Airborne transmission of influenza; Legionella in the Bronx

Today’s blog post is about the Harvard Airborne Infection Control Course and the high profile Legionella outbreak in the Bronx. At the Airborne course yesterday, we were in the laboratory at Northeastern University doing experiments like measuring velocities in ducts and testing the efficiency of HEPA filters. It was fun and gave me a new understanding of the complexity of designing safe and effective ventilation systems in healthcare facilities. Although the majority of the Airborne course has focused on TB, we also had a great lecture by Dr. Al Demaria from the Massachusetts Department of Public Health about the airborne transmission of influenza and other pathogens (measles, smallpox, anthrax, etc). I have a personal as well as professional interest in the transmission of influenza, as I think I caught the flu in the hospital last winter.

What I enjoyed the most about Dr. Demaria was his historical perspective on influenza transmission. Dr. Demaria lectured us about two important studies, the historic 1961 VA Hospital Livermore Study and a 1979 Alaska airplane study. It’s worth knowing that influenza is usually thought to be transmitted by large droplets which will typically fall to the ground within 3 meters of the infected person and be expected to infect individuals in direct contact, or via surfaces. Airborne transmission (small particle aerosols, < 10 µm in mass diameter) also could play a role. The extent of airborne transmission is uncertain, however, and would be important in the event of novel pandemic influenza virus with high pathogenicity and sustained human-to-human transmission.

In the Livermore study, UVGI was installed in one VA building and not in another (see figure below), and the influenza attack rate was much lower where UVGI had been installed. This raised the possibility of airborne transmission. The Alaska study was of a commercial airliner that was delayed on the tarmac in Homer, Alaska for 4.5 hours with a poorly functioning ventilation system. The risk for transmission of flu was related to the amount of time passengers spent on the plane and not on their proximity to the index case, and airborne transmission was thought to be likely. However, some people later rationalized that the Livermore and Alaska studies were isolated events and had not been replicated. There were also doubts that the passengers on the Alaska airplane hadn’t walked around and touched each other, thereby spreading flu by droplet/contact instead of the airborne route. The lack of attention to the Livermore/Alaska studies affected the influenza infection control guidelines released by the government many years later. As we learn more about the architectural/ engineering approaches to reducing TB transmission in healthcare facilities, we also must contemplate other pathogens such as influenza, measles, and even norovirus which may be transmitted by the airborne route.

I also wanted to write a bit about the Legionella outbreak in the Bronx. I am certainly no expert, as I’ve only taken care of two patients with Legionella in my career and have never done any research in the field. But I do know that Legionnaires’ disease is a cause of severe pneumonia and Legionnaires’ cannot be differentiated from typical bacterial pneumonia (i.e. Pneumococcal) by history, exam, or chest x-ray. Therefore, the Legionella urine antigen test must be sent, and it is an imperfect test. It only detects serotype 1 (thankfully the Bronx outbreak was serotype 1) and it has low sensitivity (although it has high specificity, so it’s a good “rule-in” test).

Focusing on the transmission of Legionella, today’s New York Times article described it as an “airborne illness” that should be unpacked a bit. First, the bacteria itself. Legionella lives in natural aqueous environments (i.e. lakes, streams, and oceans), and especially loves warm water. Think about that the next time you are taking a hot shower in that fancy hotel. Interestingly, amebas in the water support the growth and survival of legionella. Legionella can multiply thousands of times within the amebas and these organisms often live together in a slimy biofilm. When the biofilm is disrupted, there can be a sudden and massive release of Legionella bacteria into the water. If this water is then aerosolized, people can get sick.

Many people remember that the 1976 Legionnaires’ disease outbreak at the Bellevue-Stratford Hotel in Philadelphia was due to a cooling tower. After inhalation of an infectious aerosol +/- microaspiration of Legionella into the lungs, a fraction of people get sick. Usually, the people who get sick are in closer proximity to that cooling tower, water spa, water fountain, or water mister. The duration of exposure and presence in an area downstream of the contaminated device are also risk factors. (Importantly, Legionella is not spread person-to-person, so there will never be an explosive pandemic of Legionella around the world like there can be with influenza).

What about the description of Legionella as “airborne?” It’s different than TB or measles because legionella depends on the interaction of air and water whereas TB/measles are spread in the air alone. Lets take the example of a water cooling tower (see below). The tower has a pipe providing incoming water from the building’s condenser, air intakes for fans, and demisters. Aerosolized water enters the building through fresh air intakes. In one legionella outbreak in Ohio, the biocide system of the cooling tower reservoir likely malfunctioned, leading to legionella overgrowth and transmission of aerosols. We have created this problem ourselves with modern plumbing.

