Uncommon clinical presentations and diagnostic difficulties of antiphospholipid syndrome associated with cryptococcal meningitis: A case study

Abstract

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombosis and obstetric morbidity. We report a 23-year-old female with APS who developed cryptococcal meningitis (CM) following immunosuppressive therapy. Diagnosed via cerebrospinal fluid (CSF) culture and MRI showing infarction, she had concomitant renal and hepatic failure, making amphotericin B contraindicated. Consequently, an individualized regimen comprising voriconazole and 5-fluorocytosine (5-FC) was initiated, resulting in significant clinical improvement. This case underscores that CM is a serious opportunistic infection in patients undergoing immunosuppression for APS, highlighting the need for vigilant monitoring and tailored antifungal strategies for multi-organ dysfunction.

1. Introduction

Long-term management of antiphospholipid syndrome (APS) frequently involves immunosuppressive treatments, such as the use of glucocorticoids alongside calcineurin inhibitors. These therapies are effective in managing the hypercoagulable state but may adversely affect natural immune responses and T cell-mediated defenses against fungal infections [1]. Cryptococcal meningitis (CM) is a severe opportunistic infection occurring in 2–12 per 100,000 non-HIV immunosuppressed individuals annually, with a 20–30 % case-fatality rate, leading to serious health implications [2]. Notably, APS is characterized by specific pathological alterations, including antiphospholipid antibody-mediated vascular endothelial damage, enhanced monocyte activation, and complement pathway dysregulation. These may hinder central nervous system (CNS) clearance of Cryptococcus. To the best of our knowledge, cases of CM in primary APS are exceedingly rare [3]. Furthermore, evidence-based consensus is lacking regarding the selection of antifungal medications for patients with concurrent liver and kidney dysfunction, creating substantial challenges in clinical decision-making.

This article discusses a 23-year-old woman diagnosed with APS who experienced CM following five-month of immunosuppressive treatment. It aims to explore three clinical inquiries that remain inadequately addressed. Firstly, there might be a link between the duration of immunosuppressive therapy and risk of opportunistic infection; in this instance, the five-month period between the initiation of immunosuppression and the onset of meningitis indicates a potential vulnerability during this timeframe. Furthermore, given the patient's concurrent hepatic and renal dysfunction, amphotericin B—a nephrotoxic first-line agent—was contraindicated. Consequently, an alternative regimen of voriconazole and 5-fluorocytosine (5-FC) was evaluated for efficacy and safety. Lastly, when clinical symptoms overlap, it is essential to develop effective strategies to differentiate between thrombotic complications related to APS (such as headaches from cerebral infarction) and the initial neurological signs of CM. This case does not elucidate a novel mechanism; rather, it illustrates offering practical clinical implications that can be further examined in these intricate clinical situations, highlighting the need for vigilant monitoring of opportunistic infections in patients with APS.

2. Case presentation

A 23-year-old woman presented with intrauterine fetal death in May 2023, requiring pregnancy termination, and was subsequently diagnosed with severe preeclampsia when her blood pressure reached 200/100 mmHg. Following treatment with four antihypertensive medications including metoprolol tartrate, terazosin hydrochloride, felodipine sustained-release and carvedilol for inadequately controlled blood pressure, she experienced bilateral lower leg edema and acute kidney injury. In July 2023, she was referred to the Affiliated Hospital of Guizhou Medical University. Laboratory investigations demonstrated a lupus anticoagulant (LA) level of 41.90 seconds, anti-phosphatidylethanolamine antibody 193.35 ng/mL, anti-annexin A5 antibody 225.70 ng/mL, IgM anti-thrombin antibody 24.56 U/mL, IgM anti-phosphatidylinositol antibody 33.35 U/mL and plasma protein C activity of 180 %, while anticardiolipin antibodies and anti-β2-glycoprotein I antibodies were negative. A renal biopsy confirmed focal proliferative sclerosing IgA nephropathy with 10 % crescent formation, supporting a diagnosis of APS. She was administered methylprednisolone (500 mg daily for 3 days), underwent three plasma exchange sessions, and required hemodialysis, resulting in clinical improvement. Upon discharge, her immunosuppressive regimen included mycophenolate mofetil at 0.75 g twice daily, cyclosporine at 50 mg twice daily, and prednisone acetate at 35 mg once daily. The patient was readmitted on November 8, 2023, with progressively worsening headache, nausea, and vomiting. Physical examination revealed severe anemia, blood pressure 174/95 mmHg, and coarse breath sounds bilaterally. Laboratory results indicated hemoglobin 59 g/L, creatinine 497 μmol/L, ultrasensitive C-reactive protein 81.52 mg/L, alanine aminotransferase (ALT) 111 U/L, type III procollagen 64.24ng/mL, laminin 205ng/mL and hyaluronic acid 530.2 ng/mL. Timeline of important events is shown in Fig. 1.

Fig. 1.

Timeline of important events. LA: Lupus anticoagulant; LP: Lumbar puncture; ICP: Intracranial pressure; CSF: Cerebrospinal fluid.

On November 16, 2023, the patient experienced an unprovoked seizure accompanied by a loss of consciousness. A cranial magnetic resonance imaging (MRI) revealed an acute lacunar infarction in the right basal ganglia and semioval center (Fig. 2A), along with abnormal signal areas in the left temporal lobe (Fig. 2B and C). A lumbar puncture indicated an intracranial pressure of 370 mmH₂O, with CSF nucleated cells at 775 × 10⁶/L, CSF total protein (U-TP) 387 mg/L; while initial India ink stain was negative, the subsequent two follow-up tests yielded positive results (Table 1). Meanwhile, cerebrospinal fluid culture on Sabouraud dextrose agar confirmed Cryptococcus neoformans (Fig. 2E and F). Following the diagnosis of CM, treatment was initiated with voriconazole, starting with a loading dose followed by a maintenance dose of 0.2 g intravenously every 12 hours, combined with oral 5-FC 150 mg every 6 hours. Due to a creatinine clearance of less than 15 mL/min, amphotericin B was contraindicated. Intracranial pressure was managed with mannitol 125 mL every 8 hours. Sodium valproate infusion controlled seizures. Prednisone was tapered to 20 mg daily, and anticoagulation was halted. Hemodialysis sessions were maintained three times weekly. After two weeks of this regimen, the patient reported relief from headaches and no further seizures. A lumbar puncture on December 23, 2023, indicated a decrease in intracranial pressure to 260 mmH₂O (Table 1), with nucleated cells dropping to 8 × 10⁶/L; cranial MRI showed a reduction in the size of the left temporal lobe lesions (Fig. 2D).

Fig. 2.

MRI Images of the Brain and Microscopic and Culture Presentation of Cryptococcus neoformans. A: 2023 Dec 05 Brain MRI DWI/T2-FLAIR shows acute lacunar cerebral infarction in the right basal ganglia region and semioval center. B and C: 2023 Dec 05 Brain MRI DWI/T2-FLAIR + ADC shows abnormal signal foci in the left temporal lobe. D: 2024 Jan 20 Repeat head cranial MRI DWI/T2-FLAIR shows resolution of the abnormal signal shadow in the left temporal lobe. E: Microscopic observation of India ink smear proven: positive for Cryptococcus neoformans. F: Cerebrospinal fluid culture on Sabouraud dextrose agar (SDA) at 30 °C for 72 hours, with the organism identi fied by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), result is strongly positive.

Table 1.

Summarizes the serial cerebrospinal fluid analysis results, including pressure, routine parameters, biochemistry, India ink staining, and CSF culture findings.

Date	Pressure (mmH2O)	NC (cells/mL)	U-TP (mg/L)	GLU (mmol/L)	CL-(mmol/L)	India ink stain	CSF Culture
2023 Nov 17	370	775	387	2.67	132	–	++++
2023 Dec 6	340	3	379	4.54	128	+	++++
2023 Dec 23	260	8	284	2.27	127	+	–

Abbreviations: U-TP: Total protein in cerebrospinal fluid; GLU: glucose. NC: Nucleated cells, CSF: Cerebrospinal fluid.

At the six-month follow-up, significant improvement in functional status was observed, enabling independent ambulation and activities of daily living. She reported no headache or fever symptoms related to infection or new thrombotic events. Laboratory findings indicated stable liver function (ALT 38 U/L) while confirming the persistence of chronic kidney disease (Creatinine 791 μmol/L), consistent with her known history.

3. Discussion

A young woman with APS commenced aggressive immunosuppressive therapy following pregnancy termination. Her diagnosis of APS was established per the 2023 ACR/EULAR classification criteria, based on a history of arterial thrombosis, intrauterine fetal demise, and twice positivity for LA [4]. In November 2023, she experienced a sudden deterioration characterized by severe headache, vomiting, and fever. Cerebrospinal fluid analysis confirmed the presence of CM, revealing an intracranial pressure of 370 mmH₂O, while cranial MRI indicated acute cerebral infarction and abnormal signals in the temporal lobe. This case highlights the association between immunosuppressive therapy and the development of opportunistic infections. The use of cyclosporine led to a significant decrease in CD4⁺ T-lymphocytes by blocking the calcineurin-nuclear factor of activated T-cells (NFAT) signaling pathway, while mycophenolate mofetil further compromised monocyte phagocytosis. The combined effects of these medications severely hindered the intracellular clearance of Cryptococcus [5]. Notably, studies have shown that antiphospholipid antibodies (aPL) may cause endothelial injury by increasing phosphatidylserine expression on endothelial cell surfaces, creating binding sites for Cryptococcus capsular polysaccharides. This results in a dual pathological process of immunosuppression and microvascular damage [6,7]. This mechanism may explain the discordant CSF findings in our patient: India ink staining was negative while fungal culture showed strong positivity. This pattern differs from typical HIV-associated cryptococcal meningitis, where both tests are usually positive [8].

The patient presented with concomitant renal and hepatic failure, necessitating a careful treatment balance. Deoxycholate amphotericin B was unsuitable due to nephrotoxicity and poor dialysis clearance, leading to the selection of voriconazole and 5-FC [9]. Voriconazole is minimally renally metabolized and primarily hepatically cleared via cytochrome P450 2C19 (CYP2C19) [10], while 5-FC is effectively dialyzed with its metabolite fluorouracil (half-life 3–6 hours) [11]. Voriconazole dosing was adjusted for hepatic dysfunction, achieving CSF clearance without organ function deterioration, demonstrating regimen viability with dialysis support. However, initial assessment overlooked critical differential diagnosis factors; headaches initially attributed to APS-related thrombosis warranted earlier consideration of CM rather than APS. Intracranial pressure in CM can exceed 300 mmH₂O in immunosuppressed patients, and early-stage CM may present with non-specific MRI signals misinterpreted as vascular lesions. This diagnostic pitfall highlights that new neurological symptoms in immunosuppressed patients require CM exclusion before attributing them to APS activity.

Furthermore, the identification of concomitant IgA nephropathy signifies a more complex renal pathology than APS thrombotic microangiopathy alone, suggesting potential synergistic injury. This finding compels a reattribution of the acute kidney injury and intensifies the therapeutic dilemma, as the standard APS immunosuppression (e.g., mycophenolate mofetil, cyclosporine) has limited efficacy against IgA nephropathy. This limitation potentially exacerbates renal progression while contributing to the net immunosuppression that led to cryptococcal meningitis. Consequently, long-term management must evolve from a singular focus on thrombosis prevention to a continuous balancing of this goal with infection vigilance and direct control of glomerular inflammation, directly addressing the core clinical paradox outlined in this case.

CM following APS presents a therapeutic paradox: the immunosuppression essential for thrombosis prevention can enable opportunistic infections, while anticoagulation heightens the risk of intracranial hemorrhage in the setting of meningitis and thrombocytopenia. While the 2023 ACR/EULAR APS classification criteria provide robust guidance for thrombosis prevention [4], they lack protocols for immunosuppression de-escalation after a life-threatening opportunistic infection. Evidence-based tapering requires synthesis of three guidelines: ECMM and ISHAM cryptococcal guidelines (2024) emphasizing immunosuppression reduction during antifungal therapy [12], EULAR/ERA-EDTA lupus nephritis recommendations (2019 update) proposing mycophenolate discontinuation with azathioprine substitution [13], and AST-IDCOP transplant protocols (2021) advocating stepwise antimetabolite withdrawal first [14]. A proposed three-phase protocol should use objective infection control guideposts to guide transitions.

During the induction phase (weeks 0–8), clinical decision-making requires balancing infection control and thrombosis prevention. These conflicting goals necessitate a three-step approach: First, the discontinuation of mycophenolate mofetil should be considered. This is due to its association with a 2.8-fold increased risk of cryptococcal infection compared to azathioprine, along with the potential synergistic risk of myelosuppression when used concomitantly with 5-FC [15]. This risk is particularly critical in patients presenting with severe anemia and renal insufficiency. Second, when adjusting the immunosuppressive regimen, we chose to continue low-dose cyclosporine (target C₀ 50–100 ng/mL). This approach aims to utilize its immunomodulatory effects for APS control, while also considering research suggesting its potential synergistic effect with antifungal agents [16,17]. Regarding the management of the primary disease, therapeutic anticoagulation should be withheld until the platelet count stabilizes above 50 × 10⁹/L. This is a key measure to reduce the risk of fatal intracranial hemorrhage, as the risk of cerebral bleeding is significantly increased in active CM accompanied by thrombocytopenia [18]. Finally, corticosteroids should be rapidly tapered to a prednisone equivalent of ≤7.5 mg per day, given evidence that the risk of infection doubles with approximately every 10 mg increase in dose [19,20].

When the patient enters the consolidation phase (months 2–6), after achieving ≥2 negative cerebrospinal fluid cultures, the focus of treatment should shift towards establishing a long-term maintenance plan based on individualized risk assessment. This assessment should comprehensively consider several evidence-based risks: 1) triple aPL positivity, which can lead to a several-fold increase in thrombosis recurrence risk [21,22]; 2) a history of arterial thrombosis or catastrophic APS, indicating a relatively high recurrence risk [23]; 3) T-cell immunodeficiency is present, with studies showing that in HIV patients, a CD4 count <200 cells/μL suggests an increased risk of opportunistic infections [13,24]; and 4) functional asplenia and persistent renal insufficiency (eGFR<30 mL/min), which increases infection-related mortality [25,26]. For a patient like this one, with multiple high-risk factors such as LA positivity, end-stage renal disease, and a history of arterial thrombosis, the treatment strategy tends to be conservative. A regimen of low-dose cyclosporine monotherapy combined with hydroxychloroquine may be adopted, as the latter can reduce thrombosis risk without significantly increasing risk of opportunistic infection [27,28]. The reintroduction of anticoagulation must be extremely cautious, undertaken only after the infection is controlled and platelet counts have stabilized [29,30]. Consideration may be given to using hydroxychloroquine as foundational therapy during reintroduction to navigate the high-risk period for thrombosis. Tapering of cyclosporine should be contingent upon evidence of adequate treatment duration, or sustained seroconversion of aPL to negative, coupled with no clinical evidence of thrombotic recurrence [31].

Although this strategy is effective, there are also some shortcomings in the treatment process. These gaps include: the initial diagnostic workup lacked rapid cryptococcal antigen testing owing to reagent shortages, resulting in diagnostic delay; and the absence of a follow-up lumbar puncture precludes microbiological confirmation of cure. Furthermore, due to resource limitations, therapeutic drug monitoring (TDM) was not performed throughout treatment. TDM is essential to guide voriconazole dose reduction and optimal post-hemodialysis 5-FC dosing. Looking forward, this case highlights the urgent need for clinical trials focused on APS-specific immunosuppression de-escalation after opportunistic infections. Emerging data on JAK-STAT inhibitors showing lower cryptococcal risk than calcineurin inhibitors, and the potential of aPL avidity assays to identify patients who can safely minimize immunosuppression are promising directions. The proposed risk-adaptive strategy, informed by serial monitoring of aPL profiles and drug levels, effectively navigates the core clinical dilemma by minimizing iatrogenic immunosuppression while preserving essential control over APS.

CRediT authorship contribution statement

Zhengxiang Lv: Writing – original draft, Resources, Investigation, Formal analysis, Data curation, Conceptualization. Xiaodong Liu: Writing – review & editing, Visualization, Validation, Software. Ping Xu: Writing – review & editing, Validation, Supervision, Project administration, Investigation.

Ethical statement

This case report has been conducted in accordance with the ethical standards of your Group 302 Hospital and the principles of the Declaration of Helsinki. Informed consent was obtained from the patient for the publication of this case report and its accompanying clinical data and images. Every effort has been made to protect the privacy and confidentiality of the patient.

Conflict of interest

The authors declare that there are no conflicts of interest.

Abbreviations

5-FC

5-Fluorocytosine.

aβ2GPI

anti-β2-glycoprotein I antibodies

ACR

American College of Rheumatology

ADC

Apparent Diffusion Coefficient

aCL

anticardiolipin antibody

aPL

antiphospholipid antibodies

APS

Antiphospholipid Syndrome

AST-IDCOP

American Society of Transplantation Infectious Diseases Community of Practice.

ALT

Alanine Aminotransferase

CD4

Cluster of Differentiation 4

CM

Cryptococcal Meningitis

CNS

Central Nervous System

CSF

Cerebrospinal Fluid

CYP2C19

Cytochrome P450 2C19

DWI

Diffusion-Weighted Imaging

ECMM

European Confederation of Medical Mycology

eGFR

estimated Glomerular Filtration Rate

EULAR

European League Against Rheumatism

FLAIR

Fluid-Attenuated Inversion Recovery

HIV

Human Immunodeficiency Virus

IgA

Immunoglobulin A

ISHAM

International Society for Human and Animal Mycology

JAK-STAT

Janus Kinase - Signal Transducer and Activator of Transcription

LA

Lupus Anticoagulant

MALDI-TOF MS

Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry

MRI

Magnetic Resonance Imaging

NFAT

Nuclear Factor of Activated T-cells

SDA

Sabouraud Dextrose Agar

TDM

Therapeutic Drug Monitoring

U-TP

Total protein in cerebrospinal fluid