Adverse Events Following Immunization Dr S.M.Zahraei Center for Disease Control Ministry of Health and Medical Education Detect Report Investigate Respond

TREND OF DIPHTHERIA IMMUNIZATION COVERAGE & CASES (1984 –2003 , I. R TREND OF DIPHTHERIA IMMUNIZATION COVERAGE & CASES (1984 –2003 , I.R.IRAN)

TREND OF PERTUSSIS IMMUNIZATION COVERAGE & CASES (1984 –2003,I.R.IRAN)

TREND OF NEONATAL TETANUS IMMUNIZATION COVERAGE & CASES (1984 –2003,I TREND OF NEONATAL TETANUS IMMUNIZATION COVERAGE & CASES (1984 –2003,I.R.IRAN)

TREND OF MEASLES IMMUNIZATION COVERAGE & CASES (1984 –2003,I.R.IRAN)

TREND OF POLIO IMMUNIZATION COVERAGE & CASES (1984 –2003,I.R.IRAN)

TREND OF BCG IMMUNIZATION COVERAGE (1984 –2003,I.R.IRAN)

TREND OF HEPATITIS B IMMUNIZATION COVERAGE (1994 –2003,I.R.IRAN) Prevalence rate of H.B : Survey 1991 : 3 % Survey 1999 : 1. 7 %

AEFI is a medical incident that takes place after an immunization, causes concern, and is believed to be caused by immunization Vaccine reaction caused by vaccine’s inherent properties Programme error caused by error in vaccine preparation, handling or administration

Coincidental Injection reaction Unknown happens after immunization but not caused by it a chance association Injection reaction anxiety or pain of injection not vaccine Unknown cause can not be determined

Cluster of AEFI >=2 cases of the same adverse event following immunizations related in time, geography or in the vaccine administered Why is it important to monitor for clustering?

Potential Objectives For AEFI Surveillance System Detect, correct, and prevent programme errors Identify problems with vaccine lots or brand Prevent false blame from coincidental events Maintain confidence by properly responding to parent/community concerns while increasing awareness (public and professional) about vaccine risks

Generate new hypotheses about vaccine reactions that are specific to the population Estimate rates of occurrence on AEFI in the local population, compared with trial and international data (particularly for new vaccines being introduced)

DETECTING AND REPORTING AEFIs

Which Events To Report? Death, hospitalization, or other severe/unusual events Toxic shock syndrome Severe local reaction Sepsis Injection site abscess (bacterial/sterile) BCG lymphadenitis AEFIs causing concern or suspicion of vaccine involvement

Which Reports To Investigate? Investigate if possible programme error serious event of unexplained cause above expected rate (not just numbers) potential damage to the immunization programme Certain events (toxic shock syndrome, sepsis, abscess,and BCG lymphadenitis) are likely to arise from programme errors and must always be investigated

Programme Errors Non-sterile injection infection Incorrect preparation abscess (inadequate shaking) drug effect (use of drug instead of vaccine/diluent)

Injection in wrong site local reaction/abscess (wrong tissue level) nerve damage Vaccine frozen local reaction Contraindication ignored avoidable severe reaction

Serious Events Anaphylactoid reaction (acute hypersensitivity reaction) Anaphylaxis Persistent (more than 3 hours) inconsolable screaming Hypotonic hyporesponsive episode Seizures, including febrile seizures (6-12 days for measles/MMR; 0-2 days for DTP) Encephalopathy (6-12 days for measles/MMR; 0-2 days for DTP)

Serious Events (cont…) Acute flaccid paralysis (4-30 days for OPV recipient; 4-75 days for contact) Brachial neuritis (2-28 days after tetanus containing vaccine) Thrombocytopaenia (15-35 days after measles/MMR) Disseminated BCG infection Osteitis/osteomyelitis

True contraindications are rare Current serious febrile illness delay vaccine administration History of severe AEFI after previous dose Evolving neurological disease avoid whole cell pertussis vaccine (e.g. uncontrolled epilepsy) Type 1 hypersensitivity to egg - avoid yellow fever & influenza but can use vaccines made in chick fibroblasts Symptomatic HIV avoid BCG and yellow fever

Contraindications Adopted from Plotkin pg 66-67 Anaphylactic reaction to neomicin, streptomycin or polymyxin B IPV Immunodeficiency, or immunodeficient household contact* OPV Encephalopathy within 7 days of administration DTP Anaphylactic reaction to vaccine or vaccine constituent Severe febrile illness All vaccines Contraindication Vaccine Contraindications Certain contraindications apply to all vaccines. An anaphylactic reaction to a vaccine contraindicates further doses of that vaccine. If an individual has had an anaphylactic reaction to a vaccine constituent, any vaccine containing that constituent is contraindicated. Moderate or severe illness with or without fever is a contraindication to vaccination. However, mild intercurrent illnesss with low grade pyrexia is not a contraindication to vaccination. Nor are previous mild to moderate local reactions, or fever after previous doses. Concurrent antimicrobial therapy and recent exposure to infectious disease are not contraindications. A history of penicillin or other allergies either in the recipient or their family is also not a contraindication to vaccination. OPV and MMR vaccine are contraindicated in immunocompromised patients. In HIV infected individuals their use is advocated despite the risk of pathogenicity in symptomatic patients, because of the benefits in protection against the vaccine-preventable disease. * Risk benefit assessment when administered to HIV positive individuals

Contraindications Anaphylactic reaction to common baker’s yeast Adopted from Plotkin pg 66-67 Anaphylactic reaction to common baker’s yeast Hepatitis B Anaphylactic reaction to egg, immunodeficiency Yellow fever None Hib Anaphylaxis, pregnancy, immunodeficiency* MMR Contraindication Vaccine Contraindications See previous page * Risk benefit assessment when administered to HIV-positive individuals

THANK YOU FOR YOUR ATTENTION

Anaphylaxis Type 1 hypersensitivity reaction Circulatory failure Bronchospasm +/- laryngospasm/laryngeal oedema respiratory distress May include pruritis, flushing, angioedema, seizures, vomiting, abdominal cramps & incontinence Occurs in previously sensitized individuals

Anaphylaxis Reported less from developing countries Less sensitization? Less reporting? Anaphylaxis is rare (1/1 000 000 vaccinations) Fainting is common Untrained staff may misdiagnose fainting/dizziness for anaphylaxis or vice versa Administration of adrenaline in a faint may be dangerous PROMPT MANAGEMENT IS VITAL!

Seizures Particularly associated with measles and DTP vaccination (pertussis component) febrile seizures Temp >38 afebrile seizures Temp normal Febrile seizures more common with pertussis An association with non-febrile seizures has not been proven Seizures Seizures have been particularly associated with measles and the pertussis component of DTP vaccination Febrile seizures: a seizure occuring in association with pyrexia (temperature>38 degrees celsius) Afebrile seizures: a seizure occuring in an apyrexial patient. Febrile seizures more common with Pertussis vaccination than with other vaccines. Any vaccine which provokes febrile response may potentially precipitate febrile seizures in a child. Such seizure are not associated with long term sequelae and do not predispose children to the development of epilepsy in later life.

Adverse Reactions To BCG Disseminated BCGits widespread infection, 1-12 months after BCG usually in immunocompromised individual confirm by isolation of Mycobacterium bovis BCG strain treat with antituberculous regimen including Rifampicin and Isoniazid Osteitis/osteomyelitis infection of the bone with M bovis BCG strain management as above Adverse reaction to BCG vaccination Disseminated BCG: Widespread infection.with Mycobacterium bovis may develop 1-12 months after BCG . This usually occurs in immunocompromised individuals. It may be confirmed microbiologically by isolation of Mycobacterium bovis BCG strain. Patients with disseminated BCG should be treated with an antituberculous regimen including Rifampicin and Isoniazid. Osteitis/Osteomyelitis: Infection of the bone with M bovis BCG strain may occur. Patients developing this complication are managed in the same manner as those with disseminated BCG. Described particularly in Scandinavia and Eastern Europe. Association particularly with the Goteberg strain. Treatment: BCG strain is resistant to PZA - therefore need to consider addition of ethambutol.

