A case report of coinfection with Penicillium marneffei and Mycobacterium tuberculosis in a 29-year-old male patient who was diagnosed with Immune Thrombocytopenic Purpura and received oral Prednisolone since 6 months. Patient was successfully treated with Inj Amphoptericin B and oral Itraconazole and completed concomitant anti-tuberculous therapy. To the best of our knowledge this is the first case of Penicillium marneffei and Mycobacterium tuberculosis co infection reported in a HIV negative host. The current case report highlights the importance of clinician awareness of concurrent infections with Penicillium and other pathogens in immunocompromised patients.
T. marneffei, a temperature-dependent dimorphic fungus previously known as Penicillium marneffei, is an important pathogen of HIV-associated opportunistic infection in endemic areas. It was first isolated from liver of the bamboo rat (Rhizomys sinensis) in 1956, and subsequently from an HIV-infected human in 1988. In endemic areas, which include Southeast Asia, Southern China, Hong Kong, north east India, and Taiwan, T. marneffei can cause fatal disseminated infection in immunocompromised hosts by inhalation of fungal conidia into the lungs.
Concomitant infection with T. marneffei and other opportunistic pathogens is plausible because the majority of cases of severe mycosis due to T.marneffei occur in patients with advanced HIV infection with CD4+ T cell count below 100 cells/microlitre. But in a non HIV patient T. marneffei infection is very rare with concomitant tuberculous infection. The diagnosis and treatment is challenging in the clinical setting. In the current case report, a concurrent infection with T.marneffei and mycobacterium tuberculosis-isolated from bronchial wash, in a young male patient who was HIV negative. A literature review was performed to provide new insight into treatment of this rare concurrent infection.
A 29-year-old gentleman, working as a salesman at a Maruti showroom, presented with fever of 1-month duration with evening rise of temperature, cough for 1 month, which was productive with mucopurulent sputum, breathing difficulty for 1 month, initially grade 1 mMRC and later progressed to grade 3 in 1 week, with history of loss of appetite and loss of weight. 10 years back he had an episode of Cerebral Venous Thrombosis and was treated with Warfarin at that time and later discontinued treatment. 6 months back he had an episode of focal seizure and was started on Sodium Valproate since then and also found to have high homocysteine level and he was started on tab Dabigatran. At that time he was diagnosed with ITP and since then he is taking tab Wysolone 30mg. The patient had no recent or direct contact with specific plants including rotten sugar canes nor has a recent travel history. On presentation patient was febrile, conscious oriented, had hypotension and bilateral pedal oedema, on auscultation of chest there were coarse inspiratory crepts on right infra scapular and infra axillary areas, all other system examinations were unremarkable. Initial investigations showed CRP:154.3mg/ litre, Total Count :10k/microlitre, Platelet count:130K/micro litre, LFT: Total bilirubin: 1.20/SGOT:101/SGPT:73, Protein 5.1, Albumin:2.7, RFT was normal, PT INR - 1.41. Initial chest Xray and HRCT Thorax showed bilateral miliary nodules.
He was started on Inj Cefoperazone sulbactam empirically and other supportive measures. His blood pressure was not maintaining at steady level, he was put on 100mg Hydrocortisone stress dose of steroids after consulting with Endocrinologist. As his LFT was deranged Sodium Valproate was changed to Levetiracetam after consulting with Neurologist. His blood and sputum culture showed no growth. So, it was decided to do Bronchoscopy and TBLB 3 days following admission after stopping oral anticoagulants.
BAL smear was positive for Acid Fast Bacilli and in GENE EXPERT MTB was detected(low) with no rifampicin resistance. BAL CYTOLOGY showed Acid Fast Bacilli in the cell block sections and fungal elements on special stain, which showed yeast cells and hyphae.
TRANSBRONCHIAL LUNG BIOPSY:
Showed chronic granulomatous inflammation; consistent with Tuberculosis. He was started on Modified ATT as his LFT was deranged. But after 2 days of starting ATT, patient’s condition deteriorated, he had frequent fever spikes and there was drop in saturation level to 85% at room air. ABG was done which showed Type 1 respiratory failure. Due to suspicion of secondary infection a repeat CRP was done which was increased to -188. Then he was started on Inj Meropenem and steroid dose was reduced to 20 mg. Repeat chest Xray showed bilateral diffuse infiltrates. He started coughing out yellowish mucopurulent sputum with brownish specs. At that time the bronchial wash fungal culture report came and it showed growth of Pencillium.
So, it was decided to start Inj Amphotericin B 150mg iv once daily in 500ml (due to financial constrains liposomal amphotericin was not given). After 2 days of amphotericin B, patient improved clinically, fever spikes decreased and oxygen saturation improved. Serial RFT monitoring was done and amphotericin injection was continued for 14 days. His LFT improved and there was reduction in CRP. Repeat chest Xray showed some clearance with right side minimal pleural effusion.
He was discharged with modified antitubercular drugs (Tab R-Cinex 300/450 mg od/Tab Levofloxacin 750mg od/Tab Ethambutol 800 mg od) and Tab Wysolone 10 mg. He was advised to continue Itraconazole 200 mg tid (higher dose to counter interaction with Rifampicin) for 2 months. Patient continued ATT with serial LFT monitoring and his chest Xray showed complete resolution after 1 month of treatment.
