Mycopathologia (2015) 180:217–222 DOI 10.1007/s11046-015-9903-4
Disseminated Aspergillosis in the Immunocompetent Host: A Case Report and Literature Review Shinhye Cheon . Min Kyu Yang . Chung-Jong Kim . Taek Soo Kim . Kyoung-Ho Song . Se Joon Woo . Eu Suk Kim . Kyoung Un Park . Hong Bin Kim
Received: 17 February 2015 / Accepted: 19 May 2015 / Published online: 29 May 2015 Ó Springer Science+Business Media Dordrecht 2015
Abstract Disseminated aspergillosis is very rare in immunocompetent hosts and is typically associated with a poor prognosis. We describe the case of a 66-year-old, immunocompetent man who developed pneumonia, endophthalmitis and probable spondylitis caused by Aspergillus species. The patient was successfully treated with antifungal drugs. We reviewed the English-language literature between 1980 and 2012 for disseminated aspergillosis cases in immunocompetent hosts, using the keywords ‘‘dissemin*’’ and ‘‘aspergillo*.’’ Disseminated aspergillosis
in immunocompetent hosts is very rare in the literature. However, awareness of possible dissemination of Aspergillus spp. is necessary in patients who have a probable lung lesion and in cases with unusual presentation of a disseminated infection, even if the patient has no risk factors. Keywords Immunocompetent host Disseminated aspergillosis Endophthalmitis Spondylitis
Introduction S. Cheon C.-J. Kim K.-H. Song E. S. Kim (&) H. B. Kim Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-ro, 173 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 463-707, Republic of Korea e-mail: [email protected] S. Cheon C.-J. Kim K.-H. Song E. S. Kim H. B. Kim Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea M. K. Yang S. J. Woo Department of Ophthalmology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea T. S. Kim K. U. Park Department of Laboratory Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
Aspergillus species are fungi that are widely distributed in the air, water and soil. They can cause various types of disease including colonization, hypersensitivity reactions and invasive infections [1]. Disseminated aspergillosis develops in association with immunosuppression in situations such as hematological malignancy, bone marrow transplant, organ transplant, solid cancer and long-term use of steroid or chemotherapy [2]. The frequency of invasive aspergillosis has risen sharply since the 1980s due to the increasing use of immunosuppressants such as steroids, and novel organ transplant procedures [3]. Although Aspergillus infections can occur in immunocompetent hosts, invasive aspergillosis is very rare in such hosts. We described a case of pneumonia, endophthalmitis and probable spondylitis caused by Aspergillus spp. in an immunocompetent host. In
123
218
addition, we presented a literature review of disseminated aspergillosis in immunocompetent hosts.
Case Report A 66-year-old male patient visited the emergency room complaining of blurred vision, conjunctival infection and pain in both eyes since the day before. He was afebrile and had no respiratory symptoms. Several months previously, he experienced pain in the lower back. His lower back pain had neither improved nor worsened. He appeared acutely affected by conjunctival injection, but other physical examination was normal. He had been considered in complete remission after drug treatment for tuberculosis at the age of 17. He had no past medical history including history of liver disease or diabetes, except for conservative treatment in a clinic for the back pain a month ago. He had once smoked 10 packs/year but quit 30 years ago. His family history was nonspecific. He drank alcohol sporadically and had no recent history of outdoor activities or contact with pets. The patient’s vital signs in the emergency room were blood pressure 120/80 mmHg, pulse rate 72/min, 20 breaths/min and body temperature 37.2 °C. White blood cell count was 10,880/mm3 (76.4 % neutrophils), hemoglobin 11.9 g/dL and platelets 293,000/mm3. Total protein was 7.7 g/dL, albumin 4.4 g/dL, AST 23 IU/L, ALT 20 IU/L, total bilirubin 0.5 mg/dL, urea nitrogen 24.0 mg/dL, creatinine 0.83 mg/dL, sodium 144 mmol/L, potassium 4.1 mmol/L and C-reactive protein 6.97 mg/L. His corrected visual acuity was 20/250, OD, and hand motion at 30 cm, OS. Slit lamp examination showed severe (3?) cellular reaction in the anterior chamber of the right eye. Cellular reaction in the anterior chamber of the left eye was very severe (4?), and fibrinoid membrane formation was present. Due to the severe vitreous opacity, a detailed assessment of the retina was impossible. Based on these results, bilateral endophthalmitis was clinically diagnosed and vitrectomy was performed. No viruses or bacteria grew in cultures of the vitreous humors of the eyes. Aspergillus fumigatus was identified in fungal cultures from both vitreous humors, and these were positive in a fungal polymerase chain reaction (PCR). Voriconazole was injected intravitreously 2 days after vitrectomy, and intravenous injection was started thereafter.
