International Journal of Infectious Diseases 23 (2014) 1–3
Contents lists available at ScienceDirect
International Journal of Infectious Diseases journal homepage: www.elsevier.com/locate/ijid
Case Report
Penicillium marneffei infection within an osteolytic lesion in an HIV-negative patient Guang-nan Liu a,1, Juan-shu Huang a,b,1, Xiao-ning Zhong a, Jian-quan Zhang a, Zhao-xia Zou c, Mei-ling Yang a, Jing-min Deng a, Jing Bai a, Mei-hua Li a, Cong-zheng Mao a, Zhi-yi He a,* a
Respiratory Medicine, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, 530021, Guangxi, China Respiratory Medicine, The Central Hospital of Xiangtan City, Hunan, China c Division of Neurosurgery, City of Hope National Medical Center, Duarte, California, USA b
A R T I C L E I N F O
Article history: Received 17 September 2013 Received in revised form 6 December 2013 Accepted 21 December 2013 Corresponding Editor: Sunit Singh, Hyderabad, India Keywords: Penicillium marneffei Penicilliosis marneffei Osteolytic lesion
S U M M A R Y
Penicillium marneffei is a thermally dimorphic pathogenic fungus that causes systemic infection similar to disseminated cryptococcosis. P. marneffei is endemic in Southeast Asia, usually infecting HIV-infected individuals; infection of HIV-negative individuals is extremely rare. Here, we describe a disseminated P. marneffei infection within an osteolytic lesion in an HIV-negative patient. A 40-year-old Chinese woman presented with intermittent fever, generalized lymphadenopathy, and a skin rash. Following a sternum biopsy, the patient was diagnosed with P. marneffei infection. An emission computed tomography bone scan revealed the presence of increased radioactivity in the left clavicle and sternum, indicative of an osteolytic lesion. In addition to reporting this very rare case, we also present a brief review of the literature, highlighting the differences in clinical manifestations between HIV-positive and HIV-negative patients infected with P. marneffei as it applies to our case. ß 2014 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/3.0/).
1. Introduction
2. Case report
Penicillium marneffei is one of a small number of species of dimorphic fungi that grows as a mycelium at 25 8C and as a yeast at 37 8C in Southeast Asia. The first human infection occurred in 1973, as reported by Disalvo et al.1 While Penicillium strains are not usually associated with infection, P. marneffei infection can be fatal in immunocompromised individuals, including those who are HIVpositive. The route of transmission is not completely clear, but it is hypothesized to enter the host by inhalation from a contaminated reservoir and disseminate to other organs by hematogenous spread. Further, its dimorphic nature is thought to contribute to its pathogenicity, with conversion to the yeast phase within the host related to progression of disease.
On May 9, 2012, a 40-year-old Chinese woman was admitted complaining of intermittent fever, generalized lymphadenopathy, and a skin rash for 7 months. The patient was from Congzuo County in the Guangxi region of southern China. She had been treated previously for bacteremia, tuberculosis, and Mycobacterium tuberculosis, but the fever and lymphadenopathy had persisted and there was no clinical improvement. In March 2012, a right cervical lymph node biopsy revealed chronic pyogenic inflammation, but staining for fungi and acid-fast bacilli was negative. She had lost 10 kg, and 10 months prior to hospital admission she was diagnosed with subacute thyroiditis at a local hospital and was administered dexamethasone orally (5 mg/dl) for nearly 2 months. She appeared pale and chronically ill on the day of admission to The First Affiliated Hospital of Guangxi Medical University, and a physical examination revealed a high-grade fever. Multiple instances of erythema were present on the face, arms, and legs. Lymphadenopathy was present over the bilateral neck, bilateral axillary, and bilateral inguinal lymph nodes. A full blood panel was
* Corresponding author. Tel.: +86 15292270730; fax: +86 07715350920. E-mail address: [email protected] (Z.-y. He). 1 Contributed equally to this work. Guang-nan Liu and Juan-shu Huang are both the first author.
