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PRACTICAL EPIDEMIOLOGY for students and residents



”Victor Babeș” Editions

Timișoara 2019


Editura „Victor Babeş”

Piaţa Eftimie Murgu nr. 2, cam. 316, 300041 Timişoara Tel./ Fax 0256 495 210

e-mail: [email protected] www.umft.ro/editura

Director general: Prof. univ. dr. Dan V. Poenaru Director: Prof. univ. dr. Andrei Motoc

Colecţia: MANUALE

Coordonator colecţie: Prof. univ. dr. Sorin Eugen Boia

Translated by: Carmen Tarniceru

Indicativ CNCSIS: 324

© 2019

Toate drepturile asupra acestei ediţii sunt rezervate.

Reproducerea parţială sau integrală a textului, pe orice suport, fără acordul scris al autorilor este interzisă şi se va sancţiona conform legilor în vigoare.

ISBN 978-606-786-151-8




















































Immunization represents the active induction or temporary conferral process of immunity, by administering various immunobiological products.

It can be:

1. Active – which determines the induction of own antibodies production, by vaccine and anatoxin administration, unlike the 2. Passive – which temporarily transfers immunity by high-tech

antibodies administration, as total immunoglobulin, specific or specific serums.

The immunization and vaccination terms are not synonyms.

While immunization describes an immunity induction or supply process by active or passive means, vaccination strictly refers to the administration of a vaccine or anatoxin. Consequently, vaccination does not guarantee immunization!


It represents the insertion into the human body of non-toxic and avirulent antigens, which can stimulate and induce an immune response similar to the one produced naturally.

Active immunisation generally gives long term immunity, for a period of months or years (e.g.: after diphtheria-tetanus vaccination, the protection persists for approx. 10 years). However, there are exceptions as well, like the flu vaccine which, due to its viral agent particularities, needs to be repeated annually.

Post-vaccine immunity is only installed after a certain period of latency, weeks to months, needed to produce own antibodies in protective titre. In immediate risk situations, this interval was left unprotected, it can be covered by the administration of passive immunization agents – immunoglobulins or specific serums.



The practice uses several classifications of vaccines. The most usual are:

A. Depending on the nature of the antigen:

1. antiviral vaccine – for example, the flu, measles, rubella, poliomyelitis, hepatitis viral A/B, rabies vaccines;

2. antibacterial vaccines – like the tuberculosis vaccine (BCG), diphtheria, tetanus, typhoid, pneumococcal vaccines;

3. mycosis vaccines – with a small scale of use compared to the first two categories (e.g. candida vaccine);

4. protozoal vaccines – like the vaccine candidates against malaria with sporozoites, merozoites or gametocyte antigens, each with a limited efficiency. Worldwide, great efforts are made in order to make such vaccines effective, by obtaining multivalent formulas, with a concomitant action on the various stages of the parasite agent.

B. In relation to the number of antigenic components:

1. monovalent vaccines, where the antigen comes from one single microbial species – for example the BCG only contains strains of Mycobacterium tuberculosis bovis;

2. complex vaccines, which contain several types of strains of the same species, like in the flu vaccine (with 2 strains of flu virus A and one or 2 type B) or in the poliomyelitis vaccine (with strains of 1 and 3 polio virus serotypes);

3. combined vaccines, which combine several antigens coming from different species, in order to simplify vaccination programs. Now, there are in Romania:

bivalent product – diphtheria-tetanus for adults (dT);

trivalent – acellular diphtheria-tetanus-pertussis (DTPa), measles-rubella-mumps;

tetravalent – DTPa + inactive polio vaccine (Tetraxim- Sanofi Pasteur);

pentavalent - DTP/DTPa + inactivated polio + Haemophilus influenzae type b (PentAct-Hib-Sanofi Pasteur/Pentaxim- Sanofi Pasteur)

and hexavalent - the 5 previous components are also added the recombined HBsAg DNA (Infanrix Hexa – GlaxoSmithKline/ Hexacima-Sanofi Pasteur).


C. According to the method to prepare the vaccine:

1. Live corpuscular vaccine, attenuated or super-attenuated – which include living microorganisms, with low virulence by repeatedly passing culture media, by passages at various animal hosts or by genetic mutations. It awards a persistent protection, like the natural post-infectious one, however it can generate multiple and severe post- vaccine reactions. Such products are the BCG and most of the antiviral vaccines – poliomyelitis with live strains, measles, rubella.

Due to their high reactogenicity, contraindicated to persons with immunosuppressants of various etiologies. As well, the teratogenic risk imposes their exclusion from the vaccination programme for pregnant women.

2. Inactivated corpuscular vaccines – which include full inactivated (killed) bacterial/viral particles by heat or formalin. Induced post- vaccine immunity is smaller compared to that determined by previous products, however, adverse reactions are lower. The same category includes as well cellular pertussis vaccines, hepatitis A or inactivated poliomyelitis vaccine.

3. Bacterial anatoxins – are products from the exotoxins of microorganisms by the neutralization of toxigenesis, but keeping the immunogenic capacity. The initially obtained native anatoxin is optimized by purification and absorption on mineral support, and purified and absorbed anatoxin will come out. Such procedure will increase the efficiency of immune stimulation. The most used anatoxins are tetanus – ATPA and diphtheria – ADPA.

4. Subunit vaccines, with antigenic fragments – contain an antigen or an antigenic function with the main role in triggering the production of antibodies. The removal of various cellular protein components, of nucleic acids, without major importance for immunogenicity, leads to a significant decrease of adverse reactions. Frequently used are the flu vaccines with surface antigens type hemagglutinin and neuraminidase (Influvac-Solvay Pharmaceuticals, Fluarix- GlaxoSmithKline) or those with fragments and from the virion (Vaxigrip-Sanofi Pasteur). Usual as well are the vaccines obtained by molecular recombination, like hepatitis B - 2nd generation (Engerix B-GlaxoSmithKline; Euvax B-Sanofi Pasteur; Recombivax HB- Merck&Co) or 3rd generation, which contain recombined HBsAg DNA.

5. Idiotype vaccines – their conformation is similar to that of the initial antigenic determinant. These products were applied on various


the vaccine candidates with covering proteins – idiotype gp120 or idiotype vaccines CD4.[1] In the field of HIV/AIDS infection, the researches in the field of vaccinology bump into multiple deontological, ethical and social problems. Although the manifestation of the epidemiologic process of the HIV/AIDS infection is presently influenced, by the antiretroviral treatment, we hope, for the future, to obtain as well effective vaccine products.

