Kaposi sarcoma herpesvirus viral load in bronchoalveolar lavage as a diagnostic marker for pulmonary Kaposi sarcoma.

OBJECTIVE: Kaposi sarcoma is a vascular tumor that affects the pulmonary system. However, the diagnosis of airway lesions suggestive of pulmonary Kaposi sarcoma (pKS) is reliant on bronchoscopic visualization. We evaluated the role of Kaposi sarcoma herpesvirus (KSHV) viral load in bronchoalveolar lavage (BAL) as a diagnostic biomarker in patients with bronchoscopic evidence of pKS and evaluated inflammatory cytokine profiles in BAL and blood samples. DESIGN: In this retrospective study, we evaluated KSHV viral load and cytokine profiles within BAL and blood samples in patients who underwent bronchoscopy for suspected pKS between 2016 and 2021. METHODS: KSHV viral load and cytokine profiles were obtained from both the circulation and BAL samples collected at the time of bronchoscopy to evaluate compartment-specific characteristics. BAL was centrifuged and stored as cell pellets and KSHV viral load was measured using primers for the KSHV K6 gene regions. RESULTS: We evaluated 38 BAL samples from 32 patients (30 with HIV co-infection) of whom 23 had pKS. In patients with airway lesions suggestive of pKS, there was higher KSHV viral load (median 3188 vs. 0 copies/10 6 cell equivalent; P  = 0.0047). A BAL KSHV viral load cutoff of 526 copies/10 6 cells had a sensitivity of 72% and specificity of 89% in determining lesions consistent with pKS. Those with pKS also had higher IL-1ß and IL-8 levels in BAL. The 3-year survival rate for pKS patients was 55%. CONCLUSION: KSHV viral load in BAL shows potential for aiding in pKS diagnosis. Patients with pKS also have evidence of cytokine dysregulation in BAL.

Transcriptional landscape of Kaposi sarcoma tumors identifies unique immunologic signatures and key determinants of angiogenesis.

BACKGROUND: Kaposi sarcoma (KS) is a multicentric tumor caused by Kaposi sarcoma herpesvirus (KSHV) that leads to morbidity and mortality among people with HIV worldwide. KS commonly involves the skin but can occur in the gastrointestinal tract (GI) in severe cases. METHODS: RNA sequencing was used to compare the cellular and KSHV gene expression signatures of skin and GI KS lesions in 44 paired samples from 19 participants with KS alone or with concurrent KSHV-associated diseases. Analyses of KSHV expression from KS lesions identified transcriptionally active areas of the viral genome. RESULTS: The transcript of an essential viral lytic gene, ORF75, was detected in 91% of KS lesions. Analyses of host genes identified 370 differentially expressed genes (DEGs) unique to skin KS and 58 DEGs unique to GI KS lesions as compared to normal tissue. Interleukin (IL)-6 and IL-10 gene expression were higher in skin lesions as compared to normal skin but not in GI KS lesions. Twenty-six cellular genes were differentially expressed in both skin and GI KS tissues: these included Fms-related tyrosine kinase 4 (FLT4), encoding an angiogenic receptor, and Stanniocalcin 1 (STC1), a secreted glycoprotein. FLT4 and STC1 were further investigated in functional studies using primary lymphatic endothelial cells (LECs). In these models, KSHV infection of LECs led to increased tubule formation that was impaired upon knock-down of STC1 or FLT4. CONCLUSIONS: This study of transcriptional profiling of KS tissue provides novel insights into the characteristics and pathogenesis of this unique virus-driven neoplasm.

CE: HIV-Associated Kaposi Sarcoma in the Combination Antiretroviral Therapy Era.

