Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can result in a prolonged multisystem disorder termed long COVID, which may affect up to 10% of people following coronavirus disease 2019 (COVID-19). It is currently unclear why certain individuals do not fully recover following SARS-CoV-2 infection. Summary: In this review, we examine immunological mechanisms that may underpin the pathophysiology of long COVID. These mechanisms include an inappropriate immune response to acute SARS-CoV-2 infection, immune cell exhaustion, immune cell metabolic reprogramming, a persistent SARS-CoV-2 reservoir, reactivation of other viruses, inflammatory responses impacting the central nervous system, autoimmunity, microbiome dysbiosis, and dietary factors. Key Messages: Unfortunately, the currently available diagnostic and treatment options for long COVID are inadequate, and more clinical trials are needed that match experimental interventions to underlying immunological mechanisms.

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to a broad spectrum of manifestations ranging from asymptomatic infection to fatal coronavirus disease 2019 (COVID-19), which has evolved as new variants emerge combined with immunity due to vaccination and infection [1, 2]. Following acute infection, a sizeable proportion of individuals experience prolonged symptoms that can significantly impact daily function, quality of life and cause disability. Long COVID is sometimes referred to as “post-acute sequelae of COVID-19 (PASC) or post-COVID condition (PCC).” Long COVID is a multisystemic disease with symptoms including fatigue, post-exertional malaise, joint and muscle pain, and sleep disturbance. In addition, system-specific manifestations such as cardiopulmonary, neurocognitive, or gastrointestinal symptoms, as well as neuropsychiatric symptoms including anxiety and depression can occur [3]. Long COVID remains a clinical diagnosis where onset of symptoms occurs within 3 months of SARS-CoV-2 infection and requires symptoms to persist for at least 2 months in the absence of an alternative diagnosis. Although the exact pathomechanism of long COVID onset remains elusive, some of the symptoms are associated with organ damage sustained during acute COVID-19, while others can be linked to the development of post-infectious conditions, such as fatigue. Multisystem involvement in individual patients is common, with one study reporting the median number of symptoms reported at any given time to be eight [4]. The most common symptoms reported in this cohort were fatigue, post-exertional malaise, palpitations, chest pain, stomach upset/nausea, memory problems, muscle pain, and joint pain. Symptoms may only occur following initial recovery from an acute COVID-19 episode or persist from the initial illness and may also fluctuate or relapse over time [5].

The exact number of people currently suffering from long COVID is unclear but based on a conservative estimated incidence of 10% of infected people (over 651 million documented COVID-19 cases worldwide), at least 65 million individuals around the world may have long COVID [6]. However, this number may be much higher given the many undocumented cases of COVID-19 and asymptomatic SARS-CoV-2 infections. Long COVID has been described in all age groups and importantly the majority of cases are in patients who had a mild acute illness that did not require hospitalization [7]. A recent cohort study suggests that a significant proportion of individuals who experience long COVID symptoms following mild SARS-CoV2 infection will recover within the first year [8]. Why some patients recover while in others the illness persists is unclear.

In this review, we discuss the potential mechanisms underpinning the pathophysiology of long COVID, in particular mechanisms involving the immune system (Fig. 1). These mechanisms are thought to include an inappropriate immune response to acute SARS-CoV-2 infection, immune cell metabolic reprogramming, a persistent SARS-CoV-2 reservoir, an effect of reactivation of other viruses such as Epstein-Barr virus (EBV), inflammatory responses impacting the central nervous system (CNS), autoimmunity (including effects on the autonomic nervous system), coagulopathy, and microbiome dysbiosis [9, 10]. Given the breadth of symptoms described by long COVID patients, it is possible that distinct or a combination of multiple immune mechanisms are relevant for specific patient subgroups.

Fig. 1.

Immune mechanisms potentially impacting long COVID symptoms.

Fig. 1.

Immune mechanisms potentially impacting long COVID symptoms.

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Immune responses to SARS-CoV-2 infection during the acute and recovery stages have been shown to be associated with risk of long COVID. Levels of circulating immune mediators and biomarkers, such as cortisol, serotonin, IL-8, CCL4, IL-4, and thymic stromal lymphopoietin remain altered in long COVID patients compared to control volunteers for several months following acute infection [11‒13]. In addition to autoimmunity and hyperinflammation, which are more fully discussed elsewhere [9, 14], an inadequate immune response or immune dysfunction might predispose to, or associate with, long COVID. Specific peripheral blood cell (PBMC) subsets have been shown to be decreased, or absent, in patients, including effects on CD127lowCD8+ cells, CD4+ cells, and B cells [15]. Elevated expression of the exhaustion markers programmed cell death protein 1 (PD1) and T-cell immunoglobulin and mucin-domain containing-3 (TIM3) has been noted in several studies [11, 16] suggesting that T-cell exhaustion could contribute to symptomology, although studies demonstrating causal effects of loss of T-cell function are still lacking.

