Immunosuppressed Population Research Articles

MRNA vaccines in the rheumatologist's future

BackgroundVaccines taking advantage of mRNA technology have been long in development. ObjectivesTo review the status of approved mRNA vaccines for infectious diseases as well as those in development. MethodsSystematic literature review of clinical and immunologic studies of mRNA vaccines against infectious diseases. ResultsCurrently approved mRNA vaccines include those against SARS CoV-2 virus. They are immunogenic and provide good protection against severe disease. A number of mRNA vaccines for influenza are in development including in phase 3 studies. Other such vaccines in development include those targeting Epstein-Barr Virus (EBV), Cytomegalovirus (CMV), varicella (VZV), and respiratory syncytial virus (RSV). Many of these vaccines will likely be indicated for immunosuppressed populations including those with autoimmune inflammatory diseases. ConclusionsA number of mRNA vaccines against viral pathogens are in early to late phase development. The ability to rapidly change vaccine constituents and target complex targets, make mRNA vaccines likely to be adopted in the future.

Clinical Utility of SARS-CoV-2 Serological Testing and Defining a Correlate of Protection.

Herein, we review established clinical use cases for SARS-CoV-2 antibody measures, which include diagnosis of recent prior infection, isolating high titer convalescent plasma, diagnosing multisystem inflammatory syndrome in children (MIS-C), and booster dosing in the immunosuppressed and other populations. We then address whether an antibody correlate of protection (CoP) for SARS-CoV-2 has been successfully defined with the following considerations: Antibody responses in the immunocompetent, vaccine type, variants, use of binding antibody tests vs. neutralization tests, and endpoint measures. In the transition from the COVID-19 pandemic to endemic, there has been much interest in defining an antibody CoP. Due to the high mutability of respiratory viruses and our current knowledge of SARS-CoV-2 variants defining a CoP for prevention of infection is unrealistic. However, a CoP may be defined for prevention of severe disease requiring hospitalization and/or death. Most SARS-CoV-2 CoP research has focused on neutralization measurements. However, there can be significant differences in neutralization test methods, and disparate responses to new variants depending on format. Furthermore, neutralization assays are often impractical for high throughput applications (e.g., assessing humoral immune response in populations or large cohorts). Nevertheless, CoP studies using neutralization measures are reviewed to determine where there is consensus. Alternatively, binding antibody tests could be used to define a CoP. Binding antibody assays tend to be highly automatable, high throughput, and therefore practical for large population applications. Again, we review studies for consensus on binding antibody responses to vaccines, focusing on standardized results. Binding antibodies directed against the S1 receptor binding domain (S1-RBD) of the viral spike protein can provide a practical, indirect measure of neutralization. Initially, a response for S1-RBD antibodies may be selected that reflects the peak response in immunocompetent populations and may serve as a target for booster dosing in the immunocompromised. From existing studies reporting peak S1-RBD responses in standardized units, an approximate range of 1372-2744 BAU/mL for mRNA and recombinant protein vaccines was extracted that could serve as an initial CoP target. This target would need to be confirmed and potentially adjusted for updated vaccines, and almost certainly for other vaccine formats (i.e., viral vector). Alternatively, a threshold or response could be defined based on outcomes over time (i.e., prevention of severe disease). We also discuss the precedent for clinical measurement of antibodies for vaccine-preventable diseases (e.g., hepatitis B). Lastly, cellular immunity is briefly addressed for its importance in the nature and durability of protection.

Recurrent respiratory papillomatosis disease course in immunosuppressed populations.

