ArticlePDF AvailableLiterature Review

Abstract

Fever of unknown origin (FUO) can be caused by a wide group of diseases, and can include both benign and serious conditions. Since the first definition of FUO in the early 1960's, several updates to the definition, diagnostic and therapeutic approaches have been proposed. This review outlines a case report of an elderly Italian male patient with high fever and migrating arthralgia who underwent many procedures and treatments before a final diagnosis of Adult-onset Still's disease was achieved. This case report highlights the difficulties in diagnosing certain causes of FUO that requires a very high index of suspicion. The main causes of FUO in paediatric and adult patients will be reviewed here, underlying the fact that a physician should also consider the possibility that a patient with FUO may have a monogenic autoinflammatory disease (AID). The identification of AIDs requires a careful evaluation of both history and clinical details that may reveal important clues to identify the correct aetiology. We also provide a comprehensive account of specific signs and symptoms that could suggest possible diagnoses and guide the work-up of FUO and non-genetic periodic fevers in children.
S-10 Clinical and Experimental Rheumatology 2018
1Infectious Diseases Unit, Department
of Medical and Surgical Sciences, Alma
Mater Studiorum University of Bologna;
2Paediatric Clinic, University of Brescia
and ASST Spedali Civili di Brescia, Italy.
Luciano Attard, MD
Marina Tadolini, MD
Domenico Umberto De Rose, MD
Marco Cattalini, MD
Please address correspondence to:
Marina Tadolini, MD,
Via Massarenti 11,
40138 Bologna, Italy.
E-mail: marina.tadolini@unibo.it
Received on November 27, 2017, accepted
on December, 7, 2017.
Clin Exp Rheumatol 2018; 36 (Suppl. 110):
S10-S24.
© Copyright CliniCal and
ExpErimEntal rhEumatology 2018.
Key words: fever of unknown origin,
autoinammatory disease, infections,
malignancies, non-genetic periodic
fevers, non-infectious inammatory
diseases, children.
Funding: This paper is part of a
supplemental issue supported by an
unrestricted grant from Novartis Farma,
Italy through a service agreement with
Health Publishing & Services Srl. Health
Publishing & Services Srl provide
editorial assistance. Article Processing
Charges were also funded by Novartis
Farma, Italy.
Competing interests: M. Cattalini received
speaker’s fees and consultancy honoraria
from AbbVie, Novartis and SOBI. All the
other authors declare no competing
interests.
ABSTRACT
Fever of unknown origin (FUO) can
be caused by a wide group of dis-
eases, and can include both benign
and serious conditions. Since the rst
denition of FUO in the early 1960s,
several updates to the denition, di-
agnostic and therapeutic approaches
have been proposed. This review out-
lines a case report of an elderly Ital-
ian male patient with high fever and
migrating arthralgia who underwent
many procedures and treatments before
a nal diagnosis of Adult-onset Still’s
disease was achieved. This case report
highlights the difculties in diagnosing
certain causes of FUO that requires a
very high index of suspicion. The main
causes of FUO in paediatric and adult
patients will be reviewed here, under-
lying the fact that a physician should
also consider the possibility that a pa-
tient with FUO may have a monogenic
autoinammatory disease (AID). The
identication of AIDs requires a care-
ful evaluation of both history and clini-
cal details that may reveal important
clues to identify the correct aetiology.
We also provide a comprehensive ac-
count of specic signs and symptoms
that could suggest possible diagnoses
and guide the work-up of FUO and
non-genetic periodic fevers in children.
Introduction
Fever of unknown origin (FUO) ac-
counts for around 3% of hospital ad-
missions and has a high impact on
health care systems (1, 2). Indeed,
more than 200 different causes of FUO
have been reported (3).
The rst denition of FUO dates back
to the early 1960’s, when it was dened
by Petersdorf and Beeson as a Body
temperature of more than 38.3°C on
several occasions, lasting for more
than 3 weeks and no diagnosis after
1 week of hospitalisation” (4). Re-
nements to the denition have since
been proposed, including removing the
requirement for in-hospital evaluation
due to an increased sophistication of
outpatient evaluation. Expansion of the
denition has also been suggested to
include sub-categories of FUO. In par-
ticular, in 1991 Durak and Street re-de-
ned FUO into four categories: classic
FUO; nosocomial FUO; neutropenic
FUO; and human immunodeciency
virus (HIV)-associated FUO, and pro-
posed three outpatient visits and re-
lated investigations as an alternative to
1 week of hospitalisation” (5).
In 1997, Arnow and Flaherty updated
the FUO denition and considered the
type of diagnostic panel to be more im-
portant than the duration of investiga-
tions (6). They considered the follow-
ing list to be the “Minimum diagnostic
evaluation to qualify as FUO”: com-
prehensive history; repeated physical
examination; complete blood count, in-
cluding differential and platelet (PLT)
count; routine blood chemistry, includ-
ing lactate dehydrogenase (LDH), bili-
rubin, and liver enzymes; urinalysis,
including microscopic examination;
chest radiograph; erythrocyte sedimen-
tation rate (ESR); antinuclear antibod-
ies; rheumatoid factor; angiotensin
converting enzyme; routine blood cul-
tures (at least three) while not receiv-
ing antibiotics; cytomegalovirus IgM
antibodies or virus detection in blood;
heterophile antibody test in children
and young adults; tuberculin skin test;
computerised tomography (CT) of ab-
domen or radionuclide scan; HIV an-
tibodies or virus detection assay; and,
further evaluation of any abnormalities
detected by the above tests (6).
Following on from this, a number of di-
agnostic algorithms have been proposed.
Notably, the inclusion of 18 uorodeox-
yglucose-positron emission tomography
18F-FDG PET among the investigations
has improved and shortened the diag-
nostic work-up of FUO (7).
Overview of fever of unknown origin in adult
and paediatric patients
L. Attard1, M. Tadolini1, D.U. De Rose2, M. Cattalini2
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Clinical and Experimental Rheumatology 2018
Fever of unknown origin / L. Attard et al.
Case report: an adult patient
An Italian male patient aged 69 years
old, with a mechanical aortic valve, was
admitted to the Internal Medicine ward
due to high fever (up to 39°C) and mi-
grating arthralgia, which had started ten
days prior. Before being admitted, he
had been treated with clarithromycin,
which was stopped due to the occur-
rence of skin rash, and later with amox-
icillin-clavulanate, without resolution
of the fever. At admission he presented
with papular skin rash in the pretibial
region, bilaterally. Blood investiga-
tions showed white blood cells (WBC)
15,600/mmc, PLT count 405,000/mmc,
ESR 114 mm/h, C-reactive protein
(CRP) 29 mg/dl, beta-2 microglobulin
7.8 mg/L, procalcitonin (PCT) 2.2 mg/
dl, LDH 894 U/L; Interferon-gamma
Release Assay (IGRA) test was in-
determinate. Widal test, serology for
Brucella and HIV, human herpesvirus
(HHV)-8, cytomegalovirus (CMV),
Epstein-Barr virus (EBV), hepatitis A
virus, hepatitis B virus (HBV), hepatitis
C virus (HCV), enterovirus, parvovirus
B19, Dengue, Chikungunya, Trepone-
ma, Francisella, Bartonella, Borrelia,
Rickettsia, Coxiella, Leishmania, Toxo-
plasma, Chlamydia, and Mycoplasma
did not show any active infections.
Polymerase chain reaction (PCR) for
HCV, HBV, CMV, EBV, and HHV-
6 were negative. More than 10 blood
cultures for bacteria and mycobacteria
were negative. Chest x-ray, chest and
abdominal CT scan, transthoracic and
transoesophageal echocardiography,
and colonoscopy were all negative.
18F-FDG PET showed multiple me-
diastinal and abdominal lymph nodes
uptake (SUV max 15), diffuse splenic
(SUV max 6.5), and diffuse bone up-
take. Laterocervical lymph node biopsy
and bone marrow biopsy and aspirate
showed non-specic reactive hyperpla-
sia, and immunohistochemistry showed
the predominance of CD8 positive
lymphocytes; PCR for Leishmania and
Mycobacterium tuberculosis, and my-
cobacterial cultures on these samples
were negative.
