Secondary haemophagocytic lymphohistiocytosis: Experience from the Uppsala University Hospital by Torbjörn Karlsson; doi: 10.3109/03009734.2015.1064500; URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4816886/

Secondary haemophagocytic lymphohistiocytosis:  Experience from the Uppsala University Hospital 

- A severe inflammatory response that presents as a fever, nausea, and swelling
- Has been observed in tandem with COVID-19 pulmonary symptoms
- Involves overproduction of cytokines (key proteins in the immune system)
- Immunosuppression can be helpful in calming the immune system and mitigating this extreme immune response

Smith College

- Cytokine Storm Syndrome
    -  Secondary Haemophagocytic Lymphohistiocytosis
- Common Variable Immunodeficiency 
- Figure illustrating how pathogenic T cells and inflammatory monocytes enter pulmonary circulation and incite an inflammatory storm and immune disorder 
- Severe Combined Immunodeficiency

Immunological Diseases as a Comorbidity of COVID-19

- Acute Respiratory Distress Syndrome (ARDS)
- Cytokine Release/Storm Syndrome 
- Multi-Organ failure 
- Multisystem Inflammatory Syndromes (MIS)
- Secondary Haemophagocytic Lymphiohistocytosis
- Vascular Hyperpemeability 



Downstream Inflammatory Pathogenesis of Cytokine Storms in COVID-19

Mehta, Puja et al. “COVID-19: consider cytokine storm syndromes and immunosuppression.” Lancet (London, England) vol. 395,10229 (2020): 1033-1034. doi:10.1016/S0140-6736(20)30628-0
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270045/

COVID-19: consider cytokine storm syndromes and immunosuppression

Secondary Haemophagocytic Lymphiohistocytosis and COVID-19

- Common Variable Immunodeficiency (CVID) is a disorder which lowers the immune systems defenses and makes patients more susceptible to infections in the lungs, sinuses, and ears
- A 53 y/o patient with CVID was admitted with COVID-19
- Patient was already receiving intravenous immunoglobulin (IVIG) for their CVID
- Levels of patient’s immunoglobulin were taken upon arrival and it was noted that their IgG was normal, but IgM and IgA were low and undetectable respectively
- Patient received additional IVIG daily as well as supplemental oxygen in the form of a nasal cannula and then intubation
- Patient was extubated after 3 days and eventually weaned back to room air as well as discharged on day 14 due to clinical improvement
- The paper also noted that there were 2 similar cases of CVID patients receiving supplemental IVIG in Italy who also made a similar recovery
- It was also stated that while testing was not performed for cytokine storm syndrome, 53 y/o did develop some acute respiratory distress syndrome during their treatment

Common Variable Immunodeficiency 

An inflammatory storm may result from pathogenic T cells and inflammatory monocytes with high levels of IL-6 secretion entering pulmonary circulation in large quantities. This occurrence can also cause an immune disorder in COVID-19 patients with severe complications.  

Figure illustrating how pathogenic T cells and inflammatory monocytes enter pulmonary circulation and incite an inflammatory storm and immune disorder 

- SARS-CoV-2 infection associated with hepatitis in an infant with X-linked severe combined immunodeficiency

Severe Combined Immunodeficiency

- Eight children with the recent onset hyperinflammatory shock were chosen for the study (symptoms similar to Kawasaki disease)
- 4 children came from families with exposure to COVID-19
- 7 children presented with inflammation in both lungs
- All of the children tested negative for the virus
- 1 of the children was secluded due to having adenovirus and enterovirus
- 1 child had a coronary aneurysm
- Another child had an irregular heartbeat and faced a refractory shock; the child eventually died due to a stroke
- During the first day of the study, the children were intravenously given immunoglobulin and antibiotics
- 6 children were given aspirin
- After 4-6 days, all the children were discharged
- After discharge, two children tested positive for COVID-19, one of them being the child that died (post-mortem report) 
- Overall, 7/8 children survived


Hyperinflammatory shock in children with family exposure to COVID-19

MIS-C "is a condition where different body parts can become inflamed, including the heart, lungs, kidneys, brain, skin, eyes, or gastrointestinal organs. This rampant inflammation has been recorded in multiple organ systems; yet, clinical research into the pathogenesis of the disease is insufficient. However, we know that many children with MIS-C were exposed or infected with SARS-CoV-2. Currently, the lack of a universal case definition of MIS-C has limited the number of cases that are accurately diagnosed and hampered with proper treatment of the disease. Further research into the clinical, epidemiological and immunological nature of MIS-C is desperately needed. MIS-C can be serious, even deadly, but most children who were diagnosed with this condition have gotten better with medical care."

Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19

Cytokine storms increase risk of vascular hyperpermeability and multiorgan failure. When vascular permability is increased by pro inflammatory cytokines (and other factors), large amounts of fluid and blood cells enter the alveoli. This results in dyspnoea (difficulty of breathing) and even respiratory failure. When the high concentration of cytokines is not addressed, they can even lead to death. 

Vascular Hyperpemeability and Multi-organ failure in COVID-19

Secondary haemophagocytic lymphohistiocytosis (sHLH) is a hyperinflammatory syndrome that leads to fatal hyper cytokinaemia with multiorgan failure. It is characterized by unremitting fever, hyperferritinaemia, and cytopenias. Pulmonary involvement (ARDS) also occurs in 50% of patients. A cytokine profile similar to sHLH is associated with COVID-19 severity, and it is suggested through data on patients with elevated ferritin that hyperinflammation from SARS- CoV-2 is connected to mortalitiy.  

Secondary haemophagocytic lymphohistiocytosis (sHLH) and COVID-19

There is strong evidence that COVID-19 patients diagnosed with Acute Respiratory Distress Syndrome (ARDS) can attribute this phenotype to the cytokine storms taking place in their immune system's response. 

Acute Respiratory Distress Syndrome (ARDS) in COVID-19

Although the leading cause of mortality from COVID-19 is acute respiratory distress syndrome (ARDS), new data demonstrates the potential of cytokine storm syndrome in patients with severe COVID-19. 

Severe COVID-19 patients should have hyperinflammation screenings for laboratory markers, including increased levels of ferritin, decreased platelet counts, or erythrocyte sedimation rate. The HScore table should be applied when deciding potential therapy options and in the consideration of immunosuppression to reduce inflammation and improve mortalitly. 

- Biomarkers of cytokine storm syndrome and status in COVID-19
- Treatments for cytokine storm syndrome and potential utility in COVID-19

Cytokine Release Syndrome and COVID-19

Hyperinflammatory syndromes result from elevated levels of inflammatory biomarkers, such as interleukin (IL)-6, and are sometimes developed in patients with severe COVID-19.  Some examples of hyperinflammatory syndromes are macrophage activation syndrome and cytokine release syndrome. Hyperinflammatory syndromes stem from cytokine storm syndromes and can lead to mortality and morbidity.  

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