HIV-negative case of Talaromyces marneffei pulmonary infection with a TSC2 mutation

Abstract

Talaromyces marneffei is a rare dimorphic pathogenic fungus that can induce severe infections in human immunodeficiency virus (HIV)-infected patients. However, such infections have also been reported in non-HIV hosts. This current case report describes a very rare case of a T. marneffei pulmonary infection in an HIV-negative patient with a mutation in the tuberous sclerosis complex subunit 2 ( TSC2) gene. A 24-year-old male patient presented with cough and expectoration for 6 months. Computed tomography showed multiple ground-glass opacities and cystic and cavitated lesions in both lungs. Next generation sequencing (NGS) of the bronchoalveolar lavage fluid was performed to confirm T. marneffei pulmonary infection. The results were further verified using bronchoscopy specimen cultures. This was an HIV-negative patient without a travel history to endemic zones and his blood exon sequencing results showed a mutation in the TSC2 gene. To date, he has recovered well with voriconazole therapy. In summary, patients with TSC2 mutations that induce bronchopulmonary dysplasia may be potential hosts for T. marneffei. Early and timely diagnosis is important for improving prognosis. NGS plays a critical role in the diagnosis of T. marneffei pulmonary infection.

Rapid Genomic Diagnosis of Fungal Infections in the Age of Next-Generation Sequencing

“…Pneumocystis jirovecii is the predominant fungus reported (~25% of the fungi detected), followed by Aspergillus species (~22%), Candida species (~16%), Cryptococcus species (~7%), Rhizopus species (~6%), Fusarium species (~4%), Alternaria species, Talaromyces marneffei and other Sordariomycetes (~3% each), Histoplasma capsulatum, other yeasts and Mucor species (~2% each), as well as some other rare fungal species (collectively~5%) (Figure 2). Excluding P. jirovecii, which is generally unculturable, out of the remaining 274 fungi detected by NGS, only 105 (~38%) were recovered by fungal culture from the same or different specimens from the respective patients [26,[29][30][31][32][33][34][35][36][37][38][39]43,45,46,49,52,54,57,59,62,64,66,67,71,73,76,77]. cies (~22%), Candida species (~16%), Cryptococcus species (~7%), Rhizopus species (~6%), Fusarium species (~4%), Alternaria species, Talaromyces marneffei and other Sordariomycetes (~3% each), Histoplasma capsulatum, other yeasts and Mucor species (~2% each), as well as some other rare fungal species (collectively ~5%) (Figure 2).…”

“…cies (~22%), Candida species (~16%), Cryptococcus species (~7%), Rhizopus species (~6%), Fusarium species (~4%), Alternaria species, Talaromyces marneffei and other Sordariomycetes (~3% each), Histoplasma capsulatum, other yeasts and Mucor species (~2% each), as well as some other rare fungal species (collectively ~5%) (Figure 2). Excluding P. jirovecii, which is generally unculturable, out of the remaining 274 fungi detected by NGS, only 105 (~38%) were recovered by fungal culture from the same or different specimens from the respective patients [26,[29][30][31][32][33][34][35][36][37][38][39]43,45,46,49,52,54,57,59,62,64,66,67,71,73,76,77]. The majority of P. jirovecii infections diagnosed by NGS were reported in case series [34,36,39,41,48,53,55,58,62,64,65,67,72,75].…”

“…In addition to P. jirovecii, the epidemiology of the 11 cases of T. marneffei infections diagnosed by NGS are also different from talaromycosis in other patients (Table 1) [33,38,42,45,49,59,66,68,73,74,77]. T. marneffei is a thermally dimorphic fungus endemic in Southeast Asia.…”

“…Another two patients were clinically diagnosed to have tumour (lymphoma in case 6 [59] and iris tumour in case 8 [68]). More than 60% of the 11 patients were HIV-negative [33,38,42,49,59,66,73,77], most likely the main reason why T. marneffei was not suspected in the first place. When talaromycosis was confirmed in a HIV-negative patient and no other obvious immunocompromised status was found, other primary immunodeficiency conditions, such as presence of anti-interferon-gamma autoantibody, hyper-IgE syndrome and hyper-IgM syndrome, should be looked for [78].…”

“…For example, genetic testing was performed in case 5 because the patient was HIV-negative and she had a history of recurrent infections in her childhood and loss-of-function STAT3 mutation was discovered [49]. Similarly, TSC2 mutation was detected in the patient in case 11 [77]. It is notable that patients with T. marneffei infections can be tested positive by the serum galactomannan assay [79], as shown in 2 of the 11 patients (cases 9 [73] and 10 [74]), because the immunoreactive β-galactofuransyl side chain of Aspergillus galactomannan [80] is also present in the cell wall of Talaromyces species of section Talaromyces [81], which encompasses T. marneffei [82].…”