- Email: [email protected]
Lung nodular lesions in heart transplant recipients
CLINICAL LUNG AND HEART/LUNG TRANSPLANTATION
Lung Nodular Lesions in Heart Transplant Recipients Patricia Mun ˜oz, MD, PhDa Jesu ´s Palomo, MDb Pedro Guembe, MDc Marta Rodrı´guez-Creixe´ms, MD, PhDa Paloma Gijo ´n, MDa and a Emilio Bouza, MD, PhD Purpose: To describe the characteristics and etiology of lung nodules after heart transplantation (HT). Patients and Methods: During a 6-year period 147 patients received HT and 130 survived more than 1 week. Nodular lesions were demonstrated after HT in 13 patients (10%). Results: Median age was 53 years, and all patients were male. Nodules were detected 23 to 158 days after HT (median, 66 days). An etiologic diagnosis was made in all but 1 case: Aspergillus (5), Nocardia–Rhodococcus (4), and cytomegalovirus (CMV) (3). Previous severe infection was present in 50% of the patients and rejection in 33% (75% with nocardiosis). Initially all patients with Nocardia but only 1 patient with aspergillosis were asymptomatic. The most common symptoms were fever (67%) and cough (50%). Central nervous system (CNS) involvement appeared in only one Aspergillus-infected patient. An average of 1.8 diagnostic procedures per patient were performed. Median time to establish a diagnosis was 8 days (0 to 24). Median hospital stay was 36 days and reached 60 in patients with Aspergillus. No patient died, although aspergillosis, which must be suspected in the presence of dyspnea, pleuritic pain, and CNS symptoms, caused the highest morbidity. Overall diagnostic yield was 60% for transtracheal aspiration, 70% for bronchoalveolar lavage, and 75% for transthoracic aspiration. Conclusions: Ten percent of HT patients developed lung nodules that were mainly caused by Aspergillus, Nocardia, and CMV. The time of appearance and some clinical manifestations may suggest the etiology and may help in the empirical treatment. J Heart Lung Transplant 2000;19:660–667.
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nfection of the lower respiratory tract occurs in 20% to 40% of heart transplant (HT) recipients and is a leading cause of morbidity and mortality.1,2 Chest X-rays predominantly show alveolar or inter-
stitial infiltrates of variable extent. However, nodular lesions are not uncommon. The differential diagnosis of a lung nodule in a normal host includes many malignant and benign processes.3 However, in
From the Clinical Microbiology–Infectious Diseases Division,a Hospital General Universitario “Gregorio Maran ˜o ´n,” Madrid, Spain; Cardiology Division,b Hospital General Universitario “Gregorio Maran ˜o ´n,” Madrid, Spain; and Radiology Division,c Hospital General Universitario “Gregorio Maran ˜o ´n,” Madrid, Spain. Submitted November 24, 1999; accepted March 30, 2000. Reprint requests: Patricia Mun ˜oz, MD. Servicio de Microbiologı´a y Unidad de Enfermedades Infecciosas–VIH. Hospital Gen-
eral Universitario “Gregorio Maran ˜o ´n.” Doctor Esquerdo 46, 28007 Madrid, Spain. Telephone: 34-91-586.84.52. Fax: 34-91-5044906. Email: [email protected] Copyright © 2000 by the International Society for Heart and Lung Transplantation. 1053-2498/00/$–see front matter PII S1053-2498(00)00119-4
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immunosuppressed patients, the most common causes are potentially life-threatening opportunistic infections that may be treated and prevented.4,5 Unfortunately, the prevalence and etiology of infections that cause lung nodular lesions in HT patients have not been sufficiently defined. We have detected single or multiple lung nodules on the chest radiograph in 10% of our HT patients. We report data on the timing, clinical manifestations, and yield of diagnostic techniques chosen to demonstrate the etiology.
PATIENTS AND METHODS During a 6-year period, 144 patients underwent 147 cardiac transplantations at our institution. Fourteen patients died in the immediate post-operative period. The remaining 130 patients constitute the study population. The standard immunosuppression regimen consisted of cyclosporin A, azathioprine, and prednisone, plus post-operative induction therapy with murine monoclonal antibodies or 3 doses of antithymocyte globulin. Rejection episodes were diagnosed and treated by following standard recommendations. All patients received the pneumococcal vaccine before transplantation and a short course of post-surgical antibacterial and antifungal prophylaxis with norfloxacin and nystatin. No cotrimoxazole prophylaxis was provided to these patients. Prophylaxis against cytomegalovirus (CMV) was only given to seronegative receptors with seropositive donors, and this was not the case in any of the patients with lung nodules. Post-operatively, chest radiographs were routinely performed at least once per week during the 1st month and then at each follow-up (as well as when clinically indicated). We defined a lung nodule as a focal, rounded, or ovoid lesion in the lung parenchyma that was less than 4 cm in diameter. Whenever a chest radiograph revealed a nodular lesion, we performed a complete clinical evaluation and a CT scan. We aggressively pursued the etiology of pneumonias in HT patients. Transtracheal aspirate (5 patients), bronchoscopy with bronchoalveolar lavage and/or transbronchial biopsy (10 patients), and transthoracic fluoroscopic or computed tomography– guided needle aspiration (5 patients) were performed as clinically indicated. We initiated no empiric therapy before the procedures in any of these cases. We processed specimens according to standard microbiologic recommendations and stained and cul-
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tured them for virus, bacteria, fungi, mycobacteria, and parasites. We also processed all specimens for cytology examination. The criteria for etiologic diagnosis of pulmonary infection were as follows: new radiographic nodule and culture evidence of a specific organism in a significant sample. Sputum cultures were not considered unless a true pathogen was recovered. In the case of CMV nodules, we accepted diagnosis only after conclusive exclusion of other etiologies, demonstration of active disseminated CMV infection, and complete resolution of signs and symptoms after only ganciclovir therapy. Therapy was administered according to standard practice.
