infection in bone marrow transplant recipients · regardless of the conditioning regimen in use, an...

Infection in Bone Marrow Transplant Recipients

JOEL D. MEYERS, M.D. Seaffle, Washington

From the Program in Infectious Diseases, Fred Hutchinson Cancer Research Center, and the Uni- versity of Washington School of Medicine, Seaffle, Washington. This work was supported by grants from the National Cancer Instttute, Department of Health and Human Services (CA-18029, CA- 30924, and CA-15704). Requests for reprints, should be addressed to Dr. Joel D. Meyers, Fred Hutchinson Cancer Research Center, 1124 Colum- bia Street, Seattle, Washington 98104.

infection in marrow transplant recipients is determined primarily by the evolving immunologic milieu of each patient. Profound neutro- psnia and disruption of anatomic barriers are the most important risk faqors for bacterial and fungai infections in the initial period after transplant. After this period, the occurrences of acute and then chronic grafl-versus-host disease (GVHD) are the most important influences on the risk of infection. Major infections after the period of init!ai engrqftment include viral infections (especially cytomegalovirus), fungai infections (due to Aspctrgiiius and Candida), and rarely protozoai infections. GVHD appears to in&a- both the incidence and severity of cytomegaiovirus infection. Bacterial jnfec- tions also coqtipue to occur, due predominantly to coaguiase- negative Staphylococcus, as in the neutropenic perigd. Patients with chronic GVHD have continued abnormalities of host defenses, which may be further suppressed by treatment for GVHD. Major efforts have been directed toward preveyting infection. !n the neutropenic period, these include use of the protective environment, which has also $een asseciat+ with a lower incidence of acute GVHD among patients who reqeived transpian$ for apiastic anemia. The uqe of seronegative blood prpducts is highly effective in preventing primary cytomega!ovirus infection among seronegative’ patients. Among patients being treated for chronic GVHD, trimethoprim/suifamethoxazoie prophylaxis has been asso@ated with 8 lower risk of infection.

Infection in marrow transplant rec/pients is determined by multiple factors, including the underlying iflness and previous treatment of the patient, the conditioning regimen, the occurrence of graft-versus-host disease (GVHD) after transplant, and the epidemiologic milieu of the patient and the transplant unit. Loss and reconstitution of immunity are issues central to marrow transplantation. The conditioning regimens used to pre- pare patients for allogeneic (non-twin) transplant are intended to ablate host immunity to permit engraftment of the marrow. This is conceptually different from renal or cardiac transplantation in which host immunity is suppressed, but not destroyed. The marrow infusion itself contains both hematopoietic and immunologic precursors, and the immune system of the marrow donor is “transplanted” along with the bone marrow. An additional purpose of the conditioning regimen among patients undergoing transplantation for malignancy is eradication of the cancer. Thus, these patients are conditioned with regimens that include total body irradiation or additional cytotoxic agents. in contrast, patients undergoing transplantation for apiastic anemia usually receive only high-dose cyclophospha-

July 28,1988 The Amsrlcsn Journal of Madlclne Volume 81 (suppl 1A) 27

SYMPOSIUM ON PROBLEM INFECTIONS-MEYERS

Figure i. Predisposing risk factors and common infections by time after marrow transplant. Reproduced from Meyers JD: Infections in marrow recipients. In: &Ian- dell GL, et al, eds. Principles and prac- tice of infectious diseases. New York:, Wiley, 1984.

PNEUMONIA BACTERIAL NONBACTERIAL (INTERSTITIAL) b

VIRAL HSV CMV vzv

ENCAPSULATED + --------

RlSK FACTOR vq /ACUTE GVHD + ~~ 1 ICHRONIC GVHD --- l I I I 1

0 50 100 12

T DAYS AFTER TRANSPLANT MONTHS marrow infusion

mide for conditioning. The differing toxicities and immunologic effects of these regimens also contribute to the risk of infection.

After transplant, various immunosuppressive regimens have been given to prevent the occurrence of acute GVHD. In recent yeara, cyclosporine has gained wide- spread acceptance for this purpose [l]. Previously, methotrexate was used most commonly, and regimens con- taining both cyclosporine and methotrexate are currently being studied. An alternative approach to the prevention of GVHD involves the depletion of mature T-cells in the infused marrow by using monoclonal antibody and com- plement treatment of the marrow in vitro before infusion [2]. This continues to show promise as a highly effective means of preventing the occurrence of GVHD, although T-cell depletion has the potential complications of a longer period of neutropenia until engraftment (see later) and a higher rate of failure to engraft.

There are exceptions to th/s general situation. Patients with profound immune suppression before transplant, such as those with combined immunodeficiency syndromes, may require less intensive conditioning regimens, whereas patients in whom GVHD cannot develop, such as those receiving syngeneic (twin) transplants, may not require post-transplant immunosuppression. These variants will be addressed subsequently as they relate to the spectrum and risk of infection. However, other details of the multiple conditioning regimens in use at this time will not be addressed.

SEQUENCE OF RISK FACTOfiS FOR INFECTION

Regardless of the conditioning regimen in use, an initial period of profound neutropenia invariably develops in marrow transplant recipients, during which time the recipients resemble patients undergoing induction therapy for acute leukemia. The duration of severe neutropenia is in- fluenced by the regimen used for preventing acute GVHD.

For example, patients who receive methotrexate have a significantly longer period of neutropenia compared with patients who receive only cyclosporine, in whom the median period of severe neutropenia (absolute circulating granulocyte count of less than 1,000/mm3) is approximately 18 days [l]. As alluded to earlier, patients receiving T-cell-depleted marrow, as well as those receiving autologous marrow transplants, may have longer periods of neutropenia [2,3]. Patients in whom engraftinent fails or rejection occurs also have prolonged periods of severe neutropenia, and will generally die of infectious complications unless a second transplant can be performed.

The other major risk factor during this early period is disruption of mucosal barriers due to the toxicity of conditioning. This is most obvious in the oropharynx (“oral mucositis”), but presumably the gastrointestinal mucosa is damaged as well, as evidenced by the frequent occurrence of dysphagia or odynophagia and diarrhea. More intensive conditioning regimens are associated with more severe mucosal disruption. Patients who receive methotrexate after transplant appear to have more severe and prolonged oral mucositis as well. Anatomic barriers are also interrupted by the long-term indwelling central venous catheters that are now in universal use.

