Alexandra Jablonka

High Frequencies of Polyfunctional CD8+ NK Cells in Chronic HIV-1 Infection Are Associated with Slower Disease Progression

ABSTRACT Natural killer (NK) cells are effector and regulatory innate immune cells and play a critical role in the first line of defense against various viral infections. Although previous reports have indicated the vital contributions of NK cells to HIV-1 immune control, nongenetic NK cell parameters directly associated with slower disease progression have not been defined yet. In a longitudinal, retrospective study of 117 untreated HIV-infected subjects, we show that higher frequencies as well as the absolute numbers of CD8+ CD3− lymphocytes are linked to delayed HIV-1 disease progression. We show that the majority of these cells are well-described blood NK cells. In a subsequent cross-sectional study, we demonstrate a significant loss of CD8+ NK cells in untreated HIV-infected individuals, which correlated with HIV loads and inversely correlated with CD4+ T cell counts. CD8+ NK cells had modestly higher frequencies of CD57-expressing cells than CD8− cells, but CD8+ and CD8− NK cells showed no differences in the expression of a number of activating and inhibiting NK cell receptors. However, CD8+ NK cells exhibited a more functional profile, as detected by cytokine production and degranulation. IMPORTANCE We demonstrate that the frequency of highly functional CD8+ NK cells is inversely associated with HIV-related disease markers and linked with delayed disease progression. These results thus indicate that CD8+ NK cells represent a novel NK cell-derived, innate immune correlate with an improved clinical outcome in HIV infection.

Seroprevalence of antibodies and antigens against hepatitis A–E viruses in refugees and asylum seekers in Germany in 2015

Background Migration because of miscellaneous political crises in countries in the Middle East and Africa is a global challenge for whole Europe from an economic, social, and public health view. There is an urgent need to generate comprehensive, evidence-based data to expedite further screening and vaccination strategies. Methods A total of 604 individuals ranging in age from 2 to 68 years who enrolled at a single reception center were tested for the prevalence of serologic markers for hepatitis virus types A, B, C, D, and E (HAV, HBV, HCV, HDV, HEV), respectively. Results Anti-HAV antibody prevalence was 91.2 and 70.3% in children younger than 18 years of age. The prevalence of anti-HEV antibodies was 20.1% among the individuals. 3.0% were positive for hepatitis B surface antigen, whereas 15.2% tested positive for anti-hepatitis B core antigen. None of the refugees tested positive for anti-HDV. 14.1% of refugees were vaccinated against hepatitis B and had a protective anti-hepatitis B surface level of at least 10 mIU/ml. Significant differences in vaccination status were found between the regions (Eastern Mediterranean Region with 77/482 (16.0%; 95% confidence interval=12.7–19.3%) versus African Region with 1/55 (1.8%; 95% confidence interval=0–5.0%). The prevalence of anti-HCV antibodies was 1.2% (n=7), with 0.7% HCV RNA positivity; 16.7% of hepatitis B surface antigen-positive individuals were HCV coinfected (n=3). Conclusion The prevalence of refugees with previous exposure to hepatitis viruses was higher than that in the general German population, but lower than in other migrant populations in Germany. The vaccination status against hepatitis B was poor.

Cost–effectiveness of TNF-α inhibition in active ankylosing spondylitis: a systematic appraisal of the literature

Ankylosing spondylitis (AS) is the most frequent prototype of spondyloarthritides. Substantial direct costs and productivity losses often arise in young patients. Currently, tumor necrosis factor (TNF) inhibitors are the only approved therapy escalation when usual care (physiotherapy and NSAIDs) proves to be insufficient. Owing to their high medication costs, TNF inhibitors are a target of cost–effectiveness analyses. There is consistent evidence regarding the use of TNF inhibitors according to recommendations in patients with active AS finding TNF inhibitors to be cost effective from a societal perspective. However, there are relevant uncertainties (discontinuation rate and progression rate) in the long-term estimates of the cost–effectiveness analyses analyzed. Whether TNF inhibitors are cost effective from an insurance perspective in the long run will have to be addressed by models based on observational data.

