Discussion
To our knowledge, this is the first documented case in peer-reviewed literature of tongue necrosis secondary to histoplasmosis. Histoplasmosis is the most common endemic mycosis found in the United States and is the most likely fungus to cause infection resulting in hospitalization [5]. Most individuals exposed to histoplasma spores develop a subclinical infection and are asymptomatic. Those that develop acute symptoms typically present with pulmonary manifestations such as dyspnea and cough [6]. Disseminated disease may occur in patients who have a particularly high level of exposure or have immune dysfunction, such as those with autoimmune disease, those taking immune modulators, and those with inborn errors of immunity [7].
While cases of tongue necrosis have been well described in the setting of GCA, there is a paucity of literature on the occurrence of tongue necrosis as a result of fungal infection, and none published that are specifically the result of histoplasma infection [1-4]. Tongue necrosis has been seen in the setting of mucormycosis in three published cases (Table 2). These three patients had conditions that resulted in immune dysfunction, predisposing them to fungal infection [5-7]. Our patient would also be considered as having had immune dysfunction in the setting of SLE with high disease activity and long-term steroid and MMF administration.
Specifically, both SLE and the MMF used to treat SLE are associated with dysfunction in T-cell activity. Because the Th17 subset of T-cells is necessary for coordinating and regulating neutrophilic clearance of fungal infections, this is likely a root cause for this patient’s susceptibility to histoplasmosis and severity of infection. The additional challenge is that T-cells play important roles in resolving inflammatory states. After all, the three previously reported cases of mucormycosis-induced tongue necrosis were associated with conditions that resulted in impaired neutrophil-mediated inflammation. In this case, we speculate that T-cell dysfunction led to a paradoxical state in which there were elements of both immune deficiency (systemic fungal infection) and hyperinflammation (HLH/MAS). This, in turn, raises a clinical dilemma in immunomodulatory treatment. We elected to administer IVIG and anakinra since they are unlikely to impair T-cell defenses, and there may be a protective element of IVIG when administering high-dose steroids to treat the cytokine storm. Nevertheless, the patient’s burden of disease led to progression of sepsis to shock.
Tongue necrosis and cytokine storm (HLH/MAS) share common predisposing triggers, including infection, malignancy, and autoimmune disease. We believe histoplasmosis was the trigger for cytokine storm in our patient in the setting of T-cell dysfunction secondary to SLE and immune modulation. Laboratory findings, radiographic studies, and histopathology allowed us to exclude malignancy, thromboembolism, and vasculitis from our list of differential diagnoses for the cause of tongue necrosis. Treatment of the infection and the hyperinflammation resulted in immediate improvement but the prognosis of disseminated histoplasmosis remained poor. This case highlights the importance of maintaining a high index of clinical suspicion for fungal infection in those with immune dysfunction.