sign in sign up
<<
Home , Big Three (Costa Rica), Continuous fever, Dental abscess, Fever of unknown origin, Intermittent fever, Remittent fever

Overview of of unknown origin in adult and paediatric patients L. Attard1, M. Tadolini1, D.U. De Rose2, M. Cattalini2

1Infectious Unit, Department ABSTRACT been proposed, including removing the of Medical and Surgical Sciences, Alma (FUO) can requirement for in-hospital evaluation Mater Studiorum University of Bologna; be caused by a wide group of dis- due to an increased sophistication of 2Paediatric Clinic, University of Brescia eases, and can include both benign outpatient evaluation. Expansion of the and ASST Spedali Civili di Brescia, Italy. and serious conditions. Since the first definition has also been suggested to Luciano Attard, MD definition of FUO in the early 1960s, include sub-categories of FUO. In par- Marina Tadolini, MD Domenico Umberto De Rose, MD several updates to the definition, di- ticular, in 1991 Durak and Street re-de- Marco Cattalini, MD agnostic and therapeutic approaches fined FUO into four categories: classic Please address correspondence to: have been proposed. This review out- FUO; nosocomial FUO; neutropenic Marina Tadolini, MD, lines a case report of an elderly Ital- FUO; and human immunodeficiency Via Massarenti 11, ian male patient with high fever and (HIV)-associated FUO, and pro- 40138 Bologna, Italy. migrating arthralgia who underwent posed three outpatient visits and re- E-mail: [email protected] many procedures and treatments before lated investigations as an alternative to Received on November 27, 2017, accepted a final diagnosis of Adult-onset Still’s “1 week of hospitalisation” (5). on December, 7, 2017. was achieved. This case report In 1997, Arnow and Flaherty updated Clin Exp Rheumatol 2018; 36 (Suppl. 110): highlights the difficulties in diagnosing the FUO definition and considered the S10-S24. certain causes of FUO that requires a type of diagnostic panel to be more im- © Copyright Clinical and very high index of suspicion. The main portant than the duration of investiga- Experimental Rheumatology 2018. causes of FUO in paediatric and adult tions (6). They considered the follow- patients will be reviewed here, under- ing list to be the “Minimum diagnostic Key words: fever of unknown origin, lying the fact that a physician should evaluation to qualify as FUO”: com- autoinflammatory disease, , also consider the possibility that a pa- prehensive history; repeated physical malignancies, non-genetic periodic tient with FUO may have a monogenic examination; , in- , non-infectious inflammatory autoinflammatory disease (AID). The cluding differential and platelet (PLT) diseases, children. identification of AIDs requires a care- count; routine blood chemistry, includ- ful evaluation of both history and clini- ing lactate dehydrogenase (LDH), bili- cal details that may reveal important rubin, and enzymes; urinalysis, clues to identify the correct aetiology. including microscopic examination; We also provide a comprehensive ac- chest radiograph; erythrocyte sedimen- count of specific tation rate (ESR); antinuclear antibod- that could suggest possible diagnoses ies; rheumatoid factor; angiotensin and guide the work-up of FUO and converting enzyme; routine blood cul- non-genetic periodic fevers in children. tures (at least three) while not receiv- ing ; IgM Introduction antibodies or virus detection in blood; Fever of unknown origin (FUO) ac- heterophile antibody test in children Funding: This paper is part of a counts for around 3% of hospital ad- and young adults; tuberculin skin test; supplemental issue supported by an missions and has a high impact on computerised tomography (CT) of ab- unrestricted grant from Novartis Farma, health care systems (1, 2). Indeed, domen or radionuclide scan; HIV an- Italy through a service agreement with more than 200 different causes of FUO tibodies or virus detection assay; and, Health Publishing & Services Srl. Health have been reported (3). further evaluation of any abnormalities Publishing & Services Srl provide The first definition of FUO dates back detected by the above tests (6). editorial assistance. Article Processing to the early 1960’s, when it was defined Following on from this, a number of di- Charges were also funded by Novartis Farma, Italy. by Petersdorf and Beeson as a “Body agnostic algorithms have been proposed. temperature of more than 38.3°C on Notably, the inclusion of 18 fluorodeox- Competing interests: M. Cattalini received speaker’s fees and consultancy honoraria several occasions, lasting for more yglucose-positron emission tomography from AbbVie, Novartis and SOBI. All the than 3 weeks and no diagnosis after 18F-FDG PET among the investigations other authors declare no competing 1 week of hospitalisation” (4). Re- has improved and shortened the diag- interests. finements to the definition have since nostic work-up of FUO (7).

S-10 Clinical and Experimental Rheumatology 2018 Fever of unknown origin / L. Attard et al.

Case report: an adult patient lowed by normalisation of acute phase ography, and colonoscopy were nega- An Italian male patient aged 69 years reactants. However, due to a relapse of tive. Chest high-resolution CT showed old, with a mechanical aortic valve, was these parameters (PCT 62 mg/ml, CRP bilateral peripheral micronodules and admitted to the Internal Medicine ward 27 mg/dl, lactic acid 24 mg/dl, ferritin multiple mediastinal lymphadenopa- due to high fever (up to 39°C) and mi- 6921 ng/ml, LDH 1512 U/L) the pa- thies. The patient was initially treated grating arthralgia, which had started ten tient was switched to meropenem and with piperacillin-tazobactam without days prior. Before being admitted, he linezolid with apyrexia for 7 days. Fol- effect, and then, due to an impairment had been treated with clarithromycin, lowing this, the patient experienced a of acute phase reactants (PCT 65 mg/ which was stopped due to the occur- relapse of fever. Candida spp. was iso- dl), teicoplanin and fluconazole were rence of skin , and later with amox- lated in , and the patient added with resolution of fever. The pa- icillin-clavulanate, without resolution was treated with caspofungin. Due to tient was discharged after 30 days and of the fever. At admission he presented a recurrence of skin rash on the arms, referred to the Fever of Unknown Ori- with papular skin rash in the pretibial legs, and trunk, the patient underwent gin outpatient clinic, Infectious Dis- region, bilaterally. Blood investiga- skin biopsy, which raised the suspicion ease Unit. At that time he was apyretic; tions showed white blood cells (WBC) of psoriasis. He was then treated with he reported asthenia and marked loss of 15,600/mmc, PLT count 405,000/mmc, topical steroids with fast improvement body weight (10 kg over the previous 2 ESR 114 mm/h, C-reactive protein of the skin rash. At the same time, fever months). WBC were 7,490/mmc (Neu- (CRP) 29 mg/dl, beta-2 microglobulin and joint disappeared and blood trophils: 63%, Eosinophils 9.2%), ESR 7.8 mg/L, procalcitonin (PCT) 2.2 mg/ tests were normal. He was then dis- 92 mm/h, CRP 3.38 mg/dl, beta-2 mi- dl, LDH 894 U/L; Interferon-gamma charged after 35 days in a good clinical croglobulin 8 mg/L, interleukin-6 19.8 Release Assay (IGRA) test was in- condition with a diagnosis of recurrent ng/ml, serum amyloid A 5.23 mg/dl, determinate. Widal test, for infections due to the onset of psoriatic fibrinogen 405 mg/dl, LDH 525 U/L, Brucella and HIV, human herpesvirus arthritis. and ferritin 2,370 ng/ml. After 10 days (HHV)-8, cytomegalovirus (CMV), Five years later, the patient reported he reported a recurrence of high fever Epstein-Barr virus (EBV), A to the Emergency Department due to and joint pain. According to his clini- virus, hepatitis B virus (HBV), hepatitis a recurrence of fever (up to 38°C), cal history and laboratory features, a C virus (HCV), enterovirus, parvovirus , loss of body weight, and diagnosis of Adult-onset Still’s disease B19, Dengue, , Trepone- arthralgia over the previous month. (AOSD) was formulated based on four ma, Francisella, , Borrelia, Before reporting to hospital, he had major and three minor Yamaguchi cri- Rickettsia, Coxiella, Leishmania, Toxo- been treated with amoxicillin-clavu- teria. Antibodies to Strongyloides ster- plasma, , and lanate for 6 days without benefit. He coralis were positive and he was treat- did not show any active infections. complained of a transient rash on the ed with oral ivermectin for 2 days be- Polymerase chain reaction (PCR) for back. WBC were 16,670/mmc (Neu- fore starting steroids. After the start of HCV, HBV, CMV, EBV, and HHV- trophils: 93%), CRP 5.93 mg/dl, LDH steroid treatment, the patient achieved 6 were negative. More than 10 blood 600 U/L; chest x-ray was negative. He complete recovery after a period of one cultures for bacteria and mycobacteria was admitted for further investigations: month. He did not show any febrile were negative. Chest x-ray, chest and blood tests showed WBC 20,000/mmc episodes nor other symptoms while on abdominal CT scan, transthoracic and (: 92%), haemoglobin 10.9 steroid treatment. transoesophageal echocardiography, g/dl, beta-2 microglobulin 6.8 mg/L, The diagnostic and therapeutic ap- and colonoscopy were all negative. PCT 1.9 mg/dl, ferritin 7,500 ng/ proaches carried out in this patient 18F-FDG PET showed multiple me- ml, and thyroid function was normal. were particularly aggressive as a blood diastinal and abdominal lymph nodes Two sets of blood cultures were nega- stream was suspected in con- uptake (SUV max 15), diffuse splenic tive. IGRA test was negative. Widal sideration of his aortic mechanic valve (SUV max 6.5), and diffuse bone up- test and serology for Brucella and and high values of PCT. The sponta- take. Laterocervical biopsy CMV, Toxoplasma, Chlamydia, Bor- neous remission of fever (related to and bone marrow biopsy and aspirate relia, EBV, HIV, Treponema, Pallidum, AOSD) was considered twice to be the showed non-specific reactive hyperpla- Leptospira, Rickettsia, Bartonella, As- effect of treatment. Howev- sia, and immunohistochemistry showed pergillus, Histoplasma, Coxiella, and er, the correct interpretation of signs, the predominance of CD8 positive Leishmania ruled out active infections. symptoms and lab tests (e.g. hyperfer- lymphocytes; PCR for Leishmania and CMV DNA PCR and blood smears for ritinemia) would have spared useless Mycobacterium , and my- were negative as was Galacto- high cost diagnostic tests, less invasive cobacterial cultures on these samples mannan and Cryptococcal antigen on procedures and treatments, and would were negative. serum. Abdominal ultrasound was also probably have achieved the final diag- Soon after admission, the patient was negative. 18F-FDG PET showed mild nosis much earlier, with significant ad- started on daptomycin, piperacillin- multiple mediastinal, axillary, and in- vantage to the individual and a reduced tazobactam and rifampin due to sus- guinal lymph nodes uptake. Transtho- cost in health resources. Whilst PCT is pected prosthetic , fol- racic and transoesophageal echocardi- considered a strong predictive marker

Clinical and Experimental Rheumatology 2018 S-11 Fever of unknown origin / L. Attard et al.

