Necrotizing pulmonary aspergillosis and ventricular assist device infection: case report and review of literature

Necrotizing pulmonary aspergillosis and Aspergillus device infection are rare and have potentially fatal complications after left ventricular assist device (LVAD) implantation. To date, few cases of patients surviving Aspergillus device infection have been published, with survival reported only after device removal. We present a patient implanted with an LVAD in whom necrotizing pulmonary aspergillosis with device involvement was successfully treated by segmentectomy and prolonged antifungal treatment without device exchange or removal. Similar cases in the literature were searched for and are discussed in view of the severity of this complication.     

Cytokine profile in lung transplant recipients with Aspergillus spp colonization

We studied cytokine profiles in BAL of LTRs with Aspergillus spp colonization who did not progress to IPA in the absence of antifungal prophylaxis. This was a retrospective, single center case‐control study. BAL samples were analyzed for cytokines. Patients with Aspergillus spp in BAL who did not receive prophylaxis and did not develop IPA were compared to LTRs with Aspergillus spp that received prophylaxis, LTRs with IPA and controls. Twenty‐one patients with Aspergillus colonization who did not develop IPA, seven patients with suspected IPA who received prophylaxis, 4 IPA and 19 controls were included. IPA group had significantly higher levels (median [IQR]) of MIP‐1 beta compared to the Suspected IPA group (5 vs 5 P: 0.03). The Suspected IPA group had significantly higher levels of IL‐12 (11.38 vs 1 P: 0.0001), IL‐1 RA (86.11 vs 23.98 P: 0.0118), IP‐10 (22.47 vs 0.86 P: 0.0151), HGF (40.92 vs 16.82 P: 0.0055), and MIG (169.62 vs 5 P: 0.0005) than Colonization group. We have identified a unique cytokine signature in patients with Aspergillus colonization that do not develop IPA. Our study forms basis for a larger study to use these cytokines profile to identify patients at a lower risk of developing IPA.     

Combined real‐time PCR and galactomannan surveillance improves diagnosis of invasive aspergillosis in high risk patients with haematological malignancies

Invasive aspergillosis (IA) is a leading complication of intensive treatment for haematological malignancies. Earlier diagnosis should facilitate effective antifungal therapy and prevent progression to invasive disease, which is often lethal. Polymerase chain reaction (PCR) assays, targeting the 28S and ITS ribosomal gene regions respectively, were evaluated for early detection of Aspergillus DNA and for diagnostic utility in patients receiving treatment in two busy haematopoietic stem cell transplant centres. Patients undergoing intensive chemotherapy, autologous or allogeneic transplant were eligible for inclusion in the study. EDTA blood and serum samples for circulating Aspergillus biomarkers, including galactomannan (GM), were collected twice‐weekly on a prospective basis from all study patients who were categorized according to international consensus criteria for defining invasive fungal disease (IFD). Of 278 patients recruited there were 44 probable IA cases and only one proven case. Moderate sensitivity and specificity, poor positive predictive value (50–80%), but good negative predictive value (>80–90%) were common to both PCR assays. Overall biomarker performance could be improved by combining positive results of either PCR assay with GM taken within a 12‐d period. The addition of PCR to GM monitoring in high‐risk patients with haematological malignancies provides greater diagnostic accuracy in invasive aspergillosis.     

Diaporthe soft tissue infection in a heart transplant patient

Infections caused by Diaporthe species are very uncommon. We describe a heart transplant recipient 14 years post transplant who developed a soft tissue fungal infection due to a Diaporthe species that responded well to surgical excision and posaconazole therapy. The Aspergillus galactomannan index was markedly elevated, and returned to normal following treatment. Solid organ transplant patients remain at risk of infection long after transplantation and should be counseled about risk avoidance.     

Late aspergilloma of a renal allograft without need for operative management: a case report and review of the literature

Aspergillus infection localized to the renal allograft is a rare and potentially life‐threatening infection and typically requires a combination of operative and medical management. We report the case of a renal allograft aspergilloma in a renal transplant patient presenting 2 years post transplant, successfully managed non‐surgically. To our knowledge, this is the first report of a patient presenting with an allograft aspergilloma so long after transplantation and being successfully managed with antifungal therapy alone.     

