WHO REGIONAL OFFICE FOR AFRICA COVID-19 RAPID POLICY BRIEF SERIES SERIES 1: COVID-19 CASE COVID-19’

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WHO REGIONAL OFFICE FOR AFRICA COVID-19 RAPID POLICY BRIEF SERIES SERIES 1: COVID-19 CASE COVID-19’ DIAGNOSIS AND CASE MANAGEMENT

NUMBER 005-01: Early warning Signs/indicators for severe COVID-19 Based on information as at 19 August 2020

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Rapid Policy Brief Number: 005-01 - Early warning Signs/indicators for severe COVID-19

WHO/AF/ARD/DAK/13/2020

© WHO Regional Office for Africa 2020

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RAPID POLICY BRIEF 1

NUMBER: 005-01

RESEARCH DOMAIN: COVID- 19’diagnosis and Case management

TITLE: Early warning Signs/indicators for severe COVID-19

RAPID POLICY BRIEF NUMBER: 005-01

1 RAPID POLICY BRIEF NUMBER: 005-01

2 RESEARCH DOMAIN: COVID-19’diagnosis and Case management

3 TITLE: Early warning Signs/indicators for severe COVID-19

4 DATE OF PUBLICATION: 25/08/2020

5 BACKGROUND

Coronavirus disease 2019 (COVID-19) was first identified in Wuhan, China, in December 2019.

Available reports indicate that by mid-September 2020, over 30 million people had been infected with SARS-Cov2, the virus that causes COVID-19, and close to one million people had died. Nearly all patients who have died of COVID-19 have developed severe disease before death. This policy brief therefore presents evidence on the early warning indicators of severe COVID-19 that health workers should be aware of while caring for COVID-19 patients. The evidence presented originates from a systematic review of literature on early warning signs of severe COVID-19 disease.

6 SEARCH STRATEGY / RESEARCH METHODS

A systematic search of various databases for primary studies on early warning signs of severe COVID-19 was conducted between 13^th and 19^th august 2020. In addition, manual search of articles referenced in the primary studies was undertaken, and articles that met the inclusion criteria were included in the review. English, French and Portuguese study of any study design and done between 1^st December 2019 to 19^th August 2020 were included in the review provided they reported on the indicators of severe COVID-19 disease.

The systematic search identified 78 potential studies. However, only 16 studies met the inclusion criteria. Details of the data bases searched, articles identified and data extraction are provided elsewhere. Due to heterogeneity of the results, descriptive analysis of the findings was done.

7 SUMMARY OF GLOBALLY PUBLISHED LITERATURE RELATED TO THE SUBJECT

Several early warning indicators of severe COVID-19 disease were reported by the studies. These included demographic characteristics of the patients, clinical manifestations of COVID-19, existing comorbidities, and biomarkers of severe COVID-19 identifiable through laboratory tests.

1. COVID-19 Symptoms and signs.

Fever, fatigue, dry cough, diarrhea, chest tightness and shortness of breath are the most common clinical manifestations of severe COVID-19 reported by the studies [3, 4, 5]. Among these symptoms, fever is the most common clinical manifestation of COVID-19, followed by cough.

According to the studies, cough is often associated with shortness of breath (dyspnea) and a

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marked decline in oxygen saturation in blood – which are the early clinical manifestations of acute respiratory distress syndrome (ARDS).

2. Demographic characteristics of the patients

One study reported that the risk of progression to severe COVID-19 increased with increase in age, with the risk particularly higher among older patients (>60 years) compared to younger patients.

This finding was confounded by cigarette smoking and underlying comorbidities as those who progressed faster were mostly either cigarette (tobacco) smokers or had chronic illnesses such as diabetes mellitus or both [6]. The studies also indicate that males are more likely to develop severe COVID-19 than females.

3. Existing comorbidities.

Existing comorbidities are a potential indicator of severe COVID-19 and death. According to the studies, patients who had underlying chronic diseases such as diabetes mellitus, hypertension, heart disease, chronic obstructive respiratory disease, and cancer progressed faster to severe COVID-19 or died compared to those without any underlying chronic illness [7].

4. Bio-Markers.

Several biomarkers have been reported by studies to be associated with severe COVID-19, and their presence therefore represent an early warning sign when identified in a laboratory investigation. One study reported that high levels of interleukin 6 (IL-6) and lactic acid in the blood of patients with SARS-Cov2 is an indication of progression to severe COVID-19 [8]. However, use of lactic acid levels in the blood as an early warning sign of severe COVID-19 should be done with caution, especially when a patient also has elevated lactate dehydrogenase given that lactate dehydrogenase reduces the level of lactic acid in the blood. In fact, some studies have proposed use of an elevated lactate dehydrogenase in the blood as an early warning sign of severe COVID- 19 due to its association of myocardial infarction [9].

