Pulmonary diffusing capacity for carbon monoxide and nitric oxide after COVID-19: A prospective cohort study (the SECURe study).

Many patients exhibit persistently reduced pulmonary diffusing capacity after coronavirus disease 2019 (COVID-19). In this study, dual test gas diffusing capacity for carbon monoxide and nitric oxide (DL,CO,NO) metrics and their relationship to disease severity and physical performance were examined in patients who previously had COVID-19. An initial cohort of 148 patients diagnosed with COVID-19 of all severities between March 2020 and March 2021 had a DL,CO,NO measurement performed using the single-breath method at 5.7 months follow-up. All patients with at least one abnormal DL,CO,NO metric (n = 87) were revaluated at 12.5 months follow-up. The DL,CO,NO was used to provide the pulmonary diffusing capacity for nitric oxide (DL,NO), the pulmonary diffusing capacity for carbon monoxide (DL,CO,5s), the alveolar-capillary membrane diffusing capacity and the pulmonary capillary blood volume. At both 5.7 and 12.5 months, physical performance was assessed using a 30 s sit-to-stand test and the 6 min walk test. Approximately 60% of patients exhibited a severity-dependent decline in at least one DL,CO,NO metric at 5.7 months follow-up. At 12.5 months, both DL,NO and DL,CO,5s had returned towards normal but still remained abnormal in two-thirds of the patients. Concurrently, improvements in physical performance were observed, but with no apparent relationship to any DL,CO,NO metric. The severity-dependent decline in DL,NO and DL,CO observed at 5.7 months after COVID-19 appears to be reduced consistently at 12.5 months follow-up in the majority of patients, despite marked improvements in physical performance.

Close monitoring and early intervention: management principles for cystic fibrosis in Denmark.

Cystic fibrosis (CF) care in Denmark has been characterized by close monitoring and pre-emptive treatment of lung disease and other CF-related complications. Continuous evaluation through data collection and commitment to clinical research has incrementally improved outcomes. This approach has been in line with best practices set forth by European Standards of Care but has also gone beyond Society standards particularly pertaining to early treatment with high-dose combination antimicrobial therapy. Despite a high prevalence of severe CF variants, lung function has been among the best in Europe. In this review, the Danish approach to management of CF prior to the introduction of new CF modulator treatment is explained and benchmarked. Downsides to the Danish approach are discussed and include increased burden of treatment, risk of antimicrobial resistance, side-effects and costs.

Outcome of elexacaftor/tezacaftor/ivacaftor therapy in patients with cystic fibrosis and solid organ transplantation.

We report a case series of four patients with cystic fibrosis (CF) and previous solid organ transplantation (SOT) receiving elexacaftor/tezacaftor/ivacaftor therapy for 6 months or more. Data was collected retrospectively. The treatment was well tolerated and all patients reported subjective improvements.

Relation of Pulmonary Diffusing Capacity Decline to HRCT and VQ SPECT/CT Findings at Early Follow-Up after COVID-19: A Prospective Cohort Study (The SECURe Study).

A large proportion of patients exhibit persistently reduced pulmonary diffusion capacity after COVID-19. It is unknown whether this is due to a post-COVID restrictive lung disease and/or pulmonary vascular disease. The aim of the current study was to investigate the association between initial COVID-19 severity and haemoglobin-corrected diffusion capacity to carbon monoxide (DLco) reduction at follow-up. Furthermore, to analyse if DLco reduction could be linked to pulmonary fibrosis (PF) and/or thromboembolic disease within the first months after the illness, a total of 67 patients diagnosed with COVID-19 from March to December 2020 were included across three severity groups: 12 not admitted to hospital (Group I), 40 admitted to hospital without intensive care unit (ICU) admission (Group II), and 15 admitted to hospital with ICU admission (Group III). At first follow-up, 5 months post SARS-CoV-2 positive testing/4 months after discharge, lung function testing, including DLco, high-resolution CT chest scan (HRCT) and ventilation-perfusion (VQ) single photon emission computed tomography (SPECT)/CT were conducted. DLco was reduced in 42% of the patients; the prevalence and extent depended on the clinical severity group and was typically observed as part of a restrictive pattern with reduced total lung capacity. Reduced DLco was associated with the extent of ground-glass opacification and signs of PF on HRCT, but not with mismatched perfusion defects on VQ SPECT/CT. The severity-dependent decline in DLco observed early after COVID-19 appears to be caused by restrictive and not pulmonary vascular disease.

