Two cases of Talaromyces marneffei tracheobronchial infection in HIV-negative patients

Abstract

AbstractSection Objectives

In recent years, the incidence and prevalence of Talaromyces marneffei (TM) have been on the rise. This infection predominantly affects immunocompromised or immunodeficient individuals, especially those with acquired immunodeficiency syndrome (AIDS). There has been a notable increase in the incidence of TM and its associated infections. The majority of cases occur within immunocompromised or immunodeficient populations, with a high prevalence among AIDS patients. However, cases are also occasionally detected in HIV - negative individuals. Due to the insidious and slow - growing nature of TM, the disease can be misdiagnosed as other conditions such as tuberculosis, bacterial pneumonia, and lung cancer, particularly in non - endemic regions. Such misdiagnosis significantly impacts the patient’s prognosis.

AbstractSection Methods

Two HIV-negative patients with TM infection from non - endemic areas were hospitalized with a high suspicion of co-infection with lung cancer and poor symptomatic treatment response. These patients underwent a comprehensive diagnostic workup, including lung puncture biopsy, sputum, blood, pleural, and peritoneal fluid cultures, as well as Metagenomics Next Generation Sequencing (mNGS) analysis. Eventually, both patients were diagnosed with TM tracheobronchial infection.

AbstractSection Results

The patients were treated with voriconazole antifungal therapy, combined with methylprednisolone (used for reducing inflammation, relieving spasms, and treating asthma) and acyclovir (used for treating viral infections). The 49 - year - old patient was cured and discharged from the hospital, while the 79 - year - old male patient’s condition continued to deteriorate, and he ultimately died.

AbstractSection Conclusion

It has been determined that TM infection, presenting primarily with respiratory symptoms, is highly susceptible to misdiagnosis in the early stages of the disease. This can lead to treatment delays and a negative impact on the prognosis. It is crucial for medical professionals to be more aware of the possibility of TM infection in non - HIV - infected and non - endemic populations. Collecting respiratory and lung tissue specimens from the infection sites at the earliest possible stage is essential for diagnosing TM infection. Integrating mNGS and mass spectrometry results is crucial for improving the detection and early diagnosis of TM infection, which is of great value for enhancing the efficacy of clinical treatment and the prognosis of patients.

AbstractSection Clinical trial number

Not applicable.

Introduction

Talaromyces marneffei (TM) initially named Penicillium marneffei, was isolated from the liver ofbamboo rats [1]. TM is a thermally dimorphic fungus endemic to northern Thailand, Vietnam, Myanmar, southern China, and northeastern India [2]. It is noteworthy that TM is the only known pathogenic thermotropic fungus in the genus Penicillium, with mortality rates ranging from 8 to 40% in Guangxi Province, China [3]. TM is a biphasic fungus, which means it has two phases. In the first phase, which occurs at 28 °C, the fungus grows as a mycelial network. In the second phase, which occurs at 35 °C, the fungus produces a white or brown yeast. Mycelial phase colonies are downy, velvety, and yellow-green or gray-green. They have broom-like branches and conidial chains. The fungus produces a wine-red pigment that can diffuse into the agar [1].

It has been determined that the human immunodeficiency virus (HIV) poses a significant risk factor for TM disease, accounting for 16% of all HIV-related hospitalizations in South-East Asia. The symptoms of the disease are nonspecific, which can lead to delays in diagnosis and treatment, and consequently, increased mortality rates [4]. In recent years, several factors have led to a significant rise in the number of immunocompromised individuals. These include the aging population, the widespread use of immunosuppressive drugs, and ongoing research into associated autoantibodies or genetic mutations. This increase has resulted in a growing number of TM infections among non-HIV-infected patients. The respiratory system is the most frequently and earliest affected in cases of TM infection, accounting for approximately 66.7% of cases. These infections are often mistaken for tuberculosis or lung cancer [5]. Currently, clinical reports of tracheobronchial TM infection are exceedingly rare. The condition is characterized by several factors, including its insidious onset, varied presentations, and high rates of misdiagnosis due to its non-specific symptoms. Additionally, the disease is notable for a high complication rate, complex treatment requirements, and rapid progression that often leads to high mortality [1]. Clinical inexperience resulting in delayed or misdiagnosis is a significant contributor to high mortality rates among non-HIV-infected and non-endemic populations. The current study reports two unusual cases of TM tracheobronchial infection in non-HIV-infected and non-endemic patients with strong suspicion of lung cancer.

