The unique COVID-19 presentation of patients with B cell depletion - definition of the "persistent inflammatory seronegative COVID" (PISC).

Patients with genetic and acquired humoral immunodeficiency present with an atypical COVID-19 course. Persistent viral shedding with multiple viral relapses continue in these patients for weeks. [1] Lymphopenia, recent anti-CD20 therapy, chimeric antigen receptor T cell therapy (CAR-T), hypogammaglobulinemia and hematopoietic stem cell transplantation are associated with virological persistence. [2] These patients have low seroconversion rates following SARS-CoV-2 vaccination, and are predisposed to SARS-CoV-2 infection and severe disease. [3].

Clinical cases of protracted illness with intermittent flares/relapses of clinical COVID-19 have also been described, requiring hospital readmissions. [1,2] The protracted course reported among B cell depleted patients includes prolonged/intermittent systemic and/or respiratory symptoms, along with persistent respiratory viral shedding, as well as absence of seroconversion. [4,5] Waxing and waning of symptoms occurs over several weeks from diagnosis, with one study reporting median duration of symptoms of 62 days with a maximum of 300 days. Persistence of PCR positivity and infection during the first 12 months following anti-CD20 therapy have been reported to be associated with mortality. [1].

In addition to several case reports, the largest two series up to date reported overall 28 patients with protracted/relapsing COVID-19 course, mostly after anti-CD20 therapy. [1,2] Included patients had considerable rates of severe-critical illness and mortality[6]. Parra et al. reported nine patients out of 52 following anti-CD20 therapy (17%) who had recurrence/relapse[5]. The authors used a definition of recurrence/relapse previously suggested for the general population (i.e., clinical recurrence of symptoms compatible with COVID-19, accompanied by positive/persisting PCR within 90 days of primary infection), however extended the timeframe of possible relapse to over 90 days. [7] Recurrence/relapse was reported at a median of 51 days (range 36-105) after acute infection, with four patients having more than one relapse. All relapsed patients received anti-CD20 during the 6 months prior to COVID-19, most presented with fever, dyspnea and cough. [1] Lee et al. reported 19 patients with readmissions due to COVID related clinical symptoms, most of them within a year of anti-CD20. Median duration of PCR positivity among these patients was 59 days (range 26-344), and five patients died during follow up. Sequencing of viral isolates supported ongoing infection over reinfection. [2].

Not all SARS-CoV-2 infections in B cell depleted patients lead to a protracted clinical course, likely due to an effective T cell response. Hence, persistent viral shedding and seronegativity are insufficient to explain this condition. [4, 7] There is growing evidence that these patients have an abnormal/dysregulated T cell response [8, 9]. This abnormal T cell function leads to a hyper inflammatory response which does not lead to eradication of the virus. This response leads to fever, severe prostration, pneumonitis, and elevated inflammatory markers.[2] The inflammatory component may be responsive to corticosteroids that some of these patients received.[6].

The diagnosis of this entity may be easily missed. A time lag between the initial, often mild, SARS-CoV-2 infection and the inflammatory phase; the non-ubiquitous nature of nasopharyngeal shedding; and the uncommon feature of an hyper inflammatory response in immunocompromised patients all contribute to misdiagnosis.

There are no specific recommendations for the treatment of these patients. The 9th European Conference on Infections in Leukemia (ECIL) provides recommendations for treatment of COVID-19 in hematology patients in general. [10] In practice, B cell depleted patients and COVID-19 are often treated with antiviral drugs, steroids and antibody preparations, with no clear recommendations on type, timing and dose. [9] In the absence of a clear definition of the condition, currently there is wide variability in the treatment regimens of the acute event and even more so, of relapse episodes. The lack of definition and awareness to this entity may lead to delayed diagnosis and unnecessary antibiotic use. In addition, these patients are often managed as severe COVID according to clinical trials that usually did not include this type of patients and lack external validity.

