Neisseria meningitidis is an exclusively human bacterium often carried asymptomatically in the nasopharynx but also responsible for invasive meningococcal disease (IMD), whose presentations include meningitis and purpura fulminans (PF).1 IMD is a public health problem and a leading cause of mortality and morbidity worldwide.1 Since 2015, cases of IMD due to N. meningitidis serogroup W (NmW) have been increasing in Europe due to the emergence of new hyperinvasive strains belonging to clonal complex 11.2 NmW strains are also known to be more common in patients with complement deficiencies.3,4 Hyperinvasive meningococcal isolates belong to clonal complexes characterized by rapid invasion of the bloodstream and proliferation.5,6 These isolates also induce an intense inflammatory response that can lead to PF with a generalized necrotic purpuric rash and septic shock progressing to multiorgan failure within a few hours.6 Although third-generation cephalosporins are strongly bactericidal against N. meningitidis, the mortality and morbidity of PF remain high, due to the development of an uncontrolled inflammatory reaction.6
Here, we report an unusual case of a 12-year-old girl with NmW IMD in whom a generalized necrotic purpuric rash developed 48 hours after the initiation of appropriate antibiotic therapy with a third-generation cephalosporin. Immunologic evaluation revealed C6 deficiency.
A previously healthy 12-year-old girl presented at 2 pm to our pediatric emergency department with high-grade fever (39°C) and pain in her right wrist since the morning. Both parents were from the Union of the Comoros and had an unremarkable medical history. One paternal and one maternal grandparent were first cousins. She was born and had always resided in France. There was no recent history of trauma, travel or antibiotic therapy. The only physical finding was painful motion limitation of the right wrist. The radiograph of the wrist was normal, and ultrasonography showed no synovitis. The white blood cell count (WBC) was 15·109/L with 13.9·109/L neutrophils, C-reactive protein (CRP) was 1.7 mg/dL and procalcitonin was 8.9 ng/L (Table 1). At 6 pm, she started experiencing generalized pain and an alteration in her level of consciousness (Glasgow Coma Scale, 12/15). There was no focal neurologic deficit. Her temperature was still 39°C, her heart rate 137/min and her blood pressure 139/60 mm Hg, with normal peripheral perfusion. Blood samples for cultures were drawn. Cerebrospinal fluid analysis showed 214 WBC/mm3 (91% neutrophils), 186 red blood cells/mm3, 3.9 mmol/L glucose (glycemia, 6 mmol/L), 0.50 g/L protein and a negative Gram stain. Intravenous ceftriaxone (75 mg/kg/d) and acyclovir (500 mg/m2/8 hours) were started, and she was hospitalized. The next day, the blood culture was positive for N. meningitidis. The cerebrospinal fluid was negative by culture but positive by polymerase chain reaction for N. meningitidis. The N. meningitidis isolate was serogroup W and fully susceptible to β-lactams. Whole-genome sequencing showed that the isolate was among the NmW isolates currently emerging in Europe (UK2013-strain) and belonging to the hyperinvasive clonal complex (CC) Sequence type (ST)-11 (cc11).7 CRP was 223 mg/L, procalcitonin 24 ng/L, WBC 21.4·109/L with 19·109/L neutrophils, platelets 81·109/L and creatine phosphokinase 850 IU/L. She had generalized muscle pain but no skin rash or petechiae. Her consciousness and neurologic examination were normal. The acyclovir was stopped. Nalbuphine was added to acetaminophen to relieve the pain. After 48 hours of ceftriaxone, when her temperature was still 39°C, necrotic purpuric lesions started to develop over the left hand and both feet. These lesions extended rapidly to the legs and arms, and she experienced severe generalized joint and muscle pain. No new medication had been added before the onset of the rash. There was no evidence of shock, but she was transferred to the intensive care unit for close monitoring for 24 hours. Her hemodynamic status remained normal, and morphine was introduced instead of nalbuphine. CRP was 180 mg/L, platelets 88·109/L and hemostasis was normal. Despite the effectiveness of ceftriaxone against N. meningitidis, the patient was switched to cefotaxime because ceftriaxone is reserved for outpatients at our institution. Immunoglobulin levels and immunoglobulin G subclasses, lymphocyte immunophenotyping and blood smear were normal. Total complement fraction was 0%, and the specific terminal fraction assay revealed complete C6 deficiency. A homozygous deletion was found in exon 7 of the C6 gene (821delA).
