Post-acute sequelae of SARS-CoV-2 infection (Long COVID) in older adults

Abstract

Long COVID, also known as PASC (post-acute sequelae of SARS-CoV-2), is a complex infection-associated chronic condition affecting tens of millions of people worldwide. Many aspects of this condition are incompletely understood. Among them is how this condition may manifest itself in older adults and how it might impact the older population. Here, we briefly review the current understanding of PASC in the adult population and examine what is known on its features with aging. Finally, we outline the major gaps and areas for research most germane to older adults.

Introduction

SARS-CoV-2 brings significant health concerns both in terms of acute infections and post-acute sequelae. Although most people appear to make a full recovery from acute COVID-19, many suffer a wide range of health effects that can involve multiple organ systems and incur a range of disabilities to the point that the prolonged sequelae of COVID-19 have been called “a mass disabling event.” Indeed, conservative estimates place the number of people suffering from this syndrome at 65–70 million worldwide. Although grouped together as “Long COVID” or “PASC” (post-acute sequelae of SARS-Co-V2; in the text, we will use the terms “Long COVID” and “PASC” interchangeably), the symptom complex is variable, and the prognosis is largely uncertain. An important step in arriving at an actionable definition of PASC is the recent publication of a framework built from symptoms that were derived from a prospective cohort study [1]. However, this proposed framework groups together patients of all adult ages (> 18 years of age) and does not provide a clear picture of Long COVID in older adults.

Older adults suffered disproportionally from COVID-19 before the advent of vaccination and remained one of the most vulnerable groups throughout the pandemic. Although the prevalence of PASC does not seem to be directly proportional to the significant morbidity and mortality rates seen in older adults, several studies suggested that the risk of developing Long COVID increases with age [2–6]. However, little is known about the incidence of persistent and new clinical sequelae caused by SARS-CoV-2 infection among adults aged ≥ 65 years, and this lack of understanding complicates care. Therefore, the natural course of post-acute sequelae of SARS-CoV-2 infection needs to be precisely defined in older adults.

It should be recognized that there are unique challenges in defining the clinical picture and course of PASC in older adults (Table 1). It is well known that older adults often have an atypical presentation of illness, understood as presenting with a disease state that is missing some of the traditional core features of the illness as usually seen in younger patients [7]. Atypical presentations usually include either an altered presentation of illness, a vague presentation of illness, or non-presentation of illness (i.e., underreporting). Examples include symptoms of dyspnea or confusion rather than crushing chest pain for acute myocardial infarction, or generalized weakness and falls rather than fever and cough for acute pneumonia [8–10]. The reasons for these atypical presentations are unknown, but many hypotheses are offered, including diminished physiologic reserves, or altered autonomic nervous system responses. If what we have learned about clinical presentations in older adults holds true, we have reason to suspect that Long COVID in older adults will also have an atypical picture and may not be captured in our current framework.

Table 1.

The challenges of defining PASC and its prevalence in older adults

Causes	Impact
Altered immunologic responses	-Atypical presenting symptoms
Altered autonomic system responses	-Atypical presenting symptoms
Decreased reserves	-Atypical presenting symptoms
Multimorbidity	-Confounding baseline symptoms
Functional disability	-May be unclear if more than usually impaired
Cognitive disability	-Patient not able to describe symptoms -May be unclear if more than usually impaired
Polypharmacy	-Confounding baseline symptoms
Frailty	-Atypical presenting symptoms
Ageism (external or internalized)	-Denial of the importance of symptoms -Underreporting of symptoms -Assumption that increasing disability is normal for age

In addition, with aging, there is an accumulation of chronic diseases and geriatric syndromes, and these baseline conditions may impact how the older adult experiences or reports symptoms of Long COVID. Approximately 80% of adults over age 65 have at least one chronic condition; 50% have two or more [11]. Over one-fourth of older adults fall each year, and nearly 10% of older adults have Alzheimer’s disease or related dementia [12, 13]. More than half of older adults take four or more prescription medications, as well as over-the-counter drugs. In the setting of comorbidity, functional disability, and cognitive impairment, the recognition, impact, and reporting of typical Long COVID symptoms, such as brain fog and generalized weakness, may be affected [14, 15].

There is also evidence that incidence and prevalence among older adults may be underreported for several reasons [16]. They may not be troubled by symptoms as much as younger people, or they may ascribe their symptoms to one of their other chronic conditions or a medication effect. They may not respond to internet-based surveys or questionnaires. They may not be comfortable reporting some symptoms, such as memory problems or falls, out of concern that clinicians, family, or friends may judge them as vulnerable, and threaten their ability to live independently. The evidence that Long COVID may be more common in older adults but then drops off after age 70 may, therefore, reflect either a true decline in Long COVID with advanced age, a mortality effect, or underreporting [17].

In this review, we explore current literature and highlight key findings to shed light on gaps in our current knowledge and prioritize future areas of research including epidemiology, risk factors, molecular mechanisms and immune picture, clinical signs, and symptoms. We view this as a critical first step in characterizing the impact of PASC in older adults.