ABSTRACT: Kaposi sarcoma is a tumor caused by Kaposi sarcoma herpesvirus, also known as human herpesvirus 8. Its occurrence is associated with an immunocompromised state. Kaposi sarcoma that occurs among people living with HIV (PLWH) is known as epidemic Kaposi sarcoma. Despite the decline in HIV-associated complications because of the introduction of combination antiretroviral therapy two decades ago, Kaposi sarcoma continues to affect PLWH worldwide. It affects young African American men more than other age and racial groups and can result in multiorgan dysfunction, leading to short-term and chronic debilitating symptoms as well as death. While some patients with epidemic Kaposi sarcoma are managed as outpatients, others may require higher levels of care and their acuity may fluctuate throughout their life span. Therefore, nurses, regardless of their specialty, may experience caring for a patient with epidemic Kaposi sarcoma at some point in their career. Learning about this condition and the needs of patients who have it will help nurses provide effective care. Here, the authors describe Kaposi sarcoma in general as well as the epidemiology, characteristics, and management of epidemic Kaposi sarcoma. They also describe specific nursing considerations in the care of PLWH who have the disease.

Characteristics of patients admitted to the ICU with Kaposi sarcoma herpesvirus-associated diseases.

OBJECTIVE: There are four conditions caused by Kaposi sarcoma herpesvirus (KSHV): Kaposi sarcoma, KSHV-associated multicentric Castleman disease (MCD), primary effusion lymphoma (PEL), and KSHV inflammatory cytokine syndrome (KICS). These KSHV-associated disorders (KADs) often occur in people with HIV and can lead to multiorgan dysfunction requiring admission to the ICU. However, little is known about patient outcomes in this setting. METHODS: A retrospective study of patients with KADs admitted to the ICU between 2010 and 2021 was conducted, examining KAD admission diagnoses, HIV characteristics, selected cytokine profiles, and ICU interventions. Primary outcomes were 60-day and median overall survival from ICU admission to death from any cause. RESULTS: Forty-seven patients (all but one with HIV coinfection) were included. At ICU admission, 44 patients (94%) were on antiretroviral therapy with a median CD4 + count of 88 cells/µl and HIV viral load of 23 copies/ml. The most common presentation was respiratory failure alone (19%) or with hypotension (17%). Twenty-two (47%) patients had presumed KICS (with or without Kaposi sarcoma) at admission and an additional KAD was diagnosed in 36% of these patients. IL-6 levels did not vary across KAD subtype. Twenty (43%) patients received KAD-directed therapy in the ICU. Sixty-day survival was 70% and median overall survival was 9 months. CONCLUSION: The majority of patients with HIV and KADs admitted to the ICU had well controlled HIV. Additional KAD were diagnosed during ICU admission in a proportion of patients who presented with presumed KICS. Critical illness did not preclude a subset of patients from receiving KAD-directed therapy in the ICU.

Safety, Activity, and Long-term Outcomes of Pomalidomide in the Treatment of Kaposi Sarcoma among Individuals with or without HIV Infection.

PURPOSE: Kaposi sarcoma (KS) is caused by Kaposi sarcoma herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8). KS, which develops most frequently among people with HIV, is generally treated with chemotherapy, but these drugs have acute and cumulative toxicities. We previously described initial results of a trial of pomalidomide, an oral immunomodulatory derivative of thalidomide, in patients with KS. Here, we present results on the full cohort and survival outcomes. PATIENTS AND METHODS: Participants with KS with or without HIV were treated with pomalidomide 5 mg once daily for 21 days per 28-day cycle with aspirin 81 mg daily for thromboprophylaxis. Participants with HIV received antiretroviral therapy. Response was defined by modified version of the AIDS Clinical Trial Group KS criteria. We evaluated tumor responses (including participants who had a second course), adverse events, progression-free survival (PFS), and long-term outcomes. RESULTS: Twenty-eight participants were enrolled. Eighteen (64%) were HIV positive and 21 (75%) had advanced (T1) disease. The overall response rate was 71%: 95% confidence interval (CI) 51%-87%. Twelve of 18 HIV-positive (67%; 95% CI, 41-87%) and 8 of 10 HIV-negative participants (80%; 95% CI, 44%-97%) had a response. Two of 4 participants who received a second course of pomalidomide had a partial response. The median PFS was 10.2 months (95% CI: 7.6-15.7 months). Grade 3 neutropenia was noted among 50% of participants. In the follow-up period, 3 participants with HIV had other KSHV-associated diseases. CONCLUSIONS: Pomalidomide is a safe and active chemotherapy-sparing agent for the treatment of KS among individuals with or without HIV.

Characteristics and outcomes of KSHV-associated multicentric Castleman disease with or without other KSHV diseases.

