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Smallpox (Variola)
Cardiovascular Presentations
Abdominal aortic aneurysm
Acute coronary syndrome (NSTEMI)
Acute coronary syndrome (STEMI)
Acute decompensated heart failure
Acute limb ischemia
Acute mesenteric ischemia
Aortic dissection
Aortic stenosis
Atrial fibrillation and flutter
Bradyarrhythmia and heart block
Cardiac arrest
Deep vein thrombosis
Myocarditis
Pericarditis
Pulmonary embolism
Stable angina
Superficial thrombophlebitis
Superior vena cava syndrome
Supraventricular tachycardia
Syncope (cardiogenic)
Unstable angina
Ventricular tachycardia
Respiratory Presentations
Acute bronchitis
Acute respiratory failure
Aspiration pneumonia
Asthma exacerbation
Bronchiolitis
Community-acquired pneumonia
COVID-19 pneumonia
COPD exacerbation
Croup
Croup (laryngotracheobronchitis)
Epiglottitis
Hemothorax
Hospital-acquired pneumonia
Pleural effusion
Pneumothorax (traumatic)
Pulmonary contusion
Spontaneous pneumothorax
Neurological Presentations
Bell's palsy
Benign paroxysmal positional vertigo
Brain abscess
Cauda equina syndrome
Cervical radiculopathy
Concussion (mild traumatic brain injury)
Encephalitis
Guillain-Barré syndrome
Hemorrhagic stroke (intracerebral)
Ischemic stroke
Lumbar radiculopathy
Malignant spinal cord compression
Migraine
Peripheral neuropathy (acute)
Retropharyngeal abscess
Schizophrenia (acute exacerbation)
Seizure (breakthrough:known epilepsy)
Seizure (first-time)
Spinal cord injury
Status epilepticus
Subarachnoid hemorrhage
Tension headache
Transient ischemic attack
Traumatic brain injury (moderate-severe)
Vestibular neuritis
Viral meningitis
Gastrointestinal Presentations
Acute appendicitis
Acute cholecystitis
Acute diverticulitis
Acute pancreatitis
Anal fissure
Choledocholithiasis and cholangitis
Clostridioides difficile colitis
Gastritis
Gastroenteritis (viral and bacterial)
Gastroesophageal reflux disease
Incarcerated or strangulated hernia
Inflammatory bowel disease flare
Large bowel obstruction
Lower GI hemorrhage
Peptic ulcer disease
Perforated viscus
Small bowel obstruction
Upper GI hemorrhage
Genitourinary and Reproductive Presentations
Acute prostatitis
Acute urinary retention
Ectopic pregnancy
Epididymitis
Orchitis
Ovarian torsion
Paraphimosis
Pelvic inflammatory disease
Priapism
Pyelonephritis
Renal laceration
Ruptured ovarian cyst
Testicular torsion
Tubo-ovarian abscess
Urinary tract infection (uncomplicated)
Urolithiasis (renal colic)
Vaginal bleeding (non-pregnant)
Infectious Disease Presentations
Acute sinusitis
Acute tonsillitis
Acute upper respiratory infection
Animal bite
Bacterial meningitis
Cellulitis
Conjunctivitis (bacterial)
Dental abscess
Endocarditis
Febrile neutropenia
Fournier gangrene
Hand-foot-mouth disease
Hepatitis (acute)
Herpes zoster
HIV-related illness
Human bite
Impetigo
Infected diabetic foot ulcer
Infectious mononucleosis
Influenza
Necrotizing fasciitis
Osteomyelitis
Otitis externa
Parasitic infection
Periorbital cellulitis
Peritonsillar abscess
Scabies
Sepsis
Septic arthritis
Spontaneous bacterial peritonitis
Tick-borne illness (Lyme disease)
Tinea infection
Tuberculosis
Viral exanthem
Wound infection
Trauma Presentations
Achilles tendon rupture
ACL and mceniscus tear
Ankle fracture
Ankle sprain
Burn
Calcaneus fracture
Cervical spine fracture
Clavicle fracture
Dental avulsion
Distal radius fracture
Drowning
Elbow fracture and dislocation
Electrical injury
Facial bone fracture
Facial laceration
Femur fracture
Fingertip amputation
Forearm fracture (radius and ulna)
Frostbite
Hand:finger laceration
Heat exhaustion
Heat stroke
