Table 1.
Postmortem Histopathology Consistent With Lung Superinfections in Patients With COVID-19a
| Pt No. [Ref] | Lung Infxn, No. (%) | Case Details | Commentsc | ||||
|---|---|---|---|---|---|---|---|
| Age(s), Sex | Clinical History, Time to Deathb | Abx Treatment | Relevant Histopathology | Microbiology | |||
| 1 [10] | 10/21 (48) | 66–96 y, 80% M | Cough 50%, fever 38%, 25% dyspnea 0–9 d | Not stated | “Superimposed bacterial bronchopneumonia,” ranging from “early” to “severe” | Gram-positive cocci in alveoli (1 pt) | Autopsies, pts from Switzerland, through April. Causes of death in 8/10 pts listed as “SARS-CoV-2-associated respiratory failure with superimposed bacterial bronchopneumonia.” “Severe and extensive bronchopneumonia without typical features of DAD” described in 3 pts. 4 localized pneumonia, 6 severe or diffuse. |
| 2 [11] | 4/12 (33) | 54–87 y, 50% M | Not stated | None | “No DAD but extensive granulocytic infiltration of alveoli and bronchi, resembling bacterial focal bronchopneumonia” | Not stated | Autopsies, pts from Germany, through April. Causes of death listed as pneumonia, pneumonia and septic encephalopathy, bronchopneumonia, purulent bronchitis. Not clear if pneumonia causing death ascribed to SARS-CoV-2 or bacteria. “Macroscopically differentiating viral pneumonia with subsequent DAD (a histologic diagnosis) from bacterial pneumonia was not always possible.” |
| 3 [12] | 1/4 (25) | 59 y, M | Fever 52 d | Not stated | “Abundant intra-alveolar neutrophilic infiltration, consistent with superimposed bacterial bronchopneumonia” | Not stated | Postmortem biopsy, pt from China, February or earlier. “Abundant intra-alveolar neutrophilic infiltration, consistent with superimposed bacterial bronchopneumonia.” |
| 4 [13] | 1/2 (50) | 42 y, M | Cough, fever, dyspnea 48 h | Not stated | “Acute bronchopneumonia, focal aspiration” | Postmortem lung tissue: E. coli, P. mirabilis | Autopsy, pt from USA, March. Cause of death listed as “complications of hepatic cirrhosis.” “Acute bronchopneumonia with aspiration” listed as significant condition. Pt died in community. |
| 5 [14] | 2/3 (67) | 70 y, W; 27 y, M | 1) Vomit, abdominal pain, dyspnea 2 d; 2) cough, dyspnea 6 d | 1/2, no details | “Focal areas of rich neutrophilic infiltration” | Not stated | Autopsies, pts from Romania, through May. Causes of death listed as “direct lung injury due to viral pneumonia.” 1 death with pneumonia in community. |
| 6 [15] | 1/2 (50) | 65 y, M | Fever, respiratory failure 16 d | Yes, no details | Alveolar wall destruction, diffuse inflammatory infiltrate, “concentrated inflammatory exudate filling the airspaces” | Not stated | Postmortem biopsies, pts from China, March or earlier. Histopathology “suggestive of an organizing phase of DAD complicated by bacterial pneumonia”; “acute DAD may favor the development of bacterial pneumonia.” |
| 7 [16] | 3/10 (30) | 22–78 y, M | Dyspnea, CVA (1), mechanical ventilation (1) 12–27 d | Not stated | “Interstitial neutrophilic infiltrate,” “patchy acute bronchopneumonia,” broad, aseptate hyphal co-infection in 1 pt | Not stated | Autopsies, pts from UK, through April. Causes of death DAD in 2 pts. |
| 8 [17] | 6/11 (55) | 70–91 y, 83% M 6–11 d | Not stated | 5/6: BL-BLI 4, carbapenems 2, macrolides 2 | “Reactive neutrophilic infiltrates,” “bronchopneumonia...ranging from (mostly) focal to confluent” in 6 pts, “adjacent to infraction” in 5 pts | Not stated | Autopsies, pts from Austria, through 14 April. Predominant causes of death DAD, respiratory insufficiency, and thromboses. Deaths included community cases. 2/11 received mechanical ventilation. |
| 9 [18] | 10/11 (91) | 67–89 y, 50% M 8–20 d | Fever, chills, dyspnea 4–36 d | Not stated | DAD with “bronchopneumonia associated with purulent bronchitis” | Not stated | Autopsies, pts from Austria, through 13 May. “Most focal bronchopneumonia.” Data here exclude 8 pts also included in [17]. |
