Inflammatory monocytes are detrimental to the host immune response during acute infection with Cryptococcus neoformans.

Cryptococcus neoformans is a leading cause of invasive fungal infections among immunocompromised patients. However, the cellular constituents of the innate immune response that promote clearance versus progression of infection upon respiratory acquisition of C. neoformans remain poorly defined. In this study, we found that during acute C. neoformans infection, CCR2+ Ly6Chi inflammatory monocytes (IM) rapidly infiltrate the lungs and mediate fungal trafficking to lung-draining lymph nodes. Interestingly, this influx of IM is detrimental to the host, since ablating IM or impairing their recruitment to the lungs improves murine survival and reduces fungal proliferation and dissemination. Using a novel conditional gene deletion strategy, we determined that MHC class II expression by IM did not mediate their deleterious impact on the host. Furthermore, although ablation of IM reduced the number of lymphocytes, innate lymphoid cells, and eosinophils in the lungs, the effects of IM were not dependent on these cells. We ascertained that IM in the lungs upregulated transcripts associated with alternatively activated (M2) macrophages in response to C. neoformans, consistent with the model that IM assume a cellular phenotype that is permissive for fungal growth. We also determined that conditional knockout of the prototypical M2 marker arginase 1 in IM and deletion of the M2-associated transcription factor STAT6 were not sufficient to reverse the harmful effects of IM. Overall, our findings indicate that C. neoformans can subvert the fungicidal potential of IM to enable the progression of infection through a mechanism that is not dependent on lymphocyte priming, eosinophil recruitment, or downstream M2 macrophage polarization pathways. These results give us new insight into the plasticity of IM function during fungal infections and the level of control that C. neoformans can exert on host immune responses.

Clinical impact of advanced chronic kidney disease in patients with non-HIV pulmonary cryptococcosis.

BACKGROUND: Pulmonary cryptococcosis is an uncommon infectious disease that can develop in both immunocompromised and immunocompetent patients. The severity of chronic kidney disease (CKD) was reported to be one of the risk factors for pulmonary cryptococcosis, but its clinical characteristics have not been fully assessed. The purpose of this study was to clarify the clinical characteristics of advanced CKD in patients with pulmonary cryptococcosis. METHODS: The present study retrospectively investigated 56 patients who had non-human immunodeficiency virus (HIV) pulmonary cryptococcosis and were treated at Saga University Hospital between 2005 and 2018. The clinical characteristics were evaluated and compared between patients with estimated glomerular filtration rate (eGFR) > 45 mL/min/1.73 m2 (n = 42, early CKD) and those with eGFR < 45 mL/min/1.73 m2 (n = 14, advanced CKD. RESULTS: Compared with patients with early CKD, those with advanced CKD had significantly higher rate of disseminated cryptococcosis (21.4% vs. 2.4%, p = 0.03); lower percentage of patients who recovered after treatment (63.6% vs. 92.5%, p = 0.02); and more frequent clinical features of fever (57.1% vs. 19.0%, p < 0.01), pleural effusion (21.4% vs. 2.4%, p = 0.03), high white blood cell count (8550/mL vs. 6150/mL, p = 0.01) and C-reactive protein (CRP) (2.1 mg/dL vs. 0.2 mg/dL, p = 0.02), and low level of serum albumin (3.0 g/dL vs. 3.8 g/dL, p < 0.01). Multivariate analysis adjusted by immunosuppressive drug use indicated the significant factors of fever (odds ratio or ß value [95% confidence interval] 6.4 [1.65-20.09], p < 0.01), high white blood cell count (1293.2 [110.2-2476.2], p = 0.03), C-reactive protein (0.89 [0.18-1.59], p = 0.01) and low level of serum albumin (- 0.34 [- 0.54 - - 0.14], p < 0.01) in patients with eGFR < 45 mL/min/1.73m2. CONCLUSION: Advanced CKD was associated with poor clinical characteristics and outcomes in patients with non-HIV pulmonary cryptococcosis. TRIAL REGISTRATION: The patients in this study were registered retrospectively.

Characteristics of patients with mild to moderate primary pulmonary coccidioidomycosis.

