Graft Versus Host Disease: A TGH Special

During your time at TGH, you will likely encounter the entity of Graft Versus Host Disease (GVHD). It is  not a common disease; however, it is commonly seen at TGH due to our immune-suppressed patients, especially in transplanted patients. Let's first discuss the types of stem cell/bone marrow transplant (aka Hematopoietic cell transplantation).

Autologous: Hematopoietic cells are harvested from the bone marrow or peripheral blood prior to high-dose myeloablative chemotherapy/radiotherapy. The cells are then later reinfused back into the same patient during a period of prolonged bone marrow failure in order to help restore hematopoiesis. This type of transplant is used in lymphoma and myeloma, and has previously been used in patients with some solid tumors. 

Allogeneic: Stem cells are harvested from the bone marrow of healthy donors or newborn umbilical cord and are infused to reconstitute a host hematopoeitic system following myeloablative therapy. Allogenic stem cell transplants carry the same risks as autologous transplants, with the additional risk of graft-versus-host-disease.

Graft Versus Host Disease (GVHD)
GVHD occurs when donated lymphocytes attack normal host tissues because they are recognized as 'foreign.' GVHD is a common consequence of allogenic bone marrow transplantation, occurring in up to 40% of patients. It is a potential complication of all transplantation, including transfusion of blood products, but is particularly concerning in stem cell transplantations due to the inherent immune suppression of patient's undergoing stem cell or bone marrow transplantation. Due to their immune-suppressed nature, it is often difficult to differentiate infections from GVHD in patients who have received allogeneic transplants.

Risk Factors for GVHD
- Degree of HLA mismatching 
- Older age
- The use of peripheral blood/bone marrow samples instead of umbilical cord blood 

Sites Most Commonly Affected by GVHD
Skin - Lichen planus-like or morphea-like changes, sclerotic features. Diagnosis can be made without biopsy. 
Gut - Mucosal sloughing, severe cramps with secretory diarrhea. Diagnosis made on biopsy
Liver - Cholestatic hepatitis with nausea and vomiting.
Lungs - Bronchiolitis obliterans. Diagnosis made on biopsy.

Forms of GVHD
Acute
This form usually occurs before 100 days post-transplant and can present with a classic maculopapular or bullous rash, cholestasis with elevated bilirubin, nausea & vomiting, and abdominal cramps with diarrhea. Acute GVHD can occur more than 100 days after transplant, and is known as Late-Onset Acute GVHD.

Chronic
The chronic form more resembles other autoimmune disorders, presenting with arthritis, scleroderma-like skin changes or lichen planus, sicca syndrome, and chronic hepatitis with rising bilirubin. Patients may sometimes present with features of both chronic and acute GVHD, in which case they are labeled with an 'Overlap' syndrome.

Treatment
Because GVHD is immune-mediated, it is often treated with glucocorticosteroids. This therapy can be local (topical for skin, enteric for gut) or systemic (oral or IV). Other therapies include cyclosporine, MMF, and azathioprine. Complications related to the disease and its treatment must be monitored carefully.

Hypertrophic Obstructive Cardiomyopathy

This week during morning report we discussed a young woman who presented with chest pain, positive serum troponin, and a known history of hypertrophic cardiomyopathy (HCM). Let's discuss the physical examination findings and management of this condition.

Physical Examination
Classic findings for HCM on physical examination are seen in patients with left ventricular outflow tract (LVOT) obstruction. Patients with none or small gradients may have no physical examination findings.

A. Auscultation:

LVOT Obstruction - This murmur is similar sounding to aortic stenosis, in that it is a systolic crescendo-decrescendo murmur heard across the precordium. However, a major distinction between the murmurs is that the HCM murmur increases with any maneuver that decreases pre-load, whereas aortic stenosis either decreases or is not affected by these maneuvers. This is because decreased pre-load leads to a smaller LV cavity and thus causes more dynamic obstruction during systole. See below for details on the difference between the murmur of HCM and aortic stenosis.

SAM (systolic anterior motion) - This murmur is heard best in the mitral area and is due to the in-drawing of the mitral leaflets during systole, causing a murmur that is similar in sound to mitral regurgitation. SAM contributes to LVOT obstruction and is an important physical exam finding.

S4 - An S4 is commonly heard in HCM, best auscultated using the bell of the stethoscope in the apex. This sound is heard in aortic stenosis only in advanced cases.

B. Other findings

- Paradoxical splitting of the S2 is heard when the LVOT obstruction is severe.

- The carotid upstroke is often brisk and bifid. Bifid means two upstrokes are palpable - the initial pulsation due to LV contraction, a softening of the pulse due to dynamic obstruction, and a second impulse at the end of systole as the ventricular pressure overcomes the obstruction.

- The apical pulse may also be bifid. When an S4 is also palpable, this is known as the rarely seen "triple ripple." In general, the apical pulse will be diffuse and strong.

Management

1. Non-medical - Patients with HCM should be counselled to avoid situations which cause peripheral vasodilation or dehydration. This includes avoiding strenuous exercise, alcohol intake, and diuretics if possible.

2. Pharmacological Therapy- In order to increase diastolic ventricular filling time (and thus increase pre-load), negative chronotropic medications are indicated in patients with HCM. This includes beta-blockers and nondihydropiridine calcium channel blockers. The next line of therapy is negative ionotropic therapy with disopyramide, which is also an anti-arrythmic medication.

3. Surgical Myomectomy - In patients who remain symptomatic despite medications, surgical therapy is indicated. The procedure involves excising the basal septum and is highly successful. It can cure SAM and therefore reduce LVOT obstruction, and is considered the gold standard operative management of HCM.

4. Alcohol Ablation - In this procedure, alcohol is injected into a septal perforating artery via coronary artery catheterization. It is a less invasive therapy than surgical myomectomy, but myomectomy has more proven long-term efficacy.

5. Implanted Defibrillator - Consideration for this therapy is based on assessment for risk of sudden cardiac death, including family history of sudden cardiac death, wall thickness, genetic defect, gradient of outflow obstruction, and history of arrhythmia. Patients with HCM are at-risk for arrythmias due to disorganized myocytes and relatively poorly perfused myocardial perforators due to thickened myocardium.

That's all, folks!

Here's the obligatory NEJM article on HCM.

Here's a review article by one of the pioneers of HCM research, Dr. Doug Wigle from TGH.