TNFα aggravates detrimental effects of SARS-CoV-2 infection in the liver.

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus does not only lead to pulmonary infection but can also infect other organs such as the gut, the kidney, or the liver. Recent studies confirmed that severe cases of COVID-19 are often associated with liver damage and liver failure, as well as the systemic upregulation of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNFα). However, the impact these immune mediators in the liver have on patient survival during SARS-CoV-2 infection is currently unknown. Here, by performing a post-mortem analysis of 45 patients that died from a SARS-CoV-2 infection, we find that an increased expression of TNFA in the liver is associated with elevated mortality. Using publicly available single-cell sequencing datasets, we determined that Kupffer cells and monocytes are the main sources of this TNFα production. Further analysis revealed that TNFα signaling led to the upregulation of pro-inflammatory genes that are associated with an unfavorable outcome. Moreover, high levels of TNFA in the liver were associated with lower levels of interferon alpha and interferon beta. Thus, TNFα signaling in the infected SARS-CoV-2 liver correlates with reduced interferon levels and overall survival time.

Predictors of Loneliness among Homeless Individuals in Germany during the COVID-19 Pandemic.

PURPOSE: The aim of the study was to identify the frequency of loneliness and to examine the factors associated with loneliness among homeless individuals in Germany during the COVID-19 pandemic. METHODS: Data were taken from the 'national survey on the psychiatric and somatic health of homeless individuals during the COVID-19 pandemic'. The data collection took place from 26th July to 17th September 2021 (the analytical sample included n = 491 observations). The well-established UCLA-3 tool was used to quantify loneliness. Independent variables included sex, age, marital status, the existence of children and pets, level of education, country of origin, duration of homelessness, alcohol and drug consumption, mental health concerns and concerns regarding COVID-19 illness. Multiple logistic regressions were used to examine the predictors of loneliness. RESULTS: The frequency of loneliness was 41.7% for the total sample. Multiple logistic regression analysis stratified by gender showed that a higher likelihood of loneliness was associated with being born in Germany, being middle aged (40 to 49 years compared to 18 to 29 years), having mental health problems and a short period of homelessness (1 month compared to longer periods) among women. In men, a higher likelihood of loneliness was associated with a higher fear of COVID-19 and a short period of homelessness. CONCLUSIONS: Our study revealed a high frequency rate of loneliness among homeless individuals. The study results highlight the associations between some explanatory variables (i.e., the duration of homelessness and mental health problems). Identifying the factors associated with loneliness may help to adequately address the problems of homeless individuals at risk of loneliness. Longitudinal studies are required to confirm our findings.

New Postmortem Perspective on Emerging SARS-CoV-2 Variants of Concern, Germany.

We performed autopsies on persons in Germany who died from COVID-19 and observed higher nasopharyngeal SARS-CoV-2 viral loads for variants of concern (VOC) compared with non-VOC lineages. Pulmonary inflammation and damage appeared higher in non-VOC than VOC lineages until adjusted for vaccination status, suggesting COVID-19 vaccination may mitigate pulmonary damage.

Young COVID-19 Patients Show a Higher Degree of Microglial Activation When Compared to Controls.

The severe acute respiratory syndrome-corona virus type 2 (SARS-CoV-2) is the cause of human coronavirus disease 2019 (COVID-19). Since its identification in late 2019 SARS-CoV-2 has spread rapidly around the world creating a global pandemic. Although considered mainly a respiratory disease, COVID-19 also encompasses a variety of neuropsychiatric symptoms. How infection with SARS-CoV-2 leads to brain damage has remained largely elusive so far. In particular, it has remained unclear, whether signs of immune cell and / or innate immune and reactive astrogliosis are due to direct effects of the virus or may be an expression of a non-specific reaction of the brain to a severe life-threatening disease with a considerable proportion of patients requiring intensive care and invasive ventilation activation. Therefore, we designed a case-control-study of ten patients who died of COVID-19 and ten age-matched non-COVID-19-controls to quantitatively assess microglial and astroglial response. To minimize possible effects of severe systemic inflammation and / or invasive therapeutic measures we included only patients without any clinical or pathomorphological indication of sepsis and who had not been subjected to invasive intensive care treatment. Our results show a significantly higher degree of microglia activation in younger COVID-19 patients, while the difference was less and not significant for older COVID-19 patients. The difference in the degree of reactive gliosis increased with age but was not influenced by COVID-19. These preliminary data warrants further investigation of larger patient cohorts using additional immunohistochemical markers for different microglial phenotypes.

