Prolonged and recurrent fevers in children

Journal of Infection (2014) 68, S83eS93

www.elsevierhealth.com/journals/jinf

Prolonged and recurrent fevers in children Gary S. Marshall* University of Louisville School of Medicine, 571 S. Floyd St., Suite 321, Louisville, KY 40202, USA Accepted 20 September 2013 Available online 10 October 2013

KEYWORDS Fever of unknown origin; Periodic fever; Occult infection; Autoinflammatory diseases; PFAPA syndrome

Summary Some children referred for prolonged fever are actually not having elevated temperatures; the approach here requires dissection of the history and correction of health misperceptions. Others have well-documented fevers associated with clinical, laboratory, or epidemiologic findings that should point to a specific diagnosis. “Fever-of-Unknown-Origin” (FUO) is the clinical scenario of daily fever for
14 days that defies explanation after a careful history, physical examination, and basic laboratory tests. The diagnostic approach requires a meticulous fever diary, serial clinical and laboratory evaluations, vigilance for the appearance of new signs and symptoms, and targeted investigations; the pace of the work-up is determined by the severity of the illness. Approximately half of children with FUO will have a self-limited illness and will never have a specific diagnosis made; the other half will ultimately be found to have, in order, infectious, inflammatory, or neoplastic conditions. Irregular, intermittent, recurrent fevers in the well-appearing child are likely to be sequential viral illnesses. Monogenic autoinflammatory diseases should be considered in those who do not fit the picture of recurrent infections and who do not have hallmarks of immune deficiency. Stereotypical febrile illnesses that recur with clockwork periodicity should raise the possibilities of cyclic neutropenia, if the cycle is approximately 21 days, or periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome, the most common periodic fever in childhood. ª 2013 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Introduction In 1871, Wunderlich established 98.6  F (range, 97.2e99.5) (37.0  C, range 36.2e37.5), as the normal human body temperature, suggesting that temperatures above 100.4  F (38.0  C) were “suspicious”.1 Contemporary authors have argued that, given the wide variation between and within individuals, the concept of a “normal” body temperature should be abandoned.2 Sites of measurementdrectum, mouth,

axilla, tympanic membrane, temporal arterydvary in the degree (no pun intended) to which they approximate core body temperature.3 Technique also matters; for example, oral temperatures are only accurate in those who can keep their mouths closed and the thermometer under their tongues. Fever, or elevated core body temperature, is one of the most reliable indicators that something is wrong, yet all of the above make it difficult to define exactly what fever is. Most pediatricians would agree that inserting a glass or

* Tel.: þ1 (502) 852 3774; fax: þ1 (502) 852 3939. E-mail address: [email protected] 0163-4453/$36 ª 2013 The British Infection Association. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jinf.2013.09.017

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digital thermometer into the rectum is the most accurate way to measure core body temperature. This is feasible, however, only up to about 3 years of age. Oral temperatures, if properly done, are a close-enough approximation to core body temperature; this technique becomes feasible around 5 years of age. Between 3 and 5, one may have to settle for axillary temperatures (most physicians add 1  F [0.6  C] to approximate core body temperature). The Brighton Collaboration, a research network focused on vaccine safety, defines fever as “the endogenous elevation of at least one measured body temperature of
38  C,”4 irrespective of device used, anatomic site, age, or environmental conditions. For purposes of this discussion, undifferentiated fever refers to the situation where a previously healthy child presents with fever as the chief complaint, without signs or symptoms of a specific clinical illness (e.g., upper respiratory tract infection, viral exanthem, etc.). A distinction is drawn between undifferentiated fever and fever without source, which refers to the special situation of an acute fever in an otherwise well-appearing child under 3 years of age, where there is well-documented risk for occult serious bacterial infection.5 Fig. 1 shows a conceptual framework for categorizing patients who present with undifferentiated fever.

Prolonged fever In prolonged fever, the patient comes to medical attention because the illness has lasted beyond what might be

expected for a self-limited viral illness, i.e., beyond a week or so.

Not-Fever-of-Unknown-Origin Some such patients will actually not be having fever, at least not according to any medical definition, despite the complaintdthis might be termed Not-Fever-of-Unknown-Origin, to distinguish it from (true) Fever-of-Unknown-Origin, as below. In evaluating patients with the complaint of prolonged fever, providers should be aware that elevated temperatures are seen with ovulation and after meals, exercise, and even chewing gum. Moreover, there is a normal diurnal variation in temperature, with lows in the morning and highs in the afternoondin some healthy adults, temperatures during the day may fluctuate by as much as 2.4  F (1.3  C).2 There are usually clues to the diagnosis of Not-Fever-of-Unknown-Origin6: the child appears healthy and has a normal physical exam; the weight is stable and growth and development are normal. The parents may have misconceptions about health and illnessdin particular, what temperatures constitute true fever (parents may say, for example, that 99  F [37.2  C] is a fever because the child’s temperatures “normally run low”). Complicated medical histories, behavioral problems, and multiple school absences for subjective complaints may point to a vulnerable child. Family stressors and fear of malignancy may be present. The approach should in carefully documenting the “fever” history, probing for underlying causes, correcting misconceptions, and reassuring parents.

