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id.cmv-immunocompromised.core.v1

CMV disease + reactivation in immunocompromised hosts (HSCT / SOT / advanced HIV / biologic) — AST IDCOP 2019; ASBMT/IDSA HSCT; DHHS 2024 OI; Marty NEJM 2017 PMID 29211658

infectious_diseaseacutechronicadultneonatalacuteinpatientoutpatient
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CMV-immunocompromised dossier — AST IDCOP 2019 (Razonable Clin Transplant) + ASBMT/IDSA HSCT (Tomblyn 2009) + DHHS 2024 OI (clinicalinfo.hiv.gov) + Marty NEJM 2017 letermovir PMID 29211658 + Avery CID 2022 SOLSTICE maribavir PMID 34864943 + Kimberlin NEJM 2015 congenital CMV PMID 25738669. Covers CMV disease + reactivation in HSCT (allo > auto), SOT (lung > heart > liver-pancreas > kidney), advanced HIV (CD4 < 100; retinitis at CD4 < 50), and biologic / chronic-steroid users. Explicitly distinct from immunocompetent CMV (self-limited mononucleosis-like syndrome; out of scope). Three regimen axes: (1) Pre-emptive + tissue-invasive ganciclovir family — valganciclovir 900 mg PO BID pre-emptive + IV ganciclovir 5 mg/kg q12h × 14-21 d tissue-invasive → foscarnet 60 mg/kg q8h UL97-resistant → maribavir 400 mg PO BID UL97 with intact target (Avery SOLSTICE CID 2022 PMID 34864943); cidofovir 5 mg/kg weekly + probenecid as third/fourth-line. (2) Letermovir 480 mg PO daily × 100-200 d post-allogeneic HSCT for R+ / D+/R+ (Marty NEJM 2017; FDA Prevymis 2017); 240 mg if on cyclosporine (CYP3A DDI); CYP3A inducers (rifampin, phenytoin) prohibited. (3) Congenital CMV with CNS — valganciclovir 16 mg/kg PO BID × 6 months (Kimberlin NEJM 2015 PMID 25738669) for symptomatic neonate; lifelong audiology + ophtho + neurodev f/u. Severity triggers (10): cmv_retinitis_threatening_vision (life-threatening — zone 1 emergency + intravitreal + systemic + IRIS-watch + routes to id.hiv-initial.chronic.v1), cmv_pneumonitis_in_hsct (life-threatening — high-dose ganciclovir + IVIG + ICU; very high mortality), cmv_colitis_with_severe_diarrhea_or_bleeding (severe — endoscopy + biopsy owl-eye inclusions + IHC + IV ganciclovir × 14-21 d), cmv_encephalitis_or_ventriculitis (life-threatening — CSF PCR + MRI + ganciclovir + foscarnet combination considered + ICU), cmv_resistance_to_ganciclovir (severe — UL97/UL54 genotyping + foscarnet or maribavir + T-cell therapy referral for refractory HSCT), letermovir_prophylaxis_eligible_hsct (mild — Marty NEJM 2017 anchor), iris_post_art_in_cmv_retinitis (severe — paradoxical worsening 2-6 wk + continue ART + treat OI + steroid if severe + routes to id.hiv-initial.chronic.v1), congenital_cmv_with_cns_involvement (life-threatening — valganciclovir 16 mg/kg PO BID × 6 mo per Kimberlin 2015), cmv_viremia_above_treatment_threshold_in_sot (severe — pre-emptive valganciclovir + weekly PCR), cmv_d_pos_r_neg_high_risk_recipient (severe — universal prophylaxis OR pre-emptive monitoring per AST IDCOP 2019). Three setting playbooks: outpatient transplant / HIV clinic (pre-emptive PCR surveillance + valganciclovir + letermovir prophylaxis + secondary prophylaxis until immune recovery) + inpatient (IV ganciclovir induction × 14-21 d + IS reduction + site-specific endoscopy/biopsy + resistance testing) + ICU (CMV pneumonitis + encephalitis + disseminated + refractory; high-dose ganciclovir + IVIG; combination therapy; T-cell therapy referral). Workups: workup.cmv_transplant (engine anchor) + cross-routes to workup.hiv_initial (id.hiv-initial.chronic.v1), workup.invasive_aspergillosis (id.invasive-aspergillosis.core.v1 — co-infection ddx for