SummaryBackgroundWhile CMV viral load (CMV-VL) is commonly used to guide preemptive therapy in the post-transplant setting, there is little data correlating viremia with clinical endpoints. We therefore investigated the association of CMV-VL with mortality in the first year after hematopoietic cell transplantation (HCT).MethodsThis cohort study included patients who received an allogeneic HCT between 01 January 2007 and 28 February 2013, were CMV seropositive or had a seropositive donor, and underwent weekly plasma CMV monitoring by PCR through day 100 post-transplant. Cox proportional hazards models were used to estimate the association of CMV-VL at different thresholds with overall by 1 year post-transplant, adjusting for the use of preemptive therapy and other factors such as neutropenia, and graft-versus-host disease. Secondary endpoints were non-relapse mortality and CMV end organ disease by 1 year post-transplant.FindingsAmong 926 patients, the cumulative overall mortality was 30·0% (95% CI 26·9–33·0) by 1 year. CMV-VL of ≥250 IU/ml was associated with increased risk of early (day 0–60 post-transplant) death (adjusted HR 18·1, 95% CI 8·8–37·4). The risk was attenuated after day 60 (adjusted HR 1·8, 95% CI 1·4–2·4). Similar associations were observed for higher CMV-VL thresholds. CMV-VL was also associated with increased risk of non-relapse mortality and demonstrated a dose-response relationship. The adjusted HR (95% CI) for CMV-VL of any positive CMV-VL below 500, 501–1000, and >1000 IU/ml were 1·4 (0·9–2·1), 2·6 (1·3–4·9), and 5·0 (3·1–8·1), respectively.InterpretationCMV viremia is associated with increased risk of overall and non-relapse mortality in the first year after HCT, independent of the use of preemptive therapy and with evidence of a postitive dose-response relationship. These data establish the suitability of viral load as a surrogate clinical endpoint for clinical trials for CMV vaccines, biologics, and drugs.FundingMerck & Co., Inc., National Institute of Health (K23-AI097234, K24HL093294, HL088021, CA78902, CA18029, HL122173)

Background An association between IL-6 levels and cytokine storm syndrome in COVID-19 patients has been suggested. Cases with higher IL-6 levels have more rapid progression and a higher complication rate. On the other hand, COVID-19 cases with anosmia have a milder course of the disease. Objective We aimed to investigate whether there is a relationship between serum IL-6 levels and presence of anosmia in COVID-19 patients. Methods Patients with a confirmed diagnosis of COVID-19 based on laboratory (PCR) were stratified into two groups based on presence of olfactory dysfunction (OD). In all cases with and without anosmia; psychophysical test (Sniffin' Sticks test) and a survey on olfactory symptoms were obtained. Threshold (t) – discrimination (d) – identification (i), and total (TDI) scores reflecting olfactory function were calculated. Clinical symptoms, serum IL-6 levels, other laboratory parameters, and chest computed tomography (CT) findings were recorded. Results A total of 59 patients were included, comprising 23 patients with anosmia and 36 patients without OD based on TDI scores. Patients with anosmia (41.39 ± 15.04) were significantly younger compared to cases without anosmia (52.19 ± 18.50). There was no significant difference between the groups in terms of comorbidities, smoking history, and symptoms including nasal congestion and rhinorrhea. Although serum IL-6 levels of all patients were above normal values (7 pg/mL), patients with anosmia had significantly lower serum IL-6 levels (16.72 ± 14.28 pg/ml) compared to patients without OD (60.95 ± 89.33 pg/ml) (p = 0.026). Conclusion Patients with COVID-19 related anosmia tend to have significantly lower serum levels of IL-6 compared to patients without OD, and the lower IL-6 levels is related to milder course of the disease. With the effect of low cytokine storm and IL-6 level, it may be said that anosmic cases have a milder disease in COVID-19.

Confirmation of RSV infection in the lower respiratory tract provides prognostic information that may help prioritize therapies. Supplemental oxygen-free days as a clinical endpoint may allow smaller sample sizes for trials evaluating RSV antivirals.