6. Vaccines with stable non-pathogenic mutants – they offer an protective immune response in diseases where the cell-mediated immunity is important. Although during the evaluation/application phase, they proved their superiority to certain classical vaccines, less immunogenic and much more reactogenic. Same situation is that of the typhoid vaccine with stable non-pathogenic mutants, but there is the possibility to develop other dysenteric, cholera, malaria, rotavirus vaccine candidates.

7. DNA vaccines – still under study, determine the stimulation of cell immunity by inserting a foreign DNA in the genome of the host cell.[1] They stimulate the immune cell response, compared to most of the vaccines addressed to humoral immunity. This type of vaccine product is a hope for the effective prophylaxis of VHC viral hepatitis or of the pathology caused by high antigenic variability viruses (the flu virus or HIV). Although advantageous by the fact that the human body contact to a live vaccine strain is avoided, there are as well some potential oncogenic risks, by incorporating the DNA in the host cell chromosomes or by inhibiting the tumour suppressor genes.[2]

D. From the point of view of vaccine compulsoriness:

1. Compulsory vaccines – administered to the entire population according to the vaccine calendar, periodically updated within the National Immunization Programs. These programs can vary from one country to another, depending on the epidemiological situation, the geographic area and the material resources of the healthcare system.

Harmonization has been a tendency lately, especially European, according to the requirements of the Worldwide Health Organization.

In Romania, the National Immunization Program 2019 includes the following compulsory vaccines:

Tuberculosis – with live attenuated vaccine BCG;

poliomyelitis – with IPV inactivated vaccine;

diphtheria- tetanus- pertussis – with non-cell DTP within the hexavalent product (DTPa-IPV-Hib-HBsAg recombined DNA) or tetravalent (DTPa-IPV), followed by dTpa from 14 years old;


Haemophilus influenzae type b – concomitantly to the 2 previous vaccines, within the hexavalent product (DTPa-IPV-Hib-HBsAg recombined DNA);

hepatitis B with HBsAg recombined DNA (mono- or hexavalent vaccine);

measles-rubella-mumps – trivalent vaccine with MMR live attenuated strains;

Pneumococcal Conjugate Vaccine.

Table no. I National Vaccine Calendar – Romania 2019 – in force [3]

* hexavalent vaccine.

2. Vaccines applied in cases with high epidemiologic risk – indicated to the tourists who visit various endemic areas, in case of natural calamities, floods, earthquakes, wars, with massive disorganization of social life or in other cases of major epidemic potential. This category also includes the vaccine for hepatitis A, typhoid, meningococcal, yellow fever etc. There were in 2005 reported some measles outbreaks at the children from the survival camps in the Aceh region, after the tsunami which had devastated the coasts of the Indian Ocean. Under such conditions, The WHO organized a campaign of vaccination, in order to put an end to the development of a possible epidemics. [4]

Recommended age Vaccine Comments

The first 24 hours HEP B In maternity

2 – 7 days BCG

2 months DTPa-IPV-Hib-HEP B*

Pneumococcal Conjugate Vaccine

General Practitioner

4 months DTPa-IPV-Hib-HEP B*

Pneumococcal Conjugate Vaccine

General Practitioner

11 months DTPa-IPV-Hib-HEP B*

Pneumococcal Conjugate Vaccine

General Practitioner

12 months MMR General Practitioner

5 years MMR General Practitioner

6 years DTPa-IPV General Practitioner

14 years DTPa General Practitioner


3. Vaccines applied under high individual risk conditions – addressed to the individuals who can contact more frequently a certain infectious disease or who can develop more severe clinical forms, due to personal risk factors. They can be:

Professional – the healthcare staff has a firm indication for the vaccine for hepatitis B, but also for flue or rubella immunisation.

The teachers, public employees and other categories with special social importance can be vaccinated flu. The teachers or military staff will be object of additional immunizations, in compliance with the epidemic potential of the mission.

Age older than 65 years old is considered an endangered factor, so that these persons have an indication for flu and pneumococcal vaccination, in order to limit complications and post-infectious mortality.

Pre-existing pathology (chronic diseases, malignant haematological affections, oncologic pathology, immunosuppression) interferes with the practice of active immunoprophylaxis. Therefore, the patients with chronic obstructive bronchopneumopathy have firmer indication for pneumococcal and influenza vaccine, and immunodepression leads to the replacement of live vaccines with inactivate/

subunitary products, but as well to the administration of pneumococcal vaccine, chickenpox or Haemophilus influenzae b vaccination.


The following principles need to be met in an action of vaccine planning:

1. The age group with maximum receptivity or with the highest risk to develop severe disease types will be protected. Therefore, the pertussis component vaccine starts at the age of 2 months, because maternal pertussis antibodies are not protective for the child.

2. The seasonality of certain infectious diseases is to be met, by organizing the vaccination campaign before the epidemic season. For example, influenza vaccine is applied in Octobers and Novembers, before a possible epidemics during winter-spring time (for the regions with temperate climate).

3. One also needs to meet the immunisation schemes, established for each and every vaccine. To be taken into account the minimum age


for the vaccine, the route of administration proper to each and every product, the number and size of the doses, the rhythm of boosters as well as the intervals between various immunisations. Between the live vaccine products, to generally meet an interval of minimum 30 days, while in case of inactivated vaccines or of vaccines with antigenic fragments, such pause it not to be applied.

4. One needs to meet the permanent or temporary indications and contraindications.

5. Before the vaccine campaign, the following need to be assured: the material basis represented by various biological products, the medical instrumentation needed as well as the compulsory refrigerating conditions during the transportation and storage of vaccines (in order to provide a constant temperature range of 4-8C, monitoring by way of a chart of temperature).

6. The medical staff needs to be trained related to the correct vaccination technique, to the indications, contraindications, and possible post-vaccine side effects.

7. The records for the immunisations needs to be rigorous. They shall be registered in the individual sheet of the patient, in the special vaccination registry, and in the vaccination book. The newly born receive in maternities a vaccination booklet, which shall include all the subsequent immunisations during the period of their childhood up to 14 years of age. For teenagers, adults or persons from the extra- territory, vaccination certificates are to be issued. They shall mention:

the trade name of the product, the producer, the series and number of the batch, the date of administration, validity, size of the dose, number of the booster, route of administration, signature of the medical staff in charge with the vaccination and possibly, some remarks related to immediate effects. Starting with 2011, the physicians have had the obligation to account for the dates related to vaccines (compulsory or optional) and on-line in the National

Electronic Immunisation Registry


8. The patients left behind need to recover as soon as possible.

9. In case of major events, the Vaccine Adverse Event Reporting System (Sistemul de Supraveghere al Reacţiilor Adverse Postvaccinale Indezirabile – RAPI) is to be immediately notified.