pulmonary), workup.candidemia (id.candidemia.core.v1 — co-infection ddx), workup.pcp_pneumonia (PCP ddx for HSCT pneumonitis). Calculators: calc.ckd_epi_2021 (mandatory — ganciclovir + valganciclovir + foscarnet all require renal dose adjustment; ganciclovir myelosuppression risk increases with renal accumulation; foscarnet nephrotoxicity requires baseline + serial creatinine) + calc.qsofa (optional sepsis screen for shock physiology). Sibling differentiation: id.opportunistic-infection.hiv-transplant.v1 (parent overlay — full OI cascade), id.hiv-initial.chronic.v1 (HIV substrate + ART optimisation), id.invasive-aspergillosis.core.v1 (fungal co-infection ddx for pulmonary), id.candidemia.core.v1 (fungal co-infection bloodstream). Manifest pointer reused from prisma/seed/manifests/id.hiv-initial.chronic.v1.ts per id.opportunistic-infection.hiv-transplant.v1 precedent — a dedicated CMV manifest is out of shard scope. Phenotype matrix (site × host × viral-load band × resistance × severity) and Bayesian linkage (CMV PCR > 10K LR+ ~ 10 tissue-invasive, owl-eye inclusions LR+ → ∞, doubling time < 1 wk progression, T_treat_preemptive threshold, T_treat_invasive at tissue, T_resistance ≥ 2 wk persistent, T_letermovir_prophylaxis HSCT R+ or D+/R+, T_universal_prophylaxis_SOT D+/R-, cross-dossier routing to id.hiv-initial.chronic.v1 + id.opportunistic-infection.hiv-transplant.v1 + neph.aki.core.v1) documented in the co-located brief + research bundle; first-class TS fields remain schema-blocked (deferred to shard schema proposal cache — see id.sepsis.core.v1 brief). Open gaps / PRODUCTION blockers: (1) RxCUIs for ganciclovir / valganciclovir / foscarnet / maribavir / letermovir / cidofovir / IVIG not yet validated via scripts/research/rxnav-validate.ts; (2) manifest reuses id.hiv-initial.chronic.v1.ts pointer per nearest-precedent; (3) Avery SOLSTICE CID 2022 PMID 34864943 + Kimberlin congenital CMV NEJM 2015 PMID 25738669 pending PubMed loop next pass; (4) Marty NEJM 2017 PMID 29211658 verified locally; (5) AST IDCOP 2019 + ASBMT/IDSA HSCT + DHHS 2024 OI are multi-paper consensus / web-anchored — no single canonical PMID; (6) CMV-specific 3rd-party HLA-matched T-cell therapy referenced narratively only (emerging therapy; center-specific); (7) cidofovir referenced as third/fourth-line salvage (high nephrotoxicity); (8) pediatric non-congenital CMV flagged for future peds.cmv.v1 (this dossier covers adult + congenital with CNS only); (9) targeted dossier test file pending (relies on tests/dossiers/dossier-contract.test.ts).

Entry points (10)

  • lab_abnormality
    CMV PCR rising on weekly post-HSCT / post-SOT surveillance — pre-emptive therapy threshold (AST IDCOP 2019; Marty NEJM 2017 PMID 29211658)
    cmv_pcr_rising_post_transplant
  • lab_abnormality
    Detectable CMV viremia in advanced HIV (CD4 < 100) with new symptoms — pre-emptive valganciclovir (DHHS 2024 OI)
    cmv_pcr_above_center_threshold_advanced_hiv
  • symptom
    New visual disturbance / floaters / scotomata / blurred vision in CD4 < 50 OR transplant recipient — emergent ophtho for CMV retinitis (DHHS 2024 OI)
    visual_disturbance_in_advanced_hiv_or_transplant
  • symptom
    Severe diarrhea ± GI bleeding in HSCT / SOT / advanced HIV — endoscopy + biopsy for CMV colitis ("owl-eye" inclusions + IHC) (AST IDCOP 2019)
    severe_diarrhea_or_gi_bleed_in_immunocompromised
  • symptom
    Hypoxia + diffuse interstitial infiltrate in HSCT recipient — CMV pneumonitis is life-threatening (ASBMT/IDSA HSCT; Tomblyn 2009)
    hypoxia_with_diffuse_infiltrate_in_hsct
