A 32-year-old Caucasian woman, with a postural orthostatic tachycardia syndrome (POTS), hypermobile type Ehlers Danlos Syndrome (hEDS), and a cluster of mast cell activation disorders, developed COVID-19 in late March 2020. With a lifelong history of recurrent infections, the patient was started on subcutaneous gammaglobulin supplement, then intravenous gammaglobulin preparations, four years prior. She has also been prescribed medications targeting the MC compartment, to due to hypersensitivity reactions impacting her skin as well as respiratory, gastro-intestinal and urogenital tracts. Her diagnoses include interstitial cystitis, hypersensitivity gastroenteritis, rhinitis, chronic spontaneous urticaria, multiple drug sensitivities, anaphylaxis and asthma. Like many patients, who present with typical features of mast cell activation (MCA) and experience some relief with medications, that targeted the MC compartment, the diagnosis of mast cell activation syndrome (MCAS) had not been confirmed, due to lack of objective markers of MCA. Without laboratory confirmation of persistent or recurrent MCA, many patients remain under-diagnosed and under-treated for years, receiving sub-optimal medical treatment for this hypersensitivity syndrome. In the distant past, she was also treated with low molecular weight heparin and Eliquis (apixaban) for a deep vein thrombosis (DVT) following a PICC line's traumatic placement.
With a recent move, the patient was referred to our Allergy/Immunology practice, to establish local care of her primary immunodeficiency and susceptibility to hypersensitivity reactions. Following an initial consultation, the patient was given a lab requisition to assess her immunoglobulin levels and check for validated markers of MCA, including serum tryptase and histamine. Shortly thereafter, the patient developed a low-grade fever, headache, trouble breathing, chills, body aches. She obtained a COVID nasal swab test, but the test center failed to process the sample adequately. Over the next three days, she continued the gamma-globulin infusion as well as use of histamine blockers, montelukast, ketotifen, cromolyn, and pain relievers. The fever persisted, and she also reported light sensitivity, anorexia, increased cough, nausea, vomiting, and bowel incontinence. With increasing gastrointestinal and respiratory distress, the patient sought care at he local emergency department. There, the rapid test for SARS- CoV2 was positive, and the patient was admitted for COVID-19. The hospital also processed the laboratory requisition to assess for MCAS validated markers, which revealed a serum tryptase of 8.8ng/ml. This level was above the previously reported baseline level of 5.3 ng/ml, from July 2016.
Notable laboratory values on admission for COVID-19 were an elevated D-Dimer of 0.66 mg/L (greater than0.49 mg/L) and a decreased Prothrombin Time of 9.3 seconds (less than 12 seconds). The patient received intravenous hydration, dexamethasone, intravenous antibiotics, oxygen supplementation, and low molecular heparin. The latter addressed a newly formed DVT. The patient was able to return home after a three-day hospital stay, resuming her treatments for chronic rhinosinusitis, POTS, and MCA disorder, newly confirmed MCAS. The patient remained in quarantine for 21 days post hospitalization, along with the three other family members, who also tested positive for SARS-CoV2 infection. Her young children were asymptomatic, and her husband required supportive care for upper airway inflammation. To date, there have been no signs of long-term hauler symptomology by the patient or her family.
Table 1
Date
|
Tryptase level
|
7/11/2016
|
5.3 ng/ml
|
3/12/2020
|
8.8 ng/ml**
|
5/6/2020
|
5.6 ng/ml
|
10/28/2020
|
6.4 ng/ml
|
** during non-ICU hospitalization for COVID-19
|
|
In summary, this patient with a cluster of syndromes, including autonomic dysfunction, hypermobile Ehlers Danlos Syndrome (hEDS), and primary immunodeficiency (PID), exhibited evidence of sustained MC mediator release for the first time, following SARS-CoV2 exposure. She developed COVID-19, requiring general medical floor support for dehydration, treatment of a DVT and an asthma exacerbation. With this observation, the patient fulfilled the three criteria for the MCAS diagnosis, proposed by the World Health Organization Mast Cell Disorders working conference in 2010: (1) typical signs and symptoms of hypersensitivity reactions; (2) substantial transient increase in serum total tryptase level or an increase in other mast cell-derived mediators such as histamine or prostaglandin D2 (or their urinary metabolites); and, (3) a response of clinical symptoms to agents that attenuate mast cell mediators. 8 Although still within the commercial laboratory reference range, below 11 ng/ml, the patient had a marked increase in serum tryptase of 2.2 ng/ml, a + 20% increase from her baseline, measured before and after SARS-CoV2 infection. er signs and symptoms, involving the skin, gastrointestinal, respiratory, and urogenital tracts, now meet the proposed criteria for MCAS, years after onset of this hypersensitivity syndrome.1 8
Increasing lines of evidence indicate that MCs are key coordinators of both homeostasis and inflammation, throughout the body.9 Equipped with numerous pathogen receptors and an array of potent mediators, MCs can respond to a range of infectious and non-infectious insults, with distinct profiles of chemical mediators. Direct engagement of MCs, via TLRs, results in de novo production and secretion of pro-inflammatory cytokines, such as and IL-1 and IL-6. While indirect activation of MC, by Ig R or CR engagement, not only leads de novo production and secretion of pro-inflammatory cytokines, but rapid release of prestored proteases, heparin, platelet-activating factor, and histamine.I 2 I 0 Moreover, MCs have been shown to initiate then curb different inflammatory cascades, with influence over nearby lymph node composition, the recruitment of innate and adaptive immune responses to site of infection, such as macrophages and lymphocytes, respectively, and then suppression of recruited components of the immune system, upon detection of contained or subsiding infection.
Given the key role that MC play in the orchestration and resolution of inflammation, MC activation must be tightly regulated. This is to not only coordinate a tailored, effective response to impending dangers, but also to prevent pathology associated with inappropriate or excessive inflammation, such as NC-MCAS and COVID-19 associated hyper-inflammatory syndrome.1 10 Recent reports highlight the role of chemical mediators derived from the surrounding epithelium and endothelium as crucial regulators of MC activation, such as IL-33 and Thymie Stromal Lymphopoietin. 11
SARS-CoV-2 to angiotensin-converting enzyme 2 (ACE2) receptor on the respiratory epithelium, causing cell death.3 The subsequent epithelial cell death and tissue damage, due to virus replication, lead to the release of damage-associated molecular patterns (DAMPs), also known as alarmins. Detection of alarmins likely activates resident immune cells and triggers different inflammatory cascades, dependent of the state of the tissue and the nature of the detected insult. Recent reports highlight the role of macrophages and innate lymphoid cells as part of the first response to SARS-CoV-2.3 However, the strategic position of mast cells, situated below the lining of the respiratory epithelium and clustered near blood vessels and peripheral nerves, implicate the often overlooked MCs. In addition to potential recognition of SARS-CoV-2 via ACE2 receptor, MCs can directly recognize SARS-CoV2 via PAMP receptors, such as Toll-Like receptors (TLR) 3, 4 and 7, and indirectly, through IgRs and CRs.12 Depending on the recognition of SARS-COV-2 by receptors on MCs, different MC activation mediator release patterns will follow. Direct recognition of SARS CoV-2, with TLR engagement, does not trigger MC degranulation. Instead, TLR binding of SARS-CoV-2 reportedly leads to de novo production and secretion of cytokines, such as IL-1 and IL-6, as well as lipid-mediator production. Alternatively, indirect MC activation via SARS-CoV-2, bound to Ig, for example, triggers MC degranulation of prestored chemical mediators, including tryptase, histamine and production of newly generated factors, such as lipid mediators and cytokines, including IL-1 and IL-6, and chemokines.11 13 14
Here, we present a case of a woman with pre-existing non-clonal, MCA disorders, who exhibited a detected MC activation event following SARS-CoV-2 infection. Though she suffered with multi-organ system involvement, NC-MCA disorders and had modest relief of symptoms, with a classic allergy or type I hypersensitivity medications, this patient was not formally diagnosed with MCAS, due to lack of validated MC activation markers. Of note, lack of the MCAS diagnosis did not prevent utilization of medications that target certain MC activation pathways, specifically treatments that antagonize MC degranulation or MC mediators, such as cromolyn as well as histamine and lipid metabolites antagonists, respectively. Only upon SARS-CoV-2 infection, a sustained elevation of serum tryptase was detected, utilizing the formula of 2ng/ml / + 20% of the baseline serum tryptase. This increase of serum tryptase was seen, despite recent use of prednisone and her daily cocktail of histamine and leukotriene blockade. These observations suggest that MC activation participated in local tissue response to SARS-CoV-2 and was associated with COVID-19 associated hyper-inflammatory syndrome. The patient primarily required supportive care, including intravenous hydration, dexamethasone, short-acting beta-agonists, histamine blockade, leukotriene antagonists, temporary supplemental oxygen therapy via nasal cannula, and anti-coagulation. Within two weeks of her hospitalization, for COVID-19 related respiratory, gastrointestinal, and hematological complications, her NC-MCAS associated symptoms returned to baseline and was subsequently started on dupilumab, to attain better asthma control. The patient's serum tryptase first tested two months later, returned to her baseline as well, thus confirming the diagnosis of non-clonal MCAS. Moreover, this patient's course, following SARS-CoV-2 infection, lends support to previous reports surmising the protective effect of pre-existing inflammatory disorders or the medications used to manage these hypersensitivity syndromes to COVID-19 associated morbidity and mortality.14