Late Cytomegalovirus Disease after Hematopoietic Cell Transplantation: Significance of Novel Transplantation Techniques.

Pre-emptive therapy (PET) and letermovir prophylaxis are effective in preventing CMV disease within the first 100 days after allogeneic hematopoietic cell transplantation (HCT) but are associated with late-onset CMV disease. We retrospectively examined the clinical manifestations, risk factors, prevention algorithm, and outcome of late CMV disease in CMV seropositive day 100 survivors transplanted between 2001-2017 (PET cohort) and 2018-2021 (letermovir cohort). There were 187 episodes of late CMV disease among 2469 day 100 survivors and the estimated cumulative incidence of first late CMV disease was 6.7% (95% CI 5.6-%-7.6%) with no difference between the PET 6.7% (95% CI 5.7%-7.8%) and the letermovir group 5.4% (95% CI 3.2%-8.3%). 32 (1.3%) patients had a second episode of late CMV disease. In multivariable Cox regression models, post-transplant cyclophosphamide was associated with an increased risk of gastrointestinal CMV disease. CMV viremia detected before day 100, corticosteroid treatment after day 100 at dose ≥1mg/kg, acute and chronic GvHD, lymphopenia, HLA mismatched related donors status and recipient age were also associated with late CMV disease. HLA mismatched donor status and late use of corticosteroids (≥1 mg/kg) were risk factors for late CMV disease recurrence. Late CMV disease occurred most frequently in a setting of prolonged low-level untreated viremia and was independently associated with death by year two after HCT. In summary, late CMV disease continues to occur in the current era. Improved prevention strategies for late CMV disease are needed.

Relationship between disease severity and serum IL-6 levels in COVID-19 anosmia.

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.

Supplemental Oxygen-Free Days in Hematopoietic Cell Transplant Recipients With Respiratory Syncytial Virus.

Background: Clinically meaningful endpoints for respiratory syncytial virus (RSV) treatment trials are lacking for hematopoietic cell transplant (HCT) recipients. We evaluated supplemental oxygen use among HCT recipients with RSV infection. Methods: Subjects were grouped according to the presence of upper respiratory tract infection (URTI) without lower respiratory tract infection (LRTI), URTI progressing to LRTI, and LRTI at presentation. LRTI was defined as a positive lower respiratory tract sample with or without radiographic abnormality (defined as proven or probable LRTI, respectively) or a positive upper respiratory tract sample with radiographic abnormality (possible LRTI). Supplemental oxygen-free days were defined as any day while alive after diagnosis of RSV infection during which ≤2 L of supplemental oxygen per minute was received. Results: Among 230 patients, supplemental oxygen use by day 28 after the first diagnosis of RSV infection was lowest in patients presenting with URTI (31 of 197 [16%]). Supplemental oxygen use was lower in patients with possible LRTI (12 of 45 [27%]) than in those with proven/probable LRTI (29 of 42 [69%]). Patients presenting with proven/probable LRTI had a median of 16 fewer supplemental oxygen-free days than those presenting with URTI (P < .0001). Death only occurred among patients with proven/probable LRTI (11 of 42 [26%]). Conclusions: 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.

Cytomegalovirus viral load and mortality after haemopoietic stem cell transplantation in the era of pre-emptive therapy: a retrospective cohort study.

BACKGROUND: Although cytomegalovirus viral load is commonly used to guide pre-emptive therapy in the post-transplantation setting, few data are available correlating viraemia with clinical endpoints. We therefore investigated the association between cytomegalovirus viral load and mortality in the first year after haemopoietic stem cell transplantation. METHODS: In this retrospective cohort study, we included patients from the Fred Hutchinson Cancer Research Center, WA, USA, who received an allogeneic haemopoietic stem cell transplantation between Jan 1, 2007, and Feb 28, 2013, were cytomegalovirus seropositive or had a seropositive donor, and underwent weekly plasma cytomegalovirus monitoring by PCR through to day 100 post-transplantation. Cox proportional hazards models were used to estimate the association of cytomegalovirus viral load at different thresholds with overall mortality by 1 year post-transplantation, adjusting for the use of pre-emptive therapy and other factors such as neutropenia, and graft-versus-host disease. FINDINGS: Of the 1037 patients initially selected for inclusion in this cohort, 87 (8%) patients were excluded because of missing cytomegalovirus testing and 24 (2%) were excluded because of their participation in cytomegalovirus prophylaxis trials. In the remaining 926 patients included in this study, the cumulative overall mortality was 30·0% (95% CI 26·9-33·0) 1 year after haemopoietic stem cell transplantation. 95 patients developed cytomegalovirus disease; death was directly attributable to cytomegalovirus disease in three (1%) of 263 patients who died in the first year after transplantation. A cytomegalovirus viral load of 250 IU/mL or greater was associated with increased risk of early (day 0-60 post-transplantation) death (adjusted hazard ratio [HR] 19·8, 95% CI 9·6-41·1). The risk was attenuated after day 60 (adjusted HR 1·8, 95% CI 1·3-2·3). Similar associations were noted for higher cytomegalovirus viral load thresholds. INTERPRETATION: Cytomegalovirus viraemia is associated with an increased risk of overall mortality in the first year after haemopoietic stem cell transplantation, independent of the use of pre-emptive therapy, and with evidence of a positive dose-response relationship. These data indicate the suitability of viral load as a surrogate clinical endpoint for clinical trials for cytomegalovirus vaccines, biologics, and drugs. FUNDING: Merck and Co, National Institutes of Health.