Valganciclovir modulates the tumor necrosis factor axis molecules expression and CD4+ T-cell subsets in disseminated Kaposi Sarcoma patients.

Valganciclovir (VGC) was used in a randomized clinical trial in patients with disseminated Kaposi Sarcoma/human immunodeficiency virus (DKS/HIV) as add-on therapy to evaluate the proinflammatory axis tumor necrosis factor (TNF) and its receptors (TNFRs) in T cells. Two treatment schedules were used: an experimental regime (ER) and a conventional treatment (CT). Mononuclear cells from patients with DKS/HIV were obtained at baseline (W0), 4 (W4), and 12 weeks (W12). Ten DKS/HIV patients received CT (antiretroviral therapy [cART]) and 10 ER (valganciclovir [VGC] initially, plus cART at the fourth week). HIV+ without KS and HIV- patient groups were included as controls. Correlation between T-cell subsets and HHV-8 viral load (VL) and a multivariate linear regression was performed. Data showed that DKS/HIV patients have an increased frequency of CD8+ T cells, which display a high density of CD8 expression. The ER scheme increases naïve and central memory CD4+ T cells at W4 and W12 of follow-up and induces a balanced distribution of activated CD4+ T-cell subsets. Moreover, ER decreases solTNFR2 since W4 and CT decreased the transmembrane forms of TNF axis molecules. Although CT induces a positive correlation between HHV-8 VL and TNFRs, the use of ER positively correlates with TNF and TNFRs levels through follow-up and a moderate correlation with HHV-8 VL and TNF soluble levels. In conclusion, VGC, as an add-on therapy in DKS/HIV patients, gradually modulates the activation of CD4+ T-cell subsets and the TNF/TNFRs axis, suggesting a better regulation of the inflammatory status.

Severe acute respiratory syndrome coronavirus 2 infection in hematopoietic stem cell transplant recipients in Mexico City.

BACKGROUND: Hematopoietic stem cell transplant (HSCT) recipients are among patients with highest risk of adverse coronavirus disease 2019 (COVID-19) outcomes. OBJECTIVE: We compared clinical outcomes in post-HSCT patients with COVID-19 before and during the Omicron period. STUDY DESIGN: This was a retrospective study including patients post-HSCT with severe acute respiratory syndrome coronavirus 2 infection from April 2020 to March 2023 at Instituto Nacional de Cancerología, Mexico City. We describe their clinical characteristics and report the variables associated with severe clinical disease, hospitalization, and death. RESULTS: Fifty-three patients were included; 31 (58.5%) from the pre-Omicron period and 22 (41.5%) from the Omicron period. Median age was 42-years old (interquartile range 26-53), and 31 patients (59%) were men. Only four patients (16%) had received a vaccine prior to COVID-19 diagnosis in the pre-Omicron period versus 20 (91%) in the Omicron period (p < 0.001). COVID-19 severe cases were more common before Omicron: seven patients (23%) versus two patients (9%). Only one patient (3%) received an antiviral in the pre-Omicron period compared to 11 patients (50%) during the Omicron period (p < 0.01). COVID-19-associated mortality was almost double in the pre-Omicron period (16% vs. 9%, p = 0.6). CONCLUSIONS: This study reports patients with a high proportion of severe outcomes during the first 2 years of the pandemic. Outcomes improved during Omicron with better access to vaccines and antivirals and no in-hospital cases. Variables associated with worse outcomes were similar to other reports. Strengthening infection control measures in the hospital and better access to preventive strategies and therapeutic options are mandatory in these high-risk patients.

Immune Deficiency/Dysregulation Associated Lymphoid Proliferations, EBV+ In Persons Living With HIV.