Olfactory and Gustatory Outcomes Including Health-Related Quality of Life 3-6 and 12 Months after Severe-to-Critical COVID-19: A SECURe Prospective Cohort Study.

Background: Long-term follow-up studies of COVID-19 olfactory and gustatory disorders (OGDs) are scarce. OGD, parosmia, and dysgeusia affect health-related quality of life (HRQoL) and the ability to detect potential hazards. Methods: In this study, 29 patients reporting OGD 1 month after severe-to-critical COVID-19 were tested at 3-6 months and retested at 12 months in case of hyposmia/anosmia. We used Sniffin Sticks Threshold, Discrimination, and Identification (TDI) test, Sniffin Sticks Identification Test (SIT16), Brief Smell Identification Test (BSIT), taste strips, and HRQoL. The patients were part of the prospective SECURe cohort. Results: Overall, 28% OD (TDI), 12% GD, 24% parosmia, and 24% dysgeusia (questionnaire) at 3-6 months (n = 29) and 28% OD (TDI), 38% parosmia, and 25% dysgeusia (questionnaire) at 12 months (n = 8) were observed. OGD decreased HRQoL: For 13%, it had a negative effect on daily life and, for 17%, it affected nutrition, 17% reported decreased mood, and 87-90% felt unable to navigate everyday life using their sense of smell and taste. A comparison of SIT16 and BSIT to TDI found sensitivity/specificity values of 75%/100% and 88%/86%. Conclusions: This is the first study to examine TDI, SIT16, BSIT, taste strips, and HRQoL up to 1 year after severe-to-critical COVID-19. The patients suffering from prolonged OGD, parosmia, and dysgeusia experienced severely decreasing HRQoL. We recommend including ear-nose-throat specialists in multidisciplinary post-COVID clinics.

Persistence of cervical high-risk human papillomavirus in women living with HIV in Denmark - the SHADE.

BACKGROUND: Women living with HIV (WLWH) have high rates of persistent high-risk human papillomavirus (hrHPV) infections and cervical cancer. We aimed to assess the distribution of hrHPV genotypes, risk factors of type-specific hrHPV persistence, and high-grade squamous intraepithelial lesions or worse (≥HSIL) in WLWH in Denmark. METHODS: From the prospective Study on HIV, cervical Abnormalities and infections in women in Denmark (SHADE) we identified WLWH with a positive hrHPV test during the study period; 2011-2014. HIV demographics were retrieved from the Danish HIV Cohort Study and pathology results from the The Danish Pathology Data Bank. Logistic regression was used to identify risk factors associated with persistent hrHPV infection (positivity of the same hrHPV type in two samples one-two years after the first hrHPV positive date) and ≥ HSIL. RESULTS: Of 71 WLWH, 31 (43.7%) had persistent hrHPV infection. Predominant hrHPV genotypes were HPV58, 52, 51, and 35 and most frequently observed persistent genotypes were HPV52, 33 and 31. CD4 < 350 cells/µL predicted genotype-specific hrHPV persistence (adjusted OR 4.36 (95%CI: 1.18-16.04)) and ≥ HSIL was predicted by prior AIDS (adjusted OR 8.55 (95% CI 1.21-60.28)). CONCLUSIONS: This prospective cohort study of well-treated WLWH in Denmark found a high rate of persistent hrHPV infections with predominantly non-16/18 hrHPV genotypes. CD4 count < 350 cells/µL predicted hrHPV persistence, while prior AIDS predicted ≥HSIL.

