Contains fulltext :
                  229566.pdf (Publisher’s version ) (Open Access

Arkel, A.L.E. van

Belderbos, H.N.A.

Bentvelsen, R.G.

Rijpstra, T.A.

Verweij, P.E.

Wijngaarden, P. van

Radboud Repository

COVID-19-associated Pulmonary Aspergillosis

NARCIS 

Leiden University Scholary Publications

COVID-19-associated pulmonary aspergillosisArkel, A.L.E. van; Rijpstra, T.A.; Belderbos, H.N.A.; Wijngaarden, P. van; Verweij, P.E.;Bentvelsen, R.G.CitationArkel, A. L. E. van, Rijpstra, T. A., Belderbos, H. N. A., Wijngaarden, P. van, Verweij, P. E., &Bentvelsen, R. G. (2020). COVID-19-associated pulmonary aspergillosis, 202(1), 132-135.doi:10.1164/rccm.202004-1038LE Version: Publisher's VersionLicense: Creative Commons CC BY-NC-ND 4.0 licenseDownloaded from: https://hdl.handle.net/1887/3184180 Note: To cite this publication please use the final published version (if applicable).of intermittent iNO therapy made this approach reasonable forour patient.This patient was remotely managed by clinicians and wasmore amenable (as a physician herself) to self-monitoring andself-directed therapy than the ordinary patient would be. This isnot a typical case, and although the clinical improvement sheexperienced may not be wholly generalizable, her care representsa first step toward support for outpatient use of iNO to treatexacerbation of PH symptoms due to COVID-19. This approachshould not replace best clinical practices when patients presentwith more substantial symptoms and progressive worsening.Although this case may serve as a proof of concept, itdoes not prove the utility of iNO for treating respiratorymanifestations of COVID-19. Well-designed clinical trials areneeded to evaluate the effectiveness of iNO in the setting ofCOVID-19. If this approach is demonstrated to be effective,outpatient iNO may serve to not only improve clinical outcomesbut also reduce the strain on inpatient resources in the currentpandemic. nAuthor disclosures are available with the text of this letter atwww.atsjournals.org.Roham T. Zamanian, M.D.*Stanford University School of MedicineStanford, CaliforniaandVera Moulton Wall Center for Pulmonary Vascular DiseaseStanford, CaliforniaCharles V. Pollack, Jr., M.D.University of Mississippi School of MedicineJackson, MississippiMichael A. Gentile, R.R.T.Vero BiotechAtlanta, GeorgiaMoira Rashid, M.D.Private PracticeLong Beach, CaliforniaJohn Christian Fox, M.D.University of California Irvine Emergency MedicineOrange, CaliforniaKenneth W. Mahaffey, M.D.Stanford University School of MedicineStanford, CaliforniaVinicio de Jesus Perez, M.D.Stanford University School of MedicineStanford, CaliforniaandVera Moulton Wall Center for Pulmonary Vascular DiseaseStanford, California*Corresponding author (e-mail: zamanian@stanford.edu).References1. Gattinoni L, Coppola S, Cressoni M, Busana M, Rossi S, ChiumelloD. COVID-19 does not lead to a “typical” acute respiratorydistress syndrome. Am J Respir Crit Care Med 2020;201:1299–1300.2. Centers for Disease Control and Prevention. Coronavirus disease2019 (COVID-19); [accessed 2020 Apr 2]. Available from: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/index.html.3. Yorke J, Deaton C, Campbell M, McGowen L, Sephton P, Kiely DG,et al. Symptom severity and its effect on health-related quality oflife over time in patients with pulmonary hypertension: a multisitelongitudinal cohort study. BMJ Open Respir Res 2018;5:e000263.4. Ryan JJ, Melendres L, Zamanian RT, Oudiz RJ, Chakinala M,Rosenzweig EB, et al. Care of patients with pulmonary arterialhypertension during the coronavirus (COVID-19) pandemic. Pulm Circ2020;10:2045894020920153.5. Sokol GM, Konduri GG, Van Meurs KP. Inhaled nitric oxide therapy forpulmonary disorders of the term and preterm infant. Semin Perinatol2016;40:356–369.6. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, LindnerJR, et al.; ACCF/AHA. ACCF/AHA 2009 expert consensus documenton pulmonary hypertension: a report of the American College ofCardiology Foundation Task Force on Expert Consensus Documentsand the American Heart Association: developed in collaboration withthe American College of Chest Physicians, American ThoracicSociety, Inc., and the Pulmonary Hypertension Association.Circulation 2009;119:2250–2294.7. Hasuda T, Satoh T, Shimouchi A, Sakamaki F, Kyotani S, Matsumoto T,et al. Improvement in exercise capacity with nitric oxide inhalation inpatients with precapillary pulmonary hypertension. Circulation 2000;101:2066–2070.8. Teman NR, Thomas J, Bryner BS, Haas CF, Haft JW, Park PK, et al. Inhalednitric oxide to improve oxygenation for safe critical care transportof adults with severe hypoxemia. Am J Crit Care 2015;24:110–117.9. Gebistorf F, Karam O, Wetterslev J, Afshari A. Inhaled nitric oxide foracute respiratory distress syndrome (ARDS) in children and adults.Cochrane Database Syst Rev 2016;2016:CD002787.10. Chen L, Liu P, Gao H, Sun B, Chao D, Wang F, et al. Inhalation ofnitric oxide in the treatment of severe acute respiratorysyndrome: a rescue trial in Beijing. Clin Infect Dis 2004;39:1531–1535.Copyright © 2020 by the American Thoracic SocietyCOVID-19–associated Pulmonary AspergillosisTo the Editor:Late December 2019, China reported an outbreak of coronavirusdisease (COVID-19) caused by severe acute respiratorysyndrome coronavirus 2 (SARS-CoV-2). This has become aglobal threat, with high attack rates, ICU admissions, andmortality. Initial cohort studies reported a substantial casefatality rate in patients admitted to the ICU, of whom halfdeveloped secondary infections (1). Late February, the SouthernThis article is open access and distributed under the terms of the CreativeCommons Attribution Non-Commercial No Derivatives License 4.0(http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usageand reprints, please contact Diane Gern (dgern@thoracic.org).Author Contributions: A.L.E.v.A., T.A.R., H.N.A.B., and R.G.B. collectedclinical and microbiological data. A.L.E.v.A. and R.G.B. drafted themanuscript and revised the final version. All authors revised and contributedto the final version.Originally Published in Press as DOI: 10.1164/rccm.202004-1038LE on May12, 2020CORRESPONDENCE132 American Journal of Respiratory and Critical Care Medicine Volume 202 Number 1 | July 1 2020 Table1.PatientCharacteristics,ClinicalCourse,andOutcomePatientSexandAgeinYearsMedicalHistoryDaysafterSymptomOnsettoCAPAOnsetAPACHE-IIatICUAdmissionDaysafterICUAdmissiontoCAPAOnsetBronchoscopyFindingsMicrobiologicalFindings(DaysafterSymptomOnsetofSampleAcquisition)CAPAClassification(10)Outcome(DaysafterSymptomOnset)1M,83Cardiomyopathy;prednisolon0.13mg/kg/dfor28dpreadmission10163NotperformedTrachealaspirate–culturedAspergillusfumigatus(7);serumGMindex0.4(8)PossibleDied(12)2M,67COPDGOLDIII;Post-RTxNSCLC2014;prednisolon0.37mg/kg/dfor2dpreadmission10163NotperformedTrachealaspirate–culturedAspergillusfumigatus(5)PossibleDied(11)3M,75COPDGOLDIIa8155MucoidwhitesputumleftbronchusBAL-culturedAspergillusfumigatus(8);BALGMindex4.0(8)ProbableDied(12)4M,43None211014UnrevealingBALGMindex3.8(18);serumGMindex0.1(16)ProbableSurvived5M,57Bronchialasthma;fluticason1.94mcg/kg/dfor1mopreadmission13155UnrevealingBAL-culturedAspergillusfumigatus(11);BALGMindex1.6(11);serumGMindex0.1(13)ProbableDied(20)6M,58None421528NotperformedSputum-culturedAspergillusfumigatus(36,40,43,47,and50)PossibleSurvivedMedian——11.5155———12dDefinitionofabbreviations:APACHE-II=AcutePhysiologyandChronicHealthEvaluationII;CAPA=COVID-19–associatedpulmonaryaspergillosis;COPD=chronicobstructivepulmonarydisease;COVID-19=coronavirusdisease;GM=galactomannan;GOLD=GlobalInitiativeforChronicObstructiveLungDisease;NSCLC=non–small-celllungcarcinoma;RTx=radiationtherapy.CORRESPONDENCECorrespondence 