Immunocompromised Host

IL, Interleukin; TNF, tumor necrosis factor; VZV, varicella-zoster virus.

^* Immunosuppression is greater when used as a bolus for antirejection rather than when used as initial induction therapy.

Modified from Fishman JA, Issa NC: Infections in organ transplantation: risk factors and evolving patterns of infection. Infect Dis Clin North Am 24:273-283, 2010, and Danovitch G: Immunosuppressive medications and protocols for kidney transplantation. In Danovitch G (ed): Handbook of Kidney Transplantation. Philadelphia, Lippincott Williams & Wilkins, 2004, pp 72-134.

5 How does the timing of solid organ transplantation affect a patient’s risk for infection?

See Table 40-2.

^{Table 40-2} Risk of Infection and Time from Transplantation

Reactivation of Latent Recipient Infections

Reactivation of Latent Donor Derived

Fungal Infections

Atypical Bacterial

Late Viral Infections

VZV, Varicella-zoster virus.

^* Generally thought to be the time of greatest immunosuppression.

Modified from Fishman J: Infection in solid organ transplant recipients. N Engl J Med 357:2601-2614, 2007, and Syndman DR: Epidemiology of infections after solid-organ transplantation. Clin Infect Dis 33(Suppl 1):S5, 2001.

6 Describe the timing of infection in hematopoietic stem cell transplant recipients

Preengraftment: generally accepted as the first 2 to 4 weeks after transplantation and lasting until the engraftment of the transplant. During this period patients often have profound neutropenia and may have neutropenic fever and the ensuing complications. Patients are at risk for bacterial infections from their own endogenous bowel flora (Escherichia coli, Klebsiella, and Pseudomonas) and from skin flora such as Staphylococcus and Streptococcus because of invasive intravenous (IV) lines or skin breakdown. The longer the duration of neutropenia, the greater is the risk of invasive fungal infection with opportunistic fungi, such as aspergillus. Reactivation of latent viruses, such as CMV and herpes simplex virus (HSV), can occur during this period as well, leading to systemic infection.

Early postengraftment: the period from the time of neutrophil engraftment until day 100. With the exception of those patients who still have indwelling catheters, bacterial infection is less common during this time period. Patients who have difficulties with engraftment or those in whom graft-versus-host disease (GVHD) may develop, requiring increased doses of steroids, are at risk for invasive fungal infections as well as viral infections (CMV and HSV).

Late postengraftment: ranging from around day 100 until immunity is restored. Patients are generally at risk for encapsulated bacterial infections (Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis), fungal infections (Candida spp. and Aspergillus spp.), and late CMV infection.

7 What is the initial recommended work-up of suspected infection in the immunocompromised host?

History and physical. Clinical clues regarding unusual exposures can assist in creating a broad differential for suspected infection. Certain physical examination findings can be indicative of certain types of infection, and through physical examination, including visualization of the oropharynx, skin, and perirectal areas, looking for occult abscess is important.

However, it is important to recognize that digital rectal examinations should not be performed in patients with neutropenia, nor should they be allowed to have rectal instillation of contrast for abdominal computed tomography (CT) scans, because of the risk of hematogenous dissemination of the patients’ endogenous bowel flora.

Questions that may provide clinical clues to source of infection:

Blood cultures. Two sets should be obtained. If a patient has an indwelling central venous catheter a set should be collected from each lumen; at least one peripheral set should be obtained as well.

Complete blood cell count with differential; serum creatinine, blood urea nitrogen, electrolytes, and liver function tests.

Cultures should be obtained from other sites of potential infection: urine, sputum, and stool.

Imaging. A chest radiograph is clinically indicated for those patients complaining of respiratory symptoms or with objective findings such as changes in oxygenation, chest pain, or cough. Abdominal imaging may be indicated for those with abdominal complaints: nausea, vomiting or diarrhea, abnormal liver function testing, or evidence of gram-negative bacteremia.

