A Case of Critically Ill Infant of Coronavirus Disease 2019 With Persistent Reduction of T Lymphocytes

Supplemental Digital Content is available in the text.

T he current outbreak of the coronavirus disease 2019 (COVID-19) from the epicenter Wuhan city in Hubei Province has spread to numerous countries. Many publications have described the clinical and the laboratory characteristics of the critically ill adult patients. [1][2][3] However, our understanding of the spectrum of pediatric cases, treatment of critically ill patients and their ability of transmitting the coronavirus that causes COVID-19 still remains inadequate because very few pediatric cases of COVID-19 have been reported.
In this article, we describe the complete clinical course and follow-up data of a critically ill infant with COVID-19 presenting with life-threatening clinical features including high fever, septic shock, recurrent apnea, petechiae and acute kidney injury.

CASE PRESENTATION
An 8-month-old male infant with poor growth and malnutrition started coughing on January 25, 2020, after a routine hospital visit for physical examination a week earlier. His mother denied the history of any direct contact with COVID-19 patients. His cough was aggravated on January 31, and he was subsequently hospitalized. He had medical history of neonatal cardiac surgery (atrial and ventricular septal defects and aortic stenosis repairs) and pneumonia twice during his early infancy (Table S1,  On the first day of the admission (7th illness day), upon evaluation, dull heart sounds, mottled skin, cold fingers and petechiae were found. The infant had wheezing and recurrent apnea and was supplied oxygen delivered by nasal cannula at 2 L/ min. He had body temperature of 38.3°C with recurrent apnea, and the percutaneous oxygen saturation dropped to 60%-70% on several occasions. Chest radiograph showed increased density, profusion and thickened lung texture before the endotracheal intubation, small spot-like and patchy fuzzy shadow. He was given ventilator-assisted breathing via endotracheal intubation. The image of chest radiograph was improved a little after endotracheal intubation ( Figure S1, Supplemental Digital Content 1, http://links.lww.com/INF/D942).
His urine output was 0.4 mL/kg·h with gross hematuria, and his lowest blood pressure recorded was 85/37 mm Hg. The SARS-CoV-2 nucleic acid tests of the nasopharyngeal swab and rectal swab were positive, and the other viral respiratory pathogens tests were negative ( the level of lactate dehydrogenase was increased (Tables 1 and 2). C3 and C4 were in the normal range. Initial treatment was the first dose of intravenous immune globulin (1 mg/kg·d, hospitalization days 1-2, illness days 7-8), methylprednisolone (1.5 mg/kg twice a day, hospitalization days 1-5, illness days 7-11) combined with the supportive therapy such as fluids and electrolytes, low-dose diuretics and dopamine to maintain blood pressure. Despite the above treatment, the patient still had fever (up to 38.6°C) and maintained a poor peripheral circulation. Lopinavir/ritonavir (12.5/3.125 mg/kg, twice daily) was introduced on the evening of hospitalization day 7 (illness day 13), followed by a second dose of intravenous immune globulin (1 mg/kg·d, hospitalization days 8-9, illness days 14-15), methylprednisolone (2 mg/ kg·d, hospitalization days 8-14, illness days 14-20 days, tapering) ( Table 1). The infant continued febrile on hospitalization days 8 and 9 with a body temperature of up to 39.6°C and a decrease in lymphocyte count to 0.38 × 10 9 /L. On the 4th and 10th days of hospitalization (10th and 16th illness days), 2 doses of granulocyte colony-stimulating factor were administered to improve the neutrophil count (decreased to 0.3 × 10 9 /L). The pyrexia started subsiding on hospitalization day 10 (day 3 of lopinavir/ritonavir administration), and an improvement blood pressure was observed. By the 15th day of hospitalization day (day 8 of lopinavir/ritonavir administration), he became afebrile and was off ventilator support.

DISCUSSION
Because critically ill pediatric cases with COVID-19 are unusual, little is known about the characteristics in this age group with such severity of illness.
This infant had typical critical features including high fever, septic shock, recurrent apnea, gross hematuria, hypofibrinogenemia, lymphopenia and acute kidney injury. The initial clinical manifestation of his critical condition was septic shock, which is similar to adults. 3 Adult data showed that elderly patients with a history of comorbidities were more likely to progress to severe disease, 4 because those comorbidities associated with low-grade systemic inflammation, such as diabetes and hypertension. 5 The defects in T-cell and B-cell function of elder patients could lead to a deficiency in control of viral replication and more prolonged proinflammatory responses, potentially leading to poor outcome. 6 The medical history of cardiac surgery, pneumonia, failure to thrive and malnutrition of this infant might trigger the chronic inflammatory state and predisposing risk factors for the progression to critical stage. Therefore, more emphasis should be put on infants with comorbidities especially involved the immune system and immunodeficiency during the global epidemic phase of COVID-19.
Research about the clinical features of 8 severe pediatric patients with COVID-19 showed no significant decrease in peripheral CD3+, CD4+ and CD8+ T lymphocytes. 7 It also has been observed in other noncritically ill (including severe cases) COVID-19 pediatric patients. 8,9 However, this is completely different in our case. Significant decrease in CD3+, CD4+ and CD8+ lymphocytes was observed during hospitalization of this infant. The circulating lymphocytes, mainly CD3+, CD4+ and CD8+ T cells, dramatically declined and were sustained for at least 68 days. Data of adults also showed that lymphopenia and reduction of CD4+ and CD8+ T cells were the clinical features observed in severe COVID-19 patients. [1][2][3][4] The reduction of T cells also was the typical feature of this critically ill infant. The lymphocytes subsets were not checked in this infant: however, the complete white test showed that the count of the lymphocytes was in the normal range when he was 6 months old (Table S2, Supplemental Digital Content 1, http://links.lww.com/ INF/D942). CD4+ T cells play an important role in immune system and orchestrate the deletion and amplification of immune cells. The depletion of CD4+ T cells leads to an enhanced immune-mediated interstitial pneumonitis and delayed clearance of SARS-CoV from the lungs. 10 These data highlight that the reduction of CD4+ T cells might be related to disease severity of COVID-19, including in children.
Despite the reduction of CD4+ lymphocytes, an accumulation of effector memory CD4+ T cells (CD4+TEM) (53.13% in CD4+ lymphocytes, 0.145 × 10 9 /L) was found in this infant. This indicates the presence of memory T-cell response, and SARS-CoV-2 had not altered the capacity of accumulation of CD4+TEM.
The patient's nasopharyngeal swab nucleic acid tests remained positive for 49 days and are the longest positive nasopharyngeal test duration reported in children with COVID-19, surpassing a reported surviving adult case where the nasopharyngeal swab was positive for COVID-19 up to 37 days. 3 The analysis of 10 pediatric patients who had mild COVID-19 indicated that nasopharyngeal viral shedding was about 2-3 weeks. 9 None, however, had severe lymphopenia. An adult cohort study showed the nasopharyngeal virus was continuously positive until death in nonsurvivors of COVID-19. 3 The longer nasopharyngeal viral shedding in this infant may be related to the high nucleic acid load and the reduced ability of virus clearance after methylprednisolone use. The use of steroid also affects lymphocyte count. It remains e90 | www.pidj.com