PFAPA Syndrome - Symptoms, Causes, Diagnosis, Treatment

Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA Syndrome)

What is Pfapa syndrome? - How is Pfapa syndrome treated? - What should be the care of children with Pfapa syndrome? - What causes Pfapa syndrome? - What are the symptoms of Pfapa syndrome? - How is Pfapa syndrome diagnosed? - PFAPA treatment


What is PFAPA Syndrome?

PFAPA Syndrome is a recurrent fever syndrome that usually begins in early childhood. Children develop acute phase reactants that return to normal between attacks. Children with PFAPA grow and develop normally, are not susceptible to infections and do not show prolonged sequelae. Since its initial definition in 1987, numerous cases of PFAPA have been reported worldwide and the understanding of the syndrome has increased considerably. In 1987, Marshall et al. Aphthous stomatitis, cervical adenitis, and pharyngitis: A symptom specific for children between the ages of 2 and 5 years, usually characterized by fever attacks lasting 3-6 days, every 3 gün8 weeks associated with one of the three most common symptoms.

PFAPA:

Periodic fever [periodic fever] - PF

Aphthous stomatitis - A

Pharyngitis - P

Adenitis - A

These symptoms are called "PFAPA Syndrome". The etiology and pathophysiology are not clearly defined.

Acute phase reactants in blood (eg, C-reactive protein, ESR) may be elevated during firing periods, but generally not high among attacks. Neutropenia or other symptoms (eg diarrhea, rash, cough) are not available (source: PFAPA Syndrome - Pediatrics - Merck Manuals Professional Edition). Generally, PFAPA syndrome disappears spontaneously during puberty but there is evidence that this condition may continue until adulthood. Patients are asymptomatic between attacks and normal growth is evident (source: PFAPA syndrome: a review on treatment and outcome). In the pathogenesis, the contribution of infection, the abnormal host immune response, or a combination of both. PFAPA Syndrome is a cytokine-related disorder, an important tool in immune system regurgitation. Dramatic transient responses to cortisone group drugs may occur. Tonsillectomy and adenoidectomy are appropriate for selected patients and children with long-term disease duration that affect the quality of life, and are resistant to selected medical therapy and children. (Source: Clinical features and genetic background of the periodic Fever syndrome with aphthous stomatitis, pharyngitis, and adenitis: a single center longitudinal study of 81 patients).

PFAPA is characterized by periodic fever, aphthous ulcers, pharyngitis and neck lymphadenopathy, but other symptoms such as abdominal pain, joint pain and headache have been described.

PFAPA Syndrome Causes

PFAPA Syndrome is the most common periodic fever syndrome in children. Elevated serum proinflammatory cytokine levels indicate the irregularity of natural immunity in the pathogenesis of PFAPA. However, it is not yet clear what kind of innate immune molecules / pathways actually exist. Many patients with PFAPA develop tonsillitis in febrile attacks and tonsillectomy corrects periodic fever immediately and completely. This fact shows that the tonsils are the primary site of immune disorder in PFAPA. That is, a product secreted by tonsils is thought to be responsible for exaggerated response by the immune system (source >>Innate immunity-related Gene Expression Profiling Reveals Two Distinct Endotypes in PFAPA Syndrome).

Difficulty in diagnosis and treatment of PFAPA syndrome

PFAPA syndrome is the most common cause of periodic fever in childhood. Nowadays, it is considered as part of the extended family of autoinflammatory diseases, but a genetic or molecular marker has not yet been identified, so its etiology is still unknown. The diagnosis is mainly based on clinical criteria, but it is sometimes difficult to distinguish it from other hereditary periodic fever syndromes, especially in young children. Fever attacks in PFAPA have spontaneous resolution and in patients with elevated symptoms, the syndrome ends spontaneously over time. Treatment is still a matter of debate. Generally, administration of a single oral corticosteroid stops the attacks. Tonsillectomy and adenoidectomy are an alternative option for treatment.

PFAPA syndrome is difficult to identify and treat!