http://dx.doi.org/10.1016/j.ijid.2013.12.019 1201-9712/ß 2014 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
2
G.- Liu et al. / International Journal of Infectious Diseases 23 (2014) 1–3
Figure 1. An ECT bone scan showing increased radioactive concentration in the sternum and left clavicle. (A) The initial scan showed high levels of radioactivity, May 31, 2012. (B) August 9, 2012; (C) October 12, 2012; (D) November 20, 2012: the abnormal radioactivity decreased gradually over time.
obtained and the laboratory results are shown in Table S1 in the Supplementary Material. The patient was HIV-negative and negative for other blood-borne pathogens, including hepatitis B virus and Syphilis pathogens. Further, she had normal T lymphocyte cell counts (Supplementary Material, Table S1). Computed tomography scans revealed bilateral spotted flake shadows on both lungs (Supplementary Material, Figure S1). At that time, the patient was diagnosed with non-tuberculous mycobacteria, but
was unresponsive to isoniazid, rifampin, moxifloxacin, and cefoxitin therapy. After 3 weeks, the patient complained of aches in her left clavicle and sternum. A follow-up lung CT showed the left clavicle and sternum to have deteriorated significantly and surrounding tissues were swollen (Supplementary Material, Figure S2). An emission CT (ECT) bone scan showed abnormal increased radioactive concentration in the sternum and left clavicle (Figure 1A). A subsequent sternum biopsy specimen
G.- Liu et al. / International Journal of Infectious Diseases 23 (2014) 1–3
culture confirmed the diagnosis of P. marneffei infection (Supplementary Material, Figure S3). The patient was treated with, and responded well to, amphotericin B at 50 mg/dl via intravenous administration starting on June 4, 2012. Her fever returned to normal and her chest pain also disappeared gradually 5 days after treatment. She continued to receive antifungal treatment. A series of bone ECT and lung CT scans showed the radioactivity concentration to taper off gradually in her left clavicle and sternum (Fig. 1, B–D) and all of her laboratory results returned to normal.
3. Discussion P. marneffei within an osteolytic lesion in an HIV-negative person is a rarely reported diagnosis. This patient’s corticosteroid treatment for subacute thyroiditis, which affected the patient’s immune function, possibly increased her chance of infection. The symptoms that lead to the diagnosis of P. marneffei infection are often non-specific and it tends to be regularly misdiagnosed. Cases of P. marneffei in non-HIV-infected patients are rare and other reports have shown that there are different clinical manifestations between HIV-positive and HIV-negative patients,2,3 including: (1) a delay in penicilliosis diagnosis in HIV-negative patients due to common misdiagnosis, leading more often to chronic progression of the disease when compared to HIV-positive patients;2,3 (2) significantly higher levels of total white cell counts in HIV-negative patients vs. HIV-positive patients;3 (3) higher incidences of fungemia in HIV-positive patients, whereas a tissue specimen is often necessary for diagnosis in HIV-negative hosts;2 (4) higher serum antigen titers in HIV-positive patients, while serum antibody levels are found to be higher in HIV-negative patients,2 as determined by a P. marneffei-specific mannoprotein Mp1p ELISA;2 (5) different histopathological reactions, including granulomatous and suppurative reactions, are seen in patients with ‘normal’ immune systems, while anergic and necrotizing reactions are seen in patients with compromised immune systems.3 All of these differences are more than likely associated with the different immune status and neutrophil functions of HIVnegative and HIV-positive patients. P. marneffei infection in bone is rare, which indicates that systemic disturbance can be severe. Of note, previous reports of P. marneffei infection presenting in osteolytic lesions, specifically in flat bones, long bones of the extremities, and the small bones of the hands and feet, have mostly involved HIV-negative patients;3,4 the reasons for this phenomenon are still not fully understood. The
3