| 10 [9] | 1/4 (25) | 78 y, W | Fever, chills, vomiting 12 h | None | “Focal inflammatory exudate with neutrophils” | Not performed | Autopsy, pt from Germany, through April. Patient was found dead at home. Likely cause of death was “inflammation associated pulmonary edema and acute cardiac failure.” A second patient with ventilator-associated pneumonia due to K. oxytoca was diagnosed and treated antemortem, but relatively infrequent neutrophils on histopathology “argued against significant bacterial superinfection.” |
| 11 [19] | 11/14 (79) | 55–94 y, 64% M | SOB (11), fever (11), cough (10) 6–50 d | 11/11: BL-BLI 8, clindamycin 2, carbapenems 1, macrolides 1 | DAD with “superimposed acute bronchopneumonia,” “dense accumulation of neutrophils within the airways and alveoli” | Postmortem cx: S. aureus, 4; K. pneumoniae, P. aeruginosa, 1 each | Autopsies, pts from Austria, through 14 May. Acute bronchopneumonia considered major cause of death in 2 pts. |
| 12 [20] | 8/17 (47) | 53–77 y, all M | 3–14 d, symptoms not stated | 7/8, no details | “Acute pneumonia or bronchopneumonia” | Not stated | Autopsies, pts from Belgium, through April. Causes of death: MOF 4, septic shock 2, cardiogenic shock 1, respiratory failure 3, mesenteric ischemia 1. “It is difficult to conclude whether DAD reflected the natural time course of the viral disease or was secondary to superimposed complications, such as nosocomial infections.” |
| 13 [21] | 1/1 (100) | 93 y, W | Cough, prostration 20 d | Amp-sulbactam, ceftriaxone | “Acute bronchopneumonia,” “alveolar space infiltration of numerous neutrophils,” “bacterial colonies were detected” | Not stated | Autopsy, pt from Japan, April or earlier. Bronchopneumonia was felt to be likely secondary to primary viral infection and DAD. |
| 14 [22] | 4/12 (33) | Not stated | Not stated | Not stated | “Granulocyte-dominated focal confluent bronchopneumonia was dominant,” “mixed forms of DAD and purulent pneumonia” | Not stated | Autopsies, pts from Germany, through 18 April. First 80 consecutive autopsies performed in Hamburg, but histopathology only reported for 12. Four pts had evidence of “superinfected bronchopneumonia (no bacteriologic diagnosis was made postmortem).” |
| 15 [23] | 3/14 (21) | 73–84 y, all W | Respiratory distress 2, SOB, fever, cough, N/V 2–23 d | Not stated | “Areas of neutrophilic inflammation,” “acute bronchopneumonia” | Not detected | Autopsy, pt from USA, through March. Only 1/3 had bronchopneumonia as ICD-10 coded diagnosis. 2 other patients with ICD-10 coded pneumonia did not have histopathologic evidence on autopsy. |
| 16 [24] | 1/1 (100) | 76 y, W | Nasal congestion, chills, fever, hypoxia 11 d | Ceftriaxone, azithromycin | “Rare foci with neutrophilic and histiocytic infilrates in alveolar spaces” | Not stated | Autopsy, pt from USA, date unclear. Comfort measures only. Primary cause of death was “DAD due to SARS-CoV-2.” “Focal pneumonic process, consistent with superimposed bronchopneumonia.” |
| 17 [26] | 2/6 (33) | 33 y, W; 70 y, M | Cough, cardiac arrest, duration not stated | Not stated | “Superimposed bronchopneumonia (likely bacterial infection)” | Not stated | Autopsies, pts from UK, through April. Bronchopneumonia superimposed on DAD. One patient found dead at home. |
| 18 [27] | 3/7 (43) | 50–77 y, 100% M | Fever, cough, respiratory failure 6–31 d | Not stated | “Superimposed bacterial lobar pneumonia” | Not stated | Autopsies, pts from USA, April. |
| 19 [28] | 1/1 (100) | 59 y, M | Cough 5 d | None | “Focal neutrophilic infiltration...in some airspaces and bronchial wall suggested the beginning of a secondary bacterial pneumonia” | Not stated | Autopsy, pt from Switzerland, April or earlier. Patient found dead at home. Cause of death “ARDS due to severe diffuse DAD as a result of severe infection with SARS-CoV-2.” |
