Infectious Disease Alert Updates
Carol Kemper
May 1, 2024 8 minutes read
By Carol A. Kemper, MD, FIDSA
Medical Director, Infection Prevention, El Camino Hospital, Palo Alto Medical Foundation
The Burden of Clostridioides difficile Infection
SOURCE: Feuerstadt P, Theriault N, Tillotson G. The burden of CDI in the United States: A multifactorial challenge. BMC Infec Dis 2023;23:132.
This article outlines the clinical, social, and economic burden of Clostridioides difficile infection (CDI) in the United States and its shifting epidemiology. CDI is no longer an infection exclusive to healthcare facilities. As I reviewed this article, I reflected on the recent experience of an acquaintance, vacationing in Mexico, who required hospitalization for three days with severe dehydration and incapacitating diarrhea and was diagnosed with CDI. She had taken no antibiotics. She was told this infection was “acquired only in hospitals.” Not true.
We are all familiar with the rough statistics of CDI, especially in hospitalized patients, resulting in extended hospital stays, increased costs, and substantial morbidity and mortality. CDI represents at least 1% of all hospital admissions. But were you aware that about 500,000 cases of CDI are reported annually in the United States, resulting in roughly 30,000 deaths? Annual CDI-associated mortality often is greater than mortality from influenza in this country. Recent Veterans Administration data showed that 30-day mortality from CDI ranged from 6% to 11%, but the associated annual mortality, considering relapsed infection over the course of a year, may be as high as 25%. At least 8% of severe hospital infections result in colectomy.
Traditionally, CDI has been regarded as a nosocomial infection. However, the burden of healthcare-associated infection has been steadily decreasing by 36% from 2011 to 2017. This is likely the result of improved testing paradigms, more aggressive infection prevention practices, and antimicrobial stewardship. At the same time, community-associated CDI has doubled, with up to 63.3 cases/100,000 persons, and now outweighs the incidence of CDI associated with hospital admission. Overuse of antibacterials in the community must be a contributing factor. But, of interest, community-associated CDI cases tend to be younger, and 40% have no reported antibiotic exposure within the previous four months. The reasons behind this shifting epidemiology and risk factors for community infection are not well understood. But I suspect it has much to do with an increased burden of intestinal colonization in the community. Our hospital data suggest that 11% to 12% of skilled nursing facility/long-term care patients and 32% of dialysis patients are colonized; patients with a history of CDI also are at increased risk for persistent colonization. This increasing reservoir must create a risk for the community.
Beyond the clinical burden, CDI has significant impact on quality of life, with possible long-lasting emotional and social scars, as well as significant professional impact — which is likely under-appreciated. One survey of outpatient CDI cases reported that 47% had to stop working because of active diarrhea — but another 26% had to stop working even after the acute diarrhea resolved. Other data show that patients with CDI were unable to perform their usual work duties for an average of 118 days. In Silicon Valley, it’s not uncommon to have highly educated, highly paid professionals laid low by this illness, bewildered and desperate to get back to work; their careers — and sometimes their companies — depend on their ability to work. The more vulnerable, especially those with lower paying or unskilled jobs, are financially devastated. Based on my own experience with severe gastroenteritis for just three days over Christmas — I could not work, let alone risk getting in the car to retrieve my own stool kit. Imagine weeks of diarrhea, unable to eat normal foods, unable to socialize, afraid to have friends or family over for dinner or share a meal, not counting the fear of relapse.
Financially, healthcare costs for hospital-associated CDI are estimated at ~ $5 billion annually, with the first episode costing $39,000 and relapsing/recurrent episodes costing the healthcare system $49,000. However, direct medical costs may be much greater, starting at $72,000 for the first episode and up to $132,000 for the first recurrence. However, these costs do not adequately reflect the revenue loss to hospitals. Further, the Centers for Medicare and Medicaid Services may now reduce overall Medicare payments to hospitals that rank in the worst-performing quartile of all hospitals on hospital-acquired conditions, such as hospital-onset CDI, adding further financial burden to hospitals challenged with increased hospital-onset C. difficile rates.
However, we seldom consider outpatient treatment costs for individuals afflicted by CDI. One survey suggested that an initial episode costs $8,695 in out-of-pocket expenses, including costs for one course of CDI treatment, while the cost of a relapse is $4,355. Those costs could be devastating for more vulnerable individuals. The updated 2021 Infectious Diseases Society of America CDI treatment guidelines, which recommended fidaxomicin as first-line therapy, likely added to this burden of expense — the cost for the drug alone ranges from $3,845 to $5,245 for a 10-day supply. Many patients simply cannot afford the cost of fidaxomicin — and treatment may be delayed, while pharmacies, insurance companies, and physician offices negotiate what treatment may be provided. And I can tell you, a recent GI profile panel (using the BioFire PCR Platform) cost me $1,405 out of pocket (my health insurance refused to cover the cost).
Over the last few years, there has been a great deal of focus on hospital-associated CDI and interventions to reduce the risk in the hospital and improve outcomes. More research is needed to understand the reasons for the shifting epidemiology of this infection into the community, and into more vulnerable populations, and how to improve treatment outcomes.
The Globe May Be Warming, but People Are Cooler
SOURCE: Ley C, Heath F, Hastie T, et al. Defining usual oral temperature ranges in outpatients using an unsupervised learning algorithm. JAMA Intern Med 2023;183:1128-1135.
What is normal? Patients like to tell me their normal temperature is “not normal.” Our idea of a normal temperature came from the work of a German physician who screened 25,000 patients and concluded in an 1868 publication that the normal human body temperature was 98.6 °F. That number has stuck with us for 150 years. Are people now cooler?
Body temperature is highly variable, depending on the time of day, menstrual cycle, body weight and height, metabolism, hydration status, etc., not to mention illness and general health. This fascinating cross-sectional study assessed oral body temperatures for adult outpatient encounters to internal medicine and family practice clinics in a single large medical system from 2008-2017. Primary diagnosis, medications, age, sex, height, weight, time of day, and day of the month were abstracted from the electronic medical record for each encounter. A filtering algorithm was used to remove encounters with a diagnosis possibly affecting body temperature — leaving only those clinical diagnoses unrelated to temperature.
A total of 618,306 adult patient encounters were recognized, and 36% were removed by the filtering algorithm for non-included diagnosis. That left 396,195 encounters for 126,705 patients. The mean age was 52.7 years, and 57.4% were female. This data set yielded a mean oral temperature of 97.95 °F (36.64 °C), with the central 95% of temperatures ranging from 96.17 °F to 99.19 °F (35.95 °C – 37.33 °C). Interestingly, the mean oral temperature never reached 98.6 °F (37 °C) for any of the subgroups examined.
Linear regression and linear mixed-effects modeling were applied separately to women and men, and identified the hour of the day, age, height, weight, and month as independent predictors of body temperature. During the day, body temperature peaked at approximately 4 p.m. and then rapidly decreased. Surprisingly, men more consistently experienced a drop in temperature around 45 to 55 years of age, although both men and women got cooler as they aged. There was a slight increase in temperature with increasing weight in both sexes, and a slight decrease in temperature with increased height.
The authors suggest that the current “normal” body temperature is closer to 97.9 °F and our previous concept of the body being warmer at 98.6 °F should be “retired.” If you believe the original 1868 findings, then body temperatures appear to have been declining, possibly from improved general health, reductions in chronic infections, and improved dental health, to name a few reasons. The idea that humans have been cooling at a rate of -.05 degrees F every decade for the last 150 years is fascinating.
Methotrexate for Chikungunya Arthritis
SOURCE: Amaral JK, Bingham CO, Taylor PC, et al. Therapy for chikungunya arthritis: A study of 133 Brazilian patients. Am J Trop Med Hyg 2023;109:542-547.
