An Exceptional Case of Streptococcal Toxic Shock Syndrome

Netherlands Journal of Critical Care

An exceptional case of Streptococcal Toxic Shock Syndrome

BM van der Oord1, C Hol2, B Manten1

1 Department of Intensive Care Medicine, Meander Medical Centre, Amersfoort, The Netherlands 2 Department of Microbiology, Meander Medical Centre, Amersfoort, The Netherlands

Abstract - Streptococcal Toxic Shock Syndrome (TSS) is caused by an infection with Group A Streptococcus (GAS). Streptococcal pyrogenic exotoxins type A (SPEA) and/or type B (SPEB) are found in the majority of cases of severe GAS infections and play an important role in virulence. These exotoxins can activate the immune system by bypassing the usual antigen-mediated immune response sequence, resulting in the release of large quantities of inflammatory cytokines. These cytokines cause capillary leak and tissue damage, leading to shock and Multi Organ Failure. Overall mortality is 30 to 80 percent, despite aggressive modern therapy [1,2,3,4]. Even though early symptoms can be vague and unspecific, as in our case, it is important to suspect and diagnose TSS at an early stage, because early treatment may have a beneficial effect on outcome.

Keywords - Streptococcal Toxic Shock Syndrom, TSS, immunoglobulin-therapy

Introduction will be present. In this case report, we will present a patient with Group A Streptococcus is an aerobic gram positive coccus, also fatal strep TSS from an unexpected, and not yet described origin. known as S.pyogenes, that can cause severe skin and soft tissue infections and lead to multiple organ failure. Group A Streptococcal Case TSS is defined as any Group AS treptococcus infection associated A 56-year-old man with a medical history of liver cirrhosis (Child- with the acute onset of shock and organ failure. Most common Pugh B) due to alcohol abuse, and hypertension, was sent to the portals of entry (chronically colonized sites) are the skin, pharynx, emergency room because of rapidly developing dyspnoea and rectum, vagina, or cervix – though strep TSS is also a rare compli- swelling of the left cheek. He had been healthy before this hospi- cation of pharyngitis. In 45 percent of patients who develop severe tal visit with no history of recent complaints. No dental problems GAS infection, a portal of entry cannot be identified. were mentioned and the patient had his own teeth; dentist check- The infection may start at a site of minor trauma or injury, after up status was uncertain. His first symptoms had started about 24 surgical procedures, or develop alongside a viral infection such as hours before and consisted of spontaneous and sudden severe varicella or influenza. The most common presenting symptom of pain, worsening with movement of the jaw, without initial swelling. necrotizing fasciitis, in cases in which this complication develops Before presenting to the emergency room, rapid swelling of the left in an invasive GAS infection is abrupt, severe pain on the affected cheek which spread to the side and below the mandible devel- site, with a lack of visible abnormalities on examination though oped, accompanied by local but spreading exanthema. All this did sometimes a deep painful diffuse infiltrate may be palpated. Early not react to antibiotics prescribed by the patient’s GP. According systemic manifestations include an influenza-like syndrome, fever, to NGH standards for soft tissue infections, Flucloxacillin was myalgia and often confusion (55%) [1]. Clinical signs of soft tissue started: 4dd 500mg orally. As the swelling progressed further to infection, such as localized swelling and exanthema, occur in 80 the neck swallowing became difficult and dyspnoea began. percent of patients. The exanthema will be diffuse and scarlatina- In the emergency room physical examination of the patient like in only 10 percent of cases. showed a very dyspnoeic obese man (100kg/178cm) with threat- Laboratory findings include a high percentage of immature ened upper airway due to severe swelling with dark red erythema. neutrophils, elevated serum creatinine and serum creatine ki- The swelling was very painful at bimanual palpation. No signs of nase, myoglobinuria and haemoglobinuria (due to toxin-induced pharyngitis were present. Blood pressure was low at 110/45, pulse haemolysis) and, together with hypotension, may lead to acute rate 118/min r.a. and central body temperature (37.3 C) was nor- renal failure. Shock, Diffuse Intravascular Coagulopathie (DIC) mal. Heart and pulmonary auscultation revealed no abnormalities, and Acute Respiratory Distress Syndrome (ARDS) can develop. only gynecomastia was obvious. The abdomen was obese with Hypoalbuminaemia and disproportional hypocalcaemia often oc- hepatosplenomegaly, spider naevi and some ascites. There was cur. In approximately 60 percent of cases positive blood cultures erythema palmare of both hands. Blood samples were drawn and the patient was intubated and transported to the ICU. Correspondence Laboratory values: Hb 7.3 mmol/l, Leucocytes 2.5 x10 9/l, Lymphocytes 10.0 %, Thrombocytes 28. CRP 44 mg/l, Sodium BM van der Oord 126 mmol/l, Potassium 3.1 mmol/l, Calcium 1.21 mmol/l, Urea E-mail: [email protected] 15.2 mmol/l, Creatinine 184 umol/l, Albumine 17 g/l, Glucose 8.9