Soon after admission, the patient was
started on daptomycin, piperacillin-
tazobactam and rifampin due to sus-
pected prosthetic endocarditis, fol-
lowed by normalisation of acute phase
reactants. However, due to a relapse of
these parameters (PCT 62 mg/ml, CRP
27 mg/dl, lactic acid 24 mg/dl, ferritin
6921 ng/ml, LDH 1512 U/L) the pa-
tient was switched to meropenem and
linezolid with apyrexia for 7 days. Fol-
lowing this, the patient experienced a
relapse of fever. Candida spp. was iso-
lated in blood culture, and the patient
was treated with caspofungin. Due to
a recurrence of skin rash on the arms,
legs, and trunk, the patient underwent
skin biopsy, which raised the suspicion
of psoriasis. He was then treated with
topical steroids with fast improvement
of the skin rash. At the same time, fever
and joint pain disappeared and blood
tests were normal. He was then dis-
charged after 35 days in a good clinical
condition with a diagnosis of recurrent
infections due to the onset of psoriatic
arthritis.
Five years later, the patient reported
to the Emergency Department due to
a recurrence of fever (up to 38°C),
night sweats, loss of body weight, and
arthralgia over the previous month.
Before reporting to hospital, he had
been treated with amoxicillin-clavu-
lanate for 6 days without benet. He
complained of a transient rash on the
back. WBC were 16,670/mmc (Neu-
trophils: 93%), CRP 5.93 mg/dl, LDH
600 U/L; chest x-ray was negative. He
was admitted for further investigations:
blood tests showed WBC 20,000/mmc
(Neutrophils: 92%), haemoglobin 10.9
g/dl, beta-2 microglobulin 6.8 mg/L,
PCT 1.9 mg/dl, ferritin 7,500 ng/
ml, and thyroid function was normal.
Two sets of blood cultures were nega-
tive. IGRA test was negative. Widal
test and serology for Brucella and
CMV, Toxoplasma, Chlamydia, Bor-
relia, EBV, HIV, Treponema, Pallidum,
Leptospira, Rickettsia, Bartonella, As-
pergillus, Histoplasma, Coxiella, and
Leishmania ruled out active infections.
CMV DNA PCR and blood smears for
Malaria were negative as was Galacto-
mannan and Cryptococcal antigen on
serum. Abdominal ultrasound was also
negative. 18F-FDG PET showed mild
multiple mediastinal, axillary, and in-
guinal lymph nodes uptake. Transtho-
racic and transoesophageal echocardi-
ography, and colonoscopy were nega-
tive. Chest high-resolution CT showed
bilateral peripheral micronodules and
multiple mediastinal lymphadenopa-
thies. The patient was initially treated
with piperacillin-tazobactam without
effect, and then, due to an impairment
of acute phase reactants (PCT 65 mg/
dl), teicoplanin and uconazole were
added with resolution of fever. The pa-
tient was discharged after 30 days and
referred to the Fever of Unknown Ori-
gin outpatient clinic, Infectious Dis-
ease Unit. At that time he was apyretic;
he reported asthenia and marked loss of
body weight (10 kg over the previous 2
months). WBC were 7,490/mmc (Neu-
trophils: 63%, Eosinophils 9.2%), ESR
92 mm/h, CRP 3.38 mg/dl, beta-2 mi-
croglobulin 8 mg/L, interleukin-6 19.8
ng/ml, serum amyloid A 5.23 mg/dl,
brinogen 405 mg/dl, LDH 525 U/L,
and ferritin 2,370 ng/ml. After 10 days
he reported a recurrence of high fever
and joint pain. According to his clini-
cal history and laboratory features, a
diagnosis of Adult-onset Still’s disease
(AOSD) was formulated based on four
major and three minor Yamaguchi cri-
teria. Antibodies to Strongyloides ster-
coralis were positive and he was treat-
ed with oral ivermectin for 2 days be-
fore starting steroids. After the start of
steroid treatment, the patient achieved
complete recovery after a period of one
month. He did not show any febrile
episodes nor other symptoms while on
steroid treatment.
The diagnostic and therapeutic ap-
proaches carried out in this patient
were particularly aggressive as a blood
stream infection was suspected in con-
sideration of his aortic mechanic valve
and high values of PCT. The sponta-
neous remission of fever (related to
AOSD) was considered twice to be the
effect of antibiotic treatment. Howev-
er, the correct interpretation of signs,
symptoms and lab tests (e.g. hyperfer-
ritinemia) would have spared useless
high cost diagnostic tests, less invasive
procedures and treatments, and would
probably have achieved the nal diag-
nosis much earlier, with signicant ad-
vantage to the individual and a reduced
cost in health resources. Whilst PCT is
considered a strong predictive marker
S-12 Clinical and Experimental Rheumatology 2018
Fever of unknown origin / L. Attard et al.
of bacterial infections, especially sep-
sis, some FUO-causing diseases may
also increase this protein. Among these,
AOSD and DRESS (Drug reaction with
Systemic Symptoms) can dramatically
increase PCT values (8-11).
FUO in adults
Among the causes of FUO in adults, the
so-called “big three” categories are: “in-
fections”, “non-infectious inammatory
diseases (NIID)”, and “malignancies”;
a fourth category, known as “miscella-
neous”, assembles diseases not tting
the previous categories (see Table I)
(12). The rate of undiagnosed FUOs has
dropped from over 75% in the 1930’s to
less than 10% in the 1950s. However,
the rate of FUOs classied as “undiag-
nosed” has increased steadily over the
last decade (12).
According to the trend over time of
fever and acute phase reactants incre-
ment, FUO may be dened as “contin-
uous” or “recurrent”. Recurrent FUO
was dened as classic FUO with fever-
free intervals associated with normali-
sation of acute phase reactants lasting
at least 2 weeks (13, 14).
Recurrent or episodic FUO is probably
the most intriguing subtype of FUO and
the most challenging to diagnose. A re-
current fever pattern is an independent
predictive factor of missed nal diag-
nosis, which is reached in 24-52% of
recurrent FUOs versus 69-82% in con-
tinuous FUOs (15-20).
Recurrent FUO was responsible for
around 18-42% of cases in a large series
of patients with FUO (17). A large num-
ber of patients have a prolonged disease
duration, which may last up to several
years (17). The symptom-free period
may vary from weeks to years.
The so-called “big three” categories
account only for 20-30% of recurrent
FUOs causes (17). Among “infections”,
osteomyelitis, endocarditis, infected
vascular prosthesis, deep seated ab-
scesses, prostatitis, cholangitis, mas-
toiditis, as well as infections by Yers-
inia, Borrelia, Coxiella, Mycobacteria
(tuberculosis and non-tuberculous my-
cobacteria), and malaria due to Plasmo-
dium ovale or P. vivax may present with
a recurrent pattern of FUO (17). Among
“malignancies”, the “Pel-Ebstein fever”
pattern of Hodgkin’s lymphoma and
Non-Hodgkin’s lymphoma (21) is no-
torious, however colon carcinoma may
also be characterised by recurrent fever
(17). As far as “NIIDs” are concerned,
AOSD typically shows a recurrent FUO
Bacterial
1. Subacute endocarditis
2. Abdominal, pelvic and renal
abscess
3. Spondylodiscitis
4. Chronic prostatitis
5. Periapical dental abscess
6. Vascular graft infection
7. Extrapulmonary and miliary
tuberculosis
8. Typhoid fever
9. Bartonellosis
10. Borreliosis
11. Brucellosis
12. Non-tuberculous mycobacteria
13. Q fever
14. Whipple disease
15. Actinomycosis
16. Syphilis
17. Listeriosis
Viral
1. CMV
2. EBV
3. Multicentric Castleman’s
disease
Fungal
1. Histoplasmosis (disseminated)
Parasitic
1. Visceral leishmaniosis
2. Malaria
3. Toxoplasmosis
4. Amoebic abscess
1. AOSD
2. Polymyalgia rheumatica/giant
vessels arteritis
3. Sarcoidosis
4. Polyarteritis nodosa
5. Systemic lupus erythematous
6. Rheumatoid arthritis
7. Small vessels vasculitis
8. Takayasu’s arteritis
9. Kikuchis’ disease
10. Polyarticular gout
11. Behçet’s disease
12. Late-onset rheumatoid arthritis
1. Lymphoma (HL, NHL)
2. Solid tumours (renal cell
carcinoma, hepatocellular
carcinoma, tumour metastatic
to the liver)
3. Myelodysplastic syndrome
4. Leukaemia
5. Atrial myxoma
6. CNS tumours
1. De Quervain thyroiditis
2. Drug fever
3. Factitious fever
4. Inammatory bowel diseases
5. Sweet syndrome
6. Deep vein thrombosis/pulmo-
nary embolism
7. Hypersensitivity pneumonia
8. Schnitzler syndrome
9. Hemophagocytic syndrome
Hereditary AutoInammatory
Diseases (AIDs)
1. Familial Mediterranean fever
(FMF)
2. Tumour necrosis factor
receptor-associated periodic
syndrome (TRAPS)
3. Cryopyrin-associated periodic
syndromes (CAPS)
4. Mevalonate kinase deciency
(MKD)
Table I. Causes of fever of unknown origin in adults [modied from Cunha et al. 2015 (54)].