Even after recovery of the circulating neutrophil count, function is not normal [4,5]. A similar situation exists with regard to the resident macrophages, such as those in the lung [8]. Nevertheless, the initial period of risk of bacterial and fungal infection resolves as the neutrophil count increases. Thereafter, the infectious experience of each patient is determined by the pace of reconstitution of the immune system, presuming that other events such as graft rejection do not supervene.

Many studies have been conducted of the various com- ponents of the immune response and the kinetics of their recovery after marrow transplant. Antigen-specific responses, such as T-cell responses to various viral anti-

28 July 28,lSM The American Journal of Mediclne~ Volume 81 (suppl 1A)

gens or antibody production to bacterial antigens such as pneumococcal polysaccharide, usually take longer to re- cover. Some of these responses, such as T-cell proliferation to herpesvirus antigens, have been shown to require antigenic re-exposure in the form of active infection [7], although even recurrent pneumococcal infection may not be sufficient to elicit specific antibody production in some patients [8]. In contrast, nonspecific responses such as lymphocyte proliferation to mitogenic stimulation [7], natural cytotoxic responses to tumor cell targets [9], or total immunoglobulin levels [lo] may become normal within the first several months after transplant.

The major event that influences the course of immunologic reconstitution after allogeneic marrow transplant, and thus the risk of infection, is the occurrence of acute and later chronic GVHD and its treatment. The mechanisms by which GVHD predisposes to infection are not entirely clear. The syndrome of acute GVHD may include ulceration of the gastrointestinal tract, with the attendant risk of bacterial infection through the gut wall as well as local infections such as esophageal candidiasis. Patients with acute GVHD have been found to have abnormalities of granulocyte function as another possible factor predisposing to infection [4]. Treatment of acute GVHD with immunosuppressive agents such as corticosteroids and especially with antithymocyte globulin may further increase this risk. Patients with either acute or chronic GVHD have been found to have nonspecific suppressor cells that reduce both specific T-cell function and immunoglobulin production [l l-131. After the period of initial neutropenia, the occurrence of acute and then chronic GVHD are clearly the most important events influencing the risk of infection.

SEQUENCE OF INFECTIONS

This sequence of risk factors determines the general sequence of infections after marrow transplant (Figure 1). The initial period of profound neutropenia is characterized by bacterial infections (predominantly bacteremia), some candidal infections, and also herpes simplex virus (HSV) infection. The latter occurrence appears to be related to the ease with which HSV reactivates during any immunosuppressive stress. The incidence of such reactivation among seropositive patients (usually 70 to 80 percent) is similar among those undergoing leukemic induction therapy [14], renal transplantation [15], or marrow transplantation [7]. Oropharyngeal HSV infection occurring during the initial period of neutropenia may cause severe local disease, predispose to secondary bacterial infection [16], and occasionally cause severe disease of other organs, including HSV esophagitis [17] or HSV pneumonia [18]. Use of acyclovir for both treatment [19] and prophylaxis [20,21] has substantially reduced the clinical significance of HSV infection in the early period after transplant, although later cases of oral or genital mucocutaneous HSV infection or HSV esophagitis may still occur.


All of the risk factors associated with invasive candidal infection are not defined. However, persistent neutropenia as occurs among patients with delayed engraftment or graft rejection or who had severe neutropenia before transplant (e.g., patients with severe aplastic anemia) has been associated with a higher incidence of invasive fungal infection [22]. The significance of detectable candidal colonization remains controversial. However, colonization of several anatomic sites or persistent colonization of the oropharynx or gastrointestinal tract has been related to subsequent invasive infection in some studies [22,23]. As in other immunocompromised patients, those with candi- demia represent only a minority of all patients with invasive candidal infection, and fungemia is an insensitive in- dicator of serious fungal disease. In recent years, the syndrome of focal hepatic (and splenic) candidiasis [24] has been increasingly recognized, although whether this is a true increase or merely reflects the increasing number of marrow transplant recipients is unknown. Amphotericin B remains the drug of choice for treatment of proved invasive fungal infection, despite potential problems with nephrotoxicity when given to patients who are also receiving cyclosporine.

The most common proved infection during the neutropenic period is bacteremia. Fever is an invariable accompaniment of bacteremia (and of the neutropenic period in general), whereas hypotension occurs in only a minority of patients. The spectrum of organisms causing bacteremia during this period is similar to that observed in other groups of neutropenic patients, and consists primarily of coagulase-negative Staphylococcus and Enterobacteria- ceae (Table I). The high incidence of coagulase-negative staphylococcal infection has been related to the universal use of long-term indwelling central venous catheters in some [25], although not all [26], studies. The observation that the risk of bacteremia in marrow transplant recipients remains constant for as long as the catheter is in place, and especially that it does not decrease when the neutropenic period ends (271, would appear to suggest a patho- genic role for the central venous catheter. Treatment of most bacteremias is accomplished without removal of the line [27,28]. However, infections due to Staphylococcus aureus, coagulase-negative Staphylococcus, JK dipther- oid, or Candida species may be difficult to cure without removing the catheter. Moreover, infections of the exit site or persistent bacteremia with organisms known to colo- nize plastic catheters (e.g., coagulase-negative Staphylo- coccus) should be considered specific indications for catheter removal. Major efforts addressed to the prevention of bacterial and fungal infections during this initial period are discussed in the next section. Infections after Initial Marrow Engraftment. The major infections that occur after the period of initial engraftment include viral infections (especially those due to DNA viruses such as cytomegalovirus or adenovirus), fungal infections, and protozoa1 infections (Figure 1). In past years,

July 28, 1996 The American Journal of Medicine Volume 91 (suppl 1A) 29


TABLE I Spectrum of Organisms Causing Bacteremia after Marrow Transplant

Before Alter Engraftment Enpraftmeaf

Staphylococcus (coagulase-negative) 11 14 Staphylococcus (coagulase-positive) 2 4 Cotynebacterium species 2 3 Streptococcus viridans 4 2 Other gram-positive species 9 5 Total gram-positive species 28 (57%) 28 (64%)

Enterobacteriaceae 11 9 Pseudomonas species 4 0 Other aerobic gram-negative species 1 0 Total gram-negative species 16 (33%) 9 (20%)

