Post-COVID-19 fatal Aspergillus endocarditis: A case report.

BACKGROUND: Aspergillus endocarditis (AE) is a rare fatal infection. The infection is often reported in patients with prosthetic heart valves, immunosuppressed, broad-spectrum antimicrobial use regimens, and drug abusers. METHODS: Herein, we report a rare case of native mitral valve AE in a 63-year-old man, with a probable COVID-19-associated invasive pulmonary aspergillosis nine months ago treated with antifungals. RESULTS: In the last admission, the lethargy, neurological deficit, and septic-embolic brain abscess in brain MRI led to suspicion of infective endocarditis. Transesophageal two-dimensional echocardiography and color Doppler flow velocity mapping showed a large highly mobile mass destroying leaflet and severe mitral regurgitation. The Surgical valve replacement is performed. The surgical valve replacement is performed. Direct microscopic examination and culture of the explanted and vegetative mass revealed Aspergillus section Fumiagati confirmed by molecular method. Despite the administration of voriconazole and transient improvement the patient expired. CONCLUSION: As AE is a late consequence of COVID-19-associated invasive pulmonary aspergillosis, therefore, long-term follow-up of invasive aspergillosis, and prompt diagnosis of surgical and systemic antifungal therapy treatment, are warranted to provide robust management.

Lung epithelial and myeloid innate immunity in influenza-associated or COVID-19-associated pulmonary aspergillosis: an observational study.

BACKGROUND: Influenza-associated pulmonary aspergillosis (IAPA) and COVID-19-associated pulmonary aspergillosis (CAPA) affect about 15% of critically ill patients with influenza or COVID-19, respectively. These viral-fungal coinfections are difficult to diagnose and are associated with increased mortality, but data on their pathophysiology are scarce. We aimed to explore the role of lung epithelial and myeloid innate immunity in patients with IAPA or CAPA. METHODS: In this observational study, we retrospectively recruited patients who had been admitted to the intensive care unit (ICU) of University Hospitals Leuven, Belgium, requiring non-invasive or invasive ventilation because of severe influenza or COVID-19, with or without aspergillosis, between Jan 1, 2011, and March 31, 2021, whose bronchoalveolar lavage samples were available at the hospital biobank. Additionally, biobanked in vivo tracheobronchial biopsy samples from patients with IAPA or CAPA and invasive Aspergillus tracheobronchitis admitted to ICUs requiring invasive ventilation between the same dates were collected from University Hospitals Leuven, Hospital Network Antwerp (Belgium), and Amiens-Picardie University Hospital (France). We did nCounter gene expression analysis of 755 genes linked to myeloid innate immunity and protein analysis of 47 cytokines, chemokines, and growth factors on the bronchoalveolar lavage samples. Gene expression data were used to infer cell fractions by use of CIBERSORTx, to perform hypergeometric enrichment pathway analysis and gene set enrichment analysis, and to calculate pathway module scores for the IL-1ß, TNF-α, type I IFN, and type II IFN (IFNγ) pathways. We did RNAScope targeting influenza virus or SARS-CoV-2 RNA and GeoMx spatial transcriptomics on the tracheobronchial biopsy samples. FINDINGS: Biobanked bronchoalveolar lavage samples were retrieved from 166 eligible patients, of whom 40 had IAPA, 52 had influenza without aspergillosis, 33 had CAPA, and 41 had COVID-19 without aspergillosis. We did nCounter gene expression analysis on bronchoalveolar lavage samples from 134 patients, protein analysis on samples from 162 patients, and both types of analysis on samples from 130 patients. We performed RNAScope and spatial transcriptomics on the tracheobronchial biopsy samples from two patients with IAPA plus invasive Aspergillus tracheobronchitis and two patients with CAPA plus invasive Aspergillus tracheobronchitis. We observed a downregulation of genes associated with antifungal effector functions in patients with IAPA and, to a lesser extent, in patients with CAPA. We found a downregulated expression of several genes encoding proteins with functions in the opsonisation, recognition, and killing of conidia in patients with IAPA versus influenza only and in patients with CAPA versus COVID-19 only. Several genes related to LC3-associated phagocytosis, autophagy, or both were differentially expressed. Patients with CAPA had significantly lower neutrophil cell fractions than did patients with COVID-19 only. Patients with IAPA or CAPA had downregulated IFNγ signalling compared with patients with influenza only or COVID-19 only, respectively. The concentrations of several fibrosis-related growth factors were significantly elevated in the bronchoalveolar lavage fluid from patients with IAPA versus influenza only and from patients with CAPA versus COVID-19 only. In one patient with CAPA, we visualised an active or very recent SARS-CoV-2 infection disrupting the epithelial barrier, facilitating tissue-invasive aspergillosis. INTERPRETATION: Our results reveal a three-level breach in antifungal immunity in IAPA and CAPA, affecting the integrity of the epithelial barrier, the capacity to phagocytise and kill Aspergillus spores, and the ability to destroy Aspergillus hyphae, which is mainly mediated by neutrophils. The potential of adjuvant IFNγ in the treatment of IAPA and CAPA should be investigated. FUNDING: Research Foundation Flanders, Coronafonds, the Max Planck Society, the Fundação para a Ciência e a Tecnologia, the European Regional Development Fund, "la Caixa" Foundation, and Horizon 2020.

