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© Borgis - Postępy Nauk Medycznych 6/2016, s. 414-418
*Teresa Jackowska1, 2, Małgorzata Nieścior2, Monika Grzelczyk-Wielgórska2
Invasive Streptococcus pyogenes infections – cases review**
Inwazyjne zakażenia Streptococcus pyogenes – opisy przypadków
1Department of Pediatrics, Centre of Postgraduate Medical Education, Warsaw
Head of Department: prof. Teresa Jackowska, MD, PhD
2Department of Pediatrics, Father Jerzy Popiełuszko “Bielański” Hospital, Independent Public Health Care Institution in Warsaw
Head of Department: prof. Teresa Jackowska, MD, PhD
Streszczenie
Streptococcus pyogenes jest patogenem, który może wywoływać zakażenia o różnorodnym przebiegu, zarówno ze względu na ciężkość zakażenia, jak i obraz kliniczny. Jest czynnikiem etiologicznym zakażeń dróg oddechowych (gardła, ucha środkowego, zatok obocznych nosa, zapalenia płuc) oraz skóry i tkanek miękkich, mogących prowadzić do martwiczego zapalenia powięzi, a także zapalenia stawów, zapalenia opon mózgowo-rdzeniowych. Celem pracy było przedstawienie pięciu przypadków z inwazyjnym zakażeniem paciorkowcowym, leczonych w oddziale pediatrycznym.
Dzieci w wieku od 3-10 lat były hospitalizowane w latach 2010-2014 w Klinicznym Oddziale Pediatrycznym w Warszawie z powodu zakażenia inwazyjnego o etiologii Streptococcus pyogenes. Każdy z pacjentów prezentował całkowicie odmienny obraz kliniczny zakażenia.
U pacjentów potwierdzono obecność paciorkowca gr. A według Lancefielda (GAS) w lokalizacji fizjologicznie jałowej. Początkowo stosowano leczenie empiryczne, które zmieniono na antybiotykoterapię celowaną po otrzymaniu antybiogramu.
Obraz kliniczny paciorkowcowych zakażeń inwazyjnych jest różnorodny. Szybkie postawienie właściwego rozpoznania oraz celowana antybiotykoterapia gwarantują powodzenie leczenia.
Summary
Streptococcus pyogenes is a pathogen causing infections of various course regarding both the severity, as well as clinical picture. It is the etiological factor of the upper respiratory tracts infections (pharyngitis, otitis media, sinusitis, pneumonia), as well as skin and soft tissues infections, which may lead to necrotising fasciitis, arthritis and meningitis. The aim of this study was to present 5 cases of invasive streptococcus infections, treated in paediatric department
Paediatric patients (aged 3 to 10 years) were hospitalised (from 2010 to 2014) at the Warsaw Clinical Paediatric Department due to invasive infection of Streptococcus pyogenes etiology. Each of the patients displayed markedly different clinical picture of infection.
Patients were confirmed to have streptococcus infection of the Group A (according to Lancefield grouping) in physiologically sterile location. Empiric therapy was conducted initially and switched to antibiotic therapy after receiving an antibiogram.
The clinical picture of invasive streptococcal infections is diverse. A quick diagnosis and aimed antibiotic therapy ensure successful treatment.
Introduction
Streptococcus pyogenes (Group A streptococcus according to Lancefield grouping, GAS) is one of the most frequent infecting pathogen in children, occurring in the form of asymptomatic carriage, localised disease, organ disease and sepsis (1, 2). It may be the cause of different infections, such as pharyngitis and tonsillitis, lymphadenitis, scarlet fever, localized abscess (middle ear, sinuses, lungs, pleura, the meninges, appendages, joints and bones) as well as necrotising fasciitis, sepsis and toxic shock syndrome (1, 3). A group A streptococcal infection may result in complications, such as rheumatic fever with heart involvement and glomerulonephritis (1, 3). The incidence of invasive disease caused by Streptococcus pyogenes (S. pyogenes) in the world is estimated to be equal to 663 thousands cases a year (including 163 thousands deaths) (2). Polish National Institute of Public Health epidemiological reports from the last 3 years indicate constant increase in group A streptococcal invasive infections. In the year 2011 there was 3455 infections per year at incidence rate of 9.0/100 thousands; in the year 2012 there was 4286 infections per year at incidence rate of 11.1/100 thousands; in the year 2013 there was 5294 infections per year at incidence rate of 13.7/100 thousands; in the year 2014 there was 5597 infections per year at incidence rate of 14.54/100 thousands (4). This is probably associated with increasing virulence of the streptococcus and the presence of the M protein which blocks the complement system and inhibits phagocytosis (1, 3). Invasive infections are most prevalent in immunodeficient patients and patients with chronic diseases, although they occur also in immunocompetent patients (3).
