Central nervous system infections in patients with anti-interferon-γ autoantibodies: case series and review of the literature

Abstract

Background

Recently, increased reports reveal that anti-interferon-gamma (IFN-γ) autoantibodies (AIGAs) are strongly associated with several severe disseminated infections. However, reports on AIGAs with central nervous system (CNS) infections are rare. Here, we described three AIGAs-positive adults who had persistent or recurrent disseminated infections caused by Talaromyces marneffei (TM), nontuberculous mycobacteria (NTM), mycobacterium tuberculosis (TB), or other pathogens, accompanied with CNS infections. In addition, we conducted a thorough literature review of AIGAs-positive patients with CNS infections.

Case presentation

We report three HIV-negative cases of recurrent disseminated infections including CNS, and AIGAs were measured. All patients had no history of underlying diseases or immunosuppression and presented with fever, cough, and headache. They were negative for HIV antibodies but positive for AIGAs. The patients were diagnosed with CNS infections based on cerebrospinal fluid (CSF) examination and next-generation sequencing (NGS). All patients received anti-infective treatment according to different pathogens, and their condition remained stable without recurrence.

Conclusions

In adults with severe and recurrent infections of multiple organs without known immunodeficiency, adult-onset immunodeficiency (AOID) associated with AIGAs should be considered. In AIGAs-positive patients, the blood–brain barrier (BBB) may be disrupted, leading to susceptibility to CNS infections.

Introduction

The serum neutralizing AIGAs can underlie AOID [1, 2]. Patients with AIGAs are mostly reported in Asians [1–3]. AIGAs are closely associated with severe disseminated infections, which can be due to multiple intracellular pathogens, such as TM, NTM, Salmonella typhi, varicella-zoster virus (VZV), and Candida [1, 2, 4, 5]. In this report, we describe three healthy Chinese adults with CNS infections, and AIGAs were detected in serum. We also review the existing literature and provide a thorough compilation of previously reported CNS infections cases associated with AIGAs.

Case reports

Patient 1

A 47-year-old male was admitted to our hospital for treatment, presenting with persistent fever, headache for six months, and rash for two months. He was previously hospitalized in the neurology department of another hospital. CSF analysis showed weakly positive protein on qualitative testing, elevated total protein (475 mg/L), hypoglycorrhachia (2.87 mmol/L), and normal chloride (124.6 mmol/L). CSF smear and cultures were negative. A diagnosis of viral meningitis was made, and the patient improved after acyclovir therapy. His past medical history was unremarkable. The physical examination revealed edematous erythema on his face, neck and limbs. The neurological examination was normal. Skin biopsy revealed nonspecific inflammation with lymphocytic infiltration; however, no culture of skin tissue was performed. Chest computed tomography (CT) revealed patchy changes (Fig. 1A), while head CT (Fig. 2A) showed no significant abnormalities. During hospitalization, the patient developed enlargement of neck and inguinal lymph nodes, along with pain. Histopathologic examination of an inguinal lymph node revealed reactive hyperplasia of lymph node sinus cells. But NGS of the inguinal lymph node revealed Epstein-Barr virus (EBV) infection. Immunoglobulin A (IgA) and DNA of EBV were detected in the serum. To exclude nasopharyngeal carcinoma, a nasopharyngeal CT scan and nasopharyngoscopy were performed, and nasopharyngeal masses were identified. However, pathology showed marked neutrophilic infiltration, suggesting Sweet’s syndrome (SS). The total number of white blood cells (WBC) in CSF was 8 * 10⁶/L, the protein content was 235.3 mg/L, and the chlorine level was 125 mmol/L (Table 1). CSF smear, ink staining, Gram stain, the cryptococcal antigen test, and culture were all negative. The NGS revealed EBV in the CSF. He was diagnosed with viral meningitis, and considering the patient had SS, he received corticosteroid treatment and supportive care, resulting in significant improvements in both neurological symptoms and skin lesions. Subsequently, recurrent fever and cough developed with worsening pulmonary lesions on CT. Sputum NGS identified Legionella, while nasopharyngeal tissue culture grew NTM (unclassified). Treatment with moxifloxacin, ethambutol, clarithromycin and doxycycline led to gradual improvement, with subsequent clinical stability.

