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- Hindawi Publishing Corporation
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- Copyright © 2022 F. Staels et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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- 2090-6609
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- 2090-6617
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- 10.1155/2022/9057000
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Abstract
Hindawi Case Reports in Immunology Volume 2022, Article ID 9057000, 6 pages https://doi.org/10.1155/2022/9057000 Case Report Terminal Complement Pathway Deficiency in an Adult Patient with Meningococcal Sepsis 1,2 3,4 5 6 6 F. Staels , W. Meersseman, P. Stordeur , K. Willekens , S. Van Loo, 6 7,8 9,10 2,3 A. Corveleyn, I. Meyts , G. Meyfroidt, and R. Schrijvers Department of Microbiology, Immunology and Transplantation, Laboratory of Adaptive Immunology, KU Leuven, Leuven, Belgium Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium Department of General Internal Medicine, University Hospitals Leuven, Leuven, Belgium Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical Infectious and Inammatory Disease, KU Leuven, Leuven, Belgium Belgian National Reference Center for the Complement System, Laboratory of Immunology, LHUB-ULB, Universit´e Libre de Bruxelles, Brussels, Belgium Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium Department of Microbiology, Immunology and Transplantation, Laboratory for Inborn Errors of Immunity, KU Leuven, Leuven, Belgium Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium Department of Cellular and Molecular Medicine, Laboratory of Intensive Care, KU Leuven, Leuven, Belgium Department of Intensive Care, University Hospitals Leuven, Leuven, Belgium Correspondence should be addressed to F. Staels; frederik.staels@kuleuven.be and R. Schrijvers; rik.schrijvers@uzleuven.be Received 16 September 2021; Accepted 26 April 2022; Published 23 May 2022 Academic Editor: Ahmad Mansour Copyright © 2022 F. Staels et al. is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. e complement system is an essential part of our innate immune system. ree enzymatic activation pathways are described, all converging into a common terminal pathway which causes lysis of the target cell. Late complement deƒciencies (LCDs) are typically diagnosed in children or adolescents with invasive meningococcal disease (IMD). However, IMD can also be a ƒrst manifestation in adulthood and should prompt for the evaluation of the LCD. We report the case of a young adult with IMD who was found to have a LCD, caused by a compound heterozygous mutation in C6. His vaccination status was optimized and prophylactic antibiotic treatment was initiated. By means of this case, we would like to raise awareness of underlying LCD in (young) adults presenting with IMD by N. meningitidis. Screening for complement deƒciencies after IMD, followed by genetic testing, can be lifesaving and allows for genetic counselling. In addition, we discuss the diagnosis and treatment of LCD. C5 to C5b which recruits C6, C7, C8, and C9 to form the 1. Introduction membrane-attack-complex (MAC) [1, 2]. is complex forms a pore in the membrane, leading to lysis of the e complement system is part of our innate immunity, pathogen. Complement deƒciencies in the early pathway are functioning as a ƒrst line of defense against bacterial in- associated with diverse autoimmune diseases such as sys- fections. It is organized in three pathways: the classical temic lupus erythematosus (SLE) [3] with or without in- pathway (CP), alternative pathway (AP), and lectin pathway fectious susceptibility (mostly by encapsulated bacteria). In (LP) [1, 2]. ese pathways, initiated through di“erent contrast, deƒciencies in the terminal pathway (LCD) are mechanisms, converge to a common terminal pathway typically seen in a pediatric population presenting with (Figure 1(a)). In the terminal pathway, C5 convertase cleaves 2 Case Reports in Immunology