A Master of Disguise: Disseminated Fungal Disease Revealing Immunodeficiency

Abstract

Disseminated fungal infection (DFI) is the presence of a fungal pathogen in the blood and/or any other deep-seated site due to vascular spread. It represents a rare but life-threatening infectious complication in immunocompromised patients. In this case report, we present a 19-year-old male with weakness of the limbs, headache, and slurred speech. He was a known case of endobronchial fungal infection with worsening neurological symptoms. Motor examination revealed reduced tone and strength, while respiratory examination revealed bilaterally decreased air entry. Fundoscopic examination revealed papilledema. Immunological evaluation demonstrated elevated IgE and IgG levels and a reduced CD16/56 natural killer cell count, indicating defective innate immunity. Radiological examination, including computed tomography (CT), positron emission tomography-computed tomography (PET-CT), and magnetic resonance imaging (MRI), demonstrated nodules with opacities and mediastinal and cervical lymphadenopathy in the chest, as well as multiple supratentorial and infratentorial lesions, extensive edema, and nodular leptomeningeal thickening on neuroimaging. The patient is hypothesized to have dysfunctional ryanodine receptors (RyR) rather than typical CGD. The patient was managed with antifungal therapy along with antiepileptic and antiedema drugs.

Introduction

Chronic granulomatous disease (CGD) is a rare inherited immune disorder (approximately 1 in 250,000) in which white blood cells cannot kill certain bacteria and fungi, leading to severe, recurrent infections and the formation of inflammatory nodules (granulomas) [1]. In CGD, genetic mutations affect the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme complex, which prevents phagocytes from generating a respiratory burst. Without this burst, the cells cannot produce toxic oxygen radicals to destroy pathogens, allowing opportunistic fungi to spread into a disseminated fungal infection (DFI) [2].

DFI is a fatal condition in which fungi spread through the bloodstream to infect two or more noncontiguous organs, primarily affecting immunocompromised individuals [3]. Dysfunctional ryanodine receptors (RyR) induce a chronic intracellular calcium leak from the endoplasmic reticulum, which depletes internal storage pools [4]. Synchronously, loss of the localized calcium spikes required for structural cell remodeling impairs phagocytosis [5,6]. Consequently, this allows an opportunistic, vasoinvasive DFI to rapidly cross tissue barriers into the bloodstream [7,8].

Disseminated fungal disease (DFD) lacks a unique clinical signature. Its symptoms, including high fever, cough, and organ inflammation, closely mimic common bacterial sepsis, viral infections, or autoimmune disorders (such as CGD), prompting doctors to treat the wrong illness first [9]. The pathogen-killing defect caused by defective RyR functionally mimics the immune system failure seen in inherited CGD [10]. Management of DFD involves a combination of surgical intervention, effective antifungal therapy, and supportive care [11].

In this study, we report a 19-year-old male with DFD and a known history of endobronchial fungal infection, highlighting the diagnostic challenge of differentiating a CGD mimic from classical CGD.

Case presentation

A 19-year-old male presented with weakness of the right upper and lower limbs for four days, headache for one week, slurred speech for four days, and an episode of vomiting on the day before presentation. He was a known case of biopsy-proven endobronchial fungal infection due to Aspergillus fumigatus and had earlier been advised oral voriconazole therapy for two months. Despite treatment, his neurological symptoms progressively worsened, necessitating further evaluation. Considering the severe invasive fungal infection in a young individual, a pre-existing immunodeficiency state, specifically a CGD-like disorder, was suspected. There was no history of similar illness in the patient or his family. The patient was also completely immunized according to the national immunization schedule.

On clinical examination, the patient was conscious, oriented, and afebrile. Neurological examination demonstrated mild right facial weakness with slurred speech. Motor examination revealed reduced tone and power (4/5) in the right upper and lower limbs, with unimpaired motor function on the left side, consistent with right hemiparesis. Bilateral plantar responses were extensor, indicating upper motor neuron involvement secondary to central nervous system pathology. Fundoscopic examination demonstrated papilledema, indicating increased intracranial pressure. Respiratory system examination revealed bilaterally decreased air entry with coarse crepitations, consistent with ongoing pulmonary involvement.

