Immunocompromised patients - PACT - ESICM

Task 1. Recognising the immunocompromised patient in ICU p.2• Examination – Does the patient haveSigns of chronic disease, e.g. finger clubbing, ascites?Palpable lymphadenopathy? Is there a palpable spleen?Signs of chronic steroid therapy?Are there potential ports of entry for infection? e.g. tunnelledcatheters, ventriculoperitoneal shunt, urinary catheterThe critically ill patient is frequently unconscious or unable togive a good history. Look for visual evidence ofimmunosuppression – e.g. arterio-venous fistula, sternotomyscar for heart transplant, 'Mercedez Benz' scar following livertransplantation, transplanted kidney.Nutritional status – does the patient appear to be malnourished?Consider the possibility of gastrointestinal disease e.g.inflammatory bowel disease or unusual diseases such ashelminth and tropical parasites.For more information on history-taking and examination, see the PACT moduleon Basic clinical examination.In the next five patients admitted to your ICU, identify the factors that mightcompromise their immune function.In the International Code of Botanical Nomenclature 2001, Pneumocystis carniiwas renamed P. jiroveci and it was recategorised from protozoan to a fungus.PCP is now the approved acronym for pneumocystis pneumonia. Pneumocystiscarnii now refers only to a rodent pathogen.A 54-year-old married man was admitted to our hospital in respiratory distressnecessitating immediate intubation upon admission. His wife, who had called theambulance, gave a history of dry cough and increasing fatigue for four weeks prior toadmission. He was taken to the intensive care unit and commenced on benzylpenicillin and ciprofloxacin. Chest radiography revealed a ground glass appearanceand hydrocortisone, trimethoprim-sulfamethoxazole and acyclovir were added,pending a definitive diagnosis. There was no other significant history from his wifebut on examination, cervical lymphadenopathy was found. Lymphopenia was notedon the full blood count. A few hours after admission, a man claiming to be a partnerarrived on the unit and informed us that the patient had had extramarital sexualencounters. The patient underwent bronchoscopy and an HIV test and the diagnosisof PCP secondary to HIV infection was made.Infection in the immunocompromised patientThe investigation of infection in patients with immunesuppression involves the identification of the cause of infection(using imaging, microbiological and serological testing) and theinvestigation of the degree of immunosuppression.The search forinfections in theimmunocompromisedpatient is often difficultand requires tenacity. Apositive diagnosis of theinfectious causeimproves the chance ofrecovery

Task 1. Recognising the immunocompromised patient in ICU p.3ImagingAlthough imaging may identify a source of infection, it does not contribute tothe identification of the pathogen in most cases. Imaging may simply confirmyour suspicions and direct further microbiological sampling. For example, thesite of an abscess may be defined so that surgical drainage can be carried out.A chest radiograph may reveal tuberculosis or bronchiectasis both of whichare associated with ongoing low level immunosuppression.Ultrasound may also be useful for identifying and draining fluid-filledstructures (for instance safe drainage of pleural effusions) and can be carriedout in the ICU.CT scans are a useful diagnostic tool but transfer to the radiology departmentmust be undertaken by appropriately trained personnel. Certainly chest CTscans are more sensitive than plain chest films. High resolution CT scans of thechest can help in the diagnosis of suspected invasive fungal infection (IFI).Imaging of other areas (e.g. nasal sinuses) should be considered when searchingfor potential sources of infection.Magnetic Resonance Imaging (MRI) is usually reserved for patients withneurological disorders. Monitoring and ventilating patients in the MRI scannerrequires special MRI-compatible equipment and should be performed inconsultation with the MRI department. As machines become more powerful andscan times are reduced, use of MRI in the critically ill may increase.Other imaging possibilities. Occasionally, the nuclear medicinedepartment may be helpful in making a diagnosis. White cell scans andgallium scans are sometimes used to identify abscesses within deep tissue(such as a psoas abscess).Transferring the patient to an imaging department presents a challenge to theintensivist. A risk assessment is made prior to transfer to ensure that the patient doesnot come to any harm whilst away from the ICU.Write an assessment of the risks and benefits of transferring the patient fromthe ICU to the scanner. Will the results of the scan change or enable more focusedtherapy? Do these benefits outweigh the risks?You will find additional information about various imaging techniques andpatient transfer in the PACT modules on Clinical imaging and Transportation.

Task 1. Recognising the immunocompromised patient in ICU p.4Hinds CJ, Watson JD. Intensive Care: A Concise Textbook. 3rd edition. SaundersLtd; 2008. ISBN: 978-0-7020259-6-9. p.334-347. Unusual pathogens –diagnosis and treatmentMicrobiological investigation/Septic work-upSending adequate and appropriate samples to the microbiology laboratory is a keyaspect of managing the immunocompromised patient; the most importantintervention, in the patient with severe sepsis, is the timely (within 1 hour)commencement of appropriate antimicrobial therapy together with concurrentresuscitation.Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, et al. Duration ofhypotension before initiation of effective antimicrobial therapy is thecritical determinant of survival in human septic shock. Crit Care Med2006; 34(6): 1589–1596. PMID 16625125Garnacho-Montero J, Garcia-Garmendia JL, Barrero-Almodovar A, Jimenez-Jimenez FJ, Perez-Paredes C, Ortiz-Leyba C. Impact of adequateempirical antibiotic therapy on the outcome of patients admitted to theintensive care unit with sepsis. Crit Care Med 2003; 31(12): 2742–2751.PMID 14668610PACT module on Sepsis and MODSMicrobiological examination of fluid- or tissue specimens involves bothqualitative culture and, in many cases, quantitative analysis. For example, forthe diagnosis of ventilator-acquired pneumonia (VAP), combined qualitativeand quantitative analysis is often performed on bronchoalveolar lavage (BAL)fluid or tracheal aspirates.Hinds CJ, Watson JD. Intensive Care: A Concise Textbook. 3rd edition. SaundersLtd; 2008. ISBN: 978-0-7020259-6-9. p.167–168. DiagnosisMicrobiological analysis can be performed on practically anyspecimen. Most frequently, sputum, urine and cerebrospinalfluid. Urine, CSF and sputum samples can be immediatelyexamined usually using Gram staining. Additionally, samplesmay be cultured under various conditions and using a range ofgrowth media.Microbiologicalexamination maysometimes have a relativelylow sensitivity but is vital toensure appropriate,antimicrobial therapySerum samples can be analysed for evidence of an acute immune response bymeasuring non-specific antibodies, e.g. cold agglutinins in Mycoplasmapneumoniae. However, it is important that convalescent samples are analysedto confirm that the infection is acute.

Task 1. Recognising the immunocompromised patient in ICU p.5urine.Remember Legionella antigen can be rapidly detected inSome bacteria produce toxins that can be detected in body fluids e.g.Clostridium difficile toxin in the stool of patients with diarrhoea.Microbiological cultures may take several days (and in the case of mycobacteria,several weeks) to identify an organism. The need for immediate therapy obligesthe clinician to use empiric antibiotic therapy for patients with signs of infection– unexplained fever, rigors, hypotension, requirement for circulating volumereplacement, tachycardia, tachypnoea or acidosis. This sometimes leads to astepwise escalation in treatment (if there is not an efficacious response to thefirst-line antibiotics) during which further antimicrobials are added to broadenthe spectrum of cover over several hours or days. For example, initial failure ofconventional broad-spectrum antibacterial agents often prompts the addition ofan antifungal agent in high-risk groups.In the hospital setting and in patients already mechanically ventilated,nosocomial infection can be difficult to diagnose with certainty; it is known thatunder those circumstances inadequate empirical therapy is associated with aworse outcome. In this setting broad antimicrobial cover is often employed,guided by local patterns of bacterial flora and resistance patterns. This broadspectrumapproach is then followed by de-escalation as diagnostic informationbecomes available.Kumar A, Ellis P, Arabi Y, Roberts D, Light B, Parrillo JE, et al; CooperativeAntimicrobial Therapy of Septic Shock Database Research Group.Initiation of inappropriate antimicrobial therapy results in a fivefoldreduction of survival in human septic shock. Chest 2009; 136(5): 1237–1248. PMID 19696123This empiricism, while necessary and of undoubted benefit, arguably results inover-treatment of some patients. This is especially true of antifungal therapy,where it is estimated that fewer than 15% of neutropenic patients with a feveractually have invasive fungal infection. Until there is an improvement in therapidity and accuracy of the available diagnostic tests, this approach isunavoidable. However, as soon as culture results are available, anti-infectivetherapies should be reviewed to allow more focused treatment. This isimportant to limit the emergence of resistant organisms, as well as to reduce therisk of antibiotic side-effects.In solid organ transplant recipients, there must also be a high index of suspicionfor viral infection. CMV (cytomegalovirus) serostatus mismatch (where thedonor is sero-positive for CMV but the recipient is serologically negative) shouldbe treated prophylactically following transplantation. CMV reactivation must betreated aggressively if there is any sign of deterioration. Monitoring of CMVlevels by polymerase chain reaction (PCR) is important in patients at risk.

Task 1. Recognising the immunocompromised patient in ICU p.6Pneumocystis (P. jiroveci) pneumoniaThis infection occurs in patients with cell-mediated immunosuppression and is nowseen most commonly in patients with AIDS. It is relatively uncommon in patientsfollowing transplantation and cytotoxic agent treatment because of the protocoliseduse of antibiotic prophylaxis.Serological investigationsDifficulties in reaching a microbiological diagnosis with conventional cultureshave prompted the development of several novel approaches. These include:• Antigen testing for cryptococcus and galactomannan (a cell wallconstituent of Aspergillus species);• Quantitative PCR for DNA (CMV, EBV, herpes simplex);• Reverse transcriptase PCR (rtPCR) for RNA (HIV);• Urinary antigen for Legionella pneumophilia;• PCR for HSV and EBV;• Mycelial phase antigen for Histoplasma capsulatum.Muldrew KL. Molecular diagnostics of infectious diseases. Curr Opin Pediatr2009; 21(1): 102–111. Review. PMID 19242246Investigation of immune deficiency statusRemember, a defect in any of the components of the immune system can resultin immune compromise.Q. Which routine investigations are likely to detect immunecompromise?A. There is no single definitive test of immune function. Qualitative markers ofimmunosuppression include the presence of neutropenia, lymphopenia orhypogammaglobulinaemia. Plain radiography of the chest may reveal atypicalappearances (PCP or tuberculosis) suggesting the possibility of immunosuppression.

Task 1. Recognising the immunocompromised patient in ICU p.7Full blood countThe white cell population consists of five sub-types: neutrophils, lymphocytes,monocytes, eosinophils and basophils. A differential count may assist in thediagnosis of specific disorders.Neutrophils have a key role in defence against bacteria, but are also involved inprotection against fungi and viruses. The absolute number of circulatingsegmented neutrophils (absolute neutrophil count; ANC) is a predictor ofinfection risk. As the ANC falls below 1 x 10 6 /l, susceptibility to infectionincreases dramatically. In certain diseases, such as myelodysplastic syndrome,neutrophil function is abnormal even when the neutrophil count is normal.Q. How does the differential white cell count change during abacterial infection? List examples of diseases where there is anisolated rise in one of the leukocyte subsets.A. Cytokine expression (especially IL-6) during acute bacterial infection causesdemargination of neutrophils and a raised neutrophil count. There is often a ‘left shift’in the morphology of the neutrophils on microscopy because of the increase inimmature forms. In severe sepsis, consumption of neutrophils and bone marrowsuppression may cause a neutropenia and so a neutrophilia or neutropenia shouldnever be ignored.The differential white cell countFactors that can lead to changes in specific white cell subsets include:• Neutrophilia:Acute infections (by far the commonest cause from bacterial, viral andfungal agents)Administration of corticosteroids and Cushing’s diseaseMetabolic; occurs in diabetic ketoacidosis, pre-eclampsia, statusepilepticus, status asthmaticus and uraemia, especially uraemicpericarditisAcute haemorrhageMalignant neoplasms (both solid organ and haematological)Poisoning; with lead, mercury, digitalis, camphor, antipyrine,phenacetin, quinidine, pyrogallol, turpentine, arsphenamine, andvenomsHereditary and idiopathic.• LymphocytesPertussis or whooping cough (Bordetella pertussis) is frequentlyaccompanied by a lymphocytosis (usually 20.0–30.0 x 10 9 /l, but mayexceed 50.0 x 10 9 /l) of small mature appearing lymphocytes.• MonocytesMonocytosis (monocytes > 1.0 x 10 9 /l in adults) occurs most frequentlyin the recovery phase of infection, but is also seen in myeloproliferativedisorders. Monocytosis may result from viral, fungal, rickettsial, andprotozoal infectionsPhagocytosis of erythrocytes, leukocytes, and platelets by monocytesand histiocytes is seen in the ‘haemophagocytic syndrome’ which isassociated with viral or bacterial infections and T-cell malignantlymphoma.

