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).



Phagocytosis
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.

References 

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

References

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

Saturday, April 18, 2015

Mariatu


I wrote a post in December in which I talked about Mariatu, a 9 year old girl with profound neurological symptoms that we saw in the confirmed ward. Those of us who took care of her had serious doubts that she would survive, but we put a lot of work into taking care of her.

Our hard work paid off and she got better. During my last trip through the Ebola treatment unit (ETU), Mariatu smiled at me, which was the best going-away gift I could have received.

A few of months ago, Christian Bain sent me photographs of Mariatu as she was being discharged from the ETU. She was gaunt, but she was smiling and she was an Ebola survivor.

I wondered what happened to her after she was discharged from the ETU. Was she able to go home? Did she have family to go home to? Did she have residual neurological deficits? I asked some of my colleagues who were in Sierra Leone about her. Martha Phillips wrote, "She was discharged to Government Hospital and nearly died there, but Guy and Christian and Dani [Kloepper] intervened, and she did survive."

This week Christian and Dani sent me some recent photographs of her. She's home with her family and she looks great! Those photographs make me very happy and I wish I could share them with you, but Mariatu is a former patient of mine and I am ethically, if not legally obliged to respect her confidentiality.

Mariatu's survival was due to the hard work of a lot of people. Working with her was usually a two- and sometimes a three-person job. Although she was able to sit up and feed herself when I left, she was still very sick. I doubt that Mariatu would have survived without the care that she received and the guidance that I received from Tracy Kelly, a pediatric nurse practitioner.

For me, Mariatu's survival is the pinnacle of all of the successes we achieved in Maforki. Caring for her was challenging; it required investments of time, effort, and compassion from a group of outstanding health care providers. Those of us who cared for Mariatu ran the risk of suffering disappointment and heartbreak if she died. I don't think any of us felt that it was a risk not worth taking.

Thank you Christian and Dani for the joy the photographs of Mariatu give me. Thank you for your part in her survival.

Thank you to all of my colleagues at Maforki.

Monday, April 13, 2015

Demolishing the Maforki Ebola Treatment Unit

Christian Bain is one of the extraordinary nurses I worked with in Port Loko. He arrived in Sierra Leone shortly after I did and stayed after I left. He was recently evacuated with 15 other people who had been exposed to another health worker who developed Ebola virus disease (EVD). He's back in Sierra Leone and has been sending me photographs of the Maforki Ebola Treatment Unit (ETU) as it is being demolished:






 
 
 

 Of the four of us who arrived in Maforki in early November, Chris, Jennifer, Larry, and me, I am the only person who has not returned to Sierra Leone. Larry was one of the people evacuated last month. Chris and Jennifer are still there.

Chris and Larry

Jennifer with Paul Farmer

One of the doctors who arrived in Port Loko shortly before I left noted that I was "outside of the demographic"; I was the only person with a young child at home. The rest either had no children or had adult children.

I don't know what happened at the government hospital in Port Loko. I don't even know the name of the health worker who developed EVD and was evacuated to National Institutes of Health Clinical Center. I never saw the inside of the government hospital while I was in Port Loko.

I can tell you that, after taking the CDC's Ebola safety course, I felt adequately prepared to work in an ETU. One of the things we were told repeatedly is that our own safety was our first priority and not to walk into a situation in which there was any doubt about our personal safety. I took that message very seriously.

I will also tell you that I worked with some of the most admirable, compassionate people I have ever met, many of whom quit jobs to work in the Ebola response. Everyone I worked with, both expatriate and local staff, was highly professional and brought a wealth of knowledge, skills, and experiences to the table. Working with them was one of the most rewarding experiences of my life.

 





The Ebola epidemic is not over and there is still a lot of work that needs to be done. Because immunization programs were interrupted by the epidemic, there could be more measles deaths than Ebola deaths in West Africa. Other health care services were unavailable during the epidemic and many children are only now returning to school.

Partners In Health and other non-governmental organizations will remain in West Africa after the Ebola epidemic ends to help rebuild the health care infrastructure. I would be proud to work with PIH again.

A couple of my colleagues in Port Loko have blogs that I highly recommend:

A Canticle for Lazarus Martha Phillips arrived in Port Loko shortly before I left. Her writing is heartfelt, poetic, and inspiring. Time spent reading her blog is time well-spent!

Nurse Nick Nick Sarchet is quoted in the New York Times article published yesterday about Partners In Health and their work in Port Loko. Nick had an exposure while I was in Port Loko and was evacuated in December (Breach). He returned to Sierra Leone in February and was evacuated again last month.


Nick and Paul Farmer

Christian and me

Sunday, March 8, 2015

Meningitis

Every couple of months I'll get a call from a person who heard that a friend or a coworker has meningitis and wants to know what to do about it. Meningitis can be deadly. Some of the bacteria that can cause meningitis are transmitted from person-to-person. People who have had contact with a person with certain types of meningitis should be treated with antibiotics to prevent illness.