Classical pathway (CP) MBL pathway Alternative pathway (AP) MBL/Ficolins/collectin-11 INITIATION C1q Factor H C3 (H2O) PROTEASES MASP-1/2/3 C1r/s Factor B, Factor D C3a C2b C2 Ba C4a C4 Factor H Factor H C3bBb Properdin C4bC2a Factor I Factor I C3 C3a C3 C3a C3b C3bBb3b Properdin C4b2a3b Factor I Factor H Terminal pathway C5a C5 C5b C6, C7, C8, C9 MAC (a) Components Test Result missing CH50 Very low/absent C1q/r/s, C2, C4 Factor B, D, AP50 Very low/absent properdin Very low/absent C3, C5-9 CH50 and AP50 Low + low C3 level Factor H, I (b) Figure 1: (a) Activation of the CP, AP, and LP. In the CP, C1q binds antigen-antibody complexes. After binding, C1r and C1s proteases cleave C4 and C2 resulting in the formation of a C4b2a (CP C3 convertase). (is C3 convertase cleaves C3 into C3a and C3b forming the C4b2a3b (CP C5 convertase) which initiates the common terminal pathway and the formation of a MAC complex. In the AP, spontaneous hydrolysis of C3 forms C3(H2O) which associates with factor B and D to form the C3bBb (AP C3 convertase). Similar to CP, C3 is cleaved leading to the formation of a C3bBb3b complex (AP C5 convertase) and subsequent activation of the terminal pathway. (e LP occurs through different initiators that bind high-density sugars of pathogens. After this binding, LP-associated serine proteases (MASP) form a complex with the recognition molecules to allow the cleavage of C4 and C2, similar to the CP. Properdin functions as a stabilizer of the membrane bound C3bBb and C3bBb3b. Factor H functions as a negative regulator of CP and AP by blocking formation of the AP C3 convertase, cleavage, and inactivation of C4b and preventing C1q binding to its ligands. Factor I mediates the cleavage and inactivation of C3b and C4b, blocking the formation of the C3 convertase. Red arrows indicate inhibitory routes, and green arrows indicate stabilizing routes. (b) Interpretation of CH50 and AP50 values in the diagnosis of complement deficiencies. Further testing for individual components in the complement pathway should be performed depending on this result. invasive meningococcal disease caused by Neisseria men- 2.Case Presentation ingitidis (IMD) [4, 5]. However, IMD can also manifest in An 18-year-old Surinam patient (Figure 2(a)), born to non- adulthood unmasking an underlying LCD [6]. We report the case of an 18-year-old man who presented with IMD and consanguineous parents, presented with high grade fever (39.9 C), vomiting, diffuse myalgia, headache, and petechial was confirmed to have a LCD due to a compound hetero- zygous mutation in C6 resulting in absent C6 levels. bleeding on the arms and trunk. Clinical evaluation showed Case Reports in Immunology 3 AR C6 deficiency ND wt/m 12 3 II m/mm/m m/m p.Arg531*/p.Asp627Thrfs*4 (a) (b) 5 kb c.301-1G>A c.445+3A>c c.2381+2T>c p.R48 K p.S91* p.S277Afs*43 p.R455* p.Y514* p.R596* p.C867R 1aa N - 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 - c 1 48 100 149 196 242 309 390 431 486 562 619 656 701 764 794 875 934 p.I80Sfs*43 p.Q274Rfs*46 p.Q380Sfs*7 p.C521* p.C606* (c) Figure 2: (a) Family pedigree and genotype. Compound heterozygosity was found in the index patient for c.1879delG, p.Asp627(rfs 4 (classified as known pathogenic) and c.1591C> T, p.Arg531 (predicted as a complete loss of function, unreported) and homozygosity was found in the siblings for c.1879delG. (e mother was carrier for c.1879delG. Genetic material of the father was not accessible (familial reasons) and no further exploration on the inheritance mechanism was performed. (b) Clinical presentation of purpura fulminans at second admission. (c) Top: C6 gene structure, containing 18 exons, and pathogenic intronic mutations (n � 3) affecting the splicing of C6 are shown (orange); bottom: C6 protein structure encoded by the corresponding exons (italic) with known pathogenic missense/nonsense mutations in black (n � 8) and frameshift mutations in blue (n � 4), source: Human Gene Mutation Database. (e position of the pathogenic mutations in the index patient is