Monitoring and investigation of complications after vaccinations

Monitoring postvaccinal complications (PVO) is a system of constant monitoring of the safety of MIBP in the conditions of their practical application. The monitoring tasks are also to determine the nature and frequency of complications after vaccination for each drug and the factors contributing to the development of complications after vaccination. WHO is considering the investigation of complications after vaccination and as a means of increasing public confidence in vaccination and increasing its coverage of the population.

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

WHO recommends primary recording of all adverse events in the post-vaccination period, followed by decoding their possible association with immunization. All fatal cases, all hospitalization cases, all other conditions about which doctors or the public have suspicions about their possible connection with vaccination are also taken into account. Monitoring involves several consecutive steps:

• Supervision of the safety of domestic and imported MIBP by identifying adverse events after their use;
• epidemiological investigation and analysis of data adjustment and other actions;
• final evaluation; Determination of factors contributing to complications after vaccination.

Monitoring of complications after vaccination is carried out at the district, city, regional, regional, republican levels, in healthcare organizations of all types of property. It is necessary to identify those responsible for monitoring and to familiarize with it the medical personnel of the primary level and hospitals, which patients are treated in days and weeks after vaccination. It is important to instruct parents of vaccinated children and adults about the conditions with which they should seek help. The quality of monitoring is assessed taking into account the timeliness, completeness and accuracy of registration, promptness of the epidemiological investigation, the effectiveness of the measures taken and the absence of negative impact of the adverse event on the level of coverage of the population 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 syndrome, serum sickness syndrome, etc.).
3. Encephalitis.

[1], [2], [3], [4],

Monitoring of complications after vaccination

1. Vaccine-associated poliomyelitis.
2. Disorders of the central nervous system with generalized or focal residual manifestations that led 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. Arthritis is chronic, caused by rubella vaccine.

Unfavorable 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-Barre syndrome (except isolated facial nerve paresis);
• encephalopathy: convulsions with impaired consciousness for 6 hours or more and / or pronounced changes in behavior for 1 day or more;
• encephalitis occurring within 1-4 weeks after vaccination: the same signs as in encephalopathy + CSF pleyocytosis and / or virus isolation;
• meningitis;
• cramps: without focal signs - febrile and afebrile.

Other adverse reactions:

• allergic reactions: anaphylactic shock, anaphylactic reaction (laryngospasm, angioedema, urticaria), rashes on the skin;
• 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 at 6-16 months;
• long crying / crying: more than 3 hours;
• sepsis: with excretion of the pathogen from the blood;
• syndrome of toxic shock: develops in a few hours with a lethal outcome in 24-48 hours;
• other serious and unusual violations within 4 weeks after vaccination, incl. All deaths in the absence of other causes.

Information on post-vaccination complications is subject to state statistical accounting. When establishing the diagnosis of air defense, suspicion of complications after vaccinations, an unusual reaction, the doctor (paramedic) is obliged to help the patient, including. Timely hospitalization in a hospital. He must also register this case in a special registration form or in the register of infectious diseases (f. 060 / y) on specially marked sheets of the journal (with subsequent clarifications).

The list of diseases subject to registration, investigation and information of the higher bodies of the State Sanitary and Epidemiological Service

Diagnosis	Term after vaccine introduction:
	DTP, ADP, other inactivated vaccines and MIBP	Korevaya, mumps and other live vaccines
Abscess at injection site	up to 7 days
Anaphylactic shock, reaction, collapse	first 12 hours
Generalized rash, polymorphic exudative erythema, Quincke's edema, Lyell's syndrome , other severe allergic reactions	up to 3 days
Syndrome of serum sickness	up to 15 days
Encephalitis, encephalopathy, encephalomyelitis, myelitis, neuritis, polyradiculoneuritis, Guillain-Barre syndrome	up to 10 days	5-30 days
Serous meningitis	10-30 days
Afebrile cramps	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 lethal cases with a temporary connection with vaccinations	up to 30 days
Vaccine-associated poliomyelitis:
in vaccinated	up to 30 days
In contact with grafted	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 in the history of the newborn (f 097 / y) or the child (P2 / y), the medical chart of the child (f. 026 / y), the outpatient (f. 025-87), the inpatient (003 -1 / y), call card SMP (ф.10 / у) or applied for anti-rabies help (ф. 045 / у) and in the vaccination certificate (ф 156 / у-93). About single cases of uncomplicated strong local (edema, hyperaemia> 8 cm) and general (temperature> 40 °, febrile convulsions) reactions, as well as light manifestations of cutaneous and respiratory allergies, higher authorities are not informed.

About the diagnosis (suspicion) of the air defense doctor (paramedic) must immediately inform the head physician of the health facility. The latter within 6 hours after the diagnosis is sent information to the city (district) center of Rospotrebnadzor and is responsible for the completeness, reliability and timeliness of accounting.

Emergency notification of the complication after vaccination, the territorial center of Rospotrebnadzor sends to the center of Rospotrebnadzor in the subject of the Russian Federation on the day of information receipt together with the number of series, in which the frequency of strong reactions is higher than the established one.

If an unusual reaction (complication, shock, death) is detected after the application of the MIBP, the center in the subject of the Russian Federation sends a preliminary emergency report to the Federal Service for Consumer Protection of the Russian Federation. The final report is submitted no later than 15 days after the completion of the investigation. The act of investigating 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 GISK them. LA Tarasevich (see below) who can additionally request medical documentation, and in case of a lethal outcome - an autopsy report, histological preparations, blocks and formalin archive. Information on the drug series is also sent to GISK when its reactogenicity exceeds the limits specified in the application instruction. Acts of investigation of complications after BCG are also sent to the Republican Center for Complications of BCG to BCG-M.

Investigation of post-vaccination complications

Clinical analysis

Each case of suspected complication after vaccination, requiring hospitalization, and also resulting in a fatal outcome, should be investigated by a commission of specialists appointed by the chief physician of the Rospotrebnadzor center in the subject of the Russian Federation.

Patognomonicheskih symptoms that allow to unequivocally consider the case postvaccinal complication does not exist. All symptoms can be caused by an infectious or non-infectious disease that coincides with the vaccination, with which it must be differentiated, using all available methods.

Most of the deaths are due not to complications after vaccinations, but to diseases that could be cured if properly diagnosed. Here are the clinical criteria useful in investigating complications after vaccinations:

• general reactions with fever, febrile seizures for DTP, ADS and ADS-M appear no later than 48 hours after vaccination;
• response to live vaccines (except for immediate allergic reactions in the first few hours after vaccination) can not occur before the 4th day and more than 12-14 days after the administration of measles, 36 days after OPV administration and 42 days after the mumps vaccine and trivaccine ;
• Meningeal phenomena are characteristic for complications only after the introduction of mumps vaccine;
• encephalopathy is not characteristic of mumps and poliomyelitis vaccines and toxoids; it rarely occurs after DTP, the possibility of developing post-vaccination encephalitis after DTP is currently denied;
• the diagnosis of postvaccinal encephalitis requires, first of all, the exclusion of other diseases that can occur with cerebral symptoms;
• neuritis of the facial nerve (Bell's paralysis) is not a complication of vaccination;
• allergic reactions of the immediate type develop no later than 24 hours after any type of immunization, and anaphylactic shock no later than 4 hours later;
• intestinal, renal symptoms, cardiac and respiratory failure are uncharacteristic for complications of vaccination;
• 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 for rubella vaccination;
• lymphadenitis caused by BCG is more likely to occur on the side of the vaccine, the painlessness of the lymph node is typical, the color of the skin above the lymph node is usually unchanged.

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

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

When investigating any complications after vaccinations, you should ask for the distribution sites of the advertised series about unusual reactions to its use and the number of vaccines (or used doses). Also, we should analyze the requests for medical care for 80-100 grafted in this series (with inactivated vaccines - for 3 days, live viral vaccines administered parenterally for 5-21 days).

In the development of neurological diseases, a virological and serological study is required for antibodies of the IgM class, as well as for paired sera (1st at the earliest possible time, and 2 nd for 2-4 weeks) for influenza, parainfluenza, herpes simplex virus , herpesvirus type 6, enteroviruses (including Coxsackie, ECHO), adenoviruses, tick-borne encephalitis virus (in the endemic zone in the spring-summer period). When carrying out lumbar puncture, the cerebrospinal fluid (including sediment cells) should also be examined for vaccine viruses (when vaccinated with live vaccines). Material in virological, the laboratory should be delivered in a frozen state or at the temperature of melting ice.

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

[5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16],

Investigation of lethal cases in the post-vaccination period

Processes in the post-vaccination period leading to fatal outcomes need a particularly detailed investigation to establish the true causes of death. Vaccination, as well as the introduction of other MIBP can be a provoking factor leading to the manifestation of a hidden disease, decompensation of the chronic process, as well as weighting of ARI in the post-vaccination period.

Frequent in the past, the diagnosis of "postvaccinal encephalitis" has never been confirmed in a pathoanatomical investigation (except for cases of infectious-allergic encephalitis after the introduction of an anti-rabies Fermi vaccine with a residual amount of live fixed rabies virus). Modern rabies vaccines do not lead to such complications.

In children, vaccinated in the prodromal period of acute respiratory infections, intestinal infections, with congenital sluggish infections in the post-vaccination period, acute conditions with hemodynamic disturbances in the central nervous system due to their generalization (influenza, herpes, Coxsaki A and B, ECHO viruses, salmonellosis, meningococcemia and other). Severe forms of postvaccinal pathology can occur against the background of immunodeficient conditions, endocrine system lesions (eg, nezidioblastosis), CNS tumors (gliomas and gliomas of the brain stem cells).

Another diagnosis, often exhibited in case of death in the post-vaccination period, is "anaphylactic shock", which is also very rarely confirmed with a second examination. In adults, fatal outcomes sometimes show rare diseases, such as myocardial myoma, leading to death on the first day after the administration of ADS-AM toxoid.

Study of sectional material

Performing an autopsy

Analysis of sectional data allows you to outline a plan for further research. Many years of experience in the investigation of lethal outcomes showed that histological examination is the main one in diagnosing and establishing the causes of death. Therefore, taking the material for histological examination should be as complete as possible and include organs that usually do not take for microscopy (organs of the endocrine system, bone marrow, lymph nodes, including regional to the injection site, tonsils, skin and subcutaneous tissue with the adjacent muscle in the location of the drug, all parts of the digestive system, including the appendix, the main sections of the central nervous system, including ependyma and vascular plexuses of the third ventricle, the central part and the lower horn of the lateral ventricles; particularly important in the investigation of cases of measles and mumps to exclude specific for these infections and ependimatitov plexites.

The organs tested for the presence of a viral antigen

Infection	Research bodies
Influenza, parainfluenza, adeno-, RS-viral	Lungs, bronchi, paratracheal and peribronchial lymph nodes, soft dura mater
Coxsackie In	Myocardium (left ventricle, papillary muscle), brain, diaphragm, small intestine, liver
Coxsackie A	Brain tissue, soft dura mater
Herpes Type I	Myocardium, liver, brain
Measles	Trachea, bronchi, lungs, central nervous system, soft dura mater
Parotite	Trachea, bronchi, lungs, soft dura mater, brain, ependyma of the ventricles of the brain
Tick-borne encephalitis	Brain and spinal cord
Polio	Spinal cord
Hepatitis B	Liver
Rabies	Ammon horn, stem part of the brain
ECHO - viral	Myocardium, liver, brain

Histological examination

Fixation. The optimal size of the pieces is 1.5x1.5 cm, the fixer is a 10% formalin solution. The head and spinal cord are fixed separately, the ratio of the volume of pieces to the amount of fixative is not less than 1: 2. Fixed pieces of organs sent for re-examination in the GISK them. L.A. Tarasevich, should be numbered and marked, the number and types of bodies should be noted in the accompanying documentation.

Preparation of histological preparations. Paraffin or celloidin sections are stained with hematoxylin-eosin, CNS lesions are also stained according to Nissl, other methods are used, if necessary.

Virological research (ELISA). To conduct an immunofluorescence study (ELISA) immediately after dissection, pieces of non-fixed organs are taken. Preparations for ELISA are fingerprints or swabs of organs on a clean, well-defatted slide. The presence of viral antigen in tissues indicates the possibility of infection, the results of ELISA are compared with pathomorphological data for the final diagnosis. If possible, also take material for the production of PCR and other available techniques.

For differential diagnosis of rabies, the ammonium horn tissue, the trigeminal ganglion (located under the dura mater on the temporal bone pyramid), and the submandibular salivary gland are additionally examined. The fixation and processing of the material are set out in a special instruction. It is mandatory to conduct the ELISA-express diagnostics: the rabies virus antigen is detected both in direct and indirect coloring, preferably on cryostat sections. The antigen is found in the cytoplasm of neurons and outside cells along the course of the conducting pathways. In other cellular elements: glia, vessels, etc. There is no glow.

Histological study of drugs, diagnosis, preparation of epicrisis are conducted in the department where the autopsy was performed. A copy of the autopsy report, the results of a histological and virological examination, a formalin archive, paraffin blocks, and ready histological preparations are sent to GISK them. L. A. Tarasevich, who sends a conclusion about the conducted studies to the institution where the autopsy was performed and to the Rospotrebnadzor Center in the subject of the Russian Federation.

Control of reclamation series

The decision on the further application of the MIBP reclamation series or on its repeated control is accepted by the GISK them. L. A. Tarasevich. To control the preparation of the series that caused complications after vaccinations, inactivated vaccines and toxoids - 50 ampoules are sent to GISK; measles and mumps vaccine - 120 ampoules; poliomyelitis vaccine - 4 bottles; anti-rabies vaccine - 40 ampoules, BCG vaccine - 60 ampoules; tuberculin-10-20 ampoules; antitetanus, antidiphtheria, etc. Serums - 30 ml.

The final conclusion from the investigation materials

Registration of complications after vaccinations, examination of materials, request for missing data, presentation of summary data on air defense in Rospotrebnadzor is carried out by GISK them. L. A. Tarasevich. The final report on each case requiring hospitalization or ended with a fatal outcome is the commission for the examination of complications after vaccinations under the Federal Service for Consumer Rights Protection of the Russian Federation, all materials of the GISK them. L. A. Tarasevich represents the commission no later than 15 days after the completion of the investigation, regardless of the presence or absence of its connection with vaccination. The conclusion of the commission Rospotrebnadzor sends to the Federal body for social protection of the population, and for foreign drugs - to the representative offices of firms.