Monkeypox: catching up with the next viral outbreak

 - Kenny Lin, MD, MPH

The World Health Organization (WHO) has been tracking an outbreak of monkeypox in 23 non-endemic countries that, as of May 26, included at least 257 laboratory confirmed and 120 suspected cases, including 15 confirmed cases in the U.S. This outbreak is highly unusual because many infected persons do not have a history of travel to an endemic country or contact with infected animals. During the only other large U.S. outbreak (involving 77 individuals) of monkeypox in 2003, patients contracted the virus through contact with infected prairie dogs purchased as pets; a case-control study found that case patients were more likely than controls to have cleaned cages and bedding of a sick animal or touched a sick animal. Although no patients died, 19 were hospitalized. In July 2021, monkeypox was diagnosed in a Dallas, Texas emergency department in a traveler returning from Nigeria. This patient was hospitalized for one month, and no secondary infections developed in any of the 223 identified U.S. contacts.

Monkeypox is a zoonotic double-stranded DNA poxvirus that causes clinical disease in humans that is similar to, but less severe than, smallpox. It is endemic to western and central Africa, particularly the Democratic Republic of Congo. The virus was originally isolated from a monkey in 1958, and the first human case was identified in 1970. African rodents are believed to be the virus's natural reservoir. Transmission occurs through contact with bodily fluids, skin or mucosal wounds, respiratory droplets, or contaminated objects. The usual incubation period is 7-14 days, and symptoms resolve within 14-21 days. Infected persons are considered to be contagious for one day before and 21 days after the onset of symptoms. 

Since routine smallpox vaccination ended in the U.S. in the 1970s, a large proportion of the population is susceptible to monkeypox infection. JYNNEOS, a live, nonreplicating vaccine that is recommended by the Advisory Committee on Immunization Practices for prevention of smallpox and monkeypox in persons at occupational risk aged 18 years or older, may be given for post-exposure prophylaxis within 4 days from the date of exposure to prevent disease and is preferred over the older smallpox vaccine (ACAM2000) due to a lower risk of adverse effects, though 100 million doses of the latter have been stockpiled in the event of a widespread bioterrorist attack.

Early reports from the current outbreak suggest that it has been causing minimal prodromal symptoms (fever, chills, lymphadenopathy) and that the rash is first appearing in patients' genital or perianal areas before progressing to the extremities, rather than more typically beginning in the mouth and face. Although monkeypox is not considered a sexually transmitted infection, many of the initial confirmed case patients are men who have sex with men. It remains unclear if, or to what extent, human-to-human transmission of monkeypox is occurring. "Given the current unfolding outbreak," advised two physicians from the Johns Hopkins Center for Health Security, "clinicians seeing patients with new onset of febrile illness and rash should consider monkeypox, especially if lymphadenopathy is also present."

Along with SARS-CoV-2, monkeypox is another example of the potential of increasingly frequent interactions between humans and wildlife to spread infectious diseases. As this latest viral outbreak continues to evolve, it underlines the importance of physicians and veterinarians taking a One Health approach to optimizing the health and well-being of humans and animals.

COVID vaccine after infection may decrease long COVID symptoms

 - Jennifer Middleton, MD, MPH

Post-COVID, or "long COVID," remains a challenging condition to manage, as the evidence base regarding effective treatment options remains limited. An observational cohort study from the United Kingdom (UK), however, has found that COVID-19 vaccination after COVID-19 infection may decrease these frustrating symptoms.

This study's researchers used data from a large UK database, the COVID-19 Infection Survey. Since April of 2020, UK survey workers visited the home of every person with documented COVID-19 infection and requested permission to enroll them in the survey along with permission to return regularly (weekly for the first month and then monthly thereafter) to test for reinfection and ask about persistent symptoms. The observational cohort study used this database to identify persons who both answered a survey question about long COVID symptoms and had received a COVID-19 vaccine after their acute infection.

The observational cohort researchers identified 28,356 persons from this survey who had both received a COVID-19 vaccination at some point after COVID-19 infection and responded to a question regarding the presence or absence of long COVID:

 [The] first vaccine dose was associated with an initial 12.8% decrease (95% confidence interval −18.6% to −6.6%, P<0.001) in the odds of long covid, with subsequent data compatible with both increases and decreases in the trajectory (0.3% per week, 95% confidence interval −0.6% to 1.2% per week, P=0.51). A second dose was associated with an initial 8.8% decrease (95% confidence interval −14.1% to −3.1%, P=0.003) in the odds of long covid, with a subsequent decrease by 0.8% per week (−1.2% to −0.4% per week, P<0.001)

While these results sound promising, the researchers note that median follow-up after a second dose was only 67 days; it's also important to remember that cohort studies can only establish correlation, not causation. Still, this study might help us persuade persons who are un- or under-vaccinated for COVID-19 to receive a vaccine after a COVID-19 diagnosis. The benefit to vaccination after acute COVID-19 infection may extend beyond ameliorating long COVID; As Dr. Lin wrote on the blog earlier this year, two previous cohort studies suggest that vaccination further reduces the risk of subsequent COVID-19 infection compared to the "natural" immunity that results from infection alone. Patients with COVID-19 can be vaccinated as soon as they complete isolation unless they received monoclonal antibodies or convalescent plasma (then the Centers for Disease Control and Prevention recommends waiting for 90 days). 

