Delayed Diagnosis and Multi-TKI Intolerance: A Case Report of CML Concurrent With COVID-19.

Introduction: The hematological manifestations of corona virus disease 2019 (COVID-19) can confound the diagnosis and therapy of other diseases. In this paper, we firstly reported a case of chronic myeloid leukemia (CML) of delayed diagnosis and intolerance to tyrosine kinase inhibitors (TKIs) concurrent with COVID-19. Case Presentation: A 56-year-old female was diagnosed as COVID-19 with no obvious leukocytosis [white blood cell (WBC), ≤17 × 109/L] or splenomegaly until ablation of the virus. Bone marrow aspiration was conducted to establish the diagnosis of CML. She accepted an adjusted dosage of imatinib initially and had to suspend it after myelosuppression (day 41). After hematopoietic therapy, imatinib was given again (day 62), but she was still non-tolerant, and nilotinib at 150 mg twice a day was prescribed from day 214. At just about 4 weeks later, nilotinib was discontinued due to myelosuppression. Then, it was reduced to 150 mg per day and was re-initiated (day 349), but she was still non-tolerant to it. Similarly, from day 398, flumatinib at 200 mg per day was tried, but she was non-tolerant. Her white blood cell or platelet count fluctuated markedly with poor therapeutic response. Considering that she was relatively tolerant and responsive to imatinib, the medication was re-initiated at 200 mg and reduced to 100 mg per day. Her follow-up revealed stable WBC and PLT counts. The latest BCR-ABL-210/ABL was decreased to 0.68% at about 6 months after imatinib was re-initiated, which means an improved response. Conclusion: The offset effect between CML and SARS-CoV-2 infection was supposed to be the underlying mechanism for the absence of leukocytosis or splenomegaly. The impact of immune network by SARS-CoV-2 preserved and disrupted the patient's response to TKIs despite the virus' ablation. We suggest that a continued elevation of basophils may be a useful indicator for CML concurrent with COVID-19, and individualized treatment with adjusted dosage and suitable type of TKIs should be considered to improve the patient's health outcome.

Multi-organ proteomic landscape of COVID-19 autopsies.

The molecular pathology of multi-organ injuries in COVID-19 patients remains unclear, preventing effective therapeutics development. Here, we report a proteomic analysis of 144 autopsy samples from seven organs in 19 COVID-19 patients. We quantified 11,394 proteins in these samples, in which 5,336 were perturbed in the COVID-19 patients compared to controls. Our data showed that cathepsin L1, rather than ACE2, was significantly upregulated in the lung from the COVID-19 patients. Systemic hyperinflammation and dysregulation of glucose and fatty acid metabolism were detected in multiple organs. We also observed dysregulation of key factors involved in hypoxia, angiogenesis, blood coagulation, and fibrosis in multiple organs from the COVID-19 patients. Evidence for testicular injuries includes reduced Leydig cells, suppressed cholesterol biosynthesis, and sperm mobility. In summary, this study depicts a multi-organ proteomic landscape of COVID-19 autopsies that furthers our understanding of the biological basis of COVID-19 pathology.

Progression to fibrosing diffuse alveolar damage in a series of 30 minimally invasive autopsies with COVID-19 pneumonia in Wuhan, China.

AIMS: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), infection has been deemed as a global pandemic by the World Health Organisation. While diffuse alveolar damage (DAD) is recognised to be the primary manifestation of COVID-19 pneumonia, there has been little emphasis on the progression to the fibrosing phase of DAD. This topic is of great interest, due to growing concerns regarding the potential long-term complications in prolonged survivors. METHODS AND RESULTS: Here we report a detailed histopathological study of 30 autopsy cases with COVID-19 virus infection, based on minimally invasive autopsies performed between February and March, 2020. The mean age was 69 years, with 20 (67%) males and 10 (33%) females and frequent (70.0%) underlying comorbidities. The duration of illness ranged from 16 to 82 (median = 42) days. Histologically, the most common manifestation was diffuse alveolar damage (DAD) in 28 (93.3%) cases which showed predominantly acute (32%), organising (25%) and/or fibrosing (43%) patterns. Patients with fibrosing DAD were one decade younger (P = 0.034) and they had a longer duration of illness (P = 0.033), hospitalisation (P = 0.037) and mechanical ventilation (P = 0.014) compared to those with acute DAD. Patients with organising DAD had a longer duration of illness (P = 0.032) and hospitalisation (P = 0.023) compared to those with acute DAD. CONCLUSIONS: COVID-19 pneumonia patients who develop DAD can progress to the fibrosing pattern. While we observed fibrosing DAD in fatal cases, whether or not surviving patients are at risk for developing pulmonary fibrosis and the frequency of this complication will require further clinical and radiological follow-up studies.

Pathological Findings in the Testes of COVID-19 Patients: Clinical Implications.

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), involves multiple organs. Testicular involvement is largely unknown. OBJECTIVE: To determine the pathological changes and whether SARS-CoV-2 can be detected in the testes of deceased COVID-19 patients. DESIGN, SETTING, AND PARTICIPANTS: Postmortem examination of the testes from 12 COVID-19 patients was performed using light and electron microscopy, and immunohistochemistry for lymphocytic and histiocytic markers. Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the virus in testicular tissue. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Seminiferous tubular injury was assessed as none, mild, moderate, or severe according to the extent of tubular damage. Leydig cells in the interstitium were counted in ten 400× microscopy fields. RESULTS AND LIMITATIONS: Microscopically, Sertoli cells showed swelling, vacuolation and cytoplasmic rarefaction, detachment from tubular basement membranes, and loss and sloughing into lumens of the intratubular cell mass. Two, five, and four of 11 cases showed mild, moderate, and severe injury, respectively. The mean number of Leydig cells in COVID-19 testes was significantly lower than in the control group (2.2 vs 7.8, p < 0.001). In the interstitium there was edema and mild inflammatory infiltrates composed of T lymphocytes and histiocytes. Transmission EM did not identify viral particles in three cases. RT-PCR detected the virus in one of 12 cases. CONCLUSIONS: Testes from COVID-19 patients exhibited significant seminiferous tubular injury, reduced Leydig cells, and mild lymphocytic inflammation. We found no evidence of SARS-CoV-2 virus in the testes in the majority (90%) of the cases by RT-PCR, and in none by electron microscopy. These findings can provide evidence-based guidance for sperm donation and inform management strategies to mitigate the risk of testicular injury during the COVID-19 disease course. PATIENT SUMMARY: We examined the testes of deceased COVID-19 patients. We found significant damage to the testicular parenchyma. However, virus was not detected in testes in the majority of cases.