Article

The costs for wound care play a significant role in total health care costs and are expected to rise dramatically. A 2018 Medicare analysis estimated chronic wound care cost $28.1 to $96.8 billion in supplies, hospitalization, and nursing care: Most costs were accrued in outpatient wound care.¹ The global market for advanced wound care supplies is projected to reach $13.7 billion by 2027, and negative wound pressure therapy alone is projected to grow at a compound annual growth rate of 5% over the analysis period 2020 to 2027.² Chronic wound care also impacts the patient physiologically, socially, and psychologically. One study compared the 5-year mortality of a patient with a diabetic foot ulcer (30.5%) as similar to those patients with cancer (31%).³ Yet the investment in cancer research far outstrips wound care research.

There is no perfect wound dressing for all chronic wounds, but there is expert consensus on interventions that facilitate wound healing. In 2021, Nuutila and Eriksson stated that wound dressings should fulfill the following criteria: protection against trauma, esthetically acceptable, painless to remove, easy to apply, protection for the wound from contamination and further trauma, a moist environment, and an optimal water vapor transmission rate.⁴ Balanced moisture control is considered essential for healing chronic wounds. Indeed, moisture control within the wound bed may be the most important factor in chronic wound management and healing. The body communicates through a liquid medium, and if that medium is compromised, communication and marshaling of the immune and healing responses may become inefficient.⁴ Too much moisture, exudate, or fluid in the wound, and the healing is slowed; too little moisture in the wound results in a compromised responses from the body’s immune system, thus delaying healing. In 1988, Dyson and colleagues demonstrated that moist wound care was superior for the inflammatory and proliferative phases of dermal repair compared with dry wound care. The results showed that 5 days after injury, 66% of the cells in the moist wound were fibroblasts and endothelial cells vs 48% of those in the dry wounds.⁵

The question of dry vs moist wound care has resulted in various wound dressings that produce favorable moisture balance. Moisture balance in a wound creates the ideal environment for wound healing. Sound wound care practices promote the following physiologic responses: increased probability of autolytic debridement; increased collagen synthesis; keratinocyte migration and reepithelization; decreased pain, inflammation, scarring, and necrosis;enhancement of cell-to-cell signaling; and increase in growth factors.^5,6 All these processes are mediated through proper wound moisture control. In addition to proper moisture control, antibiotics added to the wound care milieu (either directly to the wound or systemically) may have a place in chronic wound care. In 2013, Junker and colleagues reported that low-dose antibiotics combined with appropriate moisture balance in wounds demonstrated less scar tissue compared with dry wound care.⁶

Approaches to chronic wound care are worlds apart: In developing nations the care of chronic wounds often involves traditional management with local products (eg, honey, boiled potato peels, aloe vera gel, banana leaves), whereas in developed nations, more expensive and technologically advanced products are available (eg, wound vacuum, saline wound chamber, hyperbaric oxygen therapy, antibacterial foam). Developing countries often do not have access to technologically advanced wound care products. Local products are often used by local healers, priests, and shamans. The use of these wound interventions in developing countries has produced satisfactory results. In contrast, developed countries have multiple chronic wound care products available (Table).

CASE Presentation

An athletic, healthy 60-year-old Utah National Guard member presented to the George E. Wahlen Department of Veterans Affairs Medical Center in Salt Lake City, Utah, 6 days after experiencing a spider bite. For the first 6 days, the patient applied bacitracin at home. On day 7, the patient noticed that the wound was enlarging and appeared to be fluctuant. The patient was prescribed clindamycin 300 mg 4 times daily on an outpatient basis, which was taken on days 7 to 14.

The wound’s total surface area continued to expand, and the patient returned to the Salt Lake City Veterans Hospital wound care clinic on day 17 stating that the wound was very painful and more fluctuant. The wound care nursing staff were consulted, the wound was debrided, and attempts to drain the wound resulted in minimal exudate expressed from the wound. Clindamycin was increased to 450 mg 4 times daily. However, the wound continued to enlarge and become more painful.

On day 20, the patient reported to nursing services and was admitted to the Salt Lake City Veterans Hospital general surgery department with mental status changes and symptoms of septicemia (Figure 1).

Discussion

Traditional Wound Care

Honey. Honey has been used as a treatment for wounds for almost 3000 years. It has antiseptic and antibacterial properties and contributes to a moist wound care environment. In 2011, Gupta and colleagues reported on the use of honey in 108 patients with burns of < 50% of the total body surface area.⁷ This report stated that delay in seeking medical care increased wound infection rates, contamination, time to sterilization, and healing. Compared with silver sulfadiazine cream, honey dressings improved the time to wound healing (33 days vs 18 days, respectively), decreased the time to wound sterilization (1 day vs no sterilization), and had better outcomes (37% vs 81%, respectively) with fewer hypertrophic scars and postburn contractures.⁷

Separate studies in 2011 and 2010 from Fukuda and colleagues and Majtan and colleagues, respectively, reported that honey eliminates pathogens from wounds, augments correct moisture balance, and elevates cytokine activity.^8,9 Additional studies in 2006, 2008, and 2014 by Henriques and colleagues, Van den Berg and colleagues, and Majtan suggested that honey reduces reactive oxygen species, is responsible for direct antimicrobial effects in a healing wound, inhibits free radical production, and promotes antitumor activity, respectively.^10-12 Van den Berg and colleagues suggested that buckwheat honey is the most effective honey in reducing reactive oxygen species.¹¹

Sterile banana leaves. In medically underserved and rural areas, boiled banana leaves are used to treat burns and nonhealing wounds. In a 2015 study, Waffa and Hayah compared gauze dressings with sterile banana leaves wound dressing in patients with partial thickness burns. Topical antibiotics were added to each type of dressing. The results suggested that the banana leaf dressings were easier to remove, patients reported less pain overall, less pain with dressing changes, and demonstrated a decreased time to healing when contrasted with gauze.¹³ In 2003, Gore and Akolekar compared autoclaved banana leaves with boiled potato peels in the treatment of patients with partial thickness burns. The time to epithelialization, eschar formation, and skin graft healing were equal in both groups. However, banana leaves were 11 times cheaper and rated easier to prepare than boiled potato peels.¹⁴ In a study comparing petroleum gauze with sterile banana leaves, Chendake and colleagues reported that in measures of overall pain and trauma during dressing changes, patients with contused and sutured wounds on the face and neck achieved better outcomes with boiled banana leaves compared with petroleum gauze.¹⁵

Boiled potato peels. This treatment is used in rural areas of the world as an adjunct for wound care. In 2015, Manjunath and colleagues theorized that the use of boiled potato peels in patients with necrotizing fasciitis decreased the acidic environment created by the bacteria. Additionally, the study asserted that the toxic wound environment created by the bacteria was neutralized by the potassium content in the peel, and the flavonoids in the peel acted as a free radical scavenger.¹⁶ In 2011, Panda and colleagues, using povidone-iodine as a baseline control, reported that peel extract and a peel bandage of sweet potato showed an increased wound closure percentage measured by enhanced epithelialization.¹⁷ This increased epithelialization was attributed to the antioxidant effect of the peels enhancing collagen synthesis.¹⁷

In contrast, in 1996, a study by Subrahmanyam compared autoclaved potato peel bandages with honey dressings as adjuncts in burn patients with < 40% of the total body surface area affected. The author reported that 90% of the wounds treated with honey were sterile in 7 days, while infection persisted in the potato peel group after 7 days. In the same study, 100% of the wounds treated with honey were healed in 15 days vs 50% in the potato peel group.¹⁸ In 1990, Keswani and colleagues compared boiled potato peels with plain gauze as adjuncts in the treatment of burn patients and concluded that although the potato peels had no antibacterial effect, the wounds in both groups had identical bacterial species. But the wounds treated with the potato peels showed reduced desiccation, permitting the survival of skin cells, and enhanced epithelial regeneration.¹⁹

Aloe vera. First recorded by the Egyptians and Greeks, aloe vera gel has been used for centuries in many cultures for a variety of ailments, particularly burns and chronic wounds. In a 2016 wound healing study performed on rats, Oryan and colleagues demonstrated that aloe vera gel was superior to saline used as the baseline control. Aloe vera gel used in a dose-dependent fashion demonstrated increased tissue levels of collagen and glycosaminoglycans compared with controls. Aloe vera gel modulated wound inflammation, increased wound contraction, wound epithelialization, decreased scar tissue size, and increased alignment and organization of the scar tissue.²⁰

Gauze. Iodoform gauze is a highly absorbent wound product. Sterile gauze promotes granulation and wound healing. It is well suited for wounds with minimal drainage. However, although gauze is inexpensive, it is easily overwhelmed by the moisture content in the wound, requiring frequent dressing changes (up to 3 times a day), ideally by nursing staff. The resulting increase in nursing care may actually increase the cost of wound care compared with other care modalities.

Petroleum gauze is often used in the care of acute and chronic wounds. However, petroleum-impregnated gauze has a water vapor transmission rate that needs to be remoistened every 4 hours. If the affected area is not remoistened during the exudative phase of wound healing, it may precipitate a delay in healing and increase pain and the prevalence of clinical infections compared with hydrocolloid, film, or foam dressings. Bolton suggested stopping the use of petroleum gauze as the control in studies because it does not provide a balanced and moist wound healing environment.²¹

Advanced Wound Treatments

Film products. Film products, including plastic food wrap, can be used as wound dressings and meet many of the necessary criteria for enhancing wound healing. These include moisture permeability, carbon dioxide, oxygen transfer, and wound protection. Transmission of moisture varies among products known as the moisture vapor transpiration rate. Film dressings have no absorptive qualities and are unsuited for highly exudative wounds.^22,23 Adding polymers, antibacterial, and bioactive agents may increase the wound care properties of film dressings.²² Film dressings excel in protecting shallow nonexudative wounds, are waterproof, and help protect the wound. These products are transparent, allowing clinicians to monitor the progress of the wound without removing the covering, and allowing the dressing to remain in place longer, which decreases the repeated trauma that can occur with dressing changes. Film dressings for wounds differ from those used for IV dressings and should not be used interchangeably.²³

Bioactive wound care. These solutions contribute to a moist wound-healing environment. Found naturally in brown seaweed, alginate-containing compounds were used by sailors for centuries to heal wounds. This was known in traditional medicine as the mariner’s cure. Alginate dressings are highly absorbent and can absorb up to 20 times their weight, which makes them desirable for use in highly exudative wounds. First synthesized more than 50 years ago, newer products contain bioactive compounds that prevent tissue damage, stimulate wound healing, improve cell proliferation and migration, and enhance metabolite formation.^24-26

In 2018, Aderibigbe and Buyana reported that polymers in the form of hydrogels were able to absorb fluid, making them a suitable choice for minimally exudative wounds. However, in their distended state, the hydrogel subgroup of these products became unstable (perhaps making them a poor choice for extensively exudative wounds), tended to dehydrate, and often needed a secondary dressing, which could lead to wound maceration.²² Most commonly used for wounds with minimal exudate, these dressings shine when used in nominally exudative dry wounds to promote autolytic debridement and hydrate the wound that has formed an eschar.

Hydrocolloid dressings are another type of bioactive wound dressing. These dressings are composed of 2 layers: an inner hydrophilic layer and an outer vapor-permeable layer that promote a moist wound environment. Hydrocolloid dressings assist in hydrating dry eschar wounds and have slight absorbency for exudative wounds. These dressings are not designed to be changed daily and can remain in place for 3 to 6 days. In a 2008 extensive review article, Thomas compared the utility of these dressings in patients with superficial or partial thickness burns, donor sites, surgical wounds, and minor traumatic wounds with basic wound dressings. The results of the review suggested that hydrocolloid dressings conferred statistically significant advantages in measures of decreased pain, healing times (decreased in donor sites by 40%), mobility restriction, and number of dressing changes.²⁷ Although more expensive than basic dressings, the longevity of the hydrocolloid dressing helps defray the original cost. Unfortunately, as these dressings remain in place and continue absorbing exudate, they can take on a very unpleasant odor.

A 2013 Cochrane database review comparing hydrocolloids with foams, alginate, basic wound dressing, and topical treatment found no statistical difference between hydrocolloids and basic wound dressings in patients with diabetes who have noncomplex foot ulcers.²⁸ In 2014, Pott and colleagues suggested a slight superiority in the performance of polyurethane foam dressings over hydrocolloid dressings used in pressure ulcers in older adults.²⁹ In a large pooled analysis in 2010, Davies compared foam to hydrocolloid dressings used in exudative wounds and reported that in 11 of 12 studies, foam dressings were superior to hydrocolloid in terms of exudate management, conformity to the wound, ease of use, decreased trauma and pain at dressing changes, and reduced odor of the wound.³⁰

Foam dressings. These products are typically composed of silicone or polyurethane. Consisting of 2 to 3 layers with a hydrophilic surface, foams are cut to approximate the wound size and serve to wick the macerated wound products to a secondary dressing above the foam. The micropores in the foam matrix absorb exudate from the wound bed while maintaining moisture equilibrium in the wound by donating back moisture to the wound, creating an environment conducive to wound healing. Foam dressings can be combined with various antiseptics (silver, GV/MB, etc) and serve as a delivery vehicle of those products directly to the wound surface.

A 2011 review comparing 8 studies found no difference among foam products available at that time in the use for chronic wounds.³¹ However, newer products on the market today have produced intriguing results with chronic wounds.

In 2017, Woo and Heil observed that chronic wounds treated with foam products containing GV/MB produced significant improvement when measured at week 4 in the areas of mean wound surface area (42.5%), decrease in baseline Pressure Ulcer Scale for Healing scores (from 13.3 to 10.7), wound coverage by devitalized tissue reduced (from 52.6% to 11.4%), and mean upper and lower wound infection scores were reduced by 75%.³² Further, the researchers reported a moist wound bed was achieved at dressing changes with polyvinyl alcohol (PVA) foam dressing. This led to the presumption that adequate moisture balance and autolytic debridement were facilitated using GV/MB antibacterial PVA foam dressings.

Many foam products on the market today exert an antibacterial effect on the wound bed. Antibiotic properties of various foam dressings create a microenvironment hostile to bacterial growth.³² In addition, the antibacterial properties combined with foam products contribute to the following: autolytic debridement, absorptive qualities (which reduce the bioburden of the wound), and maintenance of moisture in the wound bed. These qualities contribute significantly to the effectiveness of foam products with antibacterial properties.³² The correct balance of moisture in the wound has been identified as a superior environment and perhaps the most important component in chronic wounds.⁴ Foam dressings are less painful to change, easier to change, and in this case report, contributed to faster wound healing than gauze alone. In 2016, a study by Lee and colleagues suggested that the makeup of the foam product, defined as smaller pore and uniform cell size (foam density), resulted in greater permeability and better moisture absorption and retention capacity, contributing to improved wound healing.³³

In 2004, Sibbald and colleagues reported that in a 4-week study of nonhealing chronic wounds, foam wound dressing impregnated with sustained-release silver compared with foam dressing without silver resulted in a reduction in wound size (50% vs 30%, respectively), decreased fluid leakage (27% vs 44% respectively), and reduction in ulcer size measured from baseline (45% vs 25%, respectively).³⁴

In a 2006 study, Varma and colleagues compared sterilized, saline-soaked, nonmedicated polyurethane industrial upholstery foam in nonhealing wounds used in patients with diabetes with conventional techniques using topical antibiotics, hydrocolloid or hydrogel dressings as necessary, and desloughing agents as controls. At the end of a 3-month follow-up period, 100% of the wounds of the foam group had healed compared with 29.2% of the control group. Additionally, the time to wound healing was less than half for the foam group (22.5 days) compared with the control group (52 days), and the time to granulation and epithelialization was faster in the foam group.³⁵

In a 2012 meta-analysis, Aziz and colleagues reported that silver-impregnated dressings and topical silver were no better or worse than controls in preventing wound infection and promoting the healing of burn wounds.³⁶ The authors also noted that the nonsilver dressing groups continuing povidone-iodine, ionic hydrogel, or silicone-coated dressing showed reduced healing time compared with the silver-containing group.³⁶ This is intriguing because silver has long been used as a standard for the treatment of burn wounds.

Wound vacuum dressings. These dressings are very effective on highly exudative wounds involving a large surface area. However, wound vacuum dressing changes are time intensive and often painful to change. This is a foam dressing placed in the wound and attached to a vacuum device. The wound and foam are then covered with an impermeable membrane and attached to a negative pressure device that exerts a small negative pressure within the wound bed. This negative pressure increases the flow of blood to the less oxygenated areas in the center of the wound, promoting an increased concentration gradient of blood and nutrients and enhancing the evacuation of exudative material from the wound. Thus, a wound vacuum assists in forming an excellent moist wound-healing environment. Reporting in a review article in 2019, Agarwal and colleagues suggested that intermittent negative pressure was superior to constant negative pressure in wound healing due to the increased blood flow in the off phase, and 125 mm Hg negative pressure was optimal for wound healing.³⁷ This type of wound care has been touted as superior in wound care circles, and it may be; however, its cost, time commitment, and painful dressing changes along with cumbersome equipment make the choice difficult for some patients.

Conclusions

Although there is no perfect wound dressing, some wound care products seem to perform better due to fewer adverse effects and a much lesser cost. Important aspects of wound care appear to be time from injury to wound care, cleanliness of the wound, moist wound environment, cost, ease of use, and pain of dressing changes.

Primitive wound care products perform admirably in many situations. Modern medicated foam dressings containing antibacterial properties may have beneficial properties compared with other wound care products; however, comparison studies are lacking and need broad-based, randomized, controlled trials to confirm utility. Finally, any choice of wound care product must be tailored to the particular wound and individual patient needs. More large, robust, randomized controlled trials are needed.

Acknowledgments

The authors thank Sarah Maria Paulsen and Rosemary Ellen Brown Smith for their editing, proofreading, and preparation of the manuscript.

The costs for wound care play a significant role in total health care costs and are expected to rise dramatically. A 2018 Medicare analysis estimated chronic wound care cost $28.1 to $96.8 billion in supplies, hospitalization, and nursing care: Most costs were accrued in outpatient wound care.¹ The global market for advanced wound care supplies is projected to reach $13.7 billion by 2027, and negative wound pressure therapy alone is projected to grow at a compound annual growth rate of 5% over the analysis period 2020 to 2027.² Chronic wound care also impacts the patient physiologically, socially, and psychologically. One study compared the 5-year mortality of a patient with a diabetic foot ulcer (30.5%) as similar to those patients with cancer (31%).³ Yet the investment in cancer research far outstrips wound care research.

There is no perfect wound dressing for all chronic wounds, but there is expert consensus on interventions that facilitate wound healing. In 2021, Nuutila and Eriksson stated that wound dressings should fulfill the following criteria: protection against trauma, esthetically acceptable, painless to remove, easy to apply, protection for the wound from contamination and further trauma, a moist environment, and an optimal water vapor transmission rate.⁴ Balanced moisture control is considered essential for healing chronic wounds. Indeed, moisture control within the wound bed may be the most important factor in chronic wound management and healing. The body communicates through a liquid medium, and if that medium is compromised, communication and marshaling of the immune and healing responses may become inefficient.⁴ Too much moisture, exudate, or fluid in the wound, and the healing is slowed; too little moisture in the wound results in a compromised responses from the body’s immune system, thus delaying healing. In 1988, Dyson and colleagues demonstrated that moist wound care was superior for the inflammatory and proliferative phases of dermal repair compared with dry wound care. The results showed that 5 days after injury, 66% of the cells in the moist wound were fibroblasts and endothelial cells vs 48% of those in the dry wounds.⁵

The question of dry vs moist wound care has resulted in various wound dressings that produce favorable moisture balance. Moisture balance in a wound creates the ideal environment for wound healing. Sound wound care practices promote the following physiologic responses: increased probability of autolytic debridement; increased collagen synthesis; keratinocyte migration and reepithelization; decreased pain, inflammation, scarring, and necrosis;enhancement of cell-to-cell signaling; and increase in growth factors.^5,6 All these processes are mediated through proper wound moisture control. In addition to proper moisture control, antibiotics added to the wound care milieu (either directly to the wound or systemically) may have a place in chronic wound care. In 2013, Junker and colleagues reported that low-dose antibiotics combined with appropriate moisture balance in wounds demonstrated less scar tissue compared with dry wound care.⁶

Approaches to chronic wound care are worlds apart: In developing nations the care of chronic wounds often involves traditional management with local products (eg, honey, boiled potato peels, aloe vera gel, banana leaves), whereas in developed nations, more expensive and technologically advanced products are available (eg, wound vacuum, saline wound chamber, hyperbaric oxygen therapy, antibacterial foam). Developing countries often do not have access to technologically advanced wound care products. Local products are often used by local healers, priests, and shamans. The use of these wound interventions in developing countries has produced satisfactory results. In contrast, developed countries have multiple chronic wound care products available (Table).

CASE Presentation

An athletic, healthy 60-year-old Utah National Guard member presented to the George E. Wahlen Department of Veterans Affairs Medical Center in Salt Lake City, Utah, 6 days after experiencing a spider bite. For the first 6 days, the patient applied bacitracin at home. On day 7, the patient noticed that the wound was enlarging and appeared to be fluctuant. The patient was prescribed clindamycin 300 mg 4 times daily on an outpatient basis, which was taken on days 7 to 14.

The wound’s total surface area continued to expand, and the patient returned to the Salt Lake City Veterans Hospital wound care clinic on day 17 stating that the wound was very painful and more fluctuant. The wound care nursing staff were consulted, the wound was debrided, and attempts to drain the wound resulted in minimal exudate expressed from the wound. Clindamycin was increased to 450 mg 4 times daily. However, the wound continued to enlarge and become more painful.

On day 20, the patient reported to nursing services and was admitted to the Salt Lake City Veterans Hospital general surgery department with mental status changes and symptoms of septicemia (Figure 1).