Main causes of classic FUO in adults
Infections NIID Malignancy Miscellaneous
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 inammatory diseases.
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Clinical and Experimental Rheumatology 2018
Fever of unknown origin / L. Attard et al.
pattern (22, 23); Behçet’s disease and
inammatory bowel disease (IBD) may
also present with recurrent fever (17).
Among the fourth category “miscella-
neous”, recurrent FUO may be related
to hypersensitivity pneumonia and lung
embolism (17), and autoinamma-
tory disorders such as hemophagocytic
lymphohistiocytosis and Schnitzlers
syndrome (24-26). Finally, the heredi-
tary periodic fever syndrome known
as familial Mediterranean fever (FMF)
shows a regular “periodic” succession
of fever together with spikes of acute
phase reactants. The diagnostic work-
up of these diseases needs to include
genetic tests, taking into consideration
that, at least for FMF and especially in
adulthood, the negativity of the avail-
able genetic tests cannot rule out the ge-
netic disease (27-30).
In addition, the so-called “three minor
categories” of FUO (factitious fever,
drug-related fever, and habitual hyper-
thermia), are frequently forgotten by
less experienced clinicians and should
be considered as well as possible causes
of recurrent FUOs. Since these condi-
tions are easy to rule out, they should
always be investigated before starting a
classical FUO work-up (31).
FUO in children
Paediatricians deal everyday with fe-
brile children. Indeed, fever, dened as
a rectal temperature >38.0°C (100.4°F),
is one of the most common reasons for
seeking medical evaluation for chil-
dren and infants, and the most common
cause for which children are brought
to emergency departments (32). In the
majority of cases the cause of fever is
easily identiable with no or few exams
and appropriate treatment is straight-
forward (33). Nonetheless, fever in
children requires special consideration
and in a minority of cases the clinical
picture may be complicated by its per-
sistence in the absence of obvious caus-
es (FUO), or by the recurrence of fever
episodes (recurrent fevers). This review
will focus on the latter two conditions.
An initial consideration for the discus-
sion of fever in children is that meas-
uring the temperature in children can
be difcult, especially when they are
uncooperative or restless. In addition,
parents use different methods to meas-
ure temperature (34). Rectal measure-
ment is preferred in most children,
since it is more accurate than the use
of peripheral thermometers (tympanic
membrane, temporal artery, axillary
Bacterial
1. Abscess
2. Bartonellosis
3. Brucellosis
4. Leptospirosis
5. Mastoiditis
6. Mycoplasma pneumoniae
7. Osteomyelitis
8. Pyelonephritis
9. Rat bite fever
10. Salmonellosis
11. Sinusitis
12. Tuberculosis
13. Non-tuberculous mycobacteria
14. Tularemia
15. Kingella kingae
Viral
1. Cytomegalovirus
2. Epstein-Barr virus
3. Human immunodeciency virus
Fungal
1. Blastomycosis (non-pulmonary)
2. Histoplasmosis (disseminated)
3. Cryptosporidium
Other
1. Leishmaniasis
2. Lymphogranuloma venereum
3. Malaria
4. Psittacosis
5. Q fever
6. Rocky Mountain spotted fever
7. Toxoplasmosis
8. Visceral larva migrans
Oncological
1. Leukaemia
2. Lymphoma
3. Langerhans cell histiocytosis
4. Neuroblastoma
5. Hemophagocytic lymphohistiocytosis
Inflammatory
1. Behçet’s disease
2. Inammatory bowel disease
3. Hyperthyroidism
4. Granulomatosis (with polyangiitis)
5. Juvenile idiopathic arthritis
6. Kawasaki disease
7. Polyarteritis nodosa
8. Sarcoidosis
9. Systemic lupus erythematous (SLE)
10. Antiphospholipid antibody syndrome
11. Subacute thyroiditis
Periodic fever
1. Periodic fevers, aphthous stomatitis, pharyn-
gitis, cervical adenitis (PFAPA)
2. Cyclic neutropenia
Autoinammatory diseases (AIDs)
1. Familial Mediterranean fever (FMF)
2. Tumour necrosis factor Receptor-Associated
Periodic Syndrome (TRAPS)
3. Cryopyrin-associated Periodic Syndromes
(CAPS)
4. Mevalonate Kinase Deciency (MKD)
5. Others (Deciency of the IL-1-receptor an-
tagonist [DIRA]; Majeed syndrome [MS];
Autoinammation with infantile enterocol-
itis [AIEC]; Blau syndrome/early-onset sar-
coidosis; NLRP12-associated autoinamma-
tory disorder; STING-associated vasculopa-
thy with onset in infancy [SAVI])
Other
1. Diabetes insipidus
2. Factitious fever
3. Munchausen’s syndrome by proxy
4. Familial dysautonomia
5. Pancreatitis
6. Serum sickness
7. Kikuchi-Fujimoto disease
8. Drug fever
9. Sweet syndrome
Table II. Causes of fever of unknown origin (FUO) in children [modied from Antoon et
al. 2015 (33) and Chusid 2017 (37)].
Causes of FUO in children
Infectious Causes Non-infectious Causes
S-14 Clinical and Experimental Rheumatology 2018
Fever of unknown origin / L. Attard et al.
Table III. Approach to fever of unknown origin (FUO) in children according to history [modied from Antoon et al. 2015 (33), Chusid
2017 (37), and Torreggiani et al. 2016 (55)].
Duration and pattern of fever
Continuous fever Temperature remains elevated throughout the day but Pneumonia; meningitis; urinary tract infection
does not uctuate more than 1°C in 24 hours.
Remittent fever Temperature remains elevated throughout the day and Endocarditis; Brucellosis; Typhoid infection (Wunderlich’s curve)
uctuates 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 uctuates 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 relapsing fever (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; cyclic neutropenia; 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
uid; maternal swabs; neonatal asphyxia; prematurity (56).
Infants 1–3 months Remember that late-onset sepsis 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 pathology (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, sh, 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 Escherichia coli or Salmonella
cheeses infections
History of pica (ingestion of dirt) Toxocara (visceral larva migrans) infection
Travels: endemic countries for some pathogens
Lyme disease 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)
Visceral leishmaniasis 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-
munodeciency virus, hepatitis B or C, or even malaria or typhoid in their country of origin (58).
S-15
Clinical and Experimental Rheumatology 2018
Fever of unknown origin / L. Attard et al.
or oral) (34, 35), although it may be
contraindicated in some conditions
(i.e. neutropenic, oncologic or immu-
nocompromised children) (36). It is
also important to remember that, in the
normal child, body temperature has a
circadian rhythm, with temperature as
low as 36°C in the early morning and
as high as 37.5°C in the late afternoon
(37). Mean basal temperature also var-
ies according to age, gender, body hab-
itus, time of day, activity level, men-
strual cycle, and other factors (33).
