Infections following organ transplantation (Including Solid Organ and Hematopoietic Stem cell): Presenting with Pulmonary infiltrates

Pulmonary infiltrates are common in hematopoietic stem cell transplant (HSCT) and solid organ transplant recipients, and may be caused by bacterial, fungal, viral, or parasitic infections as well as noninfectious causes. Although a wide variety of causes are possible, an understanding of the time post-transplant, the degree of immunosuppression of the recipient and the recipient’s previous environmental exposures can help to focus the differential diagnosis. Immunocompromised patients frequently do not produce purulent sputum, and bronchoalveolar lavage (with or without transbronchial biopsy, depending on the platelet count) and/or open lung biopsy may be required to make the diagnosis. A microbiologic diagnosis is preferred whenever possible, as broad-spectrum empiric therapy in this population may lead to toxicity.

Pulmonary infections in immunocompromised hosts may present with dry or productive cough, shortness of breath, tachycardia, tachypnea and hypoxemia, with or without fever, hypotension, chills or sweats. Such infections can progress rapidly, particularly in highly immunosuppressed patients. Signs of lung consolidation on physical examination may be absent, and chest radiography may reveal more extensive involvement than suspected on the basis of symptoms.

Opportunistic pathogens should be considered from the start. Although a transplant recipient (particularly one more than a year post-transplant who is on stable low-dose immunosuppression) may present with community-acquired pneumonia, a severely ill transplant recipient should never simply be assumed to have conventional community-acquired pathogens. It is also important to be aware that quinolone resistance (ciprofloxacin, levofloxacin, moxifloxacin) is common in this population due to use for neutropenia prophylaxis or previous courses of antibiotic therapy for infections.

• Obtain chest radiograph (PA/lateral preferred if possible).

• Obtain cultures of blood, including all lumens of indwelling catheters; send expectorated sputum (if produced) for Gram stain and culture (sometimes also fungal AFB, and Nocardia stain and culture, particularly if bronchoscopy will not be performed).

• Consider nasopharyngeal swab for respiratory viruses (influenza, parainfluenza, RSV, adenovirus, human metapneumovirus) particularly in the setting of an outbreak or seasonal timing, and/or with diffuse or patchy infiltrates on chest radiograph.

• Send blood for CMV quantitative PCR (or local lab CMV test such as antigenemia).

• Depending on stability and clinical situation, consider chest CT, bronchoalveolar lavage with or without transbronchial biopsy, and open lung biopsy.

• Maintain adequate oxygenation; intubate if indicated.

• Transfuse platelets if pulmonary hemorrhage is suspected.

• Cultures of blood, sputum, urine, nasopharyngeal swab as above.

• Initiate broad-spectrum antibiotic therapy (particularly in the neutropenic patient) with coverage for Gram-negative bacilli (including Pseudomonas), Gram-positive cocci (including MRSA) and atypical organisms (Legionella, Chlamydia, Mycoplasma) see below.

• If the patient is a lung transplant recipient who has had previous issues with airway stenting, necrosis or dehiscence, discuss with the Lung Transplant Team regarding urgent bronchoscopy and intervention.

• Review the patient’s prior cultures to see if there are any known prior respiratory colonizing organisms.

• If BAL is performed, send a full ID-BAL panel (see below) rather than just a routine culture for bacteria.

• Consider filgrastim (G-CSF) in the neutropenic patient.

• Consider stress doses of steroids if adrenal insufficiency is a possibility.

• Check for hypogammaglobulinemia (total IgG level in mg/dl).

• Follow isolation precautions as per the hospital’s Infection control policies (e.g., for suspected influenza).

In addition to routine cultures of blood, urine, sputum as above, check quantitative CMV PCR on blood, urine antigens for Legionella pneumophila and Streptococcus pneumoniae, and consider quantitative EBV DNA, human herpesvirus-6 PCR, cryptococcal antigen, fungal antibody panel, Aspergillus galactomannan antigen on blood, beta-d-glucan on blood, Histoplasma serum and urine antigens.

Consider nasopharyngeal swab for respiratory viral panel for influenza, parainfluenza, RSV, adenovirus and other respiratory viruses; PCR is preferred over viral culture for rapidity of results.

If bronchoalveolar lavage (BAL) is performed, send stains/cultures and/or PCRs for the following: routine bacteria, fungi, mycobacteria (AFB), Nocardia, Legionella, Pneumocystis, CMV and respiratory viruses. If Aspergillus galactomannan antigen is available on BAL fluid, this is more helpful than on blood. PCR for Mycoplasma and Chlamydia also may be useful if available.

If possible to obtain, transbronchial biopsy adds valuable information to the BAL, for example regarding allograft rejection in a lung transplant recipient; Transbronchial biopsy also may reveal CMV inclusions and/or positive CMV immunostain indicative of CMV pneumonitis; or it may show hyphae indicative of invasive fungal infection even in the absence of a positive BAL fungal culture.

Patterns on chest radiography can give clues to diagnosis. The chest CT provides far more information than the standard chest radiograph. Diffuse patterns are most consistent with fluid overload, viral pneumonia, Pneumocystis, alveolar hemorrhage or drug toxicity. Lobar infiltrates are most characteristic of bacterial pneumonia whereas patchy and multifocal infiltrates can indicate bacterial, viral or sometimes other etiologies. Rapidly progressive multilobar infiltrates should suggest Staph. aureus, Gram-negative bacteria, Legionella, viral or occasionally fungal etiologies.

