TAFRO syndrome and cardiac events
TAFRO syndrome is defined as a subtype of idiopathic multicentric Castleman’s disease (iMCD) that has been recognized as having a severe clinical course. Masaki et al. proposed the diagnostic criteria and severity classification in 2015, and there have been several recently reported clinicopathological analyses and consensus guidelines for the treatment of iMCD based on the accumulated data [2,3,4,5]. Our case fulfilled the diagnostic criteria of TAFRO syndrome according to the guideline, and was classified as grade 4 (severe) severity. Our case is rare not only because of many life-threating events such as repetitive severe infections, sick sinus syndrome and cardiac arrest, but also because of the myocardial and skeletal muscle calcification that occurred two months after his disease onset. Other cases have also survived despite a very severe clinical course [9,10,11], although none of them experienced systemic calcification.
Many TAFRO syndrome cases have recovered with the use of biological products (such as tocilizumab or rituximab), glucocorticoids, immunosuppressants (such as cyclosporine A or sirolimus), and occasionally, with chemotherapy. In terms of cardiac dysfunction, Yasuda et al. reported two cases of TAFRO syndrome with cardiomyopathy and lowered ejection fraction (EF) [6]. They performed CHOP (cyclophosphamide, adriamycin, vincristine and prednisolone) therapy as treatment, and assumed that the cardiomyopathy was an adverse effect of adriamycin. Hiramatsu et al. showed a case of TAFRO syndrome with reversible cardiomyopathy, in which they opined that the high concentration of plasma IL-6 was the cause of cardiomyopathy [7]. However, these cases did not have any associated calcification.
The etiology of myocardial/systemic calcification
Myocardial calcification itself only occurs very rarely. There are traditionally two pathways causing myocardial calcification: metastatic and dystrophic. Metastatic calcification occurs with hypercalcemia and/or abnormality of calcium/phosphate metabolism [12]. This form of calcification can occur anywhere in the body, but is more likely in areas of high alkalinity, such as the gastric mucosa or systemic arteries; therefore, calcification due to this etiology can exist systemically. On the other hand, dystrophic calcification occurs secondary to cellular damage and necrosis, with calcium deposits replacing necrotizing cells. Other etiologies of dystrophic calcification include trauma, infections, inflammation, neoplasms and drugs [12]. Myocardial infarction is a common cause of myocardial calcification. Septic shock is also a cause of this form of calcification; hypotension during shock and catecholamine use can cause myocardial damage, which eventually results in calcium deposits even if plasma calcium concentration is normal [12, 13]. In our case, the etiology of myocardial and skeletal muscle calcification was considered more likely to be metastatic than dystrophic due to the following reasons. First, there was a failure of calcium/phosphate metabolism due to the presence of progressive renal dysfunction with hemodialysis and low vitamin D levels. There was also excessive replenishment of calcium, with an amount of 7.8 mmol of calcium gluconate hydrate per day on average, which could have accelerated calcium deposition in systemic tissues. We did not administer intravenous vitamin D agents, except for the minimal amount of vitamins administered through total parenteral nutrition, which might have been a possible cause for prolonged low calcium levels. Second, both myocardial and skeletal muscle calcification were detected on CT scans at the same time, which was within a month after the initial identification of hypocalcemia and subsequent overloading of calcium (Fig. 3). Third, although we temporarily used catecholamines, there were no other conditions explaining the dystrophic calcification, such as septic shock or myocardial infarction. Fourth, hypercytokinemia, including elevated IL-6 caused by TAFRO syndrome, could also have contributed to this unusual situation. Plasma calcium levels remained low and were almost unchanged when calcium gluconate hydrate was administered, which suggested that the administered calcium probably leaked out of the vessels and was absorbed by peripheral tissues. Increase of vasopermeability is another possible etiology for the calcified deposits, which could explain its occurrence in the absence of hypercalcemia.
In conclusion, this case of TAFRO syndrome achieved a successful recovery with tocilizumab therapy along with prolonged hospitalization, although he experienced the unexpected complication of myocardial and skeletal muscle calcification probably via a metastatic pathway triggered by drug administration. In acute clinical settings, the tendency is to urgently correct abnormal laboratory data, especially electrolyte abnormalities. However, TAFRO syndrome is known to be associated with hypercytokinemia and organ dysfunction with an unknown pathophysiology; hence, the general management of such cases should be carefully handled, anticipating unexpected complications.