The COVID-19 pandemic has resulted in the loss of millions of lives, although a majority of those infected have managed to survive. Consequently, a set of outcomes, identified as long COVID, is now emerging. While the primary target of SARS-CoV-2 is the respiratory system, the impact of COVID-19 extends to various body parts, including the bone. This study aims to investigate the effects of acute SARS-CoV-2 infection on osteoclastogenesis, utilizing both ancestral and Omicron viral strains. Monocyte-derived macrophages (MDM), which serve as precursors to osteoclasts, were exposed to both viral variants. However, the infection proved abortive, even though ACE2 receptor expression increased post-infection, with no significant impact on cellular viability and redox balance. Both SARS-CoV-2 strains heightened osteoclast formation in a dose-dependent manner, as well as CD51/61 expression and bone resorptive ability. Notably, SARS-CoV-2 induced early pro-inflammatory M1 macrophage polarization, shifting towards an M2-like profile. Osteoclastogenesis-related genes (RANK, NFATc1, DC-STAMP, MMP9) were upregulated, and surprisingly, SARS-CoV-2 variants promoted RANKL-independent osteoclast formation. This thorough investigation illuminates the intricate interplay between SARS-CoV-2 and osteoclast precursors, suggesting potential implications for bone homeostasis and opening new avenues for therapeutic exploration in COVID-19.

We estimated the dynamics of the neutralizing response against XBB sublineages and T cell response in PWH with previous AIDS and/or CD4<200/mm 3 receiving the bivalent original strain/BA.4-5 booster dose (bBD) in fall 2022. Samples were collected before the shot (T0), 15 days (T1), 3 (T3), and 6 months (T6) after. PWH were stratified by immunization status: hybrid immunity (HI; vaccination plus COVID-19) vs. non-hybrid immunity (nHI; vaccination only). At T1, 16% and 30% of PWH were non-responders in terms of anti-XBB.1.16 or anti-EG.5.1 nAbs, respectively. At T3, a significant waning of anti-XBB.1.16, EG.5.1 and -XBB.1 nAbs was observed both in HI and nHI but nAbs in HI were higher than in nHI. At T6 both HI and nHI individuals displayed low mean levels of anti-XBB.1.16 and EG.5.1 nAbs. Regarding T cell response, IFN-γ values were stable over time and similar in HI and nHI. Our data showed that in PLWH, during the prevalent circulation of the XBB.1.16, EG.5.1, and other XBB sublineages, a bBD mRNA vaccine might not confer broad protection against them. With a view to the 2023/2024 vaccination campaign, the use of the monovalent XBB.1.5 mRNA vaccine should be urgently warranted in PWH to provide adequate protection.

