Key points

Introduction

In the wake of the coronavirus disease 2019 (COVID-19) pandemic, the world faces a new challenge beyond the acute phase of infection: long COVID. Emerging as a consequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, Long COVID or post-acute sequelae of SARS-CoV-2 (PASC) presents a complex and prolonged disease course that extends far beyond the initial acute illness with different definitions putting a time course of anywhere from symptoms at 4 weeks to 3 months and lasting years. Defined by a myriad of new, recurring, or ongoing fluctuating and unpredictable signs and symptoms persisting after an acute COVID-19 infection, long COVID can impact many organ systems including respiratory, vascular, cardiac, neurologic, autonomic, gastrointestinal, immunologic, endocrinologic, and musculoskeletal. Other terms have been used to refer to this disease state including the aforementioned PASC, post-COVID syndrome, and post-COVID conditions. This article will use long COVID, a term created by the patient community and now given a standardized definition by the National Academy of Science, Engineering, and Medicine.

Delving into the history and background of long COVID unveils a landscape rife with unanswered questions and evolving understanding as often occurs with infection-associated chronic conditions. Initially characterized by its association with acute COVID-19 infection, long COVID has since emerged as a distinct entity, marked by its persistence and variability in symptomatology. Despite concerted efforts to unravel its pathophysiological mechanisms and identify risk factors, diagnostic and treatment modalities for long COVID remain inadequate.

An intriguing aspect of long COVID lies in its disproportionate impact on women. While mortality and acute morbidity from COVID-19 infection tend to be lower in females compared to males, females find themselves overrepresented among patients grappling with long COVID. Women are more likely than men to ever have long COVID, and women are also more likely than men to currently have long COVID. Notably, factors traditionally associated with a heightened risk of severe acute COVID-19, such as advanced age or male sex, fail to align with the increased prevalence of long COVID among women. The reasons underlying disparities in sex and gender distribution between acute and chronic COVID-19 manifestations continue to elude definitive explanation but are being researched.

This article explores considerations specific to the rehabilitation of women affected by long COVID. Identifying that there have always been well-known health disparities for females—who are also more impacted by other infection-associated chronic conditions like myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) or dysautonomia coronavirus disease 2019—it is essential to recognize the health equity concerns and provide the best rehabilitation care for these individuals. Multi-disciplinary collaborative consensus guidance statements have been developed that address multiple symptoms related to long COVID (eg, fatigue, cognitive deficits, cardiovascular sequelae, respiratory sequelae, autonomic dysfunction, neurologic disorders, mental health conditions, and pediatric impacts ). These statements specifically also address issues related to health equity inclusive of assessments and solutions to address biologic sex differences. By considering the historic context of stigmatized infection-associated chronic conditions and understanding the background of long COVID’s multiple signs, symptoms, and related conditions, we aim to shed light on the unique challenges and opportunities in addressing long COVID in this demographic. Through a comprehensive understanding of the intersection between sex, gender, and long COVID, we hope to pave the way for more effective rehabilitation strategies tailored to the needs of women enduring the lingering effects of this novel coronavirus.

Epidemiology

The estimated prevalence of long COVID varies depending on how studies define long COVID, the population studied, and the methodology. A global metanalysis systematic review reported the prevalence to be 54% for hospitalized patients and 34% for non-hospitalized, with a wide range contributing to this estimate (9%–81%). Albeit wide ranges in overall prevalence, they all consistently reported higher prevalence in females (49%) versus males (37%). The Centers for Disease Control estimates that 6.9% of all US adults have experienced long COVID. Women are predominantly affected (8.5%) compared to males (5.2%), with over 14 million American women living with long COVID. A large cross-sectional US study identified middle age, female sex, lack of a college degree, and severity of acute COVID-19 infection as risk factors for long COVID. UK data on non-hospitalized patients with Long COVID noted risk factors including female sex, belonging to an ethnic minority, socioeconomic deprivation, smoking, and obesity, with an increased risk along a gradient of decreasing age.

Several theoretic explanations are proposed to explain the female preponderance in Long COVID, including hormonal differences that perpetuate a hyperinflammatory status, stronger immunoglobulin G production, and the hypothesis that women are generally more attentive to their body and related distress. Long COVID shares similar features with post-acute infectious syndromes, such as ME/CFS and post-treatment Lyme disease, which also disproportionately affect female patients. In 1970, 2 psychiatrists in the United Kingdom (UK) reviewed reports of 15 outbreaks of benign ME. They concluded that these outbreaks were psychosocial phenomena caused by one of two mechanisms, either mass hysteria on the part of the patients or altered medical perception of the community . They based their conclusions on the higher prevalence of the disease in females and the lack of physical signs in these patients. The historic perception that the etiology of these clinical entities is non-organic has pervaded through modern medicine, which as a community, generally questions the existence or seriousness of this disease in females. Scientific advancement and a growing interest in understanding sex differences promise to advance the biologic underpinnings of the factors playing a role in the high female prevalence.

Clinical presentation

Assessment/evaluation

The comprehensive assessment and evaluation protocol for long COVID patients is designed to address the multifaceted nature of this condition, recognizing its wide-ranging impacts on physical health, cardiopulmonary health, neurologic function, cognitive abilities, and mental well-being. Beyond the initial evaluation, ongoing monitoring over time and management are essential components of care. Regular reassessment of activity performance and functional status allows for adjustments in treatment strategies to meet evolving patient needs. By incorporating standardized measures and patient-reported outcomes, health care providers can track progress, identify areas of improvement, and tailor interventions accordingly. Moreover, the psychosocial aspect of long COVID cannot be understated. The integration of mental health screening and consideration of social determinants of health ensures a holistic approach to patient-care. Collaborative efforts with specialists across disciplines facilitate a comprehensive understanding of the condition and enable a coordinated approach to management. Regular follow-up appointments serve not only to monitor physical and cognitive progress but also to provide ongoing support and guidance to patients as they navigate the challenges of long COVID.

Performing a thorough physical examination is crucial for both ruling out treatable causes of the presenting symptoms and for clinically diagnosing long COVID. This examination should be preceded by a detailed history that also characterizes the severity of symptoms experienced and their impact on quality-of-life. Key areas of focus during the physical examination include neurologic, cardiovascular, pulmonary, musculoskeletal, and psychiatric assessments. It is important to review vital signs and consider additional components such as 10-minute passive stand test for those with postural symptoms, dizziness, fatigue, cognitive impairment, or malaise. Ambulatory pulse oximetry may be warranted for those with respiratory symptoms, fatigue, or malaise. Given the high prevalence of autonomic dysfunction and orthostatic intolerance in women with long COVID, further autonomic testing could include a National Aeronautics and Space Administration (NASA) lean test, tilt table testing, and/or thermoregulatory sweat testing.

In evaluating persons who menstruate and pregnant persons with long COVID, a comprehensive and sensitive approach is paramount. Health care providers should consider the unique physiologic and hormonal influences that may influence symptom presentation and severity. The history should include menstruation history and exogenous hormone use. Pregnant individuals may also require alternative diagnostic testing that prioritizes the safety of both the woman and the developing fetus while ensuring accurate diagnosis and appropriate management of the health condition. See Table 1 for selected considerations and recommendations related to biologic sex and gender.

Finally, as our understanding of long COVID evolves, it becomes necessary to adopt a flexible and adaptive approach to both assessment and management. Ongoing research into the long-term effects of COVID-19 plays a pivotal role in informing clinical practice and will prompt refinements in treatment protocols and rehabilitation strategies. Continuous education and training for health care professionals are vital to keep pace with emerging evidence and best practices in the care of individuals with long COVID. By remaining receptive to evolving knowledge and patient needs, health care teams can uphold the delivery of high-quality, evidence-based care.

