Multisystem Processes & Disorders

Cytomegalovirus: presentation by host immune status

Clinical Overview and When to Suspect CMV

— Healthy adult with heterophile-negative mononucleosis (fever, malaise, atypical lymphocytes, transaminitis) lasting weeks

— Solid organ transplant (SOT) recipient 1–6 months post-transplant with fever, cytopenias, hepatitis, GI symptoms, or graft dysfunction

— Hematopoietic stem cell transplant (HSCT) patient with pneumonitis or GI ulceration after engraftment

— HIV with CD4 <50 cells/µL and visual floaters/blurring (retinitis), bloody diarrhea (colitis), or odynophagia (esophagitis)

— Newborn with microcephaly, periventricular calcifications, sensorineural hearing loss (SNHL), petechial "blueberry muffin" rash, or hepatosplenomegaly

— Critically ill ICU patient on prolonged steroids/immunomodulators with unexplained fever or worsening

Board pearl: Step 3 stems anchor on host immune state first — match the syndrome (mono vs retinitis vs pneumonitis vs congenital) to the host before choosing the test. Picking PCR in blood for a retinitis question or serology in a transplant patient is the classic distractor.

Cytomegalovirus (CMV, HHV-5) is a ubiquitous β-herpesvirus establishing lifelong latency in myeloid lineage cells; US seroprevalence ~50–80% by adulthood, higher with age, lower socioeconomic status, and non-white race

Disease expression is almost entirely a function of host immune status — the same virus produces mononucleosis in the immunocompetent, end-organ disease in transplant recipients, retinitis/colitis in advanced HIV, and devastating congenital syndromes in fetuses

When to suspect CMV — by host context:

Transmission: body fluids (saliva, urine, blood, semen, breast milk, transplanted organ); daycare workers and parents of toddlers are classic occupational exposures

Latency reactivation drivers: T-cell depletion (calcineurin inhibitors, anti-thymocyte globulin, alemtuzumab), steroids, sepsis, HIV-related CD4 loss, advanced age

Presentation Patterns and Key History

— Prolonged fever (often 2–6 weeks), malaise, myalgias, mild pharyngitis (less prominent than EBV), hepatosplenomegaly, transaminitis

— Heterophile (Monospot) negative; atypical lymphocytosis present

— Ampicillin/amoxicillin rash less classic than in EBV but can occur

— Rare: Guillain-Barré, hemolytic anemia, ITP, myocarditis, colitis in elderly/IBD patients

— Highest risk: donor-positive/recipient-negative (D+/R−) kidney, lung, heart, liver, intestine recipients

— Peak risk window: 1–6 months post-transplant, or after prophylaxis ends ("late-onset CMV")

— CMV syndrome: fever, malaise, leukopenia/thrombocytopenia, mild transaminitis, viremia

— Tissue-invasive disease: colitis (diarrhea, hematochezia), hepatitis, pneumonitis, nephritis (allograft), retinitis (less common than HIV)

— Reactivation typical; pneumonitis carries highest mortality

— GI disease, marrow suppression, delayed engraftment

— Retinitis (most common): painless floaters, blurry vision, scotomata, peripheral field loss; "pizza pie" exudates with hemorrhage on fundoscopy

— Colitis: weight loss, abdominal pain, bloody diarrhea

— Esophagitis: solitary linear ulcer (vs HSV's multiple shallow ulcers, Candida's plaques)

— Polyradiculitis, ventriculoencephalitis (rare)

— IUGR, microcephaly, periventricular calcifications, chorioretinitis, SNHL (may be late-onset and progressive), hepatosplenomegaly, jaundice, thrombocytopenia

— Maternal primary infection in pregnancy carries highest fetal transmission/severity, but reactivation can also transmit

Key distinction: Heterophile-negative mononucleosis with hepatitis = think CMV or acute HIV — always order an HIV RNA in this stem.

Immunocompetent (CMV mononucleosis):

Solid organ transplant:

HSCT (allogeneic):

HIV/AIDS (CD4 <50):

Congenital CMV (most common congenital infection in US):

Physical Exam Findings (and Organ-Specific Assessment)

— Immunocompetent mono: low-grade fever, mild cervical adenopathy (less prominent than EBV), splenomegaly in ~25%, hepatomegaly, occasional morbilliform rash

— Transplant CMV syndrome: febrile, often appears "viral" with myalgia and fatigue out of proportion to focal findings; check incision/graft site

— AIDS patient: cachexia, oral thrush (CD4 marker), assess vision and abdomen carefully

— Eye (retinitis): dilated fundoscopy mandatory in any AIDS patient with CD4<50 and visual symptoms — fluffy white perivascular infiltrates with hemorrhage ("pizza pie," "ketchup and cottage cheese"); follows vascular distribution; may be peripheral and asymptomatic initially