Comment on “The risk assessment of uveitis after COVID-19 diagnosis”Patrick Wu,1 Chin-Yuan Yii,2 Su-Boon Yong3,4,5College of Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USADivision of Gastroenterology and Hepatology, Department of Internal Medicine, Landseed International Hospital, Taoyuan, TaiwanDepartment of Allergy and Immunology, China Medical University Children’s Hospital, Taichung, TaiwanDepartment of Medicine, College of Medicine, China Medical University, Taichung, TaiwanCenter for Allergy, Immunology, and Microbiome (A.I.M.), China Medical University Hospital, Taichung, Taiwan.Corresponding authors:Chin-Yuan Yii, MDDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Landseed International Hospital, Taoyuan, TaiwanAddress: No.77, Guangtai Rd., Pingzhen Dist., Taoyuan City 32449, Taiwan Telephone: +886 3 494 1234Email: yiichinyuan@gmail.com2. Su-Boon Yong, MD PhDDepartment of Medicine, College of Medicine, China Medical University, Taichung, TaiwanAddress: No. 2, Yuh-Der Road, Taichung City 404, TaiwanTelephone: 00886-4-22052121Email: yongsuboon@gmail.comFirst author:Patrick Wu, BSCollege of Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USAAddress: 5000 Lakewood Ranch Blvd, Bradenton, FL 34211, USATelephone: +1(301)3375805Email: PWu36911@med.lecom.eduData availability statement: Not applicable. This letter to the editor does not require data collection.Funding statement: Not applicable. Authorship for letter to the editor did not receive any funding.Conflict of interest disclosure: The authors do not have any conflict of interests to declare.Ethics approval statement: Not applicable.Patient consent statement: Not applicable.Permission to reproduce material from other sources: Not applicable.Clinical trial registration: Not applicable.AbstractSeveral suggestions were made for the study by Hsia et al1 regarding uveitis risk following COVID-19 diagnosis. We recommend the authors align the racial composition of study groups more closely with that of U.S. demographics. In addition, we recommend the study to include possibility of false negatives from PCR testing. Lastly, we suggest the authors to consider cases of self-limiting uveitis and relapses independent of COVID-19.Keywords: uveitis risk, COVID-19, racial composition, PCR testing, self-limiting uveitis, relapsesTo the Editor,We read with great interest the study by Hsia et al1regarding the risk assessment of uveitis after COVID-diagnosis. We appreciate the authors’ attention to detail by eliminating possible confounding variables that may contribute to uveitis development. Furthermore, we were impressed by the robust study design incorporating propensity score matching, long follow-ups, and immense study size of more than 4 million patients using the TriNetX analytics platform.Nevertheless, to enhance this study, we recommend the following considerations.First, this study utilized the US research network, covering about 92 million patients to form a COVID-19 cohort and a non-COVID-19 control group, each with 2 million patients, of which 62.5% and 62.4% were white, respectively. This underrepresents the white population by 13% compared to the 75.5% white representation in the 2022 US census. Future studies should align the racial composition of study groups more closely with national demographics.Second, the authors identified COVID-19 cases based on positive PCR tests or antibody immunoassays. Yet, Binny et al’s study in New Zealand illustrates how PCR test sensitivity fluctuates across the COVID-19 infection timeline, influenced by viral load and patient age.2 The sensitivity of PCR tests peaks at 92.7% between 4 to 5 days post-infection, then drops to 88% from 5 to 14 days, while specificity remains near 100%.2 This indicates a higher likelihood of false negatives and very low false positives in PCR testing. Highlighting this significant limitation in the discussion section would be beneficial.Third, this study excluded those diagnosed with uveitis within 6 months before COVID-19 infection, potentially overlooking undiagnosed, self-limiting cases that may resurface post-infection. 10% of intermediate uveitis cases resolve on their own, and anterior uveitis, while often self-limiting, can cause severe complications.3,4 Moreover, uveitis relapses, as reported in Grunwald et al’s study, could occur independently of COVID-19, leading to misattribution of these cases to COVID-19.5 These aspects represent potential limitations of the study that warrant discussion.In conclusion, the study by Hsia et al1 is a major milestone towards incorporating uveitis assessment among COVID-19 patients in healthcare guidelines. This study has tremendous potential to save numerous patients from glaucoma, cataracts, and permanent vision loss. To improve this study, we recommend authors to adjust study groups so that white patients are adequately represented, discuss the possibility of false negatives from PCR testing, and consider cases of self-limiting uveitis and relapses independent of COVID-19.Acknowledgements: noneReferencesHsia NY, Hsu AY, Wang YH, Li JX, Chen HS, Wei JC, Lin CJ, Tsai YY. The risk assessment of uveitis after COVID-19 diagnosis: A multicenter population-based study. J Med Virol. 2023 Oct;95(10):e29188. doi: 10.1002/jmv.29188. PMID: 37881132.Binny RN, Priest P, French NP, Parry M, Lustig A, Hendy SC, Maclaren OJ, Ridings KM, Steyn N, Vattiato G, Plank MJ. Sensitivity of Reverse Transcription Polymerase Chain Reaction Tests for Severe Acute Respiratory Syndrome Coronavirus 2 Through Time. J Infect Dis. 2022 Dec 28;227(1):9-17. doi: 10.1093/infdis/jiac317. PMID: 35876500; PMCID: PMC9384503.Maggon R. INTERMEDIATE UVEITIS PARS PLANITIS. Med J Armed Forces India. 2001 Jan;57(1):84-5. doi: 10.1016/S0377-1237(01)80106-4. Epub 2011 Jul 21. PMID: 27365593; PMCID: PMC4925061.Islam N, Pavesio C. Uveitis (acute anterior). BMJ Clin Evid. 2010 Apr 8;2010:0705. PMID: 21736765; PMCID: PMC2907596.Grunwald L, Newcomb CW, Daniel E, Kaçmaz RO, Jabs DA, Levy-Clarke GA, Nussenblatt RB, Rosenbaum JT, Suhler EB, Thorne JE, Foster CS, Kempen JH; Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Risk of relapse in primary acute anterior uveitis. Ophthalmology. 2011 Oct;118(10):1911-5. doi: 10.1016/j.ophtha.2011.02.044. Epub 2011 Jun 16. PMID: 21680024; PMCID: PMC3179829.