Discussion

Traditional Wound Care

Honey. Honey has been used as a treatment for wounds for almost 3000 years. It has antiseptic and antibacterial properties and contributes to a moist wound care environment. In 2011, Gupta and colleagues reported on the use of honey in 108 patients with burns of < 50% of the total body surface area.⁷ This report stated that delay in seeking medical care increased wound infection rates, contamination, time to sterilization, and healing. Compared with silver sulfadiazine cream, honey dressings improved the time to wound healing (33 days vs 18 days, respectively), decreased the time to wound sterilization (1 day vs no sterilization), and had better outcomes (37% vs 81%, respectively) with fewer hypertrophic scars and postburn contractures.⁷

Separate studies in 2011 and 2010 from Fukuda and colleagues and Majtan and colleagues, respectively, reported that honey eliminates pathogens from wounds, augments correct moisture balance, and elevates cytokine activity.^8,9 Additional studies in 2006, 2008, and 2014 by Henriques and colleagues, Van den Berg and colleagues, and Majtan suggested that honey reduces reactive oxygen species, is responsible for direct antimicrobial effects in a healing wound, inhibits free radical production, and promotes antitumor activity, respectively.^10-12 Van den Berg and colleagues suggested that buckwheat honey is the most effective honey in reducing reactive oxygen species.¹¹

Sterile banana leaves. In medically underserved and rural areas, boiled banana leaves are used to treat burns and nonhealing wounds. In a 2015 study, Waffa and Hayah compared gauze dressings with sterile banana leaves wound dressing in patients with partial thickness burns. Topical antibiotics were added to each type of dressing. The results suggested that the banana leaf dressings were easier to remove, patients reported less pain overall, less pain with dressing changes, and demonstrated a decreased time to healing when contrasted with gauze.¹³ In 2003, Gore and Akolekar compared autoclaved banana leaves with boiled potato peels in the treatment of patients with partial thickness burns. The time to epithelialization, eschar formation, and skin graft healing were equal in both groups. However, banana leaves were 11 times cheaper and rated easier to prepare than boiled potato peels.¹⁴ In a study comparing petroleum gauze with sterile banana leaves, Chendake and colleagues reported that in measures of overall pain and trauma during dressing changes, patients with contused and sutured wounds on the face and neck achieved better outcomes with boiled banana leaves compared with petroleum gauze.¹⁵

Boiled potato peels. This treatment is used in rural areas of the world as an adjunct for wound care. In 2015, Manjunath and colleagues theorized that the use of boiled potato peels in patients with necrotizing fasciitis decreased the acidic environment created by the bacteria. Additionally, the study asserted that the toxic wound environment created by the bacteria was neutralized by the potassium content in the peel, and the flavonoids in the peel acted as a free radical scavenger.¹⁶ In 2011, Panda and colleagues, using povidone-iodine as a baseline control, reported that peel extract and a peel bandage of sweet potato showed an increased wound closure percentage measured by enhanced epithelialization.¹⁷ This increased epithelialization was attributed to the antioxidant effect of the peels enhancing collagen synthesis.¹⁷

In contrast, in 1996, a study by Subrahmanyam compared autoclaved potato peel bandages with honey dressings as adjuncts in burn patients with < 40% of the total body surface area affected. The author reported that 90% of the wounds treated with honey were sterile in 7 days, while infection persisted in the potato peel group after 7 days. In the same study, 100% of the wounds treated with honey were healed in 15 days vs 50% in the potato peel group.¹⁸ In 1990, Keswani and colleagues compared boiled potato peels with plain gauze as adjuncts in the treatment of burn patients and concluded that although the potato peels had no antibacterial effect, the wounds in both groups had identical bacterial species. But the wounds treated with the potato peels showed reduced desiccation, permitting the survival of skin cells, and enhanced epithelial regeneration.¹⁹

Aloe vera. First recorded by the Egyptians and Greeks, aloe vera gel has been used for centuries in many cultures for a variety of ailments, particularly burns and chronic wounds. In a 2016 wound healing study performed on rats, Oryan and colleagues demonstrated that aloe vera gel was superior to saline used as the baseline control. Aloe vera gel used in a dose-dependent fashion demonstrated increased tissue levels of collagen and glycosaminoglycans compared with controls. Aloe vera gel modulated wound inflammation, increased wound contraction, wound epithelialization, decreased scar tissue size, and increased alignment and organization of the scar tissue.²⁰

Gauze. Iodoform gauze is a highly absorbent wound product. Sterile gauze promotes granulation and wound healing. It is well suited for wounds with minimal drainage. However, although gauze is inexpensive, it is easily overwhelmed by the moisture content in the wound, requiring frequent dressing changes (up to 3 times a day), ideally by nursing staff. The resulting increase in nursing care may actually increase the cost of wound care compared with other care modalities.

Petroleum gauze is often used in the care of acute and chronic wounds. However, petroleum-impregnated gauze has a water vapor transmission rate that needs to be remoistened every 4 hours. If the affected area is not remoistened during the exudative phase of wound healing, it may precipitate a delay in healing and increase pain and the prevalence of clinical infections compared with hydrocolloid, film, or foam dressings. Bolton suggested stopping the use of petroleum gauze as the control in studies because it does not provide a balanced and moist wound healing environment.²¹

Advanced Wound Treatments

Film products. Film products, including plastic food wrap, can be used as wound dressings and meet many of the necessary criteria for enhancing wound healing. These include moisture permeability, carbon dioxide, oxygen transfer, and wound protection. Transmission of moisture varies among products known as the moisture vapor transpiration rate. Film dressings have no absorptive qualities and are unsuited for highly exudative wounds.^22,23 Adding polymers, antibacterial, and bioactive agents may increase the wound care properties of film dressings.²² Film dressings excel in protecting shallow nonexudative wounds, are waterproof, and help protect the wound. These products are transparent, allowing clinicians to monitor the progress of the wound without removing the covering, and allowing the dressing to remain in place longer, which decreases the repeated trauma that can occur with dressing changes. Film dressings for wounds differ from those used for IV dressings and should not be used interchangeably.²³

Bioactive wound care. These solutions contribute to a moist wound-healing environment. Found naturally in brown seaweed, alginate-containing compounds were used by sailors for centuries to heal wounds. This was known in traditional medicine as the mariner’s cure. Alginate dressings are highly absorbent and can absorb up to 20 times their weight, which makes them desirable for use in highly exudative wounds. First synthesized more than 50 years ago, newer products contain bioactive compounds that prevent tissue damage, stimulate wound healing, improve cell proliferation and migration, and enhance metabolite formation.^24-26

In 2018, Aderibigbe and Buyana reported that polymers in the form of hydrogels were able to absorb fluid, making them a suitable choice for minimally exudative wounds. However, in their distended state, the hydrogel subgroup of these products became unstable (perhaps making them a poor choice for extensively exudative wounds), tended to dehydrate, and often needed a secondary dressing, which could lead to wound maceration.²² Most commonly used for wounds with minimal exudate, these dressings shine when used in nominally exudative dry wounds to promote autolytic debridement and hydrate the wound that has formed an eschar.

Hydrocolloid dressings are another type of bioactive wound dressing. These dressings are composed of 2 layers: an inner hydrophilic layer and an outer vapor-permeable layer that promote a moist wound environment. Hydrocolloid dressings assist in hydrating dry eschar wounds and have slight absorbency for exudative wounds. These dressings are not designed to be changed daily and can remain in place for 3 to 6 days. In a 2008 extensive review article, Thomas compared the utility of these dressings in patients with superficial or partial thickness burns, donor sites, surgical wounds, and minor traumatic wounds with basic wound dressings. The results of the review suggested that hydrocolloid dressings conferred statistically significant advantages in measures of decreased pain, healing times (decreased in donor sites by 40%), mobility restriction, and number of dressing changes.²⁷ Although more expensive than basic dressings, the longevity of the hydrocolloid dressing helps defray the original cost. Unfortunately, as these dressings remain in place and continue absorbing exudate, they can take on a very unpleasant odor.

A 2013 Cochrane database review comparing hydrocolloids with foams, alginate, basic wound dressing, and topical treatment found no statistical difference between hydrocolloids and basic wound dressings in patients with diabetes who have noncomplex foot ulcers.²⁸ In 2014, Pott and colleagues suggested a slight superiority in the performance of polyurethane foam dressings over hydrocolloid dressings used in pressure ulcers in older adults.²⁹ In a large pooled analysis in 2010, Davies compared foam to hydrocolloid dressings used in exudative wounds and reported that in 11 of 12 studies, foam dressings were superior to hydrocolloid in terms of exudate management, conformity to the wound, ease of use, decreased trauma and pain at dressing changes, and reduced odor of the wound.³⁰

Foam dressings. These products are typically composed of silicone or polyurethane. Consisting of 2 to 3 layers with a hydrophilic surface, foams are cut to approximate the wound size and serve to wick the macerated wound products to a secondary dressing above the foam. The micropores in the foam matrix absorb exudate from the wound bed while maintaining moisture equilibrium in the wound by donating back moisture to the wound, creating an environment conducive to wound healing. Foam dressings can be combined with various antiseptics (silver, GV/MB, etc) and serve as a delivery vehicle of those products directly to the wound surface.

A 2011 review comparing 8 studies found no difference among foam products available at that time in the use for chronic wounds.³¹ However, newer products on the market today have produced intriguing results with chronic wounds.

In 2017, Woo and Heil observed that chronic wounds treated with foam products containing GV/MB produced significant improvement when measured at week 4 in the areas of mean wound surface area (42.5%), decrease in baseline Pressure Ulcer Scale for Healing scores (from 13.3 to 10.7), wound coverage by devitalized tissue reduced (from 52.6% to 11.4%), and mean upper and lower wound infection scores were reduced by 75%.³² Further, the researchers reported a moist wound bed was achieved at dressing changes with polyvinyl alcohol (PVA) foam dressing. This led to the presumption that adequate moisture balance and autolytic debridement were facilitated using GV/MB antibacterial PVA foam dressings.

Many foam products on the market today exert an antibacterial effect on the wound bed. Antibiotic properties of various foam dressings create a microenvironment hostile to bacterial growth.³² In addition, the antibacterial properties combined with foam products contribute to the following: autolytic debridement, absorptive qualities (which reduce the bioburden of the wound), and maintenance of moisture in the wound bed. These qualities contribute significantly to the effectiveness of foam products with antibacterial properties.³² The correct balance of moisture in the wound has been identified as a superior environment and perhaps the most important component in chronic wounds.⁴ Foam dressings are less painful to change, easier to change, and in this case report, contributed to faster wound healing than gauze alone. In 2016, a study by Lee and colleagues suggested that the makeup of the foam product, defined as smaller pore and uniform cell size (foam density), resulted in greater permeability and better moisture absorption and retention capacity, contributing to improved wound healing.³³

In 2004, Sibbald and colleagues reported that in a 4-week study of nonhealing chronic wounds, foam wound dressing impregnated with sustained-release silver compared with foam dressing without silver resulted in a reduction in wound size (50% vs 30%, respectively), decreased fluid leakage (27% vs 44% respectively), and reduction in ulcer size measured from baseline (45% vs 25%, respectively).³⁴

In a 2006 study, Varma and colleagues compared sterilized, saline-soaked, nonmedicated polyurethane industrial upholstery foam in nonhealing wounds used in patients with diabetes with conventional techniques using topical antibiotics, hydrocolloid or hydrogel dressings as necessary, and desloughing agents as controls. At the end of a 3-month follow-up period, 100% of the wounds of the foam group had healed compared with 29.2% of the control group. Additionally, the time to wound healing was less than half for the foam group (22.5 days) compared with the control group (52 days), and the time to granulation and epithelialization was faster in the foam group.³⁵

In a 2012 meta-analysis, Aziz and colleagues reported that silver-impregnated dressings and topical silver were no better or worse than controls in preventing wound infection and promoting the healing of burn wounds.³⁶ The authors also noted that the nonsilver dressing groups continuing povidone-iodine, ionic hydrogel, or silicone-coated dressing showed reduced healing time compared with the silver-containing group.³⁶ This is intriguing because silver has long been used as a standard for the treatment of burn wounds.

Wound vacuum dressings. These dressings are very effective on highly exudative wounds involving a large surface area. However, wound vacuum dressing changes are time intensive and often painful to change. This is a foam dressing placed in the wound and attached to a vacuum device. The wound and foam are then covered with an impermeable membrane and attached to a negative pressure device that exerts a small negative pressure within the wound bed. This negative pressure increases the flow of blood to the less oxygenated areas in the center of the wound, promoting an increased concentration gradient of blood and nutrients and enhancing the evacuation of exudative material from the wound. Thus, a wound vacuum assists in forming an excellent moist wound-healing environment. Reporting in a review article in 2019, Agarwal and colleagues suggested that intermittent negative pressure was superior to constant negative pressure in wound healing due to the increased blood flow in the off phase, and 125 mm Hg negative pressure was optimal for wound healing.³⁷ This type of wound care has been touted as superior in wound care circles, and it may be; however, its cost, time commitment, and painful dressing changes along with cumbersome equipment make the choice difficult for some patients.

Conclusions

Although there is no perfect wound dressing, some wound care products seem to perform better due to fewer adverse effects and a much lesser cost. Important aspects of wound care appear to be time from injury to wound care, cleanliness of the wound, moist wound environment, cost, ease of use, and pain of dressing changes.

Primitive wound care products perform admirably in many situations. Modern medicated foam dressings containing antibacterial properties may have beneficial properties compared with other wound care products; however, comparison studies are lacking and need broad-based, randomized, controlled trials to confirm utility. Finally, any choice of wound care product must be tailored to the particular wound and individual patient needs. More large, robust, randomized controlled trials are needed.

Acknowledgments

The authors thank Sarah Maria Paulsen and Rosemary Ellen Brown Smith for their editing, proofreading, and preparation of the manuscript.

The costs for wound care play a significant role in total health care costs and are expected to rise dramatically. A 2018 Medicare analysis estimated chronic wound care cost $28.1 to $96.8 billion in supplies, hospitalization, and nursing care: Most costs were accrued in outpatient wound care.¹ The global market for advanced wound care supplies is projected to reach $13.7 billion by 2027, and negative wound pressure therapy alone is projected to grow at a compound annual growth rate of 5% over the analysis period 2020 to 2027.² Chronic wound care also impacts the patient physiologically, socially, and psychologically. One study compared the 5-year mortality of a patient with a diabetic foot ulcer (30.5%) as similar to those patients with cancer (31%).³ Yet the investment in cancer research far outstrips wound care research.

There is no perfect wound dressing for all chronic wounds, but there is expert consensus on interventions that facilitate wound healing. In 2021, Nuutila and Eriksson stated that wound dressings should fulfill the following criteria: protection against trauma, esthetically acceptable, painless to remove, easy to apply, protection for the wound from contamination and further trauma, a moist environment, and an optimal water vapor transmission rate.⁴ Balanced moisture control is considered essential for healing chronic wounds. Indeed, moisture control within the wound bed may be the most important factor in chronic wound management and healing. The body communicates through a liquid medium, and if that medium is compromised, communication and marshaling of the immune and healing responses may become inefficient.⁴ Too much moisture, exudate, or fluid in the wound, and the healing is slowed; too little moisture in the wound results in a compromised responses from the body’s immune system, thus delaying healing. In 1988, Dyson and colleagues demonstrated that moist wound care was superior for the inflammatory and proliferative phases of dermal repair compared with dry wound care. The results showed that 5 days after injury, 66% of the cells in the moist wound were fibroblasts and endothelial cells vs 48% of those in the dry wounds.⁵

The question of dry vs moist wound care has resulted in various wound dressings that produce favorable moisture balance. Moisture balance in a wound creates the ideal environment for wound healing. Sound wound care practices promote the following physiologic responses: increased probability of autolytic debridement; increased collagen synthesis; keratinocyte migration and reepithelization; decreased pain, inflammation, scarring, and necrosis;enhancement of cell-to-cell signaling; and increase in growth factors.^5,6 All these processes are mediated through proper wound moisture control. In addition to proper moisture control, antibiotics added to the wound care milieu (either directly to the wound or systemically) may have a place in chronic wound care. In 2013, Junker and colleagues reported that low-dose antibiotics combined with appropriate moisture balance in wounds demonstrated less scar tissue compared with dry wound care.⁶

Approaches to chronic wound care are worlds apart: In developing nations the care of chronic wounds often involves traditional management with local products (eg, honey, boiled potato peels, aloe vera gel, banana leaves), whereas in developed nations, more expensive and technologically advanced products are available (eg, wound vacuum, saline wound chamber, hyperbaric oxygen therapy, antibacterial foam). Developing countries often do not have access to technologically advanced wound care products. Local products are often used by local healers, priests, and shamans. The use of these wound interventions in developing countries has produced satisfactory results. In contrast, developed countries have multiple chronic wound care products available (Table).

CASE Presentation

An athletic, healthy 60-year-old Utah National Guard member presented to the George E. Wahlen Department of Veterans Affairs Medical Center in Salt Lake City, Utah, 6 days after experiencing a spider bite. For the first 6 days, the patient applied bacitracin at home. On day 7, the patient noticed that the wound was enlarging and appeared to be fluctuant. The patient was prescribed clindamycin 300 mg 4 times daily on an outpatient basis, which was taken on days 7 to 14.

The wound’s total surface area continued to expand, and the patient returned to the Salt Lake City Veterans Hospital wound care clinic on day 17 stating that the wound was very painful and more fluctuant. The wound care nursing staff were consulted, the wound was debrided, and attempts to drain the wound resulted in minimal exudate expressed from the wound. Clindamycin was increased to 450 mg 4 times daily. However, the wound continued to enlarge and become more painful.

On day 20, the patient reported to nursing services and was admitted to the Salt Lake City Veterans Hospital general surgery department with mental status changes and symptoms of septicemia (Figure 1).

Discussion

Traditional Wound Care

Honey. Honey has been used as a treatment for wounds for almost 3000 years. It has antiseptic and antibacterial properties and contributes to a moist wound care environment. In 2011, Gupta and colleagues reported on the use of honey in 108 patients with burns of < 50% of the total body surface area.⁷ This report stated that delay in seeking medical care increased wound infection rates, contamination, time to sterilization, and healing. Compared with silver sulfadiazine cream, honey dressings improved the time to wound healing (33 days vs 18 days, respectively), decreased the time to wound sterilization (1 day vs no sterilization), and had better outcomes (37% vs 81%, respectively) with fewer hypertrophic scars and postburn contractures.⁷

Separate studies in 2011 and 2010 from Fukuda and colleagues and Majtan and colleagues, respectively, reported that honey eliminates pathogens from wounds, augments correct moisture balance, and elevates cytokine activity.^8,9 Additional studies in 2006, 2008, and 2014 by Henriques and colleagues, Van den Berg and colleagues, and Majtan suggested that honey reduces reactive oxygen species, is responsible for direct antimicrobial effects in a healing wound, inhibits free radical production, and promotes antitumor activity, respectively.^10-12 Van den Berg and colleagues suggested that buckwheat honey is the most effective honey in reducing reactive oxygen species.¹¹

Sterile banana leaves. In medically underserved and rural areas, boiled banana leaves are used to treat burns and nonhealing wounds. In a 2015 study, Waffa and Hayah compared gauze dressings with sterile banana leaves wound dressing in patients with partial thickness burns. Topical antibiotics were added to each type of dressing. The results suggested that the banana leaf dressings were easier to remove, patients reported less pain overall, less pain with dressing changes, and demonstrated a decreased time to healing when contrasted with gauze.¹³ In 2003, Gore and Akolekar compared autoclaved banana leaves with boiled potato peels in the treatment of patients with partial thickness burns. The time to epithelialization, eschar formation, and skin graft healing were equal in both groups. However, banana leaves were 11 times cheaper and rated easier to prepare than boiled potato peels.¹⁴ In a study comparing petroleum gauze with sterile banana leaves, Chendake and colleagues reported that in measures of overall pain and trauma during dressing changes, patients with contused and sutured wounds on the face and neck achieved better outcomes with boiled banana leaves compared with petroleum gauze.¹⁵

Boiled potato peels. This treatment is used in rural areas of the world as an adjunct for wound care. In 2015, Manjunath and colleagues theorized that the use of boiled potato peels in patients with necrotizing fasciitis decreased the acidic environment created by the bacteria. Additionally, the study asserted that the toxic wound environment created by the bacteria was neutralized by the potassium content in the peel, and the flavonoids in the peel acted as a free radical scavenger.¹⁶ In 2011, Panda and colleagues, using povidone-iodine as a baseline control, reported that peel extract and a peel bandage of sweet potato showed an increased wound closure percentage measured by enhanced epithelialization.¹⁷ This increased epithelialization was attributed to the antioxidant effect of the peels enhancing collagen synthesis.¹⁷

In contrast, in 1996, a study by Subrahmanyam compared autoclaved potato peel bandages with honey dressings as adjuncts in burn patients with < 40% of the total body surface area affected. The author reported that 90% of the wounds treated with honey were sterile in 7 days, while infection persisted in the potato peel group after 7 days. In the same study, 100% of the wounds treated with honey were healed in 15 days vs 50% in the potato peel group.¹⁸ In 1990, Keswani and colleagues compared boiled potato peels with plain gauze as adjuncts in the treatment of burn patients and concluded that although the potato peels had no antibacterial effect, the wounds in both groups had identical bacterial species. But the wounds treated with the potato peels showed reduced desiccation, permitting the survival of skin cells, and enhanced epithelial regeneration.¹⁹

Aloe vera. First recorded by the Egyptians and Greeks, aloe vera gel has been used for centuries in many cultures for a variety of ailments, particularly burns and chronic wounds. In a 2016 wound healing study performed on rats, Oryan and colleagues demonstrated that aloe vera gel was superior to saline used as the baseline control. Aloe vera gel used in a dose-dependent fashion demonstrated increased tissue levels of collagen and glycosaminoglycans compared with controls. Aloe vera gel modulated wound inflammation, increased wound contraction, wound epithelialization, decreased scar tissue size, and increased alignment and organization of the scar tissue.²⁰

Gauze. Iodoform gauze is a highly absorbent wound product. Sterile gauze promotes granulation and wound healing. It is well suited for wounds with minimal drainage. However, although gauze is inexpensive, it is easily overwhelmed by the moisture content in the wound, requiring frequent dressing changes (up to 3 times a day), ideally by nursing staff. The resulting increase in nursing care may actually increase the cost of wound care compared with other care modalities.

Petroleum gauze is often used in the care of acute and chronic wounds. However, petroleum-impregnated gauze has a water vapor transmission rate that needs to be remoistened every 4 hours. If the affected area is not remoistened during the exudative phase of wound healing, it may precipitate a delay in healing and increase pain and the prevalence of clinical infections compared with hydrocolloid, film, or foam dressings. Bolton suggested stopping the use of petroleum gauze as the control in studies because it does not provide a balanced and moist wound healing environment.²¹

Advanced Wound Treatments

Film products. Film products, including plastic food wrap, can be used as wound dressings and meet many of the necessary criteria for enhancing wound healing. These include moisture permeability, carbon dioxide, oxygen transfer, and wound protection. Transmission of moisture varies among products known as the moisture vapor transpiration rate. Film dressings have no absorptive qualities and are unsuited for highly exudative wounds.^22,23 Adding polymers, antibacterial, and bioactive agents may increase the wound care properties of film dressings.²² Film dressings excel in protecting shallow nonexudative wounds, are waterproof, and help protect the wound. These products are transparent, allowing clinicians to monitor the progress of the wound without removing the covering, and allowing the dressing to remain in place longer, which decreases the repeated trauma that can occur with dressing changes. Film dressings for wounds differ from those used for IV dressings and should not be used interchangeably.²³

Bioactive wound care. These solutions contribute to a moist wound-healing environment. Found naturally in brown seaweed, alginate-containing compounds were used by sailors for centuries to heal wounds. This was known in traditional medicine as the mariner’s cure. Alginate dressings are highly absorbent and can absorb up to 20 times their weight, which makes them desirable for use in highly exudative wounds. First synthesized more than 50 years ago, newer products contain bioactive compounds that prevent tissue damage, stimulate wound healing, improve cell proliferation and migration, and enhance metabolite formation.^24-26

In 2018, Aderibigbe and Buyana reported that polymers in the form of hydrogels were able to absorb fluid, making them a suitable choice for minimally exudative wounds. However, in their distended state, the hydrogel subgroup of these products became unstable (perhaps making them a poor choice for extensively exudative wounds), tended to dehydrate, and often needed a secondary dressing, which could lead to wound maceration.²² Most commonly used for wounds with minimal exudate, these dressings shine when used in nominally exudative dry wounds to promote autolytic debridement and hydrate the wound that has formed an eschar.

Hydrocolloid dressings are another type of bioactive wound dressing. These dressings are composed of 2 layers: an inner hydrophilic layer and an outer vapor-permeable layer that promote a moist wound environment. Hydrocolloid dressings assist in hydrating dry eschar wounds and have slight absorbency for exudative wounds. These dressings are not designed to be changed daily and can remain in place for 3 to 6 days. In a 2008 extensive review article, Thomas compared the utility of these dressings in patients with superficial or partial thickness burns, donor sites, surgical wounds, and minor traumatic wounds with basic wound dressings. The results of the review suggested that hydrocolloid dressings conferred statistically significant advantages in measures of decreased pain, healing times (decreased in donor sites by 40%), mobility restriction, and number of dressing changes.²⁷ Although more expensive than basic dressings, the longevity of the hydrocolloid dressing helps defray the original cost. Unfortunately, as these dressings remain in place and continue absorbing exudate, they can take on a very unpleasant odor.

