. ( 14 Rechov Ma1che1 Yisrael, 'Afridar-Ashkelon. · .

28th April 1961.

Dr. Albert B. Sabin, The Children's Hospital R•?search Foundation, Cincinnati, OHIO.

D·aa r Dr. Sa bin, Dr. Nassry a nd I cannot tell you how grateful we are for your very p rompt replf( and advice on 9ur paper "Does Measles predispose to I'oliomyelitis • You have g iven us a lesson in the epidemiology of polio v-rhich has taught us a great deal, and it vras as if you were in theroom with us. 'I'his lesson and your encourageme nt we sha,ll always treasure a nd we h9,ve triedour best. to meet the high standards you set for the writing of a paper. 1'/e see noy.,r that it wa s a mista ke not to have sent you togethe r lv ith the first dra ft, a literal translation of our ori r.~: inal article in the "Harefuah", since v1e did t t:.ere t a ke up a nwnber..., of the points you raised in your lette r of the 15th Februa ry, although not as thoroughly as you Hould h a ve liked. I a m therefore app ending this translation now, together with our second draft for the paper itse lf, ltrhich takes account of tbe conunents in your le"4ter a nd also of the various criticisms and note s writte n in the margin of the first dra ft. In a ddit1on, we should like here to consider in greater detail, one by one, the points you h c:we r a ised in the light of a further look at our data:

1) AGE. We've analysed our data agalin as r egards age, and especially a s regards the point ive had not considered of a higher incidence of polio within the unde r 4 yea,r-olds, in those a ged 7-23 months. Vle 've found:

AGE IN MONTHS: 0-11 12-23 24-35 36-47 48-60 Totals

Even-Shmuel Area 3(1) 4(1) 7(2) 1 15(4) Ashkelon Region 22(4) 21(3) 10(2) 3 1 57(9) Deaths are shown in brackets. This brought out the intere sting ne1.-.r fact that 7 of the 15 cases, with 2 deaths in Even-Shmuel were in the 24-35 month age group, unlilce the tre nd for the Re gion and country as <>­ whole, which favoured the 7-23 month group. First we considered that this might be due simply to their being more childre n in Even-Shmuel in the 24-35 month age group. Dr. M:assry s a ys it ivould involve him in a treme ndous a.mount of work to detail the exa ct age in months of all the children in the area, at the time of the epidemic, but we do have records of births in Even-Shmuel by year of birth, v-rhich are similar and 1.-.rhich show:: Children in Even-Shmuel Year of Birth Nos, of childre n. 1958 (up to outbrea k of p olio) 64 1957 103 1956 98 1955 95 1954 66 Total 426 .

As the children aged 24-35months at the time of the polio, will have b~en born bet1treen June 1955-Junel956, if t h eir had been Any relative increase in the nwnber in this age group, one would expect the Table to show this.

/Next ;

Next we considered the possibility that these 7 children had not been properly vaccinated with Salk Vacc,1ne. In tact however, 6 or them had had 3 injections' and one' 1 injection. (cr. - .Salk Vaccinations, below). Next we considered, possible better correlati'on of these 7 child­ ren -with measles: AGE IN IviONTHS: 0-11 12-23 24-35 36-47. I olio with measles 2 4 5 1 Polio without me a sles 1 2 Tota ls 3 4 7 1

3 children were from Uz a , 3 from l!, yta n and one from Sha l va, vrh ich s eems - again- a represent a tive distribution. \·Je could find no correl a tion with injections given prior to the polio, nor with previous anaem i a , nor had these 7 b ~?e n i n a poor nutr itional state on the outbrea k of the polio. Th ou~h i ntere sting, we have no explanation for this age distr ibu­ tion, a nd \:.rill welcome suggestions.

2) SALK VACC I NP... TION. 'l'he following Table det a ils t he m.m1ber of Sa lk Va ccdme Inje ctions, t be children v.r ho contracted polio, had had. Deaths in brackets.

No . of Sa lk Va ccine Numbers of children with Poliomyelitis Inje ctions given Even-Shmuel Area Ashkelon Region

3 7(1) 14(1) 2 6(2) 28(4) 1 2(1) ~- .S(l) 0 0 1op~ 0-3 15(4~ 57 9 This seems to be against the c onc entration of ca ses in Even-Shmuel having been due to poorer va ccination with Salk Va ccine. One wants to know of course what the qver-all Salk Vaccina tion position was at the time of the polio in ~ en-Shmuel, and we summarise this here: Nos. of children who at the time of Settlement. the polio had !:lad 0-3 in.]ecs, of Salk 0 1 2 3 Eytan lb 63(1) b2(1) 38(3) Ahuzam 12 71 71(1) 53 Noam 11 61 59 36 Uza 16 82(1) 61(3) 59{3) 10 §.2__ 8_2 ( 1 ) Q1_{].__L Totals b5 300T2T 342Tbr 247\7T. The figures in brackets show in which groups by number of inject­ ions the polio cases occurred. The table r efers to children born 1954 through 1958 and also includes Noam. No special r elation- ship with fevrer injections is seen. The table summarises a more detailed one which is further broken down by age of birth. It seems tha t a.) vacc ination ,.,a s very similar in the various settlements a nd b) surprisingly efficient for t hose children born 1954 thDough 1957. In the case of children born 1958 a nd aged up to about 6-7 months at the time, their numbers in the various settleme nts are identical to thOse in the column tinder 0 injections. 'I'hey alone had not had the nwnber of injections laid down by r.U nistry of Health instructio-ns,beca.use of a lack of vacc ine at the time . e hasten to add that the word efficient above r efers sim ly to the number of injections given a nd not to their effectivity. We believe that techni"!:ally the giving of Salk Vaccine \vas faulty /since ,

< - (..f..- . ~ ~" it was first given a ll over Israel in 1956/ 7 intraderma lly, and even in 1958 only 21 cc injections were ·being given, apart from a nti­ genicity problems, but we ar e sure you will be far more informed about these technical difficulties at tha t time, than we are. How­ ever, we have assumed that these technica l shortcomings applied equally to all children given the va ccine (instructions as to tech­ nique having been changed simultaneously throughout t he country), a nd can t hink of no wa y tha t this might have selectively af fected the Even-Shmuel cases. The following data may be r elavent to t his question of the lack of effectiveness of Sal k Vaccine given before the very virulent polio outbreak. On the 17th and aga&n on the 21st October 1958, I took r bloods in all from 58 children in Uza - a.ged from 3 months to 7 years, and including 6 of the 7 who had contracted polio about 4 months · previously. Dr. Goldblum wa s interested and agreed to do their antibodies (using titre of 1/4) and these were the r e sults.: UZA- ANTIBODIES TO POLIOVIRUS=S FOUND IN 58 CHILDRE:N , OCTOBER 1958 In To T.zEe 1. T;ype 2 TlJ2e 2 16 children + + + 14 children + 0 +- 12 children + + 0 12 children + 0 0 3 childr en 0 0 0 1 child 0 0 58 children 54 28 ~

The 6 children who had contracted polio shO'tled the following:

Ase in months Polio- Fell No1 of Name when bled Virus(Cause)Ill Sal k v. 1. TI(Pe 1 .58 3 -t- 0 0 1 .58 3 + 0 0 " 1 .58 3 + 0 0 " 1 ~ 58 3 + 0 + Negative 58 3 ~ 0 + II 1 .58 1 + 0 + not .54 0 ... + 0 done The l a st child was included as she too had had polio - in 1954. The absence of any antibodies found to Poliovirus Type 2 and in only half to Type 3, mus t indica te s ome t hing as to the ineffectiveness of the particular Sal k Va ccine then in use. We are also interested in knowing whether t her e is a nything in the t heory of cross-immunity. If I r emember correctly, we wer e once told t hat it wa s believed possible t hat infection with one Type of poliovirus ma y prot e~ t - though weakly - against a nother. Obviously t h is is not gener ally believed since we have instructions to give Sal k Vaccine to cases iovho have had polio as well, since they may intheory contract a s econd attack with another Type. Here, following on infection ~Ar ith a known virulent type 1 poliovirus, t here would seem to have been no effect of cross-irrillt unity on Type 2. (If t her e is a nyth ing i n t hat t heory at all - we would \ welcome references). In 4 children no a nt~bod1es to type 1 was found, and in three of these . no antibodies to types 2 and 3 a s well. Some particulars of t hese : ------

4. , \ Age in months Dates given Salk Vacc. Antibodies found NAME. when bled. 1st In,Jec. 2nd. 3rd to Type 1. 2 1 2,. .58 .58 0 0 0 .57 • 57 58 0 0 0 .58 58 0 0 0 .57 .57 .58 0 0 -t

These children had apart from Salk Vaccine, been closely exposed to the Type 1 ep idemic in Uza in June-July, yet had failed to develop antibodies to Type 1 poliovirus. As ·far as I know, antibodies to other enteric viruses were not studied.

3) Gamma-globulin. Apart from Eytan, where gamma-globulin was given after the polio ep idemic there had spent itself, no gamma. -globulin was given in Even-Shmuel. The giving of gamma-globulin in ~­ Shmuel was therefore not a factor we had to evaluate. As regards I the giving of gamma-globulin in , I~~et~i~d to present the results more clearly in the light of your ~a. The decision to give gamma-globulin there, a nd the reasoning behind it- i.e. the hope it might protect against the polio as well ... was arrived at in consultation with Dr. Davies of the Epidemiological Dept. of the Ministry. · 4) Measles in Noam. Dr. r..1assry has checked on his r ecords. There were only a f ew sporadic cases of measles in Noam. Again something we'd forgotten to inquire into. 5) Measles in the other settlements listed in the Table • vlhen I wa s engaged in collecting dat a in 1958, on the polio in the Askelon Region as a ,,,rhole, I specifically inquired into this. Notifications were bad a nd it was impossibl e to get r eally accurat e information fro t h e doctors concerned, a nd I fina l ly gave it up as a bad job. Hm"­ ever in .Ashkelon, Zoha.r and possibly in Kirya t Ga t, t her e ,was a ca se ea ch of polio with r eceding measles. Our impres sion however from t he doctors a t the time was that nothing comparable in numbers and severity to the measles ep idemic in Even-Shmuel and Revaha was seen i n other parts of the Ashkel on Region at t he time. Oux contacts with these doctor s '''horn we knev.r persona lly v1ere frequent, a nd they certamnly would have draw n our a ttention - a s t he doctor in Revaha d id - to a s evere ep idem ic. I would also have seen the hospital­ ized cases in Kapl an Hospital of mea sles complications, had there bee any. Tbe same unfortunately holds for other areas. I made inquiries in Tel Hashomer Hospital which hosp italised polio ca ses from a very large area, and in the Ep idem iological Department of the Ministry, as r egards this point, but could get no figures, as the fact of their having had or not had r ecent measles was not recorded. £). Frovocative role of injections. In 10 cases out of the 57 in the Ashkelon Region, we could correlate the s ite of injections with t he limb paralysis (Injectio'ns of penicill in, Vit.D and Imferon given within 2 weeks of onset of polio). On the other hand, many children had been given these injections at this time, especially penicillin for sore throats, without ill effects. (Exact figures unobtainable). The same goes for t he Even-Shmuel children. Of the 12 children who had both mea sles and polio, only 2 had not had injections of one of t he above. Of the 10 who had injections within 2 weeks before onset of illness, 3 were given these injections on the day of onset of the pre- paralytic phase. Dozens of the children with measles, but without poliomyelitis, were given injections wholesale during this period. We have no figures, but Dr• Massry does not believe that those children vrho fell ill with polio, had selectively been given more injections. In addition to the measles,there were mild cases of Upper Respiratory Infections at the time, the treatment for wh ich - often by the male nurses - 'i'ras penicillin injections. Not having controls we cannot take this matt er further. We attempted to get some more data on injections given to t he 57 cases in the Region /at 5.

a t the time, but were unsuccessful i.e. the da ta I had recorded on whether these 57 had or had not had provocative injections, were incomplete. We were very interested in the theory you have given us to explain the predisposition viz. that vascular changes produced by measles might increa se the amount of poliovirus entering from the blood intot the C.N.s. We would be grateful for any references on this point, and if this is a new original theory of yours, \'le must of course a cknovlledge it as such. Vve shall keenly a\'lait your further comments on this data, how much of it is r el evant to the subject matter, which form our paper should t ake, and whether you woul d like us further to r eview t h is data. Once a gain, Dr. Sabin, let me assure you how much Dr. Ma ssry and I have appr ecia ted the advice a nd consideration you have g iven our paper.

With many thanks,

YourJ; s i)l9greiJ, {A. - - ~ (Dr.) A. Bloch. ------· ------~

HAREFUAH. Journal of the Medical Association of Israel. Vol. LVll, No. 7 - _1st October 1959.

POLIOMYELITIS AND MEASLES 'IN THE EVEN-SHMUEL AREA by A. Bloch and s. Massry. Mother and Child Welfare Clinics, Ministry of Health, Ashkelon. Even-Shmuel Health Centre, Kupat Cholim, Negev.

In June, 1958, parallel to the position in the rest of the country, an epidemic of poliomyelitis began in the .Ashkelon Region. There were 57 cases until the end 6f the year, including only 2 with the non-paralytic form. , 9 children diecl. (See Fig. ·1)

'i

I ;, r· I

The age of theaffected children ranged from 4 to 60 months. The cause of the epidemic was a type 1 poliovirus, excepting only the single case in Jan. 1958 wh~re type 2 was isolated. Salk vaccine had been given according to the Ministry of Health instructions. The course of the epiclemic '\vas similar to that in the rest of the country, as described in a preliminary communivation by Davies,(Harefuah 55:40,1958). ' . From the beginning •t was apparent that the incidence of cases in the Even-Shmuel area was very high relative to that in the rest of the Ashkelon Region. (See Table 1 ) • TABLE 1. - Incidence of poliomyelitis in a number of settlements in the Ashkelon Region. Place. No. of children under No. of polio Incidence 4 Iears of age. cases 12er 1000. X Eytan 65 5 76.8 X Uza 93 7 '74.6 x ~; shalva 83 2 24.0 Kommem1ut 73 1 13.6 X Ahuzam 74 1 13.5 Shderot 438 6 13.4 Bet Ezra 93 1 10.7 Zavdiel 113 2 10.6 I 2 I Maabara B - Ashkelon 200 10.0 ! Revacha 112 1 8.9 ! 550 4 7.2 ~ X Noam 86 0 0 ! Even-Shmuel Area 401 15 3'7 .4 Ashkelon Region 10,280 57 5.5

X Settlements of the Even-Shmuel Area. 2.

In addition, we noticed that in most of the children with polio­ myelitis, measles had preceded their illness. We shall here attempt to present certain facts and explanations for this phenomenon. METHODS, The general state of health of children in the Even-Shmuel Area be!ore ~ AD4 t4ur1ng the polio epidemic was evaluated. This was done by the authors who in the course of their work had come to know the children of the area well, In assessing the general state of health of the children before the epidemic, we were assisted by experienced nurses, who had each worked in their respective settlements for a long time. The haemoglobin levels were estimated by the authors using Sahli haemoglobinometers. These were done routinely in all children who clinically had appeared to be a naemic. The following points were specifically inquired into: 1} The previous epidemiological picture of poliomyelitis in the area. 2} Ethnic group. 3) Overcrowding (No. of persons per room). 4) Salk vaccination. 5) Other inoculations. 6) Injections given before the illness. 7) Other epidemics preceding the poliomyelitis. 8) Other illnesses preceding the poliomyelitis. 9) The general state of health of the affected children, before the epidemi lO)Anaemia. FACTUAL DATA, The Even-Shmuel Area consists of the following settlements, Ahuzam, Eytan, Noam, Uza, Shalva and the Even~Shmuel Rural Centre. The settlements had been in existence some 8 years. In all these years only sporadic cases of poliomyelitis had accurred.