It is difficult to identify and treat this disease because the physical findings are not the specific diagnosis of this particular entity. The distinguishing feature of this mysterious syndrome is the recurrence of sudden onset high fever at regular intervals in early childhood. Fires are characterized by a temperature ranging from 39 ° C to 42 ° C, lasting 3 to 7 days and repeated every 3 to 6 weeks. Parents often report that their children are sluggish or restless just before the onset of fever attacks. The fever cycle is associated with one or more of the following: aphthous stomatitis, pharyngitis, and cervical adenopathy. Not all three symptoms can be present or evaluated with each fever; For example; a small child's refusal to eat or drink may be due to pharyngitis and resulting odynophagia. Rarely, patients experience rash, headache, abdominal pain or joint pain. Between periods of fever, the child is asymptomatic and experiences the expected growth and developmental process.

Is the Form and Structure of Tonsils in Children with PFAPA Syndrome Different From Other Children?

In children with PFAPA syndrome, there was no difference in the form and structure of the tonsils during the examination. So, if you think your child has PFAPA syndrome, don't think you can find a difference in the structure of the tonsils during the examination!

In most cases, physical examination results are not clear. At times, tonsils or tonsils are defined as erythematous, leading to throat cultures that are almost always negative for group A hemolytic streptococci. If routine laboratory studies are performed, the results may be normal, but acute episodes often have white blood cell counts or erythrocyte sedimentation rate.

Which substances in the blood rise in the period of attack in Pfapa syndrome?

The cause of PFAPA is unknown. A single dose of corticosteroid treatment, PFAPA exacerbation of the symptoms, the symptoms of infection rather than inflammatory cytokines suggest that.

Preliminary studies of cytokines in patients with PFAPA show that several cytokines have been elevated during febrile episodes, especially interferon-gamma, tumor necrosis factor and interleukin-6 and significantly higher levels of IL-1, TNFα and IL-12p70.

It is thought that an abnormal host immune response to the tonsils or commensal microorganisms not yet identified in the oral mucosa may cause symptoms.

Does PFAPA syndrome occur in adults?

Since its clinical description in 1987, the syndrome, termed "periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis" syndrome (PFAPA), has been accepted as pediatric age-specific. Several cases of PFAPA in adults have been reported in recent literature.

Generally, PFAPA syndrome improves in adolescence, but there is growing evidence that this condition can continue to adulthood.

What is the genetic transition of PFAPA syndrome?

The onset of the disease is usually before the age of 5 years and usually passes through adolescence. Patients are asymptomatic between attacks and normal development. Additives contributing to the pathogenesis include infection, abnormal host immune responses, or a combination of both. PFAPA syndrome is an immune-mediated disease characterized by cytokine dysfunction; furthermore, strong family cluster reveals a potential genetic origin of the syndrome. The presence of variants in inflammation-associated genes, mostly NLRP3 and MEFV, suggests that these genes play a likely role in the pathogenesis of PFAPA. However, none of these variants alone appear to be associated with the etiology of the disease by suggesting an oligenic or polygenic background. Rarely, any close or extended family members that are similarly affected are identified.

The genetic origins of PFAPA are one of the most discussed features of this syndrome. Although generally considered to be a sporadic disease, familial clustering has been observed, indicating the existence of a possible inherited component. Detection of families with more than one member affected by PFAPA is unusual, and a positive family history of recurrent fever may be detected in about half of PFAPA patients (source >> Analysis of the genetic basis of periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome). Clearly, the pathogenesis of the disease is bound to the immune system, but no convincing information has been obtained about the etiology and in particular the genetic basis of PFAPA.

Is there  any preventive medicine for PFAPA syndrome?

No results were obtained in the treatment of PFAPA syndrome symptoms with non-steroidal anti-inflammatory agents and anti-pyretic drugs. Glucocorticoids are very effective in canceling attacks, but there is limited data on the effectiveness of any preservative drug in PFAPA.

Diagnostic Criteria for PFAPA Syndrome

Currently, the diagnosis of PFAPA is based on clinical criteria, but these criteria have not been confirmed in a patient cohort. In addition, Gattorno et al. He found that a significant number of patients with monogenic periodic fever met the diagnostic criteria for PFAPA syndrome, which emphasized the poor specificity of existing classification criteria. Patients should therefore be screened clinically or genetically for other known periodic syndromes before diagnosing PFAPA.