Undifferentiated Fever

Prolonged

Not-Fever-ofUnknown-Origin Patient not truly having fevers

Recurrent

Fever-of-NotUnknown-Origin

Fever-ofUnknown-Origin

Diagnosis readily achievable

Daily fever ≥14 days

Unusual presentation of common disease Common presentation of unusual disease

Infectious

Intermittent Fever

Periodic Fever

Sequential self-limited illnesses

Cyclic neutropenia

Autoinflammatory disorders

PFAPA syndrome

Inflammatory

Neoplastic

Miscellaneous

No diagnosis

Figure 1

Algorithm for undifferentiated fevers in children (See text for explanation).

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Fever-of-Not-Unknown-Origin Other patients will present with bona-fide prolonged fever, but with diagnoses that become apparent after a careful history, physical exam, and relatively simple, non-invasive testsdthis might be termed Fever-of-Not-Unknown-Origin. Making the diagnosis here does not necessarily require engagement of a sub-specialist. Many times the cause of fever is an uncommon presentation of a common illness, like bacterial sinusitis without much in the way of nasal drainage (but, perhaps, with bifrontal headache) or pneumonia without cough or chest pain (but with, perhaps, increased voice transmission and dullness to percussion). The key to making these diagnoses is thinking outside the box and selecting targeted diagnostic tests. Other times Fever-of-Not-Unknown-Origin is caused by a common presentation of an uncommon disease. Thus, for example, prolonged fever accompanied by any combination of rash, conjunctivitis, changes in the oral mucosa or peripheral extremities, or cervical lymphadenopathy should prompt evaluation for Kawasaki disease, including measurement of acute phase reactants and echocardiographic visualization of the coronary arteries. In endemic areas, cough and infiltrate on chest X-ray, especially if hilar or mediastinal lymphadenopathy is present, should prompt serological testing for histoplasmosis. In any geography, the same findings should prompt tuberculin skin testing and investigation into possible epidemiologic links. Bruising, bleeding, splenomegaly, and/or lymphadenopathy should lead to an examination of the peripheral smear, looking for blasts. If it’s summertime and the patient has leukopenia, thrombocytopenia and elevated hepatic transaminases, consideration should be given to a serologic work-up and empiric treatment for a tickborne rickettsiosis. History of an abnormal heart value, a changing murmur, and embolic phenomena should lead to blood cultures, echocardiography, and consideration of subacute bacterial endocarditis. You get the picture.

Fever-of-Unknown-Origin The designation of Fever-of-Unknown-Origin (FUO) is reserved for those children who are truly having fever and in whom no diagnosis is apparent after the above considerations. The concept of FUO as an entity was crystallized in

Table 1

the classic 1961 paper by Petersdorf and Beeson, which reported a series of 100 adults with illness greater than 3 weeks, fever over 101  F (38.3  C) “on several occasions”, and no diagnosis after 1 week in the hospital (interesting historical note: in the title of the paper, the “U” means “Unexplained”, and in the running header, it means “Undetermined”).7 This paper set the stage for thinking about 3 main categories of diagnoses in adults with FUO, namely infectious (39% of cases), neoplastic (21%), and inflammatory (19%), in addition to a miscellaneous category (21%). However, the definition of FUO used in this paper lacks specificity (what does “on several occasions” mean?) and is unworkable today, as hospital admissions for diagnostic purposes may not be covered by insurance. Between 1972 and 1998, 5 important case series of children with FUO were published.8e12 As can be seen in Table 1, some of the definitions used in those papers suffer from the same problems as the Petersdorf and Beeson definition. A reasonable definition of FUO for clinical purposes would be similar to the one employed by Jacobs and Schutzeda core body temperature of at least 100.5  F (38.1  C) measured at least once a day for at least 14 consecutive days. The fever curve looks something like that shown in Fig. 2, Panel A. Our understanding of the final diagnoses in patients with FUO derive from these case series and others, which are generated largely by academicians at tertiary care referral centers. This introduces an important bias, as referral patterns differ from one locale to another. Thus, for example, final diagnoses among children referred to an academic medical center with an active, open-door outpatient consultation service might be different from those reported from a similar center that sees only inpatients, or that has restrictions on who is seen in clinic. Likewise, referrals may be heavily influenced by the local insurance market, as there may be barriers to referral. Fig. 3 shows the final diagnoses among children reported in the aforementioned pediatric case series, stratified by those reported in the 1970s and those reported in the 1990s (there have been no similarly large case series from the U.S. published in the last 15 years). One thing is evident: for children in whom a specific diagnosis is ultimately made, the “Big 3” diagnostic categoriesdinfectious, inflammatory, and neoplastic, in that orderdcontinue to dominate. However, the proportion of all children who never receive a specific diagnosis has increased; in fact, this is now arguably the most common outcome of referral for FUO. What is going on?

