The immunosuppressed patient

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Chapter 42 The immunosuppressed patient

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

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:

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

The incidence of HIV-associated pneumonia changed with the use of HAART, with bacterial pneumonia becoming increasingly common. Pneumonia in HIV patients is more often bacterial than due to an opportunistic agent, and is 10 times more common in HIV patients than in non-HIV patients. The common community-acquired bacteria are the usual culprits, with most pneumonia being caused by Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus.

PCP (Pneumocystis jiroveci (carinii) pneumonia)

Since the introduction of HAART in 1996, the incidence of PCP as an AIDS-defining illness has declined, although it remains the most frequent serious opportunistic infection. The disease occurs in patients with a CD4⁺ count below 200 cells/μL, particularly when antibiotics prophylaxis has not been used.

Fever, cough and shortness of breath are the usual presenting symptoms. The respiratory examination may reveal few signs other than tachypnoea and accessory muscle use. Oxygen saturations are often reduced and severe cases may be cyanosed at presentation.

Investigations

The chest X-ray typically reveals bilateral diffuse reticular or granular opacities. The extent of these changes may be less than expected by the degree of hypoxaemia.

Arterial blood gas analysis assists in grading severity and planning treatment. Mild to moderate cases have a PaO₂ > 70 mmHg on room air (A-a gradient < 35 mmHg, or O₂ saturations > 94% on room air), whereas severe cases have a PaO₂ < 70 mmHg on room air (A-a gradient > 35 mmHg, or O₂ saturations < 94% on room air).

Diagnosis

A provisional diagnosis is made on clinical findings and chest X-ray. Definitive diagnosis requires direct visualisation of Pneumocystis cysts or trophic forms from respiratory specimens (induced sputum or broncho-alveolar lavage).

Management

1. Trimethoprim-sulfamethoxazole is the treatment of choice for mild to moderate PCP, in oral doses of 5 mg/kg + 25 mg/kg to 7 mg/kg + 35 mg/kg 8-hourly for 21 days. If sulfamethoxazole is contraindicated, dapsone 100 mg PO daily with trimethoprim 300 mg PO 8-hourly is an alternative. Patients who are also intolerant of trimethoprim can be treated with atovaquone 750 mg orally, 12-hourly.

2. Severe disease is treated with intravenous trimethoprim-sulfamethoxazole 5 mg/kg + 25 mg/kg IV 6-hourly for 21 days. Patients who are intolerant of or unresponsive to this may be treated with intravenous pentamidine 4 mg/kg up to 300 mg daily.

3. Pulmonary inflammation contributes to lung injury in PCP, so corticosteroids are given in severe disease. Prednisolone is given at 40 mg 12-hourly for 5 days, then 40 mg daily for 5 days, then 20 mg daily for 11 days.

4. Antibiotic cover for community-acquired pneumonia may be added, particularly when the patient has purulent sputum.

5. Non-invasive positive pressure ventilation is indicated in the non-obtunded patient with hypoxaemic respiratory failure, and it may avert the need for mechanical ventilation. Unless there are clear contraindications to intubation, such as end-stage malignancy or dementia, intubation and ventilation are appropriate in the patient with severe respiratory failure, as the prognosis from a first episode of PCP is good. Recurrent episodes may be complicated by cyst formation and pneumothorax.

Tuberculosis (TB)

Worldwide, this is the most important HIV-associated opportunistic pneumonia. Reactivation or primary infection can occur at high CD4⁺ counts (> 400 cells/μL) and the disease becomes more common with declining counts. In the severely immunocompromised, extrapulmonary sites of infection are more frequent.

Presenting symptoms are cough, haemoptysis, fever, shortness of breath, sweats and weight loss. The onset is typically insidious. The diagnosis is more likely in patients from countries where Mycobacterium tuberculosis is endemic.

Investigations and diagnosis

The chest X-ray shows upper lobe cavitation or hilar adenopathy with diffuse infiltrates. Pleural effusions may be present. Miliary TB is uncommon in patients with poor cell-mediated immunity. Extrapulmonary manifestations or presentations are more common in patients with HIV infection.

Diagnosis remains difficult, as sputum microscopy is often negative, but PCR assays may be useful, though a negative result does not exclude the diagnosis. Fine needle aspiration of extrapulmonary sites is often diagnostic.

