Incidence of Cytomegalovirus disease and viral replication kinetics in seropositive liver transplant recipients managed under preemptive therapy in a tertiary-care center in Mexico City: a retrospective cohort study.

BACKGROUND: In the absence of an adequate prevention strategy, up to 20% of CMV IgG+ liver transplant recipients (LTR) will develop CMV disease. Despite improved reporting in CMV-DNAemia, there is no consensus as to what the ideal CMV-DNAemia cutoff for a successful preemptive strategy is. Each transplant centre establishes their own threshold. We aimed to determine the effectiveness of our preventive strategy in CMV IgG+ LTR, and evaluate CMV replication kinetics. METHODS: In this retrospective study we determined the incidence of CMV disease in the first 6 months following transplantation in CMV seropositive LTR in a tertiary-care centre in Mexico. Secondary outcomes were determining the number of patients who required preemptive therapy (treatment cutoff ≥ 4000 UI/ml), adherence to the centre's prevention protocol and calculation of viral replication kinetics. RESULTS: One-hundred and twenty-four patients met inclusion criteria. Four patients (3.2%) developed CMV disease. Ninety-six (85%) had detectable DNAemia and 25 (22%) asymptomatic patients received preemptive therapy, none of them developed CMV disease. The highest viral loads were observed on the second posttransplant month. The number of viral load measurements decreased over time. Patients with DNAemia ≥ 4000 UI/ml had a faster viral load growth rate, shorter viral load duplication time, and higher basic reproductive number. Viral load growth rate and autoimmune hepatitis were associated with development of DNAemia ≥ 4000 UI/ml. CONCLUSION: Cytomegalovirus disease occurred in 3.2% of the study subjects. Preemptive therapy using a threshold of CMV ≥ 4000 UI/ml was effective in reducing the incidence of end-organ disease. The viral replication parameters described in this population highlight the importance of frequent monitoring, a challenging feat for transplant programs in low- and middle-income countries.

Donor source and post-transplantation cyclophosphamide influence outcome in allogeneic stem cell transplantation for GATA2 deficiency.

GATA2 deficiency was described in 2011, and shortly thereafter allogeneic hematopoietic stem cell transplantation (HSCT) was shown to reverse the hematologic disease phenotype. However, there remain major unanswered questions regarding the type of conditioning regimen, type of donors, and graft-versus-host disease (GVHD) prophylaxis. We report 59 patients with GATA2 mutations undergoing HSCT at National Institutes of Health between 2013 and 2020. Primary endpoints were engraftment, reverse of the clinical phenotype, secondary endpoints were overall survival (OS), event-free survival (EFS), and the incidence of acute and chronic GVHD. The OS and EFS at 4 years were 85·1% and 82·1% respectively. Ninety-six percent of surviving patients had reversal of the hematologic disease phenotype by one-year post-transplant. Incidence of grade III-IV aGVHD in matched related donor (MRD) and matched unrelated donor recipients (URD) patients receiving Tacrolimus/Methotrexate for GVHD prophylaxis was 32%. In contrast, in the MRD and URD who received post-transplant cyclophosphamide (PT/Cy), no patient developed grade III-IV aGVHD. Six percent of haploidentical related donor (HRD) recipients developed grade III-IV aGVHD. In summary, a busulfan-based HSCT regimen in GATA2 deficiency reverses the hematologic disease phenotype, and the use of PT/Cy reduced the risk of both aGVHD and cGVHD.

Pulmonary Manifestations of GATA2 Deficiency.

BACKGROUND: GATA2 deficiency is a genetic disorder of hematopoiesis, lymphatics, and immunity caused by autosomal dominant or sporadic mutations in GATA2. The disease has a broad phenotype encompassing immunodeficiency, myelodysplasia, leukemia, and vascular or lymphatic dysfunction as well as prominent pulmonary manifestations. RESEARCH QUESTION: What are the pulmonary manifestations of GATA2 deficiency? STUDY DESIGN AND METHODS: A retrospective review was conducted of clinical medical records, diagnostic imaging, pulmonary pathologic specimens, and tests of pulmonary function. RESULTS: Of 124 patients (95 probands and 29 ascertained), the lung was affected in 56%. In addition to chronic infections, pulmonary alveolar proteinosis (11 probands) and pulmonary arterial hypertension (nine probands) were present. Thoracic CT imaging found small nodules in 54% (54 probands and 12 relatives), reticular infiltrates in 40% (45 probands and four relatives), paraseptal emphysema in 25% (30 probands and one relative), ground-glass opacities in 35% (41 probands and two relatives), consolidation in 21% (23 probands and two relatives), and a typical crazy-paving pattern in 7% (eight probands and no relatives). Nontuberculous mycobacteria were the most frequent organisms associated with chronic infection. Allogeneic hematopoietic stem cell transplantation successfully reversed myelodysplasia and immune deficiency and also improved pulmonary hypertension and pulmonary alveolar proteinosis in most patients. INTERPRETATION: GATA2 deficiency has prominent pulmonary manifestations. These clinical observations confirm the essential role of hematopoietic cells in many aspects of pulmonary function, including infections, alveolar proteinosis, and pulmonary hypertension, many of which precede the formal diagnosis, and many of which respond to stem cell transplantation.

