Invasive pulmonary aspergillosis (IPA) and pneumocystis jiroveci pneumonia (PCP) are life-threatening opportunistic infections that occur in immunocompromised hosts. Early diagnosis and treatment of these opportunistic infections is essential to the survival of immunocompromised patients. We report a 60-year-old man undergoing short-term steroid therapy after surgical resection of a brain tumor infected with combined invasive pulmonary aspergillosis and pneumocystis jiroveci pneumonia diagnosed by bronchoscopy with bronchoalveolar lavage. Our case demonstrated that short-term systemic steroid therapy in non-HIV patients with underlying chronic lung conditions and malignancies was a risk factor for IPA and PCP, and for a combination of these infections

Hisada, Takeshi

Iida, Tomohiro

Ishizuka, Tamotsu

Kaira, Kyoichi

Mori, Masatomo

Shimoyama, Yasuyuki

Sunaga, Noriaki

Takahashi, Yuga

Yanagitani, Noriko

Okayama University Scientific Achievement Repository

Acta Medica OkayamaVolume 61, Issue 4 2007 Article 8AUGUST 2007Coinfection of Invasive PulmonaryAspergillosis and Pneumocystis JiroveciPneumonia in a Non-HIV PatientKyoichi Kaira∗ Yasuyuki Shimoyama† Yuga Takahashi‡Tomohiro Iida∗∗ Noriko Yanagitani†† Noriaki Sunaga‡‡Takeshi Hisada§ Tamotsu Ishizuka¶ Masatomo Mori‖∗Gunma University,†Gunma University,‡Gunma Univesity,∗∗Gunma University,††Gunma University,‡‡Gunma University,§Gunma University,¶Gunma University,‖Gunma University,Copyright c©1999 OKAYAMA UNIVERSITY MEDICAL SCHOOL. All rights reserved.Coinfection of Invasive PulmonaryAspergillosis and Pneumocystis JiroveciPneumonia in a Non-HIV Patient∗Kyoichi Kaira, Yasuyuki Shimoyama, Yuga Takahashi, Tomohiro Iida, NorikoYanagitani, Noriaki Sunaga, Takeshi Hisada, Tamotsu Ishizuka, and MasatomoMoriAbstractInvasive pulmonary aspergillosis (IPA) and pneumocystis jiroveci pneumonia (PCP) are life-threatening opportunistic infections that occur in immunocompromised hosts. Early diagnosisand treatment of these opportunistic infections is essential to the survival of immunocompromisedpatients. We report a 60-year-old man undergoing short-term steroid therapy after surgical resec-tion of a brain tumor infected with combined invasive pulmonary aspergillosis and pneumocystisjiroveci pneumonia diagnosed by bronchoscopy with bronchoalveolar lavage. Our case demon-strated that short-term systemic steroid therapy in non-HIV patients with underlying chronic lungconditions and malignancies was a risk factor for IPA and PCP, and for a combination of theseinfections.KEYWORDS: pneumocystis jiroveci pneumonia, invasive pulmonary aspergillosis, steroid ther-apy, pulmonary∗Copyright (C) OKAYAMA UNIVERSITY MEDICAL SCHOOL PMID: 17726513Coinfection of Invasive Pulmonary Aspergillosis and Pneumocystis Jiroveci Pneumonia in a Non-HIV PatientKyoichi Kaira＊,  Yasuyuki Shimoyama,  Yuga Takahashi,Tomohiro Iida,  Noriko Yanagitani,  Noriaki Sunaga,Takeshi Hisada,  Tamotsu Ishizuka,  and Masatomo MoriDepartment of Medicine and Molecular Science,  Gunma University GraduateSchool of Medicine,  Maebashi,  Gunma 371ﾝ8511,  Japannvasive pulmonary aspergillosis (IPA) is a life-threatening fungal infection that predominantly aﬀ ects severely immunocompromised patients,  par-ticularly those with prolonged neutropenia,  organ transplantation,  or high-dose corticosteroid therapy [1,  2].  Pneumocystis jiroveci pneumonia (PCP) is also a life-threatening opportunistic infection which occurs in immunocompromised hosts,  especially patients with acquired immunodeﬁ ciency syndrome (AIDS).  PCP is increasing in frequency in other immunosuppressed patients,  including organ trans-plant recipients and those with malignancy who are treated with steroids and chemotherapeutic regimens [1,  3].  