Table of Contents
For a child with prolonged fever + hepatosplenomegaly + persistent leukocytosis, I would use the following as a bedside differential/workup table, with particular attention to infections relevant to Nepal and hematologic disease.
1. Infectious causes
| Differential | History: ask for | Examination clues | Key investigations |
|---|---|---|---|
| Tuberculosis | Contact, chronic cough, weight loss, night sweats, poor appetite; household exposure | Cervical/generalized nodes, wasting, respiratory signs, hepatosplenomegaly | CXR; TST/IGRA; Xpert MTB/RIF/Ultra from appropriate specimen; culture; node FNAC/biopsy if present |
| Enteric fever | Prolonged fever, contaminated food/water, travel/outbreak exposure, abdominal symptoms | Toxicity may be mild; abdominal tenderness, hepatosplenomegaly; relative bradycardia is unreliable in children | Blood culture before antibiotics; CBC, LFT; stool culture in selected cases |
| Malaria | Residence/travel to endemic Terai areas, mosquito exposure, intermittent/chills pattern | Pallor, jaundice, splenomegaly, hepatomegaly; thrombocytopenia | Thick + thin smear + malaria RDT; repeat smear if high suspicion |
| Visceral leishmaniasis | Prolonged fever, travel/residence in endemic region, weight loss | Massive splenomegaly, hepatomegaly, pallor, wasting | rK39/other serology; CBC; confirmatory parasitologic testing when indicated |
| Brucellosis | Cattle/goat/sheep exposure, raw/unpasteurized milk, occupational exposure, undulating fever | HSM, lymphadenopathy, arthritis; sometimes nonspecific | Blood cultures; Brucella serology/PCR where available |
| EBV | Sick contacts, sore throat, fatigue | Posterior cervical nodes, pharyngitis/tonsillar enlargement, HSM | CBC differential, atypical lymphocytes; EBV VCA IgM/IgG ± EBNA; LFT |
| CMV | Sick contacts; congenital/perinatal history in younger child | HSM, lymphadenopathy; prolonged fever | CMV IgM/IgG ± PCR in selected cases; LFT |
| Scrub typhus | Rural/forest exposure, mite exposure, recent outdoor activity | Eschar, rash, lymphadenopathy; hepatosplenomegaly; thrombocytopenia | Scrub typhus IgM/ELISA ± PCR |
| Leptospirosis | Floodwater/freshwater, rodents, animal urine | Conjunctival suffusion, jaundice, renal involvement, myalgia | CBC, renal/LFT; Leptospira PCR/IgM |
| Dengue | Mosquito exposure, acute febrile illness | Rash, bleeding, abdominal tenderness, hepatomegaly; usually thrombocytopenia | CBC trend; NS1/PCR early, IgM later |
| Disseminated fungal infection | Immunodeficiency, prolonged antibiotics, steroid/immunosuppressive therapy | HSM, lymphadenopathy, skin/mucosal lesions | Blood cultures, fungal biomarkers/cultures; imaging/tissue diagnosis |
| HIV | Maternal risk, transfusion, recurrent/opportunistic infections, growth failure | Generalized nodes, HSM, oral candidiasis, wasting | HIV Ag/Ab testing; confirmatory algorithm; viral load/CD4 where appropriate |
| Toxoplasmosis | Cat/feces exposure, undercooked meat; immunocompromised state | Cervical nodes, HSM occasionally | Toxoplasma IgM/IgG ± PCR in selected cases |
| Toxocariasis | Dogs/cats, soil exposure, pica | Hepatomegaly, fever, eosinophilia, sometimes ocular disease | CBC with AEC, Toxocara serology |
| Hydatid disease | Dog/sheep exposure | Usually mass/organ-specific findings rather than fever | USG/CT; Echinococcus serology |
2. Hematologic / malignant causes
| Differential | History | Examination | Investigations |
|---|---|---|---|
| ALL | Fever, fatigue, weight loss, bone/joint pain, bruising, recurrent infections | Pallor, petechiae, lymphadenopathy, HSM, bone tenderness | CBC + differential + PBS, retic, LDH/uric acid; bone marrow + flow cytometry if suspected |
| AML | Fever, fatigue, bleeding, infections, bone pain | Pallor, petechiae, HSM, gingival hypertrophy, chloromas | CBC/PBS; marrow morphology + flow cytometry/cytogenetics/molecular studies |
| Lymphoma | Fever, weight loss, night sweats, pruritus; node enlargement | Firm/painless nodes, mediastinal signs, HSM | CBC, LDH/uric acid; CXR/USG/CT as indicated; excisional lymph-node biopsy |
