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CHAPTER

92Unusual InfectionsSankar Swaminathan

IntrodUctIon

This chapter describes the epidemiology, clinical presenta-tion, diagnosis, therapy, and prevention of several relatively unusual infections. Although the incidence of these infections in the United States is low, they have the potential to cause rapidly progressive disease, and to present unique problems in management and infection control in the critical care set-ting. Since rapid treatment is essential in many of these infec-tions, prompt diagnosis is also important. Additionally, many of the organisms causing these infectious diseases have gained new relevance as potential biologic warfare agents. The epi-demiology, clinical presentation, and management of infec-tions resulting from an intentional release of micro-organisms may differ significantly from disease resulting from traditional modes of spread. In addition to an intentional bioterrorist attack, large social disruptions that affect housing, public hygiene, and mass migration have the potential to allow epi-demic transmission of some of these agents. Outbreaks of dis-eases previously thought to be under control have occurred as a result of natural disasters and human activities, both in the United States and abroad. Climate change has led to changes in disease prevalence in many parts of the globe due to chang-ing habitats of disease vectors. Finally, globalization, leading to increasing travel of humans, transport of animals and plant materials, increases the likelihood that hitherto unusual infec-tions will become more prevalent in the United States. Recog-nition of such unusual infections will require familiarity with their epidemiology and clinical presentation and will allow diagnosis and treatment in a timely fashion.

tUlaremIa

Tularemia is a multisystem zoonotic infection caused by a gram-negative coccobacillus, Francisella tularensis. Tularemia, named after Tulare County, California, where the disease was first characterized in ground squirrels (1), has been recognized since the 1800s and is primarily transmitted through con-tact with infected animals, contaminated food and water, or arthropod bites (2). Tularemia has been listed as a Tier 1 agent (3). The Department of Health and Human Services/Centers for Disease Control and Prevention (HHS/CDC) has desig-nated those select agents and toxins that present the greatest risk of deliberate misuse with the most significant potential for mass casualties or devastating effects to the economy, criti-cal infrastructure; or public confidence as Tier 1 agents. High-priority agents include organisms that pose a risk to national security because they can be easily disseminated or transmitted from person to person, result in high mortality rates and have the potential for major public health impact, might cause pub-lic panic and social disruption and require special action for public health preparedness (4).

Epidemiology

The incidence of tularemia in the United States has declined since the 1950s, and is currently less than 200 cases per year (5–7). Cases occur throughout the continental United States and Alaska in small sporadic clusters. Most cases are cen-tered around Missouri, Kansas, Oklahoma, and Arkansas. Incidence is also high in other Western states such as South Dakota and Wyoming. Tularemia primarily occurs during the summer months, most likely due to the increased exposure to biting arthropods. Cases also occur during the fall and winter and are linked to hunting and handling infected ani-mals. Perhaps because of a greater likelihood of exposure to animals and arthropods, there is a 3 to 1 preponderance of male to female cases. Most recent cases in the United States have been in young adults, although a significant percent-age of cases occurs among children below the age of 14 (8). Inhalational exposures have occurred in Martha’s Vineyard in Massachusetts and were associated with mowing grass and cutting brush (9).

In the United States, ticks and biting flies are the most important arthropod vectors. Major animal reservoirs are lagomorphs (rabbits and hares), and rodents including prairie dogs, squirrels, and rats. Mosquitoes were implicated as a pri-mary vector in Scandinavia in one large outbreak (10). Direct contact with infected animals is another significant mode of transmission (11). Hunting, trapping, butchering animal car-casses, and handling meat are all risk factors for tularemia. Contamination of food and water by rodents and other car-riers has also been linked to human infection. The organism survives well in cold, moist conditions and can withstand freezing. Finally, cats and other carnivores may transiently carry organisms in their mouths or claws and thereby transmit infection to humans (12). Pets may also increase the likelihood of tick-borne transmission to humans. Inhalational exposure may occur in the laboratory or as the consequence of a delib-erate release of weaponized Francisella cultures. Human-to-human transmission of tularemia is not known to occur.

Clinical Presentation

Tularemia has been classically described as presenting in one of six syndromes: ulceroglandular, oculoglandular, glandular, pharyngeal, typhoidal, and pneumonic (13). However, it is clear that individual patients may have symptoms of several of these types simultaneously. After initial entry into the host, either through cutaneous inoculation, ingestion, or inhalation, Francisella organisms multiply at the site of infection (14); a vigorous inflammatory response ensues, leading to subsequent necrosis. The organism multiplies within macrophages and travels to regional lymph nodes, kidney, liver, lung, and spleen (15). The meninges and pericardium are occasionally involved secondarily in untreated tularemia. Inhalation or cutaneous inoculation of 10 to 50 organisms is sufficient for infection

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1144 SECTion 9 infectiouS DiSeaSe

(16,17). Symptoms usually begin 3 to 5 days after infection, although longer incubation periods are possible (18).

Differences in clinical presentation may be partly attrib-utable to the type and route of infection. Thus tick-borne infection is more likely to result in skin lesions on the head and neck, trunk, and perineum, whereas animal-associated infections more commonly result in upper extremity lesions (19). Ingestion of contaminated water or food is more likely to cause pharyngeal infection. Inoculation into mucous mem-branes of the eye results in the oculoglandular syndrome, an ocular lesion with local lymphadenopathy. Inhalation of the organism leads to the pneumonic form of tularemia, although other forms of tularemia can also cause prominent pulmonary involvement through hematogenous dissemination. A typhoi-dal form of tularemia occurs in less than 30% of cases, in which there are no characteristic localized mucocutaneous or glandular signs or symptoms. The distinction between typhoi-dal and nontyphoidal infections appears to reflect differences in the host response. In nontyphoidal forms, there is a vigorous inflammatory reaction and the prognosis is good in compari-son to typhoidal infection, which has a higher mortality and in which pneumonia is more common (19). Certain strains of F. tularensis may be associated with higher mortality, up to 24%, but it is 2% overall (20).

In general, the onset of systemic symptoms in tularemia is abrupt, and includes fever, headache, myalgia, coryza, cough, malaise, and chest pain or tightness. In mucocutaneous infec-tion, the presenting complaint is usually painful lymphadenop-athy, which may precede or follow the skin lesion; in the purely glandular form, there is no apparent skin lesion. Skin lesions usually begin as erythematous, painful papules which progress to necrotic ulcers that are slow to heal. Enlarged lymph nodes are also slow to resolve and may suppurate. In ocular infection, a painful conjunctivitis occurs. Pharyngeal tularemia presents as an exudative pharyngitis with adenopathy that is unrespon-sive to standard therapy. Tularemic pneumonia is characterized by fever, cough, and pleuritic pain, but sputum production and hemoptysis are unusual. A relative bradycardia, with a nor-mal pulse despite an elevated temperature is common (40%) in tularemia, and may be a useful diagnostic finding (19). Chest x-ray findings include hilar adenopathy, patchy or less commonly, lobar infiltrates, and pleural effusions.

Although there has not been a documented biologic attack with weaponized tularemia, several probable aspects of such an occurrence are worth noting to allow early recognition and management. If there were an aerosolized release of organ-isms, cases are likely to be pneumonic, although aerosolized tularemia would also be likely to result in ocular and cutane-ous forms (2). Occurrence of tularemia in urban settings and among healthy individuals should also prompt suspicion of a biologic attack. Onset of symptoms is expected to be rapid, and as described above, closely resemble the acute onset of influ-enza. The differential diagnosis of pneumonia due to an aero-solized biologic weapon attack would include anthrax, plague, and Q fever. Important distinguishing characteristics between these etiologies would include a more rapid and fulminant course in both anthrax and plague. In addition, pneumonic anthrax would not be expected to cause bronchopneumonia, but would result in mediastinal widening. Pneumonic plague results in frankly purulent sputum with hemoptysis and rapid progression. Laboratory testing is important in distinguishing between these various entities (see below), but initial empiric

treatment will, by necessity, require diagnosis based primarily on clinical and epidemiologic data.

Diagnosis

Cultures for F. tularensis require incubation on special sup-portive media. The laboratory must be notified in advance if tularemia is suspected, both to perform appropriate testing as well as to institute protective measures to prevent infec-tion of laboratory workers. Cultures of pharyngeal washings, sputum, and fasting gastric aspirates are most likely to yield positive results whereas blood samples are usually negative (21). Direct fluorescent staining of specimens or PCR can be performed by specialized laboratories for relatively rapid diagnosis. Serology is positive approximately 10 days after infection. While serology is not helpful for diagnosis of acute infection, it is useful for confirmation of suspected cases. It is important to promptly contact the hospital epidemiologist or infection control practitioner, and the local health depart-ment in cases of tularemia to aid in management and diagno-sis of suspected outbreaks. It is also imperative to notify the microbiology laboratory if tularemia is suspected to prevent exposure and infection of laboratory personnel.

Treatment

The first-line treatment for tularemia is streptomycin, with gentamicin as an acceptable alternative, although experience with gentamicin is relatively sparse. Quinolone therapy has been reported to be successful although failures have also been reported. Relapse despite appropriate therapy has been noted in 38.6% of patients (22). Treatment regimens for most of the select agents have been devised for either a contained casualty setting or a mass casualty setting (Table 92.1). The recommenda-tions for the latter situation take into account the likelihood that services may be limited and parenteral or inpatient therapy may not be possible. The first-line treatment of tularemia in a con-tained casualty setting is an aminoglycoside, either streptomycin or gentamicin (2,23). Alternatives are doxycycline, chloram-phenicol, or ciprofloxacin, given intravenously. Treatment with aminoglycosides or ciprofloxacin should be given for a minimum of 10 days, and with doxycycline or chloramphenicol for 14 to 21 days. In a mass casualty setting or for postexposure prophy-laxis, oral doxycycline or ciprofloxacin for 14 days is recom-mended. As is the case with other organisms described later in this chapter, several potentially toxic antibiotics that are not rou-tinely given to children or pregnant women are included in the recommended treatment regimens. For example, the use of tet-racyclines and quinolones carries the risk of potential side effects in pregnant women and children. Nevertheless, given the high mortality of tularemia, these agents are recommended as accept-able alternatives if aminoglycosides cannot be administered or are not available. The CDC website should be consulted for the most current details regarding the CDC recommendations for treatment as well as more detailed information regarding usage in renal failure and in special situations (23).

PlagUe

Plague, caused by the gram-negative bacillus Yersinia pestis, is one of the oldest and most feared illnesses known to man.

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CHAPTER 92 unusual infections 1145

Millions of people were killed by three pandemics occurring in AD 540, the Middle Ages, and in the late 19th century (24,25). Plague has been developed by various groups and nations as a biologic weapon since the 1950s, and has been listed as an important potential agent of bioterrorism (4).

Epidemiology

Plague is primarily a rural disease that occurs in all continents except Australia (24). Although most common in rural set-tings in developing nations, sporadic clusters occur regularly in the United States. For example, 107 cases were reported in the United States between 1990 and 2005, with a median number of seven cases per year (8). However, in 2006, 13 cases were reported in the first 10 months of the year (8). Most cases occur between spring and autumn in the Western states where the disease in enzootic in wild rodents. Humans are infected by being bitten by infected rodent fleas, or han-dling infected animals, either domestic pets or wild animals. Worldwide, the most important reservoir is the domestic rat, but as in the United States, sylvatic foci (in wild animals) also exist (26). Human-to-human transmission can occur in pneu-monic plague, but requires close contact. The last known case acquired in this manner in the United States was reported in 1925 (27).

Clinical Manifestations

The three main types of plague are bubonic, septicemic, and pneumonic. Although there is no current experience with pneumonic plague acquired from a biologic attack, the clinical presentation is expected to differ from that of natural infection and is discussed below.

Bubonic Plague

This is the most common type of plague, occurring in 76% of the cases reported in the United States between 1990 and 2005 (8). Large numbers of bacteria are inoculated at the site of the flea bite and multiply locally, followed by rapid replication in nearby lymph nodes (26). The incubation period is between 2 and 7 days. There is abrupt onset of fever, chills, and head-ache. The characteristic bubo typically develops as a smooth, firm oval mass which is extremely tender. The overlying skin is warm and erythematous, but suppuration is rare. The pri-mary lesion is often inapparent, but can develop into an ulcer. The most common site of the buboes is in the femoral lymph nodes, but they are also seen in inguinal, cervical, and axillary locations depending on the location of the inoculation. Bacte-remia occurs in about 25% of cases and, in untreated cases, the mortality approximates 50% (8,26). In untreated cases, deterioration is usually rapid, with progression of typical signs of shock and death occurring as early as 2 to 3 days.

Septicemic Plague

This is defined as plague in the absence of an apparent bubo. As with other systemic infections without clear localization, diag-nosis of septicemic plague is often delayed and the prognosis is thus poorer. In the United States from 1990 to 2005, 18% of reported plague cases were defined as septicemic, although 38% of the cases in 2006 were of this variety (8). A useful clue to the diagnosis of septicemic plague is that gastrointestinal symptoms of nausea and vomiting, diarrhea, and abdominal pain were prominent in several recent cases (8). Disseminated intravascular coagulation may develop rapidly with cutaneous and visceral hemorrhage. Rapidly progressive gangrene may also develop in this setting. Both septicemic plague and pneu-monic plague are fatal if untreated. Even with treatment, mor-tality rates of 33% in septicemic plague were reported from New Mexico in the 1980s (28).

Pneumonic Plague

This presentation may develop secondary to either bubonic or septicemic plague. The incidence of secondary pulmonary involvement approximates 12% (24). Recent cases of primary pneumonic plague in the United States have either occurred from laboratory accidents or from exposure to cats (29). Pneu-monic plague is similar to other acute pneumonia with abrupt onset of fever and dyspnea. Watery or purulent, and bloody sputum is produced and is highly infectious. Transmission is by respiratory droplets, and therefore, simple respiratory iso-lation with droplet precautions is sufficient. The CXR usually reveals bronchopneumonia, and multilobar consolidation or cavitation may be seen (30). Primary pneumonic plague is a rapidly progressive condition with a mortality rate of approxi-mately 50% (27).

Clues to plague arising as the result of a biologic attack include cases outside areas of known enzootic infection; occurrences in an area without associated rodent die-offs,

TaBle 92.1 Treatment Recommendations for Tularemia

Contained Casualty Setting

adultsPreferred choices

Streptomycin, 1 g im twice daily

Gentamicin, 5 mg/kg im or iV once daily

Alternative choices

Doxycycline, 100 mg iV twice daily

chloramphenicol, 15 mg/kg iV 4 times daily

ciprofloxacin, 400 mg iV twice daily

ChildrenPreferred choices

Streptomycin, 15 mg/kg im twice daily (not to exceed 2 g/d)

Gentamicin, 2.5 mg/kg im or iV 3 times daily

Alternative choices

Doxycycline

if weight 45 kg or more, 100 mg iV

if weight less than 45 kg, 2.2 mg/kg iV twice daily

chloramphenicol, 15 mg/kg iV 4 times daily.

ciprofloxacin, 15 mg/kg iV twice daily

Pregnant WomenSame as adults above except chloramphenicol is not

recommended

Mass Casualty Setting

adults, including pregnant womenDoxycycline, 100 mg orally twice daily

ciprofloxacin, 500 mg orally twice daily

ChildrenDoxycycline

if weight 45 kg or more, 100 mg iV

if weight less than 45 kg, 2.2 mg/kg iV twice daily

ciprofloxacin, 15 mg/kg iV twice dailya

for full details and most current treatment recommendations, the reader is referred to the cDc website (23).

aciprofloxacin dosage should not exceed 1 g/d in children.

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and numerous cases of pneumonia in otherwise healthy patients (30). In general, routine laboratory tests are not markedly different from those seen in other causes of ful-minant pneumonia and sepsis. The white blood cell count is often markedly elevated and fibrin degradation products are detectable in cases where disseminated intravascular coagu-lation is present (31).

Diagnosis

The peripheral white blood cell count is invariably elevated and blood cultures are often positive. High-grade bacteremia may permit direct visualization of bacteria in the blood smear (31). Specialized laboratory tests to definitively and rapidly identify Y. pestis are not widely available. When plague is suspected, coordination with state public health officials and the CDC will allow more specialized tests and suscep-tibility testing to be performed. Blood, sputum, lymph node aspirates, and lesion swabs should be examined by Gram or Wright–Giemsa stain for the presence of bipolar-staining gram-negative bacilli, which appear to have the appearance of safety pins. The laboratory should be alerted to the pos-sibility of plague so that appropriate biosafety procedures can be followed.

Treatment

The recommendations for therapy of plague provided here are derived from the recommendations of the Working Group on Civilian Biodefense and the CDC (30). Treatment recommendations for plague are complicated by the lack of clinical efficacy trials, lack of experience with widespread pneumonic plague, and potentially unpredictable clinical responses in infections due to a biologic attack. While some recommendations are not FDA-approved uses of the antibi-otics, they are the consensus recommendations for the best alternatives for therapy in various situations and clinical scenarios.

The historically proven effective antibiotic therapy for plague has been streptomycin. Because of the limited avail-ability of streptomycin, gentamicin—used successfully to treat plague—is the recommended alternative (32). Doxycycline and quinolones are effective against plague and are recommended alternatives. While ciprofloxacin is the officially recommended quinolone, levofloxacin has also been FDA-approved for treat-ment of plague. For pregnant women and children, the use of tetracyclines and quinolones carry the risk of potential side effects. Nevertheless, given the high mortality of plague, these agents are recommended as acceptable alternatives if amino-glycosides cannot be administered or are not available. In the setting of a mass casualty, oral regimens are recommended as these allow treatment of large numbers of people and they are also useful in settings where parenteral therapy may not be possible.

The recommended duration of therapy for plague (Table 92.2) is 10 days and oral therapy should be substituted when the patient’s condition improves. Duration of postexposure prophylaxis to prevent plague infection is 7 days. For full details regarding usage in pregnant women and children as well as in special settings including renal failure, please consult the CDC website where the most current recommendations may be found (32,33).

anthrax

An extremely rare disease in the United States until the bioter-rorism attacks of 2001, anthrax is caused by a gram-positive spore-forming bacillus, Bacillus anthracis. However, anthrax was tested as a biologic weapon by the United States in the 1960s and by several other countries until at least the 1970s. The technology to produce highly infectious anthrax spores and disseminate them widely as an aerosol exists and is known to have been developed for use as a biological warfare agent (34). It is therefore important for all physicians to be aware of

TaBle 92.2 Recommendations for Treatment of Patients with Pneumonic Plague in Contained and Mass Casualty Settings and for Postexposure Prophylaxis

Contained Casualty Setting

adultsPreferred choices

Streptomycin, 1g im twice daily

Gentamicin, 5 mg/kg im or iV once daily or 2 mg/kg loading dose followed by 1.7 mg/kg im or iV three times daily

Alternative choice:

Doxycycline:

100 mg iV twice daily or

200 mg iV once daily

ciprofloxacin, 400 mg iV twice daily



Streptomycin, 15 mg/kg im twice daily (maximum daily dose 2 g)

Gentamicin, 2.5 mg/kg im or iV 3 times daily†

Alternative choices:

Doxycycline:

if 45 kg or more, give adult dosage

if less than 45 kg, give 2.2 mg/kg iV twice daily (maximum 200 mg/d)

ciprofloxacin, 15 mg/kg iV twice daily


in children, ciprofloxacin dose should not exceed 1 g/d, and chloramphenicol should not exceed 4 g/d. children younger than 2 yr should not receive chloramphenicol.

Pregnant womenSame as adults above except chloramphenicol is not

recommended.

Mass Casualty Setting and Postexposure Prophylaxis

adults, including pregnant womenPreferred choices

Doxycycline, 100 mg orally twice daily

ciprofloxacin, 500 mg orally twice daily

Alternative choices

chloramphenicol, 25 mg/kg orally 4 times daily


Doxycycline:

if 45 kg or more give adult dosage

if less than 45 kg then give 2.2 mg/kg orally twice daily

ciprofloxacin, 20 mg/kg orally twice daily

Alternative choices

chloramphenicol, 25 mg/kg orally 4 times daily (maximum 200 mg/dL)

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the manifestations of anthrax and especially of the expected characteristics of an outbreak due to a biological attack.

Epidemiology

There are three major modes of infection with anthrax: inha-lational, cutaneous, and gastrointestinal. Cutaneous anthrax is the most common type of anthrax. However, it is still extremely rare in the United States with 224 cases having been reported in the 50 years from 1944 to 1994 (35). Barring expo-sure to intentionally produced anthrax, inhalational anthrax is even less common and occurs primarily in those with occupa-tional or laboratory exposure. Prior to 2001, there were only 18 cases of inhalational anthrax reported from 1900 to 1978 (36). Gastrointestinal anthrax is most commonly reported where improperly cooked meat contaminated with large num-bers of anthrax bacilli has been consumed (37).


The presentation of anthrax due to a biologic attack is still incompletely characterized. Most of the information relevant to inhalational anthrax from anthrax manufactured as a bio-logic weapon is from the 2001 US attacks and an uninten-tional release in Sverdlosk, Russia, in 1979 (38). There were 11 cases of inhalational anthrax resulting from the exposures in 2001. Several aspects of the pathophysiology of inhala-tional anthrax are highly relevant to the clinician. Infection occurs after spores are inhaled and deposited in the alveoli. The spores are phagocytosed by macrophages and transported to regional lymph nodes where they germinate and replicate vegetatively (39). There may be a period of extended latency in the lymph node because of spores that remain dormant. Therefore, although the usual period of incubation is 2 to 6 days, cases have occurred as late as 6 weeks after exposure to aerosolized anthrax (38). When replication does occur, toxin production leads to edema, necrosis, and hemorrhage.

Typical symptoms are fever and chills, chest discomfort and dyspnea, severe fatigue, and vomiting. Two stages may occur with an initial period of improvement followed by rapid deterioration. The initial finding on chest x-ray is a widened mediastinum due to mediastinal lymph node involvement (40). A hemorrhagic mediastinal lymphadenitis ensues, often accompanied by bloody pleural effusions. Eight of 11 patients in 2001 developed bloody pleural effusions, and 10 of 11 had radiologic evidence of mediastinal adenopathy (41). Although anthrax does not cause a typical bronchopneumonia, pulmo-nary infiltrates, or consolidation were observed in 8 of 11 cases. In addition, in an autopsy series from the Sverdlosk out-break, primary focal hemorrhagic necrotizing pneumonia was described in 11 of 42 cases (42).

An important point emphasized by Lucey is that while there are three known modes of exposure—inhalational, cuta-neous, and gastrointestinal—anthrax may actually present as meningitis, which was the initial presentation of the index case in 2001 (34). Further, as many as 50% of inhalational anthrax cases may develop meningitis (42). Anthrax causes a rapidly progressive hemorrhagic meningitis with characteristic large gram-positive bacilli in the CSF. Similarly, although the por-tal of infection is the lung, hemorrhagic submucosal lesions may develop in the gastrointestinal tract along with mesenteric infection; such lesions were seen in 39 of 42 of the autopsy

cases reported in the Sverdlosk outbreak and in one 2001 case (42,43). Importantly, this patient presented with primarily gastrointestinal symptoms (43).

The diagnosis of inhalational anthrax may be difficult, especially in the early stages. In addition to the signs and symp-toms listed above, tachycardia and severe diaphoresis may be present. Rhinorrhea or sore throat is common in viral respira-tory infections, but were uncommon in inhalational anthrax (44). A high index of clinical suspicion should be maintained especially as the risk of exposure may be unknown in the early stages of a biologic attack. Blood cultures are invariably positive if obtained prior to antibiotics.

Cutaneous anthrax is also expected to occur as a result of a biologic anthrax attack. Cutaneous cases occurred up to 12 days after the exposure in the Sverdlovsk outbreak (38). The initial lesion is a papule or macule leading to ulceration at the site of inoculation within 2 days, followed by vesicula-tion. The lesion is painless although it may be highly pruritic, and the vesicular fluid contains large amounts of bacteria. The characteristic depressed, black eschar that subsequently develops is painless. Surrounding edema is often a prominent feature of cutaneous anthrax lesions. In the one case of cutane-ous anthrax that developed in a 7-month-old infant in 2001, microangiopathic hemolytic anemia and renal insufficiency occurred (45).

Diagnosis

Blood cultures should be obtained promptly if anthrax is sus-pected; blood smears should be examined for the presence of organisms. Chest x-ray and chest CT scans should be obtained to look for evidence of mediastinal widening, pleural effusions, and parenchymal abnormalities. Thoracentesis of any pleural effusions should be performed and lumbar puncture should be done as indicated. The clinical microbiology laboratory and the state public health department should both be noti-fied of the possibility of anthrax. If indicated, specimens can be sent to specialized laboratories participating in the Labora-tory Response Network for specific testing such as immuno-histochemical staining or PCR. Cutaneous lesions, especially vesicle fluid, should be swabbed for stain and culture. Punch biopsy of the periphery of lesions may also be performed and analyzed by immunohistochemistry or PCR if the Gram stain is negative. Nasal swabs are not sensitive indicators of expo-sure or infection and should not be used to diagnose or rule out infection in individual patients (46). Sputum culture is generally negative in inhalational anthrax.

Treatment

The current recommendations for therapy of anthrax pro-vided here are derived from the recommendations of the CDC expert panel on anthrax treatment and prevention (Tables 92.3 to 92.5) (47). As with recommendations for plague, the recommendations are based on expert opinion and a risk–benefit calculation that takes into account the extremely high mortality of inhalational anthrax. As such, the recommendations include therapy with drugs that are not specifically FDA-approved for anthrax and drugs that may have potential side effects in pregnant women and children. Adjunctive measures that may be helpful are discussed after antibiotic therapy.

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antibiotic Regimens

Several factors are important in choosing an empiric regimen for inhalational anthrax and other systemic forms of anthrax. The 60% survival rate in the 2001 cases, which were treated with multidrug regimens, was superior to historical experi-ence. Partly because of these data, the CDC has recommended the use of a quinolone and at least one other bactericidal agent capable of achieving therapeutic levels in the CNS, plus a third drug, for the initial treatment of systemic anthrax with confirmed or possible meningitis. Other factors considered were the possibility of engineered or primary drug resistance. Although penicillin is FDA-approved for anthrax, the presence of inducible β-lactamases dictate against the use of penicillin alone. Parenteral therapy is recommended initially. Once men-ingitis has been ruled out, the regimen may be simplified, and

these recommendations are summarized in Table 92.4. Rec-ommendations for cutaneous anthrax consist of treatment with a single drug, preferably a quinolone or a tetracycline (see Table 92.5).

The duration of therapy is an important consideration both in treatment and in postexposure prophylaxis. Although the longest period of latency in the Sverdlovsk episode was reported to be 43 days, viable spores have been demonstrated in the mediastinal lymph nodes of monkeys as late as 100 days after exposure, and disease has occurred 98 days after exposure (48,49). In addition, antibiotic treatment may prevent disease, but it also prevents the development of an effective immune

TaBle 92.3 Intravenous Treatment for Systemic anthrax with Possible/Confirmed Meningitisa

Bactericidal agent (Fluoroquinolone)

ciprofloxacin, 400 mg every 8 hr

or

Levofloxacin, 750 mg every 24 hr

or

moxifloxacin, 400 mg every 24 hr

PLuS

Bactericidal agent (β-lactam)

for all strains, regardless of penicillin susceptibility or if susceptibility is unknown

meropenem, 2 g every 8 hr

or

imipenem, 1 g every 6 hrb

or

Doripenem, 500 mg every 8 hr

or

alternatives for penicillin-susceptible strains

Penicillin G, 4 million units every 4 h

or

ampicillin, 3 g every 6 hr

PLuS

Protein synthesis inhibitor

Linezolid, 600 mg every 12 hrc

or

clindamycin, 900 mg every 8 hr

or

rifampin, 600 mg every 12 hrd

or

chloramphenicol, 1 g every 6–8 hre

aDuration of treatment: 2–3 wk or more until clinical criteria for stability are met (see text). Patients exposed to aerosolized spores will require prophylaxis to com-plete an antimicrobial drug course of 60 d from onset of illness (see technical appendix table 2 [postexposure prophylaxis]). Systemic anthrax includes anthrax meningitis; inhalation, injection, and gastrointestinal anthrax; and cutaneous anthrax with systemic involvement, extensive edema, or lesions of the head or neck. Preferred drugs are indicated in boldface. alternative drugs are listed in order of preference for treatment for patients who cannot take first-line treat-ment, or if first-line treatment is unavailable.

bincreased risk for seizures associated with imipenem/cilastatin treatment.cLinezolid should be used with caution in patients with thrombocytopenia because

it might exacerbate it. Linezolid use for more than 14 d has additional hemato-poietic toxicity.

drifampin is not a protein synthesis inhibitor. however, it may be used in combina-tion with other antimicrobial drugs on the basis of its in vitro synergy.

eShould only be used if other options are not available because of toxicity concerns.from cDc technical appendix available through http://www.ncbi.nlm.nih.gov/

pmc/articles/Pmc3901462/.

TaBle 92.4 Intravenous Therapy for Systemic anthrax When Meningitis Has Been excludeda

Bactericidal Drug

for all strains, regardless of penicillin susceptibility or if susceptibility is unknown

ciprofloxacin, 400 mg every 8 hr

or


or


or

meropenem, 2 g every 8 hr

or

imipenem, 1 g every 6 hrb

or

Doripenem, 500 mg every 8 hr

or

Vancomycin, 60 mg/kg/d intravenous divided every 8 h (maintain serum trough concentrations of 15–20 μg/mL)

or


Penicillin G, 4 million units every 4 hr

or

ampicillin, 3 g every 6 hr

PLuS

Protein synthesis inhibitor

clindamycin, 900 mg every 8 hror

Linezolid, 600 mg every 12 hrc

or

Doxycycline, 200 mg initially, then 100 mg every 12 hrd

or

rifampin, 600 mg every 12 hre

aDuration of treatment: for 2 wk until clinical criteria for stability are met (see text). Patients exposed to aerosolized spores will require prophylaxis to complete an antimicrobial drug course of 60 d from onset of illness (see technical appendix table 2 [postexposure prophylaxis]). Systemic anthrax includes anthrax meningi-tis; inhalation, injection, and gastrointestinal anthrax; and cutaneous anthrax with systemic involvement, extensive edema, or lesions of the head or neck. Preferred drugs are indicated in boldface. alternative drugs are listed in order of prefer-ence for treatment for patients who cannot take first-line treatment, or if first-line treatment is unavailable.

bincreased risk for seizures associated with imipenem/cilastatin treatment.cLinezolid should be used with caution in patients with thrombocytopenia because

it might exacerbate it. Linezolid use for more than 14 d has additional hemato-poietic toxicity.

da single 10–14 d course of doxycycline is not routinely associated with tooth staining.

erifampin is not a protein synthesis inhibitor. however, it may be used in combination with other antimicrobials drugs on the basis of its in vitro synergy.

from cDc technical appendix available through http://www.ncbi.nlm.nih.gov/pmc/articles/Pmc3901462/.

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response. Therefore, treatment regimens are recommended for 60 days with close follow-up after discontinuation of antibiot-ics. Postexposure prophylaxis recommendations are given in Table 92.6, and consist of a single oral drug, similar to the recommendations for the treatment of cutaneous anthrax.

Corticosteroids

Although data are lacking, corticosteroids may be helpful in cutaneous anthrax with edema and in bacterial meningitis (50–52). Therefore, the consensus recommendations are to use corticosteroids in patients on prior steroid therapy, cases with edema, especially of the head and neck, meningitis, and vasopressor-resistant shock (47).

Procedures and Surgical Interventions

Aggressive thoracostomy tube placement and drainage of pleural effusions are recommended to maximize pulmonary function and to remove the potentially deleterious effects of toxin-containing effusions. Surgery, while generally not indi-cated, may be required in cases of gastrointestinal anthrax or in cases of deep soft tissue infection.

antibody Treatment

There are two antibody preparations which could potentially be used for anthrax. The first, raxibacumab, is a recombinant, humanized monoclonal antibody directed against protective antigen (PA) of the anthrax bacillus. It has proven efficacy in rabbits and monkeys and was well tolerated in a Phase I human trial (53,54). Raxibacumab has been approved by the FDA for treatment and postexposure prophylaxis. The second antibody preparation consists of anthrax immune globulin from pooled human sera from patients immunized with anthrax vaccine. Like raxibacumab, it is also effective in animal studies and was well tolerated in humans (47,55). This anthrax immune globu-lin preparation is not FDA-approved but could be used under an Investigational New Drug (IND) protocol or an Emergency Use Authorization during a declared emergency.

Prevention

Postexposure prophylaxis with antibiotics should be adminis-tered to all exposed patients as soon as possible after exposure and continued for 60 days (see Table 92.6). A three-dose series of Adsorbed Vaccine Anthrax may be administered combined with antibiotic prophylaxis (56).

VIral hemorrhagIc FeVer

The major diseases that will be considered in this section are Marburg, Ebola, and Lassa fevers. Marburg and Ebola viruses are filoviruses, whereas Lassa virus is an arenavirus with differ-ent clinical characteristics. Nevertheless, they have the potential to create similar problems in hospital management because of the sometimes dramatic nature of the illness and the potential for human-to-human transmission. The largest outbreak of Ebola to occur to date began in Western Africa in 2014 and is ongoing at the time of publication. There is now an extensive body of guidelines and practice recommendations regarding evaluation, diagnosis, and treatment of Ebola virus disease (EVD) from vari-ous nongovernmental organizations, the World Health Organi-zation (WHO), and the CDC. A summary of the most pertinent recommendations is provided here, but due to the complex and evolving nature of the ongoing outbreak, the reader is advised to consult the CDC website for the most recent recommendations.

Epidemiology and Virology

Ebola (EBOV) and Marburg (MARV) viruses are related, but serologically noncross-reactive. There are five species of EBOV: Bundibugyo ebolavirus (BEBOV), Côte d’Ivoire ebolavirus (CIEBOV), Reston ebolavirus (REBOV), Sudan ebolavirus (SEBOV), and Zaire ebolavirus (ZEBOV). Since 1976, there have been approximately a dozen outbreaks of Ebola in Africa, with mortality generally ranging from 53% to 88% (57). Most cases have been due to ZEBOV, although

TaBle 92.5 Oral Treatment for Cutaneous anthrax Without Systemic Involvementa

For all Strains, Regardless of Penicillin Susceptibility or if Susceptibility is Unknown

Ciprofloxacin, 500 mg every 12 hror

Doxycycline, 100 mg every 12 hror

levofloxacin, 750 mg every 24 hror

Moxifloxacin, 400 mg every 24 hror

clindamycin, 600 mg every 8 hrb

or


amoxicillin, 1 g every 8 hr

or

Penicillin Vk, 500 mg every 6 hr

aPreferred drugs are indicated in boldface. alternative drugs are listed in order of preference for treatment for patients who cannot take first-line treatment, or if first-line treatment is unavailable. Duration of treatment is 60 d for bioterrorism-related cases and 7–10 d for naturally acquired cases.

bBased on in vitro susceptibility data, rather than studies of clinical efficacy.

TaBle 92.6 Recommendations for Postexposure Prophylaxis of anthrax

For all Strains, Regardless of Penicillin Susceptibility or if Susceptibility is Unknown

Ciprofloxacin, 500 mg every 12 hror

Doxycycline, 100 mg every 12 hror


or


or

clindamycin, 600 mg every 8 hrb

or


amoxicillin, 1 g every 8 hr

or

Penicillin Vk, 500 mg every 6 hr

aPreferred drugs are indicated in boldface. alternative drugs are listed in order of preference for treatment for patients who cannot take first-line treatment or if first-line treatment is unavailable.

bBased on in vitro susceptibility data rather than studies of clinical efficacy.from cDc technical appendix available through http://www.ncbi.nlm.nih.gov/

pmc/articles/Pmc3901462/.

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an outbreak of 425 cases in Uganda due to SEBOV occurred in 2000 and 2001 (58). Mortality with ZEBOV is higher than with SEBOV, with the lowest mortalities reported for BEBOV (59–61). The natural reservoir is thought to include fruit bats with transmission to nonhuman primates, but the details of the enzootic cycle remain to be fully resolved (62).

Ebola transmission has ranged from 3% to 17% in house-hold contacts (63). Transmission is related to contact with sicker patients in later stages of disease, when viremia may reach very high titers in bodily fluid and in skin (58,63–65). Nosocomial transmission is associated with percutaneous exposure and mucous membrane or cutaneous exposure to infected body fluids. The skin of patients is also infected and may serve as a source of secondary transmission (66).

Initial infection of humans has been associated with con-tact with wild game, particularly “bush meat” from nonhu-man primates and with bats. Secondary transmission is linked to contact with blood and other bodily fluids during provision of health care, by reuse of contaminated needles and syringes, and to preparation of the bodies of victims for burial dur-ing traditional rites which involve bathing and touching the bodies of the deceased. Droplet and, possibly, small-particle aerosol transmission is thought to have occurred in the Reston outbreak but has not been documented in human-to-human transmission (66). Pigs may also be a reservoir for REBOV, although there are no documented human cases of disease associated with transmission from swine (67).

During the latest outbreak in Africa, the countries of Guinea, Sierra Leone, and Liberia have been most severely affected. As of March 2015, there have been almost 25,000 cases with approximately 10,000 deaths (Table 92.7). In addi-tion, there was limited transmission to Nigeria, Mali, and Sen-egal, with 20, 9, and 1 cases, respectively. There is currently no ongoing transmission in those countries and they have been declared free of EVD. There have been several imported cases of EVD diagnosed in the United States. The first case diagnosed in the United States was a traveler from Liberia who arrived while incubating EVD and the second was a phy-sician who was also asymptomatic on arrival but was incu-bating an infection acquired while providing medical services in Guinea prior to returning to the United States. Two health care workers were infected in the United States while caring for the patient from Liberia. One nurse was infected while caring for an EVD patient in Spain. There have also been sev-eral health care workers transferred to the United States for further medical treatment. All of these patients survived with the exception of the Liberian patient. There have been eight cases of documented human infection with REBOV in the United States from contact with imported monkeys from the

Philippines. Infections with this Reston strain of Ebola virus have been subclinical.

Marburg virus has been associated with six outbreaks since the disease was recognized in 1976 in German and Yugoslav laboratory workers infected by African green mon-keys of Ugandan origin (68). Since then, there have been six other clusters of infection in Africa, the most recent in Angola and the Democratic Republic of Congo. Involving more than 400 people, the mortality was 83% and 90%, respectively, in these last two outbreaks. MARV infections are transmitted by exposure to infected primate blood or cell culture or probably by direct exposure to virus from fruit bats (66,69–71). Secondary transmission occurs from expo-sure to blood and body fluids, as well as by intimate contact.

Lassa virus causes a chronic infection of rodents, and is endemic throughout West Africa (72). Transmission to humans is through exposure to infected rodents, primarily through con-tact with urine from chronically and asymptomatically animals (73). Person-to-person transmission is thought to be primarily via contact with infected bodily fluids, although aerosol trans-mission may also occur. Incubation is between 7 and 21 days. Other arenaviruses are present worldwide in rodent reservoirs and are a potential source of new clinical syndromes (72).


The clinical picture of Ebola and Marburg infections is similar (66). The incubation period is usually between 8 and 10 days with an overall range of 2 to 21 days. Abrupt onset of fever, weakness, myalgias, and headache is typical. A characteristic maculopapular rash is described by day 5 of the illness. Nau-sea and vomiting, abdominal pain, diarrhea, and hypotension may occur by 4 to 7 days, followed by confusion, bleeding, and shock. Bleeding is usually not profuse although a bleed-ing diathesis is seen in at least 50% of patients; chest pain and pharyngitis are also common. Photophobia, lymph node enlargement, jaundice, and pancreatitis are all manifestations of widespread organ involvement. CNS involvement may manifest as obtundation or coma. By the second week, there is either a period of defervescence and improvement, or further deterioration with multiorgan system failure. Disseminated intravascular coagulation, as well as hepatic and renal fail-ure may ensue; convalescence is often protracted. As described above, Ebola–Reston has not led to any known human deaths. There is viremia with infection of all organs, leading to necro-sis in areas of viral replication (74). Pathogenesis is thought to be also due to cytokine release leading to increased vascular permeability and hemodynamic instability (75).

Lassa fever presents with relatively nonspecific signs and symptoms, making recognition of cases in the initial stages difficult (72,76). A combination of fever, retrosternal pain, pharyngitis, and proteinuria has been suggested to be indica-tive of Lassa fever (76). A diffuse capillary leak syndrome in the second week of illness is a cardinal manifestation of this disorder. Mortality of hospitalized cases ranges from 15% to 25%. Seventh cranial nerve deafness is a common sequela of Lassa infection, occurring in approximately one-third of cases (77); persistent vertigo is another reported side effect (78). The pathogenic mechanism of Lassa fever is not well understood, but there is variable necrosis in affected organs and the sys-temic manifestations of vascular dysfunction may be due to soluble macrophage-derived factors.

TaBle 92.7 Incidence of eVD in africa 2014 to 2015

Country Total Cases

(Suspected, Probable, and confirmed)

Laboratory-confirmed cases

total Deaths

Guinea 3,331 2,911 2,192

Liberia 9,482 3,150 4,241

Sierra Leone 11,696 8,469 3,663

total 24,509 14,530 10,096

adapted from the cDc: http://www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/case-counts.html.

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Diagnosis

A history of travel to endemic areas and a clinical syndrome compatible with viral hemorrhagic fever (VHF) are key ele-ments of making a diagnosis. Nevertheless, a cluster of cases with signs and symptoms indicative of VHF may the first clue of a biologic attack. Specialized testing for Marburg and Ebola, including PCR and direct antigen visualization in clini-cal samples, is available through reference laboratories and the CDC. Contact with local public health authorities and the CDC will allow testing according to approved protocols. An extensive series of protocols has been established for handling of clinical samples to prevent exposure of clinicians and labo-ratory personnel and is available on the CDC website at http://www.cdc.gov/vhf/ebola/healthcare-us/laboratories/specimens.html. Lassa virus is easily cultured as the levels of viremia are usually high; RT-PCR may also be used to identify Lassa virus.

Treatment

Treatment of Marburg and EVD is primarily supportive. There is no proven effective specific antiviral therapy. Riba-virin and interferon have been previously ineffective. Several recent patients who have survived were treated with a combi-nation of four monoclonal antibodies directed against Ebola virus antigens and open trials with this product are underway. Whether administration of serum from convalescent patients is useful in the treatment of EVD is unknown. Unnecessary movement or manipulation of the patient should be avoided. Contact and respiratory isolation of the patient is necessary including use of goggles and face shields to prevent expo-sure to body fluids (79). Prevention of nosocomial exposure and infection is of paramount importance. The complexities of protocols for the use of appropriate personal protective equipment and infection control are beyond the scope of this chapter and CDC guidelines should be followed in all cases of suspected or proven viral hemorrhagic fever. Transfer to specialized treatment centers may also be appropriate. Vac-cines that have shown promise in primate models are currently under evaluation but are not available for routine clinical use.

In cases of Lassa fever, where the aspartate transaminase levels exceed 150 IU/L, early treatment with intravenous riba-virin has been reported to be beneficial in tapering doses over 12 days (80).

SmallPox

Smallpox is caused by infection with variola, a double-stranded DNA orthopoxvirus. Smallpox, one of the most feared and lethal diseases known to man, was virtually eliminated as a natural threat by vaccination (81). By 1980, WHO declared it to be eradicated worldwide, with the last case known to have occurred naturally in 1977. In the United States, univer-sal childhood vaccination ended in 1972. Thus, most people in the United States today are susceptible to smallpox infection. The anthrax attacks in 2001 again raised the possibility of smallpox being used as a biologic weapon. Smallpox is clas-sified as a Tier 1 bioterrorism agent, a high-priority organism that poses a risk to national security (3,4) and should be con-sidered one of the most dangerous agents because of its high infectiousness, capability for rapid spread, the lack of effective

treatment, and the capacity to induce mass social disruption and overburden the public health system.

Epidemiology

Smallpox is spread by direct close contact via large droplet inhalation (82); there are no known animal reservoirs. Spread can also occur by contact with lesions or infected fomites. Household spread has been reported to range from 30% to 80% (83). Smallpox outbreaks were most common during the winter and early spring (84). All ages are susceptible although, historically, vaccination rates and prior infection modulated the attack rates among different groups. Patients are most con-tagious when they have a rash although they may be infectious during the symptomatic prodrome prior to the development of skin lesions (see below). Incubation is from 7 to 17 days, during which period the patient is not infectious.


During the prodromal phase, the patient experiences high fever with back pain and prostration (81). The rash follows within a day or two, with more lesions on the face, oral mucosa, and extremities than on the trunk—termed a centrifugal pattern. The lesions begin as macules, progress to vesicles, and then finally pustules over the first week. Fever is usually persis-tent throughout the period of rash development. The lesions are deep seated, firm, painful, and—importantly for the diagnosis—all lesions are at the same stage of development at each phase. All of these characteristics of the rash serve to differentiate it from the rash of chickenpox, which is super-ficial, lesions appear in crops, are centripetal in distribution, and are associated with a relatively mild prodrome. The extent of the smallpox rash correlates with mortality, which may range from 10% to 75%; in fatal cases, death usually occurs by the second week. The lesions begin to crust over after 7 to 9 days, and the patient is noninfectious only after all scabs have fallen off. Scarring and pitting result in the characteristic pock-marked appearance of survivors. The pathologic dam-age in smallpox is generally confined to the skin and mucous membranes, although virus is present throughout the internal organs (81). The systemic manifestations and fatalities are attributed to toxinemia and antigenemia.

Vaccine-modified smallpox presents as a milder illness with fewer lesions and mortality less than 10% (81). A hemor-rhagic form of smallpox may occur in which there is diffuse erythema, followed by petechial hemorrhages; it is reported to have mortality approaching 100% (85). In malignant or “flat” smallpox, discrete lesions do not develop, but confluent rubbery lesions are present (86). A form of smallpox known as variola minor, with much milder symptoms and mortality less than 10%, is now known to be due to a genetically distinct strain of the virus (87).

Diagnosis

Specimens of vesicular or pustular fluid should be obtained for culture and electron microscopic examination; these are transported in double-sealed leak-proof containers designed for transport of body fluids. Specimens should be handled only in BSL-4 laboratories and public health authorities should be notified if a case of smallpox is suspected to assist with

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specimen handling. The diagnosis of orthopoxvirus infection can be made by electron microscopic examination and specia-tion can be performed by molecular techniques such as PCR and DNA sequencing.

Treatment and Prevention

While a full discussion of infection control and vaccination protocols is beyond the scope of this text, the following prin-ciples should be followed (88). The patient should be isolated, and contact and airborne precautions should be instituted when a case of smallpox is suspected. All personnel who had face-to-face contact with the patient should be vaccinated, as should all personnel who had contact with the patient while the latter was febrile. Local health authorities should be con-tacted immediately and the CDC will provide assistance with prioritizing contacts for vaccination and monitoring. It should also be noted that contraindications to vaccinations do not apply to high-risk exposures. Treatment is primarily sup-portive, and is aimed at maintaining hemodynamic stability and treating secondary infections. Vaccination is most effec-tive when administered within 72 of exposure, but may miti-gate symptoms and severity of disease if administered after 72 hours. A vaccinia immune globulin product may be avail-able from the CDC to manage vaccine adverse effects.

monkeyPox

Monkeypox is a disease clinically similar to smallpox that has been sporadically reported in Africa since 1960. Pronounced lymphadenopathy is an additional sign of monkeypox that may help differentiate it from smallpox (89,90). Monkeypox is thought to be endemic in rodents and transmitted to humans via direct animal contact, with occasional human-to-human transmission. In 2003, there was a large cluster of human cases in the United States associated with prairie dogs that had become infected by imported African rodents (91). Although there were no fatalities, several patients required hospitaliza-tion. Vaccination against smallpox is thought to ameliorate symptoms and lessen the likelihood of infection. Cidofovir, an antiviral agent, has activity against monkeypox in vitro, and may be used in severe infection, although there are no clinical data regarding its effectiveness (92).

malarIa

Malaria, the fourth largest killer of children under five, causes over 350 million clinical episodes and one million deaths per year. While a comprehensive discussion of the management of malaria will not be possible here, we will cover the recognition and treatment of severe malaria, which may be encountered in the critical care setting in a nonendemic setting. As such, this chapter will focus on infection with Plasmodium falciparum, the strain of the parasite which is most likely to cause high-level parasitemia and severe, life-threatening malaria.

Epidemiology

Malaria is endemic throughout much of the world, with the greatest number of cases in Africa and Asia (93). Malaria has

been officially eradicated in the United States since 1970, but approximately 1,200 cases are reported annually (94), mostly in travelers from endemic areas. Other cases are due to local transmission from infected mosquitoes (so-called “airport malaria”), congenital malaria, and malaria acquired from blood transfusion. Local transmission of malaria in the United States has occurred at least 11 times since 1970, with 20 prob-able cases (95). In a recent outbreak in Florida, seven cases were verified as being caused by the same strain of P. vivax (95). Thus, domestic transmission of malaria is possible espe-cially in warmer regions of the United States.

In endemic areas, many adults are partially immune to malaria and, although infected, may even be asymptomatic. Children are particularly prone to infection and to develop-ing severe disease. Other high-risk groups include pregnant women, asplenic individuals, and other immunocompromised hosts.


Malaria typically has an incubation period of 1 to 3 weeks. However, this may be extended by partial immunity or chemo-prophylaxis. Therefore, it has been suggested that any traveler returning from an endemic area should be considered at risk for development of malaria for as long as 3 months (96). The clinical presentation is usually nonspecific: fever and headache are universally present, and myalgia, sweats, and weakness are common. Paroxysmal and cyclical fever, while classically asso-ciated with malaria, are not consistently present. Especially in the case of falciparum malaria, the fever is often continuous. While other infections are common in malaria-endemic areas, malaria should be considered as one of the most likely diagno-ses in any patient with a consistent clinical picture and travel history. If malaria is suspected, prompt infectious disease con-sultation is indicated, to help with management and assess the likelihood of alternate diagnoses.

The pathogenesis of malaria is complex and related to both direct effects of the parasite on erythrocytes and the vas-culature, and indirect effects on cytokine production, tissue oxygen consumption, and other systemic effects (96). Several aspects of the biology of P. falciparum are relevant to the development of severe malaria. P. falciparum sequesters itself in the venous microcirculation of virtually all tissues, includ-ing the brain. Hypoglycemia is common during P. falciparum infection and is thought to be due to oxygen consumption by replicating parasites as well as due to increased tissue metabo-lism. Severe anemia may occur and is due to lysis of infected erythrocytes as well as to clearance of uninfected erythrocytes, and decreased erythrocyte production. Thus the anemia in severe malaria is often normochromic and normocytic. This combination of factors aggravates tissue hypoxia and leads to metabolic acidosis. A capillary leak syndrome due to parasite sequestration and cytokine production may lead to pulmo-nary edema. Renal failure in malaria is multifactorial and is more common in adults than children. Hemoglobinuria may be severe enough to cause dark urine, termed, when present, blackwater fever.

Diagnosis

The gold standard for diagnosis of malaria remains micro-scopic identification of parasites on the blood smear. However,

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rapid diagnostic tests (RDTs) based on antigen detection are becoming widely available and facilitate diagnosis within minutes. These tests allow the identification of the infection as falciparum or non-falciparum, and are highly sensitive and specific, although sensitivity and specificity decline with lower levels of parasitemia. Examination of thick and thin blood smears should be performed immediately by trained person-nel. If the initial examination is negative, smears should be repeated every 12 to 24 hours for a total of 48 to 72 hours (94). When parasites are detected, the percentage of parasit-emia can be calculated by counting the number of infected and noninfected RBCs. The number of WBCs in the micro-scopic field can also be used as an internal standard to aid in estimated parasite density and percentage when thick smears are examined. Malaria is a nationally notifiable disease and the state health authorities should be notified when a diag-nosis of malaria is made. The Centers for Disease Control and Prevention maintains a 24-hour malaria hotline to assist clinicians with the management of suspected and confirmed malaria cases (97).

Treatment

It should be emphasized that patients, particularly those who are nonimmune, may deteriorate rapidly. Thus hospitalization of patients during the initial phase of treatment is prudent. Furthermore, nonimmune patients may have severe illness before manifesting high degrees of parasitemia. Therefore, patients who manifest any of the symptoms or signs of severe malaria and have any degree of parasitemia on blood smear should be treated as a case of severe malaria. The WHO has promulgated criteria for the diagnosis of severe malaria (Table 92.4 and footnote to Table 92.8) (98). Cases that meet these criteria should be treated with intravenous therapy. Intrave-nous quinidine gluconate and artesunate are currently the only available parenteral drugs recommended for severe malaria in the United States. Artesunate is recommended by the WHO in preference to quinidine for the treatment of severe malaria and has now been used for many years in other countries. Artesu-nate may be obtained under an IND protocol from the CDC if patients have severe disease, a high level of parasitemia, an

TaBle 92.8 Recommendations for Treatment of Severe Malaria from all Regions

adult DosageQuinidine gluconatea plus one of the following: doxycycline, tetracycline, or clindamycin

Quinidine gluconate: 6.25 mg base/kg ( = 10 mg salt/kg) loading dose iV over 1–2 hr, then 0.0125 mg base/kg/min ( = 0.02 mg salt/kg/min) continuous infusion for at least 24 hr. an alternative regimen is 15 mg base/kg ( = 24 mg salt/kg) loading dose iV infused over 4 hr, followed by 7.5 mg base/kg ( = 12 mg salt/kg) infused over 4 hr every 8 hr, starting 8 hr after the loading dose (see package insert). once parasite density is less than 1% and patient can take oral medication, complete treatment with oral quinine. Quinidine/quinine course = 7 d in Southeast asia, 3 d in africa or South america.

Doxycycline: if patient not able to take oral medication, give 100 mg iV every 12 hr and then switch to oral doxycycline (as soon as patient can take oral medication (100 mg po bid). for iV use, avoid rapid administration. treatment course = 7 d.

tetracycline: 250 mg po 4 times daily.

clindamycin: 20 mg base/kg/d po divided 3 times daily. if patient not able to take oral medication, give 10 mg base/kg loading dose iV followed by 5 mg base/kg iV every 8 hr. Switch to oral clindamycin (oral dose as above) as soon as patient can take oral medication. for iV use, avoid rapid administration. treatment course = 7 d.

investigational new Drug (contact cDc for information):

artesunate followed by one of the following: atovaquone/proguanil (malarone™), Doxycycline (clindamycin in pregnant women), or mefloquine

Pediatric DosageQuinidine gluconatea plus one of the following:

Doxycycline,b tetracycline,b or clindamycin

Quinidine gluconate: Same mg/kg dosing and recommendations as for adults.

Doxycycline: 2.2 mg/kg po every 12 hr.

if patient not able to take oral medication, may give iV. for children 45 kg, use same dosing as for adults. for iV use, avoid rapid administration. treatment course = 7 d.

tetracycline: 25 mg/kg/day po divided 4 times daily.

clindamycin: 20 mg base/kg/day po divided 3 times daily. if patient not able to take oral medication, give 10 mg base/kg loading dose iV followed by 5 mg base/kg iV every 8 hr. Switch to oral clindamycin (oral dose as above) as soon as patient can take oral medication. for iV use, avoid rapid administration. treatment course = 7 d.

investigational new drug (contact cDc for information): artesunate followed by one of the following: atovaquone-proguanil (malarone), clindamycin, or mefloquine

aPersons with a positive blood smear or history of recent possible exposure and no other recognized pathology who have one or more of the following clinical criteria (impaired consciousness/coma, severe normocytic anemia, renal failure, pulmonary edema, aRDS, circulatory shock, disseminated intravascular coagulation, spon-taneous bleeding, acidosis, hemoglobinuria, jaundice, repeated generalized convulsions, and/or parasitemia of more than 5%) are considered to have manifestations of more severe disease. Severe malaria is most often caused by P. falciparum. Patients diagnosed with severe malaria should be treated aggressively with parenteral antimalarial therapy. treatment with iV quinidine should be initiated as soon as possible after the diagnosis has been made. Patients with severe malaria should be given an intravenous loading dose of quinidine unless they have received more than 40 mg/kg of quinine in the preceding 48 hr or if they have received mefloquine within the preceding 12 hr. consultation with a cardiologist and a physician with experience treating malaria is advised when treating malaria patients with quinidine. During administration of quinidine, blood pressure monitoring (for hypotension) and cardiac monitoring (for widening of the QrS complex and/or lengthening of the Q–tc interval) should be monitored continuously and blood glucose (for hypoglycemia) should be monitored periodically. cardiac complications, if severe, may war-rant temporary discontinuation of the drug or slowing of the intravenous infusion. Pregnant women diagnosed with severe malaria should be treated aggressively with parenteral antimalarial therapy. Doxycycline and tetracycline are not indicated for use in children less than 8 years old. for children less than 8 yr old with chloroquine-resistant P. falciparum, atovaquone–proguanil and artemether–lumefantrine are recommended treatment options; mefloquine can be considered if no other options are available.

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inability to take oral medications, a lack of timely access to intravenous quinidine, quinidine intolerance, or contraindica-tions or quinidine failure. Postartemisinin delayed hemolysis (PADH) can occur 1 to 3 weeks after therapy with artesunate. Two aspects of quinidine therapy in this setting are impor-tant to remember. The first is the possibility of ventricular dysrhythmias; prolongation of the Q–TC interval is commonly seen during quinidine therapy and careful monitoring of the electrocardiogram and electrolytes are mandatory. Combi-nation with other drugs that may prolong the Q–TC interval should be avoided. The second is the propensity of quinidine and quinine to cause hypoglycemia. Given the likelihood of hypoglycemia in severe malaria due to the disease itself, serum glucose must be carefully monitored and supplemented as necessary. Given these considerations, quinidine should be administered in an intensive care unit, with the assistance of a cardiologist as needed.

It is recommended by the CDC that exchange transfusion be considered in cases where parasitemia exceeds 10% or when severe complications are present (99,100). Although the benefits have not been proven in a randomized trial, exchange transfusion has the potential benefit of both reduc-ing parasite burden and circulating cytokines and toxins. Exchange transfusion is recommended until parasitemia is below 1%. The CDC may also be contacted for advice at the Malaria Hotline.

rocky moUntaIn SPotted FeVer

Rocky Mountain spotted fever (RMSF) is a disease that pres-ents with nonspecific signs and symptoms, for which there is not a specific RDT. Unless treated appropriately, RMSF has a high mortality. It is therefore important for the practicing clinician to have a high index of suspicion for RMSF and to be familiar with its epidemiology, clinical manifestations, and treatment.

Epidemiology

RMSF is caused by Rickettsia rickettsii, an intracellular bacte-rium that is transmitted in the United States primarily by the dog tick, Dermacentor variabilis, in the Eastern states, and the wood tick, Dermacentor andersonii, in the Rocky Mountain States, as well as by the brown dog tick, Rhipicephalus san-guineus, throughout the United States. Ticks are also the pri-mary reservoir for R. rickettsii. Despite the name, most cases of RMSF occur in the Southeastern United States, and over 60% of reported cases are from North Carolina, Missouri, Tennessee, Oklahoma, and Arkansas (101). However, cases have been reported in all 48 continental states except Vermont and Maine (102). The incidence of RMSF has risen sharply over the past decade, and is now over 6 cases per million, with approximately 2,000 cases reported per year in the United States. Most cases occur between April and September with a peak in June and July. Although children have been reported to be at highest risk of RMSF, the peak incidence currently is in those aged 55 to 64 (101,102). Although males are reported to be at higher risk, a recent study of children with RMSF found more cases among girls than boys (103). Most bites are unnoticed and the tick must be attached for 6 to 10 hours for feeding and infection to take place.

Clinical Manifestations and Pathogenesis

The rickettsial organisms primarily target and infect endothe-lial cells (104). The primary pathology consists of diffuse cell injury and increased vascular permeability caused by cell-to-cell spread of the organisms after initial hematogenous and lymphatic seeding. Infection occurs in virtually all internal organs and vascular injury occurs in lung, heart, brain, gastro-intestinal tract, and skin, as well as other sites.

Symptoms typically begin 2 to 14 days after the tick bite. Virtually all patients experience the classical triad of fever, headache, and rash (103,105,106). However, it should be emphasized that the rash is only present in about 50% of cases within the first 3 days. Rash usually appears by the 2nd to 5th day, but is absent in about 10% of patients. The rash is often faint in the initial stages and may be more difficult to detect in patients with dark skin (106). It begins as a blanching, pink maculopapular exanthem, most commonly beginning at the wrists and ankles, and develops into palpable lesions that spread centrally. The rash subsequently becomes petechial and may involve the palms and soles. Progression to petechiae is a sign of progressive disease. Commonly associated symptoms occurring in more than 50% of patients are myalgias, nau-sea, vomiting, and abdominal pain. The serum AST is often elevated and thrombocytopenia and hyponatremia occur in up to 50% of cases (106). Atypical symptoms such as cough, diarrhea, or sore throat may predominate in children, compli-cating diagnosis.

CNS abnormalities occur in about 25% and carry a poor prognosis. CSF abnormalities are observed in one-third of patients and consist of pleocytosis and elevated protein levels, although the CSF glucose is usually normal. A fulminant form of the disease, with death occurring in the first five days, has been described; glucose-6-phosphate dehydrogenase deficiency has been linked to this form of the disease (107). Neurologic deficits and limb loss are the most serious sequelae observed in survivors of RMSF (108).

Diagnosis

Delay in diagnosis and delay in seeking medical attention are associated with poor outcome in RMSF. Therefore, empiric therapy should not await the result of laboratory testing. Factors that are likely to lead to delay in diagnosis include absence of rash or delayed appearance of the rash, no his-tory of tick bite, and presentation early in the course of dis-ease (106,109,110). R. rickettsii can be isolated in culture or demonstrated by immunohistochemistry in tissue specimens. Blood culture or PCR is insensitive due to the low number of circulating organisms. Serology is useful for confirmation of diagnosis. Diagnosis should, therefore, be made on the basis of epidemiologic and clinical findings described above.

Treatment

The recommended therapy for RMSF in both adults and chil-dren is doxycycline, administered at a dose of 100 mg twice daily for adults and 2.2 mg/kg body weight twice daily for children under 45 kg (111). Treatment of suspected RMSF should be instituted promptly with doxycycline either intra-venously or orally. Doxycycline for RMSF is not contraindi-cated in children (111). Outcome is superior with doxycycline

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compared to other antibiotic regimens. Therapy is continued for 7 to 14 days and a minimum of 3 days after the patient has defervesced.

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• The epidemiology, clinical presentation, and manage-ment of infections resulting from an intentional release of microorganisms may differ significantly from disease resulting from traditional modes of spread.

• The HHS/CDC has designated those select agents and toxins that present the greatest risk of deliberate misuse with the most significant potential for mass casualties or devastating effects to the economy, critical infra-structure or public confidence as Tier 1 agents.

• Recommendations for a mass casualty setting take into account the likelihood that services may be limited and parenteral or inpatient therapy may not be possible. Therefore, several potentially toxic antibiotics that are not routinely given to children or pregnant women are included in the recommended treatment regimens.

• While there are three known modes of exposure—inha-lational, cutaneous, and gastrointestinal—anthrax may present as meningitis, and as many as 50% of inhala-tional anthrax cases may develop meningitis.

• A prolonged latency period may occur after anthrax exposure. Postexposure antibiotic prophylaxis is there-fore continued for 60 days with subsequent monitoring of the patient.

• Nonimmune malaria patients may have severe illness before manifesting high degrees of parasitemia. There-fore, those who meet criteria for severe malaria and have any degree of parasitemia should be hospitalized and treated with intravenous therapy.

• Close cooperation with the CDC and local public health authorities should be initiated in all cases of suspected viral hemorrhagic fever and transfer to specialized care facilities should be considered.

• The rash of RMSF may not be present initially or may never develop. Delay in diagnosis and delay in seeking medical attention are associated with poor outcome in RMSF. Therefore, empiric therapy should not await the result of laboratory testing.

• Smallpox is highly infectious. The patient should be isolated, and contact and airborne precautions should be instituted when a case of smallpox is suspected. Specimens should be handled only in BSL-4 laborato-ries and public health authorities should be notified to assist with specimen handling.

key Points

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