Pulmonary infections in patients who have received solid organ transplants

Pulmonary Infections in Patients Who Have Received Solid Organ Transplants Wallace T. Miller, Jr

N THE LAST two decades, organ transplantation has increasingly become an important therapy for patients with end-stage diseases of a variety of organs, especially of the kidney, liver, heart, and lung. One year survival of recipients receiving these transplanted organs now approaches 70% t o 80% in many transplant centers. 1 Thousands of these organs are being transplanted each year in the United States and so it has become important for the general radiologist to become familiar with the long-term complications of organ transplants. 2-4 The immunosuppression caused by anti-rejection medications, corticosteriods, cyclosporine, azathioprine, OKT3, and others, renders the solid organ transplant patient susceptible to a wide variety of infections. Improvements in the dosing and quality of these anti-rejection medications, especially the institution of cyclosporine A, have resulted in dramatic declines in the incidence of life-threatening infections. 5,6 However, despite this, infections especially pneumonia are among the most common cause of morbidity and mortality in transplant patients, m,5,7-~1 Sixty-six percent to 85% of transplant will experience some infection in the year following transplantation, and up to 67% of these will require hospitalization, many of which will be life-threatening. Although most deaths in transplant recipients are multifactorial, up to 89% of deaths will be associated with infection and infection may be the cause of death in as many as 40% of transplant patients. 12,13 Solid organ transplant recipients, like many abdominal and thoracic surgical patients, are at increased risk for pneumonia for several reasons: (1) prolonged hospitalization, (2) endotracheal tube injury to the trachea, and (3) impaired clearance of respiratory secretions due to anesthesia and dimin-

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From the Department of Radiology, University of Pennsylvania Medical Center, Philadelphia, PA. Address reprint requests to Wallace Z Miller, Jr, MD, Department of Radiology, University of Pennsylvania Medical Center, 3400 Spruce St, Philadelphia, PA 19104. Copyright 9 2000 by V~B. Saunders Company 0037-198X/00/3502-00065 l O.00/0 doi: l O.1053/ro.2000.6153

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ished cough. Lung and heart-lung transplant recipients are at further increased risk associated with denervation of the lung and surgically impaired mucociliary transport resulting from the transplantation of a donor lung. 7 One study showed that prolonged surgical time increased incidence of infectious complications in liver transplant patients. ~2 As a group, all types of solid organ transplants will be susceptible to a similar range of pulmonary infections. This is because all transplants receive a similar group of anti-rejection medications, which are the primary cause of the increases susceptibility of transplant recipients to pneumonia. The most common sites of infection tend to be in the area of the transplant and are probably related the risk of surgery. This means that lung and heart transplants have a greater incidence of pulmonary and other thoracic infections. However, pneumonia also is among the more common infections in kidney and liver transplants. Bacterial and pneumocystis pneumonia were the third and fifth most common infections in a series of 101 liver transplants. 12 In general, most infectious complications will occur within the first year following transplantation and the more recent the transplant the higher the risk of infection. 5,1~ Most serious infections, those which are life-threatening or require hospitalization, occur within the first 2 months of transplantation. ~~ This is especially true of viral and fungal infections, 93% to 100% of which have occurred in this time period, a~ Similarly the third to the sixth month after transplant will have more frequent infectious complications than 6 months to 1 year following transplant. Infections may also have deleterious effects on the transplant patient other than the direct risks associated with the infection. Chronic rejection of lung transplants appears to be integrally related to pulmonary infections.14 The incidence of bronchiolitis obliterans, the histological manifestation of chronic rejection, increased with the incidence of cytomegalovirus (CMV) infections and other pulmonary infections in lung transplants. Graft loss in liver transplantation was a result of systemic infection in 19% of cases in one series? ~

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BACTERIAL PNEUMONIA AND THE EARLY POSTOPERATIVE PERIOD

Bacterial infections are the most common infectious complication of solid organ transplantation. Patients receiving thoracic surgical procedures, such as heart or lung transplant recipients are especially at risk of bacterial pneumonia, although it is also a common cause of infection in kidney and liver transplants. Thirty-one percent of heart transplants developed bacterial pneumonia. 5 Bacterial pneumonia accounted for 50% of infections in heart lung transplants in the first year following transplantation. 13-16On the other hand, only 8% to 14% of liver transplants developed bacterial pneumonia.10,]2,15 Bacterial pneumonia can be subdivided into two general groups, early postoperative pneumonias and later community acquired pneumonias. In the first few months following transplantation, at least one third of lung transplant patients will develop one or more episodes of bacterial pneumonia. 16,17 Most are due to aerobic gram-negative bacilli, such as Pseudomonas, Enterobacter, Seratia, and Acinetobacter species. 5,~4,16 Occasionally, anaerobic bacteria such as Bacteroidesfragilis are also recovered. 14 Use of prophylactic antibiotics and exclusion of infected lung transplant donors have reduced the incidence of early bacterial pneumonia.18 Community-acquired pneumonia's account for approximately one quarter of all bacterial pneumonia's. These are most commonly due to Staphylococcus aureus, Streptococcus pneumonia, Hemophilus influenzae, and Legionella pneumophilia. 15,16,18.19 Most solid organ transplant patients with bacterial pneumonia will present with fever, worsening gas exchange, and an abnormal chest radiograph.~4 Thus, the radiologist may play an important role in initially detecting disease. Unfortunately, in lung transplant patients, this presentation often does not differ from acute rejection and bronchoscopy and transbronchial biopsy is often necessary to make the diagnosis. 18-20 Bacterial pneumonias in solid organ transplants do not significantly differ from similar pneumonias in other patients. They will most often present as one or several focal alveolar infiltrates (Fig 1). Pleural effusions may also occur. After 1 month, bacterial pneumonias become much less frequent. Among lung transplant recipients, 8% will develop a bacterial pneumonia greater

Fig 1. Postoperative pseudomonas pneumonia. This 54year-old man was recovering from a heart transplant 2 days earlier when fever and leukocytosis were noted, AP chest radiograph demonstrates focal consolidation in the left lower lobe behind the cardiac silhouette compatible with postoperative pneumonia. Sputum cultures demonstrated growth of Pseudomonas aeruginosa.

