Background: Human herpesvirus-8 (HHV-8), or Kaposi sarcoma (KS)-associated herpesvirus (KSHV), causes severe disease in people with profound immunosuppression. Yet, diagnosing KS can be challenging given the diverse manifestations and current limited usual care diagnostic methods (UC; polymerase chain reaction, histopathology). Methods: Pathogen-agnostic plasma microbial cell-free DNA sequencing was applied to banked samples from 116 outpatients included in 2 previous prospective studies of patients with antiretroviral treatment-naïve, advanced HIV (CD4 count ≤100 cells/µL). We then reviewed clinical and laboratory data for any people who tested positive for HHV-8 by mcfDNA sequencing or UC at baseline. Results: HHV-8 was detected in 21 (18%) outpatients with advanced HIV by any method, with males comprising the majority (86%) and one-third originally from non-US countries (including Africa, Central America, and the Caribbean). Adding mcfDNA sequencing to UC proportionally increased HHV-8 detection by 38%, while also identifying in 18 (86%) people other microbes of potential interest, including common herpesviruses, Mycobacterium tuberculosis, and Pneumocystis jirovecii. Conclusions: Plasma mcfDNA sequencing may improve UC in detection of HHV-8 infection, especially in immunocompromised outpatients, in whom early detection may facilitate appropriate management to prevent severe KS disease. The potential added benefit of the detection of other pathogens by mcfDNA sequencing may be particularly relevant for this population.

BACKGROUND:Despite suppressive antiretroviral therapy (ART), 15%-30% of people with human immunodeficiency virus (HIV) experience a limited recovery of CD4 T cells. Although autoantibodies against the CD4 receptor have previously been identified in people with HIV (PWH), little is known about their longitudinal impact on CD4 T-cell reconstitution. METHODS:Anti-CD4 autoantibodies were evaluated by the fluid-phase luciferase immunoprecipitation systems immunoassay in ART-naive people with advanced HIV (CD4 count ≤100 cells/µL), PWH with CD4 count >200 cells/µL, long-term nonprogressors, people with idiopathic CD4 lymphopenia, people with autoimmune lymphoproliferative syndrome, and healthy volunteers without HIV. In the participants with advanced HIV, we assessed the association of anti-CD4 autoantibodies at ART initiation with CD4 recovery over a median follow-up of 192 weeks. RESULTS:Anti-CD4 autoantibodies were identified in 29% (61/210) of ART-naive participants with advanced HIV but were absent in people without HIV. Female PWH showed a 4-fold higher prevalence (P < .001) of anti-CD4 autoantibodies compared to males. After ART initiation, people with advanced HIV with anti-CD4 autoantibodies exhibited an overall slower rate of CD4 reconstitution (5.8 vs 6.6 cells/µL/month, P = .007) and lower week 192 CD4 count (268 vs 355 cells/µL, P = .037). Incidental, clinically indicated immunosuppressive therapy in these participants was associated with an improved rate of CD4 reconstitution (P = .0019) and higher week 192 CD4 count (551 vs 268 cells/µL, P = .019). CONCLUSIONS:People with advanced HIV harboring anti-CD4 autoantibodies at ART initiation demonstrated a slower rate and extent of CD4 reconstitution after 4 years. Incidental immunosuppressive therapy was associated with increased CD4 counts in these participants.

