Migration: Public Health Issues (Polio, Hepatitis A, Hepatitis B, Tuberculosis, Diphtheria)

Biologicals (1997) 25, 187–193

Migration: Public Health Issues (Polio, Hepatitis A, Hepatitis B, Tuberculosis, Diphtheria) Michael Schwanig Paul-Ehrlich-Institut, Paul-Ehrlich-Straße 51–59, D-63225 Langen, Germany

Quality control of vaccines is closely linked to epidemiological changes by vaccination. It is important to notice that epidemiological changes in a vaccine-preventable disease can only be achieved if vaccine coverage of at least 80–85% can be reached. This goal is closely connected with the quality of the vaccines used. The acceptance of a vaccination programme is highly dependent on the expected protection rate versus the expected or experienced adverse events. Migration in connection with the need of protection from the diseases can be interpreted in two ways: migration to the endemic area or migration from the endemic arena. Both influence the risk of infection in different ways depending on the diseases. While two of these infections, diphtheria and tuberculosis, are causing an increasing threat due to imports, mainly from eastern Europe, and the low protection rate in the population, the other diseases are more likely to become a risk when going to the endemic areas. Polio No cases of poliomyelitis were reported in European countries in the first quarter of 1996. This is indeed a unique development in the history of poliomyelitis in Europe. It brings strong hopes for achieving the goal of interrupting transmission of wild polio viruses in Europe by 1997, preceding the certification of poliomyelitis eradication in Europe by the year of 2000.1 The situation in Albania has to be considered separately and is mainly due to the extreme political and social changes in this country. The remarkable three-month absence of reported poliomyelitis cases in Europe is yet another indicator of the successful impact of Operation MECACAR, the campaign to eradicate poliomyelitis in the MEditerranean and CAucasian regions and the Central Asian Republics. This MECACAR was initiated by IICC. In July 1994, in Kyoto, Japan, 1045–1056/97/020187 + 07 $25.00/0/bg970082

a group of international development agencies and government representatives decided to form an Interagency Immunization Co-ordinating Committee in order to assist the NIS in: (1) control of diseases preventable by immunization; (2) ensuring primary vaccination of children; and (3) attaining vaccine independence. The secretariat of IICC is located in the WHO Regional Office for Europe in Copenhagen. In this campaign almost 60 million children under 5 years have been vaccinated with two doses of OPV. This effort reduced the number of reported poliomyelitis cases from 159 in the second half of 1994 to 17 in the same period in 1995. For the NIS countries and Turkey an update of the ongoing National Immunisation Days (NID) programme and the number of recently reported cases are listed in Table 1. The example of polio eradication shows that epidemiological problems arising from free movement of persons, mainly from eastern Europe, in the last few years can best be solved by mass vaccination in the endemic areas, thus also protecting the rest of Europe. In a historical example, the protective effectiveness of a nationwide vaccination programme with polio vaccine was clearly shown in two endemic outbreaks in the Netherlands (citation from Ref. 3). After general introduction of IPV vaccination in 1957 in this country, two outbreaks in communities which refused vaccination for religious reasons showed that in 1978, there were 110 cases and in 1992 67 cases of paralytic poliomyelitis occurred in the unprotected population of approximately 200 000. This is shown in Figure 1. During the 1978 outbreak there was no case of poliomyelitis outside the community, indicating that there was no circulation of the virus in the general (vaccinated) population. In 1992 one case of poliomyelitis in a unvaccinated child outside the closed community indicated some spread of the virus. This clearly indicates that a 7 1997 The International Association of Biological Standardization

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Table 1. NIDs in 19962

Country

Date 1st round Coverage NID (1996) (%)

Armenia Azerbaijan Georgia Kazakhstan

20–30 April 25–30 March 8–12 April 11–16 March

Kyrgyzstan Russia Federation Tajikistan Turkey Turkmenistan Uzbekistan Romania Ukraine Albania

Fed. Rep. of Yugoslavia

Date 2nd round NID (1996)

97

27–30 May 25–30 April 13–17 May 22–27 April

10–12 April 18–22 March

98 99

14–16 May 22–26 April

15–20 April 95 17–23 April 1–6 April 10–13 April (later in 1996) (later in 1996) 8–10 April

