Diffuse Lymphadenopathy Syndrome as a Flare-Up Manifestation in Lupus and Mixed Connective Tissue Disease Following Mild COVID-19.

BACKGROUND Manifestations of Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, are highly variable among healthy populations. In connective tissue disease patients, the spectrum of clinical manifestations is even broader. In mild COVID-19 patients, diffuse lymphadenopathy (DL) has not been described as a late manifestation, and only severe COVID-19 has been associated with lupus flare-ups. Herein, we report 3 cases of connective tissue disease patients that presented with DL after diagnosis and complete resolution of mild COVID-19 disease. CASE REPORT Case 1. A 28-year-old man with inactive lupus, mixed connective tissue disease (MCTD), and a history of lung and cutaneous involvement. He presented with fever, polyarthralgia, and multiple lymphadenopathies 3 weeks after COVID-19 disease resolution. After evaluation, immunosuppressive treatment was initiated, with rapid response. Case 2. A 25-year-old woman with inactive lupus with a history of articular, hematologic, and cutaneous involvement. Four weeks after resolution of COVID-19 disease, she presented with malaise and cervical lymphadenopathies. After laboratory testing and imaging, she was treated for lupus flare-up, with rapid response. Case 3. A 68-year-old woman with inactive lupus with a history of articular and cutaneous involvement. Four weeks after COVID-19 resolution, she presented with malaise and cervical and axillary lymphadenopathies. After extensive evaluation, immunosuppressive treatment resulted in a rapid response. CONCLUSIONS After 3 to 4 weeks of mild, outpatient-treated COVID-19 and complete resolution of symptoms, 3 patients with connective tissue disease presented diffuse lymphadenopathy associated with inflammatory and constitutional symptoms. Infectious and neoplastic causes were thoroughly ruled out. All patients responded to reintroduction of or an increase in immunosuppressive therapy. We recommend considering the diffuse lymphadenopathy as a possible post-acute COVID-19 syndrome (PACS) manifestation in these patients, mainly when they are in the inactive phase.

Co-Infecting Pathogens Can Contribute to Inflammatory Responses and Severe Symptoms in COVID-19 (preprint)

Background: The current pandemic of COVID-19 is posing a major challenge to public health on a global scale. While it is generally believed severe COVID-19 results from over-expression of inflammatory mediators (i.e. a “cytokine storm”), it is still unclear whether and how co-infecting pathogens contribute to disease pathogenesis. To address this, we followed the entire course of disease in severe COVID-19 cases to reveal the presence and abundance of all potential pathogens present - the total “infectome” - and how they interact with the host immune system in the context of severe COVID-19 disease.Methods: We considered one severe and three critical cases of COVID-19, as well as a set of healthy controls, with longitudinal samples (throat swab, whole blood and serum) taken in each case. Total RNA sequencing (meta-transcriptomics) was performed to simultaneously reveal pathogen diversity and abundance, as well as host immune responses, within each sample. A Bio-Plex method was used to measure serum cytokine and chemokine levels.Findings: Eight pathogens were identified in these COVID-19 patients - Aspergillus fumigatus, Mycoplasma orale, Myroides odorantus, Acinetobacter baumannii, Candida tropicalis, herpes simplex virus and human cytomegalovirus - that appeared at different stages of disease course. Notably, the dynamics of inflammatory mediators in the serum as well as respiratory tract were better associated with the dynamics of the infectome as a whole rather than SARS-CoV-2 alone. Correlation analysis revealed that pulmonary injury was directly associated with cytokine levels, which in turn was associated with the proliferation of SARS-CoV-2 and the co-infecting pathogens.Interpretation: The cytokine storm that resulted in aggravated acute lung injury and death involved the highly complex and dynamic entire infectome of each patient, of which SARS-CoV-2 was a component. These results call for a precision-medicine approach to investigating both the infection and the host response on a daily basis as a standard means of infectious disease characterization.Funding: Guangzhou Institute of Respiratory Health Open Project (Funds provided by China Evergrande Group) - Project No. (2020GIRHHMS01), Guangdong Province “Pearl River Talent Plan” Innovation and Entrepreneurship Team Project (2019ZT08Y464), Macao Science and Technology Development Fund (0042/2020/A), Science research project of the Guangdong Province (2019B030316028), Special Project for Scientific and Technological Development and Emergency Response in COVID-19 Prevention and Control of Guangdong Province (2020A111129028), Special Project for Research and Promotion of Prevention and Control Techniques of COVID-19 and Emergency Response in Dongguan City (202071715001114), Jack Ma Foundation (2020-CMKYGG-02), Guangzhou Medical University High-level University Clinical Research and Cultivation Program ([2017] 159 and 160) and ARC Australian Laureate Fellowship (FL170100022).Declaration of Interests: We declare no competing interests.Ethics Approval Statement: The ethics committee of the FAHGMU (Ethics No. 2020-85) and Dongguan’s People’s Hospital (KYKT2020-005-A1) approved the sampling procedure and the use of patient samples for this study. Informed consent was obtained from each patient.