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The Pediatric Infectious Disease Journal • Volume 34, Number 1, January 2015
has been reported in individuals with LNB.13,14 This finding was a further stimulus for CSF examination that revealed lymphocytic pleocytosis, and enabled detection of borrelial antibodies in CSF and demonstration of borrelial intrathecal antibody production. Pleocytosis and intrathecal synthesis of specific antibodies are the cornerstones for the diagnosis of LNB12 and enabled a reliable diagnosis of LNB in our patient. The presence of LNB with optic disc edema of the inflamed eye is indicative for borrelial etiology of panophthalmitis which was further substantiated by the favorable outcome after antibiotic treatment.
This work was supported by (1) 12th five-year-major-projects of China’s Ministry of Public Health. Grant 2012zx10004-213 (2) the PREDICT Surveillance Animal-Human Interface Project of GVF. Grant Gvf: 06-09-057-02. Benefitted from intellectual developments (or contributions) from the PREDICT project of the US Agency for International Development (USAID) Emerging Pandemic Threats Program. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the CDC. The authors have no funding or conflicts of interest to disclose. Address for correspondence: Changwen Ke, MD, Guangdong Provincial Center for Disease Control and Prevention, San Francisco, CA. E-mail: [email protected]. Copyright © 2014 by Lippincott Williams & Wilkins DOI: 10.1097/INF.0000000000000492
REFERENCES 1. Steere AC. Lyme disease. N Engl J Med. 2001;345:115–125. 2. Stanek G, Wormser GP, Gray J, et al. Lyme borreliosis. Lancet. 2012;379:461–473. 3. Strle F, Stanek G. Clinical manifestations and diagnosis of lyme borreliosis. Curr Probl Dermatol. 2009;37:51–110. 4. Reiber H, Peter JB. Cerebrospinal fluid analysis: disease-related data patterns and evaluation programs. J Neurol Sci. 2001;184:101–122. 5. Päivönsalo-Hietanen T, Tuominen J, Saari KM. Uveitis in children: population-based study in Finland. Acta Ophthalmol Scand. 2000;78:84–88. 6. Dhoot DS, Martin DF, Srivastava SK. Pediatric infectious posterior uveitis. Int Ophthalmol Clin. 2011;51:113–128. 7. BenEzra D, Cohen E, Maftzir G. Uveitis in children and adolescents. Br J Ophthalmol. 2005;89:444–448. 8. Mikkilä H, Seppälä I, Leirisalo-Repo M, et al. The etiology of uveitis: the role of infections with special reference to Lyme borreliosis. Acta Ophthalmol Scand. 1997;75:716–719. 9. Huppertz HI, Münchmeier D, Lieb W. Ocular manifestations in children and adolescents with Lyme arthritis. Br J Ophthalmol. 1999;83:1149–1152. 10. Mattéi J, Pélissier P, Richard O, et al. Lyme uveitis: 2 case reports. Arch Pediatr. 2011;18:49–53. 11. Sauer A, Hansmann Y, Jaulhac B, et al. Ocular Lyme disease occurring during childhood: five case reports. J Fr Ophtalmol. 2012;35:17–22. 12. Stanek G, Fingerle V, Hunfeld KP, et al. Lyme borreliosis: clinical case definitions for diagnosis and management in Europe. Clin Microbiol Infect. 2011;17:69–79. 13. Moses JM, Riseberg RS, Mansbach JM. Lyme disease presenting with persistent headache. Pediatrics. 2003;112(6 pt 1):e477–e479. 14. Kan L, Sood SK, Maytal J. Pseudotumor cerebri in Lyme disease: a case report and literature review. Pediatr Neurol. 1998;18:439–441.
MILD INFLUENZA A/H7N9 INFECTION AMONG CHILDREN IN GUANGDONG PROVINCE Xianqiao Zeng, MSc,*† Wei Mai, MB,‡ Bo Shu, MB,§ Lina Yi, PhD,*† Jing Lu, PhD,*† Tie Song, MPH,* Haojie Zhong, MB,* Hong Xiao, PhD,* Dawei Guan, MPH,* Jie Wu, PhD,* Lijun Liang, MPH,* Corina Monagin, PhD,¶ Xin Zhang, MPH,* and Changwen Ke, MD* Abstract: We describe the clinical and epidemiologic characteristics of 7 children infected with A/H7N9 in Guangdong Province during the winter of 2013–2014. Our results indicate that the mild or asymptomatic characteristics common in H7N9-infected children could pose challenges to our surveillance system becoming a hidden threat to the public health of China and the world. Key Words: H7N9, children cases, mild symptom, viral exposure, environmental samples Accepted for publications June 25, 2014. From the *Guangdong Provincial Center for Disease Control and Prevention; †Guangdong Provincial Institutes of Public Health, Guangzhou; ‡Center for Disease Control and Prevention, Zhaoqing; §Center for Disease Control and Prevention, Zhongshan, China; and ¶Metabiota, Inc., San Francisco, CA.
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utbreak of a novel avian-origin reassorted influenza A (H7N9) virus in China initially emerged in early 2013, causing 132 infections with 32 mortalities through 8th May.1,2 Immediately after the first dramatic appearance of the virus at March 2014 around the Yangtze River delta region, it entered a “silent stage” before re-emerging again in an outbreak in Guangdong province during the winter of 2013–2014. Unlike A(H1N1)pdm09 and the standard seasonal influenza virus H3N2 that both have a low mortality rate, the proportions of deaths among novel H7N9 infections reached 3 0%.2 The majority of laboratory confirmed cases were found in patients with serious acute illness while only several mild/moderate infections were identified in younger adults, indicating that seriousness of infection may be linked to the patient's age.3,4 Here, we describe the epidemiologic and clinical characteristics of all cases of child infections with A/H7N9, as of February 10, 2014, in Guangdong province. These findings will provide increased insight into the body’s response against H7N9 infection in children, which also benefits the early diagnosis of the disease. Moreover, the mild/asymptomatic symptoms of infected children could pose certain challenges to influenza surveillance systems. A surveillance system that is not vigilant and does not include mild/asymptomatic illness, could possibly miss new reassortants with interpersonal transmission capacity.
