Prevention of Hepatitis A

1. Control of Reservoir

• Fecal shedding peaks during the incubation period (15-45 days), before symptoms appear
• A large proportion of infections (up to 50% in adults) are subclinical
• There is no specific antiviral treatment

2. Control of Transmission (Non-Vaccine Measures)

• Hand washing - before eating, after using the toilet, after handling food
• Safe water supply - purification through flocculation, filtration, and adequate chlorination
• Sanitary disposal of excreta - prevents contamination of water, food, and milk
• Food safety - thorough cooking destroys HAV; avoid raw shellfish from contaminated waters
• Good personal hygiene in food handlers, day-care settings, and healthcare workers

3. Protection of Susceptible Individuals

A. Active Immunization - Hepatitis A Vaccine

• Protective efficacy after 2 doses: ~94%
• Seroconversion: virtually 100% in healthy individuals
• Protection begins ~4 weeks after the first dose
• Anti-HAV antibody titers persist for at least 20-27 years after vaccination (possibly lifelong)
• Can be co-administered with other vaccines without reduced efficacy
• A combination Hep A + Hep B vaccine (Twinrix) is available for adults ≥18 years
• A combination Hep A + typhoid vaccine also exists, useful for travelers
• An accelerated schedule (days 0, 7, 21) is effective for last-minute travelers

B. Who Should Be Vaccinated?

• All children starting at 12-23 months (two-dose schedule per ACIP)
• Unvaccinated individuals through age 18

• Travelers to endemic countries (Africa, Asia, parts of Latin America)
• Men who have sex with men (MSM)
• Injection drug users and persons reporting drug use
• Homeless persons
• Persons with chronic liver disease
• Patients receiving clotting factor concentrates (hemophilia)
• Laboratory workers handling HAV
• Non-human primate handlers
• Day-care center employees and contacts
• Persons in institutions for the developmentally delayed
• Military personnel
• Healthcare workers (especially those handling stool/fecal material)

C. Passive Immunization - Immunoglobulin (IG)

• Efficacy: 80-90% when given before or within 14 days of exposure
• Protection begins within hours of injection
• Use is declining because vaccines are superior for most situations

• Infants aged <12 months (cannot receive vaccine)
• Persons with contraindications to hepatitis A vaccine
• Immunocompromised adults and those with chronic liver disease: use both vaccine AND IG (at different IM sites) for postexposure prophylaxis
• Outbreak containment when early response is critical

• Up to 1 month: 0.1 mg/kg
• Up to 2 months: 0.2 mg/kg
• Longer travel: repeat 0.2 mg/kg every 2 months

4. Pre- and Post-Exposure Prophylaxis Summary

5. Vaccination in Outbreak Settings

Breakthrough Infections

Prevention and Control of Hepatitis B

1. Active Immunization - Hepatitis B Vaccine

History and Types

• Before 1982, prevention relied solely on passive immunoprophylaxis
• 1982: First vaccine - plasma-derived HBsAg particles from healthy HBsAg carriers
• 1987: Replaced by recombinant yeast-derived vaccine (HBsAg particles, non-glycosylated but immunologically identical)
• Four licensed recombinant vaccines are now available in the United States

Available Vaccines

• All injections are IM into the deltoid (not gluteal, which has lower immunogenicity)
• Heplisav-B (2-dose, 1 month apart) achieved seroprotection rates of 95% in adults 18-55 years vs 81% for Engerix-B, and is particularly advantageous for older adults and those with type 2 diabetes
• PreHevbrio showed higher seroprotection rates in adults ≥45 years (89% vs 73.1%) - useful in older non-responders
• Twinrix can also be given on an accelerated 4-dose schedule (days 0, 7, 21-30, then 12 months)
• Contraindication: severe yeast allergy (for Engerix-B, Recombivax, Heplisav-B); PreHevbrio is the only vaccine safe in yeast allergy, but is not for use in pregnant women

Who Should Be Vaccinated?

