01Approach to the Critical Patient/attcp31

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

02History/hx48

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

03Physical Exam/exam34

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)

04Differential Diagnosis/ddx41

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

05Laboratory Tests/lt40

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

06Diagnostic Tests/dt55

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

07Disposition/dispo29

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

08Treatment/t64

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

09Special Populations/sp47

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

10Background/b66

Epidemiology

›Historical disease burden

›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

›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

›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

›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

›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

›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

›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

›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

›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

›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

›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

›B03: Smallpox

›Note: variola major and variola minor both coded as B03

›Bioterrorism context: additional external cause codes may apply

11Patient Discharge Instructions/pdi41

copy discharge instructions

›Discharge instructions for smallpox (variola) - for chart

›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

›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

›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

›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

›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

›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

›Fever above 39 degrees C (102.2 degrees F)

›Difficulty breathing or shortness of breath

12References/r39

Guidelines and key sources

›Henderson DA, Inglesby TV, Bartlett JG, et al.

›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

›Diagnosis and Management of Smallpox

›N Engl J Med. 2002;346(17):1300-1308

›Comprehensive clinical management review

›Adalja AA, Toner E, Inglesby TV

›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.

›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

›Smallpox

›Lancet. 2006;367(9508):425-435

›Clinical classification system and CDC evaluation algorithm

›Billioux BJ, Mbaya OT, Sejvar J, Nath A

›Neurologic Complications of Smallpox and Monkeypox: A Review

›JAMA Neurology. 2022;79(11):1198-1205

›Neurologic complication incidence and management

›Saalbach KP

›Treatment and Vaccination for Smallpox and Monkeypox

Evidence & Review

Evidence & Review