The AFP By Topic on COVID-19 includes this editorial on long COVID along with this Curbside Consultation on COVID-19 vaccine hesitancy, and the AAFP is also offering free CME on "Managing Effects of Long COVID" if you'd like to learn more.

Mitigating the hidden toll of alcohol use during the pandemic

 - Kenny Lin, MD, MPH

Over the past two years, many of my patients have been drinking more alcohol than in the past, reflecting a troubling national response to COVID-19 pandemic-related stress that Dr. Jennifer Middleton highlighted in a previous AFP Community Blog post. Two recently published studies assessed the increased death toll of unhealthy drinking habits. Alcohol-related deaths occur due to direct effects of alcohol on the body, such as alcoholic hepatitis (severe cases have a 16-30% mortality rate at 28 days and 56% at one year) or via indirect contributions to fatal traffic and nontraffic injuries (e.g., drowning, falls, aspiration, hypothermia, firearm injuries).

The first study used death certificate data from the National Center for Health Statistics to compare numbers and rates of alcohol-related deaths among individuals 16 years or older in 2019 and 2020. Both the absolute number and age-adjusted rate of deaths involving alcohol increased by about 25%, greater than the 16-18% increases in all-cause deaths and death rate during this period. The largest increases (37-40%) were observed in adults aged 25 to 44 years. A second study used data from the National Vital Statistics System to evaluate mortality trends in adults with the diagnosis of alcohol use disorder (AUD) before (2012-2019) and during (2020-2021) the pandemic. Similarly, deaths with AUD listed as a primary or contributing cause during 2020 and 2021 exceeded projected deaths based on pre-pandemic data by 25% and 22%, respectively, with the 25 to 44 year-old age group demonstrating the largest increases (40% and 34%).

For patients who survive alcoholic hepatitis and other alcohol-related life-threatening injuries, it is critical to offer evidence-based medical therapy for AUD, outlined in a 2020 AFP article. Since the effects of AUD may not be clinically evident, the U.S. Preventive Services Task Force recommends screening and brief behavioral counseling interventions in adolescents and adults to reduce unhealthy alcohol use. Managing alcohol withdrawal syndrome and referring patients to Alcoholics Anonymous and other 12-step facilitation programs for AUD are also important mitigation strategies for primary care clinicians.

What about patients who have long been told that having a glass of wine with dinner is good for the heart? Setting aside the question of whether patients underestimate personal alcohol consumption, a large (n=371,463) United Kingdom cohort study recently challenged the theory that light alcohol consumption lowers cardiovascular risk. Investigators found that after adjustment for healthier lifestyles, light alcohol use (up to 1 drink per day) was associated with increased risk for hypertension and coronary artery disease compared to no use. Heavy use (more than 2 drinks per day) was associated with exponentially increasing cardiovascular risks.

Is adenovirus responsible for the hepatitis outbreak in children?

 - Jennifer Middleton, MD, MPH

The cause of the hepatitis outbreak in children across the United States and Europe remains a mystery, with over 100 cases of concern identified in the United States (US). Some cases have been associated with adenovirus infection, and the US Centers for Disease Control and Prevention's (CDC) current health advisory advises physicians to test all children with acute hepatitis of unknown etiology for adenovirus.

The outbreak first came to attention on April 12, 2022, when the European Centre for for Disease Prevention and Control reported 70 cases of "severe acute hepatitis" in previously healthy children under the age of 16, most between the ages of 2 to 5 years, across England and Scotland in the weeks prior. Most children presented with jaundice, though some presented with vomiting. All had significantly elevated liver transaminases (>500 U/L) and negative testing for known hepatitis viruses (hepatitis A, B, C, D, and E). Some (exact figures not provided) had positive SARS-CoV-2 tests, and some had positive adenovirus tests.

A few days later, on April 21, 2022, the US CDC issued a health advisory regarding a cluster of similar hepatitis cases at a children's hospital in Alabama: "Case-finding efforts at this hospital identified...a total of nine patients admitted from October 2021 through February 2022; all five that were sequenced had adenovirus type 41 infection identified." All of these children were previously healthy, all tested negative for hepatitis A, B, and C, and all tested negative for SARS-CoV-2 infection. That same day, the CDC issued a health alert, requesting that physicians "report any suspected cases of hepatitis of unknown origin to their local and state health departments."

A CDC Mortality and Morbidity Weekly Report (MMWR) last week reviewed the details of the 9 cases in Alabama. The children were from different areas of the state and were not otherwise connected:

Elevated transaminases were detected among all patients (alanine aminotransferase [ALT] range = 603–4,696 U/L; aspartate aminotransferase [AST] range = 447–4,000 U/L); total bilirubin ranged from normal to elevated (range = 0.23–13.5 mg/dL, elevated in eight patients). All patients received negative test results for hepatitis viruses A, B, and C, and several other causes of pediatric hepatitis and infections were ruled out including autoimmune hepatitis, Wilson disease, bacteremia, urinary tract infections, and SARS-CoV-2 infection. None of the children had documented history of previous SARS-CoV-2 infection. 

Cases have now been documented in additional European countries as well as Israel. Going forward, the more data the CDC can gather, the greater its chances of solving this puzzle - and, potentially, identifying treatment and/or mitigation measures to benefit patients. Physicians in the US can help by:

1. Notifying the CDC (ncirddvdgast@cdc.gov) and/or your state health department "of children <10 years of age with elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) (>500 U/L) who have an unknown etiology for their hepatitis (with or without any adenovirus testing results, independent of the results) since October 1, 2021."
2. Testing children with hepatitis of unknown etiology for adenovirus 41: "NAAT (e.g. PCR) is preferable and may be done on respiratory specimens, stool or rectal swabs, or blood." 

If you'd like to refresh your knowledge regarding hepatitis, there's an AFP By Topic on Hepatitis (and Other Liver Diseases) that includes comprehensive overviews of diagnosis and treatment.

In patients with heart failure, a low-sodium diet does not improve outcomes

 - Kenny Lin, MD, MPH

A common contributor to acute exacerbations of chronic heart failure is having one or more high-sodium meals prior to the onset of symptoms. It seems reasonable, then, to recommend that patients with heart failure adhere to a low-sodium diet to reduce readmissions and mortality and improve quality of life. But until recently, there was limited evidence to support or refute this line of thinking. In a 2014 editorial, American Family Physician associate editor Barry Weiss, MD discussed several studies showing that a low-sodium (less than 1,800 mg per day) diet produced no benefits and increased mortality compared to a normal diet in heart failure patients in the outpatient and inpatient settings. Consequently, he advised that "based on current evidence and until further studies are completed, patients with heart failure should probably be discouraged from reducing their sodium consumption to less than 2,300 mg per day."

Two subsequent systematic reviews of studies of dietary sodium restriction in heart failure also questioned low-sodium dogma. A 2018 review of 9 randomized trials with 479 participants with heart failure found insufficient data on cardiovascular-associated and all-cause mortality, stroke, and myocardial infarction and conflicting evidence on changes in New York Heart Association functional class. Similarly, a 2021 systematic review and meta-analysis of 10 trials (1011 participants) found that low-sodium diets did not improve quality of life and possibly increased readmission rates and mortality. However, most trials included fewer to 100 participants, leaving open the possibility that a larger trial powered to detect differences in clinical outcomes could still show benefits.

Last month, the Study of Dietary Intervention under 100 mmol in Heart Failure (SODIUM-HF) trial, with 806 participants from 26 sites in Australia, Canada, Chile, Colombia, Mexico, and New Zealand reported its primary findings. All participants in this pragmatic randomized trial were receiving optimally tolerated guideline-directed medical treatment for chronic heart failure. Participants were randomly assigned to usual care or a low sodium diet of <100 mmol/day (<1,500 mg/day). The primary outcome was a composite of cardiovascular-related hospitalization, emergency department visit, and all-cause mortality within 12 months. Median sodium intake decreased in the low-sodium group from 2,286 mg to 1,658 mg/day and in the usual care group from 2,119 mg to 2,073 mg/day by the end of the trial. However, in an intention-to-treat analysis, researchers found no statistical differences between the groups in the composite outcome or in each of the individual outcomes.

As Dr. Weiss cautioned in his AFP editorial, "the possibility that aggressive sodium restriction may lead to unfavorable outcomes in patients with heart failure should not ... be misconstrued as meaning that we should lose our focus on reducing sodium intake in the general population." Indeed, there is good evidence that population-level interventions are effective in preventing cardiovascular disease, including a large Chinese randomized trial of a salt substitute that Dr. Jennifer Middleton discussed in a previous AFP Community Blog post. That's why recent guidance for industry from the U.S. Food and Drug Administration that aims to reduce the average American's daily sodium intake from 3,400 mg to 3,000 mg/day over the next few years could also have a positive public health impact.