Prediction of Radiation-induced Lymphopenia following Exposure of the Thoracic Region and Associated Risk of Infections and Mortality.

AIMS: Large blood volumes are irradiated when the heart is exposed to radiation. The mean heart dose (MHD) may be a good surrogate for circulating lymphocytes exposure. We investigated the association between MHD and radiation-induced lymphopenia and explored the impact of the end-of-radiation-therapy (EoRT) lymphocyte count on clinical outcomes. MATERIALS AND METHODS: In total, 915 patients were analysed: 303 patients with breast cancer and 612 with intrathoracic tumours: oesophageal cancer (291), non-small cell lung cancer (265) and small cell lung cancer (56). Heart contours were generated using an interactive deep learning delineation process and an individual dose volume histogram for each heart was obtained. A dose volume histogram for the body was extracted from the clinical systems. We compared different models analysing the effect of heart dosimetry on the EoRT lymphocyte count using multivariable linear regression and assessed goodness of fit. We published interactive nomograms for the best models. The association of the degree of EoRT lymphopenia with clinical outcomes (overall survival, cancer treatment failure and infection) was investigated. RESULTS: An increasing low dose bath to the body and MHD were associated with a low EoRT lymphocyte count. The best models for intrathoracic tumours included dosimetric parameters, age, gender, number of fractions, concomitant chemotherapy and pre-treatment lymphocyte count. Models for patients with breast cancer showed no improvement when adding dosimetric variables to the clinical predictors. EoRT lymphopenia grade ≥3 was associated with decreased survival and increased risk of infections among patients with intrathoracic tumours. CONCLUSION: Among patients with intrathoracic tumours, radiation exposure to the heart contributes to lymphopenia and low levels of peripheral lymphocytes after radiotherapy are associated with worse clinical outcomes.

Lymphopenia and neutropenia are associated with subsequent incident proteinuria in Danish patients with systemic lupus erythematosus.

Objective: The aim of this study was to investigate whether incident proteinuria in patients with systemic lupus erythematosus (SLE) was preceded by changes in blood lymphocytes and neutrophil counts and/or neutrophil-lymphocyte ratio (NLR).Method: SLE patients with no proteinuria before or at the time of classification were included. Longitudinal data on SLE manifestations, vital status, and SLE-associated medications were collected during clinical visits and chart review. Laboratory data were collected through a nationwide database. Lymphopenia, severe lymphopenia, and neutropenia were defined as values below 0.8 × 109, 0.5 × 109, and 2.0 × 109 cells/L, respectively. High NLR was defined as values above the median. Proteinuria was defined by at least two measurements of elevated urine protein excretion (> 0.5 g/day). Hazard ratios (HRs) were calculated by Cox modelling using time-dependent continuous and binary covariates based on multiple laboratory measurements adjusted for use of immunosuppressants.Results: In total, 260 SLE patients were available for the analysis, of whom 30 (12%) developed incident proteinuria following the diagnosis of SLE. Median follow-up time was 73.5 months. Lymphocyte and neutrophil counts, but not NLR, were associated with incident proteinuria. HRs for incident proteinuria were 2.71 for lymphopenia [95% confidence interval (CI) 1.20-6.11], 4.73 for severe lymphopenia (95% CI 1.93-11.59), and 2.54 for neutropenia (95% CI 1.14-5.65).Conclusion: Lymphopenia and neutropenia predicted the risk of first-time proteinuria independently of immunosuppressants.

Risk factors during pregnancy and birth-related complications in HIV-positive versus HIV-negative women in Denmark, 2002-2014.

