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Drugs for COVID-19: A Publishing Epidemic

written by Dr. Stephen A. Berger

As of April 9, PubMed listed 2,868 scientific publications that incorporate the word “COVID”.   323 of these (11.3%) were related to drugs under study for the treatment of the disease. No fewer than thirty-one such drugs had been proposed since this pandemic first appeared on the planet four months earlier.   

Graph 1 depicts the cumulative numbers of COVID-19 infection (per 100,000 global population) and introductions of relevant drugs into the Literature from February 14 to April 3. Note that both increased by a factor of approximately 16-fold during this period.

In a biological sense, the “doubling time” for drug publication is similar to that of COVID-19 infection. Indeed, just as there is an incubation period between acquisition of the disease and the reporting of a given case, there is a delay period between submission of an article and its appearance in PubMed (one suspects that this process has been streamlined during the current emergency). There may even be an element of “contagion” at work in the publishing “explosion”.  

Many of the papers on COVID are repetitive, and an increasing number are reactive; ie, published in support – or in criticism – of other papers. The most notable example involves the use of Hydroxychloroquine. 

Inevitably, a wide variety of existing antiviral drugs have been proposed for the treatment of COVID-19. These agents are already used for the treatment of Influenza, Hepatitis C, HIV / AIDS, and other infections. Initial results suggest that many of these, which are commonly administered in clinical practice (Oseltamivir, Paramivir, Zanamivir, Ganciclovir, Acyclovir) lack activity against SARS-CoV-2, the agent of COVID-19.   Others that have been mentioned include Favipiravir,  Galidesivir, Interferon-alpha, Interferon-beta, Lepdipasvir, Lopinavir, Remdesivir, Ribavirin, Ritonavir,   Sofusbuvir, Telbivudine, Tenofovir, and Velpatasvir. Remdisivir and Lopinavir (used in the treatment of Ebola and HIV / AIDS, respectively) have attracted much interest in recent days. 

The treatment of COVID-19 has increasingly focused on drugs that either block viral attachment or modulate the vascular and immune responses which cause the actual “disease”. Anecdotal reports and small case series have suggested that Chloroquine and Hydroxychloroquine, drugs used in the treatment of malaria and certain inflammatory diseases, are effective in controlling these processes. Colchicine, Ivermectin, Metronidazole, Statin drugs, Sarilumab, Teicoplanin, and Tocilizumab may act through similar mechanisms. Not surprisingly, many publications have also examined the use of Traditional Chinese Medicines and serum obtained from patients who had recovered from COVID-19.

In some cases, these drugs have been advocated for both the prevention and the treatment of COVID-19. As such, the concept of “prevention” also extends to hospital personnel and individuals in the community who will no longer be at risk from the treated patient. Although the element of drug side effects is often mentioned in relevant publications, few point out that patients most likely to receive these agents (elderly people with underlying diseases) are likely to be receiving other drugs that could interact with the agent in question.  

The following is an alphabetical list of drugs that have been considered for the treatment of COVID-19, indicating the number of relevant publications indexed by PubMed to April 10, 2020. 

Drugs Proposed for the Treatment of COVID-19: Publications Indexed on PubMed

Drug or Other Agent Publications – number
Arbidol 5
Azithromycin 3
Baricitinib 6
Chloroquine 45
Convalescent serum 16
Colchicine 1
Emetine 2
Favipiravir 5
Galidesivir 1
Homoharringtonin 1
Hydroxychloroquine 35
Interferon alpha 4
Interferon beta 3
Ivermectin 1
Lepdipasvir 1
Lopinavir 31
Metronidazole 1
Nicotinamide 1
Remdesivir 20
Ribavirin 14
Ritonavir 29
Sarilumab 1
Sofusbuvir 2
Statins 4
Teicoplanin 1
Tenofovir 1
Tilorone 1
Tocilizumab 14
Traditional Chinese Medicine 46
Telbivudine 1
Velpatasvir 1
Vitamin B12 1

Cryptosporidiosis in Sweden

The incidence of cryptosporidiosis in Scandinavia has increased dramatically in recent years.  As shown in the following chart, rates in Sweden per 100,000 population are approximately twice those reported in the United States – and almost four-fold those reported in the European Region as a whole.  [1-3]

References:

  1. Gideon e-Gideon multi-graph tool,   https://www.gideononline.com/cases/multi-graphs/
  2. Berger S. Infectious Diseases of Sweden, 2019. 416 pages , 143 graphs , 1,146 references. Gideon e-books,  https://www.gideononline.com/ebooks/country/infectious-diseases-of-sweden/
  3. Berger S. Cryptosporidiosis: Global Status, 2019.  147 pages , 53 graphs , 2,041 references.  https://www.gideononline.com/ebooks/disease/cryptosporidiosis-global-status/

Note featured on ProMED

 

 

Coccidioidomycosis in the United States

Although largely limited to the western and southwestern states, Coccidioidomycosis is more commonly reported than legionellosis. More Americans die from Coccidioidomycosis than from the other two regional mycoses, Blastomycosis and Histoplasmosis. [1,2]

 

While Coccidioidomycosis is best known as a disease of California (“Valley Fever”) , highest incidence is reported from Arizona.  These data are even more striking when adjusted for relative population size (cases per 100,000 population).

 

References:

  1. Berger S. Infectious Diseases of the United States, 2019. 1,422 pages , 513 graphs , 18,048 references.  Gideon e-books,  https://www.gideononline.com/ebooks/country/infectious-diseases-of-the-united-states/
  2. Gideon e-Gideon multi-graph tool,   https://www.gideononline.com/cases/multi-graphs/

India: Diphtheria, Pertussis and Tetanus

Although global incidences of Diphtheria, Pertussis and Tetanus declined dramatically during the second half of the twentieth century, relatively high rates for these diseases continue to be reported from India.  India accounted for 17.7% of the total World’s population in 2018, but reported 46% of global Tetanus, 53% of global Diphtheria (and only 10.2% of global Pertussis) that year.  Similarly, 68% of the population of Southeast Asia (SEA) live in India, while that country accounted for 85% of Diphtheria, 75% of Pertussis and 90% of tetanus for SEA in 2018. [1-4]   Trends for these data are charted in the following three graphs. [5]

References:

  1. Berger S. Infectious Diseases of India, 2019. 620 pages , 109 graphs , 6,807 references. Gideon e-books, https://www.gideononline.com/ebooks/country/infectious-diseases-of-india/
  2. Berger S. Diphtheria: Global Status, 2019. 389 pages , 451 graphs , 699 references. Gideon e-books, https://www.gideononline.com/ebooks/disease/diphtheria-global-status/
  3. Berger S. Tetanus: Global Status, 2019. 561 pages , 816 graphs , 390 references. Gideon e-books, https://www.gideononline.com/ebooks/disease/tetanus-global-status/
  4. Berger S. Pertussis: Global Status, 2019. 417 pages , 514 graphs , 1,028 references. Gideon e-books, https://www.gideononline.com/ebooks/disease/pertussis-global-status/
  5. Gideon e-Gideon multi-graph tool,   https://www.gideononline.com/cases/multi-graphs/

Venereal Diseases in Europe

As of 2017, the reported incidence of syphilis in the European Union is higher that that of HIV infection.   In the following chart, I’ve contrasted trends of venereal diseases for the region. [1]  Data are derived from GIDEON www.GideonOnline.com and the Gideon e-book series. [2]  Note that gonorrhea is most common, followed by syphilis, HIV / AIDS and lymphogranuloma venereum (LGV).  In fact, if current trends continue, LGV infection may become more common than AIDS in the near future.  As depicted in the second chart,  reported cases of chlamydial infection are higher than the combined total for all other venereal diseases, and continue to be rise at an alarming rate.

References:
1. Gideon e-Gideon multi-graph tool,   https://www.gideononline.com/cases/multi-graphs/

2. Berger S. Infectious Diseases of the World, 2019. 1,750 pages , 456 graphs , 42,302 references. Gideon e-book series,  https://www.gideononline.com/ebooks/country/infectious-diseases-of-the-world/

Diphtheria in Thailand

Although two fatal cases of diphtheria were recently reported in Thailand [1], rates of this disease have declined dramatically since the 1970’s.  In fact, Thailand can serve as an icon for the effectiveness of vaccination.  In the following graph, I’ve contrasted rates of diphtheria, pertussis and tetanus with WHO estimates of DPT vaccine uptake.  The second graph depicts the effect of DPT vaccination on diphtheria mortality in this country. [2,3]

References:

  1. http://www.promedmail.org/post/6453182
  2. Berger S. Infectious Diseases of Thailand, 2019. 506 pages , 169 graphs , 2,339 references. Gideon e-books,  https://www.gideononline.com/ebooks/country/infectious-diseases-of-thailand/
  3. Gideon e-Gideon multi-graph tool,   https://www.gideononline.com/cases/multi-graphs/