Infection with influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a significant risk to human life, health, and the global economy. Vaccination is one of the most effective strategies in the fight against infectious viruses. In this study, we, for the first time, have evaluated the immunogenicity and protective effect of an influenza/SARS-CoV-2 Omicron subunit combined vaccine adjuvanted with MF59 and administered to BALB/c mice. Results showed that the combined vaccine induced high levels of IgG, IgG 1, and IgG 2a antibodies, as well as influenza A H1N1/California/2009 virus-specific hemagglutination-inhibiting antibodies in BALB/c mice. Moreover, this subunit combined vaccine induced high titers of neutralization antibodies against SARS-CoV-2 Omicron BA.5 pseudovirus and effectively reduced the viral load of authentic SARS-CoV-2 Omicron BA.5.2 variant in the cell culture supernatants. These results suggested that this subunit combined vaccine achieved protective effect against both H1N1 A/California/07/2009 strain and SARS-CoV-2 Omicron BA.5.2 variant. It is therefore expected that this study will establish the scientific foundation for the next-step development of combined vaccines against other strains or variants of IAV and SARS-CoV-2.

Background & Aims: Intrahepatic cholangiocyte organoids (ICOs) model was evaluated for host differences in HBV infection, cellular responses, antiviral and immunomodulator responses. Methods: 12 ICOs generated from liver resections and biopsies were assessed for metabolic markers and functional HBV entry receptor expression throughout differentiation. Structural changes relevant to HBV infection were characterised using histology, confocal and electron microscopy examinations. Optimal ICO culture conditions for HBV infection using HepAD38 (genotype D) and plasma derived HBV (genotype B & C) were described. HBV infection was confirmed using HBcAg immunostaining, qRT-PCR (RNA, cccDNA, extracellular DNA) and ELISA (HBsAg and HBeAg). Drug response to antiviral and immunosuppressive agent, and cellular responses (interferon-stimulated genes (ISG)) to interferon-α and viral mimic (PolyI:C) were assessed. Results: ICOs underwent metabolic and structural remodeling following differentiation. Optimal HBV infection was achieved in well-differentiated ICOs using spinoculation, with time and donor dependent increase in HBV RNA, cccDNA, extracellular DNA, HBeAg and HBsAg. Donor dependent drug-responsiveness to entry inhibitor and JAK inhibitor was observed. Despite having a robust ISG response to interferon-α and PolyI:C, HBV infection in ICOs did not upregulate ISGs. Conclusions: Human ICOs support HBV infection and replication with donor dependent variation in viral dynamics and cellular responses. These features can be utilised for development of personalised drug testing platform for antivirals.