Defining fever of unknown origin in children.

Reference (year)

Temperature (
) 

F



C

Method

Frequency

Duration

Outpatients: 3 weeks Inpatients: 1 week 2 weeks Outpatients: 3 weeks Inpatients: 1 week 3 weeksa
14 days

McClung (1972)

102.1

38.9

Rectal

Multiple occasions

Pizzo (1975) Lohr (1977)

101.4 101.1

38.6 38.4

Rectal Not specified


5 occasions Multiple occasions

Steele (1991) Jacobs (1998)

100.5 100.5

38.1 38.1

Oral or rectal Core temperature


2 occasions per week
1 occasion every day

a

Normal urinalysis and chest X-ray required.

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Percent

100

1970s

1990s

50

0 Infectious

Inflammatory Neoplastic

Other

No diagnosis

Figure 3 Causes of FUO in children. The graph compares final diagnoses among children evaluated for fever of unknown origin in the 1970s (N Z 240) and the 1990s (N Z 255). Data from references.8e12

Figure 2 Fever patterns. Different fever curves suggest different etiologies. Relentless daily fevers (Panel A) suggest an underlying infectious, rheumatologic, or malignant condition, although in many children such fevers are ultimately self-limited and no definitive diagnosis is made. Intermittent, irregularly spaced episodes of fever of varying duration (Panel B) suggest an autoinflammatory disease, unless the patient is simply having recurrent viral illnesses. High fevers of abrupt onset that occur with clockwork periodicity (Panel C) are classic for PFAPA syndrome; cyclic neutropenia should be considered if the periodicity is approximately 21 days.

In all likelihood, children with FUO caused by identifiable underlying diseases are being diagnosed outside of academic centers, and thus never make their way into published case series. Thus, for example, children with inflammatory or autoimmune disorders are screened by available serological tests and then, when the diagnosis is suspected, are referred to rheumatologists. Likewise, the availability of detailed imaging studies (solid tumors), flow cytometry (hematologic malignancies), and sophisticated chemistries (neuroblastoma) results in straightaway referral to the oncologist, suspected diagnosis in hand. Notice that infections of the respiratory tract, tuberculosis, and endocarditis, which accounted for a substantial proportion of infectious disease diagnoses in the 1970s, were not reported in the series from

the 1990s (Fig. 4)dits not that children are no longer getting these infections, perhaps, its just that they are being diagnosed and treated by those who do not write papers on FUO. A similar trend has been seen among adult patients.13 Other things have changed over time. New infections that cause prolonged fever have appeared on the radar screen; examples include cat scratch disease, Lyme disease, and ehrlichiosis (Fig. 4). Diagnoses like mononucleosis may have become more prominent in the 1990s due to the widespread availability of EpsteineBarr virus serology at tertiary care centers. Fig. 5 shows bacterial diagnoses among children with FUO reported from developed and developing countries. Differences reflect both local epidemiologydnote, for example, the occurrence of brucellosis and typhoid fever in developing countriesdas well as the availability of diagnostic modalitiesdthis may explain, for example, why abscesses more commonly appear in case series from developing countries, reflecting perhaps the fact that imaging studies are not readily available outside of referral centers. One can only speculate why osteomyelitis is more commonly reported in developed countries. Among the chronic inflammatory and autoimmune disorders that can present as FUO are inflammatory bowel disease, juvenile idiopathic arthritis, systemic lupus

1970s

Upper respiratory tract Lower respiratory tract Urinary tract Central nervous system Tuberculosis Endocarditis Mononucleosis Osteomyelitis Cat scratch disease Tularemia Lyme disease Ehrlichiosis Other 0

10

20

30

1990s

40

Percent

Figure 4 Infectious causes of FUO in the U.S. The graph compares final infectious disease diagnoses among children evaluated for fever of unknown origin in the 1970s (N Z 240) and the 1990s (N Z 255). Data from references.8e12

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erythematosis (SLE), rheumatic fever, Wegener’s granulomatosis, sarcoidosis, histiocytic lymphohistiocytosis, and Behcet disease. Malignancies include leukemia, lymphoma, neuroblastoma, hepatoma, and soft tissue sarcomas. There are a whole host of miscellaneous causes of FUO, including drug fever, dysautonomia, diabetes insipidus, ectodermal dysplasia, hyperthyroidism, pulmonary embolus, and hematoma. In addition, clinicians must be aware of the possibilities of Munchausen syndrome by proxy and factitious fever. In patients with FUO, the severity of the illness (magnitude and intensity of fever and associated “red flags” such as night sweats, weight loss, and localizing findings) dictates the pace of the work-up.14,15 The approach for well-appearing children without “red flags” is given in Fig. 6. The initial visit includes a careful history, with particular attention paid to delineating the fever pattern and dissecting the presenting illness. Occasionally, it becomes obvious that the FUO is nothing more than a series

of nonspecific viral illnesses, blended together in the parents’ mind. On the other hand, the daily variation in temperature may itself provide the clue; for example, temperatures in patients with JIA may be subnormal in the mornings and high in the afternoons. The diagnosis may be stumbled upon in a detailed review of systems. Periorbital edema?dthink primary EBV infection. Loose stools?dinflammatory bowel disease. Palpitations?d hyperthyroidism. From an infectious disease point of view, the questions range from the sublime to the ridiculous. New kitten in the house?dthink cat scratch disease. Recent travel?dtyphoid fever. Unpasteurized goat’s milk?dbrucellosis. Jumped on a beaver dam?dblastomycosis. Exposed to a discarded sheep placenta?dQ fever. You get the picture. In adults, an evidence-based, structured approach to FUO has been offered, beginning with routine studies such as a complete blood count (CBC), peripheral smear, comprehensive metabolic panel (CMP), lactate dehydrogenase (LDH), urinalysis, blood cultures (3 specimens separated in time from different sites), anti-nuclear antibody (ANA), rheumatoid factor, human immunodeficiency virus (HIV) antibody, chest X-ray (CXR), and selected serologies.13 If these tests are unrevealing, the algorithm proceeds, in order, to discontinuation of nonessential medications (drug fever); abdominal CT or technetium-99 nuclear medicine scan (abscess, lymphoma, solid tumor); application of the Duke criteria (endocarditis); Doppler ultrasound of the lower extremities (deep vein thrombosis); and consideration of temporal artery biopsy (temporal arteritis), liver biopsy (various diagnoses), and laparoscopy (various diagnoses). Studies have also found bone marrow biopsy16 and positron emission tomography (PET)17 to be useful. In pediatrics, because the underlying causes of FUO differ, the approach also differs. It begins with a complete history and physical exam, and the results of any previous work-up are cataloged. The basic laboratory studies shown in Fig. 6 are done, along with targeted studies if there are historical findings, physical abnormalities, or epidemiologic circumstances suggesting the possibility of these diagnoses (Table 2). The parents are asked to maintain a fever and

First Visit

Third Visit

Developed

Mycoplasma Rickettsiosis Lyme disease Abscess Endocarditis Brucellosis Typhoid fever Septicemia Cat scratch disease Pyelonephritis Tuberculosis Urinary tract Osteomyelitis 0

10

Developing

20

30

Percent

Figure 5 Bacterial infections in children with FUO in developed and developing countries. The graph compares final bacterial diagnoses among children evaluated for fever of unknown origin in developed (N Z 153) and developing (N Z 338) countries, from a systematic review of papers published between 1972 and 2008. Data from references.45

Second Visit

Initial Hx and PE Previous lab results CBC with smear CMP ESR and CRP U/A and UCx BCx CXR

Interval Hx and PE CBC with smear CMP ESR and CRP

Interval Hx and PE CBC with smear CMP ESR and CRP

Targeted studies

Targeted studies

Targeted studies

Fever/symptom diary

Fever/symptom diary

Figure 6 Diagnostic approach to FUO (See text for explanation). Abbreviations: BCx: blood culture; CBC: complete blood count; CMP: comprehensive metabolic panel; CRP: C-reactive protein; CXR: chest X-ray; ESR: erythrocyte sedimentation rate; Hx: history; PE: physical examination; U/A: urinalysis; UCx: urine culture.

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G.S. Marshall Targeted studies in children with FUO.

Test Infectious diseases Tuberculin skin test, IGRA Histoplasma serology EBV serology Bartonella serology Brucella serology Toxoplasma serology Francesella serology HIV Ab/Ag or PCR Stool culture for Salmonella Autoimmune/autoinflammatory Antinuclear Ab, RF, C3, C4, slit lamp exam ASO, anti-DNAse-B Ab Malignancy Flow cytometry, LDH, UA, bone marrow aspirate Catecholamine screen, mIBG scan CT, PET Miscellaneous Thyroid function profile Sinus CT Echocardiogram Endoscopy Abdominal U/S or CT Bone scan

Diagnosis

Reason for suspicion

Tuberculosis Histoplasmosis EBV infection Cat scratch disease Brucellosis Toxoplasmosis Tularemia HIV infection Typhoid fever

Exposure to active case, homeless shelter, travel, immigration Residence in Ohio Valley, bird exposures Fatigue, lymphadenopathy, cytopenias, elevated transaminases Exposure to kittens, chronic granulomatous papule Consumption of unpasteurized milk products Exposure to cats, consumption of poorly cooked meat Tick bite with eschar, rabbit hunting Sexually active, mononucleosis-like illness, cytopenias Travel to developing country, hepatosplenomegaly, rose spots

Various rheumatologic diseases Rheumatic fever

Rash, arthritis, cytopenias, renal dysfunction, acute phase reaction Migratory polyarthritis, erythema marginatum, heart murmur

