Reactivation Of Cytomegalovirus Infection Research Articles

Epcoritamab SC + R-Mini-CHOP Leads to High Complete Metabolic Response Rates in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma Ineligible for Full-Dose R-CHOP: First Disclosure from Arm 8 of the Epcore NHL-2 Trial

Background: Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is a standard of care for previously untreated (1L) diffuse large B-cell lymphoma (DLBCL); however, some patients are not candidates for full-dose R-CHOP due to advanced age, frailty, or underlying comorbidities. For these patients, various attenuated treatment regimens have been evaluated, with low-dose R-CHOP (R-mini-CHOP) being widely adopted as a standard 1L regimen. However, outcomes are suboptimal, with overall response rates (ORRs) and complete metabolic response (CMR) rates around 70% and 40-60%, respectively, and a 2-y progression-free survival rate of only 47%, leaving substantial room for improvement. Epcoritamab, a subcutaneous (SC) CD3xCD20 bispecific antibody, was approved by the US FDA for the treatment of adults with relapsed or refractory DLBCL, not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after ≥2 lines of systemic therapy. In the 1L setting in patients with high-risk DLBCL, epcoritamab SC with full-dose R-CHOP had a favorable safety profile and showed promising efficacy, including an ORR of 100% (Falchi et al, ASCO 2023). Here we report initial data from arm 8 of the EPCORE™ NHL-2 study (NCT04663347; phase 1/2) evaluating epcoritamab SC + R-mini-CHOP in 1L DLBCL. Methods: Adults with 1L CD20 + DLBCL who were not considered candidates for full-dose R-CHOP due to age ≥75 y or age ≥65 y with comorbidities (reduced left ventricular ejection fraction, history of myocardial infarction [>6 mo prior to enrollment], exertional chest pain, arrhythmia [grade ≤2], hypertension requiring treatment, or diabetes) were enrolled. Patients received epcoritamab SC (QW, cycles 1-2 [21 d each]; Q3W, cycles 3-6 [21 d each]; Q4W, cycles 7-8 [28 d each]) with R-mini-CHOP in cycles 1-6 (Q3W). A safety run-in was conducted to confirm acceptability of the safety profile. The primary endpoint of arm 8 was ORR as assessed by PET-CT per Lugano criteria. Results: As of April 24, 2023, 28 patients had received epcoritamab SC 48 mg + R-mini-CHOP. The median age was 81 y, 14 patients (50%) had IPI 3-5, 10 patients (36%) had bulky disease (>6 cm), and 15 patients (54%) had stage IV disease. At the data cutoff, median follow-up was 6.2 mo (range, 2.5+ to 11.7), with 9 patients (32%) having completed treatment and 15 patients (54%) still on treatment. R-mini-CHOP median relative dose intensity was ≥94%. There were no dose-limiting toxicities. The most common treatment-emergent AEs (TEAEs) of any grade were cytokine release syndrome (CRS; 43%), neutropenia (32%), fatigue (25%), anemia (21%), constipation (21%), and hypokalemia (21%). TEAEs decreased over time; 3 patients (11%) discontinued epcoritamab SC due to TEAEs. One grade 5 TEAE (cytomegalovirus infection reactivation) was recorded. CRS events were primarily low grade (grade 1-2: 39%, grade 3: 4%, grade ≥4: 0%), timing was predictable, and a majority of events were observed after the first full dose (cycle 1, day 15); all events resolved, with a median time to resolution of 3 d (range, 1-7). No ICANS events were reported. All 20 efficacy-evaluable patients had a response (ORR, 100%), with 17 patients (85%) achieving CMR. Median time to response was 1.4 mo ( Figure). At both month 6 and month 9, most patients who achieved CMR remained in CMR, suggesting durability of response. The study is ongoing and updated results will be presented. Conclusions: Epcoritamab SC + R-mini-CHOP showed encouraging efficacy with high response rates in patients with 1L DLBCL who cannot tolerate full-dose R-CHOP, including elderly, frail, and high-risk patients. There were no new safety signals, and findings were consistent with previously reported data, supporting the feasibility of the combination. These results warrant further investigation of epcoritamab-based therapies in 1L DLBCL.

Changes in the blood flow in the uterine and umbilical arteries during the second trimester of pregnancy in exacerbation of bronchial asthma associated with reactivation of cytomegalovirus infection

