Matías A. Loewy
As the pandemic progresses and COVID-19 cases multiply worldwide, new questions are emerging about the nature of the immune response to the infection. "If I experience a symptom, I imagine the battle between my immune system and the virus, and what cytokines are being released," said Dr. Michael Saag, an infectious disease specialist at the University of Alabama at Birmingham, who contracted the disease and said he had never experienced anything like it.
Below are some enigmas that scientists and doctors are trying or beginning to answer, and which could define epidemiological analyses, therapeutic behaviors, and preventive approaches.
When do antibodies against the virus appear?
Antibodies against SARS-CoV-2 can appear between 5 and 7 days after the onset of clinical symptoms, although the response is variable: a Chinese study not yet peer-reviewed on 173 patients showed that less than 40% had seroconversion before day 7, although the proportion grew to 100%, 94.3%, and 79.8% for total antibodies, immunoglobulin M, and immunoglobulin G, respectively, after day 15.[1]
Another Australian study documented the kinetics of the robust immune response in a 47-year-old patient with non-severe COVID-19, and detected antibody-secreting plasma cells from day 7, with a peak on day 8.[2] According to Dr. Fernando Fariñas, director of the Institute of Pathology and Infectious Diseases of Malaga and member of the scientific committee of the io Foundation, in Spain, "it is speculated that the later these antibodies appear, the worse the condition will evolve."[3]
How long do these antibodies last? Are they protective?
Nobody knows. On her Twitter account, Dr. Krutika Kuppalli, a professor in the division of infectious diseases and geographic medicine at the Center for Innovation in Global Health at Stanford University School of Medicine in Stanford, USA, wrote: “We know that patients develop an antibody response, but it is not yet clear whether they are protective and for how long.”
In an interview with Medscape Spanish Edition, Dr. William Moss, executive director of International Vaccine Access at the Johns Hopkins Bloomberg School of Public Health in Baltimore, USA, noted: “We still need to learn what antibody levels are protective against reinfection or disease, and for how long those antibody levels persist. Many respiratory viral infections result in long-term protective immunity, and that could be the case for SARS-CoV-2, but we don’t know for sure yet. As the availability of antibody tests increases—and many laboratories are working on that—we will be able to answer these very important questions.”
Can reinfection occur? This question is related to the previous one. Although some possible, but unconfirmed, cases of reinfection have been reported, most doctors and researchers believe that patients become immune, at least in the short and medium term. A recent Chinese study in rhesus monkeys, exposed to SARS-CoV-2 one month after the first infection, and which showed no symptoms or evidence of viral replication, suggests that the primary infection could protect against subsequent exposures. [ 4 ] In any case, it is unknown whether these antibodies reflect the initial immune response or a more lasting immunological memory.
There is no convincing evidence that reinfection has occurred (in human patients), Dr. Angela Rasmussen, Ph.D., a virologist at the Center for Infection and Immunity , Columbia Mailman School of Public Health , in New York, USA, stated on the 25th on Twitter #AskReuters .
The situation could change if the virus were to mutate substantially, but that doesn't seem to be the case. We aren't seeing those mutations occurring, nor are we seeing people getting sick again. But it's a new virus, and we're constantly learning, noted Dr. Paula Zingoni, a family medicine specialist and Master of Public Health, who is the Director of Operational Planning for the City of Buenos Aires.
"Immunity to some viral infections can be short-lived if the virus mutates rapidly. But we have some evidence that SARS-CoV-2 does not appear to have a high mutation rate, so long-term protective immunity is possible," Dr. Moss told Medscape in Spanish .
4. What determines whether some people become severely ill while others show only mild symptoms? There is no single answer, and factors such as general health status, genetic predisposition, degree of exposure to the virus, and even the type of care received can all play a role. In an article published in Cell Death & Differentiation , scientists from China and Italy proposed that the immune response to viral infection occurs in two phases: [ 5 ] during incubation and non-severe stages, the adaptive immune response can eliminate the virus and prevent progression; but when the virus spreads, it can cause massive destruction of affected tissues, and the damaged cells induce inflammation in the lungs that is mediated by macrophages and pro-inflammatory granulocytes.
