John Bartlett's Take on Critical Infectious Disease Topics

New Pathogens, New Epidemics, and Super-Spreaders

John G. Bartlett, MD

Disclosures

March 10, 2017

In a new series on leading-edge developments in the field of infectious diseases, Dr John Bartlett comments on the wide array of infectious disease threats to human health that appeared in 2016 and have continued to be problematic in 2017. This first article in the series focuses on emerging pathogens, outbreaks and epidemics, and the "super-spreaders" responsible for the rapid-fire transmission of global infectious diseases.

New Pathogens

Several new or emerging pathogens have been described recently.

John G. Bartlett, MD, Professor of Medicine, Emeritus, Johns Hopkins University School of Medicine

Candida auris. The first seven cases involving this recently defined fungus were reported in the United States in November 2016.[1] The Centers for Disease Control and Prevention (CDC) warned that C auris appears to be transmitted primarily in healthcare facilities and has caused several hospital-based outbreaks in the United States and Europe.[2,3] This fungus is difficult to identify and is relatively resistant to most antifungal agents, in part because it forms an antifungal biofilm.[4] The CDC issued an alert concerning this fungus after on an outbreak occurred in England that affected 40 patients in the intensive care unit, despite aggressive infection control efforts.[5] All cases should be reported to the CDC.

[Editor's note: At the time of publication, the CDC reports that the emergence of C. auris is ongoing in the United States, particularly in New York State ( see Candida auris Cases in the United States ). There are now 35 cases reported, a large increase since November 2016. Healthcare providers must be aware of the seriousness of multidrug-resistant C. auris, how to identify and report it, and institute infection control measures ( see Candida auris Interim Recommendations for Healthcare Facilities and Laboratories ).

Mycobacterium chimaera. This newly described pathogen has been reported to cause devastating infections after open-heart surgery. The apparent source of these infections was an aerosol generated by contaminated Stockert 3T heater–cooler devices used intraoperatively for extracorporeal circulation, according to a review of 18 cases.[5,6] On the basis of these reports, the CDC and the US Food and Drug Administration issued warnings about the risks associated with these specific devices. Note that M chimaera is a distinct species from M avium.

Fusobacterium necrophorum. This fastidious obligate anaerobe is now implicated in the development of pharyngitis and peritonsillar abscesses, although it is best known for its role in Lemierre syndrome.[7–10] A review of 300 children with pharyngitis in Boston showed that 79 children (26%) had group A streptococcus, 10 (3%) had F necrophorum, and four (1%) had group C/G streptococcus.[11]

Few labs will attempt to detect F necrophorum because of complexity, in terms of the time, skill, and cost required to culture the anaerobes in the upper-airway flora and to identify this agent. The good news is that a point-of-care polymerase chain reaction is being developed that will detect all three treatable agents that cause pharyngitis: group A streptococcus, group C streptococcus, and F necrophorum.

The 2016 guidelines for the treatment of pharyngitis from the American College of Physicians[12] recommend that antibiotic treatment should be restricted to patients with a positive rapid group A streptococcal test. However, some authorities, including Dr Robert Centor ( known for the Centor criteria for pharyngitis ), note that F necrophorum plus group C streptococcus actually cause a substantial number of treatable cases, making these antibiotic restrictions unnecessarily strict.[7–10] Dr Centor favors metronidazole for the treatment of Fusobacterium species, but some prefer to use penicillin for all three pathogens.

Enterovirus D68. This agent has been detected in multiple patients presenting with severe respiratory illnesses, with or without central nervous system involvement.[13,14] The pathogen appears to represent a new clade (clade D) in the EVD68 strains that were epidemic in the United States in 2014, when 1153 cases were reported in 49 states.[14–16]

Most of the patients had a severe respiratory tract infection. The central nervous system consequences include an acute flaccid paralysis, similar to paralytic polio, which occurs almost exclusively in children. MRI imaging has shown cervical spinal cord gray-matter lesions.[16] Cerebrospinal fluid analysis obtained within 7 days of the onset of respiratory tract symptoms has shown pleocytosis, and bronchoalveolar lavage samples are usually positive for EV-D68.

All patients survived, and most had neurologic improvement, although with some residual weakness at 1 year.[17] More recent reports also implicate an alternative agent from the Picornaviridae family (cosavirus Z-1) in some cases of nonpolio acute flaccid paralysis, and enterovirus C105 has been implicated in a similar syndrome in Europe and Africa.[18,19]

Vibrio parahaemolyticus ST631. This new strain of V parahaemolyticus is the leading cause of foodborne disease related to shellfish (primarily raw oysters) in North America. At least 35 cases involving this new strain have been reported in the United States. It is thought that the change in strains reflects global warming, which is primarily having an effect on the Atlantic Ocean habitat.[20]

New Epidemics

The world of infectious diseases has always been characterized by epidemics of the unexpected. Examples in the past 30 years include Staphylococcus aureus toxic shock syndrome, hepatitis C, AIDS, the NAP-1 strain of Clostridium difficile,West Nile virus, Lyme disease, anthrax (used in the 2001 bioterrorism attack), iatrogenic fungal meningitis, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), S aureus USA 300 strain, Legionella pneumophila, multiple foodborne outbreaks (Salmonella, Listeria, Escherichia coli O157), and, most recently, the Ebola and Zika viruses.

The world of infectious diseases has always been characterized by epidemics of the unexpected.

The CDC reports that in recent years, there has been a significant increase in Legionnaires' disease in the United States, with at least 5000 patients infected in 20 outbreaks.[21] They also estimate that about 48 million Americans (about one in six) acquires a foodborne infection each year.[22] The CDC now uses gene sequencing to identify sources of foodborne disease, Legionella outbreaks, and other epidemics.[23] This powerful epidemiologic tool can provide irrefutable evidence of an outbreak's source, leading to rapid intervention.