Legionnaires' disease in transplant recipients: A 15‐year retrospective study in a tertiary referral center

Legionnaires' disease (LD) can be fatal among high‐risk transplant recipients. To understand the epidemiology of LD, we reviewed 15‐year longitudinal data from a center in Seattle, Washington that cares for both solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients. We identified all laboratory‐confirmed LD and extracted data on species, diagnostic modalities, clinical presentation, management, and outcomes from medical records. Among 32 patients with LD, transplant recipients made up the majority of diagnoses (22, 69%; SOT 10, HCT 12). Approximately 0.8% of transplant recipients who underwent Legionella‐specific testing were positive. Non‐pneumophila Legionella species (LNLP), which are not detected by urinary antigen test, accounted for half the cases, led by Legionella micdadei (32%). The severity and outcome between Legionella pneumophila and LNLP infections were similar (attributed mortality, 36% vs 27%); all LNLP deaths occurred in transplant recipients with L. micdadei. The clinical and radiological features mimicked other opportunistic pathogens; 32% (n=7) were not on empiric treatment at the time of diagnosis. These data add to the emerging literature describing the importance of LD and highlight the need for both routine Legionella testing on transplant recipients with pulmonary findings and empiric Legionella‐active antibiotic therapy.     

Type 2 diabetes in young adults in Central Auckland: demography and complications

Background

Type 2 diabetes (T2D) in young adults is associated with a high risk of diabetes complications.

Aims

To investigated the demography and the emergence of complications of young adults with T2D in the central Auckland region where there has been substantial immigration.

Methods

In total, 310 young adults with T2D (<40 years) were registered with the Auckland Diabetes Centre in 2015. We documented demographic, anthropometric and metabolic variables and prevalence and the emergence of complications.

Results

Three demographic groups accounted for 243 participants (78%): 135 (44%) were migrants of Asian or Pacific Island origin, diagnosed a median 9 years after migration at a mean age of 28 ± 6 years; 88 (29%) were New Zealand‐born Pāsifika descent, with a high prevalence of morbid obesity and 37 (12%) had major mental illness or intellectual disability. At diagnosis, the median HbA1c was 80 mmol/mol, and in 28%, it was ≥100 mmol/mol. A median 6 years after diagnosis, 56% had some degree of retinopathy, with the prevalence related both to the duration of diabetes and glycaemic control (P = 0.001). Forty‐four percent of subjects had abnormal albuminuria at diagnosis (12% with macroalbuminuria). Increased albuminuria was strongly associated with obesity (P = 0.002). The development of CKD stages 4–5 was related both to the severity of retinopathy and degree of albuminuria at diagnosis (P = 0.0001). Major cardiovascular events were related to the severity of retinopathy at diagnosis (P = 0.0001).

Conclusions

New migrants, New Zealand‐born Pāsifika and patients with mental illness or an intellectual disability comprise the bulk of young onset T2D. The disease is aggressive, and by the age of 40, patients are already developing advanced complications.     

Identification of emerging FLT3 ITD‐positive clones during clinical remission and kinetics of disease relapse in acute myeloid leukaemia with mutated nucleophosmin

FLT3 internal tandem duplication (ITD) mutations are frequently detected at diagnosis in cytogenetically normal acute myeloid leukaemia (CN‐AML) and predict unfavourable outcome. FLT3 ITD is an unstable aberration and may be lost or acquired at relapse. Recent whole genome sequencing studies have suggested that FLT3 ITD⁺ve AML relapse may evolve from small subclones undetectable at diagnosis by routine polymerase chain reaction (PCR). We developed a patient‐specific real‐time quantitative‐PCR (RQ‐PCR) to implement FLT3 ITD detection in six AML patients whose blasts carried wild‐type FLT3 at diagnosis and who relapsed with FLT3 ITD by routine PCR. Patient‐specific forward primers were designed after cloning and sequencing the FLT3 ITD in each case. The assay allowed retrospective detection of FLT3 ITD in diagnostic samples of 4/6 cases and to establish the kinetics of clonal evolution preceding relapse. After conventional chemotherapy, all patients had early relapse despite having been classified as NPM1⁺ve/FLT3 ITD^?ve at presentation, with shorter remissions being observed in four patients re‐classified as FLT3 ITD⁺ve by the new assay. Notably, FLT3 ITD clone became detectable by conventional PCR in three patients tested during remission after initial treatment. Our data underscore the need of identifying low FLT3 ITD levels, which are probably associated with relapse in otherwise good prognosis CN‐AML.     

A 4‐gene expression score associated with high levels of Wilms Tumor‐1 (WT1) expression is an adverse prognostic factor in acute myeloid leukaemia

Wilms Tumor‐1 (WT1) expression level is implicated in the prognosis of acute myeloid leukaemia (AML). We hypothesized that a gene expression profile associated with WT1 expression levels might be a good surrogate marker. We identified high WT1 gene sets by comparing the gene expression profiles in the highest and lowest quartiles of WT1 expression in two large AML studies. Two high WT1 gene sets were found to be highly correlated in terms of the altered genes and expression profiles. We identified a 17‐probe set signature of the high WT1 set as the optimal prognostic predictor in the first AML set, and showed that it was able to predict prognosis in the second AML series after adjustment for European LeukaemiaNet genetic groups. The gene signature also proved to be of prognostic value in a third AML series of 163 samples assessed by RNA sequencing, demonstrating its cross‐platform consistency . This led us to derive a 4‐gene expression score, which faithfully predicted adverse outcome. In conclusion, a short gene signature associated with high WT1 expression levels and the resultant 4‐gene expression score were found to be predictive of adverse prognosis in AML. This study provides new clues to the molecular pathways underlying high WT1 states in leukaemia.     

Recombinant K28 antigen in ELISA in the diagnosis of canine visceral leishmaniosis

Crude total antigen (CTA) from Leishmania infantum and recombinant antigen K39 (rK39) and recombinant antigen K28 (rK28) were compared using an ELISA for the diagnosis of canine visceral leishmaniosis (CVL). Forty‐two blood samples from healthy dogs from a nonendemic area and 80 blood samples from an endemic area for dogs with visceral leishmaniosis (VL), confirmed with positive parasitological tests for Leishmania spp., were used in an ELISA. The parasitological diagnosis was chosen as a gold standard. The ELISA with rK28 antigen showed sensitivity of 100% and specificity of 100%, high agreement with CTA and rK39, indicating that the rK28 antigen is useful for ELISA serological diagnosis of CVL.     

Prototheca wickerhamii algaemia: an emerging infection in solid organ transplant recipients

Prototheca wickerhamii is an alga that rarely causes human disease but has been reported increasingly among immunocompromised individuals. We report a fatal case of P. wickerhamii in a renal transplant recipient who presented with a cutaneous lesion that led to disseminated disease despite treatment with voriconazole. We reviewed previous cases of protothecosis involving solid organ transplant recipients in the literature and discussed the value of newer microbiology platforms, i.e., matrix‐assisted laser desorption ionization time‐of‐flight mass spectrometry (MALDI‐TOF), to achieve early diagnosis and impact outcomes.     

Molecular diagnostics of myeloproliferative neoplasms

Since the discovery of the JAK2 V617F mutation in the majority of the myeloproliferative neoplasms (MPN) of polycythemia vera, essential thrombocythemia and primary myelofibrosis ten years ago, further MPN‐specific mutational events, notably in JAK2 exon 12, MPL exon 10 and CALR exon 9 have been identified. These discoveries have been rapidly incorporated into evolving molecular diagnostic algorithms. Whilst many of these mutations appear to have prognostic implications, establishing MPN diagnosis is of immediate clinical importance with selection, implementation and the continual evaluation of the appropriate laboratory methodology to achieve this diagnosis similarly vital. The advantages and limitations of these approaches in identifying and quantitating the common MPN‐associated mutations are considered herein with particular regard to their clinical utility. The evolution of molecular diagnostic applications and platforms has occurred in parallel with the discovery of MPN‐associated mutations, and it therefore appears likely that emerging technologies such as next‐generation sequencing and digital PCR will in the future play an increasing role in the molecular diagnosis of MPN.     

A case report of fatal disseminated Mycobacterium colombiense infection in a renal transplant recipient

We report the first case of disseminated Mycobacterium colombiense infection in a solid organ transplant recipient. Co‐infection with Cryptococcus neoformans led to fatal multisystem organ failure. We review the pathogen and host factors contributing to these opportunistic infections.     

Role of Functional IFNL4, IFNLR1, IFNA,IFNAR2 Polymorphisms in Hepatitis B virus‐related liver disease in Han Chinese population

Recent studies show that variants in some interferon genes together with interferon receptor genes are associated with the outcome of infectious diseases. We examined the association between the risk of hepatitis B virus (HBV)‐related liver disease and the functional polymorphisms within IFNL4, IFNLR1, IFNA1, IFNA2, IFNA5 and IFNAR2 genes (14 loci in all) in a Han Chinese population. A total of 3128 people participated and were divided into 5 groups: healthy controls, natural clearance, chronic hepatitis B(CHB), liver cirrhosis and hepatocellular carcinoma (HCC). Significant associations were observed for 4 variants in IFNAR2, IFNLR1 with HBV infection, and IFNLR1‐rs4649203 was associated with HBV recovery. Moreover, we demonstrated the clear relevance of 5 polymorphisms in IFNA1, IFNA2, IFNL4 with HCC. Three SNPs in IFNL4 gene may be important susceptible factors for the progression of HBV‐related liver disease by trend chi‐square test. The IFNL4 haplotype conformed by rs12971396_G, rs8113007_T and rs7248668A was more frequent in HCC than CHB and LC group. Three polymorphisms in the 5′ region of the IFNL4 gene are associated with the progression of HBV‐related liver disease. IFNA1‐ rs1831583 and IFNA2‐ rs649053 are associated with the development of HCC. IFNLR1‐ rs4649203, rs7525481 are predictors for HBV infection, and rs4649203 is a predictor of spontaneous clearance. IFNAR2 ‐rs1051393, rs12233338 may be predictive markers of HBV infection in the Chinese population.     

