The immunosuppressed patient

Chapter 42 The immunosuppressed patient



Judy Alford, Anthony Kelleher


Patients with immunosuppression present with emergencies related to their increased susceptibility to infection and to their underlying condition.


The most frequently encountered causes of immunocompromise vary according to the location and specialisation of the institution, with cancer, AIDS and solid organ transplant being the commonest conditions. Other causes of immunocompromise are immunosuppressive and/or cytotoxic therapy for non-malignant disease, post-splenectomy, congenital immune defects and marrow failure due to drugs or infection.


The signs and symptoms of infection are often diminished and patients may present with subtle and non-specific findings and deteriorate rapidly. Fever may be the sole presenting symptom, but even that may be masked by the presence of drugs such as corticosteroids. Therefore, infection must be considered in the differential diagnosis of the immunocompromised patient presenting with non-specific symptoms.


The immune system consists of innate and adaptive components. Innate immunity stems from intact epithelial barriers, phagocytic cells (neutrophils and macrophages), natural killer cells and the complement system. Innate immunity does not require prior exposure to the infective agent for rapid activation.


Adaptive immunity is conferred by lymphocytes and their products. T cells act against intracellular microbes and provide cell-mediated immunity. Humoral immunity is conferred by B cells and the antibodies they produce, which are active against extracellular microbes.


Failure of a component of the immune system leads to vulnerability to different infective agents.


T cell defects occur in acquired immune deficiency syndrome (AIDS), immunosuppressive therapy and congenital severe combined immune deficiency (SCID) and leave patients susceptible to bacterial sepsis, infections with intracellular bacteria (tuberculosis (TB), Listeria), viral infections (cytomegalovirus (CMV), Epstein-Barr (EBV), varicella), fungal infections (Candida, Cryptococcus, Pneumocystis) and protozoal infection (Toxoplasma).


B cell defects occur in haematological malignancies, myeloma, AIDS and congenital disorders such as common variable immune deficiency. Patients are predisposed to infection by encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria), staphylococci, giardia and enterovirus.


Granulocyte defects including neutropenia result from chemotherapy, marrow aplasia or infiltration, drug reactions, myelodysplasia and rarely from congenital defects. Patients are vulnerable to infection by gram negative bacilli including Pseudomonas, gram positive cocci such as staphylococci and viridans streptococci, and fungi such as Candida and Aspergillus.


Complement defects lead to susceptibility to infection with Neisseria and pyogenic bacteria, as well as predisposing to autoimmunity.


Asplenia predisposes to severe infections due to encapsulated bacteria including Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis.


In addition to infections, fever in the immunocompromised patient may be due to malignancy, drugs and allograft rejection.


Improvements in the management of the conditions associated with immunodeficiency have led to improved long-term survival and better quality of life for these patients. Nonetheless, there remains the potential for severe infections with rapid deterioration and death. Early aggressive care is essential, which includes early, rapid investigation, early institution of broad spectrum antibiotics, application of treatment protocols for sepsis and the use of ventilatory support where indicated. Non-infective causes such as rejection must be considered, especially in transplant patients. Early ICU referral and a team approach involving treating haematologists, oncologists, human immunodeficiency virus (HIV) specialists or transplant physicians is essential in the deteriorating patient. The patient’s wishes should be ascertained early, particularly in those with severe advanced disease or chronic progressive conditions that have been unresponsive to intervention.



CANCER PATIENTS


Cancer patients are at risk of severe infection due to immunosuppression induced by their disease and its treatment. Most at risk are patients undergoing therapy for haematological malignancies or stem cell transplant, who have severe and prolonged neutropenia. The risk of infection rises as the neutrophil count falls.



Febrile neutropenia


Febrile neutropenia is defined as fever above 38.0°C in a patient with a neutrophil count < 0.5 × 109/L or < 1 × 109/L with predicted decline.