Kaposi sarcoma (KS)-associated herpesvirus (KSHV)-associated multicentric Castleman disease (MCD) is a relapsing and remitting systemic lymphoproliferative disorder characterized by severe inflammatory symptoms most common among people living with HIV (PLWH). Patients with KSHV-MCD may present with concurrent KSHV-associated diseases, such as KS and/or primary effusion lymphoma (PEL). We evaluated clinical and immunologic characteristics, the effects of concurrent KSHV malignancies, and treatments from the largest prospective natural history study of participants with KSHV-MCD within the United States. Treatment options administered at investigator discretion included high-dose zidovudine with valganciclovir (AZT/VGC), rituximab, or rituximab with liposomal doxorubicin (R-Dox) during KSHV-MCD flares. Survival analyses and prognostic factors were explored for all participants. Sixty-two participants with HIV were enrolled, including 20 with KSHV-MCD alone, 34 with KSHV-MCD and KS, 1 with KSHV-MCD and PEL, and 7 with all KSHV-associated diseases. Forty-four percent of KSHV-MCD diagnoses were made at our institution. Forty-four participants received rituximab-based therapies, 20 of whom had maintenance AZT/VGC or interferon. Participants receiving R-Dox and then maintenance AZT/VGC had the highest 5-year progression-free survival (89%). Cytokine profiles during KSHV-MCD flares did not differ by the presence of concurrent KSHV-associated diseases. The 10-year survival was 71% (95% confidence interval [CI], 56% to 82%) for all participants. A concurrent diagnosis of PEL negatively impacted survival (PEL hazard ratio, 5.4; 95% CI, 1.8 to 16.8). KSHV-MCD is an underdiagnosed condition among PLWH, including those with KS. KSHV-MCD has an excellent prognosis with appropriate treatment. Physicians should be alert for patients with multiple KSHV diseases, which impact optimal treatment and survival outcomes. This study was registered at www.clinicaltrials.gov as #NCT00099073.

Use of pembrolizumab with or without pomalidomide in HIV-associated non-Hodgkin's lymphoma.

BACKGROUND: Non-Hodgkin's lymphoma (NHL) is currently the most common malignancy among people living with HIV (PLWH) in the USA. NHL in PLWH is more frequently associated with oncogenic viruses than NHL in immunocompetent individuals and is generally associated with increased PD-1 expression and T cell exhaustion. An effective immune-based second-line approach that is less immunosuppressive than chemotherapy may decrease infection risk, improve immune control of oncogenic viruses, and ultimately allow for better lymphoma control. METHODS: We conducted a retrospective study of patients with HIV-associated lymphomas treated with pembrolizumab±pomalidomide in the HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute. RESULTS: We identified 10 patients with stage IV relapsed and/or primary refractory HIV-associated NHL who were treated with pembrolizumab, an immune checkpoint inihibitor, with or without pomalidomide. Five patients had primary effusion lymphoma (PEL): one had germinal center B cell-like (GCB) diffuse large B cell lymphoma (DLBCL); two had non-GCB DLBCL; one had aggressive B cell lymphoma, not otherwise specified; and one had plasmablastic lymphoma. Six patients received pembrolizumab alone at 200 mg intravenously every 3 weeks, three received pembrolizumab 200 mg intravenously every 4 weeks plus pomalidomide 4 mg orally every day for days 1-21 of a 28-day cycle; and one sequentially received pembrolizumab alone and then pomalidomide alone. The response rate was 50% with particular benefit in gammaherpesvirus-associated tumors. The progression-free survival was 4.1 months (95% CI: 1.3 to 12.4) and overall survival was 14.7 months (95% CI: 2.96 to not reached). Three patients with PEL had leptomeningeal disease: one had a complete response and the other two had long-term disease control. There were four immune-related adverse events (irAEs), all CTCAEv5 grade 2-3; three of the four patients were able to continue receiving pembrolizumab. No irAEs occurred in patients receiving the combination of pembrolizumab and pomalidomide. CONCLUSIONS: Treatment of HIV-associated NHL with pembrolizumab with or without pomalidomide elicited responses in several subtypes of HIV-associated NHL. This approach is worth further study in PLWH and NHL.

