- Email: [email protected]
Pulmonary Nocardiosis in a Heart Transplant Patient: Case Report and Review of the Literature
Pulmonary Nocardiosis in a Heart Transplant Patient: Case Report and Review of the Literature François Haddad, MD,a Sharon A. Hunt, MD,b Mark Perlroth, MD,b Hannah Valantine, MD,b Ramona Doyle, MD,c and Jose Montoya, MDd Pulmonary infection with Nocardia is an uncommon but serious infection found in immunocompromised patients. We describe a rapidly progressive pulmonary nocardiosis in a heart transplant patient. We then review the common clinical features of Nocardia infection in transplant recipients, outlining the challenges in its diagnosis and management. We also review the differences between Pneumocystis jiroveci prophylaxis regimens with respect to concomitant prophylaxis of Nocardia and other opportunistic infections. J Heart Lung Transplant 2007;26:93–7. Copyright © 2007 by the International Society for Heart and Lung Transplantation.
Pulmonary nocardiosis is an uncommon but serious infection found in immunocompromised patients.1,2 In a series of 620 consecutive heart transplant patients at the Stanford University Medical Center between 1980 and 1996, pulmonary nocardiosis was seen in 19 patients.1 In the same series, the incidence of pulmonary nocardiosis was found to decrease after the introduction of Pneumocystitis jiroveci (PCP) prophylaxis with trimethoprim–sulfamethoxazole (TMP-SMX), suggesting effectiveness of TMP-SMX for Nocardia prophylaxis and PCP. In this report, we first describe the course of a heart transplant patient who presented with rapidly progressive pulmonary nocardiosis while on pentamidine inhalation therapy for PCP prophylaxis. We then discuss the clinical features of Nocardia infection in transplant recipients, outlining the diagnostic and therapeutic challenges. CASE REPORT A 69-year-old man with end-stage ischemic cardiomyopathy underwent orthotopic heart transplantation in September 2005. His pre-transplant history was relevant for cardiac cachexia and exposure to tuberculosis as a child. Although the patient did not present any symptom of infection, his pre-transplant PPD (purified protein derivative) skin test showed an induration of 30
From the aHeart Failure, Heart Transplant and Pulmonary Hypertension Service and From the bCardiovascular Disease, cMedicine, Pulmonary and Critical Care and dInfectious Diseases, Stanford University Medical Center, Palo Alto, California. Submitted September 10, 2006; revised September 10, 2006; accepted November 13, 2006. Reprint requests: François Haddad, MD, Stanford University Medical Center, Stanford University, 770 Welch Road, Fourth Floor, Palo Alto, CA 94304-5715. Telephone: 650-723-5168. Fax: 650-723-3780. E-mail: [email protected] Copyright © 2007 by the International Society for Heart and Lung Transplantation. 1053-2498/07/$–see front matter. doi:10.1016/ j.healun.2006.11.002
mm, and a computerized tomography (CT) scan of the chest revealed a small 7-mm nodule in the left upper lobe. Fine-needle aspiration demonstrated a granuloma, and both stain and culture were negative for mycobacterium, Nocardia, Actinomyces or fungi. The patient was started on oral isoniazid (INH) 300 mg/day and oral pyridoxine 50 mg/day for a total duration of 9 months. After 6 months of therapy, the pulmonary nodule decreased significantly in size and, in September 2005, he underwent uncomplicated orthotopic heart transplantation. Induction therapy consisted of daclizumab 1 g/kg intravenously (IV) every 2 weeks for 4 weeks. His immunosuppressive regimen consisted of oral cyclosporine 125 mg twice daily, oral mycophenolate mofetil 1,000 mg twice daily and tapering corticosteroid doses. His early post-transplant course was remarkable for persistent leukopenia (white blood cell [WBC] count 2.0 ⫻ 109/liter, ANC 1.2 ⫻ 109/liter), which led to the replacement of our usual TMP-SMX PCP prophylaxis with aerolized pentamidine 300 mg every 4 weeks. His toxoplasmosis serology status was donor negative, recipient negative, and his cytomegalovirus (CMV) serology was donor negative, recipient positive. Routine biopsies did not reveal any significant rejection (all Grade 0 or 1R) and graft function remained normal. In February 2006, the patient was admitted to the hospital with a 2-week history of low-grade fever, night sweats, cough and weight loss. His occupational history was relevant for gardening activity, mostly pruning, in December 2005. His immunosuppressive regimen consisted of oral cyclosporine 125 mg twice daily, oral mycophenolate mofetil 1,000 mg twice daily and oral prednisone 4 mg twice daily. On physical examination, the patient appeared cachexic, with a blood pressure of 110/50 mm Hg, heart rate 118 beats/min, respiratory rate 22 breaths/min and temperature 38.4°C. There was no adenopathy or skin rash. 93
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Electrocardiogram revealed sinus tachycardia. Laboratory findings showed marked leukocytosis with a predominance of neutrophils (WBC 18.2 ⫻ 109/liter with 70% neutrophils), normocytic anemia (hemoglobin 9.4 g/dl), hypoalbuminemiat 2.3 g/dl and an increased erythrocyte sedimentation rate (ESR 64 mm/h; normal ⬍20 mm/hour). Chest X-ray revealed a new left upper lobe mass. CT scan confirmed the presence of a consolidated left upper lobe mass that measured 8.2 ⫻ 9.6 cm in the transverse plane (Figure 1). The differential diagnosis included fungi-active tuberculosis, atypical mycobacterial infection, pulmonary nocardiosis, actinomycosis or lymphoproliferative disorder. To rule out dissemination from an infection process, a CT scan of the head was done, which did not reveal any abnormal findings. Empiric treatment was started with IV liposomal amphotericin B at a dose of 3 mg/ kg/day to cover fungal infections and IV TMP-SMX at a dose of 15 mg/kg/day to cover pulmonary nocardiosis. Moxifloxacin therapy was also initiated to cover community-acquired pneumonia and for its potential synergistic effect with TMP-SMX for Nocardia infection. Although there was also concern for tuberculosis,