Major outbreaks in the past year include more than 400 reported cases of mumps, many of which occurred on college campuses.[24] Previous mumps vaccination does not exclude this diagnosis. The recommendation is for students to receive a third MMR vaccination if they have already had two doses.[24] There have also been many cases of measles, primarily in unvaccinated people.[25] Possibly the most unusual outbreak was the "zombie outbreak," which involved 18 people and was caused by a synthetic cannabinoid circulating in a New York City neighborhood.[26]

A review of epidemics in the winter would not be complete without mention of influenza.[27] This year brings no surprises; H3N2 and H1H1 are the strains to watch for. Perhaps more interesting is the enormous number of recombinations, largely from poultry, including H5N5 in Nigeria and Poland; H5N8 in China, the Czech Republic, the Netherlands, and South Korea ; H7N6 in Chile; and N7H6 in Chile and China.

These observations are important to human health because of the increasing ability of influenza viruses to cross the poultry barrier (bird flu) and the swine barrier (swine flu), which led to a highly lethal global epidemic starting in 2009. Also of concern is the increasing resistance of influenza strains to available antiviral drugs. Thus, the production of vaccines that keep pace with changes in influenza strains and the development of antivirals for treatment will be a challenge.

Ebola and Zika are possibly the two most concerning recent epidemics, particularly because of their serious health consequences, such as the birth defects and Guillain–Barre syndrome associated with Zika virus infection. One particularly unusual finding is the persistence of the Zika virus in the host, primarily in semen and blood; it can be transmitted months after all clinical evidence of infection has resolved.[28]

This postrecovery viral persistence has also been noted with Ebola infection. The consensus that the CDC and World Health Organization response was far too slow prompted Bill Gates to chastise the infectious diseases community for not being better prepared for devastating epidemics such as Ebola.[29]

The rebuttal is the extraordinary diversity of pathogens summarized above. It is almost impossible to plan for the next unpredictable epidemic because the challenges and pathogens are epidemiologically unique. Furthermore, the benefit of hindsight shows that the $113 million investment to establish 55 Ebola centers in the United States[30] was far too much and far too late. In contrast, it appears that the predicted course of the Zika epidemic in the United States— starting in Florida and Texas and then moving up the Atlantic coast— has been largely accurate.[31]

But planning for the next "big one" might be easier because of known factors, such as global warming,[32] the current experience with Zika, and the earlier experience with West Nile virus—another mosquito-borne arboviral infection—which started in New York City and then traversed the country.[33–37]

A response is needed not only for Zika, but for epidemics of other mosquito-borne arbovirus infections, including dengue, chikungunya, Japanese B encephalitis, St. Louis encephalitis, Usutu, Eastern and Western equine encephalitis, Mayaro, and yellow fever.[38]

Most of these arbovirus infections are associated with similar climate risks, but they are also associated with potentially severe arthritic or central nervous system complications.[36] The common denominator appears to be the need for effective mosquito control in vulnerable geographic areas.

Particularly worrisome is chikungunya, a name meaning "bent-up," in reference to the disabling arthritis associated with the infection that can last months or years.[39,40] The disabling long-term consequences are well illustrated by the experiences of policemen who became infected when they attended a meeting on Reunion Island during an epidemic. About half of this cohort still had disabling arthritis at 30-month follow-up.[41]

The Aedes aegypti mosquito, prevalent in the United States, is responsible for most of the country's mosquito-borne infections. In 2016, about 500 cases of chikungunya were reported in the United States. Nearly all were imported by returning travelers, although some were locally transmitted in Florida.[36]

The Aedes aegypti mosquito... is responsible for most of the country's mosquito-borne infections.

Anthony S. Fauci, MD, and David M. Morens, MD, from the National Institutes of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health, predicted 3 years ago that chikungunya would become an epidemic problem in the United States.[39] Thus, mosquito control for this and other arboviral pathogens is critical, particularly in vulnerable locations.[29] This explains the high priority given to the experimental vaccine (AGSv) now in phase 1 trials at NIAID, which is intended to protect people against all mosquitoes and the diseases they transmit.

Super-Spreaders

The relatively new and important concept of super-spreaders in the infectious diseases world emphasizes the need for better guidance in predicting and responding to selected pathogens with somewhat unusual routes of transmission. For example, a physician was hospitalized with SARS in Hong Kong, and this single patient became the source of more than 600 cases in four countries, including 31 cases in healthcare workers and 143 deaths.[42] In another outbreak, a businessman hospitalized for pneumonia involving MERS in South Korea in 2015 became the source of 186 cases and 33 deaths.[43–46] In both examples, molecular testing showed that the hospital environments occupied by these patients were loaded with the respective pathogens.[45,46]

Another example is the epidemic of infections involving highly resistant Enterobacteriaceae at the National Institutes of Health Clinical Center.[47,48] The result was 18 infected patients and six deaths caused by infections with various species of Enterobacteriaceae. The source was microbial resistance elements that were widely distributed in the hospital environment and detected by gene sequencing,[47,48] prompting the CDC to caution healthcare workers about the need for environmental decontamination. The "super-spreaders" appellation was originally applied to source patients, but the CDC cautions that it is the nosocomial super-spreader environment that is the problem.

Also relevant here is the experience in the United Kingdom, where gene-sequencing technology was a critical component in the extraordinary success in reducing C difficile infection rates.[49] This adds a whole new dimension to infection control, one that promises to be far more readily available as gene sequencing becomes faster and cheaper. In fact, the lab report of the future might state that the pathogen in your patient is the same as one from a patient in India or from another patient on the same ward.[50]

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