— GI (colitis/esophagitis): abdominal tenderness, guaiac-positive stool, odynophagia; assess hydration and orthostatics

— Lung (pneumonitis): tachypnea, hypoxia, bibasilar crackles; often subtle exam with disproportionate hypoxemia — pulse ox on ambulation is key

— Liver (hepatitis): RUQ tenderness, mild hepatomegaly, occasional jaundice

— Neuro (encephalitis/polyradiculitis): altered mentation, cranial nerve deficits, ascending weakness with saddle anesthesia and urinary retention (cauda equina pattern)

— Microcephaly (head circumference <3rd %ile), petechiae/purpura ("blueberry muffin"), hepatosplenomegaly, jaundice, hypotonia

— Hearing screen abnormalities — but normal newborn hearing screen does not exclude congenital CMV; SNHL often appears later

Step 3 management: In any HIV patient with CD4 <50 and any visual complaint, the next step is urgent ophthalmology referral for dilated funduscopy — not blood PCR. Retinitis is a clinical/ophthalmologic diagnosis and delay risks permanent vision loss.

General exam by host:

Targeted exam by suspected end organ:

Newborn exam (congenital CMV):

Diagnostic Workup — Initial Labs and Imaging

— Atypical lymphocytosis (immunocompetent mono); leukopenia, thrombocytopenia, anemia (transplant/HSCT)

— Elevated AST/ALT (mild–moderate), elevated LDH, occasionally hyperbilirubinemia

— Quantitative CMV PCR (plasma/whole blood, IU/mL on WHO scale): the workhorse for immunocompromised hosts — used for diagnosis, prognosis, and monitoring response. Rising viral load = progressing disease

— CMV IgM and IgG serology: primarily for immunocompetent mono diagnosis and for pre-transplant donor/recipient serostatus stratification; not useful for active disease in immunocompromised (cannot mount reliable antibody)

— CMV IgG avidity: distinguishes recent (low avidity) vs remote (high avidity) primary infection — critical in pregnancy to estimate fetal risk

— pp65 antigenemia: older semiquantitative assay, largely replaced by PCR

— Pneumonitis: CXR (bilateral interstitial infiltrates) → high-resolution CT (ground-glass opacities, often with nodular component); check pulse ox

— Colitis: stool studies to exclude C. difficile and bacterial pathogens; abdominal CT if severe (bowel wall thickening, mesenteric stranding)

— Hepatitis: hepatitis A/B/C, EBV, autoimmune panel to exclude alternatives

— Encephalitis: MRI brain (periventricular enhancement), LP with CMV PCR on CSF

Board pearl: Quantitative plasma CMV PCR is the right first test in a transplant recipient with fever and cytopenias. Serology in this setting is a trap distractor — they are usually IgG positive at baseline and cannot seroconvert reliably under immunosuppression.

CBC and chemistries:

CMV-specific testing — match test to host:

Site-specific initial imaging/studies:

HIV patients: CD4 count + HIV viral load are mandatory context

Diagnostic Workup — Advanced and Tissue Confirmatory Studies

— Classic finding: "owl's eye" intranuclear inclusions with surrounding halo; cytomegalic cells (enlarged, basophilic)

— IHC or in situ hybridization confirms when morphology equivocal

— GI disease (colitis, esophagitis, gastritis): endoscopy with biopsy of ulcer base (not edge — CMV is in endothelium/stroma, HSV is in squamous epithelium at edges); blood PCR can be negative in 30–50% of GI CMV — do not exclude based on plasma PCR alone

— Pneumonitis (especially HSCT): bronchoalveolar lavage (BAL) with CMV PCR, viral culture, and cytology; quantitative BAL PCR helps distinguish disease from shedding

— Retinitis: dilated ophthalmologic exam by experienced clinician is diagnostic; vitreous PCR rarely needed except in atypical cases

— CNS disease: CSF CMV PCR (high specificity), MRI with contrast

— Allograft involvement (e.g., transplant kidney): allograft biopsy when graft dysfunction with CMV viremia

— Newborn urine or saliva PCR within first 21 days of life is diagnostic (after 21 days cannot distinguish congenital from postnatal)

— Dried blood spot PCR has lower sensitivity; head US/MRI, ophthalmology, audiology evaluation

Key distinction: GI CMV disease can occur with negative plasma PCR — if colitis or esophagitis is suspected, proceed to endoscopy with biopsy rather than relying on blood testing alone.