In Arizona, USA, primary pulmonary coccidioidomycosis accounts for 15%-29% of community-acquired pneumonia. To determine the evolution of symptoms and changes in laboratory values for patients with mild to moderate coccidioidomycosis during 2010-2012, we conducted a prospective 24-week study of patients with primary pulmonary coccidioidomycosis. Of the 36 patients, 16 (44%) were men and 33 (92%) were White. Median age was 53 years, and 20 (56%) had received antifungal treatment at baseline. Symptom scores were higher for patients who received treatment than for those who did not. Median times from symptom onset to 50% reduction and to complete resolution for patients in treatment and nontreatment groups were 9.9 and 9.1 weeks, and 18.7 and 17.8 weeks, respectively. Median times to full return to work were 8.4 and 5.7 weeks, respectively. One patient who received treatment experienced disseminated infection. For otherwise healthy adults with acute coccidioidomycosis, convalescence was prolonged, regardless of whether they received antifungal treatment.

Clinical case of the month: a 22-year-old man with AIDS presenting with shortness of breath and an oral lesion.

Since the development of combination antiretroviral therapy (cART), the incidence and mortality associated with Kaposi sarcoma (KS) have been reduced, although not eliminated. Clinical presentations of KS range from simple skin involvement to disseminated disease, including involvement of the oral cavity and viscera, which portends a more ominous prognosis. Multiple case reports and data from clinical trials indicate that administration of systemic corticosteroids may aggravate KS. We present a case of disseminated KS following administration of prednisone for presumed immune reconstitution inflammatory syndrome (IRIS) associated with fungal pneumonia in an HIV-infected individual. The discussion that follows outlines the pathophysiology and clinical presentations associated with KS and existing data for the role of corticosteroids in promoting KS progression.

Stroke-associated pneumonia: major advances and obstacles.

BACKGROUND: Stroke-associated pneumonia (SAP) has been implicated in the morbidity, mortality and increased medical cost after acute ischemic stroke. The annual cost of SAP during hospitalization in the United States approaches USD 459 million. The incidence and prognosis of SAP among intensive care unit (ICU) patients have not been thoroughly investigated. We reviewed the pathophysiology, microbiology, incidence, risk factors, outcomes and prophylaxis of SAP with special attention to ICU studies. METHODS: To determine the incidence, risk factors and prognosis of acute SAP, PubMed was searched using the terms 'pneumonia' AND 'neurology intensive unit' and the MeSH terms 'stroke' AND 'pneumonia'. Non-English literature, case reports and chronic SAP studies were excluded. Studies were classified into 5 categories according to the setting they were performed in: neurological intensive care units (NICUs), medical intensive care units (MICUs), stroke units, mixed studies combining more than one setting or when the settings were not specified and rehabilitation studies. RESULTS: The incidences of SAP in the following settings were: NICUs 4.1-56.6%, MICUs 17-50%, stroke units 3.9-44%, mixed studies 3.9-23.8% and rehabilitation 3.2-11%. The majority of NICU and MICU studies were heterogeneous including different neurovascular diseases, which partly explains the wide range of SAP incidence. The higher incidence in the majority of ICU studies compared to stroke units or acute floor studies is likely explained by the presence of mechanical ventilation, higher stroke severity causing higher rates of aspiration and stroke-induced immunodepression among ICU patients. The short-term mortality of SAP was increased among the mixed and stroke unit studies ranging between 10.1 and 37.3%. SAP was associated with worse functional outcome in the majority of stroke unit and floor studies. Mortality was less consistent among NICU and MICU studies. This difference could be due to the heterogeneity of ICU studies and the effect of small sample size or other independent risk factors for mortality such as the larger neurological deficit, mechanical ventilation, and age, which may simultaneously increase the risk of SAP and mortality confounding the outcomes of SAP itself. The pathophysiology of SAP is likely explained by aspiration combined with stroke-induced immunodepression through complex humeral and neural pathways that include the hypothalamic-pituitary-adrenal axis, parasympathetic and sympathetic systems. CONCLUSIONS: A unified definition of SAP, strict inclusion criteria, and the presence of a long-term follow-up need to be applied to the future prospective studies to better identify the incidence and prognosis of SAP, especially among ICU patients.