Table I. Causes of fever of unknown origin in adults [modified from Cunha et al. 2015 (54)].

Main causes of classic FUO in adults

Infections NIID Malignancy Miscellaneous

Bacterial 1. AOSD 1. (HL, NHL) 1. De Quervain 1. Subacute endocarditis 2. /giant 2. Solid tumours (renal cell 2. Drug fever 2. Abdominal, pelvic and renal vessels arteritis , hepatocellular 3. Factitious fever 3. carcinoma, tumour metastatic 4. Inflammatory bowel diseases 3. Spondylodiscitis 4. to the liver) 5. Sweet syndrome 4. Chronic prostatitis 5. Systemic erythematous 3. 6. Deep vein thrombosis/pulmo- 5. Periapical 6. 4. Leukaemia nary embolism 6. Vascular graft infection 7. Small vessels 5. Atrial myxoma 7. Hypersensitivity 7. Extrapulmonary and miliary 8. Takayasu’s arteritis 6. CNS tumours 8. tuberculosis 9. Kikuchis’ disease 9. Hemophagocytic syndrome 8. 10. Polyarticular 9. 11. Behçet’s disease Hereditary AutoInflammatory 10. Borreliosis 12. Late-onset rheumatoid arthritis Diseases (AIDs) 11. 1. Familial Mediterranean fever 12. Non-tuberculous mycobacteria (FMF) 13. 2. Tumour necrosis factor 14. Whipple disease receptor-associated periodic 15. syndrome (TRAPS) 16. 3. Cryopyrin-associated periodic 17. syndromes (CAPS) 4. Mevalonate kinase deficiency Viral (MKD) 1. CMV 2. EBV 3. Multicentric Castleman’s disease

Fungal 1. (disseminated)

Parasitic 1. Visceral leishmaniosis 2. Malaria 3. 4. Amoebic abscess

AOSD: Adult onset Still’s disease; CMV: cytomegalovirus; EBV: Epstein-Barr virus; FUO: fever of unknown origin; HL: Hodgkin’s lymphoma; NHL: non- Hodgkin’s lymphoma; NIID: non-infectious inflammatory diseases. of bacterial infections, especially sep- According to the trend over time of years (17). The symptom-free period sis, some FUO-causing diseases may fever and acute phase reactants incre- may vary from weeks to years. also increase this protein. Among these, ment, FUO may be defined as “contin- The so-called “” categories AOSD and DRESS (Drug reaction with uous” or “recurrent”. Recurrent FUO account only for 20-30% of recurrent Systemic Symptoms) can dramatically was defined as classic FUO with fever- FUOs causes (17). Among “infections”, increase PCT values (8-11). free intervals associated with normali- , endocarditis, infected sation of acute phase reactants lasting vascular prosthesis, deep seated ab- FUO in adults at least 2 weeks (13, 14). scesses, prostatitis, cholangitis, mas- Among the causes of FUO in adults, the Recurrent or episodic FUO is probably toiditis, as well as infections by Yers- so-called “big three” categories are: “in- the most intriguing subtype of FUO and inia, Borrelia, Coxiella, Mycobacteria fections”, “non-infectious inflammatory the most challenging to diagnose. A re- (tuberculosis and non-tuberculous my- diseases (NIID)”, and “malignancies”; current fever pattern is an independent cobacteria), and malaria due to Plasmo- a fourth category, known as “miscella- predictive factor of missed final diag- dium ovale or P. vivax may present with neous”, assembles diseases not fitting nosis, which is reached in 24-52% of a recurrent pattern of FUO (17). Among the previous categories (see Table I) recurrent FUOs versus 69-82% in con- “malignancies”, the “Pel-Ebstein fever” (12). The rate of undiagnosed FUOs has tinuous FUOs (15-20). pattern of Hodgkin’s lymphoma and dropped from over 75% in the 1930’s to Recurrent FUO was responsible for Non-Hodgkin’s lymphoma (21) is no- less than 10% in the 1950s. However, around 18-42% of cases in a large series torious, however colon carcinoma may the rate of FUOs classified as “undiag- of patients with FUO (17). A large num- also be characterised by recurrent fever nosed” has increased steadily over the ber of patients have a prolonged disease (17). As far as “NIIDs” are concerned, last decade (12). duration, which may last up to several AOSD typically shows a recurrent FUO

S-12 Clinical and Experimental Rheumatology 2018 Fever of unknown origin / L. Attard et al. pattern (22, 23); Behçet’s disease and Table II. Causes of fever of unknown origin (FUO) in children [modified from Antoon et inflammatory bowel disease (IBD) may al. 2015 (33) and Chusid 2017 (37)]. also present with recurrent fever (17). Causes of FUO in children Among the fourth category “miscella- neous”, recurrent FUO may be related Infectious Causes Non-infectious Causes to hypersensitivity pneumonia and lung embolism (17), and autoinflamma- Bacterial Oncological 1. Abscess 1. Leukaemia tory disorders such as hemophagocytic 2. Bartonellosis 2. Lymphoma lymphohistiocytosis and Schnitzler’s 3. Brucellosis 3. Langerhans cell histiocytosis syndrome (24-26). Finally, the heredi- 4. 4. Neuroblastoma tary periodic fever syndrome known 5. Mastoiditis 5. Hemophagocytic lymphohistiocytosis 6. Mycoplasma pneumoniae as familial Mediterranean fever (FMF) 7. Osteomyelitis shows a regular “periodic” succession 8. of fever together with spikes of acute 9. Rat bite fever phase reactants. The diagnostic work- 10. 11. up of these diseases needs to include 12. Tuberculosis genetic tests, taking into consideration 13. Non-tuberculous mycobacteria that, at least for FMF and especially in 14. adulthood, the negativity of the avail- 15. able genetic tests cannot rule out the ge- Viral Inflammatory netic disease (27-30). 1. Cytomegalovirus 1. Behçet’s disease In addition, the so-called “three minor 2. Epstein-Barr virus 2. Inflammatory bowel disease 3. Human immunodeficiency virus 3. categories” of FUO (factitious fever, 4. Granulomatosis (with polyangiitis) drug-related fever, and habitual hyper- 5. Juvenile idiopathic arthritis thermia), are frequently forgotten by 6. less experienced clinicians and should 7. Polyarteritis nodosa 8. Sarcoidosis be considered as well as possible causes 9. Systemic lupus erythematous (SLE) of recurrent FUOs. Since these condi- 10. Antiphospholipid antibody syndrome tions are easy to rule out, they should 11. always be investigated before starting a Fungal Periodic fever classical FUO work-up (31). 1. (non-pulmonary) 1. Periodic fevers, aphthous , pharyn- 2. Histoplasmosis (disseminated) gitis, cervical adenitis (PFAPA) FUO in children 3. Cryptosporidium 2. Cyclic Paediatricians deal everyday with fe- Autoinflammatory diseases (AIDs) brile children. Indeed, fever, defined as 1. Familial Mediterranean fever (FMF) a rectal temperature >38.0°C (100.4°F), 2. Tumour necrosis factor Receptor-Associated is one of the most common reasons for Periodic Syndrome (TRAPS) 3. Cryopyrin-associated Periodic Syndromes seeking medical evaluation for chil- (CAPS) dren and infants, and the most common 4. Mevalonate Kinase Deficiency (MKD) cause for which children are brought 5. Others (Deficiency of the IL-1-receptor an- to emergency departments (32). In the tagonist [DIRA]; Majeed syndrome [MS]; Autoinflammation with infantile enterocol- majority of cases the cause of fever is itis [AIEC]; Blau syndrome/early-onset sar- easily identifiable with no or few exams coidosis; NLRP12-associated autoinflamma- and appropriate treatment is straight- tory disorder; STING-associated vasculopa- forward (33). Nonetheless, fever in thy with onset in infancy [SAVI]) children requires special consideration Other Other and in a minority of cases the clinical 1. 1. Diabetes insipidus picture may be complicated by its per- 2. 2. Factitious fever sistence in the absence of obvious caus- 3. Malaria 3. Munchausen’s syndrome by proxy 4. 4. Familial dysautonomia es (FUO), or by the recurrence of fever 5. Q fever 5. episodes (recurrent fevers). This review 6. Rocky Mountain 6. Serum sickness will focus on the latter two conditions. 7. Toxoplasmosis 7. Kikuchi-Fujimoto disease An initial consideration for the discus- 8. Visceral larva migrans 8. Drug fever 9. Sweet syndrome sion of fever in children is that meas- uring the temperature in children can parents use different methods to meas- since it is more accurate than the use be difficult, especially when they are ure temperature (34). Rectal measure- of peripheral thermometers (tympanic uncooperative or restless. In addition, ment is preferred in most children, membrane, temporal artery, axillary

Clinical and Experimental Rheumatology 2018 S-13 Fever of unknown origin / L. Attard et al.

Table III. Approach to fever of unknown origin (FUO) in children according to history [modified from Antoon et al. 2015 (33), Chusid 2017 (37), and Torreggiani et al. 2016 (55)].

