Emerging Infections 7

Severe acute respiratory syndrome (SARS) coronavirus (CoV) infection, in addition to infections originating in the laboratory, was detected in four patients with no possible laboratory exposure during December 2003 and January 2004. These four epidemiologically unrelated patients likely acquired the infection through exposure to infected animals in live-game-animal markets in Guangdong. A number of possible agents were detected in the course of investigating patients with suspected SARS, including human metapneumovirus and chlamydia. In the absence of an epidemiological history of exposure, clinical findings are not pathognomic of SARS. Therefore, a positive virological laboratory finding of SARS CoV infection is required for confirmation of the diagnosis. Evidence of SARS CoV replication in the lungs and intestine is provided by detection of virus particles through electron microscopy, by virus isolation, and by the detection of viral antigens and nucleic acid through immunohistology and in situ hybridization. Experimental infections in relevant animal models are important for understanding pathogenesis and evaluating therapeutic and vaccine strategies. The clinical management of patients with SARS includes respiratory support with intensive care when appropriate, prevention of nosocomial transmission, and the possible use of antivirals and immunomodulators. Aspects of its pathogenesis and transmission allowed the human disease outbreak to be quickly interrupted. The global response to SARS demonstrated that a rapid mobilization and coordination of relevant expertise is possible, when faced with a global emerging disease threat. It also highlighted the need for improved international regulations governing the reporting of and response to unusual infectious-disease syndromes.

Advances in the care of immunocompromised hosts have been driven by the development of a variety of increasingly potent immunosuppressive agents for use in solid-organ and hematopoietic stem cell transplant recipients. Routine prophylaxis with trimethoprim-sulfamethoxazole and antiviral agents has reduced the incidence of Pneumocystis pneumonia, nocardiosis, and respiratory, urinary, and gastrointestinal infections due to susceptible pathogens and cytomegalovirus (CMV) infection. Data from retrospective studies allow some generalizations about respiratory viral infections in transplant recipients. Direct detection of viral antigens in respiratory tract specimens using monoclonal antibodies may have increased sensitivity compared with the rapid, commercially available methods. The possibility that immune status plays a pivotal role in the transmission of severe acute respiratory syndrome (SARS) was suggested by the identification of individuals who appeared to be “super spreaders” of infection. Adenoviral disease is best described in pediatric liver transplant recipients but is also described in individuals following kidney, small bowel, lung, and heart transplantation. Vaccination is recommended annually, as much of the burden of influenza is related to secondary superinfections, graft rejection (in lung transplant recipients), or graft-versus-host disease (in HSCT recipients). Respiratory viral infections are a risk factor for graft rejection, particularly chronic graft rejection in lung transplant recipients.

This chapter highlights many aspects of the West Nile virus (WNV) that is an emerging pathogen, including its epidemiology in the Americas, new clinical syndromes, new modes of transmission and their impacts on public health, and progress in the development of therapeutics and vaccines. Virology, entomology, ecology, and pathogenesis are discussed only to the extent required to provide background for the main topics. Strains of WNV can be divided into two genetic lineages by phylogenetic analysis of the complete genome sequence or of the E protein gene sequence. The major mosquito vector in Africa and the Middle East is Culex univittatus, with Culex picilipes, Culex neavei, Culex decens, Aedes albocephalus, or Mimomyia spp. important in some areas. Further evidence that WNV could produce severe neurological disease was obtained in the early 1950s during experiments with WNV as an experimental cancer therapy. Advanced age is the most important risk factor for death. Surveillance data indicate that case fatality rates for persons with WNV neuroinvasive disease increase from 1% among persons under 40 years of age to 36% among persons 90 years old and older. Reduction of vector populations by public mosquito control programs is another mainstay of WNV prevention in North America. New clinical syndromes and new modes of transmission were identified, including transmission by transfused blood. This led to universal WNV screening of donated blood in the United States and Canada.