Pneumocystis elicits a STAT6-dependent, strain-specific innate immune response and airway hyperresponsiveness.

It is widely held that exposure to pathogens such as fungi can be an agent of comorbidity, such as exacerbation of asthma or chronic obstructive pulmonary disease. Although many studies have examined allergic responses to fungi and their effects on pulmonary function, the possible pathologic implications of the early innate responses to fungal pathogens have not been explored. We examined early responses to the atypical fungus Pneumocystis in two common strains of mice in terms of overall immunological response and related pathology, such as cell damage and airway hyperresponsiveness (AHR). We found a strong strain-specific response in BALB/c mice that included recruitment of neutrophils, NK, NKT, and CD4 T cells. This response was accompanied by elevated indicators of lung damage (bronchoalveolar lavage fluid albumin and LDH) and profound AHR. This early response was absent in C57BL/6 mice, although both strains exhibited a later response associated with the clearance of Pneumocystis. We found that this AHR could not be attributed exclusively to the presence of recruited neutrophils, NKT, NK, or CD4 cells or to the actions of IFN-γ or IL-4. However, in the absence of STAT6 signaling, AHR and inflammatory cell recruitment were virtually absent. Gene expression analysis indicated that this early response included activation of several transcription factors that could be involved in pulmonary remodeling. These results show that exposure to a fungus such as Pneumocystis can elicit pulmonary responses that may contribute to morbidity, even without prior sensitization, in the context of certain genetic backgrounds.

Pulmonary mucormycosis.

Mucormycosis (formerly zygomycosis) is a life-threatening opportunistic mycosis that infects a broad range of hosts with qualitative or quantitative defects in innate immunity, including patients with severe neutropenia, recipients of corticosteroids or other immunosuppressive medications, poorly controlled diabetes mellitus, and those with iron overload states. Mucormycosis has recently emerged as breakthrough sinopulmonary infection in hematologic patients and recipients of transplantation being on antifungal prophylaxis with Aspergillus-active antifungals that lack activity against Mucorales. Unlike pulmonary aspergillosis, the prognosis and outcome of pulmonary mucormycosis have not improved significantly over the last decade, mainly because of difficulties in early diagnosis and the limited activity of current antifungal agents against Mucorales. Recent evidence suggests a critical role for iron metabolism and fungal-endothelial cell interactions in pathogenesis of mucormycosis, and holds promise for development of novel therapeutic strategies. Currently, prompt initiation of antifungal therapy with a lipid amphotericin B-based regimen, reversal of underlying host factors, and aggressive surgical approach offers the best chances for survival of patients infected with this devastating mycosis.

Pulmonary cryptococcosis.

Cryptococcosis is an invasive fungal infection (IFI), caused predominantly by Cryptococcus neoformans or Cryptococcus gattii, that affects both immunocompromised (IC) and non-IC patients. Although the most serious disease manifestation is meningoencephalitis, cryptococcal pneumonia is underdiagnosed and may disseminate to the central nervous system (CNS) and other sites depending upon host defenses and administration of appropriate antifungal therapy. The clinical presentation of pulmonary cryptococcosis varies along a spectrum from asymptomatic infection to severe pneumonia and respiratory failure, and the radiological presentation can be characterized by an array of findings, including nodules, consolidation, cavitary lesions, and a diffuse interstitial pattern. Diagnosis most often relies upon isolation of Cryptococcus from a pulmonary specimen in the appropriate clinical and radiological context. Treatment recommendations include induction therapy with an amphotericin B preparation and flucytosine for IC patients and those with severe disease and fluconazole for mild-to-moderate, localized disease. Knowledge of the pathophysiology, epidemiology, clinical presentation, and treatment of pulmonary cryptococcosis may lead to greater recognition of this underdiagnosed IFI and improved outcomes.

Pulmonary histoplasmosis.