These opportunistic infections are usually diagnosed during an autopsy or when it is too late to treat them.  A high degree of suspicion is necessary to diagnose these infections.  Here,  we describe a fatal case of combined IPA and PCP in a patient not infected with human immunodeﬁ ciency virus (HIV).Case Report　 A 60-year-old man was diagnosed with renal cell carcinoma and was treated with nephrectomy in Oct.  1997.  For 8 years after the operation,  he had been generally well without any signs of recurrence.  The patient had a history of smoking and chronic obstruc-tive respiratory disease (COPD).  In Sept.  2005,  he was diagnosed with a metastatic brain tumor of renal cell carcinoma by surgical resection.  To improve the IInvasive pulmonary aspergillosis (IPA) and pneumocystis jiroveci pneumonia (PCP) are life-threaten-ing opportunistic infections that occur in immunocompromised hosts.  Early diagnosis and treatment of these opportunistic infections is essential to the survival of immunocompromised patients.  We report a 60-year-old man undergoing short-term steroid therapy after surgical resection of a brain tumor infected with combined invasive pulmonary aspergillosis and pneumocystis jiroveci pneumonia diag-nosed by bronchoscopy with bronchoalveolar lavage.  Our case demonstrated that short-term systemic steroid therapy in non-HIV patients with underlying chronic lung conditions and malignancies was a risk factor for IPA and PCP,  and for a combination of these infections.Key words:  pneumocystis jiroveci pneumonia, invasive pulmonary aspergillosis, steroid therapy, pulmonary coinfectionActa Med.  Okayama,  2007Vol.  61,  No.  4,  pp.  235ﾝ238http ://www.lib.okayama-u.ac.jp/www/acta/CopyrightⒸ 2007 by Okayama University Medical School.Case ReportReceived October 13, 2006 ; accepted January 15, 2007. ＊Corresponding author. Phone : ＋81ﾝ27ﾝ220ﾝ8136 ; Fax : ＋81ﾝ27ﾝ220ﾝ8136E-mail : kkaira1970＠yahoo.co.jp (K. Kaira)1Kaira et al.: Coinfection of Invasive Pulmonary Aspergillosis and PneumocystisProduced by The Berkeley Electronic Press, 2007cerebral edema after surgical resection of the brain tumor,  we initiated corticosteroids (betamethasone 5 mg daily for 7 days,  followed by betamethasone 2 mg daily for 14 days,  and followed by betametha-sone 1 mg daily for 14 days).  He was then treated with radiation therapy.  There was no evidence of dis-ease other than the brain tumor.  A computed tomo-graphic (CT) scan of the chest revealed mild emphyse-matous changes but no bulla-like formations.　 In Oct.  2005,  the patient presented a cough,  spu-tum,  and high fever.  On physical examination,  he was comfortable and in no apparent distress.  Laboratory data revealed a white blood cell count of 8,300 cells per mm3 with a diﬀ erential of 78ｵ neutrophils and 10ｵ lymphocytes,  and C-reactive protein (CRP) of 14.6 mg/dl.  Chest radiography revealed inﬁ ltrative shadow throughout the right lung ﬁ eld.  A chest CT revealed multiple cystic lesions and alveolo-interstitial inﬁ ltrates in the right upper lobe (Fig.  1A).  Empirical treatment with intravenous cefozopran 2.0 g/day and minocycline 200 mg/day was initiated.　 On hospital day 3,  the patient was still febrile,  and pulmonary inﬁ ltrates had increased.  Thus,  he was treated with intravenous meropenem 1.0 g/day and ciproﬂ oxacin 600 mg/day.  Sputum was repeatedly negative for malignant cells,  acid-fast bacilli,  asper-gillus,  and candida.  Bacteriological investigation of blood culture also did not reveal any microorganism.  An enzyme-linked immunosorbent assay (ELISA) test for HIV was negative.  However,  an aspergillus anti-gen test in the serum done with an ELISA revealed positive results.  The antifungal therapy of micafungin 236 Acta Med.  