Copresentation of Common Variable Immune Deficiency and Sweet Syndrome

Sweet syndrome is characterized by the constellation of pyrexia; leukocytosis; and eruption of painful, edematous, dermal, and neutrophil-dense plaques that occur in the setting of infection or malignancy or are drug induced.^3,4 Although not fully elucidated, the pathogenesis is thought to involve the effects of cytokines that precipitate neutrophil activation and infiltration inducing a hypersensitivity reaction and escalation of the immunologic cascade.³ Because SS can represent a paraneoplastic phenomenon or a dermal manifestation of a solid neoplasm or hematologic dyscrasia, it is important to rule out occult malignancy.³ The mainstay of treatment is systemic corticosteroids to which classical SS lesions readily respond. Alternatively, topical or intralesional corticosteroids may be used as adjuvant therapy. Alternate first-line treatments include potassium iodide and colchicine. Second-line therapies include indomethacin, cyclosporine, dapsone, and other immunosuppressive agents.⁵ The lesions may become superinfected with bacterial pathogens requiring antimicrobials.³ Spontaneous resolution seldom occurs. The risk for relapse is lifelong following spontaneous or therapy-induced clinical remission.³ There is a growing body of literature of SS-associated conditions.

Common variable immune deficiency is a collection of disorders resulting in antibody deficiency and recurrent infections.⁶ Despite the humeral defects in CVID, patients paradoxically may develop various autoimmune, hematologic, and inflammatory disorders.⁷ Sweet syndrome, first described in 1964, is a constellation of fever, neutrophilia, and neutrophilic dermatosis of unknown pathogenesis.⁸ Copresentation of CVID and SS has not been commonly reported. O’Regan et al⁸ described a 17-year-old adolescent boy with both SS and CVID but SS preceded the diagnosis of CVID. In our case, the patient presented with CVID first and then manifested SS 1 year later.

Common variable immune deficiency is the most frequent symptomatic primary immunodeficiency in adults. Because adults with CVID have varied manifestations, CVID is thought to be late-onset antibody failure. The genetic basis of these disorders has not been identified in the majority of individuals. More than 100 genetic defects have been ascribed to primary immunodeficiencies,⁹ though none are consistently found to be associated with CVID. The majority of CVID cases are sporadic, but the positive family history in our patient suggests a familial form. Approximately 10% to 20% of patients have an identified heritable cause of CVID.¹⁰ Our patient’s diagnosis of CVID was confirmed by meeting the diagnostic triad set by the European Society for Immunodeficiencies¹¹ of marked reduction of IgG and IgA or IgM plus onset after 2 years of age, recurrent infections, and defective vaccination response. Additional complications including autoimmunity, malignancy, and granulomatous inflammation were extensively ruled out.

The etiology of SS is unknown and its pathogenesis not fully elucidated, though it is presumed to be a hypersensitivity reaction.¹² Sweet syndrome can be classified into 3 major subtypes: classical or idiopathic, malignancy associated, or drug induced.³ Our patient’s presentation is consistent with the classical variant, as malignancy was ruled out and the patient was not on any medication other than IVIG at the time of diagnosis. The treatment of SS consists of systemic steroids, initially high dose followed by a prolonged taper over 4 to 6 weeks.³ This treatment causes a pronounced and sustained decrease in serum IgG due to increased catabolism during drug administration and decreased synthesis during and for a variable time after drug administration.¹³ In refractory cases, intravenous pulse administration of methylprednisolone sodium succinate for 3 to 5 days may enhance the response to standard therapies.⁵

The concurrent development of neutrophilic dermatoses/SS in an individual with CVID has not been fully described. There is a credible association of SS with infections, inflammatory bowel disease, pregnancy, malignancy, and medications, as well as a possible association with Behçet disease, erythema nodosum, relapsing polychondritis, rheumatoid arthritis, sarcoidosis, and thyroid disease.⁵ The association between immunoglobulin deficiencies and SS is markedly unusual. Despite regular IVIG replacement, adequate treatment of CVID did not seem to modulate SS flares in our patient. A case report in a pediatric patient does not provide specific guidance regarding treatment options.⁸

A particularly challenging aspect of our case was tailoring a treatment regimen to suppress SS flares. We have attained partial response to the refractory cutaneous lesions (decreased frequency and amplitude of outbreaks) with IVIG replacement 200 g every 4 weeks in combination with metronomic cyclophosphamide 50 mg daily (use of a repetitive, low-dose daily chemotherapy regimen to minimize side effects). Intermittent SS flares were managed acutely with pulse high-dose steroids. We report a case of SS with CVID, raising the plausibility of correlated pathogenesis. However, the exact mechanisms remain undefined.