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id.cmv-immunocompromised.core.v1PRODUCTION
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_diseaseacutechronicadultneonatal
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Encounter flow

12/12 authored

Canonical 12-phase frame with authored status for this dossier.

Current phase

Frame

Detailed

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)

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immunocompromise substrate + scope confirmed

Patient inputs (15)

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)

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)

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)

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)

Ganciclovir myelosuppression (neutropenia + thrombocytopenia) baseline + monitoring; G-CSF rescue if severe; AST IDCOP 2019

Ganciclovir + valganciclovir + foscarnet ALL require renal dose adjustment; foscarnet nephrotoxicity monitoring; baseline before induction (AST IDCOP 2019; FDA labels; DailyMed)

CMV encephalitis / ventriculitis — periventricular enhancement; CSF PCR confirms; ddx HHV-6 / HSV / autoimmune limbic encephalitis (DHHS 2024 OI)

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)

HIV-CMV substrate — retinitis classic at CD4 < 50; end-organ disease at CD4 < 100; secondary prophylaxis decisions based on immune recovery (DHHS 2024 OI)

IRIS risk + ART timing; ART optimisation in CMV retinitis (DHHS 2024 OI)

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)

CMV hepatitis baseline + monitoring; biopsy if dx uncertain; rule out rejection in SOT (AST IDCOP 2019)

CMV pneumonitis — diffuse interstitial / ground-glass infiltrate in HSCT; ddx PCP / aspergillosis / drug pneumonitis (ASBMT/IDSA HSCT; AST IDCOP 2019)

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)

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)

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Severity triggers (10)

10 need judgement
  • informationallife_threateningcmv_retinitis_threatening_vision (DHHS 2024 OI)
    Visual disturbance + characteristic "pizza-pie" retinal hemorrhages + exudate along vascular arcades + CD4 < 50 OR transplant recipient — zone 1 (foveal-threatening) lesion is an ophthalmology emergency
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationallife_threateningcmv_pneumonitis_in_hsct (ASBMT/IDSA HSCT; Tomblyn 2009)
    Diffuse interstitial / ground-glass infiltrate + hypoxia + CMV PCR positive in HSCT recipient — alveolar hemorrhage + respiratory failure; very high mortality without aggressive therapy
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationallife_threateningcmv_encephalitis_or_ventriculitis (DHHS 2024 OI)
    Altered mental status + focal neurologic deficit + CSF PCR positive for CMV + MRI showing periventricular enhancement or compatible findings — high mortality without aggressive therapy
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationallife_threateningcongenital_cmv_with_cns_involvement (Kimberlin NEJM 2015 PMID 25738669)
    Symptomatic congenital CMV neonate with CNS involvement (microcephaly, chorioretinitis, intracranial calcifications, sensorineural hearing loss); confirmed by CMV PCR + clinical findings
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseverecmv_colitis_with_severe_diarrhea_or_bleeding (AST IDCOP 2019; DHHS 2024 OI)
    Severe diarrhea ± hematochezia + abdominal pain in HSCT / SOT / advanced HIV with positive CMV PCR — endoscopy + biopsy for "owl-eye" intranuclear inclusions + IHC
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseverecmv_resistance_to_ganciclovir (AST IDCOP 2019; Avery CID 2022 PMID 34864943)
    Persistent CMV viremia (> 1,000 IU/mL) for ≥ 2 wk despite appropriate ganciclovir/valganciclovir dosing with confirmed adherence + adequate exposure — UL97 (most common) or UL54 mutation on resistance genotyping
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalsevereiris_post_art_in_cmv_retinitis (DHHS 2024 OI)
    HIV-ART-naive patient with active CMV retinitis on ART start — paradoxical worsening 2-6 wk post-ART with new inflammatory features (uveitis, vitreitis, retinal vasculitis, macular edema)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseverecmv_viremia_above_treatment_threshold_in_sot (AST IDCOP 2019)
    Quantitative CMV PCR above center-specific threshold (typically 1,000-10,000 IU/mL WHO IS) on weekly surveillance post-SOT — pre-emptive valganciclovir
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseverecmv_d_pos_r_neg_high_risk_recipient (AST IDCOP 2019)
    D+/R- SOT recipient (lung > heart > liver-pancreas > kidney) — highest risk for primary CMV infection post-transplant; universal prophylaxis OR pre-emptive PCR monitoring per AST IDCOP 2019
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalmildletermovir_prophylaxis_eligible_hsct (Marty NEJM 2017 PMID 29211658)
    R+ OR D+/R+ allogeneic HSCT recipient pre-engraftment OR through engraftment; expected immunosuppression duration > 100 d — letermovir 480 mg PO daily × 100-200 d (240 mg with cyclosporine; CYP3A-inducer DDI)
    Trigger could not be auto-evaluated — needs clinician judgement.

