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Misdiagnosing Legionellosis or Legionnaires’ Disease Can Be Fatal. But Why Is It Still Common?

Yellow water is poured from the tap into the glass: standard Legionellosis testing procedure

by Chandana Balasubramanian

Pathogen of the month: Legionella

Doubt strikes fear into the hearts of many. But it is a powerful tool in the hands of medical professionals and researchers. Being uncertain is the impetus that drives truth-seeking peer-to-peer verification and differential diagnoses that can help save lives.

Take Legionnaires’ disease. It is one of the leading causes of pneumonia worldwide [1]. If left untreated without the right antibiotics, it can be fatal. In the United States alone, the economic burden of just one year of Legionnaires’ disease cases can be over 800 million US dollars [2].

Surprisingly, it is often overlooked. So much so that even the World Health Organization or WHO states, “Since many countries lack appropriate methods of diagnosing the infection or sufficient surveillance systems, the rate of occurrence is unknown. In Europe, Australia, and the USA, there are about 10–15 cases detected per million population per year [1].”

A great place to begin addressing these challenges is if clinicians are willing to embrace doubt when faced with diagnosing pneumonia-like symptoms.

What causes Legionnaires’ Disease or Legionellosis?

There were many historical events in 1976. NASA unveiled their first space shuttle, Apple Computers was born, and the first Rocky movie was released. Unfortunately, it was also the year a tragic event led to the discovery of Legionnaires’ disease.

On July 21st, 1976, 4000 delegates from the American Legion, America’s largest veterans’ service organization, traveled to Philadelphia for a convention. Within a few weeks, almost 200 got sick with an upper respiratory illness, and 29 died. It took nearly five months of investigations to identify the pathogen – Legionella – as the cause [3].

Legionnaires’ disease or Legionellosis is caused by the bacteria Legionella. It lives in water and soil and can cause health issues when it grows in showerheads and faucets, hot tubs, and in stagnant water and air conditioning systems in large buildings. We are susceptible to infection by Legionella when we inhale water droplets with the bacteria in it or come in contact with contaminated soil. Legionellosis is not spread through direct human-to-human transmission. It has an incubation period of 2 to 10 days.

Legionella is widely found in warm water environments, so most cases of Legionnaires’ occur in the summer and early autumn. Legionnaires’ is a public health issue. Cassell et al. caution that utmost care must be taken when COVID-19 restrictions are lifted worldwide. Going back to work or school in buildings left unoccupied or unused during lockdowns is a risk factor for Legionellosis [4]. 

Paterna, Valencia, Spain: 03.05.2020; The legionella training
Paterna, Valencia, Spain, 2020; The Legionella training

 

Why is Legionnaires’ Disease often misdiagnosed or overlooked?

According to Reller et al. [5], a wrong Legionellosis diagnosis is often due to:

  1.     The inability to distinguish Legionnaires’ disease from other types of pneumonia, clinically and radiographically,
  2.     Failure to order diagnostic tests for Legionella infection, and
  3.     Inadequacies in current diagnostic tests and protocols.

The majority of Legionnaires’ disease cases each year remain undiagnosed; the world still awaits better diagnostic tests and protocols for Legionellosis. But the issue of “failure to order diagnostic tests for Legionella infections” can be fixed. The Urine Antigen Test (UAT) and sputum tests prescribed for Legionella are inexpensive, so cost is not the issue.

The solution lies in training medical professionals to embrace doubt and challenge their confirmation biases. Clinicians who take a few minutes to input a patient’s pneumonia and accompanying symptoms on a robust, clinical decision support tool like GIDEON (Global Infectious Diseases and Epidemiology Network) can better understand how to proceed

For example, when the COVID-19 pandemic hit, experts cautioned clinicians to be on the alert for Legionellosis as well. The concern was that clinicians might repeatedly be testing community-acquired pneumonia patients for COVID-19 but not Legionellosis – which would delay diagnosis and treatment. Since initial clinical presentations for the two are similar, clinical decision tools can be extremely useful.

GIDEON, for example, has a built-in feature to help clinicians challenge their confirmation biases. A ‘Why Not?’ feature helps clinicians understand why a specific diagnosis does not show up on the list of probable causes of a patient’s symptoms.

Legionnaires’ disease, misdiagnosed as Malaria, can be fatal because malarial drugs do not work against Legionella. It is even more critical to get the right diagnosis early. 

 

Legionellosis Misdiagnosed as Malaria

Take the example of the agricultural expert from Israel wrongly diagnosed with malaria instead of Legionellosis. He had traveled to India to work on a farming project in 2005. A week later, when he returned to Israel, he developed fever, headache, vomiting, and muscle pain. In two days, he felt better, but the symptoms reappeared but with cough, shortness of breath, and rigors in tow. The patient was highly lethargic, hypotensive, and blood tests showed elevated bilirubin and creatinine levels.

Because of his recent travel to India, doctors thought it was Malaria. He was started on malarial medication while laboratory tests were being processed. But when blood smears proved negative for Malaria, his doctors wondered if it was Dengue.

Luckily for him, his doctors decided to challenge their cognitive biases and conducted a differential diagnosis. They entered the patient’s symptoms in the popular DDx or differential diagnosis tool, GIDEON. To their surprise, neither Malaria nor Dengue showed up as possibilities. But given the symptoms and the incubation period, Legionellosis turned out to be the prime (and accurate) suspect. This saved his life because standard malarial therapy does not work against Legionellosis.

Legionellosis diagnosis on GIDEON application - two devices

Conclusion

Misdiagnosing Legionnaires’ disease can be fatal, lead to a public health crisis, and add hundreds of millions to an already astronomically high healthcare burden. One of the main reasons it is often overlooked is that clinicians may not think about testing for Legionellosis when treating a patient with pneumonia.

Equipping clinicians with the right clinical diagnosis tools can help them validate their assumptions. Not only that, using a tool like GIDEON, clinicians can also challenge their confirmation biases and learn why a diagnosis does not apply to a specific set of symptoms.

Getting to the correct answer starts with harboring and encouraging healthy doubt in initial diagnoses. As the famous philosopher, Voltaire said, “Doubt is not a pleasant condition, but certainty is absurd.”

 

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References

[1] WHO, World Health Organization, “Fact Sheet: Legionellosis,” WHO, February 16th, 2018. [Online]. Available: https://www.who.int/news-room/fact-sheets/detail/legionellosis. [Accessed 08 07 2021].
[2] K. R. C. E. a. S. C. M. Baker-Goering, “Economic Burden of Legionnaires’ Disease, United States, 2014,” Emerg Infect Dis., vol. 27, no. 1, pp. 255-257, 2021.
[3] J. E. M. e. al., “Legionnaires’ disease: Isolation of a bacterium and demonstration of its role in other respiratory diseases,” N. Engl. J. Med., vol. 297, no. 22, pp. 1197-1203, 1977.
[4] K. Cassell, “Legionnaires’ disease in the time of COVID-19,” Pneumonia, vol. 13, 2021.
[5] L. R. e. al., “Diagnosis of Legionella Infection,” Clinical Infectious Diseases, vol. 36, no. 1, pp. 64-69, 2003.

Vaccine Heroes

Louis Pasteur in his laboratory,1885
Louis Pasteur, the inventor of four vaccines, in his laboratory, 1885

 

The COVID-19 pandemic has been an eye-opener regarding the detrimental impact of microbial species on the human body. Vaccines act as vital tools for developing immunity against various infectious organisms through the recognition of targeted pathogens by the immune system. (Find more information on the mechanism of action of multiple types of vaccines here).

The initial development of vaccines resulted from the tireless efforts of many prestigious researchers who selflessly pursued the prevention of infectious diseases. Here is a brief sneak peek into the contributions of a few of these scientists whose invaluable efforts have saved millions of lives.

 

Portrait of vaccine hero Louis Pasteur

Louis Pasteur

In the 1880s, Louis Pasteur developed vaccines for four potentially fatal infections, including Chicken Cholera, Anthrax, Swine Erysipelas, and Rabies. He was the first to introduce the use of live attenuated pathogens to develop immunity against the causative organisms (1). The vaccine for Chicken Cholera (Pasteurella multocida) was the first to be developed in a laboratory. Pasteur received several medals and honors, including the Leeuwenhoek Medal from the Royal Netherlands Academy of Arts and Sciences for his contributions to microbiology in 1895 (2).

 

Rabies cases and rates worldwide, 1990 – 2015

Rabies cases and rates worldwide, 1990 - 2015

 

 

Waldemar Mordecai Wolffe Haffkine

Waldemar Mordecai Wolffe Haffkine

Waldemar Haffkine developed the first vaccines for Cholera and Plague, in the 1890s (3). Haffkine tested these inoculations on himself before initiating mass human trials. He conducted most of his studies in India, a hub of Cholera and Plague, and his monumental work saved the lives of millions of people.

 

Plague cases and rates 1948 – 2018

Plague cases and rates 1948 - 2018

 

Jesse William Lazear, 1866 - 1900

Jesse William Lazear

Dr. Jesse Lazear was an American physician who played a critical role in understanding the transmission of Yellow fever, a life-threatening viral infection (4). It was later revealed that he “allowed himself to be bitten by mosquitoes that had fed on the blood of patients with yellow fever,” which eventually led to his demise. His sacrifice was crucial in establishing the relationship between mosquitoes and Yellow fever, which later formed the basis of the development of key preventative strategies.