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Mycopathologia (2015) 180:217–222
Human immunodeficiency virus (HIV) antibody was negative, and the lymphocyte subsets identified were CD3 1126 cells/mm3 (87 %), CD4 736 cells/ mm3 (57 %) and CD8 332 cells/mm3 (26 %). In addition, IgG was 1350 mg/dL, IgA 272 mg/dL and IgM 79 mg/dL. A neutrophil H2O2 dihydrorhodamine examination was negative with 99.9 % of the oxidized peak. Serum galactomannan antigen level was 1.75 (reference range 0–0.49). A chest X-ray obtained during hospitalization showed a consolidation in the left upper lobe. Six months before admission, the patient had attended an outpatient clinic for assessment of the cause of his back pain, and a chest X-ray and lumbar magnetic resonance imaging (MRI) were performed. The size of the consolidation in the chest X-ray had increased, as compared to the previous image. Therefore, a chest computed tomography (CT) scan and CT-guided aspiration and biopsy were performed on the 2-cmsized consolidation with ground glass opacity on the left upper lobe on the seventh day of hospitalization (Fig. 1). The tissue section did not reveal any fungus in pathologic specimen; however, subsequently, Aspergillus spp. was cultured from the specimen. The patient complained of back pain while taking voriconazole orally. A reexamination of the previous spine MRI images revealed infectious spondylitis on the 5th and 6th cervical vertebrae, 8th, 9th and 12th thoracic vertebrae, as well as on the entire lumbar and sacral regions (Fig. 2). Bone biopsy on the lumbar region was performed on the 15th day of hospitalization. Tissue culture was negative for bacteria, fungi and acid-fast bacilli. However, it was presumed that the infection began as pulmonary aspergillosis and subsequently disseminated to cause endophthalmitis and spondylitis; hence, antifungal agents were continued. Due to side effects of each of the drugs, we changed the prescription for voriconazole, amphotericin B and liposomal amphotericin B, to oral itraconazole in sequence. However, after oral itraconazole, the back pain became severe and spinal MRI was performed again on the 108th day due to an increase in the serum galactomannan antigen index to 5.4. The MRI showed that the infectious spondylitis had deteriorated. On the 134th day, bone biopsy and tissue culture were performed. The bone biopsy showed fibrocartilaginous tissue and sclerotic bony fragments with chronic inflammation, but it was negative for fungal or acid-fast bacillus staining. After
Mycopathologia (2015) 180:217–222
Fig. 1 Chest computed tomography on the fifth day of hospitalization. a A nodular low-attenuated consolidation with focal calcification in left upper lobe lingular segment (arrows). b A peripheral ill-defined ground glass opacity and branching opacity in left upper lobe lingular segment (arrows)
administration of oral voriconazole for about 5 months, the back pain had improved and the serum galactomannan antigen index was negative (Fig. 3). After 1 year, vision was recovered in the right eye but lost in the left eye. Pneumonic infiltration had decreased, and the back pain had almost disappeared.