Duration and pattern of fever Temperature remains elevated throughout the day but Pneumonia; ; does not fluctuate more than 1°C in 24 hours.

Remittent fever Temperature remains elevated throughout the day and Endocarditis; Brucellosis; Typhoid infection (Wunderlich’s curve) fluctuates more than 1°C in 24 hours.

Intermittent fever Temperature is elevated for some hours in a day, later Tuberculosis; Malaria (Quotidian fever with a 24-hour periodicity cycling back to normal for the remaining hours. for Plasmodium falciparum or P. knowlesi; Tertian fever with a 48-hour periodicity for P. vivax or P. ovale; Quartan fever with a 72-hour periodicity for P. malariae malaria); Systemic Juvenile Idiopathic Arthritis (sJIA).

Septic fever Temperature remains elevated and often fluctuates Septicaemia up to 5°C in 24 hours.

Pel-Ebstein fever Regular alternation of high-grade fever that keeps Hodgkin’s lymphoma; infectious diseases rising and falling approximately every 7–10 days.

Relapsing fever Recurring episodes of high fever usually lasting Louse-borne (Borrelia recurrentis, seen mostly in 3 to 7 days, followed by a few days with a normal Africa and associated with poverty and crowding) and tick-borne temperature. relapsing fever (other Borrelia species such as B. hermsii, distributed worldwide).

Recurrent fever Recurring febrile episodes usually associated with PFAPA syndrome; ; AIDs the same predictable symptoms, with seeming remission of the disease and fever-free intervals.

Age Newborns Check for relevant perinatal risk factors for Severe Bacterial Infection (SBI): maternal premature rupture of membranes >18 h for term newborns and >12 h for preterm newborns; maternal intrapartum fever >38°C; foul-smelling amniotic fluid; maternal swabs; neonatal asphyxia; prematurity (56).

Infants 1–3 months Remember that late-onset could occur up to 90 days of life and are acquired from the caregiving environment. Investigate about these following risk factors: prematurity; Central venous catheterisation (duration >10 days); nasal can- nula or continuous positive airway pressure (CPAP) use; H 2-receptor blocker or proton pump inhibitor (PPI) use, and GI tract (57).

Children and adolescents Investigate GI symptoms, growth failure, malnutrition, pubertal delay, and bone demineralisation: approximately 20– 30% of all patients with Crohn’s disease present when they are younger than 20 years of age. Also, other autoimmune diseases often start in adolescence.

History of exposure to wild or domestic animals Birds Psittacosis Cats Bartonellosis, Toxoplasmosis Dogs Salmonella infections Lizards, snakes, fish, and turtles Salmonella infections (even without direct contact with infants and toddlers because of contamination of the child’s environment with fecal material) Rabbits Salmonella infections, tularemia Rat exposure Rat bite fever Squirrels Toxoplasmosis, Rickettsia

Ingestion of contaminated food or water Unpasteurised milk and soft Brucellosis; intestinal tuberculosis; listeriosis; Campylobacter, enteropathogenic or Salmonella cheeses infections History of pica (ingestion of dirt) Toxocara (visceral larva migrans) infection

Travels: endemic countries for some pathogens Northern hemisphere temperate regions: Europe (particularly in Slovenia, Austria, United Kingdom), North America Malaria Sub-Saharan Africa, South East Asia, Central and South America Relapsing fever Africa, Western United States, Mexico, Central and South America, Mediterranean region, Central Asia Rickettsia Almost everywhere Tularemia (Francisellatularensis) North America (USA, Canada, Mexico), Europe (Finland and Sweden) and Asia (Russian Federation, Kazakhstan, Turkmenistan) Indian subcontinent, East Africa, Brazil, Southern Europe

Adopted children may have been infected before adoption in their country of origin with a variety of infectious agents including tuberculosis, human im- munodeficiency virus, hepatitis B or C, or even malaria or typhoid in their country of origin (58).

S-14 Clinical and Experimental Rheumatology 2018 Fever of unknown origin / L. Attard et al.

Table III. continued

Medication history Drugs - Drug fever: common causes could be antimicrobial agents, anticonvulsants, antidepressants, antineoplastic agents, cardiovascular drugs, histamine-2 blockers, immunosuppressants, NSAIDs (33). - Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: is a rare, potentially life-threatening ad- verse drug reaction with cutaneous manifestations and internal organ involvement that occurs in both adults and children, 2 to 6 weeks after drug administration (see RegiSCAR criteria) (59). - Sweet syndrome (SS), an infrequent skin disease characterised by sudden onset of fever, leukocytosis, neutrophilia, and tender erythematous plaques infiltrated by neutrophils). SS presents three clinical settings: classic (or idiopathic), malig- nancy associated, and drug induced. In drug-induced SS, there is a temporal relation between the drug administration and the symptom development (60).

Previous abdominal or pelvic Occult intra-abdominal abscess (most commonly in the subphrenic space, liver, right lower quadrant, and retroperitoneal , trauma or history of space). diverticulosis or peritonitis

Contact with infected person Tuberculosis A contact investigation should be considered if the index patient has a confirmed or suspected pulmonary, laryngeal, or pleural tuberculosis.

Suggestive case history findings Attack provoked by cold exposure Familial cold autoinflammatory syndrome (FCAS)

Attack in the first year of life, Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) typically after a childhood vaccination

Immunosuppression Primary immunodeficiency When episodes became more severe in frequency and characteristics, different sets of warning signs can be used if a primary immunodeficiency (PID) is suspected. Among these, the 10 warning signs developed by the Jeffrey Modell Foundation (2009) are the most known (61).

Human Immunodeficiency Mycobacteria and cytomegalovirus are opportunistic infections in patients with HIV infection that often cause aspecific virus (HIV) symptoms, including fever.

Leukaemia and lymphoma Consider constitutional symptoms (as unexplained weight loss, paleness, asthenia, night sweats, itching) and : acute leukaemia and lymphoma are another important neoplastic group that can cause FUO.

Factitious disorders Factitious fever (FF) FF is responsible for around 2.2–9.3% of FUO cases in some series: therefore, it should be suspected in school-age chil- dren and adolescents with a history of persistent fever, normal clinical and laboratory findings, prolonged absence from school, and a normal temperature when admitted to hospital (62).

Munchausen’s syndrome by proxy Of infants brought to a clinic in Australia because of serious illness, 1.5% were cases of Munchausen syndrome by proxy. Pay attention to how parents describe episodes and how many exams they have already ruled out (63).

AID: autoinflammatory disease; GI: gastrointestinal; NSAIDs: nonsteroidal anti-inflammatory drugs; PFAPA: periodic fever, , pharyngi- tis, cervical adenitis; USA: United States of America. or oral) (34, 35), although it may be including both benign and serious con- 39). When comparing data between de- contraindicated in some conditions ditions (see Table II). Infections are veloped and developing nations, infec- (i.e. neutropenic, oncologic or immu- the main causes of FUO in children, tion is consistently the most common nocompromised children) (36). It is accounting for 51% of cases accord- cause of FUO, but the type of infection also important to remember that, in the ing to data from a meta-analysis of 18 varies; bacterial infections, and Bar- normal child, body temperature has a studies from industrial countries and tonella infections were more common- circadian rhythm, with temperature as emerging economies (38). Conversely, ly diagnosed in developed countries, low as 36°C in the early morning and malignancy accounts for a higher per- whereas brucellosis, typhoid fever, as high as 37.5°C in the late afternoon centage (11%) of FUOs in adults than it tuberculosis, rickettsial infections, and (37). Mean basal temperature also var- does in children (6%). Rheumatologic were more common in de- ies according to age, gender, body hab- conditions (16%) are also a more im- veloping nations. Viral aetiologies for itus, time of day, activity level, men- portant cause of fever in adults than in FUO were more commonly identified strual cycle, and other factors (33). children (9%). It is also important to in the developed countries, particu- note that between 25–30% of children larly Epstein-Barr Virus infection (38). Causes of FUO in children with FUO remain without a final diag- Among the chronic inflammatory and As already introduced, FUO can be nosis, even after a thorough work-up autoimmune disorders that can present caused by a wide group of diseases, and after resolution of the fever (38, as FUO, the more common in children

Clinical and Experimental Rheumatology 2018 S-15 Fever of unknown origin / L. Attard et al.

Table IV. Approach to fever of unknown origin (FUO) in children according to physical examination [modified from Antoon et al. 2015 (33), Chusid 2017 (37), and Torreggiani et al. 2016 (55)].