Management

Treatment is specialised, involving multiple agents and complicated by interactions between antiretrovirals and antitubercular drugs. Early specialist referral is essential. If the diagnosis of open TB is considered likely, the patient must be isolated.

Central nervous system (CNS) infections

A number of agents infect the CNS, causing the acute or subacute onset of seizures, headache, fever, neck stiffness, confusion or focal deficits. However, symptoms may be non-specific and space-occupying lesions may be present in the absence of clinical signs. Therefore, there should be a low threshold for the performance of a CT scan and/or lumbar puncture in patients with late stage HIV-infection. With the increasing longevity of these patients and the increased risk of vascular complications, cerebrovascular accident (CVA) should be included in the differential diagnosis of CNS presentations.

Toxoplasma gondii

This protozoan is widespread in the community, but it rarely causes disease until CD4⁺ counts drop below 100 cells/μl. The incidence is decreased with prophylaxis with trimethoprim and sulfamethoxazole.

Presenting features are altered mental state, focal signs, headache, fever and seizures.

Investigations

The diagnosis is made by contrast CT, which shows ring-enhancing lesions.

Toxoplasma serology is supportive, and cerebral toxoplasmosis is very unlikely in a patient with negative serology. In this case the diagnosis is likely to be primary CNS lymphoma.

Management

1. Treatment is with sulfadiazine 1–1.5 g orally or IV 6-hourly plus oral pyrimethamine 50–100 mg loading dose then 50–75 mg daily, for 3 to 6 weeks.

2. Clindamycin 600 mg 8-hourly is used if the patient is hypersensitive to sulfonamides.

3. If sulfadiazine is used, folinic acid 20–25 mg/day should be added to reduce marrow toxicity.

4. Anticonvulsants should be started to prevent seizures.

5. The use of steroids is not recommended, unless the lesions are associated with substantial oedema and exerting significant mass effect.

AIDS dementia

Patients with the AIDS dementia complex exhibit a gradual decline in memory and/or psychomotor function, ataxia and personality changes. It may also present with signs of spinal cord myelopathy. The syndrome usually affects patients with CD4⁺ counts below 200 cells/μL but may occur earlier. Drugs, infections and metabolic derangements can exacerbate dementia in affected patients. CT scans of the brain show atrophy.

There is no specific treatment, although HAART may improve symptoms.

Progressive multifocal leukoencephalopathy (PML)

Progressive CNS infection with JC virus usually occurs in patients with CD4⁺ counts below 100 cells/μL. PML presents with seizures, focal weakness, cranial nerve palsies, visual field deficits, cerebellar signs and confusion.

Investigations

CT scans are relatively insensitive and, while these may reveal focal hypodensities, they are often non-contributory.

MRI usually shows characteristic white matter changes with cortical sparing; the absence of these changes does not exclude the diagnosis.

JC virus can be identified in CSF by PCR, but this test is offered only in specialist laboratories.

Management

HAART may improve symptoms; however, there is no specific treatment.

Gastrointestinal tract (GIT) infections

Candidiasis

Candida albicans frequently affects the oropharynx and/or the oesophagus, to an extent that is unusual in immunocompetent patients. Oesophageal candidiasis presents with oropharyngeal or retrosternal pain, dysphagia or odynophagia. There may be bleeding. White plaques with underlying erythema cover the affected areas.

Management

1. While simple oral candida will respond to topical treatment with amphotericin or nystatin solutions or lozenges, oesphageal involvement requires systemic treatment with fluconazole or, occasionally, itraconazole.

2. Resistant cases may be treated with voriconazole or amphotericin B.

3. Fluconazole may be used for secondary prophylaxis or maintenance therapy

Cyclospora, Isospora, Cryptosporidium parvum

May all cause chronic diarrhoea. Cryptosporidium is less common since the advent of HAART. These infections should be considered in those presenting with chronic gastrointestinal symptoms, especially if resistant to therapy. The disease is often refractory to treatment.

Bacterial infections

Camplylobacter jejuni, Salmonella or Shigella infections occur with increased frequency and severity of manifestations compared to the non-infected population. They may be more resistant to treatment than the uninfected population.

Viral hepatitis

A significant number of HIV patients, particularly those who are intravenous drug users, are also infected with hepatitis B or C. Antiretroviral drugs may worsen hepatic dysfunction and fluctuating immune function may be associated with flares of viral hepatitis. The treatment of hepatitis in the HIV patient is complex, and early specialist referral is essential.

Systemic infections

Herpes simplex

Severe mucocutaneous infections occur more frequently than disseminated infection. These may be in the form of chronic, aggressive, poorly healing perianal ulcers.

Management

Treatment is with famciclovir, valaciclovir or acyclovir. These drugs may be used as suppressive therapy to prevent frequent recurrences.

Herpes zoster (HZV)

Recurrent zoster infections are often an early indicator of progressive CD4⁺ T cell depletion. These remain dermatomal despite severe immunosuppression, though extent of blistering may be severe and haemorrhagic. CNS infections with herpes viruses should be considered in the differential diagnosis of an encephalitic picture.

Cytomegalovirus (CMV)

Opportunistic CMV infection affects patients with CD4⁺ counts below 50 cells/μL. CMV retinitis presents with floaters, decreasing acuity and field loss. Fundoscopy reveals peripheral flame haemorrhages and exudates. However, the retinal lesions are often very peripheral and so can be missed. Dilation of the pupil and ophthalmological review are required to exclude diagnosis. Any part of the GIT may be involved, with colitis, oesophagitis and gastritis being common presentations. CNS involvement causes encephalopathy and a polyradiculopathy. Interstitial pneumonitis is rare in HIV, in contrast to solid organ transplant recipients. CMV adrenalitis presents with symptomatic adrenal insufficiency, hyponatraemia or hyperkalaemia.

Investigations

Detection of CMV RNA or DNA by nucleic acid testing in plasma or CSF is an aid to diagnosis. The presence of the classical inclusion bodies on bisopsy of involved tissue is required for a definitive diagnosis of GIT disease or pneumonitis.

Management

CMV is usually treated with valganciclovir, ganciclovir and, in problematical or resistant cases, foscarnet or cidofovir with probenecid. A specialist in HIV medicine should be consulted, along with urgent ophthalmology review in cases of suspected retinitis.

Mycobacterium avium-intracellulare complex (MAC)

This occurs in patients with CD4⁺ counts below 50 cells/μL. The incidence has decreased with the use of HAART and azithromycin prophylaxis. It presents as a systemic infection with fever, weight loss, night sweats, neutropenia, anaemia and lymphadenopathy. The diagnosis is made by blood culture.

Management

Treatment is with ethambutol plus either clarithromycin or azithromycin, with consideration of the addition of rifabutin in severely immunocompromised patients.

MALIGNANCY

HAART has changed the epidemiology of AIDS-related malignancies. The incidence of non-Hodgkin’s lymphoma has declined, especially primary CNS lymphoma (seen in patients with profound immunosuppression and CD4⁺ counts below 50 cells/μL). Most still present with advanced disease (extranodal, meningeal, GIT and bone marrow disease are common) and B symptoms. There has been improved survival with combination chemotherapy and HAART.

Kaposi’s sarcoma has also become much less common over the last decade. This malignancy is associated with infection with human herpes virus 8 and occurs with CD4⁺ counts less than 300 cells/μL. Skin involvement usually presents as painless, hyperpigmented purple nodules or plaques, but in pressure areas these may become painful and/or ulcerate. Especially in later disease, lesions may be more systemic, and be associated with lymphatic obstruction in the limbs and also involve the oropharynx, GIT (causing pain, ulceration, obstruction, bleeding or perforation). Involvement of the lung (with pleural effusion, pulmonary infiltrates or hilar adenopathy) is a poor prognostic sign. Treatment consists of antiretrovirals in early stage disease, with chemotherapy in advanced disease. Systemic involvement especially of the lung is resistant to intervention.

Cervical cancer remains a common problem in HIV-infected women, with no impact on the disease from antiretrovirals. Treatment is as for the immunocompetent patient. Human papilloma virus (HPV) infection may also cause premalignant and malignant changes in the rectum of HIV-infected men who have sex with men (MSM).

Non-AIDS-defining malignancies are becoming more common with increasing longevity.

IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME (IRIS)

With the widespread use of HAART, complications arise from the recovering immune system directing an inflammatory response against antigens associated with infectious agents.

IRIS presents as worsening signs or symptoms of infection in late stage patients (< 100 CD4⁺ cells/μL at commencement of therapy) who have recently commenced antiretroviral therapy (ART). It usually manifests within 4 weeks, and may begin within days, although occasionally it develops after months of treatment.