Immune reconstitution inflammatory syndrome (IRIS) is a well-recognized complication in people with HIV (PWH) starting antiretroviral therapy (ART), but data on IRIS in hematopoietic cell transplantation (HCT) recipients are limited. To address this gap, we conducted a narrative review of the literature on IRIS in HCT recipients, including 21 studies encompassing 53 patients. The majority of reported patients had inborn errors of immunity (IEI) and developed IRIS associated with Bacillus Calmette-Guérin (BCG)-infection from prior vaccination ("BCG-IRIS"). The remainder had IRIS linked to other infections, most commonly Aspergillus and Non-tuberculous mycobacteria ("non-BCG-IRIS"). The median time between transplant and IRIS was 3 months; however, some patients developed IRIS multiple years posttransplant. BCG-IRIS was predominantly unmasking, while non-BCG-IRIS was mostly associated with a new infection acquired after HCT alongside immune recovery and/or changes in immunosuppression ("post-HCT infection IRIS"). Inflammatory biomarkers and tissue pathology were helpful in distinguishing IRIS from uncontrolled infection. Initiation or continuation of appropriate antimicrobial therapy in the peri-transplant period was foremost in the prevention and treatment of IRIS. Use of steroidal and nonsteroidal immunosuppression was common, while surgery was used as an adjunctive measure to infection control. Recrudescence of IRIS symptoms was common with discontinuation or decrease in immunosuppression. About one-third of the patients were reported to have graft-versus-host disease, and the rate of graft failure was 8%. The mortality rate was 15%, with most deaths attributed to superimposed infections. Through this review, we aim to highlight that IRIS is an under-recognized entity in HCT recipients and future research is needed to explore its pathogenesis, risk factors, and management in this complex patient population.

Tuberculous meningitis (TBM) has considerable mortality and morbidity, and it often presents therapeutic challenges when complicated by paradoxical reactions (PRs). Here, the clinical course of four cases of TBM patients complicated by PRs in a longitudinal TB cohort is described while also providing insights from the larger clinical cohort. Research flow cytometry, biomarker analysis, and drug concentrations were performed on available samples. All participants were initiated on standard antituberculosis therapy (ATT) and enrolled at the onset of PRs (PR group) or 2-4 months after the start of ATT (controls). The four TBM participants highlighted here presented with fevers, headaches, neurological deficits, and fatigue at the initial presentation. Upon diagnosis, all were initiated on rifampin, isoniazid, pyrazinamide, and ethambutol (RHZE) at standard doses and on corticosteroids. The median time to first PR was 37 days with recrudescence of initial TBM signs and symptoms at the time of PR. At the time of referral, all participants had low drug concentrations requiring dose optimization and regimen intensification as well as recrudescent flares upon corticosteroid taper, with one individual developing enlargement of tuberculoma 1 year following completion of ATT. Based on biomarkers and flow cytometry, PRs are characterized by elevated interferon-gamma and ferritin levels in the plasma compared to controls. In the TBM participants, T-cell activation with elevated levels of inflammatory biomarkers in the cerebrospinal fluid (CSF) was seen at the time of PR. These unique and highly detailed TBM cases provide insights into the pathogenesis of PRs, which may assist with future diagnostics and treatment.

IntroductionCOVID-19 patients can develop autoantibodies against a variety of secreted and membrane proteins, including some expressed on lymphocytes. However, it is unclear what proportion of patients might develop anti-lymphocyte antibodies (ALAb) and what functional relevance they might have.MethodsWe evaluated the presence and lytic function of ALAb in the sera of a cohort of 85 COVID-19 patients (68 unvaccinated and 17 vaccinated) assigned to mild (N=63), or moderate/severe disease (N=22) groups. Thirty-seven patients were followed-up after recovery. We also analyzed in vivo complement deposition on COVID-19 patients’ lymphocytes and examined its correlation with lymphocyte numbers during acute disease.ResultsCompared with healthy donors (HD), patients had an increased prevalence of IgM ALAb, which was significantly higher in moderate/severe disease patients and persisted after recovery. Sera from IgM ALAb+ patients exhibited complement-dependent cytotoxicity (CDC) against HD lymphocytes. Complement protein C3b deposition on patients’ CD4 T cells was inversely correlated with CD4 T cell numbers. This correlation was stronger in moderate/severe disease patients.DiscussionIgM ALAb and complement activation against lymphocytes may contribute to the acute lymphopenia observed in COVID-19 patients.

We report 3 complicated and prolonged cases of mpox in people with advanced human immunodeficiency virus (HIV) not on antiretroviral therapy (ART) at mpox diagnosis. Multiple medical countermeasures were used, including prolonged tecovirimat treatment and immune optimization with ART initiation. Immunofluorescence of skin biopsies demonstrated a dense immune infiltrate of predominantly myeloid and CD8+ T cells, with a strong type I interferon local response. RNAscope detected abundant replication of monkeypox virus (MPXV) in epithelial cells and dendritic cells. These data suggest that prolonged mpox in people with advanced HIV may be due to ongoing MPXV replication, warranting aggressive medical countermeasures and immune optimization.

