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Id Subject Object Predicate Lexical cue
T1 0-73 Sentence denotes Late histopathologic characteristics of critically ill COVID-19 patients:
T2 74-152 Sentence denotes Different phenotypes without evidence of invasive aspergillosis, a case series
T3 154-162 Sentence denotes Abstract
T4 163-170 Sentence denotes Purpose
T5 171-280 Sentence denotes Pathological data of critical ill COVID-19 patients is essential in the search for optimal treatment options.
T6 282-302 Sentence denotes Material and methods
T7 303-398 Sentence denotes We performed postmortem needle core lung biopsies in seven patients with COVID-19 related ARDS.
T8 399-512 Sentence denotes Clinical, radiological and microbiological characteristics are reported together with histopathological findings.
T9 514-542 Sentence denotes Measurement and main results
T10 543-625 Sentence denotes Patients age ranged from 58 to 83 years, five males and two females were included.
T11 626-725 Sentence denotes Time from hospital admission to death ranged from 12 to 36 days, with a mean of 20 ventilated days.
T12 726-921 Sentence denotes ICU stay was complicated by pulmonary embolism in five patients and positive galactomannan on bronchoalveolar lavage fluid in six patients, suggesting COVID-19 associated pulmonary aspergillosis.
T13 922-1030 Sentence denotes Chest CT in all patients showed ground glass opacities, commonly progressing to nondependent consolidations.
T14 1031-1220 Sentence denotes We observed four distinct histopathological patterns: acute fibrinous and organizing pneumonia, diffuse alveolar damage, fibrosis and, in four out of seven patients an organizing pneumonia.
T15 1221-1293 Sentence denotes None of the biopsy specimens showed any signs of invasive aspergillosis.
T16 1295-1306 Sentence denotes Conclusions
T17 1307-1473 Sentence denotes In this case series common late histopathology in critically ill COVID patients is not classic DAD but heterogeneous with predominant pattern of organizing pneumonia.
T18 1474-1645 Sentence denotes Postmortem biopsy investigations in critically COVID-19 patients with probable COVID-19 associated pulmonary aspergillosis obtained no evidence for invasive aspergillosis.
T19 1647-1657 Sentence denotes Highlights
T20 1658-1774 Sentence denotes • Probable COVID-19 associated pulmonary aspergillosis is common in mechanically ventilated COVID-19 ARDS patients.
T21 1775-1851 Sentence denotes • Late fase histopathology in critically ill COVID patients is heterogenic.
T22 1852-1947 Sentence denotes • In prolonged COVID-19 related ARDS organizing pneumonia is a predominant histologic pattern.
T23 1949-1964 Sentence denotes 1 Introduction
T24 1965-2335 Sentence denotes Up to 20% of hospitalized coronavirus disease 2019 (COVID-19) patients are admitted to the intensive care unit (ICU) because of acute hypoxemic respiratory failure. [[1], [2], [3], [4]] These patients usually present with bilateral patchy ground glass opacities on computed tomography (CT) thorax fulfilling the definition for acute respiratory distress syndrome (ARDS).
T25 2336-2770 Sentence denotes Often an atypical high compliance phenotype (L-type) is observed during mechanical ventilation in COVID-19 patients in contrast to mechanical ventilation characteristics typically seen in ARDS with low lung compliance phenotype (H -type). [5,6] During ICU stay the radiologic presentation of bilateral patchy ground glass opacities as present at admission often progress to consolidations with or without fibrotic characteristics [7].
T26 2771-2918 Sentence denotes Two earlier observed features may play a critical role in the severity of this disease: thromboembolic complications and early onset aspergillosis.
T27 2919-3032 Sentence denotes The cumulative incidence of venous thromboembolism reported was 49% in COVID-19 patients admitted to the ICU [8].
T28 3033-3128 Sentence denotes Presumed pulmonary aspergillosis may be present in as much as 19% of ICU COVID-19 patients [9].
T29 3129-3347 Sentence denotes Since the physiology in COVID-19 related ARDS as well as its complications seems to differ from “typical’ ARDS, an insight into the pulmonary tissue pathology of this new infectious disease is of the utmost importance.
T30 3348-3483 Sentence denotes The scarcely available pathological data in COVID-19 patients show diffuse alveolar damage, closely related to ARDS [[10], [11], [12]].
T31 3484-3719 Sentence denotes The clinical relevance of COVID-19-associated pulmonary aspergillosis (CAPA) as well as survival benefit with antifungal treatment and associated mortality are under debate since histopathological evidence of CAPA is not obtained [13].
T32 3720-3841 Sentence denotes We examined postmortem obtained lung tissue in seven patients, with COVID related ARDS who needed mechanical ventilation.