Tissue biopsy with histopathology + immunohistochemistry (IHC): gold standard for tissue-invasive CMV disease when end-organ involvement is suspected but blood PCR is negative or discordant

Site-specific confirmatory workup:

Congenital CMV diagnostics:

Resistance testing: UL97 and UL54 gene mutation analysis when viral load fails to decline on appropriate ganciclovir/valganciclovir therapy after 2 weeks

Risk Stratification and First-Line Management Logic

— Supportive care only; spontaneous resolution over weeks

— Antivirals not indicated unless severe organ involvement (rare myocarditis, GBS, refractory hemolysis)

— High risk: D+/R− (no preexisting immunity to donor strain), lung/intestine recipients, ATG/alemtuzumab induction

— Intermediate: R+ regardless of donor

— Low: D−/R− (give CMV-negative or leukoreduced blood products)

— Prevention strategies:

▪ Universal prophylaxis: valganciclovir 900 mg daily for 3–6 months (longer for lung/intestine, D+/R−)

▪ Preemptive therapy: weekly CMV PCR monitoring; treat when threshold viral load crossed

— Letermovir prophylaxis (CMV terminase inhibitor) FDA-approved for CMV-seropositive allo-HSCT recipients through day +100 (extended to day +200 in high risk); has dramatically reduced clinically significant CMV

— Preemptive PCR monitoring twice weekly early post-transplant

— No routine antiviral prophylaxis; ART initiation is the cornerstone of prevention

— Dilated fundoscopy screening every 3 months while CD4 <50

— No FDA-approved intervention proven to prevent transmission; hygienic counseling (handwashing after diaper changes/saliva contact with toddlers) is the evidence-based prevention

— Valacyclovir in maternal primary infection (under specialist care) reduces vertical transmission in some studies

Step 3 management: For a kidney transplant recipient with fever and CMV viral load >1,000 IU/mL plus cytopenias — start valganciclovir, reduce immunosuppression (lower mycophenolate dose), monitor weekly PCR until two consecutive negatives.

Immunocompetent mononucleosis:

Solid organ transplant — risk tiers:

HSCT:

HIV with CD4 <50:

Pregnancy:

Pharmacotherapy — First-Line Drug Regimen

— Induction: ganciclovir 5 mg/kg IV q12h OR valganciclovir 900 mg PO BID × at least 2–3 weeks (and until viral load undetectable on 2 consecutive samples ≥1 week apart)

— Maintenance: valganciclovir 900 mg daily, duration determined by host (HIV: until CD4 >100 for 3–6 months on ART; transplant: typically 1–3 months secondary prophylaxis)

— Severe/life-threatening disease (pneumonitis, CNS, severe colitis with malabsorption): start with IV ganciclovir, transition to oral when stable and absorbing

— Myelosuppression (neutropenia, thrombocytopenia, anemia) — dose-limiting; check CBC twice weekly

— Nephrotoxicity (less than foscarnet but real), renal dose adjustment required

— Teratogenicity, carcinogenicity, gonadotoxicity — counseling and contraception

— G-CSF for ganciclovir-induced neutropenia (ANC <1000)

— Reduction of immunosuppression in transplant — usually decrease antimetabolite (mycophenolate) first; preserve calcineurin inhibitor unless severe

Board pearl: A transplant patient on valganciclovir whose viral load rises after 2 weeks of therapy needs resistance testing (UL97/UL54) and switch to foscarnet or maribavir — not simply a dose increase.

Ganciclovir (IV) and valganciclovir (oral prodrug): first-line for treatment of CMV disease across host categories

Mechanism: nucleoside analog; phosphorylated initially by viral UL97 kinase (not host thymidine kinase like acyclovir for HSV); inhibits viral DNA polymerase (UL54)

Major toxicities:

Adjuncts:

Letermovir: prophylaxis only (HSCT, increasingly in kidney transplant); not for treatment of established disease

Maribavir: oral UL97 inhibitor approved for refractory/resistant CMV post-transplant; does not cause myelosuppression — useful when ganciclovir intolerance

Procedures and Second-Line/Salvage Pharmacology

— Dose: 60 mg/kg IV q8h induction; renally adjusted

— Toxicities: nephrotoxicity (volume preload with saline before each dose), electrolyte derangements — hypocalcemia, hypomagnesemia, hypokalemia, hypophosphatemia (or hyperphosphatemia); seizures; penile/vulvar ulcers

— Monitor electrolytes and creatinine every other day

— Intravitreal ganciclovir or foscarnet injections for sight-threatening retinitis (zone 1, near macula/optic nerve) combined with systemic therapy

— Ganciclovir intraocular implant historically used; now rarely available

— Systemic therapy is mandatory in addition to local — protects fellow eye and treats extraocular disease

— Colectomy reserved for CMV colitis with perforation, massive hemorrhage, or toxic megacolon failing medical therapy

— Vitrectomy for retinal detachment complication of healed retinitis

CCS pearl: For severe CMV retinitis with macular involvement in AIDS — order ophthalmology consult, IV ganciclovir induction, intravitreal ganciclovir injection, start/optimize ART, and dilated fundoscopy every 1–2 weeks during induction.

