Childhood leukaemia is the principal subtype of paediatric cancer and, despite success in treatment, its causes remain enigmatic. A plethora of candidate environmental exposures have been proposed, but most lack a biological rationale or consistent epidemiological evidence. Although there might not be a single or exclusive cause, an abnormal immune response to common infection(s) has emerged as a plausible aetiological mechanism.

Infection, immune responses and the aetiology of childhood leukaemia

Each year in the United States, an estimated 40,000 children are born with congenital cytomegalovirus (CMV) infection, causing an estimated 400 deaths and leaving approximately 8000 children with permanent disabilities such as hearing or vision loss, or mental retardation. More children are affected by serious CMV-related disabilities than by several better-known childhood maladies, including Down syndrome, fetal alcohol syndrome, and spina bifida. Congenital CMV is a prime target for prevention not only because of its substantial disease burden but also because the biology and epidemiology of CMV suggest that there are ways to reduce viral transmission. Because exposure to the saliva or urine of young children is a major cause of CMV infection among pregnant women, it is likely that good personal hygiene, especially hand-washing, can reduce the risk of CMV acquisition. Experts agree that such measures are likely to be efficacious (i.e., they will work if consistently followed) and the American College of Obstetricians and Gynecologists recommends that physicians counsel pregnant women about preventing CMV acquisition through careful attention to hygiene. However, because of concerns about effectiveness (i.e., Will women consistently follow hygienic practices as the result of interventions?), the medical and public health communities appear reluctant to embrace primary CMV prevention via improved hygienic practices, and educational interventions are rare. Current data on the effectiveness of such measures in preventing CMV infection are promising, but limited. There is strong evidence, however, that educational interventions can prevent other infectious diseases with similar transmission modes, suggesting that effective interventions can also be found for CMV. Until a CMV vaccine becomes available, effective educational interventions are needed to inform women about congenital CMV prevention. Perhaps no single cause of birth defects and developmental disabilities in the United States currently provides greater opportunity for improved outcomes in more children than congenital CMV. Given the present state of knowledge, women deserve to be informed about how they can reduce their risk of CMV infection during pregnancy, and trials are needed to identify effective educational interventions.

/pdf/washing-our-hands-of-the-congenital-cytomegalovirus-disease-1lgnckrblc.pdf

Washing our hands of the congenital cytomegalovirus disease epidemic.

In this Review, I present evidence supporting a multifactorial causation of childhood acute lymphoblastic leukaemia (ALL), a major subtype of paediatric cancer. ALL evolves in two discrete steps. First, in utero initiation by fusion gene formation or hyperdiploidy generates a covert, pre-leukaemic clone. Second, in a small fraction of these cases, the postnatal acquisition of secondary genetic changes (primarily V(D)J recombination-activating protein (RAG) and activation-induced cytidine deaminase (AID)-driven copy number alterations in the case of ETS translocation variant 6 (ETV6)–runt-related transcription factor 1 (RUNX1)+ ALL) drives conversion to overt leukaemia. Epidemiological and modelling studies endorse a dual role for common infections. Microbial exposures earlier in life are protective but, in their absence, later infections trigger the critical secondary mutations. Risk is further modified by inherited genetics, chance and, probably, diet. Childhood ALL can be viewed as a paradoxical consequence of progress in modern societies, where behavioural changes have restrained early microbial exposure. This engenders an evolutionary mismatch between historical adaptations of the immune system and contemporary lifestyles. Childhood ALL may be a preventable cancer.

/pdf/a-causal-mechanism-for-childhood-acute-lymphoblastic-22sefjym14.pdf

A causal mechanism for childhood acute lymphoblastic leukaemia.

Objective. —Escherichia coli0157:H7 infection can cause hemorrhagic colitis and hemolytic uremic syndrome. Since 1988 the Minnesota Department of Health has carried out surveillance for this infection. To assess the occurrence of person-to-person transmission within day-care facilities, we investigated facilities where an infected child attended after onset of symptoms. Design. —Parents of children less than 5 years old withE coli0157:H7 infection were interviewed from July 1988 through December 1989. If the child attended day care after onset, stool cultures were obtained from other children in attendance and their parents were interviewed. If there was presumptive evidence of ongoingE coli0157:H7 transmission in a facility, all preschool children were excluded from attending day-care facilities until two consecutive stool cultures were negative. Results. —Sixty-eight cases ofE coli0157:H7 infection were identified in Minnesota during the 18-month period, including 29 cases identified through investigations at nine day-care facilities. There was evidence of person-to-person transmission in all nine facilities. The median number of infected children per facility was two (range, two to 18), and the median attack rate was 22% (range, 3% to 38%). The median age of the primary case at each facility was 26 months (range, 12 to 59 months). There was no evidence of further transmission at facilities where children were temporarily excluded until two consecutive stool cultures were negative. Conclusion. —Person-to-person transmission ofE coli0157:H7 is common when infected preschool children attend day care while symptomatic. The number of unrecognized day-care outbreaks in the United States may be substantial due to the lack of routine testing for this pathogen in stool cultures, the absence of public health surveillance in many regions, and incomplete follow-up of infected children. Temporary exclusion of all children was an effective control strategy in this population, but additional investigations are needed to determine the optimal intervention. (JAMA. 1993;269:883-888)

Transmission of Escherichia coli 0157:H7 Infection in Minnesota Child Day-care Facilities

Nearly one thousand different types of viruses are known to infect humans and it is estimated that they account for approximately 60% of all human infections (Horsfall 1965).