Pulmonary histoplasmosis is an important cause of morbidity in the United States. Several outbreaks of acute pulmonary histoplasmosis have been linked to potentially preventable environmental exposures. Progressive disseminated histoplasmosis, which is seen frequently in the growing population of immunocompromised hosts, often presents with prominent pulmonary manifestations and is more commonly encountered in hospitalized patients than acute, subacute, or chronic pulmonary histoplasmosis. A battery of diagnostic studies including serology, antigen, cytology/histopathology, and culture should be obtained in suspected cases of histoplasmosis. The yield of antigenuria detection is highest when the multiple body fluids are tested; the level of antigenuria correlates with severity of disease. Amphotericin B is the treatment of choice for severe pulmonary or disseminated histoplasmosis, and itraconazole is effective for mild to moderately severe infection. Posaconazole exhibits promise as a salvage agent. Antifungal prophylaxis is not routinely recommended for at-risk populations. Measures to minimize environmental contamination may reduce the risk of epidemic-type acute pulmonary histoplasmosis related to high-risk exposures.

Pulmonary blastomycosis.

Blastomyces dermatitidis is acquired in almost all cases via inhalation, and pulmonary disease is the most frequent clinical manifestation of blastomycosis. Pulmonary disease can range from asymptomatic infection to rapidly severe and fatal disease. Most cases will present as pneumonia, either acute or chronic, or as a lung mass. In rare cases pulmonary blastomycosis is associated with the acute respiratory distress syndrome. Blastomycosis can present as isolated pulmonary disease or along with coexisting extrapulmonary disease that usually will involve the skin, bony structures, genitourinary tract, or central nervous system. Diagnosis is largely based on isolation of the organism via culture or visualization of the organism in clinical specimens. Detection of urinary Blastomyces antigen is a recent addition to diagnostic options. Itraconazole is the drug of choice for most forms of the disease; amphotericin B is reserved for the more severe forms. Newer azoles such as voriconazole and posaconazole have a limited role in the treatment of pulmonary blastomycosis.

Pulmonary coccidioidomycosis.

Coccidioidomycosis refers to the spectrum of disease caused by the dimorphic fungi Coccidioides immitis and Coccidioides posadasii. Clinical manifestations vary depending upon both the extent of infection and the immune status of the host. Coccidioidomycosis has been reported to involve almost all organ systems; however, pulmonary disease is the most common clinical manifestation. The incidence of coccidioidomycosis continues to rise, and primary coccidioidal pneumonia accounts for 17 to 29% of all cases of community-acquired pneumonia in endemic regions. The majority of patients with coccidioidomycosis resolve their initial infection without sequelae; however, several patients develop complications of disease ranging in severity from complicated pulmonary coccidioidomycosis to widely disseminated disease with immediately life-threatening manifestations. This review focuses on complications of pulmonary coccidioidomycosis with an emphasis on the management of primary coccidioidal infection, solitary pulmonary nodules, pleural effusions, cavitary disease, acute respiratory distress syndrome (ARDS), miliary disease, and sepsis.

Pulmonary paracoccidioidomycosis.

Paracoccidioidomycosis is a subacute or chronic systemic mycosis caused by Paracoccidioides brasiliensis, a soil saprophyte and thermally dimorphic fungus. The disease occurs mainly in rural workers in Latin America and is the most frequent endemic systemic mycosis in many countries of South America, where almost 10 million people are believed to be infected. Paracoccidioidomycosis should be regarded as a disease of travelers outside the endemic area. The primary pulmonary infection is subclinical in most cases, and individuals may remain infected throughout life without ever developing clinical signs. A small proportion of patients present with clinical disease. The lungs are frequently involved, and the pulmonary clinical manifestations must be differentiated from many other infectious and noninfectious conditions. Diagnosis should be based on epidemiological, clinical, and microbiological data. Effective treatment regimens are available to control the fungal infection, but most patients develop fibrotic sequelae that may severely hamper respiratory and adrenal function and the patient's well-being.

Pneumonia and lung infections due to emerging and unusual fungal pathogens.

Invasive mold infections affecting the lungs are increasing in incidence and diversity. Severely immunocompromised patients are particularly vulnerable to infection from unusual, normally nonpathogenic fungi that are found naturally in the environment. Certain fungi such as Scedosporium and the dematiaceous fungi also cause lung disease in hosts without overt immune compromise. The impacts of these emerging pathogens range from airway colonization to locally invasive lung, and disseminated, disease. Diagnosis requires isolation and identification of the etiologic agent by either or both phenotypic and molecular biology methods. Evidence of tissue invasion on histopathology is often required to distinguish infection from colonization. Diagnostic imaging techniques are nonspecific, and there are no reliable serological biomarkers of infection. Many rare molds and yeasts demonstrate reduced in vitro susceptibility to antifungal agents. Although amphotericin B formulations remain clinically useful for many of these infections, voriconazole and posaconazole are more effective for some of these difficult-to-treat pathogens. Surgical resection of diseased tissue and support of the host immune system are often required to optimize outcomes.

