Edited by: Hans Van Rostenberghe, University of Science Malaysia, Malaysia
Reviewed by: Andreas Gerber-Grote, Zurich University of Applied Sciences, Switzerland; Laura Ferreras-Antolín, NHS England, United Kingdom
This article was submitted to Pediatric Infectious Diseases, a section of the journal Frontiers in Pediatrics
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Few data are available on invasive group A
Group A
Neonatal infections are mainly caused by group B
We aimed to describe the characteristics of IGASI in <3-month-old infants in France.
An IGASI was defined by the isolation of GAS from blood cultures or from other sites that would be normally sterile. In France, microbiology units of the whole country are encouraged to send the invasive GAS isolates to the French National Reference Centre for streptococci (CNR-Strep).
The records of the CNR-Strep were retrospectively queried to identify all the neonates and infants <90 days of life who were declared to have an IGASI between January 1, 2007, and December 31, 2016.
Then, each center was contacted and asked to send the hospitalization report to the first author, who collected the initial clinical and laboratory data and the clinical outcome (length of stay, complication, and transfer to intensive care unit) on a standardized anonymized paper case report form. Patients or their parents were not contacted to obtain additional or missing data. Severe IGASIs were defined as the presence of at least one of the following criteria: respiratory distress requiring mechanical ventilation, hemodynamic disorders requiring fluid resuscitation, or use of vasopressive amines, seizures, or hospitalization in the intensive care unit.
Virulence genes (
Characteristics of patients with invasive Group A
Age [median (range), in days] | 38 (0; 88) |
0–3 days | 5 (19.2) |
4–28 days | 6 (23.1) |
29–60 days | 8 (30.8) |
61–89 days | 7 (26.9) |
Gestational age [median (IQR), in weeks] | 40 [39; 40] |
Birth weight [median (IQR), in g] | 3,510 (3,200; 3,800) |
Birth weight [median (IQR), in percent] | 66.5 (35.8–81.3) |
Intrapartum fever | 3 (11.5) |
ROM <37 weeks of gestation | 1 (3.8) |
Prolonged ROM (>18 h) | 1 (3.8) |
Abnormal fetal heart rate | 2 (7.7) |
Neonatal cardiac surgery | 2 (10.4) |
Time between first clinical sign and first consultation [median (range), in days] | 0 (0; 14) |
Fever | 16 (61.5) |
Difficult breathing | 9 (34.6) |
Poor feeding | 7 (26.9) |
Skin rash | 5 (19.2) |
Rhinitis | 4 (15.4) |
Hypotonia | 4 (15.4) |
Diarrhea | 3 (11.5) |
Vomiting | 2 (7.7) |
Seizure | 1 (3.8) |
Fever | 10 (38.5) |
Expiratory grunting | 9 (34.6) |
Pallor | 8 (30.8) |
Subcostal retraction | 12 (46.2) |
Abnormal pulmonary auscultation |
7 (26.9) |
Oxygen support | 5 (19.2) |
Hemodynamic disorders |
11 (42.3) |
Hypotonia | 4 (15.4) |
Cutaneous sign | 11 (42.3) |
Anemia‡ | 5 (19.2) |
White blood cell count [median (IQR), in G/L] | 15.1 (13.1; 21.3) |
Neutropenia |
5 (19.2) |
Thrombocytopenia |
7 (26.9) |
Initial [median (IQR), in mg/L] | 126 (44; 161) |
Maximum [median (IQR), in mg/L] | 181 (108; 261) |
Hyponatremia | 2 (7.7) |
Hypernatremia | 1 (3.8) |
Hepatic cytolysis >1N |
2 (7.7) |
Cholestasis (bilirubin >18 μmol/l or gamma glutamyl transferase >2N) |
2 (7.7) |
Lactic acid >7 mmol/l | 3 (11,5) |
Renal insufficiency (serum creatinine >N for age) |
1 (3.8) |
Pulmonary hypertension | 4 (15.4) |
Endocarditis | 1 (3.8) |
Pericardial effusion | 1 (3.8) |
Pleural effusion | 5 (19.2) |
Alveolar opacities | 4 (15.4) |
Blood culture positive for GAS | 21/23 (91.3) |
Cerebrospinal fluid culture positive for GAS | 1/20 (5.0) |
Pleural fluid culture positive for GAS | 4/4 (100.0) |
Joint fluid culture positive for GAS | 1/1 (100.0) |
|
8 (30.8) |
|
2 (7.7) |
|
3 (11.5) |
|
1 (3.8) |
|
1 (3.8) |
|
3 (11.5) |
|
1 (3.8) |
|
1 (3.8) |
|
1 (3.8) |
|
1 (3.8) |
|
1 (3.8) |
|
2 (7.7) |
|
1 (3.8) |
|
10 (38.5) |
|
26 (100) |
|
8 (30,8) |
|
5 (19.2) |
|
7 (26.9) |
|
8 (30.8) |
We compared the severe and non-severe infection groups for each characteristic found in at least five patients. Fisher's exact test and Mann–Whitney
The study has been approved by the Robert-Debré ethical committee (number 2016/318). As the data were obtained retrospectively with no involvement of the patients or their parents, no written informed consent was required by the ethical committee, in accordance with the local legislation. An information letter was sent to the parents. Data collection was approved by the French National Data Protection Commission (number 2002616v0).
