- Have a framework of how to approach hypoxia in a lung transplant patient
The case stem below only includes highlights or summaries of his medical history and laboratory findings. For a complete history or laboratory findings, click on the blue text. The focus of this case is on teaching a framework to approaching hypoxia post-lung transplantation, which is summarized in a table included in the “What is your differential…?” section. Skip down to the “Additional Learning” section for a personal refresher or take a detour to teach this section which will add ~ 10 – 15 min. The bonus question on the diagnostic utility of bronchoscopy after initiation of antibiotics is also optional and will add 2-3 min to your overall lecture.
65 yo M with a history of BOLT for COPD ~10 years ago presents with four days of subjective fevers, dyspnea and nonproductive cough. He denies any URI symptoms (sore throat, congestion, rhinorrhea), chest pain, orthopnea, LE swelling. He denies any recent sick contacts.
He has a complicated PMH (full medical history and medication list) notable for CMV D+/R- BOLT ~ 10 years ago that was complicated by acute cellular rejection 3 weeks prior to presentation. He was hospitalized and treated with rabbit-derived ATG (r-ATG) and 3 days of high dose steroids. He is on tacrolimus and prednisone for immunosuppresion; Bactrim and valganciclovir for prophylaxis.
On exam, he was febrile to 38.9C, HR 131, RR 22, SBP 100-140s/90s, SaO2 93% on 2LNC. He is in no respiratory distress and has crackles at the bases only. He has dry mucus membranes, normal JVP and no LE edema. His initial labs were notable for a BUN 23, Cr of 1.3 (from baseline of 0.9), WBC 24 with 95% neutrophils (full labs). EKG showed sinus tachycardia without ischemic changes.
CXR on admission and on HD1 (after 2L IVF) showed:
What is your differential diagnosis for hypoxia in this patient?
Hypoxia and dyspnea in a lung transplant patient can be separated into three major categories of complications: rejection, infections, and other (which includes airway/vascular complications, malignancy and and recurrent lung disease). Time from transplant can be useful in differentiating these complications. His SIRS physiology (fever, tachycardia, leukoctyosis) along with his recent history of high levels of immunosuppresion should prompt high suspicion for an infectious etiology.
Typically after the first 6 months, community acquired infections and late viral infections (CMV, HSV) are most common. Our patient’s risk of infections is slightly unique in that he’s recently received r-ATG and high dose steroids for rejection and is more significantly immunosuppressed than the average patient 10 years out from transplant. He is at highest risk for nosocomial infections and CMV (given his D+/R- status). Non-infectious causes could include rejection (which can be associated with low grade fevers), PTLD, or drug reaction.
What additional work-up would you want?
- ABG: 7.46/27/64/19 on 2 L NC
- Infectious work-up
- Blood cultures x 2 drawn and ultimately negative
- Extended respiratory viral panel negative
- Sputum culture (ideally BAL culture) – bacterial culture, fungal culture, PJP stain, Aspergillus PCR. We did not obtain a sputum culture in anticipation of bronchoscopy in the coming days.
- Strep urinary Ag negative
- Legionella urinary Ag negative
- CMV PCR negative
- EBV PCR negative
- Urinalysis normal
- BNP 123 (mildly elevated, ULN 101)
- CT chest (+/- PE protocol) to better characterize pulmonary infiltrates (after CXR on HD1). CT imaging can play an important role in identifying post-transplant complications – especially when CXR shows nonspecific abnormal findings or is normal in a patient with respiratory sympoms13. While CT findings for rejection and many infections are nonspecific, there are characteristic imaging findings for some infections that may help narrow the differential. It additionally may identify lung areas to target on bronchoscopy and anatomic abnormalities such as airway or vascular stenoses. We did not pursue CTPE because we felt infectious etiologies more likely explained his hypoxia.
He had rapidly escalating increasing oxygen requirements and respiratory distress over the first 24 hours, requiring up to 60% FiO2 via high flow nasal cannula. A repeat ABG showed 7.26/53/68/24 on 60% FiO2 (interpret ABG). He was transferred to the ICU and intubated.
He received a bronchoscopy on HD2 which identified a R bronchus intermedius narrowing with inability to pass the bronchoscope past this. There were minimal secretions noted. The BAL fluid was sent for bacterial and fungal cultures which ultimately came back negative. PCRs for PJP and Aspergillus were also negative (full BAL results).
On HD4, he underwent a rigid bronchoscopy with dilation of his bronchus intermedius.
His hypoxemia was attributed to both his bronchial stenosis (which may have been his initial presentation) that was complicated by a post-obstructive or healthcare associated pneumonia. His vancomycin was stopped after his MRSA nares swab was negative and he was transitioned from cefepime to piperacillin-tazobactam for better anaerobic coverage for possible post-obstructive pneumonia. He continued on azithromycin. His oxygenation slowly improved throughout his hospital course and was extubated on HD5 and was discharged on 4L NC.
His BAL cultures were ultimately negative. What is the yield of a bronchoscopy for diagnosing pneumonia in an immunosuppressed patient? How is this affected by the initiation of antibiotics? (~ 2-3 min)
The overall diagnostic yield of bronchoalveolar lavage and bronchoscopy in transplant patients ranges from 30-73%7-9. In lung transplant patients, the diagnostic yield may be on the higher end of this range with Lehto, et al. 2005 reporting a diagnostic yield of 61%. The yield is also highest in the first 6 months when most opportunistic infections and nosocomial infections are diagnosed8. Yield is also higher with radiographic findings of alveolar infiltrates over nodular or reticular infiltrates9.