Case report 1

A 79-year-old male patient presented with a cough, expectoration of yellow mucus, fever with a maximum temperature of 39.2 °C, and poor mental health due to cold exposure one month earlier. The local hospital diagnosed a right upper lung tumor with right hilar and mediastinal lymph node metastasis, combined with infection. However, the administration of symptomatic anti-infective treatment proved ineffective, necessitating a transfer to our hospital for further management. The patient was noted to be alert, but exhibited symptoms of poor mental health.There was no record of previous travel, and the results of the HIV test were negative. On the first day of admission, the patients vital parameters were as follows: temperature 37.2 °C, heart rate 87 beats/min, respiratory rate 22 beats/min, blood pressure 123/73 mmHg.The presence of infectious indicators was significantly elevated, as indicated by the following measurements: C-reactive protein (CRP) 128.00 mg/L, interleukin 6 (IL-6) 77.88 pg/ml, procalcitonin (PCT) 0.13 ng/ml, white blood cell count (WBC) 23.57 × 10^9/L, and neutrophilic nucleated granulocyte percentage (N%) 82.4%. The patient’s immunological indexes revealed elevated levels of IgA (4140.00 mg/L), IgE (224.00 IU/ml), and IgG (17.20 g/L), while IgM (454.00 mg/L), CD3 (46.10%), CD4 (34.40%), and CD8 (10.10%) were decreased (Table 1).His additional serum tumor markers, Mycobacterium tuberculosis, Aspergillus, and fungus were all negative. On the 2nd day of admission, the chest enhanced Computed Tomography(CT) of the patient showed: lung cancer in the upper lobe of the right lung with obstructive pneumonia and pulmonary atelectasis, and lymph node metastasis in the right hilar and mediastinal lung ( Fig. 1A and D).The patient was treated with piperacillin sodium and tazobactam sodium, along with ambroxol to reduce phlegm, as part of symptomatic empirical treatment, which proved ineffective.

Table 1 Results of laboratory test indicators at different time points during treatment of patient case 1

Fig. 1

(A-D)The enhanced CT scan of the chest in Case 1 shows the presence of a lung cancer lesion in the upper lobe of the right lung, accompanied by obstructive pneumonia and atelectasis. Moreover, it reveals right hilar and mediastinal lymph node metastases

On the third day of admission, the patient underwent fiberoptic bronchoscopy, which revealed infiltrative bronchial stenosis in the apical segment of the upper lobe of the right lung, with infiltrative neoplastic nodules at the openings, indicative of right lung cancer (Fig. 2A and B).The brush film from fiber-optic microscopy revealed a substantial presence of neutrophils and detached bronchial mucosal epithelial cells. The lung puncture biopsy indicated chronic pyogenic inflammation. Chest ultrasonography showed an abundance of fluid in the pleural cavity on both sides of the mediastinum. Approximately 700 milliliters of yellowish-clear pleural effusion was extracted and sent for analysis.The initial sputum and pleural fluid cultures of the patient yielded C.albicans; however, the results were negative for tuberculosis, with no malignant cells detected. Consequently, the patient was treated with antifungal therapy, primarily fluconazole.