than 1 month following transplantation as opposed to one third of recipients less than 1 month following transplantation. 21,22 Nocardia species are a rare cause of infection in solid organ transplant recipients. Nocardia asteroides is the most commonly isolated species in pulmonary and systemic infections although N. brasilensis, N. farcinica, N. otitidiscaviarum, and N. transvalensis may also cause disease in humans. 22-25 These organisms are opportunistic bacteria, which do not usually infect normal hosts but may be an important cause of infection in immunocompromised hosts. Although, the skin and central nervous system are occasionally the initial site of disease, most nocardial infections in transplant patients are pneumonias. 22 Incidence of Nocardia infection in solid organ transplants is approximately 4% but has ranged from zero to 36% in various centers. 5,1~ In one series of renal transplants it accounted for 4% of all deaths and 6% of deaths caused by infection. However, Nocardia infections may be decreasing as a result of the use of cyclosporine. 5,22In comparison with other bacterial pneumonias, Nocardia pneumonia characteristically occurs late in the stage of transplant patients. One of the largest series of nocardial pneumonias in heart transplant

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patients, recorded a median time of 225 days following transplantation. 5 Similarly, in heart-lung transplants, Nocardia was characteristically encountered greater than 1 year following transplantation. 13 The clinical and radiographic presentation of nocardial infections in transplants is similar to that seen in other groups. 22 The most common symptoms are cough, fever, and pleuritic chest pain. 34 However, some patients will present as an asymptomatic mass on screening chest radiographs. Nocardia pneumonia will most often appear as a solitary nodule or nodular infiltrate (Fig 2). 22,33,35 Cavitation is common. Because of the nodular appearance, this will often be confused with a malignancy such as post-transplant lymphoproliferative disorder, lung carcinoma, or pulmonary metastasis. As previously mentioned, these may lack symptoms of infection, fever, and cough, and therefore, a high index of suspicion is necessary to diagnose this unusual condition. Diagnosis may be made by sputum culture, bronchoscopy with bronchoalveolar lavage, percutaneous needle aspiration, or open lung biopsy. POSTOPERATIVE MEDIASTINITIS: EMPYEMA AND STERNAL WOUND INFECTIONS IN LUNG AND HEART TRANSPLANTATION

Historically, mediastinitis in the weeks following transplantation was an important cause of morbidity and mortality for lung transplant recipients] 2,18,36,37This was primarily due to leaks from the airway anastamosis. Improved techniques for sealing the anastamosis, originally the omental flap and more recently the use of the telescoping anastamosis, has resulted in dramatic reductions in airway breakdown and subsequent mediastinitis. 38-4~ Chest radiographs will often miss this complication of lung transplant surgery. However, computed tomography (CT) will often demonstrate small fluid and/or air collections near the bronchial anastamosis. 38-40 Sternal wound infections are an uncommon but reported complication of heart and lung transplants. This was reported in 7% to 15% of heart or heart-lung transplants, s,~6 A variety of species were encountered, including Staphylococcus aureus, enterococcus, Mycoplasma species, and polymicrobial infections, s,~6 This is most often a clinical diagnosis based on sternal instability of the two

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Fig 2. Nocardia pneumonia. This PA chest radiograph was obtained as part of an annual clinical evaluation of this 53-year-old patient 1 year after heart transplantation. The patient was clinically asymptomatic. (A) PA chest radiograph demonstrates a cavitary nodular infiltrate in the left upper lobe. Differential considerations would include invasive aspergUlosis, Nocardia pneumonia, and post-transplantation lymphoproliferative disorder. (B) CT images at the level of the aortic arch again demonstrate a cavitary nodule with a second adjacent satellite nodule. Open lung biopsy demonstrated nocardia pneumonia.

halves of the sternum or on drainage of infected fluid via the sternal wound. However, CT may demonstrate substernal fluid collections, which may be indicative of an anterior mediastinal abscess. Empyemas may rarely be encountered following thoracic transplants. These were most often Staphylococcal or Streptococcal species. 14 Chest radiographs will usually demonstrate areas of loculated fluid. CT will also reveal loculated fluid and may also reveal an enhancing pleural rind and the split pleura sign. 41

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VIRAL INFECTIONS: THE REACTIVATION MONTHS: 1-4 POST TRANSPLANT

Most serious pulmonary viral infections in the solid transplant community are caused by viruses not usually associated with pulmonary disease in the normal patient. These are primarily the herpes group of viruses: cytomegalovirus (CMV), herpes simplex virus (HSV), varicella-zoster virus (VZV), and Epstein-Barr Virus ( E B V ) . 7 These are most often reactivation infections of dormant organisms residing in the transplant recipient or in the transplanted organ. As such, these are most often disseminated infections that have pulmonary manifestations. Occasionally, common communityacquired respiratory viruses such as respiratory syncytial virus and adenovirus may also produce respiratory compromise in solid organ transplants. 7 Unlike the herpes group viruses, these are more often primary tracheobronchial and pulmonary infections acquired by inhalation of aerosolized infectious particles. The increased incidence of viral infections is primarily due to impaired cell-mediated immunity as a result of immunosuppressive drug regimens. 7 Routine viral cultures is the mainstay of diagnosis of viral infections and viral pneumonitis. All the viruses commonly found in organ transplants may be recovered in cell culture. 7

Cytomegalovirus Ettinger and Trulock 1 state, "Other than allograft rejection, the most significant problem facing the organ transplant recipient is cytomegalovirus (CMV) infection." Infection with CMV, has been associated with increased susceptibility to bacterial, fungal and protozoal superinfection, increased risk of chronic rejection and increased overall mortality in all forms of solid organ transplants. 12,42,43 CMV has a 40% to 100% prevalence in the general adult population, and therefore, most cases are a result of reactivation of endogenous virus in the host or transplanted tissue. 44-47 The greatest risk of disease is in seronegative recipients of seropositive donors. 1,48,49 Because this is a reactivation infection, most pneumonias due to CMV will occur in the first few months following infection. CMV is the most common viral infection in solid organ transplant recipients. CMV replication in transplants may take one of four basic clinical