Causes of FUO in children
As already introduced, FUO can be
caused by a wide group of diseases,
including both benign and serious con-
ditions (see Table II). Infections are
the main causes of FUO in children,
accounting for 51% of cases accord-
ing to data from a meta-analysis of 18
studies from industrial countries and
emerging economies (38). Conversely,
malignancy accounts for a higher per-
centage (11%) of FUOs in adults than it
does in children (6%). Rheumatologic
conditions (16%) are also a more im-
portant cause of fever in adults than in
children (9%). It is also important to
note that between 25–30% of children
with FUO remain without a nal diag-
nosis, even after a thorough work-up
and after resolution of the fever (38,
39). When comparing data between de-
veloped and developing nations, infec-
tion is consistently the most common
cause of FUO, but the type of infection
varies; bacterial infections, and Bar-
tonella infections were more common-
ly diagnosed in developed countries,
whereas brucellosis, typhoid fever,
tuberculosis, rickettsial infections, and
abscesses were more common in de-
veloping nations. Viral aetiologies for
FUO were more commonly identied
in the developed countries, particu-
larly Epstein-Barr Virus infection (38).
Among the chronic inammatory and
autoimmune disorders that can present
as FUO, the more common in children
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 inltrated 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
surgery, 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 conrmed or suspected pulmonary, laryngeal, or
pleural tuberculosis.
Suggestive case history ndings
Attack provoked by cold exposure Familial cold autoinammatory syndrome (FCAS)
Attack in the rst year of life, Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS)
typically after a childhood
vaccination
Immunosuppression
Primary immunodeciency When episodes became more severe in frequency and characteristics, different sets of warning signs can be used if a
primary immunodeciency (PID) is suspected. Among these, the 10 warning signs developed by the Jeffrey Modell
Foundation (2009) are the most known (61).
Human Immunodeciency Mycobacteria and cytomegalovirus are opportunistic infections in patients with HIV infection that often cause aspecic
virus (HIV) symptoms, including fever.
Leukaemia and lymphoma Consider constitutional symptoms (as unexplained weight loss, paleness, asthenia, night sweats, itching) and intermittent
fever: 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 ndings, 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: autoinammatory disease; GI: gastrointestinal; NSAIDs: nonsteroidal anti-inammatory drugs; PFAPA: periodic fever, aphthous stomatitis, pharyngi-
tis, cervical adenitis; USA: United States of America.
S-16 Clinical and Experimental Rheumatology 2018
Fever of unknown origin / L. Attard et al.
Table IV. Approach to fever of unknown origin (FUO) in children according to physical examination [modied from Antoon et al. 2015
(33), Chusid 2017 (37), and Torreggiani et al. 2016 (55)].
General appearance
Fatigue 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
Erythema nodosum IBD; JIA; SLE; BD; Parvovirus B19; and various infectious diseases
Eschar Tularemia (Francisella tularensis 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
Rashes or fever blisters Pneumococcal; streptococcal; malarial and rickettsial infections
Seborrheic rash Histiocytosis
Urticarial macular rash Serum sickness; FCAS; Muckle-Wells syndrome; neonatal-onset multisystem inammatory disease
(NOMID)
Eyes
Conjunctivitis Viruses (EBV, Newcastle disease, measles); Kawasaki disease; Leptospirosis; Tuberculosis; SLE
Conjunctivitis associated with fever attacks FCAS
Ischaemic retinopathy Polyarteritis nodosa
Periorbital oedema and conjunctivitis during ares TRAPS
Petechial conjunctival haemorrhage Infective endocarditis
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 inammation and loss of teeth Leukaemia
Hyperemia of the pharynx Infectious mononucleosis; 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 candidiasis Immunodeciencies
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
Lymphadenopathy 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 rheumatic fever; endocarditis
Dyspnea/tachypnea, abnormal breathing sounds Pneumonia; Lung involvement of AIDs; SLE
Heart murmur Endocarditis; Acute rheumatic fever; Pericarditis
Relative bradycardia Brucellosis; drug fever
Abdomen and pelvis
Abdominal pain IBD; FMF; HIDS; TRAPS; Parvovirus B19 infection; relapsing fever
Abdominal tenderness 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; liver abscess
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; Trench fever (Bartonella Quintana infection); chronic meningococcemia;
rat bite fever; brucellosis
AID: autoinammatory 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 autoinammatory syndrome; FMF: familial Mediterranean fever; HIDS:
hyperimmunoglobulinemia D with periodic fever syndrome; HIV: human immunodeciency virus; HSV: Herpes simplex virus; IBD: inammatory 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-17
Clinical and Experimental Rheumatology 2018
Fever of unknown origin / L. Attard et al.
are IBD, and Crohn’s Disease in par-
ticular. Among neoplasia, the more
common causing FUO are lymphoma
and leukaemia. Rheumatic conditions,
such as the systemic form of juvenile
idiopathic arthritis are also a possibil-
ity. There are a lot of miscellaneous
and rare causes of FUO, including drug
fever, dysautonomia, diabetes insipi-
dus, ectodermal dysplasia, pulmonary
embolus, and haematoma (40).
It is reassuring to observe that, in a
retrospective study published in 2016,
the majority of children referred to a
Paediatric Infectious Disease outpa-
tient service for unexplained fevers
did not have a serious illness (41). In
fact, 95% of 221 included patients had
no fever, self-limited illnesses, condi-
tions for which no specic diagnosis
was made (but fevers resolved), or
mild-to-moderate illnesses (which may
or may not have warranted treatment).
Similarly, only 1 patient in this study
was diagnosed with a malignancy, in
contrast to a number and variety of
malignancies seen in earlier studies.
This discrepancy could be secondary
to the fact that most of the studies on
FUO, from which epidemiological data
are retrieved, are based exclusively on
inpatient populations. In other words,
it is very important to consider that in
everyday clinical practice the presence
of a child with FUO could be much less
worrisome than what is known from
the literature (41). One crucial point
is to carefully consider the general ap-
pearance of the child presenting for
FUO: the presence or absence of signs
of systemic involvement and the pres-
ence or absence of “red ags” (as will
be discussed later) for serious condi-
tions should dictate the pace of further
work-up (42).
Approach to the child with FUO
As already pointed out, the rst use-
ful step in approaching a child with
FUO is to try to differentiate between
the “big three” categories of causes.
A thorough medical history could be
very useful, revealing important clues
to identify the correct aetiology (see
Table III). Medical history should look
not only for the obvious, such as his-
tory of travel, animal contacts etc., but
also to information that are often over-
looked, such as how the temperature
was taken, how many fever spikes the
child has during the day, whether the
fever spike is accompanied by signs or
symptoms, etc. Frequently, an accurate
history review by an experienced cli-
nician can result in rapid diagnosis of
a previously perplexing case (37). For
example, a child who appears to have
had an extended febrile illness may
simply be experiencing a consecutive
series of self-limited minor infections
(“Pseudo-FUO”) (42, 43). This is es-
pecially likely if the child is attending
school for the rst time or has older
siblings who bring home infectious
agents. Daycare attendance is a com-
Table V. Work-up of fever of unknown origin in paediatric patients.
First level work-up
Complete blood count with differential count; peripheral blood swear
C-reactive protein; ESR; ferritin; procalcitonin
Renal and hepatic function tests; LDH
Urine: routine and microscopy examination with culture
Throat swab culture
Mantoux intradermal or IGRA test
Cardiologic evaluation with echocardiography
Abdominal ultrasound
Chest X-ray (to rule out inltrates, effusions, or enlarged hilar lymph nodes)
Second level/Categorical work-up
Infectious diseases Specic antibody or molecular test for EBV, CMV, Toxoplasma,
Parvovirus, HIV, Salmonella, Brucella, Bartonella, Yersinia, Borre-
lia, Leishmania;
• Blood culture (including quantitative cultures drawn from central
catheters and peripheral veins);
• Stool culture;
• Cerebrospinal uid culture if indicated;
• Thick and thin blood smears for malaria;
• Whole-body Tc-99m MDP bone scan for suspected bone infection;
• Head MRI for suspected central nervous system infections.
