LitCovid-sentences  

PMC:7340597 / 1949-29959 JSONTXT 14 Projects

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Id Subject Object Predicate Lexical cue
T23 0-15 Sentence denotes 1 Introduction
T24 16-386 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 387-821 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 822-969 Sentence denotes Two earlier observed features may play a critical role in the severity of this disease: thromboembolic complications and early onset aspergillosis.
T27 970-1083 Sentence denotes The cumulative incidence of venous thromboembolism reported was 49% in COVID-19 patients admitted to the ICU [8].
T28 1084-1179 Sentence denotes Presumed pulmonary aspergillosis may be present in as much as 19% of ICU COVID-19 patients [9].
T29 1180-1398 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 1399-1534 Sentence denotes The scarcely available pathological data in COVID-19 patients show diffuse alveolar damage, closely related to ARDS [[10], [11], [12]].
T31 1535-1770 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 1771-1892 Sentence denotes We examined postmortem obtained lung tissue in seven patients, with COVID related ARDS who needed mechanical ventilation.
T33 1893-2016 Sentence denotes The histopathologic findings, together with clinical features, radiological and microbiological findings are reported here.
T34 2017-2138 Sentence denotes This report may contribute to new insights in the pathogeneses of COVID-19 as well as suggestions for treatment strategy.
T35 2140-2150 Sentence denotes 2 Methods
T36 2152-2184 Sentence denotes 2.1 Study population and design
T37 2185-2497 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 2498-2633 Sentence denotes SARS-CoV-2 was diagnosed using real-time reverse transcription polymerase chain reaction (RT-PCR) on sputum and/or bronchial aspirates.
T39 2634-2972 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 2973-3111 Sentence denotes Bronchoscopy, with or without lavage, and testing for pulmonary aspergillosis were performed at the discretion of the attending physician.
T41 3112-3277 Sentence denotes Pulmonary aspergillosis was diagnosed using clinical, radiological and mycological data and included galactomannan (serum and sputum), tracheal or bronchial culture.
T42 3278-3402 Sentence denotes For galactomannan (GM) testing from bronchoalveolar lavage (BAL) fluid Platelia Aspergillis antigen ELISA (Biorad) was used.
T43 3403-3576 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 3577-3732 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 3734-3780 Sentence denotes 2.2 Postmortem needle core biopsy of the lung
T46 3781-3914 Sentence denotes With permission from the patients' families, postmortem core needle biopsies were performed on both lungs within an hour after death.
T47 3915-4019 Sentence denotes Lung biopsies were ultrasound and CT guided and combined with surface anatomic landmarks as a reference.
T48 4020-4113 Sentence denotes A minimum of three histologic 14 gauge true cut needle biopsies were performed in both lungs.
T49 4114-4204 Sentence denotes Biopsy specimens were fixed in formalin, embedded in paraffin, and cut into 3 μm sections.
T50 4205-4333 Sentence denotes Hematoxylin and eosin (H&E), and periodic acid–Schiff with diastase (PAS-D) stains were applied according to routine procedures.
T51 4335-4360 Sentence denotes 2.3 Statistical analysis
T52 4361-4430 Sentence denotes Descriptive statistics were used to describe patient characteristics.
T53 4431-4487 Sentence denotes For statistical analysis IBM SPSS version 25.0 was used.
T54 4488-4579 Sentence denotes The local Medical Ethics Committee (Medical Research Committees United) approved the study.
T55 4581-4591 Sentence denotes 3 Results
T56 4593-4615 Sentence denotes 3.1 Clinical features
T57 4616-4709 Sentence denotes During the study period, seven patients underwent postmortem needle core biopsy of the lungs.
T58 4710-4795 Sentence denotes Patients age ranged from 58 to 83 years (median 74 year) and five patients were male.
T59 4796-4862 Sentence denotes None of the patients had a history of (chronic) pulmonary disease.
T60 4863-4980 Sentence denotes One patient used immunosuppressive medication before hospital admission, in this case a short course of prednisolone.
