key: cord-0940910-b1g7e687 authors: Aksakal, Alperen; Kerget, Buğra; Kerget, Ferhan; Aşkın, Seda title: Evaluation of the relationship between macrophage migration inhibitory factor level and clinical course in patients with COVID‐19 pneumonia date: 2021-07-22 journal: J Med Virol DOI: 10.1002/jmv.27189 sha: 63fa128b013b562980adcc417c08761547199766 doc_id: 940910 cord_uid: b1g7e687 The COVID‐19 pandemic, which has ravaged our world for more than a year, still shapes our agenda with a scale of intensity that fluctuates over time. In our study, we aimed to determine the correlation between serum migration inhibitory factor (MIF) level and disease severity in COVID‐19 with different prognoses. Between 15 October 2020 and 20 January 2021, 110 patients over the age of 18 who were diagnosed with COVID‐19 and 40 volunteer healthcare personnel were included in our study. MIF levels were measured by enzyme‐linked immunosorbent assay. In the comparison of serum MIF values in the patient and control group, it was observed that the MIF level was significantly higher in patients with both moderate and severe COVID‐19 levels compared to the control group (p = 0.001, 0.001). In the comparison of serum MIF values of moderate to severe COVID‐19 patients, it was observed that MIF level was higher in severe patients (p = 0.001). In the receiver operating characteristic curve analysis performed to differentiate between severe and moderate COVID‐19 patients with MIF levels, the area under the curve was observed as 0.78. When the cutoff value of the MIF level was taken as 4.455 ng/ml, the sensitivity was 83% and the specificity was 62%. Failure to adequately balance the pro‐inflammatory cytokines synthesized in COVID‐19 with anti‐inflammatory effect is the most important reason for the aggravation of the disease course. Playing a role in pro‐inflammatory cytokine synthesis, MIF can provide important information about the disease prognosis in the early period. COVID-19 related macrophage activation syndrome (MAS) is an immune system condition in which excessive cytokines are produced as a result of excessive activation of immune system cells and causes systemic hyperinflammation in its later stages. 2, 3 It usually leads to multiple organ failure and a high mortality rate. MAS is characterized by increased expression of pro-inflammatory cytokines. Without any therapeutic intervention, it can cause strong inflammation, severe tissue damage, and even death of the patient. Many studies have found that cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1, play an important role in MAS. 2, 4, 5 Macrophage migration inhibitory factor (MIF) is a pleiotropic pro-inflammatory cytokine first isolated from T lymphocytes and inhibits the random migration of macrophages. 6, 7 Synthesis of MIF, whose synthesis decreases to a minimal level under low inflammatory activity, increases in its synthesis with high inflammatory activity, and besides its inflammatory activity, it carries out the apoptosis of the cells that play a role in inflammatory activity by inhibiting p53. MIF is recognized as a multifunctional molecule that activates the production of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and interferon (IFN). 8 MIF, which is constitutively expressed from various cells, is found in almost every tissue. 6 The fact that a strong relationship has been found between the increasing level of MIF level in sepsis and autoimmune diseases and the clinical course and prognosis in the studies conducted has been a hope that it can be used for therapeutic purposes in the future. In our study, we aimed to compare the serum MIF level in patients with MAS, which is one of the most important causes of morbidity and mortality in COVID-19 patients and to determine the relationship with the clinical course. Between 15 October 2020 and 20 January 2021, 110 patients over the age of 18 were diagnosed with COVID-19 by the real-time polymerase chain reaction (PCR) method, and 40 volunteer healthcare personnel over the age of 18 who were asymptomatic and who were PCR negative after nasopharyngeal swab were included in our study. High-resolution computed tomography (HRCT) was performed in a standardized manner in patients at high risk for COVID-19. According to the HRCT results, patients with bilateral ground-glass opacity, subsegmental consolidation or linear opacities, paving stone appearance, and inverted halo sign with peripheral localization were evaluated as typical findings, while patients with radiologically atypical findings were admitted as patients with compatible clinical complaints. After the patients were admitted to the clinic, their hematological parameters, biochemical parameters including liver and kidney function tests, coagulation parameters, ferritin, D-Dimer, troponin-I, CRP, and arterial blood gas parameters were measured. The current parameters