Medical Mystery Solved — Hunting for a Diagnosis | NEJM

Summary

A 47-year-old man's mysterious illness was diagnosed as alpha-gal syndrome, an allergic reaction to red meat, likely caused by a lone star tick bite during hunting in Michigan. The case highlights the impact of climate change on the spread of ticks and the emergence of new allergies. The patient's recovery involved avoiding red meat and treatment with glucocorticoids and antihistamines.

Takeaways

• 🏥 Mr. A, a 47-year-old man, visited an emergency department with symptoms of faintness, swollen eyelids, itchy rash, and gastrointestinal issues, which could have various causes.
• 🔍 The potential unifying diagnosis for Mr. A's symptoms is mast cell activation, which can be triggered by environmental factors, food, medications, and underlying conditions like mastocytosis.
• 💊 Mr. A had a history of medical conditions including type 2 diabetes, kidney stones, and ADHD, and was taking medications including naproxen and an antacid for his symptoms.
• 🌡 His physical examination revealed a fast heart rate, low blood pressure, and hives, but no signs of infection or organ enlargement.
• 🧬 Laboratory tests showed an elevated white cell count, low serum sodium, reduced kidney function, high lactic acid, and elevated troponin and procalcitonin levels, indicating possible anaphylaxis or infection.
• 🚑 Mr. A's condition worsened with hypotension and tachycardia, suggesting anaphylaxis or septic shock, and he was treated with IV fluids, antibiotics, and medications to reduce histamine release.
• 🍽️ The patient's symptoms recurred after eating beef, and further questioning revealed a recent deer hunting trip, suggesting a new allergy to alpha-gal, a sugar found in nonprimate mammals.
• 🦟 Alpha-gal allergies are often caused by tick bites, particularly from the lone star tick, which has expanded its range due to climate change, affecting regions like southeastern Michigan where Mr. A resides.
• 🛑 Mr. A was diagnosed with alpha-gal syndrome, treated with glucocorticoids and antihistamines, and advised to avoid red meat to prevent further anaphylactic episodes.
• 🌡️ The case highlights the impact of environmental changes, such as climate change, on the prevalence of certain allergens and the importance for physicians to consider these factors in diagnosis.
• 📈 The patient's recovery and subsequent allergy testing confirmed the presence of alpha-gal IgE antibodies, emphasizing the role of environmental exposures in the development of new allergies.

Q & A

What were the initial symptoms that Mr. A presented to the Michigan emergency department with in January 2021?

Mr. A initially presented with feeling faint, swollen eyelids, an itchy rash, watery bowel movements without blood after eating, and over the following days, he experienced diffuse crampy abdominal pain, nausea, and occasional vomiting.

What is the potential unifying diagnosis that could explain all of Mr. A's symptoms?

The potential unifying diagnosis is the activation of mast cells, which mediate allergic reactions and can induce multiorgan symptoms through the release of histamine and other mediators.

What are some possible triggers for mast cell activation mentioned in the script?

Possible triggers for mast cell activation include environmental exposures, food, medications, and underlying conditions that are associated with increased mast cell number, such as mastocytosis or mast-cell activation syndromes.

What is hereditary or drug-induced angioedema, and why is it an unlikely explanation for Mr. A's symptoms?

Hereditary or drug-induced angioedema is a condition that causes swelling under the skin. It is an unlikely explanation for Mr. A's hives and hypotension because it does not typically account for these specific symptoms.

What medical conditions did Mr. A have a history of, and what medications was he taking?

Mr. A had a history of type 2 diabetes, 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.

What laboratory findings were consistent with infection or anaphylaxis in Mr. A.'s case?

Mr. A.'s white-cell count was very elevated and was mostly composed of neutrophils, which is consistent with infection or anaphylaxis. His serum sodium level was low, kidney function was reduced, and the lactic acid level was high, indicating inadequate tissue perfusion.