Background: The 5th edition of the World Health Organization Classification of Hematolymphoid Tumors recently defined immune deficiency/dysregulation (IDD)-associated-lymphoid-proliferations in HIV settings, where information is scarce, often gone under or misdiagnosed. Objectives: To describe the clinical picture, histopathology, and outcomes of IDD-associated-lymphoidproliferations Epstein-Barr virus+ (EBV) in people living with HIV without organ transplantation, antiretroviral therapy (ART) treated. Materials and Methods: HIV+ patients diagnosed with IDD-associated-lymphoid-proliferations seen at an academic medical center in Mexico from 2016 to 2019 were included. Immunohistochemical studies, in situ hybridization, and polymerase chain reaction analysis for EBV and LMP1 gene deletions were performed and correlated with clinical data. Results: We included 27 patients, all men who have sex with men, median age 36 years (interquartile range [IQR] 22-54). The median baseline CD4+ T cells were 113/mL (IQR 89-243), the CD4+/CD8+ ratio was 0.15 (IQR: 0.09-0.22), and the HIV viral load was 184,280 copies/mL (IQR: 76,000-515,707). Twenty patients (74.07%) had IDD-associated-lymphoid-proliferations hyperplasia plasma cell type EBV+, 3 (11.1%) had hyperplasia mononucleosis-like type (IM-type), 1 patient (3.70%) had florid follicular hyperplasia, 3 (11.1%) IDD-associated-lymphoid-proliferations polymorphic type, and there were 22 cases (81.4%) of synchronic Kaposi Sarcoma. Two patients were diagnosed with Hodgkin lymphoma following a second positron emission tomography-computed tomography scan-guided biopsy. The median follow-up was 228 weeks (IQR 50-269); 6 patients died (22.2%) of causes unrelated to IDD-associated-lymphoid-proliferations related. Conclusion: IDD-associated-lymphoid-proliferations EBV+ occured in severely immunosuppressed HIV+ patients, a high percentage of whom had concomitant Kaposi sarcoma. The prognosis was good in patients treated only with ART.

Mortality in patients with hematological malignancies, febrile neutropenia, and septic shock.

INTRODUCTION: Patients with severe neutropenia who develop septic shock (SS) have high mortality. This study aimed to evaluate the risk factors and mortality of SS in patients with HM and febrile neutropenia. METHODOLOGY: We included all patients with hematological malignancies (HM) who presented fever and severe neutropenia, admitted to an oncological tertiary care center in Mexico City for one year. RESULTS: Two hundred ninety-two episodes of fever and severe neutropenia were documented; 68 patients (23.2%) developed SS. Documented clinical infection was different between SS and non-SS patients (94.1% vs. 63.4%, p < 0.001); pneumonia was the most frequent infection (36.8% vs. 23.2%, p = 0.02). Also, in SS vs. non-SS, there were more positive cultures (69.1% vs. 38.4%, p < 0.001), higher frequency of Gram-negative bacteria (89.3% vs. 63.9%, p < 0.001), particularly Escherichia coli (68% vs. 44.2%) and Klebsiella spp. (23.4% vs. 15.1%). There were no differences when multidrug-resistant (MDR) microorganisms were compared. In the multivariate analysis, associated risk factors for SS were: prolonged neutropenia, a documented site of infection, and having received highly myelosuppressive chemotherapy. Risk factors for mortality at 30 days were: older patients, prolonged neutropenia, and SS. CONCLUSIONS: Severe and prolonged neutropenia was associated with SS development and mortality at 30 days. ICU management should be offered to all critically ill patients with HM if long-term survival of the underlying malignancy is expected.

Fungal-associated pneumonia in patients with hematological malignancies.

PURPOSE: Patients with hematologic malignancies (HM) are at high risk of invasive lung fungal infections (ILFI). To describe the main characteristics, treatment, and outcomes for five years in adult patients with HM and fungal pneumonia. METHODS: We conducted a retrospective study at Instituto Nacional de Cancerología (INCan), a referral tertiary care oncology hospital with 135 beds in Mexico City, Mexico. We included all cases of fungal pneumonia in patients with HM from January 1, 2017, to December 31, 2022. Cases were classified as proven, probable, and possible according to EORTC/MSG criteria 2021. RESULTS: Two hundred ten patients were included; the mean age was 40 years. The most frequent HM was acute lymphoblastic leukemia (n=74) and acute myeloid leukemia (n=68). One hundred forty patients (66.7%) had severe neutropenia for a median of 16 days. All patients had a CT thorax scan; in 132 (62.9%), multiple nodules were documented. Serum galactomannan (GM) was positive in 21/192 (10.9%) and bronchoalveolar lavage in 9/36 (25%). Fifty-three patients (25.2%) died in the first month. In the multivariate analysis for mortality in the first 30 days, hypoalbuminemia, shock, possible ILFI, and inappropriate antifungal treatment were statistically associated. CONCLUSIONS: In high-risk HM patients, CT thorax scan and GM help diagnose ILFI. An appropriate antifungal improves mortality.

Impact of COVID-19 pandemic in the care of people living with HIV and cancer at an oncologic center in Mexico.

BACKGROUND: People living with HIV(PLWH) and cancer are among the most vulnerable patients and require constant access to medical services. We compared the characteristics of PLWH and cancer in Mexico, before and during the COVID-19 pandemic. METHODS: Patients admitted 1 year before (pre-pandemic) and 1 year after the start of the pandemic (pandemic) were included. Clinical characteristics, HIV-related variables, and 90-day mortality were compared. Data are described a proportions (N,%) and central tendency measures. A multiple regression model for variables associated with 90-day mortality was performed. RESULTS: Seventy-nine patients were seen in the pre-pandemic period; 92 during the pandemic. Main diagnoses were Kaposi Sarcoma and lymphoma. CD4+ cell count at diagnosis was lower during the pandemic: 81 cells/mm3 vs. 128 cells/mm3, p = .035. CD4+<100 cells/mm3 at first consultation increased from 41% to 58% during the pandemic (p = .041). Only BMI <20 kg/m2 was associated to death (aOR 8.27, 95%CI 1.74-39.25) (p = .008). The pandemic period was not associated with a higher 90-day mortality. CONCLUSIONS: PLWH and cancer presented to care with advanced disease overall. This was more pronounced during the pandemic period. Mortality was associated with AIDS-related variables regardless of study period. This underscores the need for strategies to maintain in-person access to health-care services for PLWH.

Impact of valganciclovir therapy on severe IRIS-Kaposi Sarcoma mortality: An open-label, parallel, randomized controlled trial.

INTRODUCTION: High HHV-8 viral load (VL) in Kaposi Sarcoma (KS) has been associated with Severe Immune Reconstitution Inflammatory Syndrome (Severe-IRIS-KS), which can occur after initiating cART, and leads to high mortality, particularly in patients with pulmonary involvement. We investigate if valganciclovir (as an anti-HHV-8 agent) initiated before cART reduces the mortality associated with Severe-IRIS-KS and the incidence of Severe-IRIS-KS. METHODS: Open-label parallel-group randomized clinical trial in AIDS cART naïve patients with disseminated KS (DKS) as defined by at least two of the following: pulmonary, lymph-node, or gastrointestinal involvement, lymphedema, or ≥30 skin lesions. In the experimental group (EG), patients received valganciclovir 900 mg BID four weeks before cART and continued until week 48; in the control group (CG), cART was initiated on week 0. Non-severe-IRIS-KS was defined as: an increase in the number of lesions plus a decrease of ≥one log10 HIV-VL, or an increase of ≥50cells/mm3 or ≥2-fold in baseline CD4+cells. Severe-IRIS-KS was defined as abrupt clinical worsening of KS lesions and/or fever after ruling out another infection following cART initiation, and at least three of the following: thrombocytopenia, anemia, hyponatremia, or hypoalbuminemia. RESULTS: 40 patients were randomized and 37 completed the study. In the ITT analysis, at 48 weeks, total mortality was the same in both groups (3/20), severe-IRIS-KS attributable mortality was 0/20 in the EG, compared with 3/20 in the CG (p = 0.09), similar to the per-protocol analysis: 0/18 in the EG, and 3/19 in the control group (p = 0.09). The crude incidence rate of severe-IRIS-KS was four patients developed a total of 12 episodes of Severe-IRIS-KS in the CG and two patients developed one episode each in the EG. Mortality in patients with pulmonary KS was nil in the EG (0/5) compared with 3/4 in the CG (P = 0.048). No difference was found between groups in the number of non-S-IRIS-KS events. Among survivors at week 48, 82% achieved >80% remission. CONCLUSIONS: Although mortality attributable to KS was lower in the EG the difference was not statistically significant.

Cellulitis in patients with chronic lower-limb lymphedema due to HIV-related Kaposi sarcoma.

OBJECTIVE: Chronic Lower Limb Lymphedema (CL-LL) secondary to Kaposi sarcoma (KS) has not been recognized as a risk factor for cellulitis. The aim was to describe the clinical spectrum and use of antimicrobial prophylaxis in patients with cellulitis and CL-LL due to KS. METHODS: HIV patients with KS, CL-LL, and at least one episode of cellulitis seen at the AIDS Cancer Clinic at INCan in Mexico from 2004 to 2019 were included. Demographic and clinical data were obtained from medical records. RESULTS: Thirty-nine men all with CL-LL were included. Clinical factors associated with cellulitis were groin and/or lymph-node KS infiltration (69.2%), onychomycosis and/or tinea pedis (44.7%), ulcerated lesions (38.4%), and obesity (2.5%). Eighteen (46.1%) were hospitalized in the first episode and eight (20.5%) in recurrence. Six (25.3%) died, two of toxic shock syndrome (TSS), and one of septic shock. Fourteen (35.8%) had at least one recurrent episode of cellulitis. Twenty-five (64.1%) received prophylaxis. Patients without prophylaxis had significantly more unfavorable outcomes (hospitalization and recurrences) than those with prophylaxis. CONCLUSIONS: CL-LL due to KS is a risk factor for cellulitis and severe complications in patients with a long life expectancy. Antimicrobial prophylaxis needs to be explored as it could prevent complications.

Valganciclovir as Add-On Therapy Modifies the Frequency of NK and NKT Cell Subpopulations in Disseminated Kaposi Sarcoma Patients.

Human herpesvirus-8 infection (HHV-8) is the causative agent of Kaposi sarcoma (KS) and is highly prevalent among people living with HIV (KS/HIV). It has been reported that valganciclovir (VGC) reduces HHV-8 replication in KS/HIV patients. However, currently it is unclear if VGC modifies the frequency and induces changes in markers of immune regulation of immune cells necessary to eliminate HHV8-infected cells, such as Natural Killer (NK) and NK T cells (NKT). This study evaluated the effect of VGC used as antiviral HHV8 therapy in KS patients on the frequency of NK and NKT subpopulations based on the CD27 and CD57 expression, and the immunosenescence markers, PD-1 and KLRG1. Twenty KS/HIV patients were followed-up at baseline (W0), 4 (W4), and 12 weeks (W12) of the study protocol. Among them, 10 patients received a conventional treatment scheme (CT), solely antiretroviral therapy (ART), and 10 patients received a modified treatment regime (MT), including VGC plus ART. In both groups, bleomycin/vincristine was administrated according to the treating physician's decision. The soluble levels of IL-15, PD-L1, PD-L2, and E-cadherin were quantified across the follow-up. Our results showed that the higher IL-15 levels and lower NK frequencies cells in KS/HIV patients reach almost normal values with both treatments regimes at W12. CD27+ NK and NKT cell frequencies increased since W4 on KS/HIV patients with MT. Furthermore, PD-1 expression decreased while KLRG1 increased on NK and NKT subpopulations at W12, and it is accompanied by increased PD-L1 plasma level since W4. Our study highlights the disruption of NK and NKT subpopulations in patients with KS/HIV and explores VGC treatment's contribution to immune reconstitution during the first weeks of treatment.

Clinical characteristics and outcomes in a cohort of oncologic patients with COVID-19 during the first year of the pandemic in Mexico.

