More than a ‘Hundred Days War’: Persistent SARS-CoV-2 infection in a patient with ANCA-associated vasculitis

Case Presentation

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A woman was diagnosed with proteinase 3 anti-neutrophil cytoplasm antibody (PR3-ANCA)–positive granulomatosis with polyangiitis (GPA) when she presented with rapidly progressive glomerulonephritis in 1995. After a relapse in 1998, she developed end-stage kidney disease and subsequently underwent renal transplantation in 2003. In 2017, she had a second relapse with cavitary lung nodules and alveolar hemorrhage. She received rituximab induction followed by maintenance (500 mg every 6 months; last infusion August 2020) and continued anti-rejection medications (360 mg mycophenolic acid and 50 mg cyclosporine, each twice daily).

In mid-September 2020, at age 49, the patient developed anosmia and fatigue. On October 2, she tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Symptoms initially improved but then deteriorated, and in late November she was hospitalized with progressive dyspnea and hypoxia. SARS-CoV-2 testing (reverse transcription polymerase chain reaction [RT-PCR]) remained positive with a cycle threshold (Ct; inversely proportional to viral load) of 21.08 (1). Chest computed tomography (CT) showed new bilateral lower lobe ground-glass opacities on a background of GPA-related nodular scarring and bronchiectasis. PR3-ANCA was undetectable, and there were no features of active vasculitis. The patient was treated with 50 mg prednisone daily for suspected post–COVID-19 organizing pneumonia (2). Her hypoxia improved, and she was discharged from hospital after 1 week.

In mid-December, while taking 30 mg prednisone daily, the patient was re-admitted with hypoxia and progression of ground-glass opacities on CT. ANCA remained negative, with undetectable CD19 and CD20. Bronchoscopy was negative for hemorrhage or opportunistic infections, including Pneumocystis jirovecii (by PCR), aspergillosis, and other microbial pathogens by culture and antigen testing. SARS-CoV-2 RT-PCR was persistently positive, and the Ct had decreased from 32.9 (pre-admission) to 17.54, consistent with ongoing viral replication (1). She received remdesivir (10 d), dexamethasone (4 mg for 5 d, followed by tapering over 2 wk), and intravenous immunoglobulin (IVIg; 0.4 g/kg) for secondary hypogammaglobulinemia (immunoglobulin G [IgG] 4.6 g/L, N >7g/L). Repeat imaging showed a reduction in ground-glass opacities, Ct increased to 31.63, and the patient was discharged in mid-January.

She was re-admitted in February 2021 with worsening dyspnea, hypoxia, and new ground-glass opacities in the right upper and middle lobes. Although an initial nasal swab was negative for SARS-CoV-2, a bronchoalveolar lavage was positive (Ct 21.75), whereas fungal culture and biomarker testing remained negative. She re-started remdesivir (for 10 d), corticosteroids (4 mg dexamethasone daily for 5 d, followed by gradual prednisone taper), additional IVIg (IgG 4.3 g/L), and IV bamlanivimab (anti-SARS-CoV-2 spike protein monoclonal antibody), with both clinical and radiological improvement. As of August 2021, her lung function remains impaired (forced vital capacity 29% predicted, diffusion capacity 29% predicted), but she has not had a further clinical relapse of COVID-19 and no indication for repeat SARS-CoV-2 testing. ANCA remains negative, although CD19 and CD20 have re-populated, a full year after her last rituximab infusion. Illumina sequencing was performed on five of the viral genomes from samples taken between October and December 2020.

Diagnosis

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SARS-CoV-2 viral genomes were confirmed to be from the same viral lineage (Nexclade: 20C/PangoLineage B.1.505), indicating a long-term, persistent infection rather than a new infection with a different strain.

