Invasive Aspergillosis Associated with Severe Influenza Infections

Nancy Crum-Cianflone MD MPH Scripps Mercy Hospital, San Diego, CA USA

Abstract Background (cont.) Results Results (cont.)

Background: Bacterial superinfections are well-described complications of influenza • Typically, invasive aspergillosis occurs among severely immunosuppressed hosts Case-Control Study • Systematic Review of the Literature infection, however few data exist on invasive fungal infections in this setting. The Hematologic malignancies, neutropenia, and transplant recipients 48 medical ICU patients underwent influenza testing; 8 were diagnosed with influenza  N=52 and present cases (n=5) = 57 total cases • All influenza-positive patients had ventilator-dependent respiratory failure  A summary of the cases is shown in Table 2 pathogenesis of invasive aspergillosis may be related to respiratory epithelium • Isolation of Aspergillus sp. in the immunocompetent host without these conditions may be initially considered as a colonizer or non-pathogen Of the 8 patients with severe influenza infection, six (75%) had Aspergillus sp. isolated  Increasing number of cases over time: disruption and viral-induced lymphopenia. • 4 A. fumigatus, 1 A. fumigatus and A. versicolor, and 1 A. niger isolated • First cases described in 1979, followed by three cases in the 1980s, two cases in the 1990s, two cases in • However, recent cases have suggested that Aspergillus may rapidly lead to invasive • Since A. niger was of unknown pathogenicity this case was excluded the 2000’s, and 48 cases from 2010 to the 1st quarter of 2016 demonstrating an increasing trend of aspergillosis superinfection (p<0.001) Methods: A retrospective study was conducted among severe influenza cases requiring disease in the setting of severe influenza infection [2,3] Of the 40 patients negative for influenza admitted to the same ICU, none had Aspergillus ICU admission at a large academic hospital (2015-2016). Data collected included • Patient Characteristics Table 2: Summary of 57 Cases of Invasive Aspergillus during Influenza Infection: Current Cases and Literature Review Characteristic Number (%)* or Median (range) Aspergillus Data respiratory cultures; medical conditions; laboratory and radiographic data; and outcome. • The pathogenesis of invasive aspergillosis in this setting may include:  Study population characteristics are shown in Table 1 • Of the 5 patients with Aspergillus sp. superinfection, median age was 59 years (range 47-86) Demographics Days from influenza to Aspergillus 6 (0-32)*  Viral disruption of the respiratory epithelium Age, years 53 (23-86) diagnosis Aspergillosis was defined using EORTC guidelines. A systematic literature review and all were male • Local damage to the tracheobronchial mucosa and disruption of normal ciliary clearance Sex, male 38 (67%) Sites of Aspergillosis*** • None had an immunosuppressive underlying medical condition or receiving immunosuppressants prior to (PubMed; 1963-2015) of cases in the English language of aspergillosis complicating Underlying Medical Conditions at Lung 57 (100%)  Impaired local immunity admission influenza was conducted. Admission Tracheobronchitis 9 (16%) • Influenza may impair local phagocytosis by alveolar macrophages as well as reduce natural • Influenza Data Vitamin“Classic underlying D deficiency disease”** has been18 (32%) increasingly recognizedSystemic among persons worldwide6 (11%) [41]. killer cell functionality and other immune responses via cytokine imbalances  The influenza type was A (H1N1) (n=2) and influenza B (n=3) Underlying condition, yes 46 (81%) Species Results: Of the 48 ICU patients with influenza testing (nasopharyngeal PCR and/or  Viral-induced systemic Th1/Th2 changes Types of conditions*** A. fumigatus 40 (70%)  All patients received anti-influenza medications Cancer 12 (21%) A. fumigatus and A. versicolor 1 (2%)  Viral-induced lymphopenia [4-8] respiratory viral culture), 8 were diagnosed with severe influenza infection. Of these, six • Aspergillus Superinfection Neutropenia 9 (16%) A. fumigatus and A. nidulans 1 (2%) (75%) had Aspergillus sp. isolated (4 A. fumigatus, 1 A. fumigatus and A. versicolor, Diabetes 9 (16%) A. niger 1 (2%)  Timing between influenza and Aspergillus was a median 3 days (range 0-8) Transplantation 8 (14%) A. terreus 1 (2%) and 1 A. niger) from respiratory cultures a median of 3 days (range 0-8) after influenza  All aspergillosis cases had diffuse pulmonary consolidative infiltrates Underlying lung disease 7 (12%) Not reported 13 (23%) diagnosis [3 influenza A(H1N1); 3 B]. Since A. niger was of unknown pathogenicity, this Methods • One also had fungal tracheobronchitis (Figure 1) Immunosuppressant use at admission 18 (32%) EORTC/MSG Criteria Immunosuppressed host (based on 20 (35%) Proven 21 (37%) case was excluded from the analyses. Of the 40 patients negative for influenza • Galactomannan and/or β-glucan levels were evaluated in 4 patients, and 3 (75%) condition and/or medication use) Probable 14 (25%) • Study Design: had positive results Possible 22 (39%) admitted to the same ICU, none had Aspergillus isolated. No patient with Aspergillus Influenza-Related Data Antifungal therapy, yes 53 (93%)  A case-control study was conducted among patients tested for influenza infection who were admitted • Overall, case 1 met the EORTC/MSG criteria for probable aspergillosis and cases was immunosuppressed. Galactomannan and/or β-glucan levels were positive in 75% Type Outcomes to the medical ICU at a large academic hospital (400-bed) during the 2015-2016 influenza season 2-5 for possible aspergillosis A 53 (93%) of patients tested. All aspergillosis cases had diffuse pulmonary consolidative infiltrates, Mechanical