Adverse Events Following Immunisation - Clinical Management

• Summary
• Management of Mild Reactions
• Serious Reactions
• Specific Reactions
• Reporting Adverse Reactions

Summary

The management of most AEFIs is symptomatic, rarely requiring specific management.

For the common local reactions, the first step is a correct diagnosis. This is to ensure that the reaction is not some other (coincidental) event, such as an infection that needs treatment. Whilst local reactions are easy to diagnose, systemic reactions are not specific and a wide range of symptoms have been reported. The distinguishing feature is that these symptoms usually only last a day or so.  There is no specific treatment for the common reactions, nor is there usually any need as they resolve by themselves. For symptom control, paracetamol (at a dose of 15mg/kg every four hours – maximum of four doses per day) is recommended for easing pain or fever, if these are present.

Similarly, most of the more rare and serious reactions are also self-limiting and do not usually require treatment. Occasionally, thrombocytopaenia (caused by MMR) can be sufficiently severe to require replacement platelet therapy.

For most severe reactions (including HHE, prolonged screaming, brachial neuritis, aseptic meningitis, encephalopathy) there is no specific treatment and only supportive care is provided, although further medical review to be clear of the diagnosis is usually warranted. It is especially important to support parents who will be very distressed by these reactions. Time will be the major healing factor.

The one vaccine reaction that all vaccinators need to recognise and be able to treat is anaphylaxis. However, anaphylaxis is so rare that most vaccinators would only expect to see, at most, one event over a lifetime of vaccinating. This means that regular training in the management of anaphylaxis is required.

Clinical Management of Adverse Events Following Immunisation (AEFI)

Management of Mild Reactions

Generic Reactions:

• Local site (injection site) reactions (including mild erythema, pain)– examine site to rule out cellulitis or abscess formation. Note erythema is common, and does not necessarily mean cellulitis.  Induration greater than 20cm in diameter is considered a severe local reaction and should be reported to the appropriate authorities. Cellulitis is a rare side effect. Rest, ice and fluids.  Paracetamol 15mg/kg orally q4h up to 1g qid orally q4h can be given to relieve discomfort. Frequent fluid intake should be encouraged.
• Mild Systemic (fever, malaise, drowsiness, myalgia, nausea, diarrhoea) – As above, plus tepid sponging for fever. Symptomatic treatment for nausea or diarrhoea is not usually needed. Fever does not need to be treated, beyond giving extra fluids, unless there is a history of febrile convulsions, or there is discomfort or distress present.
• Analgesic Use: Paracetamol 15mg/kg orally q4h (max four does in 24 hours) can be given to reduce fever, pain and discomfort following immunisation. Prophylactic use is not generally necessary, except in cases of known previous reactions causing distress, or a history of febrile convulsions. Use of NSAIDs (antiinflammatories) in children should be avoided due to the theoretical risk of Reye’s encephalopathy. 
  Specific Reactions:
• Arthralgia and arthritis – may occur after MMR or rubella vaccination (2-4 weeks after vaccination), particularly in adults (approximately 15% of women). It is normally self-limiting. Paracetamol or NSAIDs (in adults only) may be given for analgesia.
  An association between rubella immunisation and acute arthritis was demonstrated in one study, but the result was of borderline statistical significance. (Tingle AJ, Mitchell LA, Grace M et al.  Randomised double-blind placebo-controlled study on adverse effects of rubella immunisation in seronegative women.  Lancet 345:1071-4) No evidence exists for an association between rubella immunisation and chronic arthritis.
• Rash/Conjunctivitis/Coryza – A faint rash (non-infectious) may follow 6-12 days after MMR immunisation and be accompanied by mild coryza and/or conjunctivitis, in other words ‘vaccine measles’. This is not infectious. Rest and extra fluid intake should be encouraged. Paracetamol may be given for symptomatic relief. These should be short-lived symptoms, and any persistent symptoms require medical assessment.
• Parotid or submandibular swelling – usually unilateral and may occur 5-12 days after MMR. Paracetamol can be given as mild analgesia. This is usually self-limiting and does not cause facial nerve palsy.
  