| 20 [29] | 5/10 (50) | 64–90 y, not stated | Not stated | Not stated | “Minor neutrophil infiltration was indicative of secondary infection and/or aspiration” | Not stated | Autopsies, performed in 10 of 12 consecutive patients from Germany who died with SARS-CoV-2 infection, through 19 April. DAD was dominant histopathologic finding in all pts. |
| 21 [30] | 5/8 (63) | 37–75 y, 80% M | Fever, cough, myalgia, dyspnea | Not stated | “Acute bronchopneumonia” | Not stated | Autopsies, pts from USA, dates unclear. Average of 5 sections of lung examined for each pt. All pts had evidence of DAD. Deaths occurred in community (2) and in-hospital (3) cohorts. |
| 22 [31] | 6/10 (60) | 33–83 y, 50% M | Fever, dyspnea, cough most common 3–16 d | Not stated | “Secondary suppurative pneumonia,” which was “intense” and “mild” in 5 and 1, respectively | Not stated | Ultrasound-guided minimally invasive autopsies, pts from Brazil, through April. Cases described as “secondary bacterial pneumonia.” All pts had DAD. |
| 23 [32] | 1/10 (10) | Not stated | Not stated | Cefepime | “Focal acute inflammatory infiltrate suggestive of a secondary infection. The neutrophils...were partly degenerated and entrapped in fibrin, possibly representing NETs” | Not stated | Autopsy, pt from USA, through March. Meaning of histopathologic finding at left is unclear. “A notable finding was the absence of observed secondary infection in our patients. Although most of the patients received antibiotic therapy…. The absence of bacterial infection suggests that this was not the main cause of death.” |
| 24 [33] | 1/1 (100) | 31 y, W | Loss of consciousness | None | “In the alveolar exudate, there were...only scant PMNs and lymphocytes. Focal areas of intra-alveolar hemorrhage and bacterial proliferation were also present” “Liver microabscesses” | Postmortem: “mixed flora...on blood, lungs, liver, spleen and CSF” | Autopsy, pt from Switzerland, March or earlier. Death occurred at home. “An early phase of secondary bacterial infection was noticed within the alveoli, with margination of PMNs.” Cause of death: “pulmonary changes related to SARS-CoV-2 and high fever without implication of a secondary bacterial infection.” |
| 25 [34] | 3/7 (43) | 46–75 y, 67% M | Fever 100%, dyspnea 67% 6–16 d | Cefepime, 1/3 | “Marked intra-alveolar accumulation of neutrophil-rich inflammatory cells was observed, which is compatible with acute pneumonia” | Not stated | Needle biopsies, pts from Iran, dates unclear. Histopathologic findings “can be interpreted as acute pneumonia resulting from superimposed bacterial infection.” |
| 26 [35] | 1/2 (50) | 54 y, M | Dyspnea, cough 12 d | Vanco, pip-tazo | “Marked intra-alveolar acute inflammation focally involving all lobes except LLL, diagnostic of acute bronchopneumonia” | Blood: Enterococcus faecalis, coagulase-negative Staphylococcus Sputum: negative |
Autopsy, pt from USA, dates unclear. “Superimposed acute bronchopneumonia.” Cause of death: “SARS-CoV-2 infection occurring in the setting of diabetes and underlying cardiovascular disease leading to respiratory and subsequent multiorgan system failure.” |
| 27 [36] | 4/8 (50) | Median, 73.5 y, 50% M | Fever, cough, dyspnea most common 7–13 d | Not stated | Diffuse or focal bronchopneumonia with filling of alveolar spaces by neutrophils | Immunostain and/or PCR: + Streptococcus spp. in 3 pts | Autopsies, pts from USA, dates unclear. Diffuse (1) and focal (3) bronchopneumonia. |
| 28 [37] | 2/2 (100) | 72–73 y, M | Respiratory failure 1–4 d | None | “Intra-alveolar accumulation of neutrophils” | Not stated | Autopsies, pts from USA, through March. Immunostaining revealed prominent complement. “Tissue neutrophilia may be attributable to the neutrophil chemoattractant properties of complement” rather than bacterial bronchopneumonia. |
