Talaromycosis is associated with high mortality in immunocompromised children[10]. Opportunistic infection with dimorphic fungus associated with IEI has gradually gained attention. Some types of IEI are specifically prone to fungal infection. We report an international retrospective study of talaromycosis in IEI patients, reporting the genetic, immunological, and clinical characteristics of disease. The diseases of talaromycosis with IEI are common in severe combined immunodeficiency (IL-2R, ADA) and combined immunodeficiency (RELB, CD40L, STAT3), antibody deficiencies (CVID caused by NFKB2 deficiency), intrinsic and innate immunity defects (IL12RB1 deficiency, IFNGR1 deficiency, CARD9, and STAT1-GOF), and autoinflammatory disorders (COPA gene defect), in which XHIM, STAT1-GOF, and HIEs (STAT3-LOF) are the most susceptible diseases for development of IEI-associated talaromycosis[4, 11, 12].
The majority of IEI with talaromycosis patients are diagnosed by nonspecific manifestations, biological, and atypical imaging features, so talaromycosis can be commonly misdiagnosed. IEI is always suspected upon diagnosis with talaromycosis in non-HIV patients. The onset characteristics and clinical manifestations of T. marneffei infection are much similar to those of HIV and IEI patients[5, 13]. Common clinical manifestations of talaromycosis patients with HIV are fever, weight loss, lymphadenopathy, respiratory symptoms, gastrointestinal complications, and skin lesions[14]. Central umbilicated papules are a typical characteristic of talaromycosis but are not common in HIV-positive children (21.4%)[14]. Bone marrow involvement is less common in HIV patients, while osteolytic lesions can occur in non-HIV patients. 16% (8/50) of IEI patients with talaromycosis developed skeletal system involvement and 24% (12/50) patients and rash or skin damage occasionally occurred. Many patients were misdiagnosed with tuberculosis due to similar clinical manifestations at onset. In addition, patients presenting with fever, hepatosplenomegaly, multiple lymphadenopathies, and thrombocytopenia are frequently suspected to have hematologic diseases. In conclusion, in patients with the above symptoms in summer or autumn, and who live in or have a travel history to endemic areas such as southern China and Southeast Asia, T. marneffei infection should be considered.
Imaging features IEI with talaromycosis were diverse and variable[15, 16]. Chest CT imaging features manifested as diffuse nodules, ground-glass opacities, pleural effusion, and multimediastinal lymphadenopathy. Pulmonary manifestations and chest CT scan findings of talaromycosis should be distinguished from tuberculosis, pulmonary cryptococcosis, aspergillosis, pneumocystis carinii, candidiasis, or malignant lung tumors[17]. T. marneffei confined to the gastrointestinal tract is very rare. Abdominal CT imaging revealed thickening of the bowel wall or narrowing of the lumen and extensive abdominal lymphadenopathy. Swollen abdominal lymph nodes could potentially be misdiagnosed as gastrointestinal lymphoma, leukemia, or other gastrointestinal tumors. Gastrointestinal endoscopy and biopsy were performed in some patients[18]. In HIV patients, T. marneffei bone involvement was rarely reported. Multiple studies have reported that non-HIV patients with talaromycosis develop different degrees of skeletal involvement. In a study of 15 non-HIV talaromycosis patients without underlying disease, seven patients (7/15, 46.67%) had flat bones or long bone destruction with osteolytic lesions or bone hyperplasia[15]. In another study, bone destruction occurred in 14 cases (14/35, 40%)[19]. Therefore, we consider osteomyelitis and/or skeletal changes to be more likely in non-HIV or immunocompromised or normal patients.
CRP and PCT indexes can be normal or slightly elevated by general fungal infection, and are significantly elevated by fungal sepsis. In severe fungal infections, trilineage damage is common regardless of HIV status. Compared to patients with normal immune function, HIV patients had significantly lower serum albumin and uric acid, while ALT, AST, LDH, TBil, and DBil were increased[20]. CD4+ T cells, CD8+ T cells, C3, and C4 have different degrees of changes[20]. Multiple studies had demonstrated that respiratory failure, shock, high urea levels, and significantly lower PLT are predictive of poor outcomes and prognosis in HIV patients with talaromycosis. In deceased patients, AST/ALT rate was 3.07, which is significantly higher than that in survivors (1.96)[21]. Similar findings were present in Histoplasma, with significantly higher AST/ALT than in other localized lung diseases. Therefore, AST/ALT could be an indicator for increased risk of mortality in talaromycosis. In IEI with talaromycosis patients, the mean AST/ALT was 2.52 (11/50), with a range of 0.57–5.25. ASL/ALT in deceased and surviving patients was 2.49 (4/11) and 2.54 (7/11), respectively. Studies had also identified that CD8+ T cells are significantly decreased in deceased patients, and CD4+/CD8+ T cell ratios are significantly increased in HIV patients. Among IEI with talaromycosis patients, nearly 50% of the deceased patients had significantly decreased CD8+ T cells. The mean value of CD4+T/CD8+ T cell ratio was 2.97 (7/14) in all deceased patients and 1.96 (32/36) in surviving patients. Six deceased patients (6/7) had significantly elevated CD4+/CD8+ T cell ratios, 11 survivors (11/32) exhibited elevated CD4+/CD8+ T cell ratios, and the rest (21/32)were reduced or normal. Therefore, immunological profiling of talaromycosis patients should not be limited to CD4+ T cell counts but rather should comprehensively measure CD4+ T cells, CD8+ T cells, and the CD4+/CD8+ ratio[16, 21]. Follow up data for of AST, ALT, and other tests were lacking in IEI patients, and the relationship between IEI and hepatic injury in the context of talaromycosis needs to be further studied. Hepatic injury is a nonspecific manifestation of IEI with talaromycosis, but early occurrence of hepatic injury could be indicative of poor prognosis.