Recurrent respiratory papillomatosis is a benign manifestation of human papillomavirus types 6 and 11 in the respiratory tract. Disease is recurrent, and factors predicting these recurrences and severity of disease are incompletely characterised. This retrospective cohort study examined the relationship of immunosuppression with recurrent respiratory papillomatosis morbidity. A retrospective cohort of 97 adult patients with recurrent respiratory papillomatosis treated at a tertiary referral centre from 2005 to 2020 was conducted. Measures assessed included inter-surgical interval, Voice Handicap Index ('VHI-10') and anatomical Derkay scores. Bivariate analyses comparing average inter-surgical interval, Voice Handicap Index and Derkay scores in immunosuppressed and healthy patients were insignificant. When controlling for diabetes mellitus and comparing immunosuppressed to healthy patients, inter-surgical interval and Voice Handicap Index change were insignificant (p = 0.458 and p = 0.465, respectively). Recurrent respiratory papillomatosis morbidity for immunosuppressed patients did not significantly differ from that of immunocompetent patients.

Emergomycosis, an Emerging Thermally Dimorphic Fungal Infection: A Systematic Review.

Emergomycosis is an endemic mycosis caused by the Emergomyces species. Infections due to this agent have been reported globally. Hence, the present systematic review on Emergomyces infections was conducted to study the disease epidemiology, underlying diseases and risk factors, causative agents, and treatment and outcome. The MEDLINE, Scopus, Embase, and Web of Science databases were searched systematically with appropriate keywords from January 1990 to October 2022. A total of 77 cases of emergomycosis were included in the analysis. Emergomycosis was most commonly seen in patients with human immunodeficiency virus (HIV) infection (n = 61, 79.2%) and HIV-uninfected patients with or without other comorbidities (n = 16, 20.8%). The underlying disease and risk factors significantly associated with emergomycosis in the HIV-infected patients were CD4+ T-cell counts less than 100 cells/mm3 (n = 55, 90.2%), anaemia (n = 30, 49.2%), and thrombocytopenia (n = 17, 27.9%), whereas in the HIV-uninfected patients, treatment with immunosuppressive drugs (n = 10, 62.5%), renal disease (n = 8, 50%), transplant recipients (n = 6, 37.5%), and diabetes mellitus (n = 4, 25%) were the significant risk factors associated with emergomycosis. Emergomyces africanus (n = 55, 71.4%) is the most common causative agent, followed by E. pasteurianus (n = 9, 11.7%) and E. canadensis (n = 5, 6.5%). E. africanus was most often isolated from HIV-infected patients (n = 54, 98.2%), whereas E. pasteurianus was most common in HIV-uninfected patients (n = 5, 55.6%). The all-cause mortality rate of the total cohort is 42.9%. No significant variation in the mortality rate is observed between the HIV-infected patients (n = 28, 36.4%) and the HIV-uninfected patients (n = 5, 6.5%). In conclusion, with an increase in the immunosuppressed population across the globe in addition to HIV infection, the case burden of emergomycosis may increase in the future. Hence, clinicians and mycologists should be vigilant and clinically suspicious of emergomycosis, which helps in early diagnosis and initiation of antifungal treatment to prevent disease mortality.

Immunosuppression is a risk factor for worse survival and disease‐specific death in cutaneous squamous cell carcinoma

AbstractBackgroundPrevious literature on cutaneous squamous cell carcinoma (cSCC) suggests that the incidence, rate of metastasis, and tumour severity of cSCC are higher in immunosuppressed patients than in immunocompetent patients. However, current literature lacks an extensive comparison of cSCC clinical characteristics and outcomes in immunosuppressed patients.ObjectivesWe compared cSCC tumour characteristics and disease‐related outcomes to help guide the clinical management of immunosuppressed patients.MethodsWe conducted a retrospective review of histopathologic and clinical data from 935 cSCC cases (19.5% immunosuppressed) from the Mayo Clinic.ResultsImmunosuppression was associated with younger age (69.3 vs. 74.8 years old, p < 0.0001), male gender (78.6% vs. 67.2%, p = 0.003), and higher grade cSCC tumour characterized by moderate or poor differentiation (25.7% vs. 15.8%, p = 0.009; 9.2% vs. 7.2%, p = 0.009, respectively). No significant differences were found in other tumour characteristics, including clinical tumour dimension, Brigham and Women's Hospital tumour staging or cumulative risk of metastasis and recurrence. Immunosuppressed patients had an increased risk of disease‐specific death on univariate analysis (hazard ratio [HR] [95% confidence interval, CI] 2.05 [1.13–3.74], p = 0.0128). Overall survival in the immunosuppressed population was worse (adjusted HR [95% CI] 1.83 [1.42–2.35], p < 0.001) and, notably, solid organ transplant recipients had the lowest overall survival when stratifying immunosuppressed patients by immunosuppression type (HR [95% CI] 1.62 [1.17–2.24], p < 0.0001).ConclusionsIn our study, immunosuppression status was predictive of poor differentiation of tumours and a reduction in overall and cSCC‐specific survival. Current staging systems for cSCC do not include immunosuppression as a risk factor and incorporating immune status may be beneficial for accurate risk stratification.

