Newer Targets for Treatment of Asthma: A Glimpse into the Future

Asthma, a chronic respiratory disease characterized by inflammation and narrowing of the airways, affects millions of people worldwide. Despite existing treatment options, asthma remains uncontrolled in a significant proportion of patients, necessitating research into novel therapeutic targets. This article explores some of the promising new targets currently being investigated for the treatment of asthma.

Biologic Therapies

Biologic therapies, which target specific molecules involved in the immune response, have emerged as a promising area of asthma treatment.

1. Anti-Interleukin-5 (IL-5) and Anti-IL-5R Therapies: IL-5 plays a key role in the maturation and survival of eosinophils, a type of white blood cell involved in asthma inflammation. Biologics such as mepolizumab, reslizumab, and benralizumab target IL-5 or its receptor (IL-5R), reducing eosinophilic inflammation and the frequency of asthma exacerbations.
2. Anti-Interleukin-4 (IL-4) and Anti-Interleukin-13 (IL-13) Therapies: IL-4 and IL-13 are also crucial in the immune response leading to asthma. Dupilumab, a biologic drug that inhibits both IL-4 and IL-13, has shown promise in the treatment of moderate-to-severe asthma.

Bronchial Thermoplasty

Bronchial thermoplasty is a novel non-pharmacological intervention for severe asthma. It involves applying controlled thermal energy to the airway walls during a series of bronchoscopy procedures, reducing the amount of airway smooth muscle and thereby diminishing the airways' ability to constrict.

Targeting Neutrophilic Asthma

While eosinophilic asthma has been the focus of many new therapies, neutrophilic asthma, another subtype of the disease, has proven more challenging. However, new targets are being explored:

Anti-Interleukin-17 (IL-17) Therapy: IL-17 has been associated with neutrophilic inflammation in asthma. Anti-IL-17 therapies are being investigated for their potential to reduce neutrophilic airway inflammation.

Anti-Interleukin-8 (IL-8) Therapy: As a potent neutrophil attractant, IL-8 is another potential target in neutrophilic asthma. Research is ongoing to develop therapies that can block IL-8 or its receptor.

Phosphodiesterase-4 (PDE4) Inhibitors: PDE4 inhibitors, such as roflumilast, can reduce inflammation and are being investigated for use in severe neutrophilic asthma.

Emerging Targets

Other potential treatment targets include toll-like receptors (TLRs), which play a role in the immune response, and chitinase-like proteins (CLPs), associated with inflammation and tissue remodeling in asthma.

The landscape of asthma treatment is evolving, with promising new therapies targeting the underlying pathophysiology of the disease. As our understanding of asthma's complex immunological and physiological processes deepens, we can expect even more sophisticated and effective treatments to emerge, offering hope for those living with this chronic condition. However, as with any new therapeutic strategies, these potential treatments must undergo rigorous testing for safety and efficacy before they can be incorporated into routine clinical practice.

What is severe sepsis and septic shock ?

Severe sepsis refers to sepsis-induced tissue hypoperfusion or organ dysfunction with any of the following thought to be due to the infection.

• Sepsis-induced hypotension
• Serum Lactate levels above upper limits of laboratory normal
• Urine output < 0.5 mL/kg/hr for more than two hours inspite of adequate fluid resuscitation
• Acute lung injury with PaO 2 /FIO 2 < 250 in the absence of pneumonia as infection source
• Acute lung injury with PaO 2 /FIO 2 < 200 in the presence of pneumonia as infection source
• Creatinine > 2 mg/dL 
• Bilirubin > 2 mg/dL 
• Platelet count < 100,000 microL –1
• Coagulopathy (INR > 1.5)

Sepsis-induced hypotension is defined as a systolic blood pressure (SBP) < 90 mmHg or mean arterial pressure (MAP) < 70 mmHg or a SBP decrease > 40 mmHg or less than two standard deviations below normal for age in the absence of other causes of hypotension.

Components of Sepsis-induced tissue hypoperfusion are

1. Infection-induced hypotension
2. Elevated lactate
3. Oliguria.  

Septic shock - Septic shock is defined as sepsis-induced hypotension persisting despite adequate fluid resuscitation, which may be defined as infusion of 30 mL/kg of crystalloids Septic shock is due to marked reduction in systemic vascular resistance, this is often associated with an increase in cardiac output.

Major complications of sepsis(Cardiopulmonary,Renal,Coagulation,Neurologic)

Sepsis is usually associated with multiple target organ dysfunction.Major complications are seen in cardiac, respiratory, renal, neurological and coagulation system.

1) Cardiopulmonary complication in sepsis

Ventilation perfusion mismatch (V/Q – mismatch) produces a fall in arterial PO2 early in the course of illness.Progressive diffuse pulmonary infiltrates and arterial hypoxemia (PaO2/FIO2, <200) are  early indicators of the development of the acute respiratory distress syndrome (ARDS). 

ARDS develops in ~50% of patients with diagnosed with severe sepsis or septic shock.

Depression of myocardial function is common in sepsis

This is manifested as increased end-diastolic and systolic ventricular volumes with a decreased ejection fraction.Myocardial suppression develops within 24 hours in most patients admitted with severe sepsis.

2) Renal complications

ATN, acute cortical necrosis, interstitial, nephritis, or drug induced damage are the major renal complications in sepsis.Most cases renal failure is occur secondary to acute tubular necrosis (ATN) induced due to hypotension or capillary injury. Drug-induced renal damage may also complicate therapy, especially when hypotensive patients are treated with aminoglycoside antibiotics.Oliguria, azotemia, proteinuria, and nonspecific urinary casts are frequently found.

3) Coagulation abnormality

Thrombocytopenia is seen in 10–30% of patients, the underlying mechanisms are not clear.In patients with DIC the platelet counts are usually very low (<50,000/L) ,this low counts may be secondary to diffuse endothelial injury or due to microvascular thrombosis.

4 ) Neurologic complications  

Critical illness polyneuropathy is the most common neurologic complications.This is commonly seen when the septic illness lasts for weeks or months, problem due to "critical-illness" polyneuropathy is that it may prevent weaning from ventilatory support and patients experience distal motor weakness.Electrophysiologic studies are helpful to rule out other conditions such as GBS , metabolic disturbances, and toxin activity .

What is sepsis? (SIRS,MODS explained)

Sepsis is a clinical syndrome which complicates severe infection. In sepsis there is cardinal signs of inflammation that is vasodilation, leukocyte accumulation, increased microvascular permeability. This signs are seen in tissues that are remote from the infection.

Systemic inflammatory response syndrome (SIRS) is a similar clinical syndrome that is seen in association with noninfectious insult such as  acute pancreatitis, pulmonary contusion.

What is MODS ?

The basic abnormality in sepsis and SIRS is dysregulation of the inflammatory response there may be a massive and uncontrolled release of proinflammatory mediators which initiates a chain of events that lead to widespread tissue injury. This will lead to multiple organ dysfunction syndrome (MODS), which results in  high mortality associated with these syndromes.

Multiple organ dysfunction syndrome is the end of the severity of illness spectrum of both SIRS and sepsis. MODS is classified as primary or secondary.

Primary MODS

Following are the features of Primary MODS.

1. Primary MODS is the result of a well-defined insult.
2. In this condition organ dysfunction occurs early.
3. The organ dysfunction may be directly due to the insult itself (eg, renal dysfunction due to rhabdomyolysis).

Secondary MODS 

In this situation the  organ failure is not directly due to the insult itself, but occur as a  consequence of the host’s response (eg, acute respiratory distress syndrome in patients with pancreatitis)

The progressive abnormalities of the certain organ-specific parameters are used to diagnose MODS They are  given below

1. PaO 2 /FiO 2 ratio.
2. Platelet count.
3. Serum bilirubin.
4. Serum creatinine (or urine output).
5. Glasgow coma score.
6. Hypotension.