Long COVID following mild SARS-CoV-2 infection: characteristic T cell alterations and response to antihistamines

Abstract

Long COVID is characterized by the emergence of multiple debilitating symptoms following SARS-CoV-2 infection. Its etiology is unclear and it often follows a mild acute illness. Anecdotal reports of gradual clinical responses to histamine receptor antagonists (HRAs) suggest a histamine-dependent mechanism that is distinct from anaphylaxis, possibly mediated by T cells, which are also regulated by histamine. T cell perturbations have been previously reported in post-viral syndromes, but the T cell landscape in patients who have recovered from mild COVID-19 and its relationship to both long COVID symptoms and any symptomatic response to HRA remain underexplored. We addressed these questions in an observational study of 65 individuals who had recovered from mild COVID-19. Participants were surveyed between 87 and 408 days after the onset of acute symptoms; none had required hospitalization, 16 had recovered uneventfully, and 49 had developed long COVID. Symptoms were quantified using a structured questionnaire and T cell subsets enumerated in a standard diagnostic assay. Patients with long-COVID had reduced CD4+ and CD8+ effector memory (EM) cell numbers and increased PD-1 (programmed cell death protein 1) expression on central memory (CM) cells, whereas the asymptomatic participants had reduced CD8+ EM cells only and increased CD28 expression on CM cells. 72% of patients with long COVID who received HRA reported clinical improvement, although T cell profiling did not clearly distinguish those who responded to HRA. This study demonstrates that T cell perturbations persist for several months after mild COVID-19 and are associated with long COVID symptoms.

Keywords: COVID-19; diagnostic tests; immunologic tests; routine.

Figure 1

Response to histamine receptor antagonist (HRA) in symptomatic patients. (A) Mean symptom burden (±SD) in symptomatic patients before and after HRA treatment (n=25). (B) Change in symptom burden in symptomatic patients who did (n=25) and did not (n=24) receive HRA. Red line denotes median. p values indicated Wilcoxon matched pairs signed-rank test.

Figure 2

CD4+ and CD8+ effector memory (EM) T cells in patients with long COVID and the asymptomatic fully recovered group. (A) Circulating CD4+ EM T cells (×10⁹/L) in healthy volunteers (black), asymptomatic recovered (blue) and symptomatic long COVID (red) participants. Dashed line, LLN (lower limit of normal). Healthy volunteers: mean 0.276×10⁹/L, range 0.140×10⁹/L–0.735×10⁹/L. Asymptomatic: mean 0.211×10⁹/L, range 0.079×10⁹/L–0.359×10⁹/L. Symptomatic: mean 0.154×10⁹/L, range 0.020×10⁹/L–0.433×10⁹/L. p values <0.05 indicated Kruskal-Wallis test. (B) Receiver operating characteristic curve of CD4+ EM T cell number in symptomatic (long COVID) and asymptomatic participants. Red dashed line, random classifier. (C) Circulating CD8+ EM T cells (×10⁹/L) in healthy volunteers (black), asymptomatic (blue) and symptomatic (red) participants. Dashed line, median of normal range. Healthy volunteers: mean 0.209×10⁹/L, range 0.077×10⁹/L–0.444×10⁹/L. Asymptomatic: mean 0.144×10⁹/L, range 0.056×10⁹/L–0.594×10⁹/L. Symptomatic: mean 0.117×10⁹/L, range 0.007×10⁹/L–0.306×10⁹/L. (D) Receiver operating characteristic curve of CD8+ EM T cell number in symptomatic (long COVID) and asymptomatic participants. Red dashed line, random classifier. AUC, area under curve (c-statistic).

Figure 3

Central memory (CM) T cell programmed cell death protein 1 (PD-1) and CD28 levels distinguish patients with long COVID from the asymptomatic fully recovered group. (A) PD-1 antigen density expressed as median fluorescence intensity (MFI, arbitrary units (AU)) in CD4+ (left) and CD8+ CM T cells. CD4+ CM: Healthy volunteers, mean 292 AU, range 246–321 AU. Asymptomatic, mean 313 AU, range 279–381 AU. Symptomatic, mean 313 AU, range 259–383AU. p values <0.05 indicated Kruskal-Wallis test. CD8+ CM: Healthy volunteers, mean 292 AU, range 249–329 AU. Asymptomatic, mean 344 AU, range 274–477 AU. Symptomatic, mean 352 AU, range 256–451 AU. (B) CD28 antigen density in CD4+ (left) and CD8+ CM T cells. CD4+ CM: Healthy volunteers, mean 496 AU, range 435–532 AU. Asymptomatic: mean 528 AU, range 453–572 AU. Symptomatic: mean 508 AU, 437–563 AU. CD8+ CM: Healthy volunteers: mean 469 AU, range 420–512 AU. Asymptomatic: mean 499 AU, range 438–547 AU. Symptomatic: mean 472 AU, range 395–532 AU. Significant p values are indicated.