J Epidemiol Community Health 2000;54:907–911 907 Delayed infection, family size and malignant lymphomas P Vineis, L Miligi, P Crosignani, A Fontana, G Masala, O Nanni, V Ramazzotti, S Rodella, E Stagnaro, R Tumino, C Viganò, C Vindigni, A Seniori Costantini Abstract increase is real and not artefactual—that is, Background—The annual incidence of attributable to improved diagnostic ability.10 non-Hodgkin’s lymphomas (NHL) is in- Within the SEER programme in the USA, the creasing by 3%–4% in diVerent parts of the strongest increments in time trends for NHL in developed world. Excesses of NHL have 1978–1988 occurred for high grade NHL been observed in populations exposed to (15% per year, versus 3% among low grade and immunosuppressants and to HIV, but 2% among intermediate grade NHL).1 The these causes do not explain the increasing fact that highly malignant grades show the trends. It is suggested that delayed infec- most evident increase confirms that the trend is tion could explain NHL trends, through an not an artefact attributable to increased Servizio di impairment of the Th1/Th2 lymphocyte diagnostic sensitivity. Epidemiologia dei patterns. Well established risk factors for NHL are Tumori, Ospedale S Methods—In a population-based study on immunosuppression in transplanted patients Giovanni Battista e 1388 patients with NHL, 354 with Hodg- (with a 100-fold increased risk) and in HIV Università di Torino, kin’s disease (HD) and 1718 healthy infected patients.9 The causes of HD are more via Santena 7, I-10123 11 Torino, Italy controls, the age of first occurrence of uncertain. It is reasonable to believe that both P Vineis bacterial and viral diseases was investi- malignancies are related to impairment of the gated. Clinical records were perused in immune system in response to external stimuli. Centro per lo Studio e one centre to check the anamnestic data. Human immune system responses are hetero- la Prevenzione Findings—The age of occurrence of bac- geneous and may involve antagonism between Oncologica, Firenze, Italy terial and viral diseases was significantly T helper (Th) lymphocyte subsets (Th1 and L Miligi higher among NHL patients than in the Th2) and their cytokines. A pathogenetic role G Masala controls. The association between later of interleukin (IL) 10 in NHL has been A Seniori Costantini age at first bacterial or viral disease was proposed. IL10 has a strong immunosuppres- limited to small families (OR= 1.95; 95% sive action via inhibition of Th1 type cy- National Cancer 12 Institute, Milano, Italy confidence intervals 1.26, 3.00, for age 4–8 tokines. A polarised Th1 response has been P Crosignani at first infection; OR=1.91; 1.19, 3.06, for invoked in the pathogenesis of several infec- C Viganò age 9+, compared with less than 4). The tious diseases, and also of peptic ulcer after association was more obvious for bacterial infection from Helicobacter pylori.13 A positive Local Health Unit, diseases (possibly for the lower degree of reaction to tuberculin was associated with a Novara, Italy cytokine profile biased towards Th1, and A Fontana misclassification). High grade lympho- mas showed the strongest association. The predicted a lower incidence of asthma.14 Aller- Istituto Oncologico later age of occurrence of bacterial or gic respiratory diseases such as bronchial Romagnolo, Forlì, Italy viral diseases in NHL patients is consist- asthma are believed to result from the repeated O Nanni ent with a higher incidence of lymphomas expression in airway tissues of Th2 polarised T observed in higher social groups. No clear cell immunity to inhaled allergens. The Th1/ Cancer Registry, Latina, Italy association was found between HD and Th2 switching process is influenced by a V Ramazzotti age at first bacterial or viral diseases. number of host and environmental factors that Interpretation—It is proposed that de- are poorly understood. Prominent among these Local Health Unit, layed infection could explain the increas- are factors that aVect the kinetics of maturation Verona, Italy ing NHL trends, through an impairment of immune competence during the early S Rodella of the Th1/Th2 lymphocyte patterns. The postnatal period. It is hypothesised that the National Cancer model of delayed infection has been principal impetus for postnatal development of Institute, Genova, Italy proposed also to explain increasing preva- a normal Th1/Th2 balance is provided via E Stagnaro lence rates of asthma. contact with Th1 stimulatory micro-organisms at the body’s major mucosal surfaces.15 16 Cancer Registry, Several diseases have been characterised as Ragusa, Italy R Tumino The aetiology of lymphomas is still largely showing a Th1 dominant or Th2 dominant unknown. The known risk factors explain only lymphocyte pattern. In the first category rheu- Department of a small proportion of the cases that occur in the matoid arthitis, multiple sclerosis, sarcoidosis Pathology, University world.1–9 Time trends in recent decades show and