RESULTS We noted single or multiple lung nodules in the chest X-rays of 13 patients (10%) of the 130 who survived the immediate post-transplantation period. All were males and the median age at the time of transplantation was 53 years (range, 35 to 63). The median lapse of time from transplantation to the detection of the pulmonary nodule was 66 days (range, 16 to 158 days). Etiologic diagnosis was established in 12 of the 13 cases and remained unknown in 1 patient. This patient was a 61-year-old man who underwent a computerized tomography (CT) scan on Day 30 post-transplantation due to suspicion of post-surgical mediastinitis. His CT revealed the presence of 3 bilateral asymptomatic lung nodules. One of the nodules was aspirated by means of a transthoracic CT-guided biopsy, and all cultures were negative. Nodules resolved spontaneously in the following days and were attributed to round atelectasis. Aspergillus was the causative organism in 5 cases, Nocardia asteroides in three, Rhodococcus equi in 1, and CMV in the remaining 3. We found no case of post-transplant lymphoproliferative disease in this series. As shown in Table I, Aspergillus infection was detected early after transplantation (median, 38 days; range, 23 to 158), whereas Nocardia and Rhodococcus infections developed only later (median, 100 days; range, 89 to 100). Nodules due to CMV occurred 16 to 89 days after HT (median, 27 days). Overall, one third of the patients suffered previous rejection (30%). Rejection was more frequent in patients infected with Nocardia (Table I). However, probably due to the small number of cases, differences did not reach statistical significance. One half of the patients had suffered CMV disease before nodules were diagnosed, and 2 of the patients
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TABLE I Epidemiologic, clinical, and analytic data of heart transplant patients with lung nodules etiologically diagnosed Number Median age (range) Underlying heart disease Coronary Valvular Myocardiopathy Day of detection after transplant (range) Previous rejection (%) Previous infection (%) Clinical manifestations (%) Radiologic finding Fever Cough Dyspnea Pain CNS symptoms Hemoptysis Analytical data (%) Hypoxia Leukopenia
Aspergillus
CMV
5 53 (35–63)
3 54 (38–57)
3/1 55 (43–61)
12 53 (35–63)
4 1 – 38 (23–158) 1 (20) 2 (40)
1 – 2 27 (16–89) 0 1 (33)
2 1 1 100 (89–100) 3 (75) 3 (75)
7 2 3 66.5 (16–158) 4 (33) 6 (50)
Nocardia/Rhodococcus
2 (40) 4 (80) 3 (60) 3 (60) 4 (80) 1 (20) 1 (20)
1 (33) 2 (33) 1 (33) 1 (33) 0 0 0
4 (100) 2 (50) 2 (50) 0 1 0 0
2 (40) 2 (40)
1 (33) 1 (33)
3 (75) –
(25)
Total
7 (58) 8 (67) 6 (50) 4 (33) 5 (42) 1 (8) 1 (8) 6 (50) 3 (25)
The patient whose etiology could not be filiated is excluded from the tables. CMV, cytomegalovirus; CNS, central nervous system.
had had previous bacterial complications (Haemophilus influenzae pneumonia and mediastinitis). Nodules appeared as asymptomatic radiologic findings in routine checkups in 58% of the cases and were detected because of clinical complaints in the remaining one half. As can be seen in Table I, all patients with Nocardia infection were initially asymptomatic. Most common clinical manifestations were fever (8 patients, 67%), cough (6 patients, 50%), pleuritic pain (5 patients, 42%), and dyspnea (4 patients, 33%). Patients with Aspergillus, were, in general terms, more symptomatic and were the only ones in our series to present neurologic manifestations and hemoptysis. Analytical data were not very useful for the presumptive diagnosis of the lesions (Table I). Regarding radiologic characteristics, CMV nodules were always solitary (Figure 1), whereas those caused by Nocardia were always multiple and bilateral. Aspergillus produced multiple lesions in 3/5 cases (60%). Nodules caused by Aspergillus were cavitated in 2/5 patients (Figure 2), and 3/4 patients with Nocardia had enlarged lymph nodes (Table II). Computerized tomography proved to be very useful in showing the real extent of the disease. After CT examination, 1 radiologically solitary nodule caused by Aspergillus and 2 by Nocardia proved to be multiple, and in the case of Nocardia, bilateral.
Etiologic diagnosis was established within a median of 8 days (0 to 24) (Table II). A median of 1.8 invasive techniques per patient was necessary to achieve the diagnosis. Overall diagnostic yield was 60% for transtracheal aspiration, 70% for bronchoalveolar lavage (BAL), and 75% for transthoracic aspiration. Bronchoalveolar lavage was the first positive technique in 58% of the patients. The only complications were a minor pneumothorax after a transbronchial biopsy and minor hemoptysis after a transthoracic needle aspiration. Direct microscopic examination of the respiratory samples (Gram stain, potassium hydroxide, or cotton blue preparations) were positive in 3/5 cases of aspergillosis and in 3/4 cases of nocardiosis. Patients exhibited important morbidity and their median hospital stay was longer than 1 month (36 days), reaching more than 2 months (60 days) in the cases of aspergillosis. No related death was detected, and we have found no recurrences to date (Table II).
DISCUSSION The presence of lung nodules in HT patients has been only anecdotally reported.6 However, the incidence of such radiologic presentation in other solidorgan recipients has ranged from 10% to 13%.7–10 In
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FIGURE 2 Cavitated nodule caused by Aspergillus fumigatus in a heart transplant recipient.
FIGURE 1 Solitary nodule caused by cytomegalovirus in a heart transplant recipient.
our experience 10% of all HT patients presented lung nodules in their evolution. To our surprise, 12 of our 13 cases had proven infectious etiology (Aspergillus, Nocardia–Rhodococcus, and CMV) and had some clinical characteristics that may suggest the etiology. Undoubtedly, differences in the prophylaxis scheme, the intensity of the immunosuppressive regimen, or the possibility of outbreaks or specific nosocomial problems could imply differences in the relative importance of each pathogen.
