Page 216 - Haematologica May 2022

Case Reports
nisone was substituted with prednisone (1 mg/day) at hospital discharge one week later. This schedule was maintained for a further two weeks, reduced to a half dosage for three more weeks, then tapered over the fol- lowing three weeks. IL-2R levels decreased to 1.170 U/mL and 740 U/mL after two and three weeks of steroid treatment, respectively, and reached normal levels (460 U/mL) after four weeks. NK cells also returned to normal levels. The patient is doing well and follow-up is still ongoing.
To the best of our knowledge, this is the first case of KD associated with HLH following COVID-19 vaccina- tion. HLH is a severe hyperinflammatory syndrome, sec- ondary to aberrant cytokine production and uncontrolled histiocyte activation, following infections, in particular EBV, hematological malignancies, autoimmune diseases, hematopoietic stem cells or organ transplantation. It is characterized by cytopenia, unremitting fever, hepatic dysfunction and a fatal multiple organ failure without early recognition and prompt treatment. The first line of treatment is steroids and/or immunoglobulins, with etoposide added in poor responders.5 KD is a self-limiting histiocytic necrotizing lymphadenitis that commonly occurs in Asia, although it is present globally.6 It is char- acterized by fever, lymphadenopathy and leukopenia, may be associated with a skin rash and is mainly charac- terized by transient red, millet-sized maculopapules.7 Since no skin biopsy was carried out, it remains unclear whether the patient’s skin rash was associated with KD or was a possible adverse effect of teicoplanin (Figure 1, A-B). KD pathogenesis is unknown, although it is believed to be a consequence of an aberrant T cells and histiocyte immune response to an immunogenic antigen. An association with organisms such as toxoplasma, cytomegalovirus, varicella-zoster virus, EBV, human her- pes virus-6, HIV, and yersinia enterocolitica, has been suggested, although convincing evidence has yet to be presented. Moreover, a possible association with autoim- mune disorders, including antiphospholipid antibody syndrome and mixed connective tissue disease, has been reported.1 Steroids and immunoglobulins treatment may be beneficial. The association between HLH and KD has been described in both children and adult patients and has a potentially fatal outcome if left untreated.3,4,8 Some authors have reported that that CD8+ T lymphocytes in patients with HLH-KD may be excessively activated, altering the course of the self-limited KD progress and resulting in HLH.8
Both HLH and KD following BNT162b2 mRNA COVID-19 vaccination have recently been described.1,2 Notably, after mass vaccination against COVID-19, a vaccine-associated hypermetabolic lymphadenopathy (VAHL) in the axillary or supraclavicular lymph nodes, ipsilateral to the vaccination site, has been reported.9,10,11 This is frequently observed after BNT162b2 administra- tion, with higher intensities following the booster dose, and lasting until three weeks after vaccination. We hypothesize that our patient first developed a left-axillary VHAL following two ipsilateral vaccine dose inocula- tions, followed by a systemic inflammatory response syndrome (SIRS) with KD features in the axillary lymph nodes, and HLH symptoms as a systemic inflammatory reaction. Dermal histiocytes and macrophages represent the first resident antigen-presenting cell (APC) transfect- ed by the mRNA vaccine that presents antigenic peptides on major histocompatibility (MHC) class I and MHC class II molecules of CD4+ and CD8+ cells, resulting in immune response expansion. Additionally, intramuscular vaccine injection leads to a local increase in proinflamma-
tory cytokines, which form an immune-stimulatory envi- ronment in draining axillary lymph nodes.12 It remains unclear whether an alternate arm inoculation in our patient might have been less immune-reactive.
In conclusion, we have described the first case of KD associated with HLH following COVID-19 vaccination. This is a rare event and does not compromise the safety and efficacy of the BNT162b2 mRNA vaccine in the fight against COVID-19. Physicians should be aware of rare systemic inflammatory reactions that require early diag- nosis and treatment.
Giovanni Caocci,1 Daniela Fanni,2 Mariagrazia Porru,3 Marianna Greco,1 Sonia Nemolato,2 Davide Firinu,3 Gavino Faa,2 Angelo Scuteri3 and Giorgio La Nasa1
1Department of Medical Sciences and Public Health, Haematology, University of Cagliari, Businco Hospital; 2 Department of Medical Sciences and Public Health, Pathology, University of Cagliari, S.Giovanni di Dio and Businco Hospital and 3Department of Medical Sciences and Public Health, Internal Medicine, University of Cagliari, Policlinico Hospital, Cagliari, Italy
Correspondence:
GIOVANNI CAOCCI - giovanni.caocci@unica.it doi:10.3324/haematol.2021.280239
Received: October 25, 2021.
Accepted: December 20, 2021.
Pre-published: December 30, 2021.
Disclosures: no conflicts of interest to disclose.
Contributions: GC, GF, AS and GLN conceived and designed the study; GC, MP, DF, AS and GLN managed patients; DF, SN and GF carried out the pathological analysis; MG carried out the immunophenotype and interleukin analysis: GC wrote the manuscript; GC, DF, MP, DF, MG, SN, GF, AS, GLN approved the final draft of the manuscript.
Acknowledgments: we thank Dr. Mariano Cabiddu and Dr. Giovanna Manconi for patient management in the early phases; Prof. Fabio Medas for performing lymph node biopsy; Dr. Salvatore Labate for CT images and Dr. Valeria Fresu for interleukin analysis.
Compliance with ethical standards: all procedures performed in stud- ies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or compa- rable ethical standards
Data sharing statement: the data that support the findings of this study are available from the corresponding author, upon reasonable request.
Informed consent: informed consent was obtained from the patient, including the publication of personal images..
References
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2. Tang LV, Hu Y. Hemophagocytic lymphohistiocytosis after COVID- 19 vaccination. J Hematol Oncol. 2021;14(1):87.
3. Nishiwaki M, Hagiya H, Kamiya T. Kikuchi-Fujimoto disease com- plicated with reactive hemophagocytic lymphohistiocytosis. Acta Med Okayama. 2016;70(5):383-388.
4.Duan W, Xiao Z-H, Yang L-G, Luo H-Y. Kikuchi’s disease with hemophagocytic lymphohistiocytosis: a case report and literature review. Medicine (Baltimore). 2020;99(51):e23500.
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