Retroviruses are a large and diverse group of enveloped RNA viruses in the family Retroviridae that replicate in a unique way, using a viral reverse transcriptase enzyme to transcribe the RNA genome into linear double-stranded DNA. Among viruses capable of causing zoonotic infections, defined for the purposes of this chapter as primary infections resulting from direct animal exposure, only some are capable of secondary spread. The approach advocated focuses on the study of individuals who are highly exposed to the blood and body fluids of primates, either through contact in laboratories and primate centers or through the hunting and butchering of wild non-human primate (NHP) game, and the detailed follow-up of individuals with zoonotic infections and their contacts for evidence of secondary transmission. The gorilla simian foamy virus (SFV)-infected persons in this study reported having received significant bite wounds from gorillas. Researchers have recently examined the diversity of human T-lymphotropic viruses (HTLVs) among primate bushmeat hunters in Cameroon who had documented SFV infections and who thus may be at risk for infection with additional simian retroviruses. Three new retroviruses previously undocumented in humans, including the simian foamy viruses, HTLV-3, and HTLV-4, have all been identified in persons exposed to the blood and body fluids of NHPs.

Enterobacteriaceae with reduced susceptibility to carbapenems are an emerging, worldwide problem. In most cases, the reduced carbapenem susceptibility is attributable to acquisition of one of a variety of ß-lactamases with carbapenem-hydrolyzing properties. Carbapenem resistance can be mediated by the acquisition of carbapenem-hydrolyzing ß-lactamases. In Japan, IMP enzymes have been recovered from isolates of Serratia marcescens and Enterobacter spp. and conferred resistance to ceftazidime and imipenem. Occasional isolates of Klebsiella pneumoniae carrying IMP metallo-ß-lactamases have also been recovered in Japan. Enterobacteriaceae carrying KPC ß-lactamases are emerging and pose serious challenges to therapy. Approximately 90%of KPC-possessing K. pneumoniae isolates are susceptible to polymyxin B, and the antibiotic exhibits a concentration-dependent killing effect. The addition of rifampin to polymyxin B provided bactericidal activity in 15/16 tested isolates in one report and resulted in a lower inhibitory concentration of polymyxin B. The fact that other carbapenem-hydrolyzing enzymes emerged prior to the commercial release of carbapenems also suggests that other properties of these enzymes may justify their existence or that other antibiotics in nature could be substrates and exert selection pressures. Also complicating potential antibiotic control strategies is the fact that other resistance genes often accompany the carbapenemase gene, including those for other ß-lactamases, amikacin, gentamicin, streptomycin, tobramycin, and trimethoprim-sulfamethoxazole. Due to these associations, it has been suggested that selective pressure from non-ß-lactam antibiotics (e.g., aminoglycosides) may encourage concomitant carbapenem resistance.

The burden of pneumonia prevented by conjugate pneumococcal vaccine may be underestimated by consideration only of the vaccine impact against X-ray-confirmed pneumonia. An analyses of the South African data suggest that the burden of disease prevented, or vaccine-attributable reduction (VAR) in disease burden, is higher against clinically confirmed pneumonia than against X-ray-confirmed disease. The impact of Haemophilus influenzae type b (Hib) conjugate vaccine on pneumonia in HIV-infected children has not been established, although the vaccine has activity against invasive Hib disease in these children similar to that of pneumococcal conjugate. There is abundant evidence that conjugate pneumococcal vaccines reduce the carriage of vaccine serotypes and in that way reduce the burden of invasive disease in the elderly. By inference, therefore, the vaccine should prevent both bacteremic and nonbacteremic pneumococcal pneumonia by herd immunity. A consistent finding in studies of pediatric viral pneumonia has been evidence of bacterial coinfection. The mechanism of the interaction may be as varied as the synergy between the pneumococcus and the influenza virus on apoptosis of neutrophils; virus-induced interleukin-1 and tumor necrosis factor upregulation of the platelet-activating factor receptor, which mediates bacterial invasion; or the influenza virus strain neuraminidase activity, which degrades mucin and enhances secondary pneumococcal pneumonia in mice. The vaccine probe approach allows direct investigation of the concurrence of bacterial and viral pathogens in children with pneumonia. Children (and possibly adults) hospitalized with presumed viral pneumonia require antibiotics, even if the bacterial superinfection cannot be confirmed by culture.