 

Max Theiler

Max Theiler

Max Theiler received the Nobel Prize in Medicine or Physiology “for his discoveries concerning Yellow fever and how to combat it” in 1951 (5). He pioneered the work on the development of a safe, standardized vaccine for the disease. In his studies, he used mice instead of rhesus monkeys, which were considered to be the main reservoir of the infection. Following this, mice continued to serve as standard tools for the study of zoonotic diseases by future researchers (6).

 

Yellow fever cases and rates worldwide, 1950 – 2016

Yellow fever cases and rates

 

 

Pearl Kendrick (left) and Grace Eldering. Photo credit: Michigan Women’s Hall of Fame
Pearl Kendrick (left) and Grace Eldering. Photo credit: Michigan Women’s Hall of Fame

Grace Eldering & Pearl Kendrick

Both scientists conducted in-depth studies on Pertussis (whooping cough), which then became the basis of the development of a vaccine (7). Interestingly, both Grace Eldering and Pearl Kendrick suffered from whooping cough in their childhood, which was said to be the motivation behind their work. They were also involved in combining the Pertussis vaccine with those of Diphtheria and Tetanus to produce the DPT vaccine.

 

Pertussis cases and rates worldwide, 1980 – 2018

Pertussis worldwide 1980 - 2018

 

Portrait of John Franklin Enders

John Franklin Enders

John Franklin Enders is referred to as “The Father of Modern Vaccines.” In 1954, he, along with Thomas H. Weller and Frederick C. Robbins, received the Nobel Prize in Physiology or Medicine for the successful in-vitro culture of the Poliomyelitis viruses (poliovirus) (8). Subsequently, Enders and his colleagues worked on developing a vaccine against the Measles virus, resulting in the availability of a live attenuated Measles virus vaccine and a deactivated Measles virus vaccine – marketed by Merck & Co. and Pfizer, respectively (9).

 

Measles cases and rates worldwide, 1980 – 2019

Measles worldwide cases and rates

 

 

The names mentioned above are just a few of the many scientists whose dedication, hard work, and intellect helped develop safe and effective vaccines, providing immeasurable contributions to our healthcare system.

 

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References

  1. FLEMING A. Louis Pasteur. Br Med J. 1947 Apr 19;1(4502):517-22. doi: 10.1136/bmj.1.4502.517.
  2. “Leeuwenhoek Medal”, Royal Netherlands Academy of Arts and Sciences [Online]. Available. https://www.knaw.nl/en/awards/laureates/leeuwenhoekmedaille
  3.     Hawgood BJ. Waldemar Mordecai Haffkine, CIE (1860-1930): prophylactic vaccination against Cholera and bubonic Plague in British India. J Med Biogr. 2007 Feb;15(1):9-19. doi: 10.1258/j.jmb.2007.05-59.
  4.     Reed W, Carroll J, Agramonte A, Lazear JW. Classics in infectious diseases. The etiology of yellow fever: a preliminary note. Walter Reed, James Carroll, A. Agramonte, and Jesse W. Lazear, Surgeons, U.S. Army. The Philadelphia Medical Journal 1900. Rev Infect Dis. 1983 Nov-Dec;5(6):1103-11.
  5.     “Max Theiler Biographical”, The Nobel Prize [Online]. Available https://www.nobelprize.org/prizes/medicine/1951/theiler/biographical/
  6.     Norrby E. Yellow fever and Max Theiler: the only Nobel Prize for a virus vaccine. J Exp Med. 2007 Nov 26;204(12):2779-84. doi: 10.1084/jem.20072290.
  7.     Shapiro-Shapin CG. Pearl Kendrick, Grace Eldering, and the pertussis vaccine. Emerg Infect Dis. 2010 Aug;16(8):1273-8. doi: 10.3201/eid1608.100288.
  8.     “John F. Enders Biographical”, The Nobel Prize [Online]. Available https://www.nobelprize.org/prizes/medicine/1954/enders/biographical/
  9.     Katz SL. John F. Enders and measles virus vaccine–a reminiscence. Curr Top Microbiol Immunol. 2009; 329:3-11. doi: 10.1007/978-3-540-70523-9_1.

Tracking Dengue: An Interview With Alisa Aliaga-Samanez

The rapid spread of Dengue could lead to a global pandemic, and so the geographical extent of this spread needs to be assessed and predicted. There are also reasons to suggest that transmission of Dengue from non-human primates in tropical forest cycles is being underestimated.

Alisa Aliaga-Samanez sitting by the computer
Alisa Aliaga-Samanez

 

Exactly one month ago, on June 7th, PLOS Neglected Tropical Diseases published a research article Worldwide dynamic biogeography of zoonotic and anthroponotic Dengue. The study is the first high-resolution analysis of how the risk of Dengue transmission has been changing geographically since the late 20th century, indicating the virus (DENV) has been making a home in previously low-risk areas, potentially due to global warming and deforestation. 

We spoke with the corresponding author Alisa Aliaga-Samanez, who worked alongside Marina Cobos-Mayo, Raimundo Real, Marina Segura, David Romero, Julia E. Fa, and Jesús Olivero, to learn more about the importance of this study and her experience working with GIDEON data. 

 

How did you find out about GIDEON?  

We got to know GIDEON thanks to an article published in PNAS by Kris A. Murray and colleagues entitled “Global biogeography of human infectious diseases.”

 

What were the reasons behind choosing the GIDEON database as one of your data sources?

We know that GIDEON is one of the most complete data sources worldwide on zoonoses, so we wanted to use it to build our database. For that reason, the project where I work at the University of Malaga funded our access to GIDEON.

 

What is the importance of biogeography studies like this one to public health management?  

Biogeographical studies, through modeling, applied to pathogens, allow us to understand the distribution of infectious diseases. The occurrence of disease cases is related to social factors but also to environmental variables that determine the degree to which certain environments favor the occurrence of disease, even where it has not been recorded. Thanks to the tool we use in our study, we are able to propose different management strategies depending on which factors favor the risk of transmission in different regions of the world. We took into account three possible biogeographical scenarios related to Dengue transmission risk: (1) zones with favorable conditions for viruses and vectors, (2) favorable conditions for virus only, and (3) favorable conditions for vectors only. Besides, our biogeographical approach helped us to analyze the extent of the areas where non-human primates could be involved in sylvatic Dengue cycles.

 

Do you believe the risks of the Dengue pandemic are exacerbated by global warming?  

We think global warming may be one of the factors that could be favoring vectors to adapt to new environments. A study published by Messina and colleagues in 2019 concluded that the World’s population at risk of Dengue could experience an almost 60% increase by 2080. In addition, they suggested that outbreaks could reach areas in continents such as Australia, Argentina, Japan, eastern China, and southern Europe.

Melting ice
Photo by William Bossen on Unsplash

 

In your experience, how effective study such as yours at influencing change in government and health policies, and do you think work like this will be taken more seriously following the COVID-19 pandemic?  

We have seen that governmental bodies such as WHO or CDC rely on scientific studies to manage risk areas, but we feel that this work is being limited in Africa, for example. On the other hand, some diseases already have a vaccine available, such as yellow fever, but its application might not be well managed in some African countries, where large outbreaks occur. In the case of Dengue, a vaccine has already been developed, but it is only licensed for people aged 9-45 years in some countries. The WHO recommends that the vaccine should only be administered to people with confirmed previous Dengue virus infection. As we show in our paper, Dengue is currently spreading together with its vectors. The COVID-19 pandemic should serve to demonstrate that global pandemics are possible and, so, must be prevented.

 

What value did having access to global spatio-temporal data add to your study?  

GIDEON helped us to get quick access to the available information on the disease. This allowed us to build our databases in a short time and to validate our models with recent cases in order to assess the reliability of the tool we use and to predict new areas favorable for new Dengue cases.

 

What are your thoughts regarding data availability on sylvatic transmitted Dengue?  

Most of the available data on human cases do not differentiate whether they were caused by sylvatic or urban transmission. Some research studies in certain local areas may be able to determine this, but globally there is no such information. Our biogeographic outputs related to Africa and Asia are consistent with the scarce information available and provide the context in which on-the-ground prospections on sylvatic Dengue should be addressed. This is especially important in South America, where sylvatic Dengue has not been detected yet (although the presence of sylvatic Yellow Fever and other evidences are starting to suggest its existence).

Aedes aegypti Mosquito. Close up a Mosquito Mosquito on leaf,Mosquito Vector-borne diseases,Chikungunya.Dengue fever.Rift Valley fever.Yellow fever.Zika virus.
Aedes aegypti mosquito, the vector of Dengue

 

What areas do you think GIDEON could improve to make our data more useful to you in the future?  

We appreciate the great work GIDEON does in collecting data globally. We found the new GIDEON interface very useful. Perhaps it would make it easier in the future, if it is possible, to distinguish between imported and autochthonous cases within the database. It is true that in many cases the database does mention it but not for all countries.

 

About Alisa:

Alisa Aliaga-Samanez has a degree in Biology from the Federico Villarreal University (Peru) and a Master’s degree in Biodiversity and Environment from the University of Malaga (Spain). Currently, she is working at the Animal Biology Department of the University of Malaga, being part of the Biogeography, Diversity and Conservation Group,  developing her Ph.D. thesis. The thesis is focused on the study of primate biogeography, applied to conservation and human health. She is currently mapping vector-borne zoonotic diseases through global distribution modeling. 

