Designing and optimizing clinical trials for long COVID.

Long COVID is a debilitating, multisystemic illness following a SARS-CoV-2 infection whose duration may be indefinite. Over four years into the pandemic, little knowledge has been generated from clinical trials. We analyzed the information available on ClinicalTrials.gov, and found that the rigor and focus of trials vary widely, and that the majority test non-pharmacological interventions with insufficient evidence. We highlight promising trials underway, and encourage the proliferation of clinical trials for treating Long COVID and other infection-associated chronic conditions and illnesses (IACCIs). We recommend several guidelines for Long COVID trials: First, pharmaceutical trials with potentially curative, primary interventions should be prioritized, and both drug repurposing and new drug development should be pursued. Second, study designs should be both rigorous and accessible, e.g., triple-blinded randomized trials that can be conducted remotely, without participants needing to leave their homes. Third, studies should have multiple illness comparator cohorts for IACCIs such as myalgic encephalomyelitis (ME/CFS) and dysautonomia, and screen for the full spectrum of symptomatology and pathologies of these illnesses. Fourth, studies should consider inclusion/exclusion criteria with an eye towards equity and breadth of representation, including participants of all races, ethnicities, and genders most impacted by COVID-19, and including all levels of illness severity. Fifth, involving patient-researchers in all aspects of studies brings immensely valuable perspectives that will increase the impact of trials. We also encourage the development of efficient clinical trial designs including methods to study several therapies in parallel.

Female reproductive health impacts of Long COVID and associated illnesses including ME/CFS, POTS, and connective tissue disorders: a literature review.

Long COVID disproportionately affects premenopausal women, but relatively few studies have examined Long COVID's impact on female reproductive health. We conduct a review of the literature documenting the female reproductive health impacts of Long COVID which may include disruptions to the menstrual cycle, gonadal function, ovarian sufficiency, menopause, and fertility, as well as symptom exacerbation around menstruation. Given limited research, we also review the reproductive health impacts of overlapping and associated illnesses including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), postural orthostatic tachycardia syndrome (POTS), connective tissue disorders like Ehlers-Danlos syndrome (EDS), and endometriosis, as these illnesses may help to elucidate reproductive health conditions in Long COVID. These associated illnesses, whose patients are 70%-80% women, have increased rates of dysmenorrhea, amenorrhea, oligomenorrhea, dyspareunia, endometriosis, infertility, vulvodynia, intermenstrual bleeding, ovarian cysts, uterine fibroids and bleeding, pelvic congestion syndrome, gynecological surgeries, and adverse pregnancy complications such as preeclampsia, maternal mortality, and premature birth. Additionally, in Long COVID and associated illnesses, symptoms can be impacted by the menstrual cycle, pregnancy, and menopause. We propose priorities for future research and reproductive healthcare in Long COVID based on a review of the literature. These include screening Long COVID patients for comorbid and associated conditions; studying the impacts of the menstrual cycle, pregnancy, and menopause on symptoms and illness progression; uncovering the role of sex differences and sex hormones in Long COVID and associated illnesses; and addressing historical research and healthcare inequities that have contributed to detrimental knowledge gaps for this patient population.