Intermediate and Late Complications of Lung Transplantation




LUNG TRANSPLANT REJECTION


Definitions





  • Acute rejection: a rapid onset of worsening lung function, typically in the first year after transplant, often accompanied by radiographic deterioration with histologic appearance of lymphocytic vascular invasion on biopsy.



  • Chronic rejection: a clinical symptom referred to as bronchiolitis obliterans syndrome (BOS) clinically manifested by a persistent drop in lung function in the absence of potentially reversible etiologies typically occurring more than 6 months after transplant sugery.



Acute Rejection





  • Incidence




    • Very common with estimates of one or more episodes in first year after transplant between 27-85%



    • True incidence rates not well described because nonuniformity in definition of acute rejection is common.




  • Clinical presentation




    • Symptoms include




      • Malaise



      • Dyspnea



      • Low-grade fever




    • Signs




      • Drop in lung function, typically FEV 1 or FVC



      • Abnormal findings on chest x-ray study




        • Infiltrates



        • Pleural effusions




      • Hypoxia



      • Elevation in white blood cell count, often with peripheral eosinophilia





  • Risk factors




    • HLA mismatching




      • Owing to time constraints at time of surgery, human leukocyte antigen (HLA) matching is often not possible.



      • Associated with episodes of acute rejection as well as worse long-term survival.



      • “Virtual” cross-matching in which potential donors’ HLA profiles are known and can be compared against recipients’ HLA antibodies may improve short and long-term outcomes by minimizing HLA mismatches; however, data on this technology are evolving.




    • High levels of recipient anti-HLA antibodies




      • Measured by panel reactive antibodies associated with increased rates of acute rejection and decreased survival



      • Development of anti-HLA antibodies after transplant also reported to increase risk for acute rejection




    • Cytomegalovirus (CMV) mismatch/infection




      • Relationship not clear at this point




    • Community-acquired viral infections



    • Gastroesophageal reflux disease (GERD)




  • Diagnosis




    • Transbronchial biopsies via flexible fiberoptic bronchoscope




      • Gold standard



      • Generally minimum of six biopsies taken from single side



      • Use of surveillance bronchoscopy (SB) controversial




        • Approximately two thirds of lung transplant programs perform SB.



        • Biopsies are performed at fixed intervals in first year in asymptomatic individuals looking for occult rejection and infection.



        • Recent finding of low-grade rejection linked to the development of BOS infers benefit to early diagnosis and treatment; however, data showing this are scant.



        • A recent study showed that 31.5% of biopsies taken as part of SB were “clinically useful,” and argued for the use of SB universally.





    • Clinical symptoms




      • Not sensitive or specific




    • Pulmonary function




      • Not sensitive or specific




    • Radiographic abnormalities




      • Neither chest x-ray study (CXR) or computed tomography (CT) scanning is adequately sensitive or specific and cannot differentiate rejection from infection.




    • Exhaled breath condensate




      • Essentially not helpful




    • Hepatocyte growth factor




      • Serum marker recently shown to be elevated in both infection and acute rejection, although this still must be validated.





  • Pathology




    • Hallmarked by presence of perivascular and mononuclear cell infiltrates.



    • Acute rejection has traditionally been considered a T-cell mediated event, however, humoral rejection has gained interest recently.



    • Lymphocytic airway infiltration and lymphocytic bronchiolitis have long been recognized in lung transplant; however, clinical importance in both acute and chronic rejection is evolving.




  • Grading




    • Grading scheme updated in 2007.



    • ABCD grading scheme ( Table 39-1 and Figs. 39–1 through 39–8 )




      • A: acute vascular mononuclear cell infiltration




        • A0: no evidence of rejection



        • A1: scattered, infrequent perivascular mononuclear infiltrates in alveolated lung parenchyma



        • A2: more frequent perivascular mononuclear infiltrates are seen surrounding venules and arterioles and are readily recognizable at low magnification, often with presence of perivascular eosinophils



        • A3: easily recognizable cuffing of venules and arterioles by dense perivascular mononuclear cell infiltrates, which are commonly associated with endothelialitis and frequent eosinophilic and neutrophilic involvement



        • A4: diffuse perivascular, interstitial and air-space infiltrates of mononuclear cells with prominent alveolar pneumocyte damage and endothelialitis




      • B: acute bronchiolar mononuclear cell infiltration




        • B0: no bronchiolar inflammation



        • B1R: mononuclear cells within submucosa of the bronchioles (R: “revised” from 1996 scheme)



        • B2R: larger and more numerous mononuclear cells within the submucosa with evidence of epithelial damage



        • BX: ungradeable due primarily to technical problems not allowing adequate inspection of bronchioles




      • C: presence of chronic airway rejection (obliterative bronchiolitis)




        • C0: not present



        • C1: dense eosinophilic hyaline fibrosis in the submucosa of membranous and respiratory bronchioles, resulting in partial or complete luminal occlusion




      • D: presence of chronic vascular rejection




        • Fibrointimal thickening of arteries and veins seen only on open lung biopsy, not transbronchial biopsy



        • May represent progressive humoral rejection




      TABLE 39-1 ▪

      ▪ REVISED WORKING FORMULATION FOR CLASSIFICATION AND GRADING OF PULMONARY ALLOGRAFT REJECTION




























































      A Acute rejection
      Grade 0 None
      Grade 1 Minimal
      Grade 2 Mild
      Grade 3 Moderate
      Grade 4 Severe
      B Airway inflammation
      Grade 0 None
      Grade 1R Low grade
      Grade 2R High grade
      Grade X Ungradable
      C Chronic airway rejection – Obliterative Bronchiolitis
      0 Absent
      1 Present
      D Chronic vascular rejection Accelerated graft vascular sclerosis

      From Stewart S, Fishbein MC, Snell GI, Berry GJ, Boehler A, Burke MM, et al. Revision of the 1996 working formulation for the standardization of nomenclature in the diagnosis of lung rejection. J Heart Lung Transplant 2007;26:1229–1242.