of the patients were repeated daily. The 150 people included in our study were divided into three groups. Exclusion criteria include the presence of chronic or clinically significant infectious or inflammatory conditions in the past month, asthma, chronic obstructive pulmonary disease (COPD), malignancy, invasive surgery in the past month, uncontrolled hypertension, patients with high fasting blood glucose, diabetes cerebrovascular disease, kidney disease, and coronary artery disease. Anamnesis and laboratory parameters obtained during hospitalization were used to evaluate the patients in terms of exclusion criteria. In terms of coronary artery disease, asthma, COPD, and diabetes, consultations were made by cardiology, chest diseases, and internal medicine clinics. The temperature measured axillary in patients and above 37.3°C was defined as fever. In patients with fever under treatment for COVID-19, blood, urine, and sputum cultures for possible bacterial and fungal superinfections were taken and empirically given antibiotherapy was revised according to the culture results. Acute respiratory failure was diagnosed and graded according to the Berlin 2015 diagnostic criteria. 9 If the daily cardiac-specific troponin level of the patients was observed above normal, they were evaluated in terms of newly developed cardiac pathologies by echocardiography. As coagulopathy, prothrombin time was 3 s above normal and at partial thromboplastin level 5 s above normal. Three strategies to treat the patients according to their severity were implemented according to the Turkish Ministry of Health was COVID-19 adult diagnosis and treatment guidelines. Patients with signs such as refractory fever, CRP and ferritin levels that remained high or continued to rise, D-dimer elevation, cytopenia manifesting as thrombocytopenia or lymphopenia, abnormal liver function tests, hypofibrinogenemia, or elevated triglyceride levels in spite of treatment were monitored for MAS. As it is important to have a difference in consecutive measurements rather than a threshold value for laboratory findings, we have determined the diagnosis of MAS according to the successive follow-up of clinical and laboratory data of patients. If these parameters continued to deteriorate during follow-up with no apparent secondary bacterial infection, we treated patients with methylprednolone in doses of 250 mg/day or more for 3 days, however, if the patient did not respond to treatment, tocilizumab at a dose of 8 mg/kg (maximum 400 mg/day) was administered for MAS unless contraindicated. Clinical and laboratory response was evaluated after 24 h. If an adequate response was not observed, treatment was repeated at the same dose. Figure 1 ). In the ROC curve analysis performed to differentiate between severe and moderate COVID-19 patients with MIF levels, the area under the curve was observed as 0.78. When the MIF level was taken as the cutoff value of 4.455 ng/ml, the sensitivity was 83% and the specificity was 62% (Figure 2 ). In line with the data of our study, it was observed that the levels of ferritin, LDH fibrinogen, CRP, and D-Dimer, which was shown to have prognostic significance in COVID-19, increased in correlation with the severity of the disease. In addition, it was observed that the MIF level, which forms the basis of our study, increased with the severity of the disease. It was observed that the MIF level was inversely correlated with age. Cytokine storm syndrome has a clinical picture similar to sepsis, as it is characterized by multiple organ failure, clinically persistent fever, hyperferritinemia, and potentially death. Induction of cytokine storm has different etiologies, such as iatrogenic, inflammatory, or infectious. 12, 13 Cytokine storm syndrome, which is virally induced during the COVID-19 process, occurs more severely in patients associated with a specific genetic predisposition. 14, 15 According to the report of McGonagle et al. 16 such as TNF-α, IL-1β, IL-6, and IFN. 6, 7 It has been shown that the MIF level measured in patients hospitalized with sepsis and acute respiratory failure may be associated with poor prognosis in the early period, and it has also been suggested that the regulation of MIF level can be used in the treatment of these patients. It has also been stated that MIF suppresses glucocorticoid production, which plays an important role in the anti-inflammatory effects. 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Zhonghua Jie He He Hu Xi za Zhi = Zhonghua Jiehe He Huxi Zazhi = Chinese J Tuberc Respir Dis Macrophage migration inhibitory factor: a counter-regulator of glucocorticoid action and critical mediator of septic shock Evaluation of the relationship between macrophage migration inhibitory factor level and clinical course in patients with COVID-19 pneumonia The authors declare that there are no conflict of interests.