Introduction

Tuberculosis (TB) is the world’s leading killer amongst infectious diseases. In 2017, 1.6 million people died from TB, making it one of the top ten causes of mortality worldwide.¹ TB is preventable and curable, but elimination remains a challenge. Worldwide, the regions with the highest number of cases of TB are Southeast Asia and Africa, accounting for approximately two-thirds of the reported cases.² As such, the elimination of TB is a key priority of the WHO,³ included in the Sustainable Development Goals (SDGs) with a target to “end the epidemics of AIDS, TB, malaria and neglected tropical diseases and combat hepatitis, water-borne diseases and other communicable diseases” by 2030.³

In the United States specifically, public health initiatives within health departments and TB control programs had a tremendous impact on the prevention and management of TB.⁵ Although it remains a concern, the rate of TB in the United States continues to drop slowly. A total of 9,105 TB cases (a rate of 2.8 cases per 100,000 persons) were reported in the US in 2017. This is a decrease from the number of cases reported in 2016 and the lowest case count on record.⁶ However, due to the ongoing public health implications of the disease, TB remains a focus area in the Healthy People agenda for the nation. Included in the specific topics and objectives are goals to reduce TB, increase the completion rate of all TB patients who are eligible to complete therapy, and to increase the percentage of contacts to sputum smear-positive TB cases who complete treatment after being diagnosed with latent TB infection (LTBI) and initiated treatment for LTBI.⁷

Elimination of TB will require a worldwide effort to decrease transmission for active cases, access to quick treatment, as well as strategies to screen for and manage latent TB infection. The USPSTF recommends screening for latent TB infections in populations at increased risk.⁸ Cases of active TB must be treated quickly, as the disease is contagious, with an estimated capacity of a single person with untreated and active disease to infect as many as 15 people within a year.¹ Drug resistance is also a concern, with over half a million new cases of TB in 2017 demonstrating resistance to first-line therapy, including 82% with multi-drug resistant TB (MDR-TB).¹ Effective treatment requires adherence to complex medication regimens over several months.⁹ Management requires trained health care providers who are able to provide long-term, patient-centered care.

Case (part 1)

BR is a 38-year-old female nurse who works full time at a local academic hospital within the United States. A couple of months ago, she traveled to India in order to spend time with her family and experience the community in which her parents were raised. During the month BR spent in India, she was in close contact with various friends and family, as well as many members of the local community. Upon her return to the US, BR returned to her job as a bedside nurse, moved in with her fiancé, and resumed volunteering on the weekends at a local homeless shelter. She is also excited for an upcoming trip to Singapore but is anxious about the 24 hours of flying that it will involve.

Due to her role as a healthcare worker, BR was recently required to be screened for TB during the hospital’s annual TB testing period. Much to BR’s surprise, the healthcare worker who read her PPD skin test reaction stated that she had a positive result of 11 millimeters. Thinking that this could be a false-positive test, BR agrees to get further testing completed including a chest x-ray.

1. How common is TB worldwide and within the US? Which countries have the highest incidence of TB? Which countries have the highest rates of drug resistant TB?

Approximately 10 million people around the world are infected with TB yearly. In the United States, the most recent data from 2017 shows 9,105 cases of TB with at least one case reported in all 50 states. The countries with the highest incidence of TB are numerous and include India, Indonesia, China, Nigeria, Pakistan, South Africa, Bangladesh, Democratic Peoples Republic of Korea, Philippines, Democratic Republic of Congo, Ethiopia, Myanmar, United Republic of Tanzania, Mozambique, Lesotho, Liberia, Viet Nam, Russian Federation, Thailand, Kenya, Brazil, Uganda, Afghanistan, Cambodia, Zambia, and Zimbabwe. The countries with the highest rates of multidrug resistant TB are Moldova, Ukraine, Russian Federation, and Uzbekistan.

2. What are some factors that have contributed to the rise and fall of TB infections around the world? What are some barriers to combating the disease worldwide?

