01Approach to the Critical Patient/attcp60

Immediate stabilization

›Airway and breathing priorities

›Respiratory failure risk

›SpO2 < 90% on room air

›PaO2 < 60 mmHg

›Rapidly progressive dyspnea with miliary pattern

›If respiratory failure, early intubation planning

›Rapid sequence intubation preparation

›Avoid prolonged NIV in immunocompromised host with fungal infection

›Supplemental oxygen to maintain SpO2 92–96%

›Circulation and shock recognition

›Septic shock pattern

›SBP < 90 mmHg or MAP < 65 mmHg

›Lactate >= 2 mmol/l

›Present in 10–20% of fulminant disseminated histoplasmosis

›Adrenal crisis pattern

›Refractory hypotension despite fluids

›Bilateral adrenal enlargement on imaging

›Hyponatremia and hyperkalemia on electrolytes

›If septic shock, IV fluid resuscitation and vasopressors

›Norepinephrine first-line vasopressor

›Stress-dose hydrocortisone 100 mg IV if adrenal crisis suspected

›Broad spectrum antifungals within 1–2 hours of critical presentation

›Liposomal amphotericin B preferred for fulminant disease

Monitoring and targets

›Monitoring bundle

›Continuous pulse oximetry and cardiac monitor

›SpO2 target 92–96%

02History/hx68

Onset and constitutional symptoms

›Temporal pattern

›Subacute onset over 1–2 months most common

›Prolonged fever, weight loss, fatigue

›Median time to diagnosis approximately 32 days

›Fulminant onset in 10–20% with advanced immunosuppression

›Rapid progression to septic shock

›Low CD4 count < 50 cells/mm³ highest risk

›Constitutional symptoms

›Fever — nearly universal

›Night sweats

›Chills and rigors

›Weight loss

›Progressive over weeks to months

›Anorexia and cachexia

›Fatigue and malaise

Organ-specific symptoms

›Pulmonary symptoms

›Cough in approximately 50% of cases

›Productive or nonproductive

›Dyspnea on exertion

›Pleuritic chest pain if pericarditis or effusion

›Gastrointestinal symptoms

›GI involvement present in 50–70% of cases

›Nausea, vomiting, diarrhea

›Abdominal pain

›Odynophagia from oropharyngeal ulcers

›Neurologic symptoms

03Physical Exam/exam55

Vitals and general appearance

›Hemodynamic assessment

›Temperature — fever nearly universal; hypothermia as severe sepsis marker

›High fever > 39 C

›Hypothermia in fulminant presentations

›Blood pressure

›SBP < 90 mmHg or MAP < 65 mmHg indicating shock

›Orthostatic hypotension suggesting adrenal insufficiency

›Heart rate — tachycardia common with fever and hypovolemia

›Oxygen saturation — baseline on room air

›General appearance

›Cachectic and ill-appearing

›Weight loss visible

›Temporal wasting

Head, eyes, ears, nose, throat

›Oropharyngeal exam

›Oropharyngeal and palatal ulcers — high diagnostic yield

›Ulcerative, necrotic base lesions

›More prominent in Latin American endemic strains

›Lymphadenopathy — cervical and submandibular

›Generalized lymphadenopathy common

Pulmonary and cardiac exam

›Lung findings

›Crackles — diffuse or focal

›Miliary pattern infiltrates

›May be normal early in disease

›Decreased breath sounds at bases — effusion

›Cardiac findings

04Differential Diagnosis/ddx49

Life-threatening mimics

›Pulmonary and disseminated infections

›Tuberculosis — most common clinical mimic

›Overlapping symptoms, imaging, and epidemiology

›Co-infection with histoplasmosis common

›ICD-10: A15.0–A19.9

›Cryptococcosis

›Overlapping CNS and disseminated presentations in HIV

›India ink and cryptococcal antigen differentiate

›ICD-10: B45.1

›Non-tuberculous mycobacterial infection (MAC)

