*3.5. Autopsy in a Patient with COVID-19 with Siddiqi Stage III Disease*

One 56-year-old patient with a bilateral lung transplantation 2 years ago due to interstitial lung disease, probably IPF, died 16 days after being diagnosed with COVID-19 by detection of SARS-CoV-2 infection. The cause of death was a severe ARDS. He presented in the emergency department of our hospital, reporting fever, acute dyspnea and a non-productive cough. On admission, he had a temperature of 39.5 ◦C (auricular), a heart rate of 95/min., an oxygen saturation of 93% without supplemental oxygen, a blood pressure of 146/95 mmHg and a normal heart- and lung auscultation. Among the relevant comorbidities, the patient suffered from an impaired renal function due to calcineurin inhibitors, worsened by the acute viral infection (at admission eGFR 16 ml/min., previously 30 mL/min.), and had been diagnosed with central and subsegmental pulmonary embolism four months before admission. He was on coumarin treatment for this. CT of the chest showed a right-sided consolidation in the upper lobe, with concomitant right-sided GGO, without signs of air trapping. After four days, the chest CT showed severe progression with new bilateral infiltrates in the lower lobes, and progression of GGO and bilateral crazy-paving pattern). Due to severe ARDS the patient needed intubation for invasive mechanical ventilation. He was treated with dexamethasone 6 mg iv. for 10 days (after 10 days, prednisone 15 mg was continued), remdesivir and pragmatically with meropenem, levofloxacin, and amphotericin. The immunosuppression with ciclosporin was continued; however, MMF was discontinued due to lymphocytopenia and thrombocytopenia. Six days later, still on mechanical ventilation support, he developed an obstructive shock due to a total left-sided tension pneumothorax, probably due to barotrauma (Figure 1a–e). Initially, he was treated with chest tube drainage (20 Ch.), sand after two days a second chest tube (28 Ch.) was inserted, followed by another chest tube (28 Ch.) two days later due to insufficient lung expansion. Other complications in this patient were atrial fibrillation, protracted thrombocytopenia and renal failure requiring hemofiltration.

In the bronchoalveolar lavage (BAL), performed immediately after intubation, PCR of SARS-CoV-2 was positive. In the BAL, no microorganisms were grown, and the Aspergillus antigen (galactomannan) was negative (index < 0.5). Bronchoscopy showed no endobronchial mucus retention (Figure 1f,g). In addition, the serological Aspergillus antigen was negative (index < 0.5), so was the PCR for Bordetella pertussis and parapertussis. Chlamydia pneumoniae and psittaci, Legionella pneumophila and other species, as well as

Mycoplasma pneumoniae were all negative in the BAL. The aerobic and anaerobic samples from blood cultures were negative. Microbiological investigations of the vena jugularis and arteria radialis catheters were negative. The patient still had considerable subcutaneous emphysema (Figure 1h) developed progressive multiorgan failure and after 16 days in the intensive care unit, treatment was discontinued after the unanimous decision of the medical team and the family of the patient.

The patient died that same day, and an autopsy was performed. The post mortal SARS-CoV-2 PCR was still positive, and the SARS-CoV-2 concentration in the tracheobronchial secretion showed 56 million SARS-CoV-2 copies/mL. Pathology examination further showed the typical COVID-19 diffuse endothelitis in both lungs and in the epicardial and intramyocardial blood vessels. Capillaries in heart and lung showed diffuse peripheral thrombi with fibrine and leucocytes, which are also well-known COVID-19 findings. In the lung parenchyma, there was extensive multifocal hemorrhagic infarction, and multifocal acute bronchopneumonia, as well as diffuse alveolar damage (DAD). The multifocal acute bronchopneumonia suggested bacterial superinfection, although (with ongoing broad-spectrum antibiotics and amphotericin B) no bacteria or Aspergillus could be cultured in any of the samples. An additional finding in the autopsy was an early stage bowel necrosis and a centrilobular hepatic necrosis.

## **4. Discussion**

In this case series, 18 LTRs with different severity degrees of COVID-19 have been described. Although we have a small number of patients and statistics are descriptive, there tends to be a male predominance with elderly patients with a more severe COVID-19 stage (IIB and III). The extrapulmonary symptoms were predominant in most of the LTRs in our case series.

As has been seen in immunocompetent patients as well, in our case series the LTRs had a more severe COVID-19 stage with a higher body mass index (BMI). The mortality in severe COVID-19 (stage III) was 100%, and these patients were not only older and had higher BMI values, but they also all had the other COVID-associated main risk factors, namely hypertension, chronic kidney disease and cardiovascular disease. Moreover, the patients with severe COVID-19 also had a higher CRP value, lower hemoglobin, higher leucocytes, neutrophils, and higher LDH values. In contrast to the literature reports on immunocompetent patients with COVID-19, the transaminases in our patients, did not show relevant elevations.

Most patients had blood group A, followed by 0. Both patients with severe COVID-19 had blood group 0.

The AIFELL score, a triage tool used to assess risk in COVID-19 patients, was also low in the Siddiqi stage I, higher in stage II and the highest in stage III patients. All patients were treated with long-term immunosuppressive drugs in the pre-COVID stage, including prednisone in all patients, and in most patients MMF and a calcineurin inhibitor. The most common calcineurin inhibitor was tacrolimus. Six patients (two of them had chronic hemodialysis) have been treated with remdesivir, and five with dexamethasone. One patient was treated with COVID-19 convalescent plasma.

Only 6 out of 18 patients were treated in the ambulatory setting, all other patients were hospitalized, with a mean hospitalization duration of 20 days.

In the following paragraphs, we will discuss some of the above-mentioned special aspects of our case series.
