Audiological profile of adult Long COVID patients.

INTRODUCTION: Hearing loss is one of the self-reported symptoms of Long COVID patients, however data from objective and subjective audiological tests demonstrating diminished hearing in Long COVID patients has not been published. MATERIALS AND METHODS: Respondents of a large Long COVID online survey were invited to the ENT-department for an otologic exam. The participants were split into three groups based on their history of SARS-CoV-2 infection and persistence of symptoms. Respondents with a history of a SARS-CoV-2 infection were allocated to the Long COVID group, if they reported persistent symptoms and to the Ex COVID group, if they had regained their previous level of health. Participants without a history of SARS-CoV-2 infection made up the No COVID control group. In total, 295 ears were examined with otoscopy, tympanograms, pure tone audiometry and otoacoustic emissions. Ears with known preexisting hearing loss or status post ear surgery, as well as those with abnormal otoscopic findings, non-type A tympanograms or negative Rinne test were excluded. RESULTS: Compared to the No COVID and Ex COVID groups, we did not find a clinically significant difference in either hearing thresholds or frequency specific TEOAEs. However, at 500 Hz the data from the left ear, but not the right ear showed a significantly better threshold in the Ex COVID group, compared to Long COVID and No COVID groups. Any of the other tested frequencies between 500 Hz and 8 kHz were not significantly different between the different groups. There was a significantly lower frequency-specific signal-to-noise-ratio of the TEOAEs in the Long COVID compared to the No COVID group at 2.8 kHz. At all other frequencies, there were no significant differences between the three groups in the TEOAE signal-to-noise-ratio. CONCLUSION: This study detected no evidence of persistent cochlear damage months after SARS-CoV-2 infection in a large cohort of Long COVID patients, as well as those fully recovered.

Zidovudine-Mediated Autophagy Inhibition Enhances Mitochondrial Toxicity in Muscle Cells.

Nucleoside reverse transcriptase inhibitors (NRTI), such as zidovudine (AZT), are constituents of HIV-1 therapy and are used for the prevention of mother-to-child transmission. Prolonged thymidine analogue exposure has been associated with mitochondrial toxicities to heart, liver, and skeletal muscle. We hypothesized that the thymidine analogue AZT might interfere with autophagy in myocytes, a lysosomal degradation pathway implicated in the regulation of mitochondrial recycling, cell survival, and the pathogenesis of myodegenerative diseases. The impact of AZT and lamivudine (3TC) on C2C12 myocyte autophagy was studied using various methods based on LC3-green fluorescent protein overexpression or LC3 staining in combination with Western blotting, flow cytometry, and confocal and electron microscopy. Lysosomal and mitochondrial functions were studied using appropriate staining for lysosomal mass, acidity, cathepsin activity, as well as mitochondrial mass and membrane potential in combination with flow cytometry and confocal microscopy. AZT, but not 3TC, exerted a significant dose- and time-dependent inhibitory effect on late stages of autophagosome maturation, which was reversible upon mTOR inhibition. Inhibition of late autophagy at therapeutic drug concentrations led to dysfunctional mitochondrial accumulation with membrane hyperpolarization and increased reactive oxygen species (ROS) generation and, ultimately, compromised cell viability. These AZT effects could be readily replicated by pharmacological and genetic inhibition of myocyte autophagy and, most importantly, could be rescued by pharmacological stimulation of autophagolysosomal biogenesis. Our data suggest that the thymidine analogue AZT inhibits autophagy in myocytes, which in turn leads to the accumulation of dysfunctional mitochondria with increased ROS generation and compromised cell viability. This novel mechanism could contribute to our understanding of the long-term side effects of antiviral agents.

[Hepatitis A immunity in refugees in Germany during the current exodus]. / Hohe Hepatitis-A-Immunitätsrate bei Flüchtlingen in Deutschland.

BACKGROUND: Germany is facing a huge humanitarian challenge with rapidly rising numbers of refugees entering the country. Data on hepatitis A seroprevalence and infection in refugees and asylum seekers in Europe during the current refugee exodus is scarce. OBJECTIVES: To assess hepatitis A (HAV) seroprevalence and immunity in refugees arriving in northern Germany in 2015. MATERIALS AND METHODS: A cross-sectional study of 235 refugees seeking shelter in reception centers in Northern Germany in August 2015 was performed, as acute Hepatitis A had been detected in one refugee in this camp. In order to analyze acute HAV infection and overall immunity, serological screening for HAV antibodies (combined IgG and IgM) was performed. The immunity threshold was defined as <20 IU/l. In all positive screening results, separate IgM testing was performed to detect acute infections. RESULTS: Males accounted for 84.3 % of HAV screened refugees and the mean age of refugees was 29.1 ± 11.2 years. Children and adolescents below the age of 18 years made up 8.8 % of the migrants. Overall HAV immunity within the cohort was 90 %, and a mild age-dependent increase in HAV immunity was observed, with 81.1 % immunity in children <18 years and a 100 % seropositivity in subjects >50 years. One 20-year-old female refugee had positive IgM results with high HAV antibodies, most likely due to subacute HAV infection. CONCLUSIONS: This comparably high rate of HAV protected refugees in our cohort supports the notion that the probability of large HAV outbreaks in current German refugee centers is low. However, depending on their current living situation, HAV vaccination should be considered for each refugee child, and healthcare providers and personnel working in refugee centers should be vaccinated against HAV.