Aim. To evaluate changes in blood flow in the uterine and umbilical arteries in the second trimester of gestation in women with exacerbation of bronchial asthma associated with reactivation of cytomegalovirus infection (CMVI).Materials and methods. Using Doppler analysis, 115 patients were examined at 21-24 weeks of pregnancy, uncomplicated and complicated by exacerbation of mild to moderate asthma of cytomegalovirus etiology. The first group was represented by 30 seronegative women with uncomplicated pregnancy. The second group included 30 patients with mild asthma in the stage of exacerbation associated with CMVI, leading to chronic compensated placental insufficiency. The third group consisted of 30 patients with exacerbation of moderate asthma caused by CMVI reactivation, which initiated the development of chronic compensated placental insufficiency. The fourth group consisted of 25 women with moderate asthma in the acute stage against the background of the acute phase of CMVI, leading to the formation of chronic subcompensated placental insufficiency.Results. In women in the second group, in comparison with the first group, the following changes were determined: in the right uterine artery, the systolic-diastolic ratio (SDR) was, respectively, 2.75±0.07 and 2.04±0.03 rel. units (р<0.001), pulsation index (PI) – 1.15±0.04 and 0.76±0.02 rel. units (p<0.001), resistance index (RI) – 0.63±0.01 and 0.51±0.01 rel. units (p<0.001); in the left uterine artery, SDR was, respectively, 2.84±0.09 and 1.98±0.05 rel. units (p<0.001), PI – 1.20±0.05 and 0.74±0.03 rel. units (p<0.001), RI – 0.64±0.01 and 0.49±0.01 rel. units (p<0.001); in the absence of statistically significant differences in the indicators of SDR in the umbilical artery – 3.62±0.09 and 3.41±0.06 rel. units, respectively (р>0.05), PI – 1.23±0.03 and 1.19±0.03 rel. units (p>0.05) and RI – 0.73±0.01 and 0.70±0.01 rel. units (p>0.05). In the third group, in comparison with the second one, vascular resistance did not differ significantly in the right, left uterine arteries and the umbilical cord artery. In patients of the fourth group, in contrast to the third one, higher values of resistance to blood flow were observed: in the right uterine artery – SDR (3.41±0.07 and 2.87±0.07 rel. units, p<0.001), PI (1.48±0.07 and 1.18±0.03 rel. units, p<0.001), RI (0.70±0.01 and 0.65±0.01 relative units, p<0.001); in the left uterine artery – SDR (3.33±0.11 and 2.88±0.09 rel. units, p<0.01), PI (1.45±0.05 and 1.19±0.05 rel. units, p<0.001), RI (0.70±0.01 and 0.68±0.01 rel. units, p<0.01); and also in the umbilical artery – SDR (4.39±0.13 and 3.65±0.12 rel. units, p<0.001), PI (1.45±0.04 and 1.24±0.03 rel. units, p<0.001), RI (0.79±0.01 and 0.72±0.01 rel. units, p<0.001).Conclusion. In the pathogenesis of reduced blood flow in the basin of the uterine and umbilical arteries in women with exacerbation of moderately severe asthma of cytomegalovirus etiology, leading to the development of chronic subcompensated placental insufficiency, compared with uterine cord hemodynamics in asthma in the acute stage, caused by reactivation of CMVI in the second trimester of gestation, which initiates the formation of a chronic compensated form of placental dysfunction in the third trimester of pregnancy, an important role is played by viral stimulation of vasoconstrictor responses.

Changes in immunity during the second trimester of pregnancy in women with exacerbation of bronchial asthma associated with reactivation of cytomegalovirus infection

Aim. To evaluate changes in immunity in the second trimester of pregnancy in women with exacerbation of bronchial asthma associated with reactivation of cytomegalovirus infection (CMVI).Materials and methods. The concentration of secretory immunoglobulin A (sIgA), immunoglobulin A (IgA), immunoglobulin G (IgG), immunoglobulin M (IgM) and circulating immune complexes (CIC) was studied in 112 women at 21-24 weeks of uncomplicated pregnancy and pregnancy complicated by exacerbation of mild-to-moderate asthma associated with CMVI. The first group included 30 women seronegative for CMV, with an uncomplicated pregnancy. The second group consisted of 30 patients with exacerbation of mild asthma, initiated by the acute phase of CMVI, which induces the development of chronic compensated placental insufficiency. The third group consisted of 27 patients with moderate asthma in the acute stage against the background of the acute phase of CMVI, leading to the formation of chronic compensated placental insufficiency. The fourth group included 25 patients with exacerbation of moderate asthma with CMV etiology, initiating the development of chronic subcompensated placental insufficiency.Results. In women of the second group, the concentration of sIgA was 5.91±0.371 mg/L, IgA – 2.64±0.089 mg/mL, IgG – 15.4±0.791 mg/mL, IgM – 2.32±0.144 mg/mL, CIC – 0.176±0.004 optical density units (in the first group, respectively, 4.31±0.266 mg/L, p<0.001; 2.37±0.06 mg/mL, p<0.05; 13.3±0.293 mg/mL, p<0,05; 1.11±0.06 mg/mL, p<0.001; 0.092±0.005 optical density units, p<0.001). In patients of the third group, in contrast to the second one, no differences in immunity parameters were detected. In the fourth group, in comparison with the third one, lower parameters of sIgA (3.21±0.213 mg/L, p<0.001), IgA (1.43±0.081 mg/mL, p<0.001), as well as higher IgG values were detected (19.8±0.418 mg/mL, p<0.001), IgM (2.94±0.082 mg/mL, p<0.01) and CIC (0.198±0.005 optical density units, p<0.05).Conclusion. In patients with moderate asthma with exacerbation against the background of CMVI reactivation, which initiates the formation of chronic subcompensated placental insufficiency, in contrast to women with moderate asthma in the stage of CMVI exacerbation in the second trimester of pregnancy, leading to chronic compensated placental insufficiency in the third trimester of gestation, a more pronounced imbalance of humoral immunity and autoimmune disorders are found, which are important in the development of chronic placental dysfunction.

