Serum Galactomannan Research Articles

Clinical Application of Metagenomic Next-Generation Sequencing in Patients with Hematologic Malignancies Suffering from Sepsis

Background: Sepsis remains a common but fatal complication among patients with immune suppression. We aimed to investigate the performance of metagenomic next-generation sequencing (mNGS) compared with standard microbiological diagnostics in patients with hematologic malignancies. Methods: We performed a prospective study from June 2019 to December 2019. Adult patients with hematologic malignancies and a clinical diagnosis of sepsis were enrolled. Conventional diagnostic methods included blood cultures, serum galactomannan for Aspergillus, cryptococcal antigen and cytomegalovirus (CMV) viral loads. Blood samples for mNGS were collected within 24 h after hypotension developed. Results: Of 24 patients enrolled, mNGS and conventional diagnostic methods (blood cultures, serology testing and virus RT-PCR) reached comparable positive results in 9 cases. Of ten patients, mNGS was able to identify additional pathogens compared with conventional methods; most of the pathogens were virus. Conclusion: Our results show that mNGS may serve as adjunctive diagnostic tool for the identification of pathogens of hematologic patients with clinically sepsis.

COVID-19-Associated Pulmonary Aspergillosis in Patients with Acute Leukemia: A Single-Center Study.

Patients with coronavirus disease 19 (COVID-19) have increased susceptibility to secondary respiratory infections including invasive pulmonary aspergillosis (IPA). COVID-19-associated pulmonary aspergillosis (CAPA) is difficult to diagnose and can be associated with increased mortality especially in severe immunodeficiency such as hematological malignancies. Our study evaluates IPA in COVID-19 patients defined as COVID-19-CAPA among patients with acute leukemia (AL). A retrospective single-center study analyzed 46 patients with COVID-19 infection and acute leukemia, admitted to the Clinic for Haematology, Clinical Center of Serbia, Belgrade between the 2 April 2020 and 15 May 2021. During hospitalization, all participants were diagnosed with probable IPA according to the previous consensus definitions. Positive serology and galactomannan (GM) detection values in bronchoalveolar lavage (BAL) and serum were used as microbiological criteria. COVID-19 associated probable IPA was found in 22% (9/41) tested patients, where serum GM and IgM anti-Aspergillus antibodies were positive in 12% (5/41) and 10% (4/41) had positive serology for aspergillosis. One patient died while eight recovered during follow-up. Our study showed that COVID-19 might be a risk factor for IPA development in patients with AL. Early diagnosis and prompt treatment are required as reported mortality rates are high.

COVID-19-Associated Pulmonary Aspergillosis, Fungemia, and Pneumocystosis in the Intensive Care Unit: a Retrospective Multicenter Observational Cohort during the First French Pandemic Wave.

ABSTRACTThe aim of this study was to evaluate diagnostic means, host factors, delay of occurrence, and outcome of patients with COVID-19 pneumonia and fungal coinfections in the intensive care unit (ICU). From 1 February to 31 May 2020, we anonymously recorded COVID-19-associated pulmonary aspergillosis (CAPA), fungemia (CA-fungemia), and pneumocystosis (CA-PCP) from 36 centers, including results on fungal biomarkers in respiratory specimens and serum. We collected data from 154 episodes of CAPA, 81 of CA-fungemia, 17 of CA-PCP, and 5 of other mold infections from 244 patients (male/female [M/F] ratio = 3.5; mean age, 64.7 ± 10.8 years). CA-PCP occurred first after ICU admission (median, 1 day; interquartile range [IQR], 0 to 3 days), followed by CAPA (9 days; IQR, 5 to 13 days), and then CA-fungemia (16 days; IQR, 12 to 23 days) (P < 10−4). For CAPA, the presence of several mycological criteria was associated with death (P < 10−4). Serum galactomannan was rarely positive (<20%). The mortality rates were 76.7% (23/30) in patients with host factors for invasive fungal disease, 45.2% (14/31) in those with a preexisting pulmonary condition, and 36.6% (34/93) in the remaining patients (P = 0.001). Antimold treatment did not alter prognosis (P = 0.370). Candida albicans was responsible for 59.3% of CA-fungemias, with a global mortality of 45.7%. For CA-PCP, 58.8% of the episodes occurred in patients with known host factors of PCP, and the mortality rate was 29.5%. CAPA may be in part hospital acquired and could benefit from antifungal prescription at the first positive biomarker result. CA-fungemia appeared linked to ICU stay without COVID-19 specificity, while CA-PCP may not really be a concern in the ICU. Improved diagnostic strategy for fungal markers in ICU patients with COVID-19 should support these hypotheses.IMPORTANCE To diagnose fungal coinfections in patients with COVID-19 in the intensive care unit, it is necessary to implement the correct treatment and to prevent them if possible. For COVID-19-associated pulmonary aspergillosis (CAPA), respiratory specimens remain the best approach since serum biomarkers are rarely positive. Timing of occurrence suggests that CAPA could be hospital acquired. The associated mortality varies from 36.6% to 76.7% when no host factors or host factors of invasive fungal diseases are present, respectively. Fungemias occurred after 2 weeks in ICUs and are associated with a mortality rate of 45.7%. Candida albicans is the first yeast species recovered, with no specificity linked to COVID-19. Pneumocystosis was mainly found in patients with known immunodepression. The diagnosis occurred at the entry in ICUs and not afterwards, suggesting that if Pneumocystis jirovecii plays a role, it is upstream of the hospitalization in the ICU.

