Determinants of Prognosis in Talaromyces marneffei Infections with Respiratory System Lesions
Talaromyces marneffei (T. marneffei) is an opportunistic fungal pathogen that poses a significant health threat, particularly in Southeastern Asia and southern China. This deep fungal infection can involve various systems, including the skin, respiratory system, digestive system, and reticuloendothelial system, leading to localized or disseminated infections. Among these, respiratory system involvement is common but often overlooked, leading to misdiagnosis and delayed treatment. This study aimed to investigate the characteristics, prognostic factors, and reasons for misdiagnosis of T. marneffei infections with respiratory system lesions, providing critical insights into the management of this condition.
Background and Significance
Talaromycosis, caused by T. marneffei, is an endemic fungal infection in Southeastern Asia. It is particularly prevalent among individuals with compromised immune systems, such as those with human immunodeficiency virus (HIV) infection. The infection is known for its high recurrence and mortality rates, especially in HIV-negative patients. Respiratory system involvement is frequently misdiagnosed as tuberculosis, leading to inappropriate long-term anti-tuberculosis treatment. This misdiagnosis can result in refractory pneumonia, systemic spread, and fatal complications, such as structural damage to the tracheal cartilage, severe tracheostenosis, and tracheal absence.
Historically, T. marneffei infections were primarily associated with skin involvement, but recent animal studies suggest that the respiratory system may be the first system to exhibit significant signs of infection. This hypothesis is supported by evidence that rats become infected by inhaling aerosolized conidia from environmental sources. However, clinical evidence in humans is limited, highlighting the need for further research.
Study Design and Methods
This retrospective study evaluated data from patients admitted to the First Affiliated Hospital of Guangxi Medical University between January 1, 2003, and January 1, 2015. Patients with confirmed diagnoses of T. marneffei respiratory system infections involving the upper (pharynx and larynx) and/or lower respiratory tracts (trachea, bronchi, and lungs) were included. Patients with T. marneffei infections not involving the respiratory system were excluded.
Diagnostic criteria for T. marneffei infections included isolation of the fungus from clinical specimens (e.g., blood, bone marrow, lymph nodes, sputum, skin scrapings, or bronchoalveolar lavage fluid [BALF]) using standard culture techniques. Alternatively, the infection was diagnosed through light microscopy using cytology and histopathology specimens stained with periodic acid-Schiff or Wright-Giemsa. The yeast form of T. marneffei has a characteristic morphology with a transverse septum.
Enrollment criteria for T. marneffei respiratory system infections required either direct identification of T. marneffei in respiratory system specimens or abnormal chest radiography findings with clinical symptoms and exclusion of other diseases. Patients were followed up until January 1, 2015, or the time of death. Outcomes were categorized as effective (sustained response after antifungal treatment), relapse (temporary clinical response with subsequent relapse), or death.
Patient Characteristics
Of the 126 patients diagnosed with T. marneffei infection during the study period, 63 (50.0%) had respiratory system involvement. Among these, 30 were HIV-positive, and 33 were HIV-negative. The infection involved the upper respiratory tract in seven (11.1%) HIV-positive patients. Thirteen (20.6%) patients had local T. marneffei pneumonia, and 46 (73.0%) had disseminated T. marneffei infection. The mean age of patients was 39.5 ± 17.6 years, ranging from 1 to 72 years.
Twenty-four (38.1%) patients were misdiagnosed as having pulmonary tuberculosis, and five (7.9%) were misdiagnosed as having bacterial pneumonia. The median time from onset to confirmation of diagnosis was 105 days, ranging from 11 to 912 days.
Clinical Features and Laboratory Findings
Common clinical and respiratory symptoms included fever, cough, expectoration, and crackles, followed by thoracalgia, dyspnea, and respiratory failure. White sputum was the most common form, with yellowish and blood-streaked sputum also observed. Upper respiratory tract symptoms included sore throat, hoarseness, dysphagia, pharyngeal and laryngeal lumps, and mucosal ulcerations.
Laboratory findings revealed a mean white blood cell count of 15.9 ± 11.8 × 10^9 cells/L, with seven patients having counts below 3.5 × 10^9 cells/L. Decreased hemoglobin concentrations, CD4+ lymphocyte percentage, and CD8+ lymphocyte percentage were also observed. Twelve patients exhibited dyspnea and type I respiratory failure with hypoxemia.
Endoscopy and High-Resolution Computed Tomography
All 63 patients underwent chest computed tomography (CT), which revealed one or more abnormal characteristics in one or both lungs. Common findings included patchy exudates, fibrous cords, pleural effusion, ground glass opacities, and nodular lesions, followed by cavitary lesions, alveolar consolidation, miliary lesions, and tracheobronchial stenosis.
Seven patients underwent electronic and endoscopic nasopharyngoscopy, which showed pharyngeal and laryngeal ulcers and/or lumps. Thirty patients underwent fiberoptic bronchoscopy, revealing inflammatory changes, tracheobronchial stenosis, and nodules or masses in the tracheal wall. One patient underwent thoracoscopy, which revealed pleural adhesions and multiple small nodules on the visceral pleura.
Etiologic Evidence for T. marneffei Respiratory System Infection
Sixty-six point seven percent (66.7%) of cases were directly confirmed through positive respiratory system specimen culture or cytologic/histopathologic analysis. The remaining cases were diagnosed based on chest radiography findings, clinical symptoms, and exclusion of other diseases, with confirmation through samples from the skin, blood, lymph nodes, bone marrow, and pleural membrane.
Treatment and Outcome
Seven patients did not receive antifungal therapy and died due to severe systemic inflammatory responses. Among the 56 patients who received antifungal therapy, 15 died during the first round of treatment due to worsened clinical conditions and organ failure. Eight patients relapsed due to improper withdrawal of antifungal therapy. Forty-one patients were effectively treated using intravenous amphotericin B and fluconazole, followed by oral itraconazole. There was no statistically significant difference in prognosis between different treatments.
Overall Survival
Univariate analysis indicated that HIV infection, the time range from onset to confirmation of diagnosis, CD4/CD8 ratio, and CD4+ T-cell percentage were significantly associated with overall survival. However, only the time from onset to confirmation of diagnosis remained a significant independent predictor of all-cause mortality in multivariate analysis (odds ratio: 0.083, 95% confidence interval: 0.021–0.326, P < 0.001).
Discussion
T. marneffei infections involving the respiratory system are common but often misdiagnosed as tuberculosis. This misdiagnosis leads to delayed treatment and poor outcomes. The respiratory system may be the first and most commonly involved organ, with inhaled aerosolized conidia from environmental sources being a potential mode of transmission.
The critical determinants of prognosis include HIV infection, CD4/CD8 ratio, CD4+ T-cell percentage, and the time from onset to confirmation of diagnosis. Rapid and accurate diagnosis is crucial for improving prognosis. Clinicians should consider T. marneffei infection in patients with tuberculosis-like symptoms but without tuberculosis etiology and poor response to anti-tuberculosis treatment.
Conclusion
T. marneffei infections involving the respiratory system are common and often misdiagnosed as tuberculosis. The major prognostic factors include HIV infection, CD4/CD8 ratio, CD4+ T-cell percentage, and the time from onset to confirmation of diagnosis. Rapid and accurate diagnosis is essential for improving outcomes. Clinicians should be vigilant in considering T. marneffei infection in patients with tuberculosis-like symptoms but without tuberculosis etiology and poor response to anti-tuberculosis treatment.
doi.org/10.1097/CM9.0000000000000345
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