Online Health Chat with Andrew Zeft, MD and Camille Sabella, MD

December 4, 2013


According to the American College of Rheumatology only 15 percent of children diagnosed with recurrent fever exhibit signs into adulthood, but that is little comfort for the children who suffer from this painful syndrome. When your child has recurrent episodes of fever, sore throat and swollen glands, it is helpful to figure out when it’s a virus and when it may be something more. Fortunately, most children experience mild illnesses as they mature during the development of their immune systems. However, children may also experience more severe medical conditions requiring further care. Some of these illnesses include, but are not limited to, strep throat, epiglottitis and mononucleosis.

These illnesses vary in their presentation as well as severity. Even after the first visit, when symptoms don’t get better, either lasting longer than anticipated or worsening—or if the parent thinks “something just isn’t right”—it’s time to consult a medical specialist to find out if an underlying medical condition needs to be diagnosed and treated. Various treatment options exist to better control symptoms and help children lead happier, healthier lives.

About the Speaker

Andrew Zeft, MD is a board-certified pediatric rheumatologist and pediatrician in the Center for Pediatric Rheumatology at Cleveland Clinic Children’s. He completed his fellowship in pediatric rheumatology at Children’s Hospital and Regional Medical Center, in Seattle, and a fellowship in pediatric cardiology at Mount Sinai Medical Center, in New York, NY, following his pediatric residency at Tulane University Hospital, in New Orleans. He graduated from medical school at the Medical College of Wisconsin, in Milwaukee. Dr. Zeft currently sees patients on Cleveland Clinic’s main campus and at the Twinsburg Family Health and Surgery Center.

Camille Sabella, MD is a pediatric specialist in the Center of Pediatric Infectious Diseases at Cleveland Clinic Children’s. He is board certified in general pediatrics and pediatric infectious disease. He completed his fellowship in pediatric infectious disease at Stanford University Hospital, in Stanford, CA, after his residency and internship in pediatrics at Children’s Hospital Medical Center of Akron. He graduated from medical school at Northeastern Ohio University College of Medicine, in Rootstown, OH. Dr. Sabella currently sees patients at Cleveland Clinic’s main campus.

Let’s Chat About Recurrent Fever – When It’s a Virus, When It’s Something More

Differential Diagnosis: Periodic Fever Syndrome

SBC: How do you distinguish periodic fever syndrome from repeated viral infections?

Camille_Sabella,_MD_: Fevers in children are very common, and in most cases are caused by viral infections. Children with viral infections usually, but not always, have signs other than fever that give you clues as to the cause of the illness. For example, a runny nose and cough is very common with viral upper respiratory tract infections. When a child is having repeated episodes of fever on a regular basis without other signs of a viral illness, then we consider the possibility of a periodic fever syndrome—especially if the episodes of fever are occurring on a regular, almost predictable basis. Children with periodic fever syndromes will have other signs and symptoms, such as sores in the mouth, rashes, joint pains and abdominal pain, that can serve as clues as to the specific diagnosis.

Augusta: How many colds or viral infections that are accompanied by a fever are normal per year in young children?

Camille_Sabella,_MD_: Upper respiratory tract infections caused by viruses are very common in children. Young children will commonly have 12 to 18 upper respiratory infections per year, especially if they attend preschool or child care centers. Fevers are commonly present during these episodes and may occur with or without other signs, such as cold symptoms and cough.

Denmark: What are the most likely symptoms besides fever that would occur if it is periodic fever syndrome?

Andrew_Zeft,_MD: There can be a variety of symptoms which are due to systemic inflammation. Mouth sores (stomatitis), large lymph nodes, joint pain (arthritis), rash, vomiting or diarrhea due to gastrointestinal flare. Headache or sore throat can occur. Eye redness can also occur.

SBC: If you are concerned about a periodic fever syndrome, how do you determine the type of doctor to see first? Where do you begin?

Camille_Sabella,_MD_: The first place to begin is to have a discussion with your primary care physician or pediatrician. They can help you determine whether a periodic fever syndrome is likely and what the next steps are. If the primary care physician is concerned about the possibility of a periodic fever syndrome, he or she may have you keep a diary of fever episodes and any other associated signs and symptoms. A referral is often made to a pediatric infectious diseases specialist or a pediatric rheumatologist, depending on the resources and expertise that is available in your area.

Vincento: If a child is getting frequent viral infections (about 12 to 18 per year), how is it determined that there is nothing else serious going on?

Camille_Sabella,_MD_: A careful history and physical examination is the key to determining whether this is a normal phenomenon or if there is something more serious causing these infections. A history of mild colds and upper respiratory infections that resolve quickly, normal growth, lack of serious infections, and a normal physical examination are very reassuring. Your pediatrician or primary care provider can guide you if you are concerned.

Vincento: Does the timing of the frequency of fevers help determine whether it is periodic fever syndrome or viral?