Adverse Reactions To BCG Suppurative lymphadenitis occurs within 2-6 months of BCG vaccination Case Definition 1 lymph node> 1.5 cm in size/draining sinus over a lymph node usually occurs in the axilla, on the same side as innoculation Management heals spontaneously over months only treat if sticking to skin or draining surgical drainage and local installation of antituberculous drug systemic Rx is ineffective Suppurative lymphadenitis: This occurs within 2- 6 months of BCG vaccination. Case Definition: 1 lymph node> 1.5 cm in size OR draining sinus over a lymph node Suppurative lymphadenitis usually occurs in the axilla, on the same side as innoculation. Management: The lesion will heal spontaneously over months One only needs to manage actively if the involved nodes stick to skin or form draining sinuses. Management in such cases would involve surgical drainage and local installation of antituberculous drug. Note:Systemic Rx is with antituberculous drugs is ineffective in such cases.

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Tetanus Vaccine Brachial neuritis Presents with pain in shoulder and upper arm Followed by weakness +/- wasting of arm and shoulder muscles Sensory loss not prominent Occurs 2-28 days after vaccination Possibly a manifestation of immune complex disease Management is symptomatic Tetanus vaccine Brachial Neuritis This presents with pain in shoulder and upper arm. This is followed by weakness with or without wasting of arm and shoulder muscles. Sensory loss not prominent. Dysfunction is limited to the nerve plexus of the arm, without involvement of other peripheral or central nervous system structures. Brachial neuritis occurs 2-28 days after vaccination. The pathogenesis is not clearly understood. It is possibly a manifestation of immune complex disease. Usually associated with the administration of multiple doses. Management is symptomatic.

Encephalopathy And Encephalitis Possibly associated with measles & pertussis vaccine Case definition of encephalopathy 2 out of 3 of seizures alteration of consciousness lasting for one day or more distinct change in behavior for one day or more Temporal relationship within 48 hrs with DTP within 7-12 days after measles or MMR Encephalopathy and encephalitis The development of encephalopathy and encephalitis are possibly associated with Measles and Pertussis vaccine It is NOT certain that these vaccines are causative. Case definition of encephalopathy: 2 out of 3 of: 1. Seizures 2. Alteration of consciousness lasting for one day or more 3. Distinct change in behaviour for one day or more A temporal relationship with the administration of the vaccine must also exist Within 48hrs with DTP Within 7-12 days after measles or MMR

Encephalitis And Measles Vaccination An analysis of claims for encephalitis following measles vaccine in the USA found clustering of events 8-9 days after vaccination (Wetbel 1998, Duclos 1998) This supports, but does not prove, the possibility that measles vaccine was causative Risk is less than 1 case per million Encephalitis and measles vaccination An analysis of claims for encephalitis following measles vaccine in the USA found clustering of events 8-9 days after vaccination (Wetbel 1998, Duclos 1998) This supports, but does not prove, the possibility that measles vaccine was causative. Risk is less than 1 case per million

Hypotonic Hypotesive Episode Mainly associated with DTP Case definition Event of sudden onset occurring within 48 (usually less than 12) hours of vaccination and lasting from one minute to several hours In a child < 10 years of age ALL of the following must be present limpness (hypotonic) reduced responsiveness pallor or cyanosis - or failure to observe/recall Transient, self-limiting, NOT a contraindication to further vaccination Hypotonic hypotensive episode (HHE or shock-collapse) Mainly associated with DTP Case definition: An event of sudden onset occurring within 48 (usually less than 12) hours of vaccination and lasting from one minute to several hours. In a child < 10 years of age 3. ALL of the following must be present -Limpness (hypotonic) -Reduced responsiveness -Pallor or cyanosis- or failure to observe/ recall HHE is a transient, self limiting reaction of unknown pathogenesis. It is NOT a contraindication to further vaccination.

