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WASHINGTON – Understanding a child’s fever history and other symptoms is essential to accurately determining what is causing a fever and what kind of management, if any, it requires, Dr. Kathryn M. Edwards explained at the American Academy of Pediatrics annual meeting.
Dr. Edwards aimed largely to help clinicians distinguish between familial recurrent fever syndromes and the syndrome PFAPA (Periodic Fever, Aphthous Stomatitis, Pharyngitis, Cervical Adenitis). Although familial cases of PFAPA have been reported, the syndrome’s etiology isn’t fully understood.
She began with a review of fever definition and pathogenesis, and used a series of case studies to introduce various fever syndromes. Although the simplest definition is an above-normal body temperature, fever is best thought of not as “a single value, but rather a range depending on time, place, individual, and measurement site,” Dr. Edwards explained. An inflammatory response, fever may result from an infection or occur secondarily to other conditions. The inflammatory response begins after both monocytes and macrophages release cytokines that stimulate the brain’s thermoregulatory center, inducing prostaglandin production.
Recurrent and periodic fever overview
Unlike a fever of unknown origin, recurrent and periodic fevers occur regularly in repeated cycles or intermittently over a period of time. The most important step in identifying what’s going on with a child’s recurrent/periodic fever is taking a complete fever history, including not only exposures and travel, but also family history and ethnicity. Clinicians can provide parents with a fever diary that tracks fever date and time, the temperature, other symptoms, medication administered, and other relevant information because “knowing the fever pattern is critical,” Dr. Edwards emphasized. A good fever history also requires clinicians to conduct a comprehensive physical exam, be aware of temperature norms for a child’s age and sex, and diligently evaluate a child’s growth parameters.
Using a flowchart adapted from Long’s article in “Pediatric Clinics of North America,” Dr. Edwards pointed out that recurrent fever may result from identified infections or may be stereotypical and episodic without an infection. The source of multiple viral infections is generally environmental, such as day care or cigarette smoke exposure. Multiple bacterial infections involving different organ systems may indicate an immunodeficiency, whereas recurrent infections in the same organ system require assessment specific to that system. Among stereotypical recurrent fevers, irregular episodes likely indicate a monogenic fever syndrome, while more predictable episodes could be cyclic neutropenia or PFAPA.
“There are a couple remarkable differences between PFAPA patients and patients with repeated viral infections,” said Dr. Edwards , professor of pediatrics at Vanderbilt University, Nashville, Tenn. “One is the frequency of the fevers, how often they come,” which underscores the need for a meticulous fever history, she explained. A parent might perceive that the fevers come once a month, but it’s essential to know whether they truly come like clockwork or whether they are more sporadic. “In addition, between the episodes, the children get nothing else,” she said, “and certainly they’re not infectious. Nobody else gets sick.”
Recognizing PFAPA
Children with PFAPA show normal growth and development, and no symptoms between very regular intervals of fever (above 38.3º C) with sore throat, mouth sores, and/or glandular swelling in the absence of an infection. About two-thirds of patients report headache, sore throat and/or mouth ulcers, and more than three quarters report swelling of the lymph nodes. About half experience abdominal pain or nausea.
PFAPA typically has an early age of onset and is diagnosed after exclusion of cyclic neutropenia and other fever syndromes. Episodes last an average of 3-4 days with intervals gradually becoming less frequent as the child ages. In one study, intervals at onset lasted an average of 28 days, but gradually extended to a mean 159 days during long-term follow-up in which average syndrome duration ranged from 5 to 7 years. Studies show a family history of recurrent fever in 10%-60% of patients, and recurrent tonsillitis in one parent is twice as likely among children with PFAPA.
Primary treatments for PFAPA include corticosteroids, cimetidine, and tonsillectomy, with anakinra, colchicine, and montelukast comprising additional options. Although the fever should subside within 4-12 hours after a corticosteroid dose of 1-2 mg/kg, a quarter of children may require a second dose within the next 12-24 hours, and corticosteroids treatment may increase episode frequency in up to half of children. By contrast, cimetidine is used prophylactically – twice daily over 6 months – and has led to remission in approximately a quarter of patients, although some experience recurrence after stopping treatment. The most successful intervention for curing PFAPA is tonsillectomy: Episodes completely stopped in 70%-97% of children in European and U.S. studies. But Dr. Edwards said the surgery should not be a first-line intervention.
