Case 1: Pneumonia with hypotension and a rash

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A four-year-old boy presented to a secondary level centre in transfer from a small community hospital. He had been unwell for six days. His initial problem was abdominal pain, but on day 3 of his illness he developed fever and diarrhea. He had no specific respiratory complaints, but nevertheless, a chest x-ray (CXR) was performed and was normal. His symptoms persisted and he began developing respiratory distress. One day before transfer, he was admitted to the community hospital with a diagnosis of pneumonia confirmed on CXR and was started on intravenous cefuroxime. No blood culture was performed. He continued to have fever and required oxygen to maintain oxygen saturation above acceptable levels. Furthermore, he experienced significant hypotension (70/50 mmHg), which was treated with normal saline boluses.

On initial evaluation, he had a temperature of 38.7°C, a heart rate of 150 beats/min, a respiratory rate of 60 breaths/min, a blood pressure of 100/60 mmHg and an oxygen saturation of 97% in 1 L of oxygen by nasal prongs. He looked unwell and was in moderate to severe respiratory distress. He had bilateral nonpurulent conjunctivitis, and some tender anterior and posterior auricular nodes. There was pain and decreased air entry over the right chest. He also had a diffuse maculopapular rash and red, swollen lips and hands.

Initial laboratory investigations in the referral hospital indicated a hemoglobin of 129 g/L, white blood cell count of 2.3×10⁹/L, platelets of 187×10⁹/L, erythrocyte sedimentation rate of 39, urea of 10.6 mmol/L, creatinine of 82 μmol/L and normal liver function tests.

A repeat CXR in the secondary hospital revealed a worsening right-sided pneumonia and pleural effusion, despite being on antibiotics. The patient was started on cefuroxime, vancomycin and clindamycin. Culture performed on the chest tube drainage revealed the etiology of his symptoms.

CASE 1 DIAGNOSIS: TOXIC SHOCK SYNDROME

At the tertiary care centre, 680 mL of purulent fluid was drained from the pleural space; a culture of the fluid was positive for Streptococcus pyogenes (group A streptococcus). The patient was diagnosed with group A streptococcal toxic shock syndrome. He received a 14-day course of intravenous penicillin and clindamycin, and made a full recovery. Kawasaki syndrome was considered as a possible diagnosis due to conjunctivitis, pyrexia, rash (ultimately desquamation of hands and feet), thrombocytosis and an erythrocyte sedimentation rate of 130. However, no coronary ectasias were visualized by echocardiography and the patient responded appropriately to intravenous antibiotics.

Toxic shock syndrome (TSS) can result from infection with either Staphylococcus aureus or S pyogenes. Staphylococcal toxic shock was first described in menstruating teenagers and young women who were using high-absorbency tampons. Changes in the absorbency of tampons in recent decades have led to a substantial reduction in the incidence of such cases. The major risk factor for group A streptococcal toxic shock in children is varicella zoster virus infection. Both forms of toxic shock are more common in children, presumably due to an absence of adequate superantigen neutralizing antibodies.

TSS is thought to be mediated by toxins known as super-antigens. These antigens bind to T-cell receptors, resulting in massive proliferation and activation of T-cells, leading to the production of large quantities of cytokines including tumour necrosis factor and interleukin-1. This nonspecific immunostimulatory process causes a ‘cytokine storm’, which in turn leads to the development of TSS.

The criteria established for the diagnosis of staphylococcal and streptococcal TSS are listed in Tables 1 and 2.

TABLE 1.

Staphylococcal toxic shock syndrome: Clinical case definition

Fever >38.9°C (>102°F) Presence of diffuse macular rash (sunburn appearance) Desquamation one week to two weeks after onset of illness Hypotension Involvement of three or more of the following systems: - gastrointestinal: history of vomiting or diarrhea - musculoskeletal: severe myalgia, increased creatine phosphokinase - mucous membranes: hyperemia of conjunctiva, oropharyngeal or vaginal mucosae - renal: abnormal results of renal function/urinalysis - hepatic: elevated transaminases and bilirubin levels - hematological: thrombocytopenia - central nervous system: altered consciousness or disorientation

In addition, normal results of blood, cerebrospinal fluid and throat cultures (although blood may be positive for staphylococci in less than 5% of cases). Toxic shock syndrome is probable when at least four of five criteria are fulfilled. Data from recommended reading 2

TABLE 2.

Streptococcal toxic shock syndrome: Clinical case definition

Isolation of group A streptococcus From a normally sterile site (blood, cerebrospinal fluid, peritoneal fluid, tissue biopsy specimen) From a normally nonsterile site (throat, sputum, vagina) 2. Clinical signs of severity Hypotension, and Two or more of the following signs: - renal impairment - coagulopathy (platelets <100×109) or disseminated intravascular coagulation - liver involvement (increased transaminases or total bilirubin) - adult respiratory distress syndrome - generalized erythrodermatous macular rash that may desquamate - soft tissue necrosis, including necrotizing fasciitis or myositis

An illness fulfilling criteria 1A, 2A and 2B can be defined as a definite case. An illness fulfilling criteria IB, 2A and 2B can be defined as a probable case if no other etiology for the illness is identified. Data from recommended reading 2

In general, it is not possible to differentiate between staphylococcal and streptococcal TSS based on clinical manifestations or laboratory features. Confirmation of the diagnosis rests on the detection of the organism in culture. Blood cultures are positive in 50% or more of streptococcal TSS cases, but in less than 5% of staphylococcal TSS cases.

Treatment of TSS includes supportive therapy (fluid resuscitation, inotropic agents), anticipatory management of multisystem organ failure and parenteral antibiotics. Intravenous penicillin and clindamycin is the preferred treatment option for culture-confirmed group A streptococcal TSS. If a specific etiologic diagnosis has not been established, treatment should include a lactamase-resistant antistaphyloccocal agent such as cloxacillin or cefazolin.

Intravenous immunoglobulin (IVIG) is recommended for the treatment of group A streptococcal TSS. Pathophysiologically, the rationale for using IVIG is that invasive group A streptococcal infections may be associated with inadequate levels of neutralizing antibody against streptococcal superantigens and other important antigens such as the M protein. There is evidence from a comparative observational study that treatment with IVIG may be lifesaving in patients with streptococcal TSS (5). In addition, a recent randomized, double-blind, placebo-controlled trial was conducted in Europe to determine if IVIG is beneficial in treating this condition. The results were inconclusive because of the small sample size, but the study did provide further support for IVIG as an adjunctive therapy in streptococcal TSS. Other adjunctive treatments have included steroids, plasmapheresis and monoclonal antibodies, although the indications for use of these therapies are controversial.

The incidence of invasive group A streptococcal disease among household members of cases is between 18 and 122 times that of the general population. At the present time, most public health authorities in Canada recommend that all household contacts receive chemoprophylaxis with penicillin, amoxicillin, a first-generation cephalosporin, clindamycin or erythromycin for a period of 10 days. All household contacts of our patient received appropriate chemoprophylaxis and none developed invasive group A streptococcal disease.

CLINICAL PEARLS

• Clinicians should be aware of the clinical manifestations of TSS and consider this diagnosis when faced with a patient with pneumonia or other focal infections who also has hypotension and/or multisystem involvement.

• TSS can be caused by S aureus or group A streptococcus infection.

• Adjunctive IVIG therapy should be considered for all patients with suspected or proven group A streptococcal TSS.

• Chemoprophylaxis is recommended for all household contacts of a patient with invasive group A streptococcal disease.