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scenario.~4 Most commonly, there is asymptomatic shedding of the virus in blood, urine, and pulmonary secretions. 7A2,13,14,16,44,45,5~ In most cases this is not clinically significant with an overall low mortality. Some patients will present with a syndrome of self-limited fever and constitutional symptoms, such as malaise, myalgias, arthralgias, anorexia, and fatigue, known as CMV syndrome. CMV pneumonitis with an increased A-a gradient, fever, cough, dyspnea, tachypnea, and radiographic infiltrates represents the third common clinical presentation. CMV pneumonia has been reported in 5% to 30% of renal transplants, 16% to 34% of heart or heart-lung transplants or lung transplants, and 2% to 32% of liver transplants. 1~176 Clinical outcome of CMV pneumonia is quite variable and ranges from a mild self-limited illness to a rapidly fatal infection. 53 However, CMV pneumonia is reported to have up to 75% mortality if untreated. 44,51 In addition, CMV pneumonia has been associated with increased chronic graft rejection in lung transplants. 44,45,6~ It may also predispose patients to bacterial and fungal superinfection of the lung. 42'56-6~Last and least commonly, patients may present with disseminated infection with multiple organ system involvement, such as retinitis, pneumonitis, colitis, and hepatitis. Disseminated infection is especially dangerous with a high mortality. ~2 Chest radiographs of patients with CMV pneumonia will often appear normal or minimally abnormal. In one series lung transplant patients, less than one third of histologically proven episodes of CMV pneumonitis were accompanied by radiographic abnormalities. 6~ In another, only 39% of renal transplant patients with CMV or PCP pneumonia had parenchymal opacities on chest radiography. 62 However, there were no deaths in patients without radiographic findings but 18% of those with chest radiographic opacities died. When abnormal, the chest radiograph will most often demonstrate diffuse "interstitial" infiltrates. 46'48'52"53,62-64 These may appear as accentuation of interstitial lines, particularly Kerly A and B lines or these may appear as diffuse hazy opacity, which may be likened to ground glass. Nodules or focal consolidation have also been reported but are distinctly rare. CT scans, especially thin-section, "high-resolution," CT is more sensitive for the detection of CMV pneumonia. This will usually

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appear as ground glass opacities. Imaging findings of CMV pneumonia mimic the radiographic appearance of pneumocystis pneumonia and interstitial pulmonary edema from congestive heart failure, which are the most common differential diagnoses. Acute rejection of lung transplants may also appear as diffuse ground glass or interstitial infiltrates and is a third differential diagnosis in this population.~4 When severe, CMV pneumonitis may lead to diffuse alveolar infiltrates and mimic adult respiratory distress syndrome (ARDS). CMV is frequently recoverable from urine and saliva without evidence of clinical disease. Therefore, histological evidence of tissue invasion, the characteristic intracellular viral inclusion bodies, is necessary to prove infection with CMV. 7 However, recovery of CMV from bronchoalveolar lavage of a solid organ transplant patient with the characteristic radiographic appearance and no other definable cause is tantamount to the diagnosis of CMV pneumonia and will usually be treated accordingly. 7 Although there have been no controlled trials conducted in transplant patients, most experienced clinicians believe gancyclovir to be efficacious in the treatment of CMV pneumonia. 7,~4 Not only does this appear to shorten the length of infection, but it also appears to reduce the incidence of relapses. Before the use of gancyclovir, the mortality of CMV pneumonia was as high as 54% and has been reduced to 12% with the institution of gancyclovir.65, 66

Herpes Simplex Virus Like CMV, most of the adult population is infected with HSV, which in most cases is subclinical. 46-67 Most seropositive solid organ transplant patients will experience the symptomatic reactivation of HSV infection as painful vesicular skin lesions after transplantation. 65 However, dissemination is rare and when it occurs is often fatal. 68 HSV pneumonia is uncommon and has been reported in 0.8% to 2.9% of adult liver transplant patients, 1% to 10% of heart transplant patients, 1.5% of kidney transplant patients, and 4% to 10% of heart-lung transplant patients. 10,32,53,55,69,70 Most HSV infection is due to reactivation of latent virus in the host. Unlike CMV, transmission of HSV via donor organ tissues is rare. 68 Like other reactivation infections, infection characteristically occurs in the few months following transplantation.

WALLACE T. MILLER, JR

HSV pneumonia has been reported to occur from 12 to 47 days after transplantation. 32,57,71 Patients nearly always have mucocutaneous disease before the onset of pulmonary symptoms. 68,72 Dyspnea, cough, and fever herald the onset of pneumonia. Augmentation of immunosuppression may increase the risk of HSV pneumonia in those patients who were seropositive for the virus before transplantation. 7~HSV is often seen in association with other pulmonary i n f e c t i o n s . 46'72 The chest radiograph will most often demonstrate multifocal or diffuse consolidation and is a manifestation of diffuse hematogenous dissemination of the virus. 7 Unifocal infiltrates may be seen but are less common. 46 CT manifestations have not been reported. Mortality from HSV pneumonia in this population is high. Four of six liver transplants with HSV pneumonia died, characteristically after a rapidly progressive systemic disease. 1~ This reflects the disseminated nature of herpes pneumonia in solid organ transplant patients. Definitive diagnosis requires demonstration of characteristic histopathologic changes in lung biopsy tissue, monoclonal immunofluorescent staining of tissue, or tissue culture identification of HSV in lung tissues. As with CMV, asymptomatic viral shedding in respiratory secretions is not uncommon and does not necessarily indicate active infection. 7 Intravenous acyclovir is the therapy of choice for pulmonary and other visceral HSV infection. 7~ Prophylactic administration of acyclovir has reduced the incidence of reactivation and may prevent deaths from this serious opportunistic infection. 73

Varicella Zoster Virus Varicella, the primary infectious manifestation of this virus, may occur in susceptible pediatric transplant patients. 74,v5 Between 5% and 25% of adult solid organ transplant recipients will develop zoster, otherwise known as "shingles. ''74,76,77 This painful vesicular rash in a dermatomal distribution represents reactivation of latent virus harbored in the peripheral nerve cells. Reactivation may occur in any individual but is more commonly encountered in patients with depressed immune systems and in severely immunocompromised individuals, such as transplant recipients, hematogenous dissemination is more likely to occur. 7 Like HSV pneumonia, VZV pneumonia is the

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pulmonary manifestation of hematogenously disseminated disease, in most cases, 50% to 74%, the zoster rash and associated thoracic or abdominal pain will precede pneumonia by 1 or 2 days. 78 Pneumonia will usually be associated with pleuritic chest pain, hemoptysis, dyspnea, cough, malaise, and fatigue. VZV pneumonia characteristically presents with diffuse ill defined, "fuzzy" nodular densities. 78The nodules are usually approximately 5 to 15 mm in diameter and are usually uniformly spread throughout the lung. This pattern is often called the acinar nodular pattern and is radiographically identical in immunocompetent and immunocompromised hosts. The diagnosis of VZV pneumonia should be suspected in anyone with the characteristic skin exanthem and the characteristic radiographic acinar nodular pattern, v Without specific antiviral therapy with intravenous acyclovir, 25% of solid organ transplants will die. This has been reduced to 11% when therapy is administered. 78 Like HSV infection, acyclovir prophylaxis appears to reduce the incidence of VZV infection and if administered at the time of zoster appearance, it may prevent dissemination of the infection.V9,8o

