COVID-19 with severe acute respiratory distress in a pregnant woman leading to preterm caesarean section: A case report.

We report the case of a 25-year-old pregnant woman, parity one, at 34 + 2 weeks of gestation, with a body mass index of 41 kg/m2 but no other comorbidities. There was a family history of COVID-19 among her one-year-old son, husband, brother, father and mother. She was admitted with chest pain and a nasopharyngeal swap positive for COVID-19. Due to the severity of the infection, a multidisciplinary team of anaesthesiologists, intensivists, obstetricians, neonatologists, and infectious disease specialists recommended delivery by caesarean section at 35 + 0 weeks of gestation, with combined spinal and epidural anaesthesia. Three days after delivery, the patient developed severe acute respiratory distress syndrome (ARDS) and was intubated for 25 days. The neonate was observed in the neonatal intensive care unit and no vertical transmission occurred. This case highlights the importance of the timing of delivery, the need for extended postpartum observation and a beneficial effect of inhaled nitric oxide after delivery for women with COVID-19.

Identification of a novel mutation in the factor VIII gene causing severe haemophilia A.

BACKGROUND: Deficiency in coagulation factor VIII encoded by F8 results in the X-linked recessive bleeding disorder haemophilia A (HEMA). Here we describe the identification of a novel variant in the factor VIII gene, F8, in an adult male patient with severe haemophilia A. CASE PRESENTATION: The patient was diagnosed in early childhood and subsequently co-infected with Hepatitis C and HIV acquired during early blood transfusion for haemophilia in the 1980ies. The identified F8 deletion, c.5411_5413delTCT, p.F1804del lies within a conserved part of the molecule, is predicted by bioinformatic software to be deleterious by the loss of Phenylalanine, and has not been previously described in any database. CONCLUSION: This novel F8 deletion as a cause of haemophilia A did not result in generation of inhibitory antibodies to Factor VIII treatment and may have impact on (prenatal) diagnosis, genetic counselling, and treatment decisions in the affected family as well as in other families diagnosed with this F8 mutation. Finally, this novel mutation should be included in the panel of known genetic variants in F8 when searching for the genetic etiology in patients suspected of HEMA.

The challenge of discriminating between HIV-1, HIV-2 and HIV-1/2 dual infections.

OBJECTIVES: Discrimination between HIV-1 and HIV-2 is important to ensure appropriate antiretroviral treatment (ART) and epidemiological surveillance. However, serological tests have shown frequent mistyping when applied in the field. We evaluated two confirmatory tests, INNO-LIA HIV I/II Score and ImmunoComb HIV 1/2 BiSpot, for HIV type discriminatory capacity. METHODS: Samples from 239 ART-naïve HIV-infected patients from the Bissau HIV Cohort in Guinea-Bissau were selected retrospectively based on the initial HIV typing performed in Bissau, ensuring a broad representation of HIV types. INNO-LIA results were interpreted by the newest software algorithm, and three independent observers read the ImmunoComb results. HIV-1/HIV-2 RNA and DNA were measured for confirmation. RESULTS: INNO-LIA results showed 123 HIV-1 positive samples, 69 HIV-2 positive and 47 HIV-1/2 dually reactive. There was agreement between INNO-LIA and HIV-1/HIV-2 RNA and DNA detection, although not all HIV-1/2 dually reactive samples could be confirmed by the nucleic acid results. Overall, the observers found that the ImmunoComb results differed from the INNO-LIA results, with agreements of 90.4, 91.2 and 92.5%, respectively, for HIV-1, HIV-2 and HIV-1/2. The combined kappa-score for agreement between the three observers was 0.955 (z-score 35.1; P < 0.01). Of the HIV-2 mono-reactive samples (INNO-LIA), the three observers interpreted 24.6-31.9% as HIV-1/2 dually infected by ImmunoComb. None of these samples had detectable HIV-1 RNA or DNA. CONCLUSIONS: There was accordance between INNO-LIA calls and nucleic acid results, whereas ImmunoComb overestimated the number of HIV-1/2 dually infected patients. Confirmatory typing is needed for patients diagnosed with HIV-1/2 dual infection by ImmunoComb.

Hepatocellular carcinoma in patients with chronic hepatitis C and cirrhosis in Denmark: A nationwide cohort study.

