Spectrum and Management of Complement Immunodeficiencies (Excluding Hereditary Angioedema) Across Europe

Abstract

Complement immunodeficiencies (excluding hereditary angioedema and mannose binding lectin deficiency) are rare. Published literature consists largely of case reports and small series. We collated data from 18 cities across Europe to provide an overview of primarily homozygous, rather than partial genotypes and their impact and management.
Patients were recruited through the ESID registry. Clinical and laboratory information was collected onto standardized forms and analyzed using SPSS software.
Seventy-seven patients aged 1 to 68 years were identified. 44 % presented in their first decade of life. 29 % had C2 deficiency, defects in 11 other complement factors were found. 50 (65 %) had serious invasive infections. 61 % of Neisseria meningitidis infections occurred in patients with terminal pathway defects, while 74 % of Streptococcus pneumoniae infections occurred in patients with classical pathway defects (p < 0.001). Physicians in the UK were more likely to prescribe antibiotic prophylaxis than colleagues on the Continent for patients with classical pathway defects. After diagnosis, 16 % of patients suffered serious bacterial infections. Age of the patient and use of prophylactic antibiotics were not associated with subsequent infection risk. Inflammatory/autoimmune diseases were not seen in patients with terminal pathway, but in one third of patients classical and alternative pathway defects.
The clinical phenotypes of specific complement immunodeficiencies vary considerably both in terms of the predominant bacterial pathogen, and the risk and type of auto-inflammatory disease. Appreciation of these phenotypic differences should help both immunologists and other specialists in their diagnosis and management of these rare and complex patients.

Full text

ORIGINAL RESEARCH
Spectrum and Management of Complement Immunodeficiencies
(Excluding Hereditary Angioedema) Across Europe
A. J. Turley &B. Gathmann &C. Bangs &M. Bradbury &S. Seneviratne &
L. I. Gonzalez-Granado &S. Hackett &N. Kutukculer &H. Alachkar &S. Hambleton &
H. Ritterbusch &P. Kralickova &L. Marodi &M. G. Seidel &G. Dueckers &J. Roesler &
A. Huissoon &H. Baxendale &J. Litzman &P. D. Arkwright
Received: 13 December 2014 /Accepted: 28 January 2015
#Springer Science+Business Media New York 2015
Abstract
Introduction Complement immunodeficiencies (excluding
hereditary angioedema and mannose binding lectin defi-
ciency) are rare. Published literature consists largely of
case reports and small series. We collated data from 18
cities across Europe to provide an overview of primarily
homozygous, rather than partial genotypes and their im-
pact and management.
A. J. Turley
Paediatric Immunology, University of Manchester, Manchester, UK
B. Gathmann :H. Ritterbusch
For the ESID Registry working party, Center for Chronic
Immunodeficiency (CCI), University Medical Centre Freiburg and
University of Freiburg, Freiburg, Germany
C. Bangs
Immunology, Royal Manchester Infirmary, Manchester, UK
M. Bradbury
Paediatric Nephrology, Royal Manchester Children’sHospital,
Manchester, UK
S. Seneviratne
Immunology, Royal Free Hospital, London, UK
L. I. Gonzalez-Granado
Pediatric Immunodeficiencies Unit, Hospital Universitario 12
Octubre, Madrid, Spain
S. Hackett
Paediatric Immunology, Birmingham Heartlands, Birmingham, UK
N. Kutukculer
Paediatric Immunology, Ege University, Izmir, Turkey
H. Alachkar
Immunology, Salford Royal Foundation Trust, Manchester, UK
S. Hambleton
Paediatric Immunology, University of Newcastle, Newcastle, UK
P. Kralickova
Allergology & Clinical Immunology, Faculty Hospital Hradec
Kralove, Hradec Kralove, Czech Republic
L. Marodi
Medical & Health Science Center, University of Debrecen,
Debrecen, Hungary
M. G. Seidel
Pediatric Hematology-Oncology, Medical University-Graz,
Graz, Austria
G. Dueckers
HELIOS Clinic, Childrens Hospital Krefeld, Krefeld, Germany
J. Roesler
Kinder und Jugendmedizin, Universitatsklinkkum Carl Gustav
Carus, Dresden, Germany
A. Huissoon
Immunology, Birmingham Heartlands Hospital, Birmingham, UK
H. Baxendale
Immunology, Addenbrookes Hospital, Cambridge, UK
J. Litzman
Clinical Immunology & Allergology, St. Anne’s University Hospital
and Facultyof Medicine, Masaryk University, Brno, Czech Republic
P. D. Arkwright
Paediatric Immunology, Royal Manchester Children’s Hospital,
Manchester, UK
P. D. Arkwright (*)
Department of Paediatric Allergy and Immunology, Royal
Manchester Children’s Hospital, Oxford Rd.,
Manchester M13 9WL, UK
e-mail: peter.arkwright@nhs.net
J Clin Immunol
DOI 10.1007/s10875-015-0137-5

Methods Patients were recruited through the ESID registry.
Clinical and laboratory information was collected onto stan-
dardized forms and analyzed using SPSS software.
Results Seventy-seven patients aged 1 to 68 years were iden-
tified. 44 % presented in their first decade of life. 29 % had C2
deficiency, defects in 11 other complement factors were
found. 50 (65 %) had serious invasive infections. 61 % of
Neisseria meningitidis infections occurred in patients with ter-
minal pathway defects, while 74 % of Streptococcus
pneumoniae infections occurred in patients with classical
pathway defects (p<0.001). Physicians in the UK were more
likely to prescribe antibiotic prophylaxis than colleagues on
the Continent for patients with classical pathway defects. Af-
ter diagnosis, 16 % of patients suffered serious bacterial infec-
tions. Age of the patient and use of prophylactic antibiotics
were not associated with subsequent infection risk.
Inflammatory/autoimmune diseases were not seen in patients
with terminal pathway, but in one third of patients classical
and alternative pathway defects.
Conclusion The clinical phenotypes of specific complement
immunodeficiencies vary considerably both in terms of the
predominant bacterial pathogen, and the risk and type of
auto-inflammatory disease. Appreciation of these phenotypic
differences should help both immunologists and other special-
ists in their diagnosis and management of these rare and com-
plex patients.
Keywords Complement .immunodeficiency .
meningococcemia .Streptococcus pneumoniae .
atypical hemolytic uremic syndrome .glomerulopathy .
vaccination .antibiotics
Abbreviations
aHUS Atypical hemolytic uremic syndrome
ESID European Society for Immunodeficiencies
GOF Gain of function
HAE Hereditary angioedema
MBL Mannose binding lectin
MCP Membrane cofactor protein
PNH Paroxysmal noctural hemoglobinuria
SLE Systemic lupus erythematosus
Introduction
In Europe, as in other parts of the world, primary complement
immunodeficiencies associated with clinical disease are rare
and make up less than 5 % of all primary immunodeficiency
diseases (esid.org/Working-Parties/Registry/ESID-Database-
Statistics) [1–3]. Low mannose binding lectin (MBL) concen-
trations are present in 25 % of Eurasians and 50–60 % of
people from sub-Sahara, but the vast majority of people re-
main healthy [4]. Hereditary angioedema (HAE) occurs in up
to 1/10,000 individuals but does not predispose to infection
and is only associated with autoimmune disease if poorly con-
trolled [5]. We conducted a European-wide survey focusing
on rare non-MBL/HAE primary complement immunodefi-
ciency disorders. The aim was to document the relative prev-
alence of individual factor deficiencies in Europe, highlight
differences in clinical phenotype and factors that predispose to
infection risk, as well as the impact and variation in manage-
ment of these conditions.
