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Viruses Dec 2020BK virus (BKV) is a polyomavirus with high seroprevalence in the general population with an unremarkable clinical presentation in healthy people, but a potential for... (Review)
Review
BK virus (BKV) is a polyomavirus with high seroprevalence in the general population with an unremarkable clinical presentation in healthy people, but a potential for causing serious complications in immunosuppressed transplanted patients. Reactivation or primary infection in kidney allograft recipients may lead to allograft dysfunction and subsequent loss. Currently, there is no widely accepted specific treatment for BKV infection and reduction of immunosuppressive therapy is the mainstay therapy. Given this and the sequential appearance of viruria-viremia-nephropathy, screening and early detection are of utmost importance. There are numerous risk factors associated with BKV infection including genetic factors, among them human leukocyte antigens (HLA) and killer cell immunoglobulin-like receptors (KIR) alleles have been shown to be the strongest so far. Identification of patients at risk for BKV infection would be useful in prevention or early action to reduce morbidity and progression to frank nephropathy. Assessment of risk involving HLA ligands and KIR genotyping of recipients in the pre-transplant or early post-transplant period might be useful in clinical practice. This review summarizes current knowledge of the association between HLA, KIR and BKV infection and potential future directions of research, which might lead to optimal utilization of these genetic markers.
Topics: Alleles; BK Virus; Biomarkers; Disease Susceptibility; HLA Antigens; Humans; Immunocompromised Host; Kidney Transplantation; Killer Cells, Natural; Polyomavirus Infections; Prognosis; Receptors, KIR; Research
PubMed: 33317205
DOI: 10.3390/v12121417 -
Frontiers in Medicine 2022Autoinflammatory diseases (AID) are rare diseases presenting with episodes of sterile inflammation. These involve multiple organs and can cause both acute organ damage...
INTRODUCTION
Autoinflammatory diseases (AID) are rare diseases presenting with episodes of sterile inflammation. These involve multiple organs and can cause both acute organ damage and serious long-term effects, like amyloidosis. Disease-specific anti-inflammatory therapeutic strategies are established for some AID. However, their clinical course frequently includes relapsing, uncontrolled conditions. Therefore, new therapeutic approaches are needed. Janus Kinase inhibitors (JAKi) block key cytokines of AID pathogenesis and can be a potential option.
METHODS
A systematic review of the literature in accordance with the PRISMA guidelines was conducted. Three databases (MEDLINE, Embase and Cochrane Central Register of Controlled Trials) were searched for publications regarding the use of JAKi for AID. Data from the included publications was extracted and a narrative synthesis was performed. Criteria for defining treatment response were defined and applied.
RESULTS
We report data from 38 publications with a total of 101 patients describing the effects of JAKi in AID. Data on Type I Interferonopathies, Adult-Onset Still's Disease (AOSD), Systemic Juvenile Idiopathic Arthritis (sJIA), Familial Mediterranean Fever (FMF), and Behçet's Syndrome (BS) was identified. From a total of 52 patients with type I interferonopathies, in seven patients (7/52, 13.5%) a complete response was achieved, most (35/52, 67.3%) showed a partial response and a minority (10/52, 19.2%) showed no treatment response. For AOSD, a complete or a partial response was achieved by eleven (11/26, 42.3%) patients each. Two sJIA patients achieved complete response (2/4, 50%) and in two cases (2/4, 50%) a partial response was reported. Half of FMF patients showed a complete response and the other half had a partial one (3/6, 50.0%). Amongst BS patients most achieved a partial response (8/13, 61.5%). Five patients showed no response to therapy (5/13, 38.5%). Overall, the most frequent AEs were upper respiratory tract infections (17), pneumonia (10), BK virus viremia (10) and viruria (4), herpes zoster infection (5), viral gastroenteritis (2) and other infections (4).
CONCLUSION
The results from this systematic review show that JAKi can be beneficial in certain AID. The risk of AEs, especially viral infections, should be considered. To accurately assess the risk benefit ratio of JAKi for AID, clinical trials should be conducted.
PubMed: 35833101
DOI: 10.3389/fmed.2022.930071 -
American Journal of Transplantation :... Feb 2023BK virus DNAemia (BKPyV) and nephropathy are common after kidney transplant; however, there are limited data on BK infections in nonrenal solid organ transplant...