Cirrhosis in patients with chronic hepatitis C increases the risk of hepatocellular carcinoma (HCC), and surveillance with ultrasound (US) and alpha-fetoprotein (AFP) is recommended. This study aimed to estimate changes in the HCC incidence rate (IR) over time, HCC stage and prognosis, and AFP and US performed in patients with hepatitis C and cirrhosis. Eligible patients were identified in the Danish Database for Hepatitis B and C, and data from national health registries and patient charts were obtained. Tumour stage was based on Barcelona-Clinic Liver Cancer stage, TNM classification and size and number of lesions combined into stages 0-3. We included 1075 patients with hepatitis C and cirrhosis, free of HCC and liver transplant at baseline. During 4988 person years (PY), 115 HCC cases were diagnosed. The HCC incidence rate increased from 0.8/100 PY [CI95% 0.4-1.5] in 2002-2003 to 2.9/100 PY [2.4-3.4] in 2012-2013. One-year cumulative incidence of at least one AFP or US was 53% among all patients. The positive predictive value of an AFP ≥ 20 ng mL-1 was 17%. Twenty-three (21%) patients were diagnosed with early-stage HCC (stage 0/1) and 84 (79%) with late stage. Median survival after HCC for early-stage HCC disease was 30.1 months and 7.4 months for advanced HCC (stage 2/3). The incidence rate of HCC increased over time among patients with hepatitis C and cirrhosis in Denmark. Application of AFP and US was suboptimal, and most patients were diagnosed with advanced HCC with a poor prognosis.

Endothelial dysfunction, increased inflammation, and activated coagulation in HIV-infected patients improve after initiation of highly active antiretroviral therapy.

OBJECTIVES: Endothelial dysfunction and inflammation have been demonstrated to be markers of cardiovascular risk. We investigated the effects of HIV infection per se and the antiretroviral treatment prescribed on the levels of risk factors of cardiovascular disease. METHODS: This was a prospective study of 20 treatment-naïve, nonsmoking, HIV-positive patients examined before and after 3 months of treatment with a protease inhibitor (PI)-containing regimen followed by 3 months of treatment with nonnucleoside reverse transcriptase inhibitor (NNRTI)-containing therapy. Parameters of inflammation, endothelial function and coagulation were examined. The results were compared with those for an age- and gender-matched, nonsmoking, healthy control group. RESULTS: Compared with controls, treatment-naïve HIV-infected patients exhibited endothelial dysfunction [flow-mediated dilation (FMD) 108 vs. 111% for HIV-infected vs. control groups, respectively; P < 0.05] and activation [von Willebrand factor 2.0 vs. 0.9 U/l; soluble intercellular adhesion molecule (sICAM) 313 vs. 211 ng/L, respectively; P < 0.01]. Inflammation [C-reactive protein (CRP) 24 vs. 8.6 nmol/L; fibrinogen 9.4 vs. 8.6 µmol/L, respectively; P < 0.05] and coagulation/fibrinolysis (D-dimers 0.55 vs. 0.23 µg/mL, respectively; P < 0.01) were increased. Initiating therapy resulted in normalization of FMD and a significant decrease in endothelial activation and CRP. CONCLUSION: Endothelial dysfunction together with increased inflammation and coagulation were more prevalent in untreated HIV-infected patients compared with controls. These cardiovascular risk factors improved with treatment, although not all parameters normalized after 6 months.

Previously unrecognized advanced liver disease unveiled by transient elastography in patients with Haemophilia and chronic hepatitis C.