Camille_Sabella,_MD_: In general, periodic fever syndrome occurs on a regular basis and with approximately the same interval between episodes. However, there can be a spectrum as to the periodicity of the episodes with periodic fever syndromes. Viral infections do not usually have a periodicity, and occur more commonly in the winter months. However, when they are occurring frequently, it may appear that they are occurring on a regular basis. Keeping a diary of fever and associated signs and symptoms can remove some of the subjectivity, and can help determine the likelihood of a periodic fever syndrome.

DbJsLk: Is there an age range when periodic fever syndrome is typically seen, whether babies,  school-aged children or teenagers?

Camille_Sabella,_MD_: The age range depends on the specific periodic fever syndrome, but is most characteristically in the early toddler age group (from one to three years old). However, the syndrome can start earlier and can have a later onset as well.

Periodic fever, Aphthous-Stomatitis, Pharyngitis, adenitis (PFAPA)

GraceM: Would you explain PFAPA please?

Camille_Sabella,_MD_: PFAPA—or periodic fever, aphthous-stomatitis, pharyngitis, adenitis—refers to an illness where the child will have periodic fevers associated with mouth ulcers and lesions, sore or red throat, and swollen glands in the neck. The fevers occur on a periodic basis, like every four to six weeks, and any of the other features may or may not be present.

josomom: You say that only 15 percent of children diagnosed with periodic fever syndromes will have symptoms into adulthood. Is this in regards to all periodic fever syndromes—of more specific ones such as PFAPA (periodic fever, aphthous-stomatitis, pharyngitis, adenitis)? As the mother of a daughter who has a mutated NLRP3 gene variant R488K, it is my understanding that she will not "outgrow" it and that this will cause symptoms for life.

Andrew_Zeft,_MD: The 15 percent statistic also includes the many patients who present in childhood with periodic fevers, but do not also have an underlying genetic diagnosis. PFAPA episodes typically resolve in late childhood, but there are cases of PFAPA that may even develop as late as adulthood. Your daughter's NLRP3 gene variant suggests her autoinflammatory disorder is more lifelong. However, since episodes may be triggered by stressful stimulae (such as infection and environment) then episodes may be less or more with time. It does depend on how severe her case is along the spectrum of the cryopyrinopathy syndromes with NLRP3 mutations.

Luckydaisy: My daughter has had recurrent fevers since she was seven months old. She is now four and one half years old. All of her fevers occur with sore throat, white spots on the throat, and stomach pain. Half of the time she experiences vomiting. These fevers have periodicity, and come in two- or four-week spurts. She developed photosensitivity dermatitis and developed an eczema-type rash on the face with fever. She has joint pain about 25 to 35 percent of the time with the fevers. She sees a rheumatologist at a well-known hospital that originally diagnosed her with systemic juvenile-idiopathic arthritis (JIA) because of high ESR/CRP (erythrocyte sedimentation rate/c-reactive protein) levels. After Naprosyn® (naproxen) didn't work, the doctors decided to try single-doses of prednisolone at fever onset. It worked great! They diagnosed her with PFAPA (periodic fever, aphthous-stomatitis, pharyngitis, adenitis). We saw an otolaryngologist who disagreed with the rheumatologist. Although he knew about PFAPA, he disagreed with this diagnosis because her episodes are spread out with no periodicity and her neck lymph nodes don't swell. They recommended that we look at other periodic fevers. Her rheumatologist said we should take out her tonsils before we go that path. I am left to make the decision. I am curious to see if PFAPA fits best or if I should get a second opinion?

Camille_Sabella,_MD_: PFAPA certainly is possible—even if her fevers are spread out. Although the fever episodes generally occur every four to six weeks, there can be a wide spectrum of time between episodes. Also, the neck swelling does not always occur with every episode. It sounds like the rheumatologist and otolaryngologist need to help you make that decision, or you need a second opinion from someone who is very familiar with PFAPA and other periodic fever syndromes.

Cryopyrin-Associated Autoinflammatory Syndrome (CAPS)

josomom: Do you have any advice for people with fever syndromes who are having a hard time finding medical help? Even the specialists at Children's Hospital Colorado have told me I know more about cryopyrin-associated autoinflammatory syndrome (CAPS) than them. They were happy to run all the tests I asked for and prescribe the medication I wanted her on (Ilaris [canakinumab]). However, I feel like I am the one running the show, and I don't feel qualified to be in charge of her medical needs. The rheumatologist sent a request for her to be seen at National Institutes of Health (NIH), but I have heard—because of budget cuts—it will take a long time to get in if we get in at all. What do I do? Who do I turn to when I have a question?

Andrew_Zeft,_MD: Because of the rarity of cryopyrinopathy conditions, pediatric rheumatologists have variations in their individual experience and knowledge of these conditions. NIH offers a wealth of knowledge on these conditions. There are specific pediatric rheumatologists in the country who have an interest and broader experience with CAPS patients. The team at Cleveland Clinic Children’s has experience with CAPS patients and can be helpful answering questions and coordinating care.

NLRP3 R488K Variant

josomom: Is anyone at Cleveland Clinic familiar with the NLRP3 R488K variant? I ask because it is pretty rare and has atypical symptoms when compared to typical cryopyrin-associated autoinflammatory syndrome (CAPS). If someone there is familiar with it at Cleveland Clinic, I would be interested in my daughter being seen there. And if so, how do I go about getting her seen there?

