Sepsis in the Immune Compromised Patient Case File

Sepsis in the Immune Compromised Patient Case File

Eugene C. Toy, MD, Manuel Suarez, MD, FACCP, Terrence H. Liu, MD, MPH

Case 20

A 45-year-old renal transplant patient has persistent fevers on ICU day 4. He was  diagnosed with pneumonia confirmed by chest x-ray,  and  his laboratory  tests  identified neutropenia. He received cyclosporine to prevent rejection of his graft,  and he is no longer dependent on hemodialysis since his transplant. His absolute neutrophil count (ANC) is 90 cells/mm3 (normal >1500 cells/mm³)  with a white blood cell count (WBC) of 1000 cells/mm3. Reverse isolation (protecting the  patient from his environment)  and triple antibiotic therapy with IV vancomycin,  levofloxacin, and ceftazidime were started empirically. A central  line is placed for fluid support. Blood, urine, and sputum specimens were taken for Gram stain, routine culture, acid fast stain and culture, fungus smears and cultures, and cytoogy. The patient has a  history of being purified protein derivative (PPD) positive 20 years ago, and he currently works as a nurse in an acute care hospital. Despite  the empiric antimicrobial therapy,  he continues to appear ill and has a temperature of 101.3°F.

⯈ What is the best management for this patient? 

⯈ What is the cause(s) for immunosuppression with this patient?

ANSWER TO CASE 20:

Sepsis in the Immune-Compromised Patient

Summary: This 45-year-old male renal transplant patient on immunosuppressive therapy (including cyclosporine) is admitted to the ICU with pneumonia and neutropenia. He is a nurse with a history of being PPD positive and is no longer hemodialysis-dependent. Broad-spectrum antimicrobial therapy was started and a CVP was placed. He remains febrile and toxic after 4 days of treatment in the ICU. 

• Best management: Start IV antifungal therapy. Adjust antimicrobials based on culture reports and clinical response (improvement or lack of improvement) . 
• Cause(s) for immunosuppression: Renal transplant, severe cyclosporineinduced neutropenia, and an indwelling catheter.

ANALYSIS

Objectives

1. To discuss immunosuppression and its causes in the intensive care setting.
2. To know the likely pathogens based on types of immunosuppressed patients in the ICU.
3. To know the immune dysfunction in sepsis and the proinflammatory and anti inflammatory states.
4. To know the potential methods for monitoring the immune status of a critically ill patient.

Considerations

The patient is an immunosuppressed 45-year-old man with risk factors for infection from antibiotic-resistant bacteria and fungi: renal transplantation and its attendant immunosuppressive therapy, neutropenia, antimicrobial therapy (alteration in flora and potential selection of resistant organisms) , indwelling catheters (renal transplant patient with hemodialysis catheter), hospitalization, prior occupational exposure to methicillin-resistant Staphylococcus aureus (MRSA), vancomycinresistant enterococci (VRE), vancomycin-intermediate Staphylococcus aureus (VISA) and multidrug-resistant organisms (MDROs) as well as being a practicing nurse. Additionally, he has a positive PPD test. An antifungal agent should be added to this patient's antimicrobial regimen, because of his immunosuppressed status. Candida species would be greatest threat, as they are now the fourth leading cause of blood stream infection (BSI) in the ICU. The antibiotics currently used may be adequate to control most bacterial infections in this setting; however, he is at risk for resistant organisms including: MRSA, VISA, VRE, and gramnegative MDROs. The patient is immunosuppressed to assist survival of his renal transplantation, and his persistent neutropenia is due to his therapy (cyclosporine). Since he has not responded to standard antimicrobial therapy, an antifungal agent (a triazole such as Fluconazole or echinocandin such as Cancidas) should be added while culture reports are pending. His antibiotic regimen should also be reassessed and possibly changed to cover the earlier-noted bacterial organisms, realizing the possibility of treatment failure with the vancomycin, ceftazidime, and levofloxacin. Further, the history of a positive PPD and potential work exposure to tuberculosis puts him at risk for reactivation or possibly a case of primary TB.

