Abstract
TAFRO syndrome is a rare systemic inflammatory disease. Its pathogenesis mainly involves excessive cytokine secretion and autoimmune dysfunction. Although its etiology is unclear, some viral infections have been reported to cause it. Here, we report a case of severe systemic inflammation mimicking TAFRO syndrome that arose after COVID-19. A 61-years-old woman suffered from a continuous fever, ascites, and edema after contracting COVID-19. She developed progressive thrombocytopenia, renal failure, and elevated C-reactive protein levels. She was tentatively diagnosed with multisystem inflammatory syndrome in adults (MIS-A) and received steroid pulse therapy. However, she exhibited worsening fluid retention and progressive renal failure, which are not typical of MIS-A. A bone marrow examination showed reticulin myelofibrosis and an increased number of megakaryocytes. Although a definitive diagnosis of TAFRO syndrome was not made according to current diagnostic criteria, we determined that her symptoms were clinically consistent with those of TAFRO syndrome. Combination therapy, including steroid pulse therapy, plasma exchange, rituximab, and cyclosporine, improved her symptoms. There are pathological similarities between hyperinflammation that arises after COVID-19 and TAFRO syndrome in terms of the associated cytokine storms. COVID-19 may have triggered the development of systemic inflammation mimicking TAFRO syndrome in this case.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
TAFRO syndrome is a systemic inflammatory disease characterized by thrombocytopenia, anasarca, reticulin fibrosis, renal dysfunction, and organomegaly [1, 2]. Although the etiology of TAFRO syndrome is unclear, its pathogenesis mainly involves excessive cytokine secretion and autoimmune dysfunction [3]. Multicentric Castleman disease (MCD) is another inflammatory disorder, which is characterized by polyclonal lymphadenopathy resulting from a cytokine storm driven by interleukin (IL)-6 [4, 5]. Human herpes virus-8 (HHV-8) can cause MCD, which is categorized as HHV-8-associated MCD [4]. On the other hand, it is unclear whether viral infections can cause TAFRO syndrome [3]. A previous report suggested that viral infections, such as Epstein-Barr virus infections, may occasionally be involved in the development of TAFRO syndrome [6].
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19) pandemic. Although COVID-19 is known to exhibit pulmonary manifestations, it also harms other organ systems through cytokine storms, endothelial cell damage, and thrombo-inflammation, in addition to direct viral toxicity [7, 8]. COVID-19 can produce hematological, cardiovascular, renal, gastrointestinal, endocrinological, and neurological manifestations [7]. Additionally, several studies have described autoimmune diseases, such as systemic lupus erythematosus, antiphospholipid syndrome, and Guillain–Barre syndrome, occurring after COVID-19 [9,10,11,12]. However, no cases of TAFRO syndrome that arose after COVID-19 have been reported. Here, we describe a case of severe systemic inflammation mimicking TAFRO syndrome that arose after COVID-19.
Case report
A 61-years-old female with no relevant medical history was admitted to our hospital because of a continuous fever, which had developed after COVID-19. She had received her third vaccination against COVID-19 four months before contracting COVID-19. She had received the Pfizer-BioNTech BNT162b2 vaccine for all three vaccinations. Three weeks before admission, she developed a fever and was diagnosed with COVID-19 based on a polymerase chain reaction (PCR) test. Three days after being diagnosed with COVID-19, her fever subsided. However, seven days after being diagnosed with COVID-19, she developed a fever again, accompanied by right hypochondrial pain. The laboratory tests performed on admission to the previous hospital showed a decreased platelet count (10.0 × 104/μL) and an elevated C-reactive protein (CRP) level (14.8 mg/dL). At that time, an antigen test for SARS-CoV-2 was negative. She was tentatively diagnosed with cholecystitis and treated with antibiotics. Although the abdominal pain resolved, the fever persisted, as did the high CRP level. A transthoracic echocardiogram revealed a small amount of pericardial effusion, which led to a suspicion of pericarditis. However, she developed renal impairment and was transferred to our hospital to undergo hemodialysis and further examination to obtain a diagnosis.
On admission to our hospital, she did not have a fever, as it had been treated with a non-steroid anti-inflammatory drug, but exhibited pitting edema and ascites. There were no skin eruptions, conjunctivitis, or abnormal neurological findings. Laboratory tests revealed progressive thrombocytopenia (8.4 × 104/μL), renal failure (serum creatine, 4.7 mg/dL), an elevated CRP level (13.6 mg/dL), and a high D-dimer level (58.1 μg/dL). A PCR test of a nasal swab for SARS-CoV-2 was negative. Other laboratory test results are shown in Table 1. Her cytokine levels, including those of IL-6 (41.8 pg/mL), vascular endothelial growth factor (VEGF, 4230 pg/mL), and the soluble IL-2 receptor (2735 U/mL), were elevated. Computed tomography revealed pleural effusion, pericardial effusion, and ascites without lymphadenopathy or splenomegaly (Fig. 1a and b). She was positive for anti-Sjögren’s syndrome type A antigen (SS-A) antibodies (≥ 240 U/mL). A labial salivary gland biopsy exhibited a focus score of 1.3 [13]. Although her histological salivary gland manifestations were compatible with Sjögren’s syndrome, she had no glandular manifestations. Therefore, she was not diagnosed with Sjögren’s syndrome (Fig. 1c) [14, 15]. A tentative diagnosis of multisystem inflammatory syndrome in adults (MIS-A) was made, based on the patient’s clinical course; i.e., her symptoms arose after a COVID-19, and steroid pulse therapy was initiated.
After the steroid pulse therapy, she continued to exhibit high CRP levels, and her ascites deteriorated (Fig. 1d). Therefore, TAFRO syndrome was suspected since the small amount of pericardial fluid, the absence of skin eruptions, and the patient’s worsening fluid retention and progressive renal failure were not typical of MIS-A. A bone marrow biopsy showed increased levels of megakaryocytes and reticulin fibers (Fig. 1e and f). Finally, we determined that her symptoms were clinically consistent with those of TAFRO syndrome [1]. Her TAFRO syndrome was classified as severe. Her age and elevated D-dimer level suggested a poor prognosis [16].
As the first round of steroid pulse therapy did not improve her symptoms, rituximab (375 mg/m2, once a week for four weeks) was administered (Fig. 1d). In addition, plasma exchange was performed to remove cytokines in addition to the steroid pulse therapy and rituximab, as described previously [17]. Two weeks after admission, dysarthria and right hemiplegia developed. Magnetic resonance imaging revealed a cerebral infarction in the left corona radiata (Fig. 2a). The patient’s prolonged high D-dimer levels suggested that her cerebral infarction had probably been caused by a hypercoagulable state induced by TAFRO syndrome. Recombinant thrombomodulin was administered intravenously for the hypercoagulable state. After anticoagulation therapy, including a change from recombinant thrombomodulin to oral edoxaban, no re-infarction or cerebral bleeding occurred. Three weeks after admission, the patient’s elevated CRP levels and renal insufficiency had been ameliorated. Hemodialysis was withdrawn three weeks after the initial dose of rituximab had been administered. Although the patient’s fluid retention improved, her platelet count did not increase (Fig. 1d). The administration of cyclosporine A improved her thrombocytopenia. Three months after being diagnosed, she was discharged without fluid retention (Fig. 2b and c).
Discussion
COVID-19 sometimes causes a hyperinflammatory response, induced by an excessive reaction to the virus, and produces immune-mediated manifestations [18]. Such inflammatory responses can result in various systemic inflammatory autoimmune diseases. In our case, after the patient’s initial symptoms of COVID-19 had subsided the fever recurred and her high CRP levels persisted despite a negative PCR test result for SARS-CoV-2. She was initially diagnosed with MIS-A based on the presence of thrombocytopenia; elevated CRP levels; elevated IL-6 levels; and pericardial effusion, which was probably due to pericarditis. However, her thrombocytopenia, renal failure, and ascites worsened after corticosteroid therapy for MIS-A. These clinical findings and her bone marrow histology resulted in a provisional diagnosis of TAFRO syndrome. She was treated based on this diagnosis, which improved her thrombocytopenia, renal failure, and ascites. This is the first reported case of severe systemic inflammation mimicking TAFRO syndrome to arise after COVID-19.
Many patients are asymptomatic or have mild symptoms after being infected with SARS-CoV-2. On the other hand, in 20% of cases COVID-19 may become severe or even critical. Most of these severe cases are caused by hyperresponsiveness of the immune system [11]. A hyperinflammatory response can cause cytokine storm syndrome, in which IL-6 plays a major role [11, 18]. In cytokine storm syndrome induced by COVID-19 or other conditions, such as an adverse effect of chimeric antigen receptor T-cell (CAR-T) therapy, the IL-6 level is elevated, and IL-6 blockade by tocilizumab ameliorates the condition [18,19,20,21]. Interferon-γ, IL-1, tumor necrosis factor, and VEGF levels are also elevated in cytokine storms. Cytokine storms can lead to the prolonged activation of signaling pathways and induce inflammatory cell death, which can result in more cytokines being produced and generate a positive feedback loop between cytokine release and cell death [19, 22]. Thus, cytokine storms can cause various inflammatory diseases, such as acute respiratory distress syndrome (ARDS), multisystem inflammatory syndrome (MIS), and hemophagocytic syndrome [18, 19, 22].
In addition to ARDS in the acute phase, a hyperinflammatory state can occur in multiple systems 4–6 weeks after a SARS-CoV-2 infection, which is termed MIS-C in children and MIS-A in adults [23, 24]. MIS was first reported in pediatric cases as MIS-C [23, 25]. MIS-C involves the cardiovascular and gastrointestinal systems. A similar state of multisystem hyperinflammation has been reported in adults as MIS-A [26]. Although the pathophysiology of MIS-A remains unclear, a case definition has been proposed [27]. In our case, symptoms derived from a hyperinflammatory state occurred two weeks after a COVID-19 infection. Based on the patient’s inflammatory status after COVID-19, she was initially diagnosed with MIS-A. However, little cardiac illness was seen. In addition, skin rashes, conjunctivitis, and neurological abnormalities were absent. Although her CRP and IL-6 levels were elevated, her symptoms differed from those of typical MIS-A [24, 26,27,28].
The pathogenesis of TAFRO syndrome mainly involves a cytokine storm, in which IL-6 and VEGF predominate [3, 29]. Although the molecular mechanism underlying TAFRO syndrome is not fully understood, cytokines and autoimmune cells stimulate effector cells, producing many cytokines through a positive feedback loop, which results in a cytokine storm [2, 3]. TAFRO syndrome and MCD are related diseases. MCD is also characterized by the overexpression of IL-6. In HHV-8-associated MCD, the viral homolog of IL-6 drives symptoms accompanied by a cascade of other cytokines, including human IL-6 [30]. Although the pathogen that causes TAFRO syndrome has not been established, some studies have suggested that viral and bacterial infections may be associated with the development of TAFRO syndrome [3]. COVID-19 also induces cytokine storms, which involve IL-6 and VEGF. Therefore, COVID-19 may be able to trigger TAFRO syndrome. A previous report suggested that COVID-19 may become severe in patients with TAFRO syndrome [31]. Another report indicated that TAFRO syndrome can develop after vaccination against COVID-19 and have a fatal outcome [32]. Here, we report a case of severe inflammation mimicking TAFRO syndrome that arose after COVID-19. Further evaluations are warranted to elucidate whether the COVID-19-induced overexpression of IL-6 can directly cause TAFRO syndrome.
Previous reports have not adequately discussed whether systemic inflammation that causes TAFRO syndrome-like manifestations following COVID-19 should be called TAFRO syndrome. When diagnosing TAFRO syndrome, infectious diseases need to be excluded. Although our patient developed fluid retention, renal failure, and thrombocytopenia, a PCR test for COVID-19 performed at this time was negative. Since TAFRO syndrome is a clinical term, we diagnosed her with TAFRO syndrome according to the diagnostic criteria [1]. However, there are several sets of diagnostic criteria for TAFRO syndrome, and a previous study proposed three categories of TAFRO syndrome: idiopathic MCD (iMCD)-TAFRO, possible iMCD-TAFRO, and TAFRO without iMCD or other co-morbidities [29, 33]. Within this classification, our patient would be classified as having TAFRO without iMCD or other co-morbidities. In the latter classification, COVID-19 cytokine storm syndrome was listed as an exclusion criterion. However, COVID-19 cytokine storm syndrome and TAFRO syndrome share a similar pathogenesis, involving excessive cytokine levels, and it is difficult to precisely distinguish between them. Although there is no established treatment for cytokine storms that occur after COVID-19, our case suggests that severe systemic inflammation mimicking TAFRO syndrome that arises after COVID-19 may be successfully treated according to the treatment strategies for TAFRO syndrome. Further studies are required to define the differences between COVID-19 cytokine storm syndrome and TAFRO syndrome.
COVID-19 can trigger the new onset of various autoimmune diseases [34]. In addition, COVID-19 can be severe in patients with autoimmune diseases, including Sjögren’s syndrome [35, 36]. Our patient was positive for anti-SS-A antibodies, and her salivary gland histological findings were compatible with Sjögren’s syndrome. Although she was not diagnosed with Sjögren’s syndrome because she had no symptoms associated with the condition, she may have been predisposed to Sjögren’s syndrome. Patients with TAFRO syndrome occasionally present similar manifestations to severe Sjögren’s syndrome [37, 38]. Therefore, a predisposition to autoimmune conditions, such as positivity for anti-SS-A antibodies, may be a risk factor for developing TAFRO syndrome after COVID-19.
In conclusion, our case suggests that manifestations mimicking TAFRO syndrome can occur after COVID-19. There are pathological similarities between hyperinflammation that arises after COVID-19 and the development of TAFRO syndrome. In this case, COVID-19 may have triggered the development of TAFRO syndrome by inducing a cytokine storm.
Data availability
The data supporting this study's findings are not publicly available due to the need to protect patient privacy, but are available on reasonable request from the corresponding author, HH.
References
Masaki Y, Kawabata H, Takai K, Tsukamoto N, Fujimoto S, Ishigaki Y, et al. 2019 updated diagnostic criteria and disease severity classification for TAFRO syndrome. Int J Hematol. 2020;111:155–8.
Masaki Y, Arita K, Sakai T, Takai K, Aoki S, Kawabata H. Castleman disease and TAFRO syndrome. Ann Hematol. 2022;101:485–90.
Chen T, Feng C, Zhang X, Zhou J. TAFRO syndrome: a disease that known is half cured. Hematol Oncol. 2022. https://doi.org/10.1002/hon.3075.
Dispenzieri A, Fajgenbaum DC. Overview of Castleman disease. Blood. 2020;135:1353–64.
Fujimoto S, Sakai T, Kawabata H, Kurose N, Yamada S, Takai K, et al. Is TAFRO syndrome a subtype of idiopathic multicentric Castleman disease? Am J Hematol. 2019;94:975–83.
Simons M, Apor E, Butera JN, Treaba DO. TAFRO syndrome associated with EBV and successful triple therapy treatment: case report and review of the literature. Case Rep Hematol. 2016;2016:4703608.
Gupta A, Madhavan MV, Sehgal K, Nair N, Mahajan S, Sehrawat TS, et al. Extrapulmonary manifestations of COVID-19. Nat Med. 2020;26:1017–32.