In order to prevent such post-vaccine effects and to avoid ineffective immunisation, one needs to know and meet any and all the contraindications of vaccines. They can be:

1. permanent contraindications – their existence compels to give up the administration of the vaccine, indefinitely. The following fall under such category:

anaphylactic personal antecedents, to the vaccine or its components – for example anaphylaxis to the egg protein leads to giving up vaccines prepared based on chick-embryos (influenza, measles);

live attenuated vaccines cannot be administered to pregnant women and to patients suffering from congenital immunodepressions, acquired or iatrogenic. Vaccination, for such children, will use inactivated products or products with antigenic fragments;

the revaccination with cell/non-cell DTP is not indicated for children with encephalopathy developed in the first 7 days after pertussis vaccine. The infants with neurologic pathology need to be evaluated rigorously but the risks after the administration of DTPa are small.

2. temporary contraindications – impose the postponement of the vaccinations for the entire period of such pathological condition.

Subsequently, after his or her recovery, the child needs to be vaccinated in accordance to his or her age and vaccination schedule.

They are represented by:

acute diseases with moderate or severe evolution, with or without fever, up to the end of the disease process;

febrile conditions with temperature exceeding 37.5C;

administration of blood or immunoglobulin products – which is prerequisite to temporize vaccination by 2 weeks before and 3 months after administration;

the immunosuppressive, chemical treatment and/or radio-therapy, systemic corticotherapy (with doses of at least 2 mg/kg/day, for at least 2 weeks) lead to the postponement of immunisations with live antigens, for the whole period of the treatment plus 3 more months after completion.[2]

3. Precautions –are mainly related to the administration of products which contain pertussis components (DTPc/DTPa), if the following occurred during a previous dose:


hyperpyrexia  40,5C;

strong crying of more than 3 h, in the first 48 h;

hypotonic-hyporeactive status, in the first 48 h;

febrile/afebrile seizures, in the first 3 days after vaccination.

In such cases, vaccination is only indicated if its benefits outweigh potential risks.


slight or moderate local reactions;

slight breathing intercurrences, in afebrile status;

slight or average diarrhea;

treatment by antibiotics;

convalescence after acute diseases;

severe post-vaccine antecedents in family;

prematurity (the BCG is temporized up to 2 months, as for the rest the doses and the administration schedule are similar to those used for the full-term new-born children);

the natural alimentation of the infant (only for the oral poliomyelitis vaccine, a pause of 3 hours before and after administration is a must);

allergic antecedents to penicillin or other non-specific allergies;

contact with a pregnant woman (children with pregnant moms will be vaccinated according to the ordinary schedule).


Post-vaccine side effect is considered a medical accident arisen at most 1 month after vaccination and which can be or not be caused by a vaccine or vaccination. [5] Only in the case of the BCG, certain side effects can last a period of 12-16 months after vaccination.

The tolerance of the population to side effects is minimum, as vaccination addressed to healthy persons and, it sometimes has compulsory character.

The following post-vaccine side effects are declared by telephone, in the following 24 h from identification, to the epidemiologist with jurisdiction on the concerned territory:

1. Severe local reactions - lymphangitis, lymphadenitis, abscess at the place of inoculation (consecutive especially for BCG vaccination),


erythema/swelling extended to the nearby joint or lasting for more than 3 days, or which lead to hospitalization;

2. Reactions from the CNS – acute paralysis (motor neurone disease) consecutive to poliomyelitis vaccination; the Guillain-Barre syndrome; encephalopathies; encephalitis; meningitis; febrile/

afebrile seizures;

3. Other severe side effects which need hospitalization (anaphylactic reactions, toxic-septic syndrome, collapse, hyperpyrexia, arthralgia, very strong myalgia, with serious alteration of the general condition) or which lead to the death of the vaccinated person.

Depending on the cause, the post-vaccine side effects can be classified in:

1. Reactions induced by the vaccine – represented by certain particular reactions of a person at a certain vaccine product, effects which would not appear in the absence of vaccination;

2. Reactions enhanced by the vaccine - which can occur as well in other situations at susceptible persons, but which are precipitated by the vaccination;

3. Coincident reactions - which would have appeared even if the person had not been vaccinated, without a causal relation to the immunisation product;

4. Reactions related to the vaccination schedule – due to production faults, manipulation or administration errors, deficiencies in preserving the vaccine;

5. Post-vaccine reactions due to unknown cause – when not falling under any of the previous categories.[2]


The immunisation obtained after the vaccine depends on various factors:

1. Depending on the vaccine – type, quality of the antigenic stimulus used, route of inoculation, size of the dose, route of administration;

2. Depending on the vaccinated person – age, nutrition status, existence of infections and congenital/acquired/iatrogenic immunodepressions, stress;

3. Depending on the person which makes the vaccine – related to the competence and responsibility of the physician.

The vaccine efficiency is checked by 2 criteria:

A. Epidemiological criterion – multi-annual morbidity is studied in order to mark out the decrease of the incidence and the loss of the


seasonal character of the disease, for all vaccinated persons compared to unvaccinated persons or in the vaccination period compared to the period before the vaccination. For the poliomyelitis vaccine, one shall follow the exclusion from circulation of the savage pathogenic agent and its replacement to vaccine strains.

B. Immunologic criterion - the specific antibodies are titrated at vaccinated individuals, with the determination of the seroconversion frequency and of the average level touched by the antibodies titre. At the level of the population, we organize collective serologic surveys.

In case of other vaccinations, we test post-vaccine allergy (for example, the IDR to tuberculin).

The vaccine effectiveness needs to be researched in the case the incidence of the disease does not decrease concomitantly to the increase of the vaccination coverage or in case infectious pathology occurs at several patients, with proper vaccine antecedents.