Clinician integrity and limits to patient autonomy.

A 28-year-old man with chronic granulomatous disease developed worsening respiratory status in the setting of chronic bacterial and fungal infections. The attending physician recommended transfer to the intensive care unit (ICU), but the patient declined. The patient understood that the nurses in the ICU have expertise in caring for patients with poor respiratory function. He also understood that he faced an increased risk of dying if he remained on the medical ward. At the same time, the patient was familiar with the nurses on the medical ward and felt comfortable there. Unsure of whether it was appropriate for clinicians to agree to provide less than optimal care for a critically ill patient, the clinicians on the medical ward requested a bioethics consultation. This article reviews the ethical issues that arise when patients ask clinicians to provide less than optimal care. Although it is well established that clinicians ought to respect patient autonomy, that obligation conflicted, in the present case, with the clinicians' sense of professional integrity. Future research on this vital but underexplored topic is needed to determine the extent to which clinicians' professional integrity places limits on the types of patient requests to which they should agree.

Characteristics and consequences of airway colonization by filamentous fungi in 201 adult patients with cystic fibrosis in France.

A total of 657 sputum samples from 201 cystic fibrosis adult patients were collected during a 24-month period (2005-2006). We retrospectively analyzed the fungal colonization of the respiratory tract of these individuals by linking medical records and microbiological data. Filamentous fungi were isolated from specimens of 65.6% of the patients, with Aspergillus fumigatus being the predominant species recovered as it was found in specimens of 56.7% of the patients. We observed no difference for gender, pancreatic status and cirrhosis in patients with or without A. fumigatus colonization. We found a higher percentage of recovery of Pseudomonas aeruginosa, Stenotrophomonas maltophilia and nontuberculous mycobacteria in patients with A. fumigatus colonization. During the follow-up period of the study, 8.9% of the patients were diagnosed with allergic bronchopulmonary aspergillosis (ABPA). By a multivariate analysis we demonstrated that Scedosporium apiospermum was significantly associated with ABPA (Odds ratio = 13 [2-80]) as opposed to A. fumigatus (Odds ratio = 1.58 [0.49-5.05]).

Clinical associations and prevalence of Scedosporium spp. in Australian cystic fibrosis patients: identification of novel risk factors?

Risk factors for the association of Scedosporium in cases of cystic fibrosis (CF) and its clinical implications are poorly understood. Clinical, lung function and laboratory data of adult CF patients in Sydney (April 2008-March 2009) were prospectively analysed for such risk factors. Expectorated sputa were cultured for bacteria and examined for fungi using standard mycological and Scedosporium-selective media, and by an internal transcribed spacer region-targeted multiplex PCR assay. Scedosporium spp. (n = 4 each of Scedosporium prolificans, Scedosporium aurantiacum and Pseudallescheria boydii/ Scedosporium apiospermum complex [non-S. aurantiacum]) were recovered from 12 of 69 (17.4%) patients. Samples of 11 of the patients yielded isolates on Scedosporium- selective media (vs. 6 [8.7%] by non-selective culture) and one additional patient was noted by PCR. Of these patients, 83.3% were co-colonized with other moulds, most frequently Aspergillus fumigatus. Colonization was not associated with best FEV1/predicted, corticosteroid or antifungal therapies. By univariate analysis, patients with Scedosporium colonization were significantly less likely to be colonized with mucoid Pseudomonas aeruginosa (P = 0.025), while prior therapy with antistaphylococcal penicillins was a risk factor for colonization (P = 0.045). Bacterial colonization and antimicrobial exposure likely influence Scedosporium colonization, which is optimally detected with selective media. Studies are required to confirm independent risk factors for Scedosporium colonization and to determine its impact on lung disease.

Molecular diagnosis of disseminated adiaspiromycosis due to Emmonsia crescens.

