Infections

I. DERANGEMENT OF IMMUNE FUNCTION IN UREMIA

A. Etiology. In dialysis patients, there is impairment of several aspects of lymphocyte and granulocyte function. Unidentified uremic toxins are thought to be responsible; malnutrition or vitamin D deficiency can sometimes be contributory factors.

B. Clinical implications

1. Increased susceptibility to infection

a. Frequency of bacterial infections. Bacterial infections occur more often in dialysis patients than in their nonuremic counterparts; the increase is probably related more to frequent violation of normal skin and mucosal barriers than to immune system dysfunction.

b. Severity of bacterial infections. Owing to the presence of a vascular access, infections in hemodialysis patients are often associated with bacteremia, and there is a substantial risk of serious complications such as endocarditis, osteomyelitis, and epidural abscess. Use of a hemodialysis catheter is associated with a threefold increase in hospitalization and death from septic complications as compared with use of a native or graft fistula. In peritoneal dialysis patients, peritonitis is rarely associated with systemic infection.

c. Role of hemodialysis membrane or peritoneal dialysis solution. Some of the immune defects previously attributed to uremia may be due, in part, to periodic exposure of the blood to certain dialysis membranes or to lack of removal of putative inhibitors of immune function by low-flux membranes. However, in the HEMO study, infection-related deaths were not reduced by utilization of biocompatible, high-flux dialyzers (Allon, 2004). In peritoneal dialysis patients, peritoneal neutrophil function is depressed owing to removal of opsonins (immunoglobulin and complement) in the dialysate and to regular exposure to low pH, high osmolality, and glucose degradation products present in some dialysis solutions.

II. DERANGEMENT OF TEMPERATURE CONTROL IN UREMIA

A. Baseline hypothermia in uremic patients. In about 50% of hemodialysis patients, the predialysis body temperature is subnormal. The reason for this is unknown.

B. Reduced pyrexic response associated with infections. Uremia per se does not appear to affect the temperature response to pyrogens. In addition, the degree of interleukin-1 (IL-1) production by stimulated uremic monocytes is normal. However, because of baseline hypothermia, and possibly because of frequently coexisting malnutrition, severe infections in some dialysis patients may be associated with an attenuated or absent fever response.

III. BACTERIAL INFECTIONS IN DIALYSIS PATIENTS

A. Related to the access site

1. Hemodialysis patients. Prevention, diagnosis, and treatment of vascular access infections are described in Chapters 9 (venous catheters) and 8 (fistulas and grafts). Several additional clinical points are emphasized here.

a. Bacteremia versus pyrogen reaction. The dialysis patient with bacteremia generally presents with chills and fever and may appear quite toxic. On occasion, however, symptoms and signs of infection are remarkably few or absent. Although redness, tenderness, or exudate at the access site may help to incriminate it as the source of the infection, in many cases an infected access site can appear normal. Delayed treatment of sepsis in dialysis patients is an important cause of morbidity and mortality. In general, patients with venous hemodialysis catheters and fever should be assumed to have catheter-related bacteremia and treated with broad-spectrum antibiotics pending results of blood cultures.

1. Pyrogen reaction. Low-grade fever during hemodialysis may be related to pyrogens present in the dialysis solution rather than to actual infection. The time course of fever may be somewhat helpful in making the distinction between pyrogen reaction and infection: Patients with pyrogen-related fever are afebrile prior to dialysis but become febrile during dialysis; fever resolves spontaneously after cessation of dialysis. Patients with access site–related bacteremia are often febrile prior to institution of dialysis and, in the absence of treatment, fever persists during and after dialysis. There is one exception to the rule: Fever and chills that occur shortly after catheter manipulation (for instance, commencement or cessation of dialysis) suggests catheter-associated bacteremia. Use of high-flux dialysis (especially in conjunction with bicarbonate dialysate) and dialyzer reuse are associated with an increased incidence of pyrogenic reactions. Blood cultures should always be obtained in any febrile hemodialysis patient, even when a pyrogen reaction is the suspected cause of the fever and, in most cases, antibiotics should be administered until infection is excluded.