A 2013 Cochrane database review comparing hydrocolloids with foams, alginate, basic wound dressing, and topical treatment found no statistical difference between hydrocolloids and basic wound dressings in patients with diabetes who have noncomplex foot ulcers.²⁸ In 2014, Pott and colleagues suggested a slight superiority in the performance of polyurethane foam dressings over hydrocolloid dressings used in pressure ulcers in older adults.²⁹ In a large pooled analysis in 2010, Davies compared foam to hydrocolloid dressings used in exudative wounds and reported that in 11 of 12 studies, foam dressings were superior to hydrocolloid in terms of exudate management, conformity to the wound, ease of use, decreased trauma and pain at dressing changes, and reduced odor of the wound.³⁰

Foam dressings. These products are typically composed of silicone or polyurethane. Consisting of 2 to 3 layers with a hydrophilic surface, foams are cut to approximate the wound size and serve to wick the macerated wound products to a secondary dressing above the foam. The micropores in the foam matrix absorb exudate from the wound bed while maintaining moisture equilibrium in the wound by donating back moisture to the wound, creating an environment conducive to wound healing. Foam dressings can be combined with various antiseptics (silver, GV/MB, etc) and serve as a delivery vehicle of those products directly to the wound surface.

A 2011 review comparing 8 studies found no difference among foam products available at that time in the use for chronic wounds.³¹ However, newer products on the market today have produced intriguing results with chronic wounds.

In 2017, Woo and Heil observed that chronic wounds treated with foam products containing GV/MB produced significant improvement when measured at week 4 in the areas of mean wound surface area (42.5%), decrease in baseline Pressure Ulcer Scale for Healing scores (from 13.3 to 10.7), wound coverage by devitalized tissue reduced (from 52.6% to 11.4%), and mean upper and lower wound infection scores were reduced by 75%.³² Further, the researchers reported a moist wound bed was achieved at dressing changes with polyvinyl alcohol (PVA) foam dressing. This led to the presumption that adequate moisture balance and autolytic debridement were facilitated using GV/MB antibacterial PVA foam dressings.

Many foam products on the market today exert an antibacterial effect on the wound bed. Antibiotic properties of various foam dressings create a microenvironment hostile to bacterial growth.³² In addition, the antibacterial properties combined with foam products contribute to the following: autolytic debridement, absorptive qualities (which reduce the bioburden of the wound), and maintenance of moisture in the wound bed. These qualities contribute significantly to the effectiveness of foam products with antibacterial properties.³² The correct balance of moisture in the wound has been identified as a superior environment and perhaps the most important component in chronic wounds.⁴ Foam dressings are less painful to change, easier to change, and in this case report, contributed to faster wound healing than gauze alone. In 2016, a study by Lee and colleagues suggested that the makeup of the foam product, defined as smaller pore and uniform cell size (foam density), resulted in greater permeability and better moisture absorption and retention capacity, contributing to improved wound healing.³³

In 2004, Sibbald and colleagues reported that in a 4-week study of nonhealing chronic wounds, foam wound dressing impregnated with sustained-release silver compared with foam dressing without silver resulted in a reduction in wound size (50% vs 30%, respectively), decreased fluid leakage (27% vs 44% respectively), and reduction in ulcer size measured from baseline (45% vs 25%, respectively).³⁴

In a 2006 study, Varma and colleagues compared sterilized, saline-soaked, nonmedicated polyurethane industrial upholstery foam in nonhealing wounds used in patients with diabetes with conventional techniques using topical antibiotics, hydrocolloid or hydrogel dressings as necessary, and desloughing agents as controls. At the end of a 3-month follow-up period, 100% of the wounds of the foam group had healed compared with 29.2% of the control group. Additionally, the time to wound healing was less than half for the foam group (22.5 days) compared with the control group (52 days), and the time to granulation and epithelialization was faster in the foam group.³⁵

In a 2012 meta-analysis, Aziz and colleagues reported that silver-impregnated dressings and topical silver were no better or worse than controls in preventing wound infection and promoting the healing of burn wounds.³⁶ The authors also noted that the nonsilver dressing groups continuing povidone-iodine, ionic hydrogel, or silicone-coated dressing showed reduced healing time compared with the silver-containing group.³⁶ This is intriguing because silver has long been used as a standard for the treatment of burn wounds.

Wound vacuum dressings. These dressings are very effective on highly exudative wounds involving a large surface area. However, wound vacuum dressing changes are time intensive and often painful to change. This is a foam dressing placed in the wound and attached to a vacuum device. The wound and foam are then covered with an impermeable membrane and attached to a negative pressure device that exerts a small negative pressure within the wound bed. This negative pressure increases the flow of blood to the less oxygenated areas in the center of the wound, promoting an increased concentration gradient of blood and nutrients and enhancing the evacuation of exudative material from the wound. Thus, a wound vacuum assists in forming an excellent moist wound-healing environment. Reporting in a review article in 2019, Agarwal and colleagues suggested that intermittent negative pressure was superior to constant negative pressure in wound healing due to the increased blood flow in the off phase, and 125 mm Hg negative pressure was optimal for wound healing.³⁷ This type of wound care has been touted as superior in wound care circles, and it may be; however, its cost, time commitment, and painful dressing changes along with cumbersome equipment make the choice difficult for some patients.

Conclusions

Although there is no perfect wound dressing, some wound care products seem to perform better due to fewer adverse effects and a much lesser cost. Important aspects of wound care appear to be time from injury to wound care, cleanliness of the wound, moist wound environment, cost, ease of use, and pain of dressing changes.

Primitive wound care products perform admirably in many situations. Modern medicated foam dressings containing antibacterial properties may have beneficial properties compared with other wound care products; however, comparison studies are lacking and need broad-based, randomized, controlled trials to confirm utility. Finally, any choice of wound care product must be tailored to the particular wound and individual patient needs. More large, robust, randomized controlled trials are needed.

Acknowledgments

The authors thank Sarah Maria Paulsen and Rosemary Ellen Brown Smith for their editing, proofreading, and preparation of the manuscript.

The United States’ initial public health response to the COVID-19 pandemic included containment measures that varied by state but generally required closing or suspending schools, nonessential businesses, and travel (commonly called lockdown).¹ During these periods, hospitalizations for serious and common conditions declined.^2,3 In Massachusetts, a state of emergency was declared on March 10, 2020, which remained in place until May 18, 2020, when a phased reopening of businesses began.

Although the evidence on the mental health impact of containment periods has been mixed, it has been suggested that these measures could lead to increases in alcohol-related hospitalizations.⁴ Social isolation and increased psychosocial and financial stressors raise the risk of relapse among patients with substance use disorders.^5-7 Marketing and survey data from the US and United Kingdom from the early months of the pandemic suggest that in-home alcohol consumption and sales of alcoholic beverages increased, while consumption of alcohol outside the home decreased.^8-10 Other research has shown an increase in the percentage—but not necessarily the absolute number—of emergency department (ED) visits and hospitalizations for alcohol-related diagnoses during periods of containment.^11,12 At least 1 study suggests that alcohol-related deaths increased beginning in the lockdown period and persisting into mid-2021.¹³

Because earlier studies suggest that lockdown periods are associated with increased alcohol consumption and relapse of alcohol use disorder, we hypothesized that the spring 2020 lockdown period in Massachusetts would be associated temporally with an increase in alcohol-related hospitalizations. To evaluate this hypothesis, we examined all hospitalizations in the US Department of Veterans Affairs (VA) Boston Healthcare System (VABHS) before, during, and after this lockdown period. VABHS includes a 160-bed acute care hospital and a 50-bed inpatient psychiatric facility.

Methods

We conducted an interrupted time-series analysis including all inpatient hospitalizations at VABHS from January 1, 2017, to December 31, 2020, to compare the daily number of alcohol-related hospitalizations across 3 exposure groups: prelockdown (the reference group, 1/1/2017-3/9/2020); lockdown (3/10/2020-5/18/2020); and postlockdown (5/19/2020-12/31/2020).

The VA Corporate Data Warehouse at VABHS was queried to identify all hospitalizations on the medical, psychiatry, and neurology services during the study period. Hospitalizations were considered alcohol-related if the International Statistical Classification of Diseases, Tenth Revision (ICD-10) primary diagnosis code (the main reason for hospitalization) was defined as an alcohol-related diagnosis by the VA Centralized Interactive Phenomics Resource (eAppendix 1, available online at doi:10.1278/fp.0404). This database, which has been previously used for COVID-19 research, is a catalog and knowledge-sharing platform of VA electronic health record–based phenotype algorithms, definitions, and metadata that builds on the Million Veteran Program and Cooperative Studies Program.^14,15 Hospitalizations under observation status were excluded.

To examine whether alcohol-related hospitalizations could have been categorized as COVID-19 when the conditions were co-occurring, we identified 244 hospitalizations coded with a primary ICD-10 code for COVID-19 during the lockdown and postlockdown periods. At the time of admission, each hospitalization carries an initial (free text) diagnosis, of which 3 had an initial diagnosis related to alcohol use. The population at risk for alcohol-related hospitalizations was estimated as the number of patients actively engaged in care at the VABHS. This was defined as the number of patients enrolled in VA care who have previously received any VA care; patients who are enrolled but have never received VA care were excluded from the population-at-risk denominator. Population-at-risk data were available for each fiscal year (FY) of the study period (9/30-10/1); the following population-at-risk sizes were used: 38,057 for FY 2017, 38,527 for FY 2018, 39,472 for FY 2019, and 37,893 for FY 2020.

The primary outcome was the daily number of alcohol-related hospitalizations in the prelockdown, lockdown, and postlockdown periods. A sensitivity analysis was performed using an alternate definition of the primary outcome using a broader set of alcohol-related ICD-10 codes (eAppendix 2, available online at doi:10.1278/fp.0404).

Statistical Analysis

To visually examine hospitalization trends during the study period, we generated a smoothed time-series plot of the 7-day moving average of the daily number of all-cause hospitalizations and the daily number of alcohol-related hospitalizations from January 1, 2017, to December 31, 2020. We used multivariable regression to model the daily number of alcohol-related hospitalizations over prelockdown (the reference group), lockdown, and postlockdown. In addition to the exposure, we included the following covariates in our model: day of the week, calendar date (to account for secular trends), and harmonic polynomials of the day of the year (to account for seasonal variation).¹⁶

We also examined models that included the daily total number of hospitalizations to account for the reduced likelihood of hospital admission for any reason during the pandemic. We used generalized linear models with a Poisson link to generate rate ratios and corresponding 95% CIs for estimates of the daily number of alcohol-related hospitalizations. We estimated the population incidence of alcohol-related hospitalizations per 100,000 patient-months for the exposure periods using the population denominators previously described. All analyses were performed in Stata 16.1.

Results

During the study period, 27,508 hospitalizations were available for analysis. The 7-day moving average of total daily hospitalizations and total daily alcohol-related hospitalizations over time for the period January 1, 2017, to December 31, 2020, are shown in the Figure.

The incidence of alcohol-related hospitalizations in the population dropped from 72 per 100,000 patient-months to 10 per 100,000 patient-months during the lockdown period and increased to 46 per 100,000 patient-months during the postlockdown period (Table).

Discussion

During the spring 2020 COVID-19 lockdown period in Massachusetts, the daily number of VABHS alcohol-related hospitalizations decreased by nearly 80% compared with the prelockdown period. During the postlockdown period, the daily number of alcohol-related hospitalizations increased but only to 72% of the prelockdown baseline by the end of December 2020. A similar trend was observed for all-cause hospitalizations for the same exposure periods.

These results differ from 2 related studies on the effect of the COVID-19 pandemic on alcohol-related hospitalizations.^10,11 In a retrospective study of ED visits to 4 hospitals in New York City, Schimmel and colleagues reported that from March 1 to 31, 2020 (the initial COVID-19 peak), hospital visits for alcohol withdrawal increased while those for alcohol use decreased.¹⁰ However, these results are reported as a percentage of total ED visits rather than the total number of visits, which are vulnerable to spurious correlation because of concomitant changes in the total number of ED visits. In their study, the absolute number of alcohol-related ED visits did not increase during the initial 2020 COVID-19 peak, and the number of visits for alcohol withdrawal syndrome declined slightly (195 in 2019 and 180 in 2020). However, the percentage of visits increased from 7% to 10% because of a greater decline in total ED visits. This pattern of decline in the number of alcohol-related ED visits, accompanied by an increase in the percentage of alcohol-related ED visits, has been observed in at least 1 nationwide surveillance study.¹⁷ This apparent increase does not reflect an absolute increase in ED visits for alcohol withdrawal syndrome and represents a greater relative decline in visits for other causes during the study period.

Sharma and colleagues reported an increase in the percentage of patients who developed alcohol withdrawal syndrome while hospitalized in Delaware per 1000 hospitalizations during consecutive 2-week periods during the pandemic in 2020 compared with corresponding weeks in 2019.¹¹ The greatest increase occurred during the last 2 weeks of the Delaware stay-at-home order. The Clinical Institute Withdrawal Assessment of Alcohol Scale, revised (CIWA-Ar) score of > 8 was used to define alcohol withdrawal syndrome. The American Society of Addiction Medicine does not recommend using CIWA-Ar to diagnose alcohol withdrawal syndrome because the scale was developed to monitor response to treatment, not to establish a diagnosis.¹⁸

Although the true population incidence of alcohol-related hospitalizations is difficult to estimate because the size of the population at risk (ie, the denominator) often is not known, the total number of hospitalizations is not a reliable surrogate.¹⁹ Individuals hospitalized for nonalcohol causes are no longer at risk for alcohol-related hospitalization.

In our study, we assume the population at risk during the study period is constant and model changes in the absolute number—rather than percentage—of alcohol-related ED visits. These absolute estimates of alcohol-related hospitalizations better reflect the true burden on the health care system and avoid the confounding effect of declining total ED visits and hospitalizations that could lead to artificially increased percentages and spurious correlation.²⁰ The absolute percentage of alcohol-related hospitalizations also decreased during this period; therefore, our results are not sensitive to this approach.

Several factors could have contributed to the decrease in alcohol-related hospitalizations. Our findings suggest that patient likelihood to seek care and clinician threshold to admit patients for alcohol-related conditions are influenced by external factors, in this case, a public health lockdown. Although our data do not inform why hospitalizations did not return to prelockdown levels, our experience suggests that limited bed capacity and longer length of stay might have contributed. Other hypotheses include a shift to outpatient care, increased use of telehealth (a significant focus early in the pandemic), and avoiding care for less severe alcohol-related complications because of lingering concerns about exposure to COVID-19 in health care settings reported early in the pandemic. Massachusetts experienced a particularly deadly outbreak of COVID-19 in the Soldiers’ Home, a long-term care facility for veterans in Holyoke.²¹

Evidence suggests that in-home consumption of alcohol increased during lockdowns.^8-10 Our results show that during this period hospitalizations for alcohol-related conditions decreased at VABHS, a large urban VA medical system, while alcohol-related deaths increased nationally.¹³ Although this observation is not evidence of causality, these outcomes could be related.

In the 2 decades before the pandemic, alcohol-related deaths increased by about 2% per year.²² From 2019 to 2020, there was a 25% increase that continued through 2021.¹³ Death certificate data often are inaccurate, and it is difficult to determine whether COVID-19 had a substantial contributing role to these deaths, particularly during the initial period when testing was limited or unavailable. Nonetheless, deaths due to alcohol-associated liver disease, overdoses involving alcohol, and alcohol-related traffic fatalities increased by > 10%.^13,23 These trends, along with a decrease in hospitalization for alcohol-related conditions, suggest missed opportunities for intervention with patients experiencing alcohol use disorder.

Limitations

In this study, hospitalizations under observation status were excluded, which could underestimate the total number of hospitalizations related to alcohol. We reasoned that this effect was likely to be small and not substantially different by year. ICD-10 codes were used to identify alcohol-related hospitalizations as any hospitalization with an included ICD-10 code listed as the primary discharge diagnosis code. This also likely underestimated the total number of alcohol-related hospitalizations. An ICD-10 code for COVID-19 was not in widespread use during our study period, which prohibited controlling explicitly for the volume of admissions due to COVID-19. The prelockdown period only contains data from the preceding 3 years, which might not be long enough for secular trends to become apparent. We assumed the population at risk remained constant when in reality, the net movement of patients into and out of VA care during the pandemic likely was more complex but not readily quantifiable. Nonetheless, the large drop in absolute number of alcohol-related hospitalizations is not likely to be sensitive to this change. In the absence of an objective measure of care-seeking behavior, we used the total daily number of hospitalizations as a surrogate for patient propensity to seek care. The total daily number of hospitalizations also reflects changes in physician admitting behavior over time. This allowed explicit modeling of care-seeking behavior as a covariate but does not capture other important determinants such as hospital capacity.

Conclusions

In this interrupted time-series analysis, the daily number of alcohol-related hospitalizations during the initial COVID-19 pandemic–associated lockdown period at VABHS decreased by 80% and remained 28% lower in the postlockdown period compared with the prepandemic baseline. In the context of evidence suggesting that alcohol-related mortality increased during the COVID-19 pandemic, alternate strategies to reach vulnerable individuals are needed. Because of high rates of relapse, hospitalization is an important opportunity to engage patients experiencing alcohol use disorder in treatment through referral to substance use treatment programs and medication-assisted therapy. Considering the reduction in alcohol-related hospitalizations during lockdown, other strategies are needed to ensure comprehensive and longitudinal care for this vulnerable population.

The United States’ initial public health response to the COVID-19 pandemic included containment measures that varied by state but generally required closing or suspending schools, nonessential businesses, and travel (commonly called lockdown).¹ During these periods, hospitalizations for serious and common conditions declined.^2,3 In Massachusetts, a state of emergency was declared on March 10, 2020, which remained in place until May 18, 2020, when a phased reopening of businesses began.

Although the evidence on the mental health impact of containment periods has been mixed, it has been suggested that these measures could lead to increases in alcohol-related hospitalizations.⁴ Social isolation and increased psychosocial and financial stressors raise the risk of relapse among patients with substance use disorders.^5-7 Marketing and survey data from the US and United Kingdom from the early months of the pandemic suggest that in-home alcohol consumption and sales of alcoholic beverages increased, while consumption of alcohol outside the home decreased.^8-10 Other research has shown an increase in the percentage—but not necessarily the absolute number—of emergency department (ED) visits and hospitalizations for alcohol-related diagnoses during periods of containment.^11,12 At least 1 study suggests that alcohol-related deaths increased beginning in the lockdown period and persisting into mid-2021.¹³

Because earlier studies suggest that lockdown periods are associated with increased alcohol consumption and relapse of alcohol use disorder, we hypothesized that the spring 2020 lockdown period in Massachusetts would be associated temporally with an increase in alcohol-related hospitalizations. To evaluate this hypothesis, we examined all hospitalizations in the US Department of Veterans Affairs (VA) Boston Healthcare System (VABHS) before, during, and after this lockdown period. VABHS includes a 160-bed acute care hospital and a 50-bed inpatient psychiatric facility.

Methods

We conducted an interrupted time-series analysis including all inpatient hospitalizations at VABHS from January 1, 2017, to December 31, 2020, to compare the daily number of alcohol-related hospitalizations across 3 exposure groups: prelockdown (the reference group, 1/1/2017-3/9/2020); lockdown (3/10/2020-5/18/2020); and postlockdown (5/19/2020-12/31/2020).

The VA Corporate Data Warehouse at VABHS was queried to identify all hospitalizations on the medical, psychiatry, and neurology services during the study period. Hospitalizations were considered alcohol-related if the International Statistical Classification of Diseases, Tenth Revision (ICD-10) primary diagnosis code (the main reason for hospitalization) was defined as an alcohol-related diagnosis by the VA Centralized Interactive Phenomics Resource (eAppendix 1, available online at doi:10.1278/fp.0404). This database, which has been previously used for COVID-19 research, is a catalog and knowledge-sharing platform of VA electronic health record–based phenotype algorithms, definitions, and metadata that builds on the Million Veteran Program and Cooperative Studies Program.^14,15 Hospitalizations under observation status were excluded.

To examine whether alcohol-related hospitalizations could have been categorized as COVID-19 when the conditions were co-occurring, we identified 244 hospitalizations coded with a primary ICD-10 code for COVID-19 during the lockdown and postlockdown periods. At the time of admission, each hospitalization carries an initial (free text) diagnosis, of which 3 had an initial diagnosis related to alcohol use. The population at risk for alcohol-related hospitalizations was estimated as the number of patients actively engaged in care at the VABHS. This was defined as the number of patients enrolled in VA care who have previously received any VA care; patients who are enrolled but have never received VA care were excluded from the population-at-risk denominator. Population-at-risk data were available for each fiscal year (FY) of the study period (9/30-10/1); the following population-at-risk sizes were used: 38,057 for FY 2017, 38,527 for FY 2018, 39,472 for FY 2019, and 37,893 for FY 2020.

The primary outcome was the daily number of alcohol-related hospitalizations in the prelockdown, lockdown, and postlockdown periods. A sensitivity analysis was performed using an alternate definition of the primary outcome using a broader set of alcohol-related ICD-10 codes (eAppendix 2, available online at doi:10.1278/fp.0404).

Statistical Analysis

To visually examine hospitalization trends during the study period, we generated a smoothed time-series plot of the 7-day moving average of the daily number of all-cause hospitalizations and the daily number of alcohol-related hospitalizations from January 1, 2017, to December 31, 2020. We used multivariable regression to model the daily number of alcohol-related hospitalizations over prelockdown (the reference group), lockdown, and postlockdown. In addition to the exposure, we included the following covariates in our model: day of the week, calendar date (to account for secular trends), and harmonic polynomials of the day of the year (to account for seasonal variation).¹⁶

We also examined models that included the daily total number of hospitalizations to account for the reduced likelihood of hospital admission for any reason during the pandemic. We used generalized linear models with a Poisson link to generate rate ratios and corresponding 95% CIs for estimates of the daily number of alcohol-related hospitalizations. We estimated the population incidence of alcohol-related hospitalizations per 100,000 patient-months for the exposure periods using the population denominators previously described. All analyses were performed in Stata 16.1.

Results

During the study period, 27,508 hospitalizations were available for analysis. The 7-day moving average of total daily hospitalizations and total daily alcohol-related hospitalizations over time for the period January 1, 2017, to December 31, 2020, are shown in the Figure.

The incidence of alcohol-related hospitalizations in the population dropped from 72 per 100,000 patient-months to 10 per 100,000 patient-months during the lockdown period and increased to 46 per 100,000 patient-months during the postlockdown period (Table).

Discussion

During the spring 2020 COVID-19 lockdown period in Massachusetts, the daily number of VABHS alcohol-related hospitalizations decreased by nearly 80% compared with the prelockdown period. During the postlockdown period, the daily number of alcohol-related hospitalizations increased but only to 72% of the prelockdown baseline by the end of December 2020. A similar trend was observed for all-cause hospitalizations for the same exposure periods.

These results differ from 2 related studies on the effect of the COVID-19 pandemic on alcohol-related hospitalizations.^10,11 In a retrospective study of ED visits to 4 hospitals in New York City, Schimmel and colleagues reported that from March 1 to 31, 2020 (the initial COVID-19 peak), hospital visits for alcohol withdrawal increased while those for alcohol use decreased.¹⁰ However, these results are reported as a percentage of total ED visits rather than the total number of visits, which are vulnerable to spurious correlation because of concomitant changes in the total number of ED visits. In their study, the absolute number of alcohol-related ED visits did not increase during the initial 2020 COVID-19 peak, and the number of visits for alcohol withdrawal syndrome declined slightly (195 in 2019 and 180 in 2020). However, the percentage of visits increased from 7% to 10% because of a greater decline in total ED visits. This pattern of decline in the number of alcohol-related ED visits, accompanied by an increase in the percentage of alcohol-related ED visits, has been observed in at least 1 nationwide surveillance study.¹⁷ This apparent increase does not reflect an absolute increase in ED visits for alcohol withdrawal syndrome and represents a greater relative decline in visits for other causes during the study period.