There are few quality studies that evaluate how empiric antibiotic therapy may change diagnostic yield for pulmonary infections. While empiric therapy may decrease the diagnostic yield of bronchoscopy, empiric therapy should be started if infection is suspected in a transplant patient. Generally, bronchoscopy is still useful if performed within 3 days7.
TAKE HOME POINTS:
- Complications post-lung transplant can be broadly separated into three broad categories: rejection, infections and other complications (which includes airway/vascular and malignant). Time from transplant can be useful in differentiating between some of these different complications.
- CT imaging can be helpful in narrowing the differential of post-transplant hypoxia especially if CXR findings are nonspecific or unrevealing.
- Empiric antimicrobial therapy should be started if infection is suspected in a transplant patient. Generally, bronchoscopy is still useful if performed within 3 days of initial presentation.
ADDITIONAL LEARNING (~10-15 min):
The below table gives a broad framework of how to think about different complications with relation to time from transplant. The below section gives more detailed information on each of the different sections.
Lung transplant patients are at particularly high risk of post-transplant pulmonary infections not only because of their immunosuppressed status but also because of an impairment of normal mucociliary clearance and disruption of the lymphatics. Death rate is highest in the first year following transplant with infection as the leading cause of death4.
Click here or on the diagram below for detailed information about bacterial, fungal and viral causes of infection.
Acute rejection should be considered in any lung transplant patient with acute onset hypoxia or dyspnea in a lung transplant patient. Most cases of acute rejection occur in the first 6 months. Occurences after 6 months are often related to medication nonadherence. Acute cellular rejection is most common and is diagnosed with tissue biopsy. Imaging findings are rejection are nonspecific. Chronic rejection, or bronchiolitis obliterans, can also cause dyspnea and hypoxia but tends to have a more indolent course.
Click here or on the diagram below to see table comparing acute, humoral and chronic rejection.
Other complications can include airway/vascular complications, recurrent primary disease, and post-transplant lymphoproliferative disorder (PTLD). Many airway and vascular complications occur at anastomotic sites, such as bronchial stenosis. Internists see less vascular anastomotic complications, but should be cognizant of PE as a frequent and common cause of hypoxia after lung transplantation.
Click here or on the diagram below for detailed information.
The above list is not a comprehensive of all the post-transplant complications, but only the most common complications. Other infectious complications include Legionella and HSV/VZV. Other vascular complications include pulmonary vein thrombosis or bronchial artery thrombosis. diaphragmatic injury and pleural complications (hemothorax, pneumothorax, chylothorax) can also occur in the early post-transplant setting but are often managed by the surgical team. For more information, refer to the bolded references below for additional information.
- Naranjo, D & Charterina, SA. 2016. What can happen after lung transplantation and the importance of the time since transplantation: Radiological review of post-transplantation complications. Radiologia. 58:257-267.
- Clajus, C, et al. 2015. Therapeutic approach to respiratory infections in lung transplantation. Pulmonary Pharmacology and Therapeutics. 32: 149-154
- Kotloff, RM & Ahya, VN. 2004. Medical complications of lung transplantation. European Respiratory Journal. 23: 334 – 342.
- Alexander, BD & Tapson, VF. 2001. Infectious complications of lung transplant. Transplant Infectious Disease. 3: 128 – 137.
- Kotloff, RM, Ahya, VN, & Crawford, SW. 2004. Pulmonary Complications of Solid Organ and Hematopoietic Stem Cell Transplantation. American Journal of Respiratory and Critical Care Medicine. 170: 22-48.
- Tejwani, V, et al. 2016. Complications of Lung Transplantation: A Roentgenographic Perspective. CHEST. 149(6): 1535-1545.
- Harris, B, et al. 2013. Diagnostic Bronchoscopy in Solid-Organ and Hematopoeitic Stem Cell Transplantation. Annals of the American Thoracics Society. 10(1): 39-49.
- Lehto, JT, et al. 2005. Bronchoscopy in the diagnosis and surveillance of respiratory infections in lung and heart-lung transplant recipients. Transplant International. 18(5): 562–571
- Brownback KR & Simpson SQ. 2013. Association of bronchoalveolar lavage yield with chest computed tomography findings and symptoms in immunocompromised patients. Annals of Thoracic Medicine. 8:153-159
- Pilewski, J. Chronic lung transplant rejection: Bronchiolitis obliterans. In: UpToDate, Hollingsworth, H. (Ed), UpToDate, Waltham, MA. (Accessed on January 13, 2016.)
- Pilewski, J. Evaluation and treatment of acute lung transplant rejection. In: UpToDate, Hollingsworth, H. (Ed), UpToDate, Waltham, MA. (Accessed on January 13, 2016.)
- Hachem, RR. Evaluation and treatment of antibody-mediated lung transplant rejection. In: UpToDate, Hollingsworth, H. (Ed), UpToDate, Waltham, MA. (Accessed on January 13, 2016.)
- Collins, J, et al. 2000. CT findings after lung transplantation. American Journal or Roentgenology. 175(3): 811 – 818.
- Kahan, ES, et al. 2007. High Incidence of Venous Thromboembolic Events in Lung Transplant Recipients. The Journal of Heart and Lung Transplantation. 26(4):339 – 344