Fig. 2

(A-B) In Case 1, fibreoptic bronchoscopy demonstrated infiltrative stenosis of the bronchus in the apical segment of the right upper lobe. In addition, infiltrative neoplastic nodules were observed at the openings, highly suspicious of right lung cancer.(C-D) In Case 2, fibreoptic microscopy revealed localised granulomatous hyperplasia of the right upper lobe bronchus, with luminal narrowing, granulomatous elevation with ulcer - like changes, and mucosal swelling

On the fifth day of admission, sputum, bronchoalveolar lavage fluid, blood culture and pleural fluid specimens were dispatched for examination. Among them, the sputum smear revealed the presence of “one river, two banks” fungal spores, which were suspected to be TM (Fig. 3A). Following the positive results of the blood and pleural fluid cultures, red mycelium was observed under Gram staining (Fig. 3B). Finally, the sputum, bronchoalveolar lavage fluid, blood culture and pleural fluid of the patient were cultured positive for the fungus, which was identified as TM by by Bruker Matrix-assisted laser desorption ionization tandem time-of-flight mass spectrometer(MALDI-TOF MS) (Fig. 4). The growth of TM was observed in a filamentous form at 28 °C (Fig. 3C and D), and in a yeast-like form at 36 °C (Fig. 3E). The lactophenol cotton wool blue stain exhibited a dark blue colouration (Fig. 3F). The combination of these findings and clinical features resulted in a diagnosis of TM tracheobronchopulmonary infection mixed with C.albicans infection.The patient received symptomatic treatment consisting of voriconazole (300 mg/day, Intravenously, IV), an antifungal agent, methylprednisolone, an anti-inflammatory agent, an antispasmodic agent, and asthma medication for a period of 10 days. On the fifteenth day of admission, the patient exhibited a slight decrease in infection indicators and blood cultures were negative. However, subsequent sputum culture analysis revealed the presence of C.albicans and TM, with a minor pleural effusion observed on both sides. The patient exhibited a worsening of symptoms during nighttime hours, and the results of the chest enhanced CT scan did not demonstrate significant improvement.

Fig. 3

(A) Gram staining of a sputum smear revealed dachshund - like yeast - like cells with a central septum. (B) The results of blood and pleural fluid cultures were positive, and red mycelium was visible microscopically upon Gram-staining. (C) Talaromyces marneffei shows filamentous growth at 28°C. (D) At 36°C,Talaromyces marneffei exhibits yeast-like characteristics. (E) PTalaromyces marneffei stains dark blue in lactophenol cotton blue

Fig. 4

The Bruker MALDI-TOF MS analysis yielded a score of 2.3, identifying the organism as Talaromyces marneffei

On the 18th day of admission, the condition of the patient suddenly worsened, with symptoms including shortness of breath, impaired consciousness and respiratory failure. The patient was resuscitated. On the 20th day of admission, the condition of the patient continued to worsen, and he was given non-invasive ventilator-assisted respiratory therapy and transferred to the Respiratory Intensive Care Unit (RICU). There, he was given antibacterial piperacillin and tazobactam (4.5 g/8 h, IV) and antifungal amphotericin B (1.0 mg/d, IV) as symptomatic treatments. On the 21st day of admission, the patient exhibited symptoms of progressive anaemia, thrombocytopenia, coagulation dysfunction, and impaired liver function, accompanied by increased bilirubin levels. On the 23rd day of admission, the patient began to exhibit elevated BNP and increased TPN-T levels, accompanied by paroxysmal atrial fibrillation. In response, the patient was administered cediran to regulate ventricular rate. On the 25th day, the patient exhibited severe acute kidney injury to anuria, and was placed on bedside continuous haemodialysis. On the 28th day of admission, the results of the alveolar lavage fluid test revealed the presence of Human Cytomegalovirus infection (9.97E + 03 copies/ml) by real-time quantitative PCR. On the 29th day of hospitalisation, a chest CT review revealed that the condition of both lungs had deteriorated.

On the 30th day of admission, following a departmental discussion and a synthesis of the overall situation of the patient, a change of treatment was initiated. The patient was switched to itraconazole (200 mg/qd, orally) antifungal, ganciclovir (250 mg/d, IV) antiviral therapy, and gammaglobulin shock treatment for a period of four days. However, there was no significant improvement in the state of the patient, and her temperature continued to fluctuate at 38 °C. On the 35th day of hospitalisation, the patient exhibited severe systemic multi-organ failure and accelerated deterioration of his condition, ultimately succumbing to failure to rescue. The timeline illustrating the entire treatment process of the patient is presented in Fig. 5.