Task 1. Recognising the immunocompromised patient in ICU p.8• Eosinophilia:Allergy, parasitic diseases are the most common but it may also be seenin: liver cirrhosis, Loeffler syndrome, Vasculitis (Churg-Strausssyndrome), tumours (lymphoma), dermatitis herpetiformis, malignanteosinophilic syndrome, hypereosinophilic syndrome.• Basophilia• Chronic myeloid leukaemia• Allergic reactionsA low total lymphocyte count may be seen in patients with AIDS and bonemarrow depression but lymphopaenia may also occur in patients receivingsteroids azathioprine or mycophenolate, those with adrenal suppression, severemalnutrition, prior antilymphocyte therapy and in Guillain-Barré syndrome(see the PACT module on Neuromuscular conditions). While the totallymphocyte count is important, the T helper cell or CD4 cell count (see later)can be used to quantify the risk of infection. The CD4 count is used as aprognostic indicator, along with the viral load, in HIV infection and AIDS.Biochemical markers of infectionC-reactive protein (CRP) levels and the erythrocyte sedimentation rate (ESR)are non-specific markers of inflammation. The ESR is no longer routinelyperformed in most ICUs. Some units use the daily change in CRP as an earlywarning of impending infection although current evidence suggests it has littleutility as a predictive marker, tending to rise only during or after the onset ofsepsis.Silvestre J, Póvoa P, Coelho L, Almeida E, Moreira P, Fernandes A, et al. Is C-reactive protein a good prognostic marker in septic patients? IntensiveCare Med 2009; 35(5): 909–913. Epub 2009 Jan 24. PMID 19169668Hämäläinen S, Kuittinen T, Matinlauri I, Nousiainen T, Koivula I, Jantunen E.Neutropenic fever and severe sepsis in adult acute myeloid leukemia(AML) patients receiving intensive chemotherapy: Causes andconsequences. Leuk Lymphoma 2008; 49(3): 495–501 PMID 18297526Procalcitonin is used as a bedside test of impending sepsis. Whilst not currentlyin routine use, there is evidence to suggest it may have a role in the diagnosis ofsepsis in the critical care setting, including patients with immunocompromisesuch as haemato-oncology patients.Nakamura A, Wada H, Ikejiri M, Hatada T, Sakurai H, Matsushima Y, et al.Efficacy of procalcitonin in the early diagnosis of bacterial infections in acritical care unit. Shock 2008 Dec 22 [Epub ahead of print; doi:10.1097/SHK.0b013e3181994cc3] PMID 19106812Sandri MT, Passerini R, Leon ME, Peccatori FA, Zorzino L, Salvatici M, Riggio D,Cassatella C, Cinieri S, Martinelli G. Procalcitonin as a useful marker ofinfection in hemato-oncological patients with fever. Anticancer Res 2008;28(5B): 3061–3065. PMID 19031957

Task 1. Recognising the immunocompromised patient in ICU p.9TREM (triggering receptor on myeloid cells) -1 is a molecule expressed onphagocytic cells in response to infection with bacteria or fungi and is alsoelevated during a systemic inflammatory response. TREM-1 has been shown tobe a sensitive and specific marker for infection in critically ill patients and mayalso be useful for prognosis. However, the use of TREM-1 is not routine atpresent.Gibot S, Cravoisy A, Levy B, Bene MC, Faure G, Bollaert PE. Soluble triggeringreceptor expressed on myeloid cells and the diagnosis of pneumonia. NEngl J Med 2004; 350(5): 451–458. PMID 14749453Gibot S, Cravoisy A, Kolopp-Sarda MN, Béné MC, Faure G, Bollaert PE, Levy B.Time-course of sTREM (soluble triggering receptor expressed on myeloidcells)-1, procalcitonin, and C-reactive protein plasma concentrationsduring sepsis. Crit Care Med 2005; 33(4): 792–796 PMID 15818107Immunosuppression is not an all or nothing phenomenon;there are degrees of immune compromise. Similarly immune function is notstatic and can change during the course of an illness.Certain specific tests of immune function exist. Most of these tests are researchtools and are not performed frequently in the critically ill.Other tests of immune functionInnate immune response HLA-DR expression on circulating monocytesMannose-binding lectin levelsAntibody-mediated immunityT-lymphocyte quantity andsubsetsAbsolute neutrophil countComplement systemSerum immunoglobulins – total and subgroupsSystemic antibody responses-Polysaccharide antigens-Protein antigensB-lymphocyte quantity and subsetsDelayed hypersensitivity skin testTuberculin skin testingBlood T-cell numbers and T-cell subsets (CD4 orCD8)Blood neutrophil numbersTests for oxidative killing mechanismsLeukocyte expression of CR3 (CD18 integrins)Neutrophil migration assaysBacteria or Candida killing assaysQuantification of individual componentsFunctional assays of the classical and alternativepathway

Task 2. Understanding the immune response in the critically ill patient p.102. UNDERSTANDING THE IMMUNE RESPONSE IN THECRITICALLY ILL PATIENTHost defence mechanisms consist of integumental (physical barrier) function,the innate immune response and the adaptive immune response.These are the threecomponents of the host’s defences that invading micro-organisms must breach tocause infection. About 99% of organisms are repelled by the physical barriers.Approximately 1% of organisms are eliminated by the innate response, leaving a tinyproportion (estimated to be 0.1%) to be killed by the adaptive response.The three layers of the immune responsePhysical barriersInnate immune responseAdaptive immune responseskin, cilia, stomach acidity, lysozyme,normal floramannose-binding lectin, phagocytic cells,natural killer cells, complement system,acute phase proteinshumoral response, cell-mediated responsePhysical barriersThe physical (integumental) barriers consist of the skin andepithelial covering of mucosa. Other physical barriers includestomach acidity and cilia on respiratory epithelium whosenatural beating moves foreign material up the airway so that itcan be expelled by coughing. The normal epithelial bacterialflora, e.g. in the pharynx, offers an additional layer of defenceagainst invasion by pathogenic organisms by competing withpathogenic strains for nutrition and space and producingantimicrobial substances that inhibit their growth.Kartagener syndrome is ahereditary disease affectingone of the physical barriersto infection. The syndromeconsists of a triad of situsinversus (transposition) ofthe viscera, abnormalfrontal sinuses andimmobility of the cilia,causing chronic pulmonaryinfections such asbronchiectasis and sinusitis

Task 2. Understanding the immune response in the critically ill patient p.11THINK: about the ways in which the physical barriers of the immune system arebreached in patients being treated in the intensive care unit.The innate immune responseHinds CJ, Watson JD. Intensive Care: A Concise Textbook. 3rd edition. SaundersLtd; 2008. ISBN: 978-0-7020259-6-9. p.84–87. The innateimmune/inflammatory responseThe innate immune system is capable of reacting to foreignantigen in the absence of previous exposure. It is a rapidlyacting, non-specific first line of defence against invadingorganisms and consists of phagocytic cells induced by a varietyof cytokines, natural killer cells (a subset of lymphocytes) andprotein cascades such as the complement system. Only whenthe innate immune system is overwhelmed, bypassed or evadeddoes the adaptive immune system come into play.The innateresponse lacksmemoryThe host response is initiated through a wide variety of pattern recognitionreceptors (PRR) on the surface and within cells of the innate immune system.These include phagocytic cells such as neutrophils, mast cells, dendritic cellsand natural killer (NK) cells, a subset of T-lymphocytes. The PRR respond tounique cellular constituents not found in vertebrates. These are referred to aspathogen-associated molecular patterns (PAMPs) and include cell surfaceproteins, glycoproteins and other cellular constituents such as DNA.Lipopolysaccharide (LPS) and lipotechoic acid are components of the cell wallsof Gram-negative and Gram-positive bacteria respectively. Other PAMPsinclude beta-glycans derived from the cell walls of fungi and bacterial DNA. Inaddition to PAMPs, PRR are activated by a number of danger-associatedmolecular patterns (DAMPs). DAMPs are molecules produced by host cellulardamage such as high-mobility group box (HMGB), heat shock proteins andS100 proteins that are released following trauma or burn injury. As well astriggering an innate immune response, DAMPs amplify the response to PAMPs.Binding to PRR activates a cascade of intracellular signals resulting in theactivation of cytosolic nuclear factor κB (NF-κB). NF-κB binds to transcriptionsites within the nucleus inducing an array of ‘inflammatory’ genes. Theseinclude genes that encode for acute phase proteins, pro-inflammatory cytokines,coagulation factors and inducible nitric oxide synthase.Defects in NF-κB activation are associated with an increase in the incidence ofimmunosuppression and septic shock.Bustamante J, Boisson-Dupuis S, Jouanguy E, Picard C, Puel A, Abel L, et al.Novel primary immunodeficiencies revealed by the investigation ofpaediatric infectious diseases. Curr Opin Immunol 2008; 20(1): 39–48.Review. PMID 18083507

Task 2. Understanding the immune response in the critically ill patient p.12Cinel I, Opal SM. Molecular biology of inflammation and sepsis: a primer. CritCare Med 2009; 37(1): 291–304. Review. PMID 19050640Acute phase reactionHinds CJ, Watson JD. Intensive Care: A Concise Textbook. 3rd edition. SaundersLtd; 2008. ISBN: 978-0-7020259-6-9. p.87–88. Acute-phase proteinsand complementFollowing Toll-like receptor engagement and the activation of pro-inflammatorycascades, soluble pattern recognition receptors (PRR) are secreted by the liver,vascular endothelium and innate immune cells. These PRRs are part of theacute phase response that includes a heterogeneous group of approximately 20proteins, including a number that can be considered functional ancestors ofantibodies. They are highly conserved in the animal kingdom. Pentraxin is aterm that was first used for the prototypical acute phase protein, CRP (Creactiveprotein). This term was coined because of its ultrastructuralappearance. CRP and serum amyloid P (SAP) are short pentraxins and areproduced in the liver in response to IL-6. PTX3 is a long pentraxin producedwidely throughout the body. The pentraxins are multifunctional and interactwith a number of ligands including complement, extracellular proteins,apoptotic cells, extracellular matrix and pathogens. They are important in theinnate defense against many pathogens including bacteria, viruses and fungi butappear to be relatively specific individually. For example PXT3 shows activityagainst fungal infection and SAP against viral infection in the respiratory tract.Other acute phase proteins have different functions. Mannose-binding lectin(MBL) binds to repeating sugar moieties, fibrinogen enhances coagulation andferritin binds iron reducing its availability for microbes.Mannose-binding lectin is involved in the defense against a wide range ofbacterial, viral, fungal and protozoal pathogens. MBL binds to repeatingcarbohydrate moieties and directly or via complement activation, opsonises abroad range of pathogens for phagocytosis.MBL gene polymorphisms are common in the general population. There aremultiple genetic variations resulting in widely varying serum concentrations. Asa consequence MBL is the most commonly deficient molecule in the innateimmune system. In the UK population, 2–7% are seriously deficient leading toan increased risk of infection. Children deficient in MBL are particularly at riskof meningococcal disease. In adults MBL deficiency has been associated with anincreased risk of severe sepsis, in particular from encapsulated organisms aswell as worse outcomes.Q. In which situations will an inherited reduction in MBL result in aparticularly severe deficit in the immune response?A. In situations where adaptive immune response is already compromised. Forexample, following bone marrow transplantation or when immunosuppressive drugsare used. Interestingly, patients transplanted with a liver from a donor, later found tobe deficient in MBL, have an increased risk of infection and organ failure posttransplantation.

Task 2. Understanding the immune response in the critically ill patient p.13Q. What genetic factors contribute to the severity of disease statesseen in the ICU?A. It has been shown that patients with decreased expression of mannose-bindinglectin have an increase in severity of meningococcal septicaemia.THINK: What is the role of genetic polymorphism in the severity of disease statesseen within the ICU?Other plasma proteins decrease – the so-called ‘negative acute phase proteins’.Classically albumin falls acutely, as do transferrin and transcortin. It has beensuggested that this reduction in plasma binding sites increases the freeconcentration of hormones during times of acute stress.The functions of the acute phase proteins are complex and deficiencies areassociated with complex disease states including autoimmune disorders andcardiovascular disease. Variation in the CRP gene promoter is associated withsystemic lupus erythematousus (SLE), a condition associated with a number ofprimary immunodeficiencies.Castelli GP, Pognani C, Meisner M, Stuani A, Bellomi D, Sgarbi L. Procalcitoninand C-reactive protein during systemic inflammatory response syndrome,sepsis and organ dysfunction. Crit Care 2004; 8(4): R234-242. Epub 2004Jun 10. PMID 15312223Kuipers S, Aerts PC, Cluysenaer OJ, Bartelink AK, Ezekowitz RA, Bax WA, et al. Acase of familial meningococcal disease due to deficiency in mannosebindinglectin (MBL). Adv Exp Med Biol 2003; 531: 351–355. Review.PMID 12916805Ip WK, Takahashi K, Ezekowitz RA, Stuart LM. Mannose-binding lectin andinnate immunity. Immunol Rev 2009; 230(1): 9–21. Review. PMID19594626Cervera C, Balderramo D, Suárez B, Prieto J, Fuster F, Linares L, et al. Donormannose-binding lectin gene polymorphisms influence the outcome ofliver transplantation. Liver Transpl 2009; 15(10): 1217–1224 Erratum in:Liver Transpl 2009; 15(12): 1905. PMID 19790141The adaptive immune systemThe adaptive response depends on the clonal selection oflymphocytes predestined to recognise the foreign antigen.Antigen presentationThe adaptive response hasmemory and subsequentresponses are quantitativelyand qualitatively superiorDendritic cells play the major antigen-presenting role, although other cells suchas monocytes and macrophages are also able to fulfill this function. Initiation ofthe adaptive response involves phagocytosis and processing of foreign antigenby antigen-presenting cells. Presentation takes place within lymphoid tissues(lymph nodes and spleen). Fragments of bacteria are opsonised and presentedwithin the clefts of cell surface proteins known as the class II majorhistocompatibility complex (MHC). These proteins, HLA-DR, -DP, -DQ, interact

Task 2. Understanding the immune response in the critically ill patient p.14with the cell surface receptors of T lymphocytes and are directly responsible forthe initiation of the adaptive immune response. The activated T cells, CD4 or'helper' lymphocytes, secrete cytokines to recruit and complete the immuneresponse. Other families of activated lymphocytes become memory cells readyfor subsequent infection.B lymphocytes express antibody on their surface and areactivated by soluble foreign antigen. Whole antigen isinternalised, processed and expressed on the surface inassociation with class II MHC proteins. The clonal selection ofplasma cells producing high-affinity antibodies is dependent onthe assistance of activated CD4 T lymphocytes (hence 'helper'cells) in association with the B cell MHC-antigen complex andthe T-cell receptor within lymph node follicles.The expression ofHLA-DR isfrequentlydepressed in thecritically illAcquired defects in antigen presentation are seen in critically ill patients.Reduction in HLA-DR expression on circulating monocytes is associated withadverse outcomes in patients following major trauma and critical illness.Kox WJ, Volk T, Kox SN, Volk HD. Immunomodulatory therapies in sepsis.Intensive Care Med 2000; 26 Suppl 1: S124-S128. Review. PMID10786969.Full text (pdf)T helper cellsCD4 or T helper cells can be split into subsets that initiate the differing arms ofthe adaptive response. Th1 cells are 'pro-inflammatory' and produce gammainterferon and interleukin 2. They are important in stimulating cell-mediatedimmunity and are responsible for inflammation at the site of infection. Th2 cellsare anti-inflammatory and produce interleukin 4, interleukin 5 and interleukin13. They are essential for B lymphocyte clonal expansion, tissue healing and theproduction of highly specific antibody. The differentiation of precursor Th0 cellsinto the two subtypes, is dependent upon local cytokine concentration, antigenload and mode of antigen presentation.The ratio of Th1 to Th2 cells is important as they produce different patterns ofcytokine response. Th1 and Th2 responses appear to be mutually exclusive aseach response initiates reciprocal inhibition of the other.