General appearance Endocarditis; systemic JIA; oncologic diseases Weight loss Tuberculosis; tumours; IBD; HIV infection Short stature IBD; pituitary gland involvement Skin Absence of sweating during fever Dehydration due to vomiting, diarrhoea or central or nephrogenic diabetes insipidus; anhidrotic ec- todermal dysplasia Decreased body hair and hypohidrosis Anhidrotic ectodermal dysplasia Erythema migrans Lyme disease IBD; JIA; SLE; BD; Parvovirus B19; and various infectious diseases Eschar Tularemia ( infection) Evanescent macular salmon-coloured rash Systemic JIA (usually present during periods of fever elevation, lasting a few hours) Malar erythema SLE (malar erythema is one of the SLICC criteria for diagnosis) Palpable purpuric lesions Polyarteritis nodosa Petechiae Endocarditis; meningococcal meningitis (less commonly in children with chronic meningococce- mia); viral infection; rickettsia or fever blisters Pneumococcal; streptococcal; malarial and rickettsial infections Seborrheic rash Histiocytosis Urticarial macular rash Serum sickness; FCAS; Muckle-Wells syndrome; neonatal-onset multisystem inflammatory disease (NOMID) Eyes Conjunctivitis (EBV, Newcastle disease, ); Kawasaki disease; Leptospirosis; Tuberculosis; SLE Conjunctivitis associated with fever attacks FCAS Ischaemic retinopathy Polyarteritis nodosa Periorbital oedema and conjunctivitis during flares TRAPS Petechial conjunctival haemorrhage Proptosis Orbital tumour, thyrotoxicosis or metastasis Retinitis CMV infection; toxoplasmosis; syphilis Uveitis JIA; sarcoidosis; SLE; IBD; BD; vasculitis Nose and oropharynx Abnormal pupillomotor function Hypothalamic or autonomic dysfunction Anomalous dentition (pointed or cone shaped teeth) Anhidrotic Ectodermal Dysplasia Dry eyes Familial dysautonomia; SLE; Polyarteritis nodosa; Sjӧgren’s syndrome Gingival hypertrophy and oral ulcers Langerhans cell histiocytosis (64) Gingival hypertrophy or inflammation and loss of teeth Leukaemia Hyperemia of the pharynx ; CMV infection; toxoplasmosis; Kawasaki disease; leptospirosis Oral ulcers Crohn’s disease; BD; Cyclic neutropenia; PFAPA; HIDS; HSV; drug fever Pain on percussion of the sinus Sinusitis Purulent or persistent nasal discharge Sinusitis Recurrent oral Immunodeficiencies Red, dry, cracked lips Kawasaki disease Smooth tongue devoid of fungiform papillae and taste buds Familial dysautonomia (or Riley-Day syndrome) (65) Ears Hearing impairment CINCA Lymph nodes and neck Tuberculosis; Non-tuberculous mycobacteria; lymphoma; leukaemia; Kawasaki disease; Kikuchi – Fujimoto disease; Bartonellosis; Tuberculosis; Lymphogranuloma venereum; HIV infection; cyclic neutropenia; PFAPA; systemic JIA; HIDS; EBV infection; FCAS Meningeal irritation Meningitis Chest Bradycardia (due to a conduction defect) Acute ; endocarditis Dyspnea/tachypnea, abnormal breathing sounds Pneumonia; Lung involvement of AIDs; SLE Endocarditis; Acute rheumatic fever; Relative bradycardia Brucellosis; drug fever Abdomen and pelvis Abdominal pain IBD; FMF; HIDS; TRAPS; Parvovirus B19 infection; relapsing fever Abdominal or rigidity Abscess; hepatitis; peritonitis Genital ulcers BD Hepatomegaly Lymphoma; metastatic carcinoma; relapsing fever; granulomatous hepatitis; hemophagocytic lym- phohistiocytosis; Q fever; typhoid fever; viral infections; salmonellosis; brucellosis; bartonellosis; endocarditis; malaria; leukaemia Liver edge tenderness Bartonellosis; Splenomegaly Systemic JIA; HIDS; FMF; TRAPS; EBV infection; relapsing fever; chronic meningococcemia; brucellosis; malaria; visceral leishmaniasis Perirectal lymphadenopathy or tenderness at rectal examination Deep pelvic abscess; iliac adenitis; pelvic osteomyelitis Back and joints Back pain Discitis; Osteomyelitis Joint swelling, limited range of motion JIA; osteomyelitis; leukaemia; systemic JIA; FMF; HIDS; TRAPS; CAPS; BD; Parvovirus B19 infection; relapsing fever; ( infection); chronic meningococcemia; rat bite fever; brucellosis AID: autoinflammatory disease; BD: Behçet’s disease; CAPS: cryopyrin-associated periodic syndrome; CINCA: chronic infantile neurological, cutaneous, and ar- ticular syndrome; CMV: cytomegalovirus; EBV: Epstein-Barr virus; FCAS: familial cold autoinflammatory syndrome; FMF: familial Mediterranean fever; HIDS: hyperimmunoglobulinemia D with periodic fever syndrome; HIV: human immunodeficiency virus; HSV: virus; IBD: inflammatory bowel disease; JIA: juvenile idiopathic arthritis; PFAPA: periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis; SLE: systemic lupus erythematosus; TRAPS: TNF recep- tor-associated periodic syndrome.

S-16 Clinical and Experimental Rheumatology 2018 Fever of unknown origin / L. Attard et al. are IBD, and Crohn’s Disease in par- Table V. Work-up of fever of unknown origin in paediatric patients. ticular. Among neoplasia, the more First level work-up common causing FUO are lymphoma Complete blood count with differential count; peripheral blood swear and leukaemia. Rheumatic conditions, C-reactive protein; ESR; ferritin; procalcitonin such as the systemic form of juvenile Renal and hepatic function tests; LDH idiopathic arthritis are also a possibil- Urine: routine and microscopy examination with culture Throat swab culture ity. There are a lot of miscellaneous Mantoux intradermal or IGRA test and rare causes of FUO, including drug Cardiologic evaluation with echocardiography fever, dysautonomia, diabetes insipi- Abdominal ultrasound dus, ectodermal dysplasia, pulmonary Chest X-ray (to rule out infiltrates, effusions, or enlarged hilar lymph nodes) Second level/Categorical work-up embolus, and haematoma (40). It is reassuring to observe that, in a Infectious diseases • Specific antibody or molecular test for EBV, CMV,Toxoplasma, retrospective study published in 2016, Parvovirus, HIV, Salmonella, Brucella, Bartonella, Yersinia, Borre- lia, Leishmania; the majority of children referred to a • Blood culture (including quantitative cultures drawn from central Paediatric Infectious Disease outpa- catheters and peripheral veins); tient service for unexplained fevers • Stool culture; did not have a serious illness (41). In • Cerebrospinal fluid culture if indicated; • Thick and thin blood smears for malaria; fact, 95% of 221 included patients had • Whole-body Tc-99m MDP bone scan for suspected bone infection; no fever, self-limited illnesses, condi- • Head MRI for suspected central nervous system infections. tions for which no specific diagnosis was made (but fevers resolved), or Oncologic diseases • Bone marrow biopsy and aspiration when malignancy is suspected; • 24-hour urine collection for total catecholamines, vanillylmandelic mild-to-moderate illnesses (which may acid, and metanephrines, and blood pressure/heart rate monitoring or may not have warranted treatment). for suspected ; Similarly, only 1 patient in this study • Uric acid for suspected leukaemia and lymphoma (consider tumour was diagnosed with a malignancy, in lysis syndrome); • Chest-abdomen-pelvic CT scan for suspected masses (or pyogenic contrast to a number and variety of collections) and related enlarged lymph nodes; malignancies seen in earlier studies. • Positron emission tomography/computerised tomography (PET/ This discrepancy could be secondary CT) in order to detect , infections and inflammation. to the fact that most of the studies on Autoimmune/Rheumatological • Antinuclear antibodies, extractable nuclear antigens antibodies, FUO, from which epidemiological data disorders anti-native DNA antibodies wherever an arthritis is suspected; are retrieved, are based exclusively on • C3, C4, CH50; inpatient populations. In other words, • Thyroid function tests. it is very important to consider that in Immunodeficiency • Immunoglobulins and lymphocyte surface marker analysis for hu- everyday clinical practice the presence moral and cellular immunodeficiencies; of a child with FUO could be much less • Consider antibody titres to known vaccinations; worrisome than what is known from • Assessment of function (e.g. Dihydrorhodamine 123). the literature (41). One crucial point Gastrointestinal • Upper GI series and barium enema to detect changes or abnormali- is to carefully consider the general ap- ties in oesophagus, stomach, duodenum, and colon; pearance of the child presenting for • Bowel ultrasound for the assessment of Crohn’s disease FUO: the presence or absence of signs • EGD test (esophagogastroduodenoscopy) and colonoscopy with bi- opsies in order to detect inflammatory GI disorders; of systemic involvement and the pres- • ASCA, ANCA, LKM, ASMA antibodies for suspected inflamma- ence or absence of “red flags” (as will tory GI disorders. be discussed later) for serious condi- tions should dictate the pace of further ANCA: anti-neutrophil cytoplasmic antibodies; ASCA: anti-Saccharomyces cerevisiae antibodies; ASMA: anti-smooth muscle antibody; CT: computed tomography; EBV: Epstein-Barr virus; ESR: work-up (42). erythrocyte sedimentation rate; GI: gastrointestinal; HIV: human immunodeficiency virus; LDH: lac- tate dehydrogenase; LKM: liver kidney microsome; MDP: methylene diphosphonate; MRI: Magnetic Approach to the child with FUO resonance imaging. As already pointed out, the first use- ful step in approaching a child with also to information that are often over- example, a child who appears to have FUO is to try to differentiate between looked, such as how the temperature had an extended febrile illness may the “big three” categories of causes. was taken, how many fever spikes the simply be experiencing a consecutive A thorough medical history could be child has during the day, whether the series of self-limited minor infections very useful, revealing important clues fever spike is accompanied by signs or (“Pseudo-FUO”) (42, 43). This is es- to identify the correct aetiology (see symptoms, etc. Frequently, an accurate pecially likely if the child is attending Table III). Medical history should look history review by an experienced cli- school for the first time or has older not only for the obvious, such as his- nician can result in rapid diagnosis of siblings who bring home infectious tory of travel, animal contacts etc., but a previously perplexing case (37). For agents. Daycare attendance is a com-

Clinical and Experimental Rheumatology 2018 S-17 Fever of unknown origin / L. Attard et al.

Table VI. Non-genetic periodic fevers in children.

Pathogenesis Fever pattern and associated symptoms

Bacteria Focal occult infections Endocarditis could be low-grade pathogen difficulty Fever is often the only symptom: avoid inappropriate administration of detected (such as a HACEK organism or a viridians antibiotics that can suppress bacterial growth in blood cultures. ) (66).

Brucellosis Brucellosis is caused by ingestion of unpasteurised Brucella melitensis: milk or undercooked meat from infected animals, - : up to many weeks; or close contact with their secretions. Only four - Symptoms may be delayed for months; species can cause human brucellosis: Brucella abortus, - High fever spikes usually occur every afternoon (68). B. melitensis, B. suis, and B. canis (67).

