Pathogenesis of Invasive Pulmonary Aspergillosis in Transplant Recipients

Purpose of Review

Transplant patients are at high risk for invasive pulmonary aspergillosis, and the associated mortality is high. The purpose of this study is to review the pathogenesis of invasive pulmonary aspergillosis (IPA) in transplant patients.

Recent Findings

The pathogenesis of aspergillosis is multifactorial and results from a complex interplay between the pathogen and host. It is well recognized that Aspergillus causes IPA in immunocompromised patients. Recent studies have shown that Aspergillus might also cause diseases likely attributed to an unmodulated immune response in certain transplant recipients such as bronchopulmonary aspergillosis or bronchiolitis obliterans syndrome in lung transplant recipients.

Summary

This review focuses on two crucial axes of the damage response framework applicable to aspergillosis: (1) Aspergillus virulence attributes that enable it to survive and proliferate in the host (thermotolerance, stress and hypoxic response, secretion of secondary metabolites) and (2) host response with specific focus on innate immunity and angiogenesis.

     

Pathogenesis and Pathology of Invasive Aspergillosis

Purpose of Review

Invasive aspergillosis occurs in immunosuppressed individuals and is associated with high morbidity and mortality. Understanding the host defenses and pathogen characters is important in the causation of disease.

Recent Findings

Neutropenia and/or corticosteroid administration increase the risk of invasive infections and majority are due to Aspergillus fumigatus. The size of the conidia, thermotolerance, hydrophobins and melanin on conidial surface, adaptability to host environment, and angioinvasive nature contribute to pathogenecity. The large conidial size, hot and humid environment, and constant exposure to high spore content are implicated in the pathogenesis of chronic invasive infections in a normal host due to Aspergillus flavus. Pathology depends on the immune status and varies from granuloma with fibrosis or suppuration to abscess or infarction.

Summary

The risk factors and the interplay of host pathogen in the pathogenesis of invasive aspergillosis are reviewed. Genetic predisposition and identification of such genetic factors are necessary for prevention and treatment.

     

Recurrence of allergic bronchopulmonary aspergillosis after adjunctive surgery for aspergilloma: a case report with long-term follow-up

Background

Coexistence of aspergilloma and allergic bronchopulmonary aspergillosis (ABPA) has rarely been reported. Although the treatment for ABPA includes administration of corticosteroids and antifungal agents, little is known about the treatment for coexisting aspergilloma and ABPA. Furthermore, the impact of surgical resection for aspergilloma on ABPA is not fully understood. Here, we present an interesting case of recurrent ABPA with long-term follow-up after surgical resection of aspergilloma.

Case presentation

A 53-year-old man with a medical history of tuberculosis was referred to our hospital with cough and dyspnea. Imaging revealed multiple cavitary lesions in the right upper lobe of the lung, with a fungus ball and mucoid impaction. The eosinophil count, total serum immunoglobulin E (IgE), and Aspergillus-specific IgE levels were elevated. Specimens collected on bronchoscopy revealed fungal filaments compatible with Aspergillus species. Based on these findings, a diagnosis of ABPA with concomitant aspergilloma was made. Although treatment with corticosteroids and antifungal agents was administered, the patient’s respiratory symptoms persisted. Therefore, he underwent lobectomy of the right upper lobe, which resulted in a stable condition without the need for medication. Twenty-three months after discontinuation of medical treatment, his respiratory symptoms gradually worsened with a recurrence of elevated eosinophil count and total serum IgE. Imaging revealed recurrent bronchiectasis and cavities with mucoid impaction in the right lower lobe, suggesting relapse of aspergilloma and ABPA. Corticosteroids and antifungal agents were re-administered; aspergilloma improved slightly over a 5-year period, and ABPA remained well controlled with low-dose prednisolone (5?mg/day).

Conclusions

We describe the long-term follow-up outcomes of a patient with concomitant ABPA and aspergilloma, who underwent surgical resection for aspergilloma. Physicians should carefully monitor patients with coexisting ABPA and aspergilloma, as the condition may relapse after remission, even despite surgical resection for aspergilloma. Additionally, surgical resection for aspergilloma could result in resolution of ABPA.

