A case of Acremonium strictum peritonitis

During the past two decades opportunistic fungal infections have emerged as important causes of morbidity and mortality in patients with severe underlying illnesses. A few cases of Acremonium spp. infections have been described in immunocompromised patients, but they have on occasion been reported as the cause invasive disease in immunocompetent individuals. Peritonitis is a common clinical problem that occurs in patients with end-stage renal disease treated by continuous ambulatory peritoneal dialysis (CAPD). Yeasts, or rarely molds, may also cause peritonitis in patients on CAPD and we present here a case caused by Acremonium strictum.     

Granulomatous fungal and non-tuberculous mycobacterial infestation complicating chronic lung disease: Outcomes in patients undergoing lung transplantation

IntroductionGranulomatous infections are common in patients with chronic lung disease. We aim to study the incidence and clinicopathological features of granulomatous infections in a cohort of patients undergoing lung transplantation for end-stage chronic lung disease.MethodsPathology reports of 50 explanted native lungs of patients who underwent lung transplantation since 2015 at our institution were reviewed. Four cases with granulomatous lesions were identified. Correlation was made with clinical findings in the 4 cases.ResultsThe granulomatous infections include non-necrotizing cryptococcal pneumonitis (case 1), necrotizing pneumonia due to Scedosporium sp. and Mycobacterium avium Complex (MAC) (Cases 2 and 3), and invasive Aspergillus pneumonia (Case 4). One patient received pre-transplant fungal prophylaxis (Case 4). Post-transplant infectious complications included invasive (Cases 2 and 4) and non-invasive (Case 1) fungal infections and bacterial pneumonia (Cases 1 and 2). Two patients (Cases 3 and 4) developed acute cellular rejection (ACR) in the first 30 days. The third patient (Case 1) was identified with ACR in the 9 months post-transplant and chronic lung allograft dysfunction at 29 months. In terms of mortality, 1 patient (Case 1) died at 30 months post-transplant from pseudomonal sepsis and chronic graft failure. Two patients with invasive fungal infections (Cases 2 and 4) are on secondary prophylaxis and doing well. One patient (Case 3) remains infection-free and on MAC prophylaxis.ConclusionsIn our case series, patients with chronic lung diseases with superimposed granulomatous infestations frequently experienced post-transplant complications. These include invasive infections and repeat ACRs that predispose patients to chronic graft dysfunction. Pre- and post-transplant antifungal prophylaxis reduces fungal load and complication risk post-transplant.     

Prophylaxis and treatment for invasive fungal infections in solid organ transplant recipients]

Solid organ transplantation is becoming increasingly common in Japan. Despite invasive fungal infections being less common than bacterial and viral infections, fungal infections still result in a higher mortality rate. Empiric and pre-emptive therapy plays an important role in management of invasive fungal infections, because successful treatment is difficult after a definite diagnosis of an invasive disease, especially invasive aspergillosis. Given this situation, to improve outcome, high risk patients need to be identified and antifungal prophylaxis is mandatory in preventing the development of the disease. However, antifungal prophylaxis for solid organ transplant recipients remains controversial. New antifungal agents might change the choice of fungal prevention and treatment.     

