Clinical Pharmacology

"Adverse Drug Event of the month"

Probable DPT induced Generalized Tonic Clonic seizure

A one and half-year-old male child presented to the paediatric outpatient department of our institute with history of one episode of a seizure. He had received the booster dose of Diphtheria-Pertussis-Tetanus (DPT) vaccine at 14.30 hours in the afternoon (in this paper, day 1 is taken as the day on which DPT vaccine was received by the patient) the same day he developed fever with running nose at 17.00 pm. At 21.00 pm, he had an episode of generalized tonic clonic seizure with uprolling of eyeballs, frothing at mouth and involuntary passage of stools. The episode lasted for 2 minutes and was not followed by any post-ictal phenomenon in the form of altered sensorium or neurological deficit. Patient had received 3 doses
of DPT vaccine in 6, 10 and 14 weeks without any convulsions.

The seizures were treated with injection diazepam that was administered intra-venously. During hospitalization, he was given syrup paracetamol ¾ teaspoonful wherever axillary temperature exceeded 38⁰C. Laboratory investigations revealed haemoglobin concentration of 10.5gm%, total WBC count of 16,300/cm³. Serum concentrations of sodium and potassium were 120 and 4mEq/L respectively. Random blood Glucose level was 86mg% while serum level of alkaline phosphate was 10.72 IU/L. The peripheral smear did not demonstrate any malaria parasites. The patient did not have any seizures after admission and was discharged without any signs or symptoms of seizure on day 4.

Using the Naranjo’s, adverse drug reactions (ADR) probability scale we made a causality assessment, which categorized this reaction as probable (a score of 6 was obtained). The Naranjo’s algorithm categorises adverse reactions as definite (score > 9), probable (score between 5- and 8), possible (score 1-4) and doubtful (score < 1).(Naranjo C.A., et.al, 1981) DPT vaccine consists of diphtheria and tetanus toxoids and pertussis vaccine consisting of killed organisms. As the pertussis component consists of whole cell killed organisms, the pertussis vaccine is also known as whole cell vaccine and designated as wP. It is a combination vaccine and a single injection provides immunity against three important killer diseases namely, diphtheria, pertussis and tetanus. In addition, the pertussis component in DPT vaccine enhances the potency of the diphtheria toxoid. The composition of the vaccine is shown in Table 1.The vaccine is highly immunogenic and offers significant long-term protection. Two types of DPT vaccines are available: plain and adsorbed. Adsorption is usually carried out on a mineral carrier like aluminium phosphate or hydroxide. Studies have shown that adsorption increases the immunological effectiveness of the vaccine. (Park K., 2002).

It has been shown that young infants respond well to immunization with potent vaccine and toxoids even in the presence of low to moderate levels of maternal antibodies. Hence, primary immunization is commenced at 6 weeks of age and 3 doses are provided at an interval of 4 weeks (Table. 2 and Table 3). Booster vaccination of DPT is administered at 18 months of age. The second booster vaccination is given at 5 years of age. However, at this age only DT (Diphtheria and Tetanus), toxoid is used and pertussis component is not provided. This is done in the belief,that at age over 5 years pertussis infection does not pose a great threat to life but risk of serious complications associated with pertussis component is disproportionately higher.

The administration of any dose is contra-indicated in the presence of severe illness requiring hospitalisation, shock-like state, uncontrolled seizure disorder and progressive neurological disease. Cerebral palsy and febrile seizures are not progressive neurological disease and hence children with any of these disorders should not be deprived of DPT vaccination. Similarly, presence of minor illness such as mild fever, cough and loose motions do not contra-indicate administration of a DPT dose[^2]. The vaccine should be administered deep intra-muscularly as it contains mineral carrier or adjuvants. In infants and younger children, the vaccine is given in the antero-lateral aspect of the thigh and in older children it is given in the deltoid. It should not be administered in the buttocks, as there is always a chance that the vaccine would get injected in the abundant gluteal fat. In addition, injection at this site is associated with a risk of injury to the sciatic nerve. Fever and mild local reactions are the common side effects that follow immunization.

It is estimated that 2 to 6% vaccinees develop fever of 39⁰C or higher, and that 5-10% of vaccine recipients experience swelling, induration and pain lasting for more than 48 hours. Hypersensitivity reaction, hypotensive-hyporesponsive shock and post-vaccination encephalopathy are the most dreaded complications associated with DPT vaccine. Neurological complications are thought to be primary due to the pertussis component of the vaccine and the estimated risk is 1:1,70000 doses administered.

Encephalopathy manifests with alteration of sensorium or generalized or focal seizures that persist for more than a few hours. Occurrence of hypotensive-hyporesponsive shock or post-vaccination encephalopathy is a contra-indication of further doses of the pertussis component. This should be explained to the guardians. Other manifestations that indicate occurrence of encephalopathy include: seizures with or without fever occurring within 3 days of immunization and persistent, severe, inconsolable screaming or crying for 3 or more hours within 48 hours of immunization. Usually, these are not associated with permanent sequels. Previously, occurrence of these events also meant withdrawal of pertussis component from doses to be received in future. However, it is now recommended that all factors should be considered while advising regarding DPT vaccination in future in these children.

Association of severe reactions made the whole- cell pertussis vaccine highly unpopular among many communities and countries and spurred research for safer vaccines. Some European countries even went to the extent of withdrawing (whole-cell) pertussis vaccination; only to find an increased incidence of and increased morbidity due to pertussis amongst infants and young children in the community. An acellular pertussis vaccine (Designated as aP) is now available. It contains purified, inactivated components of B. pertussis. The acelluar vaccine is as potent as the whole cell vaccine, but it is still associated with neurological complications described with whole-cell vaccine, albeit at a much lower frequency. It is also credited with lesser incidence of local side effects as well as decreased incidence of severe reactions like seizures and hypotensive episodes. However, the vaccine is expensive and it is unlikely that it would be included in the Indian National immunization schedule in near future.

References:

1. Khubchandani RP (1999). Immunization. In: API Text Book of Medicine 6th edition, Saini GS(ed), Mumbai, pp.1136.

2. Naranjo C.A., Busto U., Seller E.M., Sandor P., Ruiz I., Roberts E.A., Janecek E., Domecq C. & Greenblatt D.J. (1981).
A method for estimating the probability of adverse drug reaction. Clinical pharmacology & therapeutics 30: 239-245.

3. Park K. (2002). Epidemiology of Communicable diseases. In: Preventive and Social Medicine, 17th edition, (India),pp.126.

4. Committee on Immunization, Indian Academy of Pediatrics. IAP Guidebook on Immunization second edition. Mumbai, Indian Academy of Pediatrics,2001 P 47.


Adverse event reported by:
Department of Pediatrics,
Seth GS Medical college,
KEM Hospital,
Parel,
Mumbai- 400012.
India.