Fatal hemophagocytic lymphohistiocytosis with intravascular large B-cell lymphoma following coronavirus disease 2019 vaccination in a patient with systemic lupus erythematosus: an intertwined case

Abstract

Hemophagocytic lymphohistiocytosis (HLH) has been recognized as a rare adverse event following the coronavirus disease 2019 (COVID-19) vaccination. We report a case of neuropsychiatric symptoms and refractory HLH in a woman with systemic lupus erythematosus (SLE) after receiving her COVID-19 vaccine treated with belimumab, later found to have intravascular large B-cell lymphoma (IVLBCL) at autopsy. A 61-year-old woman with SLE was referred to our hospital because of impaired consciousness and fever. One month prior to consulting, she received her second COVID-19 vaccine dose. Afterward, her consciousness level decreased, and she developed a high fever. She tested negative for SARS-CoV-2. Neuropsychiatric SLE was suspected; therefore, glucocorticoid pulse therapy was initiated on day 1 and 8. She had thrombocytopenia, increased serum ferritin levels and hemophagocytosis. The patient was diagnosed with HLH and treated with etoposide, dexamethasone and cyclosporine. Despite treatment, the patient died on day 75; autopsy report findings suggested IVLBCL as the underlying cause of HLH. Differentiating comorbid conditions remains difficult; however, in the case of an atypical clinical presentation, other causes should be considered. Therefore, we speculate that the COVID-19 vaccination and her autoimmune condition may have expedited IVLBCL development.

Keywords:

• COVID-19
• vaccination
• systemic lupus erythematosus
• hemophagocytic lymphohistiocytosis
• intravascular large B-cell lymphoma

1. Introduction

The coronavirus disease 2019 (COVID-19) pandemic has put a strain on hospitals. Vaccination can reduce COVID-19 incidence, severity and mortality; its benefits are recognized even in autoimmune disease patients [1, 2]. However, various rare adverse events have also been reported, including exacerbated clinical symptoms in autoimmune diseases, such as ­systemic lupus erythematosus (SLE) [3–6]. Hemophagocytic lymphohistiocytosis (HLH) has been reported as a rare adverse event [7–10]. HLH is a life-threatening hyperinflammatory syndrome exhibiting atypical histiocyte proliferation triggered by various conditions, such as infections, malignancy and autoimmune disorders [11–14]. We report a case of neuropsychiatric SLE (NPSLE)-like symptoms, refractory HLH and autopsy findings suggestive of intravascular large B-cell lymphoma (IVLBCL) post-COVID-19 vaccination in a patient with subdued SLE activity. Although differentiating comorbid conditions remains difficult, other causes should be considered in the case of an atypical clinical presentation.

2. Case reports

A 61-year-old woman presented to our hospital with impaired consciousness. Her medical history was significant for rheumatoid arthritis (diagnosed at 39 years old) and SLE with myelitis (diagnosed at 47 years old). At the onset of SLE myelitis, she was treated with glucocorticoid (GC) pulse therapy and 13 courses of intravenous cyclophosphamide (a total of 8.45 g of cyclophosphamide). After initial therapy, her clinical condition improved, and the GC was gradually tapered. She was treated with prednisolone (PSL, 7.5 mg/day), tacrolimus (2.5 mg/day) and belimumab (200 mg/week); prior to the consult, she was stable. In July and August 2021, she received her first and second COVID-19 vaccine (BNT162b2) doses. By August end, 1 month prior to admission, she experienced general joint pain and weakness in the bilateral lower limbs. Upon admission, she had impaired consciousness (Glasgow Coma Scale: E1V1M5), right concomitant deviation, clonic spasms, left-sided paralysis and fever (40.2 °C). Her SARS-CoV-2 reverse transcriptase polymerase chain reaction (RT-PCR) test result using a nasopharyngeal swab was negative. Laboratory tests revealed leukocytosis and elevated levels of serum C-reactive protein (CRP), lactate dehydrogenase (LDH) and ferritin (Table 1). The anti-ds-DNA antibody and anti-SSA antibody were negative, although the anti-DNA antibody was positive at the onset of SLE (64.1 IU/mL) and turned negative after initial therapy. Cerebrospinal fluid (CSF) test results revealed slight elevation in cell count (9/mL), increased protein and interleukin-6 (IL-6) levels (protein, 170 mg/dL; IL-6, 24.1 pg/mL [normal range, <7 pg/mL]), with glucose levels remaining within the normal range (54 mg/dL in CSF and 104 mg/dL in serum). Computed tomography (CT) revealed no splenomegaly or lymphadenopathy. Culture and viral PCR test results were all negative. NPSLE development was suspected, although serum complement (C3 and C4) levels were not decreased; therefore, GC pulse therapy (methylprednisolone 1000 mg) was administered intravenously daily for 3 days (days 1–3), followed by PSL 60 mg/day, and belimumab was discontinued; these treatments improved her fever, consciousness level and neuropsychiatric symptoms.

