Clinical Case
Presentation
MODERATOR: DR. ALKA YADAV
Patient’s Details
Name : PARTEEK
Age : 11 MONTHS
Sex : Male
Residence : ROHTAK, HARYANA
History
Chief complaints:
• Fever since 8 days prior to admission
•H/o irritability and decrease oral acceptance since 1 day
History of present illness:
Fever was abrupt in onset, moderate to high grade , reminant in nature , relieved with
medication only to recur.
•Not a/w rash
•No H/O cough, cold , difficulty in breathing
•No H/o diarrhoea, vomiting
•No H/O altered sensorium or abnormal body movements
•No H/o jaundice or any bleeding from any site
History of past illness:
Developmentally normal child with no relevant past history
No H/O any hematological or other chronic illness in the family
Birth History:
Term Normal vaginal delivery with bwt 2.8 kg
1st birth order
Breast feeds established immediately after birth
Feeding History:
Exclusive breast feeding upto 6 months
Weaning started at 6 months
Complimentary feeds
Socio economic status:
Kuppuswami scale: Lower middle class
Immunization history:
Complete till now
Last immunized at 9 months
EXAMINATION
• Vitals : Febrile(temp:102deg F)
RR = 30/-
HR = 110/-
SPO2 (RA) = 97%
PP = good volume in all four limbs
• ANTHROPOMETRY:
WEIGHT: 7.2 KG(< 3rd centile)
LENGTH :73 CM(b/w 15th -50th centile)
• RESPIRATORY: Air entry equal on both sides
No added sounds
•PER ABDOMEN: Soft
Spleen palpable 6cm below left costal margin
Liver palpable 2cm below right costal margin
Bowel sounds present
•CARDIOVASCULAR: S1S2 normal
No murmur appreciated
•CENTRAL NERVOUS SYSTEM: Irritable
No gross neurological deficit
• Provisional Diagnosis
Acute febrile illness with Hepatosplenomegaly
• Differential Diagnosis
Enteric fever
Dengue fever
Malaria
Splenic sequestration crisis
Acute leukemias
Baseline investigation
CBC: 10.0, 6000, 56, 40, 8,4, 2, pl- 1.0 lac, PBF , NcNc to McHc picture No e/o hemolysis
PBF FOR MP: negative
Dengue card test: NS1Ag positive
Serum Electrolytes 139/4.1
EMERGENCY MANAGEMENT
•IV ACCESS
•VITAL MONITORING
•IV FLUIDS
•IV ANTIBIOTICS(Ceftriaxone ) and inj Falcigo
Course in Hospital
Fever x 8 days
Day 1
D/D’S
MALARIA Managed conservatively with IV
DENGUE Antibiotics and Antimalarials
ENTERIC
CBC
CXR
High fever spikes
DAY 3 Blood culture
Worsening RD
Widal
OXYGEN THERAPY
Urine r/e and
Vancomycin culture
added
Fever spikes persisted
Day 6
Worsening RD Investigated further
Persistent pancytopenia LFT/RFT
HFNC CRP
BGA
ESR
MERO ADDED
High grade fever persisted
Day 9 s/o CHF ECG tachycardia
Lasix and dobutamine started Echo planned
Mero/linezolid
IVIG given over 48
Day 12 Echo s/o myocarditis hrs
Possibility of acute leukemia
Day 15 RD improved
and HLH was kept
Child shifted to NP
BM was done
i/v/o persistent fever spikes, pancytopenia
Other supportive work up was
andsplenomegaly,though liver size was
sent
regressed
BM s/o normocellular marrow with
hemophagocytosis
Day 19 Started on HLH 2004 protocol HLH (5 out of 8 criteria)
Antibiotics were stopped after 14 days of duration.
Hb and platelet counts improved and was discharged after 24 days of hospitalization under
hemodynamically stable condition
INVESTIGATIONS
Complete Hemogram
2/9 5/9 9/9 11/9 12/9 17/9 20/9
Hb 10.0 6.7 6.5 4.8 PCV 7.8 8.0 12
TLC 6000 3100 6600 5200 6200 6300 4500
DLC 56/4 22/71/5 33/62/2 40/50/5 23/71/2 34/61 37/60/2
0/8/ /2 /2 /4 3/2 /1
4
Platelet 1.1 93000 75000 74000 90000 130000 150000
s
PBF McH McHc McHc McHc McHc McHc NcNc
c
Renal Function Test/Liver Function Tests
2/9 12/9
Blood urea 34 17
S.CREATININE 0.4 0.4
Liver Function Test
5/9 9/9 11/9 12/9 18/9 26/9
AST QNS 221 251 178 165 57
ALT 851 319 376 169 116 94
ALP 224 576 514 257 159 215
S.PROTEIN 6.0 4.5 4.0 5.4 5.0 4.0
ALBUMIN 3.8 2.9 2.1 2.7 3.0 2.1
AG RATIO 1.7 1.1 1.1 1.0 1.0 1.1
TOTAL 0.6(D-0.1 1.0 1.5 1.0 1.2 0.8
SERUM I-0.5)
BILIRUBIN
Lipid Profile
12/9 18/9 20/9 26/9
S.Triglycerides Grossly lipemic 351 261 201
S.Cholesterol 76 74 56
S.HDL 21 15 15
S.LDL 36 38 34
S.VLDL 52 32 41
Other Investigations
• WIDAL : To 1:80
Th 1:40
• Blood and urine cultures: sterile(5/9,8/9,14/9)
• HPLC : HbA 92%
HbF 5%
HbA2 2.8%
• G6PD : Normal
• S.Ferritin : >1000 ng/ml
• CPK-MB:
11/9 17/9
192 17
Protein C 57.8%
Protein S 46.8%
Antithrombin III 58.5%
Factor V Leiden 1.69
Fibrinogen C 1.25
INR 1.00
PTTK(T/C) 35.5/28.0
D Dimer 1583
ECHO(14/9)
•Dilated LV
•Ejection fraction 30%
•Mild MR
Myocarditis
Bone Marrow Aspiration
•Normocellular to hyercellular
•M:E : Normal
•Evidence of hemophagocytosis
•No evidence of atypical cells or excess of blasts
•Reticulin iron grade increased
•Megakaryocytes are decreased.