Task 2. Understanding the immune response in the critically ill patient p.15The development of the adaptive immune responseThere is renewed interest in the use of stress dose glucocorticoids for the treatment ofseptic shock. Augmentation of the compensatory anti-inflammatory response syndrome(CARS) may be one mechanism through which they exert beneficial effectsCompensatory anti-inflammatory responsesyndromeHinds CJ, Watson JD. Intensive Care: A Concise Textbook. 3rd edition. SaundersLtd; 2008. ISBN: 978-0-7020259-6-9. p.101–103. Compensatory antiinflammatoryresponse syndrome

Task 2. Understanding the immune response in the critically ill patient p.16The molecular biology of the systemic inflammatory response is complex. Sinceit was first recognised that inflammation is important in the pathogenesis ofsepsis it has become apparent that the induction of the pro-inflammatorycytokine cascade is only half of the story. Just as coagulation is a balancebetween the pro-coagulant and anticoagulant cascades, so the immune systemhas developed an anti-inflammatory system to counterbalance the proinflammatoryprocess.This process can be seen in animal models of caecal ligation and puncture. Asearly as 24 hours following the initial insult, septic animals have a markedlyimpaired ability to clear a secondary intrapulmonary challenge of bacteriacompared to non-septic control animals. This effect persists for many weeksfollowing the initial insult and is apparent in patients within the intensive careunit who are ‘anergic’ i.e. do not respond to an immune stimulus, and at risk ofdeveloping infections with organisms of low virulence that you would normallyexpect only in seriously immunocompromised patients, e.g following cancerchemotherapy or in those with haematological malignancy.The initial systemic hyperinflammation is caused by production ofinflammatory cytokines, especially tumour necrosis factor-α (TNF-alpha),interleukin 1, interleukin 6 and interferon gamma.The causes of immunosuppression in critical illness include:• Change in lymphocyte sub-populations so that Th2 cells predominate• Anergy – the lack of reaction to an immune stimulus• Loss of adaptive immune cells via apoptosis• Direct immunosuppressive effect of apoptotic cells• Loss of lymphoid tissue• Reduction in expression of MHC II (HLA-DR) on macrophages• Effects of drugs (e.g. sedatives, inotropes)• Production of anti-inflammatory cytokines (e.g. transforming growthfactor β1, interleukin 10, interleukin 13)• Other causes include neuroendocrine, metabolic and hormonalchangesPossible course of pro- and anti-inflammatory interactionsThis graph depicts changes in immune function, either pro- or anti-inflammatory, over timefollowing an acute event. The dashed line at the centre represents unity, and the coloured linesrepresent the response in three hypothetical patientsAdapted from Hotchkiss RS, Karl IE. The Pathophysiology and Treatment of Sepsis. N Engl JMed 2003; 348(2):138-150. PMID 12519925

Task 2. Understanding the immune response in the critically ill patient p.17THINK: Does every patient start from the same baseline?Anti-inflammatory cytokines and soluble receptors are produced in largeamounts during sepsis. They downregulate production of pro-inflammatorycytokines and have been shown to protect animals from sepsis and endotoxininducedshock. Interleukin 10, interferon α, transforming growth factor β,interleukins 4, 6, and 13 are known to have anti-inflammatory effects.Interleukin 6, for example, induces a broad array of acute phase proteins thathelp to limit inflammation, such as α-1-acid-glycoprotein or C-reactive protein.However, evidence suggests that the excessive production of anti-inflammatorymediators is associated with a worse outcome. In fact, increased IL-10 levelsand IL-10 to TNFα ratio are associated with a poor outcome following sepsis.IL-10 acts as a potent inhibitor of pro-inflammatory cytokine production andalso inhibits the expression of MHC class II and NF-κB. Monocyte deactivationoccurs in patients with systemic inflammatory response syndrome(SIRS)/sepsis from many causes. The cells lose the ability to mount aninflammatory response and instead switch to the production of antiinflammatoryIL-10 and IL-1ra. Another major characteristic of monocytes inpatients with sepsis and severe SIRS is a decrease in the expression of HLA-DR(MHC class II). The reduction in HLA-DR inhibits the monocytes’ ability tointeract with lymphocytes and induce an adaptive immune response. Clinicalrecovery is accompanied by normalisation of HLA-DR expression and cytokineproducingcapacity, which reflects a functional reconstitution of the innateimmune response.The glucocorticoid receptor (GR) and nuclear factor κB (NF-κB) aretranscription factors with opposite effects on immune and inflammatoryresponses. These receptors can translocate into the nucleus where they regulategene expression and thus regulate the immune response. Glucocorticoidhormones, via GR, suppress inflammation by inhibiting the transcription ofseveral cytokines, chemokines and cytokine receptors. Activated NF-κB, on theother hand, enhances the expression of many of the cytokines and chemokinesthat are repressed by GR. In fact the activated GR can be considered anantagonist to NF-κB.

Task 2. Understanding the immune response in the critically ill patient p.18The systemic inflammatory response and the compensatory anti-inflammatoryresponseThe full article plus figure is available athttp://edrv.endojournals.org/cgi/content/full/20/4/435

Task 3. Managing the immunocompromised patient p.193. MANAGING THE IMMUNOCOMPROMISED PATIENTClinical management is considered under the headings of ‘neutropenia’ and ofthe possible site-specific infections.Hinds CJ, Watson JD. Intensive Care: A Concise Textbook. 3rd edition. SaundersLtd; 2008. ISBN: 978-0-7020259-6-9. p.351–354. Intensive care forpatients with malignant diseaseThe neutropenic patientNeutropenia is most often induced by cancer chemotherapy orconditioning prior to stem cell transplantation (SCT). Thefrequency and severity of infection is inversely proportional tothe neutrophil count. The risks are particularly high when thecount drops to below 0.1 x 10 6 /l. You can find furtherinformation about the side effects of cytotoxic drugs on thefollowing websitehttp://www.bccancer.bc.ca/HPI/DrugDatabase/default.htmAll cytotoxic drugs, with theexception of vincristine andbleomycin, may cause bonemarrow suppression. Thiscommonly occurs 7 to 10days followingadministration, but isdelayed with certain drugssuch as carmustine,lomustine and melphalanBone marrow suppression is a consequence of most cytotoxic drugs. It may beregarded as a side effect when treating solid tumours or a treatment effect whenthey are used in haematological malignancy. Both the degree ofmyelosuppression and the length of time taken to recover are proportional tothe intensity of the treatment. Those subjected to myeloablative regimens usedfor conditioning the bone marrow for transplantation represent a particularlychallenging group when admitted to the intensive care unit.The rate of decline and the duration of neutropenia are also importantprognostic factors and correlate with severity of infection and outcome. Some ofthe other factors dictating outcome relate to the severity and nature of theunderlying illness, nutritional status and the function of physical barriers toinfection (integumental function).Fever in the neutropenic patientInfectious complications remain the most important cause ofdeath in patients with haematological malignancies. Aggressiveinvestigation and early institution of broad-spectrum antibiotictherapy are mandatory.See PACT module on PyrexiaFever in this context isdefined as centraltemperature >38 °C ontwo occasionsseparated by more thantwo hours or a singleepisode >38.3 °CQ. A patient with neutropenia develops fever. How would youapproach investigation and treatment?A. Any neutropenic patient who develops fever should be investigated and, if sepsis issuspected, immediately commenced on targeted or broad-spectrum antibiotics.Investigations should include blood cultures and chest X-ray. Other investigations will

Task 3. Managing the immunocompromised patient p.20depend on the site specificity of the signs and symptoms. The removal of long-termindwelling intravenous catheters should be considered and if being conserved, it asappropriate to try to exclude the catheter as the source of sepsis by quantitative ortimed blood cultures taken simultaneously from the CVC and peripheral blood. If thecatheter is being conserved, a possibility is to instill appropriate antibiotics into thecatheter lumen as ‘antibiotic lock therapy’. Approximately 80% of patients withneutropenia and fever are considered to be infected but the organism is identified inless than 50%. Localising signs and symptoms are often absent but if present help toguide initial antibiotic choice and duration of therapy.Initial therapyThe first epidemiological studies of infection patterns inneutropenic patients were conducted in the 1970s. Since thenthere have been considerable changes in the nature of causativepathogens. The predominant infecting organisms have changedduring this time from more susceptible predominantly Gramnegativebacteria to multiresistant Gram-positive bacteria (S.aureus, enterococci), more resistant Gram-negative bacteria (P.aeruginosa, Acinetobacter, Enterobacter spp.) and fungi. Manyfactors have influenced this change including increased patientsurvival, use of broad-spectrum antibiotics selecting forresistant organisms and the increased use of indwellingintravenous catheters and devices.The differencebetween infection andcolonisation is thatcolonisation does notcause clinical evidenceof sepsis. For someclinical cultures e.g.BALs, quantitativeculture criteria existwhich may suggesteither colonisation orinfectionFundamental to the successful management of patients with febrile neutropeniais the prescription of effective antibiotics. As mentioned above, current availablediagnostic tests are not sufficiently rapid or precise to exclude infection andbroad-spectrum antibiotic cover, prescribed at the earliest opportunity, reducesthe risks associated with delayed treatment.The choice of antibiotic regime will depend on local practice and regionalinfectious epidemiology. The following factors should be considered:• The apparent site of infection (the working diagnosis)• The most likely infecting organism(s) – related to the above• Local resistance patterns• Pre-existing organ dysfunction• Patient allergies• Previous antibiotic exposure.There are several approaches possible to the prescription of antibiotics at theonset of fever/sepsis in a neutropenic patient. Traditionally a β-lactamcombined with an aminoglycoside has been the initial empiric therapy of choice.Concerns regarding aminoglycoside toxicity and the development of extendedspectrum cephalosporins, carbapenems and ureidopenicillins, have led totreatment with a single agent in some institutions. Monotherapy with acarbapenem (imipenem-cilastatin, meropenem), an extended spectrum antipseudomonalcephalosporin (such as ceftazidime or cefepime) orpiperacillin/tazobactam can be used. Recent evidence suggests that the use ofan aminoglycoside in addition to these monotherapeutic agents does not confera significant advantage.

Task 3. Managing the immunocompromised patient p.21The use of additional antibiotic therapy to treat resistant Gram-positive bacteriasuch as vancomycin, teicoplanin or linezolid is controversial. In many countriesthe incidence of methicillin-resistant Staphylococcus aureus (MRSA) andglycopeptide-resistant enterococci is high. The temptation to start empiricglycopeptides at the onset of fever can be difficult to resist but the risk factorsbelow give guidance.Finding evidence of benefit to support this approach is, however, difficult. Anumber of factors suggest that a glycopeptide should be used:• Known colonisation with MRSA• Blood cultures positive for Gram-positive organisms• Catheter- or device-related infection• Skin, soft tissue and bone infection• Recent hospitalisation or period of residency in a nursing home• Recent prophylaxis with ciprofloxacin ortrimethoprim/sulfamethoxazole – known to increase the risk ofGram-positive infection• Substantial mucosal damage with an increased risk of streptococcalinfection• Evidence of systemic inflammatory response syndrome (SIRS) ororgan dysfunction. This is because both of these suggest seriousinfection and an increased risk of progression to organ failure anddeath.In these circumstances, initial empiric treatment should be broader butnarrowed later once culture information is available.Fever/sepsis persisting for 48 hours despite broad-spectrum antibacterialagents warrants the introduction of an antifungal agent. Liposomalpreparations of amphotericin B have been the mainstay of treatment, but recentguidelines have advocated the use of newer agents such as the echinocandins(e.g. caspofungin) and extended spectrum azoles (voriconazole) because of theirlower toxicity. The use of prophylactic antifungal agents may influence thedecision to start therapeutic antifungals.The type and severity of infection predicts outcome in neutropenic patients.Complex infections involving solid organs i.e. lung, liver, spleen, bones, kidneys,meninges, large areas of skin, have a much worse outcome than isolatedbacteraemia, bacteruria or infection of the upper respiratory tract.See the PACT module on Severe infection for more information on fungalinfection.Thursky KA, Playford EG, Seymour JF, Sorrell TC, Ellis DH, Guy SD, et al.Recommendations for the treatment of established fungal infections.Intern Med J 2008; 38(6b): 496–520. PMID 18588522Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr KA, etal; Infectious Diseases Society of America. Treatment of aspergillosis:clinical practice guidelines of the Infectious Diseases Society of America.Clin Infect Dis 2008; 46(3): 327–360. PMID 18177225

Task 3. Managing the immunocompromised patient p.22Managing respiratory failure in the neutropenic patientNeutropenic patients are most commonly referred to the ICU with respiratoryfailure. Respiratory failure is common following cancer chemotherapy andparticularly stem cell transplantation. Infectious causes are found inapproximately half of all cases.Two common forms of radiographic presentation are seen: focal changessuggestive of pneumonia and diffuse interstitial or alveolar infiltrates.Diffuse infiltrates on the chest X-ray associated with hypoxaemia are commonlyseen early in the post engraftment stage. These are often due to acute lunginjury and frequently resolve with supportive therapy and diuresis. More severehypoxaemia may require Continuous Positive Airway Pressure (CPAP) and/orBiphasic Positive Airway Pressure (BIPAP). Non-invasive ventilatory support isused in an attempt to reduce the risks of nosocomial infection associated withintubation of the trachea.It has become standard practice to manage patients with noninvasiveventilatory support during the last ten years. Howeverrecent data has challenged this view (Depuydt et al) althoughformal randomised trials are required. Guidelines are availablefor the investigation and management of pulmonary infiltratesin patients with febrile neutropenia.Although invasivemechanical ventilationhas been associated withan increased risk ofnosocomial infection,intubation should not bedelayed should thepatient fail to respond tonon-invasive respiratorysupportSee also the PACT modules on Respiratory failure and Mechanical ventilationNava S, Hill N. Non-invasive ventilation in acute respiratory failure Lancet 2009;374(9685): 250-259. Review. PMID 19616722Depuydt PO, Benoit DD, Roosens CD, Offner FC, Noens LA, Decruyenaere JM.The impact of the initial ventilatory strategy on survival in hematologicalpatients with acute hypoxemic respiratory failure. J Crit Care 2010; 25(1):30–36. PMID 19682849Maschmeyer G, Beinert T, Buchheidt D, Cornely OA, Einsele H, Heinz W, et al.Diagnosis and antimicrobial therapy of lung infiltrates in febrileneutropenic patients: Guidelines of the infectious diseases working partyof the German Society of Haematology and Oncology. Eur J Cancer 2009;45(14): 2462–2472 Epub 2009 May 23. Review. PMID 19467584Q: What further investigations for the aetiology should beconsidered in a ventilated neutropenic patient with deterioratinglung function?A: Fungal pneumonia, PCP, viral pneumonia and non-infectious causes should beconsidered. Investigations may include bronchoalveolar lavage (BAL), high-resolutionchest CT and serology for atypical pneumonia. Thorascopic or open lung biopsy isoccasionally indicated but carries significant risks and yields are low. Other non-

Task 3. Managing the immunocompromised patient p.23infectious causes include pulmonary haemorrhage, ARDS and bronchiolitis obliteransorganising pneumonia (BOOP).Fungal infections can be extremely difficult to treat successfully. Highresolution CT scanning and BAL will guide therapy and provides an indicationof the response to therapy. A diagnostic test based on the detection ofgalactomannan in blood has a sensitivity of approximately 70% and a goodspecificity. However, the test often becomes positive after other confirmatorytests and there remains significant debate over the utility of this investigation inclinical practice. Fungal infection usually presents with focal radiographicfeatures and Aspergillus is a common aetiology in the immunocompromisedpatient. It is important that institutions managing patients who may developinvasive fungal infections have protocols for the investigation and managementof this complication.Aspergillus infectionHigh resolution CT scanning is now the investigation of choice for imaging of respiratoryaspergillosis. Common findings include nodules with surrounding ground glass shadowing(see figure) and the ‘halo’ sign. Whilst not diagnostic, such findings are highly suggestive ofinvasive fungal infection. Wherever possible, confirmation of diagnosis (e.g. bybronchoalveolar lavage) should be attempted.The aetiology of pneumonia presenting late following SCT (>100 days) is similarto that presenting early. Diffuse infiltrates may be due to bacterial, fungal orviral infection but chest X-ray infiltrates due to non-infectious causes are morecommon. These include graft versus host disease and bronchiolitis obliterans.These diagnoses are often made by exclusion of infectious causes, butcharacteristic changes such as air-trapping which can be seen on high resolutionCT of the chest, requires scanning during inspiratory and expiratory phases.Managing site specific infection in the neutropenic patientMouth and oesophagus are common sites of inflammation and secondaryinfection. Mucositis induced by cancer chemotherapy can be severe andpresents a portal of entry for infection. Fungal and viral infection must beconsidered in febrile patients with necrotising ulceration of the mouth.Vesicular lesions imply the presence of herpes simplex.