Relapsing fever (Borreliae) Ticks bites may go unnoticed. Borrelia recurrentis Borrelia recurrentis: is transmitted by the human , Pediculus - Incubation period: 3–10 days; humanus (69). - Febrile episodes with abrupt onset and a duration of 3–5 days.

Bartonellae Cat scratch disease is caused by , Cat scratch disease: associated with a history of cat scratch or bite (70). -Incubation period: 1–3 weeks; Trench fever is caused by B. quintana, transmitted -Prolonged febrile episodes without other obvious symptoms in by the human body louse, Pediculus humanus (71). 5–10% of cases. Trench fever: - Incubation period: 2–3 weeks; - Febrile episodes with a duration of 1–3 days, associated with , shin pain, and dizziness that recur every 4–6 days.

Tuberculosis Extrapulmonary diseases without clear localising A disseminate form called TB sepsis (Landouzy’s disease) can be features are the most frequent presentations as FUO. fulminant or subacute: patients, frequently older children, developed Bacteriological confirmation is difficult. several weeks of continuous fever (72).

Chronic meningococcemia A persistent meningococcal bacteremia (mostly by - Intermittent febrile episodes with a duration of at least 1 week, serogroup B) could occur also in immunocompetent associated with migratory arthralgia and cutaneous vasculitis patients; it may sometimes be associated with a (erythematous macules and papules, nodules, petechiae or purpura); complement deficiency (73). - During afebrile periods, the patient seems healthy. - In the initial days of the illness, bacterial cultures are frequently negative, so if clinical suspicion is high, antibiotic treatment should be initiated early.

Rat-bite fever Streptobacillus moniliformis or Spirillum minus -Febrile episodes with headache, , and vomiting; on resolution of could be transmitted by rodents (not only bites but these symptoms (2-4 days), characteristic maculopapular rash and also by close contact, such a kiss) (74). migrating polyarthralgia occur (75).

Virus Epstein Barr Virus (EBV) EBV infection usually occurs within the first few Infectious Mononucleosis: years of life and does not cause clinically important - Incubation period: 4-7 weeks; illness. However, if primary infection is delayed - Febrile episodes are associated with pharyngitis, typically symmetric until adolescence or beyond, it is associated with the lymphadenopathy, and fatigue. Urticarial and maculopapular rashes clinical syndrome of infectious mononucleosis (76). are rare except among those patients given beta-lactam antibiotics Very rarely, patients, particularly children, suffer erroneously, 90% of whom will develop a rash (78). from severe and recurrent or persistent symptoms. These can be associated with a persistently high EBV load and a failure in the normal maturation of the antibody response. Different systemic type EBV infection-associated lymphoproliferative diseases have been reported (77).

Cytomegalovirus (CMV) The infection is usually asymptomatic in In immunocompetent hosts, the most common clinical presentation is immunocompetent individuals but it can cause severe mononucleosis-like syndrome (CMV mononucleosis). diseases in immunocompromised patients and pregnant women, inducing congenital infection (79).

Parvovirus B19 Parvovirus B19V is transmitted mainly by the Febrile episodes are associated with , headache, and respiratory route. As infection causes acute anaemia rather than respiratory symptoms. (transient aplastic crisis) when the patient’s bone marrow is susceptible because of underlying erythroid stress, anaemia is chronic (pure red blood cell aplasia) when the immune system fails to mount a neutralising antibody response (80).

S-18 Clinical and Experimental Rheumatology 2018 Fever of unknown origin / L. Attard et al.

Table VI. continued

Pathogenesis Fever pattern and associated symptoms

Fungi Histoplasmosis Among clinical forms of Histoplasma capsulatum Fever-associated symptoms include, night sweats, weight loss, and infection, a Chronic disseminated histoplasmosis fatigue. Hepatosplenomegaly is found in 89% of infants. Chest has been described. Patients often experience radiographs are characterised by lobar or diffuse infiltrates, cavitation symptoms for months before being diagnosed (81). and/or hilar adenopathy. However, a normal chest X-ray has been reported in 40% to 50% of immunocompromised patients.

Coccidioidomycosis , also known as Valley fever, The primary infection may present with fever, weight loss, sweating, is an infection caused by inhalation of Coccidioides cough, and chest pain. Other symptoms may include arthralgia and spp. spores (82). cutaneous manifestations, such as erythema nodosum and .

Blastomycosis Clinical characteristics of granulomatous Fever and poor oral intake were more likely in patients with Blastomyces spp. infection can include asymptomatic pulmonary infection than in those with extrapulmonary infection, infection, pulmonary infection, or extrapulmonary respectively. disease (bone, genitourinary, cutaneous, and central nervous system infections) (83).

Parasites Malaria (Plasmodium spp.) Malaria is transmitted among humans by female - Quotidian fever with a 24-hour periodicity for Plasmodium falciparum mosquitoes of the genus Anopheles: in sub-Saharan or P. knowlesi malaria Africa, Plasmodium falciparum is the predominant - Tertian fever with a 48-hour periodicity for P. vivax or P. ovale malaria Plasmodium species; P. vivax is the most prevalent - Quartan fever with a 72-hour periodicity for P. malariae malaria outside Africa. The clinical manifestations of malaria, In children, symptoms are varied and often mimic other common the severity and course of a clinical attack depends childhood illness particularly gastroenteritis, meningitis/, on the species and strain of the infecting plasmodium or pneumonia. parasite and on characteristics of the child. The Fever is the key symptom, but the characteristic regular tertian and malaria paroxysm results from the lysis of quartan patterns are seen in <25% of children; however, children are parasitised red blood cells and release of merozoites more likely to have high fever (>40°C), which may also lead to febrile into the circulation at the completion of asexual convulsions. reproduction. Fever and chills are accompanied by constitutional symptoms, alternating with periods of fatigue but otherwise relative wellness (84).

Visceral Leishmaniasis (VL) Leishmania and infantum donovani infection Some authors described how clinical and laboratory features of VL (Kala-Azar or Black fever) is transmitted to humans may clearly mimic SLE, mostly for chronic infection (85). by sandflies of Phlebotomus spp. VL manifestations are a consequence of the host immunologic response against the parasite. Splenomegaly (eventually accompanied by hepatomegaly and lymphadenopathy) is secondary to hyperplasia of the infected reticuloendothelial system. Pancytopenia can be explained by hypersplenism, hemophagocytosis, chronic inflammation, and dietary factors.

Oncologic diseases Hodgkin’s lymphoma A classic pattern of Pel-Ebstein fever is characteristic Patient experience fevers which cyclically increase then decrease over of (although not pathognomonic for) Hodgkin’s an average period of one or two weeks (87). lymphoma. Infectious agents need to be considered too (86).

Wilms’ tumor (WT) Wilms’ tumor (nephroblastoma), an embryonal Up to 23% of children present with fever. Most children with Wilms’ malignancy of the kidney, is the most common renal tumor present with an asymptomatic palpable mass found by a parent tumour of childhood, often diagnosed in first years or physician. Abdominal pain, gross haematuria, and hypertension of life (88). could be frequent findings at diagnosis.

Neuroblastoma Neuroblastoma is the third most common paediatric The clinical features of neuroblastoma are non-specific and include tumour in childhood, and 90% of cases are diagnosed abdominal pain, irritability, and arthralgia. Recurrent fever with no by 5 years of age (89). signs of infection is another classic presentation of neuroblastoma. Affected children may present paraneoplastic syndromes as opsomyoclonus at the time of diagnosis.

Pheochromocytoma A pheochromocytoma is a rare, catecholamine- Intermittent fever, chills and weight loss have been reported before the secreting tumour that may precipitate life-threatening diagnosis of a pheochromocytoma by some authors (91). hypertension. The tumour is malignant in 10% of cases but may be cured completely by surgical removal (90).

Clinical and Experimental Rheumatology 2018 S-19 Fever of unknown origin / L. Attard et al.

Table VI. continued

Pathogenesis Fever pattern and associated symptoms

Castleman’s disease Paediatric Castleman’s disease (CD) most commonly Diagnosis of multicentric CD should be considered in children with occurs in the unicentric form, which typically is fever, elevated CRP, and lymphadenopathy who exhibit progression asymptomatic and cured by lymph node excision, and a negative evaluation for bacterial infection, malignancy, and although systemic manifestations are possible. rheumatologic conditions (92). Multicentric CD (rare in paediatric populations) can progress to severe pancytopenia, multiorgan failure, or malignancy.

Inflammatory diseases Inflammatory bowel diseases Among the common causes of recurrent fever, it is In Crohn’s disease, fever may precede the other typical manifestations important to mention Crohn’s disease, especially in of inflammatory bowel disease, such as abdominal discomfort or loose adolescents (93). Microcytic hypochromic anaemia stools, by weeks or months. and growth retardation are useful diagnostic clues (94).

Behçet’s disease (BD) BD is a systemic inflammatory disease with a Recurrent fevers were not significantly associated with the diagnosis variable vasculitis. Paediatric onset is very rare of BD in the cited PEDBD cohort, but they were present in 44% and carries a strong genetic component. (68/156) of patients of the largest prospective cohort to date (95). An international expert consensus has recently proposed new classification criteria for children with BD: three of six items are required to classify a patient as having paediatric BD (95).

Systemic lupus The presentation of lupus in childhood and Constitutional symptoms such as fatigue, fever, and weight loss are erythematosus (SLE) adolescence can be quite variable, similar to that very common (99). in adults with SLE. Fever is not included in latest SLICC (Systemic Lupus International Collaborating Clinics) diagnostic criteria for SLE (2012) (96). Fever could be a clinical presenting feature of childhood-onset SLE, as reported by different authors, ranging from 39% to 71% (97, 98).

Systemic juvenile Systemic juvenile idiopathic arthritis is International League of Associations for Rheumatology (ILAR) idiopathic arthritis (s-JIA) clinically distinct from other types of JIA. criteria have been developed to establish the diagnosis of s-JIA: Quotidian fevers are a classic feature of s-JIA, arthritis in one or more joints with or preceded by fever of at least but only 64% of patients actually present with this 2-weeks duration that is documented to be daily (“quotidian”) for at fever pattern (100). least 3 days and is accompanied by one or more of the following: evanescent (non-fixed) erythematous rash, generalised lymph node enlargement, hepatomegaly and/or splenomegaly, and serositis.

Kawasaki disease (KD) Kawasaki disease must be considered in the Classic clinical criteria to establish the diagnosis of KD comprehend of any child with prolonged intermittent high fever (5 days) and at least four of the following five fever and compatible laboratory features, even in features: (1) Bulbar conjunctival injection, generally without exudate the absence of the classic clinical signs. Prompt and often with limbal sparing; (2) Oral changes: redness of the throat, therapy (a single 2 g/kg dose of intravenous strawberry tongue, redness of the lips, sometimes with bleeding or gamma globulin) is required, because delayed or peeling of the lips; (3) Rash: erythematous maculopapular, unrecognised KD can lead to lifelong heart disease scarlatiniform, or erythema multiforme, sometimes with marked groin or death in previously healthy children. erythema and desquamation; (4) Extremity changes: redness and swelling of the hands and feet during the first week; typical periungual desquamation occurs in the second or third week; (5) Cervical lymphadenopathy 1.5 cm or more in diameter (101).

Kikuchi-Fujimoto disease Kikuchi-Fujimoto disease or histiocytic KFD has an acute or subacute onset, with low-grade fever, upper (KFD) necrotising lymphadenitis is a rare and benign respiratory symptoms and a unilateral cervical lymphadenopathy of cause of lymphadenopathy (102). posterior cervical lymph nodes (with firm, tender or painful enlarged lymph nodes), over a period of 2–3 weeks (103).

FUO: fever of unknown origin; TB: tuberculosis; SLE: systemic lupus erythematosus. mon cause of frequent viral infections absence of “red flags” are crucial in presence of weight lost, or as well as bacterial infections caused deciding the intensity of further inves- asthenia, the presence of pale skin and by pneumococci or Kingella (44). tigations. Moreover, specific signs and mucous membranes, the presence of After obtaining a complete medical symptoms could suggest possible diag- petechiae, generalised lymphadenopa- history, a thorough medical examina- noses and guide the work-up (see Table thy or hepatosplenomegaly, signs of tion will be done. As already pointed IV). The most important “red flags” dehydration, and severe bone pain. out, evaluation of the general appear- for serious conditions are a miserable- If the history and medical evaluation ance of the child and the presence or looking child who refuses to play, the is reassuring, the physician could de-

S-20 Clinical and Experimental Rheumatology 2018 Fever of unknown origin / L. Attard et al. cide to keep the child under observa- cyclic neutropenia and periodic fever necessary to address the different caus- tion and wait for the fever to resolve or with aphthous stomatitis and adenitis es of recurrent fevers. As for FUO, the other signs to appear. In this case, strict syndrome (PFAPA) (42, 45). three main categories of recurrent fe- follow-up is warranted and asking the In cyclic neutropenia, blood neutrophil vers are infections, neoplasia, and au- parents to keep a “fever diary” could counts reach a nadir every 21 days, re- toimmune/inflammatory. It is beyond be a useful tip (42). In the majority of sulting in fever, malaise, mouth ulcers, the scope of this review to describe all cases, some blood-work are asked for, and bacterial infections, most common- these forms, which are summarised in even in conditions that do not appear to ly of the airways (otitis, pneumonia). Table VI. Once the “big three” are ex- be serious. We believe reasonable first- The disease is caused by mutations in cluded, the physician should consider step laboratory investigations should the neutrophil elastase gene (ELANE), the possibility the patient has a mono- include complete blood count, blood which is inherited through an autoso- genic autoinflammatory disease (AID). smear, ESR, CRP, kidney and liver mal dominant pattern and leads to a The characteristics of these syndromes function tests, muscle enzymes, LDH, reduced production and accelerated are reviewed elsewhere in this vol- urinalysis, and, in younger children, apoptosis of myeloid progenitor cells ume. From a general point of view, the urine culture. Other first-level work-up in the bone marrow. In cases of clini- physician should be aware that AIDs should be guided by clinical suspicion cal suspicion, it is necessary to obtain with the differential of recurrent fevers and could include chest x-ray, echo- weekly haemograms of the patient have, as their most striking feature, the cardiography, abdominal ultrasound, consecutively for 6 weeks, in order to recurrence of stereotyped episodes of pharyngeal swab, and urine culture document a drop in neutrophil levels. fever with variable signs of systemic (see Table V). In cases where the medi- Definitive diagnosis is made by gene and multi-organ inflammation. Once cal history is not reassuring or the child testing. Patients usually respond well again, the identification of AIDs re- presents with signs or symptoms of se- to treatment with granulocyte colony- quires a careful evaluation of both his- rious condition, further work-up will stimulating factor (46). tory and clinical details and, if a mono- be decided upon hospital admission, PFAPA syndrome, first described in genic AID is suspected, the next step and guided by the main hypothesis (see 1987, is the most common periodic fe- would be to identify the most probable Table VI). ver in children. Distinctive features of one. For this purpose it is important to PFAPA syndrome are: the recurrence consider: Approach to the child with recurrent of stereotyped episodes of fever plus – The family history: the possible fever: when to suspect an the typical signs of pharyngitis (almost presence of more than one affected autoinflammatory disease 90% of patients), lymphadenopathy individual within a family may be Sometimes the fever becomes a clini- (75% of patients), and oral aphtosis very useful in identifying the in- cal dilemma not because it is without (30% of patients). Other possible signs heritance pattern. Moreover, some an apparent cause, but for its recur- and symptoms are abdominal pain and AIDs are more common within spe- rence. The sentence “my child has al- arthralgia. The episodes are typically cific ethnicities. ways fever” is one of the commonest self-limiting and affected children – The age at onset: this is an important paediatricians could hear in their rou- show normal growth and develop- piece of information to rule out me- tine practice. In the majority of cases, ment. The fever episodes are typically valonate kinase deficiency (MKD), a skilled paediatrician could easily aborted by the prompt administration since this syndrome has not been discuss this statement with the parents of steroids, the disease usually resolves described to have an adult onset. and demonstrate that what the child is spontaneously after a few years, and – The duration of the attacks: each one experiencing is just the normal recur- tonsillectomy is effective in more than of the four main monogenic AIDs rence of infections, as expected in the 90% of children with PFAPA, while it has a characteristic duration of fever paediatric age. For this purpose, it is is probably less effective in adult pa- episodes, and this information will crucial to underline again the impor- tients. Indeed, once believed to be an be of much help in differentiating tance of a “fever diary” and to take exclusively paediatric disease, it is now them. some time to clearly observe the evo- known that PFAPA may also affect – The free interval between the epi- lution of the clinical picture over time, adults (47-49). Although PFAPA was sodes: the extreme regularity of the if there are no “red flags” for danger- considered the only “non-monogenic attack is more typical for PFAPA ous situations. From a practical point periodic fever”, Cheung et al. recently syndrome than monogenic AIDs. of view, when approaching a child performed whole exome sequencing – The sign(s)/symptom(s) that recur with recurrent fever, it may be useful in 82 unrelated PFAPA patients and regularly at every fever episode and to differentiate between “periodic” and identified a frameshift variant in the possibly dominate the clinical pic- “recurrent” fevers. The term “periodic” CARD gene (CARD8-FS); the mutant ture: even though monogenic AIDs refers to a situation where fever epi- CARD8-FS protein was unable to bind show a large overlap of clinical sodes recur very regularly and, to our the NOD domain of the NLRP3 inflam- manifestations, each one of them has knowledge, there are only two clinical masome (50). more specific clinical signs or symp- entities that are true periodic fevers: After ruling out periodic fevers it is toms (for example, monocytic fascii-

Clinical and Experimental Rheumatology 2018 S-21 Fever of unknown origin / L. Attard et al.

