All posts by Alireza FakhriRavari

With recent outbreaks of the Monkeypox virus in Europe and the United States, interest in Monkeypox prevention and treatment has increased. Similar to Variola, the causative agent of smallpox, the Monkeypox virus belongs to the genus Orthopoxvirus. It is a large, complex, double-stranded DNA virus that can infect homo sapiens as well as non-human primates. In fact, it can infect a wide variety of mammalian species. Current evidence points to rodents as key reservoir hosts. Transmission occurs via saliva/respiratory excretions or contact with lesion exudate or crust material, either via contact with infected animals or person-to-person transmission. The secondary attack rate among unvaccinated contacts within households is about 9%, so it is much less transmissible than smallpox. Wearing a face mask and avoiding close contact can reduce the risk of transmission.

The incubation period is about 2 weeks (~7-17 days) and an initial febrile prodrome is followed by generalized headache and fatigue. A key distinguishing feature of monkeypox, when compared to smallpox and varicella-zoster, is the presence of lymphadenopathy in most patients (but not all). Fever usually declines up to 3 days after rash onset with subsequent development of lesions as first macular, then papular, then vesicular, and pustular. About 40% of patients develop complications such as bacterial skin infections, respiratory disorders, gastrointestinal disorders, and keratitis. The overall mortality rate is about 10%, up to 15% in unvaccinated children.

There are 2 distinct phylogenetic clades of Monkeypox viruses: the West Africa clade and the Congo Basin clade. The West Africa clade, endemic in West Africa, generally exhibits a less severe illness with a mortality rate of about 3-4%. The Congo Basin clade, which occurs in Central Africa, exhibits a more severe illness with a mortality rate of about 10-11%. Nextstrain.org is now tracking reported Monkeypox genome data. The recent outbreaks in Europe and the United States seem to be based on the West African clade.

The 2022 ACIP Guidelines for Preexposure Vaccination of Persons at Risk for Occupational Exposure to Orthopoxviruses was recently published. There are currently 2 orthopoxvirus vaccines available: ACAM2000, which is a live replication-competent vaccinia virus, and Jynneos, which is a replication-deficient modified vaccinia Ankara.

CDC recommends preexposure vaccination for persons at risk for occupational exposure to orthopoxviruses, persons who administer ACAM2000 or care for patients with infection with replication-competent viruses.

ACAM2000 is approved for anyone over the age of 1 year, in the absence of contraindications, and Jynneos is approved for persons over the age of 18 years. While Jynneos is recommended as an alternative to ACAM2000, it’s important to keep in mind contraindications to receipt of ACAM2000.

Full guideline text can be found here: https://www.cdc.gov/mmwr/volumes/71/wr/mm7122e1.htm

Treatment options for orthopoxviruses are limited. Acyclovir, ganciclovir, foscarnet, and HIV NRTIs and NNRTIs are inactive in vitro. Entecavir has in vitro activity, but there’s limited evidence for its use for poxviruses. Cidofovir has in vitro activity and established animal data but it’s limited to its severe toxicity profile with many black box warnings. Tecovirimat and brincidofovir are oral options that have recently been approved via FDA’s Animal Rule for the treatment of smallpox and may be used for the treatment of monkeypox.

The choice between brincidofovir (dosed twice daily for 14 days) and tecovirimat (dosed once weekly for 2 doses) is based on many factors including tolerability, adherence, potential risks of carcinogenecity, teratogenecity, and infertility. Overall, tecovirimat seems to have an advantage over brincidofovir due to its apparently better safety profile (based on very limited evidence, primarily driven by animal studies).

More information can be found here:

What is Omicron? The new B.1.1.529 variant (Omicron) clade 21K, which harbors many mutations, particularly in the spike protein, was first detected in South Africa. Unlike the other variants of concern, B.1.1.529 has emerged independently from mid-2020 strains of SARS-CoV-2.

Why South Africa? It is possible, but unlikely, that this variant emerged in South Africa. South Africa has excellent scientists, a great surveillance program, transparency, and sharing of data!

