PMC:7340597 / 21013-28577
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7340597","sourcedb":"PMC","sourceid":"7340597","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7340597","text":"4 Discussion\nWe report pathology in deceased critically ill ICU COVID patient in the late phase of disease to be heterogeneous. Histopathologically, we observed four distinct histopathological patterns: AFOP, DAD, fibrosis and, in four out of seven patients an organizing pneumonia (OP). 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]]. In two recent autopsy studies of 21 and 12 deceased COVID-19 patients, prevalence of DAD was 76% and 67% respectively. None of the patients had the postmortem diagnosis of organizing pneumonia [10,11]. In the study of Ackermann and colleagues, pulmonary histology of all seven studied patients showed DAD [19]. 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.\nMost 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. 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. 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. Secondary OP can be seen in association with many types of non-specific lung injury, including viral infections and drug reactions. OP is reported following severe influenza infections [[20], [21], [22], [23], [24]] and Middle East Respiratory Syndrome [25]. 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]. Estimated elapsed disease time in the AFOP group was 20 days versus 6 days in the DAD patients. In our opinion this supports the theory that pathology changes over time.\nAlthough the exact pathogenesis of OP remains unknown, it is thought that OP is a consequence of alveolar epithelial injury. This initial epithelial injury is followed by leakage of plasma proteins, leading to a cascade of host responses with hyperinflammation [27,28]. Subsequent fibroblast recruitment and connective tissue and fibroblast organisation is seen within the alveolar space. 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]. 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. ACE 2 is a negative regulator of the renin-angiotensin system (RAS) and this depletion of ACE2 upregulates the RAS [30]. An activated RAS can induce Fibroblastic Growth Factor. ACE2 also plays a role in regulating the effect of VEGF [31]. 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.\nBeing 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. 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. We found no studies reporting possible relations between antifungal therapy and OP.\nIn retrospect, chest CT scans of each of the patients showed a different development during hospital admission, concordant with the histopathological diagnosis (Table 2). Development of peripheral nondependent consolidations warrant further investigation in the presence of an organizing pneumonia. Excluding nosocomial infections in such cases is essential. The diversity in histopathological findings correlating with radiological findings is interesting considering possible therapeutic implications and should be subject for further research. 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].\nRecently 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. Criteria and risk factors for invasive pulmonary aspergillosis are well defined in immunocompromised populations. 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]. 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]. 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]. Secondary infection due to lung tissue damage develop within a median of 17 days [34]. CAPA data are scarce but increasingly reported, although histological confirmation is still absent [9,13,35,36]. Of the first 31 COVID-19 patients admitted to our ICU, six where highly suspected for COVID-19 associated pulmonary aspergillosis (CAPA) [9]. In this case series, BAL fluid galactomannan was positive in six out of the seven cases, concluding in the clinical diagnosis of probable CAPA.\nTo our surprise, none of the lung biopsies showed any presence of invasive aspergillosis. 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. For instance, the three deaths in the CAPA report from France were attributed to bacterial septic shock, and not to aspergillosis. 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. Further research on the presence of CAPA, its case definition and the necessity for antifungal treatment and (relative) contraindication for steroid treatment is needed.\nWe 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. 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]. 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 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