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To the Editor:
We were interested to read the article by Ra et al.1 on a prospective study of 29 patients with and 28 patients without post-acute consequences of SARS-CoV-2 infection (PASC) with regard to viral persistence, immunological response and laboratory parameters. It was found that the PASC group had higher levels of nucleocapsid (NP) antigen, IL-2, IL-17A, VEGF, RANTES, sCD40L, IP-10, I-TAC and granzyme A, 1 and 3 months after COVID-19.1 The NP antigen and various cytokines involved in the immune response were also found to be elevated one and three months after COVID-19.1 The study is convincing, but some points should be discussed.
The first point is that it was not sufficiently ruled out that NP antigen and cytokine levels were already elevated before COVID-19.1 It is also not mentioned how an additional infection was excluded after COVID-19 but before the first follow-up and between the first and second follow-up. Therefore, it should be added to the exclusion criteria that patients with known chronic or acute infections, immunological diseases or malignancies before COVID-19 and those with these additional diseases after COVID-19 must be added to the exclusion criteria. Patients with conditions such as solid organ malignancies, hematologic malignancies or previous transplants, as listed in Table 1 of the index article, should be excluded from the evaluation.
The second point is that additional comorbidities and comedications were not sufficiently excluded. As several other comorbidities may also be associated with elevated cytokines, it would have been mandatory to include all comorbidities of the included patients.
The third point is that the PASC group was small. To make the statistical analysis more reliable, larger groups and a multicenter approach are needed. A study group of 29 patients is not sufficient to draw reliable conclusions.
The fourth point is that SARS-CoV-2 infection was diagnosed not only by reverse transcription polymerase chain reaction (RT-PCR) but also by antigen testing.1 Since antigen tests have a lower sensitivity and specificity than the RT-PCR tests, one should know how many of the patients with a negative antigen test had a positive RT-PCR.
The fifth point is that the development of PASC depends not only on the immune response against the virus, but also on whether only the lungs or also extra-pulmonary organs were affected. The more organs affected by the acute SARS-CoV-2 infection, the more severe the course of PASC usually is.
In summary, it can be said that the index study has limitations that put the results and their interpretation into perspective. Addressing these limitations could strengthen the conclusions and support the results of the study. Before characterizing the post-acute consequences of SARS-CoV-2 infection based on viral and immunological parameters, alternative causes for their increase must be excluded.
Authors’ Response to the Letter
We would like to appreciate Dr. Finsterer for valuable comments on our recent publication, “Viral, Immunologic, and Laboratory Parameters in Patients With and Without Post-Acute Sequelae of SARS-CoV-2 Infection (PASC)”.1
First, it is quite possible to assume that the levels of cytokines were affected by comorbidities and additional infection before and after COVID-19. Since the frequencies of patients with underlying diseases were similar in PASC and non-PASC groups, it is highly likely that the background cytokine levels acted similarly in both groups. As Dr. Finsterer suggested, we analyzed cytokine levels excluding underlying diseases: diabetes mellitus, chronic kidney disease, chronic liver disease, cardiovascular diseases, solid tumor, hematologic malignancy, hematopoietic stem cell transplant, and solid organ transplant. In addition, we analyzed all cases excluding those with transplants or malignancies that affect immunity of the host. As a result, we found a trend similar to the Fig. 2 in the publication. Moreover, in the review of the history of patients with multiple COVID-19 infections, we observed an interval of over 6 months between each infection. The elevated levels of cytokines and nucleocapsid antigens by previous infection might have very few effects on the current data.
Second, our study enrolled patients diagnosed by RT-PCR and rapid antigen test (RAT); however, none of patients underwent both tests concurrently. Among 57 patients, 56 were diagnosed only by positive RT-PCR results and one was diagnosed only by positive RAT result. It seems difficult to respond to this because among the study population, there were no patients who tested both RT-PCR and RAT.
Finally, we originally constructed a cohort with a larger number of patients and the current publication is the report of preliminary data from our cohort. It might be difficult to draw reliable conclusions from our study. As Dr. Finsterer mentioned, not only host immune responses but organs affected by SARS-CoV-2 infection are also important in the development of PASC. To complement these points, analyses of single cell or bulk RNA sequencing, chest computed tomography, and brain functional magnetic resonance imaging in a larger number of patients are ongoing.
We would like to extend our gratitude to Dr. Finsterer for his thorough review and valuable insights regarding our article. We believe this response has provided comprehensive clarification on the issues he raised.
Ji-Soo Kwon and Sung-Han Kim
Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
Address for Correspondence: Sung-Han Kim, MD, PhD, FIDSA. Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea. kimsunghanmd@hotmail.com
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