Finally, a provocative idea from Prof David Fisman, an ID doctor from Toronto. Fisman argued that the ongoing rise in legionellosis in the US could be at least partly due to climate change. That could be the case. A recent article from Portugal described a large Legionnaire’s outbreak. Meteorological data indicated that winds, humidity, and a cloud of sand and dust lifted by a storm in the Sahara desert covered Portugal and increased airborne concentrations of small particulate matter and may have contributed to Legionella’s spread.

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Livermore VA

Cooling Tower

Bellevue Stratford Hotel

Bellevue Stratford Hotel

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Legionella Outbrea, Portugal

Airborne Infection Control Course at HSPH

For two weeks I am participating in a course at the Harvard School of Public Health entitled “Building Design and Engineering Approaches to Airborne Infection Control.” The course is a collaborative endeavor between Harvard, Brigham and Women’s Hospital, Partners and Health, and the Mass Design Group. We have an energetic group of students from around the world. The course is focused on engineering and architectural approaches to reducing TB transmission in congregate settings (i.e. natural ventilation, mechanical ventilation, Ultraviolet Germicidal Irradiation, etc). We are measuring pressure gradients in negative pressure rooms, learning about computer aided design programs, and climbing on building rooftops inspecting ventilation systems. I wish I had taken this course 5 years ago, before I started working in Mozambique. We would have been much more effective in our efforts to improve TB infection control at Maputo Central Hospital. The HSPH course demonstrates the importance of engineering approaches for making health care facilities safer.

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UVGI fixture


My Periodic Table

Oliver Sacks, shining brilliantly as always:

“Next to the circle of lead on my table is the land of bismuth: naturally occurring bismuth from Australia; little limousine-shaped ingots of bismuth from a mine in Bolivia; bismuth slowly cooled from a melt to form beautiful iridescent crystals terraced like a Hopi village; and, in a nod to Euclid and the beauty of geometry, a cylinder and a sphere made of bismuth.”


Of Mice and Men: The Basic Science of Tuberculosis

Today, some basic basic science. The August 1 issue of the Journal of Infectious Diseases has two interesting articles which use mice to investigate the pathogenesis of TB, hence, the John Steinbeck title. Hopefully we’ll all learn something along the way!

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The first article, written by researchers from Seattle, is entitled “Interferon γ and Tumor Necrosis Factor Are Not Essential Parameters of CD4+ T-Cell Responses for Vaccine Control of Tuberculosis.”  Mice and cytokines, yikes (eyes glazing over)– I definitely didn’t take “Mouse Immunology 101″ during medical school.

So the world desperately needs a new TB vaccine. The BCG vaccine was developed by Albert Calmette and Camille Guérin almost 100 years ago. It has some efficacy and is still used widely but clearly isn’t good enough to stop TB transmission.


In addition, MDR-TB and XDR-TB are a growing threat, as I’ve described elsewhere on this blog. Unfortunately, a 2013 Lancet clinical trial of the MVA85A vaccine in South African infants did not show efficacy against TB. That MVA85A vaccine was a subunit boosting vaccine and was designed to enhance whatever protection is already provided by BCG, but it didn’t work. 

Here’s the “big picture” as I understand it. The adaptive immune system evolved to protect us from microbes. CD4+ T cells mostly act by producing cytokines that communicate with other cells of the innate or adaptive immune systems. CD4+ T cells can be subdivided into several subgroups based on the cytokines they produce (i.e. TH1, TH2, and TH17).

CD4+ T cells, interferon γ (IFN-γ), and tumor necrosis factor (TNF) are thought to be essential for the control of TB. Recall that activated antigen presenting cells (APCs) make cytokines that influence the type of T helper cell that is produced. For example, in the figure below, an APC gets this CD4+ T cell jazzed up to become an effector T cell (Th1 cell) and that pumps out IFN-γ. Then, the macrophage becomes activated and gets better at killing the bacteria. IFN-γ also stimulates macrophages to produce more IL-12, which in turn potentiates TH1 cell development (setting up a positive feedback loop).  But TB is one tough cookie. After infecting the macrophages, it is thought to kill them, leading to caseous necrosis (more on this later).

IFN-γ is essential to prevent progressive, fatal infection with TB. Clinically, we frequently use interferon gamma release assays (IGRAS), such as TSPOT and Quantiferon TB Gold, in the place of skin testing (PPD/TST). IGRAS measure T cell release of IFN-γ following stimulation by antigens unique to TB.

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What about TNF? It’s another cytokine that is synthesized by activated macrophages and T cells and serves to activate other cells in the immune system. But TNF blockers (like infliximab) cause can cause people with latent TB to reactivate and develop active TB. I’ve seen it happen and it isn’t pretty.

