Clinical case 1

A 2 year old girl presents at your clinic on a Friday afternoon because of fever and difficulty in walking. Her mother
explains that she has been having spiking fevers in the last 10 days. The fever is almost daily and remittent. Since
yesterday she is worsening with fever spikes and weakness. The little girl has had some non-itching rash, thought to be
due to the amoxicillin that was prescribed by the local paediatrician a week ago. Despite antibiotic treatment, she
continues to have fever every evening and she is very restless and miserable. Furthermore, the mother complains that it
is now very difficult to get her daughter out of bed in the morning as she is tired and that she limps for some time. She
didnt fall over, and never presented any swollen joints.
In the last period she has started to attend the nursery and she has been ill with fever for about 5-6 episodes in the last
4 months. All these episodes were treated with antibiotics after about 4 days of fever, with either a good response or a
persistent fever lasting for a few days. Sometimes the girl complains of abdominal pain.
At examination she is mildly febrile and grumpy; her mother reports that her daughter was limping in the morning but
now she is not willing to walk at all. There are a few erythematous macules on her body. Examination of the oral mucosa
and eyes is normal. She has a cervical lymphadenopathy on the right side. The abdominal examination is difficult: she
complains of pain. No organomegaly is noticed. Articular examination reveals a limitation of motion of her right knee that
appears to be painful.

1. What would be your next steps for management?

a. Confidently give the mother a diagnosis, prescribe some routine blood tests to perform in her local hospital next
Monday and reassure mum that this is not severe.
False. this girl has been ill for a while now, and the treatment she received is not able to control the process. There is
too much diagnostic uncertainty to be confident of any diagnosis at this stage. Furthermore according to the mother she
is worsening. Waiting for two more days should be avoided.
b. Switch to another type of antibiotics, because of a suspected allergy to amoxicillin, and add oral corticosteroids, in
order to control the pain and the inflammatory status.
False. As of now, you dont have evidence of a bacterial infection. If you are considering septic arthritis, a joint
aspiration is mandatory followed by intravenous antibiotics until culture and sensitivities are available to guide antibiotic
choice. Moreover, administering corticosteroids when the diagnosis is uncertain is fraught with danger. For example, if
the child turns out to have leukaemia, use of steroids alone is associated with a higher risk of a poor outcome.
c. You admit the child to a paediatric unit for further investigations and close review.
True. This is a sick child without a clear diagnosis who deserves further investigation and close inpatient observation by
staff trained in paediatrics. You need to perform investigations to make a diagnosis. The documentation of the fever
pattern is especially important. A spiking pattern with a temperature that returns to normal in between may suggest a
diagnosis of a viral infection, malignancy or systemic-onset JIA (SoJIA). A persistent high fever suggests Kawasaki
disease or an infectious process. Furthermore, periodic fever syndromes are characterized by persistent and recurrent
fever.
d. Refer the girl to a paediatric rheumatologist for an urgent outpatient review?
False. this would result in a further delay in the diagnosis . There are still several diagnoses which might require
emergency action, including Kawasaki disease, Systemic-onset JIA, malignancy or septic arthritis.

2. Which six of the following diseases are in your differential diagnosis?

a. Viral illness?
True. the most common reason for children to develop a transient febrile illness, especially with cervical
lymphadenopathy.

b. Kawasaki Disease (KD)?

True. one should always consider this vasculitis in a febrile child, younger than 5 years of age. However she has no eye
or mouth manifestations, nor features in the extremities. But some kinds of incomplete KD may present in this way.
c. Malignancy?
True. especially leukaemia should be considered in the differential diagnosis of a young child with persistence of fever
and leg pain. Although rare, neuroblastoma should also be considered, also because she has been complaining of
abdominal pain.
d. Septic arthritis?
True. septic arthritis and osteomyelitis present with fever and pain, and a bad general condition. These are
rheumatologic emergencies which should be considered early in any febrile child.
e. Periodic Fever Syndromes?
True. Diseases such as Familial Mediterranean Fever and Hyper IgD syndrome may present with fever and arthritis.
However, they have a recurrent pattern which is apparently missing in this child. Although a very rare condition,
cryopyrin-associated periodic syndrome (CAPS) may also be considered in the differential diagnosis since these
patients present with fever and urticarial rash. Furthermore, they can manifest articular symptoms and they sometimes
have accompanying neurological features such as headache, papilledema, sensorineural deafness, and aseptic
meningitis (CINCA/NOMID).
f. Discitis?
False. this condition is extremely rare in children, especially at this age.
g. Systemic onset juvenile idiopathic arthritis (SoJIA)?
True. although rare, spiking fever, rash and arthritis are consistent with this diagnosis.

