Post-HPV-Vaccination Mast Cell Activation Syndrome: Possible Vaccine-Triggered Escalation of Undiagnosed Pre-Existing Mast Cell Disease?

For nearly a decade, case reports and series have emerged regarding dysautonomias—particularly postural orthostatic tachycardia syndrome (POTS)—presenting soon after vaccination against human papilloma virus (HPV). We too have observed a number of such cases (all following vaccination with the Gardasil product), and have found several to have detectable mast cell activation syndrome (MCAS) as well as histories suggesting that MCAS was likely present long before vaccination. We detail 11 such cases here, posing a hypothesis that HPV vaccination (at least with the Gardasil product) may have triggered or exacerbated MCAS in teenagers previously not recognized to have it. Only recently recognized, MCAS is being increasingly appreciated as a prevalent and chronic multisystem disorder, often emerging early in life and presenting with inflammatory ± allergic phenomena following from known mast cell (MC) mediator effects. There is rising recognition, too, of associations of MCAS with central and peripheral neuropathic disorders, including autonomic disorders such as POTS. Given the recognized potential for many antigens to trigger a major and permanent escalation of baseline MC misbehavior in a given MCAS patient, we hypothesize that in our patients described herein, vaccination with Gardasil may have caused pre-existing (but not yet clinically recognized) MCAS to worsen to a clinically significantly degree, with the emergence of POTS and other issues. The recognition and management of MCAS prior to vaccinations in general may be a strategy worth investigating for reducing adverse events following HPV vaccinations and perhaps even other types of vaccinations.

Sézary syndrome preceded by mycosis fungoides and complicated by tumor lysis syndrome and macrophage activation syndrome

Sir, Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common malignancies of cutaneous T-cell lymphoma [1]. Herein, we report a case of SS complicated by tumor lysis syndrome and macrophage activation syndrome. A 54-year-old patient, followed since October 2017 for mycosis fungoides and undergoing various treatments (PUVA therapy, methotrexate, chlorambucil + prednisone), presented with an aggravation of lesions toward extensive and intensely pruritic. A clinical examination revealed dry erythroderma, scratch marks, wart plaques, an accentuation of frontal wrinkles and nasolabial folds (leonine facies), palmoplantar fissuring keratoderma, xanthopachyonychia of all nails, and a carapace-like appearance of the scalp (Figs. 1 – 3). Generalized lymphadenopathy, hepatomegaly, and a state of anasarca-type edema caused by hypoalbuminemia were also found. A skin biopsy revealed lymphoproliferation of CD4+ T-cells and an aberrant loss of pan-T antigens. The CD4-to-CD8 ratio was at 48.5% and Sézary cells were 6960 (absolute value). A lymph node biopsy showed a dense infiltration of Sézary cells. A PET scan revealed hypermetabolism in the entire skin and at the lymph node level. Tumor lysis syndrome was evident, with high levels of blood uric acid (at 182 mg/L), elevated LDH (at 924 U/L), and functional kidney failure. Macrophage activation syndrome was also present, with fever, anemia and thrombocytopenia, liver cytolysis, hypertriglyceridemia, and hyperferritinemia. The patient received an albumin infusion, oral corticosteroid therapy to treat the syndrome, and rasburicase for hyperuremia. Despite this, the patient died before multiagent chemotherapy could have been started. On rare occasions, SS may be preceded by a prior history of classic MF. The International Society for Cutaneous Lymphomas (ISCL) recommends that such cases be designated “SS preceded by MF” [2]. Traditionally, SS is defined as a leukemic form of CTCL associated with erythroderma. Sézary cells are a population of large lymphocytes in the peripheral blood, with grooved and lobulated nuclei, in the case of SS, numbering 1000 cells/mL or more [2]. The histopathologic findings in the skin often resemble those observed in MF, with less prominent epidermotropism. As in MF, immunohistochemical studies showing a CD4 predominance and loss of pan-T-cell markers may be helpful. Lymph node involvement is characterized by the complete effacement of the nodal architecture by the infiltrating Sézary cells (2). The poor prognostic factors in Sézary syndrome include an advanced stage of the disease, an older age at onset, and large cell transformation [3]. While high response rates may be achieved with systemic chemotherapy, they are frequently short-lived and associated with significant toxicities [2]. The management of SS is complicated and requires multidisciplinary collaboration between dermatologists, hematologists, biologists, and reanimators.