133 Netherlands emerged as a hotspot for COVID-19, and wenoticed cases of invasive pulmonary aspergillosis (IPA)occurring in patients with COVID-19 admitted to the ICU.Here, we describe the clinical characteristics of COVID-19–associated pulmonary aspergillosis (CAPA) cases and thefrequency in our ICU.In the first 3 weeks of the outbreak, 135 adult patientswith laboratory-confirmed COVID-19 were admitted to theAmphia Hospital Breda, a 700-bed teaching hospital. Of thesepatients, 31 (23%) required mechanical ventilation on ICU.Eleven ICU patients with COVID-19 developed a secondaryinfection, of whom six (19.4%) were presumed to have IPA. Weidentified Aspergillus fumigatus in five patients, and in threepatients, the Aspergillus antigen galactomannan (GM) (PlateliaAspergillus; Biorad) was found positive on BAL fluid (Table 1).Three patients had preexisting lung diseases, but none werepositive for the European Organisation for Research andTreatment of Cancer (EORTC) and Mycoses Study GroupEducation and Research Consortium (MSGERC) host factor (2).Three patients received corticosteroids before ICU admission;however, either the dose received was ,0.3 mg/kg/d or theduration was ,3 weeks. No other immunosuppressivemedication was given before CAPA diagnosis, and all weretreated for COVID-19 with chloroquine and lopinavir/ritonavir.There were no significant differences in clinical characteristicsbetween ICU patients with COVID-19 with presumed CAPAand those without presumed CAPA (Table 2). CAPA occurredafter a median of 11.5 days (range, 8–42) after COVID-19symptom onset and at a median of 5 days (range, 3–28) afterICU admission. Chest computed tomographic scan wasperformed in one patient without apparent signs of fungalinfection. In one patient, the bronchoscopy was abnormal, withmucoid white sputum in the left bronchus. Serum GM testednegative in three patients. Voriconazole and anidulafungincombination therapy was initiated in five patients, and onepatient received liposomal amphotericin B. Four (66.7%)patients died at a median of 12 ICU days (11–20). Autopsieswere not performed because of concerns for the risk ofcontamination.DiscussionWe observed a high incidence (19.4%) of presumed aspergillosis inour cohort of 31 ICU patients, which might indicate that patientswith COVID-19 are at risk for developing IPA.Secondary fungal infections are increasingly being reportedin patients with COVID-19. Studies from Wuhan, China,reported secondary fungal infections in 3 of 9 (33.3%) patientsand in 6 of 17 (35.3%) critically ill patients (3, 4). Subsequentreports from Europe indicate that IPA may be found inassociation with severe COVID-19. Lescure and colleaguesdescribed an ICU patient with COVID-19 with antifungaltreatment for A. flavus who died on Day 24 after symptom onset(5). A research letter reports a fatal case of pulmonaryaspergillosis coinfection in an immunocompetent patient (6). Acase series from France reported presumed CAPA in 9 of 27(33.3%) ICU patients with COVID-19, and a series fromGermany reported CAPA in 5 of 19 (26.3%) ICU patients. All-cause mortality was three of nine (33.3%) in the French CAPAseries and four of five (80%) in the German series (7, 8). Thishigh incidence of secondary aspergillosis in COVID-19 casesresembles the high rates (16% and 23%) of influenza-associatedpulmonary aspergillosis (IAPA) that have been reported in ICUsin the Netherlands and Belgium (9). One problem is that there isno case definition for CAPA. However, a case definition forIAPA was recently proposed by an expert panel, and this couldbe used to classify patients with CAPA (10). In the IAPA casedefinition, host factors are not used to classify patients becauseIAPA may develop in any patient with severe influenza.Diagnostic criteria include proven influenza infection withclinical symptoms and a GM