1,3-β-D-glucan tests did not provide optimal sensitivity in either HIV patients or IEI patients[14]. Seventy percent (7/10) of patients who underwent 1,3-β-D-glucan assay testing in the study were positive. Culture and biopsy of specimens, including blood, bone marrow, lymph nodes, and BALF, are common detection methods for T. marneffei identification and yield high positivity rates. Urine, nasal swabs, and ear swabs yield lower positivity rates. Blood culture is relatively time-consuming and insensitive to early infection, with a misdiagnosis rate as high as 50%. The mortality rate of talaromycosis increased from 24–50% when antifungal treatment was delayed[22]. The sensitivity was 100%, and specificity was 98.7%, for mNGS in diagnosis of T. marneffei infection. The time required for T. marneffei detection was approximately 26 hours by mNGS, which is much shorter than that of culture or histopathology[4, 13]. mNGS has been widely used in IEI to detect pathogens more accurately and rapidly. mAb-4D1 and mAb-Mp1p enzyme immunoassays have also been developed, and exhibit higher sensitivity and specificity than blood cultures[23, 24].
Amphotericin B and itraconazole are effective therapeutic agents to control T. marneffei infection. Most of the patients in the study were treated with a combination of multiple antifungal drugs. Compared to HIV-positive patients, IEI patients require a longer duration of antifungal therapy. Some patients died of serious complications such as MODS, ARDS, HLH, septic shock, and DIC[25, 26]. The treatment regimen recommended by international guidelines for management HIV patients with T. marneffei is Amphotericin B in the induction period for 2 weeks, followed by oral itraconazole for 10 weeks[1, 13, 27]. Patients with normal immune function do not require maintenance therapy[28]. Some HIV patients are also cured with intravenous voriconazole for 10–14 days followed by oral voriconazole for 12 weeks[27, 28]. Voriconazole has also been reported to be effective in cases refractory to Amphotericin B and itraconazole treatment monotherapies[10, 29]. The nephrotoxic and hepatotoxic effects of Amphotericin B limit its use in children[30]. Voriconazole is highly effective and was identified as a well-tolerated treatment option for non-HIV children with disseminated T. marneffei infection in a study of non-HIV children in southern China[10]. Itraconazole is used more commonly in developing countries due to its improved tolerance and decreased expense relative to Amphotericin B, despite the improved efficacy of Amphotericin B in preventing mortality[27, 31]. For patients living in areas in which T. marneffei is endemic, especially those with IEI or who are immunocompromised, the present study suggests prophylactic treatment with itraconazole should be administered for recurrence of infection.
Regarding the mechanism of talaromycosis, T. marneffei commonly occurs in patients with CD4+ T counts < 100 cells/µl[32]. T cell numbers and/or functional defects such as XHIM, SCID, and RELB underscore the importance of cellular immunity for T. marneffei defense[33]. The increased susceptibility to talaromycosis in STAT3-LOF, STAT1-GOF, and CARD9 deficient IEI patients also underscores the role of Th17 in the host defense against T. marneffei as Th17 deficiency occurs in these three IEI genotypes[12, 34–37]. The clinical manifestations and susceptibility pathogens in AIGA are similar to those of AIDS, and this pathology was therefore previously described as “AIDS-like syndrome.” AIGA is the most frequently occurring talaromycosis among non-HIV patients, in addition to the IL12RB1 and IFNGR1-deficient IEI patients also harboring T. marneffei infection, which indicated that the IL-12/IFN-γaxis is likely involved in the host T. marneffei defense[3, 38, 39]. The precise mechanisms by which COPA gene mutations increase susceptibility to opportunistic T. marneffei infection are currently unknown[25, 40].
Routine specialist diagnosis and treatment of IEI are relatively uncommon in the geographic regions with the highest incidence of T. marneffei. We therefore suggest that the actual number of talaromycosis patients with IEI is grossly underestimated. Therefore, T. marneffei infection should be more routinely tested in IEI patients in southern China and Southeast Asia.