Complement C9 deficiency as a novel risk factor for invasive Candida esophagitis in children: a single case in-depth analysis

Abstract

Background

The complement system constitutes a critical component of innate immunity against fungal pathogens. Complement component 9 (C9), an essential constituent of the membrane attack complex (MAC), plays a pivotal role in pathogen elimination. However, isolated C9 deficiency has not been previously reported in association with fungal esophagitis.

Case presentation

We present the case of a nearly 7-year-old girl who suffered from progressive dysphagia, nausea, and vomiting for more than two months. Esophagogastroduodenoscopy revealed esophageal stricture, and histopathological examination of mucosal biopsies confirmed Candida albicans infection. Despite multiple endoscopic dilations, symptomatic recurrence occurred monthly. Whole-exome sequencing identified a pathogenic variant confirming isolated C9 deficiency. Combined systemic antifungal therapy with fluconazole and repeated endoscopic dilatation achieved sustained symptomatic resolution.

Conclusion

Isolated C9 deficiency may represent a susceptibility factor for recurrent fungal esophagitis with stricture formation in children. Complement screening should be considered in unexplained recurrent cases. Combined antifungal therapy and endoscopic intervention achieved sustained remission in this patient.

Background

The complement system is critical for innate immunity against microbial infections. Complement component 9 (C9) forms the membrane attack complex (MAC) with proteins C5b C6 C7 and C8. Activated C9 polymerizes to create membrane pores causing cell lysis [1, 2]. This process effectively eliminates Gram-negative bacteria [3]. C9 deficiency is a common genetic complement disorder that increases susceptibility to meningococcal meningitis [4]. The Arg95Stop mutation occurs in 1 in 1000 individuals in homozygous form and affects 1 in 15 people in heterozygous form [5].

Candida esophagitis (CE) caused by Candida albicans affects 0.32% to 2.5% of patients undergoing upper endoscopy [6, 7]. It occurs more often in immunocompromised individuals but can also affect healthy patients [8]. Known risk factors include HIV malignancy diabetes and certain medications [9]. Some cases develop without obvious predisposing factors suggesting underlying immunological issues [10]. Complement deficiencies increase bacterial infection risks but their role in fungal infections remains unclear. The complement system supports antifungal immunity through opsonization and pathogen lysis [11]. Current studies on complement-Candida interactions primarily demonstrate that complement-mediated anti-Candida immunity relies on C3 (opsonization, phagocytosis enhancement) [12], C5 (C5a-driven inflammation and neutrophil recruitment) [13, 14], and C6/C7 (direct antifungal effects via early membrane attack complex assembly) [15]. Deficiencies in C3, C5, or C6/C7 each confer susceptibility to candidiasis, demonstrating their non-redundant, sequential roles in host defense. The link between C9 deficiency and fungal esophagitis has not been previously reported.

This case suggests a potential association between isolated C9 deficiency and recurrent invasive candidal esophagitis in children, which may expand the recognized clinical spectrum of C9 deficiency beyond neisserial infections. These observations hint at a possible role of the terminal complement pathway in mucosal defense against fungal pathogens, though further studies are warranted to establish a definitive causal relationship. This case underscores the value of considering complement function assessment in the diagnostic workup of children with unexplained recurrent fungal esophagitis, potentially contributing to improved immunodeficiency screening strategies for pediatric patients with recurrent infections.

Case presentation

A 6-year-and-11-month-old girl was admitted to the Children’s Hospital of Zhejiang University School of Medicine in February 2025 due to progressively worsening difficulty swallowing over the past two months, accompanied by nausea and vomiting after meals, which had restricted her diet to mainly congee and soft noodles. Two months earlier, an initial evaluation at a local hospital had shown esophageal dilation on chest CT. Subsequent gastroscopy revealed a 6-cm-long esophageal stricture located 14 cm from the incisors, with thick white exudates adherent to the mucosa and proximal esophageal dilation. She underwent five endoscopic dilation procedures using 7-mm and 9-mm bougies, which only marginally improved the luminal diameter from 6 mm to 7 mm. Despite these interventions, her symptoms recurred monthly, leading to her referral to our hospital for further management.

The patient, a second child born to non-consanguineous parents, was delivered at full term (40 weeks) via spontaneous vaginal delivery with a birth weight of 2.6 kg. She has a history of recurrent pulmonary bacterial infections and failure to thrive. Over two years ago, she was admitted to our institution’s Department of Pulmonology presenting with fever, cough, and malnutrition. Initial investigations included a chest CT, which revealed pulmonary infection along with distal esophageal dilation with wall thickening; fiberoptic bronchoscopy, which demonstrated only inflammatory changes of the bronchi; and gastroscopy, which identified scattered white curd-like deposits in the esophagus that were difficult to wipe away. Esophageal mucosal biopsy culture confirmed Candida albicans infection. The therapeutic regimen consisted of intravenous fluconazole at 6 mg/kg daily for one week, followed by oral fluconazole at the same dosage, in combination with piperacillin-tazobactam administered intravenously for one week for the pulmonary infection. However, her parents did not adhere to follow-up recommendations. The patient has been hospitalized four times at local hospitals for conditions including sepsis, oral thrush, and failure to thrive. Additionally, she has received outpatient treatment for a retroauricular abscess, suppurative otitis media, and mastoiditis, the latter requiring incision and drainage.

The mother had an intellectual disability of unknown origin, and the patient has a healthy 17-year-old maternal half-sibling from a different father, with no known family history of primary immunodeficiency. At admission, the child weighed 13.4 kg (below the 3rd percentile) and measured 95 cm in height (below the 5th percentile), appearing alert but noticeably thin. Physical examination revealed pharyngeal hyperemia and multiple white membranous deposits on the tongue and both sides of the buccal mucosa. Breath sounds were coarse bilaterally without wheezing, while cardiac, abdominal, and neurological assessments showed no abnormalities.

The assessment of cell-mediated immunity showed only mild deviations from normal reference ranges for select parameters. The CD19 level was elevated at 36.05% (normal range: 19.0–29.0%), while CD3 was slightly reduced at 61.35% (normal range: 62.0–70.0%). CD4 levels fell within the lower end of the reference range at 30.35% (normal range: 30.0–40.0%), whereas CD8 was marginally decreased at 19.7% (normal range: 20.0–27.0%). Natural killer (NK) cells, identified as CD3-negative, CD16-positive, and CD56-positive, were below the expected range at 5.6% (normal range: 7.0–16.0%). The CD4-to-CD8 ratio was within the normal range at 1.54 (normal range: 1.2-2.0). These findings suggest potential variations in immune cell distribution that may warrant further clinical evaluation (Table 1).

Table 1.

Immunological laboratory findings

Parameter	Result	Reference Range	Units
Lymphocyte Subsets
CD19+ (B cells)	36.05	19.0–29.0	%
CD3+ (T cells)	61.35	62.0–70.0	%
CD4+ (Helper T cells)	30.35	30.0–40.0	%
CD8+ (Cytotoxic T cells)	19.7	20.0–27.0	%
CD3-CD16 + CD56+ (NK cells)	5.6	7.0–16.0	%
CD4/CD8 ratio	1.54	1.2-2.0
Immunoglobulins & Complement
IgG	27.6	5.00-10.60	g/L
IgA	1.53	0.34–1.38	g/L
IgM	1.93	0.44–1.44	g/L
Complement C3	1.533	0.900–1.800	g/L
Complement C4	0.387	0.100–0.400	g/L
Total IgE	< 17.7	0.0-100.0	IU/mL
Other abnormalities
Hemoglobin(Hb)	92	>115	g/L

Laboratory evaluation of humoral immunity demonstrated significantly elevated IgG levels (27.60 g/L, normal range 5.00–10.60 g/L), with mildly increased IgA (1.53 g/L, normal 0.34–1.38 g/L) and IgM (1.93 g/L, normal 0.44–1.44 g/L), while IgE remained within normal limits at less than 17.7 IU/mL (reference range 0.0-100.0 IU/mL). Complement components C3 (1.533 g/L) and C4 (0.387 g/L) were both within their respective normal ranges (Table 1). Hematological evaluation revealed moderate anemia (Hb 92 g/L, normal >115 g/L). Thyroid function and inflammatory indices were normal, and cranial MRI demonstrated no abnormalities.

Initial imaging studies, including a chest CT scan, revealed distal esophageal dilation measuring approximately 21.5 mm (Fig. 1A). An upper gastrointestinal contrast study further showed segmental stenosis in the mid to upper esophagus, spanning the T1 to T5 vertebral levels, characterized by irregular and rigid walls along with distal dilation (Fig. 1B). Additional evaluation through 24-hour pH impedance monitoring indicated prolonged bolus clearance and liquid retention in the mid to distal esophagus. 24-hour esophageal pH monitoring revealed a Boix-Ochoa score of 0.97 (normal: <11.99), excluding gastroesophageal reflux as a contributing factor. Whole-exome sequencing identified a homozygous C9 R116X mutation, confirming a diagnosis of isolated complement C9 deficiency (Fig. 2). Endoscopic examination identified a 9-mm esophageal stricture 12–17 cm from the incisors. Wire-guided balloon dilation was performed sequentially with 10-mm and 11-mm dilators (60-second inflation time each). The mucosa appeared congested and irregular, with scattered white plaques visible (Fig. 3). Biopsy findings confirmed chronic esophagitis accompanied by mild active inflammation (0–3 eosinophils/HPF; Fig. 4), and cultures were positive for Candida albicans. Biopsies from the gastric antrum and duodenal bulb demonstrated mild chronic inflammation without active inflammation. The patient was treated with oral fluconazole at a dose of 50 mg per day for 3 weeks, which successfully resolved symptoms. A two-month follow-up examination using upper gastrointestinal contrast imaging demonstrated improvement in the stricture (Fig. 1C). At ten months after discharge, the patient remained symptom-free with no signs of recurrence, and long-term follow-up continues to monitor progress.

Fig. 1.

A Reconstructed chest CT revealing a dilated segment of the esophagus, as indicated by thearrow. (B+C) Upper gastrointestinal contrast studies. B Pretreatment findings showing esophagealstenosis with irregular walls. C Significant improvement two months after esophageal dilation andantifungal therapy

Fig. 2.

Genetic analysis identifying the homozygous C9 R116X mutation in the patient. Themutation affects the MACPF domain critical for membrane insertion

Fig. 3.

Gastroscopic examination showing hyperemic esophageal stricture mucosa with whiteplaque formation characteristic of Candida infection

Fig. 4.

Histopathological findings of the esophageal mucosa showing chronic esophagitis withmild active inflammation and fungal elements

Discussion

The complement system is a highly evolved and ancient immune defense mechanism that serves dual roles in protecting against pathogen invasion and maintaining tissue homeostasis [1]. It is activated via three main pathways-classical, alternative, and lectin-each initiating a cascade of enzymatic reactions [16]. These reactions involve the cleavage of complement components C4 and C2, the formation of C3 and C5 convertases, and the recruitment of C6, C7, C8, and C9, culminating in the assembly of the membrane attack complex (MAC) on target cell surfaces [1]. The MAC exerts its bactericidal effect by forming transmembrane pores that disrupt cell membrane integrity, leading to rapid lytic destruction. Among its components, C9 plays a pivotal role by expanding the MAC’s diameter and enhancing its efficiency. Through binding, unfolding, and inserting into the target membrane, C9 significantly boosts the MAC’s ability to induce swift lysis, thereby reinforcing the body’s innate immune defenses [17, 18].

Hereditary or acquired deficiencies in terminal complement components C5 to C8 are well-established risk factors for severe infections, particularly those caused by Neisseria meningitidis and Neisseria gonorrhoeae [4, 19]. C9, a single-chain glycoprotein, contains multiple domains, including thrombospondin (TSP), low-density lipoprotein receptor A (LDLa), epidermal growth factor-like (EGF-like), and MAC perforin (MACPF) domains. The MACPF domain, which is perforin-related, plays a crucial role in membrane insertion and cell lysis by penetrating the phospholipid bilayer [17]. Isolated C9 deficiency is predominantly observed in Asian populations, where affected individuals are often asymptomatic, though it is exceedingly rare in non-Asian groups. In Japan, C9 deficiency is among the most common complement deficiencies, with reported prevalence rates ranging from 0.036% to 0.10% [5]. Research has identified a statistically significant link between C9 deficiency and meningococcal meningitis in Japanese patients, with deficient individuals facing a roughly 1,400-fold higher risk of meningococcal disease compared to those with normal complement function [20].

While this patient had no history of meningococcal infection, they did experience recurrent pulmonary bacterial infections, likely caused by Streptococcus pneumoniae, the predominant pathogen in bacterial pneumonia, despite the absence of definitive microbiological confirmation. Previous studies suggest that Streptococcus pneumoniae secretes phosphoglycerate kinase, which binds to complement protein C9, inhibiting MAC assembly and membrane insertion, thereby reducing MAC’s bactericidal effects [21]. Consequently, it is hypothesized that the patient’s C9 deficiency impaired MAC-mediated bacterial clearance, contributing to recurrent pulmonary infections.