Aliaga uses high-resolution global maps and the most up-to-date databases to analyze geographical changes in the risk of zoonotic disease transmission. In addition, in these analyses, she considers the biogeographical contribution of primates in increasing the risk of transmission. She seeks to determine the potential natural range of endemic and emerging zoonotic diseases in the world, with the aim of suggesting specific management strategies according to the spatial distribution of risk factors.

Click here to read the open-access article: Worldwide dynamic biogeography of zoonotic and anthroponotic Dengue 

 

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Pathogen of the month: Mycobacterium tuberculosis

Mycobacterium tuberculosis (M. tuberculosis), a non-motile, obligately aerobic, intracellular bacterium known to cause Tuberculosis (TB), was discovered by Robert Koch in 1882 [1]. TB primarily affects the lungs along with the abdomen, bones, nervous system, reproductive system, liver, and lymph glands [2].

Pulmonary Tuberculosis ( TB ) : Chest x-ray show alveolar infiltration at both lung due to mycobacterium tuberculosis infectio
Pulmonary Tuberculosis ( TB ): Chest x-ray shows alveolar infiltration at both lungs due to Mycobacterium tuberculosis infection

 

Global Burden of Tuberculosis

The World Health Organization (WHO) has reported a 22% decrease in TB-related mortality between 2000-2015, with a gradual 1.5% decrease in the annual rate. However, despite this trend and successful control of disease transmission, TB continues to have a significantly higher rate of morbidity. In 2015, six countries (China, India, Nigeria, Pakistan, Indonesia, and South Africa) accounted for 60% of TB-related deaths [3].

 

Global cases of Tuberculosis between 1965-2019

Worldwide Tuberculosis cases and rates, 1965 - today

 

Pathogenicity of Mycobacterium tuberculosis

Mycobacterium tuberculosis is transmitted in the form of droplet nuclei exhaled by individuals affected with laryngeal/pulmonary TB. It enters the body via the nasal cavity/mouth and travels to the alveoli of the lungs, where it recruits macrophages to the lung surface, in turn transporting the bacteria to the deeper tissues [4]. Another round of macrophage recruitment to the originally infected locus forms an organized aggregate of differentiated macrophages and immune cells called a granuloma. The infected granuloma undergoes necrosis, promoting bacterial growth and transmission to the next host [5].

Diagnosis of TB

Some patients with TB may present with non-specific findings such as anemia, weight loss, fever of unknown origin, and fatigue; while others may be asymptomatic and show no abnormalities on physical examination [6]. Thus, the physician should collect body fluids/tissues for Acid-Fast bacilli (AFB) smear and culture.  Only a positive culture can confirm the diagnosis of TB.

Confirmatory and diagnostic tests for TB:

– Culture, followed by Ziehl-Neelsen (AFB) staining

– A Chest X-ray to confirm the diagnosis in case of positive culture, indicating active disease

– Gene-based tests and nuclear amplification to identify the bacterial strains using DNA-based molecular techniques, such as GeneXpert [7].

 

Ziehl-Neelsen staining

AFB staining is the traditional method of TB diagnosis, as it is inexpensive and provides rapid results [8]. Mycobacterium species retain dyes when heated and treated with acidified organic compounds. The most common acid-fast staining method for M. tuberculosis is the Ziehl-Neelsen stain method, in which a specimen is fixed, stained with carbol-fuchsin dye, and decolorized with an acid-alcohol mixture. After counter-staining the smear with methylene blue or a similar dye, AFB appear red against a contrasting blue background [9].  In general, a sputum sample must contain at least 10,000 organisms/mL to visualize these bacteria at 100x magnification. 

Symptoms and ways of infection of tuberculosis. Medical vector infographics, poster

Latent TB vs. Active TB

Latent TB represents the condition where the body’s immune system restricts the growth of M. tuberculosis bacterium, making the individual appear asymptomatic [10].

An individual with latent TB infection shows

– no symptoms.

– is not infectious (cannot spread TB).

– tests positive for TB blood/skin tests.

– may eventually develop active TB if the immune system weakens.

Active TB represents a condition where the body’s immune system is unable to restrict the growth of M. tuberculosis, rendering patients both ill and contagious. 

The symptoms of TB depend on the affected area.

a. General symptoms include:

  1. Night sweats
  2. Weight loss
  3. Prolonged fever
  4. Loss of appetite
  5. Fatigue

b. Symptoms of Pulmonary TB (infected lungs):

  1. Shortness of breath, which progressively worsens
  2. A persistent cough that produces phlegm and sometimes blood, persisting  > 3 weeks. 

c. Symptoms in the case when other areas of the body are infected:

  1. Swellings in the neck or other regions
  2. Pain in a joint or affected bone
  3. Abdominal pain
  4. Headache
  5. Confusion
  6. Seizures

 

Treatment

According to the World Health Organization (WHO), first-line treatment for TB may include combinations of five essential drugs: Rifampicin (R), Isoniazid (H), Pyrazinamide (Z), Ethambutol (E), and Streptomycin (S) [11].  Patients with TB undergo a standardized treatment for 6 to 9 months, including an initial two-month course of Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol, followed by another 4-month course of Isoniazid and Rifampicin [12].

For patients with Multi Drug-Resistant Tuberculosis (MDR-TB), directly-observed therapy (DOT) is used. In DOT, drugs are administered at least six days/week under the direct observation of the physician [13, 14]

BCG vaccine

Bacillus Calmette-Guerin (BCG), a vaccine for TB, was introduced in 1921 to control tuberculosis in humans. It is administered at birth, primarily in regions with a high disease burden, such as India, South Africa, and Pakistan [15]. Widespread immunization using BCG vaccine has facilitated a reduction in TB cases globally [16].

 

Risk factors

Five-to-ten percent of people with latent TB who do not receive appropriate treatment will eventually develop active TB disease [17]

Individuals at a higher risk of contracting TB include:

– Those who have traveled to or are living in a country with a high prevalence of TB. 

– Those living in crowded conditions

– Those who have been in close contact with a person infected with TB

– Children ages <= 5 years who have tested positive for TB

– People who reside or work with persons at high risk for TB, such as those in hospitals, correctional facilities, homeless shelters, residential homes for HIV-infected individuals, and nursing homes

Additionally, immune dysfunction associated with diabetes mellitus, HIV infection, cancer chemotherapy, malnutrition, and advanced age is associated with an increased risk of contracting TB. 

Additional conditions associated with high risk for tuberculosis include silicosis, substance abuse, malignancy, organ transplantation, corticosteroid therapy, Crohn’s disease, and rheumatoid arthritis.

Tuberculosis and HIV

Co-infection by TB and HIV places a diagnostic and therapeutic burden on the health care system. HIV infection has been shown to increase the risk of reactivation of latent TB by 20-fold. [18].

 

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References

  1.     K. R, Die Aetiologie der Tuberculose [The aetiology of Tuberculosis.], Berlin: Berliner Klinische Wochenschrift, 1882.
  2. F. K. Dye C, Disease Control Priorities in Developing Countries, New York:: Oxford University Press, 2006.
  3. Z. J. B. Q. H. H. B. L. Y. J. L. Q. L. J. Pan Z, “The Gap Between Global Tuberculosis Incidence and the First Milestone of the WHO End Tuberculosis Strategy: An Analysis Based on the Global Burden of Disease 2017 Database.,” 2020.
  4. CDC, How TB Spreads, CDC, 2016.
  5. G. M. J. Jr., “Microbial pathogenesis of Mycobacterium Tuberculosis: dawn of a discipline,” Cell, no. 104, pp. 477-485, 2001.
  6. J. D. E, Mycobacterial diseases of the lung and bronchial tree: Clinical and laboratory aspects of Tuberculosis, Boston: Brown and Company, 1974.
  7. [Online]. Available: https://www.ncbi.nlm.nih.gov/books/NBK441916/.
  8. B. J. R. Elizabeth A. Talbot, Molecular Medical Microbiology, 2015.
  9. R. l. Kradin, Diagnostic Pathology of Infectious Disease, 2018.
  10. World Health Organization, Guidelines on the management of latent Tuberculosis infection, Geneva: WHO, 2015.
  11. World Health Organization, Implementing the WHO Stop TB Strategy: A Handbook for National Tuberculosis Control Programmes.
  12. Gideononline, “www.gideonoline.com,” Gideon, 2021. [Online]. Available: https://app.gideononline.com/explore/diseases/Tuberculosis-12470.
  13. A. F. Z. L. F. E. Terracciano E, [Tuberculosis: an ever present disease but difficult to prevent], Ig Sanita, 2020.
  14. M.-R. K. R. R. C. R. Chaulk CP, Eleven years of community-based directly observed therapy for Tuberculosis, JAMA, 1995.
  15. “www.journals.plos.org,” [Online]. Available: https://journals.plos.org/plosmedicine/article/figures?id=10.1371/journal.pmed.1001012.
  16. Z. a. Lancione, “Using data science to improve knowledge around a century old vaccine,” The BCG Atlas, 2020.
  17. CDC. [Online]. Available: https://www.cdc.gov/tb/topic/basics/risk.htm.
  18. G. C. G. R. N. P. Getahun H, “HIV infection-associated Tuberculosis: the epidemiology and the response,” Pubmed, 2010.

Disease Outbreaks and Economics: an Interview with Prof. Rodolphe Desbordes

“Our results indicate that factors fostering a disease outbreak in one country can quickly lead to the emergence of a disease outbreak in another country.”

