Life-Threatening Community-Acquired Infections: Toxic Shock Syndrome, Overwhelming Postsplenectomy Infection, Meningococcemia, Malaria, Rocky Mountain Spotted Fever, and Others

Mary T. Bessesen

This chapter covers several infections of low incidence and high mortality, a combination of factors that challenges the physician to recognize a life-threatening disease he or she may never have seen before and institute appropriate therapy promptly. To assist in this challenge, as these diseases are discussed, key historical points and clinical clues will be emphasized.

The critically ill febrile patient should undergo a thorough history and physical examination. Family members may need to be interviewed if the patient is too ill to participate fully in the history. Key points of the exposure history include travel, employment, hobbies, and exposure to pets, wildlife, and livestock. This portion of the interview will yield better results if it is carried out in a slow-paced conversational fashion, allowing the patient or family member to chat a bit. It is less focused than a standard social history and review of symptoms due to the heterogeneous nature of the exposures being sought. A complete physical examination should be performed. In assessing vital signs, one must evaluate hypothermia (temperature less than 36°C) in the same light as fever (temperature higher than 38°C). Laboratory studies should include a complete blood count with platelet and differential counts; prothrombin and partial thromboplastin times; electrolytes, including calcium and magnesium; blood glucose; renal and liver functions; two sets of blood cultures, urine for culture and urinalysis; and a chest radiograph. If a serious infection is under diagnostic consideration, the hematology laboratory should supplement the automated differential leukocyte count with a manual differential count by microscopic examination of the peripheral blood film. This may require a specific request from the physician, especially if the total leukocyte count falls within the normal range.

Toxic Shock Syndromes

There are two toxic shock syndromes commonly recognized, one caused by Staphylococcus aureus (S. aureus), and the other caused by Streptococcus pyogenes (S. pyogenes) (group A streptococcus). To further complicate this picture, it has recently been reported that group C and group G streptococci may occasionally cause toxic shock syndrome [1]. In addition, Clostridium sordellii has been reported to cause a similar, but clinically distinct, toxic shock syndrome in obstetric patients, injection drug users, and recipients of musculoskeletal tissue allografts. Each of these three syndromes is discussed in the following sections.

Staphylococcal Toxic Shock Syndrome

Staphylococcal toxic shock syndrome (TSS) was first described in 1978 [2], and gained notoriety in the early 1980s when menstrual-associated cases struck large numbers of young women [3]. It is a multisystem disease characterized by acute onset of high fever, hypotension, diffuse macular rash, severe myalgia, vomiting, diarrhea, headache, and nonfocal neurologic abnormalities. The primary focus of staphylococcal infection may be mucosal, typically vaginal, associated with tampon or diaphragm use, or a wound. Currently there are four well-recognized forms of staphylococcal TSS: menstrual [3], postsurgical [4], influenza associated [5], and recalcitrant erythematous desquamating syndrome in acquired immunodeficiency syndrome (AIDS) [6].

Etiology

Staphylococcal toxic shock syndrome is a toxin-mediated illness caused by S. aureus strains that produce superantigens (SAgs). Menstrual-associated TSS is almost always caused by a strain that carries the SAg TSS toxin-1 (TSST-1), which is able to cross-intact mucous membranes. Nonmenstrual TSS may be caused by any of 15 described SAgs, but is most commonly associated with TSST-1, staphylococcal enterotoxin B (SEB), or staphylococcal enterotoxin C (SEC) [7]. Staphylococcal enterotoxins B and C are not absorbed across mucous membranes, but can cause TSS in cases of staphylococcal infection of wounds. There are rare case reports of staphylococcal TSS associated with nosocomial strains of methicillin-resistant S. aureus (MRSA) [8]. TSS has not been a feature of the epidemic of the community-associated MRSA strain, USA300, nor was TSS identified in a large collection of USA300 isolates [9].

