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* Department of Pediatrics, Baylor College of Medicine, Houston, Texas
Texas Children's Hospital, Houston, Texas
Medical Research Unit in Clinical Epidemiology, Mexican Social Security Institute, Durango, Mexico
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ABSTRACT |
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Methods. We identified adolescent patients meeting criteria for severe sepsis requiring admission to the PICU. Patient records were reviewed, and isolates were obtained for susceptibility testing and DNA extraction. Isolates were tested for the presence of virulence genes (cna, tst, lukS-PV, and lukF-PV) and enterotoxin genes (sea, seb, sec, sed, seh, and sej) by polymerase chain reaction. Genomic fingerprints were determined by repetitive-element polymorphism polymerase chain reaction and pulse-field gel electrophoresis. SCCmec cassette type was determined.
Results. Fourteen adolescents with severe CA S aureus infections were identified between August 2002 and January 2004. All were admitted to the PICU with sepsis and coagulopathy. Twelve patients had CA-MRSA infections; 2 had CA methicillin-susceptible Staphylococcus aureus (MSSA) infections. The mean age was 12.9 years (range: 10-15 years). Thirteen patients had pulmonary involvement and/or bone and joint infection; 10 patients had 
2 bones or joints infected (range: 2-10); 4 patients developed vascular complications (deep venous thrombosis); and 3 patients died. All isolates were identical or closely related to the previously reported predominant clone in Houston, Texas (multilocus sequence type 8, USA300), and carried lukS-PV and lukF-PV genes as well as the SCCmec type IVa cassette (12 MRSA isolates) but did not contain cna or tst. Only 1 strain carried enterotoxin genes (sed and sej).
Conclusions. Severe staphylococcal infections in previously healthy adolescents without predisposing risk factors have presented more frequently at Texas Children's Hospital since September 2002. CA MRSA and clonally related CA MSSA characterized as USA300 and sequence type 8 have been isolated from these patients.
Key Words: community-acquired Staphylococcus aureus • methicillin-resistant • severe sepsis
Abbreviations: CA, community acquired • MRSA, methicillin-resistant Staphylococcus aureus • PVL, Panton-Valentine leukocidin • TCH, Texas Children's Hospital • PCR, polymerase chain reaction • REP-PCR, repetitive-element polymorphism polymerase chain reaction • PFGE, pulse-field gel electrophoresis • MSSA, methicillin-susceptible Staphylococcus aureus • ST, sequence type
Staphylococcus aureus is a frequent cause of infections in children, ranging from skin and soft tissue to invasive life-threatening infections.1 Although antibiotic therapy has reduced the mortality associated with S aureus septicemia from 80% to 20%,2 staphylococcal sepsis remains a significant clinical problem, not only for hospital-acquired infections but also for community-acquired (CA) infections. Although CA methicillin-resistant S aureus (MRSA) isolates often are resistant only to methicillin and usually associated with skin and soft tissue infection, CA-MRSA isolates may also cause invasive and severe infections and even deaths in apparently healthy pediatric patients.3–5
The molecular analysis of nosocomial and CA S aureus strains in the United States has shown that CA-MRSA isolates usually do not carry the tst gene, associated with toxic shock syndrome, but do harbor genes encoding other superantigen toxins capable of producing toxic shock–like illness.6 CA-MRSA organisms harboring the genes encoding Panton-Valentine leukocidin (PVL) also have been associated with a severe course and poor prognosis in patients with pneumonia.7,8 Severe staphylococcal septicemia has been associated with serious underlying disease, intravenous drug abuse, or recent antibiotic or immunosuppressive therapy.9 Almost 30 years ago, Shulman and Ayoub described the rare occurrence of staphylococcal sepsis in the absence of predisposing factors in older children.10 Thus, the finding of several adolescents with severe infection caused by CA MRSA in a relatively short period of time prompted this review and a molecular characterization of the isolated strains.
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METHODS |
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TOPABSTRACTMETHODSCase ReportsRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Severe sepsis was defined as sepsis associated with organ dysfunction, hypoperfusion, or hypotension.12–14 Patients who met criteria for severe sepsis and were admitted to the pediatric intensive care unit (PICU) were selected from the database. Charts were rereviewed for these patients and pediatric risk-of-mortality scores were obtained to assess predicted mortality rates.15 Patients >10 years old with sepsis were included in the study to best compare our findings with those of Shulman and Ayoub.10 Children with S aureus infections seen in consultation by the Infectious Disease Service at TCH were identified in the computer database of the service. Children with severe sepsis as defined above were determined by review of the electronic medical records.
