|Year : 2015 | Volume
| Issue : 1 | Page : 161-165
Disseminated penicilliosis marneffei in immunocompetent patients: A report of two cases
Feng Ye1, Qun Luo1, Ying Zhou1, Jiaxing Xie1, Qingsi Zeng2, Guoqin Chen3, Danhong Su4, Rongchang Chen1
1 Department of Respiratory Medicine Guangzhou Institute of Respiratory Diseases , State Key Laboratory of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China
2 Department of Radiology , First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China
3 Department of Pathology, First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China
4 Department of Microorganism, First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China
|Date of Submission||23-Jun-2014|
|Date of Acceptance||24-Oct-2014|
|Date of Web Publication||5-Jan-2015|
Department of Respiratory Medicine Guangzhou Institute of Respiratory Diseases , State Key Laboratory of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China
Source of Support: None, Conflict of Interest: None
Disseminated penicilliosis marneffei is rarely seen in immunocompetent persons. We report here two cases of disseminated penicilliosis marneffei in immunocompetent hosts. Penicillium marneffei disseminated to the brain in one patient and to the bone marrow in the other patient. Both patients received amphotericin B liposome. The cases illustrate the importance of considering penicilliosis marneffei as causes of systemic infections in immunocompetent patients.
Keywords: Disseminated, immunocompetent hosts, penicilliosis marneffei
|How to cite this article:|
Ye F, Luo Q, Zhou Y, Xie J, Zeng Q, Chen G, Su D, Chen R. Disseminated penicilliosis marneffei in immunocompetent patients: A report of two cases. Indian J Med Microbiol 2015;33:161-5
|How to cite this URL:|
Ye F, Luo Q, Zhou Y, Xie J, Zeng Q, Chen G, Su D, Chen R. Disseminated penicilliosis marneffei in immunocompetent patients: A report of two cases. Indian J Med Microbiol [serial online] 2015 [cited 2019 Nov 15];33:161-5. Available from: http://www.ijmm.org/text.asp?2015/33/1/161/148433
| ~ Introduction|| |
Penicilliosis marneffei is a lethal form of systemic fungiosis due to Penicillium marneffei. With its recent upright trend in incidence, the disease has emerged as a serious public health concern in Southeast Asia  and its incidence has reached 12.3% in some regions in China.  Penicilliosis marneffei is more common in immunocompromised hosts; in Thailand, it ranks third in opportunistic infections behind tuberculosis and cryptococcosis in patients with acquired immunodeficiency syndrome (AIDS). ,, In Hong Kong, penicilliosis marneffei lags only behind Pneumocystis pneumonia and tuberculosis in immunocompromised hosts.  However, it is extremely rare to find systemic Penicillium marneffei infections in immunocompetent persons. Here, we report disseminated penicilliosis marneffei in two immunocompetent hosts.
| ~ Case Reports|| |
A 37-year-old male patient was admitted because of recurrent episodes of coughing and fever for 1 month. The cough, which started 1 month ago, was irritating and nonproductive. The body temperature reached as high as 40°C. The patient developed night sweats, chest pain, chest tightness, dizziness, headache and pain in both shoulders. He had received antibiotics including ceftriaxone, azithromycin and vancomycin and anti-tuberculosis medications including isoniazid, rifampin, ethambutol and pyrazinamide at two other hospitals, but showed no apparent improvement. His body weight decreased more than 9 kg in the interim. The patient was otherwise healthy with no underlying disease. He denied drug use and contact with pets or rats. He also denied any history of homosexual contact.
Physical examination upon admission showed a body temperature of 38.9°C, a pulse of 88/min, a respiration rate of 20/min, and a blood pressure of 129/74 mmHg. The patient appeared normally developed and was mentally alert. An enlarged left supraclavicular lymph node, 1 × 1.5 cm 2 in size, and an enlarged left inguinal lymph node, 1 × 1 cm 2 in size, were palpated and both were non-tender, movable and non-adherent. Migrant papules were palpable in many parts of the body [Figure 1]. The bilateral chest was symmetrical. The chest was tender, especially on the left 2 nd intercostal space. His respiration was smooth. The bilateral lung field was clear with no rales. The heart and liver were normal. Chest roentography revealed occupying lesion in the left upper lobe [[Figure 2]a]. Chest computed tomography (CT) scan showed left upper lobe consolidation, atelectasis and enlargement of multiple mediastinal lymph nodes [[Figure 2]b and c]. In addition, a moderate amount of pericardial effusions was noted and there were chronic inflammatory changes in the lower basal segment of the left lung. The admission diagnoses were occupying disease on the upper left pulmonary lobe and obstructive pneumonia.