Prevalence of cervical, oral, and anal human papillomavirus infection in women living with HIV in Denmark - The SHADE cohort study.

BACKGROUND: Women living with HIV (WLWH) have elevated risk of human papillomavirus (HPV) related cancers. OBJECTIVES: To assess prevalence, distribution and concordance of cervical, oral, and anal HPV infection, and predictors of oral and anal HPV in WLWH in Denmark. STUDY DESIGN: WLWH followed in the Study on HIV, cervical Abnormalities and infections in women in Denmark (SHADE) were enrolled and examined for cervical, oral, and anal HPV infection. Logistic regression models were used to identify predictors of anal and oral HPV. RESULTS: A total of 214 of 334 WLWH had sufficient DNA for analysis at all three anatomical sites and were included in analyses. Cervical, oral, and anal high-risk (hr) HPV prevalence were 28.0%, 3.7% and 39.3%. Most frequent i) cervical, ii) oral and iii) anal hrHPV genotypes were i) hrHPV58 (8.4%), 52 (5.1%), 16 (5.1%) and 51 (5.1%); ii) 52 (1.4%) and iii) 51 (9.3%), 58 (8.9%), 16 (7.0%) and 18 (7.0%). Among present cervical, oral, and anal hrHPV genotypes, 6.7%, 12.5% and 17.9% were targeted by the 2-or 4-valent HPV vaccines, whereas 50.0%, 50.0% and 42.9% of hrHPV genotypes were covered by the 9-valent HPV vaccine. Anal HPV infection was predicted by cervical HPV infection (adjusted OR 4.47 (95%CI 2.25-8.89)). CONCLUSION: Cervical and anal HPV infection were highly prevalent in WLWH. Non-16/18 hrHPV genotypes were predominant at all anatomical sites. Almost half of all hrHPV infections at the three anatomical sites could have been prevented by childhood/adolescent vaccination with the 9-valent HPV vaccine.

Prevalence and significance of Mycoplasma genitalium in women living with HIV in Denmark.

OBJECTIVE: Mycoplasma genitalium (M. genitalium) is a sexually transmitted pathogen associated with urethritis, cervicitis, and pelvic inflammatory disease. Previous studies have shown a strong association between M. genitalium and HIV infection, therefore screening and treatment for M. genitalium has been suggested as part of HIV prevention strategies. The objective of this study was to determine the prevalence of M. genitalium in women living with HIV (WLWH) in Denmark, and to compare the result with data on symptoms from the lower abdomen, sexual habits and immune status. 234 women, recruited from Danish HIV centres as part of a larger observational study on aspects of living with HIV as a woman (the SHADE study), were included. RESULTS: We tested cervical samples for M. genitalium by specific PCR. We found three samples positive (1.3%). The women were between 30 and 50 years old, all were of Asian origin, sexually active, and on antiretroviral treatment with supressed HIV RNA and CD4 count >350 cells/µL. None reported symptoms from the lower abdomen. The prevalence of M. genitalium infection in WLWH in Denmark is low, thus systematic screening for M. genitalium in this group does not seem relevant.

HIV disclosure and stigma among women living with HIV in Denmark.

OBJECTIVE: To identify disclosure, stigma and predictors of non-disclosure among women living with HIV in Denmark. METHODS: A questionnaire study of women living with HIV in Denmark was performed. The enrolment period was from February 2013 to March 2014. Logistic regression was used to estimate predictors of non-disclosure. RESULTS: A total of 234 participants were included. The majority (94%) had disclosed their HIV status to at least one person outside their healthcare environment, although 29% had disclosed to fewer than three people. Confidantes were mostly partners (96%), siblings (63%), friends (63%) and children (41%). The primary reason for non-disclosure was a feeling that it did not concern others (55%), although reactions upon disclosure were mainly positive in 53%. Predictors of non-disclosure were being of black or Asian ethnicity. Following their HIV diagnosis, 40% no longer dared to have sex, 40% felt isolated and 23% felt that others were afraid and kept a physical distance. In contrast, after disclosure 75% felt better at taking decisions about life and 50% were in closer contact with family and friends. CONCLUSION: Almost one-third of participants disclosed their HIV diagnosis to fewer than three people and black or Asian ethnicity predicted non-disclosure. HIV-related stigma regarding sex and contact with others is still highly prevalent; however, reactions to disclosure were mainly positive and associated with secondary positive gains. We strongly urge healthcare professionals to initiate a dialogue regarding stigma and disclosure with women living with HIV with a view to increasing disclosure and minimising stigmatisation in this vulnerable population.