In this study, hesperetin was shown to inhibit the replication of multiple poxviruses, including buffalopox virus (BPXV), vaccinia virus, and lumpy skin disease virus (LSDV). Hesperetin mainly suppressed viral protein synthesis without affecting other steps of the viral life cycle such as attachment, entry, and budding. In a chromatin immunoprecipitation (CHIP) assay, we further demonstrated that hesperetin-induced reduction in BPXV protein synthesis is due to disruption of the binding of the 5’ cap of viral mRNA with the cellular translation initiation factor eIF4E. The molecular docking and MD simulation studies, also confirmed binding of the hesperetin with the cap-binding pocket of eIF4E, in a similar conformation as m7GTP binds. In a BPXV egg infection model, hesperetin was shown to suppress the development of pock lesions on the chorioallantoic membrane, as well as the associated mortality of the chicken embryos. Most importantly, long-term culture of BPXV in the presence of hesperetin did not induce the generation of drug-resistant viral mutants. In conclusion, we for the first time demonstrated the antiviral activity of hesperetin against poxviruses, besides providing novel mechanistic insights into the antiviral action of hesperetin.

In May 2022, a cluster of non-travel-related cases of human mpox were reported in the UK. The outbreak has since spread world-wide infecting over 85,000 patients and causing over 100 deaths. Recent data clearly suggest that patients infected with Human Immunodeficiency Virus (HIV) with CD4 counts less than 200 cells per mm 3 suffer significantly worse outcomes than immunocompetent patients. The available countermeasures lack robust clinical data and are deployed based on in vitro and animal studies as well as extrapolations from use against other poxviruses. In many cases, despite administration of these available treatments, initiation of antiretroviral therapy, and management of Immune Reconstitution Inflammatory Syndrome (IRIS), patients die. This review summarizes available data, identifies knowledge gaps and proposes recommendations on the management of severe mpox in PLWH.

Title: Interstitial Lung Diseases and COVID19 Pneumonia

Respiratory syncytial virus is associated with lower respiratory tract infections. As several types and genotypes can circulate at the same time, genomic characterisation is important for timely epidemiological control and treatment measures. In the last 6 seasons (2017-2023), 191236 nasopharyngeal swabs were processed for respiratory viruses. The incidence of RSV reached 7% in the pre-pandemic season. RSV was most frequent in children under 5 years of age (12.6%), but was also significant in those over 70 years of age (5.63%). The measures taken to control SARS-Cov2 infection were useful for RSV control and the incidence decreased to 1.8%, but caused a change in the types. Pre-pandemic, the majority circulating types were RSV-B/RSV-B/RSV-A and in pandemic it was RSV-B/RSV-B. In the last season, RSV-B and RSV-A were detected in the same proportion. Genetic characterization showed three new clades. This has been taken into account in order to take the correct measures.

Background: Human papillomaviruses (HPV) of the genus Betapapillomavirus can infect both cutaneous and mucosal sites, but research on its natural history at mucosal sites remains scarce. We examined the risk factors and co-detection patterns of HPVs of the Betapapillomavirus and Alphapapillomavirus genera in cervical samples of the Ludwig-McGill cohort study. Methods: We assessed a subset of 505 women from the Ludwig-McGill cohort study from São Paulo, Brazil. Cervical samples over the first year of follow-up were tested for DNA of over 40 alphapapillomavirus types and 43 betapapillomavirus types using a type-specific multiplex genotyping PCR assay. We assessed the risk factors for prevalent and incident betapapillomavirus type detection, and whether types were detected more frequently together than expected assuming independence using permutation tests, logistic regression, and Cox regression. Results: We observed significant within-genus clustering but not cross-genus clustering. Multiple betapapillomavirus types were co-detected in the same sample 2.24 (95%CI: 1.65-3.29) times more frequently than expected. Conversely, co-detections of alphapapillomavirus and betapapillomavirus types in the same sample occurred only 0.64 (95%CI: 0.51-0.83) times as often as expected under independence. In prospective analyses, positivity to one HPV genus was associated with a non-significant lower incidence of detection of types in the other genus. Lifetime number of sex partners and new sex partner acquisition were associated with lower risks of prevalent and incident betapapillomavirus detection. Conclusion: Betapapillomaviruses are commonly found in the cervicovaginal tract. Results suggest potentially different mechanisms of transmission for betapapillomavirus genital infections other than vaginal sex.