Foscarnet: pyrophosphate analog directly inhibiting viral DNA polymerase — does not require UL97 phosphorylation, so retains activity against most UL97-mutant (ganciclovir-resistant) strains

Cidofovir: nucleotide analog, dosed weekly with probenecid + IV saline preload to mitigate severe nephrotoxicity; reserve for refractory disease

Maribavir: oral, 400 mg BID, for refractory or resistant post-transplant CMV in adults — does not treat CNS or retinal disease (poor penetration); avoid concurrent ganciclovir (antagonism)

CMV hyperimmune globulin (CMV-IVIG): adjunct in CMV pneumonitis in HSCT (controversial benefit); used in some pregnancy protocols (unproven)

Intravitreal therapy for CMV retinitis:

Surgical/procedural considerations:

Special Populations — Elderly and Renal/Hepatic Impairment

— CMV mononucleosis in adults >40 often presents as prolonged FUO with hepatitis rather than classic pharyngitis/lymphadenopathy — frequently misdiagnosed as drug reaction or autoimmune hepatitis initially

— CMV colitis can occur in elderly ICU patients with prolonged steroid use, complicating C. difficile or ischemic colitis pictures

— Higher baseline polypharmacy increases interaction risk with ganciclovir/valganciclovir (additive myelosuppression with TMP-SMX, mycophenolate, azathioprine)

— Valganciclovir is dose-adjusted by CrCl: 450 mg daily at CrCl 40–59, 450 mg every other day at 25–39, 450 mg twice weekly at 10–24, not recommended in hemodialysis at standard doses — use IV ganciclovir at dialysis-adjusted dose post-HD

— Ganciclovir IV induction reduced to 2.5 mg/kg q24h at CrCl <25 and post-HD dosing thereafter

— Foscarnet requires meticulous renal dose adjustment with creatinine recheck every 1–2 days; contraindicated effectively at CrCl <0.4 mL/min/kg

— Cidofovir contraindicated at SCr >1.5 mg/dL or CrCl <55 or proteinuria ≥2+

— Ganciclovir/valganciclovir are renally cleared — no hepatic dose adjustment, but monitor LFTs as CMV itself causes hepatitis

— Maribavir: no dose adjustment in mild–moderate hepatic impairment; data limited in severe

Step 3 management: In a 72-year-old kidney transplant recipient with eGFR 28 and CMV viremia — use valganciclovir 450 mg every other day with twice-weekly CBC, reduce mycophenolate, and recheck CMV PCR weekly.

Elderly immunocompetent patients:

Renal impairment — dose adjustments (critical and high-yield):

Hepatic impairment:

Drug interactions: valganciclovir + mycophenolate → additive leukopenia (consider dose reduction or G-CSF support); avoid concurrent zidovudine (additive marrow toxicity)

Special Populations — Pregnancy, Pediatrics, and Congenital CMV

— Most maternal infections are asymptomatic; some present as mono-like illness

— Diagnosis: IgM positive + low IgG avidity suggests recent primary infection (highest fetal risk, ~30–40% transmission)

— Non-primary infection (reactivation/reinfection) carries lower transmission (~1–2%) but can still cause severe congenital disease

— Workup if maternal infection confirmed: detailed fetal US, amniocentesis ≥21 weeks and ≥6 weeks after maternal infection for amniotic fluid CMV PCR

— Prevention: hygienic precautions (handwashing after toddler contact, no food sharing) — only evidence-based intervention

— ~10% symptomatic at birth, of whom 40–60% develop long-term sequelae

— Of asymptomatic infants, 10–15% develop late-onset SNHL — leading non-genetic cause of childhood SNHL

— Diagnosis: PCR of saliva or urine within first 3 weeks of life

— Treatment of symptomatic congenital CMV (CNS involvement, chorioretinitis, SNHL): oral valganciclovir 16 mg/kg/dose BID × 6 months — improves hearing and neurodevelopmental outcomes (per CASG 112 trial)

— Monitor CBC weekly initially (neutropenia common)

— Pediatric HSCT and SOT follow adult monitoring/preemptive paradigms with weight-based dosing

— Daycare attendance is the leading source of primary CMV in young children; counsel pregnant household members on hygiene

Board pearl: Oral valganciclovir × 6 months is the standard of care for symptomatic congenital CMV with CNS involvement — improves long-term hearing and neurodevelopmental outcomes. Asymptomatic congenital CMV is generally not treated.

Maternal CMV in pregnancy:

Congenital CMV — most common congenital infection in the US (~1 in 200 live births):

Pediatric immunocompromised hosts:

Complications and Adverse Outcomes

— Retinitis: retinal detachment (10–30% within 6 months of diagnosis, especially after immune recovery), permanent vision loss, immune recovery uveitis (IRU) with ART initiation

— Colitis: perforation, massive lower GI hemorrhage, toxic megacolon, stricture

— Pneumonitis: ARDS, respiratory failure, high mortality in HSCT (historically 50–80%)

— Hepatitis: rarely fulminant; cholestatic pattern in transplant

— Encephalitis/ventriculitis: hydrocephalus, cognitive deficits

— Polyradiculitis: persistent cauda equina deficits

— Acute and chronic allograft rejection — CMV is independently associated with rejection

— Bronchiolitis obliterans syndrome in lung transplant

— Cardiac allograft vasculopathy in heart transplant

— Increased risk of opportunistic infections (PJP, invasive fungi, EBV-PTLD) due to CMV's immunomodulatory effect

— Increased post-transplant diabetes and cardiovascular events

— Progressive SNHL (can appear or worsen up to age 6), cerebral palsy, intellectual disability, seizure disorders, vision impairment from chorioretinitis

— Ganciclovir/valganciclovir: severe neutropenia → bacterial/fungal superinfection

— Foscarnet: AKI, severe electrolyte derangements precipitating seizures or arrhythmia (QT prolongation from hypocalcemia/hypomagnesemia)

Key distinction: Worsening retinitis 4–8 weeks after starting ART in a previously treated patient = immune recovery uveitis (IRIS), not necessarily treatment failure — manage with steroids, not just antiviral escalation.

Direct end-organ complications:

Indirect/immunomodulatory effects in transplant:

Congenital sequelae:

Therapy-related complications:

Immune reconstitution inflammatory syndrome (IRIS): worsening retinitis or vitritis after ART start in HIV; manage with continued anti-CMV therapy + topical/systemic steroids in select cases

When to Escalate — ICU, Consult, and Inpatient Triage

— CMV pneumonitis with hypoxia (SpO2 <90% on room air or rising O2 requirement), bilateral infiltrates, or any HSCT recipient with confirmed CMV pneumonitis

— CMV colitis with perforation, hemodynamic instability, transfusion-dependent GI bleed, or toxic megacolon

— CMV encephalitis with altered mentation, seizures, or hydrocephalus

— Severe foscarnet electrolyte derangements (symptomatic hypocalcemia with tetany/QT prolongation/seizure)

— Profound neutropenia (ANC <500) with sepsis physiology

— Infectious diseases: any CMV disease in immunocompromised host; refractory/resistant CMV; pregnancy with documented infection

— Transplant team: for all CMV in SOT/HSCT recipients — immunosuppression modulation is collaborative

— Ophthalmology: any AIDS patient with CD4 <100 and visual symptoms, any suspected retinitis, IRU management

— GI: for endoscopy/biopsy in suspected GI disease

— Maternal-Fetal Medicine + Pediatric ID: maternal primary CMV or suspected congenital infection

— Hematology: for HSCT recipients

— Outpatient oral valganciclovir acceptable for: stable transplant patient with CMV syndrome or mild end-organ disease, able to tolerate PO, reliable follow-up, baseline labs available

— Admit for IV ganciclovir when: severe disease, GI involvement with malabsorption, hemodynamic instability, profound cytopenias, CNS involvement, pneumonitis, or social barriers to compliance

CCS pearl: For CMV pneumonitis in an HSCT recipient — admit to ICU, IV ganciclovir 5 mg/kg q12h, consider CMV-IVIG adjunct, ID and transplant consult day 1, daily CBC, every-other-day CMV quantitative PCR, low threshold for intubation.

ICU-level care indicators:

Mandatory subspecialty consults:

Inpatient vs outpatient management:

Transfer considerations: patients requiring HSCT, complex resistant CMV management, or vitreoretinal surgical intervention should be transferred to tertiary center

Key Differentials — Other Herpesviruses and Viral Mimics

— Heterophile (Monospot) positive (CMV negative), more prominent pharyngitis with exudates, posterior cervical lymphadenopathy, classic ampicillin rash

— Splenomegaly more prominent; transaminitis common in both

— Diagnosis: EBV VCA IgM, EBNA, EA serologies

— Heterophile-negative mono-like syndrome with fever, rash (truncal maculopapular), pharyngitis, mucocutaneous ulcers, lymphadenopathy

— Diagnose with HIV RNA PCR (4th-gen Ag/Ab may be negative early); HIV antibody alone insufficient in window period

— Always order HIV testing in any "CMV mono" workup

— HSV: multiple shallow ulcers, well-demarcated, often with vesicles, biopsy of ulcer edge (squamous epithelium); Cowdry A intranuclear inclusions

— CMV: single or few large linear/serpiginous deep ulcers, biopsy of ulcer base (endothelium/stroma); owl's eye inclusions

— Candida: white plaques, no ulcers, KOH/PAS shows hyphae

Key distinction: Heterophile-negative mononucleosis triad to memorize → CMV, EBV (heterophile may be falsely negative early), acute HIV, and toxoplasmosis — work all four into your initial workup.