Worldwide researches in the field of vaccinology are pretty active nowadays, in order to:

establish an effective prophylaxis against emerging diseases (HIV, hemorrhagic fever, the Lyme disease);

fight against re-emerging diseases (TB, malaria, convulsive cough, diphtheria) partly determined by the growth of chemotherapy resistance of the pathogenic agents, by the decrease of the protective antibodies at adult age or by the lack of effective vaccines;

to obtain real vaccines against germs with high antigenic variability (the influenza virus);

as well as to obtain prophylactic and therapeutic conduct, in certain chronic diseases with infectious competence: - gastro- duodenal ulcer (by the etiological involvement of the Helicobacter pylori),

- neoplasia (cervical – for which 3 papilloma vaccines are already used: tetravalent Gardasil/ Silgard - Merck Sharp & Dohme, bivalent Cervarix -GlaxoSmithKline) and the latest appeared, Gardasil 9, with antigens from 9 HPV subtypes - 6, 11, 16, 18, 31, 33, 45, 52 and 58.

- prion diseases – spongiform encephalitis and the Creutzfeldt- Jakob disease,

- multiple sclerosis,

- cardiovascular diseases (by the association with Chlamydi pneumoniae).


Most of the vaccines presently used are just a little reactogenic, due to the new production technologies, focused on antigenic subunits (proteins purified or polysaccharides), on genetic engineering or on live vectors. During the new millennium, they have licensed new vaccines amongst which:

the pneumococcal vaccine conjugated by 13 components;

the attenuated live influenza vaccine, cold adapted;

the tetravalent meningococcal vaccine conjugated polysaccharides;

zoster vaccine;

human papillomavirus vaccine with 9 components;

and the pentavalent rotavirus resorted vaccine,

which proves the quick dynamics of researches in vaccinology.[6]




Tuberculosis is presently considered a re-emerging disease, with universal spread, both due to classical risk factors (poor social- economical conditions, disadvantaged minorities, alcoholism, malnutrition), and due to the HIV pandemics, with high susceptibility amongst immunodepressants or due to the occurrence of antituberculostatics multi-resistant strains.

The BCG vaccine is prepared from a live strain of Mycobacterium tuberculosis bovis with attenuated virulence, derived from the Calmette-Guerin original strain, which was obtained by successive passages for 13 years old on glycerinated potatoes, with ox bile.

Form of presentation: the BCG is delivered in brown glass vials, with live bacterial mass, lyophilised, with appearance of white powder, non- adherent on the walls. The Sauton’s medium is used as solvent, which is a clear, colourless fluid, delivered in separate vials. After the suspension, the vaccine comes homogenous, slightly opalescent and needs to be administered in maximum 1 h after the preparation. To be kept in the dark and at 2-8C.

Administration: to be inoculated strictly id. 0.1 ml suspension, in the posterior external area of the left arm, after previous disinfection of teguments with alcohol. The correct injection leads to the formation of a papule with the diameter of 5-6 mm, with appearance of an orange peel which shall persist for 30 minutes. In 1-3 weeks, a small erythematous shiny nodule shall appear at the injection site, which turns into a pustule, with or without subsequent fistulisation and the occurrence of central crust. After the removal of the crust, a depigmented slightly bumpy scar (marker of the previous vaccination) appears, but it can actually miss, especially at infants.[7] An ordinary post-vaccine reaction lasts for a period of 3 months, while ulcerated is extended up to 4-6 months.

Post-vaccine allergy is installed in 6-8 weeks, it can be marked out by the IDR at tuberculin and decreases step by step, lasting for approx. 20 years.[7] The BCG vaccination is efficient for the prophylaxis of the disseminated tuberculosis or of the tuberculous meningitis, especially amongst children below 5 years old, preventing massive lymphatic and hematogene dissemination, but it cannot fight against primo-infection or the reactivation of latent infection. As well, it offers


good protection against Mycobacterium leprae and some effects against other non-tuberculous micobacteria.

The vaccine coverage (the relation between the number of vaccinated individuals / number of vaccinable individuals ×100) needs to be higher than 95%, in order for the protective effect to be obtained at the level of the population.

The vaccination schedule includes:

BCG primary course administered in maternity, in the first 2-7 days of life or up to the age of 2 months (in case of infants with body weight below 2500g);

Reading the post-vaccine scar at all infants between 5 and 10 months. The dose will not be repeated to the persons without post-vaccine scar or with a diameter below 3 mm, but only the children not vaccinated BCG are to be recovered.


Indefinite – represented by the symptomatic HIV infection, congenital immunodeficiencies, leukemia, lymphomas, generalized oncologic pathology, immunosuppressive treatments, pregnancy and positive reactions to tuberculin. In developed countries, the infants infected by HIV are not vaccinated with the BCG, but the WHO recommends it for the people living in areas with a high risk of tuberculosis;

Temporary- represented by the body weight below 2500 g at birth, the acute febrile diseases, the period of infectious diseases, dystrophias, malnutrition, transitory immune deficits. 6 weeks after vaccination, avoid immunosuppressive treatments which can prevent the installation of tuberculin allergy.

Post-vaccine complications consist of:

Abscesses at the spot of the inoculation, regional lymphadenopathies, lymphangitis (determined by the deeper inoculation of the vaccine, arisen at approx. 1% of the vaccinated individuals);

Osteitis /osteomielitis in the first 8-16 months after vaccination or

Disseminated infection with M. tuberculosis bovis vaccine strain, manifested 1-12 months from vaccination. These generalized manifestations are rare at immunocompetent individuals, with more frequent occurrence at immunodepressed individuals.

The BCG vaccination strategy is very much different from one country to another, depending on the current epidemiological situation. In the strongly developed countries, (USA, Western Europe etc.) selective vaccination of the risk groups is performed – children exposed to multi-


resistant bacillus strains, TB contacts not vaccinated with IDR at negative tuberculin, without being applied to the entire population.

There are no certain serologic tests for quantifying the protective immunity after the tuberculous infection or BCG vaccination.[7]

Despite all this, IDR at tuberculin (Mantoux test) has been used for a long time, in order to mark out the post-vaccine response, in order to detect the M. tuberculosis infection at symptomatic or asymptomatic persons, as well as for the evaluation of cellular mediated immunity.

Testing in Romania is performed by 2 units/0.1 ml PPD, purified protean fraction from tuberculin (the filtrate of a 6 week human tuberculous bacillus culture, in glycerinated medium). The PPD is delivered as vials of 1 ml products and is used in average for 6 tests. It is administered strict id. in the medial third part of the forearm. The correct inoculation is followed by the appearance of a papule of approx. 5 mm, which persists for 10 min. The reading of the reaction is to be done 72 h afterwards, writing down the transversal diameter of the area, as well as its appearance in case of blistering, necroses, ulcerations, without taking into account simple erythemaatoase reactions.

The reaction is negative when the diameter of the papule falls between 0-9 mm.

Positive reactions are interpreted differently, depending on the age and existence of the vaccine scar.


In the absence of the vaccine scar, the positive reaction (≥ 10 mm) represents bacillus infection and needs chemoprophylaxis or the tuberculostatic treatment;

In the presence of the vaccine scar:

- children between 0-5 years of age are checked by radiographies in case of tuberculin reactions of 10-14 mm, with tough induration or with the appearance of blistering, necrosis, general reactions, either in case of induration over 15 mm, with ordinary appearance;

- children over 5 years of age and youngsters are checked b radiographies in case of reactions of 10-19 mm, with tough induration or with the appearance of blistering, necrosis, general effects, or in case of induration larger than 20 mm, with ordinary appearance.

There can be also falsely positive effects, resulted from erroneous interpretations (reading the erythema and not the induration), by the appearance of cellulites or of the allergic phenomena Arthus. Falsely negative reactions can be due to anergy or to the lack of epidermis elasticity.



Poliomyelitis is an infectious disease rarely manifested clinically (between 4-8% of the cases), which can lead to an affection of the Central Nervous System (less than 1% of the cases). After an acute period, 10-15% of the patients with paralytic form will suffer from permanent damage, as paralysis and muscle atrophy.[2]

The national polio vaccination programs had a decisive contribution to the reduction of the disease incidence and even to its eradication in large geographical areas. The number of polio cases have decreased by more than 99% since 1988 (with an estimate number of 350,000 cases in more than 125 endemic countries), getting to be 33 cases reported in 2018. Only regions from 3 countries (Afghanistan, Nigeria and Pakistan) persisted to be endemic – which represents the smallest geographical area from the millenary history of the disease.[8] Outbreaks appeared in 2013 in some non-endemic countries as well (Somalia, Ethiopia, Cameroon and Syria). The WHO is presently striving to liquidate the residual epidemiologic outbreaks, in order to eradicate it globally.

The last case, in Romania, of savage virus polio was recorded in 1992, and starting with 2002, all the European countries (Romania included) were declared free from savage viral strains. But the possibility of import cases, with the reestablishment of transmitting it to populations with lo vaccine coverage, is a permanent threat. In the epidemics from Tajikistan, in the first half of 2010, with 293 cases of flaccid acute paralysis, out of which 83 confirmed with savage polio virus type 1, some cases reached as well the territory of Russia, polio-free country for at least 8 years.[9]

Syria has reported 24 cases of poliomyelitis (up to March 4, 2014), mostly children younger than 2 years old, due to the dramatic reduction of vaccination coverage due to the military conflict in the region.[10] Additionally, the WPV1 virus was isolated from the samples collected for the routine surveillance of residual waters, in 2 towns in South Israel (Beer Sheva and Rahat), especially in the areas inhabited by Bedouins or Arab-Jews communities.[11] This circulation has also been marked out in 2014.[12] The presence of outbreaks in the Middle East leads to high risks, both for Europe, and for the rest of the world, as each day Syria is left by around 6,000 refugees, most of them to Turkey and Egypt, main tourist areas for Europeans. [13] Plus the fact that some parents refuse to vaccinate their children, considering that poliomyelitis is a disease of the past – therefore vaccination coverage is low in countries like Bosnia/Herzegovina, Ukraine, Austria, insufficient in order to prevent its transmission in case of re-entry.


In such a context, the specific prophylaxis is maintained in the immediate actuality, by polio vaccination with Salk parenteral inactivated vaccine, or Sabin live attenuated vaccine, with oral administration.

A. The inactivated poliomyelitis vaccine IPV, prepared for the first time by J.Salk, contains strains of 1,2,3 polio virus serotypes inactivated with formalin, able to produce specific seroneutralized antibodies. The vaccine was brought again in our daily lives after the cases of paralytic polio after the vaccination, with attenuated live product. Although less immunogenic, IPV does not present such a risk, and therefore it has also been reintroduced in Romania as well in 2008, in the compulsory vaccination of infants / children, but also of the persons with various immunosuppresions (HIV included), of their family contactants or of adults with a risk (lab personnel, medical staff getting in touch with savage polio virus excretory, travellers to endemic and epidemic areas for this pathology). It has been reintroduced for more than 10 or 20 years in the countries with high economical standards in Europe, North America.

The commercial products contain either just the IPV (Imovax polio – Sanofi Pasteur), or they are combined vaccines which include as well DTP/DTPa (Tetraxim-Sanofi Pasteur), Haemophilus influenzae type b (Pentaxim- Sanofi Pasteur, with DTPa+IPV+Hib) and hepatitis B (Infanrix Hexa – GlaxoSmithKline with DTPa+IPV+Hib+ HBV).

The IPV efficiency is of 90-96% in the prevention of paralytic poliomyelitis and of 100% in the occurrence of seroneutralized antibodies, after the administration of 3 doses of vaccine. The immune response persists on long term (10-18 years), for more than 95% of the vaccinated individuals by 3 or 4 doses. Ig A occur at the level of the mucosa, but are 3-4 times less versus post-vaccination with live attenuated component.[2]

B. Trivalent attenuated live poliomyelitis vaccine - VPO, prepared by A.Sabin, includes live strains from 1,2,3 polio virus serotypes, attenuated by genetic mutations. It protects by the induction of humoral immunity, with the production of circulating antibodies, as well as by local immunity, with formation of intestinal Ig A and at the level of the oropharyngeal mucosa. This local immunity assures protection against re-infection, opposing to the multiplication of the savage strains and diminishing their circulation. The elimination of vaccine viruses by faecal may lead to occult immunisation of the persons in the entourage of the vaccinated individual (“oil stain” coverage). Such repeated passages may select neurovirulent mutants, able to determine paralytic poliomyelitis with vaccine virus.


The VPO is administered easily orally, has a low price, a good compliance at the population level, but presents the disadvantage to generate paralytic accidents (peripheral motor neuron syndrome), at the vaccinated individuals or their contacts. It still remains the product most used in poor countries or in countries under development.

Its efficiency is of approx. 95% in developed countries and smaller in the others (70-90%).[14] The antibodies stay present for a long time, which explains the absence of the disease at the vaccinated adults in antecedents.

Starting with April 2016, WHO recommended the introduction of inactive polio or live bivalent strains vaccine (1+3), as consequence of the worldwide eradication of the viral 2 subtype.

Form of presentation:

The inactivated vaccine (component in the tetra- or hexavalent product) is delivered as syringe preloaded with 0.5 ml opalescent solvent (+/- 1 lyophilized vial in case of hexavalent vaccine). To be stored at 2-8C and the freezing needs to be avoided;

Sabin’s vaccine is found in uni- or mult-dose plastic vials, which contain a light rose clear fluid. They are not allowed to sour or change colour. Stored in freezing conditions -10/-20C, for 1-2 years. After defrost, to be kept at 2-8C, and can be used in maximum 1 month time.

In Romania, the current vaccination schedule includes:

The administration of 3 doses of IPV, by intramuscular route, at 2, 4, 11 months, as component within the hexavalent product– 0.5 ml;

Revaccination is practiced at the age of 6 years old, by 1 dose of IPV+DTPa (tetravalent). [3]

The administration of the inactivated product is intramuscular, at infants and small children in the region of the hip, at the joint of superior 1/3 to the medium, 2-3 cm laterally from the medial line or in deltoid at older children and adults.

The live strains vaccine (still used in various regions of the globe) is administered per bone, in dose of 0.2 ml (2 drops), according to a schedule similar to that presented above. The general rules for the administration of the VPO are:

Appearance of regurgitation or vomit in the first 5-10 min. after administration, leads to the vaccination being repeated within the same session;

The maternal milk consumption is to be avoided for minimum 3 h before and after the administration of the vaccine. Immediately after vaccination, the infant can receive tea;


Intramuscular injections, surgical interventions which can be temporized or dental extractions are contraindicated for 30 days after the vaccine (any parenteral treatment is IV administered);

Intercurrent febrile conditions will be fight against with antipyretic therapy, in the first 6 weeks from vaccination.

In endemic areas, in the areas with circulation of savage viruses (in the previous 3 years), where vaccine coverage is below 80%, with great migrations of the population or close to endemic territory, additional vaccinations like “the national immunisation days”, which is the “mopping-up” are organized. Children below 5 years receive 2 more doses of VPO, at interval of 1 month, irrespective of their vaccine antecedents.

Contraindications and side effects for each and every type of vaccine, are presented comparatively in table no. II :

Table no. II Contraindications and side effects in case of IPV versus VPO 23vaccination


ATTENUATED LIVE POLIO VACCINE Permanent contraindications

Represented by anaphylactic reactions at a previous dose of IPV or at vaccine components - streptomycin, neomycin, polymyxin B.

Not indicated for the vaccination of children infected with HIV*, with congenital immunodeficiencies or a different etiology (hematologic diseases, solid tumours, long term immunosuppressive therapy), as well as for their family contacts.

Precautions for pregnant women or adults (more than 18 years).

Temporary contraindications Represented by the febrile acute diseases.

Represented by febrile acute diseases, medium clinical and severe forms of diarrhoeal disease.

Side effects

Rare, especially local - erythema, swelling and pain, 2-3 days after the vaccination.

generally minor – discreet pharyngitis, 1-2 stools of low consistency; febrile condition.

Rarely, post-vaccine acute flaccid paralysis can occur, with persistent neurologic deficit of more than 60 days, in an interval of 4-30 days from administration, at the vaccinated person and of 4-75 days, at the contacts of the individual vaccinated.

The risk of post-vaccine poliomyelitis is of approx. 1 case every 790,000 doses for primary course and of 1 every 2.6 million doses, for boosters. This risk is very high at the immunodepressed individuals.[14]

* In developing countries, where the condition of HIV infected is not known at birth and IPV vaccination is not available, the WHO recommends the administration of the


The VPO vaccination needs to be continued in the countries with persistent savage viral strains circulation, while in those with interrupted circulation or large vaccine coverage, one can go to sequential schedules or only IPV schedules.[15]

Post-vaccine flaccid acute paralysis has had in Romania a high incidence compared to other geographic areas, mainly due to the intramuscular injections administered quite frequently to the small child.[14,15] In order to avoid such cases, VPO vaccination was dropped for IPV vaccination, enacting in 2008 a combined schedule (IPV primary course and VPO boosters), and starting with 2010, IPV has been administered exclusively.


After the introduction of the population’s vaccination against diphtheria (in Europe around 1930), the disease changed its character from endemic-epidemic in sporadically.[2] But around 1990, it became re-emerging in the states of the former Soviet Union, on the background of vaccine relaxation especially at adult age, with consecutive accumulation of susceptible persons, in parallel with the growth of the number of carriers of Corynebacterium diphteriae or of the atypical clinical cases, selected especially from the disadvantage groups of population (alcoholic, drug consumers etc.). The seriousness of the disease is determined by the toxic syndrome, occurred as consequence of the diffusion of diphtheria exotoxin diffusion in the body.

Vaccination prevents this toxic syndrome, by inducing seroneutralized antibodies to B fragment of diphtheria anatoxin, preventing the penetration of the toxin in the cell.

The diphtheria vaccine component is performed usually concomitantly to the tetanus and pertussis vaccine, by the use of various related products. There are multiple such products:

1. Diphtheria-tetanus-pertussis DTP vaccine – contains diphtheria anatoxin obtained from the exotoxin of the Parck-Williams no.8 strain of Corynebacterium diphteriae, with marked toxigenesis;

tetanus anatoxin obtained by the detoxification of the toxin in the Clostridium tetani 21D strain and inactivated corpuscular pertussis vaccine. Determines the simultaneous immunisation to the 3 pathogenic agents, in order to simplify the vaccination calendar.

2. Trivalent vaccines with acellular pertussis component – DTPa (e.g.: Infanrix-GlaxoSmithKline, Daptacel-Sanofi Pasteur). They


contain the pertussis toxoid next to one or more antigenic structures:

filamentous hemagglutinin, agglutinogens, pertactin. The vaccine is less immunogenic but even less reactogenic compared to corpuscular vaccines.

3. There presently are tetravalent, pentavalent and hexavalent vaccines which contain DTPa – Tetraxim (DTPa+IPV, from Sanofi Pasteur), Pentaxim (DTPa + IPV + conjugated polysaccharide of Haemophilus influenzae type b, from Sanofi Pasteur) or Infanrix Hexa (DTPa+IPV+Hib+HEP B – from GlaxoSmithKline).

4. The diphtheria-tetanus bivaccine – An adult type vaccine is used (dT), with a content 5 times more reduced of diphtheria anatoxin compared to the paediatric product (DT), for the vaccination of persons older than 14 years. We recommend today the administration of DTP a (Adacel-Sanofi Pasteur), where the pertussis component is as well adult type.