prevailing hypothesis is that osteolytic lesions are typically a site of neutrophil accumulation and release of proteolytic enzymes. Considering HIV-positive patients have decreased neutrophil function, it is no surprise that P. marneffei infection is rarely seen in these instances. Considering the presence of disseminated P. marneffei infection and osteolytic lesions, we thought that the patient needed stronger antifungal treatment for a longer period than individuals with nonosteolytic P. marneffei infections. The patient was first treated with amphotericin B (50 mg) for nearly 2 months with a good treatment response, showing that her general physical condition had improved greatly, and the bone ache disappeared completely. Follow-up ECT bone scans showed the radioactive concentration to decrease gradually during the 3-month course of treatment. P. marneffei-infected osteolytic lesions in non-HIV-infected patients is rare and easily misdiagnosed. We have described in detail the case of an HIV-negative woman with disseminated P. marneffei infection in an osteolytic lesion and compared the differences in clinical manifestations between HIV-positive and HIV-negative patients. Ethical approval: The patient included in the study gave full informed consent, and ethical approval for this study was provided by the Ethics Committee of The First Affiliated Hospital of Guangxi Medical University. Conflict of interest: The authors report that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.ijid.2013.12.019. References 1. Disalvo A, Fickling A, Ajello L. Infection cause by Penicillium marneffei: description of the first natural infection in man. Am J Clin Pathol 1973;60:259–63. 2. Zhang JQ, Yang ML, Zhong XN, He ZY, Liu GN, Deng JM, et al. A comparative analysis of the clinical and laboratory characteristics in disseminated penicilliosis marneffei in patients with and without human immunodeficiency virus infection (In Chinese). Zhonghua Jie He He Hu Xi Za Zhi 2008;31:740–6. 3. Deng Z, Ribas JL, Gibson DW, Connor DH. Infections caused by Penicillium marneffei in China and Southeast Asia: review of eighteen published cases and report of four more Chinese cases. Rev Infect Dis 1988;10:640–52. 4. Chan YF, Woo KC. Penicillium marneffei osteomyelitis. J Bone Joint Surg Br 1990;72:500–3.
Contents lists available at ScienceDirect
International Journal of Infectious Diseases journal homepage: www.elsevier.com/locate/ijid
Case Report
Penicillium marneffei infection within an osteolytic lesion in an HIV-negative patient Guang-nan Liu a,1, Juan-shu Huang a,b,1, Xiao-ning Zhong a, Jian-quan Zhang a, Zhao-xia Zou c, Mei-ling Yang a, Jing-min Deng a, Jing Bai a, Mei-hua Li a, Cong-zheng Mao a, Zhi-yi He a,* a
Respiratory Medicine, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, 530021, Guangxi, China Respiratory Medicine, The Central Hospital of Xiangtan City, Hunan, China c Division of Neurosurgery, City of Hope National Medical Center, Duarte, California, USA b
A R T I C L E I N F O
Article history: Received 17 September 2013 Received in revised form 6 December 2013 Accepted 21 December 2013 Corresponding Editor: Sunit Singh, Hyderabad, India Keywords: Penicillium marneffei Penicilliosis marneffei Osteolytic lesion
S U M M A R Y
Penicillium marneffei is a thermally dimorphic pathogenic fungus that causes systemic infection similar to disseminated cryptococcosis. P. marneffei is endemic in Southeast Asia, usually infecting HIV-infected individuals; infection of HIV-negative individuals is extremely rare. Here, we describe a disseminated P. marneffei infection within an osteolytic lesion in an HIV-negative patient. A 40-year-old Chinese woman presented with intermittent fever, generalized lymphadenopathy, and a skin rash. Following a sternum biopsy, the patient was diagnosed with P. marneffei infection. An emission computed tomography bone scan revealed the presence of increased radioactivity in the left clavicle and sternum, indicative of an osteolytic lesion. In addition to reporting this very rare case, we also present a brief review of the literature, highlighting the differences in clinical manifestations between HIV-positive and HIV-negative patients infected with P. marneffei as it applies to our case. ß 2014 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/3.0/).