Isolates recovered from these patients were grown on tryptic soy agar plates containing 5% sheep blood (BBL Beckton Dickinson, Cockeysville, MD) for DNA isolation. Template DNA from each strain was isolated by using the UltraClean microbial DNA kit as recommended by the manufacturer (Mo Bio Laboratories, Solano Beach, CA). Susceptibility to vancomycin was determined by microbroth dilution and categorized according to the 2004 National Committee for Clinical Laboratory Standards interpretative guidelines.16
Fingerprinting
All isolates were typed by repetitive-element polymerase chain reaction (REP-PCR) and pulse-field gel electrophoresis (PFGE). REP-PCR was performed by using a commercial REP-PCR fingerprinting kit according to manufacturer instructions (Bacterial Barcodes, Houston, TX). A PTC-200 Peltier thermocycler PCR system (MJ Research, Reno, NV) was used for the PCR, and the amplicons were separated by electrophoresis on a 1.5% agarose gel in 1x TAE (0.04 M Tris-HCl/0.001 M EDTA).
PFGE was performed as follows: Agarose plug preparation and restriction enzyme digestion were performed by using the GenPath group 1 reagent kit (Bio-Rad Laboratories, Hercules, CA) according to manufacturer instructions. The plugs were digested with SmaI (GenPath kit) and loaded into the wells of a 1% agarose gel (Bio-Rad). Electrophoresis was performed in a CHEF-DR III (Bio-Rad) at 14°C by using the Harmony protocol parameters17: block 1 had an initial switch time of 5 seconds, a final switch time of 15 seconds, and a run time of 10 hours at 6 V/cm. Block 2 had an initial switch time of 15 seconds, a final switch time of 60 seconds, and a run time of 13 hours at 6 V/cm.
REP-PCR and PFGE fingerprints were visualized by UV light after ethidium-bromide staining and compared digitally by Pearson correlations/unweighted pair-group method with arithmetic mean using GelComparII computer software (Applied Maths, Kortrijk, Belgium). The relationship between strains was determined based on previously published criteria.18
Multilocus Sequence Type
Multilocus sequence typing was performed according to the instructions posted at the MLST Web site (www.mlst.net), and the sequence type (ST) was determined by using the Staphylococcus multilocus sequence type database located at Imperial College, London, and funded by the Wellcome Trust.
Determination of SCCmec Type
The SCCmec type was determined by using methods by Okuma et al.19 Positive controls were NCTC 10492, (SCCmec type I), N315 (SCCmec type II), 85/2082 (SCCmec type III), and CA 05 (SCCmec type IVa).
PCR Studies of Selected Genes
Primers for cna, PVL genes (luk-S-PV and luk-F-PV), and staphylococcal enterotoxin genes (sea, seb, sec, sed, seh, and sej) are described elsewhere.20,21 Primers for tst (5'-gtaagccctttgttgcttgc-3' and 5'-tgtggatccgtcattcattg-3') were designed by using a primer design program (Primer3, www.genome.wi.mit.edu/genome_software/other/primer3.html). Positive controls were UAMS-1 (cna), ATCC 51651 (tst), TCH clinical strain 584 (PVL genes), 85/2082 (sea), NCTC 10492 (seb), N315 (sec), clinical isolate 2949 (sed and sej), and MW2 (seh). The accuracy of the enterotoxin and tst PCR assays was confirmed by sequencing PCR products from the positive controls and performing BLAST analysis (www.ncbi.nih.gov/BLAST). The cna and PVL gene assays were confirmed previously.21
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RESULTS |
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Three of the cases occurred in the month of October 2003, coinciding with the peak of the 2003 influenza virus season in Houston.
Clinical Manifestations
Bone and Joint infections
Of the 14 children, 13 (93%) had bone and joint infections. Three children had septic arthritis of the knee joint, and the remaining 10 (71%) had multiple bones and joints involved with >2 sites affected simultaneously (range: 2–10). Of the 10 patients with >2 bones and joints affected, 8 also had pyomyositis of the neighboring muscles. S aureus was isolated from 1 bone/joint aspirates in 12 of the 13 patients.
Pulmonary
Of the fourteen patients, 13 (93%) had pulmonary involvement. Seven (50%) had bilateral nodular densities consistent with septic emboli seen on chest radiographs; these patients also had bone and joint infection. Three patients had bilateral air-space disease with multiple pneumatoceles, and 2 had complicated parapneumonic effusions. Eleven (79%) required endotracheal intubation secondary to respiratory failure. Nine of these patients (64%) grew S aureus from tracheal aspirates. Only 1 patient was admitted with primary pulmonary disease and was also coinfected with influenza A virus.
Cardiovascular
All patients had a transthoracic echocardiogram, and none demonstrated vegetations. Only 1 patient had a transesophageal echocardiogram performed, which was also negative. Only 1 patient had left ventricular dysfunction on echocardiogram. The autopsy of 2 patients showed bacterial infiltrates in myocardium and endocardium, but no vegetations were seen on the valves.
