Early childhood infectious diseases and the development of asthma up to school age: a birth cohort study
BMJ 2001; 322 doi: https://doi.org/10.1136/bmj.322.7283.390 (Published 17 February 2001) Cite this as: BMJ 2001;322:390
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The stereotype outlined by Zwitter (May 25 2001) for a typical
Hodgkin's disease patient can be viewed from another angle. The first or
only child of a well to do family in a single family house with few
playmates and few childhood infections may conjure up an alternate
impression. As mentioned previously ( 6 Feb 2000 -Childhood Leukaemia :
Why First born ?) such children may have a particularly strong parental
bond and are generally handled and cuddled more often. As 'first
prototype' they are recipients of undivided attention and affection and
particularly precious.
A failure to find a single virus responsible for the development of
Hodgkin's disease may have resulted from a search in the wrong place. In
cat leukaemia the continued presence of virus does not appear to be
necessary once endogenous oncogene has been permanently switched on
(Jarrett W F H, Cancer : New horizons. In Practise 1982 115-118).
In addition to viral probes of cases themselves perhaps a search in
maternal blood might be rewarding ?. The converse to Zwitter et al's
thesis that Hodgkin's disease is a failure of immune regulation due to
'over protection' from virus might instead be an exaggerated degree of
closeness to an as yet unrecognized infective agent (e.g. retrovirus).
Meanwhile the suggestion that asthma risk is lower in children with
respiratory infections in the first year of life is at variance with my
own paediatric experience. A high incidence of infant bronchiolitis due
to RSV has had a significant association with the later development of
asthma. Regarding 'infection' as a prognosticator for future asthma
development the operative word would appear to be 'mild'.
James E Parker
Competing interests: No competing interests
SIMILAR PREDISPOSING FACTORS TO ASTHMA AND HODGKIN'S DISEASE
Children with frequent mild infections during the first year of life
have a lower risk for developing asthma up to school age (1). The German
longitudinal study thus confirms previous reports that exposition to
infectious agents stimulates maturation of the immune system. The early
type 2 response characterised by the production of interleukins 4 and 5,
of IgE, eosinophilia and predisposition to atopy and asthma is replaced by
type 1 response with secretion of interferon ? and much more effective
elimination of viruses (2).
Atopy and asthma may not be the only diseases to which children with
few infections are inclined. While Hodgkin's disease is a heterogeneous
disorder with a typical bimodal incidence curve and marked geographical
differences, the risk factors for children and young adults in developed
countries have been clearly described. A typical patient with Hodgkin's
disease, most often of the nodular sclerosis type, would be the first or
the only child of a well-to-do family, have an educated mother, spend the
childhood in a single-family house with few playmates, and have few
childhood infections (3, 4).
A link between these epidemiological observations and the
pathogenesis of Hodgkin's disease remains unclear. The prevailing view is
that Hodgkin's disease is a rare consequence of a late infection with a
certain common virus. When compared to infections early in childhood, such
'late' infections are generally more severe and may result in more
chronicity of virus replication (5). Among the candidate viruses, Epstein-
Barr virus was most intensively studied and was occasionally found in the
affected cells. However, contrary to epidemiological predictions, the
lowest freqency of Epstein-Barr virus positive cases was among the young
adults with the nodular sclerosis type of Hodgkin's disease (6, 7). So
far, we have no evidence that a single virus is responsible for the
development of Hodgkin's disease.
We have proposed an alternative explanation of the epidemiological
findings: Hodgkin's disease might be a rare consequence of an "untrained"
immune system on the basis of which a variety of microbial or other
environmental stimuli could trigger the disease (8).
Hodgkin's disease and asthma share similar predisposing factors and
are characterised by eosinophilia in the blood and in the affected tissue.
It appears that a delayed or incomplete maturation of the immune system
predisposes to asthma and other atopic diseases and to development of a
proliferative disorder known as Hodgkin's disease.
References
1 Illi S, von Mutius E, Lau S, Bergmann R, Niggemann B, Sommerfeld C,
et al. Early childhood infectious diseases and the development of asthma
up to school age: birth cohort study. Br Med J 2001; 322:390-395.
2 Prescott SL, Macaubas C, Smallacombe T, Holt BJ, Sly PD, Holt PG.
Development of allergen-specific T-cell memory in atopic and normal
children. Lancet 1999; 353:196-200.