Long COVID definition

A significant barrier in our attempt to characterize the impact of PASC in older adults is the fact that empirical, organization-based definitions of Long COVID/PASC vary, sometimes widely, by source, and many are not very specific. For example, the US Department of Health and Human Services classifies Long COVID as “Signs, symptoms, and conditions that continue or develop after initial COVID-19 infection,” whereas the US Centers for the Disease Control and Prevention (CDC) define post-COVID-19 conditions as the umbrella term for the wide range of physical and mental health consequences experienced by some patients that are present four or more weeks after SARS-CoV-2 infection, including by patients who had initial mild or asymptomatic acute infection. Slightly more specific are temporal definitions by the UK National Institute for Health and Clinical Excellence, which distinguishes “Ongoing symptomatic COVID-19” as “Symptoms that are unexplained by an alternative diagnosis and persist for 4 to 12 weeks after acute COVID-19” from the “Post-COVID-19 syndrome,” defined as “Symptoms that are unexplained by an alternative diagnosis and persist for more than 12 weeks after acute COVID-19.” The next level of more specific definitions are those from the World Health Organization, which states “Post-COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis,” and the US National Institutes of Health, which define PASC as “Ongoing, relapsing, or new symptoms or conditions present 30 or more days after SARS-CoV-2 infection” and note that “The definition will be revised in an iterative manner based on existing and new data, medical literature, and feedback from the scientific community.”

The most thorough attempt to define PASC by prospective analysis of reported symptoms relative to a control group in a large RECOVER [1] study identified 37 symptoms that were reported significantly more frequently in the infected relative to the uninfected group and distilled 12 among them that were the most predictive of PASC in the same cohort [1]. The 37 symptoms showed clustering into four main cluster subgroups, with prominent clinical features as follows: loss of or change in smell or taste in cluster 1; gastrointestinal symptoms and dizziness with post-exertional malaise, and fatigue, but no smell or taste changes, in cluster 2; brain fog, post-exertional malaise, and fatigue in cluster 3; and fatigue, post-exertional malaise, dizziness, brain fog, GI symptoms, and palpitations in cluster 4 [1]. These findings are awaiting confirmation in an independent participant cohort.

Our methodology as outlined below reflects our strategy to capture the relevant Long COVID literature despite the lack of a uniform definition.

Methods

To evaluate the state of knowledge about Long COVID among older adults, as compared to younger adults and children, we performed a search for research articles through the NCBI search engine PubMed. We did a combined search for articles containing the term “Elderly” in any field and the MESH term “Post-Acute COVID-19 Syndrome.” Then, we did a combined search for the MESH terms “Post-Acute COVID-19 Syndrome” and “Aged,” followed by a combined search for the MESH term “Aged” and for the term “Long COVID” in any field. We combined the three searches, which together resulted in a non-overlapping list of 889 publications. Finally, we used the standard PubMed filters “Aged: 65 + years” and “Human” to exclude animal studies and to focus on studies in older adults. The timeline for this systematic literature search was through January 31, 2024, although a handful of papers we considered particularly illuminating were included even with later publication dates.

Combining the results of these searches and filters yielded a total of 606 non-overlapping research articles. We hand-triaged those 606 articles using the following criteria: Post-acute COVID-19 syndrome was the topic of the study, not just one of the discussion points; the article contained a discussion about or comparison of Long COVID in older adults to younger adults; and the article did not contain only descriptive information about a case or case series. The hand-triage was conducted by at least two independent evaluators, and articles with 100% agreement on all three criteria were accepted. Articles without 100% agreement for one or more criteria were not included. Additionally, articles with disagreement were marked for further discussion and were accepted or rejected by consensus. Eighty-two articles came through the triage. Fifty-nine of those were primary research articles and constituted the publications we have used to inform our discussions. They are cited where appropriate in the References. Of note, the section “Molecular Underpinnings of PASC and their Changes with Old Age” includes additional original research articles and systematic reviews which are cited where appropriate in the References.

Epidemiology

It is important to note that comparisons in the literature are often based on sparse empirical evidence, frequently acquired in a variety of different settings (hospitals, community, assisted living), typically lacking uniform data quality, and collected using different methodological designs. Therefore, one should view epidemiological evidence critically and interpret it with caution.

With that in mind, the distribution of Long COVID throughout different populations varies greatly among studies (Table 2). For example, some of the data presented supports the public notion that PASC occurs more frequently in older adults. Yet, the mere definition of “older” can vacillate from > 30 to ≥ 75 years depending on the reference [6, 18]. Despite the lack of a unified definition, many studies identify old age as a common association or risk factor for PASC [6, 18–30]. In fact, a recent prospective cohort study reported that older patients were up to five times more likely to develop Long COVID [18]. Curiously, contradictory publications present data to support that older age was not associated with a higher risk or prevalence of PASC [31–36]. For instance, when it comes to the specifics of persistent smell and taste disorders, one study reported the risk to be greater in younger individuals [37]. One problem with several of these studies was not only the definition of PASC, but also the definition of younger and older ages for cohort inclusion. For example, in ref. 37, authors have used a group 49.19 ± 14.68 years old as “younger.” Additionally, a study conducted in a Peruvian senior center found that there was a surprisingly low frequency of PASC at about 4% [33] (Table 2). This is confirmed by the CDC’s Household Pulse Survey on Long COVID (compiled in bi-weekly periods since June 2022) that asked about post-COVID symptoms lasting 3 months or longer, where the incidence of Long COVID declined from 16–20% in 18–59 year olds to 11–15% in 60–69 years old, and to 8–10% in 70–79 and older [38]. Another study used the Behavioral Risk Factor Surveillance System (BRFSS), an annual state-based system of telephone surveys conducted by the Centers for Disease Control and Prevention (CDC), and corroborated higher PASC levels in those younger than 65 years of age [39]. Although the number of papers identified in this review supporting old age as an important association or risk factor seems to outweigh those that do not, there is plenty of uncertainty due to study design, PASC and age definition variability, and other confounders to conclude that further robust and rigorous research is warranted on PASC incidence and prevalence across ages.

Table 2.