Acute Flaccid Paralysis Vaccine associated paralytic poliomyelitis Occurs within 4-30 days of receipt of OPV or 4-75 days after contact with vaccine recipient Case Following a national immunization day in 1996, cases of paralysis were reported after receiving OPV. On laboratory analysis, the wild virus was found, showing that the children had been infected with wild poliovirus before immunization. The cases of poliovirus were coincidental, and not caused by the vaccine.

Yellow Fever Vaccine Encephalitis Post-vaccination encephalitis in infants < 6 months Onset – 7-21 days from vaccination No significant risk in older children and adults Insufficient data on safety in symptomatic HIV+ patients = do not vaccinate Contraindicated in pregnancy unless significant risk of contracting yellow fever exists Yellow Fever Vaccine Encephalitis: Post-vaccination encephalitis may occur in infants under 6 months of age. Onset is 7-21 days after vaccination. There is no significant risk in older children and adults Insufficient data on safety in symptomatic HIV+ patients, therefore the vaccine should be avoided in such patients Use if the vaccine is contraindicated in pregnancy (unless a significant risk of contracting yellow fever exists.) Reports of deaths associated with

Multiple organ failure Yellow Fever Vaccine Multiple organ failure Small number of case reports Clinical presentation: fever, myalgia, headache, and confusion, followed by severe multisystemic illnesses “The temporal association …(illness onset 2-5 days after vaccination), serological responses, isolation of variant vaccine virus from serum and cerebrospinal fluid, and demonstration of yellow fever virus antigen in liver tissue collectively suggest a causal association between yellow fever vaccine and the severe multisystemic illness in these patients.”

Unproven Associations And Public Concerns Influenza vaccine and Guillaine Barré Syndrome MMR and autism, Crohn’s disease Polio and HIV Hepatitis B and multiple sclerosis DTP and permanent brain damage DTP and increased risk of mortality Aluminium and macrophagic myofasciitis Bovine spongiform encephalopathy (BSE) Thiomerosal Multiple vaccines given simultaneously Influenza vaccine and GBS: The 1976 swine influenza virus was associated with an increase of Guillain- Barre Syndrome (GBS). The rate, that exceeded the background rate, was slightly less than 10 per million. CDC 1998.The risk from subsequent vaccines, prepared from different virus strains, is less clear. A recent study found an overall elevated risk of GBS of 1.7 in the 6 weeks following vaccination in the 1992-1993 and 193-194 seasons. This represented n excess of 1 or 2 cases per million vaccine recipients (Lasky et al, 1998) MMR and Autism: There is at present no conclusive evidence to suggest an association between MMR and autism. The alleged association is based on studies with methodological problems, and has been refuted. (Duclos and Ward, 1998) Polio and HIV:The postulated link between polio vaccine and the origins of the HIV epidemic have been disproved. Hepatitis B and Multiple Sclerosis: At present available data, though limited, does not demonstrate a causal association. In France where the concern was raised, the background rate of demyelinating disease was 1-3 cases per 100 000. Notification rate of demyelinating disease in temporal association with Hep B vaccination was 0.6 per 100 000. DTP and permanent brain damage: The USA Safety Committee agreed in 1994 that there was insufficient evidence to conclude that pertussis vaccine could cause permanent brain damage. (Edwards et al, 1999) Aluminium and macrophagic myofasciitis- more research needed. Based on available evidence at present, there is no health risk from the administration of alumnium containig vaccines.