219
Fig. 2 Magnetic resonance imaging of the spine 6 months before admission. a Bony destruction of end plates and decreased height of disk, C5–6. Bony destruction, diffuse enhancement at end plates of T12–S1 and T8–9 (arrows). b High enhancement at the vertebral body of L2–4
Discussion We searched PubMed with the keywords dissemin* and aspergillo* and found 943 papers. We reviewed all English-language cases and case series published
123
220
Mycopathologia (2015) 180:217–222
Fig. 3 Patient’s clinical course
between 1980 and 2012 and examined the clinical features and results of disseminated aspergillosis in immunocompetent hosts. Cases with long-term use of antibiotics that could predispose to fungal infection, as well as cases of iatrogenic disseminated aspergillosis occurring after injection or insertion of prostheses, were excluded. Cases in outbreaks after a tsunami or trauma and cases involving intravenous drug abuse were also excluded. Immunocompetent hosts are considered to be patients without predisposing characteristics that include (1) long-term neutropenia with or without hematological malignancy, (2) advanced solid organ malignancy, (3) organ and marrow or stem cell transplantation, (4) immunosuppressive therapy including corticosteroid and tumor necrosis factor (TNF)-a antagonist, (5) acquired immunodeficiency syndrome, (6) hereditary immunodeficiency syndrome, (7) chronic granulomatous disease, (8) DM, (9) toddlers and pregnant women and (10) chronic alcoholics or alcohol abusers. Diagnostic criteria of invasive aspergillosis were used as reported [4]. Invasive aspergillosis was defined when patients had invasive aspergillosis and there was histological evidence of tissue invasion by small and uniform, dichotomously branching hyphae that were septate at regular intervals, and/or culture findings positive for Aspergillus spp. from tissue or lung. Disseminated invasive aspergillosis was defined when the infection
123
by Aspergillus spp. affected C2 organ systems and non-contiguous organs were involved [4]. According to these criteria, five cases have been reported in the literature as disseminated aspergillosis in immunocompetent hosts [5–9] (Table 1). None of the patients had an underlying disease. Four of these patients visited the hospital because of fever but the fifth, an 80-year-old female patient, visited on account of blurry vision, as in our case. While the patient who was not treated with an antifungal agent for aspergillosis died, two of those who were treated with an antifungal agent for aspergillosis survived. Patients for whom antifungal treatment was started several months after the first symptoms of the disease did not survive. This shows that rapid diagnosis and treatment are essential to treat disseminated aspergillosis. The port of entry of disseminated aspergillosis was most frequently considered as the lungs, although Aspergillus colonization of the gastrointestinal tract is known to cause disseminated aspergillosis via the bloodstream. In the present case, the disease was presumed to have originated in the lungs and infected the eyes and the spine via the bloodstream. Most of the cases had lung involvement as in our case, but in two female patients, a 64-year-old and a 43-year-old, no lung involvement was found [6, 7]. In the former, the gastrointestinal tract was considered the port of entry for Aspergillus because of the possibility that dissemination of Aspergillus that had colonized the liver
Mycopathologia (2015) 180:217–222
221
Table 1 Clinical findings and management in previous case reports of disseminated aspergillosis in immunocompetent hosts Age/sex
Underlying condition
Involvement
Diagnosis
Species
Treatment
Course
Year/ reference
32/M
Benign teratoma
Lung, myocardium, kidney, skin
Biopsy, culture
A. fumigatus
(-)
Died
1990/[5]
64/F
Gastroresection
Skin, liver
Cured
1990/[6]
None
Spleen, pleura, pericardium, meninges, kidney, skin, colon
Aspergillus sp. A. fumigatus
Ketoconazole ? AMB
43/F
Biopsy, culture Biopsy, culture
AMB
Died
1998/[7]
34/M
None