METHODS Case Source and Classification Data of the laboratory confirmed A/H7N9 child infections were all collected in Guangdong Province by a joint field investigation team comprising staff of the Centers for Disease Control and Prevention at the municipal and provincial level. The patients in this study were classified according to the means by which they were identified. For confirmed A/H7N9 cases identified by influenza-like illness (ILI) surveillance, they were categorized into cases discovered by ILI surveillance while the confirmed cases identified by surveillance of the close contacts were categorized into cases discovered by enhanced ILI surveillance. In addition, patients from temperature check at customs by border inspection and quarantine, a routine mean to prevent the cross-border transmission of novel A/H7N9 virus, were cataloged as cases of border inspection and quarantine. Case definitions, surveillance for identification of A/ H7N9 cases and laboratory test assays of all the above-mentioned cases were the same as previous report.2,4
Surveillance of Close Contacts and Environmental Samples in the Exposure Location Close contacts were defined as individuals known to have been within 1 m, or had direct contact with respiratory secretions or fecal material, of a patient with confirmed H7N9 virus infection any time from the day before the onset of illness. Identified close contacts were monitored daily for 7 days for symptoms of illness and throat swabs were collected from those close contact cases in which symptoms developed to test for the presence of © 2014 Lippincott Williams & Wilkins
© 2014 Lippincott Williams & Wilkins
Not tested Not tested Not tested Dexamethasone/ ribavirin/Compound Amionprine and Antipyrine injection
39.1°C No Yes
Patient 2
7.9 × 10E9/L Not tested 72.9% Oseltamivir phosphate
38.5°C No No
Enhanced ILI surveillance No Yes Yes NA Fever, Anorexia
15.1.2014 23.1.2014 14.1.2014 Exposure in poultry market
Guangzhou 5 Female 14.1.2014 14.1.2014
*As indicated by lung consolidation on chest radiograph. NA indicates not available; WBC, white blood cell; LYM, Lymphocytes; NEUT, Neutrophils.
Highest body temperature Pneumonia* Upper respiratory tract infection WBC LYM NEUT Receiving antiviral treatment
No Yes No NA Rhinorrhea, Cough, Fever, Throat congestion
Sputum Throat swab Family cluster case Environmental positive rates Presenting symptoms
Admission to hospital Recovery or discharge date Laboratory -confirmed date Type of exposure
ILI surveillance
4.11.2013 12.11.2013 4.11.2013 Exposure in poultry market
Location Age Sex Illness onset date First diagnosis date
Finding route
Patient 1
Dongguan 3.5 Male 29.10.2013 1.11.2013
Case
7.99 × 10E9/L 18.4% 72.2% Not clear
38.4°C No No
No Yes No NA Rhinorrhea, Cough, Fever, Sore throat
ILI surveillance
27.1.2014 30.1.2014 27.1.2014 Not clear
Guangzhou 17 Male 22.1.2014 23.1.2014
Patient 3
Not tested Not tested Not tested Never treated with antiviral drugs
38.2°C No No
Border inspection and quarantine No Yes No NA Fever, Throat congestion
Shenzhen 6 Male 27.1.2014 Never visiting any medical facility Never admitted 31.1.2014 30.1.2014 Poultry exposure around the home
Patient 4
12.98 × 10E9/L 9.64% 80.44% Not clear
39.5°C No Yes
Enhanced ILI surveillance No Yes Yes 25% Rhinorrhea, Cough, Fever, Throat congestion
1.2.2014 8.2.2014 1.2.2014 Poultry exposure around the home
Zhongshan 2.5 Female 31.1.2014 1.2.2014
Patient 5
9.69 × 10E9/L Not tested Not tested Oseltamivir phosphate
38°C No No
No Yes Yes 44.3% Fever
30.1.2014 5.2.2014 1.2.2014 Poultry exposure around the home ILI surveillance
Zhaoqing 5 Male 28.1.2014 29.1.2014
Patient 6
Patient 7 Zhaoqing 4 Female 26.1.2014 26.1.2014
Not tested Not tested Not tested Oseltamivir phosphate
3.2.2014 10.2.2014 2.2.2014 Poultry exposure around the home Enhanced ILI surveillance No Yes Yes 44.3% Rhinorrhea, Cough, Fever, Throat congestion 39.3°C No Yes
TABLE 1. Epidemiological Characteristics, Clinical Characteristics and Environmental Data of 7 Cases of Children Infected with A/H7N9.
The Pediatric Infectious Disease Journal • Volume 34, Number 1, January 2015 Mild Influenza A/H7N9 Infection
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the H7N9 virus.4 Environmental specimens from poultry feces, the surfaces of epilators (machines that remove poultry feathers), surfaces of chopping/butchering blocks/boards, the surfaces of cages and from sewage on the ground were all sampled at the exposure location of laboratory confirmed patients with separate cotton-tipped swabs (Copan Italia, via perotti 10-Brescia, Italy). The swabs were then inserted into tube containing 3 mL of virus transport medium (Copan Italia). For the use of all abovementioned human samples and personal information, written informed consents from all participants (their parents or legal guardian) involved in the research were obtained. This study was approved by the ethics committee of the Guangdong Provincial Center for Disease Control and Prevention, and was in compliance with the Helsinki Declaration.
