Severe Cytomegalovirus Infection Research Articles

Severe gastrointestinal cytomegalovirus infection in a patient diagnosed with late onset combined immunodeficiency

Late onset combined immunodeficiency (LOCID) is a rare variant of common variable immunodeficiency (CVID), typically affecting adult patients who present with opportunistic infections (OI) and/or low CD4+ T lymphocytes. Diagnostic delay is common due to the rareness of this entity, increasing morbidity and mortality. We report on a 66-year-old male who developed a severe gastrointestinal cytomegalovirus (CMV) infection, refractory to antiviral treatment and anti-cytomegalovirus specific human immunoglobulin administration, with a fatal outcome due to an undiagnosed LOCID.

Contribution of fetal blood sampling to determining the prognosis of congenital cytomegalovirus infections: a case-cohort study in Switzerland

Cytomegalovirus is responsible for the most common congenital infection, affecting 0.5% to 1.0% of live births in Europe. Congenital cytomegalovirus infection can be diagnosed during pregnancy by viral DNA amplification in the amniotic fluid, but the prognosis of fetuses without severe brain abnormalities remains difficult to establish on the basis of prenatal imaging alone. To identify predictors of moderate to severe symptomatic cytomegalovirus infection among fetal blood parameters and to propose an algorithm on the basis of these parameters and on prenatal imaging that would provide the best positive and negative predictive values. Fetal blood sampling at 21-28 weeks gestation was performed in fetuses with congenital cytomegalovirus infection confirmed by amniocentesis after maternal infection in the first-trimester or periconceptional period. We compared the levels of hemoglobin, thrombocytes, γ-glutamyl transpeptidase, aspartate aminotransferase, alanine aminotransferase, β2-microglobulin, immunoglobulins G and M, and cytomegalovirus DNA viral loads in amniotic fluid and fetal blood between those with moderate to severe symptomatic infection and those with asymptomatic to mild infection (median follow-up of 36 months for live births). Among 58 fetuses included, 25 (43%) had a moderate to severe symptomatic infection: 16 with severe cerebral abnormalities, 5 with multiple signs or symptoms at birth, 2 with bilateral sensorineural hearing loss, and 2 with neurodevelopmental delay. The values of thrombocytes, aspartate aminotransferase, β2 microglobulin, Immunoglobulin M, and cytomegalovirus viral loads differed significantly between fetuses with moderate to severe symptomatic infection and those with asymptomatic to mild infection. The optimal strategy to predict moderate to severe symptomatic infection was to first perform fetal brain imaging, followed by fetal blood sampling with the following cutoffs: thrombocytes <120,000/mL, viremia ≥5 log10/mL, and β2 microglobulin ≥12 mg/L). This recursive algorithm had a negative predictive value of 100% for moderately to severely symptomatic infection. The combination of thrombocytes, β2-microglobulin, and cytomegalovirus viral load in fetal blood can be used for prognosis determination, particularly in cytomegalovirus-infected fetuses without severe brain abnormalities at the time of prenatal diagnosis. Future studies should evaluate whether these parameters remain useful in infected fetuses who have been treated with valacyclovir before fetal blood sampling.

Typical hemophagocytic syndrome associated with cytomegalovirus infection in an immunocompetent patient: a case report and literature review.

Cytomegalovirus (CMV) infection is currently prevalent in populations throughout the world, and 56%‍-94% of the global population is seropositive for CMV. CMV infection mainly affects immunocompromised hosts. In these cases, it can cause significant symptoms, tissue-invasive disease, and many sequelae including death (Dioverti and Razonable, 2016). The vast majority of healthy adults with CMV infection experience an asymptomatic course; when symptomatic, it manifests as a mononucleosis-like syndrome in approximately 10% of patients (Sridhar et al., 2018). The gastrointestinal tract and central nervous system appear to be the most frequent sites of severe CMV infection in immunocompetent individuals (Rafailidis et al., 2008). However, CMV infection is relatively rarely recorded in immunocompetent hosts.