Thirty-seven infants younger than 90 days old were initially identified from 25 cities and 12 regions, but medical records were not retrieved for 11 patients. The characteristics of the 26 included patients (15 males; 57.7%), from 18 cities and 10 regions, are shown in
History about household contacts with GAS infection was available in only 19 cases. Out of these, 14 (73.7%) had a positive history: 7/19 (36.8%) were exposed to a maternal infection (bacteremia or gynecological infection), among whom four mothers were hospitalized for toxic shock syndrome and two died; 5/19 (26.3%) of the household contacts had pharyngitis/tonsillitis; and 2/19 (10.5%) had a cutaneous infection. Among the nine neonates, a positive history of household contacts was more common than in the 10 infants more than 28 days old [8/9 (88.9%) and 6/10 (60%), respectively;
Among the 26 included patients, 18 (69.2%) had bacteremia, three (11.5%) had pleural effusions or pneumonia with bacteremia (one was complicated with endocarditis), three (11.5%) had pleural effusions without bacteremia, one (3.8%) had meningitis with brain abscess, and one (3.8%) had septic arthritis of the knee. Sixteen (61.5%) out of 26 patients had fever preceding admission, and 10/26 (38.5%) had fever at admission (
Laboratory findings, at presentation to the hospital, are shown in
Blood cultures were collected from 22/26 (84.6%) patients and grew GAS from 21/22 (95.5%). One out of 20 (5%) sampled cerebrospinal fluids (CSFs) grew GAS, and this patient developed a cerebral abscess. Four patients had positive culture from pleural fluid (one of them also had a positive blood culture), and one patient had a positive culture from joint fluid.
The genetic characteristics of the GAS strains are reported in
Treatments are reported in
Treatment and outcomes of patients with invasive group A
Intravenous antibiotics | 24 (92.3) |
Duration [median (range), in days] | 10 (3; 49 |
Switch to oral amoxicillin | 7 (26.9) |
Duration [median (range), in days] | 7 (5; 90) |
Total duration of intravenous + oral antibiotics [median (IQR), in days] | 10 (7; 15) |
Surgery | 4 (15.4) |
Transfusion | 9 (34.6) |
Fluid resuscitation | 8 (26.9) |
Catecholamine | 6 (23.1) |
Length of hospitalization stay [median (range) in days] | 9 (1; 52) |
Transfer to intensive care unit | 13 (50.0) |
Length of hospitalization stay [median (range) in days] | 12 (4; 35) |
Septic shock | 7 (26.9) |
Seizures | 3 (11.5) |
Intratracheal intubation | 8 (30.8) |
Noninvasive ventilation | 1 (3.8) |
Death (within 6 months after the onset of infection) | 2 (7.7) |
Patients with severe IGASI more commonly had abnormal respiratory symptoms, neutropenia, and a higher CRP level (
Comparison between patients with severe and non-severe IGASI.