Peripheral Vascular Disease
Four patients had vascular complications (29%). The common iliac vein was thrombosed in 1 patient, 2 had saphenous and popliteal vein thrombosis, and 1 had femoral vein thrombosis. All 4 patients had bone infections adjacent to their thromboses. Two of these patients had chest radiographs consistent with septic emboli. None of the patients had a family history of thrombosis, and subsequent evaluations for hypercoagulable state are still in progress. These thromboses developed early in the course of the infection and therefore did not seem to be related to prolonged immobilization. Two patients had low levels of protein C on presentation that later increased to normal levels.
Renal
Seven patients were admitted in acute pre–renal failure, and 1 patient had nephrotic syndrome on admission.
Skin
Eleven patients presented with skin lesions that ranged from hives to erythema multiforme-like rash to papular-pustular lesions (Fig 1). The content of these pustules was cultured and grew S aureus.
Clinical Course and Outcome
Of the 14 patients, 13 (93%) were bacteremic. The average duration of positive blood cultures was 4 days (range: 1–11 days). Eight (57%) patients were bacteremic for 4 days. These patients also had >2 bone/joint sites affected and had pulmonary lesions. The mean duration of fever was 13 days (range: 2–35 days), and the mean PICU stay was 30 days. Eight patients required surgical drainage of joints or incision and drainage of bone abscesses.
Three of the 14 patients died. MRSA was isolated from 2 of these patients and MSSA from 1. These 3 patients had septic arthritis of the knee without any other joints involved and pulmonary metastatic disease.
Patients were treated for the primary disease, which in the majority of cases was osteomyelitis. Only patients with vascular complications were treated as endovascular infections and received vancomycin for the complete 6 weeks of therapy; in addition, prolonged oral clindamycin was administered to 3 of these 4 patients
Laboratory
The initial white blood cell count ranged from 2700/mm3 to 40000/mm3 (mean absolute neutrophil count: 9700/mm3; range: 550-37430/mm3). Four patients were leukopenic on admission, and 2 of them died. All patients had elevated erythrocyte sedimentation rates (mean: 80.6 mm/hour) and C-reactive proteins (mean: 33.5 mg/dL). All patients had positive D dimers and fibrin split products. Mean platelet count was 174000/mm3 (range: 72000-469000/mm3). Although not all patients had hypofibrinogenemia, the disseminated intravascular coagulation panels were interpreted as suggestive of disseminated intravascular coagulation by the pathology service. Aspartate aminotransferase and alanine aminotransferase were also found to be elevated in 9 patients; serum albumin levels were low as well (mean: 2.43 g/dL). Hyponatremia was a common feature (mean: 130 mmol/L), and creatinine was >1.5 mg/dL in 5 of the 14 patients.
Antibiotic Susceptibility
The MRSA isolates from these patients had a similar antibiotic susceptibility pattern: all were susceptible by disk diffusion to clindamycin, gentamicin, vancomycin, and trimethoprim-sulfamethoxazole. All the MRSA isolates were resistant to erythromycin, with no inducible resistance to clindamycin. Vancomycin minimal inhibitory concentrations were obtained by microbroth dilution and ranged from 0.5 to 1.0 µg/ml. The 2 MSSA isolates were also susceptible to clindamycin and trimethoprim-sulfamethoxazole.
Molecular Analysis
Twelve isolates were methicillin resistant, and all carried the SCCmec type IV. All MRSA isolates were tst- and cna-negative, results consistent with previous findings for the predominant CA-MRSA clone circulating in Houston.21 Genes encoding for PVL were present in all isolates including the MSSA strains. The enterotoxin PCR assays were negative for all strains except 1 MSSA isolate that carried the enterotoxins genes sed and sej (Table 2).
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DISCUSSION |
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TOPABSTRACTMETHODSCase ReportsRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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In surveillance of S aureus infection at TCH since August 2001, 74% of CA S aureus isolates in children have been methicillin (oxacillin) resistant. Ninety-five percent of the MRSA isolates have been recovered from patients with skin and soft tissue infections and 5% in patients with invasive disease. However, before September 2002, severe life-threatening CA-MRSA infections had not been frequently seen in otherwise healthy children at TCH.
The resemblance of the 14 patients described in this report to those described by Shulman and Ayoub is striking. In both studies, multiple bone and joint infections as well as metastatic pulmonary disease are noticeable. Only 1 of our patients presented with a necrotizing pneumonia similar to that described in the patients in Minnesota, and this patient was coinfected with influenza A virus. None of our patients fulfilled criteria for toxic shock syndrome.24
Two younger children without underlying medical conditions (18 months and 4 years old) were also admitted to the PICU with severe CA-MRSA infections over the time period studied. In these 2 children, the sites of infection were lungs (pneumonia) and femur (osteomyelitis), respectively. Their isolates were identical to the predominant clone described in the adolescent patients. The 18-month-old patient admitted with pneumonia was coinfected with influenza A and died shortly after admission. Autopsy findings were consistent with necrotizing pneumonia.