[Low seroprevalence of syphilis and HIV in refugees and asylum seekers in Germany in 2015]. / Niedrige Seroprävalenz von Syphilis und HIV bei Flüchtlingen in Deutschland im Jahr 2015.

Background | Currently only estimates exist of seroprevalence of syphilis and human immunodeficiency virus (HIV) in refugees arriving in Germany during the current refugee crisis. Objectives | To assess the prevalence of syphilis and human immunodeficiency virus (HIV) in refugees arriving in northern Germany in 2015. Materials and methods | In a cross-sectional study in 790 patients from all age groups tests for serological markers of treponema pallidum and in 789 patients for human immunodeficiency virus (HIV) were performed in August 2015 in reception centers in northern Germany. Results | The overall prevalence of treponema pallidum antibodies was 0.13 % (1/790; [95 % CI: 0 - 0.4]). HIV antibodies were positive in two refugees from sub-Saharan Africa (2/789; 0.25 %, [95 % CI: 0 - 0.6]). Conclusions | This study showed a low prevalence of treponema pallidum antibodies and human immunodeficiency virus infection (HIV) in a German refugee cohort, not significantly different from German controls.

Histone deacetylase inhibitors induce apoptosis in myeloid leukemia by suppressing autophagy.

Histone deacetylase (HDAC) inhibitors (HDACis) are well-characterized anti-cancer agents with promising results in clinical trials. However, mechanistically little is known regarding their selectivity in killing malignant cells while sparing normal cells. Gene expression-based chemical genomics identified HDACis as being particularly potent against Down syndrome-associated myeloid leukemia (DS-AMKL) blasts. Investigating the antileukemic function of HDACis revealed their transcriptional and post-translational regulation of key autophagic proteins, including ATG7. This leads to suppression of autophagy, a lysosomal degradation process that can protect cells against damaged or unnecessary organelles and protein aggregates. DS-AMKL cells exhibit low baseline autophagy due to mammalian target of rapamycin (mTOR) activation. Consequently, HDAC inhibition repressed autophagy below a critical threshold, which resulted in accumulation of mitochondria, production of reactive oxygen species, DNA damage and apoptosis. Those HDACi-mediated effects could be reverted upon autophagy activation or aggravated upon further pharmacological or genetic inhibition. Our findings were further extended to other major acute myeloid leukemia subgroups with low basal level autophagy. The constitutive suppression of autophagy due to mTOR activation represents an inherent difference between cancer and normal cells. Thus, via autophagy suppression, HDACis deprive cells of an essential pro-survival mechanism, which translates into an attractive strategy to specifically target cancer cells.

[HIV 2012 : research update]. / HIV 2012 : Aktuelle Forschungsergebnisse.

HIV therapy is able to achieve complete viral suppression in up to 90% of patients. Thus, most patients will benefit from long-term effective and tolerable therapy combinations. Antiretroviral therapy, however, can still lead to side effects, is costly, and its success is dependent on sufficient health system resources and access to different drug combinations. Established tools in prevention and novel approaches to avoid spread of HIV infection are crucial to combat the epidemic. Recent advances in research about how drug regimens stop viral transmission ("treatment as prevention"), how the immune system defends against HIV (natural killer cells, broad neutralizing antibodies), and how cellular factors restrict viral replication are import milestones on the long way to stopping the global epidemic and to fostering vaccine development.

A Multicenter, Open Labeled, Randomized, Phase III Study Comparing Lopinavir/Ritonavir Plus Atazanavir to Lopinavir/Ritonavir Plus Zidovudine and Lamivudine in Naive HIV-1-Infected Patients: 48-Week Analysis of the LORAN Trial.