Cases overview
Between 2010 and 2014, five paediatric patients (three females and two males) were hospitalised at the Clinical Paediatrics Department of Bielański Hospital in Warsaw with an invasive disease caused by group A streptococcus. The youngest patient was 3 years and 3 months old, and the oldest patient was 10 years old. Four patients were hospitalized from January to March, and one female patient with the diagnosis of soft tissue inflammation of the shin was hospitalized in July. All the paediatric patients were in a good condition, without immune disorder history (tab. 1).
Tab. 1. Patients’ characteristics
 Girl
(JK)
Patient 1
Girl
(ZW)
Patient 2
Girl
(AW)
Patient 3
Boy
(AW)
Patient 4
Boy
(MP)
Patient 5
Age (years)3 3/123 6/127 3/128 4/1210
DiagnosisPneumonia and pleuritisSoft tissue inflammationLeft temporal lobe abscess in the course of acute middle ear inflammationAcute sinusitis.
Pneumonia and pleuritis
Right shoulder inflammation in the course of GAS sepsis.
Acute sinusitis. Scarlet fever
S. pyogenes cultivated, group APleural fluidWound smearAbscess cultureBlood cultureBlood culture, throat smear
Hospitalization duration (days)2424 (16 + 28)
44
21 5 and further treatment in department of surgery in other hospital
Initial treatmentCefotaxime, clindamycinCeftriaxoneCeftriaxoneCefotaxime,
clindamycin
Cefotaxime, clindamycin
Targeted therapyCrystalline penicillin, clindamycinCrystalline penicillin, clindamycinCeftriaxone,
clindamycin, meropenem
Crystalline penicillin, clindamycin,
linezolid
Crystalline penicillin, clindamycin
Female patient 1
Female patient (JK) aged 3 years and 3 months was admitted to the paediatric department with dyspnoea (SpO2 86%), dry cough and fever lasting for 3 days, with the temperature up to 39°C. Pneumonia was diagnosed with pleural reaction. Blood culture test result was proper. There was a need for pleural cavity drainage and 750 mL of fluid was extracted. The fluid culture showed an increase in S. pyogenes number. During hospitalization general condition improved (fig. 1 and 2).
Fig. 1. Patient 1 (JK). Almost total shading of the left lung with mediastinum shift to the right
Fig. 2. Patient 1 (JK). 8th day of the treatment [ndash] clinical picture improvement
Female patient 2
Female patient (ZW) aged 3 years and 3 months was admitted to the paediatric department with the right shin swelling, fever up to 40°C and diarrhoea, which occurred twenty four hours before admission. Soft tissue inflammation of the shin and prerenal azotemia was diagnosed. The starting point of the infection was the wound caused by a mosquito bite. Although third generation cephalosporin was included in the treatment, the general condition of the girl deteriorated. Acute phase proteins concentration increased (CRP from 136.7 mg/l to 426 mg/l), as well as white blood cells (WBC from 17.1 thous./μl to 22.9 thous./μl), with insignificant decrease of procalcitonin concentration (PCT from 76.5 ng/ml to 58.6 ng/ml). During the first three days of the treatment the female patient still had a fever and her urea level was raised (72.4 ng/ml). Physical examination revealed meningism symptoms (neck stiffness, Brudzinski’s symptom). To rule out meningitis a lumbar puncture procedure was performed with the correct result. Several ultrasound examinations of the shin and surgical consultation was performed to rule out necrotising fasciitis. There were no indications for surgical intervention. After receiving the wound culture (S. pyogenes) result, the treatment was switched to crystalline penicillin with clindamycin. The general condition of the girl started to improve as fever as well as oedema and infiltration of the right shin subsided. After 4 days of antibiogram compliant treatment (penicilin, clindamycin susceptibility), the CRP and PCT values decreased considerably (51.6 mg/l and 1.2 ng/ml) accordingly).