Workflow calculators

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TREATMENTrequiredDrives dose adjustment
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Recommended regimen

CMV pre-emptive + tissue-invasive treatment ladder — valganciclovir / IV ganciclovir → foscarnet → maribavir (AST IDCOP 2019; ASBMT/IDSA HSCT; DHHS 2024 OI; Avery CID 2022 PMID 34864943)
axis: cmv_preemptive_and_treatment_ganciclovir_familystep 1 - Step 1 — Pre-emptive valganciclovir for viremia above threshold (AST IDCOP 2019)
Selected step "Step 1 — Pre-emptive valganciclovir for viremia above threshold (AST IDCOP 2019)" — CMV PCR above center-specific threshold (typically 1,000-10,000 IU/mL WHO IS) in active surveillance post-SOT / HSCT OR advanced HIV with detectable viremia; ganciclovir-sensitive; oral absorption intact
  • valganciclovir
    first line
    nucleoside_analog_prodrug
    900 mg PO BID (induction) → 900 mg PO daily (maintenance / pre-emptive single-dose regimen per center protocol) • PO • BID induction → daily maintenance (max: 900 mg BID)
    triggers: preemptive_PCR_threshold_breach, oral_absorption_intact_no_GI_disease
    AST IDCOP 2019 first-line for pre-emptive therapy; high oral bioavailability (~60%); renal dose adjustment required (CrCl 40-59 → 450 mg BID; CrCl 25-39 → 450 mg daily; CrCl 10-24 → 450 mg q48h)
    rxcui 275891

outpatient playbook — drug actions (5)

  1. 1. pre-emptive valganciclovir
    rxcui 275891
    900 mg PO BID induction × until PCR negative × 2 + minimum 14 d • PO • BID
    trigger: CMV PCR > center-specific threshold (typically 1,000-10,000 IU/mL WHO IS) in active surveillance (AST IDCOP 2019)
    AST IDCOP 2019 pre-emptive valganciclovir first-line; high oral bioavailability; renal dose adjustment required
  2. 2. letermovir prophylaxis (HSCT)
    rxcui 1988648
    480 mg PO daily × 100-200 d (240 mg daily if on cyclosporine) • PO • daily
    trigger: R+ OR D+/R+ allogeneic HSCT recipient pre-engraftment (Marty NEJM 2017 PMID 29211658)
    Phase III RCT — reduced clinically significant CMV infection 37.5% vs 60.6%; cyclosporine DDI reduce dose to 240 mg/d (FDA label)
  3. 3. universal prophylaxis valganciclovir (SOT D+/R-)
    rxcui 275891
    900 mg PO daily × 200 d (kidney) or 100 d (other SOT) • PO • daily
    trigger: D+/R- SOT (especially kidney) — AST IDCOP 2019 universal-prophylaxis arm
    Pre-emptive PCR monitoring is an acceptable alternative per same guideline; both arms have evidence
  4. 4. maintenance valganciclovir (HIV CMV retinitis secondary prophylaxis)
    rxcui 275891
    900 mg PO daily until CD4 > 100 × 3-6 mo + VL suppressed • PO • daily
    trigger: Post-induction CMV retinitis in HIV; immune recovery threshold not yet met (DHHS 2024 OI)
    DHHS 2024 OI — discontinue when CD4 > 100 × 3-6 mo + VL suppressed
  5. 5. ART optimisation in CMV retinitis
    Per HIV regimen • PO • per regimen
    trigger: Advanced HIV with CMV retinitis — ART defer ~ 2 wk after retinitis induction to reduce IRIS severity (DHHS 2024 OI)
    DHHS 2024 OI — defer ART ~ 2 wk; continue treating retinitis through ART start; ophtho follow-up 2-6 wk post-ART for IRIS