Background: Cytomegalovirus (CMV) infection is one of the most common complications after hematopoietic cell transplantation (HCT). Regardless of preemptive therapy for CMV infection, CMV disease still occurs in approximately 10% of seropositive HCT recipients, resulting in high mortality. A number of studies have reported the association between CMV infection or disease and single-nucleotide polymorphisms (SNPs), however the results have not been validated in independent cohorts. We performed a candidate gene validation study of previously reported SNPs using a large genome-wide association study (GWAS) cohort. Patients and methods: This GWAS cohort included donor-recipient (D/R) pairs who received the first allogeneic transplantation between 1990 and 2011 at the FHCRC. Of an overall cohort of 4855 D/R pairs, 2193 Caucasian CMV seropositive recipients and their donors (seropositve or seronegative) were analyzed. Two CMV phenotypes were analyzed: any infection within 100 days (only among 1585 recipients transplanted after 1995, antigenemia-based preemptive therapy administered) and CMV disease within 1 year after HCT. Published SNPs associated with CMV infection or disease were collected by a PubMed search using the keywords ‘cytomegalovirus' and ‘SNP' or ‘polymorphism.' A p-value of less than 0.05 was required for validation. Genomic DNA samples from donors and recipients were analyzed using the Affymetrix GeneChip Genome-Wide Human SNP Array 5.0 (for one third of subjects) and Ilummina OmniExpress Beadchip Array (for the remainder). When the candidate SNPs were not included in the arrays, we imputed genotypes using IMPUTE software. Among genotyped and imputed SNPs, only SNPs with a minor allele frequency ≥0.05, call rate ≥90%, and Hardy-Weinberg equilibrium ≥0.0001 were analyzed. Donor serostatus, age, year of transplantation, donor type, HLA disparity, and intensity of conditioning regimen were used as adjustment factors as appropriate. Results: Among the 2193 HCT recipients in our cohort, 1009/1585 (64%) had CMV infection and 354/2193 (16%) had CMV disease. We identified 52 SNPs in 31 publications that reported significant associations between SNPs and CMV infection or disease (median number of subjects in these studies, 215; range, 37-1770). A total of 32 SNPs were available for the analysis. For CMV infection, six SNPs in four genes (TLR9, MCP1, CCR5, and CD209) in recipient or donor met our validation criteria (Table). For all SNPs but one, however, the direction of the association was opposite to that reported in the previous studies. We validated one SNP association (TLR9/rs5743836) in the recipient exactly as originally reported (adjusted HR, 1.16; 95% CI, 1.00-1.34, p=0.043). The donor genotype at this SNP was also significantly associated with CMV infection (adjusted HR, 1.47; 95% CI, 1.02-2.14, p=0.041) (Table), but an association with donor genotype was not assessed in the original publication. As for CMV disease, a different TLR9 SNP (rs352140) in donors was identified as significant (adjusted HR, 0.74; 95% CI, 1.02-2.14, p=0.029), although the ethnicity is different from the reported cohort (Table). None of the candidate SNPs in the recipient genome were associated with CMV disease. Conclusions: Of 32 SNPs that were previously reported to be associated with either CMV infection or disease, we were only able to validate two, both in TLR9. Most of the previously reported SNP associations for CMV infection or disease were not replicated in this large GWAS cohort. The inability to replicate these SNP associations does not necessarily negate the original discoveries, since many factors, including the sample size, could account for the different results. Our findings suggest that results of SNP association studies should be confirmed in multiple independent large cohorts and the biological mechanisms underlying the associations should be examined before clinical application. Unbiased discovery approaches are needed to determine the genetic associations of CMV infection and disease. Table 1 Table 1. Disclosures Boeckh: Chimerix Inc.: Consultancy, Research Funding; Viropharma Inc.: Research Funding; Genentech/Roche: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Clinigen: Consultancy.

