Original Article: Unexplained Lymphadenopathy: Evaluation and Differential Diagnosis

Issue Date: December 1, 2016

See additional reader comments at: https://www.aafp.org/afp/2016/1201/p896.html

To the Editor: I read with interest Drs. Gaddey and Riegel's excellent review article on unexplained lymphadenopathy. To the complex differential diagnosis of this common problem, I would add an increasingly recognized entity known as PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and adenopathy). Also known as Marshall syndrome, this symptom complex was first described in 1987¹ and was initially thought to be a rare disease seen only in children. Over the past decade, however, it has been increasingly reported among young adults.

A typical episode is characterized by abrupt onset of fever, chills, sore throat or mouth pain, and tender cervical lymph nodes; in other words, a rather typical presentation of strep throat! A prodrome of fatigue may precede the fever. In the case of PFAPA, rapid strep test results are negative, throat culture yields no growth, and heterophile antibody test results are normal. Further testing might reveal moderate leukocytosis and an elevated erythrocyte sedimentation rate. Marshall syndrome does not respond to antibiotics.

The recurrent nature of Marshall syndrome sets it apart from more mundane illnesses and suggests one of the periodic fever syndromes. Episodes may occur every month or so and last four to five days, with complete resolution between each course of illness. The case definition specifies six recurrences. Exclusion of cyclic neutropenia is accomplished by a complete blood count. The pathophysiology of PFAPA has yet to be defined, although it appears to be a type of autoinflammatory disorder, with decreased numbers of activated T cells accompanying monthly flare-ups.

Physicians who provide continuity of care are in the best position to recognize PFAPA and initiate proper treatment. Once diagnosed, a single dose of oral prednisone (1 mg per kg) results in rapid resolution of current symptoms. However, there is some concern that this treatment leads to more frequent occurrences.

In carefully selected cases, tonsillectomy (with or without adenoidectomy) has been shown to bring about lasting remission.² Cimetidine (Tagamet) has also been employed to induce remission with some success. More recently, the drug anakinra, which acts on interleukin-1, shows promise.

The diagnosis of Marshall syndrome is one of exclusion, and a high index of suspicion is required. The prognosis of patients diagnosed with PFAPA is excellent, with most persons achieving spontaneous remission over time.³