Fig. 1.

Chest CT. Patient 1 (A) Patchy and nodular increased density shadows were seen in both lungs, with mediastinal lymph node enlargement. Patient 2 (B) A mass in the lower lobe of the right lung with hilar and mediastinal lymphadenopathy. Patient 3 (C) Patchy infiltrates in both lungs

Fig. 2.

Brain CT. Patients 1 (A) and 2 (B) showed old cerebral infarctions

Table 1.

Summary of laboratory data of all three patients in our series

Results	Patient 1	Patient 2	Patient 3	Reference range
WBC(109/L)	10.99	18.47	19.18	3.5–9.5
CRP(mg/L)	176.1	96.16	182.43	0–10
ESR (mm/h)	74	67	101	0–20
PCT(ng/ml)	0.597	1.01	5.24	0–0.05
IgG(g/L)	10.1	14.76	22.13	8.6–17.4
IgE(IU/mL)	101	48.7	183.7	< 100
Blood glucose(mmol/L)	4.03	4.21	3.67	3.9–6.1
Results of CSF
Coascious disturbance	Clear	Clear	Clear	Clear
Pressure	51 drops/min	145mmH2O	67 drops/min	80-180mmH2O
Protein(g/L)	235.3	464.4	672	150–450
Glucose(mmol/L)	3.16	3.26	3.47	2.5–4.5
Chlorine level(mmol/L)	125	125.3	125.1	120–132
Total number of white blood cells(106/L)	8	10	34	-
The Pandy test	Negative	Negative	Positive	Negative
Titer of Anti-IFN-γ antibodies	> 1:2500	> 1:2500	> 1:2500	Negative

Patient 2

A previously healthy 63-year-old woman presented with a one-week duration of fever, cough, and headache. She had no history of organ transplantation, leukemia, diabetes, or autoimmune disease. Complete blood count analysis showed markedly increased white cells and neutrophil ratio (Table 1). Sputum acid-fast staining and microbial culture were negative. Chest CT revealed a right lower lobe mass with hilar and mediastinal lymphadenopathies (Fig. 1B), and brain CT showed no abnormalities (Fig. 2B). Streptococcus pneumoniae and Stenotrophomonas maltophila were identified using metagenomic next-generation sequencing (mNGS) from the alveolar lavage fluid. Antibacterial treatment was not effective. In addition, she started to present with an exacerbating headache. A lumbar puncture was performed based the patient’s clinical condition (Table 1). TB and EBV were identified using mNGS from the CSF. TB meningoencephalitis was suspected, and antituberculosis regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol was initiated. The patient gradually improved after empirical anti-tuberculosis treatment, and a clinical diagnosis of tuberculous meningitis was made. Her clinical condition remained stable during subsequent outpatient follow-up.

Patient 3

The patient, a 60-year-old Chinese man with no previous disease history, was admitted to our hospital with pain in the neck-shoulder region and fever for one month. Prior to coming to our hospital, he had been treated with various antibiotics in other hospitals. TM was cultured from his blood, but symptoms persisted. He was discharged after four days, but his condition worsened with the development of cervical and supraclavicular lymphadenopathy. The patient’s inflammatory markers were significantly abnormal (Table 1). Chest CT revealed bilateral pulmonary infiltration (Fig. 1C). The emission CT showed a significantly increased uptake in multiple bones. He was diagnosed with disseminated TM infection and was treated with voriconazole. Two days later, he developed persistent headache, but without vomiting, blurred vision, or changes in muscle strength. No pathological findings were evident on neither physical nor neurological examination. Lumbar puncture revealed clear CSF, with a WBC count of 34*106/L, protein 672 mg/L, and glucose 3.47 mmol/L (Table 1). CSF stains for bacteria, fungi, and acid-fast bacilli were all negative, and the CSF culture was also negative. CSF was sent for detection by mNGS, and the test showed Cytomegalovirus (CMV) infection. The patient’s unexplained symptoms, linked to viral meningitis, improved with antifungal and analgesic treatment. Four months later, he discontinued antifungal treatment. Three months after discontinuing the medication, he experienced recurrent fever, cough, and expectoration, resulting in hospitalization. Blood cultures again grew TM, and NGS confirmed TM, CMV, and EBV coinfection. He improved with intravenous amphotericin B and ganciclovir and remained stable on outpatient follow-up.

Immunological investigations

We quantified plasma AIGAs titers by enzyme-linked immunosorbent assay (ELISA) using serially diluted patient sera and categorized positive results into three tiers (1:100, 1:500, and 1:2500) based on dilution endpoints. We assessed the neutralization of IFN-γ-induced STAT-1 phosphorylation in THP-1 cells by Western blot. Patients were classified as AIGAs-positive if they met both criteria: (1) an indirect ELISA OD > 0.5 at 1:100 dilution; (2) detectable neutralizing activity on Western blot. All patients were AIGAs-positive with high titers (> 1:2500) and diagnosed with AOID, which was associated with AIGAs (Table 1).

Discussion and conclusions

We report three HIV-negative Chinese adults who had multiple organ infections, including CNS, most likely due to AIGAs. Extensive PubMed, Embase and Google Scholar searches yielded only seven articles reporting a total of seven CNS infection cases with AIGAs. The average age of the cases was 53.6 (range 39–65 years), and five were female. The majority of these patients were Asian (71.4%), and none had a previous history of immunodeficiency disease. The most common CNS-related symptom was headache (71.4%), followed by limb weakness (28.6%) and vision loss (14.3%). Bacteria and viruses can be the causative agents, as reported in the literature, with viruses seemingly the most commonly isolated organisms in our series. The main diagnostic methods are NGS of CSF and cultures of brain specimens from various regions. Among these patients, one was empirically diagnosed with CNS infection based on CSF results and brain magnetic resonance imaging (MRI) findings [6]. Moreover, these patients all were co-infected with multiple species in other parts of the body during the course of infections or at the same time. After the pathogens were identified, the patients’ symptoms improved following active anti-infective treatment. For CNS infections, we can opt for medications that easily penetrate the BBB. In our series of patients, the symptoms of patients with brain viral infection can also be improved with supportive management. Our study is the first to observe, describe and summarize intracranial infection with positive AIGAs. A compilation of articles reporting CNS infections with AIGAs is presented in Table 2.

Table 2.

Summary of epidemiology, clinical features, treatment and outcome of all reported patients who had central nervous system infections associated with anti-IFN-γ autoantibodies

ID	Ethnicity	Sex/age (years)	Comorbidity	Manifestation	Pathogens of CNS infection	Diagnostic method	Co-infetion of other sites	Treatment	Outcome
1 [7]	Chinese	F/51	No	Cough, fever, rash, paroxysmal headache, lose consciousness, neck stiffness, weakened limb muscles	Intracranial infection	Brain MRI, CSF examination	P. acnes, Yeast-like fungal spores, Malassezia, Malassezia globoides	CTX, AMK, AZM, RFP, EMB, FLC	Survived
2 [6]	Caucasian	F/65	No	NA	Toxoplasmosis	Biopsy	MAC, S. enterica	SDZ/PYZ, RFP, EMB, CAM	NA
3 [8]	Chinese	M/54	No	Fever, coughing with expectoration, dizziness, headache, gait imbalance	N. farcinica	Purulent fluid culture of brain tissue	TM	VRZ, SMX-TMP, MXF	Survived
4 [9]	Caucasian	F/39	Asthma	Shortness of breath, seizures, left-sided weakness, headaches, fevers, weight loss, night sweats	MAC	Culture from brain and meningeal specimens	MAC	RFP, EMB, AZM	Survived
5 [10]	Thai	F/53	No	Right cervical mass, fever, weight loss, fatigue, vision loss in left eye	VZV	CSF analysis for VZV-DNA by PCR	Cryptococcosis,M. abscessus	AmB, FLC, AMK, IMI, AZM, LVF, ACV	Survived
6 [11]	Chinese	F/59	No	Fever, headache, malaise, neck mass, chest and back pain	L. monocytogenes	NGS analysis of CSF	TM, L.monocytogenes, M. kansasii	LAmB, VRZ, PIP-TAZ, AMP, MER, AMK, TIG, CAM, LNZ, EMB, RFP	Survived
7 [12]	Chinese	M/54	No	Experienced cough, hemoptysis, dyspnea, high fever, chest pain, bone pain, persistent headache, lower back pain	L. monocytogenes	NGS analysis of CFS	B. cepacia, S. aureus, TM, M. kansasii	MER, PIP-TAZ, LAmB, VRZ, AMP, TIG, AMK, LNZ, EMB, CAM, RFP,	Survived