5. The monovalent vaccine – the adsorbed diphtheria vaccine (VDA) contains purified diphtheria and adsorbed anatoxin, paediatric or adult type. It has restricted indications at unvaccinated persons for diphtheria, at the bacillus carriers or in the diphtheria outbursts.

Form of presentation: The commercial vaccines which include DTPa, are found as syringes preloaded with opalescent suspension, 5 ml/1 dose and need to be homogenized before administration. To be kept in dark and between 4-8 C.

The Administration is intramuscular, deeply, at the infant, in the thigh region, upon the joint of the upper 1/3 to the medial, 2-3 cm laterally from the medial line or in the deltoid at teenagers and adults.

Vaccination schedule:

Primary course contains 3 doses each of 0.5 ml DTPa im., at 2,4,11 months concomitantly with the IPV, Haemophilus influenzae type b and Hepatitis B (hexavalent vaccine);

Revaccination is to be performed at 6 years old, with a dose of 0.5 ml DTPa im. Combined with IPV (tetravalent vaccine)

And at 14 years old, a dose of 0.5 ml dTpa;

Subsequently, every 10 years, boosters with 0.5 ml dT or dTpa im., in order to preserve the protecting antibodies.

In case a booster is delayed, from various reasons, the vaccination schedule is to be continued, without being taken over from the beginning.

The vaccine efficiency after at least 3 doses, is more than 95% at children below 15 years old and in average of 70% at adult.[16] The protecting level of serum antibodies is considered to be 0.1 UI/ml, while long term protection is related to values of 1 UI/ml.[16] The post-vaccine


nontoxigenic, of Corynebacterium diphteriae, but the disease cases are rare and with much more benign evolution. The vaccine coverage needs to be more than 90% at children and more than 80% for adult age, in order to prevent a possible epidemic.


temporary are represented by the febrile conditions, the status period of acute infectious diseases, TB or evolutional chronic diseases. At the persons with blood coagulation disorders, the vaccine will be administered im., in the moment risks are minimum, and post-vaccine local compression needs to be extended (minimum 2 minutes).[16]

permanent are related especially to the pertussis component in the related vaccines. Encephalopathy with debut in the first 7 days after the first dose, contraindicates the administration of the pertussis component. Another permanent contraindication is the anaphylaxis after a previous dose.

After the administration of the vaccines with pertussis component, the following can occur: hyperpyrexia (fever higher or equal to 40.5C), collapse/shock, persistent crying (more than 3 h) in the first 48 hours after vaccination, convulsions in the first 3 days after immunisation. In such situations, the continuation of the schedule with the diphtheria and tetanus vaccine is preferred.

The introduction of the acellular pertussis vaccine reduced a lot the incidence of such secondary reactions.

Post-vaccine side effects:

Local reactions may occur: erythema, nodule, pain at the place of inoculation, with favourable evolution 2-3 days afterwards or general, represented by transitory conditions;

The diphtheria anatoxin can determine, especially to adults, delayed hypersensitivity (Arthus phenomenon). Therefore, vaccines for the use of adults contain a smaller quantity of diphtheria anatoxin;

Tetanus anatoxin can determine brachial plexus neuropathy (1 case/200,000 doses), algodystrophy syndrome, Guillain-Barre syndrome (0.4 cases/1 million doses), anaphylaxis (1 case/100,000 doses);

The classical pertussis component can generate persistent crying (3.15%), convulsions (1 case/1750 vaccinated individuals), hypotonia-hyporeflexia syndrome (0.06%), exceptionally post- vaccine encephalopathy (1 case/2.4 million vaccinations). [1,17]

In order to reduce such reactogenicity, the acellular pertussis vaccine entered the market instead of the corpuscular.



We estimate worldwide that there appear annually 40 million cases of convulsive cough, out of which care 360,000 evolve towards death, and 50,000 remain with long term neurologic sequela, especially in developing countries.[17] There are 2 types of pertussis vaccine:

1. The inactivated corpuscular vaccine – contains chemically inactivated Bordetella pertussis bacillus. To be used only in association to the diphtheria and tetanus anatoxin, eventually with inactivated polio, Haemophilus influenzae type b or hepatitis B vaccines. To be administered to children younger than 3 years old, after such an age, there is a high risk of side effects. After 4-5 doses, the protecting antibodies appear at more than 80-90% of the vaccinated individuals, the length of its effect persisting for 6-12 years.[2] The contraindications, precautions upon vaccination and the side effects were presented in the previous chapter. Due to the higher reactogenicity, such a component was excluded from the calendar of compulsory vaccinations in some developed countries (England, in the 70s), which determined the re-emergence of convulsive cough and of epidemic phenomena. Efforts have been subsequently made in order to obtain an effective vaccine, with lower reactogenicity, and the acellular product entered the market.

2. Acellular vaccine – contains pertussis toxoid, next to one or more antigenic structures: filamentous hemagglutinin, agglutinogens, pertactin. It has been initially used in Japan, in order to replace the cellular component afterwards from the related vaccines, in most of the developed countries (in the 90s). This product was introduced in Romania in the National Immunisation Program at the end of 2008.

The pertussis toxin is chemically or genetically inactivated, and then included in the vaccine as toxoid. It can also be administered at ages older than 3 years, the in force administration schedule being presented at the diphtheria component. Real contraindications are the anaphylaxis and encephalopathy with debut after 7 days from the administration of a previous dose of pertussis component. The children with pre-existing neurologic pathology can have an indication of vaccination with the product, taking into account the lower risks.

For the individuals with febrile convulsions in their antecedents, pyretic medication will be administered before the immunisation and in the first 24 h. Following the vaccination, the immune response appears at 90% of the individuals. An adult type trivalent vaccine dTpa (Adacel-Sanofi Pasteur) has recently appeared, with a lower quantity of pertussis antigens, and used as booster, every 10 years, for teenagers and adults (especially in the persons getting in touch with



The tetanus, fatal in 40-50% of the cases, is determined by the Clostridium tetani bacillus, manifested by an infection localized at the level of the admission gate and by neuromuscular hyperexcitability consecutive to the diffusion of bacterial exotoxin (tetanospasmin) in the body. Neonatal tetanus is even more serious, with fatality between 50- 90%, and the survivals can develop severe neurological sequelae and development retard.

By vaccination and proper post-exposure conduct, this pathology can be managed up to removal. In order to touch such a target, vaccine coverage for the tetanus component needs to be more than 95%.

