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On October 23rd, the New Jersey Department of Health confirmed an outbreak of adenovirus at the Wanaque Center for Nursing and Rehabilitation. At that time, 18 children had become ill and 6 had died. Since that report and the resulting media coverage, an additional 9 children have been diagnosed with the infection, and there have been 4 more fatalities.

Adenovirus, or more accurately the family of adenoviruses, isn’t one of those sexy infectious agents that gets a lot of press, like that flesh-eating bacteria or those brain-eating amoebas. But it’s a very safe bet that anyone reading this post, unless they are an extremely precocious toddler, has fought off more than one adenovirus serotype during their lifetime. In fact, adenovirus infections, which are common in every country and in every season, are the culprit in up to 10% of all febrile illnesses in young children and virtually 100% of adults have antibodies in their blood signaling a prior infection.

But adenovirus infections aren’t commonly fatal. They aren’t even commonly severe. They typically just cause what would be described as the common cold, though perhaps are more likely to be accompanied by a sore throat and a pink eye. That being said, they certainly have the potential to cause severe and fatal disease, particularly in children with compromised immune systems. And they are also associated with a number of less common, and much more interesting, presentations.

A brief, yet satisfying primer on human adenovirus infections!

As previously mentioned, there isn’t just one adenovirus out there ruining people’s week with a bad cold and, or ending the lives of an unlucky few. There are actually 7 species of adenovirus that infect humans, designated as A through G, which consist of more than 60 serotypes between them. A few of these, which I’ll discuss shortly, are more likely to cause problems than others.

Adenoviruses are very immunogenic. When we are infected by a particular serotype, there is typically a vigorous response from both the innate and adaptive immune system. At the same time, these viruses are known to make use of a number of immune-modulating mechanisms to evade recognition and survive long enough to replicate. These mechanisms, which are way beyond the scope of this post, may also play a role in the persistent shedding of adenoviruses for weeks after a patient has recovered from the acute illness.

Persistence of virus in the body can last much longer in those with compromised immune systems. There are also reports of acute adenovirus illness occurring in the recipients of an infected solid organ transplant. And there are concerns, thus far unproven, of the possibility of herpes-like reactivation of prior adenovirus infection as a result of the extreme immune suppression required for bone marrow transplantation. The hypothesis is that there may be latent virus hanging out in tonsillar tissue or intestinal lymphocytes potentially for years.

After most adenovirus infections, antibodies are produced which are specific to, and reduce the likelihood of future infection with, that serotype. Cell-mediated immunity, particularly involving the production of memory CD+ T cells, plays the most important role, however, in acquiring protection against multiple serotypes. This is why immune deficiencies, especially those involving cell-mediated immunity, are present in the majority of fatal cases.

As in the outbreak making the rounds over the past couple of weeks, adenovirus infections frequently pop up when people, usually young children, are clustered closely together. Daycare centers, summer camps, army barracks, and even hospitals have been associated with large numbers of cases and difficulty containing spread from person to person, which can occur via multiple routes. Breathing in floating particles, eating contaminated foods, and touching contaminated surfaces are all possible routes of transmission. It’s a hardy virus that requires bleach, formaldehyde, or killing it with fire to remove it from hard surfaces.

Serotypes 3, 2, 1, 4, 7, and 14 have been the most commonly reported over the past 15 years or so, but you have to take this information with a large grain of salt. We really don’t have a good grasp of which serotypes cause the most illness because the overwhelming majority of patients aren’t tested since they have mild disease. And specific typing isn’t always performed in patients with severe, or even fatal infections. And while testing has improved over recent years with more widespread availability of PCR technology, it is far from perfect.

The variety of clinical presentations associated with adenovirus infections is astounding, and depends on the specific serotype as well as the age and immune function of the patient. Though the most common picture is that of a typical viral upper respiratory infection, it is more likely to also involve sore throat that mimics infection with group A streptococcus (“strep throat”) and conjunctivitis (“pink eye”). Lower respiratory involvement, particularly in young children, is also common in infection with several serotypes, but serotype 7 is the most significant.

Another presentations of infection with various adenoviruses is pharyngoconjunctival fever, which is a known mimic of a dangerous childhood vasculitis called Kawasaki Disease. In fact, this condition is so worrisome and notoriously squirrelly in its early course, that our gain is turned up so high (11?) we know that we are mixing it up with an adenovirus infection sometimes. But a missed diagnosis of Kawasaki is just too dangerous to risk.