Her fever persisted until day 6 after admission. Repeated blood cultures were negative. Transthoracic echocardiography was normal and a total body scan found no collection. The purpuric rash stopped extending after 6 hours. Morphine discontinuation became possible on day 8. Cefotaxime was continued for a total of 7 days of third-generation cephalosporin treatment. She was discharged on day 13, and her muscle pain resolved fully 2 days later. One month later, her skin was normal. As part of the management of C6 deficiency, she was immunized against meningococci ACYW and B. Prophylactic oracillin was started. Complement was normal in all siblings. Three siblings were heterozygous for the mutation in exon 7 of the C6 gene (821delA).
PF is a life-threatening condition of extensive purpura with hemodynamic failure. PF occurs in 25.8% of patients with IMD in France and carries a high mortality rate of 22%.3 A purpuric rash develops within the first 20 hours of IMD in 42%–70% of patients, reflecting the prothrombotic nature of IMD and tropism of N. meningitidis for blood vessels.8 Purpuric lesions and disseminated intravascular coagulation develop when a high N. meningitidis load is present in the bloodstream.6 The complement system plays a central role in several host defense and inflammatory responses, including defense against N. meningitidis mediated through formation of the membrane attack complex.9 Deficiencies in the Terminal complement Pathway Deficiency (TPDs, C5-C9) are therefore associated with an increased susceptibility to IMD. The frequency and distribution of TPDs vary across populations. Thus, C6 deficiency seems more common in blacks,10 with a prevalence of about 1 of 1600 in African Americans.11 Moreover, IMD tends to be less severe and less often fatal in patients with TPD compared with those in the general population.10 Interestingly, IMD was more often due to atypical N. meningitidis isolates in patients with TPD than in the general population (eg, 44% and 6%, respectively, for N. meningitidis serogroup Y).3,4
An unusual feature in our patient was the delayed onset of the purpuric rash after the initiation of appropriate treatment. The C6 deficiency in our patient may have contributed to the delayed rash by impairing membrane attack complex formation, thereby delaying bacterial lysis and the clearance of bacterial components and/or immune complexes. In this context of impaired immunity, antibiotics can participate in the development of systemic inflammatory response syndrome (SIRS) by increasing the concentration of circulating bacterial components released by bacterial lysis. Moreover, the isolate in our patient was among the hyperinvasive isolates of the clonal complex ST-11 of the new expanding UK 2013-strain isolates, which have been associated with atypical clinical presentations (such as gastrointestinal manifestations) possibly related to a greater tendency of these organisms to induce vasculitis.7,12 IMD cases due to NmW first increased in Europe in the year 2000 and were linked to the Anglo-French-Hajj strain but decreased subsequently in France, accounting for only 4% of cases in children and in the general population until 2015.3 Since 2015, however, NmW cases have been increasing in France and other European countries, due to the emergence of new strains belonging to clonal complex 11 and related to the South American–United Kingdom isolates.2 The case reported here suggests a need for increasing the awareness of physicians about atypical IMD presentations seen with the emerging NmW isolates. Finally, the delayed purpuric rash and excessive SIRS may have been related to genetic factors independent from those causing C6 deficiency, such as prothrombotic polymorphisms (including factor V Leiden and FIIG20210A heterozygosity).13 Clinical deterioration in patients with PF may be due chiefly to persistent SIRS and disseminated intravascular coagulation triggered by effects of N. meningitidis on the endothelium and subsequently progressing even after the bacteria are cleared from the bloodstream.6
In conclusion, we report an unusual case of generalized necrotic purpuric rash developing 48 hours after the initiation of appropriate third-generation cephalosporin therapy in a 12-year-old girl with IMD due to NmW. The course was favorable, with no shock, and she recovered completely without limb sequelae. This typical but late presentation of IMD led to the diagnosis of C6 deficiency, emphasizing the need for investigating complement components in patients with IMD due to unusual isolates and/or with unusual presentations, in addition to the standard immunologic workup for severe infections due to encapsulated bacteria. In case of confirmed complement deficiency, complement testing is also recommended among siblings.
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