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Ok, back to the first JID article. The activity of TH1 cells that simultaneously produce IFN-γ and TNF has been proposed as a candidate mechanism of vaccine efficacy. But the failed MVA85A vaccine trial means we need to look more closely at this. So the authors used a mouse model of T-cell transfer and aerosolized TB infection to assess the contributions of TNF and IFN-γ to vaccine efficacy. To do that, they gave mice a vaccine called “ID93+GLA-SE” (who knew you could vaccinate mice for TB!) The ID93 vaccine apparently elicits a high frequency of multifunctional TH1 cells and reduces pulmonary TB by approximately 90% in vaccinated mice (i.e. it limits TB infection).  After immunization with the ID93 vaccine, the researchers isolated T cells from the donor mice and transferred them intravenously into naive, uninfected recipients. Then, mice were infected with M. tuberculosis H37Rv and assessed for bacterial burdens.

But what is H37Rv? It is a strain of tuberculosis which was originally isolated from human lungs in 1905 by Dr. Edward R. Baldwin. H37 originally gained attention for its virulence in the guinea pig model. Nowadays, you can purchase H37Rv from an organization called ATCC which is located in Manassas, Virginia. 110 years later, it is still used widely in scientific experiments. More on H37Rv later.

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Now on to results from the paper. As seen in this graph below, mice were not protected by vaccination with ID93, indicating that CD4+ T cells are necessary to transfer protection against aerosolized TB. However, neither CD4+ T cell–produced TNF nor host cell responsiveness to IFN-γ were necessary for protection. The authors’ conclusion is that induction of TH1 cells that coexpress IFN-γ and TNF is not a requirement for vaccine efficacy against TB.  However, IFN-γ and TNF are essential for control of TB in nonvaccinated animals.

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What did I take away from this first paper, besides that fact that I clearly need to take “Mouse Immunology 101″ and we aren’t getting an effective TB vaccine anytime soon?  I learned that CD4+ T cells are necessary and sufficient for vaccine efficacy. But IFN-γ and TNF are not needed for vaccine-elicited control of aerosolized TB. Therefore, induction of TH1 cells is not needed for the generation of protective immunity against TB by vaccination. More basic science studies are needed before additional TB vaccine trials are launched.

Now, on to the second JID study, by researchers in the UK, entitled “The Extracellular Matrix Regulates Granuloma Necrosis in Tuberculosis.” This study I found a lot easier to follow, perhaps because their article was full of color figures and photos (not just black and white bar graphs)! The British researchers are questioning a central tenet of TB pathogenesis, that caseous necrosis leads to extracellular matrix destruction (Figure A, below). When we say “caseous” necrosis, we mean cheeselike (human tissue, destroyed by TB, looks like cheese). In this set of experiments, the researchers infected mice with TB (the H37Rv strain used in the Seattle article and a more recently isolated strain of TB). They concluded that collagen / extracellular matrix destruction happens first, leading to cell death and caseous necrosis later (see Figure B).

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Surprisingly, the British researchers found that the H37Rv strain of tuberculosis did not cause caseous necrosis or formation of multinucleate giant cells in infected mice. However, these pathologies were observed after infection with a recently isolated clinical strain of M. tuberculosis. The authors write:

“This implies that the prolonged laboratory culture of H37Rv since its isolation from a patient in 1905 has resulted in loss of currently unidentified factors that cause giant cell formation and caseous necrosis despite being able to proliferate rapidly.”

I’m certainly not a basic scientist, but I would like to ask the Seattle researchers what they think of this. Given that the H37Rv strain may have changed significantly since 1905, is it appropriate to have been used in the Seattle study?

Dr. Tim Lahey, an infectious diseases doctor at Dartmouth responded on Twitter, “lab adaptation is a valid concern. Even greater is that mice don’t develop latency so model applicability to us is uncertain.”

Treating Hepatitis C in people living with HIV

It was a sunny San Diego day in 2010 at the UCSD Medical Center. I sat in a conference room on the 6th floor and listened to my attending physician Dr. David Wyles as he gave us an overview of the new pipeline of drugs for Hepatitis C. He said (paraphrasing here), “there are so many new medications. The protease inhibitors, NS5A inhibitors, NS5B inhibitors. Treatment is going to change dramatically in the next few years.” I remember feeling a bit overwhelmed as he described the ongoing clinical trials. Treatment of Hepatitis C was so straightforward back then in 2010 (for the doctors). All we really had was Pegylated Interferon and Ribavirin. But that was all about to change.

