TABLE 5.
Immunologic findings and infectious agents.
| Finding | ME/CFS | Long COVID |
| Immunologic studies | ||
| Decreased natural killer (NK) cell function, in vitro |
Positive studies: (236, 237, 242–255) Negative studies: (256, 257). |
Negative studies: (258) |
| Ion channel abnormalities in NK cells | Positive studies: (236, 237) | |
| Increased numbers of NK cells |
Positive studies: (243, 248, 252) Negative studies: (257) |
Positive studies: (258) Negative studies: (259) |
| Abnormal cytokine production |
Positive studies: increased pro-inflammatory cytokines (e.g., IL-1A, IL-17a, tumor necrosis factor-α) and “anti-inflammatory” cytokines (e.g., IL-1 receptor antagonist, IL-4, and IL-13) (260–273). Increased cytokines seen particularly in the first 3 years of illness (260, 274). Systematic review finds correlations of specific cytokine elevations to specific symptoms (275). TH2 cytokines may be elevated relative to TH1 cytokines (266). Spinal fluid cytokine levels also reflect inflammation with a TH2 pattern (276). Negative studies: (277–283) |
Positive studies: increased levels of certain pro-inflammatory cytokines, including IL-1ß, IL-6, and TNF (207, 284–292). However, reduced levels of several pro-inflammatory cytokines/cytokine receptors and chemokines (IL-18, TNF-RII, MCP-1/CCL-2) (293). SARS-CoV-2 spike protein induces production of proinflammatory cytokines by microglial cells (294). Negative studies: (295) |
| Cytokine levels correlate with severity of symptoms | Positive studies: (271) |
Positive studies: (296) Negative studies: (295) |
| Increased levels of circulating immune complexes |
Positive studies: (245, 297) Negative studies: (298) |
|
| Increased numbers of activated CD8+ cytotoxic cells | Positive studies: (252, 299–301) | Positive studies: (258, 284, 286, 288) |
| T cell exhaustion in long-term illness | Positive studies: (260, 274, 302) | Positive studies: (258) |
| B cell abnormalities |
Positive studies: increased numbers of CD21+, CD19+, activated CD5+, and CD24+ B cells (243, 303–305). Gene expression pattern suggesting impaired B cell differentiation and survival (306). Increased levels of B lymphocyte activating factor (307). Increased frequency of HLA alleles associated with autoimmunity (DQB1, KIR3DL1, and KIRDS1) (308–310). Antigen-driven clonal B cell expansion (311, 312). |
Positive studies: (288) Negative studies: (259, 286) |
| Increased levels of autoantibodies |
Positive studies: multiple polymorphisms linked to autoimmunity (313). Increased antinuclear antibodies (314, 315), anticardiolipin and antiphospholipid antibodies (208, 316, 317), antineuronal antibodies (318), antiganglioside antibodies (209) and antiserotonin antibodies (209). Autoantibodies against CNS and autonomic nervous system targets correlate with the presence and severity of symptoms (319). |
Positive studies: in acute COVID, there are many autoantibodies, including to neural/autonomic targets (320). Autoantibodies also found in Long COVID (219, 321–323). Autoantibodies can be functionally active and correlated with symptoms (219, 296, 321, 322, 324, 325). Some autoantibodies may be associated with decreased risk of Long COVID (326, 327). Some autoantibodies that are clearly involved in the pathophysiology of acute COVID do not appear to have a role in Long COVID (328). |
| Increased apoptosis of white blood cells |
Positive studies: increased apoptosis (329–331). Upregulation of apoptosis-associated genes or microRNAs (332–336). Negative studies: (337, 338) |
Positive studies: SARS-CoV-2 spike protein induces apoptosis of microglial cells (294). |
| Characteristic histocompatibility antigens (HLA) |
Positive studies: HLA-DQ1 and -DQ2 (308, 339, 340). Negative studies: (341) |
|
| Alterations in leukocyte transcriptome | Positive studies: compared to recovered COVID-19, significant differences in genes linked to cell cycle, CD4+ cells, genes related to monocyte and myeloid cell function (259). | |
| Increased numbers of T regulatory cells |
Positive studies: (342, 343) Negative studies: (252) |
Positive studies: (258) |
| Mast cell activation syndrome | Suggestive studies: (136, 344, 345) | |
| Pattern of micro-RNA expression implicating inflammation | Positive studies: (346) | |
| Distinctive methylome implicating inflammation | Positive studies: (347) | |
| SARS-CoV-2 | ||
| Evidence of reservoirs of SARS-CoV-2 nucleic acid and antigen in multiple tissues | Not applicable | Positive studies: (11, 348–353) |
| Non-SARS-CoV-2 viral agents | ||
| Reactivation of latent herpesviruses |
Positive studies: (354–359) Negative studies: (360) |
Positive studies: in acute COVID-19, reactivation EBV is frequent (361) (or only modest) (362, 363), as is reactivation of HHV-6, HHV-7 and CMV (361, 363, 364). Positive studies in Long COVID: (7, 365, 366) |
| Gut microbiome studies | ||
| Proinflammatory gut and oral microbiome with dysbiosis | Positive studies: (367–370) |
Positive studies (gut microbiome): (371–373) Positive studies (oral microbiome) (372) |
| Evidence of accelerated senescence | ||
| Various markers of senescence, in various cell types, including senescence-associated secretory phenotype (SASP) and shortened telomere length | Positive studies: (374, 375) | Positive studies: (375–377) |