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Waterhouse-Friderichsen Syndrome After Infection With Group A Streptococcus

2001; Elsevier BV; Volume: 76; Issue: 11 Linguagem: Inglês

10.4065/76.11.1167

1942-5546

Petros C. Karakousis, Kathleen Page, Michael Varello, Paul J. Howlett, Donald D. Stieritz,

Infections and bacterial resistance

We report a case of Waterhouse-Friderichsen syndrome associated with group A streptococcus (GAS) toxic shock syndrome in a previously healthy man. The patient presented with neck pain and fevers of 2 days' duration. Computed tomography of the neck revealed a mass in the retropharyngeal space, suggesting an abscess. Despite prompt treatment with appropriate antibiotics, the patient experienced a fulminant course and died within 8 hours of presentation. Antemortem blood cultures grew GAS positive for exotoxins A, B, and C. Postmortem examination revealed bilateral adrenal hemorrhage, consistent with Waterhouse-Friderichsen syndrome. Immunohistochemical analysis of the adrenal glands revealed the presence of GAS antigens. However, no disseminated intravascular coagulation was evident. This case demonstrates that adrenal hemorrhage can occur without associated coagulopathy and may result directly from the action of bacterial toxins. We report a case of Waterhouse-Friderichsen syndrome associated with group A streptococcus (GAS) toxic shock syndrome in a previously healthy man. The patient presented with neck pain and fevers of 2 days' duration. Computed tomography of the neck revealed a mass in the retropharyngeal space, suggesting an abscess. Despite prompt treatment with appropriate antibiotics, the patient experienced a fulminant course and died within 8 hours of presentation. Antemortem blood cultures grew GAS positive for exotoxins A, B, and C. Postmortem examination revealed bilateral adrenal hemorrhage, consistent with Waterhouse-Friderichsen syndrome. Immunohistochemical analysis of the adrenal glands revealed the presence of GAS antigens. However, no disseminated intravascular coagulation was evident. This case demonstrates that adrenal hemorrhage can occur without associated coagulopathy and may result directly from the action of bacterial toxins. Group A β-hemolytic streptococcus (GAS) is an important human pathogen that causes various clinical conditions, including pharyngitis, rheumatic fever, pyoderma, necrotizing fasciitis, and toxic shock syndrome.1Stevens DL Invasive group A streptococcus infections.Clin Infect Dis. 1992; 14: 2-11Crossref PubMed Scopus (638) Google Scholar2Francis J Warren RE Streptococcus pyogenes bacteraemia in Cambridge—a review of 67 episodes.Q J Med. 1988; 68: 603-613PubMed Google Scholar The high morbidity and mortality of GAS infections declined with the advent of effective antibiotics but increased again in the 1980s.1Stevens DL Invasive group A streptococcus infections.Clin Infect Dis. 1992; 14: 2-11Crossref PubMed Scopus (638) Google Scholar During this period a toxic shock–like syndrome associated with GAS infections, characterized by sudden onset of hypotension and organ failure, was first recognized.3Stevens DL Tanner MH Winship J et al.Severe group A streptococcal infections associated with a toxic shock-like syndrome and scarlet fever toxin A.N Engl J Med. 1989; 321: 1-7Crossref PubMed Scopus (976) Google Scholar The changing epidemiology and virulence of GAS infections during the 1980s were associated with an increase in the proportion of the antiphagocytic M protein types 1 and 3, as well as the production of pyrogenic exotoxins capable of stimulating large populations of T cells through nonspecific binding of major histocompatibility complex molecules and T-cell receptors (superantigens).1Stevens DL Invasive group A streptococcus infections.Clin Infect Dis. 1992; 14: 2-11Crossref PubMed Scopus (638) Google Scholar Predisposing factors to GAS bacteremia include immunosuppression, malignancy, diabetes mellitus, and injection of illicit drugs.2Francis J Warren RE Streptococcus pyogenes bacteraemia in Cambridge—a review of 67 episodes.Q J Med. 1988; 68: 603-613PubMed Google Scholar However, in several case series of invasive GAS infection, most patients had no underlying illness. A prospective study from Britain evaluating 67 episodes of confirmed GAS bacteremia found that 62% of patients had no known predisposing conditions.2Francis J Warren RE Streptococcus pyogenes bacteraemia in Cambridge—a review of 67 episodes.Q J Med. 1988; 68: 603-613PubMed Google Scholar The pre-dominant portal of entry for infection was the