Hip fracture
Humeral shaft fracture
Knee dislocation
Knee sprain
Lightning injury
Mandible fracture
Metacarpal fracture
Metatarsal fracture
Muscle strain
Nasal fracture
Non-accidental trauma
Orbital fracture
Patella fracture
Phalanx fracture (finger)
Proximal humerus fracture
Pulmonary contusion
Rib fracture
Rotator cuff tear (acute traumatic)
Scalp laceration
Scaphoid fracture
Shoulder dislocation
Skull fracture
Splenic laceration
Sternal fracture
Supracondylar pediatric fracture
Tendon laceration (hand:wrist)
Thoracic and lumbar spine fracture
Tibia:fibula fracture
Tibial plateau fracture
Toe fracture
Traumatic epistaxis
Traumatic hyphema
Toxicologic Presentations
Acetaminophen toxicity
Alcohol intoxication
Alcohol withdrawal
Anticholinergic toxicity
Anticoagulant overdose
Benzodiazepine overdose
Benzodiazepine:sedative overdose
Beta-blocker and calcium channel blocker toxicity
Carbon monoxide poisoning
Caustic ingestion
Digoxin toxicity
Drug eruption
Foreign body ingestion
Opioid intoxication
Opioid overdose
Opioid withdrawal
Organophosphate
Salicylate toxicity
Serotonin syndrome
Stimulant intoxication (cocaine, methamphetamine)
Tricyclic antidepressant overdose
Psychiatric Presentations
Acute anxiety
Acute psychosis
Agitation:behavioral emergency
Bipolar disorder
Conversion disorder
Major depressive episode
Neuroleptic malignant syndrome
Suicidal ideation and attempt
Musculoskeletal and Rheumatologic Presentations
Acute low back pain (mechanical)
Bursitis
Cervical radiculopathy
Costochondritis
Gout (acute)
Lumbar radiculopathy
Pseudogout
Tendinitis
Dermatology Presentations
Acute eczema (Eczema acute flare)
Allergic contact dermatitis
Erythema multiforme
Henoch-Schönlein purpura
Pressure injury
Psoriasis (acute flare)
Stevens-Johnson syndrome
Toxic epidermal necrolysis
Urticaria (acute)
Environmental and Exposure Presentations
Envenomation (snake, spider, insect)
High-altitude illness
Hypothermia
Hematologic and Oncologic Presentations
Acute chest syndrome
Coagulopathy
Hyperviscosity syndrome
Sickle cell crisis (vaso-occlusive)
Symptomatic anemia
Thrombocytopenia (severe)
Tumor lysis syndrome
Pediatric-Specific Presentations
Bronchiolitis
Croup
Emergency delivery
Febrile seizure
Kawasaki disease
Neonatal jaundice
Neonatal sepsis
Nursemaid's elbow
Pediatric fever 0 to 28 days
Pediatric fever 29 to 60 days
Pediatric fever 61 to 90 days
Pyloric stenosis
Slipped capital femoral epiphysis
Intussusception
Endocrine and Metabolic Presentations
Adrenal crisis
Diabetic ketoacidosis
Hypercalcemia
Hyperosmolar hyperglycemic state
Hypertensive emergency
Hypertensive urgency
Hypoglycemia
Myasthenia gravis crisis
Myxedema coma
Severe hyperkalemia
Severe hyponatremia
Thyroid storm
ENT and Maxillofacial Presentations
Acute laryngitis
Acute otitis media
Acute pharyngitis
Cerumen impaction
Epistaxis (anterior)
Nasal foreign body
Otitis externa
Tympanic membrane perforation
Ophthalmologic Presentations
Acute angle-closure glaucoma
Central retinal artery occlusion
Chemical eye injury
Corneal abrasion
Corneal ulcer
Globe rupture
Ocular foreign body
Orbital cellulitis
Retinal detachment
Obstetric Presentations
Hyperemesis gravidarum
Painful vaginal bleeding in pregnancy
Placenta previa
Placental abruption
Preeclampsia:eclampsia
Preterm labor
Threatened:inevitable:incomplete abortion
Systemic and Miscellaneous Presentations
Anaphylaxis
Angioedema
Cannabis-induced hyperemesis
Smallpox (Variola)
POCUS
Procedures
Calculators
Resuscitation
ECG Guide
Back
Clinical Assessment Checklist
Browse categories and answer follow-up questions to refine your symptom profile.