T33 3842-3965 Sentence denotes The histopathologic findings, together with clinical features, radiological and microbiological findings are reported here.
T34 3966-4087 Sentence denotes This report may contribute to new insights in the pathogeneses of COVID-19 as well as suggestions for treatment strategy.
T35 4089-4099 Sentence denotes 2 Methods
T36 4101-4133 Sentence denotes 2.1 Study population and design
T37 4134-4446 Sentence denotes All patients with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) admitted to the ICU due to acute hypoxemic respiratory failure between 22 March 2020 and 30 April 2020 and with available postmortem needle core biopsy of the lung were eligible for inclusion in this case series.
T38 4447-4582 Sentence denotes SARS-CoV-2 was diagnosed using real-time reverse transcription polymerase chain reaction (RT-PCR) on sputum and/or bronchial aspirates.
T39 4583-4921 Sentence denotes Routine ICU management included, among other things, selective digestive tract decontamination (SDD), chloroquine until the Dutch National Institute for Public Health and Environment advised against its use at the end of March 2020, and high dose anticoagulation with low-molecular-weight heparin (LMWH) (nadroparin 87 IE/kg twice daily).
T40 4922-5060 Sentence denotes Bronchoscopy, with or without lavage, and testing for pulmonary aspergillosis were performed at the discretion of the attending physician.
T41 5061-5226 Sentence denotes Pulmonary aspergillosis was diagnosed using clinical, radiological and mycological data and included galactomannan (serum and sputum), tracheal or bronchial culture.
T42 5227-5351 Sentence denotes For galactomannan (GM) testing from bronchoalveolar lavage (BAL) fluid Platelia Aspergillis antigen ELISA (Biorad) was used.
T43 5352-5525 Sentence denotes Recently, a case definition for influenza associated pulmonary aspergillosis (IAPA) was proposed by an expert panel, which could be used to classify patients with CAPA [14].
T44 5526-5681 Sentence denotes Diagnostic criteria include proven infection with clinical symptoms and a GM index of ≥1 on BAL or of ≥0ꞏ5 on serum; or Aspergillus spp. cultured from BAL.
T45 5683-5729 Sentence denotes 2.2 Postmortem needle core biopsy of the lung
T46 5730-5863 Sentence denotes With permission from the patients' families, postmortem core needle biopsies were performed on both lungs within an hour after death.
T47 5864-5968 Sentence denotes Lung biopsies were ultrasound and CT guided and combined with surface anatomic landmarks as a reference.
T48 5969-6062 Sentence denotes A minimum of three histologic 14 gauge true cut needle biopsies were performed in both lungs.
T49 6063-6153 Sentence denotes Biopsy specimens were fixed in formalin, embedded in paraffin, and cut into 3 μm sections.
T50 6154-6282 Sentence denotes Hematoxylin and eosin (H&E), and periodic acid–Schiff with diastase (PAS-D) stains were applied according to routine procedures.
T51 6284-6309 Sentence denotes 2.3 Statistical analysis
T52 6310-6379 Sentence denotes Descriptive statistics were used to describe patient characteristics.
T53 6380-6436 Sentence denotes For statistical analysis IBM SPSS version 25.0 was used.
T54 6437-6528 Sentence denotes The local Medical Ethics Committee (Medical Research Committees United) approved the study.
T55 6530-6540 Sentence denotes 3 Results
T56 6542-6564 Sentence denotes 3.1 Clinical features
T57 6565-6658 Sentence denotes During the study period, seven patients underwent postmortem needle core biopsy of the lungs.
T58 6659-6744 Sentence denotes Patients age ranged from 58 to 83 years (median 74 year) and five patients were male.
T59 6745-6811 Sentence denotes None of the patients had a history of (chronic) pulmonary disease.
T60 6812-6929 Sentence denotes One patient used immunosuppressive medication before hospital admission, in this case a short course of prednisolone.
T61 6930-7010 Sentence denotes Median time from hospital to ICU admission was 0 days (interquartile range 0–4).
T62 7011-7075 Sentence denotes Time from hospital admission to death ranged from 12 to 36 days.
T63 7076-7138 Sentence denotes Patients deceased at median of 21(range 9–36) ventilated days.
T64 7139-7216 Sentence denotes In five out of seven patients ICU stay was complicated by pulmonary embolism.
T65 7217-7384 Sentence denotes Adopting the proposed definition of CAPA by van Arkel et al. [9], six patients were classified as having probable CAPA (Table 1 ), based on a positive GM on BAL fluid.
T66 7385-7483 Sentence denotes In those patients, combination antifungal therapy with voriconazole and anidulafungin was started.