It is not clear what factors have played a role in the emergence of these severe cases seen at TCH. Shulman and Ayoub hypothesized in their study that a restriction in hexachlorophene use could have been a contributing factor through a potential increase in colonization of patients with S aureus. In another study from Africa22 in which 27 children with severe staphylococcal infections with no clear predisposing factors are described, poor environmental and personal hygiene was presumed to be an associated factor.
The deaths in children without typical risk factors in Minnesota-North Dakota in 1999 raised the concern of a highly virulent MRSA clone that had established itself in the community.23,25–27 The MW2 strain was isolated from 1 of these patients and subsequently sequenced completely.28 This strain carried several virulence genes not present in other S aureus strains and was genetically defined as ST1 by multilocus sequence typing. In 2000, Mongkolrattanothai et al4 also isolated strains from 4 pediatric patients in Chicago, Illinois, who presented with severe sepsis syndrome. These strains were closely related to MW2. Two of the isolates were CA MSSA, which were indistinguishable from each other by PFGE and differed from the MRSA isolates by 2 bands (shown to contain the SCCmec type IV cassette).
Since 2002 a predominant clone, ST8, has been circulating in Houston.21 This clone is characterized by the presence of genes encoding for PVL, causes predominantly skin and soft tissue infections, and is most likely identical to the CA-MRSA strain USA300, which is present in various geographical regions of the United States.29–31
Two other clones circulate in Houston at a much lower level (ST30 and ST1). We had hypothesized that the less common ST1, likely related to the MW2 strain (which caused the pediatric deaths in Minnesota and severe disease in Chicago), also would be associated with the severe cases observed at our hospital. On the contrary, we found that all staphylococcal isolates recovered from these patients were closely related to (MSSA isolates) or indistinguishable from (MRSA isolates) the predominant CA-MRSA clone in Houston (ST8).
This clone is responsible for causing a wide spectrum of diseases ranging from simple soft tissue infections to severe cases such as those described in this report. In accordance with the observations by Mongkolrattanothai et al,4 the MSSA and MRSA isolates in our study were closely related, suggesting the possible derivation of CA MRSA from a CA MSSA by acquisition of the SCCmec type IV cassette and horizontal transfer in the community.21
Secondary bacterial infections, especially with S aureus, are not uncommon in epidemics of influenza. The association between influenza virus and staphylococcal pneumonia has been established, and the clinical presentation includes a characteristic necrotizing pneumonia.1 Gillet et al8 described patients (median age: 14.8 years) with CA S aureus necrotizing pneumonias who had complaints of flu-like symptoms several days before their hospital admission. Whether initial viral infections lead to changes in the respiratory mucosa that resulted in enhanced bacterial adhesion was unclear. The majority of these patients were infected with strains carrying the PVL genes (luk-S-PV and luk-F-PV), rarely carried by European strains. In Houston, virtually all CA-MRSA strains carry the PVL genes, and the association between these genes and severe cases is less obvious. However, Martinez-Aguilar et al32 recently reported that more severe complications such as deep venous thrombosis are seen in patients with musculoskeletal infections caused by CA S aureus isolates carrying the PVL genes than in patients with these infections caused by S aureus isolates lacking the PVL genes. In addition to PVL genes, the staphylococcal enterotoxin genes have been implicated as important virulence determinants in the multifactorial pathogenicity of S aureus. In the 4 cases from Chicago,4 all strains carried PVL genes, sea and seh. The MRSA isolates carried sec, and MSSA isolates carried seb. In our 14 patients, only 1 MSSA strain carried any of the enterotoxin genes (sed and sej) that were sought.
The 2003–2004 influenza season in Houston began earlier than in previous seasons, with a peak of cases occurring in October 2003. Three of the 14 children with severe sepsis were admitted in the month of October 2003. Ten of our patients had viral cultures performed, but only 1 had influenza A isolated. This patient presented with necrotizing pneumonia.
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ACKNOWLEDGMENTS |
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We thank Linda Lambert for skillful technical assistance. We are also grateful to Dr Mark Smeltzer (University of Arkansas, Little Rock, AK) for providing control strain UAMS-1 and Dr Keiichi Hiramatsu and Dr Teruyo Ito (Department of Bacteriology, Juntendo University, Tokyo, Japan) for the control strains for SCCmec types I–IV.
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FOOTNOTES |
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Address correspondence to Sheldon L. Kaplan, MD, Texas Children's Hospital, Mail Code 3-2371, 6621 Fannin St, Houston, TX 77030. E-mail: skaplan{at}bcm.tmc.edu
No conflict of interest declared.
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