Hypersensitive Pneumonitis

 

Hypersensitive pneumonitis

        PKGhatak,MD

The term sensitivity is easily understood but where the normal sensitivity ends and hypersensitivity starts are difficult. In medicine, that question is answered by the use of separate terms - for normal sensitivity as Inflammation and hypersensitive as Allergy.

Inflammation.

The four cardinal signs of inflammation are heat, pain, redness, and swelling, and one can add loss of function. The mechanism of inflammation is well known in the medical field for a long time

Allergy.

This term is universally understood because allergic conditions are very common and the incidence of allergy is increasing.

Allergy and Autoimmune reactions are basically the same except the triggering agent in allergy is a foreign agent, whereas, the Immune reactions are due to the body's immune system starts a war against the body's own organ/tissue /cell.

The physiological responses to either inflammation or allergy / autoimmune are mediated by the same cells - dendritic cells, macrophages and WBC cells. These cells are collectively called Immunocytes. The individual immunocyte communicates with each other by locally-acting cytokines called paracrine and within different components of the same cell called autocrine. In an earlier blog that subject was described in a comprehensive way – “Immunocytes and Immunomodulation”.

What is Pneumonitis.

Inflammation of the lungs from non-infectious agents as well as living organisms can cause Pneumonitis. There is a wide difference in the way the body reacts to allergy and infections. In allergy, the foreign agent is merely recognized as an undesirable substance and must be eliminated. Once the body mounts a response, the continued presence or invasion of tissue by the agent is not necessary, but repeated exposures are necessary. In the case of infection, the tissue invasion and the continued presence of invaders result in inflammatory reactions.

What agents cause Hypersensitive Pneumonitis.

Three distinct groups are recognized.1. Organic substances are both living or inert agents, 2. The Inorganic chemicals.3. Biological agents including drugs.

Is there any other name for hypersensitive pneumonitis.

In the past, hypersensitive pneumonitis was reported under various names based on the causative agents or the people in the profession expose to those agents. A shortlist of previous names is Farmers lung, Silo fillers disease, Bagassosis, Grain handler lung, Bird breeders/bird fancier's lung, Suberosis in cork workers in Spain, Lung disease of Cheese workers, Humidifier/air conditioners repairmen, Paprika splitters, Chemical workers, Plastic workers, Urethrae workers, Rubber workers, Foam workers, Mushroom pickers, Textile workers, Mollusk shell handlers and the list is growing.

How the immune cells cause pneumonitis.

The process begins the same way – the Dendritic cells of the connective tissue of the lung touch the foreign substance with their arms, like the arms of an octopus, and capture the agent and hand over it to the macrophages in order to kill and digest. Macrophages pass the antigen (digested product) to CD4, Th1 and Th17 cells. These cells release IFN (interferon) gamma, TFN (tissue necrosis) alpha, IL (interleukin) 17 and IL22. These are the distress calls for the Lymphocytes and macrophages to come and neutralize the invaders. IL22 prevents the degradation of lymphocytes and the lymphocyte number dominates among the assembled cells.

The pathologists describe the lesions as granulomas. In the center, a dense accumulation of nonnuclear cells, chiefly lymphocytes, is seen. This layer is surrounded by giant cells. Within some of the giant cells, cholesterol crystals are present within the cytoplasm and appear as clefts called Asteroid bodies. In one word it is called a noncaseating granuloma.

In repeated exposure to the agent, the CD4 and Th2 cells release cytokines and result in Fibroblasts migration in the lung interstitial tissues. The fibrosis distorts and destroys the alveoli and bronchiole and the resultant fibrosis and the nature of fibrosis is described as Honeycombing, centrilobular fibrosis, peribronchiolar and bridging fibrosis. In pathological terms - it is Interstitial pneumonitis.

Pathologists also call the entity Extrinsic Allergenic Alveolitis. A combination of type lll (immune complex) and type lV hypersensitive pneumonitis.

Who described this entity first.

In 1700 Dr. Bernardino Ramazzini, an Italian physician, noted asthma like conditions in grain workers during workdays and not on holidays. In1874 a physician in Iceland, Dr. Jon Finsen describes a similar lung disease among farmworkers who were required to handle hay. The symptoms appeared 4 to 8 hours after exposure. Subsequently, episodic asthma was noted in people stripping barks of oak trees, later fungal spores were identified under the bark. These spores were small enough to enter the alveoli of the lung and were responsible for the disease.

Symptoms of Hypersensitive pneumonitis.

These signs are nonspecific. Wheezing, chest pain, unproductive cough, fever headaches, and muscle pain are common symptoms; generally, appear 4 to 8 hours after exposure. The first time exposure to agents goes unnoticed during the initial phase of sensitization.

Diagnosis.

Hypersensitive pneumonitis is an exciting field of work like detectives, work on murder cases. Epidemiologists love to work in this field. Painstaking and careful analytical work is needed to find the cause.

General diagnostic work and laboratory findings are described in an earlier blog - "Idiopathic pulmonary fibrosis (IPF)". Microbiological and chemical identification of the offending substance in the biopsy tissue or lung washing fluid is required for the final diagnosis. IgM precipitating antibodies to the offending agent may not be present initially but 2 to 3 weeks later IgG precipitating antibodies will be present.

