COVID-19-associated lymphopenia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Oluwabusola Fausat Adogba, MD[2]

Synonyms and keywords:Lymphocyte changes in COVID-19, sars-cov-2 related lymphopenia

Overview

Coronavirus disease 2019 (COVID-19) has been considered as a global pandemic since its first emergence in Wuhan, China. On March 12, 2020, the World Health Organization declared the COVID-19 outbreak a pandemic. There is no established system for the classification regarding COVID-19 related lymphopenia. Four hypothetical mechanisms regarding lymphopenia in covid19 infection are direct infection of lymphocyte, direct destroying of lymphocytic organs, inflammatory cytokines such as TNFɑ, IL-6, lymphocyte inhibition.

Historical Perspective

• Coronavirus disease 2019 (COVID-19) has been considered as a global pandemic since its first emergence in Wuhan,China.
• On March 12, 2020, the World Health Organization declared the COVID-19 outbreak a pandemic.
• Since the first descriptive study lymphocyte count has been a marker of interest.

Classification

• There is no established system for the classification regarding COVID-19 related lymphopenia.

Pathophysiology

• There are four hypothetical mechanisms regarding lymphopenia:
  • Direct infection of lymphocytes
  • Direct destroying lymphatic organs
  • Inflammatory cytokines such as TNF-ɑ, IL-6, etc inducing lymphopenia
  • Inhibition of lymphocytes by metabolic molecules such as hyperlactic acidemia

Causes

• The SARS-CoV-2 (COVID-19) viral infection is the known cause of lymphopenia in COVID-19 patients. To read more click here

Differentiating COVID-19 related Lymphocytopenia from other Diseases

• Lymphocytopenia, is associated and must be differentiated from the following diseases which includes the following:
  • After influenza
  • After snakebite
  • Anesthesia
  • Antibody deficiency syndrome
  • Aplastic Anemia
  • Banti's Syndrome
  • Burns
  • Congenital immune deficiency
  • Cushing's Disease
  • Dermatomyositis
  • Drugs, toxins
  • Exudative enteropathy
  • Felty's Syndrome
  • Heavy exercise
  • HIV
  • Hodgkin's Lymphoma
  • Inflammatory Bowel Disease
  • Lymphocyte tuberculosis
  • Measles
  • Paroxysmal nocturnal hemoglobinuria
  • Polycythemia
  • Postoperative
  • Pregnancy
  • Sarcoidosis
  • Scarlet Fever
  • Secondary hypersplenism
  • Single non-Hodgkin's lymphomas
  • Surgery
  • Systemic Lupus Erythematosus
  • Trauma
  • Tuberculosis
  • Uremia
  • Whipple's Disease
  • Zinc deficiency

Epidemiology and Demographics

• The incidence of the coronavirus disease 2019 (COVID-19) as of June 28, 2020 is approximately 9,843,073 cases worldwide with 495,760 deaths.
• Patients of all age groups may develop COVID-19. However, the elderly population and immunocompromised individuals are more likely to develop severe cases of COVID-19.

Risk Factors

• People of any age with certain underlying medical conditions are at increased risk for severe illness from COVID-19. These medical conditions include:
  • Chronic kidney disease
  • Chronic obstructive pulmonary disease
  • Immunocompromised state (weakened immune system) from solid organ transplant
  • Obesity (body mass index [BMI] of 30 or higher)
  • Serious heart conditions, such as heart failure, coronary artery disease, or cardiomyopathies
  • Sickle cell disease
  • Type 2 diabetes mellitus

Screening

• Lymphopenia on admission has been associated with predicting the severity of clinical outcomes. Approximately, a three-fold increase in severity has been associated with lymphopenia on admission.
• A routine complete blood count (CBC) with differential can be used for monitoring and predicting disease progression and severity in patients.

Natural History, Complications, and Prognosis

• Lymphopenia is the most common laboratory finding in COVID-19, and is found in as many as 83% of hospitalized patients.
• COVID-19 related lymphocytopenia starts acutely in the course of the disease, with other manifestations of the disease.
• Lymphopenia is lymphocyte count of less than 1.5 × 109/L. It is associated with a 3-fold increased risk of severe COVID-19 infection.
• Patients with lymphopenia on admission have been associated with poor prognostic outcomes.
• Recent studies have shown that 85% of severely ill patients have lymphopenia. Futhermore, patients who have died from COVID-19 infection showed significantly lower lymphocyte level than survivors.
• Common hematologic complications of coronavirus also include neutrophilia and thrombocytosis.