Factors associated with necrotizing soft tissue infections in pediatric population at a high-complexity reference centre

AimTo characterize the pediatric population that presented necrotizing soft tissue infection at the Fundación Hospital Pediátrico la Misericordia (HOMI) MethodsThis was a retrospective study of pediatric patients with diagnosis of necrotizing soft tissue infections treated by the pediatric surgery service at HOMI, a referral hospital for oncological pediatric patients over a 5-year period (2017 to 2021). A descriptive analysis was performed. ResultsThe study included 52 patients, 65.4% were female, the average age was 8.1 years (sd: 5.53). The infection was most frequently located in the perineum (59.6%). Early symptoms were present in 88.5% (pain being the most frequent) and late symptoms in 73.1%. All but one patient had identifiable risk factors for infection, immunocompromised was the most frequent (73.1%), followed by oncological diagnosis (51.9%) and surgical procedures (abdominoperineal, colostomy and bone marrow biopsy, with 13.3% each one) All patients underwent surgical debridement (mean 3 procedures per patient, SD: 2.0) and 32.7% underwent colostomy. The most isolated microorganism in the tissues in monomicrobial and polymicrobial infections was Escherichia coli (11.5% in each group). 57.7% required management in the Intensive Care Unit. The average mortality was 23.1%, being higher in patients with acute lymphoblastic leukemia and neutropenia (35.0%). ConclusionIn the present study, the highest frequency of soft tissue infections was in the immunosuppressed and oncological population. The characteristics of our study and mortality were different from those described in the literature due to the predominance of this population.

Abstract P187: Comparative Analysis Of Covid-19 Vaccine Efficacy In Heart Transplant Recipients On Standardized Immunotherapy Regimens

Background: International data on COVID-19 infection in immunosuppressed populations is limited. Heart transplant (OHT) recipients requiring immunotherapy are at risk for potentially increased complications with COVID-19 infection, including long-covid and oxidative stress during initial infection. The availability of vaccination and temporal trends in this population has not been well described. We report outcomes in immunosuppressed patients during the initial years of the COVID pandemic. Methods: All patients who underwent heart transplantation at Mayo Clinic in Florida were reviewed from March 2019 to October 2021. Patients were divided into two groups: those diagnosed with COVID-19 (based on a positive SARS-CoV-2 RT-PCR) and those not. A p value of 0.05 was considered significant using the Chi-squared test. Results: A total of 98 patients were reviewed. Of these, 49 were COVID-19-positive (CP), and 49 were negative (CN). The cohort was well matched, with a median age of 58 years (49 - 65) in both groups. 20 females in the CP group and 9 in the CN group. Diabetic status (p = .07), history of hypertension (p=.5), BMI (p=.41), GFR (p=.19), and ejection fraction (p=.29) were not significantly different between the two groups. Immunosuppression was not significantly different for CP or CN patients, with a median trough tacrolimus level of 7.68 vs. 8.70 (p = .26). The median time from transplant to CP was 384 days (237 - 677). The CN group’s median follow-up after transplant was 947 days (737 - 1191). CP hospitalization rate was 24% (5 Pfizer, 3 unvaccinated, 4 Moderna) with only 1 death. Hospitalized patients’ markers of inflammation were: IL6 19.2 (12-48), D-dimer 1408 (763 - 2227), and CRP 54 (20 - 90). The CP group was more vaccinated than the CN group (92% vs. 78%, p = .025). More CP patients received the Pfizer vaccine compared to Moderna (p = .018). Conclusion: We found that patients after OHT on similar immunotherapy regimens did not carry the same risk of contracting Covid-19 despite being vaccinated. CP patients were generally infected in the first 1.5 years after OHT. This may indicate an increased infection rate due to a weakened immune system or lack of bivalent boosters before 2022. Vaccine efficacy in this population should be evaluated in larger studies.