8 What infectious causes should be considered in a patient without a spleen who has suspected sepsis?

Patients who have undergone splenectomy represent a special subset of the immune-compromised host. The spleen functions to produce opsonizing antibody and facilitates the clearance of encapsulated bacteria, organisms that can otherwise evade antibody and complement binding. Whether from surgical removal or functional asplenia (radiation, Hodgkin disease), these patients are at risk from a fulminant sepsis syndrome, known as postsplenectomy syndrome (PSS) or overwhelming postsplenectomy infection (OPSI), which carries a mortality rate approaching 70%. PSS is characterized as a fulminant sepsis, meningitis, or pneumonia that occurs days to years after splenic removal. Although the risk of severe infection is highest in the first few years after removal, fatal cases of PSS have been well documented even decades after the initial splenectomy. Encapsulated organisms such N. meningitidis, H. influenzae, and S. pneumoniae are the three most cited etiologic agents. In addition, Capnocytophaga canimorsus can lead to fulminant infection after dog bites. Babesia microti in North America and Babesia bovis in Europe, in those with appropriate travel history, can cause severe disease in hosts without a spleen. Salmonella species, although not a prominent pathogen, is a common cause of illness in children with sickle cell disease and splenic dysfunction. A wide variety of other bacteria have also been implicated in anecdotal reports.

9 What is the initial treatment for a patient without a spleen who is seen with sepsis?

In addition to aggressive supportive care, treatment of suspected postsplenectomy sepsis involves appropriate empiric antibiotic therapy directed at encapsulated organisms. Although S. pneumoniae is responsible for 50% of cases, oftentimes no etiologic agent is cultured. Empiric antibiotic choices should include coverage for Streptococcus, allowing for concerns of penicillin resistance, β-lactamase–producing organisms, and broad gram negative to include Neisseria and H. influenzae. Antibiotic allergy and local antibiotic resistance need to be taken into consideration when choosing an initial empiric regimen. However, combinations such as vancomycin and ceftriaxone or moxifloxacin or vancomycin and cefepime plus moxifloxacin would be reasonable starting regimens while awaiting microbiologic results.

10 What is the differential diagnosis in an immunocompromised patient who is seen with a central nervous system (CNS) infection?

Infections of the CNS are a medical emergency. Although compromised hosts are more susceptible to certain pathogens on the basis of their underlying immune defect, they are also at risk for the same infections as the general population. The clinical presentation of disease may be more subacute in the immunocompromised patients and can offer clues as to the microbiologic entity, especially when the nature of the immune defect of the host is taken into consideration as well. An understanding of the net state of immunosuppression of the patient can provide insight into creating a differential diagnosis of the nature of CNS infection based on clinical presentation. See Table 40-3.

11 What is the initial diagnostic approach to an immunocompromised patient who is seen with a suspected CNS infection?

Work-up should include the following:

Imaging study

CT scan can reveal acute hemorrhage, mass effect, bony or subdural lesions.

Magnetic resonance imaging can better evaluate the brain parenchyma, evidence and characteristics of mass lesions, brainstem and spinal cord lesions, edema.

Lumbar puncture

Opening pressure

Cerebrospinal fluid (CSF)

Cell count and differential

Glucose, protein, and lactate

Gram stain and bacterial culture

Cryptococcal antigen

Acid-fast smear and culture

Fungal smear and culture

Polymerase chain reaction (PCR) for HSV and other viral causes as clinically appropriate

and influenced by seasonal and geographic variation: enterovirus, West Nile virus (WNV), eastern equine encephalitis, western equine encephalitis, sick contacts, and degree of immunosuppression

Biopsy

If no definitive answer can be obtained from lumbar puncture, aspiration or biopsy of CNS lesions may be required for definitive diagnosis.

12 Do special considerations exist for the treatment of meningitis and mass lesions in the immunocompromised host?

Although infection of the CNS is life threatening, it is important to recognize that noninfectious mimics of CNS infections exist that should be taken into consideration as well and will not be discussed in detail here.