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no empiric therapy was started immediately, although the patient was isolated in a laminar-flow room. Stains and cultures from a specimen obtained from bronchoalveolar lavage fluid were negative for acid-fast organisms and other pathogens. A fine-needle biopsy of the mass revealed only necrotic material. To make a definitive diagnosis and to exclude a malignant process, we proceeded with a video-assisted thoracoscopic lung biopsy. Microscopic examination of the tissue showed numerous granulomas with multiple micro-abscesses, with no visible organism on staining. Three weeks later, preliminary cultures suggested an organism of the genus Actinomycetes, which was later confirmed to be Nocardia asteroides by the Mycobacteria/ Nocardia Research Laboratory of the University of Texas Health Science Center. N asteroides was susceptible to TMP-SMX and moxifloxacin. With the initiation of therapy, the patient’s symptoms progressively improved over 2 weeks, fever resolved, nutritional status improved (10-kg weight gain and an increase in albumin to 4.3 g/dl in 2 months), and the size of the mass decreased significantly (Figure 1). After 4 weeks of therapy, oral TMP-SMX DS (double strength)
Figure 1. Upper left: Chest X-ray showing left upper lobe mass on February 8, 2006. Upper right: initial CT scan demonstrating the left upper lobe mass on February 8, 2006. Lower left: CT scan after 2 weeks of therapy, demonstrating a decrease in mass. Lower right: CT scan after 5 months of therapy.
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twice daily replaced IV therapy and was scheduled to be continued for a total of 1 year to minimize the possibility of relapse. TMP-SMX prophylaxis with SS (single-strength dosing daily) will be continued for life. Moxifloxacin was discontinued after 4 months of combined therapy. DISCUSSION Nocardia is a genus of aerobic Actinomycetes that may be responsible for localized or disseminated infection.1–3 Nocardia spp are aerobic gram-positive, weakly acid-fast bacteria that exhibit characteristic filamentous branching.3 Members of the N asteroides complex represent the most frequent cause of nocardiosis in humans.1– 6 Other species include N farcinica, N nova, N otitidiscaviarum, N transvalensis and N brasilensis.1– 6 Nocardia spp are ubiquitous soil organisms that live as soil saprophytes.3 The aerosol route is the major portal of entry to the body and the lungs are the most common site of infection.2 Other modes of entry include ingestion of contaminated food or direct inoculation of the organism as a result of trauma. Human-tohuman transmission or animal-to-animal transmission has not been documented. Nocardiosis is particularly common in patients with depressed cellular immunity such as transplant recipients, patients with leukemias, lymphomas or acquired immunodeficiency virus (AIDS), or patients receiving prolonged corticosteroid or cytotoxic therapy.7 In large series, only 33% of infected patients were immunocompetent.8 Important clinical features of Nocardia infection include: (1) diverse radiographic and clinical presentation; (2) ability of the organism to disseminate to virtually any organ, especially the central nervous system (about 33% of patients); and (3) tendency to relapse or progress despite appropriate therapy. Pulmonary nocardiosis can present as either an acute and often necrotizing pneumonia, commonly associated with cavitation or as a slowly enlarging pulmonary nodule or infiltrate, often with an associated empyema. Slowly progressive fever, chills, productive cough, sweats, weight loss, anorexia and occasionally hemopthysis have been noted in patients with cavitating disease.2 The diagnosis of Nocardia requires isolation and identification of the organism from a clinical specimen. Delay in establishing the correct diagnosis is common and can be explained by the non-specific nature of radiographic and clinical findings and by the inherent difficulty in cultivating Nocardia.9,10 To establish a diagnosis of nocardiosis, aggressive invasive procedures such as fine-needle aspiration, transbronchial biopsy, CT-guided biopsies and thoracoscopic or open-lung biopsies are required in almost 50% of patients.9 Any
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specimen collected should be cultured under aerobic and anaerobic conditions. On gram stain, Nocardia will appear as branching gram-positive bacilli that are indistinguishable from Actinomyces. In contrast to Actinomyces, however, Nocardia can be weakly stained with modified acid-fast stain. Growth usually appears within several days to several weeks. Because Nocardia is not a commensal of the human body, positive cultures from tissue or normally sterile body fluids should never be ignored. The differential diagnosis of nocardiosis is extensive and should include actinomycosis, tuberculosis, atypical mycobacterial infection, cocciidioidomycosis, aspergillosis, mucormycosis, cryptococcosis, bacterial infections (Rhodococcus equi and gram-negative bacilli), pulmonary infarction and lymphoproliferative disorders (Table 1). Clinical experience has shown that