Sharma and colleagues reported an increase in the percentage of patients who developed alcohol withdrawal syndrome while hospitalized in Delaware per 1000 hospitalizations during consecutive 2-week periods during the pandemic in 2020 compared with corresponding weeks in 2019.¹¹ The greatest increase occurred during the last 2 weeks of the Delaware stay-at-home order. The Clinical Institute Withdrawal Assessment of Alcohol Scale, revised (CIWA-Ar) score of > 8 was used to define alcohol withdrawal syndrome. The American Society of Addiction Medicine does not recommend using CIWA-Ar to diagnose alcohol withdrawal syndrome because the scale was developed to monitor response to treatment, not to establish a diagnosis.¹⁸

Although the true population incidence of alcohol-related hospitalizations is difficult to estimate because the size of the population at risk (ie, the denominator) often is not known, the total number of hospitalizations is not a reliable surrogate.¹⁹ Individuals hospitalized for nonalcohol causes are no longer at risk for alcohol-related hospitalization.

In our study, we assume the population at risk during the study period is constant and model changes in the absolute number—rather than percentage—of alcohol-related ED visits. These absolute estimates of alcohol-related hospitalizations better reflect the true burden on the health care system and avoid the confounding effect of declining total ED visits and hospitalizations that could lead to artificially increased percentages and spurious correlation.²⁰ The absolute percentage of alcohol-related hospitalizations also decreased during this period; therefore, our results are not sensitive to this approach.

Several factors could have contributed to the decrease in alcohol-related hospitalizations. Our findings suggest that patient likelihood to seek care and clinician threshold to admit patients for alcohol-related conditions are influenced by external factors, in this case, a public health lockdown. Although our data do not inform why hospitalizations did not return to prelockdown levels, our experience suggests that limited bed capacity and longer length of stay might have contributed. Other hypotheses include a shift to outpatient care, increased use of telehealth (a significant focus early in the pandemic), and avoiding care for less severe alcohol-related complications because of lingering concerns about exposure to COVID-19 in health care settings reported early in the pandemic. Massachusetts experienced a particularly deadly outbreak of COVID-19 in the Soldiers’ Home, a long-term care facility for veterans in Holyoke.²¹

Evidence suggests that in-home consumption of alcohol increased during lockdowns.^8-10 Our results show that during this period hospitalizations for alcohol-related conditions decreased at VABHS, a large urban VA medical system, while alcohol-related deaths increased nationally.¹³ Although this observation is not evidence of causality, these outcomes could be related.

In the 2 decades before the pandemic, alcohol-related deaths increased by about 2% per year.²² From 2019 to 2020, there was a 25% increase that continued through 2021.¹³ Death certificate data often are inaccurate, and it is difficult to determine whether COVID-19 had a substantial contributing role to these deaths, particularly during the initial period when testing was limited or unavailable. Nonetheless, deaths due to alcohol-associated liver disease, overdoses involving alcohol, and alcohol-related traffic fatalities increased by > 10%.^13,23 These trends, along with a decrease in hospitalization for alcohol-related conditions, suggest missed opportunities for intervention with patients experiencing alcohol use disorder.

Limitations

In this study, hospitalizations under observation status were excluded, which could underestimate the total number of hospitalizations related to alcohol. We reasoned that this effect was likely to be small and not substantially different by year. ICD-10 codes were used to identify alcohol-related hospitalizations as any hospitalization with an included ICD-10 code listed as the primary discharge diagnosis code. This also likely underestimated the total number of alcohol-related hospitalizations. An ICD-10 code for COVID-19 was not in widespread use during our study period, which prohibited controlling explicitly for the volume of admissions due to COVID-19. The prelockdown period only contains data from the preceding 3 years, which might not be long enough for secular trends to become apparent. We assumed the population at risk remained constant when in reality, the net movement of patients into and out of VA care during the pandemic likely was more complex but not readily quantifiable. Nonetheless, the large drop in absolute number of alcohol-related hospitalizations is not likely to be sensitive to this change. In the absence of an objective measure of care-seeking behavior, we used the total daily number of hospitalizations as a surrogate for patient propensity to seek care. The total daily number of hospitalizations also reflects changes in physician admitting behavior over time. This allowed explicit modeling of care-seeking behavior as a covariate but does not capture other important determinants such as hospital capacity.

Conclusions

In this interrupted time-series analysis, the daily number of alcohol-related hospitalizations during the initial COVID-19 pandemic–associated lockdown period at VABHS decreased by 80% and remained 28% lower in the postlockdown period compared with the prepandemic baseline. In the context of evidence suggesting that alcohol-related mortality increased during the COVID-19 pandemic, alternate strategies to reach vulnerable individuals are needed. Because of high rates of relapse, hospitalization is an important opportunity to engage patients experiencing alcohol use disorder in treatment through referral to substance use treatment programs and medication-assisted therapy. Considering the reduction in alcohol-related hospitalizations during lockdown, other strategies are needed to ensure comprehensive and longitudinal care for this vulnerable population.

The United States’ initial public health response to the COVID-19 pandemic included containment measures that varied by state but generally required closing or suspending schools, nonessential businesses, and travel (commonly called lockdown).¹ During these periods, hospitalizations for serious and common conditions declined.^2,3 In Massachusetts, a state of emergency was declared on March 10, 2020, which remained in place until May 18, 2020, when a phased reopening of businesses began.

Although the evidence on the mental health impact of containment periods has been mixed, it has been suggested that these measures could lead to increases in alcohol-related hospitalizations.⁴ Social isolation and increased psychosocial and financial stressors raise the risk of relapse among patients with substance use disorders.^5-7 Marketing and survey data from the US and United Kingdom from the early months of the pandemic suggest that in-home alcohol consumption and sales of alcoholic beverages increased, while consumption of alcohol outside the home decreased.^8-10 Other research has shown an increase in the percentage—but not necessarily the absolute number—of emergency department (ED) visits and hospitalizations for alcohol-related diagnoses during periods of containment.^11,12 At least 1 study suggests that alcohol-related deaths increased beginning in the lockdown period and persisting into mid-2021.¹³

Because earlier studies suggest that lockdown periods are associated with increased alcohol consumption and relapse of alcohol use disorder, we hypothesized that the spring 2020 lockdown period in Massachusetts would be associated temporally with an increase in alcohol-related hospitalizations. To evaluate this hypothesis, we examined all hospitalizations in the US Department of Veterans Affairs (VA) Boston Healthcare System (VABHS) before, during, and after this lockdown period. VABHS includes a 160-bed acute care hospital and a 50-bed inpatient psychiatric facility.

Methods

We conducted an interrupted time-series analysis including all inpatient hospitalizations at VABHS from January 1, 2017, to December 31, 2020, to compare the daily number of alcohol-related hospitalizations across 3 exposure groups: prelockdown (the reference group, 1/1/2017-3/9/2020); lockdown (3/10/2020-5/18/2020); and postlockdown (5/19/2020-12/31/2020).

The VA Corporate Data Warehouse at VABHS was queried to identify all hospitalizations on the medical, psychiatry, and neurology services during the study period. Hospitalizations were considered alcohol-related if the International Statistical Classification of Diseases, Tenth Revision (ICD-10) primary diagnosis code (the main reason for hospitalization) was defined as an alcohol-related diagnosis by the VA Centralized Interactive Phenomics Resource (eAppendix 1, available online at doi:10.1278/fp.0404). This database, which has been previously used for COVID-19 research, is a catalog and knowledge-sharing platform of VA electronic health record–based phenotype algorithms, definitions, and metadata that builds on the Million Veteran Program and Cooperative Studies Program.^14,15 Hospitalizations under observation status were excluded.

To examine whether alcohol-related hospitalizations could have been categorized as COVID-19 when the conditions were co-occurring, we identified 244 hospitalizations coded with a primary ICD-10 code for COVID-19 during the lockdown and postlockdown periods. At the time of admission, each hospitalization carries an initial (free text) diagnosis, of which 3 had an initial diagnosis related to alcohol use. The population at risk for alcohol-related hospitalizations was estimated as the number of patients actively engaged in care at the VABHS. This was defined as the number of patients enrolled in VA care who have previously received any VA care; patients who are enrolled but have never received VA care were excluded from the population-at-risk denominator. Population-at-risk data were available for each fiscal year (FY) of the study period (9/30-10/1); the following population-at-risk sizes were used: 38,057 for FY 2017, 38,527 for FY 2018, 39,472 for FY 2019, and 37,893 for FY 2020.

The primary outcome was the daily number of alcohol-related hospitalizations in the prelockdown, lockdown, and postlockdown periods. A sensitivity analysis was performed using an alternate definition of the primary outcome using a broader set of alcohol-related ICD-10 codes (eAppendix 2, available online at doi:10.1278/fp.0404).

Statistical Analysis

To visually examine hospitalization trends during the study period, we generated a smoothed time-series plot of the 7-day moving average of the daily number of all-cause hospitalizations and the daily number of alcohol-related hospitalizations from January 1, 2017, to December 31, 2020. We used multivariable regression to model the daily number of alcohol-related hospitalizations over prelockdown (the reference group), lockdown, and postlockdown. In addition to the exposure, we included the following covariates in our model: day of the week, calendar date (to account for secular trends), and harmonic polynomials of the day of the year (to account for seasonal variation).¹⁶

We also examined models that included the daily total number of hospitalizations to account for the reduced likelihood of hospital admission for any reason during the pandemic. We used generalized linear models with a Poisson link to generate rate ratios and corresponding 95% CIs for estimates of the daily number of alcohol-related hospitalizations. We estimated the population incidence of alcohol-related hospitalizations per 100,000 patient-months for the exposure periods using the population denominators previously described. All analyses were performed in Stata 16.1.

Results

During the study period, 27,508 hospitalizations were available for analysis. The 7-day moving average of total daily hospitalizations and total daily alcohol-related hospitalizations over time for the period January 1, 2017, to December 31, 2020, are shown in the Figure.

The incidence of alcohol-related hospitalizations in the population dropped from 72 per 100,000 patient-months to 10 per 100,000 patient-months during the lockdown period and increased to 46 per 100,000 patient-months during the postlockdown period (Table).

Discussion

During the spring 2020 COVID-19 lockdown period in Massachusetts, the daily number of VABHS alcohol-related hospitalizations decreased by nearly 80% compared with the prelockdown period. During the postlockdown period, the daily number of alcohol-related hospitalizations increased but only to 72% of the prelockdown baseline by the end of December 2020. A similar trend was observed for all-cause hospitalizations for the same exposure periods.

These results differ from 2 related studies on the effect of the COVID-19 pandemic on alcohol-related hospitalizations.^10,11 In a retrospective study of ED visits to 4 hospitals in New York City, Schimmel and colleagues reported that from March 1 to 31, 2020 (the initial COVID-19 peak), hospital visits for alcohol withdrawal increased while those for alcohol use decreased.¹⁰ However, these results are reported as a percentage of total ED visits rather than the total number of visits, which are vulnerable to spurious correlation because of concomitant changes in the total number of ED visits. In their study, the absolute number of alcohol-related ED visits did not increase during the initial 2020 COVID-19 peak, and the number of visits for alcohol withdrawal syndrome declined slightly (195 in 2019 and 180 in 2020). However, the percentage of visits increased from 7% to 10% because of a greater decline in total ED visits. This pattern of decline in the number of alcohol-related ED visits, accompanied by an increase in the percentage of alcohol-related ED visits, has been observed in at least 1 nationwide surveillance study.¹⁷ This apparent increase does not reflect an absolute increase in ED visits for alcohol withdrawal syndrome and represents a greater relative decline in visits for other causes during the study period.

Sharma and colleagues reported an increase in the percentage of patients who developed alcohol withdrawal syndrome while hospitalized in Delaware per 1000 hospitalizations during consecutive 2-week periods during the pandemic in 2020 compared with corresponding weeks in 2019.¹¹ The greatest increase occurred during the last 2 weeks of the Delaware stay-at-home order. The Clinical Institute Withdrawal Assessment of Alcohol Scale, revised (CIWA-Ar) score of > 8 was used to define alcohol withdrawal syndrome. The American Society of Addiction Medicine does not recommend using CIWA-Ar to diagnose alcohol withdrawal syndrome because the scale was developed to monitor response to treatment, not to establish a diagnosis.¹⁸

Although the true population incidence of alcohol-related hospitalizations is difficult to estimate because the size of the population at risk (ie, the denominator) often is not known, the total number of hospitalizations is not a reliable surrogate.¹⁹ Individuals hospitalized for nonalcohol causes are no longer at risk for alcohol-related hospitalization.

In our study, we assume the population at risk during the study period is constant and model changes in the absolute number—rather than percentage—of alcohol-related ED visits. These absolute estimates of alcohol-related hospitalizations better reflect the true burden on the health care system and avoid the confounding effect of declining total ED visits and hospitalizations that could lead to artificially increased percentages and spurious correlation.²⁰ The absolute percentage of alcohol-related hospitalizations also decreased during this period; therefore, our results are not sensitive to this approach.

Several factors could have contributed to the decrease in alcohol-related hospitalizations. Our findings suggest that patient likelihood to seek care and clinician threshold to admit patients for alcohol-related conditions are influenced by external factors, in this case, a public health lockdown. Although our data do not inform why hospitalizations did not return to prelockdown levels, our experience suggests that limited bed capacity and longer length of stay might have contributed. Other hypotheses include a shift to outpatient care, increased use of telehealth (a significant focus early in the pandemic), and avoiding care for less severe alcohol-related complications because of lingering concerns about exposure to COVID-19 in health care settings reported early in the pandemic. Massachusetts experienced a particularly deadly outbreak of COVID-19 in the Soldiers’ Home, a long-term care facility for veterans in Holyoke.²¹

Evidence suggests that in-home consumption of alcohol increased during lockdowns.^8-10 Our results show that during this period hospitalizations for alcohol-related conditions decreased at VABHS, a large urban VA medical system, while alcohol-related deaths increased nationally.¹³ Although this observation is not evidence of causality, these outcomes could be related.

In the 2 decades before the pandemic, alcohol-related deaths increased by about 2% per year.²² From 2019 to 2020, there was a 25% increase that continued through 2021.¹³ Death certificate data often are inaccurate, and it is difficult to determine whether COVID-19 had a substantial contributing role to these deaths, particularly during the initial period when testing was limited or unavailable. Nonetheless, deaths due to alcohol-associated liver disease, overdoses involving alcohol, and alcohol-related traffic fatalities increased by > 10%.^13,23 These trends, along with a decrease in hospitalization for alcohol-related conditions, suggest missed opportunities for intervention with patients experiencing alcohol use disorder.

Limitations

In this study, hospitalizations under observation status were excluded, which could underestimate the total number of hospitalizations related to alcohol. We reasoned that this effect was likely to be small and not substantially different by year. ICD-10 codes were used to identify alcohol-related hospitalizations as any hospitalization with an included ICD-10 code listed as the primary discharge diagnosis code. This also likely underestimated the total number of alcohol-related hospitalizations. An ICD-10 code for COVID-19 was not in widespread use during our study period, which prohibited controlling explicitly for the volume of admissions due to COVID-19. The prelockdown period only contains data from the preceding 3 years, which might not be long enough for secular trends to become apparent. We assumed the population at risk remained constant when in reality, the net movement of patients into and out of VA care during the pandemic likely was more complex but not readily quantifiable. Nonetheless, the large drop in absolute number of alcohol-related hospitalizations is not likely to be sensitive to this change. In the absence of an objective measure of care-seeking behavior, we used the total daily number of hospitalizations as a surrogate for patient propensity to seek care. The total daily number of hospitalizations also reflects changes in physician admitting behavior over time. This allowed explicit modeling of care-seeking behavior as a covariate but does not capture other important determinants such as hospital capacity.

Conclusions

In this interrupted time-series analysis, the daily number of alcohol-related hospitalizations during the initial COVID-19 pandemic–associated lockdown period at VABHS decreased by 80% and remained 28% lower in the postlockdown period compared with the prepandemic baseline. In the context of evidence suggesting that alcohol-related mortality increased during the COVID-19 pandemic, alternate strategies to reach vulnerable individuals are needed. Because of high rates of relapse, hospitalization is an important opportunity to engage patients experiencing alcohol use disorder in treatment through referral to substance use treatment programs and medication-assisted therapy. Considering the reduction in alcohol-related hospitalizations during lockdown, other strategies are needed to ensure comprehensive and longitudinal care for this vulnerable population.

Veterans speak of losing their innocence and longing to regain it. They ask: “Why can’t I just go back to the way I was?”

Jonathan Shay, Achilles in Vietnam ¹

On July 17, 2023, several media outlets covering military and federal news carried a story about the US Department of Veterans Affairs (VA) plan to conduct a major survey of moral injury in veterans.² This is not the first such survey: There have been numerous previous studies conducted by both VA and non-VA investigators.³ Moral injury has been increasingly recognized as the signature wound of service members, especially those who fought in Operation Enduring Freedom and Operation Iraqi Freedom.⁴ This new VA survey can provide crucial information because we know so little about moral injury or how to help those with the condition.

At the time of this writing, there has been no official VA public statement about the study. At face value, this seemed to be strange, given that the groundbreaking research could improve the diagnosis and therapy of moral injury. According to a June 2023 VA Office of Research and Development internal announcement, the primary goal of the study is to determine the prevalence of moral injury among US veterans. The secondary goals of the study are to (1) compare those who develop moral injury and those who do not after exposure to similar traumas; and (2) conduct interviews about thoughts and experiences from 20 veterans who identify as having moral injury and 20 who do not but who have similar exposure to morally injurious events.

Data for the study will be collected through an extensive online survey from a nationally representative sample of 3000 post-9/11 war veterans. The sample will include at least 950 who served in a war zone and at least 400 who are aged 18 to 54 years. The respondents will be paid $20 for the 30 to 45 minutes survey. The collection and analysis of data are expected to take 3 or more years.

The modern version of moral injury is often associated with Jonathan Shay, MD, a VA psychiatrist.⁵ Shay wrote about the origin of moral injury found in Homer’s The Iliad and The Odyssey and how the poems offer ancient echoes of his therapy with modern-day combat veterans.¹

There is no universal agreement on the definition of moral injury. A working definition of moral injury used in the VA suggests that it describes the difficulties that people face after doing high-stakes actions that violate a sense of what is right and just or after being forced to experience others’ immoral actions.⁶

Two conditions are necessary for moral injury to occur. First, an individual acts or witnesses an action that contravenes their core ethical principles. Secondly, that occurrence is experienced as a breach of the person’s moral barrier. Military personnel killing civilians to protect their lives and those of their fellow troops is a tragic example of moral injury. The translation of this for health care professionals may be the inability to save severely wounded service members in the combat theater due to the exigencies of war.⁷

Experts in moral injury emphasize the importance of distinguishing the phenomenon from posttraumatic stress disorder (PTSD). Unlike many psychiatric disorders, both moral injury and PTSD have known etiologies: traumatic events. An individual may have 1 or both conditions, and each can manifest anger, guilt, shame, and loss of trust in others. One way that moral injury can be distinguished from PTSD is that it goes beyond the psychological to compromise the moral and often spiritual beliefs and values of the individual. One of the characteristics that makes us human is that we have a conscience to guide us in navigating the moral field of human life, but moral injury scrambles the internal compass that discerns right and wrong, good and bad. When an individual commits an action or witnesses the perpetration of an action that crosses their personal moral boundary, their integrity is shattered, and they may lose faith in their intrinsic worth. These beliefs prevent many service members from disclosing their distress, leading some commentators to refer to moral injury as a silent or invisible wound.⁸

The timing of the VA’s launching of a study of moral injury of this size and scope may reflect 3 recent developments: Not unexpected in VA matters, one is political, another is benefits, and the last pertains to health care.

First, August marks the second anniversary of the withdrawal of American troops from Afghanistan. Many Afghans who assisted US forces during the war were not evacuated. For some of the troops who served in the country, these events as well as the chaotic end to the long war were experienced as a contravening of an ethical code, resulting in moral injury.⁹

Second, many of those service members are now calling on the federal government to recognize and respond to the detrimental impact of the withdrawal, including the high prevalence of moral injury in troops who served in Afghanistan.¹⁰ Moral injury at this time is not considered a psychiatric diagnosis; hence, not eligible for VA benefits. However, many of the psychological manifestations of moral injury, such as depression and anxiety, are established service-connected disorders.

Third, several VA studies have demonstrated that moral injury either alone or combined with PTSD substantially elevates the risk of suicide.¹¹ Since preventing suicide is a major strategic priority for the VA, the importance of learning more about the epidemiology of moral injury is the necessary first step to developing therapeutic approaches. At a time when organized medicine is becoming increasingly technological and fragmented, launching this unprecedented survey demonstrates the VA’s commitment to delivering holistic and humanistic care of the service member: body, mind, and spirit.

This project also sends a strong message to those who lobby for shifting funding from the VA to community care or call for privatization. Veterans are different: They experience unique disorders borne of the battles they fought for our freedom. The VA has the specialized knowledge and skills in research and health care to develop the knowledge to ground innovative treatments for conditions like moral injury, PTSD, and traumatic brain injuries. VA chaplains and mental health professionals have pioneered assessment instruments and promising therapies for moral injury. Their distinctive expertise unrivaled in the civilian sector benefits not only veterans but also the wider community where there is a growing awareness of the devastating impact of moral injury, particularly on health care professionals.¹² And there may have been no other time in history when this broken, violent world was more in need of moral healing and peace.

Veterans speak of losing their innocence and longing to regain it. They ask: “Why can’t I just go back to the way I was?”

Jonathan Shay, Achilles in Vietnam ¹

On July 17, 2023, several media outlets covering military and federal news carried a story about the US Department of Veterans Affairs (VA) plan to conduct a major survey of moral injury in veterans.² This is not the first such survey: There have been numerous previous studies conducted by both VA and non-VA investigators.³ Moral injury has been increasingly recognized as the signature wound of service members, especially those who fought in Operation Enduring Freedom and Operation Iraqi Freedom.⁴ This new VA survey can provide crucial information because we know so little about moral injury or how to help those with the condition.

At the time of this writing, there has been no official VA public statement about the study. At face value, this seemed to be strange, given that the groundbreaking research could improve the diagnosis and therapy of moral injury. According to a June 2023 VA Office of Research and Development internal announcement, the primary goal of the study is to determine the prevalence of moral injury among US veterans. The secondary goals of the study are to (1) compare those who develop moral injury and those who do not after exposure to similar traumas; and (2) conduct interviews about thoughts and experiences from 20 veterans who identify as having moral injury and 20 who do not but who have similar exposure to morally injurious events.

Data for the study will be collected through an extensive online survey from a nationally representative sample of 3000 post-9/11 war veterans. The sample will include at least 950 who served in a war zone and at least 400 who are aged 18 to 54 years. The respondents will be paid $20 for the 30 to 45 minutes survey. The collection and analysis of data are expected to take 3 or more years.

The modern version of moral injury is often associated with Jonathan Shay, MD, a VA psychiatrist.⁵ Shay wrote about the origin of moral injury found in Homer’s The Iliad and The Odyssey and how the poems offer ancient echoes of his therapy with modern-day combat veterans.¹

There is no universal agreement on the definition of moral injury. A working definition of moral injury used in the VA suggests that it describes the difficulties that people face after doing high-stakes actions that violate a sense of what is right and just or after being forced to experience others’ immoral actions.⁶

Two conditions are necessary for moral injury to occur. First, an individual acts or witnesses an action that contravenes their core ethical principles. Secondly, that occurrence is experienced as a breach of the person’s moral barrier. Military personnel killing civilians to protect their lives and those of their fellow troops is a tragic example of moral injury. The translation of this for health care professionals may be the inability to save severely wounded service members in the combat theater due to the exigencies of war.⁷

Experts in moral injury emphasize the importance of distinguishing the phenomenon from posttraumatic stress disorder (PTSD). Unlike many psychiatric disorders, both moral injury and PTSD have known etiologies: traumatic events. An individual may have 1 or both conditions, and each can manifest anger, guilt, shame, and loss of trust in others. One way that moral injury can be distinguished from PTSD is that it goes beyond the psychological to compromise the moral and often spiritual beliefs and values of the individual. One of the characteristics that makes us human is that we have a conscience to guide us in navigating the moral field of human life, but moral injury scrambles the internal compass that discerns right and wrong, good and bad. When an individual commits an action or witnesses the perpetration of an action that crosses their personal moral boundary, their integrity is shattered, and they may lose faith in their intrinsic worth. These beliefs prevent many service members from disclosing their distress, leading some commentators to refer to moral injury as a silent or invisible wound.⁸

The timing of the VA’s launching of a study of moral injury of this size and scope may reflect 3 recent developments: Not unexpected in VA matters, one is political, another is benefits, and the last pertains to health care.