Bacterial meningitis. Treatment in the immunocompromised host should include coverage for the usual bacterial pathogens (N. meningitidis, H. influenzae, and S. pneumoniae), with attention to the possibility of penicillin-resistant S. pneumoniae, Staphylococcus aureus (especially in those with indwelling lines or shunts), and also Listeria monocytogenes. Often compromised patients with Listeria meningitis will be seen with subacute meningitis. However, the organism will usually grow in CSF cultures in 24 to 48 hours; thus empiric therapy should be continued until cultures are negative.

Mass lesions. Several viral, fungal, and parasitic pathogens can present as mass lesions in an immunocompromised host and masquerade as tumor or bacterial abscess. Significant efforts should be made to establish a microbiologic or tissue diagnosis of CNS lesions because the differential is quite broad, making empiric therapy challenging and not recommended.

13 What is the definition of neutropenia?

Neutropenia is defined as an absolute neutrophil count (ANC) of < 500 cells per cubic millimeter. The term may also be applied to those patients in whom an ANC decrease to < 500 cells per cubic millimeter is expected within the next 2 days. Some patients will have a relatively normal ANC yet still have profoundly impaired phagocytosis. These patients are said to have functional neutropenia and are still at risk for opportunistic infections despite their normal counts.

14 Describe empiric therapy for the hospitalized patient with febrile neutropenia

Patients with febrile neutropenia require empiric IV antibiotic therapy with an antipseudomonal β-lactam agent, such as meropenem, imipenem-cilastatin, piperacillin-tazobactam, or cefepime. Additional antibiotics (quinolones, vancomycin) may be added if concern exists for resistant organisms, vancomycin-resistant enterococcus (VRE), methicillin-resistant S. aureus (MRSA), resistant gram-negative rods, presence of hypotension, or suspicion of a pulmonary infection.

15 Describe the initial antibiotic regimen in a patient with febrile neutropenia who is allergic to penicillin

The majority of patients who report an allergy to penicillin will tolerate cephalosporins and carbapenems. However, in those patients with an immunoglobulin (Ig) E–mediated immediate-type hypersensitivity reaction (hives, bronchospasm), these drug classes should be avoided. In this group of patients, alternative therapeutic options include ciprofloxacin and clindamycin or vancomycin and aztreonam.

16 What are the most common bacterial causes of community-acquired pneumonia in the immunocompromised host?

S. pneumoniae, H. influenzae, or Moraxella catarrhalis are the most common pathogens. In patients with cell-mediated immune defects, legionnaires disease is the most common atypical pathogen. Compared with normal hosts, oral anaerobes as a result of oropharyngeal aspiration, Mycoplasma, and Chlamydia are less-common causes of infection in the compromised host. Pseudomonas aeruginosa, an unusual respiratory pathogen in normal hosts, has been implicated as a cause of community-acquired pneumonia in patients with cystic fibrosis or bronchiectasis and in patients living with AIDS.

17 What is the differential diagnosis for an immunocompromised patient with fever and pulmonary infiltrates?

Respiratory compromise in the immunocompromised host carries with it a significant mortality rate with estimates between 30% and 90%. Although the physician must consider noninfectious causes of pulmonary infiltrates (Box 40-1), infectious causes require early recognition and treatment. The differential is based on understanding of the immune defect and characterization of the radiographic pattern of infiltrate, in conjunction with the timing of onset of symptoms. However, it is vital to recognize that no one radiographic appearance is pathognomonic for a specific infection (Table 40-4).

18 What is the role of bronchoalveolar lavage (BAL) and lung biopsy in the diagnosis of pulmonary infiltrates?

See Figure 40-1.

Figure 40-1 Diagnostic algorithm for evaluating pulmonary infiltrates in ill patients with cancer.

From White P: Evaluation of pulmonary infiltrates in critically ill patients with cancer and marrow transplant. Crit Care Clin 17:647-670, 2001.

19 Describe the clinical course of Pneumocystis carinii pneumonia (PCP) infection and treatment

This organism was first associated with human disease in 1951 when it was discovered as the cause of severe pneumonitis in severely malnourished infants. Since that time, it has been associated with patients taking long-term steroids and those receiving certain chemotherapeutic regimens. However, it became famous as the major pathogen of patients with HIV infection.

Although this infection was linked with HIV infection, the advent of highly active antiretroviral therapy (HAART) has resulted in effective immune reconstitution, as well as effective prophylactic regimens, thus resulting in a decreased susceptibility to infection. However, we see the incidence of this particular infection increasing among those receiving cytotoxic chemotherapy. Interestingly in patients with HIV the clinical course is usually fairly indolent with complaints of several weeks of cough and increasing dyspnea; at the time of presentation the degree of hypoxemia is usually moderate with little to no peripheral leukocytosis. This is in contrast to the population without HIV, in which the infection can present quite acutely with severe hypoxemia and respiratory failure. Chest radiographs often demonstrate bilateral or asymmetric interstitial infiltrates (more common in the population with HIV). See Table 40-5.

^{Table 40-5} Treatment of PCP Infection: Moderate to Severe Disease

PO, Oral; SMX, sulfamethoxazole; TMP, trimethoprim.

^* Some helpful conversions: 16 mg TMP per mL of Bactrim; Bactrim DS = 800 mg TMP/160 mg SMX; Bactrim SS = 400 mg TMP/160 mg SMX.

^† Dosing is based on the TMP component.

Modified from Bartlett JG, Gallant JE, Pham PA: Medical Management of HIV Infection. Durham, N.C., Knowledge Source Solutions, 2009, p 449, and Rubin RH, Young LS: Clinical Approach to Infection in the Compromised Host, 4th ed. New York, Kluwer Academic/Plenum Publishers, 2002, pp 265-289.

20 How is the diagnosis of PCP made?

For all the above, samples should be stained with Giemsa and toluidine blue or silver stain. In addition, immunohistochemical analysis using monoclonal antibody directed against the surface epitope of the organism and cytopathologic analysis that reveals foamy eosinophilic material that fills the alveoli and is fairly characteristic may be helpful.

Serum markers:

21 When are steroids indicated in the treatment of PCP infection?

Steroids are recommended in addition to antibiotic therapy in patients who have a PaO₂ of less than 70 mm Hg on room air arterial blood gas or who have an A – a gradient of > 35 mm Hg. Steroids given in the first 72 hours of treatment can lessen the decreases in oxygenation and improve survival. Steroid dosing should consist of prednisone 40 mg daily (or equivalent) orally for 5 days then decreasing to 20 mg daily to complete a total course of 21 days.

22 What are the most common causes of esophageal disease in those undergoing cytotoxic chemotherapy and BMT?

Esophageal disease from both infectious and noninfectious (i.e., GVHD, chemotherapy-induced mucositis) causes is common in this patient population. The normal mucosal barrier is often disrupted by chemotherapeutic agents, and this mucosal disruption can then become a portal of entry for bacteria. Most patients with esophageal disease are initially seen with dysphagia, odynophagia, nausea, or retrosternal pain.

The most common causes of esophageal infection in this patient population are as follows:

HSV: often presents with oropharyngeal ulcers, which can be quite friable and lead to gastrointestinal (GI) bleeding. The infection can have white exudates and is often mistaken for Candida. The ulcer appearance is not pathognomonic, has similar appearance to that of chemotherapy-induced mucositis, and is best diagnosed by culture or direct fluorescent antibody test of the lesions. Oral trauma from nasogastric (NG) tubes or endotracheal tubes can lead to extension of infection from oral pharynx into lower respiratory tract. This can lead to dissemination and, in certain patients, development of HSV pneumonia.

Candidal esophagitis: most common cause of esophageal infections in compromised hosts. Classic manifestation is thick white plaques adherent to the posterior pharynx and buccal mucosa. Widespread use of azoles for prophylaxis has increased the risk of fluconazole-resistant candidal species.