2. Contamination of hemodialysis machines or solutions. Occasionally, bacteremia may result from contamination of hemodialysis machines. These are generally gram-negative and occasionally fungal infections. Outbreaks of such infections have been caused by inadequate disinfection of water treatment or distribution systems or reprocessed dialyzers (Rao, 2009). Contamination of the waste drain ports of the hemodialysis machine has also been described.

b. Prophylactic antimicrobial administration

1. Prophylaxis prior to an invasive procedure likely to result in bacteremia. Although there is no definite evidence in the literature, it is our policy to administer antimicrobial prophylaxis to hemodialysis patients prior to invasive procedures associated with a substantial risk of bacteremia because of the abnormal vascular communication present. These include dental procedures (especially extractions); gastrointestinal (GI) procedures such as esophageal stricture dilation, sclerotherapy for esophageal varices, and endoscopic retrograde cholangiography with biliary obstruction (not necessary for routine endoscopy with or without biopsy); and genitourinary procedures including cystoscopy, urethral dilation, and transurethral prostate resection. The recommended antimicrobial is amoxicillin 2.0 g given 1 hour before the procedure (or ampicillin 2.0 g IM or IV given 30 minutes before the procedure). In penicillin-allergic patients, either clindamycin 600 mg by mouth or IV (dental or esophageal procedures) or vancomycin 1.0 g IV (other GI and genitourinary procedures) can be substituted.

2. Long-term, continuous prophylaxis. The skin and nasal carriage rate of Staphylococcus aureus in hemodialysis patients is about 50%. Intranasal mupirocin ointment is effective in eradicating the carrier state and in uncontrolled studies has decreased the incidence of staphylococcal infection. Decision analysis suggests that weekly use of this agent in all patients without screening will decrease infection rates and is cost effective (Bloom, 1996). However, a major concern is the development of mupirocin resistance with chronic use. In general, there is insufficient evidence to support routine Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA) decolonization.
On the other hand, a reduction in catheter-related bacteremia has been demonstrated by use of prophylactic topical antimicrobial ointments at the catheter exit site, the use of prophylactic catheter locking solutions, fastidious catheter care, and the use of vascular access managers and quality initiative programs (Lok and Mokrzycki, 2011). Their use is particularly beneficial in patients who have nasal carriage of Staphylococcus aureus. Dry gauze dressings rather than transparent film dressings are recommended because transparent film dressings pose a greater threat of exit site colonization (Conly, 1989). A surgical mask worn by the patient and nurse any time the catheter is accessed reduces the spread of infectious droplets and reduces contamination of the catheter site.

c. Vancomycin-resistant gram-positive infections. Concern about an increasing prevalence of vancomycin-resistant enterococci (VRE) in hospitalized patients has resulted in recommendations that vancomycin use be restricted in dialysis patients. Because of the relatively high incidence of staphylococcal organisms resistant to antistaphylococcal penicillins and cephalosporins, it is currently our policy to utilize vancomycin as initial therapy of life-threatening suspected S. aureus infections (e.g., catheter-related bacteremia). If sensitivity results warrant, vancomycin can be discontinued in several days, and prolonged treatment with an alternative antibiotic can then be employed. Certain cephalosporins (e.g., cefazolin) have a very prolonged half-life in end-stage kidney disease (ESKD) patients and can be dosed conveniently postdialysis.

2. Peritoneal dialysis patients.

a. Antimicrobial prophylaxis. In the absence of other indications for prophylaxis, we do not routinely administer antibiotics prior to invasive procedures unless a vascular access is present. Long-term, continuous prophylaxis is discussed in Chapter 27.

B. Unrelated to the access site

1. Urinary tract infection (UTI). In dialysis patients, the incidence of UTI is high, especially in patients with polycystic kidney disease.

a. Clinical presentation. In oliguric patients, the symptoms of cystitis are similar to those in nonuremic individuals, although gross hematuria is unusually common and occurs in up to one-third of cases. Anuric patients may present with suprapubic discomfort or foul-smelling urethral discharge and progress to pyocystis (see below).

b. Diagnosis. Voided urine samples from oliguric patients, even from those voiding only a few milliliters per day, are usually sufficient for diagnosis. Urethral catheterization and bladder lavage may cause infection and should be reserved for the symptomatic anuric patient. The presence of pyuria is not a useful finding to rule in or rule out infection. Absence of visible bacteria does not rule out UTI. A urine culture is essential to make the diagnosis. As in nonuremic patients, a colony count greater than 10³ in a properly collected urine specimen is considered to be suggestive of infection, but there are no good studies in dialysis patients.

c. Treatment. Optimally, antimicrobial therapy should be based on sensitivity testing of the organism involved. If empirical therapy is warranted, penicillin, ampicillin, cephalexin, a fluoroquinolone, or trimethoprim should be used because they are safe and may attain adequate urine levels in ESKD patients. Male patients from susceptible populations (Asian and Mediterranean) should be tested for glucose-6-phosphatase deficiency before receiving trimethoprim–sulfamethoxazole. In female dialysis patients, trimethoprim–sulfamethoxazole is generally chosen over ampicillin for treatment of recurrent UTIs; trimethoprim–sulfamethoxazole is less likely to be associated with the emergence of resistant organisms in the fecal flora, the source of most urinary pathogens in women.

The most appropriate treatment schedule for dialysis patients with cystitis has not been well studied. A urine culture should be repeated on the third or fourth day of treatment documenting that the urine shows no growth, and therapy should be continued for a total of 5–7 days. Ten days of antimicrobial therapy is warranted in patients with adult polycystic kidney disease because of their increased susceptibility to pyogenic complications of UTIs. A follow-up urine culture should be obtained 7–10 days after completing therapy.

It is difficult to achieve adequate urinary drug levels of ticarcillin, doxycycline, sulfisoxazole, and the aminoglycosides in dialysis patients; hence, these agents are not recommended for treatment of cystitis. However, when the responsible urinary pathogen is resistant to trimethoprim–sulfamethoxazole, cephalexin, fluoroquinolones, and the penicillins, one of these alternative drugs can be employed if its use is supported by the results of bacterial sensitivity. The use of nalidixic acid, nitrofurantoin, tetracycline, or methenamine mandelate is generally contraindicated in anuric patients due to the prolonged half-lives of these agents and the accumulation of toxic metabolites.

If repeated culture and sensitivity testing show bacterial resistance, the antimicrobial therapy should be adjusted. If the original infecting organism is still sensitive to the initial therapy, the dosage should be increased if possible or intravesical antimicrobial therapy should be administered. If a source of bacteria, such as a staghorn calculus, is identified, it must be removed to cure the UTI permanently. Bacterial persistence is a recurrent infection from a source within the urinary tract. It is suspected if infections with the same bacteria return immediately after treatment is completed. Causes include infected cysts, infection stones (e.g., staghorn calculus), and bacterial prostatitis. Reinfection is a recurrent infection caused by the same or different species of bacteria entering the urinary tract at varied intervals. Reinfection is not usually due to an identifiable anatomic lesion but rather to reintroduction of bacteria from a source outside the urinary tract, most frequently the rectal flora. Vesicoenteric and vaginal fistulas are rare causes of reinfection.

All patients with recurrent infection should be evaluated for residual urine and urethral stenosis, urethral stricture, or bladder outlet obstruction. A renal ultrasonographic study and plain film tomograms of the kidney should be obtained in dialysis patients with possible bacterial persistence. Computed tomography (CT) with and without contrast infusion may be used if ultrasonographic findings are indeterminate. Cystoscopy is recommended if hematuria occurs or to help rule out enterovesical fistula in patients with pneumaturia. Ureteral catheter localization studies should also be performed if bacterial persistence is suspected. Patients found to have a congenital or acquired anatomic abnormality responsible for their infections should have the defect removed surgically. The safety of long-term antimicrobial prophylaxis in dialysis patients with frequent urinary bladder reinfections is not known. Low-dose trimethoprim–sulfamethoxazole and cephalexin would probably be the safest drugs to use.

d. Upper urinary tract infections and pyogenic complications. Upper tract infections in dialysis patients occur most commonly as a result of retrograde ascent of urinary pathogens in the urinary tract. Rarely, acute pyelonephritis occurs in dialysis patients from a hematogenic route. Patients with cystic kidneys and especially those with adult polycystic disease are particularly susceptible to upper tract infection and its complications. Infected cysts, pyonephrosis, and renal and perirenal abscesses may develop.

A patient with an infected cyst or renal or perirenal abscess usually presents with dysuria, recurrent UTIs, fever, night sweats, abdominal or flank pain, or sepsis. Occasionally, the patient may be asymptomatic. A tender, tense mass may be palpable in the flank or abdomen. With systemic symptoms, these patients may develop dehydration due to poor fluid and food intake, sweating, and fever.

Leukocytosis is commonly present. Urine culture will identify the responsible organism if the parenchymal infection communicates with the collecting system. However, culture results can be negative when an infected cyst does not communicate with the urinary tract, or when there is pyonephrosis due to a cyst or stone that completely obstructs the ureter. Ultrasonography or CT may identify infected cysts and provide a point of reference for determining response to antimicrobial therapy. The use of indium-111 (¹¹¹In) leukocyte imaging and gallium-67 (⁶⁷Ga) citrate single photon emission computed tomography (SPECT) transaxial imaging in localizing infected cysts has been described and may be considered when findings from ultrasonography or CT are inconclusive.