M male, F female, NA not available, N. farcinica Nocardia farcinica, MAC Mycobacterium avium complex, VZV Varicella-zoster virus, S. enterica Salmonella enterica, M. abscessus Mycobacterium abscessus, P. acnes Propionibacterium acnes, M. kansasii Mycobacterium kansasii, S. aureus Staphylococcus aureus, B. cepacia Burkholderia cepacia, VRZ voriconazole, SMX-TMP sulfamethoxazole-trimethoprim, MXF moxifloxacin, SDZ/PYZ sulfadiazine/pyrimethamine, RFP rifampicin, EMB ethambutol, CAM clarithromycin, AZM azithromycin, AmB amphotericin B, FLC fluconazole, AMK amikacin, IMI imipenem, LVF levofloxacin, ACV acyclovir, CTX ceftriaxone, LAmB liposomal amphotericin B, PIP-TAZ piperacillin-tazobactam, AMP ampicillin, MER meropenem, TIG tigecycline, LNZ linezolid

IFN-γ is secreted by T lymphocytes, including CD4 + and CD8 +, and NK cells [10, 13]. It has been shown to play important roles in both innate and adaptive immunity [14, 15]. It plays an important role against intracellular pathogens, such as mycobacteria, TM, VZV, Cryptococcus [1, 4, 5, 16]. Autoantibodies to IFN-γ were able to block IFN-γ binding, inhibiting the early aspects of IFN-γ signal transduction, such as STAT-1 phosphorylation, and inhibiting at least some of the downstream biological consequences of IFN-γ binding, such as the IFN-γ-dependent up-regulation of TNF-α and IL-12 production [3]. Therefore, it leads to immunodeficiency, and increases the susceptibility to infection. Previous studies have shown that AIGAs in adults are strongly associated with two specific HLA class II alleles: HLA-DRB1*16:02/DQB1*05:02 and HLA-DRB1*15:02/DQB1*05:01 [2, 4, 5, 10, 16–18]. But the disease does not appear to be inheritable, and research is still lacking on the familial genetic mechanism of AIGAs. Furthermore, environmental stimuli may trigger the disease, including infections and exposure to toxins [1, 19]. Indeed, the mechanism of the production of autoantibodies to IFN-γ remains unclear.

AIGAs have been reported to be associated with disseminated infections that have damaged multiple organs. CNS involvement is relatively uncommon, and usually occurs in immunocompromised patients. Breakdown of the BBB is a common feature of many diseases of the CNS. Disruption of the BBB results in the loss of nutrient/oxygen delivery, rapid infiltration of immune cells, and brain swelling [7, 20]. Autoimmune diseases were not observed in our patients during the course. They are all infected with different opportunistic pathogens, and developed different neurological symptoms such as headache, limb weakness, and decreased vision. We consider that there may be intracranial infection and potentially immunodeficiency. The cell count, glucose, and protein in CSF were normal or slightly elevated, and viral DNA or RNA could be detected by NGS testing in the CSF. This conforms to the clinical diagnostic criteria for viral meningitis [21]. High serum titers of AIGAs also confirmed our conjecture. VZV infection is also a common type of infection in AIGAs-positive patients. A recent report has documented that it may be related to the reactivation of VZV in AIGAs-positive patients [22]. In addition to VZV, AIGAs-positive patients also showed a significant increase in antibody levels against other herpesvirus members (including CMV and EBV) [23]. These results suggest that elevated levels of antibodies against multiple herpesviruses may reflect immunosuppression caused by a loss of IFN-γ, and support the important role of IFN-γ in controlling multiple different herpesvirus infections. It is reported that the clinical usefulness of EBV PCR in CSF is not significant [24]. However, the patients also suffered from opportunistic infections in other parts of the body and AIGAs-related immunodeficiency. In this case, herpesviruses may be reactivated, similar to VZV, leading to CNS infection. Therefore, intracranial infection should be suspected. We believe that these viral infections are secondary infections caused by immunodeficiency associated with AIGAs. The type and number of viruses can reflect the severity of the disease, and more importantly, the severity also depends on changes in antibody titers and the presence of other pathogens, such as NTM and TM. However, more research is needed to explore the relationship between EBV reactivation and AIGAs onset.

