Multiple pathogen infections accompanied with ocular pathologies in a patient with high-titer Anti-IFN-γ autoantibodies: a case report

Abstract

The typical clinical characteristic of patients with anti-IFN-γ autoantibodies (AIGAs) is primarily associated with infection caused by intracellular pathogens. With continued research, additional clinical characteristics have been gradually uncovered. Here, we present a case of multiple pathogen infections accompanied by ocular pathologies in a patient with high titers of AIGAs. The patient, a 53-year-old female patient, was admitted to our hospital after finding a mass in the right supraclavicular fossa. She was successively diagnosed with Talaromyces marneffei, Aspergillus flavus and Nontuberculous mycobacteria (NTM) infections. Then, she received a complete course of antifungal agents for nearly 3.5 years and anti-NTM treatment for nearly 3 years, with discontinuation upon symptom improvement. However, there was a rapid recurrence of the infection upon cessation of the drug despite improvement in the patient’s symptoms. Moreover, when the recurrent infection stabilized, the patient exhibited immune conjunctivitis and dry eye, which was successfully treated by tacrolimus eye drops and lubricant. Patients with high-titer AIGAs are more prone to experiencing recurrence and/or persistent infection, as well as immune disorders.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12879-024-10217-2.

Introduction

Individuals with adult-onset immunodeficiency syndrome caused by anti-IFN-γ autoantibodies (AIGAs) have mainly been reported in Taiwan, Thailand [1], Hong Kong and Southern China [2]. AIGAs positivity has been identified as a particularly strong risk factor for intracellular infection in patients without HIV, including Talaromyces marneffei (TM), nontuberculous mycobacteria (NTM) and other intracellular pathogens [3, 4]. However, diagnosis can be challenging due to non-specific symptoms and diverse manifestations, particularly in HIV-negative individuals, which would lead to poor prognosis. In this report, we report a case of ocular impairment accompanied with elevated serum immune markers in patients with AIGAs under stable infection control, which is considered to be immune-related. There are fewer reported cases of ocular pathologies associated with AIGAs. Additionally, the patient was successfully managed with tacrolimus eye drops. Our aim is to raise awareness of the clinical manifestations in adult-onset immunodeficiency syndrome, particularly immune impairment, and attempts to study the possible immune deficiency mechanism.

Case presentation

A 53-year-old female patient, who was a native of Guangxi and resided in China, was admitted to hospital in October 2017 due to the incidental discovery of a mass in the right supraclavicular fossa. The laboratory test revealed elevated erythrocyte sedimentation rate (ESR) and immunoglobulin G (IgG) levels, with values of 107.0 mm/h and 34.0 g/L, respectively. Additionally, positive results were obtained for antinuclear antibody (ANA, 1:320), anti-SSA, and anti-RO52 antibodies, while showing negative result for anti-HIV antibody (Table 1). Chest computed tomography (CT) suggested enlarged lymph nodes (right supraclavicular fossa, bilateral neck, bilateral axilla and mediastinum) (Fig. 1A). Pathological examination of the right supraclavicular lymph nodes suggested granulomatous inflammation. After empirical antituberculosis therapy with isoniazid, rifapentine, ethambutol, and pyrazinamide, the patient subsequently developed recurrent low-grade fever. With a suspect of primary Sjogren’s syndrome complicated with lymphoma, biopsies were performed on lymph node and labial gland. The biopsy of lymph node revealed chronic inflammation and excluded lymphoma, and the biopsy of labial gland biopsy did not support the diagnosis of Sjogren’s syndrome. Emission computer tomography of salivary gland is normal. Meanwhile, when asked about the patient’s medical history, she reported an absence of symptoms such as dryness in gustatory and ocular sensations. In summary, there was insufficient evidence for the diagnosis of SS or lymphoma. During the hospitalization, T. marneffei was found in Sabouraud’s agar in both blood and lymph node tissue cultures, confirming a diagnosis of TM infection. Following antifungal treatment with voriconazole (VRC) 0.2 g twice daily, the patient’s symptoms had been improved.

Table 1.

Laboratory data and pathological condition during patient ’s hospitalization

Time	Laboratory data				Pathological condition
	WBC (× 109/L)	CRP (g/L)	ESR (mm/h)	IgG (g/L)
2017.10	4.67	24.7	107.0	34.0	Revelation of T. marneffei infection
2018.08	9.07	31.1	99.0	25.1	Revelation of A.flavus and M. intracellulare infection
2021.09	7.74	87.8	113.0	34.5	Infection recurred after discontinuation of medication
2021.12	4.97	4.7	73.0	27.6	Ocular pathologies
2022.02	7.55	< 0.80	41	17.8	After treatment of ocular pathologies

Normal range: WBC: 3.5–9.5 × 10⁹/L; CRP: 0-10 mg/L; ESR: 0–20 mm/H; IgG: 8–18 g/L. WBC: white blood cell; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; IgG: immunoglobulin G

Fig. 1.