successful treatment of nocardiosis requires the use of extended courses of antibiotic therapy and surgical drainage when appropriate.11–12 A high percentage of Nocardia isolates are sensitive to trimethoprim–sulfamethoxazole.13 Resistance to sulfonamides is most common among N farcinica and N ostitidiscaviarum isolates. In vitro susceptibility testing and clinical experience have also demonstrated that third-generation cephalosporins, extended spectrum fluroquinolones, imipenem and linezolid can also be effective against Nocardia. Combination therapy with two agents is initiated in severe life-threatening infections, disseminated disease and in patients who are immunocompromised. Parenteral therapy is changed to an oral regimen after 3 to 6 weeks depending on clinical response. Clinical improvement is usually seen within 10 days of therapy.3 The optimal duration of therapy has not been determined, but most experts recommend a prolonged course of at least 6 months in immunocompetent patients and 12 months in immunocompromised patients or those with cerebral involvement.2,10 Inadequate antibiotic therapy duration may result in relapse. Surgical drainage is usually performed in the presence of brain abscesses, empyema and SC abscesses. The overall mortality rate of patients with pulmonary nocardiosis is in the range of 15% to 30%. Patients with an acute course, disseminated disease, especially central nervous system nocardiosis or infection caused by N farcinica, may have a worse prognosis.2,3,8,10,11 The decrease in incidence of nocardiosis in transplant recipients in the last 15 years most probably reflects the effectiveness of TMP-SMX, the preferred regimen for PCP prophylaxis. In fact, compared to other Pneumocystis jiroveci (carinii) prophylaxis regimens, TMP-SMX is also effective in reducing the incidence of toxoplasmosis, nocardiosis, listeriosis and other gram-positive and -negative bacterial infections
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Table 1. Comparative Features of Pulmonary Nocardiosis and Other Opportunistic Pulmonary Infections Infectious syndrome Nocardiosisa
Microbiology and reservoir Aerobic gram stain positive; acid-fast (weakly); soil saprophyte
Major risk factors Immunocompromised (especially T-cell immunity); male more than female
Actinomycosisa
Facultative anaerobic gram stain positive, not acid fast; commensal of oropharynx
Tuberculosis
Acid-fast mycobacterium; Endemic regions; immunocompromised obligate aerobic; (especially T-cell humans are the only immunity); alcoholism reservoir
Alcoholism; poor oral hygiene; dental disease; lung disease; male:female ratio (3:1)
Atypical mycobacteriuma Acid-fast mycobacterium, Age, alcoholism, male non-TB; ubiquitous in gender, lung disease; the environment immunocompromised (especially T-cell immunity) Coccidioidomycosis Dimorphic fungi; Endemic regions (lower spore-forming; GMS deserts of the western stain positive; soil hemisphere); immunocompromised Cryptococcosis
Fungi; spore forming; GMS stain positive; soil, bird droppings
Immunocompromised; especially HIV infection
Aspergillosis (invasive)
Fungi, spore-forming; GMS stain positive; ubiquitous in the environment
Immunocompromised; prolonged neutropenia; corticosteroid use; lung disease (granulomatosis)
Mucormycosis (zygomycosis)
Fungi; spore-forming; GMS stain* positive; PAS stain* positive; ubiquitous in the environment Fungi by DNA analysis; GMS stain* positive; worldwide, humans, animals
Diabetes; immunocompromised; malnutrition
Pneumocystis jiroveci (PCP)
Plumonary and clinical features Treatment (usual regimen) TMP-SMX (first), Necrotizing pneumonia, carbapenem (second); cavitation, nodule, mass or combination Tx 6–12 empyema; metastatic spread months Tx; drainage if (brain 33%); relapse possible indicated Slowly progressing pneumonia; Penicillin 6–12 months; Drainage if indicated granulomas with cavitation; extension through chest wall possible with draining sinuses; possible sulfur granules on pathology Anti-tubercular regimen, Hilar adenopathy, pleural usually 4-drug regimen; effusion, infiltrates of upper usually good response lobes; possible cavitation (20% of re-activation disease); disseminated disease possible Specific anti-mycobacterial Upper-lobe cavitary lesion; regimen depending on nodular bronchiectasis; species disseminated forms possible in immunocompromised patients Amphotericin B or Flu-like illness; acute itraconazole or pneumonia; nodules, cavities fluconazoleb; surgery if (may rupture); chronic fibrocavitary or indicated reticulonodular pneumonia Nodules, lobar infiltrate, pleural Amphotericin B ⫹ flucytosine followed by effusions, adenopathy; fluconazole cavitation rare; disseminated disease (CNS) common Voriconazole, or Patchy infiltrates or nodules amphotericin B or “halo sign” on CT scan (rare itraconazole or in solid-organ transplant voriconazole ⫹ patients) cavitation possible caspofungin (CNS, bone, skin) late in the course; dissemination possible Early surgical debridment Diffuse pneumonia with amphotericin B; role of infarction, nodule, pleural posaconazole uncertain effusion; cavitation possible; at this time disseminated disease occurs
Immunocompromised Diffuse bilateral infiltrates; corticosteroid use; HIV pulmonary effusion or infection adenopathy rare
TMP-SMX ⫹ corticosteroids (in moderate to severe pneumonia)
CNS, central nervous system; GMS, Gomori Methenamine Silver; HIV, human immunodeficiency virus; PAS, periodic acid–Schiff; Tx, therapy. a All efforts should be put in place to send isolate for susceptibility testing of commonly used anti-microbials. b Depending on presentation.