Nodular infiltrates, particularly cavitary nodular lesions, are often associated with fungal, mycobacterial or nocardial infections, although occasionally Pneumocystis or conventional bacteria such as Pseudomonas can have a nodular appearance. Post-transplant lymphoproliferative disease (PTLD) may present with multiple pulmonary nodules +/- extrapulmonary localization. There are many exceptions to these generalizations in immunocompromised patients.

Diagnostic thoracentesis is helpful in the setting of large pleural effusions if the platelet count and coagulation parameters are adequate. It is important to send more than just cultures: Cell count and differential, protein, glucose, LDH, pH, as well as stains and cultures for bacteria, fungi, and mycobacteria are helpful. In some circumstances, additional tests such as cytology, amylase or triglycerides may be indicated.

In addition to diagnostic testing and radiography, a thorough history of environmental exposures including travel, pets and hobbies can provide clues to the etiology of pulmonary infiltrates. If the patient is intubated or obtunded, such history is best obtained from a family member or close friend. For example, gardening, farming, construction, other extensive outdoor exposures and marijuana smoking are risk factors for invasive mold infections, particularly aspergillosis, as well as some unusual bacterial infections such as nocardiosis and nontuberculous mycobacterial infection.

Exposure to contaminated water sources (including in the hospital) is a risk factor for Legionella. Exposure to crowds, ill contacts (particularly small children), and some occupations (schoolteacher, child care provider) are risk factors for community-acquired respiratory viruses such as influenza, parainfluenza and respiratory syncytial virus.

If the patient is a lung transplant recipient, pre-transplant colonization (particularly in patients with cystic fibrosis or bronchiectasis) can provide clues to post-transplant infections. Examination of culture and susceptibility data from previous months provides a starting point for initial empiric antibiotic therapy while awaiting cultures. In many lung transplant recipients, cultures are obtained from both the donor and recipient lungs on the day of transplant, and pathogen-directed therapy is initiated to prevent colonization from becoming invasive infection.

In addition, many lung transplant centers perform surveillance bronchoscopies at defined intervals to screen for rejection and the BAL fluid is usually sent for a full panel of microbiology studies. If this information is available, it is useful in formulating a regimen, since colonization at one point in time is apt to develop into full-blown infection later in the immunosuppressed patient.

Knowledge of the antimicrobial prophylaxis that the patient has been receiving has important implications for what infections they might develop. For example, if the patient has not been on Pneumocystis prophylaxis or is receiving aerosolized pentamidine (a less effective prophylaxis) rather than trimethoprim-sulfamethoxazole or dapsone, suspect Pneumocystis, particularly if the patient is within one year post-transplant.

Recent cessation of CMV prophylaxis (e.g., valganciclovir) makes CMV pneumonitis more likely (particularly in the high-risk patient: donor-seropositive/recipient-seronegative or D+/R- in solid organ transplantation, and donor-seronegative/recipient-seropositive or D-/R+ in HSCT).

Some transplant recipients (particularly HSCT, lung, liver or intestinal transplant recipients) may already be receiving long-term antifungal prophylaxis such as fluconazole, itraconazole, voriconazole or micafungin. Thus, if invasive fungal infection is suspected, organisms may be those which might not be covered by such prophylaxis (for example, mucormycosis in a patient on voriconazole prophylaxis).

Many noninfectious etiologies can mimic infection in the transplant recipient with pulmonary infiltrates. Transfusion-associated lung injury may occur, but the timing and rapid resolution as well as exclusion of infectious etiologies can help make this diagnosis. Pulmonary hemorrhage is most common in severely thrombocytopenic patients and may be also suspected by the appearance of bloody fluid on BAL.

Lung allograft rejection may mimic pneumonia; an infiltrate seen only in the transplanted lung can be a clue (in a single-lung transplant recipient), but a tissue diagnosis is important, particularly since treatment involves intensification of immunosuppression.

Medication-associated pneumonitis may occur in patients who have had prior chemotherapy (such as busulfan, bleomycin or methotrexate) or who are receiving sirolimus as part of an immunosuppressive regimen. Sirolimus-associated interstitial pneumonitis is a well-described entity that can occur with or without fever, but is a diagnosis of exclusion. Recent initiation of sirolimus therapy and an interstitial pattern should put this high on the list, although delayed onset may also occur.

If sirolimus is discontinued due to suspicion of sirolimus-associated interstitial pneumonitis, consultation with the patient’s transplant team is necessary in order to provide alternative immunosuppression to prevent allograft rejection.

Radiation pneumonitis may occur in HSCT patients who have undergone prior radiation therapy for their underlying cancer or as part of their conditioning regimen for their transplant. Radiation pneumonitis typically has a delayed onset and is manifested by hypoxemia and patchy infiltrates. Treatment is with steroids after infectious etiologies have been addressed.

Pulmonary edema is common, particularly in transplant recipients with renal insufficiency, with underlying cardiac renal dysfunction, and in patients receiving large amounts of blood products, fluids and antibiotics. Echocardiography to assess cardiac function is helpful in these situations.