depicted (red, purple). signs of meningeal irritation and skin petechiae. Laboratory reference platelets 150–400 ×10 /μL), impaired renal analysis showed elevated inflammatory parameters (CRP function (creatinine 1.81, reference 0.72–1.21 mg/dL), and a 360 mg/L, reference <5 mg/L; neutrophils 11.3 ×10 /μL, metabolic acidosis (arterial pH 7.31; lactate 99.1 mg/dL, reference reference 1.5–5.7 ×10 /μL). Blood cultures were negative, 5.5–14.4 mg/dL; bicarbonate 13.4 mmol/L, reference and the patient received empirical treatment with cef- 21–28 mmol/L; pCO2 27.4 mmHg, reference 35–48 mmHg). triaxone (2 g BID). Lumbar puncture was not performed due Blood cultures were positive for N. meningitidis. Transtho- to anticoagulation for an unprovoked pulmonary embolism racic echocardiography showed a decreased left ventricular 5 months earlier. (e patient rapidly improved under ejection fraction (25%, reference 55–70%). Fluid resuscita- antibiotic treatment, suggesting an infectious cause of tion and vaso- and inopressors were initiated for a combined meningitis. septic and cardiogenic shock. Because of progressive hypoxic Nine months later, he was readmitted to the intensive respiratory failure, mechanical ventilation was initiated. care unit with diffuse myalgia, fever (39.6 C), abdominal Antibiotics (ceftriaxone 2 g BID and amikacin 1 g once) were pain, headache, and somnolence. Blood analysis showed initiated. However, despite early treatment initiation, he elevated inflammatory parameters (CRP 164 mg/L, neu- progressively developed purpura fulminans (Figure 2(b)) 3 3 trophils 6.2 ×10 /μL), thrombopenia (90 ×10 /μL, with diffuse intravascular coagulation and rhabdomyolysis 4 Case Reports in Immunology CH50 and AP50 results is shown in Figure 1(b). If CP of his limbs complicated by a compartment syndrome ne- cessitating amputation of his left upper arm and multiple components are missing (C1q/r/s, C2 or C4), CH50 will be very low or absent with a normal AP50. If AP components fasciotomies of other limbs. After five months on the in- tensive care unit, the patient was discharged for intensive are missing (factor B, D or properdin), AP50 will be very low rehabilitation. (e occurrence of recurrent meningitis, once or absent with a normal CH50. In case both AH50 and CH50 confirmed due to N. meningitidis serogroup Y, raised sus- are very low or absent, a C3 defect or LCD (C5–9) should be picion of a complement deficiency. Functional testing suspected or in rare cases, factor H or I deficiency. After revealed a decreased classical and alternative pathway ac- determination of CH50 and AP50, further quantification of tivity, with normal C3 and C4 suggesting a LCD (Table 1). individual complement levels can be performed depending Genetic testing revealed the presence of compound het- on the results. In our patient, both CH50 and AP50 were erozygous mutations in C6 (Figure 2(a)). (e C6 level was very low (CH50) or absent (AH50) with normal C3 levels (Table 1). Further quantitative determination of the late proved to be deficient (Table 1), confirming the pathoge- nicity of the mutations. (e screening of siblings demon- components (C5–9) revealed that C6 levels were undetectable (Table 1). Both whole exome and targeted sequencing of the strated that both were affected. (e patient and siblings received conjugated meningococcal vaccines for serotypes C6 gene in the index patient revealed a compound hetero- A/C/W/Y and B, pneumococci, and H. influenzae type zygous mutation c.1879delG, p.Asp627(rfs 4 (classified as B. Prophylactic antibiotics (azithromycin 3x/week) were known pathogenic) and c.1591C> T, p.Arg531 (predicted as started. a complete loss of function, unreported). Both his siblings were screened for CH50 and AP50 activity and also found to be defective caused by absent C6 levels, while his mother had 3.Discussion normal CH50 and AP50 activity. Surprisingly, his siblings had Establishing a diagnosis of an inherited complement defi- the c.1879delG, p.Asp627(rfs 4 in homozygosity. Genetic ciency