Fungal-associated pneumonia in patients with hematological malignancies.

PURPOSE: Patients with hematologic malignancies (HM) are at high risk of invasive lung fungal infections (ILFI). To describe the main characteristics, treatment, and outcomes for five years in adult patients with HM and fungal pneumonia. METHODS: We conducted a retrospective study at Instituto Nacional de Cancerología (INCan), a referral tertiary care oncology hospital with 135 beds in Mexico City, Mexico. We included all cases of fungal pneumonia in patients with HM from January 1, 2017, to December 31, 2022. Cases were classified as proven, probable, and possible according to EORTC/MSG criteria 2021. RESULTS: Two hundred ten patients were included; the mean age was 40 years. The most frequent HM was acute lymphoblastic leukemia (n = 74) and acute myeloid leukemia (n = 68). One hundred forty patients (66.7%) had severe neutropenia for a median of 16 days. All patients had a CT thorax scan; in 132 (62.9%), multiple nodules were documented. Serum galactomannan (GM) was positive in 21/192 (10.9%) and bronchoalveolar lavage in 9/36 (25%). Fifty-three patients (25.2%) died in the first month. In the multivariate analysis for mortality in the first 30 days, hypoalbuminemia, shock, possible ILFI, and inappropriate antifungal treatment were statistically associated. CONCLUSIONS: In high-risk HM patients, CT thorax scan and GM help diagnose ILFI. An appropriate antifungal improves mortality.

Infecciones fúngicas en pacientes con COVID-19 / Fungal infections in patients with COVID-19

En diciembre de 2019 se identificó en Wuhan, China, un nuevo coronavirus denominado SARS-CoV-2, agente causal de la epidemia de neumonía atípica COVID-2019, que el 11 de marzo de 2020 fue declarada pandemia por la OMS.Hasta el 30 de septiembre de 2020, en Argentina fueron confirmados 751.001 casos y más de 16.937 muertes.La frecuencia y el impacto de las coinfecciones que afectan a los pacientes infectados por SARS-Cov-2 se ha estudiado junto con el avance de la pandemia. Entre las debidas a hongos se encuentran las fungemias por Candida sp, la aspergilosis invasora, las micosis sistémicas endémicas y la neumocistosis. Presentamos las distintas coinfecciones micosis-COVID-19 que fueron asistidas en nuestra institución entre abril y septiembre de 2020, y se realiza un análisis de las características de estas infecciones en pacientes con y sin sida. En este período se internaron 2837 pacientes, 2287 tuvieron diagnóstico confirmado de COVID-19. La coinfección de COVID-19 con micosis pulmonares o sistémicas fue menor al 1%.Dieciocho pacientes presentaron infecciones fúngicas pulmonares o sistémicas. Ocho padecieron candidemias, cinco criptococosis meningeas, dos histoplasmosis, dos aspergilosis invasoras agudas probables y una aspergilosis pulmonar crónica. La estadía prolongada en terapia intensiva facilitó las fungemias por Candida sp, los casos de histoplasmosis y criptococosis parecen relacionarse con la enfermedad avanzada por VIH y no con COVID-19. Los enfermos con un componente inflamatorio basal alto con neumonía grave por coronavirus se relacionan más con micosis invasoras que los enfermos VIH positivos con niveles bajos de LTCD4+

On December 2019 a new coronavirus (SARS-CoV2) result in atypical pneumonía epidemic, it was identified in Wuhan China and it was called COVID-19. Then on March 11 was declared pandemic by the WHO.Until September 30, 2020 in Argentina 751,001 cases and more than 16,937 deaths have been confirmed. The frequency and impact of co-infections affecting SARS-Cov2 infected patients has been studied with the advance of the pandemic. Among those due to fungi are Candida sp fungemias, invasive aspergillosis, endemic systemic mycoses, and pneumocystosis.We present the different mycosis-COVID-19 co-infections that were assisted in F. J. Muñiz Hospital between April and September of this year and review the characteristics of these infections in patients with and without AIDS is carried out.In this period, 2,837 patients were admitted in the Muñiz hospital, 2,287 had a confirmed diagnosis of COVID-19.Co-infection of COVID-19 with pulmonary or systemic mycoses was less than 1%.Eighteen patients had pulmonary or systemic fungal infections. Eight suffered from candidemia, five meningeal cryptococcosis, two histoplasmosis, two probable acute invasive aspergillosis, and one chronic pulmonary aspergillosis.Prolonged stay in intensive care facilitated fungemia due to Candida sp. Histoplasmosis and cryptococcosis cases seem to be related to advanced HIV disease and not to COVID-19.Patients with a high baseline inflammatory component with severe coronavirus pneumonia are more associated with invasive mycoses than HIV-positive patients with low levels of LTCD4 +

Impact of biofilm formation and azoles' susceptibility in Scedosporium/Lomentospora species using an in vitro model that mimics the cystic fibrosis patients' airway environment.

BACKGROUND: Scedosporium species are the second most isolated filamentous fungi from cystic fibrosis (CF) patients; however, little is known about their virulence aspects in a CF environment. In this context, the current study aimed to evaluate the (i) antifungal susceptibility profiles, (ii) ability to form biofilm and (iii) impact of biofilm formation on the susceptibility to azoles in 21 clinical isolates of Scedosporium recovered from CF patients. METHODS: Scedosporium apiospermum (n=6), S. aurantiacum (n=6), S. minutisporum (n=3) and Lomentospora prolificans (n=6) were firstly used to compare the antifungal susceptibility profile using a standard culture broth (RPMI-1640) and a mucin (M)-containing synthetic CF sputum medium (SCFM). The ability to form biofilms was investigated in polystyrene microtiter plates containing Sabouraud-dextrose (a classical medium), SCFM and SCFM+M. Mature biofilms were tested for their susceptibility to azoles by microdilution assay. RESULTS: Our results showed that the minimum inhibitory concentrations (MICs) for planktonic conidia ranged from 0.25 to >16.0 mg/L for voriconazole and 1.0 to >16.0 mg/L for posaconazole. Overall, the MICs for azoles increased from 2- to 8-folds when the susceptibility tests were performed using SCFM+M compared to RPMI-1640. All fungi formed robust biofilms on polystyrene surface at 72 h, with a significant increase in the MICs (ranging from 128- to 1024-times) against both azoles compared to the planktonic cells. CONCLUSION: These findings confirm the challenge of antifungal treatment of CF patients infected with Scedosporium/Lomentospora and also demonstrated a strong biofilm formation, with extensive increase in antifungal resistance, triggered underconditions mimicking the CF patient airway.

Chronic ethanol consumption compromises neutrophil function in acute pulmonary Aspergillus fumigatus infection.

Chronic ethanol consumption is a leading cause of mortality worldwide, with higher risks to develop pulmonary infections, including Aspergillus infections. Mechanisms underlying increased susceptibility to infections are poorly understood. Chronic ethanol consumption induced increased mortality rates, higher Aspergillus fumigatus burden and reduced neutrophil recruitment into the airways. Intravital microscopy showed decrease in leukocyte adhesion and rolling after ethanol consumption. Moreover, downregulated neutrophil activation and increased levels of serum CXCL1 in ethanol-fed mice induced internalization of CXCR2 receptor in circulating neutrophils. Bone marrow-derived neutrophils from ethanol-fed mice showed lower fungal clearance and defective reactive oxygen species production. Taken together, results showed that ethanol affects activation, recruitment, phagocytosis and killing functions of neutrophils, causing susceptibility to pulmonary A. fumigatus infection. This study establishes a new paradigm in innate immune response in chronic ethanol consumers.

Alcoholism is a chronic disease that has many damaging effects on the body. Over long periods, excessive alcohol intake weakens the immune system, putting consumers at increased risk of getting lung infections such as pneumonia. Some forms of pneumonia can be caused by the fungus Aspergillus fumigatus. This microbe does not tend to be a problem for healthy individuals, but it can be fatal for those with impaired immune systems. Here, Malacco et al. wanted to find out why excessive alcohol consumers are more prone to pneumonia. To test this, the researchers used two groups of mice that were either fed plain water or water containing ethanol. After 12 weeks, both groups were infected with Aspergillus fumigatus. The results showed that alcohol-fed mice were more susceptible to the infection caused by strong inflammation of the lungs. Normally, the immune system confronts a lung infection by activating a group of defense cells called neutrophils, which travel through the blood system to the infection site. Once in the right spot, neutrophils get to work by releasing toxins that kill the fungus. Malacco et al. discovered that after chronic alcohol consumption, neutrophils were less reactive to inflammatory signals and less likely to reach the lungs. They were also less effective in dealing with the infection. Neutrophil released fewer toxins and were thus less able to kill the microbial cells. These findings demonstrate for the first time how alcohol can affect immune cells during infection and pave the way for new possibilities to prevent fatal lung infections in excessive alcohol consumers. A next step would be to identify how alcohol acts on other processes in the body and to find a way to modulate or even revert the changes it causes.

[Pulmonary mycosis in patients with diabetes mellitus. Clinical characteristics and risk factors]. / Micosis pulmonares en pacientes con diabetes mellitus. Características clínicas y factores de riesgo.

BACKGROUND: Diabetes mellitus is a public health problem in Mexico, and the trend of the disease is increasing. From 2000 to 2017, 7.32 million new cases were diagnosed, with pulmonary mycoses being one of the most serious complications. AIMS: To describe the frequency and the clinical characteristics of patients diagnosed with pulmonary mycoses, and to identify the risk factors associated with this entity. METHODS: Case-control study, paired by gender (1:1-3) and age (± 5 years), that analyzed patients with pulmonary mycosis (mucormycosis, histoplasmosis, coccidioidomycosis, blastomycosis, aspergillosis, cryptococcosis, paracoccidioidomycosis) and studied the risk factors present in each patient. RESULTS: From the 162 patients studied, 56 suffered pulmonary mycosis and 106 were controls. The median of the age was 51 and 50 years for the cases and for the controls, respectively. Multiple logistic regression analysis showed that patients with diabetes mellitus had an odds ratio of 8,3 (p < 0.001), and patients with a history of tuberculosis had an odds ratio of 8,8 (p < 0.001). CONCLUSIONS: Our results show that 52% of the patients with pulmonary mycoses had a history of diabetes mellitus. Diabetes mellitus is a relevant risk factor for pulmonary mycoses, which are usually diagnosed in advanced stages and have a high mortality.

[Pulmonary histoplasmosis in an immunocompetent patient]. / Histoplasmose pulmonaire chez un patient immunocompétent avec nodules pulmonaires multiples évoluant vers la nécrose.

INTRODUCTION: Acute pulmonary histoplasmosis (APH) is rare in an immunocompetent patient. We report a case of APH diagnosed by culture of broncho-alveolar lavage (BAL) in a patient presenting a pseudo-tumoral form with nodules progressing to cavitation. OBSERVATION: A 41 year-old male smoker was hospitalized with a persistent fever, dry cough and dyspnoea on exertion. The first CT scan showed a reticulo-nodular interstitial infiltrate with lymphadenopathy that progressed rapidly to multiple pulmonary nodules with central cavitation. Bronchial endoscopy, with BAL culture, provided the diagnosis of Histoplasma capsulatum, variety capsulatum. The infection may have occurred during work in a hangar in Guadeloupe that was scattered with bats' guano. After two months of treatment by itraconazole, the patient's condition improved clinically and radiologically with reduction of the nodules and their cavitation. CONCLUSION: This case presents an immunocompetent patient with pulmonary histoplasmosis and multiple, radiologically atypical, nodules. The diagnosis was established by BAL culture.

Disseminated Cryptococcosis After Liver Transplant: A Case Report.

Cryptococcosis is an opportunistic infection caused by the Basidiomycota Cryptococcus neoformans (Cryptococcus gattii), which affects immunosuppressed patients and less frequently immunocompetent patients. Solid-organ transplant recipients are a particularly high-risk group, depending on the net state of immunosuppression. In these patients, the infection usually appears after the first year after transplant, although it may occur earlier in liver transplant recipients. In most cases, the infection is secondary to the reactivation of a latent infection, although it may be due to an unidentified pretransplant infection by primary infection. Less frequently, it may be transmitted by the graft. The lung and central nervous system are most frequently involved. Extrapulmonary involvement is seen in 75% of the cases, and disseminated disease occurs in 61%, with mortality ranging from 17% to 50% when the central nervous system is involved. Here, we report a case of disseminated cryptococcosis (lymphadenitis, meningitis, pulmonary nodules, and possibly sacroiliitis) in a patient after liver transplant, with good clinical and microbiological outcomes and without relapse.

Enhanced expression of NLRP3 inflammasome components by monocytes of patients with pulmonary paracoccidioidomycosis is associated with smoking and intracellular hypoxemia.

Paracoccidioidomycosis (PCM) is a systemic mycosis caused by thermally dimorphic fungi of the genus Paracoccidioides that affects predominantly 30-60-year-old male rural workers. The main clinical forms of the disease are acute/subacute, chronic (CF); almost all CF patients develop pulmonary fibrosis, and they also exhibit emphysema due to smoke. An important cytokine in this context, IL-1ß, different from the others, is produced by an intracellular multimolecular complex called inflammasome that is activated by pathogens and/or host signs of damage. Inflammasome has been recognized for its contribution to chronic inflammatory diseases, from that, we hypothesized that this activation could be involved in paracoccidioidomycosis, contributing to chronic inflammation. While inflammasome activation has been demonstrated in experimental models of Paracoccidioides brasiliensis infection, no information is available in patients, leading us to investigate the participation of NLRP3-inflammasome machinery in CF/PCM patients from a Brazilian endemic area. Our findings showed increased priming in mRNA levels of NLRP3 inflammasome genes by monocytes of PCM patients in vitro than healthy controls. Similar intracellular protein expression of NLRP3, CASP-1, ASC, and IL-1ß were also observed in freshly isolated monocytes of PCM patients and smoker controls. Increased expression of NLRP3 and ASC was observed in monocytes from PCM patients under hypoxia in comparison with smoker controls. For the first time, we showed that primed monocytes of CF-PCM patients were associated with enhanced expression of components of NLRP3-inflammasome due to smoke. Also, hypoxemia boosted this machinery. These findings reinforce the systemic low-grade inflammation activation observed in PCM during and after treatment.

Chronic progressive pulmonary paracoccidioidomycosis in a female immigrant from Venezuela.

Paracoccidioidomycosis (PCM) is a fungal infection caused by Paracoccidioides brasiliensis and P. lutzii. It is endemic to South and Central America. While PCM frequently remains latent, the disease can reactivate years after the initial infection. As the disease is rare outside the endemic area, and symptoms can mimic other pulmonary diseases, correct diagnosis can be challenging for clinicians in developed countries. In this report, we present the case of a 57-year-old female Venezuelan immigrant with PCM. She was initially misdiagnosed with sarcoidosis and treated with corticosteroids, leading to an exacerbation of the infection requiring intensive care. Because cultivation of Paracoccidioides sp. is slow and unsensitive, we opted for microscopic observation of fungal elements and molecular testing on a tissue biopsy and bronchoalveolar lavage (BAL) together with antibody detection. This allowed the diagnosis of PCM, enabling specific management. PCM and other imported mycoses should be considered as a differential diagnosis in patients originating from South and Central America displaying symptoms suggestive of sarcoidosis. The reviews of this paper are available via the supplemental material section.

Placental and pulmonary cryptococcosis associated with fungemia in patient with acquired immunodeficiency syndrome.

Cryptococcosis is a systemic mycosis with a chronic or subacute progression caused by the inhalation of dehydrated yeasts or basidiospores. The causative agents are C. gattii and C. neoformans. The latter is more commonly associated with cellular immunodeficiency and is not rare in patients with Acquired Immunodeficiency Syndrome (AIDS). Cryptococcosis is common in pregnant women with AIDS; however, it is uncommon for the placenta to be affected, with few reported cases in the literature. We present the case of a pregnant woman with AIDS who had placental and pulmonary cryptococcosis associated with fungemia, with a satisfactory clinical outcome obtained after therapy.

Quantitation of pulmonary fungal burden in Paracoccidioides brasiliensis-infected mice by real-time PCR.

Although colony-forming unit (CFU) counting is widely used to quantify fungal load in tissue from animal experimentally infected with Paracoccidioides brasiliensis, several technical disadvantages have been described. Here we developed highly accurate quantitative PCR (qPCR) assays to determine the relative P brasiliensis load in lungs from infected mice. SYBR Green- and TaqMan-based assays using primers and probe for the 43-kDa glycoprotein (gp43) gene detected as little as 270 gene copies (about 2 fg of DNA) per reaction. Although qPCR assays cannot distinguish between living and dead yeasts, we found a highly positive linear correlation between CFU and qPCR.

Comparison of serum PCT and CRP levels in patients infected by different pathogenic microorganisms: a systematic review and meta-analysis.

To avoid the abuse and misuse of antibiotics, procalcitonin (PCT) and C-reactive protein (CRP) have been used as new approaches to identify different types of infection. Multiple databases were adopted to search relevant studies, and the articles that satisfied the inclusion criteria were included. Meta-analyses were conducted with Review Manager 5.0, and to estimate the quality of each article, risk of bias was assessed. Eight articles satisfied the inclusion criteria. The concentrations of both PCT and CRP in patients with bacterial infection were higher than those with non-bacterial infection. Both PCT and CRP levels in patients with G- bacterial infection were higher than in those with G+ bacterial infection and fungus infection. In the G+ bacterial infection group, a higher concentration of CRP was observed compared with fungus infection group, while the difference of PCT between G+ bacterial infection and fungus infection was not significant. Our study suggested that both PCT and CRP are helpful to a certain extent in detecting pneumonia caused by different types of infection.

Micosis pulmonares en niños: un enfoque diagnóstico / Pulmonary mycosis in children: a diagnostic approach

Pulmonary mycoses are invasive fungal infections that occur more and more frequently. The rising number of patients with immunodeficiencies, HIV infection, hematopoietic stem cell and solid organ transplant recipients, as well as the use of immunosuppressive therapies have increased the incidence of this disease. Diagnosis remains a challenge because the most accurate procedure is the isolation of the germ through culture of body fluids which have low sensitivity and a long development time (4-6 weeks). The diagnosis of pulmonary mycoses is based on the presence of risk factors, clinical and/or radiological symptoms suggestive of fungal infection and a positive microbiological test. Due to the fact that pulmonary mycoses are not usually considered in the differential diagnosis in the initial clinical evaluation of diseases and that the studies to establish the diagnosis are complex, they are diagnosed late when they have already become chronic with a high risk of morbidity and mortality

Las micosis pulmonares son infecciones invasivas que se presentan cada vez con mayor frecuencia en la población. El aumento del número de pacientes con inmunodeficiencias, infección por VIH, receptores de trasplante de células hematopoyéticas y órgano sólido, así como el uso de terapias inmunosupresoras ha incrementado la incidencia de esta enfermedad. El diagnóstico continúa siendo un reto debido a que el estándar de oro es el aislamiento del germen mediante cultivo de líquidos corporales los cuales tienen baja sensibilidad y un tiempo de desarrollo prolongado (4-6 semanas). El diagnóstico de las micosis pulmonares se basa en la presencia de factores de riesgo, cuadro clínico y/o radiológico sugestivo de infección fúngica y el estudio microbiológico positivo. Debido a que las micosis pulmonares habitualmente no se consideran dentro del diagnóstico diferencial en la evaluación clínica inicial de las enfermedades, asociado a la complejidad de estudios para establecer el diagnostico, las micosis pulmonares se diagnostican en forma tardía cuando ya existe enfermedad crónica, con alto riesgo de morbimortalidad

[Clinical problems in medical mycology: Problem number 51]. / Problemas clínicos en micología médica: problema número 51.

A 48 year-old immunocompetent woman, who had a nodular lesion in the neck and a dense infiltrate at the lower lobe of the left lung, presented at the Mycology Unit of Muñiz Hospital of Buenos Aires City. The pulmonary infiltrate disappeared spontaneously 3 months later. The histopathological study of the nodular lesion showed capsulated yeasts (mucicarmin and alcian blue positive stains) compatible with Cryptococcus. The mycological study of a new sample, obtained by a nodular puncture, allowed the isolation of yeasts, identified as Cryptococcus gattii (VGII). Latex test for Cryptococcus capsular antigen in serum was positive (1/100). CSF cultures rendered negative results. Fluconazole at a daily dose of 800mg was given during 45 days with partial improvement; as cultures from a new clinical sample were positive for Cryptococcus, the antimycotic was changed to itraconazole 400mg/day for 5 months, with an excellent clinical response.

[Clinical problems in medical mycology: Problem number 52]. / Problemas clínicos en micología médica: problema número 52.

The case of a 60 year old woman with hemoptysis and a thin-walled cavitary lesion at the upper lobe of the right lung is presented. The woman presented at the Mycology Unit of the Muñiz Hospital in Buenos Aires City 3 months after the beginning of her clinical manifestations. A hyaline micelial fungus with chlamido-arthroconidias was isolated from the bronchoalveolar lavage. Immunodiffusion and counter-immnunoelectrophoresis with coccidioidin and histoplasmin rendered positive results against both antigents, and skin tests with coccidioidin and histoplasmin were also positive with strong reactions. The isolated fungus was identified as Coccidioides posadasii at the National Microbiology Institute Carlos Malbrán, by means of a molecular technique. The patient was treated with itraconazole by oral route at a daily dose of 200mg with good clinical response, but due to the persistence of the lung cavity, a surgical removal of the upper lobe of the right lung had to be scheduled.

Comparison of serum PCT and CRP levels in patients infected by different pathogenic microorganisms: a systematic review and meta-analysis

To avoid the abuse and misuse of antibiotics, procalcitonin (PCT) and C-reactive protein (CRP) have been used as new approaches to identify different types of infection. Multiple databases were adopted to search relevant studies, and the articles that satisfied the inclusion criteria were included. Meta-analyses were conducted with Review Manager 5.0, and to estimate the quality of each article, risk of bias was assessed. Eight articles satisfied the inclusion criteria. The concentrations of both PCT and CRP in patients with bacterial infection were higher than those with non-bacterial infection. Both PCT and CRP levels in patients with G− bacterial infection were higher than in those with G+ bacterial infection and fungus infection. In the G+ bacterial infection group, a higher concentration of CRP was observed compared with fungus infection group, while the difference of PCT between G+ bacterial infection and fungus infection was not significant. Our study suggested that both PCT and CRP are helpful to a certain extent in detecting pneumonia caused by different types of infection.