Febrile neutropenia in haematological malignancies

Fever is the principle sign of infection in neutropenic patient and frequently may be the only evidence of infection. The pattern of fever in neutropenia is non-specific and not pathognomonic of any type of infections or non-infectious process and can be suppressed by the antipyretic effects of drugs such as corticosteroids. Neutropenia, resulting from cytotoxic chemotherapy is the most common risk factor for severe infections in hematological malignancies. The duration of neutropenia also contributes significantly to the risk of serious infections. This risk is significantly greater a lower neutrophil counts, such that 100% patients with ANC <100 cells/microl lasting 3 weeks or more develop documented infections. The prompt initiation of empirical antibiotics in febrile neutropenia has been the most important advance in the management of the immunocompromised host. The initial empirical antibiotic regimen started at presentation of the febrile episode frequently requires modifications especially in high-risk febrile neutropenia. Neutropenic patients who remain febrile despite 4-7 days of broad spectrum antibacterial therapy are at a high risk of invasive fungal infection. Empirical antifungal therapy with Amphotericin B in persistently febrile neutropenic patients and other high risk patients has shown to reduce the risk of invasive fungal infection by 50-80% and the risk of fungal infection related mortality by 23-45% in 1980's. The IDSA has recommended that amphotericin B at 0.5-0.7 mg/kg/day be administered till marrow recovery. This approach is limited however by the adverse effects caused by drug infusion (fever, chills, myalgias, nausea, hypotension and bronchospasm). Lipid formulations which improve the therapeutic ratio of the traditional formulation are available. The safety and efficacy of these formulations is well established. These formulations have comparable efficacy and are less nephrotoxic than conventional amphotericin B.A lipid formulation of amphotericin B is appropriate as initial empirical therapy or as definitive therapy for proven mycosis in high risk patients receiving concomitant nephrotoxic drugs (cyclosporine), those with pre-existing renal impairment and those with protracted neutropenia during which dose limiting toxicity may occur.     

Epidemiology of invasive fungal infections in neonates and children

Invasive fungal infections are major causes of morbidity and mortality in neonates and in both immunocompromised and immunocompetent children. Although these infections have been well characterized in adults, the incidence and analysis of risk factors, diagnostic tools, treatments and outcomes have not been well described for large cohorts of paediatric or neonatal patients. Paediatric exclusion has limited our knowledge of the epidemiology and pathophysiology of paediatric fungal disease, and has also resulted in a paucity of data regarding the safety and efficacy of paediatric antifungal therapy. Previous paediatric cooperative models in other disciplines have successfully advanced our understanding and treatments of childhood diseases, but in the past there has not been a similar organization for paediatric invasive fungal infections. Although there are numerous other reviews outlining the differences in paediatric antifungal dosing pharmacokinetics, there are only smaller epidemiological reports depicting the exact distribution and outcomes of paediatric invasive fungal infections treated with these antifungals. This review will highlight some of the available epidemiological data on paediatric invasive fungal infections.     

Risk factors for systemic fungal infections in liver transplant recipients

The risk factors for systemic fungal infections were analysed retrospectively in 186 orthotopic liver transplant procedures performed in 152 patients between June 1985 and January 1993. The total incidence of systemic fungal infections was 16.5 % (25/152). The incidence of disseminated candidiasis, aspergillosis, and combined candidiasis and aspergillosis was 6.5 % (n=10), 7.2 % (n=11) and 2.6 % (n=4), respectively. Mortality associated with systemic fungal infections was 80 % (20 of 25 patients). There were ten cases of disseminated candidiasis, with 4 patients surviving, and 11 cases of invasive aspergillosis, with 1 patient surviving. All patients with combined systemic fungal infection died. To identify perioperative risk factors, 39 variables were used to compare patients with systemic fungal infections versus those without fungal infections. Fourteen variables were significantly associated with systemic fungal infections by univariate analysis. A consecutive logistic regression analysis revealed that the amount of fresh frozen plasma transfused due to poor initial function of the allograft and acute renal failure requiring hemofiltration were independently significant risk factors for systemic fungal infections. There was no statistical correlation between systemic fungal infections and the underlying liver disease, previous long-term corticosteroids and the postoperative immunosuppressive therapy. Risk factors identified in this study should be considered in the postoperative care of the individual liver transplant recipient. In our study a poor initial function of the hepatic allograft substantially increased the risk of systemic fungal infection.     

Human immunodeficiency virus and fungal infections

The discovery of HIV was largely due to the presence of Pneumocystis pneumonia (PCP) in young patients that did not have the usual known causes of immune deficiencies in the early 1980s. Currently, treatment with highly active anti-retroviral therapy (HAART) and the use of prophylaxis for PCP have lowered the frequency of fungal infections; however, these infections continue to cause morbidity and mortality in those patients that fall out or are not in care. The frequency of specific fungal diseases in HIV patients will depend on the prevalence of fungi in the particular geographic location. Nowadays, superficial and invasive Candida infections, PCP, and cryptococci are the most frequent fungal infections seen in HIV positive patients worldwide. The role of pathology in diagnosing fungal infections is crucial because a lesion may be biopsied without obtaining mycology cultures, certain organisms may take several weeks to grow, or the sample sent to the mycology laboratory may not have the organism. Following we will describe fungal infections that are particularly frequent in HIV infected patients and their key pathological features.     

