Cox’s Conference: Thrombotic Thrombocytopenic Purpura

In this week’s Ambulatory Cox’s Conference, Dr. Esther de Boer presented a case of a young female who presented with altered mental status in the setting of severe thrombocytopenia. Our expert discussant, Dr. Nagalla guided us through the differential diagnosis of microangiopathic hemolytic anemia (MAHA).

The differential diagnosis for our patient with altered mental status and severe thrombocytopenia included intracranial hemorrhage in the setting of immune thrombocytopenia (ITP), cerebral vascular accident in the setting of heparin-immune thrombocytopenia (HIT), thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulation (DIC) in the setting of sepsis, paroxysmal nocturnal hemoglobinuria (PNH), HELLP syndrome in the setting of pregnancy, acute liver failure, and tick-born illnesses such as ehrlichiosis. In addition to severe thrombocytopenia, the patient was also found to have severe anemia and evidence of hemolysis on laboratory evaluation. A peripheral smear revealed numerous schistocytes consistent with MAHA. The patient was started on plasma exchange and an ADAMTS13 activity level was sent off which later returned as < 5% and a high ADAMTS13 inhibitor titer consistent with acquired TTP.

Thrombotic Thrombocytopenic Purpura Pearls:

  • TTP is defined as a severe deficiency in ADAMTS13 (less than 10%). It can be hereditary due to inherited mutations (Upshaw-Shulman Syndrome) or acquired by formation of an autoantibody against ADAMTS13.
  • ADAMTS13 is a protein that cleaves von Willebrand factor (vWF). Deficiency in this protein leads to formation of platelet microthrombi in the microvasculature.1

Clinical Presentation:

  • Patients can present with non-specific symptoms such as fatigue, generalized weakness, GI symptoms (nausea, vomiting, abdominal pain), dyspnea, petechiae (or other bleeding), headaches and altered mental status.
  • The classic “pentad” of TTP which includes thrombocytopenia, fever, acute renal failure, and severe neurologic findings is rare and occurs in <5% of patients.2
  • Laboratory evaluation will show severe thrombocytopenia, anemia, and evidence of hemolysis with elevated LDH, low haptoglobin, and increased unconjugated bilirubin. Hemolysis can also elevate the AST, but not the ALT.

Diagnosis:

  • When TTP is suspected, urgent review of the peripheral blood smear is needed.
  • Schistocytes and thrombocytopenia on a peripheral smear is concerning for TTP.
  • ADAMTS13 activity and inhibitor testing should be sent before starting treatment.
  • The diagnosis is confirmed with ADAMTS13 activity < 10%. Acquired TTP will show the presence of ADAMTS13 inhibitor.

Treatment:

  • The mainstay of treatment for TTP is therapeutic plasma exchange. If TTP is suspected, plasma exchange should be initiated while ADAMTS13 testing is pending.
  • The addition of glucocorticoids to plasma exchange and use of rituximab have been shown to improve outcomes and decrease the need for plasma exchange sessions.3
  • Plasma exchange should be continued daily until platelet count recovery.

References:

  1. George JN, Nester CM. Syndromes of thrombotic microangiopathy. N Engl J Med 2014; 371:654.
  2. Griffin D, Al-Nouri ZL, Muthurajah D, et al. First symptoms in patients with thrombotic thrombocytopenic purpura: what are they and when do they occur? Transfusion 2013; 53:235.
  3. Som S, Deford CC, Kaiser ML, et al. Decreasing frequency of plasma exchange complications in patients treated for thrombotic thrombocytopenic purpura-hemolytic uremic syndrome, 1996 to 2011. Transfusion 2012; 52:2525.

Cox’s Conference: Mucormycosis

In this week’s Ambulatory Cox’s Conference, Dr. Jasmine Sukumar presented a case of a 50 year old man with history of alcohol cirrhosis, uncontrolled diabetes, and rectal cancer on chemotherapy who presented with right sided vision loss for 1 day. Our expert discussant, Dr. Pearlie Chong guided us through infectious complications to consider in an immunocompromised host.