|Figure 1: Migrant papules in a 37-year-old male patient with disseminated penicilliosis marneffei|
Click here to view
|Figure 2: (a) Chest roentography revealed occupying lesion in the left upper lobe. (b) and (c) Chest CT scan showed left upper lobe consolidation, atelectasis and enlargement of multiple mediastinal lymph nodes|
Click here to view
Laboratory studies revealed a white blood cell (WBC) count of 23.49 × 10 9 /L (neutrophils 78.2%), a red blood cell (RBC) count of 3.7 × 10 9 /L, and a haemoglobin content of 92 g/L. The erythrocyte sedimentation rate (ESR) was 23 mm/h, the C-reactive protein (CRP) content was 12.92 mg/dL, and the rheumatic factor content was 21 IU/mL. The renal and liver function was normal. Arterial blood gas analysis results were as follows: pH, 7.506, P CO2 , 30.98 mmHg, P O2 , 67.59 mmHg, and HCO 3 - , 24.3 mmol/L on O 2 at 2 L/min. The patient was negative for Widal test, Weil-Felix test, serum cryptococcal antigen latex agglutination test, and Candida galactomannan antigen test. Serum mycoplasma pneumonia antibody, anti-tuberculin antibody, anti-legionella antibodies and HIV antibodies were negative. The (1-3)-β-D-glucan content was 500 pg/mL. Sputum smears were negative for acid-fast bacilli and for fungi and sputum cultures were negative for bacteria and fungi.
Two days after admission, the patient suddenly developed spasm of the extremities and convulsions. Cranial MRI showed infective changes in the right parietal lobe, the left frontal lobe and temporal lobe, the meninges, and the diploe [[Figure 3]a-d]. In addition, retropharyngeal abscess was noticed on the right at the level of the 2 nd and 3 rd cervical vertebra [[Figure 3]e]. B mode ultrasound revealed a subcutaneous mass in the right shoulder and a mixed echo mass in the bilateral supraclavicular area, but no blood flow was detected. Bone marrow biopsy revealed active proliferation of bone marrow cells with an increased ratio of the myeloid to the erythrocytic lineage. The erythrocytic lineage was dominated by mature cells. Many cells with giant segmented nuclei were observed and mature plasma cells were readily observable. Silver and iron staining were negative. Immunohistochemistry revealed that MPO was positive in most cells, CD15, CD20, CD3, CD5, PAX-5, and CD117 were positive in scant cells, CD34 was positive and CK was negative; suggesting reactive bone marrow. Fiberoptic bronchoscopy revealed multiple submucosal nodules in the terminus of the left trachea [[Figure 4]a] and pathological examination showed squamous metaplasia of the epithelia with massive infiltration by neutrophils, lymphocytes and histiocytes. Yeast-like fungi were observed [[Figure 4]b]. Methylamine silver and PAS staining was positive [[Figure 4]c and d], showing ovoid, elliptic and sausage-shaped, septated fungi while AB and acid-fast staining was negative. Biphasic fungal culture of aspirates of the right shoulder mass yielded yeast phase at 35°C with no production of red pigment [[Figure 5]a] and mycelia at 25°C with massive production of red pigment [[Figure 5]b]. Sausage-shaped yeast-like cells with septation were observed under the microscope [[Figure 5]c and d], and pulmonary fungal infection with Penicillium marneffei was considered. The final diagnoses were disseminated Penicilliosis marneffei with secondary seizure. The patient was given intravenous amphotericin B liposome for an accumulated dose of 4.15 g, the fever subsided after 5 days and the patient recovered and was discharged from the hospital. However, the patient relapsed after prematurely discontinued prescribed medication without physician permission. The patient was then given oral itraconazole, 20 mL bid for 3 months. At the 3 month follow up, chest CT and head MRI showed resolution of lesion [[Figure 6]a and b].