NETH J CRIT CARE - VOLUME 15 - NO 1 - FEBRUARY 2011 27 Netherlands Journal of Critical Care BM van der Oord, C Hol, B Manten

mmol/l, Lactate 4.5, PT-INR 2.1, APTT 53. CRP, though elevated, ed and antibiotics were given in adjusted dosages (Benzylpenicillin did fail to show the severity of the disease, whereas lymphopenia 9 milj U/24 hours = 75% of normal dosage and Clindamycin unad- was profound. No prior data were available for this patient. justed). While inotropic therapy had to be severely increased due At the ICU the patient’s condition deteriorated fast with devel- to a deteriorating situation, as a last option to treatment, intrave- opment of severe hypotension and ARDS, no reaction to volume nous immunoglobulin was given (Nanogan 2 gram/kg) [5]. Therapy resuscitation. Inotropics were started, as well as hydrocortisone changes did not result in any improvement of the situation after and antibiotics. Based on the possible etiological microbial agents almost 72 hours of treatment, with progressive ischaemia of limbs in this rapidly deteriorating swelling of the neck in this patient, due to circulation failure and the necessary high doses of inotro- such as oral anaerobes, S.aureus, group A.streptococcus and pics. It was then decided to cease treatment. Autopsy showed an H.influenzae, a choice was made for augmentin and ciprofloxacin. acute necrotizing infection of the larynx, soft tissue and fasciae of A puncture of the local swelling revealed no bacteria, maybe due the neck, most impressive around the area of the submandibular to the GP’s earlier treatment with antibiotics. gland. The liver, heart and spleen showed haemochromatosis, and Blood cultures also failed to show any bacterial growth, again the liver and heart had signs of moderate damage due to alco- probably because of the early start of antibiotics. Because the ex- hol (cirrhosis, cardiomyopathy). All organs showed signs of severe act diagnosis was not yet known, after some stabilisation, a CT- sepsis. scan of the head and neck (figures I and II) was made that showed impressive parapharyngeal infiltration on the left side, but no ab- Discussion scess, subcutaneous emphysema or thrombophlebitis were seen. In retrospect, because of the patient’s severe condition ( disorien- There were no evident signs of fasciitis necroticans, but an ob- tation, difficult speech) when presented to our hospital, there were struction of the submandibular gland was suspected. The ear-nose- only a few anamnestic clues as to where this sudden and rapidly throat specialist was asked to evaluate the case and diagnosed progressive infection originated from. It took some time to suspect this obstruction of the left submandibular gland as an impressive and prove the diagnosis of strep TSS from this peculiar site, until salivary stone. The infiltrated region was incised and drained of gram stain and culture showed the presence of S.pyogenes. We purulent fluid for bacterial culture that revealed only S.pyogenes. know, however, that S. pyogenes is an important cause of respi- This S.pyogenes with pyrogen toxin production, confirmed by the ratory infections (nasopharyngitis, tonsillitis and scarlatina). The RIVM, showed a polysaccharide type B of the outer wall. At drain- differential diagnosis should also consider infection by oral anaer- age there were no signs of fasciitis necroticans. Antibiotic strategy obes (Plaut Vincent and Ludwig’s angina), unilateral Strep erysip- was changed to Benzylpenicillin 12 milj U/24 hours continuously elas of the cheek, Lemiére’s syndrome, H.influenza (para-)diffuse and Clindamycin 3dd 600mg intravenously. Because of total renal pharyngitis/epiglottitis/cellulites, S.aureus and/or streptococcal failure Continuous Veno-Venous Haemofiltration (CVVH) was start- infection of a salivary stone. In our case there were only few symp-

Figure 1. Impressive parapharyngeal infiltration on the left side, Figure 2. Obstruction of the left submandibular gland by an but no abscess or signs of fasciitis necroticans. impressive salivary stone.

28 NETH J CRIT CARE - VOLUME 15 - NO 1 - FEBRUARY 2011 Netherlands Journal of Critical Care An exceptional case of Streptococcal Toxic Shock Syndrome

