Much has been written about the coronavirus disease 2019 (COVID-19) in pregnancy and its attendant risks to the mother and/or the fetus. Caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the COVID-19 spectrum of severity ranges from asymptomatic to critically severe disease. The reasons for this variation remain unclear but are speculated to be the result of dysregulated cytokine release as part of an inflammatory immune response gone haywire – the cytokine storm.
A new paper explores the changes in cytokines that occur in a pregnant woman while infected with SARS-CoV-2.
The difference in cytokine release may spell the difference between survival and death in COVID-19, as shown by the difference in outcomes when steroids are used in critical cases – a reduction in mortality by just over a third. However, the timing of steroids appears to be key to this beneficial effect, with early administration being at best ineffective and at worst dangerous.
The current study, published in the journal Cytokine, deals with the results of serum cytokine analysis in a small group of pregnant women with and without COVID-19 in the third trimester in a single New York City hospital between March 22 and April 30, 2020. These women presented either for childbirth or because of severe COVID-19 symptoms.
All the 44 COVID-19-positive cases and the 25 controls were classified as mild-moderate or severe disease. They were tested by polymerase chain reaction (PCR) at admission and then by serologic testing for acute-phase immunoglobulin (Ig) M and IgG antibodies to the SARS-CoV-2 spike protein.
These results were combined to assess the time point of the infection in each woman, assuming seroconversion to occur at a median of 11 days from the first positive PCR test and 13 days from the onset of symptoms.
Early infection was diagnosed if IgM and IgG were both negative but PCR positive. Middle infection meant IgM+ but IgG+/-, and Late infection meant IgM- but IgG+. The validity of this classification was indicated by the fact that the median days from symptom onset were shorter by 2.5 days in Early infection compared to Middle or Late infection.
What did the study show?
Most of the patients delivered during the current admission, with half of the patients in the positive and negative groups having presented for labor. Risk factors were comparable in both groups, except for body mass index, which was higher in the Positive group, and autoimmune disease, which was higher in the control group.
Most patients presented with asymptomatic infection or mild-moderate symptoms. However, women in the Positive group had higher IL-18, IL-1Ra, and IP-10 values, irrespective of whether they were in labor. These cytokines also tended to be higher with more severe disease.
The two markers that were unequivocally higher in severe vs. asymptomatic infection was HGF and IL-2Ra.
Further analysis showed that several cytokines, including IL-18, IP-10, and IL-1Ra, peaked in Early infection, but IL-8 fell. Both the latter and IP-10 returned to normal by Middle Infection. While IL-18 remained raised throughout this period, it fell to baseline by Late infection, while IL-2Ra decreased at this time point.
However, serologic testing showed no correlation with severity of disease or most vital signs, except for the systolic blood pressure, which was higher in early and middle infection. The different cytokines analyzed were also not correlated in controls or seronegative women, but IL-18, IL-1Ra, and IP-10 showed a strong association in all seropositive women.
What are the implications?
This study shows that pregnant women with COVID-19 show differences in the levels of various cytokines compared to controls. The differences consisted of the presence of IL-18, IL-1Ra, and IP-10 in COVID-19, while HGF and IL-2Ra were biomarkers of severe disease and Late infection.
Using these biomarkers, it was possible to identify the phase of infection since IL-8 was low in the acute phase before the antibody response set in but returned to normal afterward. IL-18 remained higher throughout the acute phase. Also known as IFNγ inducing factor, this cytokine is an activator of type 1 T helper cells (Th1 cells), leading to the production of IFNγ when IL-12 is also present.
IL-1Ra is a specific IL-1 antagonist, IL-1 being a mediator of innate inflammation. IL-1Ra also rises during SARS-CoV-2 infection, reflecting disease severity, and may remain high for up to 15 days. Anakinra is a recombinant human IL-1Ra that was initially thought to offer promise in treating hospitalized COVID-19 patients but has not fulfilled its promise so far.
The results corroborate earlier studies that demonstrated the rise of IL-18 in COVID-19, increasing with disease severity, but also add the observation that IP-19 also follows the same trajectory. The researchers showed that IP-10 levels fall to baseline by the time the patient seroconverts for the first time. Indeed, this cytokine is induced by IFNγ and is linked to T-cell responses, thus potentially playing a part in resolving the early immune response to the virus.
Some other studies showed an association between severity and serologic status, but this was not identified here, perhaps because no patients were critically ill, and all were admitted for birth. However, the three cytokines IL-18, IL-1Ra, and IP-10 showed a robust correlation in the seropositive phase.
The lack of earlier correlation could stem from the presence of one or more, as yet unobserved, factors active in acute infection. Conversely, it may be that the cytokine response follows a common pathway once humoral immunity sets in.
Overall, the study suggests that the cytokine response in pregnancy resembles that seen in the general population, with the most marked changes in acute infection. Secondly, serologic markers showed a different cytokine profile according to the time course of the infection, suggesting that “by assessing cytokine levels according to serology status, researchers may be able to stratify the immune response to SARS-CoV-2 for all infected patients.”
The researchers conclude, “the specific and differing patterns of quickly changing individual cytokine levels may prove useful as markers of future disease course, outcomes, and even suggest therapeutic targets or guide timing of interventions.”