Oncologic diseases • Bone marrow biopsy and aspiration when malignancy is suspected;
• 24-hour urine collection for total catecholamines, vanillylmandelic
acid, and metanephrines, and blood pressure/heart rate monitoring
for suspected pheochromocytoma;
• Uric acid for suspected leukaemia and lymphoma (consider tumour
lysis syndrome);
• Chest-abdomen-pelvic CT scan for suspected masses (or pyogenic
collections) and related enlarged lymph nodes;
• Positron emission tomography/computerised tomography (PET/
CT) in order to detect neoplasms, infections and inammation.
Autoimmune/Rheumatological • Antinuclear antibodies, extractable nuclear antigens antibodies,
disorders anti-native DNA antibodies wherever an arthritis is suspected;
• C3, C4, CH50;
• Thyroid function tests.
Immunodeciency Immunoglobulins and lymphocyte surface marker analysis for hu-
moral and cellular immunodeciencies;
• Consider antibody titres to known vaccinations;
• Assessment of neutrophil function (e.g. Dihydrorhodamine 123).
Gastrointestinal • Upper GI series and barium enema to detect changes or abnormali-
ties in oesophagus, stomach, duodenum, and colon;
• Bowel ultrasound for the assessment of Crohn’s disease
• EGD test (esophagogastroduodenoscopy) and colonoscopy with bi-
opsies in order to detect inammatory GI disorders;
• ASCA, ANCA, LKM, ASMA antibodies for suspected inamma-
tory GI disorders.
ANCA: anti-neutrophil cytoplasmic antibodies; ASCA: anti-Saccharomyces cerevisiae antibodies;
ASMA: anti-smooth muscle antibody; CT: computed tomography; EBV: Epstein-Barr virus; ESR:
erythrocyte sedimentation rate; GI: gastrointestinal; HIV: human immunodeciency virus; LDH: lac-
tate dehydrogenase; LKM: liver kidney microsome; MDP: methylene diphosphonate; MRI: Magnetic
resonance imaging.
S-18 Clinical and Experimental Rheumatology 2018
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 difculty 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.
streptococcus) (66).
Brucellosis Brucellosis is caused by ingestion of unpasteurised Brucella melitensis:
milk or undercooked meat from infected animals, - Incubation period: 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 body louse, 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 Bartonella henselae, 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
headache, 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 conrmation is difcult. 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 deciency (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, chills, 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 rst 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 malaise, headache, and myalgia
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-19
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 inltrates, 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 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 erythema
multiforme.
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/encephalitis,
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 sandies 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 inammation, 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 rst years or physician. Abdominal pain, gross haematuria, and hypertension
of life (88). could be frequent ndings at diagnosis.
Neuroblastoma Neuroblastoma is the third most common paediatric The clinical features of neuroblastoma are non-specic 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).
S-20 Clinical and Experimental Rheumatology 2018
Fever of unknown origin / L. Attard et al.
mon cause of frequent viral infections
as well as bacterial infections caused
by pneumococci or Kingella (44).
After obtaining a complete medical
history, a thorough medical examina-
tion will be done. As already pointed
out, evaluation of the general appear-
ance of the child and the presence or
absence of “red ags” are crucial in
deciding the intensity of further inves-
tigations. Moreover, specic signs and
symptoms could suggest possible diag-
noses and guide the work-up (see Table
IV). The most important “red ags”
for serious conditions are a miserable-
looking child who refuses to play, the
presence of weight lost, anorexia or
asthenia, the presence of pale skin and
mucous membranes, the presence of
petechiae, generalised lymphadenopa-
thy or hepatosplenomegaly, signs of
dehydration, and severe bone pain.
If the history and medical evaluation
is reassuring, the physician could de-
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.
Inammatory diseases
Inammatory 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 inammatory 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 inammatory disease with a Recurrent fevers were not signicantly 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 classication 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-xed) 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
differential diagnosis of any child with prolonged intermittent high fever (5 days) and at least four of the following ve
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 rst 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 rm, 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.
S-21
Clinical and Experimental Rheumatology 2018
Fever of unknown origin / L. Attard et al.
cide to keep the child under observa-
tion and wait for the fever to resolve or
other signs to appear. In this case, strict
follow-up is warranted and asking the
parents to keep a “fever diary” could
be a useful tip (42). In the majority of
cases, some blood-work are asked for,
even in conditions that do not appear to
be serious. We believe reasonable rst-
step laboratory investigations should
include complete blood count, blood
smear, ESR, CRP, kidney and liver
function tests, muscle enzymes, LDH,
urinalysis, and, in younger children,
urine culture. Other rst-level work-up
should be guided by clinical suspicion
and could include chest x-ray, echo-
cardiography, abdominal ultrasound,
pharyngeal swab, and urine culture
(see Table V). In cases where the medi-
cal history is not reassuring or the child
presents with signs or symptoms of se-
rious condition, further work-up will
be decided upon hospital admission,
and guided by the main hypothesis (see
Table VI).
Approach to the child with recurrent
fever: when to suspect an
autoinammatory disease
Sometimes the fever becomes a clini-
cal dilemma not because it is without
an apparent cause, but for its recur-
rence. The sentence “my child has al-
ways fever” is one of the commonest
paediatricians could hear in their rou-
tine practice. In the majority of cases,
a skilled paediatrician could easily
discuss this statement with the parents
and demonstrate that what the child is
experiencing is just the normal recur-
rence of infections, as expected in the
paediatric age. For this purpose, it is
crucial to underline again the impor-
tance of a “fever diary” and to take
some time to clearly observe the evo-
lution of the clinical picture over time,
if there are no “red ags” for danger-
ous situations. From a practical point
of view, when approaching a child
with recurrent fever, it may be useful
to differentiate between “periodic” and
“recurrent” fevers. The term “periodic”
refers to a situation where fever epi-
sodes recur very regularly and, to our
knowledge, there are only two clinical
entities that are true periodic fevers:
cyclic neutropenia and periodic fever
with aphthous stomatitis and adenitis
syndrome (PFAPA) (42, 45).
In cyclic neutropenia, blood neutrophil
counts reach a nadir every 21 days, re-
sulting in fever, malaise, mouth ulcers,
and bacterial infections, most common-
ly of the airways (otitis, pneumonia).
The disease is caused by mutations in
the neutrophil elastase gene (ELANE),
which is inherited through an autoso-
mal dominant pattern and leads to a
reduced production and accelerated
apoptosis of myeloid progenitor cells
in the bone marrow. In cases of clini-
cal suspicion, it is necessary to obtain
weekly haemograms of the patient
consecutively for 6 weeks, in order to
document a drop in neutrophil levels.
Denitive diagnosis is made by gene
testing. Patients usually respond well
to treatment with granulocyte colony-
stimulating factor (46).
PFAPA syndrome, rst described in
1987, is the most common periodic fe-
ver in children. Distinctive features of
PFAPA syndrome are: the recurrence
of stereotyped episodes of fever plus
the typical signs of pharyngitis (almost
90% of patients), lymphadenopathy
(75% of patients), and oral aphtosis
(30% of patients). Other possible signs
and symptoms are abdominal pain and
arthralgia. The episodes are typically
self-limiting and affected children
show normal growth and develop-
ment. The fever episodes are typically
aborted by the prompt administration
of steroids, the disease usually resolves
spontaneously after a few years, and
tonsillectomy is effective in more than
90% of children with PFAPA, while it
is probably less effective in adult pa-
tients. Indeed, once believed to be an
exclusively paediatric disease, it is now
known that PFAPA may also affect
adults (47-49). Although PFAPA was
considered the only “non-monogenic
periodic fever”, Cheung et al. recently
performed whole exome sequencing
in 82 unrelated PFAPA patients and
identied a frameshift variant in the
CARD gene (CARD8-FS); the mutant
CARD8-FS protein was unable to bind
the NOD domain of the NLRP3 inam-
masome (50).