Introduction: Acute viral gastroenteritis is a common illness especially in developing countries. Globally, the role of human astroviruses (HAstV) in gastroenteritis among children and elderly is well documented. But there exists a substantial dearth of information on HAstV strains circulating in Nigeria. Method: Viral like particles (VLPs) were purified from stool samples from children diagnosed with acute flaccid paralysis (AFP) between January and December 2020 from five states in Nigeria, using the NetoVIR protocol. Extracted viral RNA and DNA were subjected to a reverse transcription step, and subsequent random PCR amplification. Library preparation and Illumina sequencing were performed. Using the Virome Paired-End Reads (ViPER) pipeline, raw reads were processed into genomic contigs. Phylogenetic and pairwise identity analysis of the recovered HAstV genomes was performed. Results: Six near complete genome sequences of HAstV were identified and classified as HAstV 4 (n=1), HAstV5 (n=1), HAstV8 (n=1) and MLB-3 (n=3). The HAstV5 belonged to a yet unclassified sub-lineage which we tentatively named HAstV-5d. Phylogenetic analysis of ORFs 1a, 1b and 2 suggested recombination events inside the MAstV1 species. Furthermore, phylogenetic analysis implied a geographic linkage between the HAstV5 strain from this study with two strains from Cameroon across all the genomic regions. Conclusion: We report for the first time the circulation of HAstV genotypes 4, 8 and MLB-3 in Nigeria and present data suggestive for the existence of a new sub-lineage of HAstV5. To further understand the burden, diversity, and evolution of HAstV increased research interest as well as robust HAstV surveillance in Nigeria is essential.

Background Understanding the cellular host factors that promote and inhibit viral entry is important for identifying viral countermeasures. CRISPR whole genome screens can be used to rapidly discover host factors that contribute to or impair viral entry. However, when using the live viruses and cellular lethality for selection, these screens can identify an overwhelming number of genes without specificity for the stage of the viral infection cycle. New screening methods are needed to identify host machinery contributing to specific steps of viral infection. Here, we developed a CRISPR whole genome screen and counter screen strategy based on a pseudoviral platform that allowed identification of genes specific to SARS-CoV-2 spike and vesicular stomatitis virus glycoprotein VSV-G mediated entry. Methods To focus the screen onto the entry step, we used non-lytic fluorescent reporters in combination with a comparative counter screen strategy to distinguish host genes affecting the pseudoviral reporter from those unique to envelope-mediated entry. Screening of SARS-CoV-2 spike and VSV-G on the same lentiviral pseudovirus allowed identification of entry-specific genes relative to genes associated with retro-transcription, integration, and reporter expression from the lentiviral pseudovirus. Second, a Cre-Gag fusion protein in the pseudovirus was used to bypass retro-transcription and integration by directly activating a floxed GFP reporter upon entry to reduce the number of gene hits and increase specificity for viral entry. Results Our approach correctly identified SARS-CoV-2 and VSV-G receptors ACE2 and LDLR, respectively and distinguished genes associated with retroviral reporter expression from envelope-mediated entry. Moreover, the CRE-Gag fusion/flox reporter increased the screen specificity for viral entry associated genes. Validation of a few hits demonstrates that this approach distinguishes envelope-specific host factors from genes affecting reporter expression. Conclusion Overall, this approach provides a new strategy for identifying host genes influencing viral entry without the confounding complexity of live-viral screens which produce long gene lists associated with all aspects of viral pathogenesis and replication. This approach provides a pathway for increasing the specificity of CRISPR whole genome screens for identifying host genes contributing to specific steps in viral infection.