Understanding the bacillary load and host interaction to design a point-of-care test to diagnose tuberculosis

Designing of a Point-of-care test to diagnose tuberculosis (TB) is not an easy task. This viewpoint stems from the dichotomous diagnostic approach, based on the bacillary load estimated in latent tuberculosis infection (LTBI), thanks to the isoniazid chemoprophylaxis strategy, as well as the importance of imaging to differentiate between LTBI and TB. It integrates the “TB spectrum” elucidated through positron emission tomography-computed tomography scan (PET-CT) to highlight the dynamic nature of TB lesions. Additionally, it emphasizes the relevance of animal models that support this perspective, including the drainage of bacilli through foamy macrophages, which aids in understanding LTBI and its chemoprophylaxis, and the significance of lung anatomy in TB induction. Especially the role of interlobular septa and the encapsulation process and its role in lung lobe predilection impact disease progression. Moreover, it acknowledges the gender bias in TB, as its incidence is significantly higher in men across various socioeconomic circumstances, suggesting an unidentified biological mechanism. For a comprehensive approach, the impact of stress and cortisol levels is suggested as a new parameter to be considered, given their association with poverty, and social inequity, and their tendency to be higher in men. All this information has to be contemplated when designing an accurate point-of-care test. The test should encompass the complexity of TB and necessarily integrate both bacillary and host response parameters. It also should cover the diagnosis of extrapulmonary TB, and pay attention to immunosuppressed and pediatric population.

The Medical Relevance of Toxoplasma Infections in Terms of the Safety of Blood Recipients under Immunosuppression-A Meta-Analysis.

Laboratory diagnosis of Toxoplasma gondii infection plays a crucial role in ensuring the safety of blood recipients, especially in the case of immunosuppressed people, such as organ transplant patients. Toxoplasmosis, caused by the parasite Toxoplasma gondii, is a potential threat to people with weakened immune systems, and blood transfusions from infected donors can lead to severe complications. In this publication, we analyze the medical relevance of Toxoplasma infection in the context of the safety of blood recipients, focusing on the immunosuppressed patient population. We present various diagnostic methods, such as serological, molecular, and microscopic tests, which can detect the presence of Toxoplasma gondii in donors' blood. We also discuss the importance of adequately interpreting diagnostic results, considering risk factors, and detectability of the infection. We pay special attention to high-sensitivity and -specificity diagnostic techniques, which allow us to minimize the risk of Toxoplasma gondii transmission to blood recipients. Our findings have important implications for clinical practice and organ transplantation guidelines, emphasizing the need to diagnose and monitor Toxoplasma infections in blood donors and recipients.

Cutaneous Manifestations of Mycobacterium tuberculosis: A Literature Review.

Tuberculosis is an ancient disease that humanity struggled with for centuries and continues to struggle with. The bacteria Mycobacterium tuberculosis often infects the lungs through respiratory transmission and manifests itself through various symptoms, including cutaneous infections. Cutaneous tuberculosis (CTB) comprises about 1% to 1.5% of all extrapulmonary manifestations and is often accompanied by polymorphous lesions, including papules, nodules, plaques, ulcers, gummas, and verrucous lesions. CTB is most commonly observed in low-income, HIV, and immunosuppressed populations, similar to intrapulmonary manifestations. The main pathogen for CTB is M. tuberculosis but less commonly with M. bovis and BCG vaccine, and the modes of transmission are largely classified into exogenous and endogenous CTB. Current treatment options for CTB include oral therapy of antibiotic medications such as rifampicin, streptomycin, ethambutol, isoniazid, and pyrazinamide, which is occasionally combined with surgical intervention.