A review of Long COVID epidemiology

Ref	Article	Country	Study design	N	Average age in years (SD)	Women, N (%)	% of study participants with one or more PASC-related symptoms
[46]	Shanbehzadeh, S., et al. (2023)	Iran	Cross-sectional	N = 121	70.69 (6.73)	61 (49.6)	72%
[31]	Daitch, V., et al. (2022)	Israel, Switzerland, Spain, Italy	Prospective cohort	N = 2333	51.25 (16.39)	1145 (49.2)	67.2%
[21]	Damiano, R. F., et al. (2023)	Brazil	Prospective cohort	N = 710	55 (14)	343 (48.30)	91%;
[32]	Aydin, S., et al. (2021)	Turkey	Prospective cohort	N = 116	48.90 (17.74)	60 (51.7)	52.5%
[22]	Messin, L., et al. (2021)	France	Retrospective observational	N = 74	52.3 (18)	44 (59.50)	71.62%
[33]	Contreras, P. J., et al. (2022)	Peru	Retrospective observational	N = 113	71.3 (7.2)	79 (69.9)	4.40%
[40]	Zhang, D., et al. (2023)	China	Prospective cohort	N = 207	70.8 (5.7)	158 (76.30)	81.20%
[167]	Haran, J. P., et al. (2021)	USA	Prospective cohort	N = 27	62.6 (12.5)	8 (29.60)	37%
[168]	Aly, M. and H. G. Saber (2021)	Egypt	Retrospective cross-sectional	N = 115	73.18 (6.42)	115 (100%)	77.4%
[34]	Dagher, H., et al. (2023)	USA	Prospective cohort	N = 312	57 (18–86)	181 (58%)	60%
[41]	Bellan, M., et al. (2021)	Italy	Prospective cohort	N = 200	62 (51–71)	78 (39.0)	39.5%
[43]	Lauria, A., et al. (2022)	Italy	Cross-sectional	N = 100	73.4 (6.1)	35 (35%)	83%
[44]	Jiménez-Rodríguez, B. M., et al. (2022)	Spain	Prospective cohort	N = 217	59 (49–68)	101 (46.5%)	73.3%
[26]	Saberian, P., et al. (2022)	Iran	Cross-sectional	N = 447	49.6 (16.0)	189 (42.2%)	77.2%
[35]	Peghin, M., et al. (2021)	Italy	Bidirectional prospective cohort	N = 599	53 (15.8)	320 (53.4%)	40.2%
[28]	Tosato, M., et al. (2021)	Italy	Cross-sectional	N = 165	73.1 (6.2)	63 (38.4%)	83%
[18]	Abu Hamdh, B. and Z. Nazzal (2023)	Palestine	Prospective cohort	N = 669	35. 9 (11.5)	288 (43%)	41.6%
[169]	Guaraldi, G., et al. (2023)	Italy	Cross-sectional	N = 232	58.0 (50.0–67.0)	91 (39.2%)	74.6%
[29]	Ioannou, G. N., et al. (2022)	USA	Retrospective cohort	N = 198,601	60.4 (17.7)	21659 (10.9%)	13.5%
[6]	Cohen, K., et al. (2022)	USA	Retrospective cohort	N = 133,366	76.9 (7.7)	75256 (56.4)	32%

The female sex has been reported to have either a clear positive or a neutral association to PASC. However, the publications reviewed here reported female sex having a strong association with Long COVID or defined female sex as a strong risk factor for Long COVID symptoms [18, 20, 21, 23, 25, 26, 30, 34, 35, 40–45]. These articles outnumbered by 5:1 those showing more neutral data, with no significant correlation between either male or female sex and PASC [32, 33, 46]. Of note, one study that collected data from over 4000 individuals located in the UK, Sweden, and USA found that women were more likely to be affected by PASC than men in all age groups except for those ≥ 70 years [19].

Data regarding Long COVID in specific ethnic and racial groups was also variable. The same CDC Household Pulse Survey found the highest prevalence of PASC in Hispanic/Latino and in non-Hispanic other races of multiple races (17–21% and 17–24% in most surveyed periods) and lower in non-Hispanic Blacks, non-Hispanic Asians, and non-Hispanic Whites (7–15%) [38]. Similar conclusions were reached by another study [47], whereas a third study found a higher prevalence in American Indian or Alaska Natives [39]. A recent paper published in Brazil identified “ethnicity endorsed as brown” as a variable associated with poor cognitive performance in PASC [21]. A study conducted in the USA, on the other hand, found no significant differences in racial and ethnic likelihood to develop PASC [23]. Furthermore, a retrospective cohort study utilizing data derived from the US Department of Veteran Affairs Health Care System found that documented Long COVID care was significantly associated with Black or American Indian/Alaska Native race and Hispanic ethnicity [29]. Overall, most studies suggest increased incidence and prevalence in ethnic Hispanics [38]. The impact of other ethnicities and races needs more research, as do causes for such disparities. It is also important to note that beyond incidence and prevalence, Long COVID has a disproportionate impact on vulnerable populations due to broad disparities, including those determined by race, ethnicity, and socio-economic status [48–54]. How that affects older adults as a vulnerable population, as well as older adults within the above vulnerable populations, remains to be studied.

The incidence of PASC also varies throughout the literature—from as low as about 4% to as high as > 80% [33, 40]. It is important to mention that this incidence seems to vary depending on the type of study conducted. For example, many of the reviewed papers collected their data from chart review and, therefore, relied on the correct documentation and coding for PASC and PASC-related symptoms to calculate the incidence or prevalence. The multitude of reasons an individual may not seek official medical treatment for Long COVID, as described above, could greatly impact the accuracy of conclusions made from mined data due to underreporting.