Bacterial vaginosis, human papilloma virus and herpes viridae do not predict vaginal HIV RNA shedding in women living with HIV in Denmark.

BACKGROUND: Bacterial vaginosis (BV) has been found to be associated with HIV acquisition and transmission. This is suggested to be due to higher HIV RNA levels in cervicovaginal fluids in women living with HIV (WLWH) with BV, as bacteria associated with BV may induce viral replication and shedding in the genital tract despite undetectable HIV RNA plasma viral load. We examined the prevalence and diagnostic predictors of BV and HIV-1 RNA vaginal shedding in women living with HIV (WLWH) in Denmark, taking into account the presence of human papillomavirus (HPV) and herpes viridae. METHODS: WLWH between 18-51 years were recruited from six Departments of Infectious Diseases in Denmark during enrolment in the SHADE cohort; a prospective cohort study of WLWH attending regular outpatient care. BV was diagnosed by microscopy of vaginal swabs and PCR was used for detection of BV-associated bacteria, HPV, herpes viridae, and vaginal HIV viral load. RESULTS: Median age of the 150 included women was 41 years; ethnicity was predominantly White (35%) or Black (47%). The majority (96%) was on ART and had undetectable (85%) plasma HIV RNA (<40 copies/mL). BV was diagnosed in 32%. Overall, 11% had detectable vaginal HIV RNA. Both before and after adjustment for BV, age, ethnicity, plasma HIV RNA, CD4 cell count, herpes viridae and HPV, we found no significant predictors of HIV RNA vaginal shedding. CONCLUSION: In well-treated WLWH, BV, herpes viridae or HPV do not predict vaginal HIV RNA shedding. This implies that HIV shedding does not seem to be increased by BV.

Prevalence and distribution of cervical high-risk human papillomavirus and cytological abnormalities in women living with HIV in Denmark - the SHADE.

BACKGROUND: Women living with HIV (WLWH) are at increased risk of persistent human papillomavirus (HPV) infection, cervical dysplasia and cervical cancer compared with women from the general population (WGP). We assessed the prevalence and distribution of cervical high-risk (hr) HPV infection and cytological abnormalities in WLWH compared with WGP in Denmark. Predictors of HPV and cytological abnormalities were estimated in WLWH. METHODS: WLWH consecutively enrolled in the Study on HIV, cervical Abnormalities and infections in women in Denmark (SHADE) in 2011 and were examined for cervical HPV and cytological abnormalities. WLWH were matched on age and prior cytological findings with WGP from an earlier study. HIV demographics were retrieved from the nationwide Danish HIV Cohort Study. Logistic regression was used to estimate predictors of hrHPV and cytological abnormalities. RESULTS: Of 334 included WLWH 26.4 % were positive for hrHPV as opposed to 16.6 % WGP (p < 0.0001). WLWH had a higher number of multiple infections (>1 h genotype present) (38.5 % versus 25.7 %, p = 0.030). Hr genotypes in descending order of frequency were HPV58 (7.1 %), 52 (5.4 %), and 16 (4.8 %) in WLWH versus HPV16 (4.1 %), 52 (2.8 %) and 58 (2.4 %) in WGP. Predictors of hrHPV in WLWH were short duration of HAART (adjusted OR per year 0.90 (95 % CI 0.84-0.96)), AIDS prior to inclusion (adjusted OR 3.61 (95 % CI 1.75-7.46)), ≥5 lifetime sexual partners (adjusted OR 2.20 (95 % CI 1.08-4.49)), sexual debut <16 years of age (adjusted OR 2.05 (95 % CI 1.03-4.10)) and CD4 < 350 cells/µL (adjusted OR 2.53 (95 % CI 1.20-5.40)). Cytological abnormalities were prevalent in 10.4 % vs. 5.2 % (p = 0.0003) of WLWH and WGP. In WLWH with hrHPV, short duration of HAART predicted cervical dysplasia (adjusted OR per year 0.83 (95 % CI 0.71-0.97)). CONCLUSIONS: WLWH presented with more cervical hrHPV infections and cytological abnormalities, and a different distribution of hrHPV genotypes compared with WGP. Cervical hrHPV and cytological abnormalities were predicted by short duration of HAART.