tis for TRAPS [TNF receptor-associ- DE LA MOTA C, ALVAREZ-COCA J et al.: phohistiocytosis: the same entities? Curr ated periodic syndrome], - Procalcitonin, a high acute phase reactant Opin Rheumatol 2003; 15: 587-90. in antiepileptic hypersentivity syndrome in 25. LAUTENSCHLAGER S, ITIN PH: [Schnitzler like erythema for FMF, urticaria-like pediatric age. Eur J Paediatr Neurol 2012; syndrome]. Hautarzt 1993; 44: 781-4. rash for CAPS [cryopyrin-associated 16: 200-2. 26. LIPSKER D, VERAN Y, GRUNENBERGER periodic syndrome], and vomiting 10. MULDERS-MANDERS C, SIMON A, BLEEK- F, CRIBIER B, HEID E, GROSSHANS E: The for MKD). If at least one of these ER-ROVERS C: Fever of unknown origin. Schnitzler syndrome. Four new cases and Clin Med (Lond) 2015; 15: 280-4. review of the literature. Medicine (Balti- symptoms is present in the clinical 11. SCIRE CA, CAVAGNA L, PEROTTI C, BRU- more) 2001; 80: 37-44. picture then the clinical diagnosis SCHI E, CAPORALI R, MONTECUCCO C: 27. FEDERICI L, RITTORE-DOMINGO C, KONE- may be quite straightforward. Diagnostic value of procalcitonin meas- PAUT I et al.: A decision tree for genetic urement in febrile patients with systemic diagnosis of hereditary periodic fever in un- Final confirmation will be obtained autoimmune diseases. Clin Exp Rheumatol selected patients. Ann Rheum Dis 2006; 65: with genetic analysis. This approach is 2006; 24: 123-8. 1427-32. relatively easy with some clinical ex- 12. WRIGHT WF, MACKOWIAK PA: Fever of 28. PADEH S, LIVNEH A, PRAS E et al.: Familial perience and in the case of a very typi- Unknown Origin. In: BENNETT JE, DOLIN Mediterranean fever in children presenting R, BLASER MJ, eds. Mandell, Douglas, and with attacks of fever alone. J Rheumatol cal clinical history. Unfortunately, it is Bennett’s Principles and Practice of Infec- 2010; 37: 865-9. not infrequent that, especially in adult tious Diseases, 8th Edition. London, United 29. PADEH S, SHINAR Y, PRAS E et al.: Clinical patients, the disease manifests itself Kingdom: Elsevier Health Sciences, 2015: and diagnostic value of genetic testing in in oligosymptomatic forms. In such 3904. 216 Israeli children with Familial Mediter- 13. HOT A, PÉRARD L, COPPÉRÉ B et al.: Diag- ranean fever. J Rheumatol 2003; 30: 185- cases, the final diagnosis relies on a nostic étiologique des fiévres récurrente à 90. very high index of suspicion and may l’age adulte: a propos de 95 observations. 30. URETEN K, GONULALAN G, AKBAL E et al.: require evaluation by a physician with Rev Med Interne 2006; 27: S289. Demographic, clinical and mutational char- expertise in these diseases. One help- 14. VIDAL E: Fiévres récurrentes non géné- acteristics of Turkish familial Mediterrane- tiques. Rev Med Interne 2006; 27: S261-3. an fever patients: results of a single center in ful measure in identifying patients with 15. BLEEKER-ROVERS CP, VOS FJ, de KLEIJN Central Anatolia. Rheumatol Int 2010; 30: AIDs and in deciding which genetic EM et al.: A prospective multicenter study 911-5. test to run may come from two sets of on fever of unknown origin: the yield of a 31. de KLEIJN EM, KNOCKAERT DC, van der published criteria, developed for chil- structured diagnostic protocol. Medicine MEER JW: Fever of unknown origin: a new (Baltimore) 2007; 86: 26-38. definition and proposal for diagnostic work- dren and adults, and also from the diag- 16. de KLEIJN EM, vandenBROUCKE JP, van up. Eur J Intern Med 2000; 11: 1-3. nostic criteria published by experts in der MEER JW: Fever of unknown origin 32. WING R, DOR MR, McQUILKIN PA: Fever in the field (51-53). (FUO). I A. prospective multicenter study the pediatric patient. Emerg Med Clin North of 167 patients with FUO, using fixed epi- Am 2013; 31: 1073-96. demiologic entry criteria. The Netherlands 33. ANTOON JW, POTISEK NM, LOHR JA: Pedi- Acknowledgments FUO Study Group. Medicine (Baltimore) atric Fever of Unknown Origin. Pediatr Rev The authors acknowledge Dr Melanie 1997; 76: 392-400. 2015; 36: 380-90; quiz 91. Gatt for Health Publishing & Services 17. KNOCKAERT DC: Recurrent fever of un- 34. NIVEN DJ, GAUDET JE, LAUPLAND KB, known origin,. In: CUNHA BA, ed. Fever MRKLAS KJ, ROBERTS DJ, STELFOX HT: Srl, for her English language assistance. of unknown origin New York: Information Accuracy of peripheral thermometers for healthcare, 2007:133-49. estimating temperature: a systematic review References 18. KNOCKAERT DC, VANNESTE LJ, BOBBAE- and meta-analysis. Ann Intern Med 2015; 1. IIKUNI Y, OKADA J, KONDO H, KASHIWA- RS HJ: Recurrent or episodic fever of un- 163: 768-77. ZAKI S: Current fever of unknown origin known origin. Review of 45 cases and sur- 35. El-RADHI AS, PATEL SP: Temperature meas- 1982-1992. Intern Med 1994; 33: 67-73. vey of the literature. Medicine (Baltimore) urement in children with : an evalua- 2. MOURAD O, PALDA V, DETSKY AS: A com- 1993; 72: 184-96. tion. Br J Nurs 2007; 16: 1313-6. prehensive evidence-based approach to 19. KNOCKAERT DC, VANNESTE LJ, VANNESTE 36. NIEHUES T: The febrile child: diagnosis and fever of unknown origin. Arch Intern Med SB, BOBBAERS HJ: Fever of unknown ori- treatment. Dtsch Arztebl Int 2013; 110: 764- 2003; 163: 545-51. gin in the 1980s. An update of the diagnostic 73. 3. KNOCKAERT DC, VANDERSCHUEREN S, spectrum. Arch Intern Med 1992; 152: 51-5. 37. CHUSID MJ: Fever of Unknown Origin in BLOCKMANS D: Fever of unknown origin 20. VANDERSCHUEREN S, KNOCKAERT D, Childhood. Pediatr Clin North Am 2017; in adults: 40 years on. J Intern Med 2003; ADRIAENSSENS T et al.: From prolonged 64: 205-30. 253: 263-75. febrile illness to fever of unknown origin: 38. CHOW A, ROBINSON JL: Fever of unknown 4. PETERSDORF RG, BEESON PB: Fever of un- the challenge continues. Arch Intern Med origin in children: a systematic review. explained origin: report on 100 cases. Medi- 2003; 163: 1033-41. World J Pediatr 2011; 7: 5-10. cine (Baltimore) 1961; 40: 1-30. 21. KAUFMANN Y, MANY A, RECHAVI G et al.: 39. GAETA GB, FUSCO FM, NARDIELLO S: Fe- 5. DURACK DT, STREET AC: Fever of un- Brief report: lymphoma with recurrent cy- ver of unknown origin: a systematic review known origin--reexamined and redefined. cles of spontaneous remission and relapse- of the literature for 1995-2004. Nucl Med Curr Clin Top Infect Dis 1991; 11: 35-51. -possible role of apoptosis. N Engl J Med Commun 2006; 27: 205-11. 6. ARNOW PM, FLAHERTY JP: Fever of un- 1995; 332: 507-10. 40. PIZZO PA, LOVEJOY FH, JR., SMITH DH: known origin. Lancet 1997; 350: 575-80. 22. FAUTREL B, ZING E, GOLMARD JL et al.: Prolonged fever in children: review of 100 7. KNOCKAERT DC: Recurrent fevers of un- Proposal for a new set of classification cri- cases. Pediatrics 1975; 55: 468-73. known origin. Infect Dis Clin North Am teria for adult-onset still disease. Medicine 41. STATLER VA, MARSHALL GS: Characteris- 2007; 21: 1189-211, xi. (Baltimore) 2002; 81: 194-200. tics of Patients Referred to a Pediatric In- 8. BONACI-NIKOLIC B, JEREMIC I, NIKOLIC 23. MERT A, OZARAS R, TABAK F et al.: Fever fectious Diseases Clinic With Unexplained M, ANDREJEVIC S, LAVADINOVIC L: High of unknown origin: a review of 20 patients Fever. J Pediatric Infect Dis Soc 2016; 5: procalcitonin in a patient with drug hyper- with adult-onset Still’s disease. Clin Rheu- 249-56. sensitivity syndrome. Intern Med 2009; 48: matol 2003; 22: 89-93. 42. MARSHALL GS: Prolonged and recurrent 1471-4. 24. GROM AA: Macrophage activation syn- fevers in children. J Infect 2014; 68 (Suppl. 9. CANTARIN-EXTREMERA V, CASTANO- drome and reactive hemophagocytic lym- 1): S83-93.

S-22 Clinical and Experimental Rheumatology 2018 Fever of unknown origin / L. Attard et al.