There is now accumulating evidence that receipt of prophylaxis or treatment with voriconazole and the severity of the immunosuppression appear to work in conjunction to favor increase in the incidence of zygomycosis in hematopoietic stem cell transplantation (HSCT) recipients. This increase in zygomycosis stands in contrast to prior reports of breakthrough infections seen when fluconazole or itraconazole was used for antifungal prophylaxis in HSCT recipients. The importance of iron availability in the pathogenesis of zygomycosis is underscored by the increased incidence of zygomycosis in patients on deferoxamine therapy or with iron overload. Sinus disease is estimated that about two-thirds of the cases of sinus zygomycosis occur in diabetic patients, often in the presence of diabetic ketoacidosis. Opacification of the paranasal sinuses, fluid levels, bone destruction, and osteomyelitis are the main radiographic findings associated with sinus zygomycosis. Among the different sites, primary pulmonary infection is more frequently associated with disseminated zygomycosis. The presenting signs, symptoms, and radiographic findings of zygomycosis are nonspecific and should be interpreted with respect to the underlying condition of the patient. Despite the recent advances in antifungal therapy, zygomycosis continues to be one of the most fulminant mycoses in humans. Correction of the patient’s underlying condition that predisposes to zygomycosis is one of the cornerstones of successful management of this devastating infection. Surgical debridement is of critical importance for the successful management of zygomycosis. Zygomycetes cause disease in a number of susceptible hosts with different predisposing conditions, including surgery, burns, trauma, diabetes mellitus, and treatment with deferoxamine.

This chapter discusses the military's clinical experience with severe infection caused by multidrug-resistant (MDR) Acinetobacter spp. in wounded personnel. Acinetobacter is primarily associated with nosocomial infections, accounting for 1% of nosocomial bloodstream infections (BSIs) and 3% of nosocomial pneumonias in U.S. hospitals, according to the Centers for Disease Control and Prevention National Nosocomial Infection Surveillance report. The majority of infections have involved wounds and osteomyelitis. There have also been a number of cases of bacteremia and a few isolated cases of pneumonia, empyema, peritonitis, urinary tract infections, sinusitis, and meningitis. Treatment of Acinetobacter infections in personnel stationed in or returning from Southwest Asia has become a major challenge. The majority of isolates were resistant to ampicillin, cefepime, ceftazidime, cefotaxime, ciprofloxacin, levofloxacin, gentamicin, tobramycin, piperacillin, and trimethoprim-sulfamethoxazole. Our current recommendation for treatment of active-duty personnel with Acinetobacter infections is directed based on susceptibility testing. The outbreak of infections with MDR Acinetobacter in military personnel has resulted in the institution of new infection control standards in military medical centers caring for these casualties. Osteomyelitis caused by MDR Acinetobacter seems to initially respond to a multifaceted approach, including appropriate surgical debridement, carefully selected antimicrobial therapy based on susceptibility patterns, and careful follow-up.

This chapter deals with the smallpox vaccine, its benefits, its risks, and the current state of its use. To ensure the future availability of appropriate amounts of smallpox vaccine, the U.S. government has funded the manufacture of tissue culture vaccine; the most likely candidate is an Acambis/Baxter Laboratories’ product, grown in Vero monkey kidney cell culture. It is critical to emphasize that the vast majority of vaccinees (nearly all) undergo vaccination without serious complications. The potential vulnerabilities to adverse events after smallpox vaccination are described. It is known that in the era when smallpox vaccination was routine, many patients with hypogammaglobulinemia but with intact T-cell function underwent smallpox vaccination without incidents, presumably because their T-cell immunity was sufficient to contain the virus and to rid the body of infected skin cells, preventing further spread to other areas of the body. It also known that a few individuals with progressive vaccinia virus infection had a lack of T-cell function but intact antibody capacity to various degrees. These individuals had lesser degrees of progression, often without viremic spread. Due to our lack of knowledge of the degree of susceptibility, if any, of individuals with non-T-cell immunodeficiencies, the recommendation has evolved to exclude such individuals from elective smallpox vaccination. The minimal reactions are split into noninfectious consequences of smallpox vaccination and infectious complications.