Coordinated national programs with adequate funding led to the fall of TB infections. In addition, drug discovery lead to great advances in the elimination of TB. Streptomycin and para-aminosalicylic acid were used to treat TB starting in 1944, then the triple therapy regimen of streptomycin, para-aminosalicylic acid and isoniazid in 1952 allowed for cure of TB. The course of therapy was shortened from 18 months to 9 months with the addition of isoniazid and rifampin in the 1970’s; and lastly, in the 1980’s, the addition of pyrazinamide made treatment courses 6 months in duration. However, with antimicrobial therapy comes drug resistance. Drug resistance is one of the greatest challenges in TB control. Needed are new medications and regimens with efficacy against drug-resistant TB with shorter treatment durations.

Some other factors that have contributed to the rise and fall are the HIV/AIDS epidemic and IV drug use. These both contributed to the resurgence of TB. Rates of latent TB are high among injection drug users, and HIV infection can activate latent TB as well as accelerate the course of the disease. Human migration, especially from rural to urban areas also influences the spread of TB.

The challenges to combatting the diseases are great. Tuberculosis control requires all nations to coordinate screening, prevention, and treatment at multiple levels. Some barriers to this are access to adequate health care, stigma, shortage of health care workers, inadequately funded health care systems with challenges in medication supply chain, lack of rapid diagnostic tests, and long courses of treatment. In addition, research and development for new medications are lacking.

3. How are tuberculin skin testing reactions interpreted? Does the classification of positive tuberculin skin test reactions differ depending on patient risk factors?

Tuberculin skin test reactions should be read within 48-72 hours after administration and should be measured in millimeters of the induration. The reading should be based on a palpable, raised, hardened area or swelling and not on erythema. Reactions are interpreted based on measurement of the induration, person’s risk of being infected, and risk of progression to disease if infected.

An induration of 5 millimeters or more are considered positive in HIV infected persons, persons with recent contact with a person with TB disease, persons with fibrotic changes on chest x-ray, patients with organ transplants, or immunosuppressed individuals. An induration of 10 or more millimeters are considered positive in recent immigrants from high-prevalence countries, injection drug users, residents and employees of high risk settings, mycobacteriology laboratory personnel, children less than 4 years of age and infants, children, or adolescents exposed to high risk adults. An induration of 15 millimeters or more is considered positive in any person with no known risk factors for TB.

Case (part 2)

After some consideration, BR decided that she was too busy planning her rapidly approaching Singapore trip to squeeze in doctors’ appointments and, therefore, would postpone any further testing until her arrival back in the US. She argued that “she didn’t look sick and had no cough” and could not possibly be infectious. Five days later BR boarded a flight from John F. Kennedy airport in New York to Hong Kong International airport and then a separate flight from Hong Kong to Singapore Changi airport. Enduring the 24 hours of travel she proceeded to enjoy her trip according to her itinerary and two weeks later reversed her trip from Singapore to Hong Kong and then from Hong Kong to New York.

4. Which factors influence the extent to which communicable diseases are transmitted? How is TB transmitted, and why is that important to public health?

Populations living in poverty and/or crowded conditions or lacking access to adequate nutrition are at a higher risk of contracting a communicable disease. Low-income countries and impoverished areas in large cities in developed countries typically have the highest rates of TB.

TB bacteria are spread through the air from one person to another through coughing, speaking, spitting or any action where a person exhales. People who are in close proximity may inhale droplets containing TB and become infected. This is important from a public health perspective because of the potential of the disease to be spread from person to person via air droplets. Persons who are infected must be treated to prevent the spread of disease.

5. How do you explain to BR some of her risk factors for contracting TB?

Explain to BR that her close contact with persons, who may be infected with TB, increases her risk of contracting TB. Her employment as a nurse at a local hospital and her work at a local homeless shelter put BR in close contact with populations that are more likely to be infected with TB. BR could also have been exposed to individuals with TB during her time within local communities in India, as India is believed the be one of the countries with the highest burden of TB.