Epidemic infectious disease outbreak with person analyzing virus strain and worldwide situation. SARS-CoV-2 pathogen causing coronavirus covid-19 pandemic disrupting social and economic life

 

In March 2021, the Journal of Mathematical Economics published a research paper, Spatial dynamics of major infectious diseases outbreaks: A global empirical assessment. The article explored the spatial dependence of outbreaks and the role of globalization, analyzing 20 years’ worth of major outbreaks in developed and developing countries. The study found empirical evidence that ‘local outbreaks of many different infectious diseases can quickly spread to other countries’. Mortality consequences were found to be ‘much more severe in developing countries’.

 

Economics professor Rodolphe Desbordes
Prof. Rodolphe Desbordes

We spoke with the author Rodolphe Desbordes, a Professor of Economics at SKEMA Business School, about the importance of this research and the reasons behind choosing GIDEON as the data source.

Prof. Desbordes has widely published in the fields of International Economics and Economic Development. His current research interests encompass applied econometrics, determinants of political regime changes, and the links between biodiversity, economic activity, and zoonotic diseases.

 

 

How did you find out about GIDEON? 

I was looking for data with worldwide coverage on outbreaks of infectious diseases. I was really surprised not to find this information easily (e.g. provided by the WHO). In a few papers, I noticed their use of GIDEON.

 

What were the reasons behind choosing the GIDEON database for your analysis? 

I am really an applied macroeconomist, often interested in very global issues. For this reason, I need databases with long (time) and wide (spatial) coverage to run estimations. GIDEON was the perfect database for the epidemiological project I had in mind. In addition, for a non-specialist, the information provided on each disease was crucial to a better understanding of disease-specific characteristics.

 

How could healthcare systems benefit from a more econometric approach? 

Adopting an econometric approach is useful to reveal broad patterns, isolate the effects of specific factors, and carry out projections. This type of approach must be done in conjunction with expert knowledge of local conditions.

 

What is the importance of taking epidemiological data into account in the context of international policymaking? 

Deming said that “without data, you are just another person with an opinion”. Data are essential to guide domestic and international policymaking. Lots of data still need to be produced, in order to strengthen surveillance systems.

 

Do you consider developed countries’ decision to donate COVID-19 vaccines a step towards achieving a GPG (Global Public Good), and do you see this becoming more commonplace?

Some people have argued that the current pandemic is a rehearsal for the coming climate change crisis. It is essential that developed countries stop acting as if they live on a different planet where bad things do not happen to them. An unfortunate advantage of global crises is that even self-interested rich countries contribute to the Global Public Good. However more needs to be done. Donating vaccines is an encouraging sign.

 

Do you believe the current pandemic will encourage a more global view of public health concerns and their associated impact on economies? 

This is a tough question! We have been warned repeatedly about the risks of emerging infectious diseases. But, unfortunately, we did not act to prevent global pandemics from happening. One may hope that we will draw out the right lessons from the current pandemic. However, I am skeptical. For policymakers, the future always seems far away and purely national issues much more pressing than uncertain existential risks.

 

What value did having access to global data add to your study?

As an applied economist, I value excellent data on a novel and interesting issue more than anything else. The GIDEON database allowed me to publish in an excellent journal and, most importantly, carefully model the spatial diffusion of infectious diseases in a globalized world.

 

How would you have gone about collecting the outbreaks data if the GIDEON database did not exist? 

One possibility would have been to exploit the Global Burden of Disease data. However, despite the provider’s best efforts, the reliability of these data remains uncertain, and diseases are aggregated in relatively coarse categories.

 

In your article, you mentioned the GIDEON database is under-exploited – do you believe it could further contribute to the field of Economics and how? 

Infectious diseases have now become a hot topic in Economics. For various reasons, including data availability, the effects of many diseases were neglected. I hope that my use of the GIDEON database will alert researchers to this incredible information source and encourage more epidemiological research.

 

Click here to read the open-access article Spatial dynamics of major infectious diseases outbreaks: A global empirical assessment

 

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Diagnosing Emerging Infectious Diseases Early: How Epidemiology Can Help Clinicians on the Frontline

Doctor wearing protective gloves working on laptop computer,analyzing Coronavirus info data,COVID-19 response case info,U.S. state rank cases per capita,percent infected info and population numbers
Patient travel history or epidemiological data is the missing link in the differential diagnosis

 

by Chandana Balasubramanian

In 2019, a crew of nine pilots and astronauts broke a world record. They flew around the Earth in just 46 hours. More incredible is that they did not fly in a never-before-seen, advanced aircraft prototype. They flew a commercially available jet plane.

The future is already here.

It’s a small world; it’s getting smaller by the minute

Based on the new world record, it could take less than a weekend for an emerging infectious disease to spread all over the globe. And chances are, it may take a week or more before it gets detected based on the incubation period.

Unfortunately, healthcare providers at the frontlines of infectious disease management face a significantly higher risk of infection. The risk extends beyond healthcare workers to their families and communities.

As the world grapples with the impact of COVID-19 and its mutations, it’s a good time to ask: What can health systems worldwide do to detect emerging infectious diseases imported from other countries early?

1. Think beyond the travel ban

Recent research empirically demonstrated that local outbreaks of various Infectious Diseases could “quickly spread to other countries through the international movement of people and goods, with potentially disastrous health consequences [1].”

While this fact may not be news to clinicians and Infectious Disease specialists, the study also shows a close spatial dependence between the health conditions in one country and another – a spillover effect. The study used GIDEON (Global Infectious Disease and Epidemiology Online Network), a database covering all Infectious Disease outbreaks.

An epidemic in one country can become a pandemic in others – irrespective of travel and other physical barriers to entry. Studies of previous epidemics show that even a 90% travel restriction between countries merely delays the arrival of an emerging infection by a few weeks. Another study by Quilty et al. reported that airport-based screening measures to detect COVID-19 missed 46% of cases because of the incubation period [2].

So, while a travel ban and thermal screening can help a country buy some time to prepare for an outbreak, epidemic, or pandemic, they cannot stop or prevent a new infection from spreading to foreign shores.

***

2. Record travel history as standard protocol

Travel has always been one of the fastest ways to introduce a pathogen to a new environment. And as two clinicians, Trish Perl and Connie Savor Price, argue in a recent ‘Annals of Internal Medicine’ article, travel history must be treated as the fifth vital sign in emergency rooms and all physician evaluations [3].

The doctors make a strong case that including a patient’s travel history as part of a vital signs check can “help put symptoms of infection in context and trigger us to take a more detailed history, do appropriate testing, and rapidly implement protective measures.”

Monkeypox in the UK, 2021

For example, in May 2021, the World Health Organization received notification from the United Kingdom of a confirmed case of monkeypox in an individual who had just traveled from Nigeria. Monkeypox has an incubation period of six to thirteen days, but according to WHO, it can range anywhere from five to twenty-one days. Eventually, the infection spread to another family member, and they were isolated. Differential diagnosis considerations for monkeypox include chickenpox, measles, bacterial infections, scabies, syphilis, and medication-associated allergies. In such a case, taking the patient’s travel history can help healthcare workers take the necessary precautions even before the PCR results.

COVID-19 in the United States, 2019

The first case of COVID-19 in the US was reported in Washington when the patient returned from Wuhan, China. Based on the patient’s travel history and symptoms, healthcare professionals could isolate and send clinical specimens to be tested by the CDC overnight. Hospitals in the United States were already on alert for patients from Wuhan presenting with symptoms, and testing could be prioritized accordingly.

Ebola in the United States, 2014

Let’s look at an example where a patient’s travel history would have helped protect healthcare professionals. In 2014, a man traveled from West Africa and admitted himself into a hospital in Dallas with fever, abdominal pain, dizziness, headache, and nausea. Without an integral piece of the puzzle – his travel history – he was treated for sinusitis and sent home. The hospital suspected Ebola only when he returned three days later with persistent fever, abdominal pain, and diarrhea. Unfortunately, within this time, this patient had infected healthcare professionals, ambulance transport personnel, and the patient’s caregivers.

Monkeypox and Ebola are not as contagious as COVID-19 and its variants, and Ebola is not contagious until symptoms appear, making containment easier. But emerging infectious diseases and their variants might be.

Infectious Disease specialists, clinicians, researchers, and medical librarians will need to be vigilant against the next outbreak. Epidemiological data plays an integral role in facilitating improved clinical decisions and saved lives.

***

3. Identify initial cases of known diseases in new settings

In a GIDEON survey of 363 clinicians in the US, UK, and Canada, 35% stated that they would consult a colleague for a second opinion before making clinical decisions. As a close second, 30% indicated that they trust their judgment. This means that 65% of the survey respondents trusted human judgment over Point-of-Care tools.

Twitter survey of clinicians and use of differential diagnosis tools

But the stakes are higher when dealing with highly transmissible emerging infections. The importance of first-time diagnosis accuracy is compounded due to the rising urgency to prevent the next epidemic or pandemic.

Consider the dramatic difference in transmission rates between SARS-CoV-2 and its variants:

  • The B.1.1.7, the ‘Alpha’ SARS-CoV-2 variant, is 43% to 90% more transmissible than its predecessor and led to a surge in hospitalizations across the UK and 114 more countries in a mere few months [4].
  • 1.617.2 or the ‘Delta’ variant is estimated to be 40% to 60% more infectious than the Alpha, estimated by disease modelers at Imperial College, London, with an R0 as high as 8 [5].