Associated signs of infection may be present such as tachypnoea, tachycardia, altered mental state, dehydration and acidosis. Localising signs may be absent; however, a thorough examination of the lungs, oropharynx, skin, catheters, perineum and perianal area, sinuses and urinary tract is essential and may reveal the site of infection. Non-specific symptoms in the absence of fever may still indicate infection, especially if the patient is on high-dose corticosteroids.



Investigations


Investigations should include urea, electrolytes, creatinine (UEC), full blood count (FBC) and liver function tests (LFT), chest X-ray, urinalysis and swabs from any skin lesions. Two sets of blood cultures should be obtained, one from any indwelling catheter that may be present. There should be a low threshold for the collection of specimens for culture.


Cerebrospinal fluid (CSF) is not routinely cultured, but should be if CNS infection is suspected. However, in the rapidly deteriorating patient, or in those with a coagulopathy, lumbar puncture may need to be delayed or forgone. Antibiotic administration should not be delayed by the need for lumbar puncture.


Stool should be sent for culture if diarrhoea is present. The patient with abdominal signs will require imaging by ultrasound or computerised tomography (CT); however, this should not delay surgical consultation, as signs of peritonitis are minimal in the neutropenic patient.


CT scans of the sinuses should be obtained if there is facial pain or swelling, as severe, invasive fungal sinusitis occurs in these patients.



Management



Broad spectrum antibiotics


Broad spectrum antibiotics should be started immediately after cultures have been obtained. Delay in initiating appropriate antibiotic therapy is associated with increased mortality. Coverage for gram negatives, including Pseudomonas aeruginosa, is essential. Recommended regimens vary between institutions. The following antibiotics are suitable:


• ceftazidime 2 g IV 8-hourly

or


• piperacillin 4 g + tazobactam 0.5 g IV 8-hourly

or


• ticarcillin 3 g + clavulanate 0.1 g IV 6-hourly

plus gentamicin 4–6 mg/kg IV daily


or


• cefepime 2 g IV 12-hourly.


Vancomycin


Gram positive bacteraemia due to Staphylococcus epidermidis, Staphylococcus aureus, viridans streptococci and enterococci is very common. The routine use of vancomycin is not recommended, although it should be given if the patient is in shock, is known to have methicillin resistant S. aureus (MRSA) or has a clinically infected catheter. The recommended dose is 25 mg/kg up to 1 g IV 12-hourly. Vancomycin is often added if fever persists beyond 48 hours.



Antifungals


Antifungals are not routinely used in the initial treatment of febrile neutropenia, unless there is evidence of fungal infection such as sinusitis. They may be introduced when fever persists beyond 96 hours, especially in patients with pulmonary infiltrates.


A subgroup of low-risk neutropenic patients may be managed at home with oral therapy. This should only be done in consultation with the treating haematologist or oncologist.



Colony-stimulating growth factors


Recombinant colony-stimulating growth factors may be used in high risk patients with sepsis or organ failure, after consultation with a haematologist or the patient’s treating physician.



Noninvasive ventilation


Noninvasive ventilation used early in the course of hypoxaemic respiratory failure may reduce the need for intubation and improve survival.



Fever in the non-neutropenic cancer patient


Cancer patients with a normal granulocyte count remain susceptible to infections when their adaptive immune response is impaired by treatment with steroids or chemotherapy, or by haematological malignancy. T cell defects increase the risk of infection with intracellular pathogens like Listeria, Salmonella, mycobacteria and fungi. Patients with impaired humoral immunity are at risk of infection by encapsulated bacteria, often manifesting as pneumonia.



NONINFECTIOUS COMPLICATIONS OF CANCER AND ITS TREATMENT



Spinal cord compression


This is most common in the thoracic spine (70% of cases), although it may involve any level. It is most frequently due to metastatic breast, lung or prostate cancer, or lymphoma. An epidural abscess or discitis should be considered in patients who have had lumbar puncture or intrathecal therapy, or who are at risk of bacteraemia.


Pain usually occurs before the development of neurological symptoms. Once symptoms such as weakness, sensory loss and sphincter dysfunction begin, treatment must occur within hours to give the patient a chance of recovery.