  • symptom
    Odynophagia + dysphagia in advanced HIV / SOT — EGD for CMV esophagitis (large shallow ulcers + IHC) vs HSV / Candida (DHHS 2024 OI; AST IDCOP 2019)
    odynophagia_dysphagia_in_immunocompromised
  • symptom
    Altered mental status + focal deficit + immunocompromise — CSF PCR + MRI for CMV encephalitis / ventriculitis (DHHS 2024 OI)
    altered_mental_status_in_immunocompromised
  • history
    Symptomatic congenital CMV neonate with CNS involvement (microcephaly, chorioretinitis, intracranial calcifications, hearing loss) — ganciclovir / valganciclovir × 6 mo (Kimberlin NEJM 2015 PMID 25738669)
    congenital_cmv_symptomatic_neonate_with_cns_involvement
  • history
    R+ OR D+/R+ allogeneic HSCT recipient pre-engraftment — letermovir 480 mg PO daily × 100-200 d post-HSCT (Marty NEJM 2017 PMID 29211658)
    hsct_recipient_eligible_for_letermovir_prophylaxis
  • history
    D+/R- SOT recipient (lung > heart > liver-pancreas > kidney) — universal prophylaxis OR pre-emptive PCR monitoring (AST IDCOP 2019)
    sot_d_pos_r_neg_high_risk_recipient

Required inputs (15)

  • immunocompromise_substraterequired
    history • used at ENTRY
    Defines CMV risk profile — HSCT vs SOT vs advanced HIV vs biologic / chronic-steroid; drives prophylaxis + pre-emptive vs treatment paradigm (AST IDCOP 2019; ASBMT/IDSA HSCT; DHHS 2024 OI)
  • cmv_pcr_quantitativerequired
    lab • used at INITIAL_WORKUP
    Pre-emptive monitoring threshold (center-specific 1,000-10,000 IU/mL WHO IS) + diagnosis support for tissue-invasive disease; > 10K IU/mL LR+ ~ 10 (AST IDCOP 2019; Marty NEJM 2017)
  • cmv_donor_recipient_serostatusrequired
    history • used at CONTEXT
    D+/R- highest risk SOT (lung > heart > liver-pancreas > kidney); D+/R+ or R+ drives letermovir prophylaxis in HSCT (AST IDCOP 2019; Marty NEJM 2017)
  • transplant_type_and_date
    history • used at CONTEXT
    Time-from-transplant defines CMV window (peak 30-100 d post-transplant); organ-specific risk; HSCT pre-engraftment vs post-engraftment GVHD differs (AST IDCOP 2019; ASBMT/IDSA HSCT)
  • cd4_count
    lab • used at CONTEXT
    HIV-CMV substrate — retinitis classic at CD4 < 50; end-organ disease at CD4 < 100; secondary prophylaxis decisions based on immune recovery (DHHS 2024 OI)
  • hiv_viral_load
    lab • used at CONTEXT
    IRIS risk + ART timing; ART optimisation in CMV retinitis (DHHS 2024 OI)
  • current_immunosuppressionrequired
    medication • used at CONTEXT
    Calcineurin (tacrolimus / cyclosporine) requires letermovir dose reduction to 240 mg/d (FDA label DDI); mTOR; anti-metabolite; steroid dose; biologic (alemtuzumab, ATG, rituximab) — drives net state of immunosuppression (AST IDCOP 2019)
  • creatininerequired
    lab • used at TREATMENT
    Ganciclovir + valganciclovir + foscarnet ALL require renal dose adjustment; foscarnet nephrotoxicity monitoring; baseline before induction (AST IDCOP 2019; FDA labels; DailyMed)
  • cbcrequired
    lab • used at INITIAL_WORKUP
    Ganciclovir myelosuppression (neutropenia + thrombocytopenia) baseline + monitoring; G-CSF rescue if severe; AST IDCOP 2019
  • lft
    lab • used at INITIAL_WORKUP
    CMV hepatitis baseline + monitoring; biopsy if dx uncertain; rule out rejection in SOT (AST IDCOP 2019)
  • electrolytes_ca_mg_k_po4
    lab • used at MONITORING
    Foscarnet chelates divalents → hypocalcemia + hypomagnesemia + hypokalemia + hyperphosphatemia / hypophosphatemia; baseline + q 2-3 d during induction; symptomatic hypocalcemia + seizure documented (AST IDCOP 2019; FDA foscarnet label)