First, August marks the second anniversary of the withdrawal of American troops from Afghanistan. Many Afghans who assisted US forces during the war were not evacuated. For some of the troops who served in the country, these events as well as the chaotic end to the long war were experienced as a contravening of an ethical code, resulting in moral injury.⁹

Second, many of those service members are now calling on the federal government to recognize and respond to the detrimental impact of the withdrawal, including the high prevalence of moral injury in troops who served in Afghanistan.¹⁰ Moral injury at this time is not considered a psychiatric diagnosis; hence, not eligible for VA benefits. However, many of the psychological manifestations of moral injury, such as depression and anxiety, are established service-connected disorders.

Third, several VA studies have demonstrated that moral injury either alone or combined with PTSD substantially elevates the risk of suicide.¹¹ Since preventing suicide is a major strategic priority for the VA, the importance of learning more about the epidemiology of moral injury is the necessary first step to developing therapeutic approaches. At a time when organized medicine is becoming increasingly technological and fragmented, launching this unprecedented survey demonstrates the VA’s commitment to delivering holistic and humanistic care of the service member: body, mind, and spirit.

This project also sends a strong message to those who lobby for shifting funding from the VA to community care or call for privatization. Veterans are different: They experience unique disorders borne of the battles they fought for our freedom. The VA has the specialized knowledge and skills in research and health care to develop the knowledge to ground innovative treatments for conditions like moral injury, PTSD, and traumatic brain injuries. VA chaplains and mental health professionals have pioneered assessment instruments and promising therapies for moral injury. Their distinctive expertise unrivaled in the civilian sector benefits not only veterans but also the wider community where there is a growing awareness of the devastating impact of moral injury, particularly on health care professionals.¹² And there may have been no other time in history when this broken, violent world was more in need of moral healing and peace.

Veterans speak of losing their innocence and longing to regain it. They ask: “Why can’t I just go back to the way I was?”

Jonathan Shay, Achilles in Vietnam ¹

On July 17, 2023, several media outlets covering military and federal news carried a story about the US Department of Veterans Affairs (VA) plan to conduct a major survey of moral injury in veterans.² This is not the first such survey: There have been numerous previous studies conducted by both VA and non-VA investigators.³ Moral injury has been increasingly recognized as the signature wound of service members, especially those who fought in Operation Enduring Freedom and Operation Iraqi Freedom.⁴ This new VA survey can provide crucial information because we know so little about moral injury or how to help those with the condition.

At the time of this writing, there has been no official VA public statement about the study. At face value, this seemed to be strange, given that the groundbreaking research could improve the diagnosis and therapy of moral injury. According to a June 2023 VA Office of Research and Development internal announcement, the primary goal of the study is to determine the prevalence of moral injury among US veterans. The secondary goals of the study are to (1) compare those who develop moral injury and those who do not after exposure to similar traumas; and (2) conduct interviews about thoughts and experiences from 20 veterans who identify as having moral injury and 20 who do not but who have similar exposure to morally injurious events.

Data for the study will be collected through an extensive online survey from a nationally representative sample of 3000 post-9/11 war veterans. The sample will include at least 950 who served in a war zone and at least 400 who are aged 18 to 54 years. The respondents will be paid $20 for the 30 to 45 minutes survey. The collection and analysis of data are expected to take 3 or more years.

The modern version of moral injury is often associated with Jonathan Shay, MD, a VA psychiatrist.⁵ Shay wrote about the origin of moral injury found in Homer’s The Iliad and The Odyssey and how the poems offer ancient echoes of his therapy with modern-day combat veterans.¹

There is no universal agreement on the definition of moral injury. A working definition of moral injury used in the VA suggests that it describes the difficulties that people face after doing high-stakes actions that violate a sense of what is right and just or after being forced to experience others’ immoral actions.⁶

Two conditions are necessary for moral injury to occur. First, an individual acts or witnesses an action that contravenes their core ethical principles. Secondly, that occurrence is experienced as a breach of the person’s moral barrier. Military personnel killing civilians to protect their lives and those of their fellow troops is a tragic example of moral injury. The translation of this for health care professionals may be the inability to save severely wounded service members in the combat theater due to the exigencies of war.⁷

Experts in moral injury emphasize the importance of distinguishing the phenomenon from posttraumatic stress disorder (PTSD). Unlike many psychiatric disorders, both moral injury and PTSD have known etiologies: traumatic events. An individual may have 1 or both conditions, and each can manifest anger, guilt, shame, and loss of trust in others. One way that moral injury can be distinguished from PTSD is that it goes beyond the psychological to compromise the moral and often spiritual beliefs and values of the individual. One of the characteristics that makes us human is that we have a conscience to guide us in navigating the moral field of human life, but moral injury scrambles the internal compass that discerns right and wrong, good and bad. When an individual commits an action or witnesses the perpetration of an action that crosses their personal moral boundary, their integrity is shattered, and they may lose faith in their intrinsic worth. These beliefs prevent many service members from disclosing their distress, leading some commentators to refer to moral injury as a silent or invisible wound.⁸

The timing of the VA’s launching of a study of moral injury of this size and scope may reflect 3 recent developments: Not unexpected in VA matters, one is political, another is benefits, and the last pertains to health care.

First, August marks the second anniversary of the withdrawal of American troops from Afghanistan. Many Afghans who assisted US forces during the war were not evacuated. For some of the troops who served in the country, these events as well as the chaotic end to the long war were experienced as a contravening of an ethical code, resulting in moral injury.⁹

Second, many of those service members are now calling on the federal government to recognize and respond to the detrimental impact of the withdrawal, including the high prevalence of moral injury in troops who served in Afghanistan.¹⁰ Moral injury at this time is not considered a psychiatric diagnosis; hence, not eligible for VA benefits. However, many of the psychological manifestations of moral injury, such as depression and anxiety, are established service-connected disorders.

Third, several VA studies have demonstrated that moral injury either alone or combined with PTSD substantially elevates the risk of suicide.¹¹ Since preventing suicide is a major strategic priority for the VA, the importance of learning more about the epidemiology of moral injury is the necessary first step to developing therapeutic approaches. At a time when organized medicine is becoming increasingly technological and fragmented, launching this unprecedented survey demonstrates the VA’s commitment to delivering holistic and humanistic care of the service member: body, mind, and spirit.

This project also sends a strong message to those who lobby for shifting funding from the VA to community care or call for privatization. Veterans are different: They experience unique disorders borne of the battles they fought for our freedom. The VA has the specialized knowledge and skills in research and health care to develop the knowledge to ground innovative treatments for conditions like moral injury, PTSD, and traumatic brain injuries. VA chaplains and mental health professionals have pioneered assessment instruments and promising therapies for moral injury. Their distinctive expertise unrivaled in the civilian sector benefits not only veterans but also the wider community where there is a growing awareness of the devastating impact of moral injury, particularly on health care professionals.¹² And there may have been no other time in history when this broken, violent world was more in need of moral healing and peace.

CASE Pregnant woman with intense itching

A 28-year-old woman (G1P0) is seen for a routine prenatal visit at 32 3/7 weeks’ gestation. She reports having generalized intense itching, including on her palms and soles, that is most intense at night and has been present for approximately 1 week. Her pregnancy is otherwise uncomplicated to date. Physical exam is within normal limits, with no evidence of a skin rash. Cholestasis of pregnancy is suspected, and laboratory tests are ordered, including bile acids and liver transaminases. Test results show that her aspartate transaminase (AST) and alanine transaminase (ALT) levels are mildly elevated at 55 IU/L and 41 IU/L, respectively, and several days later her bile acid level result is 21 µmol/L.

How should this patient be managed?

Intrahepatic cholestasis of pregnancy (ICP) affects 0.5% to 0.7% of pregnant individuals and results in maternal pruritus and elevated serum bile acid levels.^1-3 Pruritus in ICP typically is generalized, including occurrence on the palms of the hands and soles of the feet, and it often is reported to be worse at night.⁴ Up to 25% of pregnant women will develop pruritus during pregnancy but the majority will not have ICP.^2,5 Patients with ICP have no associated rash, but clinicians may note excoriations on exam. ICP typically presents in the third trimester of pregnancy but has been reported to occur earlier in gestation.⁶

Making a diagnosis of ICP

The presence of maternal pruritus in the absence of a skin condition along with elevated levels of serum bile acids are required for the diagnosis of ICP.⁷ Thus, a thorough history and physical exam is recommended to rule out another skin condition that could potentially explain the patient’s pruritus.

Some controversy exists regarding the bile acid level cutoff that should be used to make a diagnosis of ICP.⁸ It has been noted that nonfasting serum bile acid levels in pregnancy are considerably higher than those in in the nonpregnant state, and an upper limit of 18 µmol/L has been proposed as a cutoff in pregnancy.⁹ However, nonfasting total serum bile acids also have been shown to vary considerably by race, with levels 25.8% higher in Black women compared with those in White women and 24.3% higher in Black women compared with those in south Asian women.⁹ This raises the question of whether we should be using race-specific bile acid values to make a diagnosis of ICP.

Bile acid levels also vary based on whether a patient is in a fasting or postprandial state.¹⁰ Despite this variation, most guidelines do not recommend testing fasting bile acid levels as the postprandial state effect overall is small.^7,9,11 The Society for Maternal-Fetal Medicine (SMFM) recommends that if a pregnancy-specific bile acid range is available from the laboratory, then the upper limit of normal for pregnancy should be used when making a diagnosis of ICP.⁷ The SMFM guidelines also acknowledge, however, that pregnancy-specific values rarely are available, and in this case, levels above the upper limit of normal—often 10 µmol/L should be considered diagnostic for ICP until further evidence regarding optimal bile acid cutoff levels in pregnancy becomes available.⁷

For patients with suspected ICP, liver transaminase levels should be measured in addition to nonfasting serum bile acid levels.⁷ A thorough history should include assessment for additional symptoms of liver disease, such as changes in weight, appetite, jaundice, excessive fatigue, malaise, and abdominal pain.⁷ Elevated transaminases levels may be associated with ICP, but they are not necessary for diagnosis. In the absence of additional clinical symptoms that suggest underlying liver disease or severe early onset ICP, additional evaluation beyond nonfasting serum bile acids and liver transaminase levels, such as liver ultrasonography or evaluation for viral or autoimmune hepatitis, is not recommended.⁷ Obstetric care clinicians should be aware that there is an increased incidence of preeclampsia among patients with ICP, although no specific guidance regarding further recommendations for screening is provided.⁷

PHOTO: CHAJAMP/SHUTTERSTOCK

Continue to: Risks associated with ICP...

Risks associated with ICP

For both patients and clinicians, the greatest concern among patients with ICP is the increased risk of stillbirth. Stillbirth risk in ICP appears to be related to serum bile acid levels and has been reported to be highest in patients with bile acid levels greater than 100 µmol/L. A systematic review and meta-analysis of ICP studies demonstrated no increased risk of stillbirth among patients with bile acid levels less than 100 µmol/L.¹² These results, however, must be interpreted with extreme caution as the majority of studies included patients with ICP who were actively managed with attempts to mitigate the risk of stillbirth.⁷

In the absence of additional pregnancy risk factors, the risk of stillbirth among patients with ICP and serum bile acid levels between 19 and 39 µmol/L does not appear to be elevated above their baseline risk.¹¹ The same is true for pregnant individuals with ICP and no additional pregnancy risk factors with serum bile acid levels between 40 and 99 µmol/L until approximately 38 weeks’ gestation, when the risk of stillbirth is elevated.¹¹ The risk of stillbirth is elevated in ICP with peak bile acid levels greater than 100 µmol/L, with an absolute risk of 3.44%.¹¹

Management of patients with ICP

Laboratory evaluation

There is no consensus on the need for repeat testing of bile acid levels in patients with ICP. SMFM advises that follow-up testing of bile acid levels may help to guide delivery timing, especially in cases of severe ICP, but the society recommends against serial testing.⁷ By contrast, the Royal College of Obstetricians and Gynaecologists (RCOG) provides a detailed algorithm regarding time intervals between serum bile acid level testing to guide delivery timing.¹¹ The TABLE lists the strategy for reassessment of serum bile acid levels in ICP as recommended by the RCOG.¹¹

In the United States, bile acid testing traditionally takes several days as the testing is commonly performed at reference laboratories. We therefore suggest that clinicians consider repeating bile acid level testing in situations in which the timing of delivery may be altered if further elevations of bile acid levels were noted. This is particularly relevant for patients diagnosed with ICP early in the third trimester when repeat bile acid levels would still allow for an adjustment in delivery timing.

Antepartum fetal surveillance

Unfortunately, antepartum fetal testing for pregnant patients with ICP does not appear to reliably predict or prevent stillbirth as several studies have reported stillbirths within days of normal fetal testing.^13-16 It is therefore important to counsel pregnant patients regarding monitoring of fetal movements and advise them to present for evaluation if concerns arise.

Currently, SMFM recommends that patients with ICP should begin antenatal fetal surveillance at a gestational age when abnormal fetal testing would result in delivery.⁷ Patients should be counseled, however, regarding the unpredictability of stillbirth with ICP in the setting of a low absolute risk of such.

Medications

While SMFM recommends a starting dose of ursodeoxycholic acid 10 to 15 mg/kg per day divided into 2 or 3 daily doses as first-line therapy for the treatment of maternal symptoms of ICP, it is important to acknowledge that the goal of treatment is to alleviate maternal symptoms as there is no evidence that ursodeoxycholic acid improves either maternal serum bile acid levels or perinatal outcomes.^7,17,18 Since publication of the guidelines, ursodeoxycholic acid’s lack of benefit has been further confirmed in a meta-analysis, and thus discontinuation is not unreasonable in the absence of any improvement in maternal symptoms.¹⁸

Timing of delivery

The optimal management of ICP remains unknown. SMFM recommends delivery based on peak serum bile acid levels. Delivery is recommended at 36 weeks’ gestation with ICP and total bile acid levels greater than 100 µmol/L as these patients have the greatest risk of stillbirth.⁷ For patients with ICP and bile acid levels less than 100 µmol/L, delivery is recommended between 36 0/7 and 39 0/7 weeks’ gestation.⁷ This is a wide gestational age window for clinicians to consider timing of delivery, and certainly the risks of stillbirth should be carefully balanced with the morbidity associated with a preterm or early term delivery.

For patients with ICP who have bile acid levels greater than 40 µmol/L, it is reasonable to consider delivery earlier in the gestational age window, given an evidence of increased risk of stillbirth after 38 weeks.^7,12 For patients with ICP who have bile acid levels less than 40 µmol/L, delivery closer to 39 weeks’ gestation is recommended, as the risk of stillbirth does not appear to be increased above the baseline risk.^7,12 Clinicians should be aware that the presence of concomitant morbidities, such as preeclampsia and gestational diabetes, are associated with an increased risk of stillbirth and should be considered for delivery planning.¹⁹

Postpartum follow-up

Routine laboratory evaluation following delivery is not recommended.⁷ However, in the presence of persistent pruritus or other signs and symptoms of hepatobiliary disease, liver function tests should be repeated with referral to hepatology if results are persistently abnormal 4 to 6 weeks postpartum.⁷

CASE Patient follow-up and outcomes

The patient was counseled regarding the diagnosis of ICP. Following shared decision making, the patient opted to undergo twice weekly nonstress tests but was aware to carefully monitor fetal movements due to the unpredictability of stillbirth in ICP. The patient also opted to trial ursodeoxycholic acid for relief of maternal symptoms. Two weeks after her initial diagnosis, repeat total bile acid levels were stable at 22 µmol/L. Therefore, following extensive counseling, the patient opted to undergo induction of labor at 38 weeks’ gestation, with a normal outcome for mother and neonate. ●

CASE Pregnant woman with intense itching

A 28-year-old woman (G1P0) is seen for a routine prenatal visit at 32 3/7 weeks’ gestation. She reports having generalized intense itching, including on her palms and soles, that is most intense at night and has been present for approximately 1 week. Her pregnancy is otherwise uncomplicated to date. Physical exam is within normal limits, with no evidence of a skin rash. Cholestasis of pregnancy is suspected, and laboratory tests are ordered, including bile acids and liver transaminases. Test results show that her aspartate transaminase (AST) and alanine transaminase (ALT) levels are mildly elevated at 55 IU/L and 41 IU/L, respectively, and several days later her bile acid level result is 21 µmol/L.

How should this patient be managed?

Intrahepatic cholestasis of pregnancy (ICP) affects 0.5% to 0.7% of pregnant individuals and results in maternal pruritus and elevated serum bile acid levels.^1-3 Pruritus in ICP typically is generalized, including occurrence on the palms of the hands and soles of the feet, and it often is reported to be worse at night.⁴ Up to 25% of pregnant women will develop pruritus during pregnancy but the majority will not have ICP.^2,5 Patients with ICP have no associated rash, but clinicians may note excoriations on exam. ICP typically presents in the third trimester of pregnancy but has been reported to occur earlier in gestation.⁶

Making a diagnosis of ICP

The presence of maternal pruritus in the absence of a skin condition along with elevated levels of serum bile acids are required for the diagnosis of ICP.⁷ Thus, a thorough history and physical exam is recommended to rule out another skin condition that could potentially explain the patient’s pruritus.

Some controversy exists regarding the bile acid level cutoff that should be used to make a diagnosis of ICP.⁸ It has been noted that nonfasting serum bile acid levels in pregnancy are considerably higher than those in in the nonpregnant state, and an upper limit of 18 µmol/L has been proposed as a cutoff in pregnancy.⁹ However, nonfasting total serum bile acids also have been shown to vary considerably by race, with levels 25.8% higher in Black women compared with those in White women and 24.3% higher in Black women compared with those in south Asian women.⁹ This raises the question of whether we should be using race-specific bile acid values to make a diagnosis of ICP.

Bile acid levels also vary based on whether a patient is in a fasting or postprandial state.¹⁰ Despite this variation, most guidelines do not recommend testing fasting bile acid levels as the postprandial state effect overall is small.^7,9,11 The Society for Maternal-Fetal Medicine (SMFM) recommends that if a pregnancy-specific bile acid range is available from the laboratory, then the upper limit of normal for pregnancy should be used when making a diagnosis of ICP.⁷ The SMFM guidelines also acknowledge, however, that pregnancy-specific values rarely are available, and in this case, levels above the upper limit of normal—often 10 µmol/L should be considered diagnostic for ICP until further evidence regarding optimal bile acid cutoff levels in pregnancy becomes available.⁷

For patients with suspected ICP, liver transaminase levels should be measured in addition to nonfasting serum bile acid levels.⁷ A thorough history should include assessment for additional symptoms of liver disease, such as changes in weight, appetite, jaundice, excessive fatigue, malaise, and abdominal pain.⁷ Elevated transaminases levels may be associated with ICP, but they are not necessary for diagnosis. In the absence of additional clinical symptoms that suggest underlying liver disease or severe early onset ICP, additional evaluation beyond nonfasting serum bile acids and liver transaminase levels, such as liver ultrasonography or evaluation for viral or autoimmune hepatitis, is not recommended.⁷ Obstetric care clinicians should be aware that there is an increased incidence of preeclampsia among patients with ICP, although no specific guidance regarding further recommendations for screening is provided.⁷

PHOTO: CHAJAMP/SHUTTERSTOCK

Continue to: Risks associated with ICP...

Risks associated with ICP

For both patients and clinicians, the greatest concern among patients with ICP is the increased risk of stillbirth. Stillbirth risk in ICP appears to be related to serum bile acid levels and has been reported to be highest in patients with bile acid levels greater than 100 µmol/L. A systematic review and meta-analysis of ICP studies demonstrated no increased risk of stillbirth among patients with bile acid levels less than 100 µmol/L.¹² These results, however, must be interpreted with extreme caution as the majority of studies included patients with ICP who were actively managed with attempts to mitigate the risk of stillbirth.⁷

In the absence of additional pregnancy risk factors, the risk of stillbirth among patients with ICP and serum bile acid levels between 19 and 39 µmol/L does not appear to be elevated above their baseline risk.¹¹ The same is true for pregnant individuals with ICP and no additional pregnancy risk factors with serum bile acid levels between 40 and 99 µmol/L until approximately 38 weeks’ gestation, when the risk of stillbirth is elevated.¹¹ The risk of stillbirth is elevated in ICP with peak bile acid levels greater than 100 µmol/L, with an absolute risk of 3.44%.¹¹

Management of patients with ICP

Laboratory evaluation

There is no consensus on the need for repeat testing of bile acid levels in patients with ICP. SMFM advises that follow-up testing of bile acid levels may help to guide delivery timing, especially in cases of severe ICP, but the society recommends against serial testing.⁷ By contrast, the Royal College of Obstetricians and Gynaecologists (RCOG) provides a detailed algorithm regarding time intervals between serum bile acid level testing to guide delivery timing.¹¹ The TABLE lists the strategy for reassessment of serum bile acid levels in ICP as recommended by the RCOG.¹¹

In the United States, bile acid testing traditionally takes several days as the testing is commonly performed at reference laboratories. We therefore suggest that clinicians consider repeating bile acid level testing in situations in which the timing of delivery may be altered if further elevations of bile acid levels were noted. This is particularly relevant for patients diagnosed with ICP early in the third trimester when repeat bile acid levels would still allow for an adjustment in delivery timing.

Antepartum fetal surveillance

Unfortunately, antepartum fetal testing for pregnant patients with ICP does not appear to reliably predict or prevent stillbirth as several studies have reported stillbirths within days of normal fetal testing.^13-16 It is therefore important to counsel pregnant patients regarding monitoring of fetal movements and advise them to present for evaluation if concerns arise.

Currently, SMFM recommends that patients with ICP should begin antenatal fetal surveillance at a gestational age when abnormal fetal testing would result in delivery.⁷ Patients should be counseled, however, regarding the unpredictability of stillbirth with ICP in the setting of a low absolute risk of such.

Medications

While SMFM recommends a starting dose of ursodeoxycholic acid 10 to 15 mg/kg per day divided into 2 or 3 daily doses as first-line therapy for the treatment of maternal symptoms of ICP, it is important to acknowledge that the goal of treatment is to alleviate maternal symptoms as there is no evidence that ursodeoxycholic acid improves either maternal serum bile acid levels or perinatal outcomes.^7,17,18 Since publication of the guidelines, ursodeoxycholic acid’s lack of benefit has been further confirmed in a meta-analysis, and thus discontinuation is not unreasonable in the absence of any improvement in maternal symptoms.¹⁸

Timing of delivery

The optimal management of ICP remains unknown. SMFM recommends delivery based on peak serum bile acid levels. Delivery is recommended at 36 weeks’ gestation with ICP and total bile acid levels greater than 100 µmol/L as these patients have the greatest risk of stillbirth.⁷ For patients with ICP and bile acid levels less than 100 µmol/L, delivery is recommended between 36 0/7 and 39 0/7 weeks’ gestation.⁷ This is a wide gestational age window for clinicians to consider timing of delivery, and certainly the risks of stillbirth should be carefully balanced with the morbidity associated with a preterm or early term delivery.