UNSTRUCTURED The novel coronavirus disease 2019 (COVID-19) continues to spread over the world and there is still no specific treatment. Beside many drug studies, there is not enough data about the place of cellular therapies. In this study, we used second passage cGMP grade umbilical cord-derived Mesenchymal Stromal Cell (MSC) via a combined intratracheal/intravenous route as a novel administration protocol. After the treatment, the values of inflammatory biomarker C-reactive protein of all patients decreased significantly [(before MSC therapy, mean: 84,8 mg/L (2,4-272 mg/L); after MSC administration, mean: 6,5 mg/L (0,3-25,3 mg/L)], procalcitonin decreased for 6 of 7 patients, increasing lymphocyte count was detected in 5 of 7 patients and pulmonary functions PaO2/FiO2 and Positive End-Expiratory Pressure (PEEP) improved in 5 of 7 patients within 7 days after MSC therapy. At the time of MSC administration, all 7 patients were receiving mechanical ventilation. After MSC therapy, 4 of 7 patients were weaned from mechanical ventilation. Although this study has limitations, the outcomes are promising for the advanced stages of COVID-19 pneumonia.

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ÖZ KızamıkParamyxoviridae ailesinin morbillivirus genusunun üyesi olan kızamık (measles) virüsü, ateş ve dökün-tülerle seyreden bulaşıcı bir hastalıktır. Bulaş oranı oldukça yüksektir. Temas sonrası ev halkının %90'ı enfekte olur. Virüsler ilk olarak solunum yollarında lokal olarak ürerler. Buradan lökositler ile retiküloen-dotelyal sisteme taşınırlar, bu döneme primer viremi denir. RES hücrelerinin nekrozu sonrası ortaya çıkan virüslerin lökositlere reinvazyonu ile de sekonder viremi ortaya çıkar. Virüs gerek kan gerek lenf sistemi ile tüm vücudu enfekte eder. Kızamığa karşı bağışık olan annelerin bebekleri doğumdan sonra 8 aylığa kadar bağışıktırlar. İnkübasyon süresi 10-14 gündür. Temasdan sonraki 11. günde prodromal bulgular, 14. günde ise döküntüler oluşur. Prodrom döneminde halsizlik, iştahsızlık, hafif ateş, miyalji, kuru öksürük, gözde yanma-batma-sulanma ve burun akıntısı görül-mektedir. Prodrom döneminin sonunda kızamığın patognomonik lezyonu olan kopling lekeleri ortaya çı-kar. Bu lezyonlar yanak mukozasında alt molar dişler hizasında yer alan ortası kızarık, çevresi hiperemik 1-2 mm çapında lezyonlardır. Hiperemik zeminde tuz serpintisi şeklinde görülmektedir. Kopling lekeleri döküntüden 48 saat önce ortaya çıkar ve 12-72 saat sonra kaybolur. Yanak mukozası dışında konjuctiva, vajinal ve intestinal mukozadada enantemler görüle-bilir. Döküntüler kulak arkasından saç çizgisi boyunca başlar ve ilk 24 saat içinde tüm boyuna yüz, kolların ve göğüsün üst kısımlarına yayılarak birleşme eğilimindedir. Daha sonraki dönemlerde ise döküntü-ler tüm kollar, sırt, karın ve uyluğa yayılır. Ayaklara ulaştığında ise oluşum sırasını izleyerek solmaya baş-lar. Üzerine basınca kaybolan makülopapüler tarzdadır. Döküntüler başlangıçta pembe renklidir, 3-4 gün sonra kahverengileşir, çok ender olarak el içi ve ayak tabanını tutar ve 6-7 gün sonra hafif pullanarak solar. Döküntülerle beraber postero-auriküler lenfadenopati vardır. Öksürük ateşin düşmesiyle azalır, konjonktivit ise döküntü sonuna kadar devam eder. Ateşin 3-4 gün devam etmesi komplikasyon olabileceğini düşündü-rür. Gebelerde kızamık doğumsal anomaliye neden olmamaktadır. Kızamık her zaman aynı tablo ile karşı-mıza çıkmayabilir. Kızamığı bazen farklı şekillerdede görebiliriz. Atipik kızamık daha çok inaktif kızamık