      Figure 39-1


      Rejection grade A0—normal pulmonary venule (hematoxylin and eosin; original magnification 400×).



      Figure 39-2


      Rejection grade A1—minimal infiltration of mononuclear cells around small vessel (hematoxylin and eosin; original magnification 200×).



      Figure 39-3


      Rejection grade A2—prominent perivascular aggregate of mononuclear cells observable at scanning power (hematoxylin and eosin; original magnification 200×).



      Figure 39-4


      A3—prominent aggregate of mononuclear cells with infiltration into surrounding interstitium (hematoxylin and eosin; original magnification 100×).

      Rights were not granted to include this figure in electronic media. Please refer to the printed book.



      Figure 39-5


      Rejection grade A4—infiltrate of mononuclear cells around vessel with adjacent hyaline membranes of diffuse alveolar damage (hematoxylin and eosin; original magnification 400×).



      Figure 39-6


      Rejection grade B1R (low-grade) lymphocytic bronchiolitis—mild peribronchiolar infiltrate of mononuclear cells (hematoxylin and eosin; original magnification 200×).



      Figure 39-7


      Rejection grade B2R (high-grade) lymphocytic bronchiolitis—extensive infiltrate of mononuclear cells through bronchiolar wall (hematoxylin and eosin; original magnification 100×).



      Figure 39-8


      Rejection grade C1 (obliterative bronchiolitis)—terminal bronchiole obliterated by intraluminal fibrosis (Masson Trichrome; original magnification 40×).

      Rights were not granted to include this figure in electronic media. Please refer to the printed book.




  • Prevention




    • Optimization of immunosuppression



    • Use of induction therapy at time of transplant (anti-interleukin-2 [IL-2] receptor monoclonal antibodies, antilymphocyte/anti-thymocyte globulin, or anti-CD3 monoclonal antibodies)




      • Limited data suggest that rates of acute rejection are decreased with induction.




    • Choice of calcineurin inhibitor – cyclosporine (CsA) versus tacrolimus (Tac)




      • Mixed data favoring the use of Tac over CsA in several studies have shown superior rates of acute rejection or with conversion from CsA to Tac, but with no overall changes in survival.




    • Use of mycophenolate mofetil (MMF) over azathioprine




      • No convincing evidence MMF decreased rate of acute rejection





  • Treatment




    • Mainstay of treatment is a short course of high-dose systemic steroids, typically 500 mg to 1000 mg intravenous (IV) methylprednisolone (Solu-Medrol, Pfizer, New York, NY) for 3 days



    • Many centers also increase dosing of other immunosuppressive medications after an episode of acute rejection




Chronic Rejection





  • Incidence




    • Very common, in fact nearly 50% of patients have evidence of chronic rejection (BOS) at 5 years.




  • Clinical presentation




    • Characteristic decline in lung function in BOS.



    • Biopsy is not needed to establish diagnosis.



    • Defined as a drop in FEV 1 to less than 20% from baseline, where the baseline is the average of two measurements separated by a minimum of 3 weeks in the absence of another potential cause of loss of lung function, that is, airway stenosis or infection.



    • Graded stages 0 to 3 with a new classification developed in 2002 called 0-p ( Table 39-2 ), which refers to “potential” BOS.



      TABLE 39-2 ▪

      ▪ 2002 CLASSIFICATION OF BRONCHIOLITIS OBLITERANS SYNDROME






















      Class Features
      BOS 0 FEV 1 > 90% of baseline and FEF 25–75 > 75% of baseline
      BOS 0-p FEV 1 81% to 90% of baseline and/or FEF 25–75 ≤ 75% of baseline
      BOS 1 66% to 80% of baseline
      BOS 2 51% to 65% of baseline
      BOS 3 50% or less of baseline

      From Estenne M, Maurer JR, Boehler A, Egan JJ, Frost A, Hertz M, et al. Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant 2002;21:297–310.




  • Risk factors




    • Episodes of severe rejection



    • Episodes of persistent mild acute rejection



    • CMV pneumonitis



    • Lymphocytic bronchiolitis



    • GERD




  • Diagnosis




    • Transbronchial biopsy




      • Obliterative bronchiolitis (OB), the pathologic correlate of BOS, is missed frequently by transbronchial as OB tends to be a patchy process with significant portion of the allograft unaffected.




    • Pulmonary function testing




      • Alterations in FEV 1 and FEF 25-75 are expected, as are implicit in definition of BOS.



      • May be lowered in many clinical scenarios not related to transplant




    • Single-breath washout tests




      • Changes in the slope of the alveolar plateaus using nitrogen and helium have been shown to be predictive of declines in lung function attributable to BOS.




    • Other tests including measurements of exhaled nitric oxide, exhaled breath condensate, induced sputum, bronchoalveolar lavage (BAL) cellular concentration, and CT scanning.




  • Pathology




    • “Obliterative bronchiolitis describes dense eosinophilic hyaline fibrosis in the sub-mucosa of membranous and respiratory bronchioles, resulting in partial or complete luminal occlusion” (see Fig. 39-8 )




  • Grading





  • Treatment




    • No intervention has conclusively shown benefit for patients with established BOS.



    • Most interventions aim to stabilize or decrease rate of decline of lung function rather than reversing decline



    • Avoidance, when possible, of known risk factors



    • Alteration of immunosuppression




      • Change cyclosporine A (CsA) to tacrolimus (Tac)




        • May help for early BOS; no benefit over the long term





    • Inhaled CsA




      • Not approved by the U.S. Food and Drug Administration. Large prospective placebo-controlled trial looking at rate of acute rejection showed no benefit. However, improved survival and BOS-free survival were observed with use of inhaled CsA.




    • Statins




      • Limited studies have shown benefit in reducing the incidence of BOS in patients started on a statin during the first postoperative year, presumably from its anti-inflammatory effects.




    • Azithromicin




      • Pooled data have shown a reverse decline in pulmonary function in a subset of patients, suggesting a diverse pathogenesis of BOS




    • Retransplantation




      • Although initial data suggested significantly worse outcomes for retransplantation surgery, more recent data suggest that 5-year survival rates are approaching those of first-time transplants.



      • Given the shortage of transplantable organs, some centers have argued this practice given poorer outcomes.







INFECTIONS FOLLOWING LUNG TRANSPLANTATION


Introduction





  • Infections are the leading cause of morbidity and attributable mortality following lung transplantation, in both single and double lung transplants.



  • Infections account for up to 50% of deaths, with chronic rejection the second leading cause. Infections can also complicate patients with chronic rejection.



  • Two thirds of infections involve the respiratory system.



  • Infections can complicate both the early and late stages, although the risk is highest in the first 100 days following lung transplant.



General Factors Predisposing to Infection





  • Immunosuppression :




    • Impaired cell-mediated immunity



    • Neutropenia (e.g., adverse side effect of medications)



    • Cytolytic therapy



    • Augmented immunosuppression for rejection episodes



    • Posttransplant hypogammaglobulinemia




  • Impaired lung defenses:




    • Denervation:




      • Depressed cough reflex



      • Impaired mucociliary clearance




    • Impaired lymphatic drainage



    • Primary graft dysfunction




  • Environment:




    • Transplant lungs are continuously exposed to external environment and conditions.




  • Donor Transmission:




    • Prolonged ventilation



    • Aspiration



    • Latent infections (e.g., tuberculosis [TB], endemic fungi)



    • Increased use of extended criteria lung donors




  • Recipient conditions




    • Harboring resistant organisms (e.g., in sinuses in patients with cystic fibrosis)



    • Latent infection in native lung with single-lung transplant



    • Reflux and silent aspiration



    • Inadequate prophylaxis (e.g., perioperative, pneumocystis, CMV, fungal)




  • Airway




    • Anastomotic stenosis with impaired clearance of secretions



    • Anastomotic stenosis with enhanced colonization



    • Airway dehiscence



    • Anastomotic infection (e.g., aspergillosis)




  • Presence of chronic rejection (bronchiolitis obliterans)




    • Bronchiectasis



    • Chronic colonization



    • Augmented immunosuppression



    • Impaired clearance




  • Comorbid conditions




    • Diabetes



    • Renal dysfunction



    • Nutritional depletion and cachexia



    • Breakdown of skin and mucosal barriers




Post-Lung Transplantation Infection Timeline





  • Period 1: first month post-transplant




    • Usual bacterial postoperative infections are the most common (90%)




      • Pneumonia



      • Urinary tract infections



      • Wound infection



      • Line-associated blood stream infection




    • Donor-colonizing organisms, active or latent infection



    • Recipient-colonizing organisms, active or latent infection



    • Infection related to surgical complications:




      • Bleeding with retained hemothorax, leading to empyema



      • Anastomotic issues associated with infectious compli-cations




    • Herpes simplex



    • Note: Notable absence of opportunistic infections



    • Also see chapter 38 on peri-operative management and early complications




  • Period 2: 1 to 6 months after transplant surgery




    • Opportunistic infections:




      • Fungal (e.g., Aspergillus, Cryptococcus and so on)



      • Viral (e.g., CMV, Epstein-Barr virus [EBV])



      • Pneumocystis



      • Mycobacterial



      • Nocardia



      • Listeria




    • Immunomodulating viruses can in conjunction with standard immunosuppressive therapy, enhance the predilection to opportunistic infection



    • Infection in this period may be modified by prophylactic therapies



    • Prophylaxis can prevent or delay the onset of opportunistic infections to period 3 (e.g., CMV).




  • Period 3: greater than 6 months after transplant surgery




    • Absence of BOS and receiving low-level immunosuppression:




      • Significantly reduced incidence of opportunistic infections



      • Community-acquired pneumonia



      • Respiratory viruses




    • Presence of BOS:




      • Owing to high-level immunosuppression, continue to see opportunistic infections.



      • Chronic colonization with resistant bacteria and other organisms, often refractory to clear



      • Multiple recurrent infections



      • Chronic viral infections





Specific Pathogens


Bacterial Infections





  • Bacterial pathogens are responsible for the largest proportion of infections.



  • During the first year, up to 70% of patients have experienced a bacterial infection, mostly resulting in pneumonia.



  • Other sites of bacterial infection include urinary tract; blood stream (line), pleural space wound, airway, mediastinum.



  • The cumulative incidence after the first year remains high (30%–40%)



  • Common bacterial pathogens: These depend on timeline, level of immunosuppression, and presence or absence of BOS




    • A large prospective analysis of pneumonia in lung transplant recipients was recently reported.




      • Early and intermediate periods accounted for the largest number of infections.



      • In patients in whom a cause of pneumonia was determined, bacteria accounted for 82.7% of cases. Of these, gram-negative bacilli accounted for 77%, gram-positive cocci accounted for 18%, and nocardia for 5%.



      • In this series, the most common gram-negative organisms in descending order were Pseudomonas aeruginosa, Acinetobacter baumanii, Escherichia coli, Klebsiella pneumoniae, and Stenotrophomonas maltophilia. Staphylococcus aureus was responsible for all gram-positive infections.



      • These prospective data mirror retrospective analyses.