›Similar presentation in advanced HIV

›Blood cultures and molecular testing differentiate

›ICD-10: A31.0–A31.9

›Hematologic emergencies

›Lymphoma

›Fever, weight loss, hepatosplenomegaly, pancytopenia

›B-cell lymphoma common in HIV

›ICD-10: C81–C86

›Hemophagocytic lymphohistiocytosis

›Can be triggered by histoplasmosis itself

›Markedly elevated ferritin, cytopenias, splenomegaly

›ICD-10: D76.1

Regional and geographic mimics

›Other endemic mycoses

›Blastomycosis

›Similar endemic geography in Ohio/Mississippi Valley

›Skin lesions and pulmonary involvement overlap

05Laboratory Tests/lt67

Antigen and culture diagnostics

›Histoplasma urine antigen

›Lateral flow assay — point-of-care test

›Sensitivity 96%, specificity 96% in disseminated disease

›Best single initial test for rapid ED diagnosis

›Also available as quantitative ELISA for monitoring

›Urine antigen monitoring during therapy

›Levels decline with treatment response

›Antigenuria recurs in approximately 90% of patients who relapse

›Histoplasma serum antigen

›Complementary to urine antigen testing

›Combined urine and serum antigen maximizes sensitivity

›Blood cultures (lysis-centrifugation technique)

›Positive in > 85% of HIV-associated disseminated histoplasmosis

›Lysis-centrifugation method preferred over standard aerobic bottles

›Results take 1–4 weeks — not useful for acute management

›Serology (complement fixation and immunodiffusion)

›Sensitivity only 41–69% in HIV-positive patients

›Not reliable in severely immunocompromised hosts

›Useful in immunocompetent patients with subacute presentations

Hematologic and metabolic labs

›Complete blood count with differential

›Pancytopenia — hallmark of disseminated disease

›Leukopenia — hemoglobin < 10 g/dL suggests severe disease

›Thrombocytopenia with DIC risk

›If pancytopenia severe, evaluate for HLH

›Comprehensive metabolic panel

›Liver enzymes

06Diagnostic Tests/dt82

Scoring Systems

›Hoyos Pulgarín Diagnostic Score for Histoplasmosis in HIV

›Variables in the scoring system

›Hemoglobin < 10 g/dL

›Leukopenia

›Elevated LDH

›AST/ALT ratio > 2

›CD4 < 50 cells/mm³

›Score interpretation

›Cutoff >= 4 points yields 82.9% specificity

›Published in Open Forum Infectious Diseases 2025

›Useful for clinical suspicion in resource-limited settings

›HLH-2004 Diagnostic Criteria (for HLH complication)

›Requires 5 of 8 criteria

›Fever, splenomegaly, cytopenias (2+ cell lines)

›Hypertriglyceridemia and/or hypofibrinogenemia

›Hemophagocytosis on bone marrow biopsy

›Low/absent NK cell activity

›Ferritin >= 500 µg/L

›Elevated soluble CD25 (IL-2 receptor)

›HScore calculator also useful

›Score > 169 has 93% sensitivity, 86% specificity for HLH

MRI

›MRI brain for CNS disease

›Indications

›Headache, confusion, seizures, or focal neurological deficits

›Any suspected CNS histoplasmosis

›Expected findings

›Focal parenchymal lesions — ring-enhancing granulomas

›Meningeal enhancement — basilar meningitis pattern

›Hydrocephalus from meningeal involvement

›Protocol

›Gadolinium contrast essential

›DWI sequences to assess for infarction

›MRI superior to CT for posterior fossa and meningeal disease

›MRI abdomen (if CT not available or adrenal assessment needed)

›Bilateral adrenal enlargement on T2 sequences

›Distinctive finding for histoplasmal adrenalitis

›May show necrosis or hemorrhage in glands

CT

›CT chest

›Indications

›Cough, dyspnea, or abnormal CXR

›All moderate-to-severe presentations

›Expected findings

›Miliary nodules < 3 mm throughout both lungs

›Mediastinal and hilar lymphadenopathy

›Airspace consolidation

›Cavitary lesions in chronic disease

›Important limitations

›Normal CT does not exclude disseminated histoplasmosis

›Miliary pattern may be subtle early in disease

›CT abdomen and pelvis

›Indications

›Abdominal pain, hepatosplenomegaly, or suspected adrenal involvement

›Expected findings

›Hepatomegaly with heterogeneous enhancement

›Splenomegaly — moderate to marked

›Abdominal and retroperitoneal lymphadenopathy

›Bilateral adrenal enlargement — distinctive finding for PDH

›Adrenal findings are particularly distinctive

›Bilateral involvement common in histoplasmal adrenalitis

›Differs from adrenal metastasis which is often unilateral

›CT head

›Initial assessment when MRI not immediately available

›Exclude mass lesions and hydrocephalus before LP

›May show hypodense parenchymal lesions or meningeal enhancement

Ultrasound

›Bedside abdominal ultrasound

›Hepatosplenomegaly assessment

›Rapid bedside evaluation of organ enlargement

›Spleen > 13 cm in adults suggests splenomegaly

›Free fluid detection

›Ascites from hypoalbuminemia or portal hypertension

›Cardiac ultrasound (echocardiography)