EBV mononucleosis:

Acute HIV (acute retroviral syndrome):

HSV esophagitis (vs CMV esophagitis):

HHV-6 and HHV-7: reactivation post-transplant can mimic CMV; encephalitis after HSCT classically HHV-6; testing by serum PCR

Adenovirus in HSCT/SOT: hemorrhagic cystitis, pneumonitis, hepatitis, colitis — overlaps significantly with CMV; treat with cidofovir

Acute viral hepatitis (A, B, C, E): consider in mono-like illness with hepatitis predominance; check hepatitis panel

Parvovirus B19: marrow suppression in transplant — can mimic CMV cytopenias; check parvovirus PCR

Key Differentials — Other-Category Mimics

— Especially relevant in transplant patients on TMP-SMX, antibiotics, anticonvulsants; eosinophilia, rash, multi-organ involvement

— DRESS itself is associated with HHV-6/CMV reactivation — can be both, not either/or

— Older woman with fever, hepatitis, hypergammaglobulinemia, ANA/SMA positive — consider in prolonged CMV-mimic with negative viral workup

— Patients with steroid-refractory UC frequently have CMV reactivation in inflamed colon — biopsy with IHC of colon at any steroid-refractory flare

— Treatment of CMV may rescue the "refractory" flare

— Co-infections common; bilateral ground-glass in transplant/HIV — broaden workup with BAL: bacterial cultures, PJP DFA/PCR, galactomannan, β-D-glucan, fungal cultures, alongside CMV PCR

— Skin rash, diarrhea, hepatitis — overlaps with CMV; biopsy critical, and the two coexist frequently (GVHD treatment with steroids precipitates CMV)

— Fever, cytopenias, lymphadenopathy in EBV-driven proliferation; LDH high, mass lesions on imaging

— Ring-enhancing brain lesions vs CMV ventriculitis (periventricular enhancement)

— Chorioretinitis: toxo causes focal necrotizing lesions, CMV causes hemorrhagic perivascular lesions

Board pearl: Steroid-refractory ulcerative colitis flare → biopsy for CMV with IHC before escalating to infliximab or colectomy — missed CMV is a high-yield exam and clinical trap.

Drug-induced hepatitis or DRESS syndrome:

Autoimmune hepatitis:

Inflammatory bowel disease flare with CMV superinfection:

Bacterial pneumonia, PJP, fungal pneumonia in immunocompromised:

Graft-versus-host disease (GVHD) post-HSCT:

Post-transplant lymphoproliferative disorder (PTLD):

Toxoplasmosis (HIV CD4 <100):

Lymphoma: B symptoms, lymphadenopathy, hepatosplenomegaly — consider in prolonged "mono" not resolving

Secondary Prevention and Long-Term Plan

— Secondary prophylaxis with valganciclovir 900 mg daily for 1–3 months after viral load is undetectable, especially in D+/R− or high-immunosuppression patients

— Continue routine CMV PCR monitoring monthly for at least 3 months post-treatment, then per local protocol

— Reduce immunosuppression (especially mycophenolate) to lowest level compatible with graft preservation

— Continue letermovir or preemptive monitoring until immune reconstitution (typically day +100 to +200, longer with GVHD or extended immunosuppression)

— CMV-specific T-cell adoptive therapy is emerging for resistant disease

— Maintenance/secondary prophylaxis with valganciclovir 900 mg daily until CD4 >100 cells/µL for ≥3–6 months on suppressive ART

— Continue ART without interruption; monitor for IRIS

— Ophthalmology surveillance every 3 months while on suppression

— Audiology assessment every 3–6 months in infancy, then yearly through school age (late-onset and progressive SNHL)

— Developmental pediatrics, early intervention services, ophthalmology screening

— Valganciclovir with renal-dose-appropriate prescription

— CBC/BMP weekly to biweekly during therapy

— TMP-SMX (PJP prophylaxis) but monitor for additive cytopenias

— Ensure immunosuppression dose reconciliation in transplant patients

— CMV-seronegative or leukoreduced blood products for D−/R− recipients lifelong

Step 3 management: AIDS patient post-CMV retinitis with CD4 now 180 sustained for 6 months on suppressive ART → discontinue secondary CMV prophylaxis, continue ART, continue ophthalmology surveillance.

Solid organ transplant — after completing CMV treatment:

HSCT:

HIV/AIDS — after CMV retinitis or other end-organ disease:

Congenital CMV survivors:

Discharge medication checklist (CCS-flavored):

Follow-Up, Monitoring Parameters, and Counseling

— Quantitative CMV plasma PCR weekly until undetectable on two consecutive samples ≥1 week apart, then continue minimum 2 weeks of therapy

— CBC twice weekly (ganciclovir/valganciclovir neutropenia surveillance) — hold or reduce dose at ANC <500 or platelets <25,000; consider G-CSF

— BMP twice weekly (renal dose adjustment) and weekly LFTs

— For foscarnet: daily-to-every-other-day creatinine, calcium (ionized if possible), magnesium, phosphate, potassium; ECG if electrolyte instability

— Transplant: monthly CMV PCR × 3–6 months, then per institutional protocol

— HIV: CD4 and viral load every 3 months; dilated fundoscopy every 3 months until CD4 reconstitution

— Congenital CMV: serial audiology, neurodevelopmental, ophthalmology

— Pregnant women and women of childbearing age: hand hygiene after diaper changes/toddler saliva exposure; no shared utensils with young children; this is the single most effective preventive strategy for congenital CMV

— Transplant recipients: signs of CMV recurrence (fever, fatigue, GI symptoms, visual changes); medication adherence; avoid live vaccines

— HIV patients: ART adherence is the durable answer to CMV; report visual floaters/blurring immediately

— All patients on valganciclovir: contraception (men and women) due to teratogenicity/gonadotoxicity; avoid pregnancy during and 90 days after therapy

— Congenital CMV: enroll in early intervention; cochlear implant evaluation if profound SNHL

— Post-CNS CMV: neurorehabilitation, PT/OT

— Visual rehabilitation for irreversible retinitis sequelae

Board pearl: Treatment endpoint for CMV viremia is two consecutive undetectable PCRs ≥1 week apart with at least 2 weeks of therapy completed — not just clinical resolution.

On-treatment monitoring (induction phase):

Post-treatment / outpatient monitoring:

Counseling points by population:

Rehabilitation:

Ethical, Legal, and Patient Safety Considerations

— Valganciclovir/ganciclovir carry black-box warnings for teratogenicity, carcinogenicity, and impaired spermatogenesis — document counseling and offer contraception for both partners during and 90 days after treatment (males) / through treatment plus 30 days (females)

— In symptomatic congenital CMV, discuss benefits (improved hearing, neurodevelopment) vs risks of 6-month valganciclovir (neutropenia) — shared decision-making with parents

— Transplant patients discharged on valganciclovir: ensure renal-dose-adjusted prescription, lab monitoring orders sent to outpatient lab, follow-up appointment within 1–2 weeks, and clear handoff between inpatient and transplant clinic

— Failure to taper or stop prophylaxis appropriately is a common medication error

— Reconciling immunosuppression after CMV episode is high-risk — explicit written plan needed

— CMV is not a reportable disease in most jurisdictions, but congenital CMV is reportable in some states; check local requirements

— Daycare and occupational exposure counseling for healthcare/childcare workers who are pregnant

— CMV-seronegative or leukoreduced products for CMV-seronegative transplant candidates, premature neonates, and intrauterine transfusions — institutional protocol error here causes preventable disease

— Ganciclovir handling: cytotoxic precautions — gloves, no crushing valganciclovir tablets (or use commercial oral solution)

— Drug interactions: valganciclovir + zidovudine or TMP-SMX → severe neutropenia

— Missed congenital diagnosis: testing must occur within first 21 days of life — outside this window, distinguishing congenital from postnatal infection is impossible, with treatment implications

Step 3 management: A transplant patient discharged on valganciclovir without renal dose adjustment for new AKI develops profound pancytopenia — this is a transition-of-care medication error; root cause = absent medication reconciliation at discharge.

Informed consent and reproductive counseling:

Transition-of-care risks (high Step 3 yield):

Mandatory reporting and public health:

Blood product safety:

Patient safety pitfalls:

High-Yield Associations and Rapid-Fire Clinical Facts

Board pearl: If the stem mentions "periventricular calcifications" in a newborn → CMV. "Scattered/diffuse intracranial calcifications" + chorioretinitis + hydrocephalus → toxoplasmosis. Both can cause SNHL but CMV is far more common.

"Owl's eye" intranuclear inclusions with perinuclear halo on biopsy = pathognomonic CMV

Heterophile-negative mononucleosis in adult >30 with prolonged fever and hepatitis → CMV (also rule out acute HIV)

CD4 <50 is the threshold for CMV retinitis risk in HIV

"Pizza pie" or "ketchup and cottage cheese" retina = CMV retinitis

D+/R− kidney transplant = highest CMV risk SOT category

Letermovir = HSCT prophylaxis; maribavir = refractory/resistant treatment

UL97 mutation = ganciclovir resistance; UL54 mutation = pan-resistance including foscarnet/cidofovir

Foscarnet electrolyte triad = hypocalcemia, hypomagnesemia, hypokalemia (± hypo/hyperphosphatemia); seizure risk

Congenital CMV = leading non-genetic cause of childhood SNHL; periventricular calcifications (vs toxoplasmosis = scattered/diffuse calcifications)

Diagnosis of congenital CMV requires saliva/urine PCR within first 21 days of life

Symptomatic congenital CMV with CNS disease → valganciclovir × 6 months

CMV colitis can have negative blood PCR — biopsy of ulcer base

CMV esophagitis = single large linear ulcer (vs HSV multiple shallow, Candida plaques)

Steroid-refractory UC → biopsy for CMV before escalating

Treatment endpoint = 2 consecutive undetectable PCRs ≥1 week apart, minimum 2 weeks therapy

Stop secondary prophylaxis in HIV when CD4 >100 sustained ≥3–6 months on ART

CMV-negative or leukoreduced blood for CMV-seronegative transplant candidates and premature neonates

Most common congenital infection in developed countries = CMV

Immune recovery uveitis (IRU) = worsening eye inflammation after ART start in previously treated CMV retinitis

Board Question Stem Patterns

— 35-year-old with 4 weeks of fever, fatigue, mild splenomegaly, transaminitis, atypical lymphocytes, negative Monospot

— Answer: CMV serology (IgM/IgG) for diagnosis; rule out acute HIV with RNA PCR; supportive care

— Kidney transplant 3 months ago (D+/R−), now with fever, leukopenia, fatigue, mild ALT elevation

— Answer: quantitative plasma CMV PCR; if positive → valganciclovir and reduce mycophenolate

— HIV patient, CD4 30, complains of floaters and blurry vision; fundoscopy shows hemorrhages and fluffy exudates

— Answer: ophthalmology consult, IV ganciclovir (and intravitreal injection if zone 1), start ART, ongoing surveillance

— Lung transplant on valganciclovir 3 weeks, viral load rising

— Answer: resistance testing (UL97/UL54), switch to foscarnet or maribavir, reduce immunosuppression

— UC flare not responding to IV steroids, scope shows deep ulcers

— Answer: biopsy with CMV IHC; treat if positive before escalating biologics

— Newborn with microcephaly, periventricular calcifications, petechial rash, hepatosplenomegaly, failed hearing screen

— Answer: urine or saliva CMV PCR within 21 days; if positive with symptoms/CNS involvement → oral valganciclovir × 6 months

— Pregnant woman, daycare worker, with mono-like illness; CMV IgM positive, IgG positive with low avidity

— Answer: recent primary infection — refer MFM, fetal US, amniocentesis at appropriate timing; counseling

— AIDS patient with odynophagia, scope shows single linear ulcer, biopsy of base shows owl's eye inclusions

— Answer: CMV esophagitis → valganciclovir/ganciclovir + ART optimization

Key distinction: When the stem gives you host immune status + organ-specific symptom + a diagnostic clue (heterophile-negative, owl's eye, periventricular calcifications, pizza-pie retina), the answer is almost always CMV — then choose the right test/treatment for that host.

Stem 1 — Immunocompetent mono mimic:

Stem 2 — Transplant CMV syndrome:

Stem 3 — AIDS retinitis:

Stem 4 — Refractory transplant CMV:

Stem 5 — Steroid-refractory UC:

Stem 6 — Congenital CMV:

Stem 7 — Pregnancy exposure:

Stem 8 — Esophagitis differential:

One-Line Recap

CMV is a ubiquitous β-herpesvirus whose clinical face is dictated entirely by host immune status — mononucleosis in the healthy, tissue-invasive end-organ disease in transplant and HSCT recipients, retinitis/colitis/esophagitis at CD4 <50 in HIV, and the most common (and most underdiagnosed) congenital infection — so diagnosis and management always begin by anchoring on the host.

Board pearl: Match the host to the syndrome, the syndrome to the test, and the test to the treatment — CMV questions reward this disciplined sequence every time.

Test selection: quantitative plasma CMV PCR for immunocompromised hosts; serology with IgG avidity for immunocompetent and pregnancy; biopsy with IHC for tissue-invasive disease (especially GI, where blood PCR may be negative); saliva/urine PCR within 21 days of life for congenital diagnosis

First-line treatment: valganciclovir (oral) or ganciclovir (IV) for induction × at least 2 weeks until two consecutive undetectable PCRs; foscarnet or maribavir for ganciclovir-resistant or refractory disease; symptomatic congenital CMV → valganciclovir × 6 months

Prevention: letermovir prophylaxis in HSCT, valganciclovir prophylaxis or preemptive monitoring in SOT, ART (with CD4 reconstitution) as durable prevention in HIV, hygienic counseling for pregnant women, CMV-negative/leukoreduced blood for seronegative transplant candidates and premature neonates

Step 3 traps to avoid: ordering serology in a transplant patient (use PCR), missing CMV colitis because blood PCR is negative (biopsy the ulcer base), forgetting to test for acute HIV in heterophile-negative mono, missing the 21-day window for congenital diagnosis, and failing renal-dose adjustment of valganciclovir at discharge — a transition-of-care safety event