For patients with ICP who have bile acid levels greater than 40 µmol/L, it is reasonable to consider delivery earlier in the gestational age window, given an evidence of increased risk of stillbirth after 38 weeks.^7,12 For patients with ICP who have bile acid levels less than 40 µmol/L, delivery closer to 39 weeks’ gestation is recommended, as the risk of stillbirth does not appear to be increased above the baseline risk.^7,12 Clinicians should be aware that the presence of concomitant morbidities, such as preeclampsia and gestational diabetes, are associated with an increased risk of stillbirth and should be considered for delivery planning.¹⁹

Postpartum follow-up

Routine laboratory evaluation following delivery is not recommended.⁷ However, in the presence of persistent pruritus or other signs and symptoms of hepatobiliary disease, liver function tests should be repeated with referral to hepatology if results are persistently abnormal 4 to 6 weeks postpartum.⁷

CASE Patient follow-up and outcomes

The patient was counseled regarding the diagnosis of ICP. Following shared decision making, the patient opted to undergo twice weekly nonstress tests but was aware to carefully monitor fetal movements due to the unpredictability of stillbirth in ICP. The patient also opted to trial ursodeoxycholic acid for relief of maternal symptoms. Two weeks after her initial diagnosis, repeat total bile acid levels were stable at 22 µmol/L. Therefore, following extensive counseling, the patient opted to undergo induction of labor at 38 weeks’ gestation, with a normal outcome for mother and neonate. ●

CASE Pregnant woman with intense itching

A 28-year-old woman (G1P0) is seen for a routine prenatal visit at 32 3/7 weeks’ gestation. She reports having generalized intense itching, including on her palms and soles, that is most intense at night and has been present for approximately 1 week. Her pregnancy is otherwise uncomplicated to date. Physical exam is within normal limits, with no evidence of a skin rash. Cholestasis of pregnancy is suspected, and laboratory tests are ordered, including bile acids and liver transaminases. Test results show that her aspartate transaminase (AST) and alanine transaminase (ALT) levels are mildly elevated at 55 IU/L and 41 IU/L, respectively, and several days later her bile acid level result is 21 µmol/L.

How should this patient be managed?

Intrahepatic cholestasis of pregnancy (ICP) affects 0.5% to 0.7% of pregnant individuals and results in maternal pruritus and elevated serum bile acid levels.^1-3 Pruritus in ICP typically is generalized, including occurrence on the palms of the hands and soles of the feet, and it often is reported to be worse at night.⁴ Up to 25% of pregnant women will develop pruritus during pregnancy but the majority will not have ICP.^2,5 Patients with ICP have no associated rash, but clinicians may note excoriations on exam. ICP typically presents in the third trimester of pregnancy but has been reported to occur earlier in gestation.⁶

Making a diagnosis of ICP

The presence of maternal pruritus in the absence of a skin condition along with elevated levels of serum bile acids are required for the diagnosis of ICP.⁷ Thus, a thorough history and physical exam is recommended to rule out another skin condition that could potentially explain the patient’s pruritus.

Some controversy exists regarding the bile acid level cutoff that should be used to make a diagnosis of ICP.⁸ It has been noted that nonfasting serum bile acid levels in pregnancy are considerably higher than those in in the nonpregnant state, and an upper limit of 18 µmol/L has been proposed as a cutoff in pregnancy.⁹ However, nonfasting total serum bile acids also have been shown to vary considerably by race, with levels 25.8% higher in Black women compared with those in White women and 24.3% higher in Black women compared with those in south Asian women.⁹ This raises the question of whether we should be using race-specific bile acid values to make a diagnosis of ICP.

Bile acid levels also vary based on whether a patient is in a fasting or postprandial state.¹⁰ Despite this variation, most guidelines do not recommend testing fasting bile acid levels as the postprandial state effect overall is small.^7,9,11 The Society for Maternal-Fetal Medicine (SMFM) recommends that if a pregnancy-specific bile acid range is available from the laboratory, then the upper limit of normal for pregnancy should be used when making a diagnosis of ICP.⁷ The SMFM guidelines also acknowledge, however, that pregnancy-specific values rarely are available, and in this case, levels above the upper limit of normal—often 10 µmol/L should be considered diagnostic for ICP until further evidence regarding optimal bile acid cutoff levels in pregnancy becomes available.⁷

For patients with suspected ICP, liver transaminase levels should be measured in addition to nonfasting serum bile acid levels.⁷ A thorough history should include assessment for additional symptoms of liver disease, such as changes in weight, appetite, jaundice, excessive fatigue, malaise, and abdominal pain.⁷ Elevated transaminases levels may be associated with ICP, but they are not necessary for diagnosis. In the absence of additional clinical symptoms that suggest underlying liver disease or severe early onset ICP, additional evaluation beyond nonfasting serum bile acids and liver transaminase levels, such as liver ultrasonography or evaluation for viral or autoimmune hepatitis, is not recommended.⁷ Obstetric care clinicians should be aware that there is an increased incidence of preeclampsia among patients with ICP, although no specific guidance regarding further recommendations for screening is provided.⁷

PHOTO: CHAJAMP/SHUTTERSTOCK

Continue to: Risks associated with ICP...

Risks associated with ICP

For both patients and clinicians, the greatest concern among patients with ICP is the increased risk of stillbirth. Stillbirth risk in ICP appears to be related to serum bile acid levels and has been reported to be highest in patients with bile acid levels greater than 100 µmol/L. A systematic review and meta-analysis of ICP studies demonstrated no increased risk of stillbirth among patients with bile acid levels less than 100 µmol/L.¹² These results, however, must be interpreted with extreme caution as the majority of studies included patients with ICP who were actively managed with attempts to mitigate the risk of stillbirth.⁷

In the absence of additional pregnancy risk factors, the risk of stillbirth among patients with ICP and serum bile acid levels between 19 and 39 µmol/L does not appear to be elevated above their baseline risk.¹¹ The same is true for pregnant individuals with ICP and no additional pregnancy risk factors with serum bile acid levels between 40 and 99 µmol/L until approximately 38 weeks’ gestation, when the risk of stillbirth is elevated.¹¹ The risk of stillbirth is elevated in ICP with peak bile acid levels greater than 100 µmol/L, with an absolute risk of 3.44%.¹¹

Management of patients with ICP

Laboratory evaluation

There is no consensus on the need for repeat testing of bile acid levels in patients with ICP. SMFM advises that follow-up testing of bile acid levels may help to guide delivery timing, especially in cases of severe ICP, but the society recommends against serial testing.⁷ By contrast, the Royal College of Obstetricians and Gynaecologists (RCOG) provides a detailed algorithm regarding time intervals between serum bile acid level testing to guide delivery timing.¹¹ The TABLE lists the strategy for reassessment of serum bile acid levels in ICP as recommended by the RCOG.¹¹

In the United States, bile acid testing traditionally takes several days as the testing is commonly performed at reference laboratories. We therefore suggest that clinicians consider repeating bile acid level testing in situations in which the timing of delivery may be altered if further elevations of bile acid levels were noted. This is particularly relevant for patients diagnosed with ICP early in the third trimester when repeat bile acid levels would still allow for an adjustment in delivery timing.

Antepartum fetal surveillance

Unfortunately, antepartum fetal testing for pregnant patients with ICP does not appear to reliably predict or prevent stillbirth as several studies have reported stillbirths within days of normal fetal testing.^13-16 It is therefore important to counsel pregnant patients regarding monitoring of fetal movements and advise them to present for evaluation if concerns arise.

Currently, SMFM recommends that patients with ICP should begin antenatal fetal surveillance at a gestational age when abnormal fetal testing would result in delivery.⁷ Patients should be counseled, however, regarding the unpredictability of stillbirth with ICP in the setting of a low absolute risk of such.

Medications

While SMFM recommends a starting dose of ursodeoxycholic acid 10 to 15 mg/kg per day divided into 2 or 3 daily doses as first-line therapy for the treatment of maternal symptoms of ICP, it is important to acknowledge that the goal of treatment is to alleviate maternal symptoms as there is no evidence that ursodeoxycholic acid improves either maternal serum bile acid levels or perinatal outcomes.^7,17,18 Since publication of the guidelines, ursodeoxycholic acid’s lack of benefit has been further confirmed in a meta-analysis, and thus discontinuation is not unreasonable in the absence of any improvement in maternal symptoms.¹⁸

Timing of delivery

The optimal management of ICP remains unknown. SMFM recommends delivery based on peak serum bile acid levels. Delivery is recommended at 36 weeks’ gestation with ICP and total bile acid levels greater than 100 µmol/L as these patients have the greatest risk of stillbirth.⁷ For patients with ICP and bile acid levels less than 100 µmol/L, delivery is recommended between 36 0/7 and 39 0/7 weeks’ gestation.⁷ This is a wide gestational age window for clinicians to consider timing of delivery, and certainly the risks of stillbirth should be carefully balanced with the morbidity associated with a preterm or early term delivery.

For patients with ICP who have bile acid levels greater than 40 µmol/L, it is reasonable to consider delivery earlier in the gestational age window, given an evidence of increased risk of stillbirth after 38 weeks.^7,12 For patients with ICP who have bile acid levels less than 40 µmol/L, delivery closer to 39 weeks’ gestation is recommended, as the risk of stillbirth does not appear to be increased above the baseline risk.^7,12 Clinicians should be aware that the presence of concomitant morbidities, such as preeclampsia and gestational diabetes, are associated with an increased risk of stillbirth and should be considered for delivery planning.¹⁹

Postpartum follow-up

Routine laboratory evaluation following delivery is not recommended.⁷ However, in the presence of persistent pruritus or other signs and symptoms of hepatobiliary disease, liver function tests should be repeated with referral to hepatology if results are persistently abnormal 4 to 6 weeks postpartum.⁷

CASE Patient follow-up and outcomes

The patient was counseled regarding the diagnosis of ICP. Following shared decision making, the patient opted to undergo twice weekly nonstress tests but was aware to carefully monitor fetal movements due to the unpredictability of stillbirth in ICP. The patient also opted to trial ursodeoxycholic acid for relief of maternal symptoms. Two weeks after her initial diagnosis, repeat total bile acid levels were stable at 22 µmol/L. Therefore, following extensive counseling, the patient opted to undergo induction of labor at 38 weeks’ gestation, with a normal outcome for mother and neonate. ●

The patient's history of psoriasis, along with his current skin and scalp plaque flares, symmetrical joint symptomatology, laboratory studies, and x-rays, suggest a diagnosis of symmetrical psoriatic arthritis (PsA). The rheumatologist considers ordering additional imaging to assess for subclinical enthesitis and dactylitis, and discusses treatment next steps with the patient, given inadequate control with a TNF inhibitor. 

Symmetrical polyarthritis is one of the most common types of PsA and involves five or more joints in the hands, wrists, ankles, and/or feet. Among patients with PsA, 60% to 80% experience plaque psoriasis before joint-symptom onset; time to joint-symptom onset in these patients typically occurs within 10 years of a plaque psoriasis diagnosis. Involvement of DIP joints differentiates PsA from rheumatoid arthritis, as does the absence of subcutaneous nodules and a negative result for rheumatoid factor. About 30% of all people with plaque psoriasis will develop PsA, which affects an estimated 1 million people in the United States annually. Symptoms typically appear between the ages of 35 and 55 years; women are more likely than men to develop symmetrical PsA. 

There are no specific diagnostic tests for PsA. Rheumatologists generally use the assessment known as the Classification Criteria for Psoriatic Arthritis, (CASPAR), which can help reveal established inflammatory articular disease through a point system based on the presence/absence of various factors. On laboratory studies, the most common characteristic abnormalities of PsA are elevated ESR and CRP levels and negative rheumatoid factor in most patients. Other abnormalities that may be present in patients with PsA include elevated serum uric acid concentration and serum immunoglobulin A, and reduced levels of circulating immune complexes. Physicians also use imaging studies, such as radiography, ultrasonography, and MRI, to help differentiate PsA from other articular diseases.

While the pathogenesis of PsA remains unclear, research has shown that disease development is associated with a complex interplay of immune-mediated inflammatory responses; genetic and environmental factors may also be involved. In addition, patients with PsA are more likely to have a high risk for comorbidities, including obesity, type 2 diabetes, hypertension, hyperlipidemia, and cardiovascular events, compared with the general population.

When patients with PsA experience both skin and joint symptoms, a multidisciplinary approach to care is advised. Multidisciplinary teams play a key role in educating patients about their treatment plans and managing their PsA symptoms. The teams also help patients determine the best approaches to exercise to help maintain current joint function, as well as helpful adjustments in daily activities that will make it easier to accommodate their disease. 

Nonsteroidal anti-inflammatory drugs, whether self-prescribed or prescribed by a physician, are a common initial treatment to manage joint symptoms of PsA. Current American College of Rheumatology treatment guidelines, however, encourage early treatment with disease-modifying antirheumatic drugs (DMARDs) because approximately 40% of patients with PsA develop erosive and deforming arthritis. Several DMARDs are available, including older drugs like methotrexate, as well as newer biologic agents, such as TNF inhibitors, interleukin (IL)-17 inhibitors, IL-12/23 inhibitors, and Janus kinase inhibitors. In addition, guidelines recommend early and customized physical therapy and rehabilitation approaches for patients with PsA.

Herbert S. Diamond, MD, Professor of Medicine (retired), Temple University School of Medicine, University of Pittsburgh; Chairman, Department of Medicine Emeritus, Western Pennsylvania Hospital, Pittsburgh, PA.

Herbert S. Diamond, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

The patient's history of psoriasis, along with his current skin and scalp plaque flares, symmetrical joint symptomatology, laboratory studies, and x-rays, suggest a diagnosis of symmetrical psoriatic arthritis (PsA). The rheumatologist considers ordering additional imaging to assess for subclinical enthesitis and dactylitis, and discusses treatment next steps with the patient, given inadequate control with a TNF inhibitor. 

Symmetrical polyarthritis is one of the most common types of PsA and involves five or more joints in the hands, wrists, ankles, and/or feet. Among patients with PsA, 60% to 80% experience plaque psoriasis before joint-symptom onset; time to joint-symptom onset in these patients typically occurs within 10 years of a plaque psoriasis diagnosis. Involvement of DIP joints differentiates PsA from rheumatoid arthritis, as does the absence of subcutaneous nodules and a negative result for rheumatoid factor. About 30% of all people with plaque psoriasis will develop PsA, which affects an estimated 1 million people in the United States annually. Symptoms typically appear between the ages of 35 and 55 years; women are more likely than men to develop symmetrical PsA. 

There are no specific diagnostic tests for PsA. Rheumatologists generally use the assessment known as the Classification Criteria for Psoriatic Arthritis, (CASPAR), which can help reveal established inflammatory articular disease through a point system based on the presence/absence of various factors. On laboratory studies, the most common characteristic abnormalities of PsA are elevated ESR and CRP levels and negative rheumatoid factor in most patients. Other abnormalities that may be present in patients with PsA include elevated serum uric acid concentration and serum immunoglobulin A, and reduced levels of circulating immune complexes. Physicians also use imaging studies, such as radiography, ultrasonography, and MRI, to help differentiate PsA from other articular diseases.

While the pathogenesis of PsA remains unclear, research has shown that disease development is associated with a complex interplay of immune-mediated inflammatory responses; genetic and environmental factors may also be involved. In addition, patients with PsA are more likely to have a high risk for comorbidities, including obesity, type 2 diabetes, hypertension, hyperlipidemia, and cardiovascular events, compared with the general population.

When patients with PsA experience both skin and joint symptoms, a multidisciplinary approach to care is advised. Multidisciplinary teams play a key role in educating patients about their treatment plans and managing their PsA symptoms. The teams also help patients determine the best approaches to exercise to help maintain current joint function, as well as helpful adjustments in daily activities that will make it easier to accommodate their disease. 

Nonsteroidal anti-inflammatory drugs, whether self-prescribed or prescribed by a physician, are a common initial treatment to manage joint symptoms of PsA. Current American College of Rheumatology treatment guidelines, however, encourage early treatment with disease-modifying antirheumatic drugs (DMARDs) because approximately 40% of patients with PsA develop erosive and deforming arthritis. Several DMARDs are available, including older drugs like methotrexate, as well as newer biologic agents, such as TNF inhibitors, interleukin (IL)-17 inhibitors, IL-12/23 inhibitors, and Janus kinase inhibitors. In addition, guidelines recommend early and customized physical therapy and rehabilitation approaches for patients with PsA.

Herbert S. Diamond, MD, Professor of Medicine (retired), Temple University School of Medicine, University of Pittsburgh; Chairman, Department of Medicine Emeritus, Western Pennsylvania Hospital, Pittsburgh, PA.

Herbert S. Diamond, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

The patient's history of psoriasis, along with his current skin and scalp plaque flares, symmetrical joint symptomatology, laboratory studies, and x-rays, suggest a diagnosis of symmetrical psoriatic arthritis (PsA). The rheumatologist considers ordering additional imaging to assess for subclinical enthesitis and dactylitis, and discusses treatment next steps with the patient, given inadequate control with a TNF inhibitor. 

Symmetrical polyarthritis is one of the most common types of PsA and involves five or more joints in the hands, wrists, ankles, and/or feet. Among patients with PsA, 60% to 80% experience plaque psoriasis before joint-symptom onset; time to joint-symptom onset in these patients typically occurs within 10 years of a plaque psoriasis diagnosis. Involvement of DIP joints differentiates PsA from rheumatoid arthritis, as does the absence of subcutaneous nodules and a negative result for rheumatoid factor. About 30% of all people with plaque psoriasis will develop PsA, which affects an estimated 1 million people in the United States annually. Symptoms typically appear between the ages of 35 and 55 years; women are more likely than men to develop symmetrical PsA. 

There are no specific diagnostic tests for PsA. Rheumatologists generally use the assessment known as the Classification Criteria for Psoriatic Arthritis, (CASPAR), which can help reveal established inflammatory articular disease through a point system based on the presence/absence of various factors. On laboratory studies, the most common characteristic abnormalities of PsA are elevated ESR and CRP levels and negative rheumatoid factor in most patients. Other abnormalities that may be present in patients with PsA include elevated serum uric acid concentration and serum immunoglobulin A, and reduced levels of circulating immune complexes. Physicians also use imaging studies, such as radiography, ultrasonography, and MRI, to help differentiate PsA from other articular diseases.

While the pathogenesis of PsA remains unclear, research has shown that disease development is associated with a complex interplay of immune-mediated inflammatory responses; genetic and environmental factors may also be involved. In addition, patients with PsA are more likely to have a high risk for comorbidities, including obesity, type 2 diabetes, hypertension, hyperlipidemia, and cardiovascular events, compared with the general population.

When patients with PsA experience both skin and joint symptoms, a multidisciplinary approach to care is advised. Multidisciplinary teams play a key role in educating patients about their treatment plans and managing their PsA symptoms. The teams also help patients determine the best approaches to exercise to help maintain current joint function, as well as helpful adjustments in daily activities that will make it easier to accommodate their disease. 

Nonsteroidal anti-inflammatory drugs, whether self-prescribed or prescribed by a physician, are a common initial treatment to manage joint symptoms of PsA. Current American College of Rheumatology treatment guidelines, however, encourage early treatment with disease-modifying antirheumatic drugs (DMARDs) because approximately 40% of patients with PsA develop erosive and deforming arthritis. Several DMARDs are available, including older drugs like methotrexate, as well as newer biologic agents, such as TNF inhibitors, interleukin (IL)-17 inhibitors, IL-12/23 inhibitors, and Janus kinase inhibitors. In addition, guidelines recommend early and customized physical therapy and rehabilitation approaches for patients with PsA.

Herbert S. Diamond, MD, Professor of Medicine (retired), Temple University School of Medicine, University of Pittsburgh; Chairman, Department of Medicine Emeritus, Western Pennsylvania Hospital, Pittsburgh, PA.

Herbert S. Diamond, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

Yeung LK, Alschuler DM, Wall M, et al. Multivitamin supplementation improves memory in older adults: a randomized clinical trial. Am J Clin Nutrition. 2023;118:273-282. doi:10.1016/j.ajcnut.2023.05.011.

EXPERT COMMENTARY

Preservation of function, both physical and cognitive, is key to long-term health and well-being. Age-related loss of function drives millions of people to spend an enormous amount of money each year on unregulated therapies—vitamins, supplements, infusions, hormones, and “natural” products—all toward the promise of improvement or preservation of physical strength, sexual function, and maintenance of lean body mass and cognitive abilities. Yeung and colleagues set out to determine whether the daily use of a multivitamin/mineral supplement (Centrum Silver) would impact memory in older adults.¹

Details of the study

The COSMOS-Web study was designed to test the authors’ primary hypothesis that daily dietary flavanols would improve memory over 1 year.¹ This study was embedded within the larger COSMOS (COcoa Supplement and Multivitamin Outcomes Study) trial, in which 21,442 people were recruited to assess the impact of flavanols and multivitamin supplements on cardiovascular and cancer outcomes.

Results of another ancillary study, the COSMOS-Mind trial (n = 2,262, average age 73, 60% female), reported no improvement with flavanols compared with placebo on a battery of tests of cognitive function administered by phone. In COSMOS-Mind, however, it was concluded that a daily multivitamin/mineral supplement improved the composite score of cognitive tests compared with placebo, particularly in participants with a history of cardiovascular disease.²

The COSMOS-Web trial recruited an additional cohort within the larger COSMOS trial from 2016–2017 (n = 3,562, average age 71, 67% female) to participate in this study specifically geared to assess memory, using the web-based ModRey test (a test of memory validated for use in a nonimpaired population). To qualify for enrollment, participants had to have access to an internet-connected computer. They were randomly assigned in a 2 x 2 study design to receive a daily multivitamin supplement or placebo; each of these cohorts was further divided into a flavanol supplementation or a placebo group. Analysis of the data showed no association between flavanol use and performance on any of the measures of memory or cognitive function.³

The COSMOS-Web trial assessed episodic recall, a function of hippocampus-mediated cognition that is particularly vulnerable to the effects of aging as demonstrated previously by neuroimaging and neuropsychological studies. The authors deployed a battery of 3 tests via a web platform for patients to complete online and independently.

The prespecified primary outcome was performance on episodic recall as measured by the ModRey test after 1 year of supplementation with multivitamins versus placebo. The ModRey test presents a series of 20 words at 3-second intervals to participants. At the conclusion of the last word, participants were asked to recall as many words as they could; after completing the 2 additional tasks, participants were asked again to recall the words. A secondary outcome of this test is the ratio of delayed to immediate recall.

Two additional tests were administered to assess cognitive performance related to different brain regions, the ModBent test (assessing novel object recognition) and the Flanker task (a measure of executive function). There was a placebo run-in phase during which participants’ adherence to daily supplement intake was ascertained. Participants were excluded if they demonstrated less than 75% adherence to study pills during the run-in placebo phase. The cognitive tasks were presented at study initiation and at yearly intervals for 3 years. The authors chose to use the results at 1 year as their primary outcome to assess the impact of supplementation during the period when adherence would be highest.

Results. At baseline, the placebo cohort recalled 7.2 words of 20 compared with 7.1 in the supplement group. In both groups there was a practice effect, with improvement in scores in the placebo group to 7.65 words and in the multivitamin group to 7.81 words. The improvement from baseline was statistically significantly better (0.71 words) in the multivitamin cohort than in the placebo group (0.45 words). There was no improvement in either group in the ModRey memory retention test (ability to recall the words after 15 minutes) or in the ModBent or Flanker tests. At 3 years of treatment, the placebo group improved by 0.92 words (SD, 3.22) whereas the multivitamin group improved by 1.13 words (SD, 3.39). These changes remained statistically significant.

The group with cardiovascular disease had lower baseline performance on the ModRey test. With supplementation, however, the improvement in this cohort was significantly greater than in those without cardiovascular disease at 1 year. The authors acknowledged that the changes were small and may not have been noticeable to the individuals, but they argued that even small changes as demonstrated in this study can have large health benefits at a population level.