High levels of C-reactive protein in the blood is another biomarker proposed by studies as an early warning sign of severe COVId-19 [10,11]. C-reactive proteins are associated with lung lesions in patients with severe pneumonia. It is thought that an elevated level of C-reactive proteins is linked to the overproduction of inflammatory cytokines in severe patients with COVID‐19.

5. Blood cells count.

Blood cell counts are also an important indicator of severe COVID-19. One study reported that patients with severe COVID-19 often have abnormally high levels of white blood cells and abnormally low levels of lymphocytes and platelets [12]. According to one study, patients with

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NUMBER: 005-01

severe COVID-19 are about three times more likely to have a reduction in their absolute lymphocyte count than those without severe disease (OR = 2.426, P = 0.010) [13].

The studies also suggest that the following parameters linked to platelet (PLTs) function and activity could provide a great deal of information on potential severity of COVID-19, as they are associated with hyper-activation of coagulation, as well as development of thrombosis and microthrombosis commonly seen in COVID-19 patients, especially presence of immature platelets, reduced mean volume, increased PLTs distribution width, PLT-derived microparticles (PMPs) combined with D-dimer [14].

6 studies have shown that immature platelet fraction can be effectively used as marker of PLTs activation and increased risk of thrombosis. Larger PLTs contain more dense granules, produce more thromboxane A2, platelet factor A and beta-thromboglobulin, and are consequently more reactive with greater prothrombotic potential than smaller PLTs. Moreover, increased immature PLT fraction can predict a decrease in PLT count during coagulopathy. A key marker of PLTs activation for COVID-19 patients could also be the PLTs distribution width that has been reported to be increased in venous thrombosis as well as in several hypercoagulative state, such as in cardiovascular diseases. An additional PLTs parameter particularly active in thrombus formation is the reticulated PLTs that reflect increased PLTs consumption during the thrombosis progression and/or prelude to the development of thrombosis. In fact, reticulated PLTs may reflect an increased PLT turnover in the setting of a normal PLTs count and this aspect could be of critical importance in the early diagnosis of COVID-19. Another efficient parameter that can be also combined with PLT distribution width, PLTs count, and D-dimer is the PLT-derived microparticles (PMPs) that play a critical role in thromboembolism through direct cell-to-cell contact interactions or release of active components.

8 SUMMARY OF AFRICA-SPECIFIC LITERATURE ON THE SUBJECT Not found

9 POLICY FINDINGS

The studies show that there are clear early warning signs of severe COVID-19 that health care providers can use as a guide for timely instituting measures to reduce the risk of death among COVID-19 patients. The most common clinical manifestations of COVID-19 are:

fever, fatigue, dry cough, diarrhea, chest tightness and shortness of breath, and most patients with severe COVID-19 developed fever, cough, dyspnea, and markedly decline in oxygen saturation, which are the early clinical manifestations of Acute Respiratory Distress Syndrome.

The results of studies indicate that demographic characteristics and behavior such as older age, male sex and higher likelihood of being a smoker are risk factors for severe COVID-19.

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The same studies reported that blood cells counts (WBC count, lymphocyte count, platelet count) deserve close monitoring; the increase of WBC, decrease of absolute lymphocytes and platelets could serve as early warning laboratory manifestations for severe COVID-19.

Furthermore, the alteration of PLTs parameters in association with the prolonged prothrombin time, increase of D-dimer, and decrease of fibrinogen in COVID-19 patients are of key importance to diagnose and/or monitor the worsening of coagulation. In the most serious form, this worsening of coagulation leads to an inadequate blood supply to different organs and contributing to multiple organ failure/dysfunction, thus giving rise to disseminated intravascular coagulation (DIC) disease [15].

The risk of developing severe COVID-19 in patients with a serum CRP of ≥65.08 mg/L is 8.9 times that in patients with a serum CRP≤65.08 mg/L. At elevated concentrations, CRP, which is an acute-phase protein, is correlated with an increased risk of organ failure and death for patients admitted to the Intensive Care Unit. Further, prolonged periods of high CRP concentrations are associated with adverse outcomes.

A decreased lymphocyte counts on admission and an increased concentration of serum CRP could serve as early warning signs in patients who are at risk of developing severe COVID-19.

A strong recommendation is for clinicians to closely monitor bio-markers such as IL-6, lactate dehydrogenase and serum ferritin as markers for potential progression to critical illness when they are high. Moreover, high lactate dehydrogenase levels are also associated with tissue injury occurring in various diseases, including pulmonary disorders such as pneumonia, and liver and kidney dysfunctions; therefore, corresponding treatments should be taken timeously to prevent further deterioration of the patient’s condition. Similarly, as COVID-19 can also cause pneumonia as well as heart, liver, kidney, and other organ dysfunctions, the patients may die from heart failure, shock, acute respiratory distress syndrome, arrhythmia, or renal failure [16].

