Post-HPV-Vaccination Mast Cell Activation Syndrome: Possible Vaccine-Triggered Escalation of Undiagnosed Pre-Existing Mast Cell Disease?
Abstract
:1. Introduction
2. Case 5
3. Case 6
4. Case 10
5. Case 11
6. Discussion
7. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Case No. and Demographics at Initial Evaluation for MCAS | Symptoms Pre-Dating Gardasil Vaccination | Symptoms Emerging Following Gardasil Vaccination | Key Laboratory Results (Normal Range) |
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Case 1: 18-year-old female | Premature twin delivery, mild early developmental delay. Frequent idiopathic spontaneous epistaxis since 8 years old. Bilateral knee pain since age 10, attributed to Osgood–Schlatter disease—casting unhelpful. At 16, erythromycin was started to treat acne but did not help; two months later, her feet became erythematous and blistered and started “burning from the inside out”. Biopsy of the erythema found only non-specifically inflamed tissue. | At 17, starting about six weeks after her first Gardasil vaccination, emergence in a short period of many new problems, including vasodynamic instability (hypertension at times to 190/103, but also hyperadrenergic POTS at times), palpitations, pulsatile tinnitus, diffusely migratory waxing/waning flushing, syncope, chest pain, diffusely migratory paresthesias in all the distal extremities, tremors, difficulty focusing vision, cognitive dysfunction (especially memory; also occasional catatonia), insomnia, anorexia, diffusely migratory joint and bone pain, severe fatigue and extreme exertional intolerance, hypermobile Ehlers–Danlos syndrome (hEDS), odor sensitivities, hives, headache, and throat numbness. | 1. 24 h urinary prostaglandin D2 777 ng (normal 100–280) 2. Plasma heparin 0.07 anti-Factor Xa units/mL (upper normal 0.02 [37]) |
Case 2: 19-year-old female | At age 1, amoxicillin-induced urticaria. By age 4, idiopathic episodes of anxiety, dysphagia, and dyspnea. Panic attacks began after a grandparent’s death when she was 5. At 11, daily vomiting for a month upon switching schools due to a bullying incident. At 13, an incident of athletics-related heat stroke. At 14 (one year after menarche), substantial dysmenorrhea began. | At 15, starting about two months after her first Gardasil vaccination, emergence in a short period of many new problems including severe fatigue, pruritic oral sensitivity to a variety of foods, persistent non-bloody diarrhea, evidence of prior Epstein–Barr virus infection, PPI- and steroid-refractory eosinophilic esophagitis (EoE, later resolved, thought due to dietary changes), PPI and steroid reactivities (including extreme exhaustion, irritability, and hunger), brain fog, severe joint and muscle pains, temperature sensitivities, hot flashes, freezing episodes, marked worsening of anxiety, presyncopal and syncopal episodes, lockjaw and surgical site infection following impacted wisdom teeth extraction, reaction to codeine with marked weakness and memory loss, extreme ranges of environmental and food allergies (including gluten and soy), possible polycystic ovarian syndrome (PCOS), severe headaches, subjective fevers, flushing, feeling cold much of the time, fatigue (often to the point of exhaustion), malaise, diffusely migratory aching/pain, diffusely migratory pruritus, unprovoked soaking sweats (mostly nocturnal), weight loss, constant hunger, irritation of the eyes, difficulty focusing vision (but ophthalmologic evaluations for this had all been negative), epistaxis (both nares had to be cauterized), easy bleeding, easy bruising, sinonasal congestion, coryza, post-nasal drip, intranasal sores, oral pruritus, occasional sore throats, fear of dysphagia (but not actual dysphagia itself), dyspnea (acute spells of this had driven her to the ED, where evaluations had consistently been unrevealing), palpitations, non-anginal chest discomfort/pain, gastroesophageal