key: cord-1044549-vil1vy7b authors: Ho, Hsi-en; Peluso, Michael J; Margus, Colton; Matias Lopes, Joao Pedro; He, Chen; Gaisa, Michael M; Osorio, Georgina; Aberg, Judith A; Mullen, Michael P title: Clinical outcomes and immunologic characteristics of Covid-19 in people with HIV date: 2020-06-30 journal: J Infect Dis DOI: 10.1093/infdis/jiaa380 sha: ebb38d3df2f22ebae50faa01d7d9c9ab95e6bd3f doc_id: 1044549 cord_uid: vil1vy7b We performed a retrospective study of Covid-19 in people with HIV (PWH). PWH with Covid-19 demonstrated severe lymphopenia and decreased CD4+ T cell counts. Levels of inflammatory markers, including C-reactive protein, fibrinogen, D-dimer, interleukin-6, interleukin-8, and TNF-alpha were commonly elevated. In all, 19/72 hospitalized individuals (26.4%) died and 53 (73.6%) recovered. PWH who died had higher levels of inflammatory markers and more severe lymphopenia than those who recovered. These findings suggest that PWH remain at risk for severe manifestations of Covid-19 despite ART and that those with increased markers of inflammation and immune dysregulation are at risk for worse outcomes. M a n u s c r i p t BACKGROUND The impact of co-infection with SARS-CoV-2 in people with HIV (PWH) is incompletely understood [1] [2] [3] . Data on clinical outcomes in large and diverse cohorts of PWH is needed to understand the manifestations, including immunologic outcomes, of this novel co-infection. Manifestations of Covid-19 range from asymptomatic infection to acute respiratory distress syndrome (ARDS) and multi-organ failure [4] . Case series have demonstrated severe disease in a variety of immunocompromised populations, including those who have received solid organ transplants and those on chronic immunosuppression [5, 6] . In two recent reports of suspected or confirmed Covid-19 in PWH, most cases were described as mild [2, 3] . HIV infection is characterized by a chronic inflammatory state and varying degrees of immune dysfunction, even in the presence of suppressive antiretroviral therapy (ART) [7] . There are several mechanisms by which HIV may impact outcomes of SARS-CoV-2 co-infection. First, Covid-19 is associated with perturbations in immune function, most notably lymphopenia [4] . While the underlying mechanisms are unclear, PWH may be particularly vulnerable and the implications of severe lymphopenia in this population are unknown. Second, limited reports of PWH with Covid-19 initially led to suggestions that PWH could be at lower risk of severe disease, either due to epidemiologic factors or a limited ability to mount the uncontrolled inflammatory response associated with poor outcomes [8] . However, PWH are capable of generating pronounced inflammatory responses to other co-infections, leading to the possibility that such responses during SARS-CoV-2 co-infection could be severe. Third, some antiretroviral drugs may exhibit activity against SARS-CoV-2. Reverse transcriptase inhibitors (e.g., tenofovir) are being investigated [9] , while current FDA-approved protease inhibitors have little effect [10] . All of these factors could potentially modify the disease course of Covid-19 in PWH. A c c e p t e d M a n u s c r i p t We systematically identified all individuals with a diagnosis of HIV infection presenting to 5 New York City emergency departments between March 2, 2020 and April 15, 2020 who had a positive nucleic acid amplification test for SARS-CoV-2. Performing a manual chart review of the electronic medical record, one clinician-reviewer recorded demographic data, HIV history, presenting symptoms and signs, general laboratory and HIV parameters during the Covid-19 presentation, and outcomes for all patients. A second clinician-reviewer independently reviewed each data field. We recorded HIV history including the duration of infection, self-reported or clinician-reported nadir CD4+ T cell count if noted in the medical record, and the most recent CD4+ T cell count and plasma HIV RNA level from the pre-Covid period in the subset of individuals for whom these data were available. We defined the pre-Covid period as the time period between January 1, 2019 and December 31, 2019. We recorded the most recent documented ART regimen and noted whether the regimen contained either tenofovir disoproxil (TDF) or tenofovir alafenamide (TAF), or a protease inhibitor (including darunavir, lopinavir, atazanavir, or ritonavir). We tabulated comorbid disease, home medications, and smoking status as noted in the past medical history and clinical notes. We tabulated the presence of key symptoms of Covid-19 in the initial emergency department note and admission note; symptoms were recorded as present or absent/not recorded. We recorded whether the initial vital signs in the emergency department were abnormal, defined as temperature >=100.4F, systolic blood pressure <90 mmHg, and oxygen saturation by pulse oximetry measured <92%. A c c e p t e d M a n u s c r i p t We recorded laboratory values including HIV parameters during the presentation, nadir blood cell counts, peak levels of liver function tests and inflammatory markers, the results of other microbiology tests, and the results of the initial chest X-ray. We recorded whether the patient was discharged from the emergency department or admitted. For those admitted, we recorded the highest level of care received (intensive care unit [ICU] vs general medical ward), the highest level of oxygen support administered (nasal canula or facemask, high-flow oxygen or non-invasive positive pressure ventilation, mechanical ventilation, or extracorporeal membrane oxygenation), and the administration of Covid-19 related therapies. We tabulated whether admitted patients died or recovered and were discharged from the hospital. Data were reviewed until an outcome could be recorded. We summarized presenting characteristics using descriptive statistics. For patients who had HIV parameters available from the pre-Covid period, we performed within-subject comparisons of results from the period prior to the pandemic and those during the Covid-19 presentation using A c c e p t e d M a n u s c r i p t Table S1 compares those who died (n=19) with those who recovered (n=53). Those who died were more likely to require ICU care (68.4% vs. 11.3%, p<0.0001) and ventilator support (57.9% vs 7.6%, p<0.0001), and to have a lower nadir absolute lymphocyte count (0.4 vs 0.9 x10 3 cells/uL, p=0.0005). Inflammatory