Bacteroides species 2 1 Yeasts 3 6

Total blood isolates 49 44 Total patients positive 40 30 Total patients studied 283 270

Note: Values in table represent numbers of blood isolates (pement- age of total blood isolates) of each type, except where indicated. Adapted from Meyers JD: Infection in recipients of bone marrow transplant. In: Remington JS, Swarfz MN, eds. Current clinical topics in infectious diseases. New York: McGraw-Hill, Inc., 1985; 261- 292.

pneumonia due to Pneumocystis carinii was common, but it is now rare because of trimethoprim/sulfamethoxazole prophylaxis [29]; this agent is also the drug of choice for treatment of Pneumocystis carinii infection. Toxoplasma gondii infection occurs rarely [30-321, and has usually been diagnosed at autopsy despite the recent report of recovery of toxoplasma from blood cultures of three marrow transplant recipients [33]. Serologic testing has not been useful. Infection generally involves the brain, heart, and lungs, and is almost always due to reactivation of latent organisms.

Both candidal and aspergillar infections (as well as other rarer fungal infections) occur during this period. The exact incidence is unknown, but it has been found that as many as 22 percent of patients who received transplants because of leukemia and 44 percent of those who received transplants because of aplastic anemia have invasive fungal infection at the time of autopsy [34]. Although many of these infections presumably began during the initial period of neutropenia, a substantial proportion become evident only after initial engraftment. In some insti- tutions, Aspergillus infection has become a major cause of death [35], related in part to epidemiologic factors increasing the likelihood of exposure. Patients who undergo transplants in rooms with laminar airflow appear to have a lower incidence of aspergillar infection [36]. Other risk factors associated with these later fungal infections are in-

completely defined. As mentioned earlier, neutrophil function may not be normal even after quantitative recovery, especially among patients with acute GVHD [4]. The con- tribution of previous broad-spectrum antibiotic treatment would appear inconsequential, since virtually all patients receive such treatment. The role of corticosteroids or antithymocyte globulin used in the treatment of GVHD remains to be determined.

Candidal esophagitis represents a minority of cases of proved infectious esophagitis [17]. It tends to occur later after transplant than viral esophagitis, but is otherwise clinically indistinguishable and requires endoscopic ex- amination and specific microbiologic and histologic studies for diagnosis. Atypical presentations of localized As- pergillus infection of the oropharynx may occur, which also requires biopsy for diagnosis [371. In contrast to the generally dismal prognosis of patients with aspergillosis of visceral organs, those with localized Aspergillus infection of oral sites may achieve cures with aggressive, prolonged amphotericin B treatment in association with marrow engraftment. As in other immunocompromised patients, recovery of Aspergillus in cultures from any site should be considered to represent invasive infection until proved otherwise.

Serious viral infections play a more prominent role in marrow recipients than in other organ allograft recipients. Reasons for this may include the ablation of virus-specific immunity by transplant conditioning (compared with sup pression but not ablation in other patients) and the effi- ciency of reactivation of latent viruses by the conditioning regimens or other characteristics of the marrow transplantation milieu. The latter circumstance determines the high rate of virus infection, whereas the former determines the severity of infection. It may be considered that all virus infections after marrow transplant are “primary” infections, despite epidemiology suggesting virus reactivation, since it is the transplanted immune system that must re- spond. As mentioned earlier, antigen-specific responses may require antigenic re-exposure after transplant for reconstitution, with the first infection after transplant in effect constituting the primary exposure for that immune system.

There is an important association between acute GVHD and virus infection after marrow transplant. An early observation was that most severe or fatal viral infections occurred among patients with acute GVHD [36], and this association has been repeatedly reconfirmed [39,40]. In- deed, the lack of GVHD after syngeneic transplant has been considered a major reason for the rarity of serious cytomegalovirus infections in such patients [41]. A recent study has uncovered an additional role for acute GVHD, by finding a significant increase in the incidence of viral (in this case, cytomegalovirus) infection (Figure 2) [42]. It thus appears that GVHD both increases the incidence of cytomegalovirus infection, and increases the severity of infection when it occurs. Although it is likely that the graft-

39 July 28,1996 The Anwrlcan Journal of MedIche Volume 91 (suppl 1A)


versus-host reaction reactivates latent cytomegalovirus among previously seropositive patients by unknown mechanisms, as has also been shown in animal models [43], the reason that GVHD increases the incidence of primary cytomegalovirus infection among seronegative patients remains unclear. It may merely be due to an increased transfusion requirement among such patients, which increases the likelihood of exposure.

H SEROPOSITIVE PATIENTS WM ACUTE GVHD D a SEROPOSITIVE PATENTS WITHOUT ACUTE GVHD M SERONEGATIVE PATIENTS WITH ACUTE GVHD

0 a SERONEGATIVE PATIENTS WITHOUT ACUTE GVHD 100

1

The opposite relationship, that cytomegalovirus (or other viral) infection is associated with an increase in the incidence of GVHD, has also been postulated. Recent data from Sweden suggested that the occurrence of cytomegalovirus infection predisposed to the occurrence of chronic GVHD [44]. The putative mechanism may be that an immune response directed at cytomegalovirus antigens displayed on cell surfaces in concert with the HLA complex includes a component directed at cellular antigens in the absence of viral antigens. It is clear that cytomegalovirus infection and GVHD are highly associated. However, in a study that simultaneously analyzed multiple factors, such as the age of the patient and the relative timing of cytomegalovirus infection and GVHD, no evidence that cytomegalovirus infection predisposed to either acute or chronic GVHD was found [42]. The relationship between cytomegalovirus infection and GVHD appeared to be unidirectional: acute GVHD increased the incidence of cytomegalovirus infection, but not vice versa.