Sexually transmitted infections and use of contraceptives in women living with HIV in Denmark - the SHADE cohort.

BACKGROUND: No Danish guidelines for screening of sexually transmitted infections (STIs) in women living with HIV (WLWH) exist, except for annual syphilis testing. Drug-drug interaction between hormonal contraceptives and some types of highly active antiretroviral therapy (HAART) occurs. We assessed prevalence of STIs, contraceptive choices and predictors of condom use in a cohort of WLWH in Denmark. METHODS: WLWH consecutively enrolled during their outpatient visits from 2011 to 2012. Gynaecological examination and an interview were performed at entry and 6-month follow-up. Inclusion criteria were HIV-1 infection and ≥ 18 years of age. Exclusion criteria were pregnancy, alcohol- or drug abuse impeding adherence to the protocol. At entry, participants were tested (and where appropriate, treated according to guidelines) for Chlamydia trachomatis, Neisseria gonorrhoeae, syphilis, and herpes simplex (HSV-1 and HSV-2). At follow-up, predictors of condom use were estimated in sexually active WLWH. RESULTS: In total, 334 of the 1,392 eligible WLWH in Denmark were included (median age and HIV duration: 42.5 and 11.3 years). Chlamydia trachomatis was present in four individuals (1 %), and six (2 %) tested positive for HSV-2 by PCR. None were positive for Neisseria gonorrhoeae, HSV-1 or had active syphilis. At follow-up, 252 (76 %) participated; 168 (70 %) were sexually active. Contraceptives were used by 124 (75 %); condoms were preferred (62 %). Having an HIV-negative partner predicted condom use (adjusted OR 3.89 (95 %CI 1.49-10.11)). In the group of participants of reproductive age without pregnancy desires 13 % used no birth-control. Possible drug-drug interaction between hormonal contraceptives and HAART was found in 13/14 WLWH receiving both kinds of medication. CONCLUSION: The prevalence of STIs in WLWH in Denmark was low. The need for annual STI screening is questionable. Condoms were preferred contraceptives, especially in WLWH with an HIV-negative partner. In this cohort, 13 % of WLWH of reproductive age were at risk of unintended pregnancies due to lack of birth-control. Finally, in the subgroup of WLWH receiving both hormonal contraceptives and HAART possible drug-drug interactions could occur.

Thromboelastography on plasma reveals delayed clot formation and accelerated clot lyses in HIV-1 infected persons compared with healthy controls.

BACKGROUND: Thromboembolic events among HIV infected persons are a recognized clinical problem but the underlying mechanisms are poorly understood. To assess whether coagulation and fibrinolysis differ between long-term treated HIV infected individuals (HIV+) and healthy controls (CON), we investigated functional plasma coagulation by thrombelastography (TEG) and plasma markers of endothelial and platelet activation. METHODS: In 67 successfully long-term treated HIV+ and 15 CON we analyzed stored plasma samples by TEG, with or without addition of tissue-type plasminogen activator (tPA), and measured levels of C-reactive protein, thrombomodulin, syndecan-1, sVE-cadherin, soluble CD40 ligand (sCD40L), adrenaline and noradrenaline. RESULTS: Compared to CON, HIV+ had delayed clot formation (reaction (R)-time 14.2 min. vs. 11.2 min., p = 0.0004) and reduced clot formation rapidity (angle 22.6° vs. 48.6°, p = <0.0001). Clot lyses induced by tPA was accelerated in HIV+ displaying enhanced clot degradation after 30 and 60 min (53.9% vs. 24.2%, p < 0.0001 and 77.4% vs. 59.9%, p < 0.0001, respectively). sCD40L and TEG R-time correlated negatively in both HIV+ and CON (Rho =-0.502, p < 0.001 and rho =-0.651, p = 0.012). DISCUSSION: No previous studies have examined plasma coagulation by TEG in HIV, however, we have previously demonstrated that HIV+ display hypocoagulability in whole blood by TEG in accordance with the results of this study. Others have reported of HIV associated changes in the hemostatic system in a pro-coagulant direction based on measurements of isolated components of the coagulation pahways. In disease conditions, the flowing blood may change from "normal" to hyper- or hypocoagulant or to hyper- or hypofibrinolytic. A balance may exist in the flowing blood, i.e. between blood cells and the plasma phase, so that pro-coagulant blood cells are balanced by a hypocoagulable plasma phase; thus alterations that may promote thromboembolic events in the patient may at the same time appear as a hypocoagulable profile when evaluated in vitro. CONCLUSION: Plasma from long-term treated HIV infected persons displays a hypocoagulable profile with reduced fibrinolytic resistance as compared to healthy controls.

Factors Associated With Plasma IL-6 Levels During HIV Infection.

BACKGROUND: Elevated interleukin 6 (IL-6) levels have been linked to cardiovascular disease, cancer and death. Persons with human immunodeficiency virus (HIV) infection receiving treatment have higher IL-6 levels, but few data are available on factors associated with circulating IL-6. METHODS: Participants in 3 trials with IL-6 measured at baseline were included (N = 9864). Factors associated with IL-6 were identified by linear regression. Demographic and HIV variables (nadir/entry CD4(+) cell count, HIV RNA level, antiretroviral therapy regimen) were investigated in all 3 trials. In the SMART (Strategies for Management of Anti-Retroviral Therapy) trial, CD4/CD8 ratio, smoking, comorbid conditions, serum lipids, renal function (estimated glomerular filtration rate [eGFR]), and educational level were assessed. RESULTS: Demographics associated with higher IL-6 levels were older age and lower education, whereas black race was associated with lower IL-6. Higher HIV RNA levels were associated with higher IL-6 levels, and higher nadir CD4(+) cell counts with lower IL-6 levels. Compared with efavirenz, protease inhibitors were associated with higher and nevirapine with lower IL-6 levels. Smoking and all comorbid conditions were related to higher IL-6. IL-6 levels increased with decreasing eGFR and decreasing serum lipids. CONCLUSIONS: Higher levels of IL-6 were associated with older age, nonblack race, higher body mass index, lower serum lipid levels, HIV replication, low nadir CD4(+) cell count, protease inhibitor use, comorbid conditions, and decreased eGFR. Multiple factors affect inflammation in HIV and should be considered in studies of IL-6 as a biomarker of clinical outcomes.

Determinants of IL-6 levels during HIV infection.

INTRODUCTION: Elevated IL-6 levels have been linked to increased risk of cardiovascular disease (CVD), cancer and death. Compared to the general population, treated HIV+ persons have 50-100% higher IL-6 levels, but few data on the determinants of IL-6 levels during HIV infection currently exist. MATERIAL AND METHODS: Participants in three international HIV trials (SMART, ESPRIT and SILCAAT) with IL-6 plasma levels measured at baseline were included (N=9864). Factors independently associated with log2-transformed IL-6 level were identified by multivariate linear regression; exponentiated estimates corresponding to fold differences (FDs) in IL-6 were calculated. Demographics (age, gender, race, BMI) and HIV-specific variables (nadir and entry CD4 counts, HIV-RNA, use of different ART regimens) were investigated in all three trials. In SMART (N=4498), smoking, comorbidities (CVD, diabetes, hepatitis B/C [HBV/HCV]), HDL-cholesterol, renal function (eGFR) and educational level were also assessed. RESULTS: Demographics associated with higher IL-6 were older age (FD [95% CI]: 1.09 [1.08-1.11] per 10 yr) and higher BMI (1.02 [1.01-1.04] per 5 kg/m(2)), whereas black race was associated with reduced IL-6 (0.96 [0.93-0.99]). As for HIV variables, patients not receiving ART (1.36 [1.29-1.43]) and with higher HIV-RNA (1.24 [1.01-1.52] for >100,000 vs. ≤500 copies/mL) had increased IL-6. Participants taking protease inhibitors (PI) had higher IL-6 (1.14[1.09-1.19]). Higher nadir CD4 count (0.98 [0.97-0.99]/100 cells/µL) was related to lower IL-6. All evaluated comorbidities were related to higher IL-6; FDs in IL-6 were 1.08 [1.04-1.12] for smoking, 1.12 [1.02-1.24] for CVD, 1.07 [1.00-1.16] for diabetes and 1.12 [1.02-1.24] for HBV (1.15 [1.02-1.30]) and 1.53 [1.45-1.62] for HCV. IL-6 increased with decreasing eGFR (0.98 [0.97-1.00]/10 mL/min) and HDL-cholesterol (0.98 [0.96-0.99]/10 mg/mL). Lower education was related to higher IL-6 (1.09 [1.03-1.15] for high school vs. bachelor's degree). CONCLUSIONS: Higher IL-6 levels were associated with older age and non-black race, higher BMI and lower HDL-cholesterol, ongoing HIV replication, low nadir CD4 counts, comorbidities and decreased renal function. This suggests that there are multiple causes of inflammation in treated HIV infection. A possible contribution from PI use was also observed. Contribution from inflammation to explain variation in clinical outcomes for these factors should be investigated.

Discrepant coagulation profile in HIV infection: elevated D-dimer but impaired platelet aggregation and clot initiation.

OBJECTIVES: In HIV infection, cardiovascular disease (CVD) has emerged as a clinical problem, and elevated D-dimer has been reported. The pathophysiologic mechanisms underlying this remain unclear. We aimed to investigate whether untreated HIV-infected individuals display evidence of functional coagulopathy and whether this was associated with microbial translocation. DESIGN: The study population consisted of 50 HIV-infected untreated individuals and 50 HIV-infected individuals on combination antiretroviral therapy (cART). Groups were matched for age, sex and current CD4cell count. METHODS: Coagulation analyses included D-dimer and the functional haemostatic whole blood tests, thromboelastography (TEG) and platelet aggregation (Multiplate, impedance aggregometry). Microbial translocation was assessed by plasma levels of lipopolysaccharide (LPS). RESULTS: A larger proportion of untreated individuals compared with treated individuals had D-dimer above normal reference range (27.7 vs. 2.2%, P = 0.001). In both treated and untreated individuals, delayed clot initiation with TEG R-time above upper reference range (18 and 28%, respectively, both P < 0.001) and TEG angle below lower reference range [14% (P = 0.004) and 24% (P < 0.001), respectively] was found. In untreated individuals, 64.6% had aggregation response below threshold in at least two of four tests compared with 36.7% in treated individuals (P = 0.010). Untreated individuals with increased D-dimer levels were relatively hypercoagulable by thromboelastography. Furthermore, in untreated patients, a negative association between microbial translocation and platelet aggregation was found. CONCLUSION: Elevated D-dimer in untreated HIV-infected individuals was confirmed. However, in both untreated and treated individuals, reduced platelet aggregation and clot initiation was found. The impact of reduced platelet function in HIV infection and a potential role of microbial translocation warrant further investigation.

Persistent inflammation and endothelial activation in HIV-1 infected patients after 12 years of antiretroviral therapy.

