A lot of these children will seem more ill than their vomiting will suggest,” he added. “They’ll have a heart rate of 180 [beats per minute] that is out proportion to how they look.”

Fluid therapy does not improve tachycardia and may even worsen it, indicating that dehydration is not the underlying cause, said Dr. Shannon. Children with viral myocarditis also often have acute upper-right quadrant pain as a result of hepatic distension, he said.

Laboratory findings can be very helpful. Cardiac troponin T is almost always elevated in children with myocarditis (Pediatr. Emerg. Care 2012;28:1173-8), and erythrocyte sedimentation rate also may be high. Electrocardiography can show a variety of focal or diffuse abnormalities, none of which are pathognomonic for the condition, Dr. Shannon said. Focal abnormalities can mimic an ST segment elevation myocardial infarction (STEMI), he added.

On chest x-ray, the heart margins also are often normal because the heart has not yet enlarged to compensate for impaired function, said Dr. Shannon. “This is a poorly functioning, normal-sized heart,” he added. Chest films often will reveal interstitial edema that might be misinterpreted as interstitial pneumonia, in keeping with the child’s recent illness.

Treatment of acquired myocarditis is based on supportive care, said Dr. Shannon, adding that use of immunomodulators in children with myocarditis is controversial. “If they have low blood pressure, they need volume, even if their heart rate gets higher,” he added. “If they don’t tolerate fluid therapy, they need inotropes and sometimes intubation.”

Dr. Shannon reported no conflicts of interest.

SAN DIEGO– Pediatricians are at risk of misdiagnosing myocarditis despite its severity. That’s because children tend to present with abdominal symptoms and a history of a recent viral illness that lacked signs of cardiac involvement, Dr. Kevin Shannon said.

“Typically, they have a bout of flu, they seem to be getting better, and then they start vomiting or having stomach pain again,” he said at the annual meeting of the American Academy of Pediatrics.

Viruses ranging from adenovirus to varicella have been implicated in myocarditis in children (J. Clin. Microbiol. 2010;48:642-5; Pediatr. Cardiol. 2011;32:1241-3). Pediatricians should watch for patients who were recently ill and are now presenting with an apparent relapse and tachycardia that is worse than how they appear overall, said Dr. Shannon, a pediatric cardiologist at the University of California, Los Angeles, Medical Center. “A lot of these children will seem more ill than their vomiting will suggest,” he added. “They’ll have a heart rate of 180 [beats per minute] that is out proportion to how they look.”

Fluid therapy does not improve tachycardia and may even worsen it, indicating that dehydration is not the underlying cause, said Dr. Shannon. Children with viral myocarditis also often have acute upper-right quadrant pain as a result of hepatic distension, he said.

Laboratory findings can be very helpful. Cardiac troponin T is almost always elevated in children with myocarditis (Pediatr. Emerg. Care 2012;28:1173-8), and erythrocyte sedimentation rate also may be high. Electrocardiography can show a variety of focal or diffuse abnormalities, none of which are pathognomonic for the condition, Dr. Shannon said. Focal abnormalities can mimic an ST segment elevation myocardial infarction (STEMI), he added.

On chest x-ray, the heart margins also are often normal because the heart has not yet enlarged to compensate for impaired function, said Dr. Shannon. “This is a poorly functioning, normal-sized heart,” he added. Chest films often will reveal interstitial edema that might be misinterpreted as interstitial pneumonia, in keeping with the child’s recent illness.

Treatment of acquired myocarditis is based on supportive care, said Dr. Shannon, adding that use of immunomodulators in children with myocarditis is controversial. “If they have low blood pressure, they need volume, even if their heart rate gets higher,” he added. “If they don’t tolerate fluid therapy, they need inotropes and sometimes intubation.”

Dr. Shannon reported no conflicts of interest.

SAN DIEGO– Pediatricians are at risk of misdiagnosing myocarditis despite its severity. That’s because children tend to present with abdominal symptoms and a history of a recent viral illness that lacked signs of cardiac involvement, Dr. Kevin Shannon said.

“Typically, they have a bout of flu, they seem to be getting better, and then they start vomiting or having stomach pain again,” he said at the annual meeting of the American Academy of Pediatrics.

Viruses ranging from adenovirus to varicella have been implicated in myocarditis in children (J. Clin. Microbiol. 2010;48:642-5; Pediatr. Cardiol. 2011;32:1241-3). Pediatricians should watch for patients who were recently ill and are now presenting with an apparent relapse and tachycardia that is worse than how they appear overall, said Dr. Shannon, a pediatric cardiologist at the University of California, Los Angeles, Medical Center. “A lot of these children will seem more ill than their vomiting will suggest,” he added. “They’ll have a heart rate of 180 [beats per minute] that is out proportion to how they look.”

Fluid therapy does not improve tachycardia and may even worsen it, indicating that dehydration is not the underlying cause, said Dr. Shannon. Children with viral myocarditis also often have acute upper-right quadrant pain as a result of hepatic distension, he said.

Laboratory findings can be very helpful. Cardiac troponin T is almost always elevated in children with myocarditis (Pediatr. Emerg. Care 2012;28:1173-8), and erythrocyte sedimentation rate also may be high. Electrocardiography can show a variety of focal or diffuse abnormalities, none of which are pathognomonic for the condition, Dr. Shannon said. Focal abnormalities can mimic an ST segment elevation myocardial infarction (STEMI), he added.

On chest x-ray, the heart margins also are often normal because the heart has not yet enlarged to compensate for impaired function, said Dr. Shannon. “This is a poorly functioning, normal-sized heart,” he added. Chest films often will reveal interstitial edema that might be misinterpreted as interstitial pneumonia, in keeping with the child’s recent illness.

Treatment of acquired myocarditis is based on supportive care, said Dr. Shannon, adding that use of immunomodulators in children with myocarditis is controversial. “If they have low blood pressure, they need volume, even if their heart rate gets higher,” he added. “If they don’t tolerate fluid therapy, they need inotropes and sometimes intubation.”

Dr. Shannon reported no conflicts of interest.