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Dealing confidently with reactions to first immunisations

arental anxiety about childhood vaccines has never been greater. GPs have a tough enough time convincing parents to accept the MMR vaccine at 13 months. But the job of 'persuader' feels almost impossible if an infant reacts badly to an uncontroversial vaccines at the start of the primary immunisation programme.

Clarity about possible causes of adverse reactions, and clear communication with parents, can go a long way to restoring parental faith in the immunisation programme.

Typical reaction to DTP-Hib

A baby receives its first set of primary immunisations. During evening surgery you get a call from the parents saying that since early afternoon the baby has been screaming uncontrollably, won't feed and that both injection sites are red and swollen ­ what should they do?

You arrange to see the baby who is crying and obviously very upset: the injection site in the left thigh where DTP-Hib was administered is red and swollen with induration extending circumferentially from the hip to the knee: there is a small 1cm diameter erythematous lesion at the Men C site. Baby's axillary temperature is 36.5°C: at the time of immunisation the temperature was recorded as 36.1°C. You recommend six-hourly paracetamol.

But by 9pm there is no change and the parents take the child to A&E.

Facing the parents

The child is admitted to the paediatric unit for observation and started on ibuprofen with good effect so that by 2am they are less irritable and have taken one feed. Baby continues to improve and is discharged later that day apyrexial and with only minimal swelling at the vaccine site: 48 hours later the induration has disappeared although a small hard nodule remains.

The parents come to see you a week later and say the episode really upset and worried them. They ask what caused it and if

the baby will be okay to have the next two doses. How do you respond and what would you recommend?

How common are these reactions?

As many as two in five infants experience minor fever, irritability and local tenderness following primary immunisations. These are generally simply managed with paracetamol.

Very infrequently, as the scenario illustrates, more worrying adverse events may occur. These can usually be managed in the same way (with hospitalisation rarely required) but may raise parental concerns about subsequent vaccinations.

Are the symptoms vaccine-related?

The first key question is whether this baby's signs and symptoms were related to vaccination. In this scenario the answer is clearly Yes, given there was a visible reaction at an injection site within two or three hours of immunisation. The time interval between event onset and the alleged cause is important when attributing causality. If the baby had presented 72 hours later with more systemic features, then other diagnoses (like an intercurrent infection) would have to be considered.

Trauma or inflammation?

Having identified this as an adverse vaccine event and reported it through the Yellow Card system, you should question the likely cause. Appearance gives some clues ­ the baby had an extensive local reaction with circumferential induration involving the joint above and below the injection site. Trauma could be an explanation, for example a haematoma, but the features are far more suggestive of an inflammatory reaction ­ red, swollen, tender and hot.

Identifying the cause

Identifying the vaccine component or components that might have caused an acute inflammatory reaction is more complicated than would first appear. Modern vaccines contain antigens, a delivery system and an adjuvant, together with various other excipients including carrier proteins (with conjugate vaccines), preservatives, antibiotics and contaminants from the manufacturing process. A number of these are capable of causing inflammation when injected.

Potential culprits

The baby was given DTP-Hib at the site that became inflamed. This combination vaccine contains two toxoid antigens (diphtheria and tetanus), a polysaccharide antigen derived from the capsule of Haemophilus influenzae type b conjugated to a carrier protein (a very small amount of tetanus toxoid) and killed Bordetella. Pertussis organisms. These antigens are adsorbed on to crystals of aluminium hydroxide, which act as both the delivery system and the adjuvant. Thiomersal is the preservative, tris is the buffer and there are trace amounts of sucrose. How do any of these cause the adverse local events experienced by this baby?

A potent activator of the innate immune response

Injected vaccine antigens are phagocytosed by macrophages in the skin, subcutaneous tissues and muscle. These cells perform a sentry function for the innate immune system, and recognition of foreign antigen (in this case the vaccine) causes recruitment of neutrophils through cytokine release. Endotoxin, a constituent of some microbes, is a particularly potent activator of the innate response. Since endotoxin is also found in whole-cell whooping cough vaccine, this could have been one cause of the baby's inflammatory reaction.

When poor storage is to blame

Aluminium salts have been used both as delivery systems and adjuvants for many years. Adsorbing antigens on to the crystal delivers them more effectively to the cells of the adaptive immune system, generating protective antibodies and memory cells, improving the quality of the response (the adjuvant effect). Aluminium salts can give acute inflammation at the injection site if the vaccine was stored in conditions which caused the crystals to flocculate ­ freezing does this. Domestic fridges are unsuitable since they cycle and drop the temperature below freezing.