3 Gutensohn NM, Cole P. Childhood social environment and Hodgkin's
disease. N Engl J Med 1981; 304:135-140.
4 Paffenbarger RS, Wing AL, Hyde RT. Characteristics in youth
indicative of adult-onset Hodgkin's disease. J Natl Cancer Inst 1977;
58:1489-1491.
5 Mueller N. An epidemiologist's view of the new molecular biology
findings in Hodgkin's disease. Ann Oncol 1991; 2(S2):23-28.
6 Glaser SL, Lin RJ, Stewart SL, Ambinder RF, Jarrett RF, Brousset P
et al. Epstein-Barr virus-associated Hodgkin's disease: epidemiologic
characteristics in international data. Int J Cancer 1997; 79:375-382.
7 Jarrett RF, MacKenzie J. Epstein-Barr virus and other candidate
viruses in the pathogenesis of Hodgkin's disease. Semin Hematol 1999;
36:260-269.
8 Zwitter M, Lesnicar H. Hodgkin's disease as a failure of immune
regulation: a reinterpretation of the epidemiological findings. Neoplasma
1986; 33: 107-115.
Matjaz Zwitter, MD, PhD
Head, Department of Radiotherapy, Institute of Oncology, Zaloska 2, 1000
Ljubljana, Slovenia.
Correspondence to: mzwitter@onko-i.si
competing interests: none
Competing interests: No competing interests
The study by Illi et al (1) is suggestive of a protective role of
early upper respiratory tract infections against the development of asthma
later in life. Concerning lower respiratory tract infections, a positive
association with the development of asthma has been proposed. However, as
these infections were found significantly higher in children with a family
history of atopy, the authors conclude that they rather represent
manifestations of children already predisposed to asthma.
We have recently analysed the preliminary results of a prospective study
of infants with bronchiolitis during the first year of life. We have
enrolled all the 238 infants hospitalised in two major Paediatric
Departments of Crete from January 1999 to April 2000. Using a rapid test
for respiratory syncytial virus (RSV) antigen on nasopharyngeal secretions
(Abbott Test Pack RSV Rapid Diagnostic Kit), the infants were classified
as RSV-positive and RSV-negative. The outcome was evaluated on the basis
of annual parental interview. Criteria for classification in the severe
recurrent wheezing group included the need for asthma prophylaxis regimens
or for hospitalisation due to respiratory distress. Among the 133
children, who completed their first year of follow-up, the RSV-positive
group (n=71) did not show any predisposition to develop severe recurrent
wheezing. Remarkably, RSV- negative infants (n=62) seemed to be more prone
to severe recurrent wheezing as compared to RSV- positive infants (chi
square test, p= 0.058; relative risk 1.51, 95% confidence intervals 0.975
to 2.34). Positive family history was significantly more frequent in the
infants who developed severe wheezing, than those with mild or no wheezing
episodes (chi square test, p<_0.01. p="p"/>The relationship of RSV infection in early life and the later development
of asthma has not been yet defined. Both studies indicating RSV as a risk
factor predisposing to asthma through allergic sensitisation (2) and
studies appearing RSV responsible for the development of asthma without
increasing the risk for allergy have been published (3). In our study RSV
infection appears unrelated with subsequent development of severe
recurrent wheezing within the next year. In agreement with Illi et al, our
findings indicate that severe wheezing in early life occurs more often in
predisposed children and that infection is rather a trigger than a cause.
References
1. Illi S, von Mutius E, Lau S, Bergmann R, Niggeman B, Sommerfeld C, Wahn
U and the MAS Group. Early childhood infectious diseases and the
development of asthma at school age: a birth cohort srudy. BMJ 2001; 322:
390-5.
2. Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman B. Respiratory
syncytial virus bronchiolitis in infancy is an important risk factor for
asthma and allergy at age 7. Am J Resp Crit Care Med 2000; 161: 1501-7.
3. Stein RT, Sherrill D, Morgan WJ, Holberg CJ, Halonen M, Taussig LM,
Wright AL, Martinez FD. Respiratory syncytial virus in early life and the
risk of wheeze by age 13 years. Lancet 1999; 354: 541-5.
