What are the guidelines for cytomegalovirus (CMV) prophylaxis, monitoring, pre‑emptive therapy, and treatment in pediatric solid‑organ transplant (SOT) and hematopoietic stem‑cell transplant (HSCT) recipients, and how does human herpesvirus‑6 (HHV‑6) reactivation influence management?

CMV and HHV-6 in Pediatric Transplantation

CMV: The Dominant Viral Pathogen Post-Transplant

All pediatric solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients at risk for CMV—defined as any CMV-seropositive recipient or any CMV-seronegative recipient with a CMV-seropositive donor—must receive either antiviral prophylaxis or pre-emptive viral monitoring from engraftment through day 100 post-transplant. 1

Risk Stratification by Serostatus

CMV risk stratification determines the entire prevention strategy:

• Highest risk (D+/R−): CMV-seronegative recipients receiving organs/grafts from CMV-seropositive donors face the greatest morbidity and mortality burden from primary CMV infection 2
• High risk (R+): All CMV-seropositive recipients (regardless of donor status) are at risk for viral reactivation, with 50-60% experiencing CMV reactivation in allogeneic HSCT despite prophylaxis 1
• Intermediate risk (D+/R+): Reactivation of recipient virus or donor-derived reinfection can occur 2
• No risk (D−/R−): These patients require no antiviral prophylaxis but must receive only leukocyte-reduced or CMV-seronegative blood products (≤1×10⁶ leukocytes/unit) to prevent transfusion-associated CMV 1, 2

Two Evidence-Based Prevention Strategies

Clinicians must choose between universal prophylaxis or pre-emptive therapy—both are equally valid approaches with different operational requirements:

Strategy 1: Universal Prophylaxis

• Administer ganciclovir (or valganciclovir in SOT) to all at-risk patients from engraftment through day 100 post-HSCT 1
• For SOT recipients: valganciclovir 900 mg once daily (dose-adjusted for renal function) for 3-6 months post-transplant 2
• Advantage: simpler protocol, no need for intensive laboratory monitoring
• Disadvantage: exposes all at-risk patients to drug toxicity (neutropenia, thrombocytopenia) 1

Strategy 2: Pre-emptive Therapy (Preferred for D+/R− HSCT)

Pre-emptive therapy is specifically preferred over universal prophylaxis for CMV-seronegative HSCT recipients with CMV-seropositive donors (D+/R−) because the attack rate of active CMV infection is low when leukocyte-reduced blood products are used 1

Pre-emptive protocol requirements:

• Screen at-risk allogeneic HSCT recipients ≥1 time per week from day 10 through day 100 post-transplant 1, 3
• Initiate IV ganciclovir immediately when CMV pp65 antigenemia is detected, when CMV viremia is confirmed, or after ≥2 consecutive positive CMV-DNA PCR tests 1
• Continue treatment until two consecutive negative results, typically through day 100 1
• Advantage: restricts ganciclovir to patients with documented infection, reducing unnecessary drug exposure 1
• Disadvantage: requires rapid, sensitive laboratory testing (CMV pp65 antigenemia or quantitative PCR) with results available within 24-48 hours 1

Centers without access to CMV pp65 antigenemia testing or quantitative PCR should use universal prophylaxis rather than pre-emptive therapy 1

Diagnostic Testing Hierarchy

The choice of monitoring test determines success of pre-emptive strategies:

1. CMV pp65 antigenemia (preferred): Most rapid, sensitive, and has good positive predictive value for clinical disease 1
2. Quantitative CMV-DNA PCR (plasma): Very sensitive but lower positive predictive value; useful during neutropenia when leukocyte counts are too low for antigenemia testing 1
3. Viral culture (shell-vial or routine): Less sensitive, requires ≥48 hours to weeks for results—less satisfactory than antigenemia or PCR 1