Norovirus outbreaks in german refugee camps in 2015

Purpose Refugees often live in confined housing conditions with shared kitchen and sanitary facilities, rendering susceptible to communicable diseases. We here describe the outbreak, spread and self-limiting nature of a norovirus outbreak in a German refugee camp in the winter of 2015. Methods During a norovirus outbreak, data on clinical symptoms, nationality and living conditions was obtained in a refugee camp in northern Germany in the winter of 2015. Furthermore secondary data on norovirus outbreaks in 2015 was assessed. Results Amongst n = 982 refugees, n = 36 patients (3.7 %) presented with acute norovirus gastroenteritis. The vast majority of cases were children, only the first patient was admitted to the hospital. Intensified hygiene measures were implemented on day 2 of the outbreak, but new cases peaked on day 21 and occurred until one month after the first case. Different cultural backgrounds, eating habits and hygiene standards amongst the refugees made it particularly challenging to implement stringent isolation and hygiene measures. Despite these predisposing factors, only minor norovirus outbreaks were reported in refugee camps in 2015. Conclusion Adults refugees had a low attack rate of symptomatic norovirus infection, while small children are at high risk. Infection spreads despite hygiene measures and camp sites and staff should be prepared for the particular challenges of such situations with a particular focus on cultural-background specific implementation of hygiene measures.

First Association of Interleukin 12 Receptor Beta 1 Deficiency with Sjögren’s Syndrome

Introduction Interleukin 12 receptor beta 1 (IL12Rβ1) deficiency is a primary immunodeficiency resulting mainly in susceptibility to opportunistic infection by non-tuberculous, environmental mycobacteria and severe infection caused by Salmonella spp. Till now, less than 300 patients with IL12Rβ1 deficiency have been reported. Among them, only three have been described to develop autoimmunity. Case presentation We present the case of a 50-year-old male with IL12Rβ1 deficiency due to compound heterozygosity [c. 1623_1624delGCinsTT (pGln542Stop) and c.1791 + 2T > C (donor splice site)], who—18 months after diagnosis of disseminated BCGitis—presented with recurrent fever and sicca syndrome. No indication of an infectious origin of these symptoms could be found at that point. The diagnosis of a Sjögren’s syndrome (SS) was made on the basis of fulfilled American-European consensus classification criteria, including a positive minor salivary gland biopsy. Conclusion Apart from persistent antigenic stimulation, which may drive autoimmune inflammation in primary immunodeficiency, evidence on the involvement of interleukin 12 in pathogenesis of SS suggests that the same immunological mechanism may underlie both defense against infection and the maintenance of tolerance. To our knowledge, this is the first report of a case of autoimmunity in the form of SS in a patient with a primary immunodeficiency and one of the rare cases of IL12Rβ1 deficiency with manifested autoimmunity.

Molecular Epidemiology of the HIV Epidemic in Three German Metropolitan Regions – Cologne/Bonn, Munich and Hannover, 1999–2016

Using HIV sequence data to characterize clusters of HIV transmission may provide insight into the epidemic. Phylogenetic and network analyses were performed to infer putative relationships between HIV-1 partial pol sequences from 2,774 individuals receiving care in three German regions between 1999–2016. The regions have in common that they host some of the largest annual festivals in Europe (Carnival and Oktoberfest). Putative links with sequences (n = 150,396) from the Los Alamos HIV Sequence database were evaluated. A total of 595/2,774 (21.4%) sequences linked with at least one other sequence, forming 184 transmission clusters. Clustering individuals were significantly more likely to be younger, male, and report sex with men as their main risk factor (p < 0.001 each). Most clusters (77.2%) consisted exclusively of men; 41 (28.9%) of these included men reporting sex with women. Thirty-two clusters (17.4%) contained sequences from more than one region; clustering men were significantly more likely to be in a position bridging regional HIV epidemics than clustering women (p = 0.027). We found 236 clusters linking 547 sequences from our sample with sequences from the Los Alamos database (n = 1407; 31% from other German centres). These results highlight the pitfalls of focusing HIV prevention efforts on specific risk groups or specific locales.

