Biologics & ABPA - what are they and what can they do?

Biologic medications (also known as biologics) are a class of drugs derived from living organisms or their cells. These treatments are used for various conditions, especially those involving the immune system, such as autoimmune diseases, cancers, and chronic inflammatory disorders. Here’s a breakdown of biologics:

1. What Are Biologics?

  • Biologics are large, complex molecules made using biotechnology. They can be derived from living organisms such as bacteria, yeast, or animal cells.
  • Unlike traditional medications (chemically synthesized), biologics are produced through genetic engineering or cell culture techniques.

2. Types of Biologic Drugs:

  • Monoclonal Antibodies (mAbs): These are engineered antibodies designed to target specific proteins or cells, such as tumor cells or immune system components. Examples include drugs like adalimumab (Humira) for rheumatoid arthritis and rituximab (Rituxan) for certain cancers.
  • Interferons: Proteins that modify immune system activity. They are used for conditions like multiple sclerosis and hepatitis C.
  • Vaccines: Biologic drugs used to stimulate the immune system to protect against infectious diseases (e.g., the flu vaccine, COVID-19 vaccines).
  • Cell and Gene Therapies: These involve altering genes or using stem cells to treat genetic disorders or cancers. CAR T-cell therapies are an example for cancer treatment.

3. Conditions Treated by Biologics:

  • Autoimmune Disorders: Such as rheumatoid arthritis, Crohn’s disease, and psoriasis.
  • Cancer: Biologics like monoclonal antibodies and immune checkpoint inhibitors target cancer cells.
  • Infections: Some biologics, including vaccines, protect against infections like hepatitis, flu, and COVID-19.
  • Chronic Inflammatory Conditions: Such as asthma and inflammatory bowel disease (IBD).

4. Advantages of Biologics:

  • Targeted Action: Biologics can target specific parts of the immune system or cells involved in disease, leading to more effective treatments with fewer side effects compared to traditional drugs.
  • Personalized Treatments: Some biologics can be customized based on a patient's genetics, improving outcomes for certain conditions.

5. Limitations and Side Effects:

  • Expensive: Biologics tend to be more expensive than traditional medications due to the complex production process.
  • Injection or Infusion: Many biologics are administered through injections or intravenous infusions rather than oral tablets.
  • Immune System Effects: Since biologics modify immune system function, they can increase the risk of infections and other immune-related side effects.

Examples of Biologic Medications:

  • Humira (adalimumab) for autoimmune diseases.
  • Keytruda (pembrolizumab) for cancer treatment.
  • Enbrel (etanercept) for rheumatoid arthritis.

Biologics are reshaping the treatment landscape, particularly in conditions where traditional medications were less effective.

In the case of Allergic Bronchopulmonary Aspergillosis (ABPA), biologic medications are increasingly being explored and used as part of treatment, particularly for patients with more severe or resistant forms of the disease. ABPA is an allergic reaction to the fungus Aspergillus, which can lead to airway inflammation and lung damage. Biologic medications, often aimed at modulating the immune system, help in managing this complex condition, especially when conventional treatments like corticosteroids fail to control symptoms or lead to significant side effects.

How Biologics Help in ABPA Treatment:

  1. Targeting Immune System Pathways:
    • Biologics used in ABPA primarily work by targeting specific immune system pathways that drive the inflammatory response triggered by the Aspergillus fungus.
    • For example, biologics that target interleukin-5 (IL-5), such as mepolizumab (Nucala), can help reduce eosinophil levels, a type of white blood cell involved in allergic reactions and inflammation in ABPA. Dupixent, another biologic, targets IL-4 and IL-13, which are cytokines involved in the inflammatory cascade in ABPA, potentially improving lung function and reducing exacerbations .
    • Omalizumab (Xolair) acts directly on the patients IgE antibodies, preventing them triggering allergic inflammation
  2. Reducing Steroids - For ABPA patients who require long-term corticosteroid use, biologics may offer an alternative, reducing dependence on steroids and lowering the risk of long-term steroid side effects (e.g., osteoporosis, diabetes, and weight gain).
    • Biologics can provide a more targeted approach, addressing the underlying immune mechanism, rather than just suppressing the overall immune response with steroids .
  3. Clinical Evidence:
    • In trials, biologics like mepolizumab have shown improvements in asthma control and reduced exacerbations, suggesting potential benefits for ABPA patients with significant asthma components.
    • Dupilumab has also demonstrated potential benefits in patients with ABPA and associated asthma, showing improvements in lung function and reduction in eosinophil levels, thus addressing both the underlying inflammation and allergic reactions .
  4. Safety and Efficacy:
    • While biologics are typically used in cases where standard treatments (steroids, antifungals) are not sufficient or appropriate. These medications are generally well-tolerated, but they do carry risks, such as increased susceptibility to infections due to immune system modulation** .