Background: The immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines is variable in individuals with different inborn errors of immunity or acquired immune deficiencies and is yet unknown in people with idiopathic CD4 lymphopenia (ICL). Objective: We sought to determine the immunogenicity of mRNA vaccines in patients with ICL with a broad range of CD4 T -cell counts. Methods: Samples were collected from 25 patients with ICL and 23 age- and sex -matched healthy volunteers (HVs) after their second or third SARS-CoV-2 mRNA vaccine dose. Anti -spike and anti -receptor binding domain antibodies were measured. T -cell receptor sequencing and stimulation assays were performed to quantify SARS-CoV-2-specific T -cell responses. Results: The median age of ICL participants was 51 years, and their median CD4 count was 150 cells/mu L; 11 participants had CD4 counts <_100 cells/mu L. Anti -spike IgG antibody levels were greater in HVs than in patients with ICL after 2 and 3 doses of mRNA vaccine. There was no detectable significant difference, however, in anti -S IgG between HVs and participants with ICL and CD4 counts >100 cells/mu L. The depth of spike -specific T -cell responses by T -cell receptor sequencing was lower in individuals with ICL. Activation -induced markers and cytokine production of spike -specific CD4 T cells in participants with ICL did not differ significantly compared with HVs after 2 or 3 vaccine doses. Conclusions: Patients with ICL and CD4 counts >100 cells/mu L can mount vigorous humoral and cellular immune responses to SARS-CoV-2 vaccination; however, patients with more severe CD4 lymphopenia have blunted vaccine -induced immunity and may require additional vaccine doses and other risk mitigation strategies. (J Allergy Clin Immunol 2024;153:503-12.)

Abstract Background Immune reconstitution inflammatory syndrome (IRIS) was first described in patients with HIV and opportunistic infections starting antiretroviral therapy, but may be seen following hematopoietic cell transplantation (HCT) in patients with pre-existing infections. GATA2 deficiency is a genetic disorder with a marked susceptibility to mycobacterial infections, and is treated definitively with HCT. The clinical factors and pathogenesis of IRIS in HCT require further investigation. Methods We conducted a retrospective review of 32 patients with GATA2 deficiency and mycobacterial infections who completed > 6 months of follow-up after HCT. Uniform criteria were used to define cases of IRIS (Image 1). IRIS cases were classified as either early (post-HCT day < 60), intermediate (days 61-120), or late (day > 120). Image 1. Post-Hematopoietic Cell Transplant IRIS Criteria Criteria were adapted to hematopoietic cell transplantation from the AIDS Clinical Trial Group IRIS criteria. Results Clinical characteristics are shown in Image 2. IRIS was identified in 12 (35%) patients (Images 2-3). These patients were more likely to have disseminated infection (P=0.03), an elevated pre-HCT ferritin (P=0.03), and a lower day 30 post-HCT CD4 count (P=0.04). Median time to IRIS was 100 days (Image 4). Pre-transplant duration of mycobacterial therapy correlated with time to IRIS (Pearson’s r=0.58, P=0.05). Conditioning regimens using total body irradiation with or without cyclophosphamide were associated with longer time to IRIS (hazard ratio=0.04, P=0.02). A rise in CD3 chimerism was seen during early cases of IRIS, but not intermediate to late (P=0.002). IRIS emerged during tapering of systemic immunosuppressive therapy in 33% of cases. IRIS was managed conservatively (50%), by intensification of anti-mycobacterial treatment (8%) or by intensification of immunosuppression (42%). Conclusion Development of mycobacterial IRIS after HCT for GATA2 deficiency was associated with disseminated infection, a high pre-transplant ferritin, and low day 30 CD4 count. These findings suggest that antigen burden, a hyperinflammatory state leading into transplantation, and CD4 nadir after HCT have a role in its pathogenesis. Early cases of IRIS may emerge during lymphoid engraftment and CD4 recovery, whereas late cases may emerge with decreases in immunosuppressive therapy and more intensive conditioning regimens. Clinical outcomes were similar to non-IRIS patients. Disclosures All Authors: No reported disclosures