Vassiliki Angelakou, MD
Department of Paediatrics,
Venizelion General Hospital,
Heraklion, Crete, Greece
Maria Bitsori, MD
Department of Paediatrics
University Hospital of Heraklion,
POB 1352, 711 10 Heraklion, Crete, Greece
Emmanouil Galanakis, MD, PhD (Phil)
Department of Paediatrics,
University Hospital of Heraklion,
POB 1352, 711 10 Heraklion, Crete, Greece
Competing interests: No competing interests
Editor
Illi et al have reported that repeated viral infections, other than
lower respiratory tract infections, early in life may reduce the risk of
developing asthma up to school age[1].
Asthma is common in children and its prevalence in this age group is
increasing such that asthma is now a major health problem in children
worldwide[2]. The reasons for this reported increase are likely to be
multi-factorial and the role of childhood infections remains unclear.
Illi et al have added to this debate by demonstrating the possible
protective action of viral infections in the first year of life. We would
argue that the authors could have demonstrated this effect more
conclusively by selective inclusion of results from their cohort.
The population used was that selected to participate in a different
study, the longitudinal multicentre allergy study (MAS). The selection
criteria for this resulted in 499 of the 1314 participants being selected
as they were at risk of developing atopy (2 or more atopic family members
or elevated cord blood IgE). As the results of outcome measures were
considered collectively, the risk-group acted as a confounding factor
within the cohort. Other factors not accounted for include environmental
variations such as housing, pets, local heavy industry, gestational age
and gender differences.
The authors suggest the mechanism of protection against developing
asthma from viral infections is the stimulation of the immune system
towards the Th1 phenotype. It is well known that infants with risk factors
for atopy develop a slower Th1 response, hence the atopic risk group may
have had a less marked immunological reaction to infection than would a
randomly selected cohort. We would postulate that by considering the
remainder of the study group separately a more marked protective effect
may be demonstrated.
Protective effects were stated as mainly due to 2 sub-groups of viral
infections- runny nose and herpes virus. However, we believe that it is
unacceptable to assume that a viral infection is the only cause of
rhinitis and, in particular not to consider atopy within the aetiology.
The use of immunological testing in cases of rhinitis would have allowed
diagnosis of viral types. This information would be useful in targeting
future therapy resulting from these findings, such as the introduction of
a vaccine in the first year of life that may protect against the
development of atopy and asthma.
1. Illi S, von Mutius E, Lau S et al. Early childhood infectious
diseases and the development of asthma up to school age: a birth cohort
study. BMJ 2001 332: 390-395
2. Anderson HR, Butland BK, Strachan DP. Trends in prevalence and
severity of childhood asthma. BMJ. 1994;308:1600-1604
Competing interests: No competing interests
Sir,
We read the recent report of Illi et al (1) with interest. The
authors have highlighted that repeated mild upper respiratory viral
infections at less than 1 year of life would protect children from
developing asthma later in life. They suggest that such infections
stimulate the immature immune system towards a Th1 phenotype, thereby
reducing the risk of asthma.
These observations prompt us to look at the same issue in a different
perspective. The ISAAC study (2) has clearly shown a high prevalence of
asthma and atopy in the western world as opposed to developing countries
such as in Asia and Africa. This high prevalence has been linked to
‘western life style’, indoor environment, pet ownership and better hygiene
(2).
It has been suggested that reduced reactivity to mycobacterial
antigens early in life has been associated with increased prevalence of
atopy. Exposure to Mycobacterium tuberculosis (MTB) is known to induce a
strong Th1 immune response and we know that its incidence is highest in
the developing world and hence as a definitive preventive measure BCG
vaccination is offered as early as day 1 of life in countries such as
India, Sri Lanka and Pakistan. This is in contrast to the western world,
where BCG vaccination is administered at school leaving age by which time
asthma and atopy would have already manifested. Studies in Japan (3) have
shown an inverse association between atopy and tuberculin responses and a
recent study has also shown that pulmonary MTB down-regulates Th2
responses in affected patients (4). Moreover, in an allergen challenge
model of asthma, vaccination of subjects with M. vaccae has shown to
significantly attenuate late phase asthmatic responses to allergen and
this was associated with decreased allergen-induced IL-5 production by
peripheral blood mononuclear cells (5).
If induction of a strong Th1 immune response early in life were to
protect individuals from the development of atopy, specific but simple and
safe intervention such as administration of BCG vaccine very early in life
could induce the desired immune response and protect from development of
asthma later in life. This theory has to be investigated in carefully
designed control studies and this approach would be more specific than
relying on upper respiratory infections, which occurs purely by chance!