BK virus DNAemia (BKPyV) and nephropathy are common after kidney transplant; however, there are limited data on BK infections in nonrenal solid organ transplant recipients. We examined the frequency, clinical and pathologic features, and kidney and lung outcomes of BKPyV and BK virus native kidney nephropathy (BKVN) in lung transplant recipients at our center. Among 878 recipients transplanted from 2003 to 2019, 56 (6%) developed BKPyV at a median of 30.1 months after transplant (range, 0.6-213) and 11 (1.3%) developed BKVN at a median of 46 months after transplant (range, 9-213). The incidence of end-stage kidney disease was significantly higher in patients with peak viral load ≥10 000 copies/mL (39% vs 8%, P < .001). All cases of BKVN were in patients with peak viral load of ≥10 000 copies/mL, and 55% of these patients developed end-stage kidney disease. Despite the reduction of immunosuppression to treat BKVN, only 1 patient developed acute rejection, and lung function was stable >1 year. BKPyV and nephropathy are more common after lung transplantation than previously reported. Routine screening for BKPyV should be considered in all lung transplant recipients.
Topics: Humans; Polyomavirus; Kidney Diseases; Kidney; Nephritis, Interstitial; Lung Transplantation; BK Virus; Polyomavirus Infections; Transplant Recipients; Kidney Failure, Chronic; Tumor Virus Infections
PubMed: 36804135
DOI: 10.1016/j.ajt.2022.11.007 -
Therapeutic Advances in Infectious... 2021BK virus (BKV)-related haemorrhagic cystitis (HC) is an important cause of morbidity following allogeneic haematopoietic stem cell transplantation (HSCT). The various... (Review)
Review
BK virus (BKV)-related haemorrhagic cystitis (HC) is an important cause of morbidity following allogeneic haematopoietic stem cell transplantation (HSCT). The various risk factors include high-level BKV viruria and/or viremia, myeloablative conditioning, acute graft host disease (GVHD), cytomegalovirus viremia, and unrelated or HLA-mismatched donor. The presence of high plasma BK viral load and cytopenias have been implicated as important predictors for protracted disease course. These patients frequently require hospitalisation which may extend for several weeks. Supportive measures in the form of analgesics, intravenous hydration, bladder irrigation, and transfusion support remain the mainstay of management. Various drugs have been used with limited success in this setting. These include antiviral drugs, fluoroquinolones, leflunomide, growth factors, clotting factors, estrogens, and prostaglandins. The role of adoptive cellular immunotherapy has also been explored but lacks clinical validation. The strategies aimed at expediting urothelial repair like hyperbaric oxygen therapy (HBOT), intravesical fibrin glue and platelet-rich plasma (PRP) are emerging. Some patients with severe disease do require surgical intervention to relieve urinary obstruction. The frequent co-occurrence of acute GVHD and CMV disease further complicates the management in such patients. There is an unmet need for effective and evidence-based options for the prevention and management of this disease. Due to lack of robust data supported by randomised trials, the acceptability of the available guidelines to simplify the treatment is expected to be low. Despite the availability of various treatment options, the management of BKV-related HC in day-to-day practice continues to be a challenge. The aim of this article is to put forward an up-to-date review of the preventive and therapeutic strategies for BKV-related HC.
PubMed: 33614030
DOI: 10.1177/2049936121991377 -
Critical Care (London, England) Sep 2023One of five global deaths are attributable to sepsis. Hyperferritinemic sepsis (> 500 ng/mL) is associated with increased mortality in single-center studies. Our...
BACKGROUND
One of five global deaths are attributable to sepsis. Hyperferritinemic sepsis (> 500 ng/mL) is associated with increased mortality in single-center studies. Our pediatric research network's objective was to obtain rationale for designing anti-inflammatory clinical trials targeting hyperferritinemic sepsis.
METHODS
We assessed differences in 32 cytokines, immune depression (low whole blood ex vivo TNF response to endotoxin) and thrombotic microangiopathy (low ADAMTS13 activity) biomarkers, seven viral DNAemias, and macrophage activation syndrome (MAS) defined by combined hepatobiliary dysfunction and disseminated intravascular coagulation, and mortality in 117 children with hyperferritinemic sepsis (ferritin level > 500 ng/mL) compared to 280 children with sepsis without hyperferritinemia. Causal inference analysis of these 41 variables, MAS, and mortality was performed.