The results of the COSMOS-Web trial corroborate the findings of the COSMOS-Mind study with respect to the benefits of multivitamin/mineral supplementation on cognitive test performance, particularly in a population with preexisting cardiovascular disease. The tests used across the 2 studies were different, which lends greater reliability to the findings.

Study strengths and limitations

A major strength of this study is its careful, rigorous design as a double-blind, placebo-controlled trial in a large patient population. Great care was devoted to ensuring study medication adherence. Another strength is that the cognitive tests chosen for the COSMOS-Web trial have been validated in cognitively normal populations, not those already impaired.

A limitation, however, is in the demographics of the study. The patient population was overwhelmingly White (93%), 67% were female, and they were well educated (94.8% having completed some college or beyond). Their baseline health was good; only 4.7% had a history of cardiovascular disease. Although generalizability of the study results from this population may be concerning,relative benefits of supplementation in this healthy, generally well-nourished and educated group may be lower than might be expected in a more nutritionally and educationally challenged population.

Finally, the difference between the placebo and active supplementation groups was small. Whether this less-than-1-word difference in immediate memory recall is noticeable by a patient is questionable. Both groups improved in their test performance over time—a consequence of serial cognitive tests of any kind. Although the authors calculated that the difference in recall translates to a 3-year reduction in age-related memory decline, it is hard to reconcile that with the fact that both groups actually improved over the 3 years of the study. ●

Acknowledgement

The author would like to thank JoAnn Manson, MD, DrPH, NCMP, for her assistance in evaluating the study.

Yeung LK, Alschuler DM, Wall M, et al. Multivitamin supplementation improves memory in older adults: a randomized clinical trial. Am J Clin Nutrition. 2023;118:273-282. doi:10.1016/j.ajcnut.2023.05.011.

EXPERT COMMENTARY

Preservation of function, both physical and cognitive, is key to long-term health and well-being. Age-related loss of function drives millions of people to spend an enormous amount of money each year on unregulated therapies—vitamins, supplements, infusions, hormones, and “natural” products—all toward the promise of improvement or preservation of physical strength, sexual function, and maintenance of lean body mass and cognitive abilities. Yeung and colleagues set out to determine whether the daily use of a multivitamin/mineral supplement (Centrum Silver) would impact memory in older adults.¹

Details of the study

The COSMOS-Web study was designed to test the authors’ primary hypothesis that daily dietary flavanols would improve memory over 1 year.¹ This study was embedded within the larger COSMOS (COcoa Supplement and Multivitamin Outcomes Study) trial, in which 21,442 people were recruited to assess the impact of flavanols and multivitamin supplements on cardiovascular and cancer outcomes.

Results of another ancillary study, the COSMOS-Mind trial (n = 2,262, average age 73, 60% female), reported no improvement with flavanols compared with placebo on a battery of tests of cognitive function administered by phone. In COSMOS-Mind, however, it was concluded that a daily multivitamin/mineral supplement improved the composite score of cognitive tests compared with placebo, particularly in participants with a history of cardiovascular disease.²

The COSMOS-Web trial recruited an additional cohort within the larger COSMOS trial from 2016–2017 (n = 3,562, average age 71, 67% female) to participate in this study specifically geared to assess memory, using the web-based ModRey test (a test of memory validated for use in a nonimpaired population). To qualify for enrollment, participants had to have access to an internet-connected computer. They were randomly assigned in a 2 x 2 study design to receive a daily multivitamin supplement or placebo; each of these cohorts was further divided into a flavanol supplementation or a placebo group. Analysis of the data showed no association between flavanol use and performance on any of the measures of memory or cognitive function.³

The COSMOS-Web trial assessed episodic recall, a function of hippocampus-mediated cognition that is particularly vulnerable to the effects of aging as demonstrated previously by neuroimaging and neuropsychological studies. The authors deployed a battery of 3 tests via a web platform for patients to complete online and independently.

The prespecified primary outcome was performance on episodic recall as measured by the ModRey test after 1 year of supplementation with multivitamins versus placebo. The ModRey test presents a series of 20 words at 3-second intervals to participants. At the conclusion of the last word, participants were asked to recall as many words as they could; after completing the 2 additional tasks, participants were asked again to recall the words. A secondary outcome of this test is the ratio of delayed to immediate recall.

Two additional tests were administered to assess cognitive performance related to different brain regions, the ModBent test (assessing novel object recognition) and the Flanker task (a measure of executive function). There was a placebo run-in phase during which participants’ adherence to daily supplement intake was ascertained. Participants were excluded if they demonstrated less than 75% adherence to study pills during the run-in placebo phase. The cognitive tasks were presented at study initiation and at yearly intervals for 3 years. The authors chose to use the results at 1 year as their primary outcome to assess the impact of supplementation during the period when adherence would be highest.

Results. At baseline, the placebo cohort recalled 7.2 words of 20 compared with 7.1 in the supplement group. In both groups there was a practice effect, with improvement in scores in the placebo group to 7.65 words and in the multivitamin group to 7.81 words. The improvement from baseline was statistically significantly better (0.71 words) in the multivitamin cohort than in the placebo group (0.45 words). There was no improvement in either group in the ModRey memory retention test (ability to recall the words after 15 minutes) or in the ModBent or Flanker tests. At 3 years of treatment, the placebo group improved by 0.92 words (SD, 3.22) whereas the multivitamin group improved by 1.13 words (SD, 3.39). These changes remained statistically significant.

The group with cardiovascular disease had lower baseline performance on the ModRey test. With supplementation, however, the improvement in this cohort was significantly greater than in those without cardiovascular disease at 1 year. The authors acknowledged that the changes were small and may not have been noticeable to the individuals, but they argued that even small changes as demonstrated in this study can have large health benefits at a population level.

The results of the COSMOS-Web trial corroborate the findings of the COSMOS-Mind study with respect to the benefits of multivitamin/mineral supplementation on cognitive test performance, particularly in a population with preexisting cardiovascular disease. The tests used across the 2 studies were different, which lends greater reliability to the findings.

Study strengths and limitations

A major strength of this study is its careful, rigorous design as a double-blind, placebo-controlled trial in a large patient population. Great care was devoted to ensuring study medication adherence. Another strength is that the cognitive tests chosen for the COSMOS-Web trial have been validated in cognitively normal populations, not those already impaired.

A limitation, however, is in the demographics of the study. The patient population was overwhelmingly White (93%), 67% were female, and they were well educated (94.8% having completed some college or beyond). Their baseline health was good; only 4.7% had a history of cardiovascular disease. Although generalizability of the study results from this population may be concerning,relative benefits of supplementation in this healthy, generally well-nourished and educated group may be lower than might be expected in a more nutritionally and educationally challenged population.

Finally, the difference between the placebo and active supplementation groups was small. Whether this less-than-1-word difference in immediate memory recall is noticeable by a patient is questionable. Both groups improved in their test performance over time—a consequence of serial cognitive tests of any kind. Although the authors calculated that the difference in recall translates to a 3-year reduction in age-related memory decline, it is hard to reconcile that with the fact that both groups actually improved over the 3 years of the study. ●

Acknowledgement

The author would like to thank JoAnn Manson, MD, DrPH, NCMP, for her assistance in evaluating the study.

Yeung LK, Alschuler DM, Wall M, et al. Multivitamin supplementation improves memory in older adults: a randomized clinical trial. Am J Clin Nutrition. 2023;118:273-282. doi:10.1016/j.ajcnut.2023.05.011.

EXPERT COMMENTARY

Preservation of function, both physical and cognitive, is key to long-term health and well-being. Age-related loss of function drives millions of people to spend an enormous amount of money each year on unregulated therapies—vitamins, supplements, infusions, hormones, and “natural” products—all toward the promise of improvement or preservation of physical strength, sexual function, and maintenance of lean body mass and cognitive abilities. Yeung and colleagues set out to determine whether the daily use of a multivitamin/mineral supplement (Centrum Silver) would impact memory in older adults.¹

Details of the study

The COSMOS-Web study was designed to test the authors’ primary hypothesis that daily dietary flavanols would improve memory over 1 year.¹ This study was embedded within the larger COSMOS (COcoa Supplement and Multivitamin Outcomes Study) trial, in which 21,442 people were recruited to assess the impact of flavanols and multivitamin supplements on cardiovascular and cancer outcomes.

Results of another ancillary study, the COSMOS-Mind trial (n = 2,262, average age 73, 60% female), reported no improvement with flavanols compared with placebo on a battery of tests of cognitive function administered by phone. In COSMOS-Mind, however, it was concluded that a daily multivitamin/mineral supplement improved the composite score of cognitive tests compared with placebo, particularly in participants with a history of cardiovascular disease.²

The COSMOS-Web trial recruited an additional cohort within the larger COSMOS trial from 2016–2017 (n = 3,562, average age 71, 67% female) to participate in this study specifically geared to assess memory, using the web-based ModRey test (a test of memory validated for use in a nonimpaired population). To qualify for enrollment, participants had to have access to an internet-connected computer. They were randomly assigned in a 2 x 2 study design to receive a daily multivitamin supplement or placebo; each of these cohorts was further divided into a flavanol supplementation or a placebo group. Analysis of the data showed no association between flavanol use and performance on any of the measures of memory or cognitive function.³

The COSMOS-Web trial assessed episodic recall, a function of hippocampus-mediated cognition that is particularly vulnerable to the effects of aging as demonstrated previously by neuroimaging and neuropsychological studies. The authors deployed a battery of 3 tests via a web platform for patients to complete online and independently.

The prespecified primary outcome was performance on episodic recall as measured by the ModRey test after 1 year of supplementation with multivitamins versus placebo. The ModRey test presents a series of 20 words at 3-second intervals to participants. At the conclusion of the last word, participants were asked to recall as many words as they could; after completing the 2 additional tasks, participants were asked again to recall the words. A secondary outcome of this test is the ratio of delayed to immediate recall.

Two additional tests were administered to assess cognitive performance related to different brain regions, the ModBent test (assessing novel object recognition) and the Flanker task (a measure of executive function). There was a placebo run-in phase during which participants’ adherence to daily supplement intake was ascertained. Participants were excluded if they demonstrated less than 75% adherence to study pills during the run-in placebo phase. The cognitive tasks were presented at study initiation and at yearly intervals for 3 years. The authors chose to use the results at 1 year as their primary outcome to assess the impact of supplementation during the period when adherence would be highest.

Results. At baseline, the placebo cohort recalled 7.2 words of 20 compared with 7.1 in the supplement group. In both groups there was a practice effect, with improvement in scores in the placebo group to 7.65 words and in the multivitamin group to 7.81 words. The improvement from baseline was statistically significantly better (0.71 words) in the multivitamin cohort than in the placebo group (0.45 words). There was no improvement in either group in the ModRey memory retention test (ability to recall the words after 15 minutes) or in the ModBent or Flanker tests. At 3 years of treatment, the placebo group improved by 0.92 words (SD, 3.22) whereas the multivitamin group improved by 1.13 words (SD, 3.39). These changes remained statistically significant.

The group with cardiovascular disease had lower baseline performance on the ModRey test. With supplementation, however, the improvement in this cohort was significantly greater than in those without cardiovascular disease at 1 year. The authors acknowledged that the changes were small and may not have been noticeable to the individuals, but they argued that even small changes as demonstrated in this study can have large health benefits at a population level.

The results of the COSMOS-Web trial corroborate the findings of the COSMOS-Mind study with respect to the benefits of multivitamin/mineral supplementation on cognitive test performance, particularly in a population with preexisting cardiovascular disease. The tests used across the 2 studies were different, which lends greater reliability to the findings.

Study strengths and limitations

A major strength of this study is its careful, rigorous design as a double-blind, placebo-controlled trial in a large patient population. Great care was devoted to ensuring study medication adherence. Another strength is that the cognitive tests chosen for the COSMOS-Web trial have been validated in cognitively normal populations, not those already impaired.

A limitation, however, is in the demographics of the study. The patient population was overwhelmingly White (93%), 67% were female, and they were well educated (94.8% having completed some college or beyond). Their baseline health was good; only 4.7% had a history of cardiovascular disease. Although generalizability of the study results from this population may be concerning,relative benefits of supplementation in this healthy, generally well-nourished and educated group may be lower than might be expected in a more nutritionally and educationally challenged population.

Finally, the difference between the placebo and active supplementation groups was small. Whether this less-than-1-word difference in immediate memory recall is noticeable by a patient is questionable. Both groups improved in their test performance over time—a consequence of serial cognitive tests of any kind. Although the authors calculated that the difference in recall translates to a 3-year reduction in age-related memory decline, it is hard to reconcile that with the fact that both groups actually improved over the 3 years of the study. ●

Acknowledgement

The author would like to thank JoAnn Manson, MD, DrPH, NCMP, for her assistance in evaluating the study.

Given the patient's diagnosis of stage IV MCL, the presentation of diffuse skin lesions, and the histopathologic and immunophenotyping results of those lesions, this patient is diagnosed with secondary cutaneous MCL. The hematologist-oncologist discusses the findings with the patient and presents potential next steps and treatment options. 

MCL is a type of B-cell neoplasm that, with advancements in the understanding of non-Hodgkin lymphoma (NHL) in the past 30 years, has been defined as its own clinicopathologic entity by the Revised European-American Lymphoma and World Health Organization classifications. Up to 10% of all NHLs are MCL. Clinical presentation includes advanced disease with B symptoms (eg, night sweats, fever, weight loss), generalized lymphadenopathy, abdominal distention associated with hepatosplenomegaly, and fatigue. Skin manifestations are not as common as other extranodal manifestations. Primary cutaneous MCL occurs in up to 6% of patients with MCL; secondary cutaneous involvement is slightly more common, occurring in 17% of patients with MCL. Secondary cutaneous MCL usually presents in late-stage disease. Men are more likely to present with MCL than are women by a ratio of 3:1. Median age at presentation is 67 years. 
 
Diagnosing MCL is a multipronged approach. Physical examination may reveal lymphadenopathy and hepatosplenomegaly. Lymph node biopsy and aspiration with immunophenotyping in MCL reveals monoclonal B cells expressing surface immunoglobulin (Ig), IgM, or IgD, that are characteristically CD5+ and pan B-cell antigen–positive (eg, CD19, CD20, CD22) but lack expression of CD10 and CD23 and overexpress cyclin D1. Bone marrow aspirate/biopsy are used more for staging than for diagnosis. Blood studies, including anemia and cytopenias secondary to bone marrow infiltration (with up to 40% of cases showing lymphocytosis > 4000/μL), abnormal liver function tests, and a negative Coombs test also help diagnose MCL. Secondary cutaneous MCL is diagnosed on the basis of an MCL diagnosis along with diffuse infiltration of the skin, with multiple erythematous papules and nodules coalescing to form plaques; skin biopsy and immunohistopathology showing monotonous proliferation of small- to medium-sized lymphoid cells with scant cytoplasm; irregular cleaved nuclei with coarse chromatin; and inconspicuous nucleoli as well as a spared papillary dermis.

Pathogenesis of MCL involves disordered lymphoproliferation in a subset of naive pregerminal center cells in primary follicles or in the mantle region of secondary follicles. Most cases are linked with translocation of chromosome 14 and 11, which induces overexpression of protein cyclin D1. Viral infection (Epstein-Barr virus, HIV, human T-lymphotropic virus type 1, human herpes virus 6), environmental factors, and primary and secondary immunodeficiency are also associated with the development of NHL.

Patient education should include detailed information about clinical trials, available treatment options, and associated adverse events as well as psychosocial and nutrition counseling. 

Chemoimmunotherapy is standard initial treatment for MCL, but relapse is expected. Chemotherapy-free regimens with biologic targets, which were once used in second-line treatment, have increasingly become an important first-line treatment given their efficacy in the relapsed/refractory setting. Chimeric antigen receptor T-cell therapy is also a second-line treatment option. In patients with MCL and a TP53 mutation, clinical trial participation is encouraged because of poor prognosis.

Timothy J. Voorhees, MD, MSCR, Assistant Professor of Internal Medicine - Clinical, Division of Hematology, The Ohio State University James Comprehensive Cancer Center, Columbus, OH.

Timothy J. Voorhees, MD, MSCR, has disclosed the following relevant financial relationships:
Received research grants from: AstraZeneca; Morphosys; Incyte; Recordati.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

Given the patient's diagnosis of stage IV MCL, the presentation of diffuse skin lesions, and the histopathologic and immunophenotyping results of those lesions, this patient is diagnosed with secondary cutaneous MCL. The hematologist-oncologist discusses the findings with the patient and presents potential next steps and treatment options. 

MCL is a type of B-cell neoplasm that, with advancements in the understanding of non-Hodgkin lymphoma (NHL) in the past 30 years, has been defined as its own clinicopathologic entity by the Revised European-American Lymphoma and World Health Organization classifications. Up to 10% of all NHLs are MCL. Clinical presentation includes advanced disease with B symptoms (eg, night sweats, fever, weight loss), generalized lymphadenopathy, abdominal distention associated with hepatosplenomegaly, and fatigue. Skin manifestations are not as common as other extranodal manifestations. Primary cutaneous MCL occurs in up to 6% of patients with MCL; secondary cutaneous involvement is slightly more common, occurring in 17% of patients with MCL. Secondary cutaneous MCL usually presents in late-stage disease. Men are more likely to present with MCL than are women by a ratio of 3:1. Median age at presentation is 67 years. 
 
Diagnosing MCL is a multipronged approach. Physical examination may reveal lymphadenopathy and hepatosplenomegaly. Lymph node biopsy and aspiration with immunophenotyping in MCL reveals monoclonal B cells expressing surface immunoglobulin (Ig), IgM, or IgD, that are characteristically CD5+ and pan B-cell antigen–positive (eg, CD19, CD20, CD22) but lack expression of CD10 and CD23 and overexpress cyclin D1. Bone marrow aspirate/biopsy are used more for staging than for diagnosis. Blood studies, including anemia and cytopenias secondary to bone marrow infiltration (with up to 40% of cases showing lymphocytosis > 4000/μL), abnormal liver function tests, and a negative Coombs test also help diagnose MCL. Secondary cutaneous MCL is diagnosed on the basis of an MCL diagnosis along with diffuse infiltration of the skin, with multiple erythematous papules and nodules coalescing to form plaques; skin biopsy and immunohistopathology showing monotonous proliferation of small- to medium-sized lymphoid cells with scant cytoplasm; irregular cleaved nuclei with coarse chromatin; and inconspicuous nucleoli as well as a spared papillary dermis.

Pathogenesis of MCL involves disordered lymphoproliferation in a subset of naive pregerminal center cells in primary follicles or in the mantle region of secondary follicles. Most cases are linked with translocation of chromosome 14 and 11, which induces overexpression of protein cyclin D1. Viral infection (Epstein-Barr virus, HIV, human T-lymphotropic virus type 1, human herpes virus 6), environmental factors, and primary and secondary immunodeficiency are also associated with the development of NHL.

Patient education should include detailed information about clinical trials, available treatment options, and associated adverse events as well as psychosocial and nutrition counseling. 

Chemoimmunotherapy is standard initial treatment for MCL, but relapse is expected. Chemotherapy-free regimens with biologic targets, which were once used in second-line treatment, have increasingly become an important first-line treatment given their efficacy in the relapsed/refractory setting. Chimeric antigen receptor T-cell therapy is also a second-line treatment option. In patients with MCL and a TP53 mutation, clinical trial participation is encouraged because of poor prognosis.

Timothy J. Voorhees, MD, MSCR, Assistant Professor of Internal Medicine - Clinical, Division of Hematology, The Ohio State University James Comprehensive Cancer Center, Columbus, OH.

Timothy J. Voorhees, MD, MSCR, has disclosed the following relevant financial relationships:
Received research grants from: AstraZeneca; Morphosys; Incyte; Recordati.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

Given the patient's diagnosis of stage IV MCL, the presentation of diffuse skin lesions, and the histopathologic and immunophenotyping results of those lesions, this patient is diagnosed with secondary cutaneous MCL. The hematologist-oncologist discusses the findings with the patient and presents potential next steps and treatment options. 

MCL is a type of B-cell neoplasm that, with advancements in the understanding of non-Hodgkin lymphoma (NHL) in the past 30 years, has been defined as its own clinicopathologic entity by the Revised European-American Lymphoma and World Health Organization classifications. Up to 10% of all NHLs are MCL. Clinical presentation includes advanced disease with B symptoms (eg, night sweats, fever, weight loss), generalized lymphadenopathy, abdominal distention associated with hepatosplenomegaly, and fatigue. Skin manifestations are not as common as other extranodal manifestations. Primary cutaneous MCL occurs in up to 6% of patients with MCL; secondary cutaneous involvement is slightly more common, occurring in 17% of patients with MCL. Secondary cutaneous MCL usually presents in late-stage disease. Men are more likely to present with MCL than are women by a ratio of 3:1. Median age at presentation is 67 years. 
 
Diagnosing MCL is a multipronged approach. Physical examination may reveal lymphadenopathy and hepatosplenomegaly. Lymph node biopsy and aspiration with immunophenotyping in MCL reveals monoclonal B cells expressing surface immunoglobulin (Ig), IgM, or IgD, that are characteristically CD5+ and pan B-cell antigen–positive (eg, CD19, CD20, CD22) but lack expression of CD10 and CD23 and overexpress cyclin D1. Bone marrow aspirate/biopsy are used more for staging than for diagnosis. Blood studies, including anemia and cytopenias secondary to bone marrow infiltration (with up to 40% of cases showing lymphocytosis > 4000/μL), abnormal liver function tests, and a negative Coombs test also help diagnose MCL. Secondary cutaneous MCL is diagnosed on the basis of an MCL diagnosis along with diffuse infiltration of the skin, with multiple erythematous papules and nodules coalescing to form plaques; skin biopsy and immunohistopathology showing monotonous proliferation of small- to medium-sized lymphoid cells with scant cytoplasm; irregular cleaved nuclei with coarse chromatin; and inconspicuous nucleoli as well as a spared papillary dermis.

Pathogenesis of MCL involves disordered lymphoproliferation in a subset of naive pregerminal center cells in primary follicles or in the mantle region of secondary follicles. Most cases are linked with translocation of chromosome 14 and 11, which induces overexpression of protein cyclin D1. Viral infection (Epstein-Barr virus, HIV, human T-lymphotropic virus type 1, human herpes virus 6), environmental factors, and primary and secondary immunodeficiency are also associated with the development of NHL.

Patient education should include detailed information about clinical trials, available treatment options, and associated adverse events as well as psychosocial and nutrition counseling. 

Chemoimmunotherapy is standard initial treatment for MCL, but relapse is expected. Chemotherapy-free regimens with biologic targets, which were once used in second-line treatment, have increasingly become an important first-line treatment given their efficacy in the relapsed/refractory setting. Chimeric antigen receptor T-cell therapy is also a second-line treatment option. In patients with MCL and a TP53 mutation, clinical trial participation is encouraged because of poor prognosis.

Timothy J. Voorhees, MD, MSCR, Assistant Professor of Internal Medicine - Clinical, Division of Hematology, The Ohio State University James Comprehensive Cancer Center, Columbus, OH.

Timothy J. Voorhees, MD, MSCR, has disclosed the following relevant financial relationships:
Received research grants from: AstraZeneca; Morphosys; Incyte; Recordati.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

The patient's history, symptomatology, and assessments suggest a diagnosis of nonalcoholic fatty liver disease (NAFLD). The primary care physician recommends referral to a hepatologist for evaluation and possible liver biopsy. 

NAFLD involves an accumulation of triglycerides and other fats in the liver (unrelated to alcohol consumption and other liver disease), with the presence of hepatic steatosis in more than 5% of hepatocytes. NAFLD affects 25% to 35% of the general population, making it the most common cause of chronic liver disease. The rate increases among patients with obesity, 80% of whom are affected by NAFLD. 