A CASE OF FATAL INVASIVE PULMONARY ASPERGILLOSIS IN A PATIENT WITH ANTI-MDA5 DERMATOMYOSITIS

TOPIC: Chest Infections TYPE: Medical Student/Resident Case Reports INTRODUCTION: Invasive pulmonary aspergillosis (IPA) is classically associated with solid/hematologic organ transplant, hematologic malignancy, and severe neutropenia. The presence of anti-melanoma differentiation-associated gene-5 (MDA-5) autoantibodies in dermatomyositis confers a higher risk of rapidly progressing interstitial lung disease (RP-ILD) resulting in high mortality. We present a case of a patient with a history of diagnosed anti-MDA5 dermatomyositis who developed acute fulminant IPA. CASE PRESENTATION: We report a case of a 65-year-old female with a history of MDA-5 positive dermatomyositis who presented to the hospital with symptoms of dyspnea, fever, and hypoxemia. A CT scan demonstrated bilateral peripheral patchy ground-glass opacities (image 1). The differential diagnosis was broad and included bacterial vs viral vs pneumocystis pneumonia. Upon presentation, she had been on 24 days of prednisone on a dose of 60mg for the first 14 days and 40mg daily for the last 10 for her recent diagnosis of dermatomyositis. Also on the differential was the possibility of RP-ILD. She was started on high-dose steroids at 60mg prednisone daily and broad-spectrum antibiotics. Given high clinical suspicion for RP-ILD, she was started on IVIG therapy. Bronchoscopy with bronchoalveolar lavage grew mold. A repeat CT days later demonstrated dramatically worsening bilateral pulmonary infiltrates with a consolidative pattern (image 2). The patient's clinical status worsened and required intubation for worsening respiratory failure. Eventually, galactomannan resulted positive on the initial and repeat BAL specimens (Ag Index 5.75, 3.62 respectively) with positive serum galactomannan (Ag index 3.33) making IPA the most likely diagnosis. She was started on voriconazole and micafungin with little clinical response and suffered from progressive respiratory decline leading to death. DISCUSSION: Our patient had anti-MDA-5 dermatomyositis with likely RP-ILD who experienced a rapid respiratory decline in the span of weeks. What makes this case interesting is the fulminant lung injury that occurred without a clear and early known diagnosis. Most notably the highest possibilities were RP-ILD and infection, now known to be from Aspergillus spp. The relationship between IPA in chronic respiratory diseases (CRD) particularly interstitial lung diseases is still unclear. There is some evidence to suggest even a short course of steroids may lead to substantial risk in those with underlying CRD such as dermatomyositis-related ILD. This may be the case in our patient who had been on high-dose prednisone before her presentation. CONCLUSIONS: There is the possibility that anti-MDA-5 positive dermatomyositis increases susceptibility to IPA, possibly through a mechanism related to RP-ILD. If characterized further, it may warrant more aggressive surveillance and treatment for invasive pulmonary fungal infections in these patients. REFERENCE #1: Naaraayan, A., Kavian, R., Lederman, J., Basak, P., & Jesmajian, S. (2015). Invasive pulmonary aspergillosis - case report and review of literature. Journal of community hospital internal medicine perspectives, 5(1), 26322. https://doi.org/10.3402/jchimp.v5.26322 REFERENCE #2: Sontheimer R. D. (2017). MDA5 autoantibody-another indicator of clinical diversity in dermatomyositis. Annals of translational medicine, 5(7), 160. https://doi.org/10.21037/atm.2017.03.94 DISCLOSURES: No relevant relationships by Merwise Baray, source=Web Response No relevant relationships by Deepa Lazarous, source=Web Response No relevant relationships by Robert Varipapa, source=Web Response No relevant relationships by Samuel Wopperer, source=Web Response