Leukemia/lymphoma, various malignancies Neuroblastoma

Fatigue, bruising, bleeding, lymphadenopathy, weight loss, cytopenias Opsoclonusemyoclonus, diarrhea

Solid tumors/lymphoma

Localizing symptoms

Hyperthyroidism Sinusitis Endocarditis IBD Abdominal abscess Osteomyelitis

Nervousness, irritability, tachycardia, tremors Headache, congestion Fatigue, murmur, splenomegaly, hematuria, thrombocytopenia Loose stools, weight loss, acute phase reaction, anemia Abdominal discomfort Musculoskeletal complaints

Abbreviations: Ab: antibody; Ag: antigen; ASO: anti-streptolysin-O; C3: complement component 3; C4: complement component 4; CT: computed tomography; EBV: EpsteineBarr virus; HIV: human immunodeficiency virus; IBD: inflammatory bowel disease; IGRA: interferon gamma release assay; LDH: lactate dehydrogenase; mIBG: (radio-ionated) meta-iodobenzylguanidine; PCR: polymerase chain reaction; PET: positron emission tomography; RF: rheumatoid factor; U/S: ultrasound; UA: uric acid.

Data modified from references.14,15

symptom diary and the patient is brought back in a week, or earlier if anything changes. Unwarranted antimicrobial therapy is avoided. At the second visit, the interval history and test results are reviewed, the physical examination and basic laboratory studies are repeated, and targeted studies are reconsidered. New symptoms may prompt a new line of investigation. For example, increasing lymphadenopathy might prompt a lymph node biopsy; loose stools might prompt endoscopy; or rash, anemia and thrombocytopenia might prompt an ANA screen. Trends in acute phase reactants such as the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) can be very informativeddownward trends mean whatever is causing the fever may be resolving, whereas upward trends may mean something is being missed. The process is reiterated at subsequent weekly visits until one of two things happens: a definitive diagnosis is made, or the fever resolves.

Recurrent fever Patients with recurrent fever present with a history of multiple episodes of fever. There have usually been many

visits to primary care providers, immediate care centers and/or emergency rooms; nonspecific diagnoses have been made and antimicrobial therapy may have been prescribed.

Intermittent fever Kids get sick all the time. The average child under 2, for example, has 6 or 7 respiratory illness per year (most of which are viral), unless they attend day care or have school-aged siblings, in which case they may has as many as 10.18 That’s almost one a month. In as much as some of these illnesses are accompanied by fever, and other illnesses are acquired, histories of recurrent and unpredictable febrile illnesses are quite common. How does one differentiate the child who is having sequential viral illnesses from the one whose fevers indicate something more ominous? A fever and symptom diary is one of the most useful tools to employ here. Particular attention should be paid to variation in associated symptoms from episode-to-episode. For example, one episode with sore throat, followed by an episode associated with nausea, followed by one with red eyes and a transient rash is suggestive of recurrent viral illnesses, particularly if one or another family member is

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also sick when the patient is sick. Children with recurrent, self-limited viral illnesses will appear well and have a normal physical examination, or may have findings that arise downstream of viral respiratory infection, such as otitis media with effusion, post-nasal drainage, and “allergic shiners”. Normal basic screening laboratory studies, including a CBC, CMP, and ESR, can go a long way in reassuring parents that there is no serious underlying disease. In those with a family history of immune deficiency, failure to thrive, and/or a history of treatment with intravenous antimicrobials, immune deficiency should be considered.19

It is unusual for a single infectious disease to present with recurrent fever over a long period of time.20 One scenario where this might occur is in the patient with a deepseated infectiondoccult abdominal abscess, let’s say, or osteomyelitisdthat is partially treated by empiric courses of antibiotics (all the more reason not to use antimicrobials without a definitive diagnosis). Paroxysmal fever cycles occur every 2e3 days in malaria, and the diagnosis is suspected based on travel history and associated findings such as hemolysis, jaundice, and hepatosplenomegaly. Relapsing fever is caused by infection with Borrelia recurrentis (louse-borne, seen mostly in Africa and associated with

