Monday, May 25, 2015

Immune responses to vaccines: innate immunity

After spending most of the weekend working in my garden, I spent today relaxing, barbequing, and spending time with my family.

Andrew and my garden
Right to left: Andrew, his Grandpa Esvelt, and his Uncle Seth
I don't know about you, but I remember very little about the human immune system from grade school and high school. I remember that white blood cells eat (phagocytize) bad stuff and I remember Raquel Welch being attacked by antibodies in The Fantastic Voyage (Maybe you're not that old).

Of course, I learned more about the immune system in nursing school and in my postgraduate curriculum. A lot of what I've learned about the immune system is from my reading about the pathology and pathophysiology of malaria. Like a lot of other diseases, many of the symptoms of malaria are caused by immune responses to the infection. As I mentioned in my post on hepatitis, hepatotropic viruses themselves do not damage the liver. The damage is caused by immune responses that kill infected liver cells.

The immune system is much more complex than phagocytic leukocytes (Greek: phagō, to eat; leukos, white; kytos-, cell) and Raquel Welch. In fact, immunity is mediated through several systems that work together. White blood cells not only eat invading pathogens and secrete antibodies, they also produce chemical messengers like interleukins that mediate inflammation and other cytokines that mobilize other white blood cells. There are also dozens of different types and subtypes of white blood cells that perform different functions.

There is no way I can adequately discuss all of the intricacies of the subject of medical textbooks. My purpose is to introduce some of the major players in immune responses to diseases and vaccines. I started writing this several weeks ago and got bogged down in too many details, so I'm going to start with innate immunity and save adaptive immunity, that is, why we give vaccines in the first place, for a later post.

Self versus non-self

The first priority of the immune system is recognizing "self" from "non-self," that is, anything that isn't part of our bodies. There are molecules on the surface of cells that are used by the different components of the immune system to identify those cells as self. Likewise, there are molecules on the surfaces of pathogenic organisms that the components of the immune system recognize are non-self. Cells that are infected with certain pathogens will place those molecules on their surface to target themselves to be killed to prevent other cells from being infected.

Innate immunity

Innate immunity refers to non-specific mechanisms the body uses to protect itself from infection. Skin, mucous membranes, and stomach acid are barriers that prevent pathogenic organisms from entering the body. Complement is a system of proteins that, among other things, tears holes in cells that are not recognized as self. The aptly-named natural killer cells (NK) kill cells that are infected with viruses and some type of tumor cells.

Phagocytic cells like macrophages ("big eaters") and dendritic cells are antigen-presenting cells (APCs). They are part of the innate immune system, but they perform an essential function in mobilizing adaptive immune responses. Most cells use major histocompatibility complex (MHC) molecules to "present" part of proteins found inside of the cell on its surface. It allows specialized white blood cells to "see" what's happening inside of the cell. MCH proteins on cell infected with viruses present viral antigens on the cell surface. This allows NK cells and cytotoxic lymphocytes (CTL) to target the cell for destruction. Antigen presenting cells use MHC molecules to present proteins to white blood cells that are part of the adaptive immune system.

Inflammation is another innate response to injury or infection that stimulates adaptive immune responses.

Antigens are foreign substances that cause antibody response. Allergens are a type of antigen. An antigen may have several epitopes, which are areas on the molecule to which antibodies can attach. For example, an influenza virus has several antigens on its surface including hemagglutinin, neuraminidase, and M2 ion channel. Influenza vaccines use epitopes or "antigenic sites" of the hemagglutinin head to stimulate production of antibodies that will attach to that part of the virus. Unfortunately, the hemagglutinin head changes shape (antigenic drift) so that antibodies to those epitopes will not bind to the antigen. Some researchers have suggested using epitopes on the hemagglutinin stalk or on the M2 ion channel as vaccine antigens.
CDC, 2014

Next: adaptive immunity.


Kroger, A. T., Pickering, L. K., Wharton, M., Mawle, A., Hinman, A. R., & Orenstein, W. A. (2015). Immunization. In J. E. Bennett, R. Dolin, & M. J. Blaser (Eds.) Mandell, Douglas, and Bennett's principles and practice of infectious diseases, 8th ed. [Electronic version]. Saunders.
Pickering, L. K & Orenstein, W. O. (2012). Active immunization. In S. S. Long, L. K. Pickering, & C. G. Prober (Eds.) Principles and practice of pediatric infectious diseases, 4th ed. [Electronic version]. Elsevier.
Playfair, J. H. L., & Chain, B. M. (2005). Immunology at a glance, 8th ed. Malden, MA: Blackwell Science.
Siegrist, C-A. (2013). Vaccine immunology. In S. A. Plotkin, W. A. Orenstein, & P. A. Offit (Eds.) Vaccines, 6th ed. [Electronic version]. Saunders.
Sompayrac, L. (2003) How the immune system works, 2nd ed. Malden, MA: Blackwell Science.


