Non-Infectious Causes of Fever and Vasoplegia After Stem Cell Infusion
Fever and vasoplegia immediately following stem cell infusion are most commonly caused by cytokine release from the infused cellular product itself, particularly with peripheral blood stem cells (PBSC), higher CD34+ cell doses, HLA-mismatched grafts, and female donors—this is a self-limited transfusion reaction, not infection. 1, 2, 3
Primary Mechanism: Cytokine-Mediated Infusion Reaction
The fever and vasoplegia you're observing represent an instant blood-mediated inflammatory reaction (IBMIR) triggered by the stem cell product itself 4:
- Onset timing: Fever typically begins within 2.5 hours (range 0-18 hours) after infusion, with peak temperatures at 7.8 hours (range 3.5-23 hours) post-infusion 2
- Temperature pattern: Median peak temperatures reach 39.0°C (range 38.1-40.5°C) 1
- Incidence: Occurs in 81-82.5% of haploidentical transplant recipients 1, 3
- Resolution: 91% of febrile episodes resolve within 96 hours of cyclophosphamide administration 1
Specific Risk Factors for Post-Infusion Fever
High-risk features that predict this reaction 2, 3:
- Female donor (strongest predictor in multivariate analysis) 2
- Higher peripheral leukocyte count in donor blood 2
- Higher CD34+ cell dose (median 5.00 vs. 3.08 × 10⁶/kg in non-febrile patients) 3
- Higher CD3+ cell dose (12.8 vs. 4.5 × 10⁷/kg) 3
- PBSC source (71% vs. 9% with marrow grafts) 3
- Greater degree of HLA mismatches 3
- Myeloablative conditioning (50% vs. 9% with reduced intensity) 3
Vasoplegia Mechanism in This Context
The vasoplegia component is mediated by 4:
- Tissue factor (TF) expression on infused mesenchymal stromal cells triggering coagulation cascade 4
- Cytokine release from necrotic cells and damaged blasts (IL-1β, TNF-α, thrombin) 4
- Capillary leak syndrome (CLS) manifestations including hypoalbuminemia, edema, hypotension, and hyponatremia 4
Clinical Presentation Pattern
Key distinguishing features from infection 1, 2:
- No hemodynamic collapse requiring ICU admission 1
- No respiratory compromise 1
- No identifiable infectious focus in 81% of cases 2
- Self-limited course without specific antimicrobial intervention 1
Management Approach
Immediate supportive measures 4:
- Premedications: Acetaminophen, diphenhydramine, methylprednisolone, and famotidine 4
- Symptomatic treatment: Additional acetaminophen, meperidine, antiemetics, H1- and H2-histamine antagonists 4
- For vasoplegia/CLS: Parenteral albumin and diuretics for hypoalbuminemia and edema 4
- Anticoagulation consideration: Patients receiving mesenchymal stromal cells with high TF expression may benefit from prophylactic anticoagulation 4
Empiric antibiotics are still indicated 4, 5:
- Fever should prompt empiric antimicrobial therapy based on institutional protocols while awaiting cultures 4
- Blood cultures from all central venous catheter lumens are mandatory 4
- This approach is necessary because infection cannot be definitively excluded at presentation 4
Critical Pitfalls to Avoid
- Do not assume all post-infusion fever is benign: While 81% are non-infectious, 19% have documented infection requiring appropriate workup 2
- Do not delay antibiotics in unstable patients: Even though most fevers are cytokine-mediated, empiric coverage is warranted until infection is excluded 4, 5
- Do not overlook CLS manifestations: Monitor albumin levels closely as hypoalbuminemia is the earliest and most consistent sign of capillary leak 4
- Recognize this does not predict poor outcomes: Development of post-infusion fever has no impact on overall survival, event-free survival, or GVHD-free/relapse-free survival 1, 3