3. Do the findings at physical examination help you to exclude any of your differential diagnoses?
a. Viral illness?
No, although the absence of rhinitis and pharyngitis makes this less likely.
b. Kawasaki disease?
No. In this case, mucosal changes and conjunctivitis are absent, but remember that cases of incomplete Kawasaki
disease (i.e. not satisfying the full KD criteria) exist and still can be associated with significant coronary artery disease.
c. Malignancy?
No, there may be no specific clinical features of malignancy and a high index of suspicion must be maintained
d. Septic arthritis?
No, although the child with septic arthritis or osteomyelitis is usually very unwell and febrile, however in this case, the
ongoing treatment with antibiotics may mask some symptoms.
e. Periodic Fever?
No, this diagnosis requires a set of criteria, the response to treatment and a genetic test in some cases.
f. SoJIA?
No, the complaints are consistent with a diagnosis of SoJIA.
You arrange to have the child admitted to the local Childrens Hospital, but by now it is late on Friday afternoon and
routine laboratory specimens may not get processed until Monday. The junior staff want to know which tests to order
urgently and if you want them to organise any consultations for the evening.

4. What do you ask them to do? What would be your suggestions for management as soon as she is admitted?
a. Do you change her antibiotics?
No. Before changing antibiotics, we should know the results of the clinical laboratory examinations and blood cultures, in
order to determine whether an infection is ongoing.
b. Would you start her on some immediate corticosteroids while they do the work-up?
No. You are still not sure of the diagnosis. Corticosteroids are not appropriate at this stage. And especially if you
consider viral infection , malignancy or leukaemia they should not be given before further investigations and a bone
marrow aspiration.
c. Do you want a paediatrician to review the child again in the same evening when she is a bit quieter?
Yes, there is no substitute for a meticulous physical examination, even of uncooperative young children. Moreover, the
daily fever pattern of SoJIA often peaks in the evening, and the typical, evanescent, salmon pink rash is most prominent
at times of fever.
You will need some tests to make a diagnosis.
5. Which tests do you request?
a. An urgent full blood count, peripheral blood smear and ESR.
True. this may provide the answer for the following diagnostic possibilities:
Bacterial infection: raised full blood count (FBC) and neutrophilia.
Viral infection: low FBC and prevalence of lymphocytes.
Leukaemia: particularly if you also ask for a manual differential cell count or peripheral blood smear so that lymphoblasts
can be detected. A warning feature for leukaemia is thrombocytopaenia (an indication for bone marrow examination).
Beware of the pre-leukaemic state where diagnostic blasts are not present in peripheral blood samples or even
bone marrow.
SoJIA: may also have prominent leukocytosis, predominantly neutrophilia. SoJIA can be associated with Macrophage
activation syndrome (MAS), which is characterised by low platelets, with or without leukopenia (as well as high ferritin,
paradoxically low ESR, increased liver enzymes, triglyceridemia and hypercholesterolemia).
Kawasaki Disease (KD): more likely to be associated with marked thrombocytosis.
The presence of anaemia or an elevated ESR will not help to differentiate between these diagnostic possibilities.
b. To order an urgent abdominal ultrasound and urinary catecholamines?
False. this is probably not necessary as an urgent examination. If diagnostic uncertainty about neuroblastoma remains,
these exams are valuable
c. To order a rheumatoid factor and antinuclear antibody titres?
False. these tests have neither diagnostic specificity nor sensitivity for childhood arthritis. These are commonly abnormal
in transient viral illnesses (up to 30%), leukaemia and other inflammatory conditions.
d. To order a septic screen (urinalysis, culture and blood culture)?
True. this is mandatory because we have not been able to exclude partially treated sepsis yet. If there is a suspicion of
septic arthritis, a joint aspiration might be necessary (although culture of the synovial fluid might be false-negative, due
to the use of antibiotics). A septic screen provides information about general infections as well.
e. To order Streptococcal and Viral serology?
False. this is not an urgent investigation. Moreover, the index of suspicion of rheumatic fever is low, because there is no
history of pharyngitis, there is no migrant arthritis and the rash is different from erythema marginatum. It is useful to
perform this investigation after the weekend, if you still have no diagnosis.
f. To order an echocardiogram?
True. there is a possibility that this child has Kawasaki disease and there is clear evidence that early treatment with IVIG