Tendency in Pulmonary Aspergillosis Investigation during the COVID-19 Era: What Is Changing?

Aspergillosis is a disease caused by Aspergillus, and invasive pulmonary aspergillosis (IPA) is the most common invasive fungal infection leading to death in severely immuno-compromised patients. The literature reports Aspergillus co-infections in patients with COVID-19 (CAPA). Diagnosing CAPA clinically is complex since the symptoms are non-specific, and performing a bronchoscopy is difficult. Generally, the microbiological diagnosis of aspergillosis is based on cultural methods and on searching for the circulating antigens galactomannan and 1,3-ß-D-glucan in the bronchoalveolar lavage fluid (bGM) or serum (sGM). In this study, to verify whether the COVID-19 period has stimulated clinicians to pay greater attention to IPA in patients with respiratory tract infections, we evaluated the number of requests for GM-Ag research and the number of positive tests found during the pre-COVID-19 and COVID-19 periods. Our data show a significant upward trend in GM-Ag requests and positivity from the pre-COVID to COVID period, which is attributable in particular to the increase in IPA risk factors as a complication of COVID-19. In the COVID period, parallel to the increase in requests, the number of positive tests for GM-Ag also increased, going from 2.5% in the first period of 2020 to 12.3% in the first period of 2021.

[COVID-19-associated pulmonary aspergillosis in critically ill patients: experience of a Chilean public hospital]. / Aspergilosis pulmonar asociada a COVID-19 en pacientes críticos: experiencia de un hospital público chileno.

BACKGROUND: Aspergillus spp. fungal coinfections have been described in critically ill COVID-19 patients. AIM: To describe the clinical characteristics, diagnosis, treatment and evolution of patients with acute respiratory distress syndrome with COVID-19, who present with COVID-19 associated pulmonary aspergillosis (CAPA) in a single public hospital. METHODS: Retrospective review of clinical records during 12 months in patients diagnosed with CAPA by cultures of respiratory samples or determination of galactomannan (GM). RESULTS: Probable CAPA was diagnosed in 11 patients (average APACHE II score of 11.7). Respiratory samples were obtained in 73% of cases by bronchoalveolar lavage and in 27% by tracheal aspirate. A. fumigatus was isolated in 4 cultures, A. niger, A. terreus and Aspergillus spp on one occasion each and the cultures were negative in 4 samples. Respiratory sample GM was performed in 7 patients, median: 3.6 (IQR: 1.71 - 4.4). In 10 patients, serum GM was performed, median: 0.5 (IQR: 0.265 - 0.9 75) with 50% of them > 0.5. Two patients showed classic findings suggestive of CAPA on computed tomography. All received antifungal therapy with voriconazole, mean time 14 days. Four patients died. CONCLUSIONS: The presence of CAPA should be a diagnosis to be considered in critically ill COVID-19 patients.