Treatment and prevention of Hypersensitive premonitions.

Removal of the causative agent from the work environment is essential. If that is not possible then the susceptible workers must be given jobs in other areas where such exposures do not happen.

Medical therapy begins with 40 to 80 mg of prednisone a day till the symptoms are controlled then a lower dose for maintenance is required. In addition, other modalities like bronchodilators, expectorants, analgesics and oxygen supplements may be required.

Prognosis. 

The prognosis is good in most cases if early diagnosis and prevention measures are taken.

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Radiation Pneumonitis

 

Radiation Pneumonitis.

Radiant energy disrupts nucleoprotein synthesis and ultimately kills the cells. The rapidly diving cells are more severely impacted than the rest. Radiation therapy is an integral part of the treatment of malignant diseases.

Radiation of lungs for lung cancer is second only to surgery and often are combined. Localized breast cancers are treated with lumpectomy and radiation more frequently than mastectomy and chemotherapy. Metastasis of carcinoma and sarcoma in the lungs are also frequently treated with radiation along with immunotherapy. Incidence of Bone Marrow Transplantation and Stem Cell transplantation have increased in this decade and radiation of lungs is a part of the whole body radiation for the preparation for these procedures.

Adverse effects of radiation, though fewer than chemotherapy agents produce radiation pneumonitis.

In most instances about 2 months after completion of radiation therapy, the patients develop symptoms of pneumonitis, however, the onset may be delayed for 8 months or still rarely, develop at the same time the patient is undergoing radiation therapy which most instances are given over a 4 to 6 weeks period.

Risk factors for radiation pneumonitis.

Females are more prone but the precise underlying reason is not known. Elderly people, smokers, patients with chronic obstructive lung disease (COPD) and when radiation has to give on a wide area of the chest and high dose radiation is required are more prone to pneumonitis. Concomitant use and or pre and post use of many drugs are risk factors. Some of these drugs are actinomycin D, cyclophosphamide, doxorubicin methotrexate, bleomycin, vincristine, mitomycin and some the immunotherapy agents like erlotinib, sunitinib, docetaxel.

Pathophysiology of radiation pneumonitis.

The epithelium of the tracheobronchial tree, alveolar cells and endothelial cells of pulmonary capillaries are affected more severely. Inflammatory reactions are dominated by edema, inflammatory cell recruitment, the release of TNF(tissue necrosis factor) alpha, IL1 and IL6 (inter interleukin), TGF(transforming growth factor)beta, COX2 and other cytokines. The death of cells is followed by sloughing of the surface layer. The remaining epithelial cells regenerate and begin to invade the alveolar surface. Due to the absence of surfactant atelectasis begins. Loss of surface area of capillary bed follows. Decrease in lung volumes, reduced diffusion capacity of oxygen, ventilation-perfusion mismatch, intrapulmonary shunting and undersaturation of hemoglobin are the results of these changes and account for symptoms and severity of the illness. Fibrosis once begins remained unchecked unless intervention is undertaken.

Symptoms.

The patient complaints are dry cough. Soon tightness of the chest, and chest pain on coughing and deep breathing develop. Rapid breathing and shortness of breath follow. Oxygen saturation falls below the normal levels.

Diagnosis.

Chest x-ray show fine net-like shadows and some atelectasis which are new and not present prior to initiation of radiotherapy. Tests for bacterial and viral infections are negative. High resolution CT chest is necessary for a sound diagnosis, MRI and PET scans are also done in difficult cases. Functional lung volume and vital capacity along with diffusion capacity are performed as a part of PFT (pulmonary function test). Taken from all the factors, the degree of severity of pneumonitis can be categorized in separate classes and can be used as prognosis indicators.

Treatment.

Most radiation pneumonitis responds to high dose corticoid therapy. Prednisone 60 to 100 mg /day for 2 weeks followed by gradual reduction of prednisone dose stretched over 2 years is the standard treatment protocol. Oxygen is prescribed when O2 saturation is lower than 90%. Aspirin, NSAID (nonsteroidal anti inflammatory drugs), COX 2 enzyme inhibitors are also used.

Newer treatment agents.

Monoclonal antibodies, small molecules oral agents, cytokine inhibitors are new armaments and are used more and more in order to use steroids at lower doses to minimize the side effects of steroids. The rationale for the use of these agents is discussed in previous articles under Coid-19, Immunocytes & immunomodulation and Idiopathic pulmonary fibrosis.

Role of antioxidants in the treatment.

On theoretical grounds the use of antioxidants makes sense. However, in actual practice, the beneficial effects are difficult to prove. A soy product, Isoflavone, statins (inhibitors of HMG-COA reductase) and ACE1 inhibitor-captopril, and a renin-angiotensin inhibitor are said to have shown promise. These agents influence Glutathione peroxidase (RH), superoxide dismutase and prevent the formation of free oxygen radicals by converting H2O2: to H20 and ROH according to the formula RH +  H202 = H2O + ROH.                                          

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