01Approach to the Critical Patient/attcp30

Immediate Stabilization

›Time-critical recognition triggers

›Toxic phase onset: jaundice after initial febrile illness followed by remission

›Hemorrhagic manifestations: hematemesis, melena, oozing from venipuncture sites

›Encephalopathy: confusion, agitation, stupor, coma

›Hypotension refractory to initial fluid resuscitation

›Oliguria or anuria suggesting acute renal failure

ABC Priorities

›Airway and breathing

›Intubation for GCS < 8 or encephalopathic deterioration

›Aspiration precautions: NGT with active hematemesis

›Supplemental oxygen targeting SpO2 > 94%; ARDS protocol if required

›Circulation

›Two large-bore IV access; arterial line for hemodynamic monitoring in ICU

›Norepinephrine as first-line vasopressor for persistent hypotension

›Avoid aggressive fluid resuscitation: patients do not respond dramatically to volume unlike dengue

Hemodynamic Monitoring Goals

›Hemodynamic targets in toxic phase

›MAP > 65 mmHg

›Urine output > 0.5 mL/kg/hour

›Lactate clearance monitoring every 2 hours in shock

›Intra-abdominal pressure monitoring in ICU per Colombian Consensus 2025

Team Activation and Consult Triggers

›Mandatory specialist consultations

›Infectious disease: confirmed or suspected yellow fever

›Hepatology and liver transplant team: factor V < 50%, INR > 2.5, encephalopathy, or ammonia > 70 mmol/l

›Nephrology: AKI requiring renal replacement therapy (73% of severe cases required RRT)

›Critical care: any toxic phase presentation

02History/hx42

Exposure and Travel History

›Travel and exposure timeline

›Travel to or residence in sub-Saharan Africa or tropical South America within 3–6 days of symptom onset (incubation 3–6 days)

›Outdoor or forest/sylvatic exposure (jungle transmission cycle via Aedes or Haemagogus mosquitoes)

›Occupational risk: forestry workers, farmers, military personnel in endemic zones

›Vaccination status: prior YF-VAX dose with date and administration site

›Previous flavivirus infections: dengue, Zika, West Nile (cross-reactivity complicates serology)

Biphasic Illness Timeline

›Phase 1: infection/viremic phase (days 1–3)

›Abrupt onset high fever up to 40 degrees C

›Severe headache, lumbosacral back pain, generalized myalgias

›Nausea, vomiting, anorexia, dizziness, prostration

›Brief remission: up to 48 hours of apparent improvement

›Clinical deception: patient may appear to be recovering

›Phase 2: toxic/intoxication phase (onset ~day 4–5)

›Recurrence of fever with jaundice

›Epigastric pain

›Hemorrhagic manifestations: hematemesis, melena, epistaxis, gingival bleeding, petechiae

›Renal insufficiency: dark urine, decreased urine output

›Cardiovascular instability

›Occurs in approximately 12–15% of infected patients

Hemorrhagic and Alarm Symptoms

›Bleeding history

›Hematemesis: coffee-grounds or frank blood

›Melena, hematuria

›Easy bruising, gingival bleeding, heavy menses

›Oozing from venipuncture sites

›Neurologic alarm symptoms

03Physical Exam/exam32

Vital Signs

›Vital sign findings

›High fever up to 40 degrees C in viremic phase

›Faget's sign: relative bradycardia despite high fever (pathognomonic finding)

›Hypotension in severe/toxic phase

›Tachypnea suggesting ARDS or metabolic acidosis

Skin and HEENT

›Integumentary and head/neck findings

›Scleral icterus: jaundice appearing after initial febrile phase

›Dermal icterus

›Petechiae, ecchymoses, purpura

›Conjunctival injection

›Gingival bleeding, epistaxis

›Oozing from venipuncture or IV sites

Abdominal Examination

›Abdominal findings

›Epigastric tenderness

›Absence of significant hepatomegaly (notable finding despite severe hepatic injury)

›Signs of pancreatitis: pancreatitis reported in 24% of severe cases

›Ascites in severe hepatic failure

Neurologic Assessment

›Neurologic findings

›Glasgow Coma Scale: encephalopathy grading

›Asterixis: hepatic encephalopathy

›Agitation, confusion, stupor, coma

›Seizure activity

Cardiovascular Examination

›Cardiac findings

04Differential Diagnosis/ddx16

Life-Threatening Mimics

›Conditions requiring immediate differentiation

›Leptospirosis: closest mimic; also causes jaundice, hemorrhage, DIC, renal failure; distinguish by conjunctival suffusion, water exposure history, positive leptospira serology/PCR