After ruling out periodic fevers it is
necessary to address the different caus-
es of recurrent fevers. As for FUO, the
three main categories of recurrent fe-
vers are infections, neoplasia, and au-
toimmune/inammatory. It is beyond
the scope of this review to describe all
these forms, which are summarised in
Table VI. Once the “big three” are ex-
cluded, the physician should consider
the possibility the patient has a mono-
genic autoinammatory disease (AID).
The characteristics of these syndromes
are reviewed elsewhere in this vol-
ume. From a general point of view, the
physician should be aware that AIDs
with the differential of recurrent fevers
have, as their most striking feature, the
recurrence of stereotyped episodes of
fever with variable signs of systemic
and multi-organ inammation. Once
again, the identication of AIDs re-
quires a careful evaluation of both his-
tory and clinical details and, if a mono-
genic AID is suspected, the next step
would be to identify the most probable
one. For this purpose it is important to
consider:
The family history: the possible
presence of more than one affected
individual within a family may be
very useful in identifying the in-
heritance pattern. Moreover, some
AIDs are more common within spe-
cic ethnicities.
The age at onset: this is an important
piece of information to rule out me-
valonate kinase deciency (MKD),
since this syndrome has not been
described to have an adult onset.
The duration of the attacks: each one
of the four main monogenic AIDs
has a characteristic duration of fever
episodes, and this information will
be of much help in differentiating
them.
The free interval between the epi-
sodes: the extreme regularity of the
attack is more typical for PFAPA
syndrome than monogenic AIDs.
The sign(s)/symptom(s) that recur
regularly at every fever episode and
possibly dominate the clinical pic-
ture: even though monogenic AIDs
show a large overlap of clinical
manifestations, each one of them has
more specic clinical signs or symp-
toms (for example, monocytic fascii-
S-22 Clinical and Experimental Rheumatology 2018
Fever of unknown origin / L. Attard et al.
tis for TRAPS [TNF receptor-associ-
ated periodic syndrome], erysipelas-
like erythema for FMF, urticaria-like
rash for CAPS [cryopyrin-associated
periodic syndrome], and vomiting
for MKD). If at least one of these
symptoms is present in the clinical
picture then the clinical diagnosis
may be quite straightforward.
Final conrmation will be obtained
with genetic analysis. This approach is
relatively easy with some clinical ex-
perience and in the case of a very typi-
cal clinical history. Unfortunately, it is
not infrequent that, especially in adult
patients, the disease manifests itself
in oligosymptomatic forms. In such
cases, the nal diagnosis relies on a
very high index of suspicion and may
require evaluation by a physician with
expertise in these diseases. One help-
ful measure in identifying patients with
AIDs and in deciding which genetic
test to run may come from two sets of
published criteria, developed for chil-
dren and adults, and also from the diag-
nostic criteria published by experts in
the eld (51-53).
Acknowledgments
The authors acknowledge Dr Melanie
Gatt for Health Publishing & Services
Srl, for her English language assistance.
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... The recent literature shows that, in developing countries, the cause of FUO remains primarily infectious due to several factors: the increased prevalence of certain infections causing FUO, such as human immunodeficiency virus (HIV), tuberculosis, leishmaniasis, and malaria; the highest proportion of vaccine-preventable diseases; and reduced public health prevention's programs, poor access to healthcare facilities, and reduced availability of diagnostic tests [28,29]. In addition, the inadequate knowledge and diagnostic capacity of some recent causes, such as hemophagocytic lymphohistiocytosis (HLH), limit the share of noninfectious forms [3]. ...
... According to a recent Chinese study of 1288 cases of FUO, the share due to infectious diseases decreases with increasing age from 73% to 44%, and bacterial infections are the main cause in children below 1 year of age, while viral infections are between 1 and 6 years [27]. Neoplastic or autoimmune diseases become more frequent at later ages [22,28]. This trend is also confirmed by Yachie et al., who compared the causes of FUO in children and adulthood when autoimmune and neoplastic forms are more represented [31]. ...
... Finally, it is necessary to carefully look for signs of localization to reveal infectious diseases of organs or systems, such as abdominal abscesses, pyelonephritis, osteomyelitis, pyomyositis, etc., requiring immediate medical and/or surgical interventions. Certainly, the presence of some signs and symptoms, such as weight loss, night sweats, itching, asthenia, pallor, petechiae, and the deterioration of general conditions, as well as the simple refusal to play, represents alarm signals, so-called "red flags", which require a rapid and thorough diagnostic workup [6,28]. It is useful to emphasize the need to repeat the physical examination several times to re-evaluate or appreciate new or modified clinical signs compared to the first evaluation; this repetition is essential, as up to 25% of signs appear after the first assessment [8]. ...
Article
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Fever of unknown origin (FUO) can be caused by four etiological categories of diseases. The most common cause of FUO in children is represented by infections, followed by inflammatory conditions and neoplastic causes; a decreasing quote remains still without diagnosis. Despite the fact that several diagnostic and therapeutic approaches have been proposed since the first definition of FUO, none of them has been fully validated in pediatric populations. A focused review of the patient’s history and a thorough physical examination may offer helpful hints in suggesting a likely diagnosis. The diagnostic algorithm should proceed sequentially, and invasive testing should be performed only in select cases, possibly targeted by a diagnostic suspect. Pioneering serum biomarkers have been developed and validated; however, they are still far from becoming part of routine clinical practice. Novel noninvasive imaging techniques have shown promising diagnostic accuracy; however, their positioning in the diagnostic algorithm of pediatric FUO is still not clear. This narrative review aims to provide a synopsis of the existent literature on FUO in children, with its major causes and possible diagnostic workup, to help the clinician tackle the complex spectrum of pediatric FUO in everyday clinical practice.
... Some of the common investigations performed in FUO include complete blood count (hemoglobin, platelet, and leukocyte count), CRP, ESR, blood chemistry, urine tests (microscopic, culture, and sensitivity), and chest x-rays [8,9]. According to Arnow and Flaherty, additional laboratory tests should be performed for this condition to meet the minimal diagnostic evaluation criteria and qualify as FUO [10]. Any abnormalities detected in those tests are investigated in detail [10]. ...
... According to Arnow and Flaherty, additional laboratory tests should be performed for this condition to meet the minimal diagnostic evaluation criteria and qualify as FUO [10]. Any abnormalities detected in those tests are investigated in detail [10]. However, the absence of any established cut-off value related to laboratory parameters limits the clinical usefulness of these investigations for the evaluation of FUO. ...
... The diagnosis of CAPS often presents several difficulties, and the diagnostic delay can be consistent. Despite the early disease onset, in large case series, the mean diagnostic delay is 14 years (4,11). In this regard, the absence of specific serum biomarkers and the low sensibility of the genetic testing (high percentage of patients without NLRP3 mutations) explain the importance of the physician's awareness. ...
... In the described case, although the patient presented clinical and laboratory features suggestive of CAPS (and, specifically, CINCA syndrome), the diagnosis was complicated by the incomplete disease expression at disease onset. Specifically, the absence of hearing impairment, which is one of the most relevant warning signs of CINCA (11), could partly explain the initial diagnostic delay. ...
Article
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Chronic infantile neurological cutaneous articular (CINCA) syndrome is an autoinflammatory disease encompassed in the group of cryopyrin-associated periodic syndromes (CAPS). Patients suffering from CINCA have an elevated risk of developing chronic sequelae, including deforming arthropathy, chronic meningitis, neurodevelopmental delay, and neurosensorial hearing loss. The diagnosis of CINCA presents several difficulties, as the clinical phenotype could be difficult to recognize, and almost half of the patients have negative genetic testing. In this paper, we describe the case of a patient presenting with the typical phenotype of neonatal-onset CINCA who resulted negative for NLRP3 mutations. Based on the clinical judgment, the patient underwent treatment with anti-interleukin-1 (IL-1) agents (anakinra and, later, canakinumab) resulting in a complete clinical and laboratory response that allowed confirmation of the diagnosis. Additional genetic investigations performed after the introduction of anti-IL-1 therapy revealed a pathogenic mosaicism in the NLRP3 gene. After a 12-year follow-up, the patient has not experienced chronic complications. Although genetics is rapidly progressing, this case highlights the importance of early diagnosis of CINCA patients when the clinical and laboratory picture is highly suggestive in order to start the appropriate anti-cytokine treatment even in the absence of a genetic confirmation.
