Ep 132: A 72-Year-Old with Fatigue and Dyspnea on Exertion
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This is Katarina Heidhausen, Executive Editor of Harrison's Principles of Internal Medicine. Harrison's Pod Class is brought to you by McGraw-Hill's Access Medicine, the online medical resource that delivers the latest content from the best minds in medicine. And now, on to the episode. Hi, everyone. Welcome back to Harrison's Pod Class. We're your co-hosts. I'm Dr. Kathy Handy. And I'm Dr. Charlie Wiener, and we're joining you from the Johns Hopkins School of Medicine.

Welcome to episode 132, a 72-year-old with fatigue and dyspnea on exertion. Kathy, today's patient is a 72-year-old woman who presents with two weeks of increasing fatigue and dyspnea on exertion. She denies any weight loss, fevers, chills, nausea, vomiting, or diarrhea. She still works as an accountant, but has not sought much medical care over the last few years and has not had routine cancer screening. She's active and takes no medications.

Her physical examination is normal except for pallor of the mucous membranes and a stool showing occult blood. On lab testing, you find that her electrolytes are normal, but her CBC reveals a hemoglobin of 4 grams per deciliter with a normal white cell count and platelets of 600,000.

Well, she notably has anemia, which certainly could be the reason for her fatigue and dyspnea. And also notable about what she mentioned is that she has a positive stool occult test and that she hasn't had any routine cancer screening. U.S. Preventative Services Task Force recommends colon cancer screening for those between the ages of 45 and 75 who are at average risk of cancer and in good health. So first, she needs a blood transfusion, but then would also recommend that she get a colonoscopy and an EGD.

Yep, that's exactly what's planned. But given the degree of anemia, she's admitted for the transfusion in advance of the procedures. She's given two units of PAC red blood cells, which take her hemoglobin to 6.2. However, approximately four hours after the second unit of blood, she develops rapidly worsening shortness of breath and hypoxemia that requires high flow nasal cannula.

And what about her vitals and physical exam now? I would also start with an EKG and a chest x-ray. Well, her physical exam shows that she's not febrile, but she is tachypneic to the 20s, high 20s in fact. Her heart rate is sinus at 110 and her blood pressure is elevated at 140 over 60. Her neck veins are not elevated, but she has bilateral lower lobe crackles that are new since she came in. POCUS shows interstitial edema, but no effusion.

Her skin examination is normal. She does get a chest x-ray, which shows a normal-sized heart, but there's bilateral interstitial edema. And ECG shows only sinus tachycardia and no other acute changes. Okay, so it sounds like she has non-cardiac pulmonary edema, and this is in the context of a recent blood transfusion. So this would be trolley. Tell me more and define your eponym, please.

So TRALI or transfusion-related acute lung injury is characterized by the occurrence of or worsening of hypoxia and non-cardiogenic pulmonary edema. And this is with bilateral interstitial infiltrates on chest x-ray that happen during or within six hours of an infusion.

There can be delayed cases that occur up to 72 hours after transfusion. Trolley may be difficult to distinguish from other causes of hypoxia, such as circulatory overload, and it's among the most common causes of transfusion-related fatalities. Okay, well, that gets us right to the question. The question asks, what is the mechanism of this patient's transfusion reaction? Option A is bacterial contamination of the transfused red blood cells. Option B is citrate toxicity.

Option C is fluid overload. Option D is preformed antibodies that lyse transfused donor red blood cells. Or option E is transfusion of donor plasma that contains high titer anti-HLA class 2 antibodies that bind recipient cognate antigen.

Well, all of those can cause a transfusion reaction, but the answer in this case is E. So Trolley is mediated by donor plasma anti-HLA antibodies. They trigger a cytokine and chemokine response, and that leads to leukocyte aggregation in the pulmonary vasculature. That causes an additional inflammatory reaction too.

Recipient factors associated with an increased risk of TRALI include smoking, chronic alcohol use, shock, liver transplantation, cancer surgery, mechanical ventilation, and positive fluid balance. Okay, well, if this patient is TRALI, how do you treat her? The only treatment is supportive, which is the same as other causes of non-cardiogenic pulmonary edema, such as ARDS.

You mentioned that the other options in this question could also cause transfusion reactions. Let's go through those quickly. Transfusion, a transmitted bacterial infection, remains a significant concern, notably with plasma components stored at room temperature. And that allows for bacterial proliferation and results in an increased risk during storage.

However, some gram-negative bacteria, such as Yersinia, can grow at 4 degrees Celsius and therefore may be implicated in infection related to RBC transfusions. Recipients of a contaminated transfusion may develop abrupt fever and chills during transfusion and up to several hours after, which can deteriorate to shock, DIC, and even death.

Endotoxin formed within the blood components may be implicated. Now, if suspected, after sampling the blood for bacterial culture, broad-spectrum antibiotics should also be promptly initiated. What about citrate toxicity? I've not heard of that one. That is one of the potential complications of massive transfusion, like when more than 5 to 10 units of packed red cells are given over a couple of hours.

Citrate, which is commonly used to anticoagulate stored blood components, chelates calcium, so the patient can get symptomatic hypocalcemia. Calcium supplementation is often added in cases of massive transfusion. And fluid overload? That also has a clever acronym, TACO, or transfusion-associated cardiac overload. It's common in under-recognized transfusion adverse reaction, which is now thought to be the main cause of death, actually, from transfusion risk since TRALI has been mitigated.

Risk factors for TACO include older age, renal failure, pre-existing fluid overload, cardiac dysfunction, administration of a large volume of blood components, and an excessive rate of transfusion in relation to the patient's hemodynamic tolerance. And I assume it presents similar to other forms of volume overload.

Yeah, the typical findings are dyspnea, hypoxia, bilateral and predominantly alveolar infiltrates on chest x-ray, systolic hypertension, and an elevated BNP. Clinicians should be aware of patients at risk of volume overload and moderate transfusion rates and consider even concomitant use of diuretics. Okay, well, prior to that last discussion, I thought I liked all tacos. Okay.

You mentioned antibodies that lyse red cells. That was option D. Tell me more about that. Those are the hemolytic reactions. Immune-mediated acute hemolysis occurs when the recipient's preformed antibodies lyse transfused donor red blood cells. These reactions may occur during or even within 24 hours after transfusion. There are a variety of mechanisms in donor red blood cell antigens that the recipient antibodies can recognize.

Pre-transfusion testing can and should typically identify these antibodies and lessen the risk to patients. And how do these patients present typically? Acute hemolytic reactions may present with hypotension, tachycardia, tachypnea, fevers, chills, chest pain, and back pain, and hemoglobinuria and hemoglobinemia. In the most severe cases, DIC, acute renal failure, shock, and death may occur.

Delayed hemolytic reactions with icterus and persisting or worsening anemia are the main clinical manifestations, and those result from an anamnestic response. These reactions may occur in patients previously sensitized to RBC antigens who have a negative alloantibody screen at the time of transfusion due to low antibody levels.

Great. So the teaching point in today's case is that TRALI, or transfusion-related acute lung injury, is mediated by the transfusion of donor HLA antibodies that recognize antigens in the recipient. Clinically, the presentation looks like ARDS and the treatment is supportive. Plus, there are a variety of immunologic and non-immunologic complications associated with transfusion of red blood cells and plasma components.

If you liked this episode, you can find this question and others like it on Harrison Self-Review, and you can read more about it in the chapter on transfusion therapy and biology. Visit the show notes for links to helpful resources, including related chapters and review questions from Harrison's. And thank you so much for listening. If you enjoyed this episode, please leave us a review so we can reach more listeners just like you.