Disseminated Talaromyces marneffei infection initially presenting as cutaneous and subcutaneous lesion in an HIV-Negative renal transplant recipient: a case report and literature review

Talaromyces marneffei (T. marneffei), initially named Penicillium marneffei, was isolated from the liver of bamboo rats [1]. It is currently the only known pathogenic thermally dimorphic fungus in the genus Penicillium. Specifically, it forms white or brownish yeast-like colonies at 36 °C, while it grows in a mold form at 28 °C. Characteristically, the colonies of T. marneffei exhibit a “broom-like” structure, and produce a soluble wine-red pigment that diffuses into the agar at 28 °C [2]. T. marneffei infection can be classified into localized and disseminated types, which are associated with the functional status of the host immune system. Disseminated T. marneffei infection usually involves the liver, spleen, lymph nodes, intestines, and soft tissues, resulting in a high mortality rate [3].

T.marneffei is generally thought to be the most common opportunistic fungal infection among acquired immune deficiency syndrome (AIDS) patients in South China and Southeast Asia [4]. In recent years, with the development of organ transplantation, the widespread use of immunosuppressive agents, and the continuous exploration of related autoantibodies or gene mutations, the immunodeficient population has increased significantly, leading to a growing incidence of talaromycosis caused by T. marneffei infection. However, missed diagnosis and misdiagnosis are not uncommon because talaromycosis is rare with occult onset, diverse clinical manifestations and diverse radiographic manifestations [5]. Moreover, talaromycosis is often associated with many complications, resulting in complex treatment and serious side effects. Hence, the prognosis of T. marneffei is usually poor, with rapid progression and a high mortality rate. Here, we report a case of disseminated T. marneffei infection in an HIV-negative renal transplant recipient from non-endemic area with an initial presentation of skin rash and subcutaneous nodule for the first time. It’s also the second case of T. marneffei infection in a kidney transplant recipient who developed rare gastrointestinal bleeding. Additionally, we summarized the characteristics of T. marneffei in diagnosis and treatment, and especially presented the dangerous gastrointestinal bleeding in T. marneffei-infected kidney transplant patients in combination with the relevant literature.

A 54-year-old male was admitted to the hospital on August 6, 2022, due to swelling and pain in his right hand after a crushing injury. The patient reported that over a year ago, he gradually developed scattered rashes and subcutaneous nodules throughout his body, mainly concentrated on the head, face, abdomen, and right upper limb. The patient had neither fever, cough, or sputum production nor abdominal pain, diarrhea, headache, chest pain, or hemoptysis. The patient had undergone renal transplantation 11 years prior due to uremia induced by idiopathic membranous nephropathy and was chronically treated with immunosuppressive agents and steroids after surgery. The current dosage was tacrolimus 1 mg qm, 0.5 mg qn; prednisone 2 tablets qd; and mycophenolate mofetil (MMF) 1 capsule tid. The patient had a history of hypertension and diabetes but no history of AIDS or tuberculosis. The patient had a 10-year history of hepatitis B and had been undergoing long-term antiviral treatment with adefovir dipivoxil at a dosage of 10 mg per day.

The breath sounds were coarse in both lungs, and a few wet rales could be heard in the right lower lung. There were no murmurs or additional heart sounds in the auscultation areas of each valve. Subcutaneous nodules were scattered throughout the body and partially ulcerated. There was no palpable enlargement of the superficial lymph nodes, bilateral tonsils, subcostal liver/spleen, or percussion pain in the bilateral renal regions. A lung computed tomography (CT) scan showed multiple nodules in the bilateral lungs, inflammation in the bilateral lower lobes, and thickened pleura in the right side. Mediastinal lymph nodes were not obviously enlarged (Fig. 1).

Blood routine test results suggested white blood cell (WBC), 11.43 × 10⁹/L; hemoglobin (Hb), 97 g/L; and C-reactive protein (CRP), 17.01 mg/L. Abnormal biochemistry results were as follows: alanine aminotransferase (ALT), 5 U/L; aspartate aminotransferase (AST), 7 U/L; prealbumin (PA), 115 mg/L; urea, 23.6 mmol/L; blood creatinine (Cr), 251 µmol/L; glucose, 12.8 mmol/L. Abnormal coagulation routine test results were as follows: von Willebrand Factor (vWF), 334%; Antithrombin III (ATIII), 76%.