In the early stages of disease, the lymphoproliferation is most often a polyclonal proliferation of lymphocytes, which will often disappear following reduction in immunosuppressive medications. In the later phases of this disorder, it appears as though a malignant clone is selected. This form of the disease is most often rapidly fatal and usually fails to respond to reductions in immunosuppression as well as standard antilymphoma chemotherapy. The most common radiographic manifestation of PTLD is one or multiple, uniform, nonenhancing masses in large organs including the lung, liver, kidney, bowel, and brain (Fig 3). 83,84"86Lymphadenopathy may occur in 15% to 37% of cases, either in isolation or association with organ masses. 83.84,86 Endobronchial masses resulting in lobar atelectasis have also been reported. 83,84,86 As mentioned previously, the therapy of choice for PTLD is the maximally acceptable reduction in immunosuppressive medications. In the case of renal transplants, the immunosuppressive drugs may be stopped entirely, resulting in rejection of the transplant and the necessity of restarting dialysis. Other organ transplants do not have this alternative; however, even small reductions in the dose of immunosuppressive medications may result in the complete resolution of disease. Failure to respond to reductions in immunosuppression has a poor prognosis with most patients dying from the

Ebstein Barr Virus and Post-Transplant Lymphoproliferative Disorder Like all the latent herpes viruses, EBV infection is common among transplant patients with a 25 % to 82% incidence in this populations. 81,82This is most commonly asymptomatic shedding of the virus. However, EBV infection appears to be causally related to the development of post-transplant lymphoproliferative disorder (PTLD), which may develop in 1% to 10% of transplant patients. 83 PTLD is a spectrum of lymphoproliferative abnormalities ranging from a benign febrile illness associated with lymphadenopathy to a rapidly fatal malignant lymphoma. 84 PTLD appears to be a result the combination of immune suppression caused by anti-rejection medications with lymphoproliferation induced by reactivation of EBV. 88,89Before the use of cyclosporine, PTLD most often occurred years after transplantation. However, with more potent immunosuppressive drugs, PTLD appears to develop sooner after transplantation and with greater frequency. 84With current immunosuppressive regimens the peak incidence of PTLD appears to be in the third month following transplantation. 85

Fig 3. Post-transplantation lymphoproliferative disorder. This 46-year-old patient developed fever 9 months after kidney transplant. A chest radiograph (not shown) revealed a solitary right upper pulmonary nodule, CT image through the upper lobes demonstrates a well-defined nodule in the right upper lobe, No other radiographic abnormality was demonstrated. Open lung biopsy demonstrated post-transplantation lymphoproliferative disorder.

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disease, despite attempts at control with conventional chemotherapy. 87,88

Respirator 3' Syncytial Virus Respiratory syncytial virus (RSV) is a common environmental pathogen and may cause bronchiolitis and pneumonia in children and adults. Contracted by inhalation of infected aerosolized droplets, RSV is a highly contagious organism. Outbreaks primarily occur in the late winter and spring and commonly cause fever, cough, dyspnea, and otatgia with clinical signs of rales, rhonchi, or wheezes. In immunocompetent adults, this is usually self-limited outpatient illness. Children may be hospitalized for respiratory impairment due to airway narrowing and obstruction. 7 RSV pneumonia has been reported in both renal and cardiac transplant patients.89-9 i Radiographically interstitial opacities, alveolar consolidation, and pleural effusions have been reported in transplant recipients which parallels the radiographic appearance in the general population (Fig 4). 80-91

All five of the renal transplants patients reported to have RSV infection cleared their infections spontaneously, and the cardiac transplant cleared in association with aerosolized ribavarin administration. 89-91 Thus, RSV pulmonary infection appears to

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be a self-limited respiratory infection in solid organ transplants without important consequences.

Adenovirus Adenovirus is a common community-acquired cause of respiratory infections in the general population. The incidence of this infection in the solid organ transplant population is not known. However, it has been reported in 3 of 52 adult liver transplant recipients and in 22 of 262 pediatric liver transplant recipients in two series in which they w e r e recorded. 92,93

Like the herpes group viruses, adenovirus appears to be capable of establishing latent infections. In immunocompromised patients, it most often presents with the rapid onset of fever, chills, malaise, and lethargy and may occasionally produce myalgias, arthralgias, and headache. 7 The most common radiographic presentation is of bilateral alveolar opacities. However, interstitial opacities, nodules, and effusions have been reported. 46,94

Outcome of adenoviral pneumonia in immunocompromised patients ranges from a self-limited illness to a rapidly fatal infection with mortality rates reported to be as high as 54%.94 Of four renal transplant patients who were reported to have acquired adenoviral pneumonia, three died. Unfortunately, no specific treatment for adenoviral infections has been shown to be effective, but supportive care may aid in survival. 7 FUNGAL INFECTIONS IN CHRONIC IMMUNOSUPPRESSION

Fig 4, Community-acquired viral pneumonia. This 33-yearold woman had received a pancreas-kidney transplant 13 months earlier. She complained of fevers and a dry cough. Chest radiograph demonstrates diffuse interstitial opacities with a linear pattern. Subsequent clinical course demonstrated this to be a community-acquired viral pneumonia.

Fungal pneumonias are a rare but potentially devastating complication of solid organ transplantation. These infections fall into two major categories of organisms. Those organisms that occur exclusively in immunocompromised hosts such as Aspergillus, Candida, and Mucor species and endemic fungi with increased virulence in immunocompromised hosts such as Histoplasma, Coccidioides, Cryptococcal, and blastomyces species. Invasive aspergillosis and disseminated candidiasis are the most common fungal infection in solid organ transplant patients and account for 80% of fungal infections. 95 Approximately 80% of these infections will occur within the first 2 months following transplantation, although the risk of infection persists for the lifetime of the transplant. 13,95 In most hospitals, one or the other of

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these organisms will predominate and the other organism may be quite uncommon. Endemic fungal infections are rare in all transplant centers but may occur in regions in which they are endemic. The incidence of fungal infections varies among types of transplants and is as low as 5% among kidney transplant patients to as high as 40% among liver transplant patients. 95 Although fungal infections may be an isolated event, they often simultaneously occur with other bacterial or viral infections.12