T67 7484-7635 Sentence denotes Three out of six patients were on corticosteroids (60 mg prednisolone daily) at the time of CAPA diagnosis and corticosteroid treatment was terminated.
T68 7636-7778 Sentence denotes Indication for steroid treatment in these patients was a suspicion of an organizing pneumonia on chest CT or signs of progression to fibrosis.
T69 7779-7921 Sentence denotes Nosocomial infections including signs for pulmonary aspergillosis were excluded by bronchoscopy with BAL before steroid treatment was started.
T70 7922-8043 Sentence denotes Radiologic findings of chest CT and histologic results of the lungs biopsies of all seven patients are shown in Table 2 .
T71 8044-8096 Sentence denotes Table 1 Patient characteristics and clinical course.
T72 8097-8381 Sentence denotes Case Sex, age (years) Medical history Total hospital days Total ventilated days Berlin classification of ARDS Compliance phenotype PE BAL fluid GM and culture (days post hospital admission) CAPA Chloroquine Prednisolone use during hospital admission Duration of prednisolone treatment
T73 8382-8437 Sentence denotes 1 M, 77 None 12 10 Severe Low Yes GM negative No Yes No
T74 8438-8539 Sentence denotes 2 F, 73 None 20 16 Severe High Yes GM index 4.4 (day 19) Aspergillus fumigatus Probable No Yes 8 days
T75 8540-8619 Sentence denotes 3 F, 58 None 30 26 Severe Low Yes GM index 3.4 (day 20) Probable Yes Yes 5 days
T76 8620-8735 Sentence denotes 4 M, 68 None 21 21 Moderate Low Yes GM index 5.7 (day 1) Aspergillus fumigatus Enterococcus faecium Probable Yes No
T77 8736-8840 Sentence denotes 5 M, 78 HT, CKI 22 21 Moderate Low No GM index 4.3 (day 20) Enterococcus faecium Probable Yes Yes 2 days
T78 8841-8914 Sentence denotes 6 M, 83 HT, DM 13 9 Moderate Low No GM index 1.7 (day 11) Probable Yes No
T79 8915-9016 Sentence denotes 7 M, 74 None 36 36 Severe Low Yes GM index 4.4 (day 24) Enterococcus faecalis Probable Yes Yes 4 days
T80 9017-9249 Sentence denotes ARDS acute respiratory distress syndrome; BAL broncho-alveolar lavage; CAPA, COVID-19 associated pulmonary aspergillosis; CKI, chronic kidney injury; DM, diabetes mellitus; GM, galactomannan; HT, hypertension; PE pulmonary embolism.
T81 9250-9311 Sentence denotes Table 2 Radiological Chest CT scan and histological findings.
T82 9312-9382 Sentence denotes Case Radiological findings Histological findings description Diagnosis
T83 9383-9673 Sentence denotes 1 GGO, crazy paving, non-dependent consolidation, subpleural sparing, segmental and subsegmental PE Intra-alveolar fibromyxoid/fibroblastic bodies (25%), micro-thrombi, thrombi in lager vessels, hyperplasia with atypia, multinucleated giant cell, intranuclear inclusion bodies, no hyphae OP
T84 9674-9927 Sentence denotes 2 GGO, crazy paving, resolving consolidation, bronchiectasis, segmental and subsegmental PE Extensive fibrosis with destruction of alveolar structures, hyperplasia with atypia, multinucleated giant cell, intranuclear inclusion bodies, no hyphae Fibrosis
T85 9928-10196 Sentence denotes 3 GGO, large dependent consolidation, bronchiectasis, subsegmental PE Inflammatory infiltrate, hyaline membranes, sporadic intra-alveolar fibroblastic plug, micro-thrombi, hyperplasia with atypia, multinucleated giant cell, intranuclear inclusion bodies, no hyphae DAD
T86 10197-10516 Sentence denotes 4 GGO, crazy paving, non-dependent consolidation, bronchiectasis, segmental and subsegmental PE Intra-alveolar fibroblastic tissue, with a diffuse component of fibrinous exudate, widening of alveolar septa, micro-thrombi, hyperplasia with atypia, multinucleated giant cell, intranuclear inclusion bodies, no hyphae AFOP
T87 10517-10702 Sentence denotes 5 GGO, consolidation Intra-alveolar fibromyxoid/fibroblastic bodies (32%), micro-thrombi, hyperplasia with atypia, multinucleated giant cell, intranuclear inclusion bodies, no hyphae OP
T88 10703-10916 Sentence denotes 6 GGO, consolidation Intra-alveolar fibromyxoid/fibroblastic bodies (80%), widening of alveolar septa, micro-thrombi, hyperplasia with atypia, multinucleated giant cell, intranuclear inclusion bodies, no hyphae OP
T89 10917-11182 Sentence denotes 7 GGO, crazy paving, consolidation, bronchiectasis, subsegmental PE Intra-alveolar fibromyxoid/fibroblastic bodies (27%), mild widening of alveolar septa, micro-thrombi, hyperplasia with atypia, multinucleated giant cell, intranuclear inclusion bodies, no hyphae OP
T90 11183-11335 Sentence denotes AFOP acute fibrinous and organizing pneumonia, DAD diffuse alveolar damage, GGO, ground glass opacities; OP organizing pneumonia; PE pulmonary embolism.
T91 11336-11499 Sentence denotes To further investigate histopathologic findings we now present the detailed clinical course of four patients with four different histopathological characteristics.
T92 11500-11676 Sentence denotes Because of complexity and importance of the distinct patterns and their relation with radiologic findings and treatment, we preferred to discuss them separately in more detail.
T93 11677-11746 Sentence denotes Chest CT imaging of the four discussed patients are shown in Fig. 1 .
T94 11747-11781 Sentence denotes Fig. 1 Chest CT scans of case 1–4.
T95 11782-11920 Sentence denotes For each patient image A represents chest CT at hospital admission, image B follow up CT-scan (note: chest CT of case 4 was not repeated).
T96 11921-12068 Sentence denotes 1A: bilateral areas of GGO, patchy subpleural non-dependant consolidations 1B: progression of dens subpleural consolidations with air-bronchograms.
T97 12069-12179 Sentence denotes 2A GGO in both lungs, combined with crazy-paving pattern, subtle bronchiectasis are present in affected areas.
T98 12180-12304 Sentence denotes 2B GGO persisted, without progression to consolidations, more pronounced fibrotic reticulation with traction bronchiectasis.
T99 12305-12374 Sentence denotes 3A diffuse bilateral GGO with large gravity dependant consolidations.
T100 12375-12473 Sentence denotes 3B persistent GGO and consolidation, newly formed cyst-like lesions in middle and ventral regions.
T101 12474-12573 Sentence denotes 4A bilateral areas of GGO, patchy non-dependant peripheral consolidations with mild bronchiectasis.
T102 12575-12609 Sentence denotes 3.2 Case 1 – Organizing pneumonia
T103 12610-12768 Sentence denotes A 77-year old male without significant medical history was evaluated in our emergency department (ED) with complaints of general weakness, fever and dyspnoea.
T104 12769-12983 Sentence denotes Initial chest CT showed extensive bilateral areas of ground-glass opacity with both central and peripheral distribution, patchy subpleural non-dependant consolidations and areas with subpleural sparing (Fig. 1-1A).
T105 12984-13143 Sentence denotes Soon after admission patient was in need of mechanical ventilatory support and developed acute renal failure for which renal replacement therapy was initiated.
T106 13144-13359 Sentence denotes After six days of mechanical ventilation chest CT-angiography showed pulmonary emboli along with new areas of ground-glass opacity and progression of dens subpleural consolidations with air-bronchograms (Fig. 1-1B).
T107 13360-13418 Sentence denotes A nosocomial infection was ruled out by bronchial culture.
T108 13419-13583 Sentence denotes Patient's neurologic status deteriorated and CT head revealed brain ischemia due to infarction of the area supplied by the left and right posterior cerebral artery.
T109 13584-13625 Sentence denotes The patient died 12 days after admission.
T110 13626-13734 Sentence denotes Postmortem pathologic examination revealed that the overall architecture of the lung tissue remained intact.
T111 13735-13867 Sentence denotes However, a prominent amount of fibromyxoid or fibroblastic bodies was present in the alveoli with surrounding histiocytes (Fig. 2A .
T112 13868-13941 Sentence denotes The extent of involved lung tissue was estimated at around 25% (Table 2).
T113 13942-14026 Sentence denotes No remnants of hyaline membranes or prominent alveolar fibrinous exudate were found.
T114 14027-14165 Sentence denotes Microthrombi in small blood vessels of the alveolar septa were seen, as well as an organizing thrombus in a larger sized vessel (Fig. 2E).
T115 14166-14280 Sentence denotes The histologic findings in this case point towards an epithelial, and vascular phenotype of a SARS-CoV2 infection.
T116 14281-14321 Sentence denotes No fungi were present in de PAS-D stain.
T117 14322-14392 Sentence denotes This histologic pattern is characteristic for an organizing pneumonia.
T118 14393-14426 Sentence denotes Fig. 2 Microscopic lung findings.
