CASE

A 3-year-old male presents to a pediatric emergency department after having 6 days of fevers. Today, he is fever free. However, he is now refusing foods and even most drinks, which is why his parents brought him in. Mom had been giving ibuprofen and acetaminophen around the clock at home, but she stopped when the fevers went away. His parents do not know why he had the fever and cannot discern a source. The patient’s parents report that, since having COVID-19 last year, he“gets sick all the time, and when he gets sick, he always has high fevers that last a long time.” His pediatrician noted that this was an atypical pattern and referred them to immunology for work up, but the parents are unaware of any diagnosis. They are still waiting for an appointment to see immunology. The patient has a physical exam notable for swollen tonsils with exudative pharyngitis and dry mucus membranes.

DIAGNOSIS

PFAPA syndrome… have you heard of it?

DISCUSSION

PFAPA syndrome is the most common cause of recurrent fevers in children. It was discovered relatively recently, in 1987, and its prevalence has grown as awareness increases. It can usually be stopped in its tracks with a single pill, but it is another disease providers have to keep track of. So, let’s get going!

Generally, what is PFAPA?

PFAPA (fa-pa, or pee-fa-pa, both are used) is a fun-to-say abbreviation of Periodic Fever, Aphthous stomatitis, Pharyngitis, and (cervical) Adenitis. This aptly named syndrome typically presents in young children with 3-7 days of fever recurring every 2-8 weeks, in addition to some of the eponymous “PFAPA” symptoms. Patients are otherwise normal and asymptomatic between episodes. The diagnosis is clinical; guidelines and best practices are being solidified as the syndrome gains notoriety in the pediatric and ENT world.[1] So far, only one study has evaluated prevalence. It found 1 out of 4000 children <5 years have this condition.[2] This is believed to be an underestimate. Experts believe this condition is under-diagnosed and often masquerades as “frequent URI infections,” as was described by the family in our case. 

 Who gets it?

PFAPA overwhelmingly presents by school age (90% by 5 years). Most patients will experience shorter, less frequent episodes over time until it resolves within six years of onset.[3] However, a smaller subset of patients will endure this syndrome for decades, and rarely it can persist until adulthood.[1] Males are slightly more likely to have this condition, with 55-65% predominance.[4] It clusters in families, sometimes demonstrating autosomal dominant inheritance, and shares genetic underpinnings with other Behçet's spectrum disorders, with some overlap and cooccurrence. Familial varieties may exhibit different, often more severe, characteristics.

What causes it?

Generally, it is believed to be caused by immune system dysregulation. In the patient’s immune micro-environment, this dysregulation may lead to ulcer development from invasion of microorganisms. Other factors such as tonsillar organization and function and an individual’s microbiome may play a role.

What about the family’s claim that this pattern started “after he got COVID last year?”

According to a recent paper, there is anecdotal evidence from experts identifying COVID-19 as a trigger for this syndrome.[4]

What does it look like? How is it diagnosed?

Periodic fevers are a hallmark feature. The fevers are usually fairly high, 102-104 degrees, last about 3-5 days (sometimes up to a week), and occur with remarkable regularity, usually every 4-6 weeks (with a range of 2-8 weeks). Clinical suspicion of this syndrome should prompt a fever journal. Fever journals should include symptoms leading up to fever, sick contacts, and treatments/responses (in particular: response to antibiotics or steroids). To solidify a diagnosis of PFAPA, five or more periodic fevers should be documented. Thus, it is unsurprising that the average age at onset is <2yrs old, but the average age of diagnosis is 4yrs old.[5]

Apart from fevers, the most common symptoms are pharyngitis (90%), cervical adenitis (80%), and aphthous stomatitis (60%). Pharyngitis can be exudative or erythematous. In the very young, pharyngitis often presents as drooling or decreased oral intake.[4] Adenitis presents as enlarged, tender nodes in the anterior cervical chain.  Other common but nonspecific symptoms occur in a minority of patients and include muscle and joint aches, malaise, headache, and GI symptoms such as abdominal pain, diarrhea, and vomiting. Diagnosis is also based on absence of signs: children must have normal growth, development, and a lack of sick contacts or other pathology which would explain these episodes (e.g. ear or upper respiratory tract infections). Finally, positive response to steroids is actually part of the proposed diagnostic criteria. A simplified heuristic which should raise red flags for PFAPA would be a pediatric patient with regular recurrent episodes of pharyngitis and fever who is culture negative and otherwise healthy.