Changes in the cytokine status in women with exacerbation of bronchial asthma due to reactivation of cytomegalovirus infection in the second trimester of pregnancy

Aim. To study changes in the cytokine status in women with exacerbation of bronchial asthma caused by reactivation of cytomegalovirus infection (CMVI) in the second trimester of gestation.Materials and methods. The concentration of pro-inflammatory cytokines (TNFα, IL-1β, IFNγ, IL-2) in blood serum was assessed in 112 women in the second trimester of pregnancy, uncomplicated and complicated by exacerbation of asthma caused by reactivation of CMVI. The first group included 30 women seronegative for CMVI with uncomplicated pregnancy. The second group consisted of 30 patients with exacerbation of mild asthma associated with CMVI, initiating the formation of chronic compensated placental insufficiency. The third group consisted of 27 patients with exacerbation of moderate asthma induced by CMVI reactivation leading to the development of chronic compensated placental insufficiency. The fourth group included 25 women with exacerbation of moderate asthma due to the acute phase of CMVI, which induces the development of chronic subcompensated placental insufficiency.Results. It was found that in the blood serum of women of the first group, the concentration of TNFα was (Me) 21.5 (13.8–30.1) pg/mL, IL-1β – 18.2 (13.6–34.0) pg/mL, IFNγ – 137.4 (109.5‒174.2) pg/mL and IL-2 – 29.8 (21.0‒38.9) pg/mL. In patients of the second group, compared with the first one, there was an increase in the level of TNFα by 3.79 times (p=0.000001), IL-1β – by 4.8 times (p=0.000001), IFNγ – by 1.73 times (p=0.000001) and IL-2 by 2.91 times (p=0.000001). In the third group, unlike the second one, no significant differences were found between the concentrations of TNFα, IL-1β, IFNγ, and IL-2. In patients of the fourth group, in comparison with the third group, higher values of TNFα (1.35 times, p=0.00507), IL-1β (1.86 times, p=0.000001), IFNγ (1.31 times, p=0.000167), and IL-2 (1.5 times, p=0.0056) were registered.Conclusion. During exacerbation of moderate asthma of cytomegalovirus etiology, leading to chronic subcompensated placental insufficiency, in comparison with exacerbation of moderate asthma caused by reactivation of CMVI, initiating the formation of chronic compensated placental insufficiency, activation of the systemic inflammatory response is most pronounced, leading to stimulation of the migration of monocytes, lymphocytes and neutrophils to the focus of inflammation at the level of small bronchi; also leading to disruption of intersystem relationships and to hemodynamic dysfunction of the placenta.

The incidence of infection in tumor and eye fluid system, and specific humoral immunity to herpes viruses in patients with uveal melanoma

Studies aimed at a direct research of human herpes viruses (HHVs) in the tumor material and eye media have not been carried out so far. Research goal to establish the frequency of detection HHVs DNA in the biomaterial of the eye and blood and to assess the specific humoral immunity to the causative agents of herpes virus infections in patients with uveal melanoma. 38 patients with the uveal tract tumor were examined for the presence of DNA of HHV types 1 and 2 (HSV-1, 2), Cytomegalovirus (CMV), Varicella Zoster virus (VZV), EpsteinBarr virus (EBV) and herpes viruses 6 and 8 types (HHV-6, HHV-8) in tumor tissue, vitreous body, aqueous humour and blood plasma by real-time polymerase chain reaction; blood serum was studied by enzyme-linked immunosorbent assay (ELISA) for IgG and IgM antibodies to HHVs. EBV DNA was present in tumor tissue in 20.6% of cases, in vitreous body in 4.2%, in blood plasma in 2.7%, and was not found in aqueous humor. Ig G antibodies to HSV-1, 2 and CMV were detected in 97.3% of cases, VZV 94.6%, HHV-6 32.4%, antibodies to HHV-8 were not detected. 20 patients (55.6%) had reactivation of chronic HSV-1, 2 infection, and 14 (38.9%) patients had reactivation of CMV infection. Markers of chronic EBV infection were found in all patients, its atypical reactivation was observed in 2 cases (5.4%). Our findings suggest the possible participation of EBV in the oncogenesis of the uveal tract and emphasize the need for further in-depth study of this problem.

Immuno-hormonal and dopplerometric characteristics of placental insufficiency in pregnant women with exacerbation of chronic bronchitis associated with reactivation of cytomegalovirus infection

