PAUL L. ARONSON
HISTORY OF PRESENT ILLNESS
The patient is a 3-year-old girl of Sri Lankan descent who was born in the United States. She presented to the emergency department with a fever of 105°F for the past 2 days. She complained of abdominal, knee, and elbow pain while febrile, but she was eating normally without a change in appetite and having no problems ambulating. She has had no complaint of headache, sore throat, rhinorrhea, cough, diarrhea, or vomiting. This has been a recurrent problem since 8 months prior when the family took a trip to one of the national parks. Upon returning from that trip she had her first episode of fever with a temperature to 104°F. That episode lasted 5 days. At that time she complained of a frontal headache, chills, rigors, and abdominal pain. She saw her regular pediatrician who diagnosed a viral syndrome. Her mother reports that the episodes occur at the end of every month. During her second febrile episode, she was told that the headache and abdominal pain were secondary to sinusitis with post-nasal drip and she was treated for clinical sinusitis with a 3-week course of antibiotics. She continued to have identical episodes every month. She had been treated a total of three times for acute sinusitis based on clinical diagnosis. Mom reports that she has not had any weight loss, rash, upper respiratory symptoms, cough, or joint swelling with these episodes. She has not traveled outside of the country or had any known tick bites. She has been seen by her regular doctor on multiple occasions during the episodes with normal examinations, multiple normal complete blood counts, and normal Lyme serology. She has had no tuberculosis exposure. She has had normal growth and development and is completely normal between episodes. Her mother does state that the doctor often tells her that her throat is “a little red,” but all throat cultures have been negative.
The patient had a normal birth history. She has had no hospitalizations or surgeries and has allergic rhinitis. Her only medications are acetaminophen and ibuprofen during these febrile episodes. She was appropriately immunized and had a negative tuberculin skin test within the last 3 months. Her family history was negative for gastrointestinal disease, autoimmune disease, childhood illnesses, arthritis, cancer, or tuberculosis. She attended day care and the family has no pets.
T 39.9°C; HR 112 bpm; RR 28 bpm; BP 106/73 mmHg
Weight 19.8 kg (95th percentile); Height 104 cm (90th percentile)
In general, the patient was talkative, pleasant, and in no acute distress. Her sclerae were anicteric, there was no conjunctival injection, and tympanic membranes were normal. The oropharynx was erythematous without tonsillar exudates, and there were no oral lesions noted. Neck examination revealed shotty cervical lymphadenopathy. Chest and heart examinations were normal. Abdominal examination revealed normoactive bowel sounds, diffuse tenderness without peritoneal signs, and no organomegaly. Neurologic examination was intact, and the skin showed no rashes or discoloration.
Complete blood count showed a WBC count of 15 800/mm3 with 64% segmented neutrophils, 22% lymphocytes, and 13% monocytes. The hemoglobin was 11.2 g/dL and platelets were 323 000/mm3. Liver function tests, basic metabolic panel, and immunoglobulin levels were all normal. Urinalysis, urine culture, blood culture, chest radiograph, rapid streptococcal antigen and throat culture, Lyme antibodies, Epstein-Barr virus and cytomegalovirus serologies, anti-nuclear antibody (ANA), stool culture, stool ova and parasites, malaria smear, CT scan of the head and sinuses, and gallium scan with triple phase bone scan were all negative. Erythrocyte sedimentation rate was elevated at 66 mm/h.
COURSE OF ILLNESS
Apart from the mild leukocytosis and elevated erythrocyte sedimentation rate, the patient’s workup was negative. She became afebrile on hospital day 6 and was discharged home with close follow-up. Her complete blood count was checked two times a week for 2 months and her absolute neutrophil count was always normal. During the febrile episodes she always had an elevated white blood cell count and erythrocyte sedimentation rate that normalized when she was afebrile. The diagnosis was suggested by the constellation of symptoms including the recurrent fever and pharyngitis.
DISCUSSION CASE 7-7
Periodic or recurrent fever has several definitions in the literature. The most common features are that the fever is at least 38.4°C (some sources require higher fever of at least 39°C) and continues for 3-6 days, occurs at least three times over a 6-month period, has no identifiable etiology, is not accompanied by symptoms such as upper respiratory tract infection, and occurs at intervals that are separated by at least 1 week (and usually <4 weeks). The intervals without symptoms can be of variable duration or occur in a predictable pattern.
The causes of recurrent fever can be divided by category of diagnosis (Table 7-3) or whether the recurrences occur at irregular or regular intervals. There are several etiologies that could be attributed to recurrent fevers occurring at irregular intervals. These include infectious diseases that range from viral infections (i.e., Epstein-Barr virus, parvovirus B19, herpes simplex virus, repeated upper respiratory tract infections), bacterial infections (i.e., occult transient bacteremia, recurrent urinary tract infections, chronic meningococcemia, dental abscess, brucellosis, Yersinia infections, and mycobacterial infection), and parasitic infections (i.e., relapsing malaria with Plasmodium vivaxor ovale, reactivation of Plasmodium malariae). Other etiologies of recurrent fevers that occur at irregular intervals include inflammatory diseases (i.e., inflammatory bowel disease, systemic juvenile idiopathic arthritis, Behçet disease), neoplasms such as lymphoma, and drug fevers. Viral infections and undiagnosed causes are the most common causes of recurrent fevers that occur with irregularity.
TABLE 7-3. Etiologies of recurrent fever by diagnostic category.