Although coinfection of T. marneffi with other opportunistic pathogens is plausible as T. marneffei infection mostly occurs in immunocompromised hosts, reports of co infection are scarce. In a case series that reviewed 24 patients with T. marneffei infection, two HIV-negative patients were coinfected with disseminated M. intacellulare and M. fortuitum, respectively. Clinical presentation of these disseminated infections may mimic each other, and a proper diagnostic approach is necessary to avoid insufficient treatment. From this point of view, we think that the present case is clinically informative. On thorough literature search we could not find any case of Mycobacterium tuberculosis and Penicillium marneffei co infection in a non HIV patient. Some investigators have demonstrated that non-HIV hosts without any immunosuppressant may have impaired cell-mediated immunity, resulting from the derangement of cytokine cascades, including overproduction of suppressive cytokine, interleukin (IL)-10, and cytokine deficiency in the IL-12/interferon-g pathway.
There is a significantly seasonal variation in infection rates of Penicillium, with an increased incidence in the rainy season. Some investigators have suggested that soil exposure, especially during the rainy season, is a critical risk factor associated with infection by P. marneffei.
The most common presentation of T. marneffei infection is fever and weight loss, occurring in more than 75% of patients. Other manifestations are anaemia, skin lesions, lymphadenopathy, hepatomegaly, and pulmonary disease, in decreasing order of frequency. Skin lesions are seen in 71% of patients, and include generalized papules, central umbilicated papules, and acne-like lesion. In our case there was lung and liver involvement. Patient also had hypoalbuminemia and anaemia.
Here we reported a case involving a healthy host without HIV infection but who was on steroid therapy for ITP developed Penicillium coinfection with TB.
P.marneffei grows as yeast bodies inside phagocytes. Immunosuppression after infection is a commonly encountered problem in affected patients. Causes of immune depletion may include prednisolone therapy, initial misdiagnosis, and disease progression. Because of the long duration of prednisolone therapy in the present case, the P.marneffei infection is associated with high mortality because it is commonly misdiagnosed in the early stages.
P.marneffei is identified by culture and pathological examination. P.marneffei grows as a yeast at 37°C, but as a mold at 25°C on Sabouraud dextrose agar, exhibiting a soluble red pigment that diffuses into the medium. The yeast form of PM has a characteristic morphology, including a transverse septum and sausage-shaped organisms that can be demonstrated by pathological and cytological examination.
Tuberculosis is the most common misdiagnosis for the following reasons: (i) relevant literature and research on PM are limited; (ii) PM has been strongly emphasized as a common opportunistic infection of patients with AIDS; (iii) the signs, lung imaging findings and pathological examination results are similar to those of tuberculosis; and (iv) in the early stages, there is a low concentration of viable lesions and a low culture positive rate.
PM infection in normal hosts is characterized by an insidious onset, various clinical manifestations, and common misdiagnosis, leading to high mortality rates. Fortunately our patient was a young male with no HIV infection and with only lung and liver involvement and he was successfully treated with antifungals and he completed 6 months of ATT without further worsening of LFT and eventually he was cured.
1. Chitasombat M, Supparatpinyo K: Penicillium marneffei infection in immunocompromised host. Curr Fungal Infect Rep 2013, 7:44–50.
2. Hu Y, Zhang J, Li X, Yang Y, Zhang Y, Ma J, Xi L: Penicillium marneffei infection: an emerging disease in mainland China. Mycopathologia 2013, 175(1–2):57–67.
3. Le T, Huu Chi N, Kim Cuc NT, Manh Sieu TP, Shikuma CM, Farrar J, Day JN: AIDS-associated Penicillium marneffei infection of the central nervous system. Clin Infect Dis 2010, 51(12):1458–1462.
4. Zhang JQ, Yang ML, Zhong XN, He ZY, Liu GN, Deng JM, Li MH: A comparative analysis of the clinical and laboratory characteristics in disseminated Penicillium marneffeii patients with and without human immunodeficiency virus infection. Chin J Tuberc Respir Dis 2008, 31(10):740–746.
5. Wong SS, Wong KH, Hui WT, Lee SS, Lo JY, Cao L, Yuen KY: Differences in clinical and laboratory diagnostic characteristics of penicilliosis marneffei in human immunodeficiency virus (HIV)- and non-HIV-infected patients. J Clin Microbiol 2001, 39(12):4535–4540.
6. Ustianowski AP, Sieu TP, Day JN: Penicillium marneffei infection in HIV. Curr Opin Infect Dis 2008, 21(1):31–36.
7. Yousukh A, Jutavijittum P, Pisetpongsa P, Chitapanarux T, Thongsawat S, Senba M, Toriyama K: Clinicopathologic study of hepatic Penicillium marneffei in Northern Thailand. Arch Pathol Lab Med 2004, 128(2):191–194.
8. Kummasook A, Cooper CR Jr, Sakamoto A, Terui Y, Kashiwagi K, Vanittanakom N: Spermidine is required for morphogenesis in the human pathogenic fungus, Penicillium marneffei. Fungal Genet Biol 2013, 58–59:25–32.
9. Luo DQ, Chen MC, Liu JH, Li Z, Li HT: Disseminated Penicillium marneffei infection in an SLE patient: a case report and literature review. Mycopathologia 2011, 171(3):191–196.
10. Jan IS, Chung PF, Wang JY, Weng MH, Hung CC, Lee LN: Cytological diagnosis of Penicillium marneffei infection. J Formos Med Assoc 2008, 107(6):443–447.
11. Cao C, Liu W, Li R, Wan Z, Qiao J: In vitro interactions of micafungin with amphotericin B, itraconazole or fluconazole against the pathogenic phase of Penicillium marneffei. J Antimicrob Chemother 2009, 63(2):340–342.
12. Sirisanthana T, Supparatpinyo K, Perriens J, Nelson KE: Amphotericin B and itraconazole for treatment of disseminated Penicillium marneffei infection in human immunodeficiency virus-infected patients. Clin Infect Dis 1998, 26(5):1107–1110.