Treatment of Active CMV Infection

• First-line: Valganciclovir (oral) or IV ganciclovir remain the agents of choice 1, 4
• Oral valganciclovir is safe and effective as pre-emptive therapy in pediatric HSCT patients, reduces hospital stay, and is preferred for outpatient management 5
• Second-line: Foscarnet for patients intolerant of ganciclovir or for suspected drug resistance, though it carries higher nephrotoxicity risk 1
• Newer agent: Letermovir (480 mg/day oral or IV, or 240 mg/day with cyclosporine) for 14 weeks post-HSCT reduces clinically significant CMV infection from 61% to 38% in allogeneic HSCT recipients, with lower toxicity than ganciclovir but risk of rapid resistance emergence 1

Critical Timing: The Three Post-Transplant Phases

CMV risk varies by post-transplant phase, which guides monitoring intensity:

• Phase I (pre-engraftment, <30 days): Neutropenia and mucosal barrier breakdown dominate; bacterial/fungal infections are primary concerns 1, 3
• Phase II (30-100 days post-HSCT): CMV is the dominant viral pathogen during this phase—impaired cell-mediated immunity and acute GVHD create peak CMV risk 1, 3
• Phase III (>100 days): Patients with chronic GVHD remain at risk for late CMV reactivation, VZV, EBV-related post-transplant lymphoproliferative disease, and encapsulated bacterial infections 1

Pediatric-Specific Considerations

• Prophylaxis failures occur in approximately 40% of high-risk pediatric HSCT recipients despite appropriate prophylaxis 6
• Multiple viral infections (≥2 viruses) during the first 100 days post-HSCT are significantly associated with chronic GVHD (P<0.001) and secondary graft failure (P=0.001) in pediatric allogeneic recipients 6
• CMV DNAemia incidence is significantly higher in CMV-seropositive pediatric recipients (36%) versus seronegative recipients (2%, P=0.0002) 7
• Three out of nine pediatric patients with CMV DNAemia developed CMV disease despite adequate pre-emptive treatment, highlighting the need for vigilant monitoring 7

HHV-6: The Underrecognized Co-Pathogen

Clinical Relevance in Transplantation

While the provided guidelines focus predominantly on CMV, HHV-6 reactivation occurs commonly after allogeneic HSCT and can complicate the post-transplant course, particularly during the same Phase II period (30-100 days) when CMV reactivation peaks 1. HHV-6 can cause:

• Encephalitis (most serious manifestation)
• Bone marrow suppression
• Delayed engraftment
• Potential contribution to GVHD pathogenesis

Intersection with CMV Management

Multiple viral reactivations (including HHV-6 alongside CMV) during early post-transplant period reflect severe immunological derangement and identify pediatric patients at increased risk for chronic GVHD and graft failure 6. This underscores the importance of:

• Monitoring for multiple viral pathogens simultaneously during Phase II
• Recognizing that HHV-6 reactivation may complicate or mimic CMV disease
• Considering HHV-6 testing in patients with unexplained encephalopathy, fever, or marrow suppression despite negative CMV surveillance

Management Approach

Unlike CMV, there are no standardized prophylaxis or pre-emptive therapy protocols for HHV-6 in the provided guidelines. However:

• Foscarnet and ganciclovir have activity against HHV-6 1
• Treatment is typically reserved for documented HHV-6 disease (especially encephalitis) rather than asymptomatic viremia
• The overlap in antiviral coverage means CMV prophylaxis/treatment may provide some HHV-6 suppression

Common Pitfalls and How to Avoid Them

• Pitfall: Assuming D−/R− patients need prophylaxis—they do not, but they absolutely require screened blood products 1, 2
• Pitfall: Using pre-emptive strategy without adequate laboratory infrastructure—this leads to delayed diagnosis and treatment failure 1
• Pitfall: Stopping monitoring at day 100 in patients with chronic GVHD—these patients remain at risk for late CMV reactivation 1
• Pitfall: Attributing all post-transplant fever/symptoms to CMV alone—consider co-infections including HHV-6, especially with neurologic symptoms 6
• Pitfall: Failing to dose-adjust valganciclovir for renal function—this increases toxicity risk 2