T119 14427-15049 Sentence denotes A, case 1: intra-alveolar fibroblastic bodies, consistent with organizing pneumonia, (H&E, 10×) B, case 2: loss of alveolar architecture with extensive fibrosis (H&E; 10×) C, case 3: inflammatory infiltrate with neutrophils and lymphocytes, note the hyaline membranes (arrows), suggestive for diffuse alveolar damage. (H&E, 20×) D, case 4: prominent fibrinous exudate in alveoli as seen in AFOP (H&E; 10×) E: thrombus in larger vessel (H&E, 5×) F: cytopathogenic changes in pneumocytes due to viral infection seen in all cases: hyperplasia, multinucleated giant cells (asterisks), intranuclear inclusion bodies (H&E, 40×).
T120 15051-15073 Sentence denotes 3.3 Case 2 – Fibrosis
T121 15074-15171 Sentence denotes A 73-year old female was transferred to our ICU due to shortage of ICU beds in a nearby hospital.
T122 15172-15264 Sentence denotes Prior to ICU admission, she was healthy but complained of diarrhoea and shortness of breath.
T123 15265-15421 Sentence denotes Non-contrast chest CT at initial hospital admission showed multiple bilateral areas of ground-glass opacity along the bronchovascular bundles and periphery.
T124 15422-15486 Sentence denotes There were some small areas of consolidation in the upper lobes.
T125 15487-15552 Sentence denotes Subtle bronchiectasis were present in affected areas (Fig. 1-2A).
T126 15553-15641 Sentence denotes Her respiratory condition required mechanical ventilation in prone position due to ARDS.
T127 15642-15726 Sentence denotes After seven days, prednisolone treatment was started because of lack of improvement.
T128 15727-15807 Sentence denotes Repeat chest CT-angiography showed segmental pulmonary emboli in the right lung.
T129 15808-15882 Sentence denotes Ground-glass opacities persisted while the consolidations had disappeared.
T130 15883-15993 Sentence denotes A reticular pattern combined with GGO was more pronounced with increasing traction bronchiectasis (Fig. 1-2B).
T131 15994-16085 Sentence denotes BAL was performed twice, but GM and culture showed no signs of additional fungal infection.
T132 16086-16174 Sentence denotes After one week of high dose glucocorticoid therapy BAL was repeated with a GM index 4.4.
T133 16175-16230 Sentence denotes Fungal cultures showed growth of Aspergillus fumigatus.
T134 16231-16317 Sentence denotes Therefore, prednisolone treatment was discontinued and antifungal treatment initiated.
T135 16318-16449 Sentence denotes CT head was performed because of the development of an epileptic insult and showed small foci of haemorrhage in both frontal lobes.
T136 16450-16567 Sentence denotes Neurologic condition worsened and progressive cerebral haemorrhage on follow up CT head was seen with poor prognosis.
T137 16568-16658 Sentence denotes Palliative treatment was started and the patient deceased 27 days after onset of symptoms.
T138 16659-16770 Sentence denotes Microscopic examination of lung tissue of this case showed an almost complete loss of normal lung architecture.
T139 16771-16856 Sentence denotes Alveolar structures were unrecognizable and replaced by extensive fibrosis (Fig. 2B).
T140 16857-16961 Sentence denotes What remained were several foci of pneumocytes, bronchial epithelium, and blood vessels without thrombi.
T141 16962-17004 Sentence denotes In the PAS-D stain no fungi were observed.
T142 17005-17065 Sentence denotes The prominent pattern in this patient is pulmonary fibrosis.
T143 17067-17104 Sentence denotes 3.4 Case 3 – Diffuse alveolar damage
T144 17105-17208 Sentence denotes A 58-year old female was admitted to the ICU and needed mechanical ventilation due to severe hypoxemia.
T145 17209-17416 Sentence denotes Chest CT-angiography showed dubious unilateral sub-segmental pulmonary emboli and diffuse bilateral ground-glass opacities with anteroposterior gradient along with large dependant consolidations (Fig. 1-3A).
T146 17417-17587 Sentence denotes On the 8th day of mechanical ventilation, BAL was performed and CT-scan was repeated because of deteriorating pulmonary condition with increasing inflammatory parameters.
T147 17588-17710 Sentence denotes Chest CT-angiography showed bilateral sub-segmental pulmonary emboli, persistent ground-glass opacities and consolidation.
T148 17711-17878 Sentence denotes Newly formed coarse cyst-like lesions in the middle and ventral regions (non-dependant regions) were noted, probably due to ventilator induced lung injury (Fig. 1-3B).
T149 17879-18000 Sentence denotes Considering lack of respiratory improvement and progression of fibrosis on radiological imaging prednisolone was started.
T150 18001-18104 Sentence denotes After five days prednisolone was stopped because of a positive GM index of 3.4 from repeated BAL fluid.
