The viral etiology of acute respiratory infections in children in Uganda

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Bulletin f the Wrld Health Organizatin, 55 (5): 625-631 (1977) The viral etilgy f acute respiratry infectins in children in Uganda. SOBtSLASK?,1 S. R. K. SEBKAR,2 P. S. E. G. HARLAD,3. SKRT,'. A.

1 Bulletin f the Wrld Health Organizatin, 55 (5): (1977) The viral etilgy f acute respiratry infectins in children in Uganda. SOBtSLASK?,1 S. R. K. SEBKAR,2 P. S. E. G. HARLAD,3. SKRT,'. A. FAYKA,' & A. D. SOEJ 4 The rle f viruses in respiratry diseases fyung children in Uganda was studied. A viral etilgy was established in 36%Y f the infectins investigated. The mst imprtant pathgens were fund t be respiratry syncytial virus andparainfluenza viruses, which were respnsible fr 26%Z f infectins investigated. They caused bth upper and lwer respiratry tract diseases. There was little r n seasnal variatin in the etilgy f these infectins. Adenviruses were fund t be less imprtant and were etilgically related t nly 4 % f respiratry disease cases. nfluenza viruses and enterviruses were als fund t be assciated with respiratry infectins. Hwever, they were less frequent and their rle was insignificant. The rle f multiple virus infectins was als insignificant. nsiderable knwledge n the viral etilgy f acute respiratry infectins has been accumulated (1, 2, 3). Hwever, mst f these data riginate frm studies carried ut in cuntries with a temperate climate, whereas the prblem has been studied t a lesser extent in the trpics. n many develping cuntries little is knwn n the subject, althugh acute diseases f the respiratry tract, particularly in children, are an imprtant public health prblem (4) and lngitudinal studies f rural Ugandan children have shwn that kwashirkr may develp fllwing the anrexia that ften accmpanies infectins, including thse f the respiratry tract (17). n additin, a knwledge f the etilgy f such infectins is a prerequisite fr any steps leading t their cntrl. The prblem is therefre f great cncern t WHO, and it was decided t begin t study this questin in Uganda, where a WHO Team fr Special Studies in irlgy has been perating since LHead, WHO irus Study Team, Entebbe, Uganda. Present address: Medical Officer, irus Diseases, Wrld Health Organizatin, 1211 Geneva 27, Switzerland. Requests fr reprints shuld be addressed t Dr Sbeslavsky. ' nsultant Paediatrician, Department f Paediatrics, Mulag Hspital, Makerere University, Kampala, Uganda. ' Paediatrician, Medical Research uncil hild utritin Unit. Present address: Prfessr, Department f hild Health, University f the West ndies, Mna, Kingstn 7, Jamaica. Technical Officer, WHO irus Study Team, Entebbe, Uganda. MATERAL AD METHODS Study area The study was carried ut frm April 1972 t Octber 1973, in clse cllabratin with the Department f Paediatrics, Mulag Hspital, Kampala, and with the child welfare clinics f the Medical Research uncil, in an area surrunding the cities f Kampala and Entebbe. The altitude f the regin is abut 13 m and the temperature is mderate, usually nt exceeding 28 r falling belw 9. The rainy seasns (April-June and Octber-December) are distinct frm the dry seasns, althugh the relative humidity is high thrughut the year. The three-mnth mean temperatures, relative humidity, and rainfall f the area, as established during the study perid, are shwn in Table 1. Study ppulatin The study ppulatin cnsisted f inpatients and utpatients aged -3 years with acute upper r acute lwer respiratry tract disease classified as upper respiratry infectin (UR), brnchitis, brnchilitis, r brnchpneumnia. The clinical diagnsis was established after physical examinatin and auscultatin f the patients. X-rays were taken nly in exceptinal cases. The cntrl grup cnsisted f children f the same age and frm the same area suffering frm kwashirkr but with n signs f respiratry disease. Bth sexes were represented apprximately equally in bth grups

626. SOBESLASKY ET AL. Table 1. Three-mnth mean temperatures, relative humidity, and rainfall in the Kampala-Entebbe regin, April 1972-September 1973 April-June July- Octber- January-.

