What to Do in Case Of.......: A Reference Diagnostic Guide in Thoracic Organ Transplantation

Horne.

Section I: GASTROINTESTINAL DISEASES

CHAPTER 1: DIARRHEA

Saima Aslam and Kate Gould

I. General Concepts and Definitions

Diarrhea consists of ≥ 3 unformed stools per 24-hour period. Alternatively, it can also be defined as an increased frequency and/or decreased consistency of stools from the patient’s baseline. Acute diarrhea generally lasts for several days, persistent diarrhea lasts for ≥10-14 days, and chronic diarrhea refers to diarrhea ≥1 month.

II. Etiologies

A. Specific infections

1. Viruses: Cytomegalovirus (CMV), norovirus, sapovirus, rotavirus, enteric adenovirus, coxsackie virus.

2. Bacteria: Clostridium difficile, Salmonella sp, Campylobacter s p, Escherichia coli, Shigella sp, Vibrio sp, Listeria monocytegenes, Yersiniasp, Staphylococcusaureus, Bacillus cereus, Clostridium perfringens, Archaebacteria .

3. Protozoa: Giardia lamblia, Entamoeba histolytica, Cryptosporidium parvum, Cytoisospora belli, Cyclospora cayetanensis, Dientamoeba fragilis, Blastocystis hominis .

4. Fungi: Histoplasma capsulatum, Microsporidia sp.

5. Mycobacteria: Mycobacterium tuberculosis, M. avium complex.

6. Helminths/Parasites: S trongyloides stercoralis, Balantidium coli, Schistomosoma sp, Toxocara sp, Trichinella spiralis, Clonarchis sp, Fasciola hepatica .

B. Noninfectious

1. Drugs: mycophenolate mofetil (MMF), laxatives, antibiotics, tacrolimus, cyclosporine A, sirolimus, everolimus, azathioprine.

2. Post-transplant lymphoproliferative disease (PTLD).

3. Tube feeds, oral contrast.

4. Malabsorption syndromes.

5. Abdominal disorders: diverticulitis, appendicitis, abdominal abscess, ischemic colitis, neutropenic enterocolitis, typhlitis, inflammatory bowel disease (IBD; Crohn’s disease and ulcerative colitis), proctitis (gonorrhea, syphilis, herpes simplex virus, Chlamydia trachomatis ), radiation enteritis, eosinophilic gastroenteritis.

III. Clinical Assessment

A. When evaluating patients with diarrhea, one of the foremost clinical considerations is to evaluate the severity of dehydration and to treat it appropriately in addition to identifying/ treating the underlying etiology. A syndromic approach may provide diagnostic clues in order to identify the etiology.

B. Specific syndromes

IV. Diagnosis

A. First tier diagnostics

1. Stool sample for fecal leukocytes, C. difficile PCR (or ELISA testing if PCR is not available), microscopy for ova and parasites (generally 3 daily samples are needed), bacterial culture (specify for Salmonella , Shigella , Campylobacter , Vibrio , Yersinia and E. coli 0157:H7), and mycobacterial stain and culture.

2. Computed tomography (CT scan of the abdomen and pelvis (with IV and PO contrast if renal function allows) and chest X-ray.

3. Blood sample for CMV PCR and bacterial culture (2 sets), complete blood count with differential, electrolytes, blood urea nitrogen and creatinine, liver function test, serum lactate.

B. Second tier diagnostics

1. Stool sample for E. histolyctica PCR (may be first tier depending on geographic variance), rotavirus antigen, norovirus antigen, adenovirus antigen, G. lambia immunostain/ELISA, Crysptosporidium immu-nostain/ELISA.

2. Blood for S. stercoralis serology (again dependent on geographic variance), Interferon Gamma Release Assays for tuberculosis (or a PPD).

3. Urine sample for H. capsulatum antigen.

4. Colonoscopy or sigmoidoscopy with biopsy. Need to send tissue for both pathology (including CMV immunostains, fungal and mycobacterial stains) as well as culture-bacterial, fungal and mycobacterial.

