• atient 1 and Patient 2 are two sisters, 13 and 11 years old, respectively, previously vaccinated with two doses of mRNA SARS-CoV-2 vaccine. They got a mild SARS-CoV-2 infection in March 2022 when no restrictions were applied in Italy, masking was not mandatory anymore, and Omicron was the prevalent wave. The infection was characterized by a low-grade fever for 1 day and a headache. The sisters were symptom-free for 3 weeks; afterward, both developed extreme fatigue, joint pain, and cognitive/memory problems.

• The US Centers for Disease Control and Prevention estimates that as of May 5, 2022, the US has had roughly 81 million cases of COVID-19 and 994 187 COVID deaths. Even the lower-end estimate of 12% of people with 3 or more symptoms of long COVID implies that 9.6 million people in the US may have developed long COVID—roughly 10 times the number of COVID-19 deaths. It is not known how long people with long COVID will be symptomatic, but recovery in the first year of long COVID for affected individuals may be very slow.⁴
• Reduced health is not the only consequence of long COVID. People with the condition work and earn less than they would have otherwise. One survey found that 44% of people with long COVID were out of the labor force and 51% worked fewer hours.⁵ In the economy as a whole, more than 1 million people may be out of the workforce at any given time because of long COVID.⁶
• This reduction in labor supply is a direct earning loss. If 1 million people are out of the labor force because of long COVID, the lost income would be more than $50 billion annually. People out of the workforce because of long COVID disproportionately worked in service jobs, including health care, social care, and retail.⁷ The widely noted shortage of workers in these sectors is driving up both wages and prices. Part of the recent surge in inflation in the US may thus be related to long COVID.
• People who are no longer able to work may also apply for Social Security Disability Insurance. To date, there has been no sustained increase in disability insurance applications since the onset of COVID-19. This is good news, though it bears watching as disability centers continue reopening from their COVID-19 shutdowns.
• Increased medical spending is another consequence of long COVID. The medical costs for treating long COVID have not been estimated, but costs have been estimated for similar conditions. If treatment of long COVID is similar to treatment of myalgic encephalomyelitis (chronic fatigue syndrome), these estimated costs could be about $9000 per person annually.⁸

• In an October 2020 analysis, we estimated⁹ the then-nascent COVID-19 pandemic might result in $2.6 trillion of cost as a result of long COVID. Unfortunately, our estimate seems very much on target.

   
• olicy implications. Investing in treatments for long COVID is obviously a high priority.

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• Introduction

   

  The coronavirus pandemic of 2019-2023 has caused over 6,880,000 deaths in over 676,600,000 confirmed cases worldwide by early 2023 [1]. The etiologic agent of COVID-19 disease is the Betacoronavirus SARS-CoV-2, first identified in late 2019 in Wuhan, China [2-4]. Variants emerged that were more infectious and supplanted earlier forms, namely Alpha, Beta, Delta, and Omicron; pathogenicity and case fatality rate (CFR) decreased progressively and reached a minimum with the Omicron variant [5]. At this point early in 2022, the pandemic was said to be over, and that the endemic phase of COVID-19 had begun [6].

    

  Subvariants of the Omicron strain arose, each more infectious than the previous ones [1,3,5,6]. Major subvariants included Omicron BA.2/BA.4 (mid-2022), Omicron BA.5 (late 2022), and Omicron XBB.1.5 (early 2023) [5]. The latter is a recombinant of Omicron BA.2.10.1 and BA.2.75 [7]. It was expected that the CFR of these subvariants should have decreased as did all previous forms, but this has not proven to be the case [1,5]. Here, we report an exponential increase in the pathogenicity of these later Omicron subvariants, and we model the CFR of the next major form of SARS-CoV-2 Omicron.
• Unexpectedly, the case fatality rate began to rise from the parent Omicron strain through subvariants BA.2/BA.4, BA.5, and XBB.1.5. The CFR of Omicron XBB.1.5 (0.0086) is close to that of the Delta strain (0.0124). The expanded scale of the orange inset in Figure 1 shows that the increase from Omicron subvariant to subvariant is not linear but, instead, appeared to approximate exponential growth.
• we extrapolated the curve to the putative next major Omicron variant and found a predicted CFR of 0.0413. This value is 2.5 times greater than that of the Alpha variant and is nearly 60% of the original Wuhan strain CFR.
• Extrapolation is fraught with unavoidable error, and this is a limitation of our study; however, we note that swings in the functions during exponential curve fitting placed the predicted CFR of the Omicron successor near 0.04, regardless. The excellent goodness-of-fit of both models (R² ≥$\ge$ 0.9930) suggests that the error associated with extrapolation has been minimized.

• Conclusions

   

  Present results show that SARS-CoV-2 Omicron subvariants have increased in pathogenicity to XBB.1.5 which has a CFR near that of the Delta strain. Recent increases in CFR are exponential, and we fit these data to a positive exponential function with high confidence (R² = 0.9992). Extrapolation to the next putative Omicron subvariant suggested that the CFR should be in the vicinity of 0.04, which would make it more dangerous than the Alpha variant and 60% as lethal as the original Wuhan strain. Though we hope that this does not come to pass, caution is yet warranted at this time.

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• Protective measures are essential to prevent long-COVID in children. We need to understand the long-COVID pathophysiology and symptomatology to support clinical management systems, establish rehabilitation programs, and design guidelines and therapeutic research. Long-COVID represents a significant public health concern, and there are no guidelines to address its diagnosis and management. Our meta-analyses further support the importance of continuously monitoring the impact of long-COVID in children and adolescents and the need to include all variables and appropriate control cohorts in studies to better understand the real burden of pediatric long-COVID.