There are obvious factors that physicians must consider when diagnosing a patient
with a mysterious illness — their history, symptoms, physical exam, and test results.
But another factor physicians need to add to this list is possible effects of climate
change or other environmental changes. The following true story is a case in point.
Mr. A., a 47-year-old man, went to a Michigan emergency department in January 2021 because
he felt faint, had swollen eyelids, and an itchy rash. For the past 3 weeks,
he had been having watery bowel movements, without blood, after eating, and for the past 5 days,
he was also noting diffuse crampy abdominal pain and nausea with occasional vomiting.
Each of the patient's symptoms may have various causes. For example, his feeling
faint might be a result of intravascular volume depletion from his GI problems,
while the latter might reflect infection or malabsorption from
an underlying condition such as celiac disease. A potential unifying diagnosis that could explain
all of his symptoms is the activation of mast cells, which mediate allergic reactions. With
their release of histamine and other mediators, mast cells can induce multiorgan symptoms.
Their activation can be triggered by environmental exposures, food, medications, and also by
underlying conditions that are associated with increased mast cell number, such as mastocytosis
or mast-cell activation syndromes. Other considerations include
hereditary or drug-induced angioedema (swelling under the skin), but this
is an unlikely explanation for the hives and hypotension.
Let's continue with the patient's symptoms and history.
Mr. A. had type 2 diabetes and a history of kidney stones, rapid heartbeat, high triglyceride levels,
and ADHD. He was taking medications for these conditions and had started taking naproxen and
an antacid for his abdominal symptoms. Mr. A hadn't traveled outside Michigan
recently, eaten any new foods, or knowingly been around sick people.
His temperature, respiratory rate, and oxygen saturation were normal, but his heart rate was
fast, and his blood pressure was low. His lips were slightly swollen, and his abdomen was soft
and tender, but there were no swollen lymph nodes or enlarged liver or spleen. He had hives on his
scalp, neck, shoulders, abdomen, and groin. Mr. A.'s symptoms, rapid heart rate,
and hypotension may point to anaphylaxis, which involves mast-cell activation and
can be caused by foods, medications, insect bites or stings. These allergic reactions are commonly
mediated by IgE antibodies. We can rule out the GI
problems and autoimmune conditions. NSAIDs can cause a related clinical
syndrome with hives and angioedema. This reaction also involves mast-cell activation and histamine
release but is not usually IgE-mediated. Labs will give us more information.
Mr. A.'s white-cell count was very elevated and was mostly composed of neutrophils,
which is consistent with infection or anaphylaxis. He was not anemic. His serum sodium level was low,
and kidney function was reduced. The lactic acid level was high, indicating inadequate
tissue perfusion. His serum troponin level was elevated, raising concern about inadequate blood
flow to the heart; a procalcitonin level was also elevated, suggesting infection. Septic
shock could lead to elevations in both. An electrocardiogram showed tachycardia
and other signs of possible cardiac ischemia. Mr. A.'s blood pressure then rapidly decreased.
Four liters of IV fluids raised his blood pressure, but his heart rate remained rapid.
At this point, the patient is showing further signs of possible shock,
making hereditary or drug-induced angioedema unlikely. His symptoms
could be explained by histamine release. He should be given epinephrine for possible
anaphylaxis. Sepsis should also be considered, though is less likely.
A CT scan of the abdomen and pelvis revealed only diverticulosis and a
small stone in the left kidney, which didn't explain the symptoms and signs.
Mr. A.'s heart rate increased again, and his blood pressure fell. He received two
more liters of IV fluids, plus broad-spectrum antibiotics, H2 blockers, and glucocorticoids,
after which his heart rate slowed, and his blood pressure improved.
Treatment for septic shock and anaphylaxis have been started. Epinephrine should be
administered immediately to reduce histamine release and to cause vasoconstriction and
increase cardiac output. Labs have not returned yet,
but it's important to know the tryptase and histamine levels to determine
whether the issue is anaphylaxis or another histamine-producing cause, such as mastocytosis.
A serum C4 level was measured and was high, further arguing against hereditary
angioedema. Mr. A. was given 10 more liters of IV fluids, which improved his hypotension,
kidney function, and lactate level. He received epinephrine and was admitted to the ICU.
So the patient's recent gastrointestinal symptoms, particularly diarrhea after meals progressing
to abdominal pain and nausea, suggests that the initial stages of illness were localized to mast
cells in the GI tract. The increasing severity of symptoms before admission may be due to allergic
sensitization resulting from repeated exposures to the trigger. Some event may have brought on
a new allergy. Common causes in adults are fish, shellfish, peanuts, and tree nuts.
In patients with systemic mastocytosis, release of mediators from mast cells may be triggered by
a range of exposures; among these, medications, stress, exercise, and medical procedures.
An enlarged liver or spleen and certain blood count abnormalities would suggest mastocytosis,
but these findings are often not present, and
their absence does not rule out this diagnosis.
The next day, Mr. A.'s abdominal pain and rash
had abated considerably, and his white-cell count had dropped. Blood
and urine cultures returned negative, and he was taken off the antibiotics.
But on his fourth day in the hospital, Mr. A. had tightness in his chest, difficulty breathing,
and a worsening rash. His tachycardia and hypotension were back, and he had reduced
oxygen saturation and wheezing. Epinephrine relieved his symptoms almost immediately.
Blood work from the first day came back showing elevated serum IgE and tryptase
levels. An allergy consultation was requested. We now know that he has elevated tryptase levels,
which suggests mast-cell involvement and an IgE-mediated trigger.
His recurrent symptoms on day 4 suggest reexposure to the same precipitant.
After repeated successful anaphylaxis treatment, and further questioning, Mr. A. noted that he'd
eaten beef about 4 hours before his symptoms worsened on day 4, though he had no previous
problems with red meat. He also mentioned that he is a deer hunter and had recently been hunting
white-tailed deer in southeastern Michigan, and had eaten venison 2 days before he came to the ED.
This new information is highly suggestive of an alpha-gal allergy.
Alpha-gal, or galactose-alpha-1,3-galactose, is a carbohydrate present in all nonprimate mammals.
Humans exposed to alpha-gal from other mammals may develop alpha-gal–directed IgE antibodies,
and therefore acquire a new allergic response to red meat. The most common vector for this
kind of exposure in humans in the U.S. is the lone star tick. Saliva from this tick
may contain alpha-gal from mammals on which the tick has fed, in particular, white-tailed deer.
The lone star tick was originally endemic to the eastern and southeastern United States. It has
more recently expanded its range into the upper Midwest, the Northeast, and eastern Canada. Its
expanded geographic range has been attributed to climate change, in the form of warmer weather and
changes in precipitation, as well as changes in habitat and in the abundance of mammalian hosts.
Mr. A. was probably bitten by an infected tick while on a recent hunting trip.
Mr. A. was diagnosed with alpha-gal syndrome and discharged with tapering doses of glucocorticoids
and antihistamines, and instructions to avoid red meat. When he had allergy testing 15 months later,
his tryptase level was normal, but he had alpha-gal IgE. He had
avoided eating red meat and had no further episodes of anaphylaxis.
Mr. A. lived and hunted in southeastern Michigan, where the previously rare lone
star tick is increasingly common. Physicians should be aware that as the climate changes,
so too will the nature of challenges to their patients health and well-being.