CMV: can cause infection throughout the entire GI tract. The ulcers do not have a unique appearance and may resemble those of HSV or chemotherapy-induced mucositis. Cultures should be interpreted with caution because trauma and underlying illness may lead to mucosal shedding; biopsy samples of oral and esophageal lesions should be taken for clear diagnosis.

23 What is typhlitis, and how is it treated?

Typhlitis, also known as neutropenic enterocolitis, is thought to ensue after a constellation of factors including mucosal injury of the bowel wall due to cytotoxic chemotherapy, impaired host defenses, and neutropenia. It is typically seen in patients with neutrophil counts less than 500/mm³; those affected often have abdominal pain, fever, nausea, diarrhea, and bloody diarrhea. The diagnosis carries a mortality rate of between 40% and 50%. Concomitant bacteremia, due to normal bowel flora, is common.

The disease has a predilection for the cecum because of its relative lack of vascularization compared with the remainder of the colon; however, other sites of bowel involvement have been described. Radiographs of the abdomen are usually nonspecific, although they may demonstrate evidence of obstruction or free air. CT scans may reveal cecal wall thickening, pneumatosis, free air, or abscess formation. The use of rectal contrast or barium enemas should be avoided in patients with neutropenia because of the high risk of bowel wall perforation. Work-up should include abdominal radiographs, CT scan of abdomen without rectal contrast, blood cultures, stool cultures including stool for Clostridium difficile testing, and surgical evaluation.

Treatment includes IV volume resuscitation and broad-spectrum antibiotic therapy (see Box 40-2).

24 Describe some of the common causes of community-acquired bacterial enteritis in the immunocompromised patient

Patients with compromised immune systems are at risk for development of the same community infections as normal hosts, but they may be more severe. In addition, because of low neutrophil counts or loss of mucosal integrity they may be more prone to development of bacteremia from their own endogenous bowel flora. Some of these infections can lead to dissemination outside the GI tract and lead to more severe disease in immunocompromised hosts.

Listeria. The common food-borne illness caused by this organism leads to outbreaks in immunocompromised and normal hosts alike. However, dissemination outside of the GI tract is increased in those with chronic lymphocytic leukemia, corticosteroid use, allogenic BMT, and pregnancy. Certain chemotherapeutic drugs such as fludarabine will increase this risk as well.

Salmonella. This is associated with a deficiency in cell-mediated immunity such as corticosteroid use and HIV infection. These hosts are at risk for disseminated Salmonella infection.

C. difficile.C. difficile has been associated with a higher mortality risk among BMT recipients compared with a normal host. Increased rates of infection among immunocompromised patients are likely due to frequent antibiotic therapy, increased rates of colonization, and frequent hospital admissions.

25 Describe the most common causes of viral enteritis in the immunocompromised patient

26 What is the best approach to manage HAART therapy for patients with HIV in the ICU?

In patients with HIV receiving HAART the therapy should be continued whenever possible to prevent the development of resistance. This may not be possible in some patients when HAART complications such as renal failure and/or liver disease are complicating the patients’ clinical course. Administering HAART to patients who take nothing by mouth can be complicated because some of the medications cannot be crushed for administration through an NG tube, and not all of them are available in liquid form. If HAART medications do need to be stopped it is essential that all HAART be held at the same time. Discontinuation of only part of a patient’s HAART regimen can lead to antiviral resistance and ensuing treatment complications down the road.

27 Should antirejection medications be altered for the solid organ transplant recipient with severe sepsis?

In patients with life-threatening infections, withdrawal or reduction of immunosuppressive medications can be an effective treatment modality to assist in the reduction of immunosuppression. However, cessation of antirejection medications can lead to graft rejection and failure, and so changes in medications need to be considered on an individual basis. These decisions regarding medication adjustments should be carried out with the close assistance of the transplant team whenever possible.

Important facts to consider when considering reduction of immunosuppression: