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Neutrophil (PMNL) function defects occur as a consequence of HIV infection. This study examined PMNL apoptosis in patients with the acquired immunodeficiency syndrome (AIDS) to determine if accelerated apoptosis contributes to impaired function. PMNL were isolated from 10 HIV-infected patients with CD4 ϩ lymphocyte counts Ͻ 200/mm 3 without signs of active infection and 7 healthy volunteers. PMNL were stained with acridine orange and ethidium bromide after 0, 3, 6, and 18 h in culture, and examined for the morphologic changes of apoptosis and viability by fluorescent microscopy. Apoptosis was also demonstrated by electron microscopy, flow cytometry, and DNA gel electrophoresis.Apoptosis was minimal at 0 h, but PMNL from AIDS patients exhibited significantly greater apoptosis than controls at 3 h (22.5 Ϯ 11.5 vs. 8.9 Ϯ 6.9%, P ϭ 0.015), 6 h (38.1 Ϯ 14.2 vs. 18.1 Ϯ 4.5%, P ϭ 0.003), and 18 h (71.3 Ϯ 19.0 vs. 38.8 Ϯ 16.7%, P ϭ 0.002). Viabilities were Ն 88.0% for both groups from 0-6 h, but by 18 h viability was significantly decreased for the HIV group (58.8 Ϯ 12.4 vs. 83.5 Ϯ 10.4%, P ϭ 0.001) due to an increase in non-viable apoptotic cells. Incubation with serum from AIDS patients had no effect on control PMNL, and incubation with control serum did not reduce the rate of apoptosis of PMNL from AIDS patients. Incubation with granulocyte colony-stimulating factor (G-CSF) in vitro significantly decreased apoptosis for PMNL from AIDS patients.PMNL from patients with AIDS exhibit markedly accelerated apoptosis ex vivo. In vivo, apoptosis and functional impairment of PMNL may contribute to the risk of secondary infections, and cytokine therapy may be of potential clinical benefit in this circumstance. ( J. Clin. Invest. 1996. 98:2714-2719.)

HIV-seropositive (HIV+) drug users show impaired performance on measures of integrity of prefrontal–subcortical systems. The Iowa Gambling Task (GT) is mediated primarily through ventromedial–prefrontal systems, and poor performance on this measure (“cognitive impulsivity”) is common among substance dependent individuals (SDIs) as well as patients with disease involving prefrontal–subcortical systems (e.g., Huntington disease). We hypothesized that HIV+ SDIs might be more vulnerable to cognitive impulsivity when compared with HIV-seronegative (HIV−) SDIs because recent studies report evidence of additive effects of HIV serostatus and drug dependence on cognition. Further, working memory is considered a key component of GT performance and is reliably impaired among HIV+ SDIs compared to controls. We administered the GT to 46 HIV+ and 47 well-matched HIV− males with a past or current history of substance dependence. In addition, we evaluated correlations between subjects' scores on the GT and on a delayed nonmatch to sample (DNMS) task in order to test if working memory deficits accounted for cognitive impulsivity among the HIV+ subjects. The HIV+ subjects performed significantly more poorly on the GT compared to the HIV− group but this effect could not be explained by working memory deficits. Implications of these findings for future basic and applied studies of HIV and substance dependence are discussed. (JINS, 2004, 10, 931–938.)

Background Anti-inflammatory therapies such as IL-6 inhibition have been proposed for COVID-19 in a vacuum of evidence-based treatment. However, abrogating the inflammatory response in infectious diseases may impair a desired host response and predispose to secondary infections. Methods We retrospectively reviewed the medical record of critically ill COVID-19 patients during an 8-week span and compared the prevalence of secondary infection and outcomes in patients who did and did not receive tocilizumab. Additionally, we included representative histopathologic post-mortem findings from several COVID-19 cases that underwent autopsy at our institution. Results 111 patients were identified, of which 48 had received tocilizumab while 63 had not. Receiving tocilizumab was associated with a higher risk of secondary bacterial (50% vs. 28.6%, p=0.021 and fungal (8.3% vs. 0%, p=0.078) infections. Consistent with higher number of infections, patients who received tocilizumab had higher mortality (39.6 vs. 17.4%, p=0.016). Seven cases underwent autopsy. In 3 cases who received tocilizumab, there was evidence of pneumonia on pathology. Of the 4 cases that had not been given tocilizumab, 2 showed evidence of aspiration pneumonia and 2 exhibited diffuse alveolar damage. Conclusions Experimental therapies are currently being applied to COVID-19 outside of clinical trials. Anti-inflammatory therapies such as anti-IL-6 therapy have the potential to impair viral clearance, predispose to secondary infection, and cause harm. We seek to raise physician awareness of these issues and highlight the need to better understand the immune response in COVID-19.

