1. 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

2. Pulmonary infection : Learning objectives
Know the frequent causative agents of pulmonary infection after transplantation.
Understand effective strategies for prophylaxis and diagnosis of pulmonary infections
Know how to select antibiotic therapy to treat common causes of pulmonary infection

3. Person-to-person: Influenza
Pulmonary infection: the most common infection, highest mortality after solid organ transplantation
Person-to-person: Influenza
Environmental:
Fungi
Reactivation:
CMV
Person-to-person includes donor derived infection
Comorbidities: Age, DM, pre-transplant immune suppression (desensitization, or vasculitis, etc.)
Some studies show 40% incidence death due to lung infection (hoyo 2012)
Lung>heart>liver>kidney in incidence
Increased risk with augmentation of immune suppression, patient comorbidities including advanced age

4. Time course of risk for pulmonary infection
Induction
Maintenance immunosuppression
Prophylaxis
Nosocomial infection
Reactivation
Opportunistic
Phase 1
First month
Phase 2
Months 1-6
Community-acquired
Phase 3
>6 months
Transplant
2/3 of all lung infiltrates post-transplant are of infectious etiology
PCP and CMV prophylaxis with Bactrim and Valcyte
Bactrim also prevents Nocardia infection
Pre transplant exposures can reactivate, also REM donor derive transmission
Kupeli, Curr Opin Pulm Medicine 2004

5. Common etiologies of pulmonary infection
BACTERIA
Community or hospital acquired pneumonia
Mycobacteria
VIRUSES
Community acquired respiratory viruses
CMV
FUNGI
Endemic fungi
Molds (Aspergillus)

6. 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

7. 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
Quantiferon gold or PPD is low yield and not appropriate for use in diagnosis of active infection
10% of patients with pna may have normal CXR
Low threshold for ordering Chest CT

8. 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
Group A Strep, toxic shock
Chest CT gives more information than CXR, but is still nonspecific for cause of infection

9. 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
Other reports have shown higher yields, up to 85%
Generally safe and well tolerated
Kupeli et al, Transplant Proceedings 2011; Kupeli et al., Curr Op Pulm Med 2012

10. Empiric treatment based on risk profile
Community acquired pneumonia
Haemophilus influenzae, Streptococcus pneumoniae, Mycoplasma, Legionella, viruses
Fluoroquionolone, or ceftriaxone plus azithromycin
Hospital acquired pneumonia
Staphylococcus aureus, Enterobacteraciae, Acinetobacter, Pseudomonas; aspiration
Vancomycin plus pipercillin tazobactam, levaquin
Kupeli curr opinon pulmonary medicine
IDSA guidelines
Atypicals include Chlamydia
Hap, also healthcare associated pna, VAP
Cefepime is alternative to pipercilin/tazobactam
Concern for multidrug resistant organisms
ESBL, CRE, MDR Pseudomonas, fungi
Empiric broad spectrum therapy
(penem, aminoglycoside, colistin, etc)

11. Mycobacteria MTB Rapid growers (e.g. M. abscessus) MAC (MAI)
Pre-transplant screening recommended
Incidence of MTB 14% in developing countries, 0.5-6% in low endemic areas
Often high mortality
MTB
Mycobacterium avium complex/Mycobacterium avium-intracellulare
TB risk is % in areas of low endemicity
TB often extrapulmonary, and often high mortality (19-40%)
NTM is another consideration: RGM M abscessus, fortuitum, cheloneae
Rapid growers (e.g. M. abscessus)
MAC (MAI)
Caution for drug-drug interactions with rifampin or rifabutin use

12. 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
Seen in clinic 3 days PTA with cough, CXR done, read as ‘atelectasis’
Chest x-ray is often unrevealing in transplant recipients

13. 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
BAL also positive for RSV
Low threshold for further evaluation in vulnerable patients

14. Community acquired respiratory viruses (CARV)
Influenza
Respiratory syncytial virus (RSV)
Human metapneumovirus
Parainfluenza
Adenovirus
Rhinovirus
Diagnosis via PCR testing of nasopharyngeal swab or respiratory source
Rx Influenza with oseltamivir or zanamivir
Consider ribavirin for RSV, especially in lung transplant
Some are seasonal, others year young
Consider ribavirin for RSV

15. 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
Infection may predispose to other infections
Also VZV, HSV, EBV (PTLD)
Kotloff et al., 2004; Kotton, 2010

16. 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

17. 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
BAL by culture; peripheral CMV also positive
“Bad news comes in threes” (the Transplant ID motto), not “Occam’s Razor”

18. Clinically Important Fungi
Yeast
Endemic Fungi
Molds
Coccidioides
Histoplasma
Blastomycosis
Candida
Cryptococcus
PCP
Aspergillus
Scedosporium, others
PCP is less common with routine TMP/SMX prophylaxis
Agents of Mucormycosis

19. Distribution of fungal infections by transplant type
Poor survival rate even with modern diagnosis and therapy
TRANSNET Surveillance cohort
Pappas et al., CID 2010

20. Distribution of dimorphic endemic fungi
Histoplasmosis distribution in the Americas
McPherson: Henry's Clinical Diagnosis and Management by Laboratory Methods, 2011

21. 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

22. Diagnosis of invasive fungal infections is challenging
Need culture for ID and sensitivity
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

23. Empiric antifungal treatment
Endemic fungi (non-severe)
Fluconazole, itraconaozle
Aspergillosis
Voriconazole*
Liposomal Amphotericin B
Agents of mucormycosis
Diagnosis is essential
Liposomal Amphotericin B, possibly combination Rx
Severe invasive fungal infection
*Watch for drug-drug interactions with tacrolimus

24. And last but not least…parasites
Strongyloides: Donor derived or reactivation

25. Think about the etiology of pulmonary infections:
Person-to-person
BACTERIA
Environmental
VIRUSES
Reactivation
FUNGI
Prevent the evil decree
Early diagnosis and targeted treatment to improve outcomes
To devise strategies for prevention:
Vaccination, Antibiotic prophylaxis (TMP/SMX, Valcyte, azoles), Patient education

26. 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

27. References
Fishman JA. Infections in immunocompromised hosts and organ transplant recipients: Essentials. Liver Transpl Oct 26;17(S3):S34–7.
Küpeli E, Eyüboğlu FÖ, Haberal M. Pulmonary infections in transplant recipients. Curr Opin Pulm Med May;18(3):202–12.
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.
Kotloff RM, Ahya VN, Crawford SW. Pulmonary Complications of Solid Organ and Hematopoietic Stem Cell Transplantation. American Journal of Respiratory and Critical Care Medicine Jul;170(1):22–48.
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 Mar 1;44(Supplement 2):S27–S72.
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 p. 388–416.
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] Feb 15;167(4):603–62.
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 Dec;62(12):1947–55.
Ison MG. Respiratory viral infections in transplant recipients. Antivir. Ther. (Lond.). 2007;12(4 Pt B):627–38.
Kotton CN, Kumar D, Caliendo AM, et al., International Consensus Guidelines on the Management of Cytomegalovirus in Solid Organ Transplantation. Transplantation Apr;89(7):779–95.