Aspergillosis Aspergillus species are a group of ubiquitous molds that are found throughout the world in soil, decaying vegetation, and human foodstuffs. A. flavus and A. fumigatus are the most common cause of disease in humans but A. niger and A glaucus have also been reported to cause human disease. These saprophytes are normally not pathogenic in humans but may affect a variety of individuals with altered systemic or local immune function. Like other fungal infections, aspergillosis is initiated by inhalation of aerosolized spores. Because of the ubiquitous nature of these organisms, this event is a daily process for most individuals, and therefore, the size of the innoculum and the level of immunosuppression both appear to be important in determining those who become infected. 78 Forty to 90% of lung transplants patients have Aspergillus species recoverable from respiratory secretions but tissue invasive disease is relatively infrequent, diagnosed in 0% to 22% of these patients. 10,12,16,42,96-[01Alveolar macrophages, which block spore germination, and neutrophils, which eradicate Aspergillus hyphae, are the primary mechanisms whereby the immune system controls Aspergillus infestation. Thus, neutropenia is the primary risk factor for development of Aspergillus infection. Corticosteroids, which impair neutrophil function, also increase the risk of aspergillosis. Because of prolonged imnmnosuppression and especially the long-term use of corticosteriods, aspergillosis may occur over a wide time period following solid organ transplantation. Earlier reports suggested that the greatest risk of aspergillosis occurred in the early post-transplantation period, especially the first 6 months following transplantation. 8,12 However, a recent study of lung transplant patients found 15 months post transplantation to be the mean time of Aspergillus infec-

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tion. 6~ Prolonged use of antibiotics and prolonged operative time during transplantation appears to increase the risk of Aspergillus infection in the early post operative period. 12 CMV viremia and CMV pneumonitis also increase the risk of aspergillosis. 12.58-6~Aspergillosis is a highly lethal infection in transplant recipients. In heart and lung transplants patients, aspergillosis resulted in a 25% to 100% mortality rate. 5,8,99,1~176 Unlike most of the other fungal infections in transplant patients where pulmonary manifestations are a result of systemic dissemination of the organism, aspergillosis most commonly presents as a primary pulmonary disorder, in 61%, and is less commonly disseminated, in 39%. However, when disseminated, aspergillosis has nearly 100% mortality.100,101 The most common extrapulmonary site is the central nervous system. 8 Patients characteristically present with fever and a new pulmonary infiltrate unresponsive to antibiotics, s Cough and pleuritic chest pain are also common. Most Aspergillus infections in solid organ transplants are the result of acute tissue invasion of the lung parenchyma. The characteristic radiographic presentation is of one or multiple nodular or patchy infiltrates (Fig 5). 60,63,102Aspergillosis is among the most common causes of nodules in solid organ transplants and accounted for 25% of radiographically detected nodules in one series of 64 lung transplant patients. 1~ The most common differential diagnoses are post transplant lymphoprolifera-

Fig 5. Invasive aspergillosis. Routine chest radiograph follow-up in this 39-year-old man who had received a lung transplant 6 months previously demonstrated several pulmonary nodules (not shown). CT image at the level of the pulmonary veins demonstrates two nodular foci with areas of surrounding ground glass attenuation. The CT halo sign is strongly suggestive of aspergillus infection. Transbronchial biopsies demonstrated Aspergillushyphae.

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tive disorder (PTLD), nocardia pneumonia, and bacterial abscess or round pneumonias.~~ Occasionally, invasive aspergillosis may appear as a wedgeshaped opacity bordering along the pleural surface. The wedge shape reinforces the fact that the radiographic opacity may be due to either an inflammatory response to the organism, or to pulmonary infarction. Aspergillus species are known to be angioinvasive organisms, which frequently lead to pulmonary infarction. Unlike invasive aspergillosis in bone marrow transplant patients, central cavitation of pulmonary opacities appears to be common in the solid organ transplant population. 8 In addition, in the authors experience, the air crescent sign virtually never occurs in the solid organ transplant population. CT may show these to primarily effect the subpleural lung. The CT halo sign, a combination of a central area of consolidation surrounded by a halo of ground glass opacity, has been associated with invasive aspergillosis and may be a clue to the diagnosis (Fig 5). The halo has been show to represent an area of hemorrhage surrounding the central infusion consolidation. 6~176 Unfortunately, this has been shown to be a nonspecific sign and may be produced by other fungal infections, lymphoma, and other entities.l~ Although invasive aspergillosis is the most common clinical and radiographic manifestation of Aspergillus infection in solid organ transplant patients, other manifestations have been reported including aspergillomas from semi invasive aspergillosis and empyemas.l~176 In lung transplant patients, Aspergillus species can infect the tracheobronchial tree with special predilection for the bronchial anastamosis. 62,64,1~ This is most often detected via bronchoscopy but can occasionally be discovered on CT scans as a polypoid tissue growth within the lumen of the mainstem bronchus, at the site of the anastamosis (Fig 6). 52,99,105 Care should be taken not to confuse this with the normal telescoped bronchial anastamosis. 40'106 When the bronchial anastamosis is created a small portion, approximately 1 or 2 millimeters, of the transplant bronchus is placed within the native bronchus. This telescoped anastamosis reduces the incidence of bronchial dehiscence. However, it also produces a small tissue flap that projects into the lumen of the bronchus. Invasive tracheobronchial aspergillosis will appear as a larger irregular polypoid growth. This form of Aspergillus infection characteristically occurs in

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b~ Fig 6. Tracheobronchial aspergillosis. This 61-yearoold man had received a left lung transplant for idiopathic pulmonary fibrosis 3 months previously, He complained of dyspnea on exertion, Chest radiograph (not shown) failed to reveal a cause for his dyspnea, CT image through the mainstem bronchi demonstrates a polypoid mass in the left main stem bronchus adjacent to the bronchial anastomosis, This finding is strongly suggestive of tracheobronchial aspergillosis. Note the reticular interstitial lung disease in the nontransplanted right lung characteristic of idiopathic pulmonary fibrosis. Transbronchial biopsies of the left bronchial mass revealed

Aspergillus fumigatus.

the early post operative period, usually within the first 4 months following transplantation. 52 Because of the ubiquitous nature of Aspergillus species, the recovery from respiratory secretions is often suspect. It can contaminate a microbiology laboratory or exist as a nonpathogenic saprophyte in the upper respiratory tract. 8 In one series of 151 lung transplant patients, Aspergillus species were recovered in 69 (46%) of patients of which only 5 (3%) resulted in invasive aspergillosis. 99 Unfortunately, these five deaths accounted for 13% of all patient deaths. Because of the high mortality, recovery of Aspergillus species should always be of concern. Transbronchial and surgical biopsies demonstrating tissue invasion of the organism or transthoracic needle aspirations demonstrating Aspergillus organisms in cytology are the gold standard for diagnosis of active infection and should be performed whenever aspergillosis is suspected. Amphotericin B remains the treatment of choice for aspergillosis.