T151 18105-18145 Sentence denotes Fungal culture remained negative though.
T152 18146-18202 Sentence denotes Her respiratory status stabilised but remained critical.
T153 18203-18325 Sentence denotes After pausing the sedation, the patient remained unresponsive and CT head showed ischemia with small areas of haemorrhage.
T154 18326-18461 Sentence denotes In light of her pour neurologic and respiratory prognosis, treatment was ended and patient expired after 26 days on ventilator support.
T155 18462-18561 Sentence denotes In the core needle biopsy specimens the lung tissue largely preserved its preexisting architecture.
T156 18562-18714 Sentence denotes Histologic findings included an inflammatory infiltrate consisting of neutrophils and lymphocytes, and only a sporadic intra-alveolar fibroblastic plug.
T157 18715-18849 Sentence denotes The striking, distinctive feature of this case was the presence of thin, delicate hyaline membranes along the alveolar wall (Fig. 2C).
T158 18850-18898 Sentence denotes Again, micro thrombi were observed in this case.
T159 18899-18949 Sentence denotes No fungi could be demonstrated in the PAS-D stain.
T160 18950-19063 Sentence denotes Together with the clinical characteristics, these histologic findings were suggestive of diffuse alveolar damage.
T161 19065-19119 Sentence denotes 3.5 Case 4 – Acute fibrinous and organizing pneumonia
T162 19120-19263 Sentence denotes A 68-year old male without medical history of cardiopulmonary disease, was presented at the ED in a critical condition with fever and dyspnoea.
T163 19264-19383 Sentence denotes Patient was in need of endotracheal intubation and mechanical ventilation in prone position to improve his oxygenation.
T164 19384-19521 Sentence denotes To exclude secondary infection, BAL was performed and revealed a positive GM and cultured Aspergillus fumigatus and Enterococcus faecium.
T165 19522-19576 Sentence denotes Antifungal therapy was added to his treatment regimen.
T166 19577-19771 Sentence denotes Chest CT-angiography showed segmental pulmonary emboli along with extensive bilateral areas of ground-glass opacity with reticulation and multiple patchy non-dependant peripheral consolidations.
T167 19772-19859 Sentence denotes In contrast to normal areas, the abnormal areas showed mild bronchiectasis (Fig. 1-4A).
T168 19860-19933 Sentence denotes The patient remained unresponsive after cessation of sedative medication.
T169 19934-20024 Sentence denotes CT head showed extensive bilateral cerebellar ischemia with small haemorrhagic components.
T170 20025-20147 Sentence denotes After three weeks of mechanical ventilation his respiratory status worsened and treatment was ended due to poor prognosis.
T171 20148-20205 Sentence denotes The patient passed away 21 days after hospital admission.
T172 20206-20303 Sentence denotes Biopsy specimens showed a pattern of lung injury, that was partially identical to that of case 1.
T173 20304-20403 Sentence denotes Intra-alveolar depositions of fibroblastic tissue were found, consistent with organizing pneumonia.
T174 20404-20571 Sentence denotes However, a predominant, diffuse component of fibrinous exudate in the alveoli was present, which was not the case in the aforementioned case with organizing pneumonia.
T175 20572-20706 Sentence denotes Other histologic findings were a chronic inflammatory infiltrate, and mild interstitial changes, including widening of alveolar septa.
T176 20707-20769 Sentence denotes Microthrombi in small septal blood vessels were also observed.
T177 20770-20844 Sentence denotes Neither remnants hyaline membranes nor prominent eosinophils were present.
T178 20845-20891 Sentence denotes Additional PAS-D stain did not show any fungi.
T179 20892-21011 Sentence denotes The overall histologic pattern of this case was classified as acute fibrinous and organizing pneumonia (AFOP), Fig. 2D.
T180 21013-21026 Sentence denotes 4 Discussion
T181 21027-21141 Sentence denotes We report pathology in deceased critically ill ICU COVID patient in the late phase of disease to be heterogeneous.
T182 21142-21301 Sentence denotes Histopathologically, we observed four distinct histopathological patterns: AFOP, DAD, fibrosis and, in four out of seven patients an organizing pneumonia (OP).
T183 21302-21509 Sentence denotes Interestingly, our findings are in contrast to previously reported postmortem studies in COVID-19 patients in which DAD is the most common predominant pattern [[10], [11], [12],[15], [16], [17], [18], [19]].
T184 21510-21628 Sentence denotes In two recent autopsy studies of 21 and 12 deceased COVID-19 patients, prevalence of DAD was 76% and 67% respectively.
T185 21629-21711 Sentence denotes None of the patients had the postmortem diagnosis of organizing pneumonia [10,11].
T186 21712-21820 Sentence denotes In the study of Ackermann and colleagues, pulmonary histology of all seven studied patients showed DAD [19].
T187 21821-22035 Sentence denotes Although the organizing stage of DAD may overlap with the histopathological features of OP in lung biopsy, the histologic hallmark of DAD, namely remnants of hyaline membranes were not present in our four OP cases.
T188 22036-22306 Sentence denotes Most plausible explanation for the more common pattern of OP in our study population when compared to previous mentioned studies is the difference in length of hospital and ICU stay correlating with more advanced disease and longer treatment with mechanical ventilation.
T189 22307-22454 Sentence denotes In the studies mentioned above the mean hospital stay was six days or less and most of the patients did not receive mechanical ventilatory support.
T190 22455-22611 Sentence denotes In our present series mean hospital stay of 22 days is significant longer and all patients died in the ICU with a mean of 20 days on mechanical ventilation.
T191 22612-22743 Sentence denotes Secondary OP can be seen in association with many types of non-specific lung injury, including viral infections and drug reactions.
T192 22744-22870 Sentence denotes OP is reported following severe influenza infections [[20], [21], [22], [23], [24]] and Middle East Respiratory Syndrome [25].
T193 22871-23064 Sentence denotes Most recently, Copin et al. reported postmortem biopsies on six patients with COVID and reported in five patients with phenotype H and AFOP histology in contrast to their patient with DAD [26].
T194 23065-23160 Sentence denotes Estimated elapsed disease time in the AFOP group was 20 days versus 6 days in the DAD patients.
T195 23161-23234 Sentence denotes In our opinion this supports the theory that pathology changes over time.
T196 23235-23359 Sentence denotes Although the exact pathogenesis of OP remains unknown, it is thought that OP is a consequence of alveolar epithelial injury.
T197 23360-23504 Sentence denotes This initial epithelial injury is followed by leakage of plasma proteins, leading to a cascade of host responses with hyperinflammation [27,28].
T198 23505-23623 Sentence denotes Subsequent fibroblast recruitment and connective tissue and fibroblast organisation is seen within the alveolar space.
T199 23624-23841 Sentence denotes Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) play a central role in organizing pneumonia and are highly expressed in intraluminal fibromyxoid lesion in organizing pneumonia [29].
T200 23842-24013 Sentence denotes Interestingly, binding to ACE2 receptor is recognized as a critical initial step for SARS-CoV-2 to entry alveolar type II cells, resulting in loss of ACE2 at the membrane.
T201 24014-24134 Sentence denotes ACE 2 is a negative regulator of the renin-angiotensin system (RAS) and this depletion of ACE2 upregulates the RAS [30].
T202 24135-24190 Sentence denotes An activated RAS can induce Fibroblastic Growth Factor.
T203 24191-24252 Sentence denotes ACE2 also plays a role in regulating the effect of VEGF [31].
T204 24253-24407 Sentence denotes Therefore, depletion of ACE2 due to the high affinity of SARS-CO-V2 to ACE2 might play a role in the pathogenesis of COVID19 related organizing pneumonia.
T205 24408-24643 Sentence denotes Being aware that medication can be the cause of OP it is notable is that in our study six out of seven patients received chloroquine, at that time the advised treatment by the Dutch National Institute for Public Health and Environment.
T206 24644-24871 Sentence denotes Although chloroquine use is associated with cardiovascular disorders, pulmonary side effects, i.e. drug induced interstitial lung disease, are not described before, and therefore an unlikely cause of the observed histologic OP.
T207 24872-24955 Sentence denotes We found no studies reporting possible relations between antifungal therapy and OP.
T208 24956-25126 Sentence denotes In retrospect, chest CT scans of each of the patients showed a different development during hospital admission, concordant with the histopathological diagnosis (Table 2).
T209 25127-25254 Sentence denotes Development of peripheral nondependent consolidations warrant further investigation in the presence of an organizing pneumonia.
T210 25255-25314 Sentence denotes Excluding nosocomial infections in such cases is essential.
T211 25315-25502 Sentence denotes The diversity in histopathological findings correlating with radiological findings is interesting considering possible therapeutic implications and should be subject for further research.
T212 25503-25704 Sentence denotes Although steroids are not routinely recommended to be used in de early phase of SARS-CoV-2 pneumonia, they might have a role in the late phase of COVID19 when an organizing pneumonia is suspected [32].
T213 25705-25914 Sentence denotes Recently there is increasing awareness and concern for development of secondary infection in COVID patients e.g. invasive aspergillus co-infection, a contra-indication for (long-term) systemic steroid therapy.