     

Role of Serological Tests in the Diagnosis of Mold Infections

Purpose of Review

To understand the role of antibody detection in the diagnosis of infections caused by filamentous fungi (molds). Rapid and accurate profiling of infection-causing fungal pathogens remains a significant challenge in modern health care. Classical fungal culture and serology continue to be relevant even though over the past few decades, antigen (biomarker) assays such as ELISA and lateral flow devices have been developed and validated.

Recent Findings

This article reviews the current antibody detection systems (serological tests) for the diagnosis of mold infections associated with pulmonary disease and introduces new developments. Classic and more recently developed serological techniques and their performance characteristics, including immunodiffusion, complement fixation, and ELISA.

Summary

The diseases covered are allergic bronchopulmonary aspergillosis, chronic pulmonary aspergillosis, invasive aspergillosis, mucormycosis, diseases caused by filamentous basidiomycetes, infection caused by Talaromyces marneffei and pythiosis. Serology remains a cornerstone for fungal diagnostic testing.

     

Three dimensional rotational angiography for assessment of coronary arteries during melody valve implantation: introducing a technique that may improve outcomes

Background

Adverse events from Melody valve implantation may be catastrophic. To date a role for three dimensional rotational angiography of the aortic root (3DRAA) during Melody valve implantation has not been established.

Objectives

To describe the role of 3DRAA in the assessment of Melody valve candidacy and to demonstrate that it may improve outcomes.

Methods

All patients who underwent cardiac catheterisation for Melody valve implantation and 3DRAA between August 2013 and February 2015 were reviewed.

Results

31 patients had 3DRAA with balloon sizing. Ten were deemed not Melody candidates (5 coronary compression, 2 aortic root distortion with cusp flattening, 2 RVOT was too large, and 1 had complex branch stenosis and a short landing zone). Of the 21 patients who were Melody candidates, 12 had conduits, 6 prosthetic valves and 3 native RVOTs. In patients with conduits, the technique of stenting the conduit prior to dilation was used after measuring the distance between the conduit and the coronary arteries on 3DRAA. In the Melody patients, we had 100% procedural success and no serious adverse events (coronary compression, tears, stent fracture or endocarditis).

Conclusion

As a tool for case selection, 3DRAA may facilitate higher procedural success and decreased risk of serious adverse events. Furthermore, 3D rotational angiography allows stenting of the conduit prior to dilation, which may prevent tears and possibly endocarditis.

     

Three stage axillary lymphatic massage optimizes sentinel lymph node localisation using blue dye

Aims

This paper describes a simple technique of axillary and breast massage which improves the successful identification of blue sentinel nodes using patent blue dye alone.

Methods

Patent blue dye was injected in the subdermal part of the retroaroelar area in 167 patients having surgical treatment for invasive breast cancer. Three stage axillary lymphatic massage was performed prior to making the axillary incision for sentinel lymph node biopsy. All patients had completion axillary sampling or clearance.

Results

A blue lymphatic duct leading to lymph nodes of the first drainage was identified in 163 (97%) of the patients. Results are compared with 168 patients who had sentinel lymph node biopsy using blue dye without axillary massage. Allergic reactions were observed in four patients (1.2%).

Conclusion

Three stage axillary lymphatic massage improves the successful identification of a blue sentinel lymph node in breast cancer patients.

     

Hypocapnia is a biological marker for orthostatic intolerance in some patients with chronic fatigue syndrome

Context

Patients with chronic fatigue syndrome and those with orthostatic intolerance share many symptoms, yet questions exist as to whether CFS patients have physiological evidence of orthostatic intolerance.

Objective

To determine if some CFS patients have increased rates of orthostatic hypotension, hypertension, tachycardia, or hypocapnia relative to age-matched controls.

Design

Assess blood pressure, heart rate, respiratory rate, end tidal CO2 and visual analog scales for orthostatic symptoms when supine and when standing for 8 minutes without moving legs.

Setting

Referral practice and research center.

Participants

60 women and 15 men with CFS and 36 women and 4 men serving as age matched controls with analyses confined to 62 patients and 35 controls showing either normal orthostatic testing or a physiological abnormal test.

Main outcome measures

Orthostatic tachycardia; orthostatic hypotension; orthostatic hypertension; orthostatic hypocapnia or combinations thereof.