  • hrct_chest
    imaging • used at INITIAL_WORKUP
    CMV pneumonitis — diffuse interstitial / ground-glass infiltrate in HSCT; ddx PCP / aspergillosis / drug pneumonitis (ASBMT/IDSA HSCT; AST IDCOP 2019)
  • dilated_fundoscopy
    imaging • used at INITIAL_WORKUP
    CMV retinitis "pizza-pie" hemorrhages + exudate along vascular arcades; zone 1 (foveal-threatening) vs zone 2/3; emergent ophtho at CD4 < 50 (DHHS 2024 OI)
  • mri_brain
    imaging • used at BRANCHING_WORKUP
    CMV encephalitis / ventriculitis — periventricular enhancement; CSF PCR confirms; ddx HHV-6 / HSV / autoimmune limbic encephalitis (DHHS 2024 OI)
  • pregnancy_status
    history • used at CONTEXT
    Ganciclovir + valganciclovir teratogenic — pregnancy contraindication; foscarnet has been used in life-threatening CMV during pregnancy (case reports); pre-conception counseling for transplant recipients planning pregnancy (FDA labels; AST IDCOP 2019)

12-phase flow (12)

  1. 1FRAME
    Adult immunocompromised CMV — HSCT / SOT / advanced HIV / biologic-DMARD / chronic steroid. Immunocompetent CMV (self-limited mononucleosis-like syndrome) explicitly out of scope. Congenital CMV with CNS involvement included (Kimberlin NEJM 2015) (AST IDCOP 2019; ASBMT/IDSA HSCT; DHHS 2024 OI)
    inputs: immunocompromise_substrate
    advance: immunocompromise substrate + scope confirmed
  2. 2ENTRY
    Surveillance PCR threshold breach OR symptomatic presentation (retinitis, colitis, pneumonitis, encephalitis, esophagitis, hepatitis) OR letermovir-prophylaxis-eligible HSCT OR D+/R- SOT prophylaxis decision OR symptomatic congenital CMV with CNS (AST IDCOP 2019; Marty NEJM 2017; Kimberlin NEJM 2015 PMID 25738669)
    inputs: immunocompromise_substrate, cmv_pcr_quantitative
    advance: CMV trigger validated
  3. 3CONTEXT
    Document net state of immunosuppression — D/R CMV serostatus, transplant type + date, time-from-transplant, current immunosuppression regimen, prior CMV history, prior prophylaxis, CD4 + HIV VL if applicable, pregnancy status (AST IDCOP 2019)
    inputs: cmv_donor_recipient_serostatus, current_immunosuppression, transplant_type_and_date, cd4_count
    advance: host risk profile documented
  4. 4RED_FLAGS
    Vision-threatening retinitis (zone 1 foveal) → ophtho emergency + intravitreal therapy; CMV pneumonitis in HSCT with hypoxia → ICU + high-dose ganciclovir + IVIG; encephalitis / ventriculitis → ICU + ganciclovir + foscarnet combination; severe GI bleeding from CMV colitis → endoscopy + transfusion (DHHS 2024 OI; ASBMT/IDSA HSCT; AST IDCOP 2019)
    inputs: cmv_pcr_quantitative
    advance: life-threatening CMV escalation triggered if present
  5. 5INITIAL_WORKUP
    Quantitative CMV PCR (WHO IU/mL preferred); CBC + creatinine + LFTs baseline; site-specific workup — dilated fundoscopy (retinitis), HRCT chest (pneumonitis), EGD / colonoscopy + biopsy with H&E + IHC ("owl-eye" inclusions), CSF PCR + MRI (encephalitis) (AST IDCOP 2019; DHHS 2024 OI; ASBMT/IDSA HSCT)
    inputs: cmv_pcr_quantitative, cbc, creatinine
    actions: workup.cmv_transplant
    advance: PCR + site-specific workup pending culture / PCR / biopsy
  6. 6BRANCHING_WORKUP
    Site-specific cascades: dilated fundoscopy + retinitis zone-mapping (retinitis); EGD + biopsy + IHC (esophagitis); colonoscopy + biopsy + IHC (colitis); HRCT + BAL + biopsy (pneumonitis — ddx PCP / aspergillosis / drug); CSF PCR + MRI (encephalitis); liver biopsy + ddx rejection (hepatitis); UL97 / UL54 resistance genotyping if persistent viremia ≥ 2 wk on appropriate therapy (AST IDCOP 2019; Lurain Clin Microbiol Rev 2010)