The differential diagnosis for our patient with acute persistent vision loss included diabetic retinopathy with vitreous hemorrhage, retinal detachment, glaucoma, retinal artery or vein occlusion, optic neuritis, and giant cell arteritis. On exam the patient was found to have swelling and redness of the right eye with associated cranial nerve deficits. Based on the exam and the patient’s past medical history, we had to consider potentially less common etiologies of vision loss including intracranial malignancy (or metastasis), CMV retinitis, or invasive fungal infection. Imaging of the head and sinuses revealed thickening of the right ethmoid and maxillary sinus as well as a large soft-tissue mass in the retroorbital area. Surgical biopsies were performed that showed broad, irregularly branched hyphae with rare septations consistent with Rhizopus oryzae.

Mucormycosis Pearls:

·     Mucormycosis is a life-threatening fungal infection that typically affects immunocompromised patients as well as those with diabetes mellitus.

·     Infections in humans are most commonly caused by Rhizopus, Mucor, and Rhizomucor. These organisms are ubiquitous in nature and commonly found in soil and decaying vegetation.

·     In addition to immunocompromised patients, those with hemochromatosis (particularly those receiving deferoxamine therapy) and burn/trauma patients are also at risk of mucormysosis.

Clinical Presentation:

·     Most common clinical presentation in rhino-orbital-cerebral infection caused by inhalation of spores into the paranasal sinuses.

o     Common presenting complaints are fever, headache, nasal congestion, purulent nasal discharge, and sinus pain.

o     If the infection spreads beyond the sinuses, nearby structures can be involved resulting in perinasal swelling, palate eschars, and erythema or necrosis of the skin overlying the sinuses or orbit.

o     Signs of orbital involvement include periorbital edema, proptosis, and blindness as in our patient. Spread to the nearby cavernous sinus can result in cranial nerve palsies.1

·     Mucormycosis can also present with pulmonary, gastrointestinal, cutaneous, renal, or isolated CNS involvement. Disseminated disease occurs in severely immunocompromised patients.

·     Interestingly, many diabetic patients had ketoacidosis at the time of presentation.2

Diagnosis:

·     As Mucormycosis is a rapidly progressive, fatal disease, prompt diagnosis and empiric treatment is crucial.

·     Diagnosis relies on identification of the organism in tissue by histopathology, which requires a tissue biopsy. Cultures often yield no growth.

·     The 1,3-beta-D-glucan assay and the Aspergillus galactomannan assay will be negative in these patients.

Treatment:

·     Treatment requires both surgical deridement of involved tissues as well as antifungal therapy.

·     It is also important to eliminate any potential predisposing factors for this infection including hyperglycemia, deferoxamine administration, immunosuppressive medications, and neutropenia.

·     First line therapy is intravenous amphotericin B at 5-10mg/kg daily. After a patient has shown clinical improvement, the patient can be transitioned to posaconazole.3

·     Some data suggests improved patient outcomes with addition of caspofungin to amphotericin B compared to amphotericin B monotherapy. However larger studies are needed to establish whether combination therapy is truly beneficial.4

·     Despite appropriate antifungal therapy, aggressive surgical debridement is required for adequate disease control.

References:

1.     Yohai RA, Bullock JD, Aziz AA, Markert RJ. Survival factors in rhino-orbital-cerebral mucormycosis. Surv Ophthalmol 1994; 39:3.

2.     McNulty JS. Rhinocerebral mucormycosis: predisposing factors. Laryngoscope 1982; 92:1140.

3.     McCarthy M, Rosengart A, Schuetz AN, et al. Mold infections of the central nervous system. N Engl J Med 2014; 371:150.

4.     Reed C, Bryant R, Ibrahim AS, et al. Combination polyene-caspofungin treatment of rhino-orbital-cerebral mucormycosis. Clin Infect Dis 2008; 47:364.

Cox Conference: Ipilimumab-Induced Hypophysitis

In this week’s Ambulatory Cox’s Conference, Dr. Namrah Siddiq presented a case of a man with history of malignant melanoma on ipilimumab who presented with nausea, vomiting, and altered mentation. Further evaluation discovered that the patient had severe hyponatremia. Our expert discussant, Dr. Jessica Abramowitz guided us through immune checkpoint inhibitor related endocrinopathies.

Our differential diagnosis for an elderly patient with nausea, vomiting, and altered mental status initially included commonly encountered illnesses including viral gastroenteritis, urinary tract infection, dehydration, small bowel obstruction, malignancy (gastrointestinal tract tumor or metastatic disease), medication side effects, and metabolic disturbances. After we discovered the patient had a history of melanoma and was on ipilimumab, an immune checkpoint inhibitor that targets CTLA-4, our differential broadened to include ipilimumab-related enterocolitis, hepatitis, and hypophysitis. In the setting of severe hyponatremia, the patient was found to have an AM cortisol of 1 mcg/dL, undetectable TSH, and low free T4. Findings were consistent with hypophysitis, a known adverse effect of immune checkpoint inhibitors.

Immune Checkpoint Inhibitor Induced Hypophysitis Pearls:

  • Immune checkpoint inhibitors are a type of immunotherapy that use a patient’s immune system to fight their disease. They have provided significant benefit for a range of different cancer types and in patients who may not have had good treatment options in the past.
  • A number of immune-mediated adverse reactions have been described including enterocolitis, hepatitis, dermatitis, pneumonitis, nephritis, encephalitis/aseptic meningitis, myocarditis, and endocrinopathies (thyroid disease, diabetes, hypophysitis, and adrenal insufficiency). – NEJM paper.1
  • Hypophysitis is an inflammation of the pituitary gland with varying effects on pituitary hormone function. Most commonly presents with central adrenal insufficiency but may have central hypothyroidism, diabetes insipidus, or hypogonadism.
  • Hypophysitis has been described in 11-17% patients on ipilimumab. Ipilimumab in particular appears to most commonly be associated with hypophysitis.2

Clinical Presentation:

  • Patients will typically present with a constellation of symptoms including headache and vision changes along with symptoms of the various hormone deficiencies:
    • ACTH Deficiency – More mild symptoms ranging from fatigue, anorexia, weight loss, nausea/vomiting, postural hypotension, and tachycardia to severe symptoms including vascular collapse or death. Patients may have hyponatremia due to inappropriate secretion of antidiuretic hormone.
    • TSH Deficiency – Fatigue, cold intolerance, decreased appetite, constipation, dry skin, bradycardia, menstrual irregularies, and anemia.
    • FSH/LH Deficiency – Amenorrhea, infertility, hot flashes, and low libido.

Diagnosis:

  • Tests to order include electrolytes (BMP), morning cortisol, TSH and free T4, and ACTH.
  • Can consider ordering LH, FSH, and testosterone levels in males or premenopausal females with complaints of fatigue, loss of libido, and mood changes.
  • Consider MRI of brain with pituitary/sellar cuts in patients with multiple endocrine abnormalities.3
  • Patients with hypophysitis will have low ACTH and low cortisol, low or normal TSH with a low free T4, and low testosterone or estradiol with low LH and FSH.
  • Metabolic abnormalities can occur. In the case of central adrenal insufficiency and hypothyroidism, will have hyponatremia. With central diabetes insipidus, patients can have hypernatremia and volume depletion.

Treatment:

  • Temporarily withhold ipilimumab for symptomatic endocrinopathies.
  • Initiate appropriate hormone replacement therapy. In this case, the patient was started on stress dose steroids, hydrocortisone 150mg per day divided into 3-4 doses. He was also started on IV levothyroxine for thyroid hormone replacement.
  • It is important to use steroids with both glucocorticoid and mineralocorticoid effects such as hydrocortisone.
  • When a patient has hypophysitis with adrenal insufficiency and hypothyroidism, it is important to give the corticosteroids prior to thyroid hormone to prevent precipitating adrenal crisis.
  • After the endocrinopathies are stabilized on replacement hormones, patients can be restarted on ipilimumab with close monitoring by an endocrinologist.
  • Educate patients on increasing steroids during times of illness or surgery. They should also be told to get a medical alert bracelet for adrenal insufficiency. 3

References:

  1. Postow MA, Sidlow R, Hellman MD. Immune-Related Adverse Events Associated with Immune Checkpoint Blockade. NEJM 2018.
  2. Faje A. Immunotherapy and hypophysitis: clinical presentation, treatment, and biologic insights. Pituitary 2016; 19:82.
  3. Brahmer JR, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2018.