REFERENCES
1. Illi S, von Mutius E, Lau S, Bergmann R, Niggermann B, Sommerfeld
C, Wahn U, and the MAS Group. Early childhood infectious diseases and the
development of asthma up to school age: a birth cohort study. BMJ 2001;
322: 390-395.
2. The International Study of Asthma and Allergies in Childhood
(ISAAC) Steering Committee. Worldwide variation in prevalence of symptoms
of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. The
Lancet 1998; 351(9111): 1225-1232
3. Shirakawa T, Enomoto T, Shimazu S, Hopkin JM. The inverse
association between tuberculin responses and atopic disorder. Science
1997; 275(5296): 77-79.
4. Ohrui T, Zayasu K, Sato K, Matsui T, Sekizawa K, Sasaki H.
Pulmonary tuberculosis and serum IgE. Clin Exp Immunol 2000; 122(1): 13-
15.
5. Camporota L, Corkhill A, Long H et al. Effects of intra-dermal
injection of SRL-172 (killed myobacterium vaccae suspension) on allergen-
induced airway responses and IL-5 generation by PBMC in asthma. Am J
Respir Crit Care Med 2000; 161(3): A477.
Dr Mamidipudi Thirumala Krishna MRCP, PhD
Specialist Registrar in Allergy and Clinical Immunology and Honorary
Clinical Lecturer
Dr Sundeep Santosh Salvi MD, PhD
Clinical Research Fellow
Address for correspondence:
Dr Mamidipudi Thirumala Krishna MRCP, PhD
University Medicine,
Level D Centre Block,
Southampton General Hospital,
Southampton SO16 6YD,
UK
E mail: mtkrishna@yahoo.com
Competing interests: No competing interests
Dear Sir
The paper by Illi et al is in agreement with our prospective study in
finding that a report of lower respiratory tract infections in the first
year of life is associated with an increased risk of asthma at 7 years of
age (1).However we also found in this prospective study of 863 children
followed from birth to 7 years of age that a history of a cold ( upper
respiratory tract infection) documented by home interview at one month was
also associated with an increased risk of asthma (ARR 1.27(1.05, 1.53) at
7 years of age. Like the report of runny nose episodes by Illi et al, our
outcome was determined by parental report, but we examined the construct
validity of our URTI report and found URTI to be postively associated with
winter, resident density, maternal smoking and bottle feeding, suggesting
that this report was likely to reflect early upper respiratory tract
infection. As Illi et al point out events in early life have been
postulated to be particularly relevant to the subsequent development of
atopic disease.Thus, our data are not consistent with the concept that
viral infection at a critical period in very early life will protect
against the subsequent development of asthma.
In the same study, we found that the apparent protective effect of
larger family size on asthma appeared to be operative at age seven but not
at one month of age and that children with no siblings were more likely
to have asthma with an age of onset after four years but not with onset
earlier in life , suggesting that the critical time for the protective
effect of large household size on asthma is not necessarily during the
first year of life.
1 Ponsonby AL, Couper D, Dwyer T, Carmichael A, Kemp A Relationship
between
early life respiratory illness, family size over time, and the development
of asthma and hay fever: a seven year follow up study. Thorax 1999
Aug;54(8):664-9
Dr Anne-Louise Ponsonby
Canberra Clinical School,
University of Sydney Canberra,
AUSTRALIA 2614
Professor Andrew Kemp
Head Department Immunology
Royal Childrens Hospital,
Parkville, Melbourne,
AUSTRALIA 3052
Competing interests: No competing interests
Margaret Hayes suggested that breast feeding might have confounded
our results on the association of early infectious diseases and the
development of asthma in childhood.
The prospective Multicenter Allergy Study assessed breast feeding in
detail. In this study, however, breast feeding showed no association with
a doctor's diagnosis of asthma, wheeze ever or current wheeze at the age
of 7 years. Similarly, no association of breast feeding and asthma was
seen in the subgroup of children with asthmatic mothers. Hence, when
adjusting the multivariate models for breast feeding for less or more than
16 weeks, the association between early infectious diseases and the
outcome variables remained statistically significant and of unchanged
magnitude.