Female patient 3
Female patient (AW) aged 7 years and 3 months was transported by emergency service in critical state, unconscious, with anisocoric, unreactive (rigid) pupil (5 points according to Glasgow Score). Immediate cranial CT revealed left temporal lobe abscess, as a result of acute middle ear inflammation (fig. 3). After intubation and establishing venous access, the patient was immediately directed to neurosurgery department of Pomnik Centrum Zdrowia Dziecka Institute for the abscess evacuation. After performing neurosurgical intervention and 15 days of hospitalization in the abovementioned Institute, the patient was admitted again in the paediatric department, to continue with the antibiotic therapy. Antibiotic therapy, which included crystalline penicillin treatment, was continued for 28 days, which resulted in almost complete recovery. On the day of the discharge the third cranial nerve paresis was still present. The patient was discharged with recommendation for rehabilitation and general cleansing of the oral cavity, due to extensive caries. After 5 months since the first hospitalization, the girl did not show any aberrations in neurological examination apart from slightly slowed speech.
Fig. 3. Patient 3 (AW). Left temporal lobe abscess
Male patient 4
Male patient (AW) aged 8 years and 4 months was admitted to the hospital with acute sinusitis. In the third day of hospitalization growing dyspnoea was noted, and the patient required passive oxygen therapy. X-ray examination enabled to diagnose bilateral pneumonia with bilateral pleural reaction. Moreover, the patient underwent cardiological consultation several times due to the suspicion of developing myocarditis (limbs oedema, enlarged left ventricle features > 90 pc in echocardiography examination, lowered contractility, enlargement of parenchymal organs of the abdominal cavity), which was ruled out during subsequent observation.
Male patient 5
Male patient (MP) aged 10 years was referred to hospital due to ethmoidal sinusitis with the suspicion of generalized infection. The boy had fever for 2 days with temperature up to 39°C, complained about sore throat and his skin showed a fine macular rash. On the admission day facial oedema occurred with left eye bruising. Additionally, physical examination revealed skin hyperaesthesia (Filatow triangle present). Rapid streptococcus antigen test result was positive. Acute sinusitis and scarlet fever was diagnosed. From the second day of hospitalization the boy begun to report pain in the right shoulder, left forearm and calves, without joint swelling features. On the fifth day of hospitalization, based on advancing inflammatory process in the acromioclavicular joint, fluid excess in the shoulder joint with the joint capsule elevation, inflammatory granulation tissue with damage of the first layer of hyaline cartilage and its degradation, the inflammation of the right acromioclavicular joint was diagnosed in the course of generalized infection of S. pyogenes etiology. The patient was transferred to the Pediatric Orthopedic Department to perform a surgical intervention.
In conclusion, all of the patients apart from one had a short medical history at the admission to the department, with the duration between ten and twenty hours to 3 days. Only with one patient the medical history covered 2 weeks. The general condition of the patients at the moment of the admission was diverse, from relatively good to severe, and did not correlate with subsequent course of the disease. The condition of three patients worsened significantly during hospitalization.
Five discussed patients were diagnosed during laboratory examinations (tab. 2) with inflammatory markers elevation (all of the patients), hyponatraemia (all of the patients), features of acute prerenal azotemia (1st and 2nd patient) as well as features of cholestasis (5th patient).
Tab. 2. Laboratory tests results at the admission
 Girl
(JK)
Patient 1
Girl
(ZW)
Patient 2
Girl
(AW)
Patient 3
Boy
(AW)
Patient 4
Boy
(MP)
Patient 5
CRP (mg/L) (normal range – 0-5 mg/L)34913645348.255
PCT (ng/mL) (normal range < 0.5 ng/mL)[ndash]76.57.84.7726
WBC (thous./μL) (normal range – 4-12 thous./uL)12.217.138.1612.39.4
Urea (mg/dL) (normal range < 50 mg/dL)57.45813.09.725.4
AST (U/L) (normal range < 32)12[ndash]16.86.0189.3
ALT (U/L) (normal range < 33)161914.467.8242.4
Sodium (mmol/L) (normal range 135-145 mmol/L)129131123130.8133.1
CRP [ndash] acute phase protein; PCT [ndash] procalcitonin; WBC [ndash] white blood cells; AST [ndash] aspartate transaminase; ALT [ndash] alanine transaminase
In the case of one patient (5th patient) the physical examination at the admission revealed the symptoms of scarlet fever of Streptococcus pyogenes etiology. This diagnose was confirmed with StreptA rapid diagnostic test and by positive results of blood and throat swab culture. In the case of the other patients, the results from cultures (blood, pleural fluid and wound swab) acquired on the second and the third day enabled confirmation of the diagnosis and inclusion of aimed antibiotic therapy. All of the GAS strains were confirmed to be vulnerable to erythromycin, clindamycin, penicillin and tetracycline.
Because of the lack of communication it was not possible to gather any information regarding the condition of the patient with inflammation of the acromioclavicular joint. The other patients were not diagnosed with permanent consequences of invasive group A (according to Lancefielda) (2)) streptococcal infection. In four of five patients the starting point of the invasive GAS infection was the infection of the respiratory tract.
Discussion
Streptococcus pyogenes was described for the first time by Louis Pasteur in 1879 (2). In the beginning of the XX century, before the era of antibiotics, this bacterium was the second (after Streptococcus pneumoniae) cause of meningitis. Currently, this bacterium is only responsible for 1% of central nervous system infections (5).
The most common result of GAS infection is pharyngitis and dermatitis. Invasive group A streptococcal infection is diagnosed when the pathogen is found in physiologically sterile environment, for instance cerebrospinal fluid and pleural cavity, as well as when it is accompanied by severe infection, for instance meningitis, arthritis and necrotising fasciitis (5, 6). Isolation of GAS from unsterile location with the symptoms of Streptococcal Toxic Shock Syndrome (STSS), soft tissue necrosis or meningitis with no other cause of infection, enables diagnosis of invasive infection.
In children, invasive infections occur as arthritis, pneumonia, pleuritis and bone inflammation. Necrotising fasciitis is rarely diagnosed (7). In 25% of the cases of invasive streptococcal disease, “the infection gateways” are not determined. Increased risk of invasive infection was observed in the youngest paediatric patients, elderly patients and patients with diabetes, chronic cardiovascular system diseases, respiratory system diseases, secondary immunodeficiency as well as in drug addicted patients and alcoholic patients (3, 7, 8). Children after varicella infection (mainly patients above 12 years of age) and H1N1 influenza are more often susceptible to invasive streptococcal infections. Increased risk of complications was observed in patients receiving NSAIDs (non-steroidal anti-inflammatory drugs), which weaken the activity of granulocytes, increase the production of cytokines as well as cover symptoms of the disease and may delay its proper diagnosis (7-9).
Invasive infections occur mainly in winter and early spring. Seasonality of infections in patients hospitalized in our department confirm these findings.
Non purulent complications such as Sydenham’s chorea, glomerulonephritis and rheumatic fever appear very rarely in the course of invasive infections (7).
Streptococcus virulence depends on different factors, of which the M protein (several dozens of serotypes) is the most important. Toxins produced by streptococcus have the characteristics of superantigens, which means they cause a massive realease of cytokines, which in turn, causes multiple organ dysfunction syndrome (action scheme of the toxins responsible for STSS). Currently, there are ongoing studies regarding 30-valent vaccine (based on M protein) against streptococcus (7, 10).
Streptococcus pyogenes strains isolated from the patients of Bielański Hospital in Warsaw were susceptible to penicillin, clindamycin, tetracyclines and cefotaximum. The growing resistance to clindamycin in 1.2% (German literature) to 4.9% (Polish literature) of the strains was noted in the literature (7, 11). Resistance to penicillin was not observed. Therefore it is recommended to use both penicillin and clindamycin, in order to also cover clindamycin resistant strains (3, 8, 11). Animal model study showed ineffectiveness of penicillin used in monotherapy (12). Moreover, strains resistant to macrolides were observed – 5.1% (Germany) to 9.8% (Poland); chloramphenicol – 0.5% (Germany) to 12% (Poland); tetracyclines – 11.6% (Germany) to 46.3% (Poland) (11). Strains resistant to cefotaxime and linezolid were not isolated (3, 11).