DEXAMETHASONE AND AMPHOTERICIN B TO THE RESCUE: A CASE OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS

TOPIC: Critical Care TYPE: Fellow Case Reports INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a rare disease characterized by immune system overstimulation resulting in widespread inflammation, a cytokine surge, and multisystem organ failure. HLH is associated with significant mortality, so early recognition and a multidisciplinary approach to treatment are key for improved survival. CASE PRESENTATION: A 59-year-old kidney and pancreas transplant recipient presented with diarrhea, fevers, altered mental status, and acute kidney injury. He was transferred to the ICU due to respiratory distress and was started on antibiotics. CT scan of the chest and abdomen showed a small right lower lobe consolidation and mild splenomegaly. Sputum, urine, and blood cultures were negative. Serum fungitell was elevated and Aspergillus galactomannan serum antigen was positive. Serum Histoplasma antigen was >25ng/mL and urine Histoplasma antigen was 7.8ng/mL. Amphotericin B was started and hematology was consulted for presumed HLH secondary to histoplasmosis with elevated ferritin (7559 ng/mL) and triglycerides (227). Bone marrow aspirate demonstrated foamy histocytes and hemophagocytic histiocytes as well dimorphic fungal forms in the interstitium and within a granuloma on GMS stain consistent with Histoplasma. Dexamethasone was initiated at 10mg/m2. Soluble IL-2R was 14,120 U/mL. He clinically improved on dexamethasone and was transitioned from amphotericin to itraconazole. DISCUSSION: At least 5 out of 8 of the following criteria must be met for a diagnosis of HLH: fever, splenomegaly, cytopenia, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis in bone marrow, spleen or lymph nodes, low/absent NK-cell activity, ferritin ≥ 500 mg/L, and soluble CD25 ≥2400 U/mL. This patient had 6/8 of the diagnostic criteria for HLH: fever, splenomegaly, hypertriglyceridemia, ferritin >500, high soluble IL-2 receptor, and hemophagocytosis in bone marrow. A multidisciplinary discussion involving critical care, hematology, and transplant infectious disease was held about initiating Etoposide due to rising ferritin (based on evidence supporting the use of Etoposide in pediatric patients with HLH), however, data is lacking regarding how to treat adult patients with HLH and histoplasmosis. He was clinically improving without Etoposide and there was concern that Etoposide would make his histoplasmosis more difficult to treat, so he was not given Etoposide. Histoplasma is a known but rare cause of HLH (<50 published cases). Due to the rarity of HLH and its risk for mortality, it is important to have a high index of suspicion to test for HLH in an immunosuppressed patient who presents with fevers. CONCLUSIONS: Working with a multidisciplinary team was essential to both the diagnosis and management of HLH due Histoplasma due to a lack of evidence about optimal treatment. Research is needed to improve outcomes for patients with HLH due to Histoplasma. REFERENCE #1: Hayden, A., Park, S., Giustini, D., Lee, A. Y., & Chen, L. Y. (2016). Hemophagocytic syndromes (HPSs) including hemophagocytic lymphohistiocytosis (HLH) in adults: A systematic scoping review. Blood reviews, 30(6), 411–420. https://doi.org/10.1016/j.blre.2016.05.001 REFERENCE #2: Bergsten, E., Horne, A., Aricó, M., Astigarraga, I., Egeler, R. M., Filipovich, A. H., Ishii, E., Janka, G., Ladisch, S., Lehmberg, K., McClain, K. L., Minkov, M., Montgomery, S., Nanduri, V., Rosso, D., & Henter, J. I. (2017). Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood, 130(25), 2728–2738. https://doi.org/10.1182/blood-2017-06-788349 REFERENCE #3: Filipovich A. H. (2009). Hemophagocytic lymphohistiocytosis (HLH) and related disorders. Hematology. American Society of Hematology. Education Program, 127–131. https://doi.org/10.1182/asheducation-2009.1.127 DISCLOSURES: No relevant relationships by Maureen McElligott, source=Web Response No relevant relationships by Meilinh Thi, source=Web Response

VACCINATED WITH A TWIST: BREAKTHROUGH COVID-19 IN AN IMMUNOCOMPROMISED PATIENT

TOPIC: Chest Infections TYPE: Medical Student/Resident Case Reports INTRODUCTION: With ongoing efforts to vaccinate the public against SARS-CoV2, there have been reports of breakthrough COVID-19 cases. We report a case of an immunocompromised patient who was infected despite being fully vaccinated. CASE PRESENTATION: 63-year-old female with COPD, rheumatoid arthritis on abatacept, prednisone, & methotrexate (MTX), and Sweet syndrome presented to the ED with acute non-exertional chest pain, palpitations, and dyspnea at rest. She denied fevers or chills but reported diarrhea and vomiting. She had no history of or exposure to COVID-19 and had completed her 2-dose mRNA SARS-CoV-2 vaccination 45 days prior. On presentation she was in respiratory distress, hypotensive, tachycardic, and tachypneic. She was saturating at 86% on room air, requiring supplemental O2. Physical exam was significant for scattered bilateral wheezes. CBC showed no leukocytosis. CRP was elevated. Lactic acid, ferritin and LDH were within normal limits. D-dimer was higher than the age-adjusted cutoff;CTA of the chest revealed no PE but showed bilateral ground glass opacities with consolidations. She tested positive for SARS-CoV-2. She was admitted for severe sepsis from COVID-19 pneumonitis and started on dexamethasone and remdesivir. SARS-CoV-2 IgG antibodies were positive. Given her immunocompromised status, bronchoscopy with BAL was performed and revealed copious thick secretions. Gram stain and bronchial brushings were negative for bacterial etiologies. Lavage culture was positive for aspergillus antigen and cytology revealed markedly enlarged reactive cells. Galactomannan serum antigen was positive. She was discharged on day 9 with a prolonged course of voriconazole. She had residual dyspnea on exertion but did not require supplemental O2. A nasal swab to test for variant strains was still pending. DISCUSSION: The COVID vaccine proved effective in preventing severe COVID-19 infections but trials excluded immunocompromised patients. This case of infection despite vaccination and detectable IgG titers reveals suboptimal protection. From data on pre-existing vaccines in immunocompromised patients, MTX is known to reduce immunogenicity. Our patient remained on immunosuppressants after vaccination, which may have contributed to her subsequent viral and fungal infections. Rheumatology guidelines suggest holding MTX for one to two weeks after vaccination to improve vaccine response. Employing this strategy will maximize immunogenicity against SARS-CoV-2 in immunocompromised patients. CONCLUSIONS: The American College of Rheumatology recommends vaccinating patients with rheumatological conditions against SARS-CoV-2. This case highlights individual patient factors to consider in the battle against COVID-19 in immunosuppressed patients. Non-viral infections must also be considered despite the ongoing pandemic. Determining protective antibody titers can guide booster vaccine recommendations. REFERENCE #1: Sonani B, Aslam F, Goyal A, Patel J, Bansal P. COVID-19 vaccination in immunocompromised patients. Clin Rheumatol. 2021;40(2):797-798. doi:10.1007/s10067-020-05547-w REFERENCE #2: Day AL, Winthrop KL, Curtis JR. The effect of disease-modifying antirheumatic drugs on vaccine immunogenicity in adults. Cleve Clin J Med. 2020;87(11):695-703. Published 2020 Nov 2. doi:10.3949/ccjm.87a.20056 REFERENCE #3: COVID-19 Vaccine Clinical Guidance Summaryfor Patients with Rheumatic and Musculoskeletal Diseases DISCLOSURES: No relevant relationships by Vernon Chan, source=Web Response No relevant relationships by Dana Daoud, source=Web Response No relevant relationships by Jeet Lund, source=Web Response

COVID‐19‐associated subacute invasive pulmonary aspergillosis

BackgroundThough invasive pulmonary aspergillosis is a well known complication of COVID‐19 pneumonia, indolent forms of aspergillosis have been rarely described.MethodsWe prospectively collected the clinico‐radio‐microbiological data of 10 patients of subacute invasive pulmonary aspergillosis (SAIA), who presented to our hospital with recent history of COVID‐19 pneumonia along with cavitary lung disease, positive IgG (against Aspergillus) with or without positive respiratory samples for Aspergillus spp.ResultThe mean age of presentation of SAIA was 50.7 ± 11.8 years. All the patients had recently recovered from severe COVID‐19 illness with a mean duration of 29.2 ± 12 days from COVID‐19 positivity. Cough was the predominant symptom seen in 8/10 (80%) patients followed by haemoptysis. 7/10 (70%) patients were known diabetic. While serum galactomannan was positive in 5/9 patients (55.5%), fungal culture was positive in 2/7 patients (28.5%) and polymerase chain reaction (PCR) for Aspergillus was positive in three patients. Eight (80%) patients presented with a single cavitary lesion; pseudoaneurysm of pulmonary artery was seen in two patients and post‐COVID‐19 changes were seen in all patients. All patients were treated with voriconazole, out of which four (40%) patients died during the follow‐up period.ConclusionSAIA should be considered in the differential diagnosis of cavitating lung lesions in patients with recent history of COVID‐19 in the background of steroid use with or without pre‐existing diabetes.

Imaging Characteristics of Invasive Pulmonary Fungal Infection Secondary to Hematological Diseases and Comparison before and after Treatment.

Fungal infections have become crucial factors that threaten the prognosis and survival of blood disease patients. Here, we aim to analyze the epidemiological characteristics and early and advanced CT (computed tomography) manifestations of patients with invasive pulmonary fungal infections secondary to blood system diseases. 65 hospitalized patients from October 2018 to October 2020 with invasive pulmonary fungal infections secondary to blood diseases were enrolled. Blood diseases were recorded according to clinical and imaging data, and the serum galactomannan test (GM test) was conducted. Two senior radiologists analyzed the CT data and recorded the distribution of the lesions and CT signs. We analyzed and counted the first chest CT scan images of patients with nodule/mass type secondary to hematological diseases and invasive pulmonary fungal infection. The first CT nodules or mass-type lesions were statistically significant in nodule size, the number of lesions, distribution, and accompanying signs. Pulmonary fungal infection was common in both lungs during 7-day, 14-day, and 30-day follow-up CT. We also found that the nodular mass type was the main manifestation in the positive group of the GM test. Both the positive group and the negative group had the highest incidence of nodules. The incidence of air crescent signs in nodules or mass lesions in the positive group was higher than in the negative group, and the difference was statistically significant. To conclude, follow-up CT signs after antifungal treatment were highly sensitive to the early diagnosis of hematological diseases and secondary invasive pulmonary Eumycetes infection, which could be used for clinical treatment to provide help. GM test results were also related to CT manifestations such as air crescent sign, cavity, and halo sign.

Predictors of Early and Late Mortality for Patients with Hematologic Malignancy and Invasive Mold Disease.

Background: Invasive mold infections (IMI) are leading infectious causes of mortality among patients with hematological malignancies. Objectives: To determine the relative contribution of host, disease, and treatment-related factors to patient survival. Methods: An observational, retrospective cohort study reviewing the medical records of patients with hematological malignancy and IMI (2006–2016). Causes of death were classified up to 90 days after diagnosis. Kaplan–Meier and Cox regression analyses were used to determine risk factors for early, late, and overall mortality. Results: Eighty-six patients with IMI were included; 29 (34%) and 41 (47%) died within 6 and 12 weeks of diagnosis, respectively. Death was attributed to IMI in 22 (53.6%) patients, all of whom died within 45 days of diagnosis. Risk factors for early mortality were elevated serum galactomannan, treatment with amphotericin B, IMI progression 3 weeks after diagnosis, and lymphoma undergoing HCT. Late mortality was associated with relapsed/refractory malignancy and elevated serum galactomannan. Conclusions: In this single-center study of patients with IMI, infections were the most frequent causes of death, and time-dependent risk factors for death were identified. These results may help direct risk-assessment and monitoring of patients undergoing treatment of IMI.

Clinical study of invasive pulmonary aspergillosis following influenza A H1N1.

This study to analyze the clinical characteristics of patients with invasive pulmonary aspergillosis (IPA) following influenza A (H1N1) infection.We retrospectively analyzed 10 cases with IPA following H1N1 infection. The clinical manifestations, laboratory examination results, chest computed tomography, and treatments were analyzed.Clinical manifestations: all 10 cases had typical flu-like symptoms at the onset of the disease, among which 7 patients developed dyspnea in the late stage, and 8 patients had hemoptysis. Laboratory examination: the absolute and percentage of peripheral blood lymphocytes in all 10 patients were declined, among which 5 cases were with decreased CD3+ CD4+ T cells/lymphocytes; 9 cases with increased bronchoalveolar lavage fluid galactomannan; 6 cases with increased serum galactomannan; 1 case with bronchoalveolar lavage fluid cultured aspergillus fumigatus; and 2 cases with aspergillus by second-generation sequencing. Chest computed tomography: all patients showed multiple diffused ground-glass opacities at the beginning, along with linear or reticular interstitial changes. Two cases had multiple subarachnoid nodules with halo signs, 3 cases had consolidation in multiple segments of both lungs, 2 cases had cavities, and 4 cases were with pleural effusion. Treatment: 10 patients were treated with antiviral and anti-Aspergillus drugs after admission. Four patients received respiratory support. All 10 cases were cured and discharged.Early diagnosis of IPA in influenza A (H1N1) patients is the key to successful treatment.

Invasive aspergillosis in solid organ transplantation: Diagnostic challenges and differences in outcome in a Spanish national cohort (Diaspersot study).

The diagnosis of invasive aspergillosis (IA) can be problematic in solid organ transplantation (SOT). The prognosis greatly varies according to the type of transplant, and the impact of prophylaxis is not well defined. The Diaspersot cohort analyses the impact of IA in SOT in Spain during the last 10years. Proven and probable/putative IA was included. We analysed 126 cases of IA. The incidences of IA were as follows: 6.5%, 2.9%, 1.8% and 0.6% for lung, heart, liver and kidney transplantation, respectively. EORTC/MSG criteria confirmed only 49.7% of episodes. Tree-in-bud sign or ground-glass infiltrates were present in 56.3% of patients, while serum galactomannan (optical density index >0.5) was positive in 50.6%. A total of 41.3% received combined antifungal therapy. Overall mortality at 3months was significantly lower (p<0.001) in lung transplant recipients (14.8%) than in all other transplants [globally: 48.6%; kidney 52.0%, liver 58.3%, heart 31.2%, and combined 42.9%]. Fifty-four percent of episodes occurred despite the receipt of antifungal prophylaxis, and in 10%, IA occurred during prophylaxis (breakthrough infection), with both nebulised amphotericin (in lung transplant recipients) and candins (in the rest). Invasive aspergillosis diagnostic criteria, applied to SOT patients, may differ from those established for haematological patients. IA in lung transplants has a higher incidence, but is associated with a better prognosis than other transplants. Combination therapy is frequently used for IA in SOT. Prophylactic measures require optimisation of its use within this population.

Serum Lateral Flow assay with digital reader for the diagnosis of invasive pulmonary aspergillosis: A two-centre mixed cohort study.

BackgroundDetection of galactomannan (GM) from bronchoalveolar lavage fluid (BALF) or serum is broadly used for diagnosis of invasive aspergillosis (IA), although the sensitivity of GM from serum is lower in non‐neutropenic patients. We evaluated the Aspergillus galactomannan Lateral Flow assay (LFA) with digital readout from serum in a mixed cohort of patients.MethodsWe performed a retrospective two‐centre study evaluating the LFA from serum of patients with clinical suspicion of IA obtained between 2015 and 2021 at the University of California San Diego and the Medical University of Graz. The sensitivity and specificity was calculated for proven/probable aspergillosis versus no aspergillosis. Correlation with same‐sample GM was calculated using Spearman correlation analysis and kappa statistics.ResultsIn total, 122 serum samples from 122 patients were analysed, including proven IA (n = 1), probable IA or coronavirus‐associated pulmonary aspergillosis (CAPA) (n = 27), and no IA/CAPA/non‐classifiable (n = 94). At a 0.5 ODI cut‐off, the sensitivity and specificity of the LFA was 78.6% and 80.5%. Spearman correlation analysis showed a strong correlation between serum LFA ODI and serum GM ODI (ρ 0.459, p < .0001). Kappa was 0.611 when both LFA and GM were used with a 0.5 ODI cut‐off, showing substantial agreement (p < .001).DiscussionThe LFA with digital read out from serum showed good performance for the diagnosis of probable/proven aspergillosis, with substantial agreement to GM from serum. Like the LFA from BALF, the LFA from serum may serve as a more rapid test compared to conventional GM, particularly in settings where GM is not readily available.

