Management of Osteoarthritis Pain

                                                 Dr. KS Dhillon

What is osteoarthritis

Osteoarthritis (OA) is the outcome of a range of disorders that result in structural and functional failure of synovial joints where the dynamic equilibrium between the breakdown and repair of joint tissues is overwhelmed [1].

Abnormal mechanical stresses on healthy cartilage can lead to structural failure of articular cartilage.  It can also result from pathologically impaired cartilage degenerating under the influence of normal physiological strains [1]. Although two subsets of OA are described, i.e primary and secondary OA, in the majority of cases the pathogenesis is multifactorial, involving environmental and genetic factors. Occupational factors, trauma, body weight, recreational activities, developmental abnormalities, denervation of joints, collagen gene mutations, and inherited as well as acquired errors of metabolism play a role in the pathogenesis of OA.

Osteoarthritis may cause pain, physical disability, as well as psychological distress [2]. There are many individuals who have structural changes in the joint which are consistent with OA but are asymptomatic.

The proportion of individuals with radiographic OA of the knee who have knee pain can range from 15% to 81% and those with knee pain who have radiographic osteoarthritis ranges from 15-76% [3]. The reasons for this discordance between radiographic changes and knee pain in patients with OA remains ill-defined.

Symptomatic OA of the knee with pain on most days and radiographic features consistent with OA is present in about 12% of individuals aged 55 years and above [4].

OA is more prevalent in the hand as compared to the knee. OA of the base of the thumb when symptomatic can cause substantial pain, instability, deformity, and loss of motion leading to functional impairment [5]. About 5% of women and 3% of men after the age of 70 have symptomatic OA of the thumb with impairment of hand function [6].

The hip OA prevalence is about 9% in Caucasian populations [7] and the prevalence is very low in Asian, black, and East Indian populations. This indicates that the prevalence of hip OA is very low [8]. The prevalence of symptomatic OA of the hip OA is about 4% [9].

Symptoms and signs of OA

Pain is the predominant symptom in patients with OA. The onset of pain is usually insidious. It is often deep-seated, not localized, and activity-related or mechanical. In the advanced stage of the disease, the pain may occur at rest and at night [10].

Other symptoms include stiffness, joint instability, buckling or giving way, reduced function, swelling, crepitus, and loss of motion in the joint.

Some of the signs of OA include joint tenderness, crepitus, bony enlargement, reduced range of joint motion, pain on passive joint motion, deformity, instability of the joint, swelling of joint, muscle wasting, and altered gait [10]. 

Diagnosis of OA

The diagnosis of OA is made on the basis of the history and physical examination. X-rays are done to confirm the clinical suspicion and to rule out other conditions. No laboratory tests are needed for the diagnosis of OA.

The radiographic features commonly used to define OA include osteophytes, joint space narrowing, subchondral sclerosis, cyst formation, and bony contour abnormalities (e.g. femoral head). The most widely used grading system is the one introduced by Kellgren and Lawrence [11]. The grading system has 4 grades of OA based on radiological examination;

Grade 0: No OA; when there are no features of OA.

Grade 1: Doubtful OA; when there are minimal osteophytes of doubtful

               significance.                                                                                 

Grade 2: Minimal OA; when there are definite osteophytes but the joint  

               Is normal.

Grade 3:  Moderate OA; when there is moderate decrease in joint space

Grade 4:  Severe OA; when joint space is markedly reduced with 

                subchondral sclerosis.

                   

Treatment of OA

There are pharmacological, non-pharmacological, and surgical approaches to the treatment of OA. Treatment is essentially symptomatic. Patient education is at the core of the management of patients with symptomatic OA. Presently, there are no effective disease-modifying drugs available nor is a cure in sight. There is a widely held view, though erroneously, that OA is inevitably a progressive disease. Studies have shown that 12 to 17% of patients can show improvement over the years, 22.5 to 27% can remain the same, and 56 to 64% can get worse [12,13]. However radiographic changes, symptoms, and function must be seen as independent outcome measures since they do not always correlate.

Non-Pharmacological Treatment

Exercise

All guidelines on the treatment of OA recommend exercise for the treatment of OA, especially for the knee. It has not been established which is the best form of exercise but aerobic and strengthening exercises have shown modest effects on pain relief. Exercises for patients with OA have to be individualized and patient-centric. It is most likely to be sustained if it is part of the patient’s daily routine or when it is done in groups. There is no evidence that exercises will accelerate the OA provided injury is prevented [14].

Weight loss

All guidelines advocate weight loss for those patients who are overweight. Studies have shown that obesity is a risk factor for developing OA, as well as a risk factor for progression of OA. Random controlled trials (RCTs) have also shown that weight loss reduces pain and improves function in patients with knee OA.  A 5% weight reduction for those who are overweight is recommended for significant benefit. Calorie reduction should go hand in hand with exercise. However, there is no evidence that weight reduction will slow the progression of OA and there is also no evidence that it will benefit patients with hip OA [14].

Footwear and orthotics

Most RCTs show that there is no benefit of footwear and orthotics in the management of OA of the knee and there are no studies for hip OA. There have been two studies espousing the benefits of lateral and medial insoles for knee OA. However, most believe that the symptomatic pain relief may be due to a placebo response. If the orthotic is not too expensive it may be offered as an adjunct to other therapy [14].

Knee braces, patellar bracing and walking aids

There is no firm evidence that these devices are beneficial in the treatment of OA. At best there is weak evidence of some benefit of these modalities of treatment. They could be used as an adjunct in the treatment with other forms of treatment [14].

Transcutaneous electrical stimulation (TENS) 

TENS is not recommended in patients with knee and/or hip OA. The studies examining the use of TENS have been of low quality with small size and variable controls. This makes comparisons across trials difficult. Generally, studies have demonstrated a lack of benefit for patients with knee OA.

Pharmacological Treatment

Simple analgesics and paracetamol

All guidelines recommend paracetamol or its equivalent for the treatment of OA. Its efficacy has been well established for knee OA but there is less evidence for its efficacy for OA of other sites. Though it is less effective as compared to nonsteroidal anti-inflammatories (NSAIDs) for symptomatic relief, the cost and lesser side effects gives it an edge over NSAIDs. However, the lack of knowledge and belief in its efficacy among professionals and patients need to be overcome [14].

Topical NSAIDs and Capsaicin

Although some studies have shown the effectiveness of topical NSAIDs and Capsaicin for short-term use in the treatment of OA, many believe that there is a considerable chance of a placebo effect as well as publication bias. There is weak (Grade D) evidence for use of such treatment modalities in OA of the knee. These modalities can be used as an adjunct for short term treatment [14].

NSAIDs and COXIBS

There is a large body of evidence on the effectiveness of NSAIDs and Coxibs in the treatment of symptoms of OA. However, their effectiveness is small and is of short duration. These drugs due to their potential side effects should be used for the shortest duration whenever possible. NICE (National Institute for Health and Clinical Excellence, UK) having conducted some cost-effectiveness studies has recommended the use of these drugs with proton pump inhibitors (PPIs) when indicated. According to NICE guidelines, Celebrex is the most cost-effective of these drugs in the UK. For patients with gastrointestinal and cardiovascular risks, NSAIDs were not a cost effective alternative to paracetamol, with risk outweighing the benefits. The guidelines also recommend that patients with OA who are on Aspirin should consider other alternatives before using this class of drugs. All patients should be informed of the possible side effects of the use of these drugs. Despite evidence that paracetamol may be inferior to NSAIDs for pain relief in OA, the risk-harm trade-off and the cost places paracetamol ahead of NSAIDs [14].

Opioids

Evidence for use of opioids in the treatment of arthritis is weak. Their use is recommended for moderate to severe OA. The benefits for pain are moderate and for function small. Their usefulness is limited by their well-known side effects. There is a lack of long-term data on the efficacy and safety of their use in OA [14].

