February CE Article

February CPE Article

A Global Pandemic: Once a History Lesson Now a Modern-Day Reality –A Comparison Between the Spanish Flu and COVID-19 Pandemic

Author: Jessica Mattingly, 2021 PharmD Candidate; Abigail Quinlin, 2021 PharmD Candidate; Amy Priest, 2022 PharmD Candidate; Emily Frederick, PharmD, BCPS The author declare that there are no financial relationships that could be perceived as real or apparent conflicts of interest. Universal Activity #0143-0000-21-001-H06-P &T 1.0 Contact Hours Expires 3/12/24 Learning Objectives: At the conclusion of this Knowledge-based article, the reader should be able to: 1. Compare and contrast influenza H1N1 with COVID-19. 2. Assess the severity of the viral infections. 3. Review “treatments” for each viral process.

With the COVID-19 pandemic still causing global health and safety concerns and dominating news cycles, it may be difficult to recall a time the nation has ever previously been so strained by a healthcare crisis. However, this is not the first time such a large-scale pandemic has rocked the nation and likely not the last. One notable historical example of a large-scale pandemic is the 1918 influenza pandemic (also referred to as the Spanish Flu). Though over 100 years have passed since the onset of the 1918 influenza, many references and comparisons have been drawn between it and COVID-19. Though the two pandemics differ in their causative agents, they also share some parallels such as the global response to each. The Spanish influenza spread globally between 1918-1920 and was caused by the orthomyxovirus, subtype H1N1. This virus wreaked havoc initially in Europe before eventually spreading throughout the United States in “waves”1. The initial wave in the United States resulted in mass illnesses, but relatively low mortality rates that are similar to annual influenza mortality rates. As the infection rates from the first wave decreased another wave was looming. The next wave struck a few months later and spread throughout Europe. The spread of this wave was thought to be partially due to shipping goods and the subsequent contacts made upon carrier ships docking at shore. This wave contributed to the majority of infections and deaths attributable to the virus. The final wave of the pandemic struck the United States in early 1919. This final wave had a lower rate of infection than the second waved but still retained a similar mortality rate as compared to the second wave2. In total, it was estimated that the Spanish Flu lead to more than 500 million cases of infection and greater than 50 million individuals losing their lives due to the virus1. It has been postulated that the impacts of Spanish Flu could have been exacerbated by several factors including uncleanliness and overcrowding. The symptoms of infection varied based on the severity of illness, but patients often presented with symptoms such as fever, headache, nosebleed, pneumonia, encephalitis, blood-streaked urine, and coma. Those infected were also at risk of acquiring a secondary bacterial pneumonia infection that further increased the possibility of complications and increased the mortality rate1. At the time when the 1918 influenza shocked the world, science was less advanced compared to today and there were not any known vaccines or medications that were effective in mitigating it. Non-pharmacologic treatment options were conceptualized and applied in certain cases, but success was limited. For example, in China, people sprayed their houses with lime water or powder