| 29 [38] | 5/38 (13) | 32–86 y, not stated | Not stated | Not stated | Four pts had bacterial abscesses (1 or 2 per lung, <5 mm diameter) | Not stated | Autopsies in 38 consecutive pts from Italy, through 24 March. 4 bacterial abscesses “were presumed to have formed after hospital admission.” No microbiology. |
| 30 [39] | 2/23 (9) | 49 y, M (empyema), no other details | Not stated | None | “Significant neutrophilic infiltrate within alveoli” (1), “right pleura necroinflammatory infiltrate...confirming diagnosis of empyema (1) | Empyema postmortem cx: “mixed flora...consistent with postmortem contamination” | Autopsies, pts from USA, through April. Pt with empyema found dead at home. |
| 31 [40] | 17/68 (25) | 48–95 y, 82% M | Dyspnea 82%, cough 53%, fever 41% | Abx 71%, no details | “Associated acute bacterial pneumonia” | Not stated | Autopsies, pts from Italy and USA, through 25 April. Pneumonia, “mostly bacterial” 14, lung abscess 1. |
| 32 [41] | 10/40 (25) | 38–97 y, not stated | Not stated | Not stated | Bronchopneumonia listed as “minor microscopic pattern” | Not stated | Autopsies, pts from USA, through early May. 7 bacterial bronchopneumonias were identified. Bronchopneumonia and other “minor microscopic patterns” were “improbable causes of death.” |
| 33 [8] | 2/8 (25) | Not stated | Symptoms not stated 7–25 d | Not stated | “Neutrophilic infiltrates” (1), “bronchopneumonia was extensive and necrotizing and associated with bacterial overgrowth” (1) | Not performed | Autopsies, pts from USA, through May. “Since culture results were not available, we cannot exclude artifactual postmortem bacterial overgrowth. The distribution of neutrophils in areas of acute bronchopneumonia differed from the neutrophilic component associated with acute DAD: more localized and peribronchiolar distribution of a more marked neutrophilic infiltrate in the former compared to more diffuse interstitial distribution of neutrophils with mild alveolar accumulation in the latter.” |
| 34 [42] | 1/1 (100) | 65 y, M | Fever, dyspnea 21 d | Antibiotics, but details not provided | “Purulent discharge in most areas of the alveolar spaces” | Not provided | Postmortem biopsy, pt from China, March or earlier. Died of multisystem organ failure. Death “might have been associated with uncontrolled secondary bacterial infection.” |
| 35 [43] | 8/8 (100) | 69–96 y, 87% M | Not stated 6–100 d | Not stated | “Acute bronchopneumonia” | Postmortem cx + 6/8 (S. aureus 3, E. faecium 1, E. cloacae 1, “usual flora” 1) | Autopsies, pts from USA, dates unclear. “Acute bronchopneumonia” cause of death in 7/8. “While acute bronchopneumonia is usually caused by bacterial infection, it might be possible this particular virus elicits an acute bronchopneumonia pattern, especially in cases that are negative by culture.... Negative cultures in cases might also be due to sampling as cultures were taken from periphery of the lungs before they were perfused with formalin and sectioned.” Cases were seen with and without DAD. |
| 36 [45] | 4/9 (44) | 44–66 y, 100% M | Fever, cough, dyspnea 100% 6–35 d | Azithromycin (3), BL/BLI (3), carbapenem (3), linezolid (2) | “Typical bacterial bronchopneumonia with bronchiocentric neutrophilic infiltrate” (3), large venous thrombus containing “small aggregates of mycotic spores” (1) | Respiratory cx: P. aeruginosa (2), E. coli, S. aureus (1 each) | Autopsies, pts from Italy, through 17 April. Bronchopneumonias occurred in setting of late fibrous (proliferative) DAD. Causes of death considered multifactorial. |
| 37 [46] | 12/30 (40) | Median, 69 y, 67% M | Cough 73%, Fever 67%, fatigue 43% 16–82 d | 100%, but no details provided | “Secondary or coincident microorganism infections” | Sputum cx: A. baumannii (12), K. pneunoniae (7), S. maltophilia (2), P. aeruginosa, E. coli, S. aureus (1 each) | Ultrasound-guided minimally invasive autopsies, pts from USA, dates unclear. In 2 patients, bronchopneumonia was evident in absence of DAD. |