95

13–18 May 18–24 May 6–11 May 10–13 May

97

99 98

May

(September– October 96)

Last reported poliomyelitis June 95 November 95 April 95 (March 96) (1992) November 95 December 94 December 95 October 95 April 95 May 94 March 95 (1990?) (74 suspected and 16 (8) confirmed cases in 96. Wild-type (*) 10 cases in 92 1 case in 94 3 cases in 95

*Data from May 1996. The identified cases increased later in the year 1996. All identified cases were Type I.

high vaccination coverage can protect from virus spread. This seems to be true not only with vaccination by OPV but, as in this case, with IPV. With the decrease of poliomyelitis in Western Europe the question of vaccination induced polio cases, as illustrated for Germany in Table 2, is becoming of increasing importance. As some other countries that use only OPV, Germany is actually discussing changing to a primary series of IPV. Hepatitis A The panel discussion on ‘‘Prospects for Control of Hepatitis A’’ at the International Symposium on Active Immunisation Against Hepatitis A in Vienna (27–29 January, 1992) stated that vaccination against hepatitis A should be given to travellers going from industrialized countries to developing countries.4 As developing countries, most countries in Asia, Africa and Latin America were included. In addition to those in Europe, Romania and Bulgaria and some of the NIS countries were considered as areas at risk. As recent publications indicate in Europe, the Mediterranean countries still have a high incidence of hepatitis A. The southern Italian

regions (Bari, Apulien) were mentioned.5 This seems to be the actual situation in 1996. For Europe, Steffen6 summarized the situation as follows: ‘‘Each year approximately 14 million Europeans travel to developing countries in Africa, Asia, and Latin American as well as to infrequently visited countries in eastern Europe. Without protection, travellers develop symptomatic hepatitis A at the rate of 3 to 6 cases per 1000 people per month of stay. Those who eat and drink under poor hygienic conditions have an even higher risk, 20/1000/month. 120 100 80 60 40 20 0

1978

1992

Figure 1. Number of cases in an unvaccinated population of 200 000 people in the Netherlands during a polio outbreak.

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189

Table 2. Poliomyelitis cases in Germany (1991–1995) Year 1991 1992 1993 1994 1995 All years

Total

Wild-type

Vaccine-induced

Contact polio

3 3 1 2 3 12

— 2 (imported) — — — 2

3 1 1 1 1 7

— — — 1 (imported) 2 3

Studies show that hepatitis A is the most frequent vaccine-preventable disease in travellers to developing countries. Immunity to hepatitis A virus is infrequent among northern European travellers, except for those born before 1945, with a history of jaundice, or who lived for more than 1 year in a developing country.’’ A similar opinion, on the risk of infection for North Americans was given by Wolfe:7,11 Morbidity from hepatitis A in American travellers may be greater than currently recorded. Risks for acquiring hepatitis A are widespread in developing countries, and a single lapse from appropriate hygiene for food or water is sufficient to cause infection. In Peace Corps personnel, a strictly regulated policy of immune serum globulin (ISG) at 4-month intervals reduced the rate of hepatitis A to 0⋅1–0⋅3 cases (from 1⋅6–2⋅1 cases)/100 persons/year. Data from United States Foreign Service personnel, for whom there is no mandated ISG policy, show hepatitis A to be the most commonly reported immunization-preventable infection; rates are 0⋅06– 0⋅16/100 person-years, depending on the area of the world. With the availability of a hepatitis A vaccine, frequent travellers or those who stay long-term in hepatitis-endemic areas can attain higher antibody concentrations and much longer protection than is currently available from ISG.’’ The prevention of hepatitis A infection by passive immunoglobulin protection seems to be no longer necessary. At the conference in Vienna it was also found to be not really necessary to add immunoglobulin with the first vaccination, unless the traveller is leaving within less than one week and is at high risk. As actual data seems to indicate, Hepatitis A is increasing again in Europe. Data from Germany are shown in Figure 2. The attack rate per 100 000 inhabitants has thus increased from around 6⋅75 to 7⋅9. This is not an alarming, but notable, increase. Most of these cases are secondary infections due to spreading in public institutions, like schools or kindergarten, or by