RESULTS Epidemiological and Clinical Characteristics The 7 patients, 4 of whom were males, were identified by the national sentinel surveillance system for ILI (patient numbers 1, 3 and 6), the enhanced ILI surveillance (patients 2, 5 and 7) and border inspection and quarantine (patient 4), respectively, of whom the age ranged from 2.5 to 17 years (mean, 13 years). The patients lived in 5 different cities within and beyond the Pearl River delta region, and date of symptom onset ranged from October 29, 2013 to January 31, 2014. Five of them (patients 2, 4, 5, 6 and 7) had a confirmed history of exposure to live poultry, including chicken, and patients 2, 5 and 7 were close contacts of known H7N9 patients. Apart from patient 4 who was not admitted to any medical facility, the other 6 patients visited clinics or hospitals 1 or 2 days after symptoms onset and were sent to a hospital within next 24 hours, and 1 patient within 2 days of laboratory confirmation. As on February 10th, all patients were subsequently discharged and patient 4 (who was not admitted to the hospital) displayed no symptoms 4 days after illness onset (Table 1). The clinical characteristics of most patients included fever (patients 1–7), throat congestion (patients 1, 4, 5 and 7), cough and rhinorrhea (patients 1, 3, 5 and 7). Patients 1, 5 and 7 reported with an upper respiratory tract infection. All 7 patients had mild disease without requiring intensive care and none had pneumonia (Table 1). The above-mentioned symptoms were consistent with that observed in other cases of H7N9-infected children.2 Noticeably, 4 of 7 children were from family clusters. The patients 2 and 5, whose parents had a confirmed H7N9 infection with acute respiratory distress syndrome, were identified through enhanced ILI surveillance. In another family cluster, 2 cousins, patients 6 and 7, subsequently displayed symptoms of illness and were detected respectively through ILI surveillance and enhanced ILI surveillance. Yet close contact adults of these 2 patients, (ie, their parents) were confirmed negative to H7N9 infection in the laboratory tests.
Environmental Contamination and Exposure To better understand the patients’ exposure to the H7N9 virus, environmental samples from local poultry markets and their residence were collected and subjected to laboratory testing immediately after H7N9 cases were confirmed. Among 104 specimens collected from Zhongshan city, 26 (25%) tested positive for H7N9 while the positive rate for specimens collected from Zhaoqing city was 44.3% (62/140). The majority of positive specimens were collected from poultry feces, the surfaces of chopping/butchering boards and the surface of cages. Notably, through laboratory testing, we have also identified the H7N9 virus in cages from patients 6 and 7s’ residence, which provides strong evidence to support human infection through viral exposure.
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DISCUSSION H7N9 infections, believed to result from exposure to live poultry, are usually characterized by acute respiratory distress syndrome and intensive care. Previous studies have suggested that the severity of H7N9 infection may be age-dependent, yet few have looked into cases of younger age, particularly child infection.2,5 Here, we have presented for the first time, epidemiological and clinical characteristics of 7 H7N9 cases of child infection in Guangdong province. Our results indicate that opposite to most serious, acute cases, all seven H7N9-infected children, with the age ranging from 2.5 to 17 years (mean, 13 years), displayed mild symptoms such as fever below 40°C, cough and throat congestion (rather than pneumonia) since illness onset. Consistent with these characteristics, the above-mentioned illness symptoms were also observed in 2 males in Shanghai (ages, 2 and 4 years old) and 1 male child 9 years old from Fujian province.2,6 Although there are reports of a 7-year-old female in Beijing with H7N9 infection suffering high fever (more than 40°C) and pneumonia, she soon recovered and did not present any illness symptoms 15 hours after being treated with Oseltamivir Phosphate,6 suggesting there may exist certain mechanisms in a child responsible for quick viral clearance and the associated mild symptoms. Also, we speculate that sensitivity to infection in a child might be higher than that in adults in regard to H7N9 exposure, as was proven correct in A(H1N1)pdm09 infection during virus outbreak in Italy by a population serologic survey.5 And the identification of age-dependent infection, close contact adults free from infection, in 3 of 6 cases with a confirmed history of exposure to live poultry provide another supporting evidences to our hypothesis given the similar exposure history shared between adults and children. However, the limited family cluster cases in this study hinder us to further confirm this sensitivity with meaningful statistical analyses. The appearance of family clusters may also suggest the possibility of human-to-human transmission. No direct evidence to date was found and H7N9 exposure, illustrated by the high H7N9-positive rate, is still believed to be the main cause of cases in this study. Taken together, the characteristics of mild/asymptomatic symptoms and the highly virus-contaminated environment may likely lead to underestimates of child infections, which is also referred to as the phenomena of “clinical iceberg”.2 The presentation of the 4-year-old H7N9-infected male child without any symptoms in close contact with a 7-year-old Beijing patient illustrate real challenges posed by such “clinical icebergs” for our sentinel surveillance system.6 The concerns are that in the H7N9-contaminated environment, younger children, a population at high risk for seasonal influenza, can be coinfected by both viruses. Such children with their mild/asymptomatic symptoms if not identified would become a generator as well as a hidden infective source of novel virus and hence make the epidemic more difficult to control. To avoid this, vigilance to surveillance of younger H7N9-infected cases or children among close contacts should be reinforced, and most importantly complete disinfection of high-risk environments such as poultry markets should be conducted so as to eliminate the source of infection.
ACKNOWLEDGMENTS We would like to thank the Guangzhou CDC, Shenzhen CDC, Zhongshan CDC, Zhaoqing CDC and Dongguan CDC for collecting and offering information of the H7N9 patient and environmental samples. This study was made possible by the generous support of the American people through the US Agency for International Development (USAID) Emerging Pandemic Threats PREDICT. The contents are the responsibility of the authors and do not necessarily reflect the views of USAID or the US Government. © 2014 Lippincott Williams & Wilkins
The Pediatric Infectious Disease Journal • Volume 34, Number 1, January 2015
REFERENCES 1. Lin PH, Chao TL, Kuo SW, et al. Virological, serological, and antiviral studies in an imported human case of Avian Influenza A(H7N9) virus in Taiwan. Clin Infect Dis. 2014;58: 242–246. 2. Ip DK, Liao Q, Wu P, et al. Detection of mild to moderate influenza A/H7N9 infection by China’s national sentinel surveillance system for influenza-like illness: case series. BMJ. 2013;346:f3693. 3. Cowling BJ, Freeman G, Wong HY, et al. Preliminary inferences on the agespecific seriousness of human disease caused by avian influenza A(H7N9) infections in China, Euro Surveill. 2013;18:20475. 4. Li Q, Zhou L, Zhou M, et al. Preliminary report: epidemiology of the Avian Influenza A (H7N9) outbreak in China. N Engl J Med. 2013;1–11. 5. Merler S, Ajelli M, Camilloni B, et al. Pandemic influenza A/H1N1pdm in Italy: age, risk and population susceptibility. PLoS One. 2013;8:e74785. 6. Zhu YM. A limited understanding of hazard of influenza A virus subtype H7N9 in children. CJCP. 2013;15:409–411.
