CBD:

A child with
Prolonged Fever
Group 1

NUR BAITI MAD NOR SUKD 1701024

CHIA JING LYN SUKD1603269
ALY MORSY SUKD1701194
 Case Scenario
A 2-year-old previously well girl presented with 12-day-history of
high spiking of fever to a district hospital. There was reduced oral
intake and activity especially during spiking of the fever. She was
brought to see GP a few times and was treated with different types
of antibiotics. However, her fever persisted, resolved only
temporarily by the Paracetamol and ibuprofen. She had otherwise
no cough or runny nose. Neither did she have any GI symptoms of
diarrhea and vomiting.
On examination, she was fretful and lethargic looking. Her lungs
were clear and CVS examination was unremarkable. Her liver was 2
cm palpable and spleen’s tip was felt below the left costal margin.
 QUESTION
1. What further history and examination finding you
would like to ask and look ?
2. What investigation you would like to do?
3. What do you understand about PUO?
4. What would be the likely differential diagnoses for this patient?
5. Any further investigation you would like to do (if you have not done
before)?
6. What is your provisional diagnosis now?
7. How would you confirm your diagnosis?
8. What complication has occurred?
9. Please outline your principle of management.
 HISTORY
● History of Presenting Illness -

○ Onset and duration- 12 days

○ Course and pattern of fever
○ Triggers/ exacerbating factors
○ Associated symptoms
○ Severity- reduced oral intake and activity

● Infection screening/ Systemic review-

○ Respiratory- cough, hemoptysis, dyspnea

○ CVS- Chest pain
○ GI- Abdominal pain, diarrhoea, vomiting, jaundice
○ GU- Frequency, dysuria, foul smelling urine, reduced urine output
○ CNS- loss of consciousness, drowsy, headache, neck stiffness, photophobia, seizures
○ MSC- Joint pain, muscle pain
○ Dermatological- Rashes (petechial), bruising
○ Any recent infection/travel history/ ill contact, if so ask about severity and resolution
● Past medical/surgical history- Recent hospitalization ? Underlying medical
condition (when diagnosed, control, treatment), any surgery done- (e.g
congenital heart disease, insertion of prosthetic heart valves

● Antenatal, Perinatal, Postnatal- Uneventful ? / Any complications

● Drug history/ Allergies- Medications, chemotherapy

● Immunization- Up to date ?

● Family history- Any family history of malignancy, any recent contact with TB
infected individual in the family

● Social history- Recent travel, accommodation and amenities, river ,Swimming

PHYSICAL EXAMINATION
★ Assess Vital signs- (Temperature, Blood Pressure, Heart Rate,
Respiratory Rate and Oxygen Saturation)

★ General appearance- toxic looking/ well, respiratory distress,

pain, drowsiness/ reduced activity, pallor/jaundice/cyanosis/rashes,
inconsolable cry, nutritional , status (small for age?)

★ Anthropometry- Serial Weight/Stature measurements- Failure

to thrive ? Low BMI ? Significant weight loss (>10% body weight)

★ General examination- Capillary refill time, Pulse, temperature

of peripheries, cyanosis, clubbing, Blanching/ non blanching
rashes, Eyes (pallor, jaundice), oral ulcers/hygiene/central
cyanosis, extremities (pedal oedema)
RESPIRATORY EXAMINATION

● Chest wall movement/ deformities/ subcostal recession/surgical scars

● Focal dullness on percussion- consolidation
● Air entry/breath sounds/wheeze or crepitations

CARDIOVASCULAR EXAMINATION

● Precordium inspection- bulge, pulsations, scars, deformities

● Apex beat. Thrills, parasternal heaves
● S1 and S2, any added sounds- murmurs
GASTROINTESTINAL EXAMINATION

● Abdominal distention, any visible pulsation, is the abdomen moving with

Respiration

● Palpate the abdomen to see abdomen is it soft and any tenderness, any
mass was felt like hepa,tosplenomegaly assess patient has ballotable
kidney or not, percuss the nine regions of the abdomen to see is it
Resonant.

● Check for any presence of fluid thrill and shifting dullness, auscultate
for normal bowel sound and any sound of aortic or renal bruit
CENTRAL NERVOUS SYSTEM EXAMINATION

● Assess mental status/ GCS/ state

of arousal

● Upper limb/ lower limb- Tone

power reflexes

● Kernig’s/ Brudzinski tests- Meningitis

● Cranial nerves- check pupils

reactive to light/ photophobia
FOLLOW-UP SCENERIO

She was treated empirically with IV antibiotic in the ward but her fever
persisted. She was then transferred to Tertiary Hospital and the diagnosis of
pyrexia of unknown origin was made.
 PUO-PYREXIA OF UNKNOWN ORIGIN
PYREXIA OF UNKNOWN ORIGIN (PUO)

DEFINITION-

● Recorded temperature of >38 c >3 weeks, No explainable diagnosis despite initial investigations done in
hospital for 1 week. 3 days of inpatient care/ 3 outpatient visits/ 1 week of intensive ambulatory
investigation.

ETIOLOGY-

● Infections (30%)- TB, HIV, abscesses, infective endocarditis

● Malignancy (20%)- lymphoma, leukemia
● Connective tissue disorders (15%)- SLE, vasculitis
● Miscellaneous (20%)- Drug reactions, thyrotoxicosis, factitious fever
● Idiopathic (15%)
 Follow Up Scenario
She was treated empirically with IV antibiotic in the ward but her
fever persisted. She was then transferred to Tertiary Hospital and the
diagnosis of pyrexia of unknown origin was made.

4. What would be the likely differential diagnoses

5. Any further investigations you would like to do that has not been
done
 Differential Diagnosis
● Leukemia:
Points for: Fever, hepatosplenomegaly, and lethargy is present.
Points against: No pallor, petechiae or ecchymosis, no bone or joint pain, no
lymphadenopathy

● Lymphoma:
Points for: Hepatosplenomegaly, fatigue
Points against: No pallor, lymphadenopathy, no weight loss, fever is mild in
lymphoma, no chest pain, no cough
● Malaria:
Points for: Fever, hepatosplenomegaly, drowsiness, poor appetite
Points against: No rigors, no sweating, no headache, no flu like symptoms,
no nausea or vomiting, no pallor, no jaundice.

● Enteric Fever:
Points for: Fever, hepatosplenomegaly, malaise.
Points against: No headache, no cough or sore throat, no diarrhea, no
abdominal pain, no relative bradycardia.
● Systemic lupus erythematosus:
Points for: Fever, hepatosplenomegaly, lethargy, poor appetite
Points against: No rash, no oral or nasopharyngeal ulcers, no arthritis, no
photosensitivity, no myalgia, no hematuria, no seizure

● Infective Endocarditis:
Points for: Fever, splenomegaly, malaise
Points against: No anorexia, no nausea/vomiting, no cough, no murmur,
hepatomegaly seen in this case, no roth spots, no janeway lesions, no
splinter hemorrhages, no osler nodes.
● Epstein-Barr virus infection:
Points for: Fever, hepatosplenomegaly, lethargy, reduced appetite
Points against: No pharyngitis, no lymphadenopathy, no headache, no
photophobia, no cough, no nausea, no abdominal pain

● Tuberculosis:
Points for: Fever, hepatosplenomegaly, lethargy, poor appetite
Points against: Inadequate history of TB contact, night sweats, failure to
thrive, no cough, no weight loss, no chest tightness.
● Human Immunodeficiency Virus:
Points for: Fever, hepatosplenomegaly, malaise, reduced activity
Points against: No weight loss, no headache, no lymphadenopathy, no
rash, no nausea or vomiting, no myalgia, no diarrhoea, no night sweats

● Kawasaki disease:
Points for: Fever
Points against: No conjunctivitis, no rash, no lymphadenopathy, no
swollen tongue, no skin peeling, no palm/sole swelling, splenomegaly
seen in this case, no cracked lips.
 Further Investigations
Full Blood Count (FBC)
● In the case of acute lymphoblastic leukemia, a reduction in hemoglobin
results in anemia. There is also a reduction in platelets
(thrombocytopenia), and the white blood cell count may be reduced,
normal, or elevated.
● In lymphoma, important to look for anemia, neutropenia, and
thrombocytopenia.
● In EBV infection, it is important to look for leukocytosis and
thrombocytopenia.
● In SLE, thrombocytopenia, leukopenia, and anemia can be seen.
● Kawasaki disease may present with leukocytosis which shows a typical rise
in platelet count in the second week of illness.
Peripheral Blood Film (PBF)
● This is performed to look for blast cells in acute lymphoblastic leukemia
● There may be atypical lymphocytes in Epstein Barr virus infection
● If Malaria is suspected, a thick and thin smear is performed since the
thick smear looks for the different stages in life cycle of the Malaria
species as well as enables detection even at low number of parasites
whereas a thin smear is used in the identification of the malaria
species.
● Blood culture: Performed for all the differential diagnoses as the child is
febrile.
● Sputum culture: Used to confirm the presence of tuberculosis. In young
children induced sputum via an indwelling nasogastric tube can be used to take
samples on waking.
● Blood Urea Serum Electrolytes: Done to assess and monitor acute
lymphoblastic leukemia.
● Lactate dehydrogenase: To assess degree of cell burden in leukemia and to
assess the risk of tumour lysis.
● CRP: Important to look for as it can be elevated in Kawasaki disease.
● Chest X-ray: To look for any mediastinal mass that are typically found in
leukemia or non-hodgkin’s lymphoma.
● Tuberculin skin test: To look for presence of TB infection
● Viral serology: To detect presence of Epstein Barr Virus
● Serology for antinuclear antibody (ANA): To check for SLE
● HIV DNA/RNA and antibody tests: To check if falling in HIV
● Urine/Stool culture: To check for typhoid fever
● Bone marrow aspiration/biopsy: Required to diagnose ALL
● Immunophenotyping: To find out subtype of leukemia
 Follow Up

Blood tests are as follow.

9
Total WCC – 45 x10 /L ( Elevated) ( Normal- 4-11)
Hb -- 8.7 gm/L (Reduced) (Normal 10.5-14)
9
Platelet – 79 x10 /L ( Reduced) (Normal 150- 400)

6. What would be your provisional diagnosis now

7. How would you confirm your diagnosis
 Provisional Diagnosis
Acute lymphoblastic leukemia
● Points supporting for:
○ Fever
○ Hepatosplenomegaly
○ Lethargy
○ Poor appetite
○ Reduced activity
○ Elevated white cell count
○ Low hemoglobin levels
○ Thrombocytopenia.
 Confirmative Investigations
● Peripheral blood film
○ Presence of blasts cells
● Bone marrow aspiration
○ Presence of immature blasts cells
● Lumbar puncture
○ CSF examination for blasts cells and to look
out for any meningeal involvement
 Follow Up
Repeated Full Blood Count showed:
Total WCC – 105 x109/L (↑↑↑)
Hb 8 gm/L (↓)
Platelet 65 x109/L (↓)

8. What complication has occurred?

9. Please outline your principle of management.
 Complications
● Oncologic emergency (Haematological)
○ Hyperleukocytosis: defined as TWBC > 100,000/mm³ in patients with acute
leukaemia
● Mechanism:
○ Leukostasis, vascular occlusion, damage to blood vessels causing bleeding
● Symptoms:
○ Lungs: Pulmonary infiltrates causing dyspnoea, hypoxaemia and right ventricular
failure
○ CNS: causing headache, papilledema, seizures, haemorrhage or infarction
○ Others: renal failure, priapism, dactylitis, tumor lysis syndrome
 Management of complications
Management of hyperleukocytosis:

● Stabilize patient (resuscitation if required)