Approach to the Critical Patient
Immediate recognition and isolation
Single suspected case triggers international public health emergency
▶
Immediate airborne and contact precautions
Negative pressure room if available
Full PPE for all healthcare workers regardless of vaccination status
Notify state/local health department immediately; do not wait for confirmation
Bioterrorism response activation
▶
Contact CDC Emergency Operations 770-488-7100 (24/7)
Concurrent law enforcement and bioterrorism response notification
WHO notification through national public health authority
Hemodynamic and airway priorities
Airway threats
▶
Oropharyngeal enanthem causing severe dysphagia
Respiratory compromise from bronchopneumonia in confluent disease
If airway threatened, proceed to definitive airway control
Hemodynamic targets
▶
SBP > 90 mmHg
MAP > 65 mmHg
IV fluid resuscitation for hemorrhagic variant with hypotension
High-acuity escalation triggers
▶
Hemorrhagic smallpox: petechiae, purpura, mucosal bleeding
Flat (malignant) smallpox: soft confluent lesions, CFR 94-97%
Encephalitis: altered consciousness, seizures
Respiratory failure requiring mechanical ventilation
Monitoring and consults
Monitoring bundle
▶
Continuous pulse oximetry with SpO2 target 92-96%
Cardiac monitoring for hemodynamic instability
Neurological status assessment every 2-4 hours in severe disease
Mandatory consultations
▶
Infectious disease specialist
Public health epidemiologist
Critical care for hemorrhagic or flat-type smallpox
Dermatology for lesion characterization if diagnosis uncertain
History
Exposure and epidemiologic context
Exposure history
▶
Any modern case implies deliberate bioterrorism release or laboratory accident
Face-to-face or household contact with a suspected case
Occupational: laboratory workers handling orthopoxviruses, military personnel
Travel history in context of bioterrorism investigation
Incubation timeline
▶
Incubation period 7-17 days (mean 10-14 days)
Timeline from potential exposure to symptom onset
Prodromal symptoms
Constitutional prodrome (1-4 days before rash)
▶
Abrupt high fever 38.9-40.6 degrees C
Severe prostration and malaise
Headache
Backache in up to 90% of patients
Chills and rigors
Vomiting
Severe abdominal pain
Rash characteristics
Rash progression timeline
▶
Enanthem on oral mucosa approximately 24 hours before exanthem
Exanthem starts on face, spreads to extremities and trunk within 24-48 hours
Macules day 1-2, papules day 2-4, vesicles day 4-5, pustules day 7, crusting 2-3 weeks
Key distinguishing features
▶
All lesions in same stage of development on any given body region
Centrifugal distribution: face and extremities > trunk
Lesions on palms and soles
Deep-seated, firm, round, well-circumscribed lesions
Absence of lymphadenopathy distinguishes from mpox
No crops of lesions at different stages distinguishes from varicella
Risk factors and past history
Vaccination history
▶
Prior smallpox vaccination (pre-1980s) may confer partial protection
Vaccination scar typically at deltoid; individuals born before approximately 1972 in US
Modified/milder disease course in previously vaccinated individuals
High-risk conditions
▶
Unvaccinated status: global vaccination ceased in the 1980s, vast majority susceptible
Pregnancy: disproportionately high risk for hemorrhagic smallpox; CFR 28% vs 8% in non-pregnant
Immunosuppression: HIV, organ transplant, active chemotherapy
Young children and elderly: higher morbidity and mortality
Healthcare workers without recent vaccination: high-risk occupational exposure
Eczema/atopic dermatitis: risk for eczema vaccinatum if vaccination considered
Cardiac history: myopericarditis risk with ACAM2000 vaccine (5.7 per 1000 vaccinees)
Review of systems
Systems review
▶
Constitutional: fever, rigors, prostration, malaise universal in prodrome
Dermatologic: rash character, distribution, stage of evolution, palms and soles involvement
HEENT: oral enanthem, dysphagia, eye involvement including keratitis
Respiratory: cough, dyspnea, pneumonia symptoms
Neurologic: headache, backache, delirium, seizures, altered consciousness
GI: abdominal pain, vomiting, diarrhea
MSK: arthritis or joint pain especially in children; osteomyelitis variolosa in 2-5%
Lymphatic: absence of lymphadenopathy
Physical Exam
Vital signs
Hemodynamic assessment
▶
High fever 38.9-40.6 degrees C during prodrome
Tachycardia
Hypotension in severe or hemorrhagic cases
Respiratory rate elevation in bronchopneumonia
Skin examination
Rash characterization
▶
Deep-seated, firm, round, well-circumscribed vesicles or pustules
All lesions in same stage of development on any single body region
Centrifugal distribution: denser on face and extremities, sparser on trunk
Mandatory inspection of palms and soles for lesions
Lesion depth assessment: press to determine if deep-seated versus superficial
Hemorrhagic variant findings
▶
Petechiae
Purpura and ecchymoses
Mucosal bleeding
Head and neck examination
Oropharyngeal examination
▶