Aim. To give immune-hormonal and dopplerometric characteristics of placental insufficiency in pregnant women with exacerbation of chronic bronchitis associated with reactivation of cytomegalovirus infection (CMVI).Ma­terials and methods. The concentration of IL-ie, IL-2 and progesterone was studied in the blood serum, and the pulsation index (PI) in the right uterine artery (RUA) was determined in 80 patients at 21-24 weeks of gestation, uncomplicated and complicated by exacerbation of chronic simple bronchitis due to reactivation of CMVI. In a retrospective analysis, 3 groups were formed. The first group - 30 women with CMV-seronegative physiological pregnancy; the second - 25 patients with chronic bronchitis in the acute stage, initiated by the acute phase of CMVI, leading to chronic compensated placental in­sufficiency (CCPI); the third - 25 women with exacerbation of chronic bronchitis CMVI etiology, causing the development of chronic subcompensated placental insufficiency (CSPI) in the third trimester of gestation.Results. In the first group, the concentration of IL-ie was 22.8±0.02 pg/mL, IL-2 - 30.6±2.34 pg/mL, progesterone - 130.8±8.19 nmol/L, and the value of PI in RUA - 0.83±0.04 rel. units. In patients of the second group, compared with the first, the level of IL-ie in­creased by 3.82 times (p<0.00i), IL-2 - by 2.55 times (p<0.00i) and PI in the RUA - by i.40 times (p<0.00i) against the background of a decrease in the progesterone concentration by i.47 times (p<0.00i). The third group compared with the first was characterized by an increase in the concentration of IL-ie by 6.87 times (p<0.001), IL-2 - by 3.19 times (p<0.001) and PI in RUA by i.66 times (p<0.00i) with lower levels of progesterone (i.93 times, p<0.00i). In the third group, in contrast to the second one, an increase in IL-ie was observed by 1.79 times (p<0.001), IL-2 - by 1.24 times (p<0.05) and PI in RUA - by i.i7 times (p<0.05), as well as a decrease in progesterone levels by i.3i times (p<0.0i). There was an in­crease in the relationship of PI in RUA with the concentration of IL-ie (r=0.69; p<0.001), IL-2 (r=0.75; p<0.001) and progesterone (r=-0.55; p<0.01).Conclusion. A more pronounced systemic inflammatory reaction, leading to inhibition of progesterone synthesis and increased resistance to blood flow at RUA develops in exacerbation of chronic bronchitis in the second trimester of gestation against the background of reactivation of CMVI, which initiates the development of CCPI, in comparison with the exacerbation of bronchopulmonary pathology of a similar etiology, which determines the formation of subsequent CCPI.

Changes in immunological parameters and umbilical blood flow in pregnant women during exacerbation of chronic bronchitis associated with cytomegalovirus infection

Aim. To evaluate changes in immunological parameters and umbilical blood flow in pregnant women with exacerbation of chronic bronchitis associated with cytomegalovirus infection (CMVI).Materials and methods. The concentration of secretory immunoglobulin A (sIgA), immunoglobulin E (IgE), circulating immune complexes (CIC), interleukin- 6 (IL-6), interleukin-4 (IL-4) and systolic-diastolic ratio (SDR) in the umbilical artery was studied in 80 women with exacerbation of chronic bronchitis in the second trimester of pregnancy, uncomplicated and complicated by the acute phase of CMVI. The first group was represented by 30 women with cytomegalovirus seronegative physiological pregnancy; the second – 25 patients with exacerbation of chronic bronchitis caused by reactivation of CMVI, complicated by the development of chronic compensated placental insufficiency (CCPI); the third – 25 women with chronic simple bronchitis in the acute stage in the setting of the acute phase of CMVI, initiating the formation of chronic subcompensated placental insufficiency (CSPI) at 30-34 weeks of gestation.Results. In the first group, the concentration of sIgA in blood serum was 4.3±0.26 mg/L, IgE – 3.64±0.23 IU/mL, CIC – 0.091±0.005 AU, IL-6 – 2.41±0.21 pg/mL, IL-4 – 30.1±2.19 pg/mL, cortisol – 527.2±20.95 nmol/L, and SDR in the artery umbilical cord – 3.41±0.06 relative units. In women of the second group, in comparison with the first one, there was an increase in the concentration of sIgA by 1.40 times (p<0.01), IgE – by 1.95 times (p<0.001), CIC – by 1.83 times (p<0.001) , IL-6 – 2.61 times (p<0.001), IL-4 – 1.29 times (p<0.05), cortisol – 1.35 times (p<0.001) in the absence of statistically significant differences the magnitude of vascular resistance in the umbilical artery. In the third group, in comparison with the first one, there was a decrease in sIgA values by 1.26 times (p<0.05) in the setting of an increase in the concentration of IgE by 2.56 times (p<0.001), CIC – by 2.09 times (p<0.001 ), IL-6 – by 3.65 times (p<0.001), IL-4 – by 1.64 times (p<0.001), cortisol – by 1.52 times (p<0.001) and SDR in the umbilical artery – 1.27 times (p<0.001). In women of the third group, in contrast to the second one, a decrease in the concentration of sIgA by 1.77 times (p<0.001), as well as an increase in IgE by 1.31 times (p<0.01), CIC ‒ by 1.14 times (p<0.001), IL-6 ‒ 1.39 times (p<0.001), IL-4 ‒ 1.27 times (p<0.05), cortisol ‒ 1.13 times (p<0.05) and SDR in the umbilical artery ‒ 1.21 times (p<0.001). A direct correlation was established between IL-6 and cord blood flow (r=0.53; p<0.01), as well as an inverse relationship between sIgA and cortisol (r=-0.44; p<0.05).Conclusion. In the second trimester of gestation, exacerbation of chronic simple bronchitis caused by reactivation of CMVI, which initiates the development of CSPI, in contrast to chronic bronchitis in the acute stage, associated with the acute phase of chronic CMVI, which induces the formation of CCPI, is accompanied by an imbalance of nonspecific local and systemic immune responses, as well as stress-reaction, which leads to the growth of SDR in the umbilical artery.