43. KLEIMAN MB: The complaint of persistent 59. HUSAIN Z, REDDY BY, SCHWARTZ RA: nucleosis and Epstein-Barr virus. Expert fever. Recognition and management of DRESS syndrome: Part I. Clinical perspec- Rev Mol Med 2004; 6: 1-16. pseudo fever of unknown origin. Pediatr tives. J Am Acad Dermatol 2013; 68: 693 77. IMASHUKU S: Systemic type Epstein-Barr Clin North Am 1982; 29: 201-8. e1-14; quiz 706-8. virus-related lymphoproliferative diseases 44. YAGUPSKY P, PORSCH E, ST GEME JW, 3rd: 60. CASARIN COSTA JR, VIRGENS AR, MESTRE in children and young adults: challenges for Kingella kingae: an emerging pathogen in LO et al.: Sweet Syndrome. J Cutan Med pediatric hemato-oncologists and infectious young children. Pediatrics 2011; 127: 557- Surg 2017: 1203475417690719. disease specialists. Pediatr Hematol Oncol 65. 61. JEFFREY MODELL FOUNDATION. Available 2007; 24: 563-8. 45. GATTORNO M, CAORSI R, MEINI A et al.: from: http://www.info4pi.org. Accessed: 78. PULLEN H, WRIGHT N, MURDOCH JM: Differentiating PFAPA syndrome from mo- June 2017. Hypersensitivity reactions to antibacterial nogenic periodic fevers. Pediatrics 2009; 62. EISENDRATH SJ, FEDER A: Management of drugs in infectious mononucleosis. Lancet 124: e721-8. factitious disorder. In: FELDMAN MD, EI- 1967; 2: 1176-8. 46. DALE DC, WELTE K: Cyclic and chronic SENDRATH SJ, eds. The Spectrum of Facti- 79. ZEDTWITZ-LIEBENSTEIN K, DIAB-ELSCH- neutropenia. Cancer Treat Res 2011; 157: tious Disorders Washington, DC: American AHAW M, FRASS M: Human Cytomegalovi- 97-108. Psychiatric Press, 1996: 195-213. rus Infection in Nonimmunocompromised 47. CATTALINI M, SOLIANI M, RIGANTE D et 63. ELWYN TS, AHMED I, FELDMAN MD: Patients: A Retrospective Analysis and Re- al.: Basic Characteristics of Adults with Factitious Disorder Imposed on Self view of the Literature. Intervirology 2016; Periodic Fever, Aphthous Stomatitis, Phar- (Munchausen’s Syndrome). 2016. Avail- 59: 159-62. yngitis, and Adenopathy Syndrome in Com- able from: http://emedicine.medscape.com/ 80. QIU J, SODERLUND-VENERMO M, YOUNG parison with the Typical Pediatric Expres- article/291304-overview. Accessed: June NS: Human Parvoviruses. Clin Microbiol sion of Disease. Mediators Inflamm 2015; 2017. Rev 2017; 30: 43-113. 2015: 570418. 64. KUMAR YP, AGRAWAL J, MOHANLAKSHMI 81. FISCHER GB, MOCELIN H, SEVERO CB, OLI- 48. VIGO G, ZULIAN F: Periodic fevers with J, KUMAR PS: Langerhans cell histiocytosis VEIRA FDE M, XAVIER MO, SEVERO LC: aphthous stomatitis, pharyngitis, and adeni- revisited: Case report with review. Contemp Histoplasmosis in children. Paediatr Respir tis (PFAPA). Autoimmun Rev 2012; 12: 52- Clin Dent 2015; 6: 432-6. Rev 2009; 10: 172-7. 5. 65. TOKITA N, SEKHAR HK, SACHS M, DALY 82. CENTERS FOR DISEASE C, PREVENTION: 49. VITALE A, ORLANDO I, LOPALCO G et al.: JF: Familial dysautonomia (Riley-Day syn- Increase in reported coccidioidomycosis- Demographic, clinical and therapeutic drome). Temporal bone findings and otolar- -United States, 1998-2011. MMWR Morb findings in a monocentric cohort of adult yngological manifestations. Ann Otol Rhi- Mortal Wkly Rep 2013; 62: 217-21. patients with suspected PFAPA syndrome. nol Laryngol Suppl 1978; 87: 1-12. 83. FROST HM, ANDERSON J, IVACIC L, MEECE Clin Exp Rheumatol 2016; 34 (Suppl. 102): 66. McGREGOR AC, MOORE DA: Infectious J: Blastomycosis in Children: An Analysis S77-81. causes of fever of unknown origin. Clin of Clinical, Epidemiologic, and Genetic 50. CHEUNG MS, THEODOROPOULOU K, LU- Med (Lond) 2015; 15: 285-7. Features. J Pediatric Infect Dis Soc 2017; 6: GRIN J, MARTINON F, BUSSO N, HOFER M: 67. ULUG M, YAMAN Y, YAPICI F, CAN-ULUG N: 49-56. Periodic Fever with Aphthous Stomatitis, Clinical and laboratory features, complica- 84. SCHUMACHER RF, SPINELLI E: Malaria in Pharyngitis, and Cervical Adenitis Syn- tions and treatment outcome of brucellosis children. Mediterr J Hematol Infect Dis drome Is Associated with a CARD8 Variant in childhood and review of the literature. 2012; 4: e2012073. Unable To Bind the NLRP3 Inflammasome. Turk J Pediatr 2011; 53: 413-24. 85. SANTANA IU, DIAS B, NUNES EA, ROCHA J Immunol 2017; 198: 2063-9. 68. Brucellosis. Available from: http://www. FA, SILVA FS, JR., SANTIAGO MB: Visceral 51. CANTARINI L, IACOPONI F, LUCHERINI OM mayoclinic.org/diseases-conditions/brucel- leishmaniasis mimicking systemic lupus et al.: Validation of a diagnostic score for losis/symptoms-causes/dxc-20214311. Ac- erythematosus: Case series and a systematic the diagnosis of autoinflammatory diseases cessed: June 2017. literature review. Semin Arthritis Rheum in adults. Int J Immunopathol Pharmacol 69. CUTLER SJ: Relapsing Fever Borreliae: A 2015; 44: 658-65. 2011; 24: 695-702. Global Review. Clin Lab Med 2015; 35: 86. SCHATTNER A, KESHET N: Pel-Ebstein cy- 52. FEDERICI S, SORMANI MP, OZEN S et al.: 847-65. clic fever: not just lymphoma. Am J Med Evidence-based provisional clinical classi- 70. CHANG CC, LEE CJ, OU LS, WANG CJ, 2010; 123: e3. fication criteria for autoinflammatory peri- HUANG YC: Disseminated cat-scratch dis- 87. HILSON AJ: Pel-Ebstein fever. N Engl J Med odic fevers. Ann Rheum Dis 2015; 74: 799- ease: case report and review of the litera- 1995; 333: 66-7. 805. ture. Paediatr Int Child Health 2016; 36: 88. GREEN DM: The diagnosis and management 53. GATTORNO M, SORMANI MP, D’OSUALDO 232-4. of Wilms’ tumor. Pediatr Clin North Am A et al.: A diagnostic score for molecular 71. FOUCAULT C, BROUQUI P, RAOULT D: Bar- 1985; 32: 735-54. analysis of hereditary autoinflammatory tonella quintana characteristics and clinical 89. HATTEN J, McGUFFIN A, MOGUL M: Incon- syndromes with periodic fever in children. management. Emerg Infect Dis 2006; 12: spicuous Presentation of Metastatic Neuro- Arthritis Rheum 2008; 58: 1823-32. 217-23. blastoma. W V Med J 2016; 112: 38-41. 54. CUNHA BA, LORTHOLARY O, CUNHA CB: 72. BOFINGER JJ, SCHLOSSBERG D: Fever of 90. BROUWERS FM, EISENHOFER G, LENDERS Fever of unknown origin: a clinical ap- unknown origin caused by tuberculosis. In- JW, PACAK K: Emergencies caused by pheo- proach. Am J Med 2015; 128: 1138 e1- e15. fect Dis Clin North Am 2007; 21: 947-62, chromocytoma, neuroblastoma, or gangli- 55. TORREGGIANI S, FILOCAMO G, ESPOSITO viii. oneuroma. Endocrinol Metab Clin North S: Recurrent Fever in Children. Int J Mol 73. MIGUEL-GOMEZ L, BAGAZGOITIA L, HER- Am 2006; 35: 699-724, viii. Sci 2016; 17: 448. MOSA-GELBARD A, SANCHEZ-NEILA N, 91. KANG JM, LEE WJ, KIM WB et al.: Systemic 56. SIMONSEN KA, ANDERSON-BERRY AL, DE- LOPEZ-DE PEDRO A, QUINONES-CONEO inflammatory syndrome and hepatic inflam- LAIR SF, DAVIES HD: Early-onset neonatal K: Chronic meningococcemia in an immu- matory cell infiltration caused by an inter- sepsis. Clin Microbiol Rev 2014; 27: 21-47. nocompetent child. J Paediatr Child Health leukin-6 producing pheochromocytoma. 57. GRAHAM PL, 3rd, BEGG MD, LARSON E, 2016; 52: 853-4. Endocr J 2005; 52: 193-8. DELLA-LATTA P, ALLEN A, SAIMAN L: Risk 74. COSTA-PINTO J, MORLEY C, HAUSER S: A 92. SMITH C, LEE-MILLER C, DISHOP MK, COST factors for late onset gram-negative sepsis case of rat bite fever in a 12-year-old boy. J C, WANG M, ASTURIAS EJ: Multicentric in low birth weight infants hospitalized in Paediatr Child Health 2017; 53: 84-6. presenting with fever. J the neonatal intensive care unit. Pediatr In- 75. WALKER JW, REYES LB: Rat Bite Fever: A Pediatr 2014; 165: 1261-5. fect Dis J 2006; 25: 113-7. Case Report and Review of the Literature. 93. ROSEN MJ, DHAWAN A, SAEED SA: Inflam- 58. AMPOFO K: Infectious disease issues in Pediatr Emerg Care 2016: [Epub ahead of matory Bowel Disease in Children and Ado- adoption of young children. Curr Opin print]. lescents. JAMA Pediatr 2015; 169: 1053-60. Pediatr 2013; 25: 78-87. 76. VETSIKA EK, CALLAN M: Infectious mono- 94. MILLER LC, SISSON BA, TUCKER LB,

Clinical and Experimental Rheumatology 2018 S-23 Fever of unknown origin / L. Attard et al.

SCHALLER JG: Prolonged fevers of un- 97. HIRAKI LT, BENSELER SM, TYRRELL PN, al.: International League of Associations for known origin in children: patterns of pres- HEBERT D, HARVEY E, SILVERMAN ED: Rheumatology classification of juvenile idi- entation and outcome. J Pediatr 1996; 129: Clinical and laboratory characteristics and opathic arthritis: second revision, Edmon- 419-23. long-term outcome of pediatric systemic ton, 2001. J Rheumatol 2004; 31: 390-2. 95. KONE-PAUT I, SHAHRAM F, DARCE-BELLO lupus erythematosus: a longitudinal study. 101. ROWLEY AH: The complexities of the diag- M et al.: Consensus classification criteria J Pediatr 2008; 152: 550-6. nosis and management of Kawasaki disease. for paediatric Behçet’s disease from a pro- 98. KING KK, KORNREICH HK, BERNSTEIN BH, Infect Dis Clin North Am 2015; 29: 525-37. spective observational cohort: PEDBD. Ann SINGSEN BH, HANSON V: The clinical spec- 102. DUMAS G, PRENDKI V, HAROCHE J et al.: Rheum Dis 2016; 75: 958-64. trum of systemic lupus erythematosus in Kikuchi-Fujimoto disease: retrospective 96. PETRI M, ORBAI AM, ALARCON GS et al.: childhood. Arthritis Rheum 1977; 20: 287- study of 91 cases and review of the litera- Derivation and validation of the Systemic 94. ture. Medicine (Baltimore) 2014; 93: 372- Lupus International Collaborating Clinics 99. TUCKER LB: Making the diagnosis of sys- 82. classification criteria for systemic lupus temic lupus erythematosus in children and 103. MATHEW LM, KAPILA R, SCHWARTZ RA: erythematosus. Arthritis Rheum 2012; 64: adolescents. Lupus 2007; 16: 546-9. Kikuchi-Fujimoto disease: a diagnostic di- 2677-86. 100. PETTY RE, SOUTHWOOD TR, MANNERS P et lemma. Int J Dermatol 2016; 55: 1069-75.

S-24 Clinical and Experimental Rheumatology 2018