Approach To:

Pneumonia and Sepsis in an Immune Compromised ICU Patient

DEFINITIONS

ABSOLUTE NEUTROPHIL COUNT (ANC): The absolute number of neutrophils per microliter (mm³) is the percentage of neutrophils in the WBC. ANCs of <100/mm³ is neutropenia and creates a high risk for certain pathogens/opportunistic organisms such as Aspergillus sp., especially if neutropenia lasts >7 days.

For example, WBC = 1000/mm3 with 10% neutrophils = 10% = 1,000 X 0.1 = ANC of 100/mm³.

IMMUNNOSUPPRESSION: A decreased or lack of host's immune response and ability to fight infection.

OPPORTUNISTIC PATHOGENS (OIs): Organisms (bacterial, viral, fungal, parasitic), which are usually not pathogens in immunocompetent hosts.

MRSA: Staphylococcus aureus resistant to methicillin due to the presence of β-lactamases.

VISA: Staphylococcus aureus which is partially resistant to vancomycin based on decreased penetration of vancomycin across the cell wall.

MDRO: Gram-negative rod-shaped bacteria, which are resistant to multiple antimicrobials. This resistance is usually plasmid mediated (eg, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Enterobacter sp., Acinetobacter sp.).

SIRS: SIRS is nonspecific and can be caused by ischemia, inflammation, trauma, infection, or a combination of several insults. SIRS is not always related to infection and is defined as 2 or more of the following variables: fever of more than 38°C or <36°C, heart rate exceeding 90 beats/minute, respiratory rate exceeding 20 breaths/minute or a PACO2 level of <32 mm Hg, an abnormal white blood cell count ( >12,000/μL or <4000/μL or > 10% bands).

SEPSIS: Sepsis is a clinical term used to describe SIRS with defined or suspected infection, with or without organ dysfunction. Sepsis is a complex syndrome that is difficult to define, diagnose, and treat. It is a range of clinical conditions caused by the body's systemic response (SIRS) to an infection; if severe sepsis develops, accompanied by single or multiple organ dysfunction or failure, there is a high risk of death. Sepsis is a major cause of mortality, killing approximately 1400 people worldwide

every day.

CLINICAL APPROACH

Immunosuppression maybe subdivided into congenital, acquired, and iatrogenic or drug/therapy origins (see Table 20-1). The most common inherited cause in adults is described as a common variable immunodeficiency (CVI), where there is insufficient production of antibodies to infectious agents. CVI can be treated with pooled human immune globulin supplementation. Immunosuppression can result from infections such as HIV (the virus that produces AIDS), measles, and cancers. HIV/AIDS and lymphomas can cause significant decreases in T-cell-mediated immunity. AIDS has emerged as the most common cause of suppressed cell, mediated immunity (CMI). Fortunately, HAART (highly active anti-retroviral therapy) and the application of antimicrobial prophylaxis have made a deep impact on the survival of AIDS patients. Therapy-induced immunosuppression may be caused by a variety of drugs and treatments. These include corticosteroids, azathioprine, methotrexate, mycophenolate mofetil, cyclophosphamide, infliximab, rituximab, an increasing number of chemotherapeutic agents, and irradiation or radiation therapy, to list a few.

Infection Prevention

The immune system's primary function is to prevent infection. When the immune system is suppressed, dysfunctional, or absent, the patient's ability to combat infections is reduced and the incidence of infections is increased. These infections may arise from microorganisms called "opportunistic infections"(OI) that do not normally cause infectious diseases. Infections are usually more severe in immunosuppressed patients, and have a greater potential to result fatally. The best methods to protect these patients are to avoid unnecessary or overly aggressive immunosuppressive therapy as much as possible, avoid exposure to infectious agents, and reconstitute the immune system when possible. Other preventive strategies include appropriate immunizations, prophylactic antimicrobials, and following isolation and handwashing policies.

