Robert J. Biggar

Risk of Human Papillomavirus–Associated Cancers Among Persons With AIDS

BACKGROUNDnAlthough risk of human papillomavirus (HPV)-associated cancers of the anus, cervix, oropharynx, penis, vagina, and vulva is increased among persons with AIDS, the etiologic role of immunosuppression is unclear and incidence trends for these cancers over time, particularly after the introduction of highly active antiretroviral therapy in 1996, are not well described.nnnMETHODSnData on 499 230 individuals diagnosed with AIDS from January 1, 1980, through December 31, 2004, were linked with cancer registries in 15 US regions. Risk of in situ and invasive HPV-associated cancers, compared with that in the general population, was measured by use of standardized incidence ratios (SIRs) and 95% confidence intervals (CIs). We evaluated the relationship of immunosuppression with incidence during the period of 4-60 months after AIDS onset by use of CD4 T-cell counts measured at AIDS onset. Incidence during the 4-60 months after AIDS onset was compared across three periods (1980-1989, 1990-1995, and 1996-2004). All statistical tests were two-sided.nnnRESULTSnAmong persons with AIDS, we observed statistically significantly elevated risk of all HPV-associated in situ (SIRs ranged from 8.9, 95% CI = 8.0 to 9.9, for cervical cancer to 68.6, 95% CI = 59.7 to 78.4, for anal cancer among men) and invasive (SIRs ranged from 1.6, 95% CI = 1.2 to 2.1, for oropharyngeal cancer to 34.6, 95% CI = 30.8 to 38.8, for anal cancer among men) cancers. During 1996-2004, low CD4 T-cell count was associated with statistically significantly increased risk of invasive anal cancer among men (relative risk [RR] per decline of 100 CD4 T cells per cubic millimeter = 1.34, 95% CI = 1.08 to 1.66, P = .006) and non-statistically significantly increased risk of in situ vagina or vulva cancer (RR = 1.52, 95% CI = 0.99 to 2.35, P = .055) and of invasive cervical cancer (RR = 1.32, 95% CI = 0.96 to 1.80, P = .077). Among men, incidence (per 100 000 person-years) of in situ and invasive anal cancer was statistically significantly higher during 1996-2004 than during 1990-1995 (61% increase for in situ cancers, 18.3 cases vs 29.5 cases, respectively; RR = 1.71, 95% CI = 1.24 to 2.35, P < .001; and 104% increase for invasive cancers, 20.7 cases vs 42.3 cases, respectively; RR = 2.03, 95% CI = 1.54 to 2.68, P < .001). Incidence of other cancers was stable over time.nnnCONCLUSIONSnRisk of HPV-associated cancers was elevated among persons with AIDS and increased with increasing immunosuppression. The increasing incidence for anal cancer during 1996-2004 indicates that prolonged survival may be associated with increased risk of certain HPV-associated cancers.

Autoimmune diseases in women with Turner's Syndrome

OBJECTIVEnIn terms of number of X chromosomes, women with Turners syndrome cytogenetically resemble men. An increased risk of autoimmune diseases has been observed among women with Turners syndrome. This study was undertaken to investigate whether the autoimmune disease profile in women with Turners syndrome is characterized by diseases with a female or male predominance.nnnMETHODSnUsing the Danish Cytogenetic Central Register, the Danish National Patient Register, and the Danish Civil Registration System, we estimated relative risk of 46 different autoimmune diseases in a cohort of 798 Danish women with Turners syndrome followed up for 12,461 person-years between 1980 and 2004. Standardized incidence ratios (SIRs) of first hospitalization for autoimmune disease and 95% confidence intervals (95% CIs) were used as measures of relative risk.nnnRESULTSnThe overall risk of autoimmune disease among women with Turners syndrome was twice that among Danish women in general (SIR 2.1 [95% CI 1.6-2.7]). For autoimmune diseases with a female predominance, the SIR among women with Turners syndrome was 1.7 (95% CI 1.2-2.4), whereas the SIR for autoimmune diseases with a male predominance among these women was 3.9 (95% CI 2.5-5.8). Associations were strongest for Hashimoto thyroiditis (SIR 14.6 [95% CI 6.7-27.1]), a strongly female-predominant condition, and type 1 diabetes mellitus (SIR 4.1 [95% CI 2.5-6.3]).nnnCONCLUSIONnWomen with Turners syndrome are at excess risk of autoimmune diseases, notably autoimmune diseases characterized by male predominance.