Investigations



• Plain films of the spine show tumour in 70–90%.

• Urgent MRI scanning will localise the lesion.


Management



1. Obtaining MRI images should not delay treatment with corticosteroids in the patient with neurological signs. An initial dose of dexamethasone 20 mg IV is followed by 4 mg 6-hourly.

2. Radiotherapy to the affected area is the treatment of choice, with surgery used in selected cases with spinal instability.


Hypercalcaemia


Increased osteolysis releases calcium and phosphate into the circulation. This can be caused by primary (myeloma or leukaemia) or metastatic bone lesions (commonly breast or lung) or by the action of paraneoplastic hormone-like substances.


The severity of symptoms depends on the rate of increase of calcium, with more acute hypercalcaemia causing worse symptoms for a given level of serum calcium.


CNS symptoms range from lethargy and weakness to coma. Polyuria and renal impairment occur, along with gastrointestinal disturbance (nausea, vomiting, constipation and abdominal pain).


The diagnosis is made by measuring the serum ionised calcium. The ionised calcium can be calculated from the total serum calcium:



image



Hypokalaemia is common. The patient may be significantly dehydrated and have renal impairment.



Management



1. Hydration with oral fluids or normal saline is the initial step in treatment, and may be sufficient in mild cases.

2. Once dehydration has been corrected, diuretics may be used to promote calciuria.

3. Bisphosphonates (pamidronate 90 mg infusion over 4–24 hours or zolendronate 1–4 mg over minutes) can be used to reduce the calcium level further.


Superior vena cava (SVC) obstruction


The SVC may be obstructed by compression, infiltration or thrombosis and is usually a complication of malignancy (particularly lung, breast or testicular cancer, or lymphoma). Occasionally it occurs as a complication of a central venous catheter (CVC), or from a benign lesion such as a goitre, constrictive pericarditis or aortic aneurysm.


Symptoms and signs are more prominent when the patient is supine, including periorbital and facial oedema (also trunk, arms), shortness of breath (SOB), cough, chest pain and dysphagia. On examination there may be neck vein distension, facial plethora and cyanosis, along with tachypnoea.



Investigations


An important differential diagnosis is pericardial tamponade. A bedside ultrasound scan can rule out an effusion.


The chest X-ray usually reveals a mass in the mediastinum, which may be accompanied by pulmonary lesions or a pleural effusion.



Management



1. Treatment is directed at the tumour and involves radiotherapy or chemotherapy.

2. Elevating the head of the bed can alleviate some symptoms. Corticosteroids may be useful if the tumour is sensitive.

3. SVC stenting is a further treatment option.


Tumour lysis syndrome


This occurs within days of commencing treatment for sensitive tumours, although it may occur spontaneously. Rapid cell death releases products of cell breakdown into the circulation, leading to hyperuricaemia, hyperkalaemia, hyperphosphataemia and hypocalcaemia. Renal failure and metabolic acidosis may develop. It most frequently complicates haematological malignancies and small cell lung cancer.


The clinical manifestations include neuromuscular cramps, tetany and arrhythmias. Oliguria and acute renal failure may develop from uric acid precipitation in the renal tubules.



Management



1. Initial treatment is hydration with normal saline and treatment of hyperkalaemia.

2. Urinary alkalinisation (50–100 mg NaHCO3/L fluid, urine pH > 7) is of benefit in hyperuricaemia; however, in the presence of hyperphosphataemia and hypocalcaemia, alkali therapy can exacerbate symptoms.

3. Once adequate hydration has been established, diuretics may be added to maintain a high urine output.

4. Severe cases complicated by acute renal failure may require dialysis.


Hyperviscosity


Very high white blood cell (WBC) counts (> 100 × 109/L) associated with haematological malignancies (acute leukaemias, chronic myeloid leukemia (CML)) cause increased blood viscosity, which impairs flow in the microcirculation. The cerebral and pulmonary circulations are particularly susceptible. Hyperviscosity syndrome also occurs with high levels of paraproteinaemia, especially with IgM paraproteins, such as in Waldenstrom’s macroglobulinaemia.