Task 3. Managing the immunocompromised patient p.24Sinus tenderness, periorbital oedema or purulent naso-pharyngeal secretionssuggest sinus infection. CT scanning and referral to the Ear, Nose and Throat(ENT) specialists to facilitate sample collection may be indicated. Fungi(Aspergillus, Mucor) should always be considered in a neutropenic patientpresenting with sinus symptoms or sinus fluid collections. In the intubatedpatient, consider replacing a nasogastric tube with an orogastric tube. Nasotrachealintubation is avoided in the ICU.Intra-abdominal infections are difficult to diagnose in sedated, critically illpatients. However the diagnosis should be considered if the patient fails toimprove, in the presence of an unexplained pyrexia and new organdysfunction/biochemical derangement. A combination of clinical examination,interpretation of liver function test abnormalities, imaging and communicationwith the surgical team will assist patient management. High serumtransaminases may be associated with viral hepatitis or hepatic veno-occlusivedisease in patients following SCT. After targeted cultures, polymicrobial‘abdominal’ antibiotic therapy including cover for anaerobes should beconsidered. Infection with Clostridium difficile should be excluded in allpatients with diarrhoea and stool should be sent for toxin analysis.Sigmoidoscopy and biopsy can help with the diagnosis of both C. difficile andCMV enterocolitis but should only be undertaken with caution as thealternative, less invasive, CT scanning of the abdomen may be diagnostic.Typhilitis may cause localised abdominal pain and progress to perforation.Treatment includes broad-spectrum antimicrobials against enteric organismsand general supportive measures.Outcome of intensive care in patients with neutropeniaHinds CJ, Watson JD. Intensive Care: A Concise Textbook. 3rd edition. SaundersLtd; 2008. ISBN: 978-0-7020259-6-9. p.354–356. PrognosisPatients requiring intensive care following SCT have a worse prognosis if theyreceive donor marrow (allogeneic transplantation) than if they are given theirown marrow (autologous transplantation). The need for organ support, inparticular intubation and mechanical ventilation, is a poor prognostic sign. Themortality in this group has been reported between 70% and 100% but seems tobe improving. There is some recent evidence that the use of non-invasiveventilation may be associated with a reduced mortality in patients requiringventilatory support.Huynh TN, Weigt SS, Belperio JA, Territo M, Keane MP. Outcome and prognosticindicators of patients with hematopoietic stem cell transplants admittedto the intensive care unit J Transplant. 2009; 2009: 917294 Epub 2009Sep 15 PMID 20130763http://www.cancer.org/docroot/ETO/content/ETO_1_2X_Infections_in_People_with_Cancer.asp

HIV Disease and the lymphopenic patientTask 3. Managing the immunocompromised patient p.25Hinds CJ, Watson JD. Intensive Care: A Concise Textbook. 3rd edition. SaundersLtd; 2008. ISBN: 978-0-7020259-6-9. p. 347–351. Acquiredimmunodeficiency syndromeHIV is now a treatable condition. The majority of those living with the virusremain fit and well on treatment for many years. While the availability of HighlyActive Antiretroviral Therapy (HAART) has transformed the outcome forindividuals with HIV infection, a significant number of patients continue to beadmitted to ICU with complications, a proportion of whom will die. Infectionwith HIV is associated with increased susceptibility to infection with more than100 different viruses, bacteria, protozoa and fungi.As long-term survival for those with HIV infection has improved, so theindications for ICU admission have changed. In one study, sepsis resulting frombacterial infection was now a more frequent cause of admission thanPneumocystis carinii (now called jiroveci) pneumonia. Another studysuggested that ICU mortality of patients with HIV is comparable to othermedical patients. In that study, more than a quarter of patients had newlydiagnosed HIV infection. Patients receiving HAART did not have a betteroutcome.Rosenberg AL, Seneff MG, Atiyeh L, Wagner R, Bojanowski L, Zimmerman JE.The importance of bacterial sepsis in intensive care unit patients withacquired immunodeficiency syndrome: implications for future care in theage of increasing antiretroviral resistance. Crit Care Med 2001; 29(3):548–556. PMID 11373418Dickson SJ, Batson S, Copas AJ, Edwards SG, Singer M, Miller RF. Survival ofHIV-infected patients in the intensive care unit in the era of highly activeantiretroviral therapy. Thorax 2007; 62(11): 964-968. PMID 17517829Late diagnosis has been associated with increased mortality and morbidity andan impaired response to HAART. Only 50 to 70% of HIV positive patientsachieve significant virological suppression with HAART and there is a decline inthe response to therapy over time. HAART is associated with a number ofserious and troublesome side effects which may prevent the patient from takingtheir full dose, thereby reducing effectiveness. While antiretroviral treatmentundoubtedly improves outcomes in the long-term HIV infected patient, thedecision to start HAART in the ICU following a new diagnosis of HIV remainscontroversial. In contrast to the evidence cited above, other studies havesuggested that continuing or initiating HAART in critically ill patients improvesoutcome.

Task 3. Managing the immunocompromised patient p.26Croda J, Croda MG, Neves A, De Sousa dos Santos S. Benefit of antiretroviraltherapy on survival of human immunodeficiency virus-infected patientsadmitted to an intensive care unit. Crit Care Med 2009; 37(5): 1605-1611.PMID 19325488Q. When faced with an acute admission of an AIDS patient inrespiratory failure, what therapies would you begin?A. A third generation cephalosporin such as cefotaxime, along with cover for atypicalpneumonias (e.g. clarithromycin) would be appropriate. If PCP is a possibility,treatment with trimethoprim-sulfamethoxazole is indicated, together withhydrocortisone in those who are hypoxaemic. Acyclovir should be given when viralpneumonia is suspected.Antiretroviral Therapy is associated with many adverse effects and dosing in theICU can be particularly difficult, particularly in the presence of renal or hepaticimpairment. HAART is frequently delivered as combination therapy. For someagents parenteral preparations are not available. All Nucleoside ReverseTranscriptase Inhibitors and protease inhibitors require caution in patients withhepatic impairment.See the AIDSinfo website http://www.aidsinfo.nih.gov/ for more information.Q. What are the side effects of HAART?A. An incomplete list is:• Insulin resistance or diabetes mellitus• Hyperlipidemia• Ischaemic heart disease• Gastrointestinal side effects• CNS disorders• Peripheral polyneuropathy• Renal impairment• Hepatotoxicity• Haematological abnormalities• Allergies• Lactic acidosis• Pancreatitis• Avascular necrosis• Osteopenia/osteoporosis/osteonecrosis• Increased bleeding episodes in haemophiliacsCasalino E, Wolff M, Ravaud P, Choquet C, Bruneel F, Regnier B. Impact ofHAART advent on admission patterns and survival in HIV-infectedpatients admitted to an intensive care unit. AIDS 2004; 18(10): 1429–1433. PMID 15199319

Task 3. Managing the immunocompromised patient p.27Narasimhan M, Posner AJ, DePalo VA, Mayo PH, Rosen MJ. Intensive care inpatients with HIV infection in the era of highly active antiretroviraltherapy. Chest 2004; 125(5): 1800–1804. PMID 15136393CD4 count is a marker of likely disease progression. CD4 counts can be used toestimate the risks for particular conditions, as shown in the table below.CD4 count – a marker of likely disease progressionCD4 count (x 10 6 /l)Infection250-500 TuberculosisBacterial pneumoniaOral candidiasis150-200 Kaposi’s sarcoma – caused byhuman herpes virus 8Lymphoma75-125 PCPCerebral toxoplasmosisCryptococcal meningitisM. avium intracellulare infection

Task 3. Managing the immunocompromised patient p.28Infection following solid organ transplantationFor more information on organ transplantation, see the PACT module on Organdonation and transplantation.Time line for infection in solid organ transplantationThe spectrum of infection seen following solid organ transplantation (SOT)reflects the organ system involved, the pathogens contaminating the patient’slocal environment (whether in hospital, on the ward or at home) or reactivationof quiescent colonisation. For example a respiratory viral infection developingafter SOT may be due to reactivation following pre-operative exposure ratherthan hospital acquired de novo; certain systemic mycoses may also representreactivation following previous community exposure.The type of infection will be influenced by time from surgery, the environment,and the degree of immunosuppression.Infection during the first two months following transplantationMost infections occurring during the first month post transplantation arerelated to surgical and technical complications. These include bacterial andCandida wound infections, pneumonias, urinary tract infections, catheterrelatedsepsis and infected drainage tubes.Mucocutaneous and rarely visceral herpes simplex virus (HSV) infection isusually due to reactivation of the host's latent strain after iatrogenicimmunosuppression. Prophylactic acyclovir has reduced the incidence of HSVinfection.Rarely infection may arise from the donor organ. Bacterial or fungal infectionsusually cause local complications such as suture line rupture or local abscess.Following cardiac transplantation systemic toxoplasmosis and active herpessimplex virus have been transmitted by the donor organ.Untreated infection in the recipient prior to operation will become moresevere following transplantation and immune suppression.Treat infection before transplantation. Ideally, recipients shouldbe free from infection at the time of transplantation. Antibiotics should beadministered if there is evidence of infection in the donor or the recipient.Transplantation is often postponed if there is clear sepsis in the recipient.THINK: Are there any particular micro-organisms prevalent in your ICU that pose aparticular risk to immunocompromised patients? Are these especially common inyour country?

Task 3. Managing the immunocompromised patient p.29Perioperative and ICU-related infectionIt is standard practice fororgan recipients to receiveeither anti-CMV prophylaxis(ganciclovir, valganciclovir)Infection during the second to sixth monthsor pre-emptive therapy basedon regular scheduled CMVsurveillance (such as CMVThe subsequent months are associated with opportunisticantigenaemia or PCR DNAinfections as a consequence of immunosuppressive therapy.detection methods) duringThese are due to pathogens such as CMV, Pneumocystis the high risk period of 1–6jiroveci, Aspergillus spp. and other mycelial fungi such as monthsNocardia as well as M. tuberculosis. Other viral infectionsoccurring between one and sixth months are Epstein-Barr virus(EBV), hepatitis B & C, human herpes virus 6 and 7. These tendto reactivate and exert clinically significant effects.Although CMV can occur at the end of the first week following transplantation,it is more common after approximately one month (and for up to six months inlung recipients). CMV may present as invasive disease (such as hepatitis orpneumonitis) or systemic infection (characterised by viral shedding).10 to 50% of recipients develop CMV disease depending on the serologicalstatus of the donor and recipient. It is important to note, however, that CMVinfection:• Occurs most commonly following transplantation with a seropositivedonor• Causes a variety of clinical presentations• Can induce graft dysfunction• Exacerbates immunosuppression.Q. How can you recognise CMV infection in the ICU?A. In immunocompromised patients CMV induces a variety of syndromes including:fever and leukopenia, hepatitis, pneumonitis, oesophagitis, gastritis, colitis, retinitis.Symptoms often begin with prolonged fever, malaise, anorexia, fatigue, night sweats,myalgia and arthralgia. Investigations may reveal liver function abnormalities,leukopenia, thrombocytopenia and atypical lymphocytosis during these episodes. Theremay be a dry cough, dyspnoea and hypoxia in those with pneumonia. Chest X-rayfindings may include bilateral interstitial or reticulonodular infiltrates beginning in the

Task 3. Managing the immunocompromised patient p.30periphery of the lower lobes and spreading centrally and superiorly. Localisedsegmental, nodular or alveolar patterns are less commonly seen. GI involvement maybe localised or extensive. Fatal CMV infections are often associated with persistentviraemia and multiple organ involvement. Progressive pulmonary infiltrates,pancytopenia, hyperamylasaemia and hypotension are characteristic. Superinfectionwith bacterial, protozoa and fungi are common.Other early manifestations (1-6 months post transplant) of CMV infection includeencephalitis, transverse myelitis and cutaneous vasculitis.Infection from six months and beyondFrom six months onward the majority of transplant recipients are free frominfection. They remain stable with relatively mild immunosuppression.However, those with multiple episodes of acute rejection or those with latechronic rejection who require higher levels of immunosuppression continue tobe at high risk of infection. Long-term immunosuppression is also associatedwith an increased risk of cancers, such as lymphomas related to chronic viralinfection with EBV.Those receiving a liver transplant for complications of hepatitis B infection areat risk of re-infecting their graft. This risk is exacerbated by theirimmunosuppression. In hepatitis B infection a combination of pooled humanhepatitis B immunoglobulin and the antiviral agent lamivudine, is used toprevent re-infection. Lifelong monitoring and therapy are required.Timing of other infections following organ transplantationPatients with organ transplants are also at risk of developingparasitic infections. These can be due to reactivation of dormantinfection, by de novo infection following transplantation, or becaused by infection of the transplanted organ.Viral infections, posttransplant, aredominated by CMVA wide variety of parasitic infections have been described in patients following asolid organ transplant. In the immunocompetent patient, morbidity andassociated mortality are relatively low when one considers the infection burdenin some parts of the world (e.g. malaria). In the immunocompromised bothmorbidity and mortality are considerably increased. The full impact of parasiticinfection is difficult to define because of the scarcity of reports. The mostcommon form of acquired infection is with parasites that spend either some ormost of their life cycle in the circulatory system or by organisms residing withinthe transplanted organ.