›Indications

›Muffled heart sounds or suspected pericardial effusion

›Hypotension unresponsive to fluids

›Assessment

›Pericardial effusion size and hemodynamic significance

›Tamponade physiology: RV collapse, respiratory variation in flow

›Pericardiocentesis guidance if tamponade

›Point-of-care chest ultrasound

›Pleural effusion detection

›B-lines pattern for pulmonary edema vs. infiltrate

›Complementary to CXR in critically ill patients

07Disposition/dispo38

Admission criteria

›Indications for hospital admission

›Moderate-to-severe disseminated histoplasmosis requiring IV therapy

›Approximately 96% of PDH patients require hospitalization

›All patients requiring IV liposomal amphotericin B

›Specific high-risk features mandating admission

›Hemodynamic instability or shock

›Respiratory failure

›Altered mental status or CNS involvement

›Significant pancytopenia or coagulopathy

›Suspected HLH, adrenal crisis, or pericardial tamponade

ICU criteria

›ICU admission indications

›Septic shock requiring vasopressors

›MAP < 65 mmHg despite fluid resuscitation

›Norepinephrine initiation

›Respiratory failure requiring mechanical ventilation

›Rapidly progressive miliary pattern

›ARDS-pattern hypoxemia

›Multiorgan dysfunction

›Renal, hepatic, or hematologic failure

›HLH with hemodynamic instability

›Pericardial tamponade requiring drainage

Transfer criteria

›Transfer to higher level of care

›Tertiary center with infectious disease expertise

›Complex cases with treatment failure or unusual organisms

›Limited antifungal availability at referring facility

08Treatment/t80

Antifungal induction therapy

›Moderate-to-severe disseminated histoplasmosis

›Liposomal amphotericin B 3 mg/kg IV daily

›Duration: Minimum 2 weeks until clinical improvement

›Preferred over deoxycholate formulation

›Response rate 88% vs. 64% with deoxycholate; mortality 2% vs. 13%

›Pre-medicate with acetaminophen and diphenhydramine to reduce infusion reactions

›Amphotericin B lipid complex 5 mg/kg IV daily

›Alternative if liposomal formulation unavailable

›Similar safety and efficacy profile to liposomal form

›Monitor renal function every 48–72 hours during amphotericin B

›IV saline hydration 500 mL before each infusion to reduce nephrotoxicity

›Electrolyte repletion — hypokalemia and hypomagnesemia common

›CNS disseminated histoplasmosis

›Liposomal amphotericin B 5 mg/kg IV daily

›Duration: 4–6 weeks (longer than non-CNS disease)

›Higher dose required for CNS penetration

›Step-down to itraconazole 200 mg PO BID–TID after induction

›Duration: Minimum 12 months or until CSF normalized

›Monitor CSF antigen levels to guide therapy duration

Consolidation and maintenance therapy

›Itraconazole step-down therapy

›Loading dose: Itraconazole 200 mg PO three times daily for 3 days

›Rapid achievement of therapeutic levels

›Maintenance: Itraconazole 200 mg PO twice daily

›Duration: Minimum 12 months for all disseminated disease

›Duration may be extended in severely immunosuppressed patients

›Formulation considerations

›Liquid formulation preferred — better bioavailability

›Capsules require food and gastric acid for absorption

›Capsules cannot be used with PPIs or H2 blockers

›Liquid taken on empty stomach for best absorption

›Drug level monitoring

›Random serum itraconazole plus hydroxyitraconazole level at 2 weeks

›Target level: 1–2 µg/mL

›Toxicity increases above 5 µg/mL

›If subtherapeutic, switch to liquid formulation or increase dose

Alternative antifungal agents

›Posaconazole (itraconazole-intolerant patients)