For neutropenic patients, reverse isolation is important. Also raw vegetables should be avoided unless they are irradiated, to prevent the transfer of bacteria to the patient's gastrointestinal system via the food. Indwelling catheters should be avoided and monitored closely when used. Attention to hand washing and the proper use of gloves, facial masks, and clothing is essential. The proper application of hand hygiene is critical in the prevention of these infections, but compliance among health-care workers is below 40%. In some cases, granulocyte colony-stimulating factor (G-CSF) is needed. Health-care associated infections are the most common adverse events resulting from hospitalization. Approximately 5% to 10% of hospitalized patients in the developed world acquire such infections.

ICU Care

Improvements in patient survival with comorbid disease and advances in critical care management have resulted in an increase in the number of patients in the ICU who are immunocompromised. An immunocompromised host may have alterations in phagocytic, cellular, or humoral immunity that increase the risk of infectious complications or provide an opportunistic process from a therapy- induced lymphoproliferative disorder or cancer.

Additionally, patients may also become immunocompromised if they have an alteration or breach of their skin or mucosal defense barriers that permits microorganisms to initiate a local or a systemic infection (eg, indwelling vascular catheters, Foley catheters, endotracheal tubes, and erosions of the mucosa or skin). Specific organisms must be considered in the setting of immunosuppression based on the type of defect(s) present.

Specific Organisms

Although the causes of fever in immunocompromised hosts are numerous and often never elucidated, some guidance to therapy is given by knowing the specific immunologic defect or defects present in the patient (Table 20-2). The duration of immune defense alteration has an extremely important effect on the types of infectious complications that are likely to occur. This includes ICU patients who are immunocompromised because of cancer or its treatment, those undergoing transplantation of bone marrow or solid organs, patients who have had a splenectomy, and patients with human immunodeficiency virus (HIV) infection or the acquired immunodeficiency syndrome (AIDS). Recognizing specific issues and challenges in the management of immunocompromised patients and focusing on infectious complications is vital in patient survival and well being in the ICU setting (see Table 20-3).

Sepsis

Sepsis is a major cause of morbidity and mortality in intensive care units (ICUs) and accounts for more than 210,000 deaths annually in the United States. The number of septic patients is increasing every year, and the mortality rate from sepsis remains high. Clinically, sepsis initially presents as a hyperinflammatory response to the immune system to attenuate the inflammation, and then progresses to an immune system down-regulation, which can result in prolonged immune dysfunction.

This period of immune hyporesponsiveness, or immunoparalysis, limits host defense against primary infections, thereby predisposing the secondary nosocomial infections, multiorgan dysfunction, and ultimately death. The pathophysiology of these events is still not completely understood.

Host Response

The host response to infection is complex and varies depending on type of infection, the infective dose (bacterial load), and host genetic factors. Microbial invasion of a healthy patient activates both the acquired and innate immune systems. During an infectious process the host's leukocytes (eg, macrophages) respond to exogenous danger signals that are the pathogens-associated molecular patterns (PAMPs). Endogenous mediators released during the anti-microbial response amplify this response. This proinflammatory state helps to localize infections by recruiting phagocytes and immune cells to the area(s) of infection, but when it is exaggerated, septic shock and multi-organ dysfunction syndrome (MODS) can result. Antigen is presented to naïve T-cells in the lymphoid organs. These cells are then primed to differentiate into either helper T (TH) type -1 or -2 cells. TH-1 cells are involved in cell-mediated immunity and secrete interferon-y (IFN-y) and IL-2, whereas TH-2 cells participate in humoral-antibody-mediated immunity and secrete IL- 10, IL-4, IL-5, and transforming growth factor-β (TGF-β). This shift to TH-2 cells is a hallmark of how the inflammatory response is down-regulated. This has been called the compensatory anti-inflammatory response syndrome (CARS). CARS may occur in patients who survive the initial SIRS/sepsis syndrome response when the proinflammatory state resolves and who then enter a state of immune suppression and dysfunction. Most deaths in sepsis occur late in the course of the syndrome

and during the later phase of immune suppression or anti-inflammatory state (Table 20-4).