... Menurut National Association of Pediatrics Nurse (NAPN), demam pada bayi berusia kurang dari 3 bulan terjadi jika suhu rektalnya melebihi 38°C. Sedangkan pada anak berusia lebih dari 3 bulan, suhu aksila atau oralnya lebih dari 38,3°C [3], [4]. ...
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Background: Paracetamol, a widely used analgesic and antipyretic medication, is commonly prescribed in government healthcare facilities. The FTIR method provides rapid measurements by analyzing spectral graphs that reveal the functional groups within the tested compounds. According to the Indonesian Pharmacopoeia, VI Edition 2020, paracetamol content in tablet formulations must range between 90.0% and 110.0%. Objective: This study aimed to evaluate the paracetamol content in tablet preparations and assess their compliance with the 2020 Indonesian Pharmacopoeia standards and the packaging labels. Method: The research was conducted experimentally using FTIR spectroscopy. A solvent mixture of ethanol and distilled water (1:1) was employed, with analyses performed over the wavelength range of 4000–400 cm⁻¹. Results: The paracetamol content was found to be highest in tablet B (100.33 ± 1.003%), followed by tablet A (100.29 ± 1.002%), tablet D (100.24 ± 1.002%), and tablet E (100.14 ± 1.001%), with the lowest levels observed in tablet C (99.69 ± 0.996%). Method validation indicated an RSD value of 0.056%, confirming that the procedure was accurate and reliable. Conclusion: The findings demonstrate that the FTIR method is suitable for the quantitative analysis of paracetamol in tablet formulations. Moreover, the results meet the standards outlined in the 2020 VI Edition of the Indonesian Pharmacopoeia.
... 2,9 In endemic areas, brucellosis is among the causes of extended-duration fever and is often categorized as a fever of unknown origin (FUO). 10 Brucella infection occurs more predominantly in individuals having reduced levels of immunity due to stress or diseases like HIV. 11 The diagnostic tests mainly used for brucellosis are the Rose Bengal Test (RBT), Serum Agglutination test (SAT), Standard Tube Agglutination Test (STAT), Enzyme-linked immunosorbent assay (ELISA), and Polymerase chain reaction (PCR). 12, 13 The prevalence of brucellosis among livestock farmers, milkmen, butchers, and veterinary practitioners was reported to be 2.6% (n=386), 18.2% (n=55), 2.5% (n=40), and 5.3% (n=19), respectively. ...
Article
Full-text available
Background: Brucellosis is a common emerging and re-emerging zoonotic disease in animals and humans globally. It has drastically changed over the past decade because of various risk factors, including the drastic growth of animal husbandry, socioeconomic, political, and global trade, travel, and immigration. Domestic animals are a natural reservoir of Brucella spp., and animal-to-human transmission occurs through the consumption of raw milk and milk products; however, it is recognized as an occupational disease of veterinarians, animal farmers, and abattoir workers as they handle infected animals and aborted fetuses or placentae. Surveillance and epidemiology of domestic animals and humans are urgently needed to eradicate this zoonotic disease effectively nationally and globally. Although serological data on the prevalence of brucellosis in different domestic animals have been reported, studies on the seroprevalence of human brucellosis are very limited in Bangladesh. Objective: A cross-sectional survey was conducted to estimate seroprevalence and risk factors of human brucellosis among high-risk individuals of Mymensingh. Materials and Methods: Bood samples were collected from 182 animal handlers, and sera were separated by standard laboratory method. They were tested using the Rose Bengal plate test (RBT) and confirmed for brucellosis by enzyme-linked immunosorbent assay (i-ELISA). Results: The overall seroprevalence of brucellosis was found to be 2.20%. Individuals over 30 years old have a higher seroprevalence of brucellosis (9.09%), while those aged 20-30 have the lowest (0.72%). Only males were found to be seropositive for brucellosis (2.5%). The study revealed that artificial inseminators had the highest prevalence of human brucellosis (10.0%), while animal owners had the lowest (5.0%). The study found that human brucellosis is most prevalent in individuals with contact durations of 10 to 20 years (6.38%), while the lowest prevalence is seen in individuals less than 10 years. The study found that the seroprevalence of human brucellosis was higher (5.80%) in individuals who consumed raw milk than those who did not. Conclusions: This study has recorded the prevalence of brucellosis at low levels among high-risk individuals in the study area. The surveillance reports on human brucellosis are still limited in South Asia, including Bangladesh. Animals are carriers of Brucella, and infection in humans is often transmitted by consumption of raw milk and milk products and contact with aborted animals. Therefore, human brucellosis could be eradicated nationally and globally by eradicating animal brucellosis, which requires a ‘One Health’ strategy. Epidemiological surveillance and prevention of zoonotic brucellosis in South Asian countries is a great challenge due to weak interdisciplinary collaboration on the ‘One Health’ concept and low socio-economic status. However, avoiding risky practices like consuming raw milk and milk products and handling aborted materials without protective equipment are required, along with control of this disease in animals.
... 2,9 In endemic areas, brucellosis is among the causes of extended-duration fever and is often categorized as a fever of unknown origin (FUO). 10 Brucella infection occurs more predominantly in individuals having reduced levels of immunity due to stress or diseases like HIV. 11 The diagnostic tests mainly used for brucellosis are the Rose Bengal Test (RBT), Serum Agglutination test (SAT), Standard Tube Agglutination Test (STAT), Enzyme-linked immunosorbent assay (ELISA), and Polymerase chain reaction (PCR). 12, 13 The prevalence of brucellosis among livestock farmers, milkmen, butchers, and veterinary practitioners was reported to be 2.6% (n=386), 18.2% (n=55), 2.5% (n=40), and 5.3% (n=19), respectively. ...
... Fever of unknown origin is a diagnostic problem, and about 30 -50% of patients remained undiagnosed despite extensive workup (3,4). The most important causes of classic FUO are infectious diseases, cancers, and non-infectious inflammatory diseases (2,4,5). ...
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Full-text available
: Investigating the source of fever of unknown origin (FUO) is usually one of the diagnostic challenges for clinicians. Furthermore, it is one of the most important causes that should always be considered is cardiac causes. In this case, we evaluated a patient with a cardiogenic cause of FUO; despite all the studies, no definite cause was found, but it responded to empiric treatment.
... Severe cases may lead to arthritis, osteomyelitis, spondylitis, epididymitis and orchitis (Franco et al., 2007). In endemic areas, brucellosis is among the causes of extended duration fever and often categorized as fever of unknown origin (FUO) (Attard et al., 2018). ...
Article
Brucellosis is a zoonosis with non-specific clinical symptoms involving multiple systems and organs. Its prevalence is low in most of EU countries, which can lead to the difficulties in laboratory and clinical diagnostic. Due to its relationship to the Ochrobactrum spp., it may be misclassified in rapid identification systems. We present a case of a 13-year-old immunocompetent girl who was examined several times for fever, fatigue, night sweats and weight loss; laboratory results showed mildly elevated C-reactive protein, anaemia and leukopenia. Four weeks before the onset of symptoms, she had been on a family holiday in Egypt. Given her symptoms, a haemato-oncological or autoimmune disease was considered more likely. The diagnosis of Brucella spondylitis was made after 4 months. The main reasons for this delay were as follows: low specificity of clinical symptoms, delay in completing the travel history, inconclusive initial serological results and misidentification of the blood culture isolate as Ochrobactrum sp. Even in countries with a low incidence of brucellosis, it is essential to educate healthcare professionals about the disease. Low specificity of symptoms and limited experience of laboratory staff may lead to late diagnosis with risk of complications and poor outcome. If Ochrobactrum spp. is detected in clinical specimens by rapid identification, careful re-evaluation must follow and all measures to prevent laboratory-acquired infections must be taken until Brucella spp. is unequivocally excluded.
