What is the approach to an infant with fever and hepatosplenomegaly?

Approach to a 9-Month-Old Infant with Fever and Hepatosplenomegaly

In a 9-month-old infant presenting with fever and hepatosplenomegaly, immediately obtain a complete blood count with differential, comprehensive metabolic panel with liver function tests, and inflammatory markers (CRP, ferritin) to identify life-threatening conditions such as hemophagocytic lymphohistiocytosis (HLH), acute leukemia, or serious infections. 1, 2

Immediate Life-Threatening Considerations

Rule Out Hemophagocytic Lymphohistiocytosis (HLH)

• HLH is a critical diagnosis that presents with fever, hepatosplenomegaly, and cytopenias—without appropriate treatment, it is usually fatal. 3
• Check for cytopenias affecting two or three cell lines, markedly elevated ferritin (often >500 ng/mL), elevated LDH, hypertriglyceridemia, and hypofibrinogenemia 3, 4
• Familial HLH typically presents in the first 2 years of life, making this age group particularly vulnerable 5
• If HLH is suspected based on fever, hepatosplenomegaly, and laboratory abnormalities, proceed urgently to bone marrow examination to identify hemophagocytosis 3, 4

Exclude Acute Leukemia

• Acute leukemia is a primary concern when fever, hepatosplenomegaly, and pancytopenia (anemia, thrombocytopenia, neutropenia) are present together. 2
• Obtain peripheral blood smear examination by a qualified hematologist/pathologist to look for blasts or abnormal cells 2
• Bone marrow examination with aspirate, biopsy, flow cytometry, and cytogenetic testing is indicated when systemic symptoms are present with peripheral blood abnormalities beyond isolated thrombocytopenia 2

Consider Serious Bacterial Infections

• In newborns and young infants with fever, hepatosplenomegaly, and shock, distinguish septic shock from cardiogenic shock due to ductal-dependent congenital heart disease 6
• Any infant with shock and hepatomegaly should be started on prostaglandin infusion until complex congenital heart disease is ruled out by echocardiography 6

Infectious Etiologies to Evaluate

Congenital and Perinatal Infections

• In HIV-exposed infants, congenital toxoplasmosis presents with hepatosplenomegaly, jaundice, thrombocytopenia, neutropenia, and CNS disease including hydrocephalus and intracerebral calcification. 6
• Congenital tuberculosis presents with inadequate feeding, failure to thrive, progressive hepatosplenomegaly, fever, and progressive pneumonia in the first weeks of life 6
• All infants whose mothers are HIV-infected and seropositive for Toxoplasma should be evaluated for congenital toxoplasmosis using Toxoplasma-specific IgM, IgA, or IgE testing 6

Tick-Borne Infections (If Exposure History Present)

• Ehrlichiosis characteristically presents with fever, leukopenia, thrombocytopenia, anemia, and hepatosplenomegaly, with a 3% case-fatality rate 2
• Rocky Mountain Spotted Fever presents with fever, hepatomegaly, and splenomegaly, with a 5-10% case-fatality rate 2

Epstein-Barr Virus (EBV)

• EBV is the most common causative agent in infection-associated hemophagocytic syndrome 4
• EBV-associated HLH can have a fatal course due to unregulated T-cell reaction releasing excessive cytokines 7, 4

Essential Diagnostic Workup

Initial Laboratory Tests

• Complete blood count with differential to assess for cytopenias, thrombocytopenia, and abnormal cells 1, 2
• Comprehensive metabolic panel including liver function tests (AST, ALT, GGT, direct and total bilirubin) 1
• Inflammatory markers: CRP, procalcitonin, and ferritin (markedly elevated ferritin supports HLH diagnosis) 1, 3
• Coagulation studies including fibrinogen and triglycerides 3, 4

Imaging Studies

• Abdominal ultrasound with Doppler to assess liver and spleen morphology, detect focal lesions, and evaluate for portal hypertension 1
• Chest radiograph if respiratory symptoms are present 1
• Echocardiography is essential if shock, hepatomegaly, cardiac murmur, or differential pulses are present to rule out congenital heart disease 6

Advanced Testing When Indicated

• Bone marrow biopsy is necessary to identify hemophagocytosis, storage cells, or malignant infiltration when systemic symptoms, organomegaly, or abnormal blood counts are present 1, 2, 3
• Peripheral blood smear examination by a hematologist/pathologist 2
• Flow cytometry and cytogenetic testing if malignancy is suspected 2

Metabolic and Storage Disorders

• Lysosomal storage diseases such as acid sphingomyelinase deficiency (Niemann-Pick disease) should be considered, particularly if splenomegaly is massive 1, 2
• These conditions present in infancy with marked abdominal distension, hepatosplenomegaly, thrombocytopenia, and leukopenia 2
• Genetic testing for SMPD1 gene is recommended if clinical suspicion is high 1

Critical Pitfalls to Avoid

• Delaying bone marrow examination when systemic symptoms or organomegaly are present can delay diagnosis of life-threatening malignancies or HLH 2, 3
• Not recognizing that splenomegaly, hepatomegaly, or lymphadenopathy on physical examination suggests serious secondary causes requiring urgent evaluation 2
• Overlooking congenital infections in young infants, particularly in HIV-exposed children 2
• Failing to consider HLH early in patients with unremitting fever, hepatosplenomegaly, and cytopenias 3
• Administering oxygen before anatomic diagnosis in infants with suspected ductal-dependent congenital heart disease, as oxygen may constrict the ductus arteriosus and reduce systemic output 6