Complement disorders include defects in more than forty
individual complement factors and receptors, which make up
this complex pathway [6]. From the spate of early reports
particularly in the late 1960s and 1970s [7–12], complement
is classically thought of as predisposing to recurrent, invasive
infections with Neisseria meningitidis [13]andStreptococcus
pneumoniae [14], as well as autoimmune diseases, particular-
ly systemic lupus erythematosus (SLE). More recently muta-
tions in complement regulatory factors have been shown to
trigger microangiopathies resulting in non-Shiga toxin-associ-
ated atypical hemolytic-uremic syndrome (aHUS) [15–17].
Over 60 % of the genetic predisposition to aHUS can be ex-
plained by homozygous or heterozygous mutations in com-
plement factor H, factor I, membrane cofactor protein,
thrombomodulin, or gain-of-function mutations in comple-
ment factor 3 or factor B. Membranoproliferative and dense
deposit glomerulopathies have also been linked to mutations
in complement regulatory factor genes [18,19]. Although
there are over seventy published case reports or small case
series of complement immunodeficiencies, there are no large
survey’s specifically comparing the relative distribution of
these conditions, complications and management. This survey
addresses this gap in the current published literature.
Methods
Patient Identification and Recruitment
Patients with complement immunodeficiencies were identi-
fied from the European Society for Immunodeficiencies
(ESID) registry. Patients with hereditary angioedema and
mannose binding lectin deficiency were excluded. Principle
Investigators at individual centres were emailed and invited to
participate. Response rate of those invited to participate was
95 %. The study had multicentre ethics committee approval.
Complement Assays
Complement measurements were done in accredited regional
immunology laboratories in country of residence of the pa-
tients using standard techniques. [20] Briefly, complement-
dependent lysis of antibody sensitized red blood cells in either
a fluid or gel were used to provide a quantitative measure of
JClinImmunol

functional activity (CH100 for the classical pathway and
AP100 for the alternative pathway). Complement factors C3
and C4 were measured using rate nephelometry. Other com-
plement components, for example factor B, H and I of the
alternate pathway and C5 to C9 of the classical pathway were
detected individually by either gel diffusion (Ouchterlony
technique) or ELISA. Subsequent gene sequencing was initi-
ated by physicians liaising with regional clinical genetics
centres.
Data Collection
Data was obtained from the existing ESID database. This in-
formation was supplemented by requesting that all Principle
Investigators complete a standardized questionnaire providing
additional anonymized demographic and clinical (infections
and autoimmune disease) information, as well as laboratory
test results (CH100, AP100 and specific complement factors,
genetic mutation screening, autoantibodies, vaccine re-
sponses) and treatment (vaccines, antibiotics, immunosup-
pressants, intensive care admissions).
Statistical Analysis
Data was collated and analyzed using IBM SPSS Statistics
20.0. For discrete variables groups were compared using
Chi-square test.
Results
Patient Demographics
Seventy-seven patients aged 1 to 68 years (median 22) from
18 cities across Europe (nine in the UK and nine on the Con-
tinent) were identified. As well as the UK, countries partici-
pating in this survey included Austria, Czech Republic, Ger-
many, Hungary, Spain and Turkey. There were more males
(60 %) than females. Two thirds of patients were white Cau-
casians and a third Asian,but there were no patientsof African
descent. 21 (27 %) patients came fromconsanguineous unions
and 43 (56 %) of patients had a family history of primary
complement immunodeficiency (Table 1). Three (4 %) with
C3 had a heterozygous rather than homozygous gene mutation
and one patient had a gain of function C3 mutation. The clin-
ical phenotypes of two of the patients with loss of function C3
deficiency have been described previously and were associat-
ed with a propensity to respiratory infections, as well as ne-
phrotic syndrome and arthritis which resolved in childhood
[21]. The 5 year old girl with the C3 gain of function mutation
had suffered from Pneumococcal pneumonia and aHUS, suc-
cessfully treated with the anti-C5 monoclonal antibody
eculizumab. 44 % of the patients presented within the first
decade of life and 76 % by the end of the second decade
(Fig. 1). Of the 17 patients who were referred after the second
decade of life, nine had a family history and five had a con-
firmed genetic mutation. Seven of these patients had a history
of meningococcal disease, five recurrent chest infections and
bronchiectasis and one nephrotic syndrome.