A screening study for COVID-19-associated pulmonary aspergillosis in critically ill patients during the third wave of the pandemic.

BACKGROUND: COVID-19-associated pulmonary aspergillosis (CAPA) has been reported as an important cause of mortality in critically ill patients with an incidence rate ranging from 5% to 35% during the first and second pandemic waves. OBJECTIVES: We aimed to evaluate the incidence, risk factors for CAPA by a screening protocol and outcome in the critically ill patients during the third wave of the pandemic. PATIENTS/METHODS: This prospective cohort study was conducted in two intensive care units (ICU) designated for patients with COVID-19 in a tertiary care university hospital between 18 November 2020 and 24 April 2021. SARS-CoV-2 PCR-positive adult patients admitted to the ICU with respiratory failure were included in the study. Serum and respiratory samples were collected periodically from ICU admission up to CAPA diagnosis, patient discharge or death. ECMM/ISHAM consensus criteria were used to diagnose and classify CAPA cases. RESULTS: A total of 302 patients were admitted to the two ICUs during the study period, and 213 were included in the study. CAPA was diagnosed in 43 (20.1%) patients (12.2% probable, 7.9% possible). In regression analysis, male sex, higher SOFA scores at ICU admission, invasive mechanical ventilation and longer ICU stay were significantly associated with CAPA development. Overall ICU mortality rate was higher significantly in CAPA group compared to those with no CAPA (67.4% vs 29.4%, p < .001). CONCLUSIONS: One fifth of critically ill patients in COVID-19 ICUs developed CAPA, and this was associated with a high mortality.

Risk Factors for Coronavirus Disease 2019 (COVID-19)-Associated Pulmonary Aspergillosis in Critically Ill Patients: A Nationwide, Multicenter, Retrospective Cohort Study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is often accompanied by secondary infections, such as invasive aspergillosis. In this study, risk factors for developing COVID-19-associated pulmonary aspergillosis (CAPA) and their clinical outcomes were evaluated. METHODS: This multicenter retrospective cohort study included critically ill COVID-19 patients from July 2020 through March 2021. Critically ill patients were defined as patients requiring high-flow respiratory support or mechanical ventilation. CAPA was defined based on the 2020 European Confederation of Medical Mycology and the International Society for Human and Animal Mycology consensus criteria. Factors associated with CAPA were analyzed, and their clinical outcomes were adjusted by a propensity score-matched model. RESULTS: Among 187 eligible patients, 17 (9.1%) developed CAPA, which is equal to 33.10 per 10,000 patient-days. Sixteen patients received voriconazole-based antifungal treatment. In addition, 82.4% and 53.5% of patients with CAPA and without CAPA, respectively, received early high-dose corticosteroids (P = 0.022). In multivariable analysis, initial 10-day cumulative steroid dose > 60 mg of dexamethasone or dexamethasone equivalent dose) (adjusted odds ratio [OR], 3.77; 95% confidence interval [CI], 1.03-13.79) and chronic pulmonary disease (adjusted OR, 4.20; 95% CI, 1.26-14.02) were independently associated with CAPA. Tendencies of higher 90-day overall mortality (54.3% vs. 35.2%, P = 0.346) and lower respiratory support-free rate were observed in patients with CAPA (76.3% vs. 54.9%, P = 0.089). CONCLUSION: Our study showed that the dose of corticosteroid use might be a risk factor for CAPA development and the possibility of CAPA contributing to adverse outcomes in critically ill COVID-19 patients.

Combination of Mycological Criteria: a Better Surrogate to Identify COVID-19-Associated Pulmonary Aspergillosis Patients and Evaluate Prognosis?