Okayama　Vol.  61,  No.  4Kaira et al.A BC DFig. 1　　Chest CT scan showing cystic lesions and alveolo-interstitial inﬁ ltrates (A),  air-space consolidation with air crescent sign and ground glass attenuation after 10 days (B),  rapid progression of pulmonary inﬁ ltrates after 14 days (C),  and a thick-walled cavitary lesion suggestive of aspergilloma after 31 days (D).2Acta Medica Okayama, Vol. 61 [2007], Iss. 4, Art. 8http://escholarship.lib.okayama-u.ac.jp/amo/vol61/iss4/8150 mg/day was started,  because it was unclear whether the pulmonary infection was secondary to invasive pulmonary aspergillosis.　 On hospital day 10,  the patient was still febrile,  and a chest CT revealed air-space consolidation with air crescent sign (Fig.  1B).  Micafungin was discontin-ued,  and voriconazol was started.  On hospital day 14,  the patient had persistent fever,  dyspnea,  and hypox-emia (PaO2:50 mmHg,  measured with nasal oxygen 5 L/min).  Chest radiographic ﬁ ndings revealed rapid progression of pulmonary inﬁ ltrates (Fig.  1C).  He developed an acute respiratory distress syndrome requiring mechanical ventilation and was transferred to the intensive care unit (ICU).　 Voriconazol 300 mg/day was continued,  and an intravenous corticosteroid (methylprednisolone 1.0 g/day) was started.  Transbronchial lung biopsy revealed necrotizing pneumonitis and numerous fungal hyphae.  Septate fungal hyphae were identiﬁ ed extending into normal lung parenchyma.  Aspergillus fumigatus was isolated from a fungal culture of lung tissue.  Moreover,  the diagnosis of pneumocystis jiroveci was made by bronchoalveolar lavage (BAL).  Combined IPA and PCP were diagnosed on hospital day 19.  Thus,  trimethoprim/sulfamethoxazole 1,200 mg/day and an adjunctive corticosteroid (prednisolone 40 mg/day) were initiated.　 On hospital day 31,  chest CT revealed aspergil-loma formation with a thin-walled cavity and improve-ment of pulmonary inﬁ ltrates (Fig.  1D),  but the patient continued to require intubation.  His condition deteriorated,  and laboratory tests revealed the fol-lowing: creatinine,  3.5 mg/dl; urea nitrogen,  79 mg/dl; white blood cell count,  22,000/ｻl,  and C-reactive protein,  22.1 mg/dl.  On hospital day 58,  the patient died of multiple organ failure and sepsis.  His family declined permission for a post-mortem examination.Discussion　 The patient received short-term low doses of a steroid,  although brain metastasis due to renal cell carcinoma was controlled by the surgical resection and whole brain radiation therapy.  He was a non-HIV and cancer patient with COPD,  but there was no evidence of recurrence other than the brain tumor.  In the pres-ent case,  therefore,  the major predisposing factors for IPA and PCP were considered to be steroid therapy.  Rello et al.  described rapid progression of IPA in patients with COPD receiving low doses or a brief course of steroid therapy [4].  Cornet et al.  described that short-term systemic corticosteroid therapy in immunocompetent patients with underlying chronic lung conditions was a risk factor for IPA and,  fur-thermore,  for its rapid evolution [5].  The number of cases reported among patients receiving brief steroid therapy has recently increased as awareness of the increased risk of IPA in these patients has grown [4,  5].　 In a retrospective analysis of the Mayo Clinic Rochester medical record registry [3],  among 30 patients with acute respiratory failure due to non-HIV-related PCP,  8 patients had received systemic corticosteroids only and 15 had received a combina-tion of both corticosteroids and chemotherapy.  The median prednisone-equivalent dose and duration of corticosteroid use prior to diagnosis of PCP was 40 mg (range,  5 to 200 mg) and 4.5 months (range,  12 days to 25 months),  respectively.  