KINGELLA KINGAE SEQUENCE TYPE-COMPLEX 14 ARTHRITIS IN A 16-MONTH-OLD CHILD IN GREECE Ioanna N. Grivea, MD, PhD,* Aspasia N. Michoula, MD,* Romain Basmaci, MD,†‡ Zoe H. Dailiana, MD, PhD,§ George Tsimitselis, MD,¶ Stéphane Bonacorsi, MD, PhD,†‡ and George A. Syrogiannopoulos, MD, PhD* Abstract: We describe the first case of Kingella kingae arthritis in a 16-month-old girl in Greece, which has been diagnosed by novel molecular techniques. A joint aspiration of her knee was performed before the initiation of antibiotics, as well as on the 5th and 14th day of empiric antimicrobial therapy. The synovial fluid white blood cell count decreased from 65,000 to 1500 cells/mm3, but the percentage of neutrophils remained 90% in all 3 specimens. Molecular analysis of the synovial fluid specimens by realtime polymerase chain reaction and multilocus sequence typing enabled us to reveal the presence of K. kingae belonging to the international sequence type-complex 14, which persisted up to the fifth day of antibiotic therapy. Key Words: Kingella kingae, septic arthritis, real-time polymerase chain reaction, multilocus sequence typing, Greece Accepted for publication July 21, 2014. From the *Departments of Pediatrics, University of Thessaly, School of Health Sciences, Faculty of Medicine, General University Hospital, Larissa, Greece; †Univ Paris Diderot, Sorbonne Paris Cité; ‡AP-HP, Laboratoire de Microbiologie, Hôpital Robert-Debré, Paris, France; Departments of §Orthopedic Surgery; and ¶Radiology, University of Thessaly, School of Health Sciences, Faculty of Medicine, General University Hospital, Larissa, Greece The authors have no conflicts of interest to disclose. Address for correspondence: George A. Syrogiannopoulos, MD, Department of Pediatrics, University of Thessaly, School of Health Sciences, Faculty of Medicine, General University Hospital of Larissa, Biopolis, 411 10 Larissa, Greece. E-mail [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 © 2014 by Lippincott Williams & Wilkins DOI: 10.1097/INF.0000000000000503
K
ingella kingae is being increasingly recognized as a pathogen responsible for bacteremia and osteoarticular infections among children aged 6–48 months.1–4 With the optimization of conventional culture methods, including the inoculation of synovial fluid into a blood culture vial,1 and the implementation of novel molecular techniques for the synovial fluid analysis,4–6 K. kingae appears to have supplanted Staphylococcus aureus as the primary pathogen responsible for septic arthritis and osteomyelitis in children under 4 years of age in some countries.3–7 However, knowledge among the © 2014 Lippincott Williams & Wilkins
Kingella Arthritis
medical community regarding the incidence and the diagnosis of this organism is insufficient, and K. kingae invasive infections are probably misdiagnosed in a large number of cases. To our knowledge, no cases of K. kingae osteoarticular infection in Greece have been reported in the English literature, probably because of difficulties encountered in the isolation of this pathogen and absence of implementation of specific molecular techniques. In Greece S. aureus, a major pathogen responsible for ostearticular infections,7,8 exhibits increased resistance to methicillin.9 Currently, it is estimated that about one fourth of staphylococcal ostearticular infections are due to Panton–Valentine leukocidin producing methicillin-resistant isolates.10 The latter observation plays an important role in the selection of empiric antibiotic therapy in our country. Improvement of K. kingae diagnosis could facilitate the antimicrobial treatment, especially the oral treatment, as K. kingae is mostly susceptible to beta-lactam antibiotics, such as amoxicillin.1,3 We describe a case of K. kingae arthritis in a toddler living in Central Greece, with special focus on the cytochemical and molecular analysis of the synovial fluid over the course of the disease.
CASE REPORT A 16-month-old girl was referred to the Department of Pediatrics of the University Hospital of Larissa with a 4-day history of fever up to 38.9°C and limping/refusal to walk. Ultrasound examination of the left hip was normal. The first hypothesis was that the child suffered from left hip transient synovitis. She was not attending a day-care center, but her 3-year-old brother was. Within the first day of hospitalization, she improved and started walking and running. There were no objective signs of osteomyelitis or septic arthritis on orthopedic and pediatric examinations. Laboratory evaluation revealed a total peripheral white blood cell (WBC) count of 13,600/mm3, an absolute neutrophil count (ANC) of 5500/mm3, C-reactive protein (CRP) of 39 mg/L and erythrocyte sedimentation rate of 45 mm/h. A blood culture remained sterile. The child defervesced after the third day of hospitalization without antimicrobial or surgical treatment. The girl remained afebrile and free of any signs and symptoms for 48 hours. At that point, the limping reappeared and the child refused to walk. The clinical examination revealed findings in another joint. Increasing erythema, edema and tenderness of the left knee and the perisynovial soft tissue were observed. The differential diagnosis of this afebrile child included septic arthritis, as well as reactive arthritis or inflammatory arthropathies. The magnetic resonance imaging of the left lower limb showed no pathologic findings from the left hip, but effusion of the left knee and intense inflammation of the adjacent soft tissue. There was no bone involvement. A transdermal joint aspiration was performed and purulent fluid was obtained (Table 1), but arthrotomy was not performed. Gram stain was negative. Laboratory findings demonstrated a total peripheral WBC count of 19,900/mm3, ANC of 11,600/mm3, CRP of 98 mg/L and erythrocyte sedimentation rate of 81 mm/hr. TABLE 1. Cytochemical and Molecular Analysis of the Synovial Fluid Over the Course of Kingella kingae Arthritis in a Greek Toddler Specimen, Day of Antibiotic Treatment Before 5th 14th
WBC Count (cells/mm3) 65,000 22,000 1500
Neutrophils Glucose RT-PCR for (%) (mg/dL) K. kingae 90 90 90
9 71 71
Positive Positive Negative
RT-PCR, real-time polymerase chain reaction.