markers including CRP, IL-6, and IL-8 were significantly higher among subsets of those who died compared with those who recovered for whom these measurements were performed (p=0.0004, p=0.03, p=0.02, respectively; Table S1, Figure S1 ). No difference was observed in age, sex, obesity, duration of HIV infection, nadir, preceding, or presenting CD4+ T cell count, or viral suppression preceding or during the Covid-19 presentation. There was no statistical difference in the proportion of individuals on tenofovir-containing regimens (73.6% vs 55.5%, p=0.15). These findings indicate that PWH, particularly those with prolonged duration of HIV infection and medical comorbidities, remain at risk for severe manifestations of Covid-19 despite suppressive ART and immune reconstitution. Substantial inflammation and immune dysregulation occurred in a subset of individuals who experienced poor outcomes. Additional work is needed to determine whether and how the pathophysiology of Covid-19 in PWH differs from the general population. A c c e p t e d M a n u s c r i p t The high prevalence of comorbidities and the presenting syndrome of Covid-19 are similar to reports in people without HIV [11, 12] and in recent series of PWH [1] [2] [3] . The degree of lymphopenia was striking, with on average a 50% reduction in ALC and CD4+ T cell count compared to historical values, although CD4 percentages remained relatively stable. Furthermore, mortality was associated with more severe lymphopenia, in agreement with the general observation that lymphopenia may predict Covid-19 severity [13] . Recent data suggest that the spike protein of SARS-CoV-2 can lead to infection of T cells [14] and that perturbations in T cell subsets might affect the cellular immune response to SARS-CoV-2 [15] . While the clinical significance of these observations remains unknown, PWH may be particularly vulnerable to such effects given residual immune dysregulation even in the presence of suppressive ART [7] . A substantial proportion of PWH died. Fatality rates among the general population with in New York during the study period vary from 10.2% to 24.5% [11, 12] . While the proportion here is similar to that described in transplant recipients and those on immunomodulatory agents [5, 6] , it is higher than that reported among PWH with confirmed or suspected Covid-19 in Spain and Germany [2, 3] . Larger studies with HIV-negative comparators will be essential to determine whether the risk in PWH, or specific subpopulations of PWH (e.g., those with detectable viremia), is elevated. PWH who died had higher levels of soluble markers of immune activation and inflammation than those who survived. Inflammation has been closely tied to disease severity in Covid-19 [16] . The frequency and degree of elevations in the hospitalized group suggest that PWH remain capable of mounting a profound inflammatory reaction in response to SARS-CoV-2 co-infection that is similar to that in other populations [8] . The relationship between markers of inflammation and non-AIDS defining morbidity and mortality in treated HIV infection is well-known and inflammation may be even more strongly associated with adverse outcomes in PWH than in the general population A c c e p t e d M a n u s c r i p t [17] . While it remains unclear whether inflammatory pathways are exacerbated or potentiated in PWH, our findings indicate that at least a subset of PWH are capable of severe inflammatory responses. It is notable that the majority of patients maintained virologic suppression below commercial assay limits despite broad immune activation. Additional work is needed to clarify the mechanisms underlying these responses, including the effects of ART, persistent immune activation, and nadir or presenting CD4+ T cell counts in the setting of Covid-19. It has been suggested that PWH treated with tenofovir might benefit from this agent's potential activity against the SARS-CoV-2 RNA polymerase [9] . We did not find a statistical difference in the use of this agent between those who died and recovered. Further work in larger populations of PWH experiencing a broader spectrum of Covid-19 severity will be needed to determine whether there is any protective effect of this agent. This study has some limitations. First, this was a retrospective chart review limited to one hospital system. Complete HIV history was not available on all patients and laboratory markers were obtained at the discretion of treating physicians. Second, a matched HIV-negative comparison group was not available and comparisons to published data are potentially confounded by disease and epidemiologic factors. Third, high rates of HIV suppression prevented us from drawing conclusions about the risk of severe Covid-19 in viremic PWH. Fourth, the SARS-CoV-2 pandemic has strained the U.S. healthcare system and testing in many locations has been limited. During the study period, testing was prioritized for sicker patients and this biased the sample toward those with more severe disease, who might be predisposed to worse outcomes. Fifth, data on race and ethnicity were limited. Disparities based on these factors are likely to be of great importance [18] , particularly in populations of PWH. A c c e p t e d M a n u s c r i p t This analysis reveals that a subset of PWH develop severe Covid-19 associated with a profound inflammatory response. Prospective studies with carefully matched control groups to identify determinants of severe Covid-19 in PWH will be crucial to understanding the biological mechanisms and clinical impact of SARS-CoV-2 co-infection in this population. A c c e p t e d M a n u s c r i p t MJP is supported by a T32 training grant AI60530-12. The authors report no conflicts of interest related to the work presented. 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JAMA 2020. b Fever, >=100 Hypotension, SBP<90 mmHg, n (%) We are grateful to the patients and the front-line providers participating in their care. We thank Dr. Steven Deeks for his input. A c c e p t e d M a n u s c r i p t HH obtained IRB approval. HH and MJP designed the data abstraction instrument. HH and CM performed the data abstraction. HH and MJP analyzed the de-identified data, which was interpreted by all authors. HH, MJP, CM, JAA, and MPM wrote the manuscript, with input from all authors. All authors edited the manuscript.A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t Figure 1