Bonville et al

The Pediatric Infectious Disease Journal  •  Volume 34, Number 6, June 2015

Chronic Meningococcemia Presenting as a Recurrent Painful Rash Without Fever in a Teenage Girl Cynthia A. Bonville, MS, Manika Suryadevara, MD, Olamide Ajagbe, MD, and Joseph B. Domachowske, MD Abstract: Chronic meningococcemia is a rare diagnosis seen in patients with recurrent fever and rash. We describe a case of chronic meningococcemia in a teenage girl who presented with a recurrent painful rash, without fever, over a period of 8 weeks. Key Words: meningococcemia, petechial rash, Neisseria meningitidis Accepted for publication November 19, 2014. From the Department of Pediatrics, State University of New York Upstate Medical University, Syracuse, NY. The authors have no funding or conflicts of interest to disclose. Address for correspondence: Manika Suryadevara, MD, Department of Pediatrics, State University of New York Upstate Medical University, 750 East Adams St, Syracuse, NY 13210. E-mail: [email protected] Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/INF.0000000000000700

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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.

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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 © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.

The Pediatric Infectious Disease Journal  •  Volume 34, Number 6, June 2015

FIGURE 1. Rash on the hands of a teenage girl diagnosed with chronic meningococcemia. 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 pathogenicspecific 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 © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Chronic Meningococcemia

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. REFERENCES 1. Salomon H. Ueber meningokokkenseptikaemie. Berl klin Wocheschr. 1902;39:1045. 2. Dock W. Intermittent fever of seven months duration due to meningococcemia (with an analysis of sixty-eight reported cases of meningococcemia). JAMA. 1924;83:31–33. 3. Clarke FB. Chronic meningococcemia: report of cases. Cal West Med. 1931;34:361–364. 4. Carbonell A, Campbell EP. Prolonged meningococcemia: report of three cases. Arch Intern Med. 1938;61:646–654. 5. Norman JK. Chronic meningococcemia; presentation of case and discussion. Mil Surg. 1945;97:455–457. 6. Day WR, Goethe RM. Chronic meningococcemia in infancy. Northwest Med. 1961;60:915–916.

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Stockmann et al

The Pediatric Infectious Disease Journal  •  Volume 34, Number 6, June 2015

7. Gore M. Chronic meningococcemia. Ann Intern Med. 1956;45:142–145. 8. Saslaw S. Chronic meningococcemia. Report of a case. N Engl J Med. 1962;266:605–607. 9. Benoit FL. Chronic meningococcemia. Case report and review of the literature. Am J Med. 1963;35:103–112. 10. Ognibene AJ, Dito WR. Chronic meningococcemia. Further com ments on the pathogenesis of associated skin lesions. Arch Intern Med. 1964;114:29–32. 11. Bloom DS. Chronic meningococcemia; epidemiology, diagnosis and treatment. Calif Med. 1965;103:87–90. 12. Frank ST, Gomez RM. Chronic meningococcemia. Mil Med. 1968;133: 918–920. 13. Nielsen LT. Chronic meningococcemia. Arch Dermatol. 1970;102:97–101. 14. Leibel RL, Fangman JJ, Ostrovsky MC. Chronic meningococcemia in childhood. Case report and review of the literature. Am J Dis Child. 1974;127:94–98. 15. Dineen JF, Poretz DM. Chronic meningococcemia. Va Med Mon (1918). 1975;102:957–958. 16. Angoff GH, Czarnetzki B, Wolinsky E. A case of chronic meningococcemia with unusual features. Am J Med Sci. 1975;269:243–246. 17. Adams EM, Hustead S, Rubin P, et al. Absence of the seventh component of complement in a patient with chronic meningococcemia presenting as vasculitis. Ann Intern Med. 1983;99:35–38. 18. Fasano MB, Sullivan K, Ibsen L, et al. Chronic meningococcemia in a child with a deficiency of the sixth component of complement. Pediatr Allergy Immunol. 1993;4:214–216. 19. Nielsen HE, Koch C, Mansa B, et al. Complement and immunoglobulin studies in 15 cases of chronic meningococcemia: properdin deficiency and hypoimmunoglobulinemia. Scand J Infect Dis. 1990;22:31–36. 20. Tuso PJ, Ahern MJ. Chronic meningococcemia. Conn Med. 1987;51: 698–702. 21. Harwood CA, Stevens JC, Orton D, et al. Chronic meningococcaemia: a ­forgotten meningococcal disease. Br J Dermatol. 2005;153:669–671. 22. Parmentier L, Garzoni C, Antille C, et al. Value of a novel Neisseria meningitidis–specific polymerase chain reaction assay in skin biopsy specimens as a diagnostic tool in chronic meningococcemia. Arch Dermatol. 2008;144:770–773.

NATIONAL TRENDS IN THE INCIDENCE, OUTCOMES AND CHARGES OF PEDIATRIC OSTEOARTICULAR INFECTIONS, 1997–2012 Chris Stockmann, MSc,*†‡ Krow Ampofo, MD,* Andrew T. Pavia, MD,* Carrie L. Byington, MD,* Anne J. Blaschke, MD, PhD,* Catherine M.T. Sherwin, PhD,†‡ Michael G. Spigarelli, MD, PhD,†‡ and Adam L. Hersh, MD, PhD* Abstract: In the United States, the incidence of osteoarticular infections among hospitalized children increased 15% from 2.07 to 2.38 cases per 1000 admissions from 1997 through 2012. The incidence of methicillinresistant Staphylococcus aureus-coded infections increased from 0.02 to 0.36 cases per 1000 admissions. Methicillin-resistant S. aureus-coded cases had a larger number of therapeutic procedures, longer hospital stays and higher hospital charges. Key Words: osteoarticular infections, children, infectious diseases, Staphylococcus aureus, MRSA Accepted for publication December 4, 2104. From the *Division of Pediatric Infectious Diseases, †Division of Clinical Pharmacology, Department of Pediatrics, and ‡Department of Pharmacology/ Toxicology, University of Utah College of Pharmacy, Salt Lake City, UT. Funding: C.S. is supported by the American Foundation for Pharmaceutical Education’s Clinical Pharmaceutical Sciences Fellowship. The authors have no conflicts of interest to disclose. Address for correspondence: Chris Stockmann, MSc, Division of Pediatric Infectious Diseases, Department of Pediatrics, University of Utah School

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of Medicine, 295 Chipeta Way, Salt Lake City, UT 84108. E-mail: Chris. [email protected] Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/INF.0000000000000686

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here are few national estimates of the burden of pediatric osteoarticular infections, including pyogenic arthritis and osteomyelitis. Historically, methicillin-susceptible Staphylococcus aureus (MSSA) has been the predominant cause of these infections.1 Within the past 15 years, the epidemiology of pediatric pyogenic arthritis and osteomyelitis has changed following the emergence of community-associated methicillin-resistant S. aureus (MRSA) infections.2 Single center studies and evaluations conducted among freestanding children’s hospitals have reported an increase in the incidence of MRSA-associated osteoarticular infections.2,3 Our objectives were to evaluate the national incidence, outcomes and hospital charges associated with pediatric pyogenic arthritis and osteomyelitis. Additionally, we compared the incidence, outcomes and charges of MRSA-coded osteoarticular infections with those caused by other organisms.

MATERIALS AND METHODS Data Source This was a retrospective cohort study that used data from the United States Agency for Healthcare Research and Quality (AHRQ) Healthcare Cost and Utilization Project (HCUP) Kids’ Inpatient Database (KID). KID is a de-identified administrative data set designed specifically to assess the use of hospital services by children. KID contains inpatient data for children hospitalized at nonfederal, nonrehabilitation, general, specialty and pediatric hospitals. In KID, hospitals are categorized by their geographic location according to US Census Regions (see Table, Supplemental Digital Content 1, http://links.lww.com/INF/C86). At its inception in 1997, 22 states contributed data. By 2012, 44 states contributed data. KID samples 10% of uncomplicated deliveries and 80% of all other admissions for children

Chronic meningococcemia presenting as a recurrent painful rash without fever in a teenage girl.

Chronic meningococcemia is a rare diagnosis seen in patients with recurrent fever and rash. We describe a case of chronic meningococcemia in a teenage...
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