skin, and the disease was characterized by rapid clinical deterioration with a mortality rate of 48%. One half of the deaths occurred within 24 hours of patient admission to the hospital. A study of 20 patients from the Rocky Mountain region with GAS toxic shock–like syndrome also noted the dramatic and fulminant course of invasive GAS infections.3Stevens DL Tanner MH Winship J et al.Severe group A streptococcal infections associated with a toxic shock-like syndrome and scarlet fever toxin A.N Engl J Med. 1989; 321: 1-7Crossref PubMed Scopus (976) Google Scholar In this series the most common clinical presentation was sudden onset of severe pain, fever, myalgia, and diarrhea, with rapid progression to shock and multiorgan failure. Most patients had evidence of soft tissue infection, and 60% had documented bacteremia. Of the 20 patients, 2 had streptococcal pharyngitis, and 4 developed a desquamative rash late in the course of disease. Despite the relatively young age of affected individuals (median age, 36 years) and the absence of underlying disease, the reported mortality was 30%.3Stevens DL Tanner MH Winship J et al.Severe group A streptococcal infections associated with a toxic shock-like syndrome and scarlet fever toxin A.N Engl J Med. 1989; 321: 1-7Crossref PubMed Scopus (976) Google Scholar We report a case of GAS toxic shock syndrome associated with Waterhouse-Friderichsen syndrome in a previously healthy man. A 32-year-old previously healthy man presented to the emergency department because of severe neck pain, odynophagia, and fevers of 2 days' duration. He denied having any recent history of dental procedures or bacterial pharyngitis. His only ill contact was his sister, who had a sore throat. He specifically denied use of nonsteroidal anti-inflammatory drugs or other medications. He denied intravenous drug use and reported an allergy to penicillin. Physical examination revealed a moderately ill-appearing, well-developed man with a temperature of 37°C, blood pressure of 91/53 mm Hg, pulse rate of 104/min, and respirations of 22/min. Examination of his head and neck was notable for fullness in the left hypopharynx, which was extremely tender to palpation. Dermatologic evaluation revealed no petechiae or purpuric rash. Findings on the remainder of the physical examination were unremarkable. Nasopharyngolaryngoscopy revealed copious mucus in the nasopharynx and submucosal fullness in the left hypopharynx at the level of the left pyriform sinus, occluding the airway by approximately 40%. Computed tomography of the neck revealed a mass in the retropharyngeal space, extending anteriorly from the oropharynx into the submandibular space and inferiorly along the left pyriform sinus and arytenopiglottic fold to the level of the thyroid cartilage, surrounding the circumference of the carotids bilaterally. Laboratory studies revealed an elevated leukocyte count of 12.0 × 109/L, with 54% polymorphonuclear leukocytes and 31% band forms; platelet count of 240 × 109/L; prothrombin time of 12.8 seconds (international normalized ratio, 1.0); and partial thromboplastin time of 28.1 seconds. Chest radiography showed no infiltrates or effusions. Peripheral blood samples were obtained for Gram stain and microbiologic culture. The patient was treated immediately with intravenous clindamycin and levofloxacin for possible sepsis secondary to a retropharyngeal abscess and with intravenous dexamethasone to reduce airway inflammation. Within 6 hours of arrival to the hospital, the patient developed a fever (temperature, 39.1°C), hypotension with systolic blood pressure of 62 mm Hg, and severe tachycardia with a pulse rate of 144/min. He received a rapid intravenous infusion of 6 L of normal saline, and intravenous dopamine, 5 mg/h, was initiated, which increased his systolic blood pressure to 90 mm Hg. Nasopharyngolaryngoscopy was repeated, and mild improvement in airway patency was noted. Less than 30 minutes later, noninvasive monitoring revealed extreme bradycardia with a pulse rate of 34/min and oxygen desaturation of 36%. The patient was found to be apneic and asystolic. Despite uncomplicated intubation and aggressive resuscitative efforts following the Advanced Cardiac Life Support guidelines of the American Heart Association, the patient died. Antemortem blood cultures revealed growth of GAS, which subsequently tested positive for production of pyrogenic exotoxins A, B, and C by specific antibodies. At autopsy, examination of the skin showed no purpuric rash and no petechial skin lesions. The neck was grossly