Complement Disorders and Clinical Features
A wide spectrum of specific complement deficiencies was
identified. 33 (43 %) were defects in the classical pathway
(C1q, C1r, C2, C4), 24 (31 %) were in the alternative pathway
(C3, factors D, H, I, P) and 20 (26 %) were terminal comple-
ment component defects (C6, C7 and C8) (Fig. 2). 25 (32 %)
patients had confirmatorygenetic as well as functional testing.
50 (65 %) had suffered serious invasive infections prior to
diagnosis, most commonly with Neisseria meningitidis or
Streptococcus pneumoniae (Table 2). 59 % had 1–2 and the
others had suffered ≥3 serious infections. 15 (20 %) had been
Tabl e 1 Demographics of 77 patients in the cohort
Parameter
Age 1–68 years, median 22 years, 24 children / 53 adults
Age referral 0–63 years, median 12 years
Gender 46 (60 %) male
Race 53 (69 %) white Caucasian, 22 (31 %) Asian
Consanguinity 21 (27 %)
Family history 43 (56 %)
City United Kingdom: Birmingham 5 %, Cambridge 1 %,
Cardiff 1 %, Hull 1 %, Liverpool 4 %, London 14 %,
Manchester 39 %, Newcastle 4 %, Nottingham 3 %,
Continental Eurasia: Brno4 %, Debrecen 3 %, Duisburg
1%,Freiburg4%,Graz1%,HradecKralove2%,
Izmir 5 %, Konigswartha 1 %, Madrid 7 %
Fig. 1 Age of referral of patients
J Clin Immunol

admitted to an intensive care unit. Three patients, two with
C1q and one with Factor I deficiency had died (two of Pneu-
mococcal meningitis in infancy and one at 54 years old of
coronary vascular disease secondary to chronic glomerulone-
phritis having had a renal transplant atthe age of 35 years old).
After diagnosis, infections were less common, occurring in
only 12 (16 %) patients. 25 % had Neisseria meningitidis
and 58 % Streptococcus pneumoniae infections. The pathway
defect, age of the patient, use of prophylactic antibiotics and
additional meningococcal vaccinations were not associated
with significant differences in subsequent infection risk.
The spectrum of disease in patients with defects in different
parts of the complement cascade varied significantly. For in-
stance, 74 % of pneumococcal disease occurred in patients
with classical pathway defects, while 61 % of meningococcal
disease occurred in patients with defects in terminal pathway
components (p<0.001) (Table3). Invasive pneumococcal dis-
ease was no more common in patients with low pneumococcal
antibody titres at diagnosis. No inflammatory/autoimmune
diseases were seen in patients with defects in terminal com-
plement. However, 37 % of patients with classical pathway
defects had SLE-like conditions affecting skin, brain and/or
kidneys, including 5 of 6 patients with C1q deficiency who
also had anti-nuclear antibodies (ANA, Sm, Rho). 39 % of
patients with alternative pathway defects had aHUS,
membranoproliferative glomerumonephritis. Two patients
with factor I deficiency suffered from recurrent Henoch-
Schönlein Purpura with a typical purpuric rash on the legs
and arthritis of both ankles. Skin biopsy demonstrated a
leukocytoclastic vasculitis. One of these patients suffered
from transient proteinuria, which was treated with oral pred-
nisolone for 3 months. In both cases the disease has resolved.
Management of Complement Immunodeficiencies
There was no significant differences in the requirement for
intensive care between complement deficiency subgroups.