Irritability, malaise & Common, more reactions Local reaction (pain, swelling, redness) Irritability, malaise & systemic symptoms Vaccine Fever >38C BCG 90-95% - - Hib - 5-15% 2-10% HepB Adults: 15%; Children: 5% - 1-6% Measles/ MMR ~10% 5% rash 5-15% Polio (OPV) - <1% <1%** Common, minor reactions These occur within a day or two of immunization (except for measles/MMR - 6 to 12 days after immunization) and they only last one to a few days. Local reactions include pain, swelling and/or redness at the injection site and can be expected in about 10% of vaccinees, except for those injected with DTP, or tetanus boosters, where up to half can be affected. BCG causes a specific local reaction that starts as a papule (lump) two or more weeks after immunization that then becomes ulcerated and heals after several months, leaving a scar. Individuals with dormant tuberculosis infection often have an accelerated response to BCG. Keloid (thickened scar tissue) from the BCG lesion is more common among Asian and African populations. Systemic reactions include fever and occur in about 10% or less of vaccinees, except for DTP where it is again about half. Other common systemic reactions (e.g., irritability, malaise, ‘off-colour’, anorexia) can also occur after DTP. For measles/MMR and OPV the systemic reactions arise from vaccine virus infection. Measles’ vaccine causes fever, rash and/or conjunctivitis, and affects 5-15% of vaccinees. It is very mild compared to ‘wild’ measles, but for severely immunocompromised individuals, it can be severe, even fatal. Vaccine reactions for mumps (swollen parotid gland) and rubella (arthralgia and swollen lymph nodes) affect less than 1% of children. Rubella vaccine causes symptoms more often in adults, with 15% suffering from arthralgia. Systemic reactions from OPV affect less than 1% of vaccinees with diarrhoea, headache, and/or muscle pain. Tetanus ~10%* ~10% ~25% DTP (pertussis) Up to 50% Up to 50% Up to 55% * Rate of local reactions likely to increase with booster doses, up to 50-85% ** Symptoms include diarrhoea, headache, and/or muscle pains

Rare, more frequent reactions 0.76-1.3 (1st dose) 0.17 (subsequent doses) 0.15 (contacts) 4-30 days Vaccine-associated paralytic poliomyelitis (VAPP) Risk is higher for first dose, adults, and immunocompromised OPV 333 33 1-50 5-12 days 15-35 days 0-1 hour Febrile seizures Thrombocytopaenia Anaphylaxis Measles /MMR 1-2 5 1-6 weeks Guillain Barré syndrome Hep B Nil known Hib 100-1000 1-700 2 2-6 months 1-12 months Suppurative lymphadenitis BCG osteitis Disseminated BCG BCG Rate per million doses Onset interval Reaction Vaccine Rare, more serious reactions Most of the rare and more serious vaccine reactions (e.g., seizures, thrombocytopaenia, hypotonic-hyporesponsive episodes, persistent inconsolable screaming) do not lead to long term problems. Anaphylaxis, while potentially fatal, is treatable without leaving any long term effects. Although encephalopathy is included as a rare reaction to measles or DTP vaccine, it is not certain that this is in fact caused by these vaccines. Seizures are mostly febrile and risk depends on age, with much lower risk in infants under the age of 4 months or over the age of six years. Reactions to measles/MMR (except allergic and anaphylaxis) do not occur if already immune (~90% of those receiving a second dose).

Rare, more frequent reactions 1000-60 000 570 20 0-1 0-24 hours 0-3 days 0-1 hour Persistent (>3 hrs) inconsolable screaming Seizures Hypotonic, hyporesponsive episode (HHE) Anaphylaxis/shock Encephalopathy DTP Nil extra to tetanus reactions Tetanus-diphtheria 5-10 1-6 6-10 2-28 days 1-6 weeks Brachial neuritis Anaphylaxis Sterile abscess Tetanus Rate per million doses Onset interval Reaction Vaccine Rare, more serious reactions Most of the rare and more serious vaccine reactions (e.g., seizures, thrombocytopaenia, hypotonic-hyporesponsive episodes, persistent inconsolable screaming) do not lead to long term problems. Anaphylaxis, while potentially fatal, is treatable without leaving any long term effects. Although encephalopathy is included as a rare reaction to measles or DTP vaccine, it is not certain that this is in fact caused by these vaccines. Seizures are mostly febrile and risk depends on age, with much lower risk in infants under the age of 4 months or over the age of six years. Reactions to measles/MMR (except allergic and anaphylaxis) do not occur if already immune (~90% of those receiving a second dose).