In conclusion, age and laboratory indicators such as elevated lactate dehydrogenase, procalcitonin and D-dimer increase are early predictors of severe COVID-19. Shortness of breath at admission, past histories of diabetes and heart disease, and abnormalities in some indicators, such as low absolute lymphocyte count, low CD4 percentage and CRP increase, indicate that the patient is already severely ill or has a significant risk of progressing to severe conditions. Moreover, coagulation function disorder is also an early indicator of the disease progression to severe. All these could serve as early warning manifestations in patients who are at risk of severe COVID-19.

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NUMBER: 005-01

10 ONGOING RESEARCH IN THE AFRICAN REGION Not found

11 AFRO RECOMMENDATIONS FOR FURTHER RESEARCH

There is a need to carry out other studies to have fairly clear evidence on warning signs for severe COVID-19; interactions between COVID-19 and underlying disease, coagulation disorders and COVID-19 deserve further attention and clarification in the African Region.

WHO/AFRO encourages producing and sharing scientifically research and knowledge related to COVID-19 for early prevention, diagnosis and treatment.

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12 REFERENCES

1. Xinkui Liu, Xinpei Yue, Furong Liu, Le Wei, Honghong Bao, Yichao Dong, Wenjie Cheng, Linpeng Yang.

Analysis of clinical features and early warning signs in patients with severe COVID-19: A retrospective cohort study. doi: 10.1371/journal.pone.0235459.

2. Yiming Lu, Kuo Sun, Shanshan Guo, Junjie Wang, An Li, Xuli Rong, Tingfang Wang, Yan Shang, Wenjun Chang, Sheng Wang. early Warning Indicators of Severe COVID-19: A Single-Center Study of Cases from Shanghai, China.

3. Lai CC, Shih TP, Ko WC, Tang HJ, Hsueh PR. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2) and coronavirus disease-2019 (COVID-19): the epidemic and the challenges. Int J Antimicrob Agents.

(2020) 55:105924. doi: 10.1016/j.ijantimicag.2020.105924.

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5. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. (2020) 395:507–

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6. Li M, Dong Y, Wang H, Guo W, Zhou H, Zhang Z, et al. Cardiovascular disease potentially contributes to the progression and poor prognosis of COVID-19. Nutr Metab Cardiovasc Dis. (2020) 7:1061–7. doi:

10.1016/j.numecd.2020.04.013.

7. Lipsitch M, Swerdlow DL, Finelli L. Defining the epidemiology of Covid-19 - studies needed. N Engl J Med.

(2020) 382:1194–6. doi: 10.1056/NEJMp2002125.

8. Yang P, Ding Y, Xu Z, Pu R, Li P, Yan J, et al. Epidemiological and clinical features of COVID-19 patients with and without pneumonia in Beijing, China. MedRxiv. (2020). doi: 10.1101/2020.02.28.20028068.

9. Aggarwal S, Garcia Telles N, Aggarwal G, Lavie C, Lippi G, Henry BM. Clinical features, laboratory characteristics, and outcomes of patients hospitalized with coronavirus disease 2019 (COVID-19): early report from the United States. Diagnosis. (2020) 7:91–6. doi: 10.1515/dx-2020-0046.

10. Singhal T. A review of coronavirus disease-2019 (COVID-19). Indian J Pediatr. (2020) 87:281–6.

doi: 10.1007/s12098-020-03263-6.

11. Gudbjarnason S, Priver DM. LDH–isoenzymes in infarcted heart muscle. Life Sci. (1968) 7:623–7.

doi: 10.1016/0024-3205(68)90084-2.

12. Jing Xu , Fengde Zhao, Mingfeng Han, Lei Ma, Ting Zhang. Analysis of the clinical characteristics and early warning model construction of severe/critical coronavirus disease 2019 patients]. https://doi.org/10.3389/fmed.2020.00432.

13. Brandon Michael Henry , Maria Helena Santos de Oliveira, Stefanie Benoit, Mario Plebani, Giuseppe Lippi. Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis. doi: 10.1515/cclm-2020-0369.

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14. Kaushal Shah, Jonathan Kamler, Alexander Phan and Dennis Toy. Imaging & other potential predictors of deterioration in COVID-19.

• 15. Francesca Salamanna, Melania Maglio ,Maria Paola Landini &Milena Fini. Platelet functions and activities as potential hematologic parameters related to Coronavirus Disease 2019 (Covid-19).

https://doi.org/10.1080/09537104.2020.1762852.

16. Wang T, Du Z, Zhu F, Cao Z, An Y, Gao Y, et al. Comorbidities and multi-organ injuries in the treatment of COVID-19. Lancet. (2020) 395: e52. doi: 10.1016/S0140-6736(20)30558-4.

BRIEF PRODUCED BY: Jean Claude Nshimirimana, Humphrey Karamagi, Kwami Dadji, Regina Titi-Ofei, Aminata B. Seydi, Benson Droti, John Appiah, Pascal Mouhouelo, Monde Mambimongo James Asamani, Hillary Kipruto, Julie Nabyonga and Felicitas Zawaira.