46 (60 %) patients had received quadrivalent meningococcal
vaccination, 55 (72 %) had received a Pneumococcal vaccine
(polysaccharide or conjugate) and 52 (68 %) were taking pro-
phylactic antibiotics, most often amoxycillin or penicillin V
(80 % of cases). Patients with defects in terminal complement
components, the group at highest risk of recurrent meningo-
coccal disease, were most likely to have received additional
quadrivalent meningococcal vaccinations (Table 3). Despite
there being no significance in the prevalence of either menin-
gococcal or pneumococcal between the UK and the continent,
physicians in the UK were more likely to prescribe antibiotic
prophylaxis than their colleagues onthe Continent for patients
with classical but not other pathway defects (80 % versus
27 %, p<0.01) (Table 4). Prescribing of penicillin and other
Fig. 2 Distribution of specific primary complement immunodeficiencies.
Grey scale: classical pathway, purple scale: terminal components, blue-
green scale: alternate pathway. GOF gain of function
Tabl e 2 Clinical features
of cohort Parameter
Pre-diagnosis infections 50 (65 %) of which 1: 34 %, 2: 26 %, 3–4: 28 %, >4 13 %
47 % had Neisseria meningitidis,45 %Streptococcus pneumoniae,
1%Haemophilus influenzae E, 1 % Group A Streptococcus
Post-diagnosis infections 12 (16 %) of which 1: 58 %, 2: 8 %, >2: 34 %
25 % had Neisseria meningitidis,58 %Streptococcus pneumoniae
Autoimmunity 21 (27 %), kidney 15 %, joints 11 %, skin 14 %, brain 3 %
Intensive care / Died 15 (20 %) / 3 (4 %) 2 Pneumococcal meningitis,
1 complications of chronic glomerulonephritis
Quadrivalent
meningococcal vaccine
46 (60 %)
Pneumococcal vaccine 55 (72 %)
Prophylactic antibiotics 52 (68 %)
Amoxycillin 47 %, penicillin V 32 %, azithriomycin 12 %, cefaclor 2 %,
cefuroxime 2 %, ciprofloxacin 2 %, co-trimoxazole 2 %
Immunosuppressants 11 (14 %), bone marrow transplantation 1 (1 %)
JClinImmunol

antibiotics did not vary significantly between UK and Conti-
nental physicians. Non penicillin antibiotics were more likely
to be prescribed for patients with classical than other pathway
defects Table 3).
One quarter of patients with defects in the classical comple-
ment pathway required immunosuppressive therapy, mainly
with corticosteroids (Table 3). A steroid sparing agent was
sometimes also required (pulse intravenous cyclophosphamide
in two patients with C1q deficiency, and cyclosporin, azathio-
prine, methotrexate or rituximab for patients with C2 or C4).
Three patients with alternative pathway defect required immu-
nosuppressive therapy: two patients with factor H deficiency
were treated with corticosteroids and one C3 gain of function
patient with eculizumab. One patient with C1q deficiency and
life-threatening CNS vasculitis was successfully cured with
hemopoetic stem cell transplantation [22] and remains well,
engrafted and off all treatment 2 years post transplantation.
Discussion
This is to our knowledge the largest published series of pri-
mary complement immunodeficiencies (excluding HAE and
MBL deficiency), collating data from 77 patients managed in
18 centres across Europe. It provides an overview of the
spectrum and variation in disease caused by these immunode-
ficiencies. The majority of patients presented within the first
two decades of life, although there were 24 % who were di-
agnosed in adulthood. Despite invasive bacterial infections
occurring in 65 % of patients, deaths were uncommon
(4 %). Twelve different complement factors defects were iden-
tified, with C2 deficiency being the most common (29 % of
the total).