Here are some comparisons of how newer, emerging pathogens and their variants compare to older, Infectious Diseases.

Pathogen Transmissibility Rate (R0)
B.1.617.2, SARS-CoV-2 Delta variant 5-8
B .1. 1. 7, SARS-CoV-2 Alpha Variant 4-5
SARS-CoV-2 (COVID-19) 2.5
SARS-CoV 2.4
Measles 1.5 (1.5-2.0)

In other words, an outbreak may already be well underway before an Infectious Disease specialist is consulted for assistance on differential diagnosis or a medical librarian is requested for location-specific disease symptoms.

As pathogens mutate, traditional methods of differential diagnosis need an upgrade. Clinicians, Infectious Disease specialists, and researchers need data from local outbreaks anywhere in the world at their fingertips to help drive decision-making and advance the global effort against Infectious Disease.

***

4. Use a differential diagnosis (DDx) tool like GIDEON’s First Case Scenario to identify Infectious Diseases – faster and more accurately

Drs Perl and Price champion the need for greater access to digital resources that integrate electronic health records with patient travel histories and can “suggest specific diagnoses in febrile returning travelers.”

One of the more well-known DDx tools is GIDEON with its First Case Scenario feature, created in partnership with the World Health Organization (WHO) after the West Nile Fever outbreak in the United States.

Using a DDx platform such as GIDEON helps:

  • narrow down possibilities,
  • lead to a faster result,
  • reduce the margin of error at the point-of-care, and
  • elevates peer-to-peer knowledge sharing on a global scale

Why is this important? Because, for example, in respiratory viral illnesses, early detection is the critical step to mitigate disease transmission but is often delayed [3]. Depending on the type of pathogen, this could lead to a greater number of hospitalizations, more morbidity, a burden on healthcare systems, and have significant ramifications on a country, its people, and the economy.

Locations marked with pins on world map, global communication network, closeup. Asking patients about their travel history can help prevent emerging infectious diseases introduction into country
Asking patients about their travel history can help prevent emerging infectious diseases introduction into the country

Having a differential diagnosis platform that incorporates a patient’s travel history can make a huge difference in how the world manages emerging infectious diseases.

Here’s an example. Suppose a patient presents with elevated body temperature, severe headache, chills, myalgia, diarrhea, and malaise.

These are nonspecific presentations and could be representative of a variety of diseases.  With international transmission now the norm, no clinician can be expected to keep track of every single emerging disease and its symptoms.

Example: Diagnosing Ebola using a DDx platform

Step 1: Focusing on most likely diseases based on symptoms and travel information
Entering a patient’s symptoms and the locations and dates of travel in a tool like GIDEON’s Bayesian analysis-driven Probability engine can help identify what diseases are most likely to correspond to the data entered. The illustration below shows Ebola as a high probability based on the patient’s symptoms and travel location.

Step 2: Conduct a differential diagnosis
The screenshot of the First Case Scenario feature below shows a 95% probability that the patient has Ebola. What if there were fewer symptoms at presentation, the likelihood of Ebola was 65%, and another disease was 25% probable? You could conduct a differential analysis by comparing the two disease symptoms on the platform, download the comparison, and order the requisite laboratory tests to confirm.

Step 3: First Case Scenario

Imagine it is 2014, and you haven’t heard of Ebola. A patient walks in with the symptoms listed above. You enter the symptoms and the patient’s travel history. Using GIDEON’s First Case Scenario, you can determine how likely it is that your patient is the first in the country to present with Ebola.

GIDEON web application screenshot displaying 95% probability of Ebola in the First Case Scenario feature
Illustration of diagnosing Ebola in a Point-of-Care setting (Screenshot: GIDEON First Case Scenario DDx tool)

***

5. Train an army of global clinicians to battle Infectious Diseases

Based on a GIDEON survey of 230 clinicians in the US, UK, and Canada, while clinicians were open to using a DDx tool to help diagnose Infectious Diseases, a lack of budget was the primary reason they did not.

One physician even stated, “I would use them every day if my institution would offer.”

But an interactive platform with a robust database of Infectious Disease symptoms that incorporates patient locations, exposure to disease-causing elements, and comparisons between two or more similar diseases can offer benefits beyond what a seasoned clinician can accomplish.

It can train the next generation of Infectious Disease-fighting doctors and healthcare professionals. For example, take GIDEON’s step-by-step Bayesian analysis toolkit. Teaching institutions, medical librarians, medical students, residents, researchers, and more can use DDx tools to help hone their diagnoses of emerging as well as well-known infectious diseases.

The tool helps you list symptoms, patient travel information (if any), and any exposure to disease-causing elements (if known). For example, the patient ate chicken in a region that recently had a Salmonella outbreak.

The tool offers a list of probable diseases in descending order of probability. It helps that the tool is dynamic because what if the patient forgot a symptom and told you about it later? A new list of probable diseases is re-calculated automatically. An added benefit is that the DDx tool is integrated with the First Case Scenario to determine if a patient’s symptoms are the first in a specific location.

Health systems and medical colleges and universities may benefit greatly from such a diagnostic solution.

Conclusion

War often provides an opportunity for innovation. After all, the internet was invented because computers at the time were enormous, and it was incredibly difficult to physically transport military intel from the United States to soldiers deployed around the world [6]. And clinicians are actively in a battle against the spread of infectious pathogens.

A global platform that offers timely location-specific intelligence about emerging infectious diseases and helps speed up clinical decisions is invaluable to future-proof the world against outbreaks, epidemics, and pandemics and save thousands of lives.

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References

[1] R. Desbordes, “Spatial dynamics of major Infectious Diseases outbreaks: A global empirical assessment,” J. Math. Econ., vol. 93, no. 102493, p. 102493, 2021.

[2] B. J. Quilty, S. Clifford, S. Flasche, R. M. Eggo, and CMMID nCoV working group, “Effectiveness of airport screening at detecting travellers infected with novel coronavirus (2019-nCoV),” Euro Surveill., vol. 25, no. 5, 2020.

[3] T. M. Perl and C. S. Price, “Managing emerging Infectious Diseases: Should travel be the fifth vital sign?” Ann. Intern. Med., vol. 172, no. 8, pp. 560–561, 2020.

[4] N. G. Davies et al., “Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England,” Science, vol. 372, no. 6538, p. eabg3055, 2021.

[5] Scientific Advisory Group for Emergencies, “Imperial College London: Evaluating the roadmap out of lockdown – modelling Step 4 of the roadmap in the context of B.1.617.2 (Delta), 9 June 2021,” Gov.uk, 14-Jun-2021. [Online]. Available: https://www.gov.uk/government/publications/imperial-college-london-evaluating-the-roadmap-out-of-lockdown-modelling-step-4-of-the-roadmap-in-the-context-of-b16172-delta-9-june-2021. [Accessed: 15-Jun-2021].

[6] B. Tarnoff, “How the internet was invented,”  The Guardian, 15-Jul-2016.

Preventing Foodborne Illness

Food quality control expert inspecting specimens of groceries in the laboratory
Food quality control expert inspecting groceries in the laboratory

 

Since 2019, World Food Safety Day is celebrated each year on the 7th of June,  to promote awareness regarding the need to develop and maintain food safety standards. These efforts are being done both to reduce the burden of foodborne disease and to minimize its impact on socio-economic systems.

Foodborne diseases constitute a major health issue worldwide. The World Health Organization (WHO) estimates that approximately 10% of the global population is infected by foodborne pathogens each year (1). Similar to other diseases, the severity of the foodborne illness varies with the type and the amount of exposure to the causative microorganism, as well as the disease-fighting potential of the affected individual.

 

Clinical Presentation of Foodborne Illnesses

Foodborne illnesses might manifest as acute diarrhea, nausea, etc., which usually resolves within 7 to 10 days; or as chronic and potentially fatal diseases such as botulism or typhoid fever.

Botulism, a common and potentially fatal disease, is caused by Clostridium botulinum. Signs and symptoms usually appear within 18 to 36 hours of food ingestion Bacterial toxins can persist in the patient’s blood for up to 12 days. Common findings include respiratory failure and neurological symptoms, such as blurred vision, paralysis, etc. (2). 

 

Foodborne cases of botulism in the United States 1979-2019

 

Botulism cases in US, 1979 - 2020, GIDEON graph

 

Prevention and Management of Foodborne Illnesses

irradiated spinach_byMikeLichtContamination of food or food products can occur at various stages of production, including growth, processing, transportation, or storage. Thus, there is a critical need to adopt appropriate measures that correspond to these variable conditions to maximize food safety and minimize the transmission of foodborne illnesses.

 

1.     Decontamination of Fresh Produce

With rapid globalization, fresh produce is now available worldwide throughout the year in the form of frozen food.  Fresh produce must undergo proper decontamination before being frozen – to prevent such diseases as norovirus infection and hepatitis A (3, 4). Some of the common techniques used for decontamination include (5):

a.     Application of antibiotics during the growth stage

b.     Proactive sampling for detection of pathogens

c.     Bacteriocins (bacteria-generated toxins to kill the competitive strains)

d.     Antimicrobial natural products and nanoparticles

e.     Bacteriophages

f.      Irradiation 

Alternatively, consumers might receive probiotics and relevant vaccines to protect them from relevant foodborne illnesses.

 

2.     Development of Public Health Surveillance Systems

A competent public health surveillance system should be implemented by the Governmental and related organizations to identify impending outbreaks in order to facilitate effective policies and goals (6, 7). Such systems help control and prevent extensive transmission by collecting and analyzing epidemiological and clinical data that provide guidelines to take appropriate measures.