● Adequate hydration/ hyper hydration at 150mls/m2/hour
● Facilitate excretion of toxic metabolites
● Reduce blood viscosity
● Avoid increasing blood viscosity
● Exercise caution in use of packed cell transfusion and diuretics
● During induction in patients with hyperleukocytosis, keep platelet count >20 000/mm³ and
coagulation profile near normal
● Exchange transfusions and leukapheresis should not be used alone as rapid rebound
usually occurs
● Concurrent chemoradiotherapy should therefore be initiated soonest possible.
 Principle of management
● Approach through history taking and physical examination

● The overall goal of pediatric oncology is to cure all patients with minimal
toxicity

● Multidisciplinary approach

● Treatment with certain chemotherapy agents and radiation therapy increases

the rate of second malignancies (etoposide, cyclophosphamide or
doxorubicin)

● Supportive care
 Surgery
● CT/MRI needed for solid tumors presenting as palpable mass or mass-related
symptoms
● Resection or biopsy
● Not all are indicated unless there’s suspected lymphoma
● Almost all pediatric lymphomas are chemosensitive and do not require surgical
resection.
● To determine the amount of tissue required and the appropriate distribution of the
tissue for testing
● A general oncologic surgery principle is to resect not just the tumor, but also, in most
cases, a surrounding margin of normal tissue to ensure the entire tumor has been
resected
 Chemotherapy
● As primary curative treatment
● Before starting treatment of the disease, anaemia may require correction with blood
transfusion, the risk of bleeding minimised by transfusion of platelets, and infection
must be treated
● Additional hydration and allopurinol (or urate oxidase when the white cell count is high
and the risk is greater) are given to protect renal function against the effects of rapid
cell lysis
 Induction
● Patients with ALL generally receive three- or four-agent induction chemotherapy based
on their initial risk group assignment

● Low- and standard-risk: vincristine, prednisone, and L-asparaginase for 4 weeks

● High risk patients: anthracycline (daunorubicin or doxorubicin)

● Intrathecal instillation of some combination of methotrexate, cytarabine, and

hydrocortisone is given to treat existing CNS leukemia or prevent its development
 Induction
● Remission is consolidated with CNS-directed therapy

● Eradication of the leukemic blasts and restoration of normal marrow function

● Current induction treatment schedules achieve remission rates of 95%.

● Higher risk patients: more intensive chemotherapy

● Patients with CNS disease detected at diagnosis and those with T-cell ALL:
cranial radiation therapy
 Maintenance therapy
● Total duration of therapy of 2 to 3 years
● Consists of intermittent vincristine and short courses (5 to 7 days) of oral
corticosteroid therapy + daily oral 6-mercaptopurine, and weekly methotrexate (orally
or IM)
● Follow up
○ Check height, weight and calculate surface area (BSA/m2) every visit and adjust
drug dosages accordingly
○ To calculate BSA = √ [Height (cm) x Weight (kg) / 3600]
○ Check FBC every 2 weeks for the first 1-2 months after starting maintenance
chemotherapy, and monthly after that if stable
 Relapse
● 2/3 of relapses occur within the first year of stopping treatment.

● CNS relapse usually manifests as headache, vomiting, abnormal sensorium or

hypothalamic symptoms (hyperphagia and abnormal weight gain).

● Testicular relapse presents as painless testicular swelling, usually unilateral

● High-dose chemotherapy + total body irradiation (TBI)

● Bone marrow transplantation- an alternative to conventional chemotherapy

 Psychosocial support
● Has an enormous and long-lasting impact on the whole family
● They need the opportunity to discuss the implications of the diagnosis and its
treatment and their anxiety, fear, guilt and sadness.
● Counselling and practical support provided
● Help with practical issues (transport, finances, accommodation and care of
siblings) is an early priority
● Provision of detailed written material for parents will help them understand
their child’s disease and treatment
● Encouraged to return to as normal a lifestyle as possible.
 Resources
● Paediatrics Protocol for Malaysian Hospitals, 4th Edition,
2019.
● Illustrated Textbook of Paediatrics, 4th edition Tom Lissauer,
Graham Clayden.
● Nelson Essentials of Paediatrics, 7th edition Karen J.
Marcdante, Robert M. Kliegman
Thank
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