RESULTS
Mortality was increased in children with hyperferritinemic sepsis (27/117, 23% vs 16/280, 5.7%; Odds Ratio = 4.85, 95% CI [2.55-9.60]; z = 4.728; P-value < 0.0001). Hyperferritinemic sepsis had higher C-reactive protein, sCD163, IL-22, IL-18, IL-18 binding protein, MIG/CXCL9, IL-1β, IL-6, IL-8, IL-10, IL-17a, IFN-γ, IP10/CXCL10, MCP-1/CCL2, MIP-1α, MIP-1β, TNF, MCP-3, IL-2RA (sCD25), IL-16, M-CSF, and SCF levels; lower ADAMTS13 activity, sFasL, whole blood ex vivo TNF response to endotoxin, and TRAIL levels; more Adenovirus, BK virus, and multiple virus DNAemias; and more MAS (P-value < 0.05). Among these variables, only MCP-1/CCL2 (the monocyte chemoattractant protein), MAS, and ferritin levels were directly causally associated with mortality. MCP-1/CCL2 and hyperferritinemia showed direct causal association with depressed ex vivo whole blood TNF response to endotoxin. MCP-1/CCL2 was a mediator of MAS. MCP-1/CCL2 and MAS were mediators of hyperferritinemia.
CONCLUSIONS
These findings establish hyperferritinemic sepsis as a high-risk condition characterized by increased cytokinemia, viral DNAemia, thrombotic microangiopathy, immune depression, macrophage activation syndrome, and death. The causal analysis provides rationale for designing anti-inflammatory trials that reduce macrophage activation to improve survival and enhance infection clearance in pediatric hyperferritinemic sepsis.
Topics: Humans; Child; Hyperferritinemia; Macrophage Activation Syndrome; Sepsis; Cytokines; Ferritins
PubMed: 37674218
DOI: 10.1186/s13054-023-04628-x -
Viruses Jul 2020Human BK polyomavirus (BKPyV) prevalence has been increasing due to the introduction of more potent immunosuppressive agents in transplant recipients, and its clinical...
Human BK polyomavirus (BKPyV) prevalence has been increasing due to the introduction of more potent immunosuppressive agents in transplant recipients, and its clinical interest. BKPyV has been linked mostly to polyomavirus-associated hemorrhagic cystitis, in allogenic hematopoietic stem cell transplant, and polyomavirus-associated nephropathy in kidney transplant patients. BKPyV is a circular double-stranded DNA virus that encodes for seven proteins, of which Viral Protein 1 (VP1), the major structural protein, has been extensively used for genotyping. BKPyV also contains the noncoding control region (NCCR), configured by five repeat blocks (OPQRS) known to be highly repetitive and diverse, and linked to viral infectivity and replication. BKPyV genetic diversity has been mainly studied based on the NCCR and , due to the high occurrence of BKPyV-associated diseases in transplant patients and their clinical implications. Here BKTyper is presented, a free online genotyper for BKPyV, based on a genotyping and a novel algorithm for NCCR block identification. genotyping is based on a modified implementation of the (BKTGR) algorithm, providing a maximum-likelihood phylogenetic tree using a custom internal BKPyV database. Novel NCCR block identification relies on a minimum of 12-bp motif recognition and a novel sorting algorithm. A graphical representation of the OPQRS block organization is provided.
Topics: Algorithms; BK Virus; Capsid Proteins; Genetic Variation; Genotyping Techniques; Phylogeny; RNA, Untranslated; Software; Virus Replication
PubMed: 32751885
DOI: 10.3390/v12080837 -
JCI Insight Nov 2023Tissue-resident lymphocytes (TRLs) are critical for local protection against viral pathogens in peripheral tissue. However, it is unclear if TRLs perform a similar role...
Tissue-resident lymphocytes (TRLs) are critical for local protection against viral pathogens in peripheral tissue. However, it is unclear if TRLs perform a similar role in transplanted organs under chronic immunosuppressed conditions. In this study, we aimed to characterize the TRL compartment in human kidney transplant nephrectomies and examine its potential role in antiviral immunity. The TRL compartment of kidney transplants contained diverse innate, innate-like, and adaptive TRL populations expressing the canonical residency markers CD69, CD103, and CD49a. Chimerism of donor and recipient cells was present in 43% of kidney transplants and occurred in all TRL subpopulations. Paired single-cell transcriptome and T cell receptor (TCR) sequencing showed that donor and recipient tissue-resident memory T (TRM) cells exhibit striking similarities in their transcriptomic profiles and share numerous TCR clonotypes predicted to target viral pathogens. Virus dextramer staining further confirmed that CD8 TRM cells of both donor and recipient origin express TCRs with specificities against common viruses, including CMV, EBV, BK polyomavirus, and influenza A. Overall, the study results demonstrate that a diverse population of TRLs resides in kidney transplants and offer compelling evidence that TRM cells of both donor and recipient origin reside within this TRL population and may contribute to local protection against viral pathogens.
Topics: Humans; Kidney Transplantation; Immunologic Memory; CD8-Positive T-Lymphocytes; Receptors, Antigen, T-Cell; Viruses
PubMed: 37751288
DOI: 10.1172/jci.insight.172681 -
Immunity, Inflammation and Disease Aug 2023BK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN) can cause a significant risk of allograft impairment after kidney transplantation (KT). Intact BKPyV-specific...
INTRODUCTION
BK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN) can cause a significant risk of allograft impairment after kidney transplantation (KT). Intact BKPyV-specific immunity is associated with viral containment. This study investigated BKPyV-specific immunological factors among KT recipients.
METHODS
This prospective study in a single transplant center from January 2019 to August 2019 assessed associations between clinical and immunological characteristics, with a focus on BKPyV-cell-specific immunity and BKPyVAN, among KT recipients aged ≥15 years. The numbers of interferon-gamma (IFN-γ)-producing CD4 T, CD8 T, natural killer (NK), and natural killer T (NKT) cells were measured after stimulation with large T antigen and viral capsid protein 1 (VP1).
RESULTS
In total, 100 KT recipients were included (mean age ± SD, 42 ± 11 years); 35% of the recipients were female patients, and 70% had received induction immunosuppressive therapy. The 1-year cumulative incidence of high-level BKPyV DNAuria (possible BKPyVAN) and (presumptive BKPyVAN) was 18%. Among 40 patients with immunological factor data, pre-KT %NK cells (hazard ratio [HR], 1.258; 95% confidence interval [CI], 1.077-1.469; p = .004) and %VP1-specific NK cells (HR, 1.209; 95% CI, 1.055-1.386; p = .006) were factors independently associated with possible and presumptive BKPyVAN. KT recipients with possible and presumptive BKPyVAN were more likely to exhibit significant mean coefficients of %NK, %VP1-specific NK, and %NKT cells at 1 month after KT than before KT (all p < .05).
CONCLUSION
Individuals with nonspecific and VP1-specific NK cells before KT and increasing numbers of these cells after KT may be at risk for high-level BKPyV DNAuria and presumptive BKPyVAN. Further studies are needed to determine the utility of BKPyV-specific innate immune surveillance in predicting the occurrence of BKPyVAN.
Topics: Humans; Female; Male; Kidney Transplantation; BK Virus; Prospective Studies; Immunosuppressive Agents; Interferon-gamma
PubMed: 37647426
DOI: 10.1002/iid3.956 -
Pathogens (Basel, Switzerland) Dec 2023Surveillance of the renal allograft recipient is essential when monitoring renal function to detect the early onset of rejection and alter therapeutic treatments to...
Surveillance of the renal allograft recipient is essential when monitoring renal function to detect the early onset of rejection and alter therapeutic treatments to treat acute rejection or other causes and improve long-term graft function. If renal function begins to deteriorate, a renal biopsy is often indicated to assess the Banff grade of potential rejection or other causes, especially in the setting of polyoma BK viral load elevation. Although BK infection in the allograft is asymptomatic, reactivation of the virus is known to be associated with the acceleration of pathologic change and a poor outcome in the allograft. BK reactivation in a transplant kidney is not uncommon, and determining inflammation related to the virus versus acute rejection is paramount for appropriate immunosuppressive therapy management. We identified a concomitant polyoma BK virus and West Nile Virus (WNV) infection in two renal transplant patients which, to our knowledge, has not previously been reported. However, other concomitant infections have been reported in renal allografts including BK virus and cytomegalovirus (CMV), CMV and hepatitis C (HCV), and HCV and human immunodeficiency virus (HIV). As WNV has become endemic in many regions of the United States, and since the transmission of the virus via transplanted organs is associated with significant morbidity and mortality, it may be prudent to consider serologic screening for WNV in living donors prior to organ procurement. Regardless, the observation we made and report here should underscore the potential for concomitant viral infections that may be masked when a renal allograft has a significant inflammatory response to BK virus.
PubMed: 38133339
DOI: 10.3390/pathogens12121456 -
Korean Journal of Pediatrics Nov 2019
PubMed: 31760720
DOI: 10.3345/kjp.2019.01123