Nosocomial infections in immunocompromised children

Immunocompromised children are at high risk for developing nosocomial infections which may cause significant morbidity and mortality in this population. In paediatric oncology, reported prevalence of nosocomial infections varies from 10 to 20%. Major predisposing factors are neutropenia, central venous catheter, corticosteroid therapy and hospital construction or renovation for invasive aspergillosis. The management of patients with febrile neutropenia should take into account the previous history of infection and the microbiologic environment of each department. Nowadays, Gram positives infections are predominant, but fungal infections remain a major threat. In organ transplant recipients, wound infections are the main early problems, followed by viral infections often due to the donor CMV seropositivity. In HIV-infected children, nosocomial infections are difficult to define, and can implicate unusual pathogens. In general, adapted preventive infection control strategy warrants prospective studies.     

Mycosis in kidney transplant patients]

Kidney transplantation therapy can be divided into two periods: the induction periods during which immunosuppressants are aggressively administered, and the maintenance periods during which treatment is continued at a maintenance dosage. During the induction periods, which usually lasts for several months after surgery, the host defense mechanism in the patient is so profoundly impaired that major infections, including deep-seated mycosis, occur in most cases. The incidence of mycosis as a result of superinfection was quite high in the l960s and l970s, when steroids and antimetabolites were the mainstay immunosuppressants, and antibacterial agents were used without any specific purpose for fear of post-transplantation infections. The new calcineurin inhibitor ciclosporin was developed around 1980 and has since become the primary immunosuppressant used to prevent graft dysfunction after transplantation. As a result of its advent, use of steroids and antimetabolites has declined. Later studies have shown that ciclosporin selectively inhibits lymphocytes and provides more information on the pattern of bacterial infections after transplantation, making it possible to optimize the use of antibacterial agents. As a result, the incidence of bacterial infections and mycosis has dramatically declined. Candida and Aspergillus are most frequently detected in post-transplantation mycosis. But Cryptococcus is also occasionally seen. Antifungal agents such as flucytosine (5-FC) and ketoconazole are effective for deep-seated mycosis such as pulmonary infections which, occurring at a relatively early stage after transplantation, threaten a patients life. However, the coadministration of ketoconazole must be carefully done because it increases blood concentrations of calcineurin inhibitors such as ciclosporin and tacrolimus by inhibiting the production of cytochrome P-450. Amphotericin B, which is effective but is associated with nephrotoxicity, is usually used in a mouthwash or inhalation therapy. Dermatomycosis such as tinea versicolor due to fragility of the skin structure is not necessarily rare even in patients with a quasi-normal host defense mechanism and good renal function at a late stage in the maintenance phase. This paper outlines change in post-transplantation mycosis in recent years and presents some case reports.     

Fungal infections in solid organ transplantation.

Fungal infections in solid organ transplant recipients continue to be a significant cause of morbidity and mortality. Candida spp. and Aspergillus spp. account for most invasive fungal infections. The incidence of fungal infection varies with type of solid organ transplant. Liver transplant recipients have highest reported incidence of candida infections while lung transplant recipients have highest rate of Aspergillus infections. Recent epidemiological studies suggest the emergence of resistant strains of candida as well as mycelial fungi other than Aspergillus in these patients. The current review incorporates the recent changes in the epidemiology of fungal infections in solid organ transplant recipients and highlights the newer data on the diagnosis, prophylaxis and treatment of fungal infections in these patients.     