reflux in the past, nausea, rare vomiting, diarrhea alternating with constipation (much more so the former), diffusely migratory abdominal discomfort including (usually post-prandial) bloating, urinary frequency, diffusely migratory weakness, a sense of diffusely migratory edema in her joints but no physically visible edema, diffusely migratory tingling/numbness (typically about the distal extremities), orthostatic and non-orthostatic presyncope, syncope, cognitive dysfunction (particularly memory, concentration, and word-finding), waxing/waning hair loss (sometimes severe), odontalgia despite good attention to dental hygiene, poor nail growth, diffusely migratory rashes (typically patchy macular erythema), “hives all the time” (most commonly on her abdomen), insomnia, frequent waking, non-restorative sleep, hypersomnolence, sleeptalking, occasional sleep paralysis, panic disorder, anxiety, laxity in multiple joints (but a spontaneously demonstrated Beighton score of 0/9), unusually vigorous reactions to insect bites (especially mosquito bites), and poor healing in general. | 1. Plasma histamine 2.0 ng/mL (normal 0.1–1.8) 2. Plasma heparin 0.05 anti-Factor Xa units/mL (upper normal 0.02 [37]) 3. 24 h urinary prostaglandin D2 384 ng/24 h (normal 100–280) |
Case 3: 24-year-old female | Frequent “colds” in infancy. Frequent “Strep infections” in childhood. Menarche at 13, with immediate dysmenorrhea and menorrhagia. At 17, frequent “stomachaches and cramping” and waxing/waning diarrhea alternating with constipation. Shortly after starting college, constipation worsened and she started suffering new allergies, episodes of idiopathic urticaria about her trunk and extremities, chronic fatigue, and waxing/waning periorbital edema. At 21, urticaria worsened, accompanied by throat closing, numbness, and pain. | At 22 she received her first Gardasil vaccination. Mild facial edema ensued a few hours later and only lasted a few hours, but then she inexplicably lost 10 pounds over the next month. The second Gardasil vaccination was given on schedule a month after the first, and two days later she began feeling very dizzy and nauseous and started vomiting, and she soon was diagnosed with POTS. Chronic sinus congestion worsened and came to include chronic bilateral ear congestion. Throat closing and facial edema began happening more often, especially after ingesting certain foods or medication products or after applying certain facial lotions, which also made her tongue feel burned. Episodes of urinary frequency and urgency and pelvic pain, without evidence of infection, emerged. Episodes of acute dyspnea (“I just cannot catch a deep breath”) emerged. Other symptoms to emerge included subjective fevers, flushing, feeling cold much of the time, fatigue (often to the point of exhaustion), malaise, headaches, diffusely migratory aching/pain, diffusely migratory pruritus, unprovoked fluctuations in weight and appetite (she had been unable to get back to her normal weight since the Gardasil treatment, plus she reported early satiety), irritation of the eyes, vision problems, tinnitus, epistaxis, easy bruising, sinonasal congestion, coryza, post-nasal drip, oral canker sores, burning tongue, irritation and numbness of the throat, proximal dysphagia, dyspnea, palpitations, non-anginal occasional chest discomfort/pain, gastroesophageal reflux, nausea, vomiting, diarrhea alternating with constipation, diffusely migratory burning abdominal discomfort including (usually post-prandial) bloating, diffusely migratory weakness (possibly secondary to pyridostigmine, she thought), periorbital and bilateral cheek edema, tingling/numbness (typically about her throat), diffusely migratory adenopathy and adenitis, orthostatic and non-orthostatic presyncope, cognitive dysfunction (particularly memory, concentration, and word-finding), hair loss since about age 17, deterioration of dentition despite good attention to dental hygiene, brittle nails, diffusely migratory rashes (typically patchy macular erythema), hives, insomnia (especially due to feeling hot and dyspneic and due to urinary urgency/frequency), frequent waking, hypersomnolence, and joint hypermobility. | 1. 24 h urinary N-methylhistamine 238 mcg/g Cr (normal 30–200) 2. Random urinary N-methylhistamine 231 mcg/g Cr (normal 30–200) |
Case 4: 15-year-old female | Eczema and allergies by age 3. At 10, a barky dry cough persisted for a year. At 12, diagnosed with asthma and started having frequent episodes of bronchitis. Subcutaneous immunotherapy was attempted but only seemed to cause worsening reactions over time, eventually recurrent anaphylaxis. Chronic fatigue emerged too. | At 14, she received her first Gardasil vaccination, “and that is when the floor just dropped out” with marked worsening of fatigue (often could not finish the schoolday), idiopathic anaphylactoid reactions every day, recurring idiopathic fevers despite extensive evaluation, reacting to foods but testing negative for allergies to these foods, reacting to chemical odors/fragrances, chronic nausea, post-prandial reflux and vomiting, diarrhea alternating with constipation, hair falling out in clumps (diagnosed as alopecia areata), and frequent palpitations as well as severe presyncope (once occasioning hospitalization for a heart rate of 180). She also developed frequent “bone pains” in her legs (osteomyelitis disproven). Other symptoms which emerged included flushing, feeling cold much of the time, headaches, diffusely migratory aching/pain, diffusely migratory pruritus, unprovoked soaking sweats (usually at night), unprovoked fluctuations in weight and appetite, irritation of the eyes, vision disturbances, epistaxis, easy bruising, sinonasal congestion, coryza, post-nasal drip, possible intranasal sores, frequent pharyngeal thrush and occasional throat sores, dyspnea, gastroesophageal reflux, nausea, vomiting, diarrhea alternating with constipation, diffusely migratory abdominal discomfort including (usually post-prandial) bloating, diffusely migratory weakness, diffusely migratory edema (mostly about the face), diffusely migratory bilateral cervical adenitis, orthostatic and non-orthostatic presyncope, cognitive dysfunction (particularly memory, concentration, and word-finding), hair loss, unusual deterioration of dentition despite decent attention to dental hygiene, diffusely migratory rashes (typically patchy macular erythema), hives, eczema, hypersomnolence, sleep paralysis, and poor healing in general. | 1. 24 h urinary 2,3-dinor-11-beta-prostaglandin-F2-alpha 16,022 pg/mg of creatinine (normal < 5205) 2. Plasma histamine 5.06 ng/mL (normal < 1.0) 3. Serum chromogranin A 113 ng/mL (normal < 93), and another serum chromogranin A 197 ng/mL (normal 0–95); both chromogranin A elevations without confounding cardiac, renal, or hepatic failure, active/recent proton pump inhibitor use, neuroendocrine cancer, or chronic atrophic gastritis |
Case 5: 21-year-old female | Since birth she has “always been having a cold” and has “always been throwing up”. Gastroesophageal reflux disease (GERD) was diagnosed in infancy. A possible UTI was treated at 1 year. She also “passed out sometimes from crying too hard”. At 6, she suffered a bout of pertussis in spite of having received the vaccine on schedule. Alternating diarrhea and constipation emerged early in school. At 10, she was only at the 5th percentile for weight. Lansoprazole was started for GERD, but this helped only modestly. Menarche came at 12, and she was immediately afflicted by dysmenorrhea and menorrhagia. At 13, upon having to stand for a long time, she suffered a full syncope. At 15 she was started on an oral contraceptive, which helped control her menstrual symptoms. She was also started on cyproheptadine, which helped stimulate her appetite only while she was actively taking it; stopping it for even just two days would lead to a relapse of many symptoms, gastrointestinal and otherwise. | At 15 she received her first two Gardasil vaccinations on schedule, without any early adverse reactions. The third vaccination was delayed. Three months after the second injection she accidentally tripped, fell down a flight of stairs, and suffered a concussion. More GI symptoms emerged in the next week (more constipation, more abdominal pain, and more vomiting) as well as urinary symptoms (marked frequency). One year after the first Gardasil vaccination she received the third, and within the next month, episodes of orthostatic hypotension, presyncope (idiopathic and at micturition), and tachycardic palpitations emerged. She soon was clinically diagnosed with POTS. Heat, prolonged standing, and smoke as well as other odors would trigger flares of assorted symptoms. Bouts of inexplicable abdominal pain required frequent ED visits. A kidney stone was found at one point and required extraction. She reacted to her dormitory room on her first day at college and had to withdraw after one semester due to “continuous nausea and vomiting” and “frequent ED visits”. At 19 she was diagnosed with anxiety but reacted to sertraline with whole-head edema. Extensive evaluations were unrevealing. She reacted with migraine headaches, muscle cramps, and dysfunctional uterine bleeding to fludrocortisone started for POTS. At the time of that initial evaluation, she reported chief complaints of dyspnea, vomiting, tachycardia, and belching. Other symptoms which emerged in time included subjective fevers, flushing, feeling cold much of the time, fatigue (often to the point of exhaustion), malaise, headaches, diffusely migratory aching/pain, diffusely migratory pruritus, unprovoked fluctuations in weight and appetite, irritation of the eyes, tinnitus, sinonasal congestion, coryza, post-nasal drip “all the time”, irritation of the mouth, irritation of the throat, proximal dysphagia, dyspnea (“I feel really tight at times in my throat and lungs, but I am told my airway is wide open and my oxygen is at 100%”), palpitations, non-anginal chest discomfort/pain, gastroesophageal reflux, nausea, vomiting, diarrhea alternating with constipation, diffusely migratory abdominal discomfort, urinary frequency, occasional dysuria (she said it would always feel as though she had a UTI, but evaluation for such was always negative; she said she had had only one true UTI in her adolescent/adult life), diffusely migratory weakness, subjective edema about the oral/cervical tissues as described above but almost never any objective edema, diffusely migratory tingling/numbness (typically about the distal extremities), diffusely migratory bilateral cervical adenitis (but not adenopathy), orthostatic and non-orthostatic presyncope, syncope rarely (as detailed above), cognitive dysfunction (particularly memory, concentration, and word-finding), some aberrant dental growth requiring multiple oral surgeries, diffusely migratory rashes (typically patchy macular pruritic erythema), insomnia, frequent waking, hypersomnolence, non-restorative sleep, sleepwalking in childhood, sleeptalking, sleep paralysis, night terrors, anxiety, panic, depression, and poor healing in general (principally excessive scarring). | 1. 24 h urinary prostaglandin D2 432 ng (normal 100–280) 2. Plasma heparin 0.17 anti-factor Xa units/mL (upper normal 0.02 [37]) |
Case 6: 23-year-old female | Recurrent joint pains since age 10; first syncopal event at age 15; and diffuse joint hypermobility. | Flu-like symptoms, hives, pruritus, allergic reactions to foods, vomiting, abdominal pain, daily nausea, weight loss, worsened arthritis, urinary frequency, dysuria, nocturia, heat intolerance, anxiety, dysmenorrhea, and fatigue. | 1. Serum prostaglandin D2 211 pg/mL (normal 35–115) |