Background: The introduction of primary HPV cervical cancer screening requires the implementation of an appropriate triage strategy that will be effective in detecting high-grade cervical disease without losing diagnostic specificity. Methods: From the 30.066 screening tests results, a total of 1086 with available high-risk human papillomavirus (HRHPV) with limited genotyping, cytology and p16/Ki67 dual-stain were selected. Two triage strategies for primary HPV screening were analyzed retrospectively based on the study group. Performance characteristics for p16/Ki67 and cytology triage in detection of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and grade 3 or worse (CIN3+) were calculated, detected in colposcopic biopsy. Results: In HPV16/18-positive cases, primary HPV with p16/Ki67 triage was significantly more specific than cytology (53.1%/16.8% for CIN2+; p<0.0001; 45.9%/17.0% for CIN3+; p<0.0001), with yielded sensitivity (95.7%/84.8% for CIN2+; p=0.0955; 100.0%/87.5% for CIN3+; p=0.0832). In other HRHPV-positive cases (N16/N18), p16/Ki67 triage was also significantly higher specific (51.3%/15.3% for CIN2+; p<0.0001; 44.5%/16.5% for CIN3+; p<0.0001), with sensitivity (92.3%/74.4% for CIN2+; p=0.0522; 90.9%/81.8% for CIN3+; p=0.5637). Diagnostic predictive values were significantly higher for p16/Ki67 triage with the highest PPV in HPV16/18-positive cases for CIN2+ (45.4%; 95% CI: 35.2-55.8; p<0.0001) and very high NPV in all HPV-positive cases regardless of detected genotype (96.3%-100.0%). The risk (1-NPV) for CIN3+ in HRHPV16/18-positive/p16/Ki67-negative women was 0.0%. Conclusions: Superior diagnostic performance compared to cytology for detecting cervical cancer precursors indicates that p16/Ki67 dual-immunostain may be a highly effective tool of triage in primary HPV screening with limited HPV 16/18 genotyping in the secondary cervical cancer prevention.

Purpose Although monoclonal antibodies specific to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are known, information about the B-cell receptor (BCR) repertoire and its change in patients during COVID-19 disease progression is underreported. Methods We used immunoglobulin heavy chain (IGH) variable region (IGHV) spectratyping and next-generation sequencing of peripheral blood B-cell genomic DNA collected at multiple time points during disease evolution to study B-cell response to SARS-CoV-2 infection in 14 individuals with acute COVID-19. Results We found a broad distribution of responding B-cell clones. The IGH gene usage was not significantly skewed but frequencies of individual IGH genes changed repeatedly. We found predominant usage of unmutated and low mutation-loaded IGHV rearrangements characterizing naïve and extrafollicular B-cells among the majority of expanded peripheral B-cell clonal lineages at most tested time points in most patients. IGH rearrangement usage showed no apparent relation to anti-SARS-CoV-2 antibody titers. Some patients demonstrated mono/oligoclonal populations carrying highly mutated IGHV rearrangements indicating antigen experience at some of the time points tested, including even before anti-SARS-CoV-2 antibodies were detected. Conclusion We present evidence demonstrating that the B-cell response to SARS-CoV-2 is individual and includes different lineages of B-cells at various time points during COVID-19 progression.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) enters the host cell by binding to angiotensin-converting enzyme 2 (ACE2). While evolutionarily conserved, ACE2 glycoproteins differ across various species and differential interactions with Spike (S) glycoproteins of SARS-CoV-2 viruses impact species specificity. Reverse zoonoses led to SARS-CoV-2 outbreaks on multiple American mink ( Mustela vison) farms during the pandemic and gave rise to mink-associated S substitutions known for transmissibility between mink and zoonotic transmission to humans. In this study, we used bio-layer interferometry (BLI) to discern the differences in binding affinity between multiple human and mink-derived S glycoproteins of SARS-CoV-2 and their respective ACE2 glycoproteins. Further, we conducted a structural analysis of a mink variant S glycoprotein and American mink ACE2 (mvACE2) using cryo-electron microscopy (cryo-EM), revealing four distinct conformations. We discovered a novel intermediary conformation where the mvACE2 glycoprotein is bound to the receptor-binding domain (RBD) of the S glycoprotein in a “down” position, approximately 34° lower than previously reported “up” RBD. Finally, we compared residue interactions in the S-ACE2 complex interface of S glycoprotein conformations with varying RBD orientations. These findings provide valuable insights into the molecular mechanisms of SARS-CoV-2 entry.