Reactivation of cytomegalovirus infection in a post-COVID patient leading to cytomegalovirus pneumonia and colitis

COVID-19 is a severe disease characterized by a multifactorial immunodeficient state in critically ill patients who have had no prior immunodeficiencies. Much of the mortality in COVID has been attributed to an unprecedented high number of secondary coinfections ranging from bacterial pneumonia to opportunistic infections such as invasive aspergillosis and mucormycosis. Case reports reporting reactivation of cytomegalovirus (CMV) infection are scanty. To the best of our knowledge, we describe one of the very few cases of a previously immunocompetent healthy individual who suffered from reactivation of CMV infection and involvement of invasive infection (CMV pneumonia and CMV colitis).

Interrelation of immunological and hemodynamic parameters of the fetoplacental system in exacerbation of chronic bronchitis of cytomegalovirus etiology

Aim. To establish the relationship of immunological and hemodynamic parameters of the fetoplacental system during exacerbation of chronic bronchitis of cytomegalovirus etiology. Materials and methods. A study was carried out of the concentration of TNFα, IgA, IgM in the blood serum and the systolic-diastolic ratio (SDR) in the right uterine artery (RUA) in 80 women in the second trimester of pregnancy, uncomplicated and complicated by exacerbation of cytomegalovirus infection (CMVI). Three groups were retrospectively distinguished. The first group included 30 patients with CMV seronegative physiological pregnancy, the second group included 25 women with exacerbation of chronic bronchitis caused by CMVI reactivation, initiating the development of chronic compensated placental insufficiency (CCPI), in the third group – 25 pregnant women with chronic bronchitis in the acute stage, induced by CMVI, leading to the formation of chronic subcompensated placental insufficiency (CSPI) in the third trimester of gestation. Results. In the first group, the concentration of TNFα in the blood serum was Me 16.4 (13.1–33.8) pg/mL, IgA – Me 2.5 (2.23–2.62) mg/mL, IgM – Me 0.99 (0.87–1.56) mg/mL, and SDR in RUA – Me 1.95 (1.87–2.30). In the second group, compared with the first one, there was an increase in the concentration of TNFα by 4.95 times (p=0.000001), IgM − by 2.51 times (p = 0.000001) and SDR in RUA by 1.25 times (p = 0.000001) with a 1.49-fold decrease in the IgA level (p = 0.000001). In the third group, compared with the first one, there was an increase in TNFα by 6.12 times (p = 0.000001), IgM − by 2.98 times (p = 0.000001) and the value of SDR in RUA by 1.70 times (p = 0.000001) against the background of a 2.31-fold decrease in IgA concentration (p = 0.000001). In patients of the third group, in comparison with the second group, higher levels of TNFα (by 1.23 times, p = 0.000001), IgM (by 1.18 times, p = 0.000001) and SDR in the RUA (by 1.35 times, p = 0.000001), as well as lower values of the IgA concentration (1.54 times, p = 0.000001). Conclusion. In women with exacerbation of chronic bronchitis caused by CMVI reactivation, leading to the formation of CSPI, in contrast to patients with a similar bronchopulmonary pathology of cytomegalovirus origin and the development of CCPI, a more pronounced activation of the systemic inflammatory response and an imbalance in the humoral component of immune system lead to an increase in vascular resistance in the RUA pool.

Reactivation of cytomegalovirus infection in sepsis and severe bacterial comorbidity

Cytomegalovirus is a frequent contributor to the infectious process in critically ill patients and may contribute to the clinical outcome of the disease. This study aimed to determine the presence and frequency of HCMV reactivation and contributing factors in critically ill patients with severe bacterial comorbidity. Plasma and sputum samples were collected from 82 patients to determine the frequency of reactivation. HCMV reactivation was determined by the detection of HCMV DNA along with the presence of IgG to HCMV. HCMV reactivation was detected in 36.6% of cases. The presence of sepsis was associated with a higher probability of HCMV reactivation (p<0.01), as well as higher HCMV viral loads both in the blood and sputum of patients in these groups. An association between the presence of HCMV in biological fluids and subsequent development of sepsis in patients with severe bacterial pathology (OR=1.5) was detected.

BK Polyomavirus Hemorrhagic Cystitis in Hematopoietic Cell Transplant Recipients.

Introduction:BK polyomavirus-associated hemorrhagic cystitis (BKPyV-HC) is a well-recognized infective complication of hematopoietic cell transplant (HCT) with increased organ dysfunction and mortality. This study was performed to describe the local incidence, risk factors, and outcomes of BKPyV infection.Methods:This retrospective case–control study was conducted between 2007 and 2016 from a tertiary hospital in South India. We identified HCT recipients diagnosed with BKPyV-HC and compared them with recipients over the same period who did not develop BK virus infection matched for age, sex, diagnosis, and donor type. We collected data from central electronic medical records and databases maintained in the departments of hematology and virology.Results:Over the study period, 1276 transplants were performed, of which 262 patients (20.5%) developed HC and 105 (8.2%) were BKPyV-positive. Grade 3 HC was most commonly (57.1%) seen, and the median time to develop BKPyV-HC was 35 (range 0–858) days. Survival was significantly lower in the cases (42.9% vs. 61%, P < 0.05). On univariate analysis, the protective effect of nonmyeloablative conditioning (P = 0.04), residual disease at the time of transplant in malignant conditions (P = 0.001), lower CD34 dose (P = 0.006), presence of acute graft versus host disease (GVHD, P < 0.001), reactivation of cytomegalovirus infection (P < 0.001), and presence of bacterial urinary tract infection (UTI) (P < 0.001) were significant factors. Multivariate logistic regression confirmed the presence of acute GVHD (P = 0.041), bacterial UTI (P < 0.001), and residual disease (P = 0.009) at HCT as significant risk factors for BKPyV-HC.Conclusions:Our study affirms the homogeneity of BKPyV-HC disease in low- and middle-income HCT settings with prior reports and the need for therapeutic strategies to reduce its resultant mortality.