Fig. 5

The key points in the treatment of the patient in case 1 are shown as a time line

Case report 2

A 49-year-old female patient presented with a cough, expectoration of yellow pus, and fever, with a maximum temperature of 39.5 °C, over the course of three months. The patient exhibited symptoms of chest tightness, chest pain, and dyspnea. The patient was hospitalized at the local county hospital for a period of three days, where a diagnosis of primary bronchopulmonary cancer of the right upper lung was made, accompanied by metastasis to the right lung hilum, mediastinum, bilateral supraclavicular fossa lymph nodes, and pleura. The patient also presented with obstructive pneumonia. Despite undergoing anti-infection therapy and other treatments, the symptoms exhibited by the patient did not show significant improvement, necessitating transfer to our hospital for further treatment.

The patient presented at the hospital with an acutely severe illness, anemia, malnutrition, and multiple enlarged lymph nodes measuring approximately 1 cm on the right side of the neck. The lymph nodes exhibited a medium texture and good mobility. The right lung was dull to percussion, and the breath sounds from the right lung were harsh. Extensive wet rales were audible. There was pitting edema in both lower limbs, with the right side being more pronounced than the left.The patient has no history of traveling to areas where AIDS is endemic.On the first day of admission, the patient was admitted for further investigations, and the results of the HIV test were negative. HGB 57 g/L, PLT 234 × 10^9/L, WBC 14.45 × 10^9/L, N 77.3%, CRP 128.00 mg/L, PCT 0.38 ng/ml. CD3 723 cells/µL, CD4 287 cells/µL, CD8 379 cells/µL (Table 2). The patient tested positive for fecal occult blood but negative for fungal (1,3)-β-D-Glucan Test(G), Galactomannan Antigen Test(GM), Interferon-Gamma Release Assay(IGRA), and blood cultures. Following admission, the patient received imipenem for anti-infection, and symptomatic supportive management such as expectoration, antipyretic, nutritional supplementation, human albumin supplementation, blood transfusion, and diuresis. On the second day of admission, the enhanced chest CT scan of the patient showed a soft tissue shadow in the upper lobe of the right lung with part of the bronchial lumen encircled and narrowed.The right lung had multiple nodules, ground-glass opacities, patchy opacities, and striations. Some of these lesions exhibited poorly demarcated margins, with vacuolated shadows.Additionally, some of the aforementioned lesions are mediastinal in location, with an increase in size and uneven enhancement of the mediastinal, cervical root, and right lung hilar lymph nodes. The presence of a tumor lesion with an obstructive pneumonia infection has been considered above. The patient exhibited minor fluid accumulation in the right pleural cavity, accompanied by suspicious nodular changes in the pleura of the right upper lung, indicating potential pleural metastases. Nodular shadows were observed in the left lung, and the left third transverse rib showed signs of bone destruction.A soft tissue shadow is also observed in the surrounding area, along with ring enhancement and a minor amount of pericardial effusion (Fig. 6). On day 7 of admission, the fiberoptic examination of the patient revealed congested and slightly swollen tracheal mucosa, granulomatous nodules, swollen rales, narrowed lumens with granulomatous hyperplasia, and ulceration (Fig. 2C and D). The fiberoptic biopsy of the patient revealed chronic active inflammation of the bronchial mucosa, accompanied by focal erosions and inflammatory granulation tissue hyperplasia.On the 9th day of admission, the sputum fungal culture and mass spectrometry results were reported as TM.The mNGS approach was employed for the DNA testing of alveolar lavage fluid, the results of which are delineated in Table 3. The sequencing results revealed the presence of TM, with a sequence number of 888, and human herpesvirus type 4 (EBV), with a sequence number of 16 (Table 3). However, the alveolar lavage bacterial culture was negative. Combining the above culture and mNGS findings and clinical features, the patient was finally diagnosed with TM infection.The patient was treated with oral antifungal therapy, comprising voriconazole (200 mg twice daily) for a duration of seven days, after which imipenem was discontinued. The temperature of the patient returned to normal and the indicators related to bacterial infection decreased, but the alveolar lavage fluid and sputum fungal culture still cultured TM.