BACKGROUND: Literature on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in cancer patients is scarce in Latin America. This population seems to have a higher risk for adverse outcomes. This study aims to correlate clinical characteristics with outcomes in patients with cancer. METHODS: We included all patients with cancer and confirmed SARS-CoV-2 infection from April 19 to December 31, 2020, at the Instituto Nacional de Cancerologia, Mexico. Clinical information was obtained from medical and epidemiological records. For the association between variables and hospitalization, invasive mechanical ventilation (IMV), and mortality, univariate and multivariate logistic regression were performed; odds ratios and 95% confidence intervals were calculated. RESULTS: Four hundred thirty-three patients were included; 268 (62%) were female, the median age was 55 years. One hundred thirty-five (31%), 131 (30%), and 93 (21%) patients had obesity, hypertension, and diabetes mellitus (DM), respectively. Three hundred forty-one (79%) had solid cancer. One hundred seventy (39%) had advanced cancer. Two hundred (46%) patients were hospitalized. Age (p < 0.01), male gender (p = 0.03), hematological malignancies (HM) (p = 0.04) and advanced cancer (p = 0.03) increased the risk for hospital admission. Forty-five (10%) patients required IMV. Age (p = 0.02); DM (p = 0.04); high C-reactive protein (p < 0.01), and lactate dehydrogenase (p = 0.03) were associated with IMV. Mortality within 30 days after diagnosis was 18% (76 cases). Associated characteristics were age (p = 0.04) and low albumin (p < 0.01). CONCLUSIONS: In this study, patients with cancer showed higher mortality, need for hospitalization, and IMV compared with other non-cancer cohorts. We did not find an increased risk in mortality for HM. Although our cohort was younger than others previously reported, age was a strong predictor of adverse outcomes. Variables associated with IMV and death were similar to those previously described in cancer patients with COVID-19.

Successive complications after anterior cervical fixation: pharyngoesophageal diverticulum, fistulization, and cervical spondylitis by Streptococcus milleri - case report and literature review.

INTRODUCTION: Pharyngoesophageal diverticulum is an uncommon complication after anterior cervical discectomy and fusion surgery. CASE PRESENTATION: Our patient was a 48-year-old woman with two previous cervical surgeries with fixation of C4-C5 and C5-C6, the last one in 2003. Two years after surgery, she presented with arthralgia, arthritis, chills, and fluctuating rash. In 2007, she presented with dysphagia, halitosis, and sputum production. She was diagnosed with a pharyngoesophageal diverticulum with a fistula to C6 vertebra and secondary spondylitis. She was taken for open surgery with removal of screws and plates, cricopharyngeal myotomy, and esophageal repair. Streptococcus milleri grew in tissue and osteosynthetic material. She received 4 months of amoxicillin and probenecid and had a complete recovery. Since 1991, 19 similar cases have been reported with one fatality. To our knowledge, this is the first reported case of diverticulum complicated with fistula and secondary spondylitis. CONCLUSIONS: In patients with a history of anterior cervical discectomy and fusion complaining of dysphagia, even years after surgery, it is mandatory to perform an esophagogram. This symptom was referred to in 88% of the cases reported in the literature.

Bloodstream infections in cancer patients. Risk factors associated with mortality.

OBJECTIVE: The aim of this study was to evaluate the clinical characteristics and risk factors associated with mortality in cancer patients with bloodstream infections (BSI), analyzing multidrug resistant bacteria (MDR). METHODS: We conducted a prospective observational study at a cancer referral center from August 2016 to July 2017, which included all BSI. RESULTS: 4220 patients were tested with blood cultures; 496 were included. Mean age was 48 years. In 299 patients with solid tumors, secondary BSI and Central Line-Associated BSI (CLABSI) were the most common (55.9% and 31.8%, respectively). In 197 hematologic patients, primary and mucosal barrier injury (MBI) BSI were the main type (38.6%). Gram-negative were the most frequent bacteria (72.8%), with Escherichia coli occupying the first place (n=210, 42.3%), 48% were Extended-Spectrum Beta-Lactamase (ESBL) producers, and 1.8% were resistant to carbapenems. Mortality at day 30, was 22%, but reached 70% when patients did not receive an appropriate antimicrobial treatment. Multivariate analysis showed that progression or relapse of the oncologic disease, inappropriate antimicrobial treatment, and having resistant bacteria were independently associated with 30-day mortality. CONCLUSIONS: Emergence of MDR bacteria is an important healthcare problem worldwide. Patients with BSI, particularly those patients with MDR bacteria have a higher mortality risk.