    • Resistant bacteria : MRSA, extended spectrum β lactamase organisms ( E. coli, Klebsiella) and multidrug-resistant organisms (Pseudomonas, Acinetobacter) are increasingly being encountered, particularly in the hospital setting.



    • Colonization with multidrug resistant organisms is common in patients with cystic fibrosis (upper airway, sinuses) and in patients with BOS, predisposing to infection. Azithromycin may be of value in these settings because the drug has anti-inflammatory properties and also impairs synthesis of Pseudomonas virulence factors.



    • Community acquired pneumonia pathogens:




      • Pneumococcal pneumonia has been reported late after transplant (median 1.3 years) in 6.4% of transplant patients. Most of the serotypes were resistant to trimethoprim-sulfamethoxazole and were accounted for in the 23-valent pneumococcal vaccine.



      • Chlamydia pneumoniae and Mycoplasma pneumoniae can produce severe pneumonia in the lung transplant patient, particularly with concomitant hypogammaglobulinemia in the case of Mycoplasma. Chlamydial infection has been associated with acute and chronic rejection.



      • Legionella pneumophila can produce severe disease in the transplant patient. Acquisition occurs both in the community setting as well as in the hospital environment, through contamination of water systems.




    • Clostridium difficile : use of multiple courses of broad-spectrum antibiotics is a major contributing factor. Severe colitis can also result in bacterial gut translocation and sepsis.




  • Uncommon bacterial pathogens




    • Nocardia




      • Nocardia species are gram-positive filamentous bacteria that are partially acid fast. At least two thirds of infections occur in immunocompromised hosts.



      • The incidence of infection following lung transplantation is low (1.85, 2.1 and 3.5% in three large series).



      • Nocardia species included: Nocardia nova (30%–49% of nocardial infections), Nocardia farcinica (28%–30%), Nocardia asteroides (23%–30%), and Nocardia brasiliensis (3%–10%). This is important because of treatment implications (see later).



      • Infection occurred late in reported series (i.e., mean of 13 to 34 months after transplant surgery and a median of 34.1 months in a third series).



      • Of note, 30% to 69% were receiving trimethoprim-sulfamethoxazole prophylaxis, suggesting that this should be relied on to prevent nocardiosis.



      • Overall, 77% to 100% of patients had pulmonary disease only. In single-lung transplant patients, the majority occurred in the native lung.



      • Pulmonary involvement includes single or multiple nodules, cavitation, interstitial infiltrates, lobar consolidation, and pleural effusions.



      • Extrapulmonary involvement: Neurologic (brain abscess most important; epidural abscess; meningitis), bone, joints, skin, kidney, and multiple other sites (rare but reported)



      • Risk factors with lung transplantation: high-dose steroids, CMV in preceding 6 months, high calcineurin inhibitor levels in the preceding month.



      • Diagnosis: compatible clinical and radiologic findings, stain (Gram and acid fast) and culture of appropriate specimens (may need tissue). Note, routine cultures require 5 to 21 days. Polymerase chain reaction (PCR) is not generally available.



      • Treatment




        • Effective antibiotics include: trimethoprim-sulfamethoxazole, amikacin, imipenem, and third-generation cephalosporins.



        • Variable resistance noted in different species: imipenem ( N. asteroides; N. brasiliensis ); N. farcinica (third-generation cephalosporins). Note: N. nova is generally sensitive to all of the above-mentioned antibiotics.



        • Principles of therapy: (1) Two- to three-drug coverage for severe infection. Susceptibility testing is key. (2) IV trimethoprim-sulfamethoxazole is used as part of first-line therapy in conjuction with amikacin and imipenem. With central nervous system (CNS) disease, include a third-generation cephalosporin. Aim for sulfonamide level of 100 to 150 μg/mL 2 hours after dose. With sulfur allergy, use alternate combinations. (3) Duration of initial therapy: 6 weeks. (4) Oral maintenance: two drugs for 12 months or life long because of relapse potential (agents: trimethoprim-sulfamethoxazole, minocycline, amoxicillin/clavulanic acid, extended spectrum fluoroquinolone). (5) Reduce level of immunosuppression, as feasible. (6) Potential surgical indications: empyema, mediastinitis, pericarditis, brain abscess




      • Outcome: Mortality rate can be high (40%) in one series.




    • Listeria:




      • Listeria monocytogenes is an aerobic or facultative anaerobic intracellular gram-positive rod. It may be found in soil and decaying vegetable matter, and can contaminate a variety of processed foods including soft cheeses.



      • Impaired cell-mediated immunity/corticosteroids are an important predisposing factor.



      • Clinical features include sepsis, meningoencephalitis, febrile gastroenteritis, pneumonia, endocarditis, and so on. It has rarely been described after lung transplantation (usually renal and liver).



      • There is a single report of pleural infection following lung transplantation.



      • Treatment principles




        • Ampicillin plus gentamicin. Imipemen or meropenem are alternatives.



        • In penicillin allergic patients, trimethoprim-sulfamethoxazole can be used. Meropenem is another possibility, although some cross-reactivity exists with penicillin. There is limited experience with linezolid.



        • Duration of therapy is 6 to 8 weeks.



        • Reduce level of immunosuppression, as feasible.





    • Burkholdaria:




      • Microbiology: Formally named Pseudomonas cepacia, the Burkholdaria cepacia complex comprises nine different genomovars or species. Genomovars I through IX have recently been given species names.



      • Consideration of Burkholdaria infections predominate in patients with cystic fibrosis, particularly those being considered for lung transplant.



      • In the United States, the majority of isolates are B. cenocepacia (genomovar III; 50%) and Burkoldaria multivorans (genomovar II; 38%). Similar trends for B. cenocepacia were reported for the United Kingdom, Canada, and Italy.



      • The clinical significance of the different genomovars in lung transplantation stems from reports of poor short-term survival following transplant surgery in patients colonized with Burkholdaria. These patients died of “cepacia syndrome” (i.e., necrotizing pneumonia and severe sepsis).



      • More recent data reports that B. cenocepacia (genomovar III) is most often associated with the cepacia syndrome and poor outcomes, with excellent outcomes in patients with non– B. cenocepacia infections.



      • Thus, genomovar testing should be performed and isolation of non– B. cenocepacia should not preclude transplantation.



      • In patients with B. cenocepacia isolates before transplant surgery, the decision to transplant or not rests with each center and is likely not an absolute contraindication. In such patients, the Toronto group had excellent 1-year survival rate using a protocol of multiple antibiotics perioperatively (inhaled and IV tobramycin, chloramphenicol, ceftazidime) and reduced goals of immunosuppression.





Mycobacterial Infections





  • Introduction




    • Incidence: In lung transplant cases, the reported incidence of Mycobacterium tuberculosis varies from less than 1% to 6.5%. For nontuberculous mycobacteria, only selected case reports and one series have been reported (see Saggar and colleagues for a comprehensive review )



    • Risk factors for mycobacterial disease




      • Residence or origin in high-prevalence endemic areas



      • Environmental factors (prevalence of a particular organism, contact, poor ventilation, etc.)



      • Latent disease in recipient (or donor)



      • High-intensity immunosuppression



      • CMV infection



      • BOS



      • Comorbid conditions (e.g., diabetes mellitus)




    • Risk reduction




      • Screen potential recipients (PPD, interferon release assays)



      • INH prophylaxis for PPD greater than 5 mm induration or significantly positive interferon release assays



      • Imaging showing old granulomatous disease



      • History positive PPD or treated TB in donor



      • Close TB contacts



      • Test for TB in donor and recipient BAL fluid specimens (stain and culture)





  • M. tuberculosis (TB)




    • Usually due to reactivation. Transmission of TB from a donor to recipient has been reported.



    • Usually manifests within the first year and most commonly in the intermediate period (1–6 months).



    • Although pulmonary involvement is most common, disseminated disease can manifest in up to a third of cases. In solid organ transplants, imaging revealed focal infiltrates (40%), military features (22%), nodules (15%), pleural effusion (13%), and interstitial changes (5%). Of note: cavitation was distinctly rare (4%). Usual diagnostic approaches apply. The key to diagnosis is a high index of suspicion.



    • Treatment considerations




      • Usual guidelines as proposed by the American Thoracic Society (ATS), The Centers for Disease Control and Prevention (CDC) and Infectious Diseases Society of America (IDSA) are followed. Treatment should likely be continued for 1 year. High mortality rates were reported for treatment courses of 6 and 9 months.



      • Susceptibility testing is essential.



      • For further details on the approach to multiple drug resistant isolates and surgical considerations, see Chapter 16 by Miller and colleagues, earlier in this text.



      • An important consideration in management is that rifampin and other rifamycins significantly reduce the serum levels of calcineurin inhibitors and sirolimus, thus increasing the risk of rejection.



      • Fluoroquinolones have been suggested as part of multidrug regimens in transplant recipients with TB.





  • Nontuberculous mycobacteria (NTB)




    • NTB can occur following lung transplantation. However, there is only one series reported together with several case reports.



    • In a series of 23 patients of a cohort of 261 lung transplant patients, NTB included Mycobacterium avium complex (13 patients), Mycobacteium abscessus (two patients), Mycobacterium kansasii (one patient), Mycobacterium asiaticum (one patient) causing lung disease. Skin infections due to Mycobacterium haemophilum occurred in five patients. Rapid growers ( Mycobacterium chelonae and Mycobacterium fortuitum ) have been reported causing pulmonary disease and wound infection, respectively. Empyema due to M. abscessus has been noted. Colonization with Mycobacterium gordonae and Mycobacterium scrofulaceum has also been reported.



    • Infections due to NTM usually occur late (i.e., >1 year) but can present in the intermediate period.



    • Treatment considerations




      • Regimens commonly use rifampin (especially important for M. kansasii ), which reduces serum levels of calcineurin inhibitors and sirolimus, thus increasing the risk of rejection, and macrolides such as clarithromycin (important for M. avium complex), which increase levels of calcineurin inhibitors, thus increasing the risk of toxicity.



      • For further details, treatment of NTB and surgical considerations, see Chapter 16 by Miller and colleagues, earlier in this text.





Fungal Infections


Note: For further details on mycology, clinical presentation, diagnosis, and treatment of specific fungal infections, including possible surgical considerations, see Chapter 16 by Miller and colleagues, earlier in this text.




  • Introduction




    • Incidence: Invasive fungal infections were reported in 2.7% of a large cohort of thoracic organ transplant recipients, most of whom were heart transplant recipients. In lung transplant recipients, the incidence was higher (9%). In a recent analysis of pneumonia following lung transplantation, fungi were the cause in 14%.



    • Candida and Aspergillus species are the most common fungal offenders.



    • Risk factors




      • Most of the overall risk factors described earlier pertain to



      • Broad-spectrum antibiotics



      • Corticosteroids



      • Neutropenia



      • Impaired alveolar macrophage function



      • IV catheters



      • Parenteral nutrition



      • Pretransplant colonization



      • Latent endemic fungal disease in recipient



      • Donor-related fungal transmission (rare)



      • Airway problems



      • BOS



      • Comorbid conditions (e.g., diabetes, malnutrition)



      • Environmental and recreational exposures (e.g., construction, gardening, endemic fungi)




    • Colonization versus infection: Distinction can be difficult after transplant surgery. Clinical disease criteria include combinations of




      • Compatible disease process



      • Pathologic demonstration and/or culture of a mold or yeast in fluid or tissue normally sterile



      • Specimens showing inflammation with or without necrotizing granulomas



      • Ancillary serologic and other tests (e.g., cryptococcal antigen)




    • Timeline for fungal infections:




      • Early: Candida, aspergillus (in recipients with pretransplant colonization).



      • Intermediate: Opportunistic fungal infections. Aspergillus (most prominent 1–4 months); Cryptococcus (most prominent 4–6 months); endemic fungi (most prominent >4 months).



      • Late: Cryptococcus; endemic fungi; new fungal pathogens (see later); late-onset aspergillus.




    • Fungal prophylaxis:




      • Recommendations by the American Society of Transplantation in 2004 were based on limited prospective uncontrolled studies. Nevertheless, important principles still apply. These include




        • Prophylaxis is essential in all high-risk patients, such as those with preoperative fungal isolates or donor bronchus–culture positive for Candida spp or other fungi.



        • Risk factors for Aspergillus include primary graft dysfunction, ischemic bronchial segments (particularly with mucosal sloughing/necrosis), anastomotic dehiscence, early recovery of aspergillus or CMV infection.



        • Because Aspergillus is responsible for a significant proportion of post lung transplant fungal infections, agents without Aspergillus cover are suboptimal, unless the subject is a low-risk patient.



        • Traditional agents used are fluconazole, inhaled amphotericin, and itraconazole.



        • In high-risk patients, newer azoles may be used. A recent study compared use of voriconazole with itraconazole with or without inhaled amphotericin, in lung transplant recipients. At 1 year, the rate of invasive aspergillosis was 1.5% in the voriconazole group compared with 23% in the comparator group.



        • With use of voriconazole, regular assay of liver enzymes is necessary, as well as serum levels of calcineurin inhibitors to avoid toxic levels and renal dysfunction. Posaconazole is another promising azole. However, it requires multiple daily dosing and intake of fatty foods to facilitate absorption.



        • Duration of prophylaxis is also not well defined. Low risk: 4 months. High risk: 1 year or indefinite.






Specific Fungal Pathogens





  • Candida




    • Colonization frequent



    • With prophylaxis or preemptive treatment, invasive complications now rare (e.g., invasive pneumonia)



    • Candidal infections now most commonly seen in association with airway anastomotic problems. Treatment includes inhaled and systemic antifungal drugs.



    • Other clinical sequelae include mucocutaneous infection, esophagitis, wound infection, line infection, pneumonia (very rare), empyema, abdominal infection, and sepsis.



    • There has been a noticeable increase in the emergence of non– Candida albicans species. This is important as some of these (e.g., Candida glabrata ) are generally resistant to fluconazole and even new azoles. In a large cohort of thoracic transplant patients in whom invasive fungal infection was reported, one third of candidal infections were non– C. albicans (e.g., C. glabrata, Candida kruzei, Candida parapsilopsis ).



    • Treatment with fluconazole is appropriate for infection with C. albicans . In non– C. albicans infections, especially C. glabrata infection, an echinocandin such as caspofungin should be used.




  • Aspergillus




    • Aspergillus airway colonization is high in lung transplant recipients (20%–46%). This is a risk factor for invasive disease. For example, about a quarter of colonizers went on to develop invasive disease and the risk was 11-fold higher in the first 6 months compared with those who were not colonized. Hence, the importance of preventive therapies. There are several aspergillus species: Aspergillus fumigatus (most common), Aspergillus flavus, and Aspergillus niger.



    • Aspergillus syndromes following lung transplantation




      • Invasive pulmonary aspergillosis (in some series, accounts for 9% of deaths). Primary site is lung allograft in single-lung recipients but can occur in the native lung.



      • Tracheobronchitis (ulcerative or pseudomembranous)



      • Aspergilloma



      • Bronchial impaction and stent infection



      • Empyema



      • Disseminated disease



      • Rhinosinusitis, CNS infection, endophthalmitis, and so on




    • Diagnosis:




      • For more details, see Chapter 16 .



      • While serum galactomannin in lung transplant patients has low sensitivity as an adjunctive test, BAL galactomannin plus compatible clinical picture has good predictive value.




    • Treatment:




      • For more details, including ISDA guidelines, see Chapter 16 .



      • For invasive pulmonary aspergillosis, voriconazole is the treatment of choice. Combination therapies are currently being evaluated.





  • Cryptococcus




    • Third most common fungal infection



    • Acquisition: primary acquisition after transplant surgery or reactivation of latent disease.



    • In patients with solid organ transplants, a third were limited to the lungs, and 53% to 72% were disseminated or involved the CNS (meningitis; brain parenchymal lesions in a third).



    • In patients with pulmonary disease, pleural effusions are not uncommon.



    • An immune reconstitution inflammatory syndrome, resembling worsening disease or relapse, has recently been described in transplant patients.



    • Diagnosis




      • For more details, see Chapter 16 .



      • In patients with single pulmonary nodules, cryptococcal antigen was commonly negative compared with patients with infiltrates and effusions.



      • With meningitis in transplant recipients, serum cryptococcal antigen was positive in 88% to 91%.




    • Treatment




      • For more details, including ISDA guidelines, see Chapter 16 .



      • Severe disease/meningitis: induction—liposomal amphotericin plus flucytosine for 2 weeks; consolidation with fluconazole (400–800 mg/d) for 8 weeks; maintenance: fluconazole (200–400 mg/d) for 6 to 12 months



      • Isolated pulmonary disease: fluconazole (400 mg/d) for 6 to 12 months





  • Geographically limited fungi (Note: For more details on coccidioidomycosis, histoplasmosis, and blastomycosis, see Chapter 16 )




    • The reported incidence in lung and other solid organ transplants ranges from 0.3% to 3%.