Hematological assessment on the day of admission revealed minor relative lymphopenia (19.1%), elevated mixed cell fraction (24.9%), and elevated absolute mixed cell count (2.5 × 10³/µL), indicative of an ongoing systemic inflammatory response. All other parameters were normal. Suspecting an immunological pathology, evaluation on the second day of admission revealed elevated serum IgG (1936 mg/dL) and serum IgE (1174 IU/mL) levels, indicating chronic immune activation. Lymphocyte subset analysis demonstrated a reduced absolute count of CD16/56 natural killer cells (37 cells/µL), reflecting defective innate immune pathways. Primary epileptiform disorders, peripheral neuropathy, and primary neuromuscular disorders were ruled out as causes of the neurological deficits, as the electroencephalogram (EEG) and nerve conduction study (NCS) findings were reported to be normal (Table 1).

Table 1. Hematological and immunological laboratory investigations.

Investigation	Findings	Reference Range
Relative lymphocyte count	19.1%	20-40%
Mixed cell fraction	24.9%	5-15%
Absolute mixed cell count	2.5 × 10³/µL	0.2–1.0 × 10³/µL
Serum IgG	1936 mg/dL	700-1600 mg/dL
Serum IgE	1174 IU/mL	<100-150 IU/mL
CD16/56 natural killer cell absolute count	37 cells/µL	90-600 cells/µL
Total CD4+ T lymphocyte	93 cells/µL	500-1500 cells/µL
Electroencephalography (EEG)	Normal	Normal
Nerve conduction study (NCS)	Normal	Normal

On the third day of admission, advanced radiological investigations, including contrast-enhanced computed tomography (CECT) chest, whole-body PET-CT, and MRI brain, were performed due to suspicion of disseminated multisystem fungal involvement. Initial CECT revealed dense consolidation with air bronchograms involving the superior and lateral basal segments of the right lower lobe, associated with multiple bilateral peribronchial branching tree-in-bud nodules, mediastinal lymphadenopathy, and minimal right pleural effusion, raising suspicion of pulmonary tuberculosis.

Subsequent positron emission tomography-computed tomography (PET-CT) imaging on the fourth day demonstrated nodules with tree-in-bud opacities, mediastinal and cervical lymphadenopathy (Figure 1), and multiple fluorodeoxyglucose (FDG)-avid supratentorial and infratentorial brain lesions with nodular leptomeningeal thickening were noted (Figure 2), suggesting DFD rather than localized tuberculosis, particularly in view of the patient’s known endobronchial fungal infection.

Figure 1. CT chest and PET-CT chest findings in disseminated fungal disease. (A) Axial CT chest image demonstrating multiple bilateral pulmonary nodules with a tree-in-bud pattern. (B) Corresponding PET-CT image showing increased FDG uptake within the pulmonary nodules, suggestive of metabolically active fungal involvement.

CT: computed tomography, PET-CT: positron emission tomography-computed tomography, FDG: fluorodeoxyglucose.

Figure 2. CT brain and PET-CT brain findings demonstrating CNS involvement. (A) Axial contrast-enhanced CT brain image showing multiple intracranial ring-enhancing lesions with surrounding edema. (B) Corresponding PET-CT brain image demonstrating increased FDG uptake within the intracranial lesions, consistent with metabolically active CNS involvement in disseminated fungal disease.

CT: computed tomography, PET-CT: positron emission tomography-computed tomography, CNS: central nervous system, FDG: fluorodeoxyglucose.

MRI of the brain taken a week later revealed multiple (>10) supratentorial and infratentorial lesions with nodular enhancement, intracavitary projections, and extensive surrounding edema, strongly suggesting DFI involving the CNS (Figure 3).

Figure 3. Axial contrast-enhanced MRI brain sections demonstrating multiple ring-enhancing lesions with surrounding vasogenic edema consistent with CNS fungal involvement.

MRI: magnetic resonance imaging, CNS: central nervous system.

