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What should I, as a pharmacist, know about long-COVID?

Background

There have been great strides to track, identify, treat, and monitor coronavirus disease 2019 (COVID-19) since its emergence and declaration as a global pandemic.1 One of the biggest challenges to identification and treatment of this novel infectious disease is the heterogeneity of signs and symptoms as well as the time for recovery. While it was initially believed that COVID-19 was mainly associated with acute symptoms, it is not uncommon for infected patients to report prolonged illness, often described as ‘long COVID.’ The Centers for Disease Control and Prevention (CDC) reported that even in young adults, without underlying medical conditions, recovery from COVID-19 can take a long time, with approximately 1 in 5 patients reporting not having returned to their usual state of health by 14 to 21 days.2

While some sources have estimated that only 10% of infected patients remain unwell beyond 3 weeks, other studies have shown that long COVID prevalence is likely much higher.3 One study in Italy reported that 87.4% of 143 patients had at least 1 persistent symptom after a mean of 60 days following initial symptom onset.4 Moreover, a study in China revealed that 76% of 1655 patients experienced at least 1 symptom at approximately 6 months after acute infection.5 The variability in prevalence in these studies could be due to the differences in patient population, severity of the COVID-19 outbreak, and follow-up time. However, what is evident from all these studies is that long COVID seems to be a common problem that patients and clinicians will encounter, and more information is becoming available.

Definitions

Because long-COVID is an emerging condition that has only been recently identified, numerous terms have been used to describe COVID-19’s long-term effects including long COVID, long-haul COVID, and chronic COVID syndrome.6,7 Sometimes, these long-term effects could be referred to by terms not specific to COVID-19 such as post-viral fatigue syndrome.8 The framework for defining the different phases of the illness is not well established, but the National Institute for Health and Care Excellence (NICE) has COVID-19 guidelines with definitions to categorize the timeline of the disease course.9,10 The guideline defines acute COVID-19 as signs and symptoms for up to 4 weeks and describes long COVID as any signs and symptoms that continue or develop after acute COVID-19. Long COVID can be classified into ongoing symptomatic COVID-19 or post-COVID-19 syndrome. Ongoing symptomatic COVID-19 is defined as signs and symptoms from 4 weeks to 12 weeks, whereas post-COVID-19 syndrome is defined as signs and symptoms that persist for more than 12 weeks that cannot be explained by an alternative diagnosis. Similarly, the CDC has proposed defining late sequelae as manifestations that extend beyond 4 weeks after the initial symptom onset.11

Possible Pathophysiology

The pathogenic mechanism of COVID-19 is still under investigation and there is yet to be a clear answer as to why only some patients experience long COVID.3,6,9  It has been proposed that the variation in viral load and differential immune response can play a role in COVID-19 sequelae.6 Persistent viral load and the type of immune response, related to the varying human histocompatibility antigen subtypes in individuals, could lead to the chronicity of COVID symptoms in a subset of patients. Moreover, long COVID sequelae could manifest due to organ damage from the acute phase of the infection.12,13 Other potential factors include persistent hyperinflammatory state, ongoing viral activity associated with a host viral reservoir, and inadequate antibody response.3,12

Clinical Presentation

Clinical presentation of long COVID is highly variable and can involve multiple organ systems including respiratory, cardiovascular, neurological, gastrointestinal, musculoskeletal, psychiatric, dermatologic, ear/nose/throat, and other general symptoms.10 Fatigue is the most commonly reported, followed by dyspnea/breathlessness. Other commonly reported symptoms include, but are not limited to, chest pain, palpitations, cognitive impairment, muscle pain, gastrointestinal upset, and skin rashes. Consequently, patients often report overall decreased quality of life impacting their return to work and physical activity.14

Table 1 summarizes the results of early studies that aimed to investigate the long-term consequences of COVID-19.2,4,5,14,15 Literature is continuously being published; therefore, this table likely does not reflect recently published articles. Because of the high variability in time to recovery, follow-up times are not standardized in these studies. Moreover, COVID-19 symptoms can persist regardless of initial severity of disease and therefore diverse populations, treated both inpatient and outpatient in different countries, have been investigated.