Impaired cerebral circulation causes headache, dizziness, confusion, seizures and visual disturbance. The fundi show venous engorgement and haemorrhages. Cardiopulmonary consequences include angina, dyspnoea, myocardial infarction and cardiac failure. There may be bleeding from mucosal surfaces.



Management



1. Treatment begins with hydration.

2. Patients should be referred for leukapheresis or plasmapheresis.


HIV INFECTION


Patients with HIV infection most commonly present with complications of immunosuppression and its treatment. With the improved prognosis of HIV in the era of highly active antiretroviral treatment (HAART), patients increasingly present with medical or surgical conditions unrelated to HIV and, while their treatment may be complicated by their HIV, their outcome and survival may be excellent.



Primary HIV infection


Within 1 to 6 weeks of infection (sometimes up to 12 weeks), 50–70% of patients develop a symptomatic illness. In most cases this is mild to moderate in severity and does not usually present to the emergency department. The seroconversion illness can resemble infectious mononucleosis. Patients develop fever, fatigue, anorexia, headache, nausea and vomiting. Myalgias and arthralgias, a non-exudative pharyngitis, rashes and diarrhoea are common. Severe cases may develop meningism or encephalitis.



Investigations


The differential diagnosis is wide, so investigations should include FBC, UEC, LFT and monospot, along with serology for CMV, EBV, hepatitis and syphilis. In those with a recent high-risk exposure it is important to think of the diagnosis. In more severe cases, immunosuppression may be profound and the seroconversion illness may be complicated by an opportunistic infection. Not uncommonly other sexually transmitted infections (STI) may occur at the same time and should be screened for.


Current HIV-1 antibody tests are usually positive by 2 weeks after the onset of symptoms (4 weeks after exposure), but earlier generation enzyme immunoassay (EIA) tests may be negative or give indeterminate results. Prior to antibody responses the virus can be detected by direct detection of viral p24 antigen or, in some centres, by nucleic acid amplification tests such as proviral DNA tests. Assays of plasma HIV-1 RNA used for monitoring HIV infection may pick up the presence of virus prior to the production of antibodies in this early stage of the infection; however, they have a substantial false positive rate in low seroprevalence settings and can give a false negative result with certain strains of the virus. Therefore this test should not be used diagnostically.



Management


During the first 6 months of HIV infection, there is uncontrolled viral replication and destruction of CD4+ T cells. Presentation with a severe seroconversion illness is associated with faster disease progression. There are ongoing trials of antiretroviral treatment in early HIV infection with the goal of controlling viral replication and slowing T cell decline; however, antiretroviral therapy in primary HIV infection is not routinely recommended. Patients should be referred to a specialist in HIV medicine early, particularly those with symptomatic seroconversion.


They should also receive risk reduction counselling as, with the high levels of virus circulating in these patients, they are highly infectious and likely to pass on the infection to others.



Opportunistic infections (OIs)


A wide range of OIs affect HIV patients once their CD4+ cell counts decline. Information that helps narrow the differential diagnosis includes a recent CD4+ count and viral load, use of antiretrovirals and prophylaxis. The knowledge of previous serology for infections such as CMV and toxoplasmosis is very useful as presentations with OIs most often represent recrudescence of previously controlled latent infections. Patients presenting for the first time with late stage disease, or those that have not sought medical care, may present with multiple opportunistic infections simultaneously. This should be considered in the diagnostic work-up.


Bacterial infections are common in HIV patients and bacterial sepsis is a more frequent cause of ICU admission than Pneumocystis jiroveci (carinii) pneumonia (PCP). Sources include pneumonia, catheter-related infections, orthopaedic and soft tissue infections, urinary tract infections (UTIs) and bacteraemia of unknown aetiology.



Pulmonary infections

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Jun 14, 2016 | Posted by in EMERGENCY MEDICINE | Comments Off on The immunosuppressed patient

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