Case 7: 20-year-old male | None. | Diffuse arthritis, knee weakness, difficulty ambulating, exertion-worsened fatigue, diffuse burning pain, lightheadedness, palpitations, headaches, cognitive dysfunction, weight loss and then recovery, fibromyalgia, and postural orthostatic tachycardia syndrome. | 1. Plasma histamine 2.8 ng/mL (normal ≤ 1.8) |
Case 8: 22-year-old female | Anxiety and behavioral rigidity since age 3, brief bout of obsessive compulsive disorder at age 8, growth hormone deficiency and central precocious puberty diagnosed at age 10, bulimia emerged at age 12, and treatment-resistant anorexia emerged at age 14. | Migraine headaches, irritable bowel syndrome—constipation, gastroparesis, abdominal pain, food intolerances, lactose and gluten intolerances unresponsive to dietary adjustments, severe depression, dizziness, lightheadedness, fatigue, cognitive dysfunction, “brain burning”, POTS, worsened OCD, multiple tick-borne infections (Bartonella, Borrelia, and Babesia, though no awareness of tick bites or classic rashes at any point), oligomenorrhea, severe mood lability, urge incontinence, dry mouth, heat intolerance, headaches, misophonia (hypersensitivity to loud noises), irritability, burping, easy bruising, lentigo reticularis, and dermatographism. | 1. Plasma histamine repeatedly elevated (10 ng/mL, 12 ng/mL, 10 ng/mL, 12 ng/mL over several months; normal 0–8) 2. Serum chromogranin A repeatedly elevated (25 ng/mL, 26 ng/mL; normal 0–15) and without any evident confounders |
Case 9: 27-year-old female | Dermatographism, disturbed sleep, cold-induced asthma, dye reactivity, frequent otitis, headaches, abdominal pain, and nausea, dysmenorrhea, migraines, Raynaud’s phenomenon, orthostatic presyncope, migratory bone pains and paresthesias, oral ulcers, folliculitis, chronic fatigue, and cognitive dysfunction. | Episodic tachycardia, worsened chronic fatigue, heightened environmental sensitivities (odors, sounds, and lights), worsened headaches, severe motion sickness, chemical sensitivities, alcohol intolerance, aquagenic urticaria, cystic acne, cyclical vomiting, diarrhea with mucus, worsened cognitive dysfunction, worsened sleep, urinary frequency, and mild alopecia. | 1. Serum chromogranin A 103 ng/mL (normal < 95) 2. Plasma histamine 2.0 ng/mL (normal ≤ 1.8) |
Case 10: 21-year-old female | Chronic constipation, frequent ear infections, dermatographism, unusual reactivities to assorted sensations and dyes, misophonia, aquagenic urticaria, folliculitis to minimal trauma, irregular menses, and non-infectious vaginitis. | Severe chronic fatigue, motion sickness, dysmenorrhea, depression, cognitive dysfunction, eczema, a burning sensation about the skin, polycystic ovarian syndrome, hypothyroidism, vertigo, post-prandial tachycardia, nausea, anorexia, and amenorrhea. | 1. Plasma histamine 2.2 ng/mL (normal 0.0–2.0) 2. Off-the-scale anti-IgE-receptor antibody level |
Case 11: 30-year-old female | Frequent infections, constipation, asthma, migraines, and food sensitivities dating to her earliest memories, hirsutism at 5, precocious puberty at 10, and hypermobile Ehlers–Danlos syndrome. | Urticaria, postural orthostatic tachycardia syndrome, psoriasis, asthma, oxalate nephrolithiasis, gallstones, diarrhea, maldigestion and worsened food as well as other sensitivities, endometriosis, HPV infection, and cervical cancer. | 1. 24 h urinary N-methylhistamine 296 mcg/g Cr (normal 30–200) 2. Serum chromogranin A 146 ng/mL (normal < 102, no confounding factors) |
System | Potential Manifestations of Mast Cell Activation Syndrome (MCAS) |
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Constitutional | Fatigue, subjective or objective hyperthermia and/or hypothermia, sweats, flushing, plethora or pallor, increased or decreased appetite, weight gain or loss, pruritus, chemical/physical sensitivities (often odd), and poor healing |
Dermatologic/integument | Rashes/lesions of many sorts (e.g., classic urticaria pigmentosa, telangiectasias, xerosis, striae, warts, tags, folliculitis, ulcers, dyshydrotic eczema, and migratory but sometimes focally persistent patchy macular erythema), migratory pruritus (sometimes aquagenic), angioedema, dermatographism, alopecia, and onychodystrophy |
Ophthalmologic | Irritated eyes, episodic difficulty focusing, and lid tremor/tic (blepharospasm) |
Otologic/osmic | Infectious or sterile otitis externa and/or media, hearing loss and/or tinnitus, dysosmia, coryza, congestion, and epistaxis |
Oral/oropharyngeal | Pain or irritation (sometimes “burning”), leukoplakia, ulcers, angioedema, dysgeusia, and dental or periodontal inflammation/decay |
Lymphatic | Adenopathy (usually sub-pathologic and spontaneously waxing/waning in size, sometimes migratory), adenitis, and splenitis |
Pulmonary | Airway inflammation at any or all levels, cough, dyspnea (usually mild, episodic, and “just cannot catch a deep breath” despite normal pulmonary function tests), wheezing, obstructive sleep apnea, and pulmonary hypertension |
Cardiovascular | Presyncope or syncope, hypertension and/or hypotension, palpitations, migratory edema, chest pain (usually non-anginal), atherosclerosis, odd heart failure (e.g., takotsubo), allergic angina (Kounis syndrome), and vascular anomalies |
Gastrointestinal | Dyspepsia, reflux, nausea, vomiting (sometimes cyclical), diarrhea and/or constipation (often alternating), angioedema, dysphagia (often proximal), bloating/gas, migratory abdominal pain from luminal or solid organ inflammation, malabsorption, and ascites |
Genitourinary | Migratory luminal and solid organ inflammation, chronic kidney disease, endometriosis, chronic back/flank/abdominal pain, infertility, and decreased libido; miscarriages may signal an MCAS-rooted anti-phospholipid antibody syndrome |
Musculoskeletal | Migratory bone/joint/muscle pain, joint laxity/hypermobility, and osteopenia and/or osteosclerosis |
Neurologic | Headache, sensory and/or motor neuropathies, seizure disorders, pseudoseizures, and dysautonomia |
Psychiatric | Mood disturbances, anxiety/panic, psychoses, cognitive dysfunction (most commonly memory and word-finding difficulties), and sleep disruption |
Endocrinologic/metabolic | Abnormal electrolytes and liver function tests, hypo- or hyperthyroidism, dyslipidemia, impaired glucose control, hyperferritinemia, nutritional deficiencies, delayed puberty, and dysmenorrheal |
Hematologic/coagulopathic | Polycythemia or anemia (macrocytic, normocytic, or microcytic), leukocytosis or leukopenia, monocytosis or eosinophilia or basophilia, thrombocytosis or thrombocytopenia, arterial and/or venous thromboembolic disease, and otherwise inexplicable “easy” bruising/bleeding; usually no histologic or molecular evidence of MC aberrancy in the marrow in MCAS |
Immunologic | Hypersensitivity reactions, increased risk for malignancy and autoimmunity, impaired healing, increased susceptibility to infection, increased or decreased levels of immunoglobulin of any isotype, and monoclonal gammopathy of undetermined significance |
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Afrin, L.B.; Dempsey, T.T.; Weinstock, L.B. Post-HPV-Vaccination Mast Cell Activation Syndrome: Possible Vaccine-Triggered Escalation of Undiagnosed Pre-Existing Mast Cell Disease? Vaccines 2022, 10, 127. https://doi.org/10.3390/vaccines10010127
Afrin LB, Dempsey TT, Weinstock LB. Post-HPV-Vaccination Mast Cell Activation Syndrome: Possible Vaccine-Triggered Escalation of Undiagnosed Pre-Existing Mast Cell Disease? Vaccines. 2022; 10(1):127. https://doi.org/10.3390/vaccines10010127
Chicago/Turabian StyleAfrin, Lawrence B., Tania T. Dempsey, and Leonard B. Weinstock. 2022. "Post-HPV-Vaccination Mast Cell Activation Syndrome: Possible Vaccine-Triggered Escalation of Undiagnosed Pre-Existing Mast Cell Disease?" Vaccines 10, no. 1: 127. https://doi.org/10.3390/vaccines10010127