MRI of the cervical spine with whole-spine screening revealed a mild diffuse disc bulge with right foraminal narrowing (Figure 4). No spinal cord compression or myelopathic changes were observed. Hence, these findings were considered incidental and insufficient to explain the focal neurological deficits.

Figure 4. MRI whole spine sagittal images demonstrating extensive spinal evaluation performed as part of disseminated fungal disease assessment.

Arrow: Mild diffuse disc bulge with right foraminal narrowing.

MRI: magnetic resonance imaging.

Multifocal pulmonary lesions, mediastinal lymphadenopathy, and multiple supratentorial and infratentorial intracranial lesions with surrounding vasogenic edema were highly consistent with DFD involving the lungs and CNS. Microscopy with the lactophenol cotton blue stain revealed fungi with septate hyphae and uniseriate phialides, confirming Aspergillus fumigatus.

Subsequently, evaluation for underlying primary immunodeficiency was performed considering severe DFD. Dihydrorhodamine (DHR) assay reported preserved oxidative burst activity in only 57% of granulocytes, whereas the remaining granulocytes showed reduced oxidative burst function. Nitroblue tetrazolium (NBT) reduction testing correspondingly showed preserved oxidative activity in about 50% of granulocytes, indicating partial phagocytic oxidative burst dysfunction. Before genetic testing could be done, the parents requested to be discharged owing to the reason that their son is the sole breadwinner of the family (implying that a further stay could hurt their financial situation even more). However, with the present investigations, we could lead with the diagnosis of severe DFD with pulmonary and CNS involvement, hypothesized to involve the mutation of the RyR channel.

The patient was earlier managed with oral voriconazole; during hospitalization, treatment was continued with intravenous voriconazole 200 mg. Antiedema measures, including oral glycerol 30 mL four times daily, were initiated to manage raised intracranial pressure associated with papilledema and multiple intracranial lesions. He was started on levetiracetam 500 mg twice daily and clobazam 10 mg once daily for preventing seizure-related complications. Intravenous amphotericin B (preferably liposomal) and combination antifungal therapy were advised in the event of clinical deterioration. Focal neurological deficits, in the form of right upper limb weakness and slurred speech, were still present at discharge. Continued antifungal therapy, serial neurological monitoring, supportive care, neurorehabilitation, and follow-ups were advised (Table 2).

Table 2. Treatment and management during hospitalization.

Treatment	Details	Purpose
Antifungal therapy	Oral voriconazole prior to admission; continued with intravenous voriconazole 200 mg twice daily during hospitalization	Management of disseminated fungal infection
Anti-edema therapy	Oral glycerol 30 mL four times daily	Reduction of raised intracranial pressure and papilledema
Neurological monitoring	Serial neurological assessment during hospitalization	Monitoring progression of intracranial involvement and neurological deficits
Antiepileptic therapy	Levetiracetam 500 mg twice daily and clobazam 10 mg once daily	Prevention of seizure-related complications
Escalation antifungal plan	Intravenous amphotericin B (preferably liposomal) and combination antifungal therapy advised if clinical deterioration occurred	Broadening antifungal coverage in severe or progressive disease
Supportive care	General supportive management and rehabilitation measures	Functional recovery and symptomatic improvement
Neurorehabilitation	Continued rehabilitation for persistent neurological deficits	Improvement of motor weakness and speech deficits
Follow-up advice	Pulmonary and neurology clinic follow-up advised	Long-term monitoring and continuation of care

Discussion

DFI is rare in the general population but represents a severe and frequently fatal complication in immunocompromised patients [3]. CGD is a primary immunodeficiency caused by defects in the NADPH oxidase complex, which prevents phagocytes from generating the reactive oxygen species needed to kill fungi and bacteria [2]. DFI typically occurs when host immune defenses, including neutrophil-mediated phagocytosis and oxidative burst, fail to restrict fungal invasion at the site of entry, most commonly the respiratory tract or skin. Subsequently, intravascular fungal invasion facilitates dissemination to distant organs through the bloodstream. Clinical manifestations of DFI are often multisystemic [3]. In this case, we report a 19-year-old male who was a known case of endobronchial fungal infection and presented with neurological and pulmonary manifestations suggesting DFI involving the brain and lungs. Differential diagnoses such as NK cell deficiency, CARD9 deficiency, and IgE deficiency should be considered, given the critically low CD16/56 cell count.