• All infants - birth dose within 12 hours of delivery (standard of care in the US since 2002); complete 3-dose series
• All unvaccinated adults - ACIP (2022) extended recommendations to all adults regardless of risk

• Healthcare workers and laboratory personnel (blood/needle-stick exposure risk)
• Sexual partners or household contacts of HBsAg-positive individuals
• Men who have sex with men (MSM)
• Injection drug users
• Persons with multiple sexual partners
• Travelers to endemic regions
• Patients on hemodialysis (require higher doses)
• Patients with chronic liver disease (including hepatitis C)
• Persons with HIV infection
• Residents/staff of correctional facilities and group homes
• Persons with diabetes mellitus

Vaccine Efficacy and Duration

• Protective anti-HBs levels (≥10 mIU/mL) are achieved in >95% of healthy young adults
• Immunogenicity is lower in: older age, obesity, smoking, renal failure, immunosuppression, HIV
• Protection is long-lasting - anti-HBs may wane but immunologic memory persists; booster doses are generally not recommended for immunocompetent individuals
• Dialysis patients: annual anti-HBs testing recommended; revaccinate if anti-HBs falls below 10 mIU/mL

2. Passive Immunization - Hepatitis B Immunoglobulin (HBIG)

3. Post-Exposure Prophylaxis (PEP)

Perinatal Exposure (Born to HBsAg-Positive Mother)

• HBIG 0.5 mL IM in thigh + hepatitis B vaccine (first dose), both within 12 hours of birth at separate sites
• Complete vaccine series at 1 and 6 months
• Efficacy: 85-95% in reducing perinatal transmission
• After the series, test the infant for HBsAg and anti-HBs at 9-12 months
• If mother's HBsAg status is unknown: give vaccine within 12 hours; if infant <2,000 g, add HBIG immediately; if ≥2,000 g, add HBIG within 7 days if status comes back positive
• For mothers with high HBV DNA (>2 × 10⁵ IU/mL), add tenofovir in the third trimester - this further reduces perinatal transmission

Percutaneous/Mucosal Exposure (Needle-Stick, Splash)

• HBIG 0.06 mL/kg IM + initiate full hepatitis B vaccine series as soon as possible (within 7 days)
• If previously vaccinated and confirmed responder (anti-HBs ≥10 mIU/mL): no treatment needed
• If previously vaccinated but non-responder: HBIG x2 doses (1 month apart) OR HBIG + revaccination with more immunogenic vaccine

Sexual Exposure

• HBIG 0.06 mL/kg IM within 14 days of exposure + initiate hepatitis B vaccine series

Summary Table: Post-Exposure Prophylaxis

4. Interrupting Transmission - Non-Vaccine Measures

Blood Safety

• Universal screening of blood donors for HBsAg, anti-HBc, and HBV DNA (NAT testing)
• Safe handling of blood products and viral inactivation procedures
• Testing of every unit of blood for HIV, HBV, HCV, malaria, and syphilis before transfusion
• Use of single-use, sterile syringes and needles

Injection Safety

• Eliminate reuse of needles and syringes in healthcare and community settings
• Engineered safety devices for needles
• Safe disposal of sharps (sharps containers)

Harm Reduction

• Needle and syringe programs for injection drug users
• Opioid substitution therapy
• Community education on not sharing needles, razors, or personal hygiene items

Sexual Transmission Prevention

• Condom use, particularly for persons with multiple partners or unknown HBsAg status
• Screening of sexual partners of HBsAg-positive individuals
• Vaccination of unvaccinated partners

Healthcare Settings

• Universal/standard precautions for all patients (blood precautions, gloves with blood/body fluid contact)
• Avoid ungloved direct hand contact with blood and body fluids
• HBV-infected healthcare workers with high viral loads: restrictions on exposure-prone procedures per occupational health guidelines

Perinatal/Vertical Transmission Prevention

• Universal HBsAg screening of all pregnant women at the first prenatal visit
• HBIG + vaccine for infants of positive or unknown-status mothers (see above)
• Antiviral therapy (tenofovir) during pregnancy for high viremia mothers
• Breastfeeding is not contraindicated if the infant receives HBIG + vaccine prophylaxis

5. WHO Global Elimination Targets (Hepatitis B by 2030)

6. Additional Note: HBV Vaccination Also Prevents Hepatitis D

Outbreak Investigation of Cholera

Background: Why Outbreak Investigation Matters

1. Confirm the diagnosis and extent of the outbreak
2. Identify the source(s) and mode(s) of transmission
3. Implement targeted control measures to stop ongoing transmission
4. Prevent future outbreaks by identifying underlying risk factors

Step 1: Verification of the Diagnosis

• Clinically suspect cholera in all cases of acute watery diarrhea during an outbreak
• Confirm by identifying Vibrio cholerae O1 (or O139) in stool specimens
• Once cholera is confirmed in a few cases, it is not necessary to culture all cases - clinical case definition can then guide surveillance

WHO Outbreak Definition (2024):

• Suspected outbreak: 2 or more suspected cholera cases OR 1 suspected case with a positive RDT within 7 days in a surveillance unit
• Immediate public health measures should begin without waiting for full laboratory confirmation

Laboratory Specimen Collection:

• Direct examination (dark field microscopy): Vibrios appear as "shooting stars"; motility ceases with anti-cholera serum - presumptive diagnosis in minutes
• Culture: Inoculate into Peptone Water Tellurite (PWT) → incubate 4-6 h at 37°C → subculture on Bile Salt Agar (BSA, pH 8.6) → screen under oblique light for vibrio colonies
• Rapid Diagnostic Tests (RDTs): Used in field conditions for rapid triage
• Confirmation by phage typing (can be referred to National Institute of Cholera and Enteric Diseases, Kolkata, or WHO International Centre for Vibrios)

Step 2: Notification

• All health workers (especially community-level) must be trained to identify and notify cases immediately to local health authorities
• Under International Health Regulations (IHR): cholera must be notified to WHO within 24 hours of occurrence by the National Government
• Cases and deaths must be reported daily and weekly until the area is declared cholera-free
• Declaration of cholera-free status: When twice the incubation period (i.e., 10 days) has elapsed since the death, recovery, or isolation of the last case

Step 3: Early Case-Finding

• Purpose: Initiate prompt treatment, detect infected household contacts, identify means of spread
• Method: House-to-house visits by trained lay health workers
• Epidemiological case sheet administered to all cases and exposed-but-unaffected persons
• Data collected: name, age, sex, occupation, travel history, onset of illness, signs/symptoms, household contacts, foods eaten, water sources, attendance at gatherings, injections/blood products received
• Search for secondary cases daily until area is declared free - look in hospitals, health centers, and among household contacts

Step 4: Establishment of Treatment Centers

• Mild dehydration (>90% of cases): Oral Rehydration Therapy (ORT) at home
• Severe dehydration: Transfer to nearest treatment center or hospital; start ORT en route
• If no hospital is within convenient distance: convert a school or public building into a temporary cholera treatment center as close to the outbreak site as possible
• Mobile teams at district level should be deployed for areas with poor health infrastructure
• Avoid transporting patients over long distances - this has been linked to disease spread

Step 5: Rehydration Therapy

• Oral Rehydration Therapy (ORT) for mild-moderate dehydration
• Intravenous fluid therapy for severe dehydration (Ringer's lactate preferred)

Step 6: Adjuncts to Therapy - Antibiotics and Chemoprophylaxis

• Fluoroquinolones, tetracycline, azithromycin, ampicillin, TMP-SMX
• Injectable antibiotics have no special advantage over oral
• Antidiarrheals, antiemetics, antispasmodics, and corticosteroids are not recommended
• If diarrhea persists beyond 48 hours: suspect antibiotic resistance

• Mass chemoprophylaxis is not advised (10,000 people must be treated to prevent one serious case; short-lived effect; failed historically)
• Indicated only for household contacts or members of a closed community with cholera
• Drug of choice: Tetracycline 500 mg twice daily for 3 days (adults); or doxycycline 300 mg single dose

Step 7: Epidemiological Investigations

a. Census of the Affected Area

• Conduct a rapid population census by age and sex through house-to-house visits
• This establishes the denominator needed to calculate attack rates (cannot be calculated without a defined "population at risk")

b. Data Analysis - Time, Place, and Person

• Construct an epidemic curve (date/time of symptom onset of each case plotted as histogram)
• The epidemic curve reveals:
  • Time relationship between cases and exposure to a suspected source
  • Whether it is a common-source (sharp peak, rapid decline) or propagated (gradual rise and prolonged tail) epidemic
  • Seasonal or cyclic patterns
• Cholera classically produces a common-source waterborne pattern - sharp peak with gradual tail as person-to-person spread continues

• Prepare a spot map (geographic distribution of cases)
• Relate case clustering to possible sources (water supply, food outlets, latrines)
• The classic historical example: John Snow's spot map in the 1854 Golden Square cholera outbreak in London - clustering around the Broad Street pump identified contaminated water as the source before germ theory was established

• Analyze by age, sex, occupation, and risk factors
• Calculate food-specific attack rates (for food-borne outbreaks) and water-source-specific attack rates
• Compare attack rates in exposed vs. unexposed groups

c. Case-Control Analysis

• Ecological factors can be studied in a case-control design
• Compare exposure to specific vehicles (food, water sources) in cases vs. controls

Step 8: Formulation of Hypotheses

• Formulate hypotheses explaining: (a) probable source, (b) causative agent, (c) modes of spread, (d) environmental enabling factors
• Rank hypotheses in order of relative likelihood
• A working hypothesis guides further targeted investigation and immediate control measures