“The role of the tonsils in all of the fever syndromes is quite fascinating, and I also think it’s interesting the parents have similar pharyngeal or oropharyngeal symptoms when they were children,” she said, noting that some research has been investigating tonsil cells for a better understanding of these syndromes.
“I think the decision to do a tonsillectomy is very dependent upon families,” she said. “I certainly don’t recommend it first thing, but there are some patients who have had these episodes for 2 or 3 years, the family is falling apart, and [the parents] are unable to go to work. In those situations, I will say this looks like something we should do.”
Familial fever syndromes
Dr. Edwards covered several familial fever syndromes during the remainder of the presentation using case studies to introduce each one. The first, familial Mediterranean fever (FMF), also known as Armenian disease, results from a mutation in the MEFV gene and occurs among those of Sephardic and Ashkenazi Jewish, Middle Eastern Arab, Armenian, Italian, North African or Turkish ethnicities.
Episodes last 12-72 hours, and clinical features include an erysipeloid rash and inflammation of various membranes, causing abdominal, chest or joint pain (serositis of the peritoneum, pleura or synovia, respectively). Treatment with colchicine can prevent FMF’s most significant complication, amyloidosis, which can otherwise lead to renal failure. About 95% of patients experience improvement, and 75% have remission with colchicine, and anakinra is an additional treatment option.
The second familial syndrome, hyperimmunoglobulinemia D with periodic fever syndrome, or hyper IgD (HIDS), has an early age of onset, typically before 12 months and with more than half before 6 months. Resulting from mutations in the MVK gene (and hence also called mevalonate kinase deficiency), HIDS primarily afflicts those with European ancestry, and about half of patients are of Dutch ancestry. Despite the syndrome’s name, about 22% of patients have normal IgD levels, and high IgD levels may indicate other conditions, so high IgD labs are not diagnostic. Diagnosis is based on genetic testing and elevated mevalonic acid levels in urine.
Stress, vaccination, or an upper respiratory infection may trigger a HIDS episode that lasts 3-7 days with clinical features that include a widespread red rash – frequently on the lower legs – as well as oral or vaginal ulcers. More than 80% of patients report swollen lymph nodes, abdominal pain, and joint pain, particularly in the knees, ankles, wrists, and elbows. More than half of patients report diarrhea, vomiting, skin lesions, headache, cold chills, or arthritis.
The final fever syndrome Dr. Edwards covered was tumor necrosis factor receptor–associated periodic syndrome (TRAPS), also called Hibernian fever. Resulting from mutations in TNFRSF1A gene, this condition first appeared in Scottish and Irish populations but can occur among any ethnicity. Episodes can last from a few days to 1-2 weeks, and can include migratory nonspecific pain, a rash, abdominal pain, joint pain, chest pain, mouth sores, puffy eyes, and various inflammatory eye symptoms, such as uveitis, iritis, and conjunctivitis.
Although PFAPA is the most common pediatric periodic fever syndrome, a thorough fever history and family history can help clinicians identify whether a familial syndrome is involved.
WASHINGTON – Understanding a child’s fever history and other symptoms is essential to accurately determining what is causing a fever and what kind of management, if any, it requires, Dr. Kathryn M. Edwards explained at the American Academy of Pediatrics annual meeting.
Dr. Edwards aimed largely to help clinicians distinguish between familial recurrent fever syndromes and the syndrome PFAPA (Periodic Fever, Aphthous Stomatitis, Pharyngitis, Cervical Adenitis). Although familial cases of PFAPA have been reported, the syndrome’s etiology isn’t fully understood.
She began with a review of fever definition and pathogenesis, and used a series of case studies to introduce various fever syndromes. Although the simplest definition is an above-normal body temperature, fever is best thought of not as “a single value, but rather a range depending on time, place, individual, and measurement site,” Dr. Edwards explained. An inflammatory response, fever may result from an infection or occur secondarily to other conditions. The inflammatory response begins after both monocytes and macrophages release cytokines that stimulate the brain’s thermoregulatory center, inducing prostaglandin production.
Recurrent and periodic fever overview
Unlike a fever of unknown origin, recurrent and periodic fevers occur regularly in repeated cycles or intermittently over a period of time. The most important step in identifying what’s going on with a child’s recurrent/periodic fever is taking a complete fever history, including not only exposures and travel, but also family history and ethnicity. Clinicians can provide parents with a fever diary that tracks fever date and time, the temperature, other symptoms, medication administered, and other relevant information because “knowing the fever pattern is critical,” Dr. Edwards emphasized. A good fever history also requires clinicians to conduct a comprehensive physical exam, be aware of temperature norms for a child’s age and sex, and diligently evaluate a child’s growth parameters.
Using a flowchart adapted from Long’s article in “Pediatric Clinics of North America,” Dr. Edwards pointed out that recurrent fever may result from identified infections or may be stereotypical and episodic without an infection. The source of multiple viral infections is generally environmental, such as day care or cigarette smoke exposure. Multiple bacterial infections involving different organ systems may indicate an immunodeficiency, whereas recurrent infections in the same organ system require assessment specific to that system. Among stereotypical recurrent fevers, irregular episodes likely indicate a monogenic fever syndrome, while more predictable episodes could be cyclic neutropenia or PFAPA.
“There are a couple remarkable differences between PFAPA patients and patients with repeated viral infections,” said Dr. Edwards , professor of pediatrics at Vanderbilt University, Nashville, Tenn. “One is the frequency of the fevers, how often they come,” which underscores the need for a meticulous fever history, she explained. A parent might perceive that the fevers come once a month, but it’s essential to know whether they truly come like clockwork or whether they are more sporadic. “In addition, between the episodes, the children get nothing else,” she said, “and certainly they’re not infectious. Nobody else gets sick.”
Recognizing PFAPA
Children with PFAPA show normal growth and development, and no symptoms between very regular intervals of fever (above 38.3º C) with sore throat, mouth sores, and/or glandular swelling in the absence of an infection. About two-thirds of patients report headache, sore throat and/or mouth ulcers, and more than three quarters report swelling of the lymph nodes. About half experience abdominal pain or nausea.
PFAPA typically has an early age of onset and is diagnosed after exclusion of cyclic neutropenia and other fever syndromes. Episodes last an average of 3-4 days with intervals gradually becoming less frequent as the child ages. In one study, intervals at onset lasted an average of 28 days, but gradually extended to a mean 159 days during long-term follow-up in which average syndrome duration ranged from 5 to 7 years. Studies show a family history of recurrent fever in 10%-60% of patients, and recurrent tonsillitis in one parent is twice as likely among children with PFAPA.
Primary treatments for PFAPA include corticosteroids, cimetidine, and tonsillectomy, with anakinra, colchicine, and montelukast comprising additional options. Although the fever should subside within 4-12 hours after a corticosteroid dose of 1-2 mg/kg, a quarter of children may require a second dose within the next 12-24 hours, and corticosteroids treatment may increase episode frequency in up to half of children. By contrast, cimetidine is used prophylactically – twice daily over 6 months – and has led to remission in approximately a quarter of patients, although some experience recurrence after stopping treatment. The most successful intervention for curing PFAPA is tonsillectomy: Episodes completely stopped in 70%-97% of children in European and U.S. studies. But Dr. Edwards said the surgery should not be a first-line intervention.
“The role of the tonsils in all of the fever syndromes is quite fascinating, and I also think it’s interesting the parents have similar pharyngeal or oropharyngeal symptoms when they were children,” she said, noting that some research has been investigating tonsil cells for a better understanding of these syndromes.
“I think the decision to do a tonsillectomy is very dependent upon families,” she said. “I certainly don’t recommend it first thing, but there are some patients who have had these episodes for 2 or 3 years, the family is falling apart, and [the parents] are unable to go to work. In those situations, I will say this looks like something we should do.”
Familial fever syndromes
Dr. Edwards covered several familial fever syndromes during the remainder of the presentation using case studies to introduce each one. The first, familial Mediterranean fever (FMF), also known as Armenian disease, results from a mutation in the MEFV gene and occurs among those of Sephardic and Ashkenazi Jewish, Middle Eastern Arab, Armenian, Italian, North African or Turkish ethnicities.
Episodes last 12-72 hours, and clinical features include an erysipeloid rash and inflammation of various membranes, causing abdominal, chest or joint pain (serositis of the peritoneum, pleura or synovia, respectively). Treatment with colchicine can prevent FMF’s most significant complication, amyloidosis, which can otherwise lead to renal failure. About 95% of patients experience improvement, and 75% have remission with colchicine, and anakinra is an additional treatment option.