Task 3. Managing the immunocompromised patient p.31Barsoum RS. Parasitic infections in organ transplantation. Exp Clin Transplant2004; 2(2): 258–267. Review. PMID 15859939Immunosuppression during pregnancyPregnancy is an immunosuppressed state. The fetus expresses antigens foreignto the mother as it is genetically different from its host. The maternal immunesystem tolerates this in most cases and the fetus is not attacked. Direct contactbetween maternal and fetally-derived trophoblastic cells occurs in the placentabut maternal immune-tolerance explains why pregnant women are at greaterrisk from certain infections.Primary infection with herpes simplex virus during the third trimester ofpregnancy can be severe and can precipitate critical illness in both mother andfetus. Presentation can be fulminant leading rapidly to multiple organ failureand death. The situation is often compounded by diagnostic delay. Maternalacute liver failure is frequent.THINK: What is the mechanism of pregnancy-induced immunosuppression?Immunosuppression following splenectomyThe immune deficit following splenectomy is incompletely understood but suchpatients will have a life-long increased susceptibility to certain infectionsparticularly those caused by encapsulated bacteria (Neisseria mengitidis,Streptococcus pneumoniae and Hemophilus influenzae). The sites of infectionare usually lung, CNS and bloodstream.Patients who undergo elective splenectomy should be immunised against theseorganisms prior to operation. Management varies in patients who requiresplenectomy as an emergency and in whom pre-operative vaccination isimpossible. Some specialists believe that immunisation is beneficial in all cases,whilst others recommend life-long prophylaxis with penicillin.Functional hyposplenism is more common than previously thought. Evidence ofreduced splenic function shown by the presence of Howell-Jolly bodies on aperipheral blood film has been reported to be present in 1 in every 200 samplesprocessed in one laboratory. The most common causes are liver disease andceliac disease but many other diseases affect splenic function.You can find out about the causes of hyposplenism on the following website andthe reference below.http://www.fpnotebook.com/GI/Spleen/Asplnc.htmHarji DP, Jaunoo SS, Mistry P, Nesargikar PN. Immunoprophylaxis in asplenicpatients. Int J Surg 2009; 7(5): 421–423. Review. PMID 19607947

4. UNDERSTANDING IMMUNE MODULATIONTask 4. Understanding immune modulation p.32Recent advances in our understanding of the immune response and especiallythe mechanisms that curtail the pro-inflammatory cascade prompted reevaluationof the extent of immunosuppression in the critically ill. There isgrowing awareness that immune dysregulation makes a significant contributionto immune suppression in the critically ill. Furthermore many of the standardICU interventions, such as sedation and inotropic support (see below), haveimmune-modulating effects. This Task will focus on the changes in immunefunction caused by treatment.Physical therapiesTotal body irradiationTotal body irradiation (TBI) is used as a conditioning process before bonemarrow transplantation. It is often used in conjunction with cytotoxic drugregimens. Patients develop a profound pancytopenia. These patients rarelyenter the ICU during this phase of treatment but of course are prone to a widevariety of infections.PlasmapheresisPossible indications for plasmapheresis in the intensive care setting include theGuillain-Barré syndrome, myasthenia gravis and thrombotic thrombocytopeniapurpura. For more information see the PACT modules on Neuromuscularconditions and Bleeding and thrombosis.The main immune effects are due to temporary removal of circulatingimmunoglobulin. Nevertheless, large trials comparing the use of plasmapheresiswith intravenous immunoglobulin in the management of Guillain-Barrésyndrome have shown no difference in the incidence of infection.Blood transfusionImmunosuppression following transfusion has been shown toincrease the risk of postoperative infection and influencestumour recurrence. These effects are thought to be due toassociated white blood cell contamination within red blood cellconcentrates. Transfusion of leuko-depleted red blood cellsreduces the incidence of fever and antibiotic use but not theincidence of infection.Blood transfusion is not abenign therapy and maybe regarded as aperipheral red blood celltransplantThere may also be immune stimulation either through ABO incompatibility orred cell alloimmunisation leading to red cell antibody formation. This is foundespecially in patients requiring multiple transfusions.Taylor RW, O'Brien J, Trottier SJ, Manganaro L, Cytron M, Lesko MF, et al. Redblood cell transfusions and nosocomial infections in critically ill patientsCrit Care Med 2006; 34(9): 2302–2308. PMID 16849995

Task 4. Understanding immune modulation p.33Dzik WH, Anderson JK, O'Neill EM, Assmann SF, Kalish LA, Stowell CP. Aprospective, randomized clinical trial of universal WBC reduction.Transfusion 2002; 42(9): 1114–1122. PMID 12430666Hébert PC, Fergusson D, Blajchman MA, Wells GA, Kmetic A, Coyle D, et al;Leukoreduction Study Investigators. Clinical outcomes followinginstitution of the Canadian universal leukoreduction program for redblood cell transfusions. JAMA 2003; 289(15): 1941–1949. PMID 12697796Drug therapiesCancer chemotherapyCytotoxic drug regimens cause cytopenia as a result of marrowtoxicity. Neutropenia is the main predictor of infection althoughboth T and B lymphocyte function may also be affected. Otherside effects of cytotoxic agents include oral mucositis,hyperuricaemia, neurotoxicity and nephrotoxicity. Mucositis isa disabling and common complication of cancer chemotherapy.Good mouth care may reduce its severity. Treatment is difficultand can pose a serious problem in the ICU. Inflamed mucosamay also act as a portal for infection.Glucocorticoids (GCs) are the oldest immune modifyingdrugs. They have complex immune effects that are dose related.They are widely used in many conditions in which immuneactivation plays a role in disease activity. Glucocorticoidschange lymphocyte populations and increase apoptosis inthymocytes and eosinophils. Polymorphic neutrophils, however,have prolonged life-cycles when steroids are used and there islittle difference in macrophage survival.Immunosuppressiveagents can beclassified accordingto the site of actionwithin the immunesystemGlucocorticoids playa vital role inimmunosuppressionfollowingtransplantationThe use of GCs in critical care has evolved over the last 30 years. Following therecognition that inflammation played an important role in the pathogenesis ofcritical illness, steroids were used, often in large doses, in an attempt to controlthe inflammatory processes, but at the expense of an increase in infection andmortality. Despite this, interest remained and further work in ARDS and inpatients with shock rekindled interest in the use of GC therapy.See the PACT module on Sepsis and MODSGCs have been investigated extensively in patients with ARDS to see if longtermtherapy reduces morbidity and mortality. There is some evidence tha GCsappear to improve lung function and reduce ventilator days compared tostandard therapy, without an increase in infectious complications. Howeverthere is an increased risk of myopathy and neuropathy and an increasedmortality if GCs are started at least 14 days after the onset of ARDS.See the PACT module on Respiratory failureThe use of GCs in septic shock has received considerable attention recently. Therationale had been based on supplementing relative adrenal insufficiency ratherthan inhibition of the inflammatory response. It appears that GC use in septicshock reduces the time on vasopressors regardless of initial response to ACTH

Task 4. Understanding immune modulation p.34(i.e. whether the patient has a suppressed adrenal response or not). However,an improvement in mortality has not been proven and subsequent analysissuggests that the biggest trial to date (CORTICUS) was underpowered.Current recommendations (see reference to Surviving Sepsis Guidelines, below)for the use of GCs in septic shock are that they can be used in patients withvasopressor resistant shock for shock reversal, at the discretion of the treatingphysician and should be tapered once vasopressors have been discontinued.Mesotten D, Vanhorebeek I, Van den Berghe G. The altered adrenal axis andtreatment with glucocorticoids during critical illness. Nat Clin PractEndocrinol Metab 2008; 4(9): 496–505. Review. PMID 18695699Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al.Surviving Sepsis Campaign: International guidelines for management ofsevere sepsis and septic shock: 2008. Intensive Care Med 2008; 34(1):17–60. PMID 18058085http://www.survivingsepsis.org/Purine analogues and antimetabolites were derived as anti-cancer drugs.Azathioprine and 6-mercaptopurine are the only members of this group atpresent. These agents are metabolised to substances that interfere with DNAand RNA synthesis during clonal expansion, reducing the production ofimmune cells. The main side effect is bone marrow suppression that limits thedose of azathioprine tolerated.Suppression of the immune response to foreign antigens on atransplanted organThere were 3513 solid organ transplants in 2008–2009 in the UK and as at July2010 there were 107 815 patients on the US waiting list for a solid organtransplanthttp://www.uktransplant.org.uk/http://www.unos.org/dataImmunosuppressive agents exert their effects by one or more of themechanisms below:• Altered lymphocyte function. This is the mainstay ofimmunosuppressive regimens used today.• Sequestration or altered lymphocyte traffic. New agents are beingdeveloped that affect lymphocyte cell traffic.• Depletion of lymphocytes. This results in intenseimmunosuppression and is now rarely performed.• Structural damage to lymphoid tissue. It is known that lymphnodes play an important role in the immune response. Antigenpresentation takes place within lymphoid tissue.

Task 4. Understanding immune modulation p.35Immunosuppression for transplantationMost immunosuppressive protocols use combinations of agents, in an attemptto reduce dose and toxicity of individual treatments. Standard regimens use aglucocorticoid, a calcineurin inhibitor (see below) and an antiproliferativeagent. The newer more selective agents being developed will hopefully result inimproved immunosuppression, graft tolerance and a reduction in both immuneand non-immune toxicity.Immunophilin-binding drugs (calcineurin inhibitors). The drug categoryname of cyclosporin A (CyA), tacrolimus (TAC), rapamycin/sirolimus (RM)derives from their ability to bind to immunophilins: cyclophilins (Cps) and FKbinding protein (FKBP). They are all derived from immunosuppressive toxinsmade by bacteria, presumably for the purpose of manipulating the immuneresponse of their hosts they infect. Immunophilins are intracellular proteinphosphatases and are abundant and ubiquitous. They play essential roles in cellproliferation, differentiation, and death. CyA engages Cps, and both TAC andRM engage with FKBP forming complexes. The new surfaces of these complexestarget important intracellular enzymes and in T cells, prevent cytokineproduction or cell proliferation. CyA and TAC inhibit the production of IL-2 butsirolimus blocks the response to IL-2 activation, thus preventing the stimulationof T and B cells.Mycophenolate inhibits DNA and RNA synthesis. It is a reversible inhibitor ofthe enzyme inosine monophosphate dehydrogenase. The production of purinenucleotides is reduced causing a relative deficiency in guanine and excessadenine. This effect is limited to lymphocytes because other non-immune cellsrecycle purines.Mode of action of some immunosuppressive agents on T helper cellsAdapted from Goddard S, Adams DH. New approaches to immunosuppression in livertransplantation. J Gastroenterol Hepatol 2002; 17(2): 116-126. PMID 11966939Monoclonal antibodies canbe humanised to inhibit thehost immune responseLegend: -ve means inhibitory. These are Th1 helper cells

Task 4. Understanding immune modulation p.36Protein-based drugs. Lymphocyte immune globulins (ALG, ATG) are activeagainst surface protein structures. They are derived from animal sera. Theyhave three effects: lysis of lymphocytes, altered traffic and altered function.These drugs are often used at the initiation of immunosuppression or as rescuetreatment for acute rejection. They have the potential to induce profound T celldepletion and therefore the risks of subsequent infection are high.Interleukin 2 receptor blockade by humanised murine monoclonalantibodies is a relatively new means of achieving immunosuppression.Daclizumab and basiliximab both block the actions of interleukin 2 but haveslightly different pharmacokinetics. Interleukin 2 receptor blockade has beenshown to reduce the need for other immunosuppressants and has enabled theuse of steroid-free protocols in certain solid organ transplants.Modern immunosuppressive regimens are very successful in theprevention of acute rejection and the preservation of early graft function in solidorgan transplantation. Most of these regimens are based around one of thecalcineurin inhibitors, cyclosporin or tacrolimus. Now that solid organtransplantation has become routine and rejection less of a problem, it hasbecome apparent that longer term graft and patient outcomes are oftendependent on renal function and other side effects of long-termimmunosuppression such as increased cardiovascular risk, diabetes andmalignancy.It is well known that renal function is adversely affected by the use ofcalcineurin inhibitors. Many studies have been performed in an attempt toreduce or eliminate the toxicity of these agents. There has been some success,but often at the expense of an increased risk of infection or malignancy.Mueller XM. Drug immunosuppression therapy for adult heart transplantation.Part 1: immune response to allograft and mechanism of action ofimmunosuppressants. Ann Thorac Surg 2004; 77(1): 354-362. Review.PMID 14726104Immunosuppressive agents can be classifiedaccording to the site of action within the immunesystemThe use of biologic agents in autoimmune disease andhaematologyBiologic agents are monoclonal antibodies that interact with a number of cellsurface receptors and other biologically active molecules.The field of biologic therapy has expanded rapidly and the rate of developmentdoes not appear to be slowing. The numbers of new drugs available and thenumber of indications continue to grow. There are currently five TNF inhibitorsin therapeutic use. They are most commonly used for rheumatoid arthritis,psoriatic arthritis, ankylosing spondilitis and inflammatory bowel disease,amongst others.

Task 4. Understanding immune modulation p.37IL-1 and IL-6 are both pro-inflammatory cytokines important in thepathogenesis of rheumatoid arthritis and have been targeted by biologicaltherapy. The anti CD20 monoclonal antibody rituximab is directed against B-lymphocytes and was first licensed as a treatment for B-cell non-Hodgkin’slymphoma. It has been used in a number of other disease states includingrheumatoid arthritis and SLE.The immune suppressant effects of biologic agents varies according to the agentand whether it is used in combination with other immune-modulating drugs butmost have shown a small but consistent increase in infectious complicationsassociated with their use.Anti-TNF drugs have been the most studied. Pharmacovigilance studies haveshown an increase in opportunistic infections with their use. Some data alsosuggest an increase in the incidence of hematological malignancy. There is alsoevidence that the anti-TNF drugs interfere with the important role TNF plays intuberculosis immunity resulting in a greater proportion of patients presentingwith extra pulmonary manifestations.IL-6 inhibitors such as tocilizumab bind to both soluble and membrane boundIL-6. This agent is used in rheumatoid arthritis and improves functional statusand radiographic changes. An increase in infectious complications has beendemonstrated.Combinations of biological agents appear to exacerbate the risk of infection.The coincident immunomodulatory effects ofcommonly used drugsThe realisation that some of the drugs used routinely in the ICU may be causingharm was highlighted by the observation of an increase in mortality associatedwith the use of the sedative agent etomidate (first reference, below). Thisintravenous anaesthetic agent was shown to inhibit basal cortisol productionand abolish the stress response. Mortality figures returned to normal followingits discontinuation.In the second reference, the authors found a single dose of etomidate to be arisk factor for relative adrenal insufficiency.Watt I, Ledingham IM. Mortality amongst multiple trauma patients admitted toan intensive therapy unit. Anaesthesia 1984; 39(10): 973-981. PMID6496912Malerba G, Romano-Girard F, Cravoisy A, Dousset B, Nace L, Lévy B, et al. Riskfactors of relative adrenocortical deficiency in intensive care patientsneeding mechanical ventilation. Intensive Care Med 2005; 31(3): 388–392. PMID 15703896 Full text (pdf)Many drugs have been shown to have more subtle effects on immune function.Agents used for prolonged periods such as sedatives, analgesics and inotropicagents have been studied most extensively.