Aspergillosis Five of our patients had Aspergillus infection, which usually appeared in the first 2 months after transplantation (median, 38 days). Aspergillus nodules may be initially symptomatic (3 cases) or asymptomatic (2 cases) and present as single (2 cases) or multiple nodules (3 cases) (Figures 3 and 4). Our good response to treatment (no related mortality) is probably due to the fact that only nodular cases are
included in this report and that high doses of liposomal amphotericin B were administered,11 followed by prolonged periods of itraconazole. One case also required lobectomy. Pulmonary aspergillosis is the most common invasive mycosis affecting HT recipients. The overall incidence of invasive aspergillosis has decreased in recent years from 25% before cyclosporin A to the present 3.3% to 14%.12–15 In a nationwide study performed in Spain, 113/4,338 solid-organ transplant recipients had invasive aspergillosis (overall incidence, 2.6%) and 41 were HT patients (incidence 4.4%).16 In a recent series that studied the characteristics of pneumonias in the 1 year post-HT, Aspergillus species was the second most common cause of pneumonia (16% of the isolates; incidence, 4.2%).17 Invasive aspergillosis is usually a relatively early complication, and in a recent series, Aspergillus lung infection appeared a median of 36 days (19 to 139) after heart transplant.17 Although Aspergillus should be considered in the differential diagnosis of every lung infection in a HT patient, the presence of a lung nodule (41% to 86% of the cases) is one of the most suggestive clinical presentations.12,18 Cavitation is also highly suggestive of Aspergillus infection.17 Despite major advances achieved in the diagnosis and management of this complication, Aspergillusrelated mortality remains high (11% to 78%), although patients with only lung nodular involvement have the best outcomes.18 The use of universal antifungal prophylaxis after HT is not recommended at the present time.
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TABLE II Radiologic characteristics, diagnostic yield, and evolution of heart transplant patients with lung nodules Aspergillus (n ⴝ 5) Radiological manifestations (%) Unique Multiple-unilateral Bilateral Right-sided Upper lobes Median number (range) Median size (cm) Cavitation Pleural effusion Lymphadenopathies Positive result (%) Transtracheal aspiration Bronchoalveolar lavage Transthoracic aspiration Sputum Positive direct examination First diagnostic technique TTA BAL TTOR Sputum Days for diagnosis (range) Days in hospital (range) Death
CMV (n ⴝ 3)
Nocardia/Rhodococcus (n ⴝ 4)
Total (n ⴝ 12)
2 (40) 1 (20) 2 (40) 4 (80) 2 (40) 2 (1–5) 2 (2–3) 2 (40) 1 (20) 1 (20)
3 (100) – – 1 (33) 1 (33) 1 2 (1–2) 0 0 2 (66)
0 0 4 (100) 3 (75) 3 (75) 3.5 (2–5) 3 (1–3) 1 (25) 1 (25) 3 (75)
5 (42) 1 (8) 6 (50) 8 (66) 6 (50) 2 (1–5) 2 (1–3) 3 (25) 2 (16) 6 (50)
2/3 (66) 2/4 (50) 2/3 (66) 4/4 (100) 3 (60)
– 3/3 (100) – 0/1 0
1/2 (50) 2/3 (66) 1/1 (100) 0/2 3 (75)
1 (20) 2 (40) 2 (40) 0 7 (4–22) 60 (40–110) 1 NRa
– 3 (100) – – 9 (3–24) 17 (14–30) 0
1 (25) 2 (50) 1 (25) 0 7 (0–15) 26 (19–40) 0
3/5 (60) 7/10 (70) 3/4 (75) 4/7 (57) 6/12 (50) 2 (17) 7 (58) 3 (25) 0 8 (0–24) 36 (14–110) 1
a The patient died because of an episode of acute rejection. BAL, bronchoalveolar lavage; NR, non-related, TTA, transtrachial aspiration; TTOR, transthoracic pulmonary needle aspiration.
Patients with Nocardia (3 cases) or Rhodococcus (1 case) infection were all initially asymptomatic, so nodules were discovered in routine radiographic
checkups. Late events always occurred more than 3 months posttransplantation (median, 100 days). Radiologically, Nocardia nodules were multiple and bilateral, possibly because of their long-term silent presentation. Previous rejection (75%) and CMV
FIGURE 3 Single nodule caused by Aspergillus
FIGURE 4 Multiple nodules caused by Aspergillus
Nocardia and Rhodococcus Infections
fumigatus in heart transplant recipients.
fumigatus in heart transplant recipients.
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infection episodes are commonly described in these patients, probably reflecting the importance of the antecedent of corticosteroid therapy and viral immunomodulatory effect as predisposing conditions for nocardiosis.19,20 In the literature, the incidence of Nocardia pneumonia after HT ranges from 2% to 13%, although it has been significantly reduced since the widespread use of cotrimoxazole prophylaxis.21,22 As in our experience, it is described as a late complication that mainly affects lung, CNS, and skin. In the series of pneumonia after HT,17 lung infection by M. tuberculosis, Nocardia, or Rhodoccus appeared later than other pneumonias (average 104.5 days vs 38 days after HT) and had the most sub-acute presentation (median, 7 days). The use of prophylactic cotrimoxazole during the first months after transplantation has significantly lowered the incidence of nocardiosis. Rhodococcus is an opportunistic pathogen that usually causes cavitated pneumonia in HIV-positive patients, but solid-organ transplant recipients may be affected as well.23 Infection is usually late (median of 49 months after transplantation), and the lungs are primarily involved in most cases. Infection presents as lung nodules in one half of the patients. Clinicians should consider Rhodococcus when evaluating a solid-organ recipient with an asymptomatic lung nodule, particularly when cultures fail to identify Mycobacteria, Nocardia, or fungal organisms. Clinical microbiology laboratories should be alerted when a Rhodoccocus infection is suspected, because it could be mistaken for a contaminant diphteroid and will not respond to standard empiric therapy.
CMV Infection Cytomegalovirus is the most common organism that infects the lungs in HT recipients. Cytomegalovirus pneumonitis commonly adopts a diffuse interstitial radiologic appearance, but focal and even nodular infiltrates are described in up to one third of patients.5,8,24 –27 Cytomegalovirus nodular infections appeared 16 to 89 days after transplantation in our experience, and from 33 to 195 days post-transplantation in the Schulman series25 and were always responsible for solitary nodules.