The second familial syndrome, hyperimmunoglobulinemia D with periodic fever syndrome, or hyper IgD (HIDS), has an early age of onset, typically before 12 months and with more than half before 6 months. Resulting from mutations in the MVK gene (and hence also called mevalonate kinase deficiency), HIDS primarily afflicts those with European ancestry, and about half of patients are of Dutch ancestry. Despite the syndrome’s name, about 22% of patients have normal IgD levels, and high IgD levels may indicate other conditions, so high IgD labs are not diagnostic. Diagnosis is based on genetic testing and elevated mevalonic acid levels in urine.
Stress, vaccination, or an upper respiratory infection may trigger a HIDS episode that lasts 3-7 days with clinical features that include a widespread red rash – frequently on the lower legs – as well as oral or vaginal ulcers. More than 80% of patients report swollen lymph nodes, abdominal pain, and joint pain, particularly in the knees, ankles, wrists, and elbows. More than half of patients report diarrhea, vomiting, skin lesions, headache, cold chills, or arthritis.
The final fever syndrome Dr. Edwards covered was tumor necrosis factor receptor–associated periodic syndrome (TRAPS), also called Hibernian fever. Resulting from mutations in TNFRSF1A gene, this condition first appeared in Scottish and Irish populations but can occur among any ethnicity. Episodes can last from a few days to 1-2 weeks, and can include migratory nonspecific pain, a rash, abdominal pain, joint pain, chest pain, mouth sores, puffy eyes, and various inflammatory eye symptoms, such as uveitis, iritis, and conjunctivitis.
Although PFAPA is the most common pediatric periodic fever syndrome, a thorough fever history and family history can help clinicians identify whether a familial syndrome is involved.
WASHINGTON – Understanding a child’s fever history and other symptoms is essential to accurately determining what is causing a fever and what kind of management, if any, it requires, Dr. Kathryn M. Edwards explained at the American Academy of Pediatrics annual meeting.
Dr. Edwards aimed largely to help clinicians distinguish between familial recurrent fever syndromes and the syndrome PFAPA (Periodic Fever, Aphthous Stomatitis, Pharyngitis, Cervical Adenitis). Although familial cases of PFAPA have been reported, the syndrome’s etiology isn’t fully understood.
She began with a review of fever definition and pathogenesis, and used a series of case studies to introduce various fever syndromes. Although the simplest definition is an above-normal body temperature, fever is best thought of not as “a single value, but rather a range depending on time, place, individual, and measurement site,” Dr. Edwards explained. An inflammatory response, fever may result from an infection or occur secondarily to other conditions. The inflammatory response begins after both monocytes and macrophages release cytokines that stimulate the brain’s thermoregulatory center, inducing prostaglandin production.
Recurrent and periodic fever overview
Unlike a fever of unknown origin, recurrent and periodic fevers occur regularly in repeated cycles or intermittently over a period of time. The most important step in identifying what’s going on with a child’s recurrent/periodic fever is taking a complete fever history, including not only exposures and travel, but also family history and ethnicity. Clinicians can provide parents with a fever diary that tracks fever date and time, the temperature, other symptoms, medication administered, and other relevant information because “knowing the fever pattern is critical,” Dr. Edwards emphasized. A good fever history also requires clinicians to conduct a comprehensive physical exam, be aware of temperature norms for a child’s age and sex, and diligently evaluate a child’s growth parameters.
Using a flowchart adapted from Long’s article in “Pediatric Clinics of North America,” Dr. Edwards pointed out that recurrent fever may result from identified infections or may be stereotypical and episodic without an infection. The source of multiple viral infections is generally environmental, such as day care or cigarette smoke exposure. Multiple bacterial infections involving different organ systems may indicate an immunodeficiency, whereas recurrent infections in the same organ system require assessment specific to that system. Among stereotypical recurrent fevers, irregular episodes likely indicate a monogenic fever syndrome, while more predictable episodes could be cyclic neutropenia or PFAPA.
“There are a couple remarkable differences between PFAPA patients and patients with repeated viral infections,” said Dr. Edwards , professor of pediatrics at Vanderbilt University, Nashville, Tenn. “One is the frequency of the fevers, how often they come,” which underscores the need for a meticulous fever history, she explained. A parent might perceive that the fevers come once a month, but it’s essential to know whether they truly come like clockwork or whether they are more sporadic. “In addition, between the episodes, the children get nothing else,” she said, “and certainly they’re not infectious. Nobody else gets sick.”
Recognizing PFAPA
Children with PFAPA show normal growth and development, and no symptoms between very regular intervals of fever (above 38.3º C) with sore throat, mouth sores, and/or glandular swelling in the absence of an infection. About two-thirds of patients report headache, sore throat and/or mouth ulcers, and more than three quarters report swelling of the lymph nodes. About half experience abdominal pain or nausea.