Enanthem on tongue, buccal mucosa, oropharynx (appears ~24 hours before exanthem)
Dysphagia assessment
Degree of mucosal involvement
Ocular examination
▶
Keratitis signs: photophobia, eye pain, decreased visual acuity
Conjunctival lesions
Lymph node examination
▶
Absence of significant lymphadenopathy (presence strongly suggests mpox instead)
Systemic examination
Respiratory examination
▶
Auscultation for bronchopneumonia: crackles, consolidation signs
Work of breathing assessment
Neurologic examination
▶
Mental status: delirium occurs in approximately 15% of patients during febrile stage
Meningismus signs
Seizure assessment (febrile seizures in approximately 7% of children under 5)
Musculoskeletal
▶
Joint swelling and tenderness especially in children
Osteomyelitis variolosa signs in pediatric patients
Differential Diagnosis
Vesiculopustular rash diagnoses
Varicella (chickenpox) - most common mimic
▶
ICD-10: B01.9
Distinguishing: superficial dewdrop vesicles, lesions in multiple stages simultaneously
Centripetal distribution (trunk > extremities), rarely on palms and soles
Milder prodrome; faster evolution
VZV PCR or DFA confirms
Mpox (monkeypox)
▶
ICD-10: B04
Distinguishing: lymphadenopathy is pathognomonic and absent in smallpox
Similar deep-seated lesions and centrifugal distribution
PCR required for definitive differentiation
Disseminated herpes simplex
▶
ICD-10: B00.7
Grouped vesicles on erythematous base; widespread in immunocompromised
Tzanck smear or HSV PCR confirms
Disseminated herpes zoster
▶
ICD-10: B02.7
Dermatomal distribution initially; may disseminate in immunocompromised
VZV PCR positive; immunocompromised history
Hemorrhagic differential
Meningococcemia
▶
ICD-10: A39.4
Non-blanching purpuric rash; rapidly progressive; CSF culture
Historically confused with hemorrhagic smallpox
Acute leukemia with DIC
▶
ICD-10: C91.0
Peripheral blood smear, bone marrow biopsy; coagulation studies
Drug eruptions and erythema multiforme
▶
ICD-10: L51.9
Medication history; target lesions in EM; Stevens-Johnson syndrome may mimic
Other mimics
Secondary syphilis
▶
ICD-10: A51.3
Painless rash including palms and soles; RPR or VDRL positive; sexual history
Generalized vaccinia
▶
ICD-10: T88.1
History of recent smallpox vaccination; widespread vaccinia lesions
Molluscum contagiosum
▶
ICD-10: B08.1
Umbilicated pearly papules; no prodrome; generally mild
Atypical measles
▶
ICD-10: B05.9
Vaccination history; Koplik spots; cough, coryza, conjunctivitis triad
Laboratory Tests
Definitive diagnostic testing
Biosafety level 4 laboratory requirement
▶
Do NOT send specimens to routine hospital laboratories
All variola testing performed at CDC or authorized BSL-4 facility
Coordinate all specimen handling through state health department
PCR testing
▶
Real-time PCR for orthopoxvirus DNA and variola-specific sequences
Most rapid and specific confirmatory test
Can distinguish variola from other orthopoxviruses
Electron microscopy
▶
Identifies characteristic brick-shaped orthopoxvirus virions
Cannot distinguish variola from other orthopoxviruses
Rapid morphological confirmation
Viral culture
▶
Growth on cell lines or chorioallantoic membrane
Confirmatory but slower than PCR
Requires BSL-4 containment
Serology
▶
Does not differentiate among orthopoxvirus species
Paired sera needed for interpretation
IgM may enhance early diagnosis
Specimen collection
Specimen types
▶
Vesicular or pustular fluid: open lesion with blunt scalpel, swab base
Scab scrapings
Blood samples
Tonsillar swabs
Collector safety
▶
Collector should ideally be recently vaccinated
Full PPE mandatory during specimen collection
Coordinate packaging and transport with public health
Routine supportive labs
Standard workup for supportive care
▶
Complete blood count: leukocytosis in bacterial superinfection, leukopenia in viral phase
Comprehensive metabolic panel: electrolyte status, renal function
Coagulation studies (PT, aPTT, fibrinogen, D-dimer): DIC evaluation in hemorrhagic variant
Blood cultures if secondary bacterial infection suspected
Lactate if hemodynamically unstable
Exclusion testing
Rule-out testing in moderate-risk cases
▶
VZV PCR to exclude varicella before pursuing variola testing
HSV PCR to exclude herpes in moderate-risk presentation
Tzanck smear: multinucleated giant cells exclude herpes but do not confirm smallpox
RPR or VDRL if secondary syphilis in differential
Diagnostic Tests
Scoring Systems
CDC smallpox evaluation algorithm
▶
Major criteria (any present raises suspicion):
Febrile prodrome ≥38.3 degrees C with prostration, headache, backache, chills, vomiting, or severe abdominal pain occurring 1-4 days before rash
Classic lesions: deep-seated, firm, round, well-circumscribed vesicles or pustules
Lesions in same stage of development on any one body part
Minor criteria
▶
Centrifugal distribution
First lesions on face or oral mucosa
Patient appears toxic or moribund
Slow lesion evolution, each stage lasting 1-2 days
Lesions on palms and soles
WHO clinical classification
▶