Pathogenesis

As research on long COVID starts to shed light on the pathophysiologic mechanisms involved, a growing number of publications highlight persistent inflammation and immune activation as a key feature of long COVID but without considering how females are more likely than males to experience these symptoms. A recent sex difference study in long COVID highlights the potentially crucial role of immune-endocrine dysregulation in sex-specific pathology. They found an overall higher symptom burden in females, an immune profile with exhausted T-cells, cytokine-secreting T cells, higher antibody reactivity to latent herpes viruses including epstein-barr virus (EBV), herpes simplex virus-2 (HSV-2), and cytomegalovirus (CMV), and lower testosterone levels than controls. Interestingly, higher testosterone levels were significantly associated with lower symptom burden in long COVID participants over sex designation.

There is also evidence on how the menstrual cycle influences long COVID symptoms, with over one-third of pre-menopausal women with long COVID experiencing worsening of premenstrual symptoms and/or exacerbation of long COVID symptoms related to their menstrual cycle. Women experiencing long COVID are often middle-aged and may also be experiencing symptoms and hormonal changes associated with peri-menopause and post-menopause syndromes. Another study reported changes in menstrual cycle duration, bleeding between periods, increased menstrual flow, and missed periods associated to long COVID.

Regarding acute COVID-19, males are at higher risk than females for severe disease and carry a higher risk of mortality. ^, The plausible mechanisms behind this finding are the upregulation of ACE2 receptors in the lungs mediated by testosterone, imbalance of expression on genes, epigenetic modification, and direct effects of sex hormones on immunologic pathways. ^,

Burden of disease

Individuals with long COVID report protracted, multisystem derangement resulting in significant disability. Women have an additional burden not only on the physiologic effects of long COVID, but also with the societal consequences of ongoing disability after COVID-19 infection. Loss of school and work participation is especially common in young women, having psychological and economic consequences. By 7 months, many patients express significant ongoing symptoms and are unable to return to previous levels of work. Due to persistent illness, nearly half of the unrecovered respondents were working reduced hours, and 23.3% were unable to work. Individuals with long COVID have a myriad of concerns that plague (eg, applying for sick leave, qualifying for disability leave, being fired from their current position, quitting their employment, and being unable to find a job that will accommodate them). Autonomic dysfunction in long COVID has been shown to have a substantial impact on an individual’s functioning and quality-of-life in the short-term, medium-term, and long-term. In a study involving 20 patients with long COVID (70% female), residual autonomic symptoms persisted in 85% of participants 6 to 8 months after COVID-19, with 60% unable to return to work. Halloot and colleagues investigated a sample of 40 long COVID POTS patients and found that disabling symptoms persisted in 100% of previously high-functioning participants even after 6 months, indicating the enduring impact of long COVID POTS. Studies show that women, people of color, sexual and gender minorities, and people without college degrees are more likely to have symptoms of long COVID and resultant activity limitations from long COVID. ^, Clinical care should take into account social determinants of health to overcome barriers including economic (medical expenses, lack of insurance, etc.), geographic (underserved areas, access to care, etc.), housing, and segregation, and occupational factors that negatively impact vulnerable and minoritized populations. ^,

Management in women and in pregnancy

The current medical interventions for long COVID are based on symptomatic management, and there are no Food and Drug Administration-approved medications for the treatment of post-COVID Conditions. The Multidisciplinary PASC Collaborative of the American Academy of Physical Medicine and Rehabilitation (AAPM&R) has published guidance statements with recommendations on the pharmacologic management of common long COVID presentations. Special consideration should be given regarding medication management for autonomic dysfunction in the female patient, particularly those of reproductive age. Most first-line medications are considered category C for pregnancy, meaning the increased risk during pregnancy cannot be ruled out. There are no pregnancy or lactation studies on fludrocortisone specifically; however, the data concerning glucocorticoid use in pregnancy suggest an increased risk for cleft palate and possible impaired fetal growth and an otherwise a relatively safe profile. The American Academy of Pediatrics classifies glucocorticoids as compatible with breastfeeding. As midodrine is an alpha-1 agonist, there is a theoretic concern that it might cause uterine arterial constriction and therefore be associated with intra-uterine growth retardation. There are no abundant human data on pregnancy or lactation concerning this agent. The pregnancy data for propranolol have not indicated an increased risk for teratogenicity; however, an association with neonatal apnea, respiratory distress, bradycardia, and hypoglycemia has been suggested. The American Academy of Pediatrics classifies propranolol as compatible with breastfeeding. Second-line agent use in the management of POTS, pyridostigmine, has no data indicating an increased risk for teratogenicity or adverse perinatal outcomes and is classified as category B for pregnancy. The World Health Organization and the American Academy of Pediatrics classify pyridostigmine as compatible with breastfeeding. Patients being started on ivabradine, a second-line medication used for heart rate control in POTS, must be advised to use contraception as this medication is considered category D for pregnancy. Animal studies have revealed evidence of embryo fetal toxicity, teratogenicity, increased post-implantation loss, and increased intrauterine and postnatal mortality. There are no controlled data on human pregnancy for ivabradine.