Results

CFS patients had higher rates of abnormal tests than controls (53% vs 20%, p < .002), but rates of orthostatic tachycardia, orthostatic hypotension, and orthostatic hypertension did not differ significantly between patients and controls (11.3% vs 5.7%, 6.5% vs 2.9%, 19.4% vs 11.4%, respectively). In contrast, rates of orthostatic hypocapnia were significantly higher in CFS than in controls (20.6% vs 2.9%, p < .02). This CFS group reported significantly more feelings of illness and shortness of breath than either controls or CFS patients with normal physiological tests.

Conclusion

A substantial number of CFS patients have orthostatic intolerance in the form of orthostatic hypocapnia. This allows subgrouping of patients with CFS and thus reduces patient pool heterogeneity engendered by use of a clinical case definition.

     

Mirizzi Syndrome: an unexpected problem of cholelithiasis. Our experience with 27 cases

Purpose

Mirizzi syndrome is a rare complication of long standing cholelithiasis. The purpose of this study is to retrospectively estimate the diagnostic and treatment methods applied in patients with Mirizzi syndrome.

Materials and methods

Our experience with 27 cases with Mirizzi syndrome is presented. They were diagnosed either by imaging techniques, or during surgical operation. All of the patients were managed surgically.

Results

8 patients were diagnosed preoperatively and the rest intraoperatively. Morbidity rate after surgery was 18,5%, and mortality rate was zero. The patients presented free of symptoms three months after surgery during the follow-up.

Conclusion

Mirizzi syndrome is rarely diagnosed preoperatively and US proved inadequate for this purpose. Surgery is the only therapy and usually provides additionally definitive diagnosis.

     

Factor XIII Val34Leu polymorphism and risk of recurrent pregnancy loss in Iranian population: a case control study

BACKGROUND

Recurrent pregnancy loss (RPL) is a heterogeneous condition and thrombophilias have been considered as a probable cause.

OBJECTIVE

The aim of this study was to investigate the prevalence of the coagulation factor XIII Val34Leu polymorphism among women with unexplained RPL.

METHODS

A total of 140 women with a history of unexplained RPL and 100 age-matched healthy fertile women were recruited. The presence of FXIII Val34Leu polymorphism among the cases and controls was investigated using PCR-RFLP method.

RESULTS

Genotype analyses of the subjects revealed that the patients had a significantly higher prevalence of V/L and L/L than the controls (P<0.05): 33.5% vs. 15%, and 9.2% vs. 2%, respectively.

CONCLUSION

These results indicate a significant association between FXIII Val34Leu polymorphism and unexplained RPL in the Iranian patient.

     

A lost opportunity for science: journals promote data sharing in metabolomics but do not enforce it

Introduction

Data sharing is being increasingly required by journals and has been heralded as a solution to the ‘replication crisis’.

Objectives

(i) Review data sharing policies of journals publishing the most metabolomics papers associated with open data and (ii) compare these journals’ policies to those that publish the most metabolomics papers.

Methods

A PubMed search was used to identify metabolomics papers. Metabolomics data repositories were manually searched for linked publications.

Results

Journals that support data sharing are not necessarily those with the most papers associated to open metabolomics data.

Conclusion

Further efforts are required to improve data sharing in metabolomics.

     

Real-Life Challenges to the Use of Antifungal Agents in Hematology Patients

Purpose of Review

One of the more serious complications of hematology and allogeneic hematopoietic stem cell transplant patients is the development of invasive fungal infections (IFIs).

Recent Findings

Due to the widespread use of prophylaxis active against Candida spp. in these populations, infections due to invasive molds, such as aspergillosis and mucormycosis, have become more predominant. Several real-life challenges complicate the optimal prophylaxis and management of patients who develop invasive mold infections. Selection of agents in this setting requires careful consideration to the strength of evidence, certainty of IFI diagnosis, side effect profile, drug interactions, and cost.

Summary

In this review, we discuss the clinical evidence behind the optimal prophylaxis and treatment of IFIs in patients with hematological malignancies and review important practical considerations that should be taken in order to apply these data effectively to real-world patients.

     

Optimization of fecal sample preparation for untargeted LC-HRMS based metabolomics

Introduction

Collecting feces is easy. It offers direct outcome to endogenous and microbial metabolites.