Chikungunya fever is a mosquito-borne viral infection resulting in a biphasic illness in many people, with sudden onset of fever, arthralgias, and rash for the first three to 14 days. Following the acute viral illness, > 40% of patients develop a post-infectious inflammatory process with a polyarthritis resembling rheumatoid arthritis. A subset of these patients (~ 14%) develops chronic joint complaints for more than three months, which can be quite severe and disabling. Commonly affected joints include the wrists, the proximal interphalangeal joints, the metacarpophalangeal joints, and the knees and ankles, sometimes with joint swelling and effusion, and occasionally tendinitis, along with fatigue, myalgias, morning stiffness, and elevated inflammatory markers. Millions of cases occur annually around the globe — with a current surge in infection in South America. Chikungunya was first recognized in 1952 in Tanzania, where it got its name from a tribal ethnic word meaning “to become contorted.”
Previous treatment guidelines for chikungunya-related arthritis symptoms recommended corticosteroids plus analgesics, while methotrexate (MTX) or other immunomodulatory/disease-modifying antirheumatic drugs were reserved for especially bad cases. In an uncontrolled study, these authors studied the effect of MTX and/or leflunomide plus dexamethasone 2 mg/day to 4 mg/day for four weeks in a group of 133 patients with immunoglobulin M (IgM)-confirmed “Chik arthritis.” Patients were assessed for joint activity and pain (using a visual analog scale [VAS]) at baseline, four weeks, and then again at about five months following completion of treatment.
The average age of the group was 59 years, and 85% were female; 79% were classified as severe disease activity based on the number of involved joints/joint swelling and VAS pain scores; only one patient was considered to have mild disease. At study entry, 67% were receiving corticosteroids (either prednisone, prednisolone, betamethasone, or dexamethasone) ranging from days to weeks, 14% were receiving opiates, pregabalin or tramadol, and 4.5% were receiving nonsteroidal anti-inflammatory drugs. The mean time between onset of symptoms and the first visit was 42 days. Patients were stratified by the acute phase (9.8%), subacute phase (87.2%), or chronic phase (> 3 months) (3%).
At the first visit, 98 patients received MTX 20 mg/week plus dexamethasone 4 mg/daily; 29 patients received MTX 20 mg/week plus dexamethasone 2 mg/daily; 15 patients with more severe diseases received MTX 20 mg/week plus leflunomide 20 mg/day plus dexamethasone.
Most patients reported improvement within two weeks of treatment. By four weeks, the mean VAS pain score had dropped from 81.8 to 13.3, the mean total joint count dropped from 17.2 to 2.8, and the mean swollen joint count dropped from 5.0 to 0.8. A significant reduction in inflammatory markers also was observed. No adverse events occurred during the four-week treatment.
A total of 123 patients were re-assessed a mean of 4.7 months following the end of treatment. Most of the patients had sustained improvement in their symptoms, with statistically significant reduction in the mean VAS pain score (27.3), and sustained reduction in the mean number of involved joints (4.8) and swollen joints (1.6).
The post-infectious inflammatory polyarthritis triggered by chikungunya viral infection resembles rheumatoid arthritis in many respects and, therefore, may respond best to anti-rheumatic immunomodulatory drugs such as MTX and/or leflunomide. Corticosteroids alone do not seem to provide adequate or sustained relief for many patients. A limitation to this study may be that the majority of patients in this study were in the acute or subacute phase, whereas only 3% had symptoms for more than three months. Still, preemptively treating patients with more acute or subacute polyarthritis with MTX and/or leflunomide plus dexamethasone resulted in substantial sustained improvement in symptoms five months later and was well tolerated.
The Burden of Clostridioides difficile Infection; The Globe May Be Warming, but People Are Cooler; Methotrexate for Chikungunya Arthritis
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