Now, five years later, Dr. Wyles has been proven right. He is first author of a new NEJM paper, Daclatasvir plus Sofosbuvir for HCV in Patients Coinfected with HIV-1. (Another paper that came out with it is Ledipasvir and Sofosbuvir for HCV in Patients Coinfected with HIV-1. My medical school mentor Dr. Pablo Tebas and ID fellowship attending physician Dr. Paul Sax are authors on that one). Both papers address how we can treat hepatitis C in people living with HIV. My questions about these drugs have less to do with their efficacy or safety (those issues will continue to be addressed as they are rolled out more widely). Rather, I am concerned by cost and human rights. There is a huge ongoing debate about costs of the drugs, who is able to access them, and who pays for them.  Many journalists have written about the cost of the drugs (including Abby Goodnough in today’s New York Times) but I don’t think the health equity aspects have received enough attention. Take some time to think about what the right to health means to you. Do you believe that everyone should receive high quality health care? What about “expendable” people like IV drug users? If your family member had HIV and Hepatitis C, what would you do to ensure that they were able to receive the best treatment?

Globally, an estimated 4 million to 5 million persons are chronically infected with both HIV and Hepatitis C and are at risk for life threatening diseases like liver cancer and cirrhosis. These new drugs are showing that it is possible to cure hepatitis C in people living with HIV. Do we have the societal will to ensure that they reach the people who need them the most?

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“STARTING” antiretroviral therapy as “TEMPRANO” (soon) as possible

I feel obliged to write something about the two slam-dunk NEJM studies, START and TEMPRANO, since it seems like everyone else is (official NEJM editorial by Salim Abdool Karim; START Journal Watch review by Raj Gandhi and TEMPRANO review by Carlos Del Rio; numerous commenters on Facebook and Twitter). Suffice it to say that momentum is growing rapidly towards immediate ART for all, irrespective of CD4 count. However, as Karim notes, there are still 36.9 million people living with HIV and “only” 15 million receiving ART (I say only in quotes because a decade ago no one would have predicted we would have 15 million people on HIV therapy in 2015).

Exciting, but I am not convinced that the money or political will is there to get all 36.9 million people on ART, properly. HIV is not a disease where you can hand someone a pill, check them off your list, and wave goodbye. Proper HIV therapy requires trained clinicians, social support, medication supply chain, laboratory (especially viral load!), and additional resources. And what about Isoniazid Preventive Therapy (IPT)? It’s one thing to run a big clinical trial in 9 care centers in the capital city of one country. It’s a very different challenge altogether to scale up IPT across a continent and around the world. Without significant new resources in the global fight against TB, there is a very real risk of people with active TB receiving IPT monotherapy and adverse events occurring. We need a ground-swelling of support from concerned individuals if everyone living with HIV is to gain access to lifesaving therapy. This is our moral obligation.


HIV Incidence and Spatial Clustering in Mozambique

A sobering paper from Manhiça, Mozambique just came out. I have not spent significant time in Manhiça but have passed through before (often buying cashews from roadside vendors). Manhiça is a small town on a highway a couple of hours north of Maputo. It has extremely high HIV prevalence (almost 40% in adults). The Centro de Investigação em Saúde de Manhiça (CISM) is a research center associated with the Spanish government. CISM conducts a number of research studies on malaria and HIV and since 1996 has been running a demographic surveillance system. In this study, the researchers estimated overall HIV incidence to be 3.6 new infections per 100 person-years at risk. They used a Spatial Scan Statistics program to identify areas with disproportionate excess in HIV prevalence. They found a cluster of high HIV prevalence near a sugar mill in Manhiça and argue that it might be a “hot spot” related to migration. However, we do not know that HIV infections actually occurred in this geographic area.

To stop HIV transmission, we must reduce HIV incidence (i.e. new HIV infections). The most effective method of doing that is getting everyone on antiretroviral therapy with an undetectable HIV viral load.  Once the viral load is undetectable, HIV transmission virtually ceases, as we learned from HPTN-052. The question is how to target ART to people most likely to transmit the HIV virus, and make sure all people have an undetectable viral load, all in an era of dwindling financial resources. Even in the United States, this is a complex undertaking, as Jon Cohen recently described in Science.

My question for the Manhiça researchers is ART coverage. Many people have been working extremely hard in Mozambique to increase access to lifesaving ART. The authors state that participants in their study with an HIV positive result were offered medical follow up at the Manhiça outpatient clinic, which included CD4 counts, clinical management and provision of ART according to national guidelines. However, we do not know what percentage of HIV positive individuals actually got on ART and achieved an undetectable viral load. As far as I know, viral load is rarely done in Manhiça. Achieving virologic suppression across a population is an enormous task (we certainly haven’t been able to do it in the United States). Manhiça has more resources than most districts in rural Mozambique but expanding access to ART remains a major challenge. Yet this is an issue well beyond drugs and money. As we saw in West Africa with Ebola, it has to do with human resources, training, and community partnerships. It would be interesting to see a qualitative study from people in Manhiça living with HIV, health workers, and community members regarding those issues.

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