Glucosamine and Chondroitin

The AAOS (American Academy of Orthopaedic Surgery) clinical practice guidelines (18th May 2013) [15] does not recommend the use of glucosamine and chondroitin for patients with symptomatic OA of the knee and the strength of their recommendation is strong. Despite the availability of extensive literature on the subject, there is no evidence that clinically important outcome has been achieved compared to placebo.

Hyaluronic Acid

The AAOS guidelines also strongly recommend against the use of hyaluronic acid for the treatment of patients with symptomatic osteoarthritis of the knee. This recommendation is based on the lack of efficacy of intra-articular hyaluronic.

Intra-articular Corticosteroids

The evidence for the use of intra-articular corticosteroids in the treatment of knee OA is inconclusive. There is a need for the use of clinical judgment for use of intra-articular corticosteroids. Patients with persistent synovitis of the knee may benefit.

NGF monoclonal antibody tanezumab

Nerve growth factor (NGF) is known to be involved in pain signaling and has been implicated in causing pain in patients with OA. In the early clinical trials of the NGF monoclonal antibody tanezumab, investigations involved the use of intravenous tanezumab where the doses were body weight-adjusted or administered as a fixed-dose (up to 10 mg). 

In some of these patients, rapid progression of osteoarthritis (RPOA) was observed. Histomorphological changes in the sympathetic nervous system were also observed in preclinical animal studies. In subsequent studies, comprehensive monitoring of joint and neurological safety was implemented.

Further trials were conducted where lower doses of tanezumab were administered subcutaneously in difficult-to-treat patients. Extensive risk mitigation and surveillance, excluded patients with evidence of or risk factors for RPOA. 

Subcutaneous tanezumab at a dose of 5mg given every 8 weeks significantly improves pain, physical function, and patient’s global assessment of OA (PGA-OA) at 24 weeks in patients with moderate-to-severe OA who have failed to respond or could not tolerate standard analgesics. 

About 1.4% of the patients receiving 2.5 mg tanezumab develop RPOA and 2.8% of patients receiving tanezumab develop RPOA.

Surgical Treatment

Arthroscopy, partial meniscectomy, and debridement of the Knee

The AAOS guidelines strongly recommend against the use of arthroscopy with lavage and/or debridement of the knee in patients with OA. Randomized control trials have shown no benefits of such a procedure as compared to physical therapy and medical treatment [16,17]. This recommendation does not apply to patients with a primary diagnosis of mechanical derangement of the knee who have concomitant OA of the knee. There is level I evidence that partial meniscectomy in patients with OA of the knee provides no benefit to the patients and that there is no scientific basis for continuing such a practice [18].

 

Osteotomies around the Knee

The AAOS guidelines recommend that a practitioner may do a valgus high tibial osteotomy for symptomatic medial compartment OA of the knee. However, the strength of the recommendation for this procedure is limited because the quality of supporting evidence is unconvincing. Low-strength case series have shown decreased pain on VAS after high tibial osteotomies. For distal femoral varus osteotomies, evaluation for the recommendation was not done due to a lack of appropriate studies.

Joint Replacement Surgery

Joint replacement surgery is a well-known effective and cost-effective intervention for the treatment of OA of the hip and the knee joints. Owing to its irreversible nature and its limited lifespan, it is usually reserved for patients with severe disabling OA which is not amenable to other forms of surgical or conservative treatment. The decision as to when in the course of the disease a joint replacement should be done has not been resolved. The indications for joint replacement remain unclear. After knee replacement, 10-20% of people are unhappy with the outcome [19]. Besides surgical technique and implant factors, much of the cause of pain and disability remains unexplained. Though socio-demographic factors such as older age, female gender, and low socioeconomic status have been associated with poorer outcomes, physiological aspects do play an important role, possibly related to central sensitization (the dysfunction of pain modulation in the CNS) [20].

The long term survival of prosthesis in total joint arthroplasty of the hip and knee has been extensively studied. More than ninety percent of hip prostheses do not need revision at 10 years and 80% of the total knee prostheses do not need revision at 15 years. However, the quality of life (QOL) SF-36 scores for patients with joint arthroplasty are not as encouraging. Rat et al, in a study of 3 and 10 years follow up of a patient cohort with hip and knee arthroplasty, showed that at 3 years the QOL scores remained limited as compared to age-matched general population and at 10 years the scores were lower than the reference population [21]. 

The risk factors for the requirement of joint replacement in patients with osteoarthritis have not been fully elucidated. However, a dose-response association between body mass index and subsequent need for hip and knee replacement has been established. A higher body mass index and obesity significantly contributes to the overall risk of undergoing a hip or knee replacement [22,23]. Total physical activity level was found to have a dose-response relationship to risk of primary knee replacement but not to hip replacement [24]. The Ontario Joint Replacement Registry 2004 report showed that 84% of patients receiving knee replacement were overweight or obese with a BMI of more than 25 [25].

It is often erroneously believed that a large proportion of patients with post-traumatic OA will need a joint replacement of the hip or the knee. An analysis of the patients who had a knee replacement in Canada, by the National Canadian Joint Replacement Registry in 2004, showed that the primary diagnosis for a total knee replacement was degenerative OA in 93%, inflammatory arthritis in 5%, post-traumatic OA in 2%, and avascular necrosis in 1% of the patients [25]. Post-traumatic OA constitutes 12% of the global burden of OA but only 2% of the total knee replacements done are for post-traumatic OA. Hence, primary degenerative OA is a bigger risk factor for a knee replacement than post-traumatic OA. 

Rademakers et al in an analysis of 109 patients with surgically treated fractures of the tibial plateau with an average follow-up of 14 years showed a 5% incidence of secondary OA of the knee which required reconstructive surgery (knee replacement, arthrodesis, or osteotomy) [26]. Mehin et al in a study involving 286 patients with tibial plateau fractures followed up for 10 years, found a 3% incidence of end-stage OA requiring reconstructive surgery [27]. Two percent of the 286 patients had a knee replacement.

Ankle joint replacement has been touted as a viable option for the treatment of end-stage ankle arthritis. However, some early reports showed failure rates as high as 72% [28]. More recent studies have reported an 89% survivorship at 10 years but the quality of evidence in support of ankle replacement is weak and fraught with bias. High quality randomized control trials comparing ankle replacements with other forms of treatment for ankle arthritis are lacking [29].

Arthrodesis of Joints

Arthrodesis of major weight-bearing joints of the lower limb such as the hip and knee was widely used for end-stage arthritis before the advent of successful joint replacement arthroplasty. Presently it is widely used for end-stage arthritis of the ankle and not for the hip and the knee where the results of hip and knee replacement are excellent. Arthrodesis provides excellent permanent pain relief but at the expense of loss of motion of the joint. Furthermore, it can cause excessive stresses on adjoining joints leading to degeneration of these joints. Hip and knee arthrodesis is still a viable option in a selected group of patients. Limited lifespan of joint arthroplasty dictates that patients who are expected to live more than 30 years may be candidates for arthrodesis of the hip or knee for end-stage arthritis of the hip and knee joint. This is especially true for those patients who are involved in heavy manual labor.

Coester et al in a study of 23 patients with ankle arthrodesis for isolated post-traumatic OA of the ankle, followed up for a mean of 22 years found that there was accelerated degeneration of the subtalar, calcaneocuboid, naviculocuneiform, tarsometatarsal, and the first metatarsophalangeal joints of the same foot as compared to the opposite foot. However, the knee joint was spared of degenerative changes in all the patients [30].

