Evolving Phenotypes of non-hospitalized Patients that Indicate Long Covid

Abstract

Many of the symptoms characterized as the post-acute sequelae of SARS-CoV-2 infection (PASC) could have multiple causes or similarly seen in non-COVID patients. An accurate identification of phenotypes will be important to guide future research and the healthcare system to focus its efforts and resources on adequately controlled age- and gender-specific sequelae of COVID-19 infection. This retrospective electronic health records (EHR) cohort study, we applied a computational framework for knowledge discovery from clinical data, MLHO, to identify phenotypes that positively associate with a past positive PCR test for COVID-19. We evaluated the post-test phenotypes in two temporal windows at 3-6 and 6-9 months after the test and by age and gender. We utilized longitudinal diagnosis records stored in EHRs from Mass General Brigham (MGB) 57 thousand patients who tested positive or negative for COVID-19 and were not hospitalized. Statistical analyses were performed on data from March 2020 to March 2021. PCR test results and subsequent diagnosis records that were recorded for the first time two months or later after the PCR test. We identified 28 phenotypes among different age/gender cohorts or time windows that positively associated with a past SARS-CoV-2 infection. All identified phenotypes were newly recorded in patients’ medical records two months or longer after a COVID-19 PCR test in non-hospitalized patients regardless of the test result. Among these phenotypes, a new diagnosis record for anosmia and dysgeusia (OR 2.17, 95% CI [1.42 - 3.25]), alopecia (OR 3.54, 95% CI [2.92 - 4.3]), chest pain (OR 1.35, 95% CI [1.16 - 1.56]), or chronic fatigue syndrome (OR 1.81-2.28, 95% CI [1.38 - 3.68]) are the most significant indicators of a past COVID-19 infection, especially among women younger than 65. Among men, edema (OR 1.83, 95% CI [1.23 - 2.66]) and disease of nail (OR 3.54, 95% CI [1.63 - 7.29]) in patients 65 and older or proteinuria (OR 2.66, 95% CI [1.61 - 4.34]) in patients under 65 are associated with a positive COVID-19 PCR test in the past few months. Our approach avoids a flood of false positive discoveries, while offering a more probabilistic flexible criterion than the standard linear phenome-wide association study (PheWAS). These findings suggest that some of the previously identified post sequelae of COVID-19 may not be accurate and that most of the PASC are observed in patients under 65 years of age.

Mid and long-term neurological and neuropsychiatric manifestations of post-COVID-19 syndrome: A meta-analysis

“…Limited data prevented calculation of uncertainties associated with the prevalence of mid to long-term symptoms however it is likely that: (1) inconsistent definitions of ‘cognitive dysfunction’ augmented findings at both time points (Supplemental Table 2) (2) prevalence of symptoms common in the community even in the absence of COVID-19 (headache and fatigue) are likely overestimated, especially long-term. Still, large retrospective cohort studies that followed patients from mid to long-term confirm similar trends in the neuropsychiatric and neurological symptoms herein reported [ 10 , 33 ].…”

“…Notably, in our sample of patients, symptoms such as anxiety, depression, brain fog, fatigue and insomnia increased in frequency from mid- to long-term follow up, which may indicate that these symptoms are more likely to develop than persist post-infection ( Fig. 3 ) [ 10 , 33 ]. Limited data prevented calculation of uncertainties associated with the prevalence of mid to long-term symptoms however it is likely that: (1) inconsistent definitions of ‘cognitive dysfunction’ augmented findings at both time points (Supplemental Table 2) (2) prevalence of symptoms common in the community even in the absence of COVID-19 (headache and fatigue) are likely overestimated, especially long-term.…”

“…This may be due to patients with COVID-19 in the community generally being younger than those in hospitals [ 39 ]. A retrospective analysis of 57,000 non-hospitalised patients identified higher prevalence rates for chronic fatigue syndrome, malaise, and fatigue in patients under 65 years old than in all patients collectively [ 33 ]. Recall bias and the lack of objective metrics to assess symptoms also likely augment reporting in the community setting [ 40 ].…”

Taste Dysfunction and Long COVID-19

“…Emerging concerns include complaints of persistent symptoms for extended periods in recovered individuals. Cellular damage due to disease and/or treatment, prolonged viral shedding, chronic immune inflammatory response, and pro-coagulant state induced by SARS-CoV-2 infection are suggested mechanisms contributing to the symptom sequelae (Estiri et al, 2021;Tran et al, 2021).…”

Can Salivary Innate Immune Molecules Provide Clue on Taste Dysfunction in COVID-19?

“…While most individuals with symptomatic illness recover completely by 4 weeks, a significant proportion of individuals experience long-term symptoms ( Centre for disease control and prevention, 2021 ). Fatigue, headaches, difficulties in concentrating/mental fog, change/loss of taste, change/loss of smell, sleep disorders, and dyspnea constitute the most frequent symptoms in long COVID-19 ( Estiri et al, 2021 ). The SARS-CoV2 virus encodes four major structural proteins, including the spike protein, the membrane protein, the envelope protein, and the nucleocapsid protein.…”