Effective Therapy of Tocilizumab on Systemic Juvenile Idiopathic Arthritis Associated Refractory Macrophage Activation Syndrome

Objectives To evaluate the safety and efficacy of tocilizumab (TCZ) on refractory macrophage activation syndrome (rMAS) associated with systemic juvenile idiopathic arthritis (sJIA-rMAS). Methods We retrospectively reviewed the charts of 14 patients diagnosed with sJIA-rMAS, who were treated with TCZ after failing conventional therapies at three hospital centers from Jan 2016 to Dec 2020. Demographic, clinical, and laboratory characteristics were recorded at the onset of MAS, before TCZ (pre-TCZ) and 14 days after TCZ (post-TCZ). Results The clinical manifestation of sJIA-rMAS included fever (100%), skin rashes (35.7%), lymphadenomegaly (42.9%), hepatomegaly (57.1%), splenomegaly (7.1%), gastrointestinal symptoms (28.6%), arthritis (14.3%), myalgia (28.6%) and polyserositis (14.3%). After TCZ treatment, fever (100%, 14/14), gastrointestinal symptoms (100%, 4/4) and myalgia (100%, 4/4) were significantly improved after one week (p< 0.05). Skin rashes, lymphadenomegaly and arthritis also improved in many patients but these parameters did not reach statistical significance. In post-TCZ group, decreases in levels of c-reactive protein, erythrocyte sedimentation rate and serum ferritin of sJIA-rMAS were observed compared with pre-TCZ (p< 0.05). Although not statistically significant, post-TCZ group showed normalization of white blood cell, platelet count, alanine aminotransferase, aspartate aminotransferase, lactic dehydrogenase and triglyceride levels compared with pre-TCZ. No disease relapse or fatality was recorded during the follow-up (25 months, range 3–60 months). Conclusions TCZ is safe and effective for the treatment of sJIA-rMAS after failure of conventional therapies.

Detection and Prediction of Macrophage Activation Syndrome in Still’s Disease

Distinguishing between macrophage activation syndrome (MAS) and a simple flare of Still’s disease (SD) may be challenging. We sought to clarify the clinical features and outcome of MAS in SD and to explore predictive factors of MAS development. Demographic and clinical data, treatments, and outcomes were recorded in a cohort of 206 SD patients. SD patients with and without MAS were compared. To explore predictive factors for the development of MAS, patients were compared at the time of SD diagnosis. Twenty (9.7%) patients experienced MAS, which was inaugural in 12 cases. Patients with MAS were more likely to have hepatomegaly (OR, 3.71; 95% CI, 1.14–11.2; p = 0.03) and neurological symptoms (OR, 4.43; 95% CI, 1.08–15.3; p = 0.04) than patients without MAS. Cytopenias, abnormal liver tests, and coagulation disorders were significantly more frequent in patients with MAS; lactate dehydrogenase and serum ferritin levels were significantly higher. An optimized threshold of 3500 μg/L for serum ferritin yielded a sensitivity (Se) of 85% and a negative predictive value (NPV) of 97% for identifying patients with/without MAS. Survival analysis showed that a high ferritin level at the time of SD diagnosis was predictive of MAS development (p < 0.001). Specific factors, including neurological symptoms, cytopenias, elevated LDH, and coagulopathy, may contribute to the early detection of MAS. Extreme hyperferritinemia at the onset of SD is a prognostic factor for the development of MAS.

Salivary Ferritin Changes in Patients with COVID-19

High ferritin serum levels can be found in patients with macrophage activation syndrome, and increased serum ferritin due to cytokine storm have been reported in severe COVID-19 patients. Saliva is being increasingly used in COVID-19 tests as a diagnostic sample for virus detection and quantification. This study aimed to evaluate the possible changes in ferritin in saliva in COVID-19 patients. In addition, the effects of different inactivation SARS-CoV-2 treatments in ferritin measurements in saliva, the correlation between ferritin in saliva and serum, and the possible effects of correction of ferritin values by total protein were assessed. Ferritin was measured in saliva from healthy (n = 30) and COVID-19 (n = 65) patients with severe, (n = 18) or mild (n = 47) disease, depending on the need for nasal flow oxygen or assisted respiration. Ferritin was also measured in paired serum and saliva samples (n = 32) from healthy and COVID-19 patients. The evaluated inactivation protocols did not affect the assay’s results except the addition of 0.5% SDS. Significantly higher ferritin was found in the saliva of COVID-19 patients (median; 25–75th percentile) (27.75; 9.77–52.2 µg/L), compared with healthy controls (4.21; 2.6–8.08 µg/L). Individuals with severe COVID-19 showed higher ferritin values in saliva (48.7; 18.7–53.9) than mild ones (15.5; 5.28–41.3 µg/L). Significant correlation (r = 0.425; p < 0.001) was found between serum and saliva in ferritin. Ferritin levels were higher in COVID-19 patients in serum and saliva, and the highest values were found in those patients presenting severe symptomatology. In conclusion, ferritin in saliva has the potential to be a biomarker to evaluate severity in patients with COVID-19.