Diagnostic Approach Regarding diagnostic techniques, CT is more sensitive than standard chest X-ray in identifying the number of lesions and may assist guided biopsy.28 In our opinion it should always be performed when a lung nodule is detected and before surgery.
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Etiologic diagnosis is mandatory considering that only 50% of empiric treatments for pneumonia in HT patients are appropriate.17 For this reason, fast diagnostic procedures that guide antimicrobial treatment are necessary. Etiologic diagnosis may be performed by using different techniques, therefore this requires careful tailoring to each patient. Transtracheal aspiration (TTA), although not widely used, has proved, for us and others, to be a rapid, easy-to-perform, and highly sensitive technique that can be carried out at the bedside and has a very low rate of complications.29 –31 We performed TTA in 5 patients (3 with Aspergillus and 2 with Nocardia infections), and the samples obtained were positive and the first diagnostic clue in 2 patients (1 aspergillosis and 1 nocardiosis). In the Vivo series,31 TTA detected 9/23 Nocardias. If TTA smears do not offer prompt diagnosis, more invasive procedures should be performed, without waiting for culture results. In Cisneros’s study,17 the sensitivity of transthoracic pulmonary needle aspiration (TTOR) was 100%. We performed TTOR in 4 patients (3 with Aspergillus and 1 with Rhodococcus infections), and samples were positive in 3 of them. Transthoracic aspiration has an excellent diagnostic yield.4,32 Using both TTA and TTOR, researchers diagnosed 17 out of 18 pulmonary infections in HT patients in 1 series.30 Accordingly, for focal pulmonary lesions, mainly if they are peripheral, our first choice is transthoracic pulmonary needle aspiration, either under fluoroscopic or CT guidance. When no diagnosis can be made or when nodules cannot be easily reached transthoracically, BAL and transbronchial or open-lung biopsy should be considered.34 –36 Bronchoscopy with BAL is the most commonly used diagnostic procedure for obtaining respiratory samples in immunocompromised patients, and it provided the diagnosis in 58% of our patients (2 with aspergillosis, 3 with CMV, and 2 with nocardiosis). The diagnostic sensitivity of BAL in Cisnero’s17 series (89%) was higher even than that of open-lung biopsy (50%). We did not have to use open-lung biopsy in any of our cases. Examination of sputum should form part of the initial diagnostic study of pneumonia after HT, and its sensitivity was 57%. However, only the isolation of microorganisms such as M. tuberculosis or endemic fungi establishes the diagnosis, and for microorganisms like Aspergillus, more invasive techniques are usually required. If Legionellosis is suspected, the investigation of urinary antigen should be requested. The differential diagnosis of pulmonary nodules
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includes many malignant and benign processes. Thromboembolic disease should always be considered when a lung nodule is detected early after the surgical procedure, but the incidence of this complication is low at the present time. We have not had any neoplasic lung nodule in our series, however, as long-term survival after cardiac transplantation improves, neoplasic complications are increasingly discovered (3% to 6%). Lymphoma, Kaposi’s sarcoma, and metastatic tumors should be included in the differential diagnosis. An invasive diagnostic procedure is usually necessary, and the presence of extrapulmonary disease must be investigated. Higher levels of immunosuppression may affect the risk of post-transplantation lymphoproliferative disorder, mainly in Epstein-Barr virus–seronegative patients. We conclude that lung nodules are frequent in HT recipients and that their etiology is mainly infectious, Aspergillus (during the first 2 months) and Nocardia (after the 3rd month) being the most common agents. The time of appearance and some clinical manifestations may suggest the etiology and may help determine empiric treatment in selected cases. Invasive diagnostic techniques are required for the diagnosis, but a stepwise approach starting with transthoracic aspiration may contribute to minimizing discomfort for the patient.
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11.
12.
13.
14.
15.
16.
17.
18. 19.
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nodules in liver transplant recipients. Medicine 1998;77: 50 – 8. Berenguer J, Mun ˜oz P, Parras F, Ferna´ndez Baca V, Herna´ndez Sampelayo T, Bouza E. Treatment of deep mycoses with liposomal amphotericin B. Europ J Clin Microbiol Infect Dis 1994;13:504 –7. Grossi P, De Maria R, Caroli A, Zaina MS, Minoli L. Infections in heart transplant recipients: the experience of the Italian heart transplantation program. Italian Study Group on Infections in Heart Transplantation. J Heart Lung Transplant 1992;11:847– 66. Denning DW, Stevens DA. Antifungal and surgical treatment of invasive aspergillosis: review of 2121 published cases. Rev Infect Dis 1990;12:1147–201. Stinson EB, Bieber CP, Griepp RB, Clark DA, Shumway NE, Remington JS. Infectious complications after cardiac transplantation in man. Ann Intern Med 1971;74:22–36. Guillemain R, Lavarde V, Amrein C, Chevalier P, Guinvarch A, Glotz D. Invasive aspergillosis after transplantation. Transplant Proc 1995;27:1307–9. The Spanish Group For Infections In Transplant Patients, Mun ˜oz P, Torre-Cisneros J, Bouza E, et al. A large multicentric study: invasive aspergillosis in transplant recipients. 36th ICAAC Meeting, 1996. (J128). The Spanish Transplantation Infection Study Group, Cisneros JM, Mun ˜oz P, Torre-Cisneros J, et al. Pneumonia after heart transplantation: a multiinstitutional study. Clin Infect Dis 1998;27:324 –31. Denning DW. Diagnosis and management of invasive aspergillosis. Current Clin Top Infect Dis 1996;277–99. Young LS, Armstrong D, Blevins A, et al. Nocardia asteroides infection complicating neoplastic disease. Am J Med 1971; 50:356. Gorensek MJ, Stewart RW, Keys TF, et al. Decreased infections in cardiac transplant recipients on cyclosporine with reduced corticosteroid use. Cleve Clin J Med 1989;56:690 –5. Krick JA, Stinson EB, Remington JS. Nocardia infection in heart transplant patients. Ann Intern Med 1975;82:18 –26. Peterson PK, Ferguson R, Fryd DS, Balfour HH, Jr, Rynasiewicz J, Simmons RL. Infectious diseases in hospitalized renal transplant recipients: a prospective study of a complex and evolving problem. Medicine 1982;61:360 –72. Mun ˜oz P, Burillo A, Palomo J, Rodrı´guez-Creixe´ms M, Bouza E. Rhodococcus equi infection in transplant recipients: case report and review of the literature. Transplantation 1997;65:449 –53. Marshall WF, Walker RC. Pulmonary cytomegalovirus infections after orthotopic liver transplantation: prospective analysis of 93 consecutive orthotopic liver transplantations. The International Symposium of Infections in the Immunocompromised Host, Peebles, Scotland, 1990. Schulman LL. Cytomegalovirus pneumonitis and lobar consolidation. Chest 1987;91:558 – 61. Primack SL, Hartman TE, Soo Lee K, Mu ¨ ller NL. Pulmonary nodules and the CT halo sign. Radiology 1994;190: 513–15. Dummer JS, White LT, Ho M, Griffith BP, Hardesty RL, Bahnson HT. Morbidity of cytomegalovirus infection in recipients of heart or heart-lung transplants who received cyclosporine. J Infect Dis 1985;152:1182–91. Muhm JR, Brown LR, Crowe JK. Detection of pulmonary nodules by computed tomography. Am J Roentgenol 1977; 128:267.
