December 19, 2017
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Diagnosing source of periodic fever in children entails collecting thorough history

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NEW YORK —  Frequent fevers and associated symptoms may point to an autoinflammatory or autoimmune disorder, such as periodic fever, aphthous stomatitis, pharyngitis, adenitis syndrome or PFAPA, the most common periodic fever syndrome of childhood, according to a presentation at the 2017 Infectious Diseases in Children Symposium.

However, a range of syndromes may develop within childhood. A detailed personal and familial history could reveal other sources of periodic fever.

“A lot of times, the parents have an idea if the same symptoms are happening over and over,” Kalpana Manthiram, MD, fellow at the NIH and adjunct assistant professor at Vanderbilt University, said in her presentation. “You, [as a physician], may also get that feeling as you see these children multiple times in the clinic.”

According to Manthiram, periodic fevers are a type of recurrent fever in which each episode has a stereotypical symptom complex. Once the fever resolves, patients will go through intervals in which no symptoms are experienced.

During the diagnosis of a syndrome that may cause periodic fevers, Manthiram said it is important to collect a thorough history by asking specific questions regarding the fever, including whether all episodes have the same presentation, if there are  asymptomatic periods and the child’s fever pattern. The regularity of the fevers and the intervals experienced are crucial for diagnosis.

“We frequently use fever diaries and fever questionnaires,” Manthiram said. “You might often find that people do not remember all of the necessary information for diagnosis when they come to the clinic. In our clinic, we give patients the diaries and questionnaires before their visit so that they have time to think about it.”

In addition, Manthiram suggests an examination during a flare to assess associated symptoms, knowing the age of onset and a familial history of recurrent fevers.

In many cases, an autoinflammatory or autoimmune syndrome may be responsible for periodic fevers, including familial Mediterranean fever (FMF) or TNF-receptor -associated periodic syndrome (TRAPS).

“Autoinflammatory is a newer term coined about 20 years ago, and it was used to describe people who have syndromes of abnormal, innate immune activation,” Manthiram said. “The innate immune system is more primitive and the first line of defense. It is much less specific than the adaptive immune system.”

The most commonly identified monogenic fever syndromes, according to Manthiram, include FMF, TRAPS, hyper-IgD syndrome and cryopyrin-associated syndromes; however, the most frequently encountered condition in the pediatric setting is PFAPA. The etiology of this condition is unknown, but its tendency to be clustered within families points to a possible genetic predisposition as nearly 25% have a family member with a related condition.

“If you ask, you can often find patients who have a parent or sibling with recurrent tonsillitis, recurrent strep throat, recurrent aphthous ulcers or tonsillectomy,” Manthiram said.

Symptoms of PFAPA include regularly occurring fevers of more than 38.3°C at an early age and constitutional symptoms in the absence of upper respiratory infection with at least one of three symptoms: aphthous stomatitis, cervical adenitis or pharyngitis. Other symptoms and signs have also been reported, including headache (65%); abdominal pain (45%); and nausea (52%). However, cases occurring in adulthood have been reported, and patients may skip episodes or have periods of remission.

For diagnosis of PFAPA, it is important that cyclic neutropenia and other intermittent fever syndromes are excluded. Once diagnosed, several options are available for treatment and preventive therapies. Corticosteroids are often used for episodic treatment of PFAPA, but Manthiram said it is important to note that many patients may experience more frequent episodes when corticosteroids are used. Cimetidine or colchicine can be used to prevent episodes. A permanent solution can be found in surgical therapy, which includes tonsillectomy.

Genetic testing may be warranted in a variety of cases. Manthiram suggested considering further investigation through testing when patients experience an onset of periodic fevers at an early or late age; when symptoms of a monogenic periodic fever syndrome include rash, arthritis, conjunctivitis, periorbital swelling, prominent vomiting, diarrhea and chest pain; if they have an ethnic background with a compatible clinical history; and if their episode has not been resolved with corticosteroids.

Furthermore, she recommended genetic testing when episodes are timed irregularly and when episodes have short or long durations.  

“There are not clear criteria for when to do [genetic testing]. It is based on our experiences and seeing patients with those syndromes,” Manthiram said. “There is genetic testing available in commercial labs. At the NIH, where we have a recurrent fever clinic, many patients do not seem to fit the diagnostic criteria for PFAPA and have negative genetic testing for these syndromes. We do not really know what they have, whether it is a polygenic disease or that we just do not yet know what genes are involved in their periodic fever.” –by Katherine Bortz

Reference:

Manthiram K. Frequent fevers: When should you worry about a periodic fever syndrome. Presented at: 2017 Infectious Diseases in Children Symposium. Nov. 18-19; New York.

Disclosures: Manthiram reports no relevant financial disclosures. Off-label uses of cimetidine, colchicine and anakinra were discussed in the presentation.