A 5-year-old female came to second opinion clinic with a 1 year history of intermittent fevers. The fevers occurred every 6 weeks for 48-72 hours with documented fevers to 102-103° F. Over the year, the fevers increased in frequency to every 3-4 weeks. She had fatigue during the fevers and mild sore throat. The patient was seen for most of these episodes. The primary care physician and an otolaryngologist documented anterior cervical adenopathy of 1.0 cm or more, and ulcerations in the mouth in most of the episodes. She was taking no medication other than acetaminophen. Review of the medical records and diaries from the family showed laboratory studies for strep pharyngitis positive one time, but all other testing for streptococcal pharyngitis were negative. Complete blood counts were normal during and between episodes, except for occasional elevated platelets, or mild leukocytosis (not at the same time) and showed no cyclicity. She also sometimes had a mildly elevated C-reactive protein. Testing for histoplasmosis and other fungal diseases were negative. She had undergone a tonsillectomy and adenoidectomy approximately 2 months ago. She had no fever for 6 weeks afterwards and then had another episode.
The past medical history showed a hospitalization for respiratory syncytial virus as an infant, and 2-3 episodes of otitis media.
The family history revealed that the family was Caucasian of northern European descent. There were no genetic abnormalities, connective tissue diseases, immunodeficiencies or children that died early in life. The younger and older siblings were healthy as were the parents.
The social history showed that the family lived on a grain farm without animals. The drinking water had been tested for infectious diseases and toxins and was negative. She had missed school because of the fevers per the school policy and fatigue but made up all her work quickly and returned to school as soon as possible. She was a good student. There was no history of travel, or exposure to persons who had traveled outside the United States or were in the military. She had two outside dogs who were healthy.
The review of systems showed no nausea/emesis, cough, normal stooling and voiding, no sweating, chills, or rashes. She had been gaining weight and height appropriately over the year.
The pertinent physical exam showed an alert female in no distress. She was afebrile with growth parameters in the 10-50%. HEENT examination showed normal mouth examination and bilateral anterior cervical lymph nodes at the angle of the mandible which were both less than 0.5 centimeters. She had some shoddy groin nodes but no other adenopathy. The rest of her examination was negative.
The laboratory evaluation included electrolytes, urinalysis, erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, immunoglobulin D and E levels, and titres for cytomegalovirus and Epstein Barr virus. All were negative. The radiologic evaluation of chest and abdominal radiographs were also negative.
The diagnosis of probable periodic fever, aphthous ulcers, pharyngitis and adenitis (PFAPA) was made. The natural history of this syndrome along with possible treatment options were discussed. The family opted to use prednisone with the fevers as a potential abortive agent. The results of the consultation were communicated to the primary care physician by telephone and letter. The patient did not return for follow-up to the second opinion clinic.
Fevers that recur can be very difficult to evaluate and treat particularly as the child often appears fairly well. Evaluation is frequently complicated by incomplete history, documentation of physical examinations, and laboratory testing. Evaluations decisions are also complicated by patient and family anxiety about potential serious disease and frustration by lack of a firm diagnosis. Families may also interpret the normal variation of common childhood illnesses that are often accompanied by fever such as common colds and ear infections, as evidence that “there is something wrong with this child.” Normal childhood illnesses are usually supported by family members with similar illnesses or attendance at child care. Occult bacteremia and urinary tract infections should also be considered in the child who presents with fever and no localizing signs.
PFAPA syndrome is characterized by predictable periodic fevers, aphthous stomatitis, pharyngitis, and cervical adenitis. Its cause is unknown and is diagnosed by a through history, physical examination, record review and judicious laboratory studies. It occurs at intervals of 3-8 weeks and usually lasts 3-8 days. The fevers usually begin around 5 years of age, with no ethnic association. PFAPA and Familial Mediterranean Fever are both reported more commonly in the area of Israel. The episodes resolve spontaneously and over time the syndrome itself resolves. Patients are well between episodes, and have normal growth and development. Associated symptoms include chills, sweating, and pain in the head, muscles, bones, joints and abdomen may occur. Infectious diseases and malignancies are uncommon causes of predictable periodic fevers. A history of unusual or severe infections should make the clinician not look at PFAPA as a cause of the periodic fever.
The differential diagnosis for PFAFA can include:
- Crohn’s disease
- Immunodeficiencies – congenial and acquired including immunoglobulin deficiencies, T-cell dysfunction/deficiency, complement and phagocytic cells dysfunction/deficiency, cyclic neutropenia and HIV
- Beçet disease
- Juvenile idiopathic arthritis
- Hereditary periodic fever syndromes
- Chronic infantile neurologic cutaneous articular syndrome
- Familial cold autoinflammatory syndrome
- Familial Mediterranean fever
- Hyperimmunoglobulinemia D with periodic fever syndrome
- Muckle-Wells syndrome
- Tumor necrosis factor receptor-associated periodic syndrome
Some studies have supported treatment by tonsillectomy and/or adenoidectomy. Prednisone (1 dose, often at 2 mg/kg/dose) given at the onset of symptoms may also abort the episode in some patients. Cimetidine is also effective in some patients. Other immunomodulators have had less efficacy.
Questions for Further Discussion
1. What signs/symptoms would make you concerned for possible malignancy as the cause of a recurrent fever?
2. What signs/symptoms would make you concerned for an unusual infectious disease as the cause of a recurrent fever?
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Padeh S, Berkun Y. Auto-inflammatory fever syndromes. Rheum Dis Clin North Am. 2007 Aug;33(3):585-623.
Shinawi M, Scaglia F. Hereditary Periodic Fever Syndromes. eMedicine. Available from the Internet at http://emedicine.medscape.com/article/952254-overview (rev. 11/2/2008, cited 2/17/09).
ACGME Competencies Highlighted by Case
1. When interacting with patients and their families, the health care professional communicates effectively and demonstrates caring and respectful behaviors.
2. Essential and accurate information about the patients’ is gathered.
3. Informed decisions about diagnostic and therapeutic interventions based on patient information and preferences, up-to-date scientific evidence, and clinical judgment is made.
4. Patient management plans are developed and carried out.
5. Patients and their families are counseled and educated.
7. All medical and invasive procedures considered essential for the area of practice are competently performed.
8. Health care services aimed at preventing health problems or maintaining health are provided.
10. An investigatory and analytic thinking approach to the clinical situation is demonstrated.
11. Basic and clinically supportive sciences appropriate to their discipline are known and applied.
13. Information about other populations of patients, especially the larger population from which this patient is drawn, is obtained and used.
19. The health professional works effectively with others as a member or leader of a health care team or other professional group.
23. Differing types of medical practice and delivery systems including methods of controlling health care costs and allocating resources are known.
25. Quality patient care and assisting patients in dealing with system complexities is advocated.
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital