Ototoxicity Review: A Growing Number of Non-Platinum-Based Chemo- and Immunotherapies.

OBJECTIVE: To raise awareness of the growing list of non-platinum-based chemo- and immunotherapeutic agents that have been associated with ototoxicity and to introduce the possible mechanism of ototoxicity of these agents. DATA SOURCES: PubMed, Embase, and Web of Science. REVIEW METHODS: A systematic review was performed following the PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-analyses). PubMed, Embase, and Web of Science databases were searched for published reports of ototoxicity from non-platinum-based chemo- and immunotherapeutic agents in adult and pediatric patients. Therapies that utilized any platinum-based agent were excluded. CONCLUSIONS: Ototoxicity from non-platinum-based chemo- and immunotherapies is an evolving problem. There were 54 reports-39 case reports and 15 cohort studies-documenting ototoxicity from 7 agents/combination therapies. Of these reports, 37 (69%) were published within the last 15 years (after 2005). No recovery of hearing was documented in 21 of 56 cases (38%). Pretreatment audiograms were uncommon (19/54 studies, 35%), despite documented ototoxic associations. IMPLICATIONS FOR PRACTICE: There is a growing number of novel, ototoxic, non-platinum-based chemo- and immunotherapeutic agents with various potential mechanisms of action. Otolaryngologists will need to prioritize awareness of these agents. This growing list of agents, many of which have reversible effects, suggest a need for standardized ototoxicity monitor protocols so that appropriate and timely management options can be implemented.

Effects of COVID-19 on telemedicine practice patterns in outpatient otolaryngology.

OBJECTIVE: Otolaryngology is considered high risk for Coronavirus Disease 2019 (COVID-19) exposure and spread. This has led to a transition to telemedicine and directly impacts patient volume, evaluation and management practices. The objective of this study is to determine the impact of COVID-19 on patient characteristics in relation to outpatient attendance, ancillary testing, medical therapy, and surgical decision making. METHODS: A retrospective case series at an academic medical center was performed. Outpatient appointments from October 2019 (pre-COVID) and March 16-April 10, 2020 (COVID) were analyzed. Prevalence rates and odds ratios were used to compare demographics, visit characteristics, ancillary tests, medication prescribing, and surgical decisions between telemedicine and in-person visits, before and during COVID. RESULTS: There was a decrease in scheduled visits during the COVID timeframe, for both in-person and telemedicine visits, with a comparable proportion of no-shows. There was a higher overall percentage of Hispanic/Latino patients who received care during the COVID timeframe (OR = 1.43; 95% CI = 1.07-1.90) in both groups, although primary language was not significantly associated with attendance. There were fewer ancillary tests ordered (OR = 0.54) and more medications prescribed (OR = 1.59) during COVID telemedicine visits compared with pre-COVID in-person visits. CONCLUSION: COVID-19 has rapidly changed the use of telemedicine. Telemedicine can be used as a tool to reach patients with severe disease burden. Continued healthcare reform, expanded access to affordable care, and efficient use of resources is essential both during the current COVID-19 pandemic and beyond. LEVEL OF EVIDENCE: IV.

Unique Challenges for Otolaryngology Patients During the COVID-19 Pandemic.

The coronavirus disease 2019 (COVID-19) pandemic has drastically altered health care delivery and utilization. The field of otolaryngology in particular has faced distinct challenges and an increased risk of transmission as day-to-day procedures involve intimate contact with a highly infectious upper respiratory mucosa. While the difficulties for physicians have been thoroughly discussed, the unique challenges of patients have yet to be considered. In this article, we present challenges for patients of otolaryngology that warrant thoughtful consideration and propose solutions to address these challenges to maintain patient-centered care both during and in the aftermath of the COVID-19 pandemic.

Oropharyngeal hemorrhage in patients with COVID-19: A multi-institutional case series.

BACKGROUND: Patients with COVID-19 who are intubated and require mechanical ventilation have been observed to have oropharyngeal bleeding necessitating otolaryngology intervention. METHODS: We report five cases of oropharyngeal hemorrhage in COVID-19 patients on mechanical ventilation requiring evaluation by otolaryngologists at George Washington University Hospital (GWUH) and Boston Medical Center (BMC) from March to April 2020. Institutional Review Board at both institutions exempted this study from informed consent because there were no identifiable patient characteristics, photographs, or imaging studies included. RESULTS: All five patients were managed conservatively; four required packing with Kerlix gauze by an otolaryngologist. Two patients had the additional requirement of extracorporeal membrane oxygenation (ECMO) and associated anticoagulation. Three patients improved with oropharyngeal packing; two had persistent bleeding. Three patients expired. Endotracheal tubes were repositioned less frequently due to the COVID-19 pandemic. CONCLUSIONS: Intubated patients with COVID-19 may have an increased risk of oropharyngeal hemorrhage. This may be due to anticoagulation, prolonged intubation, or decreased frequency of endotracheal tube repositioning. Otolaryngologists should wear appropriate PPE when managing this hemorrhagic complication.

A new cell line for assessing HIV-1 antibody dependent cellular cytotoxicity against a broad range of variants.