In some HSCT recipients, a capillary leak syndrome with associated respiratory failure can occur in the setting of engraftment (when the WBC is rapidly recovering). This may or may not involve rash, fever and hypotension. Some transplant centers use steroid prophylaxis to prevent this so-called “engraftment syndrome.” There is no specific test for this syndrome, but the timing of occurrence and the exclusion of other causes helps to secure the diagnosis.

Diagnosis of noninfectious causes of pneumonitis in transplant recipients is generally based on timing of occurrence, clinical judgment, excluding infection with appropriate cultures, and the clinical course and resolution. For hemodynamically stable patients, response to an empiric diuretic trial can be diagnostic. At times, withdrawal of a possible precipitating agent (such as sirolimus) may be the only way to make the diagnosis. Procalcitonin levels may be helpful (higher levels suggest infection and lower levels a noninfectious cause) but are still under study in this particular population.

In general, the severely ill patient with pulmonary infiltrates should be broadly covered while awaiting cultures and other diagnostic testing. That coverage should include MRSA, Gram-negative bacilli and atypical organisms such as Mycoplasma, Chlamydophila pneumoniae and Legionella. A sample regimen might be vancomycin plus piperacillin-tazobactam plus azithromycin, but many other such combinations are possible.

Utility of linezolid may be limited by severe cytopenias in some transplant recipients. Azithromycin is the preferred macrolide in patients receiving cyclosporine, tacrolimus or sirolimus. Quinolone resistance is common in this population due to prior antibiotic use. Daptomycin does not penetrate lung parenchyma. Any previous colonizing organisms (particularly multi-drug resistant organisms) from the patient’s prior cultures should be taken into account, as well as local antibiotic resistance patterns at that center.

Addition of an empiric antifungal agent may be considered in a severely ill neutropenic patient, in a patient with extensive prior antibacterial use, with known prior fungal colonization or infection, with a positive fungal biomarker such as beta-d-glucan or galactomannan, and/or with compatible radiography (nodular pulmonary infiltrates particularly if cavitation or halo sign is present). For aspergillosis, voriconazole is the considered the drug of choice in most clinical settings, with lipid amphotericin preparations and isavuconazole as alternatives. Posaconazole has activity against Aspergillus species but is more useful in prophylaxis. For immunocompromised patients with clinically severe aspergillosis, an echinocandin may be combined with voriconazole for the first 14 days, followed by voriconazole alone, based on a randomized trial of > 400 patients with hematologic malignancies by Marr et al. For zygomycosis, lipid amphotericin formulations should be used, with isavuconazole as an alternative.

CMV pneumonitis should be considered in transplant recipients, particularly within the first 6 months post-transplant, although “late CMV” can occur and can be influenced by duration of prophylaxis. CMV blood viral load is generally high, though not always. Ganciclovir should be initiated for suspected CMV pneumonitis (unless ganciclovir resistance or severe neutropenia is present, in which case consider alternative therapy such as foscarnet or cidofovir).

For proven or strongly suspected CMV pneumonitis, addition of immunoglobulin therapy (CMVIg or IVIg, e.g., on days 1, 3, 5 of therapy) has been shown to improve survival in the HSCT recipient and may be used also in CMV pneumonitis in the SOT recipient, although evidence is less strong in SOT. Dosing and regimens of immunoglobulin preparations may vary.

Community respiratory viruses can produce rapid and severe respiratory deterioration, and in the setting of an outbreak, empiric therapy for influenza can be considered (depending on resistance patterns and CDC treatment recommendations during any particular flu season).

Therapy for other respiratory viruses is less established, but ribavirin may be considered for RSV or metapneumovirus infection, and cidofovir for severe adenovirus infection. For RSV and metapneumovirus infection, oral ribavirin is increasingly used in place of inhaled ribavirin, due to probable equivalent efficacy, less toxicity to health care workers, and lower cost.

If radiation or chemotherapy-associated pneumonitis is suspected, addition of steroid therapy should be considered.

Dosages of antimicrobials should be maximal within the indicated range (especially for neutropenic or septic patients), but should be adjusted for renal dysfunction according to the manufacturers’ instructions. The following list includes some commonly used antibiotics in this setting, though it is not comprehensive; doses given are for normal renal function and should be adjusted for renal dysfunction according to the manufacturer’s nomogram.

• Acyclovir 5 mg/kg IV Q8h (mucosal HSV in an immunocompromised patient); 10 mg/kg IV Q8h (for disseminated zoster in an immunocompromised patient or one unable to take oral medications); acyclovir 400 mg po BID (e.g.) for prophylaxis.

• Amphotericin B Lipid Complex (ABLC) or Liposomal Amphotericin B – prophylaxis 3 mg/kg/day, treatment 5 mg/kg/day (premedication generally with acetaminophen, diphenhydramine, +/- hydrocortisone, normal saline).

• Amikacin – regimens vary depending on traditional or extended interval dosing (use manufacturer’s nomogram) and adjust to maintain trough level at less than 8 and peak 28-35 mcg/ml (for pneumonia or sepsis).

• Anidulafungin 200 mg IV loading dose followed by 100 mg IV once daily.

• Azithromycin 500 mg IV daily.

• Aztreonam 1-2 g IV Q6-8h.

• Caspofungin 70 mg IV x 1 dose then 50 mg IV Q12h.

• Cefazolin g IV Q8h.

• Cefepime 2 g IV Q8 h.

• Ceftazidime 1-2 g IV Q8h.

• Ceftriaxone 1 g IV Q24h (higher for endocarditis or meningitis).

• Ciprofloxacin 400 mg IV Q12h.

• Clindamycin 600-900 mg IV Q8h.

• Colistimethate 100-125 mg IV Q6-12h (generally reserved for MDR organisms – especially important to adjust for renal dysfunction – watch for nephrotoxicity).

• Cytomegalovirus immune globulin (CMVIg) 100 mg/kg-150 mg/kg IV (premedication generally with acetaminophen, diphenhydramine, +/- hydrocortisone; dosing schedules vary; used for hypogammaglobulinemia or adjunctive therapy for tissue-invasive CMV disease such as CMV pneumonitis).

• Daptomycin 6 mg/kg IV Q24h.

• Filgrastim (G-CSF) 300 mcg SQ or 480 mcg SQ can be administered daily as needed for neutropenia in the solid organ transplant recipient (it does not appear to precipitate rejection in this setting). Filgrastim should be used under the guidance of a hematologist in the HSCT recipient. When filgrastim is stopped, the WBC count may fall by up to 50%.

• Fluconazole 100-400 mg IV Q24h.

• Foscarnet – follow manufacturer’s nomogram.

• Ganciclovir 5 mg/kg IV Q12h (therapy) or 5 mg/kg IV Q24h (prophylaxis).

• Gentamicin – regimens vary depending on traditional or extended interval dosing (use manufacturer’s nomogram) and adjust to maintain trough level at less than 2 and peak 7-10 mcg/ml (for pneumonia or sepsis).

• Imipenem 500-1000 mg Iv Q6h.

• Intravenous immunoglobulin (IVIg) 400 mg/kg IV per dose; number and timing of doses varies; with acetaminophen/diphenhydramine (and sometimes hydrocortisone) premedication – used for hypogammaglobulinemia or adjunctive therapy for tissue-invasive CMV disease such as CMV pneumonitis.

• Isavuconazole 372 mg po/IV Q8h for 6 doses, then 372 mg po/IV Q24h.

• Itraconazole 200 mg Q12h.

• Levofloxacin 500 mg-750 mg IV Q24h.

• Linezolid 600 mg IV Q12h.

• Meropenem 500 mg IV Q6h-1 gram IV Q8h.

• Metronidazole 500 mg IV Q6-8h.

• Micafungin 100-150 mg IV Q24h.

• Moxifloxacin 400 mg IV Q24h.

• Oxacillin 1-2 g IV Q4-6h.

• Piperacillin-tazobactam 3.375 grams IV Q6h-4.5 grams IV Q6h.

• Posaconazole – Extended-release formulation preferred: 300 mg po Q12 x 2 doses, then 300 mg po daily. If necessary to administer via tube, use the liquid formulation, 200 mg po four times daily (treatment dose) or 200 mg po three times daily (prophylaxis) – which must be given with food containing fat.

• Tigecycline 100 mg IV x 1 dose followed by 50 mg IV Q12h.

• Tobramycin – regimens vary depending on traditional or extended interval dosing (use manufacturer’s nomogram) and adjust to maintain trough level at less than 2 and peak 7-10 mcg/ml (for pneumonia or sepsis).

• Trimethoprim-sulfamethoxazole one double-strength po daily or thrice weekly for Pneumocystis prophylaxis; 15-20 mg/kg/day of the trimethoprim component (divided Q6h) for treatment of Pneumocystis pneumonia.

• Vancomycin 1-1.5 grams IV Q12h with subsequent pre-dose levels and appropriate adjustment.

• Valganciclovir 900 mg po BID for treatment, and 450 mg po BID (or 900 mg po daily) for prophylaxis.

• Voriconazole 6 mg/kg po/IV Q12h x 2 doses then 4 mg/kg IV Q12h, with a level on Day 5 (aiming for level 2 – 5.

Note that azole antifungals and some macrolides (erythromycin, clarithromycin) raise the levels of cyclosporine, tacrolimus, sirolimus, and everolimus, and require close monitoring and adjustment of levels and doses of those agents. Azithromycin is the preferred macrolide in patients receiving these agents, as the interaction is minimal. Also note that aminoglycosides may have enhanced nephrotoxicity in patients receiving cyclosporine or tacrolimus, and alternative agents should be considered if appropriate microbiologically. Assistance of a pharmacist familiar with transplant-related issues is very helpful.

In refractory cases, particularly those in which BAL with full microbiology studies has been unrevealing, open lung biopsy should be considered. This affords the opportunity to obtain a larger piece of tissue which can also be sent for the list of microbiologic studies described above for BAL. Organisms which might fail to grow due to prior antimicrobial therapy might still be visualized on the biopsy (such as fungal hyphae on a Gomori methenamine silver stain), and morphology of these organisms can give a clue to the general group of pathogens (e.g., Aspergillus vs. Mucor) which would have implications for choice of an antifungal agent.