CT dynamic monitoring series: (A) Initial lung CT indicated no lung lesions in October, 2017. (B) Second lung CT, conducted 5 months after antifungal therapy, revealed patchy exudation with increased density and indistinct margins in the left upper lobe in August, 2021. (C) Third lung CT, conducted 4 months after stopping anti-infection therapy, showed patchy exudation in the left upper lobe in October, 2021. (D) Fourth lung CT, conducted 3 months after antifungal therapy and anti-NTM therapy, showed significant absorption of the lesion

In August 2018, she was admitted to hospital due to exacerbation of cough and progressive changes on lung CT scan (Fig. 1B). Aspergillus flavus (A.flavus) was found on sputum and lung tissue cultures, and Mycobacterium intracellulare (M. intracellulare) was cultured from the lung tissue. During hospitalization, the patient was initiated on a course of anti-NTM therapy consisting of azithromycin (AZM), ethambutol (ETM), and amikacin (AMK). Following discharge, the regimen was adjusted to AZM and ETM, while maintaining antifungal treatment with VRC. Because of the improvement of condition, she stopped the anti-NTM regimen and reduced the dose of VRC in May 2021.

However, the patient experienced a recurrence of fever in September 2021. The laboratory workup showed increased levels of C-reactive protein (CRP, 87.8 mg/L), ESR (113.0 mm/h) and lgG (34.5 g/L) (Table 1). The T-cell count was 638 /L (1185–1901 /L), and CD4 + T-cell count was 245 /L (561–1137 /L). A serum sample was collected for testing the titer of AIGAs. Serum AIGAs were measured by Enzyme-Linked Immunosorbent Assay method and positive result was yielded at 1:2500. The chest CT showed patchy exudation in the left upper lobe (Fig. 1C). Biological examination of sputum and bronchoalveolar lavage fluid (BALF) revealed no pathogenic organisms. However, considering the patient’s current high-titer of AIGAs, history of refractory infection with TM, A.flavus and M.intracellulare, as well as elevated inflammatory markers and evidence of pulmonary infection on imaging at admission, we considered the possibility of recurrent infection. Therefore, in September 2021, the administration of AZM (0.5 g daily) and ETM (0.75 g daily) for anti-NTM treatment was initiated, along with VRC at a dosage of 0.2 g twice per day for antifungal therapy.

After nearly 3-month of anti-NTM and antifungal treatment, the inflammatory markers turned to normal levels and the lung lesions were absorbed (Fig. 1D). However, she complained of bilateral ocular discomfort characterized by a sensation of foreign bodies (Fig. 2A) accompanied with elevated immune markers (ESR:73.0 mm/h, IgG: 27.6 g/L, high-titer AGIAs: 1:2500) and normal inflammatory markers (CRP: 4.7 mg/L) in December 2021 (Table 1). At our initial ophthalmic examination, the distant best-corrected visual acuity (BCVA) was recorded as 0.6 in the right eye and 0.5 in the left eye, while the intraocular pressure measured 17 mmHg and 15 mmHg for the right and left eyes respectively. Hyperpigmentation was observed in the periorbital skin of both eyes and eyelid. The conjunctiva of both eyes exhibited hyperemia and thickening. The corneal epithelium exhibited dryness, and a defect was observed in the inferior side with fluorescein staining (+). Small grayish keratic precipitates were observed posterior to the cornea in both eyes. The aqueous humor was clear and the lens exhibited transparency. The posterior segments of both eyes were good with clear vitreous bodies and normal fundus. The Schirmer test results were 4 mm/5 min for the right eye and 2 mm/5 min for the left eye; break-up time was 0 s for both eyes. The ophthalmologist diagnosed immune conjunctivitis, dry eye and inactive non-granulomatous anterior uveitis based on the aforementioned examination. Due to the presence of corneal epithelial damage, caution was exercised in administering topical steroid therapy; therefore, tacrolimus eye drops and lubricant were selected as treatment options. The patient used tacrolimus eye drops twice per day and lubricant four times per day for treatment. Following a 2-month course of tacrolimus eye drops and lubricant, notable improvement in ocular symptoms was observed (Fig. 2B, C). Additionally, the patient’s BCVA improved to 1.0 in the left eye, with no change in vision observed in the right eye. The intraocular pressure measured 18 mmHg bilaterally. The conjunctiva of both eyes exhibited mild hyperemia and thickening, which had improved compared to before. The corneal epithelium exhibited dryness, and a defect was observed in the inferior side with fluorescein staining (+). The aqueous humor was clear. Small grayish keratic precipitates were observed posterior to the cornea in both eyes, with no significant changes compared to before. Laboratory findings revealed reductions in ESR levels (41 mm/h), IgG concentrations (17.8 g/L), and AIGAs titers (1: 500) (Table 1). Due to the patient’s stable condition, VRC and ETM were discontinued in February 2023, while AZM against NTM has been continued until the present time. Overall, AZM and ETM were administered for 16months, and VRC was for 17months. No relapse of either intracellular infection or ocular pathologies had been observed during 27-month follow-up.