Note featured on ProMED

Measles: Correlation of Vaccine Uptake with Disease Rates

The following is a country-by-country analysis of measles reporting trends vs. vaccine uptake.  For purposes of consistency, incidence data and population statistics used to calculate rates per 100,000 will be limited to those published by the World Health Organization (WHO).  Resultant graphs were generated by Gideon and abstracted from the Gideon e-book series [1,2]  True estimates of vaccination update statistics are those published by WHO, in most cases available only since 1980.  Data published by the countries themselves were not used, to avoid possible bias or inconsistency when comparing data among countries. Historical disease data which precede 1980 have also been appended to graphs to further appreciate the impact of vaccination.

The reader will note that in virtually all cases, the presumed impact of vaccine uptake on disease incidence occurs when vaccine uptake exceeds 80%, and again when rates increase beyond 90%.   As such, the few countries which have not achieved 80% uptake, or have consistently reported >90% uptake since 1980 are excluded.  Graphs are not included for countries for which data are not reported, or reported only sporadically.

Individual graphs for 135 countries are presented below in alphabetical order.  In 127 (94%) of these, a clear relationship seems to exist between increasing vaccine uptake and decreasing rates of measles.  In eight cases, temporary “spikes” in disease incidence were reported during years of high vaccine uptake: Japan, Jordan, Republic of Korea, Seychelles, Solomon Islands, South Africa, Sri Lanka and Syria.

I have not attempted to perform a statistical analysis of this phenomenon, and cannot say with certainty that a confounding (third) factor does not exist.  Nevertheless, these graphs appear to indicate a favorable effect of vaccination on measles incidence.

Measles Vaccine Uptake vs. Disease rates (per 100,000)

References:

  1. Gideon e-Gideon multi-graph tool,   https://www.gideononline.com/cases/multi-graphs/
  2. Berger S. Measles: Global Status, 2019. 548 pages , 538 graphs , 5,779 references. Gideon e-books,  https://www.gideononline.com/ebooks/disease/measles-global-status/

Streptococcus suis Infection in Thailand

Currently, Streptococcus suis infection is more commonly reported in Thailand than a number of more familiar zoonoses acquired from pigs – Trichinosis, Hepatitis E, Brucellosis and Japanese encephalitis. [1,2]   See graph below

References:

  1. Berger S. Infectious Diseases of Thailand, 2019. 506 pages , 169 graphs , 2,339 references.  Gideon e-books,  https://www.gideononline.com/ebooks/country/infectious-diseases-of-thailand/
  2. Gideon e-Gideon multi-graph tool,   https://www.gideononline.com/cases/multi-graphs/

Tick-Borne Diseases of Norway

Tick-borne encephalitis (TBE) is one of eight zoonoses carried by ticks in Norway (the others are Anaplasmosis, Babesiosis, Louping ill, Lyme borreliosis, Relapsing fever, Rickettsial spotted fever and Tularemia).  As displayed in the following graphs, rates of human TBE are considerably lower than those of other tick-borne diseases in Norway, and below TBE rates reported by neighboring countries. [1-3]

 

 

References:

  1. Berger S. Infectious Diseases of Norway, 2019. 387 pages , 138 graphs , 858 references. Gideon e-books,  https://www.gideononline.com/ebooks/country/infectious-diseases-of-norway/
  2. Berger S. Tick-borne Encephalitis: Global Status, 2019. 89 pages , 49 graphs , 787 references  https://www.gideononline.com/ebooks/disease/tick-borne-encephalitis-global-status/
  3. Gideon e-Gideon multi-graph tool,   https://www.gideononline.com/cases/multi-graphs/

Note featured on ProMED

 

Venereal Diseases in Australia, the U.K. and the U.S.

As noted in a recent ProMED post, the incidence of gonorrhea, syphilis and genital chlamydial infection are increasing in the United States, United Kingdom and Australia.  http://www.promedmail.org/post/6192757   I’ve compared recent trends for these diseases in the following graphs, based on data from Gideon www.GideonOnline.com [1]  Note that highest rates for all three conditions are consistently reported by the United States.

 

Reference:

  1. Gideon e-Gideon multi-graph tool,   https://www.gideononline.com/cases/multi-graphs/

Note features on ProMED

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