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.