and burned rhubarb and atracytoldes rhizome to disinfect the air. Additionally, for prevention some recommended drinking soup that was made from mung bean and rock sugar several times a day. Herbal remedies were also attempted to treat infected patients. Despite these efforts, it was not until the late 1930’s that a viable vaccination to treat influenza was finally in the developmental stages but even still, an empiric formulation did not become available to the masses until 19454. Similar to the impacts of the Spanish Flu, COVID-19 has also rattled global society due to its high transmissibility and its lack of proven effective treatment option. Though similar in impact, COVID-19 differs from the Spanish Flu in its origin. COVID-19 is a respiratory infection caused by the SARS-COV-2 virus. The virus is theorized to have begun its infectious pathway via animal source at a market in Wuhan, China. This market was involved in the trade of fish and more “exotic” animals, such as bats – which is believed to be the original source of infection. The virus mutated from the form which infected the bat and was able to successfully infect humans in a mechanism that was previously never seen by the immune system. The first COVID-19 cases were reported in December 2019 and eventually spread throughout the world. Similar to the waves of Spanish influenza infection, the COVID-19 pandemic has been manifesting in peaks and troughs of infection rates. In March of 2020, the World Health Organization (WHO) declared COVID-19 a global pandemic5. The initial symptoms of COVID-19 infection included fever and dry cough which can progress to respiratory distress6. The CDC has published an expanded symptom list that includes chills, difficulty breathing, fatigue, body aches, headache, loss of taste or smell, congestion, runny nose, nausea, vomiting, diarrhea7. Each of these symptoms is used in health care facilities, inpatient and outpatient a like, around the nation in order to screen patients coming in for COVID-19. The virus is primarily spread through respiratory droplets (usually from coughing or sneezing) that either directly or indirectly infiltrate mucous membranes in the eyes, nose, or mouth. With this mode of transmission, a person can become infected simply from someone coughing in their face or from touching a contaminated surface and then immediately touching their face. This transmission pathway is referred to as aerosolized transmission and is the basis for the mask mandates and hand washing recommendations by the government and the CDC. Once infected, it can take up to 14 days to exhibit symptoms, but there have been reports of symptoms appearing in as little as two days postexposure. Regardless of the length of the presymptomatic period, during the asymptomatic period an infected person can still actively spread the virus. There are even individuals who have appeared asymptomatic but are still capable of transmitting infection unknowingly. In addition to being highly transmissible, COVID-19 has also proven to be particularly dangerous to patients considered to be high-risk. These patient populations include older adults and patient with certain disease states such as cancer, chronic kidney disease (CKD), chronic obstructive pulmonary disorder (COPD), solid organ transplant recipients, obesity, heart failure (HF), coronary artery disease (CAD), cardiomyopathies, sickle cell disease, or type 2 diabetes mellitus (T2DM)7. Once a person begins to show signs of COVID-19 infection, they may still present with an array of symptoms of varying severity. Some severe cases can often result in hospitalization. Such severe disease complications may include trouble breathing, pain or pressure in the chest, new onset confusion, inability to wake or stay awake, and/or a bluish tint to the lips or face. Upon admission to a hospital facility, a patient will first be screened for symptoms and then a COVID-19 test will be administered to confirm or rule out a diagnosis. There are two different types of COVID-19 tests. One method of testing screens for the presence of antibodies which indicate a history of infection. Generally, the presence of antibodies provides protection from the possibility of future infections from the same agent. However, it is currently uncertain as to whether a person previously infected with COVID-19 is protected from future exposures, and more research is needed in this realm. The other type COVID-19 test which is currently more commonly used is a viral test7. This test result indicates whether a patient currently has an infection, but its accuracy levels run the risk of generating false negatives or false

positives. Newer tests have been approved with better results – 3% risk of false positives and 1.5% risk of false negatives8. Consequently, lab values and imaging tools are often utilized in inpatient settings when symptoms suggest the presence of COVID-19 of infection, but the test results do not. Diagnostic imaging and laboratory values are used clinically to judge the diagnosis and resolution of the infection but are not definite. Rather, these tools are used with clinical judgement in order to provide the best possible treatment for patients. Certain images seen on chest x-rays include bilateral multi-focal opacities or peripheral ground glass opacities which lead to areas of consolidation upon further resolution of the disease. Opacities are seen with many disease states such as bacterial or viral pneumonia. Though imaging studies may assist in diagnosing COVID-19, diagnostic testing and best clinical judgement should be used for each patient presenting with a possible COVID-19 diagnosis. As for laboratory values in possible COVID-19 cases, leukopenia, lymphopenia, elevated aminotransferase, C-reactive protein, D-dimer, ferritin, and lactate dehydrogenase are commonly seen9. Currently, there are no definitive treatments or vaccinations for COVID-19 and no recommended preventative measures or post-exposure treatment, without severe inpatient disease. However, many possible treatment options have been speculated and treatment ideas for severe disease have examined medication mechanisms of action and clinical testing to determine validity and support further use. Current possible therapy regimens include the use of anticoagulation with dexamethasone 6 milligrams and use of remdesivir if the inclusion criteria are met. The NIH guidelines have recommendations for remdesivir based on the severity of symptoms. With limited supplies, remdesivir was recommended for hospitalized patients who require supplemental oxygen but are not on high flow oxygenation, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). Typical therapy duration is 5 days for remdesivir and 10 days for dexamethasone. In addition to the aforementioned possible treatment options, Table 1 summarizes other theorized treatment options along with their current known efficacy levels for COVID-19 treatment and their possible patient safety concerns. COVID-19 can affect people in varying severity and has a spectrum of complications. There is a surge in prothrombic molecules, and the effect typically presents in the lungs. Lung tissue becomes damaged due to the inflammation and allows fluids to infiltrate the lungs, making it difficult to breathe. The body tries to repair the damage by synthesizing fibrotic tissue, which impairs the ability of the lungs to expand and contract. This tissue further inhibits the ability to breathe and can cause chronic impairment. Furthermore, the surge in prothrombic molecules increases the risk for thrombosis which can lead to a heart attack, stroke, pulmonary embolism, or deep vein thrombosis. These conditions can have a lifelong effect on the patient and impact their quality of life. At the time of publication (11/09/2020) the US has seen 9,913,553 cases with 237,037 deaths. The state with the highest death rate is New York with 33,439 deaths while Vermont has the least with 59 deaths. However, in terms of cases California is has the most cases (964,639) and Vermont has the least (2,392).7 Though each pandemic was caused by a different virus and over 100 years separate the two public health crises, they share many parallels. Both pandemics have disrupted normal functioning of society and have instilled fear due to lack of evidencebased treatment or prevention options available. However, in each pandemic many still have attempted to use either herbal or pharmacologic therapy in a novel way in hopes some agent will be found that may prove effective in curbing infections. Finally, it can be noted that over twenty years passed before an effective vaccine for influenza reached the market. In present time, society has far advanced in medical science and technology which likely will assist in developing a vaccine to curtail the COVID-9 pandemic, but it is imperative that diligent research and clinical trials are conducted to ensure any vaccine that reaches the market is safe and effective. References: 1.

