Monitoring and investigation of complications from immunizations

Monitoring of post-vaccination complications (PVO) is a system of continuous monitoring of the safety of MIBPs in the conditions of their practical use. The objectives of monitoring are also to determine the nature and frequency of complications after vaccination for each drug and factors contributing to the development of complications after vaccination. WHO considers the investigation of complications after vaccination as a means of increasing public confidence in vaccination and increasing its coverage of the population.

The similarity of many adverse reactions of vaccination with pathology not related to vaccinations, its uncritical assessment discredits vaccination programs. But to identify unknown complications after vaccinations, it is important to take into account unusual types of pathology in the post-vaccination period. Thus, in Russia in 2000, due to allergic reactions, the use of the sorbed inactivated liquid tick-borne encephalitis vaccine was discontinued.

WHO recommends the primary recording of all adverse events in the post-vaccination period with subsequent decoding of their possible connection with immunization. All fatal cases, all cases of hospitalization, all other conditions that doctors or the population suspect of being connected with vaccination are also recorded. Monitoring includes several consecutive steps:

• supervision of the safety of domestic and imported MIBPs by identifying adverse events after their use;
• epidemiological investigation and data analysis, adjustments and other actions;
• final assessment; determination of factors that contributed to complications after vaccination.

Monitoring of complications after vaccination is carried out at the district, city, regional, territorial, republican levels, in healthcare organizations of all types of ownership. It is necessary to determine those responsible for monitoring and familiarize primary care and hospital health workers with it, to whom patients turn in the days and weeks after vaccination. It is important to instruct the parents of vaccinated children and adults about the conditions for which they should seek help. The quality of monitoring is assessed taking into account the timeliness, completeness and accuracy of registration, the efficiency of the epidemiological investigation, the effectiveness of the measures taken and the absence of a negative impact of an adverse event on the level of population coverage with vaccinations.

Complications after vaccination include severe and/or persistent health problems:

1. Anaphylactic shock.
2. 'Severe generalized allergic reactions (recurrent angioedema - Quincke's edema, Stevens-Johnson syndrome, Lyell's syndrome, serum sickness syndrome, etc.).
3. Encephalitis.

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Monitoring complications after vaccination

1. Vaccine-associated poliomyelitis.
2. Lesions of the central nervous system with generalized or focal residual manifestations leading to disability: encephalopathy, serous meningitis, neuritis, polyneuritis, as well as with clinical manifestations of convulsive syndrome.
3. Generalized infection, osteitis, osteitis, osteomyelitis caused by BCG.
4. Chronic arthritis caused by rubella vaccine.

Adverse events in the post-vaccination period recommended by WHO for registration and monitoring

Local reactions:

• abscess at the injection site: bacterial, sterile;
• lymphadenitis, including purulent;
• severe local reaction: swelling outside the joint, pain and redness of the skin for more than 3 days or the need for hospitalization.

Adverse reactions from the central nervous system:

• acute flaccid paralysis: all acute flaccid paralysis, including VAP, Guillain-Barré syndrome (except isolated facial nerve paresis);
• encephalopathy: seizures with impaired consciousness for 6 hours or more and/or significant changes in behavior for 1 day or more;
• encephalitis occurring within 1-4 weeks after vaccination: the same signs as with encephalopathy + CSF pleocytosis and/or virus isolation;
• meningitis;
• convulsions: without focal signs - febrile and afebrile.

Other adverse reactions:

• allergic reactions: anaphylactic shock, anaphylactic reaction (laryngospasm, angioedema, urticaria), skin rashes;
• arthralgia: persistent, transient;
• generalized BCG infection;
• fever: mild (up to 38.5°), severe (up to 40.0°) and hyperpyrexia (above 40.0°);
• collapse: sudden pallor, muscle atony, loss of consciousness - 1st day;
• osteitis/osteomyelitis: after BCG after 6-16 months;
• prolonged crying/screaming: more than 3 hours;
• sepsis: with the release of the pathogen from the blood;
• toxic shock syndrome: develops within a few hours and is fatal within 24-48 hours;
• other serious and unusual disorders within 4 weeks after vaccination, including all cases of death in the absence of other causes.

Information on post-vaccination complications is subject to state statistical accounting. When a diagnosis of post-vaccination complications is established, a complication after vaccination is suspected, or an unusual reaction occurs, the doctor (paramedic) is obliged to provide assistance to the patient, including timely hospitalization. He/she must also register this case in a special registration form or in the infectious diseases registration log (form 060/u) on specially designated sheets of the log (with subsequent clarifications).

