Vol 48 (2020): Supplement 1

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Comorbidities and predicting the outcome of COVID-19: the treatment results of 13,585 patients hospitalized in the Moscow Region

Molochkov A.V., Karateev D.E., Ogneva E.Y., Zulkarnaev A.B., Luchikhina E.L., Makarova I.V., Semenov D.Y.


Background: The COVID-19 pandemic is seriously affecting the society and economy of many countries, including the Russian Federation. Identifying of the major risk factors for an unfavorable outcome could help save lives and reduce the disease burden. Until now, no results of the studies on this issue based on the Russian clinical material have been published. Aim: To evaluate the effects of comorbidities on the outcome (discharge or hospital death rates) in patients hospitalized with a diagnosis of COVID-19.

Materials and methods: We analyzed a database of 13,585 patients who were treated in 66 hospitals functioning under the obligatory health insurance system of the Moscow Region, with a final diagnosis of "COVID-19, virus identified" (ICD 10 code U07.1) from April 1, 2020 to June 23, 2020 (53.7% women, 46.3% men, mean (± SD) age 56.5 ± 14.9 years (median 57 [46; 67])). In all patients, the diagnosis of COVID-19 was confirmed by polymerase chain reaction (PCR) for the SARS-CoV-2 virus in nasopharyngeal or oropharyngeal swabs. 93.8% of the patients showed signs of interstitial viral pneumonia (87.9% confirmed by computed tomography of the lungs, 5.9% by standard chest X-ray). All patients received the standard treatment according to the "Temporary Guidelines on prevention, diagnosis and treatment of the new coronavirus infection (COVID-19), version 7 (03.06.2020)” from the Ministry of Health of the Russian Federation. 1518 (11.2%) patients had at least one comorbid condition, the most frequent being arterial hypertension (AH), ischemic heart disease (IHD), and diabetes mellitus (DM). In 71 female patients, COVID-19 occurred during pregnancy. By June 23, 2020, 10761 (79.2%) patients have been discharged from hospitals with recovery, improvement, or stabilization (the latter was considered a conditionally favorable outcome). 1246 patients died, that transfers into the in-hospital death rates of about 9.2% (unfavorable outcome). The rest of 1578 (11.6%) patients continued their treatment, or were transferred to other medical units for the continuation of care. The comparative analysis included patients (total, n = 12,007) with favorable (n = 10,761) and unfavorable (n = 1246) inpatient outcomes. The age-adjusted Charlson index was used to quantify the severity of comorbidity.

Results: In the patients without any comorbidity, the in-hospital death rate was 9.4%. At least one comorbidity increased the incidence of unfavorable outcome to 13.9% (p < 0.001), and multiple comorbidities to 24.8% (p < 0.001). The following specific conditions significantly increased the likelihood of an unfavorable outcome (p < 0.05): DM, mental disorders, morbid obesity, IHD, AH, stroke (including past history), myocardial infarction (including past history), chronic heart failure, heart arrhythmias, cancer, and chronic kidney disease. Tuberculosis, HIV/AIDS, trauma / surgical disorders, and pregnancy were not associated with higher rates of unfavorable outcomes, but these patients were significantly younger than patients without comorbidities and with comorbidities with higher death rates. The age-adjusted Charlson index of > 3 was associated with a more than 2-fold increase in the in-hospital death rates (25.2%, p < 0.001).

Conclusion: Comorbidity is one of the drivers in the prognosis of in-hospital death rates in patients with COVID-19. However, it should be considered in the context of the patient age-related characteristics. The Charlson Age-Adjusted Comorbidity Index is a useful tool for assessment of the COVID-19 prognosis. The prognosis should be considered serious at a score of 3 or more.

Almanac of Clinical Medicine. 2020;48:1-10
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Extracorporeal photopheresis in the treatment of the novel coronavirus disease COVID-19 (a case series)

Kildyushevsky A.V., Molochkov A.V., Zhuravlev O.R., Mitina T.A., Belousov K.A., Zakharov S.G., Stepanova E.A., Semenov D.Y.