Risk factors

As outlined in the previous section, female sex has been identified as a common risk factor for PASC, whereas the role of older age is identified in some but challenged in other publications. Many studies suggested that a higher prevalence and number of comorbid conditions put an individual at increased risk [21, 23, 27, 29, 40, 55]. More specifically, a history of chronic kidney or lung disease and diabetes mellitus appeared to increase risk [23–25, 27, 29, 31, 41, 44, 55, 56]. An elevated BMI and smoking history have also been associated with the development of PASC [22, 23, 30, 31, 44]. A more recent study published in 2024 identified the geriatric syndrome of frailty as a risk factor for PASC [57]. Although these findings were replicated in numerous publications, it is important to highlight the fact that they are refuted in several studies as well. For example, a publication did not find any association of Long COVID with age or comorbidities in an Italian study population [35]. Similarly, a French study published the same year presented data in which the relationship between PASC and comorbidities was not statistically significant [22]. Whether and to what extent such differences could be caused by genetic factors or another source of bias is unclear at this time.

Some literature suggests that the severity of acute COVID-19 infection can be an indicator of risk of PASC, including an increased number of symptoms at onset and need for hospitalization or ICU admission linked to higher risk [6, 18, 19, 22, 25, 27, 29, 32, 35, 42, 58]. A few studies even honed in to identify specifically which acute COVID-19 symptoms were associated with PASC—advocating that the most predictive symptom for PASC is fatigue [19, 28, 46]. One might argue that this finding carries little weight in clinical practice, since many individuals who are infected with COVID-19 experience fatigue, and therefore, the data may be biased in favor of identifying this association. Again, despite the seemingly persuasive data in favor of the above risk factors, our review of the literature still identified contradictory studies, with one paper finding that neither severe disease nor hospital admission was associated with PASC [34]. Furthermore, LaVergne et al. published data to suggest that although hospitalized subjects were significantly more likely to develop PASC, there were a reasonable number of individuals who developed PASC despite not being hospitalized (23%) [58], and indeed, PASC was reported with regular frequency among patients with mild or even asymptomatic COVID-19. Therefore, results suggest that there is more to PASC risk than hospitalization alone.

In summary, older age, female sex, increased comorbidities (chronic kidney disease or lung disease), higher BMI, severe acute disease, and hospitalization or ICU admission appear to be identified as common risk factors for the development of PASC. One weakness of all the above studies is that no definition of Long COVID includes a minimum level of symptom severity or functional impairment. Moreover, many studies diverged on symptom duration since the acute infection (4 weeks; 12 weeks; 3, 6, or 12 months). Therefore, someone with a single mild symptom that causes a marginal loss of quality of life contributes as much to estimates of incidence and prevalence as a person with multiple severe symptoms and profound disability.

The protective factors identified through our literature review included higher levels of education and physical activity prior to the acute COVID-19 infection [26, 27]. Probably, the most obvious protective factor was vaccination [18, 29, 42, 45, 57]. In fact, a study by Hammel et al. suggests that the risk of PASC is further decreased by booster doses [57]. However, here, too, the estimates of effect size differ widely. In one study of 669 participants, non-vaccinated individuals were found to be almost seven times more likely to develop PASC [18] up to 90 days post-diagnosis. By contrast, a stringently controlled large prospective study with > 9000 participants also reported a significant effect of vaccination, but of a much more modest magnitude. Specifically, there was a reduction in symptoms from 32% in unvaccinated to 23% in vaccinated, which represents a total of 28.8% reduction [1]. Overall, while new data continues to emerge, further age-appropriate and age-specific research is needed to elucidate the significant risk factors in the older patient population.

Molecular underpinnings of PASC and their changes with old age

Molecular mechanisms of PASC pathogenesis remain incompletely understood and are being intensely studied. Moreover, they are being covered almost continuously in excellent expert reviews [59–68] which reflect the rapidly accumulating knowledge. Much less is known about how any of these mechanisms may be modulated by aging. We will therefore briefly review the main postulated mechanisms and the supporting evidence for their involvement and, where available, discuss the literature on how aging may modulate specific postulated mechanisms of PASC. If direct evidence is not available, then we will discuss how the aging process would be likely to modulate the mechanism in question.

Several broad and interrelated groups of molecular mechanisms have been proposed as pathogenic in PASC. Based on the preponderance of current evidence, we will discuss three such groups (Fig. 1) and will briefly mention some others, with an intention to be more discriminative than comprehensive. The three groups encompass (i) virus-related mechanisms, (ii) immune/inflammatory-related mechanisms, and (iii) coagulation/endothelial disturbances. Several other mechanisms, including protein misfolding and gut dysbiosis [62, 63, 69], have been proposed and could play a modulatory or causal role in all or in subsets of PASC patients. None of the above mechanisms, however, has reached the point of the identified “smoking gun,” where a given mechanism can be considered proven and its involvement in PASC causal. Moreover, none of the major groups of mechanisms needs to be mutually exclusive and it is possible, if not likely, that at least some would be operating simultaneously and even interact with, and potentiate, one another (Fig. 1). This likely underlies the myriad of distinct PASC clinical phenotypes, depending on the interplay of different mechanisms with one another, as well as with the genetic and epigenetic/environmental characteristics of the host. Another issue worthy of consideration is how the SARS-CoV-2 variant infection interacts with PASC development and mechanisms overall, or specifically in older adults, and here again, at the present, we have no rigorous research.

Fig. 1.