 

3.     Prophylactic Measures for People with Increased Susceptibility to Foodborne Illnesses

People who are vulnerable to foodborne infections, such as older adults, infants – and individuals with prior diseases of the immune system, liver, gastrointestinal tract, etc. should be particularly vigilant and observed preventive measures (8) including: 

a.   Adherence to a low-microbial diet and avoidance of undercooked meat, unpasteurized milk, etc.

b.  Consumption of  bottled natural water

c.   Infants should be preferably given sterile ready-to-eat formula; powdered formula should be reconstituted in boiling water and given in boiled water-  sterilized bottles

d.  Antimicrobial may be administered prophylactically during transplantation and other high-risk treatments.

 

4.     Food Safety Measures

In general, people should adopt safe food practices wherever they cook and consume food or food products (9). The cooking utensils/surfaces should be properly cleaned and sanitized. Raw and undercooked foods should be stored separately to avoid cross-contamination. Food should be cooked or reheated thoroughly, meats and seafood should be cooked to appropriate temperatures. Cooked food should be stored at < 5°C, and not for prolonged periods. Only clean, purified water should be used for cooking food to minimize any chances of waterborne infection. Raw fruits and vegetables should be properly washed before consumption.

Woman washing carrots and pomegranate in a metal sink
Raw fruits and vegetables should be properly washed before consumption.

 

At the Public Health level, comprehensive integration of government-issued guidelines and self-monitoring are needed to prevent and control foodborne illnesses.

 

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References

  1.     “Foodborne diseases”, World Health Organization. [Online]. Available: https://www.who.int/health-topics/foodborne-diseases#tab=tab_1.
  2.     “Botulism”, GIDEON Informatics, Inc, 2021 [Online]. Available: https://app.gideononline.com/explore/diseases/botulism-10230.
  3.     Nasheri N, Vester A, Petronella N. Foodborne viral outbreaks associated with frozen produce. Epidemiol Infect. 2019 Oct;147:e291. doi: 10.1017/S0950268819001791.
  4.     Chapman B, Gunter C. Local Food Systems Food Safety Concerns. Microbiol Spectr. 2018 Apr; 6(2). doi: 10.1128/microbiolspec.PFS-0020-2017.
  5.     Yang SC, Lin CH, Aljuffali IA, Fang V. Current pathogenic Escherichia coli foodborne outbreak cases and therapy development. Arch. Microbiol. 2017 June; 199(6): 811-825. doi.org/10.1007/s00203-017-1393-y.
  6.     Ward H, Molesworth A, Holmes S, Sinka K. Public health: surveillance, infection prevention, and control. Handb Clin Neurol. 2018; 153:473-484. doi: 10.1016/B978-0-444-63945-5.00027-1.
  7.     Hoelzer K, Moreno Switt AI, Wiedmann M, Boor KJ. Emerging needs and opportunities in foodborne disease detection and prevention: From tools to people. Food Microbiol. 2018 Oct; 75:65-71. doi: 10.1016/j.fm.2017.07.006.
  8.     Lund BM, O’Brien SJ. The occurrence and prevention of foodborne disease in vulnerable people. Foodborne Pathog Dis. 2011 Sep; 8(9):961-73. doi: 10.1089/fpd.2011.0860.
  9.     “Five keys to safer food manual”, World Health Organization [Online]. Available: https://www.who.int/foodsafety/publications/consumer/manual_keys.pdf

Pathogen of the Month: Vibrio cholerae, the Causative Agent of Cholera

Vibrio cholerae
This blog was written by Dr. Jaclynn Moskow

 

Vibrio cholerae (V. cholerae) is a species of Gram-negative facultatively anaerobic bacteria of curved rod-shaped with single polar flagella. V. Cholerae has been classified into approximately 200 serogroups. Strains belonging to serogroups O1 and O139 cause the vast majority of cholera cases (1).

Vibrio cholerae is found naturally in brackish riverine, estuarine, and coastal waters. Recognized hosts of the organism include algae, shellfish, chironomid egg masses, fish, waterfowl, amebae, and copepods (2). V. cholerae colonies can form biofilms on both biotic and abiotic surfaces – including on shells, zooplankton, macroalgae, ship hulls, and plastic pollution (3-5). 

 

Cholera Transmission and Disease Severity 

Cholera is primarily transmitted through the consumption of fecally contaminated water and food. Foodborne outbreaks are most frequently linked to fish, shellfish, crabs, oysters, clams, rice, millet gruel, and vegetables (6).

Most V. cholerae infections are asymptomatic or mild in nature. Individuals with asymptomatic infections may still shed bacteria in their feces and infect others (7). Approximately 10% of V. cholerae infections will progress to severe disease (8). In endemic settings, the most severe infections occur in children, while in epidemic settings, severe disease occurs in adults as frequently as it does in children (9). 

Individuals with blood type O are more likely to suffer from severe V. cholerae infection (10). The use of drugs that reduce stomach acid, such as antacids, histamine receptor blockers, and proton pump inhibitors, also increases the risk of severe infection (11). 

 

Vibrio cholerae bacteria on agar
Vibrio cholerae isolated from feces obtained from a patient with profuse diarrhea who had traveled to India. Photo courtesy of Nathan Reading

 

 

Signs and Symptoms of Cholera

Cholera has an average incubation period of 1-5 days. Patients will experience a sudden onset of painless, watery diarrhea that may be accompanied by vomiting. The diarrhea is often characterized as having a “rice water” appearance and fishy odor. Fever is uncommon in adults, but often present in children (12).

In severe cases, dehydration may lead to the rapid progression to acidosis and electrolyte imbalance. Coma may occur. Without the replacement of fluids and electrolytes, hypovolemic shock and death ensue (12).

If left untreated, cholera has a 25-50% mortality rate. Proper treatment reduces the mortality rate to less than 1% (13).

Cholera vector illustration. Labeled infection structure and symptoms scheme. Educational infographic with unsafe water and food vibrio microorganism that causes diarrhea, vomiting and dehydration.

Diagnosis and Treatment of Cholera

Cholera is diagnosed via stool culture. When a case is suspected, healthcare and medical laboratory personnel should follow stool precautions.

Mild and moderate cases of cholera can be successfully treated with oral rehydration salts, while severe cases require rehydration with intravenous fluids (14). The World Health Organization (WHO) recommends reserving antibiotics as a treatment for severe cases only, as antibiotic use has no proven effect on controlling the spread of the disease and may contribute to antimicrobial resistance (15). In severe cases, tetracycline, doxycycline, azithromycin, erythromycin, or ciprofloxacin may be used (12). Most people who recover from V. cholerae infection incur long-lasting immunity (16).

 

Cholera Prevalence

Cholera originated in India and spread across the world during the 19th century (17). Since that time, there have been seven cholera pandemics, including one that is ongoing today (18). 

Currently, approximately 1.3 billion people are at risk for cholera in endemic countries. An estimated 2.86 million cholera cases occur annually, resulting in an estimated 95,000 deaths (19).

Over the last decade, the countries reporting the most cases of cholera have included Yemen, Somalia, the Democratic Republic of Congo, Mozambique, Bangladesh, and Haiti. If you have a GIDEON account, click here to explore the Cholera outbreak map. Cholera is exceedingly rare in Europe and the United States.

 

Cholera cases by region, 1953 – 2018

Cholera-cases-by-region-1953-2018

 

Cholera Prevention

Cholera cases by region, 1953 - 2018

When traveling to an area where cholera is endemic, precautions should include adherence to proper hand hygiene, drinking only bottled water, and avoiding uncooked food.

Ongoing worldwide efforts to end the current cholera pandemic center on increasing access to clean water and sanitation and expanding accessibility to existing cholera vaccines.

 

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References 

(1) Morris, “Infections due to non-O1/O139 Vibrio cholerae”, Uptodate.com, 2019. [Online]. Available: https://www.uptodate.com/contents/infections-due-to-non-o1-o139-vibrio-cholerae

(2) “Cholera: Environmental Reservoirs and Impact on Disease Transmission”, One Health, pp. 149-165, 2014. Available: 10.1128/microbiolspec.oh-0003-2012

(3) B. Wucher, T. Bartlett, M. Hoyos, K. Papenfort, A. Persat and C. Nadell, “Vibrio cholerae filamentation promotes chitin surface attachment at the expense of competition in biofilms”, Proceedings of the National Academy of Sciences, vol. 116, no. 28, pp. 14216-14221, 2019. Available: 10.1073/pnas.1819016116

(4) C. Lutz, M. Erken, P. Noorian, S. Sun and D. McDougald, “Environmental reservoirs and mechanisms of persistence of Vibrio cholerae”, Frontiers in Microbiology, vol. 4, 2013. Available: 10.3389/fmicb.2013.00375 

(5) J. Moskow, “What Do Plastics Have To Do With Infectious Diseases and the Immune System?”, GIDEON Informatics, Inc, 2021. [Online]. Available: https://www.gideononline.com/2021/04/22/what-do-plastics-have-to-do-with-infectious-diseases-and-the-immune-system/ 

(6) G. Rabbani, W. Greenough. “Food as a vehicle of transmission of cholera”, J Diarrhoeal Dis Res, vol. 17, no. 1, pp. 1-9, 1999

