A double pathogen strike: COVID-19 and talaromycosis Co-infection in a patient with post-tuberculosis lung disease

Abstract

An 80-year-old woman from rural Guangxi with post-tuberculosis lung disease (PTLD) (hereinafter referred to as PTLD)presented with one month of cough and fever. One month prior, she had ingested raw rodent meat—a known exposure for Talaromyces marneffei. Chest HRCT showed bilateral tree-in-bud opacities superimposed on prior left lung destruction. Conventional microbiological tests, including acid-fast bacilli smears, were negative. A nasopharyngeal swab was positive for SARS-CoV-2 (cycle threshold 17). Metagenomic next-generation sequencing (mNGS) of bronchoalveolar lavage fluid identified both T. marneffei and SARS-CoV-2. Her CD4⁺ count was 344/μL and HIV serology was negative. She received nirmatrelvir–ritonavir and sequential amphotericin B followed by voriconazole, with clinical and radiological improvement. This case illustrates that PTLD may serve as a local anatomical risk factor for talaromycosis even without systemic immunodeficiency.

1. Background

Talaromyces marneffei, a thermally dimorphic fungus endemic to Southeast Asia and southern China, typically causes disseminated disease in individuals with advanced HIV infection [1,2]. However, an increasing number of cases have been reported in non-HIV hosts, particularly those with pre-existing structural lung abnormalities [3]. Post-tuberculosis lung disease (PTLD)—characterized by bronchiectasis, fibrotic cavities, and architectural distortion—affects an estimated 50% of tuberculosis survivors and predisposes to recurrent or chronic respiratory infections [4].

The coronavirus disease 2019 (COVID-19) pandemic has introduced an additional variable. SARS-CoV-2 infection can disrupt local pulmonary host defenses through direct epithelial injury, impaired mucociliary clearance, and dysregulated inflammatory responses [5]. Whether such viral injury creates a permissive niche for secondary fungal infections in structurally compromised lungs remains incompletely defined.

We report a case of concurrent COVID-19 and pulmonary talaromycosis in an elderly non-HIV patient with PTLD. The case posed a diagnostic challenge because radiographic findings overlapped and routine microbiological tests were negative. It was resolved by metagenomic next-generation sequencing (mNGS) of bronchoalveolar lavage (BAL) fluid. We discuss the potential interplay between structural lung disease, viral infection, and opportunistic fungal invasion.

2. Case presentation

An 80-year-old woman from a rural area of Guangxi, China, presented to our hospital with a one-month history of cough, low-grade fever, and progressive dyspnea. She had no known history of immunosuppressive therapy, diabetes mellitus, or malignancy. She was a non-smoker.

Her past medical history was notable for pulmonary tuberculosis diagnosed and treated 10 years earlier, with documented completion of a standard 6-month regimen. Residual left lung destruction and bilateral bronchiectasis had been noted on prior imaging. Notably, approximately one month before symptom onset, the patient had consumed raw rodent meat—a cultural practice in her locality and a recognized risk behavior for T. marneffei acquisition [6].

On admission, she was afebrile (37.8°C) with an oxygen saturation of 92% on room air. Respiratory examination revealed coarse crackles in both lung fields. No lymphadenopathy or hepatosplenomegaly was present.

Laboratory findings are summarized in Table 1. Key abnormalities included mild normocytic anemia (hemoglobin 98 g/L), monocytosis (12.9%), eosinophilia (6.6%), hypoalbuminemia (2.4 g/dL), and elevated inflammatory markers (ESR >130 mm/hr, CRP 40.1 mg/L). Arterial blood gas on room air showed mild hypoxemia (PaO₂ 66.0 mmHg) and hypercapnia (PaCO₂ 53.0 mmHg). HIV serology was negative. Her CD4⁺ T-cell count was 344/μL (reference range 400–1610/μL), which is below the conventional normal range but not in the range typically associated with opportunistic infections (usually <200/μL). This pattern is consistent with age-related decline, although other contributing factors (e.g., nutritional status, chronic inflammation from PTLD, or acute viral infection) cannot be fully excluded. We therefore describe this as mild CD4⁺ reduction without overt systemic immunosuppression.

Table 1.

Laboratory findings on admission.

Variable	Reference range	On presentation
Hematology
Hemoglobin (g/L)	110-160	98 ↓
White-cell count (×109/L)	4.0-10.0	5.44
Monocytes (%)	3-10	12.9 ↑
Eosinophils (%)	0.5-5	6.6 ↑
Platelet count (×109/L)	100-300	464 ↑
Chemistry
Albumin (g/dL)	3.3-5.0	2.4 ↓
ESR (mm/hr)	0-20	>130 ↑
CRP (mg/L)	0.0-8.0	40.1 ↑
Blood gas (room air)
pH	7.35-7.45	7.39
PaO2 (mmHg)	80-100	66.0 ↓
PaCO2 (mmHg)	35.0-45.0	53.0 ↑
HCO3− (mmol/L)	21-25	32.1 ↑
Immunology
CD4+ count (/μL)	400-1610	344 ↓
HIV	Negative	Negative

Abbreviations: ESR, erythrocyte sedimentation rate; CRP, C-reactive protein.