Fungus-associated asthma: overcoming challenges in diagnosis and treatment

With regard to fungal colonization and fungal sensitization, the goals of fungus-associated asthma management are as follows: 1) to survey fungi colonizing the airways of patients repeatedly; 2) to evaluate the tendency of the colonizing fungi to sensitize patients and the influence on clinical manifestations of asthma; 3) to follow disease development to allergic bronchopulmonary mycosis or sinobronchial allergic mycosis; and 4) to determine whether fungal eradication from the airway of patients is beneficial from the viewpoints of future risk factors. Recent developments in molecular biological analyses have facilitated the identification of basidiomycetous fungi that were not previously thought to be of concern in fungal allergy. The total control of fungus-associated asthma will be accomplished by environmental management established from the viewpoint of both the ecology and life cycle of the responsible fungi.     

Fungal infections in the immunocompromised host

Invasive fungal infections cause significant morbidity and mortality in patients with impaired immune defences. Defects in neutrophil function and neutropenia predispose to disseminated Candida, Aspergillus and Mucoraceae infections while altered T-lymphocyte mononuclear phagocyte function predisposes to infection with C. neoformans, Histoplasma and Coccidioides. Fungal infections in the immunocompromised host are difficult to diagnose and difficult to treat successfully. The diagnosis is often missed or delayed because of the non-specific clinical features, the failure to isolate or difficulty in interpreting the presence of the fungus from routine microbiological cultures, and the limited usefulness of available serological tests. The assay for cryptococcal antigen is the only currently available reliable serological test used to diagnose an invasive fungal infection. Definitive diagnosis is made by histopathological demonstration of the fungus in tissue or a positive culture from a sterile body site. Invasive procedures are often necessary to obtain adequate tissue for histology and culture. The treatment of invasive fungal infection in the immunocompromised host is amphotericin B with or without 5FC. The usual recommended dose is 1.5 to 3 g total amphotericin B over 6 to 12 weeks. The optimal dose and duration of therapy for each infection is not known. Treatment failures and relapses are common in patients who do not achieve remission of their underlying disease. Ketoconazole, a new broad-spectrum oral antifungal medication, does not appear to be effective therapy for invasive fungal infection in the immunocompromised patient based on results of small clinical trials. New diagnostic methods and therapeutic approaches are necessary to improve the outcome of these infections. Areas of current research include serological assays for fungal antigens and metabolites which may allow earlier diagnosis, treatment with combinations of antifungal agents, and the development of new antifungal agents.     

Rhino-cerebral zygomycosis after allogeneic transplant: case report and literature review

The proportion of patients with hematological malignancies (HM) who develop rare invasive fungal infections (IFI) has increased worldwide over the past few decades. Zygomycosis is an opportunistic fungal infection, which begins in the nose and paranasal sinuses due to inhalation of fungal spores. Rhino-cerebral zygomycosis is the most common form of the disease, it typically develops in diabetic or immunocompromised patients and presents as an acute fulminate infection, which is often lethal. We report a case of rhino-cerebral zygomycosis in an allotransplanted patient to emphasize early diagnosis and treatment of this potentially fatal fungal infection. We discuss different risk factors, specific diagnosis procedures and review the current concepts in management of zygomycosis.     

The interplay between inflammasome activation and antifungal host defense

Fungal infections cause significant morbidity and mortality in humans, and they are a growing problem due to the increased usage of broad-spectrum antibiotics and immunosuppressive therapies. The equilibrium between the commensal microbial flora and the immune system that protects the host against invasive fungal infection is disturbed during disease, and understanding this disturbed balance is important to develop new therapeutic interventions for the treatment of fungal infection. In the context of tolerating fungi during colonization and eliciting a vigorous immune response to eliminate invading fungal pathogens when needed, the inflammasome has been identified as an integral component of antifungal host defense. It contributes to mucosal host defense by regulating T-helper 17 (Th17) cell responses, and contributes to protective responses such as neutrophil influx during fungal sepsis. Several aspects are important for understanding the role of the inflammasome for antifungal host defense, such as the role of fungal cell wall morphology and its components in triggering the inflammasome, the pattern recognition pathways and downstream signaling cascades involved in the activation of the inflammasome, and the effects of inflammasome activation during fungal infection. The future perspectives of inflammasome research in fungal immunology, with emphasis on targeting the inflammasome for the design of future immunotherapies, is also discussed.     