(7) J. Lewnard, M. Antillón, G. Gonsalves, A. Miller, A. Ko and V. Pitzer, “Strategies to Prevent Cholera Introduction during International Personnel Deployments: A Computational Modeling Analysis Based on the 2010 Haiti Outbreak”, PLOS Medicine, vol. 13, no. 1, p. e1001947, 2016. Available: 10.1371/journal.pmed.1001947

(8) Cholera – Vibrio cholerae infection: General Information”, Centers for Disease Control and Prevention (CDC0, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Division of Foodborne, Waterborne, and Environmental Diseases (DFWED), 2020. [Online] Available: https://www.cdc.gov/cholera/general/index.html

(9) J. Harris, R. LaRocque, F. Qadri, E. Ryan and S. Calderwood, “Cholera”, The Lancet, vol. 379, no. 9835, pp. 2466-2476, 2012. Available: 10.1016/s0140-6736(12)60436-x

(10) J. Harris and R. LaRocque, “Cholera and ABO Blood Group: Understanding an Ancient Association”, The American Journal of Tropical Medicine and Hygiene, vol. 95, no. 2, pp. 263-264, 2016. Available: 10.4269/ajtmh.16-0440

(11) S. Handa, “Which classes of medications increase the risk of cholera infection?”, Medscape.com, 2018. [Online]. Available: https://www.medscape.com/answers/962643-54708/which-classes-of-medications-increase-the-risk-of-cholera-infection 

(12) “Cholera”, GIDEON Informatics, Inc, 2021. [Online]. Available: https://app.gideononline.com/explore/diseases/cholera-10390

(13) J. Fournier and M. Quilici, “Choléra”, La Presse Médicale, vol. 36, no. 4, pp. 727-739, 2007. Available: 10.1016/j.lpm.2006.11.029 

(14) “WHO | WHO position paper on Oral Rehydration Salts to reduce mortality from cholera”, Who.int, 2021. [Online]. Available: https://www.who.int/cholera/technical/en/

(15) “Cholera”, Who.int, 2021. [Online]. Available: https://www.who.int/news-room/fact-sheets/detail/cholera 

(16) J. Harris, “Cholera: Immunity and Prospects in Vaccine Development”, The Journal of Infectious Diseases, vol. 218, no. 3, pp. S141-S146, 2018. Available: 10.1093/infdis/jiy414

(17) D. Lippi, E. Gotuzzo and S. Caini, “Cholera”, Paleomicrobiology of Humans, pp. 173-180, 2016. Available: 10.1128/microbiolspec.poh-0012-2015 

(18) S. Handa, “What are the 7 pandemics of cholera”, Medscape.com, 2018. [Online]. Available: https://www.medscape.com/answers/962643-54700/what-are-the-7-pandemics-of-cholera

(19) M. Ali, A. Nelson, A. Lopez and D. Sack, “Updated Global Burden of Cholera in Endemic Countries”, PLOS Neglected Tropical Diseases, vol. 9, no. 6, p. e0003832, 2015. Available: 10.1371/journal.pntd.0003832

Yellow Fever: Past and Present

1942, Innoculating eggs with yellow fever vaccine. USPHS (United States Public Health Service) Rocky Mountain Laboratory, Hamilton, Montana
Inoculating eggs with yellow fever vaccine, 1942. USPHS (the United States Public Health Service) Rocky Mountain Laboratory, Hamilton, Montana. Photographer: John Vachon

 

written by Dr. Jaclynn Moskow

What is Yellow Fever?

The yellow fever virus, a flavivirus, is transmitted via the bites of various mosquito species. The disease has an average incubation period of 3 to 6 days. The clinical presentation of yellow fever can vary greatly, ranging from a self-limited flu-like illness to overwhelming hemorrhagic fever – with a case fatality rate of 50%. Approximately 55% of yellow fever infections are asymptomatic, 33% are categorized as mild, and 12% severe (1).

Diagram of Symptoms of Yellow fever patient

Yellow fever generally manifests with the acute onset of fever, headache, backache, myalgia, and vomiting. Conjunctival infection may be seen, accompanied by facial flushing, relative bradycardia (Faget’s sign), and leukopenia. In some cases, fever and other symptoms may remit for a few hours to several days. Upon return of symptoms, icteric hepatitis and a hemorrhagic diathesis may follow with epistaxis, bleeding from the gums and gastrointestinal tract, and petechial and purpuric hemorrhages. Weakness, prostration, protracted vomiting, and albuminuria may also be noted. At this stage, patients will experience renal failure, myocardial dysfunction, necro-hemorrhagic pancreatitis, and seizures.

Yellow fever has a case fatality rate of 10 to 60% within 7 days of disease onset (1).

 

 

The Origin and Spread of Yellow Fever

Phylogenetic analyses indicate that yellow fever originated in Africa within the last 1,500 years. Its spread to the Americas coincided with the trans-Atlantic slave trade that began during the 16th century. It is likely that mosquitoes carrying yellow fever were imported into the Americas via slave ships (2). Significant outbreaks followed as the virus was introduced into populations with no pre-existing immunity. During the 18th and 19th centuries, approximately 25 major outbreaks claimed the lives of hundreds of thousands in New York City, Philadelphia, Baltimore, and New Orleans (3). Yellow fever also arrived in Europe during this time, with notable outbreaks occurring at Spanish, Portuguese, French, and British seaports (4).

It is estimated that for every soldier who died in battle during the Spanish-American War, 13 died of yellow fever (5). Yellow fever also killed many thousands during the construction of the Panama Canal. 

William C. Gorgas (1854-1920), on the site of Panama Canal construction.
William C. Gorgas (1854-1920), on the site of Panama Canal construction. As a U.S. Army surgeon during the Spanish American War, he established methods for eradicating mosquitoes hence reducing yellow fever and malaria among soldiers in Cuba. In 1904 he applied these techniques to control disease among the Panama Canal workers. Ca. 1910.

 

 

Development of a Vaccine for Yellow Fever

USA - CIRCA 1940: A stamp printed in USA shows portrait of Dr. Walter Reed, series Scientists, circa 1940

Early attempts to develop a vaccine for yellow fever resulted in the deaths of several test subjects and researchers. In 1900, a team led by Major Walter Reed traveled to Cuba to study the disease. At this point, the medical community was largely dismissive of the theory that mosquitos were the vectors of transmission for yellow fever. Working under the assumption that the mosquito theory was indeed incorrect, Reed’s team began experimenting with mosquitos and volunteers. After receiving criticism about using human test subjects, some team members decided to instead experiment on themselves. Unfortunately, this resulted in the death of physician-scientist Dr. Jesse Lazear – but with his death, the mosquito theory began to gain acceptance (6). 

Despite the death of Dr. Lazear, yellow fever research on human test subjects continued. The Reed team conducted a second and third set of mosquito experiments, offering financial compensation in the form of gold to study participants (6). After learning that none of these latest Reed study participants had died, Cuban physician Dr. John Guiteras began his own experiments. Unfortunately, three of his 42 test subjects succumbed to the illness, and with this, yellow fever research in Cuba came to a halt (7).

Subsequent efforts to control yellow fever centered on reducing mosquito populations as opposed to vaccine development, until 1918 when the Rockefeller Foundation began conducting yellow fever research. Within a year, Japanese scientist Dr. Hideyo Noguchi, who was working with the Foundation, announced that he had successfully developed a vaccine. Individuals in the United States, Latin America, and the French African colonies began receiving his vaccine, but the legitimacy of the studies leading to its development were soon called into question, and ultimately the vaccine was pulled (7).

The Rockefeller Foundation continued its efforts, and in 1925, they sent investigators to Lagos to determine if the African and South American diseases were caused by the same pathogen. Unfortunately, this trip resulted in three more investigators contracting and dying from yellow fever, including Dr. Noguchi. Nonetheless, the Rockefeller Foundation persisted, and a few years later, another candidate vaccine was developed – this time from efforts led by Dr. Max Theiler (7).

Despite the history of physician deaths related to yellow fever experimentation, Brazilian physician Dr. Bruce Wilson volunteered to receive the first dose of the Theiler vaccine. It was designated a success, and mass production began. Soon after, the Pasteur Institute developed their own vaccine, and for the next several years, the Rockefeller Foundation vaccine was used in the West as well as in England, and the Pasteur Institute vaccine used in France and its African colonies (7).

During World War II, the Rockefeller Foundation vaccine was given to almost all US soldiers. Unfortunately, the vaccine contained blood serum, and vaccination efforts resulted in approximately 330,000 soldiers contracting hepatitis B virus infection (8). Blood serum was subsequently removed as a component of the vaccine, and in 1953 a yellow fever vaccine was licensed for civilian use in the US (9). Use of the Pasteur Institute vaccine eventually ceased due to cases of postvaccinal encephalitis, but a variant of the Rockefeller foundation vaccine is still used today. Dr. Theiler received the Nobel Prize in Physiology or Medicine for his critical role in its development.

 

Yellow Fever in 2021

Yellow fever vaccination est. coverage 1980 - 2019

Today, the Centers for Disease Control and Prevention (CDC) recommends vaccination against yellow fever for individuals 9 months and older and who are traveling to or living in areas at risk in Africa and South America (10). It is a live attenuated vaccine, and thus contraindicated in patients who are immunocompromised. The vaccine is highly effective, with a median seroconversion rate of 99% (range 81–100%) in clinical trials (11).