Serious Reactions

Reactions that can happen with all vaccines.

• Anaphylactic reaction (Type 1 Hypersensitivity and anaphylactoid reactions) A rare (1-2 per million doses), but life threatening emergency that occurs usually within 10 minutes of vaccine delivery. The more severe the reaction the more immediate the onset. All immunisation facilities should be equipped with resuscitation kits, including adrenalin and oxygen readily available to deal promptly with an anaphylactic reaction. Signs and symptoms include:
  • Respiratory
    • Severe angioedema of the tongue and lips may obstruct airflow.
    • Laryngeal oedema may manifest as stridor or severe air hunger.
    • Loss of voice, hoarseness, and/or dysphagia may occur.
    • Bronchospasm, airway oedema, and mucus hypersecretion may manifest as wheezing.
    • Hypoxia can cause altered mental status.
  • Cardiovascular
    • Tachycardia
    • Hypotension
    • Cardiovascular collapse with shock can occur immediately, without any other findings.
  • Cutaneous
    • An early sign of anaphylaxis is flushing, noted especially in the cheeks. Urticaria (hives) can occur anywhere on the body, often localizing to the palms, soles, and inner thighs. The lesions are erythematous, raised, highly pruritic, and of variable size.
    • Angioedema is also commonly observed. These lesions involve the deeper dermal layers of skin and are usually nonpruritic and nonpitting. Common areas of involvement are the larynx, lips, eyelids, hands, feet, and genitals.
    • Isolated, whole-body erythematous flushing is also occasionally observed.
  • Gastrointestinal: vomiting, diarrhoea, and abdominal distension.

Prompt resuscitation and intramuscular adrenaline (1:1000) administration is essential. Transfer to specialist emergency facilities is required for continued monitoring of vital signs. Biphasic reactions with rebound anaphylaxis commonly occur. Referral to an immunologist is required for follow-up. Further immunisations with the vaccine that caused the reaction or any vaccines with components known to have caused previous anaphylactic reactions are contraindicated.

• Febrile Convulsions – Occur in some (estimated 1 per 3000 doses) children following the spiking of a high fever from any source. Febrile seizures need to be differentiated from meningitis by history, examination and, if needed, appropriate investigations. Antipyretic prophylaxis (with paracetamol 15 mg/kg.) is recommended with subsequent immunisations to be given 30 minutes before and 4-6 hourly for 48 hours after immunisations to reduce the risk of recurrence of a febrile seizure following subsequent immunisations.
• Serum sickness type reactions (Type 3 Hypersensitivity) can occur hours to days after any immunisation as a hypersensitivity reaction to a vaccine or its components (approximately 2 per 1000 doses). Signs and symptoms include pruritus, dermatitis, urticaria, erythematous nodules, blistering, angioedema, arthralgia and fever. Rarely, haemolysis and purpura can occur. Oral antihistamines and corticosteroid therapy relieve symptoms.
  