T214 25915-26028 Sentence denotes Criteria and risk factors for invasive pulmonary aspergillosis are well defined in immunocompromised populations.
T215 26029-26239 Sentence denotes Furthermore it is a well known complication of severe influenza pneumonia with reported incidences of 19% in ICU patients admitted for influenza related acute respiratory failure with high mortality rates [33].
T216 26240-26428 Sentence denotes In COVID-19 associated pulmonary aspergillosis (CAPA) case definition is absent, although recently an expert panel proposed a classification for IAPA, which was used to classify CAPA [14].
T217 26429-26641 Sentence denotes Pathophysiology of CAPA consists of lung damage with bilateral alveolar-interstitial damage due to viral replication and cytokine storm in combination with marked low T-lymphocytes CD4 + T and CD8 + T cells [27].
T218 26642-26728 Sentence denotes Secondary infection due to lung tissue damage develop within a median of 17 days [34].
T219 26729-26841 Sentence denotes CAPA data are scarce but increasingly reported, although histological confirmation is still absent [9,13,35,36].
T220 26842-26983 Sentence denotes Of the first 31 COVID-19 patients admitted to our ICU, six where highly suspected for COVID-19 associated pulmonary aspergillosis (CAPA) [9].
T221 26984-27127 Sentence denotes In this case series, BAL fluid galactomannan was positive in six out of the seven cases, concluding in the clinical diagnosis of probable CAPA.
T222 27128-27217 Sentence denotes To our surprise, none of the lung biopsies showed any presence of invasive aspergillosis.
T223 27218-27432 Sentence denotes Lack of evidence for invasive pulmonary aspergillosis in our patients with probable CAPA raises the question whether patients with suspected CAPA truly develop invasive aspergillosis and require antifungal therapy.
T224 27433-27563 Sentence denotes For instance, the three deaths in the CAPA report from France were attributed to bacterial septic shock, and not to aspergillosis.
T225 27564-27771 Sentence denotes Although in our patients adequate antifungal treatment could be an explanation for the absence of histologic fungal features, we find this improbable as respiratory conditions deteriorated despite treatment.
T226 27772-27941 Sentence denotes Further research on the presence of CAPA, its case definition and the necessity for antifungal treatment and (relative) contraindication for steroid treatment is needed.
T227 27942-28116 Sentence denotes We acknowledge the limitations of this report and realize that due to limited sample size of pulmonary tissue, a sampling error in our histologic findings cannot be excluded.
T228 28117-28334 Sentence denotes Although conventional autopsy might be the preferred postmortem examination, postmortem ultrasound guided lung biopsies are a safe and valuable alternative, with an 83% concordance rate with conventional autopsy [37].
T229 28335-28577 Sentence denotes Especially in times of new emerging diseases, like COVID-19, histopathological investigation is essential in understanding the pathogenesis of SARS-CoV-2 infection and thereby providing information leading to possible new therapeutic options.
T230 28579-28592 Sentence denotes 5 Conclusion
T231 28593-28737 Sentence denotes We report late pulmonary pathological findings of COVID-19 ARDS to be heterogeneous and non-typical when compared to non-COVID-19 ARDS patients.
T232 28738-28826 Sentence denotes The predominant histologic pattern in our case series mainly consists of OP and not DAD.
T233 28827-28889 Sentence denotes A concordance with specific findings on chest CT is suggested.
T234 28890-28988 Sentence denotes The absence of histology proven aspergillosis provides further discussion on the presence of CAPA.
T235 28989-29173 Sentence denotes Based on these late postmortem histopathologic findings, we suggest that the empiric use of corticosteroid therapy in COVID-19 related ARDS should be reconsidered in selected patients.
T236 29174-29390 Sentence denotes Further research on the late phase of COVID19 in relation to the presence of different histologic patterns, it's concordance with radiology and the presence of COVID19 associated pulmonary aspergillosis is warranted.
T237 29392-29414 Sentence denotes Author's contributions
T238 29415-29488 Sentence denotes A.W·F, M.K.M.K, M.J.J.H.G., D.C.Y.Y. and A.W.F.M. drafted the manuscript.
T239 29489-29591 Sentence denotes N.J.M.M. and T.C.D.R critically revised the manuscript and approved the final version for publication.
T240 29592-29707 Sentence denotes All the authors reviewed the final draft of the manuscript and agreed on submitting it to Journal of Critical Care.
T241 29709-29716 Sentence denotes Support
T242 29717-29745 Sentence denotes No external funding support.
T243 29747-29754 Sentence denotes Funding
T244 29755-29879 Sentence denotes This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
T245 29881-29914 Sentence denotes Declaration of Competing Interest
T246 29915-29959 Sentence denotes The authors declare no conflict of interest.