The Journal of Heart and Lung Transplantation Volume 19, Number 7 29. Munda R, Alexander JW, First MR, Gartside PS, Fidler JP. Pulmonary infections in renal transplant recipients. Ann Surg 1978;187:126 –3. 30. Mammana RB, Petersen EA, Fuller JK, Siroky K, Copeland JG. Pulmonary infections in cardiac transplant patients: modes of diagnosis, complications, and effectiveness of therapy. Ann Thorac Surg 1983;36:700 –5. 31. Vivo F, Pond GD, Rhenman B, et al. Transtracheal aspiration and fine needle aspiration biopsy for the diagnosis of pulmonary infection in heart transplant patients. J Thorac Cardiovasc Surg 1988;96:696 –9. 32. Castellino RA, Blank RN. Etiologic diagnosis of focal pulmonary infection in immunocompromised patients by fluo-
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Lung Nodular Lesions in Heart Transplant Recipients Patricia Mun ˜oz, MD, PhDa Jesu ´s Palomo, MDb Pedro Guembe, MDc Marta Rodrı´guez-Creixe´ms, MD, PhDa Paloma Gijo ´n, MDa and a Emilio Bouza, MD, PhD Purpose: To describe the characteristics and etiology of lung nodules after heart transplantation (HT). Patients and Methods: During a 6-year period 147 patients received HT and 130 survived more than 1 week. Nodular lesions were demonstrated after HT in 13 patients (10%). Results: Median age was 53 years, and all patients were male. Nodules were detected 23 to 158 days after HT (median, 66 days). An etiologic diagnosis was made in all but 1 case: Aspergillus (5), Nocardia–Rhodococcus (4), and cytomegalovirus (CMV) (3). Previous severe infection was present in 50% of the patients and rejection in 33% (75% with nocardiosis). Initially all patients with Nocardia but only 1 patient with aspergillosis were asymptomatic. The most common symptoms were fever (67%) and cough (50%). Central nervous system (CNS) involvement appeared in only one Aspergillus-infected patient. An average of 1.8 diagnostic procedures per patient were performed. Median time to establish a diagnosis was 8 days (0 to 24). Median hospital stay was 36 days and reached 60 in patients with Aspergillus. No patient died, although aspergillosis, which must be suspected in the presence of dyspnea, pleuritic pain, and CNS symptoms, caused the highest morbidity. Overall diagnostic yield was 60% for transtracheal aspiration, 70% for bronchoalveolar lavage, and 75% for transthoracic aspiration. Conclusions: Ten percent of HT patients developed lung nodules that were mainly caused by Aspergillus, Nocardia, and CMV. The time of appearance and some clinical manifestations may suggest the etiology and may help in the empirical treatment. J Heart Lung Transplant 2000;19:660–667.
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nfection of the lower respiratory tract occurs in 20% to 40% of heart transplant (HT) recipients and is a leading cause of morbidity and mortality.1,2 Chest X-rays predominantly show alveolar or inter-
stitial infiltrates of variable extent. However, nodular lesions are not uncommon. The differential diagnosis of a lung nodule in a normal host includes many malignant and benign processes.3 However, in
From the Clinical Microbiology–Infectious Diseases Division,a Hospital General Universitario “Gregorio Maran ˜o ´n,” Madrid, Spain; Cardiology Division,b Hospital General Universitario “Gregorio Maran ˜o ´n,” Madrid, Spain; and Radiology Division,c Hospital General Universitario “Gregorio Maran ˜o ´n,” Madrid, Spain. Submitted November 24, 1999; accepted March 30, 2000. Reprint requests: Patricia Mun ˜oz, MD. Servicio de Microbiologı´a y Unidad de Enfermedades Infecciosas–VIH. Hospital Gen-
eral Universitario “Gregorio Maran ˜o ´n.” Doctor Esquerdo 46, 28007 Madrid, Spain. Telephone: 34-91-586.84.52. Fax: 34-91-5044906. Email: [email protected] Copyright © 2000 by the International Society for Heart and Lung Transplantation. 1053-2498/00/$–see front matter PII S1053-2498(00)00119-4
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immunosuppressed patients, the most common causes are potentially life-threatening opportunistic infections that may be treated and prevented.4,5 Unfortunately, the prevalence and etiology of infections that cause lung nodular lesions in HT patients have not been sufficiently defined. We have detected single or multiple lung nodules on the chest radiograph in 10% of our HT patients. We report data on the timing, clinical manifestations, and yield of diagnostic techniques chosen to demonstrate the etiology.
