Journal of Infection (1992 ) 24, 31-36

V i r u s i n f e c t i o n s o f the r e s p i r a t o r y t r a c t in H I V - i n f e c t e d c h i l d r e n

R. A. Hague,*~ S. E. B u r n s , t F. D. H a r g r e a v e s , t J. Y. Q. Mok* a n d P . L. Yap:[:

* Infectious Diseases Unit, City Hospital, Edinburgh, ~f Regional Virus Laboratory, City Hospital, Edinburgh and Edinburgh and South East

Scotland Blood Transfusion Service, Edinburgh, Scotland, U.K.

Accepted for publication I August 1991

S u m m a r y

In order to determine whether the rates of respiratory viral infection and the severity of respiratory symptoms in HIV-infected children were higher than those in non- infected children, nose and throat swabs for viral isolation were taken at 3-month intervals during the first 2 years of life from 5o children born to HIV-infected women. Similar samples were obtained during the first year of life from 19 control children born to HIV seronegative mothers. Of the 5o children, five proved to be HIV-infected while 45 were presumed to be uninfected. HIV-infected children had significantly more respiratory symptoms and a higher proportion of samples from which viruses were isolated than the non-HIV-infected children. Also, more infected episodes required admission to hospital in the HIV-infected group. There was no such difference between the non-HIV-infected and the control children. Three HIV- infected children received intravenous immunoglobulin therapy. Among these the proportion of positive samples for viral isolation was greater before than after treatment began. These results suggest that HIV-infected children are more susceptible to recurrent viral infection and that passive immunotherapy may be of benefit to such children.

Introduction

T h e susceptibil i ty of HIV- in f ec t ed chi ldren to respiratory infections caused by bacteria and o ther oppor tunis t ic organisms is wel l - recorded, 1-3 but the natural h is tory of respiratory infections due to viruses in such chi ldren has received little attention. We therefore under took a prospect ive s tudy of H I V - infected chi ldren in order to de termine whether the rates of respiratory viral isolation and the severity of respira tory symptoms in HIV- in f ec t ed were higher than in n o n - H I V - i n f e c t e d chi ldren using as controls chi ldren f rom the same socio-economic group.

Patients and methods

All the chi ldren were among those part icipat ing in the Ed inbu rgh H I V Perinatal Transmiss ion Study. 4'5 Fif ty chi ldren born to H I V seroposit ive mothers below the age of 2 years were s tudied prospect ively. Five (group A)

Address correspondence to : Dr R. A. Hague, Department of Paediatrics, Royal Victoria Infirmary, Newcastle upon Tyne NEI 4LP, U.K.

oi63-4453/92/oioo3I +06 $03.00/0 © 1992 The British Society for the Study of Infection

32 R. A. H A G U E E T A L .

proved to be infected with HIV . ~ One died at 4 months , the remaining four being aged 33-71 months. Three of these children were treated with intravenous immunoglobul in (IV IgG), 2oo m g / k g every 3 weeks as previously described. 7 Another group of 45 children (group B) were considered not to be infected with H I V since they were clinically well and repeatedly H I V ant ibody and antigen negative. As an additional control group, I9 children whose fathers were H I V seropositive bu t whose mothers were H I V seronegative were also investigated for a period of I year (group C), thereafter declining further participation.

All children in the s tudy were seen at 3 monthly intervals and symptoms suggestive of respiratory infection since the previous visit were recorded. Children were examined for signs of respiratory infection. Nose and throat swabs were taken and placed together in viral t ransport medium. One set of swabs was taken at each visit but results of specimens taken during admission to hospital were not included in this study. Results were analysed by means of the X 2 test for statistical significance.

Virological methods

Nose and throat swabs taken from each child were combined in a single vial of viral t ransport med ium containing antibiotics to suppress bacterial growth as well as fetal calf serum to stabilise the virus. The samples were t ranspor ted to the laboratory within 2 h. I f any delay was anticipated, swabs in t ransport med ium were stored at 4 °C before transport. In the laboratory, cells collected on the swabs were resuspended in a small volume of t ransport m e d i u m before they were inoculated into cultures of pr imary baboon kidney, human epithelial cells (HEp2) and human fibroblasts (MRC5) . The inoculated cells were incubated at 36 °C and examined twice weekly for evidence of a cytopathic effect. Fur ther confirmatory tests were made on cells affected. Influenza, parainfluenza, respiratory syncytial (RS), measles, and herpes simplex viruses were confirmed by means of monoclonal or polyclonal antibodies in a fluorescent ant ibody test. s Adenovirus , Coxsackie and Echo viruses were identified by neutralisation tests. 9 Rhinovirus was identified by acid stability testing. Cytomegalovirus (CMV) was identified by its characteristic cytopathic effect on M R C 5 cells.