Task 4. Understanding immune modulation p.38Sedative agentsPropofol, midazolam and ketamine all possessimmunomodulatory properties. Phagocytic and chemotacticresponses are inhibited in vitro by these drugs as is cytokinerelease. The latter is variable and depends on the drug and thecytokine studied. However, little work has been performed invivo and, other than etomidate, it has not been shown thatspecific sedatives influence mortality.The 'fight and flightresponse' affects theimmune responseOpioidsOpioids have been implicated in changes in lymphocyte sub-populations with adecrease in natural killer cells and an increase in the percentage of B and T cells.Two hormone axes are affected by opioid administration; prolactin secretionincreases whereas cortisol secretion decreases. These changes influence bothcytokine synthesis and lymphocyte migration. However, these theoretical effectshave not been shown to affect mortality.Webster NR, Galley HF. Immunomodulation in the critically ill. Br J Anaesth2009; 103(1): 70–81. Review. PMID 19474216Inotropic drugsLymphoid tissue is closely linked to the autonomic nervoussystem and is affected both directly, by non-synaptic interactionand indirectly by circulating catecholamines. Antigenpresentation and cytokine production are influenced bycatecholamines, as are the innate and adaptive immuneresponses. Immune cells are directly affected via cell surfacereceptors and by the influence of catecholamines on cytokinesecretion.The balance of theevidence suggeststhat catecholaminesareimmunosuppressiveThe nervous system also has an immunosensing function, both directly via theaction of cytokines on the brain and via the vagus nerve. There are also anumber of humoral mechanisms; cytokines are known to be activelytransported across the blood–brain barrier and can enter via thecircumventricular regions. In addition sensory vagal afferent fibres detectcytokines peripherally at low concentration. A reflex arc via the efferent vagushas been termed the ‘cholinergic anti-inflammatory pathway’. The vagussecretes acetylcholine that acts on Ach receptors on macrophages and othercytokine producing cells.Animal models using lethal doses of endotoxin and haemorrhagic shock haveshown that electrical stimulation of the efferent vagus considerably attenuatesthe inflammatory response. In contrast vagotomy increased the concentration ofinflammatory cytokines and the severity of shock. During sepsis vagalstimulation results in reduced serum levels of HMGB-1 protein, as has beenshown with the acute administration of nicotine in aseptic SIRS.

Task 4. Understanding immune modulation p.39Epinephrine and norepinephrine both tend to suppress Th1 activities and boostTh2 and humoral responses during antigen presentation. Suppression is alsomediated via direct interaction with lymphocytes. Stimulation of the β-adrenoreceptor is associated with effects that are predominantlyimmunostimulating (induction of TNF-α and interleukin 1β) but also hasimmunosuppressive consequences (inhibition of TNF-α and interleukin 1β plusinduction of interleukin 10). β2 stimulation produces a Th2 response and apredominance of immunosuppressive cytokines. The response of the humoralimmune system is more complex. In general there is an increase in antibodyproduction, especially IgE. Immune cells predominately express the β2adrenoreceptor.Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES. The sympathetic nerve – anintegrative interface between two supersystems: the brain and theimmune system. Pharmacol Rev 2000; 52(4): 595–638. Review. PMID11121511Dopaminergic immunomodulation is dominated by immunosuppressive effects,such as the induction of interleukin 6, the inhibition of TNF-α, the attenuationof the chemoattractant effect of interleukin 8 and the inhibition of endothelialadhesion. Catecholamines also alter the number and function of neutrophilsand lymphocytes.Prolonged catecholamine stimulation in patients with critical illness is anabnormal situation from an evolutionary standpoint and whereas initialcatecholamine secretion during stress may induce antibody production, longtermexposure will tend to have an immunosuppressive effect. This probablycontributes to the immune dysregulation seen in the critically ill.THINK about the causes of immunosuppression associated with multiple organfailure.Modifying the immune system in the critically illClinical trials aimed at reducing the effect of inflammatory mediators by usingantibodies against endotoxin, TNF-α antagonists of interleukin 1 or plateletactivating factor have proved to be uniformly disappointing. Not only have theseagents been found to be of no benefit, but in some cases they may increasemortality.Abraham E, Wunderink R, Silverman H, Perl TM, Nasraway S, Levy H, et al.Efficacy and safety of monoclonal antibody to human tumor necrosisfactor alpha in patients with sepsis syndrome. A randomized, controlled,double-blind, multicenter clinical trial. TNF-alpha MAb Sepsis StudyGroup. JAMA 1995; 273(12): 934–941. PMID 7884952As well as attempts to dampen the initial pro-inflammatory state associatedwith early critical illness, efforts have been made to stimulate the immunesystem in patients showing signs of immunosuppression. One group has tried to

Task 4. Understanding immune modulation p.40stimulate the immune response with gamma interferon (γINF). They found anincreased expression of HLA-DR on circulating monocytes and an improvedoutcome in this small but interesting study.Döcke WD, Randow F, Syrbe U, Krausch D, Asadullah K, Reinke P, et al.Monocyte deactivation in septic patients: restoration by IFN-gammatreatment. Nat Med 1997; 3(6): 678–681. PMID 9176497Other drugs have been identified that stimulate immune function and, in thefuture, may prove to be useful in the critically ill. Imiquimod induces cytokineproduction from Th1 cells and at present is only licensed for use topicallyagainst genital warts. It is hoped that other drugs from the same family mayoffer more promise in critical illness.Amifostine is an agent that has been shown to reduce some of the toxic effectsof both radiotherapy and some cancer chemotherapy. It is proposed thatamifostine is transformed into its active form, the free thiol (WR-1065), moreeasily by normal cells than by tumour cells, thus offering some buffering fromthe oxidative stress induced by the chemotherapeutic insult.Trials using filgrastim (a granulocyte colony-stimulating factor (G-CSF)) wereunsuccessful at reducing mortality or the complication rate from pneumonia inadults although early work in neonatal ICUs has produced some promisingresults. Research in this area is on-going and opinion is contradictory.In the reference, below, it was shown that GM-CSF could reverse innateimmune suppression in sepsis and was also associated with faster clearance ofbacteraemia and a trend towards improved survival, although the study was notpowered for outcome.Rosenbloom AJ, Linden PK, Dorrance A, Penkosky N, Cohen-Melamed MH,Pinsky MR. Effect of granulocyte-monocyte colony-stimulating factortherapy on leukocyte function and clearance of serious infection innonneutropenic patients. Chest 2005; 127(6): 2139-2150. PMID 15947332Q. What are the potential complications of stimulating the immunesystem in severe sepsis?A. Upregulation of the immune response in severe sepsis might be expected to increasesystemic inflammation and worsen organ dysfunction, perhaps counteracting thebeneficial effects of enhanced clearance of infection.Select five patients in the ICU who are receiving drugs withimmunomodulatory effects. What are the indications? Find out the effects on theimmune status. How do you confirm these?

Task 5.Preventing infection in the immunocompromised patient p.415. PREVENTING INFECTION IN THE IMMUNOCOMPROMISEDPATIENTHinds CJ, Watson JD. Intensive Care: A Concise Textbook. 3rd edition. SaundersLtd; 2008. ISBN: 978-0-7020259-6-9. p.331–334. Source and preventionof infectionPACT module on Infection control strategiesThe incidence of nosocomial infections in ICU is between 15% and 40% and is aconsequence of concentrating severely ill patients in one site, breaching theintegrity of gut and skin and alterations in the patient’s normal flora.Vincent JL, Rello J, Marshall J, Silva E, Anzueto A, Martin CD, et al; EPIC IIGroup of Investigators. International study of the prevalence andoutcomes of infection in intensive care units. JAMA 2009; 302(21): 2323-2329. PMID 19952319Q. Why does ICU admission alter commensal skin flora?A. Antibiotic therapy, changes in environmental flora, skin sterilisation duringoperative procedures and washing with soaps to reduce MRSA colonisation all alter thepatient’s natural skin flora.Because of the devastating consequences of infection in theimmunocompromised patient, prevention is a key responsibility of the intensivecare team.Hand hygieneThe most important intervention is hand hygiene. Washing hands or usingalcohol gel between patient contact dramatically reduces transmission ofbacteria.Video surveillance of staff and patients' relatives in a Japanese ICUshowed that staff were worse than relatives in adhering to the hand washing policy.Nishimura S, Kagehira M, Kono F, Nishimura M, Taenaka N. Handwashingbefore entering the intensive care unit: what we learned from continuousvideo-camera surveillance. Am J Infect Control 1999; 27(4): 367–369.PMID 10433677Pittet D. Hand hygiene: improved standards and practice for hospital care. CurrOpin Infect Dis 2003; 16(4): 327–335. Review. PMID 12861085

Task 5.Preventing infection in the immunocompromised patient p.42Rosenthal VD, Guzman S, Safdar N. Reduction in nosocomial infection withimproved hand hygiene in intensive care units of a tertiary care hospital inArgentina. Am J Infect Control. 2005; 33(7): 392-397. PMID 16153485IsolationIsolation of potentially contagious patients within the ICU should be attemptedif practical to reduce the chances of cross infection. Although isolation isrecommended for control of airborne spread of pathogens, cross-colonisationwith organisms predominantly spread by contact (such as MRSA), may only bereduced by changing behaviour of staff. In the absence of adequate isolationrooms, barrier precautions with gloves and gown combined with good handhygiene is paramount.Standards for ICU designThe ICU is a reservoir of resistant infectious organisms. Curtains, walls, floorsand air-conditioning are all potential sources of infection. The role of cleaningand decontamination should not be underestimated. At times of local epidemicsor outbreaks, the closure of part of or the whole unit should be considered toallow thorough cleaning. Hydrogen peroxide vapour decontamination has beenshown to be superior to conventional cleaning but can only be used in enclosedrooms as it is toxic to humans. Interestingly, MRSA may not be completelycleared with a conventional solution containing 5–15% non-ionic surfactant and5–15% cationic surfactant, diluted 1:500.French GL, Otter JA, Shannon KP, Adams NM, Watling D, Parks MJ. Tacklingcontamination of the hospital environment by methicillin-resistantStaphylococcus aureus (MRSA): a comparison between conventionalterminal cleaning and hydrogen peroxide vapour decontamination. JHosp Infect 2004; 57(1): 31–37. PMID 15142713Guidelines for intensive care unit design. Guidelines/Practice ParametersCommittee of the American College of Critical Care Medicine, Society ofCritical Care Medicine. Crit Care Med 1995; 23(3): 582–588. PMID7874913. http://www.sccm.orgFerdinande P. Recommendations on minimal requirements for Intensive CareDepartments. Members of the Task Force of the European Society ofIntensive Care Medicine. Intensive Care Med 1997; 23(2): 226–232.PMID 9069011. http://www.esicm.orgGuidelines exist for floor space in ICUs (see ESICM and SCCM referencesabove). The transmission of micro-organisms will occur more readily incramped conditions. There are recommendations for the number of isolationcubicles that should be available for patients with resistant organisms and forimmunocompromised patients.Routine ICU managementMeticulous adherence to simple infection control procedures within the ICU,such as hand washing, the removal of watches, removal of jackets and rolling up

Task 5.Preventing infection in the immunocompromised patient p.43sleeves, minimises the risk of organism transmission. Regular naso-pharyngealsuctioning and sitting the patient at an angle of 45° as part of a ‘ventilatorbundle’ or guidance (see reference below) may reduce the risk of ventilatorassociatedpneumonia (VAP) likely by minimisation of micro aspiration.Continuous supra-glottal suction has recently been proposed as a means ofreducing VAP. Rationalising the number of intravenous cannulae and theprovision of written guidelines for their management may avoid thecomplications of catheter-related sepsis.Hawe CS, Ellis KS, Cairns CJ, Longmate A. Reduction of ventilator-associatedpneumonia: active versus passive guideline implementation. IntensiveCare Med 2009; 35(7): 1180-1186. PMID 19308354GuidelinesCheck what written policies regarding infection control exist on your unit.Are there guidelines for the insertion and maintenance of central venous catheters? Doyou consider them effective/appropriate? Discuss with your colleagues.Antibiotic restriction/stewardship policiesThe use of antibiotic policies and antibiotic rotation should be considered tohelp reduce the development of resistant bacteria within the ICU environment.ICU clinicians should work closely with their colleagues in Microbiology andInfectious Diseases to optimise appropriate and avoid inappropriate use ofantibiotics. Hospital-based antibiotic stewardship programmes appear toimprove the quality of, and curtail inappropriate, prescribing and are associatedwith reduced drug costs and bacterial resistance – see Lesprit and Brun-Buissonbelow. Although some infections such as endocarditis and osteomyelitis requirea longer duration of antibiotic course e.g. six weeks, there is an attempt toregularise duration of antibiotic therapy for standard infections. Chastre et alcompared an eight versus 15-day course of antibiotics for VAP and showedtherapeutic equivalence. Many hospitals now use short antibiotic treatmentcourses; the Surviving Sepsis Guidelines recommend a seven-day course as thereference duration of antibiotic therapy.Chastre J, Wolff M, Fagon JY, Chevret S, Thomas F, Wermert D, et al. PneumATrial Group. Comparison of 8 vs 15 days of antibiotic therapy forventilator-associated pneumonia in adults: a randomized trial. JAMA2003; 290(19): 2588-2598. PMID 14625336Singh N, Rogers P, Atwood CW, Wagener MM, Yu VL. Short-course empiricantibiotic therapy for patients with pulmonary infiltrates in the intensivecare unit. A proposed solution for indiscriminate antibiotic prescription.Am J Respir Crit Care Med 2000; 162(2 Pt 1): 505–511. PMID 10934078Lesprit P, Brun-Buisson C. Hospital antibiotic stewardship. Curr Opin Infect Dis2008; 21(4): 344-349. PMID 18594284

