Unusual Infections


Plague is primarily a rural disease that occurs in all continents except Australia (24). Although most common in rural settings 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 handling 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 pneumonic 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 headache. 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 primary 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. Bacteremia 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, diagnosis 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 pneumonic plague are fatal if untreated. Even with treatment, mortality 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). Pneumonic 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 isolation 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 approximately 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, 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 fulminant pneumonia and sepsis. The white blood cell count is often markedly elevated and fibrin degradation products are detectable in cases where disseminated intravascular coagulation is present (31).


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 susceptibility 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 possibility of plague so that appropriate biosafety procedures can be followed.


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 antibiotics, 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 availability 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 treatment 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 aminoglycosides 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).

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


An extremely rare disease in the United States until the bioterrorism 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 the manifestations of anthrax and especially of the expected characteristics of an outbreak due to a biological attack.


There are three major modes of infection with anthrax: inhalational, 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 exposure to intentionally produced anthrax, inhalational anthrax is even less common and occurs primarily in those with occupational 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 numbers of anthrax bacilli has been consumed (37).

Clinical Manifestations

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 biologic weapon is from the 2001 US attacks and an unintentional 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 inhalational 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, pulmonary infiltrates, or consolidation were observed in 8 of 11 cases. In addition, in an autopsy series from the Sverdlosk outbreak, 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, cutaneous, 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 portal 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 symptoms listed above, tachycardia and severe diaphoresis may be present. Rhinorrhea or sore throat is common in viral respiratory 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 vesiculation. 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 cutaneous anthrax that developed in a 7-month-old infant in 2001, microangiopathic hemolytic anemia and renal insufficiency occurred (45).


Blood cultures should be obtained promptly if anthrax is suspected; 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 notified of the possibility of anthrax. If indicated, specimens can be sent to specialized laboratories participating in the Laboratory Response Network for specific testing such as immunohistochemical 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 exposure 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.


The current recommendations for therapy of anthrax provided 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.

TABLE 92.3 Intravenous Treatment for Systemic Anthrax with Possible/Confirmed Meningitisa

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 experience. 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 meningitis has been ruled out, the regimen may be simplified, and these recommendations are summarized in Table 92.4. Recommendations for cutaneous anthrax consist of treatment with a single drug, preferably a quinolone or a tetracycline (see Table 92.5).

TABLE 92.4 Intravenous Therapy for Systemic Anthrax When Meningitis Has Been Excludeda

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 response. Therefore, treatment regimens are recommended for 60 days with close follow-up after discontinuation of antibiotics. 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.

TABLE 92.5 Oral Treatment for Cutaneous Anthrax Without Systemic Involvementa


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).

TABLE 92.6 Recommendations for Postexposure Prophylaxis of Anthrax

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 indicated, 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 globulin 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.


Postexposure prophylaxis with antibiotics should be administered 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).


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 different 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 various nongovernmental organizations, the World Health Organization (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 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 household 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 contact with wild game, particularly “bush meat” from nonhuman 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 during 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 addition, there was limited transmission to Nigeria, Mali, and Senegal, 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 physician who was also asymptomatic on arrival but was incubating 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 several 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.

TABLE 92.7 Incidence of EVD in Africa 2014 to 2015

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Feb 26, 2020 | Posted by in CRITICAL CARE | Comments Off on Unusual Infections
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