AbstractBackgroundNirmatrelvir/ritonavir, the first severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protease inhibitor, reduces the risk of hospitalization and death by coronavirus disease 2019 (COVID-19) but has been associated with symptomatic rebound after therapy completion.MethodsSix individuals with relapse of COVID-19 symptoms after treatment with nirmatrelvir/ritonavir, 2 individuals with rebound symptoms without prior antiviral therapy and 7 patients with acute Omicron infection (controls) were studied. Soluble biomarkers and serum SARS-CoV-2 nucleocapsid protein were measured. Nasal swabs positive for SARS-CoV-2 underwent viral isolation and targeted viral sequencing. SARS-CoV-2 anti-spike, anti–receptor-binding domain, and anti-nucleocapsid antibodies were measured. Surrogate viral neutralization tests against wild-type and Omicron spike protein, as well as T-cell stimulation assays, were performed.ResultsHigh levels of SARS-CoV-2 anti-spike immunoglobulin G (IgG) antibodies were found in all participants. Anti-nucleocapsid IgG and Omicron-specific neutralizing antibodies increased in patients with rebound. Robust SARS-CoV-2–specific T-cell responses were observed, higher in rebound compared with early acute COVID-19 patients. Inflammatory markers mostly decreased during rebound. Two patients sampled longitudinally demonstrated an increase in activated cytokine-producing CD4+ T cells against viral proteins. No characteristic resistance mutations were identified. SARS-CoV-2 was isolated by culture from 1 of 8 rebound patients; Polybrene addition increased this to 5 of 8.ConclusionsNirmatrelvir/ritonavir treatment does not impede adaptive immune responses to SARS-CoV-2. Clinical rebound corresponds to development of a robust antibody and T-cell immune response, arguing against a high risk of disease progression. The presence of infectious virus supports the need for isolation and assessment of longer treatment courses.Clinical trials registrationNCT04401436.

The novel SARS-CoV-2 coronavirus causes a severe respiratory syndrome referred to as coronavirus disease (COVID-19). The angiotensin-converting enzyme 2 (ACE-2) plays an important role as a cellular receptor for SARS-CoV-2 and is largely expressed in lungs, kidneys, heart and the gastrointestinal tract along with being shed in plasma. The ACE-2 gene and protein show a high level of genetic polymorphism, including simple nucleotide variation, transcriptional variation, post-transcriptional changes, and putative protein mutations that could interfere with the binding or entry of SARS-CoV-2 and affect tissue damage in lungs or other organs. Genetic polymorphisms can impact SARS-CoV-2 viral entry and COVID-19 severity. This single-center study evaluated the possible role of the main ACE-2 polymorphisms (rs143936283, rs2285666, rs41303171, rs35803318, and rs2106809) as potential prognostic markers in SARS-CoV-2-infected individuals. Frozen whole blood was used for DNA isolation and genomic DNA samples were sheared using the Covaris LE220 Focused-ultrasonicator for targeting a peak size of 410 bp. Whole-genome sequencing libraries were generated from fragmented DNA using the Illumina TruSeq DNA PCR-Free HT Library Preparation Kit and sequenced on an Illumina NovaSeq 6000. We did not identify any correlation between ACE-2 polymorphisms and COVID-19 prognosis, suggesting that the interpretation and clinical use of ACE-2 genetic polymorphisms in real-world clinical settings requires further experimental and clinical validation.