(Table 2).14 In situations where side effects leading to discontinuation of TMP-SMX are not clearly related to TMP-SMX, or have resolved, reintroduction of TMPSMX should be promptly considered. In the patient
presented herein, leukopenia was most probably multifactorial and rechallenging the patient with TMP-SMX might have prevented the pulmonary nocardiosis. Avoidance of gardening and working in soil
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Table 2. Prophylaxis Regimens Against Pneumocystis jiroveci (P carinii) in Transplant Patients Regimen TMP-SMX
Recommendation and dosage Preferred agent; SS orally q day or DS orally 3 times/week
Pentamidine
Alternative agent; 300 mg inhaled every 4 weeks
Dapsone
Alternative agent; screen for G6PD deficiency; 100 mg orally q day Alternative-agent; 1,500 mg orally q day
Atovaquone
Prophylaxis against P jiroveci, Toxoplasmosis gondii, Nocardia spp, Listeria spp, other bacterial spp P jiroveci
P jiroveci, Toxoplama gondii (less effective than TMP-SMX) P jiroveci
Efficacy against P jiroveci Most effective and broader coverage Effective only where locally distributed (explains atypical PCP infections) Comparable efficacy to atovaquone Comparable efficacy to dapsone
Common side effects Leukopenia, rash, hepatotoxicity, fever, GI upset Cough or bronchospasm with administration Fever, rash, GI upset, hemolytic anemia, methemoglobinemia GI distress, rash
SS, single strength; DS, double strength; GI, gastrointestinal.
should also be emphasized in the early post-transplant period. REFERENCES 1. Montoya JG, Giraldo LF, Efron B, et al. Infectious complications among 620 consecutive heart transplant patients at Stanford University Medical Center. Clin Infect Dis 2001;33: 629 – 40. 2. Yildiz O, Doganay M. Actinomycoses and Nocardia pulmonary infections. Curr Opin Pulmon Med 2006;12:228 –34. 3. McNeil MM, Brown JM. The medically important aerobic actinomycetes: epidemiology and microbiology. Clin Microbiol 1994;7: 357– 417. 4. Hui CH, Au VW, Rowland K, Slavotinek JP, Gordon DL. Pulmonary nocardiosis re-visited: experience of 35 patients at diagnosis. Respir Med 2003;97:709 –17. 5. Kageyama A, Yazawa K, Ishikawa J, Hotta K, Nishimura K, Mikami Y. Nocardial infections in Japan from 1992 to 2001, including the first report of infection by Nocardia transvalensis. Eur J Epidemiol 2004;19:383–9. 6. Queipo-Zaragoza JA, Broseta-Rico E, Apont-Alacreu JM, SantosDurantez M, Sanchez-Plumed J, Jimenez-Cruz JF. Nocardial infection in immunosuppressed kidney transplant recipients. Scand J Urol Nephrol 2004;38:168 –73.
7. Beaman BL, Beaman L. Nocardia species: host–parasite relationships. Clin Microbiol Rev 1994;7:213– 64. 8. Lederman ER, Crum NF. A case series and focused review of nocardiosis: clinical and microbiologic aspects. Medicine (Baltimore) 2004;83:300 –13. 9. Georghiou PR, Blacklock ZM. Infection with Nocardia species in Queensland. A review of 102 clinical isolates. Med J Austral 1992;156:692–7. 10. Chapman SW. Diagnosis and treatment of nocardiosis. In: Rose BD, editor. UptoDate version 14.3. Waltham, MA: UpToDate; 2006. 11. Tripodi MF, Adinolfi LE, Andreana A, et al. Treatment of pulmonary nocardiosis in heart-transplant patients: importance of susceptibility studies. Clin Transplant 2001;15:415–20. 12. Peraira JR, Segovia J, Fuentes R, et al. Pulmonary nocardiosis in heart transplant recipients: treatment and outcome. Transplant Proc 2003; 35:2006 – 8. 13. Lopez FA, Johnson F, Novosad DM, Beaman BL, Holodniy M. Successful management of disseminated Nocardia transvalensis infection in a heart transplant recipient after development of sulfonamide resistance: case report and review. J Heart Lung Transplant 2003;22:492–7. 14. Montoya JG. Successes and limitations of antimicrobial interventions in the setting of organ transplantation. Curr Opin Infect Dis 2004;17:341–5.
