Innovations in diagnosis for lymphadenopathy across HIV Centers of Excellence in Malawi

ABSTRACT In SSA, deaths occur in 5-10% of PLWH during the first year after initiating antiretroviral therapy (ART) and causes for these early deaths are not well elucidated in most patients. Many patients present with lymphadenopathy and are empirically treated for tuberculosis (TB), even when TB testing is negative, and

may have undiagnosed lymphoproliferative disorders (LPDs). Access to lymph node biopsy and high-quality pathologic evaluation are limited and often lead to missed or delayed diagnosis which may contribute to early preventable deaths after ART initiation. The barriers to pathologic diagnosis of lymphadenopathy in Malawi

have not been extensively studied. LPDs, including lymphomas and multicentric Castleman disease (MCD) are a common causes of lymphadenopathy in PLWH, but are likely delayed and/or underdiagnosed. In the KCH Lymphoma Study, we have enrolled all patients with newly diagnosed LPDs since 2013; 123/245 (50%)

PLWH with lymphoma and 19/35 (54%) with MCD are from Lilongwe district which makes up only 10% of the catchment area. Given this marked overrepresentation of participants from Lilongwe, we hypothesize that there many undiagnosed LPDs, though a gap exists in understanding the burden of LPDs in this population.

Critically, when diagnosed appropriately, LPDs are treatable and curable in SSA. To overcome barriers to diagnosis, innovative and rapid diagnostic technologies are urgently needed to improve the speed and accuracy of LPD diagnoses at the point of care. There a number of methods for EBV and KSHV measurement including traditional PCR and a point of care device known as TINY. TINY is a loop-mediated

isothermal amplification (LAMP)-based device that allows amplification and quantification of DNA at point-of- care with operability even in settings where electricity is not available. Our collaborators have shown that TINY is sensitive and specific for diagnosing Kaposi sarcoma from skin biopsies and can potentially

diagnose Burkitt lymphoma using EBV measurement though its utility at point of care for LPDs has not been studied. This proposal addresses current gaps in knowledge by 1) assessing multifactorial causes of diagnostic delay for LPDs in Malawi, 2) comprehensively describing clinical characteristics and diagnoses in

PLWH presenting with lymphadenopathy from HIV clinics, and 3) assessing utility of EBV and KSHV measurement from FNA and blood for expedited diagnosis using standard PCR as well as TINY. In summary, this proposal will open a research focus that is distinct from my previous work as it will be my first

time studying diagnostics and implementation science and the first time working in peripheral health centers. This multidimensional proposal will build towards my long-term goal of improving outcomes for PLWH and LPDs by providing critical information about prevalence of undiagnosed LPDs, key implementation

challenges toward accurate and timely LPD diagnosis, and innovative diagnostic methods to overcome these challenges.