is crucial in patients with IMD. Up to 20% of the material of the father was not accessible (for familial reasons) patients suffering from IMD lack any of the terminal and therefore no further exploration on the inheritance complement components, or properdin, the latter leading to mechanism was performed. Before genetic confirmation, an an X-linked deficiency of the alternative pathway [7]. Me- autosomal dominant inheritance pattern could have been ningococcal isolates causing IMD in LCD patients com- conceived. However, dominant complement disorders have monly belong to minor or uncommon serogroups, especially hitherto only been associated with atypical hemolytic uremic serogroup Y, although no specific correlation between LCD syndrome in which the risk for meningococcal infections is and a certain capsular group was found [5, 8]. In this case, a deemed low, unless after eculizumab treatment [11]. (e complement deficiency was suspected after the second abnormal CH50 ruled out the only X-linked recessive presentation with IMD with isolation of Neisseria menin- complement deficiency (properdin deficiency) in the 2 gitidis serogroup Y. Screening for complement deficiencies brothers. Furthermore, no defects in CFP (encoding pro- can be performed by determination of the functional activity perdin) were found in whole exome sequencing data from the of the CP (CH50), the AP (AH50), and the MBL pathway [9]. index patient. C6 deficiency is caused by autosomal recessive (e gold standard for measuring the CH50 is based on the loss-of-function mutations in C6, with 16 mutations in 65 minimal dilution of serum that causes lysis of 50% of sheep cases reported (Figure 2(c)). (e treatment of LCD includes erythrocytes. Nowadays, in most laboratories, CH50 is optimization of vaccination status (tetravalent meningococcal measured using an automated liposome-based immunoas- vaccine A/C/W/Y and the recently available vaccine against say [10]. In this assay, sensitized liposomes containing serogroup B, H. influenzae type B, and pneumococcal vac- glucose-6-phosphate dehydrogenase (G6PD) are mixed with cines), even in asymptomatic patients. Tetravalent menin- serum together with a substrate containing G6P, nicotin- gococcal vaccine and vaccine against serogroup B are available amide adenine dinucleotide, and anti-DNP antibody. Upon in Belgium but are not included in the routine vaccination liposome lysis, an enzymatic colorimetric reaction occurs scheme and not reimbursed. Efficacy of meningococcal which is proportional to the classical complement activity. vaccination was assessed in a cohort of 45 Russian patients For measuring AH50, the gold standard assay is similar to with LCD, of whom 31 were vaccinated, with a follow up of the CH50 gold standard approach, but with the use of rabbit 3–8 years [12]. Meningitis episodes decreased significantly in erythrocytes (in contrast to sheep erythrocytes, their surface the vaccinated versus non-vaccinated group, but still occurred promotes more AP activation) and dilution of serum in a (6 episodes in 4 patients throughout follow-up). Importantly, diluent containing blockers of the CP and MBL pathway. half of these new meningitis episodes were caused by Nowadays, this is replaced by an enzyme-linked immuno- serogroup B or non-serogroupable meningococci, suggesting sorbent assay (ELISA) where a plate coated with zymosan that additional vaccination to serogroup B might improve (activator of the AP pathway) is incubated with a serum protection against meningococcal infection. Since vaccination sample and the terminal complement complex (TCC, sol- is not providing complete protection, prophylactic antibiotics uble C5b-9) is measured using an anti-TCC conjugated are routinely given to patients with LCD [13]. Randomized antibody [10]. LP is not routinely incorporated in the first controlled trials studying the effectiveness of prophylactic screening, but can be tested by incubating serum of the antibiotics are lacking because of the rarity of LCD. A pro- patient