Diagnostic dilemma in a case of chronic invasive fungal sinusitis solved using a novel diagnostic test

Fungal infections of the paranasal sinuses are a spectrum of diseases rather than one distinct entity. The prevalence of fungal sinus disease has been increasing in recent decades, especially in immunocompetent individuals. The indiscriminate use of antibiotics and immunosuppressive drugs has partially been attributed to this. The diagnosis of invasive fungal disease still imposes a challenge to medical professionals occasionally. Here we present an interesting case of a middle-aged immunocompetent male who presented to us with non-specific symptoms of chronic invasive fungal sinusitis. The routine investigations for diagnosing fungal sinusitis turned out to be futile and the result of serum galactomannan test helped to identify and treat his condition. &lt;p&gt; &lt;/p&gt;

Epidemiology and Incidence of COVID-19-Associated Pulmonary Aspergillosis (CAPA) in a Greek Tertiary Care Academic Reference Hospital.

IntroductionInvasive pulmonary aspergillosis is an emerging complication among intensive care unit (ICU) patients with COVID-19 (CAPA). In the present study, all CAPA cases during the first year of the pandemic were reviewed in critically ill patients at a 650-bed tertiary Greek COVID-19 reference hospital.MethodsData regarding patients admitted to the ICU of Attikon Hospital in Athens, Greece, between 22 March 2020 and 28 February 2021 with a positive PCR for SARS-CoV-2 infection were reviewed. Clinical and microbiological records were analysed including demographic, clinical, laboratory and radiological features, treatment and outcomes. CAPA was determined according to the recent 2020 ECMM/ISHAM definitions.ResultsA total of 179 patients were admitted in the ICU and 6 (3.3%) patients were diagnosed with CAPA (4 probable and 2 possible CAPA) with 5/6 with co-infection with multidrug-resistant (MDR) gram-negative pathogens. No patient had a history of immunosuppression. All suffered from acute respiratory distress syndrome. The median (range) time from intubation to diagnosis was 6 (1–14) days. Five patients had positive Aspergillus cultures in bronchial secretions (1 A. fumigatus, 1 A. flavus, 1 A. fumigatus + A. flavus, 1 A. fumigatus + A. terreus and 1 A. terreus) while culture was negative in one patient. All isolates were susceptible to antifungal drugs. Serum galactomannan (GM), pan-Aspergillus PCR and (1,3)-β-d-glucan (BDG) were positive in 4/6 (67%), 5/6 (83%, 3/5 in two consecutive samples) and 4/6 (67%, in consecutive samples) patients, respectively. GM and PCR positive bronchial secretions had GM indices > 9.95 and PCR Ct < 34. All were treated with antifungal drugs with 5 out of 6 receiving isavuconazole. Mortality was 67% (4/6) with 1/4 attributed to CAPA (two died as a result of bacterial septic shock and one as a result of multiorgan failure).ConclusionThe incidence of CAPA in ICU patients was 3.3% and it was associated with approximately a 17% attributable mortality in the setting of MDR gram-negative pathogen co-infections.

Diagnostics of Pulmonary Aspergillosis in Critically Ill Hematological and Non-Hematological Patients in the Intensive Care Unit By Combined Use of Galactomannan, 1-3-Beta-D-Glucan, Aspergillus Specific PCR and Conventional Culture in Concurrent Blood and Bronchoalveolar Lavage Samples — Results of a Multicenter Prospective Pilot Study

Invasive pulmonary aspergillosis (IPA) is a life-threatening infectious complication mainly affecting immunocompromised hematological patients. Therapeutic success requires early and precise diagnostics. Few data are available on the performance of current diagnostic tests in patients admitted to the intensive care unit (ICU) as the majority of diagnostic studies is conducted in hematological patients and results cannot readily be transferred to patients in the ICU setting.In a prospective multicenter study, we evaluated concurrent bronchoalveolar lavage (BAL) samples and concurrent blood samples from 44 patients admitted to the ICU who required mechanical ventilation and therefore underwent a diagnostic work-up including chest CT scan and BAL (NCT01695499). The subsequent diagnostic work-up comprised of conventional methods for direct detection of Aspergillus spp. as well as biomarkers such as galactomannan (GM) and 1-3-beta-D-glucan (BDG) and an Aspergillus specific nested polymerase chain reaction (PCR).14 patients (32%) suffered from a hematological/hematooncological disease, of which 7 had received allogeneic stem cell transplantation. 6 patients (14%) had a solid tumor requiring chemotherapy. The remaining 24 patients (54%) had no hematological or oncological disease. 11 patients were neutropenic with ANC <1.0/nl (10 belonged to the hematooncological group). According to AspICU classification (Blot et al., Am J Respir Crit Care Med 2012) 9 patients (20%) had putative IPA (3 patients with hematological malignancy). Other invasive fungal diseases (IFD) besides IPA were observed: positive growth of Rhizopus microsporus in BAL was seen in one patient. Furthermore, two cases of disseminated candidiasis with positive growth in blood culture (C.albicans, C.krusei) and one case with positive growth in ascites (C.albicans). Additionally, two cases of Pneumocystis jirovecii pneumonia (PcP) were diagnosed.Diagnostic performance of each single test and of test combinations was analyzed. GM and PCR showed superior performance in BAL (sensitivity/specificity of 56%/94% (GM) and 44%/94% (PCR) compared to 33%/97% and 11%/94% in serum). Despite a better sensitivity of 89%, BDG showed a specificity of only 31% in BAL and 26% in serum, reducing the diagnostic odds ratio (DOR) to 3.7 and 2.8, respectively. For hematological patients the mean GM optical density index (ODI) in BAL was 0.97 and in serum 0.58 compared to 0.59 and 0.16 in non-hematological patients. The strength of agreement between GM in BAL and GM in serum as calculated by Cohen's kappa intertest coherence analysis was 0.62 [0.29-0.95], which is considered to be good. BDG levels and performance of the PCR assay did not differ between hematological and non-hematological patients. The combined use of biomarkers in BAL showed a diagnostic performance of sensitivity/specificity/PPV/NPV and DOR of 89%/31%/25%/92% and 3.67. Testing of GM and BDG solely in serum resulted in a combined test performance of 89%/26%/ 24%/ 90% and 2.77. GM (BAL) combined with BDG (serum) showed high joint sensitivity of 100% with specificity of 25% (DOR 6.81). Using PCR instead of GM dropped sensitivity to 89% (specificity 23%, DOR 2.37). Diagnostic performance of combined GM and PCR testing in BAL showed sensitivity/specificity/PPV/NPV and DOR 67%/89%/60%/91% and 15.0. Cohen's kappa for PCR (BAL) vs. GM (BAL) was 0.49 [0.145 to 0.840], which is considered to be moderate. If a diagnostic algorithm defines BDG (serum) as an initial test that is, in case of a positive result, followed by a confirming test combination from BAL with strong or even exclusive specificity for Aspergillus spp. (GM, PCR and culture) a diagnostic performance is achieved with sensitivity/specificity/positive predictive value/negative predictive value of 88%/97%/88%/97% and DOR >100.This study intended as a pilot study underscores the concept of combined testing in serum and BAL for optimized detection of IPA and provides valuable data for the emerging cohort of critically ill patients, both hematological and non-hematological. Further studies with hematological ICU patients in larger cohorts are planned. DisclosuresBoch:Pfizer research grant (WS 2274964): Research Funding. Buchheidt:Pfizer research grant (WS 2274964): Research Funding.

Differences in Clinical Characteristics of Invasive Tracheobronchial Aspergillosis according to the Presence of Invasive Pulmonary Aspergillosis.

BackgroundThe association of invasive tracheobronchial aspergillosis (ITBA) with invasive pulmonary aspergillosis (IPA) is not well established. We aimed to compare clinical characteristics between patients who exhibited ITBA with IPA and those who exhibited isolated ITBA (iITBA). Additionally, the usefulness of serum or bronchial galactomannan (GM) tests in diagnosing ITBA was evaluated.MethodsThis retrospective single-center case-control study was conducted over a period of 4 years. Fifteen patients were enrolled after confirming the presence of ITBA using bronchoscopy-guided biopsy (iITBA, 7 vs. ITBA+IPA, 8). Clinical characteristics of patients and results obtained from serum or bronchial GM tests were compared between the two groups. Mortality was assessed using data collected from a 6-month follow-up period.ResultsThe ITBA+IPA group showed a higher prevalence of hematologic malignancy (75% vs. 14%, p=0.029), a greater number of patients with multiple bronchial ulcers (75% vs. 14%, p=0.029), lower platelet counts (63,000/μL vs. 229,000/μL, p<0.001), and a mortality rate which was significantly higher (63% vs. 0%, p=0.026) than the iITBA group. In the ITBA+IPA group, 57% of patients tested positive according to the serum GM assay, whereas in the iITBA group, all patients tested negative (p=0.070). The bronchial GM level was high in both groups, but there was no significant difference between them.ConclusionPatients with ITBA+IPA had a greater number of hematologic malignancies with lower platelet counts and a poorer prognosis than patients diagnosed with iITBA. Findings obtained from bronchoscopy and bronchial GM tests were more useful in diagnosing ITBA than the serum GM test results.

Diagnosis values of IL-6 and IL-8 levels in serum and bronchoalveolar lavage fluid for invasive pulmonary aspergillosis in chronic obstructive pulmonary disease

Among immunologically normal hosts, patients with chronic obstructive pulmonary disease (COPD) are considered to be at high risk of invasive pulmonary aspergillosis (IPA), and early diagnosis and treatment are the...