NAFLD should be considered in patients with unexplained elevations in serum aminotransferases (without positive viral markers or autoantibodies and no history of alcohol use) and a high risk for steatohepatitis, including obesity. The standard NAFLD assessment for biopsy specimens is the Brunt system, and disease stage is determined using the NAFLD activity score and the amount of fibrosis present.

A study of the natural history of NAFLD in patients who were followed for 3 years showed that without pharmacologic intervention, one third experienced disease progression, one third remained stable, and one third improved. An independent risk factor for progression of nonalcoholic steatohepatitis was abnormal glucose tolerance testing. In another natural history study, a 10% higher rate of mortality over 10 years was demonstrated among those with NAFLD vs controls, with the top three causes of death being cancer, heart disease, and liver-related disease. Prevalence of chronic liver disease and cirrhosis has been shown to be elevated in Latino and Japanese American populations.

Patients with NAFLD should be seen regularly to assess for disease progression and receive guidance on weight management interventions and exercise. A weight loss of more than 5% has been shown to reduce liver fat and provide cardiometabolic benefits; a weight reduction of more than 10% can help reverse steatohepatitis or liver fibrosis. In addition to weight loss management strategies, physicians should discuss the importance of controlling hyperlipidemia, insulin resistance, and T2D with their patients and share the importance of avoiding alcohol and other hepatotoxic substances.

According to the American Association of Clinical Endocrinology Clinical Practice Guideline: "There are no U.S. Food and Drug Administration-approved medications for the treatment of NAFLD; however, some diabetes and anti-obesity medications can be beneficial. Bariatric surgery is also effective for weight loss and reducing liver fat in persons with severe obesity."

Courtney Whittle, MD, MSW, Diplomate of ABOM, Pediatric Lead, Obesity Champion, TSPMG, Weight A Minute Clinic, Atlanta, Georgia.

Courtney Whittle, MD, MSW, Diplomate of ABOM, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

The patient's history, symptomatology, and assessments suggest a diagnosis of nonalcoholic fatty liver disease (NAFLD). The primary care physician recommends referral to a hepatologist for evaluation and possible liver biopsy. 

NAFLD involves an accumulation of triglycerides and other fats in the liver (unrelated to alcohol consumption and other liver disease), with the presence of hepatic steatosis in more than 5% of hepatocytes. NAFLD affects 25% to 35% of the general population, making it the most common cause of chronic liver disease. The rate increases among patients with obesity, 80% of whom are affected by NAFLD. 

NAFLD should be considered in patients with unexplained elevations in serum aminotransferases (without positive viral markers or autoantibodies and no history of alcohol use) and a high risk for steatohepatitis, including obesity. The standard NAFLD assessment for biopsy specimens is the Brunt system, and disease stage is determined using the NAFLD activity score and the amount of fibrosis present.

A study of the natural history of NAFLD in patients who were followed for 3 years showed that without pharmacologic intervention, one third experienced disease progression, one third remained stable, and one third improved. An independent risk factor for progression of nonalcoholic steatohepatitis was abnormal glucose tolerance testing. In another natural history study, a 10% higher rate of mortality over 10 years was demonstrated among those with NAFLD vs controls, with the top three causes of death being cancer, heart disease, and liver-related disease. Prevalence of chronic liver disease and cirrhosis has been shown to be elevated in Latino and Japanese American populations.

Patients with NAFLD should be seen regularly to assess for disease progression and receive guidance on weight management interventions and exercise. A weight loss of more than 5% has been shown to reduce liver fat and provide cardiometabolic benefits; a weight reduction of more than 10% can help reverse steatohepatitis or liver fibrosis. In addition to weight loss management strategies, physicians should discuss the importance of controlling hyperlipidemia, insulin resistance, and T2D with their patients and share the importance of avoiding alcohol and other hepatotoxic substances.

According to the American Association of Clinical Endocrinology Clinical Practice Guideline: "There are no U.S. Food and Drug Administration-approved medications for the treatment of NAFLD; however, some diabetes and anti-obesity medications can be beneficial. Bariatric surgery is also effective for weight loss and reducing liver fat in persons with severe obesity."

Courtney Whittle, MD, MSW, Diplomate of ABOM, Pediatric Lead, Obesity Champion, TSPMG, Weight A Minute Clinic, Atlanta, Georgia.

Courtney Whittle, MD, MSW, Diplomate of ABOM, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

The patient's history, symptomatology, and assessments suggest a diagnosis of nonalcoholic fatty liver disease (NAFLD). The primary care physician recommends referral to a hepatologist for evaluation and possible liver biopsy. 

NAFLD involves an accumulation of triglycerides and other fats in the liver (unrelated to alcohol consumption and other liver disease), with the presence of hepatic steatosis in more than 5% of hepatocytes. NAFLD affects 25% to 35% of the general population, making it the most common cause of chronic liver disease. The rate increases among patients with obesity, 80% of whom are affected by NAFLD. 

NAFLD should be considered in patients with unexplained elevations in serum aminotransferases (without positive viral markers or autoantibodies and no history of alcohol use) and a high risk for steatohepatitis, including obesity. The standard NAFLD assessment for biopsy specimens is the Brunt system, and disease stage is determined using the NAFLD activity score and the amount of fibrosis present.

A study of the natural history of NAFLD in patients who were followed for 3 years showed that without pharmacologic intervention, one third experienced disease progression, one third remained stable, and one third improved. An independent risk factor for progression of nonalcoholic steatohepatitis was abnormal glucose tolerance testing. In another natural history study, a 10% higher rate of mortality over 10 years was demonstrated among those with NAFLD vs controls, with the top three causes of death being cancer, heart disease, and liver-related disease. Prevalence of chronic liver disease and cirrhosis has been shown to be elevated in Latino and Japanese American populations.

Patients with NAFLD should be seen regularly to assess for disease progression and receive guidance on weight management interventions and exercise. A weight loss of more than 5% has been shown to reduce liver fat and provide cardiometabolic benefits; a weight reduction of more than 10% can help reverse steatohepatitis or liver fibrosis. In addition to weight loss management strategies, physicians should discuss the importance of controlling hyperlipidemia, insulin resistance, and T2D with their patients and share the importance of avoiding alcohol and other hepatotoxic substances.

According to the American Association of Clinical Endocrinology Clinical Practice Guideline: "There are no U.S. Food and Drug Administration-approved medications for the treatment of NAFLD; however, some diabetes and anti-obesity medications can be beneficial. Bariatric surgery is also effective for weight loss and reducing liver fat in persons with severe obesity."

Courtney Whittle, MD, MSW, Diplomate of ABOM, Pediatric Lead, Obesity Champion, TSPMG, Weight A Minute Clinic, Atlanta, Georgia.

Courtney Whittle, MD, MSW, Diplomate of ABOM, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

After catching COVID-19 for the second time in July 2022, Daniel Lewis suffered persistent headaches, chest pain, and a dangerously high heart rate. He recalls that he was also so exhausted packing for a family wedding that he had to take a break to rest each time he put something into his suitcase.

Instead of attending the wedding, the 30-year-old Washington data analyst visited his doctor, who diagnosed “some postviral thing” and prescribed rest. Mr. Lewis found a new doctor, went to a long COVID clinic, and saw multiple specialists, but a year later, he’s still sick – and disabled. He meets the federal criteria for long COVID (symptoms that last more than 4 weeks).

He now uses an electric wheelchair whenever he leaves his apartment, a far cry from his pre-COVID life, when he was training for a half marathon.

“Some doctors have genuinely tried to help,” he said. “Most don’t really know what long COVID is, and ... since there’s no official guidance on what to do with long COVID patients, they just throw up their hands and say there’s nothing to do.”

That could be changing – at least the part about official guidance. New findings published in JAMA indicate we’re getting closer to unraveling what long COVID is all about and may help refine how it is defined and diagnosed. The study identified the 37 most common symptoms of long COVID, an important step toward better understanding and treatment of the condition, which affects an estimated 65 million people worldwide.

Although the study provides a way to systematically identify the condition, the authors were clear that this is significant but that it is only a first step. Naming symptoms is very different from understanding what causes them, and understanding them is critical for developing effective treatments, said pulmonologist Bruce Levy, MD, a study coauthor who is interim chair of medicine at Brigham and Women’s Hospital and a professor of medicine at Harvard Medical School, both in Boston.

Researchers relied on self-reported symptoms from the 9,764 participants, all adults who are part of the ongoing Researching COVID to Enhance Recovery (RECOVER) Initiative, a longitudinal study run by the National Institutes of Health. Some patients had long COVID when they signed up for the study, some developed it afterward, and some had never had it, or if they had, they were unaware.

Other studies, most of them involving smaller groups of patients, have examined long COVID biomarkers, risk factors, and specific symptoms. Dr. Levy said it’s important to have a symptom-based definition of long COVID that draws from a large cohort of patients who reported on their experiences with symptoms during the aftermath of infection. However, he pointed out that because participants volunteered for the study and were not chosen on the basis of specific criteria, they may not be representative of the more general population of patients with long COVID.

“We need this kind of evidence – it’s important to have self-reported symptoms, because clearly, the patients know what they’re feeling,” Dr. Levy said. “But it’s only part of the picture.”

Dr. Levy said the definition of long COVID needs to be further refined by ongoing research, including objective assessments of clinical findings, laboratory testing, imaging, and biomarkers.

One of the notable findings in the JAMA study is that certain symptoms tend to occur in clusters. The biostatisticians and analysts who processed the data identified four subgroups of very common symptoms that appeared together in more than 80% of the long COVID patients: loss of or change in smell and taste; postexertional malaise and fatigue; brain fog, postexertional malaise, and fatigue; and fatigue, postexertional malaise, dizziness, brain fog, gastrointestinal issues, and palpitations.

Many of those symptoms are also associated with underlying conditions not related to long COVID, which makes an accurate diagnosis a challenge.

“Just the fact that they would cluster into four groups suggests that underlying all this is not just one unifying pathobiology,” Dr. Levy said. He stressed that clinicians need to understand what’s causing the symptoms before they can properly treat patients.

He pointed out that two of the possible disease-driving mechanisms are persistence of the virus and prolonged inflammation that is slow to resolve. For patients experiencing inflammation after the virus is gone, an anti-inflammatory therapy would be most appropriate.

But if they have persistent virus, “you would want to treat with an antiviral antibiotic and not quiet down the body’s antiviral inflammatory response,” he said. “How you treat the two potential underlying causes of long COVID could thus be almost diametrically opposed, so that’s part of the importance of figuring out what is the underlying cause of those symptoms, not just identifying the symptoms themselves.”

More studies are needed to determine whether long COVID is a syndrome or is related to a singular pathobiology, experts said.

That’s consistent with the impression of long COVID researcher Harlan Krumholz, MD, the Harold H. Hines Jr. professor of medicine (cardiology) at Yale University, New Haven, Conn.

Dr. Krumholz worries that some clinicians might use the JAMA findings to dismiss patients whose symptoms meet the criteria in the scoring system developed for the study.

“It’s important for people who read this paper to know that this is preliminary,” said Dr. Krumholz, a principal investigator of another patient-focused study designed to understand long COVID – the Yale Listen to Immune, Symptom, and Treatment Experiences Now (LISTEN) Study. “It’s a condition we don’t understand yet.”

Dr. Krumholz said he has lost track of the number of patients he knows who, like Daniel Lewis, are ill and are unable to get answers. “There is an intense sense of inadequacy on the clinical side and the research side,” he said. “Every day people ask me, ‘Are there any evidence-based strategies?’ And so far I have to say, every day, ‘No.’ I hate to say it, but it’s kind of like every patient is on their own. They’re trying different things because they can’t wait. There is an imperative to help them.”

At the end of July, the National Institutes of Health launched phase 2 clinical trials to evaluate at least four new treatments for long COVID, all part of the RECOVER initiative. By then, Mr. Lewis, who believes his myalgic encephalomyelitis/chronic fatigue syndrome was triggered by the virus, had made plans to try an alternative, experimental therapy.

“My hope is that it will fix me,” he said. “I’m excited about those kinds of hard-hitting infusion, immunological treatment.”

As for the JAMA study, he didn’t allow himself to get excited when it was released, a function of his experience as a data analyst and long COVID patient.

“I don’t think it moves the needle much yet,” he said. “It’s the first study, and we shouldn’t expect much from the first pieces of data to come out of that. If they keep following that cohort and go deeper and deeper, they’re going to find some interesting stuff that will lead to treatments.”

A version of this article first appeared on Medscape.com.

After catching COVID-19 for the second time in July 2022, Daniel Lewis suffered persistent headaches, chest pain, and a dangerously high heart rate. He recalls that he was also so exhausted packing for a family wedding that he had to take a break to rest each time he put something into his suitcase.

Instead of attending the wedding, the 30-year-old Washington data analyst visited his doctor, who diagnosed “some postviral thing” and prescribed rest. Mr. Lewis found a new doctor, went to a long COVID clinic, and saw multiple specialists, but a year later, he’s still sick – and disabled. He meets the federal criteria for long COVID (symptoms that last more than 4 weeks).

He now uses an electric wheelchair whenever he leaves his apartment, a far cry from his pre-COVID life, when he was training for a half marathon.

“Some doctors have genuinely tried to help,” he said. “Most don’t really know what long COVID is, and ... since there’s no official guidance on what to do with long COVID patients, they just throw up their hands and say there’s nothing to do.”

That could be changing – at least the part about official guidance. New findings published in JAMA indicate we’re getting closer to unraveling what long COVID is all about and may help refine how it is defined and diagnosed. The study identified the 37 most common symptoms of long COVID, an important step toward better understanding and treatment of the condition, which affects an estimated 65 million people worldwide.

Although the study provides a way to systematically identify the condition, the authors were clear that this is significant but that it is only a first step. Naming symptoms is very different from understanding what causes them, and understanding them is critical for developing effective treatments, said pulmonologist Bruce Levy, MD, a study coauthor who is interim chair of medicine at Brigham and Women’s Hospital and a professor of medicine at Harvard Medical School, both in Boston.

Researchers relied on self-reported symptoms from the 9,764 participants, all adults who are part of the ongoing Researching COVID to Enhance Recovery (RECOVER) Initiative, a longitudinal study run by the National Institutes of Health. Some patients had long COVID when they signed up for the study, some developed it afterward, and some had never had it, or if they had, they were unaware.

Other studies, most of them involving smaller groups of patients, have examined long COVID biomarkers, risk factors, and specific symptoms. Dr. Levy said it’s important to have a symptom-based definition of long COVID that draws from a large cohort of patients who reported on their experiences with symptoms during the aftermath of infection. However, he pointed out that because participants volunteered for the study and were not chosen on the basis of specific criteria, they may not be representative of the more general population of patients with long COVID.

“We need this kind of evidence – it’s important to have self-reported symptoms, because clearly, the patients know what they’re feeling,” Dr. Levy said. “But it’s only part of the picture.”

Dr. Levy said the definition of long COVID needs to be further refined by ongoing research, including objective assessments of clinical findings, laboratory testing, imaging, and biomarkers.

One of the notable findings in the JAMA study is that certain symptoms tend to occur in clusters. The biostatisticians and analysts who processed the data identified four subgroups of very common symptoms that appeared together in more than 80% of the long COVID patients: loss of or change in smell and taste; postexertional malaise and fatigue; brain fog, postexertional malaise, and fatigue; and fatigue, postexertional malaise, dizziness, brain fog, gastrointestinal issues, and palpitations.

Many of those symptoms are also associated with underlying conditions not related to long COVID, which makes an accurate diagnosis a challenge.

“Just the fact that they would cluster into four groups suggests that underlying all this is not just one unifying pathobiology,” Dr. Levy said. He stressed that clinicians need to understand what’s causing the symptoms before they can properly treat patients.

He pointed out that two of the possible disease-driving mechanisms are persistence of the virus and prolonged inflammation that is slow to resolve. For patients experiencing inflammation after the virus is gone, an anti-inflammatory therapy would be most appropriate.

But if they have persistent virus, “you would want to treat with an antiviral antibiotic and not quiet down the body’s antiviral inflammatory response,” he said. “How you treat the two potential underlying causes of long COVID could thus be almost diametrically opposed, so that’s part of the importance of figuring out what is the underlying cause of those symptoms, not just identifying the symptoms themselves.”

More studies are needed to determine whether long COVID is a syndrome or is related to a singular pathobiology, experts said.

That’s consistent with the impression of long COVID researcher Harlan Krumholz, MD, the Harold H. Hines Jr. professor of medicine (cardiology) at Yale University, New Haven, Conn.

Dr. Krumholz worries that some clinicians might use the JAMA findings to dismiss patients whose symptoms meet the criteria in the scoring system developed for the study.

“It’s important for people who read this paper to know that this is preliminary,” said Dr. Krumholz, a principal investigator of another patient-focused study designed to understand long COVID – the Yale Listen to Immune, Symptom, and Treatment Experiences Now (LISTEN) Study. “It’s a condition we don’t understand yet.”

Dr. Krumholz said he has lost track of the number of patients he knows who, like Daniel Lewis, are ill and are unable to get answers. “There is an intense sense of inadequacy on the clinical side and the research side,” he said. “Every day people ask me, ‘Are there any evidence-based strategies?’ And so far I have to say, every day, ‘No.’ I hate to say it, but it’s kind of like every patient is on their own. They’re trying different things because they can’t wait. There is an imperative to help them.”

At the end of July, the National Institutes of Health launched phase 2 clinical trials to evaluate at least four new treatments for long COVID, all part of the RECOVER initiative. By then, Mr. Lewis, who believes his myalgic encephalomyelitis/chronic fatigue syndrome was triggered by the virus, had made plans to try an alternative, experimental therapy.

“My hope is that it will fix me,” he said. “I’m excited about those kinds of hard-hitting infusion, immunological treatment.”

As for the JAMA study, he didn’t allow himself to get excited when it was released, a function of his experience as a data analyst and long COVID patient.

“I don’t think it moves the needle much yet,” he said. “It’s the first study, and we shouldn’t expect much from the first pieces of data to come out of that. If they keep following that cohort and go deeper and deeper, they’re going to find some interesting stuff that will lead to treatments.”

A version of this article first appeared on Medscape.com.

After catching COVID-19 for the second time in July 2022, Daniel Lewis suffered persistent headaches, chest pain, and a dangerously high heart rate. He recalls that he was also so exhausted packing for a family wedding that he had to take a break to rest each time he put something into his suitcase.

Instead of attending the wedding, the 30-year-old Washington data analyst visited his doctor, who diagnosed “some postviral thing” and prescribed rest. Mr. Lewis found a new doctor, went to a long COVID clinic, and saw multiple specialists, but a year later, he’s still sick – and disabled. He meets the federal criteria for long COVID (symptoms that last more than 4 weeks).

He now uses an electric wheelchair whenever he leaves his apartment, a far cry from his pre-COVID life, when he was training for a half marathon.

“Some doctors have genuinely tried to help,” he said. “Most don’t really know what long COVID is, and ... since there’s no official guidance on what to do with long COVID patients, they just throw up their hands and say there’s nothing to do.”

That could be changing – at least the part about official guidance. New findings published in JAMA indicate we’re getting closer to unraveling what long COVID is all about and may help refine how it is defined and diagnosed. The study identified the 37 most common symptoms of long COVID, an important step toward better understanding and treatment of the condition, which affects an estimated 65 million people worldwide.

Although the study provides a way to systematically identify the condition, the authors were clear that this is significant but that it is only a first step. Naming symptoms is very different from understanding what causes them, and understanding them is critical for developing effective treatments, said pulmonologist Bruce Levy, MD, a study coauthor who is interim chair of medicine at Brigham and Women’s Hospital and a professor of medicine at Harvard Medical School, both in Boston.

Researchers relied on self-reported symptoms from the 9,764 participants, all adults who are part of the ongoing Researching COVID to Enhance Recovery (RECOVER) Initiative, a longitudinal study run by the National Institutes of Health. Some patients had long COVID when they signed up for the study, some developed it afterward, and some had never had it, or if they had, they were unaware.

Other studies, most of them involving smaller groups of patients, have examined long COVID biomarkers, risk factors, and specific symptoms. Dr. Levy said it’s important to have a symptom-based definition of long COVID that draws from a large cohort of patients who reported on their experiences with symptoms during the aftermath of infection. However, he pointed out that because participants volunteered for the study and were not chosen on the basis of specific criteria, they may not be representative of the more general population of patients with long COVID.

“We need this kind of evidence – it’s important to have self-reported symptoms, because clearly, the patients know what they’re feeling,” Dr. Levy said. “But it’s only part of the picture.”

Dr. Levy said the definition of long COVID needs to be further refined by ongoing research, including objective assessments of clinical findings, laboratory testing, imaging, and biomarkers.

One of the notable findings in the JAMA study is that certain symptoms tend to occur in clusters. The biostatisticians and analysts who processed the data identified four subgroups of very common symptoms that appeared together in more than 80% of the long COVID patients: loss of or change in smell and taste; postexertional malaise and fatigue; brain fog, postexertional malaise, and fatigue; and fatigue, postexertional malaise, dizziness, brain fog, gastrointestinal issues, and palpitations.

Many of those symptoms are also associated with underlying conditions not related to long COVID, which makes an accurate diagnosis a challenge.

“Just the fact that they would cluster into four groups suggests that underlying all this is not just one unifying pathobiology,” Dr. Levy said. He stressed that clinicians need to understand what’s causing the symptoms before they can properly treat patients.

He pointed out that two of the possible disease-driving mechanisms are persistence of the virus and prolonged inflammation that is slow to resolve. For patients experiencing inflammation after the virus is gone, an anti-inflammatory therapy would be most appropriate.

But if they have persistent virus, “you would want to treat with an antiviral antibiotic and not quiet down the body’s antiviral inflammatory response,” he said. “How you treat the two potential underlying causes of long COVID could thus be almost diametrically opposed, so that’s part of the importance of figuring out what is the underlying cause of those symptoms, not just identifying the symptoms themselves.”

More studies are needed to determine whether long COVID is a syndrome or is related to a singular pathobiology, experts said.

That’s consistent with the impression of long COVID researcher Harlan Krumholz, MD, the Harold H. Hines Jr. professor of medicine (cardiology) at Yale University, New Haven, Conn.

Dr. Krumholz worries that some clinicians might use the JAMA findings to dismiss patients whose symptoms meet the criteria in the scoring system developed for the study.

“It’s important for people who read this paper to know that this is preliminary,” said Dr. Krumholz, a principal investigator of another patient-focused study designed to understand long COVID – the Yale Listen to Immune, Symptom, and Treatment Experiences Now (LISTEN) Study. “It’s a condition we don’t understand yet.”

Dr. Krumholz said he has lost track of the number of patients he knows who, like Daniel Lewis, are ill and are unable to get answers. “There is an intense sense of inadequacy on the clinical side and the research side,” he said. “Every day people ask me, ‘Are there any evidence-based strategies?’ And so far I have to say, every day, ‘No.’ I hate to say it, but it’s kind of like every patient is on their own. They’re trying different things because they can’t wait. There is an imperative to help them.”

At the end of July, the National Institutes of Health launched phase 2 clinical trials to evaluate at least four new treatments for long COVID, all part of the RECOVER initiative. By then, Mr. Lewis, who believes his myalgic encephalomyelitis/chronic fatigue syndrome was triggered by the virus, had made plans to try an alternative, experimental therapy.

“My hope is that it will fix me,” he said. “I’m excited about those kinds of hard-hitting infusion, immunological treatment.”

As for the JAMA study, he didn’t allow himself to get excited when it was released, a function of his experience as a data analyst and long COVID patient.

“I don’t think it moves the needle much yet,” he said. “It’s the first study, and we shouldn’t expect much from the first pieces of data to come out of that. If they keep following that cohort and go deeper and deeper, they’re going to find some interesting stuff that will lead to treatments.”

A version of this article first appeared on Medscape.com.