Diagnosis of coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) remains unclear especially in nonimmunocompromised patients. The aim of this study was to evaluate seven mycological criteria and their combination in a large homogenous cohort of patients. All successive patients (n = 176) hospitalized for COVID-19 requiring mechanical ventilation and who clinically worsened despite appropriate standard of care were included over a 1-year period. Direct examination, culture, Aspergillus quantitative PCR (Af-qPCR), and galactomannan testing were performed on all respiratory samples (n = 350). Serum galactomannan, ß-d-glucan, and plasma Af-qPCR were also assessed. The criteria were analyzed alone or in combination in relation to mortality rate. Mortality was significantly different in patients with 0, ≤2, and ≥3 positive criteria (log rank test, P = 0.04) with death rate of 43.1, 58.1, and 76.4%, respectively. Direct examination, plasma qPCR, and serum galactomannan were associated with a 100% mortality rate. Bronchoalveolar lavage (BAL) galactomannan and positive respiratory sample culture were often found as isolated markers (28.1 and 34.1%) and poorly repeatable when a second sample was obtained. Aspergillus DNA was detected in 13.1% of samples (46 of 350) with significantly lower quantitative cycle (Cq) when associated with at least one other criterion (30.2 versus 35.8) (P < 0.001). A combination of markers and/or blood biomarkers and/or direct respiratory sample examination seems more likely to identify patients with CAPA. Af-qPCR may help identifying false-positive results of BAL galactomannan testing and culture on respiratory samples while quantifying fungal burden accurately.

Prognostic Impact of Bronchoalveolar Lavage Fluid Galactomannan and Aspergillus Culture Results on Survival in COVID-19 Intensive Care Unit Patients: a Post Hoc Analysis from the European Confederation of Medical Mycology (ECMM) COVID-19-Associated Pulmonary Aspergillosis Study.

Critically ill patients with coronavirus disease 2019 (COVID-19) may develop COVID-19-associated pulmonary aspergillosis (CAPA), which impacts their chances of survival. Whether positive bronchoalveolar lavage fluid (BALF) mycological tests can be used as a survival proxy remains unknown. We conducted a post hoc analysis of a previous multicenter, multinational observational study with the aim of assessing the differential prognostic impact of BALF mycological tests, namely, positive (optical density index of ≥1.0) BALF galactomannan (GM) and positive BALF Aspergillus culture alone or in combination for critically ill patients with COVID-19. Of the 592 critically ill patients with COVID-19 enrolled in the main study, 218 were included in this post hoc analysis, as they had both test results available. CAPA was diagnosed in 56/218 patients (26%). Most cases were probable CAPA (51/56 [91%]) and fewer were proven CAPA (5/56 [9%]). In the final multivariable model adjusted for between-center heterogeneity, an independent association with 90-day mortality was observed for the combination of positive BALF GM and positive BALF Aspergillus culture in comparison with both tests negative (hazard ratio, 2.53; 95% CI confidence interval [CI], 1.28 to 5.02; P = 0.008). The other independent predictors of 90-day mortality were increasing age and active malignant disease. In conclusion, the combination of positive BALF GM and positive BALF Aspergillus culture was associated with increased 90-day mortality in critically ill patients with COVID-19. Additional study is needed to explore the possible prognostic value of other BALF markers.

COVID-19-associated pulmonary aspergillosis (CAPA): Risk factors and development of a predictive score for critically ill COVID-19 patients.