Schafroth et al [31] in a retrospective study of 30 patients with an arthrodesis of the hip at an average follow up of 18.2 years found that the VAS (visual analogue scale) for pain in the fused hip was an average of 1.9 (0-8), the contralateral hip 2, ipsilateral knee 2.0, contralateral knee 1.8 and low back 3.6. The average walking distance was 111 minutes (range 10 to unlimited). The average SMFA (short musculoskeletal function assessment) was 31.2 (range 9-70). They concluded that if the arthrodesis is done with optimal alignment of the limb then complaints from adjoining joints are minimal even in the long term and an acceptable quality of life is possible. Seven of the hips were eventually successfully converted to a total hip arthroplasty [31].

There is a dearth of literature on the long term outcome of arthrodesis of the knee, which is partly due to the success of knee replacement since the 1970s. Presently arthrodesis is done mainly for failed joint replacements, sepsis, Charcot joint, flail knee, tumors around the knee, and end-stage post-traumatic arthritis in young individuals who are not suitable for a knee replacement. An arthrodesis of the knee can provide a stable and painless limb especially in patients in whom a lot of walking is required for their daily activities. An arthrodesis from a functional perspective will always be superior to an above-knee amputation.

Conclusion

There is a widely held view, though erroneously, that OA is inevitably a progressive disease. Studies show that 12 to 17% of patients can show improvement over the years, 22.5 to 27% remain the same, while 56 to 64% can get worse. Radiographic changes, symptoms, and function are independent outcomes and do not correlate.

Contrary to a commonly held view, studies reveal that there is no evidence that glucosamine, chondroitin, and hyaluronic acid have any clinical outcome benefits in the management of OA of the knee. There is strong clinical evidence (RCTs) that arthroscopic lavage, partial meniscectomy, and /or debridement of the knee for OA is of no benefit to the patient.

It is often quite erroneously believed that a large proportion of patients with post-traumatic OA will require a joint replacement, however, demographics of patients undergoing knee replacement for OA show that in 93% of patients the diagnosis was degenerative OA, 5% inflammatory arthritis, 2% posttraumatic arthritis and in 1% avascular necrosis. Post-traumatic OA forms 12% of the global burden of OA but only 2% of patients undergoing knee replacement have post-traumatic OA. In surgically treated fractures of the tibial plateau, the incidence of post-traumatic OA requiring reconstructive (knee replacement, arthrodesis, or osteotomy) surgery was only 5%. Hence a large proportion of patients do not develop end-stage post-traumatic OA which would require reconstructive surgery.

Now to answer the questions posed by the retired member of the judiciary that was raised earlier. In light of present knowledge, there is sufficient evidence to express in percentages the likelihood of a person developing OA, though it cannot be expressed in absolute numbers. It would vary with the joint involved and the severity of the trauma. The degenerative process probably starts immediately at the time of injury and clinical manifestation occurs when the reparative process is overwhelmed by the degenerative process. The latent period may vary from a year to more than 20 years. We however need to remember that not all patients after an injury will develop OA. Age is a very important factor in both the risk for developing OA as well as for progression of the OA. Older age is a risk factor for both. Finally, the likelihood of developing OA and the chance of needing future surgery is very much dependent on the joint involved. 

Research in recent years has debunked many of the long-held pervasive dogmatic myths perpetuated by intuitive and unsystematic clinical experience.

 References

1. Nuki G. Osteoarthritis: a problem of joint failure. Z Rheumatol. 1999 Jun;58(3):142-7. doi: 10.1007/s003930050164. PMID: 10441841.
2. Guccione AA, Felson DT, Anderson JJ, Anthony JM, Zhang Y, Wilson PW, Kelly-Hayes M, Wolf PA, Kreger BE, Kannel WB. The effects of specific medical conditions on the functional limitations of elders in the Framingham Study. Am J Public Health. 1994 Mar;84(3):351-8. doi: 10.2105/ajph.84.3.351. PMID: 8129049; PMCID: PMC1614827.
3. Bedson J, Croft PR. The discordance between clinical and radiographic knee osteoarthritis: a systematic search and summary of the literature. BMC Musculoskelet Disord. 2008 Sep 2;9:116. doi: 10.1186/1471-2474-9-116. PMID: 18764949; PMCID: PMC2542996.
4. Peat G, McCarney R, Croft P. Knee pain and osteoarthritis in older adults: a review of community burden and current use of primary health care. Annals of the Rheumatic Diseases. 2001;60(2):91–97.
5. Armstrong AL, Hunter JB, Davis TR. The prevalence of degenerative arthritis of the base of the thumb in post-menopausal women. Journal of Hand Surgery - British Volume. 1994;19(3):340–341.
6. Zhang Y, Niu J, Kelly-Hayes M, Chaisson CE, Aliabadi P, Felson DT. Prevalence of symptomatic hand osteoarthritis and its impact on functional status among the elderly: The Framingham Study. American Journal of Epidemiology. 2002;156(11):1021–1027.
7. Felson DT, Zhang Y. An update on the epidemiology of knee and hip osteoarthritis with a view to prevention. Arthritis & Rheumatism. 1998;41(8):1343–1355. 
8. Nevitt MC, Xu L, Zhang Y, Lui LY, Yu W, Lane NE, et al. Very low prevalence of hip osteoarthritis among Chinese elderly in Beijing, China, compared with whites in the United States: the Beijing osteoarthritis study. Arthritis & Rheumatism. 2002;46(7):1773–1779.
9. Lawrence RC, Helmick CG, Arnett FC, Deyo RA, Felson DT, Giannini EH, et al. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis & Rheumatism. 1998;41(5):778–799.
10. Hunter DJ, McDougall JJ, Keefe FJ. The symptoms of osteoarthritis and the genesis of pain. Rheum Dis Clin North Am. 2008;34(3):623-643. doi:10.1016/j.rdc.2008.05.004.
11. Kellgren JH and Lawrence JS, Radiological assessment of osteo-arthrosis. Ann Rheum Dis. 1957 Dec; 16(4): 494–502.
12. Hernborg J S, Nilsson B E. The natural course of untreated osteoarthritis of the knee. Clin Orthop 1977; 123:130-7. 
13.  Massardo L, Watt I, Cushnaghan J, Dieppe P. Osteoarthritis of the knee joint: an eight year prospective study. Ann Rheum Dis.1989; 48:893–7.
14. March L, Amatya B, Osborne RH, Brand C. Developing a minimum standard of care for treating people with osteoarthritis of the hip and knee. Best Practice & Research Clinical Rheumatology 2010;24: 121–145.
15. Treatment of osteoarthritis of the knee, 2nd edition http://www.aaos.org/research/guidelines/TreatmentofOsteoarthritisoftheKneeGuideline.pdf.
16. Moseley JB, O'Malley K, Petersen NJ, et al. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. N Engl J Med 2002;347:81-88.
17. Kirkley A, Birmingham TB, Litchfield RB, Giffin JR, Willits KR, Wong CJ, Feagan BG, Donner A, Griffin SH, D'Ascanio LM, Pope JE, Fowler PJ. A randomized trial of arthroscopic surgery for osteoarthritis of the knee. N Engl J Med. 2008;359((11)):1097–107.
18. Sihvonen R, Paavola M, Malmivaara A, Itälä A, Joukainen A, Nurmi H, Kalske J, Järvinen TL, Finnish Degenerative Meniscal Lesion Study (FIDELITY) Group. Arthroscopic partial meniscectomy versus sham surgery for a degenerative meniscal tear. N Engl J Med. 2013 Dec 26; 369(26):2515-24.
19. Dieppe P, Lim K, Lohmander S. Who should have knee joint replacement surgery for osteoarthritis? International Journal of Rheumatic Diseases 2011; 14: 175–180.
20. Wylde V, Dieppe P, Hewlett S, Learmonth ID. Total knee replacement: is it really an effective procedure for all? Knee 2007;14(6):417-23.
21. Rat AC, Guillemin F, Osnowycz G, Delagoutte JP, Cuny D, Bamann C. Total hip or knee replacement for osteoarthritis: Mid- to long- term quality of life. Arthritis Care & Research. 2010;62(1): 54 – 62.
22. Liu B, Balkwill A, Banks E, Cooper C, Green J, Beral V. Relationship of height, weight and body mass index to the risk of hip and knee replacement in middle-aged women.Rheumatology (Oxford) 2007 ;4. 
23. Flugsrud GB, Nordsletten L, Espehaug B, Havelin LI, Engeland A, Meyer HE.The impact of body mass index on later total hip arthroplasty for primary osteoarthritis: a cohort study of 1.2 million persons. Arthritis Rheum. 2006; 54(3): 802-7.
24. Wang Y, Simpson JA, Wluka A, Teichtahl A, English D, Giles G et al. Is physical activity a risk factor for primary knee or hip replacement due to osteoarthritis? A prospective cohort study. The Journal of Rheumatology 2011; 38(2): 350-357.
25. Medical Advisory Secretariat. Total knee replacement: an evidence-based analysis. Ontario Health Technology Assessment Series 2005; 5(9) at http://www.health.gov.on.ca/english/providers/program/mas/tech/reviews/pdf/rev_tkr_061705.pdf.
26. Rademakers MV, Kerkhoffs GM, Sierevelt IN, Raaymakers EL, Marti RK. Operative treatment of tibial plateau fractures: five to 27 year follow-up results. J Orthop Trauma 2007; 21 : 5-10.
27. Mehin R, O’Brien P, Broekhuyse H, Blachut P, Guy P. Endstage arthritis following tibial plateau fractures: average 10 years follow-up. Can J Surg, 2012; 55(2):87-94.
28. Gougoulias, N., A. Khanna, and N. Maffulli.  How successful are current ankle replacements?: a systematic review of the  literature. Clin Orthop Relat Res 2010; 468(1):199-208.
29. Zaidi R, Cro S, Gurusamy K, Siva N, Macgregor A, Henricson A, Goldberg A. The outcome of total ankle replacement: A systematic review and meta-analysis. Bone Joint J 2013;95-B:1500–7.
30. Coester LM, Saltzman CL, Leupold J, Pontarelli W. Long term results following ankle arthrodesis for post-traumatic arthritis. J Bone Joint Surg Am, 2001 Feb 01; 83(2): 219-219.
31. Schafroth MU, Blokzijl RJ, Haverkamp D, Mass M, Marti RK. The long-term fate of the hip arthrodesis: does it remain a valid procedure for selected cases in the 21st century? Int Orthop. 2010 August; 34(6): 805–810.