Candidiasis Although there are a variety of candidal species that can produce human infection, Candida albicans is the most c o m m o n human pathogen.

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C. albicans is part of the normal human gastrointestinal flora, which acts as the reservoir for human infection. 8 Both cell-mediated immunity and neutrophil function are important in the immunological defense against Candida species. 8 Diabetes, antibiotic use, and immunosuppressive drugs all increase the risk of candidal infection. Colonization of wounds, drainage catheters, and sputum with Candida species is common and in most cases does not indicate active infection. 1~ In general, the clinical status of the patient will indicate whether cultures positive for Candida are representative of significant infection. If the patient is afebrile with well healing, clean wounds, and no respiratory or urinary tract symptoms, then recovery of Candida from these sites will most often be colonization without tissue infiltration. 10 Pulmonary infection with Candida is most often part of a disseminated infection. Isolated pneumonia remains an exceedingly rare event. Many Candida infections will be coincident with other bacterial or viral infections. 12 Patients most often present with fever, septicemia, and multisystem organ failure. Disseminated candidiasis is often a premortem event of a failing host with a mortality rate approaching 100%. 16 There is some evidence that colonization of the donor tracheobronchial tree with Candida predisposed lung transplants to disseminated candidiasis.l~ Chest radiographs usually demonstrate nonspecific widespread alveolar consolidation. In many cases this likely represents diffuse alveolar damage due to adult respiratory distress syndrome. Histological examination may demonstrate innumerable microscopic candidal abscesses in a background of diffuse alveolar damage. Occasionally, candidiasis may appear as single or multiple nodular infiltrates and resemble invasive aspergillosis. The air crescent sign may he occasionally encountered. Therapy consists of Amphotericin B and general supportive measures for respiratory impairment and septicemia.

pear to be the most important element of immune function against Mucor. Diabetic patients appear to have a biochemical defect within the macrophage, which renders them unable to inhibit the growth of Mucorales spores causing increased susceptibility to mucormycosis. ~~ Chronic renal failure and steroid use, two risk factors for the development of mucormycosis, are also known to impair neutrophil and macrophage function. Mucor species grow best in acidic high glucose medium further explaining the particular susceptibility of diabetic patients who are ketoacidotic.m9 This is an exceedingly rare infection and was seen in 0.2% of renal transplant patients in one series and accounted for only 1% of infectious deaths in another series.tl~ A sporadic infection, it may occur any time following transplantation. Patients with pulmonary mucormycosis often present with an acute illness manifesting nonspecific symptoms and signs consisting of cough, fever, dyspnea, pleuritic chest pain, and variable sputum production, u2 Most patients will present with a focal alveolar infiltrate resembling standard bacterial pneumonias (Fig 7). 113,114 Occasionally, Mucor pneumonia will appear as a pulmonary nodule. Cavitation appears in approximately 13% of cases. Amphotericin B is the primary form of therapy, with surgical excision indicated in some cases.

Mucormycosis The genera Rhizopus, Absidia, and Mucor constitute the members of the order Mucorales, which are responsible for the infection: mucormucosis. Mucor is the usual cause of human disease. These molds are commonly found in fruit, bread, and soil and are acquired by inhalation of their spores. Normal macrophage and neutrophil functions ap-

Histoplasmosis A dimorphic fungus that exists in the mycelial phase in nature and in the yeast phase in the human body, histoplasma is found in soil enriched with bird or bat excreta. 8 The organism may be found worldwide but has particular predilection to the midwestern and south central United States. Infection is acquired by inhalation of dust containing the microconidia of H. capsulatum. Within the alveoli of the host, the organism converts into the yeast form, which is pathological in humans. During active infection, the organism disseminates via the blood and lymphatics, especially to the lymph nodes, liver, and spleen, where organisms may remain dormant. 8 Infection in solid organ transplants is rare. A 0.5% incidence in renal transplant recipients has been reported in endemic areas, which increased to 2.1% during two outbreaks, uS,u6 Davies et a1117 reported five cases of histoplasmosis in approxi-

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Fig 7. Mucormycosis. This 52-year-old man had received a kidney transplant 16 months earlier for diabetic nephropathy. He presented w i t h fever, cough, and right anterior chest pain. (A) PA chest radiograph demonstrates a cavitary, masslike infiltrate in the right chest. (B) Lateral radiograph demonstrates this to be in the upper and middle lobes. (C) CT scan at the level of the carina confirms the presence of a large cavitary infiltrate in the anterior lung. Because of the history of diabetes, the possibility of mucormycosis was considered. Transbronchial biopsies demonstrated Mucor species.

mately 1,300 renal transplant patients 0.3% over 4 years in a nonendemic area. Histoplasma infection in transplants may be due to primary infection or reactivation of dormant organisms within the transplant recipient. For patients in areas of endemic histoplasma infestation, infection often will represent primary infection. However, infection in patients not residing in an endemic area, most infections represent reactivation of latent organisms/ This reactivation is thought to be secondary to the immunosuppressive effects of anti-rejection therapy. 117 Most patients will present with nonspecific symptoms such as lever. A skin rash due to dermal dissemination may also be the presenting symptom. 8 This is because most transplant patients will experience disseminated histoplasmosis, a phenom-

enon that is rare in the normal population. In one study of renal transplant recipients, 77% developed disseminated disease compared with 1.5% of nonimmunosuppressed hosts.l~5 Chest radiographs will be normal in approximately one half of cases. Four of nine cases of transplant recipients with histoplasmosis in one series, and 8 of 14 cases in another series, were normal.llS,~17 Diffuse small nodular opacities are the most common radiographic abnormality. These nodules may be very small, so-called miliary nodules, or larger medium-sized nodules ranging around 1 cm in diameter. Lymphadenopathy is rare in transplant recipients. Diagnosis is dependent on culture of the organism or histopathological identification of the yeast form of the fungus in biopsy specimens or aspi-

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rates. ~ Amphotericin B is the drug of choice in the management of histoplasmosis in transplant recipients.

demonstration of the giant spherules in tissue is diagnostic of infection with Coccidioides species. Amphotericin B remains the mainstay of therapy for this infection. 8

