A 17-year-old female presented to the emergency department with a chief complaint of recurrent painful rash. She was well until 8 weeks ago when she initially developed a painful rash on her hands and feet. During that time she recalls having a headache, severe malaise and generalized myalgias but no fever or chills. She states that it was “barely noticeable to look at” but was very painful. She did not seek any medical care at the time, and the symptoms resolved completely after 3 days. She was well for 2 weeks before the symptoms recurred. This second episode was described to be more painful, both at the site of the skin eruption and in the joints of her wrists, hands, ankles and feet. She was seen by her primary care physician and treated for contact dermatitis. The symptoms improved more slowly this time with complete resolution over 1 week. When the third episode began a week later, the pain was so severe that she sought medical attention immediately. She was again treated symptomatically and gradually returned to her healthy baseline. On the day of presentation to the emergency department, her painful rash, arthralgias and general malaise had returned for the fourth time in 8 weeks, and she was hospitalized for further evaluation.
Social history revealed that she is in a monogamous heterosexual relationship. She “usually” uses condoms. She has never had a sexually transmitted infection. She denied any exposure to animals and has not traveled outside of the area where she lives in upstate New York. She does not attend college, but once or twice a month stays overnight with her boyfriend, who lives in a college residence hall. On review of New York State immunization registry data, she had received Tdap (tetanus–diphtheria–acellular pertussis) vaccine at age 14 years and 3 doses of human papillomavirus vaccine between the ages of 14 and 16 years. She had not received meningococcal vaccine (MCV).
On physical examination, she was afebrile, but appeared anxious and uncomfortable. She had 5 small clusters of petechial lesions consisting of 2–10 discrete petechiae each. Three of these clusters were on her right hand (Fig. 1), one on her left arm and one on her right ankle. On palpation, these lesions were exquisitely painful. She had no other skin findings. Although she complained of severe arthralgias, she had no overt joint swelling. All her major muscle groups were mildly tender to palpation. Examination of her heart and lungs was normal. She had no splenomegaly. She was neurologically intact.
Laboratory evaluation showed a leukocyte count of 12,000 cells/mm3, 67% neutrophils, 30% lymphocytes and 3% monocytes. The hemoglobin was 14.5 g/dL, and the platelet count 640,000/mm3. A comprehensive metabolic panel and creatine phosphokinase were normal. Biomarkers for inflammation showed an erythrocyte sedimentation rate of 85 mm/h and a C-reactive protein of 102 mg/L. Antinuclear antibody and rheumatoid factor were negative. Serologic testing for Epstein Barr virus, human immune deficiency virus and rickettsia was negative. Chest radiography and echocardiogram were normal. Urine nucleic acid amplification testing for Neisseria gonorrhoea and Chlamydia trachomatis was negative.
Upon hospitalization, she was started empirically on intravenous ceftriaxone. On hospital day 1, her blood culture revealed Gram negative diplococci, later identified as Neisseria meningitidis serotype B. Appropriate contacts were immediately treated for exposure to invasive meningoccal infection. The patient’s symptoms had markedly improved, and the rash faded completely after 3 days of antibiotics. She remained afebrile during hospitalization and was discharged from the hospital after 5 days of intravenous ceftriaxone. Immediately before discharge, she was vaccinated with a dose of conjugate quadrivalent MCV. She was seen in follow-up 1 week after hospitalization, at which time laboratory testing of the terminal complement components and properdin was obtained and was normal.
Chronic meningococcemia was first described in the German medical literature in 1902 in a 32-year-old woman who presented with meningococcal meningitis, after 2 months of intermittent chills, fever, rash, myalgia and arthralgias.1 The illness has retained a similar description over time. The entity debuted in the English literature in 1924 in a case report of a patient with recurring symptoms lasting 7 months.2 This author went on to summarize 68 additional reported cases worldwide. Each of the cases shared the characteristics of recurrent fever, rash, arthralgias and frontal headaches but with apparent good health in between episodes.
Clark3 pointed out that the abrupt nature and chronicity of the recurrent episodes led some providers to suspect malaria strongly enough to begin antimalarial therapy. In that series, reporting cases from the pre-antibiotic era, symptoms only subsided after meningococcus was cultured from the blood and parenteral polyvalent antimeningoccic serum was administered. The dermatologic findings in these patients were described as petechial, macular or nodular in nature, and the joint complaints largely confined to the ankles and knees. Carbonell and Campbell4 presented 3 new cases of patients treated with polyvalent antimeningococcic serum, noting complications of serum sickness and suggesting for the first time that the recently introduced sulfanilamide antibiotics may prove useful in treatment. The average duration of illness in the 33 U.S. patients described was 11.9 weeks with some illnesses lasting as long as 32 weeks. In this case series, rash was the most common sign of infection, followed by intermittent fever, arthralgias, chills, headache and myalgias. Joint and muscle pain often prompted an initial diagnosis of acute rheumatic fever. Norman5 emphasized the observation that blood cultures are not usually revealing until the third week of symptoms. With the emergence of antibacterial agents, he suggested that the treatment of choice should be sulfadiazine with or without penicillin.