           Covid-19 Disease Pandemic

                                Dr. KS Dhillon

Epidemiology

It is still unknown where the covid-19 outbreak first started. A cluster of pneumonia with unknown etiology appeared in Wuhan City, Hubei Province of China in December 2019. Many of these initial patients with pneumonia visited a wet seafood market where wildlife species were sold. Virus isolation from the patients and molecular analysis carried out showed that the pathogen was a new coronavirus (CoV) and it was named 2019-nCoV.   Subsequently on 11/2/2020 WHO renamed it COVID-19 which is short for coronavirus disease 2019.

This new coronavirus is the 7th member of the Coronaviridae which is known to infect humans. CoVs are a class of genetically diverse viruses found in many host species, including birds and mammals. CoVs cause intestinal and respiratory infections in animals as well as in humans [1,2,3,4]. Coronaviruses first came into the spotlight in 2002–2003 in Guangdong Province in China where clusters of ‘atypical pneumonia’ were reported. Researchers isolated a novel CoV virus (SARS-CoV) and the disease was renamed severe acute respiratory syndrome (SARS). Further studies carried out showed that the SARS-CoV originated from bats and interspecies transmission to humans took place via an intermediate host: Himalayan palm civets or raccoon dogs (Nyctereutes procyonoides) [4,5,6]. The other well-known CoV of animal origin is the Middle East Respiratory Syndrome Coronavirus (MERS-CoV), which has a high case fatality rate, but, fortunately, it is rarely transmitted between humans.

As of 31 December 2020, 83,134,416 cases of Covid-19 have been detected. The death toll stands at 1,813,386. The figure of recovered individuals stands at 58,932,394 [7].

Many countries do not test those with mild symptoms. Li et al [8] in an analysis of the early phase of the outbreak up to 23 January 2020 estimated that 86 percent of COVID-19 infections had not been detected and that 79% of detected cases were from these undocumented infections. Studies by several authors have estimated that the numbers of infections in many countries are likely to be much higher than the reported cases [9,10]. 

The COVID-19 deaths refer to people who died after testing positive for COVID-19. These figures do not include deaths of people who die without having been tested. 

The recovery rate after COVID-19 infections is more than 95%. The time between the onset of symptoms and death ranges from 6 to 41 days and is usually about 14 days [11]. People with underlying conditions, such as a weak immune system, serious heart or lung problems, severe obesity, and the elderly are at the greatest risk of death from COVID-19 infection [12]. 

The number of deaths due to COVID-19 divided by the number of diagnosed cases within a given time interval provides the death-to-case ratio. The global death-to-case ratio is 2.2 percent (1,671,772 deaths for 75,508,468 cases) as of 18 December 2020 according to Johns Hopkins University statistics [13]. 

Infection fatality ratio (IFR) is the most important metric in assessing the death rate. The infection fatality ratio is obtained by dividing the number of deaths attributed to a disease divided by individuals infected (including all asymptomatic and undiagnosed) [14].

A peer-reviewed analysis of pre-serology data from China in March 2020 yielded an overall IFR of 0.66%. For those aged 0 to 9 years the value was 0.00161%, for those aged 50-59 years it was 0.595% and for those aged 80 and more the value was 7.8% [15]. 

In April 2020, an IFR range of 0.12–1.08% was derived from non-peer-reviewed serology surveys that showed that the IFR for COVID-19 ranges from 0.12-1.08% and that for influenza is 0.04% which makes COVID-19 deadlier than influenza by 3 to 27 times [16]. 

The CDC in the USA, in July 2020, adopted the IFR as the standard for the direct measurement for disease severity for COVID-19 and calculated that the overall 'best estimate' for planning purposes in the USA is an IFR of 0.65% [17,18].

The CDC in September 2020, computed an age-bracketed 'best estimate' for the USA of 0.003% for those aged between 0–19 years, 0.02% for 20–49 years, 0.5% for 50–69 years, and 5.4% for 70+ years [19].

Dr. Mike Ryan, director of the WHO's Health Emergencies Programme, on 6/10/2020, announced that "Our current best estimates tell us that about 10% of the global population may have been infected by this virus" [20].

Another metric that is used to assess the death rate is the case fatality ratio (CFR). The value is obtained by dividing the deaths attributed to disease by the number of individuals diagnosed to-date. 

This metric, however, can be misleading because of the delay between onset of symptom and death and also because testing focuses on individuals with symptoms, particularly on those manifesting severe symptoms [21].

Coronavirus disease 2019 (COVID-19)

Signs and symptoms

People with COVID-19 can have a wide range of symptoms ranging from mild symptoms to severe illness [22]. Symptoms usually appear 2-14 days after exposure to the virus. Some of the symptoms include:

• Fever or chills- 83% to 99%.
• Fatigue- 44% to 70%.
• Shortness of breath or difficulty breathing- 31% to 40%.
• Cough- 59% to 82%.
• Muscle or body aches- 11% to 35%.
• New loss of taste or smell- 15% to 30%.
• Coughing up sputum- 28% to 33%.
• Loss of appetite- 40% to 84%.
• Sore throat
• Headache
• Congestion or runny nose
• Diarrhea
• Nausea or vomiting

Patients with severe disease may have these signs and symptoms:

• Difficulty in breathing
• Persistent pain or pressure in the chest
• New confusion
• Inability to wake or stay awake
• Bluish lips or face
• Coughing blood
• High fever
• Kidney failure

About one in five people who are infected with the virus do not develop symptoms at any point in time. Research earlier in the pandemic suggested that the rate of asymptomatic infections could be as high as 81% [23]. A meta-analysis published in December 2020 [24], which included 13 studies involving 21,708 people, calculated the rate of asymptomatic presentation to be 17%. The asymptomatic carriers invariably do not get tested, and they can spread the disease. People also get infected from pre-symptomatic people who later develop symptoms [25]. 