PFAPA typically has an early age of onset and is diagnosed after exclusion of cyclic neutropenia and other fever syndromes. Episodes last an average of 3-4 days with intervals gradually becoming less frequent as the child ages. In one study, intervals at onset lasted an average of 28 days, but gradually extended to a mean 159 days during long-term follow-up in which average syndrome duration ranged from 5 to 7 years. Studies show a family history of recurrent fever in 10%-60% of patients, and recurrent tonsillitis in one parent is twice as likely among children with PFAPA.
Primary treatments for PFAPA include corticosteroids, cimetidine, and tonsillectomy, with anakinra, colchicine, and montelukast comprising additional options. Although the fever should subside within 4-12 hours after a corticosteroid dose of 1-2 mg/kg, a quarter of children may require a second dose within the next 12-24 hours, and corticosteroids treatment may increase episode frequency in up to half of children. By contrast, cimetidine is used prophylactically – twice daily over 6 months – and has led to remission in approximately a quarter of patients, although some experience recurrence after stopping treatment. The most successful intervention for curing PFAPA is tonsillectomy: Episodes completely stopped in 70%-97% of children in European and U.S. studies. But Dr. Edwards said the surgery should not be a first-line intervention.
“The role of the tonsils in all of the fever syndromes is quite fascinating, and I also think it’s interesting the parents have similar pharyngeal or oropharyngeal symptoms when they were children,” she said, noting that some research has been investigating tonsil cells for a better understanding of these syndromes.
“I think the decision to do a tonsillectomy is very dependent upon families,” she said. “I certainly don’t recommend it first thing, but there are some patients who have had these episodes for 2 or 3 years, the family is falling apart, and [the parents] are unable to go to work. In those situations, I will say this looks like something we should do.”
Familial fever syndromes
Dr. Edwards covered several familial fever syndromes during the remainder of the presentation using case studies to introduce each one. The first, familial Mediterranean fever (FMF), also known as Armenian disease, results from a mutation in the MEFV gene and occurs among those of Sephardic and Ashkenazi Jewish, Middle Eastern Arab, Armenian, Italian, North African or Turkish ethnicities.
Episodes last 12-72 hours, and clinical features include an erysipeloid rash and inflammation of various membranes, causing abdominal, chest or joint pain (serositis of the peritoneum, pleura or synovia, respectively). Treatment with colchicine can prevent FMF’s most significant complication, amyloidosis, which can otherwise lead to renal failure. About 95% of patients experience improvement, and 75% have remission with colchicine, and anakinra is an additional treatment option.
The second familial syndrome, hyperimmunoglobulinemia D with periodic fever syndrome, or hyper IgD (HIDS), has an early age of onset, typically before 12 months and with more than half before 6 months. Resulting from mutations in the MVK gene (and hence also called mevalonate kinase deficiency), HIDS primarily afflicts those with European ancestry, and about half of patients are of Dutch ancestry. Despite the syndrome’s name, about 22% of patients have normal IgD levels, and high IgD levels may indicate other conditions, so high IgD labs are not diagnostic. Diagnosis is based on genetic testing and elevated mevalonic acid levels in urine.
Stress, vaccination, or an upper respiratory infection may trigger a HIDS episode that lasts 3-7 days with clinical features that include a widespread red rash – frequently on the lower legs – as well as oral or vaginal ulcers. More than 80% of patients report swollen lymph nodes, abdominal pain, and joint pain, particularly in the knees, ankles, wrists, and elbows. More than half of patients report diarrhea, vomiting, skin lesions, headache, cold chills, or arthritis.
The final fever syndrome Dr. Edwards covered was tumor necrosis factor receptor–associated periodic syndrome (TRAPS), also called Hibernian fever. Resulting from mutations in TNFRSF1A gene, this condition first appeared in Scottish and Irish populations but can occur among any ethnicity. Episodes can last from a few days to 1-2 weeks, and can include migratory nonspecific pain, a rash, abdominal pain, joint pain, chest pain, mouth sores, puffy eyes, and various inflammatory eye symptoms, such as uveitis, iritis, and conjunctivitis.
Although PFAPA is the most common pediatric periodic fever syndrome, a thorough fever history and family history can help clinicians identify whether a familial syndrome is involved.
EXPERT ANALYSIS FROM THE AAP NATIONAL CONFERENCE