Step 9: Testing of Hypotheses

• Test all reasonable hypotheses statistically
• Compare attack rates in groups exposed vs. not exposed to each suspected factor
• The hypothesis consistent with all known facts is retained
• Sanitary factors to investigate: status of water supply systems, breakdowns in water treatment, food handling practices, excreta disposal, population movements

Step 10: Sanitation and Control Measures

Water Control

• Provide properly treated, safe water to the entire community for all purposes
• Urban emergency: distribute treated piped water with free residual chlorine; store in narrow-mouthed, covered containers
• Rural emergency: boiling or emergency chlorination
• Long-term: permanent piped water supply and elimination of unsafe water sources

Excreta Disposal

• Emergency provision of sanitary latrines
• Safe disposal to prevent contamination of water, food, and soil

Food Safety

• Supervise food handlers
• Inspect markets, restaurants, and food stalls
• Prohibit sale of high-risk foods (street food, raw shellfish)

Environmental Disinfection

• 0.5% sodium hypochlorite for disinfection of contaminated surfaces and fomites

Step 10 (continued): Vaccination

• Protection begins ~1 week after the last dose
• Shelf life: 3 years at 2-8°C; stable 1 month at 37°C
• The WHO maintains an international OCV stockpile for outbreak response
• Vaccination is used as part of comprehensive outbreak response, not as standalone prevention

Final Report

Key Summary: 10 Steps of Cholera Outbreak Investigation

1. Verification of the diagnosis (laboratory confirmation)
2. Notification (local/national/IHR-WHO within 24 hours)
3. Early case-finding (active community search)
4. Establishment of treatment centers
5. Rehydration therapy (<1% mortality achievable)
6. Adjunct therapy - antibiotics; selective chemoprophylaxis for household contacts
7. Epidemiological investigations (census, epidemic curve, spot map, attack rates)
8. Formulation of hypotheses
9. Testing of hypotheses (case-control, statistical analysis)
10. Sanitation measures + vaccination

Emerging and Re-Emerging Infectious Diseases

1. Definitions and Classification

Emerging Infectious Diseases (EIDs)

"Emerging infectious diseases (EIDs) are those recognized in humans for the first time."

• Examples: HIV/AIDS, Nipah virus infection, SARS, COVID-19

Re-Emerging Infectious Diseases (REIDs)

• Reappear in new locations (e.g., West Nile virus in the US/Russia in 1999)
• Reappear in resistant or phenotypically different forms (e.g., multidrug-resistant Mycobacterium tuberculosis, MRSA, drug-resistant falciparum malaria)
• Reappear after apparent control or elimination (e.g., poliomyelitis in parts of Africa, cholera in Haiti 2010)
• Reappear under unusual circumstances (e.g., deliberately released agents - anthrax bioterrorism 2001)

Subcategories of REIDs

Established/Endemic Infectious Diseases

A Third Group: "Deliberately Emerging"

2. Historical Perspective

"It appears that we have entered a new era in which emergences and re-emergences of IDs are increasing in frequency and impact."

• Harrison's Principles of Internal Medicine 22E

3. Factors Driving Emergence and Re-Emergence

HOST/HUMAN FACTORS

• Demographics and population movement - intrusion into new habitats (especially tropical forests), urban crowding
• International travel and commerce - rapid global spread of pathogens and vectors
• Sexual practices - e.g., HIV pandemic linked to commercial sex work, MSM networks, IV drug use
• Antibiotic misuse - selection pressure driving antimicrobial resistance
• Immunosuppression - HIV/AIDS expanding the pool of susceptible individuals

ENVIRONMENTAL/ECOLOGICAL FACTORS

• Deforestation and land use change - exposes farmers and animals to new arthropods and zoonotic reservoirs
  • Example: Nipah virus (Malaysia, 1998) linked to deforestation + intensive pig farming driving bats into contact with pigs
• Global climate change - expanding the geographic range of vectors (mosquitoes, ticks)
• Uncontrolled urbanization - creates vector breeding habitats (stagnant water pools)
• Primitive irrigation systems - fail to control arthropods and enteric organisms
• Floods and droughts - ecological disruption
• Live animal markets - crowded conditions enabling zoonotic spillover
  • Example: H5N1 and H7N9 avian influenza outbreaks in China linked to live poultry markets

AGENT/MICROBIAL FACTORS

• Microbial evolution and mutation - especially in RNA viruses (high mutation rates)
  • Influenza A: genetic drift (point mutations), genetic shift (hemagglutinin/neuraminidase reassortment)
  • HIV: rapid mutation evading immune control
• Antimicrobial resistance selection - from indiscriminate antibiotic use
  • MRSA, carbapenem-resistant Enterobacteriaceae (CRE), XDR-TB
• Zoonotic spillover - cross-species host switching (animal-to-human transmission)

SOCIAL/SYSTEMIC FAILURES

• Breakdown in public health infrastructure - inadequate sanitation, vector control, immunization programs
• Wars, civil unrest, natural disasters - displace populations and destroy health systems
  • Example: 2010 Haiti cholera epidemic following the earthquake
• Poverty and social inequity - limits access to prevention and treatment
• Lack of political will - delayed or absent public health response

4. Why Zoonoses Dominate

"Zoonotic infections are disproportionately common as emerging pathogens."