Role of IFN‐λs,IFN‐λs related genes and the DEPDC5 gene in Hepatitis B virus‐related liver disease

Recent studies have associated genetic variation near the interleukin 28B (IL28B/IFN‐λ3) gene with natural clearance of the hepatitis C virus (HCV) infection, and a common variant in the DEP domain containing 5 (DEPDC5) locus on chromosome 22 has been shown to affect susceptibility to hepatocellular carcinoma (HCC) in Japanese individuals with chronic HCV infection. This study was conducted to determine whether polymorphisms near or in interferon‐lambda (IFN‐λs) genes and their receptor genes such as interleukin 28 receptor, alpha (IL28RA) and interleukin 10 receptor, beta (IL10RB) as well as p21_activated kinases 4 (PAK4) and iron/zinc purple acid phosphatase‐like protein (PAPL), which are locate upstream of IFN‐λs, and lastly the DEPDC5 gene are associated with hepatitis B virus‐related liver disease in Han Chinese. The study subjects included 507 normal healthy controls, 350 individuals with natural clearance of HBV and 792 HBV‐infected patients. The patients were categorized into 157 inactive carriers (Case I), 216 active carriers (Case II), 111 cirrhotics (Case III) and 308 HCC patients (Case IV) subgroups. Seven single nucleotide polymorphisms (SNPs) were genotyped using the Matrix‐assisted Laser Desorption/Ionisation mass spectrometric (MALDI‐TOF MS) SNP genotyping assay. Rs423058 upstream of PAPL, rs2834167 in IL10RB and rs1012068 in DEPDC5 were associated with chronic HBV status, HBV natural clearance and the presence of HCC (P = 0.0004–0.024), respectively. PAPL, IL10RB and DEPDC5 polymorphisms have an impact on progression of HBV‐related liver disease. However, IFN‐λs genes as a tool to differentiate between different clinical courses of HBV infection were not useful in the Han Chinese population.     

Cerebellar abscess caused by Listeria monocytogenes in a liver transplant patient

Brain abscesses are a rare but serious complication and have been documented in transplant recipients. Aspergillus is by far the most frequent etiology of post‐transplant brain abscesses. Bacteria, apart from Nocardia, have a low association with brain abscesses in transplant recipients. We report herein the case of a 52‐year‐old man who had undergone orthotopic liver transplantation (OLT) for end‐stage liver disease and hepatocellular carcinoma secondary to chronic hepatitis, and who developed a cerebellar abscess (CA) from Listeria monocytogenes. Three months after transplantation, he presented with a 1‐week history of headache and vomiting. Computed tomography scan of the brain revealed a space‐occupying lesion in the right cerebellum, which was further confirmed by magnetic resonance imaging. Emergency surgery was planned because of pressure effect on the surrounding structures. The patient recovered smoothly from the surgery. To our knowledge, no reports of Listeria CA following OLT have been published in the English literature. This case shows that, although extremely rare, L. monocytogenes may cause CA in liver transplant recipients, and clinicians should be aware of this, so that prompt diagnosis and treatment can be instituted before serious brain damage can occur.     

BAALC and WT1 expressions from diagnosis to hematopoietic stem cell transplantation: consecutive monitoring in adult patients with core‐binding‐factor‐positive AML

No consecutive analysis of BAALC and WT1 expressions associated with core‐binding factor AML (CBF‐AML) from diagnosis to hematopoietic stem cell transplantation (HSCT) has yet been reported. We investigated BAALC and WT1 expressions using a method of real‐time quantitative polymerase chain reaction (RQ‐PCR) at diagnosis, after induction chemotherapy, at pre‐HSCT, and at post‐HSCT period in 45 consecutive patients [t(8,21) (n = 28), inv(16) (n = 17)], who received HSCT as a post‐remission treatment. BAALC and WT1 RQ‐PCR decrement ratio (DR) was also calculated at post‐induction chemotherapy, at pre‐HSCT, and at post‐HSCT compared with the diagnostic level. Higher BAALC expression at diagnosis showed significantly inferior OS (P = 0.031), EFS (P = 0.011), and higher CIR (P = 0.002) rates. At post‐HSCT, both higher BAALC and WT1 expressions showed significantly inferior OS (P = 0.005, 0.016), EFS (P = 0.002, 0.006), and higher CIR (P = 0.001, 0.003) rates. A subgroup of t(8;21) showing higher BAALC and WT1 expressions at post‐HSCT were also associated with inferior OS (P = 0.018, 0.015) and higher CIR rates (P = 0.019, 0.011). While BAALC DR showed no significant results on outcomes, WT1 DR more than 2‐log at post‐HSCT showed significantly lower CIR rate (P = 0.028). This study showed that higher post‐HSCT BAALC and WT1 expressions in patients with CBF‐AML may be good markers of minimal residual disease for the prediction of survival and relapse after HSCT.