Bullseye

It’s summertime and people are hiking and camping throughout New England. Today’s teaching conference at MGH/Brigham was given by Dr. Howard Heller regarding tick-borne illnesses. He focused on Lyme Disease because it is the most common tick-borne illness in our region. Howard emphasized that while Lyme is hyperendmic in coastal Massachusetts (Cape Cod, Martha’s Vineyard, Nantucket), the Berkshires in Western Mass are also hyperendemic. And Lyme is actually found throughout the region, and patients can get infected even in well-off enclaves like Cambridge and Newton. A few other points he made:

  • The manifestations of Lyme are protean. During tick season, be sure to consider Lyme even without a clear tick exposure when patients present with a febrile illness, rash of any sort, meningitis, Bell’s Palsy, etc.
  • Ticks are tiny and are often missed even when people are doing those tick checks. If there’s a rash in an area of the body where ticks are likely to come into contact (popliteal fossa, etc), consider Lyme, even if the rash isn’t a classic bullseye (erythema migrans). Be sure to undress the patient and do a complete dermatologic exam.
  • Diagnosis of Lyme is made by serology and should be sent to a reliable laboratory
  • Follow the IDSA guidelines (and American Academy of Neurology guidelines for CNS Lyme)
  • Be sure to test for anaplasma/babesia, as those diseases frequently co-exist with Lyme and require different treatment.

The main question I have coming out of this lecture is about the epidemiology of Lyme and the other tick-borne diseases. It is believed that an increase in the deer population in the northeastern United States and changes in land management practices have contributed to the rise in Lyme disease. But what can be done to reduce the incidence of all of these tick-borne illnesses?

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This little tick looks so friendly, right? Actually, it can pack a nasty punch

On Clostridium Difficile

Get out your blenders. Today I attended a lunchtime lecture given by Dr. Jessica Allegretti, a Brigham gastroenterologist who specializes in recurrent Clostridium difficile and fecal microbiota transplants (FMT). I don’t think I need to review the burden of disease caused by C diff, as most readers of my blog probably are aware that C diff is a major problem. The “hypervirulent strain” (NAP1/BI/027) of C diff which causes severe pseudomembranous colitis is also concerning (although NAP1 has been on the decline since 2007).  Recurrences of C diff are common and the medications we use most often, metronidazole and vancomycin, are frequently ineffective. In addition, fidaxomicin, a second line medication, is very expensive. In her lecture, Dr. Allegretti commented that “unnecessary antibiotics are rampant” in the community causing recurrent C diff. As a result, she is busy doing traditional FMT (hence the blender comment). She is also performing transplants via frozen capsules. Her frozen capsules are compounded at MIT and are given 2 days in a row in the office (30 capsules each day). Dr. Allegretti reports that the majority of patients have a rapid reversal of symptoms within 24 hours and are cured. That’s good to hear, but I think it’s a sad state of affairs when C diff is common and FMT is becoming more and more necessary. There is a lack of motivation from clinicians, patients, and the health system to reduce the unnecessary use of antibiotics. As a result, people, young and old keep getting sick from C diff. Hopefully we aren’t approaching the “antibiotic winter” described by Dr. Martin Blaser.

Immunogenicity of a Cholera Vaccine in Haitian Adults with HIV

This evening, I enjoyed catching up with a medical school friend who works extensively in Haiti. Upon returning home I found an issue of the Journal of Infectious Diseases in my mailbox. Opening it up, I discovered an article written by several of my colleagues from Mass General/ Brigham about the oral cholera vaccine in adults with HIV infection in Haiti. Caveats regarding this blog post: I don’t  claim to know much about cholera and I haven’t spoken with any of my Mass General/Brigham colleagues regarding this study.

This study is important because cholera often occurs in parts of the world where there is a high burden of HIV. For example, in Beira, Mozambique (about an hour flight north from Maputo), there was cholera in 2005-2006 and a research paper suggested that HIV infection was associated with an increased risk for cholera. Thankfully there were no outbreaks of cholera in Mozambique when I worked/lived there (2011-2012), but it was always a consideration when a patient came into the hospital with profuse diarrhea. Even though more and more people with HIV are getting on lifesaving antiretroviral therapy in Mozambique and around the world, the burden of HIV remains enormous. Cholera transmission is ongoing in many of these settings so individuals with HIV remain at risk. Now, lets journey to Haiti.