0 2 4 6 8 10 12 14 16

WEEK AFTER TRANSPLANT

Cytomegalovirus causes a variety of syndromes after marrow transplant, most prominently cytomegalovirus pneumonia, which occurs in approximately 15 percent of all patients undergoing allogeneic transplant for malignancy and which has an 85 percent fatality rate. This rate is increased among patients who are seropositive before transplant in whom reactivation of latent cytomegalovirus occurs in at least 70 percent of patients, and is decreased among seronegative patients in whom the apparent source of virus is either the donor marrow itself or other blood products [42]. Efforts to prevent primary cytomegalovirus infection have been reported from several marrow transplant centers and are reviewed later. Pneumonia due to cytomegalovirus also occurs after autologous and syngeneic transplants, but at rates of only 1 to 2 percent. Another syndrome of substantial importance is gastrointestinal infection due to this virus. Cytomegalovirus is the most common cause of infectious esophagitis, now that HSV infection has been controlled with acyclovir, and is also the most common cause of persistent nausea and vomiting after marrow transplant [17,45]. Other syndromes include hepatitis and leukopenia, retinitis, and encephalitis. It has not been possible to associate cytomegalovirus infection with graft rejection, although leukopenia often occurs in association with severe cytomegalovirus infection [46].

‘Igun, 2. Probability of cytomegalovirus infection develop- ing by the occurrence of acute GVHD among patients seronegative or seropositive to cytomegalovirus before transplant, by week after allogeneic marrow transplantation. The occurrence of acute GVHD was associated with a significant increase in the probability of cytomegalovirus infection among both seroposiffve (p = 0.003) and seronegative (p = 0.02) patients by Mantel-Cox test. Reproduced from [421.

ing vidarabine, acyclovir, and various alpha interferons, alone and in combination, has been unsuccessful [47). The acyclovir derivative, 9[2-hydroxy-1 -(hydroxymethyl)- ethoxymethyllguanine has markedly improved activity against human cytomegalovirus in vitro (481. Initial efforts in the treatment of cytomegalovirus pneumonia after marrow transplant were not successful [49], with death occurring in 14 of the first 16 patients treated. Moreover, marrow toxicity occurred in patients at higher doses or blood levels. However, an antiviral effect was clearly observed (Figure 3), and this agent continues to hold promise in both the treatment and prevention of cytomegalovirus infection. Another investigational antiviral agent that shows similar promise is phosphonoformate, or foscamet, which has been tested extensively in Sweden in open, uncontrolled trials [50]. Controlled trials with both agents should be forthcoming within the next several years.

Treatment or prophylaxis of cytomegalovirus infec- Adenovirus infections have occurred in approximately 5 tion with previously available antiviral agents, includ- percent of marrow transplant recipients, generally in the

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0 2 4 6 8 1012

Treatment Day

;igure 3. Elimination of cytomegalovirus from cultures ob- tained during treatment with B W 8759U. The probability of remaining culture-positive is shown by Kaplan-Meier plots. Sites initially positive for cytomegalovirus were the respiratory tract m in nine patients, blood (4 in five patients, and urine (0) in six patients. Reproduced from [49].

period following initial engraftment [40]. These infections appeared to be due to reactivation of latent virus. Most were asymptomatic, although 20 percent were associated with fatal visceral disease including, most commonly, pneumonia, hepatitis, or nephritis. Fastidious enteric ade- noviruses were associated with diarrhea in another series [51]. In both series, patients with acute GVHD were pref- erentially affected. Infection with Epstein-Barr virus has attracted increasing attention because of its association with fatal lymphoproliferative disease [52-541. Patients in whom fatal Epstein-Barr virus infection developed in- cluded those who received antithymocyte globulin or anti- T-cell monoclonal antibody treatment for acute GVHD or those who received T-cell-depleted marrow grafts to prevent the development of GVHD. In both circumstances, uncontrolled proliferation of cells infected with Epstein- Barr virus was thought to occur because of the absence of specific T-cell suppression of Epstein-Barr virus infection. Other virus infections, such as those due to respiratory syncytial virus, enteroviruses [51], parainfluenza virus, papovaviruses [55], and presumably others as well, also occur on a sporadic basis, but have not commonly posed problems for marrow transplant patients.

Bacterial infections continue to occur during the period after initial engraftment. In fact, the incidence and spectrum of organisms are similar to the neutropenic period (Table I). In some instances, these later bacterial infections develop in association with acute GVHD; the possible role of GVHD in suppression of macrophage-mediated host defenses was mentioned earlier. The involvement of the gastrointestinal tract in acute GVHD, with ulcerations

of the bowel mucosa, provides an obvious route of infection in these patients. Sudden onset of fever develops in other patients in the absence of GVHD, and they are un- expectedly found to be bacteremic. The role of the central venous catheter in the pathogenesis of these bacterial infections has been discussed earlier. Some of these infections are due to Enterobacteriaceae rather than coagulase-negative Staphylococcus, and the role of the catheter in these particular infections remains uncertain. Chronic GVHD. The third major period of risk begins approximately three months after transplant, at the time that chronic GVHD first develops. The overall incidence of chronic GVHD after allogeneic transplant is about 25 percent [56]. Among patients with adequate marrow engraftment in whom chronic GVHD does not develop, the major period of risk for the infections discussed earlier is over. These patients have a progressive return of immune function and eventually both normal immunity and a “normal” spectrum of infections develop. In contrast, patients with chronic GVHD have continued abnormalities in host defenses, which are further suppressed by treatment for chronic GVHD.

The typical spectrum of infections, derived by studying 96 long-term survivors [57], is listed in Table II. The most common types include sinopulmonary infections, probably related to the IgA deficiency and sicca syndrome associated with chronic GVHD, cutaneous infections, and “spontaneous” bacteremia or meningitis due to Strepto- coccus pneumoniae. The high incidence of pneumococcal infections can be attributed to the loss of and inability to make opsonizing antibody even after antigenic re-exposure [8]. lmmunoglobulin production in vitro is suppressed by the nonspecific suppressor cells present in patients with chronic GVHD [12,13], and these patients show poor antibody responses to neoantigens and pneumococcal polysaccharide in vivo [lo]. Thus, the patients who would benefit most from immunization with pneumococcal vaccine are least able to exhibit a response. Pneumococcal infections may be prevented by the use of prophylactic oral antibiotics, which is discussed later.