BACKGROUND: COVID-19-associated pulmonary aspergillosis (CAPA) is a major complication of critically ill COVID-19 patients, with a high mortality rate and potentially preventable. Thus, identifying patients at high risk of CAPA would be of great interest. We intended to develop a clinical prediction score capable of stratifying patients according to the risk for CAPA at ICU admission. METHODS: Single centre retrospective case-control study. A case was defined as a patient diagnosed with CAPA according to 2020 ECMM/ISHAM consensus criteria. 2 controls were selected for each case among critically ill COVID-19 patients. RESULTS: 28 CAPA patients and 56-matched controls were included. Factors associated with CAPA included old age (68 years vs. 62, p = .033), active smoking (17.9% vs. 1.8%, p = .014), chronic respiratory diseases (48.1% vs. 26.3%, p = .043), chronic renal failure (25.0% vs. 3.6%, p = .005), chronic corticosteroid treatment (28.6% vs. 1.8%, p < .001), tocilizumab therapy (92.9% vs. 66.1%, p = .008) and high APACHE II at ICU admission (median 13 vs. 10 points, p = .026). A score was created including these variables, which showed an area under the receiver operator curve of 0.854 (95% CI 0.77-0.92). A punctuation below 6 had a negative predictive value of 99.6%. A punctuation of 10 or higher had a positive predictive value of 27.9%. CONCLUSION: We present a clinical prediction score that allowed to stratify critically ill COVID-19 patients according to the risk for developing CAPA. This CAPA score would allow to target preventive measures. Further evaluation of the score, as well as the utility of these targeted preventive measures, is needed.

Utility of serum Galactomannan in diagnosing COVID-19 patients with suspected IPA: an observational study in resource limited settings.

OBJECTIVE: To study the utility of Galactomannan (GM) antigen as a screening marker for diagnosing invasive pulmonary aspergillosis (IPA) in coronavirus disease 2019 (COVID-19) patients. PATIENTS AND METHODS: The serum samples from patients with severe COVID-19 diseases admitted to the Critical Care Unit were collected on the 5th day of admission for GM screening. The samples were analysed by enzyme linked immune sorbent assay (ELISA) and GM index of more than 1 was considered as positive. All GM positive patients were serially followed until discharge or death. RESULTS: The GM was raised in serum of 12 out of 38 patients, indicating an incidence of possible COVID-19 associated IPA (CAPA) in 31.57% of patients. The median age of these CAPA patients was 56.5 years, males were significantly more affected than females. The inflammatory marker serum ferritin was raised in all 12 patients (median value of 713.74 ng/ml), while IL-6 was raised in 9 patients (median value of 54.13 ng/ml). None of these patients received antifungals. Their median length of hospital stay was 20 days (IQR: 12, 34 days). All these patients succumbed to the illness. CONCLUSIONS: The serum GM appears to be sensitive diagnostic tool to identify early IPA in COVID-19 patients and pre-emptive antifungal therapy could play a role in salvaging these patients.

Navigating the Uncertainties of COVID-19-Associated Aspergillosis: A Comparison With Influenza-Associated Aspergillosis.

Invasive pulmonary aspergillosis (IPA) is increasingly recognized as a life-threatening superinfection of severe respiratory viral infections, such as influenza. The pandemic of Coronavirus Disease 2019 (COVID-19) due to emerging SARS-CoV-2 rose concern about the eventuality of IPA complicating COVID-19 in intensive care unit patients. A variable incidence of such complication has been reported, which can be partly attributed to differences in diagnostic strategy and IPA definitions, and possibly local environmental/epidemiological factors. In this article, we discuss the similarities and differences between influenza-associated pulmonary aspergillosis (IAPA) and COVID-19-associated pulmonary aspergillosis (CAPA). Compared to IAPA, the majority of CAPA cases have been classified as putative rather than proven/probable IPA. Distinct physiopathology of influenza and COVID-19 may explain these discrepancies. Whether CAPA represents a distinct entity is still debatable and many questions remain unanswered, such as its actual incidence, the predisposing role of corticosteroids or immunomodulatory drugs, and the indications for antifungal therapy.

COVID-19 Infection and Late Manifestation of Pulmonary Aspergillosis.