OBJECTIVE: The primary aim of the study was to compare the metabolic side effects of a nucleoside analogue-containing regimen with a nucleoside analogue-sparing double protease inhibitor regimen. A secondary goal was to test for efficacy of a double-PI regimen. DESIGN: Multicenter, randomized, open-label, phase III clinical trial. SUBJECTS: Adult HIV-1-infected individuals naïve to antiretroviral therapy with viral load above 400 HIV-RNA copies/ml were randomized (1:1) to either 400 mg lopinavir /100 mg ritonavir (LPV/r) BID plus 150 mg lamivudine/300 mg zidovudine (CBV) BID versus LPV/r BID plus 300 mg atazanavir (ATV) QD. Main outcome measure was the virologic failure in both groups, defined as viral load ≥50 copies/ml at week 48. RESULTS: In the CBV/LPV/r-arm, 29 out of 35 patients [(83%; 95% confidence interval (CI) 66.9-92.2%] and 18 out of 40 patients (45%; 95% CI 29.7-61.5%) in the ATV/LPV/r-arm had a HIV-RNA level <50 copies/ml at week 48. The intent-to-treat analysis revealed inferior virologic response in the ATV/LPV/r arm (Chi-Q and Fisher´s Exact Test p<0.001) and resulted in premature termination of the trial. Eleven patients in the ATV/LPV/r-arm discontinued therapy because of virological failure. These failures mostly presented with low level replication (<1,000 copies/ml). Increases in CD4 cell counts was significantly more rapid in the ATV/LPV/r arm (p=0.02), but comparable at week 48. CONCLUSIONS: ATV/LPV/r had less virologic efficacy than the conventional RTI-based regimen and resulted in a high virological failure rate with low level replication.

HIV-therapy associated lipodystrophy: experimental and clinical evidence for the pathogenesis and treatment.

The introduction of highly active antiretroviral therapy (HAART) including nucleoside reverse transcriptase inhibitors (NRTI) and protease inhibitors (PI) has dramatically improved the morbidity and mortality in HIV-infected patients. Unfortunately, HAART has been associated with several side effects among which the development of lipodystrophy syndrome remains a major clinical issue. It is characterized by fat redistribution dominated by peripheral fat loss and complex metabolic alterations including dyslipidemia and insulin resistance. Dissection of the pathogenesis of the lipodystrophy syndrome is hampered by several factors: all HIV-patients receiving HAART have a chronic and often advanced illness with impact on metabolism and energy homeostasis. Secondly, almost all patients are receiving various combinations of drugs that simultaneously reduce viral replication and restore the immune system. Recently, more detailed clinical studies, experiments using animal models and in vitro systems have been successfully used to elucidate important pathogenic aspects. At the same time, partial reversion of fat loss and metabolic disturbances in HIV-patients could be achieved by omitting components of HAART or administration of metabolically active drugs. Here, we will summarize the current knowledge about the molecular alterations that are induced by antiretroviral therapy and possibly contribute to the lipodystrophy syndrome. Specific attention will be given to the role of NRTI and PI on adipocyte development, function, and mitochondrial integrity leading to fat loss, fat accumulation, and increase of serum lipids.

[Immune restoration inflammatory syndromes]. / Immunrekonstitutionssyndrome (IRIS). Ein scheinbares Paradoxon.

Increase of prevalence of certain immunodeficiencies is caused by more frequent use of immunosuppresive treatment, by advances in supportive care of immunodeficient individuals and by the pandemic spread of HIV-infection respectively. Highly active antiretroviral treatment (HAART) is able to reconstitute the impaired immunity in the HIV-infected individual and therefore to reduce morbidity and mortality. On the other hand paradoxical exacerbation of inflammatory or opportunistic diseases may develop during immunoreconstitution. By their distinct pathophysiological, clinical and therapeutic particularities these disease have been summarized as Immune Restoration Inflammatory Syndromes (IRIS). This review summarizes the variety of immunoreconstitution disorders and describes possible diagnostic pitfalls. Potential therapeutic options and an algorithm for the classification of the syndrome are proposed.

Lack of mutations in LMNA, its promoter region, and the cellular retinoic acid binding protein II (CRABP II) in HIV associated lipodystrophy.

Familial partial lipodystrophy (FPL) and lipodystrophy observed in HIV-1 infected patients receiving highly active antiretroviral therapy (HAART) share multiple clinical and metabolic features. Recently, missense mutations of LMNA encoding lamin A/C have been described in FPL providing evidence for a pivotal role of lamin A/C in the regulation of adipocytes. Moreover, the cellular retinoic acid binding protein (CRABP) has been suggested to be involved in HAART associated lipodystrophy. In this study, we excluded mutations within the complete coding region and the promoter of LMNA and the CRABP II gene in HIV-1 infected patients with lipodystrophy and also any correlation of the nucleotide polymorphism at codon 566 in exon 10 of LMNA with metabolic abnormalities. Protease inhibitors including indinavir have been shown to reduce adipocyte cell differentiation and increase apoptosis of adipocytes in vitro. Indinavir leads to altered retinoic acid signaling most likely by an activation of the RAR/RXR heterodimer, perhaps by displacing all-trans-retinoic acid from CRABP. Since LMNA is regulated by a retinoic acid responsive element (L-RARE) in the promoter region, we propose that indinavir impairs retinoic acid homeostasis and/or interact via the L-RARE within the LMNA promoter. This results in altered LMNA expression and subsequent impaired adipocyte differentiation, lipodystrophic body habitus, and metabolic disturbances in HIV infected patients receiving HAART.