contacts in the family. To influence this situation it seems to be advisable to protect persons travelling to endemic areas to a higher extent. Furthermore, people at high risk should be vaccinated to reduce spreading in the social environment. These highrisk groups are listed in Table 3. Hepatitis B The annual estimate for hepatitis B in Germany, and other central European countries is approximately 50 000 new infections.8 Approximately half of these infections will become a manifested disease. The importance of this message is not in the less than 200 persons who died directly from the hepatitis B infection but much more important is that of the 10 000 people dying annually from liver cirrhosis, 50% are assumed to be late sequelae of hepatitis B! As the actual data show, the number of registered hepatitis B cases (which is about 20% of that what is estimated to be the real number) is increasing. Thirty to 50% of these are infections from unprotected sexual contacts, some of these can be assumed to be imported from endemic areas. No precise figures are available. The strategy to protect from hepatitis B by vaccinating these risk groups (see Table 4) has shown to be ineffective in influencing the epidemiological situation. Even in the first risk group, the

7000 6000 5000 4000 3000 2000 1000 0

1994

1995

Figure 2. Hepatitis A cases in Germany.

190

M. Schwanig

Table 3. Indication for hepatitis A vaccination (I) (I) (I) (I)

1. 2. 3. 4.

Medical personnel at risk Laboratory personnel at risk Kindergarten personnel (etc.) Personnel in institutions for mentally handicapped Personnel working at sewage systems, garbage disposal Male homosexuals Hepatitis A Ab negative haemophiliacs Persons at contact with infected patients

Normal vaccination: day 0; 28; 180–360 Travel vaccination: q1 month: 0; 28; 180–360 (s.b.) Q1 month: 0; 14; 180–360 Q2 weeks: 0; 28; 180–360

(I,T) 9.

Children:

living in homes for mentally handicapped Hepatitis A negative chronic liver disease born in non-endemic areas, travelling for the first time to endemic areas

(T) 10.

Travellers to endemic areas

If necessary, vaccination should be completed after return

(I) 5. (I) 6. (I) 7. (I) 8.

I = indication for risk groups; T = indication for travel.

medical personnel, it was not possible to reach a sufficient vaccination coverage. The best way to protect from this disease is vaccination as early as possible. Taking into account the high individual suffering and the enormous costs of hepatitis B sequelae, several European countries introduced a general vaccination for infants, in parallel with the primary vaccination series, and vaccination of young adults at approximately 13 years. A vaccination at this age is assumed to be able to protect before first sexual contacts. The primary series of vaccination in parallel with the generally used infant vaccines has the advantage to ensure a relatively high coverage. Table 4. Risk groups, who should be routinely vaccinated against hepatitis B 1. 2. 3. 4. 5. 6.

Medical personnel patients undergoing dialysis or other frequent blood or blood substances (like haemophilic) transfusions patients in psychiatric institutions suffering from cerebral defects or behaviour disorders persons at contact with HB carriers (family, kindergarten, school etc.) special groups at risk (like homosexual men, drug addicts, prostitutes, prisoners) Travellers to endemic areas who are assumed to have close and/or sexual contacts with the native population.

It does not, however, protect infants born from HBs positive mothers. So, in any case of a baby born from a HBs positive mother, vaccination should he started immediately within the first 12 hours after birth. Tuberculosis TB is still one of the major infective diseases causing morbidity and mortality. It is assumed that approximately one third of the world population is infected with M. tuberculosis (10 million people newly infected annually, 3 million people die of the disease every year). For several years we have additionally faced the increasing threat of multi-resistant M. tuberculosis strains, not only in the USA but also in Russia. According to personal communication from scientists at the Gamaleya Institute in Moscow, up to 22% of the newly identified TB infections might be caused by multi-resistant strains. The only available vaccine against tuberculosis is BCG (Bacille Calmette-Gue´rin) an attenuated strain of Mycobacterium bovis. Efficacy studies with different strains of BCG have shown protection ranging from approximately 72% (British Medical Council investigations) to 0% (Madras Trail). Although meta-analysis of data from a number of such trials concluded that BCG showed an overall protective effect of 50%, there is continued

Migration: public health issues

y = –0.6x + 12.829 2 R = 0.9907

12 10 8 6

been shown that homologous recombination does occur in M. tuberculosis (or in this case BCG). This now opens the door for better understanding of the genome of Mycobacteria and to understand virulence mechanisms and develop better vaccines. DNA vaccines might be another possible solution for future Tuberculosis vaccines.

