What are we doing to ourselves?

An interesting idea emerged from conversation over dinner with a colleague recently: While it is clear that hand hygiene is foundational for both hospital and community infection prevention, there may be an immunological price to the now all-pervasive focus on hand hygiene in the general population.

Let me explain. Hygiene is one of the pillars of public health and infection prevention, though we still struggle to practice what we know globally. Semmelweis showed us the need for clean hands in the clinical environment, and the notion of ridding hands of germs has evolved since then. Today, alcohol based hand rubs (ABHRs) are prominent in daily life. People rub their hands with "hand sanitizer" before eating out, after riding the bus, after using the restroom, and even at their desks throughout the day. What could possibly go wrong with such an awareness of hand hygiene?

Potentially, nothing. The importance of hand hygiene is undisputed and indisputable in infection prevention. That said, I often see people using ABHR very frequently throughout the day and it makes me wonder if such use of ABHR is eroding not only the transient flora of our hands, but also the resident flora. What is on our hands ultimately ends up challenging the immune system, via oral ingestion, absorption through rubbing the eyes, or inoculation via scrapes and cuts on the hands and fingers. Constantly challenging the immune system with a diversity of biologic agents gives rise to broad immunity.

Might we be eroding the frequency and diversity of that challenge, and thus the strength and diversity of the immunological protection, with such pervasive use of ABHR? This general notion, that cleanliness might have deleterious, unintended community-level consequences, is not new. It's been discussed within the context of polio, for example, and there is speculation about inverse relationships between cleanliness and asthma.

I'll close by noting that ABHR is but one of the several tools society currently employs to kill the spectrum of microbes in our immediate environment. There are also antimicrobial wipes and antimicrobial soaps. The weapons of mass microbial destruction are many and proliferating. They obviously have their place in the clinic but, regarding their sometimes near-obsessive use in the community, are they helping or hurting us in the long run?

(image source: David Hartley)

A fictional hospital story: Is it really fictitious?

This vignette is an amalgam of conversations with several colleagues over the last couple years. It is completely fictitious.

Surgical site infections (SSIs) had increased in the last year at Generic General Hospital (GGH) and the president of the hospital wanted action. The infection control staff met and decided upon a set of interventions for SSIs that they then implemented in their surgical step down unit. The interventions included a campaign to raise awareness of SSI risks, an increased emphasis on hand hygiene, and the implementation of a new wound care protocol. During a 60 day trial period, intensified surveillance in the unit suggested that these interventions had reduced SSIs by 50 percent.

While it might appear to be a success story, the CEO of Generic Medical System (GMS), the owner of GGH and several sister facilities, including Generic Rehabilitation, Generic Skilled Nursing Care, and Generic Community Oncology, was curious. When briefed on the success, she wanted to know if the intervention was sustainable in the step down unit and whether it was generalizable to infection control in other GMS institutions, which also had moderate infection rates. She further asked if the resources taken from the small infection control budget at GGH for this pilot had resulted in increased incidence of HAI in other hospital wards and units. And of course she needed to know if the interventions would save money in the short and longer terms.

At a meeting called to address these questions, GGH staff decided that only continued surveillance would answer the issue of sustainability. They believed the intervention was generalizable to sister facilities (but when challenged later, they couldn't explain why, other than offering “expert opinion”). The staff didn’t have data on potential changes in the incidence of infection in other parts of GGH because the money and resources dedicated to the step down unit pilot program had resulted in decreased surveillance in other wards. One of the three infection control nurses covering the entire hospital was dedicated to the pilot, leaving a 33% reduction in person-power needed to collect and chart the statistics in the rest of GGH. Nobody had any idea of cost savings.

The CEO wasn't pleased. She explained to her leadership team the importance of sustainability, generalizability, avoidance of unintended consequences, and improving the bottom line. She noted that hospitals are zero sum enterprises: they have finite budgets, and in the absence of grants or donations to support trial patient safety interventions, what is focused on one activity must be taken away from other activities. In the example of the SSI interventions, she noted that the intensified surveillance dedicated to assessing that program diverted surveillance resources and left “blind spots” elsewhere in the institution.

She illustrated the point in the following way. Of the $10K GGH annual budget for HAI prevention, $2K was spent on posters and buttons promoting hand hygiene in the step down unit. Normally, that $10K was evenly distributed amongst wards across the hospital, but with this special project only $8K was left for routine prevention activities in other units. It wasn’t unreasonable to expect that there might be increases in HAIs in those wards, assuming the yearly $10K investment was having an effect in the first place.

To illustrate, she asked them to suppose that had been an increase in HAI in the transplant unit following the decreased prevention investment there. During the study SSI evaluation period -- the period of intensified surveillance in the step down unit -- it probably would have gone unnoticed, as part of the infection control staff were assessing the interventions in the surgical step down unit, instead of collecting routine HAI surveillance data in the rest of the hospital. In that case, the negative impact in the transplant ward would have been an unobserved and unintended consequence of the otherwise successful interventions in the surgical step down unit.