Diagnostic criterias for PFAPA

I. Fires that start regularly at an early age (<5 years)

II. Symptoms in the absence of upper respiratory tract infection with at least one of the following clinical symptoms: a) aphthous stomatitis, b) cervical lymphadenitis, c) pharyngitis

III. Total asymptomatic interval between attacks

IV. Normal growth and development

PFAPA syndrome has a positive natural history. There is no evidence that medical treatment can change the outcome, but may be effective for the treatment of attacks. Rapid remission of attacks is important for patients and their families to improve quality of life (source:  PFAPA syndrome: a review on treatment and outcome).

Long-Term Course of Disease in PFAPA Syndrome

 PFAPA syndrome is generally considered as a self-limiting disease that develops spontaneously before puberty. The growth and development of patients is normal and the long-term results are not explained. However, fever control and appropriate medical treatment are required to prevent a persistent problem due to high fever during febrile periods. PFAPA is a common auto-inflammatory disease with good prognosis in general. Regular exacerbations of PFAPA fever significantly affect the quality of life of patients and their families and interfere with regular daily activities. Delays in diagnosis may be several months or years and children may be subject to unnecessary diagnostic procedures

PFAPA Syndrome Differential Diagnosis

Other common fever causes such as viral infections should be considered. Cyclic neutropenia should be kept in mind, although it is rare with regular periodicity similar to PFAPA syndrome. In addition, less common hereditary fever syndromes such as familial Mediterranean fever, Muckle-Weils syndrome, tumor necrosis factor receptor 1 syndrome and hyperimmunoglobulinemia D syndrome can be assessed by molecular based tests. In addition, these conditions have other elements that help distinguish them from PFAPA syndrome.

Other periodic fever syndromes and diseases

PFAPA syndrome may resemble other periodic fever syndromes, but it can be distinguished from the history of fever cycle as well as the symptoms. Familial Mediterranean fever includes periodic fever, but patients with PFAPA syndrome do not have symptoms of peritonitis, erysipeloid rash, and amyloidosis. Patients with Behçet's syndrome present with ulcers in the oral cavity, but these ulcers are painful and numerous, unlike small, punctate ulcers frequently seen in PFAPA syndrome. Behçet's syndrome also includes skin lesions, ocular involvement (uveitis, vasculitis), arthritis / arthralgia, central nervous system involvement, and cardiovascular complications. Hyper-IgD syndrome occurs with lymphadenopathy and high fever, but is not as regular in nature as PFAPA syndrome. Symptoms include diarrhea, arthralgia, and maculopapular lesions different from aphthous stomatitis. Hyper-IgD syndrome usually begins in infancy not valid for PFAPA syndrome. Like familial Mediterranean fever, this disease is inherited autosomal recessive. Systemic onset juvenile rheumatoid arthritis (still disease) is associated with arthritis, rash, hepatosplenomegaly, pleuritis and pericarditis, as well as high fever and adenopathy. Fever is typically periodic and patients are patients. Familial Hibernian fever, recently renamed tumor necrosis factor receptor 1 associated syndrome, fever attacks lasting 1 to 4 weeks, as well as abdominal pain, myalgia and skin lesions occurring anywhere in the body. Although the fever of cyclic neutropenia is very similar to the PFAPA syndrome of stomatitis and pharyngitis, the old disease process is distinguished by a cyclic reduction in neutrophils, abdominal pain, and diarrhea (source >> Long-term Surgical Outcomes of Adenotonsillectomy for PFAPA Syndrome).