swollen, with a diameter of 19 cm at the thyroid cartilage. Dissection of the larynx revealed scattered areas of hemorrhage within the strap muscles bilaterally. An abscess of 1 × 1 × 0.5 cm was identified in the soft tissues lateral to the larynx and to the left of the thyroid cartilage. A histopathology section through the larynx disclosed marked submucosal infiltration by polymorphonuclear cells and many gram-positive cocci in pairs and short chains (Figure 1). On gross examination both adrenal glands were markedly congested. Microscopic examination revealed hemorrhage involving all layers of both adrenal glands, including the adrenal cortex and medulla, with several areas of necrosis scattered throughout (Figure 2). No microvascular fibrin thrombi were evident in any organ system. Immunohistochemical testing (performed at the Infectious Disease Pathology Activity at the Centers for Disease Control and Prevention) with use of an anti-streptococcus group A antibody confirmed the presence and identity of the organism in the laryngeal abscess and other tissues. The patient's rapid clinical deterioration was attributed to circulatory collapse as a result of overwhelming bacteremia and toxemia, which precipitated acute adrenocortical insufficiency and a fatal cardiac dysrhythmia. Our patient had a rapidly progressive course despite prompt administration of appropriate antibiotics. Antemortem blood cultures confirmed GAS bacteremia. In addition, autopsy findings revealed bilateral adrenal hemorrhage consistent with Waterhouse-Friderichsen syndrome. Based on a MEDLINE search of cases in the English language since 1966, this is the third reported case of Waterhouse-Friderichsen syndrome associated with GAS and the first case in an adult.4Gertner M Rodriguez L Barnett SH Shah K Group A beta-hemolytic Streptococcus and Waterhouse-Friderichsen syndrome.Pediatr Infect Dis J. 1992; 11: 595-596Crossref PubMed Scopus (19) Google Scholar5Givner LB Invasive disease due to group A beta-hemolytic streptococci: continued occurrence in children in North Carolina.South Med J. 1998; 91: 333-337Crossref PubMed Scopus (32) Google Scholar The earliest reports of this syndrome were from England in the 1900s, when Little6Little EG Cases of purpura, ending fatally, associated with haemorrhage into the suprarenal capsules.Br J Dermatol. 1901; 13: 445-467Crossref Scopus (7) Google Scholar made an association between fulminant sepsis and acute bilateral adrenal hemorrhage. In 1911 Waterhouse7Waterhouse R A case of suprarenal apoplexy.Lancet. 1911; 1: 577-578Abstract Scopus (103) Google Scholar described a case of adrenal hemorrhage in a child dying of apparent sepsis, and he reviewed several published cases. In 1918 Friderichsen8Friderichsen C Nebennierenapoplexie beim kleinen Kindern.Jb Kinderheilk. 1918; 87: 109Google Scholar wrote a similar review and added 2 more cases to the literature. Thus, sudden onset of adrenal hemorrhage in the setting of sepsis was termed Waterhouse-Friderichsen syndrome. This syndrome occurs predominantly in children, although several cases have been reported in adults. Clinically, Waterhouse-Friderichsen syndrome is characterized by sepsis with a rapidly deteriorating course leading to cardiovascular collapse and death. Usually, disseminated intravascular coagulation (DIC) is evident, manifested by abnormal results of coagulation studies, thrombocytopenia, and a purpuric or petechial rash. Postmortem studies reveal bilateral adrenal hemorrhage. Hemorrhage of the adrenal glands can also be identified by computed tomography or ultrasonography, although these tests are performed rarely. Most cases are associated with Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae.9Fox B Disseminated intravascular coagulation and the Waterhouse-Friderichsen syndrome.Arch Dis Child. 1971; 46: 680-685Crossref PubMed Scopus (38) Google Scholar Cases of Waterhouse-Friderichsen syndrome due to S pneumoniae almost always occur in patients with severe reticuloendothelial dysfunction, especially hyposplenism or splenectomy. Case reports have described Waterhouse-Friderichsen syndrome precipitated by Capnocytophaga canimorsus,10Mirza I Wolk J Toth L Rostenberg P Kranwinkel R Sieber SC Waterhouse-Friderichsen syndrome secondary to Capnocytophaga canimorsus septicemia and demonstration of bacteremia by peripheral blood smear.Arch Pathol Lab Med. 2000; 124: 859-863PubMed Google Scholar Pasteurella multocida,11Ip M Teo JG Cheng AF Waterhouse-Friderichsen syndrome complicating primary biliary sepsis due to Pasteurella multocida in a patient with cirrhosis.J Clin Pathol. 