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Acute Hepatitis and prolonged fever –
How far do we go?
Presenter:

Anita Dhanrajani - Jaslok Hospital, Mumbai

Moderator:

Ujjal Poddar – Pediatric Gastroenterologist, SGPGI, Lucknow

Panelists:

Gaurav Narula - Pediatric Oncologist, Tata Hospital, Mumbai
Prakash Vaidya – Pediatrician, Fortis Hospital, Mumbai
Geeta Billa – Hepatologist, Hiranandani Hospital, Mumbai
Acute hepatitis with prolonged
fever – how far do we go?
Dr Anita Dhanrajani
Under guidance of Dr Aabha Nagral
Jaslok Hospital And Research Centre
HISTORY
• 17 y, M
• BONCM
• Presenting complaints of fever for 10 days and
jaundice for 15 days.
• Right upper quadrant pain
• Anorexia, vomiting, malaise and fatigue
• Fever low grade, intermittent
HISTORY
• No h/o drug intake
• No history of blood transfusions, sexual
contact
• No previous history of jaundice
• No history of alcohol intake
EXAMINATION
•
•
•
•
•

Tachycardia
Icterus
Liver palpable: 4 cm, tender, firm, sharp edge
Spleen palpable: 2 cm BLCM
Enlarged submandibular lymph nodes: 2.5 cm
COURSE
•
•
•
•

Rapidly progressed to altered sensorium
Grade 3 encephalopathy – needing ventilation
Developed haematemesis and malena
Abdominal distension with presence of free
fluid
• Fever subsided
INVESTIGATIONS
CBC

Hb – 10.2gm%

WBC:
4500/mm3

P 28, L70

PC – 1.1 lacs

LFTs

T Bili – 13.8

ALP – 40 IU

SGPT –
1740
SGOT –
1028

TSP/Alb: 4.8
gm%, 1.9 gm
%

Viral
markers

IgM anti HAV –
positive

IgM anti
HEV –
Positive

HBV, HCV,
HIV negative

USG
abdomen

Mild ascites,
hepatomegaly,
splenomegaly

Coagulatio PT – 28/12
n profile

INR – 2.3

Others

S ammonia
– 110

RBS – 44 mg%

S
Blood culture
creatinine – - negative
PRIMARY DIAGNOSIS
Acute viral hepatitis (A+E) with fulminant
hepatic failure (FHF)
• Prodrome followed by jaundice and then
encephalophathy
• High bilirubin with high ALT
• Prolonged PT
• High ammonia
• IgM anti HAV plus HEV positive
FURTHER COURSE
• Encephalopathy recovered – patient
extubated
• Fever reappeared – high grade
• Tachycardia, tachypnea
• Hepatomegaly, splenomegaly and
lymphadenopathy persisted
• Continuing coagulopathy
Any thoughts?
Cause of fever?
•
•
•
•

Peritonitis (SBP)
Urinary tract infection
Ventilator induced pneumonia
Septicemia

What next?
FURTHER INVESTIGATIONS
CULTURES

BLOOD negative

URINE –
negative

ASCITIC
FLUID –
negative

SPUTUM negative

RADIOLOGY USG –
CT brain –
ascites,
normal
hepatospleno
megaly

PET CT
whole body –
adenopathy

XRAY CHEST
– normal

IMMUNOLO
GY

IgG – 1839
(N:664-1401)

IgM – 385
(N:55-141)

IgA – 200
(N:103-404)

C3 : 64 (73135)
C4 : 9.9 (1272)

VIRAL
MARKERS

CMV –
negative

EBV negative

INVASIVE

Lymph node
biopsy –
reactive
hyperplasia
with atypical

Bone marrow
biopsy - ?
myelodysplas
ia
What next?
BONE MARROW REVIEWED
Other investigations
•
•
•
•

Ferritin: 18,080 ug/L [N:15-200 ug/L]
Triglycerides: 642 mg/dl [N:150 mg/dl]
Fibrinogen: 150 mg/dl [N: 200 – 400 mg/dl]
NK cell activity and perforin levels sent – could
not be assessed due to low number of
lymphocytes
FINAL DIAGNOSIS
Secondary Haemophagocytic
Lymphohistiocytosis (HLH) – secondary to
viral hepatitis
FURTHER COURSE AND TREATMENT
•
•
•
•
•