Saturday, May 9, 2015

Tropical medicine and global nurse migration

I was recently invited to speak to a global health class at UW Tacoma about Ebola and my work in Sierra Leone. I decided to begin my talk with an overview of tropical medicine.

I've been asked about tropical medicine several times, usually after I tell someone that I have a master's degree in public health and tropical medicine. I overheard one person speculate that tropical medicine was fruit-flavored.

Maybe this is your idea of the tropics:

There are a number of different definitions of which parts of the world are "tropical." The simplest definition is the area between the Tropic of Cancer and the Tropic of Capricorn. This is the part of the earth where the sun is directly overhead at least once during the year.

Zaire, 1988

There are different climates within the tropics. Before going to Sierra Leone last year, the last time I had been in West Africa was in the late 1980s. After spending time in the highlands and plateaus of East Africa, I had forgotten how hot "tropical" Africa can be. I spent a year working in the Ethiopian Highlands where, even though I was only a few degrees from the equator, the weather was a lot like the Pacific Northwest in spring and summer - it can get quite cold at night and it rains a lot.

Climate affects disease epidemiology and tropical diseases are not evenly distributed throughout the tropics. Malaria, for example, is not transmitted above an altitude of 2,000 meter. There are also arid regions in the tropics where malaria is rarely found because there isn't enough water for the mosquito vectors to breed.

Although the heaviest tropical disease burden is in the tropics, they are not limited to that part of the world. Tropical medicine also includes non-infectious diseases. The American Society of Tropical Medicine and Hygiene (ASTMH) refers to tropical diseases as those that "disproportionately afflict the global poor."

Neglected tropical diseases (NTD) are infectious diseases that affect the poor in developing countries and that have historically received little attention. NTDs are caused by bacteria, fungi, parasites (protozoa and worms), and viruses. As the name imples, the largest burden of NTDs is in the tropics:

CDC, 2011
Although malaria is not included in the list of NTDs, its geographic distribution is characteristic of a tropical disease.

Malaria Atlas Project, 2010
We also see higher burdens of child deaths in developing countries.

UNICEF, 2012
I could spend a lot of time discussing NTDs and other infectious tropical diseases. They were a large part the tropical medicine curriculum at Tulane, infectious diseases are the topics of most of the scientific sessions and symposia at the American Society of Tropical Medicine and Hygiene (ASTMH) annual meetings, and I've had a few of them.

Diseases associated with poverty include non-infectious diseases like malnutrition, cancer, chronic diseases, and mental health issues. My tropical medicine coursework also included envenomations and intoxications; animals and plants that bite, sting, and poison people.

Around 80% of deaths due to non-communicable diseases occur in developing countries including cardiovascular disease (e.g., heart disease and stroke), cancer, chronic respiratory diseases, and diabetes (Koehlmoos et al., 2011). Every week, millions of people in developing countries are moving from rural areas into urban areas (urbanization). Seventy percent of people living in urban areas in developing countries live in slums where they may have no access to clean water, where there is poor sanitation, housing is poor and overcrowded, and where they may live in disaster-prone areas. As people move into cities, they frequently adopt high calorie diets and sedentary lifestyles that put them at risk for chronic diseases like diabetes and heart disease (Utzinger & Keiser, 2006).

Developing countries also have the highest burden of deaths due to trauma. Ninety percent of deaths from motor vehicle accidents occur in developing counties. Occupational injuries are also too common in developing countries (Koehlmoos et al., 2011). When I worked in Tanzania last year I saw one young man who had both of his arms cut off at the shoulders in a farming accident, another young man with C5 quadriplegia from an occupational injury, and several work-related severe and sometimes fatal head injuries.


I covered a number of other topics during my presentation, many of which I've discussed here; influenza, measles, the demographic transition, and, of course, Ebola. I ended my presentation, as I usually do when I speak to young people, by asking them to consider a career in nursing. Since I was addressing a global health class, I discussed the topic of a public health analysis that I wrote while I was at Tulane:

Global migration of nurses

There is a worsening global nursing shortage in both industrialized and developing countries. The international demand for nurses is driven by shortages in wealthy countries. Policymakers in wealthy countries have failed to respond to the increasing demand for health services by investing in recruitment from large pools of qualified applicants and retaining nurses in the workforce. Large numbers of applicants are turned away from nursing schools in the U.S., while the annual number of graduates from nursing programs is insufficient to meet the current and projected workforce needs. Industrialized countries have become reliant upon international nurse recruitment, and an increasing number of nurses are leaving countries with low nurse to population ratios and high disease burdens (Adams & Stilwell, 2004; Aiken, 2007; Bach, 2003; Bach, 2004; Buchan et al., 2003; Buchan & Sochalski, 2004).

Although the total number of nurses migrating to an industrialized country may be relatively small in comparison to the recipient country’s stock of nurses, the loss of highly skilled health workers from developing countries with smaller stocks of nurses has severe implications for health care services in the source country (Aiken, 2007; Brush & Sochalski; Buchan et al., 2003). The benefits to source countries from nurse migration are significant. The total annual value of remittances from laborers of all categories working abroad exceeds the annual total global developmental assistance (Marchal & Kegels, 2003; Stilwell et al., 2003). For several decades, the Philippines has encouraged migration of nurses, who contribute almost $8 billion per year to the Philippine economy in the form of remittances (Brush & Sochalski, 2007). Nurses in the Philippines earn $75 to $200 per month, but earn $3,000 to $4,000 per month working in the U.S. (Bach, 2003; Brush & Sochalski). Thousands of Filipino physicians, who earn $300 to $800 per month, have retrained as nurses for export, and thousands more are enrolled in nursing schools (Bach; Brush & Sochalski).

On the other hand, the workforce crisis in developing countries limits the capacity and sustainability of health care systems to address health issues (Kiringia et al., 2006; WHO, 2008). On average, countries in sub-Saharan Africa have insufficient numbers of trained health care workers required to provide basic services (Dovlo, 2007; Liese & Dussault, 2004). There is also a tendency towards permanent migration of nurses, which represents significant losses not only to the health care workforce, but also loss of investment on health worker education (Bach, 2003; Buchan, Parkin, Sochalski, 2003; Kiringia, Gbary, Muthuri, Nyoni, & Seddoh, 2006; Marchal & Kegels, 2003).

The demand for nurses in industrialized countries, created by the failure to train and retain nurses from their own population, has profound effects on the health workforces in developing countries (Aiken, 2007; Bach, 2003; Buchan et al., 2003; Marchal & Kegels, 2003; Pond & McPake, 2006).

My long term career goal is to return to Africa to teach nurses.
My PowerPoint presentation


Adams, O. & Stillwell, B. (2004). Health professionals and migration. Bulletin of the World Health Organization, 82(8), 560.

Aiken, L. H. (2007). U.S. nurse labor market dynamics are key to global nurse sufficiency. Health Service Research, 42(3p2), 1299-1320.

Bach, S. (2003). International migration of health workers: labour and social issues (Working Paper 209). International Labour Office: Geneva.

Bach, S. (2004). Migratory patterns of physicians and nurses: still the same story? Bulletin of the World Health Organization, 82(8), 624-625.

Brush, B. L. & Sochalski, J. (2007). International nurse migration: lessons from the Philippines. Policy, Politics, & Nursing Practice, 8(1),37-46.

Buchan, J., Parkin, T., & Sochalski, J. (2003). International nurse mobility: trends and policy implications (WHO/EIP/OSD/2003.3). World Health Organization: Geneva.

Buchan, J. & Sochalski, J. (2004). The migration of nurses: trends and policies. Bulletin of the World Health Organization, 82(8), 587-594.

Dovlo, D. (2007). Migration of nurses from sub-Saharan Africa: a review of issues and challenges. Health Services Research, 42(3p2), 1373-1388.

Kiringia, J. M., Gbary, A. R., Muthuri, L. K., Nyoni, J., & Seddoh, A. (2006). The cost of health professionals’ brain drain in Kenya. BMC Health Services Research, 6(89), doi:10.1186/1472-6963-6-89.

Koehlmoos, T. P., Anwar, D., & Cravioto, A. (2011). Global health: chronic diseases and other emergent health issues in global health. Infectious Disease Clinics of North America, 25(3), doi:10.1016.j.idc.2011.05.008.

Liese, B. & Dussault, G. (2004). The state of the health workforce in sub-Saharan Africa: evidence of crisis and analysis of contributing factors. Washington D.C.: World Bank.

Marchal, B. & Kegels, G. (2003). Health workforce imbalances in times of globalization: brain drain or professional mobility. International Journal of Health Planning and Management, 18(S1), S89-S101.

Pond, B. & McPake, B. (2006). The health migration crisis: the role of four Organisation for Economic Cooperation and Development countries. Lancet, 367, 1448-1455.

Stilwell, B., Diallo, K., Zurn, P., Dal Poz, M. R., Adams, O., & Buchan, J. (2003). Developing evidence-based ethical policies on the migration of health workers: conceptual practice. Human Resources for Health, 1(8), doi:10.1186/1478-4491-1-8.

Utzinger, J. & Keiser, J. (2006). Urbanization and tropical health – then and now. Annals of Tropical Medicine and Parasitology, 100(5 and 6), doi:10.1179/136485906X973