There are very few diseases that cause recurrent fevers at predictable and regular intervals. These causes include cyclic neutropenia, which usually recurs between 21 and 28 days, relapsing fever caused by Borrelia species, which recurs between 14 and 21 days, and PFAPA (periodic fever, aphthous ulcers, pharyngitis, and adenopathy) syndrome, which recurs between 21 and 28 days. There is also a group of hereditary causes of periodic fever that can occur at either regular or irregular intervals that should be considered. These include familial Mediterranean fever (FMF), hyper-IgD syndrome (HIDS), and tumor necrosis factor receptor-associated periodic syndrome (familial Hibernian fever or TRAPS). PFAPA and undiagnosed causes are the most common causes of recurrent fevers that occur at predictable intervals.
The clue to this patient’s disease was the regularity of her febrile episodes and associated symptom of pharyngitis.
Testing for recurrent fever is often extensive due to the broad differential diagnosis. As performed in our patient, testing usually includes complete blood counts which may demonstrate atypical lymphocytosis as seen in viral infections or neutropenia; erythrocyte sedimentation rate which may be nonspecifically elevated with infectious causes but may indicate inflammatory or rheumatologic conditions with significant elevations; serum viral and bacterial testing; specific testing for rheumatologic diseases such as ANA; and various imaging studies evaluating for occult infection or neoplasms such as lymphoma.
During one of the episodes of fever, the patient was found to have three aphthous mouth ulcers and an erythematous throat. She was diagnosed with PFAPA syndrome (periodic fever, aphthous ulcers, pharyngitis, and adenopathy).
INCIDENCE AND ETIOLOGY OF PFAPA
PFAPA syndrome is defined by recurrent and periodic episodes of fever (>39°C) that last between 3 and 6 days, occur approximately every 21-28 days, and are accompanied by certain clinical findings. There is a slight male predominance, and the disease usually manifests itself before 5 years of age. There seems to be no pattern of familial inheritance and no seasonal or geographic predilection. Although the etiology of PFAPA is not known, infectious and autoimmune causes have been implicated. PFAPA is considered the most common cause of recurrent fever that occurs at regular and predictable intervals.
Children with PFAPA generally are well children in terms of growth and development who present with predictable patterns of fever described above. The three most common clinical findings are aphthous mouth ulcers, pharyngitis, and cervical adenopathy. The aphthous mouth ulcers are frequently missed because there are very small (<5 mm), few (usually two or three), painless, and resolve very quickly. These aphthous ulcers are in contrast to the large, painful ulcers that occur with herpes simplex virus gingivostomatitis (Figure 7-7). One case series of 94 patients found reports of associated aphthous mouth ulcers in only 70% of cases of PFAPA. Pharyngitis was found in only 72% of cases and is usually nonexudative. Cervical adenopathy is the most commonly seen sign in 88% of cases and is usually confined to the cervical region and relatively unre-markable (<5 mm nodes). While symptoms such as abdominal pain, nausea, and headache can sometimes be seen, upper respiratory symptoms are rare and usually indicate a viral upper respiratory infection. The most striking features of PFAPA are its predictable recurrence and overall wellness of the patient both during the episode and when the episode resolves.
FIGURE 7-7. Herpes simplex virus gingivostomatitis.
Diagnostic criteria that have been used are clinical in nature and include much of what has already been discussed: (1) regularly recurring fevers with early (<5 years old) age of onset; (2) constitutional symptoms without upper respiratory infection and either aphthous stomatitis, cervical lymphadenitis, or pharyngitis; (3) asymptomatic intervals between episodes; (4) normal growth and development; and (5) exclusion of cyclic neutropenia. Other fever syndromes also have characteristic features (Table 7-4).
TABLE 7-4. Features associated with some fever syndromes.
Abbreviations: PFAPA, periodic fever, aphthous ulcers, pharyngitis, and adenopathy; FMF, familial Mediterranean fever; TRAPS, tumor necrosis factor receptor-associated periodic fever syndrome
Complete blood count. Included in the diagnostic criteria of PFAPA is the exclusion of the diagnosis of cyclic neutropenia. This distinction can be difficult as the two disorders have similar features. In cyclic neutropenia, neutropenia recurs approximately every 21 days. Although the fever in cyclic neutropenia usually occurs without accompanying infection, bacterial infection, in particular Pseudomonas aeruginosa, secondary to the neutropenia can occur. The best way to distinguish between the two is with a complete blood count. In PFAPA, complete blood count shows a mild leukocytosis during the episode. The white blood cell count normalizes in the absence of fever. To diagnose cyclic neutropenia, complete blood counts with differential must be checked regularly (at least twice per week for 2 consecutive months), as the neutropenia does not always occur at the time of the fever. In cyclic neutropenia, an absolute neutrophil count of less than 500/mm3 is seen and it recovers on its own.
Other studies. Additional studies may be directed at other diseases in the differential diagnosis. Testing for mutation detection can be undertaken for patients with suspected TRAPS. The IgD levels are elevated in patients with hyper-IgD syndrome though several measurements may be required for confirmation. Genetic testing is also available for FMF.
PFAPA usually persists for several years (>4 years) before spontaneous remission occurs. This remission begins with a period during which the episodes occur with decreasing frequency before resolving completely. During the years when the episodes occur, treatment includes supportive care and planning family events around the predictable fever. A single dose of corticosteroids at the beginning of the episode has been found to dramatically reduce the fever and should be the first line treatment. If this is not effective, prophylaxis with cimetidine can be attempted. Tonsillectomy has been found to effectively stop the episodes in some patients and can be considered if both corticosteroids and cimetidine are not effective. However, the risks of tonsillectomy must be weighed against the benign febrile episodes of PFAPA that usually resolve spontaneously over a period of years.
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