Does Recurrent Fever Mean Autoinflammatory Disease?

Center helps diagnose and manage these complex diseases

By Andrew S. Zeft, MD, MPH, and Steven J. Spalding, MD

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Pediatricians who encounter patients with recurrent fevers must decide whether these fevers represent infection, malignancy or a rheumatologic disease. Pediatricians typically have extensive training in and experience with the first two diagnostic categories, but many feel challenged when faced with assessing a child for a more esoteric cause.

To assist pediatricians struggling with a diagnosis, Cleveland Clinic has developed a comprehensive center specializing in the evaluation, treatment and management of children with recurrent fevers. Our Autoinflammatory Disease Comprehensive Care Center serves children diagnosed with — as well as those suspected of having — an underlying autoinflammatory disease.

A common culprit: Dysregulation of the innate immune system

Autoinflammatory diseases comprise a rapidly expanding group of conditions, many of which have a testable genetic etiology. Unlike patients with other rheumatologic diseases, those with autoinflammatory diseases do not have autoreactive T lymphocytes and typically lack pathogenic autoantibodies. Instead, genetic mutations cause dysregulation of the innate immune system, leading to episodic manifestations of systemic inflammation. Abnormal regulation of the innate inflammatory pathway has also been implicated in the pathogenesis of conditions as phenotypically diverse as gout, type 2 diabetes, atherosclerosis and epilepsy. For this reason, interaction with multiple adult-care specialists at Cleveland Clinic is essential.

Autoinflammatory diseases are characterized by recurrent episodes of fever, rash and lymphadenopathy, typically with musculoskeletal involvement. Abdominal pain is common during attacks. 1,2 Although these symptoms are often encountered by general pediatricians, their recurrent, stereotypic and recognizable pattern of presentation allows us to diagnose an autoinflammatory condition and focus on its evaluation and management. Early treatment with immunoregulatory agents may improve quality of life and reduce the risk of disease sequelae.

A specialized team approach needed

Cases of autoinflammatory disease are complex and require a specialized team approach. Our goal is to provide patients, their families and their pediatricians with a comprehensive evaluation and support team for ongoing management. Before the appointment, a member of the team reviews clinical documents to determine which subspecialists will be needed. Visits with multiple pediatric subspecialists, including rheumatologists, infectious disease experts, geneticists, ophthalmologists, otolaryngologists or gastroenterologists are then coordinated, depending on the patient’s need. The unique collaborative nature of this clinic ensures depth and breadth of expertise and promotes the delivery of expert, coordinated care.

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Large patient base fuels research

Providing care for a large number of patients with autoinflammatory disease enables us to conduct extensive research in the genetics, pathophysiology, clinical presentation and treatment of these diseases. As a result, we are able to offer all families the opportunity to participate in clinical studies.

We recently published a comprehensive review of the diagnosis and management of autoinflammatory syndromes 1 and have separately published case reports. 3,4 Additionally, one of us (S.J.S.) has been privileged to serve as principal investigator at Cleveland Clinic for an FDA-funded research trial of a novel biologic therapy for the treatment of colchicine-resistant familial Mediterranean fever, 5 while the other (A.S.Z.) represented Cleveland Clinic and our Autoinflammatory Disease Comprehensive Care Center at the U.S. Conference on Rare Diseases and Orphan Products in Washington, D.C., in October 2012.6

Innovative tools to facilitate care

Given the complexity and rarity of these conditions, our center has sought to leverage technology to improve patient access, communication and coordination of care. Patients evaluated within the center (and their families) may participate in Cleveland Clinic’s MyChart® patient electronic health record system (clevelandclinic.org/mychart) to access their lab results, radiographic studies and instructions as well as to communicate with the treatment team using their computer or smartphone.

For patients who are unable to travel to Cleveland, we offer consultation through Cleveland Clinic’s MyConsult online medical second-opinion service (clevelandclinic.org/myconsult). Educational materials for patients and providers can also be found on the Cleveland Clinic website (clevelandclinic.org/recurrentfevers). Additionally, providers interested in receiving visit materials and communications electronically can do so via our secure online DrConnect service (clevelandclinic.org/drconnect).

About the Authors

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Dr. Zeft specializes in pediatric rheumatology with a focus on children with autoinflammatory diseases. Dr. Spalding is Head of the Center for Pediatric Rheumatology.

References

  1. Zeft AS, Spalding SJ. Autoinflammatory syndromes: fever is not always a sign of infection. Cleve Clin J Med. 2012;79(8):569-581.
  2. Gurion R, Sabella C, Zeft AS. Fever and rash in children: important diagnostic considerations. Minerva Pediatr. 2013;65(6):575-585
  3. Spalding SJ, Hashkes PJ. The role of tonsillectomy in management of periodic fever, aphthous stomatitis, pharyngitis, and adenopathy: unanswered questions [letter]. J Pediatr. 2008;152(5):742-743; author reply 743.
  4. Zeft A, Bohnsack JF. Cryopyrin-associated autoinflammatory syndrome: a new mutation. Ann Rheum Dis. 2007;66(6):843-844.
  5. Hashkes PJ, Spalding SJ, Giannini EH, et al. Rilonacept for colchicine-resistant or -intolerant familial Mediterranean fever: a randomized trial. Ann Intern Med. 2012;157(8):533-541.
  6. Zeft AS, Sabella C, Goldfarb J, Spalding SJ. Developing comprehensive care centers for rare diseases in the era of healthcare reform: a case study. Abstract presented at: DIA/NORD U.S. Conference on Rare Diseases and Orphan Products; October 22-24, 2012; Washington, D.C. Drug Inf J. In press.