As you can see, an individual episode of PFAPA can be nearly indistinguishable from infectious etiologies. Although repeated infections are usually the top differential consideration, cyclical neutropenia, early IBD, lymphoma, and other periodic fever syndromes such as familial Mediterranean fever (for which there is a strong link with PFAPA) should be considered.

Treatment

Disposition from the ED is almost always home, unless dehydration or oral intake refusal are severe. Treatment options for PFAPA are medical and surgical. Medical treatments can be broken down into abortive and preventative medicines. Abortive treatments include steroids and NSAIDs. One of the most satisfying aspects of treating or diagnosing PFAPA is the response to steroids. Typically, prednisone at 0.5-2 mg/kg is given at the onset of fever. This is effective in the vast majority of patients and generally aborts the episode within hours. The most common practice pattern is to give 1 mg/kg, reassess in half a day, and redose at 2 mg/kg if fever persists. Other symptoms (e.g. ulcers) take longer to resolve, but resolution is nonetheless hastened by steroids. NSAIDs can help treat pain and fever, but don’t really alter the course of an episode. Using a dose of steroids is reasonable to help form a diagnosis of PFAPA in a patient presenting to the ED with a concerning history. Cimetidine is used as a preventative, and can even fully prevent episodes in a portion of PFAPA patients, but it does not typically have a role in the emergency setting. Immunosuppressants are also used, including colchicine and anakinra. Antibiotics do not improve outcomes.

Surgical treatments for PFAPA involve tonsillectomy, plus or minus adenectomy. Although evidence supporting surgery is not extensive, tonsillectomy appears to be curative of fevers in the majority of patients, and when it is not, it generally reduces symptom frequency. This option can be considered in some patients with PFAPA, on an outpatient basis. Follow up for PFAPA will have some institutional variation. In general, rheumatology or infectious disease and ENT are the primary specialists that manage the medical and surgical aspects of this disease.

 SUMMARY

The role of the emergency medicine physician in this syndrome is to perform a thorough history (including family history), exam, and if indicated, treat medically. Perhaps even more importantly, the family should be instructed to keep a fever journal involving all the elements outlined above and should present to the pediatrician with future episodes so symptoms can be confirmed. If strong evidence for PFAPA is present, a specialist referral may be appropriate.

CASE RESOLUTION

Our 15 kg patient was treated with 10 mg of prednisone and 150 mg of ibuprofen. His symptoms improved over the afternoon. He continued to take ibuprofen for a few days to help with his mouth and throat pain. which allowed him to take more oral hydration. The emergency physician instructed the family to discuss PFAPA with their pediatrician and to keep a detailed fever journal. The family had an appointment with infectious disease the following year, and the patient was diagnosed with PFAPA. Cimetidine was prescribed as a daily preventative. Episodes became less severe and less frequent, but they were still disruptive to the family. They saw ENT and opted for adeno-tonsillectomy. The patient had a complete resolution of symptoms about two years after the initial ED visit.

AUTHOR: Barret Zimmerman, MD is a fourth-year emergency medicine resident at Brown Emergency Medicine Residency

 FACULTY REVIEWER: Michelle Myles, MD is a clinician educator at Brown Emergency Medicine

REFERENCES

1.        Cantarini L, Vitale A, Sicignano LL, et al. Diagnostic Criteria for Adult-Onset Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA) Syndrome. Front Immunol. 2017;8(AUG):1018. doi:10.3389/FIMMU.2017.01018

2.        Førsvoll J, Kristoffersen EK, Øymar K. Incidence, clinical characteristics and outcome in Norwegian children with periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome; a population-based study. Acta Paediatr. 2013;102(2):187-192. doi:10.1111/APA.12069

3.        Wurster VM, Carlucci JG, Feder HM, Edwards KM. Long-term follow-up of children with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome. J Pediatr. 2011;159(6):958-964. doi:10.1016/J.JPEDS.2011.06.004

4.        Wang A, Manthiram K, Dedeoglu F, Licameli GR. Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome: A review. World J Otorhinolaryngol - head neck Surg. 2021;7(3):166-173. doi:10.1016/J.WJORL.2021.05.004

5.        Vanoni F, Caorsi R, Aeby S, et al. Towards a new set of classification criteria for PFAPA syndrome. Pediatr Rheumatol Online J. 2018;16(1). doi:10.1186/S12969-018-0277-2