What could be the cause of anemia and recurrent moderate-grade fever in a patient with a hemoglobin level of 9.2 g/dL, no signs of bleeding, and improved overall well-being?

Acute Hemolytic Anemia Secondary to Megaloblastic Anemia

The most likely cause of this patient's rapid hemoglobin drop from 12 to 9.2 g/dL over 24 hours with persistent fever is acute hemolytic anemia secondary to severe megaloblastic anemia (vitamin B12 or folate deficiency), which can present with high-grade fever mimicking tropical infection. 1, 2

Key Diagnostic Features Supporting This Diagnosis

Hemolytic Pattern Without Bleeding

• A 2.8 g/dL hemoglobin drop in 24 hours without visible bleeding strongly suggests hemolysis rather than blood loss 2
• Megaloblastic anemia causes ineffective erythropoiesis and intramedullary hemolysis, leading to rapid hemoglobin decline 1, 3
• The combination of fever, anemia, and absence of bleeding is characteristic of megaloblastic anemia presenting as a febrile illness 1

Fever Pattern in Megaloblastic Anemia

• Fever occurs in approximately 40% of patients with megaloblastic anemia and can reach temperatures >103°F (39.4°C) 3
• High-grade fever (>101°F) with megaloblastic anemia has a mean duration of 7.7 days (range 4-18 days) 1
• The moderate-grade fever occurring twice daily fits this pattern 1
• Fever in megaloblastic anemia typically resolves within 1-5 days (mean 2.6 days) after initiating vitamin B12 or folic acid therapy 1, 3

Clinical Improvement Despite Anemia

• The paradoxical improvement in overall well-being and good appetite despite worsening anemia is consistent with megaloblastic anemia, where systemic symptoms may improve even before hematologic parameters normalize 1
• This contrasts with infectious causes where clinical deterioration typically accompanies worsening anemia 4

Essential Immediate Laboratory Workup

First-Line Tests to Confirm Diagnosis

• Complete blood count with mean corpuscular volume (MCV) - expect MCV ≥110 fL, especially if temperature ≥103°F 1
• Peripheral blood smear - look for hypersegmented neutrophils and macro-ovalocytes 1, 2
• Reticulocyte count - typically low or inappropriately normal for degree of anemia 2
• Lactate dehydrogenase (LDH) - expect marked elevation (mean 814 ± 24 IU/L in megaloblastic anemia with fever) 1
• Unconjugated bilirubin - elevated in 75% of cases due to intramedullary hemolysis 1
• Serum vitamin B12 and folate levels - 87.5% of patients with megaloblastic anemia and fever have documented deficiency 1

Critical Tests to Exclude Alternative Diagnoses

• Thick and thin blood smears for malaria - mandatory given fever and anemia, as malaria can present identically 4, 5
• Direct Coombs test - to exclude autoimmune hemolytic anemia 2
• Haptoglobin and indirect bilirubin - to confirm hemolysis 2
• White blood cell count - leucopenia ≤3000/cumm is significantly associated with temperature ≥103°F in megaloblastic anemia 1

Immediate Management Algorithm

Step 1: Initiate Empiric Vitamin Therapy While Awaiting Results

• Start parenteral vitamin B12 (1000 mcg IM daily) immediately if megaloblastic anemia is suspected 1, 2
• Add folic acid 1-5 mg daily orally 1
• Monitor temperature closely - defervescence within 1-5 days confirms diagnosis 1, 3
• Failure of fever to resolve rapidly suggests alternative diagnosis requiring further investigation 3

Step 2: Transfusion Decision

• Do NOT transfuse at hemoglobin 9.2 g/dL in a stable patient without active bleeding, cardiovascular symptoms, or severe hypoxemia 4, 6
• The restrictive transfusion threshold of <7.0 g/dL is recommended in most hospitalized patients 4, 6
• Monitor hemoglobin daily until stable 4

Step 3: Monitor for Treatment Response

• Expect reticulocytosis within 3-5 days of vitamin therapy initiation 1
• Hemoglobin should begin rising within 1 week 1
• Temperature normalization within 1-5 days confirms megaloblastic anemia as cause 1, 3

Alternative Diagnoses to Consider

Malaria

• Must be excluded in any patient with fever and anemia, especially with travel history 4
• Plasmodium falciparum can cause rapid hemoglobin decline and fever 4
• Blood smears should be checked every 12 hours if initial smears are negative but suspicion remains high 4

Drug-Induced Hemolytic Anemia

• Ceftriaxone and other cephalosporins can cause immune-mediated hemolytic anemia 7
• Review all medications, including recent antibiotic use 7
• Severe cases including fatalities have been reported 7

Hemolytic Uremic Syndrome or TTP

• Less likely given improved clinical status and good appetite 2
• Would expect more severe systemic symptoms and potential renal dysfunction 2

Common Pitfalls to Avoid

Diagnostic Pitfalls

• Do not dismiss megaloblastic anemia as a cause of high-grade fever - it is frequently overlooked because fever is not widely recognized as a presenting feature 1, 2
• Do not delay vitamin therapy while awaiting confirmatory test results - empiric treatment is safe and diagnostic response confirms the diagnosis 1, 3
• Do not attribute fever solely to infection without checking vitamin levels - this leads to unnecessary antibiotics and delayed diagnosis 1, 2

Management Pitfalls

• Do not transfuse based solely on hemoglobin level - assess hemodynamic stability, symptoms, and oxygen delivery 4, 6
• Do not stop vitamin therapy if fever persists beyond 5 days - this suggests concurrent infection or alternative diagnosis requiring additional workup 3
• Do not overlook malaria in the differential - it can present identically and requires immediate treatment 4

Monitoring Pitfalls

• Do not assume clinical improvement means hemoglobin is stable - continue daily monitoring until hemoglobin stabilizes 4, 6
• Do not miss concurrent vitamin D deficiency - it can coexist with B12 deficiency and contribute to symptoms 2