The cutaneous infection of most importance is varicella- zoster virus (VZV) infection, which occurs in 30 percent of all patients and 45 percent of patients with chronic GVHD [58]. Median time of onset is four to five months after transplant, with the major risk period between months two and 10 (Figure 4). Virtually all these infections are due to reactivation of latent virus. After the first year, there is a low but persistent incidence of VZV infection, including some cases of normal childhood varicella. The timing of VZV infection appears to be related primarily to characteristics of the virus, and is similar in other immunocompromised patients at high risk of VZV reactivation, such as those with Hodgkin’s disease [59]. The paucity of second cases and the reduction in risk by one year after transplant has been attributed to restoration of the normal im-

32 July 28, 1988 The American Journal of Medlclne Volume 81 (suppl 1A)


mune response to VZV both in patients with and without clinical infection [60]. It is not known if restoration of the specific immune response among those without clinical infection is due to subclinical infection or to restoration (“transfer”) of the donor’s immune response. About 85 percent of patients have initial dermatomal localization of their rash, although one third of these have subsequent cutaneous dissemination. The remaining 15 percent have cutaneously disseminated rash at onset, although it is usually due to virus reactivation rather than exposure to exogenous virus. However, it is presumed that VZV infection may develop in marrow transplant recipients after exposure to exogenous virus in the first year following transplant, and VZ immune globulin prophylaxis is therefore recommended after such exposures.

TABLE II Clinical Syndromes among Patients with Late infections

TYPO Number 01 Episodes

Sinopulmonary infections

Cutaneous infections

27' 7

25 3

27 89 29 a 3

15’

Before antiviral chemotherapy was available, up to 10 percent of marrow transplant recipients with VZV infection died as a result of visceral dissemination, all but one within the first nine months after transplant. Severe local sequelae, such as bacterial superinfection and scarring, postherpetic neuralgia, or severe ophthalmic toster with blindness may develop even in patients without dissemination, and treatment of all patients with VZV infection in the first nine months after transplant is recommended. A comparative trial of vidarabine and acyclovir for VZV infection after marrow transplant clearly showed that intravenous acyclovir is superior treatment [61]. The use of orally administered acyclovir cannot be recommended because of the lack of data regarding efficacy.

Ear, nose, and throat infections

Genitourfnary infections

Central nervous system infections

Systemic infections

Bacterial or fungal pneumonia Interstitial pneumonia Bronchitis Pleurisy Sinusitis Total Varicella-zoster virus Herpes simplex virus Warts Cellulitis, furuncle,

paronychia Hyperalimentation line site

infection Total Bacterial pharyngitis/

tonsillitis Oral-esophageal candidiasis Otitis media Dental-periodontal Total Purulent conjunctivitis Herpes simplex keratitis Total Cystitis Vaginitis Total Meningitis Herpes simplex encephalitis Total Bacterial sepsis Infectious mononucleosis Measles “Acute febrile illness” Total

56

Ophthalmic infections

11 21 16

3 51 12

3 15 11

2

13 2

VZV infection after marrow transplant has several characteristics that would make it an ideal target for immunization. These include the relatively late onset after transplant, the observation that only one case of VZV infection is observed in the vast majority of patients, which indi- cates that the specific immune response is protective, and the high incidence of infection making such efforts worth- while. The live attenuated varicella vaccine may be an ideal immunogen for these patients since, as a replicating antigen, it may be more likely to induce an immune response, compared with the more limited stimulus afforded by vaccines such as pneumococcal polysaccharide. It is also susceptible to available antiviral agents should vaccine-associated disease occur [62]. However, varicella vaccine has not yet been given to any marrow transplant recipient. A trial of VZV-specific transfer factor was not effective in inducing either a specific immune response or clinical protection against VZV reactivation [63].

3 11

4 17

244

‘Four infections were caused by fungal organisms. Note: These data were derived from a study of 96 patients who sur- vived for at least six months after transplant. Nineteen had received syngeneic transplants. Forty-eight of the remaining 79 patients had chronic GVHD. Adapted from [57j.

pneumonia also occurs late after transplant, although it seems unlikely that toxicity from radiation and cytotoxic chemotherapy, which are the putative causes of this syndrome when it occurs early after transplant, would be relevant in this later period. Other, still undefined etiologies must therefore be responsible.

Pneumonia due to causes other than bacteria or fungi, including both cytomegalovirus and P. carinii pneumonia [64], occurs in patients with chronic GVHD. The incidence of these late “interstitial” pneumonias, occurring predominantly between three and 24 months after transplant, appears to be about 15 percent. The incidence is higher among patients not receiving trimethoprim/suIfamethoxa- zole prophylaxis. Interestingly, “idiopathic” interstitial

PREVENTION OF INFECTION

Prevention of infection after marrow transplant has been a subject of much interest, in part because it may have additional benefit in marrow allograft recipients vis-hvis prevention of GVHD. These efforts have been concentrated in three areas: prevention of early bacterial and fungal infection; prevention of primary cytomegalovirus infection;

July 28, 1986 The Amwlcan Journal of Medlclne Volume 81 (suppl1A) 33


1.6

1.4’

$ ‘2’

El.0 zi ; 0.80

$ b: 0.6

0.4.

0.2.

1.1 . , , , , , , , , , ,

2 4 6 8 1012141618202224262830 Month AfterTransplant

igure 4. Risk of varicella-zoster virus infection by month after marrow transplant, expressed as incidence per patient day. Reproduced from 1581.

and prevention of bacterial infection among patients with chronic GVHD. These areas are discussed in turn. Prevention of Bacterial Infection and Acute GVHD. Various approaches to tha prevention of bacterial and fungal infections during the neutropenic period have been uti!ized. These include oral nonabsorbable antibiotics [65] or selective decontamination with trimethoprim/sulfamethoxazole in conventional rooms [35], prophylactic granulocyte transfusions given during the period of most severe neutropenia [66,67& and transplantation within a protective environment consisting of a laminar airflow room, oral non-absorbable and topical antibiotics, and sterile or low- bacterial-content food [68]. The last two have been studied extensively in randomized, controlled trials. Both prophylactic granulocyte transfusions and the protective environment were shown to significantly reduce the occurrence of early infection when compared with the occur-

rence in control groups of patients who received transplants in conventional rooms [66,68]. When compared with each other, the two practices appeared to be equiva- lent (Table III) [69,70]. However, a beneficial effect on survival could not be conclusively demonstrated with either modality among patients undergoing transplants for malignancy, despite the decrease in the rate of infection. Moreover, difficulties with the use of prophylactic granulo- cytes, including transmission of cytomegalovirus infection to seronegative patients [71,72] and difficulties with compliance of both patients (because of side effects) and donors (because of clotting of shunts and a greater need for donation of platelets), have lead to the abandonment of prophylactic granulocyte transfusions.