Transmission of COVID-19

COVID-19 usually spreads from one person to another person mainly through the respiratory route when an infected person talks, coughs, sneezes, sings or breathes. The infection spreads when virus-containing particles are exhaled by an infected person. The viruses are carried by either respiratory droplets or aerosols and these viruses find their way into the mouth, nose, or eyes of people who are in close contact with an infected person [26,27]. During human-to-human transmission, an average of about 1,000 infectious SARS-CoV-2 virions are thought to initiate the new infection.

The closer and longer people interact, the more likely they are to transmit the disease. At close distances, larger droplets that fall to the ground and aerosols transmit the virus load, whereas at longer distances only aerosols carry the virus load. The larger droplets can also evaporate to form aerosols. The virus, however, is not known to be transmitted between rooms over long distances such as through air ducts. 

Airborne transmission occurs in crowded and less ventilated venues in indoor locations such as in restaurants, offices, choirs, nightclubs, gyms,  and religious venues. It also occurs in healthcare settings where aerosol-generating medical procedures are performed on COVID-19 patients.

The number of people that one infected person can infect varies. It has been estimated that one infected person can infect on an average between two and three other people [28]. This makes COVID-19 more infectious than influenza, but less than measles [29]. COVID-19 infections often spread in clusters, where infections can be traced back to one index person at a particular geographical location. There are also "super-spreading events", where many people are infected by one person.

Cause of COVID-19 disease

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is a strain of coronavirus [30]. 

Each infected person on an average can spread the infection to 5.7 persons according to estimates by epidemiological studies.

Diagnosis of CVID-19 disease

The presence of SARS-CoV-2 is detected by real-time reverse transcription-polymerase chain reaction (rRT-PCR) [31] which detects the presence of viral RNA fragments [32]. The test detects the virus RNA but not the infectious virus. The test is usually done on respiratory samples obtained by a nasopharyngeal swab. A nasal swab or sputum sample may also be used [33,34]. Usually, the results are available within a few hours.

The specificity and sensitivity of the rRt-PCR test is not known but some authors have estimated the pooled sensitivity to rRT-PCR as 89% (95%CI: 81-94%).  False negatives are as low as 2% and as high as 37%. The false positives rates are about 5% or lower.

CT scans of the chest may be useful in the clinical diagnosis of COVID-19  in a person with a high index of clinical suspicion of infection but scans are not recommended for routine screening. In early infections, bilateral asymmetric multilobar ground-glass opacities are seen at the periphery in the posterior aspect of the lungs. 

Lung consolidation, subpleural dominance, lobular septal thickening with variable alveolar filling may appear as the disease progresses.

Prevention of COVID-19 disease

Preventive measures to reduce the chances of infection include:

• Staying at home 
• Avoiding crowded places
• Wearing a mask in public 
• Keeping distance from others
• Ventilating indoor spaces
• Washing hands with soap and water often and for at least 20 sec
• Practicing good respiratory hygiene
• Avoiding touching the eyes, nose, or mouth with unwashed hands

CDC advises individuals who are diagnosed with COVID-19 or who believe they may be infected to stay home except when getting medical care. Individuals should call ahead before visiting a healthcare provider. They must wear a mask before they enter the healthcare provider's office and when they are in any room or vehicle with another person. When coughing and sneezing the mouth and nose must be covered with a tissue. Regular handwashing with soap and water should be carried out and there should be no sharing of personal household items [35,36].

The UK medicines regulator MHRA granted regulatory approval for the first COVID-19 vaccine on 2 December 2020 [37].

COVID-19 vaccine

Ideally, a pandemic vaccine should be delivered in a single shot making it possible to stretch supplies to cover a lot of people. It should trigger no side effect more significant than a sore arm. The vaccine should be easy to ship and store.

Several vaccines have been approved by national health agencies and these include ChAdOx1 nCoV-19 by Oxford University and AstraZeneca, Tozinameran from Pfizer–BioNTech (German), BBIBP-CorV by Sinopharm (China), CoronaVac by Sinovac (China), mRNA-1273 by Moderna (USA), and Gam-COVID-Vac by Gamaleya Research Institute (USSR).

The Moderna and Pfizer vaccines are mRNA vaccines. Such vaccines contain part of the coronavirus' genetic code which is injected into the body, triggering the body to begin making viral proteins, which trains the immune system to attack the virus.

The Sinovac’s CoronaVac is an inactivated vaccine. It uses killed viral particles to expose the body's immune system to the virus without risking a serious disease response. This inactivated virus vaccine is like most other traditional vaccines produced and successfully used in the past.

The mRNA vaccines on the other hand are a new type of vaccine and there is currently no successful example of them being used in the population in the past.  

By December 2020, more than 10 billion vaccine doses had been preordered by several countries [38] with Canada leading the pack. About half of the doses were purchased by high-income countries comprising about 14% of the world's population [39].

Pfizer, Moderna, and AstraZeneca have predicted a manufacturing capacity of 5.3 billion doses in 2021, which can be used to vaccinate about 3 billion people (two doses per person). 

Because of high demand from richer countries in 2020–21, people in poorer developing countries may not receive vaccinations from these manufacturers until 2023 or 2024 [38].

On 4th February the Secretary of Health and Human Services in the USA  issued a Declaration to provide liability immunity to individuals and entities  “against any claim of loss caused by, arising out of, relating to, or resulting from the manufacture, distribution, administration, or use of medical countermeasures (Covered Countermeasures), except for claims involving “willful misconduct”[40].

Similarly, the UK government announced in December 2020 that “it had granted Pfizer legal indemnity protecting the American pharmaceutical company from civil lawsuits due to any unforeseen complications arising from problems with its COVID-19 vaccine’ [41].

The liability immunity given by the USA and UK for use of COVID-19 vaccines raises questions about the safety of the vaccines. The speed at which these vaccines are being produced and rolled out raises the risks of side effects.

The Pfizer vaccine is authorized for use in people aged 16 and older while the Moderna’s is for people 18 and older. 

According to preliminary studies, the Pfizer vaccine showed efficacy of 95% at preventing symptomatic Covid infection, starting from seven days after the second dose was administered. The Moderna vaccine was 94.1% effective at preventing symptomatic Covid-19, starting from 14 days after the second dose. The vaccine’s efficacy appeared to be slightly lower in people who are 65 years. Both vaccines appear to reduce the risk of severe Covid disease. It’s not known yet if either of the vaccines prevents asymptomatic infection with the SARS-CoV-2 virus. It is also not known if vaccinated people can transmit the virus if they do become infected but don’t show symptoms. There are announcements that China's Sinovac vaccine is 91.25% effective, according to interim data from a late-stage trial in Turkey. There are, however, no trial outcome publications as yet.

In essence, these vaccines do not prevent the disease like other vaccines such as smallpox and polio vaccines do. It is also not known how long the protection from infection lasts with COVID-19 vaccines. 

Both the Pfizer/BioNTech and the Moderna vaccines require two shots: a priming shot followed by a booster shot. The interval between Pfizer vaccine doses is 21 days and for Moderna doses is 28 days.

Each dose of Pfizer’s vaccine contains 30 micrograms of vaccine whereas the Moderna vaccine dose contains 100 micrograms of vaccine. 

Vaccines that trigger a range of transient side effects in most of the recipients are known as reactogenic.

Most of the Covid-19 vaccines that have reported data so far fall into the reactogenic category. 