Diagnosis

Diagnostic Choice of Study

• Lymphopenia refers to a count of less than 1,000 lymphocytes per micro liter of blood in adults, or less than 3,000 lymphocytes per microliter of blood in children. The following tests are used to diagnose lymphopenia:
  • Complete blood count (CBC)
  • Flow cytometry

History and Symptoms

• Lymphopenia as a result of COVID-19 can present with different symptoms. People with COVID-19 have had a wide range of symptoms reported – ranging from mild symptoms to severe illness. Symptoms may appear 2-14 days after exposure to the virus. People with these symptoms may have COVID-19:
  • Fever or chills
  • Cough
  • Shortness of breath or difficulty breathing
  • Fatigue
  • Muscle or body aches
  • Headache
  • New loss of taste or smell
  • Sore throat
  • Congestion or runny nose
  • Nausea or vomiting
  • Diarrhea

Physical Examination

• There are no physical findings associated with lymphopenia.
• However patients with significant lymphopenia can show signs of the associated disorder, in this case COVID-19 symptoms.
• For more information about COVID-19 physical examination please click here.

Laboratory findings

• Lymphocyte count on CBC with differential is less than 1.5x109/L is potentially associated with severe outcomes.
• Peripheral blood smear- This maybe helpful, however there is insufficient evidence recommending routine peripheral blood smear in COVID-19 patients.
• For more information about COVID-19 laboratory findings please click here.

Electrocardiogram

• There are no ECG findings associated with COVID-19 associated lymphopenia.
• To view the electrocardiogram findings on COVID-19, click here.

X-ray

• There are no X-ray findings associated with COVID-19 associated lymphopenia.
• To view X-ray findings of COVID-19 ,click here.

Echocardiography or Ultrasound

• There are no echocardiography or ultrasound findings associated with COVID-19 associated lymphopenia.
• To view the echocardiographic findings on COVID-19, click here.

CT Scan

• There are no CT scan findings associated with COVID-19 associated lymphopenia.
• To view the CT scan findings on COVID-19, click here.

MRI

• There are no MRI findings associated with COVID-19 associated lymphopenia.
• To view the MRI findings on COVID-19, click here.

Other imaging findings

• There are no other imaging findings associated with COVID-19 associated lymphopenia.
• To view other imaging findings on COVID-19, click here.

Other Diagnostic studies

• Bone marrow biopsy, although not recommended may be helpful if there is suspicion of other disorders that can cause lymphopenia, but there is not enough evidence to support bone marrow biopsy in COVID-19 patients.
• To view other diagnostic studies for COVID-19, click here.

Treatment

Medical therapy

Immune-Based Therapy:

• There are insufficient data to recommend either for or against the use of COVID-19 convalescent plasma or SARS-CoV-2 immune globulins for the treatment of COVID-19.

• The COVID-19 treatment guidelines panel (the panel) recommends against the use of non-SARS-CoV-2-specific intravenous immune globulin (IVIG) for the treatment of COVID-19, except in the context of a clinical trial. This should not preclude the use of IVIG when it is otherwise indicated for the treatment of complications that arise during the course of COVID-19.

• There are insufficient data to recommend either for or against the use of the following agents for the treatment of COVID-19:
  • Interleukin-1 inhibitors (e.g., anakinra)
  • Interleukin-6 inhibitors (e.g., sarilumab, siltuximab, tocilizumab)

• Except in the context of a clinical trial, the panel recommends against the use of other immunomodulators, such as:
  • Interferons, because of the lack of efficacy in the treatment of severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS) and toxicity.
  • Janus kinase inhibitors (e.g., baricitinib), because of their broad immunosuppressive effect.

Surgery

• Surgical intervention is not recommended for the management of COVID-19 associated lymphopenia.

Primary Prevention

• There are no established measures for the primary prevention of COVID-19 associated lymphopenia.

Secondary Prevention

• There are no established measures for the secondary prevention of COVID-19 associated lymphopenia.