›Loading: 300 mg PO twice daily for 1 day

›Maintenance: 300 mg PO once daily

›Extended-release tablet formulation preferred

›Voriconazole (second-line alternative)

›Loading: 400 mg PO twice daily for 1 day

›Maintenance: 200 mg PO twice daily

›QTc monitoring required

›Fluconazole — inferior, not recommended

›Less effective than itraconazole

›Associated with emergence of resistance

›Not first-line for any form of histoplasmosis

›Echinocandins — contraindicated

›No activity against Histoplasma capsulatum

›Caspofungin, micafungin, anidulafungin all ineffective

Adjunctive and complication management

›Adrenal crisis management

›Hydrocortisone 100 mg IV bolus

›Followed by 50 mg IV every 6 hours until stable

›Transition to oral replacement once tolerating PO

›Fludrocortisone 0.1 mg PO daily for mineralocorticoid replacement

›HLH management

›Antifungal therapy is primary treatment

›Etoposide-based HLH-94 protocol if refractory to antifungals

›Hematology-guided decision for immunosuppressive therapy

›Dexamethasone may be used in HLH refractory cases

›With guidance from hematology

›HIV-positive patients — ART considerations

›Continue or initiate ART in HIV-positive patients

›ART initiation timing: 2–4 weeks after starting antifungal therapy

›Early ART within 2 weeks acceptable in most cases

›Monitor for immune reconstitution inflammatory syndrome (IRIS)

›Continue both ART and antifungals if IRIS occurs

›Corticosteroids for severe IRIS

›Drug interactions with itraconazole

›Itraconazole moderate CYP3A4 inhibitor

›Significant interactions with PIs, NNRTIs

›Check interactions carefully with all ART components

›TNF-alpha inhibitor patients

›Discontinue TNF-alpha inhibitor during antifungal therapy

›May reinstitute after approximately 12 months of treatment

›Require negative antigen testing before restarting

›Secondary prophylaxis

›Itraconazole 200 mg PO once daily

›For severely immunosuppressed patients with relapsed disease

›In HIV patients, may discontinue when CD4 > 150 cells/mm³ sustained on ART

09Special Populations/sp68

Pregnancy

›Risk and presentation in pregnancy

›Disseminated histoplasmosis rare in pregnancy but associated with high fetal mortality

›Immunologic changes of pregnancy increase susceptibility

›Vertical transmission has been reported

›Clinical presentation similar to non-pregnant adults

›High index of suspicion needed in endemic area residents

›Antifungal safety in pregnancy

›Azoles contraindicated in first trimester

›Itraconazole and voriconazole are teratogenic (FDA Category D/X)

›Fluconazole associated with fetal abnormalities even at standard doses

›Amphotericin B preferred throughout pregnancy

›Liposomal amphotericin B 3 mg/kg IV daily — safest option

›Crosses placenta but not associated with teratogenicity

›Monitor fetal growth and wellbeing

›After first trimester, itraconazole may be considered in severe cases

›Risk-benefit discussion with maternal-fetal medicine required

›Delivery and postpartum considerations

›Obstetric and infectious disease co-management required

›Antifungal therapy continuation postpartum

›Breastfeeding generally avoided during azole therapy

Geriatric

›Disease manifestations in older adults

›More likely to have chronic cavitary histoplasmosis rather than disseminated

›Underlying COPD or emphysema predisposes to cavitary form

›Disseminated disease may occur without identifiable immunosuppression

›Atypical presentations more common

›Fever may be absent or blunted

›Cognitive changes may mask CNS involvement

›Drug safety and pharmacokinetics

›Amphotericin B nephrotoxicity heightened in elderly

›Aggressive pre-hydration essential

›More frequent renal function monitoring (every 24–48 hours)

›Electrolyte replacement more critical — higher baseline risk

›Itraconazole drug interactions more prevalent

›Polypharmacy risk — CYP3A4 interactions

›Reduced hepatic metabolism may increase drug levels

›Start at standard doses with close monitoring

›QTc prolongation risk with azoles

›Baseline ECG required

›Avoid concurrent QTc-prolonging medications

›Disposition considerations

›Lower threshold for ICU admission in elderly

›Limited physiologic reserve

›Close monitoring for decompensation

Pediatrics

›Epidemiology and risk

›Disseminated disease most common in infants < 2 years and immunocompromised children

›Healthy children usually develop self-limited pulmonary disease

›HIV-infected children at highest risk for disseminated form

›Congenital histoplasmosis extremely rare

›Vertical transmission possible

›Clinical features in children

›Similar to adults: fever, hepatosplenomegaly, lymphadenopathy

›Failure to thrive in infants

›Respiratory failure may predominate in young infants

›CNS involvement may be first presentation in immunocompromised children

›Antifungal dosing in children

›Liposomal amphotericin B 3–5 mg/kg IV daily

›For moderate-to-severe or CNS disease

›Duration: Minimum 2 weeks for non-CNS; 4–6 weeks for CNS

›Itraconazole oral solution 5 mg/kg/day divided twice daily

›Maximum 400 mg/day

›Drug level monitoring at 2 weeks

›Liquid formulation preferred for children

›Secondary prophylaxis in HIV-infected children

›Itraconazole 5 mg/kg/day (maximum 200 mg) once daily

›Continue until CD4 percentage > 15% sustained on ART (per DHHS pediatric OI guidelines 2025)

›Neonates and infants under 2 years

›Amphotericin B deoxycholate may be used (less nephrotoxic in neonates than in older patients)

›Specialist pharmacist guidance recommended for neonatal dosing

10Background/b82

Epidemiology

›Global burden and distribution

›Histoplasma capsulatum is the most common endemic mycosis in the Americas

›Estimated 500,000 new infections per year in the United States

›Endemic in Ohio and Mississippi River Valleys — greatest concentration

›Also endemic in Central and South America, parts of Africa and Asia

›Mortality in untreated disseminated histoplasmosis 50–70%

›Fulminant cases with septic shock have highest mortality

›With appropriate treatment, mortality < 10% in non-CNS disease

›Populations at risk

›HIV/AIDS — accounts for majority of disseminated cases

›CD4 <= 200 cells/mm³ defines high-risk threshold

›Histoplasmosis is an AIDS-defining illness

›Transplant recipients — increasing incidence

›Solid organ transplant most common

›Hematopoietic stem cell transplant recipients also at risk

›TNF-alpha inhibitor recipients — emerging risk group

›Reactivation of latent infection during therapy

›Healthy individuals with heavy inoculum exposure

›Outbreak settings: Cave exploration, demolition, construction

›Usually self-limited pulmonary disease in immunocompetent hosts

›Diagnostic delays

›Median time to diagnosis approximately 32 days

›Histoplasmosis remains underdiagnosed globally

›Estimated 50,000–80,000 AIDS patients die from histoplasmosis annually worldwide

