This study retrospectively analyzed the characteristics of patients infected with SARS-CoV–2 and identified that lymphopenia acted as a good predictor for severity of COVID–19. In particular, more patients had hypertension and coronary heart disease in the group of lymphpenia. Lymphopenia was associated with inflammatory markers, grades of pneumonia severity and prolonged hospitalization. Additionally, normalization of lymphocyte count indicated the recovery of COVID–19. Especially in severe and critical cases, lymphocyte count normalizing was the first appeared predictor for disease improvement. In mild and general cases, the normalizing of CRP was the most sensitive indicator for disease improvement.
Unlike the previous report that SARS-CoV–2 may infect more men than women, the sex ratio was balanced in the present study. The patients with chronic underlying disease were about one third and the severe or critical cases accounted for about one fourth, which were less than other cohorts reported in Wuhan.[5, 4, 9] The differences could be attributed to the early insufficiency of medical resources in Wuhan, which gave priority of admission to those patients who were weak and had comorbidities. Interestingly, in patients with lymphopenia, there were more patients having hypertension and coronary heart disease (Table 1). On the contrary, more cases with hepatitis B were observed in the group of no lymphopenia.
Angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV and SARS-CoV2, is a surface molecule localized on arterial and venous endothelial cells, arterial smooth muscle cells and respiratory tract, which is a homologue of ACE. ACE and ACE2 play different roles in the rennin-angiotensin system (RAS). ACE generates angiotensin II, the increase of which was reported to be correlated to pathogenesis of heart failure and hypertension, whereas ACE2 negatively regulates the level of angiotensin II. ACE inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) decrease the level of ACE and increase the level of ACE2, which could increase the risk of SARS-CoV–2 infection. We infer that the imbalance of ACE/ACE2 axis contributed to the severity of disease, which could be the reason why more patients had hypertension and coronary heart disease were in the group of lymphopenia, since ACEIs and ARBs are commonly used drugs under these circumstances.
The characteristics and pathogenesis of COVID–19 are both similar and different to the prior severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). The major clinical symptoms resulting from these coronavirus-infected diseases include fever, cough, fatigue, myalgia and gastrointestinal symptoms.[4, 16, 2] However, the clinical manifestation of COVID–19 could be more asymptomatic. Of this cohort of patients, about 25% had no fever on admission (Table 1), which implies that it is more challenging to identify COVID–19 patients and control the pandemic over the globe.
Risk factors for adverse outcomes in patients with SARS and MERS have been investigated in previous studies.[17, 1, 16, 18, 19] Specifically, older age, comorbidity, low serum albumin, and concomitant infectious were identified as factors associated with poor outcomes. Lymphopenia was common in both SARS and MERS patients and has also been reported as an important predictor for severe disease in SARS and MERS. In the current study, about half of the patients presented with lymphopenia on admission, which was comparable with the frequency in SARS as reported, but it was lower than the frequency of lymphopenia reported in COVID–19 patients in Hubei Province. Our results revealed that lymphopenia was associated with disease severity, which is consistent with the study by Liu Y, et al that lymphopenia was positively correlated with the severity of acute lung injury in patients with COVID–19. As shown in Figure 5, the recovery of lymphocyte count was the first sign to show up in severe and critical cases before they improved and discharged, suggesting that normalizing of lymphocyte was a more sensitive indicator than CRP or CT scan for prediction of disease recovery in patients of severe and critical grades.
Lymphopenia was reported in varies types of virus-infected diseases, such as SARS[20, 6, 24], MERS[18, 21] and respiratory syncytial virus. As for the underlying mechanism of lymphopenia, previous study reported that lymphopenia in SARS may be caused by enhanced vascular sequestration associated with increased soluble vascular cell adhesion molecule–1 levels, but it remains unclear in patients with COVID–19. It has been well known that the treatment of glucocorticoid results in lymphopenia by causing the migration of lymphocytes from the peripheral blood. Meanwhile, viral infections would inevitably lead to the activation of hypothalamic-pituitary-adrenal axis under stress, resulting the up-regulation of endogenous corticosteroids, which might involve in the immunopathogenesis of lymphopenia of COVID–19.
Eosinophils only count for 0.4%–8% of leucocytes in the peripheral blood, but act as rather important inflammatory mediators and involve in innate immunity, allergies, parasitic infection and virus infection. In the current study, we found that the frequency of eosinophilia (72.2%) was higher than lymphopenia. Eosinophilia was associated with lymphopenia and its recovery also acted as an indicator for the improvement of the disease. The median recovery time of eosinophils was shorter than CRP and CT scan in severe and critical cases. Thrombocytopenia was rarely observed in our study and had no significant impact on the outcome.
Currently, no specific antiviral treatment is available for SARS, MERS and COVID–19. A range of treatments including lopinavir/ritonavir, interferon-β2b and recombinant human cytokine derived protein was used in this cohort of patients, but no improvement for outcome by any of them was observed. As a previous therapeutic measure for SARS, IVIG has not been confirmed effective for outcome improvement. In our study, no benefit from the approach of IVIG was observed, no matter patients were with lymphopenia or not. Given the high cost of IVIG and economic burden for public health systems, more investigations of this approach are needed to provide evidence for a large-scale use.
Our study has some limitations. For example, some of the laboratory examination records and treatment records were not available since this is a retrospective study. In condition, an examination of lymphocyte subsets is unavailable in most of the patients. So there was still no evidence for which subset contributed the profound lymphopenia in COVID–19 patients. On this basis, a more comprehensive and thorough investigation is necessary in the future.
In summary, by analyzing the clinical data of 115 patients with COVID–19, our results showed that lymphopenia was common and correlated with the severity of COVID–19. To the best of our knowledge, this is the first retrospective study revealing the significance of the normalizing of lymphocyte count for predicting disease improvement, putting emphasis on the need to monitor the blood cell count dynamically in the management of COVID–19.