The only asthma-related outcome variable associated with breast
feeding was bronchial hyperreactivity at the age of 7 years: 19.9% of the
children breast fed less than 16 weeks showed bronchial
hyperresponsivenes, whereas only 13.1% of those children breast fed longer
than 16 weeks did so (p=0.02). This effect was more pronounced in children
with asthmatic mothers. When adjusting the multivariate models with
bronchial hyperreactivity as outcome variable for breast feeding, breast
feeding for more than 16 weeks showed a significant protective effect. The
odds ratios for infectious diseases, however, remained unchanged by this
additional adjustment.
We can thus conclude that in our study breast feeding did not
confound the association between early infectious diseases and the
development of asthma in childhood.
Competing interests: No competing interests
Dear Editor,
The 'hygeine' hypothesis and the protective effect of early childhood
infections in reducing allergic conditions has gained much popularity over
the past 10 years and has been the subject of much immunological and
medical debate (1). However, to certain people such scientific posturing
and analysis seems to be ignoring the obvious. My father-in-law, a gruff
and no-nonsense Yorkshireman, has his own 'Pinch of muck' theory which
states that a little bit of dirt every day is good for you. He therefore
steadfastly refuses to wash any of his vegetables (home grown of course),
lets his cheese mature until it runs out of the kitchen and used to feed
his daughter (my wife) the mould which grows on top of old jam. His theory
is upheld by the fact that none of his children (where n=2) have developed
any atopic or allergic disease. He is therefore thrilled, albeit in an
understated Yorkshire kind of way, that the scientific community is
finally catching up with common sense. As for Johnston and Openshaw's
question as to 'which dirt' is best (2), well the answer to that is easy:
Yorkshire muck is far superior to any other!
1. Illi S, von Mutius E, Lau S, Bergmann R, Niggeman B, Sommerfeld C,
et al. Early childhood infectious diseases and the development of asthma
up to school age: a birth cohort study. BMJ 2001; 322: 390-395
2. Johnston SL and Openshaw PJ The protective effect of childhood
infections. BMJ 2001; 322: 376-377
Yours sincerely,
Dr Bobby Gaspar
Clinical Lecturer in Immunology/Infectious Diseases
Molecular Immunology unit,
Institute of Child Health,
30, Guilford Street,
London WC1N 1EH
Competing interests: No competing interests
While reading the article on early chilhood infections and asthma in
February 17th's edition I was struck by the lack of mention of a possible
confounding variable which has been well documented to have cause and
effect in both childhood illness and asthma. Breast-feeding is said to
have protective properties in both (Wilson et al, 1998; Howie et al,
1990). Perhaps this choice, duration of and whether mixed with cows' milk
formula or weaning before 16 weeks was taken into account. If this was the
case it would have been helpful to the reader to be able to note the
influence that this might have had on the development of asthma. This
would have been especially helpful in the light of recent news that
mothers with asthma may be more likely to have children with asthma if
they exclusively breastfeed (Reuters 2001).
References:
Wilson et al (1998) BMJ 316:21-25
Relation of infant diet to childhood health: seven year follow uo of
cohort of children in Dundee infant feeding study.
Howie et al (1990) BMJ 300:11-16
Protective effect of breastfeeding against infection.
Reuters Online (2001) 14th February
Asthmatic breast milk linked to disease in children.
A report on a study undertaken in Tucson, Arizona.
Competing interests: No competing interests
The increase in Allergy and Asthma can be ascribed to cleanliness
I agree with the study (1) that early children infectious diseases
decrease the development of asthma. There is no doubt that an increase in
the prevalence of asthma has occurred. Reports from Britain show that the
prevalence of asthma is on the rise (2). For preschool children aged 1-5
years, an approximately twofold increase in the prevalence of all types of
wheezing has been documented for the years 1990 to 1998.
It’s important that the peak incidence of all asthma is the first
to fourth years of life and thus exposures during pregnancy and early
childhood will have a major impact on the development of asthma. The
repeated infections in early childhood transmitted by contact with older
siblings infected through peers in day care, kindergarten, and school may
prevent the development of atopic immune responses.
There are “good” and “bad” germs that must be identified to prevent
bad ones from harming us and to take advantage of the good ones to
properly booster our immune responses.
References:
1. Illi, S, Mutius Erika von, Lau, S et al. Early childhood
infectious diseases and the development of asthma up to school age: a
birth cohort.BMJ,2001;322:390-395
2.Kuehni, C, Davis A, Brooke A, and Silverman, M. Are all wheezing
disorders in very young (preschool) children increasing in prevalence?
Lancet. 2001; 357:1821-1825
Competing interests: No competing interests