›Malaria (Plasmodium falciparum / blackwater fever): thick/thin blood smear or rapid diagnostic test; jaundice and renal failure possible but hemorrhage uncommon

›Dengue hemorrhagic fever: similar arboviral presentation; plasma leak syndrome and hemoconcentration more characteristic; less hepatocellular injury; NS1 antigen/dengue serology

›Other viral hemorrhagic fevers: Ebola, Marburg, Lassa, Crimean-Congo HF; usually without prominent jaundice

›Fulminant hepatitis E: especially in pregnancy; serology differentiates

Hepatic Mimics

›Conditions causing fever and jaundice

›Viral hepatitis A, B, E: serology panel

›Drug-induced liver injury: medication and toxin history

›Toxic hepatitis: acetaminophen, amanita, industrial exposures

›Alcoholic hepatitis: alcohol history and AST:ALT ratio typically 2:1

Other Infectious Mimics

›Systemic infections with jaundice or hemorrhage

›Typhoid fever: rose spots, relative bradycardia, Widal test, blood cultures

›Q fever (Coxiella burnetii): exposure to livestock, serology

›Rickettsial diseases: eschar, exposure history

›Louse-borne relapsing fever (Borrelia recurrentis): jaundice, hemorrhage, DIC; Giemsa stain of blood smear

05Laboratory Tests/lt37

Complete Blood Count

›CBC interpretation in yellow fever

›Leukopenia in first week (characteristic of viremic phase)

›Leukocytosis may appear in second week or with secondary bacterial infection

›Thrombocytopenia: correlates with hemorrhagic risk

›Neutrophil count >= 4,000/mL: independently associated with mortality

Hepatic Panel and Metabolic Studies

›Liver function and metabolic markers

›AST characteristically exceeds ALT (due to myocardial and skeletal muscle injury in addition to hepatic damage)

›Fatal cases: mean AST approximately 2,766 IU/L, ALT approximately 660 IU/L

›ICU patients: median AST 7,000 IU/L, ALT 3,936 IU/L

›AST > 1,841 IU/L and creatinine > 106 micromol/l: independently associated with death

›Hyperbilirubinemia: direct predominant

›Glucose: hypoglycemia in severe hepatic failure requires IV dextrose

Coagulation Studies

›Coagulopathy assessment

›Prolonged PT/INR: factor V < 50% triggers liver transplant consultation

›INR > 2.5: liver transplant team evaluation

›Prolonged aPTT

›Decreased fibrinogen

›Elevated D-dimer and fibrin split products

›Reduced factors II, V, VII, VIII, IX, X: consumptive coagulopathy occurs independently of hepatocellular tropism

Renal Function

›Renal markers

›Serum creatinine: elevation independently associated with death

›BUN/urea nitrogen: rising trend indicates AKI progression

›Urinalysis: hematuria, proteinuria in renal involvement

›Urine output monitoring: oliguria trigger for RRT consideration

06Diagnostic Tests/dt35

Scoring Systems

›Severity stratification tools

›MELD score: Model for End-Stage Liver Disease; guides transplant listing

›MELD > 20 indicates severe hepatic dysfunction

›Calculated from INR, bilirubin, creatinine

›Child-Pugh score: functional hepatic reserve assessment

›Class C indicates decompensated disease requiring ICU-level care

›Sequential Organ Failure Assessment (SOFA) score

›Score >= 2: organ failure; guides ICU admission and prognostication

›Mortality predictor model: older age + neutrophil count >= 4,000/mL + AST elevation + viral load >= 5.1 log10 copies/mL

›All four factors: 100% mortality in observational cohort

MRI

›MRI indications in yellow fever

›Brain MRI: acute liver failure with encephalopathy when CT non-diagnostic

›T2/FLAIR: cerebral edema, posterior reversible encephalopathy syndrome

›DWI: cytotoxic edema in severe hepatic encephalopathy

›Cardiac MRI: suspected myocarditis with elevated troponin and LV dysfunction

›Late gadolinium enhancement: myocardial infiltration in 18–27% of cases on echo

›Rare acute myocarditis confirmed on MRI or necropsy

CT

›CT indications and findings

›CT head: indicated for altered mental status, new seizures, or signs of intracranial hypertension

›Findings: cerebral edema, hemorrhage, posterior fossa lesions

›Optic nerve sheath diameter > 5.0 mm: suggests elevated ICP

›CT abdomen/pelvis: severe abdominal pain, suspected pancreatitis or hepatic complications