The biopsy can be stained for a CMV immunostain which adds information to standard histopathology (CMV viral inclusions may or may not be seen, and the immunostain adds sensitivity).

For suspected post-transplant lymphoproliferative disease (PTLD), the tissue can be processed for EBV in situ hybridization, particularly for EBER (see below).

With microbiologically appropriate treatment, expect to see stabilization of hemodynamic and respiratory parameters over several days, but keep in mind that improvement may be slower in the immunocompromised patient than in the normal host. Serial chest radiography, fever curve, supplemental oxygen requirements and pressor requirements can provide clues to clinical improvement. The WBC count is not always reliable in this population; procalcitonin and CRP levels may provide better indications of disease activity but are still being validated in this population.

Worsening oxygenation, spread of previously localized infiltrates to become multifocal or diffuse, increasing pressor requirements or other deterioration in clinical condition should prompt reassessment which may include repeating cultures, broadening antibiotic therapy including antifungal therapy, and/or proceeding to a more aggressive diagnostic modality such as open-lung biopsy.

When broad-spectrum empiric antimicrobial therapy is ineffective, consider multidrug-resistant organisms, noninfectious causes (e.g., radiation or chemotherapy-induced pneumonitis; sirolimus-associated interstitial pneumonitis), post-transplant lymphoproliferative disease (which requires a tissue biopsy for diagnosis) or unusual pathogens such as disseminated strongyloidiasis (in a patient with history of travel to or residence in endemic areas).

Serial chest radiography is helpful in the critically ill patient, but for long-term followup, repeat chest CT may be needed to assess resolution of pulmonary nodules, cavities etc., and to guide duration of therapy. If CMV pneumonitis is diagnosed, weekly monitoring of the quantitative CMV PCR viral load is helpful in guiding duration of therapy. For bacteremic patients, blood cultures should be repeated until they turn negative, and ideally should be repeated again after the completion of antibiotic therapy.

Duration of therapy is individualized to the particular patient’s situation but frequently is longer than in the nonimmunocompromised host. Involvement of an infectious disease specialist familiar with transplant recipients is helpful.

Impairment of host immune defenses from the patient’s underlying disease, from exogenously administered immunosuppression, from neutropenia or from previous or concomitant immunosuppressing infections such as CMV, can predispose to pulmonary infections with a variety of pathogens.

Old granulomatous disease (fungal, mycobacterial) even from decades ago, which has been dormant and contained in isolated scattered granulomata, can reactivate under the influence of transplant immunosuppression, producing nodules, cavities, infiltrates, and sometimes extrapulmonary or systemic disease. See “Epidemiology” below for discussion of risk factors for mold infections such as aspergillosis.

Screening for latent TB infection (LTBI) should be performed in all transplant candidates, but centers vary in their approach to prophylaxis, so TB should be considered, particularly in a patient with risk factors or in whom LTBI testing results were positive, anergic, or unknown, and who did not receive LTBI prophylaxis.

Local respiratory defenses may also be impaired and may lead to pneumonia, as in the lung transplant recipient with bronchiolitis obliterans syndrome, a progressive impairment of allograft function characterized by diminished pulmonary function tests and replacement of functioning lung tissue with fibrotic changes. Impaired cough or gag reflexes or mental status changes also may increase risk.

An example is impairment of consciousness and aspiration pneumonia in an encephalopathic liver transplant candidate or recipient. Late survivors of HSCT may develop a form of graft-vs-host disease of the lung, which resembles bronchiolitis obliterans and also predisposes to infections. Long-term immunoglobulin deficiencies may predispose to pneumonia with encapsulated organisms such as Pneumococcus and Hemophilus species.

CMV pneumonitis may result from local reactivation within the lung allograft (in a lung recipient with a CMV-positive donor), or may result from systemic CMV reactivation in any type of organ or HSCT recipient. Loss of control by CMV-specific T lymphocytes as a result of immunosuppression or myeloablative chemotherapy results in unchecked CMV replication and the development of a detectable CMV viral load in blood.

Low levels of CMV DNA are often asymptomatic, but the doubling time is rapid in immunosuppressed patients, and as the viral load rises, symptomatic CMV disease (which may be tissue-invasive in the lung) becomes more likely. CMV prevention strategies are often directed at minimizing viral load, but occasionally biopsy-proven tissue-invasive CMV disease can occur with a low or even undetectable blood viral load. However, CMV pneumonitis is most likely in the presence of a high blood CMV viral load.

Human herpesvirus-6 has been implicated as the cause of at least some of the cases of post-transplant pneumonitis that were previously thought to be idiopathic. Reactivation of HHV-6 often occurs earlier than CMV but can mimic CMV in its clinical presentation, and may also be accompanied by hepatitis, meningoencephalitis and/or pancytopenia (including graft loss or nonengraftment in HSCT patients).

When virus-specific T-lymphocytes are depleted by immunosuppressive protocols, EBV-infected lymphocytes can proliferate unchecked and post-transplant lymphoproliferative disease (PTLD) may develop. PTLD is usually first a polyclonal lymphoproliferative process, which then may progress and transform to a high-grade monoclonal B cell lymphoma that can present in any organ, but has particular affinity for the allograft (such as pulmonary nodules in a lung transplant recipient). There are various histopathologic categories of PTLD, and biopsy tissue can be processed for EBV in situ hybridization, particularly for EBER.