BI29 Crusted scabies: a complicated course in a renal transplant recipient

Abstract A 55-year-old man of Nigerian origin was admitted with a 3-month history of a generalized rash that was intensely pruritic at night. He had received a renal transplant 1 year prior for end-stage kidney disease in the context of hypertensive nephropathy. His maintenance immunosuppressive regimen includes mycophenolate mofetil, tacrolimus and prednisolone. No household contacts were affected by itch. He had been treated with the topical scabicide permethrin cream in the community, resulting in a painful fissuring of the lower limbs that prompted presentation to the emergency department. Full skin examination revealed an extensive scaling eruption, with profuse skin shedding and lichenified fissuring of the lower limbs. There were also loosely adherent, grey, hyperkeratotic scaling plaques widely extending from the genitals to mid-thigh and posterior upper limbs, with involvement of the ear lobes. There was relative sparing of the acral areas. He was initially treated empirically with oral ivermectin, oral flucloxacillin and topical clobetasol propionate ointment and paraffin gel. A full blood count revealed a prominent eosinophilia. A punch biopsy later revealed a number of scabies mites. He was prescribed ivermectin as per the Centers for Disease Control guidelines for crusted scabies in immunosuppressed populations with oral ivermectin 200 μg kg–1 on days 1, 2, 8, 9, 15, 22 and 29. Supply issues in the community delayed his treatment course. Further topical antiscabietic therapy was deferred until tolerated. He was subsequently re-admitted with methicillin-sensitive Staphylococcus aureus bacteraemia with pyelonephritis of the transplant kidney. The prescribed treatment regime of oral ivermectin, a topical keratolytic cream and topical permethrin cream daily for 7 days was completed as an inpatient. This yielded complete resolution of his crusted lesions. He responded well to a prolonged course of intravenous flucloxacillin. This case illustrates the challenge of diagnosing scabies in richly pigmented skin, as well in the immunosuppressed host (in this case due to defective T-cell responses). Maintaining a high index of suspicion is essential in the context of unexplained itch in the immunosuppressed as they may present with atypical presentations. Such vigilance will improve the recognition and management of this uncommon, potentially life-threatening infectious complication of crusted scabies in the transplant population (Wang MK, Chin-Yee B, Lo CKL et al. Crusted scabies in a renal transplant recipient treated with daily ivermectin: a case report and literature review. Transpl Infect Dis 2019; 21:e13077).

Cross-sectional investigation of mycological diagnosis challenges in Saudi Arabia.

The global incidence of fungal infection has increased dramatically over the last two decades. Fungal diseases threaten both immunocompetent, and immunocompromised patients. The current fungal diagnostics status in Saudi Arabia needs to be evaluated, especially with the increase of the immunosuppressed population. This cross-sectional study investigated the gaps in mycological diagnosis on a national level. The call interview questionnaire responses were collected to evaluate the demand for fungal assays, diagnostic methods' quality, and mycological expertise of laboratory technologists in both public and private medical intuitions. The data were analyzed using (IBM SPSS ® software version 22.0). A total of 57 hospitals from all Saudi regions participated in the questionnaire; however, only 32% received or processed mycological samples. Most participants were from the Mecca region (25%), Riyadh region (19%), and Eastern region (14%). The top fungal isolates identified were Candida spp., Aspergillus spp., and dermatophyte. Fungal investigation is highly requested by intensive care, dermatology, and obstetrics and gynecology units. Most laboratories rely on fungal culture and microscopic examination, which mostly identify Candida to the genus level, and use 37°C incubators for culture (67%). Antifungal susceptibility testing (AST) and serological and molecular methods are rarely performed and mostly outsourced. Using accurate identification and AST are the primary factors to improve fungal diagnosis in respect to turnaround time and cost. The three major obstacles identified were availability of facility (47%), reagents and kits (32%), and good training (21%). The results indicated that fungal diagnosis demand was relatively higher in high-population regions. This study highlighted the gaps in fungal diagnostics reference laboratories to encourage their improvement in Saudi hospitals.