Conclusions
Invasive streptococcal infections mainly concern healthy children. It is important to consider viral-bacterial synergistic infections (chicken pox and influenza), as well as restrain from using NSAIDs, to reduce the risk of bacterial superinfection.
The severity of the infection course is dependant on the streptococcus virulence (presence of specific superantigens and types of M protein). The time period between contracting the disease and establishing diagnosis as well as the moment of starting proper antibiogram compliant treatment are also important factors. In the case of antibiotic therapy, many experts recommend combined therapy with penicillin and clindamycin due to the fact that clindamycin resistance is currently growing.
It is important to take into consideration different clinical pictures of invasive streptococcal infection, which were described in this article in five different examples.

**Supported by the Centre of Postgraduate Medical Education in Warsaw grant number 501-1-20-19-16
Piśmiennictwo
1. Rutkowski Z: Choroby zakaźne i pasożytnicze u dzieci. PZWL, Warszawa 2001: 14-24.
2. Carapetis JR, Steer AC, Mulholland EK, Weber M: The global burden of group A streptococcal diseases. Lancet Infect Dis 2005; 5: 685-694.
3. Imohl M, Reinert R, Ocklenburg C, Linden M: Epidemiology of invasive Streptococcus pyogenes disease in Germany during 2003-2007. FEMS Immunol Med Microbiol 2010; 58: 389-396.
4. Narodowy Instytut Zdrowia Publicznego [ndash] Państwowy Zakład Higieny. Zakład Epidemiologii Główny Inspektorat Sanitarny. Departament Zapobiegania oraz Zwalczania Zakażeń i Chorób Zakaźnych u Ludzi; http://www.pzh.gov.pl/oldpage/epimeld/index_p.html.
5. Paul SP, Jerwood S: Group A streptococcal septicemia, meningitis and cerebral abscess: case report and literature review. The Turkish Journal of Pediatrics 2012; 54: 180-183.
6. Martin J, Murchan S, O’Flanagan D, Fitzpatrick F: Invasive group A streptococcal disease in Ireland 2004-2010. Euro Surveill 2011; 16(41): pii=19988; http://www.eurosurveillance.org/images/dynamic/EE/V16N41/art19988.pdf.
7. Filleron A, Jeziorski E, Michon E-L et al.: Current insight in invasive group A streptococcal infection in pediatrics. Eur J Pediatr 2012; 171: 1589-1598.
8. Committee on Infectious Diseases, American Academy of Pediatrics. Severe invasive group A streptococcal infections: A subject review. Pediatrics 1998; 101(1): 136-140.
9. Miodek M, Gawrysiak M, Kucharski P, Niedzielski J: Rozległa ropowica ściany klatki piersiowej jako powikłanie wiatrówki u 13-letniego chłopca [ndash] opis przypadku. Przegl Ped 2012; 42(1): 31-33.
10. Dale JB, Penfound TA, Chiang EY, Walton WJ: New 30-valent M-protein based vaccine evoked cross-opsonic antibodies against non-vaccine serotypes of group A streptococci. Vaccine 2011; 29: 8175-8178.
11. Szczypa K, Sadowy E, Izdebski R et al.: Group A streptococci from invasive disease episodes in Poland are remarkably divergent at the molecular level. J Cinic Microbiol 2006; 44(11): 3975-3979.
12. Stevens DL, Gibbons AE, Bergstrom R, Winn V: The Eagle effect revisited: efficacy of clindamycin, erthromycin, and penicillin in the treatment of streptococcal myositis. J Infect Dis 1988; 158: 23-28.
otrzymano: 2016-05-04
zaakceptowano do druku: 2016-05-25

Adres do korespondencji:
*Teresa Jackowska
Department of Pediatrics Centre of Postgraduate Medical Education
ul. Marymoncka 99/103, 01-813 Warszawa
tel. +48 (22) 864-11-67
tjackowska@cmkp.edu.pl

Postępy Nauk Medycznych 6/2016
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