Letermovir Improves the Outcome of Allogenic Stem Cell Transplantation with Anti-Thymocyte Globulin By Reducing Relapse

Background: After an allogenic stem cell transplantation (allo-SCT), patients face the risk of infection, and cytomegalovirus (CMV) is a common pathogen. Severe CMV infections can be fatal, so prophylaxis or early treatment is critical. To manage CMV infections precisely, letermovir is administered for prevention of CMV reactivation. Letermovir also improved patients' overall survival (OS) after allo-SCT in several studies.However, some studies have found that letermovir did not affect OS, and it is still unknown whether letermovir can improve allo-SCT outcome. We investigated whether letermovir had an impact on allo-SCT outcomes. Methods: We retrospectively studied 443 patients over the age of 18 who received allo-SCT for hematological malignancies from 2004 to 2020 in Anjo Kosei Hospital. The patients were divided into letermovir (n = 56) and non-letermovir (n = 387) groups. Letermovir was administered from day 5 after allo-SCT to day 100 unless severe adverse events were observed. We conducted pp65 antigenemia tests for monitoring CMV reactivation. Results: For patients' characteristics, the median age was 49 (range: 18-71) in the letermovir group and 53 (range: 18-72) in the non-letermovir group (p = 0.12). Acute leukemia was the most common disease in both groups. There was no difference in sex (p = 0.77). As stem cell sources, relative peripheral blood cells (PB), unrelated bone marrow, unrelated PB, and cord blood (CB) were used in both groups. In letermovir group, more patients underwent allo-SCT in recent years (p &amp;lt; 0.001) and received anti-thymocyte globulin (ATG) (p &amp;lt; 0.001). The median duration of letermovir administration was 93 days (range: 14-110). The 3-year OS rates were 66% (95%confidence interval [CI]: 52%-77%) and 44% (95%CI: 38%-49%) in the letermovir and non-letermovir groups, respectively (p &amp;lt; 0.01) (Figure 1). Interestingly, non-relapse mortality (NRM) was equivalent, and the relapse rate was 15% (95%CI: 6.7%-25%) vs. 31% (95%CI: 27%-36%) and significantly lower in the letermovir group (p &amp;lt; 0.01) (Figure 1). The cumulative CMV reactivation incidence rates at day 100 were 7.0% (95%CI: 1.1%-26%) and 45% (95%CI: 34%-59%) in the letermovir and non-letermovir groups, respectively (p = 0.037). The GVHD incidence rate in both groups was comparable. Since we observed the difference in the number of ATG administration between the two groups, we conducted the stratification analysis in patients who experienced ATG administration (n = 85). In letermovir (n = 25) and non-letermovir (n = 60) groups, 3-year OS was 84% (95%CI: 63%-94%) and 44% (95%CI: 31%-56%). NRM was equivalent, and the relapse rate was 12% (95%CI: 2.9%-28%) vs. 44% (95%CI: 31%-56%) and significantly lower in the letermovir group (p &amp;lt; 0.01). The cumulative CMV reactivation incidence rates at day 100 were 8.0% (95%CI: 1.3%-23%) and 43% (95%CI: 31%-56%) in the letermovir and non-letermovir groups, respectively (p = 0.077). The incidence rate of GVHD was equivalent between the two groups. In multivariate analysis, letermovir was recognized as a significant factor for OS (hazard ratio [HR]: 0.30, 95%CI: 0.089-0.99, p &amp;lt; 0.05) and relapse rate (HR: 0.27, 95%CI: 0.092-0.80, p &amp;lt; 0.05). In patients who have not received ATG, 3-year OS (48% (95%CI: 30%-64%) vs. 43% (95%CI: 37%-48%), p = 0.86) and relapse rate (19% (95%CI: 7.3%-34%) vs. 30% (95%CI: 25%-35%), p = 0.17) were comparable between letermovir and non-letermovir groups. NRM was also equivalent. Conclusion: Letermovir administration suppressed the reactivation rate of CMV and improved the outcome of allo-SCT. Interestingly, the letermovir group showed lower relapse rate and this effect was mainly observed in allo-SCT with ATG. Letermovir can possess the positive effect for outcome of the allo-SCT with ATG.

Safety of Cidofovir Treatment for Suspected or Confirmed Adenovirus Infection in Immunocompetent Pediatric Population.