Complement immunodeficiencies are classically consid-
ered as being inherited in an autosomal recessive pattern, or
X-linked pattern in the case of properdin deficiency. However,
partial (heterozygous) mutations in the alternative comple-
ment pathway factors e.g., factor H, factor I and MCP, and
gain of function mutations in C3 or Factor B can cause renal
disorders such as aHUS [16,21,23–25]. In contrast, carriers
of classical pathway complement (C1q, C2, C4) components
typically remain well [26]. Anti-C5 monoclonal antibody ther-
apy is effective treatment for PNH [27], aHUS and
membranoproliferative glomerulonephritis [28,29], where
previously patients progressed relentlessly to renal failure,
which recurrent after renal transplantation.
Defects in membrane attack complex components of the
terminal complement pathway were characterized by a high
prevalence of meningococcal disease affecting 61 % of cases,
while only one patient (4 %) suffering from pneumococcal
disease and none of the patients suffered from autoimmune
or autoinflammatory diseases. 80 % of these patients were
managed with additional quadrivalent meningococcal vacci-
nation and prophylactic antibiotics. The use of antibiotics as
Tabl e 4 UK versus continental European practice
UK Continent Pvalue
Number 56 (73 %) 21 (27 %)
Children (%) 25 48 0.1
Males (%) 62 52 0.4
Age at referral
(median (inter-quartile range))
14 (6–20) 8 (4–19) 0.4
Family history (%) 60 48 0.4
Pathway - classical 39 52
- alternative 36 19 0.4
- terminal 25 28
Pre-diagnosis infections 68 58 0.6
Post-diagnosis infections 15 20 0.7
Meningococcal infections 35 29 0.8
Pneumococcal infections 30 35 0.8
Prophylactic antibiotics 76 48 0.03
Quadrivalent meningococcal vaccine 67 48 0.1
Pneumococcal vaccine 77 62 0.2
Intensive Care 20 19 0.9
Numbers for each parameter are percentages or median (inter-quartile
range). P values were calculated using Chi-square statistic
Tabl e 3 Comparative characteristics depending on pathway affected
Pathway Classical Alternative Terminal P
value
Number 33 (43 %) 24 (31 %) 20 (26 %)
% males 64 46 70 0.2
% with consanguinity 23 44 15 0.1
% with family history 53 70 45 0.2
Pre-diagnosis infection
history
70 39 90 0.002
Meningococcemia 13 23 78 0.001
Pneumococcal disease 55 22 5 0.001
Post-diagnosis infection
history
25 9 10 0.2
Autoimmunity - kidney 13 30 0 0.02
Autoimmunity - joints 10 22 0 0.1
Autoimmunity - skin 17 22 0 0.1
Autoimmunity - brain 7 0 0 0.2
Quadrivalent
meningococcal vaccine
44 67 80 0.06
Pneumococcal vaccine 83 57 75 0.1
Prophylactic antibiotics 61 65 80 0.4
- penicillin as proportion of
all antibiotics
67 100 88 0.03
Immunosuppression 26 13 0 0.04
Intensive Care 13 19 32 0.3
Numbers for each parameter are percentages. Pvalueswere calculated
using Chi-square statistic
J Clin Immunol

well as booster vaccination is in keeping with previous stud-
ies, which have shown that meningococcal vaccination re-
duces but does not eliminate the risk of meningococcal disease
[30] as complement-dependent bacterocidal activity is more
important than complement-independent opsonophagocytosis
in killing Neisseria meningitidis [31].
In contrast, we found that Streptococcus pneumoniae
caused three quarters of infections in patients with classical
complement pathway defects, while only 4 of 30 (13 %) of
patients suffered from Neisseria meningitidis infections,
highlighting the differences in immune defence for these two
encapsulated bacteria. The results are in keeping with mouse
models and smaller case series, which have shown the impor-
tance of opsonophagocytosis in killing Pneumococcus [32,
33]. UK clinicians prescribed prophylactic antibiotics more
frequently for patients with classical pathway defects than
colleagues on the Continent. There was no significant differ-
ent in the number of patients with Pneumococcal sepsis in
these two regions. With the widespread use of conjugate
Pneumococcal vaccines over the last decade, the need for
ongoing use of prophylactic antibiotics in this subset of pa-
tients might be reviewed.