Ordinary smallpox approximately 90% of cases: classic pustular rash; CFR approximately 30% unvaccinated
Discrete ordinary type: CFR approximately 10%
Semiconfluent type: CFR approximately 25%
Confluent ordinary type: CFR 50-60%
Modified smallpox: milder accelerated course in previously vaccinated; rarely fatal
Variola sine eruptione: fever without rash; vaccinated contacts or infants with maternal antibodies
Flat (malignant) type approximately 7%: soft flat confluent lesions; CFR 94-97%
Hemorrhagic type approximately 2-3%: petechiae, hemorrhages; CFR approximately 98%; death by day 5-6
MRI
MRI indications in smallpox
▶
Encephalitis complication: MRI brain with gadolinium
Altered consciousness or focal neurologic deficits
Encephalitis occurs in less than 1% of cases
MRI findings in smallpox encephalitis
▶
May show diffuse white matter changes
Periventricular signal abnormalities
No pathognomonic MRI findings specific to variola encephalitis
MRI limitations
▶
Not a primary diagnostic tool for smallpox
Infection control precautions required for MRI suite
CT
CT indications
▶
Respiratory symptoms with suspected bronchopneumonia
CT chest for complicated pulmonary involvement
No pathognomonic CT findings for smallpox itself
CT chest findings in smallpox pneumonia
▶
Bilateral patchy consolidation in bronchopneumonia
Ground glass opacities
Air-space disease in secondary bacterial pneumonia
CT head indications
▶
Encephalitis with focal neurologic deficits
Prior to lumbar puncture if encephalitis suspected
Rule out structural lesion or hemorrhage
Ultrasound
Ultrasound indications
▶
Focused assessment in hemodynamically unstable hemorrhagic smallpox
Cardiac ultrasound: assess for myocarditis or pericardial effusion
Pleural ultrasound: assess for parapneumonic effusion in respiratory compromise
Point-of-care ultrasound role
▶
IVC assessment for volume status in hemorrhagic variant
B-lines assessment if respiratory failure present
No specific ultrasound findings diagnostic of smallpox
ABICAP immunofiltration assay
▶
Point-of-care assay producing results in approximately 45 minutes
Investigational; not widely available
Contact CDC for availability during outbreak
Disposition
Isolation and reporting requirements
Mandatory isolation
▶
All confirmed or suspected cases require immediate isolation
Airborne plus contact precautions for all patients
Negative pressure room preferred
Home isolation preferred when feasible to reduce nosocomial spread
Mandatory reporting
▶
Single case constitutes an international public health emergency
Immediate notification: state health department
CDC Emergency Operations Center 770-488-7100 (24/7)
WHO notification through national public health authority
Hospital admission criteria
Admit for
▶
Hemodynamic instability or shock
Hemorrhagic smallpox (CFR approximately 98%)
Flat (malignant) smallpox (CFR 94-97%)
Respiratory failure or bronchopneumonia requiring oxygen
Encephalitis or altered consciousness
Inability to maintain oral hydration
Pregnancy with severe disease
Pediatric patients with severe disease or febrile seizures
ICU admission criteria
ICU-level care triggers
▶
Mechanical ventilation requirement
Vasopressor-dependent hemodynamic instability
DIC or hemorrhagic complications
Encephalitis with ongoing seizures
Multiorgan dysfunction
Infectiousness and quarantine
Infectious period
▶
Infectiousness persists from rash onset until all scabs have separated (typically 3-4 weeks)
Contacts under surveillance for 17 days after last exposure
Monitor contacts for fever and rash during surveillance period
Treatment
Immediate isolation and public health actions
Concurrent actions
▶
Isolate patient immediately before diagnostic confirmation
Notify public health authorities immediately
Initiate contact tracing for all face-to-face and household contacts
Ring vaccination of all contacts within 2-3 days of exposure
Vaccination up to 4 days post-exposure may still attenuate disease severity
Antiviral therapy
Tecovirimat (TPOXX) - first-line antiviral
▶
FDA-approved for treatment of smallpox in adults and pediatric patients ≥3 kg
Initiate as soon as possible; 14-day course
Mechanism: inhibits VP37 envelope wrapping protein, blocking extracellular viral dissemination
Efficacy not proven in human smallpox (approved under FDA Animal Rule)
Weight-based oral dosing:
13 to less than 25 kg: 200 mg every 12 hours
25 to less than 40 kg: 400 mg every 12 hours
40 to less than 120 kg: 600 mg every 12 hours
120 kg or more: 600 mg every 8 hours
IV formulation available for patients unable to take oral medication
CYP450 interactions: check for drug-drug interactions especially with antiretrovirals
May have reduced efficacy in immunocompromised patients
Tecovirimat resistance mutations identified; particularly in immunocompromised
Alternative antivirals
Cidofovir
▶
Alternative with in vitro activity against variola
Role if tecovirimat unavailable or resistance suspected
Renal toxicity: requires adequate hydration and probenecid pretreatment