Pediatric esophageal infections are relatively rare and primarily occur in immunocompromised children. Although Candida albicans is a normal component of the gastrointestinal microbiota, it typically does not cause disease in healthy pediatric populations. Candida esophagitis (CE) predominantly affects immunosuppressed children, with contributing factors including malignant tumors, chronic metabolic or infectious diseases, or the use of immunosuppressive medications [22]. This condition typically arises secondary to acquired T cell dysfunction, chronic mucocutaneous candidiasis in the pediatric population primarily results from inborn defects affecting the dectin pathway and IL-17 immunity [23]. In light of the patient’s persistent growth retardation and history of recurrent infections since early childhood, a primary immunodeficiency disorder was strongly suspected. Surprisingly, whole-exome sequencing identified isolated complement C9 deficiency as the sole genetic abnormality. The elevated IgG and moderately increased IgA levels observed in this patient likely reflect a compensatory humoral immune response to chronic mucosal infection. The hypergammaglobulinemia observed here is consistent with previously reported cases of chronic mucocutaneous candidiasis, where sustained antigenic stimulation drives polyclonal B-cell activation [24]. The complement system is essential for defending against Candida infections, and deficiencies in key components such as C3 and C5a have been shown to increase susceptibility to candidiasis [11]. This case is of particular interest, as the absence of concurrent immunodeficiency disorders suggests that isolated complement C9 deficiency may constitute a risk factor for opportunistic fungal infections. This observation is suggestive of a possible relationship between terminal complement pathway defects and increased susceptibility to invasive candidiasis, although this association remains to be fully established. In cases of CE, the esophageal mucosa becomes fragile, with ulcerated areas covered by thick, white exudates [25, 26]. Although dysphagia and painful swallowing are the most common symptoms [27], this pediatric case was unusual because the fungal esophagitis initially showed no symptoms and was discovered by chance during an evaluation for recurrent lung infections.

Imaging studies revealed esophageal dilation, which was subsequently confirmed through gastroscopy to be due to a fungal infection. Interventions at the local hospital, including multiple esophageal dilation procedures, provided only temporary relief, with symptoms recurring repeatedly. Therefore, a comprehensive diagnostic workup was undertaken upon admission to our hospital. The absence of pathological acid reflux on 24-hour pH monitoring effectively ruled out gastroesophageal reflux disease as the underlying cause. Similarly, histopathological analysis of esophageal biopsies revealed no eosinophilic infiltration, rendering eosinophilic esophagitis an unlikely etiology. Furthermore, the parental history and endoscopic findings were inconsistent with caustic ingestion or foreign body impaction, thereby excluding these acquired causes. Collectively, these investigations narrowed the differential diagnosis, raising the possibility that an underlying chronic fungal esophagitis may have contributed to the development or persistence of the stricture. Ultimately, a combined approach of esophageal dilation and fluconazole therapy at our institution successfully achieved lasting symptom improvement. Patients with complement deficiencies require heightened vigilance, as they face an increased risk of recurrent fungal esophagitis complications, such as esophageal stenosis and dilation, necessitating aggressive antifungal treatment to mitigate these adverse outcomes.

Systemic antifungal therapy is strongly recommended for esophageal candidiasis, with commonly used agents including nystatin, fluconazole, flucytosine, itraconazole, and amphotericin B [22]. In pediatric cases of CE, fluconazole is the preferred first-line treatment due to its good tolerability, minimal drug interactions, and low recurrence rates, typically administered at a dose of 3 to 6 mg per kg daily for 14 to 21 days [9]. Alternative options for treatment include itraconazole, voriconazole, and isavuconazole. For patients who cannot take oral medications, intravenous fluconazole at 6 mg per kg or echinocandins such as micafungin, caspofungin, and anidulafungin are suitable alternatives [9].

Conclusion

This case highlights the potential value of complement function testing in children with recurrent fungal esophagitis of unclear etiology, particularly when conventional immunological assessments prove inconclusive. Our identification of complement component 9 (C9) deficiency suggests that terminal complement pathway defects may represent an underrecognized predisposing factor. However, the prevalence of C9 deficiency in this patient population remains unknown, and the pathophysiological mechanisms linking terminal complement defects to mucosal fungal susceptibility require further elucidation. Further studies are warranted to confirm this association and inform timely therapeutic intervention.

Abbreviations

C9

Complement component 9

MAC

The membrane attack complex

CE

Candida esophagitis

Authors’ contributions

ZGM completed the first draft. ZJ PKR TLF TZ and GWZ participated in data collection and helped revise the article. WYS revised the manuscript to ensure authenticity and practicability. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Funding

There is no funding support for the work.

Data availability

All data generated or analyzed during this study are included in this published article.

Declarations

Ethics approval and consent to participate

According to the statement from the Ethics Committee of the Children’s Hospital Zhejiang University School of Medicine ethical review for this study has been exempted. This report does not require approval from the ethics committee or written informed consent from the family.

Consent for publication

Written informed consent was obtained from the patient’s mother for publication of this case.

Competing interests

The authors declare no competing interests.