Papilledema, a bilateral swelling of the optic disc, occurs due to increased intracranial pressure caused by infectious CNS lesions [12]. Similarly, in our patient, fundoscopic examination revealed papilledema, which was suggestive of ongoing infectious CNS lesions. Gaikwad et al. reported a case of disseminated cryptococcosis in a patient with bilaterally decreased air entry and coarse crepitations at presentation [13]. Correspondingly, our patient also had bilaterally decreased air entry with coarse crepitations on respiratory system examination, indicating widespread and severe pulmonary invasion.

Karki et al. described a patient with disseminated Cryptococcus infection manifesting a selective innate immunodeficiency, marked by low CD16/CD56 levels (suggesting reduced natural killer cells) and elevated IgE levels. They observed severe opportunistic fungal replication, although the patient was HIV-negative [14]. Similar to previous reports, our patient also showed elevated serum IgG (1936 mg/dL) and serum IgE (1174 IU/mL) levels, suggesting chronic immune activation. Additionally, a reduced absolute count of CD16/56 natural killer cells (37 cells/µL) indicated defective innate immunity pathways. Given this context, immunodeficiency screening was performed to verify the suspected diagnosis of CGD secondary to the severe fungal infection.

Integration of CT, PET/CT, and MRI allows clinicians to effectively diagnose DFD with neuro-pulmonary involvement [15]. Similarly, in our patient, PET-CT imaging demonstrated pulmonary nodules with tree-in-bud opacities, mediastinal and cervical lymphadenopathy, and multiple FDG-avid supratentorial and infratentorial brain lesions with nodular leptomeningeal thickening, suggesting DFD rather than tuberculosis, while MRI findings revealed multiple (>10) supratentorial and infratentorial lesions with nodular enhancement, intracavitary projections, and extensive surrounding edema, which strongly suggested DFD involving the CNS.

Asseri et al. reported an 11-year-old boy with a pulmonary fungal infection caused by Candida tropicalis secondary to an underlying primary immunodeficiency disorder, CGD [16]. This emphasizes the importance of an early diagnosis of CGD. As documented by Hasa et al., the oxidative burst essential for the elimination of foreign bodies can be evaluated through the NBT slide assay and the flow cytometry-based DHR test [17]. In our patient, oxidative burst activity was preserved in only 57% of granulocytes on the DHR assay, while the NBT test demonstrated preserved oxidative activity in approximately half of the granulocytes, suggesting a CGD-like phenotype with partial phagocytic dysfunction rather than classical CGD. Finally, according to these functional immunological analyses, the immunodeficiency in our patient was attributed to defective RyR receptors rather than mutations in genes encoding the NADPH oxidase enzyme complex, leading to a CGD-mimic syndrome.

Defective RyR channels undergo pathological remodeling that causes chronic intracellular calcium leak and depletion of sarcoplasmic reticulum stores [4]. Simultaneously, loss of the localized calcium spikes required for structural cell remodeling inhibits phagocytosis and prevents the respiratory burst activation needed by macrophages to eliminate engulfed foreign bodies, resulting in immunodeficiency [5,6]. Future advancements include the widespread utility of molecular diagnosis and targeted genetic studies for better identification of RyR-associated immune dysfunction and early diagnosis of atypical presentations of immunodeficiency diseases such as CGD.

Conclusions

This case report highlights the need to consider defective RyR-associated immunodeficiency rather than classical CGD in patients with DFI. In our case, the patient presented with partially preserved oxidative burst activity along with CNS and pulmonary involvement, which led to further diagnostic difficulty.

Integration of radiological, microbiological, and immunological evaluation played a key role in establishing the diagnosis. Furthermore, early diagnosis and timely initiation of antifungal therapy aid in improving clinical outcomes and reducing disease-related morbidity.