Administer with probenecid 2 g orally 3 hours before, 1 g at 2 hours and 8 hours after
Brincidofovir
▶
Lipid conjugate prodrug of cidofovir with improved oral bioavailability
Reduced nephrotoxicity compared to cidofovir
Alternative if tecovirimat unavailable or resistance suspected
Passive immunization
Vaccinia Immune Globulin Intravenous (VIGIV)
▶
Available for passive immunization
Indicated for vaccine-related complications: eczema vaccinatum, progressive vaccinia
May have adjunctive role in prophylaxis; limited data for treatment of active smallpox
Coordinate availability through CDC Strategic National Stockpile
Contact vaccination (ring vaccination strategy)
ACAM2000 (live vaccinia vaccine)
▶
Single percutaneous inoculation (bifurcated needle technique)
Ring vaccination: vaccinate all household and face-to-face contacts
Vaccination within 2-3 days confers protective immunity; up to 4 days may attenuate
Contraindications: severe immunosuppression, eczema or atopic dermatitis, pregnancy
Cardiac risk: myopericarditis in approximately 5.7 per 1000 vaccinees
Class I recommendation for ring vaccination of exposed contacts
JYNNEOS (MVA-BN; modified vaccinia Ankara)
▶
Non-replicating attenuated vaccinia vaccine
Safer for immunocompromised patients and pregnant individuals
Two-dose series subcutaneously 4 weeks apart
Stockpiled in Strategic National Stockpile for emergency use
Supportive care
Fluid and nutrition management
▶
IV fluid resuscitation for dehydration (oropharyngeal enanthem impairs swallowing)
Soft or liquid diet during pustular phase due to oral mucosal involvement
Nutritional support and caloric supplementation for severely ill bedridden patients
Target euvolemia; monitor electrolytes
Antipyretics and analgesia
▶
Acetaminophen 1000 mg every 6-8 hours (maximum 4000 mg per 24 hours) for fever and pain
Ibuprofen 400-600 mg every 6-8 hours as alternative if no contraindications
Opioid analgesia for severe pain in hemorrhagic variant
Ophthalmologic care
▶
Topical trifluridine or vidarabine for keratitis complications
Ophthalmology consultation for ocular involvement
Secondary infection management
Bacterial superinfection
▶
Antibiotics for documented bacterial superinfection of skin lesions
Cover Staphylococcus aureus and Streptococcus pyogenes for skin superinfection
Antistaphylococcal penicillin or first-generation cephalosporin for mild-moderate
Vancomycin 25-30 mg/kg/day IV divided every 8-12 hours for MRSA concern or severe disease
Antibiotics for documented secondary bacterial pneumonia with appropriate coverage
Special Populations
Pregnancy
Maternal risk
▶
Disproportionately high risk for hemorrhagic smallpox
CFR 28% in pregnant women versus 8% in non-pregnant women (historical data)
Hemorrhagic smallpox more common in pregnant women
Fetal risks include miscarriage, stillbirth, and congenital infection
Antiviral considerations
▶
Tecovirimat data in pregnancy limited; use if benefit outweighs risk given high maternal CFR
Cidofovir is teratogenic: avoid in pregnancy unless no alternatives
VIGIV can be used in pregnancy for vaccine complications
Vaccination in pregnancy
▶
ACAM2000 (live vaccinia): contraindicated in pregnancy due to risk of fetal vaccinia
JYNNEOS (MVA-BN): non-replicating; may be considered for high-risk exposure in pregnancy
Coordinate with obstetrics and public health for vaccination decisions
Delivery considerations
▶
Airborne and contact precautions during labor and delivery
Neonatal team present at delivery if maternal active disease
Neonate requires isolation and evaluation if maternal active smallpox
Geriatric
Disease severity
▶
Elderly patients have higher morbidity and mortality
Limited or absent prior vaccination immunity (last routine vaccination in US approximately 1972)
Comorbidities compound severity: cardiopulmonary, renal, immunosenescence
Antiviral dosing
▶
Tecovirimat weight-based dosing applies; renal and hepatic monitoring
Cidofovir: heightened nephrotoxicity risk in elderly; careful monitoring
Vaccination with ACAM2000 carries higher cardiac risk in elderly with underlying heart disease
Supportive care modifications
▶
Aggressive hydration with careful fluid balance monitoring in heart failure
Nutritional support: higher risk of dehydration with oropharyngeal involvement
Pressure injury prevention during prolonged illness
Delirium monitoring: altered mental status may be exacerbated by fever and medications
Pediatrics
Disease patterns in children
▶
Higher risk of febrile seizures: approximately 7% of children under 5 years
Osteomyelitis variolosa in 2-5% of pediatric patients
Delirium approximately 15% during febrile stage
Children born after approximately 1972 have no prior vaccination immunity
Antiviral dosing (Tecovirimat, FDA-approved in pediatric patients ≥3 kg)
▶
3 to less than 13 kg: 100 mg every 12 hours
13 to less than 25 kg: 200 mg every 12 hours
25 to less than 40 kg: 400 mg every 12 hours
40 to less than 120 kg: 600 mg every 12 hours
Vaccination in children
▶
ACAM2000 can be used in pediatric contacts aged over 12 months
JYNNEOS preferred for children with eczema or immunosuppression
Eczema vaccinatum risk: avoid live vaccine in children with eczema
Seizure management
▶
Lorazepam 0.1 mg/kg IV for acute seizures (maximum 4 mg per dose)
Fosphenytoin or levetiracetam for persistent seizures
Background
Epidemiology
Historical disease burden
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Caused by variola virus (genus Orthopoxvirus, family Poxviridae)
Eradicated globally since 1980 following WHO global eradication campaign
Last natural case in 1977 in Somalia
Estimated 300 million deaths in the 20th century from smallpox
Current epidemiologic status
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CDC Category A bioterrorism agent: highest priority threat
Known virus stocks exist only at WHO-authorized repositories: CDC Atlanta and VECTOR Russia
Any modern case implies deliberate release or laboratory accident
Global population is essentially non-immune: routine vaccination ceased in the 1980s
Variola major mortality rates
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Overall CFR approximately 25-30% in unvaccinated individuals
Discrete ordinary type: CFR approximately 10%
Confluent ordinary type: CFR 50-60%
Flat (malignant) type: CFR 94-97%
Hemorrhagic type: CFR approximately 98%
Previously vaccinated individuals: substantially reduced CFR
Transmission
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Primary mode: respiratory droplets (large droplet and airborne)
Direct contact with skin lesions or contaminated fomites
Close or household contact: primary risk
Infectious from rash onset until all scabs separate (3-4 weeks)
No animal reservoir; humans are only natural host
Pathophysiology
Viral biology
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Double-stranded DNA virus; largest and most complex human pathogen
Two strains: variola major (severe, CFR 25-30%) and variola minor/alastrim (CFR less than 1%)
Replication in cytoplasm unlike most DNA viruses
Encodes multiple immune evasion proteins
Disease progression
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Respiratory mucosal entry followed by primary viremia
Replication in regional lymph nodes and spleen
Secondary viremia with seeding of skin (dermal endothelium)
Inflammatory response drives characteristic deep-seated skin lesions
Immune response peaks during pustular phase (approximately day 7-14)
Hemorrhagic pathogenesis
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Viral-mediated coagulopathy resembling DIC
Widespread endothelial damage and microvascular injury
Cytokine storm contributes to early death by day 5-6 of rash
More common in pregnant women due to immune modulation
Complications mechanism
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Pockmark scarring: destruction of sebaceous glands and dermis
Keratitis: direct viral invasion of corneal epithelium
Osteomyelitis variolosa: periosteal viral invasion in children
Encephalitis: direct CNS involvement or immune-mediated
Therapeutic Considerations
Tecovirimat mechanism and evidence
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Inhibits VP37 envelope wrapping protein
Blocks formation of extracellular enveloped virions (EEV)
Reduces systemic viral dissemination
FDA approval under Animal Rule: efficacy demonstrated in animal models (orthopoxvirus)
Human safety and pharmacokinetic data from Phase 1-2 trials
Not tested in human smallpox due to disease eradication
Vaccination efficacy
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Smallpox vaccine (vaccinia) confers cross-protective immunity against variola
Pre-exposure vaccination greater than 10 years prior may reduce but not eliminate severity
Ring vaccination post-exposure effective if given within 4 days of exposure
Post-exposure prophylaxis with vaccination superior to post-exposure antivirals alone
Strategic National Stockpile resources
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Tecovirimat (oral and IV) stockpiled
ACAM2000 and JYNNEOS vaccines stockpiled
VIGIV stockpiled for vaccine complications
Cidofovir available as alternative antiviral
CDC coordinates release through state public health authorities
ICD-10 coding
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B03: Smallpox
Note: variola major and variola minor both coded as B03
Bioterrorism context: additional external cause codes may apply
Patient Discharge Instructions
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Discharge instructions for smallpox (variola) - for chart
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You have been evaluated for suspected or confirmed smallpox (variola)
Smallpox is a serious viral infection that requires close follow-up and public health monitoring
Isolation precautions
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You must remain isolated from other people until all scabs have fallen off (typically 3-4 weeks after rash onset)
Do not have face-to-face contact with others until cleared by public health authorities
Avoid public transportation, schools, workplaces, and crowded settings
Your household contacts will be vaccinated and monitored by public health officials
Wound and skin care
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Keep skin lesions clean and dry
Do not scratch or pick at lesions to reduce scarring and prevent secondary infection
Signs of skin infection: increasing redness, warmth, swelling, pus, or worsening pain around lesions
Hydration and nutrition
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Drink adequate fluids especially if swallowing is painful due to mouth sores
Soft foods and liquids recommended if oral lesions are present
Nutritional supplements if unable to eat adequately
Medications
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Take tecovirimat (TPOXX) as prescribed for the full 14-day course even if feeling better
Take acetaminophen or ibuprofen as directed for fever and pain
Do not take aspirin in children under 18 (Reye syndrome risk)
Eye care
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Apply prescribed eye drops if keratitis was identified
Wear sunglasses to reduce photophobia discomfort
Return immediately if you develop eye pain, vision changes, or worsening eye redness
Return to emergency department immediately for
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Fever above 39 degrees C (102.2 degrees F)
Difficulty breathing or shortness of breath
Confusion, severe headache, or seizures
Signs of skin superinfection: spreading redness, increasing pain, pus
Eye pain or sudden changes in vision
Inability to drink fluids or severe vomiting
Bleeding from skin lesions or mucous membranes
Any rapidly worsening symptoms
Contact tracing
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Provide names of all close contacts to the public health officer
Anyone who was within 6 feet of you for more than a few minutes while you were symptomatic needs evaluation
Your public health officer will contact exposed individuals for vaccination
Follow-up
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Follow-up appointments arranged by public health: ophthalmology if eye involvement, orthopedics for children with joint complaints
Lifelong immunity is typically conferred after natural infection
Psychological support available: significant emotional impact from illness and isolation
References
Guidelines and key sources
Henderson DA, Inglesby TV, Bartlett JG, et al.
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Smallpox as a Biological Weapon: Medical and Public Health Management
JAMA. 1999;281(22):2127-2137
Foundational bioterrorism preparedness consensus document
Breman JG, Henderson DA
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Diagnosis and Management of Smallpox
N Engl J Med. 2002;346(17):1300-1308
Comprehensive clinical management review
Adalja AA, Toner E, Inglesby TV
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Clinical Management of Potential Bioterrorism-Related Conditions
N Engl J Med. 2015;372(10):954-962
Updated management framework for bioterrorism agents
Grosenbach DW, Honeychurch K, Rose EA, et al.
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Oral Tecovirimat for the Treatment of Smallpox
N Engl J Med. 2018;379(1):44-53
Pivotal trial supporting FDA Animal Rule approval of tecovirimat
Landmark references
Moore ZS, Seward JF, Lane JM
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Smallpox
Lancet. 2006;367(9508):425-435
Clinical classification system and CDC evaluation algorithm
Billioux BJ, Mbaya OT, Sejvar J, Nath A
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Neurologic Complications of Smallpox and Monkeypox: A Review
JAMA Neurology. 2022;79(11):1198-1205
Neurologic complication incidence and management
Saalbach KP
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Treatment and Vaccination for Smallpox and Monkeypox
Advances in Experimental Medicine and Biology. 2024
Antiviral options including cidofovir, brincidofovir, VIGIV review
Li X, Pan Z, Zhang L
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Tecovirimat: A Journey From Discovery to Mechanistic Insights in Poxvirus Inhibition
PLoS Pathogens. 2025
Mechanism of action and resistance mutations
Green MS, LeDuc J, Cohen D, Franz DR
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Confronting the Threat of Bioterrorism: Realities, Challenges, and Defensive Strategies
Lancet Infect Dis. 2019;19(1):e2-e13
Bioterrorism threat landscape and public health response
TPOXX (tecovirimat) FDA Drug Label
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Food and Drug Administration; Updated 2025-12-31
Weight-based dosing tables, indications, contraindications
SymptomDx is an educational tool for medical professionals. It does not replace clinical judgment. Verify all clinical data and drug dosages with authoritative sources.
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Smallpox (Variola)