Rationale: Most people infected with SARS-CoV-2 have asymptomatic or minor clinical manifestations and recover without any aggressive therapy. However, there are patient categories in need of specific treatment and those at high risk of severe disease. Control of viremia with antiviral therapy may not be the best therapeutic strategy, since, in addition to substantial toxicity, antiviral agents can suppress the production of antiviral antibodies and disintegrate adoptive immunity against SARS-CoV-2. Due to a high correlation between the symptoms severity in patients with COVID-19 and inflammation, anti-inflammatory corticosteroids have been proposed to treat the disease. However, clinical data do not support the systemic administration of corticosteroids for the treatment of patients with severe COVID-19. Such treatment may have a negative effect due to suppression of the adoptive immune system. In this regard, the development or use of already available of agents that modulate inflammation without compromising the adoptive immune response could be the most effective therapeutic strategy.

Aim: To evaluate clinical efficacy and safety of the cell biotherapy technique, the extracorporeal photopheresis (ECP), in the treatment of patients with moderately severe new coronavirus disease COVID-19.

Materials and methods: The study included four patients (three women and one man, age 42 to 60 years), with SARS-CoV-2 infection confirmed by gene amplification. All patients had CT-confirmed bilateral multisegmental viral pneumonia (grades > 2, i.e. with 25 to 60% involvement of the lungs). Prior to admission, all patients received antibiotics (azithromycin 500 mg daily and levo-floxacin / amoxicillin clavulanate 500 mg BID) and antipyretics for torpid fever of up to 38.5-39 °C. The outpatient treatment lasted for 8 to 14 days, with signs of progressive respiratory failure. In addition to the moderately severe and torpid course of viral pneumonia, three patients showed hematology test abnormalities, such as hypochromic anemia, leukopenia, leukopenia/lymphopenia, and moderate thrombocytopenia. Three patients had high C-reactive protein (CRP) levels. Inpatient treatment consisted of azithromycin 500 mg daily, levofloxacin 500 mg BID, hydroxychloroquine 200 mg BID, and low molecular weight heparin (enoxaparin 0.4 ml, 4000 anti-Xa IU, s.c. BID). Despite the treatment, the patients showed signs of progressive respiratory failure, with increasing dyspnea and gradual decrease in saturation from 96% to 92%. Isolation of peripheral blood mononuclear cells was done in an intermittent blood separator "Haemonetics MCS+” (USA), with subsequent cell irradiation with an extracorporeal blood irradiator (OKUFKE 320/400-600/650-01 "Yulia”, ZAO NPKF "METOM”, Russia). Ammifurin (ZAO "Pharmcenter VILAR”, Russia) was used as a photosensitizer. Three patients had two ECP sessions with an interval of 24 hours, and one patient had one ECP session.

Results: In three patients who had received two ECP sessions, there was a regression of radiographic signs of viral pneumonia from CT2 to CT1 (less than 25% of lung tissue involvement) during the next four days (96 hours). In one patient, the follow-up CT showed resolving pneumonia with less than 5% involvement of the lungs. The patients (n = 3) with baseline high CRP levels showed their normalization at 4 days after two ECP sessions. At 24 hours after a single ECP session, leukocyte count and differential, as well as platelets were restored. In three patients, viral RNA tests within 2 to 4 days after ECP were negative. These results were associated with normalization of body temperature, no further progression of respiratory failure, and a reduction in hospital stay.

Conclusion: The use of ECP in 4 patients with moderately severe SARS-CoV-2 infection has contributed to the rapid relief of clinical symptoms, resolution of the inflammation and restoration of respiratory abnormalities in all of them. These observations allow us to consider ECP as an effective and safe method of treatment for moderately severe COVID-19 and a promising adjuvant method in the high-risk patients in order to prevent an unfavorable disease outcome.

Almanac of Clinical Medicine. 2020;48:11-19
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The eye status in patients after new coronavirus infection

Ryabtseva A.A., Grishina E.E., Andryukhina O.M., Kovrizhkina A.A., Andryukhina A.S.


Rationale: The emerging new coronavirus infection caused by SARS-CoV-2 has resulted in a pandemic. Its clinical manifestations are highly variable and the death rate is high due to rapid progression to acute respiratory distress syndrome. Identified abnormalities of the eye are mainly related to conjunctival injury during manifestation of the disease.

Aim: To study the eye abnormalities in patients who have undergone COVID-19.