The opportunistic infections most commonly associated with IRIS are MAC, CMV, HZV and fungi such as Cryptococcus. Worldwide, TB is the most common cause, with up to one-third of late stage patients developing IRIS after starting ART. It occurs more frequently when HAART is given in the presence of an untreated infection. For this reason ART is usually not commenced in the presence of a known opportunistic infection. Commencement of ART is usually delayed until the active infection is cleared or the patient has commenced maintenance suppressive or prophylactic therapy.

IRIS often represents a diagnostic dilemma, as the presentation is often non-specific and atypical. The differential diagnosis includes a new OI or drug toxicity. The diagnosis is essentially one of exclusion.

PCP-associated IRIS presents with a worsening of respiratory status and occasionally unmasks clinically silent PCP. MAC- or CMV-associated IRIS presents with fevers, lymphadenopathy and systemic symptoms. CMV may present with worsening of retinitis which may result in the permanent loss of sight.

Management

Treatment involves cessation of ART and supportive care. Corticosteroids may be used to blunt the inflammatory response.

ANTIRETROVIRAL DRUGS

The introduction of HAART, combination therapy with three or four antiretroviral drugs, has led to improvements in morbidity and mortality, decreased transmission and increased quality of life. Patients often have restoration of their immune function and a fall in viral load to undetectable levels. The main classes of antiretrovirals are nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors. More recently two types of entry inhibitors (fusion inhibitors and chemokine (C-C motif) receptor 5 (CCR5)-blockers) have been licensed. In addition the first drug in a potent new class of antiretrovirals, the integrase inhibitors, has been licensed for use. Specific inhibitors include:

• nucleoside reverse transcriptase inhibitors: abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zidovudine

• non-nucleoside reverse transcriptase inhibitors: efavirenz, nevirapine

• protease inhibitors: atazanavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, darunavir, tipranavir

• fusion inhibitor: T20/enfuvirtide which is given as an injection

• CCR5 inhibitors: maraviroc

• integrase inhibitors: raltegravir.

Nelfinavir and indinavir are now rarely used. The others are usually used in combination with low-dose ritonavir (which is a protease inhibitor) and also a cytochrome P450 inhibitor which increases drug levels of the protease inhibitors. It allows the doses of the protease inhibitors to be reduced.

Drug toxicities

Lactic acidosis

Nucleoside/nucleotide reverse transcriptase inhibitors (notably didanosine and stavudine) can cause lactic acidosis via mitochondrial toxicity. Patients with a reduced creatinine clearance and lower CD4⁺ counts are at higher risk.

The severity ranges from asymptomatic acidaemia to a life-threatening syndrome. Abdominal pain and distension, nausea and vomiting are common, along with myalgias, peripheral neuropathy, dyspnoea and hepatic steatosis with raised transaminases. Cessation of drugs may lead to resolution, or there may be progressive multisystem involvement and respiratory and circulatory failure. Initial lactate levels higher than 5 may be life-threatening.

Management

1. Treatment involves cessation of ART and supportive care.

2. Riboflavin, l-carnitine and thiamine may reverse toxicity.

3. In severe cases bicarbonate therapy and haemodialysis may be needed.

Hypersensitivity reactions

Rashes are common in HIV patients and are often minor and self-limiting and do not mandate cessation of therapy. Non-nucleoside reverse transcriptase inhibitors and antibiotics (especially trimethoprim-sulfamethoxazole) are frequent causes. The more serious Stevens-Johnson syndrome is also associated with these drugs, with widespread rash and blistering, mucosal involvement and fever.

Abacavir is associated with a life-threatening hypersensitivity syndrome, usually beginning in the first 10–14 days of treatment, with rash, fever, nausea, vomiting and abdominal pain. Patients may develop interstitial pneumonitis, hypotension and respiratory failure. The cause of this is now known to be strongly linked to the carriage of HLA-B5701. All patients being considered for abacavir therapy should be screened for the carriage of this HLA-allele prior to commencement.

Nevirapine is a cause of fulminant hepatitis upon initiation of therapy, particularly in men with a CD4⁺ count > 400 cells/μL or women with a CD4⁺ T cell count > 200 cells/μL.