2 626. SOBESLASKY ET AL. Table 1. Three-mnth mean temperatures, relative humidity, and rainfall in the Kampala-Entebbe regin, April 1972-September 1973 April-June July- Octber- January-. July September December March 1973 April-une September Temperature (') Relative humidity (%) Rainfall (mm) Material cllected Thrat and nasal swabs fr the islatin f viruses and mycplasmas, and acute and cnvalescent serum samples, were cllected frm the patients fr serlgical investigatin. The thrat and nasal swabs fr virus islatin were pled immediately after cllectin in 3 ml f transprt medium (medium % albumin + a mixture f antibitics), whereas the thrat swabs fr mycplasma islatin were transprted in 3 ml f PPLO brth (Difc) supplemented with penicillin. Bth kinds f swab were kept under refrigeratin befre being further prcessed in the labratryusually within 4-6 hurs. Labratry techniques slatin experiments were carried ut in HeLa, Hep-2, and primary vervet mnkey kidney tissue cultures, as well as in mycplasma artificial brth and agar media (5). Three passages (1 days each) were perfrmed befre the specimen was cnsidered negative. dentificatin f recvered strains was perfrmed by standard haemadsrptin inhibitin r neutralizatin test prcedures (5). slated Mycplasma species were identified by the grwth inhibitin test (5). Sme f the identificatin experiments were carried ut by the WHO llabrating entre fr Animal Mycplasmas, Aarhus, Denmark. Acute and cnvalescent sera frm patients were stred at -2 and tested simultaneusly against the fllwing cmplement-fixing (F) antigens: influenza A and B; parainfluenza types 1, 2, and 3; respiratry syncytial (RS) virus; adenvirus (grup); herpesvirus hminis; and Mycplasma pneumniae. The cmplement fixatin test was perfrmed in micrtitre plates with standard methds (5). Sera were inactivated fr 3 min at 56 prir t testing; 2-8 units f antigen and 2 units f cmplement with vernight fixatin were used. Sera frm which enterviruses were recvered were als tested fr an increase in neutralizing antibdy against the strain islated. Fur-fld r higher antibdy rises between acute and cnvalescent serum samples were cnsidered as psitive, regardless f whether r nt the virus had been islated frm the patient. RESULTS Rates f virus and mycplasma recvery frm patients with varius frms f respiratry infectin, and frm the cntrl grup (kwashirkr patients), are presented in Table 2. Of 662 thrat and nasal swabs taken frm respiratry-disease patients, 18 % yielded viruses and 2%, mycplasmas. The crrespnding prprtins, fr the 222 thrat and nasal swabs taken frm kwashirkr patients, were 9% and 18%. Althugh the mycplasma recvery rates f these tw grups f patients were similar, virus recvery rates in children with kwashirkr were significantly lwer than thse fr children with respiratry infectins. There was n significant difference in the number f viruses and mycplasmas recvered Table 2. iral and mycplasma recvery rates in children -3 years f age with respiratry infectins, by clinical diagnsis, and in the cntrl grup (kwashirkr) hildren psitive fr: Diagnsis tested virus mycplasma. %. % UR Brnchitis Brnchilitis Brnchpneumnia Ttal ntrl grup (kwashirkr)

3 RAL RESPRATORY FETOS 627 D." frm male and female patients, nr was there any,d O X 8 O > ^ significant difference in virus and mycplasma recv- Q eries in patients with UR, brnchitis, r brnch- > ^ - pneumnia. The number f patients with brnchili-.2, 6c tis was t small t be evaluated. > X The(Dpattern f virus types recvered frm patients l<rv D with respiratry infectins and frm the cntrl ) - m c grup is presented in Table 3. n ttal, 116 virus " strains were recvered frm patients with O respiratry lem X infectins. Of these, adenviruses were the mst > frequently islated (33 %) fllwed by cxsackie- E viruses (2%), parainfluenza viruses (13 %), pli- c 2 viruses and herpesvirus hminis (12%), echviruses ed (9%), and RS virus (1 %). Frm the patients with c m X kwashirkr, 19 virus strains were recvered in all. Adenviruses were islated with apprximately the. X X. same frequency (38 %) frm patients with kwashir- >. O - kr as frm thse with respiratry diseases. Hwever, --, X there were differences in the types recvered. Aden- m _ l l viruses types 1, 2, and 6 were cmmn islates in - _. _ bth grups, whereas types 3,7, 11, 14, and 21 were t DQ islated nly frm the respiratry disease grup. The c E 2 recvery rates f pliviruses (16 %) and echviruses _ (1%) were als cmparable in the tw grups. X Hwever, a wider variety f virus types was seen in b. >respiratry disease patients. Herpesvirus hminis > ev was mre frequently islated in kwashirkr child- X _ ren, whereas cxsackieviruses were far less frequently B, > ^ ^ islated in this grup. n additin, n parainfluenza r m DO ^.-.- RS virus was recvered frm these patients. There ~ were n significant differences in the virus types recvered in UR, brnchitis, and brnchpneumnia patients, nr was there a significant seasnal preva- _ lence f virus types in these infectins. n apprxid ~- _mately5 % f cases, 2-3 different viruses-mainly a, cmbinatins f adenviruses and echviruses r c X X X cxsackievirus grups-were recvered simulta- E D neusly frm the same patient. 2. Unlike viruses, mycplasma species islated frm X c patients with varius respiratry diseases and frm the cntrl grup were cmparable, with the excep ), l tin f M. pneumniae, which was islated nly frm a child with kwashirkr, withut any vert respira- ( q) try disease (Table 4). The results f serlgical investigatin, regardless 'Q ZBc c M 62 _ Z F.- ) _ U6 f virus islatin, frm patients with varius frms f respiratry disease and frm the cntrl grup are presented in Table 5. Altgether 45 patients with Xi,.".w O O respiratry disease were investigated, the viral eti-. E, =" lgy being established in 36 % f cases. RS virus was -s > :".X fund t be the mst imprtant pathgen, since it Mm, Mrm 25i was respnsible fr 17% f all these infectins. ext

628. SOBESLASK ET AL. Table 4. Pattern f mycplasmas recvered frm children -3 years f age with varius frms f respiratry diseases, and frm the cntrl grup (kwashirkr).