The most common side effects are injection site pain, headaches, fatigue, joint pain, and muscle pain. Some people have reported fever. Side effects are more common after the second dose and in younger adults who have more robust immune systems.

To date, there have been no serious, long-term side effects with the use of these vaccines. There have been a handful of reports of people having allergic reactions (anaphylaxis) to the Pfizer vaccine. Such allergic reactions have so far not been seen with the Moderna vaccine. 

The safety of these vaccines for those who are pregnant or lactating has not been tested. 

Both of these vaccines require an elaborate cold chain, the term used to describe the conditions under which vaccines must be stored during distribution and when they are in the doctors’ offices, pharmacies, or public health clinics where they’ll be administered. 

The Moderna vaccine is far easier to use than Pfizer’s. Moderna’s vaccine must be shipped at -4 Fahrenheit whereas the Pfizer’s vaccine must be shipped and stored at -94 Fahrenheit. The former is the temperature of a regular refrigerator-freezer; the latter, however, requires special ultra-cold freezers that need to be topped up with dry ice every five days. Doctors’ offices and nearby pharmacies do not have ultracold freezers which makes it difficult for health care workers to dispense the Pfizer vaccine. After thawing, the Pfizer vaccine vial must be used within five days. The  Moderna’s vaccine is stable at fridge temperature for 30 days and at room temperature for 12 hours. The Sinovac vaccine can be stored in a standard refrigerator at 2-8 degrees Celsius

The minimum purchase order for Pfizer vaccine 975 doses. There are plenty of places where they do not need 975 doses to vaccinate people currently eligible for vaccination such as health workers and nursing home residents. The Moderna vaccine’s minimum order of 100 doses is a much more manageable number. The Moderna’s vaccine is shipped in 10-dose vials and the Pfizer vaccine is shipped in five-dose vials. 

Evaluation of hospitalized adults

In the evaluation of hospitalized patients with documented or suspected COVID-19 infections, features associated with severe illness are identified and organ dysfunction or other comorbidities that could complicate potential therapy are also identified [42]. 

Several laboratory tests are done to evaluate the patient although the prognostic value of many of the tests remains uncertain.

The following laboratory studies are usually done on a daily basis [42]:

●Complete blood count (CBC) with differential count (focus on the total lymphocyte count trend)

●Comprehensive metabolic panel including:

Alanine Aminotransferase (ALT)

Albumin

Alkaline Phosphatase

Aspartate Aminotransferase (AST)

Bicarbonate (HCO3)

Bilirubin, Total

Calcium Total (Ca)

Chloride (Cl)

Creatinine

Glucose

Potassium (K)

Protein, Total

Sodium (Na)

Urea Nitrogen (BUN)

●Creatine kinase (CK)

●C-reactive protein (CRP)

●Ferritin

The following studies are carried out every other day (or daily if elevated or in the intensive care unit):

●Prothrombin time (PT)/partial thromboplastin time (PTT)/fibrinogen

●D-dimer

The following studies are carried out at baseline and repeated if abnormal or if the clinical condition worsens:

●Lactate dehydrogenase, repeated daily if elevated

●Troponin, repeated every two to three days if elevated

●Electrocardiogram (ECG), with at least one repeat test after starting any QTc-prolonging agent. 

Hepatitis B virus serologies, hepatitis C virus antibody, and HIV antigen/antibody testing is also carried out. The presence of chronic viral hepatitis can affect the interpretation of transaminase elevations and exacerbate the hepatotoxicity of certain medical therapies. Any underlying HIV infection may change the assessment of the patient's risk for deterioration and could warrant initiation of antiretroviral therapy [42].

For all COVID-19 hospitalized patients an initial chest x-ray is essential. A chest x-ray is usually sufficient for initial evaluation of pulmonary complications and extent of lung involvement. Chest CT is not necessary for patients with COVID-19 infections. This is consistent with the recommendations of the American College of Radiology [43]. 

There are certain characteristic chest CT findings that may be seen in COVID-19 infections but these findings cannot reliably distinguish COVID-19 from other causes of viral pneumonia. 

Although acute myocardial injury has been described as a complication of COVID-19, routine ECG is not necessary for patients with COVID infections, even if troponin levels are increased and there is hemodynamic compromise with other cardiovascular findings suggestive of cardiomyopathy [42]. 

Secondary bacterial infection is not common among patients with COVID infections. If secondary bacterial infection is suspected, based on chest imaging or sudden deterioration, then two sets of blood cultures are taken and sputum Gram stain and culture done. 

Management of COVID-19

A simple clinical classification of COVID-19 patients divides the patients into 5 grades:

• Grade 0: Where the patients are asymptomatic with no clinical signs       
• Grade I : Outpatients with mild clinical symptoms with lower or upper respiratory tract infections.
• Grade II: Patients requiring hospitalization, with lobar or multilobar pneumonia with/without the need for supplemental oxygen, or refractory to initial treatment.
• Grade III: Patients requiring ICU treatment, noninvasive or invasive mechanical ventilatory support, or with acute respiratory distress syndrome and/or non-pulmonary involvement.
• Grade IV: Critical patients who need immunomodulatory therapy or with multiorgan failure and/or cytokine storm.

A.General Management Issues

1.Empiric treatment for bacterial pneumonia

Bacterial superinfection is not a prominent feature of COVID-19, hence routine administer of empiric therapy for bacterial pneumonia is not necessary in patients admitted for COVID-19 infections. However, if there is clinical suspicion of bacterial infection empirical antibiotic therapy can be started after sputum samples have been taken for gram stain and culture [42].

2.Empiric treatment for influenza during influenza season

The clinical features of seasonal influenza and COVID-19 overlap and it is difficult to distinguish between the two. If microbiologic testing confirms the presence of influenza, antiviral therapy for seasonal influenza can be started [42].

3.Prevention of venous thromboembolism 

Thromboembolic complications among hospitalized patients with COVID-19 are high according to several studies, particularly in patients who are critically ill. Pharmacologic prophylaxis for venous thromboembolism is hence recommended for all hospitalized patients with COVID-19. 

4.Avoiding nebulized medications

Whenever possible, inhaled medications should be administered by metered-dose inhaler. Nebulizers should be avoided whenever possible to avoid the risk of aerosolization of SARS-CoV-2 through nebulization.

If a nebulizer has to be used then the necessary precautions should be taken to prevent the spread of the COVID infection. 

5.Uncertainty about use of NSAIDs

There have been anecdotal reports which raised concerns about possible negative effects of NSAIDs because there were reports where a few young patients who received NSAIDs early in the course of the infection, experienced severe disease [42]. However, there have been other observational studies that have found no association between NSAID use and worse outcomes when compared with acetaminophen use or no antipyretic use [42].

The US NIH, WHO, and the European Medicines Agency (EMA), COVID-19 treatment guidelines do not recommend that NSAIDs should be avoided when clinically indicated in patients with COVID-19 infections.

B.COVID-19-Specific Therapy

Dexamethasone and other glucocorticoids 

Dexamethasone at a dose of 6mg daily for 10 days or until discharge, whichever is shorter, is usually recommended for severely ill COVID-19 patients who are on supplemental oxygen or ventilatory support. Other glucocorticoids can be used if dexamethasone is not available.  Hydrocortisone 150 mg, methylprednisolone 32 mg, or prednisone 40 mg daily may be used but data supporting the use of these alternatives are limited. These drugs are not used for the prevention or treatment of mild to moderate COVID-19 (patients not on oxygen) [42]. 

Patients on glucocorticoids should be monitored for adverse effects such as hyperglycemia and infections (bacterial, fungal, and Strongyloides infections).

Randomized trials support the use of glucocorticoids for severe COVID-19. A meta-analysis of seven trials which included 1703 critically ill COVID-19 patients (on respirator), glucocorticoids reduced the 28-day mortality as compared with standard care or placebo (327% versus 41.4% percent) and were not associated with an increased risk of severe adverse events [44]. 

In another systematic review carried out by Siemieniuk et al [45], the authors found that glucocorticoids probably reduced mortality and mechanical ventilation in patients with covid-19 when compared with standard care. The effectiveness of most interventions was, however,  uncertain because most of the randomized controlled trials were small and had important study limitations.

Benefit is usually not seen with glucocorticoids among patients who do not require either oxygen or ventilatory support.

Data on the efficacy of glucocorticoids other than dexamethasone are limited to smaller trials, many of which were stopped early because of a lack of definite efficacy [46,47]. 

Methylprednisolone has also not demonstrated a clear benefit. A randomized trial from Brazil that included 393 patients with suspected or confirmed severe COVID-19 showed that there was no difference in 28-day mortality rates with methylprednisolone compared with placebo (37% versus 38%) [48]. 

Glucocorticoids may also have a role in the treatment of refractory shock in critically ill patients with COVID-19. 

Remdesivir 

Remdesivir is an adenosine analogue. It incorporates into nascent viral RNA chains and results in its premature termination. Remdesivir has shown in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [49].

Some doctors use remdesivir for patients who are hospitalized with severe COVID-19 because there is some data that suggests that it reduces time to recovery [42]. It is used in patients requiring low-flow supplemental oxygen and it may reduce mortality in this population [42]. 

The optimal role of remdesivir, however, remains uncertain. WHO does not recommend the use of remdesivir in hospitalized patients because there is no clear evidence that the use of remdesivir improves patient outcomes for hospitalized patients (such as, mortality and the need for mechanical ventilation) [50,51]. The Infectious Diseases Society of America and the National Institutes of Health, however, suggest using remdesivir in hospitalized patients who require supplemental oxygen [52,53]. 

The Food and Drug Administration (FDA) in the USA approved remdesivir for hospitalized children ≥12 years and adults with COVID-19, regardless of disease severity [42]. On the first day 200 mg of remdesivir is given intravenously followed by 100 mg daily for 5 days. If there is no improvement and in patients, on mechanical ventilators, the drug can be given for 10 days. Remdesivir is not recommended in patients with renal impairment because in patients with renal impairment accumulation of the drug can occur and lead to toxicity. Liver enzymes should be checked before and during remdesivir administration. Potential drug interactions can occur if remdesivir is used with hydroxychloroquine or chloroquine. 

The Janus kinase inhibitor baricitinib can be used in combination with remdesivir in patients with COVID-19 who require oxygen or ventilatory support [42]. 

Convalescent plasma 

Convalescent plasma obtained from individuals who have recovered from COVID-19 contain antibodies that can provide passive antibody-based immunity. The main active component in the plasma is the neutralizing antibodies though other immune mediators may also be present.  Convalescent plasma with high level of neutralizing antibody titers appears to have clinical benefits when given in the early course of the disease. It is especially useful in individuals with deficits in antibody production (eg, those receiving anti-CD20 therapies) [54]. 

The role of convalescent plasma in patients with severe disease, however, is not clear.

Hydroxychloroquine/chloroquine 

Chloroquine and hydroxychloroquine can inhibit SARS-CoV-2 in vitro [59]. There are, however, several controlled trials that show that chloroquine and hydroxychloroquine do not provide clinical benefit for patients with COVID-19 [60-65]. The US FDA in June 2020, revoked its emergency use authorization for these agents in patients with severe COVID-19. They noted that the known and potential benefits do not outweigh the known and potential risks [66].

High doses of these drugs can lead to high mortality rates. They can produce QTc prolongation and arrhythmias.

Other agents

The use of other agents such as favipiravir, interferons, azithromycin (with or without hydroxychloroquine), lopinavir-ritonavir, ivermectin, sofosbuvir plus daclatasvir, the selective serotonin receptor blocker fluvoxamine, famotidine, colchicine, vitamin D, zinc, IL-1 inhibitors, other cytokine inhibitors, kinase inhibitors, complement inhibitors, bradykinin pathway inhibitors, and recombinant hematopoietic colony-stimulating factors, are not recommended because their efficacy has not been proven [42].

Management of Hypoxia, ARDS and Other complications

Patients who have severe disease very often need oxygenation support. High-flow oxygen is delivered via nasal cannulas. Noninvasive positive-pressure ventilation is often used. Since these are aerosol-generating procedures specific isolation precautions have to be taken. 

Some experts encourage hospitalized patients with COVID-19 to spend as much time as is feasible and safe in the prone position while receiving oxygen. There is some evidence that proning results in improved oxygenation [42].

The World Health Organization recommends titrating oxygen to a target SpO2 of ≥94 percent during initial resuscitation and ≥90 percent for maintenance oxygenation.

When patients develop acute respiratory distress syndrome (ARDS) then intubation with mechanical ventilation is necessary. 

In some patients, a tracheostomy may be needed for failed extubation, secretion management, airway edema, and in patients with neurological impairment such as that which impairs airway protection.

Prognosis

The severity of COVID-19 disease varies in different patients. In patients with mild disease, there may be few or no symptoms. The symptoms may resemble a common cold. Mild cases usually recover within two weeks. In patients with severe or critical disease recovery may take three to six weeks. Among those who have died, the time from symptom onset to death has ranged from two to eight weeks [67]. Patients with prolonged prothrombin time and elevated C-reactive protein levels on admission to the hospital tend to have a severe course of COVID-19 and have a higher chance of transfer to ICU [68,69].

About 10% to 20% of patients with COVID infections will experience symptoms lasting longer than a month [70,71].

Many patients who were admitted to the hospital with severe disease often report long-term problems such as fatigue and shortness of breath [72]. Besides fatigue and shortness of breath, they can have long term effects such as cough, inflammation, and injury of major organs (including the lungs and heart), as well as neurological and psychological effects. They can also have cyclical bouts of fatigue, headaches, months of complete exhaustion, and mood swings. 

Screening, Containment and Mitigation of COVID-19

There are several strategies that can be used to control an outbreak of infection in a pandemic. These include screening, containment (or suppression), and mitigation. 

Screening for COVID-19

Screening aims to identify individuals who may be infected but are showing no symptoms. Many individuals with COVID-19 virus appear healthy or may only show mild symptoms. It is very important to identify infected people so that they can be kept away from others and appropriate treatment can be instituted. The importance of correctly identifying individuals with or without COVID-19 cannot be overemphasized.  Incorrectly identifying no infection in infected individuals can spread the infection and incorrectly identifying COVID-19 in healthy people could lead to unnecessary self-isolation and further investigation.

Screening for COVID-19 includes temperature checks, asking about travel history and contact with COVID-19 cases, and doing rapid virus tests. Screening can be done in person at home, workplace, clinics, hospitals, schools, and at airports. Screening can also be done on a phone and online.

Viswanathan et al [73] carried a Chochrane review to find out the effectiveness of screening for COVID-19. These were their findings:

• Questioning individuals about symptoms at airports may slightly slow, but not stop, the importation of infected people.
• Weekly or biweekly screening of healthcare workers may reduce transmission of the infection to patients and other healthcare workers in the emergency departments.
• No studies reported on negative effects of screening.
• Screening incorrectly identified between 20 and 100 out of 100 infected people as healthy.
• Screening incorrectly identified between 0 and 38 people out of 100 healthy people as infected. 
• Asking about symptoms incorrectly identified between 40 to 100 out of 100 infected people as healthy.
• Asking about symptoms incorrectly identified between 0 to 34 out of 100 healthy people as infected. 
• Temperature taking and asking history of travel and exposure to infected/suspected infected person incorrectly identified between 77 and 100 out of 100 infected people as healthy.
• Temperature taking and asking history of travel and exposure to infected/suspected infected person incorrectly identified between 0 and 10 out of 100 healthy people as infected.
• Asking about symptoms plus temperature measurement incorrectly identified between 31 and 88 out of 100 infected people as healthy.
• Asking about symptoms plus temperature measurement incorrectly identified between 0 to 10 people out of 100 healthy people as infected. 
• One study showed that 70% of infected travellers were missed when entry and exit screening was done at airports.