In contrast, among patients undergoing transplants for aplastic anemia, use of the protective environment has been associated with a significantly reduced incidence and severity of acute GVHD and significantly improved survival rates (Figure 5) [73]. Reasons for the greater efficacy of the protective environment among patients with aplastic anemia may include reduced toxicity from the conditioning regimen and thus better compliance with the antibiotic regimen, leading to more complete decontamination. Complete decontamination (i.e., sterility of surveillance cultures) is unusual among patients undergoing transplants for malignancy [68,69]. Reduction in the incidence of GVHD among effectively decontaminated patients was predicted by animal studies [74]. If such an effect could also be achieved among patients undergoing transplants for malignancy, this could have a substantial impact on the success of allogeneic marrow transplantation since GVHD and its complications remain among the major problems. Efforts to improve the effectiveness of the protective environment are under investigation, including the use of alternative decontamination regimens that may be more acceptable to patients, and initiation of the decontamination procedures several days before the beginning of conditioning when patients are still able to comply fully with the decontamination regimen. It should be recognized that use of the protective environment increases the costs of marrow transplantation (although the exact increase is unknown), and thus prolonged use of the protective environment may be problematic on economic

TABLE Ill Incidence of Bacteremia during the Period of Neutropenia: Results of Infection Control Practices

References

1661 WI 1169,703

Prophylactic granulccyte transfusions O/29’ - 161126 (13) Protective enkonment - 10/45 (22) 16/126 (13) No specific control procedures lo/40 (25) 23144 (52) -

‘Number of patients with bacteremiakotal patients in study (percentage). Adapted from Meyers JD: Infection in recipients of bone marrow transplant. In Remington JS, Swartz MN, eds. Current clinical topics in infectious diseases. New York: McGraw-Hill, Inc., 1985; 261-292.

34 July 28.1986 The American Joumel of Medlclne Volume 81 (suppl 1A)


grounds. Nevertheless, continuing efforts are warranted because of the magnitude of the potential benefit.

Another approach is to use selective decontamination, as is already done at some centers. A preliminary study of selective decontamination conducted among 14 patients undergoing allogeneic transplantation did not suggest a beneficial effect on the incidence of acute GVHD [75]. However, this approach warrants study both for the prevention of bacterial infection, and for the possible effect on the occurrence of GVHD, using the newer antibiotics available for oral administration such as the quinolones. Prevention of Primary Cytomegalovirus Infection. There are ample data indicating that primary cytomegalovirus infection occurring among seronegative patients is usually, if not exclusively, due to transmission of virus in blood products, including the marrow itself [42,71,72]. Al- though the state of the virus within these blood products is unknown, it is generally considered to be “latent”; it clearly cannot be cultured from the blood cells of normal asymptomatic persons in most circumstances. The cell harboring cytomegalovirus is also unknown, although the leading candidate is the lymphocyte or some other long- lived mononuclear cell rather than the neutrophil. A recent study has identified cytomegalovirus RNA in the helper- inducer lymphocyte subpopulation from two normal asymptomatic seropositive persons, although the virus could not be cultured from these cells [76].

Attempts to interrupt transmission of cytomegalovirus to seronegative patients by passive immunoprophylaxis with immune plasma or globulin have been conducted by several investigators. The mechanism by which antibody would work in this situation is not entirely clear: Cytomeg- alovirus does not circulate in a cell-free state even during active infection, and thus neutralization of virus in the blood would not seem to be relevant. Although antibody alone or in concert with cells with cytotoxic activity (antibody-dependent cell-mediated cytotoxicity) might identify and destroy virus-infected cells, there is no evidence that cells carrying “latent” virus have cytomegalovirus antigens displayed on their surfaces. It may be that antibody- mediated mechanisms would not become active until the time of initial virus reactivation, but before the development of clinical disease. Thus, the goal of immunoprophylaxis may be amelioration of the manifestations of infection rather than prevention of infection per se.

Various antibody preparations have been used in different clinical protocols in these studies, and results have been discrepant. The first study reported the use of cytomegalovirus immune plasma given beginning prior to transplantation, with intermittent administration to day 120 after transplant [77]. A reduction in the incidence of symp- tomatic cytomegalovirus infection, including pneumonia, was observed, primarily among seronegative patients who did not receive prophylactic granulocyte transfusions. An intramuscular cytomegalovirus immune globulin was

CL ’ t 1 I

0 200 600 800

jgure 5. Cumulative incidence of grades II through I’ acute GVHD (top) and estimated sun&Al (bMtom) in 39 patients treated in laminar airflow rooms (LA Fj, compared with 91 patients treated outside such rooms. P values were ob- tained by the log-rank test (two-sided). Reproduced from i731.

used in the second study [78]. This globulin was given intermittently before transplant and continuing to day 77 after transplant to include the major risk period for cytomegalovirus pneumonia. In this study, cytomegalovirus infection appeared to be prevented among seronegative patients with seronegative marrow doriors who did not receive prophylactic granulocyte transfusions. The explanation for the lack of protection when granulocyte transfusions were used in these two studies is unknown, although the magnitude of the virus “inoculum” was postulated [78]. In the third study, a cytomegalovirus immune globulin modified for intravenous administration was given on days 25, 50, and 75 after transplant [79]. Results were compared with those in patients randomly assigned to receive a similar globulin without appreciable antibody against cytomegalovirus. The incidence of both cytomegalovirus infection and pneumonia was significantly reduced in this study, even though globulin administration was delayed until after the period during which most blood transfusions are given.

In the most recent trial, the use oi exclusively seronegative blood products was compared with the use of another intravenous cytomegalovirus immune globulin, which was given intermittently beginning before transplant and con-

July 28,1988 The American Journal of Medicine Volume 81 (suppl 1A) 35


tinued to day 62 after transplant [60]. There were four patient groups in this study, one of which received both mo- dalities and one which received neither. Use of exclusively seronegative blood products was found to be highly effective in the prevention of primary cytomegalovirus infection among seronegative patients with seronegative marrow donors, whereas there was no clear effect on prevention of either cytomegalovirus infection or disease attributable to the globulin. Seronegative patients with seropositive marrow donors were not protected by either modality.