In patients with cystic kidneys, antimicrobial therapy of upper tract infection should be continued for at least 3 weeks. Many antimicrobials penetrate renal cysts poorly, and the degree of antimicrobial penetration depends on whether the cysts are derived from the proximal tubule or the distal nephron. Lipid-soluble trimethoprim, ciprofloxacin, metronidazole, clindamycin, erythromycin, and doxycycline have been shown to achieve good bactericidal levels in the fluids of both types of cysts, and should be good treatment selections, depending on the suspected organism. Ciprofloxacin has been shown to sterilize infected cysts in some patients. Non–lipid-soluble antimicrobials, such as the aminoglycosides, the third-generation cephalosporins, and the penicillins, have generally failed to cure infections in polycystic kidneys, presumably because of their poor penetration into cysts derived from the distal nephron.

Patients with adult polycystic kidneys with bacterial persistence localizing to one side (as documented by ureteral catheter localization studies) should have the source of infection removed surgically. Pyonephrosis and renal and perirenal abscesses cannot be cured by antimicrobial therapy alone, and require immediate and definitive surgical intervention. Percutaneous drainage of an infected cyst under radiographic imaging may be appropriate in medically unstable patients, but surgical intervention currently remains the procedure of choice for most localized abscesses. Laparoscopic unroofing of a clearly identifiable infected cyst may be considered. Nephrectomy is indicated only when an infected cyst is unresponsive to antimicrobial therapy or cyst drainage. Delay in nephrectomy is associated with increased morbidity and mortality.

e. Pyocystis. In patients with a neurogenic bladder (e.g., diabetic patients), pyocystis (pus in the defunctionalized bladder) may be an unsuspected source of infection. Pyocystis should always be suspected in an anuric dialysis patient with fever of unknown origin. Symptoms can include suprapubic or abdominal pain, foul-smelling urethral discharge, or sepsis. Suprapubic tenderness and a distended bladder may be found on careful examination. A complete peripheral blood count often shows leukocytosis. Blood cultures may or may not be positive. Bladder catheterization reveals pus, culture of which usually grows a mixed flora. Treatment consists of adequate drainage via an indwelling urethral catheter, followed by intermittent catheterization and bladder irrigations with antimicrobial solutions until the infection clears. Parenteral antimicrobials, chosen according to culture and sensitivity reports, should be administered if systemic manifestations are present. Cystourethroscopy and possibly cystometrography should be performed to rule out a bladder outlet obstruction, a large bladder diverticulum, or a neurogenic bladder. Rarely, surgical drainage procedures or even simple cystectomy may be needed in refractory cases.

2. Pneumonia. Pneumonia is an important cause of mortality in this population; the possibility of gram-negative infection should be considered in patients dialyzed in a hospital setting. Dialysis patients may have unusual pulmonary infiltrates due to pulmonary calcification (now uncommon), which can resemble those due to pneumonia. Fluid overload sometimes can be mistaken for pneumonia, and should be suspected, especially when there are bilateral pulmonary infiltrates; such infiltrates can frequently improve after an increase in ultrafiltration. Pleural effusions are commonly exudative in character owing to uremia-associated inflammation, even in the absence of infection.

3. Intra-abdominal infections. Diverticulosis and diverticulitis occur commonly in dialysis patients, and especially in those with polycystic kidney disease. Strangulated hernia is also frequently encountered. In peritoneal dialysis patients, the differentiation between dialysis-associated peritonitis and peritonitis due to a disease process involving the abdominal viscera can be difficult (see Chapter 27). Acalculous cholecystitis has been reported. Intestinal infarction can occur as a complication of hypotension occurring during a dialysis session or between dialyses; bowel infarction should always be suspected in a dialysis patient with unexplained, refractory septic shock.

4. Tuberculosis. The incidence of tuberculosis has been estimated to be as much as tenfold higher among hemodialysis patients than among the general population. Tuberculosis in hemodialysis patients is frequently extrapulmonary; disseminated disease may occur in the absence of chest x-ray abnormalities. Difficulty in making the diagnosis is increased because delayed skin hypersensitivity to tuberculin reagent is often absent or diminished due to cutaneous anergy. New immunologic tests using interferon-gamma release assays have shown promise in ESKD patients (Segall and Kovic, 2010; Grant, 2012). A number of subtle, atypical presentations of tuberculosis can be encountered; for instance, patients may present with ascites and intermittent fever only, or with hepatomegaly, weight loss, and anorexia. The diagnosis of tuberculosis in extrapulmonary cases is usually made by demonstrating typical caseating granulomas on pleural or hepatic biopsy or by recovery of tubercle bacilli from culture of biopsy material. When the index of suspicion for tuberculosis is high, presumptive therapy with antitubercular agents is sometimes warranted. Mortality in dialysis patients with tuberculosis has been reported to be as high as 40%.