Summary:

Biologic therapies represent an option for patients with ABPA, particularly those with severe symptoms or who struggle with long-term steroid use. By targeting specific immune pathways, biologics help reduce inflammation and improve lung function without the broad immunosuppression of steroids. Drugs like mepolizumab and dupilumab are showing encouraging results, though their use in ABPA is still being refined and evaluated in clinical trials.

If you're exploring biologics for ABPA treatment, consulting with a specialist in pulmonary or immunologic disorders is crucial, as the benefits and risks of these drugs need to be carefully balanced for each individual patient.

**One common concern is whether these treatments could increase susceptibility to viral infections, particularly respiratory viruses.

Immune Modulation and Viral Infections: Omalizumab (Anti-IgE): Omalizumab reduces IgE levels, which are primarily involved in allergic reactions, not antiviral immunity. Studies show that it may actually decrease the frequency of respiratory viral infections by reducing inflammation and preventing exacerbations triggered by viruses. In clinical trials, omalizumab was not associated with increased viral infection rates and has been shown to lower asthma exacerbations caused by viral infections.

Mepolizumab and Benralizumab (Anti-IL-5): These biologics target IL-5, which reduces eosinophil counts. Eosinophils play a minor role in viral defense, but their reduction does not seem to impair the body's ability to fight viruses significantly. Data suggest that mepolizumab and benralizumab do not increase the incidence of viral infections and can reduce asthma exacerbations, including those triggered by viruses.

Dupilumab (Anti-IL-4/IL-13): Dupilumab inhibits IL-4 and IL-13 signaling, key cytokines in allergic inflammation. It is not associated with increased viral infection susceptibility in clinical trials. It may enhance antiviral defenses by reducing Th2-skewed inflammation, potentially allowing the body to mount a better response to viruses.

Evidence from Studies: Studies have consistently shown that biologics can reduce asthma exacerbations, many of which are triggered by viral infections, suggesting they do not compromise the immune system's ability to fight viruses. No significant increase in viral infections has been observed in large clinical trials for these medications, and they are generally considered safe in this context.

Conclusion: Biologic medications for asthma do not appear to increase vulnerability to viral infections. In fact, they may reduce the risk of virus-induced asthma exacerbations by controlling airway inflammation. However, patients with severe asthma or comorbid conditions should always consult their healthcare provider regarding potential risks.

by GAtherton

CPA patients have impaired neutrophil response to infection

A new paper from a research group in India has compared people who have tuberculosis (Tb) with those who have Tb and then developed chronic pulmonary aspergillosis (CPA). CPA develops in patients with Tb quite commonly and for many years it has been speculated that the mould grows on the lung scar tissue left behind by a Tb infection.

 

The researchers looked at many components of the patient’s immune system to try to see if any differed between the two as this would potentially tell them why one patient might develop CPA while another doesn’t.

 

Significantly the research team found that those patients who went on to develop CPA had reduced intensity of ‘neutrophil burst’, which is the release of reactive oxygen chemicals that are important in the fight against infection. They also had impaired Th1 cell response which is important as Th1 cells are part of the patient’s normal response to infection and they produce cytokines like interferon-gamma (IFN-γ), interleukin-2 (IL-2), and tumor necrosis factor-alpha (TNF-α). In turn, these trigger cytokines activate macrophages, enhance the phagocytic (pathogen-eating!) ability of immune cells, and stimulate the production of antibodies that mark pathogens for attack.