| 38 [47] | 5/18 (28) | Median, 61 y, 60% M | Fever most common, dyspnea, cough | Not stated | “Associated areas of bronchopneumonia with numerous neutrophils and focal necrosis” | Not stated | Autopsies and ultrasound-guided minimally invasive autopsies, pts from Spain, dates unclear. Bronchopnuemonia seen in settings of exudative, fibroproliferative, or fibrotic stage DAD. |
| 39 [48] | 6/10 (60) | Not stated | Not stated | Not stated | “Neutrophilic pneumonia was observed in...variable degrees” | Not stated | Ultrasound-guided minimally invasive autopsies, pts from Brazil, dates unclear. |
| 40 [49] | 3/7 (43) | Not stated | Not stated | Not stated | “Superimposed acute bronchopneumonia, focally necrotizing” | Antemortem respiratory and blood cx: S. aureus (1) | Autopsies, pts from USA, through May. S. aureus pneumonia and bloodstream infection diagnosed antemortem in 1 pt. Pneumonia not diagnosed antemortem in 2 pts. |
| 41 [50] | 2/4 (50) | 51–73 y, M | Not stated, 39 d | Both received antibiotics, no details | Intra-alveolar PMNs and macrophages | Not stated | Autopsies, pts from Belgium, through May. Causes of death were ARDS. “Even though NETs may also be induced by bacterial-derived mediators during a secondary infection, we found a massive presence of NETs in each patient, regardless of the status of secondary infection. It is thus unlikely that the secondary infection on its own would be solely responsible for the massive and multifocal infiltration of NETs in our study.” |
| 42 [51] | 7/18 (39) | 41–78 y, 76% M | Not stated, median, 22 (5–44) d | All received antibiotics, no details | “Exudative bronchopneumonia with neutrophilic granulocyte infiltration of bronchi and surrounding parenchyma” | Not stated | Autopsies, pts from the Netherlands, through 18 May. DAD found in all pts, bronchopneumonia predominated in 3/7. Causes of death were respiratory failure due to COVID-19, or multisystem organ failure. One pt died of superimposed bacterial peritonitis due to abdominal surgery complications. |
| 43 [52] | 7/24 (29) | 30–87 y, 80% M | Fever and cough most common, average, 13 (6–34) d | Not stated | “Supportive bronchopneumonia, alveolar spaces filled with neutrophils” | Not stated | Blind biopsies postmortem, pts from Iran, through April. Bronchopneumonias “most likely correspond to a superimposed bacterial infection.” Biopsies in 5/7 pts showed overlapping features of DAD. |
| 44 [53] | 1/3 (33) | 38 y, W | Chest pain, SOB, unknown duration | None | “Extensive neutrophilic inflammation within alveoli” | Not stated | Autopsy, pt from USA, dates unclear. Died shortly after presentation to hospital. |
| 45 [54] | 7/13 (54) | 41–90 y, 77% M | Median, 22 (6–40) d | “Nearly all pts received pip-tazo as prophylaxis” | “Florid bronchopneumonia” | P. aeruginosa (3) | Autopsies, pts from Germany, through 23 May. Bronchopneumonia deemed like to be “the consequence of secondary infection.” “Superinfections with Pseudomonas” diagnosed antemortem in 3/7 cases. COVID-19 considered cause of death in most pts. |
Abbreviations: Abx, antibiotics; ARDS, acute respiratory distress syndrome; BL/BLI, β-lactam/β-lactamase inhibitor; COVID-19, coronavirus disease 2019; CSF, cerebrospinal fluid; CVA, cerebrovascular accident; DAD, diffuse alveolar damage; LLL, left lower lobe; NETs, neutrophil extracellular traps; PCR, polymerase chain reaction; PMNs, polymorphonucleocytes; Pt, patient; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SOB, shortness of breath.
aIn other postmortem studies that examined the lungs (n = 30 studies, 85 patients), there were no histopathologic findings described that were consistent with superimposed pneumonia [25, 44, 55–82]. Therefore, histopathologic findings consistent with superimposed pneumonia were reported in 32% (200/621) of postmortem examinations and in 60% (45/75) of published reports.
bTime from onset of symptoms to death.
cDates of cases are presented as months of autopsy, 2020.