    • Acquisition: primary infection in endemic areas or reactivation of latent disease. Donor transmission has been described with lung transplantation.



    • Coccidioidomycosis




      • The incidence varies year by year in relation to local geographic conditions.



      • Disease often severe. Patients present with isolated pulmonary disease or disseminated disease plus pneumonia.



      • Diagnosis





      • Treatment




        • For more details, including ISDA guidelines, see Chapter 16 .



        • With lung transplantation, drug interactions need to be considered (all azoles increase levels of calcineurin inhibitors and sirolimus).



        • Initial therapy is with liposomal amphotericin, which has good tissue penetration, followed by lifelong suppressive therapy with fluconazole (200–400 mg/d). Newer azoles are also active, but clinical experience is limited.





    • Histoplasmosis:




      • Reactivation can produce disseminated disease



      • Can also present with fever of unknown origin and pancytopenia



      • Diagnosis:





      • Treatment;




        • For more details, including ISDA guidelines, see Chapter 16 .






  • Rare and emerging new fungal pathogens




    • Zygomycosis




      • Species include Mucor spp; Rhizopus; Cunninghamella, Absidia



      • Most commonly seen in diabetic allograft recipients



      • Previous exposure to voriconazole may be a risk factor.



      • Rhinocerebral disease, pulmonary, gastrointestinal, genitourinary, skin, and bone disease have been reported in transplant patients.



      • Treatment with lipid amphotericin plus surgery as indicated is the primary approach. Posaconazole has activity, but there is limited experience with this drug



      • For more details, see Chapter 16 .




    • Scedosporium




      • Scedosporium apiospermum (a form of Pseudoallescheria boydii ) and Scedosporium prolificans (mold)



      • Invasive pneumonia or nodular disease; empyema; mycetoma; sinusitis; fungemia; isolated organ involvement or disseminated disease



      • Resistant to amphotericin



      • Treatment: voriconazole



      • High mortality rate, especially with disseminated disease (>50%)




    • Fusarium




      • Mold



      • Neutropenia a risk factor



      • Clinical presentation includes sinopulmonary infection, disseminated disease, skin/soft tissue bone



      • Treatment: lipid amphotericin B; voriconazole




    • Paecilomyces:




      • Produce hyphae in tissue



      • Skin and sinus disease



      • Treatment: voriconazole (posaconazole and ravuconazole have good activity in vitro)




    • Pneumocystis jiroveci (formally carinii)




      • Thought to be more closely related to fungal organisms



      • Risk greatest between 1 and 6 months



      • Universal prophylaxis has virtually eliminated pneumocystis pneumonia in lung transplant recipients, provided compliance is exercised.



      • Life-long prophylaxis is recommended in lung transplant recipients, because the incidence in these patients did not decrease after the first year.



      • Prophylactic agent of choice is trimethoprim-sulfamethoxazole (one single- or double-strength tablet three times a week). In sulfur-allergic patients, inhaled pentamidine, dapsone, or atovaquone are options. Atovaquone failures have been reported.





Viral Infections





  • CMV




    • Introduction




      • CMV is a member of the herpes family of viruses



      • Responsible for significant morbidity after transplant surgery



      • Prophylactic and preemptive treatment strategies have significantly reduced mortality rates due to CMV



      • The incidence of CMV infection and disease is greatest in lung transplant recipients compared with that of other solid organ transplants



      • Without prophylaxis, the combined rate of infection and disease has been reported as high as 54% to 92%.



      • CMV may be associated with augmented immunosuppressive properties, predisposing to opportunistic infections.



      • Definitions:




        • Latent infection : primary latent infection that persists for life. In the United States, more than 50% of adults have positive serologic evidence of prior exposure



        • CMV infection : refers to evidence of active replication and shedding of the virus (positive culture from BAL and other fluids, positive PCR). Patient asymptomatic without clinical evidence of a disease process.



        • CMV disease : Evidence of CMV inclusion bodies in tissue. Usually patients are symptomatic with clinical localization. Viral copies on PCR rises sharply and progressively if the condition is left untreated.




      • Acquisition of CMV infection after transplant surgery




        • Donor transmission



        • CMV-positive blood products



        • Reactivation of latent disease





    • Risk factors




      • The lung is regarded as a primary site for CMV latency and recurrence.



      • Risk has been reported in relation to baseline CMV serologic data on donor (D) and recipient (R):




        • D+/R−: Considered high risk



        • D+/R+: Moderate risk



        • D−/R−: Low risk, particularly if seronegative blood products used




      • Enhanced immunosuppression and cytolytic therapy




    • Clinical disease




      • Timeline for infection and disease: mean of 40 and 55 days, respectively



      • Pneumonitis (need to distinguish from acute rejection because the two conditions clinically share common features; Note: acute rejection can present earlier than the CMV timeline)



      • Chest imaging: infiltrates, focal consolidation, interstitial changes, pleural effusion



      • Rare: endobronchial polyps



      • Flu-like syndrome



      • Extrapulmonary sites of disease




        • Hepatitis



        • Gastrointestinal: colitis, gastroenteritis (inflammation, ulceration, hemorrhage)



        • Bone marrow suppression: leukopenia, thrombocytopenia



        • Retinitis



        • Neurologic: meningoencephalitis; Gullian-Barré (rare)





    • Diagnosis




      • Compatible clinical picture



      • CMV PCR



      • Culture (blood, BAL, urine); rapid shell vial culture



      • Bronchoscopy (detection of typical viral inclusions in biopsy specimens). Positive BAL provides only presumptive evidence.




    • CMV prophylaxis




      • Definitions:




        • Prophylaxis : antiviral therapy to prevent infection and disease, particularly in high-risk patients.



