SARS-CoV-2-infection in the setting of autotransplants for multiple sclerosis

ABSTRACT

The severe adult respiratory syndrome virus type 2 (SARS-CoV-2) related acute respiratory distress syndrome (ARDS) has a strong immunological and inflammatory component; accordingly investigators are employing monoclonal antibodies to ameliorate the virus-induced cytokine storm such as antibodies against interleukin 6 (IL-6), tumor necrosis factors alpha (TNF-alpha) and CC chemokine receptor 5 (CCR5) (1). Cyclophosphamide (Cy) has proven its role in various settings including autoimmune diseases, and in the post-haploidentical stem cell transplant setting; Cy depletes cytotoxic and effector T cell populations while relatively sparing the regulatory T cells (Tregs) and could tip the balance away from the overtly pro-inflammatory setting (1). We present here the cases of three persons who were infected by the SARS-CoV-2 virus during the Cy-induced pancytopenia of an autologous hematopoietic stem cell transplantation (HSCT), aimed to down-regulate the immune response in multiple sclerosis (MS) (2). The surprisingly benign course of the COVID-19 in the three cases suggest that the Cy could have had a role in abrogating the inflammatory response in these persons.

KEYWORDS:

• Respiratory distress syndrome
• multiple sclerosis
• autologous hematopoietic stem cell transplantation
• SARS-CoV2
• autoimmune disease

Severe respiratory syndrome coronavirus-2 (SARS-CoV-2)-infection has strong immune and inflammatory components as does multiple sclerosis [1]. Consequently, one might expect worsening of multiple sclerosis in the context of SARS-CoV-2-infection and contrariwise. However, inflammation in these settings might be modulated by immune suppression from high-dose cyclophosphamide given before a haematopoietic cell transplant for multiple sclerosis [2–5]. We studied 3 persons receiving an autotransplant for multiple sclerosis. Two previously received anti-SARS-CoV-2 mRNA vaccines. All 3 had a benign course of SARS-CoV-2-infection, did not develop coronavirus-19 (COVID-19) and had no multiple sclerosis exacerbation. These data suggest immune modulating effects of high-dose cyclophosphamide might have reduced the inflammatory response to SARS-CoV-2-infection and prevented development of COVID-19 and worsening of multiple sclerosis.

Case reports

Clinical and laboratory co-variates are displayed in the Table 1. Subjects were previously treated for multiple sclerosis. 2 were vaccinated against SARS-CoV-2 163 and 58 days pretransplant. Real time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) testing for SARS-CoV-2 on day-12 in the 3 subjects pretransplant was negative (TaqPath™ 1-Step Multiplex Master Mix. Thermo Fisher, Frederick MD, U.S.A.). SARS-CoV-2 antigen and antibodies testing were not done. Subjects were likely infected on day-3 when a central venous catheter in hospital. On day +7 SARS-CoV-2-infection was detected by qRT-PCR TaqPath™ 1-Step Multiplex Master Mix. Thermo Fisher, Frederick MD, U.S.A.); threshold cycle levels indicated a high viral burden. At this time the subjects had low blood concentrations of granulocytes and lymphocytes but remained asymptomatic and received no anti-viral therapy. SARS-CoV-2 antigen tests done by means of Panbio Abbott Covid-19 Ag rapid tests device (Abbott, Jena, Germany) were negative on days +14, +14 and +16, but qRT-PCR tests remained positive. Subjects were instructed to postpone rituximab therapy until they became SARS-CoV-2 qRT-PCR test negative [5]. Sequencing studies revealed that the same virus infected the patients.

Table 1. General characteristics of patients studied.

	Subject 1	Subject 2	Subject 3
Sex	F	F	M
Age	40	39	41
MS type	PPMS	RRMS	RRMS
EDSS	7.5	2.5	2.5
Vaccine days before transplant	Moderna/Pfizer 163	–	J and J 58
Pretransplant qRT-PCR	Negative	Negative	Negative
qRT-PCR day +7 Ct (>34 Ct)	Positive 18	Positive 18	Positive 19
IL-6, pg/ml (<3.4)	10.4	5.84	NA
CRP. mg/L (reference < 6)	24	0	NA
D-dimer, mg/L (reference < 0.55)	1.45	0.42	NA
Antigen test (day)	Negative +16	Negative +16	Negative +14

Abbreviations. MS = multiple sclerosis; PP = primary progressive; RR = relapsing remitting EDSS, Expanded Disability Status Scale; J and J = Johnson and Johnson qRT-PCR = Ct, cycle threshold; IL-6 = interleukin 6, CRP = C-reactive protein, NA = non available.

Discussion

The subjects we describe were infected with SARS-CoV-2 with a high virus load in the context of receiving high-dose cyclophosphamide and an autotransplant for multiple sclerosis [4]. They remained asymptomatic despite severe granulocytopenia and lymphopenia without developing COVID-19 nor a worsening of their multiple sclerosis. Their relatively low serum concentrations of IL-6 and CRP contrast with persons with multiple sclerosis and SARS-CoV-2-infection suggesting high-dose cyclophosphamide may have modulated infection-associated inflammation and possibly prevented COVID-19 [2, 6]. Cyclophosphamide upregulates antiinflammatory C-C motif chemokine receptor (CCR) 4+ interleukin 4-producing T cells while normalizing CCR5+ and CXCR3 + T cells, favouring a Th2-type response. Overall, its mode of action and in vivo efficacy indicate that cyclophosphamide has a more selective immune therapeutic effect rather than serving solely as a general immune suppressant [3, 8], whereas Rituximab selectively inhibits C20 bearing lymphoid cells [8]. Mild SARS-CoV-2-infection in transplant recipients receiving high-dose cyclophosphamide with other drugs is reported as has improvement of COVID-19 in a kidney transplant recipient given cyclophosphamide [3, 7]. Since only 2 of the three patients had been vaccinated, a protective effect of vaccination and pre-existing antibodies seems unlikely. The possible protective effect of high-dose cyclophosphamide contrasts with the adverse effect of rituximab in persons with multiple sclerosis and SARS-CoV-2-infection [8].