4

1995

1994

1993

As the actual epidemiological situation indicates, there is good reason for having some concern about the risk of importing diphtheria from the eastern European countries, namely the NIS countries, even when taking into account recent progress in fighting this disease. The actual situation in the past two years in Germany is shown in Figure 4. Similar cases are reported from other European countries. Five of the cases in 1994 and two of the cases in 1995 can be attributed to infection imported from the NIS countries. One of the fatal cases in 1995 was a truck driver from the Ukraine. In this case therapy started too late to be successful. The other case was a three-year-old girl whose parents refused vaccination for her. As the individual clinical cases show, the clinical manifestation of the disease seems to be milder in most patients who had at least some history of diphtheria vaccination. This increase of diphtheria risk stresses on two important points:

1992

0

1991

Diphtheria 1990

2 1989

Total cases/100 000

14

191

y = 0.1429x + 2.8286 R2 = 0.6645

Figure 3. Tuberculosis in Germany. (*), immigrants; (q), Germans.

scepticism about this finding. The reasons for the discrepancies between the trials are still not fully understood, but the most popular hypothesis centres on exposure to environmental mycobacteria interfering with the protective effect of BCG. The absolute numbers in Figure 3 are not of essential importance. More important is the tendency of increase in the immigrant population. Even if the incidence of tuberculosis is still low in western Europe we have to look very closely to any future development on that field. Reasons for this are:10 (1) The epidemiological situation in other regions of the world is much worse and there is an increasing migration from these areas to Europe. (2) Increasing multi-resistance against most of the tuberculostatics. (3) relatively high incidence of tuberculosis in risk groups. The social behaviour of these groups is highly attributed to spread of the disease. As an example of how modern travel is increasing the risk of tuberculosis, the case of a woman who infected 15 other persons during an international flight can be mentioned.11 Until now the available tuberculosis vaccine has not been able to influence the epidemiological situation to a notable extent. New tuberculosis vaccines are urgently needed. Until recently gene replacement techniques in mycobacteria have not been successful. It has been suggested that the reason for the failure of gene replacement arises from a low level of homologous recombination in M. tuberculosis or even a complete absence of the process. In recent papers12,13 it has

(1) Diagnosis and therapy of diphtheria; (2) Vaccination status of the population Fortunately, diphtheria had become a very rare disease in countries with high vaccination coverage. But due to the possibility of carriers14 it is very unlikely that this disease can be eradicated by mass vaccination as for small pox. Diphtheria is by no means a disease only of infancy and childhood. An 7

7

6 5 4

3

3

2

2 1 0

0 1994

1995

Figure 4. Clinical cases of diphtheria in Germany. (q), total; (Q), fatal.

M. Schwanig

Table 5. Diphtheria disease. Fatal outcome correlated to the time of onset of antitoxin therapy15 Antitoxin—days after clinical No. Lethality manifestation of the disease of cases (%) 1 2 3 4 5 or q5

225 1441 1600 1276 1645

0 4⋅2 11⋅1 17⋅3 18⋅7

early diagnosis is of extremely high importance for the prognosis of the outcome. In any case of an inflammatory process in the naso-pharyngeal region, especially if purulent membranes are detectable, diphtheria should be taken as one possible diagnosis. In any case of suspected diphtheria, immediate specific therapy should be started. Even when taking into account that the data in Table 5 were collected before routine therapy with antibotics the principle of administering the antitoxin as early as possible is still essential. To confirm the diagnosis, bacterial culture should be taken before treatment. The cultures can be isolated preferably from under the diphtherial plaques. The therapy comprises a first dose of diphtheria antitoxin of approximately 20 000 IU to 40 000 IU. Additionally, erythromycin or penicillin G should be given parenterally as long as the patient is not able to take the drug orally. Active immunization against diphtheria should be undertaken during convalescence from diphtheria in every patient because this exotoxin-mediated disease does not necessarily confer immunity.16 After re-convalescence further medical control is necessary. Toxic sequelae like myocarditis are possible. In parallel with the therapy of the patient it is essential to start a prophylactic treatment of all contact-persons (face-to-face contact within the last 2 to 5 days) and identified carrier. They should be treated with erythromycin orally for 7–10 days or parenterally with depot preparation of penicillin G. After 24 hours these persons are no longer infectious. From the actual epidemiological situation we can identify the following risk groups who need a protection by vaccination: (1) travellers to endemic areas; (2) medical personnel who is likely to have first contacts with infected persons; (3) public servants with high rate of public contacts;