Before the introduction of viral inactivation procedures and viral screening of plasma-products, haemophiliacs were at high risk of infection with HCV. Those who acquired HCV infection in the 1980s, and are still alive today, may have developed significant liver fibrosis or cirrhosis. However, liver biopsy has not routinely been utilized in the evaluation of haemophiliacs with HCV in Denmark. The aim of this study was to investigate the prevalence of significant fibrosis/cirrhosis among haemophiliacs as evaluated by transient elastography (TE). Cross-sectional investigation of adult patients with haemophilia A or B. TE with liver stiffness measurements (LSM) ≥ 8 kPa were repeated after 4-6 weeks. Significant fibrosis and cirrhosis was defined as measurements ≥ 8 kPa or ≥ 12 kPa respectively. Among 307 patients with haemophilia A or B registered at the two Haemophilia centres, 141(46%) participate in this study. Forty (28.4%) had chronic hepatitis C, 33 (23.4%) past hepatitis C and 68 (48.2%) had never been infected, at screening LSM ≥ 8 kPa were found in 45.7%, 24.7% and 4.6% respectively. Among patients with chronic hepatitis C significant fibrosis was confirmed in 17.1% and cirrhosis in 2.9% by repeated LSM ≥ 8 and ≥ 12 kPa respectively. The median TE-value in never HCV-infected haemophiliacs was comparable with what has been found in healthy non-haemophiliacs. In Danish haemophiliacs where liver biopsy has not routinely been used for assessing severity of liver fibrosis, LSM identified advanced liver disease in one-fifth of cases that had not been recognized during clinical follow-up.

Mortality in HIV-infected injection drug users with active vs cleared hepatitis C virus-infection: a population-based cohort study.

Acute hepatitis C virus (HCV) infection may lead to chronic HCV-infection with detectable HCV RNA or to spontaneous clearance with no HCV RNA, but detectable HCV antibodies. It is unknown whether HCV RNA status is associated with mortality in HIV-infected injection drug users (IDUs). We conducted a nationwide population-based cohort study to examine the impact of HCV RNA status on overall and cause-specific mortality in HIV-infected IDUs. We computed cumulative mortality and used Cox Regression to estimate mortality rate ratios (MRR). We identified 392 HIV-infected patients of whom 284 (72%) had chronic HCV-infection (HCV RNA positive patients) and 108 (28%) had cleared the HCV-infection (HCV RNA negative patients). During 1286 person-years of observation (PYR), 157 persons died (MR = 122/1000 PYR, 95% CI: 104-143). The estimated 5-year probabilities of survival were 0.58 (95% CI: 0.51-0.65) in the chronically HCV-infected and 0.52 (95% CI: 0.40-0.63) in the cleared HCV group. Chronic HCV-infection was not associated with overall mortality: MRR 0.85, 95% CI: 0.59-1.21. In HIV-infected Danish IDUs, chronic HCV-infection is not associated with increased mortality compared to patients who have cleared the infection.

Predictors of antiviral treatment initiation in hepatitis C virus-infected patients: a Danish cohort study.

Predictive factors for initiation of antiviral therapy in chronically infected hepatitis C virus (HCV) patients are not fully elucidated. The aim of this study was to determine predictive factors for initiation of treatment with standard or pegylated interferon either alone or combined with ribavirin. A Danish cohort of individuals chronically infected with HCV was used and observation time was calculated from the date of inclusion in the cohort to date of death, last clinical observation, 1 January 2007, or start of HCV antiviral treatment in treatment-naïve patients. Kaplan-Meier survival analysis was used to construct time to event curves. Cox regression was used to determine the incidence rate ratios as estimates of relative risk (RR) and 95% confidence intervals (CI). A total of 1780 patients were enrolled in the study. The cumulative chance of treatment initiation over 5 years was 33.0%. We found several strong predictors of treatment initiation: elevated alanine aminotransferase [>2 times upper limit (RR = 2.17, 95% CI 1.64-2.87), >3 times upper limit (RR = 3.64, 95% CI 2.75-4.81)], genotype 2 or 3 (RR = 1.86, 95% CI 1.49-2.31) and HIV co-infection (RR = 0.28, 95% CI 0.15-0.53). To our knowledge, this study is the first to estimate factors predicting initiation of antiviral treatment in patients with chronic HCV infection on a nationwide scale. We found that several of the factors predicting initiation of antiviral treatment correlate with factors known to predict a better response to treatment and factors known to increase the progression of liver disease.

The impact of CMV on the respiratory burst of macrophages in response to Pneumocystis carinii.

Infection of human monocyte-derived macrophages with CMV decreased the respiratory burst when cells were stimulated with opsonized zymosan or Pneumocystis carinii (P. carinii). Such an effect, though smaller, was also seen with heat-inactivated CMV, but only when triggered by zymosan. The effect was most pronounced in cells obtained from CMV antibody-negative donors. Dexamethasone further reduced the respiratory burst, both in uninfected and CMV-infected cells. Interferon-gamma increased the response in uninfected cells and, to a lesser extend, in cells treated with heat-inactivated CMV, whereas no effect was seen with infective CMV. No overt productive infection or cytopathology could be detected, however, the monocytes incubated with infective but also heat-inactivated CMV formed clusters, a phenomenon that was equally pronounced in cultures from CMV antibody positive and negative-donors. These results might help explain the worse prognosis of P. carinii pneumonia in patients coinfected with CMV and receiving dexamethasone.

[Zoonoses among immigrants]. / Zoonoser blandt indvandrere.

During the last ten years Denmark has received an increasing number of immigrants, especially from the Balkans, the Middle East, and Somalia. Some of these may suffer from the zoonoses occurring in their country of origin. But apart from echinococcosis, zoonoses in these immigrants do not seem to pose a quantitatively greater problem than in Danes who have visited these areas. However it is important to have a knowledge of the symptoms and mode of transmission of zoonoses occurring in areas where the immigrants come from.

Viremia in chronic hepatitis C patients evaluated by the Amplicor RT-PCR, a nested RT-PCR, and transaminase levels.

A commercially available kit, Amplicor, was compared with a locally developed nested reverse-transcriptase (RT) PCR for qualitative detection of HCV-RNA. Sixty-one serum samples from sixty-one patients with liver disease, and 60 samples from 60 hemophiliacs without symptoms, but known to have been heavily exposed to hepatitis C virus, were investigated. There was a high degree of concordance between the two diagnostic tests (97%), the Amplicor kit being slightly more sensitive than the in-house PCR, when evaluated using serial dilutions of samples showing discrepant results. The relationship between viremia and abnormal ALT levels was studied in the two groups of patients. Among those with chronic liver disease, 8.3% of patients with viremia had normal ALT levels, whereas transaminases were normal in 20% of hemophiliacs with viremia. This points to ALT as being a poor marker of ongoing viral replication.

Alpha interferon therapy in Danish haemophiliac patients with chronic hepatitis C: results of a randomized controlled open label study comparing two different maintenance regimens following standard interferon-alpha-2b treatment.

Following a survey among all Danish haemophiliac patients 49 HIV-negative patients with chronic hepatitis C were offered enrollment in a randomized controlled open label study comparing two different maintenance regimens following standard interferon-alpha-2b treatment. Dose modifications and treatment discontinuation were based upon changes in transaminase levels. Forty-seven patients enrolled received 3 MU of alpha interferon thrice weekly (TIW) for 3 months. Twenty-six nonresponders had their dose increased to 6 MU TIW for an additional 3 months, while 21 responding patients continued on 3 MU TIW. At 6 months, 25 patients with a complete or a partial biochemical response were randomly allocated to either a fixed dose regimen (13 patients) (3 or 6 MU thrice weekly) or an individualized dose regimen (12 patients) tapering interferon dose from 3 or 6 MU by one-third every 2 months if transaminases were persistently normal. The remaining 22 biochemical nonresponders were followed for an additional 6 months without further treatment. After 12 months of treatment, 18 patients (38%) had a virological response, irrespective of regimen, and seven patients (16%) had a sustained virological and biochemical response after 6 months of follow up. Overall, the individualized treatment regimen did not seem to offer any advantage over the fixed dose regimen. The response to alpha interferon treatment in Danish haemophiliac patients with chronic hepatitis C immediately after treatment is comparable to that obtained in previous studies among nonhaemophiliacs. However, a sustained virological and biochemical response was seen in only 16% of treatment patients.

Low levels of IgG antibodies against pneumocystis carinii among HIV-infected patients.

IgG antibodies against Pneumocystis carinii (P. carinii) were detected by an ELISA method using urea-extracted material from human and rat P. carinii as the antigen. Carbohydrate formed a major part of the antigen responsible for reactivity in the ELISA assay, since periodate treatment reduced the reactivity of most sera tested. Cross-reactivity between human and rat P. carinii was detected. However, human serum recognized antigens specific for human P. carinii. With the ELISA method IgG antibody levels were compared between blood donors (n = 40), asymptomatic HIV-antibody positive patients (n = 30) and AIDS patients with (n=22) and without previous P. carinii pneumonia (PCP) (n=21). HIV-infected patients had significantly lower antibody reactivity against the microorganism compared with blood donors. Among HIV-antibody positive patients the highest antibody reactivity was seen in PCP patients. The antibody response to PCP was impaired, since an equal number of patients had an increase and a decrease in antibody reactivity. In conclusion, carbohydrate formed an important part of the P. carinii immunogenic antigen. Cross-reactivity between rat and human P. carinii was demonstrated, but reactivity was somewhat lower using antigen from rats. The antibody level was lower in HIV-infected patients and the ability to mount an antibody response to the infection was impaired, suggesting that the poor antibody response may contribute to the liability of HIV-infected patients to have PCP.

