Hypersensitive Pneumonitis

 

                                            Hypersensitive pneumonitis

                                             PKGha tak, 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 allergies 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 exposed 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, TNF (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 the migration of the Fibroblasts in the lung interstitial tissues. The fibrosis distorts and destroys the alveoli and bronchioles 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 III (immune complex) and type IV 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. In 1874 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, they 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 working 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.

******************************************************

Radiation Pneumonitis

 

                                                  Radiation Pneumonitis

                                                      PKGhatak, MD

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 the lungs for lung cancer is second only to surgery, and often 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 the lungs is a part of the whole body radiation for the preparation for these procedures.

Adverse effects of radiation, though fewer than those of 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 is most instances 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 be given over 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 of 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, IL-1 and IL-6 (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, remains 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 shows 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, and 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 COVID-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.                                          

************************************************************

Hyperbaric Oxygen Therapy

 

                                            Hyperbaric Oxygen Therapy

                                              PKGhatak, MD

 

In any coastal community where scuba diving activities and commercial sea diving are common, one can find at least one Hyperbaric Oxygen Treatment Center.

Caisson disease, commonly called Bends is an episodic arterial obstruction from Gas bubbles formation due to the release of dissolved Nitrogen and Oxygen in the blood during rapid ascent from a deep dive.

Bends also happen to passengers of an airplane, if the aircraft suddenly loses cabin pressure at an altitude of 35,000 feet or higher. Fighter pilots and submarine sailors are at risk of having bends.

Both nitrogen and oxygen are poorly soluble in blood. In blood, almost all Oxygen (O2) is carried as loosely bound oxyhemoglobin in the RBCs. 1.34 ml of O2 is bound to per 1gram of hemoglobin. O2 is prevented from forming the oxidation of ferrous iron of hemoglobin in the RBC due to the presence of antioxidants and respiratory enzymes. In normal conditions, the O2-carrying-capacity of hemoglobin is 98 to 99% saturated. Increasing either O2 concentration or pressure or both cannot increase O2 saturation any further. Only about 0.3 ml of dissolved O2 is present in 100 ml of blood. Fatty tissues contain most of the dissolved nitrogen (N2).

At one atmospheric pressure and breathing room air, the dissolved O2 is 0.3 ml/dL. When breathing 100% O2, the dissolved O2 increases to 1.5 ml/dL; at a pressure of 3 Bar, the dissolved O2 is 6ml/dL. That much of dissolved O2 is sufficient to supply all the O2 requirements of tissues and then some more.

Characteristics of dissolved O2.

Tissues in the tiny places where capillaries cannot reach and specially in areas where blood vessels are blocked due to infection or diseases, the dissolved O2 easily diffuses out of the blood into the cells. In an O2 rich environment, anaerobic bacteria cannot survive. Phagocytic activities of leukocytes increase due to enhanced peroxide actions. Fibroblast proliferation is enhanced and promotes tissue repair. High O2 generates new blood vessels and is called angiogenesis. Blood vessels are constricted in high PaO2, and that property is utilized in the treatment of thermal burns and crush injuries.

Adverse effects of high O2 environment.

O2 toxicity of the lungs may produce pneumonitis and pulmonary fibrosis. The opacity of eye lenses may develop. Various neurological symptoms including seizures may happen. Retinal changes produce various symptoms but are amenable to treatment.

Adverse Pressure effects.

Pain over the nasal sinuses, pain in the inner ear and occasional rupture of eardrums may happen. Temporary vision changes are seen from deformity of the eye lens. Toothaches from the pressure effect of filled cavities are not uncommon.

HBO therapy in Bends.

At 3 Bar pressure and breathing 100% O2, the gas bubbles dissolve back in the plasma. As blood travels to the lungs, the dissolved gases diffuse out from blood to the alveolar sacs and are expelled during exhalation. Generally, one treatment of HBO lasts about 4 hrs. with a 20-minute break every 2 hrs. in order to minimize O2 toxicity. For the treatment of Bends usually, two sessions are required for the completion of the removal of all dissolved N2.

Various types of Hyperbaric O2 apparatus.

HBO chambers of various sizes are available to accommodate single patients to multiple patients. For the treatment of the localized area of limbs, head-neck and trunk, equipment of various shapes and sizes is available. The body part to be treated is hermetically sealed with inflatable cuffs and has ports for oxygen and other agents. To minimize tourniquet effects on the tissues, the pressure is released periodically.

Indication for HBO therapy.

Besides caisson disease, air embolism is at the top of the list. Other medical conditions are gas gangrene, diabetic foot ulcers, thermal burns, anaerobic resistant infection of the skin and subcutaneous tissues, poorly healing surgical wounds and skin flaps and grafts, resistant osteomyelitis and osteonecrosis, crush injuries, acute hemorrhage in people unwilling to accept blood transfusion because of religious belief. Hard to reach intracranial abscesses, and less well defined circumstances.

Hyperbaric oxygen therapy is a lifesaving treatment device for well-defined conditions and also in the field of experimentation.

******************************

Aspergillus and Asthma

 

                                           Aspergillus and Asthma

                                           PKGhatak, MD

Aspergillum is a handheld holy water sprinkler used in church services. The spore forming fungus looks like a holy water sprinkler and the name is derived from there.

 Aspergillus is a mold that can lead to various human infections. Of the illnesses resulting from exposure to aspergillus, respiratory illnesses are common.  A certain group of people is more prone to fungal infection.

Aspergillus in sputum. 

  Aspergillus consists of many species, of which Aspergillus fumigatus (A.fumigatus), A.niger, A.flavus, are important human pathogens. Aspergillus is a saprophytic spore forming warm weather fungus. It can be found in every organic decaying substance in the presence of moisture. Besides causing human diseases, enzymes obtained from Aspergillus are used extensively in food industries. Citric acid is obtained from A.Ozoro and A. flabus is hated by farmers because it causes the spoiling of grains.

This fungus multiplies by spores. The spore can withstand a temperature of 70C. The filamentous form of the fungus is called hyphae, and the mass of hyphae is called mycelia. Hyphae and mycelia are destroyed at higher temperatures. Aspergillum produces aflatoxin, which can cause liver cancer. The fungus is easily cultured in the Sabouraud medium. It grows in 5 days.

Aspergillus produces three groups of illnesses in humans. 1. Allergic, 2. Locally infective and 3. Invasive forms.

 In nature, the Aspergillus spore is everywhere and also in the air we breathe. The spores are harmless to humans, except those who are susceptible for the following reasons.  Asthmatics, Cystic Fibrosis, chronic corticosteroid users, taking immunosuppressing medications, bone marrow transplants and solid organ transplants, people with low white cell count (WBC) and cavitary lung diseases.

Wound infection with aspergillus has been a serious problem, particularly following Coronary Graft operations. Less frequently localized infections like those of the eyes, nasal sinuses, inner ear, pleura, pericardium, and skin are seen. 

Invasive aspergillosis is generally a very serious disease. It is feared in bone marrow transplantation.

Diagnosis of Aspergillosis.

 In lung diseases.

Identification of Aspergillus in sputum stained and observed under the microscope is the most direct way to identify it. Cultures are performed for confirmation. Identifying the fungus in tissues requires a biopsy. Identification of fungus from blood and bodily secretions may not be easy, but cultures are positive. For the invasive lesions, a positive test for the fungal antigens Beta-d-glucan and Galactomannan is generally available.

In allergic aspergillosis.

Blood eosinophilia and elevated IgE levels are common, but the tests are non-specific. IgE precipitin test against the aspergillus antigen is often positive. A standard skin test is an alternative diagnostic test.

Asthma.

In asthma, airway inflammation is often due to allergies to common house dust, tree and weed pollen, shellfish, animal dandruff, cockroaches and allergies to drugs, specially to the penicillin group. And about 12% are due to hypersensitivity to Aspergillus.

Asthmatics are susceptible to repeated infections and asthma becomes chronic aspergillus spores find a foothold in the small airways.

Worsening of asthma, which does not respond to medication, is likely from aspergilla infection. Mucus plugs that are coughed up are loaded with eosinophils and back-brown materials. The brown-black material is the mycelia of Aspergillus.

Repeated bouts of aspergillus infection are the rule. Eventually, weakness of bronchial walls produces small areas of bronchiectasis and that produces hemoptysis.  On x-ray, these bronchiectatic areas appear as finger shaped shadows. Usually seen in smaller airways in the central areas of the upper lobes.

Bronchopulmonary aspergillosis.

As the aspergillus began to spread out from the bronchus to the parenchyma of the lung, it takes several clinical pictures as follows-

 1. Nodular lesions – one or more in number. Pathologically these are granulomas.

 2. Pulmonary fibrosis – repeated bouts of infection produce scarring of the lungs.

 3. Cavitary lesions with fungus ball formation are called mycetoma. Mycetoma is more often seen secondary to preexisting cavities of the lungs as in Tubercular cavitary disease, emphysema, and sarcoidosis.

4. Invasion of blood vessels and distant spread.

Aspergilla infection or hypersensitivity disease in asthma are important causes of exacerbation of asthma. In chronic asthmatics, aspergillosis can take several clinical courses. Prompt identification of the fungus and proper fungicidal medication should be prescribed early and in addition to other asthma drugs.

****************************************************************

Cystic Fibrosis and Pseudomonas

 

                                       Cystic Fibrosis and Pseudomonas

                                              PKGhatak, MD 

Cystic fibrosis (CF) is an inherited disease due to gene mutation and is transmitted by autosomal recessive mode.