Table 2 Results of laboratory test indicators at different time points during the treatment of case 2 patients

Table 3 Results of mNGS testing of specimens during the treatment of the patient in case 2

Fig. 6

(A-D) In Case 2, the contrast - enhanced CT images of the patient’s chest revealed an obstructive pneumonia infection presenting as a tumourous lesion. The right pleural cavity showed a minimal amount of fluid accumulation, while the pleura of the right upper lung exhibited suspicious nodular changes and pleural metastases, necessitating drainage

On the 16th day of hospitalization, chest CT was reviewed, suggesting insignificant absorption of the right lung lesion, increased pleural effusion on the right side, and a few new lesions in the left upper lung. Abdominal CT showed intrahepatic lymphatic stasis, swelling of the gallbladder wall; swelling of the sigmoid colon, rectal wall, abdominopelvic wall and its peripheral interstitial space, subcutaneous effusion in the lumbosacral region, and part of the intestinal interstitial space was poorly visualized.Following admission, the patient has developed multiple subcutaneous nodules on the face and limbs. The texture of the nodules is described as medium, and some of them exhibit a reddish hue. The nodules are noted to be slightly painful to the touch. There was a high level of clinical suspicion regarding the potential for a systemic disseminated infection of a TM.On the 21st day of admission, the patient underwent thoracocentesis to extract pleural fluid and send it for culture and examination. The results of this examination revealed an increase in the number of lymphocytes and hyperplastic mesothelial cells, while the culture and smear results of the pleural fluid were negative for pathogenic bacteria. On the 25th day of admission, following the commencement of active treatment, the CT review revealed a significant reduction in the size of the right lung lesion when compared with the previous one. On the 27th day of admission, the results of repeat fibreoptic microscopy showed that the right bronchial nodules and granulomatous hyperplasia had significantly improved compared with the previous period, and the surface was smooth and the lumen was patent.On the 29th day of admission, the patient exhibited a decrease in subcutaneous nodules and did not report any fever, chest or back pain, or other discomforts. Consequently, the patient met the criteria for discharge. Subsequent to discharge, the patient was instructed to continue their oral voriconazole (200 mg twice daily) antifungal consolidation therapy for a period of three months. A subsequent review of their chest and abdominal CT scans revealed no obvious abnormalities, no subcutaneous nodules, and no cough or sputum. The patient’s follow-up indicates that they have been successfully treated. The timeline illustrating the entire treatment process of the patient is presented in Fig. 7.

Fig. 7

The key points in the treatment of the patient in case 2 are shown as a time line