Opposite effects of microchimerism on breast and colon cancer

BACKGROUNDnDetection of Y chromosome, thought to originate from previous pregnancies with a male fetus, is common in women. Lower concentrations have been reported in women with breast cancer than cancer-free women. Data in women with other types of cancer are sparse. The purpose of the study was to determine whether the lower concentrations predate cancer diagnosis, and whether a possible beneficial effect was specific to breast cancer.nnnMETHODSnWe conducted a prospective case-cohort study of 50-64-year-old Danish women enrolled in the diet, cancer and health cohort. Blood samples and questionnaire data were obtained during 1993-1997 when all women were cancer-free. In 2006 all women were followed up for incident breast and colon cancer in national registers. In blinded analyses, we analysed buffy coat DNA for Y chromosome (DYS14) as a marker of male microchimerism.nnnRESULTSnWe detected male microchimerism in 70% of 272 cancer-free women, 40% of 89 women who later developed breast cancer, and 90% of 67 women who later developed colon cancer. The corresponding odds ratios were 0.30 (95% confidence interval (CI) 0.17-0.52) for breast, and 3.9 (95%CI 1.6-9.5) for colon cancer.nnnCONCLUSIONnDetection of male microchimerism was strongly associated with reduced risk of developing breast cancer and also the increased risk of developing colon cancer. Confirmatory findings based on an improved study design, failure to identify important confounders and the strength of the associations lead us to believe that microchimerism may be highly relevant to later cancer development. However, the present study does not allow us to identify the underlying biological mechanisms.

National cohort study of reproductive risk factors for rheumatoid arthritis in Denmark: a role for hyperemesis, gestational hypertension and pre-eclampsia?

Objectives: While reproductive factors might plausibly be involved in the aetiology of rheumatoid arthritis (RA), the female predominance remains unexplained. A study was undertaken to address the possible impact of live births, pregnancy losses and pregnancy complications on the subsequent risk of RA in a nationwide cohort study. Methods: National register data were used to link reproductive histories and later RA hospitalisations in a cohort of 4.4 million Danes. As a measure of relative risk associated with different reproductive histories, ratios of first inpatient RA hospitalisation rates (RRs) were used with 95% confidence intervals (CIs) obtained by Poisson regression analysis. Results: Overall, 7017 women and 3041 men were admitted to hospital with RA in 1977–2004 (88.8 million person-years). The risk of RA was inversely associated with age at birth of first child in both women and men (p for trend <0.001). Overall, nulliparity and a history of pregnancy loss were not associated with RA risk but, compared with one-child mothers, women with two (RR 0.84; 95% CI 0.78 to 0.90) or three (RR 0.83; 95% CI 0.77 to 0.91) children were at reduced risk. The risk of RA was increased in women with a history of hyperemesis (RR 1.70; 95% CI 1.06 to 2.54), gestational hypertension (RR 1.49; 95% CI 1.06 to 2.02) or pre-eclampsia (RR 1.42; 95% CI 1.08 to 1.84). Conclusions: One-child mothers and young parents are at increased risk of RA later in life, possibly due to socioeconomic factors. The novel finding of a significantly increased risk of RA in women whose pregnancies were complicated by hyperemesis, gestational hypertension or pre-eclampsia might reflect reduced immune adaptability to pregnancy in women disposed to RA or a role of fetal microchimerism in the aetiology of RA.

Digoxin use and the risk of cancers of the corpus uteri, ovary and cervix

Digoxin is a phyto‐estrogen capable of inducing hormonal effects. Use has been associated with increased risk of breast cancer, an estrogen‐sensitive malignancy. The incidence of corpus uteri (uterus) cancer is also strongly increased with exposure to estrogens. Therefore, we evaluated whether digoxin use might also increase its incidence. In all women in Denmark, we identified digoxin users from 1995 through 2008 using a nationwide pharmacy registry system. Cancer occurrence was obtained from Danish Cancer Registry. Relative risk was determined using incidence risk ratios (RR) and 95% confidence intervals (CIs) relative to non‐users after adjustment for age‐ and calendar‐time. For ovarian and cervical cancers, RRs in users and non‐users were similarly evaluated, these cancers representing gynecological cancers with weak or no associations to estrogen exposure. Of 2.1 million women, 104,648 (4.9%) had digoxin exposure and 137,493 6.5% had exposure to angina drugs but not digoxin during the study period. For uterus cancer, the RR was increased in current digoxin users (1.48, 95% CI: 1.32–1.65; N = 350). Incidence was marginally increased in former users. For ovary and cervix cancers, RRs in current digoxin users were 1.06 (95% CI: 0.92–1.22; N = 207) and 1.00 (95% CI: 0.79–1.25; N = 81), respectively. We examined risks in women using angina drugs but not digoxin to determine whether being under cardiac care affected risk. Among women using angina drugs only, RRs for uterus, ovary or cervix cancers were not statistically significant. We conclude that women currently using digoxin, a phyto‐estrogen, have an increased risk of developing uterus cancers.

Immunoglobulin subclass levels in patients with non-Hodgkin lymphoma.

Allergy/atopy has been suggested to protect against non‐Hodgkin lymphoma (NHL) and specific IgE levels are decreased in patients with NHL. We speculated that all immunoglobulin subclass levels might be downregulated in NHL and examined levels of IgM, IgD, IgA, IgE, IgG and IgG4 in 200 NHL patients and 200 age‐ and sex‐matched controls. Patients with B‐cell NHL of many types had consistently lower median immunoglobulin subclass levels than controls. In every subclass except IgD, about 10–15% of B‐cell NHL patients had absolute levels below the 2.5 percentile of controls. Subclass levels correlated with each other and many patients had more than one significantly low level. Levels were lowest for IgG4 and IgE. Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma had especially low total IgE levels. In other B‐cell NHL types, total IgE levels were decreased to a similar extent as other immunoglobulin subclasses. In conclusion, low IgE levels are only part of a more generalized loss of immunoglobulins of all subtypes in a wide variety of B‐cell NHL types. Low immunoglobulin levels appear to be a consequence of B‐cell NHL presence, and we speculate about molecular mechanisms that could reduce all immunoglobulin subclasses in B‐cell NHL.

Risk factors for Mycobacterium tuberculosis infection among children in Greenland

OBJECTIVEnTo examine the risk factors for Mycobacterium tuberculosis infection (MTI) among Greenlandic children for the purpose of identifying those at highest risk of infection.nnnMETHODSnBetween 2005 and 2007, 1797 Greenlandic schoolchildren in five different areas were tested for MTI with an interferon gamma release assay (IGRA) and a tuberculin skin test (TST). Parents or guardians were surveyed using a standardized self-administered questionnaire to obtain data on crowding in the household, parents educational level and the childs health status. Demographic data for each child--i.e. parents place of birth, number of siblings, distance between siblings (next younger and next older), birth order and mothers age when the child was born--were also extracted from a public registry. Logistic regression was used to check for associations between these variables and MTI, and all results were expressed as odds ratios (ORs) and 95% confidence intervals (CIs). Children were considered to have MTI if they tested positive on both the IGRA assay and the TST.nnnFINDINGSnThe overall prevalence of MTI was 8.5% (152/1797). MTI was diagnosed in 26.7% of the children with a known TB contact, as opposed to 6.4% of the children without such contact. Overall, the MTI rate was higher among Inuit children (OR:u2009 4.22; 95% CI: 1.55-11.5) and among children born less than one year after the birth of the next older sibling (OR:u2009 2.48; 95% CI: 1.33-4.63). Self-reported TB contact modified the profile to include household crowding and low mothers education. Children who had an older MTI-positive sibling were much more likely to test positive for MTI themselves (OR:u2009 14.2; 95% CI: 5.75-35.0) than children without an infected older sibling.nnnCONCLUSIONnEthnicity, sibling relations, number of household residents and maternal level of education are factors associated with the risk of TB infection among children in Greenland. The strong household clustering of MTI suggests that family sources of exposure are important.

