Respiratory complications, particularly bacterial infections in the lungs, are very common in patients with hematological malignancies. Immunosuppression caused by hematological malignancies can make patients’ respiratory tracts more susceptible to infections. Patients with hematological malignancies must take immediate action if they develop lung infections, as severe infections increase the risk of death, and approximately 16% of patients have a clear correlation with lung infections (1, 2). Body temperature, PCT, CRP, blood culture, sputum culture, and other detection methods are simple to carry out and extensively used for the diagnosis of such infections (2). The PCT examination, which is now an essential clinical approach for predicting bacterial infections, provides a faster result. The most significant limitation of blood culture and sputum culture methods for detecting the presence of infection is that they are slow and may have low sensitivity. Although body temperature is a simple method, the diagnosis needs further confirmation because the abnormal expression of inflammatory factors (pyrogenic cytokine IL-1) and non-infectious causes can both cause the body temperature to rise (3). In addition, in the absence of other examination equipment and technology to determine whether there is a lung infection, clinicians will consider the use of antibiotics after the body temperature rises, which has caused the proliferation of antibiotics in some areas. It may further cause the production of resistant strains. Other testing methods, such as computerized tomography (CT) examination and chest X-ray, can also be used to confirm the diagnosis. However, more skilled technicians are required to identify the results. And may be restricted by health centers, especially CT.

Interleukins are the most important group of cytokines released during infectious processes. They encompass a large variety of proteins secreted by leukocytes and endothelial cells (among others) and that contribute to cell signaling and pro mote activation, proliferation, death, and/or motility of immune cells (4). They are artificially divided into pro- and anti-inflammatory interleukins. Pro-inflammatory interleukins (including IL-1, Tumor necrosis factor(TNF), Interferon(IFN)-γ and IL-6) are supposed to be responsible for cell activation, tissue damage, and necrosis while anti-inflammatory interleukins (such as IL-4, IL-10, IL-13, IFN-α and Transforming growth factor(TGF)-β) aim to dampen and finally reverse the inflammatory process (5, 6). A lack of balance between pro-inflammatory and anti-inflammatory cytokines might cause the immune system to lose its normal function (7). The study of Th1/Th2 cytokines in infection has gotten a lot of interest in recent years. IL-6 and IL-8 are being researched more in children with hematological malignancies (8–10). There is a considerable association between the rise in IL-6 and PCT, which suggests that the rise in IL-6 may represent the patient’s infection to some extent (11). To identify cytokine indicators such as IL-2, IL-6, IL-8, IL-10, and TNF-α, clinical immunoassay techniques based on ELISA and flow cytometry (CBA) have been developed. The advantages of CBA technology include a wide detection range, ease of operation, minimal sample volume, high sensitivity, and quick operating time (12). This approach is now being used in a large number of studies to predict cytokine expression levels in lung infections in patients with hematological malignancies. It is well known that IL-6 increase can be utilized as a biomarker in children-acquired pneumonia (CAP) (13, 14). Although such differential diagnosis has gained clinical importance, it is currently only used in the investigation of lung bacterial infections in hematological malignancies in children.

Therefore, we reviewed the data of Th1/Th2/Th17 cytokines in 541 newly diagnosed adult patients with hematological malignancies in the Department of Hematology of the First People’s Hospital of Yunnan Province (data from patients who have not received any treatment). The cytokines were compared with PCT, CRP, and body temperature at the same time to investigate the particular cytokine markers in adult patients with hematological malignancies who have lung bacterial infections.