In keeping with the published literature, SLE was most
common in patients with classical pathway defects and partic-
ularly in patients with C1q deficiency were associated with
serious renal or CNS vasculitis. Over a third of patients with
alternative pathway defects had renal microangiopathies par-
ticularly aHUS and other glomerulopathies, which were not
seen in patients with other pathway defects. Interestingly, two
Spanish siblings with compound heterozygous factor I defi-
ciency (c.1610_1611insAT (exon 13)/c.559C > T (exon 4)
presented with recurrent Henoch-Schönlein purpura (typical
rash and arthritis). This is not a well recognized complication,
although at least one previous case has been reported in the
literature [34] and clinicians should be aware of this potential
assocation.
Limitations of the study include its retrospective nature and
use of a primary immunodeficiency database to identify pa-
tients. Although immunologists from across Europe actively
recruit patients onto the ESID registry and were keen to par-
ticipate in this survey, an increasing number of complement
deficiencies are diagnosed and managed by other specialists
including hematologists (e.g., SLE, paroxysmal noctural
hemoglobulinuria (due a somatic, acquired mutation in the
X-linked phosphatidylinositol glycan class A gene impairing
blood cell membrane expression of a number of proteins, in-
cluding the complement regulators CD55 and CD59 [35])),
nephrologists (e.g., SLE, aHUS, membranoproliferative glo-
merulopathies), rheumatologists (e.g., SLE, other vasculiti-
des) and ophthalmologists (e.g., age-related macular degener-
ation linked to polymorphisms in a number of complex regu-
lators (Factor 3, B, H and I) in 10 % of severe cases [36]) and
therefore the distribution and clinical phenotype are
potentially biased by the method of recruitment. Greater col-
laboration between subspecialists through joint clinics, multi-
disciplinary meetings and registries are required if this limita-
tion is to be overcome. The lack of detailed information spe-
cific to these complex immunodeficiencies available on the
ESID registry database was overcome by completion of a
more detailed questionnaire on each patient by principle
investigators.
Complement disorders have previously been thought of as
being the Bsmall print^even amongst the clinical workload of
immunology specialists. Progress in our understanding of the
complexity of the pathway and identification of increasing
numbers of diseases that complement defects can cause has
brought the part of the immune system back into the limelight
of internal medicine. The direct comparison of complement
immunodeficiencies in this study highlights the differences in
clinical phenotypes, with Pneumococcal disease being the
predominant problem in classical pathway defect, indicating
the importance of ensuring up to date Pneumococcal vaccina-
tion in this subgroup. In contrast, meningococcal disease is
less of a problem in classical pathway defects but more com-
mon in patients with terminal component defects,
emphasising that it is this group where quadrivalent
(ACW135Y) conjugate vaccine [37] and group B vaccine
[38] as well as supplementary prophylactic antibiotics should
be prioritized [39]. The recognition that defects in comple-
ment underlie a number of auto-inflammatory diseases lead-
ing to acute, or chronic renal failure that can potentially have a
poor outcome, even after kidney transplantation highlight the
need for physicians to accurately diagnose and develop bio-
logic and stem cell therapies that address the primary patho-
genesis if patients are to be treated successfully [40]. A pro-
spective, worldwide complement deficiency database involv-
ing not only immunologists but also other subspecialists, par-
ticularly nephrologists, would help to address the limitations
of the current study and help to address some of the questions
raised, such as the effectiveness or otherwise of prophylactic
antibiotics in these patients.
Declaration of interests The authors declare no conflict of interests
relevant to this study
Author contribution PDA conceived of and led the study. AT collect-
ed and collated all the data. All authors contributed to collation and
submission of their centre’s data and to the writing of the final version
of the manuscript.
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