Objectives

In a context of lack of consensus about fecal sample preparation, especially in animal species, we developed a robust protocol allowing untargeted LC-HRMS fingerprinting.

Methods

The conditions of extraction (quantity, preparation, solvents, dilutions) were investigated in bovine feces.

Results

A rapid and simple protocol involving feces extraction with methanol (1/3, M/V) followed by centrifugation and a step filtration (10 kDa) was developed.

Conclusion

The workflow generated repeatable and informative fingerprints for robust metabolome characterization.

     

Characterization of ankylosing spondylitis and rheumatoid arthritis using <Superscript>1</Superscript>H NMR-based metabolomics of human fecal extracts

Introduction

The differences in fecal metabolome between ankylosing spondylitis (AS)/rheumatoid arthritis (RA) patients and healthy individuals could be the reason for an autoimmune disorder.

Objectives

The study explored the fecal metabolome difference between AS/RA patients and healthy controls to clarify human immune disturbance.

Methods

Fecal samples from 109 individuals (healthy controls 34, AS 40, and RA 35) were analyzed by ¹H NMR spectroscopy. Data were analyzed with principal component analysis (PCA) and orthogonal projection to latent structure discriminant (OPLS-DA) analysis.

Results

Significant differences in the fecal metabolic profiles could distinguish AS/RA patients from healthy controls but could not distinguish between AS and RA patients. The significantly decreased metabolites in AS/RA patients were butyrate, propionate, methionine, and hypoxanthine. Significantly increased metabolites in AS/RA patients were taurine, methanol, fumarate, and tryptophan.

Conclusion

The metabolome variations in feces indicated AS and RA were two homologous diseases that could not be distinguished by ¹H NMR metabolomics.

     

Minimal variation of the plasma lipidome after delayed processing of neonatal cord blood

Background

Cord blood lipids are potential disease biomarkers. We aimed to determine if their concentrations were affected by delayed blood processing.

Method

Refrigerated cord blood from six healthy newborns was centrifuged every 12 h for 4 days. Plasma lipids were analysed by liquid chromatography/mass spectroscopy.

Results

Of 262 lipids identified, only eight varied significantly over time. These comprised three dihexosylceramides, two phosphatidylserines and two phosphatidylethanolamines whose relative concentrations increased and one sphingomyelin that decreased.

Conclusion

Delay in separation of plasma from refrigerated cord blood has minimal effect overall on the plasma lipidome.

     

Invasive Fungal Infection in Primary Immunodeficiencies Other Than Chronic Granulomatous Disease

Purpose of review

We aimed to review invasive fungal infections complicating primary immunodeficiencies (PID).

Recent findings

Several PID predisposing to fungal infections were recently deciphered. CARD9 deficiency selectively predisposes to fungal infections including candidiasis, aspergillosis, deep dermatophytosis, and phaeohyphomycosis, with frequent central nervous system location, especially after Candida infection. Patients with heterozygous STAT1 gain-of-function mutations are mostly predisposed to chronic mucocutaneous candidiasis but may also display, even though less frequently, invasive fungal infections. Aspergillosis complicating STAT3 deficiency is also a major concern in patients with lung cavities. Antifungal prophylaxis is recommended in this first group of patients. Previously well-reported PID are known to predispose to fungal infections, such as genetic defects impairing the IL-12/IFN-γ axis can predispose to cryptococcosis, and dimorphic fungal infections.

Summary

Patients developing invasive fungal infections including candidiasis, aspergillosis, cryptococcosis, phaeohyphomycosis, pneumocystosis, or disseminated infections caused by dimorphic fungi, without known underlying risk factors, should be explored immunogenetically in order to diagnose primary immunodeficiencies, even in the absence of previous other infectious episodes.

     

Untargeted metabolomics suffers from incomplete raw data processing

Introduction

Untargeted metabolomics is a powerful tool for biological discoveries. To analyze the complex raw data, significant advances in computational approaches have been made, yet it is not clear how exhaustive and reliable the data analysis results are.

Objectives

Assessment of the quality of raw data processing in untargeted metabolomics.

Methods

Five published untargeted metabolomics studies, were reanalyzed.

Results

Omissions of at least 50 relevant compounds from the original results as well as examples of representative mistakes were reported for each study.

Conclusion

Incomplete raw data processing shows unexplored potential of current and legacy data.