Chest high-resolution computed tomography (HRCT) confirmed known PTLD sequelae: left lung volume loss (estimated 60% reduction), mediastinal shift, and widespread bronchiectasis (Fig. 1A). The chronic PTLD-related findings were stable based on comparison with prior imaging (not shown). In contrast, the following findings were new and indicative of an active infectious process: superimposed on these chronic changes were diffuse, bilateral centrilobular tree-in-bud nodules and areas of consolidation, predominantly in the right middle and lower lobes—findings indicative of an active endobronchial process. No cavitation or miliary pattern was observed.

Fig. 1.

Chest computed tomography (CT) images at admission and 6-month follow-up.

(A) Axial CT image at admission shows left lung volume loss with mediastinal shift, bilateral bronchiectasis, and diffuse tree-in-bud nodules (white arrows) predominantly in the right middle and lower lobes. (B) Axial CT image at 6-month follow-up (post-treatment) demonstrates marked reduction of tree-in-bud nodules and consolidation. Residual bronchiectasis and left lung volume loss remain unchanged.

Diagnostic workup. Sputum smears for acid-fast bacilli (AFB) were negative on three consecutive samples. Bacterial cultures grew normal respiratory flora. A nasopharyngeal swab tested positive for SARS-CoV-2 by reverse-transcription polymerase chain reaction (RT-PCR) with a cycle threshold (Ct) value of 17, indicating high viral load. Bronchoscopy was performed, and BAL fluid was obtained from the right middle lobe. BAL fluid AFB smear and fungal culture were negative.

Metagenomic next-generation sequencing (mNGS) of the BAL fluid was performed at a commercial clinical laboratory.According to the laboratory's standard pipeline, microbial DNA was extracted, libraries were prepared, and sequencing was performed on an Illumina platform with paired-end 150 bp reads. Raw sequencing data were processed by subtracting human host sequences, and the remaining reads were aligned against microbial reference databases (including bacteria, fungi, viruses, and parasites). A pathogen was considered detected if it met the laboratory's predefined thresholds: (i) at least 5 non-host reads mapping to the species, and (ii) coverage ranking within the top 10 microbial species in the sample. The report indicated the presence of both T. marneffei and SARS-CoV-2 as the dominant microbial sequences, with no other pathogens identified at clinically significant thresholds. Quantitative read counts from the commercial report are not presented here as the raw data are not available for independent verification. Nevertheless, the qualitative finding of dual pathogen detection, in conjunction with the epidemiological history and negative conventional tests, supported the diagnosis of concurrent talaromycosis and COVID-19.

Final diagnosis. Concurrent COVID-19 and pulmonary talaromycosis in a patient with PTLD and age-related CD4⁺ attenuation but no HIV infection.

3. Management and follow-up

The patient received a dual therapeutic regimen. For COVID-19, she was treated with nirmatrelvir–ritonavir (300 mg–100 mg twice daily for 5 days). For talaromycosis, she received intravenous liposomal amphotericin B (3 mg/kg daily) for 14 days, followed by oral voriconazole (200 mg twice daily) for a planned total of 12 weeks. No corticosteroids or other immunomodulators were administered.

Clinical response was monitored by symptoms, oxygenation, and serial C-reactive protein. Fever resolved by day 4. Oxygen saturation improved to 95% on room air by day 7. A follow-up nasopharyngeal swab RT-PCR for SARS-CoV-2 at day 14 was negative. Repeat chest HRCT at 6 weeks post-discharge (Fig. 1B) showed marked reduction in tree-in-bud nodules and consolidation, with residual bronchiectasis unchanged.

At 6-month follow-up, the patient remained asymptomatic with no evidence of talaromycosis relapse. Antifungal therapy was discontinued after 12 weeks.

4. Discussion

This case makes three contributions to the existing literature. First, it suggests that T. marneffei pulmonary infection can occur in a non-HIV host with PTLD in the absence of profound systemic immunosuppression. Second, it illustrates the diagnostic challenge posed by coinfection with SARS-CoV-2 when radiographic patterns overlap. Third, it provides pragmatic evidence for the utility of mNGS in such scenarios, even when raw data cannot be made publicly available.

PTLD as a local risk factor. The traditional paradigm holds that talaromycosis requires severe CD4⁺ lymphocytopenia, typically in the setting of advanced HIV disease [2]. However, accumulating case series have described non-HIV talaromycosis in patients with diabetes, autoimmune disease treated with immunosuppressants, and—notably—pre-existing lung disease [3,7]. Our patient's CD4⁺ count was 344/μL, which is below the reference range but well above the threshold (<200/μL) associated with opportunistic infections. We interpret this as age-related decline rather than classical immunosuppression. The more relevant predisposition may be structural: bronchiectasis and fibrotic distortion in PTLD impair mucociliary clearance, alter local immune surveillance, and create niches where inhaled T. marneffei conidia can establish infection [4]. This “local vulnerability” hypothesis aligns with observations in other endemic mycoses (e.g., Histoplasma, Coccidioides), where structural lung disease increases infection risk independent of systemic immune status [8].