Anytime there’s a new variant of SARS-CoV-2, there are at least 4 concerning things to consider: 1) Is it more transmissible than currently circulating strains? 2) Does it evade neutralization by antibodies (i.e., antibodies from natural infection, immunization, or monoclonal antibodies)? 3) Does it evade immunity due to vaccination (i.e., antibodies, T cell response)? 4) Does it cause a more severe (or milder) disease?

1) Is it really more transmissible than Delta? It’s too soon to tell. Superspreader events, which are outliers, get noticed early and can result in a very high estimation of basic reproduction number (R0). However, it does seem like B.1.1.529 (Omicron) is outcompeting B.1.617.2 (Delta) in South Africa.

2) Does it evade neutralization by antibodies? Omicron seems to have many more S1 mutations than previously circulating variants, which might be very problematic. While we don’t know for sure yet, its mutation profile predicts significant immune evasion.

3) Does it evade immunity due to vaccination (i.e., antibodies, T cell response)? We don’t know yet.

4) Does it cause a more severe (or milder) disease? We don’t know yet.

We need more studies to understand this variant and its impact more. In the meantime, please get vaccinated and wear a mask!

[All images from IDTwitter]

Last night (8/12/21), the FDA extended the emergency use authorizations (EUA) for Pfizer-BioNTech’s BNT162b2 (currently for age 12 years and older) and Moderna’s mRNA-1273 (currently for age 18 years and older) to allow for the use of an additional dose in certain immunocompromised individuals, such as solid organ transplant recipients or those who are diagnosed with conditions that are considered to have an equivalent level of immunocompromise (https://bit.ly/37DWxk3).

Today (8/13/21), the CDC’s ACIP voted 11-0 to approve a 3rd dose following a primary 2-dose series in immunocompromised people. Of note, whenever possible, vaccination should be given at least 2 weeks prior to initiation of immunosuppressive therapies. Who’s considered immunocompromised? Here’s a slide from ACIP meeting:

What about individuals who received a single dose of Johnson & Johnson’s Ad26.COV2.S vaccine? No recommendations yet due to lack of data, but probably best to get at least one mRNA vaccine booster.

The good news is that influenza was very scarce last year (2020-21) in the Northern Hemisphere and remained scarce this summer in the Southern Hemisphere. As well described by Uyeki et al (doi:10.1001/jama.2021.6125), this could generally be attributed to three factors: 1) community mitigation measures (e.g., masking, social distancing, workplace closures, school closures, virtual school instruction, indoor dining restrictions), 2) behavioral changes (e.g., staying at home, working from home, reduced domestic and international travel, or international travel with subsequent quarantine upon arrival, and 3) influenza vaccination. Last flu season set a record for vaccine distribution (194 million doses), with more than 55% of adults getting immunized in the U.S. What to expect this year? Anything from a repeat of last season’s numbers to an explosion of cases is possible.

Let’s look at the first factor, community mitigation measures. Schools are open, which means that children are in a position to accelerate the transmission of influenza in the community. Many people who are vaccinated against COVID-19 have eased masking and social distancing, increasing their exposure to influenza. Indoor dining is almost back to normal, where social distancing and masking are difficult to follow. Let’s look at the second factor, behavioral changes. People are more comfortably resuming normal activities because they are vaccinated against COVID-19, including international and domestic air travel. All of these make factor three, influenza vaccination, more important than ever. The CDC released the new Prevention and Control of Seasonal Influenza with Vaccines recommendations for the 2021-22 influenza season last week. Here are a few takeaways:

https://www.cdc.gov/mmwr/volumes/70/rr/rr7005a1.htm

• Routine annual seasonal influenza immunization is recommended for all persons aged ≥6 months who do not have contraindications
• No preferential recommendation is made for one influenza vaccine product over another
• Vaccination should be offered by the end of October and continued through flu season
• For nonpregnant adults, early vaccination (i.e., in July and August) should be avoided unless there is concern that later vaccination might not be possible
• Revaccination later in the season of persons already vaccinated is not recommended
• COVID-19 vaccines can be co-administered with influenza vaccines

Influenza vaccine formulations available:

New recommendations regarding severe allergy to influenza vaccines:

• Can consider 3 different groups: egg-based vaccines, cell-cultured, and recombinant
• Precaution use should occur in an inpatient or outpatient medical setting under the supervision of a provider who can recognize and manage a severe allergic reaction

Influenza season typically peaks between Christmas and Valentine’s day, most often closer to Valentine’s day. Get your flu vaccine by November and be ready for Christmas and Valentine’s day!

The COVID vaccination campaign has been extremely successful in the United States, with highly effective mRNA vaccines from Pfizer-BioNTech (BNT162b2) and Moderna (mRNA-1273), as well as an Adenovirus-vectored vaccine from Janssen (Ad26.COV2.S). There are at least 2 questions to be answered. 1) While the vaccines seem to continue to work up to 6 months, how long will the efficacy last (hence the need for a booster)? and 2) how effective are these vaccines against the emerging variants (particularly against problematic B.1.351 and P.1 variants)? While antibodies produced from 2 doses of mRNA-1273 still seem to neutralize B.1.351 (first identified in South Africa) and P.1 (first identified in Brazil) variants, the neutralization capacity is reduced by 6.4- and 3.5-fold, respectively, which is concerning due to the possibility of breakthrough infection and waning efficacy.

There are 2 approaches to tackle this problem: 1) Administer a third booster of the original vaccine to increase the neutralization capacity and overcome the waning of antibodies, or 2) Administer a booster vaccine that matches the variant of concern (not the original vaccine).

In a pre-print paper (not peer-reviewed yet), Moderna shares the preliminary safety and immunogenicity results of a third booster shot in a phase 2 trial (http://doi.org/10.1101/2021.05.05.21256716). They enrolled adult participants from previous phase 2 or 3 trials who had received a 2-dose series of the original mRNA-1273 about 6-7 months before enrollment (no pregnant individuals). A booster dose of 50 mcg mRNA-1273 was given to 20 participants from the previous phase 2 trial. A booster dose of 50 mcg mRNA-1273.351 was given to 20 participants from the previous phase 3 trial. A 20 mg dose of mRNA-1273.351 is also being evaluated in 20 participants (results not published yet).

Boosting with mRNA-1273 resulted in a 23-, 32-, and 44-fold increase in neutralization against D614G (considered wild-type), B.1.351, and P.1 variants, respectively. Boosting with mRNA-1273.351 resulted in a 12-, 35-, and 27-fold increase in the neutralization of each variant, respectively. Of note, mRNA-1273.351 resulted in significantly higher titers against B.1.351 compared to mRNA-1273 boost. Because a correlate of protection from neutralizing antibodies has not been established yet, it remains to be seen if these boosted titers result in protection against B.1.351 and P.1 variants. The trial is ongoing and is currently evaluating a multivalent vaccine (50 mcg mRNA-1273.211) comprising of a 1:1 mix of the original mRNA-1273 (25 mcg) and mRNA-1273.351 (25 mcg). Will I personally get a third shot if authorized by the FDA? You bet! mRNA-1273.351.

Back in January 2021, I had a patient who had experienced a delayed edematous plaque (very large and painful) at the site of injection several days after she received her first dose of Moderna’s mRNA-1273. It lasted 5 to 6 days and then resolved. She was concerned about the second shot. She was still willing to get it in the same non-dominant arm but wanted to make sure that it is okay to do so. I told her it would be okay but advised her to get the jab in the other arm.

First of all, neither local injection-site reactions nor delayed-type hypersensitivity reactions are contraindications to subsequent vaccination. As reported by Dr. Blumenthal and colleagues in NEJM today, in a sample of 12 patients with delayed large local reactions to mRNA-1273, half the patients did not have a recurrence of large local reactions, a quarter had recurrent reactions that were of a lower grade than the initial dose, and the remaining quarter had recurrent reactions similar to the initial dose. Skin biopsy revealed that these were in fact type IV delayed T-cell mediated hypersensitivity reactions. The symptoms lasted a median of 6 days (range 2 to 11 days).