C. Third tier diagnostics

1. Upper GI endoscopy plus biopsy and/or jejunal aspirates for G. lamblia.

2. Laparoscopy and biopsy of lymph nodes.

D. Additional testing may be indicated depending on patient specifics as well as the presenting clinical syndrome.

V. Comments

A. MMF: A common cause of diarrhea in the outpatient setting is the use of MMF. A trial off the drug is recommended prior to looking for other causes in the absence of a clear diarrhea syndrome.

B. Empiric antibiotics: In the absence of a clear etiology are not advised. Some of the causes of nosocomial diarrhea will be a process of exclusion of infectious agents. Transplant recipients may excrete pathogens for longer than the non-immunocompromised patients and symptoms may take longer to settle as well.

C. C. difficile: Follow up samples to document clearance of an infection, especially for C. difficile, are not usually indicated. Monitor C. difficile patients closely; if symptoms do not resolve or they develop ileus/severe pain, life-saving surgery may be indicated.

VI. Recommended Bibliography

[1] Krones E, Högenauer C. Diarrhea in the Immunocompromised Patient. Gastroenterology Clinics of North America. Sept 2012; 41 (3): 677-70.1.

[2] Helderman JH, Goral S. Gastrointestinal Complications of Transplant Immunosuppression. Journal of American Society Nephrology. 2002; 13: 277-87.

[3] Luciano JA, Zuckerbraun BS. Clostridium difficile infection: prevention, treatment, and surgical management. Surg Clin North Am. 2014 Dec; 94(6): 1335-49.doi:10.1016/j.suc.2014.08.006. Epub 2014 Sep 27. Review. PMID: 25440127.

CHAPTER 2: NAUSEA AND VOMITING

Macé M. Schuurmans and Valentin Cuervas-Mons

I. General Concepts and Definitions

A. Definition: Nausea is an unpleasant sensation of being about to vomit. It can occur alone or can accompany vomiting, the forceful expulsion of gastric contents. Retching differs from vomiting in the absence of expulsion of gastric content.

B. The normal functioning of the upper gastrointestinal tract involves an interaction between the gut and the central nervous system. The motor function of the gut is controlled by the parasympathetic and sympathetic nervous systems, enteric brain neurons and smooth muscle cells. For example, extensive distension of the gut will induce pain via serosal stretch receptors whose output passes via sympathetic neurons to the central nervous system leading to nausea and/or vomiting.

C. In the thoracic transplant recipient nausea and vomiting should primarily draw attention to adverse drug events, delayed passage of bowel content in upper or lower gastrointestinal tract and localized or generalized infections. Vomiting is of special concern because drug resorption of immunosuppressants may be affected and aspiration of intestinal content may lead to infection and may therefore trigger allograft dysfunction in lung transplant recipients.

D. Nausea and vomiting (N/V) can be associated with loss of appetite, abdominal discomfort or reduced stool frequency and increased stool consistency suggesting reduced transit of intestinal contents and making gastric retention or constipation the likely explanation. In the thoracic transplant recipient constipation or stool retention frequently goes unnoticed. Sometimes even diarrhea is reported by the patient despite substantial stool retention (paradoxical diarrhea).

E. The abdominal plain film can help localize some of these conditions of reduced passage of the intestinal content, exclude free air as sign of intestinal perforation and direct further investigations or treatment. In contrast to immunocompetent patients, constipation is difficult to detect based on clinical examination and requires imaging. It may even be associated with an unexplained inflammatory reaction or suspected infection.

F. If the etiology of the nausea or vomiting is not easily determined, the diagnostic workup should be rapidly undertaken and empirical treatment (antiemetics, laxatives, correction of electrolytes and fluid depletion) should be given to prevent complications such as aspiration or kidney dysfunction.

II. Etiologies

A. Most frequent causes in cardiothoracic transplant recipients.

1. Medication adverse events: mycophenolate, tacrolimus, cyclosporine, azathioprine, antibiotics.

2. Reduced motility of upper or lower intestinal tract: gastroparesis/gastric retention or, copro-stasis/stool retention.

3. Reduction in use/dosing of prokinetics and laxatives.

4. Stomach or peptic ulcer disease: Helicobacter pylori infection.

5. Infection with norovirus or Clostridium difficile .

B. Other causes of nausea and vomiting

Medications and toxic etiologies

Infectious causes

Disorders of the gut and peritoneum

Non-ulcer dyspepsia, Peptic ulcer disease, Gastric outlet obstruction, Gastroparesis, Intestinal pseudo-obstruction, Small bowel obstruction, Distal intestinal obstruction syndrome, Colitis Perforation, Cholecystitis, Hepatitis, Pancreatitis, Appendicitis, Irritable Bowel Syndrome

Endocrinologic and metabolic causes

Pregnancy, Uremia, Diabetic ketoacidosis, Thyroid disorders, Hyperparathyroidism, Hypoparathyroidism, Addison’s disease

Central Nervous System causes

Miscellaneous causes

III. Clinical Assessment

A. History

1. Duration and severity of nausea and vomiting, gastrointestinal discomfort, dyspepsia, use of antiemetics and laxatives, stool frequency and consistency, changes in laxative treatment or other medication (including non-prescription drugs), history of food intake and nausea or vomiting of persons eating same food, early satiety, regurgitation, fullness, and bloating (suggestive symptoms of gastroparesis), vomiting of food eaten several hours earlier (suggest gastroparesis, gastric retention or gastric obstruction), abdominal distension and tenderness (suggest bowel obstruction), abdominal pain or jaundice (suggestive of organic etiology), and heartburn with nausea (suggestive of GERD).

2. Vomiting before or after intake:

- vomiting before breakfast (fasting vomiting): pregnancy, alcohol, increased intracranial pressure, and uremia;

- vomiting appearing shortly after ingestion, or a few minutes later: usually indicates irritation of the gastric mucosa;

- vomiting of partially digested food eaten several hours, or a day after a meal (retention vomiting) suggests, gastric outlet obstruction (e.g., from peptic ulcer disease or neoplasm), or gastroparesis;

- vomiting feculent or odorous material is a sign of distal smallbowel obstruction and blind-loop syndrome.

3. Presence of blood: vomiting bright red blood may be the first sign of Candida esophagitis, Cytomegalovirus or Herpes simplex esophagitis; rare cases of massive gastrointestinal hemorrhage include visceral Kaposi’s sarcoma and post-transplant lymphoproliferative disorders (PTLD); PTLD can involve the gastrointestinal tract in up to 5 % of transplant recipients; the disease is often heralded by hemorrhage or by acute abdomen from perforation or obstruction.

B. Physical examination

1. Specific findings

a. Distension

b. Main location of pain (localized, diffuse)

c. Bowel sounds

d. Signs of peritonitis on percussion

e. Tenderness on palpation

f. Digital rectal examination (mass, blood, pain)

2. Severe immunosuppression in combination with some prophylactic medication may mask typical signs and symptoms in the thoracic transplant recipient. Therefore, additional investigations are frequently advisable.

IV. Diagnosis

A. Initial basic workup: Test and clinical suspicion

1. Complete blood count: leukocytosis in an inflammatory process, reduced hemoglobin in bleeding.

2. Electrolytes including magnesium: consequences of nausea and vomiting (e.g. acidosis, alkalosis, azotemia, hypokalemia).

3. Drug levels of immunesuppressants (mycophenolate, tacrolimus, and cyclosporine).

4. C-reactive protein or erythrocyte sedimentation rate: inflammatory process.

5. Pancreatic/liver enzymes: for patients with upper abdominal pain or jaundice.

6. Radiographic testing: supine and upright abdominal plain film radiography to localize mechanical obstruction or retention of bowel content (coprostasis), free air indicating intestinal perforation.

B. Extensive workup

1. If initial basic workup remained non-conclusive or symptoms suggest specific organ dysfunction, additional tests may be advisable.

a. Pregnancy test: for any female of childbearing age.

b. Protein/albumin: chronic organic illness or malnutrition.

c. Specific toxins, microorganisms: stool: Clostridium difficile, Campylobacter, Salmonella, Shigella, Norovirus, Microsporidia and Cryptosporidia , other endemic organisms.

d. Thyroid-stimulating hormone: for patients with signs of thyroid toxicity or otherwise unexplained nausea and vomiting.

e. Viral load of Epstein-Barr Virus (EBV) and Cytomegalovirus (CMV) in peripheral blood.

f. Tissue sampling for specific pathogens.

2. Further endoscopic or imaging studies

a. Esophagogastroduodenoscopy: mucosal lesions (ulcers), proximal mechanical obstruction.

b. C13 Urea Breath Test: a rapid diagnostic procedure used to identify infections by Helicobacter pylori .

c. Computed tomography with oral and intravenous contrast media: obstruction, optimal technique to localize other abdominal pathology.

d. Upper gastrointestinal radiography with barium contrast media: mucosal lesions and highergrade obstructions; evaluates for proximal lesions.

e. Small bowel follow through: mucosal lesions and higher-grade obstructions; evaluates the small bowel to the terminal ileum.

f. Enteroclysis: small mucosal lesions, small bowel obstructions, small bowel cancer.

g. Gastric emptying scintigraphy: gastroparesis (suggestive).

h. Antroduondenal manometry: primary or diffuse motor disorders.

i. Abdominal ultrasonography: right upper quadrant pain associated with gallbladder, hepatic, or pancreatic dysfunction.

j. Colonoscopy: lower endoscopy for unclear cases including biopsy (e.g. CMV).

k. Magnetic resonance imaging of the brain: intracranial mass or lesion.

l. Cutaneous electrogastrography: gastric dysrhythmias.

V. Comments

The radiological diagnosis of stool retention (coprostasis) may rely on subtle imaging information and can be missed or considered within normal limits even by radiologists. Suggestive features are lack of air in the intestine or visible stool masses in one or more areas of the large or small intestine. Partial or complete ileus with air/fluid levels are more advanced stages.

VI. Recommended Bibliography

[1] Scorza K, Williams A, Phillips JD, et al. Evaluation of nausea and vomiting. Am Fam Physician. 2007 Jul 1; 76(1):76-84. Review. PubMed PMID: 17668843.

[2] Hornbuckle K, Barnett JL. The diagnosis and work-up of the patient with gastroparesis. J Clin Gastroenterol. 2000 Mar;30(2):117-24. Review. PubMed PMID: 10730917.

[3] Schuurmans MM, Tini GM, Zuercher A, et al. A. Practical approach to emergencies in lung transplant recipients: how we do it. Respiration. 2012; 84(2):163-75.

[4] Longstreth GF. Approach to adult with nausea and vomiting. Uptodate.com. Last updated Apr 5, 2013. Accessed 4.7.2014.

[5] Assessment of nausea and vomiting, adults. Step-by-step diagnostic approach. BMJ Best Practice. Last updated: Jul 08, 2013. Accessed 4.7.2014. http://bestpractice.bmj.com/best-practice/monograph/631.html

[6] Quigley EM, Hasler WL, Parkman HP. AGA technical review on nausea and vomiting. Gastroenterology. 2001; 120:263-286.

CHAPTER 3: GASTROESOPHAGEAL REFLUX DISEASE (GERD)

C. Ribes-Koninckx and Manreet Kanwar

I. General Concepts and Definitions

A. GERD is a chronic digestive disease caused by lower esophageal sphincter abnormality resulting in backwash (reflux) of gastric acids into the esophagus causing irritation of the esophageal lining. Irrespective of the etiology of lung disease, GERD in lung transplant (LTx) recipients is very common and is associated with decreased survival and attenuated early allograft function.

B. Incidence of erosive esophagitis (a complication of GERD) is significantly increased in solid organ transplant recipients and is associated with a higher risk for esophageal cancer. This increase was found to be associated with the type and duration of immunosuppressive therapy.

II. Etiologies

GERD is usually not caused by infectious agents. Common associations include hiatal hernia, gastroparesis, asthma, Crohn’s disease, peptic ulcers, diabetes mellitus, and scleroderma. Malnutrition, through an impaired tonus of the lower esophageal sphincter, is also a relevant GERD predisposing factor.

III. Clinical Assessment

Transplant patients with GERD may be asymptomatic or present with acute rejection, early BOS, vomiting.

Manifestations of GERD

IV. Diagnosis

A. No single symptom or cluster of symptoms can reliably be used to diagnose esophagitis or other complications of GERD or to predict which patients are most likely to respond to therapy. The reliability of symptoms to make the clinical diagnosis of GERD is high in adolescents; however, many patients can be asymptomatic. In adults, typical symptoms of GERD (heartburn and regurgitation) have modest sensitivity and specificity for detecting GERD and aspiration.

B. Most commonly used procedures to evaluate GERD

1. Upper gastrointestinal (GI) tract contrast radiography: to delineate anatomy and to occasionally document a motility disorder.

2. Esophageal pH and/or impedance monitoring: continuous 24-hour intraluminal esophageal pH monitoring is used to quantify the frequency and duration of esophageal acid exposure. It also determines an absolute number of reflux episodes detected during monitoring and the duration of reflux episodes detected.

3. Multichannel intraluminal impedance (MII): an emerging technology for detecting the movement of fluids from the stomach into the esophagus. It also identifies solid and gaseous refluxes, thereby providing more detailed information of esophageal events than pH monitoring. Combined pH/MII testing is feasible by including MII and pH electrodes on a single catheter and it is the test of choice to detect temporal relationships between reflux (acid and nonacid) and specific symptoms such as apnea and cough.

4. Gastroesophageal scintigraphy scans for reflux of 99mTc-labeled solids or liquids into the esophagus or lungs after administration of the test material into the stomach (not recommended in pediatric patients).

5. Upper endoscopy with esophageal biopsy: allows investigating the esophageal mucosa to both exclude other conditions and evaluate for esophageal injury attributable to GERD. Minimal procedural and sedation risks have to be taken into consideration.

V. Comments

A. Chronic microaspiration secondary to GERD may contribute to lung injury and development of bronchiolitis obliterans syndrome (BOS). Early surgical correction of documented GERD has been proposed as a means to potentially delay the onset of BOS and prolong allograft survival in adults before or after LTx.

B. Proton pump inhibitors do not prevent nonacid reflux and gastric aspiration.

C. Thorough testing for GERD before lung transplantation is advocated and, if identified, aggressive therapy early after transplant, including fundoplication, may prove efficacious.

D. Approach to GERD in thoracic organ transplant recipients

VI. Recommended Bibliography

[1] Murthy SC, Nowicki ER, Mason DP, et al. Pretransplant gastroesophageal reflux compromises early outcomes after lung transplantation. J Thorac Cardiovasc Surg. 2011; 142(1):47-52.

[2] In Soo Kim, Hyuk Lee, Jun Chul Park, et al. Increased Incidence of Endoscopic Erosive Esophagitis in Solid Organ Transplant Recipients. Gut and Liver 2012; 6 (3): 349-354.

[3] Grossman EJ, Shilling RA. Bronchiolitis obliterans in lung transplantation: the good, the bad, and the future. Transl Res. 2009; 153(4):153-165.

[4] Hartwig MG, Davis RD. Gastroesophageal reflux disease-induced aspiration injury following lung transplantation. Curr Opin Organ Transplant. 2012; 17(5):474-8.

[5] Hartwig MG, Anderson DJ, Onaitis MW, et al. Lin SS, Davis RD. Fundoplication after lung transplantation prevents the allograft dysfunction associated with reflux. Ann Thorac Surg. 2011; 92(2): 462-8; discussion; 468-9.

[6] Abbassi-Ghadi N1, Kumar S, Cheung B, et al. Anti-reflux surgery for lung transplant recipients in the presence of impedance-detected duodenogastroesophageal reflux and bronchiolitis obliterans syndrome: a study of efficacy and safety. J Heart Lung Transplant. 2013, 32(6):588-95.

CHAPTER 4: ABNORMAL LIVER ENZYMES

Marina Berenguer and William Stansfield

I. General Concepts and Definitions

A. Liver Function Tests (LFTs) are usually elevated in patterns associated with etiology (although they may be elevated singly as well).

