How I Manage Pulmonary Infection in the Post-Transplant Patient

Joanna Schaenman, M.D., Ph.D.David Geffen School of Medicine at UCLA

Los Angeles, CA

October 13, 2015

Pulmonary infection : Learning objectives

1.Know the frequent causative agents of pulmonary infection after transplantation.

2.Understand effective strategies for prophylaxis and diagnosis of pulmonary infections

3.Know how to select antibiotic therapy to treat common causes of pulmonary infection

Reactivation:CMV

Person-to-person:

Influenza

Environmental:Fungi

Increased risk with augmentation of immune suppression, patient comorbidities including advanced age

Pulmonary infection: the most common infection, highest mortality after solid organ transplantation

Time course of risk for pulmonary infection

Transplant

Induction

Maintenance immunosuppression

• Nosocomial infection

• Reactivation• Opportunistic

Phase 1First month

Phase 2Months 1-6

• Community-acquired

• Opportunistic

Phase 3>6 months

Kupeli, Curr Opin Pulm Medicine 2004

Prophylaxis

Common etiologies of pulmonary infection

BACTERIA• Community or

hospital acquired pneumonia

• Mycobacteria

VIRUSES• Community

acquired respiratory viruses

• CMV

FUNGI• Endemic fungi• Molds (Aspergillus)

Case 1: Fever and sepsis physiology 10 years post kidney transplant

• 47 yo woman with DM, s/p DDRT

• February developed URI symptoms, rash over thighs

• Progressive respiratory failure, fever, altered mental status, required intubation

Clinical and radiographic presentation of pneumonia is often not specific for a particular pathogen

Diagnostic approach to lung infection

Direct testing:• Sputum or tracheal aspirate for

Gram stain and bacterial, AFB, and fungal cultures

• Blood cultures• Consider bronchoscopy for

bronchoalveolar lavage• Respiratory virus testing by PCR

Indirect testing:• Consider blood or urine testing

for surrogate markers including• Coccidioides Ab• Cryptococcus ag• Histoplasma ag• Aspergillus galactomannan• Legionella urine antigen• CMV PCR

Low threshold for ordering Chest CT

Case 1: Fever and sepsis physiology 10 years post kidney transplant

• Empiric therapy: vancomycin, pipercillin/tazobactam, levaquin

• Outside hospital sputum culture positive for Streptococcus pyogenes

• Clindamycin added• Patient ultimately did

well, complete resolution of symptoms

Chest CT gives more information than CXR, but is still nonspecific for cause of infection

Yield of bronchoscopy in SOT

• Review of 47 kidney and 14 liver transplant recipients in Turkey

• 39% bronchial wash cultures were positive (47% in patients off antibiotics)

• Higher yield with transbronchial biopsy (58%)• Positive cultures included MTB, Staphylococcus

aureus, Moraxella, Klebsiella pneumoniae, E coli, Streptococcus pneumoniae, Pseudomonas, Aspergillus

Kupeli et al, Transplant Proceedings 2011; Kupeli et al., Curr Op Pulm Med 2012

Empiric treatment based on risk profile

• Community acquired pneumoniaHaemophilus influenzae, Streptococcus

pneumoniae, Mycoplasma, Legionella, viruses

• Fluoroquionolone, or ceftriaxone plus azithromycin

• Hospital acquired pneumoniaStaphylococcus aureus,

Enterobacteraciae, Acinetobacter, Pseudomonas; aspiration

• Vancomycin plus pipercillin tazobactam, levaquin

• Concern for multidrug resistant organismsESBL, CRE, MDR Pseudomonas, fungi

• Empiric broad spectrum therapy

(penem, aminoglycoside, colistin, etc)

Mycobacteria

MTB

MAC (MAI)Rapid growers (e.g. M. abscessus)

• Pre-transplant screening recommended

• Incidence of MTB 14% in developing countries, 0.5-6% in low endemic areas

• Often high mortality

Caution for drug-drug interactions with rifampin or rifabutin use

Case 2: Fever and sepsis physiology 3 mo. post kidney transplant

• 74 yo man with DM, s/p DDRT, ATG induction

• February developed URI symptoms, cough, seen in clinic but CXR showed only atelectasis

• Admitted with progressive cough, malaise

• Progressive respiratory failure, required intubation

Chest x-ray is often unrevealing in transplant recipients

Case 2: Fever and sepsis physiology 3 mo. post kidney transplant

• Empiric therapy: vancomycin, pipercillin/tazobactam, levaquin, oseltamivir

• Nasopharyngeal swab pos for RSV by respiratory viral PCR

• Ribavirin added• Progressive

respiratory failure, ARDS

Low threshold for further evaluation in vulnerable patients

• Influenza• Respiratory syncytial virus (RSV)• Human metapneumovirus• Parainfluenza • Adenovirus• Rhinovirus

Community acquired respiratory viruses (CARV)