Louise Ivers and colleagues studied Haitian individuals with HIV who had received the bivalent oral cholera vaccine BivWC which is marketed as “Shanchol.”  This is a killed whole-cell bacterial vaccine. Since the Haiti earthquake and subsequent cholera epidemic, the Haitian Ministry of Health has rolled out the BivWC vaccine in an attempt to reduce cholera transmission. In St. Marc, Haiti adults with HIV infection received the vaccine and their serum was shipped to Boston for immunological analysis. In this paper, the researchers studied 25 adults with HIV who received BivWC. The median CD4 count of these patients was 433. All but two were on ART and the two who were not on ART had CD4 counts above 500. The researchers found that adults with HIV had a decreased vibriocidal antibody response to the BivWC vaccine, especially for patients with the lowest CD4 counts. However, the majority of HIV-infected individuals still did have seroconversion to the vaccine.

Ivers and colleagues comment on the small sample size and the fact that vibriocidal antibodies are not likely to directly mediate protection from cholera, so their study does not definitively address the question of vaccine efficacy in HIV infected individuals. That makes sense. My main question for the researchers would be about the CD4 cell counts. In many parts of Sub-Saharan Africa where cholera transmission occurs and there is a high prevalence of HIV (I am thinking of Beira, Mozambique for example), there remain many people who are not on ART. People with AIDS are at high risk for opportunistic infections and diseases like cholera because of their advanced immunosuppression. Practically speaking, human resources are limited in such settings (overloaded clinics, lack of nurses, etc) but cholera transmission must be avoided at all costs. Is there enough evidence to roll out the BivWC vaccine widely in such settings? The authors comment that additional doses of vaccine might need to be given to people with low CD4 counts. What kind of studies would be needed to investigate this question?

Thanks to the power of Twitter, Louise Ivers already wrote back. She said, “vaccine safe, and reasonable seroconversion in HIV but need bigger study w/ lower cd4 counts. Vaccine also in v short supply”

St. Marc, Haiti

St. Marc, Haiti

A Klebsiella Outbreak in the Netherlands

In 2012, while living in Mozambique, I met a Dutch doctor named Koen Hulshof. We struck up a friendship and briefly worked together trying to help improve TB infection control practices at Maputo Central Hospital. Koen told me about how infectious disease control was conducted in the Netherlands and I was impressed. The Dutch seemed very organized and committed to making their health facilities safer. Now, 3 years later, I have a bit more public health/ ID experience under my belt and I still see the Dutch as infection control role models. For example, the following article about a outbreak of pan-resistant Klebsiella (KPC) affecting 6 patients in a nursing home and hospital in the Netherlands.

I’ll let you read the article yourself, but briefly, the outbreak was recognized in the summer of 2013 when a KPC isolate was detected in a 65-year-old man admitted to a large teaching hospital in the Netherlands. This event followed the repatriation of a 69-year-old woman from an ICU in Greece who had been found to be colonized with KPC. A total of 6 patients were eventually found to have KPC and the authors performed genomic typing/ whole genome sequencing (WGS) of the isolates. The authors also performed environmental cultures from patient rooms (bed, doorknob, etc) and common areas (table, keyboard, mouse, etc). Soberingly, extensive environmental contamination with KPC was found. Air sedimentation cultures were also taken by placing solid agar plates in areas of the hospital (footboard of the bed, on the sink, etc). Interestingly, KPC did grow in these air sedimentation cultures suggesting that the environment may not only be contaminated by direct contact, but also by droplets or other (airborne) particles. The authors opine, “To what extent this contributes to transmission is, as yet, unclear, and it should be noted that bacteria may survive longer on the sedimentation agars than on other inanimate surfaces.”

What lessons can we take away from this paper? Enterobacteraciae are invisible and contaminate the hospital environment. Transmission occurs when there are lapses in infection control. KPC is an ongoing threat that needs to be taken much more seriously. The possibility of droplet/airborne transmission needs investigation. There should be much more research on how to stop the nosocomial spread of KPC in hospitals and especially nursing homes, where transmission may be amplified. Anyone interested in infectious diseases epidemiology needs to make an effort to learn some genetics, because WGS is here to stay. And I need to book a plane ticket to Amsterdam to learn from my Dutch colleagues.