From a clinical perspective, it is notable that during pregnancy, patients often notice that they have better control of their orthostatic symptoms, usually beginning at the end of the first trimester. This occurs in part because blood volume is increased by about 2 L during pregnancy. This often enables a reduction or elimination of helpful medications before the pregnancy.

Discussion

Early in the pandemic, when intensive care units (ICUs) were full of gravely ill patients, physiatrists, and rehabilitation professionals provided rehabilitative care for persons who were impacted by more severe SARS-CoV-2 infections. Once deemed less/non-contagious, hospitalized patients with COVID-19 began to get therapy services based on prior protocols developed for ICU rehabilitation, including for ventilated patients. This was at times limited by access to personal protective equipment and fears of the spread of an airborne virus outside of the room. Despite the gravity of the situation and at times the need to close rehabilitation units, the field of rehabilitation medicine stepped up to provide rehabilitation across the continuum for persons with sequelae of COVID-19. ^, Inpatient rehabilitation units/hospitals prepared themselves and also began to take patients with effects of critical illness, transplants, strokes, and other devastating sequelae of COVID-19. ^, Much of the rehabilitations occurred in hospitals and inpatient units at the start of the pandemic and then there was a realization of a new group of persons who were not hospitalized were having ongoing or new symptoms requiring attention and rehabilitation services. Those persons who often developed long COVID had mild initial infections and did not get any medical attention early in the pandemic. Again, physiatrists stepped up to address this gap to address the many needs of patients with long COVID.

A comprehensive rehabilitation plan should be created based on a patient’s specific diagnosis and symptoms. Timing of initiation can occur concurrently with additional workup if there is low concern for an urgent or life-threatening additional disease process. Services considered should include physical therapy, occupational therapy, speech and language therapy, vocational therapy (along with guidance for return-to-work with or without accommodations), and neurologic rehabilitation for cognitive symptoms, including neuropsychologist evaluation and treatment. Some patients may also benefit from a multidisciplinary team inclusive of social work, psychology, and nutrition.

A physiatrist can help create a rehabilitation plan, inclusive of an individualized return to activity program. Specification of duration and intensity is recommended as some patients (those with PEM and fatigue) may benefit from much slower-paced rehabilitation strategies. ^, The strategy of the 4 P’s can be used in determining a rehabilitation plan: pacing, prioritizing, positioning, and planning. Pacing avoids PEM and/or a crash following activity that is too intense for the patient’s current functional level, which could result in prolonged periods of more intense fatigue and functional limitations. Prioritizing works on energy conservation strategies in identifying necessary tasks to prevent overexertion that may come from tackling additional tasks that can be postponed or avoided. Positioning involves modifying the placement of items to make activities easier, such as using a shower chair. Planning allows patients to plan ahead into the week by matching activities to times during the week and/or days when they may experience relatively higher energy levels.