Decreased activation of the respiratory burst in neutrophils from AIDS patients with previous Pneumocystis carinii pneumonia.

Neutrophils from human immunodeficiency virus (HIV)-negative blood donors, asymptomatic HIV-positive patients, AIDS patients with previous Pneumocystis carinii pneumonia (PCP), and AIDS patients without previous PCP were compared for their ability to activate the respiratory burst, measured as luminol-amplified chemiluminescence. P. carinii, Staphylococcus aureus, phorbol-12-myristate-13-acetate, and FMLP were used to stimulate the neutrophils. When stimulated with P. carinii, neutrophils from PCP patients had a significantly lower response than the other groups, whereas no difference was found when S aureus was used. A somewhat but not significantly lower response to P. carinii was also seen in non-PCP patients compared with HIV-negative donors. Priming of the neutrophils with recombinant granulocyte colony-stimulating factor (G-CSF) or recombinant human granulocyte-macrophage (GM)-CSF corrected this defect. A similar effect of these cytokines was seen on phagocytosis, whereas the chemiluminescence in unprimed cells did not correlate with phagocytosis.

Pneumocystis carinii-induced activation of the respiratory burst in human monocytes and macrophages.

Human monocytes and monocyte-derived macrophages were studied for their ability to phagocytose Pneumocystis carinii and produce superoxide (O2-) during the process. One x 10(6) freshly isolated monocytes, incubated with 0.1-3.75 x 10(6) P. carinii cysts, increased O2- production in a dose-related way. Antibodies were essential for the process since opsonized, but not unopsonized, pneumocysts induced O2- production significantly above the response obtained by lung tissue from rats (10.7 and 4.9 versus 3.0 fmol/cell per 90 min). The difference between pneumocysts opsonized in untreated versus complement-depleted serum was not significant (10.7 versus 12.6 fmol/cell per 90 min). Monocyte-derived macrophages also activated the respiratory burst when stimulated with pneumocysts, and this effect could be significantly increased, from 4.2 to 8.8 fmol/cell per 90 min, when cells were primed with interferon-gamma (IFN-gamma). Cells primed with IL-3 also increased O2- production, though to a lesser extent. In contrast, granulocyte-macrophage colony-stimulating factor (GM-CSF) had only a small effect on the respiratory burst in cells stimulated with P. carinii. Priming with IFN-gamma increased the rate of phagocytosis in macrophages. After incubation for 90 min or more, however, the percentage of cells with phagocytic vacuoles was only slightly higher in IFN-gamma-primed cells. When examined by electron microscopy (EM), most vacuoles contained partially or totally degraded pneumocysts. In conclusion, we have demonstrated the ability of monocytes and monocyte-derived macrophages to ingest and degrade pneumocysts, activating the respiratory burst during the process.

Local antibodies against Pneumocystis carinii in bronchoalveolar lavage fluid.

Pneumocystis carinii pneumonia (PCP) is a frequent cause of pneumonia among human immunodeficiency virus (HIV)-infected patients. Little is known, however, about the role played by humoral immunity to control the infection. This study was undertaken to elucidate the role played by local antibodies. Bronchoalveolar lavage (BAL) fluids from 18 acquired immune deficiency syndrome (AIDS) patients with PCP, 20 HIV-antibody positive patients without PCP, and 20 lung cancer patients were examined for antibodies against P. carinii by the indirect immunofluorescence method. The ratio of albumin concentration in BAL fluid to serum was used to standardize the lavage fluids. Immunoglobulin G (IgG) antibodies against P. carinii occurred less frequently, and immunoglobulin M (IgM) antibodies more frequently, in PCP patients than in other groups. Immunoglobulin A (IgA) antibodies against pneumocysts were found with the same frequency in all three groups, although the median titre was lower among HIV-antibody positive patients without PCP, compared with the other groups. When indexed (antibody titre in BAL fluid x albumin concentration in serum/antibody titre in serum x albumin concentration in BAL fluid) to express locally produced antibodies, IgG indices were significantly higher in HIV-infected patients without PCP, whereas IgM and IgA indices were significantly higher in PCP patients. These findings suggest that the local IgG response is impaired in patients with PCP, whereas the local IgA and, to some extent, the IgM responses are preserved.