Hematopoietic Cell Transplantation and Outcomes Related to Human Papillomavirus Disease in GATA2 Deficiency.

GATA2 deficiency is a bone marrow failure syndrome effectively treated with hematopoietic cell transplantation (HCT), which also addresses the predisposition to many infections (prominently mycobacterial). However, many GATA2-deficient persons who come to HCT also have prevalent and refractory human papilloma virus disease (HPVD), which can be a precursor to cancer. We analyzed 75 HCT recipients for the presence of HPVD to identify patient characteristics and transplantation results that influence HPVD outcomes. We assessed the impact of cellular recovery and iatrogenic post-transplantation immunosuppression, as per protocol (PP) or intensified/prolonged (IP) graft-versus-host disease (GVHD) prophylaxis or treatment, on the persistence or resolution of HPVD. Our experience with 75 HCT recipients showed a prevalence of 49% with anogenital HPVD, which was either a contributing or primary factor in the decision to proceed to HCT. Of 24 recipients with sufficient follow-up, 13 had resolution of HPVD, including 8 with IP and 5 with PP. Eleven recipients had persistent HPVD, including 5 with IP and 6 with PP immunosuppression. No plausible cellular recovery group (natural killer cells or T cells) showed a significant difference in HPV outcomes. One recipient died of metastatic squamous cell carcinoma, presumably of anogenital origin, at 33 months post-transplantation after prolonged immunosuppression for chronic GVHD. Individual cases demonstrate the need for continued aggressive monitoring, especially in the context of disease prevalent at transplantation or prior malignancy. HCT proved curative in many cases in which HPVD was refractory and recurrent prior to transplantation, supporting a recommendation that HPVD should be considered an indication rather than contraindication to HCT, but post-transplantation monitoring should be prolonged with a high level of vigilance for new or recurrent HPVD.

Immunology of Fungal Infections.

Complex processes mediate immunity to fungal infections. Responses vary depending on the organism, morphogenic state, and infection site. Innate immune effectors such as epithelia, phagocytes, and soluble molecules detect pathogens, kill fungi, release cytokines, and prime the adaptive response. Adaptive responses to mucocutaneous or invasive disease are markedly different but intersect at certain pathways (molecules required for IL-23 and IL-12 signaling). Many of these pathways have been elucidated from the study of inborn errors of immunity. This review explores the general aspects of antifungal immunity and delves into the mechanisms that mediate protection from frequently encountered fungi.

Recombinant human factor VIIa for alveolar hemorrhage following allogeneic stem cell transplantation.

The mortality rate of alveolar hemorrhage (AH) after allogeneic hematopoietic stem cell transplantation is greater than 60% with supportive care and high-dose steroid therapy. We performed a retrospective cohort analysis to assess the benefits and risks of recombinant human factor VIIa (rFVIIa) as a therapeutic adjunct for AH. Between 2005 and 2012, 57 episodes of AH occurred in 37 patients. Fourteen episodes (in 14 patients) were treated with steroids alone, and 43 episodes (in 23 patients) were treated with steroids and rFVIIa. The median steroid dose was 1.9 mg/kg/d (interquartile range [IQR], 0.8 to 3.5 mg/kg/d; methylprednisolone equivalents) and did not differ statistically between the 2 groups. The median rFVIIa dose was 41 µg/kg (IQR, 39 to 62 µg/kg), and a median of 3 doses (IQR, 2 to 17) was administered per episode. Concurrent infection was diagnosed in 65% of the episodes. Patients had moderately severe hypoxia (median PaO2/FiO2, 193 [IQR, 141 to 262]); 72% required mechanical ventilation, and 42% survived to extubation. The addition of rFVIIa did not alter time to resolution of AH (P = .50), duration of mechanical ventilation (P = .89), duration of oxygen supplementation (P = .55), or hospital mortality (P = .27). Four possible thrombotic events (9% of 43 episodes) occurred with rFVIIa. rFVIIa in combination with corticosteroids did not confer clear clinical advantages compared with corticosteroids alone. In patients with AH following hematopoietic stem cell transplantation, clinical factors (ie, worsening infection, multiple organ failure, or recrudescence of primary disease) may be more important than the benefit of enhanced hemostasis from rFVIIa.