Management

For severe hypersensitivity reactions, all antiretrovirals (and other potential causes such as antibiotics or anticonvulsants) should be stopped and supportive care instituted.

Other toxicities

Many other antiretrovirals (particularly protease inhibitors) can cause hepatitis. Pancreatitis occurs with stavudine, didanoside and lopinavir/ritonavir. Renal colic and haematuria may occur with indinavir. Peripheral neuropathy, which is often painful, is associated with stavudine, didanosine and zalcitabine. Myelosuppression occurs with zidovudine.

Drug interactions

Many drug interactions occur due to inhibition of induction of the hepatic cytochrome P450 system.

Of particular note are: increased sedative effects from midazolam (lorazepam is unaffected); decreased levels of methadone, causing narcotic withdrawal; increased levels of norpethidine, the toxic metabolite of pethidine; a disulfiram-like reaction with metronidazole; and increased cardiovascular effects of amiodarone, diltiazem, nifedipine and sildenafil. Systemic levels of the more potent long-acting inhaled corticorticosteriods can be driven high enough to induce Cushing’s syndrome. Short-acting low-dose inhaled steroids should be used in patients on ritonavir boosted protease inhibitors.

Cardiovascular complications

Long-term ART is associated with metabolic and cardiovascular toxicities, dyslipidaemia, atherosclerosis, endothelial dysfunction and glucose intolerance with insulin resistance.

Age-adjusted rates of coronary artery disease and myocardial infarction are elevated in HIV-positive men. The treatment of acute coronary syndromes is the same as in HIV-negative patients.

POST-EXPOSURE PROPHYLAXIS

Post-exposure prophylaxis (PEP) is the use of antiretrovirals to prevent seroconversion after potential exposure to HIV. PEP is effective when given less than 72 hours after exposure, although there is declining efficacy after 36 hours.

In non-occupational exposures, the HIV status of the source is often unknown. Assessment of the risk of HIV transmission requires knowledge of the risk of transmission from the method of exposure and the risk of the source being HIV positive. High-risk exposures include receptive anal intercourse (1/120), sharing contaminated injecting equipment (1/50), occupational needle stick (1/333), receptive vaginal intercourse (1/1000) and insertive anal or vaginal intercourse (1/1000). Although case reports of transmission exist, the risk of transmission by oral intercourse, bites, exposure to intact mucous membranes or skin and community-acquired needle stick is so low it is not measurable.

The risk of the source of exposure being HIV-positive varies between populations. In MSM, the estimated HIV rates are 14% in Sydney, 9% in Melbourne, 6% in Brisbane and 5% in Perth. Australian intravenous drug users (IVDU) have lower rates of infection than overseas cohorts, with an estimated prevalence of 1%. However, IVDU who are also MSM have a 17% rate of HIV infection. The HIV rate among heterosexuals (including sex workers) is 0.1%, unless the source is from subsaharan Africa, where the estimated rate is 7%.

Three-drug regimen

If the risk of transmission equals or exceeds 1/1000, PEP with three drugs is indicated. If the risk of transmission is between 1/1000 and 1/10,000, two-drug PEP is indicated. PEP with two drugs is considered when the risk is between 1/10,000 and 1/15,000. PEP is not recommended in lower risk exposures.

Two-drug regimen

Two-drug regimens use two nucleoside reverse transcriptase inhibitors, such as emtricitabine and tenofovir (Truvada). Three-drug regimens use either two nucleoside reverse transcriptase inhibitors and a protease inhibitor or three nucleoside reverse transcriptase inhibitors. An example of a three-drug regimen is Truvada plus stavudine. Treatment duration is 28 days.

Baseline blood should be taken, including FBC, LFT, and serology for HIV and hepatitis B and C. Screening for other sexually transmitted diseases may be undertaken at the first follow-up appointment, which should be within the next few days. Some patients require emergency contraception, immunisation for hepatitis B and tetanus immunisation. The need for safe behaviour to avoid further exposure and potential transmission should be emphasised. Repeat courses of PEP are safe and should be given as indicated. The use of PEP does not increase the rate of high-risk exposures.

SOLID ORGAN TRANSPLANTS

The immunosuppression required for the survival of transplanted organs leaves the recipient prone to infections, which are a leading cause of mortality. Infections are caused by a broad spectrum of pathogens and there may be minimal signs and symptoms at presentation, followed by rapid deterioration. Noninfectious causes of fever (rejection, malignancy and drugs) are common in the transplant population.