Pulmonary nocardiosis is an uncommon but serious infection found in immunocompromised patients.1,2 In a series of 620 consecutive heart transplant patients at the Stanford University Medical Center between 1980 and 1996, pulmonary nocardiosis was seen in 19 patients.1 In the same series, the incidence of pulmonary nocardiosis was found to decrease after the introduction of Pneumocystitis jiroveci (PCP) prophylaxis with trimethoprim–sulfamethoxazole (TMP-SMX), suggesting effectiveness of TMP-SMX for Nocardia prophylaxis and PCP. In this report, we first describe the course of a heart transplant patient who presented with rapidly progressive pulmonary nocardiosis while on pentamidine inhalation therapy for PCP prophylaxis. We then discuss the clinical features of Nocardia infection in transplant recipients, outlining the diagnostic and therapeutic challenges. CASE REPORT A 69-year-old man with end-stage ischemic cardiomyopathy underwent orthotopic heart transplantation in September 2005. His pre-transplant history was relevant for cardiac cachexia and exposure to tuberculosis as a child. Although the patient did not present any symptom of infection, his pre-transplant PPD (purified protein derivative) skin test showed an induration of 30
From the aHeart Failure, Heart Transplant and Pulmonary Hypertension Service and From the bCardiovascular Disease, cMedicine, Pulmonary and Critical Care and dInfectious Diseases, Stanford University Medical Center, Palo Alto, California. Submitted September 10, 2006; revised September 10, 2006; accepted November 13, 2006. Reprint requests: François Haddad, MD, Stanford University Medical Center, Stanford University, 770 Welch Road, Fourth Floor, Palo Alto, CA 94304-5715. Telephone: 650-723-5168. Fax: 650-723-3780. E-mail: [email protected] Copyright © 2007 by the International Society for Heart and Lung Transplantation. 1053-2498/07/$–see front matter. doi:10.1016/ j.healun.2006.11.002
mm, and a computerized tomography (CT) scan of the chest revealed a small 7-mm nodule in the left upper lobe. Fine-needle aspiration demonstrated a granuloma, and both stain and culture were negative for mycobacterium, Nocardia, Actinomyces or fungi. The patient was started on oral isoniazid (INH) 300 mg/day and oral pyridoxine 50 mg/day for a total duration of 9 months. After 6 months of therapy, the pulmonary nodule decreased significantly in size and, in September 2005, he underwent uncomplicated orthotopic heart transplantation. Induction therapy consisted of daclizumab 1 g/kg intravenously (IV) every 2 weeks for 4 weeks. His immunosuppressive regimen consisted of oral cyclosporine 125 mg twice daily, oral mycophenolate mofetil 1,000 mg twice daily and tapering corticosteroid doses. His early post-transplant course was remarkable for persistent leukopenia (white blood cell [WBC] count 2.0 ⫻ 109/liter, ANC 1.2 ⫻ 109/liter), which led to the replacement of our usual TMP-SMX PCP prophylaxis with aerolized pentamidine 300 mg every 4 weeks. His toxoplasmosis serology status was donor negative, recipient negative, and his cytomegalovirus (CMV) serology was donor negative, recipient positive. Routine biopsies did not reveal any significant rejection (all Grade 0 or 1R) and graft function remained normal. In February 2006, the patient was admitted to the hospital with a 2-week history of low-grade fever, night sweats, cough and weight loss. His occupational history was relevant for gardening activity, mostly pruning, in December 2005. His immunosuppressive regimen consisted of oral cyclosporine 125 mg twice daily, oral mycophenolate mofetil 1,000 mg twice daily and oral prednisone 4 mg twice daily. On physical examination, the patient appeared cachexic, with a blood pressure of 110/50 mm Hg, heart rate 118 beats/min, respiratory rate 22 breaths/min and temperature 38.4°C. There was no adenopathy or skin rash. 93
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Electrocardiogram revealed sinus tachycardia. Laboratory findings showed marked leukocytosis with a predominance of neutrophils (WBC 18.2 ⫻ 109/liter with 70% neutrophils), normocytic anemia (hemoglobin 9.4 g/dl), hypoalbuminemiat 2.3 g/dl and an increased erythrocyte sedimentation rate (ESR 64 mm/h; normal ⬍20 mm/hour). Chest X-ray revealed a new left upper lobe mass. CT scan confirmed the presence of a consolidated left upper lobe mass that measured 8.2 ⫻ 9.6 cm in the transverse plane (Figure 1). The differential diagnosis included fungi-active tuberculosis, atypical mycobacterial infection, pulmonary nocardiosis, actinomycosis or lymphoproliferative disorder. To rule out dissemination from an infection process, a CT scan of the head was done, which did not reveal any abnormal findings. Empiric treatment was started with IV liposomal amphotericin B at a dose of 3 mg/ kg/day to cover fungal infections and IV TMP-SMX at a dose of 15 mg/kg/day to cover pulmonary nocardiosis. Moxifloxacin therapy was also initiated to cover community-acquired pneumonia and for its potential synergistic effect with TMP-SMX for Nocardia infection. Although there was also concern for tuberculosis,
The Journal of Heart and Lung Transplantation January 2007