Background:Pneumocystis jirovecii pneumonia (PCP) is one of the most frequent opportunistic infections in people with HIV (PWH). However, there are limited data on long-term outcomes of PCP in the antiretroviral therapy (ART) era. Methods:We conducted a secondary analysis of 2 prospective studies on 307 PWH, 81 with prior PCP, with a median follow-up of 96 weeks. Laboratory data were measured at protocol-defined intervals. We reviewed clinically indicated chest computerized tomography imaging in 63 patients with prior PCP at a median of 58 weeks after PCP diagnosis and pulmonary function tests (PFTs) of patients with (n = 10) and without (n = 14) prior PCP at a median of 18 weeks after ART initiation. Results:After 96 weeks of ART, PWH with prior PCP showed no significant differences in laboratory measurements, including CD4 count, when compared with those without prior PCP. Survival rates following ART initiation were similar. However, PWH with prior PCP had increased evidence of restrictive lung pathology and diffusion impairment in PFTs. Furthermore, on chest imaging, 13% of patients had bronchiectasis and 11% had subpleural cysts. Treatment with corticosteroids was associated with an increased incidence of cytomegalovirus disease (odds ratio, 2.62; P = .014). Conclusions:PCP remains an important opportunistic infection in the ART era. While it did not negatively affect CD4 reconstitution, it could pose an increased risk for incident cytomegalovirus disease with corticosteroid treatment and may cause residual pulmonary sequelae. These findings suggest that PCP and its treatment may contribute to long-term morbidity in PWH, even in the ART era.

Clinical rebound of COVID-19 after nirmatrelvir/ritonavir treatment has been reported. We performed clinical, virologic, and immune measurements in seven patients with symptomatic rebound, six after nirmatrelvir/ritonavir treatment and one without previous treatment. There was no evidence of severe disease or impaired antibody and T-cell responses in people with rebound symptoms.

Falcone et al. (1) raise important questions regarding the role of cefiderocol in managing carbapenem-resistant Acinetobacter baumannii (CRAB) infections. The authors note the randomized controlled CREDIBLE-CR trial (RCT) that demonstrated increased mortality with cefiderocol, including a 31% numerical increase with CRAB infections (2). However, can a retrospective observational study validly address these questions?

BACKGROUND:Natriuresis with polyuria is common after aneurysmal subarachnoid hemorrhage (aSAH). Previous studies have shown an increased risk of symptomatic cerebral vasospasm or delayed cerebral ischemia (DCI) in patients with hyponatremia and/or the cerebral salt wasting syndrome (CSW). However, natriuresis may occur in the absence of hyponatremia or hypovolemia and it is not known whether the increase in DCI in patients with CSW is secondary to a concomitant hypovolemia or because the physiology that predisposes to natriuretic peptide release also predisposes to cerebral vasospasm. Therefore, we investigated whether polyuria per se was associated with vasospasm and whether a temporal relationship existed.METHODS:A retrospective review of patients with aSAH was performed. Exclusion criteria were admission more than 48 h after aneurysmal rupture, death within 5 days, and the development of diabetes insipidus or acute renal failure. Polyuria was defined as > 6 liters of urine in a 24 h period. Vasospasm was defined as a mean velocity > 120 m/s on Transcranial Doppler Ultrasonography (TCDs) or by evidence of vasospasm on computerized tomography (CT) or catheter angiography. Multivariable logistic regression was performed to assess the relationship between polyuria and vasospasm.RESULTS:95 patients were included in the study. 51 had cerebral vasospasm and 63 met the definition of polyuria. Patients with polyuria were significantly more likely to have vasospasm (OR 4.301, 95% CI 1.378-13.419) in multivariate analysis. Polyuria was more common in younger patients (52 vs 68, p <.001) but did not impact mortality after controlling for age and disease severity. The timing of the development of polyuria was clustered around the diagnosis of vasospasm and patients with polyuria developed vasospasm faster than those without polyuria.CONCLUSIONS:Polyuria is common after aSAH and is significantly associated with cerebral vasospasm. The development of polyuria may be temporally related to the development of vasospasm. An increase in urine volume may be a useful clinical predictor of patients at risk for vasospasm.

Effort-related motivational symptoms such as anergia and fatigue are common in patients with depression and other disorders. Research implicates pro-inflammatory cytokines in depression, and administration of cytokines can induce effort-related motivational symptoms in humans.