toms characteristic for primary submandibular gland infection. is down-regulated as well [6-9]. It must be stated that there are All general principles in the management of septic shock were only limited clinical data for the additional treatment with iv im- started as soon as possible. These included the following: munoglobulins [10,11]. - early recognition We started giving immunoglobulins at 2 nanogram/kg in the - early and effective antibiotic therapy first 24 hours of admission and continued for 48 hours. - source control (surgical drainage is the single most important One further point that should be noted concerns the risk factors measure in cases of an abscess or obstructed organ/gland) for strep TSS, including diabetes and alcoholism. Though persons - early haemodynamic resuscitation and continued support of all ages may be affected by this condition – most of whom - corticosteroids (refractory vasopressor-dependent shock) are not immunosupressed [2,12-17] – people with cardiovascular - tight plasma glucose-control disease, collagen vascular disease (with or without steroid use), - proper ventilator management with low tidal volume in patients trauma and alcoholism (as in our patient with Child-Pugh B liver with ARDS cirrhosis) show higher rates of infection [17]. A case control study - CVVH in renal failure showed the highest odds ratios (OR) for the following indepen- - Vitamin substitution for alcohol addiction (thiamine). dent risk factors: cirrhosis (OR 9.7), breast cancer (OR 4.0), stroke Although the antibiotic therapy that had been started in an early (OR 3.5), diabetes mellitus (OR 3.0). phase was sufficient, it could have been even more directed to- This type of infection is equally prevalent in men and women, wards this specific type of infection. This was adjusted as soon as prevalence rates are 1.5 cases/100,000 people/year. Though data the correct diagnosis confirmed by bacterial culture was known. support the use of chemoprophylaxis in patients’ close contacts, Benzylpenicillin was started, which is known to be very effective in it is unclear whether the goal is to prevent the disease in those streptococcal infections. Clindamycin was added because of its recently colonized or to decrease transmission of a strain known potent suppression of bacterial toxin synthesis and facilitation of to cause severe infection [18]. phagocytosis of S. pyogenes by inhibiting M-protein synthesis. As Many cases of streptococcal pharyngitis, erysipelas, scarlet further deterioration of the patient was noticed, immunoglobulin fever, acute rheumatic fever and post streptococcal glomeru- therapy was started because of its possible neutralizing effects lonephritis have been published. A rapidly fatal infection due to on toxins already produced and the positive effect on opsono- obstruction of a submandibular gland has (as far as we know) phagocytosis. Where antibiotics stop bacterial growth and thus not been described in literature before. Even though this type of the production of further toxins, the toxins already produced can infection is rather rare, we have to take it into consideration each still harm the patient. When toxin-concentration drops, the stimu- time a very serious and rapidly progressive case like this is treated lation of interleukin production and proliferation of T-lymphocytes in our hospital.

References

1 Stevens DL, Tanner MH, Winship J. Severe group A streptococcal infections 10 Shah SS, Hall M, Srivastava R, Subramony A, Levin JE. Intravenous immunoglobulin associated with a toxic shock-like syndrome. N Engl J Med 1989; 321:1 in children with streptococcal toxic shock syndrome. Clin Infect Dis. 2009 Nov. 1; 49:1369- 2 Stegmayr B, Bjorck S, Holm S. Septic shock induced by group A streptococcal 76. infections: Clinical and therapeutic aspects. Scand J Infect Dis 1992; 24:589 11 Darenberg J at all. Intravenous immunoglobulin G therapy in streptococcal toxic shock 3 Demers B, Simor AE, Vellend H. Severe invasive group A streptococcal infections in syndrome. Clin Infect Dis. 2003; 37:333. Ontario, Canada: 1987-1991. Clin Infect Dis 1993; 16:792. 12 Francis J, Warren RE. Streptococcus pyogenes bacteraemia in Cambridge: A review of 4 Schellekens JFP, Schouls L, Silfhout A van, Elzenaar CP, Brunings HA, 67 episodes. Q J Med 1988; 256:603. Blokpoel MJC, et al. The resurgence of group A streptococcal disease. 13 Barnham M. Invasive streptococcal infections in the era before the acquired immune Ned Tijdschrift voor Medische Microbiologie 1995; 3:78-83. deficiency syndrome: A 10 years compilation of patients with streptococcal bacteraemia. 5 Kaul R, McGeer A, Norrby-Teglund A et all. Intravenous immunoglobulin therapy for J Infect 1989; 18:231. streptococcal toxic shock syndrome--a comparative observational study. The Canadian 14 Braunstein H. Characteristics of a group A streptococcal bacteraemia in patients at the Streptococcal Study Group. Clin Infect Dis 1999 Apr;28:800-7. San bernardino County Medical Center. Rev Infect Dis 1991; 13:8. 6 Stevens DL. Rationale for the use of gamma globulin in the treatment of streptococcal 15 Schwartz B, Facklam RR, Brieman RF. Changing epidemiology of group A streptococcal Toxic shock syndrom. Clin Infect Dis 1998 Mar;26:639-41. Infection in the USA. Lancet 1990; 336:1167. 7 Barry W, Hudgins L, Donta ST, Pesanti EL. Intravenous immunoglobulin therapy for 16 Holm SE, Norrby A, Bergholm AM, Norgren M. Aspects of pathogenesis of a serious toxic shock syndrome. JAMA 1992;267:3315-6. group A streptococcal infections in Sweden, 1988-1989. J Infect Dis 1992; 166:31. 8 Takei S, Arora YK, Walker SM. Intravenous immunoglobulin contains specific 17 Perovic O, Crewe-Brown HH, Khoosal M, Karstaedt AS. Invasive group A streptococcal antibodies inhibitory to activation of T-cells by staphylococcal toxin superantigens. disease. Eur J Clin Microbiol Infect Dis 1999; 18:362. J Clin Invest 1993;91:602-7. 18 Dele Davies H, Allison McGeer, and the Ontario Group A Streptococcal Study Group. 9 Skansen-Saphir U, Andersson J, Bjork L, Andersson U. Lymphokine production Invasive group A Streptococcal infections in Ontario, Canada. N Engl J Med 1996;335: induced by streptococcal pyrogenic exotoxin-A is selectively down-regulated by 547-554. pooled human IgG. Eur J Immunol 1994;24:916-22.

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