Lung, spleen, liver, lymph node
Bronchial washing, sputum culture Biopsy
A. fumigatus
AMB ? ICZ
Cured
2006/[8]
Unknown
MICF ? VCZ
Died
2012/[9]
A. fumigatus
AMB ? VCZ ? ICZ ? VCZ
Cured
80/F
None
Lung, brain, eye
66/M
None
Lung, eye, spine
Biopsy, culture, PCR
AMB amphotericin B, ICZ itraconazole, VCZ voriconazole, MICF micafungin
occurred after perforation of a gastric ulcer. The port of entry for the 43-year-old female patient was not specified in the case report, but dissemination of Aspergillus through a skin lesion after traumatic skin damage was considered. Our case had a history of tuberculosis, and an inactive tuberculosis scar was visible in chest X-rays from other clinics several years before the visit to our hospital. In view of the possibility of an underlying lung disease such as chronic obstructive pulmonary disease (COPD), inactive tuberculosis or pneumoconiosis, the patient was thought to possess risk factors for invasive pulmonary aspergillosis [10, 11]. However, these kinds of underlying lung disease are rarely accompanied by disseminated aspergillosis. We found a total of 268 Aspergillus endophthalmitis cases by searching for aspergillo* endop* in PubMed. These were filtered using the same predisposing conditions for disseminated aspergillosis in immunocompetent hosts. Five cases were identified [9, 12–15]. Like our patient, the five patients were hospitalized complaining of symptoms such eye discomfort. A 73-year-old male patient and an 80-year-old female patient died, but all the others survived. All surviving patients had Aspergillus
endophthalmitis alone. The two patients who died had not only Aspergillus endophthalmitis but also disseminated aspergillosis that had infected other organs. Nevertheless, our patient survived despite the disseminated aspergillosis. This study had several limitations. The causative organism of the spondylitis was not established by microbiological and pathologic examinations. This is probably because the biopsy was performed after longterm administration of antifungal agent. However, the fact that administration of antifungal agent alone relieved the backache and decreased the galactomannan index is highly suggestive of spondylitis due to Aspergillus. The second limitation was that we did not confirm by microbiological or molecular genetic testing whether the Aspergillus in the eyes was the same as the Aspergillus in the lungs. However, the endophthalmitis developed when the pulmonary aspergillosis had worsened radiologically, and there was no evidence of any portal of entry other than the lung. In conclusion, disseminated aspergillosis in immunocompetent hosts is rarely reported in the literature. However, we should consider possible dissemination of Aspergillus spp. in patients who have a probable lung
123
222
Mycopathologia (2015) 180:217–222
lesion and the unusual presentation of a disseminated infection even if the patient has no risk factors for invasive aspergillosis. To achieve a good prognosis, it is important to start antifungal therapy based on early diagnostic examination on the suspicion of clinicians. Conflict of interest
None.
References 1. Ringer S, Hipler UC, Elsner P, et al. Potential role of the cellular allergen stimulation test (CAST) in diagnosis of allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis. Pediatr Pulmonol. 2007;42:314–8. 2. Herbrecht R, Bories P, Moulin JC, et al. Risk stratification for invasive aspergillosis in immunocompromised patients. Ann NY Acad Sci. 2012;1272:23–30. 3. Denning DW. Invasive aspergillosis. Clin Infect Dis. 1998;26:781–803 quiz 804-5. 4. Lehrnbecher T, Frank C, Engels K, et al. Trends in the postmortem epidemiology of invasive fungal infections at a university hospital. J Infect. 2010;61:259–65. 5. Cook DJ, Achong MR, King DE. Disseminated aspergillosis in an apparently healthy patient. Am J Med. 1990;88:74–6. 6. Vairani G, Rebeschini R, Barbazza R. Hepatic and subcutaneous abscesses due to aspergillosis. Initial diagnosis of a case by intraoperative fine needle aspiration cytology. Acta Cytol. 1990;34:891–4.