EBER are EBV viral-encoded RNAs that have been implicated in oncogenesis, and a strongly positive EBER stain is highly suggestive of PTLD in the right setting. A CD20 stain can confirm B cell origin of the EBER-positive cells. Most early-onset PTLD occurring within 6 months post-transplant is EBV-related and most frequently occurs in the EBV-mismatched patient (EBV donor seropositive, recipient seronegative in the solid organ transplant population). Be aware, however, that some PTLD (particularly late-onset, or after 1 year post-transplant) is EBV-negative; EBER studies in that case would be negative but PTLD may still be diagnosed on histopathology and clonality studies.

Pulmonary fungal infections frequently relate to environmental exposures, either recent or remote in time. Residence in endemic areas is a risk factor for the geographically limited endemic mycoses histoplasmosis, coccidioidomycosis and blastomycosis. The first two are particularly common in transplant recipients, particularly those residing in the Midwest (histoplasmosis) or the Southwest US (coccidioidomycosis).

Cryptococcosis is common in many locations and frequently relates to exposure to birds or bird droppings. Aspergillosis and other molds (filamentous fungi) may be encountered in exposure to the outdoors (especially dirt, soil, decaying vegetation) or construction (hospital or domiciliary). Patients with extensive histories of gardening, farming, landscaping, hiking, camping, exposure to construction (hospital or domiciliary) or marijuana smoking are at higher risk of invasive fungal infections due to prior colonization and reactivation in the setting of immunosuppression.

Bacterial pneumonias in transplant recipients may result from community-acquired pathogens or may be healthcare-associated. Gram-negative organisms, including multiresistant organisms, are particularly common. At some centers, Legionella is a common etiology in this setting. Nocardiosis and mycobacterial infections may also result from outdoor exposures; in addition, some mycobacterial infections are related to water exposures such as lake swimming and hot tubs.

Pneumocystis pneumonia is seen almost exclusively in immunocompromised hosts, particularly HIV/AIDS and transplant. Pneumocystis prophylaxis is universal in most transplant programs for at least the first 6-12 months post-transplant, and lung transplant recipients should receive lifelong Pneumocystis prophylaxis as they remain at risk even late post-transplant.

As discussed above, CMV pneumonitis is most common in high-risk transplant recipients: donor-positive, recipient-negative (D+/R-) solid organ and donor-negative, recipient-positive (D-/R+) HSCT recipients, although it may also occur with other combinations of CMV sero-status. Recent rejection and intensification of immunosuppression are common precipitating factors. Tissue-invasive CMV in the lung (CMV pneumonitis) may occur in any transplant recipient, but is particularly common in lung transplant and HSCT recipients.

In the HSCT patient, the classic time course of appearance of CMV pneumonitis was 50-100 days post-transplant,. Solid organ transplant recipients at risk for CMV are either managed with antiviral prophylaxis (generally for a period of 3-6 months, most commonly with valganciclovir) or pre-emptive therapy (reserving antiviral therapy for those patients who develop evidence of CMV viremia during monitoring with a sensitive early detection test such as the CMV PCR). In the current era, most HSCT programs use pre-emptive therapy (because of the risk of neutropenia from valganciclovir), and most SOT programs use prophylaxis.

Recent cessation of prophylaxis or a recently rising blood CMV viral load may suggest CMV pneumonitis. Increasing viral load despite ganciclovir or valganciclovir therapy can be a clue to ganciclovir-resistant CMV.

Ganciclovir-resistant CMV, involving mutations in the UL97 or UL54 region of CMV, should be suspected in the patient with CMV viremia and/or pneumonitis not responding to therapy, with a very high or rising viral load or a clinically worsening course. Genotyping of the CMV isolate is helpful but turnaround time is generally days to a week. Alternative therapies for ganciclovir-resistant CMV include foscarnet, combination ganciclovir/foscarnet and cidofovir. Newer drugs such as maribavir are under development for CMV, but none are currently available on compassionate use although treatment trials are expected in the near future. Consultation with a transplant infectious disease specialist is important.

Resolution of pulmonary infections depends to a great extent on the immune function of the host. Persistent neutropenia, multiorgan dysfunction and lack of improvement in oxygenation and lung function despite appropriate antimicrobials are risk factors for poor outcomes, but some infectious processes may resolve very slowly in the immunocompromised host, and slow improvement is not necessarily an indicator of treatment failure.

Ability to modify immune defects (e.g., replacement of immunoglobulin in the hypogammaglobulinemic patient, filgrastim in the neutropenic patient or reduction of immunosuppressive therapy) may make the difference in achieving a favorable outcome of the infection.

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Cordonnier, C, Bernaudin, JF, Bierling, P, Huet, Y, Vernant, JP.. “Pulmonary complications occurring after allogeneic bone marrow transplantation. A study of 130 consecutive transplanted patients”. Cancer. vol. 58. 1 Sept 1986. pp. 1047-54. (Over half of pulmonary complications were infectious, with CMV, bacterial infections and aspergillosis predominating.)

De Castro, N, Neuville, S, Sarfati, C. “Occurrence of Pneumocystis jiroveci pneumonia after allogeneic stem cell transplantation: a 6-year retrospective study”. Bone Marrow Transplant. vol. 36. 2005. pp. 879-83. (Risk factors for both early and late Pneumocystis jiroveci pneumonia, including in those HSCT recipients whose prophylaxis has been discontinued.)

Escuissato, DL, Gasparetto, EL, Marchiori, E. “Pulmonary infections after bone marrow transplantation: high-resolution CT findings in 111 patients”. AJR Am J Roentgenol. vol. 185. 2005. pp. 608-15. (Large nodules and the halo sign are associated with fungal infection, but occasionally can occur with other infectious etiologies.)

Wang, JY, Chang, YL, Lee, LN. “Diffuse pulmonary infiltrates after bone marrow transplantation: the role of open lung biopsy”. Ann Thorac Surg. vol. 78. 2004. pp. 267-72. (Utility of open lung biopsy in establishing the cause of diffuse infiltrates: idiopathic, cytomegalovirus, and other causes such as tuberculosis.)

Aduen, JF, Hellinger, WC, Kramer, DJ. “Spectrum of pneumonia in the current era of liver transplantation and its effect on survival”. Mayo Clin Proc. vol. 80. 2005. pp. 1303-6. (Pneumonia after liver transplant is less frequent in the current era; Pseudomonas is the most common early pathogen.)

Aguilar-Guisado, M, Givalda, J, Ussetti, P. “Pneumonia after lung transplantation in the RESITRA cohort: a multicenter prospective study”. Am J Transplant. vol. 7. 2007. pp. 1989-96. (Study from a large multicenter cohort in Spain; bacteria caused over 80% of pneumonia; Pseudomonas was the most common. CMV was the most common viral cause and Aspergillus the most common fungal cause.)

Campos, S, Caramori, M, Teixeira, R. “Bacterial and fungal pneumonias after lung transplantation”. Transplant Proc. vol. 40. 2008. pp. 822-4. (Pseudomonas, Staph. aureus and Aspergillus were the most frequent causes.)

Gordon, SM, LARosa, SP, Kalmadi, S. “Should prophylaxis for Pneumocystis carinii pneumonia in solid organ transplant recipients ever be discontinued?”. Clin Infect Dis. vol. 28. 1999. pp. 240-6. (Pneumocystis prophylaxis should be prolonged in lung transplant recipients, who remain at risk lifelong, in contrast to other SOT recipients.)

Hoyo, I, Linares, L, Cervera, C. “Epidemiology of pneumonia in kidney transplantation”. Transplant Proc. vol. 42. 2010. pp. 2938-40. (Pseudomonas is most common cause of healthcare-associated pneumonia, whereas Streptococcus pneumoniae is the most common cause of community-acquired pneumonia in kidney recipients. Morbidity including need for ICU admission is high.)

Mattner, F, Fischer, S., Weissbrodt, H. “Post-operative nosocomial infections after heart and lung transplantation”. J Heart Lung Transplant. vol. 26. 2007. pp. 241-9. (Explores risk factors for post-transplant infections, including in retransplanted patients.)

Mawhorter, S, Yamani, MH.. “Hypogammaglobulinemia and infection risk in solid organ transplant recipients”. Curr Opin Organ Transplant. vol. 13. 2008. pp. 581-5. (Review of a very interesting body of work on de novo post-transplant hypogammaglobulinemia, which is an underappreciated risk factor for severe infections.)

Torres, A, Ewig, S, Insausti, J. “Etiology and microbial patterns of pulmonary infiltrates in patients with orthotopic liver transplantation”. Chest. vol. 117. 2000. pp. 494-502. (Gram-negative infections predominate in the early post-transplant period, while opportunistic infections are more common in the mid-to-late period.)

Weiss, E, Dahmani, S, Bert, F. “Early-onset pneumonia after liver transplantation: microbiological findings and therapeutic consequences”. Liver Transpl. vol. 16. 2010. pp. 1178-85. (Antibiotic de-escalation was possible in 1/3 of early healthcare-associated pneumonia after liver transplantation.)

Campbell, AP, Chien, JW, Kuypers, J. “Respiratory virus pneumonia after hematopoietic cell transplantation (HCT): associations between viral load in bronchoalveolar lavage samples, viral RNA detection in serum samples, and clinical outcomes of HCT”. J Infect Dis. vol. 201. 2010. pp. 1404-13. (Correlations of severity of disease with quantitative lower respiratory viral loads.)

Cone, RW, Hackman, RC, Huang, ML. “Human herpesvirus 6 in lung tissue from patients with pneumonitis after bone marrow transplantation”. N Engl J Med. vol. 329. 1993. pp. 156-61. (Identification of HHV-6 as a pathogen in a significant fraction of patients with interstitial pneumonitis after BMT that was previously thought to be idiopathic.)

Emanuel, D, Cunningham, I, Jules-Elysee, K. “Cytomegalovirus pneumonia after bone marrow transplantation successfully treated with the combination of ganciclovir and high-dose intravenous immune globulin”. Ann Intern Med. vol. 109. 1988. pp. 777-82. (One of several papers in the late 1980s and early 1990s that dramatically improved the outlook for CMV pneumonitis after BMT, using a combination of antiviral therapy and immunoglobulin.)