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Sequence of patient detection in the hospital and nursing home

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Environmental swabs, which were inoculated on CHROmagar and EbSA plates. Red indicated presence of KPC.

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Genome typing (MLST+) of KPC producing outbreak strains. This minimum spanning tree was generated by a software program called SeqSphere, which was based on comparing 3,042 alleles that were defined as the core genome of the strains analyzed in this study. The values indicate the number of different alleles. Different colors represent different epidemic groups.

Mapping tuberculosis in Vitória, Brazil

new article was just published in CID about TB in Vitória, Brazil. I’ve never been to Brazil but have been interested in the country since I started working in Mozambique (they share the Portuguese language). Vitória is a medium-sized city located about 500 km north of Rio de Janeiro. The TB incidence in Vitória is slightly higher than Brazil’s overall burden (51 cases/100,000 population).

In this article, the authors performed genotyping of TB isolates and geospatial analysis (i.e. mapmaking). They used “old-fashioned” genotyping techniques (IS6110 RFLP / spoligotyping, as opposed to whole genome sequencing, a more modern technique) on 503 tuberculosis samples from 2003-2007. They found 242 of those isolates were clustered into 12 RFLP families and created some maps. Isolates that belonged to identical RFLP patterns (clusters) were thought to represent recent TB infection. They concluded that ongoing transmission of TB was caused by a small subset of strains in specific neighborhoods of Vitória. They recommended that a new case-finding strategy based on screening populations in neighborhoods with high-density recent transmission TB and social network analysis. Specifically, they talk about a “territory based surveillance system,” which tries to reduce TB transmission based on locations rather than personal contacts.

A few thoughts:

  • I liked the maps, but they were made using ArcGIS ESRI software which is expensive and requires a significant amount of training to learn. Are there any simpler, smartphone-based mapping programs that can be used for those with less computer expertise (i.e. nurses who work in TB control programs doing contact investigations?)
  • The spatial analysis was restricted to residential addresses at diagnosis. This is a major limitation of the article and their proposal for a “territory based surveillance system.” TB was not necessarily acquired at home, as transmission can occur at work, on public transportation, in congregate settings, etc. Their maps represent where the TB patients lived, not where they acquired infection.
  • The study was conducted on isolates from 2003 to 2007 but was published in 2015. How to dramatically speed up future studies? An 8-12 year delay between TB cases and publication isn’t unusual in global health research but is not ideal.
  • What if they had carried out their study using whole genome sequencing rather than RFLP/Spoligotyping? How would their results have differed?
  • Privacy remains a concern any time researchers are making maps using patient information, but the authors of this study clearly protected the rights of their human subjects.
  • I don’t think it’s time to abandon the traditional methods of TB outbreak/contact investigations based on this study (those methods are to describe the epidemiology of the outbreak; determine chain(s) of transmission; identify and prioritize contacts; identify transmission sites and estimate the scope of transmission; make recommendations to stop transmission). I might feel differently if the Vitória study/mapmaking had been carried out in “real time,” i.e. 2003-2007, and the maps were used by public health authorities to identify and interrupt TB transmission chains. But that was not the case. This article was published in 2015.
  • This Brazil paper goes along with another recent article from Peru which identified MDR-TB hotspots using a mapping approach and strain genotyping. The concept of TB transmission hot spots is “hot” but I think the jury is still out regarding its practical utility in the programmatic setting. National TB programs are generally underfunded and understaffed, and these approaches aren’t simple enough.  But once “Poisson regression using Gaussian process spatial smoothing” becomes more user friendly (i.e. TB data can be rapidly built into google maps) this could really take off.
Kernel density estimation (KDE) map of clustered strains (A) and empirical Bayesian odds ratio estimates (cases:controls) (B). A, The white color represents areas with the most intense concentration of clustered strains (dots). Bayesian analysis was made on a census tract scale whereas the kernel densities used points.

Kernel density estimation map of clustered strains (A) and empirical Bayesian odds ratio estimates (cases:controls) (B). A, The white color represents areas with the most intense concentration of clustered strains (dots).

Estimated predicted probabilities of tuberculosis recent transmission per neighborhood. In most of the neighborhoods where the predicted probability of clustering is >0.55, the largest restriction fragment length polymorphism families (ES19, ES14, ES1, and ES8) represent the majority of cases.