        • Preemptive therapy : antiviral treatment of infection to prevent the progression of disease.




      • Antiviral therapy:




        • Gancyclovir inhibits replication of CMV but does not treat latent infection. Thus, prophylactic regimens can delay the onset of infection.



        • The most common oral agent used for prophylaxis is valgancyclovir, a gancyclovir prodrug with an oral bioavailability of about 60% (10× greater than oral gancyclovir).



        • For prophylaxis, the generally recommended dose of valgancyclovir is 900 mg/d (dose adjustment for renal dysfunction is required). However, encouraging experience with 450 mg daily has recently been reported.



        • CMV—Intravenous immunoglobulin (IVIG) in conjunction with valgancyclovir could be considered in high-risk patients.



        • Ensure all blood products are treated to be free of CMV.



        • Duration of prophylaxis: (1) There is no consistent consensus in the literature. (2) At least 100 days (or 180 days) has been recommended. (3) Our practice is as follows: (a) D+/R−: valgancyclovir for 12 months. (b) D+/R+: valgancyclovir for 6 months. (c) D−/R+: valgancyclovir for 6 months. (d) D−/R−: acyclovir for 3 months.





    • Treatment of disease and preemptive therapy.




      • Preemptive therapy: if viremia occurs after completion of prophylaxis.



      • For preemptive therapy and treatment of disease:




        • IV gancyclovir (5 mg/kg twice a day) for 3 weeks



        • Oral valgancyclovir (900 mg twice a day) for 3 weeks.




      • CMV-resistant strains




        • Suggested by poor clinical or virologic response, recurrent infection, and so on.



        • Gancyclovir susceptibility testing is possible.



        • Treatment considerations include the use of foscarnet alone or in combination with CMV-IVIG or gancyclovir. The down side of foscarnet is enhanced renal toxicity in combination with calcineurin inhibitors. Treatment end point in such cases is reduction in viral load below assay detection.






  • Community respiratory viruses




    • Introduction:




      • Can cause significant morbidity and mortality in lung transplant recipients.



      • Incidence: Community respiratory viruses have been reported in 3% to 21% of lung transplant recipients.



      • Variability: owing to varying awareness, robustness, and stringency of detection methodologies, geographic and climatic variation, contact with susceptible population groups.



      • Seasonal variation: Respiratory syncytial virus (RSV), influenza, parainfluenza 1 and 2, and rhinovirus occur mainly in winter. Adenovirus and parainfluenza 3 occur year round.



      • Acquisition: contagious contact, reactivation of latent infection, nosocomial transmission, donor transmission (e.g., adenovirus)




    • Parainfluenza




      • Time of diagnosis: range 0.6 to 5 years, with a median of 2.1 years Serotype 3 is most common.



      • Clinical




        • Tracheobronchitis



        • Pneumonia



        • Respiratory failure in a fifth of cases (n = 24) in one series.



        • Can be associated with rejection




      • Diagnosis: BAL fluorescent antibody (FA), culture



      • Treatment: anecdotal reports of aerosolized ribavirin; mainly supportive




    • RSV




      • Onset: 2 weeks to 2 years



      • Clinical




        • Tracheobronchitis



        • Pneumonia



        • Respiratory failure in a fifth of cases (n = 24) in one series.



        • Secondary bacterial infection




      • Diagnosis:




        • BAL FA, culture, shell vial assays




      • Treatment:




        • aerosolized ribavirin in severe cases



        • RSV immune globulin





    • Adenovirus




      • DNA virus with six subgroups



      • Presentation can be early (intermediate phase) or late



      • Clinical




        • Upper respiratory tract infection



        • Pneumonia (mild to severe)



        • Coinfection with bacteria or other opportunistic infections



        • Hepatitis



        • Hemorrhagic colitis; enterocolitis



        • Hemorrhagic cystitis, nephritis



        • Disseminated disease




      • Diagnosis:




        • Culture (routine, shell vial)



        • fluorescent antibody (FA) and electron microscopy (EM) of tissue or secretions



        • Enzyme immunoassay (EIA) of respiratory specimens



        • PCR




      • Treatment:




        • Cidofovir (has renal, hematologic, and ocular side effects). Treatment of choice with severe infection or disseminated disease.



        • Limited data for zalcitabine and gancyclovir





    • Influenza




      • Rarely reported in the lung transplant literature



      • Annual influenza vaccine advisable (efficacy not well established)



      • Oseltamivir can be used in prevention in special circumstances



      • Oseltamivir can also be used in treatment (avoid amantadine/rimantidine because of resistance issues)




    • Human metapneumovirus




      • Member of the Paramyxoviridae family (first isolated in 2001)



      • Can produce disease resembling RSV




    • Herpes simplex




      • Clinical




        • Can present early after transplant surgery



        • Tracheobronchitis



        • Pneumonitis




      • Prophylaxis and treatment




        • Acyclovir for both



        • Gancyclovir prophylaxis for CMV covers Herpes simplex





    • Parvovirus B19




      • Single-stranded DNA virus



      • Sixty to ninety percent of adults have antibodies against parvovirus B19



      • Median time to onset after solid organ transplant reported as 7 weeks



      • Clinical findings in series of 98 cases post transplant




        • Anemia (99%), leucopenia (36%), thrombocytopenia (21%)



        • Pneumonitis



        • Myocarditis



        • Hepatitis




      • Diagnosis




        • Serology for immunoglobulin M (IgM) antibodies (a third negative with disease onset)



        • PCR (96%)




      • Treatment




        • IVIG





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Jun 24, 2019 | Posted by in CARDIAC SURGERY | Comments Off on Intermediate and Late Complications of Lung Transplantation
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