Posttransplant Immunosuppression

Recent new immunosuppressants have recorded a significant reduction in the incidence of acute graft rejection, and this success has not been accompanied by increases in infection or malignancy. The price for reducing the incidence of allograft rejection by these improved immunosuppressants was anticipated to be a proportional increase in the incidence of infection and malignancy. However, the newer immunosuppressants such as tacrolimus, mycophenolate mofetil (MMF), leflunomide, and sirolimus have actually shown a significant reduction in the incidence of acute rejection free of increases in infection and malignancy (Table 20-5).

Identifying Immune Dysfunction in the Septic Patient

The host immune response to sepsis is complex and involves many circulating mediators and cells. Various cytokines have been studied for their correlation with mortality. Markedly elevated levels of circulating IL-6 and soluble-TNF receptors are correlated with the severity of disease and the 28-day mortality from any cause; thus, this information may help determine when anti-inflammatory therapy may be beneficial. Blood levels of anti-inflammatory cytokines may help determine whether a patient is immunosuppressed. Elevated and sustained levels of IL-10 and high IL-10(TNF-α ratios also were predictive of a poor outcome. IL-10 and TGF-β are an immunosuppressive cytokine, and its continued presence i n the septic patient may contribute to immune dysfunction. IL-10 may prove to be a useful marker of immune dysfunction but this supposition must be supported by larger trials before its clinical application is possible (Table 20-6).

Potential Therapies Aimed at Immune Dysfunction in Sepsis

Anti-inflammatory therapies, including TNF-α antagonists, IL-1 receptor antagonists, anti-endotoxin antibodies, corticosteroids, and granulocyte colony-stimulating factor (G-CSF) have not decreased overall mortality in patients with sepsis. IV immunoglobulin (IVIG) supplies specific antibodies to certain pathologic microbial factors, such as endotoxins, and elevated level of immunoglobulins depressed in sepsis. IVIG may be used as an adjunctive therapy for severe sepsis or septic shock. Activated protein C increases mortality and is no longer used.

CLINICAL CASE CORRELATION

• See also Case 17 (Meningitis/Encephalitis), Case 18 (Antibiotics), Case 19 (Sepsis), and Case 33 (Multiorgan Dysfunction)

COMPREHENSION QUESTIONS

20.1  A previously healthy 27-year-old man was admitted to the ICU after an MVA. He was intubated, given fluid resuscitation, and blood transfusions prior to transfer to the OR for laparotomy due to a ruptured viscus (stomach ) . After surgery he was managed i n the ICU with TPN, Foley catheterization, and completed 4 days of preventive antibiotic therapy for the ruptured viscus. He was extubated on the third day in ICU, but he was maintained on TPN following the laparotomy. On the sixth day in the ICU, his temperature spiked to >102°F. Upon examination he was noted to be toxic but had no identifiable focus of infection. A chest x-ray showed no lung infiltrate. What empiric therapy would you initiate pending the result of cultures for common pathogens ?

A. Gram-negative bacterial sepsis following the ruptured viscus. Broad-spectrum antibiotics.

B. Candidemia. Start fluconazole or echinocandin (eg, caspofungin).

C. Influenza, rimantadine

D. Invasive aspergillosis; voriconazole

E. Hospital-acquired pneumonia (HAP); vancomycin and ceftazidime

20.2  A 55 -year-old man is transferred to the ICU for evaluation of a fever of 103°F, pleuritic chest pain, shortness of breath, and hemoptysis. He is 21 days status post-allogenic bone marrow transplant (BMT) for acute myelogenous leukemia (AML). Chest x-rays revealed the presence of an infiltrate and a CT of the chest revealed a cavitary lesion with a "halo" sign. He remains profoundly neutropenic (<100 neutrophils/mm³) and thrombocytopenic (10,000/mm³) . Examination reveals that he is tachypneic and tachycardic. Bronchoscopy shows hyphae budding at 45 degrees. What empiric therapy should be instituted?