index of >1 on BAL or >0.5 onserum, or Aspergillus spp. cultured from BAL (10). When weapply the IAPA case definition to our cases, three (Table 1) casescould be classified as probable CAPA on the basis of BAL GMdetection. The remaining three patients might classify aspossible CAPA, with clinical deterioration and A. fumigatusrecovered from tracheal aspirates because bronchoscopy was notperformed. However, recovery of Aspergillus from upperrespiratory samples may represent colonization and not invasivepulmonary disease.Table 2. Characteristics of Patients with versus without CAPA, Clinical Course, and OutcomeParameter Presumed CAPA (n=6) Non-CAPA (n= 25) P ValueAge, yr, median (range) 62.5 (43–83) 67 (16–79) 0.942Sex, M, n (%) 6/6 (100) 20/25 (80) 0.553EORTC/MSGERC host risk factors, n (%) 0/6 (0) 3/25 (12) 1Interval from symptom onset to ICU admission,median (range), d7 (3–14) 9 (3–15) 0.268Interval from ICU admission to ICU discharge,median (range), d10.5 (4–47) 14 (2–42) 1Interval from symptom onset to death, median(range), d12 (11–20) 17.5 (9–37) 0.570Systemic corticosteroid use, n (%) 2/6 (33.3) 3/25 (12) 0.241BAL performed, n (%) 1/6 (16.7) 6/25 (24) 1Mortality, n (%) 4/6 (66.7) 8/25 (32) 0.174Definition of abbreviations: CAPA=COVID-19–associated pulmonary aspergillosis; COVID-19= coronavirus disease; EORTC=European Organisation forResearch and Treatment of Cancer; MSGERC=Mycoses Study Group Education and Research Consortium.We used the Mann-Whitney U test or Fisher’s exact test to compare differences between patients with and without CAPA when appropriate.CORRESPONDENCE134 American Journal of Respiratory and Critical Care Medicine Volume 202 Number 1 | July 1 2020 Although 94% of patients with IAPA had positive BALGM and 71% had positive serum GM in a retrospective ICUstudy (9), the performance of GM in BAL and serum ofpatients with CAPA remains to be further evaluated, as it maydiffer from IAPA. Indeed, in three of our patients with CAPA,circulating GM was not detected in serum. In one patient, theserum GM index was 0.4, which is borderline negative.Including our case series, to date, 22 ICU patients have beenreported with presumed CAPA (5–8). Only three patients testedGM-positive in serum. It is important to investigate thediagnostic value of serum GM in CAPA, as there is ageneral reluctance to perform bronchoscopy in patients withCOVID-19 because of the risks for the patient and thepulmonologist.For CAPA, some clinical characteristics are similar to thoseof IAPA, including early symptom onset after ICU admission,absence of EORTC/MSGERC host factors, and a high ICUmortality. Invasive Aspergillus tracheobronchitis (withplaque formation), which is a common manifestation of IAPA,was, however, not registered in these patients. Three patientswere known to have chronic lung disease, which makesdifferentiation between IPA and Aspergillus colonizationchallenging.The diagnosis of IAPA has controversies because varyingfrequencies of the infection have been reported in ICUinfluenza studies. Geographical differences may explain theobserved variations, although differences in diagnostic approachesare also likely to contribute. IAPAmay remain undiagnosed becauserespiratory deterioration is considered to be caused by bacterialcoinfection rather than fungal infection, and appropriate fungaldiagnostics are not performed (11).SARS-CoV-2 infection might be a risk factor for IPA, andearly diagnosis and prompt treatment for CAPA in ICUpatients seems warranted because high mortality rates have beenreported. In our center, on suspicion of CAPA, a diagnosticworkup is performed that includes serum GM and, if feasible,bronchoscopy with BAL for fungal culture and GM. Antifungaltherapy is started in patients highly suspected of havingCAPA while awaiting results of fungal diagnostics. Until therisk of IPA in severe COVID-19 is better understood, infectiousdisease specialists, ICU physicians, pulmonologists, andclinical microbiologists should be aware of this secondaryinfection. nAuthor disclosures are available with the text of this letter atwww.atsjournals.org.Andreas L. E. van Arkel, M.D.