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7. Orem J, Mpanga L, Habyara E, et al. Disseminated Aspergillus fumigatus infection: case report. East Afr Med J. 1998;75:436–8. 8. Raja NS, Singh NN. Disseminated invasive aspergillosis in an apparently immunocompetent host. J Microbiol Immunol Infect. 2006;39:73–7. 9. Tokui K, Kawagishi Y, Inomata M, et al. Systemic dissemination of chronic necrotizing pulmonary aspergillosis in an elderly woman without comorbidity: a case report. J Med Case Rep. 2012;6:270. 10. Gefter WB, Weingrad TR, Epstein DM, et al. ‘‘Semi-invasive’’ pulmonary aspergillosis: a new look at the spectrum of aspergillus infections of the lung. Radiology. 1981;140: 313–21. 11. Binder RE, Faling LJ, Pugatch RD, et al. Chronic necrotizing pulmonary aspergillosis: a discrete clinical entity. Medicine (Baltimore). 1982;61:109–24. 12. Valluri S, Moorthy RS, Liggett PE, et al. Endogenous Aspergillus endophthalmitis in an immunocompetent individual. Int Ophthalmol. 1993;17:131–5. 13. Myles WM, Brownstein S, Deschenes J. Clinically unsuspected bilateral Aspergillus endophthalmitis. Can J Ophthalmol. 1997;32:182–4. 14. Logan S, Rajan M, Graham E, et al. A case of Aspergillus endophthalmitis in an immuncompetent woman: intraocular penetration of oral voriconazole: a case report. Cases J. 2010;3:31. 15. Mamandhar A, Bajracharya L. Endogenous Aspergillus endophthalmitis in a healthy individual. Nepal J Ophthalmol. 2012;4:179–83.
Disseminated Aspergillosis in the Immunocompetent Host: A Case Report and Literature Review Shinhye Cheon . Min Kyu Yang . Chung-Jong Kim . Taek Soo Kim . Kyoung-Ho Song . Se Joon Woo . Eu Suk Kim . Kyoung Un Park . Hong Bin Kim
Received: 17 February 2015 / Accepted: 19 May 2015 / Published online: 29 May 2015 Ó Springer Science+Business Media Dordrecht 2015
Abstract Disseminated aspergillosis is very rare in immunocompetent hosts and is typically associated with a poor prognosis. We describe the case of a 66-year-old, immunocompetent man who developed pneumonia, endophthalmitis and probable spondylitis caused by Aspergillus species. The patient was successfully treated with antifungal drugs. We reviewed the English-language literature between 1980 and 2012 for disseminated aspergillosis cases in immunocompetent hosts, using the keywords ‘‘dissemin*’’ and ‘‘aspergillo*.’’ Disseminated aspergillosis
in immunocompetent hosts is very rare in the literature. However, awareness of possible dissemination of Aspergillus spp. is necessary in patients who have a probable lung lesion and in cases with unusual presentation of a disseminated infection, even if the patient has no risk factors. Keywords Immunocompetent host Disseminated aspergillosis Endophthalmitis Spondylitis
Introduction S. Cheon C.-J. Kim K.-H. Song E. S. Kim (&) H. B. Kim Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-ro, 173 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 463-707, Republic of Korea e-mail: [email protected] S. Cheon C.-J. Kim K.-H. Song E. S. Kim H. B. Kim Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea M. K. Yang S. J. Woo Department of Ophthalmology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea T. S. Kim K. U. Park Department of Laboratory Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
Aspergillus species are fungi that are widely distributed in the air, water and soil. They can cause various types of disease including colonization, hypersensitivity reactions and invasive infections [1]. Disseminated aspergillosis develops in association with immunosuppression in situations such as hematological malignancy, bone marrow transplant, organ transplant, solid cancer and long-term use of steroid or chemotherapy [2]. The frequency of invasive aspergillosis has risen sharply since the 1980s due to the increasing use of immunosuppressants such as steroids, and novel organ transplant procedures [3]. Although Aspergillus infections can occur in immunocompetent hosts, invasive aspergillosis is very rare in such hosts. We described a case of pneumonia, endophthalmitis and probable spondylitis caused by Aspergillus spp. in an immunocompetent host. In
123
218
addition, we presented a literature review of disseminated aspergillosis in immunocompetent hosts.