|Figure 3: (a to d) Cranial MRI showed infective changes (arrows) in the right parietal lobe, the left frontal lobe and temporal lobe, the meninges, and the diploe. (e) Retropharyngeal abscess (arrow) was noticed on the right at the level of the 2nd and 3rd cervical vertebra|
Click here to view
|Figure 4: (a) Fiberoptic bronchoscopy revealed multiple submucosal nodules in the terminus of the left trachea. (b) Pathological examination showed squamous metaplasia of the epithelia with massive infiltration by neutrophils, lymphocytes and histiocytes. Yeast-like fungi were observed. (c) Methylamine silver and (d) PAS staining was positive, showing ovoid, elliptic and sausage-shaped, septated fungi|
Click here to view
|Figure 5: (a) Biphasic fungal culture of aspirates of the right shoulder mass yielded yeast phase at 35°C with no production of red pigment and (b) mycelia at 25°C with massive production of red pigment. (c) and (d) Sausage-shaped yeast-like cells with septation were observed under the microscope|
Click here to view
|Figure 6: (a) Chest CT scan shows resolution of the lesion and (b) MRI scan indicates resolution of the lesion at the 3-month follow up visit.|
Click here to view
A 32-year-old male was admitted to the hospital on August 15, 2011 because of productive cough for 5 months and subcutaneous mass and fever for 3 months. The patient started coughing 5 months ago with production of whitish sputum. His body temperature reached as high as 39°C, which was most apparent in the afternoon and dusk. Subcutaneous nodules began to appear 3 months ago, which were soft, flocculating and tender, and yellow-whitish fluid oozed out when the nodules became ulcerated. Multiple subcutaneous nodules appeared 2 months ago on the chest, abdomen and the extremities. He had received anti-infection and anti-tuberculosis therapy at other hospitals before admission to our hospital, but showed no improvement. His body weight decreased 15 kg in the interim. Physical examination findings were as follows: Body temperature, 37.4°C, pulse, 123/min, respiration, 22/min, and blood pressure, 135/75 mmHg. Multiple generalised subcutaneous nodules were seen on the chest, abdomen and the extremities with purulent secretions. Bilateral lung sounds were clear with no moist rales and rhonchi.
Blood chemistries: WBCs, 18.17 × 10 9 /L (neutrophils 90.5%), haemoglobin, 106 g/L, ESR, 75 mm/h and CRP, 22.68 mg/dL. Urine examinations: urinary β2 microglobulin, 2.14 mg/L, 24-h urinary protein, 1.82 g, and NAG, 56.3 U/L. Arterial blood gases: pH 7.468, P CO2 , 27.07 mmHg, P O2 , 93.98 mmHg, and HCO3 - , 19.3 mmol/L. Widal test, Weil-Felix test, serum cryptococcal antigen latex agglutination test, and Candida galactomannan antigen test were negative. HIV antibodies were also negative. The (1-3)-β-D-glucan content was <5 pg/mL. Aspirated purulent smears were negative for acid-fast bacilli. Chest CT revealed enlargement in the hilus and the mediastinum with partial necrosis [Figure 7]. Tracheomediastinal fistula and purulence and sternum osteomyelitis were considered with oesophageal-mediastinal fistulae to be excluded. The patient received tentative diagnoses of multiple generalised purulent masses and mediastinal lymph node enlargement with suspected penicilliosis marneffei, non-tuberculous Mycobacterium infection and lymphoma.
|Figure 7: A 32-year old male with disseminated penicilliosis marneffei. Chest CT revealed enlargement in the hilus and the mediastinum with partial necrosis.|
Click here to view
Bone marrow smear showed reactive bone marrow: the number of plasma cells was increasd, neutrophil alkaline phosphatase staining, and 100%, NAP score: 368. On August 23, aspirate culture of the purulent nodules yielded fungal mycelia consistent with P. marneffei. The ultimate diagnosis was disseminated Penicilliosis marneffei and the patient was started on intravenous amphotericin B liposome. On the same day, the patient developed septic shock and DIC, and the patient family asked for automatic discharge from the hospital because of economic concerns.
| ~ Discussion|| |
Penicillium marneffei is the only known thermally dimorphic species of Penicillium. Yeast phase conidiophores are the infectious form of Penicillium marneffei and are strongly resistant to non-specific phagocytosis. Yeast phase cells are pathogenic and cause intracellular infection by adsorption to the epithelial cells in the bronchus. Nittayananta et al.  reported that inhalation of conidiophores is the main route of transmission for Penicillium marneffei. Over the recent years, penicilliosis marneffei has seen a steady increase in incidence and is mainly prevalent in Thailand, Indonesia, Malaysia, Laos and Vietnam. In China, it is prevalent in the southern regions, including the provinces of Guangxi and Guangdong, and Hong Kong and Taiwan. ,,,, In the US and Europe, the disease is mainly seen in patients who have traveled to Southeast Asia.  P. marneffei has gradually spread from HIV-infected persons to the general population. Penicilliosis marneffei is also seen increasingly in immunocompetent hosts in China and death is reported in immunocompetent children. 