OBJECTIVE: The study investigated markers of inflammation and endothelial activation in HIV infected patients after 12 years of successful combination antiretroviral treatment (cART). METHODS: Inflammation and endothelial activation were assessed by measuring levels of immunoglobulins, ß2-microglobulin, interleukin (IL) 8, tumor necrosis factor α (TNFα), vascular cell adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1), sE-Selectin, and sP-Selectin. RESULTS: HIV infected patients had higher levels of ß2-microglobulin, IL-8, TNFα, and sICAM-1 than uninfected controls, and HIV infected patients lacked correlation between platelet counts and sP-Selectin levels found in uninfected controls. CONCLUSION: Discrete signs of systemic and vascular inflammation persist even after very long term cART.

T cell subsets in HIV infected patients after successful combination antiretroviral therapy: impact on survival after 12 years.

OBJECTIVES: Immune activation is decreased by combination antiretroviral therapy (cART) in patients infected with human immunodeficiency virus (HIV), but residual activation remains and has been proposed as a cause of premature aging and death, but data are lacking. We analyzed the relationship between T-cell subsets after 18 months of cART and overall survival during 12 years of follow up. METHODS: A cohort of 101 HIV infected patients who had undetectable plasma HIV after starting cART was included in 1997-1998. T cell subsets were analyzed by flowcytometry after 18 months of cART. Relation to survival was calculated using Kaplan-Meier curves and multiple Cox regression. RESULTS: Seventeen patients died during the observation period. The leading causes of death were non-AIDS cancer and cardiovascular disease. Higher levels of CD8 memory T cells (CD8+,CD45RO+,CD45RA-) showed a significant beneficiary effect on survival, HR of 0.95 (95% confidence interval 0.91-0.99, P = 0.016) when adjusted for age, nadir CD4 count, CD4 count, and AIDS and hepatitis C status. T cell activation was not associated with increased risk of death. CONCLUSIONS: Larger and longitudinal studies are needed to accurately establish prognostic factors, but overall results seem to suggest that prognostic information exists within the CD8 compartment.

T-cell subset distribution in HIV-1-infected patients after 12 years of treatment-induced viremic suppression.

OBJECTIVE: Residual immune activation and skewed T cell maturation may contribute to excess comorbidity and mortality in successfully treated HIV-infected patients, and long-term effects of combination antiretroviral therapy (cART) on immune reconstitution remain a debated issue. Quantitative T cell reconstitution and activation and its association with residual viremia in patients with 12 years of viremic suppression were investigated. DESIGN: Blood samples collected cross-sectionally from 71 HIV-infected patients with cART-induced viremic suppression through 12 years were compared with samples from 16 healthy controls. METHODS: Several different subsets of naive, memory, and activated T cells were analyzed in fresh whole blood by 6-color flowcytometry, and ultrasensitive quantification of HIV RNA was performed. RESULTS: HIV-infected patients had lower absolute and relative CD4 T cell counts and higher absolute and relative CD8 T cell counts than controls. HIV-infected patients had lower concentrations of naive CD4 cells than controls, but proportions were similar. HIV-infected patients had higher concentrations of CD8 T cells than controls in all the examined subsets but only a higher proportion of CD8 cells in the intermediately differentiated and activated subsets. Residual viremia did not correlate to proportions of naive CD4, CD4 recent thymic emigrants, or activated CD8 T cells. CONCLUSIONS: This study demonstrated some degree of T cell imbalance even after 12 years of successful cART. Large longitudinal studies are needed to establish whether these discrete changes have clinical relevance.

[Concurrent leptospirosis and salmonella infection]. / Samtidig leptospirose og salmonellainfektion.

We report a case of a 56-year-old man who was admitted with septicaemia of unknown origin after working in a henhouse. The patient had beginning liver and kidney failure. Salmonella Typhimurium was cultured from the stool, and DNA from Leptospira spp. was demonstrated by PCR in the urine and blood culture. Leptospirosis is a rare condition that should be remembered as a differential diagnosis in patients with relevant exposure. Leptospirosis may be diagnosed with polymerase chain reaction at an early stage of infection. Later development of antibodies will confirm the diagnosis.