Case Report A 66-year-old male patient visited the emergency room complaining of blurred vision, conjunctival infection and pain in both eyes since the day before. He was afebrile and had no respiratory symptoms. Several months previously, he experienced pain in the lower back. His lower back pain had neither improved nor worsened. He appeared acutely affected by conjunctival injection, but other physical examination was normal. He had been considered in complete remission after drug treatment for tuberculosis at the age of 17. He had no past medical history including history of liver disease or diabetes, except for conservative treatment in a clinic for the back pain a month ago. He had once smoked 10 packs/year but quit 30 years ago. His family history was nonspecific. He drank alcohol sporadically and had no recent history of outdoor activities or contact with pets. The patient’s vital signs in the emergency room were blood pressure 120/80 mmHg, pulse rate 72/min, 20 breaths/min and body temperature 37.2 °C. White blood cell count was 10,880/mm3 (76.4 % neutrophils), hemoglobin 11.9 g/dL and platelets 293,000/mm3. Total protein was 7.7 g/dL, albumin 4.4 g/dL, AST 23 IU/L, ALT 20 IU/L, total bilirubin 0.5 mg/dL, urea nitrogen 24.0 mg/dL, creatinine 0.83 mg/dL, sodium 144 mmol/L, potassium 4.1 mmol/L and C-reactive protein 6.97 mg/L. His corrected visual acuity was 20/250, OD, and hand motion at 30 cm, OS. Slit lamp examination showed severe (3?) cellular reaction in the anterior chamber of the right eye. Cellular reaction in the anterior chamber of the left eye was very severe (4?), and fibrinoid membrane formation was present. Due to the severe vitreous opacity, a detailed assessment of the retina was impossible. Based on these results, bilateral endophthalmitis was clinically diagnosed and vitrectomy was performed. No viruses or bacteria grew in cultures of the vitreous humors of the eyes. Aspergillus fumigatus was identified in fungal cultures from both vitreous humors, and these were positive in a fungal polymerase chain reaction (PCR). Voriconazole was injected intravitreously 2 days after vitrectomy, and intravenous injection was started thereafter.
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Mycopathologia (2015) 180:217–222
Human immunodeficiency virus (HIV) antibody was negative, and the lymphocyte subsets identified were CD3 1126 cells/mm3 (87 %), CD4 736 cells/ mm3 (57 %) and CD8 332 cells/mm3 (26 %). In addition, IgG was 1350 mg/dL, IgA 272 mg/dL and IgM 79 mg/dL. A neutrophil H2O2 dihydrorhodamine examination was negative with 99.9 % of the oxidized peak. Serum galactomannan antigen level was 1.75 (reference range 0–0.49). A chest X-ray obtained during hospitalization showed a consolidation in the left upper lobe. Six months before admission, the patient had attended an outpatient clinic for assessment of the cause of his back pain, and a chest X-ray and lumbar magnetic resonance imaging (MRI) were performed. The size of the consolidation in the chest X-ray had increased, as compared to the previous image. Therefore, a chest computed tomography (CT) scan and CT-guided aspiration and biopsy were performed on the 2-cmsized consolidation with ground glass opacity on the left upper lobe on the seventh day of hospitalization (Fig. 1). The tissue section did not reveal any fungus in pathologic specimen; however, subsequently, Aspergillus spp. was cultured from the specimen. The patient complained of back pain while taking voriconazole orally. A reexamination of the previous spine MRI images revealed infectious spondylitis on the 5th and 6th cervical vertebrae, 8th, 9th and 12th thoracic vertebrae, as well as on the entire lumbar and sacral regions (Fig. 2). Bone biopsy on the lumbar region was performed on the 15th day of hospitalization. Tissue culture was negative for bacteria, fungi and acid-fast bacilli. However, it was presumed that the infection began as pulmonary aspergillosis and subsequently disseminated to cause endophthalmitis and spondylitis; hence, antifungal agents were continued. Due to side effects of each of the drugs, we changed the prescription for voriconazole, amphotericin B and liposomal amphotericin B, to oral itraconazole in sequence. However, after oral itraconazole, the back pain became severe and spinal MRI was performed again on the 108th day due to an increase in the serum galactomannan antigen index to 5.4. The MRI showed that the infectious spondylitis had deteriorated. On the 134th day, bone biopsy and tissue culture were performed. The bone biopsy showed fibrocartilaginous tissue and sclerotic bony fragments with chronic inflammation, but it was negative for fungal or acid-fast bacillus staining. After