reduces the risk of coronary artery aneurysms. The detection of even minor coronary artery abnormalities in a child with
a febrile illness should prompt the use of IVIG urgently. Systemic arthritis may also have significant cardiac involvement
with development of pericarditis.
The urgent blood tests you prescribed came out showing leukocytes: 16,000/mm3, (Neutrophils 12,000, Lymphocytes
4,000), Hb 10.1 g/dl, Platelets 450,000/mm3. Peripheral blood smear was consistent with FBC. ESR is raised to 78
mm/1st hour and CRP is increased. The septic screening and echocardiogram are normal.
Over the weekend the child continues to have daily peaks of fever in the evening, and an evanescent, salmon pink rash
is most prominent at times of fever.
6. What is your diagnosis?

Answer : Systemic JIA: these are typical features for the disease.

7. Would you perform a bone marrow aspiration before starting her treatment with corticosteroids?

Answer : Yes: Since malignancy and leukemia are frequent conditions underlying fever and leg pain in small children, a
bone marrow aspiration should be included in the diagnostic work up, in order to avoid misdiagnosis and poor prognosis.
On Monday morning, when you plan to start the treatment, the child suddenly becomes restless, the fever takes a
continuous pattern. On examination you notice hepatosplenomegaly that was not reported previously. You order an
urgent complete blood count that shows an abrupt decrease of platelets to 78,000. The ESR has dropped from 78mm/hr
to 20mm/hr and the liver function tests are abnormal.
8. What has happened to this child?
a. Infection
False. The rapidity of the change in the clinical picture and the sudden fall in ESR cannot be explained by infection.
b. Malignancy
False. Again the symptoms have developed abruptly and the fall in ESR cannot be explained in the setting of
malignancy
c. Macrophage activation syndrome
True. MAS occurs in about 10% of the patients with systemic JIA. It is indeed characterized by a sudden change in
symptoms and rapid progression to multi-organ failure (MOF) if not treated. The characteristic symptoms are reviewed in
the text. Check ferritin levels and clotting for confirmation of diagnosis. A bone marrow aspiration is not necessary when
the clinical and laboratory features (increased levels of ferritin, triglyceride, liver enzymes, decreased fibrinogen) are
characteristic, especially because you have to start the treatment as soon as possible and bone marrow phagocytosis
can be absent in a high percentage of MASs (see text).
Clinical case 2
A 3 year old girl presents with a swollen left knee. The parents have noted that she is unwilling to walk in the morning
and that the knee has gradually swollen over the past weeks. On physical examination the knee is swollen and has
limited in motion on flexion and extension. The physical examination is otherwise normal.
Laboratory examinations reveal a normal complete blood count and a slightly elevated anti-streptolysin-O titer.