Nazerian Y, Ghasemi M, Yassaghi Y, Nazerian A, Hashemi SM. Role of SARS-CoV-2-induced cytokine storm in multi-organ failure: molecular pathways and potential therapeutic options. Int Immunopharmacol. 2022;113: 109428.
Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W, et al. Coagulopathy and antiphospholipid antibodies in patients with covid-19. N Engl J Med. 2020;382: e38.
Toscano G, Palmerini F, Ravaglia S, Ruiz L, Invernizzi P, Cuzzoni MG, et al. Guillain-barre syndrome associated with SARS-CoV-2. N Engl J Med. 2020;382:2574–6.
Rodriguez Y, Novelli L, Rojas M, De Santis M, Acosta-Ampudia Y, Monsalve DM, et al. Autoinflammatory and autoimmune conditions at the crossroad of COVID-19. J Autoimmun. 2020;114: 102506.
Mantovani Cardoso E, Hundal J, Feterman D, Magaldi J. Concomitant new diagnosis of systemic lupus erythematosus and COVID-19 with possible antiphospholipid syndrome. Just a coincidence? A case report and review of intertwining pathophysiology. Clin Rheumatol. 2020;39:2811–5.
Greenspan JS, Daniels TE, Talal N, Sylvester RA. The histopathology of Sjogren’s syndrome in labial salivary gland biopsies. Oral Surg Oral Med Oral Pathol. 1974;37:217–29.
Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, et al. Classification criteria for Sjogren’s syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis. 2002;61:554–8.
Shiboski CH, Shiboski SC, Seror R, Criswell LA, Labetoulle M, Lietman TM, et al. 2016 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Primary Sjogren’s Syndrome: a consensus and data-driven methodology involving three international patient cohorts. Arthritis Rheumatol. 2017;69:35–45.
Kawabata H, Fujimoto S, Sakai T, Yanagisawa H, Kitawaki T, Nara K, et al. Patient’s age and D-dimer levels predict the prognosis in patients with TAFRO syndrome. Int J Hematol. 2021;114:179–88.
Sakaki A, Hosoi H, Kosako H, Furuya Y, Iwamoto R, Hiroi T, et al. Successful combination treatment with rituximab, steroid pulse therapy, plasma exchange and romiplostim for very severe TAFRO syndrome. Leuk Lymphoma. 2022;63:2499–502.
Ramos-Casals M, Brito-Zeron P, Mariette X. Systemic and organ-specific immune-related manifestations of COVID-19. Nat Rev Rheumatol. 2021;17:315–32.
Fajgenbaum DC, June CH. Cytokine storm. N Engl J Med. 2020;383:2255–73.
Yakoub-Agha I, Chabannon C, Bader P, Basak GW, Bonig H, Ciceri F, et al. Management of adults and children undergoing chimeric antigen receptor T-cell therapy: best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE). Haematologica. 2020;105:297–316.
Shankar-Hari M, Vale CL, Godolphin PJ, Fisher D, Higgins JPT, Group WHOREAfC-TW, et al. Association between administration of IL-6 antagonists and mortality among patients hospitalized for COVID-19: a meta-analysis. JAMA. 2021;326:499–518.
Karki R, Kanneganti TD. The “cytokine storm”: molecular mechanisms and therapeutic prospects. Trends Immunol. 2021;42:681–705.
Jiang L, Tang K, Levin M, Irfan O, Morris SK, Wilson K, et al. COVID-19 and multisystem inflammatory syndrome in children and adolescents. Lancet Infect Dis. 2020;20:e276–88.
Vogel TP, Top KA, Karatzios C, Hilmers DC, Tapia LI, Moceri P, et al. Multisystem inflammatory syndrome in children and adults (MIS-C/A): case definition & guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. 2021;39:3037–49.
Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet. 2020;395:1607–8.