We present the case of a 56-year-old woman who was diagnosed with severe coronavirus disease 2019 (COVID-19) pneumonia complicated by severe acute respiratory distress syndrome who was intubated for 19 days. She recovered from COVID-19 after a month. A computed tomography (CT) scan of the chest, after a month, showed improved infiltrates with a small residual cavity within the lingula. A CT angiogram showed a more confluent density in the lingular portion on follow-up 2 months later. She developed intermittent hemoptysis after 3 months in December 2020, which persisted for almost 6 months, and CT of the chest showed the lingular nodular with resolution of the cavitation. She underwent bronchoscopy with bronchoalveolar lavage, confirming Aspergillus fumigatus by galactomannan assay and histology showing branching hyphae. Once she started treatment with itraconazole, her hemoptysis resolved. The follow-up CT of the chest after 2 months of treatment did not show a cavity or a nodule in the lingula. Our patient developed invasive pulmonary aspergillosis (IPA) as a sequela of severe COVID-19 infection. COVID-19-associated invasive pulmonary aspergillosis (CAPA) is an underrecognized complication that needs to be investigated on whether prophylactic treatment is required. Our case also demonstrates that the diagnosis of IPA needs to be considered months after COVID-19 infection when a superimposed fungal infection can occur after a viral infection if the patient continues to have persistent symptoms.

Spontaneous Hemoptysis in a Patient With COVID-19.

CASE PRESENTATION: A 65-year-old man presented with shortness of breath, gradually worsening for the previous 2 weeks, associated with dry cough, sore throat, and diarrhea. He denied fever, chills, chest pain, abdominal pain, nausea, or vomiting. He did not have any sick contacts or travel history outside of Michigan. His medical history included hypertension, diabetes mellitus, chronic kidney disease, morbid obesity, paroxysmal atrial fibrillation, and tobacco use. He was taking amiodarone, carvedilol, furosemide, pregabalin, and insulin. The patient appeared to be in mild respiratory distress. He was afebrile and had saturation at 93% on 3 L of oxygen, heart rate of 105 beats/min, BP of 145/99 mm Hg, and respiratory rate of 18 breaths/min. On auscultation, there were crackles on bilateral lung bases and chronic bilateral leg swelling with hyperpigmented changes. His WBC count was 6.0 K/cumm (3.5 to 10.6 K/cumm) with absolute lymphocyte count 0.7 K/cumm (1.0 to 3.8 K/cumm); serum creatinine was 2.81 mg/dL (0.7 to 1.3 mg/dL). He had elevated inflammatory markers (serum ferritin, C-reactive protein, lactate dehydrogenase, D-dimer, and creatinine phosphokinase). Chest radiography showed bilateral pulmonary opacities that were suggestive of multifocal pneumonia (Fig 1). Nasopharyngeal swab for SARS-CoV-2 was positive. Therapy was started with ceftriaxone, doxycycline, hydroxychloroquine, and methylprednisolone 1 mg/kg IV for 3 days. By day 3 of hospitalization, he required endotracheal intubation, vasopressor support, and continuous renal replacement. Blood cultures were negative; respiratory cultures revealed only normal oral flora, so antibiotic therapy was discontinued. On day 10, WBC count increased to 28 K/cumm, and chest radiography showed persistent bilateral opacities with left lower lobe consolidation. Repeat respiratory cultures grew Pseudomonas aeruginosa (Table 1). Antibiotic therapy with IV meropenem was started. His condition steadily improved; eventually by day 20, he was off vasopressors and was extubated. However, on day 23, he experienced significant hemoptysis that required reintubation and vasopressor support.

Invasive pulmonary aspergillosis in a COVID-19 recovered patient: unravelling an infective sequalae of the SARS-CoV-2 virus.

Dear Editor, A 55-year-female, house wife, non-smoker, morbidly obese (BMI>35) with no other co-morbidities or pre-existing lung disease presented to the emergency room with complaints of highgrade fever, cough with minimal sputum, progressive breathlessness, streaky haemoptysis, and anorexia for the past 5 days. She was admitted in intensive care unit (ICU) for severe COVID-19 pneumonia three months back and had successfully recovered after 24 days of hospitalization....

[Invasive fungal infections in ICU patients - What's New?] / Invasive Pilzinfektionen bei Intensivpatienten ­ Was gibt es Neues?