BackgroundSarcoidosis is a poorly understood chronic inflammatory condition. Infiltration of affected organs by lymphocytes is characteristic of sarcoidosis, however previous reports suggest that circulating lymphocyte counts are low in some patients with the disease. The goal of this study was to evaluate lymphocyte subsets in peripheral blood in a cohort of sarcoidosis patients to determine the prevalence, severity, and clinical features associated with lymphopenia in major lymphocyte subsets.Methodology/Principal FindingsLymphocyte subsets in 28 sarcoid patients were analyzed using flow cytometry to determine the percentage of CD4, CD8, and CD19 positive cells. Greater than 50% of patients had abnormally low CD4, CD8, or CD19 counts (p<4×10−10). Lymphopenia was profound in some cases, and five of the patients had absolute CD4 counts below 200. CD4, CD8, and CD19 lymphocyte subset counts were significantly correlated (Spearman's rho 0.57, p = 0.0017), and 10 patients had low counts in all three subsets. Patients with severe organ system involvement including neurologic, cardiac, ocular, and advanced pulmonary disease had lower lymphocyte subset counts as a group than those patients with less severe manifestations (CD4 p = 0.0043, CD8 p = 0.026, CD19 p = 0.033). No significant relationships were observed between various medical therapies and lymphocyte counts, and lymphopenia was present in patients who were not receiving any medical therapy.Conclusions/SignificanceSignificant lymphopenia involving CD4, CD8, and CD19 positive cells was common in sarcoidosis patients and correlated with disease severity. Our findings suggest that lymphopenia relates more to disease pathology than medical treatment.

The construct of "prospective memory" (PM) refers to a type of episodic memory for a future intention or "remembering what one must do." This function has been proposed as a candidate mechanism underlying behaviors of critical importance in HIV disease, including adherence with medication regimens and continued engagement in risk behavior. We administered tasks of time-based and event-based prospective memory and control tasks of retrospective and working memory to 31 HIV-seropositive and 35 HIV-seronegative substance-dependent individuals (SDIs). We found that compared with HIV- controls HIV+ participants showed deficits in time-based but not event-based PM. Retrospective, but not working, memory performance correlated significantly with time-based PM performance. In addition, performance on the time-based PM task was a significant predictor of scores on a self-report measure of risky sexual and injection practices. These preliminary data provide new and unique findings regarding the components of executive function mediated by prefrontal cortical systems that are impaired among HIV+ SDIs and their relevance to "real-world" behaviors.

Background: Anti-inflammatory therapies such as IL-6 inhibition have been proposed for COVID-19 in a vacuum of evidence-based treatment. However, abrogating the inflammatory response in infectious diseases may impair a desired host response and pre-dispose to secondary infections. Methods:We retrospectively reviewed the medical record of critically ill COVID-19 patients during an 8-week span and compared the prevalence of secondary infection and outcomes in patients who did and did not receive tocilizumab. Additionally, we included representative histopathologic post-mortem findings from several COVID-19 cases that underwent autopsy at our institution.Results: One hundred eleven patients were identified, of which 54 had received tocilizumab while 57 had not. Receiving tocilizumab was associated with a higher risk of secondary bacterial (48.1 vs. 28.1%; p = 0.029 and fungal (5.6 vs. 0%; p = 0.112) infections. Consistent with higher number of infections, patients who received tocilizumab had higher mortality (35.2 vs. 19.3%; p = 0.020). Seven cases underwent autopsy. In three cases who received tocilizumab, there was evidence of pneumonia on pathology. Of the four cases that had not been given tocilizumab, two showed evidence of aspiration pneumonia and two exhibited diffuse alveolar damage.Conclusions: Experimental therapies are currently being applied to COVID-19 outside of clinical trials. Anti-inflammatory therapies such as anti-IL-6 therapy have the potential to impair viral clearance, pre-dispose to secondary infection, and cause harm. We seek to raise physician awareness of these issues and highlight the need to better understand the immune response in COVID-19.

Distal symmetrical peripheral neuropathy (DSPN) is a particularly distressing pain syndrome associated with human immunodeficiency virus (HIV) disease. Capsaicin has been found to be effective in relieving pain associated with other neuropathic pain syndromes, and is mentioned as a possible topical adjuvant analgesic for the relief of DSPN. This multicenter, controlled, randomized, double-masked clinical trial studied patients with HIV-associated DSPN and compared measures of pain intensity, pain relief, sensory perception, quality of life, mood, and function for patients who received topical capsaicin to the corresponding measures for patients who received the vehicle only. Twenty-six subjects were enrolled in the study. At the end of 1 week, subjects receiving capsaicin tended to report higher current pain scores than did subjects receiving the vehicle (Mann-Whitney test; P = 0.042). The dropout rate was higher for the capsaicin group (67%) than for the vehicle group (18%) (chi 2 test of association; P = 0.014). There were no other statistically significant differences between the capsaicin and vehicle groups with respect to current pain, worst pain, pain relief, sensory perception, quality of life, mood, or function at study entry or at any time during the 4-week trial. These results suggest capsaicin is ineffective in relieving pain associated with HIV-associated DSPN.