Estimated predicted probabilities of tuberculosis recent transmission per neighborhood. In most of the neighborhoods where the predicted probability of clustering is >0.55, the largest RFLP families (ES19, ES14, ES1, and ES8) represent the majority of cases.

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RFLP band pattern of the 70 identified cluster strains

Map from the Peru study (link above), showing concentrated MDR-TB risk measured using household GPS location and MDR phenotype

Map from the Peru study (link above), showing concentrated MDR-TB risk measured using household GPS location and MDR phenotype

HIV resistance in Sub-Saharan Africa

This morning we enjoyed a great lecture by Dr. Dan Kuritzkes, chief of the Division of Infectious Diseases at the Brigham. Dr. Kuritzkes gave us an overview of HIV resistance mechanisms and genotypic/phenotypic testing. At the end of his lecture, I asked him about HIV resistance in Sub-Saharan Africa, where there is a very limited capacity to do viral load testing and genotypes because of scarce resources and a lack of laboratory capacity. My concern is that many people might be failing ART because of resistance that is never detected. ART stockouts, overcrowded HIV clinics, Ebola outbreaks, and transportation barriers are a few challenges that PLHIV face when trying to access lifesaving ART.

Dr. Kurtizkes replied that although HIV resistance testing as a routine clinical practice is not performed in the vast majority of health facilities in Sub-Saharan Africa, there have been a number of research studies investigating these issues (I am paraphrasing here) . Research has shown that resistance with virologic failure is common. Given the frequently used regimen of TDF-FTC-EFV, the pattern of resistance in Sub-Saharan Africa reflects the regimen. For example, we see resistance to non-nucleoside reverse transcriptase inhibitors and FTC quite commonly. With subtype C virus, the Tenofovir resistance mutation 65R is more commonly observed than with subtype B virus. However, at least one third of patients actually fail with wild type virus (not resistant virus). And, research is showing that patients who fail with a high virus load are less likely to have HIV resistance. The implication is that they fail because of non-adherence, i.e. they are not taking enough antiretroviral drugs to select for resistance mutations. That result was seen in two of the second line treatment studies, “SECOND-LINE” and EARNEST. Both showed a paradoxical result, that for patients who failed a first line efavirenz regimen and were given lopinavir/ritonavir with 2 nucleosides or raltegravir, one would have expected that nucleoside-resistant patients would do better with raltegravir because the virus wouldn’t be cross resistant. But in fact the studies found that patients with wild type virus did worse than patients with mutant virus regardless of which drug they randomized to. The implication was if people failed because they were non adherent to the first regimen, they would likely be non adherent to a second regimen and fail that one as well. A third study of darunavir, instead of lopinavir, was just completed at the ACTG, and found that patients with resistant virus were more likely to be suppressed compared to patients with wild type virus, and there was no difference if they were using raltegravir or 2 nucleosides. But in the subset of patents who were randomized to the nucleoside arm, in those who had resistance, more mutations led to worse outcomes. Among adherent patients, it made a distance if there was resistance or not, but the biggest difference was if patients took their ART or not.

My concern about quality HIV care remains. If the vast majority of HIV patients in Sub-Saharan Africa are never receiving a viral load or genotype, how can we know that we are providing them the correct treatment? Obviously quality HIV care is expensive and HIV/AIDS budgets are flat-lined as countries try to increase the number of patients on ART. But we can either pay now or pay later. Inexpensive point-of-care viral load testing and genotypes cannot arrive soon enough.

Photo I took in Uganda several years ago

The end of the Airborne Infection Course

The Airborne Infection Control course at the Harvard School of Public Health is coming to an end after two enjoyable weeks. We learned a lot about mechanical and natural ventilation, UVGI, F-A-S-T, and many other important topics.  One of the biggest challenges we face in TB infection control is how to measure impact. Process indicators are useful for administrative TB IC activities, but we have a hard time demonstrating a decreased number of TB cases even with effective interventions. If you were unable to attend the course and want to learn more, discussions are ongoing in the GHDOnline TB infection control forum. A few questions to ponder as the participants board their flights back to India, South Africa, Papua New Guinea, and many other countries:

  • How to build momentum for change in health facilities?
  • How to convince others that TB infection control is important?
  • How to demonstrate that TB infection control measures are effective (monitoring and evaluation, impact)?
  • How to advocate for the resources ($) we need?
  • How to sustain the progress we have made?
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Airborne Infection Control Course Participants, 2015