The efficacy of passive immunoprophylaxis in the prevention of primary cytomegalovirus infection or in amelioration of cytomegalovirus disease thus remains uncertain, and the explanation for the apparently discrepant results between these four studies is unknown. However, it is clear that use of seronegative blood products is highly effective for preventing primary cytomegalovirus infection among seronegative patients with seronegative marrow donors, and presumably should be used when the likelihood of serious cytomegalovirus disease is high. Addi- tional study will be needed to define the role of passive immunoprophylaxis with immune globulins, especially in view of the high cost of these products. There is little reason to believe that either of these approaches would be effective among seropositive patients, in whom cytomegalovirus infection and disease appear to be due to reactivation of endogenous virus, which is not prevented by the presence of circulating antibody [42,61]. Prevention of Infection Associated with Chronic GVHD. Prophylaxis with daily trimethoprim/sulfamethoxazole is routine among patients being treated for chronic GVHD because of the high incidence of bacterial infection. Although controlled trials have not been performed, the incidence of infection is significantly higher among patients not receiving such prophylaxis [62]. Interestingly, the occurrence of syndromes not identifiably due to bacterial infection, such as idiopathic interstitial pneumonia, is also reduced by such prophylaxis, perhaps suggesting

that an agent such as Chlamydia is responsible [63]. Among patients who cannot tolerate trimethoprim/sulfamethoxazole because of gastrointestinal side effects or apparent marrow suppression, oral penicillins have been substituted. An alternative of daily administration of oral penicillin (for S. pneumoniae) and twice-weekly administration of trimethoprim/sulfamethoxazole (for P. carinii) is currently being tested.

As mentjoned earlier, recurrent sinopulmonary infection in association with sicca syndrome, IgA deficiency, and perhaps recurrent aspiration is common among these patients [64]. Indeed chronic, debilitating, and ultimately life- threatening pulmonary disease occurs in some [65]. Treatment of these patients in some ways resembles that of patients with cystic fibrosis. In addition to antibiotic prophylaxis and treatment of proved infections, replacement therapy with intravenous immunoglobulins is now being studied in light of the observed IgG and IgA deficiencies WI. COMMENTS

In summary, serious and sometimes fatal infection is a predictable accompaniment of marrow transplantation. Advances in therapy for bacterial and some viral infections have reduced the impact of these infections on both morbidity and mortality. In contrast, infection due to fungi and to viruses such as cytomegalovirus and Epstein-Barr virus continue to play a major and ever increasing role [35]. Prevention of infection commands increasing aiten- tion, in part because of the observation that bacterial colonization or infection may itself predispose to GVHD [73]. The relationship between GVHD and infection is complex and poorly understood, although it is clear that GVHD (and perhaps its treatment) has a major influence on the acquisition and outcome of infection. Advances in the prevention and treatment of GVHD will undoubtedly have parallel benefits in the prevention of infection after marrow transplant.

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Sandford GR, Merz WG, Wingard JR, Charache P, Sara1 R: The value of fungal surveillance cultures as predictors of systemic fungal infections. J Infect Dis 1980; 142: 503-509.

Tashjian LS, Abramson JS, Peacock JE Jr: Focal hepatic candidiasis: a distinct clinical variant of candidiasis in immunocompromised patients. Rev Infect Dis 1984; 6: 689-703.

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Sanders JE, Hickman RO, Aker S, Hersman J, Buckner CD, Thomas ED: Experience with double lumen right atrial catheters. J Parenteral Enteral Nutrition 1982; 6: 95-99.

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Hirsch R, Burke BA, Kersey JH: Toxoplasmosis in bone marrow transplant recipients. J Pediatr 1984; 105: 426-428.

Shepp DH, Hackman RC, Anderson JB, Conley FK, Meyers JD: Diagnosis of Toxoplasma gondii reactivation by detection of parasitemia in tissue culture. Ann Intern Med 1985; 103: 218- 221.

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Shields AF, Hackman RC, Fife KH, Corey L, Meyers JD: Adeno- virus infections in patients undergoing bone marrow transplantation. N Engl J Med 1985; 312: 529-533.

Appelbaum FR, Meyers JD, Fefer A, et al: Nonbacterial nonfun- gal pneumonia following marrow transplantation in 100 identical twins. Transplantation 1982; 33: 265-268.

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Spencer GD, Hackman RC, McDonald GB, Cunningham BA, Meyers JD, Amos DE, Thomas ED: A prospective study of unexplained nausea and vomiting after marrow transplantation. Gastroenterology (in press).

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July 28, 1988 The American Journal of Mediclne Volume 81 (suppl 1A) 37


and renal transplant recipients. J Antimicrob Chemother (in v-3.

51. Yolken RH, Bishop CA, Townsend TR, et al: Infectious gastro- enteritis in bone-marrow-transplant recipients. N Engl J Med 1962; 306: 1009-1012.

52. Gossett TC, Gale RP, fleischman H, Austin GE, Sparkes RS, Taylor CR: lmmunoblastic sarcoma in donor cells after bone- marrow transplantation. N Engl J Med 1979; 300: 904-907.

53. Schubach WH, Hackman R, Neiman PE, Miller G, Thomas ED: A moncclonal immunoblastic sarcoma in donor cells bearing Epstein-Barr virus genomes following allogeneic marrow grafting for acute lymphoblastic leukemia. Blood 1962; 60: 160-l 67.

54. Martin PJ, Shulman HM, Schubach WH, et al: Fatal Epstein- Barr-virus-associated proliferation of donor B cells after treatment of acute graft-versus-host disease with a murfne anti-T- cell antibody. Ann Intern Med 1964; 101: 310-315.

55. O’Reilly RJ, Lee FK, Grossbard E, et al: Papovavirus excretion following marrow transplantation: incidence and association with hepatii dysfunction. Transplant Proc 1961; 13: 262-266.

56. Thomas ED: Overview of marrow transplantation. West J Med 1965; 143: 634-637.

57. Atkinson K, Farewell V, Storb R, et al: Analysis of late infections after human bone marrow transplantation: role of genotypic nonidentity between marrow donor and recipient and of nonspecific suppressor cells in patients with chronic graft-versus- host disease. Blood 1962, 60: 714-720.

56. Locksley RM, Floumoy N, Sullivan KM, Meyers JD: Varicella- zoster virus infection after marrow transplantation. J Infect Dis 1965; 152: 1172-1161.