A. Amphotericin B given IV. Open lung biopsy or transthoracic biopsy.

B. Voriconazole. Gram stain of sputum, determine galactomannan level.

C. Fluconazole IV. Bronchoscopy with transbronchial biopsy.

D. Echinocandin IV. Video-assisted thoracoscopy with directed biopsy for C and S and silver stain.

E. Treat empirically for tuberculosis.

ANSWERS TO QUESTIONS

20.1  E. The patient is at high risk for candidemia due to the ruptured viscus and upper GI surgery, indwelling lines with total parenteral nutrition (TPN), prior use of broad-spectrum antibiotics for the ruptured viscus, and blood transfusion. Other risk factors for candidemia in the ICU include neutropenia, hematologic malignancies, hemodialysis, burns, prior enteric bacteremia, and recent fluconazole use (<30 days). Unstable patients should be started preemptively or empirically on an echinocandin (eg, caspofungin): patient outcomes are related to both the early visit and choice of an effective therapy. Stable patients may be started on fluconazole pending the result of fungal cultures. Over 50% of patients in the ICU who develop candidemia are colonized with nonalbicans species of Candida (eg. Candida glabrata, C. parapsilosis, C. tropicalis, and C. lusitaniae). In ICU patients with invasive candidiasis/ candidemia the removal or replacement of indwelling venous catheters and any other catheters and an evaluation of the importance of TPN should be routine and considered in all patients whenever unless absolutely unfeasible.

20.2  B. The patient has had an allogenic bone marrow transplantation (BMT) with prolonged and severe neutropenia. The finding of a "halo" sign, and hyphae budding at 45 degrees is highly consistent with an Aspergillus lung infection seen in 10% to 20% of patients with BMT; Aspergillus is most prominent due to effective prophylaxis of Candida with current protocols. Therapy of suspected Aspergillus lung infections must be instituted as early as possible to improve outcomes. Voriconazole is now the DOC for this infection. The diagnosis of pulmonary Aspergillus infections is confirmed by demonstrating the branching hyphae at an acute angle in silver stains of tissue biopsy, as it is a vasoinvasive hyphae and has subsequent positive cultures. Finding Aspergillus in his sputum and seeing a rise in his baseline galactomannan level (done weekly posttransplant) would be consistent with the diagnosis of IAI.

CLINICAL PEARLS

⯈ Common variable immunodeficiency is the most common inherited immunodeficiency in adults. 

⯈ TH-2 cells may be important in transitioning from a hyper-inflammatory state to immune dysfunction in sepsis. 

⯈ Most deaths in sepsis occur late in syndrome and survivors show evidence of immune recovery. 

⯈ "Profound and prolonged" neutropenia is at a high risk for invasive Aspergillosis. 

⯈ Hand washing is the most important  preventive strategy to reduce hospital-acquired infections. 

References

Clifford S, Deutschman MS. Evidence Based Practice of Critical Care. Philadelphia: Saunders; 2 0 1 0 . 

Loscalzo J . Harrison's Pulmonary and Critical Care Medicine. N e w York, NY: McGraw-Hill; 2 0 1 0 . 

Pizzo PA. Fever i n immunocompromised patients. N Eng! } Med. S e p 1 6 1 999;34 1 : 893-900. 

Toy EC, Simon B, Takenaka K, Liu T, Rosh A. Case Files Emergency Medicine. 2nd ed, New York: McGraw-Hill, Lange, 2009.

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