The role of α-tocopherol and ɷ-3 polyunsaturated fatty acids in miscarriage at early stages of pregnancy with cytomegalovirus infection

Introduction. It is now generally acknowledged that cytomegalovirus infection (CMVI) is one of the main causes of miscarriage. However, the mechanism of this effect has not been sufficiently studied. At the same time, the influence of acids of the ɷ-3 family and α-tocopherol (αTP) on the placentation process through a pro-angiogenic action is shown.Aim. To study the concentration of αTP and ɷ-3 family acids in the peripheral blood and establish their role in miscarriage in CMV-seropositive women with CMVI reactivation.Materials and methods. A case-control study included 64 women in the first trimester of pregnancy (7-10 weeks), of which 36 were CMV-seropositive with CMVI reactivation (main group) and 28 were CMV-seronegative (control group). CMVI was diagnosed by the determination of class M and G antibodies by ELISA, as well as CMV DNA detected by PCR. The concentration of ɷ-3 acids of the family (eicosapentaenoic – EPA, docosahexaenoic – DHA) in blood serum was studied by capillary gas-liquid chromatography (J.P.Carreau, J.P.Dubacq). The αTP concentration was determined by the fluorometric method (L.G.Hansen, W.I.Warwich).Results. In women of the main group, a significant (p&lt;0.001) decrease in the concentration of αTP to 1.32±0.025 μg/mL was observed in the peripheral blood compared to the same indicator in the control group (1.49±0.029 μg/mL). At the same time, the levels of EPA and DHA were also statistically significant (p&lt;0.001) lower than the same indicator in the control group and amounted to 1.09±0.012 and 6.09±0.015%, respectively (in the control, 1.29±0.071 and 8.80±0.071%, respectively). Conclusion. The obtained results of the study allow us to establish the important role of disorders in the content of α-TF, EPA and DHA in the pathogenesis of miscarriage during reactivation of CMVI in the early periods of gestation, which can serve as a basis for expanding diagnostic and therapeutic measures in this pathology of pregnant women.

Immunocompromised Patients with Therapy-Refractory Chronic Skin Diseases Show Reactivation of Latent Epstein‒Barr Virus and Cytomegalovirus Infection

Reactivation of latent Epstein‒Barr virus (EBV) and/or Cytomegalovirus (CMV) infection is a dreaded complication in immunocompromised patients receiving hematopoietic stem cell transplantation. Evidence is sparse on whether subclinical reactivation of viral infection may also be of clinical relevance in dermatological patients. We screened patients (N= 206) suffering from chronic skin diseases for subclinical reactivation of EBV and CMV infection. We found that immunocompromised patients with therapy-refractory chronic skin diseases showed higher rates of subclinical reactivation of CMV and EBV infection (6.7% vs. 0% for EBV and 16.7% vs. 5.6% for CMV) and a higher prevalence of virus-specific DNA in skin tissue (30.8% vs. 0% for EBV and 21.4% vs. 0% for CMV) than nonimmunocompromised patients with chronic skin diseases. T cells isolated from lesional skin exhibited up to 14-fold increased proliferation with production of T helper type 1 and T helper type 17 cytokines on stimulation with viral proteins, providing evidence for possible aggravation of the underlying skin diseases by viral infection. Improvement of skin lesions in patients with reactivation of CMV infection (n= 4) was observed on antiviral treatment. Our data suggest that subclinical reactivation of EBV and/or CMV infection is an under-recognized condition in the dermatological patient population with chronic skin diseases.

Influence of cytomegalovirus infection on nucleoside diphosphatase activity in placenta

Introduction. Cytomegalovirus infection (CMVI) makes a significant contribution to the development of pregnancy pathologies, including dysfunction of the placenta. However, the mechanism of such an effect of CMV has not been precisely established. For the coordination of biochemical reactions in the placenta, an optimal concentration of substances, including nucleotides, is required. Nucleoside diphosphatase is an enzyme that catalyzes the hydrolysis of nucleotide diphosphates to nucleotide and phosphate.Aim. Determination of the activity of nucleoside diphosphatase in the placenta in physiological and complicated CMVI reactivation in the third trimester of pregnancy.Materials and methods. A study of 62 placentas obtained during childbirth at 38-40 weeks was carried out. The first group consisted of the placentas from women with CMVI reactivation in the third trimester of pregnancy and the second – the placenta of women without a history of infectious pathology. Diagnosis of CMVI was carried out by determining antibodies of class M and G by ELISA, as well as CMV DNA was detected by PCR. Histochemical analysis of nucleoside diphosphatase was performed according to the method of A.B.Novikoff and D.S.Goldfischer modified by Z.Lojda et al.Results. In the second group, the placenta nucleoside-diphosphatase had a pronounced activity in the syncytiotrophoblast and the connective tissue stroma of the villi. When CMVI was reactivated in the third trimester of pregnancy, a decrease in the intensity of the histochemical reaction to nucleoside-diphosphatase was found: the cytophotometric index in the first group significantly (p&lt;0.001) decreased to 13.06±0.089 rel. units (in the second group it was 14.11±0.119 relative units).Conclusion. The decrease in the activity of nucleoside diphosphatase found during the reactivation of CMVI in the third trimester of pregnancy might indicate a decrease in nucleotide metabolism in the placenta. In our opinion, the study of enzymes involved in the exchange of nucleotides will help to reveal the mechanisms by which CMV causes disturbances in the functioning of the placenta, leading to the development of complications of pregnancy.

A case of refractory pouchitis complicated by cytomegalovirus infection requiring administration of ganciclovir and infliximab

Pouchitis is a frequent complication of surgical treatment of ulcerative colitis (UC), and is typically treated using antimicrobials. If pouchitis is refractory to antimicrobials, screening for complications, such as cytomegalovirus (CMV) infection, is necessary. However, the optimal approach to management of pouchitis complicated by CMV infection is unclear. We report the case of a 41-year-old female patient with UC presenting with pouchitis associated with CMV infection; she had received subtotal colectomy/ileal pouch anal anastomosis (IPAA). She was admitted to hospital with persistent fever, epigastric discomfort, and watery diarrhea despite receiving antibiotics. Laboratory findings showed inflammation and reactivation of CMV infection accompanied by liver injury. The endoscopic findings showed inflammation of the pouch and ileal mucosa on the oral side with extensive and deep punched-out ulcers. Immunohistological staining of biopsy specimens from an ulcerated lesion demonstrated CMV infection. Therefore, we diagnosed the patient with pouchitis complicated by CMV infection. The patient was treated with ganciclovir and infliximab, which resolved her symptoms and led to the disappearance of CMV-positive cells. There has been no recurrence of pouchitis. CMV infection should be considered in patients with UC who develop refractory pouchitis.

Hemophagocytic Syndrome Secondary to Cytomegalovirus Infection in a Patient with Human Immunodeficiency Virus

Hemophagocytic Syndrome (HPS) or Hemophagocytic Lymphohistiocytosis is characterized by a dysregulation of the immune system with activation of macrophages and T lymphocytes, the product of an uncontrollable and excessive inflammatory response to different stimuli. The case of a patient with a history of Human Immunodeficiency Virus (HIV) under current treatment is presented, a clinical picture of 10 days of evolution characterized by fever, anorexia and asthenia, on physical examination skin-mucosa paleness, dehydration, generalized lymphadenopathy, hepatosplenomegaly. Paraclinical tests are performed suggesting reactivation of infection by Cytomegalovirus (CMV), in addition, during its in-hospital evolution, marked pancytopenia is evidenced, with elevated ferritin values, a bone marrow biopsy is performed, observing proliferation of Histiocytes, the patient meets the diagnostic criteria for HPS proposed by the Histiocyte Society in 2004, treatment was instituted, however it presented a torpid evolution and reached death. It is concluded that the diagnosis of HPS is complex; it is usually overlapped by the underlying diseases, as is the case of this HIV patient with reactivation of CMV infection; both viruses by themselves are related to HPS; therefore, knowledge of the clinical and laboratory criteria of this entity is necessary to make an early diagnosis and establish timely treatment, thus reducing mortality.

Features of IgG-antibodies production to individual Cytomegalovirus proteins in various eye diseases (age-related macular degeneration and central serous chorioretinopathy)

Age-related macular degeneration (AMD) and central serous chorioretinopathy (CSC) are diseases targeting the posterior segment of the eye that often lead to lowered visual functions. Pathogenesis of such disorders largely remains unclear. Among the risk factors of developing chronic inflammation, various microorganisms are considered, particularly Cytomegalovirus (CMV ). The study was aimed at analyzing the humoral response to individual viral proteins during chronic and reactivated CMV infection in AMD and CSC patients. Materials and methods. 104 CMV-seropositive patients were enrolled in the study including 75 AMD and 29 CSC subjects. IgM- and IgG-antibodies specific to CMV late viral antigens as well as IgG antibodies against the main non-structural immediate early (IE) antigen were evaluated by ELISA. IgG antibodies to individual CMV phosphoproteins such as the main non-structural immediate early protein (IE), the DNA-binding phosphoprotein pp52, and the tegument phosphoproteins (pp150, pp65, and pp28) were assessed by using Line-Immunoassay: recombinant antigens containing immunodominant protein fragments derived from viral antigens (p52, p150, p65, p28) were used. Positive (bands 2+) and strongly positive (bands 3+) data were only used for analysis. Results. It was shown that in both groups patients with chronic CMV infection had comparable rate of detected antibodies specific to individual antigens. The level of seropositivity to CMV р150 and р65 was significantly higher than that to CMV р52 and р28 (p 0.05). Patients with AMD compared to patients with CSС had significantly higher moderate positive response (2+) to all the antigens examined. Upon reactivation of chronic CMV infection in AMD patients, the level of seropositivity to all antigens was increased, the number of cases with an intensely positive response to individual antigens was elevated, but patients with moderate positive response still prevailed. However, reactivation of chronic CMV infection was observed only in 6 CSС patients, allowing to perform no comparative analysis between these two groups. Conclusion. The main difference between CMV-chronically infected patients with AMD and CSC was not found at the level of seropositivity to individual CMV recombinant antigens, but rather in magnitude of antibody production so that AMD patients in comparison to CSC patients displayed moderate antibody production (bands 2+). A marked difference was related to the level of antibodies against CMV p150: AMD patients showed moderate antibody response (bands 2+), whereas CSC subjects dominated with strong positive response (bands 3+) (p 0.05). It seems that moderate antibody production to recombinant CMV antigens examined in AMD patients occurs due to a weak expression of such viral antigens during chronic infection, resulting in long-term maintenance of antigenic stimulation leading to prolonged inflammation.