Table 1. Summary of select studies that describe persistent COVID-19 symptoms2,4,5,14–16
Author, Publication Date, Country
Care Setting
Follow-up Time (days)
≥1 Symptom at Follow-up
Most Common Symptoms*
Carfi et al., July 2020, Italy4Outpatient
60.3¥125/143 (87.4%)
All patients (n=125): fatigue (53.1%), dyspnea (43.4%), arthralgia (27.3%)
Halpin et al., July 2020, UK15 
ICU or hospital ward managed
48§NR
ICU (n=32): fatigue (72%), breathlessness (65.6%), PTSD (46.9%)
Hospital ward (n=68): fatigue (60.3%), breathlessness (42.6%), PTSD (23.5%)
Tenforde et al., July 2020, USA2Outpatient
16**¥¥59/175 (34%)
All patients (n=59): cough (43%), fatigue (35%), and dyspnea (29%)
Garrigues et al., Aug 2020,
France14		ICU and hospital ward managed
110.9§§NR
All patients (n=120): fatigue (55%), dyspnea (42%), loss of memory (34%)
Carvalho-Schneider et al., Oct 2020, France16Hospitalized and outpatient
59.7§§86/130 (66.1%)
All patients (n=130): asthenia (22.7%), flu-like symptoms^^ (21.5%), weight loss (17.2%)
Huang et al., Jan 2021, China5Hospitalized
186***1265/1655 (76%)
All patients (n=1265): fatigue or muscle weakness (63%), sleep difficulties (26%), hair loss (22%)
Abbreviations: ICU=intensive care unit; NR=not reported; PTSD=post-traumatic stress disorder
* Top 3 most common symptoms reported in the study; see full article for additional reported symptoms.
¥ Mean days since first onset of COVID-19 symptoms. 
§ Mean days since hospital discharge.
** Median days since testing positive for COVID-19. 
¥¥ Not considered long COVID based on the NICE guideline definitions.
§§ Mean days since admission.
^^ Myalgia, headache, and/or asthenia.
*** Median days since first onset of COVID-19 symptoms.

Diagnosis

Unfortunately, there is no agreed-upon diagnosis criteria for long COVID so far.1,9 The most common symptom, fatigue, is nonspecific and often has multifactorial etiologies. The presence of other symptoms is highly variable in patients and difficult to distinguish from other possible underlying conditions. Based on the NICE guidelines, long COVID identification involves suspected or confirmed acute COVID-19 displaying prolonged signs and symptoms beyond 4 weeks and ruling out alternative diagnoses.9 The guideline suggests using a screening questionnaire as a part of the initial consultation to help capture all of the possible symptoms in conjunction with clinical assessment. There has also been a proposed diagnostic criteria for long COVID which accounts for clinical features, throat swab reverse transcription polymerase chain reaction, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody, computed tomography thorax or chest Xray, history of contact with confirmed or suspected case of COVID-19, community spread, and duration of illness.17

The NICE guideline for managing the long-term effects of COVID-19 also recommends developing and validating new and existing screening tools to identify long COVID.9 Some institutions have already adopted such classification systems. For instance, the multi-disciplinary COVID-10 Clinic at The University of Cincinnati Medical Center has developed a COVID-19 sequelae subtype criteria that categorizes long COVID into types 1 to 5 based on initial symptoms, duration of symptoms, period of quiescence, and delayed onset of symptoms.18

Management

As more treatment and preventative measures are being discovered for acute COVID-19 infections, little has been studied regarding management options for long COVID.3,9,10 The general recommendations on long COVID management include offering information on symptom management and social care. In some instances, rehabilitation or specialist services may be helpful depending on the symptoms and patient characteristics.