Fear of COVID-19 among homeless individuals in Germany in mid-2021.

Aims: To investigate the prevalence and the correlates of fear of COVID-19 among homeless individuals. Methods: We used data from the "national survey on psychiatric and somatic health of homeless individuals during the COVID-19 pandemic" (NAPSHI-study) which took place in several large cities in Germany in Mid-2021 (n = 666 in the analytical sample). Mean age equaled 43.3 years (SD: 12.1 years), ranging from 18 to 80 years. Multiple linear regressions were performed. Results: In our study, 70.9% of the homeless individuals reported no fear of COVID-19. Furthermore, 14.0% reported a little fear of COVID-19, 8.4% reported some fear of COVID-19 and 6.7% reported severe fear of COVID-19. Multiple linear regressions revealed that fear of COVID-19 was higher among individuals aged 50-64 years (compared to individuals aged 18-29 years: ß = 0.28, p < 0.05), among individuals with a higher perceived own risk of contracting the coronavirus 1 day (ß = 0.28, p < 0.001) as well as among individuals with a higher agreement that a diagnosis of the coronavirus would ruin his/her life (ß = 0.15, p < 0.001). Conclusions: Only a small proportion of homeless individuals reported fear of COVID-19 in mid-2021 in Germany. Such knowledge about the correlates of higher levels of fear of COVID-19 may be helpful for addressing certain risk groups (e.g., homeless individuals aged 50-64 years). In a further step, avoiding extraordinarily high levels of fear of COVID-19 may be beneficial to avoid irrational thinking and acting regarding COVID-19 in this group.

Thromboembolic events in deceased patients with proven SARS-CoV-2 infection: Frequency, characteristics and risk factors.

BACKGROUND: Infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) results in respiratory syndromes but also in vascular complications such as thromboembolism (TE). In this regard, immunothrombosis, resulting from inflammation in SARS-CoV-2 infected tissues, has been described. Data on TE in COVID-19 are mainly based on clinical observational and/or incomplete autopsy studies. The true burden of TE and the relevance of genetic predisposition, however, have not been resolved. OBJECTIVES: Here, we report on a consecutive cohort of 100 fully autopsied patients deceased by SARS-CoV-2 infections during the first wave of the pandemic (March to April 2020). We investigated the localization of TE, potential clinical risk factors, and the prothrombotic gene mutations, factor V Leiden and prothrombin G20210A, in postmortem blood or tissue samples. RESULTS: TE was found in 43/100 autopsies. 93 % of TE events were venous occlusions, with 23 patients having pulmonary thromboembolism (PT) with or without lower-extremity deep vein thrombosis. Of these, 70 % showed PT restricted to (sub)segmental arteries, consistent with in situ immunothrombosis. Patients with TE had a significantly higher BMI and died more frequently at an intensive care unit. Hereditary thrombophilia factors were not associated with TE. CONCLUSIONS: Our autopsy results show that a significant proportion of SARS-CoV-2 infected patients suffer from TE, affecting predominantly the venous system. Orthotopic peripheral PT was the most frequent finding. Hereditary thrombophilia appears not to be a determinant for TE in COVID-19. However, obesity and the need for intensive care increase the risk of TE in these patients.

Assessing and improving the validity of COVID-19 autopsy studies - A multicentre approach to establish essential standards for immunohistochemical and ultrastructural analyses.