OBJECTIVES: We aimed to compare risk factors for adverse pregnancy outcomes in women living with HIV (WLWH) with those in women of the general population (WGP) in Denmark. Further, we estimated risk of pregnancy- or birth-related complications. METHODS: A retrospective cohort study including all WLWH who delivered a live-born child from 2002 to 2014 and WGP, matched by origin, age, year and parity, was carried out. We compared risk factors during pregnancy and estimated risk of pregnancy- and birth-related complications using multivariate logistic regression. RESULTS: A total of 2334 pregnancies in 304 WLWH and 1945 WGP were included in the study. WLWH had more risk factors present than WGP during pregnancy: previous caesarean section (CS) (24.7% versus 16.3%, respectively; P = 0.0001), smoking (14.2% versus 7.5%, respectively; P = 0.0001) and previous perinatal/neonatal death (2.3% versus 0.9%, respectively; P = 0.03). We found no difference between groups regarding gestational diabetes, hypertensive disorders, low birth weights or premature delivery. More children of WLWH had intrauterine growth retardation (IUGR) [adjusted odds ratio (aOR) 1.9; 95% confidence interval (CI) 1.1-3.2; P = 0.02]. Median gestational age and birth weight were lower in children born to WLWH. WLWH had a higher risk of emergency CS (EmCS) (aOR 1.6; 95% CI 1.2-2.1; P = 0.0005) and postpartum haemorrhage (aOR 1.4; 95% CI 1.0-1.9; P = 0.02) but not infection, amniotomy, failure to progress, low activity-pulse-grimace-appearance-respiration (APGAR) score or signs of asphyxia. CONCLUSIONS: WLWH had more risk factors present during pregnancy, similar risks of most pregnancy- and birth-related complications but a higher risk of postpartum haemorrhage and EmCS compared with WGP. Children born to WLWH had lower median birth weights and gestational ages and were at higher risk of IUGR.

Risk of infectious diseases among first-degree relatives of transplant recipients who develop CMV infection: is the infectious phenotype inheritable?

Transplant recipients are at high risk of cytomegalovirus (CMV) infection. Mechanisms explaining the variation in risk of infections are far from fully elucidated. We hypothesised that host genetics explains part of the variation in risk of infection and examined if relatives of recipients with CMV infection have higher rates of severe infections compared to relatives of recipients without this infectious phenotype. In a register-based study, we included first-degree relatives of transplant recipients and examined the risk of hospitalisation due to overall infection or viral infection and risk of death among relatives of recipients who developed CMV infection within the first year of transplantation compared to relatives of recipients without CMV. Analyses were adjusted for sex, age and calendar year. We included 4470 relatives who were followed for 103,786 person-years, median follow-up 24 years [interquartile range (IQR) 12-36]. There were a total of 1360 infection-related hospitalisations in the follow-up period, incidence rate (IR) 13.1/1000 person-years [95% confidence interval (CI), 12.4; 13.8]. 206 relatives were hospitalised with viral infection, IR 1.8/1000 person-years (95% CI, 1.6; 2.0). There was no increased risk of hospitalisation due to infections, IR ratio (IRR) 0.99 (95% CI, 0.88; 1.12), nor specifically viral infections, IRR 0.87 (95% CI, 0.63; 1.19), in relatives of recipients with CMV compared to relatives of recipients without CMV. Also, no difference was seen in analyses stratified by transplant type, family relation and CMV serostatus. The risk of hospitalisation due to infection is not increased among first-degree relatives of transplant recipients with CMV infection compared to relatives of recipients without CMV.

Assessment of mode of delivery and predictors of emergency caesarean section among women living with HIV in a matched-pair setting with women from the general population in Denmark, 2002-2014.

OBJECTIVES: We aimed to assess mode of delivery and predictors of emergency caesarean section (EmCS) in women living with HIV (WLWH) in a matched-pair setting with women from the general population (WGP) in Denmark. Further, we analysed birth plan in WLWH. METHODS: All WLWH giving birth to live-born children from 2002 to 2014 were included in the study. Data were retrieved from medical records and national registries. WLWH were matched 1:5 by age, birth year, parity and ethnicity to WGP. Multivariate logistic regression was used to estimate predictors. RESULTS: We included 389 WLWH and 1945 WGP in the study. At delivery, all WLWH were on antiretroviral therapy and 85.6% had HIV RNA <40 HIV-1 RNA copies/mL. Mean age was 32.7 years [95% confidence interval (CI) 32.1-33.2 years]. Mode of delivery differed significantly between WLWH and WGP [vaginal delivery, 33.4% versus 73.3%, respectively; elective caesarean section (ECS), 40.6% versus 9.7%, respectively; EmCS, 26% versus 17%, respectively; P < 0.0001]. Age > 40 years [adjusted odds ratio (aOR) 2.3; 95% CI 1.5-3.5], asphyxia (aOR 3.2; 95% CI 2.4-4.1), delivery during the evening and at night [aOR 2.3 (95% CI 1.7-3.0) and aOR 2.0 (95% CI 1.5-2.7), respectively], preterm delivery (aOR 3.8; 95% CI 2.6-5.6) and premature rupture of membranes (aOR 3.0; 95% CI 2.1-4.4) predicted EmCS. WLWH had a higher risk of EmCS compared with WGP [2002-2006, aOR 2.0 (95% CI 1.2-3.3); 2007-2008, aOR 2.9 (95% CI 1.4-5.9); 2009-2014, aOR 2.6 (95% CI 1.7-3.9)]. After 2007, more than half of WLWH planned to deliver vaginally. Prior caesarean section was associated with ECS (aOR 11.0; 95% CI 4.5-26.8). No mother-to-child transmission occurred. CONCLUSIONS: Increasing numbers of WLWH deliver vaginally. Despite virological suppression, more WLWH plan and deliver by ECS than WGP. WLWH had a twofold higher risk of EmCS compared with WGP.

Incidence of cervical dysplasia and cervical cancer in women living with HIV in Denmark: comparison with the general population.

OBJECTIVES: Women living with HIV (WLWH) are reportedly at increased risk of invasive cervical cancer (ICC). A recent publication found that WLWH in Denmark attend the national ICC screening programme less often than women in the general population. We aimed to estimate the incidence of cervical dysplasia and ICC in WLWH in Denmark compared with that in women in the general population. METHODS: We studied a nationwide cohort of WLWH and a cohort of 15 age-matched women per WLWH from the general population for the period 1999-2010. Pathology samples were obtained from The Danish Pathology Data Bank, which contains nationwide records of all pathology specimens. The cumulative incidence and hazard ratios (HRs) for time from inclusion to first cervical intraepithelial neoplasia (CIN)/ICC and time from first normal cervical cytology result to first CIN/ICC were estimated. Sensitivity analyses were performed to include prior screening outcome, screening intensity and treatment of CIN/ICC in the interpretation of results. RESULTS: We followed 1140 WLWH and 17 046 controls with no prior history of ICC or hysterectomy for 9491 and 156 865 person-years, respectively. Compared with controls, the overall incidences of CIN1 or worse (CIN1+), CIN2+ and CIN3+, but not ICC, were higher in WLWH and predicted by young age and a CD4 count < 200 cells/µL. In women with normal baseline cytology, incidences of CIN1+ and CIN2+ were higher in WLWH. However, when we compared subgroups of WLWH and controls where women in both groups were adherent to the national ICC screening programme and had a normal baseline cytology, incidences of CIN and ICC were comparable. CONCLUSIONS: Overall, WLWH developed more cervical disease than controls. Yet, in WLWH and controls adherent to the national ICC screening programme and with normal baseline cytology, incidences of CIN and ICC were comparable.

Encephalitis in primary HIV infection: challenges in diagnosis and treatment.

We report a case of primary HIV encephalitis, which initially presented as acute psychosis. Magnetic resonance imaging of the brain was suggestive of vasculitis and multiple infarctions, whereas a brain biopsy after six weeks of symptoms showed HIV encephalitis with microglial nodules, but no signs of vasculitis. We review previous reported cases and radiological findings in HIV encephalitis and discuss the role of antiretroviral therapy and steroids in its management.

Incidence of granulomatosis with polyangiitis (Wegener's) in Greenland and the Faroe Islands: epidemiology of an ANCA-associated vasculitic syndrome in two ethnically distinct populations in the North Atlantic area.

OBJECTIVES: Previous studies suggest that the incidence of granulomatosis with polyangiitis (Wegener's; GPA) increases along a south-north gradient in the Northern Hemisphere with an incidence of 8.0/million/year reported for the population of Northern Norway. In the present study, we assessed the incidence of GPA in the predominantly Inuit population of Greenland and in the Caucasian population of the Faroe Islands. METHODS: Greenlandic and Faroese patients affected by severe rheumatic diseases are routinely referred to the National University Hospital in Denmark for treatment. By means of the Danish National Hospital register, we identified all Greenlandic and Faroese patients treated at the hospital under a diagnosis of GPA during 1992-2011. For each patient, the GPA diagnosis was validated by medical files review. RESULTS: One patient born and living in Greenland and 6 from the Faroe Islands were identified. The incidence of GPA was 1.0/million/year (95% CI 0.02-5.6) in Greenland and 6.4/million/year (95% 2.4-14.0) in the Faroe Islands. During the period of study, no cases of GPA occurred among Greenlanders aged 0-44 years, while an incidence of 4.1/million/year (95% CI: 0.1-22.9) was calculated for those aged ≥45 years. In the Faroese population, incidences of 1.7/million/year (95% CI 0.4-9.4) and 14.8/million/year (95% CI 4.8-34.6) were calculated for the age-groups 0-44 and ≥45 years, respectively. CONCLUSIONS: The occurrence of GPA is lower among Inuit in Greenland than among Caucasians living in the Faroe Islands. This observation demonstrates that the risk of GPA varies across ethnic groups populating the northernmost regions of the world.