Discussion

TM infection is an opportunistic infection characterized by severe invasive disseminated mycosis affecting the trachea, main bronchus, lobar bronchus, and segmental bronchus. The distinctive feature of this condition is the predominance of bronchial involvement over tracheal involvement. Its clinical presentation bears similarities to bronchopulmonary carcinoma, bronchial aspergillosis, and tracheal tuberculosis, which can present a diagnostic challenge due to overlapping symptoms [13]. Compared to the relatively straightforward diagnosis of lung involvement in patients with HIV, identifying tracheobronchial nodulopathy caused by TM infection in HIV-negative individuals presents a significant challenge. This condition has been documented in a limited number of studies and is often misdiagnosed as a lung tumor or tuberculosis. The insidious nature of the disease, the complexity of diagnosis, and the high morbidity and mortality rates contribute to the challenges associated with its management [14]. Currently, there is limited research on the pathogenesis of TM, and numerous factors contribute to the development of HIV-negative TM infection.Common risk factors include advanced age, AIGA (Anti-IFN-γ autoantibody)-related immunodeficiency, autoimmune diseases, the use of glucocorticoids/immunosuppressants, and malignancy [15]. It has been established that a decline in the number of CD4 + T and CD8 + T cells signifies a substantial suppression of CD4 + Th1 and CD8 + T function, consequently leading to the host’s incapacity to eradicate the pathogen and initiate an immune response [6]. In our cases, despite the patient testing negative for both HIV and anti-IFN-γ autoantibodies, there were several predisposing factors, including reduced CD4 and CD8 T-cell counts, advanced age, anemia, malnutrition, and a history of both cold and flu symptoms.Furthermore, the immunoglobulin profiles of IgG, IgA, IgE, and IgM in the two patients demonstrated incomplete consistency in the trend of each index, exhibiting high heterogeneity, which affected the host immune system and increased the risk of infections.The median time from onset to diagnosis in this study was 45 days.The clinical manifestations included fever, cough, yellow pus sputum, and other typical symptoms of limited-access infections [16]. Throughout the infection period, the patient experienced a significant and consistent rise in inflammatory markers, indicating the severity of the illness. Fortunately, the patient was diagnosed and treated promptly, leading to a gradual decrease in these markers and a return to normal levels. It is clear that individuals with HIV-negative TM infections typically manifest symptoms more rapidly, have a faster progression of the infection, a prolonged duration of illness, more severe symptoms, and higher mortality rates compared to those with HIV-positive TM infections [17]. Research has demonstrated that age is a significant susceptibility factor for TM in HIV-negative hosts.Case 1 concerns an elderly patient suffering from restrictive lung infection.Despite effective control and stabilisation of the condition after diagnosis and active treatment, the advanced age and long-standing hypertension of the patient, in addition to a delay in treatment, resulted in a deterioration of the condition, systemic organ failure, and death. Research has demonstrated that the combination of aging and co-infections has the potential to intensify chronic inflammation, thereby stimulating augmented production and release of PCT.Furthermore, increased PCT has been identified as a pivotal element in the diagnosing of serious infections and organ dysfunction [18]. In this study, the inflammatory indicators (WBC, N%, ESR, CRP, IL-6, and PCT) of the patient remained elevated during the infection, indicating a serious and continuous deterioration in the patient’s condition. A plethora of clinical studies has unearthed the fact that diffuse TM infections characteristically involve the entire body, manifest an insidious onset, are intricate, and are associated with a high mortality rate [1]. Case 2 is a 49-year-old male patient with a history of physical fitness and no underlying diseases. The patient presented with a respiratory infection, which was diagnosed as a tracheobronchial TM infection and accompanied by a serious subcutaneous nodular rupture, as well as abdominal, liver, spleen and intestinal enlargement, and pelvic effusion.Initially, patients exhibited elevated systemic symptoms of diffusion and indicators of infection. However, following a prompt diagnosis and aggressive treatment, these indicators gradually declined, resulting in a positive response. (Table 2). Consequently, the condition of the patient improved, and they were granted discharge from the hospital.The findings of this study demonstrate that the prognosis of TM disease is not directly associated with the extent to which it is confined or systemically disseminated. Instead, the prognosis is predominantly influenced by the age of the patient, the early diagnosis and treatment, and the immune system and the underlying disease.The clinical findings indicate that TM infection in combination with other pathogens is a prevalent concern in both HIV-negative and HIV-positive patients, with Candida spp. as the most common co-infecting pathogen in HIV-positive patients, followed by HIV-negative patients [17]. In this study, patients in Case 1 were found to be co-infected with pathogens such as human cytomegalovirus and C.albicans while undergoing treatment for their infections. It is widely accepted that such co-infections have the potential to exacerbate patient conditions and influence prognoses to a certain extent.

The present study involved a systematic search of the PubMed database for cases of TM lung infection in non-HIV patients (Table 4). The mean age of the patients was 51.28 ± 10.87 years, and four cases (57.14%) were female. The predominant initial symptoms were cough and sputum (85.7%, 6/7) and fever (57.14%, 4/7). The majority of patients were observed to be in good health, with only two cases of underlying diseases documented (28.57%), including liver cirrhosis, right portal vein thrombosis (PVT), and systemic lupus erythematosus (SLE).The patients exhibited various symptoms associated with infection, including elevated WBC and PCT levels. The most frequently administered antifungals were amphotericin B and Voriconazole (71.42%, 5/7). Following a prompt diagnosis and rigorous treatment, seven patients were discharged from the hospital. It has been observed that a total of 19 patients diagnosed with HIV-negative TM infection demonstrated a variety of clinical presentations and levels of severity.The presentations included features indicative of lung tumors or tuberculosis. Five of these patients (26.3%) ultimately succumbed to their illnesses [13]. Currently, mycological cultures are used as the gold standard for diagnosing TM infections, showing a high level of accuracy. However, they are known for their lengthy incubation periods and decreased sensitivity [19]. It is important to note that certain limitations are associated with both the sensitivity of the nucleic acid assay and the target molecules of the immunoassay [20, 21]. As a novel nucleic acid detection technology, mNGS is both rapid and accurate, serving as a complementary method to the delays inherent in routine cultures [22]. The presence of TM was detected in blood cultures, sputum, alveolar lavage, and pleural and abdominal fluid specimens from the patients in this study, which was consistent with the results of mNGS and MALDI-TOF MS mass spectrometry.The patients were diagnosed with tracheobronchial TM infection.

Table 4 Summary of cases of TM infection in HIV-Negative patients

Systemic antifungal treatment regimens are the primary modality of clinical practice for treating TM disease. It has been demonstrated that the yeast-phase of TM exhibits a high degree of sensitivity to amphotericin B, posaconazole, voriconazole, and itraconazole. However, it should be noted that fluconazole can also develop resistance during clinical treatment [23]. Voriconazole is a second-generation triazole antifungal agent that has been shown to be effective against fungal infections of the TM and is considered a preferred therapeutic agent for such conditions. It is also used in patients who do not tolerate amphotericin B [24]. In addition, prophylactic use of cotrimoxazole reduces the risk of TM infection [14]. The use of systemic antifungal medications for managing tracheobronchial infections has been shown to be ineffective. The recommended use of nebulized inhalation or intratracheal administration of amphotericin B for treatment may reduce mortality and is worth exploring [25]. In the present study, voriconazole (200 mg twice daily, orally) was utilized as an antifungal agent in conjunction with intravenous amphotericin B (1 mg daily, IV) to enhance therapeutic efficacy. In cases of co-infections, the appropriate treatment regimens for the various pathogens must be selected. Additionally, the treatment of coexisting underlying lung diseases should be considered synergistically.However, it should be noted that the study is subject to several limitations. Firstly, the sample size was only 2 patients, which is considerably small and limits the generalisability of the findings. In future, it would be advisable to increase the sample size as much as possible in order to improve the validity and credibility of the results. Secondly, the post-treatment follow-up period for Case 2 patient enrolled was short and limited. Hence, a long-term follow-up would allow a more complete understanding of the effects of primary treatments.Finally, the absence of direct evidence of TM-associated pathogens in the bronchial lesion tissues of the patients in this study may have implications for the conclusions of the study.

Conclusion

To prevent misdiagnosis and the loss of optimal early treatment, it is crucial to distinguish between TM infection and lung cancer or tuberculosis. The presence of airway lesions caused by TM is a significant clinical indicator of the infection. Consequently, TM infection, along with other rare pathogen infections, should be considered in patients experiencing recurrent fever, cough with sputum, lung infiltrates, and the presence of new organisms in the airways. The aim of this case report is to increase awareness of TM infection among healthcare workers in non-endemic regions and among HIV-negative patients, as well as to improve the clinical knowledge and management skills of healthcare professionals regarding rare diseases.It is imperative that these diseases undergo bronchoscopy and pathogen culture as swiftly as possible, and that the detection and accuracy of TM are enhanced in conjunction with the novel techniques of mNGS and MALDI-TOF MS.Upon identifying a TM infection, the recommended course of action is to administer the full dosage of voriconazole in conjunction with other antibacterial treatments and treatment regimens for the underlying disease.The objective of this approach is to facilitate the development of a treatment plan that is both rational and individualized, thereby ensuring the safest and most effective treatment for the patient.