diabetes have been included,17 18 while the of Siena, Italy stable rates for Hodgkin’s disease (HD), but a second comprises Crohn’s disease, ulcerative C Vindigni considerable increase of the incidence rates for colitis, allergies (including hay fever), asthma, Correspondence to: non-Hodgkin’s lymphomas (NHL) in most atopies (including eczema), basal cell carci- Dr Vineis Western countries. The increase in NHL noma, Sézary’s syndrome, EBV associated ([email protected]) cannot be explained by the AIDS epidemic, NHL, HD, and large cell anaplastic lymphoma. Accepted for publication being larger than justified by the strength of Several similarities between lymphomas (par- 14 June 2000 association with the HIV infection. The ticularly HD) and some of the diseases that www.jech.com 908 Vineis, Miligi, Crosignani, et al have been mentioned are notable. In developing sexes, aged 20–74, residents of the areas under countries there is a peak for HD in young age, study). For case classification—based on im- while in the developed countries there is a peak munocytochemical techniques—we used the in young adults. In analytical studies, younger Working Formulation for NHL.29 The control children (less than 10) with HD tend to belong group was formed by a random sample of the to lower social groups (OR=3.6 in Gutensohn population resident in each of the areas, aged and Shapiro, 1982),19 while older children (10– 20–74. The sample was stratified according to 14) did not show social class diVerences from five year age groups and sex, and its size was their controls. This may reflect a shift in age of equal to the number of cases in the largest exposure to common infections. Young adults diagnostic group (NHL+CLL). Procedures for with HD tend to belong to higher social groups control sampling were of two types. In the (for example Cohen et al, 1964; Gutensohn and provinces of Forli and Ragusa and in the city of Cole, 1977: OR=2.6),20 21 and persons belong- Firenze the computerised and regularly up- ing to the largest families have a risk that is half dated demographic files were used. These files of persons from the smallest families. In one are maintained under national law in all cities study cases tended to have had fewer playmates and towns throughout Italy. They are central as a child, and the parents were more educated population registries that serve such multiple than controls.21 Middle age cases appeared to be purposes as voter registration, car insurance, people whose childhood provided some protec- school eligibility, and pensions. They are well tion from early infection.11 There is little to sup- validated as epidemiological data sources, are port the thesis that HD is a transmissible continually updated, and highly accurate. In disease, transmitted by person to person the other areas (where the demographic files contact. This, however, is not inconsistent with were not accessible to the investigators) an infectious aetiology. For example, subacute sampling took place through the files of the sclerosing panencephalitis is infectious (it is an National Health Service, which are updated age dependent consequence of measles infec- every six months. tion), but is not contagious. The role played by Information about the known or suspected infection in HD is also suggested by the associ- risk factors for the diseases under investigation ation with tonsillectomy, which seems to be was collected through person to person inter- related to family size.22 Tonsillectomy seems to views. Techniques for the motivation of sub- be also a risk factor for paralytic poliomyelitis23 jects to participate, such as contacts with the and multiple sclerosis.24 general practitioners, were applied. The per- Much less is known about infectious diseases sonnel in charge of the interviews was trained during childhood and NHL. However, asthma specifically for this study; the interview lasted is increasing in developed countries at a rate about one hour. Interviews were generally con- that is similar to that for NHL.25 One explana- ducted at home and were blind as to the case- tion that has been proposed is that such an control status and to the hypotheses under increase is attributable to delayed exposure to investigation. We have investigated the entire viruses and bacteria, in comparison with devel- medical history for the following diseases: oping countries and with past decades in measles, rubeola, chickenpox, pertussis, herpes developed countries. Such delayed exposure zoster, herpes labialis, herpes genitalis, mumps, would alter the maturation of the immune sys- infectious hepatitis, infectious mononucleosis, tem, based on a shift from a predominantly tuberculosis, malaria, other infectious diseases Th2 response to a Th1 response pattern during (specified by the interviewee), hay fever, childhood. Parallels between asthma and NHL allergic asthma, other (specified) allergies, pep- are worth exploring.
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