•:"1,.,.., s~vtt- · oQT\1'111 ,4flu:Z.~ •

In this area, in 1958, 15 children in all contracted polio,with 4 deaths. Their age ranged from 7 to 40 months. The highest incidence was in Uza and Eytan. The cases occurred as follows: In Ahuzam - of 74 children, one had polio and died. (We refer here to the 11l.nder 4 years age group. ) In B~a ::-, n , among 93 children, 7 fell ill; in Eytan among 65 children, 5 fell a11 with 2 deaths; in Shalva among 83 children, 2 fell ill,one of whom died. In Noam as well as in the Rural Centre there were no cases. In Kiryat Gat which adjoins Uza (houses of t heses two places are very close to each other) there were 5 cases out of 550 children under 4. · The settlers of the Area had i mm igrated from North Africa,as follows: Ahuzam-Morocco; Eytan-Tunis,JerbaJ, Noam-Morocco; Uza and Shalva - Tripoli, It would seem tha.t most cases occurred in children whose parents came from Tripoli and the island of Jerba. This however was not f•and to be the case• in other settlements of the Region; "trhose settlers came from these countries. No correlation was found bet\•r een overcrowding and the polio cases. The 15 children who fell ill with polio had been given Salk va ccine as follows: TABLE 2: Salk Vaccination in the children with poliomyelitis. No, of children No. of Salk Vaccine Died.; with polio. Injections given

7 3 1 6 2 2 2 1 1 3.

On making enquiries into the possible relation between inoculations against diphtheria, tetanus, pertussis and smallpox vaccination in these children, and the time of their illness, no relationship was found. Some of the children had, in the t wo we eks preceding their illness, received intramuscular injections of Penicill in and Imferon, and it was p ossible to show a r elationship be~ween the place of injection and the affected limb. On the other hand tens of children had been given in the same peridd intramuscular injections of Peinicillin, Detamine and Imferon vl i t hout any harmful effects. MEASLES. In the Even-Shmuel Area, the measles epidemic first appeared in March 1958. and ended in June. This epidemic appeared in the different settlements in the following order in time: Ahuzam{ March), Shalva{April), Eytan(beginning of Ma y), and Uz a ( end of Ma y). The polio epidemic began in June and ended at the end of Huly. The order in time was as follows: Uz a , Eytan; Shalva and fina lly Ahuzam. It would appear therefore that the order in which the t wo epidemics affected the settlements was reversed. In the Area, the severest measles was in the settlements of Uza and Eytan,where of 66 children under 4 who fell ill with measles,36 had pulm­ onary complications (broncho-pneumonia, l aryngo-bronchitis) including 2 with heart failure following broncho-pneumonia. As emphasised above,polio as well was at its severest in the same t wo settlements. In all the settle me nts of the Area of 315 children under the age of four, 144 had measles and of tUem 12 subsequently developed polio. This contrasts with the 171 without preceding measles of whom t a re'? subsequently developed polio. (See Table 3). TABLE 3 - Relationshthp pf ]1easles to Polio cases. Settlement No. of No. with No. with No. with children mea sles polio mea sles+ under 4. polio Uza 93 34 7 6 Eytan 65 32 5 3 Sha lva 83 42 2 2 Ahuzam 74 36 1 1 Tota l 315 144 15 12. Statistical ana l ysis of the Table shows t hat the differ ence between the percentage of children who developed polio following measles (8.3%) a nd those who had polio without preceding measles (1.8%) is 6.5%. a difference that is significant. (:p< O.Ol). About half the number of children in the age-group a-7 years a lso con­ tracted measles, but there were no ca ses of polio in this age group . The time difference between the first symp toms of measles and those of polio were: 2-3 weeks in 7; 4 weeks in 3; over 4 weeks in 2. Since the incubation period of poliomyelitis is 1-3 weeks (with extremes of 3-35 days), it would appear that most of the children had contracted polio during the exanthematous stage of t heir mea sles. Apart from measles, the children with polio had not contracted any other acute illnesse s during the period pr eceding the ir polio. · Two days following the onset of polio symptoms in the l a st (5th) case found in Eytan, gamma - globulin in a dlhse of 0.35cc./kilo was given to 22 children in that s ettleme nt lL.'1d er 4 yea rs of a ge wh ose general condition was poor,, who had severe measles, who had not been i mmunised sa tisfa ctoril with 3al k vacc ine, or who were family conta cts of par alytic cases. -~ o more children f ell ill with ~olio after this da te, although some did in the other s ettlements J.. -~ At th~g t he polio epi demic ,the general s~ate of health of t he children in the mnd er 4 age group, was divided into 3 groups: poor, sa tisfa ctory a nd good. (After perusal of M.c.w. cards together with the nurse s llhoking after the children). Polio had not preferred one or other of these group s. ANAEMIA. In Uza during the period preceding t he polio epidemic, we knew from our routine haemoglobin e stimations of 4 children out of the 93 below 4 years of age whose haemoglobin was bet ween 7-9gr am s. 3 of j;hese 4 contracted poliomyelitis. In Eytan we knew of one child only out of the 65 with a haemoglobin of the same r ange (7gm.) Tb_is child too contracted polio. (We deal here only with children whose Hb was less t han 9 gm. J udging by f ull blood counts done on some of t hem a t r eliable l aboratories our estimations were accura t e ). .. 4. D I S C U S S I 0 H