59. Dolin R, Reichman RC, Mazur MH, Whitley RJ: Herpes zoster- varicella infections in immunosuppressed patients. Ann Intern Med 1976; 69: 375-366.

60. Meyers JD, Flournoy N, Thomas ED: Cell-mediated immunity to varicella-zoster virus after allogeneic marrow transplant. J In- fect Dis 1960; 141: 479-467.

61. Shepp DH, Dandliker PS, Meyers JD: Treatment of varicella- zoster virus infection in severely immunocompromised patients: a randomized comparison of acyclovir and vidarabine. N Engl J Med 1966; 314: 206-212.

62. Shiraki K, Yamanishi K, Takahashi M: Susceptibility to acyclovir of Oka-strain varicella vaccine and vaccine-derived viruses isolated from immunocompromised patients. J Infect Dis 1964; 150: 306-307.

63. Bowden RA, Siegel MS, Steele RW, Day LM, Meyers JD: Immu- nologic and clinical response to varicella-zoster virus-specific transfer factor following marrow transplantation. J Infect Dis 1965; 152: 1324-1327.

64. Sullivan KM, Meyers JD, Flournoy N, Storb R, Thomas ED: Early and late interstitial pneumonia following human bone marrow transplantation. J Natl Cancer lnst (in press).

65. Winston DJ, Gale RP, Meyer DV, Young LS, UCLA Bone Mar- row Transplantation Group: Infectious complications of human bone marrow transplantation. Medidne (Baltimore) 1979; 56: 1-31.

tients receiving bone-marrow transplants. N Engl J Med 1976; 296: 1052-1057.

66. Clift RA, Sanders JE, Thomas ED, Williams 8, Buckner CD: Granulocvte transfusions for the prevention of infection in pa-

leukemia: effects of prophylactic measures. Infection 1963; 11: 243-250.

70. Navari RM, Buckner CD, Clift RA, et al: Prophylaxis of infection in patients with aplastic anemia receiving allogeneic marrow transplants. Am J Med 1964; 76: 564-572.

71. Winston DJ, Ho WG, Howell CL, et al: Cytomegalovirus infections associated with leukocyte transfusions. Ann Intern Med 1960; 93: 671-675.

72. Hersman J, Meyers JD, Thomas ED, Buckner CD, Clift R: The effect of granulocyte transfusions upon the incidence of cytomegalovirus infection after aflogeneic marrow transplantation. Ann Intern Med 1962; 96: 149-152.

73. Storb R, Prentice RL, Buckner CD, et al: Graft-versus-host disease and survival in patients with aplastic anemia treated by marrow grafts from HlA-identical siblings. Beneficial effect of a protective environment. N Engl J Med 1963; 306: 302-307.

74. van Bekkum DW, Roodenburg J, Heidt PJ, et al: Mitigation of secondary disease of allogeneic mouse radiation chimeras by modification of the intestinal microflora. J Natl Cancer lnst 1974; 52: 401-404.

63. 65. Ralph DD, Sprtngmeyer SC, Sullivan KM, Hackman RC,

75. Guiot HFL, van der Meer JWM, Fibbe WE, de Planque MM, Zwaan FE, Biemond I: The effects of the intestinal microflora of selectively decontaminated patients on the severity of acute graft-versus-host disease of the gut. A comparative study on selective and total decontamination in patients undergoing allogeneic bone marrow transplantation. Exp Hema- tol 1965; 13: 106-109.

76. Schrier RD, Nelson JA, Oldstone MBA: Detection of human cytomegalovirus in peripheral blood lymphocytes in a natural infection. Science 1965; 230: 1046-1051.

77. Winston DJ, Pollard RB, Ho WG, et al: Cytomegalovirus immune plasma in bone marrow transplant recipients. Ann In- tern Med 1962; 97: 11-16.

76. Meyers JD, Leszczynski J. Zaia JA, et al: Prevention of cytomegalovirus infection by cytomegalovirus immune globulin after marrow transplantation. Ann Intern Mad 1963; 96: 442- 446.

79. Condie RM, C’Reilly RJ: Prevention of cytomegalovirus infection by prophylaxis with an intravenous, hyperimmune, native, unmodified cytomegalovirus globulin. Randomized trial in bone marrow transplant recipients. Am J Med 1964; 76: 134- 141.

60. Bowden FtA, Sayers M, Floumey N, et al: Cytomegalovirus immune globulin and seronegative blood products to prevent primary cytomegalovirus infection after marrow transplant. N Engl J Med 1966; 314: 1006-1010.

61. Winston DJ, Huang E-S, Miller MJ, et al: Molecular epktemiol- ogy of cytomegalovirus infections associated wtth bone marrow transplantation. Ann Intern Med 1965; 102: 16-20.

62. Sullivan KM, Dahlberg S, Storb R, et al: Infection acquisition and prophylaxis in chronic graft-versus-host disease (GVHD) (abstr). Blood 1963; 62: 230A.

63. Meyers JD, Hackman RC, Stamm WE: Chlamydia trachomatis infection as a cause of pneumonia after human marrow transplantation. Transplantation 1963; 36: 130-134.

64. Sullivan KM, Deeg HJ, Sanders JE, et al: Late complications after marrow transplantation. Semin Hematol 1964; 21: 53-

67. Winston DJ, Ho WG, Young LS, Gale RP: Prophylactic granulocyte transfusions during human bone marrow transplantation. Am J Med 1960; 66: 693-697.

66. Buckner CD, Clift RA, Sanders JE, et al: Protective environment for marrow transplant recipients. A prospective study. Ann In- tern Med 1976; 69: 693-901.

69. Buckner CD, Clift RA, Thomas ED, et al: Early infectious complications in allogeneic marrow transplant recipients with acute

Storb R, Thomas ED: Rapidly progressive air-flow obstruction in marrow transplant recipients. Possible association between obliterative bronchiolitis and chronic graft-versus-host disease. Am Rev Respir Dis 1964; 129: 641-644.

66. lzutsu KT, Sullivan KM, Schubert MM et al: Disordered salivary immunoglobulin secretion and sodium transport in human chronic graft-versus-host disease. Transplantation 1963; 35: 441-446.

36 July 26,lS86 The American Journal of Medicine Volume 61 (suppl 1A)

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