PATIENTS AND METHODS During a 6-year period, 144 patients underwent 147 cardiac transplantations at our institution. Fourteen patients died in the immediate post-operative period. The remaining 130 patients constitute the study population. The standard immunosuppression regimen consisted of cyclosporin A, azathioprine, and prednisone, plus post-operative induction therapy with murine monoclonal antibodies or 3 doses of antithymocyte globulin. Rejection episodes were diagnosed and treated by following standard recommendations. All patients received the pneumococcal vaccine before transplantation and a short course of post-surgical antibacterial and antifungal prophylaxis with norfloxacin and nystatin. No cotrimoxazole prophylaxis was provided to these patients. Prophylaxis against cytomegalovirus (CMV) was only given to seronegative receptors with seropositive donors, and this was not the case in any of the patients with lung nodules. Post-operatively, chest radiographs were routinely performed at least once per week during the 1st month and then at each follow-up (as well as when clinically indicated). We defined a lung nodule as a focal, rounded, or ovoid lesion in the lung parenchyma that was less than 4 cm in diameter. Whenever a chest radiograph revealed a nodular lesion, we performed a complete clinical evaluation and a CT scan. We aggressively pursued the etiology of pneumonias in HT patients. Transtracheal aspirate (5 patients), bronchoscopy with bronchoalveolar lavage and/or transbronchial biopsy (10 patients), and transthoracic fluoroscopic or computed tomography– guided needle aspiration (5 patients) were performed as clinically indicated. We initiated no empiric therapy before the procedures in any of these cases. We processed specimens according to standard microbiologic recommendations and stained and cul-
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tured them for virus, bacteria, fungi, mycobacteria, and parasites. We also processed all specimens for cytology examination. The criteria for etiologic diagnosis of pulmonary infection were as follows: new radiographic nodule and culture evidence of a specific organism in a significant sample. Sputum cultures were not considered unless a true pathogen was recovered. In the case of CMV nodules, we accepted diagnosis only after conclusive exclusion of other etiologies, demonstration of active disseminated CMV infection, and complete resolution of signs and symptoms after only ganciclovir therapy. Therapy was administered according to standard practice.
RESULTS We noted single or multiple lung nodules in the chest X-rays of 13 patients (10%) of the 130 who survived the immediate post-transplantation period. All were males and the median age at the time of transplantation was 53 years (range, 35 to 63). The median lapse of time from transplantation to the detection of the pulmonary nodule was 66 days (range, 16 to 158 days). Etiologic diagnosis was established in 12 of the 13 cases and remained unknown in 1 patient. This patient was a 61-year-old man who underwent a computerized tomography (CT) scan on Day 30 post-transplantation due to suspicion of post-surgical mediastinitis. His CT revealed the presence of 3 bilateral asymptomatic lung nodules. One of the nodules was aspirated by means of a transthoracic CT-guided biopsy, and all cultures were negative. Nodules resolved spontaneously in the following days and were attributed to round atelectasis. Aspergillus was the causative organism in 5 cases, Nocardia asteroides in three, Rhodococcus equi in 1, and CMV in the remaining 3. We found no case of post-transplant lymphoproliferative disease in this series. As shown in Table I, Aspergillus infection was detected early after transplantation (median, 38 days; range, 23 to 158), whereas Nocardia and Rhodococcus infections developed only later (median, 100 days; range, 89 to 100). Nodules due to CMV occurred 16 to 89 days after HT (median, 27 days). Overall, one third of the patients suffered previous rejection (30%). Rejection was more frequent in patients infected with Nocardia (Table I). However, probably due to the small number of cases, differences did not reach statistical significance. One half of the patients had suffered CMV disease before nodules were diagnosed, and 2 of the patients
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TABLE I Epidemiologic, clinical, and analytic data of heart transplant patients with lung nodules etiologically diagnosed Number Median age (range) Underlying heart disease Coronary Valvular Myocardiopathy Day of detection after transplant (range) Previous rejection (%) Previous infection (%) Clinical manifestations (%) Radiologic finding Fever Cough Dyspnea Pain CNS symptoms Hemoptysis Analytical data (%) Hypoxia Leukopenia
Aspergillus
CMV
5 53 (35–63)
3 54 (38–57)
3/1 55 (43–61)
12 53 (35–63)
4 1 – 38 (23–158) 1 (20) 2 (40)
1 – 2 27 (16–89) 0 1 (33)
2 1 1 100 (89–100) 3 (75) 3 (75)
7 2 3 66.5 (16–158) 4 (33) 6 (50)
Nocardia/Rhodococcus
2 (40) 4 (80) 3 (60) 3 (60) 4 (80) 1 (20) 1 (20)
1 (33) 2 (33) 1 (33) 1 (33) 0 0 0
4 (100) 2 (50) 2 (50) 0 1 0 0
2 (40) 2 (40)
1 (33) 1 (33)
3 (75) –
(25)
Total
7 (58) 8 (67) 6 (50) 4 (33) 5 (42) 1 (8) 1 (8) 6 (50) 3 (25)
The patient whose etiology could not be filiated is excluded from the tables. CMV, cytomegalovirus; CNS, central nervous system.
had had previous bacterial complications (Haemophilus influenzae pneumonia and mediastinitis). Nodules appeared as asymptomatic radiologic findings in routine checkups in 58% of the cases and were detected because of clinical complaints in the remaining one half. As can be seen in Table I, all patients with Nocardia infection were initially asymptomatic. Most common clinical manifestations were fever (8 patients, 67%), cough (6 patients, 50%), pleuritic pain (5 patients, 42%), and dyspnea (4 patients, 33%). Patients with Aspergillus, were, in general terms, more symptomatic and were the only ones in our series to present neurologic manifestations and hemoptysis. Analytical data were not very useful for the presumptive diagnosis of the lesions (Table I). Regarding radiologic characteristics, CMV nodules were always solitary (Figure 1), whereas those caused by Nocardia were always multiple and bilateral. Aspergillus produced multiple lesions in 3/5 cases (60%). Nodules caused by Aspergillus were cavitated in 2/5 patients (Figure 2), and 3/4 patients with Nocardia had enlarged lymph nodes (Table II). Computerized tomography proved to be very useful in showing the real extent of the disease. After CT examination, 1 radiologically solitary nodule caused by Aspergillus and 2 by Nocardia proved to be multiple, and in the case of Nocardia, bilateral.
Etiologic diagnosis was established within a median of 8 days (0 to 24) (Table II). A median of 1.8 invasive techniques per patient was necessary to achieve the diagnosis. Overall diagnostic yield was 60% for transtracheal aspiration, 70% for bronchoalveolar lavage (BAL), and 75% for transthoracic aspiration. Bronchoalveolar lavage was the first positive technique in 58% of the patients. The only complications were a minor pneumothorax after a transbronchial biopsy and minor hemoptysis after a transthoracic needle aspiration. Direct microscopic examination of the respiratory samples (Gram stain, potassium hydroxide, or cotton blue preparations) were positive in 3/5 cases of aspergillosis and in 3/4 cases of nocardiosis. Patients exhibited important morbidity and their median hospital stay was longer than 1 month (36 days), reaching more than 2 months (60 days) in the cases of aspergillosis. No related death was detected, and we have found no recurrences to date (Table II).
DISCUSSION The presence of lung nodules in HT patients has been only anecdotally reported.6 However, the incidence of such radiologic presentation in other solidorgan recipients has ranged from 10% to 13%.7–10 In
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FIGURE 2 Cavitated nodule caused by Aspergillus fumigatus in a heart transplant recipient.
FIGURE 1 Solitary nodule caused by cytomegalovirus in a heart transplant recipient.
our experience 10% of all HT patients presented lung nodules in their evolution. To our surprise, 12 of our 13 cases had proven infectious etiology (Aspergillus, Nocardia–Rhodococcus, and CMV) and had some clinical characteristics that may suggest the etiology. Undoubtedly, differences in the prophylaxis scheme, the intensity of the immunosuppressive regimen, or the possibility of outbreaks or specific nosocomial problems could imply differences in the relative importance of each pathogen.
Aspergillosis Five of our patients had Aspergillus infection, which usually appeared in the first 2 months after transplantation (median, 38 days). Aspergillus nodules may be initially symptomatic (3 cases) or asymptomatic (2 cases) and present as single (2 cases) or multiple nodules (3 cases) (Figures 3 and 4). Our good response to treatment (no related mortality) is probably due to the fact that only nodular cases are
included in this report and that high doses of liposomal amphotericin B were administered,11 followed by prolonged periods of itraconazole. One case also required lobectomy. Pulmonary aspergillosis is the most common invasive mycosis affecting HT recipients. The overall incidence of invasive aspergillosis has decreased in recent years from 25% before cyclosporin A to the present 3.3% to 14%.12–15 In a nationwide study performed in Spain, 113/4,338 solid-organ transplant recipients had invasive aspergillosis (overall incidence, 2.6%) and 41 were HT patients (incidence 4.4%).16 In a recent series that studied the characteristics of pneumonias in the 1 year post-HT, Aspergillus species was the second most common cause of pneumonia (16% of the isolates; incidence, 4.2%).17 Invasive aspergillosis is usually a relatively early complication, and in a recent series, Aspergillus lung infection appeared a median of 36 days (19 to 139) after heart transplant.17 Although Aspergillus should be considered in the differential diagnosis of every lung infection in a HT patient, the presence of a lung nodule (41% to 86% of the cases) is one of the most suggestive clinical presentations.12,18 Cavitation is also highly suggestive of Aspergillus infection.17 Despite major advances achieved in the diagnosis and management of this complication, Aspergillusrelated mortality remains high (11% to 78%), although patients with only lung nodular involvement have the best outcomes.18 The use of universal antifungal prophylaxis after HT is not recommended at the present time.
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TABLE II Radiologic characteristics, diagnostic yield, and evolution of heart transplant patients with lung nodules Aspergillus (n ⴝ 5) Radiological manifestations (%) Unique Multiple-unilateral Bilateral Right-sided Upper lobes Median number (range) Median size (cm) Cavitation Pleural effusion Lymphadenopathies Positive result (%) Transtracheal aspiration Bronchoalveolar lavage Transthoracic aspiration Sputum Positive direct examination First diagnostic technique TTA BAL TTOR Sputum Days for diagnosis (range) Days in hospital (range) Death
CMV (n ⴝ 3)
Nocardia/Rhodococcus (n ⴝ 4)
Total (n ⴝ 12)
2 (40) 1 (20) 2 (40) 4 (80) 2 (40) 2 (1–5) 2 (2–3) 2 (40) 1 (20) 1 (20)
3 (100) – – 1 (33) 1 (33) 1 2 (1–2) 0 0 2 (66)
0 0 4 (100) 3 (75) 3 (75) 3.5 (2–5) 3 (1–3) 1 (25) 1 (25) 3 (75)
5 (42) 1 (8) 6 (50) 8 (66) 6 (50) 2 (1–5) 2 (1–3) 3 (25) 2 (16) 6 (50)
2/3 (66) 2/4 (50) 2/3 (66) 4/4 (100) 3 (60)
– 3/3 (100) – 0/1 0
1/2 (50) 2/3 (66) 1/1 (100) 0/2 3 (75)
1 (20) 2 (40) 2 (40) 0 7 (4–22) 60 (40–110) 1 NRa
– 3 (100) – – 9 (3–24) 17 (14–30) 0
1 (25) 2 (50) 1 (25) 0 7 (0–15) 26 (19–40) 0
3/5 (60) 7/10 (70) 3/4 (75) 4/7 (57) 6/12 (50) 2 (17) 7 (58) 3 (25) 0 8 (0–24) 36 (14–110) 1
a The patient died because of an episode of acute rejection. BAL, bronchoalveolar lavage; NR, non-related, TTA, transtrachial aspiration; TTOR, transthoracic pulmonary needle aspiration.