Nevertheless, my immediate response is usually a variation of the cover of The Hitchhiker's Guide to the Galaxy: Don't panic. My first clue that it's not something that the caller should worry about is the fact that I'm hearing it from a friend or coworker first and not from a doctor or a microbiology laboratory. The pathogens require a public health response are notifiable conditions, which means that health care providers and laboratories are required to notify the local health department of the county in which the patient lives.

Meningitis means inflammation of the meninges. The meninges are the membranes that cover the brain and spinal cord. There are three layers, the pia mater ("gentle mother"), arachnoid mater ("spider mother," because of its cobweb-like appearance), and the dura mater ("tough mother"). Meningitis is characterized by fever, headache, altered mental status, and stiff neck. Seizures and photophobia (discomfort in response to light. Imagine walking out of a dark room into bright sunlight) may also occur.

MedlinePlus
 
There are a lot of things that can cause meningitis: bacteria, viruses, funguses, parasites, drugs, chemicals, tumors, or anything that can cause meningeal inflammation. The central nervous system (CSN) is a sterile site, so most microorganisms that pass though the blood-brain barrier can cause meningitis (more about that later). Relatively few of the infectious causes of meningitis are transmissible from person-to-person. Many of the bacteria that can cause meningitis are normal flora; that is, they are normally present on or in our bodies. The viruses that most commonly cause meningitis usually do not cause severe illness in most people. Fungal and parasitic meningitis are rare.


There are three vaccine-preventable causes of bacterial meningitis: Haemophilus influenzae type B (Hib), Neisseria meningitidis (meningococcus), and Streptococcus pneumoniae (pneumococcus). I plan to go into more detail about each one of those in future entries. There are several risk factors for the different types of bacterial meningitis. Streptococcus agalactiae (Group B streptococcus) is the most common cause of bacterial meningitis in newborn babies. Listeria monocytogenes also affects newborn babies as well as adults over 60 years of age and people who are immunosuppressed. Neurosurgery and head trauma can increase the risk of meningitis from bacteria normally found on the skin. Gram negative bacteria, including bacteria that are normally found in the gut, can also cause bacterial meningitis. In the March 2015 issue of the American Journal of Tropical Medicine and Hygiene there is a case series of people who developed bacterial meningitis as the result of strongyloidiasis, an infection with a parasitic worm that can migrate throughout the body.

Bacterial meningitis can be fatal or cause serious long-term problems. It is treated with antibiotics, however, because many antibiotics do not easily cross the blood-brain barrier, treatment can require high doses of antibiotics, treatment with several antibiotics, toxic antibiotics, prolonged treatment, or antibiotics that easily cross the blood-brain barrier but are not as effective as those than do not. In some severe cases of bacterial meningitis, antibiotics have been injected directly into CSF. Also, some of the bacteria that cause meningitis are resistant to antibiotics, making treatment much more difficult.


Lumbar puncture ("spinal tap") is one of the most important diagnostic tests for meningitis. A needle is inserted into the spine below the spinal cord to collect cerebrospinal fluid (CSF). CSF is normally clear and colorless. Cloudy CSF is caused by a high number of white blood cells present in the fluid and is indicative of bacterial meningitis. In addition to microscopic analysis of CSF, the amounts of glucose and protein are usually measured and the fluid can be cultured to identify bacteria present in the fluid. Aseptic meningitis is the term used when bacteria do not grow from a CSF culture. It has become synonymous with viral meningitis, but tuberculous meningitis and syphilitic meningitis can also be aseptic.

MedlinePlus
 
Viral meningitis

Enteroviruses are the most common cause of viral meningitis. Enterovirus is a large family of viruses that include polioviruses, viruses that cause hand, foot, and mouth disease, and some of the viruses that cause the common cold. Recently, outbreaks of enterovirus D68 have cause severe respiratory disease and possibly caused polio-like symptoms in children in the U.S. Other viruses that can cause meningitis include mumps virus, herpes viruses (including the viruses that cause cold sores, genital herpes, and chickenpox), and arboviruses (West Nile virus, St. Louis encephalitis virus, La Crosse virus, ), and lymphocytic choriomeningitis virus. Viral meningitis is usually self-limiting, treatment is supportive, and most people with viral meningitis have no long-term effects.


Cryptococcus neoformans is a fungus that causes meningitis in immunocompromised people. Cryptococcus gattii can cause meningitis in healthy people. In 2012 there were hundreds of cases of fungal meningitis in the U.S. caused by injections with a steroid contaminated with funguses that are commonly found in the environment. Other funguses that can cause meningitis include Aspergillus, Blastomyces dermatitidis, Coccidioides (Valley fever), and Histoplasma. There are a number of antifungal drugs that can be used to treat fungal meningitis.


Parasites that can cause meningitis include amebas and worms. Naegleria fowleri is a free-living ameba that causes primary amebic meningoencephalitis (PAM). The infection, which is almost always fatal, is acquired by swimming in warm water or through sinus rinsing. Naegleria has been found in public water systems in Louisiana and there have been two deaths from PAM that were associated with sinus rinsing.

Rat lungworm (Angiostrongylus cantonensis) causes eosinophilic meningitis in humans. As the name suggests, rats are the definitive host of A. cantonensis. Snails and slugs are intermediate hosts. Humans (accidental or dead-end hosts) are infected by eating snails or eating vegetables contaminated with snail or slug slime. A. cantonensis is not native to the continental U.S., but it has been found in Louisiana and was recently found in Florida. Although the worms migrate through the brain, the disease is self-limiting, requires no specific treatment, and usually does not cause long-term complications. Baylisascaris procyonis (raccoon roundworm), Gnathostoma species, Taenia solium (pork tapeworm), and Toxocara species (cat and dog roundworms) can also cause eosinophilic meningitis. These worms cannot reproduce in the central nervous system and eventually die. Treating these infections with anthelmintic drugs can sometimes cause more inflammation than allowing the worms to die on their own, so the goal of treatment is to reduce inflammation and treat any complications of the infection.

As I mentioned above, I plan to write more about Hib, meningococcus, and pneumococcus, but there are some other topics I would like to address first, including some that were raised by people who responded to my HB 2009 entry.

Daddy's red beans & rice

 
What's this stuff?
 
I don't think I like it
 

Okay, I'll try it

I like it!


References

Adams, D. (1979). Hitchhiker's Guide to the Galaxy.

Centers for Disease Control and Prevention. (2015). Enterovirus D68. http://www.cdc.gov/non-polio-enterovirus/about/EV-D68.html.

Centers for Disease Control and Prevention. (2013). Multistate outbreak of fungal meningitis and other infections. http://www.cdc.gov/hai/outbreaks/meningitis.html.

Center for Infectious Disease Research and Policy. (2015). Report on polio-like illness in kids supports link to EV-D68. http://www.cidrap.umn.edu/news-perspective/2015/01/report-polio-illness-kids-supports-link-ev-d68.

Hochberg, N. S., Blackburn, B. G., Park, S. Y,. Sejvar, J. S., Effler, P. V., & Herwaldt, B. L. (2011). Eosinophilic meningitis attributable to Angiostrongylus cantonensis infection in Hawaii: clinical characteristics and potential exposures. American Journal of Tropical Medicine and Hygiene, 85(4). doi: 10.4269/ajtmh.2011.11-0322.

Michalopoulos, A. S. & Karatza, D. C. (2010) Multidrug-resistant Gram-negative infections: the use of colistin. Expert Review of Anti-infective Therapy, 8(9). doi:10.1586/eri.10.88.

Teem, J. L., Qvarnstrom, Y., Bishop, H. S., da Silva, A. J., Carter, J., White-Mclean, J., et al. (2013). The occurrence of rat lungworm, Angiostrongylus cantonensis, in nonindigenous snails in the Gulf of Mexico region of the United States. Hawai'i Journal of Medicine & Public Health, 72(6 Supple. 2), 11-14. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3689474.

Remeš, F., Tomáš, R., Jindrák, V., Vaniš, V,. & Setlík, M. (2013). Intraventricular and lumbar intrathecal administration of antibiotics in postneurosurgical patients with meningitis and/or ventriculitis in a serious clinical state. Journal of Neurosurgery, 119(6). doi:10.3171/2013.6.JNS122126.

Romero, J. R. (2012). Enteroviruses. In L. Goldman & A. L. Schafer (Eds.) Goldman's Cecil medicine, 24th Ed. [Electronic version]. Elsevier.

Shimasaki, T., Chung, H., & Shiiki, S. (2015). Five cases of recurrent meningitis associated with chronic strongyloidiasis. American Journal of Tropical Medicine and Hygiene, 92(3). doi: 10.4269/ajtmh.14-0564.

Tunkel, A. R., van de Beek, D., Scheld, W. M. (2015). Acute meningitis. 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]. Elsevier.

University of Florida. (2015). Rare parasite colonizing snails in South Florida. http://news.ufl.edu/archive/2015/02/uf-researchers-rare-parasite-colonizing-snails-in-south-florida.html.

Verma, A. (2008). Infections of the nervous system: bacterial infections. In W. G. Bradley, R. B. Daroff, G. Fenichel, & J. Jankovic (Eds.) Neurology in clinical practice, 5th Ed. [Electronic version]. Elsevier.