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Investigation for Complement Deficiency Following Meningococcal Disease S Hoare, O El-Shazali, J E Clark, a Fay, a J Cant

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Investigation for Complement Deficiency Following Meningococcal Disease S Hoare, O El-Shazali, J E Clark, a Fay, a J Cant 215 ORIGINAL ARTICLE Arch Dis Child: first published as 10.1136/adc.86.3.215 on 1 March 2002. Downloaded from Investigation for complement deficiency following meningococcal disease S Hoare, O El-Shazali, J E Clark, A Fay, A J Cant ............................................................................................................................. Arch Dis Child 2002;86:215–217 See end of article for authors’ affiliations Background and aims: The incidence of complement abnormalities in the UK is not known. It is sug- ....................... gested in at least three major paediatric textbooks to test for abnormalities of the complement system Correspondence to: following meningococcal disease (MCD). Dr S Hoare, Paediatric Methods: Over a four year period, surviving children with a diagnosis of MCD had complement activ- Infectious Diseases Unit, ity assessed. A total of 297 children, aged 2 months to 16 years were screened. Newcastle General Results: All children except one had disease caused by B or C serogroups. One child, with group B Hospital, Westgate Rd, meningococcal septicaemia (complicated by disseminated intravascular coagulation and who required Newcastle upon Tyne NE4 6BE, UK; ventilation and inotropic support) was complement deficient. C2 deficiency was subsequently simon.hoare@ diagnosed. She had other major pointers towards an immunological abnormality prior to her MCD. dial.pipex.com Conclusion: It is unnecessary to screen all children routinely following MCD if caused by group B or Accepted C infection. However, it is important to assess the previous health of the child and to investigate appro- 22 November 2001 priately if there have been previous suspicious infections, abnormal course of infective illnesses, or if ....................... this is a repeated episode of neisserial infection. eningococcal disease (MCD) may be associated with under 5 years of age. Four had a previous medical history of abnormalities of the complement system. Several note: two with pneumonia, and one with urinary tract infec- authoritative paediatric texts recommend screening tion with vesicoureteric reflux. The fourth case is discussed M 1–3 for complement deficiencies following MCD, but there have subsequently. There was no relevant family history of been no large UK paediatric studies to establish whether this problems potentially related to complement abnormalities in is worthwhile. These disorders, if identified, have implications any child. for management, including family studies, prophylaxis, vacci- A total of 118/824 (14%) required intensive care; there were nation, and altered thresholds for infection screening and 42 deaths (5%). In 352 there was laboratory confirmation treatment. However, testing is time consuming (especially (cultures, polymerase chain reaction (PCR), or serology) of http://adc.bmj.com/ when families need to travel long distances to clinics), needs infection with Neisseria meningitidis. Complement assays were to be done several weeks after recovery, and requires specialist performed in 212; assays were not done in 140 because of laboratory services and interpretation. Should all UK children death, non-attendance, or discharge back to distant units (fig with MCD therefore be screened for complement deficiencies, 1). Group B accounted for 203 cases, group C 138 cases, 11 or is a selective policy more appropriate? We measured were caused by non-groupable N meningitidis, and one case complement activity following recovery from MCD in an was caused by W135. unselected series of children, in order to estimate the Of the remaining 472 unconfirmed cases, 376 (who mainly incidence of undiagnosed complement deficiencies and to presented with a petechial rash but without severe sepsis or on September 28, 2021 by guest. Protected copyright. shock) were treated with antibiotics for 48–72 hours which identify factors which might warn of this diagnosis. were then stopped on obtaining negative cultures. Ninety six, although culture and/or PCR negative, had a clinical diagnosis SUBJECTS AND METHODS of MCD and were treated accordingly; 85 of this group had gel From 1996 to 1999, children with a provisional diagnosis of assays performed at follow up. Of the total of 297 complement MCD were identified. These were patients seen at, referred to, assays done, there was only one child with an abnormal result or discussed with either the Regional Paediatric Infectious (see below). Diseases Unit or the Paediatric Intensive Care Unit Retrieval Service, from units in the North East Region. Surviving Case report children with suspected or proven MCD were invited for This 4 year old child presented with a 24 hour history of high review in the clinic 6–8 weeks following discharge. Providing fever, vomiting, and a petechial rash. On admission she was there were no ongoing inflammatory processes (such as shocked and required immediate fluid resuscitation. A total of necrotic skin lesions, new/different infections, or recent 65 ml/kg of colloid was required within the first 24 hours. She surgery) CH100 and AP100 were measured in those children was intubated, ventilated, and required inotropic support with with proven MCD (based on culture and non-culture dobutamine (maximum dose 12 µg/kg/min), adrenaline methods) and in those where a clinical diagnosis had been (maximum dose 2 µg/kg/min), and subsequently noradren- made. These are gel assays and measure the integrity of the aline (0.5 µg/kg/min). High dose intravenous cefotaxime was classical and alternative pathways of complement activation.4 commenced (200 mg/kg/day). She developed a disseminated If CH100 or AP100 were abnormal, additional tests were done intravascular coagulopathy (prothrombin time 27 sec, acti- to identify the missing complement components. vated partial thromboplastin time 59.9 sec, fibrinogen 1.6 g/l, RESULTS ............................................................. A total of 824 children (age range 2 months to 16 years), with Abbreviations: MCD, meningococcal disease; PCR, polymerase chain a provisional diagnosis of MCD were identified; 60% were reaction www.archdischild.com 216 Hoare, El-Shazali, Clark, et al Total number with Arch Dis Child: first published as 10.1136/adc.86.3.215 on 1 March 2002. Downloaded from provisional diagnosis of MCD (n = 824) Laboratory confirmed Non-laboratory cases confirmed cases (n = 352) (n = 472) CH100/AP100 CH100/AP100 not Provisional diagnosis Clinical diagnosis assessed assessed of MCD rejected of MCD (n = 212) (n = 140) (n = 376) (n = 96) Died Lost to follow up Transferred to CH100/AP100 other units assessed (n = 42) (n = 42) (n = 56) (n = 85) Figure 1 Breakdown of numbers of children with a provisional diagnosis of MCD who were then screened for abnormalities of the complement system. Only one of these children was complement deficient. d-dimers 4000 ng/ml) and was treated with fresh frozen DISCUSSION plasma and cryoprecipitate. She was ventilated for five days; The complement system is a series of 19 plasma and nine her course was complicated by extensive oral infection with membrane proteins, first discovered at the turn of the twenti- Herpes simplex (requiring intravenous acyclovir), an adenovi- eth century. However it was not until the 1960s that the first ral chest infection, staphylococcal skin sepsis, a left knee effu- complement deficient patient was described.3 The system is sion, and necrotic skin areas related to her purpuric rash. Neis- usually divided into classical (where antibody–antigen inter- seria meningitidis (group B) was cultured both from blood and actions initiate the complement cascade) and alternative from a petechial lesion; she also had a positive PCR for blood pathways (which are independent of such) and are described meningococcus. elsewhere.23There are distinct geographical and ethnic influ- http://adc.bmj.com/ Previously, at the age of 4 months, she had an illness char- ences on the incidence of complement deficiencies.25Thus in acterised by high temperature, irritability, and then a focal fit. Japan, C9 deficiency may occur in up to 0.1% of the On admission to her local hospital at that time, she was population, although it is uncommon in white people. shocked and had required fluid resuscitation, high dose Conversely C2 deficiency has a frequency of 0.01% in the USA, benzylpenicillin, and cefotaxime. A septic screen revealed although it is unreported in Japan.5 Complement deficiency Pneumococcus in both blood and cerebrospinal fluid. She made was found in 6/176 Dutch patients (3%) over a 33 year a successful but slow recovery from this illness, though she period.6 Thus the threshold for screening for complement also developed respiratory syncytial virus positive bronchioli- abnormalities should reflect these epidemiological variations. on September 28, 2021 by guest. Protected copyright. tis during convalescence. There was no relevant family history Primary complement deficiencies are closely associated of note and in particular no history of meningitis, recurrent with increased susceptibility to infection, rheumatic/ infections, or unexplained deaths in infancy. Her five siblings were all in good health as were her non-consanguineous par- autoimmune diseases, or angioedema. Properdin deficiency is ents. X linked. Deficiencies in either the classical or alternative After recovering from MCD, she was allowed home and was pathways which lead to suboptimal cleavage/activation of C3 reviewed two months later in the clinic when CH100 and (an important opsonic ligand) render children more suscepti- AP100
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