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SARS-CoV-2 and beta-thalassemia

A novel coronavirus has spread through China, originating from the city of Wuhan and has caused many deaths so far. It is a highly contagious virus that has spread rapidly and efficiently. Coronavirus disease 2019 (COVID-19) is caused by a virus (SARS-CoV-2) from the same family as the lethal coronaviruses that caused severe acute respiratory syndrome (SARS-CoV) and Middle East respiratory syndrome (MERS-CoV).1
COVID-19 signs and symptoms include fever, cough, and shortness of breath. In more severe cases, infection can lead to pneumonia, serious respiratory problems and ultimately, fatalities. Thousands of people have been reported to have been infected with the virus so far.1
There is epidemiological and clinical evidence to suggest a number of novel compounds, as well as medicines licensed for other conditions, that appear to have potential efficacy against COVID-19.

There is much more to learn about the spread and severity of COVID-19. In the absence of a safe and effective vaccine or medicine, reducing viral transmission is the only strategy available where general education, and implementing the appropriate prevention and control is key.
Precautions can help suppress the risk of infection, such as washing the hands frequently with soap and water or an alcohol-based disinfectant gel, coughing into the elbow or a folded napkin/tissue, avoiding close contact with those who have symptoms, and self-isolating, but medical help must be sought if difficulty in breathing is experienced. COVID-19 can be diagnosed with diagnostic test kits and imaging techniques such as chest X-ray and pulmonary CT scans that facilitate early diagnosis of pneumonia in patients with COVID-19.

Confronting rare diseases requires universal cooperation in identifying, controlling, and preventing these diseases in subjects alreafy fragiles for their genetic condition.

Moreover, this has made it difficult for patients with many genetic conditions to continue their therapy.

Children with thalassemia major require periodic blood transfusions. Almost half of
children with β-thalassemia major are under transfused.2

With the lockdown in many countries, patients and their parents would find it difficult to visit their routine clinics for blood transfusions.
Moreover, the lockdown has drastically reduced the number of voluntary blood donations, thereby
creating a shortage at blood banks. Despite the cancellation of all elective surgeries, blood units
available for transfusion are less.3. Although viral RNA has been detected in the plasma/serum of
COVID-19 patients, the present data do not suggest the risk of transfusion transmission of SARSCoV-2. However, certain International organizations have advised deferral of blood donation for 21 days after possible exposure to a confirmed case and for at least 28 days after symptom resolution in a positive case.4
In addition, patients on iron chelation therapy may find it difficult to procure the drugs amid lockdown.

Eventually there is an underlying risk of these children contracting COVID-19. Unlike sickle cell anemia, children with thalassemia are usually not at an increased risk of fatal pulmonary complications due to COVID-19. However, splenectomy and underlying comorbidities secondary to
iron overload, notably secondary diabetes mellitus, cardiomyopathy and chronic liver disease, may increase the risk of complications and mortality in COVID-19.5

Certain solutions do exist. Blood transfusions could be carried at any nearest convenient healthcare facility instead of routine transfusion clinics. Healthcare authorities should strengthen mobile unit services for facilitating blood donation at doorstep while ensuring stringent precautions.
Till blood stocks replenish, caregivers can bring a voluntary healthy donor at the time of transfusion. Physicians should educate children and caregivers about need for strict social distancing, hand hygiene and common symptoms of COVID-19. Teleconsultations may play a role in this regard.
Children with associated comorbidities must be more cautious. Good glycemic control in patients with secondary diabetes should be ensured. Underlying subclinical hypo-adrenalism should be considered in every thalassemic child with suspected COVID-19 and supplemented with stress-dose
of glucocorticoids.