Activation by internal and external danger signals

Activation by K+ efflux, reactive oxygen species, phagosomes, inert substances

Mevalonate kinase Pyrin *Cryopyrin

NF-κB

Procaspase-1 ASC

INFLAMMASOME

Protein expression Caspase-1 Proinflammatory gene transcription

Pro-IL-1β

IL-1β ER and GOLGI APPARATUS

CELL MEMBRANE

INFLAMMATION NUCLEUS

Figure 7 Pathogenesis of inflammasomopathies. Internal (e.g., damage-associated molecular patterns) or external (e.g., pathogen-associated molecular patterns, acting through Toll-like receptors) danger signals activate gene transcription in leukocytes via NF-kB. This results in the production of pro-IL-1b, cryopyrin (also known as NALP3 and NLRP3), procaspase-1, and the adaptor molecule ASC, among other proteins. Danger signals also activate cryopyrin, which then associates with procaspase-1 and ASC to form a macromolecular complex called the inflammasome, in essence a molecular organelle whose purpose is to generate proinflammatory cytokines. Other danger or stress signals (including Kþ efflux, reactive oxygen species, and phagosome rupture), as well as the presence of irritants like gout crystals and asbestos fibers, activate the inflammasome, which cleaves procaspase-1 into caspase-1. This in turn cleaves pro-IL-1b into IL-1b, a potent proinflammatory cytokine, which is released from the cell (other cytokines like IL-18 also may be produced). The end result is inflammation. Autoinflammatory diseases (Table 3) can result from altered function of components of the inflammasome itself (so-called intrinsic inflammasomopathies) or regulatory elements external to the inflammasome (so-called extrinsic inflammasomopathies). Intrinsic inflammasomopathies include the cryopyrin-associated periodic syndromesdfamilial cold autoinflammatory syndrome, Muckle-Wells syndrome, and neonatal-onset multisystem inflammatory disease. These result from activating, gain-of-function mutations in cryopyrin (*). Extrinsic inflammasomopathies include familial Mediterranean fever, which results from gain-of-proinflammatory function or a loss-of-anti-inflammatory function mutations in pyrin, a regulatory protein that interacts with the inflammasome. Likewise, hyper-IgD syndrome results from the loss of mevalonate kinase activity, which, through a variety of signaling molecules, leads to activation of caspase-1. The end result in each of these disorders is an increase in inflammation. Key: Solid arrows represent activation or assembly. Dashed arrows represent inhibition or modulation. Abbreviations: ASC: apoptosis-associated speck-like protein with a capsase-recruitment domain; ER: endoplasmic reticulum; IL-1b: interleukin-1b; Kþ: potassium ion; NALP3: NACHT (nucleotide-binding), leucine-rich repeat, and pyrin-binding domains-containing protein 3; NF-kB: nuclear factor kappa-lightchain-enhancer of activated B cells; NLRP3: nucleotide-binding, leucine rich repeat, and pyrin domains-containing protein 3; pro-IL-1b: precursor protein to IL-1b. Adapted from references.46,47

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poverty and crowding) or other Borrelia species such as Borrelia hermsii (tick-borne, distributed worldwide). The disease is characterized by paroxysms of fever associated with chills, sweats, musculoskeletal complaints, hepatosplenomegaly and jaundice; initial relapses occur every 5e7 days but quickly become milder and less frequent. Other infections that can present with recurrent fever patterns include brucellosis, leptospirosis, and rat-bite fever. Autoinflammatory diseases should be considered in children with recurrent fevers who do not fit the picture of recurrent viral infections and do not have classic indicators of immunodeficiency. These diseases are characterized by abnormally increased inflammation mediated by cells and molecules of the innate immune system (as opposed to autoantibodies and autoreactive T-cells, as is seen in autoimmune diseases like SLE), occurring in persons with a genetic predisposition.21 Whether they result from intrinsic or extrinsic perturbations of the inflammasome (Fig. 7), the expression of mutated receptors (Fig. 8), or other mechanisms, autoinflammatory diseases have one thing in common: increased expression of inflammatory cytokines by leukocytes, leading to unchecked inflammatory responses. Table 3 lists features of some of the autoinflammatory diseases, most of which are rare. Several things should be noted. First, these are for the most part monogenic

disorders, with well-defined inheritance patterns and ethnic predilections. Second, many have onset early in life. Third, attacks occur with variable frequency and duration (Fig. 2, Panel B); for some diseases, like neonatal onset multi-system inflammatory disease (NOMID), symptoms are continuous, albeit with exacerbations and remissions. Fourth, associated signs and symptoms such as rash, serositis, splenomegaly, and arthritis are common. Finally, some of these diseases result in long-term sequelae such as amyloidosis.

Periodic fever While the above autoinflammatory diseases are often referred to as periodic fevers, the variable frequency and duration of attacks and the irregular periodicity stand in sharp contrast to what is seen in cyclic neutropenia and the periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA, pronounced “fap-ah”) syndrome. These syndromes are marked by stereotypical episodes that recur with clockwork periodicity (it should be noted that some studies point to clockwork periodicity in hyper-IgD syndrome22). In cyclic neutropenia, blood neutrophil counts reach a nadir every 21 days, resulting in fever, malaise, mouth ulcers, and bacterial infections.23 This condition is inherited in autosomal dominant fashion and is caused by