Cidofovir (CDV), a nucleoside phosphonate analogue, exhibits activity against severe cytomegalovirus and adenoviral (ADV) infection. Nevertheless, reports of elevated nephrotoxicity rates limited its use to highly vulnerable cases, mainly immunocompromised children with fulminant infection. Limited data exists regarding CDV safety in immunocompetent children. To evaluate CDV-related toxicity, mainly nephrotoxicity, in immunocompetent children with severe ADV/cytomegalovirus infection. We conducted a retrospective review of medical records for all immunocompetent children under 18 years of age treated with intravenous CDV from January 2005 to December 2019. Among the 23 patients identified, 21 were diagnosed with severe ADV infection. Median age was 15 months. Twenty-one (91%) children were admitted to the pediatric intensive care unit. Eighteen patients (78%) received standard CDV protocol (5 mg/kg CDV weekly for 2 weeks), 4 (17%) according to nephroprotective low-dose protocol and 1 patient transitioned. The median duration of CDV treatment was 14 days (range: 1-21 days). All patients received hyperhydration and probenecid with each infusion. Acute kidney injury was recorded in 1 patient (with concurrent septic shock) during CDV treatment. Two children exhibited acute kidney injury before CDV initiation, but renal function normalized during CDV treatment. One patient developed transient neutropenia (600 cells/L), apparently as a result of sepsis. No other major adverse effects were noted. Mortality rate was 3/23 (13%), unrelated to CDV toxicity. Our findings suggest that CDV-related nephrotoxicity rate in immunocompetent children may be lower than previously reported, perhaps lower than in the severely immunocompromised population.

Severe gastrointestinal cytomegalovirus infection with underlying common variable immunodeficiency in a middle aged lady

Cytomegalovirus is a common herpes virus infection found worldwide and by adulthood majority become seropositive. In immunosuppressed state it may reactivate to cause tissue invasive disease in gastro intestinal tract, liver, lungs, brain and retina with or without viremia. It is commonly seen in bone marrow transplant, organ transplant, AIDS and autoimmune disease requiring intense immunosuppressive therapy. Common variable immunodeficiency is a condition that affects both arms of the immune system and can lead to opportunistic infections. Chance is more when CD4 counts falls below 50 cells/microlt.

CD4+ but Not CD8+ T Cells are required for protection against severe guinea Pig cytomegalovirus infection

CD4+ but Not CD8+ T Cells are required for protection against severe guinea Pig cytomegalovirus infection

Halo sign in fetal cytomegalovirus infection: cerebral imaging abnormalities and postmortem histopathology in 35 infected fetuses.

To evaluate the correlation of periventricular echogenic halo (halo sign) with histopathological findings and its association with other brain imaging abnormalities in fetuses with cytomegalovirus (CMV) infection. This was a retrospective study of fetuses diagnosed with severe CMV infection based on central nervous system (CNS) abnormalities seen on ultrasound, which had termination of pregnancy (TOP) or fetal demise at a single center from 2006 to 2021. All included cases had been evaluated by conventional complete fetal autopsy. A maternal-fetal medicine expert reanalyzed the images from the transabdominal and transvaginal neurosonography scans, blinded to the histological findings. The halo sign was defined as the presence of homogeneous periventricular echogenicity observed in all three fetal brain orthogonal planes (axial, parasagittal and coronal). Cases were classified according to whether the halo sign was the only CNS finding (isolated halo sign) or concomitant CNS anomalies were present (non-isolated halo sign). An expert fetal radiologist reanalyzed magnetic resonance imaging (MRI) examinations when available, blinded to the ultrasound and histological results. Hematoxylin-eosin-stained histologic slides were reviewed independently by two experienced pathologists blinded to the neuroimaging results. Ventriculitis was classified into four grades (Grades 0-3) according to the presence and extent of inflammation. Brain damage was categorized into two stages (Stage I, mild; Stage II, severe) according to the histopathological severity and progression of brain lesions. Thirty-five CMV-infected fetuses were included in the study, of which 25 were diagnosed in the second and 10 in the third trimester. One fetus underwent intrauterine demise and TOP was carried out in 34 cases. The halo sign was detected on ultrasound in 32 (91%) fetuses (23 in the second trimester and nine in the third), and it was an isolated sonographic finding in six of these cases, all in the second trimester. The median gestational age at ultrasound diagnosis of the halo sign was similar between fetuses in which this was an isolated and those in which it was a non-isolated CNS finding (22.6 vs 24.4 weeks; P = 0.10). In fetuses with a non-isolated halo sign, the severity of additional ultrasound findings was not associated with the trimester at diagnosis, except for microencephaly, which was more frequent in the second compared with the third trimester (10/18 (56%) vs 1/8 (13%); P = 0.04). With respect to histopathological findings, ventriculitis was observed in all fetuses with an isolated halo sign, but this was mild (Grade 1) in the majority of cases (4/6 (67%)). Extensive ventriculitis (Grade 2 or 3) was more frequent in fetuses with a non-isolated halo sign (21/26 (81%)) and those without a periventricular echogenic halo (2/3 (67%); P = 0.032). All fetuses with an isolated halo sign were classified as histopathological Stage I with no signs of brain calcifications, white-matter necrosis or cortical injury. On the other hand, 25/26 fetuses with a non-isolated halo sign and all three fetuses without a periventricular echogenic halo showed severe brain lesions and were categorized as histopathological Stage II. Among fetuses with a non-isolated halo, histological brain lesions did not progress with gestational age, although white-matter necrosis was more frequent, albeit non-significantly, in fetuses diagnosed in the second vs the third trimester (10/15 (67%) vs 3/11 (27%); P = 0.06). In CMV-infected fetuses, an isolated periventricular echogenic halo was observed only in the second trimester and was associated with mild ventriculitis without signs of white-matter calcifications or necrosis. When considering pregnancy continuation, detailed neurosonographic follow-up complemented by MRI examination in the early third trimester is indicated. The prognostic significance of the halo sign as an isolated finding is still to be determined. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Incidence and severity of cytomegalovirus infection in seropositive heart transplant recipients.