% Ab-titre <0.01 IU/ml

192

70 60 50 40 30 20 10 0

30–40 (male)

30–40 (female)

60–70 (male)

60–70 (female)

Figure 5. Diphtheria antibody titre below protection in the adult population in Germany. (q), West Germany; (Q), East Germany.

(4) immigrants and refugees from endemic areas; and (5) public servants working in customs- and border-control. Persons of all age groups may be infected. Actually, adults are more at risk than children since the majority do not have sufficient protection. Figures from Germany (Fig. 5) clearly stress the importance of a life-long protection against diphtheria by vaccination. It is advisable to combine the routine vaccination against tetanus, which should be repeated every 10 years, with a diphtheria vaccination. From an age of approximately 6 years the diphtheria vaccine for adults and adolescents, which has a reduced antigen-content should be used. When starting to extend the vaccination programme to adults, and this is true not only for diphtheria vaccination, we have to ensure to provide a life-long continuous protection. If such a vaccination is not continued it would only shift the population at risk to an older age group. All the diseases mentioned in this paper can be controlled by vaccination to become a very rare disease or even eradicated by vaccination. This will need further improvement in some of the vaccines and most of all, a strategic planning to ensure a high, life-long vaccination coverage for the whole population. References 1. IICC Periodic Bulletin No. 4, May 1996. 2. Figures from WHO CD News No.: 11 March 1996 Page 2. 3. Murdin AD, Baretto L, Plotkin S. Inactivated poliovirus vaccines: past and present experiences. Vaccines 1996; 14: 735–746. 4. Proceedings of the International Symposium on

Migration: public health issues

5. 6. 7. 8. 9.

10. 11.

Active Immunization against Hepatis A. Vienna 27–29 January 1992 Vaccine, 1992; 10: 170–174. Epidemiologischens Bulletin des RKI 1996; 35/96:243. Steffen R. Hepatitis A in travellers: the European experience. J Infect Dis 1995; 171 (Suppl. 1): S24–S28. Wolfe MS. Hepatitis A and the American traveller. J Infect Dis 1995; 171 (Suppl. 1): S29–S32. Epidemiologischens Bulletin des RKI 1995; 48/95: 2. Colditz, GA, Brewer TF, Berkey CS et al. Efficacy of BCG vaccines in the prevention of tuberculosis: meta-analysis of the published literature. J Am Med Assoc 1994; 27: 698–702. Epidemiologischens Bulletin des RKI 1996; 34/96: 235–237. Kenylon TA et al. Transmission of multidrug-resistant mycobacteria tuberculosis during a long airplane flight. N Engl J Med 1996; 334: 933–938.

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12. Norman E, Dellagostin OA, McFadden JJ et al. Gene replacement by homologous recombination in Mycobacterium bovis BCG. Mol Microbiol 1995; 16: 755–760. 13. Dale JW. Gene replacement in Mycobacterium tuberculosis. First step towards new TB vaccines. Vaccines 1996; 14: 95–96. 14. Thilo W. Differentialdiagnose ‘‘Diphtherie’’ wieder aktuell? Pa¨diat Prax 1996; 51: 103–112. 15. Russel, Med. Res. Counc., Spec. Rep. Ser. No. 247. His Majesty’s Stationary Office, London, 1943—cited from Grumbach, A. Kikuth, W.: Die Infektionskrankheiten des Menschen und ihre Erreger: Band I p. 701—Georg Thieme Verlag Stuttgart (1958). 16. Red Book: Report of the Committee on infectious Diseases. American Academy of Pediatrics 1994.