What can help with these severe skin reactions? Ice packs, oral antihistamines, and topical glucocorticoids. For antihistamine, it is best to use second-generation H1-receptor antagonists like loratadine 10 mg PO daily, fexofenadine 180-360 mg PO daily or even twice a day, or cetirizine 10 mg (this one might cause drowsiness). You can also use first-generation H1-receptor antagonists like diphenhydramine 25-50 mg every 4 hours as needed (max 300 mg/day) if you want to cause drowsiness. H2-receptor antagonists might help in combination with H1-receptor antagonists, like famotidine 20 mg twice a day. Common topical corticosteroids include hydrocortisone 1%, clobetasol propionate 0.05%, or triamcinolone 0.1%.

https://www.nejm.org/doi/full/10.1056/NEJMc2102131

The idea is simple. Vaccinate as many people as possible when you have the chance as soon as the flu shot becomes available. If you ask people to come back to get their flu shot closer to the flu season (typically November to April in the Northern hemisphere), there is a chance that some of them will not come back, because that’s life. In the United States, fewer than half of the population receives the flu shot each year (37% in the 2017-2018 season and 45% in the 2018-2019 season received the flu shot). It remains to be seen whether or not the COVID-19 pandemic would make these numbers worse. Therefore, every effort must be made to improve vaccine uptake. The CDC recommends initiating vaccination campaigns as soon as the vaccine is available (i.e., in July) to allow sufficient time to vaccinate the population and avoid some persons going unvaccinated for influenza.

However, several observational studies have shown that the effectiveness of influenza vaccine wears off within a single influenza season (less than a year). For example, G. Thomas Ray and colleagues evaluated the effectiveness of the inactivated influenza vaccine from September 2010 to March 2017 and found that compared with persons vaccinated 14 to 41 days prior to being tested, persons vaccinated 42 to 69 days prior to being tested had 1.32 (95% CI, 1.11 to 1.55) times the odds of testing positive for any influenza. The odds ratio increased linearly by about 16% for each additional 28 days since vaccination. According to the CDC, peak influenza activity is typically between Christmas and Valentine’s day (December to February), more frequently during Valentine’s day (15 previous seasons) than Christmas (7 previous seasons). Based on these findings, getting the flu shot in July would essentially increase the odds of testing positive for the flu during Christmas by about 80%, 64% if the flu shot received in August, and 48% if received in September, and 32% if received in October. Of course, observational studies are subject to many limitations and biases. Some studies suggest that the waning occurs to a greater extent with H3N2 influenza A than H1N1 influenza A or influenza B. Other studies suggest that waning is greater among older adults and younger children.

On average, it takes 2 weeks for the human body to respond to the influenza vaccine and develop antibodies. Getting the flu shot as close to November as possible, when the flu season typically begins in the U.S., may improve the likelihood of having improved protection during Valentine’s day.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182205/pdf/ciy770.pdf

https://www.cdc.gov/mmwr/volumes/69/rr/rr6908a1.htm

A recent analysis from the CDC looked at a dataset of 1,320,488 laboratory-confirmed COVID-19 cases reported to CDC from January 11, 2020, to May 30, 2020. Previous analyses had determined that age ≥65 years and underlying health conditions such as cardiovascular disease, diabetes, and chronic lung disease were associated with a higher risk for severe infection and lower risk among children aged <18 years.

Insight #1: Males and females are equally likely to get infected in the United States, but males are more likely to get hospitalized, get admitted to the ICU, and die.

While the overall cumulative incidence was 403.6 cases per 100,000 persons, the incidence was 401.1 cases per 100,000 males and 406.0 cases per 100,000 females. Among men, 16% were hospitalized, 3% admitted to the ICU, and 6% died, whereas among women, 12% were hospitalized, 2% admitted to the ICU, and 5% died.

Insight #2: Hospitalizations were 6 times higher in patients with underlying conditions.

Only 287,320 (22%) of cases had sufficient data on underlying conditions. The most common underlying conditions were cardiovascular disease (32%), diabetes (30%), and chronic lung disease (18%). Overall, 14% of patients were hospitalized, 2% were admitted to an ICU, and 5% died. The rate of hospitalization was 45.4% among patients with a reported underlying condition and 7.6% among those without a reported underlying condition. Most ICU admissions were among persons with reported underlying conditions aged 60-69 years (11%) and 70-79 years (12%).

