The role of a cytokine storm in severe coronavirus disease 2019 in pregnancy

To the Editors:

We read with great interest the recent article by Hantoushzadeh et al¹ on maternal death due to coronavirus disease 2019 (COVID-19). As noted by the authors, the 7 maternal deaths caused by severe COVID-19 should prompt reexamination of any current guidelines and recommendations by professional societies. We agree with their views, and therefore, we would like to draw the readers’ attention to the cytokine storm in pregnant women with COVID-19.

As a uniquely vulnerable group, pregnant women may be predisposed to a higher risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and more complicated clinical events than the general population. There have been case reports of pregnant women with severe COVID-19 requiring mechanical ventilation and extracorporeal membrane oxygenation (ECMO)^{2 , 3} and reports of maternal and intrauterine fetal death.^{1 , 4} Accumulating evidence suggests that a cytokine storm syndrome (CSS), an overactive immune response triggered by COVID-19, rather than the virus itself, is responsible for severe symptoms and deaths in patients with COVID-19. However, there is little information on this hyperinflammatory response in pregnant women with COVID-19. We would like to present the case of a pregnant woman with COVID-19, a case that was also previously presented by Liu et al² in the Journal of Infection, who developed a severe systemic inflammatory response syndrome (SIRS), cytokine storm with acute respiratory distress syndrome (ARDS), and multiple organ failure (MOF) requiring the use of continuous renal replacement therapy (CRRT) and ECMO and fortunately survived and recovered.

On February 1, 2020, a 31-year-old woman at 35 2/7 weeks’ gestation in her third pregnancy was referred to our hospital with fever and dry cough. Pertinent laboratory results on admission showed leucopenia (white blood cell count, 1.8×10⁹/L; reference range, from 3.5×10⁹/L to 9.5×10⁹/L) and lymphopenia (lymphocytes, 0.223×10⁹/L; reference range, from 1.1×10⁹/L to 3.2×10⁹/L), impaired liver function, and remarkably elevated levels of C-reactive protein (CRP, 60.8 mg/L; reference range, <10.0 mg/L), procalcitonin (PCT, 18.19 ng/mL; reference range, <0.05 ng/mL), interleukin-6 (IL-6, >5000 pg/mL; reference range, <7.0 pg/mL; other cytokine measurements were unavailable in our hospital), and D-dimer (4743 μg/L; reference range, <256 μg/L). Unenhanced chest computed tomography showed a large opaque patchy shadow in the lower lobe of the left lung (Figure , A and B). Because of a rapid deterioration in clinical status and a concurrent surge in inflammatory biomarkers triggered by COVID-19, she developed a severe SIRS, septic shock, ARDS, and MOF, requiring an emergency cesarean delivery and mechanical ventilation. The male neonate was born with an Apgar score of 1 and did not respond to neonatal cardiopulmonary resuscitation protocol and died 2 hours after birth. Real-time polymerase chain reaction testing of the amniotic fluid or placenta for the neonate for SARS-CoV-2 infection was not performed, and the family refused autopsy for the neonate. Later, the blood culture obtained on the admission day revealed the patient had a coinfection with Streptococcus parasanguinis. The patient’s health continued to deteriorate, requiring the combined supportive treatment of CRRT, ECMO, antibiotics and antiviral treatment, immunoglobulin, and steroids. Fortunately, she responded to the treatment, survived, and subsequently recovered, and she was discharged on March 17, 2020 (Figure, C–F).

Figure.

Imaging findings of the patient

A and B, Unenhanced chest CT showing a large opaque and ground consolidation (indicated by a white arrow) in the lower lobe of the left lung. C–F, Serial anteroposterior chest x-ray images of the development and outcomes of pulmonary inflammation after hospitalization: C, on day 2, after cesarean delivery; D, on day 21, before withdrawing ECMO support; E, on day 38, before withdrawing mechanical ventilation; and F, on day 50, before discharge.

CT, computed tomography; ECMO, extracorporeal membrane oxygenation.

Wang. Role of a cytokine storm in severe COVID-19 in pregnancy. Am J Obstet Gynecol 2020.

The surge in IL-6 and remarkably elevated levels of CRP, PCT, and D-dimer, accompanied with severe leucopenia, lymphopenia, and a rapid deterioration in clinical status, suggested the presence of a CSS in this patient. This case highlights the need to be vigilant for clinical and laboratory evidence of a cytokine storm triggered by COVID-19 in pregnant women. All pregnant women with COVID-19 should be closely observed and screened for hyperinflammation. The key to clinical improvement and survival of this pregnant woman with severe COVID-19 was the rapid identification and control of the hyperinflammatory response and the reduction of inflammatory mediators by using a combination of CRRT, ECMO, and other therapies.