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Prolonged fever of two weeks duration or more poses diagnostic challenges due to a wide variety of differential diagnoses including infections, malignancies, rheumatological conditions and other rare causes. It is important to have a structured approach to make a definitive diagnosis. A good history, meticulous physical examination supported by a step wise escalation of investigations to arrive at a definite diagnosis is the key to successful management of prolonged fever. Empirical steroids, anti-tuberculous and broad spectrum antibiotic therapy should be avoided till a definite diagnosis is established. Points to Remember • A detailed history and thorough examination are the cornerstone for diagnosis in a child with prolonged fever. • Epidemiological data, contact history, previous medical history, fever pattern, focused physical examination and screening tests often provide adequate information to establish a diagnosis. • Non-invasive tests are performed first before taking up the child for invasive and expensive investigations in a step wise manner based on the clinical details. • Management includes supportive treatment as well as targeted therapy after the diagnosis is obtained. empirical broad spectrum antimicrobials, anti-malarials, anti tuberculous therapy and steroids should be avoided. References 1. Harper MB, Fleischer G. Infectious disease emergencies.
Article
Objectives: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenopathy (PFAPA) syndrome is a non-Mendelian autoinflammatory disorder until now considered to be specifically limited to paediatric age. Recently, an increasing number of reports seems to suggest that PFAPA syndrome, diagnosed by the Marshall criteria revised by Thomas et al., can also affect adults. Methods: The Marshall/Thomas criteria have been applied to 989 adult patients presenting for recurrent fever episodes: all patients enrolled were reviewed for demographic, clinical, and therapeutic data. Infectious, neoplastic, autoimmune and other autoinflammatory diseases were ruled out. Results: We identified 30 adult patients (19 males, 11 females) with a suspected PFAPA syndrome: their mean age at disease onset was 33.75±14.01 years, mean age at diagnosis 39.1±14.39 years, and mean body temperature peak 39.5±0.7°C. In addition, the mean frequency of febrile episodes was 11.58±8.97 per year. More precisely, patients complained of pharyngitis (77%), cervical adenitis (73%), asthenia (63%), arthralgia (67%), oral aphthosis (50%), myalgia (54%), cephalalgia (43%), abdominal pain (27%), nausea/vomiting (17%), periorbital pain (17%), and arthritis (10%). Six out of 30 (20%) patients had suffered from PFAPA syndrome also during childhood, and the disease had reappeared in adulthood. Conclusions: We provide the largest monocentric cohort of patients diagnosed with a suspected PFAPA syndrome in adulthood confirming that this syndrome can occur also during adulthood; moreover, due to the medical history of our patients and based on our experience, PFAPA syndrome might relapse during adulthood after a temporary remission reached in the course of paediatric age.
Article
Background: Sweet syndrome (SS) is an infrequent skin disease characterised by sudden onset of fever, leukocytosis, neutrophilia, and tender erythematous plaques infiltrated by neutrophils. Multiple conditions have been associated with this syndrome. Objectives: The aim of this study was to evaluate the clinical, epidemiological, laboratory, and histopathological findings and associations of patients with SS. Methods: We conducted a retrospective study of 83 patients with SS followed between January 1, 2006, and January 31, 2015. Results: Of the patients, 82% were female; the mean age at onset was 48 years. Clinical presentation was mainly characterised by erythematous and edematous plaques, mostly on upper extremities and trunk. Fever was observed in 32%; 60% presented leukocytosis and 39% neutrophilia. On histopathological examination, neutrophilic and lymphohistiocytic infiltrate and edema were the most frequent findings. Fourteen percent of patients had malignancy or hematologic disorders, 26% were classified as having drug-induced SS, and 24% noted recent infection. Only 2 cases occurred during pregnancy. Systemic corticosteroid was the most common choice of treatment, with excellent response. In malignancy-associated SS, the mean hemoglobin level was lower ( P = .01) and the erythrocyte sedimentation rate (ESR) was higher ( P = .04) in comparison to classic and drug-induced SS. Leukocytoclasia was associated with higher risk of recurrence ( P = .01). Conclusion: All patients with SS deserve careful investigation of possible underlying conditions. Higher ESR and lower hemoglobin levels might reinforce the need of malignancy screening. Also, leukocytoclasia appears to be a potential marker of higher recurrence rate, demanding closer and longer follow-up.
Article
Periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is a relatively common autoinflammatory condition that primarily affects children. Although tendencies were reported for this syndrome, genetic variations influencing risk and disease progression are poorly understood. In this study, we performed next-generation sequencing for 82 unrelated PFAPA patients and identified a frameshift variant in the CARD8 gene (CARD8-FS). Subsequently, we compared the frequency of CARD8-FS carriers in our PFAPA cohort (13.9%) with a healthy local population group (3.2%) and found a significant association between the CARD8-FS polymorphism and risk for PFAPA syndrome (p = 0.012; odds ratio: 4.96 [95% confidence interval, 1.33-18.47]). Moreover, CARD8-FS carriers display a distinct PFAPA phenotype that is characterized by a higher prevalence of symptoms out of flares and oral aphthosis (both p = 0.02 compared with PFAPA patients without the frameshift variant). CARD8 encodes a protein component of the NLRP3 inflammasome, which plays an important role in inflammation and contributes to the pathology of various autoinflammatory diseases. We found that the CARD8-FS variant led to a truncated CARD8 protein lacking the FIIND and CARD domains. As a result, the mutant CARD8 protein lost the ability to interact with the NOD domain of NLRP3. In summary, these results identify a new CARD8 variant associated with PFAPA and further suggest that disruption of the interaction between CARD8 and NLRP3 can regulate autoinflammation in patients.
Article
In a retrospective analysis of patients visiting the Outpatient Department of the Division of Infectious Diseases and Tropical Medicine over a period of 3 years, we found a high incidence of symptomatic nonsevere human cytomegalovirus (HCMV) infection in nonimmunocompromised patients. We present 11 symptomatic cases of HCMV infection in nonimmunocompromised patients with non-life-threatening symptoms like long-lasting depletion, fatigue, and subfebrile fever with or without muscular pain and arthralgia. Although the symptoms were not life-threatening, all of the patients suffered a prolonged duration of the disease until improvement. These cases reinforce the important fact that HCMV infections in nonimmunocompromised patients are not always asymptomatic. Therefore, HCMV infection should always be included in the differential diagnosis of patients with unspecific signs of disease like depletion, subfebrile fever, and arthralgia.
Article
Cases of rat-bite fever (RBF) were reported in the literature for more than 2000 years. Not until recently, however, were attempts made to differentiate between RBF and Streptobacillus moniliformis septic arthritis, 2 arguably different clinical entities. There are limited data regarding S moniliformis septic arthritis and the features that distinguish it from RBF, and most conclude that although clinically disparate diseases, it is difficult to differentiate between them. We report a case of a 17-year-old girl who presented with S moniliformis bacteremia and symptoms that spanned both RBF and S moniliformis septic arthritis. This case emphasizes the difficulty in differentiating the 2 clinical entities and the importance of early diagnosis, proper clinical suspicion, and prompt treatment to achieve positive outcomes.
Article
Childhood fever of unknown origin (FUO) is most often related to an underlying infection but can also be associated with a variety of neoplastic, rheumatologic, and inflammatory conditions. Repeated, focused reviews of patient history and physical examination are often helpful in suggesting a likely diagnosis. Diagnostic workup should be staged, usually leaving invasive testing for last. Advances in molecular genetic techniques have increased the importance of these assays in the diagnosis of FUO in children.
Article
Neuroblastoma is a malignant tumor arising from nerve tissue that accounts for approximately 15 percent of pediatric cancer fatalities. Primary tumors most commonly arise in sympathetic nervous tissue of the abdomen and metastasize to the bone marrow, liver, and lymph nodes. This case report depicts a 3-year-old girl who presented with a recurring fever, runny nose, and a positive test for rhinovirus suggesting a simple case of the common cold. Further investigation, however, revealed stage 4 neuroblastoma. This patient experience emphasizes the importance of having a high level of suspicion to rule out more serious underlying pathology in a seemingly unremarkable patient presentation.