The likely cause of infection varies with the length and intensity of immunosuppression. The likely exposures to infection vary with the time post-transplant, with donor- or hospital-acquired infections common in the early postoperative period, and opportunistic and community-acquired infections emerging later. Patients may have had vaccinations and chemoprophylaxis.

The unwell transplant patient may present with non-specific symptoms or fever alone.

Examination and investigations

Examination should include a thorough search for sites of infection, including the skin, mouth and retina. A specific diagnosis may be elusive. Urine, sputum and blood should be sent for culture, along with blood for serology. Any lesions should be swabbed. A chest X-ray is indicated in most cases.

Management

It is vital that the transplant team be involved in the patient’s management as early as possible. Antibiotic therapy should be broad spectrum; however, there are multiple potential interactions with immunosuppressive drugs. Macrolides are generally contraindicated.

Infections in the early post-transplant period

Within the first month after transplant, most infections are not opportunistic. Subclinical infections suffered by the donor can be transmitted to the patient (this is uncommon and is most often a viral infection). The patient is often colonised with microbes such as MRSA, Pseudomonas and fungi preoperatively, and the induction of immunosuppression can precipitate clinical disease.

Injury to the transplanted organ from ischaemia and reperfusion can give rise to a site for infection, such as in the bile ducts or lung. Wounds, intravascular catheters and drains provide further sites of potential infection. The transplanted kidney is prone to pyelonephritis, the liver to abscesses, wound infections and cholangitis, and the heart/lung to mediastinitis and pneumonia. These postoperative infections are mostly bacterial and may be resistant to antibiotics.

Intermediate period infections

Unusual and opportunistic infections emerge in the second to sixth months following transplantation. CMV can present as a systemic infection or as a pneumonitis. Nucleic acid testing (NAT) for CMV is used to detect CMV replication, allowing the diagnosis of subclinical infection and commencement of preemptive treatment according to standard protocols.

Pneumonia may be caused by a wide range of pathogens. Most cases are bacterial, but Pneumocystis, Legionella, Aspergillus, Nocardia and viruses also occur. Reactivation of latent tuberculosis can occur, often leading to disseminated disease.

HSV is the most frequent cause of CNS disease. Listeria, Cryptococcus, Toxoplasma and JC virus are other causes.

The gastrointestinal tract may be infected with CMV or Clostridium difficile.

It is important to note that graft rejection also presents with fever, as do some drug reactions.

Prophylaxis has led to decreasing incidences of PCP, HSV, CMV, Listeria, Nocardia and toxoplasmosis. The duration of prophylaxis varies between centres.

Management

Trimethoprim-sulfamethoxazole is used to prevent PCP, Toxoplasma, Nocardia, Listeria and common urinary, respiratory and gastrointestinal pathogens.

Oral antiviral agents are used against CMV and HSV.

Late infections

After 6 months post-transplant, the risk of infection declines as immunosuppression is tapered. Patients with rejection requiring ongoing high levels of immunosuppression will remain at risk of opportunistic infections; however, the majority of infections will be community-acquired diseases such as pneumonia. They are at increased risk from intracellular pathogens like Listeria, Nocardia and fungi.

Chronic viral infection may cause insidious graft injury. Recurrent disease may occur in patients who have received transplants for HCV. Renal transplants may become infected by the BK polyoma virus, causing declining graft function.

Long-term immunosuppression increases the risk of malignancy. Skin and anogenital cancers are the most common. Post-transplant lymphoproliferative disease can also develop. This has a spectrum of presentations, from an infectious mononucleosis-like illness to lymphoma.

Graft-specific problems

Acute rejection presents with systemic symptoms, including fever, along with signs of organ insufficiency. Chronic rejection develops over years, with gradual organ failure.

Heart

The transplanted heart is denervated, the loss of vagal stimulation leading to a baseline tachycardia of 100–110. Catecholamines and antihypertensive drugs are effective in these patients, although atropine will be ineffective. Myocardial ischaemia is painless, presenting as chronic cardiac failure (CCF), arrhythmias, hypotension or syncope.

Atherosclerosis is accelerated in organs with chronic rejection.

Routine biopsy detects most cases of rejection at an early, asymptomatic phase. More advanced rejection manifests as CCF, arrhythmias and low QRS voltages on the ECG.