The exposure to a high infected dose (plague with tetanigenic potential, birth with the possibility of the umbilical stump infection, in default of an aseptic conduct), can exceed the immunity granted by the previous vaccinations, so that additional preventive measures are to be taken.

Presently, besides combined vaccines, simple tetanus vaccination is performed only with purified and adsorbed tetanus anatoxin (VTA).

For adults, we recommend the dT bivaccine, eventually with dTpa three- vaccines (e.g.: Adacel-Sanofi Pasteur), in order to grant concomitant protection for other 1-2 pathologies.

The ATPA is produced by detoxification due to formalin fixation of the exotoxin of the Clostridium tetani 21D strain, aluminium phosphate (or calcium) purification and adsorption. Delivered as monodose vials / preloaded syringes of 0.5 ml, with a whitish milky liquid which needs to be homogenized before the administration (Tetavax-Sanofi Pasteur). To be kept in the dark and in a temperature range of 2 to 8C, avoiding freezing. The inoculation is intramuscular in the tight up to 3 years of age or in the deltoid muscle for the adult and big child.

Simple tetanus vaccination with VTA has the following indications:

1. Primary prophylactic immunisation of the persons without tetanus vaccine or of the adults with tetanus antibodies below the protective level – involves a primary course with 2 doses of 0.5 ml VTA im. 30 days interval, followed by a booster with a dose of 0.5 ml VTA one year after the primary course and another identical booster 5 years from revaccination I.

2. Revaccination of pregnant women with proper tetanus vaccination antecedents, in the month 7 ½ of the first pregnancy, with a dose of 0.5 ml VTA im. The unvaccinated primigravidas or those with incomplete vaccine antecedents will be subject of a 2 doses schedule at an interval of 30 days, starting with the 7th and a half pregnancy


month, with revaccinations 1 year after the administration of the 2nd dose and 5 years after. As related to a new pregnancy, the ATPA revaccination is to be performed only if more than 10 passed from the latest tetanus revaccination.

3. Emergency revaccination of complete first vaccinated persons or revaccinated persons with tetanus in antecedents, with the occurrence of a tetanigenic wound –0.5 ml VTA or dT to be administered im., optimum in maximum 24 hours from the occurrence of the wound (for major wounds and contaminated – if the individual did not receive tetanus anatoxin in the latest 5 years/for minor and uncontaminated wounds – if the person failed to receive tetanus anatoxin in the latest 10 years). In case of superficial wounds, only the ATPA is administered. Only in case of serious multiple traumas with massive blood losses, multiple open fractures, the patients infected with HIV, will be associated 3.000-20.000 UAI of tetanus serum or 200 - 500 UAI tetanus specific immunoglobulin, concomitantly to the first vaccine dose, but in a different anatomic region.[2]

The category of tetanigenic wounds includes the following:

wounds from burs, nails, chips, wounds with conditions of anaerobiosis, muddy wounds, dusty, soiled with animal defections (come from the agricultural, zootechnical, gardening sector, road accidents included), bites (animal or human), wounds with retention of foreign bodies, with anfractuous edges, devitalized tissues, open comminuted fractures, infected varicose ulcers, 2nd and 3rd degree burns, frostbites, birth or abortion without the observance of asepsis.

Under such conditions, besides the administration of the active/passive prophylaxis, the surgical drainage of the wound with large debridement is a must, as well as the removal of foreign bodies, the excision of the devitalized tissues, the hemostasis, aseptization of the wound with hydrogen peroxide 3% and antibio-prophylaxis with Penicilin or Erythromycin (for allergic individuals), for 7-10 days.

4. Accelerated vaccination of non-vaccinated individuals or of individuals with unknown/uncertain/incomplete vaccination antecedents, with the occurrence of a tetanigenic wound – to administer 3 doses of ATPA (or dT) each of 0.5 ml at an interval of 14 days, plus 1 booster 1 year after. In case of severe wounds, to combine active to passive immunisation, by tetanus seroprophylaxis (3.000-20.000 UI) or tetanus specific immunoglobulin (250 UI or if the tetanigenic wound is older than 12 h, at the persons weighting more than 90 kg and/or in the presence of massive contamination -


5. In order to treat the tetanus – to administer ATPA as well, as naturally going through the disease does not determine protective immunisation.

The minimum protecting titre of antitoxin antibodies is considered to values of more than 0.01 UAI/ml, measured by the method of in vivo neutralization. After complete vaccination, to appreciate that antitoxic immunity is efficient for approx. 10-15 years and develops at 98% of the individuals. In order to keep up the protective level at adult age, boosters are necessary with 0.5 ml dT im., administered at an interval of 10 years.[18]


The anaphylaxis or appearance of neurologic diseases after a previous dose of tetanus vaccine contraindicates the repetition of the doses;

But there are no contraindications for emergency vaccination with VTA, in case of potentially tetanigenic wound;

As well, it is not contraindicated to immunosupressed individuals (HIV infected, with hematologic, oncologic pathology, transplanted etc.).

Side effects:

Local reactions prevail – erythema, oedema, swelling, sometimes even affecting the neighbouring joint.

Subcutaneous administration can favour the growth of the incidence of such local reactions or the evolution towards an abscess;

Pyrexia can also appear, brachial plexus neuropathy (1 case/

200,000 doses), algodistrofic syndrome, Guillain-Barre syndrome (0.4 cases/1 million doses), anaphylaxis (1 case/100,000 doses), presented as well at the diphtheria vaccination with combined vaccines.

The preventive conduct of neonatal tetanus applies in case of birth under improper conditions, when asepsis cannot be assured – home birth, birth in nature, with dusty, soiled umbilical wound, or when the umbilical cord was sectioned with non-sterile instruments. The measures include the umbilical wound dressing, excision of the infected parts, antisepsis, sterile ligation of the umbilical cord, applying a sterile dressing, chemoprophylaxis with Penicilin for 7-10 days and the administration of a dose of antitetanic serum 500 UI or specific immunoglobulin 200 UI.[2]

There still existed in September 2018, 14 more countries where removal of the disease has not been validated yet, which is the threshold of below 1 case to 1000 living infants, on the entire territory.



(M.O. Also, in the case of TBC patients, although the medical system provides free specific medicines they hardly access these services because of the distance

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1 Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, Bei-Hu Branch and National Taiwan University College of Medicine, Taipei, Taiwan, 2

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1 Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, Bei Hu Branch and National Taiwan University College of Medicine, Taipei, Taiwan,

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