Cystic Fibrosis is due to a mutation in the Transmembrane conductance regulator gene (CFTR) on chromosome 7. The CFTR gene provides instructions for making a protein called the cystic fibrosis transmembrane conductance regulator. This protein functions as a channel for chloride ion transport across the membrane of cells that produce mucus, sweat, saliva, tears, and digestive enzymes. In addition to the CFTR gene, another 1,700 gene mutations are associated with CF.

In normal circumstances, the proper hydration of the surface layer and the viscosity of mucus secreted by the Goblet cells of the respiratory tract are maintained by keeping the electrolyte concentration constant. The movement of sodium ions across the cells is maintained by ATP derived active sodium channels. In Cystic Fibrosis, the Sodium channel is normal. Due to defective CFTR protein, the conductance regulator of the chloride channel and calcium activated chloride channel fail. Chloride ions are not absorbed back into the cells from the surrounding water layer. Sodium concentration also increases in the fluid secondarily in maintaining the balance of cations and anions. In a recent study, the CFTR gene mutation is identified in the cilia. The abnormal motility of cilia is due to thick, sticky mucus and not in the ciliary protein that moves the cilia.

A thin layer of low viscosity fluid separates the ciliary epithelium from a 5 micron thick mucus layer of the respiratory tract and functions as a lubricant for ciliary movement. Maintenance of normal concentrations of sodium and chloride and the resultant osmolarity of this fluid layer is essential for the coordinated ciliary movement that propels the mucus toward the vocal cord for elimination from the airways.

Patients homozygous for the abnormal CF genes show defective ciliary movement due to the high concentration of Na + Cl ions in the surrounding fluid. This abnormality leads to thick mucus accumulation in the respiratory tract, pancreas, liver, intestine and reproductive ducts. The degree of severity of the clinical states varies. CF newborns are likely to be born preterm, have a lower birth weight, lower life expectancy and occasionally a life threatening condition called meconium ileus. Most CF cases are diagnosed in early childhood, but occasional young adults present with chronic cough, recurrent sinusitis and failure to gain weight.

All newborns are required to have state mandated genetic tests on the heel blood obtained at the time of birth. Those newborns with positive genetic screening tests are followed by the Sweat Chloride test. If chloride levels are high - the diagnosis of CF is confirmed.

People carriers of one copy of the mutated CFTR gene are slightly more susceptible to URI, sinusitis, bronchiectasis and pancreatic cancer.

What is the relation of sweat chloride to the ciliary motility of respiratory epithelium.

In CF, the chloride ion fails to be absorbed back into the cells from the surrounding hyperosmolar fluid and water from the cells moves out, leading to the dehydration of cells. As sodium chloride concentration also increases in the fluid, the fluid viscosity increases and ciliary movement becomes disorganized and ineffective to propel mucus upward along the mucociliary escalator for clearing. If bacteria, like Pseudomonas aeruginosa, find their way into the lungs, then Pseudomonas bacteria can stay in contact with the epithelium longer and have time to attach themselves and invade the tissues. And inflammation begins. As the process becomes frequent, the pseudomonas change from being swimmers to swarmers. The biofilms they produce help them to coalesce together tighter and resist beta-lactamase antibiotics and then Pseudomonas become resistant to beta-lactamase antibiotics.

Pseudomonas.

 

Pseudomonas is a gram negative rod shaped, encapsulated organism. It is present ubiquitously in the soil, water, man-made materials including hospital equipment, catheters and ventilators. In culture media, it produces surface growth and produces various shades of green color, and emits a tortilla-like odor. It is aerobic bacteria but also a facultative anaerobe. It has a flagellum at one end and is a free swimmer. The colony can form biofilms that become resistant to antibiotics. The bacteria produce exotoxin A, which can inhibit protein synthesis in the immunocytes and immunocytes die as a consequence. The organism produces catalase, oxidase and citrate.

Pseudomonas aeruginosa is phagocytized in the early stage of infection. But Pseudomonas survives in the phagocytes by blocking the digestive enzymes of phagocytes. It also neutralizes IL1 beta and caspase1 as a result of the inflammation and control of the spread of infection becomes inadequate. In repeated infections, the Pseudomonas form biofilms and the colony becomes compact. And Pseudomonas changes from being free swimmers to swarmers. A subunit of the FilC protein of the flagellar protein flagellin is a chloride sensor, mutate. In CF, the Pseudomonas mutation of the FilC gene makes Pseudomonas grow more aggressively in the high chloride environment.

Cystic fibrosis, a debilitating and difficult to treat, inherited disease. Chloride ion transport disorder results in thick sticky mucus in the respiratory tract that is an opportunity for pseudomonas to colonize and then infect the lungs and cause repeated bouts of pneumonia. Pseudomonas aeruginosa thrives inside the macrophages, kills Immunocytes and neutralizes inflammatory response and inherently develops resistance to antibiotics.

This is a rare lethal combination for people suffering from CF.

In every community, the Cystic Fibrosis Foundation and the American Lung Association provide support, updated information and assistance in varieties of ways to help unfortunate sufferers and their families.

*************************************************