ventilation  Additionally, a systematic review (PubMed January 1963 - March 2016) of the English published • All cases received prompt antifungal therapy B 4 (7%) Yes 38 (67%) and all except one had lymphopenia (median 520/µl) vs. those without aspergillosis literature using the search terms “influenza” and “aspergillus” or “aspergillosis” was conducted Receipt of anti-influenza treatment 30 (53%) No 11 (19%) • Outcomes Hospitalization Data Not reported 8 (14%) (1095/µl). Mortality was 60% among influenza-Aspergillus co-infected patients, with two  Mortality occurred in 3 of 5 (60%) of patients Lymphopenia (<1000 cells/μL) 19/23 (18%) ECMO 12 (21%) survivors having significant morbidity including respiratory failure >30 days. Review of • Study Population: • The two survivors had significant post-infection morbidities Steroid use, yes 18 (32%) Mortality 26 (46%) the literature and current cases yielded n=57 (EORTC: 37% proven, 25% probable, and  Case control study: All ICU patients with influenza testing performed via nasopharyngeal swab *Denominator is 57 unless otherwise noted; the denominator for time to Aspergillus diagnosis was n=36. **Classic immunosuppressive condition included leukemia, neutropenia, and/or transplant recipient. All patients with an underlying condition were also on an 39% possible cases). An increasing number of cases were noted since 2010 mostly polymerase chain reaction (PCR) or respiratory viral culture immunosuppressant medication at admission, except for two patients. All patients receiving an immunosuppressant were also diagnosed with a classic • A case was defined as a patient with confirmed influenza infection who subsequently had a positive respiratory culture for Aspergillus underlying medical condition except in two cases: myasthenia gravis (n=1) and TTP (n=1) who were receiving steroids. linked to H1N1 influenza A; only 1/3 had classic underlying conditions for aspergillosis; • A control was a patient with confirmed influenza infection without evidence of Aspergillus on respiratory culture during the hospitalization ***More than one factor may be present, hence the percentage may exceed 100%. Figure 1: Fungal Tracheobronchitis Abbreviations: ECMO, extracorporeal membrane oxygenation; EORTC/MSG, European Organization for Research and Treatment of Cancer/Invasive Fungal 86% had lymphopenia; 78-88% had a positive fungal serologic markers; and overall  Systematic review: Published cases of confirmed influenza as demonstrated by a positive influenza Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group; PCR, polymerase chain reaction. mortality rate was 46%. viral culture, PCR, or serology • Cases involving non-specific viral infections or without confirmatory influenza testing, reports with insufficient patient information, and Table 1: Case-Control Study of Influenza with Aspergillus Superinfection among ICU Patients, 2015-2016 instances in which the Aspergillus diagnosis preceded influenza infection were excluded Conclusions Conclusion: Aspergillosis is an emerging complication of severe influenza infections even among immunocompetent hosts. Risks may include viral-induced lymphopenia, • Study Procedures: • Aspergillus is a potential emerging complication of severe influenza infections, even although further studies are needed. Prompt diagnosis (using respiratory cultures and  Data collected included respiratory cultures; medical conditions; laboratory and radiographic data; and among immunocompetent hosts outcome potentially preemptive galactomannan and/or β-glucan testing) and antifungal therapy • Progressive pulmonary infection after the initial diagnosis of influenza should raise  Aspergillosis was defined using EORTC/MSG consensus guidelines [15] are recommended given the high mortality rate. • For those with aspergillosis, data on the number of days between the diagnosis of influenza and aspergillosis, Aspergillus species, suspicion of superinfection including with Aspergillus bronchoscopy findings (if performed), supporting laboratory findings for the diagnosis of aspergillosis (galactomannan and β-glucan levels), and antifungal therapy were recorded • Risks may include viral-induced lymphopenia, however further data on the exact pathogenesis are needed Background . Study Objectives: • Reducing potential risk factors for invasive aspergillus among severe influenza cases  Evaluate the occurrence of invasive Aspergillus complicating severe influenza infections and describe should be considered including potentially limiting the use of unnecessary antibiotics • Bacterial superinfections (Streptococcus pneumoniae and Staphylococcus aureus) the risk factors and outcomes of this potential superinfection and steroids are well-described complications of influenza infections and often contribute to • Prompt diagnosis (using respiratory cultures, CT imaging, as well as potentially excess morbidity and mortality [1] • Statistical Analyses: preemptive galactomannan and β-glucan levels) and early antifungal therapy are • Case reports describing novel superinfection involving invasive Aspergillus during  Descriptive statistics including numbers (percentages) and medians (ranges) for categorical and recommended given the high mortality and morbidity associated with this severe influenza infections [2,3] continuous variables, respectively superinfection.  Comparisons were made using independent T tests and chi-square testing (Fisher’s exact tests were utilized if the cell size was <5)  Data analyses was performed using SPSS (IBM SPSS Statistics for Windows, Version 22.0. Armonk, Correspondence NY: IBM Corp, 2013) Nancy Crum-Cianflone, MD, MPH, FACP, FIDSA Aspergillus, photo from CDC Email: [email protected] ; Phone (619) 298-1443