Coccidioidomycosis Coccidioides immitis is a dimorphic fungus endemic to the southwestern United States and northern Mexico. Rarely seen outside of this range, it is a significant fungal infection in transplant recipients residing in this region. Like histoplasmosis, infections in transplants may be due to primary infection or reactivation of a latent focus. 8 Therefore, recent or remote history of travel to the endemic area may be important in recognizing this infection. Coccidioidomycosis is acquired by inhalation of contaminated soil or dust. The arthrospores found in soil, transform into giant spherules in human tissues. Host defense is primarily via cell-mediated immunity and because the anti-rejection medications used in transplant patients are specifically targeted at cell-mediated immunity, the transplant patient is at increased risk of coccidioidomycosis.8 Transplant recipients appear to be at increased risk of infection and disseminated infection over the general population. In a study of 981 patients with renal failure who resided in Arizona, 0.83% of dialysis patients contracted coccidioidomycosis, whereas 6.9% of renal transplants developed Coccioides infection. 118Most patients developed disseminated disease and 72% died of the infection. Extrapulmonary disorders included meningitis, pyleonephritis, hepatitis, and arthritis. Nine percent of 46 cardiac transplant patients residing in Arizona contracted coccidioidomycosis?19However, in this population, disease was limited to pulmonary infection and the survival, 72%, was much better than that seen in those with disseminated disease. Fever, nonproductive cough, chest pain, and malaise are the most common clinical symptoms. Infections most often occur within the first year following transplantation but have been seen from 1 month to 10 years following transplantation, tls Chest radiographs are often abnormal and reflect the disseminated nature of the infection. The pulmonary nodules and thin-walled cavities characteristic of immunocompetent hosts are uncommon in transplant patients. Instead, diffuse small nodular opacities are the most common radiographic manifestation. 119,120 Growth of the organism in culture or histological

Cryptococcosis Cryptococcus neoformans is a ubiquitous fungal organism found worldwide in soil contaminated by bird droppings. It is an encapsulated yeast that reproduces by budding. Human infection is acquired by inhalation of aerosolized water droplets contaminated by the organism. Exposure to the organism is common, but infection is rare in immunocompetent hosts. 8 Like other fungi, cellmediated immunity is the primary host defense. The suppression of cell mediated immune function by anti-rejection medications renders transpIant patients at increased risk of infection with CryptoCOCCbIS.

Central nervous system infection is the most important site of disease, with the pulmonary system acting as the portal of infection, s Consequently, most patients will present with signs of central nervous system infection such as headache, fever, focal neurological symptoms, or psychiatric disturbances. 121 Pulmonary symptoms are less frequent, although chest pain, dyspnea, and cough may occur and isolated pulmonary infections have been reported in solid organ transplants. 15 Other sites of infection include the skin, mucous membranes, and bone marrow. 122 Single or multiple well-defined pulmonary nodules, with or without cavitation, are the most common radiographic manifestation of cryptococcosis? 23 However, focal alveolar and interstitial opacities, and pleural effusions have been reported as the initial manifestation of pulmonary cryptococcal infection. The diagnosis of cryptococcal infection is often made by examination and culture of the cerebrospihal fluid. 8 Standard therapy includes amphotericin B and 5-flucytosine for 6 weeks, lz4

Blastomycosis Blastomycosis is the least common of the endemic fungi to produce disease in humans. Caused by Blastomyces dermatiditis it is most commonly found in the states surrounding the Great Lakes and in south central United States. However, it has been reported worldwide. 125The exact ecological source of the organism remains a mystery. Like Histo-

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plasma and Coccidioides species, Blastomyces dermatiditis is a dimorphic fungus that grows in the mycelia phase at room temperature but transforms into the yeast form at 37~ s Host-defense mechanisms are poorly understood but appear to be primarily cell-mediated immunity similar to those seen in histoplasmosis. 8 Reports of infections in immunocompromised hosts are rare. L26 In this limited experience, the presentations were similar to that seen in normal hosts. Most common symptoms were cough and dyspnea. However, extrapulmonary disease, especially involving the skin, bone, joints, and male genitourinary system were frequently encountered. Radiographs demonstrated focal alveolar infiltrates most commonly. 126 Bilateral patchy or nodular opacities have also been reported. Diagnosis is dependent on culture or demonstration of the yeast in pulmonary secretions or tissue. Amphotericin B is the standard therapy for blastomycosis, although ketoconazole may be an alternative therapy.

ents will usually appear as diffuse hazy or ground glass opacities on chest radiographs (Fig 8). 62-64,131 This may have a predilection for the transplanted lung in single lung transplant patients. ~3,6~ When severe, it may progress to diffuse alveolar consolidation and resemble pulmonary edema.~3~ CT will often be more sensitive for the detection of PCP and will show diffuse ground glass opacities. MYCOBACTERIAL INFECTIONS

Mycobacterial infections may be divided into two general groups: those caused by tuberculosis and those caused by nontuberculous mycobacteria. Most mycobacterial infections in solid organ transplants are due to tuberculosis. 9,132 The nontuberculous organisms most commonly associated with human infection are Mycobacterium kansasii (MK)

PROTOZOAL OPPORTUNISTS

Pneumocystis carinii is an organism of uncertain taxonomy, with some researchers classifying it as a fungus but most identifying it as a protozoan? 27 This organism is a globally distributed saprophyte that has been found in the lungs of many animals including the rat, mouse, rabbit, and dog. 1% The mode of transmission is unknown but is presumed to be spread of organisms from affected animals via inhalation. Pneumocystis carinii only causes pneumonia in patients with depressed immunity, such as those with AIDS, organ transplantation, immunosuppressive therapy, and malignancy. Pneumocystis carinii pneumonia (PCP) is an important and common cause of pneumonia in transplant patients. It as been reported in 33% of heart lung transplants and in 3% to 10% of heart transplants, 0% to 11% of liver transplants, ~~ and 6% to 14% of kidney transplants. 5,10,12'15,16,52,62,129,130 However, prophylaxis with low-dose trimethoprimsulfamethoxazol has dramatically reduced the incidence of PCP in solid organ transplant recipients. 6 Increases in imunosuppression, especially use of OKT3 may increase the risk of PCE 12 PCP may occur at any time following transplantation but commonly occurs in the 4th to 6th month following transplantation and may have up to a 47% mortality rate.~3,61 Like other patients PCP in solid transplant recipi-

Fig 8. Pneumocystis pneumonia. This 69-year-old man had received a renal transplant 8 months previously. He complained of fever, malaise, and dyspnea on exertion. A magnified view of the left upper lobe from a PA chest radiograph demonstrates faint ground glass opacities throughout the left lung. This pattern is strongly suggestive of either pneumocystis pneumonia or CMV pneumonia. Cytological evaluation of bronchial lavage fluid demonstrated Pneumocystis carinii organisms,

PULMONARY INFECTIONS IN SOLID ORGAN TRANSPLANTS

Fig 9. Mycobacterium kansasii infection. This 36-year-old man had received a renal transplant 2 years earlier, He complained of a chronic draining foot ulcer. (A) PA chest radiograph reveals multiple faint nodular opacities in the lungs bilaterally. (B) Magnification view demonstrates the pulmonary nodules to better advantage, Culture of the foot ulcer demonstrated Mycobacterium kansasii organisms.

and Mycobacterium-avium complex (MAC) although a variety of other species may cause human infection. 9,~33 There are two important differences between tuberculosis and nontuberculous mycobacteria. The first is the mode of transmission of the organism. Tuberculosis may only be acquired from an infected individual, usually through close contact with respiratory exhalations. Nontuberculous organisms are part of the normal soil flora and may be inhaled as aerosolized water droplets or may be acquired by direct inoculation of wounds. Second, nontuberculous mycobacteria are less virulent than

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tuberculosis and therefore usually produce a more mild and protracted illness. 132 Solid organ transplant recipients are at increased risk of contracting mycobacterial infections. The incidence of mycobacterial infections in transplant patients in the United States is estimated to be between 0.65% and 1.5%. ~34,~35Although low, this is 50 to 100 times the incidence in the general US population of 0.01% to 0 . 0 1 5 % . ~34'136 In Saudi Arabia, a 3.5% incidence of tuberculosis was found in the renal transplant population, 50 times higher than the general population of that country. 9 In solid organ transplants, the fraction of infections due to nontuberculous mycobacteria is larger than that seen in the general population, causing 25% to 43% of mycobacterial infections in transplants compared with 5% to 10% of mycobacterial infections in the general US population. 9,~35-139 There is no specific timetable for mycobacterial infections in transplant recipients. Infections have been reported from 1 to 96 months following transplantation and appear to be random events over this time period. 9,132 The incidence of dissemination is also unrelated the time following transplantation. Cell-mediated immunity is the primary means of controlling and eradicating mycobacterial infections. Steroids and the other anti-rejection medications thus predispose transplant recipients to developing mycobacterial infection, especially disseminated disease. 132Like many other opportunistic infections in transplant recipients, there is a high incidence of disseminated mycobacterial disease, which may be encountered in as many as 40% to 64% of cases. 9,137,140 Pulmonary infection accounts for approximately 40% of cases of mycobacterial disease in solid organ transplants with cutaneous, skeletal, and other sites of disease accounting for approximately 20% of cases. 9 Morbidity and mortality from mycobacterial infection is also increased in the transplant population, with a 30% mortality rate reported. 132 Fever is the most common presenting symptom in 50% to 86% of cases. 9,j32 Approximately one half of patients will present with c o u g h . 132 Dyspnea, chest pain, weight loss, night sweats, malaise, or arthritis will be the presenting complaint in a 15 % to 25% of patients. 9,~32The rate of progression of disease is typically somewhat faster in solid organ transplants, than in the general population. 141 In acquiring tuberculosis, slightly greater than one third of transplant recipients (11 of 28) will present with the cavitary upper lobe infiltrates characteristic of reactivation tuberculosis in the

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general population. 132 Approximately one third of transplant patients, 29% to 32%, will demonstrate a miliary pattern of small nodules on chest radiographs, a finding associated with disseminated infection. 9.~32 The chest radiograph of most of the remaining transplant patients who contract tuberculosis will appear as a solitary focal lower lobe opacity, pulmonary nodule, or pleural effusion. Solid organ transplant patients were shown to have a normal chest radiograph in 3.5% to 9.7% of tuberculosis cases.9,132 Adenopathy was also uncommon, seen in only one o f 28, 3.5%, of transplant patients. Nontuberculous mycobacteria are most likely to present as multiple moderate-sized pulmonary nodules. 133 Miliary nodules may also be seen and are associated with a high mortality. 9

CONCLUSIONS Infections, especially pneumonia and other pulmonary disorders, are among the most common complications o f solid organ transplantation and are a leading cause of death in this population. Infection can also lead to decreased graft survival and considerable morbidity in transplant patients. Therefore, it is important to maintain considerable vigilance for infectious complications in solid organ transplants. One of the most important factors in the evaluation of infections in transplant recipients is the duration of time since transplantation. This, coupled with the radiographic appearance of pulmonary infiltrates may suggest particular infectious causes. Bacterial infections, especially gram-negative nosocomial pneumonias will characteristically occur in the first month following transplantation. These will resemble pneumonias in normal hosts and will appear as unifocal or multifocal alveolar infiltrates. In the second, third, and fourth months following transplantation, solid organ transplant patients are susceptible to reactivation of dormant herpes viruses. Reactivation will most often represent viral shedding with little evidence of end organ damage. However, in those who develop viral pneumonia,

there is a high morbidity and mortality. CMV pneumonia is the most common of these infections and when radiographically apparent will usually demonstrate faint diffuse infiltration of the lung. CT scanning is more sensitive for the detection of the diffuse ground glass opacities of C M V pneumonia. Herpes pneumonias will appear as diffuse alveolar opacities, which resemble ARDS. Vailcelia pneumonia will demonstrate diffuse fuzzy nodular opacities called "acinar nodules," a pattern highly suggestive of this unusual infection. Starting at approximately 1 month after transplantation, the immunosuppression resulting from antirejection medications will render solid organ transplant recipients at increased risk for the opportunistic fungal, bacterial and protozoal pneumonias including Aspergillus, Mucor, Nocardia, and Pneumocystis pneumonia. Aspergillus and Nocardia pneumonias will characteristically present as solitary or multiple pulmonary nodules or nodular infiltrates. Pneumocystis pneumonia will appear as diffuse ground glass opacities on chest radiographs or CT scans. Mucor pneumonia will present as a rapidly progressive focal infiltrate and will be seen almost exclusively in diabetic patients. Patients in endemic areas will be at increased risk of disseminated granulomatous infections with mycobacteria and fungal organisms including, tuberculosis, nontuberculous mycobacteria, Histoplasma, Coccidioides, and Cryptococcus species. Most often these will present as multiple small "miliary nodules" but may occasionally present as one or several medium-sized nodules on the order of a few centimeters in diameter. Apical fibronodular or fibroproductive infiltrates will herald the onset of tuberculosis in some patients. As with all individuals, in the months and years following acute convalescence from the surgical procedure, some organ transplant will contract community acquired bacteria and viral pneumonias. Chest radiographic findings will resemble those seen in normal hosts.

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