Fig. 2.

(A) Ocular pathologies were observed prior to the administration of tacrolimus eye drops and lubricant. (B) Ocular pathologies showed significant improvement after the administration of tacrolimus eye drops and lubricant. (C) The corneal fluorescein staining revealed the presence of patchy fluorescein staining in both eyes

Discussion

In recent years, there has been an observed increase in the incidence of patients with positive AIGAs [3]. Many studies have demonstrated that AIGAs positivity is a significant risk factor for opportunistic infections in non-HIV patients, particularly intracellular pathogen [1, 3, 4]. Moreover, patients may develop multiple infections caused by different pathogens in diverse anatomical locations [5]. However, due to the absence of specific clinical features, this type of infection may be easily overlooked, which is more likely to result in a poor prognosis. Our study presents a case of a patient with high-titer AIGAs which was sequentially infected by T. marneffei, A.flavus and M. intracellulare.

According to current research findings, the recommended duration for antifungal therapy in HIV-negative patients with TM is at least 1 year to prevent recurrence [6], and for anti-disseminated NTM treatment, it should be at least 1 to 2 years [7]. The patient in our study received a complete course of antifungal agents for nearly 3.5 years and anti-NTM treatment for nearly 3 years, with discontinuation upon symptom improvement. However, despite the patient’s symptomatic improvement, a rapid recurrence of the infection was observed upon discontinuation of the prolonged pharmacological intervention. Furthermore, considering the patient’s concurrent infection with multiple intracellular pathogens, it raised suspicions regarding an underlying immunodeficiency. The adult-onset immunodeficiency syndrome caused by AIGAs is relatively prevalent in Guangxi, China. Moreover, it is characterized by the occurrence of multiple infections at diverse anatomical sites [3]. Given that AIGAs positivity has been identified as a particularly potent risk factor for intracellular infections in non-HIV patients, we therefore assessed the patient’s AIGAs titer. The test results revealed the presence of high-titer AIGAs, which we deemed to be associated with infection by various intracellular pathogens and the short-term recurrence of infection following drug discontinuation. Due to the impact of AIGAs on IFN-γ function, the processes of CD4⁺T cell differentiation into Th1 cells [8] and IFN-γ-induced type 1 macrophage differentiation are inhibited [9]. This leads to an increasing susceptibility to intracellular infections and a higher recurrence rate in patients with high titers of AIGAs.

Moreover, the patient exhibited ocular symptoms in a stable state of lung infection, as evidenced by normal levels of inflammatory markers and absorbed lung lesions. However, the patient’s serum immunological markers remained elevated, including AIGAs, ESR and IgG. Considering the absence of evidence indicating aggravated infection, we considered that the patient’s ocular pathologies were associated with immune disorders. The hyperpigmentation of the eyelids and the periorbital skin indicated that an inflammatory reaction had occurred in these locations, leaving behind a postinflammatory hyperpigmentation (PIH). Leukotrienes, histamine, and other cytokines stimulate the proliferation of melanocytes, leading to an overproduction of melanin which results in PIH [10]. The conjunctiva of the patient exhibited congestion and milky, thickening, which indicating inflammation reaction. The ocular surface microenvironment and the tear component changed, resulting in the occurrence of dry eye. Moreover, the corneal epithelium was damaged by the toxin protein related with immune damage, which results in an exacerbation of dryness. In summary, the inflammation of the conjunctiva and the defect of the cornea cause irritation and foreign body sensation of the patient. And the effectiveness of tacrolimus eye drops and lubricant also supports this view. Immunology mechanism often takes part in the pathogenesis of uveitis. In this case, the anterior uveitis is inactive and the patient had no symptom relative to that. Despite the administration of tacrolimus eye drops, concurrent with disease control, a notable reduction in the patient’s AIGAs titer was observed. We consider that the decline in AIGAs titer is associated with the effective management of immune manifestations. Numerous studies have reported cases of AIGAs patients presenting with intracellular bacterial infections. According to these reports, the elevated levels of AIGAs in certain individuals gradually decrease following infection control measures, even without systemic immunotherapy [5, 11, 12]. We posit that a similar mechanism underlies the reduction in AIGAs titer observed in this patient. The patients exhibiting symptoms of immune impairment may also experience a gradual decline in AIGAs titers while maintaining stable disease status without the use of systemic immunosuppressants. However, further research is required to comprehensively investigate this mechanism. Yan et al. have reported a case of allergic conjunctivitis mediated by AIGAs [13], but the number of the reported cases remains limited.