Pulmonary hypersensitivity reaction induced by efavirenz.

HIV-infected patients are at increased risk of developing adverse drug reactions such as a maculopapular rash due to antiretroviral drugs. For example, exanthema induced by non-nucleoside reverse transcriptase inhibitors leads to drug discontinuation in many patients. We present a patient with a severe pulmonary hypersensitivity reaction due to efavirenz.

Immune reconstitution syndromes in human immuno-deficiency virus infection following effective antiretroviral therapy.

Effective antiretroviral therapy leads to rapid decrease in plasma HIV-1 RNA, frequently followed by an increase in CD4 T-helper cell counts. The improvement of immune function during highly active antiretroviral therapy has important impact on natural history of AIDS-related opportunistic disorders. Here we describe cases of unusual clinical inflammatory syndromes in CMV retinitis, hepatitis C, and atypical mycobacteriosis in HIV-1 infected patients associated with the initiation of antiretroviral therapy. Pathogenetic implications and therapeutic management of these new immunopathologic syndromes are discussed.

Lipodystrophy syndrome in HIV infection: what is it, what causes it and how can it be managed?

Since the introduction of HIV-1 protease inhibitors as components of antiretroviral drug combination regimens, the clinical course of HIV disease and opportunistic infections has changed dramatically. Besides the favourable virological, immunological and clinical impact of highly active antiretroviral therapy (HAART), several adverse drug reactions have been observed in patients with HIV receiving therapy. Particularly, peripheral lipodystrophy, central adiposity, dyslipidaemia and insulin resistance have been described with a prevalence of up to 80% in patients infected with HIV, and attributed to almost all components of HAART. Hyperlipidaemia is characterised by an increase of low and very low density lipoprotein-cholesterol as well as apolipoproteins B and E. Several studies strongly suggest that there are either multiple syndromes or a variety of factors inducing different changes that influence the ultimate phenotype. Similarities between HIV-associated fat redistribution and metabolic abnormalities with both inherited lipodystrophies and benign symmetric lipomatosis suggest the pathophysiological involvement of, for example, nuclear factors like lamin A/C and drug-induced mitochondrial dysfunction. Moreover, there is some evidence that cytokines and hormones impair fat and glucose homeostasis in patients with HIV receiving HAART. Three years after the first description of HIV therapy-associated abnormal fat redistribution, there is still an ongoing discussion about the case definition, diagnostic procedure and treatment options for both body shape changes and metabolic disturbances. Regarding therapy, there is a major concern about possible complex pharmacological interactions and overlapping adverse effects between HAART and, for example, lipid-lowering therapy. In addition, the likely contribution of both nucleoside analogue reverse transcriptase inhibitors and protease inhibitors to the development of abnormal fat redistribution in patients with HIV limits options of changing to alternative effective antiretroviral drug combinations. Thus, the occurrence of hyperlipidaemia, maturity onset diabetes mellitus, and marked changes in body habitus resulted in important social and clinical consequences such as an increased risk of atherosclerosis. It also sheds new light on the use of protease inhibitors regarding risk factors for the initial treatment decision. In this article, we discuss the features, pathogenesis and treatment options for body fat redistribution and metabolic disturbances associated with HAART in HIV-1 infection.

[Lipodystrophy and metabolic disorders in anti-HIV therapy]. / Lipodystrophie und metabolische Störungen unter Anti-HIV-Therapie.

For the effective treatment of HIV infection, combinations of antiretroviral drugs that, at various points of attack, prevent viral replication are used. After the introduction of HIV-1 specific protease inhibitors, various metabolic complications and changes in body habitus manifesting as abnormal fat distribution were observed in HIV patients. These side effects, initially assigned class-specifically to the protease inhibitors, have, however, also been frequently seen under other drug combinations. Changes to body habitus as a result of fat redistribution have mostly been designated as lipodystrophy syndrome, but are now increasingly being recognized as highly heterogeneous abnormalities. Furthermore, the disturbances of glucose and fat metabolism may occur completely independently of phenotypic habitus changes. The result is that both the suspected pathophysiological relationships and the therapeutic consequences are becoming even more complex. This paper summarizes the current state of investigations into the side effects of antiretroviral therapy and their clinical consequences.