Reasons for misleading information about rates

Millions of doses of oral polio vaccine (OPV) may be administered during a national immunization day (NID) or week. If adverse events occur at the same rate as occur for the rest of the year, it could be anticipated that this will result in a more concentrated occurrence of AEFIs than usual, even if the rate stays he same. For instance, if the normal rate of sore arms following administration of DTP is twelve sore arms per 100,000 doses of DPT, and if a country gives on average 100,000 doses of DPT in one year, then we would expect those twelve sore arms to be reported over the year, approximately one per month. If now a national immunization day is carried out when 1 million doses of DTP are given in a week, we would expect 120 cases of sore arms to be reported in the week if the rate stays the same as usual. To the outside observer this might appear as an alarming outbreak of sore arms associated with the NID. In fact the rate is unchanged. This concept is important for programme managers to get across to staff, politicians and parents.

If we apply this idea to serious events such as paralysis following administration of oral polio vaccine (OPV) during or soon after NIDs, there is the potential for the situation to get out of hand. The rate of vaccine-related paralysis following administration of OPV is of the order of one case per 2-3 million doses administered. During the NIDs in China and India during 1996, around 160 million doses of OPV were administered in one week. It would not have been unusual to have had reported up to 50-80 cases of paralysis following the NIDs. In actual fact, very few cases were reported (some may have occurred but not been reported). Programme managers were aware of the expected rate and were able to monitor reports of AEFIs accordingly. It is important to balance the occurrence of the few cases of vaccine-associated adverse events with the much larger number of cases which would have occurred if the NID had not taken place.

Following an NID in a European country early in 1996, cases of paralysis were reported after they had received OPV. However, on laboratory analysis, the wild virus was found to be responsible for the cases. An outbreak had occurred at the same time as the NID and was confusing the picture. When the public was reassured by the Minister of Health and the President that a reliable external laboratory had performed the tests, a second NID was undertaken and successfully stopped more cases of polio from occurring.

Reconstitution

Most of the AEFIs reported can be linked to improper handling of measles or BCG vaccine when the administration of vaccine had been contaminated during handling and stored until a subsequent immunization session, or to the reconstitution of vaccines with an inappropriate diluent.

In some health centers and hospitals many potentially dangerous medications are kept in the same refrigerator in which vaccines are stored. These medications are packed in similar vials or ampoules to vaccines or their diluents and may be used by mistake for reconstitution of EPI vaccines. This probably happened in two countries where muscle relaxant drugs (pavulon or anectine) were incriminated. The onset of symptoms was rapid in these cases, occurring within minutes with cyanosis, hypotonia, dyspnoea or apparent shock symptoms. The affected children had "hypersalivation", most probably due to inability of swallowing saliva because of pharyngeal and throat muscles paralysis. In one country, investigation of urine revealed a metabolite of succinyl choline. Most of these paralyzing agents are excreted in the urine over the period of hours and urine should be collected from suspected patients.

Unsterile procedure during reconstitution of vaccines and/or storing and using reconstituted vaccine over a number of immunization sessions results in administration of contaminated vaccine. BCG vaccine has no preservative at all and measles vaccine can contain only traces of antibiotics. Therefore, rapid multiplication of the infecting pathogen can take place, especially when reconstituted vaccine is kept outside of refrigerator. Contamination of re-
constituted measles vaccine with Staphylococcus aureus has been documented in two countries. Similar incidents have been reported in India. Children immunized with contaminated vaccines become sick within a few hours; local tenderness and tissue infiltration, vomiting, diarrhoea, cyanosis and high temperature were the most frequent symptoms.

Events were usually associated with immunization from one vial, while many other doses of the same lot were administered in the same or other countries with no reactions. These incidents, which resulted in needless deaths or life threatening illness, as well as damage to immunization programmes, are completely preventable if proper reconstitution of vaccines and proper handling procedures are followed.

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Real-life case histories from the field

Some vaccines used in immunization programmes, such as measles, BCG, and yellow fever vaccines, are provided in lyophilized (freeze-dried) form and must be reconstituted before use with a diluent provided by the manufacturer. This is an opportunity for programmatic errors to occur in the handling of the
vaccine. Below are presented adverse events reported to the WHO in the last decade which have been attributed to errors in reconstitution and handling of lyophilized vaccines.

Country 1. In 1987, four separate AEFI clusters were registered with 3, 2, 5 and 4 cases, respectively, of "collapse" that occurred up to five minutes following immunization with measles vaccine. All 14 cases presented with hypotonia; 11 became pale; seven cases had cyanosis, dyspnoea and increased saliva secretion; three patients had depressed respiration and one patient died; others recovered in less than one hour. All involved clinics were visited. In two of the clinics vials that contained succinyl choline (anectine) and pancuronium bromide (pavulon) were found stored with vials containing vaccine and diluent. Vials containing pavulon and diluent were same size and shape; labels on a number of vials recovered could not be read.

Infra-red spectrophotometry of the urine of one of the cases revealed a metabolite of succinyl choline and thin layer chromatographic analysis of vaccine from one of the implicated vials showed the presence of pavulon.

Country 2. In one hospital in September 1992, five neonates collapsed a few minutes following immunization with BCG and OPV. Neonates were one day (1), two days (3) and five days (1) old. They had been vaccinated at the maternity ward with BCG and oral polio vaccine within a two to five minute period. The first vaccinated child collapsed three minutes after vaccination with cyanosis and apparent shock. The physician indicated that the child had had a cardiac arrest and he resuscitated it with intra-cardiac injection of adrenaline and intramuscular hydrocortisone. Subsequently, the other four neonates collapsed with similar symptoms. Three were resuscitated and one died. The medical records of the mothers of the five neonates had no significant findings. All neonates were being breast fed. The nurse who gave the vaccines was a highly qualified nurse-midwife; however, she had been assigned only a month earlier to the maternity ward where BCG vaccines were given and may have needed more training in immunization practices.

In the hospital clinic, the following drugs were found in the refrigerator in which vaccines were also kept: pancuronium chloride, suxamethonium bromide and insulin. All incriminated BCG ampoules had been emptied and no further analysis was done. The hypothesis was that the vaccine had been reconstituted with a muscle relaxant which caused the reactions.

Country 3. Three children aged one to two years received measles vaccine on 12 November 1993 at the same centre, and within about one-half hour showed symptoms of fever, vomiting, and diarrhoea,. One of the children recovered, while the other two children died 15-17 hours after vaccination. No other information was available, and there were too few details to understand the cause.

Country 4. Three infants died in early April, 1995 after administration of measles vaccine. Symptoms, developing within five hours post immunization, were fever, rash, vomiting, and diarrhoea, described by the attending health worker as "toxic shock syndrome." Reconstituted vaccine was routinely kept until it was used, and syringes were never sterilized, but washed with ordinary water and wiped with cotton wool. No testing could be done.

Country 5. Four children died and a fifth was hospitalized after receiving measles vaccine from the same vial on 2 February 1995. 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. Penicillin-resistant Staphylococcus aureus was cultivated from the incriminated vial. The same lot of measles vaccine has been distributed in more than 50 000 multi-dose units in four different countries, without reports of adverse events.

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WHO/GPV Recommendations to minimize AEFIs

Measles and BCG vaccines must be reconstituted only with the diluent supplied by the manufacturer;

Reconstituted vaccines must be discarded at the end of each immunization session and NEVER retained for use in subsequent sessions;

In the refrigerator of the immunization center, no other drugs and substances shouldbe stored beside vaccines;

Training of immunization workers and their close supervision to ensure that proper procedures are being followed are essential to prevent of deaths or injury following immunization;

Careful epidemiological investigation must be carried out in the event of an adverse events  following immunization. Complete investigation of AEFI is of critical importance to pinpoint the cause of the incident and to correct immunization practices.