no empiric therapy was started immediately, although the patient was isolated in a laminar-flow room. Stains and cultures from a specimen obtained from bronchoalveolar lavage fluid were negative for acid-fast organisms and other pathogens. A fine-needle biopsy of the mass revealed only necrotic material. To make a definitive diagnosis and to exclude a malignant process, we proceeded with a video-assisted thoracoscopic lung biopsy. Microscopic examination of the tissue showed numerous granulomas with multiple micro-abscesses, with no visible organism on staining. Three weeks later, preliminary cultures suggested an organism of the genus Actinomycetes, which was later confirmed to be Nocardia asteroides by the Mycobacteria/ Nocardia Research Laboratory of the University of Texas Health Science Center. N asteroides was susceptible to TMP-SMX and moxifloxacin. With the initiation of therapy, the patient’s symptoms progressively improved over 2 weeks, fever resolved, nutritional status improved (10-kg weight gain and an increase in albumin to 4.3 g/dl in 2 months), and the size of the mass decreased significantly (Figure 1). After 4 weeks of therapy, oral TMP-SMX DS (double strength)
Figure 1. Upper left: Chest X-ray showing left upper lobe mass on February 8, 2006. Upper right: initial CT scan demonstrating the left upper lobe mass on February 8, 2006. Lower left: CT scan after 2 weeks of therapy, demonstrating a decrease in mass. Lower right: CT scan after 5 months of therapy.
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twice daily replaced IV therapy and was scheduled to be continued for a total of 1 year to minimize the possibility of relapse. TMP-SMX prophylaxis with SS (single-strength dosing daily) will be continued for life. Moxifloxacin was discontinued after 4 months of combined therapy. DISCUSSION Nocardia is a genus of aerobic Actinomycetes that may be responsible for localized or disseminated infection.1–3 Nocardia spp are aerobic gram-positive, weakly acid-fast bacteria that exhibit characteristic filamentous branching.3 Members of the N asteroides complex represent the most frequent cause of nocardiosis in humans.1– 6 Other species include N farcinica, N nova, N otitidiscaviarum, N transvalensis and N brasilensis.1– 6 Nocardia spp are ubiquitous soil organisms that live as soil saprophytes.3 The aerosol route is the major portal of entry to the body and the lungs are the most common site of infection.2 Other modes of entry include ingestion of contaminated food or direct inoculation of the organism as a result of trauma. Human-tohuman transmission or animal-to-animal transmission has not been documented. Nocardiosis is particularly common in patients with depressed cellular immunity such as transplant recipients, patients with leukemias, lymphomas or acquired immunodeficiency virus (AIDS), or patients receiving prolonged corticosteroid or cytotoxic therapy.7 In large series, only 33% of infected patients were immunocompetent.8 Important clinical features of Nocardia infection include: (1) diverse radiographic and clinical presentation; (2) ability of the organism to disseminate to virtually any organ, especially the central nervous system (about 33% of patients); and (3) tendency to relapse or progress despite appropriate therapy. Pulmonary nocardiosis can present as either an acute and often necrotizing pneumonia, commonly associated with cavitation or as a slowly enlarging pulmonary nodule or infiltrate, often with an associated empyema. Slowly progressive fever, chills, productive cough, sweats, weight loss, anorexia and occasionally hemopthysis have been noted in patients with cavitating disease.2 The diagnosis of Nocardia requires isolation and identification of the organism from a clinical specimen. Delay in establishing the correct diagnosis is common and can be explained by the non-specific nature of radiographic and clinical findings and by the inherent difficulty in cultivating Nocardia.9,10 To establish a diagnosis of nocardiosis, aggressive invasive procedures such as fine-needle aspiration, transbronchial biopsy, CT-guided biopsies and thoracoscopic or open-lung biopsies are required in almost 50% of patients.9 Any
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specimen collected should be cultured under aerobic and anaerobic conditions. On gram stain, Nocardia will appear as branching gram-positive bacilli that are indistinguishable from Actinomyces. In contrast to Actinomyces, however, Nocardia can be weakly stained with modified acid-fast stain. Growth usually appears within several days to several weeks. Because Nocardia is not a commensal of the human body, positive cultures from tissue or normally sterile body fluids should never be ignored. The differential diagnosis of nocardiosis is extensive and should include actinomycosis, tuberculosis, atypical mycobacterial infection, cocciidioidomycosis, aspergillosis, mucormycosis, cryptococcosis, bacterial infections (Rhodococcus equi and gram-negative bacilli), pulmonary infarction and lymphoproliferative disorders (Table 1). Clinical experience has shown that successful treatment of nocardiosis requires the use of extended courses of antibiotic therapy and surgical drainage when appropriate.11–12 A high percentage of Nocardia isolates are sensitive to trimethoprim–sulfamethoxazole.13 Resistance to sulfonamides is most common among N farcinica and N ostitidiscaviarum isolates. In