Auto-drafted A&P note

outpatient

Subjective

- Possible entry pathways: CMV PCR rising on weekly post-HSCT / post-SOT surveillance — pre-emptive therapy threshold (AST IDCOP 2019; Marty NEJM 2017 PMID 29211658); Detectable CMV viremia in advanced HIV (CD4 < 100) with new symptoms — pre-emptive valganciclovir (DHHS 2024 OI); New visual disturbance / floaters / scotomata / blurred vision in CD4 < 50 OR transplant recipient — emergent ophtho for CMV retinitis (DHHS 2024 OI).

Objective

- No vitals, labs, or imaging entered for this encounter.

Assessment

**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** (id.cmv-immunocompromised.core.v1).
Phenotype framing: 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)
Scope: 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)

No severity triggers fired against current inputs.

Plan

Regimen axis: **CMV pre-emptive + tissue-invasive treatment ladder — valganciclovir / IV ganciclovir → foscarnet → maribavir (AST IDCOP 2019; ASBMT/IDSA HSCT; DHHS 2024 OI; Avery CID 2022 PMID 34864943)** — step "Step 1 — Pre-emptive valganciclovir for viremia above threshold (AST IDCOP 2019)".
1. valganciclovir 900 mg PO BID (induction) → 900 mg PO daily (maintenance / pre-emptive single-dose regimen per center protocol) PO BID induction → daily maintenance (nucleoside_analog_prodrug, first line) — AST IDCOP 2019 first-line for pre-emptive therapy; high oral bioavailability (~60%); renal dose adjustment required (CrCl 40-59 → 450 mg BID; CrCl 25-39 → 450 mg daily; CrCl 10-24 → 450 mg q48h)

Setting playbook (outpatient) — Pre-emptive PCR surveillance + initiation of valganciclovir at threshold; letermovir prophylaxis post-HSCT; universal vs pre-emptive prophylaxis in D+/R- SOT; secondary prophylaxis until immune recovery (AST IDCOP 2019; Marty NEJM 2017; DHHS 2024 OI)
2. pre-emptive valganciclovir 900 mg PO BID induction × until PCR negative × 2 + minimum 14 d PO BID — CMV PCR > center-specific threshold (typically 1,000-10,000 IU/mL WHO IS) in active surveillance (AST IDCOP 2019) (AST IDCOP 2019 pre-emptive valganciclovir first-line; high oral bioavailability; renal dose adjustment required)
3. letermovir prophylaxis (HSCT) 480 mg PO daily × 100-200 d (240 mg daily if on cyclosporine) PO daily — R+ OR D+/R+ allogeneic HSCT recipient pre-engraftment (Marty NEJM 2017 PMID 29211658) (Phase III RCT — reduced clinically significant CMV infection 37.5% vs 60.6%; cyclosporine DDI reduce dose to 240 mg/d (FDA label))
4. universal prophylaxis valganciclovir (SOT D+/R-) 900 mg PO daily × 200 d (kidney) or 100 d (other SOT) PO daily — D+/R- SOT (especially kidney) — AST IDCOP 2019 universal-prophylaxis arm (Pre-emptive PCR monitoring is an acceptable alternative per same guideline; both arms have evidence)
5. maintenance valganciclovir (HIV CMV retinitis secondary prophylaxis) 900 mg PO daily until CD4 > 100 × 3-6 mo + VL suppressed PO daily — Post-induction CMV retinitis in HIV; immune recovery threshold not yet met (DHHS 2024 OI) (DHHS 2024 OI — discontinue when CD4 > 100 × 3-6 mo + VL suppressed)
6. ART optimisation in CMV retinitis Per HIV regimen PO per regimen — Advanced HIV with CMV retinitis — ART defer ~ 2 wk after retinitis induction to reduce IRIS severity (DHHS 2024 OI) (DHHS 2024 OI — defer ART ~ 2 wk; continue treating retinitis through ART start; ophtho follow-up 2-6 wk post-ART for IRIS)