List of diseases subject to registration, investigation and information to higher authorities of the State Sanitary and Epidemiological Surveillance

Diagnosis	Time after administration of vaccines:
	DPT, ADS, other inactivated vaccines and MIPs	Measles, mumps and other live vaccines
Abscess at injection site	Up to 7 days
Anaphylactic shock, reaction, collapse	The first 12 hours
Generalized rash, erythema multiforme exudative, Quincke's edema, Lyell's syndrome, other severe allergic reactions	Up to 3 days
Serum sickness syndrome	Up to 15 days
Encephalitis, encephalopathy, encephalomyelitis, myelitis, neuritis, polyradiculoneuritis, Guillain-Barré syndrome	Up to 10 days	5-30 days
Serous meningitis	10-30 days
Afebrile seizures	Up to 7 days	Up to 15 days
Acute myocarditis, acute nephritis, thrombocytopenic purpura, agranulocytosis, hypoplastic anemia, systemic connective tissue diseases, arthritis	Up to 30 days
Sudden death, other fatal cases temporally related to vaccinations	Up to 30 days
Vaccine-associated poliomyelitis:
in vaccinated	Up to 30 days
In contacts with a vaccinated person	Up to 60 days
Complications after BCG vaccinations: lymphadenitis, including regional, keloid scar, osteitis and other generalized forms of diseases	Within 1.5 years

All data are entered into the development history of the newborn (form 097/u) or child (form P2/u), the medical record of the child (form 026/u), outpatient (form 025-87), inpatient (form 003-1/u), emergency medical service call card (form 10/u) or the person seeking anti-rabies care (form 045/u) and the vaccination certificate (form 156/u-93). Higher authorities are not informed about isolated cases of uncomplicated severe local (edema, hyperemia >8 cm) and general (temperature >40°, febrile seizures) reactions, as well as mild manifestations of skin and respiratory allergies.

The doctor (paramedic) is obliged to immediately inform the head doctor of the medical institution about the diagnosis (suspicion of) PVO. The latter, within 6 hours after the diagnosis is established, sends information to the city (district) center of Rospotrebnadzor and is responsible for the completeness, accuracy and timeliness of the records.

The territorial center of Rospotrebnadzor transmits an emergency notification of complications after vaccinations to the Rospotrebnadzor center in the constituent entity of the Russian Federation on the day the information is received, along with the batch number, during the use of which the frequency of severe reactions is higher than established.

If an unusual reaction (complication, shock, death) is detected after the use of MIBP, the center in the constituent entity of the Russian Federation sends a preliminary unscheduled report to Rospotrebnadzor of the Russian Federation. The final report is submitted no later than 15 days after the completion of the investigation. The investigation report for each case of an unusual reaction, both requiring and not requiring hospitalization (in the first case with a copy of the medical history) is sent to the L.A. Tarasevich State Investigative Committee (see below), which may additionally request medical documentation, and in the case of a fatal outcome - an autopsy report, histological preparations, blocks and a formalin archive. Information on the batch of the drug is also sent to the State Investigative Committee when its reactogenicity exceeds the limits specified in the instructions for use. Investigation reports on complications after BCG are also sent to the Republican Center for BCG Complications to BCG-M.

Investigation of post-vaccination complications

Clinical analysis

Each case of suspected complications after vaccinations that required hospitalization, as well as ended in death, must be investigated by a commission of specialists appointed by the chief physician of the Rospotrebnadzor center in the constituent entity of the Russian Federation.

There are no pathognomonic symptoms that would allow us to unambiguously consider a case to be a post-vaccination complication. All symptoms may be caused by an infectious or non-infectious disease that coincided with the vaccination, with which it must be differentiated using all available methods.