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Limited antibody response after BA.4/5 adapted booster vaccination in rheumatic patients receiving anti-TNF therapy: results of a case seriesUlf Martin Geisen1*, Mathias Voß2*, Ruben Rose2*, Franziska Neumann3, Carina Bäumler3, Sina Müller3, Lea Paltzow3, Christina Martínez Christophersen3, Merle Münier3, Elena Hildebrand1, Paula Hoff4, Ann Carolin Longardt5, Thomas Lorentz3, Jan Henrik Schirmer1, Melike Sümbül6, Florian Tran7,8, Dennis Berner1, Helmut Fickenscher2, Sascha Gerdes6, Stefan Schreiber7,8, Andi Krumbholz2,3‡, Bimba Franziska Hoyer1‡1 Medical Department I, Rheumatology, and Clinical Immunology, Christian-Albrecht University of Kiel and University Medical Center Schleswig-Holstein Campus Kiel, Kiel, Germany2 Institute for Infection Medicine, Christian-Albrecht University of Kiel and University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany3 Labor Dr. Krause und Kollegen MVZ GmbH, Kiel, Germany4 Department of Rheumatology, Endokrinologikum-Gruppe, Berlin, Germany5 Department of Pediatrics, Christian-Albrecht University of Kiel and University Medical Center Schleswig-Holstein Campus Kiel, Kiel, Germany6 Department for Dermatology, Christian-Albrecht University of Kiel and University Medical Center Schleswig-Holstein Campus Kiel, Kiel, Germany7 Institute of Clinical Molecular Biology, Christian-Albrecht University of Kiel, Kiel, Germany8 Department for Internal Medicine I, Christian-Albrecht University of Kiel and University Medical Center Schleswig-Holstein Campus Kiel* ‡These authors contributed equallyCorresponding Author: Bimba Franziska HoyerMedical Department I, Rheumatology and Clinial Immunology,University Medical Center Schleswig-HolsteinArnold-Heller-Str. 324105 KielEmail: bfhoyer@rheuma.uni-kiel.dePhone: +49 431 500 22203

The use of adeno-associated virus (AAV) vectors in gene therapy has demonstrated great potential in treating genetic disorders. However, infusion-associated reactions (IARs) pose a significant challenge to the safety and efficacy of AAV-based gene therapy. This review provides a comprehensive summary of the current understanding of IARs to AAV therapy, including their underlying mechanisms, clinical presentation, and treatment options. Toll-like receptor activation and subsequent production of pro-inflammatory cytokines are associated with IARs, stimulating neutralizing antibodies and T-cell responses that interfere with gene therapy. Risk factors for IARs include high titers of pre-existing neutralizing antibodies, previous exposure to AAV, and specific comorbidities. Clinical presentation ranges from mild flu-like symptoms to severe anaphylaxis and can occur during or after AAV administration. There are no established guidelines for pre- and post-administration tests for AAV therapies, and routine laboratory requests are not standardized. Treatment options include corticosteroids, plasmapheresis, and supportive medications such as antihistamines and acetaminophen, but there is no consensus on the route of administration, dosage, and duration. This review highlights the inadequacy of current treatment regimens for IARs and the need for further research to improve the safety and efficacy of AAV-based gene therapy.