5. Listeriosis. Listeriosis, an unusual infection in the nonimmunocompromised host, has been reported to occur in hemodialysis patients suffering from iron overload.

6. Salmonella septicemia. In dialysis patients, severe Salmonella septicemia has been noted to occur; in nonuremic patients, Salmonella enteritis rarely progresses to sepsis.

7. Yersinia septicemia. This infection has been reported in iron-loaded dialysis patients receiving deferoxamine chelation therapy.

8. Mucormycosis. This sometimes fatal infection is seen with unusual frequency in patients being treated with deferoxamine.

9. Helicobacter pylori. Although patients with ESKD frequently have upper GI complications, the prevalence of this infection appears to be the same in ESKD patients as in patients with normal renal function. Therapy is similar to that for nonuremic patients.

IV. VIRAL INFECTIONS

A. Hepatitis A. The incidence of hepatitis A in dialysis patients is no greater than in the general population, given that transmission is usually by the fecal–oral route. The disease pursues the usual clinical course in dialysis patients. Chronic hepatitis after hepatitis A infection is believed to occur rarely, if at all.

B. Hepatitis B

1. Epidemiology

a. Hemodialysis patients. The incidence of infection with hepatitis B virus (HBV) is now quite low in the United States. (Finelli, 2005). The low incidence is due to screening of the blood supply for evidence of this infection and to low transfusion requirements due to the availability of erythropoietin. However, outbreaks of hepatitis B in several hemodialysis units have occurred. Hepatitis B vaccine should be administered to all susceptible hemodialysis patients. Of note, only 50%–60% of vaccinated hemodialysis patients develop a protective antibody response; optimal vaccination techniques are discussed below.

b. Peritoneal dialysis patients. This group is at very low risk of acquiring hepatitis B infection. Nevertheless, hepatitis B can be transmitted through exposure to peritoneal effluent.

2. Clinical presentation. Hepatitis B infection is largely asymptomatic in dialysis patients. Commonly, malaise is the only complaint. The occurrence of visible jaundice is rare. The only manifestation of infection may be an unexplained, mild (two- to threefold) elevation in the serum aspartate (AST) or alanine aminotransferase (ALT) level, or even an increase from a lower to a higher level within the normal range. The serum bilirubin and alkaline phosphatase concentrations may remain normal or be elevated only slightly.

3. Chronic hepatitis B infection. Hepatitis B infection in dialysis patients often runs a protracted course and in 50% of cases progresses to a chronic, HbsAg-positive state. Development of clinically important persistent (or active) hepatitis is not nearly as common as it is in nondialysis patients. Patients with high serum ferritin levels appear to be at increased risk for developing persistent hepatitis. Treatment is indicated in HBsAg-positive patients with evidence of viral replication and abnormal transaminase levels, preferably in conjunction with liver histology. A level of 4 to 5 log₁₀ copies/mL for HBV DNA is usually taken as the threshold to start treatment. It is important to recognize that hepatitis B e antigen (HBeAg) can be negative despite active disease. Interferon, lamivudine, adefovir, or entecavir can be utilized for the treatment of chronic hepatitis B. Entecavir is the recommended first-line therapy in dialysis patients. The doses of all antiviral medications must be adjusted appropriately according to renal function. The dosing for lamivudine, adefovir, and entecavir are 100 mg by mouth daily, 10 mg by mouth daily, and 0.05 mg by mouth daily, respectively. In view of the side effects of interferon in patients on dialysis, nucleotide or nucleoside analogs are better choices.

4. Routine screening. Hemodialysis patients should be screened for HBV surface antigen (HBsAg), surface antibody (anti-HBs) and core antibody (anti-HBc) on admission to the dialysis unit (or hospital). HBsAg should then be tested monthly in all HBV-susceptible patients, including nonresponders to the vaccine, and anti-HBs with antibody titer measured annually. Testing for HBV DNA should be done if HBsAg is positive, and may be indicated in patients who are positive for anti-HBc but negative for HBsAg and anti-HBs as such patients can occasionally be infectious.

5. Prevention

a. Restricting the possibility of exposure to the virus. Epidemiologic principles can be utilized to decrease the risk of hepatitis B infection, both among patients and among dialysis staff. Table 35.1 lists some helpful precautions. Some centers recommend that patients with hepatitis B antigenemia be treated with either home hemodialysis or home peritoneal dialysis in order to decrease the chance of transmission to other patients and staff.