12-phase flow (12)

1. 1FRAME
   Adult acute end-organ CMV in transplant (SOT / HSCT) and uncontrolled HIV — pneumonia, colitis, retinitis, hepatitis, encephalitis. Distinct from `id.cmv-immunocompromised.core.v1` (umbrella for viremia surveillance + pre-emptive + letermovir prophylaxis + congenital); routes BACK to umbrella for prophylaxis + longitudinal serostatus framing (Kotton Transplantation 2018 PMID 29596116; Ljungman CID 2024 PMID 39041385)
   inputs: immunocompromise_substrate
   advance: immunocompromise substrate + acute end-organ scope confirmed
2. 2ENTRY
   Symptomatic presentation (pneumonia / colitis / retinitis / hepatitis / encephalitis) OR PCR-positive with NEW organ-specific syndrome OR biopsy "owl-eye" inclusions — routes from umbrella `id.cmv-immunocompromised.core.v1` once viremia + clinical syndrome converge (Ljungman CID 2017 PMID 27682069; Kotton Transplantation 2018 PMID 29596116)
   inputs: cmv_pcr_quantitative
   advance: end-organ CMV trigger validated (clinical + PCR ± biopsy)
3. 3CONTEXT
   Document immune substrate — HSCT (allo > auto; pre-engraftment + GVHD on steroids) vs SOT (organ + D/R serostatus + time-from-transplant) vs advanced HIV (CD4 + VL + ART history + IRIS-risk) vs iatrogenic biologic / steroid; current IS regimen + DDI map; pregnancy status (ganciclovir / valganciclovir teratogenic) (Kotton Transplantation 2018 PMID 29596116; DHHS 2024 OI)
   inputs: transplant_type_and_time_from_transplant, current_immunosuppression, cd4_count
   advance: host risk profile + immune substrate documented
4. 4RED_FLAGS
   Respiratory failure / hypoxia from CMV pneumonia in HSCT → ICU + high-dose ganciclovir + IVIG; vision-threatening retinitis (zone 1 foveal) → ophtho emergency + intravitreal; encephalitis with mass effect → ICU + neurosurgery + ganciclovir + foscarnet combination; severe GI bleed from colitis → endoscopy + transfusion; refractory disease ≥ 2 wk → resistance genotyping + salvage (DHHS 2024 OI; Kotton Transplantation 2018 PMID 29596116)
   inputs: mass_effect_or_focal_deficit
   actions: calc.qsofa
   advance: life-threatening end-organ escalation triggered if present
5. 5INITIAL_WORKUP
   Quantitative CMV PCR (WHO IU/mL); CBC + creatinine + LFTs + electrolytes (Ca, Mg, K, PO4 baseline if foscarnet planned); organ-specific workup — HRCT + BAL with cytopathology + PCR (pneumonia), dilated fundoscopy + zone-mapping (retinitis), EGD / colonoscopy + biopsy with H&E + IHC "owl-eye" (colitis / esophagitis), CSF PCR + MRI (encephalitis), liver biopsy (hepatitis — distinguish from rejection) (Kotton Transplantation 2018 PMID 29596116; DHHS 2024 OI)
   inputs: cmv_pcr_quantitative, cbc, creatinine
   actions: workup.cmv_transplant, workup.fuo, panel.cbc, panel.renal, panel.lft
   advance: PCR + organ-specific workup in flight; biopsy if feasible
6. 6BRANCHING_WORKUP
   Organ-specific cascade: pneumonia → BAL cytopathology + PCR + galactomannan (Aspergillus ddx) + PJP DFA / PCR; colitis → biopsy with IHC; retinitis → ophtho zone-mapping; encephalitis → CSF PCR + MRI + HHV-6 PCR (post-HSCT classic ddx); hepatitis → liver biopsy + rejection workup. UL97 / UL54 resistance genotyping if persistent viremia ≥ 2 wk on appropriate ganciclovir/valganciclovir (Ljungman CID 2024 PMID 39041385 resistance/refractory definitions) (Kotton Transplantation 2018 PMID 29596116)
   inputs: hrct_chest, dilated_fundoscopy
   actions: workup.hiv_initial, workup.invasive_aspergillosis, workup.candidemia, workup.pcp_pneumonia, panel.inflammation, panel.cardiac
   advance: organ + pathogen confirmed; resistance status assessed if persistent
7. 7DIFFERENTIAL
   CMV pneumonia vs PCP / invasive aspergillosis / drug-induced pneumonitis (mTOR — sirolimus / everolimus) / pulmonary edema; CMV colitis vs C. difficile / GVHD-GI / drug colitis / ischemic colitis; CMV retinitis vs HSV / VZV acute retinal necrosis / HIV retinopathy; CMV encephalitis vs HHV-6 (post-HSCT classic) / HSV / autoimmune limbic encephalitis / lymphoma; CMV hepatitis vs rejection (SOT — biopsy required) / drug-induced / viral hepatitis (Kotton Transplantation 2018 PMID 29596116; DHHS 2024 OI)
