Figure 1: Types of Immunity
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Review the innate immune system
Describe types of allergic reactions
Discuss conditions associated with immunocompromised patients
Review prehospital care options for these patients
Marie, a paramedic, and her EMT partner, Don, are dispatched to an “unknown medical problem” at a residential address. Upon arrival, they are met at the door by the patient’s wife, who tells them, “My husband doesn’t want to go to the doctor, but I know he’s not feeling well.”
The patient, a 60-year-old male, is lying on the couch complaining of abdominal pain. He says the pain started about four days ago, and describes it as “crampy,” non-radiating, non-reproduceable and 3 on a scale of 0–10. The patient has no other complaints. He has a past medical history of hypertension, lupus and diverticulosis, for which he is prescribed Adalat (nifedipine), prednisone and Imuran (azathioprine). A physical exam reveals slight pain with palpation to the patient’s upper left quadrant and a temperature of 99.2°F. The patient’s vital signs are stable and within normal limits. As Marie attempts to administer oxygen via a nasal cannula, the patient says, “Thanks for coming out here, but I just have a stomach bug and certainly do not need to go to the hospital.”
This situation is certainly plausible, if not common in EMS. The crew is presented with a patient who has a seemingly minor complaint, is stable and does not want to go to the hospital for an evaluation. Understanding both his past medical history and his medications would alert EMS providers that this patient is high risk for infection as a result of an immune system impaired by disease and medication.
Overview of the Immune System
Over millions of years of evolution, the human immune system has evolved into a highly efficient body system designed to protect humans from harmful pathogens (see Figure 1). The immunologic response in humans is coordinated by two separate immune systems: the ancient innate (natural) immune system and the more recently evolved acquired (adaptive) immune system.
The Innate Immune System
The innate immune system is comprised of cells and processes that defend the human host from infection in a nonspecific manner that does not result in long-lasting immunity. Because it does not identify a specific foreign pathogen, innate immunity is sometimes referred to as nonspecific immunity. Innate immunity is thought to be an evolutionarily older defense mechanism (compared to acquired immunity) and is found not only in humans, but is the dominant immune system in other organisms such as plants, insects and fungi. The major functions of the innate immune system include:
- Local inflammation and recruitment of immune cells to the site of an infection via the production of specialized chemical mediators called cytokines.
- Activation of the complement cascade, which is composed of plasma proteins that are synthesized in the liver by hepatocytes. These plasma proteins trigger the recruitment of inflammatory cells, identify and “tag” pathogens for elimination, disrupt the plasma membrane of infected cells, thereby killing the pathogen, and help eliminate antigen-antibody complexes.
- Identification of pathogens in human tissues, organs, blood and lymph by specialized white blood cells such as neutrophils, eosinophils, basophils, mast cells and natural killer cells.
- Activation of the acquired immune system via the process of antigen presentation.
The Acquired Immune System
The acquired immune system is composed of highly specialized cells and processes that defend the human host from infection in a highly specific manner that results in long-lasting immunity to specific pathogens. In evolutionary terms, it is newer than the innate immune system and is found in vertebrates, including humans. The major functions of the adaptive immune system include:
- Identifying and eliminating pathogens utilizing the process of antigen presentation.
- Generating a specific immune system response to eliminate the specific pathogen identified.
- Development of an “immunologic memory” in which the immune system “remembers” each pathogen it encounters via an antibody specific to that pathogen. This allows for a faster response the second time the immune system encounters a pathogen.
Acquired immunity accomplishes its functions via the actions of T lymphocytes (T cells) and B lymphocytes (B cells). T cells provide a defense against abnormal cells (such as tumors) and cells infected with a pathogen through a process termed cell-mediated immunity, or cellular immunity. B cells provide a defense against pathogens located in body fluids in a process termed antibody-mediated immunity, or humoral immunity.
In cell-mediated immunity, diseased cells are identified by cytotoxic T cells, or killer T cells, which then divide to produce more cytotoxic T cells and memory cells. Cytotoxic T cells destroy their targets by one of three ways: 1) by releasing perforin, which perforates the target cell’s cellular membrane; 2) by secreting lymphotoxin, which disrupts the target cell’s metabolism; or 3) by inducing apoptosis (genetically programmed cellular death) in cells infected with virus or bacteria, and in tumor cells. Memory T cells will remain in circulation to be used should the pathogen reappear in the future. Another type of T cell is the helper T cell, which stimulates both cell-mediated and antibody-mediated immunity when activated.
In comparison, antibody-mediated immunity is involved in a complex series of events initiated by the formation of antigen-antibody complexes that results in a sophisticated chemical attack on specific antigens. It relies on the relationship between antigens and antibodies. An antigen is any substance that results in the formation of an antibody by the immune system. Typical antigens include proteins found within bacteria, viruses and fungi. An antibody, also known as an immunoglobin, is a “Y”-shaped protein produced by B cells and used to identify and neutralize specific antigens. There are five classes of antibodies: IgA, IgD, IgE, IgG and IgM (see Table 1).
The human body has millions of different types of B cells, each with a unique antibody on its cell membrane. When a matching antigen appears in the body fluids, it binds to its respective B cell; at this time, the B cell is said to be sensitized. The B cell is then stimulated by helper T cells to differentiate into memory B cells and activated B cells, which produce and secrete antibodies specific to the antigen. The free-floating antibodies encounter and bind to their antigen, forming an antibody-antigen complex, which results in the elimination of the antigen in one or more of several ways. Antibodies can bind many antigens together, a process termed agglutination, which allows for easier recognition and disposal. Antibody-antigen complexes attract and enhance the efficacy of cells such as macrophages, eosinophils and neutrophils, which phagocytize (ingest) the antigen. In addition, the antibody-antigen complexes promote inflammation via the stimulation of mast cells and basophiles, which release chemicals such as histamine.
Hypersensitivity, or a hypersensitivity reaction, is an immune response that is excessive and produces an undesirable reaction that can be uncomfortable, harmful and occasionally fatal. For a hypersensitivity reaction to occur, a host must have been previously exposed to an antigen and sensitized. A four-group classification system for hypersensitivity reactions was created and published in 1963 and is still in use today (see Table 2).1
Allergic Reactions and Anaphylaxis
The term allergy refers to an IgE-mediated (Type 1) hypersensitivity reaction; the antigens that result in an allergic reaction (atopy) are termed allergens. Common allergens include foods (eggs, peanuts, shellfish, many others), antibiotics, local anesthetics and other medications, insect stings (hymenoptera venom, fire ant bites), latex and hormones (insulin, methylprednisolone, progesterone).
The mildest form of a Type 1 hypersensitivity reaction is an allergic, or atopic, reaction. Patients are considered atopic when they have a predisposition towards hypersensitive responses. Atopy is a localized reaction that occurs after the host is exposed to an allergen to which it is sensitized. During the second exposure, histamine released from mast cells and basophiles results in localized increased capillary permeability, vasodilation, smooth muscle contraction and sensory nerve stimulation. When released locally these effects give rise to signs and symptoms such as localized edema, urticaria (hives), flushing, pruritus, cramping and abdominal pain. Localized vasodilation and capillary permeability in the respiratory tract produce symptoms including wheezing and complaints of mild difficulty breathing.
Anaphylaxis represents the most serious manifestation of a Type 1 hypersensitivity reaction. Though the true incidence of anaphylaxis is unknown, a recent study concluded that the lifetime prevalence of anaphylaxis is about 1%–2% of the U.S. population as a whole, and another found that 1%–15% of the U.S. population is at risk of experiencing an anaphylactic reaction.2,3 Anaphylaxis is characterized by an acute multiorgan system reaction to an allergen and results in a more global distribution of increased capillary permeability, vasodilation, smooth muscle contraction and sensory nerve stimulation compared to a localized allergic reaction. Common organ systems affected include the respiratory, cardiovascular, cutaneous, gastrointestinal and central nervous systems. Signs and symptoms include:
- Upper respiratory: nasal congestion and itching, rhinorrhea, sneezing, laryngeal edema resulting in stridor, dyspnea, hoarseness and sensation of a “tight throat.”
- Lower respiratory: Bronchospasm can result in dyspnea, chest tightness, wheezing, cough, tachypnea.
- Cardiovascular: Profound fluid volume shifts can result in circulatory collapse characterized by weakness, dizziness, near-syncope and syncope. Tachycardia, hypotension and shock can be present in severe anaphylaxis.
- Cutaneous (skin): urticaria, flushing, pruritis, angioedema, cyanosis.
- Gastrointestinal: cramping, abdominal pain, nausea, vomiting, diarrhea.
- Central nervous: anxiety, apprehension, confusion, headache (all occur as a result of cerebral hypoperfusion and subsequent hypoxia).
Management of Allergic Reactions and Anaphylaxis
A patient with a mild allergic reaction that is clearly localized can be treated as a BLS patient. If the resulting urticaria and pruritis prove to be uncomfortable for the patient, administering an antihistamine such as diphenhydramine via the oral or IM route can improve patient comfort. At the first sign of any clinical manifestation of anaphylaxis, the patient should be considered an ALS patient and immediately administered 0.3 mL of epinephrine 1:1000 IM. IM administration in the vastus lateralis (thigh) has been shown to result in a more rapid maximum plasma concentration of epinephrine than IM or SQ administration in the deltoid (arm) of asymptomatic patients and may be a preferred route.4 Ideally, the patient with known hypersensitivity to an allergen will have been prescribed an EpiPen and will have self-administered epinephrine prior to EMS’ arrival. In patients with laryngeal swelling, racemic epinephrine via small-volume nebulizer can be used to reduce swelling, but it should never take the place of more definitive airway control, such as endotracheal intubation, if airway compromise is imminent. Epinephrine should be used with caution in elderly patients and in patients with known heart disease or hypertension.
Adjunctive treatment for anaphylaxis should also include antihistamines and can include corticosteroids if protocol allows. IV administration of diphenhydramine will assure that hemodynamic compromise and hypoperfusion do not interfere with rapid absorption, as could occur with IM or PO administration. Treatment with antihistamines in the emergency department is usually accomplished by using both a H1 (diphenhydramine) blocker and a H2 blocker like ranitidine, and should be considered in the prehospital environment if available. While corticosteroids such as methylprednisolone will have no immediate hemodynamic effects on the patient with anaphylaxis,5 it can help prevent the potential late-phase reaction that can occur with biphasic anaphylaxis.
For bronchospasm unrelieved with epinephrine administration, administration of an inhaled bronchodilator via small-volume nebulizer should be considered.
Maintaining an adequate blood pressure is important in the treatment of anaphylaxis. Hypotension in anaphylaxis occurs secondary to increased capillary permeability and the third-spacing of fluids. As such, fluid volume should be replaced after administration of epinephrine, which increases peripheral vascular resistance and slows the third-spacing of fluids. The exact volume of isotonic crystalloid administered should be titrated to the return of an adequately perfusing blood pressure and could be significant, as much as 5 L, in severe anaphylaxis. For hypotension refractory to fluid volume administration, a vasopressor such as IV epinephrine or dopamine can be administered as a controlled drip.
Patients who are taking beta-blockers can have an anaphylactic reaction that is refractory to adrenergic agents. While data is limited, it appears that glucagon may be effective in such situations.6 Glucagon has positive inotropic and chronotropic effects on the myocardium and can also reverse bronchospasm.
Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE, or lupus), a Type III hypersensitivity reaction, is a multisystem autoimmune connective tissue disorder in which the body’s immune system produces antibodies that target its own tissues and organs, resulting in widespread tissue destruction and inflammation. There is no one specific cause of SLE, though the abnormal humoral and cellular immune system reactions that result in the formation of these antibodies are thought to be controlled by genetic, environmental and hormonal factors.7 It results in a broad range of clinical presentations that can include the kidneys, liver, cardiovascular system, respiratory system, skin and joints. It is known as “the great imitator” because it often mimics or can be confused with other diseases. There are four types of lupus: SLE, discoid lupus erythematosus, drug-induced lupus erythematosus and neonatal lupus. Of these, SLE is the most common and serious form. Patients with SLE are at risk for many complications, and their medication regimen often includes corticosteroids and immunosuppressive agents that may cause further complications.
SLE is much more prevalent in women than men. It may occur at any age, but appears most often in people between the ages of 10 and 50. African-Americans and Asians are affected more often than other races.8
The triad of joint pain, rash and fever in a woman of childbearing age should raise the suspicion for SLE, as they are the most commonly found symptoms in patients with the disease. Fever is a common and challenging problem in patients with the disease, as it can represent a manifestation of active SLE, an active infection, malignancy, or a reaction to medications such as immunosuppressive agents.
Dermatologic manifestations include the malar or butterfly rash that is the hallmark of SLE and occurs in about 50% of patients with the disease.9 It can be exacerbated by exposure to ultraviolet light. Lesions and ulcerations of the mucous membranes can also occur. The vast majority of patients with SLE will experience arthritis and myalgias at some point in the course of the disease. In addition, many patients will have episodes of nephritis; however, many will have no symptoms from lupus nephritis until it progresses to renal failure.
Pericarditis is the most common cardiac manifestation of SLE, occurring in about 30% of patients with the disease.10 Atherosclerosis can occur prematurely in patients with the disease and is an independent risk factor for cardiovascular disease. Pulmonary hypertension, vasculitis and splinter hemorrhages can also occur. Pleural effusions are common, and patients whose SLE is treated with immunosuppressive agents are at high risk for opportunistic bacterial, viral and fungal pulmonary infections.
Headaches are the most common central nervous system manifestation of SLE, occurring in up to 61% of adults and 72% of children who have it.11 All types of seizures have been reported, with grand mal seizures being the most common. Mental disorders are common, and about 20%–40% of neuropsychiatric SLE findings arise prior to or right around the time of diagnosis.11 Patients with SLE are also at high risk for stroke, especially in the first five years of the disease.
With so many body systems involved in SLE, and with such widespread clinical manifestations, it’s easy to imagine that most prehospital care providers will encounter a patient with acute manifestations of new onset or chronic SLE with some frequency in their careers. While the EMS provider would not be expected to diagnose SLE in the field, it is beneficial to recognize that the patient with SLE has a compromised immune system and is at high risk for infection. There is no specific prehospital treatment for SLE. Treatment is supportive in nature only, and any acute complication like pericarditis, stroke or seizure should be managed in the appropriate manner.
Compared to patients with a healthy immune system, infections in immunocompromised patients are more common, more severe, progress more rapidly, are more often fatal, and are caused by a wider variety of sometimes rare organisms.12 There are many factors that can result in immunosuppression, including disruption of the skin and mucosal surfaces (burn patients, patients with gastrointestinal lesions or disease), derangements in organ function (liver, spleen, kidneys), medical disorders that directly impair the function of the immune system (HIV, lymphoma, other cancers), and treatments for disease and transplant rejection (medications, radiation). It is important for the EMS provider to recognize those individuals with a potentially compromised immune system, as it should directly impact the decision-making process regarding transport to an ED for evaluation or recommendations for follow-up with a personal physician if the patient refuses transport. In such cases, it is advantageous for the EMS provider to be aware of the patient populations with a propensity for immunocompromise so the patient can be informed of the risks involved in not seeking medical attention for something like a low grade fever that seems non-emergent.
In recent years, the number of organ transplants (kidney, lung, heart and liver) performed has been limited only by the number of available donors. With one-year survival rates for all solid organ transplants exceeding 80%, more patients are surviving longer, and subsequently more patients are experiencing complications that bring them into contact with EMS and the ED.12
Lifelong immunosuppression is generally required for all patients who have undergone organ transplants. Without immunosuppression, the transplanted organ would be identified as “non-self” by the host immune system and its cells and tissues targeted for destruction. Because of this need for immunosuppression, organ transplant patients are at high risk for infection, which is the primary cause of mortality after transplantation. Two-thirds of all transplant patients will have at least one significant infection post-transplant.13
Signs of infection in the transplant patient can be difficult to detect for a number of reasons. Transplanted organs are commonly denervated—in other words, devoid of their normal innervation. Subsequently, the patient is much less likely to experience the pain in and around that organ as typically experienced during a developing organ infection. In addition, the normal inflammatory response will be blunted due to the use of immunosuppressive medications. As a result of these complications, constitutional signs and symptoms of developing infection such as a fever could be subtle and easily overlooked or discounted. Seemingly harmless complaints may be the only indication of severe infection and the need for aggressive management in the ED.
Patients with cancer commonly have multiple insults to their immune system, particularly T and B cell impairment as a result of the disease process, chemotherapy and radiation therapy. Other factors that contribute to an increased risk of infection include the breakdown of physical barriers such as the skin and mucous membranes secondary to the disease and the effects of chemotherapy, and the frequent colonization of antimicrobial-resistant pathogens (MRSA, VRE) on the skin and gastrointestinal surface. In addition, cancer patients may have a central venous catheter or other indwelling device that serves as a conduit for pathogens into the body. These patients frequently undergo invasive diagnostic and therapeutic procedures that break the skin and increase the risk of infection. Infection is more common in patients with new-onset leukemia, lymphoma and myeloma compared to patients with solid tumors.14
Diabetics have multiple impairments that increase the risk of acquiring an infection that can subsequently go undetected. Neutrophil and macrophage functions are impaired in this population, resulting in the immune cells being less effective at adhering to and destroying pathogens that enter the host. These defects are exacerbated by poor blood glucose maintenance that results in hyperglycemia. The reason why is not completely understood. After contracting an infection, the diabetic patient is at high risk for the infection to proliferate, secondary to vascular insufficiency and poor peripheral circulation and perfusion common with the disease. The lack of adequate perfusion inhibits the immune system’s ability to access the infection site and fight the pathogen. In addition, the sensory neuropathy characteristic of diabetes may delay the identification of a worsening infection, and the patient may not feel pain.
For these reasons, the physical exam of a diabetic patient with vague or nonspecific complaints should include examination of all surfaces of the feet and legs. Any signs of infection, ulcers or wounds should be evaluated in the ED.
Alcoholism and cirrhosis
Both acute and chronic alcohol consumption increase the risk of infection through direct suppression of the immune system, depression of mental status and delay in seeking medical care.15 Acute alcohol intoxication is associated with a decrease in circulating immune cells, as well as decreased ability for them to mobilize when a pathogen is identified. This occurs in part secondary to a decrease in the circulating plasma proteins responsible for the complement cascade (part of the innate immune system) that is produced in the liver. These changes are reversible with cessation of drinking and abstaining from alcohol. In chronic alcoholics with alcoholic cirrhosis, impaired liver function weakens the immune system, and chronic malnutrition exacerbates the situation. Alcoholics also tend to have an increased incidence of bacterial colonization of the oropharynx. This, combined with a suppressed cough reflex and high risk of aspiration, increases the risk of pulmonary infections. Alcoholics are also more likely to aspirate because of withdrawal seizures, intoxication and encephalopathy.
Patients with renal failure are at risk of infection for a number of reasons, and infections are the second most common cause of death in this patient population (up to 20% of all deaths).16 The immune system is weakened by the reduced renal clearance of toxins and nutritional deficiencies. Disruption of the skin as a protective barrier by dialysis access sites, especially peritoneal access, also increases the risk of infection. As many as two-thirds of patients receiving chronic ambulatory peritoneal dialysis will develop peritonitis in the first year of dialysis. The mortality rate from sepsis in dialysis patients is increased 100 to 300 times compared to persons not receiving dialysis.17
Splenectomy, hyposplenia, asplenia
The spleen is an important part of the immune system, producing phagocytotic cells (monocytes, macrophages) that are located in connective tissue and engulf and destroy pathogens. In addition, it is a major site of antibody synthesis. As such, any derangement to the spleen will potentially result in immune system dysfunction. Common splenic disorders are asplenia, the absence of normal spleen function in which the spleen may or may not be present, and hyposplenia, the presence of a small spleen. In addition, a patient may have undergone a splenectomy, during which the spleen was removed secondary to complications resulting from disease or trauma. Functional asplenia occurs when a spleen is present but its function is impaired by disease such as sickle cell anemia, celiac disease, SLE, rheumatoid arthritis or ulcerative colitis.
Corticosteroids and other medications
Corticosteroid medications (prednisone, cortisone, hydrocortisone) are frequently prescribed for the treatment of a variety of conditions ranging from rash to arthritis to asthma. Prescribed corticosteroids mimic the effects of the naturally produced steroid hormones from the adrenal gland, and, when prescribed in doses that exceed the body’s normal levels, act to suppress inflammation. Unfortunately, corticosteroids also suppress the immune system, affecting the function of immune cells like lymphocytes, monocytes and neutrophils, and impairing the function of cell-mediated immunity. In addition, corticosteroid administration has a hyperglycemic effect, which also increases the risk of infection.
Patients particularly at risk for infection are those with gastrointestinal issues such as appendicitis, peptic ulcers and diverticulitis. The use of corticosteroids may mask the usual signs and symptoms associated with infection, making identification of a potentially life-threatening infection from, for instance, a perforated diverticula difficult to recognize. The use of corticosteroids can also result in increased infections caused by bacteria, varicella zoster and herpes simplex viruses, tuberculosis, and a wide variety of other bacteria, fungi and parasites.12
Other immunosuppressive medications are used to treat a wide variety of conditions including SLE, inflammatory bowel disease, rheumatoid arthritis and psoriasis. These include sirolimus, tacrolimus, azathioprine, mycophenolate, cyclosporine, methotrexate and cyclophosphamide.
Marie considers the exam and history findings and constructs her reply to the patient’s statement that he does not want to go to the hospital. “Sir”, she says, “I appreciate that you think this is just a stomach bug, but here’s what I’m concerned about: Your lupus and the Imuran and prednisone you take to treat it weaken your immune system. And, with your history of diverticular disease, I’m worried that you may have developed diverticulitis, which your weakened immune system might struggle to fight effectively. Worst case scenario, you could be developing an infection that you cannot effectively fight. This infection could get worse, spread to other places in your abdomen or even your blood, and make you very sick. For that reason, I recommend that you go to the hospital for an evaluation.”
Presented with this information, the patient agrees to transport with the EMS crew to the local ED. He is placed on the cardiac monitor and IV access is initiated. He is monitored during an uncomplicated trip to the receiving ED. Later, the attending physician informs Marie and Don that the patient had diverticulitis with a perforated diverticula, was likely developing peritonitis, and had been admitted to the hospital for treatment and observation.