Clinical Case Conference

November 30th, 2011Allen Hwang, MD

HPI

• 30 y/o M with h/o cystic fibrosis c/b multiple pneumonias, chronic sinusitis, pancreatic insufficiency, failure to thrive, chronic O2 requirement s/p bilateral lung transplant June, 2010 (CMV D-/R-).

HPI

• Post-operative course relatively uneventful, extubated on POD #1. However, did develop:– prednisone induced glucose intolerance– gastric dysmotility and ileus requiring NGT

decompression– self-limited atrial fibrillation– sinus tachycardia

HPI

• One month post-operatively, developed:– wound infection and PNA requiring admission and

intravenous antibiotics– chronic MDR pseudomonas pneumonia– multiple courses of outpatient antibiotics– acute cellular rejection noted on serial

bronchoscopies

HPI

• Patient endorsed some reflux-type symptoms. Given multiple episodes of rejection and chronic pneumonia, concern for GERD as underlying cause. Patient referred to GI for further evaluation.

HPI

• In clinic, the patient reported intermittent nausea, early satiety, and rare emesis containing undigested food. He has not gained any weight since his transplant surgery. Mild dyspepsia controlled with PPI.

• Of note, he denies odynophagia, abdominal pain, dysphagia, hematemesis, diarrhea, or other changes in his bowel movements.

PMH

• As mentioned, CF c/b PNA, sinusitis, panc insuff, s/p B lung transplant c/b Pseudomonal infection and rejection

• Corticosteroid induced diabetes• Sinus tachycardia

PMH

• FH: non-contributory• SH: works in office• Tob: none• Alc: none• IVDU: none

Medications

• Alendronate• ASA• Atovaquone• Calcium/VitD• Ferrous sulfate• Magnesium oxide• Metoprolol

• Mometasone• Omeprazole• Pancrelipase• Miralax• Prednisone• Tacrolimus• Valacyclovir

Allergy to Zosyn, Bactrim

Exam

• BP 110/70 P 100 T 98.1 RR 18• NAD• Trachea midline• Bibasilar rhonchi• RRR no m/r/g• soft, NT, ND, NABS, no succussion splash• Surgical scars present• Thin

Labs

• WBC 5.5, Hb 10.8, MCV 94.2, Plt 275• Albumin 4.5, Total Protein 7.6• TB 0.4, AST 17, ALT 15, AP 54• Na 140, K 4.4, Cl 106, CO2 20, BUN 44, Cr 1.42• PTT 36, INR 1.25

Labs

• Bronchoscopy/pathology– Lung, right middle and lower lobes, transbronchial

biopsy: Fragments of alveolated lung parenchyma with minimal acute cellular rejection, OISHLT Grade A1

LabsMany Pseudomonas aeruginosa, Mucoid Strain Source: Bronch Wash 11-301-03081 ORGANISM

F Piperacillin-tazobactam R F Ceftazidime R F Cefepime R F Meropenem R F Amikacin R F Gentamicin R F Tobramycin R F Levofloxacin R

What do you think?

• What is causing his nausea, vomiting, and early satiety?

• Do you believe that his GERD is contributing to his rejection and infections?

• Are there studies that you would like to perform before deciding?

Gastric emptying study

• The residual activity within the stomach is 95% at one hour, 94% at two hours, 87% at 3 hours, and 80% at 4 hours.

Barium swallow test

• Normal swallowing function and normal esophageal motility

• Patulous gastroesophageal junction with mild to moderate gastroesophageal reflux

• Retained food debris in the stomach raising possibility of gastroparesis

24-hr pH probe

24-hr pH probe

Esophageal manometry

Esophageal manometry

What to do next?

• Given this newly acquired information, do you feel that this patient’s reflux is the cause of his rejection and pneumonias?

• What do you believe is the next best course of action?

GERD and acute lung rejection

• 1,200 lung transplant in US annually• Significant improvement in 1 year survival

since 1963: >80%• Five-year survival remains significantly lower

compared to other solid organ transplants:Lung: 43% - 49% Kidney 66-78%Heart 64-74% Liver 55%-72%

Bronchiolitis Obliterans Syndrome

• Long term morbidity and mortality after lung transplantation are largely attributable to bronchiolitis obliterans syndrome (BOS), a form of chronic rejection– CMV– PNA– HLA mismatch– GERD?!!!!

GERD and BOS

• GERD has been proposed as a possible mechanism for this to happen (all theoretical):– Impaired cough reflex– Impaired mucociliary clearance (15% after transplant)– Esophageal and gastric dysmotility after transplant

(limited data; no prospective study)• Vagal nerve injury• Ischemia• Scarring• Immunosuppressive drug

Does GERD cause BOS?Observational studies

• Case series from Western Ontario with 11 heart/lung transplant patients

• 5 with BOS• All had chronic cough, delayed gastric

emptying, esophageal dysmotility

Lancet. 1990 Jul 28;336(8709):206-8.