 

In short, we now have a clearer understanding of at least one part of the immune system of a CPA patient that isn’t working as well as it should, and which would directly lead to them being more vulnerable to infection.

 

The next question is ‘why are these patients unable to produce the normal levels of neutrophil burst and Th1 cell response?’ There are several possibilities including:

 

    • Genetic disorder
    • Immunosuppressive medication
    • Chronic diseases eg diabetes, renal failure, liver disease
    • Malnutrition/eg Vitamin D deficiency
    • Alcohol abuse
    • Severe infection
    • HIV
    • Exposure to some toxins (eg mercury, lead
    • Autoimmune disorder

 

Some of these may apply to the patients in this study but it is not yet clear which are the most likely. There is more work to do!

 

What does this mean for treatment of CPA?

 

The INCAS study, sets out to assess if CPA patients benefit when they are given supplementary doses of interferon-gamma. This is one of the cytokines found to be inhibited in CPA patients in the study discussed above, so if these patients improve it is good evidence that we have found one of the important causes of susceptibility to CPA, and we will already have a medication to partly treat it.

by GAtherton

ABPA guidelines update 2024

Authoritative health-based organisations throughout the world occasionally release guidelines for doctors on specific health problems. This helps everyone give patients a consistent level of the right care, diagnosis and treatment and is particularly useful when the health problem is relatively uncommon and access to expert opinion is difficult.

The International Society for Human and Animal Mycology (ISHAM) is one such international organisation that specialises in fungal diseases. It runs a lot of 'working groups' designed to address and discuss a whole range of fungal infections, run by ISHAM members from a wide range of backgrounds.

One such group is the ABPA working group, and this group has just released an update to its clinical practice guidelines for ABPA.

The new guidelines introduce a range of changes designed to efficiently capture more cases of ABPA, enabling the patient to get the right treatment. For example they suggest reducing the requirement for a total IgE test result score of 1000IU/mL to 500. They also suggest that all new admissions who are adults with severe asthma are routinely tested for total IgE, and children who symptoms are difficult to treat should also be tested. ABPA should be diagnosed when there is radiological evidence or appropriate predisposing conditions eg asthma, bronchiectasis along with IgE >500/IgG/eosinophils.

Doctors should take care not to miss cases of fungal sensitisation caused by fungi other than Aspergillus (ABPM).

Instead of staging ABPA, they suggest putting the patient into groups that don't suggest progression of the disease.

The group suggests not routinely treating ABPA patients who have no symptoms, and if they develop acute ABPA oral steroids or itraconazole. If the symptoms keep recurring then use a combination of prednisolone and itraconazole.

Biologic medication is not appropriate as a first option for treating ABPA

Read the full guidelines here

by GAtherton

Living with CPA and ABPA

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Gwynedd was formally diagnosed with CPA and ABPA at the National Aspergillosis Centre in 2012. Below she lists some of the symptoms she experiences and what she has found helpful in managing the conditions. 

These symptoms fluctuate and can be very insignificant until a flare-up occurs. Then they can be severe enough to alter what I can do in a day. 

  • Tightening of the chest and or upper airway.
  • Inflammation can be felt as heat and a 'zingyness' in my chest.
  • Pain and discomfort over my back in my lungs.

Self-help

  • A healthy diet, as recommended by the dietetic society or as guided by a consultant or specialist nurse. 
  • Extra protein where one is underweight. 
  • Exercise is essential for my mental well-being and helps me with chest clearing.

My local respiratory consultant firmly believes in the benefits of Yoga and slower breathing to help with chest clearance and relaxation, which reduces inflammation and anxiety and aids the immune system. 

Anxiety is a side effect of ABPA & CPA as both conditions are debilitating, and fluctuations occur seemingly with no warning. It is not unreasonable to feel anxious about this diagnosis. Treatments help, as do lifestyle changes. 
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by GAtherton

Ear, Eye and Nail Aspergillus infections

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Ear, Eye and Nail Aspergillus infections

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Otomycosis
Onychomycosis
Fungal Keratitis
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Otomycosis

Otomycosis is a fungal infection of the ear, and the most frequently encountered fungal infection in ear, nose and throat clinics. The organisms responsible for otomycosis are usually fungi from the environment, most commonly Aspergillus niger. The fungi usually invade tissue that has already been damaged by bacterial infections, physical injury or excess earwax.
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Symptoms:

  • Itching, irritation, discomfort or pain
  • Small amounts of discharge
  • A feeling of blockage in the ear

In rare cases, Aspergillus infecting the ear may spread to bone and cartilage, causing a severe and life-threatening disease. This is more frequently caused by Aspergillus fumigatus than Aspergillus niger, and is associated with underlying immunocompromisation, diabetes mellitus or patients on dialysis.

A diagnosis of otomycosis is confirmed by taking debris from the infected ear, culturing it on a special agar plate and using microscopy to establish the causative organism. If the infection is deep, a biopsy should be taken for fungal culture and identification. If there is a suspicion of the infection becoming invasive, CT and MRI scans can be used to see whether the fungi has spread to any other sites.

Treatment involves carefully drying and cleaning the ear canal, using microsuction. Aural syringing should be avoided as it can lead to the infection flaring up in deeper sites of the ear. Depending on how complicated the infection is, you may need to further treat with antifungals applied to the ear. Treatment should continue for 1-3 weeks and oral antifungal therapy is only required if the antifungals applied to the skin do not work, or the condition is invasive.

With good ear canal cleaning and antifungal therapy, otomycosis is usually cured and does not relapse.

Click here for more information on otomycosis
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Onychomycosis

Onychomycosis is a fungal infection of the nail, most commonly the toenail. Fungal nail infection is common in the general adult population, with a rate of about 5-25% and increasing incidence in elderly people. Onychomycosis makes up about 50% of all nail disease.  There are a wide variety of fungi that can onychomycosis, but T. rubrum is responsible for about 80% of cases in the UK.  Aspergillus species, amongst many other fungi, can occasionally cause onychomycosis. Some infections are caused by more than one fungus.
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Symptoms of the infection will vary depending on the type of fungus involved, but thickened nails and discoloration are common.

Some of the contributing factors causing this disease are occlusive footwear, extensive water contact with nails, repeated nail trauma, genetic predisposition and concurrent disease, such as diabetes, poor peripheral circulation and HIV infection, as well as other forms of immunosuppression.

Diagnosis of the causative fungus is achieved by scraping the nail (the material under the nail is the most rewarding material). Small pieces of this are then inspected under a microscope and grown on special agar plates to determine the species responsible for the disease.

Treatment depends on the causative species and the severity of the disease. Antifungal cream or ointment applied to the affected nail is effective in some milder cases. Oral antifungal therapy or surgery to remove the nail may be required. Treatment can last from 1 week to 12+ months, depending on the case. Cure is possible, but takes a long time, as the growth of nails is slow.

The nail fold can also become infected – this is called paronychia, and is usually caused by Candida albicans and other Candida species.

Click here for more information on onychomycosis
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Fungal Keratitis

Fungal keratitis is a fungal infection of the cornea. The most common causative agents are Aspergillus flavus, Aspergillus fumigatus, Fusarium spp. and Candida albicans, although other fungi can be responsible. Trauma, especially if associated with plant material, is a common antecedent to fungal keratitis. Contact lens fluid contaminated with fungi can also cause fungal keratitis. Other possible risk factors include topical corticosteroids, traditional medicines and higher external temperatures and humidity. Bacterial keratitis is more common in contact lens wearers and the western world, whereas in India and Nepal and some other countries, fungal keratitis is at least as common as bacterial keratitis. There are estimated to be over a million cases of fungal keratitis annually worldwide, mostly in tropical countries.
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ymptoms are usually like other types of keratitis, but perhaps more prolonged in duration (5-10 days):

  • eye redness
  • pain
  • excess tears or other discharge from your eye
  • difficulty opening your eyelid because of pain or irritation
  • blurred vision
  • decreased vision
  • sensitivity to light
  • a feeling that something is in your eye

The best way to diagnose fungal keratitis is to take a scraping of infective material from the cornea. Any fungal agent in this scraping is then grown on a special agar plate for identification. Along with culturing the organism, microscopy is required due to the wide variety of potential causative fungi.

Antifungals applied directly to the eye in the form of eye drops are essential for the treatment of fungal keratitis. The frequency at which they are administered depends on the severity of the infection. In severe cases this is hourly, and can be reduced in frequency after 1 day as improvement is documented. Topical antifungal therapy has a 60% response rate with retention of vision if keratitis is severe and a 75% response if milder. For severe infections, oral therapy is also advised. The antifungal treatment given depends on the causative species. Therapy is usually continued for at least 14 days. Surgical debridement is essential for severe disease.

Fungal keratitis is associated with a ~5- fold higher risk of subsequent perforation and need for a corneal transplant than bacterial keratitis. Recovery of sight is higher if the diagnosis is made early.

Click here for more information on fungal keratitis
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by GAtherton

Differences between ABPA and CPA

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Allergic broncho pulmonary aspergillosis (ABPA) and chronic pulmonary aspergillosis (CPA) are two different types of aspergillosis. They are both chronic diseases but they differ in mechanisms and often presentation. Do you know the differences between the two?

This article will compare the biology, the symptoms and the diagnosis/treatment of the two diseases.

The Biology

An overview:

The ultimate cause of both ABPA and CPA is failed clearance of Aspergillus spores (conidia) from the lungs which leads to disease. However, the exact mechanism of how disease is caused in the two is quite different. The main difference is that ABPA is an allergic reaction to Aspergillus spores whereas CPA is an infection.

 

Let’s first look at ABPA. As previously said, ABPA is caused by an allergic reaction to Aspergillus spores. The reaction is exaggerated by co-morbid diseases like cystic fibrosis (CF) and asthma. As is described on the ABPA page, Aspergillus spores in and of themselves do not cause allergic reactions - hence they are unknowingly breathed in by everyone every day. In healthy people, the spores are quickly removed out of the lungs and body. A reaction occurs when the spores are not cleared out of the lungs, giving them time to grow and produce hyphae (long thread-like structures) that release harmful toxins. The body then produces an allergic immune response to the germinating spores and the hyphae. This allergic response involves inflammation. Inflammation is the result of lots of different immune cells rushing to the area at once to try and fight off the invaders. Whilst it is needed in an effective immune response, it also causes swelling and irritation of the airways, producing some of the main symptoms associated with ABPA such as coughing and shortness of breath.

Now let’s look at CPA. CPA, as mentioned above, is not characterised by an allergic reaction to Aspergillus spores. This disease is less clear cut than ABPA and is much less common. It is, however, caused by spores not being cleared effectively from the lungs. In this case, they set up residence in damaged lungs or cavities present within the lungs and begin to germinate there. Areas of damaged lung are much easier for infections to invade as there are fewer immune cells to fight them off (note that patients with CPA usually have a functioning immune system – ie. they are not immunocompromised). These cavities are usually the result of previous lung infections such as chronic obstructive pulmonary disorder (COPD) or tuberculosis (TB).

Some CPA patients have multiple underlying conditions. In a 2011 study, details of underlying conditions of 126 CPA patients in the UK were identified; it was found that tuberculosis, non-tuberculous mycobacterial infection and ABPA (yes, ABPA can be a risk factor for CPA) were the predominant risk factors for development of CPA (read the full study here - https://bit.ly/3lGjnyK). The Aspergillus infection can grow in damaged areas deep within the lungs and occasionally begin to invade the surrounding tissue. When this happens, immune cells in the surroundings areas usually fight off the infection and so it is prohibited from completely invading the lung tissue. This periodic spreading of the Aspergillus infection can, however, damage nearby blood vessels causing one of the main symptoms associated with CPA which is coughing up blood (haemoptysis).