Phagocytosis and stimulation of the respiratory burst in neutrophils by Pneumocystis carinii.

Phagocytosis and superoxide production of neutrophils stimulated with Pneumocystis carinii were studied using P. carinii obtained from rats and neutrophils and serum from healthy blood donors. Superoxide generation increased in a dose-related way to the number of pneumocysts added and was significantly higher when the parasites were opsonized. The use of heat-inactivated serum for opsonization reduced superoxide production somewhat, but not significantly. Preincubation of neutrophils with recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF) increased superoxide production in neutrophils stimulated with pneumocysts from 7.0 to 9.6 fmol/cell/20 min; however, the production in unstimulated cells increased by the same amount. Activation of the respiratory burst was paralleled by phagocytosis, and very few phagocytic vacuoles were found in neutrophils stimulated with unopsonized pneumocysts. By electron microscopy, various stages of cyst degradation were seen.

The C-reactive protein responses in HIV-infected patients with pneumonia.

The acute phase C-reactive protein (CRP) was measured in serum of HIV-infected patients suffering from Pneumocystis carinii pneumonia (PCP) (32 patients), bacterial pneumonia (10 patients), and in 19 immunocompetent patients with bacterial pneumonia. The HIV-infected patients with bacterial pneumonia had a significantly lower CRP level than the immunocompetent patients (50% versus 95% had an s-CRP level > 80 mg/l). No significant difference was found in the CRP response to P. carinii or bacteria in HIV-infected patients with pneumonia due to these microorganisms (20% versus 50% had s-CRP > 80 mg/l). In the group of PCP patients, a significantly lower CRP level was found in those with CD4 positive lymphocyte counts below 50 x 10(6)/l. There was no correlation between the CRP response and the severity of the PCP as estimated by the degree of hypoxia. We conclude that the CRP level cannot be used to discriminate between PCP and bacterial pneumonia in HIV-infected patients.

Effects of serotonergic and anticholinergic drugs in haloperidol-induced dystonia in Cebus monkeys.

In rodents, serotonin (5-HT) antagonists counteract behavioral and biochemical effects of neuroleptic drugs. Therefore, we have studied the effect of different 5-HT drugs and one anticholinergic drug in acute dystonia in five cebus monkeys chronically treated with haloperidol. Acute dystonia induced by subcutaneous injections of haloperidol was slightly reduced by the 5-HT antagonist methysergide (4.0 mg/kg), while mianserin, ketanserin, and ritanserin (R 55 667; a new selective and potent 5-HT receptor blocker) had no effect. This was contrasted by the marked antidystonic effect of the anticholinergic drug biperiden (0.05-1.0 mg/kg). The 5-HT agonist citalopram, a specific 5-HT uptake inhibitor, had no significant effect. It is concluded that 5-HT antagonists have no useful effect in neuroleptic-induced dystonia.

Paroxetine in the treatment of depression--a randomized comparison with amitriptyline.

Paroxetine is a new antidepressant drug with potent serotonin (5HT) uptake inhibitory properties. In this double-blind comparative study, the antidepressant effect of paroxetine and amitriptyline has been compared in 44 patients with depressive illnesses of an endogenous nature. Each drug was given for 6 weeks. The 17-item Hamilton Depression Scale was used to measure the antidepressant effect. Reported events were assessed applying a 22-item check list. Non-parametric statistical analyses were applied in the evaluation of treatment outcome for the 30 patients who completed the study. The results showed no significant differences in overall antidepressant efficacy between paroxetine and amitriptyline and that paroxetine displayed significantly fewer instances of dry mouth and orthostatic dizziness than amitriptyline. No obvious relationship was demonstrated between the plasma levels of the drugs and their clinical effects.