    inputs: hrct_chest, dilated_fundoscopy
    actions: workup.hiv_initial, workup.invasive_aspergillosis, workup.candidemia, workup.pcp_pneumonia
    advance: site + pathogen confirmed
  7. 7DIFFERENTIAL
    CMV vs HHV-6 / HSV / VZV / adenovirus / EBV (viremia + organ-specific); CMV pneumonitis vs PCP / aspergillosis / drug pneumonitis / pulmonary edema in HSCT; CMV colitis vs C. difficile / GVHD-GI / drug colitis in SOT/HSCT; CMV encephalitis vs HHV-6 / HSV / autoimmune limbic encephalitis (AST IDCOP 2019; ASBMT/IDSA HSCT; DHHS 2024 OI)
    advance: pathogen + syndrome mapped
  8. 8RISK_STRATIFICATION
    Severity per syndrome: viremia-only vs tissue-invasive vs disseminated; HSCT pneumonitis = life-threatening; retinitis zone 1 = emergent; encephalitis = life-threatening; D+/R- + organ-specific risk stratification per AST IDCOP 2019 + ASBMT/IDSA HSCT
    inputs: cmv_pcr_quantitative, cbc, creatinine
    actions: calc.ckd_epi_2021
    advance: severity tier + organ involvement + resistance status assigned
  9. 9TREATMENT
    Pre-emptive (viremia above threshold): valganciclovir 900 mg PO BID × induction; Treatment (tissue-invasive): IV ganciclovir 5 mg/kg q12h × 14-21 d → valganciclovir 900 mg PO BID maintenance; Refractory / resistant: foscarnet 60 mg/kg q8h IV OR maribavir 400 mg PO BID; Prophylaxis: letermovir 480 mg PO daily (240 mg with cyclosporine) × 100-200 d post-HSCT (Marty NEJM 2017) OR valganciclovir 900 mg PO daily × 200 d (kidney D+/R-) / 100 d (other SOT); Retinitis-specific: intravitreal ganciclovir / foscarnet + systemic; Congenital with CNS: valganciclovir 16 mg/kg PO BID × 6 mo (Kimberlin NEJM 2015 PMID 25738669); reduce immunosuppression where feasible (AST IDCOP 2019; ASBMT/IDSA HSCT; DHHS 2024 OI; Avery SOLSTICE CID 2022 (PMID 34864943))
    inputs: creatinine, cbc, current_immunosuppression
    advance: pathogen-specific + host-adjusted regimen started; renal dose-adjusted; adjunct (IVIG for HSCT pneumonitis, ophtho intravitreal for zone 1 retinitis, IS reduction) initiated where indicated
  10. 10DISPOSITION
    Outpatient transplant / HIV clinic for stable pre-emptive arm; inpatient for tissue-invasive disease + IV ganciclovir induction; ICU for HSCT pneumonitis / encephalitis / disseminated / refractory; OPAT for prolonged IV ganciclovir or foscarnet post-discharge (AST IDCOP 2019; ASBMT/IDSA HSCT)
    advance: level of care set
  11. 11MONITORING
    CMV PCR weekly during induction → bi-weekly during maintenance → monthly secondary prophylaxis; CBC q week during ganciclovir induction (myelosuppression); creatinine + electrolytes (Ca, Mg, K, PO4) q 2-3 d during foscarnet induction; LFT weekly during ganciclovir; ophtho q 1-2 wk during retinitis induction; repeat HRCT + ABG during pneumonitis (AST IDCOP 2019; FDA labels)
    inputs: cmv_pcr_quantitative, cbc, creatinine
    actions: panel.lft, panel.renal, panel.cbc
    advance: viral load trending down + clinical improvement + no resistance escape
  12. 12FOLLOWUP
    Secondary prophylaxis until immune recovery — HIV: valganciclovir 900 mg PO daily until CD4 > 100 × 3-6 mo + VL suppressed; HSCT: prophylaxis through immunosuppression duration; SOT: variable per organ + IS; congenital: ophtho + audiology + neurodevelopmental f/u lifelong (Kimberlin NEJM 2015 PMID 25738669); ART optimisation in HIV; transition to outpatient with ID f/u (AST IDCOP 2019; DHHS 2024 OI; Kimberlin NEJM 2015)
    advance: long-term secondary prophylaxis + organ-specific surveillance plan documented