Pathophysiology

›Organism biology

›Histoplasma capsulatum — dimorphic fungus

›Mycelial (mold) form in environment at temperatures < 35 C

›Yeast form at body temperature 37 C — pathogenic form

›Microconidia (2–4 µm) are the infectious particles inhaled

›Endemic ecology

›Found in soil enriched with bat and bird excreta

›Aerosolization during excavation, demolition, or disturbance of soil

›Infection progression

›Primary pulmonary infection

›Microconidia deposited in alveoli

›Convert to yeast form within macrophages

›Granuloma formation — successful containment in immunocompetent hosts

›Dissemination mechanism

›Yeast survives and replicates within macrophages

›Hematogenous spread to reticuloendothelial system

›Liver, spleen, bone marrow, lymph nodes most affected

›In immunocompromised host, granuloma formation fails — dissemination ensues

›Organ-specific pathology

›Adrenal glands — bilateral infiltration and destruction

›Bilateral adrenal enlargement characteristic

›Eventual fibrosis and calcification with chronic disease

›CNS — meningitis and parenchymal granulomas

›Basilar meningitis pattern most common

›Elevated ICP from chronic meningeal inflammation

›HLH — macrophage activation triggered by fungal antigen

›Uncontrolled macrophage activation and cytokine storm

›Cytophagocytosis of blood cells in marrow and liver

Therapeutic Considerations

›Antifungal mechanism and rationale

›Amphotericin B — fungicidal, binds ergosterol in fungal cell membrane

›Rapid kill kinetics — preferred for severe disease

›Liposomal formulation reduces nephrotoxicity without compromising efficacy

›Survival benefit demonstrated over deoxycholate formulation in RCT

›Itraconazole — fungistatic, inhibits lanosterol 14-alpha demethylase

›Effective for step-down and consolidation therapy

›Requires prolonged therapy (minimum 12 months) due to fungistatic mechanism

›Treatment monitoring strategy

›Urine Histoplasma antigen — surrogate marker for disease burden

›Quantitative ELISA allows monitoring of treatment response

›Antigen decline confirms adequate therapy

›Rising antigen suggests relapse or treatment failure

›Itraconazole serum level monitoring critical

›Subtherapeutic levels common with capsule formulation

›Absorption impaired by PPIs, H2 blockers, and low gastric acid

›Renal function monitoring during amphotericin B

›Creatinine, potassium, magnesium every 48–72 hours

›Dose adjustment rarely needed — drug rarely discontinued for renal toxicity in severe disease

›Special therapeutic scenarios

›IRIS in HIV patients starting ART

›Paradoxical worsening despite microbiological improvement

›Continue both ART and antifungals

›Corticosteroids for life-threatening IRIS

›TNF-alpha inhibitor discontinuation

›Mandatory during treatment

›Risk of reactivation of other latent infections (TB, coccidiomycosis) also present

›Secondary prophylaxis rationale

›Antigenuria recurs in approximately 90% of patients who relapse

›Lifelong prophylaxis may be required in persistently immunosuppressed patients

11Patient Discharge Instructions/pdi34

copy discharge instructions

›Diagnosis and overview

›Disseminated histoplasmosis is a serious fungal infection requiring prolonged treatment

›Caused by a fungus found in soil contaminated with bat or bird droppings

›Treatment typically lasts at least 12 months — do not stop early

›Medications

›Itraconazole instructions

›Take liquid itraconazole on an empty stomach for best absorption

›Take capsules with food and an acidic beverage (not with antacids or PPIs)

›Do not miss doses — missing doses can lead to treatment failure

›Do not stop medication without speaking to your doctor

›Complete all prescribed antifungal therapy

›Even if you feel better, the infection is not fully treated

›Activity and diet

›Adequate hydration while on amphotericin B (if prescribed at home)

›Drink plenty of fluids daily

›Avoid returning to high-risk environments

›Bat caves, bird roosts, demolition sites, chicken coops

›These environments may cause reinfection

›Follow-up care

›Return for blood and urine monitoring as directed

›Kidney function tests during amphotericin B therapy

›Itraconazole blood level check at 2 weeks

›Urine antigen levels during treatment to confirm response

›Infectious disease follow-up mandatory

›Initial follow-up within 1–2 weeks of discharge

›Return to emergency department immediately for

›Warning signs requiring immediate care

12References/r40

Guidelines and key sources

›IDSA/DHHS Opportunistic Infections Guidelines

›Benson C, Brooks J, Dhanireddy S, et al.

›Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents With HIV

›IDSA and Office of AIDS Research Advisory Council, 2025

›clinicalinfo.hiv.gov

›Kapogiannis BG, Yates F, Li W, et al.

›Guidelines for the Prevention and Treatment of Opportunistic Infections in Children With and Exposed to HIV

›Office of AIDS Research Advisory Council, 2025

›Systematic reviews and landmark studies

›Limper AH, Adenis A, Le T, Harrison TS.

›Fungal Infections in HIV/AIDS

›Lancet Infectious Diseases, 2017. PMID 28774701

›Murray M, Hine P.

›Treating Progressive Disseminated Histoplasmosis in People Living With HIV

›Cochrane Database of Systematic Reviews, 2020

›Pasqualotto AC, Le T, Vieceli T, et al.

›Histoplasmosis: A Missing Piece in the Global Efforts to End HIV Deaths

›Lancet HIV, 2026. PMID 41833293

›Global endemic mycoses guidelines

›Thompson GR, Le T, Chindamporn A, et al.

›Global Guideline for the Diagnosis and Management of the Endemic Mycoses

›Lancet Infectious Diseases, 2021. PMID 34364529

›ECMM/ISHAM collaborative guideline

›Diagnostic and scoring tools

›Hoyos Pulgarín JA, Moreno Gómez GA, et al.

›Development of a Diagnostic Score for Histoplasmosis in a Cohort of Patients With HIV

›Open Forum Infectious Diseases, 2025. PMID 40635908

Evidence & Review