The CEO lectured her staff on the phenomenon of unintended consequences, cautioning them that the degree to which changes in standard operating procedures (e.g., hospital infection control or other patient safety interventions) result in unintentional consequences is unknown and requires additional research. She lamented the lack of a research group to address these and related issues. Perhaps one day, she thought, someone would do the research and develop evidence-based guidelines on the relevant issues. Until then, the leaders of GMS had limited options for reducing HAI throughout their network of facilities.

There are several key points illustrated in the vignette. First, unintended consequences of seemingly good ideas can occur. Second, existing programs can be impacted when new initiatives are launched if additional resources aren't provided. Third, because generalizable approaches are desirable, it is critical that researchers anticipate questions such as those the CEO asked her staff.

(image source: Wikipedia)

Bacterial interference and the deliberate colonization of patients

Beginning in the mid-1940s and lasting until the late 1960s, the world saw a dramatic pandemic of staphylococcal infections. This post describes a curious historical episode in research aimed at controlling Staph outbreaks toward the end of that period.

One of the fundamental ideas in ecology is that, depending on the environment and properties of individuals, some types of individuals can out compete other types. When this happens, the less successful individuals can become incompletely or completely displaced. In the 1960s, the idea of microbial competition was actively applied to clinical medicine in a fascinating series of studies, which ultimately ended in tragedy. These studies investigated an idea known as "bacterial interference": the inability of a strain of a bacterium, in this case Staphylococcus aureus, to colonize a particular site of a host following deliberate colonization of that site with another strain of the bacterium.

The notion of using bacterial interference for controlling or preventing epidemics of Staph in hospital nurseries was evaluated and several trials were carried out. How this idea came about and how the studies were done is fascinating and is described in Boris, 1968 and references therein. As the nose is one of the main ecological niches of Staph aureus in humans, newborns were deliberately colonized with an apparently apathogenic strain of Staph aureus (called "strain 502A", after the phage typing scheme then in use) by swabbing the nose and the umbilical stump shortly after birth.

The results were dramatic. Clinical and epidemiological observation revealed a striking lack of staphylococcal disease in the infant study population and in their families. As Shinefield et al 1966 summarized the situation:

It has been clearly demonstrated that artificial colonization of the nasal mucosa of newborns with one strain of Staphylococcus aureus interferes with subsequent acquisition of a second strain of S aureus. This deliberate colonization of infants shortly after birth with a staphylococcal strain of low virulence (strain 502A) has been employed to protect infants from colonization and disease with virulent epidemic strains of S aureus.

The studies on children in university hospital environments were extended to children in a community hospital setting in Light et al, 1967, and found to be effective. Boris et al 1964 applied the idea to adults.

There were reservations discussed in the literature, however. An echo of that concern can be seen in an August 3, 1968, issue of the British Medical Journal, in a short report on a NEJM paper by Light et al describing observations of bacterial interference (not involving deliberate colonization) between Staph aureus and Pseudomonas. In the report, an anonymous author referred to the trials evaluating deliberate colonizations, mentioning that

Ethical objections have been raised to this procedure, but it seems no more objectionable from this standpoint than the use of living vaccines.

Unfortunately, adverse effects soon became known, including a death from infection with the 502A strain. Writing in 1972, Houck et al reported on complications associated with bacterial interference trials. A passage from the abstract describes the death due to septicemia,

An infant of a diabetic mother developed septicemia and meningitis, probably secondary to passing an umbilical vein catheter through the colonized umbilical stump. Staphylococcus aureus 502A and Escherichia coli were isolated from blood culture before death and from autopsy cultures of blood and peritoneum. A meningeal culture grew S aureus 502A. Gram-positive cocci were identified in liver, lung, heart, and meninges. 

They also noted that 

Only two (0.5%) minor 502A infections were seen in 444 spontaneously colonized infants. The benefits of S aureus 502A programs far outweigh their hazards. Disease due to the 502A strain is more frequent when the inoculum applied to the infant is large than when it is kept below 4,000 bacteria. The fatal case emphasizes that bacteria of extremely low virulence may produce serious disease in compromised hosts and that catheterization through a contaminated umbilical stump may induce bacteremia.

Although I haven't done an extensive search for bacterial interference programs after the publication of Houck et al 1972, these activities seem to have terminated after the death.

There are so many things to ponder regarding this curious episode in the 1960s, including how the one death in a few hundred patients, interpreted by Houck et al as a risk far outweighing the hazards, contrasts with current thresholds for attributable risk. Another is the remark that pathogens "of extremely low virulence may produce serious disease in compromised hosts", and how that notion is similar to the practice of avoiding live virus vaccines in recovering HSCT patients during immune system reconstitution.

Recently, Mukherjee and coworkers observed that the beneficial fungal yeast Pichia inhibits growth of pathogenic fungi, including Candida. Candida causes oral candidiasis (thrush) in immunocompromised and immunosuppressed patients. This is exciting; one of the study authors commented

One day, not only could this lead to topical treatment for thrush, but it could also lead to a formulation of therapeutics for systemic fungal infections in all immunocompromised patients . . . In addition to patients with HIV, this would also include very young patients and patients with cancer or diabetes.

I think it's important to know about the history of bacterial interference interventions so that past issues can be recognized and actively avoided in related future investigations.

(image source: Wikipedia)