Andrew_Zeft,_MD: We are familiar with the NLRP3 R488K variant in CAPS. We know that it can be related to atypical symptoms, such as greater abdominal pain and lower inflammatory markers, than other CAPS patients. Response to IL-1 therapy may be less characteristic. Certainly there is still a lot to understand about patients with low penetrant mutations associated with CAPS.
I would be happy to see your daughter. To make an appointment with myself or any of the other specialists in Cleveland Clinic Children’s Center for Pediatric Rheumatology, please call 216.444.9000 or call toll-free at 800.223.2273 . For more information, please visit:

Familial Mediterranean Fever

Tie-guy: My child was diagnosed with familial Mediterranean fever (FMF), but our ancestry is primarily Northern European. How is that possible?

Andrew_Zeft,_MD: The syndrome typically occurs in patients who have ancestry that originated from geographic regions around the Mediterranean. However,  patients with alternative ancestries may also have the mutations know to cause FMF. Interestingly, it has been shown that patients with FMF in Turkey tend to have improvement in the disease activity after moving to Germany.

Diagnostic Testing

Luckydaisy: If a parent wants genetic testing for their child for periodic fevers through their doctor, how would they pursue it? I know that some people do it through clinical trials and at National Institutes of Health (NIH), but I have heard of people being able to do it through their own doctors and justify it with the insurance company. Do you have insight on how this is done?

Andrew_Zeft,_MD: Genetic testing is performed on patients with periodic fever and suspected autoinflammatory disease when the physician feels the presentation is consistent enough with one of the known genetic etiologies of recurrent fever syndromes to warrant testing. Insurance and payment issues related to coverage for the testing vary. Yes, your doctor can check a preauthorization for potential testing. Typically, testing is a blood test that is sent to GeneDx—a genetic testing company. Other laboratories may perform the genetic testing as well.

ErinK: How is it determined if the fever is infectious or possibly rheumatologic in origin? What tests are run?

Camille_Sabella,_MD_: Distinguishing an infection from a rheumatologic cause is not always easy. A careful history of the illness and a thorough physical exam are essential. These will determine the next steps in the diagnosis.


Moderator: I am sorry to say that we are at the end of our chat. We appreciate your participation and hope you will join us for other chat topics in the future.  Thank you, Andrew Zeft, MD and Camille Sabella, MD for sharing your expertise and answering questions today about recurrent fever in children.

Camille_Sabella,_MD_: Thank you very much for your questions. I hope this chat was helpful to you.

Andrew_Zeft,_MD: Thank you for reaching out to us today. Hopefully our communications have been helpful.

For Appointments

To make an appointment with Andrew Zeft, MD or any of the other specialists in Cleveland Clinic Children’s Center for Pediatric Rheumatology, please call 216.444.9000 or call toll-free at 800.223.2273.  For more information, please visit:

To make an appointment with Camille Sabella, MD or any of the other specialists in Cleveland Clinic Children’s Center for Pediatric Infectious Diseases, please call 216.444.5437 or call toll-free at 800.223.2273.  For more information, please visit:

For More Information

On Cleveland Clinic

The Center for Pediatric Infectious Diseases at Cleveland Clinic Children’s evaluates children both in the inpatient and outpatient settings. Through our inpatient services, a  pediatric infectious diseases specialist is always on-call and is available daily for hospital consultations. We treat young patients with infections in the pediatric and neonatal intensive care units, including critically ill children after surgery and organ transplantation. In select cases, our infectious diseases team is able to offer home intravenous antibiotic therapy that is arranged prior to hospital discharge and managed in our outpatient area.
Additionally, a pediatric infectious diseases specialist is available for outpatient consultation. We also offer a travel clinic for children who are preparing to travel out of country. For more information on Cleveland Clinic Children’s Center for Infectious Diseases, please visit:

The Center for Pediatric Rheumatology at Cleveland Clinic Children’s is dedicated to providing cutting-edge, patient-centered care to children with a broad range of rheumatologic conditions. Our center is well recognized for excellence in the diagnosis and management of a variety of inflammatory and autoimmune disorders that affect the joints, muscles, and connective tissue. Our physicians, surgeons and scientists are known nationally and internationally for their leadership, innovation and superior patient care outcomes.

  • We are a regional, national, and international referral center for families seeking second opinion services for pediatric rheumatologic conditions, including juvenile arthritis, vasculitis and childhood autoinflammatory diseases.
  • Our facility offers patients the opportunity to participate in numerous state-of-the-art clinical trials for juvenile arthritis and vasculitis.
  • The members of the Center are dedicated to working closely with patients and coordinating efforts with referring providers to ensure families receive world-class care close to home.

Through our multidisciplinary approach and the expertise of our pediatric team members, Cleveland Clinic Children’s is able to offer high quality care in a number of specialty areas. Our team of expert doctors coordinates their efforts with a variety of pediatric subspecialist colleagues to provide world-class, comprehensive care to patients and families. For more information on Cleveland Clinic Children’s Center for Pediatric Rheumatology, please visit:

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