Type III reactions

A third mechanism involves pre-existing antibodies in tissue complexing with their antigen when released from the vaccine and causing an acute inflammatory response by attracting neutrophils and activating complement.

So-called Type III or Arthus reactions can occur after any of the three primary immunisations, although they are more usual after the third (if the baby has produced high antibody levels after the second dose) or following the first injection if large amounts of antibody have been passed across the placenta from the mother. Transfer usually starts at about 17 weeks' gestation, with tetanus the antibody most usually passed.

Local reactions can be very large, occur within a few hours of vaccination and are associated with high maternal tetanus titres.

Delayed hypersensitivity reaction

A final possible explanation for the local reaction this baby experienced is a delayed type hypersensitivity reaction (DTH), or type IV. The mechanism is analogous to the Arthus reaction but involves T lymphocytes being exposed to the antigen to which they have been sensitised ­ a positive tuberculin test is a good example of a DTH response.

Distinguishing between causes

Is it possible to tell which of these four mechanisms are responsible for this baby's acute inflammatory response? Appearance, time of onset, presence of systemic features, vaccine dose and knowledge of how your vaccines are stored give clues. If this reaction followed the first dose, it cannot be a DTH reaction since

T cells do not cross the placenta. A normal temperature or other systemic features (in the absence of pre-administered paracetamol) is less likely than when endotoxin is the cause. Correct storage of vaccine between 2-8°C

generally precludes a reaction to the aluminium.

When to use the Green Book

Distinguishing between causes (particularly an Arthus reaction and endotoxin induced acute inflammation) is not always possible from history and examination (especially if more than one mechanism was involved). This is the time to reach for the Department of Health's Green Book, an excellent source of general immunisation advice available on its website.

For management of serious adverse events (serious local reactions, convulsions or encephalopathy within 72 hours, a temperature above 39.4°C, persistent crying for more than four hours or prolonged non-responsiveness) it makes no specific recommendations but advises GPs to seek help from their local specialist on immunisation ­ usually a paediatrician or district immunisation co-ordinator.

Given the extensive nature of this local reaction and the

parents' concerns, this clearly would be a desirable course of action for this baby.

What to expect from the specialist

Your local specialist's advice will depend on what they think has caused this reaction. Preliminary research shows there is no one preferred management approach. Sherwood1 and colleagues from the University of Manchester and the Health Protection Agency found a majority of specialists would recommend replacing the whole cell pertussis with the acellular version, but significant numbers would either exclude pertussis altogether (and

continue with DT, Hib, Men C and OPV), or carry on the programme as normal.

A very small number would advise stopping the programme altogether, and one or two would assess immunological correlates of protection and immunise accordingly. Unfortunately there is no data on the success of any

of these approaches and Sherwood concluded that there was an urgent need for a trial of different management options.

Bearing in mind the lack of consensus among paediatricians about managing severe local reactions it would be useful

to discuss various options with your district's immunisation expert.

The recent increase in cases of Hib septicaemia and meningitis should be borne in mind as these could rise further if whole-cell pertussis vaccine is either excluded from the primary programme or replaced with acellular pertussis.

After analysing the event a session with the parents would be needed to see what they want to do. With detailed advice and support it should be possible to complete a programme that safely and optimally protects the baby.

Some local specialists may even offer a short period of observation after the next set of immunisations.

A properly-handled observation can be positive and reassuring without creating dependency and 'medicalisation' of what is one of the safest and most effective preventive programmes carried out in primary care.

Vaccine types used in the infant immunisation programme

The programme comprises diphtheria/tetanus/pertussis/ Haemophilus influenzae b (Hib)/Meningococcal C (Men C)/ and oral polio vaccines given at two, three and four months.

Diphtheria and tetanus are toxoid vaccines, Hib and Men C are subunit conjugate vaccines, pertussis is a killed whole-cell vaccine and polio is a live attenuated preparation containing viral strains I, II and III.

Reactions to vaccines are traumatic for all concerned ­ Dr David Baxter offers advice

on how to win back parents' confidence

Dealing confidently with reactions to first immunisations

Dealing confidently with reactions to first immunisations

Some specialists offer observations after the next

set of immunisations~

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