As the polio epidemic in the Ashkelon Region continued, we were faced with the question a s to \-rhy t here was a l a r ge concentra tion of cases particularly in the Even-Shmuel Area , whereas in settlements adjoining the area the incidence was usual. An additional o,uestion was why just this year had this ar ea been so heavily attacked, whereas in previous years there had only been isolated case s. In our attempt to answer these questions, and on going over the data, we came to the conclusion that the following f a ctors we re not of impor­ tance in explaining the observed selection: Age , ethnic group, overcrowd­ ing, Salk vaccine, other inocula tions, a cute illnesses apart from measles, and the childrens' general state of health . It is true t hat in the Even-Shmuel a r ea t he incidence of polio was high, amongst the children of immigrants from Tripoli and the Island of Jerba . On the other hand there wer e no cases in Sde Uzia which has ~Tri p olitanian, and Tlamim with J erba immigr ants. All the same, it may be interesting to pay specia l a t tention to the c;. uestion of ethnic group , w~en the 1958 epidemic comes to be considered on a national scale. The suggestion of Yekutiel ( Yekutiel F. et a l. - Bull, Wld. Hlth. Org. 12: 674,1955) t hat sudden overcrowding may expl a in twax a sudden increa se in incidence (this was used to ~xp lain the inctease with the beginning of mass i mm i gr a tion) was not found to be applicable to the circumstances of Even-Shmuel, We kne1t1 the children under age 4 well, having doll owed them through from birth, and we were therefore able at the time of the epidemic, to a ssess their general state of he8lth. We formed the impression t hat the polio attacked chilsren without pr edilection for one partivular sta te of general health - poor, satisfactory or good. This is against the current belief we have found amongst doctors in Israel that polio s el ectively attacks children ingood general condition. IS'. MEASLES, (This discussion you have a lready con~ented on, In the i:tl:::sit draft sent you it wa s ext ended somewhat).

~NAEM IA, Of 5 children known to have had a severe a naemia, 4 contracted polio. These numbers are small, but raise the possibility tha t t hese children may be more sensitive to polio (chi ldren withsevere anaemia). In future it may be worthwh ile to consider this point in a large study. GAMMA-GLOBULIN, (Th is too you have already comm ented on). s UM!J.AR y. An epidemic of poliomyelitis in the Even-Shmuel Area is described,where the incidence was very high r el a ti.ve to other parts of the Ashkelon a r ea, In trying to understand why this should be so, 10 factors were considered, The followingwere not consideredto be of importance: Age, ethnic group, overcrowding, va ccina tion with Salk vaccine, other inoculations, acute illnesses apart from measles, a nd the children's general state of health b efore theepidemic. Neasles '"~ hich preceded the epidemic wa s an important factortj' explain~ l ing the phenomenon, Of the 15 children with polio, 12 had previously f allen ill with mea sles. 4 out of 5 children vri th s evere a.naemia,fell 111 withpolio. The effectiveness of giving gamma-globulin in the special conditions obta ining in t he Israel rura l settlement, is discussed. Our tha nks are due to St aff/Nurse Isra ela Shacharon of the Even-Shmuel Health Centre for her great help i n collecting the data, to Dr. M,Davies Acting Head of the Epidem iology Dept. of t he :ru n. of Health for his comments and to Dr. J. Shapiro Head of lhhe District Health Office, Ashkelon for his help,