Male/female | 6 (46.2) | 9 (69.2) | 0.43 |
Age [median (IQR), in days] | 43 (2; 54) | 33 (15; 61) | 0.5 |
≤ 28 days | 5 (38.5) | 3 (23.1) | 0,67 |
Early onset infection (<3 days) | 4 (30.8) | 1 (7.7) | 0.32 |
Fever | 6 (46.2) | 10 (76.9) | 0.23 |
Difficult breathing | 9 (69.2) | 0 (0.0) | <0.001 |
Poor feeding | 4 (30.8) | 3 (23.1) | 1 |
Skin rash | 2 (15.4) | 3 (23.1) | 1 |
Anemia | 2 (15.4) | 3 (23.1) | 1 |
Neutropenia | 5 (38.5) | 0 (0.0) | 0.04 |
Thrombocytopenia | 6 (46.2) | 1 (7.7) | 0.07 |
CRP [median (IQR), in mg/L] | 226 (137–260) | 80 (43–116) | 0.047 |
Positive blood culture | 9 (69.2) | 12 (92.3) | 0.32 |
Pleural effusion | 5 (38.5) | 0 (0.0) | 0.04 |
|
5 (38.5) | 3 (23.1) | 0,67 |
|
6 (46.2) | 4 (30.8) | 0.69 |
|
4 (30.8) | 1 (7.7) | 0.32 |
|
5 (38.5) | 2 (15.4) | 0.38 |
|
5 (38.5) | 3 (23.1) | 0.67 |
Transfusions | 8 (61.5) | 1 (7.7) | 0.01 |
Total duration of intravenous + oral antibiotics [median (IQR), in days] | 14.5 (12.3–21) | 8 (7–10) | 0.007 |
Length of stay [median (IQR), in days] | 13 (11–26) | 7.5 (6–9) | 0.01 |
In this study, we described a relatively large series of 26 cases in a 10-year period in France.
Considering the average number of births per year (~800,000) and the completeness of the French CNR-Strep, which has been estimated to an average rate of 28%, we could estimate the incidence of IGASI in <3-month-old children at 1.6/100,000 infants per year.
Although uncommon, our study has confirmed that IGASIs are frequently associated with clinical severity in <3-month-old infants. We found that bacteremia with no focal sign and pleuro-pneumonia were the most common clinical presentations, accounting for almost 90% of cases. Clinical characteristics were similar to those published in a previous review (
We observed that the
Of note, 73.7% of the infants were household contacts of GAS infection, reaching 88.9% among neonates. This is in accordance with a study evaluating household transmission of invasive GAS in England; authors described that the risk of transmission of invasive GASI was substantially elevated in households after a single case, particularly for mothers and neonates during the neonatal period (risk ratio: 11.9; 95% confidence interval 2.0–70.3). In this population, the theoretical number needed to treat to prevent one secondary case using antibiotic prophylaxis was 50 compared to 271 for the overall population (
Our study has several limitations. Data collection was retrospective, and only 26 patients have been included despite a 10-year period in the whole country. Moreover, we could not describe the characteristics of 11 patients identified by the CNR-Strep due to the impossibility to obtain the medical records. Thus, our results may not be generalizable.
In conclusion, IGASI in <3-month-old infants remains uncommon, but 50% of patients are severely ill. The very high proportion of GAS infection in the household of these neonates suggests a need to assess whether a systematic prophylaxis and close follow-up allow avoiding these severe infections.
The datasets generated for this study are available on request to the corresponding author.
ZG conceptualized and designed the study, collected data, carried out the initial analyses, drafted the initial manuscript, and reviewed and revised the manuscript. PB, CPl, SB, CPo, VB, AFr, and AFa conceptualized and designed the study and critically reviewed the manuscript for important intellectual content. RB conceptualized and designed the study, coordinated and supervised data collection, drafted the initial manuscript, and reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Authors gratefully acknowledge Pr. De Pontual, Pr. Labrune, Pr. Mercier, Pr. Collet, Pr. Claris, Pr. Picaud, Pr. Chabrol, Pr. Nicolino, Pr. Roze, Dr. Piechaud, Dr. Pietrement, Dr. Leguen, Dr. Astruc, Dr. Werner, Dr. Bourgoin, Dr. Chamouine, and Dr. Françoise for sending the patients' hospitalization medical records.