It is hypothesized, that in a subset of Long COVID patients, inadequate immune activation during the acute phase of SARS-CoV-2 infection may contribute to the development of disease. At an early stage of the pandemic, a specific antibody signature characterized by either low IgM or low IgG3 was associated with an enhanced risk for long COVID [17]. Moreover, patients with gastrointestinal symptoms were reported to have altered virus-specific CD8+ T cells dynamics [18]. However, less is known about the innate immune response, which acts as a first-line defense to prevent viral invasion or replication. Differences in monocyte and dendritic cell subsets, including downregulated expression of the PD1 ligand (PDL1) on antigen-presenting cells, were observed at 6 months after infection [19]. One relevant innate pattern recognition receptor is mannose-binding lectin (MBL) [20] that binds and opsonizes the S and N proteins of SARS-CoV-2 [21], highlighting its important role in neutralization of SARS-CoV-2 [22]. Genetically predetermined low levels of MBL were associated with a higher risk of SARS-CoV-2 infection [20]. Importantly, a higher prevalence of MBL deficiency was reported for long COVID patients with persistent severe fatigue and post-exertional malaise (PEM) [23], which is similar to symptoms experienced by myalgic encephalomyelitis/chronic fatigue syndrome patients after EBV infection [24]. Low MBL levels were associated with high levels of several cytokines, including interleukin 6 (IL-6) and tumor necrosis factor alpha. MBL can directly reduce IL-6 and tumor necrosis factor alpha production, suggesting it is a potent regulator of the inflammatory response and may affect the severity of acute infectious diseases [25‒28]. Many studies highlighted the role of IL-6 during acute COVID-19 disease [9, 29]. High levels of IL-6 were associated with the most severe form of the disease and worse prognosis. Low MBL levels could potentially contribute to dysregulated over-production of IL-6 in patients with severe COVID-19, thereby contributing to an inadequate antiviral response, viral persistence, and long-term inflammation.

Neutrophils have been shown to play an important role in protecting against SARS-CoV-2 infection due to generation of neutrophil extracellular traps (NETs) and the production of type 1 interferons (IFNs) [30]. However, an excess of neutrophil infiltration and NET formation within the lungs may contribute to tissue injury and COVID-19 disease severity [31]. In addition, emerging evidence is linking the persistence of NETs to pulmonary fibrosis, cardiovascular abnormalities, and neurological dysfunction in long COVID [32]. NETosis was shown to persist at a greater level in long COVID patients compared to convalescent recovering patients [33]. It’s unclear what might be driving sustained activation of short-lived neutrophils in Long COVID patients, but potential mechanisms could include alterations in effector phenotypes of long-lived cells, microenvironmental changes in the bone marrow, persistent senescent cells, viral persistence, or autoantibodies.

Interactions between these important key players in adaptive and innate immunity suggest that a pre-existing immune impairment might lead to difficulties in eliminating residual virus reservoirs or infected cells. Viral persistence may then contribute to ongoing inflammation and cognitive dysfunction due to sickness behavior. Thus, there is an increasing body of evidence supporting a role for immunological dysregulation in the onset and progression of long COVID.

Viruses are obligatory parasites that depend entirely on host cells for replication. Viral infection consequently leads to changes in host cell metabolism due to increased cellular metabolic demands for virus production, toxicities (e.g., oxidative damage) and increased demand from immune cell responses to the infection. Immune metabolism includes all intracellular metabolic pathways, which allow innate and adaptive immune cells to function at a steady state and upon activation. Energy producing processes such as glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) interconnect with the tricarboxylic acid cycle, fatty acid oxidation, fatty acid synthesis, glutaminolysis, nucleic acid synthesis and provide metabolic cues to cell proliferation, migration, and function [34, 35]. SARS-CoV-2 infects multiple cell types mainly via angiotensin-converting enzyme 2 (ACE2) [36‒39] and inhibits expression of genes encoding all five OXPHOS complexes, as demonstrated in nasopharyngeal samples of infected versus non-infected individuals [40] and human respiratory epithelium [41]. In autopsy tissues from COVID-19 patients, a similar downregulation of OXPHOS encoding genes was found in the heart, kidney, and liver [40]. Many other mitochondrial processes were downregulated in several tissues, with the most striking decrease in the heart. In contrast, glycolysis and glycolysis-regulators such as hypoxia-inducible factor 1-alpha and mammalian target of rapamycin were upregulated [40]. Decreased OXPHOS and upregulation of glycolysis and hypoxia-inducible factor 1 were also demonstrated in other SARS-CoV-2 infected human cells and tissues and in COVID-19 patients [42‒46]. Infection of human lung epithelium with SARS-CoV-2 led to the release of alarmins such as IL-33 and activation of retinoic acid-inducible gene I (RIG-I) inflammasome activation with release of IL-18, accompanied by the inhibition of antiviral proteins such as CCL4 [47]. In other cells, priming and activation of inflammasomes and IL-33 secretion are at least partially dependent on glycolysis [48, 49], whereas IFN type I and III responses depend on OXPHOS [50], although the interconnectedness of these metabolic pathways complicate these findings [51]. Upregulated glycolysis and decreased OXPHOS in human CD4+T cells in patients with SARS-CoV-2-induced acute respiratory distress syndrome, led to their exhaustion and decrease in IFN-gamma release, which could be partially reversed by beta-hydroxybutyrate, a product of ketogenesis [52]. Prolonged infection and the presence of SARS-CoV-2 in several tissues and organs, including heart and brain, even months after the primary infection [53] might lead to a decrease in the metabolic fitness and function of many cell types including cardiomyocytes [54].

Cellular and organ metabolic abnormalities can also be reflected in the circulating levels of metabolites with potent immune modifying effects. During acute COVID-19, profound dysregulation of serum and tissue metabolism has been repeatedly demonstrated. Severe and fatal COVID-19 disease was characterized by altered serum levels of metabolites associated with tryptophan metabolism, polyamine metabolism, histidine metabolism, lipid metabolism, bile acid metabolism, FAO compounds, and antioxidant responses such as the plasmalogens [55‒58]. Several of these metabolites remain dysregulated in long COVID patients. Levels of glutamine, glucose, kynurenine, and choline were shown to be higher in plasma of Long COVID patients compared to healthy controls [59]. In addition, circulating levels of nitrite (a metabolite of endothelial nitric oxide), sarcosine, taurine, and several lysophospholipid species were shown to be downregulated either in comparison to healthy controls or COVID-19 recovered participants [59, 60]. Similar differences in amino acid metabolism, in particular tryptophan metabolism, were observed in another study of long COVID patients [13]. High kynurenine and IDO2 expression paired with low tryptophan levels have been also demonstrated in PBMCs and within the brain of long COVID patients [61]. This was accompanied by reduced mitochondrial function, amino acid levels, and tricarboxylic acid cycle compounds in PBMCs [61]. A recent study showed that reduced serotonin levels in long COVID patients were due to reduced tryptophan absorption, increased platelet activation, and enhanced serotonin turnover, all of which contribute to depleted circulating levels of serotonin [62].

One potential driver for ongoing immune dysfunction in long COVID patients could be related to a persistent SARS-CoV-2 reservoir in host organs [9, 63]. This concept is plausible given that other respiratory RNA viruses can persist for prolonged periods. For example, latent persistence of respiratory syncytial virus (RSV) occurs in murine models [64, 65] and guinea pigs [66] and has been associated with persistent inflammation and compromised lung function. Importantly, transient immune compromise, induced by T-cell depletion can result in RSV-reactivation [64]. In humans, RSV persistence and associated lung function decline occur in chronic obstructive pulmonary disease patients [67], who have compromised antiviral lung immunity. Influenza A virus (IVA) antigens [68] and RNA can persist in murine lungs for 4 months in association with focally increased IL-13 and mucus expression where IVA-RNA is present, resulting in chronic, asthma-like, lung disease lasting at least for 6 months [69]. Persistence of SARS-CoV-2 for 8 months with intermittent reactivation and COVID-19 relapses has been reported in 1 patient undergoing chemotherapy [70].

The gastrointestinal tract with an ACE-2 expressing epithelium [71] may also serve as an entry site and subsequent reservoir for SARS-CoV-2. Host cells involved in gastrointestinal barrier function are often ACE-2 positive [71], thus enabling SARS-CoV-2 infection. SARS-CoV-2 fecal shedding usually lasts 17.2 days on average but can continue for several months [72]. However, SARS-CoV-2 often disappears over a more extended period while long COVID symptoms may persist [73]. Biopsy studies in patients with pre-existing gastrointestinal disease including inflammatory bowel disease, irritable bowel syndrome, or gastroesophageal reflux disease [74, 75] found SARS-CoV-2 RNA or antigen in gastrointestinal mucosal tissues from 50 to 70% of patients, suggesting a viral reservoir. Long COVID symptoms were present in 65% of patients with, but not in those without, viral RNA/antigen persistence [74, 75]. These findings support the hypothesis that the gut may be an important reservoir of SARS-CoV-2 that can contribute to SARS-CoV-2 infection of multiple organ systems and/or viral persistence. However, it remains to be seen if a persistent viral reservoir is required for long COVID. Clinical studies targeting antiviral mechanisms during acute COVID-19, with metformin or nirmatrelvir, have shown reduced incidence of long COVID suggesting that efficient elimination of the virus is important for long-term outcomes [76, 77].

Another possible mechanism contributing to long COVID development could be the reactivation of latent viruses due to an altered host immune response during and following acute SARS-CoV-2 infection [78, 79]. In the lung, reactivation of herpes viruses such as herpes simplex virus 1 (HSV-1) and cytomegalovirus (CMV) frequently occurs during acute COVID-19 [80]. Their prolonged activity, due to altered antiviral immunity and in the absence of antiviral treatment, could promote prolonged pulmonary inflammation and associated respiratory symptoms. Furthermore, reactivation of human herpesvirus 6 (HHV6) and 7 (HHV7) has been observed in the skin [18, 79, 81]. Evidence for a direct connection between reactivation of latent viruses and the onset of long COVID is scarce [82]. However, this concept is supported by the more frequent detection of EBV-DNA in throat wash samples of long COVID patients several months after acute COVID-19, compared to fully recovered patients [18, 73].

Coronaviridae are neurotropic [83]. Early reports from Wuhan in patients with severe acute COVID-19 disease reported that up to 34% of patients had associated neurological complications [84]. Neuroinflammatory processes associated with COVID-19 disease encompass a wide range of conditions that acutely injure the brain. These processes can persist and may continue to involve the nervous system during long COVID. Neuroinflammatory conditions reported following SARS-CoV-2 infection include encephalopathy, ischemic brain injury, stroke, anosmia, ageusia, tinnitus, hearing loss, facial paralysis, autoimmune encephalitis of the brainstem, limbic system, and an acute disseminated form (autoimmune myelitis), new onset epilepsy, postural orthostatic tachycardia syndrome (POTS), headache, fatigue, memory loss, anxiety, depression, psychiatric illness, and disordered sleep [10, 85‒88]. With respect to neuro-immune aspects of long COVID, it is important to recognize that symptoms can occur after both acquired viral infection as well as occasionally following vaccination [89‒92]. However, this has not been included in the current WHO definition of long COVID.

There is widespread cellular distribution of ACE2 within the nervous system [93] and direct neural invasion has been demonstrated [94]. Mechanistically, SARS-CoV-2 can be actively transported throughout neurons via the dynein-kinesin mechanism and transported in a retrograde manner via transsynaptic transfer [95‒97]. Anosmia was a common feature of acute SARS-CoV-2 infection in the early waves of the pandemic, possibly due to the prevailing variants at that time. Anosmia was associated with loss of brain tissue associated with smell [88] and direct invasion of the brain by SARS-CoV-2 has been proposed to be one mechanism leading to neural damage. SARS-CoV-2 was shown to replicate in the brain with viral mRNA persisting potentially for several months [53]. SARS-CoV-2 may also enter the CNS via the enteric nervous system or choroid plexus [98].

In addition to direct infection, endothelial inflammation can cause brain injury, which can be driven by microthrombosis and endotheliitis. Endothelial inflammation and destruction of the blood-brain barrier may be a point of CNS viral entry as well as being associated with necrotizing encephalopathy [99‒103]. It has been proposed that a significant component of brain injury occurs due to the inflammatory cytokine storm [104‒106]. Cytokines were found to be elevated in the CNS during acute COVID-19 disease, which may cause long-term injury [107]. Indeed, the severity of acute COVID-19 disease does appear to be correlated with risk of neurological complications in long COVID [108]. In an animal model of pulmonary restricted SARS-CoV-2 infection, mild respiratory infection resulted in a decrease in hippocampal neurogenesis, oligodendrocytes, and loss of myelin suggesting that the immune response or elevated cytokine levels may be sufficient to cause brain injury [109].

Some studies have described an increase in autoantibodies following SARS-CoV-2 infection, as summarized by Choutka et al. [110]. Serum autoantibody levels were associated with neurological sequelae in COVID-19-associated conditions [111]. Autoantibodies may be inflammatory and result in neuro-inflammation; however, they may also result in molecular mimicry or even negate chemokine responses [112, 113]. Several of these antibodies can be related to brainstem injury and may contribute to POTS in long COVID [89, 114‒117]. Autoantibodies recognizing G protein-coupled receptors are one mechanism thought to be important for POTS and antibodies specific to the beta adreno-receptor have been reported in patients with long COVID [118]. The causal role for autoantibodies in long COVID is potentially supported by the efficacy of intravenous immunoglobulin in COVID-19-associated neuroinflammatory conditions [119, 120].

Neuroinflammation in long COVID may occur via direct neural invasion, neurovascular events, cytokine storm-associated injury, and autoimmune mechanisms. However, it is possible that multiple mechanisms may be involved, and a multihit mechanism has been described that involves priming of the brain and neuroinflammatory injury occurring with environmental stressors [121].

Human mucosal surfaces and body cavities harbor diverse communities of commensal microbes that play essential roles in regulation of host metabolic responses, epithelial barrier function, immune education, and immune regulation [122‒125]. Microbial-derived factors, such as short-chain fatty acids (SCFAs), indoles and polyamines, protect against aberrant inflammatory processes or hypersensitive responses, but also promote effector immune responses that efficiently eliminate pathogens, such as SARS-CoV-2 [126‒128]. While individual microbes, microbial components, and individual metabolites are certainly important, the overall community functional capacity and community metabolic outputs that underpin interactions with the host immune system are perhaps more relevant regarding understanding disease risk. A low-risk microbiome configuration may generate sufficient levels of several regulatory metabolites that are associated with protection from aberrant inflammatory responses. In contrast, a high-risk microbiome configuration may consistently generate multiple pro-inflammatory metabolites that may contribute to a higher risk of inappropriate immune reactivity. Several studies have identified taxonomic and functional microbiome differences that are associated with disease severity during acute COVID-19 [57, 128‒131]. Reduced abundance of well-described immune protective microbes (such as those producing SCFAs) and increased abundance of opportunistic pathogens (such as from the Enterobacteriaceae families) were often described.

Persistent changes in gut bacteria and fungi, and their metabolism have also been described for extended periods of time following SARS-CoV-2 infection, both in those with and without Long COVID. These studies are summarized in Table 1 [13, 132‒143]. Broadly similar gut microbiota findings to those associated with acute COVID-19 severity have been described in Long COVID patients such as reduced levels of SCFA producing microbes, altered tryptophan metabolism, reduced abundance of Faecalibacterium prausnitzii and Blautia obeum, and increased abundance of Ruminococcus gnavus and Bacteroides vulgatus. Interestingly, one study found that R. gnavus correlated positively with serum IL-6 levels, while F. prausnitzii and B. obeum negatively correlated with IL-6 and C-reactive protein levels in Long COVID patients [143]. Microbiome profiling may assist in the early identification of those most at risk of long COVID, while targeting the microbiome via appropriately selected probiotics and/or prebiotics may enable the immune system to recover more rapidly. However, microbiota targeting intervention studies in long COVID have not yet been reported in the literature.

Table 1.

Microbiota studies examining recovery from SARS-CoV-2 infection

ReferenceFindingsMedian sample time post-infection
131 Decreased diversity of Dorea, Coprococcus, Eubacterium_ventriosum_group, Eubacterium_hallii_group, Subdoligranulum, and Ruminococcus in the 1-year follow-up group compared with healthy controls 1 year 
Decrease abundance of Ruminococcus, Eubacterium_hallii_group and Subdoligranulum in healthy controls, asymptomatic, and symptomatic group compared with recovered patients 
132 The abundance of Cyanobacteria gradually increased in the process of recovery. Conversely, the abundance of Fusobacteriota gradually decreased 1 year 
Higher Eubacterium, Fusicatenibacter, Agathobacter, unclassified Lachnospiraceae, and Faecalibacterium. Lower Fusobacterium, Intestinibacter, Prevotellaceae, Muribaculaceae, and Mitsuokella after 1 year 
133 Patients with at least 1 COVID-19 symptom at 6 months had an increase in Streptococcus lutetiensis, Ruminococcus gnavus, Bacteroides vulgatus, Bacteroides thetaiotaomicron, Flavonifractor plautii, Bacteroides xylanisolvens, Lachnospiraceae bacterium oral taxon, Parabacteroides distasonis, Clostridium innocuum, Lactobacillus delbrueckii, Erysipelatoclostridium ramosum, Morganella morganii, Lactobacillus acidophilus, and a decrease in Collinsella aerofaciens, Roseburia faecis, Faecalibacterium prausniztii, Blautia obeum, Eubacterium rectale, Ruminococcus torques, Firmicutes bacterium CAG-83, Ruminococcus bicirculans, Adlecreutzia equolifaciens, Coprococcus comes, Dorea longicatena, Agathobaculum butyriciproducens, Dorea formicigenerans, Eubacterium sp CAG-251, Roseburia inulinivorans, Ruthenibacrerium lactatiformans, Gemigger formicilis, Enterococcus avium, Ruminococcus Lactaris, and Roseburia hominis 6 months 
134 Candida was observed in 56% of patients at 6-month follow-up. Higher abundance of Lactobacillus in some recovered patients. Enterococcus and A. onderdonkii had a lower abundance in the recovered group compared to the severe group. After the recovery of severe patients, alteration of the microbiota remained, but the mycobiota recovered its diversity comparable to that of mild infection and healthy groups 6 months 
135 Higher Acetivibrio, Aeromicrobium, Anaerotignum, Marmoricola, Mycolicibacterium, Paenarthrobacter, Stenotrophobacter, Xanthobacter, and Vitiosangium in the control group compared to the follow-up group. Higher Mycolicibacterium in participants who had immediately recovered from COVID-19. No differences were found between the immediately recovered patients and after 6 months of recovery 6 months 
136 Decreased Prevotella, Haemophilus, Streptococcus, Veillonella, Porphyromonas, Neisseria, and Alloprevotella abundance in follow-up group compared with control group 6 months 
Significant decreased abundance in Proteobacteria, Actinobacteria, Fusobacteria, Spirochaetes, and Uroviricota with the follow-up group compared with control group 
137 There was no significant difference between recovered COVID-19 patients and control group at the phylum level. Recovered patients had a significant decrease in Coriobacteriia, Eubacterium hallii group, Coriobacteriaceae, Erysipelotrichaceae UCG-003, Faecalibacterium group, Collinsella, and NK4A214 group 3 months 
Increased Acidimicrobiia in recovered patients compared with controls and an increase in the relative abundance of Flavonifractor, Eubacterium Eubacteriales, Micrococcales, Rothia, and Candidatus Microthrix 
138 Increase in Actinobacteria phylum, Escherichia, Intestinibacter, and Flavonifractor genera, Esherichia unclassified, Flavonifractor plautii, Intestinibacter bartlett, Clostridium aldenense, Clostridium bolteae, and Clostridium ramosum species. Decrease in Desulfovibrionaceae, Lachnospiraceae families, Faecalibacterium, Ruminococcus, Roseburia, Fusicatenibacter, Clostridium XVIII, Dorea, Butyricicoccus, Intestinimonas, Romboutsia, and Bilophila genera, Faecalibacterium prausnitzii, Roseburia inulinivorans, Fusicatenibacter saccharivorans, Ruminococcus bromii, Blautia faecis, Intestinimonas butyriciproducens, and Butyricicoccus pullicaecorum species 3 months 
139 Depletion of Ruminococcaceae, Bacteroidaceae, and Lachnospiraceae in COVID-19-positive patients, as well as decreased relative abundance of Adlercreutzia, Faecalibacterium, and Eubacterium brachy group. Prevotellaceae was enriched after viral clearance 8 months 
Subdoligranulum, Dialister, Faecalibacterium, Agathobacter, and Eubacterium hallii group had increased abundance 6 months post-recovery, regardless of antibiotic exposure 
Eubacterium brachy group was drastically reduced in infected patients and remained low post-recovery 
140 Postconvalescence patients with lower microbial richness had worse pulmonary functions 6 months 
141 Decrease in Lachnospiraceae family (Lachnoclostridium, Ruminococcus, Blautia, Butyrivibrio, Dorea, and Tyzzerella genera). And an increase in Bacteroides genus in COVID-19 patients at 3 months follow-up versus control 3 months 
142 Gut microbiome composition did not significantly differ between the LC group and controls, but did correlate with IL-6 and CRP levels 8 months 
13 Differences in serum levels of microbial-derived metabolites such as tryptophan metabolites 6 months and 9 months 
ReferenceFindingsMedian sample time post-infection
131 Decreased diversity of Dorea, Coprococcus, Eubacterium_ventriosum_group, Eubacterium_hallii_group, Subdoligranulum, and Ruminococcus in the 1-year follow-up group compared with healthy controls 1 year 
Decrease abundance of Ruminococcus, Eubacterium_hallii_group and Subdoligranulum in healthy controls, asymptomatic, and symptomatic group compared with recovered patients 
132 The abundance of Cyanobacteria gradually increased in the process of recovery. Conversely, the abundance of Fusobacteriota gradually decreased 1 year 
Higher Eubacterium, Fusicatenibacter, Agathobacter, unclassified Lachnospiraceae, and Faecalibacterium. Lower Fusobacterium, Intestinibacter, Prevotellaceae, Muribaculaceae, and Mitsuokella after 1 year 
133 Patients with at least 1 COVID-19 symptom at 6 months had an increase in Streptococcus lutetiensis, Ruminococcus gnavus, Bacteroides vulgatus, Bacteroides thetaiotaomicron, Flavonifractor plautii, Bacteroides xylanisolvens, Lachnospiraceae bacterium oral taxon, Parabacteroides distasonis, Clostridium innocuum, Lactobacillus delbrueckii, Erysipelatoclostridium ramosum, Morganella morganii, Lactobacillus acidophilus, and a decrease in Collinsella aerofaciens, Roseburia faecis, Faecalibacterium prausniztii, Blautia obeum, Eubacterium rectale, Ruminococcus torques, Firmicutes bacterium CAG-83, Ruminococcus bicirculans, Adlecreutzia equolifaciens, Coprococcus comes, Dorea longicatena, Agathobaculum butyriciproducens, Dorea formicigenerans, Eubacterium sp CAG-251, Roseburia inulinivorans, Ruthenibacrerium lactatiformans, Gemigger formicilis, Enterococcus avium, Ruminococcus Lactaris, and Roseburia hominis 6 months 
134 Candida was observed in 56% of patients at 6-month follow-up. Higher abundance of Lactobacillus in some recovered patients. Enterococcus and A. onderdonkii had a lower abundance in the recovered group compared to the severe group. After the recovery of severe patients, alteration of the microbiota remained, but the mycobiota recovered its diversity comparable to that of mild infection and healthy groups 6 months 
135 Higher Acetivibrio, Aeromicrobium, Anaerotignum, Marmoricola, Mycolicibacterium, Paenarthrobacter, Stenotrophobacter, Xanthobacter, and Vitiosangium in the control group compared to the follow-up group. Higher Mycolicibacterium in participants who had immediately recovered from COVID-19. No differences were found between the immediately recovered patients and after 6 months of recovery 6 months 
136 Decreased Prevotella, Haemophilus, Streptococcus, Veillonella, Porphyromonas, Neisseria, and Alloprevotella abundance in follow-up group compared with control group 6 months 
Significant decreased abundance in Proteobacteria, Actinobacteria, Fusobacteria, Spirochaetes, and Uroviricota with the follow-up group compared with control group 
137 There was no significant difference between recovered COVID-19 patients and control group at the phylum level. Recovered patients had a significant decrease in Coriobacteriia, Eubacterium hallii group, Coriobacteriaceae, Erysipelotrichaceae UCG-003, Faecalibacterium group, Collinsella, and NK4A214 group 3 months 
Increased Acidimicrobiia in recovered patients compared with controls and an increase in the relative abundance of Flavonifractor, Eubacterium Eubacteriales, Micrococcales, Rothia, and Candidatus Microthrix 
138 Increase in Actinobacteria phylum, Escherichia, Intestinibacter, and Flavonifractor genera, Esherichia unclassified, Flavonifractor plautii, Intestinibacter bartlett, Clostridium aldenense, Clostridium bolteae, and Clostridium ramosum species. Decrease in Desulfovibrionaceae, Lachnospiraceae families, Faecalibacterium, Ruminococcus, Roseburia, Fusicatenibacter, Clostridium XVIII, Dorea, Butyricicoccus, Intestinimonas, Romboutsia, and Bilophila genera, Faecalibacterium prausnitzii, Roseburia inulinivorans, Fusicatenibacter saccharivorans, Ruminococcus bromii, Blautia faecis, Intestinimonas butyriciproducens, and Butyricicoccus pullicaecorum species 3 months 
139 Depletion of Ruminococcaceae, Bacteroidaceae, and Lachnospiraceae in COVID-19-positive patients, as well as decreased relative abundance of Adlercreutzia, Faecalibacterium, and Eubacterium brachy group. Prevotellaceae was enriched after viral clearance 8 months 
Subdoligranulum, Dialister, Faecalibacterium, Agathobacter, and Eubacterium hallii group had increased abundance 6 months post-recovery, regardless of antibiotic exposure 
Eubacterium brachy group was drastically reduced in infected patients and remained low post-recovery 
140 Postconvalescence patients with lower microbial richness had worse pulmonary functions 6 months 
141 Decrease in Lachnospiraceae family (Lachnoclostridium, Ruminococcus, Blautia, Butyrivibrio, Dorea, and Tyzzerella genera). And an increase in Bacteroides genus in COVID-19 patients at 3 months follow-up versus control 3 months 
142 Gut microbiome composition did not significantly differ between the LC group and controls, but did correlate with IL-6 and CRP levels 8 months 
13 Differences in serum levels of microbial-derived metabolites such as tryptophan metabolites 6 months and 9 months 

CRP, C-reactive protein.

Malnutrition is well recognized as an important risk factor for poor immunological responses, especially related to infectious diseases [144]. Dietary components can directly or indirectly influence immune function. Nutrients that directly impact immunological processes include niacin (vitamin B3), vitamins C and E, selenium, zinc, and the omega-3 (n-3) fatty acids docosahexaenoic acid, and eicosapentaenoic acid [145, 146]. However, there is no evidence currently that these nutrients can affect long COVID outcomes and sufficient intake according to national guidance should be recommended. Vitamin D plays an important role in T-cell activation and mobilization and vitamin D deficiency has been associated with COVID-19 severity and mortality [147, 148]. One study identified lower levels of vitamin D in long COVID patients compared to those who recovered from COVID-19 [149]. In addition to specific dietary components, overall dietary patterns may be important. Diets with higher intake of antioxidant or anti-inflammatory components, such as phytochemicals and flavanols, and lower amounts of advanced glycation end products, have been associated with better outcomes following acute infection [150‒152]. However, the importance of these dietary factors to long COVID is currently unknown.

An important indirect effect of dietary components on the immune system is mediated via the microbiota, as microbial fermentation generates metabolites with immune modulatory effects [153]. Consumption of a higher diversity of fruits, vegetables, and fermented foods was associated with a reduced risk of atopic disorders and asthma in children, potentially mediated in part by microbial-derived butyrate and propionate [154]. In addition, adults who more regularly consumed plant-based or pescatarian diets seemed to have lower odds of developing severe COVID-19 [155‒157]. However, the specific plant-based substrates (e.g., fiber type, fatty acids, polyphenols) that are responsible for these positive associations are unknown. It is hypothesized that the transition to reduced diversity, low-quality, highly processed, high-energy diets have altered the metacommunity, its processes that underpin assembly and activity of the human microbiome. Consequently, there is an increased risk of inappropriate and uncontrolled immune responses that damage host tissues and function [158]. Dietary differences may underpin many of the microbial changes in long COVID described above, but these links remain to be proven. The American gut study indicates that eating 30 different plant-based foods a week might be most beneficial for the gut microbiome [159] but this has not been studied in long COVID.

Lastly, long COVID symptoms may affect nutritional intake and nutritional outcomes. These include fatigue (too tired to eat), memory and concentration problems (difficulty preparing a shopping list and following recipes), nausea, diarrhea, stomach aches, loss of appetite, changes to smell or taste (reduced willingness to eat), stress, sleep deprivation, depression, and anxiety (loss of interest in food). These are all experienced during a time of potentially enhanced nutritional needs across different age groups, which are undefined at present [145]. Eating, buying, and preparing foods can be challenging under all these circumstances. Adding strong flavors such as spices or bitter tastes like citrus may help those with altered sense of taste and smell [160]. Even though many dietary approaches have been proposed in relation to the management of long COVID, the basic principles of an overall healthy diet should not be neglected, and region-specific dietary recommendations should be followed [161‒163].

Although some progress has been made in describing the immunological factors associated with long COVID, we are still far away from coherent mechanisms linking SARS-CoV-2 infection to the diverse array of persistent and new onset symptoms that have been described in long COVID (Table 2). In addition, there has been relatively little detailed analysis of the mechanisms of long COVID resulting from infections by distinct SARS-CoV-2 variants of concern or by vaccination. The risk of long COVID symptoms appears to increase with each subsequent infection [164] indicating that we are yet to see the full impact of this virus. Even with vaccination and consequently milder presentations of acute infection across recent variant waves, the cumulative burden of long COVID has continued to rise. Efforts to diagnose, prevent, and treat acute infection need to be coupled with the same emphasis on recognizing and managing the multiple organs affected by this virus including the immune system. To better understand, the potential contribution of viral persistence and reactivation to the development of individual long COVID symptoms, studies are required that assess genomes and antigens of a broad range of viruses (virome studies) in affected organs and systemically, as well as associated immune responses. As more evidence concerning the immune mechanisms underpinning long COVID are discovered, these will also likely lead to significant breakthroughs in the understanding and treatment of other chronic post-infectious disorders. Unfortunately, the currently available diagnostic and treatment options for long COVID are inadequate, and more clinical trials are needed that match experimental interventions to underlying biological mechanisms, such as those targeting viral persistence, neuroinflammation, endothelial inflammation, immune metabolism, microbiome, and autoimmunity.

Table 2.

Summary of the key questions, unknown pathophysiological mechanisms, and research requirements to facilitate diagnosis and to move patient care from symptomatic therapy towards targeted disease modifying treatment approaches in long COVID

What remains unknown?Research needs
How many patients suffer from long COVID? Epidemiological research should define the number of patients affected by long COVID and duration of disease 
Do patients suffering from persistent symptoms after severe infection develop long COVID due to similar pathophysiological mechanisms as patients with long COVID symptoms after asymptomatic or mild infections? Precise patient stratification during acute COVID-19 disease coupled with long-term surveillance is needed 
Is there one disease mechanism that leads to a specific post-infectious syndrome or do multiple distinct mechanisms lead to several clinically similar outcomes? More precise long COVID disease definitions and biomarker characterization enabling patient stratification is required 
What are the main risk factors for long COVID disease development? Identification of vulnerable patients’ groups (e.g., those with immunodeficiencies) at risk for long COVID development is necessary to define prevention strategies 
Mechanisms leading to post-exertional malaise are largely unknown? Studies comparing patients’ samples collected before, during, and after exertion are required to elucidate disease mechanisms 
Is microbiota dysbiosis a cause or consequence of long COVID? Population-level longitudinal studies are required. A special focus should be given to host and microbial metabolomics. Intervention studies targeting microbiome mechanisms are required 
Does long COVID affect nutritional status through either reduced intake and/or increased nutritional needs? Longitudinal studies examining nutritional intake and status over time are needed 
Is there a viral reservoir that drives long COVID symptoms via immune mechanisms? Determination of long-term SARS-CoV-2 persistence in host tissues and association with immune responses and long COVID symptoms are needed 
Can dietary interventions (e.g., vitamin D, low inflammatory diets, low histamine diets, or reduced intake of advanced glycation end products) affect long COVID outcomes? Observational and intervention studies to address nutrition and long COVID outcomes may identify suitable dietary approaches to reduce the morbidity associated with long COVID 
What remains unknown?Research needs
How many patients suffer from long COVID? Epidemiological research should define the number of patients affected by long COVID and duration of disease 
Do patients suffering from persistent symptoms after severe infection develop long COVID due to similar pathophysiological mechanisms as patients with long COVID symptoms after asymptomatic or mild infections? Precise patient stratification during acute COVID-19 disease coupled with long-term surveillance is needed 
Is there one disease mechanism that leads to a specific post-infectious syndrome or do multiple distinct mechanisms lead to several clinically similar outcomes? More precise long COVID disease definitions and biomarker characterization enabling patient stratification is required 
What are the main risk factors for long COVID disease development? Identification of vulnerable patients’ groups (e.g., those with immunodeficiencies) at risk for long COVID development is necessary to define prevention strategies 
Mechanisms leading to post-exertional malaise are largely unknown? Studies comparing patients’ samples collected before, during, and after exertion are required to elucidate disease mechanisms 
Is microbiota dysbiosis a cause or consequence of long COVID? Population-level longitudinal studies are required. A special focus should be given to host and microbial metabolomics. Intervention studies targeting microbiome mechanisms are required 
Does long COVID affect nutritional status through either reduced intake and/or increased nutritional needs? Longitudinal studies examining nutritional intake and status over time are needed 
Is there a viral reservoir that drives long COVID symptoms via immune mechanisms? Determination of long-term SARS-CoV-2 persistence in host tissues and association with immune responses and long COVID symptoms are needed 
Can dietary interventions (e.g., vitamin D, low inflammatory diets, low histamine diets, or reduced intake of advanced glycation end products) affect long COVID outcomes? Observational and intervention studies to address nutrition and long COVID outcomes may identify suitable dietary approaches to reduce the morbidity associated with long COVID 

L.O’M. reports consultancy with Precision Biotics Alimentary Health, grants from GlaxoSmithKline and Chiesi, and participation in speaker bureau for Nestle, Yakult, Reckitt, and Abbott. E.U. has received honoraria for lectures, presentations (Nordmark Pharma GmbH, GEKA mbH, Allergopharma, Bencard GmbH, MacroArray Di-agnostics, Nutrica); honoraria for participation on Advisory Boards (Bencard GmbH, Desentum Oy) and is PI of research projects funded by Desentum Oy and Nordmark Pharma GmbH outside the submitted work. P.S. has received investigator-initiated funding from GSK, Hyloris, and Sanofi. J.S. reports personal consulting fees from Aimmune and Sanofi, congress sponsorship from ALK, research grants from NIHR and UKRI-MRC. M.S. reported research grants from Swiss National Science Foundation, Novartis and GSK and speaker’s fee from AstraZeneca. C.V. reports grants from Reckitt Benckiser, Food Allergy Research and Education, and National Peanut Board, and personal fees from Reckitt Benckiser, Nestle Nutrition Institute, Danone, Abbott Nutrition, Else Nutrition, and Before Brands. The remaining authors have no conflict of interest to declare.

The authors are supported by a Science Foundation Ireland research center grant 12/RC/2273_P2, a Science Foundation Ireland Frontiers for the Future Award 21/FFP-A/10000, and a SNSF Grant No. 310030_189334/1.

Eva Untersmayr contributed to review conception, wrote the immune dysfunction section, reviewed article content, and approves accuracy of submitted version; Carina Venter contributed to review conception, wrote the diet section, reviewed article content, and approves accuracy of submitted version; Peter Smith contributed to review conception, wrote the neuroimmunology section, reviewed article content, and approves accuracy of submitted version; Johanna Rohrhofer contributed to review conception, co-wrote the immune dysfunction section and the viral persistence section, reviewed article content, and approves accuracy of submitted version; Cebile Ndwandwe contributed to review conception, co-wrote the microbiota section, reviewed article content, and approves accuracy of submitted version; Jurgen Schwarze contributed to review conception, co-wrote the viral persistence section, reviewed article content, and approves accuracy of submitted version; Emer Shannon contributed to review conception, co-wrote the microbiota section, reviewed article content, and approves accuracy of submitted version; Milena Sokolowska contributed to review conception, wrote the immune metabolism section, reviewed article content and approves accuracy of submitted version; Corinna Sadlier contributed to review conception, co-wrote the introduction and conclusion sections, reviewed article content, and approves accuracy of submitted version; Liam O’Mahony contributed to review conception, co-wrote the introduction, microbiota and conclusion sections, reviewed article content, approves accuracy of submitted version, and is corresponding author.

Additional Information

Edited by: H.-U. Simon, Bern.

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