Invasive Mould Disease in Fatal COVID-19: A Systematic Review of Autopsies

Abstract

BackgroundInvasive mould disease (IMD) – most commonly pulmonary aspergillosis - is reported to affect up to a third of critically ill COVID-19 patients. Most reported cases are diagnosed with probable/putative COVID-19 associated pulmonary aspergillosis (CAPA) based on a combination of non-specific clinical, radiographic, and mycological findings, but the clinical significance – and whether these cases represent true invasive disease – is unresolved.MethodsWe performed a systematic review of autopsy series of decedents with COVID-19 for evidence of IMD. We searched PubMed, Web of Science, OVID (Embase) and MedRxiv for English- or French-language case series published between January 1, 2019 to September 26, 2020. We included series describing lung histology of ≥3 decedents, and authors were contacted for missing information as necessary.FindingsWe identified 51 case series describing autopsies of 702 decedents. Individual-level data was available for 430 decedents. The median age was 72 (IQR 61 to 80) years. Diabetes mellitus, pre-existing lung disease, and immunocompromising conditions were reported for 129 (32%), 95 (22%), and 25 (6%) decedents, respectively. The median hospitalization length was 10 (IQR 5-22) days. 51.6% of decedents had received mechanical ventilation for a median of nine (IQR 5-20) days. Treatment included immunomodulation in 60 (most often steroids or tocilizumab) and antifungals in 41 decedents. Eleven decedents (1·6%) had autopsy-confirmed IMD (6 with CAPA, 4 with invasive pulmonary mycosis not specified and 1 with disseminated mucormycosis). Among 173 decedents who received mechanical ventilation, 5 had IMD (2·9%).InterpretationAutopsy-proven IMD, including CAPA, is uncommon in fatal COVID-19.FundingThis study is unfundedCategoryReview

Mortality in critically ill patients with coronavirus disease 2019‐associated pulmonary aspergillosis: A systematic review and meta‐analysis

“…Autopsy studies show that IPA is among the most commonly missed diagnoses in ICU in‐patient deaths from any cause 55 . A systematic review of an autopsy series in decedents with COVID‐19 also revealed the presence of CAPA in 11.7%, comprising 54.5% of autopsy‐confirmed invasive mould infections 56 . One of the main caveats in the timely diagnosis of CAPA is the lack of specific clinical presentation and radiological signs of COVID‐19 pneumonia.…”

COVID-19 Associated Pulmonary Aspergillosis: Systematic Review and Patient-Level Meta-analysis

“…in the airways reflects colonization and not invasive disease. A systematic review found that autopsy-proven invasive mould disease is an uncommon finding in patients dying with COVID-19, occurring in <2% of decedents reported in autopsy case series (19). Moreover, in some reported cases of probable CAPA, post-mortem examination failed to confirm the diagnosis (20).…”

“…For example, the use of corticosteroids and other immunomodulators were infrequently reported in CAPA and non-CAPA patients, precluding meaningful comparison. The degree to which these therapies may increase risk of CAPA is unclear (19). Finally, we did not formally assess risk of bias, and it is possible that the design of some cohort studies resulted in bias towards over- or underdiagnosing CAPA.…”

COVID-19-associated pulmonary aspergillosis (CAPA): how big a problem is it?

“…in patients with severe COVID-19 [ [9] , [10] , [11] , [12] , [13] , [14] ]. Furthermore, this contrasting view is supported by an autopsy series and a recent systematic review of an autopsy series showing that proven CAPA is uncommon (<3%) [ 10 , 15 ]. Moreover, a case series did not show a worse outcome in putative CAPA cases, even in the absence of antifungal therapy [ 2 ].…”