4 628. SOBESLASK ET AL. Table 4. Pattern f mycplasmas recvered frm children -3 years f age with varius frms f respiratry diseases, and frm the cntrl grup (kwashirkr). f Mcpam pce Diagnsis mycplasmas Mycplasma species (%) (1%) M. salivarium M. rale M. hminis M. pneumniae UR Brnchitis Brnchilitis Brnchpneumnia Ttal ntrl grup (kwashirkr) came parainfluenza viruses (9 %) and adenviruses (4%). n the parainfluenza grup, type 3 was the mst cmmn (5%), fllwed by type 1 (3%) and type 2 (1 %). The rle f ther virus grups, such as influenza virus, cxsackievirus, and echvirus, was much less imprtant. The same applies t cases f respiratry infectin in which tw types f virus were invlved simultaneusly. There were cmbinatins f RS virus and adenvirus, RS virus and parainfluenza viru stype 3, RS virus and cxsackievirus type B3, and RS virus and cxsackievirus type B4. significant difference in the etilgy f infectins was seen with respect t sex. Regarding the varius clinical categries f respiratry disease, the mst frequent pathgens f the lwer respiratry tract were fund t be RS virus and parainfluenza viruses. The frmer was respnsible fr 13% f brnchitis, 25% f brnchilitis, and 2% f brnchpneumnia cases; the latter, fr 16% f brnchitis and 7% f brnchpneumnia cases. These tw categries f virus were als fund t be imprtant pathgens f upper respiratry tract infectins, in mre than 23% f which they were etilgically invlved. Adenviruses were less imprtant in these infectin, being etilgically invlved in 7% f UR, 3 % f brnchitis, and 4% f brnchpneumnia cases. The rle f ther virus grups, namely influenzavirus, cxsackievirus, and echvirus, r a cmbinatin f virus types, was f minr imprtance. A 16-fld rise f F antibdy t RS virus ccurred in a kwashirkr patient withut any sign f respiratry infectin. Table 6 shws the etilgy f respiratry infectins bserved during the study perid. There was little seasnal variatin in the prevalence f infectins due t mst f the tested viruses, especially RS virus, which was respnsible fr 15-22% f infectins in each f the seasns under study. The prevalence f parainfluenza virus infectins ranged frm 7% t 11 % except fr the perid Octber-December 1972, during which 19 % f these infectins were detected. They were due mainly t parainfluenza virus type 3, which alne was respnsible fr 14% f them. n ther seasns, the prevalence did nt exceed 5 %. Adenvirus infectins als shwed little seasnal variatin except fr the perid April-June 1972, when n such infectins were bserved. Respiratry infectins due t cxsackieviruses and echviruses were fund t be less frequent and evenly distributed thrughut the study perid. They were, hwever, nt detected between January and March 1973-the nly seasn when few cases f influenza A and B were detected. DSUSSO The results f the study cnfirmed the imprtant rle f certain respiratry viruses in the etilgy f acute respiratry disease in infants and yung children in Uganda. Mre than ne-third f the cases f this disease were f viral rigin. The mst imprtant f the viruses invlved appeared t be RS virus and parainfluenza viruses, which were invlved in 26% f all respiratry infectins investigated. Even this high prprtin may be an underestimatin when it is taken int cnsideratin that nt all RS virus infectins may be detected by cmplement fixatin tests, especially in infants and yung children. n previus studies carried ut in the trpics, RS virus and parainfluenza virus infectins were shwn t be assciated mainly with lwer respiratry tract disease, and they ccurred either spradically r in

5 RAL RESPRATORY FETOS 629 a UM u E - X E. (Dn >.O *X+ cm 6.? (A> + ca _ v- % n U.' E = 2 c (U 22rm ".-5D a +c /)-,+ a > + + W-5 2 -c - T. (U Q. ) 76 -.u cn ) D cv) w Q U.. D.(U. c c) 11 ) ). rs ) m )) n= d a ) dnib snj!aougp snjia SU (.. c2 cv). 5 c= (U.. u > m O, '5* <: cl. _ r' M w _- - r- u r- -t _ u _ u f'r c u cd D a (a a). ) (a t a) Y) n 1.g a ai) - :2.. a D.) a (A c u...n 8 a 4- m ).- tl *X> ). Lc c dnib SflJ!Auep SflJ!A SSi.24..) O L.c5 <: c il - rs E'4 r D > D u *- _ 1 S az LO c U u D (D 1-- JL D r-. l. Lu v- l ".!,. a= l.2 :E.2 8 m r-a *,(U m2. -l D3 c )c - u 1) ( u u L- % D c c D ) U) D L) -<) Xaw. ss * O -a2 <7 n <:

6 63. SOB'ESLASKY ET AL. small epidemic utbreaks during the cl mnths f the year r in the rainy seasn (6, 7, 8, 9). n this study, bth upper and lwer respiratry tract infectins due t these viruses were detected. marked seasnal distributin was bserved, a rather endemic pattern f prevalence being seen thrughut the year. The factrs influencing such prevalence are nt knwn, and further lng-term studies are needed t elucidate the prblem. Hwever, a similar pattern f prevalence was bserved als in anther trpical cuntry (1). Althugh the number f RS virus infectins detected serlgically was high, the rate at which the virus was islated frm specimens cllected frm patients was very lw. This may have been due t the adverse effect f transprt, t the lw sensitivity f the Hep-2 and HeLa cell lines used fr islatin purpses, r t the fact that specimens were cllected at a late stage in the disease, since children were ften brught t the clinic several days after the nset f the infectin. This may als explain the lw recvery rate f parainfluenza viruses frm patients cmpared with the high number f psitive results f serlgical tests. These difficulties clearly demnstrate the need fr ther techniques, such as immunflurescence, which nt nly give an answer rapidly but vercme prblems related t temperature, transprt, cell variability, and the arrival f specimens late in the curse f the illness (11). Adenviruses were the viruses mst frequently recvered in this study; hwever, they seemed t be less imprtant than RS virus and parainfluenza viruses in the acute respiratry infectins investigated. Mst f the adenvirus strains islated were f types 1 and 2, which are knwn t be cmmnly islated frm nrmal children in temperate climates (12). These strains were islated with apprximately the same frequency frm children with respiratry disease and frm the cntrl grup f children. evertheless, they were respnsible fr 7 % f upper respiratry tract infectins and the rle f higher types (especially type 7) in lwer respiratry tract disease shuld nt be verlked. n additin t adenviruses, a wide variety f enterviruses were recvered frm thrat swab specimens. Hwever, their rle in acute respiratry infectins, cmpared with that f respiratry viruses, was insignificant. nfectins in which tw different types f virus were invlved have been reprted in previus studies (6, 9, 13). n this study, we als bserved such cases, althugh they were few in number. Furthermre, it is nt entirely clear whether these were true dual infectins r whether sequential infectin ccurred. t is f interest that, in all such cases, ne f the infecting agents was RS virus. The rle f herpesvirus hminis in respiratry diseases has nt yet been clearly defined (1, 14, 15). n ur study, numerus strains f that virus were islated frm bth respiratry disease patients and cntrls. Hwever, n antibdy rises in any f the patients r cntrls were detected. The recvery f a relatively large number f plivirus strains is nt surprising, since plimyelitis is endemic in the study area and immunizatin against the disease was carried ut simultaneusly with the study. Unlike viruses, M. pneumniae played a negligible rle in the respiratry diseases f childhd investigated, since neither the rganism nr a rise in antibdy t it was detected. These findings crrespnd t thse reprted in temperate climates (16). On the ther hand, M. pneumniae was islated frm the respiratry tract f a symptmless child with kwashirkr. Hwever, n serum was available frm this case t prve the infectin. Other human mycplasma species were recvered with apprximately the same frequency frm bth grups f children, and their distributin, als, is in agreement with previus findings (16). AKOWLEDGEMETS The data given in Table 1 were cmpiled and supplied by H.. Mwakitsi frm the Hydrmeterlgical Survey f Lakes ictria, Kyga, and Albert, Entebbe, Uganda. The typing antisera were supplied by the Research Resurces Branch, AD, atinal nstitutes f Health, Bethesda, MD, USA, and by the WHO llabrating entre fr irus Reference and Research, Hustn, TX, USA. The Public Health Labratry Service, lindale, Lndn, England, supplied the cmplement-fixing antigens listed n page 626.

RAL RESPRATORY FETOS 631 RESUME L ETOLOGE RALE D'FETOS RESPRATORES AGUES HEZ LES EFATS E OUGADA Le rle des virus dans les maladies respiratires chez les nurrissns et les jeunes enfants en Ouganda a