Case (part 3)

Upon returning to the US, BR’s chest x-ray showed abnormalities and her physicians performed further testing to confirm a diagnosis of TB and to obtain a sample isolate. BR did not understand how this could be possible, since she did not have any symptoms of an active infection. While awaiting further testing on her isolate by the CDC, BR was started on standard therapy for the treatment of TB and was advised by her providers to refrain from any further travel. It was also advised that any family members, friends or coworkers that had been in close contact with BR also be tested for TB. Additional testing by the CDC of her TB isolate confirmed MDR-TB, and BR’s physicians told her that she would have to undergo more extensive treatment in isolation until she was no longer infectious.

6. What are considered common treatments for active TB and what is the typical duration of treatment?

At a minimum, patients with active TB are treated with four drugs (isoniazid, pyrazinamide, rifampin, and ethambutol) for an eight-week intensive period followed by two drugs (isoniazid and rifampin) for an additional 18 weeks.⁹

TB treatment guidelines are regularly updated, so it is important to keep current. The Centers for Disease Control and Prevention provides guidelines for treatment in the United States; however, if working internationally, it is important to investigate the national treatment guidelines in the country where you are working. Additionally, the World Health Organization prepares TB treatment guidelines.¹⁰

7. What are risk factors for multidrug resistant TB? How does treatment differ if a patient is diagnosed with MDR-TB?

Those at risk of developing MDR-TB include patients who are not adherent to their TB treatment, those who have relapsed and are being treated again for TB, people who are exposed to family members or others in proximity who have MDR-TB, and patients with weakened immune systems.

Patients with MDR-TB undergo a much more complex treatment regimen, which should take into account resistance patterns to determine what will certainly, or almost certainly, be effective. The treatment should include at least four active drugs and will often include more if the susceptibility pattern is unknown or unclear. Drug-resistant TB regimen durations are considerably longer – some as long as 24 months – often with regular injections.¹⁰

Clinicians should consult experts in this field before beginning an MDR- or XDR-TB treatment regimen.¹⁰

Case (part 4)

With the knowledge that a passenger onboard recent international flights had been traveling with active TB infection, the CDC began trying to track down all passengers and crewmembers who were on the commercial flights of which BR had been a passenger. It was highly suggested that these individuals also get tested for TB after having been in a confined space for many hours with an infected person. The CDC placed a specific focus on the flights from New York to Hong Kong, due to the duration of the flight, and extra attempts were made to get in touch with the passengers seated close to BR during the time of travel. Additionally, the hospital where BR was actively employed had to alert all employees and patients, who had been in close contact with her for extended periods of time, to consider undergoing additional TB testing.

8. What is the risk of communicable diseases being transported on board an aircraft? Does the duration of the flight have any impact on risk?

Diseases most likely to be transmitted on board aircraft include airborne and droplet borne diseases. Current evidence shows that the risk of transmission is likely low, although transmission likely occurs more frequently than reported. This is because most people do not become sick until well after their travel date, due to the long incubation period of most diseases. Although transmission of TB on board an aircraft is possible, the risk of transmission is low and generally limited to persons in close contact with an infectious case for 8 hours or longer. An even smaller number of individuals that become infected will subsequently develop active disease.

9. What is the incubation period for TB, and does that affect the timing of testing for individuals who may have been exposed?

The incubation period for TB varies, with most resources stating the incubation period is between two to twelve weeks. It is important to note that TB skin test reactions may not be positive in someone who has been recently infected with TB, because it can take several weeks after infection for a person’s immune system to react to the skin test. Individuals may require a second skin test approximately 8-10 weeks after exposure to someone with TB disease.

BR’s case of MDR-TB diagnosis and subsequent travel brings up a great deal of questions in relation to the spread, diagnosis and treatment of communicable diseases such as TB. While the WHO is working on developing programs and treatment regimens to help combat the disease, there still exist many barriers to being completely successful. One challenge to forward progress, which presents a real risk to the US, is the segment of the global community living with unrecognized, active TB. This risk is of particular importance as individuals within the US participate in high rates of global travel. As more and more people travel to and from the US each year, concerns remain regarding the potential impact on US security and the potential outcomes related to passenger contact with TB. Limited data exist surrounding these probable hazards, which further highlights the active role of government and healthcare workers in mitigating such risks.

10. Is there a role in the future for a coordinated, international approach to data collection and operational decision-making, and what is the role of the US in these discussions?

With infectious diseases and outbreaks, there is always a role for a coordinated and international approach with shared responsibility. DOTS helped to standardize treatment, but new strategies are needed to better understand ongoing transmission. TB requires persistence with partnerships.

The US plays an important role through the CDC, which has served as a leader in surveillance and training for other infectious diseases and has the capacity to represent the US in a coordinated approach. USAID works with the United Nations to ensure that funding is allocated to partners to support a coordinated effort to end TB.

11. Does the US government have the authority to isolate or quarantine individuals traveling to and from the US if they are deemed a public health risk?

Yes, the US federal government has the ability to both isolate – separate those with a contagious disease from those who are not sick – as well as quarantine – separating and restricting the movement of those exposed to monitor for the disease – those who may come into the country with a disease. They also have the ability to prevent the spread between states. State and local authorities also have the ability to quarantine and isolate contagious or potentially contagious people within their borders.

Author Commentary

Treatment for TB is a long and challenging process. It is difficult for patients and for the health systems that are funding these long, expensive treatments. While the WHO and others are spearheading shorter MDR-TB treatment regimens,¹⁰ challenges still exist in bringing the disease under control.¹¹ Newer drugs that are less toxic, require shorter treatment durations, and are less expensive are needed. While new drugs are being developed, it is a slow process. The required research and development prospects are thin,¹ and pharmaceutical industry spending in this area is continuing to decline.¹²

At one time, TB was viewed as a disease of despair – affecting those with low-incomes, substandard housing, and little access to care. TB is still linked with health disparities; however, with as many as 36% of those with active TB going unrecognized in a world with millions of people with active disease,¹ TB is a disease that knows no boundaries. This puts the US population at risk. It is clear investments also need to be made into TB screenings and prevention. While UN SDGs aim to end the TB epidemic by 2030, major gaps exist in the funding required to reach this goal.¹²

As health care providers, we need to be able to recognize the signs and symptoms of TB and to link our patients to care, but that is not enough. We need to be advocates for our patients and for our communities. We need to speak up and work with policymakers to tackle social determinants of health and TB. As pharmacists, we call ourselves the “drug experts.” TB is a disease with massive drug impacts, and if we truly are public health professionals and drug experts, we cannot stay silent.

Patient Approaches and Opportunities

While the therapeutics of TB treatment is not the focus of this chapter, it is important for public health providers – especially pharmacists – to understand patients’ treatment burden. Drug-susceptible TB treatment typically lasts at least six months with the intensive phase including four drugs.⁹ Drug-resistant TB regimens are generally considerably longer – some as long as 24 months – often with regular injections.¹⁰ These drugs also have significant side effects, and patients with the disease are often grappling with stigma. This is concerning as patients who abandon treatment midcourse not only do not improve, but they are more likely to develop a resistant form of TB. As such, it is vital that patients are adequately prepared and that trusting relationships are built so that our patients can seek guidance if support is needed during the treatment process.

Adherence to TB treatment is vital because with proper treatment TB is curable. It is important that as pharmacists we properly counsel patients on their medications and help them develop adherence strategies. These concepts need to be reinforced during every pharmacy visit. Patients who are not compliant with their medications should be connected with a public health department to investigate enrolling in a Directly Observed Therapy (DOT) program where a healthcare worker can observe the patient taking medications each day. The Missouri Department of Public Health and Senior Services, for example, has an eDOT program where healthcare providers can remotely observe the patient taking medications either in real time or via recordings.¹³

While overcoming the worldwide TB burden can seem like a daunting task, pharmacists have an opportunity to play a vital role in the battle against TB. By building relationships with our patients, we can help them to process and overcome stigma, work together to navigate cultural differences and help to increase adherence. We are also at the front lines and can help to identify patients with TB symptoms and refer them to the appropriate healthcare provider.