Until drug therapies are further validated, management options are generally nonpharmacologic therapies for long COVID symptoms (Table 2). 3,18–23 There is no specific guidance on pharmacotherapy, and management of long COVID symptoms may take some time to unveil due to the nonspecific manifestation. For instance, there is limited data on whether over-the-counter supplements are helpful, harmful, or have no effect in symptom management; therefore, these products should be used judiciously until more data is available.9 Manifestation of certain symptoms, such as left ventricular systolic dysfunction and thromboses, should be managed using guideline directed standards of care.22,23

Table 2. Proposed management options for long COVID symptoms3,18–24
SymptomManagement
General (eg, fatigue, loss of appetite)Nutritional assessment  
 
Limit activity levels
Respiratory (eg, cough, breathlessness)
Breathing exercises
 
Medication as indicated (ie, proton pump inhibitors for suspected reflux)
 
Pulmonary rehabilitation
Cardiac (eg, chest pain, palpitations)Cardiac rehabilitation (ie, dietary counseling, tobacco cessation)
 
Avoid intense cardiovascular exercise 
 
Prophylactic anticoagulation in hospitalized patients and guideline-directed anticoagulation for thrombotic episodes
 
Guideline directed management for left ventricular systolic dysfunction
 
For POTS, consider symptom management and remove offending pharmacologic agents (ie, norepinephrine reuptake inhibitors)
NeurologicalEducation on neurological symptoms (eg, loss of taste or smell) and how mild-to-moderate symptoms are expected to recover
 
Multidisciplinary rehabilitation support for severe symptoms
 
Speech therapy for swallowing or voice disorders
 
Muscle strengthening as indicated to improve mobilization
PsychologicalEducation on healthy lifestyle and mindfulness
 
Social connections (eg, online forums)
 
Self-care with diet and hydration
 
Occupational therapist, social worker, or rehabilitation psychologist referral
 
Mental health support for anxiety, depression, and PTSD
Abbreviations: PTSD=post-traumatic stress disorder

Conclusion

While there is limited evidence on pharmacotherapies for long COVID management, pharmacists can play an important role by reviewing the evidence behind proposed pharmacotherapies before making any recommendations to patients or providers. Pharmacists can also review patients’ medications and optimize regimens if any of their current therapies may be contributing to or exacerbating long COVID symptoms.24 Updates to COVID-19 management have been developing rapidly, and pharmacists should review the COVID-19 guidelines and updated literature to develop patient-specific care plans.

