Clinical Pharmacology

"Adverse Drug Event of the month"

Probable Diphtheria Pertussis Tetanus (DPT) vaccine induced encephalopathy and death


Case report:

A 3-month-old male child weighing 3.7 Kg presented to the emergency unit of this hospital with decreased activity and labored breathing since the morning of 1/05/05. He had received first dose of DPT vaccination 24 hrs back. Within 5 hrs of receiving the dose he developed fever, excessive crying and reduced spontaneous activity. He was seen in a private clinic and at our hospital and was noted to have no significant abnormality. Patient was sent home with an advice to take syrup Ibuprofen. After that the patient was asymptomatic, his previous complaints subsided and he was taking feeds normally during the intervening period the patient till next day morning when he developed labored breathing. On admission to the hospital, his heart rate was 140/min, blood pressure 76/50mmHg and was afebrile with good perfusion. On central nervous system examination his sensorium was E4 M4 VE1 according to Glasgow coma scale, his pupils were bilaterally equal in size and were sluggishly reacting to light. Superficial reflexes and deep reflexes were normal and there were no signs of meningeal or cerebellar involvement. Other systemic examination revealed normal findings. He was intubated immediately and was given intermittent positive pressure ventilation (IPPV) and external cardiac message. There was a history of generalized tonic clonic convulsions with up rolling of eyeballs without frothing at mouth after admission lasting for 10 seconds.

Laboratory investigations done on the day of admission revealed a hemoglobin concentration of 7.8gm% and total leukocyte count of 45,800/mm3. Serum concentrations of sodium and potassium were 136 and 6.6mEq/L respectively. The peripheral smear did not demonstrate any malaria parasites.

He was treated with intravenous antibiotics, intravenous Phenobarbitone, Vitamin D and intravenous Calcium Gluconate. On follow up, he was weaned off the ventilator and extubated on 10/05/05 His laboratory investigations at day 11 were hemoglobin of 11.6 gm%, total leukocyte count of 18,800/mm3 platelet concentration 80,800. Serum concentrations of sodium and potassium were 138 and 4 mEq/L respectively. Arterial blood gas concentrations were in normal range, Blood urea Nitrogen was 15mg%. On 25/5/05 patient's condition deteriorated suddenly and he died of respiratory failure. The parents of the child did not permit a post mortem.

Just before death, his laboratory investigations revealed hemoglobin concentration of 9.8%, leukocyte count 7900/mm3 platelets were adequate. Serum concentrations of sodium and potassium were 128 and 4.8 m Eq/L respectively and blood urea nitrogen was 9mg%.
Arterial blood gas concentrations revealed pH 7.4, PCo2- 21.6, Po2 -16.3, HCo3 28.7, RBS 99 mg%.

Discussion:
Using the Naranjo's Adverse Drug Reactions (ADR) probability scale we made a causality assessment, which categorized this reaction as possible (Score 3). The Naranjo's algorithm categorizes adverse reactions as definite (score > 9), probable (score between 5- and 8), possible (score 1-4) and doubtful (score < 1) (Naranjo et.al, 1981) The DPT vaccine consists of diphtheria, tetanus toxoid 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 aluminum phosphate or hydroxide. Studies have shown that adsorption increases the immunological effectiveness of the vaccine (Park K, 2002). Recently newer Acellular Pertussis vaccine is also available for use in India.

Status of Acellular Vaccine in India:

The Indian Academy Of Pediatrics Committee on Immunization (IAPCOI) endorses the continued use of whole cell pertussis vaccine (as DPT) because of its proven efficacy and safety. Acellular pertussis vaccines may undoubtedly have fewer side-effects (like fever, local reactions at injection site and irritability), but this minor advantage does not offset the inordinate costs involved in the routine use of this vaccine. Acellular pertussis vaccines are also, by no means, more effective than the whole cell pertussis vaccine. These are, therefore, not recommended for universal immunization in our country at present. There is, however, no bar to offering these vaccines to children from well-off families who opt for the prohibitive costs for the slight advantage of fewer minor side-effects (5). Use of acellular pertussis vaccine should, however, be considered in children who have had significant reactions to a previous dose of whole cell pertussis vaccine. These include:

(i) convulsions with/without fever occurring within 3 days.

(ii) persistent inconsolable crying for 3 or more hours within 48 hours.

(iii) collapse or shock-like state within 48 hours.

(iv) temperature >40.5 ºC within 48 hours.

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(Lf: Loeffler units)

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 given at an interval of 4 weeks. 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 greater than 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 hospitalization, shock-like state, uncontrolled seizure disorder, excessive crying with fever > 3 hours and progressive neurological disease. Presence of minor illness such as mild fever, cough and loose motions do not contra-indicate administration of a DPT dose [2]. The vaccine is administered deep intra-muscularly as it contains mineral carrier or adjuvants. Fever and mild local reactions are the common side effects that follow immunization.

Probable Mechanism of DPT vaccine induced neurological damage:

In implicating pertussis vaccination in the evolution of subsequent neurological residua, a careful consideration of the mechanism for vaccine-induced brain damage plays an important supporting role. Pertussis toxin has been shown to alter cellular signaling. It also affects the catecholaminergic and GABAergic systems in the brain. In addition, a direct, endotoxin-mediated attack on the endothelial cells could create a local defect of the blood-brain barrier. It is being seen that a combination of one or more bacterial toxins, asphyxia, Co2 retention and loss of cerebral autoregulation is responsible for neurological symptoms.

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 sequel. 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 in several countries including India. It contains purified, inactivated components of B. pertussis. The acellular 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.

Errors which can lead to Adverse events following immunization

• Too much vaccine given in one dose · Improper immunization site or route
  
  
• Syringes and needles improperly sterilized
  
  
• Vaccine reconstituted with incorrect diluents
  
  
• Wrong amount of diluents used
  
  
• Drug inadvertently substituted for vaccine or diluent
  
  
• Vaccine prepared incorrectly for the use, e.g. an adsorbed vaccine not been shaken properly before use
  
  
• Vaccine or diluent contaminated
  
  
• Vaccine stored incorrectly
  
  
• Vaccines are not standardized between manufacturers.
  
  
• Contraindications ignored, e.g. a child who experienced a severe reaction after a previous dose of DTP is immunized with the same vaccine Inattention when reading labels on vials resulting in mistaken content.
  
  
• Reconstituted vaccine not thrown out at the end of an immunization session and used at a subsequent one.