Clinically, bacterial infection of the lung has always been an important problem, and it affects the treatment strategy and even the course of the disease for patients with hematological malignancies. Abnormalities in the cytokine network produced by bacterial infections in the lungs are common. IL-6 plays a key role in the inflammatory response and is a major immunomodulator (18). It plays an active role in activating T helper cells, inhibiting the differentiation of T regulatory (Tregs) cells and B cells, and has the role of coordinating innate and adaptive immune responses (19). In inflammation, IL-6 binds to membrane-bound IL-6R to form an IL-6-IL-6R complex, which then binds to gp130 (glycoprotein 130) to generate signal transduction through the JAK-STAT pathway (classical signal transduction). IL-6 can also bind to soluble forms of the IL-6R before converging on gp130 (trans-signaling), or be trans-presented from dendritic cells via their membrane-bound IL-6R to T cells (trans-presentation). In general terms, classical signaling causes the physiological, anti-inflammatory, and pro-resolution effects of IL-6, with the pathological effects of the cytokine mediated by trans-signalling and trans-presentation (20). The plasma concentration of IL-6 in healthy adults ranges from 0.2 to 7.8 pg/mL, but the concentration in children ranges from 18 to 26 pg/mL (21–23). However, IL-6 concentrations can exceed 1600 pg/mL in patients with sepsis (24). The level of IL-6 in the blood has also been shown in literature search and analysis studies to have clinical usefulness in distinguishing people with severe infections (25). Like IL-6, the expression of IL-8, which has a pro-inflammatory effect, is stimulated by a variety of factors (including IL-6 and bacterial particles) (20, 26). IL-8 mediates its signal by extracellularly binding to two G protein-coupled receptors, CXC chemokine receptor 1 (CXCR1) and CXC chemokine receptor 2 (CXCR2). The CXCL8-CXCR1/2 axis recruits neutrophils at the site of infection and induces a neutrophil oxidative burst and a granule release to eliminate inflammatory stimulus and increase bacterial clearance (27, 28). Since CXCR2 is more sensitive to low ligand concentrations, CXCR2 is believed to play a more important role at recruiting neutrophils to the site of infection (including bacterial infections in the lungs), whereas CXCR1 mediates oxidative burst and granule release to combat the microbes at the site of infection (29). IL-6 and IL-8 levels are elevated not just in children with hematological malignancies, but also when there is an invasive fungal infection of the lungs in children with hematological malignancies and may signal the patients’ early death (30).

IL-10 is a well-known anti-inflammatory cytokine that can be produced by almost all immune cells and can help to maintain and restore immunological homeostasis (31, 32). Immunosuppressive properties of IL-10 are pleiotropic. By suppressing the pro-inflammatory response caused by various immune cells, IL-10 limits tissue damage and immunopathology caused during infection (31, 33, 34). During pneumococcal pneumonia in mice, high levels of IL-6, IL-1β and TNF-α are produced in the early stages of lung parenchyma and/or bronchoalveolar space infection. The production of these pro-inflammatory cytokines caused a large influx of neutrophils into the lungs of infected mice and increased tissue damage 24 hours after infection. However, an increase in IL-10 expression and a decrease in the number of neutrophils were observed 48 hours after infection (35). In addition to reducing the number of pro-inflammatory cytokines, IL-10 may also play a role in regulating the recruitment of neutrophils and the spread of bacteria from the lungs to other tissues (36).Our previous research found that an abnormal increase in IL-10 in the secondary hemophagocytic syndrome of the cytokine storm could predict the patient’s death (37). These findings indicate that IL-10 is abnormally expressed after the patient is infected. In adult patients with hematological malignancies with bacterial infection of the lungs, as an anti-inflammatory factor, the increase of IL-10 may be to inhibit the high expression of the pro-inflammatory factors IL-6 and IL-8. What needs to be explained here is that the malignant hematological disease itself may have immunosuppression in untreated patients, and cytokines may also be disordered after immunosuppression. The complex relationship among immunosuppression, infection and cytokine expression still needs to be studied in depth.

In our study, only adult patients with hematological malignancies were studied. The main reason is that we only accept patients with hematological malignancies in our daily diagnosis and treatment. Other studies reported that in the study of childhood hematological malignancies, the increase in the expression levels of IL-6 and IL-10 predicted the occurrence of infection in patients (1, 38), and the expression level of children with bacteremia was significantly higher than Children infected with the virus (1). In addition, IL-10 are also abnormally elevated in pneumonia after esophageal cancer surgery (39). Abnormal cytokines in infection are common in studies of non-tumor patients. IL-6, IL-8, and IL-10 are significantly abnormally expressed in acquired pneumonia (whether children or adult patients) (40–43). The expression of IL-6 and IL-10 in the serum of patients with enterovirus/bacterial meningitis is abnormal, while the expression of IL-6 and IL-10 in patients with bacterial meningitis is higher than that of viral meningitis (44). In 2019 coronavirus disease (COVID-19), severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), the abnormal increase in IL-6 is related to the severity of the disease (45, 46). IL-6 and IL-8 will also increase in patients with fungal infections such as Candida (47–49). IL-10 is also abnormally elevated in herpes simplex virus type I infection (50), but it is not abnormally expressed in influenza A, influenza B, and influenza-like diseases (51). In patients with periodontitis, LI-6 and IL-8 are abnormally elevated, and IL-6 in the cerebrospinal fluid after subarachnoid hemorrhage can predict infection (27, 30, 52). This seems to indicate that the increase in IL-6, IL-8 and IL-10 is a common result of infection. Other factors such as smoking, viruses, and a person’s disease can cause the increase of IL-6, IL-8 and IL-10 in the patient’s body (30, 53–55)., Our research cannot completely rule out the influence of these factors and other undiagnosed infections. These evidences seem to indicate that elevated IL-6, IL-8 and IL-10 in non-tumor patients are common results of infections (including infections of different sites and different microorganisms), so our data does not support bacterial infections in the lungs The specificity. Anti-infective treatment should be combined with underlying diseases, clinical symptoms and other test result.

The Cut-off values for IL-6, IL-8, and IL-10 reported by different researchers differ slightly (1, 10, 56, 57). Their research, as well as ours, have revealed the benefits of cytokines IL-6, IL-8, and IL-10 in accurately predicting infections with a short detection time and high sensitivity. It should be noted that the abnormal increase of IL-6, IL-8 and IL-10 in patients with hematological malignancies may not only occur when bacterial infections in the lungs occur. It may also occur when infection occurs in other parts, and when other microorganisms are infected. Therefore, when IL-6, IL-8 and IL-10 are found to be abnormally elevated, clinical symptoms and other examination results should be combined to identify the type of infectious agent, which will facilitate the choice of anti-infective drugs. In view of other people’s research and our results, we believe that cytokines, especially IL-6, IL-8 and IL-10, should be tested in patients with hematological malignancies. In this way, we may be able to use cytokines to help determine whether a patient has an infection. In addition, sometimes the newly diagnosed patients do not have obvious characteristics of lung infection (such as fever, positive sputum culture, cough, dyspnea, elevated PCT and CRP, etc.), and it is easy to ignore lung bacterial infection. Then, when there are no other clear laboratory indicators to indicate infection, one should be alert to the abnormal increase of IL-6, IL-8 and IL-10, which may indicate bacterial infection in the lungs. Our study is a retrospective single-center study with the following limitations: 1. The research of different types of diseases is not carried out separately, and other tumors are not included for comparison, so our data cannot support the specificity in hematological malignancies; 2. The data of fungi and viruses are not included, so our data does not support the specificity of IL-6, IL-8 and IL-10 in bacteria; 3. Since we only reviewed patients with bacterial infections in the lungs, our data may not support the specificity of the lungs. Our next study will focus on these deficiencies and the development of IL-6, IL-8, and IL-10 as separate tests for the diagnosis of adult hematological malignant pulmonary bacterial infections.

In summary, our data indicate that IL-6, IL-8, and IL-10 are abnormally elevated in patients with lung bacterial infections in adult hematological malignancies. At the same time, the simultaneous increase of IL-6, IL-8 and IL-10 has a better AUC than PCT/CRP/Temperature. Then, the abnormal increase of IL-6, IL-8 and IL-10 should pay close attention to the possible lung bacterial infection in patients.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by the Ethics Committee of the First People’s Hospital of Yunnan Province. The patients/participants provided their written informed consent to participate in this study.

All authors participated in the research and agreed to the publishing license. ZL analyzed the data and drafted the manuscript. ZY reviewed the analysis results and graphs. TY, RZ, and CZ designed the research plan, reviewed the manuscript and revised the main content. PH, XG, LZ, and JZ performed statistics.

This work was supported by the National Natural Science Foundation of China (82060810) and Open Project of Yunnan Blood Clinical Medical Center (2019LCZXKF-XY11, 2019LCZXKF-XY09, 2020LCZXKF-XY07 and 2021LCZXXF-XY09).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.