*Amphia HospitalBreda, the NetherlandsandElisabeth-TweeSteden HospitalTilburg, the NetherlandsTom A. Rijpstra, M.D.Huub N. A. Belderbos, M.D.Peter van Wijngaarden, M.D.Amphia HospitalBreda, the NetherlandsPaul E. Verweij, M.D., Ph.D.Radboud University Medical CentreNijmegen, the NetherlandsRobbert G. Bentvelsen, M.D.*‡Amphia HospitalBreda, the NetherlandsandLeiden University Medical CentreLeiden, the NetherlandsORCID IDs: 0000-0003-3391-9200 (A.L.E.v.A.);0000-0002-8600-9860 (P.E.V.); 0000-0002-9958-2842 (R.G.B.).*These authors contributed equally to this work.‡Corresponding author (e-mail: robbertbentvelsen@gmail.com).References1. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course andrisk factors for mortality of adult inpatients with COVID-19 inWuhan, China: a retrospective cohort study. Lancet 2020;395:1054–1062.2. Donnelly JP, Chen SC, Kauffman CA, Steinbach WJ, Baddley JW,Verweij PE, et al. Revision and update of the consensus definitionsof invasive fungal disease from the European organization forresearch and treatment of cancer and the mycoses study groupeducation and research consortium. Clin Infect Dis [online ahead ofprint] 5 Dec 2019; DOI: 10.1093/cid/ciz1008.3. Du Y, Tu L, Zhu P, Mu M, Wang R, Yang P, et al. Clinical features of 85fatal cases of COVID-19 from Wuhan: a retrospective observationalstudy. Am J Respir Crit Care Med 2020;201:1372–1379.4. Chen X, Zhao B, Qu Y, Chen Y, Xiong J, Feng Y, et al. Detectable serumSARS-CoV-2 viral load (RNAaemia) is closely correlated withdrastically elevated interleukin 6 (IL-6) level in critically ill COVID-19patients. Clin Infect Dis [online ahead of print] 17 Apr 2020; DOI:10.1093/cid/ciaa449.5. Lescure FX, Bouadma L, Nguyen D, Parisey M, Wicky PH, Behillil S,et al. Clinical and virological data of the first cases of COVID-19 inEurope: a case series. Lancet Infect Dis [online ahead of print] 27Mar 2020; DOI: 10.1016/S1473-3099(20)30200-0.6. Alanio A, Dellière S, Fodil S, Bretagne S, Mégarbane B. Prevalence ofputative invasive pulmonary aspergillosis in critically ill patients withCOVID-19. Lancet Respir Med [online ahead of print] 20 May 2020;DOI: 10.1016/S2213-2600(20)30237-X.7. Koehler P, Cornely OA, Böttiger BW, Dusse F, Eichenauer DA, Fuchs F,et al. COVID-19 associated pulmonary aspergillosis. Mycosis [onlineahead of print] 27 Apr 2020; DOI: 10.1111/myc.13096.8. Blaize M, Mayaux J, Nabet C, Lampros A, Marcelin A-G, Thellier M, et al.Fatal invasive aspergillosis and coronavirus disease in animmunocompetent patient. Emerg Infect Dis [online ahead of print] 27Apr 2020; DOI: 10.3201/eid2607.201603.9. van de Veerdonk FL, Kolwijck E, Lestrade PPA, Hodiamont CJ, RijndersBJA, van Paassen J, et al.; Dutch Mycoses Study Group. Influenza-associated aspergillosis in critically ill patients. Am J Respir Crit CareMed 2017;196:524–527.10. Verweij PE, Rijnders BJA, Brüggemann RJM, Azoulay E, BassettiM, Blot S, et al. International expert review of influenza-associatedpulmonary aspergillosis in ICU patients and recommendations for acase definition. Intensive Care Med (In press)11. Rijnders BJA, Schauwvlieghe AFAD, Wauters J. Influenza-associatedpulmonary aspergillosis: a local or global lethal combination? ClinInfect Dis [online ahead of print] 6 Jan 2020; DOI: 10.1093/cid/ciaa010.Copyright © 2020 by the American Thoracic SocietyCORRESPONDENCECorrespondence 135 

COVID-19-associated pulmonary aspergillosis

COVID-19-associated Pulmonary Aspergillosis

Abstract

Similar works

Full text

Available Versions

Radboud Repository

NARCIS

Leiden University Scholary Publications