Pathogenesis

In TSS, bacterial toxins function as superantigens. Conventional antigens presented in the context of major histocompatibility molecules on antigen-presenting cells (APC) must be processed by the APC and recognized by multiple elements of the T-cell receptor (TCR). In contrast, superantigens do not require processing by an antigen-presenting cell but instead
bind directly to the TCR to activate T-cells. Expansion of T-cell populations expressing particular TCR Vβ chains results in massive release of proinflammatory cytokines such as gamma-interferon (IF-γ), tumor necrosis factor-α (TNF-α), interleukin 1-β (IL-1β), and interleukin-2 (IL-2), leading to a capillary leak syndrome [7]. The absence of preexisting antibody to the pertinent bacterial toxin is a critical host factor in TSS. Among cases of menstruation-associated TSS, 90% do not have preexisting antibody to TSST-1. In contrast, more than 90% of healthy persons over the age of 25 years have antibody to TSST-1.

Diagnosis

Clinical Features

The classic case profile is a young (15 to 25 years old), menstruating female. However, any staphylococcal infection can predispose to TSS, including surgical wound infections, furuncles, and abscesses. Postpartum cases can occur after vaginal or cesarean delivery. Nasal reconstructive surgery carries an especially high risk of TSS. Cases may also occur after nasal packing for epistaxis.

The typical presentation is one of high fever, rash, and confusion. There may be a prodromal period of 2 to 3 days, consisting of malaise, myalgia, and chills. Patients are listless, but focal neurologic findings are not seen. Examination of patients with menstruation-associated TSS reveals vaginal hyperemia and exudate that yields S. aureus on culture. In nonmenstrual cases, a careful examination usually reveals a focus of staphylococcal infection. It is important to note that this focus may be subtle, with only serous drainage [4]. This is a toxin-mediated disease, and the local appearance is not one of intense purulence. Drainage of local infections is essential to a favorable outcome.

Laboratory Findings

Leukocytosis with marked left shift, thrombocytopenia, azotemia, sterile pyuria, and elevated transaminases are common, although nonspecific findings. Cultures of blood and cerebrospinal fluid (CSF) are usually sterile. Cultures of the local site of infection are usually, but not invariably, positive for S. aureus.

Differential Diagnosis

Streptococcal scarlet fever, measles, leptospirosis, Rocky Mountain spotted fever, Stevens–Johnson syndrome, and Kawasaki’s disease can mimic TSS. Multiorgan involvement is usually absent in streptococcal scarlet fever, and the primary focus yields S. pyogenes. Exclusion of measles, leptospirosis, ehrlichiosis, and Rocky Mountain spotted fever requires a careful history for potential exposures and serologic testing. Stevens–Johnson syndrome is characterized by target lesions and is commonly associated with exposure to medications. Kawasaki’s disease is characterized by fever and rash without multisystem involvement, is most commonly seen in children under the age of 6 years, and is associated with thrombocytosis rather than thrombocytopenia.

Treatment

The primary intervention consists of fluid resuscitation and supportive care. Any focus of staphylococcal infection must be drained. In women, a vaginal examination must be performed as soon as the patient is stabilized, and any foreign bodies (such as tampon or diaphragm) removed. After cultures of the local site and the blood are obtained, antistaphylococcal therapy should be administered intravenously.

Empiric antibacterial therapy for the critically ill patient should include an agent which is active against 100% of suspected pathogens, if feasible. At this time, the antibiotic that is most likely to cover all S. aureus isolates is vancomycin. There is in vitro evidence that clindamycin [10] and linezolid [11] inhibit staphylococcal toxin production, whereas β-lactam agents increase TSST-1 in culture supernatants, probably due to cell lysis releasing toxin [12]. The initial treatment of choice for menstrual TSS is nafcillin or oxacillin combined with clindamycin. After 48 hours, clindamycin can be discontinued. First-generation cephalosporins (cefazolin) may be substituted for an antistaphylococcal penicillin in patients with a history of non–life-threatening allergy to penicillins. If a healthcare-associated source of S. aureus infection is suspected, vancomycin should be used in place of the β-lactam agent until susceptibility tests are completed.

Intravenous immune globulin (IVIG) may be a useful adjunctive therapy. Higher doses of IVIG may be required for staphylococcal TSS than for streptococcal TSS [13].

Outcomes

The mortality of menstrual staphylococcal TSS is 3%, and 2 to 3 times higher in nonmenstrual-associated cases. Poor outcomes are associated with prolonged and refractory hypovolemic shock, acute respiratory distress syndrome, acute renal failure, electrolyte and acid-base imbalances, cardiac dysrhythmia, and disseminated intravascular coagulation (DIC) with thrombocytopenia.

Staphylococcal TSS may recur in patients with menstrual or nonmenstrual disease [14,15]. Recurrence is associated with continued use of tampons and absence of antistaphylococcal therapy for the initial episode.

Streptococcal Toxic Shock Syndrome

The clinical presentation and pathophysiology of streptococcal TSS are similar to staphylococcal TSS with a few notable differences: bacteremia is commonly seen, rash is less common, and mortality is markedly higher (30% to 70%) [7].

Like staphylococcal TSS, streptococcal TSS is a toxin-mediated disease. Streptococcal toxins that function as superantigens are streptococcal pyrogenic exotoxins A (SPE A) and B (SPE B). In addition, M-protein, a classic streptococcal virulence factor, may be released from the cell surface, bind to fibrinogen, and form large aggregates that activate intravascular polymorphonuclear leukocytes, leading to a vascular leak syndrome [16]. Blood cultures are usually positive in streptococcal TSS. Underlying infections are varied and include cellulitis, necrotizing fasciitis, postpartum myometritis, surgical wound infection, and occasionally pharyngitis [17]. Diagnosis is made by Gram stain and culture of blood and other bodily fluids.

Treatment is similar to that for staphylococcal TSS in that supportive care, including fluids, vasopressors, and ventilatory assistance, should be administered as needed, and surgical drainage of pyogenic sites is imperative. For confirmed streptococcal TSS, the antibiotic of choice is intravenous penicillin. For those who are intolerant to penicillin, other suitable agents are cephalosporins and vancomycin. Until the bacteriologic diagnosis is confirmed by culture, staphylococcal coverage should be included in the antibiotic regimen. Clindamycin is also very active against S. pyogenes. In an animal model of streptococcal myositis, clindamycin was more effective than penicillin [18]. This may be due to greater activity against high burdens of organisms (inoculum effect). An alternative explanation is that inhibition of protein synthesis blocks toxin production by the pathogen and reduces TNF production by the host [19]. A case control study has shown improved outcomes among children with invasive S. pyogenes infections whose therapy included clindamycin or erythromycin in the first 24 hours [20]. The usual adult dose of clindamycin in this setting is 600 mg per kg every 8 hours. Adjunctive therapy of streptococcal TSS with IVIG is recommended by many experts, based on retrospective studies employing doses ranging from 400 mg per kg to
2 g per kg for variable durations [21,22]. A randomized controlled trial was attempted but halted prior to completion, and it showed a trend toward improved survival in the treatment group [23]. In that trial, the dose of IVIG was 1 g per kg on day 1 and 0.5 g per kg on days 2 and 3.

Clostridium Sordellii Toxic Shock Syndrome

Clostridium sordellii is an anaerobic, Gram-positive spore-forming bacillus that has been an occasional cause of obstetric infections for many years [24]. Recently there have been reports of a TSS due to this pathogen in association with surgical and medical abortion [24,25], subcutaneous injection of black-tar heroin [26], and musculoskeletal tissue allografts [27]. The distinctive features of this syndrome are hypothermia and profound hemoconcentration. Management consists of supportive care including aggressive volume resuscitation, drainage of purulent foci, and broad-spectrum antibacterial therapy to include anaerobic organisms. Antitoxin therapy is of theoretical interest but clinically unproven.

Overwhelming Postsplenectomy Infection

Overwhelming postsplenectomy sepsis is a catastrophic illness with high morbidity and mortality in patients who have undergone splenectomy or who have severe splenic dysfunction. The spleen provides three major functions in protection from infection. It acts as a mechanical filter for infected or senescent erythrocytes; it participates in the production of soluble immune factors, including immunoglobulins and tuftsin; and it provides a site for components of the cellular immune system to act in proximity to one another [28].

Splenic function may be lost due to surgical removal, irradiation, several disease processes, and therapies [29], including sickle cell anemia, systemic lupus erythematosus, celiac disease, liver disease, acute alcoholism, high-dose corticosteroid therapy, splenic irradiation [30], and bone marrow transplantation. Normal aging has also been associated with a decrease in splenic function [31].

Splenectomy was the accepted procedure for splenic trauma for centuries, due to the belief that it served no important physiologic function, repair of trauma was difficult due to the friable nature of the organ, and expected high mortality of attempted conservative management. This prevailing wisdom was challenged in the 1970s, and currently splenic salvage is reported in 90% of cases of splenic rupture [32]. Splenic salvage in the trauma setting is associated with marked reductions in the risk of infection during the acute hospitalization, including surgical site infections and pneumonia [33]. Implantation of splenic fragments into the peritoneum has been performed in an attempt to maintain splenic function. Immune protection by these splenic fragments is incomplete at best, due to the loss of the normal splenic circulation. The presence of Howell–Jolly bodies on the peripheral blood smear indicates decreased splenic function, placing the patient at risk for overwhelming postsplenectomy infection (OPSI) [34]. Although Howell–Jolly bodies may be detected by autoanalyzers, a manual blood film should be reviewed if there is a clinical question of hyposplenism.

Epidemiology

The incidence of OPSI is impacted by many factors, including underlying disease, patient age, age at the time of splenectomy, time elapsed since splenectomy, pneumococcal vaccination, and antibiotic prophylaxis. Reported incidence rates are highest among patients with underlying thalassemia; intermediate in patients with sickle cell anemia, malignancy, or hematologic disorders; and lowest among patients who undergo splenectomy for trauma.

Encapsulated bacteria are the most common organisms causing OPSI. Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae are the organisms of greatest concern. S. pneumoniae is the most frequently isolated pathogen, representing over 50% of cases of OPSI. Other bacterial pathogens include Salmonella spp [28], Capnocytophaga canimorsus [35], which is associated with dog bites, and Campylobacter spp [36].

Asplenic individuals are also at risk for severe infection with the intraerythrocytic pathogens Babesia microti and Babesia bovis. Both organisms are transmitted by tick bites; B. microti is endemic on islands off the northeastern coast of the United States (Long Island, Nantucket Island, Martha’s Vineyard), whereas B. bovis is found in Europe. The acute phase of malaria may be more severe in splenectomized individuals, but splenectomy may be protective in the chronic phase. Atypically severe cases of Plasmodium vivax and Plasmodium ovale have been reported in splenectomized individuals, and relapse of malaria following splenectomy has occurred [28].

Diagnosis

Clinical Presentation

OPSI should be considered in any febrile patient with a history or abdominal scar consistent with splenectomy or disease process associated with hyposplenism. The initial symptoms of OPSI are fever, headache abdominal pain, vomiting, and diarrhea. There may be a nonspecific prodrome characterized by low-grade fever and myalgias. If untreated, the disease evolves into fulminant septic shock and death over 2 to 5 days [37]. In advanced cases, acute tubular necrosis, adrenal cortical necrosis, and disseminated intravascular coagulation may occur. A petechial or purpuric rash may be seen. Meningitis or pneumonia occurs in approximately one-half of cases; in the remaining cases septicemia occurs, which is presumed to arise from colonization of the pharynx.

Laboratory Features

Blood cultures yield the causative organism in most cases of OPSI. Infections of lesser severity also occur and may not be associated with detectable bacteremia. Hematologic findings of DIC (thrombocytopenia, elevated prothrombin time, D-dimer, and fibrin split products), elevated serum creatinine, and blood urea nitrogen are frequently seen. Howell–Jolly bodies are found on a peripheral blood film. In the immediate postsplenectomy period, mild elevation in the platelet and leukocyte numbers are physiologic, but a leukocyte count higher than 15,000 cells per μL after the fourth postoperative day suggests infection is likely the cause [38].

Differential Diagnosis

OPSI may be mistaken for uncomplicated sepsis if the history of asplenia or hyposplenism is not appreciated. Thrombotic thrombocytopenic purpura may also have a similar presentation, with fever, thrombocytopenia, and acute renal failure.

Management

In addition to supportive care, antimicrobial therapy should be initiated promptly. Third-generation cephalosporins are active
against S. pneumoniae, N. meningitidis, and H. influenzae in most locales. Cefotaxime 2 g intravenously every 8 hours or ceftriaxone 1 to 2 g intravenously once daily [39] may be used for uncomplicated cases. If meningitis is suspected, the dose of cefotaxime should be increased to 2 g every 4 to 6 hours; ceftriaxone should be given in a dose of 2 g twice daily. If pneumococci with high-grade resistance to penicillin and cephalosporins are prevalent in the region, vancomycin should be added until culture and susceptibility data become available. Patients with a severe allergy to penicillins and cephalosporins may be treated with vancomycin given with chloramphenicol or a fluoroquinolone [29]. Expert consultation should be sought in such cases.

Prevention

Guidelines for management of the postsplenectomy patient were published [40] prior to the advent of the quadrivalent conjugate meningococcal vaccine. Recommendations include timely vaccination with the 23-valent pneumococcal vaccine, preferably 2 weeks or longer prior to splenectomy. If that is impractical, it is recommended that patients be immunized as soon as possible postoperatively. Recent observations that antibody levels are improved if vaccination is delayed until 14 days postoperatively [41] must be weighed against the risk that vaccination may be overlooked if it is not carried out prior to hospital discharge. A reasonable compromise may be to immunize the patient at hospital discharge. Pneumococcal vaccine boosters should be administered every 5 years. Meningococcal conjugate vaccine (MCV4) should be administered to patients who are asplenic or who have splenic dysfunction. Due to the ongoing risk for meningococcal disease in asplenic persons, MCV4 vaccination should be repeated at 3- to 5-year intervals [42,43]. The conjugate H. influenzae vaccine should be administered to asplenic patients according to the standard schedule for all children [40].

Lifelong antibiotic prophylaxis is recommended by some authors [40], whereas others question this approach [28]. The data supporting prophylaxis are stronger in the pediatric population than in adults [29]. In the first 2 years following splenectomy in a child, or a patient with thalassemia or immune deficiency, antibiotic prophylaxis is recommended by most experts. Penicillin remains the drug of choice despite the emergence of resistance among some isolates. Ideally it should be dosed twice daily, but if adherence is an issue, it may be given once daily. Erythromycin may be substituted for patients who are allergic to penicillin. “Standby” antibiotics, to be taken early in the course of a febrile illness, is a strategy favored by all [28,40]. Amoxicillin-clavulanate is a good choice for this indication. Patients must be counseled to seek medical care if they are ill, and not rely on standby antibiotics alone.

Meningococcemia

The Centers for Disease Control (CDC) estimates that each year 1,400 to 2,800 cases of invasive meningococcal disease occur in the United States [42,44]. This section will cover Neisseria meningitidis bacteremia. Meningitis is covered in Chapter 79. Although infants are at highest risk for meningococcal disease, case rates also rise in the early teenage years, and 32% of cases occur among persons aged 30 years or older [44]. There are five serogroups, A, B, C, Y, and W-135. In the United States, serogroups B, C, and Y cause 93% of cases, with each representing about one third of cases. Serogroup B disease is more common among infants. Disease rates vary seasonally, with the lowest rates in the summer and early autumn months [42].

Pathophysiology

Neisseria meningitidis colonizes the nasopharynx in normal individuals by adherence to epithelial cells via pili and other adhesion factors. In the majority of individuals, it never causes disease. Invasive disease has been associated with a variety of factors, including antecedent viral infection, exposure to passive smoking, and inhalation of dry, dusty air [45]. Specific antibody and the complement system are key protective components of the host immune system. Deficiency of components of the complement system due to genetic defects or underlying disease predisposes to invasive meningococcal disease [46]. When bacteria invade the bloodstream, endotoxin activates the host immune system and proinflammatory cytokines cause a vascular leak syndrome. The endothelial thrombomodulin-endothelial protein C receptor pathway is downregulated, leading to thrombosis and purpura fulminans [47]. Profound vasoconstriction leads to peripheral ischemia and gangrene [45], and depression of myocardial contractility by cytokines contributes to shock.

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