1995; 48: 775-777Crossref PubMed Scopus (21) Google Scholar Plesiomonas shigelloides,12Curti AJ Lin JH Szabo K Overwhelming post-splenectomy infection with Plesiomonas shigelloides in a patient cured of Hodgkin's disease: a case report.Am J Clin Pathol. 1985; 83: 522-524PubMed Google Scholar N gonorrhoeae,13Swierczewski JA Mason EJ Cabrera PB Liber M Fulminant meningitis with Waterhouse-Friderichsen syndrome due to Neisseria gonorrhoeae.Am J Clin Pathol. 1970; 54: 202-204PubMed Google Scholar and Moraxella duplex.14Lewis JF Marshburn ET Singletary HP O'Brien S Fatal meningitis due to Moraxella duplex: report of a case with Waterhouse-Friderichsen syndrome.South Med J. 1968; 61: 539-541Crossref PubMed Scopus (6) Google Scholar To our knowledge, only 2 cases of Waterhouse-Friderichsen syndrome associated with GAS have been previously reported in the literature, both in infants.4Gertner M Rodriguez L Barnett SH Shah K Group A beta-hemolytic Streptococcus and Waterhouse-Friderichsen syndrome.Pediatr Infect Dis J. 1992; 11: 595-596Crossref PubMed Scopus (19) Google Scholar5Givner LB Invasive disease due to group A beta-hemolytic streptococci: continued occurrence in children in North Carolina.South Med J. 1998; 91: 333-337Crossref PubMed Scopus (32) Google Scholar The pathophysiology leading to adrenal hemorrhage is poorly understood. The leading theories postulate either exotoxin-mediated vasculitis or coagulopathy in association with DIC. Rarely, the causative organism can be cultured from the adrenal glands themselves.4Gertner M Rodriguez L Barnett SH Shah K Group A beta-hemolytic Streptococcus and Waterhouse-Friderichsen syndrome.Pediatr Infect Dis J. 1992; 11: 595-596Crossref PubMed Scopus (19) Google Scholar In 1965 Levin and Cluff15Levin J Cluff LE Endotoxemia and adrenal hemorrhage: a mechanism for the Waterhouse-Friderichsen syndrome.J Exp Med. 1965; 121: 247-260Crossref PubMed Scopus (49) Google Scholar found that administration of endotoxin in rabbits induced adrenal hemorrhage but only when the rabbits were pretreated with corticotropin. This finding suggests that adrenal hemorrhage is due to the action of an endotoxin on a stressed adrenal gland. A subsequent review of 13 cases of Waterhouse-Friderichsen syndrome showed stress-related changes in the cortices, including compact cells, pseudotubules, and degenerate cortical cells.9Fox B Disseminated intravascular coagulation and the Waterhouse-Friderichsen syndrome.Arch Dis Child. 1971; 46: 680-685Crossref PubMed Scopus (38) Google Scholar However, that series also showed extensive deposition of fibrin thrombi in many organs, including the adrenal glands, indicating the presence of DIC. A later study identified adrenal vein thrombosis in 32 of 78 cases of adrenal hemorrhage, implicating DIC as the pathophysiologic basis for this syndrome.16Fox B Venous infarction of the adrenal glands.J Pathol. 1976; 119: 65-89Crossref PubMed Scopus (101) Google Scholar We reviewed 42 reports of Waterhouse-Friderichsen syndrome in the English literature since 1966, 31 of which had laboratory evidence of DIC. The remaining 11 case reports provided no coagulation studies or platelet counts. Of these 11 patients, 5 had either a purpuric or a petechial rash, and 2 others had postmortem pathologic evidence of DIC. The remaining 4 case reports did not specifically provide any dermatologic or postmortem findings consistent with DIC.5Givner LB Invasive disease due to group A beta-hemolytic streptococci: continued occurrence in children in North Carolina.South Med J. 1998; 91: 333-337Crossref PubMed Scopus (32) Google Scholar14Lewis JF Marshburn ET Singletary HP O'Brien S Fatal meningitis due to Moraxella duplex: report of a case with Waterhouse-Friderichsen syndrome.South Med J. 1968; 61: 539-541Crossref PubMed Scopus (6) Google Scholar17Beach RC Clayden GS Eykyn SJ Waterhouse-Friderichsen syndrome caused by Haemophilus influenzae type b.BMJ. 1979; 2: 1111Crossref PubMed Scopus (14) Google Scholar18Holmes FF Weyandt T Glazier J Cuppage FE Moral LA Lindsey NJ Fulminant meningococcemia after splenectomy.JAMA. 1981; 246: 1119-1120Crossref PubMed Scopus (43) Google Scholar In this patient we documented the presence of GAS in the blood and the presence of GAS antigens in the tissues, as confirmed by immunohistochemistry studies. This case is unique in that our patient had no laboratory evidence of DIC and no dermatologic or pathologic findings consistent with DIC, suggesting that the adrenal hemorrhage was likely mediated by a bacterial toxin.