Yahav et al. have previously suggested definitions for COVID-19 reinfection, relapse and PCR re-positivity. [7] We propose revised definitions specifically for B cell depleted patients. We propose a disease entity termed “persistent inflammatory seronegative COVID”(PISC), that is probably caused by some combination between the persistence of the virus, even in low quantities, and an abnormal hyperactive inflammatory response. We suggest diagnostic criteria that combine: type of baseline immunodeficiency; clinical signs, virological persistence and seronegativity. For the comprehensive definition see Table 1 below.

Table 1

Diagnostic criteria of persistent seronegative inflammatory COVID (PISC) a:

A patient will be defined as PISC if fulfilling the following criteria and no alternative diagnosis:1. Host criterion: B cell depleting disease/therapy, including:a. Primary immunodeficiency causing hypogammaglobinemia (X-linked agammaglobulinemia, common variable immunodeficiency, other primary hypogammaglobinemia) b. Secondary immunodeficiency - anti-CD20 treatment in the past year; chronic lymphoblastic leukemia/non-Hodgkin lymphoma/multiple myeloma accompanied by hypogammaglobinemia or receiving immunotherapy directed against B-cells (bispecific antibodies or antibody-drug conjugates against CD19, CD20 or BCMA); CAR-T or allogeneic or autologous hematopoietic stem cell transplant within 1 year. And:2. Clinical criterion: prolonged/remitting fever (total > 7 days) with elevated CRP plus either one of: prostration, non-resolving cough and dyspnea (total > 14 days), abnormal chest imaging showing pneumonitis (bilateral ground glass opacities). And:3. Virological criterion, defined as either:a. Persistent/intermittent positive SARS-CoV-2 RT-PCR over longer than 21 days b b. Positive SARS-CoV-2 RT-PCR in the last 90 days + seronegativity for SARS-CoV-2 14 days after the initial infection in monoclonal antibody naïve patients c

Ana Belkin and Daphna Yahav conceptualized the paper and wrote the original draft and supervised the project. Ana Belkin, Daphna Yahav, Avshalom Leibowitz and Liat Shargian reviewed and edited the manuscript.

Seronegativity before and at onset of acute infection (regardless and despite vaccination) is a characteristic of this entity. It was not comprehensively included in the criteria for diagnosis from practical reasons – the diagnosis can be made without specialized blood test.

Positive SARS-CoV-2 from either nasopharyngeal swab or lower respiratory specimen; demonstrating the same variant by sequencing supports the diagnosis, but is not mandatory.

Undetectable levels or low titer according to local serology platform; Patients who were treated with monoclonal antibodies for prevention may have higher titers.

Host criterion: B cell depleting disease/therapy, including:

Virological criterion, defined as either:

The clinical presentation can mimic “standard” but prolonged and sometimes severe COVID infection, any other bilateral lung infection or can present as prolonged fever with prostration weeks and months after mild SARS-CoV-2 infection. The spectrum of this syndrome may range from mostly inflammatory with low viral loads and indolent progression to high viral loads with obvious pulmonary involvement and progressive clinical course. Using a single terminology will enable collecting multicenter clinical data, assessing incidence and planning prevention and treatment strategies for this specific condition. Additional data are needed to further characterize this entity. Variable cycle thresholds were reported in the series addressing these patients, however no specific cut off for the diagnosis can be yet determined; in addition, radiological features should be further characterized and differentiated from organizing pneumonia, following severe COVID.

Studies are needed to evaluate the effectiveness of monoclonal antibodies as prophylaxis in this specific population; define optimal therapy for mild disease to prevent progression to PISC; and for the persistent inflammatory phase. Properly reporting cases will also assist in defining chemotherapy/biological regimens that are associated with this condition. As the syndrome affects immunosuppressed population, a reasonable exclusion of another infection should be made.

conflicts of interest

The authors report no conflicts of interest. The study received no external funding.