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has been reported in individuals with LNB.13,14 This finding was a further stimulus for CSF examination that revealed lymphocytic pleocytosis, and enabled detection of borrelial antibodies in CSF and demonstration of borrelial intrathecal antibody production. Pleocytosis and intrathecal synthesis of specific antibodies are the cornerstones for the diagnosis of LNB12 and enabled a reliable diagnosis of LNB in our patient. The presence of LNB with optic disc edema of the inflamed eye is indicative for borrelial etiology of panophthalmitis which was further substantiated by the favorable outcome after antibiotic treatment.
This work was supported by (1) 12th five-year-major-projects of China’s Ministry of Public Health. Grant 2012zx10004-213 (2) the PREDICT Surveillance Animal-Human Interface Project of GVF. Grant Gvf: 06-09-057-02. Benefitted from intellectual developments (or contributions) from the PREDICT project of the US Agency for International Development (USAID) Emerging Pandemic Threats Program. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the CDC. The authors have no funding or conflicts of interest to disclose. Address for correspondence: Changwen Ke, MD, Guangdong Provincial Center for Disease Control and Prevention, San Francisco, CA. E-mail: [email protected]. Copyright © 2014 by Lippincott Williams & Wilkins DOI: 10.1097/INF.0000000000000492
REFERENCES 1. Steere AC. Lyme disease. N Engl J Med. 2001;345:115–125. 2. Stanek G, Wormser GP, Gray J, et al. Lyme borreliosis. Lancet. 2012;379:461–473. 3. Strle F, Stanek G. Clinical manifestations and diagnosis of lyme borreliosis. Curr Probl Dermatol. 2009;37:51–110. 4. Reiber H, Peter JB. Cerebrospinal fluid analysis: disease-related data patterns and evaluation programs. J Neurol Sci. 2001;184:101–122. 5. Päivönsalo-Hietanen T, Tuominen J, Saari KM. Uveitis in children: population-based study in Finland. Acta Ophthalmol Scand. 2000;78:84–88. 6. Dhoot DS, Martin DF, Srivastava SK. Pediatric infectious posterior uveitis. Int Ophthalmol Clin. 2011;51:113–128. 7. BenEzra D, Cohen E, Maftzir G. Uveitis in children and adolescents. Br J Ophthalmol. 2005;89:444–448. 8. Mikkilä H, Seppälä I, Leirisalo-Repo M, et al. The etiology of uveitis: the role of infections with special reference to Lyme borreliosis. Acta Ophthalmol Scand. 1997;75:716–719. 9. Huppertz HI, Münchmeier D, Lieb W. Ocular manifestations in children and adolescents with Lyme arthritis. Br J Ophthalmol. 1999;83:1149–1152. 10. Mattéi J, Pélissier P, Richard O, et al. Lyme uveitis: 2 case reports. Arch Pediatr. 2011;18:49–53. 11. Sauer A, Hansmann Y, Jaulhac B, et al. Ocular Lyme disease occurring during childhood: five case reports. J Fr Ophtalmol. 2012;35:17–22. 12. Stanek G, Fingerle V, Hunfeld KP, et al. Lyme borreliosis: clinical case definitions for diagnosis and management in Europe. Clin Microbiol Infect. 2011;17:69–79. 13. Moses JM, Riseberg RS, Mansbach JM. Lyme disease presenting with persistent headache. Pediatrics. 2003;112(6 pt 1):e477–e479. 14. Kan L, Sood SK, Maytal J. Pseudotumor cerebri in Lyme disease: a case report and literature review. Pediatr Neurol. 1998;18:439–441.
MILD INFLUENZA A/H7N9 INFECTION AMONG CHILDREN IN GUANGDONG PROVINCE Xianqiao Zeng, MSc,*† Wei Mai, MB,‡ Bo Shu, MB,§ Lina Yi, PhD,*† Jing Lu, PhD,*† Tie Song, MPH,* Haojie Zhong, MB,* Hong Xiao, PhD,* Dawei Guan, MPH,* Jie Wu, PhD,* Lijun Liang, MPH,* Corina Monagin, PhD,¶ Xin Zhang, MPH,* and Changwen Ke, MD* Abstract: We describe the clinical and epidemiologic characteristics of 7 children infected with A/H7N9 in Guangdong Province during the winter of 2013–2014. Our results indicate that the mild or asymptomatic characteristics common in H7N9-infected children could pose challenges to our surveillance system becoming a hidden threat to the public health of China and the world. Key Words: H7N9, children cases, mild symptom, viral exposure, environmental samples Accepted for publications June 25, 2014. From the *Guangdong Provincial Center for Disease Control and Prevention; †Guangdong Provincial Institutes of Public Health, Guangzhou; ‡Center for Disease Control and Prevention, Zhaoqing; §Center for Disease Control and Prevention, Zhongshan, China; and ¶Metabiota, Inc., San Francisco, CA.
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O
utbreak of a novel avian-origin reassorted influenza A (H7N9) virus in China initially emerged in early 2013, causing 132 infections with 32 mortalities through 8th May.1,2 Immediately after the first dramatic appearance of the virus at March 2014 around the Yangtze River delta region, it entered a “silent stage” before re-emerging again in an outbreak in Guangdong province during the winter of 2013–2014. Unlike A(H1N1)pdm09 and the standard seasonal influenza virus H3N2 that both have a low mortality rate, the proportions of deaths among novel H7N9 infections reached 3 0%.2 The majority of laboratory confirmed cases were found in patients with serious acute illness while only several mild/moderate infections were identified in younger adults, indicating that seriousness of infection may be linked to the patient's age.3,4 Here, we describe the epidemiologic and clinical characteristics of all cases of child infections with A/H7N9, as of February 10, 2014, in Guangdong province. These findings will provide increased insight into the body’s response against H7N9 infection in children, which also benefits the early diagnosis of the disease. Moreover, the mild/asymptomatic symptoms of infected children could pose certain challenges to influenza surveillance systems. A surveillance system that is not vigilant and does not include mild/asymptomatic illness, could possibly miss new reassortants with interpersonal transmission capacity.