Pulmonary Cavitary Tuberculosis in a Patient with SARS-CoV-2 Pneumonia

<strong>Background:</strong> COVID-19 disease caused by SARS-CoV-2 can lead to severe disease with pneumonia, respiratory failure, and death. Pathologic mechanisms include systemic inflammation with elevated IL-6 level. Glucocorticosteroids and Tocilizumab (TCZ), a monoclonal antibody that inhibits IL-6 receptors, are used to dampen systemic inflammation. We report a case of progressive cavitary tuberculosis during hospitalization for severe COVID-19 disease. <strong>Methods:</strong> Case report and data extraction of baseline demographic disease characteristics and longitudinal data extraction of clinical course, treatment and outcomes. <em><strong>Figure 1</strong></em> can be referred to for a timeline of important clinical events. <strong>Results:</strong> A 44-year-old male with severe COVID-19 disease was placed on invasive mechanical ventilation. He has a history of diabetes and serum glucose was 222 mg/dL at presentation. Interventions included a single dose of TCZ and high dose steroids, with a cumulative dose equivalent to 717 mg of prednisone. The Quantiferon TB (QT TB) test performed on day 2 of steroid administration and prior to TCZ use was negative. His respiratory status improved and he was subsequently extubated. One week later, he developed fever with leukocytosis. Serial, blood, urine, and fungal cultures, as well as serum galactomannan were negative. Serial chest X-rays showed persistent multifocal infiltrates. On day 29, chest CT scan showed a 6.6 × 9.4 × 9.5 cm soft tissue density consolidation within the right lower lobe with multiple internal airspaces and right hilar adenopathy with calcified subcarinal lymph nodes (<em><strong>Figure 2</strong></em>). A sputum culture grew Klebsiella pneumoniae. Despite treatment with broad-spectrum antibacterial and antifungal agents, fever and leukocytosis persisted. On day 35, a second scan revealed increased size of the infiltrate and cavities together with multifocal bronchiectasis and bronchiolectasis. Diabetes control was suboptimal with 45% (79/174) of serum glucose values &gt;180 (range, 50 to 450 mg/dL). Three acid-fast bacillus smears of sputum were found to be positive 3+ and the isolate was subsequently identified as Rifampinsusceptible Mycobacterium tuberculosis. He promptly improved after initiation of a four drug anti-TB treatment with prompt resolution of fever and leukocytosis. Upon further questioning, the patient reported that he had had a positive PPD test in the past after traveling to and from Haiti multiple times and was treated for 3 months in the last 10 years. <strong>Conclusions:</strong> This case illustrates that clinical deterioration in severe COVID-19 disease may be associated with the presence of coexisting pulmonary infections, including TB. While we cannot exclude reactivation of latent TB infection in the setting of incomplete TB infection chemoprophylaxis, it is more likely that the patient presented with unrecognized TB. COVID infiltrates may obscure the radiological features of TB. Multiple factors likely contributed to progressive cavitary disease including delated TB diagnosis, suboptimal diabetes control, immunosuppression, and Klebsiella pneumoniae. Timely use of CT scan when clinical response is slow or atypical for isolated COVID-19 disease together with complete microbiologic evaluation could lead to prompt recognition of coexisting pulmonary infections and improved outcomes.

Cost-Effectiveness of Serum Galactomannan Surveillance during Mould-Active Antifungal Prophylaxis

Serial galactomannan (GM) monitoring can aid the diagnosis of invasive aspergillosis (IA) and optimise treatment decisions. However, widespread adoption of mould-active prophylaxis has reduced the incidence of IA and challenged its use. We evaluated the cost-effectiveness of prophylaxis-biomarker strategies. A Markov model simulating high-risk patients undergoing routine GM surveillance with mould-active versus non-mould-active prophylaxis was constructed. The incremental cost for each additional quality-adjusted life-year (QALY) gained over a lifetime horizon was calculated. In 40- and 60-year-old patients receiving mould-active prophylaxis coupled with routine GM surveillance, the total cost accrued was the lowest at SGD 11,227 (USD 8255) and SGD 9234 (USD 6790), respectively, along with higher QALYs gained (5.3272 and 1.1693). This strategy, being less costly and more effective, dominated mould-active prophylaxis with no GM monitoring or GM surveillance during non-mould-active prophylaxis. The prescription of empiric antifungal treatment was influential in the cost-effectiveness. When the GM test sensitivity was reduced from 80% to 30%, as might be anticipated with the use of mould-active prophylactic agents, the conclusion remained unchanged. The likelihood of GM surveillance with concurrent mould-active prophylaxis being cost-effective was 77%. Routine GM surveillance remained cost-effective during mould-active prophylaxis despite lower IA breakthroughs. Cost-saving from reduced empirical antifungal treatment was an important contributing factor.

Diagnostic yield of a bronchoalveolar lavage fluid galactomannan assay in patients with negative serum galactomannan results suspected to have invasive pulmonary aspergillosis.

There are limited data in real clinical practice on the diagnostic value of a bronchoalveolar lavage (BAL) fluid galactomannan (GM) assay in patients with suspected invasive pulmonary aspergillosis (IPA) who had negative serum GM results. Thus, we investigated the diagnostic performance of a BAL GM assay in patients with negative serum GM assay results who were suspected to have IPA. This retrospective study was performed between May 2008 and April 2019 at a tertiary-care hospital in Seoul, South Korea. All patients with suspected IPA whose serum GM assays revealed negative results who sequentially underwent BAL were enrolled in this study. A total of 341 patients with suspected IPA including four cases of proven IPA, 38 cases of probable IPA, 107 cases of possible IPA and 192 patients without IPA were enrolled. Of these 341 patients, 107 (31%) with possible IPA were excluded from the final analysis. Of 42 patients with proven and probable IPA who had initial negative serum GM results, 24 (57%) had positive BAL GM results (n=24) or BAL fungal culture results (n=8). In addition, BAL revealed evidence of other opportunistic infections including Pneumocystis jirovecii pneumonia (14% [26/190]), cytomegalovirus (CMV) pneumonia (5% [9/188]) and respiratory viral pneumonia (6% [12/193]). Sequential BAL in patients with suspected IPA who had initial negative serum GM results provided additional diagnostic yield in approximately half of patients with evidence of another co-infection.