References

  1. National Institutes of Health. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. Accessed January 23, 2021. https://files.covid19treatmentguidelines.nih.gov/guidelines/covid19treatmentguidelines.pdf
  2. Tenforde MW, Kim SS, Lindsell CJ, et al. Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network — United States, March–June 2020. MMWR Morb Mortal Wkly Rep. 2020;69(30):993-998. doi:10.15585/mmwr.mm6930e1
  3. Greenhalgh T, Knight M, A’Court C, Buxton M, Husain L. Management of post-acute COVID-19 in primary care. BMJ. 2020;370. doi:10.1136/bmj.m3026
  4. Carfì A, Bernabei R, Landi F. Persistent symptoms in patients after acute COVID-19. JAMA. 2020;324(6):603. doi:10.1001/jama.2020.12603
  5. Huang C, Huang L, Wang Y, et al. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet. 2021;397(10270):220-232. doi:10.1016/S0140-6736(20)32656-8
  6. Baig AM. Deleterious outcomes in long-hauler COVID-19: the effects of SARS-CoV-2 on the CNS in chronic COVID syndrome. ACS Chem Neurosci. 2020;11(24):4017. doi:10.1021/acschemneuro.0c00725
  7. Callard F, Perego E. How and why patients made long Covid. Soc Sci Med. 2021;268:113426. doi:10.1016/j.socscimed.2020.113426
  8. Mahase E. Long covid could be four different syndromes, review suggests. BMJ. 2020;371:m3981. doi:10.1136/bmj.m3981
  9. National Institute for Health and Care Excellence (NICE). COVID-19 rapid guideline: managing the long-term effects of COVID-19 NICE guideline [NG188]. NICE website. December 18, 2020. Accessed February 12, 2021. https://www.nice.org.uk/guidance/ng188
  10. Shah W, Hillman T, Playford ED, Hishmeh L. Managing the long term effects of COVID-19: summary of NICE, SIGN, and RCGP rapid guideline. BMJ. 2021;372:n136. doi:10.1136/bmj.n136
  11. Datta SD, Talwar A, Lee JT. A proposed framework and timeline of the spectrum of disease due to SARS-CoV-2 infection: illness beyond acute infection and public health implications. JAMA. 2020;324(22):2251-2252. doi:10.1001/jama.2020.22717
  12. Centers for Disease Control and Prevention. Late Sequelae of COVID-19. Accessed January 23, 2021. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/late-sequelae.html
  13. Ngai JC, Ko FW, Ng SS, To KW, Tong M, Hui DS. The long-term impact of severe acute respiratory syndrome on pulmonary function, exercise capacity and health status. Respirology. 2010;15(3):543-550. doi:10.1111/j.1440-1843.2010.01720.x
  14. Garrigues E, Janvier P, Kherabi Y, et al. Post-discharge persistent symptoms and health-related quality of life after hospitalization for COVID-19. J Infect. 2020;81(6):e4-e6. doi:10.1016/j.jinf.2020.08.029
  15. Halpin SJ, McIvor C, Whyatt G, et al. Postdischarge symptoms and rehabilitation needs in survivors of COVID‐19 infection: A cross‐sectional evaluation. J Med Virol. 2021;93(2):1013-1022. doi:10.1002/jmv.26368
  16. Carvalho-Schneider C, Laurent E, Lemaignen A, et al. Follow-up of adults with noncritical COVID-19 two months after symptom onset. Clin Microbiol Infect. 2020;27(2):258-263. doi:10.1016/j.cmi.2020.09.052
  17. Raveendran A V. Long COVID-19: Challenges in the diagnosis and proposed diagnostic criteria. Diabetes Metab Syndr. 2021;15(1):145-146. doi:10.1016/j.dsx.2020.12.025
  18. Becker RC. COVID-19 and its sequelae: a platform for optimal patient care, discovery and training. J Thromb Thrombolysis. Published online January 27, 2021. doi:10.1007/s11239-021-02375-w
  19. Sheehy LM. Considerations for postacute rehabilitation for survivors of COVID-19. JMIR Public Heal Surveill. 2020;6(2):e19462. doi:10.2196/19462
  20. Barker-Davies RM, O’Sullivan O, Senaratne KPP, et al. The Stanford Hall consensus statement for post-COVID-19 rehabilitation. Br J Sports Med. 2020;54(16):949-959. doi:10.1136/bjsports-2020-102596
  21. Asly M, Hazim A. Rehabilitation of post-covid-19 patients. Pan Afr Med J. 2020;36:1-3. doi:10.11604/pamj.2020.36.168.23823
  22. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: A report of the american college of cardiology foundation/american heart association task force on practice guidelines. Circulation. 2013;128(16):e240-327. doi:10.1161/CIR.0b013e31829e8776
  23. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST guideline and expert panel report. Chest. 2016;149:315-352. doi:10.1016/j.chest.2015.11.026
  24. Dani M, Dirksen A, Taraborrelli P, et al. Autonomic dysfunction in ‘long COVID’: rationale, physiology and management strategies. Clin Med (Lond). 2021;21(1):e63-e67. doi:10.7861/clinmed.2020-0896

Prepared by:

Clara Lee, PharmD Candidate Class of 2021
University of Illinois at Chicago College of Pharmacy

Reviewed by:

Amanda Gerberich, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

March 2021

The information presented is current as February 12, 2021. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making. As of February 24, 2021 long COVID is now being referred to as post-acute sequelae of SARS-COV-2 infection (PASC).