›Findings: peripancreatic stranding (pancreatitis in 24% severe cases), hepatomegaly, ascites

›CT chest: suspected ARDS or pulmonary edema

›Findings: bilateral ground-glass opacities, consolidations

07Disposition/dispo24

ICU Admission Criteria

›Mandatory ICU criteria (toxic phase indicators)

›Jaundice developing after febrile phase with or without remission

›Any hemorrhagic manifestation: hematemesis, melena, active bleeding

›Renal insufficiency: rising creatinine, oliguria, anuria

›Coagulopathy: elevated INR, thrombocytopenia, factor deficiency

›Encephalopathy: confusion, GCS < 14, asterixis

›Hemodynamic instability: hypotension requiring vasopressors

›ARDS: PaO2/FiO2 < 300 mmHg

Monitored Bed Admission

›Step-down or monitored unit criteria

›Confirmed or suspected yellow fever with moderate symptoms

›Rising transaminases without overt toxic phase

›Coagulopathy without active hemorrhage

›Serial labs every 8 hours until trend established

›Close observation: rapid progression to toxic phase can occur

Transfer Criteria

›Transfer indications

›Liver transplant center: factor V < 50%, INR > 2.5, hepatic encephalopathy, ammonia > 70 micromol/l

›ECMO-capable center: refractory cardiogenic shock with myocarditis

›Transfer only when hemodynamically stabilized; document mosquito isolation measures

Discharge Criteria

›Safe discharge criteria (mild disease only)

›Absence of clinical symptoms with normal or progressively improving laboratory values

›No hemorrhagic manifestations, no jaundice, no renal impairment

›Reliable follow-up within 24–48 hours arranged

›Clear return precautions provided

›Transaminase elevations may persist up to 2 months: arrange hepatic function follow-up

08Treatment/t58

Supportive Care Fundamentals

›Core supportive principles

›No specific antiviral therapy is effective: ribavirin, sofosbuvir, and interferon alpha all failed to improve outcomes

›All management is supportive

›Acetaminophen: preferred for fever and myalgias

›Maximum dose 650 mg PO/PR every 6 hours; reduce to 325 mg if hepatic failure

›Strictly avoid aspirin and NSAIDs: elevated bleeding risk

›IV dextrose-containing fluids: target normoglycemia in hepatic failure

Fluid Resuscitation and Vasopressors

›Hemodynamic management

›IV fluid resuscitation: individualized; avoid volume overload (response unlike dengue)

›Crystalloid bolus 250–500 mL over 30 minutes for hypotension; reassess after each bolus

›Titrate to MAP > 65 mmHg, urine output > 0.5 mL/kg/hour

›Norepinephrine: first-line vasopressor for persistent hypotension

›Starting dose 0.1–0.2 mcg/kg/minute IV infusion

›Titrate by 0.05 mcg/kg/minute every 5–10 minutes

›Target MAP > 65 mmHg

›Vasopressin: adjunct vasopressor for norepinephrine-refractory shock

›Fixed dose 0.03–0.04 units/minute IV infusion

GI Hemorrhage Prevention and Management

›Hemorrhage management

›IV proton pump inhibitor: therapeutic dose for GI hemorrhage prevention

›Pantoprazole 80 mg IV bolus then 8 mg/hour continuous infusion for active bleeding

›Pantoprazole 40 mg IV twice daily for prophylaxis in severe disease

›NGT placement: evacuation of gastric blood and medication administration

›Blood products: guided by hemorrhage severity and coagulation parameters

›FFP: 10–15 mL/kg for active hemorrhage with elevated INR

›Cryoprecipitate: when fibrinogen < 1.5 g/L

›Platelet transfusion: restrict per consensus; threshold for active hemorrhage < 50 x 10^9/L

›Thromboelastography: guide blood product use in ICU

Anticonvulsant Prophylaxis

›Seizure management

›Anticonvulsant prophylaxis indicated when ammonia > 70 micromol/l

›Levetiracetam: 500 mg IV twice daily, adjusting for renal function

›Reduced seizure frequency from 28% to 17% with prophylaxis in severe cases

›Lactulose 15–30 mL PO/NG every 6–8 hours for hepatic encephalopathy

›Target 2–3 soft bowel movements per day

›Rifaximin 550 mg PO twice daily: adjunct for hepatic encephalopathy

Renal Replacement Therapy

›Renal management

›Continuous renal replacement therapy (CRRT): preferred in hemodynamically unstable patients