Adenovirus is also associated with diarrhea. In fact, it’s to blame in up to 10% of acute diarrhea episodes in young children. The liver, heart, skeletal muscle, urinary tract, and brain are also known targets of this group of viruses. But the most dangerous presentation is disseminated infection. It’s rare, and it is seen even in patients with normal immune systems, but 60-80% of patients die when the virus spreads throughout the body.

With some specific clinical presentations, we have a decent idea which serotypes are going to be involved. For example, serotypes 3 and 7 cause most of the pharyngoconjunctival fevers and 11 and 21 cause most cases of hemorrhagic cystitis (essentially an inflamed and bleeding bladder). Got diarrhea? That’s 40 and 41 for the most part. But the more common respiratory infections can be caused by many different serotypes, though severe respiratory disease is often associated with serotypes 3, 4, 7, 14, and 21. Of course, any serotype can kill someone who can’t mount an immune response.

Clear as mud, right?

The New Jersey pediatric nursing home outbreak

Outbreaks of adenovirus are common. As I mentioned above, these can happen in daycare centers, summer camps, and even neonatal intensive care units. It’s easy to spread and difficult to disinfect surfaces where it can live for weeks. Outbreaks of eye infections have been associated with insufficient chlorine levels in public swimming pools as well. So news of several cases at a childcare setting wasn’t a surprise because this sort of thing happens hundreds of time each year.

What is different about this outbreak is the number of deaths. Ten dead children in a matter of a few weeks is horrific. It should come as no surprise though that this facility cares for children who are medically fragile. I could not find information on any specific diagnoses, but several outlets have described the children involved as having compromised immune systems. The specific serotype involved in this outbreak is 7, which is known to cause more severe respiratory symptoms.

Also not surprising are the questions being raised about the care provided at this facility. Piecing together multiple reports, it appears that this likely isn’t a case of negligence, at least not egregiously so. Like many such facilities, they have had minor deficiencies in the past that were addressed. The state inspectors showed up unannounced on October 21st, two days prior to the outbreak being announced publicly, and found that hand hygiene wasn’t ideal but that the facility was doing a decent job in response to the outbreak.

I don’t think we should rush to judgement here. Preventing spread of adenovirus is very difficult. In addition to the challenges in disinfecting hard surfaces, patients can shed the virus for weeks. And patients with poor immune function can shed it for months. But handwashing, though an incredibly important means of reducing spread of most infections from patient to patient, isn’t particularly helpful with adenovirus because soap and water, even those alcohol scrubs, don’t reliably get rid of it. The report found that the things that matter, such as gloves and other protective barriers, were appropriately being used.

Why don’t we have an adenovirus vaccine?

We actually do have a safe an effective vaccine against adenovirus, just not every serotype and you can’t have it. At least you can’t have it unless you are in the United States military. Sorry.

Outbreaks of acute respiratory disease in military training camps were a recognized problem for many years before it was discovered that adenovirus infections were to blame. In 1971, recruits began taking an oral live vaccine against serotypes 4 and 7 and cases plummeted. In 1996, the manufacture just up and quit manufacturing the vaccine, resulting in the resurgence of respiratory infections and several fatalities.

In 2011, a new version of the oral vaccine was brought back into service, leading to a significant decrease, about 100-fold if you’re keeping score, of adenovirus infections in trainees. Go figure. The new vaccine still just covers serotypes 4 and 7, which is obviously good. Unfortunately in 2005 serotype 14 emerged as a significant threat in this population. Since the vaccine does provide some cross-protection against 14, it appears that the gap in vaccine coverage is what allowed serotype 14 to get a foothold.

Conclusion: Wait, there’s a vaccine?

Adenovirus infections are extremely common and typically benign. But sometimes they aren’t, as evidenced by the several dead children at this New Jersey nursing home. In this particular case, and in many others it would seem, a safe and effective vaccine against the very serotype that killed these kids sure would have been nice.

It certainly seems that use of the available vaccine, which costs $150 per person, would be cost effective, particularly if only high-risk populations are involved. There is of course the issue of using a live vaccine in patients with certain immune deficiencies. Well, vaccinate the workers and caregivers surrounding these children and provide a cocoon of protection. We should at least consider expanding its use in my opinion.