Which immune cells are detected?

ABPA:

  • As ABPA is predominantly an allergic infection, IgE antibody levels rise dramatically (>1000) as part of the body’s allergic immune response. IgE plays an important role in allergy as it stimulates other immune cells to release chemical mediators. These chemicals help to get the allergen out of your body and/or recruit other immune cells to help out as well. One of these well-known chemicals is histamine. Total IgE levels and Aspergillus-specific IgE levels are both raised in patients with ABPA.
  • IgG antibodies to Aspergillus are also often elevated; IgG is the most common type of antibody and works by binding to the Aspergillus antigens which leads to their destruction.
  • Eosinophils can be raised which work by releasing toxic chemicals that destroy the invading pathogen.

CPA:

  • Raised levels of Aspergillus IgG antibodies are present
  • IgE levels may be slightly elevated in CPA patients, but not as high as ABPA patients

Symptoms

Whilst there are overlaps in symptoms between the two diseases, some symptoms are more common with one type of aspergillosis.

ABPA is associated with allergic symptoms such as coughing and production of mucus. If you have asthma, ABPA will most likely result in worsening of your asthmatic symptoms (such as wheezing and shortness of breath). Fatigue, a fever and general feeling of weakness/illness (malaise) can also be present.

CPA is less associated with production of mucus and more with coughing and coughing up blood (haemoptysis). Symptoms such as fatigue, breathlessness and weight loss are also seen.

In a Facebook poll put out by the National Aspergillosis Centre, this question was posed separately to people with ABPA and CPA:

‘What aspect(s) of your current quality of life are you most concerned about and would like to improve the most?’

The top 5 answers for ABPA were:

  • Fatigue
  • Breathlessness
  • Coughing
  • Poor fitness
  • Wheeze

The top 5 answers for CPA were:

  • Fatigue
  • Breathlessness
  • Poor fitness
  • Anxiety
  • Weight loss/coughing/coughing up blood/side effects of anti-fungals (note these answers all got the same number of votes)

This is helpful in directly comparing symptoms reported from patients themselves.

Diagnosis/treatment

The ABPA page on this website describes the updated diagnostic criteria – see this link https://aspergillosis.org/abpa-allergic-broncho-pulmonary-aspergillosis/

Diagnosis for CPA depends on radiological and microscopic findings, patient history and laboratory tests. CPA can develop into different forms such as chronic cavitary pulmonary aspergillosis (CCPA) or chronic fibrosing pulmonary aspergillosis (CFPA) – diagnosis is slightly different for each depending on radiological findings. The most common feature found on a CT scan of a CPA patient is an aspergilloma (morphological appearance of a fungal ball). Whilst this is very characteristic of CPA it cannot alone be used to determine a diagnosis and requires a positive aspergillus IgG or precipitins test for confirmation. Lung cavities present for at least 3 months may be seen with or without an aspergilloma, that, along with serological or microbiological evidence, can indicate CPA. Other tests such as Aspergillus antigen or DNA, biopsy showing fungal hyphae on microscopy, Aspergillus PCR, and respiratory samples that grow Aspergillus in culture are also indicative. Together with symptoms described by the patient, a combination of these findings is required to make a sure diagnosis.

Treatment for both diseases usually involves triazole therapy. For ABPA, corticosteroids are often used to control the body’s response to the spores and itraconazole is the current first-line antifungal treatment. Biologics may be an option for those with severe asthma. See more about biologics here - https://aspergillosis.org/biologics-and-eosinophilic-asthma/.

For CPA, the first-line treatment is itraconazole or voriconazole and surgery may be suitable to remove an aspergilloma. Diagnosis and a treatment plan is made by a respiratory consultant.

Hopefully this has given you a clearer picture on the two diseases. The main takeaway is that ABPA is characterised by an allergic reaction to aspergillus spores whereas CPA is not.
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by GAtherton