The frequency and significance of cytomegalovirus (CMV) infection in seropositive (R+) heart transplant recipients (HTR) is unclear, with preventative recommendations mostly extrapolated from other groups. We evaluated the incidence and severity of CMV infection in R+ HTR, to identify risk factors and describe outcomes. R+ HTR from 2010 to 2019 were included. Antiviral prophylaxis was not routinely used, with clinically guided monitoring the local standard of care. The primary outcome was CMV infection within one-year post-transplant; secondary outcomes included other herpesvirus infections and mortality. CMV infection occurred in 27/155 (17%) R+ HTR. Patients with CMV had a longer hospitalization (27 vs. 20 days, unadjusted HR 1.02, 95% CI 1.00-1.02, p=.01), higher rate of intensive care readmission (26% vs. 9%, unadjusted HR 3.46, 1.46-8.20, p=.005), and increased mortality (33% vs. 8%, unadjusted HR 10.60, 4.52-24.88, p<.001). The association between CMV and death persisted after adjusting for multiple confounders (HR 24.19, 95% CI 7.47-78.30, p<.001). Valganciclovir prophylaxis was used in 35/155 (23%) and was protective against CMV (infection rate 4% vs. 27%, adjusted HR .07, .01-.72, p=.025), even though those receiving it were more likely to have received thymoglobulin (adjusted OR 10.5, 95% CI 2.01-55.0, p=.005). CMV infection is common in R+ HTR and is associated with a high burden of disease and increased mortality. Patients who received valganciclovir prophylaxis were less likely to develop CMV infection, despite being at higher risk. These findings support the routine use of antiviral prophylaxis following heart transplantation in all CMV R+ patients.

PREVALENCE AND PREDISPOSITION FACTORS THAT CAUSE CYTOMEGALOVIRUS ESOPHAGITIS

Background: Cytomegalovirus (CMV)-associated gastrointestinal disorders are typically seen in immune-compromised patients; nevertheless, a few cases have been reported in healthy hosts, despite the fact that the pathogenic mechanisms are yet unknown. Various lesions, including erythematous mucosa, erosions, and ulcers, are brought on by CMV esophagitis, albeit these inflammatory alterations can also be seen in nearby or superficial esophageal malignancies. Cancer patients with late and/or terminal stages of the disease have also been known to develop CMV-associated esophagitis due to immunosuppression brought on by chemotherapy or the physiological demands of the cancer itself.&#x0D; Objectives: To identify the prevalence of cytomegalovirus esophagitis, describe the evaluation of cytomegalovirus esophagitis and outline the causes of cytomegalovirus esophagitis.&#x0D; Methods: For article selection, the PubMed database and EBSCO Information Services were used. All relevant articles relevant with our topic and other articles were used in our review. Other articles that were not related to this field were excluded. The data was extracted in a specific format that was reviewed by the group members.&#x0D; Conclusion: Cytomegalovirus (CMV) esophagitis, which can result from illnesses including human immunodeficiency virus (HIV) infection and treatments like post-organ transplantation, long-term dialysis, and systemic steroid therapy, is mostly brought on by systemic immune deficiency. Primary CMV infection, however, can result in serious organ-specific consequences with high morbidity and fatality rates. In immune-competent people, severe CMV infections can have an impact on practically every system.