T61 4981-5061 Sentence denotes Median time from hospital to ICU admission was 0 days (interquartile range 0–4).
T62 5062-5126 Sentence denotes Time from hospital admission to death ranged from 12 to 36 days.
T63 5127-5189 Sentence denotes Patients deceased at median of 21(range 9–36) ventilated days.
T64 5190-5267 Sentence denotes In five out of seven patients ICU stay was complicated by pulmonary embolism.
T65 5268-5435 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 5436-5534 Sentence denotes In those patients, combination antifungal therapy with voriconazole and anidulafungin was started.
T67 5535-5686 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 5687-5829 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 5830-5972 Sentence denotes Nosocomial infections including signs for pulmonary aspergillosis were excluded by bronchoscopy with BAL before steroid treatment was started.
T70 5973-6094 Sentence denotes Radiologic findings of chest CT and histologic results of the lungs biopsies of all seven patients are shown in Table 2 .
T71 6095-6147 Sentence denotes Table 1 Patient characteristics and clinical course.
T72 6148-6432 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 6433-6488 Sentence denotes 1 M, 77 None 12 10 Severe Low Yes GM negative No Yes No
T74 6489-6590 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 6591-6670 Sentence denotes 3 F, 58 None 30 26 Severe Low Yes GM index 3.4 (day 20) Probable Yes Yes 5 days
T76 6671-6786 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 6787-6891 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 6892-6965 Sentence denotes 6 M, 83 HT, DM 13 9 Moderate Low No GM index 1.7 (day 11) Probable Yes No
T79 6966-7067 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 7068-7300 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 7301-7362 Sentence denotes Table 2 Radiological Chest CT scan and histological findings.
T82 7363-7433 Sentence denotes Case Radiological findings Histological findings description Diagnosis
T83 7434-7724 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 7725-7978 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 7979-8247 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 8248-8567 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 8568-8753 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 8754-8967 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 8968-9233 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 9234-9386 Sentence denotes AFOP acute fibrinous and organizing pneumonia, DAD diffuse alveolar damage, GGO, ground glass opacities; OP organizing pneumonia; PE pulmonary embolism.
T91 9387-9550 Sentence denotes To further investigate histopathologic findings we now present the detailed clinical course of four patients with four different histopathological characteristics.
T92 9551-9727 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 9728-9797 Sentence denotes Chest CT imaging of the four discussed patients are shown in Fig. 1 .
T94 9798-9832 Sentence denotes Fig. 1 Chest CT scans of case 1–4.
T95 9833-9971 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 9972-10119 Sentence denotes 1A: bilateral areas of GGO, patchy subpleural non-dependant consolidations 1B: progression of dens subpleural consolidations with air-bronchograms.
T97 10120-10230 Sentence denotes 2A GGO in both lungs, combined with crazy-paving pattern, subtle bronchiectasis are present in affected areas.
T98 10231-10355 Sentence denotes 2B GGO persisted, without progression to consolidations, more pronounced fibrotic reticulation with traction bronchiectasis.
T99 10356-10425 Sentence denotes 3A diffuse bilateral GGO with large gravity dependant consolidations.
T100 10426-10524 Sentence denotes 3B persistent GGO and consolidation, newly formed cyst-like lesions in middle and ventral regions.
T101 10525-10624 Sentence denotes 4A bilateral areas of GGO, patchy non-dependant peripheral consolidations with mild bronchiectasis.
T102 10626-10660 Sentence denotes 3.2 Case 1 – Organizing pneumonia
T103 10661-10819 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 10820-11034 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 11035-11194 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 11195-11410 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 11411-11469 Sentence denotes A nosocomial infection was ruled out by bronchial culture.
T108 11470-11634 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 11635-11676 Sentence denotes The patient died 12 days after admission.
T110 11677-11785 Sentence denotes Postmortem pathologic examination revealed that the overall architecture of the lung tissue remained intact.
T111 11786-11918 Sentence denotes However, a prominent amount of fibromyxoid or fibroblastic bodies was present in the alveoli with surrounding histiocytes (Fig. 2A .
T112 11919-11992 Sentence denotes The extent of involved lung tissue was estimated at around 25% (Table 2).
T113 11993-12077 Sentence denotes No remnants of hyaline membranes or prominent alveolar fibrinous exudate were found.
T114 12078-12216 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 12217-12331 Sentence denotes The histologic findings in this case point towards an epithelial, and vascular phenotype of a SARS-CoV2 infection.
T116 12332-12372 Sentence denotes No fungi were present in de PAS-D stain.
T117 12373-12443 Sentence denotes This histologic pattern is characteristic for an organizing pneumonia.
T118 12444-12477 Sentence denotes Fig. 2 Microscopic lung findings.
T119 12478-13100 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 13102-13124 Sentence denotes 3.3 Case 2 – Fibrosis
T121 13125-13222 Sentence denotes A 73-year old female was transferred to our ICU due to shortage of ICU beds in a nearby hospital.
T122 13223-13315 Sentence denotes Prior to ICU admission, she was healthy but complained of diarrhoea and shortness of breath.
T123 13316-13472 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 13473-13537 Sentence denotes There were some small areas of consolidation in the upper lobes.
T125 13538-13603 Sentence denotes Subtle bronchiectasis were present in affected areas (Fig. 1-2A).
T126 13604-13692 Sentence denotes Her respiratory condition required mechanical ventilation in prone position due to ARDS.
T127 13693-13777 Sentence denotes After seven days, prednisolone treatment was started because of lack of improvement.
T128 13778-13858 Sentence denotes Repeat chest CT-angiography showed segmental pulmonary emboli in the right lung.
T129 13859-13933 Sentence denotes Ground-glass opacities persisted while the consolidations had disappeared.
T130 13934-14044 Sentence denotes A reticular pattern combined with GGO was more pronounced with increasing traction bronchiectasis (Fig. 1-2B).
T131 14045-14136 Sentence denotes BAL was performed twice, but GM and culture showed no signs of additional fungal infection.
T132 14137-14225 Sentence denotes After one week of high dose glucocorticoid therapy BAL was repeated with a GM index 4.4.
T133 14226-14281 Sentence denotes Fungal cultures showed growth of Aspergillus fumigatus.
T134 14282-14368 Sentence denotes Therefore, prednisolone treatment was discontinued and antifungal treatment initiated.
T135 14369-14500 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 14501-14618 Sentence denotes Neurologic condition worsened and progressive cerebral haemorrhage on follow up CT head was seen with poor prognosis.
T137 14619-14709 Sentence denotes Palliative treatment was started and the patient deceased 27 days after onset of symptoms.
T138 14710-14821 Sentence denotes Microscopic examination of lung tissue of this case showed an almost complete loss of normal lung architecture.
T139 14822-14907 Sentence denotes Alveolar structures were unrecognizable and replaced by extensive fibrosis (Fig. 2B).
T140 14908-15012 Sentence denotes What remained were several foci of pneumocytes, bronchial epithelium, and blood vessels without thrombi.
T141 15013-15055 Sentence denotes In the PAS-D stain no fungi were observed.
T142 15056-15116 Sentence denotes The prominent pattern in this patient is pulmonary fibrosis.
T143 15118-15155 Sentence denotes 3.4 Case 3 – Diffuse alveolar damage
T144 15156-15259 Sentence denotes A 58-year old female was admitted to the ICU and needed mechanical ventilation due to severe hypoxemia.
T145 15260-15467 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 15468-15638 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 15639-15761 Sentence denotes Chest CT-angiography showed bilateral sub-segmental pulmonary emboli, persistent ground-glass opacities and consolidation.
T148 15762-15929 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 15930-16051 Sentence denotes Considering lack of respiratory improvement and progression of fibrosis on radiological imaging prednisolone was started.
T150 16052-16155 Sentence denotes After five days prednisolone was stopped because of a positive GM index of 3.4 from repeated BAL fluid.
T151 16156-16196 Sentence denotes Fungal culture remained negative though.
T152 16197-16253 Sentence denotes Her respiratory status stabilised but remained critical.
T153 16254-16376 Sentence denotes After pausing the sedation, the patient remained unresponsive and CT head showed ischemia with small areas of haemorrhage.
T154 16377-16512 Sentence denotes In light of her pour neurologic and respiratory prognosis, treatment was ended and patient expired after 26 days on ventilator support.
T155 16513-16612 Sentence denotes In the core needle biopsy specimens the lung tissue largely preserved its preexisting architecture.
T156 16613-16765 Sentence denotes Histologic findings included an inflammatory infiltrate consisting of neutrophils and lymphocytes, and only a sporadic intra-alveolar fibroblastic plug.
T157 16766-16900 Sentence denotes The striking, distinctive feature of this case was the presence of thin, delicate hyaline membranes along the alveolar wall (Fig. 2C).
T158 16901-16949 Sentence denotes Again, micro thrombi were observed in this case.
T159 16950-17000 Sentence denotes No fungi could be demonstrated in the PAS-D stain.
T160 17001-17114 Sentence denotes Together with the clinical characteristics, these histologic findings were suggestive of diffuse alveolar damage.
T161 17116-17170 Sentence denotes 3.5 Case 4 – Acute fibrinous and organizing pneumonia
T162 17171-17314 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 17315-17434 Sentence denotes Patient was in need of endotracheal intubation and mechanical ventilation in prone position to improve his oxygenation.
T164 17435-17572 Sentence denotes To exclude secondary infection, BAL was performed and revealed a positive GM and cultured Aspergillus fumigatus and Enterococcus faecium.
T165 17573-17627 Sentence denotes Antifungal therapy was added to his treatment regimen.
T166 17628-17822 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 17823-17910 Sentence denotes In contrast to normal areas, the abnormal areas showed mild bronchiectasis (Fig. 1-4A).
T168 17911-17984 Sentence denotes The patient remained unresponsive after cessation of sedative medication.
T169 17985-18075 Sentence denotes CT head showed extensive bilateral cerebellar ischemia with small haemorrhagic components.
T170 18076-18198 Sentence denotes After three weeks of mechanical ventilation his respiratory status worsened and treatment was ended due to poor prognosis.
T171 18199-18256 Sentence denotes The patient passed away 21 days after hospital admission.
T172 18257-18354 Sentence denotes Biopsy specimens showed a pattern of lung injury, that was partially identical to that of case 1.
T173 18355-18454 Sentence denotes Intra-alveolar depositions of fibroblastic tissue were found, consistent with organizing pneumonia.
T174 18455-18622 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 18623-18757 Sentence denotes Other histologic findings were a chronic inflammatory infiltrate, and mild interstitial changes, including widening of alveolar septa.
T176 18758-18820 Sentence denotes Microthrombi in small septal blood vessels were also observed.
T177 18821-18895 Sentence denotes Neither remnants hyaline membranes nor prominent eosinophils were present.
T178 18896-18942 Sentence denotes Additional PAS-D stain did not show any fungi.
T179 18943-19062 Sentence denotes The overall histologic pattern of this case was classified as acute fibrinous and organizing pneumonia (AFOP), Fig. 2D.
T180 19064-19077 Sentence denotes 4 Discussion
T181 19078-19192 Sentence denotes We report pathology in deceased critically ill ICU COVID patient in the late phase of disease to be heterogeneous.
T182 19193-19352 Sentence denotes Histopathologically, we observed four distinct histopathological patterns: AFOP, DAD, fibrosis and, in four out of seven patients an organizing pneumonia (OP).
T183 19353-19560 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 19561-19679 Sentence denotes In two recent autopsy studies of 21 and 12 deceased COVID-19 patients, prevalence of DAD was 76% and 67% respectively.
T185 19680-19762 Sentence denotes None of the patients had the postmortem diagnosis of organizing pneumonia [10,11].