Tuberculosis Specific Interferon-Gamma Production in a Current Refugee Cohort in Western Europe

Background: In 2015, a high number of refugees with largely unknown health statuses immigrated to Western Europe. To improve caretaking strategies, we assessed the prevalence of latent tuberculosis infection (LTBI) in a refugee cohort. Methods: Interferon-Gamma release assays (IGRA, Quantiferon) were performed in n = 232 inhabitants of four German refugee centers in the summer of 2015. Results: Most refugees were young, male adults. Overall, IGRA testing was positive in 17.9% (95% CI = 13.2–23.5%) of subjects. Positivity rates increased with age (0% <18 years versus 46.2% >50 years). Age was the only factor significantly associated with a positive IGRA in multiple regression analysis including gender, C reactive protein, hemoglobin, leukocyte, and thrombocyte count and lymphocyte, monocyte, neutrophil, basophil, and eosinophil fraction. For one year change in age, the odds are expected to be 1.06 times larger, holding all other variables constant (p = 0.015). Conclusion: Observed LTBI frequencies are lower than previously reported in similar refugee cohorts. However, as elderly people are at higher risk for developing active tuberculosis, the observed high rate of LTBI in senior refugees emphasizes the need for new policies on the detection and treatment regimens in this group.

Pregnancy Related Health Care Needs in Refugees—A Current Three Center Experience in Europe

Background: Immigration into Europe has reached an all-time high. Provision of coordinated healthcare, especially to refugee women that are at increased risk for adverse pregnancy outcomes, is a challenge for receiving health care systems. Methods: We assessed pregnancy rates and associated primary healthcare needs in three refugee cohorts in Northern Germany during the current crisis. Results: Out of n = 2911 refugees, 18.0% were women of reproductive age, and 9.1% of these were pregnant. Pregnancy was associated with a significant, 3.7-fold increase in primary health care utilization. Language barrier and cultural customs impeded healthcare to some refugee pregnant women. The most common complaints were demand for pregnancy checkup without specific symptoms (48.6%), followed by abdominal pain or urinary tract infections (in 11.4% of cases each). In 4.2% of pregnancies, severe complications such as syphilis or suicide attempts occurred. Discussion: We present data on pregnancy rates and pregnancy associated medical need in three current refugee cohorts upon arrival in Germany. Healthcare providers should be particularly aware of the requirements of pregnant migrants and should adapt primary caretaking strategies accordingly.

Primary immunodeficiency disorder caused by phosphoinositide 3-kinase delta (PI3Kδ) deficiency

First publication on human PI3Kδ deficiency. Two patients carrying novel homozygous loss-of-function mutation in PIK3CD, resulting in PI3Kδ deficiency, developed a primary immunodeficiency disorder characterized by hypogammaglobulinemia and inflammatory bowel disease.

Healthcare Utilization in a Large Cohort of Asylum Seekers Entering Western Europe in 2015

During the current period of immigration to Western Europe, national healthcare systems are confronted with high numbers of asylum seekers with largely unknown health status. To improve care taking strategies, we assessed healthcare utilization in a large, representative cohort of newly arriving migrants consisting of n = 1533 residents of a reception center in Northern Germany in 2015. Most asylum seekers were young, male adults, and the majority came from the Eastern Mediterranean region. Overall, we observed a frequency of 0.03 visits to the onsite primary healthcare ward per asylum seeker and day of camp residence (IQR 0.0–0.07, median duration of residence 38.0 days, IQR 30.0–54.25). Female asylum seekers showed higher healthcare utilization rates than their male counterparts, and healthcare utilization was particularly low in asylum seekers in their second decade of life. Furthermore, a significant correlation between time after camp entrance and healthcare utilization behavior occurred: During the first week of camp residence, 37.1 visits/100 asylum seekers were observed, opposed to only 9.5 visits/100 asylum seekers during the sixth week of camp residence. This first data on healthcare utilization in a large, representative asylum seeker cohort entering Western Europe during the current crisis shows that primary care is most needed in the first period directly after arrival. Our dataset may help to raise awareness for refugee and migrant healthcare needs and to adapt care taking strategies accordingly.