Genetic Susceptibility to Severe Infection in Families with Invasive Pneumococcal Disease

Severe infections may be influenced by genetic constitution. The authors examined familial aggregation of invasive infections, using invasive pneumococcal disease (IPD) as the index condition to ascertain families at risk. From Danish national registers, they identified relatives of persons with IPD from 1977 through 2005. Risks of IPD, bacterial meningitis, septicemia, and any invasive infection were analyzed for relatives of IPD cases in a prospective cohort study (23 million person-years). In total, 43,134 persons were found to have an IPD case in the family. The authors observed an increased risk of invasive infections in relatives of IPD cases most likely sharing the same household (parents, offspring, siblings, half-siblings), but only regarding those events within 1 year of the index IPD diagnosis (rate ratio = 7.4, 95% confidence interval: 2.4, 23.0). After 1 year, there were no increased risks of severe infections, including IPD, in close relatives. For other relatives, no increased risks of severe infections were observed at any time. No aggregation of invasive infections in IPD relatives was found, other than for close events among relatives who most likely shared the same household. Thus, at the population level, genetic constitution appears of little importance in the development of IPD and other severe infections.

HLA antigen sharing between mother and fetus as a risk factor for eclampsia and preeclampsia

Immune maladaption between mother and infant has been suggested to induce preeclampsia/eclampsia. When fetuses share more human leukocyte antigen (HLA) types with their mother, immune differences would be limited and thereby could affect this risk. Data from Danish women (1996-2002) with single live-birth pregnancies complicated by severe preeclampsia/eclampsia were compared to women with term pregnancies uncomplicated by hypertension. HLA A, B, and DR types were resolved at the intermediate-level typing (antigen). A total of 201 cases and 195 control mother-infant pairs had complete HLA types. The odds ratios of preeclampsia/eclampsia in mothers sharing both HLA antigens with their infants were 1.19 (95% confidence interval: 0.81-1.76) for HLA A, 0.91 (0.59-1.42) for HLA B, and 1.05 (0.5-1.59) for HLA DR antigens. No specific HLA antigens in either mother or infant appeared important after Bonferroni correction, except possibly DR01 in mothers (protective). Thus, maladaption mediated by adaptive immunity between mother and infant is not the basis for the mother developing preeclampsia/eclampsia.

Spontaneous labor onset: is it immunologically mediated?

OBJECTIVEnThe investigators tested the hypothesis that maternal-fetal immune interactions could be important in initiating spontaneous labor onset by examining if labor was delayed when fetuses share maternal HLA antigen types.nnnSTUDY DESIGNnHLA antigen types A, B, and DR in 200 Danish mother-infant pairs delivering in 42-44 weeks (postterm) were compared with 195 mother-infant pairs delivering in 37-40 weeks (term).nnnRESULTSnSharing of HLA A and B antigens was more common than expected in postterm deliveries. Odds ratios were 1.54 (95% confidence interval [CI], 1.01-2.35) and 1.75 (95% CI, 0.87-3.52), respectively (risk per shared antigen: 1.40 [95% CI, 1.04-1.90] per unit increase). Adding stringent birth-length criteria for postmaturity (92 cases; 168 controls) strengthened risks associated with antigen sharing to 1.57 (95% CI, 0.90-2.74) and 2.60 (95% CI, 1.15-5.88), respectively (risk per shared antigen: 1.60 (95% CI, 1.10-2.32).nnnCONCLUSIONnPostterm-delivered infants had more HLA A and B antigens in common with their mothers, suggesting that recognition of HLA antigen differences by adaptive immunity may have a role in triggering labor onset.