Morris SB, Schwartz NG, Patel P, Abbo L, Beauchamps L, Balan S, et al. Case series of multisystem inflammatory syndrome in adults associated with SARS-CoV-2 infection–United Kingdom and United States, March-August 2020. MMWR Morb Mortal Wkly Rep. 2020;69:1450–6.
Belay ED, Godfred Cato S, Rao AK, Abrams J, Wyatt Wilson W, Lim S, et al. Multisystem inflammatory syndrome in adults after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) vaccination. Clin Infect Dis. 2022;75:e741–8.
Kunal S, Ish P, Sakthivel P, Malhotra N, Gupta K. The emerging threat of multisystem inflammatory syndrome in adults (MIS-A) in COVID-19: a systematic review. Heart Lung. 2022;54:7–18.
Iwaki N, Fajgenbaum DC, Nabel CS, Gion Y, Kondo E, Kawano M, et al. Clinicopathologic analysis of TAFRO syndrome demonstrates a distinct subtype of HHV-8-negative multicentric Castleman disease. Am J Hematol. 2016;91:220–6.
Suda T, Katano H, Delsol G, Kakiuchi C, Nakamura T, Shiota M, et al. HHV-8 infection status of AIDS-unrelated and AIDS-associated multicentric Castleman’s disease. Pathol Int. 2001;51:671–9.
Oshima K, Kanamori H, Takei K, Baba H, Tokuda K. Severe coronavirus disease 2019 in a patient with TAFRO syndrome: a case report. Clin Infect Pract. 2022;16: 100158.
Yamada M, Sada RM, Kashihara E, Okubo G, Matsushita S, Manabe A, et al. TAFRO syndrome with a fatal clinical course following BNT162b2 mRNA (Pfizer-BioNTech) COVID-19 vaccination: a case report. J Infect Chemother. 2022;28:1008–11.
Nishimura Y, Fajgenbaum DC, Pierson SK, Iwaki N, Nishikori A, Kawano M, et al. Validated international definition of the thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly clinical subtype (TAFRO) of idiopathic multicentric Castleman disease. Am J Hematol. 2021;96:1241–52.
Zacharias H, Dubey S, Koduri G, D’Cruz D. Rheumatological complications of Covid 19. Autoimmun Rev. 2021;20: 102883.
Brito-Zeron P, Melchor S, Seror R, Priori R, Solans R, Kostov B, et al. SARS-CoV-2 infection in patients with primary Sjogren syndrome: characterization and outcomes of 51 patients. Rheumatology (Oxford). 2021;60:2946–57.
Conway R, Grimshaw AA, Konig MF, Putman M, Duarte-Garcia A, Tseng LY, et al. SARS-CoV-2 infection and COVID-19 outcomes in rheumatic diseases: a systematic literature review and meta-analysis. Arthritis Rheumatol. 2022;74:766–75.
Fujimoto S, Kawabata H, Kurose N, Kawanami-Iwao H, Sakai T, Kawanami T, et al. Sjogren’s syndrome manifesting as clinicopathological features of TAFRO syndrome: a case report. Medicine (Baltimore). 2017;96: e9220.
Grange L, Chalayer E, Boutboul D, Paul S, Galicier L, Gramont B, et al. TAFRO syndrome: a severe manifestation of Sjogren’s syndrome? A systematic review Autoimmun Rev. 2022;21: 103137.
Acknowledgements
We thank the patient and the clinical staff at Wakayama Medical University Hospital for their participation in this study.
Funding
This study was supported by the Japan Society for the Promotion of Science (JSPS) (KAKENHI Grant Number 21K16248 to HH).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflicts of interest.
Ethical approval
All procedures performed in studies involving human participants were carried out in accordance with the ethical standards of the relevant institutional and/or national research committees and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from the patient.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Tane, M., Kosako, H., Hosoi, H. et al. Severe systemic inflammation mimicking TAFRO syndrome following COVID-19. Int J Hematol 118, 374–380 (2023). https://doi.org/10.1007/s12185-023-03589-9
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12185-023-03589-9