WS18.06 The impact of cytomegalovirus on airway epithelial gene expression

Introduction: The pathogenicity of cytomegalovirus (CMV) has predominantly been recognized in immunosuppressed populations & newborns. However, a recent study in persons with CF observed that CMV seropositive individuals died from lung disease 8 years sooner than those who were seronegative. Further, CMV DNA was identified in those individuals’ sputum (Parkins 2019, ERJ). This observation aligns with increasing evidence associating CMV infection with worse outcomes in many inflammatory conditions, and a higher overall mortality. To date, models of CMV infection of human bronchial epithelial (HBE) cells have not been established, limiting our ability to study its impact in CF airways.

Phylogenetic analysis of HA and NA genes of influenza A viruses in immunosuppressed inpatients in Beijing during the 2018–2020 influenza seasons

BackgroundInfluenza A viruses have undergone rapid evolution with virulent; however, complete and comprehensive data on gene evolution and amino acid variation of HA and NA in immunosuppressed patients was few. In this study, we analysed molecular epidemiology and evolution of influenza A viruses in immunosuppressed population, and immunocompetent population were used as controls.MethodsFull sequences of HA and NA of A(H1N1)pdm09 and A(H3N2) were acquired through reverse transcription-polymerase chain reaction (RT-PCR). HA and NA genes were sequenced using the Sanger method and phylogenetically analysed using ClustalW 2.10 and MEGA software version 11.0.ResultsDuring the 2018–2020 influenza seasons, 54 immunosuppressed and 46 immunocompetent inpatients screened positive for influenza A viruses by using the quantitative real-time PCR (qRT-PCR) were enrolled. 27 immunosuppressed and 23 immunocompetent nasal swab or bronchoalveolar lavage fluid samples were randomly selected and sequenced using the Sanger method. A(H1N1)pdm09 were detected in 15 samples and the remaining 35 samples were A(H3N2) positive. By analyzing the HA and NA gene sequences of these virus strains, we found that all A(H1N1)pdm09 viruses shared high similarities to each other and the HA and NA genes of these viruses exclusively belonged to subclade 6B.1A.1. Some NA genes of A(H3N2) viruses were not in the same clade as those of A/Singapore/INFIMH-16-0019/2016 and A/Kansas/14/2017, which may have led to A(H3N2) being the dominant strain in the 2019–2020 influenza season. Both A(H1N1)pdm09 and A(H3N2) viruses showed similar evolutionary lineages patterns of HA and NA between immunosuppressed and immunocompetent patients. Compared with the vaccine strains, there were no statistically significant of HA and NA genes and amino acid sequences of influenza A viruses in immunosuppressed and immunocompetent patients. However, the oseltamivir resistance substitution of NA-H275Y and R292K have been observed in immunosuppressed patients.ConclusionsA(H1N1)pdm09 and A(H3N2) viruses showed similar evolutionary lineages patterns of HA and NA between immunosuppressed and immunocompetent patients. Both immunocompetent and immunosuppressed patients have some key substitutions, which should be of note monitored, especially those with potential to affect the viral antigen.

The Role of Excision for Treatment of Chromoblastomycosis: A Cutaneous Fungal Infection Frequently Mistaken for Squamous Cell Carcinoma.

Chromoblastomycosis is an uncommon fungal infection of the skin caused by a variety of dematiaceous fungal species that is typically contracted through direct inoculation into the skin. To collect and examine data pertaining to the clinical presentation and management of patients with chromoblastomycosis. Through a retrospective study, a pathology medical record search was performed from January 2004 to December 2020 at a single institution. A total of 9 patients were identified. Seven of 9 cases occurred in solid organ transplant recipients. All cases were located on the extremities. Six of 9 cases were clinically suspected to be squamous cell carcinoma. Seven of 9 cases were treated with surgical excision. Six of 9 patients were treated with oral antifungal medication. Four of 9 patients had received combination therapy. Eight of 9 patients had no recurrence of the disease after treatment. Chromoblastomycosis presents as verrucous papules or nodules and may clinically and histopathologically mimic squamous cell carcinoma. Immunosuppression is likely a risk factor for the development of chromoblastomycosis. This study highlights the importance of clinical awareness of this disease's clinical presentation and prevalence in immunosuppressed patient populations.

Immunomodulators for Non-Melanoma Skin Cancers: Updated Perspectives.

Non-melanoma skin cancers (NMSCs) are the most common cancers worldwide and may be associated with significant morbidity and mortality, especially in immunosuppressed populations. Successful management of NMSC must take primary, secondary and tertiary prevention strategies into consideration. In response to an improved understanding of the pathophysiology of NMSC and associated risk factors, multiple systemic and topical immunomodulatory drugs have been developed and integrated into clinical practice. Many of these drugs are efficacious in the prevention and treatment of precursor lesions (actinic keratoses; AKs), low-risk NMSC, and advanced disease. The identification of patients at high risk for the development of NMSC is critical in reducing disease morbidity. Understanding the various treatment options available and their comparative effectiveness is paramount for developing a personalized treatment regimen for such patients. This review article provides an updated overview of the various topical and systemic immunomodulatory drugs available for the prevention and treatment of NMSC, and the published data supporting their use in clinical practice.

Molecular Alterations in Cutaneous Squamous Cell Carcinoma in Immunocompetent and Immunosuppressed Hosts-A Systematic Review.

The characterization of cutaneous squamous cell carcinoma (cSCC) at the molecular level is lacking in the current literature due to the high mutational burden of this disease. Immunosuppressed patients afflicted with cSCC experience considerable morbidity and mortality. In this article, we review the molecular profile of cSCC among the immunosuppressed and immunocompetent populations at the genetic, epigenetic, transcriptomic, and proteometabolomic levels, as well as describing key differences in the tumor immune microenvironment between these two populations. We feature novel biomarkers from the recent literature which may serve as potential targets for therapy.

Psychological distress experienced by parents caring for an immunosuppressed child during the COVID-19 pandemic

The COVID-19 pandemic has proved unique in both its unpredictability and the extent to which it has continued to impact on daily life since March 2020. Among the immunosuppressed population the challenges of the COVID-19 pandemic are cumulative to the ever-present challenges of living with a long-term condition.This prospective longitudinal study explored patterns of concern experienced by 467 British parents caring for an immunosuppressed child during the first 2 years of the COVID-19 pandemic and related this to parental mental wellbeing.Most parents slowly adapted or were resilient to the ever-changing stressors of the COVID-19 pandemic. However, 12% experienced high levels of concern throughout the first 2 years of the pandemic. This group was also more likely to report emotional mental health problems towards the end of this period.The experience of emotional mental health problems among parents caring for an immunosuppressed child was related to low household income, single parenting, difficult access to greenspace, and higher level of exposure to COVID positive cases and COVID restrictions (North of England).Parents reported that optimism, reduction of isolation, and support promoted coping and management of the challenges of the COVID-19 pandemic. More reliable COVID information and periodic medical-condition-specific guidance would have been appreciated.These findings can increase clinical awareness of high-risk parental groups and make an important contribution to the planning of appropriate targeted psychological family interventions.

Molecular Characterization of AZD7442 (Tixagevimab-Cilgavimab) Neutralization of SARS-CoV-2 Omicron Subvariants.