Discussion

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This patient with depressed cellular and humoral immunity due to dual immunosuppression for GPA and renal transplantation had an ongoing SARS-CoV-2 replication spanning more than 130 days, despite several viral and host-directed therapies (Figure 1). The delay in recognizing persistent COVID-19 had implications for patient care and infection prevention and control measures. At the time of the patient’s second presentation, reports of SARS-CoV-2 persistence (and even evolution) in similar immunocompromised hosts had just begun to surface (3–5). In this case, the Ct value was useful to identify ongoing viral replication during the patient’s second admission, and could have been used even earlier, when persistent COVID-19 went unrecognized. However, Ct values obtained at a single time point are often used to infer contagiousness, which can be misleading. For example, sample quality, specimen collection, and location affect the Ct value, different diagnostic kits have different thresholds for high and low Ct values, and Ct values can change over the progression of a patient’s illness. Therefore, caution should be exercised when interpreting the value of a single Ct, which should always be done in the context of a patient’s clinical evolution (6). Although no further SARS-CoV-2 PCR testing was performed after February 2021, the patient’s clinical, biochemical, and radiographic stability are reassuring for persistent clearance of SARS-CoV-2.

IVIg is recommended for patients treated with rituximab who have secondary hypogammaglobulinemia and persistent severe infections (7), but in this case, Ig replacement was insufficient to overcome the COVID-19 pneumonitis. The role of SARS-CoV-2 monoclonal antibody therapy among hospitalized patients with COVID-19 and hypogammaglobulinemia is worth exploring in future studies. Although rituximab remains on hold, the requirement of ongoing anti-rejection therapy may place this patient at risk for future SARS-CoV-2 infection, despite having received two doses of the BNT162b2 vaccine (8). Immunocompromised patients, including those receiving T and B cell immunosuppressants, may also be at higher risk for COVID-19–associated pulmonary aspergillosis, an increasingly recognized complication among hospitalized patients with COVID-19 (9).

Key learning points from this case are two-fold: SARS-CoV-2 may persist for several months with a relapsing-remitting course in immunocompromised patients with rheumatic disease. Moreover, ongoing COVID-19 pneumonitis can be mistaken for post-COVID interstitial lung disease, and in this patient’s case, the Ct value was important for identifying active infection. Finally, optimizing vaccine-mediated protection, particularly among patients receiving rituximab, is paramount.

Figure 1: COVID-19 illness trajectory

*Ct value for first positive sample (October 2) not available; last sample taken from bronchoalveolar lavage; all others nasal swab† IVIg given to reverse hypogammaglobulinemiaCOVID-19 = Coronavirus disease 2019; SARS-CoV-2 = Severe acute respiratory syndrome coronavirus 2; Ct = cycle threshold; IVIg = intravenous immunoglobulin

Data available upon request.

Conceptualization, A Mendel, I Colmegna, MP Cheng; Formal Analysis, G Bourque, TC Lee, JH Gálvez, MP Cheng; Resources, G Bourque, JH Gálvez; Software, JH Gálvez; Writing – Original Draft, A Mendel, MP Cheng; Writing – Review & Editing, A Mendel, G Bourque, E Rajda, TC Lee, JH Gálvez, É Vinet, MP Cheng; Data Curation, A Mendel, G Bourque, E Rajda, É Vinet, MP Cheng; Funding Acquisition, G Bourque, JH Gálvez.

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The patient described in this report has read and consented to the publication of this manuscript.

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Sequencing of SARS-CoV-2 was supported by Genome Canada as part of the CanCOGeN project (JH Gálvez and G Bourque).

TC Lee reports funds from Fonds de Recherche Quebec-Santé and Canadian Institutes of Health Research during the conduct of the study. MP Cheng reports grants from the McGill Interdisciplinary Initiative in Infection and Immunity and Canadian Institutes of Health Research during the conduct of the study and personal fees from GEn1E Lifesciences (as a member of the scientific advisory board) and nplex biosciences (as a member of the scientific advisory board), both outside the submitted work. He is the co-founder of Kanvas Biosciences and owns equity in the company. In addition, MP Cheng has a pending patent for ‘Methods for detecting tissue damage, graft versus host disease, and infections using cell-free DNA profiling’ and a pending patent for ‘Methods for assessing the severity and progression of SARS-CoV-2 infections using cell-free DNA.’ The other authors have nothing to disclose.

This manuscript has been peer reviewed.

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