Most cases described to this point were in adolescents and adults, with the first infant case published from the US in 1961.6 By the early 1960s, most case series and case reports were being described from Europe, with some authors suggesting that US providers were starting empiric antibiotic therapy indiscriminately and/or before a full diagnostic evaluation was complete.7,8
The most detailed review of U.S. cases of chronic meningococcemia was published in 1963.9 Benoit9 summarized reports of 115 males and 33 females with a mean age of 26.5 years (3 months to 62 years). The male predominance was because of the high number of cases (69 men) seen in members of the military. When the military cases were excluded from the analysis, there was no gender predilection. The mean duration of symptoms in this series was 6.8 weeks. Fever and chills were present in all cases. Other commonly reported symptoms included skin rash (93.2%), arthralgia (70.3%), headache (61.5%) and history of previous upper respiratory infection (37.2%). In patients with recurrent fever (61.9%), the afebrile periods lasted between 2 and 10 days. Consistent with all prior descriptions, the patients were completely well between febrile episodes. The skin eruptions were described as maculopapular (47.6%), nodular (13.1%), petechial (11.9%) and polymorphous (27.4%). Joint signs and symptoms generally follow the fever curve, and as such, the majority of joint symptoms were intermittent. The average time to the first positive blood culture was 5.5 weeks, with a range of 1–28 weeks. Symptoms resolved in all but 1 patient within 48 hours of starting parenteral antibiotics. The author speculated that some patients develop a chronic form of meningococcemia rather than the classic fulminant, rapidly progressive infection because of specific host factors rather than pathogenic-specific factors.
By the late 1960s, it became clear that the skin lesions seen in chronic meningococcemia differ from those of acute, fulminant disease.10 In acute meningococcemia, extensive vascular thrombosis and necrosis occur following the eruption and rapid progression of the petechial and/or purpuric rash. The organism can often be seen in the skin lesions among an infiltrate of neutrophils. In contrast, the histologic findings in the skin seen in chronic meningococcemia are characterized by perivascular infiltrates of lymphocytes and macrophages with few granulocytes, no evidence of fibrin deposits or thrombosis and the absence of Gram negative diplococci.
By the mid-1960s, not long after antimicrobial agents became available for the treatment of meningococcemia, the first sulfonamide resistant isolates were described.11–13 Fortunately, most meningococci continue to be very susceptible to beta-lactam antibiotics, even today.
Pediatric cases of chronic meningococcemia are less frequently reported than cases in adults. By the mid 1970s, only 12 cases of chronic meningococcemia in children had been reported.14 In most of these cases, the classic clinical constellation of intermittent or sustained fevers associated with recurring maculopapular, nodular or petechial eruptions and migratory arthritis or arthralgias was present. However, in children, isolation of the organism on the first blood culture is common despite the shorter duration of the illness (7 days to 2 months). Despite advances in blood culturing techniques since earlier descriptions, case reports in adults continued to emphasize the low yield of blood cultures, retaining an emphasis on the need to repeat blood cultures in patients with unexplained fever and rash.15 The added subtle clinical exam finding of subungual splinter hemorrhages in a report from 1975 emphasizes the importance of a careful skin examination.16
The early insight that host factors may alter the clinical presentation of meningococcemia was realized in the early 1980s when the first patient with a terminal complement deficiency was reported with chronic meningococcal infection.17 Since that report, a terminal complement component deficiency has been described in association with chronic meningococcemia in children with C6 deficiency, C7 deficiency and properdin deficiency.18,19 A total hemolytic complement assay (CH50) can be used to screen for complement component deficiency. If the CH50 is low, further specific testing can be requested.20
The differential diagnosis for patients who ultimately are found to have chronic meningococcemia is broad and includes autoimmune disease particularly in the form of noninfectious vasculitis. Harwood et al21 described clinical deteriorations in patients treated with systemic glucocorticoids for presumed autoimmune vasculitis who were later found to have chronic meningococcemia, but it remains unclear whether the steroids were responsible for the worsening clinical course.
Although culturing skin lesions in suspected chronic meningococcemia cases have only on very rare occasions led to a microbiologic diagnosis, the emergence of molecular diagnostic pathogen-specific DNA amplification tests performed on suspicious skin lesions may evolve as a new tool. In 1 report, 2 patients with skin lesions and clinical presentations suggestive of chronic meningococcemia, but with negative blood cultures, had N. meningitidis specific DNA detected in skin biopsy material.22
In the US, the first quadrivalent conjugate MCV (MCV4) was approved by the Food and Drug Administration in 2005 and almost immediately added to the universal pediatric and adolescent immunization schedule for all 11–12-year olds. Initially recommended as a single dose vaccine, the Advisory Committee on Immunization Practices added a booster dose at age 16 years in 2010. Because our patient was immunized with both Tdap and human papillomavirus vaccines starting at age 14 years, we were surprised that she had not been immunized with MCV4. Because MCV4 capsular types include A, C, Y and W135, prior vaccination would not have prevented her infection from serotype B. In late 2014, approximately 1 year after our patient was hospitalized, the Food and Drug Administration approved the first multicomponent meningococcal B vaccine. Specific advice from the Advisory Committee on Immunization Practices on how to introduce this new vaccine into the U.S. population is under discussion.
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