Clinical outcomes of polyvalent immunoglobulin use in solid organ transplant recipients: A systematic review and meta‐analysis – Part II: Non‐kidney transplant

Immunoglobulin (IG) is commonly used to desensitize and treat antibody‐mediated rejection in solid organ transplant (SOT) recipients. The impact of IG on other outcomes such as infection, all‐cause mortality, graft rejection, and graft loss is not clear. We conducted a similar systematic review and meta‐analysis to our previously reported Part I excluding kidney transplant. A comprehensive literature review found 16 studies involving the following organ types: heart (6), lung (4), liver (4), and multiple organs (2). Meta‐analysis could only be performed on mortality outcome in heart and lung studies due to inadequate data on other outcomes. There was a significant reduction in mortality (OR 0.34 [0.17‐0.69]; 4 studies, n = 455) in heart transplant with hypogammaglobulinemia receiving IVIG vs no IVIG. Mortality in lung transplant recipients with hypogammaglobulinemia receiving IVIG was comparable to those of no hypogammaglobulinemia (OR 1.05 [0.49, 2.26]; 2 studies, n = 887). In summary, IVIG targeted prophylaxis may decrease mortality in heart transplant recipients as compared to those with hypogammaglobulinemia not receiving IVIG, or improve mortality to the equivalent level with those without hypogammaglobulinemia in lung transplant recipients, but there is a lack of data to support physicians in making decisions around using immunoglobulins in all SOT recipients for infection prophylaxis.     

Clinical outcomes of polyvalent immunoglobulin use in solid organ transplant recipients: A systematic review and meta‐analysis

Polyvalent immunoglobulin is commonly used for desensitization and treatment of antibody‐mediated rejection in kidney transplantation but its impact on other outcomes is not known. This systematic review investigated the impact of immunoglobulin prophylaxis on infection, rejection, graft loss, and death following kidney transplantation. A comprehensive literature search located 18 studies (n = 8 randomized controlled trials). None examined the effect of immunoglobulin prophylaxis in transplant recipients with hypogammaglobulinemia. Quality of included studies was variable with high to very high risk of bias. In the randomized trials, immunoglobulin use did not reduce cytomegalovirus infection (OR 0.68 [0.39, 1.21]; 6 studies, n = 295), rejection (OR 0.96 [0.50, 1.82]; 4 studies, n = 187), or graft loss (OR 1.03 [0.46, 2.30]; 6 studies, n = 265). In non‐randomized studies, immunoglobulin did not reduce cytomegalovirus infection (OR 0.63 [0.20, 1.94]; 6 studies, n = 361) or death (OR 1.32 [0.05, 38.79]; 3 studies, n = 222) but reduce rejection (OR 0.47 [0.24, 0.94]; 4 studies, n = 268) and graft loss (OR 0.15 [0.05, 0.43]; 2 studies, n = 118). Data were scarce and sample size of current evidence was small. Adequately powered randomized trials are needed to determine if immunoglobulin is an effective intervention to reduce infection, rejection, graft loss, or death following kidney transplantation with and without hypogammaglobulinemia.     

Tests for latent tuberculosis in candidates for solid organ transplantation: A systematic review and meta‐analysis

Reactivation of latent tuberculosis following solid organ transplantation has serious consequences for the recipient. The most useful diagnostic test for latent TB is not clear. We conducted a systematic review and meta‐analysis to assess the relative test performance of interferon gamma release assays (IGRAs) and the tuberculin skin test (TST) in people undergoing solid organ transplantation. The clinical or radiological risk factors were used as the proxy reference standard. Test performance was expressed as an odd ratio (OR). We identified 24 studies (N = 7811), 12 studies compared IGRAs with TST directly, nine studies evaluated only TST and three studies only IGRAs. Direct comparison between tests and clinical risk factors indicated both tests were strongly associated with the presence of clinical risk factors for TB (TST: OR 3.17; 95%CI 1.55‐6.48, IGRA: OR 2.78; 95%CI 1.55‐5.01), and radiological evidence of past TB (TST: OR 3.26; 95%CI 1.85‐5.73, IGRA: OR 3.85; 95%CI 2.16‐6.86). Relative comparison indicated IGRAs positivity was more strongly associated with presence of radiological evidence of TB than TST (relative OR: 3.24; 95%CI 1.10‐9.56). While there is no strong evidence in supporting use of IGRAs over TST for diagnosing latent TB, IGRAs positivity is more associated with the presence of radiological evidence of previous TB.     

The seroprevalence of Anaplasma phagocytophilum in global human populations: A systematic review and meta‐analysis

The tick‐borne pathogen Anaplasma phagocytophilum is an emerging infectious disease threat, but the overall A. phagocytophilum seroprevalence in humans is unclear. We performed a systematic search of English databases for literature published from 1994 to 2018. Studies reporting serological evidence of A. phagocytophilum infection in humans were included, and the information was extracted by two authors independently. As the study heterogeneity was significant, a random‐effects model was used to calculate the overall pooled seroprevalence. Data from 56 studies involving 28,927 individuals from four continents were included. The seroprevalence reported by the studies ranged from 0% to 37.26%. The overall pooled A. phagocytophilum seroprevalence in humans was 8.4% (95% CI: 6.6%–10.4%). The seroprevalence was highest in high‐risk population (13.8%) and lowest in healthy population (5.0%). The estimated A. phagocytophilum seroprevalence of febrile patient, tick‐bitten and tick‐borne diseases populations was 6.4%, 8.0% and 9.0%, respectively. This meta‐analysis demonstrated first A. phagocytophilum seroprevalence estimates in different populations (healthy, febrile patient, high‐risk, tick‐bitten and tick‐borne diseases populations); it seems likely that present surveillance efforts are missing mild or asymptomatic infections of humans.     

COVID-19 in solid organ transplant recipients: a single-center experience

Solid organ transplant (SOT) recipients may be at risk for severe COVID-19. Data on the clinical course of COVID-19 in immunosuppressed patients are limited, and the effective treatment strategy for these patients is unknown. We describe our institutional experience with COVID-19 in SOT. Demographic, clinical, and treatment data were extracted from the electronic patient files. A total of 23 SOT transplant recipients suffering from COVID-19 were identified (n = 3 heart; n = 15 kidney; n = 1 kidney-after-heart; n = 3 lung, and n = 1 liver transplant recipient). The presenting symptoms were similar to nonimmunocompromised patients. Eighty-three percent (19/23) of the patients required hospitalization, but only two of these were transferred to the intensive care unit. Five patients died from COVID-19; all had high Clinical Frailty Scores. In four of these patients, mechanical ventilation was deemed futile. In 57% of patients, the immunosuppressive therapy was not changed and only three patients were treated with chloroquine. Most patients recovered without experimental antiviral therapy. Modification of the immunosuppressive regimen alone could be a therapeutic option for SOT recipients suffering from moderate to severe COVID-19. Pre-existent frailty is associated with death from COVID-19.     

Strongyloides stercoralis infection in human immunodeficiency virus‐infected patients and related risk factors: A systematic review and meta‐analysis

Strongyloidiasis is caused by nematode infections of the genus Strongyloides, mainly Strongyloides stercoralis, and affects tens of millions of people around the world. S. stercoralis hyperinfection and disseminated strongyloidiasis are unusual but potentially fatal conditions mostly due to Gram‐negative bacteremia and sepsis, primarily affecting immunocompromised patients. Infections with immunosuppressive viruses such as human immunodeficiency virus (HIV) and Human T‐cell leucemia virus type 1 (HTLV‐1) have been reported as risk factors for strongyloidiasis. Hyperinfection syndrome has been described in HIV‐positive patients following the use of corticosteroids or during immune reconstitution inflammatory syndrome (IRIS). In this research, we conducted a global systematic review and meta‐analysis to assess the seroprevalence and odds ratios (ORs) of S. stercoralis infections in HIV‐infected patients. A total of 3,649 records were screened, 164 studies were selected and evaluated in more detail, and 94 studies were included in the meta‐analysis. The overall pooled prevalence of S. stercoralis infection in HIV positive patients was 5.1% (CI95%: 4%–6.3%), and a meta‐analysis on six studies showed that with a pooled OR of 1.79 (CI95%: 1.18%–2.69%) HIV‐positive men are at a higher risk of S. stercoralis infections (p < .0052) compared to HIV positive women.     

Bisphosphonates for preventing bone disease in kidney transplant recipients: a meta‐analysis of randomized controlled trials

An estimated 60% of kidney transplant recipients have mineral bone disease and about 0.5% break their hip within the first year after transplantation. We conducted a systematic review of benefits and harms of bisphosphonates in kidney transplant recipients. We searched CENTRAL (Issue 5, 2015) for randomized controlled trials in all languages and screened the reference list of an earlier Cochrane review. One reviewer identified the trials, extracted all data, and assessed risk of bias. Meta‐analysis used a random effects model, with results expressed as risk ratios (RR) or mean differences (MD) with 95% confidence intervals (CI). Bisphosphonates have uncertain effects on death (RR 0.45, CI 0.04–4.69) and vertebral fractures (RR 0.58, CI 0.24–1.43, I² 0%). Bisphosphonates moderately to importantly reduce the loss of vertebral bone mineral density (MD 5.98%, CI 3.77–8.18% change from baseline in g calcium/cm² at 12 months, I² 91%) and femoral bone mineral density (MD 5.57%, 3.12–8.01% change from baseline in g calcium/cm² at 12 months, I² 69%). At this stage, insufficient evidence exists to support routine use of bisphosphonates to reduce fracture risk after kidney transplantation. Data on important health outcomes are lacking, surrogate outcomes poorly reflect bone quality in kidney transplant recipients, and serious adverse events are not studied and reported systematically.     

Impact of MBL2 gene polymorphisms on the risk of infection in solid organ transplant recipients: A systematic review and meta‐analysis

Mannose‐binding lectin (MBL) is a soluble pattern recognition molecule involved in complement activation. Single nucleotide polymorphisms (SNPs) in the MBL2 gene have been associated with susceptibility to infection, although data in solid organ transplant recipients remains inconclusive. This meta‐analysis was primarily aimed at investigating the association between posttransplant bacterial and fungal infection and variant alleles of MBL2 gene SNPs in the promoter/5’ untranslated region and exon 1. Cytomegalovirus (CMV) infection and/or disease were considered secondary outcomes. PubMed, EMBASE, and Web of Knowledge were searched for relevant articles up to August 2018. Eleven studies (comprising 1858 patients) were included, with liver transplant (LT) recipients accounting for 80.4% of the pooled population. As compared to high‐MBL expression haplotypes (YA/YA, YA/XA), any MBL‐deficient haplotype was associated with an increased risk of posttransplant bacterial and fungal infections (risk ratio [RR]: 1.30; P = .04). Low/null‐MBL expression haplotypes (XA/O, O/O) also increased the risk of primary outcome (RR: 1.51; P = .008) and CMV events (RR: 1.50; P = .006). No effect was observed for individual promoter SNPs. In conclusion, MBL‐deficient haplotypes are associated with a significant, albeit moderate, increase in the risk of posttransplant infection, with this association being mainly restricted to LT recipients.     

COVID‐19 in solid organ transplant recipients: A single‐center case series from Spain

The clinical characteristics, management, and outcome of coronavirus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) after solid organ transplant (SOT) remain unknown. We report our preliminary experience with 18 SOT (kidney [44.4%], liver [33.3%], and heart [22.2%]) recipients diagnosed with COVID‐19 by March 23, 2020 at a tertiary‐care center at Madrid. Median age at diagnosis was 71.0 ± 12.8 years, and the median interval since transplantation was 9.3 years. Fever (83.3%) and radiographic abnormalities in form of unilateral or bilateral/multifocal consolidations (72.2%) were the most common presentations. Lopinavir/ritonavir (usually associated with hydroxychloroquine) was used in 50.0% of patients and had to be prematurely discontinued in 2 of them. Other antiviral regimens included hydroxychloroquine monotherapy (27.8%) and interferon‐β (16.7%). As of April 4, the case‐fatality rate was 27.8% (5/18). After a median follow‐up of 18 days from symptom onset, 30.8% (4/13) of survivors developed progressive respiratory failure, 7.7% (1/13) showed stable clinical condition or improvement, and 61.5% (8/13) had been discharged home. C‐reactive protein levels at various points were significantly higher among recipients who experienced unfavorable outcome. In conclusion, this frontline report suggests that SARS‐CoV‐2 infection has a severe course in SOT recipients.     

CMV-hyperimmune globulin for preventing cytomegalovirus infection and disease in solid organ transplant recipients: a meta-analysis

Abstract. Objective: The goal of this meta-analysis was to investigate the impact of cytomegalovirus hyperimmune globulin (CMVIG) on cytomegalovirus (CMV) infection, CMV disease, and mid-term survival in solid organ transplant recipients. Methods: Medline, EMBASE, and the Cochrane databases were searched since their inceptions until 2006. Inclusion criteria comprised: prospective randomized trials, in solid organ transplantation which received CMV prophylaxis including CMVIG on one of the treatment arms. Random effects models were used to calculate pooled risk ratios (RR) and meta-regression was employed to explain study heterogeneity. Stratified analyses were conducted and Funnel plot was used to assess publication bias. Results: Literature searches identified 11 randomized trials (698 patients; median follow-up: 12 months, range: 3–22 months) including six randomized trials (302 patients) after kidney transplantation. The analysis demonstrated a beneficial effect of the prophylactic use of CMVIG on total survival [RR (95% confidence interval; CI): 0.67 (0.47–0.95)] and prevention of CMV-associated death [RR (95% CI): 0.45 (0.24–0.84)] in solid organ transplant recipients but not kidney transplant recipients [RR (95% CI): 0.35 (0.12–1.04)]. CMV disease was significantly reduced in all recipients receiving prophylactic CMVIG [RR (95% CI): 0.697 (0.57–0.85)]. CMVIG had no impact on CMV-infections and clinically relevant rejections. Conclusions: Prophylactic administration of CMVIG after solid organ transplantation is associated with improved total survival, reduced CMV disease, and CMV-associated deaths.     

hOGG1 gene polymorphism and breast cancer risk: A systematic review and meta‐analysis study

To address the effect of hGGO1 (rs1052133) gene polymorphism on the risk of breast cancer, a meta‐analysis was performed. We pooled adjusted odds ratios (OR) as overall and three subgroups (menopausal status, ethnicity, and study setting). In overall analysis, we found a significant association when the model of inheritance was homozygote (pooled OR 1.14; 95% CI 1.01, 1.29). Subgroup analysis showed significant association for homozygote genetic models among postmenopause women (OR 1.23; 95% CI 1.01, 1.49) and Asian population (OR 1.17; 95% CI 1.01, 1.35). This study suggested that the carrier of Ser326Cys polymorphism of hOGG1, Cys/Cys vs Ser/Ser, are at higher risk for breast cancer, independent of other hormonal and environmental risk factors.     

Combination of caspofungin and low‐dose trimethoprim/sulfamethoxazole for the treatment of severe Pneumocystis jirovecii pneumonia in renal transplant recipients

Pneumocystis jirovecii pneumonia (PJP) is a severe and life‐threatening complication in immunocompromised patients. Trimethoprim/sulfamethoxazole (TMP‐SMZ) is well known for its effectiveness as prophylaxis of PJP. However, the use of TMP‐SMZ is associated with various adverse effects that may not be tolerated by critically ill patients. Caspofungin is recommended for invasive fungal infections, but the treatment of PJP after solid organ transplantation (SOT) is an off‐label use of this drug. In this study, three cases of severe PJP in renal transplant recipients treated with a combination of caspofungin and low‐dose TMP‐SMZ were presented. Initial findings indicated that the combined treatment may be beneficial for the treatment of PJP and decrease the incidence of TMP‐SMZ‐related adverse effects.     

Extracorporeal membrane oxygenation as a bridge vs. non‐bridging for lung transplantation: A systematic review and meta‐analysis

Whether extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation (BTT) can achieve a similar survival to non‐BTT remains controversial. We conducted this meta‐analysis to compare the outcomes between ECMO BTT and non‐BTT to facilitate better clinical decision‐making. Seven databases were searched for eligible studies comparing ECMO BTT and non‐BTT. The primary endpoints included survival, intraoperative indicators, postoperative hospitalization indicators, and postoperative complications. Nineteen studies (involving 7061 participants) were included in the final analysis. The outcomes of overall survival, overall survival rate, graft survival rate, in‐hospital mortality, postoperative hospital days, postoperative intensive care unit days, postoperative ventilation time, blood transfusion volume, and postoperative complications were all better in the non‐BTT group. The total mortality in ECMO bridging was 23.03%, in which the top five causes of death were right heart failure (8.03%), multiple organ failure (7.03%), bleeding (not cranial) (4.67%), cranial bleeding (3.15%), and sepsis (2.90%). In summary, Non‐BTT is associated with better survival and fewer complications compared to BTT. When ECMO may be the only option, the patient and medical team need to realize the increased risk of ECMO by complications and survival.     

Ureterovesical anastomotic techniques for kidney transplantation: a systematic review and meta‐analysis

No consensus exists about which ureterovesical anastomosis technique to use for kidney transplantation. The aim of this systematic review was to compare the existing techniques in relation to the risk of urological complications. All studies that compared ureterovesical anastomotic techniques in kidney transplantation were included. Study endpoints were urinary leakage, ureteral stricture, vesicoureteral reflux and hematuria. Subanalyses of stented and nonstented techniques were performed. Two randomized clinical trials and 24 observational studies were included. Meta‐analyses were performed on the Lich‐Gregoir (LG) versus Politano‐Leadbetter (PL) techniques and LG versus U‐stitch (U) techniques. Compared with the PL technique, the LG technique had a significantly lower prevalence of urinary leakage (risk ratio (RR): 0.47, 95% confidence interval (CI): 0.30 to 0.75) and a significantly lower prevalence of hematuria when compared with both PL and U techniques (RR: 0.28, 95% CI: 0.16 to 0.49 and RR: 0.23, 95% CI: 0.11 to 0.50, respectively), regardless of ureteral stenting. There was no difference in the prevalence of ureteral strictures or vesicoureteral reflux between the various techniques. Of the three most frequently used ureterovesical anastomotic techniques, the LG technique results in fewer urological complications than the PL and U techniques.