Most deaths are not caused by complications after vaccinations, but by diseases that could have been cured with proper diagnosis. Here are clinical criteria that are useful in investigating complications after vaccinations:

• general reactions with elevated temperature, febrile convulsions to the administration of DPT, ADS and ADS-M appear no later than 48 hours after vaccination;
• reactions to live vaccines (except for immediate-type allergic reactions in the first few hours after vaccination) cannot appear earlier than the 4th day and more than 12-14 days after the administration of measles, 36 days after the administration of OPV and 42 days after the mumps vaccine and tricyclic vaccines;
• Meningeal phenomena are characteristic of complications only after the administration of the mumps vaccine;
• Encephalopathy is not typical for mumps and polio vaccines and toxoids; it occurs extremely rarely after DPT, the possibility of developing post-vaccination encephalitis after DPT is currently denied;
• The diagnosis of post-vaccination encephalitis requires, first of all, the exclusion of other diseases that may occur with general cerebral symptoms;
• Facial nerve neuritis (Bell's palsy) is not a complication of vaccination;
• immediate-type allergic reactions develop no later than 24 hours after any type of immunization, and anaphylactic shock no later than 4 hours;
• intestinal, renal symptoms, cardiac and respiratory failure are not typical for vaccination complications;
• catarrhal syndrome can be a specific reaction only to measles vaccination - if it occurs within 5-14 days after vaccination;
• arthralgia and arthritis are characteristic only of rubella vaccination;
• Lymphadenitis caused by BCG most often occurs on the side of the vaccination, the lymph node is typically painless, and the color of the skin over the lymph node is usually unchanged.

For BCG osteitis, the typical age is 6-24 months, rarely older, the lesion is on the border of the epiphysis and diaphysis, local increase in skin temperature without hyperemia - "white tumor", swelling of the nearest joint, atrophy of the limb muscles.

Substantial help can be obtained from the sick person or his parents: about his state of health before vaccination, the time of appearance and nature of the first symptoms and their dynamics, the nature of reactions to previous vaccinations, etc.

When investigating any complication after vaccination, it is necessary to request the places of distribution of the advertised series about unusual reactions to its use and the number of vaccinated (or used doses). It is also necessary to analyze the appeals for medical care of 80-100 vaccinated with this series (within 3 days for inactivated vaccines, for live viral vaccines administered parenterally within 5-21 days).

In the development of neurological diseases, virological and serological testing for IgM antibodies is important, as well as paired serums (the 1st - as early as possible, and the 2nd - after 2-4 weeks) for influenza viruses, parainfluenza, herpes simplex virus, herpes virus type 6, enteroviruses (including Coxsackie, ECHO), adenoviruses, tick-borne encephalitis virus (in the endemic zone in the spring-summer period). When performing a lumbar puncture, cerebrospinal fluid (including sediment cells) should also be tested for vaccine viruses (in vaccinations with live vaccines). The material should be delivered to the virology laboratory frozen or at the temperature of melting ice.

In case of serous meningitis that developed after mumps vaccination or suspected VAP, special attention should be paid to the indication of enteroviruses.

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Investigation of fatal cases in the post-vaccination period

Processes in the post-vaccination period leading to fatal outcomes require a particularly detailed investigation to establish the true causes of death. Vaccination, like the introduction of other MIBPs, can be a provoking factor leading to the manifestation of a latent disease, decompensation of a chronic process, and also aggravation of ARI in the post-vaccination period.

The diagnosis of "post-vaccination encephalitis", which was common in the past, has never been confirmed by pathological examination (except for cases of infectious-allergic encephalitis after the administration of the anti-rabies vaccine "Fermi" with a residual amount of live fixed rabies virus). Modern anti-rabies vaccines do not lead to such complications.

In children vaccinated in the prodromal period of acute respiratory infections, intestinal infections, and congenital sluggish infections, acute conditions with hemodynamic disturbances in the central nervous system may occur in the post-vaccination period, caused by their generalization (influenza, herpes, Coxsackie A and B, ECHO viruses, salmonellosis, meningococcemia, etc.). Severe forms of post-vaccination pathology may occur against the background of immunodeficiency states, endocrine system lesions (for example, nesidioblastosis), and central nervous system tumors (gliomas and gliomatosis of the brain stem).

Another diagnosis often made in cases of death in the post-vaccination period is "anaphylactic shock", which is also extremely rarely confirmed by repeated examination. In adults, rare diseases are sometimes found in fatal cases, such as myocardial myoma, which led to death in the first day after the administration of ADS-AM toxoid.

Study of sectional material

Conducting an autopsy

Analysis of autopsy data allows to outline a plan for further investigation. Many years of experience in investigating fatal outcomes have shown that histological examination is the main one in making a diagnosis and establishing the causes of death. Therefore, the collection of material for histological examination should be as complete as possible and include organs that are not usually taken for microscopy (endocrine system organs, bone marrow, lymph nodes, including regional ones to the injection site, tonsils, skin and subcutaneous tissue with adjacent muscle at the injection site, all parts of the digestive organs, including the vermiform appendix, the main parts of the central nervous system, including the ependyma and choroid plexuses of the third ventricle, the central part and the inferior horn of the lateral ventricles; the latter is especially important in investigating cases associated with vaccination against measles and mumps to exclude ependymatitis and plexitis specific to these infections.