Interesting Features of PFAPA Syndrome

Both Infectious Disease and Immune System Disorders Features

Etiology of infectious / immunological fever
PFAPA syndrome shares various characteristics of both an infectious disease process and an immune system dysfunction. By analyzing the possible causes of PFAPA syndrome, Dr.Long described each symptom as evidence of infection or immune disorder. These features outweigh both theories more strongly than they support. The diversity of the patient's ethnicity is a contagious trigger, but the incidence of PFAPA syndrome has not been sufficiently seen in African-American and Spanish children, even in densely populated cities. In addition, the predominance of male subjects, decreased symptoms and spontaneous recovery in some cases, decreased duration between attacks after corticosteroid treatment, and improvement after tonsillectomy indicate an infectious cause. Immunodeficiencies, periodicity of fever, aphthous stomatitis, persisting syndrome for several years and not responding to antibiotics are recommended.

Little is known about the cause and pathogenesis of PFAPA syndrome. Tonsil has a non-specific chronic inflammation of lymphoid and follicular hyperplasia, fibrosis and cryptitis. Both congenital (interleukin [IL] -1, IL-6, as well as tumor necrosis factor α) and adaptive (interferon gamma) immunity seem to play a role. Peripheral lymphoid tissue, such as tonsils, may play a role as a reservoir for a pathogen with an irregular immune response. A hypothesis is that there is an abnormal adaptive immune response to a pathogen (virus or bacterium) in a local lymphoid tissue and leads to an increased innate immune response.8 In many patients, treatment with tonsillectomy is a condition for the microbial reservoir of the tonsils or local immune disorder, or both. source. The role of the innate immune system is also supported by the resolution of symptoms by administration of an IL-1 receptor antagonist anacinran to patients with PFAPA syndrome. The involvement of IL-1 in PFAPA syndrome is a feature very similar to some of the other periodic fever and autoinflammatory syndromes (source >> Syndrome of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA)—what it isn’t: what is it?).

Medical treatment in PFAPA syndrome

Acetaminophen, ibuprofen, aspirin, other nonsteroidal anti-inflammatory drugs, acyclovir and colchicine do not provide a clinical response, or at least temporarily reduce fever in some patients. Oral antibiotics are not effective. The use of cimetidine, an H2-blocker, was emphasized in 27% of patients treated daily for 6 to 12 months, which was effective in resolving fever. A striking effect of corticosteroids has been shown to reduce the frequency of fever. One dose of prednisone or prednisolone (1 to 2 mg / kg) can usually lead to a cessation of the fever cycle within a few hours. It is the most effective non-surgical treatment, but administration of corticosteroids does not prevent future fever cycles and shortens the interval between attacks as seen in our patient population and elsewhere.

Surgical intervention in PFAPA syndrome

Recent contributions to the literature focused on the use of surgical intervention as a treatment. Garavello et al. Reviewed the current literature by 2010 to determine the effectiveness of tonsillectomy or adenotonsillectomy on PFAPA syndrome (source >> Tonsillectomy in children with periodic fever with aphthous stomatitis, pharyngitis, and adenitis syndrome) In the analysis of 13 case studies and 2 randomized controlled trials, 83% of 149 children who had undergone surgery had complete resolution of symptoms. In cases where surgery is unsuccessful, there is insufficient information to determine what separates these patients from those who benefit from the surgery. What is striking is that PFAPA syndrome often affects the quality of life of children, as well as parents or caregivers. In addition, the financial costs of a family who cared for a child with chronic illness were not measured. Surgical intervention may be required based on the assumption of chronic tonsillar infection that triggers an autoinflammatory type response. For positive results, it is not clear whether adenoid removal is necessary in addition to tonsillectomy. However, since the substances produced in the lymphoid tissue are thought to cause this exaggerated immune response, usually tonsilectomy and nasal meat surgery are planned together.

The parents of all children treated with adenotonsillectomy are emphasized in many studies where symptoms are stopped and the quality of life of their children is improved. The better recognition and treatment of this interesting syndrome with increased awareness of the clinician will allow further intervention in the future. Not only pediatricians, but also clinicians, should be considered this clinical entity in any patient exposed to fever of unknown origin, regardless of age (source >> A comprehensive comparison between pediatric and adult patients with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenopathy (PFAPA) syndrome)

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Murat Enoz, MD, Otorhinolaryngology, Head and Neck Surgeon - ENT Doctor in Istanbul

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