Do cytomegalovirus infections affect the daratumumab treatment course in multiple myeloma patients? - Literature review.

IntroductionMultiple myeloma is a progressive and incurable hematological disease characterized by disordered and clonal multiplication of plasmacytes in the bone marrow. The main clinical manifestations are caused by the presence of neoplastic cells in bone tissue, as well as the excessive production of immunoglobulins and normal humoral immunity suppression. Daratumumab is an anti-CD38 monoclonal antibody that has promising results in managing the multiple myeloma disease.ObjectiveThis study aimed to investigate the scientific evidence concerning the impact of the cytomegalovirus infections in the daratumumab treatment course in extensively pretreated multiple myeloma patients.MethodTo this end, an integrative literature review was performed in different databases, comprising a 5-year period.ResultsThe studies analysis revealed that the cytomegalovirus infection reactivation can occur during the use of daratumumab in multiple myeloma patients previously treated, which led to treatment discontinuation, compromised the drug efficacy and favored the disease progression. Moreover, it was observed that even with prophylactic antiviral therapy there was an infection reactivation in some cases, as well as deaths, in more severe situations.ConclusionThus, even considering that few reports on such a topic are available in the scientific literature, the present review showed that cytomegalovirus reactivation can impair daratumumab therapy, mainly in multiple myeloma patients heavily pretreated. In addition, this study could contribute as a tool for the clinical decision and management of adverse effects in medical practices, demonstrating the importance of patient monitoring for the possibility of cytomegalovirus reactivation in heavily pretreated myeloma patients.

Linking indirect effects of cytomegalovirus in transplantation to modulation of monocyte innate immune function.

Cytomegalovirus (CMV) is an important cause of morbidity and mortality in the immunocompromised host. In transplant recipients, a variety of clinically important "indirect effects" are attributed to immune modulation by CMV, including increased mortality from fungal disease, allograft dysfunction and rejection in solid organ transplantation, and graft-versus-host-disease in stem cell transplantation. Monocytes, key cellular targets of CMV, are permissive to primary, latent and reactivated CMV infection. Here, pairing unbiased bulk and single cell transcriptomics with functional analyses we demonstrate that human monocytes infected with CMV do not effectively phagocytose fungal pathogens, a functional deficit which occurs with decreased expression of fungal recognition receptors. Simultaneously, CMV-infected monocytes upregulate antiviral, pro-inflammatory chemokine, and inflammasome responses associated with allograft rejection and graft-versus-host disease. Our study demonstrates that CMV modulates both immunosuppressive and immunostimulatory monocyte phenotypes, explaining in part, its paradoxical "indirect effects" in transplantation. These data could provide innate immune targets for the stratification and treatment of CMV disease.

HEMATOPOIETIC STEM CELL TRANSPLANTATION IN PATIENTS WITH PRIMARY IMMUNODEFICIENCY DERIVED FROM AN ALTERNATIVE DONOR BY USING NEW TRANSPLANT ENGINEERING TECHNOLOGIES

Analysis of the results of hematopoietic stem cell transplantation (HSCT) derived from alternative donors in patients with primary immunodeficiency syndromes. 110 HSCTs for patients with PIDs derived from alternative donors (unrelated, n = 85, haploidentical, t = 25) were performed at the Dmitry Rogachev National Medical Research Centre within 2012-2017 timeframe. In all cases, there were used conditioning regimes with reduced toxicity based on threosulfan TCRotP+/CD19+ depletion with immunomagnetic method were used as the basic cell transplant preparation. The cumulative probability of acute GVHD was 17% (95% CI 10-25) (n = 18); however, it should be noted that in 16 of 18 cases, an acute GVHD, stage II, was observed, showing a good response to the first line therapy; but acute GVHD, stage III, was documented only in 2 patients. Reactivation of cytomegalovirus infection remained one of the serious issues, with a cumulative probability of its reactivation reaching up to 50% and CMV visceral infection rate found in 15.4% cases. The conditioning regimen in patients with Wiskott-Aldrich syndrome by using granulocyte colony-stimulating factor and plerixafor demonstrated a full control over transplant dysfunction compared to control group.Rate of immunological reconstitution upon inoculation of HSCT on the platform TCRotP+/CD19+ deletion did not differ in dynamics from that one after using undepleted HSCT together with native hematopoietic stem cell sources in a historical cohort. The overall survival probability for entire PID patient cohort was 84% (95% CI 77-92). No differences in patients transplanted from unrelated and haploidentical donors were revealed by assessing any of the studied parameters.Introduction of new HSCT technologies allows us to dramatically minimize adverse outcomes of PIDs and opens new avenues for further research in cellular regulation of autoinflammatory oncological and infectious disorders resulting in lethal outcome in PID patients.