Mycopathologia (2015) 180:217–222
Fig. 1 Chest computed tomography on the fifth day of hospitalization. a A nodular low-attenuated consolidation with focal calcification in left upper lobe lingular segment (arrows). b A peripheral ill-defined ground glass opacity and branching opacity in left upper lobe lingular segment (arrows)
administration of oral voriconazole for about 5 months, the back pain had improved and the serum galactomannan antigen index was negative (Fig. 3). After 1 year, vision was recovered in the right eye but lost in the left eye. Pneumonic infiltration had decreased, and the back pain had almost disappeared.
219
Fig. 2 Magnetic resonance imaging of the spine 6 months before admission. a Bony destruction of end plates and decreased height of disk, C5–6. Bony destruction, diffuse enhancement at end plates of T12–S1 and T8–9 (arrows). b High enhancement at the vertebral body of L2–4
Discussion We searched PubMed with the keywords dissemin* and aspergillo* and found 943 papers. We reviewed all English-language cases and case series published
123
220
Mycopathologia (2015) 180:217–222
Fig. 3 Patient’s clinical course
between 1980 and 2012 and examined the clinical features and results of disseminated aspergillosis in immunocompetent hosts. Cases with long-term use of antibiotics that could predispose to fungal infection, as well as cases of iatrogenic disseminated aspergillosis occurring after injection or insertion of prostheses, were excluded. Cases in outbreaks after a tsunami or trauma and cases involving intravenous drug abuse were also excluded. Immunocompetent hosts are considered to be patients without predisposing characteristics that include (1) long-term neutropenia with or without hematological malignancy, (2) advanced solid organ malignancy, (3) organ and marrow or stem cell transplantation, (4) immunosuppressive therapy including corticosteroid and tumor necrosis factor (TNF)-a antagonist, (5) acquired immunodeficiency syndrome, (6) hereditary immunodeficiency syndrome, (7) chronic granulomatous disease, (8) DM, (9) toddlers and pregnant women and (10) chronic alcoholics or alcohol abusers. Diagnostic criteria of invasive aspergillosis were used as reported [4]. Invasive aspergillosis was defined when patients had invasive aspergillosis and there was histological evidence of tissue invasion by small and uniform, dichotomously branching hyphae that were septate at regular intervals, and/or culture findings positive for Aspergillus spp. from tissue or lung. Disseminated invasive aspergillosis was defined when the infection
123
by Aspergillus spp. affected C2 organ systems and non-contiguous organs were involved [4]. According to these criteria, five cases have been reported in the literature as disseminated aspergillosis in immunocompetent hosts [5–9] (Table 1). None of the patients had an underlying disease. Four of these patients visited the hospital because of fever but the fifth, an 80-year-old female patient, visited on account of blurry vision, as in our case. While the patient who was not treated with an antifungal agent for aspergillosis died, two of those who were treated with an antifungal agent for aspergillosis survived. Patients for whom antifungal treatment was started several months after the first symptoms of the disease did not survive. This shows that rapid diagnosis and treatment are essential to treat disseminated aspergillosis. The port of entry of disseminated aspergillosis was most frequently considered as the lungs, although Aspergillus colonization of the gastrointestinal tract is known to cause disseminated aspergillosis via the bloodstream. In the present case, the disease was presumed to have originated in the lungs and infected the eyes and the spine via the bloodstream. Most of the cases had lung involvement as in our case, but in two female patients, a 64-year-old and a 43-year-old, no lung involvement was found [6, 7]. In the former, the gastrointestinal tract was considered the port of entry for Aspergillus because of the possibility that dissemination of Aspergillus that had colonized the liver