Emmonsia crescens is a saprophytic fungus that is distributed worldwide, causing diseases mostly in rodents. It has also been described, though rarely, as an etiologic agent of pulmonary pathology in humans, potentially leading to death. A case of pulmonary adiaspiromycosis is reported in a 30-year-old immunocompetent man. The patient presented with a history of several weeks of weakness, cough, fever, and weight loss of 10 kg. Clinical and radiographic findings showed pulmonary lesions consistent with tuberculosis or histoplasmosis, but no pathogen was found with classical microbiological procedures. The diagnosis of adiaspiromycosis due to Emmonsia crescens was initially made using molecular biology techniques. Histological observations subsequently confirmed the presence of adiaspores in granulomas. To our knowledge, this is the first case of adiaspiromycosis diagnosed by PCR and sequencing. The patient was treated with itraconazole and was seen at 1 month with symptomatic improvement. Here we will discuss this rare fungal infection and its difficult treatment and diagnosis. As represented in this case, molecular biology is a powerful method to optimize diagnostic tests and therefore improve the care of the infected patient.

Effects of a DNA vaccine in an animal model of Alternaria alternata sensitivity.

Sensitivity to the fungus Alternaria is associated with asthma persistence and severity. Current therapeutic options for treating Alternaria-induced airway inflammation are limited. In this study, Brown Norway rats are used to study the effectiveness of a DNA-based vaccine delivered to the airway in attenuating the response to a major Alternaria allergen, rAlt a 2. Compared to untreated sensitized animals, or animals receiving an "out-of-frame" DNA-based vaccine, animals treated with "in-frame" DNA vaccine showed an attenuation in specific IgE antibody titers to rAlt a 2, an increase in IgG(2b) (a Th1 response), a reduction in spontaneous IL-13 release by peribronchial lymph node cell suspensions, and an attenuation in the decrease in total lung capacity 72 h post-allergen challenge. Further, histopathologic examination of the lung tissues revealed reduced pulmonary inflammation post-allergen challenge in the DNA-vaccine-treated compared to sensitized, untreated animals. We conclude that a DNA-based vaccine delivered to the airway significantly influences the immunologic, pulmonary physiologic, and histological alterations induced by challenge with a major Alternaria allergen, rAlt a 2, in sensitized animals.

Neurobehavioral and pulmonary impairment in 105 adults with indoor exposure to molds compared to 100 exposed to chemicals.

Patients exposed at home to molds and mycotoxins and those exposed to chemicals (CE) have many similar symptoms of eye, nose, and throat irritation and poor memory, concentration, and other neurobehavioral dysfunctions. To compare the neurobehavioral and pulmonary impairments associated with indoor exposures to mold and to chemicals. 105 consecutive adults exposed to molds (ME) indoors at home and 100 patients exposed to other chemicals were compared to 202 community referents without mold or chemical exposure. To assess brain functions, we measured 26 neurobehavioral functions. Medical and exposure histories, mood states score, and symptoms frequencies were obtained. Vital capacity and flows were measured by spirometry. Groups were compared by analysis of variance (ANOVA) after adjusting for age, educational attainment, and sex, by calculating predicted values (observed/predicted x 100 = % predicted). And p < .05 indicated statistical significance for total abnormalities, and test scores that were outside the confidence limits of the mean of the percentage predicted. People exposed to mold had a total of 6.1 abnormalities and those exposed to chemicals had 7.1 compared to 1.2 abnormalities in referents. Compared to referents, the exposed groups had balance decreased, longer reaction times, and blink reflex latentcies lengthened. Also, color discrimination errors were increased and visual field performances and grip strengths were reduced. The cognitive and memory performance measures were abnormal in both exposed groups. Culture Fair scores, digit symbol substitution, immediate and delayed verbal recall, picture completion, and information were reduced. Times for peg-placement and trail making A and B were increased. One difference was that chemically exposed patients had excess fingertip number writing errors, but the mold-exposed did not. Mood State scores and symptom frequencies were greater in both exposed groups than in referents. Vital capacities were reduced in both groups. Neurobehavioral and pulmonary impairments associated with exposures to indoor molds and mycotoxins were not different from those with various chemical exposures.