Furthermore, the initial patient admission revealed a positive ANA result (1:320). Subsequently, during the disease treatment, there was a concurrent reduction observed in both ANA and AIGAs titers. Therefore, we recommend that HIV-negative patients with specific pathogen infections and positive ANA antibodies should not only consider the possibility of rheumatic immune diseases but also undergo AIGAs testing to screen for the presence of adult-onset immunodeficiency.

The AIGAs titer of the patient in our study decreased during treatment, however, the majority of patients would exhibit a persistently high titer of AIGAs despite undergoing long-term antimicrobial therapy, which increases the risk of infection recurrence [3]. For patients experiencing recurrent infections, in addition to monitoring infection evaluation indicators, it is crucial to also assess immune markers and regularly re-evaluate the titer of AIGAs. In patients with pulmonary infection, it is essential to conduct repeat imaging, including magnetic resonance imaging (MRI) if necessary [14], for disease assessment. Furthermore, these patients may harbor diverse pathogens at different sites necessitating meticulous attention [5]. In cases where patients exhibit persistently high titers of AIGAs, even with maintenance therapy with antimicrobials, eradicating pathogenic microorganisms such as TM becomes challenging. Therefore, immunosuppressive therapy may be considered appropriate for patients exhibiting persistent high-titer AIGAs who experience recurrent, severe and refractory infections or significant immune compromise. Previous studies have demonstrated the favorable clinical efficacy of rituximab and cyclophosphamide in reducing the production of pathogenic autoantibodies by depleting B cells. However, it is recommended to consider a minimum duration of 6 months of antibacterial treatment prior to initiating these therapies [15, 16]. Additionally, it has been reported that corticosteroid also has the ability to reduce AIGAs titer for improving immune-related symptoms [13].

Conclusion

Patients with adult-onset immunodeficiency syndrome, who persistently presenting high-titer of AIGAs, are more likely to experience recurrent infections and may also exhibit systemic immune dysfunction, which sometimes affect local organs. Patient developed ocular symptoms accompanied by stable inflammatory indicators and primary infection lesion, but increased immunological indicators (like ESR, IgG and AIGAs titer), which is suggesting that this may be related to immune abnormalities. Topical immunosuppressant may improve symptoms in patient with ocular pathologies.

Electronic supplementary material

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Abbreviations

AIGAs

Anti-IFN-γ autoantibodies

TM

Talaromyces marneffei

NTM

Nontuberculous mycobacteria

ESR

Erythrocyte sedimentation rate

IgG

Immunoglobulin G

ANA

Antinuclear antibody

CT

Chest computed tomography

VRC

Voriconazole

A.flavus

Aspergillus flavus

M. intracellulare

Mycobacterium intracellulare

AZM

Azithromycin

ETM

Ethambutol

AMK

Amikacin

CRP

C-reactive protein

BALF

Bronchoalveolar lavage fluid

BCVA

Best-corrected visual acuity

PIH

Postinflammatory hyperpigmentation

MRI

Magnetic resonance imaging

Author contributions

SYW: conceived the concept of this study, manuscript writing, data analysis and interpretation. XL and ZYH: conceived the concept of this study, data revising, data interpretation and approval of the version to be published. SQL, HLL and YN: data analysis completed the experiment and interpretation. SYW, SQL, HLL, YN, XL and ZYH: ensuring questions related to the accuracy or integrity of the work are appropriately investigated and resolved. All authors reviewed the manuscript and approved the final version.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data availability

The study’s datasets can be obtained from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

Informed consent was obtained from the patient to publish this case report in an online open-access publication. Patient had provided written consent to publish this case. Documentation is available upon request. All identifying information has been removed from the manuscript and figures. Informed consent was obtained from the patient to publish this case report in an online open-access publication.

Consent for publication

Written informed consent to have the case details and any accompanying images published has been provided by the patient.

Competing interests

The authors declare no competing interests.