BACKGROUND: Autopsy studies have provided valuable insights into the pathophysiology of COVID-19. Controversies remain about whether the clinical presentation is due to direct organ damage by SARS-CoV-2 or secondary effects, such as overshooting immune response. SARS-CoV-2 detection in tissues by RT-qPCR and immunohistochemistry (IHC) or electron microscopy (EM) can help answer these questions, but a comprehensive evaluation of these applications is missing. METHODS: We assessed publications using IHC and EM for SARS-CoV-2 detection in autopsy tissues. We systematically evaluated commercially available antibodies against the SARS-CoV-2 proteins in cultured cell lines and COVID-19 autopsy tissues. In a multicentre study, we evaluated specificity, reproducibility, and inter-observer variability of SARS-CoV-2 IHC. We correlated RT-qPCR viral tissue loads with semiquantitative IHC scoring. We used qualitative and quantitative EM analyses to refine criteria for ultrastructural identification of SARS-CoV-2. FINDINGS: Publications show high variability in detection and interpretation of SARS-CoV-2 abundance in autopsy tissues by IHC or EM. We show that IHC using antibodies against SARS-CoV-2 nucleocapsid yields the highest sensitivity and specificity. We found a positive correlation between presence of viral proteins by IHC and RT-qPCR-determined SARS-CoV-2 viral RNA load (N= 35; r=-0.83, p-value <0.0001). For EM, we refined criteria for virus identification and provide recommendations for optimized sampling and analysis. 135 of 144 publications misinterpret cellular structures as virus using EM or show only insufficient data. We provide publicly accessible digitized EM sections as a reference and for training purposes. INTERPRETATION: Since detection of SARS-CoV-2 in human autopsy tissues by IHC and EM is difficult and frequently incorrect, we propose criteria for a re-evaluation of available data and guidance for further investigations of direct organ effects by SARS-CoV-2. FUNDING: German Federal Ministry of Health, German Federal Ministry of Education and Research, Berlin University Alliance, German Research Foundation, German Center for Infectious Research.

Young COVID-19 Patients Show a Higher Degree of Microglial Activation When Compared to Controls

The severe acute respiratory syndrome-corona virus type 2 (SARS-CoV-2) is the cause of human coronavirus disease 2019 (COVID-19). Since its identification in late 2019 SARS-CoV-2 has spread rapidly around the world creating a global pandemic. Although considered mainly a respiratory disease, COVID-19 also encompasses a variety of neuropsychiatric symptoms. How infection with SARS-CoV-2 leads to brain damage has remained largely elusive so far. In particular, it has remained unclear, whether signs of immune cell and / or innate immune and reactive astrogliosis are due to direct effects of the virus or may be an expression of a non-specific reaction of the brain to a severe life-threatening disease with a considerable proportion of patients requiring intensive care and invasive ventilation activation. Therefore, we designed a case-control-study of ten patients who died of COVID-19 and ten age-matched non-COVID-19-controls to quantitatively assess microglial and astroglial response. To minimize possible effects of severe systemic inflammation and / or invasive therapeutic measures we included only patients without any clinical or pathomorphological indication of sepsis and who had not been subjected to invasive intensive care treatment. Our results show a significantly higher degree of microglia activation in younger COVID-19 patients, while the difference was less and not significant for older COVID-19 patients. The difference in the degree of reactive gliosis increased with age but was not influenced by COVID-19. These preliminary data warrants further investigation of larger patient cohorts using additional immunohistochemical markers for different microglial phenotypes.

New Insights in the Occurrence of Venous Thromboembolism in Critically Ill Patients with COVID-19-A Large Postmortem and Clinical Analysis.

Critically ill COVID-19 patients are at high risk for venous thromboembolism (VTE), namely deep vein thrombosis (DVT) and/or pulmonary embolism (PE), and death. The optimal anticoagulation strategy in critically ill patients with COVID-19 remains unknown. This study investigated the ante mortem incidence as well as postmortem prevalence of VTE, the factors predictive of VTE, and the impact of changed anticoagulation practice on patient survival. We conducted a consecutive retrospective analysis of postmortem COVID-19 (n = 64) and non-COVID-19 (n = 67) patients, as well as ante mortem COVID-19 (n = 170) patients admitted to the University Medical Center Hamburg-Eppendorf (Hamburg, Germany). Baseline patient characteristics, parameters related to the intensive care unit (ICU) stay, and the clinical and autoptic presence of VTE were evaluated and statistically compared between groups. The occurrence of VTE in critically ill COVID-19 patients is confirmed in both ante mortem (17%) and postmortem (38%) cohorts. Accordingly, comparing the postmortem prevalence of VTE between age- and sex-matched COVID-19 (43%) and non-COVID-19 (0%) cohorts, we found the statistically significant increased prevalence of VTE in critically ill COVID-19 cohorts (p = 0.001). A change in anticoagulation practice was associated with the statistically significant prolongation of survival time (HR: 2.55, [95% CI 1.41-4.61], p = 0.01) and a reduction in VTE occurrence (54% vs. 25%; p = 0.02). In summary, in the autopsy as well as clinical cohort of critically ill patients with COVID-19, we found that VTE was a frequent finding. A change in anticoagulation practice was associated with a statistically significantly prolonged survival time.