Viruses are spread easily through closed environments such as the home, schools, workplaces, transport systems, etc. Although many of the respiratory and gastrointestinal infections caused by viruses can be asymptomatic or relatively mild and self‐limiting (coughs and colds, etc.), they still represent a significant economic burden. Increasing numbers of people who have reduced immunity to infection, for whom the consequences of infection can be much more serious, are now cared for at home. At risk groups include not only the immunocompromised but also the elderly, neonates, pregnant women, hospital patients discharged into the community, individuals using immunosuppressive drugs and also those using invasive systems (indwelling catheters) or inhalation systems or devices. Otherwise healthy family members with asthma or allergies also have increased susceptibility to infection. In the UK it is estimated that one in six people in the community belong to an ‘at risk’ group (Bloomfield 2001). World Health Organisation estimates suggest that, by 2025, there will be more than 800 million people over 65 years old in the world, two‐thirds of them in developing countries (Anon. 1998).

Viruses are probably the most common cause of infectious disease acquired within indoor environments. Close personal contact within the home and community settings, such as daycare centres and schools, makes them ideal places for the spread of viral infections. Infected individuals can shed up to 1012 virus particles per ml of faeces with the possibility of transfer of the virus by contaminated hands to surfaces in the bathroom or toilet. Viruses that cause tonsillitis, colds, croup, bronchiolitis, influenza, pneumonia and other respiratory tract infections can be spread in aerosolized droplets. Aerosols produced by coughing, sneezing and talking can be inhaled directly by a susceptible host or may settle onto surfaces. Touching hands or fomites, such as eating utensils, towels or doorknobs, inadvertently contaminated with fresh secretions or vomit, etc. from an infected person and then transferring the virus from the hands to the eyes, nose or mouth, are further routes of spread. Infants are especially vulnerable to such infections because they frequently place objects, such as toys, into their mouths. Transfer of viruses to food during handling and preparation via hands and food contact surfaces is an important route of spread of viral gastroenteritis.

Amongst health care professionals there is growing awareness that improved standards of hand, surface and air hygiene in community settings could do much to prevent the spread of viral infections within these environments. The purpose of this paper is to review the evidence base for this assumption. Since viral infections are not easily treated, prevention of infection is still the main route of control. Assessment of the impact of hygiene is made difficult by the general lack of quantitative epidemiological data and, even where evidence for cross‐contamination as a causative factor in an outbreak exists, it is always circumstantial. A further problem in assessing whether contamination found on hands or other surfaces might represent a hazard is that the infectious dose can vary significantly according to the pathogenicity of the organism and the immune status of the host. Thus the case for practising good hygiene in these settings rests largely on evidence showing that cross‐contamination can occur in these environments coupled with laboratory data demonstrating the efficacy of hygiene procedures in minimizing microbiological contamination.

/pdf/spread-and-prevention-of-some-common-viral-infections-in-1nr4q5zs4r.pdf

Spread and prevention of some common viral infections in community facilities and domestic homes

The number of day care centers and home care facilities has steadily increased in the United States. Recent interest has focused on the possible relationship between attendance at child day care facilities and the occurrence of certain infectious diseases. A variety of infectious agents have been reported as causes of illness among children and staff in day care programs. In general, however, concurrent risks for these infections among children attending and those not attending day care programs have not been established by prospective studies. A review is made of the pathogens that have been associated with infections in day care settings, patterns of occurrence of infectious diseases in day care facilities, aspects of control and prevention of these diseases, and controversies related to infectious diseases in child day care facilities. Aspects of this problem that warrant further research are outlined.

Infectious Diseases and Child Day Care

Objective. —Haemophilus influenzaetype b (Hib) conjugate vaccines are effective in preventingHaemophilusdisease in most children. The reasons why the vaccination fails in some children are unknown. This study investigated host factors in children who developed the disease despite conjugate vaccination. Design, Patients, Outcome Measures. —A convenience sample of 23 patients in whom Hib disease developed 14 days or more after conjugate vaccination was investigated for the presence of subnormal serum immunoglobulin concentrations and anticapsular antibody responses to Hib disease. We also investigated expression of the Hib idiotype 1 (Hibld-1), a serological marker of a VKII chain that comprises a major portion of the normal variable region repertoire of the antibody response to Hib polysaccharide. The results were compared with those of 149 patients in whom the unconjugated Hib polysaccharide vaccine failed and of 90 unvaccinated patients who developed the disease. Results. —Compared with children in whom the unconjugated polysaccharide vaccination failed, the relative risk of a subnormal serum concentration of IgM, IgA, IgG, and/or IgG2 in the children in whom the conjugate vaccination failed was 4.9 (95% confidence interval [Cl], 1.8 to 14;P Conclusions. —In most patients, vaccination failure is not attributable to lack of expression of the variable region gene encoding Hibld-1. However, children in whom conjugate vaccination has failed frequently have subnormal serum immunoglobulin concentrations and should be evaluated for immunodeficiency. (JAMA. 1991;266:1960-1965)

Immunoglobulin Deficiency and Idiotype Expression in Children Developing Haemophilus influenzae Type b Disease After Vaccination With Conjugate Vaccine

From the Edward Mallinckrodt Department of Pediatrics and Division of Infectious Diseases, Washington University School of Medicine, St, Louis, Missouri; the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas; the Park Nicollet Medical Center, Minneapolis, Minnesota; the Department of Pediatrics, Baylor College of Medicine, Houston, Texas; and Pennridge Pediatric Associates, Sellersville, Pennsylvania, and Temple University School of Medicine and St. Christopher's Hospital for Children, Philadelphia, Pennsylvania

Dan M. Granoff

Papers

Infectious Diseases and Child Day Care

Immunoglobulin Deficiency and Idiotype Expression in Children Developing Haemophilus influenzae Type b Disease After Vaccination With Conjugate Vaccine

Immunogenicity of four Haemophilus influenzae type b conjugate vaccines in to 19-month-old children