Individuals with cognitive impairment can benefit from speech and language therapy for cognitive evaluation and treatment, as well as a neuropsychology evaluation and treatment. Those who experience mental fatigue may also benefit from pacing of cognitive activity with gradual increase as tolerated. Other neurologic and neuromuscular symptoms may benefit from aqua therapy, vision therapy, vestibular therapy, olfactory training, and/or taste recall training programs. Therapeutic modalities can be considered for musculoskeletal and pain-related symptoms (ice/heat, myofascial release, massage, transcutaneous electrical stimulation, kinesiotaping, and desensitization techniques).

Individuals with cardiac symptoms may benefit from cardiac rehabilitation with monitoring and pacing of their activity level with a gradual increase as tolerated. However, those with new cardiac diagnoses should receive cardiac clearance prior to participation. ^, Those with pulmonary symptoms may benefit from a formal pulmonary rehabilitation program, as well as breathing techniques and airway clearance exercises and/or devices. Of note, insurance coverage for outpatient pulmonary rehabilitation was expanded to include those with suspected or confirmed COVID-19 who are experiencing persistent pulmonary symptoms for at least 4 weeks.

Autonomic rehabilitation programs should be considered for those with orthostatic intolerance or dysautonomia. Recumbent, semi-recumbent, and mat-level exercises can be utilized in those who have trouble maintaining or excessive symptoms in a standing position. Breathwork exercise, careful titration of exercises, and restorative and adaptive therapies are important components for these patients. ^, There have also been case reports for enhanced external counterpulsation as a suitable treatment method for autonomic dysfunction, fatigue, and cognitive dysfunction. ^, It cannot be understated that rehabilitation strategies after COVID-19 are individualized. The rehabilitation team should help avoid acute events and symptom flare-ups, facilitate expectations, provide psychological and emotional support, and in some cases, improve/maintain general function.

A challenge exists in rehabilitating individuals with long COVID who exhibit a phenotype similar to ME/CFS. The Institute of Medicine 2015 diagnostic criteria for ME/CFS include daily activity limiting profound fatigue for greater than 6 months, post-exertional malaise, and unrestful sleep, as well as the presence of cognitive dysfunction and/or orthostatic intolerance. These symptoms do overlap with those of long COVID and require careful consideration when creating a rehabilitation plan tailored to the specific needs and limitations of the individual. Traditional approaches such as graded exercise therapy (GET) may not be suitable for the subgroup of long COVID patients that present with PEM and or meet diagnostic criteria for ME/CFS. GET can inadvertently exacerbate symptoms of PEM and fatigue in this population. ^, Similarly, excessive aerobic or cognitive activity may also prove detrimental, triggering symptom flare-ups and prolonging recovery. It is crucial for clinicians to adopt a cautious and individualized approach to return-to-activity, prioritizing symptom management and pacing strategies over aggressive exercise regimens. In developing rehabilitation plans for individuals with long COVID resembling ME/CFS, interdisciplinary collaboration among health care professionals—physicians, nurses, physical therapists, occupational therapists, speech and language pathologists, and mental health professionals—is essential. The goal of rehabilitation in this population is not to push individuals beyond their energy envelope but rather to support them in improving functional capacity, reducing the frequency and intensity of PEM episodes, managing symptoms, and enhancing overall well-being and quality-of-life. By recognizing the potential complications associated with traditional rehabilitation approaches (eg, GET) and adopting a holistic patient-centered approach, clinicians can better support individuals with long COVID on their journey toward recovery.

There are specific considerations for long COVID rehabilitation in those with biologic sex differences, including pregnant persons, persons who menstruate, and persons who may be lactating. Some of these are expanded on in Table 1 , which comes from the AAPM&R consensus guidance statements. As always, clinicians should be aware of sex-related bias, which may add to diagnostic delays faced by female patients. This has occurred in women with dysautonomia who have been told their palpitations are due to stress and therefore delaying a diagnosis of POTS. Even prior to the pandemic, women were underdiagnosed and undertreated for cardiac conditions, inclusive of cardiac rehabilitation programs. Given this, clinicians must work to ensure equitable care and referrals. Given their changing physiology, pregnant people may experience pregnancy-related fatigue and require alternative diagnostic testing and treatment to differentiate the fatigue from long COVID. Gender-affirming care should be considered regarding its impact on fatigue (eg, exogenous hormone use, sleep, and mental health). Pregnant people may also have baseline respiratory discomfort that can be exacerbated by the effects of COVID-19. Furthermore, therapy may need to be adjusted for pregnant persons given limitations to positioning later in pregnancy. Clinicians should be aware of sex-related bias, which may add to diagnostic delays faced by female patients. Finally, when pharmaceutical treatments are being considered for pregnant or lactating persons, the pregnancy category of medications must be looked at to see if they are appropriate to be given during pregnancy or while lactating.