     

Our local experience with the surgical treatment of ampullary cancer

Background

The aim of this study is to report the outcome after surgical treatment of 32 patients with ampullary cancers from 1990 to 1999.

Methods

Twenty-one of them underwent pancreaticoduodenectomy and 9 local excision of the ampullary lesion. The remaining 2 patients underwent palliative surgery.

Results

When the final histological diagnosis was compared with the preoperative histological finding on biopsy, accurate diagnosis was preoperatively established in 24 patients. The hospital morbidity was 18.8% as 9 complications occurred in 6 patients. Following local excision of the ampullary cancer, the survival rate at 3 and 5 years was 77.7% and 33.3% respectively. Among the patients that underwent Whipple's procedure, the 3-year survival rate was 76.2% and the 5-year survival rate 62%.

Conclusion

In this series, local resection was a safe option in patients with significant co-morbidity or small ampullary tumors less than 2 cm in size, and was associated with satisfactory long-term survival rates.

     

Corneal Collagen Cross-Linking for the Management of Mycotic Keratitis

Purpose

To evaluate the efficiency of corneal collagen cross-linking (CXL) in addition to topical voriconazole in cases with mycotic keratitis.

Design

Retrospective case series in a tertiary university hospital.

Participants

CXL was performed on 13 patients with mycotic keratitis who presented poor or no response to topical voriconazole treatment.

Methods

The clinical features, symptoms, treatment results and complications were recorded retrospectively. The corneal infection was graded according to the depth of infection into the stroma (from grade 1 to grade 3). The visual analogue scale was used to calculate the pain score before and 2 days after surgery.

Main Outcome Measures

Grade of the corneal infection.

Results

Mean age of 13 patients (6 female and 7 male) was 42.4 ± 17.7 years (20–74 years). Fungus was demonstrated in culture (eight patients) or cytological examination (five patients). Seven of the 13 patients (54%) were healed with topical voriconazole and CXL adjuvant treatment in 26 ± 10 days (15–40 days). The remaining six patients did not respond to CXL treatment; they initially presented with higher grade ulcers. Pre- and post-operative pain score values were 8 ± 0.8 and 3.5 ± 1, respectively (p < 0.05).

Conclusions

The current study suggests that adjunctive CXL treatment is effective in patients with small and superficial mycotic ulcers. These observations require further research by large randomized clinical trials.

     

Phylloides tumor of the breast: a rare neoplasm,though not that innocent

Background

Cystosarcoma phylloides (CP) is an extremely rare form of breast cancer with an unpredictable clinical course. The histological characteristics of this neoplasm have not proved to offer much in the estimation of prognosis of these patients.

Patients and methods

In our clinics, in a time period of 38 years, 22 patients with cystosarcoma phylloides were treated. There were 5 cases of malignancy, 15 cases with benign tumors, and two cases histologically characterized as borderline neoplasia. Metastases were manifested in one patient. All patients were on a 5-year follow-up, except in five cases, one operated three years ago and four operated within the last two years.

Results

16 of 22 patients did not present any signs of local recurrence or metastases. There were three patients that manifested local recurrence and underwent supplementary ongectomy or mastectomy and are free of recurrence ever since. One patient with metastatic CP died.

Conclusion

Independently of its histopathological behavior, CP is a tumor difficult to be treated. Meticulous follow-up is mandatory in order to manage possible recurrence of the neoplasm.

     

Extraction of natural products from bark of <Emphasis Type="Italic">Betula pendula</Emphasis> using ionic liquids

Introduction

Aqueous–methanol mixtures have successfully been applied to extract a broad range of metabolites from plant tissue. However, a certain amount of material remains insoluble.

Objectives

To enlarge the metabolic compendium, two ionic liquids were selected to extract the methanol insoluble part of trunk from Betula pendula.

Methods

The extracted compounds were analyzed by LC/MS and GC/MS.

Results

The results show that 1-butyl-3-methylimidazolium acetate (IL-Ac) predominantly resulted in fatty acids, whereas 1-ethyl-3-methylimidazolium tosylate (IL-Tos) mostly yielded phenolic structures. Interestingly, bark yielded more ionic liquid soluble metabolites compared to interior wood.

Conclusion

From this one can conclude that the application of ionic liquids may expand the metabolic snapshot.