Potential virus–fungus synergy. The concurrent SARS-CoV-2 infection, confirmed by high viral load (Ct 17), may have been more than coincidental. SARS-CoV-2 infects airway epithelial cells and alveolar macrophages, disrupts the epithelial barrier, and impairs mucociliary clearance [5,9]. In a lung already compromised by PTLD, such viral injury could create a permissive temporal window for inhaled T. marneffei to transition from colonization to invasion. We cannot, from a single case, establish causality. However, the temporal sequence (rodent exposure → COVID-19 → symptomatic talaromycosis) is biologically plausible and merits investigation in larger cohorts.

Given the inherent limitations of a single case report, these observations should be considered hypothesis-generating rather than definitive. Future prospective cohort studies are needed to establish whether PTLD independently increases talaromycosis risk and whether SARS-CoV-2 acts as a contributing factor.

Diagnostic role of mNGS. This case adds to the growing literature on mNGS for diagnosing complex or atypical infections [10,11]. COVID-19 has been increasingly recognized as a risk factor for secondary fungal infections, including aspergillosis, candidiasis, and endemic mycoses [12,13]. Our case extends this observation to talaromycosis in the specific context of pre-existing structural lung disease.Conventional tests—sputum AFB, bacterial culture, fungal culture—were all negative. The diagnosis was established only after mNGS of BAL fluid. Even without publicly available raw data, the qualitative mNGS finding of dual pathogen detection provided critical diagnostic direction. In resource-limited settings where mNGS is not available, clinicians should maintain a high index of suspicion for talaromycosis in PTLD patients with compatible exposures, and consider empirical antifungal therapy or targeted PCR if available [6].

Limitations.This is a single case report, which limits generalizability. Comprehensive immunological phenotyping (e.g., CD4/CD8 ratio, lymphocyte subset analysis, functional T-cell assays) was not performed, and we cannot definitively exclude mild degrees of immune dysfunction beyond age-related changes. We also lacked longitudinal immune phenotyping that might have clarified the degree of virus-induced immunoparalysis. A further limitation is that the mNGS data were generated by a commercial laboratory without provision of raw sequence files or public data deposition. Consequently, quantitative read counts are not reported here, and independent verification of the sequencing results is not possible. The diagnosis therefore rests on the convergence of clinical, epidemiological, radiographic, and qualitative molecular evidence rather than on publicly verifiable sequence data. Future studies should examine whether PTLD independently predicts talaromycosis risk in endemic regions, and whether COVID-19 modifies the clinical presentation or outcome of endemic mycoses.

5. Conclusion

This case adds to the hypothesis-generating evidence that in a non-HIV patient with PTLD and mild CD4⁺ reduction, concurrent COVID-19 and pulmonary talaromycosis can present with overlapping radiographic features and negative conventional microbiological tests. The diagnosis was supported by a combination of epidemiological history, HRCT findings, and qualitative mNGS result. This case suggests that PTLD may serve as a local anatomical risk factor for talaromycosis even without systemic immunosuppression. For clinicians managing PTLD patients with unexplained pneumonia in endemic areas, we recommend: (1) eliciting a history of raw rodent meat exposure; (2) considering dual testing for SARS-CoV-2 and endemic fungi; and (3) pursuing mNGS of lower respiratory tract samples when conventional tests are unrevealing, while recognizing that raw data availability may vary by testing facility.

Availability of data and materials

All clinical data supporting this case report are included in the manuscript. The chest CT images are provided as Fig. 1. The raw mNGS sequencing data were generated by a commercial clinical laboratory and are not publicly available due to the terms of the service agreement. The mNGS report (qualitative findings only) is available from the corresponding author upon reasonable request, subject to the commercial provider's data use policies.

Ethics approval and consent to participate

This case report was approved by the Institutional Review Board of Guangxi Zhuang Autonomous Region Jiangbin Hospital. Written informed consent was obtained from the patient.

Consent for publication

Obtained.

Clinical trial number

Not applicable.

Funding

This work was supported by.

• 1.the Key Research Program of Guangxi Science and Technology Department (grant number AB21196010);
• 2.First-class Discipline Innovation-driven Talent Program of Guangxi Medical University,
• 3.the Health and Family Planning Commission of Guangxi Zhuang Autonomous Region, Self-funded Projects (grant Nos. Z-A20240492, Z-A20240515,Z-A20250219);
• 4.Joint Project on Regional High-Incidence Diseases Research of Guangxi Natural Science Foundation under Grant No.2023GXNSFBA026146;
• 5.Natural Science Foundation of China (grant numbers 82160783,82560016);
• 6.China Postdoctoral Science Foundation (grant number2023MD734158).

The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

CRediT authorship contribution statement

Yuhai Dang: Conceptualization, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing – original draft, Writing – review & editing. Jinliang Kong: Conceptualization, Funding acquisition, Resources, Writing – review & editing.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A. Supplementary data

The following is the Supplementary data to this article: