The Effect of SARS-CoV-2 Reinfection on Long-Term Symptoms in the Innovative Support for Patients With SARS-CoV-2 Infections Registry (INSPIRE)

Abstract

Background: The clinical consequences of repeated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are not clear, especially as they relate to long-term symptoms after infection. We analyzed data collected for the Innovative Support for Patients with SARS-CoV-2 Infections Registry (INSPIRE) to determine whether reinfection changes the likelihood of symptoms 3-6 months after reinfection compared with the likelihood in individuals experiencing a single infection.

Methods: Individuals reporting a single SARS-CoV-2 infection or a single reinfection were included in this analysis. A positive SARS-CoV-2 test occurring ≥90 days after a first infection was considered a reinfection. Outcomes included severe fatigue (fatigue severity score ≥25) and the presence of organ system symptoms 3-6 months after the last infection.

Results: The analysis included 886 individuals, 415 (46.8%) of whom experienced reinfection. For individuals who experienced their first infections in either the pre-Delta or Delta periods, the odds of having ≥3 symptoms 3-6 months after their most recent infection was lower in those reinfected than those with a single infection (weighted adjusted odds ratio, 0.45 [95% confidence interval, .21-.95] and 0.51 [.32-.79], respectively). However, in individuals reporting their first infection during the Omicron wave, the odds of reporting ≥3 symptoms after the most recent infection was higher in those reinfected than in those with a single infection (weighted adjusted odds ratio, 1.54 [95% confidence interval, 1.02-2.34]).

Conclusions: The timing of initial infection, reinfection, and the variants involved may play important roles in longer-term clinical outcomes. Repeated infection with Omicron variants may increase the risk of long-term symptoms.

Keywords: COVID-19; SARS-CoV-2; long COVID; post-COVID-19 syndrome; reinfection.

Figure 1.

Schematic of study survey timing and comparison groups. This analysis lined up the first reinfection episode in reinfected individuals with the sole infection for those with a single infection episode and compared outcomes in the 3–6 months following the last infection. To compare outcomes, we stratified by the variant period of the first infection. Comparison groups consisted of individuals with a single variant for those with a single infection versus the variant of the first infection followed by (designated by an arrow) the variant of the second infection for those in the reinfection group. This created comparison profiles as summarized in the figure: single pre-Delta infection versus initial pre-Delta infection followed by reinfection with pre-Delta, Delta, or Omicron (pre-Delta vs pre-Delta → pre-Delta || Delta || Omicron); single Delta infection versus initial Delta infection followed by reinfection with Delta or Omicron (Delta vs Delta → Delta || Omicron), and single Omicron infection compared with 2 Omicron infections (Omicron vs Omicron → Omicron). We also compared outcomes in individuals who had a single Omicron infection with those in individuals who had an initial Delta infection followed by an Omicron reinfection (Omicron vs Delta → Omicron).

Figure 2.

Study flow chart showing numbers of individuals enrolled in the Innovative Support for Patients with SARS-COV-2 Infections Registry (INSPIRE) cohort, those evaluated for this analysis, and final numbers of individuals included in this analysis. Variant profiles are shown for both single-infection and reinfection groups. Abbreviation: SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Figure 3.

Weighted prevalence rates of symptomatic outcomes 3–6 months after the last severe acute respiratory syndrome coronavirus 2 infection, by variant period of first infection. The transparency level of the bar represents significance. Numbers next to bars represent the rate difference (as a percentage) between single-infection and reinfection groups, with placement side of the number indicating which group has the higher rate. Abbreviation: HEENT, head, eyes, ears, nose, and throat.

Figure 4.

Weighted adjusted odds ratios with 95% confidence intervals of reported symptoms 3­–6 months after the last severe acute respiratory syndrome coronavirus 2 infection for the 4 multivariable logistic models. Abbreviation: HEENT, head, eyes, ears, nose, and throat.