Patient hematology during hospitalization for viral pneumonia caused by SARS-CoV-2 and non-SARS-CoV-2 agents: a retrospective study

Coronavirus disease (COVID-19) caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in China and has rapidly spread worldwide. As of March 3, 2021, more than 114.79 million confirmed cases and 2.5 million deaths (2.22% case fatality) in more than 200 countries have been reported [1]. Fever, fatigue and dry cough are considered the main clinical manifestations. In severe cases, dyspnea and/or hypoxemia may occur after 1 week of onset and, in extreme cases, can degenerate to acute respiratory distress syndrome, septic shock, metabolic acidosis, hemorrhage and coagulation dysfunction, multiple organ failure and death [2‐4]. Although SARS-CoV-2 is a coronavirus similar to SARS-CoV and Middle East respiratory syndrome (MERS)-CoV, a higher human-to-human transmission rate has been observed in the COVID-19 pandemic than in the SARS and MERS outbreaks, which had shorter incubation periods and higher fractions of severe cases and deaths. Until recently, several studies have revealed that some specific minor symptoms are also correlated with COVID-19, such as anosmia, ageusia, and cutaneous manifestation [5‐9].

Respiratory viruses infect and affect the upper and lower respiratory tract, respectively, in vulnerable populations, such as infants, the elderly, and immune-compromised individuals. Therefore, they could lead to pneumonia and various respiratory distress syndromes [10, 11]. These most probably result from coronavirus infections, such as MERS-CoV, SARS-CoV, and SARS-CoV-2, and other RNA viruses, such as influenza (H1N1, H5N1) and Ebola viruses, which have animal reservoirs and can cross species barriers to adapt to new environments and/or new hosts. These zoonoses may have disastrous consequences in humans [12]; the burden is even higher when they have neurological consequences. The most severe H1N1 influenza pandemic occurred in 1918, claiming over 50 million lives [13], while the last H1N1 pandemic in 2009 claimed approximately 200,000 lives worldwide [14]. Human adenoviruses [AdV], including type 55 and type 7, have been reported in the United States [15], Turkey [16], Singapore [17], and China [18].

The Chinese government applied the experience of SARS outbreak management toward controlling the COVID-19 epidemic. To date, the treatments adopted were based on previous experience with SARS, MERS, or influenza. Hematological findings are important in providing clinical teams with data on useful prognostic markers. Hematological changes in patients with COVID-19 and SARS are common. These patients usually have higher leukocyte counts and neutrophil-lymphocyte ratios, and lower lymphocyte counts and monocyte, eosinophil, and basophil percentages, especially in severe cases. Most severe cases demonstrated elevated levels of infection-related biomarkers and inflammatory cytokines [19‐21]. Another laboratory finding that can be easily measured in daily clinical practice is albumin, whose concentration levels may be associated with COVID-19 severity [22]. In 45 patients infected with AdV, leukocytosis with left shift was noted in the early course; leukopenia and thrombocytopenia were found as disease severity progressed [23]. Investigations of leukocyte and platelet (PLT) counts in the peripheral blood are useful as they may constitute ancillary exams to form assumptions.

Paliogiannis et al. [24] published their study focusing on COVID-19 and COVID-19 pneumonia differences. Although the clinical characteristics are known, studies on the kinetics of hematological changes in patients with COVID-19 are scarce. Interestingly, most studies have focused on differences and similarities between SARS-CoV-2 and other beta-coronaviruses (primarily SARS-CoV and MERS-CoV), but few of them have examined other viruses, such as influenza viruses (primarily H1N1, but also H5N1 and H7N9) and adenoviruses [25, 26]. Recent research has mostly focused on admission indicators, with few studies on changes in lymphocytes throughout the disease course. Zheng et al. [20] compared the differences in patients with COVID-19 to reveal the risk factors for severe disease. Different patients may have a different disease course (disease development or recovery period) after the disease onset, which corresponds to different changes in the white blood cell (WBC) counts. The accuracy of the analysis results for dynamic changes would be affected by using the days after disease onset as the only reference; however, this ignores the different disease course in different patients.

The COVID-19 pandemic continues, and virus transmission may last for more than 1 year [27]. Concurrently, other coronaviruses and influenza viruses may co-infect people with SARS-CoV-2 and cause more serious respiratory diseases, owing to similar clinical symptoms [28]. Whether SARS-CoV-2 or other respiratory viruses can promote each other’s spread remains unclear. Early diagnosis and treatment are very important for the prevention and control of infectious diseases. This retrospective, single-center study aimed to analyze the dynamic changes in hematological counts in four different patients with viral pneumonia at our hospital during several pneumonia outbreaks (SARS, 2003; H1N1, 2009; human AdV type 7, 2018; COVID-19, 2020) and provide reference values for the pathogenesis and prognosis of pneumonia caused by respiratory viruses.