The changing face of mycoses in patients with HIV/AIDS

The current era of effective antiretroviral therapy has led to a marked reduction in opportunistic infections (OIs) in those countries where such therapies are available. Opportunistic fungal infections are no exception, and the incidence of such infections is now 20% to 25% of that seen in the mid-1990s. Infections associated with very advanced HIV disease, such as azole-resistant candidiasis and aspergillosis, are also rarely seen, reflecting the improvement in immune function. Indeed, the most common issue now is whether patients who have had a systemic mycosis require life-long therapy as had been recommended. Preliminary data from small studies suggest that as with other OIs, it may be possible to stop suppressive therapy in patients with a history of mycosis whose CD4+ lymphocyte count rises with antiretroviral therapy. Thus, it appears that the future of HIV-associated mycoses is linked to the future of effective treatment for HIV itself.     

Infections fongiques invasives du grand prématuré

Fungal infections were frequent in premature baby (<1500 g) and were associated with significant morbidity and mortality. In this paper we review the risk factors for invasive fungal infections and clinical settings. A better understanding of the mechanism of fungal infection in preterm infants is important in treatment and prevention. The early neonatal intensive care unit course favours colonization and proliferation of fungi since many preterm infants have central catheters and are exposed to broad spectrum antibiotics and parenteral nutrition. The majority of fungal infections in preterm neonates are due to Candida, with a small number due to other yeasts such as Malassezia. Candida is an opportunistic pathogen, which adheres to the skin, mucosal, and catheter surface. C. albicans account for 50% of cases of fungal sepsis. C. parapsilosis is the second most prevalent species in very low birth weight children; its frequency increased from 1995 to 2000. Risk factors for fungal colonization are: very low birth weight, exposure to broad spectrum antibiotics, parenteral nutrition and use of corticosteroids. Colonization of the skin, gastro-intestinal tract and respiratory tract and central vascular catheter precede infection. The majority of preterm infants with fungal infections develop thrombocytopenia, but this is a common feature shared with other sepsis. The evaluation of infants with fungal sepsis should include cerebrospinal fluid examination and culture of urine with surveillance for endocarditis, renal, liver and brain abscesses and endophthalmitis. The mortality rate can reach 30%, and is higher in very low birth weight infants.     

Triple fungal infection in a patient with liver cirrhosis

The prevalence of invasive mycoses is increasing, especially among patients who are immunocompromised or hospitalized with serious underlying diseases. Such infections are associated with a high morbidity and significant mortality, requiring early diagnosis and appropriate treatment but also an optimal prophylaxis in patients with high risk factors. We report a case of triple fungal infection including an invasive pulmonary aspergillosis by Aspergillus fumigatus, a candidemia by Candida albicans and a Pneumocystis pneumonia. The overall clinical picture of this patient was liver cirrhosis with medical history of immunosuppressive treatment for Crohn disease and a non-hodgkin lymphoma. There was no antifungal prophylaxis for this patient. Under treatment, the issue was unfavourable with multivisceral failure.     

Aspergillus thyroiditis: a review of the literature to highlight clinical challenges

Aspergillus involvement of the thyroid is the most commonly reported fungal thyroiditis. Aspergillus thyroiditis (AT) has primarily been a postmortem diagnosis in immunocompromised patients with diagnosed disseminated invasive Aspergillus or high suspicion of fungal infection during life. With better treatment modalities for the comorbidities that place patients at high risk for fungal infections, as well as better antifungal therapies for Aspergillus infections specifically, the spectrum of disease and presentation of AT may be shifting from what was primarily a postmortem finding to an antemortem diagnosis, necessitating a high index of clinical suspicion and timely intervention. We present a review of the literature to better clarify clinical features, diagnostic modalities, and management considerations pertaining to this disease.     

Guidelines for the management of deep mycosis in neutropenic patients]

Invasive fungal infections (IFIs) are a major cause of morbidity and mortality in neutropenic patients with leukemia and those undergoing hematopoietic stem cell transplant (HSCT). Two major IFIs are systemic candidiasis (including candidemia, chronic disseminated candidiasis and pneumonia) and invasive pulmonary aspergillosis. Recently, the incidence of the latter has been increasing. Three levels of diagnosis are specified in the Japanese guidelines for the diagnosis and treatment of IFIs. Proven fungal infections are diagnosed by histological/microbiological evidence of fungi at the site of infection or positive blood culture (fungemia). Clinically documented fungal infections are diagnosed by typical radiological findings such as halo sign on chest CT plus positive serological/molecular evidence of fungi such as Aspergillus galactomannan, beta-glucan or fungal DNA. Possible fungal infections are diagnosed by typical radiological findings or positive serological/molecular evidence of fungi. For patients with high risk such as those undergoing HSCT, antifungal prophylaxis using oral antifungal agents is recommended. For possible fungal infections, empiric therapy with fluconazole (FLCZ) or amphotericin B (AMPH) is recommended. For patients with proven fungal infections or clinically documented fungal infections, targeted therapy is warranted. In case of candidemia, the best choice is FLCZ (400 mg/day) or AMPH (0.5-0.7 mg/kg/day), and for invasive pulmonary aspergillosis, a higher dose of AMPH (1.0-1.5 mg/kg/day) is indicated. Micafungin (MCFG), recently licensed in Japan, is an active agent for both Candida and Aspergillus. This drug seems useful for empiric and targeted therapy of IFIs.     

Invasive fungal infections: evolving challenges for diagnosis and therapeutics

Invasive fungal infections (IFI) parallel the explosive increase in the immunocompromized patient population, and are characterized by diagnostic difficulties and extreme mortality. Candidemia in a tertiary referral hospital in the Middle East confirms the current epidemiologic shift in this common blood stream pathogen towards non-malignancy cases (38%) and antifungal prophylaxis failure (20%), high presentation sepsis scores and attributable mortality (32%). Invasive aspergillosis (IA) is also associated with high mortality. Use of non-invasive computerized tomographic (CT) radiologic scanning linked to early administration of high dose liposomal amphotericin B (LAB) is associated with a reduced mortality of 9.5% compared to historical experience of 28%.Life threatening invasive aspergillosis also occurs in patients who are less obviously immunocompromized. Investigations may reveal subtle immune deficits which could place the patient at some risk for an invasive mycosis. Antifungal treatment used in combination with progenitor cell growth factors and gamma-interferon has proved successful in such situations of progressive fungal disease unresponsive to antifungal therapy alone.Pharmacologic remodeling of existing compounds by lipidisation reduces both the toxicity denominator and the efficacy numerator of the therapeutic index when compared to the parent drug. A comparative dose study of liposomal amphotericin B in aspergillosis has demonstrated equi-efficacy, generated debate over the ability of the controlled clinical trial to be capable of assessing antifungal efficacy, and illustrated that recovery from an invasive fungal infection may require maximum tolerated doses and immunomanipulation.Several new antifungal strategies are under clinical investigation. These include reformulating existing antifungals, exploitation of the growing knowledge of virulence factors to synthesize antagonists, immune reconstitution and immunoprotection. An interim analysis of an ongoing placebo controlled study of recombinant interleukin-11 to assess its efficacy in reducing sepsis in leukemia patients through prevention of chemotherapy induced gut epithelial cell apoptosis, has demonstrated a difference in the two study arms in sepsis rates and preservation of gastrointestinal epithelial cell integrity.The unique and special challenges presented by the dynamic epidemiologics of invasive fungal infections are demanding and attracting considerable responses, in the fields of diagnosis and therapeutics. Current strategies need considerable improvement, yet ongoing collaborative efforts will have a positive impact on our understanding of the fungus-host interaction and ultimately our ability to offer better care for our patients with invasive mycoses.