Rare,more frequent reactions 500-4000 in infants<6 months 5-20 7-21 days 0-1 hours Post-vaccination Encephalitis Allergic reaction/anaphylaxis Yellow fever 10-1000 1-2.3 Serious allergic reaction Neurological event Japanese encephalitis Rate per million doses Onset interval Reaction Vaccine Rare, more serious reactions Most of the rare and more serious vaccine reactions (e.g., seizures, thrombocytopaenia, hypotonic-hyporesponsive episodes, persistent inconsolable screaming) do not lead to long term problems. Anaphylaxis, while potentially fatal, is treatable without leaving any long term effects. Although encephalopathy is included as a rare reaction to measles or DTP vaccine, it is not certain that this is in fact caused by these vaccines. Seizures are mostly febrile and risk depends on age, with much lower risk in infants under the age of 4 months or over the age of six years. Reactions to measles/MMR (except allergic and anaphylaxis) do not occur if already immune (~90% of those receiving a second dose).

Rare, More Serious Reactions Incidence Suppurative lymphadenitis BCG osteitis Disseminated BCG infection 1 in 1000 to 1 in 10 000 1 in 3000 to 1 in 100 million ~1 in 1 million BCG Hib Not known HepB 1 in 6-900 000 Anaphylaxis Febrile seizures Thrombocytopaenia (low platelets) Severe allergic reaction Anaphylaxis Encephalopathy 1 in 3000 1 in 30 000 ~1 in 100 000 ~1 in 1 million <1 in 1 million Measles/ MMR/MR Rare, more serious reactions Most of the rare and more serious vaccine reactions (e.g., seizures, thrombocytopaenia, hypotonic-hyporesponsive episodes, persistent inconsolable screaming) do not lead to long term problems. Anaphylaxis, while potentially fatal, is treatable without leaving any long term effects. Although encephalopathy is included as a rare reaction to measles or DTP vaccine, it is not certain that this is in fact caused by these vaccines. Seizures are mostly febrile and risk depends on age, with much lower risk in infants under the age of 4 months or over the age of six years. Reactions to measles/MMR (except allergic and anaphylaxis) do not occur if already immune (~90% of those receiving a second dose).

Rare, More Serious Reactions Incidence Vaccine associated paralytic poliomyelitis Risk is higher for first dose, adults, and immunocompromised 1 in 2.4-3.3 million doses 1 in 750 000 first dose compared to 1 in 5.1 million for subsequent doses Polio (OPV) Brachial neuritis Anaphylaxis 0.5-1 in 100 000 1 in 100 000 to 1 in 2 500 000 Tetanus Persistent inconsolable screaming Seizures Hypotonic, hyporesponsive episode (HHE) Anaphylaxis Encephalopathy 1 in 15 to 1 in 1000 1 in 1750 to 1 in 12 500 1 in 1000 to 1 in 33 000 1-6 in million 0-1 in 1 million Pertussis (DTP- whole cell)

CASE STUDIES Cause: Vaccine reaction compounded by programme errors An outbreak of lymphadenitis three months after BCG immunization was traced to a switch to a different strain of vaccine. The investigation also highlighted a number of programme errors (vaccines not properly reconstituted, and injections not given intradermally). Cause: Vaccine reaction compounded by programme errors A one-year-old child died within 12 hours of receiving measles vaccine. It was reported as a possible anaphylaxis because of its rapid onset. Investigation found that the vaccine used was likely to have been reconstituted one day prior to this particular use. Cause: Non-sterile injection, not anaphylaxis

Cause: Non-sterile injection CASE STUDY Four children died and a fifth was hospitalized after receiving measles vaccine from the same vial. Vaccine was not refrigerated, and was transported house to house for immunization. Reactions began four to five hours after vaccination, with vomiting, unconsciousness, and meningeal irritation. S. aureus was cultivated from the incriminated vial. Cause: Non-sterile injection In another clinic three children died from shock syndrome, with symptoms developing within five hours of receiving measles vaccine. In that clinic the reconstituted vaccine was routinely kept until it was used, and syringes were never sterilized, but washed with ordinary water and wiped with cotton wool. Careful epidemiological investigation of an AEFI is needed to pinpoint the cause and to correct immunization practices.

Insulin given to 70 infants instead of DTP vaccine with 21 deaths Programmatic error Turkey India Algeria Yemen 1997 Insulin given to 70 infants instead of DTP vaccine with 21 deaths Insulin vial Vaccine vials T T DTP