Since the epidemic, a lot of effort has been put into antiviral research to find compounds effective against SARS-CoV.
Protease inhibitors (lopinavir/ritonavir) in combination with ribavirin may be of benefit as antiviral therapy, when given in the early phase of the illness.6,7 The role of interferon and systemic steroids in preventing immune-mediated lung injury requires further investigation.8,9

Savarino et al.10 hypothesized that chloroquine might be of some use for the clinical management of SARS. Chloroquine is known as an antimalarial agent and elicits also antiviral effects against several viruses including HIV type 1 (HIV-1), hepatitis B virus , herpes simplex virus type 1 and HCoV-229E.
Besides a direct antiviral effect, chloroquine is endowed with immunomodulatory activity, suppressing the production and release of tumour necrosis factor and interleukin 6, which mediate the inflammatory complications of several viral diseases.10

From a reaseach point of view, intriguingly enough, some observations have being done on the low SARS incidence in regions where  malaria is endemic.
In Italy, places like Ferrara, present a lower SARS incidence in respect to the sourrounding towns in the same Region. Even lower is the incidence, given the same amount of population, in places beyond the Po river, like Rovigo.

Moreover, a correlation between the antibodies developed to resist malaria (or perhaps thalassemia) and those necessary to "attack" Covid-19.
We might hypothesize that thalassemia or malaria played a role in keeping those areas almost intact compared to an attack as strong as that of the coronavirus.
An Italian national survay is going on which study hemoglobinopathies and  SARS-Cov2 infection.
Now, however, we should go to study the heterozygotes with a large epidemiological work to see if the hypothesis of an advantage of the beta thalassemic heterozygote really stands up. 
Such a study is easier to carry over in places like province of Rovigo, where there is a 20% of heterogygotes. Otherwise, it might be easier done directly in in vitro experiments.
It might be of interest to understand if you do not infect at all or if they present milder manifestations. Of course, this would be of clinical importance. In fact, preliminary data suggest that infected homozygotes are more resistant then general population, even if they have important comorbidities. This might be because such patients present a mild immunosuppression which probably preserve them from the SARS-Cov2 - induced cytokines storm.

All these topics will be, hopefully, answered by ongoing and future studied which are now carried out all over the scientific word, in a common effort to stop SARS-Cov2 new infections and deaths.

 

Crstiana Lo Nigro

Laboratori Centrali

EO Ospedali Galliera

Genova

 

REFERENCES

1. Morteza AK, Fakher R.  Cross-Country Comparison of Case Fatality Rates of COVID-19/SARS-COV-2. Osong Public Health Res Perspect 2020;11(2):74-80

2. Shah N, Mishra A, Chauhan D, Vora C, Shah N. Study on effectiveness of transfusion program in thalassemia major patients receiving multiple blood transfusions at a transfusion centre in Western India. Asian J Transfus Sci. 2010;4:94-8.

3. Covid-19: Lockdown creates acute shortage at blood banks. Available from: https:// timesofindia.indiatimes.com/india/covid-19-lockdown-creates-acute-shortage-at-bloodbanks/ articleshow/74958205.cms. Accessed April 3, 2020.

4. Chang L, Yan Y, Wang L. Coronavirus Disease 2019: Coronaviruses and Blood Safety. Transfus Med Rev [Internet]. 2020 [cited 2020 Apr 1]; Available from: https:// linkinghub.elsevier.com/retrieve/pii/S0887796320300146. Accessed April 3, 2020.

5. Thalassaemia International Federation. The covid–19 pandemic and haemoglobin disorders. Available from: https://thalassaemia.org.cy/wp-content/uploads/ 2020/03 /COVID-19- pandemic-and-haemoglobin-disorders_V2.pdf. Accessed April 3, 2020.


6. Li Y. Ministry of Science and Technology of China: chloroquine phosphate is effective in the treatment of novel coronavirus pneumonia. 17 Feb. http://news.ynet.com/2020/02/17/2388070t70.html.

7. Biot C, Daher W, Chavain N, et al. Design and synthesis of hydroxyferroquine derivatives with antimalarial and antiviral activities. J Med Chem. 2006. 49(9): 2845-9.

8. Fox RI. Mechanism of action of hydroxychloroquine as an antirheumatic drug. Semin Arthritis Rheum. 1993. 23(2 Suppl 1): 82-91.

9. Physiologically Based Pharmacokinetic Analyses-Format and Content Guidance for Industry. Aug 2018. https://www.fda.gov/media/101469/download.

10. Tett SE, Cutler DJ, Day RO, BrownKF. Bioavailability of hydroxychloroquine tablets in healthy volunteers. Br J Clin Pharmacol. 1989. 27(6): 771-9.