Non-pharmacologic actions:
- OPAT coordination if completing prolonged IV ganciclovir or foscarnet course post-discharge (Norris IDSA OPAT 2018)
- Adherence + DDI review at each visit (FDA labels)
- Pregnancy counseling for transplant recipients planning pregnancy on ganciclovir / valganciclovir (FDA label; AST IDCOP 2019)
- Patient education on resistance — adherence is critical; missed doses + subtherapeutic exposure drive resistance (AST IDCOP 2019)
- Ophtho referral if visual disturbance / floaters / scotomata in CD4 < 50 (DHHS 2024 OI)
- Vaccination review — CMV is not vaccine-preventable; ensure non-live vaccines per transplant / HIV protocols (ACIP 2024)

AVOID / contraindication checks:
- Ganciclovir renal dose adjust (AST IDCOP 2019; FDA label; DailyMed)
- Valganciclovir renal dose adjust (AST IDCOP 2019; FDA label; DailyMed)
- Foscarnet nephrotoxicity monitor creatinine q 2 3 d (AST IDCOP 2019; FDA label)
- Foscarnet electrolytes Ca Mg K PO4 monitor (AST IDCOP 2019; FDA label)
- Ganciclovir myelosuppression CBC q week and G CSF rescue (AST IDCOP 2019; FDA label)
- Ganciclovir valganciclovir teratogenicity pregnancy AVOID (FDA label; AST IDCOP 2019)
- Cidofovir nephrotoxicity probenecid IV hydration required (FDA label)
- Foscarnet IV hydration before each dose and symptomatic hypocalcemia seizure risk (AST IDCOP 2019; FDA label)
- Maribavir DDI CYP3A substrate monitor immunosuppressants (FDA Livtencity label)
- Cmv retinitis intravitreal plus systemic zone 1 lesion (DHHS 2024 OI)
- Resistance genotyping UL97 UL54 if persistent viremia 2 weeks (AST IDCOP 2019)

Monitoring

Regimen monitoring:
- CMV PCR weekly during induction then bi weekly then monthly (AST IDCOP 2019)
- CBC weekly during ganciclovir induction myelosuppression (AST IDCOP 2019; FDA label)
- Creatinine q 2 3 d during foscarnet induction (AST IDCOP 2019; FDA label)
- Electrolytes Ca Mg K PO4 q 2 3 d during foscarnet induction (AST IDCOP 2019; FDA label)
- LFT weekly during ganciclovir induction (AST IDCOP 2019)
- Ophtho q 1 2 wk during retinitis induction then q 3 mo secondary prophylaxis (DHHS 2024 OI)
- Repeat HRCT and ABG q few days during pneumonitis induction (ASBMT/IDSA HSCT)
- Resistance genotyping if persistent viremia 2 weeks (AST IDCOP 2019)
- Minimum duration 14 to 21 d for induction in tissue invasive disease (AST IDCOP 2019; DHHS 2024 OI)

Setting (outpatient) monitoring:
- CMV PCR weekly during induction → bi-weekly during maintenance → monthly during secondary prophylaxis (AST IDCOP 2019)
- CBC weekly during ganciclovir induction (myelosuppression); q 2-4 wk during maintenance (AST IDCOP 2019; FDA label)
- Creatinine + LFTs at baseline + q 2-4 wk during therapy (AST IDCOP 2019)
- Ophtho q 3 mo during induction CMV retinitis; lifelong f/u after vision-threatening disease (DHHS 2024 OI)
- Resistance genotyping if persistent viremia ≥ 2 wk on appropriate dosing + adherence (AST IDCOP 2019)

Follow-up plan: 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)
- Close-out criterion: long-term secondary prophylaxis + organ-specific surveillance plan documented

Monitoring phase: 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)

Disposition

Current setting: outpatient — Pre-emptive PCR surveillance + initiation of valganciclovir at threshold; letermovir prophylaxis post-HSCT; universal vs pre-emptive prophylaxis in D+/R- SOT; secondary prophylaxis until immune recovery (AST IDCOP 2019; Marty NEJM 2017; DHHS 2024 OI)