NF-κB Unfolded protein response Ligand-independent signaling Inhibition of apoptosis

mTNFR1 Proinflammatory gene transcription

NUCLEUS

TNFR1

ER

GOLGI APPARATUS

X

TNF

CELL MEMBRANE

Figure 8 Pathogenesis of TRAPS. TNF, also known a cachectin, is an inflammatory cytokine produced by macrophages, CD4positive lymphocytes, and natural killer cells. TNFR1 is expressed on most cell types. Engagement of membrane-bound TNFR1 with TNF activates a number of signaling pathwaysdsome of these lead to apoptosis, others, as in the case of immune cells, lead to transcription of proinflammatory genes. Leukocytes in TRAPS patients express both wild-type TNFR1 and mTNFR1. mTNFR1 misfolds and traffics inefficiently, accumulating in the ER and activating the unfolded protein response, which increases susceptibility of the cell to inflammatory stimuli. Aggregated mTNFR1 also may induce proinflammatory responses independent of engagement with TNF (so-called ligand-independent signaling). Wild-type TNFR1 traffics to the cell surface, engages TNF, and calls for an inflammatory response through mechanisms such as activation of NF-kB. Cleavage of membrane-bound TNFR1 releases a soluble receptor that neutralizes TNF in the environment, thus keeping the inflammatory stimulus in check. However, mTNFR1 that does happen to make it to the cell surface is inefficiently cleaved, effectively increasing the pool of free TNF available to engage membrane-bound wild-type TNFR1; this leads to increased proinflammatory signaling. The end result of all of these processes is an increase in inflammation. Abbreviations: ER: endoplasmic reticulum; NF-kB: nuclear factor kappa-light-chain-enhancer of activated B cells; TNFR1: tumor necrosis factor receptor type 1; mTNFR1: mutant tumor necrosis factor receptor type 1. Adapted from references.46,48

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mutations in the neutrophil elastase gene (ELANE), which leads to reduced production and accelerated apoptosis of myeloid progenitor cells in the bone marrow (the mechanisms by which the neutrophil counts cycle so precisely have not been elucidated). The diagnosis can be made by gene testing and by serial (Mondays, Wednesdays, and Fridays) CBCs bracketing an illness episode (the neutropenia reaches a nadir before the fever and other symptoms become prominent). Patients usually respond well to treatment with granulocyte colony-stimulating factor. PFAPA syndrome, first described in 1987,24 is the most common periodic fever in children. Distinctive features are listed in Table 4, and an exemplary fever curve is shown in Fig. 2, Panel C. The typical patient has onset of symptoms at around 3 years of age.25 Episodes occur every 4e6 weeks and last 3e4 days, with maximum temperatures as high as 104.5  F (40.3  C). Constitutional symptoms and malaise are common. Localizing symptoms such as abdominal pain, diarrhea, arthralgia, and rash have been reported in case series26; however, since there is no widely accepted research case definition of PFAPA syndrome, it is difficult to know if all of these series actually report on the same patients. CRP27 (but, curiously, not procalcitonin28) is elevated during PFAPA episodes. Table 3

Some have questioned whether PFAPA syndrome is actually a distinct clinical entity, likening it to what used to be called “recurrent tonsillitis”.29 Support for this view comes from the fact that tonsillectomy appears to be curative in a majority of patients.30,31 However, several featuresdmost notably the clockwork periodicity and aphthous ulcersdare distinctly unusual in recurrent tonsillitis. Suffice it to say that when you’ve seen a PFAPA syndrome patient, you know it. There is tantalizing evidence that PFAPA syndrome is an autoinflammatory disease. Serum inflammatory mediators are elevated during attacks, and IL-1 blockade with anikinra (an IL-1 receptor antagonist) aborts episodes.32 Genes associated with complement, inflammasome, and interferon activity are upregulated during attacks, but gene expression during asymptomatic intervals is similar to that in healthy controls. Interestingly, the overall gene expression profile during PFAPA syndrome attacks differs from that seen during attacks of hereditary fever syndromes. As familial occurrence of PFAPA syndrome has been described,33e37 there is the possibility that a heritable basis may be discovered. That being said, comprehensive DNA sequencing for the monogenic autoinflammatory fever syndromes is already

Autoinflammatory diseases.a

Feature

Inflammasomopathies Intrinsic (Cryopyrin-associated)

Protein folding disorder

Extrinsic

FCAS

MWS

NOMID

FMF

HIGDS

TRAPS

Synonyms

FCUS

e

CINCA

e

Hibernian fever

Gene defect Inheritance pattern Ethnicity Age at onset Frequency of attacks Duration of attacks Clinical findings

NLRP3 Autosomal dominant European <1 year Variable

NLRP3 Autosomal dominant European <20 years Variable

NLRP3 Sporadic

MEFV Autosomal recessive

Any <1 year Continuous

Mediterranean <20 years Variable

MKD Etiocholanolone fever MVK Autosomal recessive European <1 year 2e4 weeks

TNFRSF1A Autosomal dominant European <20 years Variable

1e2 days

2e3 days

Continuous

1e3 days

3e7 days

>7 days

Rash Conjunctivitis Headache Nausea

Rash Conjunctivitis Deafness

Serositis Splenomegaly Erysipeloid erythema

No Anti-IL-1

Yes Anti-IL-1

Rash Adenopathy Serositis Vomiting Diarrhea Arthralgia Headache No Anti-IL-1 Anti-TNF