Hematologic malignancies,  inﬂ ammatory diseases,  and solid malig-nancies were the primary diagnoses present in the majority of patients,  accounting for 90ｵ of the underlying immunosuppressive conditions.  No patient was receiving prophylactic medications for PCP prior to the onset of pneumonia.  In addition to pneumocys-tis,  aspergillus was detected in 2 of the 30 patients but was deemed to be secondary to microorganism colonization or a latent infection rather than an active disease.  Twenty-nine of the 30 patients required intu-bation,  and 20 patients did not survive to discharge from the hospital,  yielding a mortality of 66.6ｵ.  The authors concluded that the delay in intubation on admission to the ICU was associated with a higher hospital mortality rate and that PCP prophylaxis should be strongly considered for all non-HIV immuno-suppressed patients receiving prolonged systemic corticosteroid therapy.　 Coinfection with aspergillus and pneumocystis jir-oveci has been reported as a nosocomial complication in patients admitted to the ICU [1,  3].  In the present case,  both proven invasive microorganisms were com-munity acquired.  However,  it was unclear whether pulmonary infection by aspergillus occurred prior to pneumocystis jiroveci.  The radiographic evaluation revealed pulmonary aspergillosis; however,  it was diﬃ  cult to make the radiographic diagnosis of com-237Pulmonary Aspergillosis and Pneumocystis PneumoniaAugust 20073Kaira et al.: Coinfection of Invasive Pulmonary Aspergillosis and PneumocystisProduced by The Berkeley Electronic Press, 2007bined IPA and PCP.  Early bronchoscopy with BAL should be considered in order to diagnose these oppor-tunistic infections promptly.　 Our case demonstrated that short-term systemic steroid therapy in non-HIV patients with underlying chronic lung conditions and malignancies was a risk factor for IPA and PCP,  and for a combination of these infections.  In such patients,  physicians should be alert to the fact that a high degree of suspicion is necessary for the diagnosis of these opportunistic infections.Conﬂ icts of interest statement.　All of the authors declare that we have no ﬁ nancial or personal relationships with other people or organisa-tions that could inappropriately inﬂ uence our work.References 1. Marinosa M,  Soler A,  Nogues X and Pedro-Botet J: Pulmonary coinfection by pneumocystis carinii and aspergillus fumigatus in a seronegative arthritis patient treated with low-dose methotrexate.  Clin Rheumatol (2004) 23: 555ﾝ556. 2. Kenney HH,  Agrons GA and Shin JS: Invasive pulmonary aspergil-losis: radiologic and pathologic ﬁ ndings.  Radiographics (2002) 22: 1507ﾝ1510. 3. Festic E,  Gajic O,  Limper AH and Aksamit TR: Acute respiratory failure due to pneumocystis pneumonia in patients without human immunodeﬁ ciency virus infection: outcome and associated fea-tures.  Chest (2005) 128: 573ﾝ579. 4. Rello J,  Esandi ME,  Mariscal D,  Gallego M,  Domingo C and Valles J: Invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease: report of eight cases and review.  Clin Infect Dis (1998) 26: 1473ﾝ1475. 5. Cornet M,  Mallat H,  Somme D,  Guerot E,  Kac G,  Mainardi L,  Fornes P,  Gutmann L and Lavarde V: Fulminant invasive pulmo-nary aspergillosis in immunocompetent patients-a two-case report.  Clin Microbiol Infect (2003) 9: 1224ﾝ1227.238 Acta Med.  Okayama　Vol.  61,  No.  4Kaira et al.4Acta Medica Okayama, Vol. 61 [2007], Iss. 4, Art. 8http://escholarship.lib.okayama-u.ac.jp/amo/vol61/iss4/8

Coinfection of Invasive Pulmonary Aspergillosis and Pneumocystis Jiroveci Pneumonia in a Non-HIV Patient

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Coinfection of Invasive Pulmonary Aspergillosis and Pneumocystis Jiroveci Pneumonia in a Non-HIV Patient

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