Human herpes 6 virus encephalitis complicating allogeneic hematopoietic stem cell transplantation.

OBJECTIVE: To describe the presentation and management of encephalitis due to human herpes 6 virus (HHV-6) in patients who underwent allogeneic hematopoietic stem cell transplant (alloHSCT), via retrospective chart review. METHODS: Of the 243 patients who underwent alloHSCT at the NIH Clinical Center during 2009 to 2011, we retrospectively analyzed 9 diagnosed with HHV-6 encephalitis post-alloHSCT. RESULTS: Eight men and 1 woman (aged 19-60 years) met diagnostic criteria for study inclusion. The median time from HSCT to initial symptoms was 21 days. All patients presented with altered mental status and headaches. Seven patients had amnesia and 2 presented with fever of unknown etiology. Four patients had clinical seizures during the disease course. Brain MRI within 7 days was normal in all patients. Repeat MRI after 7 days showed hyperintensity in the limbic area in 3 patients. On initial testing, CSF analysis indicated acellularity and normal or minimally elevated protein; presence of HHV-6 was detected by PCR. After 7 days, mildly elevated protein and minimal pleocytosis were noted. Ganciclovir, foscarnet, or valganciclovir alone or in combination was initiated with subsequent improvement. Four patients remained alive at 1 year posttransplant; 2 had persistent memory deficits. Presence of encephalitis was associated with higher mortality post-alloHSCT. CONCLUSION: High clinical suspicion and CSF PCR testing are important for early diagnosis of HHV-6 encephalitis post-HSCT. Abnormalities on brain MRI or CSF testing may be minimal and delayed. Diagnosis and management of HHV-6 encephalitis is challenging, and a larger prospective study is needed for further research.

Rapid detection of ESBL-producing gram-negative bacteria isolated from blood: a reasonable and reliable tool for middle and low resource countries.

INTRODUCTION: Delay in appropriate treatment in patients with bacteraemia can increase morbidity, mortality, and health expenditures. We compared the Rapid Direct Test (RDT) designed to detect ESBL-producing gram-negative bacteria (GNB) directly from positive blood cultures bottles, with two conventional ESBL detection tests: Screening and Confirmatory Disk Diffusion Assay (SC-DDA) and an MIC Screening and ESBL E-test (MIC/ET). MATERIAL AND METHODS: We screened all blood cultures in a tertiary care facility from August to December 2005. We only included one positive bottle per patient in which GNB were observed. RDT: Blood from each bottle was inoculated on Mueller-Hinton agar. Ceftazidime and cefotaxime disks with and without clavulanic acid were added and incubated at 35 degrees C +/- 2 degrees C for 24 h. Results were interpreted according to CLSI recommendations for the SC-DDA and MIC/ET. All methods were performed simultaneously. Time for reporting as an ESBL-producer and cost of the tests were recorded. RESULTS: We isolated 124 GNB in 114 episodes of bacteraemia, 10 of them (8.8%) polymicrobial; 79 (63.7%) of the GNB were enteric bacteria, 44 (35.5%) glucose non-fermenter GNB and one Haemophilus influenzae. The most common microorganism was Escherichia coli in 56 episodes (45.2%), followed by Pseudomonas aeruginosa in 24 (19.3%), and Klebsiella pneumoniae in 13 (10.5%). Of the 114 episodes, 41 (36%) had at least one GNB resistant to 3rd generation cephalosporins, and 25 (21.9%) were caused by an ESBL-producing GNB. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for the RDT were 96%, 98.9%, 96% and 98.9%, respectively. Agreement by kappa index between RDT and SC-DDA was 0.95 and between the RDT and MIC/ET was 0.92. The RDT detected 24/25 ESBL-producing bacteria. The mean time to detect an isolate as an ESBL producer after a positive blood culture bottle signal was 1.02 +/- 0.19 days when using the RDT, and 3.40 +/- 0.59 days when using any other method. The difference in reporting time was 2.38 +/- 0.63 days (p < 0.0001). Our estimated cost per test was $1.54 for RDT, $2.32 for screening/ confirmatory SC-DDA, and $49.65 for MIC screening and MIC/ET. Conclusions. The RDT is a rapid, reliable and easy analysis to perform, as well as cost-effective.