1. Introduction
2. Case report
Penicillium marneffei is one of a small number of species of dimorphic fungi that grows as a mycelium at 25 8C and as a yeast at 37 8C in Southeast Asia. The first human infection occurred in 1973, as reported by Disalvo et al.1 While Penicillium strains are not usually associated with infection, P. marneffei infection can be fatal in immunocompromised individuals, including those who are HIVpositive. The route of transmission is not completely clear, but it is hypothesized to enter the host by inhalation from a contaminated reservoir and disseminate to other organs by hematogenous spread. Further, its dimorphic nature is thought to contribute to its pathogenicity, with conversion to the yeast phase within the host related to progression of disease.
On May 9, 2012, a 40-year-old Chinese woman was admitted complaining of intermittent fever, generalized lymphadenopathy, and a skin rash for 7 months. The patient was from Congzuo County in the Guangxi region of southern China. She had been treated previously for bacteremia, tuberculosis, and Mycobacterium tuberculosis, but the fever and lymphadenopathy had persisted and there was no clinical improvement. In March 2012, a right cervical lymph node biopsy revealed chronic pyogenic inflammation, but staining for fungi and acid-fast bacilli was negative. She had lost 10 kg, and 10 months prior to hospital admission she was diagnosed with subacute thyroiditis at a local hospital and was administered dexamethasone orally (5 mg/dl) for nearly 2 months. She appeared pale and chronically ill on the day of admission to The First Affiliated Hospital of Guangxi Medical University, and a physical examination revealed a high-grade fever. Multiple instances of erythema were present on the face, arms, and legs. Lymphadenopathy was present over the bilateral neck, bilateral axillary, and bilateral inguinal lymph nodes. A full blood panel was
* Corresponding author. Tel.: +86 15292270730; fax: +86 07715350920. E-mail address: [email protected] (Z.-y. He). 1 Contributed equally to this work. Guang-nan Liu and Juan-shu Huang are both the first author.
http://dx.doi.org/10.1016/j.ijid.2013.12.019 1201-9712/ß 2014 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
2
G.- Liu et al. / International Journal of Infectious Diseases 23 (2014) 1–3
Figure 1. An ECT bone scan showing increased radioactive concentration in the sternum and left clavicle. (A) The initial scan showed high levels of radioactivity, May 31, 2012. (B) August 9, 2012; (C) October 12, 2012; (D) November 20, 2012: the abnormal radioactivity decreased gradually over time.
obtained and the laboratory results are shown in Table S1 in the Supplementary Material. The patient was HIV-negative and negative for other blood-borne pathogens, including hepatitis B virus and Syphilis pathogens. Further, she had normal T lymphocyte cell counts (Supplementary Material, Table S1). Computed tomography scans revealed bilateral spotted flake shadows on both lungs (Supplementary Material, Figure S1). At that time, the patient was diagnosed with non-tuberculous mycobacteria, but
was unresponsive to isoniazid, rifampin, moxifloxacin, and cefoxitin therapy. After 3 weeks, the patient complained of aches in her left clavicle and sternum. A follow-up lung CT showed the left clavicle and sternum to have deteriorated significantly and surrounding tissues were swollen (Supplementary Material, Figure S2). An emission CT (ECT) bone scan showed abnormal increased radioactive concentration in the sternum and left clavicle (Figure 1A). A subsequent sternum biopsy specimen
G.- Liu et al. / International Journal of Infectious Diseases 23 (2014) 1–3
culture confirmed the diagnosis of P. marneffei infection (Supplementary Material, Figure S3). The patient was treated with, and responded well to, amphotericin B at 50 mg/dl via intravenous administration starting on June 4, 2012. Her fever returned to normal and her chest pain also disappeared gradually 5 days after treatment. She continued to receive antifungal treatment. A series of bone ECT and lung CT scans showed the radioactivity concentration to taper off gradually in her left clavicle and sternum (Fig. 1, B–D) and all of her laboratory results returned to normal.
