Autopsy Histopathologic Cardiac Findings in 2 Adolescents Following the Second COVID-19 Vaccine Dose

To the Editor.—We read with concern the manuscript by Gill et al¹  that described autopsy findings for 2 adolescents who died after COVID-19 vaccination. The authors correctly stated that the Centers for Disease Control and Prevention (CDC) performed testing for SARS-CoV-2 and found no evidence of SARS-CoV-2 infection in autopsy tissues from the decedents. However, the authors did not include findings from far more thorough immunohistochemical and molecular testing performed by the CDC for each patient. We believe that all of the CDC's findings should be considered carefully, and that the omission of these data has important implications for the conclusions of this paper.

On July 8, 2021, the CDC's Infectious Diseases Pathology Branch (IDPB) received formalin-fixed, paraffin-embedded (FFPE) tissues from the autopsy for patient A. Analyses of these tissues included routine hematoxylin and eosin staining for histopathologic evaluation, as well as Gram and Warthin-Starry stains for bacteria. Molecular analysis included polymerase chain reaction (PCR) assays on nucleic acid extracted from FFPE heart tissue, including SARS-CoV-2 and enterovirus reverse transcriptase PCR (RT-PCR) assays^2,3  and conventional PCR for parvovirus B19. Histopathologic findings in the heart included multifocal mixed inflammatory infiltrates and cardiomyocyte necrosis, consistent with acute myocarditis, as well as fibrosis. Gram and Warthin-Starry stains revealed no bacteria. DNA of parvovirus B19 was detected by PCR from FFPE heart tissues and results were confirmed by sequencing. Other PCR assays were negative. Parvovirus B19 can cause myocarditis⁴  and has also been detected in normal heart tissues.⁵  Nonetheless, its contribution to the observed pathology cannot be definitively excluded, and inclusion of these results in the paper would have allowed for a more comprehensive presentation of laboratory evidence on this case. Results were reported to the submitters on September 21, 2021. Of these findings, only the negative SARS-CoV-2 RT-PCR results are included in the paper.

On July 1, 2021, the IDPB received tissues obtained at autopsy of patient B. The IDPB performed a histopathologic evaluation that revealed extensive mixed inflammatory cell infiltrates involving the full thickness of the myocardium, associated with cardiomyocyte necrosis (Figure 1), as well as multiple subepicardial necrotic foci associated with predominantly neutrophilic inflammatory cell infiltrates, compatible with acute infarcts. In addition, the right and left adrenal glands revealed multifocal cortical and medullary hemorrhages (Figure 2, A), and the sinusoids of the liver contained small, lobular collections of mixed, predominantly mononuclear inflammatory cells (Figure 2, B). Further inspection revealed innumerable small, ovoid bacilli with subterminal spores in the adventitia of the adrenal glands (Figure 3, A) and connective tissues of the capsules of the liver, kidneys, and spleen (Figure 3, B). An immunohistochemical stain specific for Clostridium species demonstrated extensive staining of clostridia in each of these tissues, as well as in the microvasculature of the adrenal glands, liver, pancreas, kidneys, heart, lungs, and spleen (Figure 4, A through D). A PCR assay specific for the α-toxin gene of Clostridium septicum⁶  amplified a 270-bp fragment with complete identity to the corresponding sequence of C septicum. Molecular assays for SARS-CoV-2, enteroviruses, and parvovirus B19 were performed on nucleic acid extracted from heart tissues, as described above, and were negative.

The conclusion of IDPB, based on the composite histologic, immunohistochemical, and molecular findings, was death attributable directly to C septicum sepsis. This conclusion is supported further by several salient and well-recognized clinicopathologic characteristics of this disease. Clostridium septicum sepsis is characteristically a fatal and fulminating infection that often presents with nonspecific signs and symptoms. The infection is lethal in approximately 60% to 70% of cases, and death typically occurs within 12 to 48 hours of symptom onset.^7–9  In contrast to the report by Gill et al,¹  information reported to the Vaccine Adverse Event Reporting System¹⁰  noted that the patient described “flu-like symptoms” for 2 days before death. Clostridium septicum produces multiple toxins that cause necrosis of striated muscle cells^9,11  and inhibit influx of neutrophils to infected tissues; indeed, paucity of neutrophilic infiltrates in tissues infected with C septicum is considered a hallmark of this disease.^9,12 Clostridium septicum is not considered normal flora of the human intestinal tract,^13,14  but rather an opportunistic invader of immunologically compromised hosts, particularly persons with colonic adenocarcinoma, leukemia, diabetes, bowel ischemia, or cyclic, congenital, or acquired neutropenia.^7,8  Spontaneous infections have been described for a few pediatric patients with no recognized risk factor and for whom microscopic breaches in the mucosa of the large intestine were considered the likely portal of entry.^8,15  No representative samples of the small or large intestine were provided to the IDPB for evaluation; however, histologic evidence of bacterial invasion of the external surfaces of the adrenals, kidneys, liver, and spleen support an intraabdominal source of infection. The IDPB's initial results were reported to the submitters on August 19, 2021, and an addendum report was issued on October 22, 2021. Of these findings, only the negative SARS-CoV-2 RT-PCR result is included in the paper.

The report by Gill et al¹  unfortunately omitted many important findings provided by pathologic evaluations at the CDC that suggested an alternate cause of death for patient A and identified a specific infectious cause of death for patient B. These omissions could lead incorrectly to the assumption that COVID-19 vaccines were directly responsible for the deaths of these 2 patients. We believe that providing these important pathologic findings will allow readers a fuller perspective of the causes of death in these cases.

The authors thank Hannah Bullock, PhD (Infectious Diseases Pathology Branch, Centers for Disease Control and Prevention), for assistance with preparing the images.