Dr. Fariñas wrote that some patients may show a particular predisposition to developing a hyper-response to the infection, inducing a hyperinflammatory state through what is known as a cytokine storm . "Ultimately, this hyperinflammatory response is responsible for the patient's severe clinical condition and can even lead to death. Therefore, he stated that it is very important to control this response in this subgroup of patients."
The immune dysregulation caused by the COVID-19 virus and the macrophage activation syndrome that is triggered in severe cases " is like a fire on top of a fire that is dancing on lava while juggling on top of a volcano ," pointed out Dr. Alberto García Salido, a Spanish pediatric intensive care specialist and writer who is very active on social media.
An important document from the Argentine Society of Immunology states that the increase in inflammatory cytokines interleukin-1, interleukin-6, interleukin-8 and tumor necrosis factor-alpha precedes the inflammatory storm, while CD4+ cell lymphopenia and the increase in the T compartment of naïve CD4+ cells and the decrease in effector CD4+ cells are also a poor prognostic feature. [ 6 ]
5. Is there any cross-protection from previous infections with other coronaviruses?
In early March, a German study using serum samples from patients recovering from SARS-CoV infection, the coronavirus that causes severe acute respiratory syndrome, suggested that the neutralizing antibody response may offer some protection against SARS-CoV-2 infection .
However, that doesn't mean that patients who recovered from the 2002-2003 SARS outbreak still maintain protective antibody levels. And according to Dr. Rasmussen of Columbia University, there is still no evidence of cross-immunity with other coronaviruses.
"Antibodies from severe acute respiratory syndrome last up to 4 years (although the average in a 2007 study was 2 years); [ 7 ] those from Middle East respiratory syndrome , 2 years, and those from the common cold in childhood caused by coronavirus, from 3 to 5 years. I don't rule out that children get less sick with SARS-CoV-2 because there is some cross-protection, although this would have to be investigated," Dr. Roberto Debbag, vice president of the Latin American Society of Pediatric Infectious Diseases, told Medscape in Spanish .
Dr. Debbag also recommends influenza and pneumococcal vaccination for people over 65, especially in the Southern Hemisphere, not because they protect against COVID-19, but because they prevent the need to seek medical attention if these diseases are contracted, as well as the confusing effect they have on coronavirus infection.
Doctors Moss and Debbag have declared that they have no relevant financial conflicts of interest.
Follow Matías A. Loewy of Medscape in Spanish on Twitter @MLoewy .
For more content, follow Medscape on Facebook , Twitter , Instagram , and YouTube .
REFERENCES
- hao Jr. J, Yuan Q, Wang H, Liu W, et al. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019. medRxiv . 3 Mar 2020. doi: 10.1101/2020.03.02.20030189. Fountain
- Thevarajan I, Nguyen THO, Koutsakos M, Druce J, et al. Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19. Nature Medicine . 16 Mar 2020. doi: 10.1038/s41591-020-0819-2. Fountain
- IO Foundation. Clinical Immunology of COVID-19. What do we know so far? By Dr. Fernando Fariñas. Published March 21, 2020. Accessed electronically. Source
- Bao L, Deng W, Gao H, Xiao C, et al. Reinfection could not occur in SARS-CoV-2 infected rhesus macaques. Biorxiv. Mar 2020. doi: 10.1101/2020.03.13.990226. Fountain
- Shi Y, Wang Y, Shao C, Huang J, et al. COVID-19 infection: the perspectives on immune responses. Cell Death Differ . 23 Mar 2020. doi: 10.1038/s41418-020-0530-3. PMID: 32205856. Source
- Latin American Society of Immunodeficiencies. Coronavirus Update. March 26, 2020. Accessed electronically. Source
- Wu LP, Wang NC, Chang YH, Tian XY, et al. Duration of antibody responses after severe acute respiratory syndrome. Emerg Infect Dis . Oct 2007;13(10):1562-4. doi: 10.3201/eid1310.070576. PMID: 18258008. Source
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