7 RAL RESPRATORY FETOS 631 RESUME L ETOLOGE RALE D'FETOS RESPRATORES AGUES HEZ LES EFATS E OUGADA Le rle des virus dans les maladies respiratires chez les nurrissns et les jeunes enfants en Ouganda a ete recherche. L'etilgie virale a ete cnfirmdee dans 36% des infectins etudiees. s'est r6vel6 que les agents pathgenes les plus imprtants 6taient les virus respiratires syncytiaux (RS) et les virus parainfluenza, qui etaient respnsables de 26% de la ttalite des infectins respiratires etudiees. ls prvquaient des affectins des vies respiratires superieures et prfndes. La frequence de ces infectins ne cnnaissait que des variatins saisnnieres minimes, sinn nulles, mais la prevalence avait plut6t une allure endemique. l a ete truve que les adenvirus snt peu imprtants et n'nt de relatin etilgique qu'avec 4 % des cas de maladies respiratires. En utre, des virus grippaux de meme que des entervirus nt ete truves asscies avec des infectins respiratires, mais plus rarement, et leur r6le etait insignifiant. Les infectins virales mixtes se snt 6galement revelees peu imprtantes. REFEREES 1. HORSEFALL, F. L. & TAMM,. iral and rickettsial infectins f man, 4th ed. Philadelphia, Lippinctt, HRSTiE, A. B. nfectius diseases: epidemilgy and clinicalpractice, 2nd ed. Edinburgh, hurchill-livingstne, WHO TEHAL REPORT SEREs,. 48, 1969 (Respiratry viruses, reprt f a WHO Scientific Grup). 4. OKBUR W. HAS. & ASSAAD, F. Sme bservatins n the cmmunicable diseases as public health prblems. Bulletin f the Wrld Health Organizatin, 49: 1 (1973). 5. LEEiTE, E. H. & SHMDT,. Diagnstic prcedures fr viral and rickettsial infectins, 4th ed. ew Yrk, American Public Health Assciatin, JEGs, R. & GRAT, L. S. Respiratry viruses in Jamaica: a virlgic and serlgic study. American jurnal f epidemilgy, 86: 69 (1967). 7. BiSO, A. L. ET AL. An utbreak f acute respiratry disease in Trinidad assciated with parainfluenza viruses. American jurnal f epidemilgy, 91: 68 (197). 8. SPEE, L. & BARUA,. Respiratry syncytial virus assciated with acute respiratry infectins in Trinidadian patients. American jurnal f epidemilgy, 88: 257 (1968). 9. HAOK, R. M. ET AL. WHO respiratry disease survey in children: a serlgical study. Bulletin f the Wrld Health Organizatin, 37: 363 (1967). 1. KLOEE, W. ET AL. A tw-year respiratry virus survey in fur villages in West Bengal, ndia. American jurnal f epidemilgy, 92: 37 (197). 11. GARDER, P. S. & MQULL, J. Rapid virus diagnsis-applicatin fimmunflurescence. Butterwrth, Fx, J. P. ET AL. The virus watch prgram: a cntinuing surveillance f viral infectins in Metrplitan ew Yrk families,. Observatin f adenvirus infectins, virus excretin pattern, antibdy respnse, efficiency f surveillance, patterns f infectins, and relatin t illness. American jurnal f epidemilgy, 89: 25 (1969). 13. Fy, H. M. ET AL. ncidence and aetilgy f pneumnia, crup, and brnchilitis in pre-schl children belnging t a pre-paid medical care grup ver a fur-year perid. American jurnal f epidemilgy, 97: 8 (1973). 14. POLAD, J. D. ET AL. iruses and disease: studies in a children's hme. American jurnal f epidemilgy, 84: 92 (1966). 15. MuFsO, M. A. ET AL. Etilgy f upper respiratry tract illnesses amng civilian adults. Jurnal f the American Medical Assciatin, 195: 1 (1966). 16. HAOK, R. M. Mycplasma infectins f man. ew England jurnal f medicine, 273: 1199, 1257 (1965). 17. PsKrrr, E. M. E. Seasnal variatin in infectin and malnutritin at a rural paediatric clinic in Uganda. Transactins f the Ryal Sciety f Trpical Medicine and Hygiene, 23: 931 (1972).

Rhinovirus infections

Rhinovirus infections Pstgraduate Medical Jurnal (Nvember 1973) 49, 802-806. Rhinvirus infectins P. G. HGGNS Virus Reference Labratry, Central Public Health Labratry, Clindale Avenue, Lndn NW9 5HT Sunmary One hundred and seventy-five