Specific Reactions

• Hypotonic Hyporesponsive Episode may occur in infants and children under 10 years up to 48 hours after immunisation with pertussis-containing immunisations. (7-25 per 100000, less frequent with acellular pertussis vaccines than with the whole cell pertussis vaccines), It is characterised by hypotonia or limpness, reduced or hyporesponsiveness and pallor, cyanosis or impaired capillary refill where another underlying cause for the symptoms cannot be identified. Blood pressure and glucose remain normal. Episodes last from 1 minute to 48 hours. Resuscitation is rarely required and there is no evidence of long-term sequelae. Further pertussis immunisations are not contraindicated.
• Vaccine-associated paralytic polio (VAPP) – the oral polio vaccine can, in rare incidences, cause a paralytic illness in healthy recipients and their contacts. This is due to the attenuated virus mutating back to a virulent form on passage through the bowel. Estimates of the frequency of this suggest there is approximated one per 6.8 million doses, and a further case per 6.4 million doses among household and community contacts. The risk is greatest with the giving of the first dose (approximately 1/700,000) and is higher in adult contacts than child recipients. This does not occur with the inactivated polio vaccine (IPV). All suspected cases of VAPP should be referred for further medical assessment.
• Brachial Neuritis - may occur rarely (5-10 per million doses) after tetanus-containing immunisations.  Signs of peripheral neuropathy (altered sensation, loss of power, hypotonia, and decreased reflexes) may be demonstrated distal to the brachial plexus.  Late signs include muscle wasting (particularly supraspinatus and deltoid) and sympathetic vasomotor changes. Referral for further medical assessment is appropriate.
• BCG lymphadenitis, osteitis and disseminated BCG disease – regional lymphadenitis with oedema and tenderness on palpation of lymph nodes (25-327 per million doses) may develop 2-6 weeks after BCG immunisation and usually resolves spontaneously within several months. Surgical drainage of lymphatic sterile abscesses should be avoided. Very rarely, disseminated BCG disease may occur, including osteitis, lupus vulgaris, erythema nodosum, iritis, and fatal disseminated BCG disease in immunocompromised patients. This is more common in patients with defects in cell-mediated immunity (severe granulomatous disease, severe combined immunodeficiency, DiGeorge syndrome, interferon-gamma receptor deficiency, HIV). Unresolved lymphadenitis and disseminated BCG disease requires systemic anti-tuberculous therapy. Surgical intervention is only recommended for BCG osteitis.
• Aseptic meningitis – This is a relatively common adverse reaction (~1 in 10,000) with the Urabe strain of mumps vaccine. However, it probably does not occur, or if it does occurs very rarely,  with the more widely used Jeryl-Lynn and related strains of mumps vaccine. It is found after about 1 in a million doses, but this may represent the background rate and not be a true vaccine reaction. Episodes are usually self-limiting and resolve within 5-14 days. Beware of coincidental bacterial meningitis – keep a high level of suspicion and  refer for further medical  assessment.
• Immune Thrombocytopaenic Purpura - rarely (1 in 30000 doses) occurs 15-35 days after MMR immunisation. This manifests as a palpable petechial rash. Hypertension, bradycardia, asymmetrical neurological findings, pinpoint pupils and disturbances of balance and gait may be indicative of secondary intracranial haemorrhage in very severe cases. Medical referral is advised. Re-vaccination in moderate to severe cases is contraindicated. In mild cases, subsequent doses should only be considered in individuals who show no evidence of seroconversion. 
• Guillain-Barre Syndrome – probably related to influenza vaccination with a risk estimate of less than 1 in 1 million doses. Patients typically present with weakness, pain, ataxia, sensory abnormalities and areflexia of varying degrees and distribution. Autonomic manifestations may include orthostatic hypotension, pupillary dysfunction, urinary retention, sweating and tachycardia. Adults are at increased risk of cranial nerve involvement and the development of respiratory muscle paralysis, with secondary complications of pneumonia, sepsis and pressure ulcers. Symptoms develop and progress over a period of several weeks and may follow an episode of mild illness. Most patients will recover (mean recovery time 7 months). A previous episode of GBS (vaccine-induced or otherwise) is not an absolute contraindication to further doses of influenza vaccine. The risk of GBS versus the benefits of subsequent annual influenza immunisation should be weighed carefully.
• Encephalopathy and Encephalitis - Measles-containing vaccines are associated with these events in about 1 per million or fewer cases, which may represent a background rate. However, there is some limited evidence that suggests a causal relation, and particularly if the vaccine has been inadvertently given to an immunocompromised recipient. It presents similarly to meningitis but may also involve focal neurological signs, reduced consciousness and reduced respiration rate. Associations between pertussis-containing vaccinations and encephalopathy (including encephalitis, seizures and mental retardation) continue to be debated. It is possible that they occur at a rate of less than 1 per million doses, however, study findings are inconclusive and no specific form of encephalopathy has been associated with pertussis vaccination. Specialist referral during the acute stage of illness is required. Encephalopathy within 7 days of DTP, DTPH or DTaP vaccination is a contraindication to further doses.  
  

Reporting Adverse Events