METHODS Case Source and Classification Data of the laboratory confirmed A/H7N9 child infections were all collected in Guangdong Province by a joint field investigation team comprising staff of the Centers for Disease Control and Prevention at the municipal and provincial level. The patients in this study were classified according to the means by which they were identified. For confirmed A/H7N9 cases identified by influenza-like illness (ILI) surveillance, they were categorized into cases discovered by ILI surveillance while the confirmed cases identified by surveillance of the close contacts were categorized into cases discovered by enhanced ILI surveillance. In addition, patients from temperature check at customs by border inspection and quarantine, a routine mean to prevent the cross-border transmission of novel A/H7N9 virus, were cataloged as cases of border inspection and quarantine. Case definitions, surveillance for identification of A/ H7N9 cases and laboratory test assays of all the above-mentioned cases were the same as previous report.2,4
Surveillance of Close Contacts and Environmental Samples in the Exposure Location Close contacts were defined as individuals known to have been within 1 m, or had direct contact with respiratory secretions or fecal material, of a patient with confirmed H7N9 virus infection any time from the day before the onset of illness. Identified close contacts were monitored daily for 7 days for symptoms of illness and throat swabs were collected from those close contact cases in which symptoms developed to test for the presence of © 2014 Lippincott Williams & Wilkins
© 2014 Lippincott Williams & Wilkins
Not tested Not tested Not tested Dexamethasone/ ribavirin/Compound Amionprine and Antipyrine injection
39.1°C No Yes
Patient 2
7.9 × 10E9/L Not tested 72.9% Oseltamivir phosphate
38.5°C No No
Enhanced ILI surveillance No Yes Yes NA Fever, Anorexia
15.1.2014 23.1.2014 14.1.2014 Exposure in poultry market
Guangzhou 5 Female 14.1.2014 14.1.2014
*As indicated by lung consolidation on chest radiograph. NA indicates not available; WBC, white blood cell; LYM, Lymphocytes; NEUT, Neutrophils.
Highest body temperature Pneumonia* Upper respiratory tract infection WBC LYM NEUT Receiving antiviral treatment
No Yes No NA Rhinorrhea, Cough, Fever, Throat congestion
Sputum Throat swab Family cluster case Environmental positive rates Presenting symptoms
Admission to hospital Recovery or discharge date Laboratory -confirmed date Type of exposure
ILI surveillance
4.11.2013 12.11.2013 4.11.2013 Exposure in poultry market
Location Age Sex Illness onset date First diagnosis date
Finding route
Patient 1
Dongguan 3.5 Male 29.10.2013 1.11.2013
Case
7.99 × 10E9/L 18.4% 72.2% Not clear
38.4°C No No
No Yes No NA Rhinorrhea, Cough, Fever, Sore throat
ILI surveillance
27.1.2014 30.1.2014 27.1.2014 Not clear
Guangzhou 17 Male 22.1.2014 23.1.2014
Patient 3
Not tested Not tested Not tested Never treated with antiviral drugs
38.2°C No No
Border inspection and quarantine No Yes No NA Fever, Throat congestion
Shenzhen 6 Male 27.1.2014 Never visiting any medical facility Never admitted 31.1.2014 30.1.2014 Poultry exposure around the home
Patient 4
12.98 × 10E9/L 9.64% 80.44% Not clear
39.5°C No Yes
Enhanced ILI surveillance No Yes Yes 25% Rhinorrhea, Cough, Fever, Throat congestion
1.2.2014 8.2.2014 1.2.2014 Poultry exposure around the home
Zhongshan 2.5 Female 31.1.2014 1.2.2014
Patient 5
9.69 × 10E9/L Not tested Not tested Oseltamivir phosphate
38°C No No
No Yes Yes 44.3% Fever
30.1.2014 5.2.2014 1.2.2014 Poultry exposure around the home ILI surveillance
Zhaoqing 5 Male 28.1.2014 29.1.2014
Patient 6
Patient 7 Zhaoqing 4 Female 26.1.2014 26.1.2014
Not tested Not tested Not tested Oseltamivir phosphate
3.2.2014 10.2.2014 2.2.2014 Poultry exposure around the home Enhanced ILI surveillance No Yes Yes 44.3% Rhinorrhea, Cough, Fever, Throat congestion 39.3°C No Yes
TABLE 1. Epidemiological Characteristics, Clinical Characteristics and Environmental Data of 7 Cases of Children Infected with A/H7N9.
The Pediatric Infectious Disease Journal • Volume 34, Number 1, January 2015 Mild Influenza A/H7N9 Infection
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the H7N9 virus.4 Environmental specimens from poultry feces, the surfaces of epilators (machines that remove poultry feathers), surfaces of chopping/butchering blocks/boards, the surfaces of cages and from sewage on the ground were all sampled at the exposure location of laboratory confirmed patients with separate cotton-tipped swabs (Copan Italia, via perotti 10-Brescia, Italy). The swabs were then inserted into tube containing 3 mL of virus transport medium (Copan Italia). For the use of all abovementioned human samples and personal information, written informed consents from all participants (their parents or legal guardian) involved in the research were obtained. This study was approved by the ethics committee of the Guangdong Provincial Center for Disease Control and Prevention, and was in compliance with the Helsinki Declaration.
RESULTS Epidemiological and Clinical Characteristics The 7 patients, 4 of whom were males, were identified by the national sentinel surveillance system for ILI (patient numbers 1, 3 and 6), the enhanced ILI surveillance (patients 2, 5 and 7) and border inspection and quarantine (patient 4), respectively, of whom the age ranged from 2.5 to 17 years (mean, 13 years). The patients lived in 5 different cities within and beyond the Pearl River delta region, and date of symptom onset ranged from October 29, 2013 to January 31, 2014. Five of them (patients 2, 4, 5, 6 and 7) had a confirmed history of exposure to live poultry, including chicken, and patients 2, 5 and 7 were close contacts of known H7N9 patients. Apart from patient 4 who was not admitted to any medical facility, the other 6 patients visited clinics or hospitals 1 or 2 days after symptoms onset and were sent to a hospital within next 24 hours, and 1 patient within 2 days of laboratory confirmation. As on February 10th, all patients were subsequently discharged and patient 4 (who was not admitted to the hospital) displayed no symptoms 4 days after illness onset (Table 1). The clinical characteristics of most patients included fever (patients 1–7), throat congestion (patients 1, 4, 5 and 7), cough and rhinorrhea (patients 1, 3, 5 and 7). Patients 1, 5 and 7 reported with an upper respiratory tract infection. All 7 patients had mild disease without requiring intensive care and none had pneumonia (Table 1). The above-mentioned symptoms were consistent with that observed in other cases of H7N9-infected children.2 Noticeably, 4 of 7 children were from family clusters. The patients 2 and 5, whose parents had a confirmed H7N9 infection with acute respiratory distress syndrome, were identified through enhanced ILI surveillance. In another family cluster, 2 cousins, patients 6 and 7, subsequently displayed symptoms of illness and were detected respectively through ILI surveillance and enhanced ILI surveillance. Yet close contact adults of these 2 patients, (ie, their parents) were confirmed negative to H7N9 infection in the laboratory tests.
Environmental Contamination and Exposure To better understand the patients’ exposure to the H7N9 virus, environmental samples from local poultry markets and their residence were collected and subjected to laboratory testing immediately after H7N9 cases were confirmed. Among 104 specimens collected from Zhongshan city, 26 (25%) tested positive for H7N9 while the positive rate for specimens collected from Zhaoqing city was 44.3% (62/140). The majority of positive specimens were collected from poultry feces, the surfaces of chopping/butchering boards and the surface of cages. Notably, through laboratory testing, we have also identified the H7N9 virus in cages from patients 6 and 7s’ residence, which provides strong evidence to support human infection through viral exposure.
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DISCUSSION H7N9 infections, believed to result from exposure to live poultry, are usually characterized by acute respiratory distress syndrome and intensive care. Previous studies have suggested that the severity of H7N9 infection may be age-dependent, yet few have looked into cases of younger age, particularly child infection.2,5 Here, we have presented for the first time, epidemiological and clinical characteristics of 7 H7N9 cases of child infection in Guangdong province. Our results indicate that opposite to most serious, acute cases, all seven H7N9-infected children, with the age ranging from 2.5 to 17 years (mean, 13 years), displayed mild symptoms such as fever below 40°C, cough and throat congestion (rather than pneumonia) since illness onset. Consistent with these characteristics, the above-mentioned illness symptoms were also observed in 2 males in Shanghai (ages, 2 and 4 years old) and 1 male child 9 years old from Fujian province.2,6 Although there are reports of a 7-year-old female in Beijing with H7N9 infection suffering high fever (more than 40°C) and pneumonia, she soon recovered and did not present any illness symptoms 15 hours after being treated with Oseltamivir Phosphate,6 suggesting there may exist certain mechanisms in a child responsible for quick viral clearance and the associated mild symptoms. Also, we speculate that sensitivity to infection in a child might be higher than that in adults in regard to H7N9 exposure, as was proven correct in A(H1N1)pdm09 infection during virus outbreak in Italy by a population serologic survey.5 And the identification of age-dependent infection, close contact adults free from infection, in 3 of 6 cases with a confirmed history of exposure to live poultry provide another supporting evidences to our hypothesis given the similar exposure history shared between adults and children. However, the limited family cluster cases in this study hinder us to further confirm this sensitivity with meaningful statistical analyses. The appearance of family clusters may also suggest the possibility of human-to-human transmission. No direct evidence to date was found and H7N9 exposure, illustrated by the high H7N9-positive rate, is still believed to be the main cause of cases in this study. Taken together, the characteristics of mild/asymptomatic symptoms and the highly virus-contaminated environment may likely lead to underestimates of child infections, which is also referred to as the phenomena of “clinical iceberg”.2 The presentation of the 4-year-old H7N9-infected male child without any symptoms in close contact with a 7-year-old Beijing patient illustrate real challenges posed by such “clinical icebergs” for our sentinel surveillance system.6 The concerns are that in the H7N9-contaminated environment, younger children, a population at high risk for seasonal influenza, can be coinfected by both viruses. Such children with their mild/asymptomatic symptoms if not identified would become a generator as well as a hidden infective source of novel virus and hence make the epidemic more difficult to control. To avoid this, vigilance to surveillance of younger H7N9-infected cases or children among close contacts should be reinforced, and most importantly complete disinfection of high-risk environments such as poultry markets should be conducted so as to eliminate the source of infection.
ACKNOWLEDGMENTS We would like to thank the Guangzhou CDC, Shenzhen CDC, Zhongshan CDC, Zhaoqing CDC and Dongguan CDC for collecting and offering information of the H7N9 patient and environmental samples. This study was made possible by the generous support of the American people through the US Agency for International Development (USAID) Emerging Pandemic Threats PREDICT. The contents are the responsibility of the authors and do not necessarily reflect the views of USAID or the US Government. © 2014 Lippincott Williams & Wilkins
The Pediatric Infectious Disease Journal • Volume 34, Number 1, January 2015
REFERENCES 1. Lin PH, Chao TL, Kuo SW, et al. Virological, serological, and antiviral studies in an imported human case of Avian Influenza A(H7N9) virus in Taiwan. Clin Infect Dis. 2014;58: 242–246. 2. Ip DK, Liao Q, Wu P, et al. Detection of mild to moderate influenza A/H7N9 infection by China’s national sentinel surveillance system for influenza-like illness: case series. BMJ. 2013;346:f3693. 3. Cowling BJ, Freeman G, Wong HY, et al. Preliminary inferences on the agespecific seriousness of human disease caused by avian influenza A(H7N9) infections in China, Euro Surveill. 2013;18:20475. 4. Li Q, Zhou L, Zhou M, et al. Preliminary report: epidemiology of the Avian Influenza A (H7N9) outbreak in China. N Engl J Med. 2013;1–11. 5. Merler S, Ajelli M, Camilloni B, et al. Pandemic influenza A/H1N1pdm in Italy: age, risk and population susceptibility. PLoS One. 2013;8:e74785. 6. Zhu YM. A limited understanding of hazard of influenza A virus subtype H7N9 in children. CJCP. 2013;15:409–411.