1. Hepatitic: Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ± gammaglutamyl transpeptidase.

2. Cholestatic: Bilirubin and Alkalinine Phosphatase (Alk Phos).

3. Coagulopathic: INR and/or PTT.

B. Symptoms are usually absent, with most LFT elevations identified on screening labs. In severe disease states, accompanying signs and symptoms include nausea, vomiting, jaundice, abdominal pain, or a bleeding diathesis.

II. Etiologies

A. Etiology is strongly related to the initial diagnosis that led to transplant and to the interval between transplant and the LFT finding.

B. Predisposing conditions:

1. Heart Transplant Chronic hepatic congestion: typically, mild to moderate cirrhosis secondary to severe tricuspid regurgitation, primary right ventricular failure, right ventricular failure secondary to left ventricular failure, or pulmonary arterial hypertension secondary to left ventricular failure.

2. Lung Transplant

a. Cystic Fibrosis chronic cholestasis results in varying degrees of liver disease, from mild chronic increased Alk Phos to cirrhosis with portal hypertension. Young age at transplant may give patients more time to develop hepatic complications.

b. Primary pulmonary hypertension causes chronic hepatic congestion and varying degrees of cirrhosis.

c. Interstitial lung disease with pulmonary hypertension-chronic hepatic congestion.

d. Sarcoidosis most commonly hepatic granulomatous disease is asymptomatic. May manifest as granulomatous hepatitis and chronic cholestasis with progression to cirrhosis and portal hypertension.

e. α-1-anti-trypsin deficiency-defective protein products accumulate in the liver slowly causing cirrhosis, independent of pulmonary transplant.

C. Immediate post-transplant hepatic dysfunction

1. Known hepatic dysfunction, even if well compensated, may be severely exacerbated by the stress of the transplant operation.

a. Intraoperative hypotension secondary to cardiac manipulation or low cardiac output state may induce shock liver in a previously well compensated patient.

b. Excessive volume resuscitation intraoperatively or in the early post-operative period may result in hepatic congestion with decompensation.

c. Re-operative sternotomy or thoracotomy may be associated with significant transfusion requirement or prolonged cardiopulmonary bypass, resulting in a consumptive coagulopathy.

2. In heart transplant, causes of right ventricular dysfunction result in hepatic congestion.

3. Elevated pulmonary vascular resistance may not improve with transplant (e.g. the fixed component is greater than expected), resulting in high central venous pressure (CVP).

4. Inadequate pumping function of the right ventricle may be secondary to graft preservation issues, insufficiently sized donor heart, or severe tricuspid regurgitation secondary to technical/anastomotic issues. All result in elevated CVP.

D. Post-transplant hospitalization

1. Lung transplants suffering from primary graft dysfunction may develop pulmonary hypertension, with resultant hepatic congestion.

2. Tylenol® (acetaminophen) is commonly combined with narcotics postoperatively for synergy and careful attention to dosing prevents toxicity.

3. Azole antifungals.

E. Outpatient post-transplant

1. Broad differential: pharmacologic, infectious, toxic, neoplastic, metabolic.

2. Common Pharmacologic Agents

3. Infectious Agents: Viral such as EBV (Ebstein-Barr virus), CMV (cytomegalovirus), HAV (hepatitis A virus), HBV (hepatitis B virus)/HDV (hepatitis delta virus), HCV (hepatitis C virus), HEV (hepatitis E virus), or bacterial such as liver abscess or bacterial cholangitis.

4. Toxic: Acetaminophen overdose, NSAIDs, alcohol assumption.

5. Metabolic disorders: Nonalcoholic steatohepatitis (NASH). The metabolic syndrome (MS) is a cluster of risk factors that predisposes to major cardiovascular diseases, and to liver steatosis and fibrosis. There is a rising incidence of MS among transplanted patients, defined as post-transplant metabolic syndrome (PTMS). Subjects with worse metabolic profiles show lower survival rates and greater comorbidities. MS has been estimated to develop in 43% to 58% of SOT patients, a much higher prevalence than that seen in the general adult population (24%).

6. Neoplasia: post-transplant lymphoproliferative disorders and