This is the first report of an immunocompetent penicilliosis marneffei patient with CNS involvement in China. Dissemination of enicillium marneffei to the CNS has rarely been reported. The 1 st patient in this case report experienced CNS dissemination even though he was found to be HIV. Penicilliosis marneffei is either localised or disseminated. Localised penicilliosis is more commonly seen in skin and subcutaneous infections while the disseminated form more often involves the lungs, liver and lymph nodes.  Penicilliosis marneffei in immunocompetent hosts can be manifested as disseminated infection. Patients may have repeated episodes of remitting fever during the course of the illness, giving the false impression that empirical anti-infection or anti-tuberculosis therapy is effective. The two patients in this case report also received empirical anti-infection and anti-tuberculosis therapies at other hospitals and ours before P. marneffei was established as the causative agent of the illness. Furthermore, the manifestations of penicilliosis marneffei in immunocompetent patients are often different those who are immunocompromised. In immunocompetent hosts, focal abscesses, osteolytic destruction, purulent pneumonia and enlargement of the liver, spleen and lymph nodes are typical while they are rarely seen in AIDS patients. The property of growth at 37°C and invasion of blood vessels is a major cause of dissemination and high mortality for the disease. Approximately half of the patients have fungemia, particularly in HIV-positive patients. Penicillium marneffei often invades blood vessels and produces fungal emboli.
The gold standard for diagnosis of penicilliosis marneffei is identification of P. marneffei by fungal culture. Clinical diagnosis of penicilliosis marneffei can be based on the toxic symptoms of patients, increase in leukocyte counts, multiple organ involvement, abscesses of the skin and multiple organs. Rapid diagnosis often relies on identification of septated conidiophores from specimens from skin lesions, blood or bone marrow. Specimens from skin lesions should be taken from the border area between lesions and normal adjacent tissues as central lesions lack blood supply and are often necrotic and specimens from central lesions likely yield false negative results. Because penicillium marneffei grows intracellular, culture after lysis of cells could boost the positive yield.
The onset of penicilliosis marneffei is often subtle and because of its blood vessel invasive property P. marneffei readily spreads to other parts of the body and causes disseminated infections. Early diagnosis and effective antifungal therapy often yield a good clinical outcome. A 2- to 6-week course of intravenous amphotericin B is recommended for those with severe penicilliosis marneffei. Intrathecal administration is not recommended for patients with CNS involvement as intravenous administration is often effective. After the patients are stabilised, they can be switched to oral itraconazole or ketoconazole for 10 weeks. Long-term medication with itraconazole is recommended for patients to avoid relapse of the disease and negative blood or bone marrow culture cannot be bases for discontinuing the medication. The 1 st patient in this case report relapsed after premature termination of medication and intravenous amphotericin B liposome was used.
In conclusion, with the increase in incidence of penicilliosis marneffei in both immunocompromised and immunocompetent hosts, penicilliosis marneffei should be considered in patients with systemic infections and should be aggressively managed with antifungal therapy.
| ~ References|| |
Hu Y, Zhang J, Li X, Yang Y, Zhang Y, Ma J, et al
. Penicillium marneffei infection: An emerging disease in mainland China. Mycopathologia 2013;175:56-67.
Zhao GQ, Ran YP, Xiang Y. Penicillium marneffei infection in the mainland of China: A systematic review on its clinical and epidemiological features. Chin J Mycol 2007;2:68-72.
Nittayananta W. Penicilliosis marneffei: Another AIDS defining illness in Southeast Asia. Oral Dis 1999;5:286-93.
Ustianowski AP, Sieu TP, Day JN. Penicillium marneffei infection in HIV. Curr Opin Infect Dis 2008;21:31-6.
Vanittanakom N, Cooper CR Jr, Fisher MC, Sirisanthana T. Penicillium marneffei infection and recent advances in the epidemiology and molecular biology aspects. Clin Microbiol Rev 2006;19:95-110.
Wu TC, Chan JW, Ng C, Tsang DN, Lee M, Li PC. Clinical presentations and outcomes of Penicillium marneffei infections: A series from 1994 to 2004. Hong Kong Med J 2008;14:103-9.
Antinori S, Gianelli E, Bonaccorso C, Ridolfo AL, Croce F, Sollima S, et al.
Disseminated Penicillium marneffei infection in an HIVIVositive italian patient and a review of cases reported outside endemic regions. J Travel Med 2006;13:181-8.
Hamilton AJ, Jeavons L, Youngchim S, Vanittanakom N, Hay RJ. Sialic acid-dependent recognition of laminin by Penicillium marneffei conidia. Infect Immun 1998;66:6024-6.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]