Task 5.Preventing infection in the immunocompromised patient p.44Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al.Surviving Sepsis Campaign: International guidelines for management ofsevere sepsis and septic shock: 2008. Intensive Care Med 2008; 34(1):17–60. PMID 18058085http://www.survivingsepsis.org/Antimicrobial prophylaxisAntibiotic prophylaxis presents a dilemma. On the one hand,our commitment to reducing exposure to antibiotics iscompromised by their use. On the other hand, prophylaxis isalmost certainly beneficial in some cases. Prophylaxis is usuallylimited to a single dose except in circumstances such asprolonged surgery (>2 hrs), major blood loss (>2 L) and certainspecial indications. Many guidelines recommend 24 hrs ofperioperative prophylaxis for major surgery and this accountsfor a proportion of ICU antibiotic use. Critical care staff need tobe alert to stopping such courses of prophylaxis in accordancewith local and national guidelines, an example of which can befound at http://www.sign.ac.ukIn the immunocompromised patientFluconazole in a moderate dose may also be of value for patients such as thosewith neutropenia, HIV or liver transplant recipients. Trimethoprimsulfamethoxazoleprophylaxis during certain immunosuppressive regimens hasall but eliminated PCP as a complication. CMV prophylaxis can also beconsidered for patients at risk. HSV reactivation is common in severelyneutropenic patients and the use of acyclovir is therefore recommendedfollowing bone marrow transplant.THINK: Can the use of prophylactic antibiotic therapy be justified in an age ofincreasing bacterial resistance?Selective decontamination of the digestive tractTreatment is often basedon consensus rather thanevidence and should be inline with local resistantprofilesSelective decontamination of the digestive tract (SDD) usually consists of amixture of orally administered non-absorbable antimicrobials, sometimescombined with a low dose intravenous antibiotic. The relative contribution ofthe oral SDD paste compared with the intravenous component is uncertain.Within the intensive care community opinion is polarised. Studies havesuggested that nosocomial infections e.g. VAP (and mortality) may be reduced,at least in certain subgroups of critically ill patients. There is, however, areluctance amongst some clinicians to introduce SDD to ICUs because ofconcern that in the long term and over a large number of ICUs, despiteevidence to the contrary, SDD would select for resistant organisms.de Jonge E, Schultz MJ, Spanjaard L, Bossuyt PM, Vroom MB, Dankert J, et al.Effects of selective decontamination of digestive tract on mortality and

Task 5.Preventing infection in the immunocompromised patient p.45acquisition of resistant bacteria in intensive care: a randomised controlledtrial. Lancet 2003; 362(9389): 1011–1016. PMID 14522530van Saene HK, Petros AJ, Ramsay G, Baxby D. All great truths are iconoclastic:selective decontamination of the digestive tract moves from heresy to level1 truth. Intensive Care Med 2003; 29(5): 677-690. Review. PMID12687326Bonten MJ, Brun-Buisson C, Weinstein RA. Selective decontamination of thedigestive tract: to stimulate or stifle? Intensive Care Med 2003; 29(5):672-676. No abstract available. PMID 12825560Bode LG, Kluytmans JA, Wertheim HF, Bogaers D, Vandenbroucke-Grauls CM,Roosendaal R, et al. Preventing surgical-site infections in nasal carriers ofStaphylococcus aureus. N Engl J Med 2010; 362(1): 9–17. PMID20054045de Smet AM, Kluytmans JA, Cooper BS, Mascini EM, Benus RF, van der Werf TS,et al. Decontamination of the digestive tract and oropharynx in ICUpatients. N Engl J Med 2009; 360(1): 20–31. PMID 19118302Chan EY, Ruest A, Meade MO, Cook DJ. Oral decontamination for prevention ofpneumonia in mechanically ventilated adults: systematic review andmeta-analysis. BMJ 2007; 334(7599): 889. PMID 17387118Liberati A, D'Amico R, Pifferi S, Torri V, Brazzi L, Parmelli E. Antibioticprophylaxis to reduce respiratory tract infections and mortality in adultsreceiving intensive care. Cochrane Database Syst Rev 2009; (4):CD000022. PMID 19821262Routine surveillance of immunocompromisedpatients – is it of value?Although routine microbiological surveillance of both patient and environmentallows a profile of resistant organisms in the ICU to be described, studies havesuggested that many of the organisms are innocent bystanders and notnecessarily responsible for infection. The presence of resistant organisms in anICU does not necessarily imply that a patient is colonised; the presence of anorganism on the patient does not necessarily imply infection.In mechanically ventilated patients, it is virtually impossible to avoid trachealcolonisation. VAP can be categorised as early-onset or late-onset although thedistinction is not well defined. Early-onset VAP is usually caused byStreptococcus pneumoniae, Haemophilus influenzae and Staphylococcusaureus, whereas Enterobacteriaceae, Pseudomonas aeruginosa andStaphylococcus aureus are often isolated in those with late-onset VAP. After 30days of ventilation approximately 35% of patients will have distal airwaycolonisation. As a result, current antibiotic policy should be to introduce broadspectrumantibiotic treatment initially and de-escalate to narrower spectrumagents once an infecting organism has been identified.

Conclusion p.46CONCLUSIONThe management of patients with immunosuppression represents a significantchallenge to the Intensivist and the full intensive care team. Many patients aretherapeutically immune suppressed e.g. post transplantation and anunderstanding of the therapy and its benefits, risks and side-effects areimportant to practice in this environment. As our understanding of themechanisms of immune suppression has developed and the clinical recognitionof patients with compromised immunity has improved, we can hope for acorresponding reduction in mortality. Better laboratory tests to ‘quantify’immunosuppression would be useful, but we are a long way from discovering a'magic bullet' to improve immunocompetency.

Self-assessment p.47SELF-ASSESSMENT QUESTIONSEDIC-style Type K1. In deciding on antimicrobial therapy for a febrile neutropenic patient:A. Clinical examination is not of relevance as therapy is standardisedB. Clinical identification of a source of infection will guide therapyC. Start with broad-spectrum therapy and narrow/focus the therapy when pathogenorganism identifiedD. If there is not a response to the antibacterial regimen within 48hrs, consider additionof antifungal therapy2. Of these immunosuppressant drugs (used for transplant recipientpatients), which are calcineurin inhibitors?A. CyclosporinB. MycophenalateC. TacrolimusD. Azothiaprine3. Qualitative markers of immunosuppression include the presence of:A. NeutropeniaB. LymphopeniaC. HypogammaglobulinaemiaD. Thrombocytopenia4. The broad classification of the host barriers to microbial invasion andinfection includes:A. The integument e.g. the skinB. The innate immunity systemC. The adaptive immunity systemD. The toll-like receptor system5. Re. Infection in the first two months after solid organ transplantation:A. Tends to be caused by standard ICU bacterial/fungal pathogensB. Transmission of bacterial infection with donor organ is a causeC. Re-activation of host Herpes disease due to immune suppression is a causeD. Nocardiasis is common

Self-assessment p.48EDIC-style Type A6. The following are true of the innate immune system EXCEPT:A. Is capable of reacting to foreign antigen in the absence of previous exposureB. Is a rapidly acting, non-specific first line of defence against invading organismsC. Includes phagocytic cells and natural killer cellsD. Includes the complement system and the acute phase protein responseE. Its memory allows for an enhanced response to antigen re-exposure7. Factors which would favour the addition of a glycopeptide to an antibioticregimen include the following EXCEPT:A. Known colonisation with MRSAB. Blood cultures positive for Gram-positive organismsC. Catheter- or device-related infectionD. Recent hospitalisation or period of residency in a nursing homeE. Suspicion that a urinary tract infection is the source of the sepsis8. In assessing the risk of infection in an HIV positive patient, a CD4 countof 150–200 (x 10 6 /L) predisposes to the following infections EXCEPT:A. TuberculosisB. Bacterial pneumoniaC. Oral candidiasisD. Cytomegalovirus infectionE. Kaposi’s sarcoma (due to human Herpes virus)9. Which one of the following is FALSE regarding CMV infection in solidorgan transplant patients?A. Up to 50% of transplant recipients develop CMV diseaseB. Likelihood of acquisition of CMV disease depends on the serological status of thedonor and recipientC. Occurs most commonly following transplantation with a sero-positive donorD. Can induce graft dysfunctionE. Does not exacerbate immunosuppression

Self-assessment p.4910. In immunocompromised patients, CMV characteristically induces avariety of conditions EXCEPT:A. Fever and leukopeniaB. HepatitisC. PneumonitisD. ColitisE. Myositis11. Which of the following regarding antibiotic stewardship policies isFALSE?A. They incorporate a practice of reviewing antibiotic prescriptionsB. They are designed to encourage appropriate antibiotic therapyC. They aim to reduce emergence of bacterial multi-drug resistanceD. They are associated with reduced hospital costsE. They have been shown to slow the implementation of timely antibiotic therapy12. Which of the following is true of Fungal infections?A. Are never found in patients with life-threatening burnsB. Are an early infective complication of solid organ transplantationC. Are not a presenting feature of acute leukaemiasD. Are never life-threateningE. Are never resistant to antifungal chemotherapy13. Which is true of CARS (compensatory anti-inflammatory responsesyndrome)?A. Is easy to measureB. Is caused by alteration to the patient’s commensal organismsC. Is of shorter duration than SIRSD. Is associated with anergyE. Occurs in all patients following severe illness14. All of the following are true of Tacrolimus EXCEPT:A. Affects neutrophil functionB. Levels should be monitored dailyC. Does not have an adverse effect on renal functionD. Is available only as an enteral preparationE. Effects are enhanced by erythromycin15. All of the following are true in neutropenic patients EXCEPT:A. Severity is defined by the absolute neutrophil countB. Viral infection is uncommonC. Patient isolation is advised for profound neutropeniaD. Antifungal medication is indicated for pyrexia of unknown origin (PUO) greater than72 hoursE. They usually die of their underlying disease in ICU rather than sepsis.

Self-assessment p.50Self-Assessment answersType KQ1. Q2. Q3. Q4. Q5.A. FB. TC. TD. TA. TB. FC. TD. FA. TB. TC. TD. FA. TB. TC. TD. FA. TB. TC. TD. FType AQ6. Answer E is correctQ7. Answer E is correctQ8. Answer D is correctQ9. Answer E is correctQ10. Answer E is correctQ11. Answer E is correctQ12. Answer B is correctQ13. Answer D is correctQ14. Answer C is correctQ15. Answer E is correct

PATCH p.51PATIENT CHALLENGESA 46-year-old male patient was admitted postoperatively to the ICUfollowing a liver transplant. He had presented to the hepatology departmentthree months earlier for assessment because of deteriorating liver function due tochronic hepatitis B infection. He had significant ascites and had been treated forepisodes of spontaneous bacterial peritonitis. He was poorly nourished andhyponatraemic with impaired renal function.The donor was a 66-year-old male who had died following a subarachnoidhaemorrhage and had been in the ICU for seven days. On macroscopicexamination, the liver was 'fatty' – a sign of borderline organ function but thedecision was taken to proceed. The donor was CMV antigen positive. Theoperation was technically difficult and there was moderate blood loss.Links to other modulesPACT module on Acute hepatic failurePACT module on Organ donation and transplantationOn arrival in the ICU, the patient was mechanically ventilated and receivinginotropic support. His systolic blood pressure was 90 mmHg and he had atachycardia of 120 bpm. He was anuric despite cardiac output optimisation and abolus of frusemide (furosemide). He was on 60% oxygen and had a PaO 2 of 10.3kPa (78 mmHg), a PaCO 2 of 5.4 kPa (41 mmHg) and pH 7.26. He had metabolicacidosis with a base deficit of –10.6 and a whole blood lactate of 6.3 mmol/l andwas commenced on renal replacement therapy. The standard immunosuppressionin the unit consisted of:• Tacrolimus – a calcineurin inhibitor• Azathioprine• Corticosteroids – hydrocortisone in the initial postoperative periodComponents of immune suppression in transplant patientsImmunosuppressive drugsLinks to other modulesPACT module on HomeostasisPACT module on Acute renal failureQ. What factors make this patient susceptible to infectious complications?A. There are factors applicable to all patients following a liver transplant (mainlydue to immunosuppressive drugs) and others relevant to the individual patient.Risk factors in this case include:Recipient's chronic hepatitis B infectionRecipient's recurrent peritonitis and recurring antibiotic therapyRecipient's renal function

PATCH p.52Postoperative renal replacement therapyLength of the operationAmount of blood transfusedDonor's ageDonor's CMV statusAnticipated long ICU stayInfection following solid organ transplantationRisk factorsGayowski T, Marino IR, Singh N, Doyle H, Wagener M, Fung JJ, et al.Orthotopic liver transplantation in high-risk patients: risk factorsassociated with mortality and infectious morbidity. Transplantation1998; 65(4): 499-504. PMID 9500623Sepsis is a leading cause of death following liver transplantationespecially in the first three months. Overall the risk of infection in livertransplant recipients has been reported to be between 5 and 60% with anattributable mortality of 5–80%.Q. What prophylactic medication would you prescribe for the patient to preventinfection in the postoperative period?A. We can assume that the standard, institutional perioperative antibacterialprophylaxis for this operation has been given. Specific to the transplant, thepatient has chronic hepatitis B infection and without postoperative preventativestrategies all patients will reinfect their grafts. Current prophylactic strategies willinclude both the antiviral drug lamivudine and hepatitis B immunoglobulin(HBIG). Lamivudine is started before the transplant and the HBIG is startedintra-operatively. Both drugs are then continued indefinitely. The graft came froma CMV positive donor and so there is an increased risk of CMV reactivation overthe coming weeks. Some centres provide CMV prophylaxis routinely. This isusually started during the second month post transplant when the risk of CMVinfection is highest. PCP prophylaxis (cotrimoxazole) will also need to beconsidered.Antimicrobial prophylaxis

PATCH p.53Early versus late infectionReinfection of the patientReinfection of the graftOver the following few days his condition stabilised. He remained ventilated andanuric on continuous veno-venous haemofiltration (CVVH). Inotropic supportwas discontinued and the initial metabolic acidosis resolved but he was left with apersistently raised whole blood lactate of approximately 3 to 4 mmol/l and hisinternational normalised ratio (INR) remained prolonged at about 2.0. Thesefindings suggested early graft dysfunction. An ultrasound scan (USS) showedgood flow to and from the new organ.In high-risk patients with organ failure the chance of postoperativeinfection is high. Broad-spectrum antimicrobial prophylaxis (which mayinclude antifungal cover) is often considered. The specific agents used varybetween centres.Links to other modulesPACT module on Organ donation and transplantationQ. The nurses ask how long prophylactic antibiotics should be continued in thispatient.A. Adherence to standard principles/guidelines on prophylaxis and toinstitutional protocols is advised. However, there are no randomised controlledclinical trials comparing different prophylactic regimens or their duration in thesepatients. Local practice will dictate what regimens are used. It is unclear how longprophylactic antibiotics should be prescribed for and in an uncomplicatedtransplant three doses of standard peri-operative prophylaxis should be sufficient.Although contrary to the principles/guidelines on peri-operative antibioticprophylaxis, there is sometimes a reluctance to stop antibiotics in the earlypostoperative period – the ostensible hope being a reduction in the risks ofinfectious complications.Epidemiological data regarding the timing of infections followingtransplantation can be useful in providing a rationale for treatment.Timing of infectionsThis patient's antibiotics were stopped in this instance on the secondpostoperative day. An antifungal in prophylactic dosage and prophylaxis for PCPand hepatitis B were continued.