T186 19763-19871 Sentence denotes In the study of Ackermann and colleagues, pulmonary histology of all seven studied patients showed DAD [19].
T187 19872-20086 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 20087-20357 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 20358-20505 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 20506-20662 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 20663-20794 Sentence denotes Secondary OP can be seen in association with many types of non-specific lung injury, including viral infections and drug reactions.
T192 20795-20921 Sentence denotes OP is reported following severe influenza infections [[20], [21], [22], [23], [24]] and Middle East Respiratory Syndrome [25].
T193 20922-21115 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 21116-21211 Sentence denotes Estimated elapsed disease time in the AFOP group was 20 days versus 6 days in the DAD patients.
T195 21212-21285 Sentence denotes In our opinion this supports the theory that pathology changes over time.
T196 21286-21410 Sentence denotes Although the exact pathogenesis of OP remains unknown, it is thought that OP is a consequence of alveolar epithelial injury.
T197 21411-21555 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 21556-21674 Sentence denotes Subsequent fibroblast recruitment and connective tissue and fibroblast organisation is seen within the alveolar space.
T199 21675-21892 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 21893-22064 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 22065-22185 Sentence denotes ACE 2 is a negative regulator of the renin-angiotensin system (RAS) and this depletion of ACE2 upregulates the RAS [30].
T202 22186-22241 Sentence denotes An activated RAS can induce Fibroblastic Growth Factor.
T203 22242-22303 Sentence denotes ACE2 also plays a role in regulating the effect of VEGF [31].
T204 22304-22458 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 22459-22694 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 22695-22922 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 22923-23006 Sentence denotes We found no studies reporting possible relations between antifungal therapy and OP.
T208 23007-23177 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 23178-23305 Sentence denotes Development of peripheral nondependent consolidations warrant further investigation in the presence of an organizing pneumonia.
T210 23306-23365 Sentence denotes Excluding nosocomial infections in such cases is essential.
T211 23366-23553 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 23554-23755 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 23756-23965 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 23966-24079 Sentence denotes Criteria and risk factors for invasive pulmonary aspergillosis are well defined in immunocompromised populations.
T215 24080-24290 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 24291-24479 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 24480-24692 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 24693-24779 Sentence denotes Secondary infection due to lung tissue damage develop within a median of 17 days [34].
T219 24780-24892 Sentence denotes CAPA data are scarce but increasingly reported, although histological confirmation is still absent [9,13,35,36].
T220 24893-25034 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 25035-25178 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 25179-25268 Sentence denotes To our surprise, none of the lung biopsies showed any presence of invasive aspergillosis.
T223 25269-25483 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 25484-25614 Sentence denotes For instance, the three deaths in the CAPA report from France were attributed to bacterial septic shock, and not to aspergillosis.
T225 25615-25822 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 25823-25992 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 25993-26167 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 26168-26385 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 26386-26628 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 26630-26643 Sentence denotes 5 Conclusion
T231 26644-26788 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 26789-26877 Sentence denotes The predominant histologic pattern in our case series mainly consists of OP and not DAD.
T233 26878-26940 Sentence denotes A concordance with specific findings on chest CT is suggested.
T234 26941-27039 Sentence denotes The absence of histology proven aspergillosis provides further discussion on the presence of CAPA.
T235 27040-27224 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 27225-27441 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 27443-27465 Sentence denotes Author's contributions
T238 27466-27539 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 27540-27642 Sentence denotes N.J.M.M. and T.C.D.R critically revised the manuscript and approved the final version for publication.
T240 27643-27758 Sentence denotes All the authors reviewed the final draft of the manuscript and agreed on submitting it to Journal of Critical Care.
T241 27760-27767 Sentence denotes Support
T242 27768-27796 Sentence denotes No external funding support.
T243 27798-27805 Sentence denotes Funding
T244 27806-27930 Sentence denotes This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
T245 27932-27965 Sentence denotes Declaration of Competing Interest
T246 27966-28010 Sentence denotes The authors declare no conflict of interest.