Mycopathologia (2015) 180:217–222
221
Table 1 Clinical findings and management in previous case reports of disseminated aspergillosis in immunocompetent hosts Age/sex
Underlying condition
Involvement
Diagnosis
Species
Treatment
Course
Year/ reference
32/M
Benign teratoma
Lung, myocardium, kidney, skin
Biopsy, culture
A. fumigatus
(-)
Died
1990/[5]
64/F
Gastroresection
Skin, liver
Cured
1990/[6]
None
Spleen, pleura, pericardium, meninges, kidney, skin, colon
Aspergillus sp. A. fumigatus
Ketoconazole ? AMB
43/F
Biopsy, culture Biopsy, culture
AMB
Died
1998/[7]
34/M
None
Lung, spleen, liver, lymph node
Bronchial washing, sputum culture Biopsy
A. fumigatus
AMB ? ICZ
Cured
2006/[8]
Unknown
MICF ? VCZ
Died
2012/[9]
A. fumigatus
AMB ? VCZ ? ICZ ? VCZ
Cured
80/F
None
Lung, brain, eye
66/M
None
Lung, eye, spine
Biopsy, culture, PCR
AMB amphotericin B, ICZ itraconazole, VCZ voriconazole, MICF micafungin
occurred after perforation of a gastric ulcer. The port of entry for the 43-year-old female patient was not specified in the case report, but dissemination of Aspergillus through a skin lesion after traumatic skin damage was considered. Our case had a history of tuberculosis, and an inactive tuberculosis scar was visible in chest X-rays from other clinics several years before the visit to our hospital. In view of the possibility of an underlying lung disease such as chronic obstructive pulmonary disease (COPD), inactive tuberculosis or pneumoconiosis, the patient was thought to possess risk factors for invasive pulmonary aspergillosis [10, 11]. However, these kinds of underlying lung disease are rarely accompanied by disseminated aspergillosis. We found a total of 268 Aspergillus endophthalmitis cases by searching for aspergillo* endop* in PubMed. These were filtered using the same predisposing conditions for disseminated aspergillosis in immunocompetent hosts. Five cases were identified [9, 12–15]. Like our patient, the five patients were hospitalized complaining of symptoms such eye discomfort. A 73-year-old male patient and an 80-year-old female patient died, but all the others survived. All surviving patients had Aspergillus
endophthalmitis alone. The two patients who died had not only Aspergillus endophthalmitis but also disseminated aspergillosis that had infected other organs. Nevertheless, our patient survived despite the disseminated aspergillosis. This study had several limitations. The causative organism of the spondylitis was not established by microbiological and pathologic examinations. This is probably because the biopsy was performed after longterm administration of antifungal agent. However, the fact that administration of antifungal agent alone relieved the backache and decreased the galactomannan index is highly suggestive of spondylitis due to Aspergillus. The second limitation was that we did not confirm by microbiological or molecular genetic testing whether the Aspergillus in the eyes was the same as the Aspergillus in the lungs. However, the endophthalmitis developed when the pulmonary aspergillosis had worsened radiologically, and there was no evidence of any portal of entry other than the lung. In conclusion, disseminated aspergillosis in immunocompetent hosts is rarely reported in the literature. However, we should consider possible dissemination of Aspergillus spp. in patients who have a probable lung
123
222
Mycopathologia (2015) 180:217–222
lesion and the unusual presentation of a disseminated infection even if the patient has no risk factors for invasive aspergillosis. To achieve a good prognosis, it is important to start antifungal therapy based on early diagnostic examination on the suspicion of clinicians. Conflict of interest
None.
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