Key pathogenesis mechanisms potentially driving PASC supported by studies performed to date (03/2024). The most likely primary drivers of PASC include virus-driven mechanisms and immunoinflammatory and endothelial dysfunction mechanisms. As represented in the diagram, interactions between all three, including potential potentiation and synergy, are not only possible but very likely. See text for details

Virus-related mechanisms

Prolonged viral replication would likely produce prolonged and potentially damaging immune responses. In a similar manner, prolonged persistence of viral components, without viral replication, could sustain damaging immune responses. So far, evidence for prolonged virus replication remains unconvincing [64, 70, 71]. Replication-competent virus has been isolated from autopsies of people dying from acute COVID-19 [72, 73], but in immunocompetent persons, replicating viruses have not been isolated past 14 days of infection [64, 70, 71]. Stronger evidence, however, supports the prolonged presence of SARS-CoV-2 spike (S) and nucleocapsid (N) proteins in plasma/serum of 30–80% of PASC patients from additional cohorts [74, 75], and data have been presented based on a limited number of patients that viral mRNA can be detected in the gut cells as long as > 600 days post-acute infection [76]. It remains unclear whether this presence is more strongly correlated to PASC than to full recovery, and it is unclear whether and to what extent this may correlate to higher initial viral loads, where the best proxy would be PCR cycles where the virus was detected. One limitation of these studies is that they were all performed in plasma, and therefore, persistent virus or its particles potentially present in tissues were beyond detection.

Neither the replicating virus nor persisting viral component hypotheses were specifically tested in older adults, and so far, the existing studies have not reported increased incidence of either in the older population [64, 71, 73–75]. This is despite the fact that with aging, there is a decline in both innate and adaptive virus clearance mechanisms, which would be expected to prolong virus and/or viral molecule persistence. Ongoing intervention trials using different antiviral treatments should be informative in that regard, provided that such trials enroll sufficient numbers of older adults. The virus could also induce senescence [77–80], and this virus-induced senescence could dysregulate tissue homeostasis and organ function in a variety of ways [81–84]. Many questions remain to be answered about this mechanism, including whether it operates via increased inflammation or via direct viral pathogenesis and whether this occurs in older adults with PASC more often than in younger groups.

Most, if not all, acute infections, including SARS-CoV-2, also lead to the reactivation of persistent microbial pathogens, including persistent herpesviruses such as Epstein-Barr virus (EBV), HHV-6, and cytomegalovirus (CMV) [64, 85, 86]. The intensity of this reactivation correlates with the severity of SARS-CoV-2 infection, potentially contributing to poor prognosis. These viruses have been associated with poor prognosis of acute COVID-19. However, perhaps surprisingly, they have differed in their association with PASC, whereby EBV positivity predicted higher, and CMV positivity predicted lower incidence of PASC [86], findings that require both validation in larger cohorts as well as proper mechanistic explanations. With regard to older adults, it may be worthwhile to note that, unlike many other immune responses to acute infections, anti-CMV responses are both lasting and robust even in late life [87]. Finally, reactivation of HHV-6 has been suggested as a potential contributor to neurological symptoms and fatigue in Long COVID patients [88].

Immune/inflammatory-related mechanisms

Immune defense-based mechanisms are a pathogenesis group that includes at least three distinct mechanistic entities, which again can and in many people do operate simultaneously: (i) prolonged and dysregulated inflammation; (ii) immunopathology, whereby the mechanisms of effector immunity meant to suppress and clear the virus also damage healthy tissue in a bystander manner (this includes mast cell activation, a syndrome hypothesized to play a role in PASC [69]); and (iii) autoimmunity, whereby virus-derived antigens and/or inflammation drive loss of cell tolerance and initiation of self-aggressive autoimmune reactions. Regarding dysregulated inflammation, Ruffieux et al.[89] studied 215 patients exhibiting various disease severities, and have linked inflammatory, immune, and metabolic profiles at the transition from acute COVID-19 to recovery. These authors found a remarkable correlation between inflammation, immune, and metabolic abnormalities, clustering around C-reactive protein (CRP) as a convenient, sensitive, and robust biomarker to predict recovery trajectories. As they followed these parameters for up to a year, authors found persistent disruption of measured markers over up to 6 months specifically and selectively in the group characterized by high initial inflammation. Confirmation in larger groups of patients will be critical to validate these results. With regard to autoimmunity, extrafollicular formation of autoantibodies which was described in both severe acute COVID-19 [90] and PASC [91] strongly resembles that seen in systemic autoimmune conditions such as lupus and arthritis [90, 91]. This group of mechanisms enjoys strong experimental and clinical support from many smaller studies, where they appear to apply to significant fractions of COVID-19 patients, and the literature describing this has been extensively and recently reviewed [60, 66, 92]. None of these studies was set up to specifically address older adults, and the analysis so far has failed to reveal any specific age-related features regarding inflammatory and immune mechanisms, perhaps surprising considering the known systemic inflammatory dysregulation with aging [87, 93, 94].

One recent, and potentially highly informative study, used machine learning to analyze high-density molecular data to compare cohorts of PASC, COVID-recovered, and control participants [91]. This analysis divided PASC participants into non-inflammatory (Ni) and inflammatory (Infl) phenotypes, according to elevation of cytokines, autoantibodies, and signaling marker intermediates. Three findings of this study are notable. First, until deep machine learning was applied, many of the patterns were not clearly distinguishable between the groups, and only unbiased clustering revealed that there were two subgroups within the Long COVID population itself, as assessed by inflammatory markers—one with clearly elevated inflammation (InflPASC), and the other with inflammatory markers indistinguishable not only from COVID-19-recovered, but also from COVID-19-negative population (non-inflammatory, or NiPASC) [91]. Second, while some of the parameters used to define InflPASC were clearly and significantly elevated, InflPASC participants also exhibited an elevation of many other inflammatory markers, but not outside of reference ranges [91]. This suggested that coordinated subtle changes in distinct markers of inflammation and immune reactivity exist in InflPASC, potentially making them good candidates for immunomodulatory and/or anti-inflammatory therapy. Third, the Ni and Infl PASC subtypes did not appreciably differ in some (fatigue, dyspnea) clinical symptoms, but differed significantly for others, including brain fog in NiPASC (threefold more frequent than in InflPASC) and myalgias significantly elevated in InflPASC. An analysis of trajectories of a small subset of Ni and InflPASC participants showed a propensity of most of the InflPASC participants to further increase their immune (autoantibodies) and inflammatory (inflammatory marker levels) abnormalities over time [91]. Overall, the key strength of this study is the unbiased stratification of people with PASC based on deep molecular (proteomic) phenotyping and machine learning; given its small sample size (123 participants, of which 97 had PASC), its key weakness is relatively low power and the need for validation in a larger cohort. Nonetheless, the study suggests that the symptoms of Long COVID may be governed by both pathogenetic mechanisms (some divergent symptoms in Ni vs InflPASC) as well as by genetics, prior organ damage/diseases, and other factors that may mandate some shared disease symptoms.

This study did not note age-specific clustering of either inflammatory or autoimmune phenotypes [91]. With aging, two opposing forces would be expected to modulate immune and inflammatory responses potentially involved in Long COVID. First, autoimmune diseases typically have peak incidence around the middle age, and both the incidence and severity of most autoimmune diseases decline among older adults [87]. That trend would be expected to potentially reduce the intensity of the autoimmune component of the InflPASC phenotype. Second, the secretion of many soluble mediators of inflammation and wound healing is dysregulated with aging, with potential exacerbation of both inflammatory and fibrotic processes [87]. On balance, these age-related changes would be expected to alter Long COVID pathogenesis, and it will be important to measure and diagnose these changes using approaches similar to those from informative studies discussed here [89, 91].

Coagulation/endothelial disturbances

There is an accumulating body of evidence that dysregulation of blood clotting, including the altered biology of vascular endothelial cells, may play a broad role in the aftermath of COVID-19. This includes the formation of both microclots, which may well manifest as various symptoms reported in PASC, as well as by macroclotting events, including mortality from strokes and infarctions, which to date has not been systematically included in the epidemiological and morbidity/mortality registers as a post-COVID-19 statistic. Emerging research underscores the critical involvement of microvascular dysfunction and damage in driving the impact of COVID-19 on various organs, including the heart [95, 96], kidneys [97, 98], lungs [99, 100], and others [101]. Additionally, there is mounting evidence indicating the role of cerebromicrovascular injury and dysfunction in contributing to brain injury associated with SARS-CoV-2 infection and the persistence of neurological symptoms observed in Long COVID patients [102, 103].

Understanding the role of endothelial cells in PASC is crucial due to their susceptibility to SARS-CoV-2 infection [104–108]. These cells, lining the blood vessels, play a pivotal role in vascular function and viral interactions. They express significant amounts of angiotensin-converting enzyme-2 (ACE-2), the primary entry receptor for SARS-CoV-2, which directly infects endothelial cells [109–112]. The infection of endothelial cells coupled with the effects of the spike protein and the resulting inflammation are pivotal in COVID-19 pathogenesis [113]. This cascade induces a thromboinflammatory environment characterized by excessive reactive oxygen species production, endothelial vasodilator dysfunction, altered barrier function and capillary damage, and formation of microthrombi [113, 114]. These effects are observed in both acute and Long COVID cases [115, 116], suggesting their significance in disease progression. The prothrombotic state in the circulatory system induced by SARS-CoV-2 infection increases the risk of thrombotic events, including the formation of cardiac microthrombi [114, 117–120] and strokes [121–123]. Both arterial and venous thromboembolism are prevalent in severe COVID-19 cases [124]. Thromboinflammation may persist for months after infection, potentially resulting in the formation of microclots. Microthrombi, especially in the cerebral circulation, are implicated in Long COVID [125]. The heart also represents a prominent target of PASC, with its involvement likely stemming from factors including myocarditis and the chronic repercussions of microvascular thrombotic angiopathy [126].

COVID-19 exhibits an age-related severity gradient, with older adults experiencing increased disease severity [127]. Older adults also exhibit a higher risk of complications, including chronic neurological and vascular issues associated with PASC [102, 103]. Advancing age is also associated with post-COVID neurocognitive decline [102, 103]. In essence, the increased susceptibility of the aging microcirculation to COVID-19-related impairment can be linked to various critical factors. Aging impairs endothelial function and autoregulatory mechanisms, promotes microvascular rarefaction, exacerbates chronic inflammation, and compromises cellular resilience to oxidative stress [128]. In older adults, age-related comorbidities such as hypertension and diabetes mellitus are prevalent and are recognized to compromise microvascular function [129]. These factors worsen microvascular dysfunction triggered by COVID-19, thereby contributing to enduring neurological impairment and dysfunction in other organs. Understanding microvascular changes is therefore crucial for deciphering the neurological consequences and other manifestations of PASC.

