Influenza vaccine recommendations: Stop needling me!

Seasonal influenza is responsible for an estimated 200,000 hospitalizations and 23,000 deaths in the US annually. Each year influenza vaccines are produced based on the viruses forecast to become prevalent. There are two types of vaccine: inactivated influenza vaccine (IIV), delivered via injection, and live attenuated influenza vaccine (LAIV), delivered via a mist sprayed into the nose. Influenza vaccines typically have efficacies exceeding 60% and an estimated 46% of the American public relieves vaccine annually.

While many people are vaccinated each year, it is desirable to increase vaccination rates for at least two reasons. First, vaccine-associated immunity protects individuals from developing potentially serious or fatal disease. Second, high population coverage produces a herd immunity effect: those possessing vaccine-associated immunity cannot become infected and thus cannot infect others. This is especially important for protecting individuals for whom vaccines are contraindicated.

Individuals who are immunocompromised or immunosuppressed are such a group. Consider, for example, patients recovering from hematopoietic stem cell transplantation (HSCT) following myeloablative conditioning. In cases of imperfect donor-recipient match, patients may take immunosuppressive medications as prophylaxis against, or treatment for, graft versus host disease. During this process of immunologic tolerization, which can last months or longer, patients must avoid crowds and limit work/school and social interactions in order to avoid potentially fatal infections. And during this period it is critically important for caregivers and contacts to be vaccinated against influenza and other vaccine-preventable diseases so that they do not become infectious.

LAIV is contraindicated for caregivers of such persons in the Advisory Committee on Immunization Practices (ACIP) guidelines. Because LAIV contains live influenza viruses, a potential exists for transmission of vaccine strain viruses from vaccinees to other persons. The period of viral shedding in vaccinees is variable and relatively short lived. Vaccinated immunocompetent children, for example, shed vaccine viruses for less than 3 weeks, and evidence suggests that shedding may be much shorter lived than that. LAIV-associated shedding occurs in lower titers than is typically observed in disease-associated shedding caused by wild-type influenza viruses.

As several studies have demonstrated higher efficacy of LAIV relative to IIV in children (but see the footnote below), the ACIP has expressed

a preference for the use, when immediately available, of live attenuated influenza vaccine (LAIV) for healthy children aged 2 through 8 years, to be implemented as feasible for the 2014–15 season but not later than the 2015–16 season.

Higher protective efficacy of LAIV in children provides strong rationale for the ACIP statement. Moreover, promoting LAIV as an alternative to IIV in older patient populations may result in increased coverage in those who avoid vaccination due to fear of needles. I wonder if increased use of LAIV might pose additional risk to immunocompromised persons, however, in terms of inadvertent exposure to recent vaccinees shedding live, though attenuated, influenza viruses. Such patients may need to become more meticulous in screening visitors and contacts who may have received LAIV recently.

Footnote: During 2013-2014 there was no measurable effectiveness for LAIV against influenza A (H1N1) among children enrolled in effectiveness studies. The reasons for this are unclear.

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Better understanding the home care environment

While hospital acquired infections (HAIs) threaten the wellbeing of many patients, those who are immunocompromised or immunosuppressed, such as hematopoietic stem cell transplant (HSCT) recipients, are at particular risk. Such patients are vulnerable to infections from other people (e.g., visitors, other patients, HCWs), the environment (e.g., surfaces, unfiltered air, linens), and themselves (e.g., pathogens shed from their own GI tract).

Infection is a significant cause of mortality in this population in the months following transplant and considerable care is taken to protect patients in the hospital. When they are well enough, recipients are released to go home and receive care there, with periodic visits to clinic. Typically, they and their home care providers are trained on how to prevent infections (e.g., through appropriate central venous line care, wearing of masks, etc), and sometimes home care nurses visit to ensure appropriate care is delivered. Medical supplies (infusion pumps, line care kits, saline, heparin, etc) are delivered; the house becomes a mini-hospital for care of the patient.

The approach seems to work well from an infection prevention perspective, but it's hard to be sure given the paucity of studies in the literature on the incidence of infections in home care populations. If the home care environment is protective to the patient, it's important to understand why that is, and if it's a threat, it's important to know that as well. Understanding the risk of infection in this patient population at home versus in highly controlled environments is important.

On the one hand, there's a different infection pressure in the home relative to a hospital. Presumably it's decreased at home, as there are no surrounding patients and there are fewer contacts with HCWs per unit of time. On the other hand, there is risk from contact with their home care providers, who often interact with many other people outside the home daily.

Moreover, the microbial environment of the home, as it relates to hematology/oncology patient health, doesn't seem to be as well characterized as that of the hospital environment. Looking through the literature that does exist isn't entirely reassuring. Whereas in bone marrow transplant (and related) wards there is extensive guidance on air filtration, cleaning procedures, and protocols for visitors, the analogous issues (e.g., ventilation, dust, cleaning) in homes are much more variable. The presence of pets may add additional risk. Furthermore, recovering patients often travel to and from hospital clinics on a daily or weekly basis. The automobile can also be a mode for infection, as has been pointed out recently for Legionella.

Improved surveillance for home care infections could lead to a better knowledge of the epidemiology of these infections and potentially identification of modifiable risk factors. 

(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)