Does GERD cause BOS?Observational studies

• Case report from Duke University• Lung transplant recipient developed acute

decline in pulmonary function testing• Biopsy showed acute inflammation, no

rejection• Further testing showed severe reflux• Underwent Nissen with full recovery

Chest. 2000 Oct;118(4):1214-7.

Does GERD cause BOS?Rat studies

• WKY-to-F344 rat orthotopic lung transplant model used• Compared controls vs. 8 weekly gastric fluid aspirations• 6/9 allografts with aspiration demonstrated

bronchioles with surrounding monocytic infiltrates, fibrosis and loss of normal lumen anatomy

• None of the allografts without aspiration (n = 10) demonstrated these findings (p = 0.002)

• Aspiration was associated with increased levels of IL-1 alpha, IL-1 beta, IL-6, IL-10, TNF-alpha and TGF-beta in BAL and of IL-1 alpha, IL-4 and GM-CSF in serum

Am J Transplant. 2008 Aug;8(8):1614-21. Epub 2008 Jun 28.

Does GERD cause BOS?Retrospective studies

• At Harefield Hospital in Middlesex, UK, 59 pts with LTP underwent esophageal manometry

• Compared BOS-free survival between abnormal refluxers (37) vs. control (HR 3.6, p=0.022) and abnormal acid control (16) vs. control (NS)

J Heart Lung Transplant. 2009 Sep;28(9):870-5.

Does GERD cause BOS?Retrospective studies

• Institutional observational study from Emory• 60 LT subjects, 33 with GERD versus 27

without GERD.• Observed 51 episodes of rejection.• The rate of rejection was highest among

patients with GERD: 8.49 versus 2.58, an incidence density ratio (IDR) of 3.29 (P = .00016)

Transplant Proc. 2010 Sep;42(7):2702-6.

Does antireflux surgery prevent BOS?Observational studies

• Case series from Western Ontario with 11 heart/lung transplant patients

• 5 with BOS• All had chronic cough, delayed gastric

emptying, esophageal dysmotility• Three patients improved with antireflux

precautions• One patient improved with pyloroplasty

Lancet. 1990 Jul 28;336(8709):206-8.

Does antireflux surgery prevent BOS? Retrospective studies

• Duke University, 18/298 lung transplant patients with documented reflux

• Performed 13 laparoscopic Nissen fundoplications, four laparoscopic Toupets, and one open Nissen

• Two of the 18 patients reported recurrence of symptoms (11%), and two others reported minor GI complaints postoperatively (nausea, bloating).

• There were no deaths from the antireflux surgery. • After fundoplication surgery, 12 of the 18 patients showed

measured improvement in pulmonary function (67%).

Surg Endosc. 2002 Dec;16(12):1674-8. Epub 2002 Jul 29.

Does antireflux surgery prevent BOS? Retrospective studies

• Duke University, retrospective cohort survival analysis in no reflux, reflux no surgery, reflux early surgery, reflux late surgery

• Significantly reduced incidence of BOS

Ann Thorac Surg. 2004 Oct;78(4):1142-51; discussion 1142-51.

Does antireflux surgery prevent BOS? Retrospective studies

• Duke University study of 222 patients that underwent LTP.

• Divided into three groups: No GERD (pre/post XP pH normal), GERD no fundo, GERD with fundo

Ann Thorac Surg. 2011 Aug;92(2):462-8; discussion; 468-9.

• Among GERD patient (no fundo):

Ann Thorac Surg. 2011 Aug;92(2):462-8; discussion; 468-9.

• Between no GERD, GERD, and FUNDO groups:

Ann Thorac Surg. 2011 Aug;92(2):462-8; discussion; 468-9.

Does antireflux surgery prevent BOS? Retrospective studies

• At University of Pittsburgh, study done on the effect of anti-reflux surgery on pre-TP and post-TP patients

• Forty-three patients with ESLD and documented GERD (pre-LTx, 19; post-LTx, 24).

Arch Surg. 2011 Sep;146(9):1041-7.

How to perform Nissen fundoplication

• Step 1: Open patient• Step 2: Do a Nissen• Step 3: Close patient• Step 4: Celebratory beer

How to perform a Nissen

• Laparoscopic fundoplication with or without pyloroplasty in patients with gastroesophageal reflux disease after lung transplantation: how I do it.

Christopher S. Davis, et al. J Gastrointest Surg.;14(9):1434-1441.

Patient Course

• Patient underwent Nissen fundiplication with pyloroplasty

• Post-operatively, continues to have difficulty eating with peri-umbilical pain post-prandially, with early satiety

• GES now normal• However, less frequent cough, and resolution

of acute cellular rejection on subsequent BAL