| CML | Fatigue, weight loss, early satiety, abdominal discomfort | Marked splenomegaly, hepatomegaly; pallor | CBC differential + PBS; BCR-ABL1 testing, marrow/cytogenetics |
| JMML | Usually young child; fever, recurrent infections, pallor, rash | Splenomegaly, lymphadenopathy, pallor, skin lesions | CBC showing persistent monocytosis, PBS; marrow; molecular testing (e.g. RAS-pathway abnormalities) |
| Leukemoid reaction | Infection/inflammation symptoms | Underlying infectious focus; may have HSM | Serial CBC, PBS; neutrophilia/left shift; investigate underlying cause |
| Hemolytic anemia | Jaundice, dark urine, episodic symptoms, drugs/infection/family history | Pallor, jaundice, splenomegaly | Retic, indirect bilirubin, LDH, haptoglobin, DAT, ± Hb electrophoresis/G6PD |
3. Inflammatory / immune causes
| Differential | History | Examination | Investigations |
|---|---|---|---|
| Systemic JIA | Fever ≥2 weeks, arthritis, rash; fever often quotidian | Arthritis, evanescent salmon rash, lymphadenopathy, HSM | CBC, ESR/CRP, ferritin, LFT; diagnosis is clinical after exclusion |
| MAS secondary to sJIA | Persistent fever, acute deterioration | HSM, rash, bleeding/neurologic changes | Ferritin, TG, fibrinogen, CBC, AST/ALT, D-dimer |
| HLH | Persistent fever, family history/recurrent episodes, infection trigger | Splenomegaly, HSM, lymphadenopathy, neurologic/skin findings | Ferritin, TG, fibrinogen, CBC, LFT; sCD25/NK function/genetics in appropriate cases |
| Kawasaki disease | Fever ≥5 days, irritability | Conjunctival injection, oral changes, rash, extremity changes, cervical node | CRP/ESR, CBC, LFT, urinalysis; echocardiography |
| SLE | Fever, fatigue, rash, photosensitivity, arthralgia, oral ulcers | Rash, arthritis, alopecia, lymphadenopathy/HSM, hypertension | CBC, ESR/CRP, ANA, dsDNA, C3/C4, urinalysis/proteinuria |
4. Important noninfectious causes of HSM
| Cause | History/exam clues | Investigations |
|---|---|---|
| Gaucher disease | Chronic massive HSM, pallor, bone pain/crises, growth issues | β-glucocerebrosidase enzyme assay ± genetics |
| Niemann-Pick disease | HSM + developmental regression/neurologic signs | Enzyme/genetic testing |
| Glycogen storage disease | Hepatomegaly, growth failure, hypoglycemia; fever usually suggests a separate process | Glucose, lactate, LFT, metabolic/genetic testing |
| Chronic liver disease/portal hypertension | Jaundice, ascites, bleeding, pruritus, liver disease history | LFT, INR, albumin, viral/autoimmune/metabolic workup, USG Doppler |
Particularly important with persistent leukocytosis
Don’t just record the WBC. Break it down:
| CBC pattern | Differential to prioritize |
|---|---|
| Neutrophilia + left shift | Bacterial infection, occult abscess, leukemoid reaction, inflammatory disease |
| Very high neutrophils + basophilia + myelocytes/metamyelocytes | CML |
| Persistent monocytosis | JMML, TB, brucellosis, chronic infections |
| Absolute lymphocytosis | EBV/CMV, pertussis, viral infection, hematologic disease |
| Eosinophilia | Helminths, Toxocara, drug/allergic disease |
| Blasts | Acute leukemia until proven otherwise |
| Leukocytosis + anemia + thrombocytopenia | Strongly consider marrow disease/leukemia |
| Leukocytosis with normal morphology and active child | Infection/inflammation or leukemoid reaction more likely, but persistent marked leukocytosis requires further evaluation |
A practical initial panel for this child
Given your specific presentation, I would start with:
CBC + differential + platelets + repeat PBS
→ CRP/ESR ± PCT
→ reticulocyte count + MCV/RDW + ferritin
→ LFT/bilirubin/LDH
→ malaria RDT + thick/thin smear
→ blood culture
→ urine R/M + culture
→ USG abdomen
Then based on findings/exposure:
TB testing | EBV/CMV | Brucella | scrub typhus | leptospira | VL/rK39 | stool/parasite testing | Toxocara | HIV | HLH/MAS panel | BCR-ABL1/marrow studies.
For persistent leukocytosis + HSM specifically, I would make sure the report gives the absolute neutrophil, lymphocyte, monocyte, eosinophil and basophil counts—not just total WBC. That single detail can substantially narrow this differential.