Yellow fever is currently estimated to affect 200,000 people each year, resulting in 30,000 deaths, with 90% of cases occurring in Africa (12). Recent outbreaks have occurred in Brazil, Angola, Nigeria, and the Democratic Rep. of Congo. If you have a GIDEON account, click here to explore the Yellow Fever outbreak map. There are ongoing efforts to expand accessibility to the vaccine in these regions, as well as to implement additional vector control programs. 

The last outbreak of Yellow Fever in the United States occurred in 1905 (13). Yellow fever outbreaks ceased in Europe after World War II, when, for unknown reasons, the Aedes aegypti mosquito disappeared (14).

The absence of yellow fever in Asia is not fully understood. Some have speculated that differences in mosquito species may play a role. Another theory is that there may be a cross-immunity between yellow fever and other flaviviruses endemic to Asia, such as dengue fever. A third theory is that yellow fever has simply never been introduced into Asia (2).

 

 

 

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References

(1) “Yellow fever”, GIDEON Informatics, Inc, 2021. [Online]. Available: https://app.gideononline.com/explore/diseases/yellow-fever-12650

(2) Cathey and J. Marr, “Yellow fever, Asia and the East African slave trade”, Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 108, no. 5, pp. 252-257, 2014. Available: 10.1093/trstmh/tru043 

(3) F. Douam and A. Ploss, “Yellow Fever Virus: Knowledge Gaps Impeding the Fight Against an Old Foe”, Trends in Microbiology, vol. 26, no. 11, pp. 913-928, 2018. Available: 10.1016/j.tim.2018.05.012 

(4) M. Morillon, B. Marfart, and T. Matton, “Yellow fever in Europe in 19th Century”, Ecological Aspects of Past Settlement in Europe. P. Bennike, pp. 211-222, 2002.

(5) Staples, “Yellow Fever: 100 Years of Discovery”, JAMA, vol. 300, no. 8, p. 960, 2008. Available: 10.1001/jama.300.8.960 

(6) “Politics of Participation: Walter Reed’s Yellow-Fever Experiments”, AMA Journal of Ethics, vol. 11, no. 4, pp. 326-330, 2009. Available: 10.1001/virtualmentor.2009.11.4.mhst1-0904

(7) J. Frierson. “The yellow fever vaccine: a history”, Yale J Biol Med, vol. 83, no. 2, pp. 77-85, 2010

(8) M. Furmanski. “Unlicensed vaccines and bioweapon defense in World War II”, JAMA, vol. 282, no. 9, p. 822, 1999

(9) “Historic Dates and Events Related to Vaccines and Immunization”, Immunize.org, 2021. [Online]. Available: https://www.immunize.org/timeline/

(10)”Yellow Fever Vaccine Recommendations”, Centers for Disease Control and Prevention, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Division of Vector-Borne Diseases (DVBD), 2021. [Online]. Available: https://www.cdc.gov/yellowfever/vaccine/vaccine-recommendations.html

(11) J. Staples, A. Barrett, A. Wilder-Smith and J. Hombach, “Review of data and knowledge gaps regarding yellow fever vaccine-induced immunity and duration of protection”, npj Vaccines, vol. 5, no. 1, 2020. Available: 10.1038/s41541-020-0205-6 

(12) “Yellow Fever”, Centers for Disease Control and Prevention, Global Health, 2018. [Online]. Available: https://www.cdc.gov/globalhealth/newsroom/topics/yellowfever/index.html

(13) K. Patterson, “Yellow fever epidemics and mortality in the United States, 1693–1905”, Social Science & Medicine, vol. 34, no. 8, pp. 855-865, 1992. Available: 10.1016/0277-9536(92)90255-o 

(14) “Facts about yellow fever”, European Centre for Disease Prevention and Control, 2021. [Online]. Available: https://www.ecdc.europa.eu/en/yellow-fever/facts

 

 

How Vaccines Work

Development and manufacture process of a new vaccine. Final production of filled vials of Covid-19 vaccine. Bio science 3D illustration.

 

You may know they save lives, but have you ever wondered how vaccines work? As mass vaccination programs in response to the COVID-19 pandemic are underway, there is a heightened interest in understanding vaccines and their mechanism of action.

Vaccines stimulate the immune system to recognize and respond to specific pathogens. Differing vaccines accomplish this through a variety of mechanisms. Vaccines can be divided into five basic categories: live attenuated vaccines, inactivated vaccines, subunit vaccines including toxoids, mRNA vaccines, and viral vector vaccines.

 

Live Attenuated Vaccines

Live attenuated vaccines contain live viruses or bacteria that have been weakened to reduce virulence. Following ingestion or injection, the body mounts an immune response that is similar to what would occur if it were to encounter the natural disease. Since the pathogens used in live attenuated vaccines have been weakened, they cause only mild symptoms – or no symptoms at all. Live attenuated vaccines generally provide the longest-lasting immunity of any vaccine type.

Examples of live attenuated viral preparations include measles, mumps, rubella, varicella, rotavirus, yellow fever, oral polio vaccine, and intranasal influenza vaccine. Live attenuated bacterial vaccines include the BCG vaccine for tuberculosis and the oral cholera vaccine. In general, viral vaccines have greater efficacy than bacterial vaccines.

The eradication of smallpox was accomplished through a live attenuated vaccine, which contained a related virus (vaccinia). In the veterinary world, widespread use of a live attenuated vaccine led to the eradication of Rinderpest, also known as ‘cattle plague’, caused by a morbillivirus of the family Paramyxoviridae. 

Live attenuated vaccines are generally contraindicated in pregnant women and immunocompromised patients, such as those receiving immunosuppressive therapy or living with HIV/AIDS or congenital immunodeficiency. 

It is extremely rare for a live attenuated vaccine virus to mutate into a more virulent form and cause disease. Cases of this phenomenon have been documented with oral polio vaccine, at a reported rate of one case per 750,000 children receiving their first dose (1). As a result of these rare instances, in many countries (including the United States), the oral polio vaccine is no longer used and has been replaced by inactivated preparations.

 

How inactivated vaccines work

Inactivated vaccines, also known as killed vaccines, prime the immune system with bacteria or viruses that have been inactivated to remove all virulence. They cannot cause the disease they protect against and are generally considered safe for immunocompromised and pregnant patients. The protection provided by inactivated vaccines does not usually last as long as that provided by live attenuated vaccines, and booster doses are often recommended. 

Examples of inactivated vaccines include hepatitis A, rabies, intramuscular influenza, intramuscular polio, and variants of the pertussis vaccine. Several inactivated SARS-CoV-2 vaccines have been developed, including China’s “Sinovac”, India’s “Covaxin”, and Russia’s “CoviVac”.

 

How vaccines work: inactivated vaccine
Inactivated vaccine mechanism of action

 

How subunit vaccines work

Subunit vaccines contain fragments of a pathogen (i.e., a polypeptide or polysaccharide) often bound to other molecules. As with inactivated vaccines, these cannot produce the disease itself and are generally considered safe for immunocompromised and pregnant patients. Booster doses are often required.

Examples of subunit vaccines include hepatitis B, human papillomavirus (HPV), Haemophilus influenzae type B (HiB), herpes zoster, meningococcus B, pneumococcal, and one variant of the pertussis vaccine. Occasionally, the subunit used in these vaccines is an attenuated toxin (toxoid).  Examples of toxoid vaccines include tetanus and diphtheria.

There are several subunit vaccines for SARS-CoV-2 in various stages of clinical trials around the world.

 

Messenger RNA (mRNA) – a new type of vaccine

mRNA vaccines are a new type of vaccine and contain fragments of mRNA that encode a piece of protein from the pathogen of interest. After being vaccinated with such a vaccine, the body’s own cells incorporate the mRNA and produce the protein, which the immune system then recognizes as foreign. The Pfizer-BioNTech and Moderna COVID-19 vaccines are both mRNA vaccines. There are several additional mRNA vaccines currently in development. 

 

How vaccines work: mRNA vaccine schematic illustration
mRNA vaccine mechanism of action

 

How viral vector vaccines work

Viral vector vaccines use modified versions of viruses as “vectors” to deliver a nucleic acid of the pathogen of interest into the cell. Once inside the cell, the DNA is transcribed into mRNA, and the mRNA is translated into protein. The body then recognizes this protein as foreign and mounts an immune response, similar to that which occurs with mRNA vaccines. The Johnson & Johnson COVID-19 vaccine works in this manner.

 

How vaccines work: viral vector vaccine
Viral vector vaccine mechanism of action

 

 

Dr. Steve Berger on Vaccines

GIDEON co-founder Dr. Steve Berger, reflects on vaccines: “Vaccines continue to save millions of lives and have prevented untold misery to the human species. Although the effectiveness of individual vaccines may vary, and most may cause occasional side effects, the cost of non-vaccination – in both death and suffering – will always be much higher.”

 

Optimizing Immunity

Proper nutrition, exercise, ample sleep, and adequate levels of Vitamin D have been shown to enhance the efficacy of vaccines as well as strengthen the immune system as a whole. This is discussed in more detail in our blog: Strengthen Your Immune System! Your Guide to the Ultimate 2021 New Years Resolution

 

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References:

(1) “Poliomyelitis Prevention in the United States: Introduction of A Sequential Vaccination Schedule of Inactivated PoliovirusVaccine Followed by Oral Poliovirus Vaccine; Recommendations of the Advisory Committee on Immunization Practices (ACIP)”, Cdc.gov, 1997. [Online]. Available: https://www.cdc.gov/mmwr/preview/mmwrhtml/00046568.htm.

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