Organ manifestations of COVID-19: what have we learned so far (not only) from autopsies?

The use of autopsies in medicine has been declining. The COVID-19 pandemic has documented and rejuvenated the importance of autopsies as a tool of modern medicine. In this review, we discuss the various autopsy techniques, the applicability of modern analytical methods to understand the pathophysiology of COVID-19, the major pathological organ findings, limitations or current studies, and open questions. This article summarizes published literature and the consented experience of the nationwide network of clinical, neuro-, and forensic pathologists from 27 German autopsy centers with more than 1200 COVID-19 autopsies. The autopsy tissues revealed that SARS-CoV-2 can be found in virtually all human organs and tissues, and the majority of cells. Autopsies have revealed the organ and tissue tropism of SARS-CoV-2, and the morphological features of COVID-19. This is characterized by diffuse alveolar damage, combined with angiocentric disease, which in turn is characterized by endothelial dysfunction, vascular inflammation, (micro-) thrombosis, vasoconstriction, and intussusceptive angiogenesis. These findings explained the increased pulmonary resistance in COVID-19 and supported the recommendations for antithrombotic treatment in COVID-19. In contrast, in extra-respiratory organs, pathological changes are often nonspecific and unclear to which extent these changes are due to direct infection vs. indirect/secondary mechanisms of organ injury, or a combination thereof. Ongoing research using autopsies aims at answering questions on disease mechanisms, e.g., focusing on variants of concern, and future challenges, such as post-COVID conditions. Autopsies are an invaluable tool in medicine and national and international interdisciplinary collaborative autopsy-based research initiatives are essential.

Molecular consequences of SARS-CoV-2 liver tropism.

Extrapulmonary manifestations of COVID-19 have gained attention due to their links to clinical outcomes and their potential long-term sequelae1. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) displays tropism towards several organs, including the heart and kidney. Whether it also directly affects the liver has been debated2,3. Here we provide clinical, histopathological, molecular and bioinformatic evidence for the hepatic tropism of SARS-CoV-2. We find that liver injury, indicated by a high frequency of abnormal liver function tests, is a common clinical feature of COVID-19 in two independent cohorts of patients with COVID-19 requiring hospitalization. Using autopsy samples obtained from a third patient cohort, we provide multiple levels of evidence for SARS-CoV-2 liver tropism, including viral RNA detection in 69% of autopsy liver specimens, and successful isolation of infectious SARS-CoV-2 from liver tissue postmortem. Furthermore, we identify transcription-, proteomic- and transcription factor-based activity profiles in hepatic autopsy samples, revealing similarities to the signatures associated with multiple other viral infections of the human liver. Together, we provide a comprehensive multimodal analysis of SARS-CoV-2 liver tropism, which increases our understanding of the molecular consequences of severe COVID-19 and could be useful for the identification of organ-specific pharmacological targets.

The blood-brain barrier is dysregulated in COVID-19 and serves as a CNS entry route for SARS-CoV-2.

Neurological complications are common in COVID-19. Although SARS-CoV-2 has been detected in patients' brain tissues, its entry routes and resulting consequences are not well understood. Here, we show a pronounced upregulation of interferon signaling pathways of the neurovascular unit in fatal COVID-19. By investigating the susceptibility of human induced pluripotent stem cell (hiPSC)-derived brain capillary endothelial-like cells (BCECs) to SARS-CoV-2 infection, we found that BCECs were infected and recapitulated transcriptional changes detected in vivo. While BCECs were not compromised in their paracellular tightness, we found SARS-CoV-2 in the basolateral compartment in transwell assays after apical infection, suggesting active replication and transcellular transport of virus across the blood-brain barrier (BBB) in vitro. Moreover, entry of SARS-CoV-2 into BCECs could be reduced by anti-spike-, anti-angiotensin-converting enzyme 2 (ACE2)-, and anti-neuropilin-1 (NRP1)-specific antibodies or the transmembrane protease serine subtype 2 (TMPRSS2) inhibitor nafamostat. Together, our data provide strong support for SARS-CoV-2 brain entry across the BBB resulting in increased interferon signaling.

Robotic Tissue Sampling for Safe Post-Mortem Biopsy in Infectious Corpses.

In pathology and legal medicine, the histopathological and microbiological analysis of tissue samples from infected deceased is a valuable information for developing treatment strategies during a pandemic such as COVID-19. However, a conventional autopsy carries the risk of disease transmission and may be rejected by relatives. We propose minimally invasive biopsy with robot assistance under CT guidance to minimize the risk of disease transmission during tissue sampling and to improve accuracy. A flexible robotic system for biopsy sampling is presented, which is applied to human corpses placed inside protective body bags. An automatic planning and decision system estimates optimal insertion point. Heat maps projected onto the segmented skin visualize the distance and angle of insertions and estimate the minimum cost of a puncture while avoiding bone collisions. Further, we test multiple insertion paths concerning feasibility and collisions. A custom end effector is designed for inserting needles and extracting tissue samples under robotic guidance. Our robotic post-mortem biopsy (RPMB) system is evaluated in a study during the COVID-19 pandemic on 20 corpses and 10 tissue targets, 5 of them being infected with SARS-CoV-2. The mean planning time including robot path planning is 5.72±167s. Mean needle placement accuracy is 7.19± 422mm.

Replication of SARS-CoV-2 in adipose tissue determines organ and systemic lipid metabolism in hamsters and humans.

Zickler et al. describe SARS-CoV-2 RNA in post-mortem samples of human adipose tissue. In the hamster model, SARS-CoV-2 propagation in adipose tissue leads to specific changes in lipid metabolism, which are reflected in lipidome patterns of hamster and human plasma.

Postmortem Antigen-Detecting Rapid Diagnostic Tests to Predict Infectivity of SARS-CoV-2-Associated Deaths.

We investigated the infectivity of 128 severe acute respiratory disease coronavirus 2-associated deaths and evaluated predictive values of standard diagnostic procedures. Maintained infectivity (20%) did not correlate with viral RNA loads but correlated well with anti-S antibody levels. Sensitivity >90% for antigen-detecting rapid diagnostic tests supports their usefulness for assessment.

Cardiac SARS-CoV-2 infection is associated with pro-inflammatory transcriptomic alterations within the heart.

AIMS: Cardiac involvement in COVID-19 is associated with adverse outcome. However, it is unclear whether cell-specific consequences are associated with cardiac SARS-CoV-2 infection. Therefore, we investigated heart tissue utilizing in situ hybridization, immunohistochemistry, and RNA-sequencing in consecutive autopsy cases to quantify virus load and characterize cardiac involvement in COVID-19. METHODS AND RESULTS: In this study, 95 SARS-CoV-2-positive autopsy cases were included. A relevant SARS-CoV-2 virus load in the cardiac tissue was detected in 41/95 deceased (43%). Massive analysis of cDNA ends (MACE)-RNA-sequencing was performed to identify molecular pathomechanisms caused by the infection of the heart. A signature matrix was generated based on the single-cell dataset 'Heart Cell Atlas' and used for digital cytometry on the MACE-RNA-sequencing data. Thus, immune cell fractions were estimated and revealed no difference in immune cell numbers in cases with and without cardiac infection. This result was confirmed by quantitative immunohistological diagnosis. MACE-RNA-sequencing revealed 19 differentially expressed genes (DEGs) with a q-value <0.05 (e.g. up: IFI44L, IFT3, TRIM25; down: NPPB, MB, MYPN). The upregulated DEGs were linked to interferon pathways and originate predominantly from endothelial cells. In contrast, the downregulated DEGs originate predominately from cardiomyocytes. Immunofluorescent staining showed viral protein in cells positive for the endothelial marker ICAM1 but rarely in cardiomyocytes. The Gene Ontology (GO) term analysis revealed that downregulated GO terms were linked to cardiomyocyte structure, whereas upregulated GO terms were linked to anti-virus immune response. CONCLUSION: This study reveals that cardiac infection induced transcriptomic alterations mainly linked to immune response and destruction of cardiomyocytes. While endothelial cells are primarily targeted by the virus, we suggest cardiomyocyte destruction by paracrine effects. Increased pro-inflammatory gene expression was detected in SARS-CoV-2-infected cardiac tissue but no increased SARS-CoV-2 associated immune cell infiltration was observed.

Prospective postmortem evaluation of 735 consecutive SARS-CoV-2-associated death cases.

Coronavirus disease 19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic with significant mortality. Accurate information on the specific circumstances of death and whether patients died from or with SARS-CoV-2 is scarce. To distinguish COVID-19 from non-COVID-19 deaths, we performed a systematic review of 735 SARS-CoV-2-associated deaths in Hamburg, Germany, from March to December 2020, using conventional autopsy, ultrasound-guided minimally invasive autopsy, postmortem computed tomography and medical records. Statistical analyses including multiple logistic regression were used to compare both cohorts. 84.1% (n = 618) were classified as COVID-19 deaths, 6.4% (n = 47) as non-COVID-19 deaths, 9.5% (n = 70) remained unclear. Median age of COVID-19 deaths was 83.0 years, 54.4% were male. In the autopsy group (n = 283), the majority died of pneumonia and/or diffuse alveolar damage (73.6%; n = 187). Thromboses were found in 39.2% (n = 62/158 cases), pulmonary embolism in 22.1% (n = 56/253 cases). In 2020, annual mortality in Hamburg was about 5.5% higher than in the previous 20 years, of which 3.4% (n = 618) represented COVID-19 deaths. Our study highlights the need for mortality surveillance and postmortem examinations. The vast majority of individuals who died directly from SARS-CoV-2 infection were of advanced age and had multiple comorbidities.

Multiorgan tropism of SARS-CoV-2 lineage B.1.1.7.

Due to the development of novel functionalities, distinct SARS-CoV-2 variants such as B.1.1.7 fuel the current pandemic. B.1.1.7 is not only more transmissible, but may also cause an increased mortality compared to previous SARS-CoV-2 variants. Human tissue analysis of the SARS-CoV-2 lineage B.1.1.7 is urgently needed, and we here present autopsy data from 7 consecutive SARS-CoV-2 B.1.1.7 cases. The initial RT-qPCR analyses from nasopharyngeal swabs taken post mortem included typing assays for B.1.1.7. We quantitated SARS-CoV-2 B.1.1.7 viral load in autopsy tissue of multiple organs. Highest levels of SARS-CoV-2 B.1.1.7 copies normalized to ß-globin were detected in the respiratory system (lung and pharynx), followed by the liver and heart. Importantly, SARS-CoV-2 lineage B.1.1.7 was found in 100% of cases in the lungs and in 85.7% in pharynx tissue. Detection also in the kidney and brain highlighting a pronounced organ tropism. Comparison of the given results to a former cohort of SARS-CoV-2 deaths during the first wave in spring 2020 showed resembling organ tropism. Our results indicate that also SARS-CoV-2 B.1.1.7 has a relevant organ tropism beyond the respiratory tract. We speculate that B.1.1.7 spike protein's affinity to human ACE2 facilitates transmission, organ tropism, and ultimately morbidity and mortality. Further studies and larger cohorts are obligatory to proof this link.

Determinants of health care use among homeless individuals: evidence from the Hamburg survey of homeless individuals.

BACKGROUND: To identify the determinants of health care use among homeless individuals. METHODS: Data were taken from the Hamburg survey of homeless individuals (n = 100 individuals in the here used model, mean age 44.8 years, SD 12.5) focusing on homeless individuals in Hamburg, Germany. The number of physician visits in the past 3 months and hospitalization in the preceding 12 months were used as outcome measures. Drawing on the Andersen model of health care use as a conceptual framework, predisposing characteristics, enabling resources and need factors as well as psychosocial variables were included as correlates. RESULTS: Negative binomial regressions showed that increased physician visits were associated with being female (IRR: 4.02 [95% CI: 1.60-10.11]), absence of chronic alcohol consume (IRR: 0.26 [95% CI: 0.12-0.57]) and lower health-related quality of life (IRR: 0.97 [95% CI: 0.96-0.98]). Furthermore, logistic regressions showed that the likelihood of hospitalization was positively associated with lower age (OR: 0.93 [95% CI: 0.89-0.98]), having health insurance (OR: 8.11 [2.11-30.80]) and lower health-related quality of life (OR: 0.97 [95% CI: 0.94-0.99]). CONCLUSIONS: Our study showed that predisposing characteristics (both age and sex), enabling resources (i.e., health insurance) and need factors in terms of health-related quality of life are main drivers of health care use among homeless individuals. This knowledge may assist in managing health care use.