According to the imaging report (necrotizing fasciitis of the right hand and right elbow, purulent arthritis of the right hand, soft tissue infection of the right chest wall), the patient received abscess drainage, fasciotomy and decompression surgery on August 8th (Fig. 2). At the same time, the ruptured tissue was sent for bacterial culture and identification. The incubation was at 35℃, using blood agar and MacConkey agar. On August 9th, a morphology of mycelia was observed, and lactophenol cotton blue staining suggested “Penicillium”, which we considered a contaminant. Due to the patient’s skin rupture and exposure to air, other bacterial or fungal infections could not be ruled out. Subsequently, the cultivation of fungi was on sabouraud dextrose agar at 28℃ and 35℃ simultaneously. Later, the colonies incubated at 28℃ turned red. Although T. marneffei infection in a non-HIV renal transplantation recipient from a nonendemic area is rarely observed, this still raised our concern. Thus, we sent samples from multiple affected areas of the patient (hands, elbows, chest) for microbiological testing on August 15th. The pathogen growed in the filamentous form at 28℃ and in the yeast form at 35℃, which confirmed T. marneffei infection (Fig. 3), which was consistent with the mass spectrometry results. The chest histopathological results showed chronic suppurative inflammation with a large number of yeast-like cells with central septa, foam cell aggregation, and focal necrosis (Fig. 4), which further confirmed the result of the microbiological identification.

The laboratory features were getting worse, with a CRP level of 149.18 mg/L; a procalcitonin (PCT) level of 6.65 ng/ml; a hemoglobin (Hb) level of 65 g/L; a platelet count of 101 × 10⁹/L. The coagulation routine test results revealed prothrombin time (PT), 18.1s; activated partial thromboplastin time (APTT), 45.2s; prothrombin activity (PTA), 47%; and D-Dimer, 1.11 µg/mL. Considering the elevated neutrophils and C-reactive protein (CRP) level, piperacillin tazobactam (4.5 g/8 h) was given for antibacterial treatment. Due to the severity of the infection, oral prednisone was discontinued, tacrolimus and MMF remained at original dosage. Amphotericin B deoxycholate (initial dose: 0.5 mg/kg/d, therapeutic dose: 1.0 mg/kg/d) was given for antifungal treatment. On August 24th, the patient had melena (approximately 800 mL/d) and was diagnosed with gastrointestinal bleeding. This might have been caused by T. marneffei involvement in the gastrointestinal mucosa. At the same time, the side effects of amphotericin B in the gastrointestinal tract were also related [6, 7]. On the night of August 25th, the patient experienced abdominal pain. Emergency abdominal CT revealed free gas in the abdominal cavity and gas density shadows around the liver and abdominal cavity, indicating gastrointestinal perforation and acute peritonitis. The patient underwent surgical repair of the intestine. The antibiotics were changed to ertapenem (1 g, qd), and Adefovir was discontinued. Over the next two days, the platelet count gradually decreased, and the levels of CRP and procalcitonin (PCT) were abnormally elevated. However, the serum creatinine level remained between 206 and 260 µmol/L, and the liver function indicators aspertate aminotransferase (AST) and alanine aminotransferase (ALT) did not significantly increase. The dose of MMF was adjusted to 1 capsule bid. Furthermore, maltose-fermenting Pseudomonas aeruginosa was cultured from sputum, Burkholderia cepacia was cultured from blood, and Enterobacter cloacae and Pseudomonas aeruginosa were cultured from ascites. Subsequent blood metagenomic next-generation sequencing (mNGS) reported T. marneffei (341), cytomegalovirus (153), parvovirus (43), herpes simplex virus 1 (HSV1) (15), and epstein-barr virus (EB) (16). Clinically, ertapenem was replaced, and meropenem and ganciclovir were used for antibacterial and antiviral treatment, respectively. The dose of MMF was adjusted to 1 capsule qd for nasal feeding. Unfortunately, the patient soon developed acute respiratory failure, multiple organ dysfunction syndrome (circulatory, renal, hematological, coagulation), shock and hepatic encephalopathy. Finally, the patient’s family members abandoned treatment and requested discharge. One month later, during follow-up, the patient died after failed cardiopulmonary resuscitation.

As one of the most common opportunistic infection in patients with AIDS, T. marneffei infection has been increasingly reported as a coinfection in non-HIV populations, such as those with malignancy, organ transplantation, autoimmune diseases, etc. Due to the different mechanisms of immunodeficiency in T. marneffei patients, the clinical manifestations are often varied and complex. The most common symptoms include fever (82%), skin lesions (40.7%), hepatosplenomegaly (32%), and lymphadenopathy (33.3%). In addition, approximately one-third of patients experience gastrointestinal symptoms such as diarrhea [8]. Due to the lack of specificity in clinical indicators, the misdiagnosis rate is high. Furthermore, talaromycosis is a dangerous and rapidly progressive disease with a high mortality rate because T. marneffei can invade almost all systems and organs, including the lungs, liver, bones, and blood, and the side effects of treatment drugs are severe.