Organs examined for the presence of viral antigen

Infection	Organs for research
Flu, parainfluenza, adeno-, RS-virus	Lungs, bronchi, paratracheal and peribronchial lymph nodes, pia mater
Coxsackie B	Myocardium (left ventricle, papillary muscle), brain, diaphragm, small intestine, liver
Coxsackie A	Brain tissue, pia mater
Herpes type I	Myocardium, liver, brain
Measles	Trachea, bronchi, lungs, CNS, pia mater
Mumps	Trachea, bronchi, lungs, pia mater, brain, ependyma of the cerebral ventricles
Tick-borne encephalitis	Brain and spinal cord
Polio	Spinal cord
Hepatitis B	Liver
Rabies	Ammon's horn, brain stem
ECHO - viral	Myocardium, liver, brain

Histological examination

Fixation. The optimal size of the pieces is 1.5 x 1.5 cm, the fixative is 10% formalin solution. The brain and spinal cord are fixed separately, the ratio of the volume of the pieces to the amount of fixative is not less than 1:2. Fixed pieces of organs sent for repeated examination to the L.A. Tarasevich State Institute of Cardiology and Surgery should be numbered and marked, the number and types of organs should be noted in the accompanying documentation.

Preparation of histological specimens. Paraffin or celloidin sections are stained with hematoxylin and eosin; in case of CNS lesions, they are also stained according to Nissl; other methods are used if necessary.

Virological examination (ELISA). Immunofluorescence examination (ELISA) is performed by taking pieces of unfixed organs immediately after autopsy. ELISA preparations are imprints or smears of organs on a clean, well-defatted glass slide. The presence of a viral antigen in the tissues indicates the possibility of infection; the ELISA results are compared with pathomorphological data to make a final diagnosis. If possible, material is also taken for PCR and other available methods.

For differential diagnostics of rabies, the tissues of the Ammon's horn, trigeminal ganglion (located under the dura mater on the pyramid of the temporal bone), and submandibular salivary gland are additionally examined. Fixation and processing of the material are described in special instructions. Express ELISA diagnostics are mandatory: the rabies virus antigen is detected both by direct and indirect staining methods, preferably on cryostat sections. The antigen is detected in the cytoplasm of neurons and outside the cells along the conduction pathways. In other cellular elements: glia, vessels, etc., there is no glow.

Histological examination of the preparations, diagnosis, and preparation of the epicrisis are carried out in the department where the autopsy was performed. A copy of the autopsy protocol, the results of the histological and virological examination, the formalin archive, paraffin blocks, and finished histological preparations are sent to the L. A. Tarasevich State Scientific Institution of Cardiology, which sends a conclusion on the conducted studies to the institution where the autopsy was performed and to the Rospotrebnadzor Center in the constituent entity of the Russian Federation.

Control of claim series

The decision on further use of the claimed batch of MIBP or its repeated control is made by the L. A. Tarasevich State Inspectorate of Medical and Biological Products. To control the drug of the batch that caused complications after vaccinations, the following are sent to the State Inspectorate of Medical and Biological Products: inactivated vaccines and toxoids - 50 ampoules; measles and mumps vaccines - 120 ampoules; polio vaccine - 4 vials; rabies vaccine - 40 ampoules, BCG vaccine - 60 ampoules; tuberculin - 10-20 ampoules; anti-tetanus, anti-diphtheria and other serums - 30 ml.

Final conclusion on the investigation materials

Registration of complications after vaccinations, examination of materials, request for missing data, submission of summary data on PVO to Rospotrebnadzor is carried out by the L. A. Tarasevich State Institute of Investigation. The final conclusion on each case that required hospitalization or ended in death is made by the commission for examination of complications after vaccinations at Rospotrebnadzor of the Russian Federation, all materials of the L. A. Tarasevich State Institute of Investigation are submitted to the commission no later than 15 days after completion of the investigation, regardless of the presence or absence of its connection with vaccination. Rospotrebnadzor sends the commission's conclusion to the Federal Agency for Social Protection of the Population, and for foreign drugs - to the representative offices of the companies.