Results

A total of 3oi samples was collected over a period of 24 months. Results are summarised in Table I. Al though a few opportuni t ies for sampling were missed, these did not differ be tween groups. Group A had significantly more respiratory infections and more samples positive for viral isolation than group B. Over the first year, however , groups B and C did not differ significantly (Table II).

T h e viruses isolated are listed in Table I I I . There was no significant difference among the three groups in the propor t ion of positive virus isolations associated with symptoms. Symptoms usually accompanied infections with influenza A, parainfluenza, RS and adenovirus infections, whereas isolation of C M V or Coxsackie virus was more often asymptomatic . Six of the IO proven

Table I

Virus infections in HIV-infected children 33

Episodes of respiratory infection and virus isolation in HIV-infected and non-infected children in the first 2 years of life

G r o u p A B P*

N u m b e r of pa t ien ts 5 N u m b e r of samples 30 Age range (mean, median) 3-24 (14"5, 15)

N u m b e r of missed sampl ing 4 / 3 4 ( I I ' 8 ) oppor tun i t i e s (%)

N u m b e r of symptoma t i c episodes of 14 respi ra tory infect ion

N u m b e r of posi t ive vi rus isolations Io

45 220

3-24 (I4"O, I5 ) 22 /242 (9"1)

41

32

N,N,

N.S.

< O'OI

< 0'05

* Accord ing to the X 2 test. N.S., N o t significant.

Table II Episodes of respiratory infection and virus isolation in the two control groups of HIV-non-infected children in the first year of life

G r o u p B C P

N u m b e r of pa t ien ts N u m b e r of samples Age range (mean, median) N u m b e r of missed sampl ing oppor tun i t i e s

(%) N u m b e r of symptoma t i c episodes N u m b e r of posi t ive vi rus isolations

3 ° I9 IO4 5 I

3 - I 2 (7"5, 9) 3 - I 2 (7"9, 9) N.S. I I / I I 5 (9"6%) 6 / 5 7 (IO'5 % ) N.S.

t3 5 N.S. 15 8 N.S.

Table I I I Virus isolations from HIV-infected and non-infected children in the first 2 years of life. Comparison of symptomatic and asymptomatic children

Symptoma t i c A s y mp t o ma t i c

Virus A B A B To ta l

Adenov i rus 2 2 o I 5 Inf luenza o 3 o o 3 P a r a i n f l u e n z a 2 2 0 I 5

Respi ra tory syncytial o 3 o I 4 R h i n o v i r u s I 4 o 3 8 Cytomega lov i rus 3 I 2 5 I I Herpes s implex I o I o I 2 Coxsackie B 0 0 0 2 2 Measles 0 I 0 0 I Echov i rus o o o i 1

To ta l 8 17 2 15 42

2 JIN24

34 R. A. H A G U E E T A L .

viral infections in group A necessitated admission to hospital, compared with 9 /32 in group B, a difference which was significant (P < o'05). All three children with influenza A infection were admit ted to hospital. Others were infected with RSV (three in group B), parainfluenza (two in group A, were in group B), adenovirus (two in group A, one in group B) and measles (one in group B). None of the children required assisted ventilation or specific antiviral therapy. Al though upper respiratory tract symptoms sometimes accompanied isolation of C M V , C M V pneumonit is was not evident.

The three children from group A who suffered from recurrent infections were given infusions of intravenous immunoglobul in (IV IgG) as prophylaxis against recurrent bacterial infections. In these children, the propor t ion of positive virus isolation specimens before t reatment began was 7 / I I, compared with 3/13 subsequent ly , a decrease which also was significant (P < o'o5). None of the children was treated with zidovudine during this time.