Disposition criteria:
- Completion: PCR negative × 2 consecutive samples 1 wk apart + clinical resolution + minimum induction duration met → step down to maintenance or secondary prophylaxis arm per host (AST IDCOP 2019)
- Discharge from CMV surveillance: HSCT through d 200 with stable engraftment + immune recovery (CD4 > 100); SOT through d 100-200 per organ + IS stable; HIV after CD4 > 100 × 3-6 mo + VL suppressed (AST IDCOP 2019; DHHS 2024 OI)

Escalation triggers (move to higher acuity):
- Persistent viremia (> 1,000 IU/mL) ≥ 2 wk despite appropriate ganciclovir/valganciclovir + adherence → ED or admit for IV ganciclovir + UL97 / UL54 genotyping (AST IDCOP 2019)
- New tissue-invasive disease (retinitis / colitis / pneumonitis / esophagitis / hepatitis / encephalitis) → ED or admit for IV ganciclovir induction (AST IDCOP 2019; DHHS 2024 OI)
- New visual disturbance + CD4 < 50 → emergent ophtho + ED (DHHS 2024 OI)
- Severe diarrhea / GI bleed in transplant → ED + endoscopy (AST IDCOP 2019)
- Hypoxia + diffuse infiltrate in HSCT → ICU + ID + heme (ASBMT/IDSA HSCT)
- AKI from ganciclovir / foscarnet → dose adjust or switch + neph.aki.core.v1 cross-route (AST IDCOP 2019; KDIGO 2026)

Earlier-Return Triggers

Return-precaution thresholds (watch for):
- [LIFE_THREATENING] Visual disturbance + characteristic "pizza-pie" retinal hemorrhages + exudate along vascular arcades + CD4 < 50 OR transplant recipient — zone 1 (foveal-threatening) lesion is an ophthalmology emergency
- [LIFE_THREATENING] Diffuse interstitial / ground-glass infiltrate + hypoxia + CMV PCR positive in HSCT recipient — alveolar hemorrhage + respiratory failure; very high mortality without aggressive therapy
- [LIFE_THREATENING] Altered mental status + focal neurologic deficit + CSF PCR positive for CMV + MRI showing periventricular enhancement or compatible findings — high mortality without aggressive therapy

Citations

- AST IDCOP 2019 CMV in Solid Organ Transplantation (Razonable Clin Transplant 2019; multi-paper consensus) + ASBMT/IDSA HSCT CMV guidelines (Tomblyn 2009; ECIL series) + NIH/CDC/IDSA HIV-OI (DHHS 2024 OI; clinicalinfo.hiv.gov web-anchored) + Marty NEJM 2017 letermovir prophylaxis PMID 29211658 + Avery CID 2022 SOLSTICE maribavir PMID 34864943 + Kimberlin NEJM 2015 congenital CMV PMID 25738669 [PMID:29211658](https://pubmed.ncbi.nlm.nih.gov/29211658/)
- Cited evidence (PMID 34864943) [PMID:34864943](https://pubmed.ncbi.nlm.nih.gov/34864943/)
- Cited evidence (PMID 25738669) [PMID:25738669](https://pubmed.ncbi.nlm.nih.gov/25738669/)

Last reconciled with current guidelines: 2026-05-22.
References
  • AST IDCOP 2019 CMV in Solid Organ Transplantation (Razonable Clin Transplant 2019; multi-paper consensus) + ASBMT/IDSA HSCT CMV guidelines (Tomblyn 2009; ECIL series) + NIH/CDC/IDSA HIV-OI (DHHS 2024 OI; clinicalinfo.hiv.gov web-anchored) + Marty NEJM 2017 letermovir prophylaxis PMID 29211658 + Avery CID 2022 SOLSTICE maribavir PMID 34864943 + Kimberlin NEJM 2015 congenital CMV PMID 25738669 — PMID:29211658
  • Cited evidence (PMID 34864943) — PMID:34864943
  • Cited evidence (PMID 25738669) — PMID:25738669