Elevated IL-13 in effusions of patients with HIV and primary effusion lymphoma as compared with other Kaposi sarcoma herpesvirus-associated disorders.

OBJECTIVE: To assess the cytokine and viral profiles of effusions and peripheral blood among patients diagnosed with HIV and Kaposi sarcoma herpesvirus [KSHV, also known as human herpesvirus 8 (HHV-8)]-associated conditions. DESIGN: Retrospective comparative study evaluating clinicopathologic findings in patients with HIV and KSHV-associated conditions presenting with an effusion between 2010 and 2018. METHODS: Paired peripheral blood and effusion samples collected at the time of pathological diagnosis of KSHV-associated conditions [Kaposi sarcoma, KSHV-associated multicentric Castleman disease (KSHV-MCD), primary effusion lymphoma (PEL), or KSHV-associated inflammatory cytokine syndrome (KICS)] were evaluated for disease-specific and compartment-specific (effusion vs. blood) characteristics. We assessed 12 cytokines, KSHV viral DNA (KSHV-VL), and Epstein--Barr virus (EBV) viral DNA (EBV-VL). RESULTS: Nine patients had PEL, five patients had KSHV-MCD, and eight patients met criteria for KICS; all but one patient had concurrent Kaposi sarcoma in addition to these conditions. PEL effusions had substantially higher levels of IL-13 (median 16.9 pg/ml; interquartile range 9.7--26.9 pg/ml) compared with KSHV-MCD (median <0.114 pg/ml; P = 0.0037) or KICS (median <0.114 pg/ml; P = 0.0003) effusions. IL-13 was also higher in PEL effusions as compared with serum (median <0.12 ng/ml; P = 0.007). KSHV-VL levels were significantly higher in PEL effusions as compared with KICS effusions (median 31 × 10 vs. 569 copies/million-cell equivalent; P = 0.0005) or KSHV-MCD effusions (median 231,884 copies/million-cell equivalent; P = 0.02). CONCLUSION: PEL effusions had a distinct profile as compared to other KSHV-associated diseases with regard to elevated IL-13 and KSHV-VL. These findings may provide insights into PEL pathogenesis and aid in diagnosis.

A Pilot Study of Liposomal Doxorubicin Combined with Bevacizumab followed by Bevacizumab Monotherapy in Patients with Advanced Kaposi Sarcoma.

PURPOSE: VEGF-A is important in the pathogenesis of Kaposi sarcoma, and bevacizumab has a response rate of 31%. We explored the combination of bevacizumab with liposomal doxorubicin in patients with Kaposi sarcoma. PATIENTS AND METHODS: Patients with Kaposi sarcoma requiring systemic therapy were enrolled in one of two cohorts. Cohort 1 included patients with human immunodeficiency virus (HIV)-negative Kaposi sarcoma or with HIV-associated Kaposi sarcoma who would not be expected to respond to antiretroviral therapy (ART) alone (i.e., either stable or progressive Kaposi sarcoma on ART). Cohort 2 included all other patients with HIV-associated Kaposi sarcoma. Patients were treated with six cycles of liposomal doxorubicin with bevacizumab every 3 weeks followed by up to 11 cycles of bevacizumab alone. RESULTS: Sixteen patients were enrolled: 10 (two HIV negative) in cohort 1 and six in cohort 2. Fourteen patients had advanced disease (AIDS Clinical Trials Group T1). Overall response rate (complete and partial responses) was 56% [80% confidence interval (CI), 38%-74%] for all patients and were similar in the two cohorts. Median progression-free survival was 6.9 months (95% CI, 4.5 months-not estimable). Grade 3 and 4 adverse events attributed to therapy included hypertension (n = 5), neutropenia (n = 6), gastrointestinal hemorrhage (n = 1), and cerebral ischemia (n = 1). There was a significant decrease in VEGF-A levels from baseline to the end of six cycles of combination therapy. CONCLUSIONS: Pegylated liposomal doxorubicin in combination with bevacizumab has activity in advanced Kaposi sarcoma, but it is unclear whether the combination yields better outcomes than liposomal doxorubicin used alone.