vitro susceptibility testing and clinical experience have also demonstrated that third-generation cephalosporins, extended spectrum fluroquinolones, imipenem and linezolid can also be effective against Nocardia. Combination therapy with two agents is initiated in severe life-threatening infections, disseminated disease and in patients who are immunocompromised. Parenteral therapy is changed to an oral regimen after 3 to 6 weeks depending on clinical response. Clinical improvement is usually seen within 10 days of therapy.3 The optimal duration of therapy has not been determined, but most experts recommend a prolonged course of at least 6 months in immunocompetent patients and 12 months in immunocompromised patients or those with cerebral involvement.2,10 Inadequate antibiotic therapy duration may result in relapse. Surgical drainage is usually performed in the presence of brain abscesses, empyema and SC abscesses. The overall mortality rate of patients with pulmonary nocardiosis is in the range of 15% to 30%. Patients with an acute course, disseminated disease, especially central nervous system nocardiosis or infection caused by N farcinica, may have a worse prognosis.2,3,8,10,11 The decrease in incidence of nocardiosis in transplant recipients in the last 15 years most probably reflects the effectiveness of TMP-SMX, the preferred regimen for PCP prophylaxis. In fact, compared to other Pneumocystis jiroveci (carinii) prophylaxis regimens, TMP-SMX is also effective in reducing the incidence of toxoplasmosis, nocardiosis, listeriosis and other gram-positive and -negative bacterial infections
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Table 1. Comparative Features of Pulmonary Nocardiosis and Other Opportunistic Pulmonary Infections Infectious syndrome Nocardiosisa
Microbiology and reservoir Aerobic gram stain positive; acid-fast (weakly); soil saprophyte
Major risk factors Immunocompromised (especially T-cell immunity); male more than female
Actinomycosisa
Facultative anaerobic gram stain positive, not acid fast; commensal of oropharynx
Tuberculosis
Acid-fast mycobacterium; Endemic regions; immunocompromised obligate aerobic; (especially T-cell humans are the only immunity); alcoholism reservoir
Alcoholism; poor oral hygiene; dental disease; lung disease; male:female ratio (3:1)
Atypical mycobacteriuma Acid-fast mycobacterium, Age, alcoholism, male non-TB; ubiquitous in gender, lung disease; the environment immunocompromised (especially T-cell immunity) Coccidioidomycosis Dimorphic fungi; Endemic regions (lower spore-forming; GMS deserts of the western stain positive; soil hemisphere); immunocompromised Cryptococcosis
Fungi; spore forming; GMS stain positive; soil, bird droppings
Immunocompromised; especially HIV infection
Aspergillosis (invasive)
Fungi, spore-forming; GMS stain positive; ubiquitous in the environment
Immunocompromised; prolonged neutropenia; corticosteroid use; lung disease (granulomatosis)
Mucormycosis (zygomycosis)
Fungi; spore-forming; GMS stain* positive; PAS stain* positive; ubiquitous in the environment Fungi by DNA analysis; GMS stain* positive; worldwide, humans, animals
Diabetes; immunocompromised; malnutrition
Pneumocystis jiroveci (PCP)
Plumonary and clinical features Treatment (usual regimen) TMP-SMX (first), Necrotizing pneumonia, carbapenem (second); cavitation, nodule, mass or combination Tx 6–12 empyema; metastatic spread months Tx; drainage if (brain 33%); relapse possible indicated Slowly progressing pneumonia; Penicillin 6–12 months; Drainage if indicated granulomas with cavitation; extension through chest wall possible with draining sinuses; possible sulfur granules on pathology Anti-tubercular regimen, Hilar adenopathy, pleural usually 4-drug regimen; effusion, infiltrates of upper usually good response lobes; possible cavitation (20% of re-activation disease); disseminated disease possible Specific anti-mycobacterial Upper-lobe cavitary lesion; regimen depending on nodular bronchiectasis; species disseminated forms possible in immunocompromised patients Amphotericin B or Flu-like illness; acute itraconazole or pneumonia; nodules, cavities fluconazoleb; surgery if (may rupture); chronic fibrocavitary or indicated reticulonodular pneumonia Nodules, lobar infiltrate, pleural Amphotericin B ⫹ flucytosine followed by effusions, adenopathy; fluconazole cavitation rare; disseminated disease (CNS) common Voriconazole, or Patchy infiltrates or nodules amphotericin B or “halo sign” on CT scan (rare itraconazole or in solid-organ transplant voriconazole ⫹ patients) cavitation possible caspofungin (CNS, bone, skin) late in the course; dissemination possible Early surgical debridment Diffuse pneumonia with amphotericin B; role of infarction, nodule, pleural posaconazole uncertain effusion; cavitation possible; at this time disseminated disease occurs
Immunocompromised Diffuse bilateral infiltrates; corticosteroid use; HIV pulmonary effusion or infection adenopathy rare
TMP-SMX ⫹ corticosteroids (in moderate to severe pneumonia)
CNS, central nervous system; GMS, Gomori Methenamine Silver; HIV, human immunodeficiency virus; PAS, periodic acid–Schiff; Tx, therapy. a All efforts should be put in place to send isolate for susceptibility testing of commonly used anti-microbials. b Depending on presentation.