Rash Arthritis Conjunctivitis Splenomegaly

Amyloidosis Treatment modalities

Rash Meningitis Arthropathy Deafness Adenopathy Hepatomegaly Splenomegaly No Anti-IL-1

Yes Colchicine

Yes Anti-IL-1 Anti-TNF

Abbreviations. CINCA: chronic infantile neurological, cutaneous and articular syndrome; FCAS: familial cold autoinflammatory syndrome; FUCS: familial cold urticaria syndrome; FMF: familial Mediterranean fever; HIGDS: hyper-IgD syndrome; IL-1: interleukin-1; MKD: mevalonate kinase deficiency; MWS: Muckle-Wells syndrome; NOMID: neonatal onset multi-system inflammatory disease; TNF: tumor necrosis factor; TRAPS: tumor necrosis factor receptor-associated periodic syndrome. a Some autoinflammatory diseases result from mechanisms other than inflammasome dysregulation and altered protein folding. For example, Crohn’s disease and Blau syndrome result from abnormal activation of NF-kB. Other autoinflammatory diseases not listed in the table include PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) and DIRA (deficiency of the interleukin-1-receptor antagonist).

Data from references.49e51

S92 Table 4

G.S. Marshall Distinctive features of PFAPA syndrome.

d Fever episodes are stereotypical, circumspect, unprovoked, and recur with clockwork periodicity d Identifiable prodrome is common d There is evidence of upper respiratory tract inflammation d Rash and arthritis are absent d Acute phase reactants are elevated during episodes and normal between episodes d The child is failing to fail-to-thrive d Episodes are aborted by steroid therapy d Episodes resolve after tonsillectomy d The syndrome resolves by adolescence d There are no long-term sequelae

Data from references.25,40,44,52,53

commercially available.38 The question is, which children with recurrent fevers should be tested? Findings of a positive family history, thoracic pain, abdominal pain, diarrhea, vomiting, rash and arthralgia favor monogenic disorders rather than PFAPA syndrome; exudative pharyngitis and aphthous ulcers favor PFAPA syndrome.22 In 2008, Gattorno and colleagues39 derived and validated a diagnostic score that predicts which children with PFAPA-like symptoms are likely to test positive for one of the heritable periodic syndromes (Table 5). This score may be useful for guiding diagnostic work-ups in the clinical setting. The prognosis in PFAPA syndrome is good. In a longitudinal study, 50 of 59 patients had complete resolution of Table 5

Gaslini score.a

Variable

Codeb

Age at onset Abdominal pain

Months

Aphthous ulcers

Thoracic pain Diarrhea

Family history

0 Z Never 2 Z Sometimes or often 3 Z Always 0 Z Never 1 Z Sometimes or often 2 Z Always 0 Z Absent 1 Z Present 0 Z Never 1 Z Sometimes 2 Z Often 3 Z Always 0 Z Negative 1 Z Positive

Coefficient X

0.067

Disclosures The author has no potential conflicts of interest to disclose. This work was funded by in-kind contributions from the University of Louisville.

Value Z

a

1.494

b

1.504

c

1.958

d

0.901

e

1.503

f

For each variable, multiply the code number (e.g., 0, 1, 2, etc.) by the corresponding coefficient to obtain the value. Add the values (a þ b þ c þ d þ e þ f) to obtain the total score. In a validation set, a score >1.32 identified children who were positive for heritable periodic fever syndromes with 87% sensitivity and 72% specificity). a Named for the Giannina Gaslini Institute in Genoa, Italy, the principal investigators’ home institution. b Codes apply during each episode of fever and not during interval periods.

Data from Gattorno et al.39

fever episodes by 9 years of age; while 9 continued to have episodes, the episodes became shorter and more spread out in time, and most of them had experienced remission long periods of time.40 Steroids are very effective in aborting PFAPA episodes.30 In general, 1e2 mg/kg of prednisone is given as soon as it is clear that an episode is beginning (there is good evidence that 0.5 mg/kg is just as effective41). In general, one dose is sufficient, although additional doses may be given over the next 2 or 3 days if fevers persist. Caution needs to be exercised that the fever illness being treated is a PFAPA episode and not an intercurrent infection. As mentioned earlier, tonsillectomy is often curative, but, given the associated morbidity and risks, this option should be reserved for children whose episodes are severely disruptive to the child and family (as well as those children who have other indications for tonsillectomy).42,43 The bottom line is that most families can live with PFAPA syndrome until the child “grows out of it”. As summarized by Sarah Long, “.upbeat parents and patients with PFAPA syndrome leave our offices with their disability, relieved that we recognize the constellation and predict ultimate good health, satisfied with the notion of an upregulated immune system, and armed with a prescription for prednisone should an episode land on a birthday party or trip to Disney World”.44

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