›73% of severe yellow fever cases required RRT

›Initiate for persistent AKI with oliguria, hyperkalemia, metabolic acidosis, or fluid overload

›Dose: 20–25 mL/kg/hour effluent rate

›Intermittent hemodialysis: stable patients with renal failure

Plasma Exchange

›Plasma exchange therapy

›Early institution recommended in severe cases per expert consensus

›Removes viral antigen, cytokines, and coagulation factor consumption products

›Volume: 1–1.5 plasma volumes per session

›Frequency: daily or every other day based on clinical response

›Liver transplant team consultation concurrent with plasma exchange initiation

Prophylactic Antibiotics

›Antibiotics for severe hepatic insufficiency

›Cefotaxime 1–2 g IV every 6–8 hours for severe hepatic insufficiency

›Targets: spontaneous bacterial peritonitis and secondary bacteremia

›Fluconazole 400 mg IV loading dose then 200 mg IV daily

›Targets: Candida species in critically ill with broad-spectrum antibiotics

›Adjust all antibiotic doses for degree of renal and hepatic impairment

Prevention

›Yellow fever vaccine

›YF-VAX (live attenuated 17D strain): single subcutaneous dose 0.5 mL

›Administer at least 10 days before travel to endemic area

›Provides lifelong immunity in most individuals

›Few breakthrough cases among 540 million doses administered

›Contraindicated: immunosuppressed, age < 6 months, thymoma, severe egg allergy

09Special Populations/sp29

Pregnancy

›Pregnancy-specific considerations

›YF-VAX contraindicated in pregnancy (live attenuated virus); benefit-risk assessment required for unavoidable travel

›If vaccination deemed necessary: document informed consent and provide medical waiver letter

›Seroconversion rate 98–100% even in pregnancy

›Fulminant hepatitis E: critical differential in pregnant patient with fever and jaundice from endemic area

›Hepatitis E case fatality in pregnancy up to 25%

›Avoid aspirin and NSAIDs in all trimesters

›Acetaminophen preferred analgesic/antipyretic; use minimum effective dose

›Renal replacement therapy: CRRT preferred for hemodynamic stability

›Liver transplant consultation: same thresholds apply; multidisciplinary obstetric and hepatology involvement

Geriatric

›Geriatric-specific considerations

›Older age: independently associated with mortality in yellow fever

›Reduced hepatic reserve and regenerative capacity

›Altered pharmacokinetics: reduce acetaminophen dosing; adjust all renally-cleared medications

›Higher baseline prevalence of diabetes mellitus: worsens case fatality (80% vs 65%)

›Blunted fever response: may present with lower-grade fever despite severe infection

›YF-VAX: age >= 60 years associated with higher risk of vaccine-associated viscerotropic disease (VAVD)

›VAVD risk approximately 1 per 40,000–50,000 doses in patients >= 60 years

›Travel medicine physician consultation recommended before vaccinating elderly

›Cautious fluid resuscitation: higher risk of volume overload and pulmonary edema

Pediatrics

›Pediatric-specific considerations

›YF-VAX contraindicated in infants < 6 months; extreme caution 6–9 months

›Risk of vaccine-associated neurotropic disease higher in infants < 9 months

›Incubation period and clinical phases similar to adults

›Dosing adjustments for anticonvulsants

10Background/b30

Epidemiology

›Epidemiological data

›Yellow fever virus (YFV): a flavivirus endemic to tropical Africa and South America

›Vectors: Aedes and Haemagogus mosquito species

›Transmission cycles: sylvatic (jungle), intermediate (savanna), and urban

›Estimated 200,000 cases and 30,000 deaths annually worldwide (WHO)

›Toxic phase occurs in approximately 12–15% of symptomatic patients

›Case-fatality rate in toxic phase: 30–60% even with ICU care

›Male sex: 80–92% of severe outbreak cases were male, attributed to occupational exposure

›Brazil 2016–2020 outbreak: largest in decades, predominantly in previously unvaccinated populations

›ICD-10: A95 Yellow Fever; A95.0 Sylvatic yellow fever; A95.1 Urban yellow fever; A95.9 Unspecified

Pathophysiology

›Disease mechanisms

›Incubation period: 3–6 days after infective mosquito bite

›Viremia: YFV replicates in lymph nodes; hematogenous spread to liver, spleen, kidneys, heart

›Hepatic injury: midzonal hepatocellular necrosis (pathognomonic); spares periportal and centrilobular hepatocytes

›Histopathology: Councilman bodies (apoptotic hepatocytes), microvesicular steatosis, minimal inflammatory infiltrate

›Coagulopathy: consumptive coagulopathy occurs independently of hepatocellular tropism and massive hepatic injury

›Cardiac involvement: myocarditis and conduction abnormalities via direct viral injury and cytokine storm

›Renal injury: direct viral tubular injury and hemodynamic compromise

›Faget's sign: relative bradycardia despite high fever; mechanism includes cardiac autonomic dysfunction

›Pancreatitis: necrohemorrhagic pancreatitis in 24% of severe cases via direct viral tropism

Therapeutic Considerations

›Evidence base and treatment rationale

›No antiviral therapy effective: ribavirin, sofosbuvir, and interferon alpha failed in clinical trials

›Plasma exchange: recommended in severe cases; evidence from Colombian Consensus 2025 and Brazilian ICU cohorts

›Anticonvulsant prophylaxis: reduced seizure frequency from 28% to 17% in severe cases (Ho YL et al, 2019)

›Early CRRT: essential; 73% of severe cases in Brazilian cohort required renal replacement

11Patient Discharge Instructions/pdi21

copy discharge instructions

›Yellow Fever: What you need to know after your emergency visit

›Your diagnosis is yellow fever, a viral infection spread by mosquito bites in tropical Africa and South America

›There is no specific antiviral medicine; your body must fight this infection with supportive care

›Take acetaminophen (Tylenol) for fever or pain; do not take ibuprofen (Advil), naproxen (Aleve), or aspirin

›Drink fluids regularly to stay hydrated; eat small meals as tolerated

›Rest and avoid strenuous activity until your doctor tells you it is safe to resume

›If you are not already vaccinated, close contacts or family members traveling to endemic areas should receive the yellow fever vaccine

›Return to the emergency room immediately for any of the following

›Return of fever after a period of feeling better (this can signal the dangerous second phase)

›Yellow skin or eyes developing (jaundice)

›Vomiting blood or black tarry stools

›Blood in urine, or urine turning very dark

›Significantly decreased urine output or not urinating

›Confusion, difficulty thinking, or loss of consciousness

›Severe abdominal pain

›Bleeding from gums, nose, or unusual bruising

›Dizziness or fainting

›Follow-up instructions

›Blood tests to check liver and kidney function need to be repeated; transaminase levels may stay elevated for up to 2 months

›Attend all scheduled follow-up appointments; bring this discharge sheet with you

›If your heart was involved during this illness, cardiac follow-up may be arranged

12References/r15

Guidelines and Key Sources

›Primary guidelines and consensus documents

›Staples JE, O'Laughlin K. Yellow Fever. CDC Yellow Book 2025. CDC

›Staples JE, Gershman MD, Fischer MD. Yellow Fever Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2010

›Forero-Delgadillo AJ et al. Colombian Consensus on the Care of Critically Ill Patients With Suspected or Confirmed Severe Yellow Fever. Lancet Regional Health Americas. 2025

›Food and Drug Administration (DailyMed). YF-VAX FDA Drug Label

Key Clinical Studies

›Landmark clinical studies informing management

›Kallas EG et al. Predictors of Mortality in Patients With Yellow Fever: An Observational Cohort Study. Lancet Infect Dis. 2019

›Ho YL et al. Severe Yellow Fever in Brazil: Clinical Characteristics and Management. J Travel Med. 2019

›Ribeiro AF et al. Yellow Fever: Factors Associated With Death in a Hospital of Reference in Infectious Diseases, Sao Paulo, Brazil, 2018. Am J Trop Med Hyg. 2019

›Bailey AL et al. Consumptive Coagulopathy of Severe Yellow Fever Occurs Independently of Hepatocellular Tropism and Massive Hepatic Injury. PNAS. 2020

›Paixao GMM et al. Cardiac Involvement by Yellow Fever (PROVAR+ Study). Am J Cardiol. 2019

›de Avila RE et al. Clinical Profiles and Factors Associated With Mortality in Adults With Yellow Fever Admitted to an ICU in Minas Gerais, Brazil. Int J Infect Dis. 2020

›Monath TP. Yellow Fever: An Update. Lancet Infect Dis. 2001

›Reno E et al. Prevention of Yellow Fever in Travellers: An Update. Lancet Infect Dis. 2020

›Wang B, Wang Z. A Review of Arboviral-Induced Liver Damage. Rev Med Virol. 2025

Evidence & Review

Evidence & Review