More research and clinical understanding of the impacts of acute COVID-19 and long COVID on historically marginalized and underrepresented populations, including females, are needed. The goal will be for clinicians to provide access to more effective rehabilitative care for all persons with long COVID.

Challenges

The challenges surrounding long COVID and other infection-associated chronic conditions underscore a longstanding issue of underfunding and under-research related to these topics in health care systems worldwide. Historically, diseases that do not fit neatly into established categories or lack immediate, high-profile attention often struggle to secure the resources necessary for thorough investigation and treatment development. Long COVID, with its complex and varied persisting symptoms, exemplifies this disparity in research and funding allocation. As previously discussed, the individuals most affected by long COVID and similar conditions often find themselves marginalized within health care systems. Women, in particular, who have higher rates of long COVID, report their experiences are frequently dismissed or minimized. This further exacerbates the under-researched nature of these conditions, perpetuating a cycle of neglect and inadequate support.

Addressing these challenges requires a concerted interdisciplinary effort. Health care professionals, researchers, policymakers, patients, and advocacy groups must come together to advocate for increased funding and dedicated research into long COVID and related infection-associated chronic conditions. This interdisciplinary approach is crucial for understanding the multifaceted nature of these illnesses and developing comprehensive, patient-centered health care strategies. In addition to increased funding and research, there is a pressing need to reconstruct healthcare policy to prioritize the needs of those affected by long COVID and similar conditions. This includes ensuring that marginalized groups have equitable access to health care services and are actively involved in decision-making processes that affect their care. Creating advocacy platforms for these groups to voice their concerns and experiences is essential for promoting inclusivity and improving outcomes.

The COVID-19 pandemic exposed pre-existing health care disparities and magnified the intricate intersectionality faced by women who are from racial/ethnic minoritized groups. Across the spectrum of COVID-19 impacts, persons from racial/ethnic minoritized groups have borne a disproportionate burden, experiencing higher rates of acute infection, hospitalization, hospital readmission, death, and are now grappling with the enduring challenges of long COVID. ^, Within this context, inequities persist for individuals with long COVID who require specialized rehabilitation care, with historic trends indicating they are less likely to access the comprehensive support they require. Addressing these disparities demands a multifaceted approach that acknowledges the complex interplay of race, gender, and health care access, ensuring that marginalized communities are not further marginalized in their journey toward recovery.

Summary

Dedicated research and further clinical guidance are needed to provide equitable, culturally competent, and individualized care to women with long COVID. Addressing the challenges associated with long COVID and other infection-associated chronic conditions requires a shift in health care systems toward a more holistic and patient-centered approach. By recognizing and actively working to overcome the disparities that exist, we can strive toward better outcomes and decreased disability for women and all individuals affected by these conditions.

Clinics care points

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  Women are overrepresented and overburdened in long COVID and may face unique challenges in diagnosis and management.

  
  
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  Common symptoms of long COVID in women may include fatigue, cognitive dysfunction, respiratory issues, cardiac symptoms, and autonomic dysfunction, but there are many more.

  
  
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  Individualized and situation-dependent treatment is needed when caring for individuals with long COVID.

  
  
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  Biologic sex differences must be considered regarding symptom presentation, response to treatment, and health care needs. Clinicians should be mindful of the impact of pregnancy, menstruation, and lactation on long COVID symptoms and treatment.

  
  
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  Recognize and address the psychological impact of long COVID on women, but clinicians should not psychologize their symptoms.

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