3. Discussion P. marneffei within an osteolytic lesion in an HIV-negative person is a rarely reported diagnosis. This patient’s corticosteroid treatment for subacute thyroiditis, which affected the patient’s immune function, possibly increased her chance of infection. The symptoms that lead to the diagnosis of P. marneffei infection are often non-specific and it tends to be regularly misdiagnosed. Cases of P. marneffei in non-HIV-infected patients are rare and other reports have shown that there are different clinical manifestations between HIV-positive and HIV-negative patients,2,3 including: (1) a delay in penicilliosis diagnosis in HIV-negative patients due to common misdiagnosis, leading more often to chronic progression of the disease when compared to HIV-positive patients;2,3 (2) significantly higher levels of total white cell counts in HIV-negative patients vs. HIV-positive patients;3 (3) higher incidences of fungemia in HIV-positive patients, whereas a tissue specimen is often necessary for diagnosis in HIV-negative hosts;2 (4) higher serum antigen titers in HIV-positive patients, while serum antibody levels are found to be higher in HIV-negative patients,2 as determined by a P. marneffei-specific mannoprotein Mp1p ELISA;2 (5) different histopathological reactions, including granulomatous and suppurative reactions, are seen in patients with ‘normal’ immune systems, while anergic and necrotizing reactions are seen in patients with compromised immune systems.3 All of these differences are more than likely associated with the different immune status and neutrophil functions of HIVnegative and HIV-positive patients. P. marneffei infection in bone is rare, which indicates that systemic disturbance can be severe. Of note, previous reports of P. marneffei infection presenting in osteolytic lesions, specifically in flat bones, long bones of the extremities, and the small bones of the hands and feet, have mostly involved HIV-negative patients;3,4 the reasons for this phenomenon are still not fully understood. The
3
prevailing hypothesis is that osteolytic lesions are typically a site of neutrophil accumulation and release of proteolytic enzymes. Considering HIV-positive patients have decreased neutrophil function, it is no surprise that P. marneffei infection is rarely seen in these instances. Considering the presence of disseminated P. marneffei infection and osteolytic lesions, we thought that the patient needed stronger antifungal treatment for a longer period than individuals with nonosteolytic P. marneffei infections. The patient was first treated with amphotericin B (50 mg) for nearly 2 months with a good treatment response, showing that her general physical condition had improved greatly, and the bone ache disappeared completely. Follow-up ECT bone scans showed the radioactive concentration to decrease gradually during the 3-month course of treatment. P. marneffei-infected osteolytic lesions in non-HIV-infected patients is rare and easily misdiagnosed. We have described in detail the case of an HIV-negative woman with disseminated P. marneffei infection in an osteolytic lesion and compared the differences in clinical manifestations between HIV-positive and HIV-negative patients. Ethical approval: The patient included in the study gave full informed consent, and ethical approval for this study was provided by the Ethics Committee of The First Affiliated Hospital of Guangxi Medical University. Conflict of interest: The authors report that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.ijid.2013.12.019. References 1. Disalvo A, Fickling A, Ajello L. Infection cause by Penicillium marneffei: description of the first natural infection in man. Am J Clin Pathol 1973;60:259–63. 2. Zhang JQ, Yang ML, Zhong XN, He ZY, Liu GN, Deng JM, et al. A comparative analysis of the clinical and laboratory characteristics in disseminated penicilliosis marneffei in patients with and without human immunodeficiency virus infection (In Chinese). Zhonghua Jie He He Hu Xi Za Zhi 2008;31:740–6. 3. Deng Z, Ribas JL, Gibson DW, Connor DH. Infections caused by Penicillium marneffei in China and Southeast Asia: review of eighteen published cases and report of four more Chinese cases. Rev Infect Dis 1988;10:640–52. 4. Chan YF, Woo KC. Penicillium marneffei osteomyelitis. J Bone Joint Surg Br 1990;72:500–3.