Human immunodeficiency virus type 1 (HIV-1) studies suggest that antibody-dependent cellular cytotoxicity (ADCC) influences both virus acquisition and subsequent disease outcome. Technical issues with currently available assays, however, have limited the ability to comprehensively assess the impact of ADCC on transmission and disease progression. Commonly used ADCC assays use a target cell line, CEM.NKr-CCR5-Luc, that often does not support replication of relevant HIV-1 variants. Thus, the extent of ADCC responses against a large panel of HIV-1 strains often cannot be assessed using the currently available methods. We developed two new reporter cell-lines (MT4-CCR5-Luc and PM1-CCR5-Luc) to overcome these issues. MT4-CCR5-Luc cells are resistant, whereas PM1-CCR5-Luc cells are susceptible, to killing by a natural killer cell line, CD16+KHYG-1, in the absence of antibody. Polyclonal HIVIG gave similar ADCC estimates against HIV-1 isolate, NL4-3, regardless of which of the three cell lines were used as the targets. In contrast to CEM.NKr-CCR5-Luc and PM1-CCR5-Luc, however, MT4-CCR5-Luc target cells produce significantly higher luciferase after exposure to various HIV-1 strains, including transmitted founder variants and viruses incorporating specific envelopes of interest. This higher luciferase expression does not yield spurious results because ADCC estimates are similar when killing is assessed by both reporter protein expression and flow cytometry. Furthermore, ADCC estimates derived from MT4-CCR5-Luc cells are not skewed by non-antibody contents present in human plasma. In aggregate, the MT4-CCR5-Luc cell line can be used to estimate monoclonal antibody or plasma-induced ADCC responses against a diverse range of HIV-1 envelopes relevant for transmission and disease progression studies.

Neutralization and beyond: Antibodies and HIV-1 acquisition.

It is widely accepted that an effective HIV-1 preventative vaccine must elicit antibodies that can block virus acquisition. Although, anti-HIV-1 broadly neutralizing antibodies (bnAbs) have been isolated, unfortunately, no vaccine immunogens have been designed that can elicit these bnAbs in uninfected at-risk individuals. Some studies have suggested that other antibody functionalities, besides neutralization, such as antibody-dependent cellular cytotoxicity (ADCC), may prevent HIV-1 acquisition. In contrast to bnAbs, ADCC-inducing antibodies may be more amenable to elicitation by current vaccine technologies. This review will provide clarity about the role of nAbs and ADCC-inducing antibodies in preventing transmission, highlight mechanisms that potentially explain how ADCC-mediating antibodies may work, and speculate about the generation of these novel protective antibodies. Anti-HIV-1 ADCC-inducing antibodies may provide a new avenue for developing an effective HIV-1 vaccine.

Maternal but Not Infant Anti-HIV-1 Neutralizing Antibody Response Associates with Enhanced Transmission and Infant Morbidity.

A significant number of infants acquire HIV-1 through their infected mother's breast milk, primarily due to limited access to antiretrovirals. Passive immunization with neutralizing antibodies (nAbs) may prevent this transmission. Previous studies, however, have generated conflicting results about the ability of nAbs to halt mother-to-child transmission (MTCT) and their impact on infant outcomes. This study compared plasma neutralizing activity in exposed infants and the infected mothers (n = 63) against heterologous HIV-1 variants and the quasispecies present in the mother. HIV-exposed uninfected infants (HEU) (n = 42), compared to those that eventually acquired infection (n = 21), did not possess higher nAb responses against heterologous envelopes (P = 0.46) or their mothers' variants (P = 0.45). Transmitting compared to nontransmitting mothers, however, had significantly higher plasma neutralizing activity against heterologous envelopes (P = 0.03), although these two groups did not have significant differences in their ability to neutralize autologous strains (P = 0.39). Furthermore, infants born to mothers with greater neutralizing breadth and potency were significantly more likely to have a serious adverse event (P = 0.03). These results imply that preexisting anti-HIV-1 neutralizing activity does not prevent breast milk transmission. Additionally, high maternal neutralizing breadth and potency may adversely influence both the frequency of breast milk transmission and subsequent infant morbidity.IMPORTANCE Passive immunization trials are under way to understand if preexisting antibodies can decrease mother-to-child HIV-1 transmission and improve infant outcomes. We examined the influence of preexisting maternal and infant neutralizing activity on transmission and infant morbidity in a breastfeeding mother-infant cohort. Neutralization was examined against both the exposure strains circulating in the infected mothers and a standardized reference panel previously used to estimate breadth. HIV-exposed uninfected infants did not possess a broader and more potent response against both the exposure and heterologous strains compared to infants that acquired infection. Transmitting, compared to nontransmitting, mothers had significantly higher neutralization breadth and potency but similar responses against autologous variants. Infants born to mothers with higher neutralization responses were more likely to have a serious adverse event. Our results suggest that preexisting antibodies do not protect against breast milk HIV-1 acquisition and may have negative consequences for the baby.

Single genome amplification and standard bulk PCR yield HIV-1 envelope products with similar genotypic and phenotypic characteristics.

Recent studies suggest that single genome amplification (SGA) as compared to standard bulk PCR and virus stocks from 293T transfection versus short term passage in peripheral blood mononuclear cells (PBMC) yield a less biased representation of HIV-1 envelope characteristics. In 9 different subjects, genetic diversity, divergence, and population structure were not significantly different among SGA or bulk PCR amplified envelope V1-V3 segments. In these subjects, 293T transfection derived virus stocks with SGA or bulk PCR amplified envelopes have similar infectivity, replication kinetics, co-receptor usage, and neutralization susceptibility. While PBMC passage as compared to the 293T derived virus stocks had similar co-receptor usage, PBMC viruses were less neutralization susceptible to some specific antibodies. Our results suggest that the method of envelope sequence amplification, either SGA or bulk PCR, does not have a significant impact on the genotypic and phenotypic properties of the virus envelope quasispecies.