1. What other lab studies would you order for this patient?
a. Erythrocyte Sedimentation Rate (ESR) and CRP

True. Acute phase reactants have to be analysed to identify the extent of inflammation and for monitoring the response
to treatment, although they are not always significantly elevated in this form of the disease.
b. Complement levels
False. this is not an immune complex disease and these are not relevant.
c. Anti-nuclear antibody
True. Low titre ANA is often present in this form of the disease. It is important for the classification of the child and
predicting the prognosis of eye complications. High titre ANA would alert you to other connective tissue diseases.
d. Rheumatoid Factor
False. This test is not necessary since RF is not a feature of this presentation.
e. Joint sonography and X-ray
True. Sonography and X-ray of the involved area are obtained for detection of joint effusion and for differential
diagnosis.
The results show a slightly elevated ESR (38 mm/hr), ANA is 1:160. Urinalysis is also normal.
2. Which one of the following is your diagnosis?
a. Oligoarticular onset JIA
True. This child has an oligoarticular onset JIA since she has less than 5 joints involved at the initial phase of the
disease, she has low titre ANA and her age is compatible with the usual age of onset.
b. SLE
False. SLE may present with arthritis in children. However, we do not have any other features to suggest SLE and meet
the classification criteria. Her age is also atypical.
c. Acute rheumatic fever
False. The clinical course is not compatible with acute rheumatic fever, the elevated Anti Streptolysin-O is not sufficient
to diagnose a patient as Acute Rheumatic Fever. The arthritis of acute rheumatic fever is a migratory one. Furthermore
the joint in acute rheumatic fever is one with very active features of arthritis with a red, painful arthritis. This is not the
description for this case.
d. Systemic JIA
False. the patient does not have the systemic features required for systemic JIA.
e. FMF
False. There is no evidence of recurrent attacks of fever and arthritis or other forms of serositis.

3. Which of the following would you like to particularly warn the family about, as a complication of this disease?
a. Osteoporosis
False. Recent studies have highlighted the fact that polyarticular and systemic onset diseases maybe associated with
osteoporosis. Osteoporosis is probably one of the consequences of elevated cytokines as well as a consequence of
immobility and a side-effect of the occasionally used steroids. However this is not a major complication in oligoarticular
onset disease
b. Heart involvement
False. Heart involvement is not an issue.
c. Eye involvement which can lead to blindness

True. Eye involvement is a major complication of this type of onset. As indicated in the text routine ophthalmologic
follow-ups are required. If uveitis occurs prompt topical and often systemic treatment are required. The course of uveitis
must be followed by the ophthalmologist and paediatric rheumatologist for optimal management.
d. Kidney involvement
False. Kidney involvement is not an issue.

4. Which two of the following would you use to manage this child?
a. NSAIDs approved in children
True. NSAIDs are first choice of treatment
b. Oral corticosteroids as prednisone
False. Oral corticosteroids are not at this stage of disease
c. Intra-articular steroids
True. Intra-articular corticosteroids in the form of triamcinolone hexacetonide are applied when deemed necessary
d. AntiTNF drugs
False. AntiTNF drugs are not indicated at this stage of disease.
At follow-up after the first six months of the disease, the number of involved joints gradually increases to involve the
other knee, left ankle, both wrists to varying degrees and the PIP joint of the left index finger. Her ESR and CRP levels
increased to 47 mm/hr and 5.2mg/dl, respectively. Her haemoglobin tended to decrease and WBC and platelets were
slightly increased.
5. Has the classification of the disease of this child changed?

Answer : Yes, this patient has "extended oligoarthritis". In fact oligoarticular JIA is classified into either persistent or
extended type depending on whether the disease involves more joints after the first 6 months. Clinical and molecular
studies have shown that these patients are different from the outset and the prognosis of the extended form is worse. In
extended oligoarticular disease the acute inflammation may result in changes in the blood parameters.

6. What is your first choice of treatment in this patient?

a. Methotrexate
True. Methotrexate (MTX) is successful in inducing remission in about 1/2 to 2/3 of these patients.
b. Oral corticosteroids
False. Corticosteroids are not used regularly in paediatric patients especially because of the severe side effects on
growth and bone. In patients who do not respond to MTX, anti-TNF agents are an excellent choice as reviewed above.
c. Intravenous corticosteroids
False. Corticosteroids are not used regularly in paediatric patients especially because of the severe side effects on
growth and bone. In patients who do not respond to MTX, anti-TNF agents are an excellent choice as reviewed above.