The authors concluded that one-time screening in apparently healthy people is likely to miss people who are infected. They were also uncertain whether combined screenings, repeated symptom assessment, or rapid laboratory tests are useful.

These studies show poor sensitivity of existing screening approaches. Hence there is a need for greater emphasis on other ways to prevent transmission. These include, face covering, physical distancing, quarantine, as well as adequate personal protective equipment for frontline workers.

Containment of COVID-19

Some of the measures taken to contain the disease include [74]:

• Trace and isolate infected individuals
• School closures
• Workplace closures
• Cancellation of public events
• Restrictions on size of gathering
• Closures of public transport
• Stay-at-home requirements 
• Restrictions on internal movement
• Restrictions on international travel

All measures contribute significantly to reducing the number of COVID-19 cases. Restrictions on international and domestic travel and stay-at-home orders appear to have been most effective in containing the disease [74]. 

Mitigation Strategies for COVID-19

Mitigation activities are actions that people and communities take to slow the spread of a new virus in a pandemic and at the same time protecting all individuals, especially those at high risk for severe illness while minimizing the negative impacts of these strategies. Generally, mitigation strategies should be acceptable, feasible, and practical. They should be implemented in a manner that minimizes both morbidity and mortality from COVID-19 [75].

Some of the mitigation strategies to consider include [75]:

1.Promoting behaviors that prevent spread

• Staying home when sick and when having had contact with COVID infected person.
• Teaching and reinforcing hand hygiene practices and respiratory etiquette
• Teaching and reinforcing the use of cloth face coverings to protect others 
• Ensuring availability of sinks, soap, hand sanitizers, paper towels and/or hand dryer
• Post posters and signs that promote behaviors that prevent spread

2.Maintaining healthy environments

• Intensify disinfection and cleaning of surfaces that are frequently touched 
• Ensure ventilation systems are operating efficiently and increase  outdoor air circulation
• Ensure that water systems are safe to use
• Modify layouts to make sure that social distance of at least 6 feet between people is kept especially for persons who do not live together
• Install physical barriers to support social distancing 
• Close communal spaces if possible
• Reduce sharing of objects

3.Maintaining healthy operations

• Protecting people who are at higher risk for severe illness from COVID-19
• Helping individuals to cope with stress and encouraging them to take time to unwind and connect with others
• Maintaining awareness of all local or state regulations
• Staggering and rotating schedules
• Avoiding mixing between groups
• Pursuing virtual events. Maintaining social distancing at events, and limiting group size
• Limiting non-essential visitors, volunteers, and activities involving external groups or organizations
• Encouraging telework and virtual meetings 
• Considering options for non-essential travel in accordance with regulators
• Implementing flexible and non-punitive leave policies
• Training staff on safety protocols
• Conducting daily health checks such as temperature screening and symptom checking
• Encouraging individuals who share facilities to adhere to mitigation strategies
• Putting in place communication systems for individuals to self-report COVID-19 symptoms, a positive test for COVID-19, or exposure to someone with COVID-19
• Putting in place communication systems to notifying local health authorities of COVID-19 cases
• Putting in place communication systems for notifying individuals of any COVID-19 exposures while maintaining the confidentiality 
• Notifying individuals of the closure of any facility 

4.Preparing for when someone gets sick

• Preparing to isolate and safely transport individuals who are sick, to their home or to a healthcare facility
• Encouraging individuals who are sick to follow CDC guidelines for caring for themselves and others who are sick
• Notifying health officials of any case of COVID-19 while maintaining the confidentiality 
• Notifying those who have had close contact with an individual diagnosed with COVID-19 and advising them to stay home and self-monitor for symptoms
• Advising individuals who are sick when it would be safe for them to discontinue home isolation
• Closing off areas used by someone who is sick. Waiting more than 24 hours before cleaning and disinfecting.

Individual and organizational responsibility for implementing and enforcing the mitigation strategies is of paramount importance.

Contact tracing 

Contact tracing is used by health authorities to determine the source of infection and to prevent further transmission.

To carry out contact tracing, clinics, laboratories, and hospitals send the names of people who have been diagnosed with COVID-19 to their local health authorities [76].

The health authorities will then ask each person with COVID-19 about people with whom they have recently had close contact. The authorities will then quickly (usually within 24 hours) alert individuals who are close contacts that they have been exposed to the COVID-19 virus. The authorities don't share the name of the person who has exposed them so that the contact tracing process can remain anonymous and confidential.

Contact tracing apps are often widely used. These apps make it faster and easier to find and notify people who've been exposed to the COVID-19 virus [76].

A close contact is an individual who's been within 6 feet (2 meters) of a person with COVID-19 within two days of the person's diagnosis. Close contacts include family, friends, co-workers and health care providers.

The close contacts are asked whether they have any symptoms and they are advised to be tested for the virus. They are given several instructions on how to reduce the risk of unknowingly spreading the COVID-19 virus to others.

For close contacts who do not have symptoms and cannot be tested, or test negative for the COVID-19 virus, doctors and the health authorities will [76]:

• Advise them to self-quarantine at home for 14 days after they were exposed. They can end the quarantine after 10 days if they don't have symptoms and cannot get tested. The quarantine can end after 7 days if they tested negative for the virus. They are, however, advised to look out for symptoms for 2 weeks.
• Advise them to keep social distance from others including family members and pets. They also have to use separate bedrooms and bathrooms. 
• Advise them to monitor their health and watch out for COVID-19 symptoms.
• Advise them to check their temperature twice a day.
• Advise them to let their doctor and health department know if they develop any symptoms.
• Advise them to send daily health updates to the doctors and the health department 

For close contacts who test positive for the virus, develop symptoms, or have symptoms but cannot be tested, the doctors and the health authorities  will [76]:

• Advise them to self-isolate and recover at home for at least 10 days if they have symptoms. They have to self-quarantine for 14 days after being exposed. People with symptoms have to isolate themselves from family and pets and also use separate bedrooms and bathrooms.
• Advise them to seek medical care if they have any emergency warning signs, such as breathing difficulty or persistent chest pain.
• Advise them to monitor their symptoms and avoid spreading the COVID-19 virus to others.

Contact tracing is a powerful tool that helps to reduce the spread of the COVID-19 virus and help control the COVID-19 outbreak.

Shortages related to the COVID-19 pandemic

The fundamental outbreak response measure for the COVID-19 pandemic is the need to increase capacity and to adapt to the healthcare needs. The European Centre for Disease Prevention and Control (ECDC) and the European regional office of the WHO have issued guidelines for hospitals and primary healthcare services for shifting of resources at multiple levels. This includes focusing laboratory services towards COVID-19 testing, canceling elective procedures whenever possible, isolating and separating COVID-19 positive patients, and increasing capabilities of the intensive care unit by training personnel and increasing the number of available ventilators and beds [77,78]. In an attempt to maintain physical distancing to protect both the patients and clinicians, in some non-emergency areas the healthcare services are provided virtually [79-81].

Capacity limitations in the standard supply chains has led some manufacturers to carry out 3D printing of healthcare material such as nasal swabs and ventilator parts [82,83]. NASA developed a ventilator for COVID-19 patients in just 37 days. It was approved by FDA in April 2020 [84]. 

Conclusion

As of 31 December 2020, 83,134,416 cases of Covid-19 have been detected and the death toll stands at 1,813,386. These numbers do not accurately reflect the actual number of cases and deaths because many go undetected especially in underdeveloped and poorer countries with large populations. Covid-19 is here to stay for some time. Presently there is no cure for the disease and there appears to be no vaccine that can prevent the infection. The economic toll brought about by this pandemic is high.

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