Research on the enduring effects of COVID-19 on the cerebromicrovascular system has gained momentum [130–137], shedding light on the repercussions of endotheliitis and SARS-CoV-2-induced cerebromicrovascular dysfunction and thrombotic events. These consequences likely span a spectrum, including chronic impairment of cerebral blood flow [138, 139], blood–brain barrier (BBB) disruption [140], and perivascular inflammation. Such interconnected events can result in reduced oxygen supply to brain cells, increased thrombogenesis, release of pro-inflammatory factors, neuroinflammation, white matter damage, and disruption of cerebral microvessels’ structural integrity. Cumulatively, these factors may lead to cognitive impairment, heightened vulnerability to neurodegenerative diseases, and various neurological disorders within the spectrum of PASC [140]. Understanding and addressing cerebromicrovascular causes assume significance in mitigating the long-term brain complications associated with Long COVID [65]. Persisting viral and/or viral component presence [64] and systemic inflammation [140–145] observed in PASC may exacerbate these vascular abnormalities, raising concerns about their role in neurological symptoms and cognitive deficits. Endothelial dysfunction [146–148], the disruption of neurovascular coupling [102, 103], and potential capillary rarefaction [101] in PASC further underscore the importance of investigating the role of microvascular dysfunction in neurological manifestations [65]. Persistent microvascular inflammation associated with PASC can disrupt the BBB, leading to neuroinflammation. Alterations in the local renin-angiotensin system and activation of microglia and leukocytes contribute to cerebromicrovascular inflammation and neuroinflammation [102, 103]. Moreover, the emergence of cerebral microhemorrhages and ischemic lesions underscores the multifaceted role of cerebromicrovascular factors in the persistent effects of COVID-19 [102, 103]. Recent findings indicate a sustained rise in white matter hyperintensities, which are considered imaging markers of cerebral small vessel disease, among older individuals who have had COVID-19, indicating the enduring impact of cerebromicrovascular dysfunction in PASC [149–151]. These white matter hyperintensities can significantly affect cognitive function and overall brain health, contributing to the neurocognitive symptoms of PASC. Understanding these mechanisms is crucial for addressing the neurological consequences of SARS-CoV-2 infection comprehensively [65].

Merging studies have highlighted a possible link between COVID-19 and the worsening of Alzheimer’s disease (AD)–related pathologies [152, 153], potentially suggesting an exacerbating role of damage to the cerebromicrovascular system. Notably, individuals with mild cognitive impairment (MCI), considered a precursor to AD, might be especially vulnerable to the adverse impacts of COVID-19 on the progression of AD [102]. Investigations suggest that MCI patients who contract COVID-19 demonstrate an increased likelihood of transitioning to dementia, underscoring the importance of comprehending the complex interplay between these conditions [102].

Recent evidence indicates that persistent capillary rarefaction occurs in individuals with PASC, suggesting a systemic effect of COVID-19 on the microvasculature [101, 154]. Research indicates that COVID-19 can leave lasting effects on capillary density, with evidence of persistent rarefaction even up to 18 months post-infection [154]. However, questions remain regarding the reversibility of this observed damage and the extent to which it may occur over time. Further investigation is needed to determine whether interventions or treatments can mitigate or reverse capillary rarefaction and endothelial dysfunction in individuals with PASC, shedding light on the potential for recovery and improvement in microvascular health following SARS-CoV-2 infection.

Interaction of pathogenetic mechanisms in PASC

There are clear overlaps between the above-proposed main PASC mechanism categories because they also can conceivably fuel and amplify each other. For example, as mentioned, microclots lead to complement activation and fuel inflammation. They also trap fibrin(ogen) which stimulates protein aggregation. Inflammation itself activates endothelial cells, changing their surface properties and increasing the propensity for platelet activation. Therefore, bearing in mind (and analyzing) these mechanistic interactions in both adult and older populations is critical to understand PASC pathogenesis and potential therapies.

Clinical picture

Characterizing the clinical picture of PASC is challenging because of limited data and the highly heterogeneous clinical picture that is described in the literature. In general, fatigue, dyspnea, cognitive changes, and arthralgias/myalgias appear to be the most endorsed symptoms. In the USA, a large cohort study of Medicare beneficiaries over the age of 65 who met WHO criteria for a diagnosis of Long COVID reported, in the order of most common prevalence, the symptoms of dyspnea, fatigue/malaise/weakness, cough, chest pain, and palpitations [155].

While cardiopulmonary symptoms may be the most recognized symptoms associated with PASC, it may be the constellation of other symptoms that ultimately impact older adults the most. For example, neurologic and cognitive changes are described in Long COVID across all age groups, but cognitive impairment may be nearly two-to-three times more likely in older adults [156, 157]. Moreover, the cognitive decline found in older adults post-COVID-19 infection appears to have a greater negative impact on their overall functional status and physical decline [21, 46, 158], with consequent increased progression to frailty [159]. A study from Italy by Ferrara et al. further highlighted the risk of frailty after hospitalization. The authors noted that one out of three older adults over the age of 65 who had been previously hospitalized for COVID-19 had an unfavorable transition in their clinical frailty score in the 6-month post-hospitalization period [160]. Of note, one study published in 2024 linked PASC and liver injury, reporting on persistent liver enzyme elevations and alterations in glucose metabolism [161]. Additionally, another study concluded that malnutrition is highly prevalent in COVID-19 survivors, both of which would greatly impact frailty in this patient population [162].

Pain is commonly reported in older adults with PASC across disparate populations. In a multi-center Spanish study, 45% of older patients who were followed post-hospitalization for COVID-19 reported “pain symptoms,” and those over age 70 were most likely to report that pain symptoms limited their basic and instrumental activities of daily living [163]. About 20% of patients in a large Medicare trial reported chest pain [155], and an Italian cross-sectional study of patients 65 years or older who had been hospitalized with COVID-19 found similar rates of joint pain [28].

Shanbehzadeh et al. followed older Iranian adults over age 60 for 6 months following admission to the hospital for COVID-19 infection. They identified several predictors of physical health post-COVID-19: cognitive-communication problems, difficulties in activities of daily living, worsened pain, decreased level of physical activity, and fatigue. They found that fatigue and increased pain intensity were the strongest factors contributing to declines in quality of life [46].