Erard, V, Guthrie, KA, Seo, S. “Reduced mortality of cytomegalovirus pneumonia after hematopoietic cell transplantation due to antiviral therapy and changes in transplantation practices”. Clin Infect Dis. vol. 61. 2015. pp. 31-9. (A large study of CMV pneumonitis over several eras, from the Fred Hutchinson Cancer Research Center which has provided much of our current knowledge regarding CMV pneumonitis in HSCT.)

Horger, MS, Pfannenberg, C, Einsele, H. “Cytomegalovirus pneumonia after stem cell transplantation: correlation of CT findings with clinical outcomes in 30 patients”. AJR Am J Roentgenol. vol. 187. 2006. pp. W636-43. (Correlation of radiographic findings with likelihood of successful therapy.)

Kumar, D, Michaels, MG, Morris, MI. “Outcomes from pandemic influenza A H1N1 infection in recipients of solid-organ transplants: a multicentre cohort study”. Lancet Infect Dis. vol. 10. 2010. pp. 521-6. (Multicenter retrospective study from the H1N1 pandemic that demonstrated that early treatment is associated with decreased need for ICU admission.)

Ljungman, P, Ellis, MN, Hackman, RC, Shepp, DH, Meyers, JD.. “Acyclovir-resistant herpes simplex virus causing pneumonia after marrow transplantation”. J Infect Dis. vol. 162. 1990. pp. 244-8. (Concerning development of the rise of acyclovir-resistant viruses in HSCT.)

Bochud, PY, Chien, JW, Marr, KA. “Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation”. N Engl J Med. vol. 359. 2008. pp. 1766-77. (One of the most intriguing studies in recent years of genetic predispositions to fungal infection; this study examined 20 single-nucleotide polymorphisms in TLR's 2, 3,4, and 9.)

Danziger-Isakov, LA, Worley, S, Arrigain, S. “Increased mortality after pulmonary fungal infection within the first year after pediatric lung transplantation”. J Heart Lung Transplant. vol. 27. 2008. pp. 655-61. (Information from a large multicenter pediatric lung transplant cohort of 555 patients.)

Herbrecht, R, Denning, DW, Patterson, TF. “Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis”. N Engl J Med. vol. 347. 2002. pp. 408-15. (Landmark randomized trial demonstrating improved responses and fewer adverse effects in voriconazole-treated patients.)

Marr, KA, Carter, RA, Boeckh, M, Martin, P, Corey, L.. “Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors”. Blood. vol. 100. 2002. pp. 4358-66. (This study added lymphopenia and viral infections to the list of known risk factors for invasive aspergillosis after HSCT.)

Marr, KA, Schlamm, HT, Herbrecht, R. “Combination antifungal therapy for invasive aspergillosis; a randomized trial”. Ann Intern Med. vol. 162. 2015. pp. 81-89. (Randomized trial of 454 patients with hematologic malignancies and invasive aspergillosis, in which combination therapy with voriconazole plus anidulofungin was associated with improved 6-week mortality compared with voriconazole alone, in the subgroup diagnosed on the basis of galactomannan positivity. Based on this trial, some clinicians use initial combination therapy with voriconazole plus an echinocandin, followed by voriconazole alone, for severe aspergillosis.)

Neofytos, D, Fishman, JA, Horn, D. “Epidemiology and outcome of invasive fungal infections in solid organ transplant recipients”. Transpl Infect Dis. vol. 12. 2010. pp. 220-9. (Large epidemiologic study of invasive fungal infections in over 400 solid transplant recipients from 17 centers.)

Patterson, TF, Thompson, GR, Denning, DW. “Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America”. Clin Infect Dis. 2016. (Contains important updates; voriconazole remains the drug of choice for invasive aspergillosis, with alternatives being lipid formulations of amphotericin, and isavuconazole.)

Singh, N.. “Evidence-based approach to challenging issues in the management of invasive aspergillosis”. Med Mycol. vol. 47. 2009. pp. S338-42. (Discusses evolving evidence in controversial aspects of aspergillosis management.)

Singh, N, Lortholary, O, Alexander, BD. “An immune reconstitution syndrome-like illness associated with Cryptococcus neoformans infection in organ transplant recipients”. Clin Infect Dis. vol. 40. 2005. pp. 1756-61. (Identification of an important complication of therapy in which worsening symptoms can occur with negative cultures.)

Champion, L, Stern, M, Israel-Biet, D. “Brief communication: sirolimus-associated pneumonitis: 24 cases in renal transplant recipients”. Ann Intern Med. vol. 144. 2006. pp. 505-9. (Important to include this in the differential diagnosis of pulmonary infiltrates in transplant patients receiving sirolimus-based immunosuppression.)

Yanik, GA, Ho, VT, Levine, JE. “The impact of soluble tumor necrosis factor receptor etanercept on the treatment of idiopathic pneumonia syndrome after allogeneic hematopoietic stem cell transplantation”. Blood. vol. 112. 2008. pp. 3073-81. (Small but intriguing study on a novel therapeutic approach for idiopathic pneumonia syndrome after HSCT.)

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