Martini M, Gazzaniga V, Bragazzi NL, Baberis I.

The spanish influenza pandemic: a lesion from history 100 years after 1918. J Prev Med Hyg. 2019; 60(1):E64-E67.

Proposed Therapy Mechanism of Action

Hydroxychloroquine10 Chloroquine10 Prevents fusion to host cell membrane and blocks release of viral genome IL-1 and IL-6 inhibitors10 Inhibits cytokine storm

Mesenchymal Stem Cells9 Immunomodulary properties

Concerns

No longer recommended QTc prolongation Retinal toxicity Long half-lives (40 days) Not currently studied Infections

Insufficient data Infections Tumor growth Thrombus formation Administration site reactions

Vitamin C9

Vitamin D9 Antioxidant Free-radical scavenger Anti-inflammatory properties Receptor expressed on B and T cells and Antigen Presenting cells Insufficient data

Insufficient data

Zinc9 Increased concentrations efficiently impair replication in RNA viruses

Insufficient data Recommend against doses above the recommended dietary allowance Antithrombotic therapy9 Antagonize the prothrombic state Recommended with no contraindications -on chronic therapy continue -prophylactic doses -treat thrombosis therapeutically

Corticosteroids9

Remdesivir9 Inhibit cytokine storm

RNA chain termination Recommended on supplemental oxygen Recommended in COVID+ on supplemental Oxygen but not highflow, mechanical ventilation, or ECMO May affect point of care glucose readings

Nephrocalcinosis

Anemia Leukopenia Ataxia Paresthesia Copper deficiency Bleeding HIT thrombocytopenia

hyperglycemia

Increase in LFTs Increase in SCr Increase PTT GI symptoms

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Cheng KF, Leung PC. What happened in china during the 1918 influenza pandemic? Int J Infect

Dis. 2017; 11(4):360-364. 4. Wallace R. Medical innovations: from the 1918 pandemic to a flu vaccine. The National WWII

Museum – New Orleans. 2020 Apr; 2020 Sept.

Rico-Mesa JS, White A, Anderson AS. Outcomes in patients with COVID-19 infection taking

ACEI/ARB. Curr Cardiol Rep. 2020; 22(5):31. 6. Li Y, Bai W, Hashikawa T. The neuroinvasive po-

tential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J Med Virol. 2020 Mar 11. [Epub ahead of print]. 7. United States COVID-19 Cases and Deaths by

State. CDC. https://covid.cdc.gov/covid-datatracker/#cases_casesper100klast7days. 2020

Jan; 2020 Nov 5; 2020 Nov 5. 8. FDA – BinaxNOW COVID-19 Ag CARD. FDA. https://www.fda.gov/media/141570/download. 2020 Aug; 2020 Nov. 9. 2020 NIH COVID-19 Treatment Guidelines. Published online 2020 Jul 17. Updated 2020 Jul 30.

Accessed 2020 Aug 8.Kotwani A, Gandra S. Potential pharmacological agents for COVID-19.