Started on treatment as per HLH 2004 protocol
Dexamethasone - 10mg/m2 daily
Etoposide - 150 mg/m2 twice weekly
Cyclosporine - 6 mg/kg daily
Prophylactic co trimoxazole – 5 mg/kg thrice
weekly
• Continued antibiotics and antifungals –
Cefoperazone, Teicoplanin, Amphotericin B ,
Colistin
FURTHER COURSE AND TREATMENT
• Child developed severe neutropenia after 3
doses of etoposide (ANC <500)
• Discontinued etoposide
• Hypotension, hypoxia – required mechanical
ventilation and inotropic support
• Succumbed to illness
When to suspect HLH
CLINICAL CLUES
Unremitting , undiagnosed
prolonged fever

LABORATORY CLUES
Rapidly progressive
cytopenias

Organomegaly –
splenomegaly,
lymphadenopathy

Hyperferritinemia
Hypertriglyceridemia
Hypofibrinogenemia

Bleeding manifestations

BM or Organ biopsy with
hemophagocytosis
DIAGNOSIS OF HLH
• The diagnosis of HLH can be established if one of either 1 or 2
below is fulfilled:
1. A molecular diagnosis consistent with HLH is made.
2. Diagnostic criteria for HLH are fulfilled (5 of the 8 criteria)
• Fever
• Splenomegaly
• Cytopenias (affecting 2-3 lineages in the peripheral
blood):hemoglobin 9 g/dL, platelets 1 lac, neutrophils 10
• Hypertriglyceridemia and/or hypofibrinogenemia: fasting
triglycerides 3.0 mmol/L (ie, 265 mg/dL), fibrinogen 1.5 g/L
• Hemophagocytosis in BM, spleen, or lymph nodes
• Low or absent NK-cell activity.
TAKE HOME MESSAGE
• Secondary HLH high index of suspicion – can
complicate any viral illness.
• Investigations for primary HLH should form
part of initial work up in any given HLH case
• Initial treatment of primary and secondary
HLH – same.

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Acute hepatitis with prolonged fever1

