Recurrent generalized anhidrosis following COVID-19 vaccinations

Adverse events after coronavirus disease-2019 (COVID-19) vaccination have been reported in almost all areas of the nervous system.1 Guillain-Barré syndrome, small-fiber neuropathy, Bell palsy, acute abducens nerve palsy, and Parsonage-Turner syndrome were reported as peripheral nervous system complications. Postural orthostatic tachycardia syndrome after the messenger RNA (mRNA) vaccine was reported as an autonomic manifestation.2 In this study we report a patient with two events of acquired generalized anhidrosis after the two COVID-19 vaccinations. In the summer, a 32-year-old male presented with heat intolerance and whole-body itching for 1 month. Three days after Ad26.COV2.S (Janssen) vaccination, he started to have reduced sweating over most of his body. He denied dry mouth or eyes, urinary symptoms, sexual dysfunction, constipation, diarrhea, or other symptoms suggestive of autonomic dysfunction. He was not taking any medications. A complete neurological examination was normal. The starch-iodine test showed absent sweating on most of his body, except for the area around his neck, and both palms, soles, and parts of anterior legs (Figure 1A). The quantitative sudomotor axon reflex test (QSART) by Q-Sweat showed absent or reduced sweat output at all sites (Figure 2A). Cardiovagal and adrenergic functions were normal. Laboratory studies demonstrated normal rheumatoid factor, antinuclear antibody, and complement components. Anti-Ro/SSA and anti-La/SSB antibodies were negative. Serum immunoglobulin E level was 3 IU/mL (normal level: 0 to 100 IU/mL). The only laboratory finding outside the normal range was low serum immunoglobulin G (576 mg/dL; normal: 700 to 1600 mg/dL). He was diagnosed with acquired idiopathic generalized anhidrosis (AIGA). After high-dose intravenous methylprednisolone therapy of 1000 mg/day for 5 days, his symptoms improved. Two weeks after the first steroid treatment, the patient described his sweating as having returned to his baseline, and the QSART showed normal sweat output except at the foot site (Figure 2B). He had a general itching sensation and heat intolerance again after mRNA-1273 (Moderna) vaccination as a booster dose 4 months after the initial vaccination. The starch-iodine test showed absent sweating except for the axillae and part of his forehead (Figure 1B). QSART showed absent or reduced sweat output at all sites, more severe than his first test (Figure 2C). The serum immunoglobulin G level was 511 mg/dL. Chest computed tomography was normal. High-dose intravenous methylprednisolone therapy of 1000 mg/day was administered for 5 days. There were no remarkable morphological abnormalities of the sweat gland, but periglandular lymphoplasmacytic infiltration was observed (Figure 2E). One month after the second steroid treatment, he noted that sweating on his trunk and upper extremities had returned to normal, but he did not sweat in his lower extremities. The follow-up QSART showed some improvement again (Figure 2D). This is a case report of AIGA after COVID-19 vaccinations. AIGA is a systemic anhidrosis/hypohidrosis that occurs without a causative dermatological, metabolic, or neurological disorder. The pathophysiology of AIGA has yet to be clarified, and AIGA is associated with sudomotor neuropathy, idiopathic pure sudomotor failure, or sweat gland failure.3 The degree of lymphocytic infiltration around the eccrine glands in AIGA varies between patients. The symmetric generalized anhidrosis on the starch-iodine test without other symptoms and the decreased sweat output on QSART in our patient are compatible with the diagnosis of AIGA. Lymphocyte infiltration of the sweat glands and response to steroid therapy also support the diagnosis. Histopathological studies have shown lymphocyte infiltration around the sweat glands in some patients with AIGA, which is thought to be a result of dermal leakage of sweat after damage to, or obstruction of, eccrine sweat glands, or to cause decreased sweating via the decrease of cholinergic receptor M3 expression on sweat gland epithelial cells.3 AIGA may occur in association with autoimmune conditions such as central diabetes insipidus, hypogammaglobulinemia, and pulmonary sarcoidosis.3 Pathophysiological mechanisms for vaccine-associated polyneuropathies have been proposed: an immune-mediated hypersensitivity to the solvent/adjuvant4 or invasion of the nervous system through prolonged infection with less virulent viruses.5 It has been suggested that the vaccine adjuvant aluminum may play a pathogenic role in the development of vaccination-related small-fiber neuropathy. However, neither Ad26.COV2.S nor mRNA-1273 are inactivated or subunit vaccines with aluminum-based adjuvant.6 The pathogenesis of post-vaccination neuropathy is unclear, but the subacute onset of symptoms in our patient suggests that an autoimmune reaction related to molecular mimicry is more likely to be a mechanism than nonspecific allergic activation of pre-existing autoreactive lymphocytes.7 It is presumed that generalized anhidrosis was caused by a cross-reactive immune response, which was originally triggered by vaccination but disrupted cholinergic transmission in the eccrine glands. Although most of the body contains eccrine sweat glands, which are innervated by cholinergic fibers, the axillae, palms, and soles are also supplied by apocrine glands, which are under adrenergic control.8 The preservation of sweating on the palms and soles, and in the axillae in our patient could be due to sweating by apocrine glands. The involved areas in AIGA could be also different depending on the level of expression of the cholinergic receptor M3 damaged by the infiltrating lymphocytes.3 The patient had no history of recurrent infections, allergies, or other autoimmune diseases, but he had mild hypogammaglobulinemia during the two events. Hypogammaglobulinemia can be associated with autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis.9 Primary immunodeficiency disease may have resulted in defects in control mechanisms for self-reactive B and T cells, thus favoring the occurrence of autoimmune manifestations. However, we are uncertain as to whether he had an underlying hypogammaglobulinemia or this was a bystander effect of the vaccinations and/or AIGA itself because follow-up testing was not performed after resolution of symptoms. Hyesoo Kwon: Investigation; writing – original draft. Hye Won Lee: Data curation. Hyung Lee: Project administration; supervision. Hyun Ah Kim: Conceptualization; writing – review and editing. The authors declare no potential conflicts of interest. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. The data that support the findings of this study are available from the corresponding author upon reasonable request.