PATCH p.54A new intern questions whether selective decontamination of the digestive tract(SDD) might be appropriate for this patient.Selective decontamination of the digestive tractQ. Is there a role for SDD in this patient? Give your reasons.A. Some transplant centres use SDD routinely in postoperative transplantrecipients and reports suggest a reduction in the incidence of Gram-negativeinfections. The data, however, are uncontrolled. Controlled studies of the use ofSDD have shown a reduction in infectious complications but were largelyunderpowered for mortality. Meta-analysis of trials of SDD has shown a reductionin the incidence of both infectious morbidity and mortality in some categories ofpatients. Trials including liver transplant recipients were excluded from theanalysis, however, making it difficult to resolve the issue with the available data.Despite the level of evidence supporting SDD, the reluctance of many institutionsto use it is that SDD is considered, despite evidence to the contrary, tointrinsically pre-dispose to the emergence of resistant organisms.SDD is not part of this institution’s perioperative protocol and it is decided that itshould not be given to this patient.On the fifth postoperative day it was noted that the patient’s temperature hadrisen to 39 °C. Early morning blood samples had shown an unexpected increase inhis white cell count and liver enzymes.Fever in the neutropenic patientQ. What further actions and investigations would you do now?A. Differentiation between an infective and non-infective cause can be difficultand involves clinical examination and ancillary testing. Infection is likely and asearch for the source should be undertaken. Cultures from blood, sputum anddrain fluid, if available, should be performed. Serial CRP measurements may be ofsome assistance. Abdominal examination may suggest the abdomen as a source ofsepsis; look for loss of bowel sounds and distension. Serum amylase may behelpful if pancreatitis is suspected. A chest X-ray may show pulmonary infiltratessuggestive of infection. A USS or CT scan looking for an intra-abdominalcollection may be performed and evidence of pancreatitis may be suggested. ADoppler USS is also the initial investigation used to rule out vascularcomplications at this stage followed by angiography for confirmation. If acuterejection is suspected a liver biopsy is indicated.

PATCH p.55Septic work-upInfection versus rejectionImagingBiochemical markers of infectionEarly vascular complicationsLinks to other modulesPACT module on Organ donation and transplantationPACT module on Sepsis and MODSPACT module on Severe infectionPACT module on PyrexiaThe chest X-ray showed some left lower lobe collapse but had not changedsignificantly from the previous day. As there is not an evident source of infection,catheter-related sepsis is suspected and his CVCs and arterial catheters wereremoved (tips were sent for culture) and re-sited. Blood cultures were sent formicrobiological analysis as part of the septic work-up. An urgent ultrasound scanfailed to show any vascular insufficiency and so a liver biopsy was performed.You meet with the patient's family to explain the deterioration in his condition.Links to other modulesPACT module on Communication skillsQ. While waiting for the biopsy report what blood tests are available to helpdistinguish between rejection and infection?A. The eosinophil count is often high in acute rejection. Procalcitonin is an acutephase protein that is raised in infection but not in acute rejection episodes andmay have a role in post transplant surveillance.The definitive blood test for the diagnosis of rejection does not exist.Rejection and infection are both inflammatory processes and difficult todifferentiate. Procalcitonin may, however, be of some assistance.The biopsy report suggested moderate to severe acute rejection. The patient wasstarted on a three day course of high-dose steroids and the calcineurin inhibitordose was increased.

PATCH p.56Kuse ER, Langefeld I, Jaeger K, Kulpmann WR. Procalcitonin in fever ofunknown origin after liver transplantation: a variable to differentiateacute rejection from infection. Crit Care Med 2000; 28(2): 555–559.Q. Do you think acute rejection increases the risk of infectious complications?What is the mechanism?A. Yes. An acute rejection exacerbates immunosuppression and will thereforeincrease the risk of infection.Mechanisms of immunosuppressionDespite the increase in immunosuppression the patient’s temperature remainedhigh and his white cell count continued to climb.Q. What are your therapeutic actions at this stage?A. Even without confirmatory microbiological data, the evidence for infection isstrong despite the biopsy report showing evidence of acute rejection. You shouldstart the patient on antibiotics for a presumed infected collection in thesubhepatic space.There are often multiple problems in immunocompromisedpatients – a high index of suspicion is required. Infection and rejectionoften occur simultaneously.After the septic work-up, the patient was started on a broad-spectrum antibiotic.Meropenem (a broad-spectrum, carbopenem) was used and reviewed whenculture results were available. The extended septic work-up included a CT scan ofhis abdomen which revealed a collection around the porta hepatis. A drain wasplaced by an interventional radiologist and brown fluid was aspirated which wassent for Gram-stain and culture.Early antibiotic therapy for severe sepsisSource control for sepsisLinks to other modulePACT module on Sepsis and MODS

PATCH p.57Q. At this stage what are the most likely sites of infection and what organisms arelikely to be involved?Prompt: Solid organ transplant recipients tend to develop infections related tothe transplanted organ, e.g. biliary infections following liver transplants,pneumonia following lung transplant and urinary tract infections followingrenal transplantation.A. Infections that occur within the first month following solid organtransplantation are similar to infections seen in other non-immunocompromisedsurgical patients. The same sites and organisms are responsible, including woundinfections, pneumonia, catheter-related blood stream infections and urinary tractinfections. The causative organisms include Gram-negative followed by resistantGram-negative and Gram-positive organisms including MRSA. Later vancomycinresistantenterococci, fungi and Clostridium difficile infections become prevalent.Vincent JL, Rello J, Marshall J, Silva E, Anzueto A, Martin CD, et al; EPIC IIGroup of Investigators. International study of the prevalence andoutcomes of infection in intensive care units. JAMA 2009; 302(21):2323-2329. PMID 19952319Infections up to one monthThe following day, cultures from the subhepatic space grew a mixed flora ofaerobic Gram-negative organisms and meropenem was continued. The patient’scondition improved over the next few days but he remained ventilated and inanuric renal failure requiring CVVH.A tracheostomy was performed. His sedation was stopped, he became more alertand he began to pass urine. He was able to wean from ventilation and was readyfor transfer to an HDU on a T-piece with FiO 2 of 0.4 over the next 2–3 days. As hewas swallowing well, his tracheostomy cuff was deflated allowing him tocommunicate via a speaking valve. His abdomen was soft, bowel activity recommencedand full enteral nutrition was maintained via a nasogastic tube.Intravenous antibiotic therapy (meropenem) was stopped and he was preparedfor transfer to the Liver ward some days later on maintenanceimmunosuppressive therapy and on the ongoing antimicrobial prophylaxis asoutlined above.

PATCH p.58A 37-year-old male was admitted to the ICU eight days after anallogeneic stem cell transplant. He had been treated with chemotherapythree months earlier for relapsed acute myeloid leukaemia and had achievedcomplete remission. He was blood group A Rh (D) positive and serology showedhim to be CMV seropositive.Causes of immune suppressionThe donor for the transplant was an HLA-identical unrelated 28-year-old femalewho had had three pregnancies. She was blood group A Rh (D) positive and CMVseronegative.Conditioning for the transplant was myeloablative with total body irradiation(14.4Gy given in 8 fractions) and high dose cyclophosphamide (60 mg/kg per dayfor two days). Antimicrobial prophylaxis was with oral ciprofloxacin 500 mg twicea day. Stem cell reinfusion occurred uneventfully. Cyclosporin A and methotrexatewere used as prophylaxis against graft versus host disease.Graft versus host diseaseConditioning is the process used to ablate the host bone marrowand immune system. In patients over the age of 50 years, ‘reduced intensity’approaches are used, primarily targeting the host immune system.On day six after the transplant, the patient developed a fever of 38.5 ° C butremained normotensive and maintained a urine output of >50 ml/hr. Bloodcultures were taken simultaneously from the tunnelled central venous catheter(CVC) and peripherally. Throat swab and urine samples were sent formicrobiological culture.Fever in the transplant patientLinks to other modulePACT module on PyrexiaAntibiotic therapy with gentamicin and piperacillin/tazobactam was commenced.Blood tests showed a total white cell count of 0.1 x 10 6 /l and a C-reactive proteinof 14 mg/l. The following day, the patient was still febrile and the CRP had risen to85 mg/l. On the day of ICU admission, the patient had deteriorated, with asystolic blood pressure of 67 mmHg, O 2 saturations of 86% on 5L O 2 by mask andoliguria. Arterial blood gas analysis showed a pH of 7.24, a pO 2 of 8.8 kPa (66mmHg) and whole blood lactate was raised at 4.28 mmol/l. Both sets of blood

PATCH p.59cultures demonstrated a coliform organism resistant to ciprofloxacin, gentamicinand piperacillin/tazobactam but sensitive to meropenem. The sample from thetunnelled CVC became positive four hours before the peripheral blood culture –suggesting catheter-related infection.Suspicion/diagnosis of catheter-related infectionInfection in the transplant patientLinks to other modulePACT module on PyrexiaPACT module on Sepsis and MODSQ. Which factors make this patient susceptible to infection?A. Risk factorsMalignancyPrior chemotherapyStem cell transplant conditioning and neutropeniaImmunosuppressive drugs (cyclosporin/methotrexate)Q. What are your therapeutic actions at this stage?A. Maintenance of the meropenem (for GNB therapy pending knowledge of fullantibiogram picture), continuance of resuscitative/organ supportive measure e.g.inotropic support and removal of the source of infection – the tunnelled CVC.Respiratory function improved and mechanical ventilation was not required. Oneday later, body temperature had fallen to 37.4 ° C and systolic blood pressure was105 mmHg on inotropes. However, the patient had developed diarrhoea. Over thefollowing 36 hours, the volume of diarrhoea increased to 2.8L/24 hours.Q. What are the possible causes of diarrhoea in this case?A. Infectious e.g. C. difficile and non-infectious e.g. inter-current antibiotictherapy, earlier laxative therapy, enteral feed intolerance, graft versus hostdisease.Testing for Clostridium difficile toxin was negative and culture demonstrated nosignificant pathogens. Colonoscopy and biopsy were performed and biopsy wasreported as consistent with graft versus host disease.Q. Which factors make this patient more likely to develop acute graft versus hostdisease?

PATCH p.60A. Unrelated donor, parous female donor, sex mismatch between recipient anddonor.Treatment with intravenous methylprednisolone 1 mg/kg twice daily wascommenced with a reduction in stool volume 48 hours later. The patient returnedto the ward.Immunosuppressive (booster) therapy72 hours after returning to the ward, the patient’s respiratory functiondeteriorated, with O 2 saturations of 88% on 15L O 2 by mask, respiratory rate of36/minute and an inability to speak in sentences. He was normotensive and urineoutput was >50 mls/hour. He was readmitted to the ICU and shortly afteradmission was intubated and mechanical ventilation commenced for respiratorydistress, obtundation and hypoxaemia. He was noted to have a temperature of38.2 ° C. Neutrophil count was 0.3 x 10 9 /l.Q. What pathogens need to be considered under these circumstances?A. Bacterial; viral – CMV, RSV, influenza A/B, H1N1, zoster; fungal includingPCP.Q. What non-infectious causes could result in an acute clinical deterioration suchas this?A. Pulmonary oedema from fluid overload.Idiopathic pneumonitis (including alveolar haemorrhage).ALI/ARDS due to chemoradiotherapy.Q. What further investigations would you request/organise?A. Blood cultures.Peripheral blood PCR for CMV.Bronchoalveolar lavage, sending samples for viral PCR (CMV, influenza A/B, RSV,H1N1), fungal staining and culture, PCR for PCP.Imaging including CXR and HRCT of chest when stable.After septic work-up, treatment was commenced with meropenem, liposomalamphotericin, cotrimoxazole and ganciclovir. After 36 hours, PCR on peripheralblood had shown the presence of CMV (360,000 copies/ml of blood) and also waspositive for CMV (qualitative assay) in bronchoalveolar lavage fluid.Q. What are the risk factors for CMV pneumonitis?

PATCH p.61A. Highest risk – CMV positive recipient and CMV negative donor.The use of CMV positive blood products.The use of high dose steroids for graft versus host disease.The use of immunosuppressive agents such as cyclosporin A.Recipient age (frequency increases with increasing age).There was no apparent response to initial therapy and the patient remained onmechanical ventilation for a further 12 days. Despite supportive and specifictherapy (intravenous ganciclovir and immunoglobulin) the overall course wasdownhill. Ventilation became more difficult and support was changed to anoscillating ventilator.Links to other modulesPACT module on Respiratory failurePACT module on Mechanical ventilationNo improvement was seen and CXR infiltrates became progressively worsedespite above specific and supportive therapies. The view of the Critical Care andthe visiting medical teams was that all reasonable medical measures had beenimplemented and that the patient was not responding. The consensus view atsenior level was that the life-sustaining measures were now futile for this patient.Links to other modulesPACT module on EthicsQ. How would you approach the care of this patient? What would you say to hisnext of kin?A. The family are told at serial meetings of the patient's worsening and poorprognosis. The family’s view on what the wishes and disposition of the patient tothis form of invasive therapy will have been explored at these meetings. The focusof care may have to change now to keeping the patient comfortable by palliativemeans and indeed managing his death in an appropriate manner. After themultidisciplinary meeting at which consensus is reached, a family conference isheld where the grave prognosis of non-responsive CMV pneumonitis in stem celltransplant is reiterated, the futility of the current invasive measures is explainedand the recommendation to change to palliative care is made. Often, by the timethis is apparent to medical staff, families already have reached the conclusion thatthe treatments are disproportionately burdensome and readily accept thisrecommendation and approach. Measures are then taken to limit/stop (withdraw)the invasive interventions, ensure comfort and allow the patient to die peacefully,without medical disturbance, in the presence of his family.

PATCH p.62On reflection, complications are common following solid organ and stemcell transplantation. Transplant physicians quote procedural mortality of 10–20%following stem cell transplantation.A complicated post-operative course and the treatment of graft versus hostdisease increase the risk of infections. A high index of suspicion is required.Infection is the major early cause of morbidity and mortality, and infection can ofcourse occur despite the use of appropriate antimicrobial prophylaxis.The first patient was high risk because of his multiple comorbidities and this wascompounded when he received a suboptimal graft. Aggressive early investigationto differentiate infection from rejection (or whether both co-exist) is required.Prompt appropriate treatment is required as it is known to improve survival,particularly in severe sepsis and septic shock. If therapy is unsuccessful, as in thecase of the second patient, it is important that this be recognised at a senior leveland a consensus view on palliation be reached where appropriate.Communication with the family is very important, should start early and beongoing.