  • 1. Acute Hepatitis and prolonged fever – How far do we go? Presenter: Anita Dhanrajani - Jaslok Hospital, Mumbai Moderator: Ujjal Poddar – Pediatric Gastroenterologist, SGPGI, Lucknow Panelists: Gaurav Narula - Pediatric Oncologist, Tata Hospital, Mumbai Prakash Vaidya – Pediatrician, Fortis Hospital, Mumbai Geeta Billa – Hepatologist, Hiranandani Hospital, Mumbai
  • 2. Acute hepatitis with prolonged fever – how far do we go? Dr Anita Dhanrajani Under guidance of Dr Aabha Nagral Jaslok Hospital And Research Centre
  • 3. HISTORY • 17 y, M • BONCM • Presenting complaints of fever for 10 days and jaundice for 15 days. • Right upper quadrant pain • Anorexia, vomiting, malaise and fatigue • Fever low grade, intermittent
  • 4. HISTORY • No h/o drug intake • No history of blood transfusions, sexual contact • No previous history of jaundice • No history of alcohol intake
  • 5. EXAMINATION • • • • • Tachycardia Icterus Liver palpable: 4 cm, tender, firm, sharp edge Spleen palpable: 2 cm BLCM Enlarged submandibular lymph nodes: 2.5 cm
  • 6. COURSE • • • • Rapidly progressed to altered sensorium Grade 3 encephalopathy – needing ventilation Developed haematemesis and malena Abdominal distension with presence of free fluid • Fever subsided
  • 7. INVESTIGATIONS CBC Hb – 10.2gm% WBC: 4500/mm3 P 28, L70 PC – 1.1 lacs LFTs T Bili – 13.8 ALP – 40 IU SGPT – 1740 SGOT – 1028 TSP/Alb: 4.8 gm%, 1.9 gm % Viral markers IgM anti HAV – positive IgM anti HEV – Positive HBV, HCV, HIV negative USG abdomen Mild ascites, hepatomegaly, splenomegaly Coagulatio PT – 28/12 n profile INR – 2.3 Others S ammonia – 110 RBS – 44 mg% S Blood culture creatinine – - negative
  • 8. PRIMARY DIAGNOSIS Acute viral hepatitis (A+E) with fulminant hepatic failure (FHF) • Prodrome followed by jaundice and then encephalophathy • High bilirubin with high ALT • Prolonged PT • High ammonia • IgM anti HAV plus HEV positive
  • 9. FURTHER COURSE • Encephalopathy recovered – patient extubated • Fever reappeared – high grade • Tachycardia, tachypnea • Hepatomegaly, splenomegaly and lymphadenopathy persisted • Continuing coagulopathy Any thoughts?
  • 10. Cause of fever? • • • • Peritonitis (SBP) Urinary tract infection Ventilator induced pneumonia Septicemia What next?
  • 11. FURTHER INVESTIGATIONS CULTURES BLOOD negative URINE – negative ASCITIC FLUID – negative SPUTUM negative RADIOLOGY USG – CT brain – ascites, normal hepatospleno megaly PET CT whole body – adenopathy XRAY CHEST – normal IMMUNOLO GY IgG – 1839 (N:664-1401) IgM – 385 (N:55-141) IgA – 200 (N:103-404) C3 : 64 (73135) C4 : 9.9 (1272) VIRAL MARKERS CMV – negative EBV negative INVASIVE Lymph node biopsy – reactive hyperplasia with atypical Bone marrow biopsy - ? myelodysplas ia
  • 14. Other investigations • • • • Ferritin: 18,080 ug/L [N:15-200 ug/L] Triglycerides: 642 mg/dl [N:150 mg/dl] Fibrinogen: 150 mg/dl [N: 200 – 400 mg/dl] NK cell activity and perforin levels sent – could not be assessed due to low number of lymphocytes
  • 15. FINAL DIAGNOSIS Secondary Haemophagocytic Lymphohistiocytosis (HLH) – secondary to viral hepatitis
  • 16. FURTHER COURSE AND TREATMENT • • • • • Started on treatment as per HLH 2004 protocol Dexamethasone - 10mg/m2 daily Etoposide - 150 mg/m2 twice weekly Cyclosporine - 6 mg/kg daily Prophylactic co trimoxazole – 5 mg/kg thrice weekly • Continued antibiotics and antifungals – Cefoperazone, Teicoplanin, Amphotericin B , Colistin
  • 17. FURTHER COURSE AND TREATMENT • Child developed severe neutropenia after 3 doses of etoposide (ANC <500) • Discontinued etoposide • Hypotension, hypoxia – required mechanical ventilation and inotropic support • Succumbed to illness
  • 18. When to suspect HLH CLINICAL CLUES Unremitting , undiagnosed prolonged fever LABORATORY CLUES Rapidly progressive cytopenias Organomegaly – splenomegaly, lymphadenopathy Hyperferritinemia Hypertriglyceridemia Hypofibrinogenemia Bleeding manifestations BM or Organ biopsy with hemophagocytosis
  • 19. DIAGNOSIS OF HLH • The diagnosis of HLH can be established if one of either 1 or 2 below is fulfilled: 1. A molecular diagnosis consistent with HLH is made. 2. Diagnostic criteria for HLH are fulfilled (5 of the 8 criteria) • Fever • Splenomegaly • Cytopenias (affecting 2-3 lineages in the peripheral blood):hemoglobin 9 g/dL, platelets 1 lac, neutrophils 10 • Hypertriglyceridemia and/or hypofibrinogenemia: fasting triglycerides 3.0 mmol/L (ie, 265 mg/dL), fibrinogen 1.5 g/L • Hemophagocytosis in BM, spleen, or lymph nodes • Low or absent NK-cell activity.
  • 20. TAKE HOME MESSAGE • Secondary HLH high index of suspicion – can complicate any viral illness. • Investigations for primary HLH should form part of initial work up in any given HLH case • Initial treatment of primary and secondary HLH – same.