No change in viral set point or CD4 cell decline among antiretroviral treatment-naïve, HIV-1-infected individuals enrolled in the Danish HIV Cohort Study in 1995-2010.

OBJECTIVES: Recent studies have reported faster progression of HIV infection than anticipated based on results from earlier studies. The aim of the present study was to examine if the virulence of HIV-1 infection changed in the period 1995-2010 among chronically HIV-infected individuals in Denmark. METHODS: We included all patients registered in the Danish HIV Cohort Study, who were diagnosed in 1995-2009, had a CD4 count > 100 cells/µL at diagnosis and had at least two CD4 measurements prior to initiation of antiretroviral therapy (ART). Changes in viral set point and rate of CD4 cell decline from enrolment until the initiation of ART by calendar year of HIV diagnosis were analysed. Time to first CD4 count < 350 cells/µL was compared among patients diagnosed in 1995-2000, 2001-2005 and 2006-2010. RESULTS: We followed 1469 HIV-infected patients for a total of 5783 person-years. The median viral set point was 4.27 log10 HIV-1 RNA copies/mL [interquartile range (IQR) 3.58-4.73 log10 copies/mL]. The median CD4 cell decline per year was 57 cells/µL (IQR 10-139 cells/µL). In analyses adjusted for age, gender, origin, route of transmission and CD4 count at diagnosis, there were no associations between year of diagnosis and viral set point or CD4 cell decline. Time to first CD4 count < 350 cells/µL did not change in the study period [incidence rate ratio (IRR) 0.90 (95% confidence interval (CI) 0.76-1.06) for 2001-2005 and 1.09 (95% CI 0.79-1.34) for 2006-2010 compared with 1995-2000]. CONCLUSIONS: We found no evidence of changing trends in viral set point, CD4 cell decline or time to CD4 count < 350 cells/µL during the period 1995-2010 in a cohort of chronically HIV-infected individuals.

Causes of death among Danish HIV patients compared with population controls in the period 1995-2008.

PURPOSE: To compare the mortality and causes of death in human immunodeficiency syndrome (HIV) patients with the background population. METHODS: All adult HIV patients treated in Danish HIV centers from 1995 to 2008 and 14 controls for each HIV patient were included. Age-adjusted mortality rates (MR) and mortality rate ratios (MRR) were estimated using direct standardization and Poisson regression analyses. Up to four contributory causes of death for each person were included in analyses of cause-specific MR. RESULTS: A total of 5,137 HIV patients and 71,918 controls were followed for 37,838 and 671,339 person-years (PY), respectively. Among non-injection drug use (IDU) HIV patients, the acquired immune deficiency syndrome (AIDS)-related MR/1,000 PY declined dramatically from 122.9 [95 % confidence interval (CI) 106.8-141.4] in 1995 to 5.0 (95 % CI 3.1-8.1) in 2008. The non-AIDS-related MR did not change substantially from 6.9 (95 % CI 3.8-12.5) to 5.6 (95 % CI 3.6-8.8). The MR of unnatural causes declined from 6.9 (95 % CI 3.8-12.5) to 2.7 (95 % CI 1.4-5.1). The MRR of infections declined from 46.6 (95 % CI 19.6-110.9) to 3.3 (95 % CI 1.6-6.6). The MRR of other natural causes of death remained constant. CONCLUSIONS: After the introduction of highly active antiretroviral therapy (HAART), the AIDS-related mortality has decreased substantially, but the long-term exposure to HIV and HAART has not translated into increasing mortality from malignancy, cardiovascular, and hepatic diseases.