Table 1. Laboratory findings.

Laboratory test on admission	Results	Normal range
White blood cell (10^9/L)	12.65	3.5–8.6
Neutrophil (10^9/L)	8.39
Lymphocyte (10^9/L)	1.64
Hemoglobin (g/L)	111	116–148
Platelet (10^9/L)	177	158–348
APTT (S)	31.2	24–40
PT (S)	11.4	10–13.5
Fibrinogen (g/L)	7.37	1.5–3.5
D-D dimer (mg/L)	2.9	<1.0
AST (U/L)	19	13–30
ALT (U/L)	30	7–23
Total bilirubin (mg/dL)	0.7	0.4–1.5
Lactate dehydrogenase (U/L)	380	124–222
Serum sugar (mg/dL)	104	70–105
Creatinine (mg/dL)	0.74	0.46–0.79
Ferritin (ng/mL)	947	12–60
CRP (mg/L)	20.19	0–5
Complement 3 (g/L)	1.41	0.73–1.38
Complement 4 (g/L)	0.42	0.11–0.31
Anti-nuclear antibody	Negative	Negative
Anti-ds DNA antibody	Negative	Negative
Anti-Sm antibody	Negative	Negative
Anti-SS-A antibody	Negative	Negative
Virus
SARS-CoV2	Negative	Negative
CMV	Negative	Negative
EBV	Negative	Negative
Hepatitis B surface antigen	Negative	Negative
Hepatitis C virus antibody	Negative	Negative
HIV antibody	Negative	Negative
Cerebrospinal fluid (CSF) test
Cell count (/µL)	9	0–5
Protein (mg/dL)	170	15–60
CSF IL-6 (pg/mL)	24.1	<7
CSF sugar (mg/dL)	54	50–75
Additional test on another day
Soluble IL-2 receptor (U/mL)	8540	157–474
IL-6 (pg/mL)	41	<5
IL-18 (pg/mL)	2300	<500
Neopterin (nmol/L)	40	<5
TNF-RI (pg/mL)	6480	484–1407
TNF-RII (pg/mL)	14840	829–2262

APTT, activated partial thromboplastin time; PT, prothrombin time; AST, aspartate aminotransferase; ALT, alanine aminotransferase; CRP, C-reactive protein; SARS-CoV2, severe acute respiratory syndrome coronavirus 2; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HIV, human immunodeficiency virus; IL, interleukin; TNF-R, tumor necrosis factor receptor; Anti-ds DNA, anti-double-stranded DNA; Anti-Sm, Anti-Smit; Anti-SS-A, anti–Sjögren’s-syndrome-related antigen A.

On day 8, the patient developed a high fever again and GC pulse therapy was resumed. Laboratory tests revealed thrombocytopenia and increased levels of serum LDH (443 U/L), ferritin (1375 ng/mL) and inflammatory cytokines, such as IL-18 (Table 1). Bone marrow examination and CSF analysis revealed hemophagocytosis (Figure 1). The patient was diagnosed with HLH using the HLH-2004 diagnostic criteria [13], prompting us to treat her with etoposide 200 mg/week, dexamethasone 12 mg/day and cyclosporine 200 mg/day. Her fever subsided, and her serum ferritin levels decreased; however, she was suspected of having developed drug-induced pancytopenia. On day 20, no atypical lymphocytes or hemophagocytosis were observed in the second bone marrow examination.

Figure 1. Hemophagocytic macrophages were seen in (a) cerebrospinal fluid and (b, c, d) bone marrow. (a) Cerebrospinal fluid, Giemsa staining, ×1000, (b) Bone marrow aspiration smear, May Giemsa staining, ×1000, (c) Bone marrow trephine biopsy, Hematoxylin-eosin staining, ×400, (d) Bone marrow trephine biopsy, CD68 staining, ×60.

On day 21, she developed a high fever, pancytopenia and Candida albicans candidemia. HLH relapsed and etoposide was administered five times; however, it was ineffective. Tocilizumab 320 mg was initiated afterward. Laboratory data showed inflammation resolution. On day 67, multiple small cerebral hemorrhages were found in the patient’s parietal lobe. On day 68, she was diagnosed with bilateral pneumonia. On day 70, we administered tocilizumab 320 mg; however, this failed to improve her condition. She died on day 75 (Figure 2).

Figure 2. Clinical course. Marked elevation in the serum levels of lactate dehydrogenase and ferritin were observed despite multifactorial treatment with dexamethasone, cyclosporin, etoposide and tocilizumab. mPSL1g, GC pulse therapy; VP-16, etoposide; TCZ, tocilizumab; LDH, lactate dehydrogenase; Dex, dexamethasone; CysA, cyclosporin.

The autopsy revealed intra- and perivascular infiltration of CD20-positive atypical B lymphocytes in most organs, including the spleen, liver and lungs; these findings were consistent with IVLBCL (Figure 3). In addition, the immunohistochemical analysis revealed that the tumor cells were non-germinal center B-cell (GCB) phenotype without EBV infection (Figure 4).

Figure 3. Histopathological findings of lung tissue in autopsy. (a) Hematoxylin and eosin, (b) Ki-67 (MIB-1), (c) CD20, (d) CD3, (e) ISH-kappa, (f) ISH-lambda. Large atypical lymphoid cells with an intravascular pattern were observed. MIB-1 index of neoplastic cells was 80%. These neoplastic cells were CD20⁺, CD3⁻, in situ hybridization kappa⁺ and in situ hybridization lambda-negative.

Figure 4. Histopathological findings of lung tissue in an autopsy. (a) CD10, (b) BCL6, (c) MUM1, (d) CD5, (e) BCL2 and (f) in situ hybridization EBERs. According to the cell of origin classification, neoplastic cells were non-GCB type (CD10⁻, BCL6⁺ and MUM1⁺). Furthermore, these cells were BCL-2-positive, CD5-negative and in situ hybridization EBERs-negative.

3. Discussion

We report an IVLBCL case after COVID-19 vaccination, where the patient presented with NPSLE-like neurological symptoms and HLH with a subdued SLE disease activity background. Although COVID-19 vaccination is recommended for autoimmune disease patients [1, 2], several studies have reported SLE symptoms exacerbation post-vaccination [3–5]. Felten et al. evaluated the prevalence of COVID-19 vaccination side effects in SLE patients through a web-based survey, showing that 21 of 696 patients (3%) reported an SLE flare after a median of 3 days [3]. In these patients, the predominant symptoms were as follows: musculoskeletal symptoms, fatigue, cutaneous flares, fever and cytopenia; no neuropsychiatric manifestations were reported [3]. Izmirly reported that 9 of 79 patients experienced a disease flare after vaccination, and no neuropsychiatric symptoms were reported [4]; the patient first presented with NPSLE-like symptoms; however, the SLE flare was not confirmed because no hypocomplementemia or elevation of the anti-dsDNA antibody titer was reported.

HLH development after COVID-19 vaccination is a very rare condition; a limited number of case series is available in the current literature; no standard management protocols have been established. Wu et al. summarized 50 reports of HLH after COVID-19 vaccination using the vaccine adverse event reporting system, in which two patients were suspected to have lymphoma, although a definitive diagnosis had not been made [15]. Our patient presented with prolonged HLH despite GC and etoposide therapy; no lymphadenopathy on CT and no atypical cells in the peripheral blood, bone marrow or CSF were observed. We considered malignant lymphoma, specifically the hemophagocytic syndrome-associated variant, the so-called ‘Asian variant’ of IVLBCL [16, 17], and examined bone marrow aspiration two times, but no lymphoma cells were detected. Atypical cells found in organs during autopsy led to a definitive IVLBCL diagnosis. Although it is difficult to determine the exact timing of the IVLBCL onset, we speculate that B cells in a pre-neoplastic state that were present prior to vaccination developed IVLBCL thereafter. This is consistent with what was observed in a hemophagocytic syndrome-associated variant of IVLBCL [17]. At the onset of SLE myelitis, the patient underwent intravenous cyclophosphamide and received a total dose of 8.6 g cyclophosphamide. Cyclophosphamide is known to carry a long-term cancer risk; however, Faurschou et al. reported on carcinogenesis in a patient diagnosed with granulomatosis with polyangiitis and treated with cyclophosphamide, indicating no increased overall cancer risk in patients treated with 1–36 g of cyclophosphamide, with only non-melanoma skin cancer reported to have an increased SIR of 3.2 (95% CI: 1.5, 6.1) [18]. Therefore, the low dose of cyclophosphamide administered in this patient was not considered to be involved in the development of IVLBCL.

Several reports have been published on the association between the COVID-19 vaccine and malignant lymphoma [19–26]. Panou et al. reported two cutaneous T-cell lymphoma relapse cases where patients had been in remission for several years and relapsed after viral vector COVID-19 vaccination [19]. Brumfiel et al. reported a cutaneous CD30-positive lymphoma relapse case after mRNA COVID-19 vaccination [20]. Gambichler et al. reported a patient with primary cutaneous anaplastic large-cell lymphoma with complete remission that exacerbated one week after the first mRNA COVID-19 vaccination [21]. These reports imply that COVID-19 vaccination induces existing T-cell lymphoma recurrence. Goldman et al. described a patient who developed angioimmunoblastic T-cell lymphoma after two BNT162b2 mRNA vaccine rounds, exacerbated by a third booster dose [22]. These reports indicate a relationship between COVID-19 vaccination and T-cell lymphomagenesis. Our patient, in contrast, developed B-cell lymphoma. To the best of our knowledge, this is the first report on B-cell lymphoma development after COVID-19 vaccination.

A previous meta-analysis showed an increased malignancy risk in SLE patients [27–29]. Clarke et al. showed that malignancy risk in SLE patients was 18% higher than that in the general population, with an over 3-fold increase in the relative lymphoma risk [27]. We speculate that the COVID-19 vaccination and our patient’s autoimmune condition, which predisposes her to develop lymphoma, may have contributed to IVLBCL development. The activation of the B cell activating factor belonging to the tumor necrosis factor family (BAFF) pathway was seen in aggressive B cell lymphoma [30]. Wang et al. reported that BAFF and BAFF-R were expressed in 72.1% and 47.1% of the diffuse large B-cell lymphoma tissues, respectively, suggesting an important role in B-cell lymphoma development [31]. Recently, BAFF-R antibodies have also been considered as a therapeutic target for B-cell lymphoma [32–34]. These reports imply that belimumab discontinuation may activate the BAFF/BAFF-R pathway and accelerate B-cell proliferation, contributing to B-cell lymphoma development.

In conclusion, we report an SLE patient who developed HLH and IVLBCL after receiving two COVID-19 mRNA vaccine doses. Considering that developing HLH and lymphoma after COVID-19 vaccination are rare but life-threatening conditions, physicians should be able to recognize their atypical clinical presentations, including persistent fever and neuropsychiatric symptoms. The careful analysis of these rare cases may help elucidate the mechanism of lymphomagenesis after COVID-19 vaccination.

Acknowledgments

We would like to thank the clinical staff and office administrators for supporting our work. We would also like to thank Editage (www.editage.com) for English language editing.

Disclosure statement

YM received research grants from Kyowa Hakko Kirin Pharma, Astellas Pharma, Eisai Pharma, Ono Pharma, Pfizer Pharma, Asahi Kasei Pharma, MSD Pharma, Daiichi-Sankyo Pharma, Taisho Pharma, Taiho Pharma, Takeda Pharma, Chugai Pharma, Teijin Pharma, Nippon Kayaku and Mochida Pharma, outside the submitted work.

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This work was supported by the JSPS KAKENHI.