Insight #3: Deaths were 12 times higher in patients with underlying conditions.

Overall, 71,116 patients died, including 19.5% of patients with underlying conditions and 1.6% of those without underlying conditions. Death was most commonly reported among people aged ≥80 years.

Disclaimer: This surveillance dataset represents a subset of the total cases of COVID-19 in the U.S, there are missing data, and asymptomatic cases are not captured well.

https://www.cdc.gov/mmwr/volumes/69/wr/mm6924e2.htm

When a new contagious infectious disease emerges, there’s a sense of urgency to name it so that the scientific community can refer to it while studying it. During the early stages, however, there are a lot of unknowns such as the nature of the disease and its origin, which are barriers to seeing the whole picture. Historically, new diseases have been named after geographic locations, specific people’s names, and specific animals or food.

Naming After Geographic Locations

The H1N1 influenza virus with genes of avian origin that caused the 1918 influenza pandemic was named the Spanish Flu even though there is no universal consensus on where the virus originated. It is commonly believed that reporting infectious diseases were censored during World War I. Spain, which remained neutral throughout the war, was less likely to censor reporting of new cases. As a result, it was falsely believed that the virus originated from Spain.

Rift Valley fever (RVF), which was first identified in 1931 on a farm in the Rift Valley of Kenya, is a viral disease affecting livestock and humans who come in contact with blood or organs of infected animals. While outbreaks are reported in sub-Saharan Africa, they also occur in Egypt and Saudi Arabia (and a few other countries around this region).

The Middle East respiratory syndrome coronavirus (MERS-CoV), first identified in humans in Saudi Arabia and Jordan in 2012, is a respiratory virus that can cause severe pneumonia and multiorgan failure. Several outbreaks of human-to-human transmission have occurred outside of the Middle East, including a large outbreak in South Korea in 2015.

Ebola virus disease, a viral hemorrhagic fever of humans and other primates, was first identified in 1976. It is named after the Ebola River in central Africa. There have been over 20 known outbreaks of Ebola disease in sub-Saharan Africa, including the massive outbreak in West Africa between 2013 and 2016.

Naming After Specific People

Chagas disease, a vector-borne disease (via triatomine or “kissing” bugs) caused by the protozoan parasite Trypanosoma cruzi, was first formally described by Carlos Chagas in 1909. It is limited to areas of North America, Central America, and South America.

Creutzfeldt-Jakob disease (CJD) is a rare, rapidly progressive fatal neurodegenerative disorder caused by a prion, which was first described by German neurologist Hans Gerhard Creutzfeldt in 1920. There is no effective treatment for this disease.

Naming After Specific Animal or Food

Monkeypox, caused by the monkeypox virus, was first reported by Preben von Magnus in 1958. It is an infection that can occur in some animals including humans and it is very similar to smallpox. While the reservoir remains unknown, monkeys and humans are incidental hosts.

In 2009, an influenza A (H1N1) virus containing a unique combination of genes from swine lineages was identified in humans. During the pandemic, it was referred to as “swine flu” in the media, although it was officially called influenza A H1N1pdm09. There is a vaccine available.

WHO Guidelines

In 2015, the World Health Organization (WHO) issued guidelines for best practices for naming new human infectious diseases. They stipulated that the naming of new diseases should not make reference to geographic places, specific people, and specific animals or food. Other terms that should be avoided in disease names include cultural, population, industry or occupational references, and terms that incite undue fear. Instead, a disease name should include a generic description of the symptoms caused by the disease combined with more descriptive terms when robust information is available. The pathogen that causes the disease, if known, should be part of the disease name.

The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified in Wuhan, China, in December 2019. On February 11, 2020, the WHO officially named the disease caused by this virus coronavirus disease 2019 (COVID-19). In accordance with the naming guidelines, it is important to avoid referring to it as the “Chinese virus,” as such naming may lead to xenophobia and racism. Its rapid super-spreading globally has led to an ongoing pandemic. There is currently no proven pharmacologic treatment for this disease.