Materials and methods: Ophthalmological examination was performed in 23 patients (6 [26%] men and 17 [74%] women, median age 42.39 years) at days 44 to 85 after manifestation of COVID-19 infection in the Department of Ophthalmology, MONIKI. In addition to the standard ophthalmological examination, all patients were evaluated with optical coherence tomography (OCT), auto fluorescence, contrast and color sensitivity test with different light sources, and tear production assessment.

Results: In the late convalescence period there were complaints of dry eyes and abnormal color perception, with visual acuity being unchanged. The OCT assessment the peripapillary retina identified small hyper-reflective foci in the inner layers.

Conclusion: Eye disease in patients after COVID-19 is mainly related to the condition of the eye surface, abnormal color perception and abnormal architectonics of the inner retinal layers, which can persist for a long time during convalescence.

Almanac of Clinical Medicine. 2020;48:20-26
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Non-invasive assessment of skin microcirculation in patients with COVID-19: three clinical cases

Glazkova P.A., Kulikov D.A., Rogatkin D.A., Zhuravlev O.R., Shekhyan G.G., Glazkov А.A., Kozlova K.A., Terpigorev S.A.


Currently, there is enough data to suggest a significant role of microcirculation abnormalities in the pathophysiology of COVID-19. However, no clinical studies on noninvasive assessment of blood microcirculation in patients with the new coronavirus infection have been performed. We measured skin microcirculation by laser Doppler flowmetry in the thermal and inspiratory gasp tests in 3 patients with various courses of COVID-19. A decrease in the skin microcirculation reactivity was found in a patient with a more severe course of coronavirus infection. We believe that assessment of skin microcirculation could become a promising tool for the development of new diagnostic approaches and in future of new treatments for patients with coronavirus infection, as well as for identification of patient categories with a high risk of its severe course. Further studies are required to evaluate the clinical applicability of laser Doppler flowmetry for assessment of skin microcirculation in patients with COVID-19.

Almanac of Clinical Medicine. 2020;48:27-31
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Acute necrotizing encephalopathy of childhood. Diagnostic and treatment challenges in COVID-19 pandemic

Kitaeva V.E., Kotov A.S.


Acute necrotizing encephalopathy of childhood (ANEC) can occur in previously healthy children during a respiratory infection with fever and can manifest by epileptic seizures. Magnetic resonance imaging (MRI) typically shows bilateral lesions of the brainstem, cerebellum, thalamuses, basal neclei, and hemispheral white matter. We describe three clinical cases with an initial diagnosis of ANEC. In the first case, a 12-year old patient developed headache, leg weakness and high blood pressure during treatment of hepatitis C virus infection with PEG-interferon alfa2b. Later on she had myoclonic seizures with subsequent epileptic status, tetraparesis, confusion, and hyperthermia. Her clinical chemistry parameters showed a non-significant increase in liver enzymes levels. Cerebrospinal fluid was remarkable for increased protein level. The patient's brain MRI showed typical for ANEC bilateral thalamic lesions. The second case manifested with myoclonic seizures and subsequent epileptic status in a 17-months' old patient with a respiratory infection (vomiting, rhinitis, fever, and hyperthermia). His brain MRI showed bilateral lesions in the brainstem (dorsal part of the pons), thalamus, subcortical nuclei, white matter of the cerebral hemispheres, as well as lesions in the left hippocampus. The patient had increased urine levels of malic, 2-hydroxyisovalerianic, 3-hydroxy-isovalerianic, N-acetylaspartic, 3-hydroxybutyric, and lactic acids and increased blood levels of alanine, glutamic acid, glycine, and ornithine. By the time of the study, no hereditary metabolic disease was identified. In the third case, a 3-year old patient with a respiratory infection with vomiting and fever developed left-sided hemiparesis after she had fallen out of bed. The brain MRI revealed acute ischemic damage. Her cerebrospinal fluid was remarkable for a decreased protein level. Currently, ANEC is a diagnosis of exclusion. In the third patient, ANEC was obviously misdiagnosed. It is necessary to clarify the diagnostic criteria for the syndrome and to develop a management protocol for patients with ANEC.

Almanac of Clinical Medicine. 2020;48:32-36
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Morphological and immunohistochemical characteristics of changes in the bronchopulmonary lymph nodes in patients with a new COVID-19 coronavirus infection (based on autopsy results)

Fedorov D.N., Korosteleva P.A., Zybin D.I., Popov M.A., Tyurina V.M., Varlamov A.V.


Background: Research into the pathogenesis and morphogenesis of new coronavirus infection (COVID-19) is currently a hot topic that requires the accumulation, management and analysis of the data. Understanding the mechanisms of the disease and their characteristics would help to improve diagnostic quality, treatment efficacy and reduce mortality.

Aim: To identify morphological and immunohistochemical characteristics of the bronchopulmonary lymph node tissues in autopsied patients with COVID-19.

Materials and methods: The study was carried out on 44 autopsy samples from patients who were hospitalized and died from the new coronavirus infection COVID-19 in the Moscow Regional Research and Clinical Institute. Macroscopic, histological, and immunohistochemical assessment methods were used.

Results: We found stereotypical abnormalities in the morphology and cellular composition of the lymphoid tissue depending on the duration of the disease. These included signs of B-cell-mediated immunity suppression manifested by a decrease in the number and size of lymphoid follicles and occurs at latest after 7 days from the onset of the disease. In the patients with the disease duration of up to 14 days, the T-cell pool of the lymph nodes is represented mainly by CD4+ T-lymphocytes. With longer duration of the disease, there is a gradual increase in the number of lymphoid follicles and their sizes, with changes of the CD4+ to CD8+ T-cell ratio towards higher CD8+ counts. After 21 days of the disease, the CD4+ to CD8+ ratio levels off.

Conclusion: The results obtained indicate a direct damaging effect of SARS-CoV-2 on the lymph node tissues of the bronchopulmonary group. The possibility of secondary transient immune deficiency and infectious  complications in patients with a new coronavirus infection is discussed.

Almanac of Clinical Medicine. 2020;48:37-42
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Neutrophil extracellular traps: diagnostic and prognostic value in COVID-19

Kassina D.V., Vasilenko I.A., Gur’ev A.S., Volkov A.Y., Metelin V.B.


Rationale: An important element of antiviral defense in the pathophysiology of COVID-19 is the innate cell immunity including polymorphonuclear neutrophils prone to netotic transformation. Neutrophils can be not only a marker of acute infection, but, being a source of neutrophil extracellular traps (NET), can play a key role in the development of thrombotic complications leading to acute respiratory insufficiency in COVID-19.

Aim: To determine the diagnostic and prognostic value of NET levels in patients with COVID-19.

Materials and methods: We monitored NET levels in peripheral blood of 34 patients with COVID-19 (mean age, 67 ± 15.8 years), admitted to MONIKI hospital. The control group consisted of 54 healthy volunteers (mean age, 52 ± 11.5 years). Whole blood samples of 2 pL each were used for the preparation of monolayer smears (Giemsa stain) and calculation of at least 200 cell structures including native intact and transformed neutrophils (MECOS-C2 microscope, Medical computer systems).

Results: Patients with COVID-19 had higher NET levels, compared to those in healthy controls: 14.5% (2.9-28.6%) vs. 5.0% (1.8-11.9%, p < 0.0001). The patients who were on non-invasive respiratory support (23.5%) had a NET level of 12% (8.122.3%), whereas those on invasive mechanical ventilation (17.6%) had a 1.5-fold higher NET level of 17.9% (12.3-28.2%) (p < 0.05). In the patients who died (11.8% of the cases), the NET level amounted to 19% (16.5-26%, p < 0.05). Monitoring of blood NET levels was performed in 9 patients from the day of admittance to the day of their transfer to the intensive care unit / discharge / death. It was shown that a decrease of NET levels mirrors an improvement of the patient's clinical condition and efficacy of his/hers treatment. On the opposite, an increase of NET levels can indicate a deterioration and risk of unfavorable course.

Conclusion: We have identified some pathophysiological mechanisms in COVID-19, related to the neutrophil compartment. Patients with coronavirus infection are characterized by high NET levels which is at least 3-fold higher than that in healthy volunteers. This indicates an abnormality in immune host defense and development of an inadequate inflammatory response. An increase of NET in whole blood smears of more than 16% can be a criterion of an unfavorable prognosis of the disease course and the risk of death.

Almanac of Clinical Medicine. 2020;48:43-50
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Immunomodulatory drug therapy for the disease caused by SARS-CoV-2 infection (COVID-19)

Karateev D.E., Luchikhina E.L.