Adult-onset immunodeficiency associated with AIGAs is a rare disease with a low incidence. Although some researchers advocate for the testing of AIGAs in previously healthy individuals with unexplained disseminated NTM infections, the systematic detection of AIGAs in Asian populations is currently challenging due to the high diversity in clinical presentations, the low sensitivity of bacterial cultures, and the lack of AIGAs testing [25, 26]. For patients with one or more opportunistic infections and no immunosuppressive condition severe enough to explain these infections, consideration should be given to testing for AIGAs. However, there is no unified treatment guideline for the treatment of AIGAs. If patients with AIGAs have opportunistic infections, the choice of potent antibiotics targeted at the pathogen is the mainstay of treatment. IFN-γ therapy, anti-CD20 antibody therapy, intravenous immunoglobulin, cyclophosphamide (CTX), and plasmapheresis have been reported in small sample studies [2, 3, 27, 28]. Epitope-erased IFN-γ reactivated the IFN-γ downstream pSTAT1signaling and IL-12 production, thereby achieving the therapeutic goal, but it remains in the in vitro experimental stage [29]. In a review, the efficacy of CTX was found to be higher than that of rituximab (RTX) [2]. In contrast, a cohort study conducted in Thailand showed that the efficacy of RTX and CTX was comparable [27]. It has been reported that a rapid decline in the titer of AIGAs after 6 months of CTX therapy indicates a good prognosis [30]. In the case of continuous high AIGAs titers, clinicians should consider switching to other immunosuppressive agents with different targets, rather than extending the duration of CTX treatment. However, it is worth noting that some patients did not respond to both RTX and CTX, and others experienced a relapse after discontinuing RTX [2, 27, 28]. Therefore, more large multi-center cohort studies are needed to develop a standard treatment protocol for the disease and to improve disease outcome.

This study has several limitations: (1) incomplete clinical data, including untested CSF AIGAs levels, lack of brain MRI due to early clinical improvement, and insufficient sample size for statistical analysis. Nevertheless, our work highlights the complexity of AIGAs-associated infections and improves understanding of AIGAs-induced immunodeficiency. Overall, patients with AIGAs typically present with systemic opportunistic infections, while CNS involvement is relatively uncommon. We recommend that AIGAs testing be performed when opportunistic infections, particularly NTM or TM, are identified; conversely, when AIGAs-positive patients develop CNS symptoms, prompt CSF pathogen testing is warranted to exclude opportunistic CNS infections.

Abbreviations

AIGAs

Anti-interferon-γ autoantibodies

CNS

Central nervous system

BBB

Blood–brain barrier

CSF

Cerebrospinal fluid

mNGS

Metagenomic next-generation sequencing

MRI

Magnetic resonance imaging

AOID

Adult-onset immunodeficiency

Authors’ contributions

Zhiyi He designed the study and had full responsibility for the facticity of data. Yan Ning wrote the main manuscript text, Siqiao Liang, Xiaona Liang and Xuemei Huang prepared table and modified the main manuscript, Hanlin Liang completed the experiment. All authors read and approved the final manuscript.

Funding

This work was supported by the Guangxi Science and Technology Program (no. 2023AB22055) and the Central Leading Local Science and Technology Development Fund Project (no. 2023ZYZX1021).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Ethical approval was waived by the research ethics committee of the first affiliated hospital of Guangxi medical university. All patients provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

Consent for publication

Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

Competing interests

The authors declare no competing interests.