Fever in post-transplant (solid organ) patient

liver

Thanks Diana for an excellent case! Also thanks to our special guests Joseph Ahn and Michael Loudin for their pearls. This was a middle age patient s/p liver transplant 1 month ago presenting with fevers, abdominal pain, and fatigue found to have PTLD.

Main points:

  • (1) the approach to a patient with fevers after a recent solid organ transplant should also include asking questions related to: pre-transplant screening, peri-op course, and transplant-related medications
  • (2) the differential diagnosis of fever in a post-solid organ transplant recipient can be categorized as: (1) infection (2) rejection (3) med-related (4) PTLD or (5) progression of pre-tx underlying dz (for more on infections, see this excellent NEJM & MKSAP17 ID Ch17)
  • (3) use the 3 T's: to narrow down the differential diagnosis - TIME from transplant, TYPE of drugs used, TRANSPLANTED organ

Want to learn more?

Differential dx for post-solid organ transplant and fever

  • (1) infection
    • remember to break down roughly into (1) < 1 month (2) 1-6 months and (3) 6 months+ after the infection (see table below)
    • if < 1 month think: nosocomial (MRSA, GN's, C diff), surgical site (eg post-op bile duct stricture -> abscess formation), and donor related
    • if 1-6 months think: 2/2 opportunistic/ latent reactivation (ask: how much immunosuppression? how are prophylaxis meds being taken?)
    • if > 6 months think: community acquired (may be subtle), latent viral, fungal
  • (2) rejection - acute cellular rejection happens w/in 90 days
  • (3) medication side effect - (eg azathioprine tox)
  • (4) PTLD - illness script: EBV asso B lymphocyte proliferation 2/2 high immunosuppression 1-6+ months post-transplant presenting as mono-like illness +/- lymphadenopathy, abdominal masses
  • (5) progression of underlying disease - viral hepatitis, PBC/PSC, AIH
solid organ timeline

Medications used in post-solid organ transplant

Medications after solid organ transplant can be divided into immunosuppressive medications and prophylaxis medications

Immunosuppressives include:

  • (1) steroids
  • (2) direct cytotoxic (eg azathioprine, MMF)
  • (3) calcineurin inhibitors (eg tacro, cyclosporin)
    • be aware of: pharmacokinetics, nephrotoxicity
  • (4) mTOR inhibitors (eg sirolimus/ rapamycin)
  • (5) lymphocyte depleting (eg ATG - polyclonal, monoclonal Abs eg muronomab)

Prophylaxis usually consists of:

  • TMP-SMX - for PJP (but also toxo, some UTI's, listeria, nocardia)
      • recall that dapsone etc can be used but coverage will be less broad
  • valgancyclovir - if risk for CMV

Hypercalcemia Management

Today we discussed management of hypercalcemia of malignacy. Below is a useful table adopted from UpToDate and Sternlicht H, Glezerman IG. Hypercalcemia of malignancy and new treatment options. Ther Clin Risk Manag. 2015;11:1779–1788.

Dr. Kaitlin Brooke's Key Learning Points:

  • The majority of hypercalcemia of malignancy is PTHrP related, 20% is the result of bony metastasis with 1,25 dihydroxy Vitamin D and less than 1% are related to ectopic PTH production
  • Denosumab is effective for hypercalcemia of malignancy and not contraindicated in AKI or CKD, but can cause dangerous hypocalcemia in patients with impaired renal function
  • It is likely safe to treat patients with hypercalcemia of malignancy and sCr less than 4.5 with zoledronic acid
  • Patients with advanced underlying kidney disease and refractory severe hypercalcemia should be considered for hemodialysis
  • Hypercalcemia of malignancy indicates a poor prognosis on the order of months

Acute Liver Failure

Today we discussed an interesting case of acute liver failure in a middle aged woman, which was ultimately diagnosed as autoimmune in etiology.

Here are the learning points:

  • Acute liver failure is characterized by acute liver injury, hepatic encephalopathy, and elevated INR >1.5 in a patient without cirrhosis or preexisting liver disease.
  • It can be subdivided into hyperacute (less than 7 days), acute (7-21 days) or subacute (greater than 21 days, less than 26 weeks).
  • DDx is vast including acetaminophen toxicity, drug-induced liver injury, viral hepatitis, alcoholic hepatitis, autoimmune hepatitis, ischemic hepatopathy, sepsis, Budd-Chiari syndrome, acute fatty liver of pregnancy/HELLP, toxin exposure -- to a name a FEW!
  • Using LiverTox can help you search for possible causes of drug-induced liver injury.

Dr. Anil Sharma had excellent learning points specifically regarding autoimmune hepatitis including:

1) The diagnosis of autoimmune hepatitis is complex and based upon a number of clinical, biochemical, serologic, and histologic findings (and exclusion of other forms of liver disease).

2) AST and ALT are elevated (range from mild elevations to greater than 1000 U/L), ALP is normal to mildly elevated, serum IgG levels are also elevated, anti-smooth muscle or antinuclear antibodies are typically present, and classic histologic findings include interface hepatitis (biliary tree sparing) and lymphoplasmacytic infiltrates.

3) The newer F-actin ELISA seems to be a useful diagnostic tool for autoimmune hepatitis.

Approach to bloating

Thanks Miles for presenting an excellent case on a middle age male coming in with acute-subacute progressive constipation and bloating, new ascites with a diagnosis of peritoneal carcinomatosis of unknown primary.

peritoneal carcinomatosis

Learning points:

  • 1) When a patient comes in with bloating, ask whether alarm symptoms are present eg. anemia, unintential wt loss, progressive, new onset in elderly
  • 2) The differential diagnosis for bloating can be broken down into anatomic, malabsorption, drugs, functional, infection, and neurologic
  • 3) Biomarkers and genetic testing are helpful for diagnosis of carcinoma of unknown primary because it may identify the primary in some cases and can guide treatment. You can set up a free account to access the NCCN guidelines to learn more.

Want more info?

Differential diagnosis for bloating

  • When a patient comes in with bloating, ask about distention, gassiness, and stool quality as well as red flag sx
  • 1) anatomic
    • a) obstruction/ partial obstruction
    • b) gastroparesis
    • c) malignancy - classically ovarian carcinoma
    • d) constipation
  • 2) malabsorption - lactose intolerance, celiac, gluten sensitivity
  • 3) drugs - Ca supplements, consumption of large amts of fiber, any constipating drugs (eg opiates, antihypertensives, anticholinergics, vitD, heavy metals, etc)
  • 4) functional
    • a) functional bloating/ dyspepsia
    • b) aerophagia
    • c) IBS
    • d) dyssinergic defecation -> constipation
  • 5) infection
    • a) giardia, cyclospora
    • b) SIBO
  • 6) neurologic
    • a) dysmotility - connective tissue dz
    • b) Hirschsprung's

Ddx of radiographic "peritoneal carcinomatosis"

  • Malignancy: metastatic dz from bladder, colon, gastric, breast, pancreatic, lung, lymphoma vs
  • Non-malignancy: TB, sarcoidosis, crohn's, endometriosis
  • This NEJM has a nice table of other tumors of the peritoneum that could be considered

Hypercalcemia and malignancy

Thanks Daniel for presenting a great case! This was a case of an elderly patient with subacute-chronic fatigue and constipation presenting with hypercalcemia with both elevated PTH and PTHrp.

Main points:

  • 1) Hypercalcemia of malignancy is associated with solid and liquid tumors: breast, lung, kidney cancer & multiple myeloma, lymphoma, leukemia (think: what causes lytic lesions? also squamous solid tumors)
  • 2) EKG findings include short QT intervals and wide T waves => a combination => Osborn waves
  • 3) The approach to hypercalcemia should involve considering PTH mediated and non-PTH mediated causes

Want to learn more?

Approach to lytic lesions

Here is an excellent NEJM with a nice table (table 1) referencing the differential dx for lytic lesions

How useful is a Chloride/ Phosphorus ratio?

Great PICO question associated with this one: A popular 1975 paper found that a chloride/ phosphorus ratio of >33 is sensitive and specific for primary hyperparathyroidism. It was calculated in 34 sugical patients with proven primary hyperparathyroidism and 50 patients with other causes with an average serum calcium of 12.1 with a proposed mechanism that primary hyperPTH -> low phosphorus and disruption with bicarb may lead to reabsorption with chloride. However, some concerns re the paper include that ectopic PTH and PTHrP may have similar mechanisms leading to low phosphorus and it would not work in renal failure or patients with borderline elevated calcium levels. So, something to think about ordering but would still be important to check PTH and PTHrp (tests that may have been much more difficult to order back then).

Treatment of hypercalcemia

Here are the common agents that are used to treat hypercalcemia and +/-

Normal saline: acts in 1-2 hours & Furosemide: acts in 1-2 hours

  • Why give NS and furosemide? – hypercalcemia -> nephrogenic diabetes insipidus w dehydration and AKI

Bisphosphonates: acts in 1-2 days; (side effects: AKI, osteonecrosis of the jaw)

Calcitonin: acts in 4-6 hours; IM or SQ

Steroids: acts in days; good for ectopic 1,25OH vitD

Cinacalcet: treatment of secondary hyperparathyroidism

Denosumab: hypercalcemia of malignancy that has not responded to bisphosphonates

Vitamin D: for PTH mediated and if patient has low 25OH vitamin D

TP-NOCA

Today Linda brought us a striking case of Troponin Positive Non-obstructive Coronary Artery Myocarditis. Some learning points from Linda:

  • When facing the syndrome of MINOCA (MI w/nonobstructive coronary arteries) or TP-NOCA (troponin-positive nonobstructive coronary arteries), consider cardiac MRI to evaluate for myocarditis. The classic pattern on MR is patchy delayed gadolinium enhancement of the myocardium
  • Three distinct groups of myocarditis- idiopathic, viral, and inflammatory
  • Presentations of acute myocarditis with chest pain or dysrhythmia have higher rates (as high as 50%) of spontaneous remission.

TB or Not TB!

Whether ‘tis nobler in the mind to suffer the slings and arrows of a Quantiferon-Gold
Or to take arms against an induced sputum PCR
And by admitting, rule out
To die, to sleep
-D. Alex Perry, MD

That is the question in our noon report today.

Dr. Perry led us through a case where we were reminded to avoid premature closure. Similarly, there is a prospective multi-center French study which developed a predictive model based on risk factors including immigrant status, BCG immunization, HIV infection, homlessness, clinical symptoms and chest x-ray findings. Tattevin, P. et al “The validity of medical history, classic symptoms, and chest radiographs in predicting pulmonary tuberculosis.” Chest.1999 115:1248-55

Additionally, we discussed the differential for night sweats which helped broaden the differential. Night Sweats

  • Malignancy
    • Lymphoma
    • Solid Tumors (germ cell, meduallary thryoid carcinoma, prostate cancer, renal cell carcinoma)
  • Infections
    • Myobacterial (TB and atypical mycobacteria)
    • Bacterial (abscess, brucellosis, endocarditis, osteomyelitis)
    • Fungal
    • Viral (HIV, HCV)
  • Medications (several, a brief list is included)
    • Antidepressants (Buproprion, SSRIs, SNRIs, TCAs)
    • NSAIDs
    • Aromatase Inhibitors
    • Cholinergic Agonists
  • Substance Withdrawl (alcohol, cocaine, opioids)
  • Endocrine Disorders
    • Carcinoid
    • Hyperthryoidism
    • Pheochromocytoma
  • Menopause
  • Miscellaneous (includes panic disorder and temporal arteritis to name a few)