KINGELLA KINGAE SEQUENCE TYPE-COMPLEX 14 ARTHRITIS IN A 16-MONTH-OLD CHILD IN GREECE Ioanna N. Grivea, MD, PhD,* Aspasia N. Michoula, MD,* Romain Basmaci, MD,†‡ Zoe H. Dailiana, MD, PhD,§ George Tsimitselis, MD,¶ Stéphane Bonacorsi, MD, PhD,†‡ and George A. Syrogiannopoulos, MD, PhD* Abstract: We describe the first case of Kingella kingae arthritis in a 16-month-old girl in Greece, which has been diagnosed by novel molecular techniques. A joint aspiration of her knee was performed before the initiation of antibiotics, as well as on the 5th and 14th day of empiric antimicrobial therapy. The synovial fluid white blood cell count decreased from 65,000 to 1500 cells/mm3, but the percentage of neutrophils remained 90% in all 3 specimens. Molecular analysis of the synovial fluid specimens by realtime polymerase chain reaction and multilocus sequence typing enabled us to reveal the presence of K. kingae belonging to the international sequence type-complex 14, which persisted up to the fifth day of antibiotic therapy. Key Words: Kingella kingae, septic arthritis, real-time polymerase chain reaction, multilocus sequence typing, Greece Accepted for publication July 21, 2014. From the *Departments of Pediatrics, University of Thessaly, School of Health Sciences, Faculty of Medicine, General University Hospital, Larissa, Greece; †Univ Paris Diderot, Sorbonne Paris Cité; ‡AP-HP, Laboratoire de Microbiologie, Hôpital Robert-Debré, Paris, France; Departments of §Orthopedic Surgery; and ¶Radiology, University of Thessaly, School of Health Sciences, Faculty of Medicine, General University Hospital, Larissa, Greece The authors have no conflicts of interest to disclose. Address for correspondence: George A. Syrogiannopoulos, MD, Department of Pediatrics, University of Thessaly, School of Health Sciences, Faculty of Medicine, General University Hospital of Larissa, Biopolis, 411 10 Larissa, Greece. E-mail [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 © 2014 by Lippincott Williams & Wilkins DOI: 10.1097/INF.0000000000000503
K
ingella kingae is being increasingly recognized as a pathogen responsible for bacteremia and osteoarticular infections among children aged 6–48 months.1–4 With the optimization of conventional culture methods, including the inoculation of synovial fluid into a blood culture vial,1 and the implementation of novel molecular techniques for the synovial fluid analysis,4–6 K. kingae appears to have supplanted Staphylococcus aureus as the primary pathogen responsible for septic arthritis and osteomyelitis in children under 4 years of age in some countries.3–7 However, knowledge among the © 2014 Lippincott Williams & Wilkins
Kingella Arthritis
medical community regarding the incidence and the diagnosis of this organism is insufficient, and K. kingae invasive infections are probably misdiagnosed in a large number of cases. To our knowledge, no cases of K. kingae osteoarticular infection in Greece have been reported in the English literature, probably because of difficulties encountered in the isolation of this pathogen and absence of implementation of specific molecular techniques. In Greece S. aureus, a major pathogen responsible for ostearticular infections,7,8 exhibits increased resistance to methicillin.9 Currently, it is estimated that about one fourth of staphylococcal ostearticular infections are due to Panton–Valentine leukocidin producing methicillin-resistant isolates.10 The latter observation plays an important role in the selection of empiric antibiotic therapy in our country. Improvement of K. kingae diagnosis could facilitate the antimicrobial treatment, especially the oral treatment, as K. kingae is mostly susceptible to beta-lactam antibiotics, such as amoxicillin.1,3 We describe a case of K. kingae arthritis in a toddler living in Central Greece, with special focus on the cytochemical and molecular analysis of the synovial fluid over the course of the disease.
CASE REPORT A 16-month-old girl was referred to the Department of Pediatrics of the University Hospital of Larissa with a 4-day history of fever up to 38.9°C and limping/refusal to walk. Ultrasound examination of the left hip was normal. The first hypothesis was that the child suffered from left hip transient synovitis. She was not attending a day-care center, but her 3-year-old brother was. Within the first day of hospitalization, she improved and started walking and running. There were no objective signs of osteomyelitis or septic arthritis on orthopedic and pediatric examinations. Laboratory evaluation revealed a total peripheral white blood cell (WBC) count of 13,600/mm3, an absolute neutrophil count (ANC) of 5500/mm3, C-reactive protein (CRP) of 39 mg/L and erythrocyte sedimentation rate of 45 mm/h. A blood culture remained sterile. The child defervesced after the third day of hospitalization without antimicrobial or surgical treatment. The girl remained afebrile and free of any signs and symptoms for 48 hours. At that point, the limping reappeared and the child refused to walk. The clinical examination revealed findings in another joint. Increasing erythema, edema and tenderness of the left knee and the perisynovial soft tissue were observed. The differential diagnosis of this afebrile child included septic arthritis, as well as reactive arthritis or inflammatory arthropathies. The magnetic resonance imaging of the left lower limb showed no pathologic findings from the left hip, but effusion of the left knee and intense inflammation of the adjacent soft tissue. There was no bone involvement. A transdermal joint aspiration was performed and purulent fluid was obtained (Table 1), but arthrotomy was not performed. Gram stain was negative. Laboratory findings demonstrated a total peripheral WBC count of 19,900/mm3, ANC of 11,600/mm3, CRP of 98 mg/L and erythrocyte sedimentation rate of 81 mm/hr. TABLE 1. Cytochemical and Molecular Analysis of the Synovial Fluid Over the Course of Kingella kingae Arthritis in a Greek Toddler Specimen, Day of Antibiotic Treatment Before 5th 14th
WBC Count (cells/mm3) 65,000 22,000 1500
Neutrophils Glucose RT-PCR for (%) (mg/dL) K. kingae 90 90 90
9 71 71
Positive Positive Negative
RT-PCR, real-time polymerase chain reaction.
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