This systematic review focuses on the state-of-the-art pharmacotherapy of immune disorders in the novel coronavirus infection (COVID-19), leading to a cytokine storm and uncontrolled inflammatory response that causes severe tissue damage and multiple organ failure. A lot of theoretical, experimental and clinical data support the need for immunomodulatory (immunosuppressive) therapy for this disease. It should be emphasized that all immunomodulatory drugs for COVID-19 are prescribed off label, and the evidence base of the results of randomized trials is just being accumulated. We review the immunomodulatory therapy for COVID-19 with the following agents: glucocorticoids, hydroxychloroquine and chloro-quine, type 1 interferons, interleukin-6 antagonists (tocilizumab, sarilumab, olokizumab), interleukin-1 p inhibitor canakinumab, tumour necrosis factor inhibitors (infliximab), Janus kinase (JAK) inhibitors (tofacitinib, baricitinib, ruxolitinib), as well as drugs with other mechanisms of action (abatacept, nivolumab, tacrolimus, sirolimus, fingolimod, melphalan, cyclosporine, methotrexate). At the moment, the most reasonable is the use of interleukin-6 receptor inhibitors, intermediate and high dose glucocorticoids, and JAK inhibitors. Based on the latest data from clinical studies, especially the "Solidarity” trial, the use of hydroxychloroquine and chloroquine seems to have insufficient evidence. There are significant pathophysiological overlaps in the development of immunopathology in COVID-19 and in rheumatic diseases, and the strategy of early aggressive immunosuppressive therapy proposed by a number of researchers almost completely coincides with the current strategies for rheumatoid arthritis.

Almanac of Clinical Medicine. 2020;48:51-67
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Specifics of the perioperative management of the patients undergoing surgery for malignant neoplasms during the COVID-19 pandemic

Allakhverdyan A.S., Anipchenko A.N., Anipchenko N.N.


Background: The worse prognosis in cancer patients with COVID-19 infection in the context of the pandemic, compared to that in the general population, poses new challenges to ensure the perioperative safety.

Aim: To reduce the risk of infection for cancer patients in the perioperative period and to prevent severe COVID-19.

Materials and methods: During two months of the COVID-19 (from March to April 2020), we performed 158 surgical interventions: 49 for breast cancer, 31 for lung cancer (videothoracoscopic segmental and lobar resections), 12 for stomach cancer (8 distal and 1 proximal laparoscopic subtotal gastric resections, 3 gastrectomies), 16 laparoscopic resections for colorectal cancer, 29 resections with a reconstructive plastic for malignant skin tumors, 21 palliative and diagnostic operations (diagnostic thoracoscopy and laparoscopy, laparoscopic colostomy).

Results: Preventive administration during preparation for surgery (interferon-al-pha2b and low molecular weight heparins) and for suspected infection (antibiotics, low molecular weight heparins and dexamethasone 12 mg/day intravenously) allowed for lower rates of the new coronavirus infection (1.3%) and its severe cases (0%) during surgical treatment of malignant tumors.

Conclusion: Surgical treatment of cancer patients in the context of a new coronavirus infection pandemic should be carried out with strict adherence to anti-epidemic measures.

Almanac of Clinical Medicine. 2020;48:68-72
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Guidelines on the management of in-patients with the new coronavirus infection (COVID-19)

Molochkov A.V., Terpigorev S.A., Dreval A.V., Karateev D.E., Kildyushevsky A.V., Kulikov D.A., Likhvantsev V.V., Ovezov A.M., Ogneva E.Y., Smirnova E.V., Faenko A.P., Filippovskaya Z.S.


Almanac of Clinical Medicine. 2020;48:73-90
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Particulars of the comprehensive treatment of the patients with the new coronavirus infection (COVID-19): guidelines on the in-patient management

Molochkov A.V., Terpigorev S.A., Belousova E.A., Vatazin A.V., Dreval A.V., Zulkarnaev А.B., Karateev D.E., Kildyushevsky A.V., Kotov S.V., Kulikov D.A., Likhvantsev V.V., Ovezov A.M., Ogneva E.Y., Smirnova E.V., Faenko A.P., Filippovskaya Z.S., Fomin A.M.


Almanac of Clinical Medicine. 2020;48:91-142
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