Liver

Rejection presents with fever, right upper quadrant pain and tenderness, jaundice and elevations in transaminases.

Biliary obstruction, wound infections and cholangitis are common postoperative complications.

Kidney

Rejection presents with fever, pelvic swelling, pain and tenderness and decreased urine output. Chronic rejection takes the form of nephrosclerosis, with hypertension and declining renal function.

The kidney may be injured in trauma to the pelvis.

Lung

Rejection presents in a similar way to infection, with fever, shortness of breath, cough and hypoxia, with infiltrates on chest X-ray. Chronic rejection causes bronchiolitis obliterans.

Pancreas

Drainage of exocrine secretions into the bladder predisposes to UTI, haematuria and chronic non-anion gap acidosis (due to bicarbonate loss).

Drug toxicity

Newer immunosuppression regimens using sirolimus, mycophenylate mofetil, T cell and B cell depletion and costimulatory blockade have largely replaced high-dose steroids and azathioprine.

Corticosteroids cause decreased mobilisation and function of neutrophils, monocytes and lymphocytes. There is increased susceptibility to pyogenic bacteria due to depressed leucocyte activity at sites of inflammation. These patients may have diminished clinical signs of peritonitis. Patients are also at higher risk of severe infections with HSV and varicella-zoster virus (VZV). The risk of infection increases with lengthy treatment and doses above 20 mg/day. Corticosteroids may mask fever and chronic use causes adrenal suppression. Consideration should be given to addisonian symptoms in those on chronic corticosteroids and to increasing doses of corticosteroids in acute deterioration to ensure sufficient coverage.

Cyclosporin suppresses cellular and humoral immunity. It has a number of adverse effects including nephrotoxicity, hypertension, hyperuricaemia and seizures, along with multiple interactions with drugs and food.

Azathioprine is associated with neutropenia.

Mycophenylate generally has few side effects. It may cause gastrointestinal disturbance, leucopenia and thrombocytopenia.

Sirolimus causes an idiosyncratic noninfectious pneumonitis which resembles PCP or viral pneumonia.

Tacrolimus may lead to nephrotoxicity, neurotoxicity, hyperglycaemia or hyperkalaemia.

T cell depleting antibodies can cause fever, hypotension and pulmonary oedema, along with reactivation of viruses such as CMV and EBV.

Early discussion with the specialist caring for the patient is recommended in cases of suspected drug reactions.

IMMUNOSUPPRESSION FOR NON-MALIGNANT DISEASE

Newer immunosuppressive agents with lower toxicities have led to an expansion in the use of immunosuppression for non-malignant disease, widening the population at risk of opportunistic infection. Patients with autoimmune disease, multiple sclerosis and inflammatory bowel disease may be sufficiently immunocompromised to present with similar infections to the patient with HIV, malignancy or solid organ transplant.

Rituximab is a monoclonal antibody that depletes B cells and is used in the treatment of autoimmune diseases and haematological malignancies. Patients are susceptible to infections related to poor humoral immunity. Rituximab can cause infusional reactions due to antibodies to monoclonal components. These may be acute or delayed. The delayed reaction is a serum sickness-like illness, with fever, arthritis and rash, which is treated with steroids.

Tumour necrosis factor inhibitors, infliximab and etanercept, are used in rheumatoid arthritis and inflammatory bowel disease. There is increased susceptibility to tuberculosis and bacterial sepsis.

In addition to these agents, corticosteroids, cyclosporin, azathioprine, mycophenolate and cytotoxic drugs such as cyclophosphamide and methotrexate are used in the treatment of autoimmune diseases.

ASPLENIA

Asplenia may result from trauma, splenectomy for idiopathic thrombocytopenia (ITP), lymphoma or haematological malignancy, autosplenectomy in sickle cell disease or functional asplenia in haematological disease, sarcoid, amyloid or autoimmune disease.

Patients without a functioning spleen are predisposed to overwhelming sepsis with pneumococcus and other encapsulated bacteria. The risk is highest in the first few years after splenectomy. Early intervention in any septic presentation is essential.

Pneumococcal vaccine is routinely given; however response may be diminished in patients with severe underlying disease. Vaccinations for Haemophilus influenzae type B, influenza and meningococcus are also given, and patients take penicillin prophylaxis for 2–5 years.

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