Invasive fungal infections are gaining increasing importance in intensive care medicine. The aim of this article is to present an update on recent developments in the field of invasive fungal infection in critically ill patients. Particular emphasis is placed on the recently described invasive mold infections in patients with acute respiratory distress syndrome due to influenza or COVID-19. Detecting high-risk patients and the optimal diagnostic and therapeutic strategies play a decisive role to improve outcome.

Invasive pulmonary aspergillosis in COVID-19 critically ill patients: Results of a French monocentric cohort.

INTRODUCTION: Coronavirus disease 2019 or COVID-19 is a new infectious disease responsible for potentially severe respiratory impairment associated with initial immunosuppression. Similarly to influenza, several authors have described a higher risk of fungal infection after COVID-19, in particular for invasive pulmonary aspergillosis. The main objective here is to define the prevalence of invasive pulmonary aspergillosis (IPA) in a cohort of COVID-19 patients with moderate to severe acute respiratory disease syndrome (ARDS). MATERIAL AND METHODS: We conducted a large monocentric retrospective study investigating all the ventilated COVID-19 patients with ARDS hospitalized at Valenciennes' general hospital, France, between March 15, 2020 and April 30, 2020. In the center a systematic IPA screening strategy was carried out for all ARDS patients, with weekly tests of serum galactomannan and beta-D-glucan. Bronchoalveolar lavage with culture and chest CT scan were performed when the serum assays were positives. RESULTS: A total of 54 patients were studied. Their median age was 65 years, and 37 of the patients (71%) were male. Two patients had chronic immunosuppression and among all the patients, only 2 non-immunocompromised presented a putative IPA during their stay. CONCLUSION: The prevalence of IPA in this cohort of COVID-19 patients (3.7%) is not higher than what is described in the other ARDS populations in the literature. These results are however different from the previous publications on COVID-19 patients and must therefore be confirmed by larger and multicentric studies.

Ruxolitinib as adjunctive therapy for secondary hemophagocytic lymphohistiocytosis: A case series.

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a cytokine storm syndrome associated with mortality rates of up to 88%. Standard therapy with high-dose glucocorticoids and etoposide used in adults is extrapolated from pediatric trials, with significant toxicity in older patients and those with poor performance status. The JAK1/2 inhibitor ruxolitinib has recently gained attention as a treatment option for HLH due to its broad cytokine-modulating abilities and safety profile. Herein we report our center's experience using ruxolitinib in the treatment of adult-onset secondary HLH. CASE SERIES: We report four patients with profound secondary HLH provoked by diverse triggers, including invasive pulmonary aspergillosis on background systemic lupus erythematosus, disseminated tuberculosis, and T-cell lymphoma treated with ruxolitinib as monotherapy or combination therapy in upfront and salvage settings. RESULTS: All four patients had rapid, sustained improvement in clinical status, inflammatory markers, and hematological cell counts followed by durable remission. Three patients developed manageable infectious complications postruxolitinib. CONCLUSIONS: This series demonstrates the effective use of JAK inhibition with ruxolitinib to control pathological immune activation in critically ill patients with secondary HLH and otherwise limited therapeutic options. JAK inhibition is also an area of urgent investigation for the treatment of cytokine storm associated with COVID-19.

Invasive pulmonary aspergillosis associated with COVID-19 in a kidney transplant recipient.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might increase the risk of invasive pulmonary aspergillosis (IPA). Although several case reports and small series have been reported in the general population, scarce information is available regarding coronavirus disease 2019 (COVID-19)-associated IPA in the setting of solid organ transplantation. We describe a case of a kidney transplant recipient with severe COVID-19 that was subsequently diagnosed with probable IPA on the basis of the repeated isolation of Aspergillus fumigatus in sputum cultures, repeatedly increased serum (1 â†’ 3)-ß-d-glucan levels, and enlarging cavitary nodules in the CT scan. The evolution was favorable after initiation of isavuconazole and nebulized liposomal amphotericin B combination therapy and the withdrawal of immunosuppression.