on a mannan coated plate. Similar to the AP assay, spective study in South Africa with 40 C6 deficient patients TCC is measured using ELISA [10]. (e interpretation of reported beneficial effects of monthly benzathine penicillin G Case Reports in Immunology 5 Table 1: Summary of demographic, clinical, and complement levels in the index patient and relatives (ND: not determined). II.1 (index) I.2 II.2 II.3 Age 19 years 38 years 18 years 11 years Infections Meningococcal sepsis — — — Classical complement pathway activity (%, 66–113) <12.5 98.1 <12.5 <12.5 Alternative complement pathway activity (%, 20–60) 0 24 0 0 C3 (7.9–15.2 mg/dl) 18.1 ND 10.7 14.8 C4 (1.6–3.8 mg/dl) 3.8 ND 1.3 2.2 C5 (1.1–25 mg/dl) 34.5 ND ND ND C6 (>4.5 mg/dl) <0.5 ND <0.5 <0.5 C7 (>5.5 mg/dl) 8.9 ND ND ND C8 (>11.2 mg/dl) 19.4 ND ND ND C9 (>12.5 mg/dl) 17.5 ND ND ND in high-risk patients (≥2 episodes of meningococcal infection) References on the occurrence of new meningococcal infections [14]. [1] N. S. Merle, S. E. Church, V. 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Ponard et al., “Infec- stable serum concentrations, and convenience of the regimen) tions revealing complement deficiency in adults: a French because of the severity of the infection and the psychological nationwide study enrolling 41 patients,” Medicine, vol. 95, impact. no. 19, Article ID e3548, 2016. [7] J. Schroder-Braunstein ¨ and M. Kirschfink, “Complement Ethical Approval deficiencies and dysregulation: pathophysiological conse- quences, modern analysis, and clinical management,” Mo- (is case study was conducted in accordance with the lecular Immunology, vol. 114, pp. 299–311, 2019. principles of the Helsinki Declaration and approved by the [8] J. Rosain, E. Hong, C. Fieschi et al., “Strains responsible for ethics committee of the University of Leuven (s58466). invasive meningococcal disease in patients with terminal complement pathway deficiencies,” 9e Journal of Infectious Consent Diseases, vol. 215, no. 8, pp. 1331–1338, 2017. [9] L. Wen, J. P. Atkinson, and P. C. Giclas, “Clinical and laboratory Written informed consent was obtained from the patient. evaluation of complement deficiency,” 9e Journal of Allergy and Clinical Immunology, vol. 113, no. 4, pp. 585–593, 2004. Conflicts of Interest [10] T. D. Jaskowski, T. B. Martins, C. M. Litwin, and H. R. Hill, “Comparison of three different methods for measuring (e authors declare that they have no conflicts of interest. classical pathway complement activity,” Clinical and Diag- nostic Laboratory Immunology, vol. 6, no. 1, pp. 137–139, 1999. Acknowledgments [11] L. A. McNamara, N. Topaz, X. Wang, S. Hariri, L. Fox, and J. R. MacNeil, “High risk for invasive meningococcal disease FS (11B5520N) is fellow of the Fonds Wetenschappelijk among patients receiving eculizumab (Soliris) despite receipt Onderzoek—Vlaanderen National Fund for Scientific Re- of meningococcal vaccine,” American Journal of Transplan- search (FWO). RS and IM are FWO senior clinical inves- tation, vol. 17, no. 9, pp. 2481–2484, 2017. tigator fellows (1805518N and 1805821N, respectively) and [12] A. E. Platonov, I. V. Vershinina, E. J. Kuijper, R. Borrow, and received funding from KU Leuven C1 (C12/16/024). RS and H. Kayhty, ¨ “Long term effects of vaccination of patients de- IM are members of the European Reference Network for ficient in a late complement component with a tetravalent Rare Immunodeficiency, Autoinflammatory and Autoim- meningococcal polysaccharide vaccine,” Vaccine, vol. 21, mune Diseases (Project ID No. 739543). no. 27–30, pp. 4437–4447, 2003. 6 Case Reports in Immunology [13] M. Kuruvilla and M. T. de la Morena, “Antibiotic prophylaxis in primary immune deficiency disorders,” Journal of Allergy and Clinical Immunology: In Practice, vol. 1, no. 6, pp. 573–582, 2013. [14] P. C. Potter, C. E. Frasch, W. J. M. van der Sande, R. C. Cooper, Y. Patel, and A. 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Case Reports in Immunology – Hindawi Publishing Corporation
Published: May 23, 2022