• Sherris & Ryan's Medical Microbiology, 8th ed.

• Narrow fitness valley (e.g., sarbecoviruses/ACE2 receptor similarity between bats and humans): easy cross-species jumping
• Deep fitness valley (requires extensive mutation): less likely but possible with high-mutation-rate pathogens

• Bats: SARS-CoV, SARS-CoV-2, Nipah, Hendra, Ebola, Marburg, Rabies
• Wild birds (waterfowl): Influenza A (all human pandemic strains derived from this pool)
• Rodents: Hantavirus, Lassa fever, Plague
• Non-human primates: HIV (originally SIV), Ebola, Monkeypox
• Pigs/domestic animals: Nipah (intermediate host), Influenza reassortment

5. Major Examples

Newly Emerging

Re-Emerging

6. The Influenza A Paradigm

• Natural reservoir: Global pool of wild waterfowl and shorebirds
• All human influenza A pandemics (1918, 1957, 1968, 2009) derived from the 1918 "founder" H1N1 virus, itself of avian origin
• Escape mechanisms from immunity:
  1. Genetic drift (point mutations)
  2. Antigenic shift (reassortment of hemagglutinin/neuraminidase subtypes)
  3. Intrasubtype reassortments
  4. Glycosylation masking of external protein sites
• Challenge for vaccines: Only partially effective; protection lasts months, not years; universal flu vaccine remains elusive
• Spread aided by modernity: Pre-1889 spread took over 1 year; 2009 H1N1 spread globally in weeks by air travel

7. The SARS-CoV-2 Paradigm

• Natural reservoir: Bats (sarbecoviruses)
• ACE2 receptor on bats and humans is structurally similar - making sarbecoviruses potentially pre-adapted to infect humans
• This is why many experts anticipate future sarbecovirus emergences
• Emergence was amplified by: global air travel, dense urban populations, presymptomatic/asymptomatic transmission

8. Antimicrobial Resistance as Re-Emergence

• Carbapenem-resistant Acinetobacter species
• Neisseria gonorrhoeae (multidrug-resistant)
• Candida auris
• Clostridioides difficile
• Carbapenem-resistant Enterobacteriaceae (CRE)
• Extensively drug-resistant M. tuberculosis (XDR-TB)

9. WHO Priority Diseases (Blueprint 2018)

• Ebola virus disease (EVD)
• Marburg virus disease (MVD)
• Crimean-Congo hemorrhagic fever (CCHF)
• MERS and SARS
• Nipah and henipaviral diseases
• Rift Valley fever (RVF)
• Zika
• "Disease X" - a placeholder for an unknown future pathogen

10. Prevention and Control Framework

Surveillance

• Global disease surveillance systems (WHO Global Outbreak Alert and Response Network, ProMED, GOARN)
• Syndromic surveillance to detect unusual clusters early
• Molecular epidemiology and genomic sequencing for rapid pathogen characterization

One Health Approach

• Integrated surveillance at human-animal-environment interfaces
• Regulation of wildlife trade and live animal markets
• Sustainable land use practices to reduce deforestation
• Antimicrobial stewardship

Specific Interventions

• Vaccination and rapid vaccine platform development (mRNA platforms, as demonstrated by COVID-19)
• Vector control (insecticide use, elimination of breeding sites)
• Safe food handling and water sanitation
• Infection prevention and control in healthcare settings
• International Health Regulations (IHR) compliance for rapid outbreak notification
• Research and development for diagnostics, vaccines, and therapeutics against priority pathogens

Role of the Clinician

1. Abiding curiosity
2. Recognition of unusual presentations
3. Epidemiologic reasoning about disease acquisition
4. Identifying case clusters (common-source vs. zoonotic vs. person-to-person)
5. Estimating incubation period and infectivity duration
6. Close relationship with diagnostic laboratories
7. Collaboration with specialists and researchers
8. Partnership with public health - prompt reporting of notifiable diseases
9. Regular reading of current medical literature
10. Patient communication skills to elicit diagnostic clues