Patients with Nocardia (3 cases) or Rhodococcus (1 case) infection were all initially asymptomatic, so nodules were discovered in routine radiographic
checkups. Late events always occurred more than 3 months posttransplantation (median, 100 days). Radiologically, Nocardia nodules were multiple and bilateral, possibly because of their long-term silent presentation. Previous rejection (75%) and CMV
FIGURE 3 Single nodule caused by Aspergillus
FIGURE 4 Multiple nodules caused by Aspergillus
Nocardia and Rhodococcus Infections
fumigatus in heart transplant recipients.
fumigatus in heart transplant recipients.
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infection episodes are commonly described in these patients, probably reflecting the importance of the antecedent of corticosteroid therapy and viral immunomodulatory effect as predisposing conditions for nocardiosis.19,20 In the literature, the incidence of Nocardia pneumonia after HT ranges from 2% to 13%, although it has been significantly reduced since the widespread use of cotrimoxazole prophylaxis.21,22 As in our experience, it is described as a late complication that mainly affects lung, CNS, and skin. In the series of pneumonia after HT,17 lung infection by M. tuberculosis, Nocardia, or Rhodoccus appeared later than other pneumonias (average 104.5 days vs 38 days after HT) and had the most sub-acute presentation (median, 7 days). The use of prophylactic cotrimoxazole during the first months after transplantation has significantly lowered the incidence of nocardiosis. Rhodococcus is an opportunistic pathogen that usually causes cavitated pneumonia in HIV-positive patients, but solid-organ transplant recipients may be affected as well.23 Infection is usually late (median of 49 months after transplantation), and the lungs are primarily involved in most cases. Infection presents as lung nodules in one half of the patients. Clinicians should consider Rhodococcus when evaluating a solid-organ recipient with an asymptomatic lung nodule, particularly when cultures fail to identify Mycobacteria, Nocardia, or fungal organisms. Clinical microbiology laboratories should be alerted when a Rhodoccocus infection is suspected, because it could be mistaken for a contaminant diphteroid and will not respond to standard empiric therapy.
CMV Infection Cytomegalovirus is the most common organism that infects the lungs in HT recipients. Cytomegalovirus pneumonitis commonly adopts a diffuse interstitial radiologic appearance, but focal and even nodular infiltrates are described in up to one third of patients.5,8,24 –27 Cytomegalovirus nodular infections appeared 16 to 89 days after transplantation in our experience, and from 33 to 195 days post-transplantation in the Schulman series25 and were always responsible for solitary nodules.
Diagnostic Approach Regarding diagnostic techniques, CT is more sensitive than standard chest X-ray in identifying the number of lesions and may assist guided biopsy.28 In our opinion it should always be performed when a lung nodule is detected and before surgery.
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Etiologic diagnosis is mandatory considering that only 50% of empiric treatments for pneumonia in HT patients are appropriate.17 For this reason, fast diagnostic procedures that guide antimicrobial treatment are necessary. Etiologic diagnosis may be performed by using different techniques, therefore this requires careful tailoring to each patient. Transtracheal aspiration (TTA), although not widely used, has proved, for us and others, to be a rapid, easy-to-perform, and highly sensitive technique that can be carried out at the bedside and has a very low rate of complications.29 –31 We performed TTA in 5 patients (3 with Aspergillus and 2 with Nocardia infections), and the samples obtained were positive and the first diagnostic clue in 2 patients (1 aspergillosis and 1 nocardiosis). In the Vivo series,31 TTA detected 9/23 Nocardias. If TTA smears do not offer prompt diagnosis, more invasive procedures should be performed, without waiting for culture results. In Cisneros’s study,17 the sensitivity of transthoracic pulmonary needle aspiration (TTOR) was 100%. We performed TTOR in 4 patients (3 with Aspergillus and 1 with Rhodococcus infections), and samples were positive in 3 of them. Transthoracic aspiration has an excellent diagnostic yield.4,32 Using both TTA and TTOR, researchers diagnosed 17 out of 18 pulmonary infections in HT patients in 1 series.30 Accordingly, for focal pulmonary lesions, mainly if they are peripheral, our first choice is transthoracic pulmonary needle aspiration, either under fluoroscopic or CT guidance. When no diagnosis can be made or when nodules cannot be easily reached transthoracically, BAL and transbronchial or open-lung biopsy should be considered.34 –36 Bronchoscopy with BAL is the most commonly used diagnostic procedure for obtaining respiratory samples in immunocompromised patients, and it provided the diagnosis in 58% of our patients (2 with aspergillosis, 3 with CMV, and 2 with nocardiosis). The diagnostic sensitivity of BAL in Cisnero’s17 series (89%) was higher even than that of open-lung biopsy (50%). We did not have to use open-lung biopsy in any of our cases. Examination of sputum should form part of the initial diagnostic study of pneumonia after HT, and its sensitivity was 57%. However, only the isolation of microorganisms such as M. tuberculosis or endemic fungi establishes the diagnosis, and for microorganisms like Aspergillus, more invasive techniques are usually required. If Legionellosis is suspected, the investigation of urinary antigen should be requested. The differential diagnosis of pulmonary nodules
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includes many malignant and benign processes. Thromboembolic disease should always be considered when a lung nodule is detected early after the surgical procedure, but the incidence of this complication is low at the present time. We have not had any neoplasic lung nodule in our series, however, as long-term survival after cardiac transplantation improves, neoplasic complications are increasingly discovered (3% to 6%). Lymphoma, Kaposi’s sarcoma, and metastatic tumors should be included in the differential diagnosis. An invasive diagnostic procedure is usually necessary, and the presence of extrapulmonary disease must be investigated. Higher levels of immunosuppression may affect the risk of post-transplantation lymphoproliferative disorder, mainly in Epstein-Barr virus–seronegative patients. We conclude that lung nodules are frequent in HT recipients and that their etiology is mainly infectious, Aspergillus (during the first 2 months) and Nocardia (after the 3rd month) being the most common agents. The time of appearance and some clinical manifestations may suggest the etiology and may help determine empiric treatment in selected cases. Invasive diagnostic techniques are required for the diagnosis, but a stepwise approach starting with transthoracic aspiration may contribute to minimizing discomfort for the patient.
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16.
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18. 19.
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