Congenital cytomegalovirus infection: features of the clinical course and catamnesis according to own observations

Congenital cytomegalovirus infection is the most common congenital infection, occurs in 0.6-5% of newborns worldwide, and is considered the leading non-genetic cause of sensorineural hearing loss in children. Most newborns with a manifest form of the disease develop psychomotor and cognitive disorders, and about half of them develop visual impairment.The purpose of publication: to present a clinical case of severe congenital cytomegalovirus infection in the manifest period with multisystem manifestations (hemorrhagic syndrome, encephalitis, myocarditis, hepatitis, splenomegaly) and follow-up data at the age of 1 year.Conclusion. this clinical example demonstrates diagnostic and therapeutic difficulties in the acute period of the disease and a significant list of diseases resulting from infection. Based on the information presented, the importance and necessity of close attention to the results of a serological study of pregnant women during the entire gestation period with an assessment of the antibody titer to cytomegalovirus infection in dynamics are updated. Specific antiviral therapy, prescribed on the basis of a life-threatening course of a severe manifest form of the disease, made it possible to achieve positive dynamics in the acute period, eradicate the virus and prevent severe outcomes, including death.

Efficacy of Cytomegalovirus Specific Immunoglobulins to Reduce CMV Reactivation in Pediatric Hematopoietic Stem Cell Transplant Recipients.

Cytomegalovirus (CMV) infection is a serious complication of pediatric hematopoietic stem cell transplant (HSCT). To date, antiviral therapy has been the mainstay of prophylaxis, with conflicting results regarding the benefits of CMV-specific immunoglobulins (CMV-Ig). After introducing prophylactic CMV-Ig to HSCT recipients at risk (seropositive recipient and/or donor), we conducted a single-center retrospective study comparing the incidence and severity of CMV infection with and without CMV-Ig. We identified 49 'at risk' recipients from 76 consecutive HSCTs over 3.5 years, in addition to standard antiviral prophylaxis, 10 patients received CMV-Ig and 39 did not. There was no significant difference in donor type, cell source, conditioning, or CMV status between the groups. We observed a potential trend toward reduction of incidence of CMV reactivation in patients exposed to CMV-Ig (30%) compared with those who weren't (38.4%). Besides, no symptomatic or lethal infection was observed in the CMV-Ig group, and time to recovery seemed shorter (21 [±7] vs 51.4 [±55] days) and peak titers lower (4578 [±4788] vs 24131 [±49257]) with CMV-Ig. No adverse events were noted. The statistical significance of the results was limited by the small sample size. These data raise interest in prophylactic CMV-Ig as a safe way of potentially reducing the severity and duration of CMV reactivation in HSCT.

Incidence and Severity of Cytomegalovirus Infection in Seropositive Heart Transplant Recipients

<h3>Purpose</h3> Cytomegalovirus (CMV) infection contributes to morbidity and mortality in heart transplant recipients (HTR). Donor positive, recipient negative (D+/R-) patients are high risk and generally receive antiviral prophylaxis. The burden of CMV infection in recipient seropositive (R+) HTR is less clear, with preventative recommendations mostly extrapolated from other solid organ transplant groups. The aim of this retrospective cohort study was to define the incidence, severity of & risk factors for CMV infection in R+ HTR. <h3>Methods</h3> CMV seropositive HTR were included (2010-2019). Antiviral prophylaxis was not routinely used, with clinical monitoring the local standard of care. Data were collected from medical records, & patients followed for a year post-transplant. The incidence of CMV infection, including tissue invasive disease, was quantified, & predisposing/mitigating factors identified. We also assessed the association of CMV with adverse outcomes including prolongation of hospitalization & death. <h3>Results</h3> Our cohort included 155 R+ HTR (median age 53yrs, 72% male, 56% D+/R+, 68% basiliximab & 8% thymoglobulin induction). Valganciclovir prophylaxis was used in 35 (23%) for a median of 103 days (IQR 78-222). CMV infection occurred in 27 (17%) patients at a median onset of 67 days (41-124), median peak viral load was 1250 IU/mL (221-6539) & 18/27 (67%) required readmission. End-organ disease occurred in 22 (82%) & was most commonly gastrointestinal (52%). CMV infection was associated with a longer length of stay (27 vs. 20 days, HR 1.02, 95% CI 1.00-1.03, p=0.02), higher rate of intensive care readmission (26% vs. 9%, 4.57, 1.76-11.88, p=0.002), & increased mortality (33% vs. 8%, HR 9.11, 3.49-23.8, p<0.001). Valganciclovir prophylaxis was protective for CMV (4% vs. 27%, 0.094, 0.012-0.75, p=0.025), even though patients receiving it were more likely to have had thymoglobulin induction (31% vs. 2%, OR 27.04, 5.63-129.88, p<0.001). <h3>Conclusion</h3> CMV infection occurred in 17% of R+ HTR & was associated with a high burden of disease, worse post-transplant outcomes & increased mortality. Patients who received valganciclovir prophylaxis were less likely to develop CMV infection. These findings support the routine use of CMV preventative strategies such as antiviral prophylaxis following heart transplantation in all CMV R+ patients.

Severe Cytomegalovirus Encephalomyelitis and Polyradiculitis in the Immunocompetent: An Unusual Case of Critical Illness

Central and peripheral nervous system infection due to cytomegalovirus (CMV) is extremely rare in immunocompetent patients. Here, we present an unusual case of a young immunocompetent African-American woman who developed a severe form of CMV encephalomyelitis and polyradiculitis with a prolonged and complicated hospital course. The patient was treated with a prolonged course of antiviral medications and showed some improvement in her symptoms. This unusual presentation adds to the limited literature on the diagnosis, treatment and prognosis of severe CMV infection in immunocompetent hosts.

First-line noninvasive management of cytomegalovirus primary infection in pregnancy.

To introduce a first-line noninvasive antenatal management of maternal cytomegalovirus (CMV) primary infection based on ultrasound (US) and magnetic resonance imaging (MRI). Amniocentesis (AC) is used as a second-line tool in cases of abnormalities compatible with fetal CMV infection on US and/or MRI screening. Between January 2011 and October 2018, pregnant women referred with a CMV primary infection on antibody screening were followed up by monthly US scans and a brain MRI at approximately 32weeks. In cases with US and/or MRI abnormalities compatible with congenital CMV infection, AC was performed to confirm the diagnosis. Ninety pregnant women with a primary CMV infection were included (89 singleton and one twin pregnancy). The first-line screening by US and/or MRI was normal for 72 of 91 fetuses (79%). At birth, 19 of these 72 neonates (26%) had a positive urine sample for CMV but were asymptomatic. US and/or MRI abnormalities were identified in 19 fetuses (21%). AC confirmed a fetal CMV infection in 16 fetuses (84%); 12 pregnancies were terminated, and four were continued, with three symptomatic neonates at birth and one poor neurodevelopmental outcome at postnatal follow-up. First-line noninvasive management of maternal CMV primary infection based on serial US scans and brain MRI can be offered to identify fetuses with severe symptomatic congenital CMV infection and reduce the number of ACs without compromising the fetal outcome.

Prognosis of severe cytomegalovirus infection in newborns

Objective is to study the features of impaired activation of T and B lymphocytes in order to predicting severe cytomegalovirus infection in newborns. Materials and methods. 133 newborns with cytomegalovirus infection were examined. Immediately after diagnosing cytomegalovirus infection, all patients observed were immunologically ex amined, including assessing count of peripheral blood T and B lymphocytes, as well as their intercellular interaction by using flow cytometry immunostaining for CD3, CD3+CD28–, CD3+CD28+, CD3–CD28+, CD4, CD8, CD20, CD20+CD40+, CD28, CD40. The test was performed by using a Beckman Coulter Epics XL laser flow cytofluorometer. Depending on the condition severity, all children were divided into two groups: 1 — cytomegalovirus infection, severe form — 60 subjects (45.1%); 2 — cytomegalovirus infection, moderate form — 73 subjects (54.9%). Results of the entire set of studied indicators for cellular and humoral arms of immune system revealed statistically significant differences for the prognosis of severe cytomegalovirus infection: CD3+CD28–, CD20, CD20+CD40+, CD4. T lymphocytes with CD3+CD28+ activation markers, through which costimulating signals necessary for the activation of T helper cells are exerted cell-intrinsic features, serving as an important factor ensuring immune response. Using the “classification trees” method, we developed a differentiated approach to forecast severe cytomegalovirus infection in newborns. Systems of inequalities were obtained, four of which classify a subgroup of newborns with severe cytomegalovirus infection. The consistent application of the obtained inequalities makes it possible to isolate from the input stream of sick patients with a prognosis of the development of severe cytomegalovirus infection. The proposed diagnostic rules can be considered as screening markers for predicting a severe cytomegalovirus infection in newborns, which makes possible the timely onset of specific therapy.

The importance of immunosupression in the development of the heavy form of cytomegaloviral infection in newborn children

Objective: to study the features of disorders in T and B cell immunity and the synthesis of serum immunoglobulins of classes IgA, IgM, IgG with the aim of predicting severe cytomegalovirus infection (CMVI) in newborns.Research methods: 133 newborns with cytomegalovirus infection were examined. Lymphocytes were typed to differentiation clusters CD3, CD4, CD8, CD20 using monoclonal antibodies, IMMUNOTECH (France). The expression of membrane markers of immunocompetent cells was determined using a Beckman COULTER EpicsXLII flow laser cytofluorimeter. Depending on the severity of the condition, all children were divided into two groups: 1 — CMVI, severe form — 60 people (45,1%); 2 CMVI, moderate form — 73 people (54,9%).Results. Using the «classification trees» method, we were able to develop a differentiated approach to the prognosis of a severe form of CMVI in newborn children. Systems of inequalities were obtained, four of which classify a subgroup of newborns with severe CMVI. Conclusion: the proposed diagnostic rules can be considered screening markers for prognosis of a severe form of CMVI in newborns.

Multidrug antiviral “Rescue” therapy for severe cytomegalovirus infection after lung transplantation: a case report

Introduction Primary cytomegalovirus (CMV) infection or re-activation of prior latent CMV infection are common complications after lung transplant (LTX), associated with high morbidity and mortality [1]. Anti-CMV strategy usually includes antiviral drug prophylaxis and monitoring of CMV viral load after transplant [2]. Recently, CMV drug resistance is emerging as a severe postoperative complication with an incidence up to 4,7% [3]. Methods A 32-year-old woman, affected by pulmonary veno-occlusive disease, was listed for bilateral LTX. She had a history of Sharp's syndrome, needing high dose of steroid. Both the patient and the donor anti-CMV IgG and CMV DNA were not detectable. Because of severe pulmonary hypertension (mean pulmonary arterial pressure >60mmHg), LTX was performed with pre-emptive VA-ECMO support that was prolonged until postoperative day (POD) 7. Since POD1, both induction immunosuppressive therapy (intravenous (iv) Methylprednisolone 0,5mg/kg/die, Mycophenolate-Mophetil 2g/die, and iv Cyclosporine 1mg/kg/die with plasmatic Cyclosporine concentration target of 200ng/mL) and CMV prophylaxis (iv CMV-hyperimmune-globulin 75IU/kg every 4 days) have been started. Results On POD30 the patient developed abdominal pain, diarrhoea and lower gastrointestinal bleeding. Colonoscopy suggested an acute CMV colitis (Fig.1) and CMV-DNA was revealed in blood (>1million IU/mL) and feces. High dose Ganciclovir was promptly started, while Cyclosporine was stopped. However, the patient clinically deteriorated due to severe peritonitis. A CT scan showed diffuse pulmonary ground glass with tree-in-bud pattern (Fig.2A) and bowel distension with colon perforation (Fig.2B). A right hemicolectomy and ileostomy were immediately performed. Subsequently, the patient developed severe septic shock and acute respiratory failure (PaO2/FiO2 5milion IU/mL), despite high dose of Ganciclovir (10mg/kg/die). Because of a strong clinical suspicion of CMV drug resistance, specific molecular analysis was performed, but no relevant CMV DNA mutations potentially causing Ganciclovir resistance were found. However, iv Foscarnet (80mg/die, adjusted according to creatinine clearance) was empirically added and iv CMV-hyperimmune-globulin was potentiated (up to 75IU/kg/die). Six days later, CMV viral load started to decrease, until negativization on POD60 (Fig.3), with a significant improvement in patient clinical conditions. Unfortunately, the patient died on POD75 due to septic shock related to bronchial anastomosis dehiscence and Klebsiella Pneumoniae infection. Discussion This case has several peculiarities: - early onset of CMV infection after LTX (reported median time of 253 days [1]) despite prophylaxis; - very high viremia peak (>5million IU/mL on POD33); - rapidly progressive CMV infection, with severe abdominal complication requiring surgery; - poor response to Ganciclovir, needing multidrug antiviral therapy, despite no molecular sign of drug resistance.

Comparative Study of Mizoribine and Mycophenolate Mofetil Combined with a Calcineurin Inhibitor-Based Immunosuppressive Regimen in Patients with Alternative Donor Hematopoietic Cell Transplantation.

Cytomegalovirus (CMV) infection and graft-versus-host disease (GVHD) remain the major causes of nonrelapse mortality (NRM) in patients following alternative donor hematopoietic stem cell transplantation (HCT). Mizoribine (MZR) showed an anti-CMV effect in addition to its immunosuppressive effect in patients with renal transplantation. In this study, we aimed to evaluate the efficacy and safety of MZR combined with a calcineurin inhibitor (CNI) as a method of prophylactic immunosuppression in recipients following alternative donor HCT. Eighty patients were enrolled in the study and randomized to the MZR (n=40) or MMF (n=40) cohort before transplantation conditioning. Analyses involved a comparison of the outcomes between the 2 cohorts, as well as risk analyses of early nonrelapse mortality (NRM) and severe CMV infection. In contrast to MMF, MZR was associated with a lower but statistically nonsignificant median CMV DNA peak load (P=.075), significantly fewer episodes of persistent/refractory infection (odds ratio [OR], .12), and a lower failure rate of CMV treatment (OR, .82), but a significantly higher rate of hyperuricemia (OR, 2.75). Transplantation efficacy was comparable in the 2 cohorts regarding engraftment, the development of secondary poor graft function and GVHD, and the estimated OS and PFS. The 1-year NRM of the MZR cohort did not differ from that of the MMF cohort, whereas the rate of 1-year NRM caused by viral infections was reduced in the MZR cohort and was of borderline statistical significance (P=.05). In the multivariate analysis, lower doses of CD34+ cells in grafts (hazard ratio [HR], 3.65) and persistent/refractory CMV infections (versus no CMV infection: HR, 7.31; versus CMV infection that was not persistent/refractory: HR, 4.46) were predictors of increased 1-year NRM. The use of MMF (versus MZR cohort: OR, 11.54) and grade II-IV acute GVHD (OR, 15.32) were independent risk factors for developing persistent/refractory CMV infection. When combined with CNIs, MZR functioned well in terms of both immunosuppression and reduced severity of CMV infection; however, further studies are warranted to verify its use as a potential immunosuppressant for alternative donor HCT.

Isolated thrombotic microangiopathy of the small intestine in a patient with atypical hemolytic uremic syndrome \u2013 a case report

BackgroundAtypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by systemic thrombotic microangiopathy (TMA) reflected by hemolysis, anemia, thrombocytopenia and systemic organ injury. The optimal management of aHUS-patients when undergoing kidney transplantation to prevent recurrence in the allograft is eculizumab, an approved recombinant antibody targeting human complement component C5.Case presentationA 39 year-old woman presented with severe abdominal pain, diarrhea and emesis for 3 days. In her past medical history she had experienced an episode of aHUS leading to end stage renal disease (ESRD) in 2007 and a genetic workup revealed a heterozygous mutation in the membrane cofactor protein gene. In 2014 she underwent cadaveric kidney transplantation. Four years later she had to go back on hemodialysis due to allograft failure following a severe systemic cytomegalovirus infection resulting in transplant failure. At presentation she still received calcineurin-inhibitor therapy and reported subfebrile temperatures and pain projecting over the transplant prior to the current symptoms. A contrast enhanced CT-scan of the abdomen revealed inflammatory wall thickening of the small intestine. Diagnostic endoscopy discovered fresh blood in the small intestine without a clear source of bleeding. Histopathology of the small intestine biopsies showed severe thrombotic microangiopathy. Of note, the patient persistently had no signs of systemic hemolysis. Since the TMA of the small intestine was most likely due to aHUS, eculizumab treatment was initiated which abolished the symptoms.ConclusionHere we report a patient with thrombotic microangiopathy with predominant manifestation in a single organ, the small intestine, due to aHUS with absence of systemic signs and symptoms. aHUS patients usually require a secondary trigger for the disease to manifest. In this case, the trigger may be attributed to the dysfunctional renal transplant, which was subsequently explanted. Histology of the explanted kidney showed severe inflammation due to purulent nephritis and signs of cellular rejection. After nephrectomy, we continued eculizumab therapy until the patient completely recovered. No signs of TMA recurred after discontinuation of eculizumab, further supporting the concept of the renal transplant as the main trigger of TMA of the small intestine in our patient.