Therapeutic anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibodies (MAbs) provide immunosuppressed and vulnerable populations with prophylactic and treatment interventions against coronavirus disease 2019 (COVID-19). AZD7442 (tixagevimab-cilgavimab) is a combination of extended-half-life neutralizing MAbs that bind to distinct epitopes on the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. The Omicron variant of concern carries mutations at >35 positions in the spike protein and has undergone further genetic diversification since its emergence in November 2021. Here, we characterize the in vitro neutralization activity of AZD7442 toward major viral subvariants circulating worldwide during the first 9 months of the Omicron wave. BA.2 and its derived subvariants showed the highest susceptibility to AZD7442, while BA.1 and BA.1.1 showed a lower susceptibility. BA.4/BA.5 had a susceptibility level intermediate between BA.1 and BA.2. Mutagenesis of parental Omicron subvariant spike proteins was performed to establish a molecular model to describe the underlying determinants of neutralization by AZD7442 and its component MAbs. The concurrent mutation of residues at positions 446 and 493, located in the tixagevimab and cilgavimab binding sites, was sufficient to enhance in vitro susceptibility of BA.1 to AZD7442 and its component MAbs to levels similar to the Wuhan-Hu-1+D614G virus. AZD7442 maintained neutralization activity against all Omicron subvariants tested up to and including BA.5. The evolving nature of the SARS-CoV-2 pandemic warrants continuing real-time molecular surveillance and assessment of in vitro activity of MAbs used in prophylaxis against and the treatment of COVID-19. IMPORTANCE MAbs are key therapeutic options for COVID-19 prophylaxis and treatment in immunosuppressed and vulnerable populations. Due to the emergence of SARS-CoV-2 variants, including Omicron, it is vital to ensure that neutralization is maintained for MAb-based interventions. We studied the in vitro neutralization of AZD7442 (tixagevimab-cilgavimab), a cocktail of two long-acting MAbs targeting the SARS-CoV-2 spike protein, toward Omicron subvariants circulating from November 2021 to July 2022. AZD7442 neutralized major Omicron subvariants up to and including BA.5. The mechanism of action responsible for the lower in vitro susceptibility of BA.1 to AZD7442 was investigated using in vitro mutagenesis and molecular modeling. A combination of mutations at two spike protein positions, namely, 446 and 493, was sufficient to enhance BA.1 susceptibility to AZD7442 to levels similar to the Wuhan-Hu-1+D614G ancestral virus. The evolving nature of the SARS-CoV-2 pandemic warrants continuing real-time global molecular surveillance and mechanistic studies of therapeutic MAbs for COVID-19.

Characteristics of COVID-19 vaccinated and unvaccinated patients admitted to Careggi University Hospital, Florence, Italy

More than 11.5 billion COVID-19 vaccine doses have been administered around the world. Although vaccine effectiveness for severe infections is reported to be 89.0%, breakthrough infections are common and may lead to severe outcome in fragile population. We conducted a real-world observational study on 420 COVID-19 admitted patients from July 2021 to January 2022 in a tertiary level Italian hospital. We collected patient’s vaccination and SARS-CoV-2 serological status, SARS-CoV-2 treatments, oxygen supports, intensive (ICU) and subintensive (sub-ICU) care unit admissions, length of staying (LoS) and in-hospital mortality. One-hundred-seventy-two vaccinated and 248 unvaccinated patients were admitted during the study period. Vaccinated group (Vg) had a significantly more elevated Charlson Comorbidity Index than Unvaccinated group (UVg), and no statistical differences were found in terms of in-hospital mortality, LoS or ICU and sub-ICU admissions. Among Vg, anti-S antibodies were detected in 86.18% of patients (seropositives). Vaccinated seronegative patients’ in-hospital mortality was significantly higher than vaccinated seropositive patients (33.33% vs 10.69%, p = 0.0055): in particular, mortality rate in 45–69 years old population was higher in vaccinated seronegative group, and comparable in patients ≥ 70 years old. No differences in terms of outcome were registered between Vg and UVg, taking into account that Vg was considerably older and with more comorbidities. In line with other recent observations, higher mortality rate was evidenced for seronegative vaccinated patients. Primary prophylaxis and early treatments result to be necessary, especially for older and immunosuppressed populations.