Changes in taste and smell may also play an important role in the decline experienced by older adults with Long COVID. In one Italian cohort of patients with Long COVID, older age was found to be a predictor of long-term hyposmia, and those over age 75 were three times more likely to report hyposmia than their younger counterparts [164]. In another Italian cohort, loss of appetite and dysgeusia were the fourth and fifth most reported symptoms. The authors also found that Montreal Cognitive Assessment (MoCA) scores, an office test to assess cognitive impairment, were lower in patients with hyposmia, suggesting perhaps that adults with some baseline cognitive deficits were at higher risk of developing long-term olfactory dysfunction [28]. Of note, less than 1% of Long COVID patients in the USA reported loss of taste or smell in the large Medicare population studied [163].

Of the articles reviewed, two-thirds provided data for up to 6 months post-COVID-19 diagnosis in older adults, but there was limited data on clinical presentation and the disease course beyond that timeframe. Interestingly, fatigue, dyspnea, or arthralgias, the most common symptoms, were present up to 14 months post-COVID-19 diagnosis as reported in a minority of papers. There was also no long-term data in older adults to evaluate symptoms that lasted beyond 14 months. One study, Taquet et al., noted the risks of cognitive deficit (brain fog), dementia, psychotic disorders, and epilepsy or seizures were increased at the end of the 2-year follow-up period, but researchers did not investigate the other clinical symptoms [157]. It is also unknown which, if any, symptoms of Long COVID reverse over time in older adults.

In summary, PASC impacts multiple organ systems, including, but not limited to, cardiovascular, respiratory, neuropsychiatric, and renal, in addition to increasing all-cause mortality [165]. The current uncertainty associated with the clinical picture of Long COVID in older adults makes the diagnosis of this condition challenging. This is especially true due to symptom overlap with other common conditions seen in older adults in the outpatient setting. It is likely that a sum of the symptoms endorsed by older adults with Long COVID may lead to longer-term impairments. To allow for early recognition and management and to increase the opportunity to intervene with specialty and rehabilitation services, clinicians are advised to maintain a high index of suspicion for Long COVID in older adults who present with the symptoms described above.

Conclusion

At this point, we can mostly admit that we “know that we don’t know much” about PASC in older adults. Part of the reason for the lack of knowledge is the general limitations in the literature on PASC. These include, but are not limited to, (i) lack of uniform PASC definition (and the resulting heterogeneity of classifications of the syndrome itself); (ii) an often opportunistic, rather than prospective and deliberate, study design, and the often-associated lack of appropriate control groups, particularly the uninfected controls; (iii) underpowering of study group sizes; and (iv) cross-sectional rather than longitudinal design, with its known caveats. Compounding these problems in studies of PASC among older adults are the lack of universally accepted and consistently applied definitions of “older adults,” the failure to structure studies so that older adults and younger adults are compared in meaningful ways, and the lack of deliberate focus on older adults and/or their under-enrollment in the current studies. Needless to say, these problems influenced all three areas we considered in this review.

From the standpoint of epidemiology, because estimates of incidence and prevalence are so conflicting, we still do not have a definitive answer to whether or not age is a risk factor for PASC. Lack of clarity is particularly profound for populations in which age intersects with other characteristics such as race, ethnicity, and gender. Our knowledge of protective factors is particularly scant. While immunization status, education level, and prior physical activity are implicated as protective, other determinants of health including socio-economic status are still understudied.

From the standpoint of the molecular underpinnings of PASC among older adults, hypotheses exist about the role of virus-related mechanisms in full recovery versus the development of PASC; these hypotheses have yet to be tested in older populations. Similarly, while the role of immune/inflammatory-related mechanisms in severe acute COVID-19 and PASC has strong experimental support in many small studies, none of these studies has systematically studied older adults despite the evidence of immunity and inflammatory dysregulation with age. Finally, strong evidence exists about the coagulation/endothelial disturbances associated with COVID-19 pathogenesis, but the relationship of these to aging-related cardiovascular and neurological changes has yet to be studied extensively.

As for the clinical picture, the symptoms of PASC have not been clearly described particularly among older adults with multiple comorbidities. To some degree, the research has been hampered by what is probably underreporting given the issue of atypical presentations and failure to document symptom clusters of relevance to older versus younger adults. In addition, however, there has not been much attention given to systematic investigations that measure age-specific variables like frailty, cognitive status, functional abilities, and other geriatric syndromes. For example, frailty predicted mortality of acute COVID-19 even better than age itself, suggesting a bidirectional relationship between frailty and SARS-CoV-2 pathogenesis [166]. As a result, clinicians are left with very little direction for making accurate diagnoses and creating appropriate treatment plans.

In conclusion, this review indicates that while age has been implicated as an important contributor to PASC, our knowledge base is still quite nascent. On the one hand, this is a problem. On the other hand, it is an opportunity to concentrate attention on building the knowledge base by using consistent definitions, asking age-specific questions, and designing research studies that fully describe the course of the disease over time, use appropriate control groups, and account for the age-relevant variables that are common among older adults. In short, we believe that we urgently need studies specifically interrogating PASC in older adults from many angles and directions.

Abbreviations

AD

Alzheimer’s disease

CMV

Cytomegalovirus

CRP

C-reactive protein

EBV

Epstein-Barr virus

ICU

Intensive care unit

MCI

Mild cognitive impairment

PASC

Post-acute sequelae of SARS-CoV-2

SARS-CoV-2

Severe acute respiratory syndrome coronavirus 2

Funding

Supported by US Public Health Awards OT2HL161847 (NHLBI) and R37AG020719 (NIA) from the National Institutes of Health to J.Ž.N. and R25 AG076387 (NIA) to L.P. and M.J.F., and the Hart (M.J.F.) and Bowman (J.Ž.N.) endowments.

Declarations

Competing interests

The authors declare no competing interests.