• Diagnosis via PCR testing of nasopharyngeal swab or respiratory source

• Rx Influenza with oseltamivir or zanamivir

• Consider ribavirin for RSV, especially in lung transplant

CMV pneumonitis

• Donor positive/Recipient negative is highest risk

• Risk decreased with Valcyte prophylaxis

• Lung>heart>liver>kidney• Diagnosis via PCR testing, viral

culture, or histopathology• Treat with IV ganciclovir

Kotloff et al., 2004; Kotton, 2010

Case 3: Fever 1 year post kidney transplant

• 52 yo woman with DM, s/p DDRT

• H/o TB peritonitis• November developed

fever, chills, myalgias, fatigue, no improvement with course of levaquin

• No neurologic complaints or findings Broad diagnostic differential

for lobar pneumonia

Case 3: Fever 1 year post kidney transplant

• Empiric therapy: vancomycin, meropenem, levaquin

• Sputum culture positive for Cryptococcus gattii, Aspergillus flavus

• BAL positive for Cryptococcus and CMV; LP negative

• Started on Voriconazole

“Bad news comes in threes” (the Transplant ID motto), not “Occam’s Razor”

Clinically Important Fungi

Yeast Endemic Fungi Molds

Candida Cryptococcus CoccidioidesHistoplasmaBlastomycosis

AspergillusScedosporium, others

Agents of Mucormycosis

PCP

PCP is less common with routine TMP/SMX prophylaxis

Distribution of fungal infections by transplant type

TRANSNET Surveillance cohort

Pappas et al., CID 2010

Distribution of dimorphic endemic fungi

McP

hers

on: H

enry

's Cl

inic

al D

iagn

osis

and

Man

agem

ent b

y La

bora

tory

Met

hods

, 201

1

Histoplasmosis distribution in the Americas

Coccidioidomycosis.

• Environment is main source for exposure, but can also be donor-derived

• Reports suggest that number of infections are increasing

• Sensitivity of serologic testing is lower in immunosuppressed patients

Proia, et al. AJT 2009

Diagnosis of invasive fungal infections is challenging

• Clinical and radiographic presentation is not specific for fungal infection

• Need culture for identification and sensitivity testing• Noninvasive testing can be helpful: Aspergillus GM, antigen testing,

future PCR or breath testing

Empiric antifungal treatment

• Endemic fungi (non-severe)

• Aspergillosis

• Agents of mucormycosis

• Fluconazole, itraconaozle

• Voriconazole*

• Liposomal Amphotericin B

• Severe invasive fungal infection • Liposomal Amphotericin B, possibly combination Rx

*Watch for drug-drug interactions with tacrolimus

And last but not least…parasites

• Strongyloides: Donor derived or reactivation

Reactivation

Person-to-personEnvironmental

Think about the etiology of pulmonary infections:

BACTERIA

VIRUSES

FUNGI

To devise strategies for prevention:Vaccination, Antibiotic prophylaxis (TMP/SMX, Valcyte, azoles), Patient education

Pulmonary infection : Learning objectives

• Causative agents of pulmonary infection after transplantation include bacteria, viruses, and fungi

• Prophylaxis for PCP and CMV has decreased pneumonia incidence

• Diagnosis is important and should include sputum testing, BAL or FNA when appropriate, and noninvasive tests

• Antibiotic therapy should be based on culture-based diagnosis when possible, and on suggested clinical syndrome when unable to make clear diagnosis

References1. Fishman JA. Infections in immunocompromised hosts and organ transplant recipients: Essentials. Liver

Transpl. 2011 Oct 26;17(S3):S34–7. 2. Küpeli E, Eyüboğlu FÖ, Haberal M. Pulmonary infections in transplant recipients. Curr Opin Pulm Med.

2012 May;18(3):202–12. 3. Kupeli E, Akcay S, Ulubay G, et al. Diagnostic Utility of Flexible Bronchoscopy in Recipients of Solid Organ

Transplants. TPS. Elsevier Inc; 2011 Mar 1;43(2):543–6. 4. Kotloff RM, Ahya VN, Crawford SW. Pulmonary Complications of Solid Organ and Hematopoietic Stem

Cell Transplantation. American Journal of Respiratory and Critical Care Medicine. 2004 Jul;170(1):22–48. 5. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic

Society Consensus Guidelines on the Management of Community-Acquired Pneumonia in Adults. CLIN INFECT DIS. 2007 Mar 1;44(Supplement 2):S27–S72.

6. American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. American Journal of Respiratory and Critical Care Medicine. 2005. p. 388–416.

7. Blumberg HM, Burman WJ, Chaisson RE, et al. American Thoracic Society, Centers for Disease Control and Prevention and the Infectious Diseases Society. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. American Journal of Respiratory and Critical Care Medicine [Internet]. 2003 Feb 15;167(4):603–62.

8. McGrath EE, McCabe J, Anderson PB, American Thoracic Society, Infectious Diseases Society of America. Guidelines on the diagnosis and treatment of pulmonary non-tuberculous mycobacteria infection. Int. J. Clin. Pract. 2008 Dec;62(12):1947–55.

9. Ison MG. Respiratory viral infections in transplant recipients. Antivir. Ther. (Lond.). 2007;12(4 Pt B):627–38.

10. Kotton CN, Kumar D, Caliendo AM, et al., International Consensus Guidelines on the Management of Cytomegalovirus in Solid Organ Transplantation. Transplantation. 2010 Apr;89(7):779–95.