(Table 2).14 In situations where side effects leading to discontinuation of TMP-SMX are not clearly related to TMP-SMX, or have resolved, reintroduction of TMPSMX should be promptly considered. In the patient
presented herein, leukopenia was most probably multifactorial and rechallenging the patient with TMP-SMX might have prevented the pulmonary nocardiosis. Avoidance of gardening and working in soil
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Table 2. Prophylaxis Regimens Against Pneumocystis jiroveci (P carinii) in Transplant Patients Regimen TMP-SMX
Recommendation and dosage Preferred agent; SS orally q day or DS orally 3 times/week
Pentamidine
Alternative agent; 300 mg inhaled every 4 weeks
Dapsone
Alternative agent; screen for G6PD deficiency; 100 mg orally q day Alternative-agent; 1,500 mg orally q day
Atovaquone
Prophylaxis against P jiroveci, Toxoplasmosis gondii, Nocardia spp, Listeria spp, other bacterial spp P jiroveci
P jiroveci, Toxoplama gondii (less effective than TMP-SMX) P jiroveci
Efficacy against P jiroveci Most effective and broader coverage Effective only where locally distributed (explains atypical PCP infections) Comparable efficacy to atovaquone Comparable efficacy to dapsone
Common side effects Leukopenia, rash, hepatotoxicity, fever, GI upset Cough or bronchospasm with administration Fever, rash, GI upset, hemolytic anemia, methemoglobinemia GI distress, rash
SS, single strength; DS, double strength; GI, gastrointestinal.
should also be emphasized in the early post-transplant period. REFERENCES 1. Montoya JG, Giraldo LF, Efron B, et al. Infectious complications among 620 consecutive heart transplant patients at Stanford University Medical Center. Clin Infect Dis 2001;33: 629 – 40. 2. Yildiz O, Doganay M. Actinomycoses and Nocardia pulmonary infections. Curr Opin Pulmon Med 2006;12:228 –34. 3. McNeil MM, Brown JM. The medically important aerobic actinomycetes: epidemiology and microbiology. Clin Microbiol 1994;7: 357– 417. 4. Hui CH, Au VW, Rowland K, Slavotinek JP, Gordon DL. Pulmonary nocardiosis re-visited: experience of 35 patients at diagnosis. Respir Med 2003;97:709 –17. 5. Kageyama A, Yazawa K, Ishikawa J, Hotta K, Nishimura K, Mikami Y. Nocardial infections in Japan from 1992 to 2001, including the first report of infection by Nocardia transvalensis. Eur J Epidemiol 2004;19:383–9. 6. Queipo-Zaragoza JA, Broseta-Rico E, Apont-Alacreu JM, SantosDurantez M, Sanchez-Plumed J, Jimenez-Cruz JF. Nocardial infection in immunosuppressed kidney transplant recipients. Scand J Urol Nephrol 2004;38:168 –73.
7. Beaman BL, Beaman L. Nocardia species: host–parasite relationships. Clin Microbiol Rev 1994;7:213– 64. 8. Lederman ER, Crum NF. A case series and focused review of nocardiosis: clinical and microbiologic aspects. Medicine (Baltimore) 2004;83:300 –13. 9. Georghiou PR, Blacklock ZM. Infection with Nocardia species in Queensland. A review of 102 clinical isolates. Med J Austral 1992;156:692–7. 10. Chapman SW. Diagnosis and treatment of nocardiosis. In: Rose BD, editor. UptoDate version 14.3. Waltham, MA: UpToDate; 2006. 11. Tripodi MF, Adinolfi LE, Andreana A, et al. Treatment of pulmonary nocardiosis in heart-transplant patients: importance of susceptibility studies. Clin Transplant 2001;15:415–20. 12. Peraira JR, Segovia J, Fuentes R, et al. Pulmonary nocardiosis in heart transplant recipients: treatment and outcome. Transplant Proc 2003; 35:2006 – 8. 13. Lopez FA, Johnson F, Novosad DM, Beaman BL, Holodniy M. Successful management of disseminated Nocardia transvalensis infection in a heart transplant recipient after development of sulfonamide resistance: case report and review. J Heart Lung Transplant 2003;22:492–7. 14. Montoya JG. Successes and limitations of antimicrobial interventions in the setting of organ transplantation. Curr Opin Infect Dis 2004;17:341–5.