Approach – Differential Diagnosis
D/D’s Points in favour Points against
Enteric fever • High grade fever • Blood culture sterile
• Hepatosplenomegaly • Widal To and Th <1:160
• Deranged LFTs
• Anemia
• Thrombocytopenia
Kala - azar • High grade fever • Age of presentation 1-5 yrs
• Pancytopenia • Bone marrow examination:
• Hepatosplenomegaly Normocellular
• Altered liver enzymes
Malaria • High grade fever • Typical fever pattern
• Splenomegaly • Peripheral smear negative for
• Hepatomegaly malarial antigen(3 smears)
• Anemia
• Thrombocytopenia
Dengue fever • Pancytopenia • Age at presentation
• Splenomegaly • PBF : McHc
Normocellular bone marrow
Dengue Fever • High grade fever
• Dengue NS1Ag positive • Splenomegaly rare
• Thrombocytopenia evidenced
on serial hemogram
Acute leukemia • Pancytopenia • No evidence of blast cells on
• Hepatosplenomegaly peripheral smear
• Bone marrow examnation
normal
HLH • Fever • Normocellular bone marrow
• Pancytopenia
• Splenomegaly
• Hypofibrinogenemia and
Hyperferritinemia
Final Diagnosis:
Dengue fever with Myocarditis /Secondary Hemophagocytic lymphohistiocytosis(Dengue)
Follow up:
•Child was managed as per HLH 2004 protocol and received one cycle of chemotherapy during
hospitalization which he received uneventfully.
•Child was discharged after one cycle of immunosuppressive therapy (dexa and etoposide) with
weekly follow up advice.
•He has completed 4 weeks of chemotherapy and is clinically well on follow up examination with
regression of splenic size. Serial blood counts showed improvement.
6/10 13/10 20/10
Hb 10.0 11.7 11.8
TLC 12500 13000 12600
Platelets 2.2 1.75 5.8
•Samples for Molecular analysis for fHLH has been sent at PGIMER CHD ,report of which is
awaited.
Hemophagocytic
Lymphohistiocytosis(HLH)
HLH is a syndrome characterized by severe systemic hyperinflammation which clinically
presents with unremitting fever, cytopenias, organomegaly (hepatosplenomegaly), and raised
inflammatory markers. Patients can develop liver failure, neurological issues, coagulopathy, and
multiorgan failure.
If untreated or there is a delay in diagnosis, the syndrome can have a high mortality rate.
Pathophysiology
Etiology
Primary Secondary
HLH HLH
Infections
Malignancy
Genetic mutation Rheumatological
Metabolic
HLH Diagnostic Criteria
After initial therapy of 8 weeks, continuation therapy is given from week 9-40
•Inj.Etoposide (150 mg/m2)every 14 days
•Dexamethasone (10 mg/m2) for 3 days in pulses
•Cyclosporine A
Patients with primary HLH/reactivation subsequently move to hematopoietic stem cell
transplantation (HSCT).
Matched sibling donor, matched unrelated donor, haploidentical donor, and cord blood
transplants have all been described for HLH.
Reduced toxicity conditioning with treosulfan, fludarabine, thiotepa/alemtuzumab, treosulfan,
and fludarabine leads to stable mixed chimerism and improved survival in tune of 70–80%.
It is important to screen the sibling with genetic studies for nascent homozygous disease
before going forward with the transplant (heterozygous carriers are accepted).
Newer Therapies(Clinical Trials)
Emapalumab, monoclonal antibody directed against IFN-ү which was approved by FDA for
refractory ,recurrent or progressive HLH or patients who are not able to tolerate conventional
treatment but still there are ongoing clinical trials.
Anakinra (recombinant IL-1 receptor antagonist) useful in secondary HLH ,when given early
during the course of illness, esp in patients with underlying rheumatic disease.
Ruxolitinib , a Janus kinase inhibitor that inhibits the signaling of several cytokines inc IFN-ү -
only few human reports are available.a
Anti IL-18 directed therapy with a recombinant human IL-18 –binding protein in FHLH esp with
NLRC4 mutations or XIAP deficiency
Rituximab found beneficial in treatment of EBV-HLH.
Alemtuzumab ,another monoclonal antibody under clinical trial.