Consistent with previous works [3, 19, 20], the lymphocyte counts in all patients were lower than the normal level during the disease course. The lymphocyte count was lower in severe than in mild COVID-19 patients, possibly indicating that lymphocytopenia is related to disease severity. Lymphocytopenia has been evaluated as an independent biomarker of mortality in hospitalized patients diagnosed with community-acquired pneumonia [29] and is considered a risk factor for influenza during bacterial superinfections [30], thus determining a bad prognosis. Lymphopenia has also been associated with an increased risk of death in patients with COVID-19 [7]. Patients with lymphocytopenia would require close clinical monitoring for these potentially fatal infectious complications.

Neutrophilia and thrombocytopenia were observed in the severe COVID-19 and SARS groups. The neutrophil counts increased gradually in mild COVID-19, severe COVID-19, and SARS patients. The main neutrophil functions are phagocytosis, granules release, and cytokine production. Proinflammatory cytokines produced by neutrophils may limit virus replication and halt progression to severe disease. During disease recovery, the neutrophil counts gradually return to normal levels, implying that increasing and decreasing neutrophil counts may be signs of disease progression and recovery. Steroids may cause neutrophilia and have been used in the treatment of severe SARS and severe COVID-19. Neutrophils are reportedly susceptible to influenza A virus (IAV), and the infection is productive for pH1N1 [31]. Virus-infected neutrophils can upregulate interferons and other antiviral factors [32] that could limit viral replication. Neutropenia has been demonstrated to increase the pulmonary virus titer and the mortality rate during IAV infection, suggesting a protective role of neutrophils during influenza [33].

Upon antigen recognition, PLTs become activated and interact with WBC to facilitate pathogen clearance through WBC activation and clot formation [34]. The PLT counts of patients with AdV and mild COVID-19 were elevated at the obviously symptomatic stage and returned to normal levels at the recovery stage, while in the severe COVID-19 group, they decreased significantly after the obviously symptomatic stage. It has been reported that the most common hematological changes in patients with SARS and COVID-19 were lymphopenia and thrombocytopenia [20, 21]. Interestingly, these changes were closely related to the disease prognosis and reflected a more severe clinical course. A more sizable reduction in the PLT count was especially noted in non-survivors [35]. Viral infections elicit a systemic inflammatory response and cause an imbalance between procoagulant and anticoagulant homeostatic mechanisms [36]. Moreover, the development of autoimmune antibodies or immune complexes triggered by viral infection may contribute to thrombocytopenia development; SARS-CoV may also directly infect hematopoietic stem/progenitor cells, megakaryocytes, and PLT, inducing their growth inhibition and apoptosis [37]. Damaged lungs of patients with SARS may also induce thrombocytopenia [38]. The clinical value of a low PLT count has been assessed in a diagnostic model, which included thrombocytopenia (in addition to myalgia, fever, diarrhea, rhinorrhea, sore throat and lymphopenia) and effectively detected SARS-CoV-1 with 100% sensitivity and 86.3% specificity [39]. Elevated PLT counts at the obviously symptomatic stage in the mild COVID-19, AdV and SARS groups suggested that the PLT levels change with disease development and are related to thrombosis. Decreases in the PLT count, which were observed in the recovery period in the severe COVID-19 and SARS groups, indicated a hemorrhage risk of the disease. Patients with mild COVID-19 and AdV pneumonia may have better clinical outcomes compared to those with other pneumonias.

The monocyte count was increased during the course of H1N1 disease in our study. Monocytes are recruited into the lungs during IAV infection, and monocytes are susceptible to this infection [40]. Monocyte-derived macrophages in protection from IAV infection have been described [41].

This study had several limitations. First, as a retrospective study, not all clinical information and laboratory data could be collected, and the patients enrolled in this study were limited. Second, all participants in this study were inpatients in our hospital, and no cases of death were included. Thus, selection bias may have occurred. Third, the patient data were not from the same year and therefore a difference in the dose of hematologics was inevitable. Fourth, there was a mismatch in patient age between the groups. Interestingly, a better prognosis in the AdV group can be linked to a medium age, which is fairly lower compared to other groups. Fifth, only patients with COVID-19 were divided by severity, which was not true for the other viral pneumonia groups. Finally, no correlation analysis was performed, and the treatments provided were not specified. Therefore, the leukocytosis may be related to the therapy and not primarily to disease severity.

Patients with severe COVID-19 had higher neutrophil and lower lymphocyte and HGB counts than those with mild COVID-19 during the disease course. Patients with mild COVID-19 and AdV pneumonia had better outcomes than those with other pneumonia diseases.

One of the COVID-19 characteristics is the continuous decline in HGB count. Neutrophils are related to the aggravation of COVID-19, particularly SARS. Thrombocytopenia was noted in patients with SARS and severe COVID-19 even at the recovery stage, which is consistent with the extreme clinical outcomes. The lymphocyte count was related to the course of AdV, recovery of COVID-19, and disease development of SARS.