   advance: organ-specific differential mapped + alternative diagnoses sufficiently excluded
8. 8RISK_STRATIFICATION
   Severity tier per organ syndrome: viremia-with-syndrome (severe) vs disseminated multi-organ (life-threatening); HSCT pneumonia = life-threatening (very high historic mortality); retinitis zone 1 = emergent vision-threatening; encephalitis = life-threatening; refractory ≥ 2 wk on appropriate therapy = severe (resistance suspected); CrCl < 70 + ganciclovir / foscarnet / cidofovir → dose-reduction (Kotton Transplantation 2018 PMID 29596116; Ljungman CID 2024 PMID 39041385)
   inputs: cmv_pcr_quantitative, creatinine, cbc
   actions: calc.ckd_epi_2021
   advance: severity tier + organ involvement + resistance status assigned
9. 9TREATMENT
   Induction: non-CNS first-line valganciclovir 900 mg PO BID OR IV ganciclovir 5 mg/kg q12h × 14-21 d; CNS-disease ganciclovir IV preferred (better CSF penetration) ± foscarnet combination for severe encephalitis; HSCT pneumonia high-dose ganciclovir + IVIG 500 mg/kg q48h × ~ 10 doses; retinitis zone 1 intraocular ganciclovir + systemic; refractory / UL97 maribavir 400 mg PO BID × 8 wk (Avery SOLSTICE CID 2022 PMID 34864943 — NON-CNS only); salvage foscarnet 60 mg/kg IV q8h OR cidofovir 5 mg/kg IV weekly × 2 → q2 wk WITH probenecid 2 g PO 3 h pre + 1 g 2 h + 8 h post + IV NS hydration; reduce IS where feasible; ART optimization (HIV — defer ~ 2 wk after retinitis induction; DHHS 2024 OI); CMV-specific 3rd-party T-cell therapy referral (refractory HSCT) (Kotton Transplantation 2018 PMID 29596116; Ljungman CID 2024 PMID 39041385; DHHS 2024 OI). LETERMOVIR is NOT a treatment for established end-organ disease — prophylaxis only (Marty NEJM 2017 PMID 29211658).
   inputs: creatinine, cbc, current_immunosuppression
   advance: organ-specific induction regimen started; renal + hematologic monitoring scheduled; salvage path documented if resistance
10. 10DISPOSITION
    Outpatient PO valganciclovir maintenance for stable colitis / retinitis / mild hepatitis post-induction; inpatient for IV ganciclovir induction + tissue-invasive disease + foscarnet salvage; ICU for HSCT pneumonia with hypoxia, encephalitis, refractory disseminated; transition (post-hospital) for IV-to-PO valganciclovir switch + arranging maintenance + ART optimization + IRIS-watch + ophtho f/u (Kotton Transplantation 2018 PMID 29596116)
    advance: level of care + transition plan set
11. 11MONITORING
    CMV PCR q 2-3 d during inpatient induction → weekly during step-down → monthly during secondary prophylaxis; CBC weekly during ganciclovir induction (myelosuppression) → daily on foscarnet; creatinine + electrolytes (Ca, Mg, K, PO4) q 2-3 d during foscarnet; LFT q week during ganciclovir; ophtho q 1-2 wk during retinitis induction → q 3 mo secondary prophylaxis; repeat HRCT + ABG q few days during pneumonia; repeat MRI at 2-4 wk for encephalitis (Kotton Transplantation 2018 PMID 29596116; DHHS 2024 OI)
    inputs: cbc, creatinine
    actions: panel.cbc, panel.renal, panel.lft
    advance: viral load trending down + clinical improvement + no resistance escape; minimum 14-21 d induction met for tissue-invasive
12. 12FOLLOWUP
    Step-down to maintenance valganciclovir post-induction; secondary prophylaxis until immune recovery (HIV: CD4 > 100 × 3-6 mo + VL suppressed; HSCT through immune-reconstitution; SOT per organ + IS); ART optimization in HIV (defer ART by ~ 2 wk after retinitis induction to reduce IRIS — DHHS 2024 OI); route BACK to umbrella `id.cmv-immunocompromised.core.v1` for longitudinal D/R-driven prophylaxis decisions (especially HSCT letermovir-completion or SOT universal-vs-pre-emptive surveillance); ophtho lifelong f/u after vision-threatening retinitis (Kotton Transplantation 2018 PMID 29596116; DHHS 2024 OI; Marty NEJM 2017 PMID 29211658 — prophylaxis-only role)
    advance: secondary prophylaxis + ART + organ-specific surveillance plan documented; routed back to umbrella for longitudinal management