In one child in group B, influenza A infection was associated with a p rofound drop in the C D 4 + lymphocyte count from 2-o4x Iog/ml - 0"27 x Iog/ml and in the T 4 / T 8 cell ratio form I '9-o '5. These re turned to their previous values on recovery from the illness. We therefore analysed the effects of respiratory symptoms and viral isolation on mean T 4 cell counts for groups A and B. No significant difference in mean values was observed be tween samples taken when the children were asymptomat ic and when they had symptoms or a virus was isolated for either group, al though the mean was lower in all infected children (0"99 x io~/1 in group A and 2"69 x io9/1 in group B). Similarly, no change was seen in CD8 + lymphocyte concentrations.

D i s c u s s i o n

T h e susceptibil i ty of HIV- in fec ted children to bacterial respiratory infection is well-known, 1 and coincides with a deficiency of antibody. Since H I V - infected children also have a cellular immunodeficiency, they might be expected to be more susceptible to acute viral infections bu t only two case reports support ing this suggestion have so far been published. 1°'11

Despi te the smaller number of children proving to be HIV- in fec t ed among those we studied (5/5o) than we had anticipated, 12' 13 we found a significantly increased rate of respiratory viral isolation in the first 2 years of life compared with appropriate controls. This may be due either to H I V infection causing greater susceptibil i ty after exposure to viruses other than H I V , or to a greater virus load and more prolonged excretion during any given episode, so making viral isolation on sampling at intervals more likely. We have not seen the chronic excretion of agents such as parainfluenza virus, which has been reported by others. H Moreover , it was perhaps fortuitous that our H I V - infected children escaped RSV when infections were widely prevalent in the communi ty , since prolonged viral carriage and a mortal i ty rate as high as 20 % in severely immunocompromised HIV- in fec ted children has been reported. TM

In our study, we used two different control groups of children who had the same social background as the HIV- in fec ted children. We have thereby demonstra ted that children born to H I V seropositive mothers who are not HIV- in fec ted do not differ in their rates of respiratory infection from those not

V i r u s in fec t ions in H I V - i n f e c t e d ch i ldren 35

e x p o s e d to the r isk o f H I V infec t ion . I n all t h r ee g r o u p s , p o o r h o u s i n g , o v e r c r o w d i n g , a n d p a r e n t a l s m o k i n g hab i t s m a y h a v e c o n t r i b u t e d to a h ighe r t h a n ave rage m o r b i d i t y in th is respec t .

T h e f ind ing o f f ewer pos i t i ve v i ra l isolates in H I V - i n f e c t e d ch i ld r en fo l lowing IV I g G t h e r a p y s h o u l d be i n t e r p r e t e d w i th cau t ion s ince da ta are ava i lab le on on ly t h r e e ch i ld ren . O n e poss ib l e e x p l a n a t i o n cou ld be tha t ch i l d r en o u t g r o w suscep t ib i l i t y to v i ra l i n fec t ion a f t e r the first yea r o f life b u t th is is no t b o r n e ou t b y the ra tes in g r o u p B ch i l d r en w h i c h were c o n s t a n t b e t w e e n the 2 years . I m m u n o g l o b u l i n t h e r a p y has b e e n s h o w n to p r e v e n t E c h o v i r u s in fec t ion , 14 r e d u c e the s h e d d i n g o f R S V , 15 a n d m a y h a v e benef ic ia l effects in C M V infec t ion , 1G sugges t i ng t ha t the r e d u c t i o n o f vi ra l isolates m a y h a v e b e e n a benef ic ia l s ide-e f fec t o f IV I g G t h e r a p y .

W e c o n c l u d e t h a t r e s p i r a t o r y v i ra l in fec t ions ar ise m o r e o f t en in H I V - i n f ec t ed ch i ld ren . G i v e n the u b i q u i t o u s n a t u r e o f these agen ts and the lack o f ava i lab le specif ic t h e r a p y for t r e a t m e n t or p r o p h y l a x i s , f u r t h e r s tud ies are r e q u i r e d in l a rger g r o u p s o f H I V - i n f e c t e d ch i l d r en to assess the inc idence o f r e c u r r e n t v i ra l in fec t ions a n d the i r in f luence on the p r o g r e s s i o n o f H I V disease t o g e t h e r w i th the role o f i m m u n o t h e r a p y such as the ear ly use o f IV I g G .

(R. A. Hague was supported for this work by the Medical Research Council. We would like to thank the A I D S Virus Education and Research Trus t for financial support as well as J. Whitelaw, of the Edinburgh and South East Scotland Blood Transfus ion Service H I V immunology laboratory for providing the data on lymphocyte subsets.)

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