What is anaphylaxis, and how is it related to Mr. A.'s symptoms?

Anaphylaxis is a severe, potentially life-threatening allergic reaction that involves mast-cell activation and can be caused by various triggers such as foods, medications, or insect bites or stings. Mr. A.'s symptoms, rapid heart rate, and hypotension may point to anaphylaxis.

What treatment was administered to Mr. A. for his symptoms, and what was the outcome?

Mr. A. was given IV fluids, broad-spectrum antibiotics, H2 blockers, and glucocorticoids. He was also given epinephrine for possible anaphylaxis. After treatment, his heart rate slowed, blood pressure improved, and his symptoms abated considerably.

What is alpha-gal allergy, and how is it related to Mr. A.'s case?

Alpha-gal allergy is a condition where humans develop alpha-gal–directed IgE antibodies after exposure to alpha-gal from nonprimate mammals, leading to an allergic response to red meat. Mr. A.'s symptoms and recent deer hunting activity suggest he may have developed an alpha-gal allergy.

How did the lone star tick play a role in Mr. A.'s diagnosis, and what is its connection to climate change?

The lone star tick, which contains alpha-gal from mammals it has fed on, is the most common vector for alpha-gal exposure in humans in the U.S. Its expanded geographic range, attributed to climate change, may have led to Mr. A. being bitten and developing the allergy.

What was the final diagnosis for Mr. A., and what instructions were given for his condition?

Mr. A. was diagnosed with alpha-gal syndrome. He was discharged with tapering doses of glucocorticoids and antihistamines and was instructed to avoid red meat to prevent further episodes of anaphylaxis.

Outlines

00:00

🏥 Medical Diagnosis and Environmental Factors

The first paragraph discusses the multifaceted approach to diagnosing a patient with an unexplained illness, emphasizing the importance of considering environmental factors like climate change. The case of Mr. A., a 47-year-old man with a range of symptoms including faintness, swollen eyelids, an itchy rash, and gastrointestinal issues, is presented. The narrative explores potential causes, such as mast cell activation, and the role of environmental triggers. It also outlines the patient's medical history, current symptoms, and initial test results, suggesting possible anaphylaxis or infection, and the subsequent medical interventions taken.

05:02

🍽️ Alpha-Gal Allergy and Climate Change Impact

The second paragraph delves into the patient's progression of symptoms, suggesting an allergic reaction possibly linked to mast cell activation in the gastrointestinal tract. It discusses the potential for new allergies to develop, especially to common allergens, and the possibility of mastocytosis. The patient's improvement and subsequent relapse upon eating beef hint at an IgE-mediated response. The revelation of an alpha-gal allergy, triggered by a tick bite during a hunting trip, connects the patient's condition to the broader context of climate change affecting the range of the lone star tick. The conclusion highlights the importance for physicians to be aware of how climate change can influence health challenges, as illustrated by Mr. A.'s case.

Keywords

💡Diagnosis

Diagnosis refers to the process of identifying a disease or condition through the evaluation of a patient's medical history, symptoms, and test results. In the video's narrative, the diagnosis of Mr. A.'s mysterious illness involves considering various symptoms and their potential causes, highlighting the complexity of medical diagnosis.

💡Mast Cells

Mast cells are immune cells that play a key role in allergic reactions by releasing histamine and other mediators. The video discusses the activation of mast cells as a potential unifying diagnosis for Mr. A.'s symptoms, illustrating the role of mast cells in mediating allergic reactions and multiorgan symptoms.

💡Anaphylaxis

Anaphylaxis is a severe, potentially life-threatening allergic reaction that can involve symptoms like hives, hypotension, and rapid heart rate. The script suggests anaphylaxis as a possible diagnosis for Mr. A.'s symptoms, emphasizing the urgency and seriousness of this condition.

💡Histamine

Histamine is a compound released by mast cells during allergic reactions, which can cause inflammation and various symptoms. The video mentions histamine release as a mechanism behind Mr. A.'s symptoms, showing its importance in allergic reactions and anaphylaxis.

💡IgE Antibodies

IgE antibodies are part of the immune system and play a role in allergic reactions. The video discusses IgE antibodies as mediators of anaphylactic reactions, indicating their significance in identifying the cause of Mr. A.'s symptoms.

💡Sepsis

Sepsis is a life-threatening condition caused by the body's response to an infection, which can lead to tissue damage and organ failure. The script considers sepsis as a possible cause for Mr. A.'s symptoms, highlighting the need to differentiate between sepsis and anaphylaxis in the diagnostic process.

💡Alpha-gal Syndrome

Alpha-gal Syndrome is a condition where individuals develop an allergy to red meat due to the presence of the sugar alpha-galactose in non-primate mammals. The video reveals this as the cause of Mr. A.'s symptoms after a deer hunting trip, illustrating the impact of environmental factors on health.

💡Lone Star Tick

The Lone Star Tick is a species of tick known to carry the alpha-gal sugar, which can cause the development of red meat allergies in humans. The video connects Mr. A.'s symptoms to a possible bite from this tick, demonstrating the role of environmental vectors in disease transmission.

💡Mastocytosis

Mastocytosis is a condition characterized by an abnormal increase in mast cells in the body, which can lead to allergic reactions. The script mentions mastocytosis as a differential diagnosis, showing the range of conditions that can cause similar symptoms to Mr. A.'s.

💡Hereditary Angioedema

Hereditary Angioedema is a genetic condition that causes episodes of swelling under the skin. The video rules out this condition in Mr. A.'s case based on lab results, illustrating the process of elimination in differential diagnosis.

💡Environmental Changes

Environmental changes, such as those due to climate change, can affect the prevalence of diseases and the behavior of disease vectors. The video emphasizes the importance of considering environmental factors in modern medicine, as seen in the case of the Lone Star Tick's range expansion.

Highlights

Physicians must consider climate change and environmental factors in diagnosing patients with mysterious illnesses.

Mr. A presented with symptoms including faintness, swollen eyelids, itchy rash, watery bowel movements, abdominal pain, and nausea.

Mr. A's symptoms could be unified by mast cell activation, which can induce multiorgan symptoms.

Mast cell activation can be triggered by environmental exposures, food, medications, and underlying conditions.

Hereditary or drug-induced angioedema was ruled out as a likely cause for Mr. A's symptoms.

Mr. A had a history of type 2 diabetes, kidney stones, and other health conditions, complicating the diagnosis.

Mr. A's vital signs showed a fast heart rate and low blood pressure, indicative of potential anaphylaxis.

Labs revealed an elevated white-cell count, low sodium levels, reduced kidney function, and high lactic acid levels.

An electrocardiogram showed signs of possible cardiac ischemia, adding to the complexity of Mr. A's condition.

Mr. A's symptoms and lab results suggested anaphylaxis and possible septic shock, requiring immediate treatment.

Epinephrine was administered to Mr. A for suspected anaphylaxis, highlighting the importance of prompt treatment.

A CT scan of the abdomen and pelvis did not reveal any significant findings to explain Mr. A's symptoms.

Mr. A's condition improved with IV fluids, antibiotics, and other medications, indicating a potential response to treatment.

Elevated serum IgE and tryptase levels pointed towards mast cell involvement in Mr. A's allergic reaction.

Mr. A's recurrent symptoms suggested reexposure to an allergen, which was later identified as red meat.

Mr. A's history as a deer hunter and recent consumption of venison led to the diagnosis of alpha-gal allergy.

The lone star tick, which can carry alpha-gal, has expanded its range due to climate change, affecting more people.

Mr. A was successfully treated for alpha-gal syndrome and advised to avoid red meat to prevent future reactions.

Physicians are urged to be aware of the changing nature of health challenges due to climate change.

Transcripts

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.